SECTION 19 Rheumatological disorders Section edito

19.1 Joints and connective tissue— structure and f
19.1 Joints and connective tissue— structure and function 4379 Thomas Pap, Adelheid Korb- Pap, Christine Hartmann, and Jessica Bertrand
ESSENTIALS
Synovial joints are complex functional elements of the vertebrate
body that provide humans and animals with motion capabilities and
hence the ability for locomotion and direct physical interaction with
their environment. They are composed of different connective tissue
structures that are derived from the same developmental structures
in the embryo, but have distinct cellular and biochemical properties.
Articular cartilage and synovial membrane are key components of
synovial joints and show several peculiarities that makes them dif-
ferent from other tissues. An in-​depth knowledge of these features is
important not only for understanding key features of articular func-
tion, but also for providing explanations for important characteristics
of both degenerative and inflammatory joint diseases. This chapter
reviews the structure, biochemical composition, and function of
articular cartilage and synovium, and points to important links be-
tween physiology and pathologic conditions, particularly arthritis.
Special emphasis is put on the interaction of resident cells with both
the extracellular matrix and other neighbouring or invading cells.
Introduction
Articular joints are key components of the musculoskeletal system
that provide flexible support to neighbouring bony structures and
allow for the movement in different parts of the body. This is par-
ticularly true for synovial joints that are found mainly at the extrem-
ities and are the structural basis for key physiological activities such
as walking, climbing, and gripping. Synovial joints are composed
of different morphological structures, including bone, tendons,
cartilage, the synovial membrane, and the synovial space with the
synovial fluid. While functionally distinct and anatomically well
separated under normal conditions, these tissue structures exhibit a
high degree of communication, and growing evidence suggests that
intertissue communication is essential not only for the developing
joint during embryogenesis, but also for maintaining joint homeo-
stasis in the adult organism.
The notion that many joint diseases do not affect a single tissue
component but the joint as a whole has been expanded recently,
by the concept that intertissue communication is not merely an
epiphenomenon of these diseases but a key driving element of
their pathogeneses. Nonetheless, much of the recent biomedical
research has been focused on the analysis of the individual tissue
components of the joints rather than on their interactions. Thus,
autoimmune diseases of the joints such as rheumatoid arthritis
and psoriatic arthritis have been largely considered disorders of
the synovial membrane, in which cartilage and bone are mere
target tissues that suffer destruction from the inflamed synovium.
In turn, osteoarthritis and osteoporosis as the main degenerative
joint diseases have been looked at mainly as age-​related disorders
of cartilage and bone with only secondary involvement of adja-
cent tissues such as the synovium, tendons, and muscle. However,
such an isolated view not only neglects important aspects of
physiological joint development and function, but it also fails to
provide answers to some key questions about the pathogenesis of
these diseases. A key example is the unresolved question about
the cellular and molecular basis of organ specificity of joint dis-
eases (e.g. why does systemic autoimmunity under certain cir-
cumstances specifically affect the joints, and what are the tissue
determinants of joint manifestation?). Another important ques-
tion regards mechanisms that link embryonic development and
adult tissue remodelling, both during degenerative joint diseases
and during regeneration.
This chapter looks at synovial joints as complex organs with dis-
tinct yet highly interconnected structures. We will try to demonstrate
that this concept not only is key to understanding the development
and function of articular joints, but becomes relevant particularly
under pathological conditions such as arthritis. These not only affect
joints as a whole, but are also based on complex pathological inter-
actions between tissue components of the joints such as cartilage
and synovium.
Cartilage
Cartilage is one, if not ‘the’ key component of synovial joints.
Supported by the synovial fluid, cartilage provides a smooth and
low-​friction surface that is needed for gliding of both bony ends.
At the same time the articular cartilage functions as an elastic and
load-​absorbing tissue. The biomechanical properties of articular
cartilage are achieved by its unique structure. It is characterized
19.1
Joints and connective tissue—​structure
and function
Thomas Pap, Adelheid Korb-​Pap, Christine Hartmann, and Jessica Bertrand
section 19  Rheumatological disorders
4380
by the presence of only one cell type, the chondrocytes, which are
loosely embedded into a highly complex and organized extracel-
lular matrix (ECM) (Fig. 19.1.1). The articular cartilage is or-
ganized into at least four distinct zones that differ with respect
to the density and orientation of the cartilage fibrils, as well as
the number and shape of embedded chondrocytes. The super-
ficial zone (which because of its structural organization is also
called the tangential zone) makes up about 10% of the cartilage
thickness. It is in direct contact with the joint cavity and char-
acterized by densely packed cartilage fibrils with long-​shaped
chondrocytes in between. The middle zone makes up about 40%
of the articular cartilage and is also called the transitional zone.
It has more round-​shaped chondrocytes, which are embedded
into a less densely packed ECM. The deep or radial zone is the
thickest layer of articular cartilage, and the chondrocytes here are
oriented in perpendicular direction to the cartilage surface. The
deep radial zone is separated by the tidemark from the calcified
zone that is in direct contact with the subchondral bone.
Development
While articular cartilage is usually viewed as a covering tissue that
is placed on top of the underlying bone, it actually constitutes a spe-
cific part of the cartilaginous template, from which both the joints
and the long bones are formed during embryogenesis through
endochondral ossification. However, articular cartilage areas are not
purely remnants of the bone formation process, in which ossifica-
tion comes to a halt. Rather, it has been demonstrated that articular
cartilage differs from growth plate cartilage and that articular chon-
drocytes originate from a distinct population of mesenchymal pro-
genitor cells that can be identified very early in limb development.
These cells are derived from an area called the interzone and are
characterized by a specific molecular pattern including the expres-
sion of the growth factor Gdf5. The interzone is further subdivided
into an intermediate and outer layer, which display a differential
gene expression profile. The initial differentiation of the interzone
appears to be regulated in a permissive manner by the concerted
action of members of the Wnt-​family of molecules such as Wnt9a
(formerly known as Wnt14) and Wnt4 through activation of the
Wnt/​ß-​catenin signalling pathway. Experimental evidence suggests
that at the time of interzone formation, the Wnt/​ß-​catenin pathway
is required to suppress the chondrogenic potential of the interzone
cells, leading to a downregulation of the transcription factor Sox-​9.
Interestingly, the Sox-​9 related transcription factors, Sox-​5 and
Sox-​6, are both needed, cell-​autonomously and non​autonomously
for joint formation. Mechanisms, such as muscle contraction, are
subsequently required in maintaining joint progenitor fate in the
elbow joint, and one of the molecular mechanisms involved here is
the stretch-​activated upregulation of ß-​catenin. The synovial joints
differ by their anatomy and this is also reflected by differences in
their transcriptome profiles, which points towards the existence of
fundamental different mechanisms as to how individual joints de-
velop after interzone establishment.
The question whether this distinct environment and the early de-
termination of cellular fate in articular cartilage areas results in a
specific chondrocytic phenotype or rather constitutes a means that
prevents articular chondrocytes from differentiating further into
growth plate-​like cells remains a matter of investigation and discus-
sion. Cell-​specific inactivation of ß-​catenin in Gdf5 producing chon-
drocytes of the interzone results in largely normal joint formation
with alterations mainly in the superficial zone of articular cartilage.
As such, it is not entirely clear whether the described ß-​catenin de-
pendent mechanism in early development affects the whole of the
articular cartilage or predominantly the most superficial, tangential
zone, or whether these differences arise because of temporal distinct
functions of ß-​catenin during development.
Those cells of the mesenchymal condensations that are more
distant from the interzone also undergo chondrogenic differenti-
ation, and then longitudinal growth until the cartilage template is
formed. Subsequently, these chondrocytes differentiate further to
initiate endochondral ossification, which eventually results in the
replacement of the cartilage template with trabecular bone. In add-
ition to the transcription factor Sox-​9 that is involved most prom-
inently in chondrocyte differentiation, these steps are controlled
by genes of the Hox family and regulated by the concerted action
of different signalling proteins, particularly sonic hedgehog (shh),
indian hedgehog (ihh), and growth factors of the fibroblast growth
factor (FGF) family. Components of the ECM, particularly glyco-
proteins such as fibronectin and protein-​bound glycosaminoglycans
such as heparan sulphate proteoglycans (HS) contribute signifi-
cantly to chondrogenesis and thus to key properties of cartilage.
They are synthesized by the differentiating chondrocytes and serve
as a structuring scaffold for limb-​ and joint development. Moreover,
they are involved in creating gradients of growth factors through
binding of soluble factors. Mutations in genes encoding for HS spe-
cies such as perlecan or in enzymes that contribute to the assembly
of HS side chains lead to severe skeletal defects. As a next step in
endochondral ossification, chondrocytes from the centre of the car-
tilage template start differentiating into hypertrophic chondrocytes,
which is associated with fundamental changes in their biochemical
profile. Hypertrophic chondrocytes switch their collagen profile to
produce type X collagen and are able to calcify their surrounding
matrix. Moreover, hypertrophic differentiation is associated with
increased expression of matrix-​degrading enzymes, particularly
matrix metalloproteinase (MMP)-​13, the vascular endothelial
growth factor (VEGF), and transglutaminase 2, which acts a mo-
lecular switch of chondrocytes into a calcifying phenotype. These
changes are controlled prominently by hypoxia through expression
of hypoxia-​inducible factors (HIFs) and allow for the coordinated
degradation of cartilage matrix and the subsequent invasion of
blood vessels into the newly forming bone. Thus, while the mechan-
isms that regulate the differentiation of hypertrophic chondrocytes
and subsequent degradation of the ECM during bone development
are only partly understood, an in-​depth understanding of these pro-
cesses helps explain the cellular and biochemical structure of adult
Superficial zone
Middle zone
Deep or radial zone
Tidemark with calcified zone
Fig. 19.1.1  Zonal organization of cartilage (see text for explanation).
19.1  Joints and connective tissue
4381
joints. Recent data also suggest that joint pathologies such as osteo-
arthritis are characterized by the (re)activation of certain parts of
this embryonic programme in resting chondrocytes of the more
superficial and embryologically distinct articular cartilage.
Biology and metabolism
The primary function of the chondrocytes in the articular cartilage is
to maintain the structure of the surrounding matrix through coord-
inated production and degradation of its components (Fig. 19.1.2).
The exact mechanisms that ensure the homeostatic stability of these
resting chondrocytes remain elusive, but it is important to empha-
size that the term resting chondrocytes does not mean low metabolic
activity. Rather, these cells are characterized by the high level pro-
duction of cartilage matrix components, which not only allows for
continuous cartilage remodelling but also provides the basis for the
regenerative capacity of the cartilage.
The ECM of cartilage consists of mainly three structural elem-
ents: cartilage collagens, proteoglycans, and other non​collagenous
proteins. These elements are strongly interconnected and show dif-
ferences with respect to their amount and distribution between the
area around the chondrocytes, termed territorial matrix, and the
regions between territorial areas that are called the interterritorial
matrix.
Collagens
The main collagen of cartilage is type II collagen, which makes up
about half of all cartilage proteins and more than 90% of all car-
tilage collagens. It has a triple helical structure and forms fibrillar
suprastructures that includes type IX collagen as a fibril-​associated
collagen with interrupted triple helix (FACIT) as well as type XI col-
lagen. As has been understood recently, these additional collagens
within the collagen II fibrils are important for fibrillogenesis, that
is, for the self-​assembly of the fibrils, for the limitation of their lat-
eral growth, and also for the stabilization of the mature fibrils. In
addition, particularly type IX collagen—​through binding of small
leucine-​rich proteoglycans such as decorin—​appears to regulate
the association of fibrils and is thus responsible for structural dif-
ferences between territorial and interterritorial matrix. In addition
to collagen types II, IX, and XI, other collagens such as collagen type
VI are found in the cartilage. Collagens constitute the backbone of
the ECM in the cartilage and their turnover rate is low. Thus, the
half-​life of type II collagen has been estimated to last more than a
human lifetime, which explains why cartilage damage can be con-
sidered largely irreversible once the integrity of the collagen network
is lost. However, in contrast to what is frequently believed, the regen-
erative capacity of cartilage is considerable, and this is due largely to
the constant renewal of other key components of its ECM, namely
the glycosaminoglycans and proteoglycans.
Glycosaminoglycans and proteoglycans
Hyaluronan (HA) is a key glycosaminoglycan in cartilage. It con-
stitutes the structural basis for the formation of large water binding
aggregates with proteoglycans, mainly aggrecan. The amount of
hyaluronan in the cartilage as determined by the rate of synthesis as
well as the length of the individual hyaluronan molecules, therefore,
is an important determinant of the cartilage structure and its func-
tional properties. Other glycosaminoglycans in the cartilage include
heparan sulphate, chondroitin sulphate, and keratan sulphate, which
are usually bound to proteins in specific proteoglycans.
Aside the collagen network, such proteoglycans constitute the
most important components of the cartilage matrix with aggrecan
being the most abundant proteoglycan of cartilage. It consists of
three globular domains that are termed G1, G2, and G3. The G1 do-
main interacts with the link protein of hyaluronan and is, thus, re-
sponsible for the spatial distribution of aggrecan within the cartilage
matrix. The interglobular protein domain between G1 and G2 can
be cleaved by different metalloproteinases, including ADAMTS4
(aggrecanase-​1) and ADAMTS5 (aggrecanase-​2), as well as MMPs
such as MMP-​3 (stromelysin) and MMP-​13 (collagenase-​3). The
interglobular domain between G2 and G3 harbours attachment sites
for keratan sulphate and chondroitin sulphate side chains. These
are attached and post-​translationally modified in a multistep en-
zymatic process. The specific function of the large number of highly
sulphated chondroitin sulphate side chains is a matter for intense
study, particularly because several lines of evidence suggest that
the sulphation pattern not only is variable but changes significantly
during aging.
Proteoglycans are also found on the surface of chondrocytes.
These cell surface proteoglycans include the families of syndecans
and glypicans and are anchored to the cell either through a trans-
membrane domain (as is characteristic for the syndecans) or through
covalent binding of the C-​terminus to glycosylphosphatidylinositol
as found in glypicans (Fig. 19.1.2). They are endowed with indi-
vidually characteristic numbers of heparan sulphate or chondroitin
sulphate side chains that can bind a variety of molecules including
components of the ECM such as fibronectin and a growing list of
soluble mediators, particularly growth factors, but also cytokines
and chemokines. Our knowledge about the role of these cell sur-
face heparan sulphate proteoglycans (HSPGs) in the regulation of
chondrocyte differentiation and behaviour has increased dramat-
ically over recent years, and it has been shown that the effects of
growth factors, such as FGF-​2 and cytokines, such as osteopontin
or chemokines (e.g. CXCL10) are regulated strongly by HSPGs such
as syndecan-​4.
Integrins Syndecans Glypicans
ECM
Fig. 19.1.2  Cell-​matrix interactions in cartilage. The interaction of
chondrocytes with the extracellular matrix (ECM) plays a critical role
in regulating the differentiation of chondrocytes during physiological
development and in pathological conditions. Three classes of cell
surface molecules contribute most prominently to the interaction
of chondrocytes with ECM components: integrins, syndecans, and
glypicans. The integrins and syndecans contain intracellular domains and
can initiate signalling cascades, both independently and in collaboration
with one another.
section 19  Rheumatological disorders
4382
Biochemistry and pathology in arthritis
Osteoarthritis is the most common joint disease and a pathologic
condition that is most closely linked to changes in cartilage biology.
It is a debilitating disorder characterized by the progressive destruc-
tion of articular cartilage through uncontrolled proteolysis of ECM
and typically leads to a remodelling of affected joints. Osteoarthritis
as a disease is discussed in Chapter 19.9, but it is important to note
at this point that although the incidence of osteoarthritis increases
with age, it is not a pure ageing phenomenon. Rather, osteoarthritis is
characterized by profound alterations to the biology of chondrocytes
that show important similarities to endochondral ossification as it
occurs during embryogenesis (previously described here). Recent
data suggest that the triggers which initiate and drive the disease
process in osteoarthritis may be distinct in some respect from those
in embryonic development and more influenced by inflammation,
which is why the term ‘osteoarthritis’ has been chosen. However,
accumulating evidence supports the view that osteoarthritis consti-
tutes a quite uniform way of how chondrocytes and cartilage react
as a whole to stress that they are unable to compensate. This would
mean that although the triggers that initiate osteoarthritis and the
contribution of individual factors such as genetics, inflammation,
mechanical stress, and others may vary considerably from patient to
patient, there is ultimately a rather narrow path or programme that
characterizes its pathophysiology.
Chondrocyte de-​differentiation
During osteoarthritis articular chondrocytes revert to an immature
chondrocytic stage and even undergo pre-​hypertrophic to terminal
chondrocyte maturation, indicating that their differentiation state,
although normally permanent, is not terminal. Losing their differ-
entiated phenotype, the chondrocytes in affected cartilage enter an
endochondral ossification-​like cascade of proliferation and hyper-
trophic differentiation. This change is accompanied by marker ex-
pression for the overt hypertrophic differentiation stage, such as
alkaline phosphatase, Col10a1, with subsequent apoptotic death and
mineralization of the diseased cartilage. Therefore, recent studies
focus on the mechanisms that either stabilize the articular pheno-
type or induce chondrocyte dedifferentiation.
Osteoarthritic changes are associated with the re-​expression of
molecules and pathways in articular chondrocytes that are charac-
teristic for different stages of endochondral ossification. The above-​
mentioned transmembrane heparan sulphate proteoglycans, and
particularly syndecan-​4 are a prime example for this concept. Thus,
it was demonstrated that syndecan-​4 gets re-​expressed in both,
in human osteoarthritis and in animal models of the disease, and
correlates with its severity. Interestingly, the loss of synedcan-​4 in
genetically modified mice or its inhibition by specific antibodies
prevented mice from the development of osteoarthritis-​like changes
suggesting that, indeed, interrupting the cascade that leads to the
completion of the aberrant chondrocyte differentiation programme
may be of therapeutic value. One pathway that has been proposed
to regulate the chondrocytic differentiation during osteoarthritis
(OA) is the Wnt signalling cascade and especially Wnt3a, because
it can dose-​dependently trigger either the canonical ß-​catenin de-
pendent pathway or the non​canonical pCamKII dependent pathway.
Furthermore, both pathways react reciprocally inhibitory. However,
both the constitutive activation and repression of the canonical
ß-​catenin dependent pathway let to osteoarthritis-​like cartilage
changes in mice.
Likewise, it was demonstrated that the hypoxia-​inducible factor
HIF-​2α, which as outlined here has been implicated strongly in
endochondral ossification and in the regulation of genes involved
in chondrocyte hypertrophy, also contributes to the development of
osteoarthritis. Both, the overexpression of HIF-​2α by gene transfer
and the use of genetically modified mice that overexpress HIF-​2α in
their chondrocytes, resulted in an acceleration of osteoarthritis-​
like changes. In turn, genetic deletion of one allele of HIF-​2α clearly
reduced the severity of disease and reduced the expression of
disease-​relevant matrix-​degrading enzymes.
Destruction of articular cartilage
It has been well established that matrix-​degrading enzymes,
mainly of metalloproteinases of the ADAMTS (A Disintegrin and
Metalloproteinase with Thrombospondin motifs) and the MMP
(matrix metalloproteinases) families, are ultimately responsible for
the breakdown of ECM in osteoarthritis and thus for the progressive
loss of articular cartilage. Among the different enzymes, particularly
MMP-​13 and ADAMTS-​5 have been associated with chondrocyte-​
mediated cartilage damage and it has been demonstrated in animal
models of osteoarthritis that the loss of these enzymes or inhibition
of their activation results in less severe cartilage damage. However,
not only is it likely that the relevance of individual members of the
MMP and ADAMTS family varies during different phases of osteo-
arthritis, but it may also be hypothesized that other MMPs (e.g.
MMP-​3 or MT1-​MMP), which themselves are a critical activators
of other MMPs and cathepsins contribute to the loss of articular car-
tilage in osteoarthritis.
As during embryonic development, the induction and unbalanced
action of these enzymes results from the specific differentiation of
the chondrocytes and, therefore, these processes are very closely
linked. It needs to be emphasized, however, that cartilage matrix can
be degraded by these enzymes not only when they are released from
the chondrocytes themselves, but also when there is an increased
and unbalanced expression in neighbouring tissues such as the syn-
ovial membrane. The most prominent example for a disease where
cartilage destruction is mediated mainly by an invading synovial
membrane is rheumatoid arthritis. In this disease, which is covered
in detail in Chapter 19.5 of this book, the inflamed and hyperplastic
synovial membrane that attaches to the articular cartilage and
deeply growth into and destroys the cartilage matrix. Data from dif-
ferent animal models including the severe combined immunodefi-
ciency (SCID) mouse model of RA-​like cartilage destruction and
the human TNF-α transgenic (hTNFtg) mouse suggest that cartilage
destruction by the inflamed and hyperplastic synovium requires the
attachment and, thus, the direct contact of the synovial tissue with
the cartilage. Also, the early loss of proteoglycans from the cartilage,
which is most likely driven by the chondrocytes themselves, appears
to constitute an important prerequisite for the pannus tissue to in-
vade. This notion has been, among others, derived from studying
the sequence of destructive events in the hTNFtg mouse. It was
demonstrated in this study that the loss of cartilage components not
only is an early event in destructive TNF-α-​dependent arthritis, but
that it facilitates the attachment of the inflamed synovial membrane
to the cartilage matrix and, thus, initiates matrix degradation and
19.1  Joints and connective tissue
4383
inflammation through cell-​matrix interactions. Also, experiments
in which these hTNFtg mice were crossed with animals lacking Il-​1,
an important mediator of early proteoglycan loss, showed that the
resulting hTNFtg/​IL-​1 knockout mice develop inflammatory arth-
ritis with pannus formation. However, their cartilage is largely pro-
tected, showing no significant loss of proteoglycans and also no
attachment or invasion of the pannus tissue.
Synovial membrane
The synovial membrane is a second specific component of syn-
ovial joints. Normally, it is only a few (i.e. about four to five) cell
layers thick and consists mainly of fibroblast-​like cells that through
cell-​cell contacts form a layer that lines up the synovial membrane
against the joint cavity and the synovial fluid. The fibroblast-​like
synoviocytes have a key function in providing the joint cavity and
the adjacent cartilage with lubricating molecules such as hyalur-
onic acid, as well as with plasma-​derived nutrients. Unlike other
bordering membranes in our body, the synovial membrane has no
basal membrane, which means it differs significantly from the clas-
sical composition of an epithelium. Also, cellular contacts between
the fibroblast-​like synoviocytes lack tight junctions and desmo-
somes, which together with the absent basal membrane on the one
hand facilitates the efflux of serum components from the small ca-
pillaries into the synovial space, but on the other hand also means
that the most superficial layer of the synovial membrane, the intimal
lining layer, has to take over these functions. In this context, the ad-
hesion molecule cadherin-​11 has been shown to mediate a strong
homophilic adhesion between synoviocytes and to be largely re-
sponsible for their organization into a tissue. Consequently, the lack
of cadherin-​11 in genetically modified mice results in greatly dis-
turbed synovial architecture. This most superficial lining layer of the
synovium can be separated histologically from the looser network
of fibroblast underneath: the sublining. In addition to the fibroblast-​
like synoviocytes, which are also termed type B synoviocytes, there
are macrophages present in the synovial membrane, which are also
called type A synoviocytes. In the normal synovium, these are few
in number and mainly have phagocytic functions. In addition to
providing the synovial cavity with nutrients and lubricating factors,
production of ECM components and cross-​linking these into the
specific three-​dimensional structure is the main function of the cells
in the synovial membrane, mainly the fibroblast-​like synoviocytes.
This is an active process in which the fibroblasts have to migrate
to sites of tissue remodelling and to interact with ECM molecules
through specific surface receptors. Through these receptors, fibro-
blasts have to sense changes in the structure and composition of the
surrounding synovial tissues and they have to respond dynamically
by adjusting the production and cross-​linking of ECM components.
Cell-​matrix interactions
For the interaction with ECM components, particularly collagens,
integrin receptors are of special importance. They are heterodimeric
molecules that consist of one α and one β chain, of which at least
16 different α and 8 different β chains have been identified so far.
These can combine into at least 24 different integrins. Normally,
fibroblast-​like synoviocytes use their integrins receptors to sense
and interact with ECM components within the synovial membrane,
but under pathological conditions, they have been shown to mediate
also the interaction with cartilage collagens and other cartilage com-
ponents. For the attachment of synovial fibroblasts to ECM compo-
nents of connective tissue and cartilage, β-1-​integrins are especially
important. It is important to emphasize that the engagement of in-
tegrin receptors on the surface of fibroblast-​like synoviocytes, just
like on other cells, does not merely establish a cell-​matrix contact
but also leads to the formation of adhesive cell structures that are
called focal adhesions. These focal adhesions are characterized by
a specific rearrangement of the actin cytoskeleton as well as the re-
cruitment of a variety of adaptor molecules. As a consequence of
their formation, intracellular signalling cascades are being activated
that regulate the transcription of genes and thus, control cell prolif-
eration and survival, secretion of certain cytokines and chemokines,
as well as matrix deposition and resorption. Among the molecules
that transmit the signals from integrin clusters to the interior of
fibroblast-​like synoviocytes, the focal adhesion kinase (FAK) plays
a central role. Focal adhesion kinase is a tyrosine kinase that is re-
cruited into newly established focal contacts and in turn recruits
other adaptor proteins such as p130Cas and Grb2. These then lead
to the activation of PI3-​kinase and Src-​kinase and promote the ini-
tiation of a variety of signalling cascades, such as the Raf-​MEK-​Erk
pathway. However, many of these signalling pathways can also be
activated by focal adhesion kinase-​independent signalling mechan-
isms, particularly through growth factors but also by cytokines and
chemokines. The question of how the signals from different sources,
including those from focal adhesions, are coordinated into a specific
cellular response is a matter of intense research.
The analysis of cell-​matrix interactions of fibroblast-​like
synoviocytes is complicated by two observations. First, other and
even more complex adhesive and invasive structures have been iden-
tified and characterized over the past years and the question what
role such podosome-​like structures play in normal and pathological
joint remodelling remains unclear. While classical podosomes are
found mainly on macrophages and related cells, it has been re-
ported that podosome-​like structures such as invadopodia are also
found on other cells such as fibroblasts, particularly when they
are transformed. The second important observation has been that
in addition to integrins, other cell surface molecules are involved
in the attachment of fibroblasts to ECM components as well as in
their response to growth factors and cytokines. Among those, the
above-​mentioned HSPGs and particularly syndecans have gained
special interest recently. In the joint, syndecans are expressed not
only on chondrocytes but also on fibroblasts. Data from syndecan
knockout mice have taught us important lessons on their general
role in tissue remodelling and demonstrated that syndecan-​4 is par-
ticularly important for the response of fibroblasts to tissue injury.
While syndecan-​4 ​deficient mice show no major abnormalities,
they exhibit alterations in wound healing when challenged in dif-
ferent ways. Moreover, it could be demonstrated that the response
of syndecan-​4 deficient fibroblasts to fibronectin attachment is sig-
nificantly altered and that syndecan-​4 deficient fibroblasts have a re-
duced ability to differentiate into α-​smooth muscle actin (a-​SMA)
positive myofibroblasts. The exact mechanisms by which syndecans
are involved in the specific functions of different fibroblast popu-
lations remain to be determined, but it appears that syndecans are
section 19  Rheumatological disorders
4384
important cell surface receptors that due to their unique properties
integrate signals from ECM components and soluble factors. In this
context, most recent data have demonstrated that fibroblast-​like
synoviocytes are regulated in their specific response by proteogly-
cans, and this mechanism has been termed ‘proteoglycan switch’.
Specifically, it was shown that RPTPσ, a transmembrane tyrosine
phosphatase, is reciprocally regulated by interactions with chondro-
itin sulphate or heparan sulphate containing extracellular proteo-
glycans and that this proteoglycan switch regulates fibroblast-​like
synoviocyte function This may be particularly important under con-
ditions such as arthritis, in which either cell-​anchored proteoglycans
get overexpressed or in which fibroblast-​like synoviocytes are ex-
posed to such proteoglycans. In line with this notion, administration
of a RPTPσ decoy protein ameliorated the severity of rheumatoid
arthritis-​like disease in the K/​BxN serum transfer model.
Degradation of extracellular matrix
The fibroblasts of the synovial membrane not only are responsible
for the deposition of ECM molecules and their assembly, but they
are also involved prominently in their destruction and removal. For
the degradation of ECM components, fibroblast-​like synoviocytes
produce a diversity of matrix-​degrading enzyme. These include
members of the metalloproteinase family, including MMPs and
ADAMTS, but also different cathepsins. Most MMPs are not ex-
pressed constitutively but only upon induction by specific stimuli
such as cytokines, growth factors, or ECM molecules. The most
prominent exceptions are MMP-​2 and MT-​MMPs, which are also
regulated by these factors but expressed constitutively at significant
levels. Among the cytokines, IL-​1 is perhaps the most potent inducer
of a variety of MMPs and has been shown to strongly regulate the
expression of MMP-​1, -​3, -​8, -​13, and -​14. Growth factors such as
FGF and platelet-​derived growth factor (PDGF) can also induce
MMPs in fibroblasts and, thus, act synergistically with cytokines
such as IL-​1 on MMP expression. The third group of MMP inducers
are matrix proteins (collagen, fibronectin), and especially their deg-
radation products activate MMP expression in fibroblasts, providing
the possibility for a site-​specific MMP activation in regions of matrix
breakdown. There are several intracellular signalling pathways that
are responsible for the transcriptional activation of MMPs. Thus,
bindings sites for the activator protein-​1 (AP-​1) are present in the
promoters of nearly all MMPs, suggesting that the transcription
factors jun/​fos transcription contribute prominently to the regula-
tion of these enzymes. Indeed, there is ample evidence that all three
mitogen/​stress-​activated protein kinase (MAPK/​SAPK) families,
ERK, JNK, and p38 kinase, are involved in the regulation of MMP
expression by integrating signals upstream of jun/​fos. This has been
shown particularly for MMP-​1, -​9, and -​13.
Biochemistry and function in arthritis
The composition, molecular pattern, and also the biochemistry
of the synovial membrane changes dramatically during inflam-
mation. This is true for acute inflammatory episodes where the
accumulation of inflammatory cells with subsequent stimulation
of the local mesenchyme occurs for a limited period of time, but
even more so for chronic inflammation. The mechanisms that
regulate the switch from acute to chronic inflammation within
the synovium are not very well understood, but it has been
shown that fibroblast-​like synoviocytes contribute significantly
to this process. This has become particularly evident for rheuma-
toid arthritis, where these cells are a key part of the local im-
mune system in the joints and integrate signals form different
sources into a pathological tissue response (Fig. 19.1.3). While
responding to the stimuli in the chronically inflamed synovium,
rheumatoid arthritis fibroblast-​like synoviocytes undergo fun-
damental changes, and multiple lines of evidence suggest that
these result in a stable activation, which is maintained even in
the absence of continuous stimulation by inflammatory triggers.
As a consequence of this stable fibroblast-​like synoviocyte ac-
tivation, the disease process is perpetuated and might progress
when inflammation ameliorates. The underlying mechanisms
are not entirely clear, but the chronic exposure of fibroblast-​like
synoviocytes to inflammatory cytokines, growth factors, and the
ECM appears to result in the imprinting of an aggressive pheno-
type. To this end, they not only express a variety of cytokine re-
ceptors but also toll-​like receptors (TLRs) through which they
can react to damage-​associated molecular pattern (DAMP) and
Fc-​receptors to respond to immunglobulins.
Most of the cytokines that synovial fibroblasts respond to are
derived from invading inflammatory cells such as macrophages
or lymphocytes. TNF-α, IL-​1, and interferon-γ are prominent ex-
amples, and a critical role for these inflammatory cytokines in cel-
lular activation is supported by in vivo animal models of rheumatoid
arthritis in which the constitutive overexpression of inflammatory
cytokines results in a RA-​like disease. One most prominent example
is the human TNF-α transgenic (hTNFtg) mouse. On the other
hand, the activation of fibroblast-​like synoviocytes also results in
a vicious circle in which the activated fibroblasts themselves pro-
duce inflammatory factors including cytokines, growth factors, and
lipid mediators that act in an autocrine and paracrine fashion to
Chemokines
Growth
factors
(Pre-damaged) ECM
Synovial
fibroblasts
Transformed appearing
RA synovial fibroblasts
Stable imprinting
(epigenetic changes)
Cytokines
Fig. 19.1.3  Fibroblast-​mediated cartilage destruction in rheumatoid
arthritis. Under normal conditions, the physiological function of synovial
fibroblasts is to build a lining membrane that secretes lubricants, provides
the joint cavity and the adjacent cartilage with nutritive plasma proteins,
and to be involved in matrix remodelling. In rheumatoid inflammation,
cellular alterations following activation through inflammatory stimuli,
chemokines, and growth factors result in a tumour-​like transformation of
these cells, which exhibit a special phenotype with unique features such
as reduced susceptibility to apoptosis, expression of cartilage adhesion
molecules, and the increased production of matrix-​degrading enzymes.
The mechanisms that imprint these changes into transformed-​looking
fibroblasts are not entirely clear, but epigenetic changes have been
shown to constitute an important factor in this process.
19.1  Joints and connective tissue
4385
further promote inflammation, angiogenesis, chemoattraction, and
misbalanced tissue homeostasis in a vicious circle.
In rheumatoid arthritis, invading B cells also promote the acti-
vation of synovial fibroblasts through immunoglobulin G (IgG)
binding to the high-​affinity FcgammaR (FcgammaR I) on their sur-
face. Through this interaction the production of IL-​16 and RANTES
(chemokine (C-​C motif) ligand 5) is increased, which in turn at-
tracts T cells. It has also been shown that in rheumatoid arthritis, the
direct interaction between fibroblast-​like synoviocytes and inflam-
matory cells through CD40L (CD154) with CD40 contributes to the
disease process.
Of note, synovial fibroblasts are not only stimulated by inflam-
matory and immune cells and their mediators, but in turn also con-
tribute to the accumulation of these cells. Thus, the influx of CD4+
T cells into the proliferating synovium is enhanced by rheumatoid
arthritis synovial fibroblasts due to their production of CXCL16
and IL-​16. Rheumatoid arthritis fibroblast-​like synoviocytes are
also an important source of cytokines with IL-​2-​like activity, IL-​
15, and IL-​7, in rheumatoid arthritis joints. Rheumatoid arthritis
synovial fibroblasts have been shown to contribute to the attrac-
tion and accumulation of B cells in inflamed tissue. For example,
the secretion of SDF-​1 by synovial fibroblasts has been shown
to facilitate B cell migration and activation to the synovium. In
summary, the interaction between mesenchymal, immune, and
inflammatory cells is mediated by a tightly regulated, extremely
complex network of cytokines that results in the maintenance of
inflammation.
FURTHER READING
Archer CW, Dowthwaite GP, Francis-​West P (2003). Development of
synovial joints. Birth Defects Res C Embryo Today, 69, 144–​55.
DeLise AM, Fischer L, Tuan RS (2000). Cellular interactions and
signaling in cartilage development. Osteoarthritis Cartilage, 8, 309–​34.
Eyre D (2002). Collagen of articular cartilage. Arthritis Res, 4, 30–​5.
Fuerst M, et al. (2009). Calcification of articular cartilage in human
osteoarthritis. Arthritis Rheum, 60, 2694–​703.
Hunziker EB, Michel M, Studer D (1997). Ultrastructure of adult
human articular cartilage matrix after cryotechnical processing.
Microsc Res Tech, 37, 271–​84.
Knudson CB, Knudson W (2001). Cartilage proteoglycans. Semin Cell
Dev Biol, 12, 69–​78.
Korb-​Pap A, et al. (2012). Early structural changes in cartilage and
bone are required for the attachment and invasion of inflamed syn-
ovial tissue during destructive inflammatory arthritis. Ann Rheum
Dis, 71, 1004–​11.
Mundlos S, Olsen BR (1997). Heritable diseases of the skeleton: part
I: molecular insights into skeletal development-​transcription factors
and signaling pathways. Faseb J, 11, 125–​32.
Pearle AD, Warren RF, Rodeo SA (2005). Basic science of articular car-
tilage and osteoarthritis. Clin Sports Med, 24, 1–​12.
Poole AR, et al. (2001). Composition and structure of articular car-
tilage: a template for tissue repair. Clin Orthop Relat Res, (391 Suppl),
S26–​33.
Zwerina J, et al. (2007). TNF-​induced structural joint damage is medi-
ated by IL-​1. Proc Natl Acad Sci U S A, 104, 11742–​7.

19.10 Crystal- related arthropathies 4482 Edward R
19.10 Crystal- related arthropathies 4482 Edward Roddy and Michael Doherty
ESSENTIALS
Many crystals have been associated with arthropathies or periarticular
syndromes: only monosodium urate (gout), calcium pyrophosphate
(acute calcium pyrophosphate crystal arthritis chondrocalcinosis),
and basic calcium phosphates (mainly hydroxyapatite) are common.
Crystals implicated in joint disease are stable, hard particles that
exert biological effects via surface-​active (activation of humoral and
cell-​derived mediators, interaction with cell membranes) and mech-
anical properties. In general, smaller particle size, marked surface
irregularity, and high negative surface charge correlate with inflam-
matory potential.
Gout
Aetiology and pathogenesis—​gout is caused by the formation of
monosodium urate crystals, and the primary risk factor for its devel-
opment is hyperuricaemia. It is common (prevalence 2.49%, rising
with age). Risk factors for primary gout include being male, hyperten-
sion, obesity, insulin resistance, metabolic syndrome, excess alcohol
consumption (especially beer), and a diet rich in purines and fruc-
tose. Most act primarily by reducing efficient elimination of uric acid
via the kidney. Important risk factors for secondary gout are diuretic
therapy, chronic renal impairment, and osteoarthritis.
Clinical features—​four clinical phases are recognized. (1)
Asymptomatic hyperuricaemia:  the risk of developing gout in-
creases with the degree of hyperuricaemia, but around 95% of
hyperuricaemic patients remain asymptomatic throughout life.
(2) Acute gout: in almost all initial episodes a single peripheral joint is
involved, with the first metatarsophalangeal joint (podagra) the site
of the first attack in 50% of patients. Other common sites are the
midtarsal joints, ankle, knee, small hand joints, wrist, and elbow. The
pain is often described as ‘the worst ever experienced’. The joint and
surrounding tissues are swollen, hot, red, shiny, and extremely tender.
(3) Intercritical gout: after resolution of the first attack there is a vari-
able time period before the second, but this usually occurs within
one year and chronic symptoms usually develop within 10 years.
(4) Chronic tophaceous gout: large crystal deposits (tophi) produce
irregular firm nodules and chronic joint damage. Gout is associated
with renal disease; uric acid stones (10–​25% of patients) and chronic
urate nephropathy (endstage renal failure occurs in up to 25% of
cases of untreated chronic tophaceous gout).
Diagnosis—​proof of gout requires the identification of monoso-
dium urate crystals on polarized light microscopy of aspirates from
synovial fluid or tophus (strongly birefringent, negative sign). Although
gout is strongly associated with hyperuricaemia, serum urate is fre-
quently normal during an acute attack, and hyperuricaemia per se is
not a diagnostic test for gout.
Management—​treatment of an acute attack aims to reduce in-
flammation: options include non​steroidal anti-​inflammatory drugs,
low-​dose colchicine, joint aspiration, intra-​articular (occasion-
ally systemic) steroids, and ice packs. Alteration of uric acid levels
is avoided until the attack has resolved. Long-​term management
involves lifestyle modification advice and urate-​lowering therapy.
Encouragement concerning weight loss and restriction of the con-
sumption of alcohol (especially beer) and purine-​rich foods should
be offered to all appropriate patients with primary gout. Urate-​
lowering therapy should be titrated with the aim of lowering the
serum urate well below 360 µmol/​litre (6 mg/​dl)—​the physiological
saturation point for urate crystal formation. Allopurinol, a xanthine
oxidase inhibitor, is the usual drug of choice. Where allopurinol is
not tolerated, options are febuxostat and the uricosuric drugs (pro-
benecid, sulfinpyrazone, and benzbromarone).
Calcium pyrophosphate crystal deposition
Deposition of calcium pyrophosphate crystals in articular cartilage
can be seen on radiographs in 4.5% of adults over the age of 40.
It is almost always of unknown cause (sporadic/​idiopathic, associ-
ated with osteoarthritis), but can be associated with metabolic dis-
ease (hyperparathyroidism, haemochromatosis, hypophosphatasia,
hypomagnesaemia) or be hereditary.
Clinical features, diagnosis, and management—​the following are
common presentations. (1)  Acute calcium pyrophosphate crystal
arthritis (acute pseudogout) —​one of the commonest causes of acute
monoarthritis in older people. A typical attack develops rapidly (6–​
24 h)—​usually in the knee—​with severe pain, stiffness and swelling,
and a florid synovitis on examination. Fluid aspirated from the joint
is often turbid or bloodstained with an elevated cell count, and po-
larized light microscopy reveals calcium pyrophosphate crystals
(weakly birefringent, positive sign). Local therapy is preferred with ice
packs and aspiration (combined with intra-​articular steroid in florid
cases). (2) Osteoarthritis with calcium pyrophosphate deposition—​a
common condition that affects mainly elderly women and targets
19.10
Crystal-​related arthropathies
Edward Roddy and Michael Doherty
19.10  Crystal-related arthropathies
4483
the same large and medium-​sized joints as acute calcium pyrophos-
phate crystal arthritis. Presentation is with chronic pain, stiffness,
and functional impairment, with or without superimposed acute
attacks. Affected joints show signs of osteoarthritis with varying de-
grees of synovitis. There is no specific therapy and treatment of any
underlying metabolic disease does not influence outcome, which is
generally good. (3) Asymptomatic calcium pyrophosphate depos-
ition may be an incidental radiographic finding.
Apatite-​associated syndromes
Apatites, or basic calcium phosphates, are the usual minerals de-
posited in extraskeletal tissues (e.g. in arterial walls or tuberculous
lesions). Apatite deposition in the supraspinatus tendon is a not un-
common incidental finding, occasionally resulting in severe acute
inflammation (acute calcific periarthritis).
Introduction
Diversity and terminology
Many crystals have been associated with acute synovitis, chronic
arthropathy, or periarticular syndromes (Box 19.10.1). In practice
only monosodium urate, calcium pyrophosphate, and basic calcium
phosphates (mainly hydroxyapatite) are commonly encountered.
The taxonomy of these conditions is not universally agreed.
Difficulties arise from our poor understanding of pathogenesis, his-
torical extrapolation from gout to other crystal-​related conditions,
and multiple terms for the same clinical syndrome. Possible rela-
tionships between crystals and disease are outlined in Fig. 19.10.1.
A ‘crystal deposition disease’ is defined as a pathological condition
associated with mineral deposits that contribute directly to the path-
ology. This is probably the situation for all manifestations of gout,
for acute syndromes associated with calcium pyrophosphate, and
for acute apatite periarthritis. However, the role of nonurate crystals
in chronic arthropathy is unclear and confounded by the following
observations:
•	 Most crystals lack disease specificity and occur in a variety of
clinical settings, often unaccompanied by symptoms or other
abnormality.
•	Crystal deposition may coexist with other rheumatic disease,
most commonly osteoarthritis, and often follows, rather than
precedes, articular damage.
•	Combined deposition of several crystal species is common
(mixed crystal deposition).
For descriptive purposes, confusion may be avoided by specifying
the crystal, the site of involvement, and the clinical syndrome (e.g.
chronic urate olecranon bursitis, acute calcium pyrophosphate
crystal arthritis of the knee).
Crystal deposition and clearance
Many factors determine crystal formation and dissolution
(Fig. 19.10.2). High solute concentrations alone are often insufficient
to initiate crystal formation, and the presence of nucleating factors that
aid initial particle formation and the balance of growth-​promoting
and inhibitory factors are probably more important. Little is known of
such tissue factors, although they may in part explain:
•	 the characteristic, limited distribution of different crystals
Box 19.10.1  Crystalline particles associated with joint disease
Intrinsic
• Monosodium urate
• Calcium pyrophosphate (monoclinic, triclinic)
• Calcium phosphates
— Basic: hydroxyapatite, octacalcium phosphate, tricalcium phosphate
— Acidic: brushite, monetite
• Calcium oxalate
•	 Lipids
•	 Cholesterol
• Lipid liquid crystals
• Charcot–​Leyden (phospholipase) crystals
•	 Cystine
• Xanthine, hypoxanthine
• Protein precipitates (e.g. cryoglobulins)
Extrinsic
• Synthetic corticosteroids
• Plant thorns (semicrystalloid cellulose), especially blackthorn, rose,
dried palm fronds
• Sea urchin spines (crystalline calcium carbonate)
•	 Methylmethacrylate
Crystals
X
Crystals
Joint disease
Crystals
Joint disease
Crystals
Joint disease
Joint disease
Fig. 19.10.1   Possible relationships between crystals and joint disease.
Solute excess
(pH)
Dissolution
Inhibitory
factors
Nucleating
factors
Growth promoting
factors
CRYSTALS
(slow transition to
stable forms)
Enzymic
degradation
Reduced solute
concentration
(temperature)
(pressure)
Fig. 19.10.2   Factors affecting crystal formation.
section 19  Rheumatological disorders
4484
•	 the frequency of mixed crystal deposition (via epitaxial nucleation
and growth of one crystal on another)
•	 non​specific predisposition to crystal formation in osteoarthritic
tissues (via accompanying alterations in proteoglycan, collagen,
and lipid)
Formation of crystals in vivo is a dynamic process, although usually
slow. At any time the crystal load will depend on the rate of forma-
tion, the rate of dissolution, and trafficking of crystals away from
their site of formation (via shedding from preformed deposits with
secondary uptake by synovial and other cells).
Crystal-​induced inflammation and tissue damage
Crystals implicated in joint disease are stable, hard particles that
exert biological effects via surface-​active and mechanical properties.
With respect to acute inflammation, they are all markedly phlogistic
agents in a wide range of in vitro and in vivo systems. Surface-​active
interaction has been demonstrated with:
•	 humoral mediators (e.g. complement activation via classical and
alternative pathways, activation of Hageman factor)
•	 cell-​derived mediators (e.g. superoxide production and release of
lysozymes, chemotactic factor, and lipoxygenase-​derived prod-
ucts of arachidonic acid by neutrophils, release of interleukin l
(IL-​1), IL-​6, and tumour necrosis factor (TNF) by monocytes and
synoviocytes)
•	 cell membranes (e.g. membranolysis of lysosomes, erythrocytes,
and neutrophils, non-​lytic platelet, and neutrophil secretory
responses)
In general, monosodium urate is the most inflammatory, followed
by calcium pyrophosphate, then apatite and the less common crys-
tals. In general, smaller particle size, marked surface irregularity,
and high negative surface charge correlate with inflammatory po-
tential. Some surface effects result from direct crystal contact, but
others are mediated via adsorbed protein, particularly immuno-
globulin. Although adsorbed IgG may enhance inflammation, most
other protein binding is inhibitory. A key recent development has
been the identification of the role played by the intracellular NLRP3
inflammasome in crystal-​induced inflammation. Both monoso-
dium urate and calcium pyrophosphate crystals stimulate this to ac-
tivate and release interleukin-​1β.
Less is known of chronic crystal-​induced tissue damage. Postulated
effects include persistent synovial inflammation, altered cell metab-
olism (ingested calcium crystals may stimulate mitogenesis, fibrosis,
and calcium-​related cellular effects), and deleterious mechanical
effects from large deposits. Evidence for activation of inflamma-
tory mediators in chronic crystal-​associated synovitis is lacking,
although a chronic ‘granulomatous’ reaction often occurs around
large accretions. The physicochemical effects of hard, highly charged
crystals embedded within cartilage, or occurring as wear particles at
the surface, are largely unknown.
 Gout
Monosodium urate crystals are undoubted causal agents in gout,
which arises following supersaturation of body tissues with mono-
sodium urate. Subsequently the deposition of crystals in previously
normal tissues may elicit acute inflammation and eventual tissue
damage. Their effective removal halts progression and results in
cure. In these respects, gout is a true crystal deposition disease.
Both the incidence and prevalence of gout are rising. In the United
Kingdom, its incidence increased from 1.36 to 1.77 per 1000 person-​
years between 1997 and 2012. Similarly, prevalence rose from
1.52% in 1997 to 2.49% in 2012 in the United Kingdom, and from
2.64% in 1988–​1994 to 3.76% in 2007–​2010 in the United States.
Prevalence rises with age and there is strong predominance in men
(male:female approximately 4:1), particularly under 65 years of age.
Untreated gout evolves slowly through four clinical phases: asymp-
tomatic hyperuricaemia, acute gout, intercritical gout, and chronic
tophaceous gout.
Clinical features
Asymptomatic hyperuricaemia
Hyperuricaemia is the primary risk factor for the development of
gout and arises from either overproduction or renal underexcretion
of uric acid, or a combination of both (see Chapter 12.4). Although
hyperuricaemia and gout are strongly linked, they are not syn-
onymous. Around 95% of hyperuricaemic subjects remain asymp-
tomatic throughout life. The risk of developing gout increases with
the degree of hyperuricaemia, but even in patients with the highest
levels of serum urate (>540 µmol/​litre (9.0 mg/​dl)) annual incidence
is less than 5%, emphasizing the importance of local tissue factors
in crystal nucleation/​growth. Ultrasound studies suggest that up
to one in three hyperuricaemic patients have occult monosodium
urate deposits.
Monosodium urate crystals preferentially deposit in peripheral
connective tissues in and around synovial joints. Deposits occur first
in articular cartilage, most commonly the first metatarsophalangeal
and small joints of the feet, developing later in synovium, capsule,
and periarticular soft tissues. Crystals probably take months if not
years to grow in vivo to detectable size, implying a long asymptom-
atic phase. Absence of inflammation during this period may relate
to low crystal yield, positioning within hypovascular tissues, or in-
hibitory protein coating.
Acute attacks
The classical attack
In almost all initial episodes, a single peripheral joint is involved. The
first metatarsophalangeal joint (podagra) is the site of the first attack
in 50% of patients and is affected at some point in over 70%. This
may relate to the common occurrence of osteoarthritis at this joint.
Other common sites are the midtarsal joints, ankle, knee, small hand
joints, wrist, and elbow. The axial skeleton and large central joints
are rarely involved and never as the first site.
Attacks often wake the patient in the early morning with local-
ized irritation and aching. Within just a few hours the joint and sur-
rounding tissues are swollen, hot, red, shiny, and extremely painful.
The patient cannot bear even bedclothes to touch the joint and it is
often described as ‘the worst pain ever experienced’. Inflammation is
maximal within 24 h and is often associated with pyrexia and mal-
aise. Examination reveals florid synovitis and swelling, extreme ten-
derness, and overlying erythema. If left untreated, the attack resolves
spontaneously over 5–​15 days, often with pruritus and desquam-
ation of overlying skin.
19.10  Crystal-related arthropathies
4485
Although many attacks occur spontaneously, some situations
encourage shedding of preformed monosodium urate crystals and
triggering of acute attacks. Suggested mechanisms include mechan-
ical loosening (local trauma), partial dissolution and reduction of
crystal size (initiation of hypouricaemic treatment, reduction in uric
acid levels as part of the acute phase response), and local increase
in cytokines that encourage inflammatory responses to crystals and
facilitate crystal escape via alterations in cartilage matrix (intercur-
rent illness, surgery). Although some triggers (alcohol, dietary ex-
cess) increase local urate levels, acute crystallization is considered
unlikely.
Atypical attacks
Acute attacks may manifest as tenosynovitis, bursitis, or cellu-
litis. Many patients describe mild episodes of discomfort without
swelling lasting a day or so (petite attacks). Ten per cent (10%) of all
typical attacks involve more than one joint. Sometimes acute gout,
by triggering the acute phase response, provokes migratory attacks
in other joints over subsequent days (cluster attacks). Polyarticular
attacks are rare, usually occurring after a long history of recurrent
attacks: marked systemic upset, fever, and confusion may dominate
the clinical picture.
Intercritical periods
Following the resolution of the first attack, a variable time period
elapses before the next attack occurs. The asymptomatic interval be-
tween attacks is called the intercritical period. Some patients never
have a second attack; in others the next episode occurs after many
years; in most, however, a second attack occurs within one year. With
time, the frequency and severity of attacks and number of sites in-
volved increases, and attacks are more often pauci-​ or polyarticular.
Eventually, recurrent attacks and continuing monosodium urate de-
position cause joint damage and chronic pain. The interval between
the first attack and development of chronic symptoms is variable,
but averages about 10 years. The principal determinant is the serum
uric acid; the higher it is, the earlier and more extensive the develop-
ment of joint damage and tophaceous deposits.
Chronic tophaceous gout
Large crystal deposits (tophi) produce irregular firm nodules,
principally around extensor surfaces of fingers, hands, the ulnar
surface of the forearms, olecranon bursae, Achilles tendons, first
metatarsophalangeal joints, and the cartilaginous helix of the ear.
Marked asymmetry, both locally and between sides, is particu-
larly characteristic (Fig. 19.10.3). Monosodium urate crystals be-
neath the skin may show a white-​yellow ‘chalky’ discolouration
(Fig. 19.10.4). If untreated, tophi can enlarge into gross knobbly
swellings that may ulcerate, discharging white and gritty material
that causes local inflammation (erythema, pus) even in the absence
of secondary infection. If extensive, tophi may rarely involve the
eyelids, tongue, larynx, or heart (causing conduction defects and
valvular dysfunction).
Joints most commonly involved with signs of damage (restricted
movement, crepitus, deformity) and varying degrees of synovitis
are the first metatarsophalangeal joints, midfoot, small finger joints,
and wrists. As with tophi, joint involvement is usually asymmetrical.
Occasionally gross destruction may occur in feet and hands, and less
commonly other sites. Acute attacks may become less of a feature
as chronic symptoms become established. If untreated, the combin-
ation of extensive joint destruction and large tophi may cause gro-
tesque deformities, particularly of hands and feet. Ankylosis is a rare
late event. Although axial involvement is rare, even in late stages,
gouty involvement of hips, shoulders, spine and sacroiliac joints,
and spinal cord compression by tophi, are all reported.
Classification
Gout is traditionally classified into primary and secondary, with dif-
ferent clinical patterns and separate risk factors and associations de-
scribed for each (Tables 19.10.1 and 19.10.2).
Primary gout characteristically affects men, with an age of onset
between 30 and 60 years of age, and a predeliction for the legs, par-
ticularly the first metatarsophalangeal joint. Presentation is with
acute attacks, and untreated disease progresses to chronic tophaceous
Fig. 19.10.3   Chronic tophaceous gout affecting the hands. Note the
eccentric nature of the tophi and the asymmetry between sides.
Fig. 19.10.4   Diuretic-​induced gout in an elderly woman, showing
tophaceous deposition on pre-​existing nodal osteoarthritis; the white
monosodium urate crystals are clearly visible beneath the skin.
section 19  Rheumatological disorders
4486
gout. Over 75% of patients with primary gout are underexcretors of
uric acid. A family history of gout is common due to an inherited
isolated renal lesion that reduces fractional urate clearance. Fewer
than 10% are overproducers of uric acid. The cause usually remains
unclear, although a very few have an inherited purine enzyme defect
(see Chapter 12.4). Genome-​wide association studies have identi-
fied 28 loci influencing serum urate levels, most of which exert their
effect via genes either coding for renal urate transporters or those
influencing glycolysis.
Secondary gout, by contrast, mainly presents in older individuals
(>65 years) and shows a more equal gender distribution and equal
involvement of the arm and leg peripheral joints. Acute attacks are
said to be less frequent and tophi may be the initial manifestation.
Primary gout
Primary gout associates strongly with metabolic syndrome and
obesity, type IV hyperlipidaemia, hypertension, and insulin resist-
ance. Hypertension and obesity are independent risk factors for
the development of gout; hypertensive microvascular renal damage
leads to hyperuricaemia and, in obese patients, insulin resistance
and hyperinsulinaemia impair renal urate excretion. The association
of primary gout with these common cardiovascular risk factors not
surprisingly translates into an important association between pri-
mary gout and cardiovascular disease. Excessive consumption of al-
cohol, purine-​rich foods, sugar-​sweetened soft drinks and fructose
are also independent risk factors for primary gout. Beer drinking
confers the greatest risk, attributable in part to its high guanosine
content, followed by spirits, with wine conferring only slight risk.
The 19th century association with port is partly explained by storage
of wines in lead-​lined casks and the addition of lead to sweeten the
port: lead inhibits uric acid excretion and also promotes nucleation
of monosodium urate. Saturnine gout still occurs in individuals who
drink alcohol distilled or stored in lead-​contaminated containers
(‘moonshine’). Purine-​rich foods (e.g. meat and seafood), and soft
drinks rich in fructose are associated with increased risk of gout,
whereas consumption of dairy products, coffee, and vitamin C are
protective.
Secondary gout
The most important risk factors for secondary gout are diuretic
therapy and chronic renal impairment. Diuretics are an inde-
pendent risk factor for the development of gout, even after adjust-
ment for hypertension. Renal tubular organic anion transporters
have recently been identified, through which diuretics exert their
hyperuricaemic effect. Other drugs may predispose to gout, such
as β-​blockers, ACE inhibitors, angiotensin-​II receptor antagonists
(other than losartan), low-​dose aspirin, and ciclosporin, although
the urate-​enhancing effect of low-​dose aspirin is not thought to be
of clinical significance when compared with its cardiovascular bene-
fits in this high-​risk group. More widespread organ transplantation
and use of ciclosporin as an immunosuppressant have resulted in
transplant-​associated gout becoming a challenging problem in sec-
ondary care. In contrast, calcium-​channel antagonists and losartan
appear to protect against the development of gout. Secondary gout
is also associated with osteoarthritis, with both acute attacks of gout
and tophi occurring at Heberden’s and Bouchard’s nodes in elderly
women (Fig. 19.10.4).
There is a strong negative association between gout and rheuma-
toid arthritis. This remains unexplained, but probably reflects
impaired nucleation/​growth of monosodium urate crystals rather
than masking of monosodium urate crystal-​induced inflammation
(e.g. by crystal coating with rheumatoid factors). A less strong nega-
tive association is also reported between rheumatoid arthritis and
calcium pyrophosphate crystal deposition.
Gout and renal disease
Urolithiasis
Uric acid stones account for 5–​10% of all stones in the United
Kingdom and the United States of America, and up to 40% in Israel.
A history of renal colic can be obtained in 10–​25% of patients with
gout, the important aetiological factors being low urinary pH, low
urinary volume, and high urinary uric acid concentration. High
urinary concentrations occur in overproducers of uric acid, if renal
urate clearance is increased (uricosuric drugs, defects in tubular
reabsorption), and in situations of dehydration with lowering of
Table 19.10.1  Primary and secondary gout: clinical features
Clinical feature
Primary gout
Secondary gout
Sex
Males ≫ females
Males = females
Age
Middle-​age
Elderly
Acute attacks
Common
May be less common
Distribution
Lower limb ≫ upper limb
Lower limb = upper limb
Tophi
Develop late
Develop early
Table 19.10.2  Primary and secondary gout: clinical associations
and accompanying screening tests
Clinical association
Screening test
Primary
gout
Male
Family history
Metabolic syndrome
Hypertension
Blood pressure monitoring
Hyperlipidaemia
Fasting lipids
Insulin resistance
Fasting plasma glucose
Obesity
Alcohol
MCV, liver function tests
Purine-​rich foods
Sugar-​sweetened soft drinks and
fructose
Secondary
gout
Diuretics
β-​blockers, ACE inhibitors,
non​losartan angiotensin-​II
receptor antagonists
Chronic renal failure
Creatinine (eGFR)
Lead poisoning (rare)
Osteoarthritis
Ciclosporin (rare)
Myeloproliferative disorders (rare)
FBC, ESR
eGFR, estimated glomerular filtration rate; ESR, erythrocyte sedimentation rate; FBC, full
blood count; MCV, mean cell volume.
19.10  Crystal-related arthropathies
4487
urinary pH (diarrhoea, ileostomy). Gouty patients also have an in-
creased incidence of calcium-​containing stones, particularly cal-
cium oxalate, with no detectable uric acid nidus.
Acute uric acid nephropathy describes rapid precipitation of
uric acid crystals in renal collecting ducts with secondary acute ob-
structive renal failure. This event correlates with the amount of uric
acid excreted rather than the level of hyperuricaemia. Strongly acid
urine, which reduces uric acid solubility, potentiates the problem.
The condition occurs in ill, dehydrated patients with lymphoma or
malignancy subjected to aggressive chemotherapy without adequate
prophylactic treatment (with allopurinol and/​or recombinant
uricase). It also occurs in gouty patients with markedly accelerated
purine synthesis (e.g. following excessive exercise or epileptic seiz-
ures), when again the condition is largely avoidable by appropriate
hydration, urinary alkalinization, and allopurinol prophylaxis.
Chronic urate nephropathy
Widespread monosodium urate deposition in the interstitium of
the medulla and pyramids results in crystal-​induced inflamma-
tion with surrounding giant-​cell reaction and fibrosis, affecting in
particular the tubular epithelium of the loop of Henle and juxta-
posed interstitial tissues. Subsequent changes include glomerular
hyalinization and hypertrophy of the intima and media of arteri-
oles. Hypertensive damage, tubular obstruction, and secondary
pyelonephritis may all complicate this picture. Albuminuria and
inability to concentrate the urine maximally are early clinical mani-
festations. Progressive renal disease is an important complica-
tion of untreated chronic tophaceous gout, endstage renal failure
occurring in up to 25% of cases.
Calcium oxalate or phosphate crystals may deposit in the renal
parenchyma in advanced renal disease of any cause, but are predom-
inantly cortical in location (compared with the medullary site of
monosodium urate).
The association between parenchymal disease and less severe
gout remains controversial, being confounded in men by frequent
accompanying obesity, hypertension, and drug therapy. The minor
progression of renal insufficiency that occurs in most gouty patients,
however, is probably largely age related, and life expectancy is not
reduced.
Differential diagnosis
Acute attacks
Sepsis and other crystal-​associated synovitis are the main consid-
erations. However, the rapidity of onset of severe symptoms that
plateau within 12–​24 h is highly characteristic of crystal inflamma-
tion; sepsis presents more slowly and is progressive. Gout and sepsis
may coexist, as may monosodium urate and calcium pyrophosphate
deposition (particularly in elderly patients). Examination of aspir-
ated fluid for both crystals and sepsis (Gram stain, culture) is the
only sure way of obtaining the correct diagnosis. A wider search for
sepsis may be indicated (e.g. blood and urine cultures), particularly
in those who are ill. With less classic attacks, other conditions that
may be considered include psoriatic and acute reactive arthropathy,
acute sarcoid arthropathy, traumatic arthritis, palindromic rheuma-
tism, and exacerbation of osteoarthritis. A search for synovial fluid
crystals should be undertaken in all patients with unexplained in-
flammatory arthritis.
Chronic tophaceous gout
Other causes of arthritis and periarticular swellings/​nodules that
require differentiation are rheumatoid arthritis, generalized nodal
osteoarthritis, xanthomatosis with arthropathy, and multicentric
reticulohistiocytosis. Gout is usually less symmetrical in distribu-
tion than these conditions and, except for xanthomatosis, acute
attacks are not a feature. Nodal osteoarthritis, of course, may coexist
with gout. Aspiration (joint fluid, nodules) and plain radiographs
readily facilitate correct diagnosis.
Clinical investigation
The history and signs of classical acute or chronic tophaceous gout
are highly characteristic, and with a raised serum urate a strong
presumptive diagnosis is readily made. However, definitive con-
firmation requires demonstration of monosodium urate crystals by
compensated polarized light microscopy of fluid from a gouty joint,
bursa, or tophus. Synovial fluid in acute attacks is typically turbid
with diminished viscosity and greatly elevated cell count (>90%
neutrophils). Chronic gouty fluid is more variable, but occasionally
appears white owing to the high crystal load. Only a few drops col-
lected directly on to a slide are required for crystal identification.
Monosodium urate crystals are seen readily as strongly birefringent
(negative sign), needle-​shaped crystals, 5–​20 µm in length, within
cells or occurring freely in fluid. In tophaceous material they occur
as dense, tightly packed sheets. During intercritical periods, aspir-
ation of an asymptomatic first metatarsophalangeal joint or knee
often permits confirmation of the diagnosis by revealing monoso-
dium urate crystals.
Measurement of the serum urate level is an important investiga-
tion, both to confirm the presence of hyperuricaemia and monitor
response to treatment. Urate is a negative acute phase reactant, and
hence urate levels are frequently lowered during an acute attack of
gout. If the serum urate is found to be within the ‘normal range’
during a suspected acute attack it should be repeated during the
intercritical period.
In primary gout in a young patient, determination of
undersecretion or overproduction of uric acid is best undertaken by
measuring total urinary excretion on a low-​purine diet, but a quick
guide is given by the uric acid/​creatinine ratio estimated on a single
urine sample (normally <0.5). In young overproducers, a purine en-
zyme defect becomes more likely and should be sought. Assessment
of renal function (creatinine, urea, electrolytes, urine testing) should
always be undertaken (Table 19.10.2). Given the association of pri-
mary gout with cardiovascular disease and the metabolic syndrome,
measurement of fasting lipoprotein concentrations and glucose
should be made in all patients with primary gout. An intercritical full
blood count and measurement of ESR/​viscosity should detect any
underlying chronic myeloproliferative disease. During acute attacks
a marked acute phase response (high ESR, neutrophil leucocytosis,
thrombocytosis, elevated C-​reactive protein) is usual; modest eleva-
tions of ESR may also accompany chronic gout.
Radiographs supplement the clinical assessment of structural
damage but can also aid diagnosis. In early disease they are usu-
ally normal. During acute gout, non​specific soft tissue swelling
(rarely juxta-​articular osteopenia) may be evident. After repeated
attacks, and in chronic disease, joint space narrowing, scler-
osis, cysts, and osteophytes (that is, the changes of osteoarthritis)
section 19  Rheumatological disorders
4488
become more frequent in feet and hands. Gouty ‘erosions’ are a less
common but more specific abnormality, occurring as para-​articular
‘punched-​out’ bone defects with well-​demarcated sclerotic mar-
gins, overhanging hooks of bone, and retained bone density
(Fig. 19.10.5). They are typically asymmetric, eccentric lesions
positioned away from the ‘bare area’ of the joint, contrasting with
more symmetrical, ill-​defined marginal erosions (with osteopenia)
of rheumatoid arthritis. Tophi appear as eccentric soft tissue
swellings, occasionally with patchy calcification due to epitaxial
growth of apatite. In late disease, severe destructive change with
osteopenia may occur, and distinction from rheumatoid arthritis
or other conditions becomes more difficult. Ultrasonography and
dual-​energy computed tomography have emerging roles in the
assessment of gout, providing novel non​invasive opportunities
to visualize crystal deposits and differentiate monosodium urate
from other crystals (Table 19.10.3).
Treatment
Acute gout
The treatment aim is pain relief by reducing inflammation
and intra-​articular hypertension, which can be achieved using
non​steroidal anti-​inflammatory drugs (NSAIDs), colchicine, or
corticosteroids. For the best results, patients should be instructed
to take their medication as soon as possible following the start of
their attack. Alteration of uric acid levels is avoided until the attack
has resolved, as initiation of hypouricaemic drugs may prolong the
attack and important information concerning lifelong treatment
is best delivered when the patient has fully recovered from their
painful episode.
Rapid symptom relief may be obtained with a quick-​acting
NSAID, given in full dosage. Indometacin has traditionally been
considered the NSAID of choice but—​given its frequent renal,
gut, and nervous system side effects—​other NSAIDs are to be pre-
ferred (e.g. diclofenac or naproxen). In the presence of risk factors
for gastrointestinal toxicity (e.g. old age) a gastroprotective agent (a
proton pump inhibitor or misoprostol) should be coadministered
with a traditional NSAID, or alternatively a selective inhibitor of
cyclooxygenase-​2 (COX-​2), such as etoricoxib, can be given, al-
though long-​term use should be cautioned by the adverse cardio-
vascular profile of both COX-​2 selective agents and primary gout.
Oral colchicine is rapidly effective within a few hours. High-​dose
regimes such as 1 mg immediately, followed by 0.5 mg every 2–​3 h
until symptoms abate, very frequently cause diarrhoea, nausea,
and abdominal cramps, and are best avoided. Low-​dose colchi-
cine (e.g. 0.5 mg two or three times daily), is widely used with both
symptomatic benefit and less toxicity, and is a useful alternative if
NSAIDs are contraindicated. Intravenous colchicine, however, is
particularly toxic and should never be used. Although previously
used as a ‘diagnostic test’, the efficacy of colchicine is not specific to
gout: it also ameliorates other crystal-​associated syndromes.
Fig. 19.10.5   Characteristic radiographic changes of established gout in a
finger: joint space loss and cystic change at the distal interphalangeal joint,
‘pressure erosions’ with overhanging bony ‘hooks’ at both interphalangeal
joints, and eccentric soft tissue swelling at the proximal joint.
Table 19.10.3  European League Against Rheumatism proposal for terminology of manifestation of calcium pyrophosphate crystal
deposition
Existing term
New term
Definition
Calcium pyrophosphate
dihydrate crystals
Calcium pyrophosphate crystals
Simplified name for calcium pyrophosphate dihydrate crystals
–​
Calcium pyrophosphate deposition
Umbrella term for all instances of calcium pyrophosphate crystal occurrence
Chondrocalcinosis
Chondrocalcinosis
Cartilage calcification, identified by imaging or histological identification.
Commonly but not always due to calcium pyrophosphate deposition
Clinical presentations associated with calcium pyrophosphate deposition
–​
Asymptomatic calcium pyrophosphate
deposition
Calcium pyrophosphate deposition with no apparent clinical consequence, either
isolated chondrocalcinosis or osteoarthritis with calcium pyrophosphate deposition
Pyrophosphate
arthropathy
Osteoarthritis with calcium pyrophosphate
deposition
Calcium pyrophosphate deposition in a joint which also shows changes of OA, on
imaging or histological examination
Acute pseudogout
Acute calcium pyrophosphate crystal arthritis
Acute onset, self-​limiting synovitis with calcium pyrophosphate deposition
–​
Chronic calcium pyrophosphate crystal
inflammatory arthritis
Chronic inflammatory arthritis associated with calcium pyrophosphate deposition
19.10  Crystal-related arthropathies
4489
Joint aspiration often provides immediate relief by reducing
intra-​articular hypertension, and in difficult cases joint lavage
may terminate an attack. Intra-​articular steroid is useful for
large joints such as the knee. When NSAIDs or colchicine are
contraindicated or unsuccessful, intra-​articular steroid or oral
prednisolone (20 mg/​day) can be effective, and for troublesome
polyarticular attacks there is support for the use of parenteral
steroid. Application of ice locally to an affected joint also provides
symptomatic relief.
Long-​term management
Once any acute attack has resolved, long-​term strategies need con-
sideration. Gout is potentially curable. Treatment may involve
both considering and eliminating modifiable factors that cause
hyperuricaemia, and utilizing hypouricaemic drugs. Management
of gout may therefore require alteration in lifestyle and chronic
medication: patient compliance and motivation, which depend on
appropriate education and counselling, are essential for success.
Modification of provoking factors
Lifestyle modification is a key component of the management of
primary gout. In particular, obesity, excess alcohol consumption,
and a high-​purine diet are independent risk factors that are amen-
able to modification. Advice concerning weight loss and restriction
of the consumption of alcohol (especially beer) and purine-​rich
foods should be offered to all patients with primary gout when
appropriate.
In diuretic-​induced gout, the diuretic should be discontinued or
the dose reduced whenever possible, and this may be all that is re-
quired. However, this cannot often be achieved where the indica-
tion for the diuretic is cardiac failure rather than hypertension, and
pharmacological measures are necessary.
Urate-​lowering drug therapy
Absolute indications for urate lowering therapy are:
•	 recurrent, troublesome acute attacks, although urate lowering
therapy should be considered and discussed with the patient
earlier
•	 presence of tophi
•	 bone or cartilage damage on radiographs
•	 coexistent renal disease, uric acid urolithiasis
•	 very high uric acid levels (particularly with overproduction and
hyperexcretion)
The aim of urate-​lowering therapy is the reduction and maintenance
of serum urate well below 360 µmol/​litre (6 mg/​dl), which is below
the physiological saturation threshold of urate within the serum
(approximately 380 µmol/​litre (6.4 mg/​dl)). The lowering of urate
below this level reduces the frequency of acute attacks and crystal
load. Allopurinol, a purine non​specific xanthine oxidase inhibitor,
is the usual drug of choice, permitting flexible tailoring of dose to
reduce urate levels below the solubility limit. Allopurinol is usually
started at the relatively low dose of 100 mg daily. The serum urate
should then be checked at regular intervals (e.g. monthly) and, if
tolerated, the dose of allopurinol increased in 100 mg increments
up to a maximum dose of 900 mg daily until the serum urate lies
well below 360 µmol/​litre (6 mg/​dl). In patients with renal insuffi-
ciency, particularly older people, excretion of the active metabolite
oxipurinol is delayed and hence dose escalation should be more cau-
tious. Treatment should be lifelong. Febuxostat, a non​purine specific
xanthine oxidase inhibitor, can be used when allopurinol is contra-
indicated or not tolerated and has been shown to produce greater re-
ductions in serum urate levels than allopurinol 300 mg daily at either
of its two licensed doses (80 mg or 120 mg daily).
The uricosurics probenecid (0.5–​1.0 g twice a day) and
sulfinpyrazone (100 mg three or four times daily), which prevent
proximal tubular reabsorption of urate, are rarely used. They are
alternatives to allopurinol in patients with normal renal function
but are contraindicated in those with renal impairment, urolith-
iasis, or gross overproduction of uric acid (due to reduced effi-
cacy and risk of worsening renal function). Benzbromarone, a
potent uricosuric, is now increasingly used in parts of Europe,
and is the one uricosuric that can be used in patients with mild
to moderate renal impairment. Its availability, however, is limited,
owing to reports of occasional severe hepatotoxicity (possibly
limited to Japanese patients). Lesinurad is a novel selective uric
acid reabsorption inhibitor that has been shown to achieve greater
reductions in serum urate levels in combination with a xan-
thine oxidase inhibitor than that achieved by a xanthine oxidase
inhibitor alone.
Losartan, an angiotension-​II receptor antagonist, and fenofibrate
have mild uricosuric properties that may prove useful in patients
with hypertension and/​or hyperlipidaemia in addition to gout.
Losartan is therefore a logical alternative anti-​hypertensive agent in
diuretic-​induced gout.
Acute attacks may be provoked during the first few months of
hypouricaemic treatment, especially if initiation is with higher doses
(e.g. 300 mg allopurinol). Prophylactic colchicine (0.5 mg twice a
day) or a standard dose of NSAID given for the first two to three
months of treatment largely avoids ‘breakthrough’ attacks. With any
uricosuric, high fluid intake and urine alkalinization in the early
weeks of treatment are recommended to avoid deposition of uric
acid within the kidney.
Serious side effects are unusual with any hypouricaemic drugs.
Rare problems include toxic epidermal necrolysis, interstitial neph-
ritis and vasculitis (allopurinol hypersensitivity syndrome), neph-
rotic syndrome (probenecid), and hepatitis and marrow suppression
(both drugs). Important interactions with allopurinol occur with
coumarin anticoagulants (due to hepatic microsomal enzyme in-
hibition) and purine analogues (such as azathioprine) that are in-
activated by xanthine oxidase. Associated hypertension should be
treated, but preferably not with diuretics, which elevate serum urate
and may provoke acute attacks.
Better understanding of the pathophysiology of hyperuricaemia
and gout has led to the development of new approaches to treat-
ment. Elucidation of the role of the inflammasome and interleukin-​
1β in the causation of acute attacks has awakened interest in
using interleukin-​1 inhibitors such as anakinra, canakinumab,
and rilonacept to both treat acute attacks and prevent attacks
when initiating urate-​lowering therapy. Recombinant uricase and
pegloticase, which convert uric acid to allantoin, produce significant
reductions in serum urate levels in patients with severe gout who
are unresponsive to, or intolerant of, other urate-​lowering drugs.
Currently, however, such drugs are expensive, restricted to hospital
settings, and are not all approved for such use, hence they are re-
served for exceptional circumstances.
section 19  Rheumatological disorders
4490
Calcium pyrophosphate crystal deposition
Deposition of calcium pyrophosphate crystals (Ca2P2O7.2H2O)
in articular cartilage is a common age-​related phenomenon.
Calcium pyrophosphate crystals preferentially deposit within
fibrocartilage and are the most common cause of cartilage calcifica-
tion (chondrocalcinosis).
Calcium pyrophosphate deposition may occur in otherwise
normal cartilage or associate with structural change and clinical
arthropathy—​‘arthropathy’. A causal role for calcium pyrophos-
phate crystals in acute inflammation is accepted, but their role
in chronic arthropathy is unclear. The strong association/​overlap
with osteoarthritis led some to consider the historical term ‘pyro-
phosphate arthropathy’ not as a crystal deposition disease but as
a subset of osteoarthritis, with calcium pyrophosphate a ‘process’
marker associating with a hypertrophic bone response. In 2011,
the European League Against Rheumatism proposed a new ter-
minology for the manifestations of calcium pyrophosphate crystal
deposition (Table 19.10.3).
Radiographic chondrocalcinosis has an age-​adjusted standard-
ized prevalence of 4.5% in adults over age 40, its prevalence at the
knee rising to about 20% in those over age 80. There is an equal sex
distribution. Community studies have confirmed an association
with osteoarthritis at the knee (age, sex-​adjusted odds ratio 2.0). The
age-​standardized prevalence of osteoarthritis with calcium pyro-
phosphate deposition in the United Kingdom in people older than
40 is 2.40%.
Clinical features
Common presentations are acute calcium pyrophosphate crystal
arthritis (acute pseudogout), osteoarthritis with calcium pyrophos-
phate deposition, or as an asymptomatic incidental radiographic
finding (chondrocalcinosis). Other presentations are rare.
Acute calcium pyrophosphate crystal arthritis
This is one of the commonest causes of acute monoarthritis in older
people. Attacks may occur as isolated events or be superimposed
upon a background of chronic joint symptoms. Most attacks occur
spontaneously, but provoking factors include intercurrent illness,
surgery, and local trauma. Although any joint may be involved, the
knee is by far the commonest site, followed by the wrist, shoulder,
and ankle. Concurrent attacks in several joints are uncommon and
polyarticular attacks rare.
The typical attack develops rapidly with severe pain, stiffness,
and swelling, becoming maximal within just 6 to 24 h of onset.
Examination reveals a very tender joint with signs of florid synovitis
(increased warmth, tense effusion, restricted movement with stress
pain) and often overlying erythema. Fever is common, and elderly
patients may appear unwell or mildly confused, especially when
more than one joint is involved. Attacks are self-​limiting, usually re-
solving within 1 to 3 weeks. The identical clinical presentation of
such attacks to gout is the reason for the historical term ‘pseudogout’.
Osteoarthritis with calcium pyrophosphate deposition
This common condition affects mainly elderly women and targets
the same large and medium-​sized joints as acute calcium pyrophos-
phate crystal arthritis. Knees are the usual and most severely affected
joint. Presentation is with chronic pain, stiffness, and functional im-
pairment, with or without superimposed acute attacks. Symptoms
usually relate to just a few joints, although examination often re-
veals more widespread joint involvement. Affected joints show signs
of osteoarthritis (crepitus, bony swelling, restricted movement)
with varying degrees of synovitis (often most marked at the knee,
radiocarpal, or glenohumeral joint). Knees typically show abnor-
mality of two or three compartments; valgus or varus deformity
may occur.
Although symptoms and signs are those of osteoarthritis, co-​
occurrence with calcium pyrophosphate deposition (osteoarthritis
with calcium pyrophosphate deposition) may often be distinguished
from uncomplicated osteoarthritis by:
•	 the joint distribution—​in osteoarthritis wrist, glenohumeral, ankle,
elbow, and midtarsal involvement is less common
•	 the often marked inflammatory component
•	 superimposition of acute attacks
The outcome for osteoarthritis with calcium pyrophosphate
deposition is generally good, most patients running a relatively
benign course, particularly with respect to small and medium-​
sized joints. If progression occurs, it is usually slow and related to
knees, hips, or shoulders. Severe, rapidly progressive, destructive
arthropathy occasionally develops at these sites. This is virtually
confined to very elderly women and is associated with severe pain,
recurrent haemarthrosis (shoulder, knee), and occasional joint
leakage.
Incidental finding
As with uncomplicated osteoarthritis, clinical or radiographic evi-
dence of calcium pyrophosphate deposition and chondrocalcinosis
are not uncommon incidental findings in older people, and may
confound the cause of regional pain if a thorough history and exam-
ination are not undertaken.
Uncommon presentations
Acute tendinitis (triceps, Achilles), tenosynovitis (hand flexors,
extensors), and bursitis (olecranon, infrapatellar, retrocalcaneal)
occur uncommonly, usually in patients with widespread calcium
pyrophosphate crystals. Median and ulnar nerve compression at
the wrist may accompany flexor tenosynovitis. Rare tophaceous
deposits of calcium pyrophosphate usually present as solitary le-
sions in areas of chondroid metaplasia (usually benign cartilage
tumours).
Classification and associations
Calcium pyrophosphate deposition is traditionally classified
as: being hereditary; associated with metabolic disease; or sporadic/​
idiopathic (by far the commonest, associated with osteoarthritis).
Familial predisposition
This is reported from many countries and different ethnic groups.
Two clinical phenotypes occur:  early onset (third to fourth
decade) florid polyarticular chondrocalcinosis with variable se-
verity of accompanying arthropathy; and late onset (sixth to sev-
enth decade) oligoarticular chondrocalcinosis (mainly knee) with
arthritis resembling sporadic disease. The pattern of inheritance
19.10  Crystal-related arthropathies
4491
varies, although autosomal dominance is usual. Two chromo-
somal locations have been identified in kindreds with young-​onset
chondrocalcinosis: CCAL1 on chromosome 8 (associating with se-
vere structural arthritis), and CCAL2 on chromosome 5 (mainly
associating with isolated polyarticular chondrocalcinosis). The re-
sponsible gene at CCAL2 encodes the multipass transmembrane
transporter protein ANKH (ankylosis human) that regulates passage
of intracellular inorganic pyrophosphate to the extracelluler space.
Mutations in ANKH in British, French, and American kindreds re-
sult in greatly increased exit of pyrophosphate from chondrocytes,
sufficient to exceed the saturation point for calcium pyrophosphate
crystal formation. Other mechanisms may operate in other families.
For example, histological studies in Japanese and Swedish families
suggest a primary abnormality in cartilage matrix that promotes
calcium pyrophosphate crystal nucleation and growth.
Metabolic disease associations
Inorganic pyrophosphate is a by-​product of many biosynthetic
reactions, with a turnover of several kilograms per day. Most
extracellular inorganic pyrophosphate derives from breakdown
of extracellular ATP via the action of the NTP pyrophosphatase
plasma cell membrane glycoprotein-​1 (PC-​1). Normally this extra-
cellular pyrophosphate is rapidly converted to orthophosphate by
pyrophosphatases (particularly alkaline phosphatase) (Fig. 19.10.6).
Several metabolic diseases associate with deposition of calcium
pyrophosphate (Table 19.10.4), their association being rationalized
through putative effects on metabolism of inorganic pyrophos-
phate. Suggested mechanisms include:
•	 reduced breakdown of inorganic pyrophosphate by alkaline phos-
phatase, owing to (1) reduced levels, (2) inhibitory ions (calcium,
iron, copper), or (3) impaired complexing with magnesium
•	 enhanced nucleation by iron or copper
•	 increased calcium concentration
Osteoarthritis and joint insult
Several observations support a relationship between osteoarthritis
and deposition of calcium pyrophosphate crystals, the latter often
following rather than preceding joint damage. However, there is a
negative association between deposition of calcium pyrophosphate
and rheumatoid arthritis, with atypical radiographic features in
coexistent disease (retained bone density; marked osteophyte, cyst,
and bone remodelling) suggesting that the primary association of
calcium pyrophosphate is with hypertrophic tissue response/​osteo-
arthritis and not joint damage per se. The explanation for this associ-
ation probably relates to changes both in pyrophosphate metabolism
and in tissue factors that encourage crystal formation. Levels of
PPi
cell
Pi
ATP
ANKH
Ca++
CPPD
crystals
Mg++
1
2
3
nucleation
AlkP
cell
PC1
PPi
Fig. 19.10.6   Simplified scheme of extracellular pyrophosphate
metabolism, showing putative sites of interaction by metabolic diseases.
Hyperparathyroidism, 1,2; haemochromatosis, 1,3; hypophosphatasia,
1; Wilson’s disease, 1,3; and hypomagnesaemia, 1. Alk P, alkaline
phosphatize; ANKH, ankylosis human protein; ATP, adenosine
triphosphate; CPPD, calcium pyrophosphate dehydrate; Mg++,
magnesium; PC1, plasma cell glycoprotein-​1; PPi, pyrophosphate.
Table 19.10.4  Metabolic diseases associated with calcium pyrophosphate dihydrate (CPPD) crystal
deposition
Chondrocalcinosis
Acute calcium pyrophosphate
crystal arthritis
Osteoarthritis with calcium
pyrophosphate deposition
Definite associations
Hyperparathyroidism
+
+
–​
Haemochromatosis
+
+
+
Hypophosphatasia
+
+
–​
Hypomagnesaemia
+
+
–​
Possible associations
Hypothyroidism
+
–​
–​
Gout
+
+
–​
X-​linked hypophosphataemic rickets
+
+
+
Familial hypocalciuric hypercalcaemia
+
–​
–​
Wilson’s disease
+
–​
–​
Ochronosis
+
–​
–​
Acromegaly
+
–​
–​
section 19  Rheumatological disorders
4492
inorganic pyrophosphate in synovial fluid are increased in calcium
pyrophosphate deposition, osteoarthritis, and in metabolic diseases
that predispose to chondrocalcinosis, but are lower than normal
in rheumatoid arthritis. Calcium pyrophosphate crystals form in
pericellular sites and associate with lipid, proteoglycan depletion,
and adjacent hypertrophic chondrocytes containing lipid granules.
It is therefore possible that reduction of inhibitors (such as proteo-
glycan) and increase in promotors (such as lipid) may combine to
copromote calcium pyrophosphate formation in metabolically ac-
tive osteoarthritic tissue that associates with high levels of extracel-
lular pyrophosphate.
Investigations and diagnosis
Critical investigations are synovial fluid analysis and plain radio-
graphs. In acute calcium pyrophosphate crystal arthritis, aspirated
fluid is often turbid or bloodstained with an elevated cell count
(>90% neutrophils). Compensated polarized microscopy reveals
calcium pyrophosphate crystals as weakly birefringent (positive
sign) rhomboids or rods, about 2 to 10 µm long. Calcium pyrophos-
phate crystals are less readily identified and often less numerous
than those of monosodium urate; examination of a spun deposit
may increase detection.
Radiographic aspects relate both to calcification and arthropathy.
Chondrocalcinosis signifies extensive deposition and is not always
evident: it mainly affects fibrocartilage (particularly knee menisci,
wrist triangular cartilage, symphysis pubis), and less commonly hya-
line cartilage (Fig. 19.10.7). Although occasionally monoarticular, it
usually affects several sites. Calcification of capsule, synovium, and
tendons is less common. Chondrocalcinosis and calcification may
increase or decrease with time, diminishing chondrocalcinosis often
accompanying crystal shedding or cartilage loss.
Changes of arthropathy are those of osteoarthritis:  cartilage
loss, sclerosis, cysts, and osteophytes. However, characteristics
that suggest pyrophosphate include:
•	 distribution between and within joints that is atypical of osteo-
arthritis (e. g. glenohumeral disease; isolated or predominant
patellofemoral or radiocarpal involvement)
•	 prominence of osteophytes and  cysts
•	 prominent osteochondral  bodies
Such combined features may present a distinctive ‘hypertrophic’
appearance even in the absence of chondrocalcinosis (Fig. 19.10.8).
Marked cartilage and bone attrition with fragmentation and
loose osseous bodies may resemble a Charcot joint in destructive
arthropathy.
Metabolic predisposition is rare and routine screening of all pa-
tients is unrewarding. Nevertheless, arthritis associated with cal-
cium pyrophosphate crystals may be the presenting feature of
metabolic or familial disease, and a search is warranted in early onset
chondrocalcinosis or acute calcium pyrophosphate crystal arthritis
(<55 years), florid polyarticular chondrocalcinosis, or presence of
additional clinical or radiographic clues. A reasonable screen would
include serum calcium, alkaline phosphatase, magnesium, ferritin,
and liver function.
Differential diagnosis
The principal differential diagnosis for acute calcium pyrophosphate
crystal arthritis is sepsis or gout, both of which may coexist with
calcium pyrophosphate deposition. Gram stain and culture of joint
fluid should be undertaken even when calcium pyrophosphate (and/​
or monosodium urate) crystals are identified. Marked bloodstaining
may lead to consideration of other causes of haemarthrosis, espe-
cially a bleeding disorder or subchondral fracture.
Fig. 19.10.7   Radiographic chondrocalcinosis of the knee affecting
meniscal fibrocartilage (central, triangular) and hyaline cartilage (linear,
parallel to bone).
Fig. 19.10.8   Lateral knee radiograph showing predominant
patellofemoral involvement by ‘hypertrophic’ osteoarthritis
characteristic of osteoarthritis with calcium pyrophosphate deposition.
19.10  Crystal-related arthropathies
4493
Chronic calcium pyrophosphate crystal inflammatory arthritis is
usually readily distinguished from rheumatoid arthritis by the syn-
ovial fluid and radiographic findings, the infrequency of severe sys-
temic upset, absence of extra-​articular features, and an acute phase
response that is only modest. Proximal stiffness due to glenohumeral
involvement may suggest polymyalgia rheumatica, although clinical
examination and near normal ESR should exclude the diagnosis.
Destructive osteoarthritis with calcium pyrophosphate deposition
may simulate a neuropathic joint, although such joints are severely
symptomatic and neurological abnormality is absent.
Treatment
Acute calcium pyrophosphate crystal arthritis
As acute calcium pyrophosphate crystal arthritis usually affects only
one or a few joints in elderly patients, local therapy is preferred.
Aspiration alone often relieves symptoms, but should be combined
with intra-​articular steroid in florid cases. Local ice packs are safe
and often helpful. With respect to systemic treatments, opioids
and oral NSAIDs should be used with caution in the older people
(coprescription of a proton pump inhibitor or misoprostol with an
NSAID is indicated in those over 65; alternatively, the short-​term
use of a selective COX-​2 inhibitor may be considered). Joint lavage
is reserved for troublesome steroid-​resistant cases. Colchicine is ef-
fective but rarely warranted. Triggering illness (e.g. chest infection)
will require appropriate treatment. Rapid mobilization should be in-
stituted once the synovitis is settling.
Osteoarthritis with calcium pyrophosphate deposition
Unlike gout, there is no specific therapy, and treatment of any
underlying metabolic disease does not influence outcome. Treatment
aims are to reduce symptoms and maintain or improve function.
This may include education of the patient in appropriate use of
the affected joints, reduction in obesity, improvement of muscle
strength, use of a stick or other walking aid, and surgery for severe
disease. Chronic synovitis may be improved by intermittent steroid
injection or intra-​articular radiocolloid (yttrium-​90). As with acute
calcium pyrophosphate crystal arthritis, symptomatic drugs are to
be used with caution in older patients; simple analgesics are gener-
ally preferable to NSAIDs.
Other crystal-​related disorders
Apatite-​associated syndromes
Hydroxyapatite is the principal bone mineral. Apatites or basic cal-
cium phosphates (partially carbonate-​substituted hydroxyapatite,
octacalcium phosphate, tricalcium phosphate (rarely)) are the usual
minerals to deposit in extraskeletal tissues (e.g. tuberculous lesions,
arteries).
The [calcium × phosphate] product must be kept high to main-
tain skeletal integrity. Specific cellular mechanisms activate calcifi-
cation where appropriate (e.g. matrix vesicles in growing cartilage),
whereas other mechanisms (such as pyrophosphate and aggregated
proteoglycan) inhibit calcification elsewhere. In general, abnormal
calcification results from:
•	 elevation of the [calcium × phosphate] product, causing wide-
spread metastatic calcification
•	 alteration in the balance between inhibitory and promoting tissue
factors, resulting in local dystrophic calcification.
In rheumatic diseases, abnormal deposition of basic calcium phos-
phates may occur in periarticular tissues (particularly tendon), hya-
line cartilage, in association with osteoarthritis, or subcutaneous
tissues and muscle, principally in connective tissue diseases.
Apatite crystals are too small (5–​500 nm) to be seen by light mi-
croscopy, but particles may aggregate to form spherulites that are
visible on microscopy. Confirmation of basic calcium phosphates
requires sophisticated analytical techniques, and most clinical
diagnoses are presumptive, based on radiographic calcification, or
non​specific staining of joint fluid or histological material.
Acute calcific periarthritis
Apatite deposition in the supraspinatus tendon (Fig. 19.10.9) is a
relatively common incidental finding (about 7% of adults). It oc-
casionally results in severe acute inflammation of the subacromial
bursa, periarticular tissues, or joint itself. Periarticular sites around
the greater hip trochanter, the foot, or the hand are less commonly
affected.
Acute episodes may follow local trauma or occur spontaneously.
Within a few hours pain and tenderness are often extreme and the
area appears swollen, hot, and red. Modest systemic upset and fever
are common. Sepsis is usually considered first, but the diagnosis
is made following demonstration of radiographic calcification. If
the lesion is aspirated, thick white fluid containing many apatite
aggregates may be obtained. The condition usually resolves spon-
taneously over 1 to 3 weeks, often accompanied by radiographic dis-
persal of modestly sized calcifications (crystal shedding). NSAIDs
ameliorate symptoms, and the attack can be abbreviated by aspir-
ation and injection of steroid. Large deposits may cause mechanical
impingement and blocking of movement and require surgical re-
moval. Calcific periarthritis rarely results from metabolic abnor-
mality (renal failure, hyperparathyroidism, hypophosphatasia) and
measurements of serum calcium, alkaline phosphatase, and cre-
atinine are usually normal. Rare families are predisposed to calcific
Fig. 19.10.9   Shoulder radiograph showing florid supraspinatus tendon
calcification (calcific periarthritis).
section 19  Rheumatological disorders
4494
periarthritis at multiple sites despite no evidence of altered calcium
phosphate product.
Osteoarthritis and apatite-​associated destructive arthritis
Modest amounts of basic calcium phosphates are commonly found
in synovial fluid from osteoarthritic joints, in isolation or with cal-
cium pyrophosphate (mixed crystal deposition). Whether apatite
plays any part in inflammatory exacerbations or associates with se-
verity or progression of osteoarthritis remains uncertain.
The uncommon condition ‘apatite-​associated destructive arthritis’ is
often considered a subset of osteoarthritis. It is virtually confined to
elderly women and affects the hip, shoulder (Milwaukee shoulder),
or knee. It has the general appearance of severe large joint osteo-
arthritis but is particularly characterized by: rapid progression, often
leading to severe pain and disability within a few months of onset;
development of marked instability; large, cool effusions; and an atro-
phic radiographic appearance with marked cartilage and bone attri-
tion and little osteophyte or bone remodelling.
Aspirated fluid has normal viscosity and a low cell count but
contains large amounts of apatite aggregates, seen readily on light
microscopy following non​specific calcium staining (Alizarin Red,
acidic pH). The differential diagnosis may include sepsis (excluded
by synovial fluid culture), late avascular necrosis, or neuropathic
joint. The pathogenesis of this condition remains unclear. Although
apatite particles could contribute to tissue damage by stimulating
release of collagenase and other proteolytic enzymes from synovial
cells, it is most likely that the apatite is noncontributory and prin-
cipally reflects the severity of subchondral bone attrition. The out-
come is poor and usually requires surgical intervention.
Other apatite syndromes
Deposition of very large tophaceous periarticular apatite (tumoural
calcinosis) may occur in patients with chronic renal failure managed
by dialysis. Apatite has also been incriminated in the occasional ero-
sive interphalangeal arthropathy seen in such patients.
Other crystals
Cholesterol
Cholesterol crystals may induce acute synovitis, acute tenosynovitis,
and chronic xanthomatous tendinitis in hypercholesterolaemic
subjects. Cholesterol and other lipid crystals may also occur as a
non​specific finding in chronic synovitis, most commonly due to
rheumatoid arthritis. In this situation the lipid probably derives
from cellular debris and its pathogenic significance is uncertain.
Oxalate
Oxalate crystals have been incriminated in acute and chronic ar-
ticular and periarticular syndromes occurring in association with
either primary familial oxalosis (types I  and II) or secondary
oxalosis (Chapter 12.10). Chronic renal failure managed with dia-
lysis is the commonest cause of secondary oxalosis, particularly
if ascorbic acid supplementation has been given. Acute symmet-
rical interphalangeal and metacarpophalangeal arthritis, with or
without tenosynovitis, and digital calcific deposits are the usual
manifestation. Large joint involvement, chondrocalcinosis, and
tophaceous periarticular masses are less common. Calcium oxalate
crystals may also cause life-​threatening organ involvement, with
peripheral vascular insufficiency and digital necrosis, cardiomy-
opathy, peripheral neuropathy, and aplastic anaemia. There is no
effective treatment.
Extrinsic crystals
These rare causes of locomotor problems. Acute flares following
intra-​articular injection of corticosteroids are uncommon but may
represent iatrogenic crystal-​induced inflammation. Penetrating in-
juries involving plant thorns and sea urchin spines may cause acute
and chronic inflammatory synovitis, periostitis, or periarticular le-
sions that only resolve following surgical removal of the crystalline
material.
FURTHER READING
Abhishek A, Doherty M (2011). Pathophysiology of articular
chondrocalcinosis—​role of ANKH. Nat Rev Rheumatol, 7, 96–​104.
Choi HK, et al. (2005). Pathogenesis of gout. Ann Intern Med, 143,
499–​516.
Edwards NL, So A (2014). Emerging therapies for gout. Rheum Dis
Clin N Am, 40, 375–​87.
Jordan KM, et al. (2007). British Society for Rheumatology and British
Health Professionals in Rheumatology guideline for the manage-
ment of gout. Rheumatology (Oxford), 46, 1372–​4.
Khanna D, et al. (2012). American College of Rheumatology guidelines
for management of gout. Part 1: systematic nonpharmacologic and
pharmacologic therapeutic approaches to hyperuricemia. Arthritis
Care Res (Hoboken), 64, 1431–​46.
Khanna D, et al. (2012). American College of Rheumatology guide-
lines for management of gout. Part 2: therapy and antiinflammatory
prophylaxis of acute gouty arthritis. Arthritis Care Res (Hoboken),
64, 1447–​61.
Petrilli V, Martinon F (2007). The inflammasome, autoinflammatory
diseases, and gout. Joint Bone Spine, 74, 571–​6.
Richette P, et al. (2009). An update on the epidemiology of calcium
pyrophosphate dihydrate crystal deposition disease. Rheumatology
(Oxford), 48, 711–​5.
Roddy E, Choi HK (2014). Epidemiology of gout. Rheum Dis Clin N
Am, 40, 155–​75.
Roddy E, et al. (2013). Clinical review: gout. BMJ, 347, f5648.
Rosenthal AK, Ryan LM (2014). Nonpharmacologic and pharmaco-
logic management of CPP crystal arthritis and BCP arthropathy and
periarticular syndromes. Rheum Dis Clin N Am, 40, 343–​56.
Zhang W, et  al. (2006). EULAR evidence based recommendations
for gout—​part I diagnosis: report of a task force of the Standing
Committee for International Clinical Studies Including Therapeutics
(ESCISIT). Ann Rheum Dis, 65, 1301–​11.
Zhang W, et al. (2006). EULAR evidence based recommendations for
gout—​part II management: report of a task force of the Standing
Committee for International Clinical Studies Including Therapeutics
(ESCISIT). Ann Rheum Dis, 65, 1312–​24.
Zhang W, et al. (2011). European League Against Rheumatism recom-
mendations for calcium pyrophosphate deposition. Part I: termin-
ology and diagnosis. Ann Rheum Dis, 70, 563–​70.
Zhang W, et al. (2011). EULAR recommendations for calcium pyro-
phosphate deposition. Part II:  management. Ann Rheum Dis,
70, 571–​5.

19.11 Autoimmune rheumatic disorders and vasculiti
19.11 Autoimmune rheumatic disorders and vasculitides 4495

19.11.1 Introduction 4495 David A. Isenberg and Ia
19.11.1 Introduction 4495 David A. Isenberg and Ian Giles
CONTENTS
19.11.1	 Introduction   4495
David A. Isenberg and Ian Giles
19.11.2	 Systemic lupus erythematosus and related
disorders   4499
Anisur Rahman and David A. Isenberg
19.11.3	 Systemic sclerosis (scleroderma)   4513
Christopher P. Denton and Carol M. Black
19.11.4	 Sjögren’s syndrome   4532
Wan-​Fai Ng
19.11.5	 Inflammatory myopathies   4537
Ingrid E. Lundberg, Hector Chinoy, and Robert Cooper
19.11.6	 Large vessel vasculitis   4546
Raashid Luqmani and Cristina Ponte
19.11.7	 ANCA-​associated vasculitis   4556
David Jayne
19.11.8	 Polyarteritis nodosa   4569
Loïc Guillevin
19.11.9	 Small vessel vasculitis   4573
Richard A. Watts
19.11.10	 Behçet’s syndrome   4579
Sebahattin Yurdakul, Izzet Fresko, and Hasan Yazici
19.11.11	 Polymyalgia rheumatica   4584
Bhaskar Dasgupta and Eric L. Matteson
19.11.12	 Kawasaki disease   4590
Brian W. McCrindle
19.11.1  Introduction
David A. Isenberg and Ian Giles
ESSENTIALS
About 1 in 20 people develop an autoimmune disease, many of
which involve the musculoskeletal system. Young women are
particularly at risk, but the development at any age of symptoms
such as unexplained fever, rash, polyarthritis, Raynaud’s phenom-
enon, or mouth ulcers should encourage serological screening for
autoimmune rheumatic or vasculitic disorder.
Aetiology and pathogenesis—​common to all of the autoimmune
rheumatic diseases is the phenomenon of production of autoanti-
bodies by activated B cells. In the primary vasculitides, a pathogenic
role has been proposed for antiendothelial cell antibodies and sen-
sitized T cells, but undoubtedly the most important role is that of
antineutrophil cytoplasmic antibodies.
Diagnosis—​detection of antinuclear antibodies or rheumatoid
factor in high titre favours the diagnosis of an autoimmune rheumatic
disease and should lead to a search for more specific autoantibodies;
for example, anti-​dsDNA linked to lupus, anti-​citrullinated peptide/​
protein antibodies linked to rheumatoid arthritis, antineutrophil
cytoplasmic antibodies linked to granulomatosis with polyangiitis,
and microscopic polyangiitis. Well-​established and validated classifi-
cation criteria exist, and several have been recently revised for all the
main autoimmune rheumatic diseases and vasculitides, but there is
significant overlap between them. Physicians treating patients with
these conditions need to be constantly aware of the possibility of
organ involvement because prompt diagnosis and treatment may be
necessary to prevent irreversible damage.
Definition and epidemiology
The autoimmune rheumatic diseases are a heterogeneous group of
disorders characterized by clinical involvement of the joints, con-
nective tissues, muscles, internal organs, Raynaud’s phenomenon,
and cutaneous manifestations. They include a broad clinical spec-
trum of disease, including systemic lupus erythematosus (SLE),
rheumatoid arthritis (RA), Sjögren’s syndrome, scleroderma, derm-
atomyositis, polymyositis, antiphospholipid syndrome (APS), and
the vasculitides. This latter group of diseases all share inflamma-
tion and necrosis of blood vessels as cardinal features, and may be
divided into primary (e.g. giant cell arteritis, granulomatosis with
polyangiitis, polyarteritis nodosa, and so on), occurring in the ab-
sence of a recognized precipitating cause, or secondary to estab-
lished disease (e.g. systemic lupus erythematosus or rheumatoid
19.11
Autoimmune rheumatic disorders
and vasculitides
section 19  Rheumatological disorders
4496
arthritis) or infection (e.g. hepatitis B, C, or HIV). Recent revisions
in the commonly used terms for various vasculitides have been pro-
posed to reflect increased pathophysiologic understanding of these
conditions (see Table 19.11.1.1). In general, autoimmune rheumatic
diseases have a predilection for young women and share defects in
immune regulation leading to the production of autoantibodies, ac-
tivation of the complement system, and generation and deposition
of immune complexes.
Autoimmune rheumatic diseases affect as many as 1 in 20 people.
Some are rare, for example, systemic sclerosis; others are common,
rheumatoid arthritis affecting approximately 1% of the popula-
tion (see Table 19.11.1.2). Some are severely debilitating or life-​
threatening illnesses, while others produce minor symptoms that
require little, if any, medical intervention.
Antineutrophil cytoplasmic antibody (ANCA)-​associated
vasculitis (AAV). Diseases most commonly associated with
antineutrophil cytoplasmic antibody (antimyeloperoxidase and
antiproteinase 3 antibodies), a significant risk of renal involve-
ment, and which are most responsive to immunosuppression with
cyclophosphamide.
Immune complex vasculitis. Vasculitis with moderate to marked
vessel wall deposits of immunoglobulin and/​or complement com-
ponents, predominantly affecting small vessels (i.e.  capillaries,
venules, arterioles, and small arteries). Glomerulonephritis is
frequent.
Drugs able to induce vasculitis include sulphonamides, penicil-
lins, thiazide diuretics, and many others.
The clinical spectrum
Each of the autoimmune rheumatic diseases is a distinct entity
and can be clearly defined clinically, serologically, and in terms of
treatment and prognosis. However, many patients with these dis-
eases have nonspecific features of malaise, fever, and arthralgia, and
about 30% of patients with lupus, myositis, and Sjögren’s have at
least one other autoimmune rheumatic disease, there being much
overlap in terms of multisystem involvement, as shown in Table
19.11.1.3. Organ-​specific features (e.g. lung fibrosis, pericarditis,
and less frequently glomerulonephritis), can all occur in several of
the autoimmune rheumatic diseases and the presence of such a fea-
ture is not pathognomonic of an individual disease.
The clinical features of each patient must be considered together
with the laboratory investigations, which should include an auto-
antibody profile. A  preliminary ‘autoimmune screen’ includes
a rheumatoid factor and antinuclear antibody test as a bare min-
imum, the results of which then guide the need for further autoanti-
body testing. Immunologically, the detection of rheumatoid factor
or anti-​citrullinated peptide antibodies (ACPA) are the most im-
portant guide to establishing the diagnosis of rheumatoid arthritis
(especially at high titre). Anti-​citrullinated peptide antibodies are
present in 80% of patients with established rheumatoid arthritis and
their specificity is 85–​90% with sensitivity of 50–​60%. Furthermore,
a positive ACPA predicts the development of erosive rheumatoid
arthritis and may also be genuinely pathogenic. It is important
to note, however, that the American College of Rheumatology/​
Table 19.11.1.1  Classification of systemic vasculitis
Dominant vessel involved
Primary
Secondary
Large vessel vasculitis (LVV)
Giant cell arteritis
Aortitis associated with rheumatoid arthritis
Takayasu arteritis
Infection (e.g. syphilis)
Isolated CNS angiitis
Medium vessel vasculitis (MVV)
Polyarteritis nodosa
Infection (e.g. hepatitis B)
Kawasaki disease
Small vessel vasculitis (SVV)
Granulomatosis with polyangiitis (GPA, previously termed Wegener’s
granulomatosis)
Vasculitis secondary to RA, SLE, and SS
Eosinophilic granulomatosis with polyangiitis (EGPA, previously termed
Churg–​Strauss)
Drugs
Microscopic polyangiitis (MPA)
Infection (e.g. HIV)
Anti-​glomerular basement membrane (GBM) disease
Drugs
IgA vasculitis (Henoch–​Schönlein)
Cryoglobulinaemic vasculitis
Infection (e.g. hepatitis B, C)
Hypocomplementaemic urticarial vasculitis (Anti-​C1q Vasculitis)
CNS, central nervous system; RA, rheumatoid arthritis; SLE, systemic lupus erythematosus; SS, Sjögren’s syndrome.
Table 19.11.1.2  Occurrence of major autoimmune rheumatic
diseases in Western populations aged 15 years and over
Diseases
Annual incidence
per 1000
Point prevalence
per 1000
Rheumatoid arthritis
0.5
8.0
Systemic lupus erythematosus
0.05
0.4a
Polymyositis
0.005
0.08
Systemic sclerosis
0.01
0.1
Sjögren’s syndrome
0.3
0.27
Antineutrophil cytoplasmic
antibody-​associated vasculitis
0.02
0.2
a There is a considerable variation according to ethnic origin, thus Afro-​Caribbean
women are five times as likely to get systemic lupus erythematosus as white women.
19.11.1  Introduction
4497
European League Against Rheumatism classification criteria for
rheumatoid arthritis may still be fulfilled in the absence of rheuma-
toid factor and anti-​citrullinated peptide antibodies, and neither of
these antibodies are of value in the monitoring of the disease.
The presence and pattern of staining of antinuclear antibody is
a very useful guide to the presence of disease, as shown in Table
19.11.1.4, with the important proviso that an antinuclear antibody
is present in low titre (up to 1 in 80) in about 1 to 2% of the normal
population, and more frequently (up to 10%) in healthy people
over the age of 75 years. Hence, its presence alone at low titres does
not in itself justify the diagnosis of an autoimmune rheumatic dis-
ease: the whole clinical picture must be considered. In the case of
the vasculitides, the antineutrophil cytoplasmic antibody should
be regarded in the same manner as the antinuclear antibody, but
it should also be remembered that some autoantibodies may be
found in more than one disease, such as anti-​U1RNP (in systemic
lupus erythematosus and undifferentiated autoimmune rheumatic
disease), while others may be found in other diseases ‘beyond’ the
autoimmune rheumatic diseases, such as perinuclear staining (p-​)
antineutrophil cytoplasmic antibody, which is well recognized in
patients with inflammatory bowel disease, some chronic infec-
tions, and malignancies.
Immunopathogenesis
Autoimmune rheumatic disorders
The precise aetiologies of the autoimmune rheumatic diseases re-
main unknown, but are undoubtedly complex. Inciting agents, such
as infection, are involved, as are genetic susceptibility, hormonal fac-
tors, and both cellular and immune dysregulation.
Common to all of the autoimmune rheumatic diseases is the
phenomenon of production of autoantibodies by activated B
cells. Most of the pathogenic autoantibodies are of the IgG class
and have undergone somatic mutation in their hypervariable re-
gions, leading to a gradual increase in specificity and binding
affinity of an antibody produced by a particular clone of cells.
This latter finding is particularly true of anti-​dsDNA antibodies in
systemic lupus erythematosus and antiphospholipid antibodies in
the antiphospholipid syndrome.
The origins of autoantibody production remain an enigma.
Mechanisms that have been invoked include antigen-​driven T helper
cell responses, failure of efficient clearance of nuclear antigens which
become surface expressed following cellular apoptosis, and epitope
spreading. These might act alone, in combination with each other,
or together with other factors. Each has been proposed to lead to in-
creased B-​cell activation. Impaired tolerance appears to be the cen-
tral defect, and once this has occurred abnormal immunoregulation
leads to persistence of the inappropriate self-​directed immune
response.
Cellular mechanisms also play a role in the development of auto-
immunity in the autoimmune rheumatic diseases: T-​cell dysfunc-
tion; impaired macrophage and natural killer cell cytotoxicity;
Table 19.11.1.3  The spectrum of the autoimmune rheumatic diseases
Disease
Major organ/​system involvement
Principal immunological abnormalities
Rheumatoid arthritis
Joints, skin, eyes, lungs, heart, neurological, renal
Rheumatoid factor, IgM, G, or A, AB to CCP, central role for T
and B cells
Systemic lupus erythematosus
Skin, joints, kidneys, brain, heart, lungs
AB to polynucleotides, histones, nucleosomes, ENA, PL, C1q,
abnormalities in T and B cells and accessory cells
Poly-​/​dermatomyositis
Muscle, skin, blood vessels, Lungs
Disease-​specific AB (e.g. anti-​tRNA Synthetases such as Jo-​1)
and infiltrates of T cells in muscle
Scleroderma
Skin, gut, lungs, kidneys, heart, muscle
Disease-​specific AB (e.g. anti-​Scl-​70, anticentromere, RNA
polymerases, anti-​PDGFR); T-​cell and cytokine abnormalities
Primary antiphospholipid syndrome
Blood vessels any size, skin, pregnancy morbidity,
neurological
AB to PL, β2-​GP1, and the lupus anticoagulant
Sjögren’s syndrome
Exocrine glands, notably lacrimal and parotid
AB to ENA, SS A/​Ro, SS B/​La; major infiltrate of T cells in glands
Vasculitides (e.g. PAN, GPA, EGPA,
MPA, and GCA)
Skin, joints, muscles, lungs, central nervous system,
kidneys, blood vessels of all sizes
Cellular infiltration of blood vessel walls; disease-​related AB to
c-​ANCA or p-​ANCA
AB, antibody; p-​ANCA, perinuclear staining antineutrophil cytoplasmic antibody; c-​ANCA, cytoplasmic staining antineutrophil cytoplasmic antibody; EGPA, eosinophilic
granulomatosis with polyangiitis (Churg–​Strauss); ENA, extractable nuclear antigen; GCA, giant cell arteritis; GPA, granulomatosis with polyangiitis (Wegener’s); MPA, microscopic
polyangitis; PDGFR, platelet-​derived growth factor receptor; PL, phospholipid; PAN, polyarteritis nodosa; SS, Sjögren’s syndrome; β2-​GP1, β2-​glycoprotein 1.
Table 19.11.1.4  Antinuclear antibody use in diagnosis
Antinuclear antibody
pattern
Other autoantibodies
Disease
Nuclear
Homogenous
Chromatin, dsDNA
SLE
Histone
DIL
Speckled
Sm, U1RNP
SLE
Ro, La
SS, SCLE, CHB, NL
High titre U1RNP
Overlap/​UARD
Nucleolar
Speckled
Scl-​70, RNA Polymerase I
DcSSc
Homogenous
PM-​Scl
SSc/​PM overlap
Clumpy
U3RNP
DcSSc, PHT
Centromere
Anti-​centromere
LcSSc
CHB, congenital heart block; DcSSc, diffuse cutaneous systemic sclerosis; DIL, drug-​
induced lupus; LcSSc, localized systemic sclerosis; NL, neonatal lupus; PHT, pulmonary
hypertension; PM, polymyositis; SCLE, subacute cutaneous lupus; SLE, systemic lupus
erythematosus; SS, Sjögren’s syndrome.
section 19  Rheumatological disorders
4498
decreased clearance of immune complexes by the mononuclear
phagocytic system; increase in the number of activated B cells; cyto-
kine dysregulation; and up-​regulation of adhesion molecules have
all been reported.
Genetic factors are important, especially in the case of systemic
lupus erythematosus, where there is a higher rate of concordance in
monozygotic twins (25%) than dizygotic (3%). The best described of
the genetic contributions to autoimmune rheumatic disease is the
increased risk associated with particular human leucocyte antigen
(HLA) class II molecules. The HLA DR4 (the Dw4 and Dw14 sub-
types, notably the DR​1*0404 allele) and HLA DR1 (Dw1) are par-
ticularly associated with rheumatoid arthritis. These subtypes share
a similarity of the amino acid sequence in the third hypervariable re-
gion of the DR​1 chain, the shared epitope that has been proposed as
the underlying unit of susceptibility to rheumatoid arthritis. There
are, however, conflicting data proposing that this epitope is better
related to the severity of disease. In systemic lupus erythematosus,
among white people, the haplotype A1 B8 DR3 is associated with
an approximately tenfold increase in risk, although the primary
link may be with the complement C4 null allele with which there is
linkage disequilibrium.
Human leukocyte antigen associations are not only seen with
autoimmune rheumatic disease, but also with certain autoanti-
bodies. Anti-​Ro and La are strongly correlated with HLA DR3 and
DQ, an association that is stronger than that seen with the disease in
which these autoantibodies are most frequently encountered (sys-
temic lupus erythematosus and Sjögren’s syndrome).
Vasculitides
Human leukocyte antigen class I and class II associations are seen
throughout the primary vasculitides, whereas infectious agents and
circulating immune complexes are pathogenic in the secondary vas-
culitides. In the primary vasculitides a pathogenic role has been pro-
posed for antiendothelial cell antibodies and sensitized T cells, but
undoubtedly the most important role is that of the antineutrophil
cytoplasmic antibody. Immunofluoresence studies have localized
the antigen to the cytoplasm of granulocytes in the azurophilic
granules, and two patterns of staining are seen:  cytoplasmic (c-​)
ANCA, of which 90% of sera recognize proteinase 3; and perinuclear
staining p-​ANCA that is directed against myeloperoxidase (MPO)
in 70% of patients with p-​ANCA vasculitis. A positive c-​ANCA is
strongly associated with granulomatosis with polyangiitis, although
10% of these patients may be p-​ANCA positive, while anti-​MPO
antibodies occur in necrotizing glomerulonephritis (65%), eosino-
philic granulomatosis with polyangiitis (Churg–​Strauss) (60%), and
microscopic polyangiitis (45%).
Clinical features
As mentioned previously, the presentation of an autoimmune
rheumatic disease may be variable and non​specific, with fatigue
and arthralgia frequently the major features. In this instance, sys-
temic review should enquire for the presence of alopecia, mouth
ulcers, Raynaud’s phenomenon, rash, sicca symptoms, and lymph-
adenopathy. The presence of these would lend an autoimmune
flavour to the illness, but not necessarily help to make a precise
diagnosis. The history should also seek a possible trigger such as
a preceding infection, drugs (for example hydralazine, isoniazid,
procainamide in drug-​induced lupus), or environmental exposure
to chemicals, as may be seen in scleroderma-​like illnesses. A family
history must pay particular attention to the presence, not only of
other autoimmune rheumatic diseases, but also other autoimmune
diseases such as diabetes, pernicious anaemia, and thyroid disease,
which are often found in association with the autoimmune rheum-
atic diseases.
The protean clinical manifestations mean that an autoimmune
rheumatic disease may present not only to a rheumatologist but to
many other specialists, including those in nephrology, dermatology,
and less commonly neurology, cardiology, haematology, or even ob-
stetrics, in the case of recurrent miscarriages in antiphospholipid
syndrome.
In many cases it is not possible to make a precise diagnosis on the
first encounter with a patient. In those with mild disease, symptom-
atic relief can be obtained with a non​steroidal anti-​inflammatory
drug (NSAID), while the results of baseline investigations and an
‘immunological screen’ of antinuclear antibody and rheumatoid
factor are awaited. Modern management of rheumatoid arthritis,
however, mandates prompt diagnosis so that a disease-​modifying
drug can be used as early as possible and treatment escalated to
achieve a target of remission or very low disease activity to prevent
the development of erosive, destructive joint disease.
Since the autoimmune rheumatic diseases are systemic dis-
orders, it is always important to search for evidence of involve-
ment of any of the major organ systems. Baseline investigations
must therefore include urinalysis, a full blood count, simple
blood tests of renal and liver function, measurement of serum
inflammatory markers, an electrocardiogram (ECG), and a chest
radiograph. The simple bedside test of urinalysis is particularly
important:  the finding of proteinuria and haematuria imme-
diately identifies those who require renal investigation—​often
urgently—​and whose prognosis may be chiefly determined by the
extent of renal involvement.
Damage to major organ systems can be part of the presenting
illness in a patient with an autoimmune rheumatic disease, but may
also occur in a previously diagnosed patient with ‘stable’ disease.
Myocardial infarction can occur as the result of a vasculitic illness,
or accelerated atherosclerosis in systemic lupus erythematosus.
Pericarditis can lead to tamponade (e.g. in systemic lupus
erythematosus or rheumatoid arthritis), while myocarditis may in-
duce complex arrhythmias or even heart failure (e.g. in systemic
lupus erythematosus or polymyositis). Seizures or a disturbed level
of consciousness can occur due to cerebral infarction or meningo-
encephalitis (e.g. in systemic lupus erythematosus, antiphospholipid
syndrome, or granulomatosis with polyangiitis). Rapidly progressive
glomerulonephritis (systemic lupus erythematosus, granulomatosis
with polyangiitis or microscopic polyangiitis) may be associated
with pulmonary haemorrhage, while hypertension requires ur-
gent treatment in scleroderma renal crisis. Pneumonitis or myositis
due to systemic lupus erythematosus may be life-​threatening if not
recognized and treated appropriately with adequate immunosup-
pression. Venous or arterial thromboses are likely to complicate
the antiphospholipid syndrome, which in its primary form may be
catastrophic and characterized by widespread microvascular dis-
ease with adult respiratory distress syndrome (ARDS), profound
thrombocytopenia, and acute renal failure.

19.11.10 Behçet’s syndrome 4579 Sebahattin Yurdaku
19.11.10 Behçet’s syndrome 4579 Sebahattin Yurdakul, Izzet Fresko, and
19.11.10  Behçet’s syndrome
4579
immunosuppressants, both conventional and biologic, have been
used in refractory cases.
MAGIC syndrome: Mouth and genital ulcers
with inflamed cartilage
MAGIC syndrome describes an overlap between relapsing
polychondritis and Bechet’s disease. Clinical presentation includes
chondritis, oral aphthous ulcers, ocular inflammation, genital ul-
ceration, and arthritis. Aneurysms occur in about 20% of cases.
Treatments that have been used include prednisolone, colchicine,
azathioprine, methotrexate, and cyclophosphamide.
Cogan’s syndrome
Cogan’s syndrome is a rare disease of unknown cause that mainly
affects young adults and characteristically presents with non​specific
systemic features and ocular (interstitial keratitis) and inner ear
(vertigo, tinnitus, hearing loss) symptoms. It may be associated
with a large vessel vasculitis. Inflammatory markers are raised; im-
munological tests are typically negative; corneal biopsies may show
a lymphocytic and plasma cell infiltrate; vessel histology resembles
giant cell arteritis. Treatment is with topical or oral steroids; add-
itional immunosuppressive therapy may be needed for resistant dis-
ease. Deafness is the commonest long-​term complication.
FURTHER READING
IgA vasculitis
Audemard-​Verger A, et al. (2015). IgA vasculitis (Henoch-​Schönlein
purpura) in adults: diagnostic and therapeutic aspects. Autoimmun
Rev, 14, 579–​85.
Gonzalez-​Gay MA, Blanco R, Pina T (2014). IgA vasculitis (Henoch-​
Schönlein purpura). In: Ball GV, et al. (eds) Oxford textbook of
vasculitis, pp. 528–​46. Oxford, Oxford University Press.
Cryoglobulinaemia vasculitis
Cacoub P, et  al. (2015). Cryoglobulinaemia vasculitis. Am J Med,
128, 950–​5.
Ramos-​Casals M, et al. (2012). The cryoglobulinaemias. Lancet, 379,
348–​60.
Hypocomplementaemic urticarial vasculitis
Jachiet M, et al. (2015). The clinical spectrum and therapeutic man-
agement of hypocomplementaemic urticarial vasculitis. Arthritis
Rheum, 67, 527–​34.
19.11.10  Behçet’s syndrome
Sebahattin Yurdakul, Izzet Fresko, and Hasan Yazici
ESSENTIALS
Behçet’s syndrome is an inflammatory disorder of unknown aeti-
ology that involves arteries and veins of all sizes. Most cases are
from the countries around the Mediterranean basin, the Middle
East, and East Asia, with the highest prevalence in Turkey.
Clinical features—​typically presents in the second and third dec-
ades with recurrent oral ulcers (98% of cases), genital ulcers (85%),
acneiform lesions (85%), pathergy reaction (60% in some countries),
erythema nodosum (50%), uveitis (50%), arthritis (50%), thrombo-
phlebitis (30%), and less commonly with arterial occlusion/​an-
eurysm, central nervous system involvement, or gastrointestinal
lesions. A relapsing/​remitting course is usual. Disease is more se-
vere and mortality is higher in men. The diagnosis is clinical, labora-
tory findings are non​specific, and there is no specific diagnostic test
for Behçet’s syndrome.
Management and prognosis—​elderly people, and women
with mild mucocutaneous lesions, can be managed symp-
tomatically. Young people and men need a more aggressive
treatment approach, typically as follows (1)  mucocutaneous
lesions—​colchicine and local measures (i.e. corticosteroids);
(2)  acute severe eye involvement—​ciclosporin with or without
steroids, an anti-​tumour necrosis factor agent, or solo inter-
feron is the first agent to use, often replaced by azathioprine
to maintain remission; (3)  thrombophlebitis—​typically man-
aged with aspirin and azathioprine; (4) severe vascular disease—​
cyclophosphamide, steroids and anti-​tumour necrosis factor
agents are the preferred treatments (5)  parenchymal central
nervous system disease—​management remains problematic:
steroids, immunosuppressives, and tumour necrosis factor α
antagonists have all been tried. Major vessel disease and neuro-
logical involvement are the main causes of death. About 10–​15%
of male patients who have eye disease lose useful vision despite
treatment.
Fig. 19.11.9.6  Auricular cartilage inflammation in a patient with
relapsing polychondritis.
Reproduced from Watts RA et al. (eds) (2013). Oxford Textbook of Rheumatology, 4th
edn, by permission of Oxford University Press.
section 19  Rheumatological disorders
4580
Introduction
Hulusi Behçet, a Turkish dermatologist working in Istanbul, de-
scribed three patients with oral and genital ulceration and uveitis
with hypopyon in 1937; it soon became apparent that many other
organ systems were involved and that the condition was a wide-
spread vasculitis.
Aetiology, genetics, pathogenesis, and pathology
Behçet’s syndrome is an inflammatory disorder of unknown aeti-
ology. HLA B51 is the genetic marker which had consistently
been shown to be associated with the condition. This is now con-
firmed in several whole-​genome studies. However, non-​HLA loci
may also be operative, such as IL-​10, IL-​23R IL-​12RB2, CCR1,
STAT4, KLRC4, IL-1A-IL-1B, IRF8, CEPBP-PTPN1, and GIMAP
(GTPases of immunity associated protein). An interaction between
ERAP1 and HLA-​B51 has also been showed. Various microRNAs
have also been implicated in the pathogenesis.
Both the adaptive and innate immune systems are activated in
Behçet’s syndrome. The evidence for the former is the Th1 and
Th17 predominant cytokine profile, and a Th1 type tissue infil-
tration in cutaneous and intestinal tissues; the evidence for the
latter is the primed state of neutrophils and the presence of poly-
clonal γδ T cells in the sera. The absence of classical autoimmune
features such as specific antibodies and the intermittent nature
of the clinical findings have led some to include Behçet’s syn-
drome among the autoinflammatory syndromes. However, this
generalization is not justified when one considers the monogenic
autoinflammatory disorders (see Chapter  12.12.2), but can be
more justified when one compares Crohn’s disease with patients
with Behçet’s syndrome with mainly intestinal inflammation.
In considering the pathogenesis of Behçet’s syndrome it might
prove useful to consider particular variants of disease expression.
One notable cluster of patients is those with acne and arthritis; an-
other is those with superficial and deep vein thrombosis, and a pro-
pensity to dural sinus thrombi. These differing manifestations of
what we now regard as Behçet’s syndrome might indicate more than
one disease mechanism.
Behçet’s syndrome involves arteries and veins of all sizes, but
there are some lesions where direct evidence of injury to the vessel
wall cannot be demonstrated. Among these are the acne lesions of
the skin, where histology is no different from ordinary acne, and,
in the brain, where evidence for direct vessel wall injury is difficult
to find. There is no specific cell type that dominates in vasculitic le-
sions and immune complex deposition can be seen only in some.
Thrombophilic factors seem not to be the primary event in explaining
the hypercoagulability of Behçet’s syndrome: hypertriglyceridaemia
might be a risk factor.
Epidemiology
Behçet’s syndrome has a distinct geographical distribution, with
most cases being from the countries around the Mediterranean
basin, the Middle East, and East Asia. The prevalence ranges from
0.07/​104  in Spain to 8 to 42/​104  in Turkey. The Silk Route has
been suggested as the mechanism through which an aetiological
agent (genetic or environmental) was spread. A study performed
in North African and Asian immigrants in Paris showed that
(by contrast with the native population) Behçet’s syndrome was
nearly as frequent as the primary vasculitides among them, and
the increased prevalence was not related to the age of immigration,
suggesting a genetic rather than environmental explanation. The
condition can affect every age group, but onset before puberty or
after the sixth decade is relatively rare. Changes in disease expres-
sion such as older age at diagnosis and more frequent joint, gastro-
intestinal, and central nervous system manifestations have been
reported in Korea, probably due to changing patterns of medica-
tion, hygiene, and disease awareness. Alterations in annual preva-
lence rates have also been reported.
Clinical findings
Clinical manifestations are protean (Table 19.11.10.1) and the
disease course is characterized by unpredictable periods of recur-
rences and remissions. Although skin and mucosal lesions are most
common, the ocular, central nervous system, and large-​vessel
manifestations are more serious.
Mucocutaneous
Oral ulceration is generally the first, as well as the most frequent,
manifestation of Behçet’s syndrome. Smoking may decrease the
frequency.
Table 19.11.10.1  Clinical manifestations of Behçet’s syndrome
Manifestation
Features
Recurrent oral ulcers
(97–​99%)
Usually the first and most recurrent manifestation
Mostly minor ulcers; heal without scarring
Usually indistinguishable in appearance and
histology from recurrent aphthae
Genital ulcers (c.85%)
Mostly on the scrotum or both labiae
Less frequent on the penis
Large ulcers (>1 cm) heal with a scar
Papulopustular lesions
(c.85%)
Indistinguishable from ordinary acne
On face and back as well as unusual acne sites
(extremities)
Erythema nodosum
(c.50%)
Mostly on lower extremities
Similar to primary erythema nodosum
Confused with superficial thrombophlebitis
Pathergy reaction (60%)
60–​70% positivity in Turkey or Japan
Rarely positive in northern Europe or the United
States
Uveitis (c.50%)
Chronic, relapsing, bilateral panuveitis
Hypopyon indicates a grave prognosis
Joints (50%)
Mono-​ or oligoarticular yet symmetrical
Nondeforming, nonerosive, and self-​limited
Mostly knees, ankles, elbows, and wrists
Thrombophlebitis (30%)
Frequently superficial or deep veins of the legs
Thromboembolism is rare
Arterial occlusion/​
aneurysm (c.4%)
Entire arterial tree
Pulmonary artery aneurysms present with
haemoptyses
CNS involvement
(5–​10%)
Parenchymal (80%) and dural sinus thrombi (20%)
Peripheral neuropathy uncommon
Gastrointestinal lesions
(1–​30%)
Rare in Turkey and 30% in Japan
Mimicking inflammatory bowel diseases
19.11.10  Behçet’s syndrome
4581
Genital ulcers cause pain and discomfort (Fig. 19.11.10.1), with
the presence of genital scarring being quite useful for diagnosis.
Urethritis is not observed, in contrast to that seen in Reiter’s disease
or sexually transmitted infections.
Papulopustular or acneiform lesions are usually indistinguishable
from ordinary acne vulgaris, both in appearance and in histology.
They are usually seen on the face, upper chest, and back, but they
can also affect sites not typically affected by acne vulgaris, such as
the arms and legs. The lesions of erythema nodosum can be diffi-
cult to differentiate from superficial thrombophlebitis by the naked
eye: ultrasound examination may obviate the need for a biopsy. Less
common forms of skin lesions are papules, palpable purpura, skin
ulcers, Sweet’s syndrome, and pyoderma gangrenosum.
The pathergy phenomenon is defined as a non​specific hyperre­
activity to simple trauma. Typically, a papule or a pustule forms in
24–​48 h after skin puncture with a needle (Fig. 19.11.10.2). This is
quite specific for Behçet’s syndrome, but although found in 60 to 70%
of patients in Turkey or Japan, it is rarely observed in northern Europe
or the United States of America. A global decrease in its rate of posi-
tivity has been noted during the last decade. It can be observed in
organs other than the skin, such as attacks of uveitis after eye surgery,
synovitis after arthrocentesis, or development of an aneurysm after
puncture of an artery. However, wound healing is normal.
 Ocular
Eye involvement takes the form of a relapsing panuveitis that gen-
erally starts within the first two years of disease onset. It is more
frequent (70%) and has a more severe course in men, and in young
people (aged less than 25 years). Hypopyon uveitis, an intense in-
flammation in the anterior chamber that can be seen by the phys-
ician without any ophthalmological aids in 20% of patients with
ocular disease, is associated with severe retinal disease.
Posterior uveal inflammation with retinal vasculitis causes retinal
exudates, haemorrhages, venous thrombosis, papilloedema, and
macular disease. Smooth layered hypopyon, superficial retinal infil-
trates with retinal haemorrhages and branch retinal vein thrombosis
seem pathognomonic. Recurrent attacks of eye inflammation lead to
structural changes such as synechiae and retinal scars, which are the
main determinants of eye prognosis. Episcleritis, conjunctivitis, cor-
neal ulcerations, and lid lesions are occasionally seen. Multimodal
imaging using color fundus photography, angiography and optical
coherence tomography increases the diagnostic precision.
Musculoskeletal
Arthritis is mono-​ or oligoarticular, usually resolves in a few weeks,
and is associated with acneiform lesions. A subgroup with acne and
arthritis has increased enthesopathy when examined by ultrasonog-
raphy. Chronic synovitis with erosions and deformity can be seen,
but is rare. Back pain and sacroiliac joint involvement are not part of
the clinical picture. Synovial fluid is commonly inflammatory, with
a predominance of neutrophils, but it has a good mucin clot forma-
tion. Local myositis of the legs, or generalized similar to polymyo-
sitis, is infrequently seen, as is osteonecrosis.
Vascular
Behçet’s syndrome involves both veins and arteries. Around a third
of patients have thrombophlebitis, most frequently in the superfi-
cial or deep veins of the legs. Venous claudication is occasionally
observed. Obstruction of the superior and/​or inferior vena cava
are less frequent, and occlusion of the suprahepatic veins (Budd–​
Chiari syndrome) is rare but carries a high mortality especially
in patients with symptomatic liver disease. Thromboembolism is
rare, most probably due to the tight adherence of thrombi to the
diseased vein.
The entire arterial tree can be affected by arterial aneurysms and/​or
occlusion: the abdominal aorta is the most frequent site, followed by
the iliac, femoral, popliteal, carotid, and subclavian vessels. Pulmonary
artery aneurysms are associated with thrombophlebitis of leg veins and
inferior vena cava in 90% of patients. They present with haemoptyses,
which can be fatal, with the typical finding on chest radiography being
noncavitating single or multiple shadows (Fig. 19.11.10.3). Computed
tomography (CT) scans confirm the diagnosis.
Neurological
Disease of the CNS is also more common and more severe in
male patients. Most of those affected (80%) have parenchymal
disease, which causes pyramidal, cerebellar, and sensory signs
and symptoms, sphincter disturbances, and behavioural changes
alongside with cognitive impairment. The remaining 20% have
nonparenchymal involvement in the form of intracranial hyper-
tension due to dural sinus thrombosis presenting with headaches
Fig. 19.11.10.1  Genital ulcers in a patient with Behçet’s syndrome.
Fig. 19.11.10.2  The pathergy reaction induced by needle pricks to
the forearms.
section 19  Rheumatological disorders
4582
and papilloedema. Both types of involvement rarely occur
in the same patient. Cerebrospinal fluid examination shows
non​specific findings, but a high protein or cell count implies a
grave prognosis in the long run. Peripheral neuropathy, which is
frequently seen in other vasculitides, is uncommon in Behçet’s
syndrome.
Gastrointestinal
Gastrointestinal involvement shows geographical variation, being
rare among people who live in the Mediterranean countries al-
though frequent among those in Japan. Mucosal ulceration, pri-
marily in the ileum and colon, presents with colicky abdominal pain
and diarrhoea that mimic inflammatory bowel diseases. It usually
follows a fluctuating course, with exacerbations and remissions,
and it tends to perforate. Lack of mucosal healing and the use of
immunomodulators during the maintenance of remission are pre-
dictors of relapse.
Hepatic involvement is uncommon except for the rare Budd–​
Chiari syndrome. A slightly enlarged spleen can be found in men.
Cardiac
There have been sporadic reports of many types of conduction
problems, valvular disease, and aortitis, as well as ventricular an-
eurysms and coronary vasculitis, and endomyocardial fibrosis with
intracardiac thrombi. However, the overall frequency of cardiac
disease was no different from that seen in controls in a prospective
controlled study.
Other features
Renal involvement, seen infrequently, ranges from IgA nephropathy
to rapidly progressive glomerulonephritis. Immune complexes are not
usually found in the kidneys. Amyloidosis of the AA type occasion-
ally occurs, as observed in other chronic inflammatory states, usu-
ally presenting in men with a nephrotic syndrome, which has a grave
prognosis.
Epididymitis is a well-​recognized feature, reported in up to 20% of
cases. Voiding disturbances have also been described.
Differential diagnosis
The two conditions that most commonly cause problems in diag-
nosis are inflammatory bowel disease, especially Crohn’s dis-
ease, and multiple sclerosis. Intestinal and especially ileocaecal
ulcers are both observed in Crohn’s disease and Behçet’s syn-
drome, but fistulization and perianal ulcerations are rare in
the latter. Furthermore, the eye inflammation of Behçet’s syn-
drome is most often a panuveitis, compared with the anterior
chamber disease seen in Crohn’s disease. With regard to mul-
tiple sclerosis, optic neuritis is rare in Behçet’s syndrome, and
the characteristic MRI lesions of Behçet’s syndrome are situated
in the basal ganglia and diencephalon, whereas those in mul-
tiple sclerosis are usually seen as white matter lesions in the
periventricular areas.
Clinical investigation
Laboratory findings are non​specific. A  mild anaemia of chronic
disease and leucocytosis are seen in some patients. The erythro-
cyte sedimentation rate and C-​reactive protein may be moderately
elevated, and the latter may correlate with erythema nodosum and
acute thrombophlebitis, although these inflammatory markers
generally do not mirror clinical activity. Autoantibodies such as
rheumatoid factors and antinuclear antibodies are absent and tests
for antineutrophil cytoplasmic antibodies and anticardiolipin anti-
bodies are usually negative.
Criteria for classification
In 1990 the International Study Group for Behçet’s syndrome pro-
posed a set of classification criteria that are sensitive (95%) and
specific (98%) (Box 19.11.10.1). A revised version that takes into
account the vascular and neurological findings has a 94% sensitivity
and a 92% specificity.
Management
Treatment depends on the type and severity of symptoms, disease
duration, and the age and sex of the patient. Those who are eld-
erly, and women with mild mucocutaneous lesions, can be man-
aged symptomatically, while young people and men need a more
Fig. 19.11.10.3  Chest radiograph showing pulmonary artery
aneurysms in a patient with Behçet’s syndrome.
Box 19.11.10.1  International Study Group Criteria for diagnosis
of Behçet’s disease
• Recurrent oral ulceration (recurrent at least three times in one 12-​month
period) plus any two of the following findings:
• Recurrent genital ulceration
• Eye lesions
• Skin lesions
• Positive pathergy test
Reprinted from The Lancet, 335, International Study Group for Behçet’s Disease,
Criteria for diagnosis of Behçet’s disease, 1070–​80, 1990, with permission from
Elsevier.
19.11.10  Behçet’s syndrome
4583
aggressive approach. A  EULAR based recommendation set for
management is available (Table 19.11.10.2).
Controlled trials show that colchicine 1 to 2 mg/​day is effective
for genital ulcers, erythema nodosum, and arthritis in women. It
is beneficial only for arthritis in males. Thalidomide at 100 mg/​day
is effective for orogenital ulceration, but its well-​known adverse ef-
fects, in particular as a teratogen, hinder its more widespread use.
Dapsone 100 mg/​day is also beneficial in mucocutaneous lesions.
A recent phase 2 trial has shown that the phosphodiesterase in-
hibitor apremilast is effective in oral and most probably genital
ulcerations.
Azathioprine (2.5 mg/​kg per day) helps preserve visual acuity
in established eye disease and prevents the emergence of new
eye disease. It also has salutary effects on oral–​genital ulcers
and arthritis, and its use early in the course of disease is asso-
ciated with a more favourable outcome. A drawback is its slow
onset of action—​usually taking around four months for full effect.
Ciclosporin 3–​5 mg/​kg per day acts within weeks and is the first
agent to use in acute and severe eye involvement. It decreases the
frequency of mucocutaneous lesions as well. Adverse effects are
hypertension, renal impairment, and neurotoxicity, which require
close monitoring. Ciclosporin and azathioprine are frequently
combined, with the former used to induce remission and the latter
as a remission-​maintaining agent.
Corticosteroids are widely used in managing Behçet’s syndrome,
but in the only controlled study methylprednisolone acetate (40 mg
intramuscularly every three weeks) was useful only in controlling
erythema nodosum lesions in women. Cyclophosphamide (2–​
2.5 mg/​kg per day orally, or 500–​1500 mg as monthly intravenous
boluses) is the preferred treatment for severe vascular disease, with
steroids usually added for the initial few months.
The management of the parenchymal type of CNS disease is prob-
lematic:  steroids, immunosuppressives, interferon-​α, and tumour
necrosis factor (TNF)-​α antagonists have all been tried. Dural sinus
thrombosis is managed with brief courses of high dose steroids.
Gastrointestinal involvement is initially managed by sulfasalazine
at a dose of 2 to 6 g/​day, but sometimes bowel resection is required.
Anti-​TNF agents have been useful in selected cases.
There is debate about whether or not to use heparin or oral anti-
coagulants for the thrombophlebitis of Behçet’s syndrome. As stated
previously, pulmonary embolism is seldom observed, so antiplatelet
drugs (i.e. aspirin) are probably sufficient. We also use azathioprine to
generally suppress disease activity in the thrombophlebitis of Behçet’s
syndrome.
Surgical correction of peripheral arterial aneurysms is usually
successful (in appropriate cases), with immunosuppressives given
before surgical intervention to prevent recurrence. However, sur-
gical correction of pulmonary arterial aneurysms should not be at-
tempted because of high surgical mortality.
Data on α-​interferon and the TNFα blockers from open studies
have shown that they are also beneficial in patients who are resistant to
conventional treatments and they are used with increasing frequency
worldwide. Interferon-​α (3–​6 MU/​day) was reported to cause a partial
or complete response in patients with resistant posterior uveitis. Side
effects such as flu-​like symptoms were frequent and dose dependent.
The TNFα blocker infliximab 5 mg/​ kg was useful in controlling severe
and resistant uveitis, and other severe manifestations such as gastro-
intestinal and neurological Behçet’s syndrome and major arterial dis-
ease. A double-​blind, placebo-​controlled study with the TNFα blocker
etanercept found it to be useful in controlling most mucocutaneous
lesions of Behçet’s syndrome when used at 25 mg twice a week for a
period of 4 weeks. Adalimumab, interleukin 1 antibodies gevokizumab
Table 19.11.10.2  2018 EULAR recommendations for the management of Behçet’s syndrome
Manifestation
Recommendation
Eye disease
Any patient with inflammatory eye disease affecting the posterior segment should be on a treatment regimen that includes
azathioprine ciclosporin, IFN-α or TNF antagonists.
Systemic glucocorticoids should be used only in combination with immunosuppressives.
Severe eye disease—​Patients presenting with acute sight threatening uveitis should be treated with high dose glucocorticoids,
infliximab or IFNα. Intravitreal glucocorticoid injection is an option in selected patients.
Arterial and/​or venous
disease
There is no firm evidence to guide the management of major vessel disease. For acute deep vein thrombosis, immunosuppressive
agents such as corticosteroids, azathioprine, cyclophosphamide, or ciclosporinA are recommended. For pulmonary and
peripheral arterial aneurysms, cyclophosphamide and corticosteroids are recommended. TNFα blockers are alternatives
especially in resistant cases.
There are no controlled data on, or evidence of benefit from uncontrolled experience with anticoagulants, antiplatelet or
antifibrinolytic agents in the management of deep vein thrombosis, or for the use of anticoagulation for arterial lesions.
Gastrointestinal disease
There is no evidence-​based treatment that can be recommended for the management of gastrointestinal involvement. Agents
such as sulfasalazine, corticosteroids, azathioprine, TNFα antagonists and thalidomide should be tried before surgery, excepting in
emergencies.
Arthritis
Can be managed with colchicine in most cases. Azathioprine, IFNα and TNFα inhibitors can be used in recurrent and chronic cases.
CNS disease
There are no controlled data to guide management. For parenchymal involvement agents to be tried include corticosteroids,
IFNα, azathioprine, cyclophosphamide, methotrexate and TNFα antagonists. For dural sinus thrombosis corticosteroids are
recommended.
Ciclosporin A should not be used in central nervous system involvement unless necessary for intraocular inflammation.
Skin and mucosal disease
The decision to treat will depend on the perceived severity by the doctor and the patient. Mucocutaneous involvement should be
treated according to the dominant or codominant lesions present.
Topical measures (i.e. local corticosteroids) should be the first line of treatment for isolated oral and genital ulcers. Acne-​like lesions
are usually of cosmetic concern only, hence topical measures as used in acne vulgaris are usually sufficient. Colchicine should
be preferred when the dominant lesion is erythema nodosum. Azathioprine, TNFα antagonists, IFNα and apremilast may be
considered in resistant mucocutaneous disease.
Leg ulcers in BS might be caused by venous stasis or obliterative vasculitis. Treatment should be planned with help of a
dermatologist and a vascular surgeon.

19.11.11 Polymyalgia rheumatica 4584 Bhaskar Dasgu
19.11.11 Polymyalgia rheumatica 4584 Bhaskar Dasgupta and Eric L. Matteson
section 19  Rheumatological disorders
4584
and canakinumab and tocilizumab have been used in limited case
series with variable rates of success in refractory eye and CNS disease.
Prognosis
Young men have the highest morbidity and mortality. Women have less
severe disease than men. Major vessel disease and neurological involve-
ment are the main causes of death. Eye inflammation and its greatest
damage occur during the first two years. The disease tends to abate after
40 years of age, but CNS involvement and major vessel disease may have
a late onset (5–​10 years after diagnosis). Loss of useful vision ensues in
about 10–​15% of male patients with eye disease despite therapy.
Mortality attributable to Behçet’s syndrome decreases with time
after diagnosis, which is the opposite of the situation in rheumatoid
arthritis and systemic lupus erythematosus. This may be due both to
self-​abating disease activity, and to the fact that atherosclerosis is not
accelerated in Behçet’s syndrome in the same way that it is in rheuma-
toid arthritis and systemic lupus erythematosus. A recent study of pul-
monary arterial aneurysms has shown that the related mortality rate
has decreased from 50% to around 20% in the last decade, due to ei-
ther earlier recognition or more rational use of immunosuppressives.
Overall, the outlook for patients with eye disease and the
mucocutaneous manifestations of Behçet’s syndrome is consider-
ably better than it was in the past, but management of CNS disease
and thrombophilia/​major vascular complications, including throm-
botic events, remains problematic.
FURTHER READING
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neurological involvement in Behçet’s disease: evaluation of 200 pa-
tients. Brain, 122, 2171–​82.
Alibaz-Oner F, et al. (2015). Behçet disease with vascular involvement:
effects of different therapeutic regimens on the incidence of new re-
lapses. Medicine (Baltimore), 94, e494.
Arida A, et al. (2011). Anti TNF agents for Behçet’s disease: analysis of
published data on 369 patients. Semin Arthritis Rheum, 41, 61–​70.
Direskeneli H (2006). Autoimmunity vs. autoinflammation in Behçet’s
disease:  do we oversimplify a complex disorder? Rheumatology
(Oxford), 45, 1461–​5.
Hamuryudan V, et al. (1998). Thalidomide in the treatment of the
mucocutaneous lesions of the Behçet syndrome. A  randomized,
double-​blind, placebo-​controlled trial. Ann Intern Med, 128,
443–​50.
Hatemi G, et al. (2015). Apremilast for Behçet’s syndrome-​a phase 2,
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Hatemi G, et al. (2017). One year in review 2017: Behçet’s syndrome.
Clin Exp Rheumatol, 35 Suppl 108(6), 3–15.
Hatemi G, et al. (2018). 2018 Update of the EULAR Recommendations
for the Management of Behçet’s syndrome. Ann Rheum Dis, 77, (in
press).
Ideguchi H, et al. (2011). Behçet disease: evolution of clinical manifest-
ations. Medicine, 90, 125–​32.
International Study Group for Behçet’s disease (1990). Criteria for
diagnosis of Behçet’s disease. Lancet, 335, 1078
Kirino Y, et al. (2013). Genome-​wide association analysis identifies
new susceptibility loci for Behçet’s disease and epistasis between
HLA-​B*51 and ERAP1. Nat Genet, 45, 202–​7.
Kötter, et al. (2004). The use of interferon alfa in Behçet’s disease: a re-
view of the literature. Semin Arthritis Rheum, 33, 320–​35.
Kural-​Seyahi E, et al. (2003). The long-​term mortality and morbidity
of Behçet syndrome: a 2-​decade outcome survey of 387 patients fol-
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study of eight cases. Human Pathol, 22, 45–​51.
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Yazici H, et  al. (2007). Behçet’s syndrome; disease manifestations,
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Yazici H, et al. (2018). Behçet syndrome: a contemporary view. Nat Rev
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Yazici Y, Yazici H (eds) (2010). Behçet’s syndrome, 1st edition. Springer,
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19.11.11  Polymyalgia rheumatica
Bhaskar Dasgupta and Eric L. Matteson
ESSENTIALS
Polymyalgia rheumatica is one of the common inflammatory rheum-
atic diseases of older people. It overlaps with inflammatory arthritis
and large-​vessel vasculitis, particularly giant cell arteritis. Pathogenesis
is unclear and may involve recognition of an infectious agent by ab-
errantly activated dendritic cells.
Clinical features—​polymyalgia rheumatica is characterized by
abrupt-​onset pain and morning stiffness of the shoulder and pelvic
19.11.11  Polymyalgia rheumatica
4585
A  recent large primary care database study from the United
Kingdom reported an incidence of 84/​100 000 with a female:male
ratio of 2.0. This is the only study that also reported a marked in-
crease in the incidence of polymyalgia rheumatica throughout
the 1990s, from 69/​100 000 person-​years in 1990 to 93/​100 000
person-​years in 2001. A  similar temporal increase in incidence
has not been observed in other studies. It is unclear whether
there is a true increase in incidence of polymyalgia rheumatica,
overdiagnosis, or increased recognition of polymyalgia rheumatica
in more recent years.
The prevalence of polymyalgia rheumatica among individuals
over 50 years of age in the year 2000 is estimated at 739/​100 000, with
a higher prevalence in females than in males. The prevalence in-
creases dramatically with age: from 21/​100 000 for ages 50–​54 years
to 4213/​100 000 for ages 90–​95  years. With these prevalence es-
timates, 711 000 Americans are estimated to have polymyalgia
rheumatica. Survival was also examined in various studies and they
all indicate that survival in patients with this condition is similar to
that in the general population. This has been in part attributed to in-
creased medical surveillance during the disease course.
Pathogenesis
The current concept is that giant cell arteritis and polymyalgia
rheumatica are the opposite ends of the same pathophysiologic spec-
trum, with the absence of vascular involvement in pure polymyalgia
rheumatica. Synovitis, bursitis, and tenosynovitis around the joints
are all seen in this condition.
Inflammation is initiated inside the tissue (synovium or bursa)
with recognition of putative antigen by dendritic cells (DCs) or
macrophages. Activated DCs or macrophages secrete inflammatory
mediators, including IL-​1, IL-​6, and tumour necrosis factor alpha
(TNFα), which are responsible for the systemic features of the dis-
ease. These cells migrate to central lymphoid organs where they
present antigen to T cells, which then migrate to the synovium, en-
hance the adaptive immune response, and secrete further cytokines
promoting local inflammation. Two different T-​cell subsets, Th17
(glucocorticoid-​sensitive acute lesions) and Th1 (glucocorticoid-​
insensitive chronic lesions) may relate to the persistence of disease
in giant cell arteritis, and a similar mechanism for disease persist-
ence may be relevant to polymyalgia rheumatica.
A recent study has shown that vasoactive intestinal polypeptide,
a neuropeptide locally produced inside the synovium, can induce
a change in T-​cell phenotype from Th1 to Th2. Th2-​type cells do
not secrete interferon (IFN)-​γ, a key cytokine in giant cell arteritis,
which is a possible explanation why most patients with polymyalgia
rheumatica do not develop giant cell arteritis.
Most studies regarding circulating cytokines focus on IL-​6. These
show high levels of IL-​6 in both polymyalgia rheumatica and giant
cell arteritis. The data on other cytokines (IL-​1, IL-​2, TNFα, IFN-​γ,
IL-​10, and so on) are too scant to draw any definitive conclusions
about their role in disease pathogenesis. Most studies in polymyalgia
rheumatica have shown that levels of circulating IL-​6 decrease sig-
nificantly with the remission of clinical symptoms, hence IL-​6
blockade could be a potential target for therapy, especially in pa-
tients with polymyalgia rheumatica.
girdle muscles, with an acute phase response (elevated erythrocyte
sedimentation rate and/​or C-​reactive protein). Evaluation can be
challenging, as many clinical and laboratory features may also be
present in other conditions, including other rheumatological dis-
eases, infection, and neoplasia.
Management—​the mainstay of therapy is glucocorticoids.
Adjunctive therapy can be initiated early in the disease course
in patients with high risk of glucocorticoid-​related side effects,
severe or relapsing disease, or poor or ill sustained response to
glucocorticoids. The response to standardized therapy is hetero-
geneous, and a significant proportion of patients do not respond
completely.
Introduction
Polymyalgia rheumatica (PMR), a common inflammatory condi-
tion of older persons, is characterized by bilateral proximal pain and
morning stiffness and an acute phase response of elevated erythro-
cyte sedimentation rate (ESR) and/​or C-​reactive protein (CRP).
The condition is subject to variations of practice in primary and
secondary care, and is a common indication for long-​term gluco-
corticoid use in the community.
Accurate diagnosis and assessment of disease activity are crit-
ical to balance the benefits of glucocorticoids against the increased
risk of adverse outcomes such as diabetic complications and
glucocorticoid-​related fractures.
The diagnosis of polymyalgia rheumatica is often uncertain be-
cause numerous common mimicking conditions can present with
a polymyalgic syndrome. There is no gold standard test. An inter-
national initiative to address this diagnostic conundrum has led to
classification criteria for the polymyalgic syndrome and definition of
a meaningful clinical response. Clinicians often consider that rapid
resolution of symptoms with glucocorticoid therapy is a diagnostic
hallmark, but there is little evidence for this belief because many
mimicking conditions may also seem to respond to this therapy.
Furthermore, incomplete response to glucocorticoid therapy is not
uncommon, even in patients with confirmed polymyalgia rheumatica.
Clinical manifestations have variable severity, and half of patients have
one or more relapses in the first year of disease. The median duration
of glucocorticoid treatment is typically around 2–​3 years.
Epidemiology
The epidemiology and population burden of polymyalgia rheumatica
is documented in few studies. Incidence varies markedly according
to geographical region, with much higher rates in countries in the
northern latitudes. In northern United States, the average annual
age-​ and sex-​adjusted incidence of polymyalgia rheumatica per
100 000 population 50 years of age or over is estimated at 58.7, with
a significantly higher incidence in women (69.8) than in men (44.8).
Similar incidence estimates have been reported from Denmark
(68.3/​100 000) and Norway (112/​100 000), but lower figures in
Göteborg, Sweden (28/​100 000), Reggio Emilia, Italy (12.7/​100 000)
and Lugo, Spain (18.7/​100 000).
section 19  Rheumatological disorders
4586
Clinical features
Difficulties in diagnosing and classifying patients with polymyalgia
rheumatica are inherent to accepted definitions of the condition.
The proximal pain and stiffness syndrome, the commonly accepted
phenotype of polymyalgia rheumatica, can occur at presentation
in many other rheumatological and inflammatory illnesses, es-
pecially in older people. Polymyalgia is also associated with giant
cell arteritis in 10–​30% of cases. For all these reasons, recent guide-
lines on polymyalgia rheumatica opt for a safe and specific ap-
proach, preferring a relative underdiagnosis to an overdiagnosis of
polymyalgia rheumatica.
In an international initiative sponsored by the European
League Against Rheumatism (EULAR) and the American College
of Rheumatology (ACR), candidate classification criteria for
polymyalgia rheumatica were defined through systematic literature
review, a three-​phase consensus process, and a wider survey. These
criteria were then evaluated in a 6 month prospective cohort study
of 125 patients with new-​onset polymyalgia rheumatica and 169
non​polymyalgia rheumatica comparison subjects with conditions
mimicking the disease. Potential criteria were assessed for their
ability to discriminate polymyalgia rheumatica from other condi-
tions and a scoring algorithm was developed.
New-​onset bilateral shoulder pain in subjects aged 50 years or
older and elevation of C-​reactive protein and/​or erythrocyte sedi-
mentation rate are regarded as essential items for classification as
polymyalgia rheumatica (Table 19.11.11.1). The clinical scoring
algorithm is based on morning stiffness in excess of 45 minutes
(2 points), hip pain/​limited range of motion (1 point), absent rheuma-
toid factor (RF) and/​or anti-​citrullinated protein antibody (ACPA)
(2 points), and absence of peripheral joint pain (1 point). A score of
4 or more has 68% sensitivity and 78% specificity for discriminating
all comparison subjects from polymyalgia rheumatica. The spe-
cificity is higher (88%) for discriminating shoulder conditions
from polymyalgia rheumatica and lower (65%) for discriminating
rheumatoid arthritis from polymyalgia rheumatica.
Differential diagnosis
The presence of headache, visual symptoms, and jaw claudication
should be recognized as giant cell arteritis. About 40% of patients
with giant cell arteritis have polymyalgia at onset. The presence
of arm or leg claudication and prominence of systemic symp-
toms would suggest a large-​vessel vasculitis. See Chapter 19.11.6
for further discussion of giant cell arteritis and other large-​vessel
vasculitides.
Inflammatory arthropathies and connective tissue diseases may
have polymyalgic onset in older people. Negative rheumatoid ser-
ology is part of the polymyalgia rheumatica classification criteria
algorithm, and all patients with the condition should be monitored
for peripheral joint involvement at follow up visits.
ANCA-​associated vasculitis can also present with the polymyalgic
syndrome, and the clinician should enquire about symptoms of
mesenteric ischaemia, nasal polyps, crusting, epistaxis, sinusitis,
and late-​onset asthma. Dipstick urinalysis is essential: the presence
of significant proteinuria and/​or haematuria is not explained by a
diagnosis of polymyalgia rheumatica.
A chronic onset of symptoms also indicates an alternative diag-
nosis. Patients with fibromyalgia can sometimes be mistaken as
having polymyalgia rheumatica due to pain and tiredness, but these
patients do not describe true inflammatory stiffness and have a
prominence of depressive symptoms and poor sleep patterns with
multiple trigger points on examination. Such patients often appear
to initially respond to a trial of glucocorticoids.
The clinical examination should be focused on the differential
diagnoses. All peripheral joints must be assessed for synovitis. The
spine should be assessed for tenderness suggestive of fractures/​me-
tastases/​osteomyelitis/​discitis and to check the range of movement
for a spondyloarthropathy. Sacroiliitis should be considered when
hip symptoms dominate the clinical picture.
Painless muscle weakness might suggest an inflammatory poly-
myositis. Features of Cushing’s syndrome should be obvious on
inspection of the patient. Discoid or photosensitive rashes might
suggest systemic lupus erythematosus. The absence of peripheral
pulses, difference in bilateral blood pressures, or presence of arterial
bruits suggests a large-​vessel vasculitis. The heart, lungs, and ab-
domen should be examined routinely looking for signs of infection
or malignancy.
Neurological examination may reveal Parkinsonism, the only
common non​inflammatory condition to produce true stiffness.
The presence of a sensory or motor neuropathy in the arms points
towards a local disorder affecting the neck or back, such as disc
protrusion or discitis. The absence of systemic and lower limb symp-
toms indicates local shoulder pathology, such as bilateral adhesive
capsulitis or osteoarthritis.
Table 19.11.11.1  Polymyalgia rheumatica classification
criteria: scoring algorithm. Required criteria: age≥50 years,
bilateral shoulder aching, and abnormal C-​reactive protein and/​or
erythrocyte sedimentation ratea
Points
without US
0–​6
Points
with USb
0–​8
Morning stiffness >45 minutes
2
2
Hip pain or limited range of motion
1
1
Normal RF or ACPA
2
2
Absence of other joint involvement
1
1
At least one shoulder with subdeltoid
bursitis and/​or biceps tenosynovitis and/​or
glenohumeral synovitis (either posterior or
axillary) AND at least one hip with synovitis
and/​or trochanteric bursitis
Not applicable
1
Both shoulders with subdeltoid bursitis,
biceps tenosynovitis, or glenohumeral
synovitis
Not applicable
1
ACPA, anti-​citrullinated protein antibody; CI, confidence interval; CRP, C-​reactive
protein; ESR, erythrocyte sedimentation rate; RF, rheumatoid factor; US, ultrasound.
a A score of 4 or more is categorized as polymyalgia rheumatica in the algorithm
without US and a score of 5 or more is categorized as polymyalgia rheumatica in the
algorithm with US.
b Optional ultrasound criteria.
19.11.11  Polymyalgia rheumatica
4587
Clinical investigation
At baseline evaluation, all patients with suspected polymyalgia
rheumatica should have full blood count, urea, and electrolytes, liver
function tests, bone profile, C-​reactive protein, creatine kinase, thy-
roid function tests, immunoglobulins, and electrophoresis, basic urin-
alysis, urinary Bence Jones protein, and chest radiograph checked.
Other investigations should be tailored to the individual symp-
toms and patient, and may include serum cortisol, prostate-​specific
antigen (in men), antinuclear antibody, rheumatoid factor, anti-​
cyclic citrullinated peptide antibodies, antineutrophil cytoplasmic
antibodies, computed tomography of the chest/​abdomen/​pelvis,
spinal radiographs, magnetic resonance imaging of the spine and
sacroiliac joints, echocardiogram, and fluorodeoxyglucose positron
emission tomography CT scan.
Musculoskeletal and vascular ultrasound examination should be
considered and performed at first presentation. Patients may have
features which are a mix of bursitis, tenosynovitis, synovitis, and
large-​vessel vasculitis on imaging.
Ultrasound
Ultrasound depicts characteristic pathologic findings of shoulders
and hips that can aid in distinguishing polymyalgia rheumatica from
other diseases that may mimic it. Typical findings include subdeltoid
bursitis and biceps tendon tenosynovitis at the shoulder, and less fre-
quently synovitis of the glenohumoral joint. In the hips, ultrasound
often reveals synovitis and trochanteric bursitis. Inflammatory
shoulder lesions may be observed even in patients with normal
erythrocyte sedimentation rate values, and it has been suggested
that ultrasound may facilitate the correct diagnosis in patients with
the typical proximal symptoms of polymyalgia rheumatica who also
have a normal erythrocyte sedimentation rate.
Magnetic resonance imaging
Although more expensive than ultrasound, magnetic reson-
ance imaging (MRI) scanning also reveals features of subdeltoid/​
subacromial bursitis in patients with polymyalgia rheumatica.
Fluorodeoxyglucose positron emission tomography
A significant percentage of patients with polymyalgia rheumatica
have increased vascular uptake on fluorodeoxyglucose-​positron
emission tomography, or FDG-​PET scans suggestive of large-​vessel
vasculitis. In our experience the following situations justify a FDG-​
PET scan in the setting of either polymyalgia rheumatica or giant
cell arteritis: unexplained constitutional symptoms, limb claudica-
tion, and persistent incomplete response to glucocorticoids.
Management
The 2015 EULAR American College of Rheumatology guidelines
were developed after a survey of quality of evidence using GRADE
methodology, followed by consensus-​based decisions which also ad-
dressed values and preferences, benefits versus side effects, resource
use, and extrapolation from external evidence. The guidelines rec-
ommend these overarching principles of care:
Establish the diagnosis by ruling out mimics, considering clues to
a non​polymyalgia rheumatica diagnosis, and assessing any overlap
with inflammatory arthritis or large-​vessel vasculitis. A thorough
history, examination, and review of blood results are essential prior
to prescription of glucocorticoids. A pain diagram indicating the
site of pain may be useful in improving accuracy of polymyalgia
rheumatica diagnosis in primary care. Clues to a non​polymyalgia
rheumatica diagnosis include younger age, chronic onset, periph-
eral arthritis, spinal involvement, pronounced systemic symptoms,
either very high or normal C-​reactive protein/​erythrocyte sedi-
mentation rate, and poor response to low-​dose glucocorticoids.
Assess the severity of the condition (based on intensity of pain,
stiffness, disability, inflammatory markers)
Assess comorbidities which may be relevant to choice of
glucocorticoid dose.
Make an individualized choice of glucocorticoid dose and
other therapy based on these assessments and the patient’s
preferences.
Provide education on the condition, its treatment, and potential
complications, precautions, and monitoring requirements.
Provide advice on range of motion exercises for the shoulder
and pelvic girdle muscles.
Initial treatment
An empirical trial of glucocorticoids should not be used as an alter-
native to diligent clinical evaluation of polymyalgia rheumatica. The
EULAR American College of Rheumatology guidelines build on the
British Society for Rheumatology polymyalgia rheumatica guide-
lines and recommend using the minimum effective glucocorticoid
dose within a range of 12.5–​25 mg prednisone equivalent daily as
initial treatment (Fig. 19.11.11.1). Starting doses greater than 30 mg
daily or less than 7.5 mg daily are not recommended. Dose tapering
schedules in polymyalgia rheumatica should be individualized,
with regular monitoring of disease activity, laboratory markers,
and side effects. Although uncommonly used, intramuscular
methylprednisolone may be an option in milder cases and where a
lower cumulative glucocorticoid dose is desirable. The initial dose is
120 mg intramuscularly repeated at 3–​4-​week intervals. The dose is
then reduced by 20 mg every 2–​3 months and given monthly.
An early adjunct use of methotrexate may be considered in pa-
tients with a high risk for relapses, glucocorticoid-​induced adverse
events, or incomplete or ill sustained response to glucocorticoids.
A 70% improvement in patient-​reported global stiffness and inflam-
matory markers by four weeks indicates a complete response. Reports
show that 3–​4 weeks after starting prednisolone 15 mg daily only 55%
showed a complete response to therapy. If the initial response to treat-
ment is not complete, alternate diagnoses should be reconsidered.
Long-​term management
Low-​dose glucocorticoids with gradual tapering over one to two
years after disease control is achieved are the principal therapy for
polymyalgia rheumatica. However, owing to heterogeneity in gluco-
corticoid response between patients, treatment should be tailored
according to individual patient needs. The clinical response should
be significant (i.e. >70% global response), with lack of response
throwing doubt on the veracity of the diagnosis.
section 19  Rheumatological disorders
4588
Some patients may benefit from a more gradual glucocorticoid
taper, or a period of treatment at a stable dose, such as 5 mg pred-
nisolone for three months. The dose may also require adjustment for
disease severity, comorbid factors (e.g. diabetes, cardiorespiratory,
or renal disease), fracture risk, patient wishes, or adverse events. It
is best to avoid non​steroidal anti-​inflammatory drugs, except for
short-​term use for coexisting degenerative conditions. Bone protec-
tion for osteoporosis prevention is advised for all patients.
Relapsing polymyalgia rheumatica
Speed of glucocorticoid tapering and genetic factors have been pos-
tulated to influence the development of relapses, which are defined
as recurrence of symptoms of polymyalgia rheumatica or onset of
giant cell arteritis symptoms, such as headaches, jaw claudication,
and visual symptoms, usually with a rise in erythrocyte sedimenta-
tion rate/​C-​reactive protein. Approximately 50% of patients relapse
within the first 6–​12 months of treatment. Coexisting degenerative
conditions such as rotator cuff disease or shoulder osteoarthritis
should be noted since they may cause shoulder/​hip pain. An iso-
lated rise of erythrocyte sedimentation rate or C-​reactive protein, if
not associated with clinical features of relapse, does not require an
increase of immunosuppression.
Initial relapses may be treated with the previous higher dose which
had controlled disease symptoms. giant cell arteritis relapse requires a
high dose (40–​60 mg) of prednisolone. Beyond the first relapse, steroid-​
sparing agents such as methotrexate or azathioprine are usually used,
but leflunomide has also shown promise. Experience from completed
randomized controlled trials of biological agents, such as infliximab or
etanercept, is not generally encouraging. Ongoing trials of interleukin-​
6 blockade in giant cell arteritis also hold promise for refractory
polymyalgia rheumatica. Trials of IL-​17 and IL-​1 in polymyalgia
rheumatica have also shown glucocorticoid sparing potential.
Monitoring
Patients should be monitored for disease activity and complications,
glucocorticoid-​related complications, and for symptoms that may
suggest an alternative diagnosis. The best measures of disease ac-
tivity and treatment response in polymyalgia rheumatica appear to
be patient-​reported global pain, hip pain, morning stiffness, phys-
ical function (modified health assessment questionnaire, MHAQ),
mental function, and an inflammatory marker. Ultrasound may
have utility as an outcome measure.
Poorly responsive polymyalgia rheumatica, persistent raised in-
flammatory markers, and constitutional symptoms may indicate
large-​vessel disease. Such patients may require evaluation with
echocardiography, FDG-​PET scanning, axillary artery ultrasound,
or MRI to assess for aortitis and large-​vessel disease. Bone mineral
density measurement should be considered in all patients.
Patient fulfilling PMR case definition (primary or secondary care)
Assess comorbidities, other relevant medications and other risk factors for steroid-related side effects
Assess possible risk factors for relapse/prolonged therapy
Consider specialist referral (experience or risk of side effects, relapse/prolonged therapy and/or atypical presentation)
Document minimal clinical and laboratory data set
Increase steroid dose
Clinical improvement
at 2–4 wk?
Re-assess
Confirmation of PMR
Diagnosis
in question
Gradual tapering of
glucocorticoids
Relapse
Taper prednisone
until discontinuation
Remission
yes
no
no
yes
yes
no
Consider MTX if at high risk for side effects/
relapse and/or prolonged therapy
Diagnosis
in question
yes
no
no
yes
no
Fig. 19.11.11.1  2015 EULAR-​ACR recommendations pathway for polymyalgia rheumatica management.
MTX, methotrexate; PMR, polymyalgia rheumatica.
Reproduced from Dejaco C et al. (2015). Recommendations for the management of polymyalgia rheumatica: a European League Against Rheumatism/​
American College of Rheumatology collaborative initiative. Annals of the Rheumatic Diseases, 74: 1799–​1807, copyright 2015, with permission from BMJ
Publishing Group Ltd.
19.11.11  Polymyalgia rheumatica
4589
Summary
The diagnosis of polymyalgia rheumatica is clinically challenging
and requires a stepwise assessment with careful consideration of both
characteristic signs and symptoms and exclusion of mimicking condi-
tions. There appears to be an overlap with both giant cell arteritis and
large-​vessel vasculitis, as well as inflammatory arthritis. While not spe-
cific to polymyalgia rheumatica, subdeltoid bursitis or tenosynovitis
visible on ultrasound are helpful diagnostic features. Accepted man-
agement is with low-​dose glucocorticoids. Meticulous monitoring for
complications related to treatment and disease is required. The new
EULAR/​ACR classification criteria will facilitate methodologically ro-
bust studies and clinical trials of novel therapies which are so urgently
required for the condition (Box 19.11.11.1). The 2015 EULAR-​ACR
recommendations for the management of polymyalgia rheumatica
emphasize risk stratification and individualized choice of gluco-
corticoid treatment regimens based on demographics, comorbidities,
glucocorticoid-​related risk factors, and disease severity.
FURTHER READING
Blockmans D, et  al. (2007). Repetitive 18-​fluorodeoxyglucose posi-
tron emission tomography in isolated polymyalgia rheumatica:  a
prospective study in 35 patients. Rheumatology (Oxford), 46, 672–​7.
Caporali R, et al. (2004). Prednisone plus methotrexate for polymyalgia
rheumatica: a randomized, double-​blind, placebo-​controlled trial.
Ann Intern Med, 141, 493–​500.
Dasgupta B, et al. (1998). An initially double-​blind controlled 96
week trial of depot methylprednisolone against oral prednisolone
in the treatment of polymyalgia rheumatica. Br J Rheumatol, 37,
189–​95.
Dasgupta B, et  al. (2010). BSR and BHPR guidelines for the man-
agement of polymyalgia rheumatica. Rheumatology (Oxford), 49,
186–​90.
Dasgupta B, et al. (2012). 2012 provisional classification criteria for
polymyalgia rheumatica: a European League Against Rheumatism/​
American College of Rheumatology collaborative initiative. Ann
Rheum Dis, 71, 484–​92.
Dejaco C, et  al. (2011). Definition of remission and relapse in
polymyalgia rheumatica:  data from a literature search compared
with a Delphi-​based expert consensus. Ann Rheum Dis, 70, 447–​53.
Dejaco C, et al. (2015). 2015 Recommendations for the management
of polymyalgia rheumatica: a European league against rheumatism
and American College of Rheumatology collaborative initiative.
Arthritis Rheum, 67, 2569–​80.
Deng J, et al. (2010). Th17 and Th1 T-​cell responses in giant cell arter-
itis. Circulation, 121, 906–​15.
Doran MF, et  al. (2002). Trends in the incidence of polymyalgia
rheumatica over a 30 year period in Olmsted County, Minnesota
USA. J Rheumatol, 29, 1694–​7.
Box 19.11.11.1  Future research agenda for polymyalgia rheumatica
The group agreed that future studies in polymyalgia rheumatica should be multicentre and properly powered using an agreed, validated core outcome set
and a robust trial design that would maximize the power of studies, facilitate regulatory approvals, and allow future meta-​analysis.
Specific research questions:
Which outcome measures—​including patient-​related outcomes and response, remission, and relapse criteria—​should be used in polymyalgia
rheumatica? What is the value of a composite score? What are the most relevant treatment targets in polymyalgia rheumatica?
What is the efficacy and safety of different routes of glucocorticoid administration (oral, intramuscular, intra-​articular), different initial
glucocorticoid doses, various tapering regimens, and different flare doses?
What is the efficacy and safety of disease-​modifying anti-​rheumatic drugs (non-​TNFα biologic, conventional synthetic and conventional
targeted) in polymyalgia rheumatica? What is the optimal strategy for using DMARDs in polymyalgia rheumatica: monotherapy versus
combination therapy, early versus late introduction, and (particularly for biologics) use with or without GCs?
What is the minimal/​optimal duration of therapy and which strategies for withdrawing GCs and/​or DMARDs yield the best efficacy/​safety profile?
What is the optimal strategy for shared primary and specialty care including recommendations for specialist referral? How can patients
be better involved in treatment decisions, and are there any decision aids? What is the role of self-​management?
What is the value of tight control (i.e. treat to target) versus conventional management strategies in polymyalgia rheumatica?
How should patients with long-​standing disease and long-​term low-​dose GC therapy be managed?
What is the cost utility and effectiveness of DMARD use in polymyalgia rheumatica (versus GC use alone)?
What is the value of non​pharmacological therapies in polymyalgia rheumatica? Particularly, it is assumed but not yet demonstrated that physiotherapy
may support preservation of function and reduce the risk of adverse events related to GC use. Patients may benefit from exercise by maintaining
muscle mass and function as well as by fall prevention especially in the frail. What is the role of diet in polymyalgia rheumatica and nutrition supple-
ments (e.g. fish oil) related to outcomes?
What is the efficacy and safety of herbal preparations in polymyalgia rheumatica?
What is the role of imaging (particularly ultrasound) for the assessment and monitoring of polymyalgia rheumatica, identification of overlap with
other diseases (e.g. large-​vessel vasculitis or inflammatory arthritis) alongside clinical and patient-​reported outcomes?
Which biomarkers may be useful in polymyalgia rheumatica? Why do some patients do better than others? How can we identify these
groups and what is the biological mechanism behind it? Should different drugs be applied to different polymyalgia rheumatica subgroups?
What is the morbidity and mortality of polymyalgia rheumatica patients (with a particular focus on cardiovascular risk) in long-​term observational
studies?
What is the aetiopathogenesis of polymyalgia rheumatica? Which targeted therapies could be developed based on new knowledge of disease
mechanisms?
Bolded points indicate the top five items of the research agenda according to the opinion of the guideline panel.
Reproduced from Dejaco C et al. (2015) Recommendations for the management of polymyalgia rheumatica: a European League Against Rheumatism/​American College of
Rheumatology collaborative initiative. Annals of the Rheumatic Diseases, 74: 1799–​807, copyright 2015, with permission from BMJ Publishing Group Ltd.

19.11.12 Kawasaki disease 4590 Brian W. McCrindle
19.11.12 Kawasaki disease 4590 Brian W. McCrindle
section 19  Rheumatological disorders
4590
Ghosh P, Borg FA, Dasgupta B (2010). Current understanding and
management of giant cell arteritis and polymyalgia rheumatia.
Expert Rev Clin Immunol, 6, 913–​28.
Hutchings A, et  al. (2007). Clinical outcomes, quality of life and
diagnostic uncertainty in the first twelve months in polymyalgia
rheumatica. Arthritis Rheum, 57, 803–​9.
Lawrence RC, et al. (2008). Estimates of the prevalence of arthritis
and other rheumatic conditions in the United States Part 2. Arthritis
Rheum, 58, 26–​35.
Ma-​Krupa W, et al. (2004). Activation of arterial wall dendritic cells
and breakdown of self-​tolerance in giant cell arteritis. J Exp Med,
199, 173–​83.
Matteson EL, et al. (2012). Patient-​reported outcomes in polymyalgia
rheumatica. J Rheum, 39, 4.
Polymyalgia Rheumatica & Giant Cell Arteritis UK (PMRGCAUK).
https://​www.pmrgcauk.com
Smeeth L, Cook C, Hall AJ (2006). Incidence of diagnosed polymyalgia
rheumatica and temporal arteritis in the United Kingdom 1990–​2001.
Ann Rheum Dis, 65, 1093–​8.
Walsh LJ, et al. (1996). Use of oral glucocorticoids in the community
and the prevention of secondary osteoporosis:  a cross sectional
study. BMJ, 313, 344–​6.
19.11.12  Kawasaki disease
Brian W. McCrindle
ESSENTIALS
Kawasaki disease is an acute, self-​limited, inflammatory vasculitis of
unknown aetiology, with a peak incidence under five years of age.
Coronary complications can present in adults.
Clinical features—​diagnosis requires persistent fever for five
days or more and at least four of the following five clinical signs:
(1) non​purulent conjunctivitis, (2)  oropharyngeal inflammation,
(3) cervical lymphadenopathy, (4) polymorphous exanthem, and
(5) erythema of the palms and soles with subsequent desquam-
ation. Coronary artery dilation and aneurysms occur in 15–​25% of
untreated patients.
Management and prognosis—​primary therapy is with intravenous
γ-globulin. Thrombosis and stenosis in damaged coronary artery
segments leading to myocardial ischemia are the predominant
long-​term morbidity. In adults, new presentations of myocardial
ischaemia with coronary artery aneurysms may suggest a previous
episode of Kawasaki disease during childhood.
Introduction
Kawasaki disease is an acute, self-​limited, inflammatory vascu-
litis predominately occurring in children under five years of age,
complicated by coronary artery dilation and aneurysms, with sub-
sequent risk of thrombosis, stenosis and cardiac ischaemia, and
sudden death.
Historical perspective
Kawasaki disease was first described in Japan by Dr Tomisaku
Kawasaki, a paediatrician, in 1967. In his initial report, he described
the characteristic clinical features, but concluded that it was a self-​
limited illness with no sequelae. It has since been recognized that
Kawasaki disease is a systemic vasculitis with a predilection for the
coronary arteries, resulting in dilation and aneurysms. It has now
been described worldwide in all races, and has become the leading
cause of acquired cardiac disease in children in developed countries.
Epidemiology
While Kawasaki disease has been reported worldwide, the incidence
remains highest in Japan and children of Japanese descent, now
more than c.300 cases per 100 000 children less than five years of age.
The incidence is lowest in Caucasians at less than one-​tenth of the
rate. While most cases occur in children less than five years of age,
Kawasaki disease has been reported in older children and adolescents.
Males are more commonly affected by a ratio of 1.5:1. Recurrence is
rare, with estimates of 3–​7 episodes occurring per 1000 years of pa-
tient follow-​up. Recurrence usually occurs within two years of the
initial episode. Familial occurrences are rare; the proportion of cases
with a positive family history is 1%. Siblings may have a 10-​fold rela-
tive risk compared to the general population.
Aetiology
The aetiology of Kawasaki disease is unknown. The marked racial
differences in the incidence, together with familial occurrences, sug-
gest a genetic component. Genetic susceptibility factors have been
identified from family linkage studies and genome-​wide association
studies. Polymorphisms identified in six genes or gene regions in-
clude FcγR2a, Caspase 3 (CASP3), HLA Class II, B cell lymphoid
kinase, inositol 1,4,5-​trisphosphate kinase-​C (ITPKC), and CD40.
Some of these, and additional gene polymorphisms, have also been
shown to be associated with response to treatment and with vas-
cular complications. These genetic and signalling pathway insights
are leading to trials of novel and more specific therapies.
Epidemiologic features have also suggested an infectious aetiology.
However, many candidate pathogens have been proposed and refuted.
Examination of rare autopsy material from Kawasaki disease patients
has shown the presence of intracyoplasmic inclusion bodies in bron-
chial epithelial cells, and the presence of ribonucleic acid virus-​like
particles.
Epidemic years, particularly in Japan, have been described. The
incidence shows important seasonal variation, and is approximately
40% higher during the winter months of January through March in
the Northern Hemisphere extratropical latitudes. The incidence is
lower in the tropics and the Southern Hemisphere extratropics, with
a less pronounced peak during May through June. A novel hypoth-
esis for these seasonal peaks has emerged based on an ecologic as-
sociation between trophospheric wind patterns and fluctuations in
the incidence in Japan. The winds have been hypothesized to carry
an infectious or environmental aetiologic agent from northeastern
China, and sampling has suggested a Candida species. Of note,
extracts from Candida albicans has been one agent that has been
used to create a mouse model of Kawasaki disease. Additionally, a
19.11.12  Kawasaki disease
4591
recent focus on environmental factors has suggested support for a
‘hygiene hypothesis’, with environmental factors interacting with a
developing immune system to influence susceptibility to the causa-
tive infectious or environmental trigger.
Pathology
Examination of rare autopsy material has suggested three
processes in the arterial pathology of Kawasaki disease (Fig.
19.11.12.1). During the acute phase, severe involvement is
characterized by necrotizing arteritis, a neutrophilic process
which may variably lead to destruction of the intima, media and
elastica layers, and sometimes extend to the adventitia. The thin
rim of remaining adventitia and perivascular tissue, together
with hydrostatic pressures, leads to aneurysm development and
the rare risk of rupture. Also beginning in the first two weeks
after onset, a subacute/​chronic vasculitis may be evident, with
nonsynchronous infiltration of lymphocytes, plasma cells, and
eosinophils. This vasculitic process begins in the adventitia and
perivascular tissue and results in further inflammation and ar-
terial damage. This process can persist for months to years, and
is closely linked to a chronic process of luminal myofibroblastic
proliferation. The vasculitis induces the transition of surviving
smooth muscle cells from the media and adventitia to classic
myofibroblasts. This, combined with ongoing inflammation and
associated matrix products, leads to a proliferative process that
progressively encroaches into the lumen. Resulting circulating
factors may induce luminal myofibroblastic proliferation in
more remote vascular beds. Reduction of luminal dimensions
occurs as a result of these processes, and continued proliferation
can lead to stenoses. The development of laminar thrombus with
organization also contributes to stenoses and calcification, and
occlusive thrombus can recanalize. Both thrombosis and sten-
osis can lead to myocardial ischaemia or infarction. Evidence of
myocarditis has been reported on autopsy and in biopsy speci-
mens during the acute illness and follow-​up, but the long-​term
relevance remains unclear.
Fig. 19.11.12.1  Pathologic features of coronary artery abnormalities after
Kawasaki disease. (a) Necrotizing arteritis of a coronary artery, with a friable
fragmenting wall with neutrophils and debris extending from the lumen
to the adventitia. (b) Subacute/​chronic inflammation in a coronary artery
aneurysm, with the adventitia and media rich in inflammatory cells. The
myofibroblasts of luminal myofibroblastic proliferation, extending from the
lumen through the internal elastic lamina and into the media are mostly
obscured by inflammatory cells. (c) Subacute/​chronic inflammation and
luminal myofibroblastic proliferation causing and eccentric narrowing of a
coronary artery, with disruption of the media and internal elastic lamina at
the top, with inflammation extending into the adventitia.
From Orenstein JM et al. (2012). Three linked vasculopathic processes characterize Kawasaki
disease: a light and transmission electron microscopic study. PLoS One, 7, e38998.
Fig. 19.11.12.1  Continued
section 19  Rheumatological disorders
4592
Clinical features
Clinical and laboratory features are consistent with a generalized in-
flammatory process, and are largely nonspecific, hence timely diag-
nosis requires a high index of suspicion.
Diagnosis requires persistent fever for five days or more and at
least four of the following five clinical signs: (1) non​purulent con-
junctivitis, (2)  oropharyngeal inflammation, (3)  cervical lymph-
adenopathy, (4) polymorphous exanthem, and (5) erythema of the
palms and soles with subsequent desquamation (Fig. 19.11.12.2).
(a)
(b)
(d)
(e)
(f)
(g)
(c)
Fig. 19.11.12.2  Typical appearance of the diagnostic physical features of
Kawasaki’s disease. (a) Bilateral, non​exudative conjunctival injection with perilimbal
sparing. (b) Strawberry tongue with loss of filiform papillae and persistence of
fungiform papillae (‘seeds’ of strawberry). (c) Erythematous, fissured lips. (d) Unilateral
enlarged left jugulodigastric nodes. (e) Erythematous rash. (f) Erythema of soles,
swelling of dorsa of feet. (g) Periungual desquamation of toes in convalescent phase.
With acknowledgement to Dr T Kawasaki.
19.11.12  Kawasaki disease
4593
The desquamation following the acute illness generally follows
a characteristic pattern, beginning first in the periungual regions,
and may also occur in the diaper area in infants. Hydrops of the
gallbladder occurs in c.15% of patients, with IgA vasculitis (Henoch-
Schonlein purpura) usually easily excluded as the only other major
cause. Thrombocytosis may become profound after the first week.
Rarely, patients may have features of macrophage activation syn-
drome. With the exception of arterial involvement, all abnormalities
resolve without sequelae, although there have been rare reports of
persistent sensorineural hearing loss.
In addition to vasculitis, particularly coronary arteritis, cardio-
vascular involvement may be evident as a pancarditis, with valvul-
itis, myocarditis, and pericarditis with effusion. Rarely, patients may
develop cardiovascular collapse (Kawasaki disease shock syndrome)
or ventricular arrhythmias during the acute illness. Coronary ar-
tery changes are often evident by echocardiography at the time of
diagnosis, and are virtually diagnostic of Kawasaki disease. Rarely,
patients may die suddenly before the diagnosis is recognized from
rupture or thrombosis of a coronary artery aneurysm.
Risk factors for the development of coronary artery abnormalities.
These may include male gender, age less than one year (more so if less
than 6 months), higher C-​reactive protein level, higher white blood
cell, or neutrophil count, thrombocytopenia, anaemia, low serum
albumin level, and treatment delays, or persistent or recurrent fever.
Differential diagnosis
Kawasaki disease has similarities with several other commoner
childhood illnesses. Viral infections, such as adenovirus, entero-
virus, Ebstein-​Barr virus and measles, and bacterial infections, such
as scarlet fever, can be very similar. While traditionally the presence
of infection was presumed to exclude the diagnosis, many patients
do indeed have a concomitant infection. Possible infectious disease
symptoms are common, with gastrointestinal symptoms present in
60% and respiratory symptoms in 35% of patients during the acute
illness. Toxin-​mediated illness, such as Staphylococcal scalded skin
syndrome and toxic shock syndrome, also share similar clinical fea-
tures. Drug hypersensitivity reactions and Stevens–​Johnson syn-
drome may be difficult to differentiate from Kawasaki disease, given
that many children are presumptively treated with antibiotics before
the diagnosis of Kawasaki disease is made. Other rarer conditions to
be considered include Rocky Mountain spotted fever, leptospirosis,
juvenile rheumatoid arthritis, and acrodynia.
Clinical investigation
Ongoing clinical assessment may be necessary as patients may
not manifest all of the clinical criteria simultaneously, particularly
younger and older patients. Laboratory assessment is used to detect
associated abnormalities, exclude similar illnesses, as well as to pro-
vide additional evidence to support the diagnosis, particularly for pa-
tients with insufficient clinical criteria. Routine laboratory assessment
performed at presentation should include full blood cell count with
differential, erythrocyte sedimentation rate (ESR) and C-​reactive
protein (CRP), serum sodium, albumen, hepatic transaminases, and
urinalysis with microscopic examination of sediment. N-​terminal
pro-​brain natriuretic peptide has been proposed as a biomarker to
differentiate Kawasaki disease from other febrile conditions.
Echocardiography to detect early coronary artery abnormalities
may provide further evidence to support the diagnosis, as well as
to identify patients who may be developing severe involvement. It
should be performed at the time of diagnosis (but not delay treat-
ment), after 1–​2 weeks, and at 4–​8 weeks for uncomplicated patients.
If severe coronary artery complications are evident, echocardiog-
raphy may be performed more frequently. In addition to coronary
artery abnormalities, echocardiography may reveal pericardial ef-
fusions, valvular regurgitation, and abnormalities of both systolic
and diastolic ventricular function. Quantitative measurements of
coronary artery diameters are best related to available body surface
area specific nomograms for the definition of abnormalities. Several
sources of normative equations allow conversion to Z scores, and
classification of abnormalities should incorporate maximal Z scores,
absolute dimensions, and qualitative aspects. Echocardiography op-
timally images the proximal segments of the coronary arteries, with
distal segments less well assessed. However, it is very rare for pa-
tients to have distal involvement without some evidence of proximal
abnormalities. For selected patients with severe coronary artery ab-
normalities, additional imaging may be required to determine the
presence and extent of more distal coronary artery involvement or
involvement in other systemic arteries (such as the axillary, iliac,
femoral, and splanchnic arteries). This may include magnetic reson-
ance angiography, computed tomographic angiography or conven-
tional coronary angiography (Fig. 19.11.12.3).
Criteria for diagnosis
The diagnosis of Kawasaki disease rests on meeting the classical clinical
criteria, which includes fever of at least five days duration and the pres-
ence of at least four of the five principal clinical signs. The diagnosis can
be made earlier by experienced clinicians. Early in the illness course,
patients with features of Kawasaki disease are often mistakenly given
alternative diagnoses, particularly viral or bacterial infection, and may
have been treated empirically with antibiotics. In addition, a detailed
clinical history may note some features that may have resolved by the
time of presentation. However, for patients early in their presentation
or for those who do not have sufficient principal clinical signs, add-
itional surveillance, and laboratory testing may provide supportive
evidence and identify patients who require treatment, as per the algo-
rithm for suspected incomplete Kawasaki disease in Fig. 19.11.12.4.
About 25% of patients have incomplete Kawasaki disease. This
occurs more commonly in infants and older children or adoles-
cents, may contribute to delayed diagnosis, and carries a similar
risk of coronary artery complications as those who meet full cri-
teria for diagnosis. The presence of elevated erythrocyte sedi-
mentation rate and C-​reactive protein together with three or
more supplemental laboratory criteria should prompt treatment.
These criteria include anaemia for age, elevated white cell count
over 15 000/​mm3, thrombocytosis with platelet count more than
450 000 after seven days of fever, low albumen under 3.0 g/​dl, ele-
vated alanine aminotransaminase, and sterile pyuria (white cells
on urine microscopy of >10 per high powered field).
The presence of a positive echocardiogram performed at any time
should also prompt treatment, regardless of laboratory features.
A positive echocardiogram is defined as a Z score of over 2.5 in
the right coronary artery or left anterior descending branch; or the
presence of a coronary artery aneurysm; or the presence of three or
more other features, including ventricular dysfunction, pericardial
section 19  Rheumatological disorders
4594
effusion, mitral valve regurgitation, or coronary artery Z scores be-
tween 2 and 2.5. For patients with suspected incomplete Kawasaki
disease with a positive echocardiogram who present after the tenth
day of fever, treatment should be given if there are laboratory and
clinical signs of persistent inflammation.
Treatment
In addition to supportive management, the mainstay of therapy is
a single high dose infusion of 2 grams per kilogram of intravenous
γ-globulin (IVIG), infused over c.10 hours. Pretreatment with an
antihistamine is often used. IVIG is ideally given within the first
10 days from the onset of fever, and as soon as possible after the
diagnosis is made. Timely treatment with intravenous γ-globulin
reduces the risk of coronary artery complications to less than
4%. Patients presenting after 10 days should be given intravenous
γ-globulin if they have current fever, evidence of ongoing inflam-
mation, or evolving coronary artery abnormalities. Patients are
usually concomitantly given moderate (30–​50 mg/​kg/​day) or high
dose (80–​100  mg/​kg/​day) acetylsalycilic acid (ASA) as an anti-​
inflammatory agent, at least until they are afebrile. The dose is then
lowered (3–​5 mg/​kg/​day) for antiplatelet effects for a period of 4–​8
weeks, then discontinued if there are no coronary artery abnormal-
ities. Primary adjunctive treatment with other anti-​inflammatory
agents, such as corticosteroids or infliximab, is not indicated.
Approximately 25% of patients will continue to have fever or
initially defervesce and then have a recurrence of fever within
36 hours of conclusion of their intravenous γ-globulin infusion.
Such patients are said to be intravenous γ-globulin resistant and
may have residual clinical signs and elevated C-​reactive protein
(erythrocyte sedimentation rate may be falsely elevated after initial
intravenous γ-globulin treatment). These patients are at increased
risk for coronary artery abnormalities. An additional dose of intra-
venous γ-globulin is recommended, although pulse corticosteroid
and possibly infliximab are reasonable alternatives. For patients
with refractory disease, use of a longer course of corticosteroids,
infliximab, cyclosporine, plasma exchange, or cytotoxic agents may
be warranted. A trial in Japan of a longer course of corticosteroids
in addition to intravenous γ-globulin for initial treatment for pa-
tients predicted to be intravenous γ-globulin resistant noted some
reduction in coronary artery abnormalities. However, existing risk
scoring systems have been shown to have poor predictive capabil-
ities in non-​Asian populations.
(a)
(b)
(d)
(e)
(c)
Fig. 19.11.12.3  Imaging of severe arterial involvement complicating Kawasaki disease. (a) Multiple fusiform aneurysms along the length
of the proximal right coronary artery. (b) A large fusiform and small saccular aneurysm of the proximal left anterior descending coronary
artery branch. (c) Magnetic resonance angiogram showing aneurysmal arterial involvement in other small to medium-​sized arteries.
(d) Fusiform and saccular aneurysms of the right coronary artery with complete occlusion (arrow) of the distal exit of the aneurysm.
(e) Successful reperfusion of the distal right coronary artery with placement of a right internal mammary artery bypass graft.
19.11.12  Kawasaki disease
4595
Despite recommended treatment, c.20% of patients will develop
coronary artery dilation, c.4% aneuryms and c.1% giant aneur-
ysms. For those with aneurysms, close follow-​up and more fre-
quent echocardiograms are required during the acute illness while
involvement is progressing. In addition to low dose acetylsalycilic
acid, systemic anticoagulation with warfarin or fractioned heparin
is needed to prevent thrombotic occlusions during this high-​risk
period. If the patient with aneurysms requires a non​steroidal anti-​
inflammatory agent, usually to manage arthritis, the acetylsalycilic
acid should be switched to an alternative antiplatelet agent. For
patients with multiple giant aneurysms or recent thrombosis,
the addition of a second antiplatelet agent may be considered.
Thrombolytic agents may be necessary for patients who develop
acute thromboses.
Prognosis and long-​term management
Most patients who have had Kawasaki disease will have no or min-
imal coronary artery involvement, have an excellent long-​term
prognosis, and do not require cardiology assessments beyond 4–​
8 weeks after resolution of the acute illness. However, all patients
should have screening and management for cardiovascular disease
risk factors. The pathological sequence of coronary artery abnor-
malities is shown in Fig. 19.11.12.5. Aneurysms may show reduc-
tions in dimensions over the long-​term, primarily resulting from
luminal myofibroblastic proliferation and organization of laminar
thrombus. These reductions may result in normalization of the lu-
minal dimension and reduction in thrombotic risk, but may also
progress to stenoses and obstructions, most common at entry and
exit points of aneurysms. Thrombosed aneurysms may show or-
ganization and recanalization, and the effect on myocardial perfu-
sion of stenoses and occlusions may be mitigated by the presence
of collateralization from other branches. The risk of myocardial
ischaemia and infarction is determined by both the degree of max-
imal involvement, and the nature and cumulative effect of these
pathologic processes.
Long-​term management is focused on surveillance for myocar-
dial ischaemia and calibration of thromboprophylaxis. The greater
the degree of coronary artery involvement, the greater is the need
for assessment and medical management to be individualized. For
all patients, participation in daily physical activity should be pro-
moted, with the types of activities and the intensity level calibrated
to the risk of bleeding related to thromboprophylaxis and the risk
of myocardial ischaemia. Risk stratification guiding manage-
ment is based on both maximal coronary artery involvement and
changes over time. For patients with small aneurysms (maximal Z
score 3–5), reduction to a normal luminal dimension is likely over
a relatively short period of time. The risk of thrombosis is low, and
acetylsalicylic acid alone is sufficient for thromboprophylaxis. The
risk of ischemia is also low, although periodic lifelong follow-up
is reasonable, with infrequent testing for inducible myocardial is-
chemia (stress echocardiography, MRI or nuclear medicine stress
perfusion imaging) every 3–5 years. Echocardiography may be
omitted once the luminal dimensions are normal. For patients
with medium aneurysms (maximal Z score 5–10 with an abso-
lute dimension <8 mm), changes occur more slowly and less com-
pletely. The risk of thrombosis is also low, and acetylsalicylic acid
alone is recommended, although patients with multiple or distal
aneurysms may also be considered for an additional antiplatelet
agent. Cardiology assessment is initially frequent, and can be re-
duced to every 1–2 years as the luminal dimension approaches
normal. The risk of ischemia is low, and stress perfusion testing
is recommended every 2–3 years. For patients with large or giant
aneurysms (maximal Z score >10 or absolute dimension >8 mm),
the prognosis is less certain and reduction to a normal luminal
dimension is rare. The risk of thrombosis is initially high, and
systemic anticoagulation with warfarin or low molecular weight
Children with fever ≥5 days and 2 or 3 compatible clinical criteria OR
Infants with fever for ≥7 days without other explanation
Evaluation of Suspected Incomplete Kawasaki Disease
Assess Laboratory Tests
CRP ≥3.0 mg/dl and/or ESR ≥40 mm/hr
CRP <3.0 mg/dl and ESR <40 mm/hr
3 or more Laboratory Findings:
Anemia for age
Platelet count of ≥450000 after the
7th day of fever
Albumin ≤3.0 g/dl
Elevated ALT level
WBC count of ≥15000/mm3
Urine ≥10 WBC/hpf
OR
Positive echocardiogram
Serial clinical and
laboratory re-evaluation if
fevers persist
Echocardiogram if typical
peeling develops
Treat
NO
YES
Fig. 19.11.12.4  Evaluation of suspected incomplete Kawasaki disease.
Reproduced from McCrindle BW et al. (2017). Diagnosis, treatment, and management of Kawasaki
disease. Circulation 135:e927–e999. Copyright 2017, American Heart Association with permission
from Wolters Kluwer Health, Inc.
section 19  Rheumatological disorders
4596
heparin is recommended in addition to antiplatelet therapy. As di-
mensions reduce, the risk of thrombosis lessens, anticoagulation
can be discontinued and dual antiplatelet therapy or acetylsali-
cylic acid alone may be considered. β-blockers and statins may
be considered particularly for those with persistent aneurysms.
These patients require lifelong cardiology assessment for the de-
velopment of stenosis and ischemia, initially frequently but may
be decreased to every 2 to 5 years if normal luminal dimensions
are achieved. For patients who have had aneurysms, advanced
cardiac imaging may be performed periodically, including com-
puted tomography (angiography, coronary artery calcium) and
MRI (angiography, myocardial function, perfusion, and fibrosis/
scar). The use and frequency is calibrated to the severity and com-
plexity of coronary artery involvement, and most applicable for
those with large and giant aneurysms, even if there have been
important reductions in luminal dimensions. Conventional angi-
ography is performed less frequently, although it does afford the
opportunity for characterization of the arterial wall with intravas-
cular ultrasound or optical coherence tomography. This is useful
if a coronary artery intervention is being planned.
For patients who develop important stenoses and occlu-
sions associated with myocardial ischaemia or infarction,
revascularization should be considered. Interventional catheter
procedures have been effective, but they are often not feasible in
small patients and are associated with a high risk of recurrence.
Bypass grafting, particularly with arterial grafts, have been par-
ticularly effective and show good longevity in growing patients.
Rare patients who develop ischaemic cardiomyopathy or in-
tractable ventricular arrhythmias may undergo cardiac trans-
plantation. Previously healthy adult patients who present with
myocardial ischaemia and a new diagnosis of coronary artery
aneurysms may have had a forgotten or missed diagnosis of
Kawasaki disease during childhood.
FURTHER READING
Japanese Circulation Society Joint Working Group (2014). Guidelines
for diagnosis and management of cardiovascular sequelae in
Kawasaki disease (JCS 2013). Digest version. Circ J, 78, 2521–​62.
McCrindle BW, et al. (2017). American Heart Association Rheumatic
Fever, Endocarditis, and Kawasaki Disease Committee of the Council
on Cardiovascular Disease in the Young. Diagnosis, treatment,
and long-term management of Kawasaki disease. Circulation, 135,
e927–e999.
No coronary artery changes
Mild, transient dilatation (resolves within 4–6 weeks)
Necrotizing
arteritis
Aneurysm
formation
Myocardial infarction
Complex stenosis
Occlusive thrombus
formation
Subacute/chronic vasculitis
Luminal myofibroblastic proliferation
Laminar nonocclusive thrombosis
Organization of thrombus
and recanalization
Possible progression to a
normal luminal dimension
Ischemic heart disease
Further progression and
? possible interaction with
atherosclerosis risk factors
Calcification
Destruction of intima, elastica interna,
media and, variably, adventitia
Adventitia
Elastica interna
Intima
Media
Fig. 19.11.12.5  Pathological sequences of coronary artery abnormalities.
Reproduced from McCrindle BW et al. (2017). Diagnosis, treatment, and management of Kawasaki disease. Circulation 135:e927–e999.
Copyright 2017, American Heart Association with permission from Wolters Kluwer Health, Inc.
19.11.12  Kawasaki disease
4597
Newburger JW, et al. (1991). A single intravenous infusion of γ-globulin
as compared with four infusions in the treatment of acute Kawasaki
syndrome. N Engl J Med, 324, 1633–​9.
Orenstein JM, et al. (2012). Three linked vasculopathic processes char-
acterize Kawasaki disease: a light and transmission electron micro-
scopic study. PLoS One, 7, e38998.
Research Committee of the Japanese Society of Pediatric
Cardiology; Cardiac Surgery Committee for the Development
of Guidelines for Medical Treatment of Acute Kawasaki Disease
(2014). Guidelines for medical treatment of acute Kawasaki dis-
ease: report of the Research Committee of the Japanese Society of
Pediatric Cardiology and Cardiac Surgery (2012 revised version).
Pediatr Int, 56, 135–​58.
Z score calculator of coronary artery diameter (incorporates multiple
sources of normative formulas). http://www.parameterz.com/sites/
coronary-arteries

19.11.2 Systemic lupus erythematosus and related d
19.11.2 Systemic lupus erythematosus and related disorders 4499 Anisur Rahman and David A. Isenberg
19.11.2  Systemic lupus erythematosus and related disorders
4499
Physicians treating patients with autoimmune rheumatic diseases
need to be constantly aware of the possibility of organ involvement,
prompt diagnosis and treatment being necessary to prevent irrevers-
ible end organ damage. The immunosuppressive therapy used will
be similar, regardless of the particular diagnosis.
Precise identification of an autoimmune rheumatic disease is re-
liant upon clinical and laboratory features, of which the presence
of antinuclear antibody (and its pattern of staining), antibodies
to extractable nuclear antigens, disease-​specific antibodies, or
antineutrophil cytoplasmic antibody are crucial. There are many in-
stances where the disease may not be precisely labelled, and up to
20% of patients have features of several autoimmune rheumatic dis-
eases, most commonly systemic lupus erythematosus/​scleroderma
and systemic lupus erythematosus/​rheumatoid arthritis, or those
who would be considered to have an undifferentiated autoimmune
rheumatic disease. In the case of these latter diseases, treatment is
guided according to disease features and the pattern of organ/​system
involvement.
FURTHER READING
Aletaha D, et al. (2010). 2010 rheumatoid arthritis classification criteria:
an American College of Rheumatology/​European League Against
Rheumatism collaborative initiative. Ann Rheum Dis, 69, 1580–​8.
Goldblatt, F, O’Neill, S (2013). Clinical aspects of autoimmune rheum-
atic disease. Lancet, 382, 797–​808.
Jennette J, et al. (2013). 2012 Revised International Chapel Hill con-
sensus conference: nomenclature of vasculitides. Arthritis Rheum,
65, 1–​11.
McInnes IB, Schett G (2011). The pathogenesis of rheumatoid arth-
ritis. N Engl J Med, 365, 2205–​19.
Pons-​Estel, et al. (2010). Understanding the epidemiology and pro-
gression of systemic lupus erythematosus. Semin Arth Rheum, 39,
257–​68.
Roth AJ, et  al. (2013). Epitope specificity determines pathogenicity
and detectability in ANCA associated vasculitis. J Clin Invest, 123,
1773–​83.
Tarzi RM, Giles I (2014). Autoimmune rheumatic disorders. Medicine,
42, 119–​87.
19.11.2  Systemic lupus erythematosus
and related disorders
Anisur Rahman and David A. Isenberg
ESSENTIALS
Systemic lupus erythematosus is an autoimmune rheumatic disorder
that can present with symptoms in almost any organ or system of the
body. It is 10 times commoner in women than men, and commoner
in Afro-​Caribbeans than in other ethnic groups.
Aetiology is multifactorial, incorporating genetic, hormonal, and
environmental elements. No single abnormality of the immune
system can be considered responsible, pathogenesis depending on
the interplay of several different factors, including autoantibodies, T
lymphocytes, cytokines, the complement system, and apoptosis.
Clinical features
Common symptoms are constitutional (fatigue, anorexia), muscu-
loskeletal (arthralgia/​arthritis, myalgia), dermatological (alopecia,
butterfly rash, vasculitic skin lesions, purpura), cardiopulmonary
(breathlessness, pleurisy), and neurological (migraine, seizures, de-
pression, psychosis).
Examination may show evidence of weight loss, low-​grade fever,
lymphadenopathy, arthritis (but rarely synovitis or deformity), skin
rash, oral ulcers, dry eyes/​mouth, pleural rub, and peripheral neur-
opathy (usually sensory).
Investigation and diagnosis
Investigation commonly reveals abnormalities in the following
systems: (1) renal—​proteinuria, microscopic haematuria, impaired
glomerular filtration rate; (2)  haematological—​anaemia, leuco-
penia, lymphopenia, thrombocytopenia; and (3) cardiopulmonary—​
pulmonary function abnormalities.
The diagnosis of systemic lupus erythematosus is often made on
the basis of published classification criteria, but in essence consists of
a combination of clinical features, serological criteria, and immuno-
logical abnormalities.
Prognosis and management
Systemic lupus erythematosus can kill (mortality c.10% at 10 years
from diagnosis), but it may run a fairly indolent course in which an
initial flare is followed by many years of low-​grade activity. General
treatment measures include (1) rest—​as appropriate; (2) avoidance
of overexposure to sunlight; (3) attention to modifiable cardio-
vascular risk factors—​women with lupus between 35 and 45 years
have a 50× increased risk of coronary disease; and (4) prophylaxis/​
treatment of osteoporosis—​usually induced by steroid therapy.
Mild disease—​patients whose disease activity is confined to
arthralgia, tiredness, and/​or mild rash can often be treated symp-
tomatically (e.g. with simple analgesics and/​or nonsteroidal anti-​
inflammatory agents, often with hydroxychloroquine added).
Treatment of flares of disease—​corticosteroids and immunosup-
pressant agents are used. A mild flare of arthralgia, myalgia, and
general fatigue may be alleviated by a single intramuscular dose of
corticosteroid. More severe flares of arthritis, pleuritis, or pericarditis
require oral prednisolone (20–​40 mg daily). Renal flares require the
most aggressive treatment, generally involving both corticosteroids
(high-​dose oral and/​or intravenous pulse) and cyclophosphamide/​
mycophenolate mofetil. Biological therapies are increasingly being
used, with belimumab and rituximab most commonly prescribed.
Uncontrolled studies have suggested that it may become possible to
use biologics in early disease to avoid using corticosteroids.
Antiphospholipid antibody syndrome—​immunosuppression is rarely
useful; lifelong anticoagulation is advised for those who have suf-
fered recurrent thromboses or cerebral infarcts.
Pregnancy—​systemic lupus erythematosus may be exacerbated
during the pregnancy. Babies born to mothers with lupus who
have anti-​Ro and/​or anti La antibodies may suffer neonatal lupus,
incorporating a transient rash and (less commonly) permanent
heart block.
section 19  Rheumatological disorders
4500
Introduction
Systemic lupus erythematosus (SLE) is an autoimmune rheumatic
disorder that can present with symptoms in almost any organ or
system of the body. Classification criteria should be used to make
the diagnosis. These are shown in Tables 19.11.2.1 and 19.11.2.2
and demonstrate the wide variety of clinical and serological fea-
tures that are associated with this condition. There are two alter-
native sets of criteria. Those published by the American College of
Rheumatology (ACR) in 1997 (Table 19.11.2.1) are most widely
used in scientific papers and state that at least four of 11 criteria
must be fulfilled. The newer criteria published by the Systemic
Lupus International Collaborative Clinics (SLICC) group in 2012
(Table 19.11.2.2) stress that at least one clinical and one serological
criterion should be fulfilled, and that biopsy-​proven lupus nephritis
in the presence of antinuclear antibodies (ANA) or anti-​dsDNA
antibodies is sufficient to diagnose systemic lupus erythematosus.
The Systemic Lupus International Collaborating Clinics criteria are
more sensitive, but less specific, for systemic lupus erythematosus
than the older criteria. It is important not to be too dogmatic in
searching for ‘pathognomonic’ features of the disease, e.g. although
the characteristic butterfly rash over the face is perhaps the best-​
known sign of systemic lupus erythematosus, many patients will
never develop such a rash.
Historical perspective
Although the term ‘lupus’ has been used for several hundred years,
its meaning was vague until Cazenave and Clausit coined the term
‘lupus erythematosus’ in 1852, confining the condition to a skin
rash affecting the face. The photosensitive nature of the rash (noted
by Hutchinson in 1879) and the accompanying internal organ in-
volvement (Kaposi in 1872) helped to frame the current usage of
the term ‘systemic lupus erythematosus’ to define a multisystem dis-
order rather than a purely cutaneous condition. The development
of the LE cell test (Hargreaves in 1948) and more importantly (and
more specifically) the identification of anti-​double-​stranded (ds)
DNA antibodies by four different laboratories (in 1957) facilitated
the classification criteria by which systemic lupus erythematosus is
now widely recognized.
Aetiology and pathology
The aetiology is multifactorial, incorporating genetic, hormonal,
and environmental elements. The best-​established genetic link is
with the presence of null alleles of genes encoding early components
of the complement cascade (C1q, C2, and C4). Over 90% of patients
homozygous for C1q deficiency and 75% of those with C4 deficiency
develop a lupus-​like disease (similar clinical features but a relative
paucity of antibodies). Major histocompatibility complex (MHC)
genes, particularly HLA A1, B8, and DR3, have also been associated
with the presence of lupus in family studies, although part of this as-
sociation may be due to linkage disequilibrium with the C4 and C2
Table 19.11.2.1  Criteria of the American College of Rheumatology
for the classification of systemic lupus erythematosusa
1	 Malar rash
2	 Discoid rash
3	 Photosensitivity
4	 Oral ulcers
5	 Arthritis
6	 Serositis
(a)	 Pleuritis or
(b)	 Pericarditis
7	 Renal disorder
(a)	 Proteinuria >0.5 g/​24 h or 3+, persistently or
(b)	 Cellular casts
8	 Neurological disorder
(a)	 Seizures or
(b)	 Psychosis (having excluded other causes, e.g. drugs)
9	 Haematological disorder
(a)	 Haemolytic anaemia or
(b)	 Leucopenia or <4.0 × 109/​litre on two or more occasions
(c)	 Lymphopenia or <1.5 × 109/​litre on two or more occasions
(d)	 Thrombocytopenia <100 × 109/​litre
10  Immunological disorders
(a)	 Raised antinative DNA antibody binding or
(b)	 Anti-​Sm antibody or
(c)	 Positive finding of antiphospholipid antibodies
11  Antinuclear antibody in raised titre (in the absence of drugs known to be
associated with drug-​induced lupus)
a ‘. . . a person shall be said to have SLE if four or more of the 11 criteria are present,
serially or simultaneously, during any interval of observation.’
Tan EM et al. (1982). The 1982 revised criteria for the classification of systemic lupus
erythematosus. Arthritis and Rheumatism 25, 1271–​7.
Table 19.11.2.2  The Systemic Lupus International Collaborative
Clinics Criteria for the classification of systemic lupus erythematosusa
Clinical criteria
Immunologic criteria
Acute cutaneous lupus
ANA
Chronic cutaneous lupus
Anti-​dsDNA
Oral or nasal ulcers
Anti-​Sm
Non​scarring alopecia
Antiphospholipid antibodies (lupus
anticoagulant and/​or anticardiolipin
and/​or anti-β-​2-​GPI)
Arthritis
Low complement (C3, C4, or CH50)
Serositis
Direct Coombs test in the absence of
haemolytic anaemia
Renal involvement—​measurement of
urine protein representing 500 mg/​
day or red cell casts in urine
Neurologic
Haemolytic anaemia
Leucopenia <4000 /​mm3 or
lymphopenia <1000 /​mm3
Thrombocytopaenia <100 000 /​mm3
a A person will be said to have systemic lupus erythematosus if four or more criteria are
present, but this must include at least one clinical criterion and one immunologic criterion.
All four need not be present concurrently. There is an exception in the case of renal disease,
where systemic lupus erythematosus can be diagnosed if there is biopsy-​proven lupus
nephritis with positive ANA or anti-​dsDNA (i.e. only two criteria need be fulfilled).
Petri M et al. (2012) Derivation and validation of Systemic Lupus International
Collaborative Clinics classification criteria for systemic lupus erythematosus. Arthritis
and Rheumatism 64, 2677–​86.
19.11.2  Systemic lupus erythematosus and related disorders
4501
genes also present in that region of chromosome 6. Genome-​wide
association studies have identified other lupus-​associated genes,
which can be classified into three groups; those associated with the
innate immune response, those associated with lymphocyte activa-
tion, and those associated with clearance of immune complexes.
Hormones are likely to play a role in pathogenesis because sys-
temic lupus erythematosus is far more common in women than in
men. However, attempts to treat the condition with hormonal agents
have been largely disappointing.
Viruses may be important in triggering the autoimmune dysfunc-
tion that leads to the production of pathogenic autoantibodies in
systemic lupus erythematosus. Reactivation of BK polyomavirus in-
fection, in particular, has been associated with the presence of anti-
bodies to dsDNA in Norwegian studies, but not confirmed in other
populations.
Exposure to ultra-​violet light can precipitate a flare of lupus, usu-
ally (but not always) in the skin. This accounts for the phenomenon
of photosensitivity seen in many patients.
Certain drugs induce a form of systemic lupus erythematosus
that is generally characterized by the presence of antihistone ra-
ther than anti-​dsDNA antibodies, a milder course of disease, and
total remission when the causative drug is withdrawn. The most
common drugs involved are isoniazid, procainamide, hydralazine,
minocycline, penicillamine, tumour necrosis factor blocking agents
and anticonvulsants (see Chapter 19.12).
Abnormalities of the immune system
No single abnormality of the immune system can be considered to
be the sole cause of systemic lupus erythematosus. The pathogenesis
of the disease depends on the interplay of several different factors,
the relative importance of which may differ from one patient to an-
other. These include autoantibodies, T lymphocytes, cytokines, the
complement system, and apoptosis. Research to unravel this com-
plex system of inter-​related factors has been carried out by studying
properties of cells and tissue components derived from patients with
systemic lupus erythematosus and by studying mouse models of the
condition.
B lymphocytes and autoantibodies
Autoantibodies are those that bind to antigens present within the
tissues of the body itself. A wide variety of different autoantibodies
has been described in systemic lupus erythematosus. Those most
frequently reported are listed in Table 19.11.2.3.
Anti-​dsDNA antibodies have been cited widely as possible causa-
tive agents in systemic lupus erythematosus, particularly in lupus
glomerulonephritis. Raised titres of anti-​dsDNA antibodies are
found in 50 to 70% of patients with systemic lupus erythematosus,
but hardly ever in healthy people or those with other diseases.
Levels of these antibodies often rise and fall with disease activity,
and deposits of anti-​dsDNA antibodies occur in the glomeruli of
patients with lupus nephritis. In experimental murine models of
systemic lupus erythematosus, monoclonal anti-​dsDNA antibodies
can be shown to deposit in the glomeruli and to be associated with
proteinuria.
The titre of anti-​dsDNA antibodies present in the bloodstream
of patients with systemic lupus erythematosus can be a useful indi-
cator of disease activity. It is increasingly clear, however, that not all
anti-​dsDNA antibodies are equally likely to be associated with tissue
damage. Antibodies of the IgG isotype, which show specific high-​
affinity binding to dsDNA, generally show the closest association
Table 19.11.2.3  Major autoantibodies associated with systemic lupus erythematosus and their approximate
prevalence in patients with the disease
Autoantibodies
Antigen/​epitope
Approximate prevalence (%)
Intracellular
DNA
dsDNA, (ssDNA)
50–​70
Histone
H1, 2A, 2B, 3, 4
30–​80
Sm
B/​B’, D, E, F, G
30 (Afro-​Caribbean), c.10 (Caucasian)
U1RNP
A, C, 70 kDa ribonucleoprotein
20–​35
rRNP
Three subunits: 38, 19, 17 kDa
5–​15
Ro/​SS-​A
60, 52 kDa protein bound to cytoplasmic RNA (hY1–​hY5)
25-​35
La/​SS-​B
48 kDa protein bound to variety of RNA, U1RNA, hY RNA
10–​15
Heat shock protein (hsp)
hsp 90
30
hnRNP
A2 protein (also known as RA-​33)
30
Cell membrane
Cardiolipin
Phospholipids
20–​40
Neuronal antigen
Expressed on neuronal cell lines grown in vitro
70–​90 (+CNS), c.10 (–​CNS)
Lymphocyte
HLA component
c.75 (IgM), c.45 (IgG)
Red cell
Non-​Rh related
<10
Platelet
<10
Extracellular
Rheumatoid factor
Fc region of IgG
c.25
C1q
Complement component
20–​45
section 19  Rheumatological disorders
4502
with disease activity in patients and the greatest ability to cause renal
damage in experimental models.
More recent work has suggested that a subpopulation of B
lymphocytes, called regulatory B cells and characterized by the pro-
duction of IL-​10, may play a suppressive role in autoimmunity, and
that dysfunction of these cells may also contribute to development
of systemic lupus erythematosus.
Why are autoantibodies produced in patients with systemic
lupus erythematosus?
Studies of monoclonal anti-​dsDNA antibodies derived from pa-
tients or mice indicate that those that show the isotype and binding
properties described here often show sequence characteristics
suggestive of antigen-​driven somatic mutation. This is the pro-
cess whereby mutations accumulate in the expressed immuno-
globulin gene sequences of a B lymphocyte under the influence of
a particular antigen. The mutations are accumulated non​randomly,
such that the end-​result is an increase in specificity and affinity of
binding. This process is dependent on help from T lymphocytes and
on the presence of an appropriate antigen. Naked mammalian DNA
is, however, a poor immunogen in experimental animals, and the
concentration of free DNA in the bloodstream is low even in pa-
tients with systemic lupus erythematosus. It is therefore believed
that the antigen that stimulates production of high-​affinity anti-​
dsDNA antibodies is probably a complex of DNA and protein. Cell
fragments (blebs) derived from apoptosis are the most important
source of antigens involved in stimulating both T cells and B cells
in systemic lupus erythematosus. Nucleosomes in these blebs can
stimulate production of antinucleosome and anti-​dsDNA anti-
bodies, whereas other antigens such as Ro and anionic phospho-
lipids can trigger production of some of the other antibodies seen in
Table 19.11.2.3. Studies on stored blood samples (taken routinely
as part of military protocol) from healthy American soldiers who
subsequently developed systemic lupus erythematosus show that
the production of autoantibodies can pre-​date the onset of the dis-
ease by up to 10 years.
How do autoantibodies exert their pathogenic effects in tissues?
Deposition of IgG and complement in inflamed tissues such as
kidney and skin is a consistent feature of active systemic lupus
erythematosus. The pathogenic potential of autoantibodies in sys-
temic lupus erythematosus (particularly IgG anti-​dsDNA) may
therefore rest on their ability to deposit in these tissues and to ac-
tivate complement. Much of the work designed to find out why
autoantibodies are deposited in target tissues has concentrated on
lupus nephritis. Originally, it was felt that DNA–​anti-​DNA im-
mune complexes would form in the bloodstream and accumulate
in glomeruli as the blood was filtered there. However, it has not
been possible to demonstrate large quantities of such complexes
in the blood of patients with systemic lupus erythematosus, al-
though their clearance may well be abnormal due to complement
deficiency.
The key determinant is the presence in the tissue of an antigen
to which specific autoantibodies can bind. Anti-​dsDNA antibodies
may be targeted to the kidney due to cross-​reaction with cell surface
proteins there, or may deposit due to an interaction with histones
and heparan sulphate. According to this latter model, anti-​dsDNA
antibodies bind to DNA in nucleosomes, and the positively charged
histones in these nucleosomes bind to negatively charged heparan
sulphate in the renal basement membrane. Electron microscope
studies have indeed demonstrated the presence of nucleosome de-
posits that colocalize with deposited IgG in renal biopsies from pa-
tients with lupus nephritis. Anti-​Ro antibodies can deposit in the
fetal heart of anti-​Ro positive pregnant women with systemic lupus
erythematosus, yet not in the mother’s heart. This is believed to be
because Ro is expressed on the surface of cardiomyocytes during de-
velopment of the fetal heart, but not in adults.
Antiphospholipid antibodies
Antiphospholipid (APL) antibodies may be present in healthy
people or in those with infectious diseases such as syphilis, in which
case they have no adverse effects. They are found in 30-​40% of pa-
tients with systemic lupus erythematosus. In some, but not all of
these patients, the APL antibodies may cause arterial or venous
thromboses or miscarriages; this is known as the antiphospholipid
syndrome (APS).
APS occurring in the absence of systemic lupus erythematosus
or any other autoimmune rheumatic disease is called primary APS.
Although it was previously thought that APL antibodies exerted
their effects almost wholly through promotion of thrombus forma-
tion, it is now clear that they may have many other direct effects
on platelets, monocytes, endothelial cells, and the trophoblast. The
mechanism by which thrombosis is altered is not fully understood,
but it has become clear that APL antibodies found in APS often bind
to protein antigens associated with phospholipids rather than the
phospholipids themselves. The most important of these proteins is
β2-​glycoprotein I, and a direct test for anti-​β2-​glycoprotein I is one of
the three diagnostic tests for APS.
T lymphocytes
As the process of antigen-​driven selection of mutations in B lympho-
cytes is dependent on help from helper T lymphocytes, it would be
reasonable to suppose that antigen-​specific T cells might also con-
tribute to the pathogenesis of the disease. The isolation of T-​cell
clones reactive with DNA and/​or DNA-​binding proteins such as
histones has been demonstrated from both patients with systemic
lupus erythematosus and murine models of the disease. The clones
frequently show specificity for histone epitopes that are cryptic (i.e.
not exposed) in normal chromatin. These results reinforce the idea
that the antigenic stimulus for production of both pathogenic T cells
and autoantibodies in systemic lupus erythematosus may be a DNA/​
histone complex rather than DNA alone.
Patients with systemic lupus erythematosus have decreased
levels of the subset of T cells carrying the CD4 and CD45 Ro sur-
face markers. This population may be involved in stimulation of
suppressor T lymphocytes such that suppression in these patients
is insufficient to prevent the production and survival of autoreactive
B-​lymphocyte and helper T-​lymphocyte clones. Invariant natural
killer T cells (iNKT cells) are a small population of specialized
immunomodulatory T cells that are stimulated specifically by lipids
and which appear to be dysfunctional in some patients with sys-
temic lupus erythematosus.
Apoptosis and complement
The links between apoptosis, complement, and lupus are com-
plicated. Murphy Roths Large (MRL) lpr/​lpr mice are deficient in
19.11.2  Systemic lupus erythematosus and related disorders
4503
apoptosis because they lack the Fas protein that plays a major role
in promoting this process. These mice develop a disease very similar
to systemic lupus erythematosus, with death resulting from glomer-
ulonephritis. One possible reason for this might be the failure of the
immune system to delete by apoptosis autoreactive clones of T or B
lymphocytes, which are then able to cause autoimmune disease. By
contrast, humans with the equivalent genetic lesion to MRL lpr/​lpr
mice do not develop systemic lupus erythematosus, and other strains
of mice show an accumulation of apoptotic debris within nephritic
kidneys, which resemble those of systemic lupus erythematosus.
A  simple deficiency in apoptosis is therefore unlikely to be the
underlying mechanism in systemic lupus erythematosus.
Apoptosis leads to the production of surface blebs of cellular
material. These blebs include several antigens to which autoanti-
bodies develop in systemic lupus erythematosus, notably DNA
and associated nuclear proteins and negatively charged phospho-
lipids. A deficiency in the clearance of products of apoptosis has
been demonstrated in patients with systemic lupus erythematosus
which might allow the production of a wide spectrum of autoanti-
bodies. Removal of immune complexes containing such potentially
antigenic material may be compromised in patients with systemic
lupus erythematosus. Monocytes derived from such patients show
reduced phagocytosis of cell debris in vitro. This process may be
complement dependent, as people with homozygous C2 deficiency
process immune complexes very differently from normal controls.
Administration of fresh frozen plasma to such (rare) patients as a
source of complement is successful in ameliorating symptoms and
in normalizing (albeit transiently) their processing of immune
complexes.
C1q knockout mice develop a form of glomerulonephritis similar
to that seen in systemic lupus erythematosus, and their kidneys are
characterized by accumulations of apoptotic debris. In fact knockout
mice deficient in both the classic and alternative pathways of com-
plement develop this form of glomerulonephritis, showing that in
this model the protective effects of complement outweigh its role
as an effector of inflammation. Similarly, as noted earlier, humans
homozygous for C1q deficiency develop a form of systemic lupus
erythematosus with the frequent occurrence of nephritis.
Cytokines
Cytokines enhance the ability of cells to interact and are therefore
critically important in abnormalities in both T-​ and B-​cell func-
tions seen in patients with lupus. Table 19.11.2.4 summarizes
the major differences between the different subsets of T-​helper
(Th) cells in terms of their cytokine profiles and functions. The
balance between cytokines from Th1 and Th2 cells is essential in
determining the outcome of the immune response. Lupus might
be expected to be a disease in which Th2 cells predominate, re-
sulting in excessive help for B cells and overproduction of anti-
bodies. In support of this notion, increased levels of interleukin
10 (IL-​10) have been found in patients with lupus. This cytokine
promotes secretion of antibodies by B lymphocytes, but suppresses
Th1 cells and thus impairs cell-​mediated immunity, a character-
istic feature of the disease. Both macrophage and natural killer
cell-​mediated cytotoxicity are frequently impaired in patients with
lupus. Interferon-​γ-​induced enhancement of both types of cyto-
toxicity is also impaired, despite normal levels of interferon-​γ pro-
duction by lupus Th1 cells.
Accessory cells in lupus seem to produce insufficient amounts
of IL-​1 to provide the necessary activation signals for T cells. Both
CD4+ and CD8+ T cells have been described as producing either
normal or decreased amounts of IL-​2 in response to exogenous
antigens. Such a reduction is likely to have a profound effect on T-​
cell responses.
Interferon-​α is increasingly recognized as playing a major role
in the development of systemic lupus erythematosus. Levels of this
cytokine are raised in patients with systemic lupus erythematosus,
genetic studies show that interferon-​related genes are risk factors
for systemic lupus erythematosus, and gene expression studies show
that such genes are activated in patients with the disease. Lupus in
Table 19.11.2.4  (a) Subsets of CD4+ T cells; (b) Cytokine profiles in patients with active systemic lupus
erythematosus
Function
Cytokines
(a) Subsets of CD4+ T cells
T-​helper 1 cell
Cell-​mediated immunity
IFN-​γ, IL-​10 (humans
only), IL-​12, TNFα
T-​helper 2 cell
B-​cell help
IL-​4, IL-​10
(b) Cytokine profiles in patients with active systemic lupus erythematosus
Cytokine
Serum levela
Spontaneous
Stimulation in vitro
IFN-​γ
↑
Low
↓
TNFα
↑ (or normal)
↓ (DR2, DQw1; ↑ nephritis), ↑
(DR3, 4; ↓ nephritis)
↓
IL-​1
n.d.
↑ PBM production
↓ Monocyte production
IL-​2
↑
Low
↓
IL-​4
n.d.
Low
Low
IL-​6
↑
↑
–​
IL-​10
↑ (or normal)
↑ (or normal)
Normal
IFN-​γ, interferon-​γ; n.d., not detected; PBM, peripheral blood mononuclear cell; TNFα, tumour necrosis factor-​α.
a Serum levels of cytokines are difficult to interpret since these may be affected by soluble cytokine receptors which are shed from cells. Among
the known shed receptors are those for IL-​1, IL-​2, IL-​6, TNFα, and IFN-​γ. Soluble TNFαR and IL-​2R levels are increased in systemic lupus and
correlate with disease activity and lupus nephritis.
section 19  Rheumatological disorders
4504
the NZB/​NZW mouse model of lupus can be accelerated by the
presence of interferon-​α. Cytokines such as interferon-​α and IL-​10
are increasingly being considered as possible targets for future thera-
peutic agents in lupus.
There is some evidence that TNFα may play a protective, rather
than pathogenic role in systemic lupus erythematosus, partially
from murine models, and partly from the observation that some
patients treated with anti-​TNFα agents for other diseases develop
anti-​dsDNA antibodies.
Histopathology
The two tissues most often subjected to biopsy in systemic lupus
erythematosus are the skin and kidneys.
Skin biopsies are chiefly carried out to facilitate the diagnosis of
an atypical rash. If systemic lupus erythematosus is suspected, it is
important to take a sample of apparently normal skin as well as skin
from the rash. Both should show deposition of IgG and comple-
ment at the dermo-​epidermal junction (Fig. 19.11.2.1).
Renal biopsy may be performed to establish the diagnosis of sys-
temic lupus erythematosus when this is not certain, e.g. in a patient
with a poorly characterized multisystem disease with renal involve-
ment. In a patient with known systemic lupus erythematosus it may
be employed to help determine prognosis and decide on treatment
when renal function is deteriorating, e.g. with the development of
nephrotic syndrome and/​or declining glomerular filtration rate
(GFR). The glomerular pathology can be graded on a scale of I to
VI according to the International Society of Nephrology/​Renal
Pathology Society criteria, and scores for activity and chronicity
can be used to determine appropriate treatment and the risk of a
progressive decline in renal function. The subject of renal path-
ology in systemic lupus erythematosus is considered further in
Chapter 21.10.3.
Epidemiology
The incidence of systemic lupus erythematosus in the United
Kingdom is about five cases/​100 000 people per year and the preva-
lence is 1 in 1000. It occurs about 10 times more frequently in
women than in men, and is more common in Black ethnic groups.
A  study published in 2014 using the United Kingdom Clinical
Practice Research Datalink gave the prevalence of systemic lupus
erythematosus as 518 per 100 000 in people of Black Caribbean eth-
nicity, 180 per 100 000 in those of Black African ethnicity, and 135
per 100 000 in white people. The figures for different Asian groups
ranged from 143 to 193 per 100 000. These gender and racial differ-
ences are broadly consistent with those reported from studies in the
United States of America and the Caribbean, although the reported
prevalence of systemic lupus erythematosus in Africa is much lower.
Clinical features
Systemic lupus erythematosus is a chronic condition punctuated by
flares of acute activity. The overall severity of the disease in a par-
ticular patient depends on the nature and frequency of these flares
and the long-​term permanent damage that they cause.
The diverse clinical features of systemic lupus erythematosus mean
that the disease may present to any of a number of different special-
ists, including rheumatologists, dermatologists, nephrologists, and
general physicians. It is important to be aware of systemic lupus
erythematosus as a possible diagnosis in any patient, especially a
woman aged between 15 and 50, in whom several different organs are
inflamed either simultaneously or sequentially. The frequency of oc-
currence of symptoms in various organs is shown in Table 19.11.2.5.
Table 19.11.2.5  Cumulative prevalence of clinical features
in patients with systemic lupus erythematosus
Clinical feature
Approximate cumulative
prevalence (%)
Musculoskeletal
Arthralgia/​arthritis
90
Tenosynovitis
20
Myalgia
50
Myositis
5
Cardiopulmonary
Shortness of breath
40
Pleurisy
35
Pleural effusion
25
Lupus pneumonitis
5
Interstitial fibrosis
5
Pulmonary function abnormalities
85
Cardiomegaly
20
Pericarditis
15
Cardiomyopathy
10
Myocardial infarction
5
Fig. 19.11.2.1  Immunofluorescence microscopy showing deposition
of IgG at the dermoepidermal junction in the skin of a patient with
systemic lupus erythematosus (sometimes called the lupus band test).
(continued)
19.11.2  Systemic lupus erythematosus and related disorders
4505
According to the classification criteria published by the American
College of Rheumatology (see Table 19.11.2.1), systemic lupus
erythematosus may be diagnosed where a patient meets at least 4
of the 11 criteria specified (though not necessarily at a single time).
In everyday practice, however, these requirements may be too strin-
gent, and systemic lupus erythematosus is often suspected on the
basis of typical clinical findings in one organ or tissue combined
with the presence of appropriate autoantibodies. The Systemic Lupus
International Collaborating Clinics criteria (see Table 19.11.2.2)
recognize this specifically in the case of nephritis.
Constitutional symptoms
Patients with systemic lupus erythematosus find fatigue to be the
most troublesome feature of the disease, excessive tiredness being
both very common and difficult to treat. Hypothyroidism coexists
in 5–​10% of patients with systemic lupus erythematosus and so
thyroid function tests should be performed in the fatigued patient.
Fibromyalgia may coexist with systemic lupus erythematosus, in
which case treating the patient with corticosteroids or immunosup-
pressants may not improve their fatigue.
Weight loss and low-​grade fever may both be indicative of disease
activity. Lymphadenopathy is also recognized. The nodes may be
markedly enlarged but show no diagnostic features on biopsy, which
may nevertheless be necessary to exclude other conditions such as
lymphoma.
Musculoskeletal involvement
Arthralgia/​arthritis is the most common symptom in systemic lupus
erythematosus, occurring in 90% of patients. This may be severe but
is rarely associated with frank synovitis. Effusions may occur but the
fluid shows no diagnostic features.
Erosive arthritis is uncommon, but up to 5% of patients may have
an overlap syndrome with features of rheumatoid arthritis as well
as systemic lupus erythematosus. These patients tend to have both
serum rheumatoid factor and erosions.
When progressive deformity of the hands does occur in systemic
lupus erythematosus, it is usually due to an aggressive tenosyno-
vitis and tendon dysfunction rather than to joint damage. This leads
to reversible subluxation of the joints, often known as Jaccoud’s
arthropathy (Fig. 19.11.2.2).
Development of hip pain in patients who have been treated with
corticosteroids should raise the suspicion of avascular necrosis of
the femoral head, which may be diagnosed on a plain radiograph
or, in earlier stages, by MRI. Corticosteroids also promote osteo-
porosis, which can be diagnosed in the presymptomatic phase by
bone density scanning, but may present with the acute pain of a
vertebral fracture.
Clinical feature
Approximate cumulative
prevalence (%)
Gastrointestinal
Anorexia
40
Nausea
15
Vomiting
<10
Diarrhoea
<10
Ascites
<10
Abdominal pain
30
Hepatomegaly
25
Splenomegaly
10
Renal
Haematuria
10
Proteinuria
60
Casts
30
Serum albumin <35 g/​litre
30
Serum creatinine >125 μmol/​litre
30
Reduced 24-​h creatinine clearance
35
Cerebral
Depression
15
Psychosis
<5
Seizures
20
Hemiplegia
10
Cranial nerve lesions
10
Cerebellar signs
5
Meningitis
1
Migraine
40
Haematological
Anaemia (iron deficiency)
30
Anaemia (of chronic disease)
75
Autoimmune haemolytic anaemia
15
Leucopenia
40
Lymphopenia
80
Thrombocytopenia
25
Circulating anticoagulants
15
Dermatological
Butterfly rash
40
Erythematous maculopapular eruption
35
Discoid lupus
20
Relapsing nodular non​suppurative
panniculitis
<5
Vasculitic skin lesions
40
Livedo reticularis
20
Purpuric lesions
40
Alopecia
20–​50
Table 19.11.2.5  Continued
Fig. 19.11.2.2  Deforming Jaccoud’s arthropathy.
section 19  Rheumatological disorders
4506
Myalgia is common and a true myositis may occur in 5% of cases.
Corticosteroid-​induced proximal myopathy may also be a problem
where these drugs have been used for long periods.
Cutaneous and mucosal involvement
Photosensitivity is very common, particularly in white female pa-
tients. Patients should be advised to avoid strong sunlight and to
wear protective clothing and/​or a high-​factor sunblock.
The butterfly rash over the malar area of the face occurs in up to
one-​third of patients (Fig. 19.11.2.3). A number of other forms of
cutaneous involvement can occur, although these are less specific
for systemic lupus erythematosus. These include maculopapular
rash, discoid lesions, alopecia, panniculitis, and nailfold infarcts.
Scarring alopecia may be particularly distressing and difficult to
treat (Fig. 19.11.2.4).
A variant of systemic lupus erythematosus in which cutaneous
manifestations dominate is known as subacute cutaneous lupus.
This condition is often associated with anti-​Ro antibodies and may
be exacerbated by smoking cigarettes.
APL antibodies are associated with a non​raised lattice-​like rash
concentrated particularly over the thighs and arms: livedo reticularis
(Fig. 19.11.2.5).
Recurrent crops of oral ulcers are common enough to be rec-
ognized as one of the diagnostic criteria for systemic lupus
erythematosus. About 15% of patients develop secondary Sjögren’s
syndrome; in this condition the dry eyes and mouth may respond to
artificial tears and saliva.
Renal involvement
Glomerulonephritis is the most serious and potentially lethal
manifestation of systemic lupus erythematosus. Its presence may
be detected by the finding of haematuria and/​or proteinuria on
routine stick testing of the urine. It may present as the nephrotic
syndrome or, less commonly, as a florid nephritis with haematuria,
proteinuria, hypertension, and acute renal failure with red cell
casts in the urine. The diagnosis and management of glomerulo-
nephritis in systemic lupus erythematosus are more fully discussed
in Chapter 21.10.3.
It is important to be aware of the possibility of glomerulonephritis
in any patient with systemic lupus erythematosus (Fig. 19.11.2.6).
Measurement of blood pressure and analysis of urine should be
carried out at each consultation. Early diagnosis and treatment are
Fig. 19.11.2.3  Malar ‘butterfly’ rash.
Fig. 19.11.2.4  Severe scarring alopecia.
Fig. 19.11.2.5  Livedo reticularis.
19.11.2  Systemic lupus erythematosus and related disorders
4507
invaluable in avoiding deterioration of renal function to the extent
that dialysis or renal transplantation become necessary.
Patients with APS may develop a different type of renal lesion
characterized by thrombi in small renal vessels rather than by glom-
erulonephritis. These patients develop hypertension and impair-
ment of renal excretory function, detected as a fall in estimated
GFR (eGFR), rather than proteinuria, and are best managed by
anticoagulation rather than immunosuppression.
Respiratory involvement
The most common form of respiratory involvement in systemic
lupus erythematosus is pleuritis, manifesting either as pleuritic
chest pain or as breathlessness caused by pleural effusion. The lung
parenchyma is more rarely involved, but fibrosis can occur.
A patient with systemic lupus erythematosus may present with
shortness of breath or chest pain for several reasons. Pulmonary
emboli must be suspected in those with APL antibodies. Infections
are common in immunosuppressed patients and rib fractures may
occur, particularly in those rendered osteoporotic by treatment with
corticosteroids.
The shrinking lung syndrome is characterized by reduced lung
volumes and poor respiratory reserve in the face of a normal appear-
ance of the lung parenchyma on computed tomography (CT). It is
believed to arise from basal atelectasis in association with diaphrag-
matic dysfunction.
Cardiovascular involvement
The most common cardiac manifestation of systemic lupus
erythematosus is pericarditis, which occurs in about 15% of patients.
This generally presents with chest pain or an asymptomatic friction
rub. Pericardial effusions may occur, but are rarely large enough to
cause haemodynamic compromise.
Myocarditis and endocarditis are less common, though post-​
mortem and echocardiographic studies suggest that both may occur
without symptoms in a significant proportion of patients with sys-
temic lupus erythematosus, e.g. the classic endocarditis described
by Libman and Sacks is characterized by small vegetations that
often do not cause murmurs or cardiac compromise, but which
have been identified in up to 50% of patients with systemic lupus
erythematosus post-​mortem.
It is increasingly recognized that atherosclerosis and its sequelae
in the cerebral and cardiac circulations are more common in pa-
tients with systemic lupus erythematosus than in the general popu-
lation. Overall, patients with systemic lupus erythematosus have
5–​10-​fold greater risk of developing cardiovascular disease than
healthy people of the same age or sex. The cause of this increased risk
is complex, but includes both generic factors such as smoking and
hypertension, and disease-​associated factors such as autoantibodies
and use of corticosteroids.
Raynaud’s phenomenon occurs in about a third of patients with
systemic lupus erythematosus, although it is not usually as severe as
that seen in systemic sclerosis. Vasculitis presents with a skin rash or
ulcers that may be very difficult to heal, but rarely affects the internal
organs.
Gastrointestinal involvement
Similar to pleuritis, peritonitis may occur in patients with systemic
lupus erythematosus and must be considered in the event of ab-
dominal pain, while remembering that patients with lupus are not
protected from more common causes of this condition, e.g. appen-
dicitis. Lupus mesenteric vasculitis is a rare but severe manifestation
that presents with an acute abdomen.
Involvement of the liver and pancreas is recognized but un-
common. The term ‘lupoid hepatitis’ was previously used for a form
of autoimmune hepatitis characterized by the presence of autoanti-
bodies, but these patients do not generally have any form of systemic
lupus erythematosus and the term is misleading. Minor enlarge-
ments of the liver and/​or spleen occur in 10 to 25% of cases, but these
are usually asymptomatic and require no treatment.
Neuropsychiatric involvement
Systemic lupus erythematosus can affect the nervous system in many
ways, so that the true incidence of neuropsychiatric involvement is
difficult to quantify. Symptoms such as poor memory, change of
personality, and depression or anxiety occur in many patients. It is
difficult, however, to be sure whether these are caused by cerebral
systemic lupus erythematosus or represent a reaction to the diag-
nosis and treatment of the disease.
More florid presentations such as psychotic episodes and con-
vulsions are well recognized but rare. By contrast to the milder
symptoms noted here, these manifestations generally call for im-
munosuppression. In a large multinational study of over 1000
patients with systemic lupus erythematosus, 40% suffered from
neuropsychiatric symptoms at some time during a two-​year follow-​
up period, but in most cases these were mild, not due to active lupus,
and did not require treatment with immunosuppression.
Migraine occurs in up to 40% of patients with systemic lupus
erythematosus, particularly in the presence of APL antibodies.
Peripheral neuropathy can occur, and is usually sensory rather than
motor. Cranial nerve palsies are less common, as is transverse mye-
litis (another feature linked to APL antibodies).
Ocular involvement can include episcleritis, conjunctivitis, and
the presence of cytoid bodies (white patches on the retina). Patients
treated with high-​dose steroids may develop cataracts.
Haematological involvement
A normochromic normocytic anaemia is frequently seen in systemic
lupus erythematosus, particularly during periods of high disease
Fig. 19.11.2.6  Immunofluorescence microscopy showing deposition
of IgG in the glomerulus of a patient with lupus nephritis.
section 19  Rheumatological disorders
4508
activity. Microcytic iron-​deficiency anaemia may result from blood
loss from gastritis and ulcers in patients treated with nonsteroidal
anti-​inflammatory drugs. Anaemia may also result from chronic
renal failure in lupus nephritis.
A positive Coombs’ test, signifying the presence of antibodies to
red blood cells, is present in up to 20% of patients with systemic lupus
erythematosus but does not always indicate haemolytic anaemia.
The presence of lymphopenia (less than 1.5 × 109/​l) is common,
occurring in up to 80% of patients. Neutropenia may occur sec-
ondary to the use of cytotoxic drugs such as azathioprine or
cyclophosphamide.
Three different types of thrombocytopenia occur in systemic lupus
erythematosus. The mildest form (often seen in patients with APL) is
characterized by stable platelet levels of between 50 and 100 × 109/​l,
is rarely symptomatic, and usually requires no treatment. Other pa-
tients develop an acute autoimmune thrombocytopenia with levels
dropping rapidly below 25 × 109/​l, but usually rising when treated
with oral steroids. A third group of patients present with thrombo-
cytopenia alone, are treated with steroids, intravenous immuno-
globulins, rituximab, or (very rarely these days) splenectomy, and
some years later develop full-​blown systemic lupus erythematosus.
Thrombocytopenia is also a common features of the APS.
Other complicating disorders
About 30% of lupus patients have another autoimmune condition,
including Sjögren’s syndrome (the most common, affecting some
15 to 20% of patients with lupus), APS (10 to 15%), autoimmune
thyroid disease (hyper-​ or hypothyroidism, 5 to 10%), and (less fre-
quently) rheumatoid arthritis, myasthenia gravis, coeliac disease,
diabetes, and pernicious anaemia.
Differential diagnosis
Systemic lupus erythematosus is truly a chameleon of a disease.
Its protean clinical manifestations mean that, theoretically, it
could enter the differential diagnosis of virtually any unexplained
symptom/​feature. It is very important to remember, however, that
most people with symptoms such as fatigue, joint pain, and rash do
not have lupus, even though an internet search may have raised a
patient’s anxiety about that diagnosis.
Among its general features, fever, weight loss, anorexia, and
lymphadenopathy may easily be confused with a lymphoproliferative
cancer, hence biopsy of a swollen lymph gland may often be required
to be sure of the underlying problem. Polyarthralgia or polyarthritis
in a young woman could be due to rheumatoid arthritis or lupus. As
both rheumatoid factor and antinuclear antibodies can be found in
either condition, there is obvious room for confusion, but anti-​CCP
antibodies (rheumatoid) and anti-​dsDNA antibodies (lupus) are
more specific tests that can usually resolve the matter.
About 15% of patients presenting with ‘idiopathic’ thrombocytopenic
purpura will eventually develop lupus. Unfortunately there are usually
no clues at the onset to distinguish this 15% and very long-​term follow-​
up may be needed.
Antibodies to Ro, La, Sm, RNP (ribonucleoprotein), and dsDNA
may be detectable in the serum of patients who will develop lupus
up to 10 years before the disease becomes clinically manifest, and
rarely these antibodies are found in the healthy relatives of patients.
Occasionally lupus may present with isolated central nervous
system (CNS) disease including convulsions, schizophrenic-​like
conditions, and neuropathies. As with many other clinical fea-
tures, the most important consideration is to try to include sys-
temic lupus in the differential diagnosis. The serological tests for it
are widely available and will help to establish, quickly, the correct
diagnosis.
Clinical investigation
Autoantibodies
The most commonly requested test to screen for systemic lupus
erythematosus is the antinuclear antibody assay. A  positive
antinuclear antibody test simply indicates that the patient’s blood
contains antibodies that will bind to the nuclei of a sample of cells
used in the test. The test is a sensitive one because over 95% of pa-
tients with systemic lupus erythematosus are antinuclear antibody
positive. Although a small group of patients do seem to have persist-
ently antinuclear antibody-​negative systemic lupus erythematosus,
the absence of antinuclear antibody in a patient with suspected lupus
raises serious doubt about the diagnosis.
The specificity of the antinuclear antibody test for systemic lupus
erythematosus is not high. The titre of antibody represents the
highest dilution of the patient’s serum at which the test is still posi-
tive. Low-​titre antinuclear antibody (1 in 10) is of little significance
and may occur in healthy people. Higher titres (1 in 160 or more)
are more worrying and are found in most patients with systemic
lupus erythematosus and in some patients with other autoimmune
conditions including rheumatoid arthritis, systemic sclerosis,
and Sjögren’s syndrome. However, some people with high-​titre
antinuclear antibody may be followed in rheumatology clinics for
years without developing a frank autoimmune disease.
The finding of a positive antinuclear antibody in a patient with
symptoms suggestive of systemic lupus erythematosus should lead
to a series of other autoantibody tests. These are listed in Table
19.11.2.3 together with the identity of the target antigen and the ap-
proximate prevalence of the antibodies.
Anti-​dsDNA antibody levels are particularly useful. This test is
virtually specific for systemic lupus erythematosus (as is the anti-​Sm
antibody), especially if the immunoglobulins are of the IgG isotype.
The anti-​dsDNA result is usually quantified and this value is often
a measure of the activity of the disease, but there is a group of pa-
tients who have persistently high anti-​dsDNA antibody levels but
no clinically active disease (serologically active, clinically quiescent).
Long-​term follow-​up suggests that many but not all of these patients
will eventually flare. In one study, trial patients were treated with
high-​dose corticosteroids on the basis of anti-​dsDNA levels alone.
In comparison with a control group treated only when symptoms or
signs also suggested disease activity, the trial group had less disease
activity overall and fewer flares. However, frequent large doses of
corticosteroids resulted in significant side effects and several parti-
cipants dropped out of this arm of the trial. Anti-​dsDNA should be
used only as an adjunct to the clinical impression of disease activity
when deciding on a treatment regimen.
Anti-​Ro and anti-​La antibodies are linked to concurrent Sjögren’s
syndrome. Mothers who have these antibodies have a higher inci-
dence of neonatal lupus and should be advised about this before
19.11.2  Systemic lupus erythematosus and related disorders
4509
embarking on a pregnancy. Anti-​Ro antibodies are also associated
with photosensitivity.
There are no good antibody markers for the presence of disease of
the CNS. Antibodies to ribosomal protein P were previously thought
to have some value in the diagnosis of CNS lupus, but this has not
been borne out by later results and the test is not available routinely
in most laboratories. More recently, murine and clinical studies have
suggested that antibodies to the N-​Methyl-​D-​aspartate receptor
(anti-​NMDAR) may act on certain cerebral tissues (e.g the amyg-
dala) to cause clinical features of CNS lupus, but this test is not used
routinely in clinical practice.
APL antibodies can be recognized by one of three assays. The
enzyme-​linked immunosorbent assay (ELISA) for binding to
cardiolipin distinguishes IgM and IgG isotypes, as does a second
ELISA for anti-​β2-​glycoprotein 1 antibodies. This is helpful be-
cause the level of IgG APL antibodies is a better predictor of clinical
sequelae than that of IgM. APL antibodies can also be diagnosed by
testing the clotting properties of the blood in vitro in the Russell’s
viper venom test. An abnormal result in this assay is reported as
showing the presence of a lupus anticoagulant. The ELISAs and
lupus anticoagulant test do not always give the same result. Patients
may be positive in one but not in the others. Patients positive in all
three tests have the highest risk of thrombosis.
Coombs’ test and assays for antithyroid antibodies are often re-
quested in patients with systemic lupus erythematosus, particularly
those with coexisting anaemia or hypothyroidism.
Measures of disease activity and end-​organ damage
Blood and urine tests
The most reliable measures of highly active disease are depletion
of complement and high anti-​dsDNA levels. The erythrocyte sedi-
mentation rate (ESR) also tends to be increased in active disease,
unlike the level of C-​reactive protein (CRP). The combination of
high ESR and normal CRP in a patient with a multisystem dis-
order should raise the suspicion of systemic lupus erythematosus,
leading to appropriate autoantibody tests as described here. The
CRP may, however, be raised in the presence of infection, serositis,
or arthritis.
Complement components C3 and C4 are the most commonly meas-
ured, and both tend to fall in active systemic lupus erythematosus.
A persistently very low level of either C3 or C4 (or a high level of
their degradation products C3d or C4d), regardless of immunosup-
pressive therapy, may signify the presence of a homozygous comple-
ment deficiency disorder. Although such disorders are very rare, it
is important to diagnose them because they respond better to infu-
sions of fresh frozen plasma than to immunosuppression.
It is important to measure creatinine and electrolyte values regu-
larly and to check the urine for proteinuria and/​or haematuria.
These measures ensure that renal involvement is diagnosed early.
It must be remembered that substantial deterioration in renal func-
tion may occur before serum creatinine rises beyond the normal
range, an issue emphasized by the now routine reporting of eGFR.
If the patient can reliably perform a 24-​h urinary collection, then
creatinine clearance can provide a more precise estimate of GFR,
but this, or radio-​isotopic methods of measuring GFR, are rarely
required in routine clinical practice. Persistent proteinuria on
dipstick testing should be quantified by measuring the albumin/​
protein:creatinine ratio in a spot urinary sample (or with a 24-​h
urinary collection).
Liver function tests are abnormal in fewer than 10% of patient
with systemic lupus erythematosus, but a baseline value should be
measured, particularly in cases where potentially hepatotoxic drugs
such as azathioprine may be used. Thyroid function abnormalities,
particularly hypothyroidism, are well recognized to coexist with sys-
temic lupus erythematosus.
A full blood count should be measured regularly. Falling haemo-
globin, white cell count, and platelet counts may all occur (see
previous section, ‘Haematological involvement’). Anaemia in the
presence of a positive Coombs’ test may indicate haemolysis, which
can be confirmed by requesting a blood film and serum haptoglobins.
Infections occur commonly in patients with systemic lupus
erythematosus, particularly in those on high-​dose immunosup-
pressants. Infection may not always be accompanied by high fever
or leucocytosis, although CRP is usually raised. It is wise to carry
out blood and urine cultures whenever even mild pyrexia is accom-
panied by a deterioration in health.
Imaging
Plain radiographs are rarely useful in systemic lupus erythematosus.
There is no characteristic appearance in the joints, and chest radio-
graphs are unlikely to show abnormalities except in the presence of
infection or effusion.
Requests for more specialized imaging studies should be directed
by the clinical findings, e.g. the presence of dyspnoea and abnormal
respiratory function tests often necessitates a high resolution CT
scan of the thorax, which is the investigation of choice for diagnosis
of pulmonary fibrosis. Echocardiography is useful if pericardial ef-
fusion, myocarditis, or endocarditis are suspected clinically. Bone
density scanning is becoming increasingly important, since patients
with systemic lupus erythematosus are often at risk of osteoporosis
due to the use of corticosteroids and reduced capacity for physical
exercise during young adult life.
Criteria for diagnosis
Although strictly speaking classification and diagnostic criteria are
not synonymous, the classification criteria discussed earlier, and
shown in Tables 19.11.2.1 and 19.11.2.2, are widely used for diag-
nostic purposes.
Treatment
Systemic lupus erythematosus is a disease that still has the potential
to kill. In many cases, however, the condition runs a fairly indolent
course in which an initial flare is followed by many years of low-​
grade activity. General measures of value in the treatment of sys-
temic lupus erythematosus are shown in Table 19.11.2.6.
In the pharmacological management of a patient with systemic
lupus erythematosus, the clinician will typically seek to answer four
‘classic’ questions:
1	 Can the patient be managed without immunosuppression?
2	 If immunosuppression is needed, how should it best be started?
section 19  Rheumatological disorders
4510
3	 If immunosuppression is being used, is the current level of im-
munosuppression inadequate or excessive? How should it be in-
creased or reduced?
4	 Does the patient have any side effects from the drugs?
A fifth is increasingly being posed: would any of the new biologic
treatments be of value?
Is immunosuppression required?
Patients whose disease activity is confined to arthralgia, tiredness,
and/​or mild rash do not usually have greatly raised ESR or anti-​
dsDNA antibodies or reduced complement. These patients can often
be treated symptomatically, e.g. with agents such as paracetamol and
diclofenac to control joint pain.
The antimalarial agent hydroxychloroquine at a starting dose
of 400 mg/​day is often useful for these problems. This drug car-
ries a very low risk of retinal toxicity but it is advisable for patients
to be monitored by an optician or ophthalmologist annually after
taking hydroxychloroquine continuously for five years or more.
Regular blood tests are not required to monitor the effects of
hydroxychloroquine. Long-​term studies consistently show better
outcomes in patients on hydroxychloroquine in terms of disease-​
associated damage and cardiovascular risk factors. On balance,
therefore, many rheumatologists advise patients with systemic lupus
erythematosus to stay on this drug even when in remission.
Immunosuppression is rarely useful where the main symptoms
in a patient with systemic lupus erythematosus are those of the
APS. Aspirin at a dose of 150 to 300 mg daily is recommended for
those with mild symptoms of the disease or who have other risk fac-
tors for thrombosis. Patients who have had recurrent thromboses
or cerebral infarcts and who have persistently positive serum APL
antibodies should usually be treated with lifelong anticoagulation.
This is a major commitment for a young patient and raises par-
ticular problems in pregnancy (discussed in ‘Systemic lupus
erythematosus in pregnancy’ later in this chapter).
Some patients require a low maintenance dose of oral steroids to
control their symptoms even though laboratory indices do not in-
dicate high activity of disease. A dose of prednisolone of 5–​7.5 mg
daily is typically used in such cases. Topical steroids may be useful
where lupus activity is confined to the skin.
Judging the dose of immunosuppression
Corticosteroids and cytotoxic agents are used to treat flares of dis-
ease. A mild flare of arthralgia, myalgia, and general fatigue may
be alleviated by a single intramuscular dose of a corticosteroid
preparation such as prednisolone acetate (usually 50 to 125 mg) or
methylprednisolone (80–​120 mg).
More severe flares of arthritis, pleuritis, or pericarditis require
oral prednisolone at a dose of 20 to 40 mg daily. This usually leads
to a rapid improvement in symptoms, and the dose of prednisolone
can then be reduced by 5 mg every 1 to 2 weeks until it reaches 5 mg/​
day. It may not be possible to withdraw the drug completely for
several months.
Alternatively, a shorter course of corticosteroids can be given
intravenously. A  typical course would consist of 500 to 750 mg
methylprednisolone given over 3 to 4 h on each of three successive
days. This requires admission to hospital, making it less convenient
than oral therapy, and it is generally reserved for those patients who
are not responding to oral prednisolone or cannot tolerate that drug
in high doses.
Autoimmune haemolytic anaemia requires higher doses
(60–​80 mg/​day) of oral prednisolone, with the dose reduced in 5-​ to
10-​mg increments according to the clinical response. Azathioprine
may be required as a steroid-​sparing agent and is used at a dose of
2.5 to 3 mg/​kg per day.
Renal flares of systemic lupus erythematosus require the most
aggressive treatment, generally involving both corticosteroids and
immunosuppressants. Several regimens have been used, with de-
bate continuing as to which is best. An ‘older’ regimen of high-​
dose oral prednisolone and 750 mg intravenous cyclophosphamide
monthly for six months, then three-​monthly for two years, has fallen
into disrepute. Although reasonably effective, its side effects (espe-
cially infection and infertility) have led to the use of alternative re-
gimens, including lower doses of intravenous cyclophosphamide
(around 500 mg) every two weeks for six doses, and the use of oral
mycophenolate mofetil (generally 2–​3 g/​day) instead of cyclophos-
phamide. Trial data suggest that mycophenolate is as effective as cyclo-
phosphamide and has fewer serious side effects. In renal systemic
lupus erythematosus it is critically important to control the patient’s
blood pressure. Angiotensin converting enzyme (ACE) inhibitors,
α-​adrenergic antagonists such as doxazosin, and calcium channel
blockers such as nifedipine are the agents most commonly used.
The treatment of CNS lupus varies depending on the manifest-
ation of cerebral dysfunction. Mild cases may respond to relatively
small doses of oral steroids (up to 30 mg/​day). More florid mani-
festations such as convulsions or major psychosis require treatment
with appropriate anticonvulsants or antipsychotic drugs, higher-​
dose oral steroids (60–​80 mg/​day), and sometimes azathioprine or
intravenous pulses of cyclophosphamide in similar doses to those
used in renal systemic lupus erythematosus.
Does the patient have drug side effects?
The side effects of corticosteroids are well known. The most common
early problems are weight gain, hirsutism, easy bruising, and in-
somnia. It is difficult to prevent them, except by using the lowest
dose of steroid that is effective and reducing it as rapidly as possible
while maintaining control of the disease.
Longer-​term sequelae of corticosteroid use include increased
susceptibility to infection, osteoporosis, avascular necrosis, and
Table 19.11.2.6  Treatment of lupus—​general measures
1  Rest as appropriate; try to avoid stress
2  Avoid overexposure to heat and sunlight. Use sun protection factor 15+
(30+ in United States) if in a sunny country; avoid exposing an arm on an
open car window
3  Try to adhere to a low-​fat diet and consider adding fish oil derivatives
4  ‘Live’ vaccines should not be given to patients on >10 mg prednisolone
per day and/​or immunosuppressants. Apart from that, vaccination for
foreign travel, and so on is not contraindicated, though the precise nature
of the immune response differs from that in healthy individuals
5  Medium-​ or high-​oestrogen contraceptive pills should be avoided—​
progesterone only or the lowest possible oestrogen pill (or other
methods of contraception) are advised
6  The use of hormone replacement in the menopause remains
controversial. Many patients do tolerate it without flaring, but not all
7  Avoid smoking tobacco in order to improve skin disease and reduce risk
of cardiovascular disease and osteoporosis
19.11.2  Systemic lupus erythematosus and related disorders
4511
diabetes mellitus. The most rapid loss of bone in steroid-​induced
osteoporosis occurs within the first year of treatment, although
doses of 7.5 mg/​day or less of prednisolone are thought to have little
effect on bone. At higher doses, it may be advisable to carry out a
bone density scan and to give either calcium and vitamin D tablets
or a bisphosphonate (either etidronate or alendronate is commonly
used) as prophylaxis.
Cyclophosphamide causes alopecia, nausea, bladder toxicity, and
gonadal dysfunction that may lead to infertility. The problem of in-
fertility becomes more likely with increasing age, women over 30
given cyclophosphamide being at particular risk. Again, the best way
to prevent such problems is to use as small a cumulative dose of the
drug as is feasible. Bone marrow suppression may occur. During a
programme of cyclophosphamide pulses the white blood cell count
falls to a nadir 10 days after each pulse and should be measured at
that time to decide whether the next pulse can be given safely. Nausea
and vomiting during pulses may be so severe that antiemetics such
as metoclopramide or granisetron are necessary.
Azathioprine also causes bone marrow suppression and can
cause abnormalities of liver enzymes, which resolve once the drug
is withdrawn.
Mycophenolate is contraindicated in pregnancy so that starting
this agent may be inadvisable in young women aiming to conceive
in the next few years.
Biologic therapies
We are entering an exciting era in which improved understanding
of the causes of lupus is leading to newer therapeutic approaches.
In particular, drugs targeting B lymphocytes have been studied in
several trials. B-​cell depletion achieved by the anti-​CD20 chimaeric
reagent rituximab (1 g given on two occasions two weeks apart, or
in more severe cases using this with intravenous cyclophosphamide
750 mg twice and intravenous methylprednisolone 125–​250 mg
twice) gave very promising results in open studies, but formal phase
3 clinical trials showed no benefit of adding rituximab to standard-​
of-​care therapy. However, those trials had several design limitations
and rituximab is still widely used, especially in renal and haemato-
logical disease. The use of fully humanized anti-​CD20 monoclonal
antibodies is also being explored.
A monoclonal antibody (belimumab) directed against the B-​cell
activating factor BLyS does not deplete B cells but modulates their
activity. This drug was more effective compared to standard-​of-​care
treatment in large clinical trials in systemic lupus erythematosus
affecting the joints and skin. It has been approved for use in sys-
temic lupus erythematosus by regulatory agencies in Europe and
the United States. Further studies are ongoing. However, another
anti-​BLyS monoclonal, tabalimumab, although partially suc-
cessful in two major trials, is not being further developed. In con-
trast, atacicept which blocks two B-​cell activating factors BLyS and
APRIL, performed well in a flare prevention study and in an active
disease treatment study. Another anti-​B-​cell agent which blocks
CD22 (epratuzumab) was successful in an early study but not in a
phase 111 trial. Abatacept, which blocks the link between antigen
presenting cells and T cells, seems to be of modest benefit only. Trials
using two anti-​interferon drugs (sifalimumab and anifrolumab)
have produced encouraging early results. It is likely that the land-
scape of biologics for systemic lupus erythematosus will change con-
siderably over the next 10-​20 years
A recent open study of 50 patients described a new way of using
rituximab in patients with systemic lupus erythematosus. Newly
diagnosed patients with lupus nephritis were treated with rituximab
followed by mycophenolate, and without oral corticosteroids. The
aim was to control the disease rapidly to avoid the need for long-​
term corticosteroid therapy. Results were promising but a clinical
trial (Rituxilup) of this combination was stopped because of slow
recruitment and problems with obtaining the rituximab.
Systemic lupus erythematosus in pregnancy
Systemic lupus erythematosus itself does not usually reduce the
ability to conceive, although as described the drugs used to treat it,
notably cyclophosphamide, may induce infertility due to gonadal
failure. There is an increased risk of spontaneous abortion, particu-
larly in the presence of high-​titre APL antibodies. Pregnant mothers
with a high APL antibody level and a history of previous miscarriage
should be treated with daily heparin and aspirin until the birth of
the baby. As warfarin is potentially teratogenic, heparin may be used
from the second trimester until parturition.
Parents often ask whether their children are likely to inherit sys-
temic lupus erythematosus. Inheritance of the adult form of the dis-
ease is very rare (approximately 1% of all cases), although a transient
illness termed ‘neonatal lupus’ can occur. The characteristics of this
condition are rash, hepatitis, anaemia, and thrombocytopenia, which
usually resolve by 8 months after birth, and inflammation of the car-
diac conducting tissues that may lead to heart block in the fetus. The
cardiac problem may be diagnosed by ultrasound scans of the fetal
heart between 16 and 24 weeks’ gestation. Treatment of the mother
with 4 mg oral dexamethasone/​day may prevent progression from in-
complete to complete fetal heart block. If complete heart block occurs,
the neonate may require a cardiac pacemaker. Interestingly, children
born with neonatal lupus sometimes develop heart block later in life,
with one reported case of this problem occurring at the age of 35.
The presence of maternal anti-​Ro and anti-​La antibodies predicts
a higher risk of neonatal lupus. Where both are present the risk is
approximately 2 to 5%. It is believed that the antibodies cross the
placenta and bind to some component of the fetal cardiac tissue. Ro
itself is expressed on the surface of cardiac myocytes at some point
in fetal development and may be an important target for the anti-
bodies. This may be why the fetal heart, but never the mother’s heart,
is affected by anti-​Ro antibodies.
Although overall the risk of a flare during pregnancy is probably
no greater than at other times, systemic lupus erythematosus may
be exacerbated during the pregnancy. Corticosteroids may be used
in moderate doses without affecting the fetus, but higher doses (over
30 mg) given for long periods can potentially cause fetal adrenal sup-
pression. If lupus activity is such that these doses are required, the
risk to the fetus of not treating the disease adequately should out-
weigh any risk from the drug.
Cyclophosphamide, mycophenolate, and methotrexate are contra-
indicated in pregnancy, although there have been many successful
pregnancies in transplant recipients taking azathioprine without ob-
vious increased risk of adverse effect. Hydroxychloroquine and low
dose oral corticosteroids are safe.
It may be difficult to distinguish pre-​eclampsia from a flare of
renal lupus. Both can cause hypertension and proteinuria, but in
section 19  Rheumatological disorders
4512
pre-​eclampsia—​unlike systemic lupus erythematosus—​there are
rarely urinary casts and levels of anti-​dsDNA antibodies and comple-
ment are normal.
For further discussion of autoimmune rheumatic disorders in
pregnancy see Chapter 14.14.
Occupational and psychological aspects
of systemic lupus erythematosus
Systemic lupus erythematosus typically presents in young people, espe-
cially women. The onset of a chronic, essentially incurable condition at
a time of life when the patient is otherwise healthy and has many plans
and responsibilities is an unexpected and unwelcome burden. Many
concerns arise; in particular the outlook for fertility and the ability to
care for children are substantial worries. In those cases where the use
of high-​dose corticosteroids and immunosuppressive agents is essen-
tial, detailed explanations of the benefits and risks of these treatments
in both the short and the long term are necessary. Although a 10-​year
survival rate of 90% may appear reassuring, it is probably less so to a
25 year old who recognizes a 10% chance of dying by the age of 35.
In making the diagnosis of systemic lupus erythematosus, therefore,
the doctor must consider the effect of this condition on the overall life
of the patient as well as his or her individual organs. A sympathetic
understanding of the anxieties associated with the diagnosis is vital.
Prognosis
Mortality from systemic lupus erythematosus has fallen significantly
over the last half century. Whereas systemic lupus erythematosus
was reported to have a 50% 5-​year survival rate in the 1950s, 10-​year
survival rates rose to between 80 and 90% by the 1970s. Since then,
survival rates have improved a little, but deaths from renal failure
have become less common, while those from infection and cardio-
vascular disease have increased. Infection is generally associated
with immunosuppressive therapy, highlighting the need for better
and more accurately targeted methods of treating the underlying
immunological abnormalities in this disease.
Morbidity from systemic lupus can be considerable. From the less
serious, but troubling, severe fatigue to the necessity for renal dia-
lysis, many aspects of lupus result in it having a big effect on quality
of life. Analyses using the medical outcome survey, short form 36
(SF-​36) quality-​of-​life index have shown that patients with lupus
have impaired scores in every aspect of this index.
A  damage index for lupus, derived by the Systemic Lupus
International Collaborating Clinics group, has shown that within
10 years about two-​thirds of patients have acquired permanent prob-
lems. Furthermore, early acquisition of damage—​within 1 year of
diagnosis—​substantially increases the risk of mortality (fourfold)
within 10 years.
Controversial areas and future prospects
We do not yet have a cure for systemic lupus erythematosus, or even
a method of controlling the disease without the risk of significant
side effects. The main sources of controversy concern attempts to
develop new forms of treatment and to establish indices of disease
activity that can be used to measure the effects of these treatments.
Plasma exchange and intravenous immunoglobulin therapy have
been tried in systemic lupus erythematosus, particularly in renal
crises. Overall, the results do not suggest that either form of treat-
ment should be used routinely.
There are now many different murine models of systemic lupus
erythematosus. These differ in their clinical and serological charac-
teristics and each represents at best a partial approximation to the
human disease. This is important, because it is now possible to ad-
minister agents such as monoclonal anticytokine antibodies to these
mice and to assess the effect on the disease process, but how far such
studies can be used to predict which of these agents might be ef-
fective in humans remains unknown.
If new drugs or monoclonal antibodies are to be used in human
systemic lupus erythematosus, it is necessary, given that mortality
is now (thankfully) an uncommon end-​point, to have recognized
tools by which to judge the response to treatment. A combination
of a disease activity index, a damage index, a patient health percep-
tion index, a record of toxicity, and cost is required. Several global
score disease activity indices; for example, the Systemic Lupus
Erythematosus Disease Activity Index (SLEDAI) and the European
Community lupus activity measure (ECLAM) have been developed
and provide a ‘rough and ready’ guide to overall activity. A more
sophisticated approach based on the ‘physician’s intention to treat
principle’ has been derived by the British Isles Lupus Activity Group,
providing an ‘at a glance’ review of activity in eight different organs
or systems. A single damage index (the SLICC/​ACR damage index)
has been developed, which records a wide variety of potential per-
manent (present for at least six months) changes (e.g. avascular ne-
crosis, myocardial infarction) that can occur in patients with lupus
as part of the development of the disease. The medical outcome
survey SF-​36 provides a useful health perception index for patients
with lupus. Although not designed specifically for this condition, it
has been widely used in several ongoing drug trials, but it is likely
that a more specific lupus quality-​of-​life index will be more widely
used in future (three are being validated at present).
It is likely that the treatment of systemic lupus erythematosus in
10 years’ time will be different from that given now. Basic science re-
search is starting to identify the various strands of immune dysfunction
at the core of this disease. At the same time, drug development is pro-
viding agents that are capable of selectively targeting single cell types
or cytokines within the immune system. At least some of these agents
are likely to be relevant to the dysfunctional mechanisms in systemic
lupus erythematosus. In addition, clinicians are becoming more aware
that conditions such as atherosclerosis and osteoporosis are common
in patients with systemic lupus erythematosus. By increasing efforts
to detect and control these associated conditions, as well as seeking
to attack the underlying autoimmune disease, it should be possible to
improve the lives of patients with systemic lupus erythematosus, even
if a cure for the disease remains a distant prospect.
FURTHER READING
Arbuckle MR, et al. (2003). Development of autoantibodies before the
clinical onset of systemic lupus erythematosus. N Engl J Med, 349,
1526–​33.

19.11.3 Systemic sclerosis (scleroderma) 4513 Chri
19.11.3 Systemic sclerosis (scleroderma) 4513 Christopher P. Denton and Carol M. Black
19.11.3  Systemic sclerosis (scleroderma)
4513
Bentham J, Vyse TJ (2013). The development of genome-​wide associ-
ation studies and their application to complex diseases, including
lupus. Lupus, 22, 1205–​13.
Bosma A, et al. (2012). Lipid antigen-​presentation by CD1d(+) B cells
is essential for the maintenance of invariant natural killer T cells.
Immunity, 36, 477–​90.
Boumpas DT, et al. (1992). Controlled trial of methyl prednisolone
versus two regimens of pulse cyclophosphamide in severe lupus
nephritis. Lancet, 340, 741–​5.
Casciola-​Rosen LA, Anhalt G, Rosen A (1994). Autoantigens targeted
in systemic lupus erythematosus are clustered in two populations
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Cervera R, et al. (1993). Systemic lupus erythematosus—​clinical and
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Contreras G, et al. (2005). Sequential therapies for proliferative lupus
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Datta SK, et al. (2005). T-​helper cell intrinsic defects in lupus that break
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Ginzler EM, et  al. (2010). Non-​renal disease activity following
mycophenolate mofetil or intravenous cyclophosphamide as induc-
tion treatment for lupus nephritis: findings in a multi-​prospective
randomised open-​label parallel-​group clinical trial. Arthritis
Rheum, 62, 211–​21.
Hahn BH (2003). Systemic lupus erythematosus and accelerated ath-
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Hanly J, et al. (2010). Prospective analysis of neuropsychiatric events in
an international disease inception cohort of patients with systemic
lupus erythematosus. Ann Rheum Dis, 69, 529–​35.
Isenberg DA, et al. (2007). 50 years of anti-​dsDNA antibodies—​are we
approaching journey’s end? Rheumatology, 46, 1052–​6.
Kalaaji M, et al. (2007). Glomerular apoptotic nucleosomes are central
target structures for nephritogenic antibodies in human SLE neph-
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tides reveal a major autoepitope that primes pathogenic T and B cells
of lupus. J Immunol, 168, 2530–​7.
Koffler D, Schur PH, Kunkel HG (1967). Immunological studies con-
cerning the nephritis of systemic lupus erythematosus. J Exp Med,
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Lu TY, et al. (2009). A retrospective seven-​year analysis of the use of B
cell depletion therapy in systemic lupus erythematosus at University
College London Hospital: the first fifty patients. Arthritis Rheum,
61, 482–​7.
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farction and angina in women with systemic lupus erythematosus:
comparison with the Framingham study. Am J Epidemiol, 145,
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to-​severely active systemic lupus erythematosus. Arthritis Rheum,
62, 222–​33.
Navarra SV, et al. (2011). Efficacy and safety of belimumab in patients
with active systemic lupus erythematosus: a randomised, placebo-​
controlled phase 3 trial. Lancet, 377, 721–​31.
Petri M, et al. (2012). Derivation and validation of Systemic Lupus
International Collaborative Clinics classification criteria for
systemic lupus erythematosus. Arthritis and Rheumatism, 64,
2677–​86.
Rahman A (2004). Autoantibodies, lupus and the science of sabotage.
Rheumatology, 43, 1326–​36.
Rahman A, Isenberg DA (2008). Systemic lupus erythematosus. New
Engl J Med, 358, 929–​39.
Rees F, et al. (2016). The incidence and prevalence of systemic lupus
erythematosus in the UK, 1999–​2012. Ann Rheum Dis, 75, 136–​41.
Ruiz-​Irastorza G, et  al. (2007). A systematic review of secondary
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systemic lupus erythematosus. Arthritis Rheum, 25, 1271–​7.
19.11.3  Systemic sclerosis
(scleroderma)
Christopher P. Denton and Carol M. Black
ESSENTIALS
The scleroderma spectrum of disorders includes several diseases that
have Raynaud’s phenomenon or skin sclerosis in common, com-
prising (1) localized cutaneous scleroderma; (2) systemic sclerosis—​
the most important form of scleroderma—​limited cutaneous
systemic sclerosis, diffuse cutaneous systemic sclerosis, and overlap
syndromes (with features of another autoimmune rheumatic disease,
e.g. systemic lupus erythematosus); (3)  Raynaud’s phenomenon—​
autoimmune (with antinuclear or other systemic sclerosis-​associated
antibodies) or primary. These conditions affect women four times as
often as men, most often beginning in the fifth decade.
The cause of systemic sclerosis is not known: an attractive hypoth-
esis is that the disease represents a syndrome of dysfunctional con-
nective tissue repair with associated immunological, epithelial, and
vascular pathology, triggered by some environmental factor(s) in a
genetically and immunologically susceptible individual.
Most patients carry a hallmark autoantibody: three generally (although
not always) mutually exclusive reactivities are seen—​anticentromere;
antitopoisomerase-​1 (anti-​Scl 70); and anti-​RNA polymerase III.
Clinical features
Limited cutaneous systemic sclerosis—​formerly termed ‘CREST’
(calcinosis circumscripta, Raynaud’s, oesophagus, sclerodactyly, and
telangiectasia), this condition accounts for two-​thirds of cases of sys-
temic sclerosis. The onset of skin changes is gradual and often preceded
by several years of worsening Raynaud’s phenomenon; skin sclerosis is
limited to the face, neck, and hands distal to the wrists. Telangiectasia
and intracutaneous/​subcutaneous calcification are common. Signifi­
cant visceral disease is less frequent than in diffuse cutaneous systemic
sclerosis, affecting oesophagus (74%), lungs (pulmonary fibrosis 26%,
pulmonary hypertension 21%), kidneys (8%), and heart (9%).
Diffuse cutaneous systemic sclerosis—​patients typically present over
1–​3 years with widespread changes in skin texture, puffy oedema-
tous extremities, generalized pruritus, and profound constitutional
and inflammatory symptoms. Vasospastic symptoms are not usu-
ally prominent during the early stages. Presentation with headache,
section 19  Rheumatological disorders
4514
blurring of vision, and significant hypertension is a medical emer-
gency, portending scleroderma renal crisis and requiring immediate
action. Significant visceral disease is common, affecting oesophagus
(60% of cases), lungs (pulmonary fibrosis 41%, pulmonary hyperten-
sion 17%), kidneys (18%), and heart (12%).
Management
Immunosuppressive and other treatments—​broad spectrum immuno-
suppression remains the current mainstay of treatment for diffuse
cutaneous systemic sclerosis. The most commonly used agents
are methotrexate (particularly for skin manifestations), cyclophos-
phamide (for which there is strongest evidence of efficacy) and
mycophenolate mofetil. Intensive immunosuppression combined
with autologous stem cell rescue has been performed.
Gastrointestinal symptoms—​most patients with systemic sclerosis
have at least one gastrointestinal manifestation, usually oesophageal
dysmotility and associated reflux oesophagitis that often responds
dramatically to treatment with proton pump inhibitors.
Raynaud’s phenomenon and digital vasculopathy—​treatment ranges
from simple measures (e.g. hand warmers) to simple vasodilators
(e.g. calcium channel blockers) to advanced vascular therapy (e.g.
prostacyclin analogues, phosphodiesterase inhibitors, endothelin re-
ceptor antagonists).
Prognosis and complications
The most frequent cause of death related to systemic sclerosis is pul-
monary disease, either interstitial fibrosis or pulmonary vascular disease.
Fibrosing alveolitis—​all patients with systemic sclerosis should be
screened for lung fibrosis, but not all patients with abnormalities on
high-​resolution computed tomography will develop significant or
progressive disease. For those that do, treatment is with corticoster-
oids or cyclophosphamide.
Pulmonary arterial hypertension—​regular screening for this compli-
cation is an important aspect of management. Treatment is with pros-
tacyclin analogues, phosphodiesterase inhibitors, and endothelin
receptor antagonists, singly or in combination.
Scleroderma renal crisis—​this may be the first manifestation of sys-
temic sclerosis and typically presents with accelerated phase hyper-
tension, acute kidney injury, and microangiopathic haemolysis.
Treatment is with angiotensin-​converting enzyme inhibitors, which
have reduced mortality from over 75% to around 15%.
Prognosis—​survival in systemic sclerosis has improved to more than
80% at five years, even in the diffuse cutaneous subset. The thera-
peutic nihilism that was once prevalent is no longer appropriate—​the
disease should be regarded as often treatable, if not curable.
Introduction
Systemic sclerosis (SSc) is an autoimmune rheumatic disease
falling within the scleroderma spectrum of disorders that includes
several diseases with similar clinical and pathological features, and
which have Raynaud’s phenomenon or skin sclerosis in common.
Among these conditions systemic sclerosis is especially important
due to a high clinical burden, unmet need for treatment, and high
mortality due to severe internal organ manifestations. A  hall-
mark of systemic sclerosis is clinical heterogeneity that adds to
the challenge of diagnosis and also requires an individualized ap-
proach to management that takes into account the stage and clin-
ical subset. Updated classification criteria were developed in 2013
and represent a major advance compared to previous classification
approaches (Table 19.11.3.1).
Those disorders included within the scleroderma spectrum are
described in Table 19.11.3.2. The term ‘prescleroderma’ can be
applied to the subgroup of patients with autoimmune Raynaud’s
phenomenon who manifest an abnormal microcirculation and
scleroderma hallmark autoantibodies (anti-​centromere anti-
bodies, anti-​topoisomerase, or anti-​RNA polymerase III). Recent
efforts to identify those cases that are developing systemic scler-
osis have led to establishment of VEDOSS criteria (Very Early
Diagnosis of Systemic Sclerosis) shown in Box 19.11.3.1. It is im-
portant to make a clear distinction between systemic sclerosis and
of the localized scleroderma conditions that are summarized in
Table 19.11.3.3. The importance of distinguishing between these
conditions and their subsets lies in the different clinical features,
natural history, and patterns of visceral involvement that are char-
acteristic of each subgroup. Localized scleroderma is especially
important when it develops in childhood due to associated im-
pact on regional skeletal and soft tissue growth but all forms of
Table 19.11.3.1  The 2013 ACR/​EULAR criteria for the classification
of systemic sclerosis
Item
Subitem(s)
Weight/​scorea
Skin thickening of the
fingers of both hands
extending proximal to
the metacarpophalangeal
joints (sufficient criterion)
–​
9
Skin thickening of the
fingers (only count the
higher score)
Puffy fingers
2
Sclerodactyly of the
fingers (distal to the
metacarpophalangeal joints
but proximal to the proximal
interphalangeal joints)
4
Fingertip lesions (only
count the higher score)
Digital tip ulcers
2
Fingertip pitting scars
3
Telangiectasia
–​
2
Abnormal nailfold
capillaries
–​
2
Pulmonary arterial
hypertension and/​or
interstitial lung disease
(maximum score is 2)
Pulmonary arterial
hypertension
2
Interstitial lung disease
2
Raynaud’s phenomenon
–​
3
Systemic sclerosis-​
related autoantibodies
(anticentromere, anti-​
topoisomerase I [anti-​Scl-​70],
anti-​RNA polymerase III)
(maximum score is 3)
Anti-​centromere
3
Anti-​topoisomerase I
Anti-​RNA polymerase III
a Patients with a total score of ≥9 are classified as having definite systemic sclerosis.
Arthritis Rheum. 2013;65:2737–​47
Ann Rheum Dis. 2013;72:1747–​55
Reprinted with permission fromHoogen F et al. (2013). 2013 Classification Criteria for
Systemic Sclerosis: An American College of Rheumatology/​European League Against
Rheumatism Collaborative Initiative. Arthritis Rheum, 65, 2737–​2747. Copyright © 2013
by the American College of Rheumatology.
19.11.3  Systemic sclerosis (scleroderma)
4515
localized disease may occur in adults (Fig. 19.11.3.1). Localized
forms of scleroderma are not associated with internal organ
complications or significant vascular manifestations although it
is now recognized that localized scleroderma may coexist with
systemic disease in some cases. There is no evidence that one
condition progresses to the other but there may be some shared
aetiopathogenic features.
There have been important developments in understanding the
pathogenesis, clinical diversity, and management of the sclero-
derma spectrum disorders over the last few years. This progress
has occurred in parallel with improvements in the management
of many of the organ-​based complications of the condition. Thus
outcomes have improved, including survival for the most severe
forms of the disease, and there is a growing evidence base to
support treatments for complications and manifestations such as
skin fibrosis and lung disease. Other areas remain very challen-
ging, but advances in clinical trial design as well as growing under-
standing of pathogenic pathways that will allow logical selection of
candidate therapies for evaluation.
Aetiology
Systemic sclerosis is an uncommon complex and heterogeneous
condition, suggesting that aetiology is multifactorial and that the
events or mechanisms leading to development of systemic scler-
osis occur infrequently. Although emerging studies confirm po-
tential genetic aspects to aetiology, these probably represent a
relatively small component of the disease. This is supported by the
low overall frequency of familial systemic sclerosis, and also the
fact that many of the genetic susceptibility factors seem to only
account for a small amount of risk and are shared with many other
autoimmune or rheumatic diseases. Thus, there is likely to be a
common genetic background, but other specific factors that de-
termine the triggering or progression of systemic sclerosis. Recent
genetic studies have identified possible factors that modify the
severity or pattern of systemic sclerosis, and these factors may
shed more light on specific disease mechanisms. Outside the im-
mune system there is much more variability in the genetic results
that suggests there is more redundancy and complexity governing
non​immune aspects of the disease.
Table 19.11.3.2  The scleroderma spectrum of disorders
Localized cutaneous scleroderma
Morphoea
Localized
One or more skin lesions, often on truncal areas
Generalized
Widespread skin lesions can be reminiscent of diffuse cutaneous systemic sclerosis, but Raynaud’s phenomenon is unusual, there
is no visceral manifestations, and skin changes are less likely to be acral
Linear scleroderma
The most common form occurring in childhood. Skin changes follow a dermatomal distribution, especially on the limbs and lead
to important secondary growth defects
En coup de sabre
Midline or parasagittal variant of linear scleroderma, which manifests in childhood and is often associated with defects in
underlying fascial and skeletal structures
Systemic sclerosis
Limited cutaneous systemic
sclerosis
Skin sclerosis distal to the wrists (or ankles), over the face and neck
Often longstanding Raynaud’s phenomenon
Diffuse cutaneous systemic
sclerosis
Truncal and acral skin involvement. Presence of tendon friction rubs. Onset of skin changes (puffy or hide-​bound) within 1 year
of onset of Raynaud’s phenomenon
Overlap syndromes
Features of systemic sclerosis together with those of at least one other autoimmune rheumatic disease (e.g. SLE, RA, or polymyositis)
Systemic sclerosis sine
scleroderma
Vascular or fibrotic visceral features without skin sclerosis (less than 1% cases)
Raynaud’s phenomenon
Raynaud’s phenomenon
with positive ANA
Raynaud’s phenomenon associated with antinuclear antibodies (or other systemic sclerosis-​associated autoimmune serology),
usually also abnormal nailfold capillaroscopy. Some patients later develop systemic sclerosis especially cases fulfilling VEDOSS
criteria (see textbox 1). Others remain undifferentiated and may be termed ‘autoimmune Raynaud’s phenomenon’
Primary Raynaud’s
phenomenon
Vasospastic symptoms with normal nailfold capillaroscopy and negative autoimmune serology and no other underlying
medical/​mechanical cause
Box 19.11.3.1  Proposed criteria for the diagnosis of Very Early
Systemic Sclerosis (VEDOSS)
Proposed by EULAR Scleroderma Trial & Research group (EUSTAR)
Definite diagnosis of very early systemic sclerosis will be achieved when at
least three major criteria are satisfied, or two major plus one additional
criteria are satisfied
Major criteria
Raynaud’s phenomenon, autoantibodies (ANA, ACA, Topo I, ARA), diag-
nostic nailfold videocapillaroscopy
Additional criteria
Calcinosis, puffy fingers, digital ulcers, dysfunction of the oesophageal
sphincter, teleangectasia, ground-​glass abnormalities on chest high-​
resolution computed tomography
Definition of terms
ANA—​antinuclear antibody
ACA—​anti-​centromere antibody
ATA—​anti-​topoisomerase-​1 antibody (Scl-​70)
ARA—​anti RNA polymerase III antibody
Diagnostic nailfold capillaroscopy means early or active scleroderma-​
pattern abnormalities
section 19  Rheumatological disorders
4516
Among the autoimmune rheumatic diseases, systemic scler-
osis is remarkable for the large number of environmental agents or
factors that are implicated in disease development. This includes
various chemicals, especially silica and organic solvents. Some of
the clinical syndromes associated with exposure may fall within the
scleroderma-​like category rather than typical systemic sclerosis, but
there are sufficient shared features with the commoner forms of sys-
temic sclerosis to make these factors highly relevant.
The concept of an environmental trigger in a genetically and im-
munologically susceptible individual is attractive. The timing and
frequency of systemic sclerosis developing in adulthood suggests
that several events occurring over time may be important, plaus-
ibly a burden of events that occurs over time. There has long been
suggestion that some cases may be associated with infection. It is
possible that common immunological stimuli are relevant and that
exposure to a triggering agent or event is only relevant in a par-
ticular context.
Recent studies of concurrence of systemic sclerosis and cancer has
renewed interest in tumour antigen expression, immune-​editing,
and cross-​reactivity between mutant and wildtype protein antigens
as relevant to aetiology of systemic sclerosis, especially some cases
occurring in the context of specific autoantibody reactivity such
as anti-​RNA polymerase III. An attractive framework for systemic
sclerosis is that the disease represents a syndrome of dysfunctional
connective tissue repair with associated immunological, epithelial,
and vascular pathology. This would be consistent with many of the
descriptive mechanisms that operate and also explain pathological
similarities with other fibrotic processes in the skin (keloids) and
internal organs. Taking this further it might be considered that sys-
temic sclerosis is an almost inevitable consequence of having a func-
tional tissue repair mechanism, and that natural variability in this
process might have some selective advantage that leads it to persist
within the population.
Current models suggest that initiating events involve changes in
the vasculature and immune system, with subsequent interplay of
vascular, inflammatory, and fibrotic processes. It has been suggested
that stimulatory autoantibodies against platelet-​derived growth
factor, which can activate collagen expression in fibroblasts, may
be an important link between the immune system and fibrosis, but
this is not certain. These are among other potentially important me-
diators of intercellular cross-​talk that have been identified, which
(hopefully) will ultimately suggest logical target factors or signalling
pathways for therapeutic intervention. The culmination of these
processes eventually leads to the establishment of a fibrogenic popu-
lation of interstitial fibroblasts that produce increased amounts of
extracellular matrix. Disruption of normal tissue architecture and
Table 19.11.3.3  Localized scleroderma in adults and children
Pattern of
disease
Clinical features
Treatment
Prognosis
Plaque
morphoea
One or a few circumscribed sclerotic
plaques with hypo or hyperpigmentation
and an inflamed violaceous border
Often unnecessary. Topical steroids or
immunosuppression (e.g. tacrolimus) or
phototherapy (PUVA, UVA1) may be considered.
Severe or multiple plaques may require systemic
corticosteroids and methotrexate or other
immunosuppressive therapy.
Serial measurement to assess progress
Good prognosis; lesions less active
within 3 years but pigmentary changes
often persist
Generalized
morphoea
Widespread pruritic lesions, often
symmetrical and following the distribution
of superficial veins
Suppress inflammatory component using
corticosteroids: in children oral doses up to
15 mg/​day have been used. Intravenous infusions
often effective
Methotrexate or other immunosuppressive
maintenance therapy often used, although
benefit not proven in controlled trials. Vitamin
D-​containing creams may be useful
Topical corticosteroids rarely helpful. PUVA and
UVA1 has been used
Internal organ pathology very rare;
Raynaud’s phenomenon sometimes
associated and antinuclear antibody
present in 5% of cases. This does not
necessarily imply systemic pathology
Generally improves within five years
of onset, although textural and
pigmentary changes may persist
Linear
morphoea
Sclerotic areas occurring in a linear
distribution often on limbs and
asymmetrical; in childhood can lead to
growth defect. MRI confirms the depth
of lesions and associated musculoskeletal
defects. Serial measurements of limb
length and girth essential to monitor
progression
Suppress inflammatory component using
corticosteroids: in children oral doses up to
15 mg/​day have been used. Intravenous infusions
often effective
Methotrexate or other immunosuppressive
maintenance therapy often used, although
benefit not proven in controlled trials. Vitamin
D-​containing creams may be useful
Physiotherapy and appropriate regular exercise
important to minimize growth defect in
childhood-​onset disease
Surgical correction of limb defects may be
considered when disease is inactive
Long-​term effects of childhood-​onset
form are minimized by effective
suppression of the inflammatory
process and by good physiotherapy
Ultimately the disease tends to resolve,
but it can remain active for many years
En coup de
sabre
Linear scleroderma affecting the face
or scalp, often involving the underlying
subcutaneous tissues, muscles,
periosteum, and bone. Cerebral
abnormalities also reported including
intracranial calcification
Therapeutic options as for linear scleroderma;
systemic treatment only for active inflammatory
lesions
Scarring, growth defects, and
alopecia persist but the inflammatory
component usually resolves
19.11.3  Systemic sclerosis (scleroderma)
4517
secondary mechanisms such as ischaemia produce the pathological
and clinical features.
Epidemiology
Systemic sclerosis is a sporadic disease that has a worldwide distribu-
tion and occurs in every ethnic group. No seasonal or geographical
clustering of cases has been convincingly documented. The epidemi-
ology of systemic sclerosis has proven difficult to establish, reflecting
the clinical diversity of the disease, absence of widely accepted cri-
teria for diagnosis or classification, and the methodological chal-
lenges associated with population-​based case ascertainment. In the
United Kingdom there are approximately 300 new cases of systemic
sclerosis per year and the population prevalence has been estimated
to be 100 per million. Both these figures are significantly lower than
estimates of disease frequency in the United States of America.
Recent epidemiological survival analyses of patients with sys-
temic sclerosis suggest a reduction in mortality compared with
earlier studies, but this may partly be accounted for by the greater
awareness of milder forms of the disease. The disease most often de-
velops in the fifth decade of life, and affects women approximately
four times as often as men, with this ratio increasing during the
child-​bearing years. Appreciation that some cases of systemic scler-
osis may develop after a long preceding occurrence of Raynaud’s
phenomenon or other relevant clinical features makes definition of
the incidence challenging. systemic sclerosis is an uncommon dis-
ease that falls within the designation of an orphan disease for the
purposes of drug development and regulation.
Familial cases of systemic sclerosis are well recognized but rare,
and the only twin study did not show greater concordance in mono-
zygotic (MZ) twins suggesting that although genetic factors are
relevant to the disease they are not necessarily very specific. This
is consistent with the studies of genetic susceptibility loci that have
Fig. 19.11.3.1  Variants of localized scleroderma: (a) limited forms of morphoea (plaque type); (b) linear
forms of morphoea (linear type, en coup de sabre, Parry–​Romberg syndrome); (c) generalized forms of
morphoea (generalized disabling form of morphoea).
Reproduced from Watts RA et al. (eds) (2013). Oxford Textbook of Rheumatology, 4th edn, by permission of Oxford
University Press.
section 19  Rheumatological disorders
4518
mainly found alleles that are also implicated in development of other
autoimmune diseases. High frequency of systemic sclerosis in some
isolated populations such as the Oklahoma Choctaw Indians is not-
able, although the number of affected cases is relatively few and dili-
gent attempts to define genetic factors have been challenging.
Clear environmentally triggered systemic sclerosis cases are of
interest and may explain some of the rare clusters that have occurred.
There may be overlap with occupational cases of systemic sclerosis
and scleroderma-​like condition including toxic oil syndrome and
vinyl chloride disease. The recent description of nephrogenic sys-
temic fibrosis is interesting as it is associated with use of linear gado-
linium contrast agents in patients with renal impairment. It may be
that the gadolinium is retained in these cases and leads to dissemin-
ated vascular injury or extravasation of profibrotic cells. The lesions
developed in nephrogenic systemic fibrosis have some biochemical
features of systemic sclerosis, but clinically the syndrome is more
similar to a diffuse fasciitis than systemic sclerosis. The condition
has become less common since triggering contrast reagents were
identified and their use limited, especially in patients with signifi-
cant renal impairment.
Pathogenesis/​Pathology
Pathogenesis of systemic sclerosis involves the interplay between dif-
ferent cell types, as summarized in Fig. 19.11.3.2. Many molecular
intermediates have been shown to be expressed or function in an
altered way in systemic sclerosis. Interaction between the immune,
vascular, and mesenchymal compartments is central to the devel-
opment of typical systemic sclerosis lesions, but there are also hall-
mark changes in specialized epithelial and other structures in skin
and affected organs that may be highly relevant. A plausible model
of pathogenesis is that there is defective connective tissue repair in
response to injury.
Perturbed cellular interactions in pathogenesis systemic sclerosis
KEY
Cytokines/growth factors
e.g. ET-1, CCL2, CCL7, IL-6, IL13, IL-4
TGFβ, CTGF, PDGF, IFN, TNFα
Cell-matrix, integrin and
matricellular protein function (αvβ6
integrin, COMP, TSP1)
Functional auto-antibodies
modifying cytokine or cell signalling
Cytokine-matrix interaction and
activation–latent TGFβ, fibrillin-1
Early disease
Extracellular matrix excess
–fibrotic response to
inflammatory injury
epithelium
myofibroblast
Connective tissue
atrophy–defective
repair/regeneration
Late disease
Interstitial fibroblast
Extracellular matrix
IgG
Monocyte-
macrophage
B cell
T cell
microvascular
endothelial cell
fibrocyte
pericyte
NK cell
EPITHELIAL COMPARTMENT
Keratinocyes
Lung, kidney, and gut epithelium
Epithelial-mesenchymal transition
VASCULAR COMPARTMENT
Endothelial cells
Pericytes
Smooth muscle cells
CONNECTIVE TISSUE
COMPARTMENT
Fibroblasts and
myofibroblasts
IMMUNO-INFLAMMATORY COMPARTMENT
Innate and adaptive immune system
platelets
Fig. 19.11.3.2  Perturbed cellular interactions in pathogenesis of systemic sclerosis.
Currently the most compelling pathogenetic framework for systemic sclerosis is one of dysfunctional connective
tissue repair with altered interactions between vascular, immune, and mesenchymal cells leading to overproduction
of extracellular matrix and vascular injury. At later stages connective tissue atrophy and defective epithelial repair
may also be important. Genetic studies suggest that inherent abnormalities in immune function are important in
susceptibility to systemic sclerosis and a variety of environmental factors may trigger or amplify injury at early stages
of the disease. Altered cell-​matrix and cytokine-​matrix interaction may contribute to disease development. Some
candidate cytokines, growth factors, and other proteins implicated as mediators in pathogenesis are included in this
schematic. More detailed description is provided in the text.
19.11.3  Systemic sclerosis (scleroderma)
4519
The key issue of triggering and mechanisms of the injury have
just been discussed, but once the disease is established there is
multicompartmental abnormal cellular interaction. It is notable
that many of the features of systemic sclerosis are similar to those
occurring in normal tissue repair or regeneration, but that these
seem to occur without appropriate regulation. It is also now appreci-
ated that many of the key repair pathways represent reactivation or
recapitulation of pathways and processes involved in normal tissue
growth and development, hence lessons and mechanisms derived
from developmental biology have fuelled much of the recent growth
in understanding of systemic sclerosis cell and molecular pathology.
This is important as it provides key insights into possible pathways
and mediators that may be pivotal to the development of systemic
sclerosis and which might be targets for therapy that could tackle the
disease directly and be truly disease-​modifying.
Although traditionally viewed as a multiorgan fibrotic disease,
the pathology of systemic sclerosis is more diverse that simply an
excess of extracellular matrix. There are clear similarities in the
pathology of vascular damage occurring in multiple organ beds in
systemic sclerosis. Neointimal formation, medial thickening and
proliferation/​hypertrophy, and adventitial fibrosis, are all later fea-
tures of vasculopathy in the pulmonary, renal, and digital vascula-
ture. Similar features have been seen in other affected organ beds
including the gut, penile arteries, and coronary circulation. A key
question remains why different vascular beds are targeted and how
these organ-​based complications associate with other aspects of
the disease. Strong association with immunological aspects of sys-
temic sclerosis, especially hallmark antinuclear antibody (ANA)
reactivity, suggest that immune or immunogenetic factors may be
fundamental.
At later stages of systemic sclerosis, connective tissue atrophy
and failure of epithelial repair become more prominent and there is
emerging evidence to support a model of abnormal differentiation
of progenitor cells that would normally be involved in connective
tissue repair. Thus adipocyte progenitors appear to be defective
and may differentiate preferentially into myofibroblasts that con-
tribute to fibrosis, rather than into adipocytes that can regenerate
appropriate subcutaneous tissue, and also contribute to the hallmark
of calcinosis cutis that occurs mostly at sites of ongoing tissue is-
chaemia or damage, but is usually a feature of later stage disease.
Calcinosis represents a forms of dystrophic calcification that may
derive from abnormal progenitor cell differentiation and the in-
appropriate deposition, synthesis, or mineralization of bone matrix.
Clinical features
The clinical features of systemic sclerosis include some that are al-
most universally present at the time of diagnosis, such as Raynaud’s
phenomenon, gastro-​oesophageal reflux, dysphagia and skin changes
affecting the extremities, and others that develop later or are present
only in certain stages or subgroups of patients. It is important to con-
sider the clinical features in the context of the stage and duration of
disease, and with regard to the clinical subsets outlined next.
Classification and diagnosis
Having robust and relevant classification criteria for systemic
sclerosis underpins clinical research and also facilitates diagnosis.
Although not designed for diagnosis, classification criteria are rele-
vant and are generally used for this purpose with the proviso that
they have been developed for specificity rather than sensitivity,
hence failure to fulfil criteria does not preclude diagnosis. This is of
practical importance in healthcare systems where fulfilment of clas-
sification criteria is required for access to therapy. However, the 2013
ACR/​EULAR criteria were a major step forwards and were devel-
oped using robust methodology. They replaced the 1980 preliminary
criteria that had never been fully validated. A major problem with
these earlier criteria was lack of sensitivity, especially for limited cu-
taneous systemic sclerosis. The new criteria incorporate many more
relevant features and were developed specifically to allow a points-​
based system for classification of definite disease (Table 19.11.3.1).
Systemic sclerosis is divided into clinical subsets that are helpful
in management as they highlight the distinct patterns of disease.
A traditional subgrouping based upon the extent of skin sclerosis
defines limited and diffuse cutaneous systemic sclerosis subsets, and
in theory all cases can be allocated to one of these subsets. However,
there are other cases that have no skin involvement and these are
designated systemic sclerosis sine scleroderma. The definition of
these cases is more challenging and they may include patients that
might also be labelled as pre-​scleroderma as just discussed.
Although the two major subsets are defined by skin extent, there
are other hallmarks that differentiate them. The systemic sclerosis-​
specific antinuclear antibodyreactivities provide additional informa-
tion that can be used for subsetting, especially as they cross the two
skin-​based categories. Modern molecular classification approaches
are also emerging. Intrinsic skin phenotypes are being defined based
upon clusters of genes analysed by microarray or nano-​string plat-
forms, and these provide additional information that may eventually
also aid management or help with treatment choice. All of these ap-
proaches lead to better risk stratification of systemic sclerosis so that
those at increased risk of specific complications or more likely to
benefit from specific treatment approaches can be identified earlier.
Clinical diagnosis and differential diagnosis
Although thorough baseline and longitudinal investigation of patients
with scleroderma spectrum disorders is central to their management,
the diagnosis of scleroderma is essentially clinical. Several other
causes of skin sclerosis or poor peripheral circulation must be con-
sidered in the differential diagnosis (summarized in Box 19.11.3.2).
Marked differences between the main subsets of systemic sclerosis in
the pattern and time course of clinical features allow most patients to
be characterized into the appropriate subset.
Patients with diffuse, cutaneous systemic sclerosis typically pre-
sent over 1 to 3  years with widespread changes in skin texture,
puffy oedematous extremities, generalized pruritis, and profound
constitutional and inflammatory symptoms. Vasospastic symp-
toms are not usually prominent during the early stages, although
within 18 months of their onset most patients will describe definite
Raynaud’s phenomenon.
By contrast, the cutaneous and vasospastic symptoms of limited
cutaneous systemic sclerosis are very different. The onset of skin
changes is more gradual, often preceded by several years of Raynaud’s
phenomenon, often becoming progressively more severe, with skin
sclerosis limited to the face, neck, and hands distal to the wrists. The
main differences between the subsets of systemic sclerosis are sum-
marized in Table 19.11.3.4.
section 19  Rheumatological disorders
4520
Limited cutaneous systemic sclerosis
This was formerly termed ‘CREST’ (calcinosis circumscripta, Raynaud’s,
oesophagus, sclerodactyly, and telangiectasia) and is the most common
form of systemic sclerosis, accounting for over 60% of cases. Patients
are usually women, aged between 30 and 50 years, with longstanding
Raynaud’s phenomenon. Early in the disease there is non​pitting oe-
dema of the fingers (sausage-​shaped fingers), which—​after several
weeks or months—​is gradually replaced by thickened and shiny skin.
This is not usually so closely adherent to underlying structures that
mobility is severely impaired, which is in sharp contrast to the find-
ings in those with diffuse disease. Skin involvement does not spread
proximally on to the trunk, but the face should be examined carefully
for thin, tightly pursed lips, with furrowing and puckering of the sur-
rounding skin, and microstomia. The most striking cutaneous finding
is digital and facial telangiectasia caused by dilated capillary loops and
venules (Fig. 19.11.3.3). Other evidence of structural vascular change
is to be seen in the fingertips, where small areas of ischaemic necrosis
or ulceration are common, often leaving pitting scars and pulp atrophy.
Loss of the tufts of the terminal phalanges, confirmed on radiography,
is also presumed to be due to ischaemia. Patients with limited cuta-
neous disease often develop intracutaneous and subcutaneous calcifi-
cation. These deposits frequently occur in the fingers, particularly the
digital pads, and in periarticular tissues such as the prepatellar area
and olecranon bursa. The calcinotic masses vary in size and are often
complicated by ulceration of the overlying skin, extrusion of calcific
material, and secondary bacterial infection. Patients may complain of
dyspepsia from reflux oesophagitis: this and other visceral complica-
tions are discussed in detail next.
Diffuse cutaneous systemic sclerosis
By contrast to limited cutaneous systemic sclerosis, the onset of
diffuse disease is often abrupt. It may present with widespread,
Box 19.11.3.2  Differential diagnosis of scleroderma
Skin sclerosis
Infiltrative disorders
•	 Amyloidosis
•	 Scleromyxoedema
•	 Scleroderma of Buschke
•	 Lichen sclerosis et atrophicus
Metabolic disorders
•	 Myxoedema
•	 Porphyria cutanea tarda
•	 Congenital porphyrias
•	 Acromegaly
•	 Phenylketonuria
Inflammatory disorders
•	 Overlap connective tissue diseases
•	 Eosinophilic fasciitis
•	 Chronic graft-​vs-​host disease
•	 Sarcoidosis
Acral vasospasm
Raynaud’s phenomenon
•	 Primary Raynaud’s phenomenon
•	 Other autoimmune rheumatic disorders:
—	Systemic lupus erythematosus
—	Rheumatoid disease
—	Dermato-​/​polymyositis
Other vascular disease
•	 Haematological  :
—	Cryoglobulinaemia
—	Cold-​agglutinin disease
—	Hyperviscosity syndrome
•	 Systemic vasculitis
•	 Macrovascular disease
Table 19.11.3.4  Contrasting clinical features of the major subsets of systemic sclerosis (SSc)
Diffuse cutaneous SSc (dcSSc)
Limited cutaneous SSc (lcSSc)
33% of patients
Inflammatory features more prominent at onset
Raynaud’s phenomenon may develop later
Skin sclerosis proximal to wrists/​elbows and truncal areas
Prominent pruritus and constitutional symptoms
Tendon friction rubs associated with progressive disease
Significant visceral disease more frequent than in lcSSc: renal, pulmonary fibrosis,
pulmonary hypertension, cardiac, gut
Disease activity appears to be maximal in the first three years from onset, then
often plateaus, and skin involvement may stabilize or improve
66% of patients
Longstanding Raynaud’s phenomenon
Skin changes: hands, face, neck
Compared with dcSSc, renal disease less frequent, pulmonary hypertension,
severe gut disease, and interstitial lung fibrosis (if antitopoisomerase-​1
present)
Florid telangiectasis and calcinosis (especially anticentromere antibody
positive)
Disease activity appears to remain fairly constant over many years, with
prominent vasculopathy
Prevalence of organ-​based complications in the main systemic sclerosis subsetsa
Clinical feature
lcSSc (%)
dcSSc (%)
Overall (%)
Raynaud’s phenomenon
99
98
99
Skeletal myopathy
11
23
15
Oesophageal
74
60
69
Other severe gastrointestinal
7
8
8
Cardiac
9
12
10
Pulmonary fibrosis
26
41
31
Pulmonary hypertension
21
17
20
Renal (overall)
8
18
12
Renal (crisis)
2
10
5
a Data from patients attending The Royal Free Hospital Centre for Rheumatology.
19.11.3  Systemic sclerosis (scleroderma)
4521
symmetrical, sometimes itchy, painful swelling of the fingers, arms,
feet, legs, and face. Rapid weight loss and constitutional symptoms
of fatigue or weakness are frequent. The clinical findings in diffuse
scleroderma depend on the stage of the disease. At onset, examin-
ation of the skin will usually reveal cold, painful, swollen hands, with
swelling and stiffness already extending to the arms, feet, lower legs,
face, and trunk. This oedematous phase is usually replaced within
a few months by one of induration, when the skin becomes tight,
shiny, and bound to underlying structures. Pigmentary changes
(hyperpigmentation or hypopigmentation) accompany skin thick-
ening in many patients.
Skin involvement in diffuse scleroderma is quite different from
that in the limited form of the disease, and can be mapped semi-​
quantitatively by measuring the degree and extent of cutaneous
thickening at multiple sites, from which is derived a skin score. In
diffuse scleroderma this score increases rapidly at first, often peaking
after one to three years, and is accompanied by impaired mobility
of tendons, joints, and muscles that is clinically all too apparent.
Contractures and stretching of the skin over bony points often lead
to painful ulcers that are slow to heal, particularly over the proximal
interphalangeal joints, elbows, and ankle malleoli.
In its earliest stages, diffuse scleroderma can be confused with an
acute inflammatory arthropathy, particularly if Raynaud’s phenom-
enon is absent. The oedematous puffy skin is often accompanied by
symmetrically stiff, painful joints (hands, feet, knees, ankles, and wrists),
but the classic synovitis of rheumatoid arthritis is usually absent. The
clinical sign of tendon friction rubs should carefully be sought in this
group of patients: these have a distinctive leathery crepitus and can be
elicited during joint movement over elbows, knees, fingers, wrists, and
ankles. They frequently antedate a rapid increase in cutaneous involve-
ment, or the onset of visceral disease. Signs of carpal tunnel syndrome
may be present, due to flexor tenosynovitis at the wrist.
Mild muscle disease is common and can be detected on exam-
ination, but is not usually accompanied by an increase in plasma
creatine kinase or inflammatory changes on muscle biopsy. It is gen-
erally non​progressive. The few patients with florid changes of poly-
myositis are usually classified as having an overlap syndrome.
As with limited disease, evidence of structural vascular damage—​
sometimes extensive—​may be found in the nailfold capillaries
(Fig. 19.11.3.4) and the digital pads.
Fig. 19.11.3.3  This patient shows the typical facial features of limited
cutaneous systemic sclerosis.
Microstomia, furrowing, and puckering of the skin around the mouth, beaking of
the nose, and telangiectasia on the lips and face.
Fig. 19.11.3.4  Nailfold capillaroscopy with early, active, and late patterns of systemic sclerosis.
Reproduced from Watts RA et al. (eds) (2013). Oxford Textbook of Rheumatology, 4th edn, by permission of Oxford University
Press. Courtesy of Dr Kevin Howell, RFH Microvascular Laboratory.
section 19  Rheumatological disorders
4522
Scleroderma sine scleroderma
These patients constitute less than 2% of those with systemic scler-
osis, but they are the most difficult group to recognize. They may or
may not have Raynaud’s phenomenon, but by definition they never
have the skin changes of scleroderma; common presenting problems
include oesophagitis, malabsorption, pseudo-​obstruction, renal
failure, cardiac arrhythmias, and interstitial lung disease.
Overlap syndromes
There are patients whose disease is not easy to define: around one-​
fifth of cases of systemic sclerosis have significant overlap features,
most often myositis or arthritis. They may well fulfil criteria for
rheumatoid arthritis or idiopathic inflammatory myopathy as well
as systemic sclerosis. It should be noted that the 2013 EULAR-​ACR
criteria for classification of systemic sclerosis do not preclude the
presence of more than one diagnosis, although the clinical diagnosis
rather than classification criteria should be used in designating
overlap, and if there are no features of systemic sclerosis then an al-
ternative diagnosis should be used. Cases that have some features
of systemic sclerosis or other autoimmune rheumatic diseases but
which do not fulfil the criteria for a defined disease are best termed
undifferentiated connective tissue disease.
Investigation
Autoimmune serology
Most patients with scleroderma exhibit a hallmark autoanti-
body, and almost all have antinuclear reactivity, often with an
antinucleolar pattern on Hep2 cells. Three generally (although not
always) mutually exclusive reactivities are seen: anticentromere,
antitopoisomerase-​1 (anti-​Scl 70), and anti-​RNA polymerase III.
Rarer specificities include fibrillarin (U3RNP), PM-​Scl, and anti-​
Th/​To. Each serologically defined group shows somewhat different
clinical features, which is of some value in risk stratification for
management. There are also well-​established class II major histo-
compatibility complex (MHC) associations with the various auto-
antibodies, although some differences in association occur in
different racial groups. Clinical and immunogenetic associations
of systemic sclerosis hallmark antinuclear antibodyreactivities are
shown in Table 19.11.3.5.
Some studies that suggest that autoantibodies directed
against vascular structures and antigens may be present, and
that reactivities against cell surface receptors may be relevant
to pathogenesis. Less specific serological abnormalities are also
found in scleroderma, including hypergammaglobulinaemia,
the presence of immune complexes, low concentrations of com-
plement components, and a weakly positive rheumatoid factor.
Antibodies to SSA/​Ro and SSB/​La are found in 50% of patients
with scleroderma who also have Sjögren’s syndrome, and are
nearly always found in those with glandular lymphocytic infiltra-
tion rather than fibrosis.
Management—​general approach
Disease management starts with diagnosis and classification: when
faced with a patient with a scleroderma spectrum disorder the
first consideration is to determine whether they have features of
localized disease or systemic sclerosis. The simplest discrimin-
ators are the presence of vascular symptoms, including Raynaud’s
phenomenon, and internal organ manifestations, of which the
earliest is often reflux oesophagitis or dysphagia, but unfortunately
both Raynaud’s phenomenon and gastro-​oesophageal reflux are
common in otherwise healthy individuals (Fig. 19.11.3.5).
Table 19.11.3.5  Clinical and immunogenetic associations of systemic sclerosis hallmark antinuclear antibodyreactivities
Target antigen
Frequency (%)
Staining pattern
Clinical association
Genetic association
Centromere (ACA)
15–​40
Kinetochore
lcSSc, PAH
HLA-​DQB1
TNF-​863A
GRB10
NOTCH4
Topoisomerase-​1 (Scl70)
10–​40
Speckled
dcSSc, lung fibrosis
HLA-​DPA1/​B1
HLA-​DPB2
HLA-​DRB1
RNA polymerase III (ARA)
4–​25
Fine speckled/​nucleolar
dcSSc, Renal crisis, malignancy, PAH
HLA-​DRB1
HLA-​DRB3
HLA-​DRB4
HLA-​DQB4
EDNRA
Fibrillarin (U3RNP)
1–​5
Nucleolar/​coilin
PAH, cardiac, myositis
HLA-​DQB1
Pm-​Scl
3–​6
Nucleolar
Myositis overlap
None reported
U1RNP
5–​35
Speckled
Overlap features
HLA-​DRB1
HLA-​DPB1
Th-​To
1–​7
Nucleolar
lcSSc, PAH, lung fibrosis
None reported
U11/​U12
1–​5
Nucleolar
Lung fibrosis
None reported
dcSSc, diffuse cutaneous systemic sclerosis; lcSSc, limited cutaneous systemic sclerosis; PAH, pulmonary arterial hypertension; RNP, ribonucleoprotein; SLE, systemic lupus
erythematosus. Other rarer antinuclear antibodyreactivities have been described that may also associate with specific complications although the frequency of these reactivities is less
than more established patterns.
19.11.3  Systemic sclerosis (scleroderma)
4523
The pattern and distribution of skin involvement provide crit-
ical information about subset and classification: asymmetrical in-
volvement and acral sparing are typical of localized scleroderma,
whereas acral involvement is almost universal in systemic forms. Of
the available laboratory investigations, autoantibody testing is per-
haps the most useful, and provides additional information about
likely subset and possible organ-​based disease in systemic sclerosis.
An additional clinical investigation that helps to discriminate pri-
mary Raynaud’s phenomenon from early connective tissue disease
is nailfold capillaroscopy. There are classic morphological changes
in systemic sclerosis, including capillary drop-​out and dilatation,
whereas capillaroscopy is usually entirely normal in cases of local-
ized scleroderma.
The underlying pathogenesis of systemic sclerosis involves inter-
play between immune dysfunction, vasculopathy, and fibrosis, as
just discussed, and it is likely that effective disease modification de-
pends upon management of these facets. However, there is interplay
between the pathologies and so treatment of one aspect of the dis-
ease is likely to affect other processes, hence immunomodulatory
approaches appear to have benefits for fibrosis in skin and lung, and
there is evidence that immune mediated mechanisms may be im-
portant in some aspects of vasculopathy.
Broad spectrum immunosuppression remains the current main-
stay of treatment for diffuse systemic sclerosis: currently used strat-
egies are summarized in Table 19.11.3.6. In general, all patients
with active dcSSc should be considered for immunosuppressive
treatment, with the modality and intensity of treatment dictated by
assessment of disease severity or activity. Evidence from placebo-​
controlled clinical trials supports efficacy of methotrexate for skin,
although this was modest. Data regarding mycophenolate mofetil
come from observational cohort studies or small trials, but the most
robust evidence base is for cyclophosphamide. The SLS-​I study was
placebo controlled and showed statistical benefit for lung function
and several key secondary end points, including skin sclerosis, in
dcSSc subjects. The treatment effect persisted to 18 months for lung
function, but then diminished, suggesting longer-​term immunosup-
pression is needed. The FAST study in United Kingdom suggested
comparable treatments effect for intravenous cyclophosphamide,
but was substantially smaller.
In general, patients with overlap myositis or arthritis and
without major lung fibrosis are started on methotrexate, whereas
mycophenolate mofetil is used first line if skin or lung fibrosis are the
main manifestations requiring treatment. Cyclophosphamide may
be considered for severe or clearly progressive lung fibrosis: treat-
ment is most often given monthly for 6  months and then oral
mycophenolate mofetil substituted for a minimum of two to three
years. However, some physicians favour longer term intravenous
cyclophosphamide and have reported favourable results over 12–​
18 months. The SLS-​II study compared oral cyclophosphamide over
12 months with mycophenolate mofetil given for 24 months, and
preliminary results seem to show mycophenolate mofetil treatment
effects are similar over the first six months, which may impact on use
of cyclophosphamide, although no formal comparison with paren-
teral cyclophosphamide has been made.
The potential value of more intensive immunosuppression with
autologous stem cell rescue has been explored in registries and more
robustly in controlled trials. The results of these studies suggest that
there may be long-​term benefit from autologous stem cell rescue,
but that needs to be balanced against early treatment related mor-
tality. In the Autologous Stem Cell Transplantation International
Scleroderma (ASTIS) study there was long-​term survival benefit in
the autologous stem cell rescue treated cases compared to those re-
ceiving 12 months of IV cyclophosphamide, but the advantage was
only seen after 2 years follow up post-​transplant due to up to 10%
early treatment related mortality. In addition, there is evidence that
some cases of systemic sclerosis are doing well with less intensive
regimens, hence the key challenge remains case selection for autolo-
gous stem cell rescue. Pathways to evaluate cases of poor prognosis
systemic sclerosis have been proposed, and it will be important to
take this potentially important treatment forwards in appropriate
cases. There is particular interest in less cardiotoxic conditioning
strategies that avoid very high doses of cyclophosphamide.
Management of organ-​based complications
Despite the usefulness of an accurate subset classification of patients
with systemic sclerosis, management requires that an organ-​based
approach be taken once the subset has been assigned. This ensures
that important complications, which occur with different frequen-
cies in the different subsets, are not missed.
Vascular manifestations
Raynaud’s phenomenon
Episodic acral vasospasm, precipitated by cold or emotional stress
(Raynaud’s phenomenon), is almost universally present in patients
with systemic sclerosis, although its prominence varies considerably
between cases. The pathogenic mechanism is uncertain, but prob-
ably represents an imbalance between vasoconstrictor and vaso-
dilator mechanisms in small blood vessels, or an exaggerated release
of vasoconstrictor mediators in response to physiological levels of
dcSSc
lcSSc
Manage according to
severity and activity
of overlap features–
arthritis, myositis,
lupus
Therapy–
Vascular
Identification and treatment of organ-based complications
Therapy-
Vascular
Immunosuppressive
(Antifibrotic)
SYSTEMIC
SCLEROSIS
Overlap SSc
Fig. 19.11.3.5  Overall management strategy for patients with
systemic sclerosis.
Once diagnoses all cases of systemic sclerosis should undergo baseline clinical
assessment for stage and subset determination. The presence of overlap features
should be sought and cases stratified for risk of specific complications. Early
diffuse systemic sclerosis or major organ-​based complications usually require
immunosuppressive therapy. All cases should have symptomatic treatment of
gastro-​oesophageal reflux, Raynaud’s phenomenon, and other complications.
section 19  Rheumatological disorders
4524
stimulation by cold or emotion. Raynaud’s phenomenon is common
in otherwise healthy individuals, with some series estimating its
prevalence to be up to 15% in women, with a much lower frequency
in men. It may precede the onset of systemic sclerosis, especially the
limited cutaneous subset, by many years, whereas in diffuse cuta-
neous systemic sclerosis it generally first becomes manifest around
the time of the onset of other features of the disorder, or afterwards.
Current approaches to the management of patients with Raynaud’s
phenomenon are summarized in Table 19.11.3.7.
Although Raynaud’s is a feature of many autoimmune rheumatic
diseases it is especially prominent in systemic sclerosis, when there
are more complications. This may reflect the associated structural
vasculopathy that leads to fixed vascular insufficiency. Treatment
follows the principles of other situations with lifestyle adjustments,
avoidance of precipitants, and use of vasodilator agents, which may
be used in combination, especially for agents working on different
pathways. Interestingly, some agents that are effective in organ-​
based vasculopathy such as endothelin receptor antagonists and
ACEi have not been shown to benefit Raynaud’s in clinical trials.
In contrast, PDE5 inhibitors have been helpful and can be con-
sidered in severe Raynaud’s, especially when complications of digital
ischaemia occur.
In practice, Raynaud’s is one component of a more significant
problem of ischaemic digital vasculopathy in systemic sclerosis,
which likely reflects multiple processes including vasospasm,
structural vascular damage, altered tissue repair and healing,
(probably) intravascular thrombosis, and (occasionally) vasculitis.
These problems lead to digital ulceration and also to critical is-
chaemia with complications such as gangrene, cellulitis, and osteo-
myelitis (Fig. 19.11.3.6). In the past autoamputation was common,
but more aggressive management has improved outcome in many
cases. A mixture of local management, treatment of Reynaud’s, and
Table 19.11.3.6  Management of Raynaud’s phenomenon and digital vasculopathy in systemic sclerosis
Treatment
Examples
Comments
Simple measures
Non​drug
Hand warmers
Protective clothing
Universally helpful; also useful to minimize cold exposure and ambient temperature changes in
work environment
Pharmacological
Evening primrose oil
Fish oil capsules
Antioxidant vitamins
Evening primrose oil has been shown to be effective in controlled clinical trials
Theoretical benefit due to increased synthesis of vasodilator prostanoids
Potentially reduces oxidant stress which may contribute to Raynaud’s phenomenon symptoms and
pathology
Simple prescription vasodilators
Calcium channel blockers
Nifedipine
Amlodipine
Diltiazem
Variable and differential response to different agents. Slow titration of dose reduced the severity of
side effects. Try each drug for at least 3 weeks if possible
Serotonin antagonists
Fluoxetine
Serotonin reuptake inhibitor: readily available. Fewer vasodilatory side effects than calcium channel
blockers. Depletes platelet 5HT levels
Angiotensin receptor blockers
Losartan
Well tolerated, potential remodelling by blocking fibrogenic effects of angiotensin II. ACEIs not
effective in RP (QUINS trial)
Topical vasodilators
Topical nitrates
Shown to be effective in short-​term use but systemic effects often cause headaches. New formulations
under evaluation
Advanced vascular therapy
Parenteral vasodilators
Prostacyclin
analogues
Effective at healing ulcers and reducing severity and frequency of Raynaud’s phenomenon attacks.
Expensive and limited long-​term duration of benefit. Most data for iloprost but epoprostenol and
other prostacyclin analogues also used
Phosphodiesterase inhibitors
Sildenafil, Tadalafil
Potentiate nitric oxide (NO) signalling by reducing breakdown of cGMP. Not co-​administered with
nitrates
Endothelin receptor antagonists
Bosentan
Used to reduce digital ulcer formation but no robust evidence of benefit for uncomplicated Raynaud’s
Other systemic therapy
Antibiotics
Flucloxacillin
Erythromycin
Teicoplanin
Important adjunct to vasodilator therapy for secondary infection of digital ulcers. Prolonged systemic
treatment necessitated by poor tissue perfusion especially for severe cellulitis or osteomyelitis
Pain control
Simple analgaesics
Opiods
neuromodulators
Careful management of pain related to infection, digital ulceration, or tissue ischaemia using
combinations of oral and transcutaneous agents. Neuromodulators (e.g. gabapentin) often helpful
for ischaemic pain
Surgical procedures
Lumbar sympathectomy
Radical microarteriolysis
Debridement, amputation
Chemical or surgical
Division of adventitia of digital arteries.
Sometimes termed digital sympathectomy
Surgical or autoamputation
For severe lower limb Raynaud’s phenomenon
Useful treatment for individual critically ischaemic digits
Surgery should be as conservative as possible to allow maximum
possibility of spontaneous healing
Botulinum toxin
Botox®
Local injection around digital arteries can improve digital blood flow
and relieve pain—​sometimes termed medical sympathectomy
5 HT, 5-​hydroxytryptamine (serotonin); ACEI, angiotensin converting enzyme inhibitor.
19.11.3  Systemic sclerosis (scleroderma)
4525
comorbidity seems important. There is increased interest in digital
ulceration as a therapeutic target, and licensed therapies and treat-
ment pathways have been established. In the United Kingdom an
approved policy is now in place that recommends sildenafil ini-
tially for digital ulceration, and then intravenous prostacyclin.
Bosentan is licensed for digital ulceration as a therapy that reduces
new ulcer formation, but has not been shown to increase healing
of established ulcers.
Macrovascular disease
There have been several reports that macrovascular disease is in-
creased in patients with systemic sclerosis, and there is evidence of
altered vessel biomechanical properties. However, although asso-
ciated macrovascular disease is important and should be explored
in any case where there are risk factors or clinical pointers such as
asymmetrical or sudden tissue ischaemia, it seems likely that the ex-
cess of macrovascular disease seen in other rheumatic diseases is
not a feature of systemic sclerosis, and this certainly seems the case
for ischaemic heart disease that has not been shown to be excessive
compared with non​systemic sclerosis cohorts.
Skin manifestations
Scleroderma means ‘hard skin’ and is the hallmark of the sclero-
derma spectrum disorders. The skin lesions of scleroderma differ
between diffuse and limited cutaneous subsets, not only by their
extent and distribution, but also by the greater tendency for there
to be induration and oedema of affected tissues in diffuse cutaneous
systemic sclerosis, which may reflect a local release of cytokines or
altered endothelial permeability. The inflammatory phase evolves
into established fibrosis, sometimes leading to sheets of thickened
skin or a hide-​bound texture.
The skin sclerosis score (skin score) is a validated method for as-
sessing the extent of skin involvement and has been shown to predict
survival and to correlate with some other disease features (e.g. a rap-
idly increasing skin score is associated with an increased occurrence
of scleroderma renal crisis). Although baseline skin score associates
with outcome in many systemic sclerosis clinical trials, the relation-
ship between skin extent and organ-​based complications is less clear.
The high frequency of severe pulmonary arterial hypertension in
cases of limited cutaneous systemic sclerosis exemplifies this. In dif-
fuse cutaneous systemic sclerosis many patients have their peak skin
score within 12–​18 months of disease onset (defined by first definite
non-​Raynaud’s phenomenon manifestation of systemic sclerosis),
thus by the time they obtain specialist help such patients are often
in a stable or improving phase of skin involvement, which has major
implications in trying to assess treatment response in the skin.
Pulmonary disease
Lung complications are important and frequent in systemic sclerosis
(Table 19.11.3.8).
Table 19.11.3.7  Respiratory tract complications of systemic sclerosis
Lung disease
Pathology
Frequency
Clinical features
Investigation
Treatment
Pulmonary fibrosis
Predilection for lung bases.
Inflammatory infiltrate
precedes development
of established fibrosis.
At biopsy most patients
show an NSIP histological
pattern
Significant fibrosis in
around 25% of SSc.
Strongly associated with
antitopoisomerase-​1
autoantibody. Occurs in
both major SSc subsets
Dry cough, exertional
dyspnoea, bibasal
crepitation. Finger
clubbing uncommon
Restrictive pattern of PFT
(low FVC and DlCO). HRCT
essential investigation.
DTPA clearance accelerated,
serum KL-​6 may be elevated.
Thoracoscopic lung biopsy
in atypical cases
Recent studies suggest
modest benefit from
immunosuppression with
cyclophosphamide or
azathioprine. Other agents
under evaluation
Pleural disease
Effusions and pleurisy
uncommon except in
overlap syndromes or
renal crisis
Rare
Chest pain, dyspnoea
Chest radiograph
NSAIDs or low-​dose
prednisolone
Pneumothorax
Rupture of cyst into
pleural cavity
Rare
Chest pain, dyspnoea
Chest radiograph
Intercostal drainage.
Expansion may be poor,
especially if lung fibrosis.
Pleuradesis
Bronchiectasis
Suppurative inflammation
of airways
Rare
Chronic productive
cough
CT scan
Antibiotics, postural
drainage
Lung carcinoma
Overall probably
increased risk, especially
scar type (alveolar cell)
Rare
Variable
Contiguous CT scan/​
bronchoscopy. Biopsy
Poor prognosis. Late
diagnosis often due
to associated lung
pathology. Chemotherapy
and radiotherapy may
aggravate SSc
Pulmonary
hypertension
Most often precapillary
(Group I) PAH (60%) but
also postcapillary (Group
II) with elevated PAWP),
or associated with lung
fibrosis (Group III). PVOD
and thromboembolic PH
also occur
10–​15% overall
Exertional
breathlessness, chest
pain, loud pulmonary
P2, syncope, right
heart failure
ECG, PFT (low DlCO
preserved FVC in
isolated PHT), Doppler
echocardiography to
estimate peak PAP. Nt-​pro
BNP, Right heart catheter
study essential for diagnosis
and classification
Manage according
to consensus
recommendations (Galiè
2009). Oral PAH specific
therapy or inhaled and
parenteral prostacyclin
analogues according to
clinical severity
BAL, bronchoalveolar lavage; DlCO; CO diffusion coefficient; DTPA, diethylenetriaminepentaacetic acid; FVC, forced vital capacity; HRCT, high-​resolution CT; NSAID, non​steroidal
anti-​inflammatory drug; NSIP, non​specific interstitial pneumonia; PAP, pulmonary artery pressure; PFT, pulmonary function test PHT, pulmonary hypertension SSc, systemic sclerosis;
PAWP—​pulmonary artery wedge pressure
section 19  Rheumatological disorders
4526
Fig. 19.11.3.6  Typical clinical features in the hands of patients with systemic sclerosis.
Reproduced from Watts RA et al. (eds) (2013). Oxford Textbook of Rheumatology, 4th edn, by permission of Oxford University Press.
Table 19.11.3.8  Investigation and management of cardiac manifestations of systemic sclerosis
Cardiac
complication
Pathology
Frequency (%)
Clinical features
Investigation
Treatment
Arrhythmias
Extrasystoles,
paroxysmal
tachyarrhythmias
30
Palpitations,
syncope
ECG (including 24-​h tape or
telemetry); exercise stress test
Treat if haemodynamically significant
Conduction
defects
Fibrosis of
conduction tissue
15
Syncope,
hypotension
ECG
Pacemaker may be required
Pericardial
involvement
Pericarditis
Pericardial effusion
10% clinically
35–​50% at
post-​mortem
examination
Usually
asymptomatic
Haemodynamic
effects rare
ECG, echocardiogram
Often none required
Occasionally pericardiocentesis if diastolic
collapse on Echo
NSAIDs for pericarditis
Myocardial
involvement
Myocarditis
Myocardial fibrosis
Rare
30–​50% dcSSc
Congestive cardiac
failure, arrhythmias
Congestive cardiac
failure
ECG, echocardiogram, stress
echocardiogram, cardiac
enzymes (CK-​MB), troponin
levels, Nt-​pro—​BNP,
MRI with gadolinium, CT
angiogram, MUGA, or other
nuclear medicine studies
Left heart catheterization
Endomyocardial biopsy
Myocarditis treated with prednisolone.
And cyclophosphamide or other
immunosuppressive agent. Diastolic
heart failure managed with diuretics,
systolic heart failure with ACEIs, carvedilol,
β-blockers may be considered (care in
Raynaud’s). ICD considered if high risk of
ventricular tachyarrhythmia. Pacemakers for
bradyarrythmia and systolic heart failure
19.11.3  Systemic sclerosis (scleroderma)
4527
Parenchymal lung disease with fibrosis is very common, but not
always severe and progressive. The other most important com-
plication affecting the lung is pulmonary vascular disease, which
can lead to pulmonary hypertension. There appears to be a sus-
ceptibility phenotype for this complication, with 1–​2% of cases
developing pulmonary hypertension per annum under long-​term
follow up.
Recent progress in the assessment of pulmonary disease in pa-
tients with systemic sclerosis has refined diagnosis and classifica-
tion, and will almost certainly result in different treatment strategies
for particular subsets of patients.
Parenchymal lung disease
The most prevalent type of parenchymal lung disease is intersti-
tial lung fibrosis with a pattern typical of non​specific interstitial
pneumonia (NSIP) at biopsy or based upon the high-​resolution
computed tomography appearance (Fig. 19.11.3.7). A minority of
lung fibrosis cases show a pattern of usual interstitial pneumonia
(UIP). Other forms of interstitial lung disease may occur and
need to be considered in assessment and diagnosis. This is espe-
cially seen in patients with systemic sclerosis overlap syndromes
where the lung pathologies of associated conditions may occur.
These include organizing pneumonia associated with polymyo-
sitis or complications such as alveolitis, alveolar haemorrhage, or
alveolar proteinosis associated with other autoimmune rheumatic
diseases. Pulmonary interstitial fluid may be present, associated
with cardiac failure or hypertensive renal crisis, or features of
superadded infection. Pulmonary sarcoidosis occurs sometimes
in patients with systemic sclerosis and may need to be considered
in the differential diagnosis of parenchymal lung disease in this
condition.
Although all patients with systemic sclerosis should be screened
for lung fibrosis, it appears to affect only around 25% of those with
limited cutaneous disease and up to 40% of those with the dif-
fuse cutaneous form. It is strongly predicted by the presence of
antitopoisomerase-​1 autoantibodies and by associated major histo-
compatibility complex genotypes. Other reactivities such as anti
U11/​U12, anti-​Th-​to and anti fibrillarin may also associated with
development of lung fibrosis although these associations have not
reached statistical significance in cohort studies. The presence of
anticentromere antibodies is associated with a reduced risk. These
tests are therefore of clinical value in planning the frequency and
intensity of lung screening tests.
While the overall frequency of lung fibrosis in systemic scler-
osis is high, not all patients with abnormalities on high-​resolution
computed tomography will develop significant or progressive
disease. The most widely used staging system recommends brief
initial assessment of the high-​resolution computed tomography
to determine whether there is trivial (less than 10% of the lung
affected) or severe (more than 40%) disease, and if indeterminate
then lung function tests with an forced vital capacity (FVC)
threshold of 70% predicted can be used to separate those cases
that on average have more or less than 20% of the lung affected
on formal high-​resolution computed tomography assessment.
This has proven very helpful. Cases of mild disease should have
rigorous follow up and any trend to deterioration or progression
should prompt treatment. In diffuse disease a substantial propor-
tion of those developing severe lung fibrosis do so within three
years of onset of disease.
There has been interest in developing additional independent pre-
dictors of respiratory decline to allow better targeting of treatment.
Bronchoalveolar lavage does not add to the staging information
from high-​resolution computed tomography. Likewise, lung bi-
opsy is generally not considered helpful in typical cases of systemic
sclerosis-​associated lung fibrosis, although it remains important
in cases that have atypical features, especially if an inflammatory
pathology is suspected that may be steroid responsive. The nuclear
medicine test of diethylenetriaminepentaacetic acid (DTPA) clear-
ance scans or serum KL-​6 levels have proved informative in research
studies and may provide information that adds to that provided by
lung function tests or high-​resolution computed tomography (CT).
Serum KL-​6 is in use in some countries in management of idiopathic
lung fibrosis, but its use in longitudinal follow up and validity as a
test for routine clinical practice remains to be determined. DTPA
scans, particularly serial studies, may become useful predictors of
progression or improvement.
The mainstay of therapy for systemic sclerosis-​associated inter-
stitial lung disease has long been corticosteroids or cyclophospha-
mide, given orally or as intermittent intravenous boluses. Evidence
supporting use of cyclophosphamide is underpinned by the FAST
trial of IV cyclophosphamide and the scleroderma lung study
(SLS-​I) performed in North America. Both showed marginal su-
periority of active treatment over placebo, and the recent SLS-​II
Fig. 19.11.3.7  High-​resolution computed tomography appearance of
lung fibrosis in systemic sclerosis. (a) A thin-​section CT scan illustrating the
ground-​glass appearance of early pulmonary involvement posteriorly. A chest
radiograph taken at the same time was normal. (b) A thin-​section CT scan
illustrating extensive honeycomb shadowing and cystic air spaces involving
both lower lobes. The chest radiographic appearances at the same time were
of advanced interstitial lung disease (bibasilar reticulonodular shadowing).
Both images with grateful acknowledgement to Professors A. Wells, R. du Bois, and
B. Strickland, Departments of Respiratory Medicine and Radiology, Royal Brompton
National Heart and Lung Hospitals.
section 19  Rheumatological disorders
4528
is providing further support for the use of mycophenolate mofetil
(MMF). Treatment needs to be continued for at least 3 years to
maintain improvement. In cases that have not responded to
standard immunosuppression there are emerging data to support
use of rituximab.
In idiopathic pulmonary fibrosis, recent clinical trials of
pirfenidone, nintedanib and Mucodyne (acetylcysteine) have
shown some efficacy, and these three agents are all licensed for
treatment of this condition in some countries. Clinical studies are
underway, but at present they are not in routine use in the United
Kingdom for systemic sclerosis.
Lung transplantation may be an option for selected cases of sys-
temic sclerosis with advanced pulmonary involvement.
Pulmonary hypertension
Precapillary pulmonary arterial hypertension, designated group I,
is the most frequent form of pulmonary hypertension that occurs
in systemic sclerosis. This is diagnosed by right heart catheteriza-
tion and direct measurement of the pulmonary arterial pressure,
with pulmonary hypertension defined by mPAP of 25 mm Hg or
above, coupled with a normal pulmonary arterial wedge pressure
(by definition <15 mm Hg). Postcapillary pulmonary hypertension
(Group II), reflecting cardiac involvement from systemic sclerosis,
is associated with elevation of wedge pressure. Group III pulmonary
hypertension is associated with another lung diseases, which in sys-
temic sclerosis is generally lung fibrosis. Thromboembolic disease
and pulmonary venous occlusive disease may also occur, but less
frequently. The latter is a particular challenge as biopsy is rarely per-
formed (contraindicated|) and the compatible CT appearances are
common in systemic sclerosis. It is likely that multiple mechanisms
coexist in some cases, which may underlie the poor outcome in pa-
tients with systemic sclerosis who have pulmonary hypertension.
Patients with lung fibrosis and pulmonary hypertension seem to
have especially poor survival.
Regular screening of patients with systemic sclerosis for pul-
monary hypertension is an important aspect of management, al-
though the precise nature and frequency of screening tests remains
debated. Annual assessment of symptoms, echocardiography with
Doppler assessment of tricuspid regurgitant jet velocity, and lung
function tests to assess the presence or selective decline in DLco is
generally recommended. Screening programmes lead to the iden-
tification of cases with borderline elevation of mPAP (between 21
and 24 mm Hg). These have markedly increased risk of progression
to pulmonary hypertension over the next 1–​3 years and are a highly
enriched population for regular screening and assessment.
The first evidence of treatment benefit for pulmonary arterial
hypertension specific therapies came from a short-​term trial of
epoprosteol in systemic sclerosis. Over 24 weeks there was im-
proved exercise capacity, although no gain in survival. The devel-
opment of oral treatments for pulmonary arterial hypertension has
been a major advance. Bosentan was the first licensed oral therapy,
but other endothelin receptor antagonists have followed, also drugs
that act on the nitric oxide pathway. First of these were selective
PDE5 inhibitors that slow the breakdown of cGMP, a key secondary
mediator of nitric oxide intracellularly, and more recently soluble
guanylate cyclase agonists have been developed that also appear
beneficial. There are now prostacyclin analogues that can be given
subcutaneously, by inhalation and orally, but these have not yet been
shown effective in systemic sclerosis-​associated pulmonary arterial
hypertension.
Since the licensed therapies act on three different pathways it is lo-
gical that they can be combined. Sequential benefit has been demon-
strated in several robust clinical trials, and recent data also suggest
that initial combination therapy of a PDE5 inhibitor and endothelin
receptor antagonist may have greater benefit than monotherapy.
Oral anticoagulation is no longer used in pulmonary arterial
hypertension associated with systemic sclerosis unless there is
clear evidence of associated thromboembolic disease, since co-
hort studies suggest that survival is worsened by concomitant use
of oral anticoagulation in this condition (likely due to associated
comorbidity such as intestinal vascular disease).
In advanced pulmonary arterial hypertension (PAH) surgical
intervention may be useful for symptom control (septostomy) or
long-​term benefit (lung transplantation), but these approaches are
suitable for only a few cases.
Cardiac involvement
Investigation and management of the cardiac manifestations of sys-
temic sclerosis being summarized in Table 19.11.3.9.
Post-​mortem studies have identified at least three patterns of
myocardial involvement in systemic sclerosis, with up to 50% of
patients showing features of myocardial fibrosis. This may be dif-
fuse, in which case it may be very hard to discern non​invasively, or
focal that can be detected best on MRI scan with late gadolinium
enhancement. Other histological patterns of cardiac disease include
contraction-​band necrosis and, less frequently, inflammatory car-
diomyopathy, the latter probably occurring most often in those with
an inflammatory skeletal myopathy.
Pericarditis and pericardial effusions are well recognized as com-
plications of systemic sclerosis. They are seen particularly in the
context of severe diffuse cutaneous disease and seem to be most fre-
quently encountered in patients with an established or imminent
scleroderma renal crisis. Echocardiographic studies often reveal
small, haemodynamically insignificant effusions in patients with
scleroderma.
Electrophysiological cardiac abnormalities are commonly seen
in patients with scleroderma, especially Q–​Tc prolongation on the
12-​lead electrocardiogram (ECG). Later, conduction tissue fibrosis
may lead to varying degrees of heart block, including first-​ and
second-​degree block, or complete heart block necessitating pace-
maker implantation. Bundle-​branch blocks may reflect abnormal-
ities in the conducting tissues or be complications of ventricular
strain. Paroxysmal arrhythmias in those with occult cardiac disease
are probably an important cause of unexplained death in patients
with systemic sclerosis.
Serum measurement of creatine kinase (CK), troponin, and BNP/​
Nt-​pro-​BNP have all been used in the assessment of cardiac involve-
ment. In general, the principles of management of other forms of
cardiac failure are applied. Systolic dysfunction is treated with drugs
to optimize function and reduce afterload, including ACEi and
sometimes carvedilol or β-blockers (although these may worsen
Raynaud’s). Diastolic heart failure is treated mainly by diuresis and
preload reduction. Devises such as implantable cardioverter defib-
rillators should be considered if there is documented arrhythmia,
especially if these are associated with reduced systolic function and
focal wall fibrosis.
19.11.3  Systemic sclerosis (scleroderma)
4529
Renal disease
Several patterns of renal pathology are recognized in patients
with scleroderma:  all involve vascular abnormalities. The most
clearly defined is the scleroderma renal crisis, which describes
the occurrence of acute kidney injury in a patient with sclero-
derma, usually associated with accelerated hypertension (fur-
ther compounding the renal pathology), and in whom no other
cause for nephropathy is present. However, in addition to a
scleroderma renal crisis, many patients demonstrate less severe
renal complications, probably associated with reduced renal
blood flow and the consequent reduction in glomerular filtra-
tion rate. The mechanism of this slowly progressive form of
chronic renal disease is unclear. A few patients develop significant
glomerulonephritis.
Scleroderma renal crisis
Scleroderma renal crisis occurs in 10 to 15% of patients with dif-
fuse cutaneous systemic sclerosis and 1 to 2% of those with limited
cutaneous systemic sclerosis. Many cases occur within the first
12 months of disease, and in up to a quarter of patients with sclero-
derma renal crisis the diagnosis of systemic sclerosis is made at
the time of the renal presentation. Typical presentation is with ac-
celerated phase hypertension and progressive renal impairment.
End-​organ damage can result in encephalopathy with generalized
seizures. Microangiopathic anaemia is common and disseminated
intravascular coagulation sometimes develops.
Before the late 1970s, renal complications were a major cause of sys-
temic sclerosis-​associated death, and scleroderma renal crisis was al-
most always fatal. However, the routine use of angiotensin-​converting
enzyme inhibitors (ACEIs) has transformed outcome, with early
case–​control studies suggesting a fall in the 12-​month mortality rate
from 76% to less than 15%, although it is less clear whether these
drugs, or related agents such as angiotensin receptor blockers (ARBs),
are effective in preventing or abrogating the effects of scleroderma
renal crisis. In several independent studies the mortality or renal
outcome of scleroderma renal crisis occurring in systemic sclerosis
cases already on ACEi at the time of diagnosis appears to be worse
than those not on ACEi, which means that any use as a preventative
strategy should be cautious. Certain drugs, including ciclosporin and
corticosteroids, have been implicated as precipitants of scleroderma
renal crisis.
The high risk of sudden deterioration such as renal failure, pul-
monary oedema, or encephalopathy means that all patients with
scleroderma renal crisis should have hospital-​based treatment.
Management is with ACEIs, increasing the dose every day to achieve
a blood pressure reduction of 10 to 20 mm Hg systolic per 24 h, even
if there is continued deterioration in renal function. Patients are
also routinely given continuous low-​dose prostacyclin, which may
help control blood pressure and has potentially beneficial effects
on renal blood flow, endothelial cell function, and production of
proinflammatory or profibrotic factors, although this treatment has
not formally been proved effective.
Additional antihypertensive agents may be useful, including com-
binations of ARBs and ACEIs or calcium channel blockers, nitrates
(especially if there is pulmonary oedema), or other vasodilator
agents such as doxazocin. However, vasodilatation may be associ-
ated with relative hypovolaemia, so care must be taken to monitor
cardiac function closely.
Table 19.11.3.9  Gastrointestinal tract manifestations of systemic sclerosis
Site
Disorder
Symptom
Investigation
Treatment
Mouth
Tight skin
Dental caries
Sicca syndrome
Cosmetic
Toothache
Dry mouth
None
Dental radiograph
Salivary gland biopsy
Facial exercises
Coleman fat transfer procedure can be helpful
Dental treatment
Artificial saliva
Oesophagus
Dysmobility/​
oesophageal spasm
Reflux oesophagitis
Stricture
Dysphagia
Heartburn
Dysphagia
Barium swallow
Oesophageal scintigraphy
Manometry
Endoscopy
Proton pump inhibitors
Minimize NSAID and calcium channel
blocker use
Elevate head of bed
Avoid late meals
Stomach
Gastric paresis
NSAID-​related ulcer
Anorexia
Nausea
Early satiety
Endoscopy
Scintigram
Barium meal
Proton pump inhibitors
Metoclopramide, Domperidone
Small bowel
Hypomotility
Stasis
Bacterial overgrowth
Malnutrition
Pseudo-​obstruction
Pneumatosis intestinalis
Weight loss
Postprandial bloating
Malabsorption
Steatorrhoea
Abdominal pain
Distension
Diarrhoea with blood; benign
pneumoperitoneum
Barium follow-​through
MRI studies
Hydrogen breath test
Jejunal aspiration
Faecal microscopy
Plain abdominal radiograph
Plain abdominal radiograph
Rotational antibiotics
Erythromycin
Metoclopramide
Oral nutritional supplements
Home parenteral nutrition for severe cases
Percutaneous gastrostomy or jejunostomy if
gastro-​oesophageal disease severe
Conservative management: ‘drip and suck’
Large bowel
Hypomotility
Colonic pseudodiverticula
Pseudo-​obstruction or
volvulus (caecal/​sigmoid)
Alternating constipation and
diarrhoea
Rare perforation
Abdominal pain
Distension
Barium enema
Barium enema
Plain abdominal radiograph
Dietary manipulation
Stool expanders for constipation
Loperamide for diarrhoea (resection and
colostomy as a last resort)
Conservative management: ‘drip and suck’
Anus
Sphincter involvement
Faecal incontinence
Rectal manometry
Endoanal ultrasonography
MRI
Protective measures
Sphincter enhancement
Treat comorbidity (e.g. rectal prolapse)
Sacral nerve stimulation
section 19  Rheumatological disorders
4530
After control of blood pressure has been achieved, there is a good
case for pursuing renal biopsy, which can confirm the diagnosis,
provide prognostic information, and may occasionally reveal cases
of systemic sclerosis with inflammatory glomerular pathology that
potentially requires very different treatment to that for a classic
scleroderma renal crisis.
Although improved by the treatment described, the outcome of
a scleroderma renal crisis remains inadequate. About two-​thirds of
cases presenting to specialist centres will require renal replacement
therapy, of which about half will eventually recover sufficiently to
discontinue dialysis. This can occur up to 24 months after the crisis,
so decisions about renal transplantation should be postponed until
that time.
Chronic nephropathy
Patients who survive a scleroderma renal crisis may develop similar
but less florid proliferative changes in the interlobular and arcuate
arteries. Even those who have never had a renal crisis may show re-
duplication of elastic fibres, sclerosed glomeruli, tubular atrophy,
and interstitial fibrosis, presumably reflecting the chronic changes
of scleroderma.
Glomerulonephritis
There are a few case reports of glomerulonephritis occurring in
systemic sclerosis, including a progressive crescentic glomer-
ulonephritis in association with positive antimyeloperoxidase
autoantibodies. More commonly, biopsy reveals coincident path-
ologies such as drug-​induced injury or overlap syndromes with fea-
tures of other connective tissue disorders such as systemic lupus
erythematosus.
Gastrointestinal complications
The most common gastrointestinal manifestation in systemic scler-
osis is oesophageal dysmotility and associated reflux oesophagitis.
This is almost universally present at diagnosis but fortunately often
shows good symptomatic response to acid suppressive therapy with
proton pump inhibitors. High doses or combination of different
drug classes may be needed in refractory cases. Gastrointestinal
involvement can also occur at other sites: these are described in
Table 19.11.3.10, together with current management approaches
for each complication.
Gastric involvement typically leads to slow gastric emptying and
symptoms of postprandial fullness. This, together with sicca symp-
toms and difficulty swallowing, encourages poor nutritional intake
and is a significant contributor to the weight loss observed in pa-
tients with this disease. The earliest feature of small bowel involve-
ment is also dysmotility, leading to increased intestinal transit time,
which together with a propensity to form wide-​mouthed jejunal
diverticula leads to stagnation of the luminal contents and small
intestinal bacterial overgrowth. This may in turn lead to bloating,
flatulence, malabsorption, and chronic diarrhoea. End stage in-
volvement of the small bowel leads to profound malabsorption and
malnutrition and is a significant cause of miserable scleroderma-​
associated death. Large-​bowel manifestations include constipation
and anorectal incontinence. Alternating constipation and diar-
rhoea is common and complicates management, which is generally
empirical.
Nutritional failure and weight loss is very frequent. It is im-
portant to carefully assess the nutritional status and optimize
oral intake in the context of reduced appetite, dysphagia, mouth
and dental problems, and other symptoms such as bloating or
diarrhoea or constipation that may all reduce nutritional intake.
Enteral supplementation or tube feeding, especially jejunal tube
feeding, can be given, but some cases will need home parenteral
feeding. Although challenging in systemic sclerosis this can be a
successful approach.
Vascular manifestations in the gastrointestinal tract can be com-
plicated by haemorrhage and anaemia. Gastric antral vascular
ectasia is classically associated with intermittent severe anaemia and
the need for regular transfusion or parenteral iron administration: it
may be treated by photocoagulation.
Musculoskeletal complications
Musculoskeletal features are almost universal in established systemic
sclerosis, although often relatively well tolerated. Arthralgia and
stiffness are the most frequent symptoms. Most patients with diffuse
disease experience muscle weakness, although prominent myositis
is unusual. Flexion contractures of the interphalangeal joints are
common and can be very debilitating. Surgical intervention can be
valuable, but should focus on functional rather than cosmetic gain.
Frank arthritis is uncommon and points towards an overlap syn-
drome. Other musculoskeletal manifestations include carpal tunnel
Table 19.11.3.10  Immunosuppressive strategies used in systemic sclerosis
Agent
Clinical trial data
Methotrexate
Two placebo-​controlled trials suggest possible benefit for skin sclerosis, although this may not be clinically
significant
Cyclophosphamide
Substantial uncontrolled evidence of efficacy for skin and lung disease. Recent placebo-​controlled trials of
oral or intravenous therapy are suggestive of limited benefit for lung fibrosis
Mycophenolate mofetil
Large experience in uncontrolled studies suggests that this drug is well tolerated and not inferior to other
potent immunosuppressive agents. Small series point to benefit in lung fibrosis
Intensive immunosuppression with autologous
peripheral stem cell transplantation
Encouraging registry data have bene supported by the results of two controlled trials that suggest for some
patients there may be benefit of agitated saline contrast test (ASCT) over intravenous cyclophosphamide but
at a cost of significant treatment related mortality of up to 10%
Abatacept®, Antithymocyte globulin (ATG)
Case series and cohort studies suggest potential benefit for skin disease
Rituximab
Case series suggest possible benefit for lung and skin fibrosis but formal evidence is lacking
Tocilizumab
One phase II controlled clinical trial suggests possible benefit for skin and lung disease in early diffuse SSc
19.11.3  Systemic sclerosis (scleroderma)
4531
syndrome, tendonitis (with friction rubs—​most often in diffuse cu-
taneous disease), and the consequences of contractures—​especially
affecting the hands, but also more proximal joints in diffuse
Other organ involvement
Neurological involvement is uncommon, but in the late stages
of limited cutaneous disease a small but significant proportion
of patients develop unilateral or bilateral trigeminal neuralgia.
Impotence is a problem for men, usually occurring 1 to 2 years
after disease onset: it is thought to have a neurovascular cause, and
is refractory to treatment. Dryness of the mucous membranes is
common, leading to dyspareunia. Hypothyroidism occurs in as
many as 50% of patients with systemic sclerosis and is frequently
missed: some patients have anti-​thyroid antibodies, but lympho-
cytic infiltration in the gland is uncommon, fibrosis being the more
typical finding.
Prognosis/​Outlook
As the clinical course of particular subsets of systemic scler-
osis can to a great extent be predicted, appropriate classification
within the scleroderma spectrum is valuable in planning disease
management.
Patients with limited disease have an ‘early phase’ that lasts about
10 years, when the picture is usually dominated by vascular problems
such as Raynaud’s phenomenon, pitting scars, digital ulcers, and
telangiectasias. Later there may be worsening of the vascular disease,
both cutaneously and in the pulmonary circulation. Pulmonary
interstitial disease, usually more indolent than that seen in the dif-
fuse form, can also occur as a late complication. Gut involvement
may worsen with time, and oesophageal strictures, malabsorption,
pseudo-​obstruction, and anal incontinence are all possible late and
troublesome events in this subset.
During the early phase of diffuse disease (the first five years), the
patient is fatigued and loses weight. Hypertensive renal crisis is a
real risk, and rapid progression of pulmonary and cardiac disease
may occur. Arthritis, myositis, and tendon involvement can be most
marked at this time. After 5 years, considered to be the late stage of
diffuse disease, the constitutional symptoms settle down, the skin
and musculoskeletal problems have usually reached a plateau, and
there is progression of existing visceral disease but a reduced risk of
new organ involvement.
There have been several studies of survival in the past 50 years, and
the five-​year cumulative survival rate ranges from 34% to 73%. Even
prolonged survival does not protect against an increased mortality
risk, which continues for at least 15 years. Factors that adversely af-
fect outcome are increasing age, being male, extent of skin involve-
ment, and heart, lung, and renal disease. Most recent studies point
to a substantial improvement in survival over the last 20 years: this is
likely to be attributable to the treatment of renal crisis—​previously
almost invariably fatal—​and perhaps to better detection and treat-
ment of other major complications. In a recent single centre cohort
study it was shown that over a decade from the early 1990s to the
early 2000s there was significant improvement in five-​year survival
for unselected diffuse systemic sclerosis cases from 69% to 84%,
possibly related to better ascertainment of lung complications, the
commonest cause of systemic sclerosis-​related death now being
cardiorespiratory disease, especially pulmonary hypertension and
severe lung fibrosis.
Knowledge gaps and future developments
Although there has been substantial progress in understanding of
pathogenesis and clinical assessment of systemic sclerosis, a better
appreciation of the heterogeneity of disease, and improvements in
treatment and outcome of specific complications, the knowledge
gap remains one of the most challenging of the autoimmune rheum-
atic disease.
There remain real gaps in understanding about the aetiology of
the disease. This is because it has become apparent that the disease
is genuinely heterogeneous. It seems plausible that a multihit mech-
anism of environmental factors in a specific context will explain the
condition, but some of these factors may be commonplace in com-
parison to the rarity of systemic sclerosis and this is a real challenge
in defining aetiology. Some of the gaps in understanding systemic
sclerosis pathobiology may be filled from analysis of clinical trials
data rather than discovery science in the laboratory. Understanding
the genetics of the disease is highly relevant but will depend on epi-
genetic and whole gene sequence analysis.
There is real unmet need for treatments, despite new treatments
that have emerged. Response to drugs is often incomplete and there
has been a tendency to focus on life-​threatening aspects of the dis-
ease, whereas for patients the non​lethal burden of morbidity is often
of more immediate relevance. Calcinosis, pruritus, fatigue and ano-
rectal incontinence are common and very challenging manifestation
in urgent need of treatment options. It seems likely that better stratifi-
cation of cases, a more precise use of available treatment approaches,
and improved evaluation including the integration of serum or gen-
etic biomarkers with clinical tests will be possible. Paradoxically it
is possible that rare but well defined diseases like systemic sclerosis
may lead the way in stratified medicine and inform management of
commoner diseases.
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Cyclophosphamide versus placebo in scleroderma lung disease. N
Engl J Med, 354, 2655–​66.
Tingey T, et  al. (2013). Meta-​analysis of healing and prevention of
digital ulcers in systemic sclerosis. Arthritis Care Res (Hoboken), 65,
1460–​71.
Van den Hoogen F, et al. (2013). 2013 classification criteria for systemic
sclerosis: an American College of Rheumatology/​European League
against Rheumatism collaborative initiative. Arthritis Rheum, 65,
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Van Laar JM, et al. (2014). Autologous hematopoietic stem cell trans-
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2490–​8.
Wells AU, Denton CP (2014). Interstitial lung disease in connective
tissue disease—​mechanisms and management. Nat Rev Rheumatol,
10, 728–​39.
Williams MH, et al. (2006). Role of N-​terminal brain natriuretic pep-
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Yanaba K, et al. (2003). Longitudinal analysis of serum KL-​6 levels in
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19.11.4  Sjögren’s syndrome
Wan-​Fai Ng
ESSENTIALS
Sjögren’s syndrome is an autoimmune connective tissue disease
characterized by dryness of the eyes and mouth and lymphocytic in-
filtrates in the salivary, lachrymal, and other exocrine glands. Its cause
is not known, but it may be primary or associated with other auto-
immune diseases (secondary) and it affects women more than men
(ratio 9–​15:1).
19.11.4  Sjögren’s syndrome
4533
Clinical features—​many patients report a gritty sensation in the eyes
(or other ocular symptoms) and dryness of the mouth. Constitutional
symptoms such as fatigue are common. Other systemic manifest-
ations include Raynaud’s phenomenon, purpura, arthralgia/​arthritis,
myositis, interstitial lung disease, pleurisy, peripheral neuropathy,
myelopathy, interstitial nephritis, and lymphoma.
Investigation and diagnosis—​laboratory testing reveals raised
immunoglobulin levels, rheumatoid factors (70% of cases), and
autoantibodies against the cellular ribonucleoprotein antigens Ro
(50–​90%) and La (30–​50%). The American/​European Consensus
diagnostic criteria are most widely used, and the American College
of Rheumatology and European League Against Rheumatism have
recently published classification criteria based on weighted items.
Management—​for most patients treatment is topical and symp-
tomatic. Fatigue and arthralgia may respond to hydroxychloroquine.
Serious systemic complications are treated with steroids and cytotoxic
drugs. There is increasing interest in the use of immunodulatory drugs.
Introduction
Sjögren’s syndrome (SS) is a chronic condition of presumed auto-
immune origin characterized by inflammation of the lacrimal
and salivary glands resulting in ocular and oral dryness. Sjögren’s
syndrome, however, is a systemic condition with extraglandular
manifestations including a marked increased risk of lymphoma
development.
The term Sjögren’s syndrome was coined in recognition of the
contribution of Henrik Sjögren, a Swedish ophthalmologist who
published a doctoral thesis in 1933 describing 19 cases of women
with keratoconjunctivitis sicca and arthritis. Sjögren’s syndrome
may present with or without another autoimmune rheumatic con-
dition, referred to as primary Sjögren’s syndrome and secondary
Sjögren’s syndrome, respectively.
Aetiology
The aetiology of Sjögren’s syndrome remains elusive. Genetic suscep-
tibility and environmental triggers both play a role. Genome-​wide
association studies have identified several disease-​susceptibility
loci. Infections with various viruses have been associated with an
Sjögren’s syndrome-​like syndrome. Current evidence suggests that
environmental or endogenous antigen triggers immune cell activa-
tion and autoantibody production, leading to a self-​perpetuating
inflammatory response in genetically susceptible individuals, and
resulting in destruction of exocrine glands.
Epidemiology
The reported incidence and prevalence of Sjögren’s syndrome vary
considerably depending on the geographical locations, sampling
strategies, and classification criteria used. A recent meta-​analysis
estimated an incidence rate of 5–​9/​100 000 person-​years, and preva-
lence of 44–​78/​100 000 persons, with a female:male ratio greater than
10. Sjögren’s syndrome affects people of all ages but often presents at
40–​60 years of age. It is associated with poor health-​related quality of
life and substantial direct and indirect health-​economic cost.
Pathogenesis/​Pathology
The pathogenesis of Sjögren’s syndrome is incompletely under-
stood. The condition is characterized by focal lymphocytic in-
filtration of the salivary and lacrimal glands. Genetic and gene
expression studies have implicated both adaptive and innate im-
munity in pathogenesis, particularly the type I interferon path-
ways. Both B and T cells play key roles in the disease process.
Regulatory T  cells, NK cells, and monocytes/​macrophages may
also be important. Abnormalities in various pro-​inflammatory and
anti-​inflammatory cytokines and chemokines have been detected
in the target organs and in peripheral blood, but their pathogenetic
roles remains to be defined.
Clinical features
Initial manifestations vary but often include dry eyes, dry mouth,
musculoskeletal pain, or non​specific symptoms such as fatigue.
Symptoms may be present for many years before a diagnosis is
made.
Sicca and glandular features
Dry eyes and dry mouth are the commonest symptoms in Sjögren’s
syndrome. Patients may describe a gritty sensation in the eyes,
‘tired’ eyes, intolerance of a smoky environment or contact lens use,
crusting, or soreness of the eyelids. Xerostomia may present as al-
tered taste perception, difficulty in swallowing and speech, poor
denture retention, halitosis, dental caries, oral discomfort, oral mu-
cosal surfaces sticking together and to the teeth, and oral candid-
iasis with angular cheilitis. Dryness can also affect the nose, trachea,
pharynx, and vagina. Intermittent salivary gland swelling and recur-
rent parotitis may occur.
Systemic (extraglandular) involvement
Constitutional symptoms include fatigue, anorexia, and sweats;
low-​grade fever is common but usually mild. Fatigue can often be
disabling.
Musculoskeletal
Arthralgia and myalgia are common. Overt inflammatory arthritis
or myositis is uncommon. Mild intermittent elevation of serum cre-
atinine kinase occurs in 5–​10%. Erosive joint disease is rare.
Respiratory/​Cardiac
Tracheobronchial mucosal dryness can manifest as dry cough and
hoarseness of voice. Abnormalities in lung function tests can occur,
particularly in diffusion capacities and lung volumes, but these are
usually mild. Bronchiectasis and interstitial lung disease can also
occur, but severe manifestations are rare. Cardiac involvement is
rare. Pericarditis and pulmonary arterial hypertension have been
documented.
section 19  Rheumatological disorders
4534
Neurological
Peripheral neuropathy, including sensory, motor, mixed neuro­
pathies, and dorsal root gangliopathy, is an increasingly recognized
association. Mononeuritis multiplex and cranial neuropathies af-
fecting trigeminal, optic, and facial nerves can occur. Autonomic
symptoms (e.g. sweating, postural hypotension, dizziness) are
common. Cognitive symptoms and mental fatigue are frequently
reported. White matter changes may be seen on imaging, but se-
vere central nervous system (CNS) involvement such as multiple
sclerosis-​like syndromes, myelopathy, encephalopathy, and seiz-
ures are rare.
Genitourinary/​renal
Interstitial nephritis, renal tubular acidosis and immune complex
glomerulonephritis (especially in those with cryoglobulinaemia)
can occur, but severe renal involvement is uncommon. Urinary
manifestations include interstitial cystitis, dysuria, nocturia, fre-
quency, and urgency. Vaginal dryness, dyspareunia, and recurrent
urinary tract infections are also common.
Gastrointestinal/​hepatic
Dysphagia and gastroesophageal reflux can occur due to reduced
saliva production, pharyngoesophageal dryness, and lack of acid
clearance. Primary Sjögren’s syndrome is associated with coeliac
disease, primary biliary cirrhosis, and autoimmune hepatitis. Mild
elevation of pancreatic enzymes can occur, but serious pancreatic
complications are rare.
Cutaneous
Dry skin is very common. Cutaneous vasculitis of the small and
medium-​sized vessels, urticarial vasculitis, subcutaneous cuta-
neous lupus erythematosus, erythema multiforme, annular ery-
thema, lichen planus are recognized association. Patients with
hypergammaglobulinaemia may develop purpura, often on the
lower legs. Raynaud’s phenomenon is common but digital ulceration
and infarcts are rare.
Haematological/​immunological
Cytopenia is common but usually mild. Anaemia, hypocomple­
mentaemia, hypergammaglobulinaemia, paraproteinaemia cryo­
globulinaemia, and raised inflammatory markers also occur.
Anti-​Ro/​SSA and anti-​La/​SSB are present in 65–​85% of patients with
primary Sjögren’s syndrome. Antinuclear antibody (ANA), rheuma-
toid factor (RF), anticentromere, antithyroid, antiphospholipid,
and other autoantibodies may also be present. Several antibodies
(e.g. antimuscarinic receptor type 3, anti-​α-​fodrin) have been linked
to primary Sjögren’s syndrome pathogenesis.
Lymphoma, most commonly of the mucosal-​associated lymphoid
tissue (MALT) type, is 15–​20 times more common in patients
with primary Sjögren’s syndrome than in the general population.
Important predictors include low C4, cryoglobulinaemia, leuko-
penia, rheumatoid factor and persistent salivary gland enlargement.
Differential diagnosis
There are many causes of dry mouth, fatigue and salivary gland
swelling (Box 19.11.4.1).
Disease criteria and classification
The American European Consensus Group (AECG) classification
criteria (Box 19.11.4.2) for Sjögren’s syndrome are commonly used
for classification and diagnosis.
The American College of Rheumatology (ACR) and European
League Against Rheumatism (EULAR) have recently published
classification criteria based on weighted items: positive labial biopsy
(score 3), anti-​Ro antibody (3), positive ocular staining score (1),
positive Schirmer’s test (1), positive unstimulated oral salivary flow
(1), with a score of ≥4 meeting the inclusion criteria.
Diagnostic work-​up
Basic investigations for suspected Sjögren’s syndrome should in-
clude blood tests, urine dipstix, objective assessment of glandular
function, imaging, and biopsy of a minor salivary gland.
Blood tests:
These should include full blood count, urea, and electrolytes, liver
and thyroid function tests, creatinine kinase, lactate dehydrogenase,
inflammatory markers (ESR and CRP), immunoglobulins, serum
electrophoresis, serum complements, and autoantibody screen
(Anti-​Ro/​SSA, anti-​La/​SSB, ANA, RF, anti-​dsDNA, anticentromere)
Box 19.11.4.1  Differential diagnosis of Sjögren’s syndrome
Infective: HIV, hepatitis C virus, HTLV-​1, mumps, Epstein–​Barr virus,
cytomegalovirus, tuberculosis
Inflammatory/​immune-​mediated: Sarcoidosis, amyloidosis, IgG4-​related
disease
Malignancy: Lymphoma, other malignancies.
Iatrogenic: Graft versus host disease, head and neck irradiation,
medications
Endocrine/​metabolic: Diabetes, acromegaly, alcohol excess, cirrhosis,
lipoproteinaemia, bulimia, anorexia nervosa, endurance athletes,
chronic pancreatitis.
Miscellaneous: Fibromyalgia, chronic fatigue syndrome, sialolithiasis,
sialoadenitis.
Box 19.11.4.2  AECG (2002) Classification criteria
I.	 Ocular symptoms (dry eyes ≥3 months, gritty sensation in eyes, use of
artificial tears ≥ thrice daily)
II.	 Oral symptoms (dry mouth ≥3 months, recurrent/​persistent swollen
salivary glands, need for liquids to swallow dry foods)
III.	Ocular signs (Schirmer’s ≤5 mm/​5 min, positive vital dye staining of
eye surface)
IV.	Histopathology (focal lymphocytic sialadenitis (≥1 focusa/​4 mm2))
V.	 Oral signs (unstimulated whole saliva flow ≤1.5 ml/​15 min, abnormal
salivary scintigraphy or sialography)
VI.	Autoantibodies (anti-​Ro/​SSA or Anti-​La/​SSB)
Exclusions: Previous head or neck radiation, hepatitis C virus, or HIV
infection, sarcoidosis, amyloidosis, graft versus host disease, IgG4-​
related disease.
For primary Sjögren’s syndrome:
Either four criteria including histopathology or autoantibodies or three of
the four objective criteria (III to VI).
For secondary Sjögren’s syndrome:
The presence of a major connective tissue disease, oral or ocular symp-
toms (I or II), plus two of the three objective criteria (III, IV, V).
a A focus is defined as aggregates of ≥50 mononuclear cells in a perivascular or
periductal location, typically adjacent to normal acini.
19.11.4  Sjögren’s syndrome
4535
Objective glandular function:
Lacrimal gland function can be assessed with Schirmer’s I  test,
and salivary gland function with an unstimulated whole saliva
flow test. Selective sialometry from individual glands, sialography,
and salivary gland scintigraphy can be performed when indi-
cated. Additional ophthalmological assessments require specialist
ophthalmology input.
Imaging:
A chest radiography should be performed to exclude sarcoid and
tuberculosis. Salivary gland ultrasound or magnetic resonance
imaging (MRI) can be considered: salivary gland ultrasound is useful
for detecting glandular structural changes and initial screening for
lymphoma, which may be further investigated with MRI.
Biopsy:
Biopsy of a minor salivary gland has both diagnostic and prog-
nostic value and should be offered to all patients with suspected
primary Sjögren’s syndrome. The presence of germinal centre-​
like structures or a high focus score (≥3) in diagnostic salivary
gland biopsies is associated with a higher risk for lymphoma
development.
Clinical investigations
Disease activity and organ damage assessment
The European League Against Rheumatism (EULAR) Sjögren’s
syndrome study group have developed three sets of outcome
measures. The EULAR Sjögren’s Syndrome Disease Activity
Index (ESSDAI) measures changes in systemic disease activity
and is the sum of 12 weighted organ domains (Constitutional,
Lymphadenopathy, Glandular, Articular, Cutaneous, Pulmonary,
Renal, Muscular, Peripheral nervous system, Central nervous
system, Haematological and Biological), with each domain having
a score of no, low, moderate, or high disease activity. An alternative
ESSDAI scoring system without the biological domain has been
developed. Both are designed for use in clinical trials and in daily
clinical practice.
The EULAR Sjögren’s Syndrome Patient Reported Index
(ESSPRI) assesses the extent and severity of symptoms (dry-
ness, fatigue and pain) using 0–​10 Likert’s scales. EULAR sicca
score (ESS) assesses overall dryness burden. To assess organ
damage, two groups of investigators have developed the Sjögren’s
Syndrome Disease Damage Index and Sjögren’s Damage Index
to evaluate the accumulated, irreversible morbidity due to the
disease.
Ocular assessment
The Dry Eye Severity Grading Scheme is the most commonly used
assessment tool. Other clinical assessment may include ocular sur-
face vital staining (fluorescein, Lissamine green), tear film break up
time, tear osmolarity, and impression cytology.
Oral assessment
Input from oral medicine and dental specialists is recommended
to assess oral and dental health, check for salivary gland or lymph
gland swellings, and signs of infections. Firm or unilateral salivary
gland enlargement should prompt further investigations with
imaging and/​or biopsy to exclude lymphoma.
Management
Evidence-​based treatments are limited and there is currently no
effective disease modifying treatment available for Sjögren’s syn-
drome. The British Society for Rheumatology and the EULAR
Sjögren’s syndrome study groups has recently published manage-
ment guidelines for pSS.
 Ocular
Basic measures include avoidance of exacerbating factors for dry
eyes (see Box 19.11.4.3 and Box 19.11.4.4), good eye and lid care,
use of tear substitutes, and regular optician review.
Tear substitutes reduce tear osmolality and lubricate the ocular
surface. Regular use can alleviate dry eye symptoms and even re-
verse ocular surface changes. Many artificial tear preparations are
available. In general, low viscosity preparations (e.g. cellulose de-
rivatives) can be used as often as required, whereas medium-​/​high-​
viscosity preparations (e.g. carbomers) are used three to four times
daily. Preservative-​free preparations are recommended if used
more than three to four times daily. Lubricating ointments can
be applied before bedtime to reduce eye discomfort upon waking.
Patients should be warned of blurring of vision when using high-​
viscosity eye drops or ointments. Omega-​3-​fatty acid supplement
may also be beneficial. Topical mucolytics may alleviate symptoms
of ‘sticky eyes’.
Severe or refractory ocular manifestations require management
by specialist ophthalmologists. For ocular inflammation, topical
ciclosporin and short-​term topical glucocorticoids (beware of in-
creased risk of raised intraocular pressure and cataracts) may be
considered. Punctal occlusion (plugging or cauterization) preserves
Box 19.11.4.3.  Common exacerbating factors of sicca
symptoms
•	 Dry environment (wind, air conditioning, central heating)
•	 Irritants (dust, cigarette smoke, contact lenses)
•	 Work or leisure activities (prolonged reading or computer use)
•	 Food and drink (alcohol, caffeine)
•	 Medications (see Box 19.11.4.4)
Box 19.11.4.4  Common medications that can exacerbate sicca
symptoms
•	 α-​blockers
•	 Anticholinergics
•	 Antidepressants (especially tricyclics)
•	 Antihistamines
•	 Antihypertensives
•	 β-​blockers
•	 Diuretics
•	 Neuroleptics
section 19  Rheumatological disorders
4536
tear volume by reducing tear drainage. Autologous serum eye-​drops
are sometimes used in severe cases.
Meibomian gland dysfunction is common and can cause bleph-
aritis characterized by stinging, burning, and chronic inflammation
of the eyelids. Treatments include maintaining lid hygiene with
warm compresses, lid massage, and lid scrubs. A short course of
antibiotic/​steroid drops may be considered in the presence of in-
flammation. Prophylactic antibiotic drops at night may alleviate re-
current conjunctivitis or blepharitis.
Oral
Basic management consists of robust oral and dental hygiene (in-
clude dentures), regular dental review, avoidance of exacerbating
factors of xerostomia (see Box 19.11.4.3 and Box 19.11.4.4), use
of saliva substitutes and topical fluorides, taking of regular sips of
water, use of non​pharmacological measures to stimulate saliva pro-
duction (sugar-​free chewing gum, lozenges), and muscarinic agon-
ists (pilocarpine, cevimaline).
Saliva substitutes have limited impact on dry mouth symp-
toms and compliance is generally poor. Preparations containing
fluorides and re-​mineralizing ingredients may confer dental pro-
tection. Muscarinic agonists directly stimulate the salivary and
lacrimal glands in patients with residual glandular function.
Gradual dose titration may reduce side effects such as flushing,
headache, nausea, diarrhoea, and urinary frequency, but they
must be avoided in patients with severe heart disease and uncon-
trolled asthma.
Systemic manifestations
Constitutional
If severe, lymphoma should be excluded. Hydroxychloroquine or a
short course of corticosteroids may alleviate symptoms.
Fatigue
A  multidisciplinary approach is needed. The patient should be
screened for potential contributing factors (e.g. disturbed sleep,
stress, affective disorders, dysautonomia) and managed accordingly.
Graded exercise should be encouraged.
Musculoskeletal
Simple analgesics, hydroxychloroquine, or short courses of oral
corticosteroids can be used for arthralgia and myalgia. Evidence
for other disease modifying agents is poor. Myositis (raised cre-
atine kinase (CK)), confirmed on electromyography (EMG)
or muscle biopsy) is treated with steroids, methotrexate, or
azathioprine.
Respiratory
Conservative management usually suffices. Severe interstitial/​bron-
chial diseases with reduced pulmonary function requires cortico-
steroids, with or without cyclophosphamide.
Neurological
Gabapentin, amitriptyline, pregabalin, carbamazepine can be given
for small-​fibre neuropathy, although they may exacerbate sicca
symptoms. Mononeuritis multiplex is treated with corticoster-
oids, cyclophosphamide, or intravenous immunoglobulin. Central
nervous system vasculitis requires treatment with corticosteroids
and cyclophosphamide.
For dysautonomic symptoms, conservative measures such as ad-
equate hydration, compression stockings and avoidance of standing
from sitting or lying too quickly should be employed before consid-
ering midodrine or fludrocortisone. Severe cases should be referred
for specialist assessment and treatment.
Genitourinary/​renal
Chronic cystitis may respond to cimetidine or low-​dose steroids.
Electrolyte abnormalities in renal tubular acidosis can be cor-
rected with alkalis (e.g. sodium bicarbonate, potassium citrate).
Glomerulonephritis requires treatment with corticosteroids, cyclo-
phosphamide, or plasmapheresis. Dyspareunia due to vaginal
dryness can be managed with lubricating gels and pessaries. In post-​
menopausal women, local oestrogen preparations may also help.
Gastrointestinal
Proton-​pump inhibitors are used for gastroesophageal reflux, and
eradication therapy for those with Helicobacter pylori infections
because of the link to mucosal-​associated lymphoma development.
Autoimmune hepatitis requires treatment with corticosteroids
and azathioprine. Ursodeoxycholic acid is a useful treatment for
coexisting PBC.
Cutaneous
See Box 19.11.4.5.
Haematological/​immunological
Severe cytopenias require input from haematologists for investiga-
tion and treatments. Corticosteroids and other immunosuppressive
agents may be needed.
Lymphoma
Patients with Sjögren’s syndrome should be educated regarding the
signs and symptoms of lymphoma (persistent salivary gland or lymph
Box 19.11.4.5  Management of cutaneous manifestations
of Sjögren’s syndrome
Dry skin and pruritus: Topical emollients, antihistamines.
Photosensitivity: Avoid prolonged sun exposure, high-​factor sun block.
Hypergammaglobulinaemia-​associated purpura:  Hydroxychloroquine,
compression stockings.
Raynaud’s phenomenon: Avoid smoking and β-​blockers, calcium channel
blockers, ACE-​inhibitors, in severe cases sildenafil and intravenous
prostacycline.
Cutaneous vasculitisa: Leg elevation, avoid prolonged standing, simple
analgesia. For mild recurrent or persistent disease, use dapsone or
colchicine. For severe cases, use systemic corticosteroids or other
immunosuppressive agents (azathioprine, methotrexate, cyclophos-
phamide). For those with cryoglobulinaemia, use rituximab, plasma-
pheresis, or intravenous immunoglobulins.
Subacute cutaneous lupus erythematosusa: Hydroxychloroquine, chloro-
quine, mepracrine, dapsone, corticosteroid (topical or systemic),
methotrexate. For resistant cases, try thalidoamine, rituximab, intra-
venous immunoglobulins.
a Joint management with dermatologists recommended.

19.11.5 Inflammatory myopathies 4537 Ingrid E. Lun
19.11.5 Inflammatory myopathies 4537 Ingrid E. Lundberg, Hector Chinoy, and Robert Cooper
19.11.5  Inflammatory myopathies
4537
gland swellings, constitutional symptoms), which should prompt
them to seek medical attention. Investigation when lymphoma is
possible or suspected should include MRI or computed tomography
(CT) of neck, chest, abdomen and pelvis, and blood tests including
full blood count, biochemistry, lactate dehydrogenase, immuno-
globulins, serum protein electrophoresis, serum complements, and
cryoglobulins. Other investigations may be required in selected
cases, including bone marrow aspiration and biopsy, and oesopha-
geal-​gastro-​duodenal endoscopy and H. Pylori testing. Pulmonary
opacities should be investigated for bronchial mucosal-​associated
lymphoma.
Treatment is usually coordinated by haemato-​oncologists and
tailored to the individual patient based on symptoms, site, grade,
stage, extent of the lymphoma, and coexisting Sjögren’s syndrome
manifestations.
Prognosis
Contrary to the common belief that Sjögren’s syndrome is a benign
condition, except among those with lymphoma, a recent study has
demonstrated that Sjögren’s syndrome has an overall adjusted stand-
ardized mortality ratio of 4.7, with the leading causes of death being
cardiovascular disease, haematological malignancies, infections,
and systemic disease.
Special circumstances
Pregnancy
Patients with anti-​Ro (especially anti-​Ro52) antibodies are at risk of
recurrent miscarriage as well as fetal complete heart block and neo-
natal lupus syndrome in the newborn. Their pregnancies should be
closely monitored by obstetric ultrasound scanning and echocardi-
ography between 12 and 30 weeks of gestation, when complete heart
block most commonly develop. Neonates should be delivered in a
tertiary centre with cardiac pacing facilities. Treatment with high
dose dexamethasone or betamethasone in early pregnancy may re-
duce the risk of complete heart block developing.
Future developments
Several biological therapies targeting the dysregulated biological
pathways in Sjögren’s syndrome (e.g. B cells, T cells, type I inter-
ferons, interlukin-​6, co-stimulation molecules, kinases) are in early
to late phases of development.
FURTHER READING
Brito-​Zerón P, et al. (2016). Systemic activity and mortality in primary
Sjögren syndrome: predicting survival using the EULAR-​SS Disease
Activity Index (ESSDAI) in 1045 patients. Ann Rheum Dis, 75, 348–​55.
Seror R, et al. (2015). Validation of EULAR primary Sjögren’s syn-
drome disease activity (ESSDAI) and patient indexes (ESSPRI). Ann
Rheum Dis, 74, 859–​66.
19.11.5  Inflammatory myopathies
Ingrid E. Lundberg, Hector Chinoy, and Robert Cooper
ESSENTIALS
The idiopathic inflammatory myopathies are a heterogenous
group of disorders characterized by muscle weakness, inflamma-
tion in muscle tissue, and with frequent extramuscular involvement.
Autoantibodies are common, supporting the notion of these dis-
orders being autoimmune.
Clinical features—​Dermatomyositis is characterized by sym-
metrical, proximal muscle weakness that develops slowly, with
various cutaneous manifestations including heliotrope rash. The
muscle weakness of polymyositis is clinically indistinguishable.
Extramuscular features are common in both conditions and include
interstitial lung disease, aspiration pneumonia, arthritis, and dys-
phagia. There is an association with malignancy, particularly in pa-
tients with dermatomyositis.
Investigation and diagnosis—​Diagnosis is based on clinical fea-
tures in combination with elevated serum levels of muscle enzymes
(creatine kinase), myositis-​specific autoantibodies, and muscle bi-
opsy. Particular autoantibodies are associated with particular dis-
ease phenotypes. Novel clinical phenotypes include amyopathic
dermatomyositis, antisynthetase syndrome, and immune-​mediated
necrotizing myopathy (sometimes associated with statin treatment).
Magnetic resonance imaging can demonstrate muscle involvement,
be repeated as a method of evaluating response to therapy, and be
useful in selecting a muscle group for biopsy.
Management and prognosis—​treatment is with glucocorticoids,
usually beginning with 0.75–​1 mg/​kg/​day of prednisone. Second-​
line agents, usually azathioprine or methotrexate, are recommended
as steroid sparing. Biologics are likely to be increasingly used in the
future. Five-​year survival rate is greater than 80%, but morbidity from
both the diseases themselves and their treatments is high.
Introduction
The idiopathic inflammatory myopathies, collectively named myo-
sitis, are a group of rare diseases that are characterized clinically by
insidious onset of muscle weakness and muscle fatigue, mainly af-
fecting proximal muscles with a symmetric distribution. Typically,
inflammatory cell infiltrates are found in muscle biopsies. Other or-
gans are frequently involved such as skin, lungs, joints, gastrointes-
tinal tract, and the heart.
These heterogenous disorders can be subclassified based on clinical
and histopathological features, or by autoantibody specificities. The
idiopathic inflammatory myopathies have traditionally comprised
polymyositis (PM), dermatomyositis (DM), juvenile dermatomyo-
sitis, polymyositis/​dermatomyositis overlapping with another con-
nective tissue disease, and inclusion body myositis. More recently a
subgroup with similar clinical features but with no or scarce inflam-
mation and with pronounced muscle fibre necrosis has been identi-
fied and termed immune-​mediated necrotizing myopathy.
section 19  Rheumatological disorders
4538
Patients are often referred to rheumatology clinics as presenta-
tion of symptoms often include muscle weakness together with pain
in joints and muscle, general symptoms of inflammation, as well
as symptoms from other organs. Awareness of the multiorgan in-
volvement together with muscle weakness and muscle fatigue, and
the frequent presence of autoantibodies, should guide clinicians to-
wards a myositis diagnosis.
Aetiology
Both genetic and environmental risk factors are likely to con-
tribute to the risk of developing polymyositis and dermatomyositis.
Based on the first genome wide association studies, a strong asso-
ciation with the human leukocyte antigen (HLA) region was de-
termined. There were also associations with other genes involved
in the immune system, supporting the notion of polymyositis/​
dermatomyositis being autoimmune diseases (Box 19.11.5.1).
Genes are likely to contribute to the risk of developing poly-
myositis and dermatomyositis in the context of environmental
exposures. The most clear environmental risk factor for devel-
opment of dermatomyositis is exposure to ultraviolet light, with
the dermatomyositis/​polymyositis ratio highest in countries
closer to equator. The role of infections to trigger onset of myo-
sitis is less clear. Smoking is a risk factor to develop Jo-​1 posi-
tive myositis in patients with HLA-​DRB10301 genotype. The
immune-​mediated necrotizing myopathy clinical phenotype, as-
sociated with statins, is strongly associated with HLADRB111:01
genotype. For future studies on etiology in myositis it will be im-
portant to collect information on both genetics and environmental
exposures.
Inclusion body myositis is clinically different from polymyositis
and dermatomyositis in that it mainly affects persons over the age
of 50  years, by muscle biopsy features suggesting a degenerative
component of the disease, and by being resistant to immunosup-
pressive treatment. Less is known about the aetiology of inclusion
body myositis.
Epidemiology
The female to male incidence rate ratio in polymyositis/​dermato-
myositis varies between 1.5 and 2.4, although during childbearing
age this ratio increases to over 5:1. The frequency of inclusion body
myositis is generally higher in men compared to women, the gender
ratio varying from 0.5–​1:1 (Box 19.11.5.2).
Overall annual incidence rates indicate that idiopathic inflamma-
tory myopathies are rare diseases, at 8/​million, ranging from 1.2 to
19/​million. Overall prevalence rates are estimated at 14–​87/​million.
Higher myositis incidence has been reported in black compared to
white populations. Reported increased incidence rates over time
may in part be due to better diagnostics and increased physician
awareness.
The median time to diagnosis of overall idiopathic inflammatory
myopathies varies between 3–​6 months, but is higher for inclusion
body myositis, where the mean duration of symptoms prior to diag-
nosis is 4.1–​8 years. The peak age of disease diagnosis for idiopathic
inflammatory myopathies overall is 55 years. The age of diagnosis
for dermatomyositis has two peaks, at 5–​15 years and 45–​65 years.
Mean age at onset of inclusion body myositis ranges from 60 to
64 years.
Pathogenesis/​Pathology
An autoimmune component in the disease mechanism is suggested
by infiltrates of T and B cells in the skeletal muscle tissue and by fre-
quent presence of autoantibodies (Box 19.11.5.3).
There are two main patterns of the inflammatory cell infiltrates;
one with predominating perivascular and perimysial infiltrates
composed mainly of CD4+ T lymphocytes, macrophages and B
lymphocytes; and another with predominating endomysial infil-
trates surrounding muscle fibres, mainly composed of CD8+ T
lymphocytes, but where CD4+ T lymphocytes and macrophages are
often present (Fig. 19.11.5.1). In both type of infiltrates dendritic
cells may be present. These two different patterns of inflammatory
cell infiltrates suggest that there are different molecular pathways in-
volved in pathogenesis: the first pattern with perivascular infiltrates
suggests that blood vessels are targets of the immune reaction, and
Box 19.11.5.1  Aetiology of myositis
•	 Genetic and environmental factors are likely to contribute to risk of
developing myositis
•	 There is a strong association between myositis and HLA region
•	 Different myositis-​specific autoantibodies are associated with dif-
ferent HLA-​DR genotypes
•	 There are seasonal and regional variations in onset, suggesting envir-
onmental factors to be important risk factors for myositis
•	 Statin use may induce a necrotizing myopathy
Box 19.11.5.2  Epidemiology of myositis
•	 More common in women than in men, except inclusion body myositis
•	 Overall incidence rate 8/​million/​year, prevalence 14–​87/​million
•	 Peak age of disease diagnosis for idiopathic inflammatory myop-
athies overall is 55 years
•	 The age of disease diagnosis of dermatomyositis has two peaks, at
5–​15 years and 45–​65 years
Box 19.11.5.3  Pathogenesis/​pathology of myositis
•	 There are at least four distinct histopathological features of muscle bi-
opsies of patients with myositis, suggesting at least four different mo-
lecular pathways leading to muscle weakness and loss of muscle mass.
•	 The pathophysiology leading to muscle weakness is complex and
involves both the adaptive immune system and the non​immune or
innate immune system.
•	 T cell mediated muscle fibre cytotoxicity leading to muscle atrophy is
one molecular mechanism leading to muscle weakness.
•	 Another molecular pathway is the so-​called endoplasmic reticulum
(ER) stress affecting muscle fibre phenotype, including expression of
major histocompatibility complex (MHC) class I leading to impaired
muscle function.
19.11.5  Inflammatory myopathies
4539
the second pattern that muscle fibres are the target. However, some-
times these biopsy features may occur together, emphasizing the
complexity of the pathology of myositis.
Perivascular inflammatory infiltrates are predominantly ob-
served in patients with skin rash typical of dermatomyositis, but
may occasionally be seen in patients with other clinical myositis
subphenotypes. The endomysial pattern is mainly seen in patients
without skin rash, thus in patients with polymyositis or patients
with inclusion body myositis. Patients with inclusion body myo-
sitis may, in addition, have rimmed vacuoles, which are not specific
but suggestive of this condition in a typical clinical context (Fig.
19.11.5.2). Nuclear or cytoplasmic inclusions often require electron
microscopy to be detected. Protein accumulation in muscle fibres
is a characteristic finding in inclusion body myositis, suggesting
a disturbed protein machinery in the muscle fibres. The presence
on immunostaining of p62 or TDP43 accumulations, two proteins
involved in the protein degradation pathways, is a sensitive patho-
logical finding of inclusion body myositis. A fourth muscle biopsy
pattern is dominated by necrotic muscle fibres with no or sparse in-
flammation typically, seen in the subset called immune-​mediated
necrotizing myopathy.
Importantly, normal muscle histopathology does not exclude
myositis. Although not very common, this observation tells us
that mechanisms other than T lymphocyte mediated muscle
necrosis may lead to muscle weakness. In muscle biopsies with­
out inflammatory infiltrates and without signs of muscle fibre
degeneration, a phenotypic change of muscle fibres can be detected
by immunostaining, namely expression of major histocompatibility
complex (MHC) class I in the muscle fibres, which normally do not
express MHC class I molecules. Even though this is not specific for
myositis, it is a support for a myositis diagnosis in the relevant clin-
ical context, hence it is included as a routine stain in many muscle
laboratories. In experimental models it has been demonstrated that
up-​regulation of MHC class I molecules in muscle fibres may lead
to muscle weakness.
Another mechanism that may be involved in the pathogenesis of
myositis is metabolic disturbance, including a reduced mitochon-
drial activity in muscle fibres.
Clinical features
The main clinical features and clinical subgroups of myositis are
shown in Box 19.11.5.4 and Box 19.11.5.5.
Patients can present with acute or subacute onset of proximal,
bilateral, symmetrical muscle weakness affecting the shoulder and/​
or pelvic girdle. Myalgia is present in about 25% of cases. Upper
limb symptoms can include difficulty combing hair, or reaching
up for objects above their head. Lower limb symptoms related to
weakness include difficulty rising to a standing position and diffi-
culty climbing steps. Abdominal musculature weakness may cause
difficulty sitting up from a supine position. Pharyngeal weakness
(a)
(c)
(d)
(b)
Fig. 19.11.5.1  Polymyositis. (a) Inflammation in the endomysium surrounding individual muscle
fibres, some of which appear vacuolized and invaded by inflammatory cells. (b) Immunocytochemistry
for CD8 showing predominant CD8 cytotoxic lymphocytes within the inflammatory infiltrate.
(c) Immunocytochemistry for MHC class 1 showing widespread expression by muscle fibres.
(d) Lymphocytic vasculitis in a case of polymyositis associated with lupus.
Reproduced from Gray F et al. (eds) (2013). Escourolle and Poirier’s Manual of Basic Neuropathology, 5th ed, by permission
of Oxford University Press.
section 19  Rheumatological disorders
4540
may lead to dysphonia and dysphagia. The facial musculature is
generally spared.
Dermatomyositis is defined by characteristic rashes, including
the heliotrope rash and Gottron’s papules and signs (Fig. 19.11.5.3).
Patients may present without muscle weakness, so-​called amyopathic
dermatomyositis. ‘Mechanics hands’ refers to hyperkeratosis,
scaling and fissuring of the skin in the tips and sides of the fingers
(Fig. 19.11.5.4). Other rashes include anterior chest macular
erythema in a ‘V’ distribution (V-​sign), or on the back in a shawl-​
like distribution (shawl sign) or over the hips (holster sign) and
periungual erythema (Fig. 19.11.5.5). Skin vasculitis is a recognized
feature of juvenile dermatomyositis.
Interstitial lung disease occurs in 5–​40% of idiopathic inflam-
matory myopathies patients, more commonly in antisynthetase
or polymyositis-​Scl positive patients. Clinical signs may range
from asymptomatic disease to acute respiratory distress syndrome.
Aspiration, due to weakness of pharyngeal musculature, may lead to
aspiration pneumonia. Anti-​synthetase syndrome is defined by the
presence of an antisynthetase antibody and ≥1 of the following: myo-
sitis, interstitial lung disease, Raynaud’s phenomenon, mechanics’
hands, arthritis, and fevers.
Dysphagia is the most common gastrointestinal symptom in
the idiopathic inflammatory myopathiess, due to weakness of the
tongue and/​or pharynx, or disordered upper oesophageal motility.
Dysphagia is common in inclusion body myositis and the pres-
ence of this symptom in a patient without a skin rash should raise
suspicion of this diagnosis in a clinical context with thigh muscle
atrophy or finger flexor weakness.
Cardiac manifestations may manifest as subclinical electro-
cardiogram (ECG) abnormalities, including arrhythmias and
(a)
(b)
(c)
Fig. 19.11.5.2  (a) Muscle biopsy (haematoxylin–​eosin stain) of a patient with sporadic inclusion
body myositis (sIBM) showing endomysial collections of mononuclear cells surrounding and
sometimes invading non​necrotic muscle fibres. (b) Muscle biopsy of a patient with IBM showing
a muscle fibre with rimmed vacuoles. (c) Muscle bopsy (succinate dehydrogenase–​cytochrome c
oxidase stain) of a patient with sIBM showing an increased number of cytochrome c oxidase-​negative
muscle fibres which stain blue.
Reproduced from Hilton-​Jones D and Turner MR (eds) (2014). Oxford Textbook of Neuromuscular Disorders, by permission
of Oxford University Press.
Box 19.11.5.4  Clinical features of myositis
•	 Typical presentation of proximal muscle weakness, sometimes
with myalgia
•	 Characteristic rashes observed in dermatomyositis
•	 Extramuscular manifestations, include skin, lung, cardiac, joint, and
gastrointestinal
•	 Link with malignancy
Box 19.11.5.5  Main clinical subgroups of myositis
Polymyositis (PM)
Dermatomyositis (DM)
Inclusion body myositis (inclusion body myositis)
Antisynthetase syndrome
Immune-​mediated necrotizing myopathy
Myositis associated with other connective tissue disease
Juvenile dermatomyositis
19.11.5  Inflammatory myopathies
4541
conduction defects. Myocarditis is an under-​recognized feature in
more severe cases.
Articular manifestations occur early in idiopathic inflammatory
myopathies, in a mild, rheumatoid-​like distribution, most com-
monly in patients with antisynthetase antibodies (e.g. anti-​Jo-​1)
or myositis/​connective tissue disease-​overlap patients. Arthritis
may be a presenting symptom in patients with antisynthetase
syndrome.
Malignancy and myositis
There is a well-​described association between malignancy and
dermatomyositis, where the reported frequency of cancer is
(a)
(b)
Fig. 19.11.5.3  (b) Heliotrope rash, confluent macular erythema confined to
the upper eyelid. (b) Gottron’s papules, symmetric erythematous to violaceous
papules overlying the metacarpal and interphalangeal joints.
From Dugan E et al. (2009). Photoessay of the cutaneous manifestations of the idiopathic
inflammatory myopathies. Dermatology Online Journal, 15(2): 1.
Fig. 19.11.5.4  ‘Mechanics’ hands’.
Fig. 19.11.5.5  Periungual abnormalities in dermatomyositis.
section 19  Rheumatological disorders
4542
7–​30%. The risk is greatest for the first three years after disease
onset. Increased pick-​up in the first year may be due to surveil-
lance bias, but undoubtedly also suggests that in some patients
dermatomyositis represents a paraneoplastic phenomenon. Risk
factors for malignancy include male gender, older age at disease
onset, more severe skin or muscle disease, elevated inflammatory
markers, low serum albumin, and a positive antitranscription
intermediary factor-​1 (TIF-​1γ) antibody. The clinical conse-
quence is that for patients with dermatomyositis, following de-
tailed history-​taking and examination, laboratory evaluation
should include full blood count, inflammatory markers, routine
biochemistry, chest radiography, urinalysis, and chest/​abdomen/​
pelvis computed tomography scans. Mammography and gynaeco-
logical examination are recommended in women, and testicular
examination in men. Faecal occult blood testing and gastros-
copy/​colonoscopy should be considered, particularly in patients
with microcytic anaemia. The use of FDG-​PET scanning ap-
pears comparable to conventional screening for detecting occult
malignancy.
Autoantibodies and clinical features
In idiopathic inflammatory myopathies, an individual patient’s
antibody is predictive of their disease-​phenotype. Autoantibodies
against nuclear or cytoplasmic antigens can be detected in 80–​90%
of cases. Myositis-​specific autoantibodies are specific for inflam-
matory myositis, while myositis-​associated autoantibodies may
also be detected in other rheumatic disorders without signs of in-
flammatory muscle disease, hence they are not specific to myositis
(Table 19.11.5.1).
Differential diagnosis
Patients with myositis may present with muscle weakness and
myalgia, or with skin rash, or with other organ manifestations
such as interstitial lung disease or arthralgia/​arthritis, so the
potential for misdiagnosis is considerable and depending on
the presenting features a variety of other diseases need to be
considered. Concerning muscle weakness as a predominating
symptom, there are several myopathies and other conditions that
need to be excluded (Table 19.11.5.2).
In patients presenting with hallmark dermatomyositis (i.e. with
violacious Gottron’s papules and periorbital oedema and erythema-
tous shawl and V-​sign changes), these changes are so specific that a
dermatomyositis diagnosis should be only rarely missed. However,
in some patients, skin changes are not so dermatomyositis-​specific,
regarding their distribution and/​or colour, so misdiagnoses can
arise, including erythrodermic psoriasis, SLE, systemic Sjögren’s,
and paraneoplastic syndromes.
Clinical approach and investigations
In patients with muscle weakness or myalgia a medical history
should include family history for muscle disorders. It is vital to also
obtain an accurate drug history. Similarly, alcohol misuse is a cause
of acute and chronic myopathy. Patients may fail to volunteer symp-
toms suggestive of dysphagia or dysphonia, unless specifically asked
about these aspects, yet these can be early symptoms in idiopathic
inflammatory myopathies.
The general examination should include examination of muscle
strength. Using the manual muscle testing in eight muscle groups is
recommended (see IMACS website for instructions). One grading
scale is the Medical Research Council (MRC) scale of 0–​5, where
0 = no flicker of contraction visible, 1 = flicker of contraction vis-
ible, 2 = muscle contraction obvious and can lift somewhat against
gravity, but unable to hold against gravity, 3  =  contraction held
against gravity but unable to sustain with any extra load, 4 = good
contraction and can sustain against gravity with extra load applied,
but not normal and 5 = normal contraction. Investigation should in-
clude signs of extramuscular involvement such as skin, lungs, heart,
and joints.
Investigations should include serum levels of muscle enzymes
such as creatine kinase (CK), alanine aminotransferase (ALT),
aspartate aminotransferase (AST), aldolase, and lactate de-
hydrogenase (LDH). All could be used to monitor myositis ac-
tivity, although creatine kinase has become the preferred option.
Creatine kinase is not always elevated in active myositis, hence
normal levels do not exclude this diagnosis, and moreover there
are many causes of creatine kinase elevations other than myositis
(Table 19.11.5.3).
Muscle biopsy is one of the corner stones in the diagnostic
work up of inflammatory myopathies, both to confirm inflam-
mation and to exclude other non​inflammatory myopathies.
Histology characteristically shows infiltrations of inflamma-
tory cells with different patterns as described here under path-
ology. Notably the inflammatory cell infiltrates may be patchy,
and not always present, hence normal histopathology does not
exclude myositis. It is vital that attending laboratories have the
full immunohistochemistry capability required to appropriately
interrogate for the full range of other myopathies which could
mimic myositis, especially in the absence of a dermatomyositis
rash. It is recommended that proximal myopathy cases should be
diagnostically worked up in tertiary referral centres if misdiag-
noses are to be avoided.
As outlined in Table 19.11.5.1, there are a growing number of
myositis-​specific and associated autoantibodies (MSA/​MAA), and
these very strongly predict clinical phenotypes.
Muscle MRI scanning allows for detection of muscle oedema on
fat-​suppressed short tau inversion recovery (STIR) images (i.e. to
suggest active myositis), and comparison of T1 and short tau inver-
sion recovery images permit detection of fatty replacement and scar
tissue (i.e. to suggest irreversible muscle damage; see Fig. 19.11.5.6).
It should be noted, however, that oedema on short tau inversion re-
covery is not specific for myositis, as it can also occur with denerv-
ation (e.g. as in motor neuron disease).
Needle electromyography (EMG) testing characteristically shows
low voltage polyphasic (i.e. so-​called myopathic) potentials in the
chronic phase, with fibrillation changes also present in the acute
phase. There are no EMG features that are specific for inflammatory
myopathies, and it is important to remember that EMG interpret-
ation is operator-​dependant.
Involvement of lungs should be investigated for by pulmonary
function tests and (when appropriate) by high resolution compu-
terized tomography,and cardiac involvement should be checked for
by ECG and (when appropriate) echocardiography. Lung and heart
19.11.5  Inflammatory myopathies
4543
involvement may be clinically asymptomatic, particularly in patients
with low grade of physical activity due to muscle weakness.
Treatment
The usual approach is to combine immunosuppressive treatment
with physical exercise. Pharmacological treatment is aimed at
suppressing muscle inflammation. There are few randomized con-
trolled trial in myositis, hence recommendations are based mainly
on case series and clinical experience. Most clinicians would use
high doses of glucocorticoids, alone or in combination with a
traditional steroid-​sparing agent (e.g. methotrexate, azathioprine,
ciclosporin, mycophenylate mofetile), but none of these agents or
their combinations is assured of a successful outcome. Some pa-
tients respond well to glucocorticoids, alone or in these various
Table 19.11.5.1  Autoantibodies associated with myositis
Autoantibodies
Target autoantigen and function
Clinical phenotype
Frequency in adult IIM (%)
A. Myositis-​specific antibodies
Anti-​aminoacyl-​tRNA synthetases—​associated with antisynthetase syndrome
Anti-​Jo-​1
Histidyl
Myositis, mechanics’ hands, Gottron’s papules, arthritis,
Raynaud’s phenomenon, interstitial lung disease
11–​20
Anti-​PL-​7
Threonyl
2
Anti-​PL-​12
Alanyl
1
Anti-​EJ
Glycyl
1–​3
Anti-​OJ
Isoleucyl
1
Anti-​KS
Asparaginyl
<1
Anti-​Ha
Tyrosyl
<1
Anti-​Zo
Phenylalanyl
<1
Anti-​Ha
Tyrosinyl
<1
Antibodies associated with acute necrotizing myopathy
Anti-​SRP
Ribonucleoprotein complex comprising
6 polypeptides and 7SL RNA
(intracytoplasmic protein translocation)
Acute necrotizing myopathy, high creatine kinase (up to
25 000), severe weakness, may be refractory to treatment.
Usually respond well to steroids, but may flare on tapering
thus requiring long-​term immunosuppression
5
Anti-​HMGCR
HMG-​CoA reductase
Acute necrotizing myopathy, associated with statin use.
Proximal weakness despite statin cessation. CK 2–​35 000
unknown
Antibodies associated with adult dermatomyositis
Anti-​Mi-​2
Nucleosome remodelling histone
deacetylase complex
(nuclear transcription)
Cutaneous disease, milder muscle disease, acute onset,
good response to treatment, lower mortality rates
5–​10
(10–​20% adult DM)
Anti-​TIF1-​γ
Transcription intermediary factor 1-​γ
(nuclear transcription and cellular
differentiation)
Severe cutaneous disease, cancer-​associated myositis
5–​10
(13–​21% adult DM)
Anti-​NXP-​2
Nuclear matrix protein 2 (p140)
(nuclear transcription and RNA metabolism)
Cutaneous disease, systemic features, ILD (calcinosis more
common in juveniles)
3
Antibodies associated with amyopathic dermatomyositis
Anti-​SAE
Small ubiquitin-​like modifier activating
enzyme (post-​translational modification)
Cutaneous disease precedes muscle disease
5
Anti-​MDA5
Melanoma-​differentiation associated gene 5
(innate immune responses against viral
infections)
Ulcerating skin lesions, amyopathic dermatomyositis,
rapidly progressive interstitial lung disease
Unknown
B. Myositis-​associated antibodies
Anti-​PM-​Scl
Nucleolar protein complex
(human exosome)
SSc overlap, Raynaud’s phenomenon, interstitial lung
disease
8–​10
(50% myositis-​scleroderma
overlap syndrome)
Anti-​U1 RNP
U1 small nuclear RNP
Mixed connective tissue disease
10
Anti-​Ku
DNA-​PK regulatory subunit
SSc overlap, interstitial lung disease
20–​30
Anti-​Ro
Y1-​Y5 RNP
Sjögren’s overlap, frequently associated with Jo-​1
10–​20
Anti-​La
RNA polymerase III termination factor
Sjögren’s overlap
5
Adapted from Chinoy H., Cooper, R. G. Polymyositis and Dermatomyositis in adults. Oxford Textbook of Rheumatology, 4th edition, ed Watts R., Conaghan P., Denton C., Foster H.,
Isaacs J., Müller-​Ladner U. (Oxford) 2013.
section 19  Rheumatological disorders
4544
combinations; others respond poorly or not at all, and so progress to
suffer irreversible disability. Biological agents have been used with
limited success so far, but with some patients responding favourably
to rituximab. Presence of anti-​Jo-​1 or anti-​Mi-​2 antibodies seems
to predict response. High doses of intravenous immunoglobulins
Table 19.11.5.2  Causes of proximal muscle weakness other than idiopathic inflammatory myopathies
Inherited myopathies
Muscular dystrophies: Duchenne, fascioscapulohumeral, limb girdle, Becker, Emery-​Dreifuss, distal ocular
Congenital myopathies: nemaline, mitochondrial, centronuclear, central core
Neurologic
Denervating conditions: spinal muscular atrophies, amyotrophic lateral sclerosis
Neuromuscular junction disorders: Eaton-​Lambert syndrome, myasthenia gravis
Myotonic disease: dystrophia myotonica, myotonia congenita
Other: Guillain-​Barre syndrome, chronic autoimmune polyneuropathy (e.g. Sjögren’s type)
Metabolic
Glycogen storage diseases: acid maltase deficiency, McArdle’s disease
Lipid storage myopathies: carnitine/​carnitine palmityltransferase deficiency
Nutritional: vitamin E deficiency, malabsorption
Other: uraemia, hepatic failure, alcoholism, acute intermittent porphyria, diabetic plexopathy
Endocrine myopathies
Hyper/​hypothyroidism, acromegaly, Cushing’s syndrome, Addison’s disease, vitamin D deficiency, hyper/​hypocalcaemia, hypokalaemia
Drug-​induced myopathies
Lipid-​lowering agents, e.g. statins, and clofibrate; D-​penicillamine, chloroquine, amiodarone, vincristine, zidovudine
Infections
Acute viral: influenza, hepatitis B, echovirus, rickettsia, coxsackievirus, rubella, vaccine-​associated
Bacterial pyomyositis: staphylococcus, streptococcus, clostridium perfringens, leprosy
Parasites: toxoplasma, trichinella, schistosoma, cysticercus
Myositis/​CTD overlap
Myositis—​Overlapping with systemic sclerosis, mixed CTD, Sjögren’s syndrome, systemic lupus erythematosus, and rheumatoid arthritis
Miscellaneous
Periodic paralyses, carcinomatous neuromyopathy, acute rhabdomyolysis, myositis ossificans, microembolization by atheroma
or carcinoma, sarcoidosis with myopathy
Adapted from Oddis CV (2002). Idiopathic inflammatory myopathy: management and prognosis. Rheum Dis Clin North Am, 28: 979–​1001, copyright 2002, with permission from Elsevier.
Table 19.11.5.3  Causes of elevated creatine kinase other than
active idiopathic inflammatory myopathy
Muscle trauma
a)  Muscle injury
b)  Needle stick
c)  EMG
d)  Surgery
e)  Convulsions, delirium tremens
Diseases affecting muscle
a)  Myocardial infarction
b)  Rhabdomyolysis
c)  Metabolic or mitochondrial myopathies
d)  Muscular dystrophy
e)  Infectious myositis
g)  Amyotrophic lateral sclerosis
Drug/​toxin-​induced myopathy
a)  Lipid-​lowering agents, especially HMG-​CoA-​reductase inhibitors
b)  Alcoholic myopathy
c)  Drugs of abuse: e.g. cocaine, amphetamines, phencyclidine
d)  Malignant hyperthermia and neuroleptic malignant syndrome
e)  Other medications: e.g. zidovudine, colchicine, chloroquine, ipecac
Drug-​induced myositis
a)  D-​penicillamine
b)  Interferon
Drug-​induced creatine kinase elevation
Inhibition of excretion: e.g. barbiturates, morphine, diazepam
Endocrine and metabolic abnormalities
a)  Hypothyroidism
b)  Hypokalaemia
c)  Hyperosmolar state or ketoacidosis
d)  Diabetic nephrotic syndrome with oedema
e)  Renal failure
Elevation of CK–​BB
a)  CNS disease
b)  Tumours (GI, bronchial, other)
Elevation without disease
a)  Strenuous, prolonged, and/​or unaccustomed exercise
b)  Ethnic group (black > white)
c)  Increased muscle mass
Adapted from Targoff IN (2002). Laboratory testing in the diagnosis and management of
idiopathic inflammatory myopathies. Rheum Dis Clin North Am, 28: 859–​890, copyright
2002, with permission from Elsevier.
Fig. 19.11.5.6  MRI of the thighs in polymyositis: T1 (upper) and short
tau inversion recovery (lower) sequencing demonstrates oedema in the
anterior compartment of the muscles on the short tau inversion recovery
sequences, which is compatible with active muscle inflammation.
(Courtesy of Dr Lisa Christopher.)
19.11.5  Inflammatory myopathies
4545
(IVIG) are expensive but may have a therapeutic effect in some
otherwise drug-​resistant cases.
In patients who are completely non​responsive to immunother-
apies, a careful review of the diagnosis may disclose a misdiagnosis
(e.g a non​responsive polymyositis may in fact be a covert inclusion
body myositis, which may only be disclosed by a repeat muscle
biopsy).
Even patients who respond to immunosuppressive treatment
with suppression of inflammation may be left with impaired muscle
performance due to persisting muscle weakness and low muscle en-
durance. Combining immunosuppressive treatment with physical
exercise has been shown to be both safe and effective in restoring
physical function.
Prognosis/​outcome
The most useful outcome measure in patients with idiopathic in-
flammatory myopathies is physical function, although patients with
prominent extramuscular symptoms, such as interstitial lung dis-
ease, may require more specific assessments. Manual muscle testing
is the most often used test of muscle strength and can be easily per-
formed in clinical practice. To direct treatment decisions it is im-
portant to be able to distinguish whether poor muscle performance
and other organ involvement is due to active inflammatory dis-
ease or instead due to irreversible organ damage. The International
Myositis Assessment and Clinical Studies Group (IMACS) has de-
veloped core set activity and damage measures in idiopathic inflam-
matory myopathies (http://​www.niehs.nih.gov/​research/​resources/​
imacs/​diseaseactivity/​index.cfm).
Most patients suffer with mild to moderate degrees of disabil­
ity, with impact on quality of life. Disease progression may be
monophasic, relapsing-​remitting, chronic progressive, or remitting.
Lung involvement and paraneoplastic involvement are major con-
tributors to comorbidity. Comorbidities associated with treatment
include Cushingoid appearance, osteoporosis, and infections. Up to
50% of patients remain out of employment due.
Idiopathic inflammatory myopathies are associated with in-
creased mortality: survival rate at two years ranges from 72% to
85%, at five years 34% to 75%, and at 10 years 42% to 85%. There may
be a bimodal distribution of deaths: in the first year after onset, and
5–​10  years later. Cancer, lung, and cardiac complications, and
infection are the most common causes of death. Demographic
and clinical features associated with worse survival include male
gender, diagnostic delay, older age at onset of disease, associated
malignancy, calcinosis, and oesophageal, cardiac or respiratory
involvement.
Special circumstances/​complications
Inclusion body myositis
There is ongoing debate regarding whether inclusion body myo-
sitis is an idiopathic inflammatory myopathies subgroup member.
Patients exhibit quadriceps weakness and inflammatory cell in-
filtrations in muscle biopsies, thus mimicking polymyositis, but
in ‘classic’ inclusion body myositis patients also have the specific
clinical features of distal muscle weakness selectively affecting the
finger flexors and tibialis anterior muscles, and muscle involve-
ment may be asymmetrical. Affected patients may experience loss
of grip and report falls. In classic inclusion body myositis, patients
can also demonstrate dramatic wasting of the quadriceps and the
finger flexor muscles, which are not typical features of polymyositis.
However, discriminating inclusion body myositis from polymyositis
is vital as, unlike in polymyositis, inclusion body myositis does not
improve with immunosuppression.
Some inclusion body myositis cases do not exhibit peripheral
weakness at disease onset, and such cases are misdiagnosed as
‘drug-​resistant polymyositis’ for years, until an inclusion body
myositis diagnosis is disclosed by the development of an inclu-
sion body myositis pattern of peripheral weakness, and/​or re-
peat muscle histology confirms development of inclusion body
myositis-​specific features, including inclusion bodies and rimmed
vacuoles.
Statin-​induced myopathies
Statin-​induced myopathies are an increasing problem with the
increasing use of these drugs. A common problem is muscle cramps
and myalgias, symptoms which may be associated with elevated
serum levels of creatine kinase. In rare individuals a severe rhabdo-
myolysis may develop. These conditions are usually reversible if
statins are stopped, although improvement may take months. The
other myopathy associated with statins is a so-​called immune-​
mediated necrotizing myopathy with very high serum creatine
kinase-​levels and a newly identified autoantibody: anti-​HMG-​CoA
reductase (HMGC-​CR), which is the target of statins. This condi-
tion requires immunosuppressive treatment, to which patients usu-
ally respond well.
Areas of uncertainty, controversy, and
future developments
The results of treatment of patients with myositis is often
disappointing, hence there is an unmet need for new therapies. In
order to develop more effective treatments with fewer side-​effects we
need to achieve a better understanding of the molecular pathways
that are involved in myositis. To accomplish this we need to follow
our patients systematically and record the response to treatment in
relation to clinical subgroups where the pathophysiology is likely to
be shared by particular groups of patients. One such way forward
could be to study the effects of different targeted therapies in sub-
groups based on autoantibody profile. Clinical longitudinal studies
combined with experimental studies in which new compounds can
be tested are strongly needed.
FURTHER READING
Ibrahim F, et  al. (2015). Second-​line agents in myositis:  1-​year
factorial trial of additional immunosuppression in patients who
have partially responded to steroids. Rheumatology (Oxford), 54,
1050–​5.
Lundberg IE, Vencovsky J, Alexanderson H (2014). Therapy of myo-
sitis: biological and physical. Curr Opin Rheumatol, 26, 704–​11.

19.11.6 Large vessel vasculitis 4546 Raashid Luqma
19.11.6 Large vessel vasculitis 4546 Raashid Luqmani and Cristina Ponte
section 19  Rheumatological disorders
4546
Meyer A, et  al. (2015). Incidence and prevalence of inflamma-
tory myopathies:  a systematic review. Rheumatology (Oxford),
54, 50–​63.
Miller SA, Glassberg MK, Ascherman DP (2015). Pulmonary compli-
cations of inflammatory myopathy. Rheum Dis Clin North Am, 41,
249–​62.
Yazici Y, Kagen LJ (2002). Clinical presentation of the idiopathic
inflammatory myopathies. Rheum Dis Clin North Am, 28,
823–​32.
Zong M, Lundberg IE (2011). Pathogenesis, classification and
treatment of inflammatory myopathies. Nat Rev Rheumatol, 7,
297–​306.
19.11.6  Large vessel vasculitis
Raashid Luqmani and Cristina Ponte
ESSENTIALS
Large vessel vasculitis describes a group of primary vasculitides pre-
dominantly affecting the aorta and its major branches: its two main
types are giant cell arteritis and Takayasu arteritis, but overlap con-
ditions are increasing recognized, including isolated aortitis in older
patients.
Giant cell arteritis
Characterized by granulomatous inflammation that penetrates all
layers of the wall of medium and (often) large muscular arteries, in
particular the superficial temporal artery. Almost exclusively affects
patients aged above 50 years, typically white Caucasians.
Clinical features—​the usual presentation is with unaccustomed
headache, often accompanied by systemic symptoms and in associ-
ation with a significant acute phase response. Visual loss is a feared
complication. The temporal artery pulses can be reduced or absent,
and there may be local tenderness. Around 40–​50% of patients have
symptoms typical of polymyalgia rheumatica.
Investigation—​Patients should be seen in a rapid access service
where a temporal artery ultrasound or biopsy should be performed
as soon as the diagnosis is suspected.
Management—​prednisolone at an initial dose of 40–​60 mg/​
day, or pulsed intravenous methylprednisolone for patients with
visual symptoms. Steroid dose is slowly reduced after remission is
achieved, typically over two to three years. Tocilizumab has recently
proven to be an effective steroid-sparing agent.
Takayasu arteritis
A chronic granulomatous vasculitis characterized by stenosis, occlu-
sion, and aneurysm of large elastic arteries, mainly the aorta and its
branches, which particularly affects young women, predominantly in
Asian, Middle Eastern, and South American countries.
Clinical presentation—​the acute stage features non​specific systemic
symptoms. In the chronic stage symptoms depend on the anatom-
ical location of the vascular lesions, with typical complaints relating
to ischaemic claudication of the limbs and pain in large arteries. The
commonest physical findings are weak or absent peripheral pulses
and/​or bruits, or asymmetrical systolic blood pressure measure-
ments in the arms or legs.
Diagnosis—​most patients are diagnosed long after the disease has
become established, usually based on angiograms obtained with
magnetic resonance or computed tomography angiography.
Treatment—​is with standard immunosuppressive agents (typically
methotrexate) combined with prednisolone. In severe disease there
is a role for chemotherapy with cyclophosphamide. Inhibition of
interleukin-​6 is a promising new treatment option with less toxicity.
Surgical bypass graft procedures may be required if the disease is not
well controlled.
Introduction
Large vessel vasculitis is a term used to describe a group of pri-
mary vasculitides predominantly affecting the aorta and its major
branches. The two major subtypes of large vessel vasculitis are giant
cell arteritis and Takayasu arteritis, which have distinctive fea-
tures. Giant cell arteritis occurs predominantly in white European
women aged above 50 years while Takayasu arteritis affects women
below 40 years from the Middle East and Asia. However, there are
many similarities between giant cell arteritis and Takayasu arter-
itis, particularly in pathogenic mechanisms, histopathology, and
clinical manifestations related to large vessel involvement. It re-
mains unclear whether giant cell arteritis and Takayasu arteritis
are distinct entities or represent different phenotypes of the same
disease.
The spectrum of large vessel vasculitis encompasses other rare
conditions such as isolated aortitis and periaortitis (with or without
associated IgG4-​related disease), aortitis of Cogan’s syndrome, re-
lapsing polychondritis and Behçet´s disease with large vessel in-
volvement. Moreover, giant cell arteritis is often associated with
polymyalgia rheumatica (PMR), an immune-​mediated inflamma-
tory condition characterized by shoulder and/​or hip girdle pain and
morning stiffness, which may also be also considered to be a clinical
subtype of large vessel vasculitis.
Giant cell arteritis
Epidemiology
Giant cell arteritis occurs almost exclusively in patients aged over
50 years at the time of diagnosis. It increases with age and peaks
in those aged between 70 and 79. Females are affected two to three
times more often than males. It occurs predominantly in northern
latitudes, mainly affecting white Caucasians; it is very rare in black
and Asian races. The highest annual incidence rates have been re-
ported in northern Europe and northern United States (>18/​100 000
in individuals older than 50 years).
Aetiology
The aetiology of giant cell arteritis remains unknown, but genetic
susceptibility and environmental risks factors play a role in the de-
velopment of the disease.
19.11.6  Large vessel vasculitis
4547
The HLA-​DRB1*04 allele, expressed in 60% of giant cell arter-
itis patients, and polymorphisms of several genes, such as the ones
encoding the intercellular adhesion molecule-​1 (ICAM-​1) and
the vascular endothelial growth factor (VEGF), have been associ-
ated with increased susceptibility to giant cell arteritis or severity of
manifestations.
Cyclic patterns and fluctuations in the incidence of giant cell ar-
teritis associated with epidemics of Mycoplasma pneumonia, parvo-
virus B19 and Chlamydia pneumoniae have been described, but
the significance of these observations is unclear. In addition, histo-
logical examination of temporal artery biopsy specimens to detect
viral DNA of parvovirus B19 or herpesvirus have been negative or
inconsistent.
Histopathology
In giant cell arteritis, the inflammation is most commonly seen in
medium size arteries originating from the aortic arch, particularly
in temporal, vertebral, ophthalmic, and posterior ciliary arteries. It
typically affects the arteries focally and segmentally, leading to so-​
called ‘skip lesions’, where areas of vasculitic lesions juxtapose areas
of normal artery.
Histologically, it is characterized by transmural infiltration of
mononuclear cells (T cells and macrophages) with fragmentation of
the internal elastic lamina. Eosinophils may also be seen, but poly-
morphonuclear leukocytes are rare. Giant cells are present in over
half the cases, typically at the intima–​media junction (Fig. 19.11.6.1).
The endothelium is sometimes hyperplastic and thrombosis may
be present in sites of active inflammation at the vessel lumen. Over
time, the elastic smooth muscle layer of the media is replaced by
non​contractile fibrous tissue.
In some cases, inflammation is confined to the vasa vasorum
or/​and to the peri-​adventitial small vessels. Compared to pa-
tients with more widespread inflammatory change, patients with
isolated peri-​advential inflammation have less constitutional and
cranial symptoms, although the frequency of visual manifest-
ations is the same. Patients with isolated vasa vasorum inflam-
mation have similar clinical features to patients with transmural
inflammation.
Pathogenesis
The earliest inciting event in the pathogenesis of giant cell arteritis is
likely to be activation of resident dendritic cells within the adventitia
by Toll-​like receptors in response to an unknown stimulus or stimuli.
Activated dendritic cells produce proinflammatory cytokines, such
as interleukin-​18 (IL-​18) and IL-​6, which recruit and locally activate
T cells, particularly T helper subsets 1 and 17 (Th1 and Th17).
Th1 cells secrete interferon-​γ (IFN-​γ) and IL-​2. IFN-​γ activates
macrophages in the adventitia (which secrete IL-​1, IL-​6 and TGF​β)
and in the intima–​media junction to form giant cells and to produce
matrix metalloproteinases, leading to arterial injury. Repair mech-
anisms are activated with the secretion of platelet-​derived growth
factor (PDGF), which stimulates intimal proliferation, and VEGF,
which stimulates neoangiogenesis. The combination of these de-
structive and repair mechanisms leads to internal elastic lamina
degradation and luminal narrowing or occlusion, resulting in symp-
toms of ischaemia. IFN-​γ production is relatively steroid resistant in
giant cell arteritis. Th17 cells produce IL-​17, which appears relevant
in early disease, but its production is rapidly suppressed by gluco-
corticoid treatment.
Clinical manifestations
The onset of giant cell arteritis is usually gradual, although in some
cases it may start suddenly. Most patients present with constitutional
symptoms, such as malaise, fatigue, anorexia, and weight loss. Fever
can also be present, usually at low grade (between 37ºC and 38ºC).
Table 19.11.6.1 summarizes the published frequencies for the most
Fig. 19.11.6.1  Histopathological features of giant cell arteritis. Cross-​sectional view (H&E
staining) of a temporal artery in a patient with giant cell arteritis, showing a lymphocytic
infiltrate (green arrows), multinucleate giant cells (yellow arrows), intimal hyperplasia and
lumen narrowing (red arrow).
Image provided courtesy of the TABUL study group.
section 19  Rheumatological disorders
4548
common clinical manifestations in giant cell arteritis, highlighting
the differences between patients with more prominent inflamma-
tion of the cranial vasculature and of the extracranial arteries.
Cranial manifestations
The most common manifestations of giant cell arteritis relate to its
predilection for the cranial branches of the external carotid artery,
particularly the temporal artery (Table 19.11.6.2). New onset of
head pain (rather than headache) is the most common symptom and
it is typically felt over the temporal regions, although generalized or
occipital pain may also occur. The temporal arteries may be tender
on palpation, thickened or swollen, and pulses may be diminished
or absent. Scalp tenderness may be present, which is usually noticed
when patients touch, comb, or brush their hair. Rarely, scalp necrosis
occurs due to occlusion of the branches of the scalp arteries.
Jaw claudication is the most specific symptom for giant cell ar-
teritis, but it is not pathognomonic (amyloidosis or atherosclerosis
can also cause this symptom). Inflammation of the facial arteries re-
sults in ischaemia of the masseter muscles, which leads to pain when
chewing or talking (relieved by rest). If the lingual artery is involved,
tongue claudication may occur, although this is a very rare manifest-
ation of giant cell arteritis.
Ischaemia of the ophthalmic artery and its branches, which
supply the optic nerve and eye, is the main cause of the most severe
ocular manifestations seen in giant cell arteritis. The most common
symptoms are blindness, blurred vision, and diplopia. Visual loss
may be partial or complete, in one or both eyes, and it is generally
irreversible and pain free. It is mainly due to anterior ischaemic optic
neuropathy, caused by occlusion of the posterior ciliary arteries, and
frequently preceded by amaurosis fugax (transient visual loss). In
the acute phase of anterior ischaemic optic neuropathy fundoscopic
examination typically shows a pale optic disc oedema. Less com-
monly, visual loss may occur due to posterior ischaemic optic neur-
opathy, arterial occlusion of the central retinal artery or cilioretinal
vessels, or occipital cortex infarction in the setting of a stroke.
Arteritis of the vertebral and basilar arteries can cause transient
ischaemic attacks and stroke in up to 7% of patients with giant cell
arteritis. Other less common features of cranial giant cell arteritis
include audio vestibular dysfunction, dysphagia, cough, sore throat,
facial pain, but these rarely occur in isolation.
Extracranial manifestations
Extracranial involvement in giant cell arteritis, or large vessel giant
cell arteritis, has been described in 45–​83% of cases, varying ac-
cording to the imaging modality used. Patients with large vessel
giant cell arteritis may present with claudication, heart murmurs,
and arterial bruits or decreased/​absent pulses. Upper limbs are more
frequently affected than lower limbs, and the thoracic part of the
aorta is more commonly involved than the abdominal part. The
risk of aortic aneurysms is increased when compared to the gen-
eral population (twofold increased risk in the United Kingdom).
However, aortic aneurysms are more likely to occur late in the dis-
ease course (around 3–​4 years after the initial symptoms of giant
cell arteritis). Although controversial, both large vessel giant cell ar-
teritis and Takayasu arteritis have similar distribution and type of
aortic lesions when assessed by magnetic resonance angiography
(MRA) (97% stenoses or occlusions, and 3% aneurysms).
Giant cell arteritis and polymyalgia rheumatica
Polymyalgia rheumatica symptoms occur in about 40–​50% of pa-
tients with giant cell arteritis during the disease course. They con-
sist of aching and/​or morning stiffness of the shoulder girdle and/​
or hips, typically symmetrical, and accompanied by elevated inflam-
matory markers and pathologic ultrasound findings (subdeltoid
bursitis, biceps tenosynovitis, glenohumeral synovitis, trochanteric
bursitis, and/​or hip synovitis). In patients with isolated polymyalgia
rheumatica, around 10% will subsequently develop giant cell arter-
itis. See Chapter 19.11.11 for further discussion.
Table 19.11.6.1  Frequencies for the most common features
of giant cell arteritis
Clinical manifestations of giant cell arteritis (%)
Constitutional
symptomsa
Weight loss
43%
Fever
42%
Fatigue
39%
Myalgia
39%
Arthralgia
30%
Cranial
manifestations
Headache
70–​90%
Absent /​diminished pulses or tenderness of
the temporal arteries
30–​60%
Jaw claudication
40–​50%
Scalp tenderness
33–​50%
Visual disturbances (transient or permanent)
20–​50%
Caused by b:
–​ Anterior ischaemic optic neuropathy
91%
–​ Central retinal artery occlusion
11%
–​ Cilioretinal artery occlusion
10%
–​ Posterior ischaemic optic neuropathy
4%
Audio vestibular dysfunction (hearing loss,
tinnitus, and vertigo)
5–​25%
Respiratory symptoms (cough, sore throat,
and hoarseness)
c.9%
Stroke
3–​7%
Scalp necrosis
<5%
Tongue necrosis
<5%
Extracranial
manifestations
Polymyalgia rheumatica
40–​50%
Peripheral neuropathy
c.14%
Large vessel stenosesc
13%
Thoracic aorta aneurysm and/​or dissectionc
11%
Abdominal aorta aneurysm and/​or
dissectionc
10%
Laboratory results in patients with giant cell arteritis (%)
Inflammatory
markers
Elevated ESR and/​or elevated CRP
90–​95%
ESR >50 mm/​h
85–​90%
ESR ≥100 mm/​h
30–​60%
ESR of 40–​50 mm/​h
10%
ESR <40 mm/​h
5%
Others
Anaemia
35–​65%
Thrombocytosis
30–​60%
High alkaline phosphatase
30–​60%
CRP: C-​reactive protein, ESR: Elevated erythrocyte sedimentation rate.
a Smetana et al. 2002; b Hayreh et al. 2002; c Nuenninghoff et al. 2003.
19.11.6  Large vessel vasculitis
4549
Diagnostic investigations
Laboratory tests
High inflammatory markers are present at the onset of the disease
in most patients with giant cell arteritis. The combination of normal
values for both erythrocyte sedimentation rate (ESR) and C-​reactive
protein (CRP) makes the diagnosis very unlikely. However, particu-
larly in cases of localized disease without constitutional symptoms,
ESR and CRP values may be normal. Normochromic-​normocytic
anaemia, thrombocytosis, high fibrinogen levels, and increased liver
enzymes, particularly alkaline phosphatase, have also been described
in patients with giant cell arteritis.
Temporal artery biopsy
For many years temporal artery biopsy has been considered the
‘gold-standard’ test for diagnosing giant cell arteritis but in-
creasingly, imaging is replacing it in many hospitals because of
its relatively poor sensitivity. It should be performed as soon as
possible after the treatment is initiated, preferably within the first
7–​10 days. The length of the temporal artery biopsy required is
unclear. Segments of at least 0.5–​1 cm (post-​formalin fixation) are
considered acceptable for accurate pathological review. Despite
the high specificity of temporal artery biopsy (around 95–​100%),
it has low sensitivity for diagnosis (about 50%) due to poor sam-
pling, delay in organizing the procedure, and the segmented na-
ture of the pathological findings. Ultrasound guided biopsy has
failed to show improvement in the sensitivity of temporal artery
biopsy for diagnosing giant cell arteritis. Temporal artery biopsy
should be performed from the most symptomatic site. Bilateral
temporal artery biopsy (adding the contralateral temporal artery)
may increase diagnostic yield by up to 9–​13%, but is not routinely
recommended.
Imaging
Ultrasound has proven to be effective in diagnosing giant cell arter-
itis based on the presence of a dark ‘halo’ around the temporal artery
wall (Fig. 19.11.6.2). In unequivocal cases it has been suggested that
a positive ultrasound may replace histology and this increasing use
of imaging as a diagnostic tool is likely to replace biopsies in many
hospitals in future.
Large vessel giant cell arteritis may be diagnosed by dif-
ferent imaging techniques. An ultrasound showing homogeneous
hypoechoic wall thickness more than 1.5 mm in the large vessels (e.g.
axillary arteries) is compatible with giant cell arteritis; however, this
imaging modality cannot assess all deep large vessels, such as thoracic
aorta (frequently involved in giant cell arteritis). Magnetic resonance
imaging (MRI) and angiography (MRA) are valuable for identifying
early signs of vasculitis, particularly oedema and wall thickness, be-
fore arterial complications occur; mural contrast enhancement as
a result of vascular remodelling can lead to false-​positive findings.
18-​Fluorodeoxyglucose (FDG) positron emission tomography
(PET) cannot reliably delineate the vessel wall, but may be more
sensitive than MRI in detecting early vascular inflammation. The
combination of FDG PET with computed tomography (CT) (FDG
PET-​CT) improves the identification of anatomic areas and the dif-
ferential diagnosis with atherosclerosis. However, it is an expen-
sive test with a high radiation dose and still lacks a standardized
definition of vascular inflammation based on the intensity of FDG
uptake. CT may be useful in assessing large vessel involvement, par-
ticularly in deep vessels, but it has a low sensitivity to detect early
vessel wall alterations.
Diagnosis and classification criteria
There are no diagnostic criteria for giant cell arteritis. Classification cri-
teria were developed by the American College of Rheumatology (ACR)
in 1990 (Table 19.11.6.2). However, they lack inclusion of imaging as a
Fig. 19.11.6.2  Ultrasound of the parietal branch of the right temporal artery (left) and of the left axillary artery (right) in longitudinal view showing a
black hypoechoic rim or ‘halo’ (yellow arrows).
Table 19.11.6.2  ACR 1990 classification criteria for giant cell arteritis
1.  Age at onset >50 years
2.  New onset headache
3.  Temporal artery abnormality (tenderness to palpation or decreased pulsation)
4.  Increased ESR (>50 mm)
5.  Abnormal artery biopsy (showing vasculitis characterized by a predominance
of mononuclear infiltration or granulomatous inflammation)
The patient is classified as having giant cell arteritis if at least three of these five criteria
are present (sensitivity of 93.5% and specificity of 91.2%).
Adapted from Hunder GG et al. (1990) The American College of Rheumatology 1990
criteria for the classification of giant cell arteritis. Arthritis Rheum, 33(8): 1122–​8.
section 19  Rheumatological disorders
4550
criterion, and are not suitable for diagnosis, given they were designed
to differentiate giant cell arteritis from other vasculitides, but were
not validated to distinguish vasculitic from non​vasculitic diseases.
A major multicentre observational study in currently underway to de-
velop diagnostic criteria and revise classification criteria for systemic
vasculitis in accordance with standards defined by the ACR and the
European League Against Rheumatism (EULAR)—​The Diagnostic
and Classification Criteria for Vasculitis (DCVAS) study.
Management
Treatment
Glucocorticoids
Glucocorticoids are the mainstay of treatment in giant cell arter-
itis and they should be prescribed immediately after the diagnostic
suspicion of giant cell arteritis. In most cases they are able to pro-
vide complete symptomatic relief within 24–​48 hours. The optimal
glucocorticoid dosing regimen is still unclear. Most guidelines
recommend an initial dose between 40 mg and 60 mg/​day for in-
duction of remission and pulsed intravenous methylprednisolone
for patients presenting with visual symptoms. Daily dosing has
shown to be more effective than alternate day dosing, but single
or divided daily doses have comparable results. Glucocorticoid re-
duction should occur after resolution of clinical symptoms and la-
boratory abnormalities, typically at around 4 weeks of treatment.
The tapering regimen is variable and dependent on disease activity,
glucocorticoid toxicity, and patient compliance. The British Society
for Rheumatology (BSR) has proposed a tapering scheme of 10 mg/​
day reduction every 2 weeks down to 20 mg, followed by 2.5 mg/​day
less every 2–​4 weeks down to 10 mg/​day and then reduced by 1 mg/​
day every 1–​2 months until discontinuation.
Minor flares occur in about half the patients, usually responding
to an increase in prednisolone of 5–​10 mg/​day. A major flare with
visual or neurological symptoms usually results in escalation of
glucocorticoid to the original induction dose, together with con-
sideration of introducing other immunosuppressive therapy (see
‘Other immunosuppressive therapy’, next).
The total duration of glucocorticoid treatment varies. The average
time is two to three years, but it may exceed five years, particularly
in patients with recurrent disease or in those who develop sec-
ondary adrenal insufficiency. Moreover, the burden of high-​dose
glucocorticoids is considerable, reported in up to 86% of patients at
10-​year follow-​up, particularly due to posterior subcapsular cataract
(41%), bone fractures (38%), infections (31%), hypertension (22%),
diabetes mellitus (9%) and gastrointestinal bleeding (4%).
Other immunosuppressive therapy
Other immunosuppressive treatments have been tried for giant
cell arteritis, with the aim of allowing a safer and faster reduction
of glucocorticoids. However, results of studies have been conflicting
and generally disappointing. A modest reduction in disease relapse
and glucocorticoid exposure has been reported with methotrexate.
Azathioprine can be used, but evidence supporting its steroid-​sparing
effect is limited. In small case series, leflunomide has shown to be
effective as a steroid-​sparing agent in patients with difficult-​to-​treat
giant cell arteritis, but prospective randomized placebo-​controlled
trials are still necessary to support these findings. Retrospective
studies have demonstrated benefit in the use of more intense
immunosuppression using cyclophosphamide for steroid-​resistant
patients who have failed either methotrexate or azathioprine.
TNF inhibitors have been used in patients with giant cell arteritis,
but with disappointing results. Beneficial effects of tocilizumab, a
monoclonal IL-​6 receptor blocker, have been described in several
small case series of giant cell arteritis. A multicentre, randomized,
double-​blind, placebo-​controlled trial designed to formally evaluate
the ability of tocilizumab in maintaining disease remission has re-
cently been published demonstrating the efficacy and safety of
tocilizumab as a steroid-sparing agent after 52 weeks. Other biologic
treatments have been studied for giant cell arteritis with promising
results (e.g. abatacept and ustekinumab). Better understanding of
the biology of giant cell arteritis should lead to the identification of
more targets for more specific intervention in future.
Adjuvant therapy
In the absence of contraindications, low-​dose aspirin (75–​150 mg/​
day) should be considered in all patients with giant cell arteritis.
Although there are no randomized controlled trials evaluating its
use as an adjuvant treatment, two retrospective studies have sug-
gested that low-​dose aspirin reduces the risk of visual loss and stroke
in patients with giant cell arteritis. Bone protection with calcium,
vitamin D supplements and bisphosphonates as well as gastrointes-
tinal protection with proton pump inhibitors are recommended in
all patients with giant cell arteritis.
Disease monitoring
There are still no validated tools or biomarkers to assess treat-
ment response in giant cell arteritis. Although in clinical practice
CRP and ESR are the most commonly used inflammatory markers
for this purpose, they do not consistently reflect disease activity.
Preliminary analyses of circulating pentraxin 3 (PTX3), VEGF, IL-​6,
and antibodies against ferritin have suggested promise as potential
predictors of disease activity. However, further studies with larger
numbers of patients and longer follow-​up are warranted to assess the
value and feasibility of their routine use. Imaging has an important
role for monitoring giant cell arteritis. Using ultrasound scans, the
presence of halo correlates with ischaemic symptoms. Moreover, it
has been reported that the halo size decreases with glucocorticoid
therapy, suggesting that ultrasound may be a simple but powerful
tool to assess disease activity. In large vessel giant cell arteritis, MRI,
positron emission tomography, and ultrasound are the preferable
imaging modalities for monitoring response to treatment. Screening
for aortic aneurysms is advisable at least every 2 years by chest radio-
graph, echocardiography, positron emission tomography, or MRI.
The optimal frequency for patients’ routine care should be guided by
clinical symptoms, serum markers, and imaging; however, after dis-
ease remission, regular review is advisable for the first year.
Prognosis
The prognosis of giant cell arteritis is generally favourable. Some
studies have found an overall life expectancy similar to the gen-
eral population, while others have described a slight increase in
mortality, mostly due to cardiovascular events (stroke, myocardial
infarction, dissections, and rupture of aneurysms). Glucocorticoid-​
related adverse events have been reported in 86% of patients at
10-​year follow-​up and are also related to an increase in mortality.
Patients with large vessel giant cell arteritis have a higher incidence
19.11.6  Large vessel vasculitis
4551
of disease relapses and cumulative steroid doses when compared to
patients with cranial giant cell arteritis.
Takayasu arteritis
Epidemiology
The annual incidence of Takayasu arteritis is extremely low is most
populations studied, around 1–​3 per million. It occurs predomin-
antly in Asian populations, although patients with Takayasu arter-
itis have increasingly been recognized in other regions, such as the
United States, Europe, and South America. It has a female predom-
inance of 8–​9:1 affecting adults and children, with the peak inci-
dence occurring in the third decade of life.
Aetiology
The aetiology of Takayasu arteritis is unknown. Geographic differ-
ences in the incidence and patterns of vascular involvement sug-
gest that genetics and environmental risks factors may play a role
in the development of the disease. Mycobacterium tuberculosis,
hepatitis B, and herpes virus have been inconsistently implicated as
triggers of Takayasu arteritis. In addition, there have been several
reports of HLA associations across multiple ethnicities, particularly
HLA-​B52 (and to a lesser extent HLA-​B67 in Japanese patients).
Identification of susceptibility loci in IL6, FCGR2A/​ FCGR2A,
RPS9/​LILRB3, and an intergenic locus on chromosome 21q22 have
also been found in Takayasu arteritis.
Histopathology
The pathologic features seen in Takayasu arteritis are almost
indistinguishable from the ones found in giant cell arteritis.
Inflammation is more common in the aorta and its major branches.
Typically two distinct phases may coexist in the disease: an acute
inflammatory phase and a chronic phase characterized by intimal
hyperplasia and fibrosis of the tunica media and intima. Aortic wall
thickness is often greater in Takayasu arteritis than in giant cell ar-
teritis. Moreover, severe adventitial scarring and compact granu-
lomas are more frequently seen in Takayasu arteritis than in giant
cell arteritis.
Pathogenesis
The pathologic process of Takayasu arteritis remains poorly under-
stood. Just as in giant cell arteritis, the interaction between dendritic
cells and lymphocytes may contribute to the immune-​mediated re-
sponse seen in Takayasu arteritis. A potential target is a 65-​kD heat
shock protein (HSP-​65), which is highly expressed in the media and
vasa vasorum. Infiltration with γδ T cells, cytotoxic T lymphocytes,
T helper cells, natural killer cells, and macrophages occurs in pa-
tients with Takayasu arteritis. There is a release of proinflammatory
cytokines, such as IFN-​γ, TNFα, IL-​1, and IL-​6, and matrix
metalloproteinases, leading to arterial wall damage. Patients with
Takayasu arteritis have been reported to have higher expression
of IFN-​γ than patients with giant cell arteritis, which may explain
the increased rates of stenosis and occlusion in Takayasu arteritis.
Interestingly, the Th1-​FN γ axis is steroid sensitive in Takayasu ar-
teritis, as opposed to giant cell arteritis. Circulating anti-​endothelial
cell antibodies (AECA) have been inconsistently found in patients
with Takayasu arteritis. They may be involved in the pathogenesis of
Takayasu arteritis by activation of the endothelial cells.
Clinical manifestations
Patients with Takayasu arteritis typically have a heterogeneous clin-
ical presentation; however, a tri-​phasic pattern of disease progres-
sion has been described with a potential overlap between stages:
Phase 1:  Pre-​pulseless period, characterized mostly by constitu-
tional features, such as fatigue, low-​grade fever, weight loss, arth-
ralgia, and myalgia.
Phase 2:  Vascular inflammation predominates, characterized by
vessel pain and tenderness.
Phase 3: Inflammation has settled, but bruits and signs of ischaemia
persist as consequences of previous disease activity.
The diagnosis of Takayasu arteritis is often delayed for a substan-
tial period of time (months to years). In up to 20% of cases, the diag-
nosis is only made due to incidental findings, such as unexplained
high inflammatory markers, unequal arm blood pressures, or bruits.
Geographical differences have been reported in the vascular in-
volvement of the disease: the aortic arch and its branches are the
most frequently affected vessels in Japanese patients, as opposed to
Indian patients where the abdominal aorta is more commonly in-
volved. Lower limbs are also less affected than upper limbs.
Table 19.11.6.3 summarizes the published frequencies for the
most common clinical features of Takayasu arteritis.
Table 19.11.6.3  Frequencies of the most common features
of Takayasu arteritisa
Clinical manifestations of Takayasu arteritis (%)
Constitutional
symptoms
Fatigue
26–​56%
Arthralgia
5–​39%
Myalgia
15–​30%
Fever
9–​27%
Weight loss
2–​25%
Vascular
manifestations
Absent or diminished pulses
60–​88%
Asymmetric blood pressure
47–​81%
Bruits
62–​80%
Hypertension
35–​77%
Claudication
38–​70%
Carotidynia
14–​32%
Other
manifestations
Headache
26–​57%
Dizziness
24–​50%
Palpitations
9–​37%
Visual disturbances
5–​34%
Cutaneous manifestations
(e.g. erythema nodosum, pyoderma
gangrenosum, purpura)
3–​28%
Exertional dyspnoea
20–​27%
Syncope
16–​19%
Raynaud’s phenomenon
11–​15%
Stroke
3–​10%
Laboratory results in patients with Takayasu arteritis (%)
Elevated erythrocyte sedimentation rate
50–​83%
Elevated C-​reactive protein
51–​60%
a Data based on the clinical characteristics of 125 patients from China (Cong et al. 2010); 248
patients from Turkey (Bicakcigil et al. 2009); 108 patients from Korea (Park et al. 2005); 106
patients from India (Jain et al. 1996); and 60 patients from North America (Kerr et al. 1994).
section 19  Rheumatological disorders
4552
Diagnostic investigations
Unlike giant cell arteritis, vessel biopsies are rarely obtainable in
Takayasu arteritis. The diagnosis is mostly based on the combination
of clinical features, high inflammatory markers, and the presence of
characteristic arterial lesions on imaging.
Laboratory tests
Inflammatory markers are typically high at the onset of Takayasu ar-
teritis, just as they are in giant cell arteritis. The ESR has been reported to
be more commonly elevated than CRP. Normochromic-​normocytic
anaemia, thrombocytosis, and hypergammaglobulinaemia are also
very frequent. AECA do not seem to have any value in the diagnosis
of Takayasu arteritis.
Imaging
A clinical suspicion of Takayasu arteritis should prompt imaging
examination of the arterial tree. Although conventional angiog-
raphy is still the gold-​standard for diagnosing Takayasu arteritis, it
is an invasive procedure and is not able to detect wall thickness or
oedema, thus it is not useful for early diagnosis. Vessel stenosis is the
most common arteriographic finding, present in more than 80% of
patients at the time of diagnosis; aneurysms may be present, but typ-
ically occur later in the disease course.
Other imaging modalities have shown high sensitivity and spe-
cificity for the diagnosis of Takayasu arteritis (compared with con-
ventional angiography): 98% and 93% respectively for computed
tomography angiography (CTA) as shown in Fig. 19.11.6.3 and both
100% for magnetic resonance angiography. positron emission tom-
ography-​scans may be more sensitive than MRI in detecting vessel
inflammation and are a suitable whole-​body screening method
for diagnosing early Takayasu arteritis, especially in cases with
non​specific presenting symptoms, where the differential diag-
nosis is wide (Fig. 19.11.6.4). Ultrasound has been reported to
be more sensitive than MRI in assessing the common carotid ar-
teries. It can be used to evaluate the involvement of other vessels,
such as the axillary and subclavian arteries. It has the disadvantage
of being extremely operator dependent and not being able to access
the thoracic aorta.
Diagnosis and classification criteria
In 1988, Ishikawa proposed a set of diagnostic criteria for Takayasu
arteritis based on the age of disease presentation, clinical signs
and symptoms, laboratory findings, and angiographic abnormal-
ities. However, these criteria restricted the age of the disease onset
(<40 years) and were only tested in 96 Japanese patients (and 12
controls with other aortic diseases), not taking into account the
geographical differences in patterns of vascular involvement. These
criteria were subsequently modified by Sharma in 1995 with the re-
moval of the obligatory criteria of age and adjustment in the other
clinical and angiographic criteria (Table 19.11.6.4). They were
tested in 106 Indian and 79 Japanese patients with angiographic-
ally proven Takayasu arteritis and showed a sensitivity of 92.5% and
specificity of 95%. Classification criteria for Takayasu arteritis were
developed in 1990 by ACR, essentially with the aim of identifying a
homogeneous group of patients to include in epidemiologic studies
and clinical trials (Table 19.11.6.5). Both the existing diagnostic and
classification criteria do not include newer imaging modalities, such
as CTA, magnetic resonance angiography, positron emission tom-
ography, or ultrasound. The DCVAS study is underway to update
these criteria.
Fig. 19.11.6.3  Computed tomography angiogram of the chest with intravenous iodinated contrast of a patient with Takayasu
arteritis in axial view (left) and sagittal view (right) showing concentric wall thickening of the distal aspect of the aortic arch and the
descending thoracic aorta (yellow arrows).
19.11.6  Large vessel vasculitis
4553
Management
The rarity of Takayasu arteritis is a major limitation for random-
ized controlled trials; thus therapeutic decisions are often based
on observational studies, case series and clinician´s experience.
The management of patients with Takayasu arteritis not only in-
cludes medical treatment, but also potential surgical intervention.
Medical treatment
Glucocorticoids
Glucocorticoids are the mainstay treatment for Takayasu arteritis.
For patients with newly presenting active disease, the European
League Against Rheumatism (EULAR) recommends an initial dose
of prednisolone of 1 mg/​kg/​day (maximum 60 mg/​day) for at least
one month with subsequent gradual tapering. Although never for-
mally tested, a lower initial dose of prednisolone can be considered
in patients with no signs of ischaemia, especially if they have a high
risk of glucocorticoid-​related side effects.
Fig. 19.11.6.4  FDG PET-​CT scan of a patient with Takayasu arteritis
showing increased FDG uptake throughout the entire aorta and both
subclavian, axillary and carotid arteries (yellow arrows).
Table 19.11.6.4  Revised Ishikawa diagnostic criteria for Takayasu arteritis
Criteria
Definition
Major criteria
(1)  Left mid subclavian artery lesion
The most severe stenosis or occlusion present in the mid portion from the point 1 cm proximal to the vertebral artery
orifice up to that 3 cm distal to the orifice determined by angiography
(2)  Right mid subclavian artery lesion
The most severe stenosis or occlusion present in the mid portion from the right vertebral artery orifice to the point
3 cm distal to orifice determined by angiography
(3)  Characteristic signs and symptoms
(at least 1month duration)
Limb claudication, pulselessness or uneven pulse in limbs, undetectable blood pressure or the difference in bilateral
limb systolic blood pressure >10 mm Hg, fever, neck pain, transient amaurosis, blurred vision, syncope, palpitations,
or dyspnoea
Minor criteria
(1)  High ESR
Unexplained persistent ESR >20 mm/​h
(2)  Carotid artery tenderness
Unilateral or bilateral carotid arteries tenderness (neck muscle tenderness not included)
(3)  Hypertension
Persistent blood pressure >140/​90 mm Hg brachial or >160/​90 mm Hg popliteal
(4)  Aortic regurgitation or dilatation
Confirmed by auscultation, doppler ultrasound, or angiography
(5)  Pulmonary artery lesion
Lobar or segmental artery occlusion or presence of stenosis, aneurysm, luminal irregularity, or any combination in
pulmonary trunk or in unilateral or bilateral pulmonary arteries determined by angiography
(6)  Left mid common carotid lesion
Presence of the most severe stenosis or occlusion in the mid portion of 5 cm in length from the point 2 cm distal to
its orifice determined by angiography
(7)  Distal brachiocephalic trunk lesion
Presence of the most severe stenosis or occlusion in the distal brachiocephalic trunk artery
(8)  Descending thoracic aorta lesion
Stenosis, dilation, aneurysm, luminal irregularity, or any combination (tortuosity alone not included)
(9)  Abdominal aorta lesion
Stenosis, dilation, aneurysm, luminal irregularity, or any combination
(10)  Coronary artery lesion
Age <30 years, in the absence of risk factors like hyperlipidaemia or diabetes mellitus (documented on angiography)
The presence of two major or one major and two minor criteria or four minor criteria suggests a high probability of Takayasu arteritis.
Adapted from Sharma BK et al. (1996) Diagnostic criteria for Takayasu arteritis. Int J Cardiol, 54 Suppl: S127–​33, copyright 1996, with permission from Elsevier.
Table 19.11.6.5  ACR 1990 classification criteria for Takayasu
arteritis
Age <40 years old
Claudication of extremities
Decreased brachial arterial pulse
BP difference >10 mm Hg in systolic blood pressure between arms
Bruit over subclavian arteries or aorta
Arteriogram abnormality (narrowing or occlusion of the aorta, its proximal
branches, or large arteries in the proximal upper or lower extremities)
The patient is classified as having Takayasu arteritis if at least three of these six criteria are
present (sensitivity of 90.5% and specificity of 97.8%).
Adapted from Arend WP et al. (1990) The American College of Rheumatology 1990
criteria for the classification of Takayasu arteritis. Arthritis Rheum, 33(8): 1129–​1134.
section 19  Rheumatological disorders
4554
Other immunosuppressive therapy
Other immunosuppressive therapy is considered in patients who
relapse or are unable to tolerate corticosteroids. Based on evi-
dence from small open-​label studies, methotrexate is the first
drug of choice, followed by azathioprine. Recent evidence sup-
ports mycophenolate mofetil and leflunomide as steroid-​sparing
agents. Cyclophosphamide is reserved for severe life or vital
organ threatening conditions. Biological agents have been suc-
cessfully used to induce remission in refractory Takayasu arter-
itis, particularly tocilizumab and TNF inhibitors (etanercept and
infliximab). B cell depletion with rituximab has also shown some
benefit.
Adjuvant therapy
All patients should be prescribed low-​dose aspirin (75–​150  mg/​
day) and supplementation with calcium and vitamin D. Additional
prophylaxis of osteoporosis with bisphosphonates should be con-
sidered in accordance with local guidelines.
Surgical treatment
Revascularization procedures (e.g. angioplasty, stenting or bypass
surgery) are indicated in patients with severe stenosis. They should
be performed in the quiescent phase of the disease and in experi-
enced centres. Endovascular interventions have higher rates of re-
stenosis than surgical reconstructions, but may be appropriate in
selected patients with limited lesions.
Disease monitoring
All patients with Takayasu arteritis need long-​term monitoring
due to its progressive and relapsing nature. Unfortunately, as in
giant cell arteritis, there are no valid biomarkers for assessing
treatment response and diagnosing relapse. Takayasu arteritis
is therefore currently monitored based on the patients’ symp-
toms and signs (e.g. presence of new bruits or diminished/​ab-
sent pulses), serum inflammatory markers (ESR and CRP)
and imaging (preferably magnetic resonance angiography or
positron emission tomography; still limited evidence on ultra-
sound). Other potential serum markers to assess disease ac-
tivity have been investigated (AECA, circulating endothelial
cells, antibodies against ferritin, VEGF, IL-​6, IL-​8, IL-​18, matrix
metalloproteinase-​9, and adipokines), but with inconclusive re-
sults. High levels of plasma PTX-​3 have recently been detected in
the serum of patients with active disease, but further confirma-
tory studies are warranted.
The most frequently used criteria in clinical studies to define ‘ac-
tive disease’ in Takayasu arteritis were set by Kerr et al. in 1994
(Table 19.11.6.6). The Indian Takayasu Activity Score (ITAS2010)
is a validated tool for disease assessment in Takayasu arter-
itis (Table 19.11.6.7), derived from the Birmingham Vasculitis
Activity Score—​BVAS (a validated tool to evaluate disease activity
in small and medium-​vessel vasculitis). However, more evidence
is required of its value in accurately differentiating disease activity
from damage.
Prognosis
The prognosis of Takayasu arteritis varies according to different
studies. It is highly dependent on the type and severity of the ex-
isting vascular lesions and adverse effects of immunosuppression.
Long-​term survival rates are around 80% to 90%, decreasing to 66%
in cases of major Takayasu arteritis disease complications such as
hypertension, retinopathy, or vascular aneurysms. Disease relapses
have been reported in up to 96% of cases, with 66–​84% of patients
requiring additional immunosuppression to the standard gluco-
corticoid therapy.
IgG4-​related aortitis and periaortitis
Overview
IgG4-​related disease (IgG4-​RD) is a recently recognized fibro-​
inflammatory condition characterized by tissue infiltration of
IgG4-​positive plasma cells, fibrosis with a storiform pattern, and
a ‘tumour-​like’ swelling of the organs. Elevated serum concentra-
tions of IgG4 (>135 mg/​dl) are present in 60% to 70% of patients.
It can affect any organ system and involve one or multiple organs
simultaneously. It has been frequently described in the pancreas,
biliary tree, and gallbladder, major salivary glands, periorbital tis-
sues, lymph nodes, lungs, kidneys, retroperitoneum, and aorta.
Although reports of the disease are worldwide, its true epidemiology
is still unknown. Unusually for an inflammatory disease, it appears
to mainly affect men above 50 years of age with a male-​to-​female
ratio around 4–​6:1 (except for the variant involving head and neck
where the ratio is around 1:1).
Diagnostic criteria have been developed (Table 19.11.6.8), but in
most cases definitive diagnosis requires histological documenta-
tion of the organ involved.
IgG4-​related aortitis and periaortitis
Involvement of the aorta and its surrounding tissues has been re-
ported in around 9% of cases of IgG4-​RD. Up to 75% of cases
of patients previously classified as having ‘isolated idiopathic
thoracic aortitis’ due to incidental histological findings of vas-
cular inflammation following repair of thoracic aortic aneur-
ysms/​dissections are now known to have IgG4-​RD. In addition,
a subset of patients diagnosed with the so-​called ‘inflamma-
tory abdominal aortic aneurysm’ or ‘periaortitis’ (abdominal
aortic aneurysms with severe atherosclerosis that contain more
chronic inflammation and scarring in the adventitia than typical
atherosclerotic aneurysms) have IgG4-​RD. Moreover, IgG4-​RD
accounts for most cases of ‘idiopathic retroperitoneal fibrosis’
or Ormond’s disease, which may affect the periaortic region.
Treatment of IgG4-​RD with aortic or periaortic involvement is
with high-​dose of glucocorticosteroids. In steroid-​dependent
cases, azathioprine, methotrexate, mycophenolate mofetil, or
rituximab have been used.
Table 19.11.6.6  Criteria for active disease in patients with Takayasu
arteritisa
1.  Constitutional features, such as fever, musculoskeletal (no other cause
identified)
2.  Elevated ESR
3.  Features of vascular ischaemia or inflammation, such as claudication,
diminished or absent pulse, bruit, vascular pain (carotidynia), asymmetric
blood pressure in either upper or lower limbs (or both)
4.  Typical angiographic features
a New onset or worsening of two or more features indicates ‘active disease’
Adapted from Kerr GS et al. (1994) Takayasu Arteritis. Ann Intern Med, 120(11): 919–​929.
19.11.6  Large vessel vasculitis
4555
Table 19.11.6.7  ITAS2010—​Indian Takayasu Activity Score
Tick box only if abnormality is present and new or worse within the past 3 months
Tick box only if abnormality is ascribed to current, active vasculitis
SYSTEMIC
RENAL
None
□
None
□
Malaise/​Wt. Loss >2 kg
⚪
Hypertension (Diastolic >90 mm Hg)
●
Myalgia/​Arthralgia/​Arthritis
⚪
Hypertension (Systolic >140 mm Hg)
⚪
Headache
⚪
ABDOMEN
NERVOUS SYSTEM
None
□
None
□
Severe Abdominal Pain
⚪
Stroke
●
GENITOURINARY SYSTEM
Seizures (not hypertensive)
⚪
None
□
Syncope
⚪
Abortions
⚪
Vertigo/​dizziness
⚪
CARDIOVASCULAR SYSTEM
R
L
6a. Bruits
None
□
Carotid
⚪
⚪
Subclavian
⚪
⚪
Bruits (see 6a)
●
Renal
⚪
⚪
6b. Pulse and BP Inequality
Pulse Inequality (See 6 b)
●
Present
⚪
6c. Pulse Loss
New Loss of Pulses (See 6c)
●
Carotid
⚪
⚪
Subclavian
⚪
⚪
Claudication (See 6d)
●
Brachial
⚪
⚪
Radial
⚪
⚪
Carotidodynia
●
Femoral
⚪
⚪
Popliteal
⚪
⚪
Posterior Tibial
⚪
⚪
Aortic Incompetence
⚪
Dorsalis Pedis
⚪
⚪
Myocardial Infarct/​Angina
⚪
6d. Claudication
Cardiomyopathy/​cardiac failure
⚪
Arm
⚪
Leg
⚪
Physician Global Assessment
ESR_​_​_​_​_​_​_​
CRP_​_​_​_​_​_​_​
Active
Grumbling or persistent
Inactive
New Imaging Y/​N?
If Y—​specify _​_​_​_​_​_​_​_​_​_​_​_​_​_​_​_​_​_​_​_​_​_​_​_​_​_​_​_​_​
Scoring ITAS2010: Add all scores (see glossary)
Item scores □ = 0 ⚪ = 1 ● = 2
Scoring ITAS. A including acute phase response:
For ESR, score ITAS plus: 0 for ESR <20; 1 for ESR 21–​39; 2 for ESR 40–​59; and
3 for ESR >60 mm
For CRP score ITAS plus: 0 for CRP <5; 1 for CRP 6–​10; 2 for CRP 11–​20;
and 3 for CRP >20 mg/​dl
Adapted from Misra R et al. (2013) Development and initial validation of the Indian Takayasu Clinical Activity Score (ITAS2010). Rheumatology (Oxford), 52(10): 1795–​1801, by permission
of Oxford University Press.

19.11.7 ANCA- associated vasculitis 4556 David Jay
19.11.7 ANCA- associated vasculitis 4556 David Jayne
section 19  Rheumatological disorders
4556
FURTHER READING
Alibaz-​Oner F, Direskeneli H (2015). Update on Takayasu’s arteritis.
Presse Med, 44, e259–​65.
Dasgupta B, et  al.; BSR and BHPR Standards, Guidelines and
Audit Working Group (2010). BSR and BHPR guidelines for the
management of giant cell arteritis. Rheumatology (Oxford), 49,
1594–​7.
Hayreh SS, Zimmerman B, Kardon RH (2002). Visual improve-
ment with corticosteroid therapy in giant cell arteritis: report of
a large study and review of literature. Acta Ophthalmol Scand,
80, 355–​67.
Keser G, Direskeneli H, Aksu K (2014). Management of Takayasu
arteritis:  a systematic review. Rheumatology (Oxford), 53,
793–​801.
Luqmani R, et al. (2016). The role of ultrasound compared to biopsy
of temporal arteries in the diagnosis and treatment of giant cell
arteritis (TABUL):  a diagnostic accuracy and cost-​effectiveness
study. Health Technol Assess, 20, 1–​238.
Mukhtyar C, et al. and the European Vasculitis Study Group (2009).
EULAR recommendations for the management of large vessel
vasculitis. Ann Rheum Dis, 68, 318–​23.
Nesher G (2014). The diagnosis and classification of giant cell arteritis.
J Autoimmun, 48–​49, 73–​5.
Nuenninghoff DM, et al. (2003). Incidence and predictors of large-​
artery complication (aortic aneurysm, aortic dissection, and/​
or large-​artery stenosis) in patients with giant cell arteritis:  a
population-​based study over 50 years. Arthritis Rheum, 48, 3522–​31.
O’Neill L, et al. (2015). Giant cell arteritis and Takayasu arteritis: are
they a different spectrum of the same disease? Indian Journal of
Rheumatology. DOI:10.1016/​j.injr.2015.03.009
Palazzoa E, Palazzo C, Palazzo M (2014). IgG4-​related disease 2014.
Joint Bone Spine, 81, 27–​31
Ponte C, et  al. (2015). Giant cell arteritis:  current treatment and
management. World J Clin Cases, 3, 484–​94.
Slart RHJA, et al. (2018). FDG-PET/CT(A) imaging in large vessel
vasculitis and polymyalgia rheumatica: joint procedural recom-
mendation of the EANM, SNMMI, and the PET Interest Group
(PIG), and endorsed by the ASNC. Eur J Nucl Med Mol Imaging.
doi: 10.1007/s00259-018-3973-8.
Smetana GW, Shmerling RH (2002). Does this patient have temporal
arteritis? JAMA, 28, 92–​101.
Stone JR (2011). Aortitis, periaortitis, and retroperitoneal fibrosis,
as manifestations of IgG4-​related systemic disease. Curr Opin
Rheumatol, 23, 88–​94.
Stone J, et al. (2017). Trial of Tocilizumab in Giant-Cell Arteritis. N
Engl J Med. 377, 317–28.
19.11.7  ANCA-​associated vasculitis
David Jayne
ESSENTIALS
The antineutrophil cytoplasmic antibody-​associated vasculitides
are a grouping of three syndromes of acute and chronic inflam-
mation characterized by their clinical and histological pheno-
types. They comprise (1) granulomatosis with polyangiitis (formerly
known as Wegener’s granulomatosis), (2) microscopic polyangiitis,
and (3)  eosinophilic granulomatosis with polyangiitis (formerly
known as Churg-​Strauss syndrome).
Pathology—​the defining histological lesion is a microscopic vas-
culitis affecting arterioles, capillaries, or venules associated with few
or no deposits of immunoglobulin or complement. Granulomata,
involving or close by blood vessels, are commonly present in
granulomatosis with polyangiitis.
Clinical features—​disease involves multiple organ systems with
considerable heterogeneity in extent and severity of organ involve-
ment between patients, and overlapping clinical and histological
features between syndromes. Most patients are unwell at the time
of diagnosis with constitutional symptoms of fatigue and mal-
aise, fevers, night sweats, weight loss, headache, and polymyalgia.
The commonest specific manifestations are in the upper respira-
tory tracts (destructive lesions), trachea-​bronchi, lungs (infiltrates,
pulmonary haemorrhage), kidneys (focal, necrotizing, crescentic
glomerulonephritis), skin (purpura), and nervous system (peripheral
neuropathy, mononeuritis multiplex).
Management—​the goals of therapy are to achieve a remission
in disease activity, prevent relapse, and minimize drug toxicity and
the risk of comorbid conditions. An induction phase of 3–​6 months
with (typically) a combination of high-​dose glucocorticoids and ei-
ther cyclophosphamide or rituximab, is followed by a longer remis-
sion maintenance phase with (typically) lower dose glucocorticoid
and one of azathioprine, methotrexate, mycophenolate mofetil, or
rituximab.
Prognosis—​advanced renal failure, increasing age, a high disease
activity at diagnosis and the MPO-​ANCA subtype are adverse pre-
dictors. Infection, in part attributable to treatment, and alveolar
haemorrhage are the most common causes of early death while in-
creased risks of malignancy and cardiovascular disease contribute to
later mortality.
Introduction
The antineutrophil cytoplasmic antibody (ANCA)-​associated vas-
culitides (AAV) are a grouping of three syndromes of acute and
chronic inflammation characterized by their clinical and histo-
logical phenotypes (Fig. 19.11.7.1). They comprise granulomatosis
with polyangiitis (GPA, formerly Wegener’s granulomatosis),
microscopic polyangiitis (MPA) and eosinophilic granulomatosis
with polyangiitis (EGPA, formerly Churg-​Strauss syndrome).
They involve multiple organ systems with considerable heterogen-
eity in extent and severity of organ involvement between patients,
Table 19.11.6.8  Diagnostic criteria for IgG4-​related disease
1.  Diffuse/​ localized swelling or mass in one or more organs
2.  Elevated serum IgG4 concentrations (greater than 135 mg/​dl)
3.  Histopathological features:
(a)  Marked lympho-​plasmacytic infiltration with fibrosis
(b)  Infiltration of IgG4+ plasma cells >10/​HPF ratio of IgG4/​IgG ratio >40%
Diagnosis is definitive if all criteria are met, probable if only criteria 1 and 3 are present
and possible if only criteria 1 and 2 are fulfilled.
Adapted from Umehara et al. (2012) Comprehensive diagnostic criteria for IgG4-​related
disease (IgG4-​RD), 2011. Modern Rheumatology, 22(1): 21–​30, reprinted by permission
of Taylor & Francis Ltd (http://​www.tandfonline.com).
19.11.7  ANCA-associated vasculitis
4557
and overlapping clinical and histological features between syn-
dromes. The defining histological lesion is a microscopic vascu-
litis affecting arterioles, capillaries, or venules associated with
few or no deposits of immunoglobulin or complement. However,
involvement of larger vessels, including the aorta, can occur, im-
mune complex deposition can be more prominent, and ANCA can
be absent from the circulation. Granulomata, involving or close
by blood vessels, are commonly present in granulomatosis with
polyangiitis, but can also be seen in microscopic polyangiitis and
eosinophilic granulomatosis with polyangiitis. The autoimmune
basis for ANCA-​associated vasculitis was presumed due to the ab-
sence of a causative agent and confirmed by the subsequent associ-
ations with ANCA and HLA Class II.
History
Friedrich Wegener described a series of three autopsy cases in
Germany in 1936 with a triad of necrotizing granulomatosis with
vasculitis of the upper and lower respiratory tract, and glomer-
ulonephritis. By 1954 Goodman and Churg, in New  York, as-
sembled a review of 22 cases and confirmed the term ‘Wegener’s
granulomatosis’. At the same time, Churg and Strauss recognized
a variant vasculitic syndrome with predominant eosinophilic in-
filtration in diseased tissues, asthma, and peripheral eosinophilia,
both microscopic and medium-​sized vessel vasculitis and granu-
lomata, which became termed Churg-​Strauss syndrome. In 1948
Davson, Ball, and Platt described a microscopic form of polyarteritis
often associated with a necrotizing glomerulonephritis but without
granulomata, a finding supported by Goodman and Churg in 1954.
Through the next 40 years, there was varying uptake of the term
microscopic polyangiitis, such patients were often not differenti-
ated from polyarteritis nodosa, and those with renal involvement
were also termed ‘idiopathic’ rapidly progressive, or crescentic,
glomerulonephritis.
In 1990 the American College of Rheumatology developed clas-
sification criteria for vasculitic syndromes. This system did not
include a subgroup for microscopic polyangiitis and did not in-
clude ANCA. These criteria for granulomatosis with polyangiitis
(Wegener’s) and eosinophilic granulomatosis with polyangiitis
(Churg-​Strauss) have been used in subsequent clinical trials.
The first Chapel Hill Consensus Conference in 1993 produced
disease definitions based on clinical and histological criteria
for all the primary vasculitis syndromes, including microscopic
polyangiitis, and has served as an important foundation for vas-
culitis research. An update in 2012 subdivided small vessel vascu-
litides into ‘ANCA associated’ and ‘immune complex’ groupings,
and replaced certain eponyms, such as Wegener’s, with descriptive
terms (Fig. 19.11.7.2).
Eosinophilia
15% renal
40% ANCA
EGPA
90% renal
Mainly MPO-ANCA
Asia
Median age 65 yr
MPA
Respiratory tract
Granulomata
70% renal
Mainly PR3-ANCA
Median age 55yr
GPA
Fig. 19.11.7.1  The three subtypes of ANCA-​associated vasculitis
(GPA, granulomatosis with polyangiitis; MPA, microscopic polyangiitis;
EGPA, eosinophilic granulomatosis with polyangiitis; PR3, proteinase 3;
MPO, myeloperoxidase).
Medium vessel vasculitis
Polyarteritis nodosa
Kawasaki disease
Large vessel vasculitis
Takayasu arteritis
Giant cell arteritis
ANCA-associated vasculitis
Microscopic polyangiitis
Granulomatosis with polyangiitis
Eosinophilic granulomatosis with polyangiitis
Immune complex SVV
Anti-GBM disease
Cryoglobulinemic vasculitis
IgA vasculitis (Henoch-Schönlein)
Hypocomplementemic urticarial vasculitis
(Anti-C1q vasculitis)
Small vessel vasculitis
Fig. 19.11.7.2  The 2012 Chapel Hill Consensus Classification of primary systemic vasculitis.
Adapted from Jennette JC et al. (2013). 2012 Revised International Chapel Hill Consensus Conference
Nomenclature of Vasculitides. Arthritis & Rheumatism, 65: 1–​11, © 2013, American College of
Rheumatology.
section 19  Rheumatological disorders
4558
 ANCA
An association of autoantibodies to cytoplasmic components of
neutrophils with granulomatosis with polyangiitis (then Wegener’s)
described in 1985 became a turning point in vasculitis research
and led to major advances in the understanding of disease patho-
genesis, diagnosis, and treatment. ANCA were recognized by the
staining pattern of IgG immunoglobulins within patient sera when
overlayed on normal, fixed neutrophils. Two patterns were recog-
nized: binding to the primary azurophilic granules, ‘cytoplasmic’
or C-​ANCA, or binding around the cell nucleus, ‘peri-​nuclear’ or
P-​ANCA.
Within five years the target autoantigen for C-​ANCA was iden-
tified as the 29kd serine protease proteinase 3 (PR3), and for
P-​ANCA, the primary granule enzyme, myeloperoxidase (MPO)
(Fig. 19.11.7.3). The P-​ANCA binding was a fixation artefact and
with other techniques, autoantibodies to myeloperoxidase pro-
duced a C-​ANCA pattern. Solid phase autoantigen specific as-
says were developed and the terms PR3-​ANCA and MPO-​ANCA
adopted. Other neutrophil cytoplasm autoantibodies were detected,
for example, to lactoferrin, cathepsin G and bacterial permeability
increasing protein (BPI), but only PR3-​ANCA and MPO-​ANCA
retained a high specificity for vasculitis and were demonstrated to
have clinical utility in routine practice.
PR3-​ANCA is the predominant autoantigenic specificity
found in granulomatosis with polyangiitis and MPO-​ANCA in
microscopic polyangiitis. The frequency of ANCA positivity is
lower in early or limited presentations in granulomatosis with
polyangiitis or after the onset of immunosuppressive treat-
ment. Fewer eosinophilic granulomatosis with polyangiitis pa-
tients are ANCA-​positive and MPO-​ANCA is the predominant
serotype (Table 19.11.7.1). Dual positivity for PR3-​ANCA and
MPO-​ANCA is rare and usually a testing artefact, but is seen in
drug-​induced causes of ANCA-​associated vasculitis. It is cur-
rently recommended that both the indirect immunofluores-
cence and solid phase assays are used in routine ANCA testing
laboratories.
Epidemiology
Incidence and prevalence
The incidence of ANCA vasculitis in Europe and Japan is between
13 and 20/​million with varying distribution of the three syndromes
(Table 19.11.7.2). Granulomatosis with polyangiitis being more
common in Europe and microscopic polyangiitis more common in
Japan. Earlier incidence estimates were lower due to problems with
ascertainment. Prevalence rates in Northern Europe are 100–​250/​
million, with the number rising as patient survival has improved and
there is near complete case identification.
Geography and ethnicity
The incidence of granulomatosis with polyangiitis and eosino-
philic granulomatosis with polyangiitis is highest the further
Fig. 19.11.7.3  The patterns of antineutrophil cytoplasm autoantibodies
(ANCA) seen on indirect immunofluorescence. (a) Cytoplasmic ANCA
(C-ANCA). (b) Peri-nuclear-ANCA (P-ANCA).
Table 19.11.7.1  The frequencies of ANCA serotypes in the different
ANCA-​associated vasculitis subgroups at the time of diagnosis
PR3-​ANCA
MPO-​ANCA
Either PR3-​ANCA
or MPO-​ANCA
GPA
66%
24%
90%
MPA
27%
58%
85%
EGPA
5%
35%
40%
GPA, granulomatosis with polyangiitis; MPA, microscopic polyangiitis; EGPA,
eosinophilic granulomatosis with polyangiitis. PR3, proteinase 3; MPO, myeloperoxidase.
Table 19.11.7.2  The incidence and prevalence of ANCA-​associated
vasculitis syndromes
Incidence Europe
(/​million/​year)
Incidence Japan
(/​million/​year)
Prevalence Europe
(/​million)
GPA
8–​11
  2
140–​160
MPA
3–​10
18
60–​90
EGPA
1–​2
<1
11–​14
Total
13–​20
20
150–​250
GPA, granulomatosis with polyangiitis; MPA, microscopic polyangiitis; EGPA,
eosinophilic granulomatosis with polyangiitis.
19.11.7  ANCA-associated vasculitis
4559
from the equator whether in the Northern or Southern hemi-
sphere. This has been attributed to lower ultraviolet light ex-
posure or different microbial colonization in cooler, temperate
climates. Ethnic differences in the proportion of patients with PR3
as opposed to MPO-​ANCA exist, with approximately equal rates
in Western Europe, but a strong predominance, 95%, of MPO-​
ANCA in China and Japan.
Age and sex
The peak age of onset for granulomatosis with polyangiitis is 40–​
60  years, with a female preponderance in younger age groups.
Microscopic polyangiitis occurs approximately 10 years later, with
the frequency increasing over 70 years of age. EGPA has a peak age
of onset of 30–​50 years, but the characteristically long prodrome
complicates defining the time of disease onset. ANCA vasculitis
is a rare vasculitis in children and very rare in young children.
Granulomatosis with polyangiitis is the most common form in
childhood and is typically seen in adolescents when it behaves in a
similar manner to adults.
Aetiology
Genetics
Familial, ANCA-​associated vasculitis is very rare, with some sibling
pairs reported, and no monogenic causes have been found. A large
genome wide association survey has demonstrated that patients
with PR3-​ANCA and MPO-​ANCA are genetically distinct, and
that genetic associations are stronger with the autoantibody sero-
type than clinical syndrome of granulomatosis with polyangiitis or
microscopic polyangiitis. PR3 and MPO-​ANCA were associated
with loci in the HLA-​DQ and HLA-​DR regions of major histo-
compatibility complex (MHC) Class  II, respectively. PR3-​ANCA
positive patients were additionally associated with polymorphisms
near the gene encoding for PR3 and with α-1 antitrypsin, the major
protease inhibitor of PR3. Associations reported from candidate
gene studies include PTPN22, CTLA4, and complement C3 await
further confirmation.
Secondary causes
The causal association of ANCA vasculitis with other agents
or diseases identifies secondary vasculitis and is of importance
both in correct classification and management, as addressing
the cause will contribute to control of disease (Table 19.11.7.3).
Environmental exposure to silica, typically in coal miners, is as-
sociated with MPO-​ANCA vasculitis and the strength of associ-
ation depends on the severity of silica induced interstitial lung
disease. There is no strong evidence to support a causal asso-
ciation with other environmental exposures or occupations, or
smoking. Propylthiouracil is the most common drug-​induced
cause of ANCA vasculitis: other drugs implicated in aetiology
include penicillamine, hydralazine, and minocycline. Nasal co-
caine can cause a destructive non​vasculitic granulomatous dis-
ease of the upper respiratory tract difficult to distinguish from
localized granulomatosis with polyangiitis. This association
is further complicated by the occurrence of systemic micro-
scopic polyangiitis with the cocaine/​levamisole combination.
Drug-​induced causes of vasculitis are usually associated with
MPO-​ANCA, but other neutrophil antigens such as cathepsin
G, elastase or lactoferrin may be targeted, or may occur with
non​neutrophil autoantibodies.
ANCA vasculitis can occur in the setting of chronic bacterial
infection, such as bronchiectasis, cystic fibrosis, infective endocar-
ditis, and bacterial abscesses, when MPO-​ANCA is the predom-
inant ANCA subtype. Tuberculosis, both latent and clinically overt
infection, can be associated with an ANCA-​associated vasculitis
diagnosis. Nasal infection with Staphylococcus aureus has been
associated with relapse in granulomatosis with polyangiitis and
may play an aetiologic role supported by the respiratory epithe-
lium being the first site of injury in this syndrome. Urinary infec-
tion with E. coli has been shown to induce another antineutrophil
antibody, to leucocyte associated membrane protease (LAMP2),
through molecular mimicry, and transient antiLAMP2 antibodies
occur in patients with renal vasculitis, but the link in humans to
urinary infection is undetermined.
Although vasculitis can be caused by chronic viral infections,
including HIV, hepatitis B and C and Varicella Zoster, an aetio-
logical link of these viruses to ANCA-​associated vasculitis is not
clear. In older patients, an epithelial malignancy may be found at the
time of an ANCA-​associated vasculitis diagnosis.
MPO-​ANCA is present in 20% of patients with systemic lupus
erythematosus (SLE) and nephritis, but the significance of this is
uncertain although cases of a necrotizing, pauci-​immune glomer-
ulonephritis have been reported in SLE suggesting a genuine dual
pathology. One-​third of patients with antiglomerular basement
membrane (GBM) disease are ANCA positive, again usually MPO-​
ANCA, and these patients display features of extrarenal vasculitis
and pursue a relapsing disease course, typical of ANCA-​associated
Table 19.11.7.3  Secondary causes of ANCA-​associated
glomerulonephritis
Exposure
Autoantibody association
Environmental
Silica
MPO-​ANCA
Risk proportionate to
exposure
Drugs
Propylthiouracil
MPO-​ANCA > PR3-​ANCA
Other autoantibodies
frequent
Penicillamine
Hydralazine
Minocycline
Cocaine, especially
in combination with
levamisole
Infection
Chronic bacterial
MPO-​ANCA > PR3-​ANCA
Bronchiectasis, cystic fibrosis,
infective endocarditis
Tuberculosis
PR3-​ANCA or MPO-​ANCA
Malignancy
Other inflammatory
disorder
Systemic lupus
erythematosus
MPO-​ANCA > PR3-​ANCA
Anti-​GBM disease
PR3, proteinase 3; MPO, myeloperoxidase; GBM, glomerular basement membrane.
section 19  Rheumatological disorders
4560
vasculitis. As both ANCA and anti-​GBM antibodies are present at
the time of diagnosis the causal inter-​relation between these two dis-
orders is not known.
Pathology
Neutrophils, macrophages, and ANCA
ANCA-​associated vasculitis is a neutrophil predominant vascu-
litis of microscopic vessels. Neutrophils can be seen marginating
on the surface of the vessel wall and in the wall itself where they
cause endothelial cytotoxicity through release of free radicals, pro-
teases, and other products. There is subsequent thrombotic occlu-
sion of the lumen, extravasation of blood through ruptured vessel
walls and distal infarction. This process has been shown to be ANCA
dependent in in vitro systems and animal models, and ANCA are
thought to contribute to the pathogenesis in humans. A  murine
model of MPO-​ANCA vasculitis has been developed that is de-
pendent on MPO-​ANCA, but development of PR3 ANCA models
has been hampered by the lack of a murine homologue. There is no
robust model of ANCA-​associated granuloma formation.
ANCA antigens, stored in the primary cytoplasmic granules,
translocate to the neutrophil cell surface following priming, for ex-
ample, with tumour necrosis factor, complement factor 5a (C5a) or
interleukin-​1. They are then available for binding by ANCA, and
surface antibody is then cross-​linked by neutrophil Fc receptors that
trigger an intracellular cascade leading to neutrophil degranulation
and superoxide release. ANCA antigens are also present in macro-
phages and macrophages are present at sites of injury but their role
in the inflammatory process is less well understood. Dendritic cells
in the tissue, especially in the respiratory tract may play an initiating
or continuing role though stimulation by microbial ligands of Toll
like receptors.
Granulomata, B and T cells
In granulomatosis with polyangiitis, dense peri-​vascular areas of in-
flammation have the appearance of poorly formed granulomata with
multinucleate giant cells, macrophages, and lymphocytes. Activated
B cells and ANCA secreting plasma cells can be seen in the inflamma-
tory infiltrate along with activated CD4 and CD8 lymphocytes sug-
gesting a tertiary lymphoid organ function. The mechanisms leading
to granulomata are poorly understood, but Th1, Th17, and NK T cell
activation with sustained antigen presentation through dendritic cells
are implicated. Lymphocytes are less common at sites of small vessel
vasculitis, such as glomerulonephritis, although interstitial T cell in-
filtration occurs and has been associated with an adverse prognosis.
Complement
Scanty deposits of IgG and complement can be seen or may be com-
pletely absent. Special stains for C3 split products, C3d, and for the
C5b-​9 terminal attack complex have highlighted that alternative
complement pathway activation and complement mediated cell
lysis is occurring. A positive feedback loop has been described by
which neutrophil products, properdin and factor B, accelerate the
C3 convertase leading to cleavage of C5 and an increase in the neu-
trophil chemoattractant and primer C5a. Inhibition of C5a in a C5
receptor humanized murine model has abrogated the evolution of
ANCA vasculitis (Fig. 19.11.7.4).
Genetics
Background
Dysregulation of the
immune system
T cells
B cells
Interaction
Neutrophil
Proinflammatory
cytokine
Complement
system
Alternative
pathway
C5a
C5b c.C9
(Membrane
attack
complex)
PR3/MPO
Priming
ANCA, anti LAMP-2Ab?
anti Moesin Ab?
Cytotoxicity
Activation
NETs
Perforin
T effector
cells
Inflammation of
small vessel
ROS
Vascular endothelium
• HLA-DP, SERPINA1, PRTN3
(for GPA)
• HLA-DQ (for MPA)
• Others ... PTPN22?, CTLA4?
Environments
• Air pollutants... Silica
• Infection ... S.aureus,
E-coli
• Drug ...... Propylthiouracil,
Cocaine
Fig. 19.11.7.4  A schematic representation of the pathogenesis of ANCA-​associated vasculitis.
Reprinted from Furuta S and Jayne DRW (2013). Antineutrophil cytoplasm antibody-​associated vasculitis: recent developments.
Kidney International, 84(2): 244–​249, copyright 2013, with permission from Elsevier.
19.11.7  ANCA-associated vasculitis
4561
Clinical features
There is considerable heterogeneity between patients in the ex-
tent and severity of their clinical presentation. Certain pat-
terns of disease can be described (Table 19.11.7.4) but many
patients have unusual or incomplete presentations that com-
plicate and delay diagnosis. While clinical features, such as
purpuric rash or collapse of the nasal septum, lead to rapid
suspicion of a vasculitis, others mimic more common dis-
eases, for example, chest infections or inflammatory arthritis,
leading to delayed diagnoses and treatment. The pattern of
organ distribution differs between syndromes and ethnicities
(Table 19.11.7.5).
Prodromal phase
GPA and MPA patients exhibit symptoms for, on average, six
months before the diagnosis is made. They consist of intermit-
tent features of systemic disturbance and focal inflammatory
features, such as, a flitting arthritis, episcleritis, or purpuric
rash. In granulomatosis with polyangiitis ear, nose, and throat
symptoms predominate. The prodromal phase can be much
longer in eosinophilic granulomatosis with polyangiitis, where
Table 19.11.7.4  Common clinical presentations of ANCA-​associated vasculitis
Clinical pattern
Clinical features
Specific features
Serology
Histology
Diagnosis
‘Classical’
GPA/​Wegener’s
Destructive ENT
lesions. With or without
pulmonary disease with
or without nephritis
Nasal congestion,
epistaxis, crusting,
conductive deafness,
hoarseness, stridor
Pulmonary nodules or
cavities
Usually PR3-​ANCA,
may be negative in ENT
localized presentations
Low yield of confirmatory
histology on ENT biopsies,
higher yield on guided lung
biopsies but usually not
justified
GPA
Renal
Nephritis
Haematuria with
proteinuria with or
without elevated serum
creatinine
PR3-​ANCA or MPO-​
ANCA, fewer than 10%
are ANCA negative
High yield from renal
biopsy of a pauci-​immune,
necrotizing, crescentic
glomerulonephritis
GPA, if destructive
respiratory tract
features are present,
otherwise MPA
Pulmonary renal
syndrome
Diffuse alveolar
haemorrhage with
nephritis
Haemoptysis, dyspnoea,
pulmonary infiltrates with
nephritis
PR3-​ANCA or MPO-​
ANCA, fewer than 10%
are ANCA negative
High yield from renal
biopsy of a pauci-​immune,
necrotizing, crescentic
glomerulonephritis
GPA, if destructive
respiratory tract
features are present,
otherwise MPA
Systemic
vasculitis
At least one of: skin,
joint, eye, nerve, lung,
kidney, or other organ
vasculitis without
prominent ENT disease
Purpura, arthritis, scleritis,
neuropathy, pulmonary
infiltrates, nephritis
PR3-​ANCA or MPO-​
ANCA or ANCA negative
Skin histology is non-​
specific, renal biopsy best
if nephritis present. Nerve
biopsy if serology negative
and predominant organ
involved
Usually MPA but can
evolve into GPA
‘Classical’ EGPA/​
Churg-​Strauss
Maturity onset asthma,
non​destructive ENT
disease and vasculitic
features (nerve, heart
and gut involvement
more common than
GPA/​MPA)
Wheeze, rhinitis,
nasal polyps, sinusitis,
conductive deafness; with
neuropathy, abdominal
pain, myocarditis
Eosinophilia and
eosinophils >10% of
white cell count.
60% ANCA negative, if
positive, usually MPO-​
ANCA, and associated
with nephritis and
neuropathy
Eosinophil predominant
infiltrate. Biopsy not
required for classical
presentations but useful
for gut involvement and
nephritis
EGPA
Note; all presentations are associated with a prodrome of constitutional symptoms.
(GPA, granulomatosis with polyangiitis; MPA, microscopic polyangiitis; EGPA, eosinophilic granulomatosis with polyangiitis; PR3, proteinase 3; MPO, myeloperoxidase).
Table 19.11.7.5  The frequency of organ involvements in 735 patients recruited into European Vasculitis
Society trials
Organ involvement (%)
All patients (n = 735)
MPA (n = 332)
GPA (n = 403)
P value
Systemic
91
85
95
<0.001
Cutaneous
23
18
27
0.007
Mucous membranes/​eye
28
15
39
<0.001
Ear, nose, and throat
54
20
81
<0.001
Chest
54
42
63
<0.001
Cardiovascular
6
5
7
0.40
Abdominal
5
6
4
0.30
Renal
88
98
81
<0.001
Neurological
20
15
23
0.010
section 19  Rheumatological disorders
4562
an ‘allergic’ phase of rhinitis and asthma can precede the appear-
ance of vasculitis by many years.
Systemic
Most ANCA-​associated vasculitis patients are profoundly un-
well at the time of diagnosis with constitutional symptoms of fa-
tigue and malaise, fevers, night sweats, weight loss, headache, and
polymyalgia. In occasional elderly patients, there are no focal fea-
tures of vasculitis and this presentation can be labelled as a ‘failure
to thrive’ with diagnosis relying on serological testing.
Respiratory tract
Destructive lesions of the ear, nose or throat (ENT) region with
granulomata and vasculitis are the hallmark of granulomatosis with
polyangiitis and can be the only organ specific manifestation (local-
ized granulomatosis with polyangiitis) or be in combination with pul-
monary and renal disease, the classical triad described by Wegener.
The nasal mucosa is congested and ulcerated with large bloody crusts
developing on its surface, which detach through the nose or back of
the throat. Epistaxis and nasal congestion is common and there may be
pain across the nasal bridge and progressive collapse of the nasal car-
tilage. Similar inflammation occurs within the nasal sinuses leading to
opacification, infection, and chronic facial pain and headache. Mucosal
inflammation can be visualized on magnetic resonance (MR) imaging
and bone destruction on plain X-​ray or computed tomography (CT).
Involvement of the Eustachian tubes cause secretory otitis media,
conductive deafness, middle-​ear infection, and tympanic rupture.
Laryngeal disease results in hoarseness and subglottic stenosis. This
lesion being more frequent in younger, female, granulomatosis with
polyangiitis patients, and often appearing some months after the diag-
nosis. Ear, nose, and throat involvement is uncommon in microscopic
polyangiitis when it is non​destructive and clears rapidly with therapy.
Symptoms of pulmonary involvement include cough, haemop-
tysis, and shortness of breath. Alveolar capillaritis appears as patchy
or diffuse radiologic infiltrates, and may be asymptomatic or asso-
ciated with hypoxia and respiratory failure. In granulomatosis with
polyangiitis, multifocal infiltrates with cavities of varying size can be
seen. Thickening of the bronchial walls similar to bronchiectasis oc-
curs and localized tracheal or bronchial stenoses in granulomatosis
with polyangiitis can cause distal pulmonary collapse or infection.
Interstitial lung disease, pulmonary fibrosis, can be seen in a mi-
nority of patients at diagnosis and may slowly progress to respiratory
failure despite stability of other vasculitic manifestations. Chest CT
scanning is required to define and monitor pulmonary pathology,
supported by pulmonary function testing (Fig. 19.11.7.5).
Bronchoscopic evaluation of tracheo-​bronchial disease allows as-
sessment of vasculitic activity based on hyperemia, ulceration, and
contact bleeding, as well as later cictricial scaring. Bronchoalveolar
lavage can help define alveolar haemorrhage as serial aspirates be-
come progressively more blood stained. Histological yield from
bronchoscopic biopsies is moderate although small vessel vasculitis
can be identified. Exclusion of infections, such as tuberculosis, is ne-
cessary for atypical pulmonary presentations.
Renal
The characteristic feature of renal disease in all three ANCA vascu-
litis syndromes is a focal, necrotizing, crescentic glomerulonephritis.
Haematuria with proteinuria is almost always present, and it can be
visible and is associated with red cell casts. Renal function deteriorates
over weeks and months and ANCA vasculitis is the most common
cause of the presentation of rapidly progressive glomerulonephritis.
Renal biopsy is indicated in a patient with urinary abnormalities and
suspected vasculitis and has a high chance of demonstrating vascu-
litis in the form of a glomerular capillaritis. As glomerular lesions
progress the tuft is compressed by a crescent of epithelial and inflam-
matory cells that lead to glomerular fibrosis or rupture. Interstitial
inflammation comprises both a T cell tubulitis and severe peri-​glom-
erular inflammation. Arteritis of extraglomerular vessels occurs in
15%. Granulomata are uncommon, but seen in the interstitium in
granulomatosis with polyangiitis if they occur.
Fig. 19.11.7.5  Appearances of pulmonary involvement in ANCA-​
associated vasculitis. (a) Alveolar haemorrhage. (b) Usual interstitial
pneumonitis. (c) Subglottic tracheal narrowing. (d) Cavitating nodules
complicated by hydropneumothorax.
19.11.7  ANCA-associated vasculitis
4563
Renal function at diagnosis is the most important predictor of later
renal failure, with 50% of those presenting with a glomerular filtra-
tion rate below 50 ml/​min developing end stage renal failure or not
surviving by five years. A system of subclassification of glomerular
histology in ANCA vasculitis, the ‘Berden’ classification, has been de-
veloped based on the percentage of glomeruli affected by cellular or
fibrotic crescents. The four categories, focal, crescentic, fibrotic and
mixed correlate with risk of development of end stage renal disease
(Fig. 19.11.7.6). Other adverse prognostic factors are MPO-​ANCA
positivity, interstitial inflammation, and extraglomerular arteritis.
Fig. 19.11.7.5  Continued
50% globally
sclerotic glomeruli
Sclerotic
class
YES
YES
YES
NO
NO
NO
Focal
class
Crescentic
class
Mixed
class
50% normal
glomeruli
50% cellular
crescents
(a)
Focal
Mixed
Sclerotic
Crescentic
Follow up in years to renal failure
Renal survive
100
80
60
40
20
0
0
2
4
6
8
10
12
Focal
censored
Mixed
censored
Sclerotic
censored
Crescentic
censored
(b)
Fig. 19.11.7.6  The Berden subclassification of glomerular histology in
ANCA-​associated glomerulonephritis (a) and association with risk of end
stage renal disease (b).
Reprinted from Berden AE et al. (2010). Histopathologic Classification of ANCA-​
Associated Glomerulonephritis. J Am Soc Nephrol, 21: 1628–​1636. Copyright © 2010
by the American Society of Nephrology.
section 19  Rheumatological disorders
4564
Skin
Purpura of varying sizes and ages, predominantly on the lower
limbs, is the most frequent cutaneous manifestation of ANCA-​as-
sociated vasculitis. It is more polymorphic than in IgA vasculitis or
cryoglobulinaemia, and can coalesce to frank ulceration. Ulceration
can be the only manifestation, either single or multiple, and fea-
tures of pyoderma gangrenosum may be seen. Other features of
cutaneous disease are gum involvement, ‘strawberry’ gums, oral ul-
ceration, splinter haemorrhage in the nail beds, and painful subcuta-
neous swellings of panniculitis. Digital gangrene is a rare, dramatic
presentation.
Nervous system
Peripheral neuropathy occurs in around 20% of ANCA-​asso-
ciated vasculitis patients and is more common in eosinophilic
granulomatosis with polyangiitis. Multiple nerves are affected,
‘mononeuritis multiplex’, with a mixed motor, and sensory
deficit. Nerve conduction studies reveal an axonal neuropathy.
Involvement of the common peroneal nerve with foot drop is the
most common feature. The onset of neuropathy is at the time of
other vasculitis symptoms and may be painful in the affected limbs
or painless. During the recovery phase, neuralgic pain can become
prominent and distressing to the patient who suspects deterior-
ation. Recovery of sensation and power is slow but can lead to
full recovery of function. Cranial nerves can also be affected and
rare presentations include a small fibre painful neuropathy and
ganglionopathy.
Central nervous system involvement is rare in microscopic
polyangiitis, while in granulomatosis with polyangiitis a pachy­
meningitis presenting with severe headache occurs and is readily
demonstrated by gadolinium enhanced MR scan. Tumour-​like
granulomatous lesions occur rarely in the cerebral hemispheres
and direct extension of nasal granulomatous disease to involve the
pituitary gland or frontal hemispheres is seen. Transverse myelitis
and peri-​spinal haematomas have occurred rarely. Cerebrovascular
events when they occur during the acute vasculitic phase are usually
attributed to prior cerebrovascular disease and a pro-​thrombotic
state rather than a cerebral vasculitis.
Eye
ANCA vasculitis can affect any structure in the eye or orbit.
Granulomatosis with polyangiitis can cause a painful, necrotizing
scleritis with exposure of the uvea. Involvement of adjacent ocular
structures such as the cornea, trabecular meshwork, and ciliary
body leads to keratitis, corneal ulceration, uveitis, ocular hyper-
tension, or glaucoma episcleritis, often bilateral, is seen in both
granulomatosis with polyangiitis and microscopic polyangiitis
and resolves quickly with treatment, it can be present as a diffuse
pink colouring of the sclera and is a useful marker of systemic vas-
culitis activity. Vasculitis of the optic chiasm or optic nerve causes
sudden bilateral or unilateral blindness. Uveitis is less frequent
but retinitis, choroiditis, retinal detachment, and necrosis occur.
Central retinal artery occlusions and venous thrombosis may also
be seen. Nasal disease in granulomatosis with polyangiitis often
obstructs the naso-​lacrimal duct with a risk of abscess forma-
tion in the occluded duct and epiphora. Accumulation of orbital
granulomatous inflammation behind the eye increases pressure
in the orbit with proptosis and can be sight-​threatening. Orbital
muscles are affected through a cranial neuropathy, or granuloma-
tous myositis.
Gut
Vasculitis can affect any gastro-​intestinal structure but the small in-
testine is the most frequent site of disease, with intestinal haemor-
rhage or perforation as the presenting clinical features. Diagnosis of
less severe involvement can be difficult with normal upper and lower
intestinal endoscopy, but discontinuous bowel wall oedema on CT
or ultrasound scanning can indicate inflammation. Pancreatitis,
necrotizing cholecystitis and cholangitis are rare, granulomatous
mass lesions can be mistaken for a pancreatic tumour.
Heart
Cardiac involvement in ANCA-​associated vasculitis can present as
chest pain due to pericarditis, heart failure and dysrythmias due
to valvular heart disease or myocarditis, or be asymptomatic. The
aortic valve can be affected by damage to the valve cusps or dilata-
tion of the aortic valve ring leading to regurgitation. Disease of the
thoracic aorta is probably underdiagnosed and can present late with
aneurysm formation. Cardiac disease is more frequent in PR3 as
compared to MPO-​ANCA disease, but myocarditis is particularly
frequent in eosinophilic granulomatosis with polyangiitis, in over
50%. Coronary arteritis, spasm, and aneurysm are rare manifest-
ations. Investigations include troponin levels, echocardiography,
and cardiac magnetic resonance imaging. Soft tissue peri-​aortic
masses of presumed inflammatory tissue have been observed.
Laboratory features and imaging
As an acute inflammatory disease, elevations of C-​reactive pro-
tein (CRP) and erythrocyte sedimentation rate (ESR) are almost
always present at diagnosis, often at very high levels. Once therapy
has been initiated the value of these markers is reduced and active
disease can persist with normal levels or other factors, such as in-
fection, can influence CRP and ESR. Haemoglobin may be reduced
to the presence of chronic inflammation or chronic kidney dis-
ease or be rapidly falling in the presence of alveolar haemorrhage.
A neutrophilia is often present and has been shown to be an adverse
prognostic factor, thrombocytosis is common in granulomatosis
with polyangiitis, while thrombocytopaenia is rare and raises the
possibility of a microangiopathic process rarely seen is severe vas-
culitis. In eosinophilic granulomatosis with polyangiitis, peripheral
eosinophilia is characteristic of the disease. Thrombophilia studies
are normal.
Serum creatinine may be elevated in nephritis, while liver func-
tion is very rarely disturbed. Urine analysis reveals non​visible
haematuria with proteinuria in the presence of nephritis, and the
presence of red cell casts on urine microscopy indicates a severe
glomerulonephritis. Typically, proteinuria is below 3  g/​24 hours
and features of nephrotic syndrome are not seen at diagnosis, but
proteinuria can rise markedly during the recovery phase of severe
nephritis. The possibility of an overlap nephritis with IgA nephrop-
athy or antiglomerular basement membrane disease should also be
considered.
19.11.7  ANCA-associated vasculitis
4565
Immunologic evaluation aims to confirm the presence of ANCA
and exclude other immune causes of the presentation. There can
be cross reactivity between some antinuclear antibody (ANA) as-
says with ANCA, but specific antinuclear antigen assays, such as
antidouble stranded DNA, Ro, La are negative. Rheumatoid factor
may be positive at low titres and some ANCA vasculitis patients
are mis-​diagnosed in the prodromal phase as rheumatoid arth-
ritis. Anticyclic citrullinated peptide (CCP) antibodies are nega-
tive. Complement levels are normal and protein electrophoresis
does not reveal a paraprotein or immunoglobulin light chain re-
striction. Lupus anticoagulant and anticardiolipin antibodies are
not detected, except in rare cases of overlap syndromes, more
common in drug-​induced vasculitis, when tissue infarction can
be severe.
Microbiologic evaluation aims to exclude secondary vasculitis
caused by chronic viral infection, hepatitis B, C, or HIV, or chronic
bacterial infection, as in infective endocarditis. In granulomatosis
with polyangiitis, nasal colonization with Staphylococcus aureus has
been associated with a higher relapse rate and should be looked for.
In view of the need for immunosuppression evidence of previous
infection with varicella zoster, Epstein–​Barr virus, and cytomegalo-
virus is useful information.
Chest CT studies are abnormal in at least one-​third of ANCA-​
associated vasculitis patients with a variety of abnormalities seen.
Other imaging is directed by evidence of organ specific disease.
In nephritis renal ultrasound is typically normal although ureteric
disease can occur in eosinophilic granulomatosis with polyangiitis
causing hydronephrosis. CT and MR examination of the nose,
sinuses, and orbits defines the amount of bone destruction and
soft tissue inflammation, especially useful in granulomatosis with
polyangiitis with granulomatous disease. Evidence of aortic dis-
ease in granulomatosis with polyangiitis should be seen on chest
CT and requires further angiographic characterization. Medium
artery involvement is rare in granulomatosis with polyangiitis and
microscopic polyangiitis, although more frequent in eosinophilic
granulomatosis with polyangiitis, similar to polyarteritis nodosa.
Echocardiography and electrocardiogram (ECG) studies are indi-
cated in all granulomatosis with polyangiitis and EGPA patients, al-
though cardiac magnetic resonance imaging is more sensitive for
detection of cardiac involvement.
Diagnosis
There are currently no consensus diagnostic criteria for ANCA-​
associated vasculitis, although the 1990 American College
of Rheumatology classification criteria for Wegener’s (now
granulomatosis with polyangiitis) have been adapted with the add-
ition of ANCA serology for clinical trials, and those for Churg-​
Strauss (now eosinophilic granulomatosis with polyangiitis) remain
in use. For the purpose of eligibility into clinical trials the European
Vasculitis Society (EUVAS) have required a compatible clinical
presentation supported by ANCA-​positive serology or confirma-
tory histology or both, and exclusion of other causes of the clinical
presentation. Identification of causes of secondary forms of ANCA
vasculitis and exclusion of mimics, including atheroembolic disease,
myeloma, and the antiphospholipid syndrome, is important. For
those with presumed vasculitis the European Medicines Evaluation
Agency have devised an algorithm that categorizes patients as
granulomatosis with polyangiitis, microscopic polyangiitis, eosino-
philic granulomatosis with polyangiitis, polyarteritis nodosa (PAN),
or unclassified.
Treatment
Approaches to therapy
The goals of therapy are to achieve a remission in disease ac-
tivity, prevent relapse, and minimize drug toxicity, and the risk of
comorbid conditions (Table 19.11.7.6). An induction phase of
3–​6 months is followed by a longer remission maintenance phase.
Prolonged follow-​up is then required to manage the consequences
of vasculitic damage, drug toxicity, and increased cardiovascular
and malignancy risks.
The initial approach to treatment of granulomatosis with
polyangiitis and microscopic polyangiitis is similar with assessment
of disease extent and severity and identification of patient factors
that influence treatment choice. Attempts have been made to sub-
group patients at diagnosis according to disease severity and to iden-
tify factors predicting increased mortality risk (Table 19.11.7.7).
However, avoiding diagnostic delay and the early institution of
Table 19.11.7.6  Subgrouping of patients at diagnosis according to disease activity and extent
Subgrouping by severity
or extent
Organ involvement
Constitutional
symptoms
ANCA status
Serum creatinine
(μmol/​litre)
USA
EUVAS
Limited or non​severe
Localized
One site, typically the upper
respiratory tract in GPA
No
Positive or negative
<120
Early systemic
Any, except renal or imminent
vital organ failure
Yes
Positive
<120
Generalized or severe
Generalized (or renal)
Imminent vital organ failure
or renal vasculitis
Yes
Positive
<500
Severe
Vital organ failure, typically
renal
Yes
Positive
500
(renal presentations)
Refractory
Progressive disease despite
conventional therapy
Yes
Positive or negative
any
GPA, granulomatosis with polyangiitis; EUVAS, European Vasculitis Society; USA, United States of America
section 19  Rheumatological disorders
4566
therapy are of primary importance in all subgroups. EGPA has been
treated separately to granulomatosis with polyangiitis and micro-
scopic polyangiitis in the few therapeutic trials that have been per-
formed. Current guidelines reflect an international consensus into
how ANCA-​associated vasculitis should be managed.
Induction therapy
The combination of high-​dose glucocorticoids with either cyclo-
phosphamide or rituximab is the standard of care for new patients
with ANCA-​associated vasculitis. Cyclophosphamide is equally ef-
fective as a daily oral or pulsed intravenous (IV) administration for
the induction of remission. However, the IV protocols expose the
patient to a lower cumulative cyclophosphamide dose, less frequent
leucopaenia, and permit bladder protection. Cyclophosphamide is
continued for 3–​6 months, by which time remission will have been
achieved in 80–​90% of patients. Rituximab has similar efficacy to
cyclophosphamide with two regimens used, either 375 mg/​m2 /​week
for four weeks or 1000 mg repeated at two weeks. Daily oral pred-
nisolone regimens commence at 1.0 mg/​kg per day and reduce to
0–​10 mg/​day by six months.
A  few patients present with mild disease and no threatened
loss of organ function, when methotrexate or mycophenolate
mofetil can be considered as alternatives to cyclophosphamide or
rituximab.
Severe presentations
These are characterized by loss of organ function, such as acute
kidney injury, and the need to gain rapid control of vasculitis. IV
methyl prednisolone is widely used at total doses of 1000–​3000 mg,
without a robust evidence base. Plasma exchange improves the
chances of renal recovery in those presenting in renal failure (cre-
atinine >500 μmol), but a role in other severe settings, including dif-
fuse alveolar haemorrhage, awaits confirmation.
Assessing response
The activity of vasculitis is determined by a review of clinical fea-
tures and circulating inflammatory markers, C-​reactive protein,
and erythrocyte sedimentation rate. The Birmingham Vasculitis
Activity Score (BVAS) lists 63 items of vasculitic disease in 10
system groups and serves as a useful checklist and catalogue of
disease. An ‘on drug’ remission requires a BVAS of zero and is sup-
ported by reduction or normalization of C-​reactive protein and
erythrocyte sedimentation rate. Certain disease features, such as
nasal crusting and proteinuria, can be features of both disease ac-
tivity and irreversible damage and adjudication of response can
be difficult. ANCA levels fall with treatment but are not used as a
target for therapy.
Improvements in respiratory tract disease are accompanied
by symptomatic and radiological improvement. Subglottic and
endobronchial disease is rarely present at diagnosis but can appear
when granulomatosis with polyangiitis is clinically inactive or at
the time of relapse. It should be considered for persisting exertional
dyspnoea, recurrent respiratory tract infections, or radiological
opacities, and is best defined by CT scanning and bronchoscopy.
Pulmonary function tests are useful in monitoring individual pa-
tients but can be misleading when used for diagnosis. Changes in ear
nose and throat and ophthalmic activity can be harder to assess and
regular specialist review with nasendoscopy and direct laryngeal
visualization is recommended. Vasculitic neuropathy recovers to
variable degrees but some motor deficiency usually remains. A para-
doxical deterioration in symptoms of dysaethesiae during the re-
covery phase is common and responds to amitriptyline, gabapentin,
or pregabelin.
Eosinophilic granulomatosis with polyangiitis
A similar approach to granulomatosis with polyangiitis and micro-
scopic polyangiitis is adopted with cyclophosphamide and high-​
dose glucocorticoids disease for presentations threatening organ
damage, such as cardiomyopathy or neuropathy. Non​severe dis-
ease can be treated with glucocorticoids alone, but an immuno-
suppressive such as azathioprine or methotrexate is often used to
minimize steroid exposure and reduce relapse risk. Observational
data supports the use of rituximab when cyclophosphamide
is contra-​indicated or ineffective. The allergic components of
EGPA—​asthma, naso-​sinus disease, and rash—​are steroid respon-
sive, but often recur as glucocorticoids are reduced and can be the
most challenging manifestations to manage once the vasculitic fea-
tures are controlled.
Table 19.11.7.7  Disease state definitions in ANCA-​associated vasculitis
Activity state
Definition
Remission
Absence of disease activity attributable to active vasculitis qualified by the need for ongoing stable relapse prevention therapy.
‘Active disease’ is not restricted to vasculitis only, but includes other inflammatory features, such as granulomatous inflammation
in granulomatosis with polyangiitis or tissue eosinophilia in eosinophilic granulomatosis with polyangiitis
Response
50% reduction of disease activity score and absence of new manifestations
Relapse
Recurrence or new onset of disease attributable to active vasculitis
Major relapse
Recurrence or new onset of potentially organ-​ or life-​threatening disease
Minor relapse
Recurrence or new onset of disease which is neither potentially organ threatening nor life threatening
Refractory disease
1.  Unchanged or increased disease activity in acute ANCA-​associated vasculitis after at least four weeks treatment with standard
induction therapy, or
2.  Lack of response, defined as ≤50% reduction in the disease activity score, after at least 6 weeks of treatment, or
3.  Chronic, persistent disease defined as the presence of at least one major or three minor items on the disease activity score list,
after ≥12 weeks of treatment
Low-​activity disease state
Persistence of minor symptoms (e.g. arthalgia, myalgia) that respond to a modest glucocorticoid increase and do not necessarily
warrant an escalation of other therapies
19.11.7  ANCA-associated vasculitis
4567
Induction treatment in children and older people
The approach to therapy and responsiveness to medication is the
same in the young and the old as in other age groups, but drug selec-
tion and dosing may differ. In view of the fertility and malignancy
risks, rituximab is preferred to cyclophosphamide. Higher gluco-
corticoid doses, up to 2 mg/​kg per day, are used in children, due
to increased rates of elimination. Elderly patients are more likely to
present with renal impairment and have a high risk of infective com-
plications. It is important to reduce cyclophosphamide dose, due to
the increased susceptibility to cytopenias; lower dose glucocorticoid
regimens have had similar efficacy with fewer adverse events.
Remission maintenance therapy
Disease relapse occurs in 75% of granulomatosis with polyangiitis
and 30% of microscopic polyangiitis patients by five years. Both
azathioprine and methotrexate are recommended to reduce relapse
with a treatment duration of at least two years. The use of concomi-
tant low dose prednisolone, 5–​10 mg/​day is more variable, although
glucocorticoid withdrawal increases relapse risk. Despite these
interventions, 25–​30% will relapse by two years. Mycophenolate
mofetil is an alternative especially if chronic kidney disease is pre-
sent. Relapse risk is high after rituximab induction and repeat
dose rituximab is an effective maintenance regimen, with doses of
500–​1000 mg every six months. Rituximab is superior and probably
safer to azathioprine and prednisolone and more reliably permits
early glucocorticoid withdrawal. However, an increase in relapse
risk is seen after completion of a repeat dose rituximab course.
Circulating B cell counts and ANCA levels have been used to guide
rituximab dosing but their value remains controversial.
Relapse risk is influenced by diagnosis, ANCA serotype and serum
binding level, and type of induction and maintenance treatment
(Table 19.11.7.8). Review of these factors at two years is helpful in
deciding the duration of maintenance therapy. Other factors to con-
sider are the likely consequence of relapse if it occurs, the quality of
disease activity monitoring, and tolerability of maintenance therapy.
Management of relapse
The symptoms and signs of relapse in an individual patient reflect
those present prior to the original diagnosis. The diagnosis of relapse
needs to be differentiated from infection or other potential causes,
including malignancy. Infection may precede and precipitate relapse
and this is a particular issue with bacterial infections in respiratory
tract relapse in granulomatosis with polyangiitis. Mild relapses
without threatened organ damage can be treated with prednisolone
20 mg/​day but the risk of subsequent relapse is high and if inad-
equately treated can develop into more severe relapse. Rituximab
is more effective than cyclophosphamide for relapsing disease and
is preferred to avoid a high cumulative exposure to cyclophospha-
mide, glucocorticoid dosing is usually lower reflecting concern over
previous exposure.
Refractory disease
Progression of vasculitis despite induction therapy, failure to at-
tain disease remission, and disease relapse while receiving main-
tenance therapy are defined as refractory disease. Before therapy is
enhanced, causes for refractory disease—​including infection, malig-
nancy, and drugs—​should be considered, as well as non​concordance
with the prescribed regimen. Drug intolerance, especially to gluco-
corticoids or cyclophosphamide, and reductions in dosing due to
intercurrent infection may also lead to primary treatment failure.
This situation is associated with a high mortality due to deterior­
ating organ function and higher risks of treatment. Progressive or
non​responsive disease occurs in 5–​10% and is treated with an in-
crease in glucocorticoid, typically IV pulsed methylprednisolone
1000–​3000 mg and switching from cyclophosphamide to rituximab.
Rare failures of rituximab can be attributed to failure to achieve
B cell depletion, or if there is underlying infection. Where the re-
sponse to rituximab appears slow, pulse cyclophosphamide can be
added until response is seen, but cyclophosphamide is not routinely
required with rituximab. Alternative therapies that have been em-
ployed include high-​dose intravenous immunoglobulins, plasma
exchange, alemtuzumab (anti-​CD52), deoxyspergualin, and tumour
necrosis factor blockade.
Eosinophilic granulomatosis with polyangiitis can pursue a pri-
mary progressive course requiring repeated courses of IV steroid;
intravenous immunoglobulin and plasma exchange have also
been used. However, a more common problem in EGPA is re-
lapse as glucocorticoids are reduced. Such patients are at risk of
high glucocorticoid exposure and alternative strategies should be
pursued to permit glucocorticoid reduction to conventional main-
tenance levels. A change in immunosuppressive may be effective
in non​severe disease. Rituximab, alemtuzumab, interferon-​α and
mepolizumab, an anti-​interleukin (IL)-​5 monoclonal antibody,
have been used in this setting.
Outcomes
ANCA vasculitis has consequences on survival, organ damage,
and development of comorbidities. Quality of life can remain de-
pressed when clinical activity is absent and the late consequences of
treatment contribute to irreversible organ damage (Fig. 19.11.7.7).
Despite advances in therapy patients continue to have a mortality
rate ratio of 2–​3 compared to a control population, with advanced
renal failure, increasing age, a high disease activity at diagnosis and
the MPO-​ANCA subtype being adverse predictors. Infection, in
part attributable to treatment, and alveolar haemorrhage are the
most common causes of early death while increased risks of malig-
nancy and cardiovascular disease contribute to later mortality.
Reduced cyclophosphamide exposure with current regimens
has lowered bladder cancer and leukaemia risk but there remains
Table 19.11.7.8  Factors influencing relapse risk of ANCA-​associated
vasculitis
Clinical presentation
Serology
Treatment-​related
Diagnosis of GPA
PR3-​ANCA positive at
diagnosis
Steroid withdrawal
Ear, nose, and throat
involvement
Persistent ANCA positivity
after induction therapy
Immunosuppressive
withdrawal
Serum creatinine
<200 μmol/​litre
Rise in ANCA during
remission
Lower
cyclophosphamide
exposure
ANCA, antineutrophil cytoplasmic antibody; GPA, granulomatosis with polyangiitis
(Wegener’s).
section 19  Rheumatological disorders
4568
an overall increase in risk ratio of 2.5–​4 with non​melanoma skin
cancer being most apparent. Cardiovascular events have been as-
sociated with higher disease activity at diagnosis and MPO-​ANCA
serotype, and patients in clinical remission have abnormal endo-
thelial function, which might contribute to this risk. There is also
an increased risk of thromboembolism, occurring in 5–​15% in the
first year and is highest when vasculitis is active. It has been linked
to autoantibodies to plasminogen or tissue factor, but this requires
confirmation.
Non​healing damage
Ninety-​five per cent (95%) of patients develop at least one item of
irreversible damage as a result of vasculitis or its therapy. Damage
of the upper respiratory tract is common in granulomatosis with
polyangiitis, with deafness and chronic nasal and sinus symp-
tomatology. Twenty per cent (20% of patients develop end-​stage
renal disease by five years with more having chronic kidney dis-
ease of less severity. Renal survival is associated with serum cre-
atinine at diagnosis and the percentage of normal glomeruli in the
renal biopsy. However, even in those presenting with severe histo-
logical findings and low numbers of normal glomeruli, treatment
should be given as the chance of renal recovery is greater than for
therapy-​related death. A renal histology score has been developed
with four categories associating with a progressively worse renal
survival: focal, crescentic, mixed, and fibrotic. Treatment toxicity
contributes to damage through glucocorticoid toxicity, including
diabetes, bone disease, and cataracts; the infective and malignant
complications of immunosuppression and acquired immunodefi-
ciency a particular problem for ANCA-​associated vasculitis patients
receiving rituximab.
Future directions
The classification of vasculitis remains based on a phenotypic de-
scription, but with the definition of genetic and serologic associ-
ations it seems likely that the terms PR3 and MPO-​ANCA vasculitis
may replace granulomatosis with polyangiitis and microscopic
polyangiitis. The discovery of polymorphisms linked with the
autoantigen, a protease, and its major inhibitor, α-1 antitrypsin, has
inspired new concepts of aetiology based on dysregulated neutro-
phil maturation and autoantigen formation and control. The critical
role of complement factor 5 in animal models of ANCA-​associated
vasculitis will, if replicated in the human disease, provide a new
target for therapy, as agents blocking C5 are already in the clinic or
clinical trials. A role of the microbiome (either of the respiratory
or urinary tract) in disease initiation is suspected from current
evidence, but the mechanism is unclear and a role for antibiotics
has only been demonstrated for those chronically infected with
Staphylococcus aureus.
The combination of agents used for induction and maintenance of
remission has evolved from academic randomized controlled trials
that have led to a high level of international consensus and the pub-
lication of a series of management recommendations. Diagnostic
delay and the availability of expert advice point to the importance
of health service reform in the delivery of care to vasculitis pa-
tients that will directly benefit treatment response, treatment safety,
and longer-​term outcomes. Newer targeted agents, in particular
rituximab, have had a major impact on treatment regimens and have
led to more pharmaceutical industry investment. Important needs
for future drugs include achievement of more rapid and complete
remission while sparing glucocorticoids, and reducing relapse risk
while minimizing the need for long-​term immunosuppression.
The causes for vasculitis comorbidities, especially cardiovascular
disease, are not understood, and the relative value of agents such
as platelet inhibitors or cholesterol lowering drugs is not known.
Certain aspects of quality of life improve with therapy, but de-
pressed vitality and physical activity along with sleep disturbance
are common long-​term problems. Patient education and support,
graded exercise programmes, and lifestyle modification deserve fur-
ther exploration.
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Survival
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Malignancy
Cardiovascular
and
thrmboembolic
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Damage
Renal
ENT
Lung etc
Fig. 19.11.7.7  Multiple dimensions of long-​term outcome in ANCA-​
associated vasculitis.

19.11.8 Polyarteritis nodosa 4569 Loïc Guillevin
19.11.8 Polyarteritis nodosa 4569 Loïc Guillevin
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Masi AT, et al. (1990). The American College of Rheumatology 1990
criteria for the classification of Churg-​Strauss syndrome (allergic
granulomatosis and angiitis). Arthritis Rheum, 33, 1094–​100.
Merkel PA, et al. (2009). Comparison of disease activity measures for
anti-​neutrophil cytoplasmic autoantibody (ANCA)-​associated vas-
culitis. Ann Rheum Dis, 68, 103–​6.
Mukhtyar C, et al. (2008). EULAR Recommendations for the manage-
ment of primary small and medium vessel vasculitis. Ann Rheum
Dis, 68, 310–​7.
Ntatsaki E, et al. (2014). BSR and BHPR guideline for the management
of adults with ANCA-​associated vasculitis. Rheumatology (Oxford),
53, 2306–​9.
Pagnoux C, et al. (2008). Azathioprine or methotrexate maintenance
for ANCA-​associated vasculitis. N Engl J Med, 359, 2790–​803.
Rasmussen N, et al. (1995). European therapeutic trials in ANCA-​
associated systemic vasculitis: disease scoring, consensus regimens
and proposed clinical trials. Clin Exp Immunol, 101, 29–​34.
Stegeman CA, et  al. (1994). Association of chronic nasal carriage
of Staphylococcus aureus and higher relapse rates in Wegener
granulomatosis. Ann Intern Med, 120, 12–​17.
Stone JH, et  al. (2010). Rituximab versus cyclophosphamide for
ANCA-​associated vasculitis. N Engl J Med, 363, 221–​32.
Watts R, et  al. (2007). Development and validation of a consensus
methodology for the classification of the ANCA-​associated vascu-
litides and polyarteritis nodosa for epidemiological studies. Ann
Rheum Dis, 66, 222–​7.
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MPO-​ANCA GN. J Am Soc Nephrol, 25, 225–​31.
19.11.8  Polyarteritis nodosa
Loïc Guillevin
ESSENTIALS
Polyarteritis nodosa is a necrotizing angiitis, often associated
with hepatitis B infection, that predominantly affects medium-​
sized arteries. Patients usually have systemic features; specific
manifestations include peripheral neuropathy, mononeuritis
multiplex, skin lesions (subcutaneous nodules, purpura), hyper-
tension, renal insufficiency, gastrointestinal haemorrhage/​perfor-
ation, and orchitis. Elevated markers of inflammation are found
in most patients, but serum antineutrophil cytoplasmic anti-
bodies are not present. Standard treatment of hepatitis B negative
cases is with corticosteroids (typically initiated with intravenous
methylprednisolone) and cyclophosphamide; hepatitis B posi-
tive cases are treated with an antiviral agent, corticosteroid and
plasma exchange, with corticosteroid discontinued as soon as
disease comes under control. Severe gastrointestinal involvement
is the primary cause of early death; later deaths may result from
treatment side effects.
Introduction
Polyarteritis nodosa (PAN) is a necrotizing angiitis that predom-
inantly affects medium-​sized arteries. It is rarely seen in developed
countries, since hepatitis B virus (HBV) infection, considered
one of its major causes, has been treated or prevented by hygiene
measures, specific prophylaxis against infectious diseases, or
vaccination.
Classification criteria and diagnosis
The Chapel Hill Nomenclature defines polyarteritis nodosa as a
necrotizing arteritis of medium-​ or small-​sized arteries, very rarely
with vasculitis in arterioles, capillaries or venules, without glom-
erulonephritis or antineutrophil cytoplasm antibodies (ANCA).
Diagnosis is based on clinical manifestations, pathology, other
complementary investigations such as angiography, and ANCA-​
negativity (Table 19.11.8.1).
section 19  Rheumatological disorders
4570
Epidemiology
Polyarteritis nodosa affects all racial groups. The annual inci-
dence of polyarteritis nodosa-​type systemic vasculitis in the gen-
eral population ranges from 4.6/​1 000 000 inhabitants in England,
to 9.0/​1 000 000 inhabitants in Olmsted County, Minnesota,
and 77/​1 000 000 inhabitants in hepatitis B virus-​hyperendemic
Alaskan Eskimos. In a German study, the polyarteritis nodosa
incidence was extremely low (0.3–​0.4/​1 000 000). Comparison
of incidences in Lugo, Spain, and Norwich, United Kingdom
found, respectively, 6.2 and 9.7/​1 000 000 inhabitants. In France,
its prevalence was 34/​1 000 000 inhabitants in a northern suburb
of Paris.
Aetiology and precipitating factors
A  close polyarteritis nodosa–​hepatitis B virus-​infection re-
lationship is well recognized. In France, hepatitis B virus
infection transmitted by contaminated blood transfusions dis-
appeared decades ago. Meanwhile, intravenous drug abuse
has rapidly become a major cause of hepatitis B virus-​related
polyarteritis nodosa, as is sexual hepatitis B virus transmission to
non​vaccinated individuals at risk. The development of
antihepatitis B virus vaccines and their administration to people
at risk also explains the dramatic decrease in the number of new
cases since 1989. Moreover, polyarteritis nodosa frequency, due
to hepatitis B virus infection or not, has also decreased in par-
allel, declining from around 40% during 1972–​6 to 17% during
1997–​2002. We hypothesize that all polyarteritis nodosa results
from infection, even though a pathogen has not been isolated
from all patients.
Infections with hepatitis C, parvovirus B19, or human immuno-
deficiency virus have explained a few polyarteritis nodosa cases.
Polyarteritis nodosa has also been described in the context of can-
cers or haematological diseases, mainly malignant conditions such
as hairy-​cell leukaemia.
Histology
The histological lesion defining polyarteritis nodosa is a focal seg-
mental necrotizing vasculitis affecting medium-​sized arteries,
rarely arterioles, and only extremely rarely capillaries and venules.
The acute phase of arterial wall inflammation is characterized by
fibrinoid necrosis of the media and dense pleomorphic cellular
infiltrates, predominantly comprised of neutrophils and variable
numbers of lymphocytes and eosinophils, leading to destruction
of the normal vessel-​wall architecture. Arterial aneurysms and
thromboses can form at lesion sites. Fibrotic endarteritis character-
izes arterial healing that may lead to aneurysm regression or vessel
occlusion.
Biopsies can be diagnostic. Muscle biopsy is indicated for patients
complaining of myalgias or with general symptoms, and nerve bi-
opsy of a sensory branch of the sciatic or peroneal nerve for patients
suffering from distal sensory or sensorimotor mononeuropathy
multiplex.
Clinical features
Although polyarteritis nodosa can develop at all ages, most patients
are between 40 and 60 years old, with no sex predominance. Patients
usually have systemic features, with two-​thirds having weight loss
and fever, and half suffer from myalgias and arthralgias. Some pa-
tients are bedridden due to the peripheral neuropathy, intense pain,
and severe amyotrophy.
Neurological manifestations
Peripheral neuropathy, the most frequent polyarteritis nodosa
manifestation, affects 50–​75% of the patients and is the earliest
symptom for 23–​33% of them. Its onset is usually acute. Sensory
signs cause hypo-​ or hyperesthesia, dysesthesia and/​or frank
pain, which represent the most prominent and earliest features.
Motor deficits usually appear later, but also occur with sudden
onset. The first manifestations often affect the lower limbs, mainly
in a distal and asymmetrical distribution. The following nerves
are preferentially involved: superficial peroneal, sural, radial, cu-
bital and/​or median. In late stage polyarteritis nodosa, so many
nerves can be involved that mononeuritis multiplex can be mis-
taken for a symmetrical process. Electromyography-​documented
axonal neuropathy may be more extensive than expected based
on clinical manifestations. Mononeuropathy (simplex) is seen less
frequently.
With treatment, mononeuropathy multiplex regresses slowly
and patients may recover without sequelae, although 12–​24 months
are often necessary to obtain and evaluate maximum recovery.
However, the degree of recovery varies and is unpredictable.
Paresthesias usually persist longest, and sometimes indefinitely.
Central nervous system involvement affects c.5% of polyarteritis
nodosa patients, usually manifesting as encephalopathy, with
Table 19.11.8.1  Proposed diagnostic criteria for polyarteritis
nodosaa
Criteria
Odds ratio
95% CI
R²
Positive for PAN
HBV infection
16.85
6.30–​45.08
0.320
Myalgias
1.93
1.06–​3.53
0.517
Mononeuropathy or polyneuropathy
3.36
1.93–​5.86
0.619
Angiographic abnormalities
20.40
7.30–​56.99
0.640
Testicular pain or tenderness
5.27
1.98–​28.26
0.661
Negative (exclusion) for PAN
ANCA-​positivity
0.11
0.05–​0.23
0.668
Glomerulonephritis
0.07
0.02–​0.29
0.674
Recent asthma onset
0.01
0.01–​0.06
0.433
ANCA, Antineutrophil cytoplasm antibody; GPA, granulomatosis with polyangiitis;
EGPA, eosinophilic granulomatosis with polyangiitis; HBV, hepatitis B virus; MPA,
microscopic polyangiitis; PAN, polyarteritis nodosa.
a Based on the analysis of 582 systemic vasculitis patients with all data available in
the French Vasculitis Study Group’s database: 194 PAN (among whom 117 had
HBV-​related PAN) and 388 other systemic vasculitides (144 GPA; 115 EGPA; 101 MPA;
28 cryoglobulinemia). Henegar et al. (2008). Arthritis Rheum 58(5): 1528–​38.
19.11.8  Polyarteritis nodosa
4571
impaired cognitive function, focal or multifocal disturbances of the
brain and spinal cord, and seizures, strokes and/​or subarachnoid
haemorrhages, resulting from either cerebral artery vasculitis or a
consequence of malignant hypertension. Cerebrospinal fluid ana-
lysis is usually normal.
Cranial nerve palsies, occurring in c.1% of polyarteritis nodosa
patients, mostly affect oculomotor (III), trochlear (IV), abducens
(VI), facial (VII) and/​or acoustic (VIII) nerves.
Ocular involvement
The eye can be affected in polyarteritis nodosa, sometimes severely
(e.g. with uni-​ or bilateral choroiditis, iritis, iridocyclitis, retinal de-
tachment and/​or retinal vasculitis).
Skin manifestations
Cutaneous lesions are present in about half of patients, with cuta-
neous or subcutaneous nodules being the hallmarks of polyarteritis
nodosa. They occur along the trajectories of superficial arteries and
often disappear spontaneously within a few days.
The most common cutaneous finding is palpable purpura, often
necrotic, corresponding to subcutaneous small-​vessel vasculitis as-
sociated with medium-​sized–​vessel involvement (Fig. 19.11.8.1).
Ulcerations and livedo are less common. Livedo reticularis in
polyarteritis nodosa is typically localized to the lower limbs, backs
of the arms and, sometimes, the trunk. A biopsy of infiltrated and/​
or central lesion zones may show vasculitis. Painful ulcerations may
develop, frequently associated with indurated plaques resulting
from the coalescence of nodules.
Embolization of peripheral thrombi may cause infarction of toes
and/​or fingers or some cutaneous areas, when cholesterol emboli are
a possible differential diagnosis.
Renal manifestations
Renal artery involvement can cause mild-​to-​severe and malignant
hypertension and/​or vascular ischaemic nephropathy with renal
insufficiency, known to be a poor-​prognosis factor. Angiography
may reveal renal parenchymal infarcts and characteristic multiple
stenoses and microaneurysms of branches of celiac, mesenteric and
renal arteries (Fig. 19.11.8.2). The lesions may disappear with ef-
fective vasculitis therapy.
Renal function outcome remains unpredictable. Usually mild
hypertension, a consequence of vascular nephropathy, occurs in a
mean of 40% of polyarteritis nodosa patients.
Cardiac manifestations
Congestive heart failure is specifically due to vasculitis of the
coronary arteries or their branches, with myocardial arteriolar
infarcts in some patients. Specific cardiomyopathy can develop
as early as three to four months after the onset of polyarteritis
nodosa. Coronary aneurysms have been found, but their pres-
ence suggests Kawasaki disease rather than polyarteritis nodosa.
Valve involvement and pericarditis are rare in polyarteritis
nodosa. Arteritis of the sinus node or neighbouring nerve
fibres can cause arrhythmias and conduction disorders, mainly
supraventricular.
Gastrointestinal manifestations
Involvement of the gastrointestinal tract is one of the most se-
vere manifestations of polyarteritis nodosa, reportedly affecting
one-​third of patients, especially those with hepatitis B virus-​
related disease (50%). Gastrointestinal involvement can be the
first manifestation of vasculitis, most frequently with abdominal
pain. Gastrointestinal haemorrhage and small intestinal perfor-
ation are the most feared manifestations. When present, ischaemic
vasculitis mainly affects the small bowel, more rarely the colon or
stomach. Gallbladder or appendix vasculitis is rare but can be the
first sign of polyarteritis nodosa, sometimes isolated. Likewise,
acute necrotizing or (less commonly) chronic pancreatitis, some-
times with pseudocysts, has been diagnosed in approximately 2–​
3% of patients with polyarteritis nodosa, the prognosis of which
is extremely dismal because of the regular association with severe
small intestine ischaemia and/​or perforations. Liver and/​or spleen
infarct(s) can occur.
Angiography is the most informative investigation, able to de-
tect infarcts, haematomas, or more suggestive arterial stenoses and
microaneurysms in most patients with gastrointestinal symptoms.
Microaneurysms tend to be 1–​5 mm or more in diameter, and are
mainly found in renal, celiac, mesenteric, (less frequently) hepatic or
(more rarely) splenic arteries.
Orchitis
While rare, unilateral orchitis is one of the most characteristic mani-
festations of polyarteritis nodosa. Caused by testicular artery is-
chaemia, it is rarely the first disease manifestation.
Pulmonary manifestations
The lungs are spared in polyarteritis nodosa. Although vasculitis
of bronchial arteries has been reported in autopsy studies, this had
been clinically asymptomatic.
Fig. 19.11.8.1  Typical cutaneous lesions and livedo reticularis on a
patient with cutaneous polyarteritis nodosa.
Reproduced from Watts RA et al. (eds) (2013). Oxford Textbook of Rheumatology,
4th edn, by permission of Oxford University Press.
section 19  Rheumatological disorders
4572
Localized forms of polyarteritis nodosa
Localized disease is rare, except for the limited cutaneous forms that
represent less than 10% of all polyarteritis nodosa cases. Isolated
involvement of one skeletal muscle or muscle group and isolated
neuropathy (mononeuritis multiplex or simplex), without sys-
temic symptoms, have been described; likewise exceptional cases
involving only one organ—​appendix, gallbladder or uterus (in order
of decreasing frequency).
Laboratory tests
Elevated markers of inflammation are found in most patients.
Leukocytosis or (sometimes) eosinophilia over 1500/​mm3,
and normochromic anaemia, are common laboratory findings.
Hepatitis B surface antigen (HBsAg) should be sought system-
atically. Antineutrophil cytoplasm antibodies are not present in
polyarteritis nodosa.
Outcome and prognosis
Systemic polyarteritis nodosa is an acute disease that can be severe
and even fatal if not treated adequately. During the 5 years after
diagnosis c.25% of patients relapse, but only c.10% of hepatitis B
virus-​positive patients whose viral infection has been treated. The
clinical pattern of relapse can differ from the initial presentation,
with previously unaffected organs being involved. Although relapse
severity cannot be predicted, the most frequent clinical features at
relapse are rash and arthralgias, and these are generally less severe
than during the initial first flare.
 Deaths
A  quarter of the patients die during follow-​up, some during
the first months post-​diagnosis from treatment-​refractory
multivisceral involvement. Severe gastrointestinal involvement,
with perforations or haemorrhage, is the primary cause of early
death within the first year, and infections and heart disease are
the next most common. Later deaths may result from treatment
side effects. Hepatitis B virus infection has not been identified as
a factor of severity.
Evaluation of prognosis
In 1996 a Five-​Factor score was developed to evaluate prognosis at
the time of diagnosis of systemic necrotizing vasculitides, including
polyarteritis nodosa. A recent iteration described the following four
factors as significantly associated with higher 5-​year mortality: age
above 65  years, cardiac symptoms, gastrointestinal involvement
and renal insufficiency (stabilized peak creatinine ≥150 μmol/litre
(1.7 mg/​dl)), with each item’s presence accorded 1 point. Ear, nose,
and throat symptoms, absent in polyarteritis nodosa, were associ-
ated with a better prognosis and scored minus 1 point. For systemic
necrotizing vasculitis patients, respective 5-​year mortality rates for
aggregate scores 0, 1 or ≥2 were 9%, 21% or 40%. This knowledge
guides physicians’ therapeutic choices, with more aggressive and
higher risk treatments being reserved for those with worse predicted
outcome.
Treatment
Corticosteroids
All patients receive corticosteroids. For hepatitis B virus-​related
polyarteritis nodosa, these should be administered for a few
days only, as opposed to approximately 12  months for other
forms of polyarteritis nodosa. High doses may be useful initially.
Methylprednisolone pulses (usually 7.5–​15 mg/​kg IV over 60 min,
repeated at 24 h intervals for 1–​3 days) are widely infused to ini-
tiate treatment, especially when life-​threatening organ involvement
is present or during the extension phase of mononeuropathy multi-
plex. This regimen acts rapidly and is relatively safe. Oral cortico-
steroid (prednisone or its equivalent of methylprednisolone) is given
at a starting dose of 1 mg/​kg/​day. As the patient’s clinical status im-
proves and the biological markers of inflammation (C-​reactive
(a)
(b)
Fig. 19.11.8.2  Renal angiogram in two patients with polyarteritis nodosa demonstrating (a) numerous
microaneurysms and (b) renal artery thrombus causing significant occlusion of the renal artery and
additional evidence of tapering of the intrarenal vasculature.
Reproduced from Turner NN et al. (eds) (2015). Oxford Textbook of Clinical Nephrology, 4th edn, by permission of
Oxford University Press.
19.11.9  Small vessel vasculitis
4573
protein, erythrocyte sedimentation rate) return to normal, usually
within three weeks, tapering of prednisone dose can begin.
Cyclophosphamide
Pulse cyclophosphamide is currently preferred to oral cyclophospha-
mide. Six pulses administered within three months usually obtain
disease control, but treatment should be adjusted to the patient’s
condition: renal function, haematological data, and the disease’s re-
sponse to previous therapies. Lower dose IV cyclophosphamide for
patients above 65 years was as effective as higher dose and was asso-
ciated with fewer side effects. Because daily oral cyclophosphamide
intake (2 mg/​kg/​day for three months) caused major adverse events,
including haemorrhagic cystitis, bladder polyposis, bone-​marrow
suppression, ovarian failure and cancer (mainly bladder cancer and
haematological malignancies), it is prescribed less frequently.
Other cytotoxic agents
Azathioprine, methotrexate and several other cytotoxic agents
are reserved for patients with contraindications to cyclophospha-
mide or as maintenance therapy for a recommended duration of
12–​18 months.
Plasma exchanges
To date, there is no evidence to support the use of plasma exchange
in polyarteritis nodosa without hepatitis B virus infection.
Therapeutic specificities of hepatitis B virus-​related
polyarteritis nodosa
For hepatitis B virus-​related polyarteritis nodosa, conventional
corticosteroid and cyclophosphamide induction therapy al-
lows virus replication, favouring subsequent liver cirrhosis. Thus,
at treatment onset, the preferred strategy is to combine plasma
exchange and an antiviral agent specific for HBV infection with
corticosteroid to rapidly control the most severe life-​threatening
polyarteritis nodosa manifestations, which are common during
the first weeks of the disease. Corticosteroids are then abruptly
discontinued to enhance immunological clearance of hepatitis
B virus-​infected hepatocytes and favour seroconversion from
HBeAg-​positivity to anti-​HBeAb–​positivity. Excellent overall
therapeutic results have been obtained with this combination of
antiviral agent, corticosteroid, and plasma exchange, with up to
90% recovery and 60% seroconversion to anti-​HBe.
FURTHER READING
Guillevin L, et  al. (2005). Hepatitis B virus-​associated polyarteritis
nodosa: clinical characteristics, outcome, and impact of treatment
in 115 patients. Medicine (Baltimore), 84, 313–​22.
Guillevin L, et al. (2011). The five-​factor score revisited: assessment of
prognoses of systemic necrotizing vasculitides based on the French
Vasculitis Study Group (FVSG) cohort. Medicine, 90, 19–​27.
Henegar C, et  al. (2008). A paradigm of diagnostic criteria for
polyarteritis nodosa: analysis of a series of 949 patients with vascu-
litides. Arthritis Rheum, 58, 1528–​38.
Pagnoux C, et al. (2010). Clinical features and outcomes in 348 patients
with polyarteritis nodosa:  a systematic retrospective study of pa-
tients diagnosed between 1963 and 2005 and entered into the French
Vasculitis Study Group Database. Arthritis Rheum, 62, 616–​26.
19.11.9  Small vessel vasculitis
Richard A. Watts
ESSENTIALS
Small vessel vasculitis is vasculitis affecting predominately small
intraparenchymal arteries, arterioles, capillaries, and venules. There
are two main types: antineutrophil cytoplasmic antibody associated
(see Chapter 19.11.7) and immune complex mediated.
IgA vasculitis (Henoch-​Schönlein purpura)—​vasculitis of unknown
cause with IgA1-​dominant immune deposits. It predominantly af-
fects children and typically involves skin (usually palpable purpura of
the lower limbs), gut (abdominal pain), joints (usually oligoarticular),
and kidneys (glomerulonephritis indistinguishable from IgA neph-
ropathy). Most cases do not require specific therapy.
Cryoglobulinaemic vasculitis—​vasculitis with cryoglobulin im-
mune deposits affecting small vessels. Cryoglobulin production
can be stimulated by processes including infection (notably hepa-
titis C), autoimmunity, and malignancy. Clinical presentation is with
purpura (typically on the calves), peripheral neuropathy, nephritis,
arthralgias, and systemic symptoms. Treatment involves resolution of
the underlying cause.
Hypocomplementaemic urticarial vasculitis—​vasculitis accom-
panied by urticaria and hypocomplementemia affecting small ves-
sels and is associated with anti-​C1q antibodies.
Cutaneous vasculitis—​vasculitis confined to the skin, which may be
triggered by infection, drugs, autoimmune disease, or malignancy.
Variable vessel vasculitides—​a range of conditions including re-
lapsing polychondritis, MAGIC syndrome, and Cogan’s syndrome.
Introduction
Small vessel vasculitis was defined by the Chapel Hill Consensus
Conference (CHCC) on nomenclature of vasculitis ‘as vasculitis af-
fecting predominately small intraparenchymal arteries, arterioles,
capillaries and venules, however, medium sized arteries and veins
may also be affected’. There are two main groups of the vasculit-
ides that affect small vessels: antineutrophil cytoplasmic antibody
(ANCA)-​associated and immune complex mediated. The former are
covered in Chapter 19.11.7.
IgA vasculitis (Henoch Schönlein purpura)
IgA vasculitis (IgAV) was formerly known as Henoch Schönlein
purpura. The revised nomenclature reflects the importance of IgA in
pathogenesis. The Chapel Hill Consensus Conference defined IgA
vasculitis as ‘vasculitis with IgA1-​dominant immune deposits, af-
fecting small vessels (predominantly capillaries, venules, or arteri-
oles)’. IgA vasculitis often involves the skin and gut, and frequently
causes arthritis. Glomerulonephritis indistinguishable from IgA
nephropathy may occur.
The American College of Rheumatology produced classifica-
tion critieria in 1990 but these have relatively poor sensitivity and
section 19  Rheumatological disorders
4574
specificity. Childhood classification criteria for IgA vasculitis have
been developed (Table 19.11.9.1).
Aetiology
The aetiology of IgA vasculitis is unknown, but it frequently oc-
curs after an infection several days to weeks before. The most fre-
quently isolated organism is β-​haemolytic streptococcus. Drugs
such as a penicillin, ampicillin, erythromycin, and non​steroidal
anti-​inflammatory drugs have been reported as precipitating agents.
There is an association with HLA-​DRB1*01 in Caucasians and there
appears to be a familial association.
Epidemiology
IgA vasculitis predominately affects children with 75% of cases
occurring below the age of 10 years and is the most common type
of vasculitis in childhood. It is most common in children of Asian
(Indian Subcontinent) origin. In the United Kingdom the incidence
is 20.4/​100 000 children and 1.3/​100 000 adults aged above 16 years,
with no major gender imbalance.
Clinical features
The classical features of IgA vasculitis are involvement of the skin,
gastrointestinal tract, kidney, and joints. A  rash is present in all
cases, but may not be the presenting feature. The most common type
of rash is non​thrombocytopaenic palpable purpura. This occurs in
dependent and pressure bearing areas such as the legs and buttocks
(Fig. 19.11.9.1) with a symmetrical distribution; it less frequently
involves the arms. The rash evolves from red to purple and then be-
comes rust coloured before fading. Skin ulceration is uncommon.
The rash may be macular, papular or (less frequently) urticarial or
vesicular.
The major gastrointestinal symptoms are abdominal pain, which
may be colicky in nature, nausea, and vomiting, with melaena or
haematemesis. These features are due to bowel ischaemia and oe-
dema. Approximately 60–​75% of cases will have abdominal pain.
Joint pain typically affects the feet, ankle and knees, and less com-
monly the arms, with an oligoarticular pattern; synovitis is not al-
ways present. Development of permanent joint damage is rare. The
joint manifestations may precede the development of palpable pur-
pura by several days in up to 25% of cases.
Renal involvement is potentially the most serious manifestation
of IgA vasculitis, occurring in up to 80% of patients, most com-
monly in older children and adults. Non​visible haematuria is the
most sensitive and earliest sign suggestive of nephropathy. Renal
failure is noted in 30% of adults at presentation but is rare in chil-
dren. Nephrotic syndrome is a rare presentation. The long-​term
renal outcome is difficult to predict: spontaneous recovery from
severe kidney injury at presentation and progression in mild pres-
entations are both well described.
Other less common features include neurological involvement
with headache, encephalopathy, mental state changes, and periph-
eral neuropathies. Interstitial pulmonary disease is common but
asymptomatic, with impairment of diffusion capacity during the ac-
tive phase of disease.
Clinical investigations
Investigations reveal an acute phase response, with moderate leuko-
cytosis and thrombocytosis. Serum IgA is elevated in a minority
of patients. The presence of antineutrophil cytoplasmic antibody
should suggest an alternative diagnosis, in particular granulomatosis
with polyangiitis (Wegener’s) or microscopic polyangiitis. Renal
histology shows IgA dominant immune deposits in the walls of
small vessels and glomeruli (Fig. 19.11.9.2). The initial lesion is a
focal or diffuse proliferative glomerulonephritis; more advanced
lesions show typically a mesangial proliferative and/​or crescentic
nephritis. Skin biopsy shows a leucytoclastic vasculitis with a neu-
trophilic infiltration around the vessel walls and fibrinoid necrosis,
together with IgA immunofluorescence in the walls of small vessels.
This histology is not specific as leucocytoclasis may occur in hyper-
sensitivity vasculitis.
Differential diagnosis
The differential diagnosis is from other forms of systemic vasculitis,
in particular the antineutrophil cytoplasmic antibody-​associated
vasculides granulomatosis with polyangiitis and microscopic
polyangiitis, and from other types of skin vasculitis.
The diagnosis in children is made on the basis of history and
physical findings. In adults a biopsy may be needed to confirm the
diagnosis and determine prognosis, especially if there is renal in-
volvement. There are no diagnostic criteria for IgA vasculitis, but
classification criteria have been developed (Table 19.11.9.1).
Treatment
Most cases do not require specific therapy as the condition remits
spontaneously on average within four weeks. Rest and adequate
Table 19.11.9.1  Classification criteria for IgA vasculitis
Palpable purpura or petechiae (mandatory criterion) with lower limb
predominance in the presence of at least one of the following four features:
• Diffuse abdominal pain
• Any biopsy showing predominant IgA deposition
• Arthritis or arthralgia (acute onset, any joint)
• Renal involvement (any haematuria and/​or proteinuria)
These criteria were developed by European League against Rheumatism
(EULAR) and Paediatric Rheumatology International Trials Organization
(PRINTO)
Fig. 19.11.9.1  Purpura occurring in IgA vasculitis.
Reproduced from Watts RA et al. (eds) (2013). Oxford Textbook of Rheumatology, 4th
edn, by permission of Oxford University Press.
19.11.9  Small vessel vasculitis
4575
hydration are necessary; non​steroidal anti-​inflammatory drugs
may help arthralgia but should not be used in those with renal
impairment. Glucocorticoids and immunosuppressive drugs
are commonly used in those with severe renal or gastrointestinal
involvement, but this is controversial because there is no evidence
that they improve long-​term outcome, primarily because of the
variability in outcome and difficulty in predicting a poor prog-
nosis. A recent randomized controlled trial reported no evidence
to support the use of glucocorticoids to prevent nephropathy in
children.
Prognosis/​outcome
In most patients IgA vasculitis has a self limiting course: children
usually have a single episode of disease, but relapses occur in 20%
of adults. The long-​term morbidity and mortality is determined by
the severity of renal involvement: up to 11% of adults may develop
end-​stage renal disease.
Cryoglobulinaemic vasculitis
Cryoglobulins are immunoglulins that precipitate in vitro at
temperatures below 37°C (Fig. 19.11.9.3). They are classified
according to the clonality and type of the immunoglobulins:
type I—​monoclonal immunoglobulin, either IgM or IgG; type
II—​a mixture of monoclonal IgM and polyclonal IgG; type III—​a
mixture of polyclonal IgM and IgG. Types II and III are also
known as mixed cryoglobulins as they have both IgG and IgM
components.
Many patients with cryoglobulinaemia remain asymptom-
atic. Cryoglobulinaemic vasculitis was defined by the Chapel Hill
Consensus Conference as ‘vasculitis with cryoglobulin immune
deposits affecting small vessels (predominantly capillaries, ven-
ules, or arterioles) and associated with cryoglobulins in serum’.
Aetiology
Cryoglobulin production can be stimulated by several patho-
logical process including infection, autoimmunity, and malig-
nancy (Table 19.11.9.2). A strong association was first recognized
in 1989 between hepatitis C virus (HCV) infection and predom-
inately type II cryoglobulinaemia, and in some populations up
to 90% of patients with mixed cryoglobulinaemia have circu-
lating HCV-​RNA. Cryoglobulinaemia has also been associated
with hepatitis B virus and human immunodeficiency virus (HIV)
infection.
Fig. 19.11.9.2  Glomerulus from a patient with IgA vasculitis and
proliferative glomerulonephritis with granular mesangial deposits of IgA
(IgA immunofluorescence ×400).
Reproduced with permission from Ball GV et al. (eds) (2014). Oxford Textbook of
Vasculitis, 3rd edn, by permission of Oxford University Press.
Fig. 19.11.9.3  Cryoglobulin precipitation in a cryocrit tube.
Reproduced with permission from Ball GV et al. (eds) (2014). Oxford Textbook of
Vasculitis, 3rd edn, by permission of Oxford University Press.
Table 19.11.9.2  Major causes of mixed cryoglobulinaemia
Autoimmune diseases
Sjogren’s syndrome
Systemic lupus erythematosus
Rheumatoid arthritis
Systemic sclerosis
Antineutrophil cytoplasmic antibody-​vasculitis
Infections
Hepatitis C
Hepatitis B
HIV—​1
HTLV-​1
Hepatitis A
Malignancy
B-​cell lymphoma
Hodgkin’s lymphoma
Multiple myeloma
section 19  Rheumatological disorders
4576
Epidemiology
The incidence and prevalence of cryoglobulinaemia is unknown.
Mixed cryoglobulinaemia is the most common type, with the
proportion of type II to type III varying between studies. The
prevalence of hepatitis C virus infection in patients with mixed
cryoglobulinaemia is 30—​(nearly) 100%, with the highest preva-
lence in patients from the Mediterranean. Between 12–​56% of
hepatitis C virus-​infected patients have cryoglobulinaemia, with
the highest rates in Mediterranean patients. Cryoglobulinaemic vas-
culitis is therefore more common in areas endemic for hepatitis C
virus. It has a predilection for women (3:1).
Monoclonal (type I) cryoglobulinaemic vasculitis is a rare dis-
order, occurring infrequently in patients with lymphoprolifera­
tive disorders including multiple myeloma and Waldenström’s
macoglobulinaemia.
Pathology
Tissue injury may arise from cryoglobulin precipitation in the
microcirculation leading to vascular occlusion, or by immune
complex-​mediated inflammation. Vascular occlusion is more
common in type 1 cryoglobulinaemia, where there may be high
concentrations of cryoglobulin with hyperviscosity syndrome and
cold-​induced acral necrosis. Immune complex-​mediated vasculitis
is more common in mixed cryoglobulinaemias, particularly type II.
Clinical features
The classical triad of purpura, arthralgia, and weakness was first de-
scribed by Meltzer and colleagues in 1966, but only occurs in 40%
of patients. The clinical features of patients with cryoglobulinaemic
vasculitis are given in Table 19.11.9.3.
The most obvious feature of cryoglobulinaemic vascu-
litis is purpura due to the precipitation of immune complexes
in the small vessels of the dermis and subcutaneous tissue
(Fig. 19.11.9.4). The lesions are most typical on the calves, al-
though thighs and trunk may be involved. The purpura may be
intermittent early in the disease course, with lesions disappearing
over 12 weeks. Persistence of vasculitic lesions may lead to the de-
velopment of ulcers, characteristically over the malleoli, and this
is an indication for more intensive therapy. Ulceration and skin
necrosis is much less common in hepatitis C virus positive pa-
tients. Raynaud’s phenomenon is seen more commonly in hepa-
titis C virus negative patients.
Peripheral neuropathy has been reported in up to 69% of cases,
most commonly sensory (76%), with a mixed sensorimotor neur-
opathy and mononeuritis multiplex being much less common.
Symptomatically this presents with parasthesiae, painful dysaes-
thesia, and myalgia in the legs.
Renal involvement with a nephritic syndrome is found in
20% at diagnosis:  this may be acute or follow a more chronic
slowly progressive process. Biopsy reveals a membranoproli­
ferative glomerulonephritis characterized by immune complex
deposition.
Arthralgias affecting the hands, wrists and knees occur in about
10% of cases: these are intermittent and migratory, and not associ-
ated with evidence of synovial inflammation. Systemic symptoms
such as fever, weight loss, and myalgia are common.
Table 19.11.9.3  Clinical and biological features
of cryoglobulinaemia vasculitis
Hepatitis
C virus –​ve
monoclonal
Hepatitis
C virus –​ve
mixed
Hepatitis
C virus +ve
mixed
Number of patients
64
242
165
Age (y)
65
63
60
Female (%)
56
69
54
Clinical features
Skin (%)
86
83
76
Purpura (%)
69
75
71
Raynaud’s phenomenon (%)
30
26
-​
Necrosis (%)
28
16
1
Ulcers (%)
27
14
4
Livedo (%)
13
2
4
Joints (%)
28
40
53
Peripheral neuropathy (%)
44
52
74
Central nervous system (%)
0
2
9
Renal (%)
30
35
34
Gastrointestinal
0
5
7
Biological features
Cryoglobulin (g/​l)
1.55
0.94
1.04
C4 (g/​l)
0.09
0.07
0.09
Normal cryoglobulin level <0.05 g/​l. Normal C4 complement fraction level is
0.14–​0.40 g/​l.
Table from Terrier B and Cacoub P (2013). Cryoglobulinemia vasculitis: an update.
Current Opinion in Rheumatology, 25(1): 10–​18, with permission.
Fig. 19.11.9.4  Lower limb purpuric lesions in a patient with type II
hepatitis C virus-​related cryoglobulinaemia.
Reproduced with permission from Ball GV et al. (eds) (2014). Oxford Textbook of
Vasculitis, 3rd edn, by permission of Oxford University Press.
19.11.9  Small vessel vasculitis
4577
Differential diagnosis
The differential diagnosis includes other types of small vessel vas-
culitis such as IgA vasculitis and microscopic polyangiitis. The
presence of rheumatoid factor leads to consideration of vasculitis
associated with rheumatoid arthritis, but other typical features of
rheumatoid arthritis such as synovitis will be absent. The presence
of antinuclear antibody (ANA) suggests that there may be an asso-
ciated autoimmune disease such as systemic lupus erythematosus
or Sjogren’s syndrome.
Clinical investigations
Diagnosis is based on clinical presentation and the presence of
circulating cryoglobulins. Sample collection and handling is cru-
cial when testing for these. The blood should be collected in pre-​
warmed syringes, transported, clotted, and centrifuged at 37–​40°C.
The serum is thereafter stored at 4°C for seven days. Type I cryo-
globulins precipitate within hours, whereas mixed cryoglobulins
can take days to precipitate.
High titres of rheumatoid factor are present in 70% of patients.
Antineutrophil cytoplasmic antibodies, antinuclear antibodies, and
anticardiolipin antibodies are usually absent. Complement levels
(C4) are low in 90% of cases, as may be total haemolytic comple-
ment levels.
Viral serology, especially hepatitis C virus, should be performed
looking for evidence of a precipitating infection.
In type 1 cryoglobulinaemia an underlying B-​cell lyphoproliferative
disorder should be sought—​Waldenström’s macroglobulinaemia,
multiple myeloma, or a monoclonal gammopathy of unknown
significance.
Treatment
Treatment of type I  cryoglobulinaemic vasculitis is that of the
underlying lymphoproliferative disorder.
The standard treatment of type II and III hepatitis C virus-​
related cryoglobulinaemic vasculitis has until recently been
with pegylated interferon-​α plus ribavirin and/​or rituximab.
About 30–​40% of patients fail to respond or relapse with this
combination. The addition of a protease inhibitor (NS3/​4A in-
hibitor) improves response rates, with 65–​70% sustained viral
response but with appreciable toxicity occurring in nearly 50%.
Rituximab was shown in a randomized controlled trial to have
better efficacy than conventional immunosuppressant therapy
with corticosteroids, azathioprine, cyclophosphamide, or plasma-
pheresis. Rituximab with pegylated IFN/​ribavirin, compared
with pegylated IFN/​ribavirin alone, has a shorter time to clinical
remission, better renal response rate, and higher rates of cryo-
globulin clearance. However, developments in treatment of hepa-
titis C virus are moving at pace, and the impact of new treatments
and combinations of treatments on hepatitis C virus-​related
cryoglobulinaemic vasculitis will become apparent over the next
few years.
The treatment of non​hepatitis C virus associated type II and III
cryoglobulinaemic vasculitis is that of the underlying disease, with
the aim of improving the clinical features and suppressing produc-
tion of the cryoglobulin producing B-​cell clones.
Prognosis/​outcome
hepatitis C virus positive patients with mixed cryoglobulinaemia
vasculitis have 1-​year survival of 96% and a 10 year survival of 63%.
Deaths are mainly attributed to serious infections and end stage liver
disease. A poor prognosis is associated with severe liver fibrosis,
central nervous, renal, and cardiac involvement at baseline. In
non​infectious mixed cryoglobulinaemia vasculitis patients the one-​
year survival is 91% and the 10-​year survival 65%. Deaths were due
to infection in 50% and vasculitis flare in 20%.
Antiglomerular basement membrane disease
Antiglomerular basement membrane disease was considered by the
Chapel Hill Consensus Conference as an immune mediated small
vessel vasculitis. The condition is covered in detail in Chapter 21.8.7.
Hypocomplementaemic urticarial vasculitis
Hypocomplementaemic urticarial vasculitis (HUV) was defined
by the Chapel Hill Consensus Conference as ‘vasculitis accom-
panied by urticaria and hypocomplementemia affecting small
vessels (i.e. capillaries, venules, or arterioles), and associated with
anti-​C1q antibodies’. This association led the Conference to pro-
pose the nomenclature anti-​C1q vasculitis.
Aetiology
Up to 25% of patients have an associated autoimmune disease, most
typically systemic lupus erythematosus.
Epidemiology
The epidemiology of hypocomplementaemic urticarial vasculitis is
unknown. About 75% of cases are women. It is an uncommon cause
of cutaneous vasculitis.
Clinical features
The urticarial lesions of hypocomplementaemic urticarial vasculitis
differ from those seen in common urticaria, being of longer dur-
ation (>24 hours) and painful rather than pruritic. Arthritis occurs
in 80% of cases and is typically non​destructive. Other manifest-
ations include ocular inflammation (uveitis, scleritis and episcleritis
in 56%), angioedema (50%), and livedo reticularis (14%). Renal
involvement is relatively uncommon (14%), but features may in-
clude membranous and mesangial glomerulonephritis. A  com-
parison of patients with anti-​C1q and those without, indicates
that those with anti-​C1q antibodies have more frequent systemic
hypocomplementaemic urticarial vasculitis, angioedema, livedo
reticularis, ocular involvement, musculoskeletal involvement, and
kidney involvement, but less frequent pulmonary and gastrointes-
tinal involvement.
Differential diagnosis
The differential diagnosis is from other types of systemic vasculitis,
and systemic lupus erythematosus.
section 19  Rheumatological disorders
4578
Clinical investigations
Laboratory findings include low complement levels of components
of the classical pathway, namely C1q, C2, C3, and C4, together with
an acute phase response. Antibodies against C1q are commonly
present. These are also found in systemic lupus erythematosus
and it has been suggested that hypocomplementaemic urticarial
vasculitis represents a form of lupus. Antinuclear antibodies are
present in 50% of patients; cryoglobulins, rheumatoid factor, and
antineutrophil cytoplasmic antibody may also be present.
Skin biopsy shows a leucocytoclastic vasculitis with granular
deposition C3, C1q, and immunoglobulins in the basement
membrane zone.
Treatment
There are no randomized controlled trials on which to base
therapy. Systemic glucocorticoids are effective in controlling the
vasculitis. Hydroxychloroquine and colchicine may as effective as
corticosteroids as first line therapy. Many patients respond well
to dapsone. The urticarial lesions respond poorly to antihista-
mines. Conventional immunosuppressive agents (azathioprine,
mycophenolate mofetil and cyclophosphamide) may be effective
in resistant cases.
Prognosis/​outcome
Patients may have significant morbidity and mortality, most com-
monly caused by chronic obstructive pulmonary disease and acute
laryngeal oedema.
Cutaneous vasculitis
The term cutaneous small vessel vasculitis implies vasculitis con-
fined to the skin and is synonymous with cutaneous leucytoclastic
vasculitis, hypersensitivity vasculitis, or cutaneous necrotizing
venulitis.
Aetiology
The aetiology is multifactorial: in more than 40% of cases no trig-
gering factor is identified, 20% are secondary to infection, 10% to
drugs, 15–​20% to autoimmune disease, and 5% to malignancy. The
most common infections are β-​haemolytic streptococci and viral
infection (upper respiratory tract hepatitis and HIV). The most
common drugs include allopurinol, propylthiouracil, hydralazine,
colony-​stimulating factors, and antibiotics, but a very long list of
drugs has been implicated, often anecdotally.
Pathogenesis/​pathology
Cutaneous vasculitis is caused by immune complex deposition in
the postcapillary venules, the complexes consisting of bound foreign
antigens and antibodies that due to their size and solubility attach
to the endothelium of small blood vessels. Deposition of immune
complexes triggers an inflammatory cascade with complement acti-
vation and endothelial damage.
Clinical features
The typical lesion is palpable purpura, which is present in up to 90%
of cases. Lesions are red/​purple in colour and are 2–​5 mm in diameter.
Differential diagnosis
The differential diagnosis is from systemic vasculitis, in particular
IgA vasculitis and other causes of purpuric lesions.
Clinical investigations
Investigation is directed at confirming the diagnosis and the
confinement of the vasculitis to the skin, hence a full haemato-
logical and biochemical profile is required, together with appro-
priate autoantibody serology (ANCA, ANA, RF) and serology for
infection.
Skin biopsy shows leucocytoclasis, which is the result of neutro-
phil disintegration and the release of nuclear dust, together with fi-
brin deposition (Fig. 19.11.9.5).
Treatment
Treatment may not be required above and beyond removal of the
triggering agent, or the underlying disease. Non​ulcerating lesions
may be treated with a mild topical steroid.
Variable vessel vasculitides
Relapsing polychondritis
Relapsing polychondritis is a rare autoimmune condition that
causes inflammation and destruction of cartilage. It affects men
and women equally, with peak incidence at age 50 years. It pre-
sents with non​specific constitutional symptoms and specific
features including auricular inflammation that spares the ear
lobe (85% of cases, Fig. 19.11.9.6), and nasal chondritis (50%),
which can lead to saddle nose deformity. Stridor suggests tra-
cheal involvement, which is the most serious complication.
Arthralgia of large and small joints and of the axial skeleton is
common. Inflammatory markers are raised; immunological
tests are typically negative; 18FDG-​PET can determine the ex-
tent of inflammatory lesions and response to treatment. Mild
cases are treated with non​steroidal anti-​inflammatory drugs.
Laryngotracheal involvement requires high dose steroids; other
Fig. 19.11.9.5  Skin biopsy showing a small blood vessel with fibrinoid
necrosis, endothelial swelling and red cell extravasation consistent with
leucocytoclastic vasculitis (haematoxylin and eosin ×400).
Reproduced with permission from Ball GV et al. (eds) (2014). Oxford Textbook of
Vasculitis, 3rd edn, by permission of Oxford University Press.

19.11.9 Small vessel vasculitis 4573 Richard A. Wa
19.11.9 Small vessel vasculitis 4573 Richard A. Watts
19.9  Osteoarthritis
4473
Epidemiology and risk factors
The epidemiology of osteoarthritis is complex, which reflects the
variation in the applied definition, the specific joint involved, and
the heterogeneity of the osteoarthritis phenotype. Epidemiological
studies, particularly analyses of large prospective cohorts, provide
important information about risk factors that provide insight into
the aetiology of osteoarthritis. This is supported by several well-​
recognized associations with the prevalence and incidence of osteo-
arthritis in peripheral joints. These include both non​modifiable
(e.g. age, gender, trauma, alignment and genetic predisposition)
and modifiable (e.g. obesity, occupational injury) risk factors, the
latter being prospective interventional targets for treatment and
prevention.
Prevalence
The knee, hip, and hand are the most frequently affected joints, and
the prevalence of osteoarthritis increases with age, which is the most
important risk factor. This may represent a senescent impairment of
tissue regeneration in addition to a cumulative effect of other risk fac-
tors associated with ageing. Approximately 14% of adults older than
25 years and 34% of adults older than 64 years have clinical osteo-
arthritis of one joint or more. Symptomatic clinical osteoarthritis of
the knee, hip, and hand are more prevalent in females. The popula-
tion prevalence of osteoarthritis of the hip and knee in the United
Kingdom is also greater with than without obesity (Fig. 19.9.3).
However, in a meta-​analysis of osteoarthritis prevalence studies in
adults older than 55 years, women have higher knee and hand osteo-
arthritis prevalence but there is no significant gender difference for
hip osteoarthritis. In the same meta-​analysis no significant gender
differences were observed in the prevalence of knee, hip, or hand
osteoarthritis among adults below 55 years of age. Women tended to
have greater prevalence of osteoarthritis when non​radiographic (e.g.
clinical) methods were used for defining the condition.
In adults aged 45  years and older in the American Johnston
County project and Framingham cohorts, the prevalence of knee
radiographic osteoarthritis was 28% and 19% respectively, whereas
the symptomatic knee osteoarthritis prevalence was 17% and 7% re-
spectively. In adults aged 60 years and older, 37% and 12% had knee
radiographic osteoarthritis and symptomatic knee osteoarthritis, re-
spectively. In the United Kingdom, 18% of adults above the age of 45
have self-​reported knee osteoarthritis. In a meta-​analysis, a history
of prior knee injury increased the risk of prevalent knee osteoarth-
ritis fourfold.
In adults of 45 years or more in the USA Johnston County pro-
ject, the prevalence of hip radiographic osteoarthritis was 28%
while symptomatic osteoarthritis was 9%. In adults in the United
Kingdom over 45 years, 11% have self-​reported hip osteoarthritis.
In adults over the age of 60 years the clinical American College of
Rheumatology (ACR) criteria for hand osteoarthritis (Table 19.9.2)
were met by 8%, while typical hand osteoarthritis symptoms were
reported by 22% of adults over 70 years of age. Among adults above
the age of 50, the prevalence of symptomatic and foot radiographic
osteoarthritis was 17%.
Incidence
Generic risk factors for the incidence of the knee, hip, and hand
osteoarthritis include age and female gender. Occupational ex-
posure to increased biomechanical stresses increases the risk of hip
and knee (after adjusting for age, gender, body mass index, and pre-
vious trauma). Participation in sporting activities and the presence
of osteoarthritis in other joints increases the risk of incident hip and
knee osteoarthritis.
Age and gender
The age and sex-​standardized incidence rates of symptomatic osteo-
arthritis in adults of 20 years and older are 240, 88, and 100 (per
100 000 person-​years) for the knee, hip, and hand, respectively.
The incidence of symptomatic osteoarthritis of the knee, hip, and
hand increases with age, with women having higher rates than men,
particularly after 50 years of age. Among women the incidence of
clinical osteoarthritis of the hip and knee increases rapidly between
50 and 75 years and then decreases thereafter. However, incident
clinical hand osteoarthritis peaks in women in peri-​ and post-​
menopausal years between 55 and 60 years and decreases thereafter.
Among men the incidence of clinical osteoarthritis of the knee, hip,
and hand increases from 50 to 75 years and then decreases. A meta-​
analysis and large primary care database reported a greater risk of
osteoarthritis incidence among women for the knee, hip, and hand,
respectively (Fig. 19.9.4).
Obesity
Obesity increases the biomechanical load upon weight-​bearing
joints, which may explain its association with knee osteoarth-
ritis. Obesity is the strongest potentially modifiable risk factor in
Population prevalence of hip osteoarthritis (total) and knee
osteoarthritis (total) of selected risk factors in England
Population prevalence
2
9
16
23
30
Hip osteoarthritis (total),
Obese
Hip osteoarthritis (total),
Healthy weight
Knee osteoarthritis (total),
Obese
Knee osteoarthritis (total),
Healthy weight
Fig. 19.9.3  Population prevalence of hip and knee osteoarthritis, with
and without obesity.
From the Musculoskeletal Calculator, © Arthritis Research UK, developed by Imperial
College London.
section 19  Rheumatological disorders
4474
meta-​analyses and confers more than a threefold greater risk of inci-
dent knee osteoarthritis and a greater risk of disease-​associated knee
pain incidence and structural progression. Obesity is associated
with incident hand osteoarthritis and self-​reported knee osteoarth-
ritis, but not hip osteoarthritis. There is conflicting evidence as to
whether obesity is associated with structural progression of hip or
knee arthritis, but there is no association between body mass index
and hand osteoarthritis pain or structural progression. Obesity dir-
ectly increases the biomechanical load in weight-​bearing joints,
which may also promote the production of pro-​inflammatory cyto-
kines (including adipokines) that mediate the catabolic processes of
osteoarthritis.
Joint injury
Joint injury can cause damage to articular cartilage, bone, me-
niscus, and rupture of the anterior cruciate ligament, all of which
can cause a biomechanically adverse environment within the joint
that predisposes to further deterioration of the joint tissues. Joint
injury has been associated with subsequent incident knee pain in
a systematic review and meta-​analysis of cohort studies, and also a
ninefold greater odds of progression to end-​stage knee radiographic
osteoarthritis in 48  months among knees without baseline knee
osteoarthritis.
Bone shape and malalignment
There is increasing evidence that clinical osteoarthritis is a conse-
quence of the failure to effectively dissipate adverse biomechanical
forces within a susceptible joint. Bone shape within joints has long
been recognized as a predisposing factor for adverse biomechanics.
The presence of an aspherical femoral head (a cam-​deformity) is
associated with femoro-​acetabular impingement and is associated
with delamination of the acetabular cartilage and confers up to a
tenfold greater risk of end-​stage hip osteoarthritis within five years.
Similarly, the expansion of the three-​dimensional shape of tibial
and femoral bones is associated with incident knee radiographic
osteoarthritis. Malalignment of the knees unequally distributes
load across the medial and lateral femoro-​tibial joint compartment
which results in a varus (bow-​legged) or valgus (knock knees) de-
formity. The compartment with the greater load as a consequence of
the malalignment is more likely to develop radiographic osteoarth-
ritis and structural progression of cartilage damage.
Genetics and epigenetics
Genetic studies within family-​based studies and extreme osteoarth-
ritis phenotypes have confirmed the strength of genetic predispos-
ition to osteoarthritis. The identification of genes associated with
osteoarthritis through association studies confer only small effect
sizes, but single-​nucleotide polymorphisms (SNP) have been associ-
ated with established risk factors such as obesity (FTO) and hip bone
shape (FRZB). One SNP near the NCOA3 gene reached genome-​
wide significance level. The NCOA3 gene is clinically important
because it is expressed in articular cartilage and its expression was
significantly reduced in damaged cartilage compared to normal car-
tilage in femoral heads removed at the time of hip replacement. As
osteoarthritis is likely a complex polygenetic problem, genomics
alone will be unlikely to stratify individuals into those who will or
will not develop osteoarthritis, but may lead to the development of
new therapeutic targets.
Epigenetic studies have indicated the disruption of cartilage
homeostasis may reflect environmental factors promoting abnormal
expression of genes that disrupt the anabolic and catabolic processes
that regulate cartilage integrity. The alteration in gene expression of
KNEE OA
20.00
18.00
16.00
14.00
12.00
10.00
8.00
6.00
4.00
2.00
0.00
40–<45
45–<50
50–<55
55–<60
60–<65
65–<70
70–<75
75–<80
80–<85
85 and
older
HIP OA
HAND OA
Fig. 19.9.4  The incidence of osteoarthritis.
Age and gender-​specific incidence rates (/1000 person-​years) of knee osteoarthritis (black), hip osteoarthritis
(red), and hand osteoarthritis (green). Solid, All population; short dash line, women; long dash line, men.
Reproduced from Prieto-​Alhambra D et al. (2014). Incidence and risk factors for clinically diagnosed knee,
hip and hand osteoarthritis: influences of age, gender and osteoarthritis affecting other joints. Annals of the
Rheumatic Diseases, 73(9), 1659–​1664, copyright 2014 with permission from BMJ Publishing Group Ltd.
19.9  Osteoarthritis
4475
anti-​inflammatory or pro-​inflammatory cytokines, articular car-
tilage proteins, matrix proteases, and transcription factors may be
involved in the pathogenesis of osteoarthritis and represent im-
portant novel therapeutic targets.
Structural progression
Structural progression is usually defined as imaging evidence
of structural deterioration in a joint, though soluble biomarkers
may also reflect this process. Conventionally these have been sur-
rogate measures of cartilage damage from conventional radiog-
raphy. Radiographic structural progression can be assessed by
measuring joint space narrowing using semi-​quantitative tools like
the Osteoarthristis Research Society International (OARSI) atlas
or quantitative tools. The Kellgren Lawrence grade is a composite
measure of joint space narrowing, osteophytes, subchondral scler-
osis that is described on an ordinal scale (Table 19.9.1, Fig. 19.9.1).
Joint space width is used as a surrogate for assessing cartilage thick-
ness, but in the knee it reflects a construct of reduction in hyaline
articular cartilage thickness along with meniscal extrusion and de-
generation. The Kellgren Lawrence scoring does not represent an
interval variable where individual categories are equidistant from
each other. It is therefore important to recognize that the proportion
of knees that progress from one grade to the next are not comparable
for all starting points in the scale.
With its three dimensional visualization of joint tissues, MRI has
broadened concepts of structural progression. The quantification of
MRI cartilage volume affords advantages over conventional radiog-
raphy because structural loss of cartilage can be detected in the pre-​
radiographic osteoarthritis phase and in end-​stage osteoarthritis,
after the total loss of joint space width (‘bone on bone’ or Kellgren
Lawrence grade 4). MRI also demonstrates structures other than
cartilage (Fig. 19.9.2, Table 19.9.3) that might be used to measure
structural progression such as bone marrow lesions or bone shape.
The structural progression measured by radiographic osteoarth-
ritis of knee, hip, and hand osteoarthritis is typically slow and takes
place over several years, but matters can also remain stable over
years. Structural progression varies by joint affected. In knees the
mean annual risk of progression of Kellgren Lawrence grade is 5.6%
± 4.9% and mean rate of joint space narrowing is 0.13 ± 0.15 mm/​
year, with change occurring in only a small group of ‘progressors’.
Radiographic improvement is atypical. MRI-​determined cartilage
volume loss in knee osteoarthritis progresses at a mean rate of 4%
per annum and more than half of all knees are ‘progressors’. Loss of
cartilage volume occurs more rapidly with increasing age, body mass
index, and lower limb muscle weakness, but also with coexisting
structural changes such as bone marrow lesions and meniscal
damage (Fig. 19.9.2). Muscle weakness has not been considered to
be a risk factor for structural progression based upon a systematic
review of studies using conventional radiography (not MRI).
Symptom progression
Studies that refer to osteoarthritis ‘progression’ generally refer to
structural progression, though sometimes progression to joint re-
placement is used as a surrogate for presumed worsening of pain and
structure. Clinical osteoarthritis symptom progression is not well
defined and could refer to progression of pain severity or the new
incidence of pain within individuals usually in cohort studies. Pain
can be serially measured using numeric rating or visual analogue
scales or using standardized questionnaires that ask patients to
quantify pain severity. Among knees with radiographic osteoarth-
ritis, little change is observed in knee pain over six years except when
large increases in radiographic structural severity are observed.
bone marrow lesions and bone shape are independently associated
with future increases in knee pain severity and incident knee pain
respectively. The probability of joint replacement is increased by
increasing severity of joint pain, increasing radiographic osteoarth-
ritis severity, MRI-​demonstrated bone marrow lesions, cartilage and
meniscal damage, and synovitis that indicate joint failure.
Secondary osteoarthritis
The term ‘primary’ or idiopathic osteoarthritis is less frequently
used now, perhaps because we understand the frequency of pre-​
osteoarthritis lesions (like meniscal damage) that would often not be
detected in routine clinical practice and for which patients often have
no knowledge (probably arising from minor or forgotten trauma).
However osteoarthritis does occur secondary to other diseases.
Congenital or developmental causes include bone dysplasias such
as epiphyseal dysplasia, localized diseases such as Perthe’s disease of
the hip, congenital hip dislocation, and slipped femoral epiphysis.
Endocrinological predisposing diseases include acromegaly,
diabetes mellitus, hyperparathyroidism, and hypothyroidism.
Metabolic predisposing diseases include haemochromatosis,
ochronosis (alkaptonuria), Gaucher’s disease, and Wilson’s disease.
Finally neuropathic (Charcot joints), calcium deposition diseases
(primary pseudogout), haemoglobinopathies, and other bone and
joint diseases may also cause secondary osteoarthritis.
Impact of osteoarthritis
Individuals with osteoarthritis suffer pain which is associated with
disability and reduced quality of life. The impact of osteoarthritis
on an individual’s function, mood, relationships, occupation, and
leisure activities may be extensive. Workers with osteoarthritis re-
ported more frequent pain, greater use of healthcare resources and
costs, reduced productivity, and poorer quality of life as self-​rated
osteoarthritis severity increased.
One in eight individuals with clinical osteoarthritis suffer self-​
reported unbearable pain and one in five give up holidays, hobbies,
and leisure activities. One-​third of people with the condition retire
early, give up work, or reduce the number of hours they work be-
cause of their condition. Those who retire early do so an average
of eight years early. Furthermore, two-​thirds of sufferers report an
increase in their own costs including travel and treatment which in
total equates to a mean of £480 per person each year.
Clinical osteoarthritis is the most common worldwide cause of
mobility disability and it is increasingly accountable as a cause for
years lived with disability and limitation of quality of life.
The lived experiences of people with osteoarthritis can be influ-
enced for better or for worse by one or a combination of the fol-
lowing:  functional impairment, attitudes towards osteoarthritis
symptoms, personal perceptions of osteoarthritis, and perceived per-
ceptions of other people towards osteoarthritis. Favourable changes
in any of these may improve the lives of those living with osteoarth-
ritis (Fig. 19.9.5). A systematic review of generalized osteoarthritis
indicates this is associated with poorer quality of life, function, and
increased disability. Increasing osteoarthritis joint burden is also as-
sociated with increasing risk of depression.
section 19  Rheumatological disorders
4476
Health economic impact
Clinical osteoarthritis is associated with pain, disability, absen-
teeism, and early retirement. The socioeconomic burden ranges
from one to two-​and-​a-​half per cent of gross domestic productivity
in developed countries. The economic burden of osteoarthritis on
society and health services is tremendous. This is generated through
a combination of direct and indirect costs. Individuals with osteo-
arthritis have double the rate of absenteeism compared with con-
trols in North American and Swedish population-​based cohorts.
The mean total direct and indirect costs are two to three fold higher
and there was a 40–​50% increased risk of disability pension in com-
parison with the general population. Osteoarthritis has a tremen-
dous economic impact that will only continue to grow with its rising
prevalence.
In the United Kingdom between 1991 and 2006, 25 845 hips and
23 260 knees underwent total joint replacement. The estimated
mortality-​adjusted lifetime risk of total hip replacement (THR) at
age 50 was 11.6% for women and 7.1% for men. For total knee re-
placement (TKR) the risks were 10.8% for women and 8.1% for men.
Clinical osteoarthritis represents more than 93% of all joint replace-
ment indications and the total annual cost of joint replacements is
estimated at £852 million in the United Kingdom in 2010.
Mortality
Case series of individuals with osteoarthritis have reported both
and an increased mortality and normal mortality rates compared
with national statistics of the general population. Symptomatic
osteoarthritis of the hip and knee was reported to confer approxi-
mately a two-fold greater risk of cardiovascular (CV) and dementia-​
associated deaths. While this association did not adequately adjust
for the confounding effects of disability and comorbidity in the
general population, walking disability was found to be a major risk
factor for mortality among individuals with osteoarthritis. A sub-
sequent population cohort reported that osteoarthritis did not
confer a greater risk of CV events but disability was independently
associated with this outcome after adjusting for the presence of
symptomatic and asymptomatic radiographic osteoarthritis. An
analysis of the Framingham population cohort reported that hand
osteoarthritis did not confer a greater risk of mortality but symp-
tomatic hand radiographic osteoarthritis conferred a greater risk
of CV events than asymptomatic hand radiographic osteoarthritis.
A cohort in North America, designed to describe osteoporotic frac-
tures and recruited from secondary care, described a greater risk of
all cause and cardiovascular (CVD) mortality conferred by the pres-
ence of hip radiographic osteoarthritis compared to the absence of
radiographic osteoarthritis of the hip. This effect was independent
of poor physical function but the causal effect was significantly ex-
plained by poor physical function. Therefore a greater burden of
osteoarthritis and subsequent disability may be important risk fac-
tors for mortality.
Pathogenesis and pathological features
Osteoarthritis is a syndrome of deterioration of synovial joints that
is characterized by focal and progressive loss of the hyaline articular
cartilage of joints, bone changes beneath the cartilage, synovial in-
flammation, and debilitating pain.
There is no single pathway of pathogenesis but in order for a
structurally normal joint to become osteoarthritic, this requires a
sufficient burden of joint tissue structural damage, biomechan-
ical adversity along with a varying combination of risk factors (see
epidemiology). These inflammatory, metabolic and genetic con-
tributory factors may drive a subsequent heterogenous cascade of
biomechanical and biochemical pathologies that overwhelm normal
repair processes and establish the joint ‘failure’ that presents as clin-
ical osteoarthritis.
This pathogenesis is likely to progress through a sequence of
stages that can be described macroscopically using MRI studies and
microscopically using histological studies.
Functional impairment
Factors affecting lived
experiences of osteoarthritis
Attitudes towards
osteoarthritis symptoms
Personal perceptions of
osteoarthritis
Perceived perceptions of
other people towards
osteoarthritis
Fig. 19.9.5  The factors affecting lived experiences of osteoarthritis.
From Smith T et al. (2014). Living with osteoarthritis: a systematic review and meta-​ethnography. Scand J Rheumatol, 43(6), 441–​52,
copyright © Scandinavian Rheumatology Research Foundation, reprinted by permission of Taylor & Francis Ltd (http://​www.tandfonline.
com) on behalf of Scandinavian Rheumatology Research Foundation.
19.9  Osteoarthritis
4477
Macroscopic
In early asymptomatic stages only individual tissues are likely to be in-
volved and cartilage defects, meniscal degeneration, and bone marrow
lesions are all known to be present among individuals without knee
osteoarthritis symptoms. These lesions (Fig. 19.9.2, Table 19.9.3) are
associated with incident knee radiographic osteoarthritis and struc-
tural progression of cartilage volume or thickness loss. It is likely that a
‘domino effect’ occurs where an inciting event such as a meniscal tear
predisposes to cartilage loss, adjacent bone marrow lesions, meniscal
extrusion, and malalignment which establishes a progressive bio-
mechanically adverse environment within the joint.
Microscopic
Osteoarthritis represents whole-​joint ‘failure’. Normal joint struc-
ture and function depend upon the ability of constituent tissues to
perceive and respond to stress, strain, and load. This is particularly
true of the articular cartilage and subchondral bone. The cells within
these tissues ensure the joint’s ability to receive and dissipate stress
is maintained by homeostatic reparative processes. This includes
the chondrocytes that maintain a substantial extracellular matrix.
Chondrocytes synthesize molecules to restore the cartilage matrix,
but also produce pro-​inflammatory cytokines (e.g. interleukin-​1)
and tissue destructive enzymes (e.g. metalloproteinases) which de-
crease anabolic matrix synthesis (Fig. 19.9.6). Cartilage and joint
structural integrity and function are lost as a net catabolic process is
established during the clinical osteoarthritis process. An extension
of the calcified cartilage zone increases biomechanical forces across
the cartilage and adjacent bone. Biomechanical derangements
within the joint can stimulate the production of further catabolic
enzymes. In parallel with these cartilage derangements the cellular
activity in subchondral bone changes, probably to attempt to ad-
just to biomechanical forces. This results in resorption and the pro-
duction of an increased volume of immature unmineralized bone.
This may compromise the biomechanical support for the overlying
cartilage which may augment the biomechanical forces transmitted
through cartilage resulting in further damage. Furthermore an in-
creased permeability at the junction between the articular cartilage
and bone (osteochondral junction), driven by microcracks in the
cartilage and subchondral angiogenesis, exposes the cartilage to an
abnormal biochemical environment (Fig. 19.9.7). Synovial inflam-
mation is precipitated by cartilage debris and catabolic mediators
entering the synovial cavity. Synovial macrophages produce some
of the chemokines and metalloproteinases that degrade cartilage
(Fig. 19.9.6). This in turn amplifies synovial inflammation, cre-
ating a potentially vicious cycle between these tissues.
Pain
Pain is a characteristic feature of osteoarthritis and is typically
activity-​related or mechanically-​exacerbated and is relieved by rest.
Pain may be intermittent initially but can be more chronic over time.
As osteoarthritis becomes more advanced, patients report pain with
different qualities (such as ‘a burning sensation’) which may reflect
neuropathic pain, and central pain mechanisms including sensitiza-
tion may reduce pain thresholds.
Osteoarthritis pain is generated from damaged joint tissues where
irritative chemical, mechanical or thermal stimuli precipitate af-
ferent nociceptive neurons to depolarize and send nociceptive sig-
nals to the sensory cortex via the dorsal horn of the spinal cord.
The signals passed to and through the central nervous system may
be enhanced by central sensitization. Nociceptive fibres richly in-
nervate the synovium and subchondral bone, and while the cartilage
is aneural in normal joints, it may be innervated by new nociceptive
fibres as osteoarthritis progresses.
The concordance between conventional radiography structural
pathology and knee pain is poor. Little change in pain is observed
in knee pain in knees with radiographic osteoarthritis over six years
except when large increases in radiographic osteoarthritis structural
severity are observed.
Cartilage
Cytokines
Cartilage
destruction
Proteinases
Chondrocytes
Osteoclasts
Osteoblasts
Bone
Cytokines
Subchondral bone
Synovial
fibroblasts
Synovial
macrophages
Synovium
Cytokines
(1L–1β, 1L–6, 1L–17, TNF)
Inflammatory
cells
Intrinsic/external
stimuli
MMPs
ADAMTS–4
Aggrecan
Type II collagen
Fig. 19.9.6  Pathogenesis of osteoarthritis.
Reprinted by permission from Macmillan Publishers Ltd: Nature Reviews Rheumatology. Kapoor M
et al. (2011). Role of pro​inflammatory cytokines in the pathophysiology of osteoarthritis. Volume 7(1),
33–​42, copyright 2011.
section 19  Rheumatological disorders
4478
Conventional radiography is not as sensitive or specific in
detecting structural pathology and progression as MRI. The osteo-
arthritic joint tissue lesions detected by MRI (e.g. cartilage defects,
meniscal tears, bone marrow lesions—​see Fig. 19.9.2) are preva-
lent in knees without radiographic osteoarthritis and these are
associated with incident symptoms which highlights the import-
ance of peripheral joint structural lesions in the pathogenesis of
nociception.
Biochemical biomarkers
Biochemical biomarkers in osteoarthritis are measures of the
pathogenic process of joint deterioration that can be measured
in the blood or urine. A recent review has identified that the best
described biochemical biomarkers are in the context of hip and
knee osteoarthritis and are considered to be a measure of collagen
degradation (urinary CTX-​II, serum COMP), osteophyte burden
or synovitis (serum hyaluronic acid) and bone turnover (urine/​
serum NTX-​1). Considerable research efforts have been made to
determine if they can be used for as surrogate measures for diag-
nostic purposes or to reflect how a patient feels, functions, or sur-
vives. Currently none of these biochemical markers, are sufficiently
discriminating to be used as surrogate outcome measures.
Management
Clinical features
The National Institute for Health and Care Excellence (NICE) and
the European League Against Rheumatism (EULAR) guidelines
advise that appropriate symptoms, clinical findings, and age at onset
can be used to clinically diagnose osteoarthritis. Activity-​related
joint pain reported in patients over the age of 45 with less than
30 minutes of morning joint stiffness can be considered to have
osteoarthritis without further investigation. The likelihood is in-
creased further by risk factors (see Epidemiology and risk factors)
and joint-​specific examination findings of pathology including
knee crepitus or Heberden’s nodes in the hands.
Investigation
X-​rays and laboratory analysis of blood and synovial fluid are not
necessary for the clinical diagnosis of osteoarthritis. However in the
presence of atypical features that suggest the presence of diagnoses
other than osteoarthritis, these tests may be used for distinguishing
inflammatory arthritis, septic arthritis, or malignant bone pain.
These features include rapid progression of symptoms, a hot swollen
joint, or prolonged morning stiffness of more than one hour.
Treatment
Recent years have seen the emergence of a large number of
evidence-​based guidelines from important musculoskeletal or-
ganizations. These are based on the published literature, expert
opinion and, to a lesser extent, patient opinion (all three sources
are valid for comprehensive guidelines). There is generally broad
agreement across these guidelines in which therapies they recom-
mend, though some discrepancies are obvious in Table 19.9.4.
Treatments may vary in efficacy according to the anatomical loca-
tion of osteoarthritis; most of the published evidence derives from
knee osteoarthritis trials.
VEGF
↑ MMP3
OPG/RANK/
RANKL
Key
Osteoblast
Osteoclast
Macrophage
Chondrocyte
PDGF
NGF
Tidemark
Chondrocyte
cluster
NCC
CC
SOX9
TGX–α
WISP–1
Perivascular
nerve fibre
BV
SCB
Sclerostin
VEGF
Sclerostin
Aggrecan
HGF
Fig. 19.9.7  Pathogenesis of osteoarthritis: osteochondral disruption.
Reprinted from Suri S and Walsh DA (2012). Osteochondral alterations in osteoarthritis. Bone, 51(2), 204–​211. Copyright 2012, with permission
from Elsevier.
19.9  Osteoarthritis
4479
Holistic assessment
The management of osteoarthritis should be personally-​tailored
for each individual. This should initially include a comprehensive
assessment to ensure a robust and realistic management strategy
is achieved. The package of interventions required will differ
depending on patient needs and osteoarthritis severity but should
include learning self-​management strategies which are associated
with better functional and pain outcomes. The assessment of phys-
ical status should identify reversible risk factors like muscle weak-
ness, obesity, and the severity and distribution of joint involvement.
The assessment of functional ability should describe the arthritis-​
related limitations in the context of daily living activities and em-
ployment. Personalized management strategies should be based
upon the patient’s health education needs, health beliefs, and mo-
tivation for self-​management. These inform the personally-​tailored
strategy required to encourage and teach the importance of lifestyle
modification and exercise.
Both non​pharmacological and pharmacological interventions are
used, separately but more commonly in combination, in the treat-
ment of osteoarthritis (Table 19.9.4).
Non​pharmacological interventions
Guidelines for the management of osteoarthritis unanimously
recommend the provision of health education and to encourage
self-​management. All individuals with osteoarthritis should
comprehend their arthritis reflects a failed repair process usually
arising due to several joint insults, their personal risk factors (e.g.
obesity) and their prognosis. This information should be reinforced
at subsequent consultations and with both electronic and written
resources.
All patients with osteoarthritis should be offered advice on exer-
cise that initially focusses on local muscle strengthening and then
general aerobic fitness thereafter. A  Cochrane review finds that
land-​based knee and hip exercise programmes can reduce pain and
improve physical function. Exercise programmes must be tolerable
and realistic to promote adherence and should therefore be tailored
to the severity of the osteoarthritis at presentation. It is unlikely
that a patient with painful knee osteoarthritis, that cannot perform
a straight leg raise, will significantly benefit from walking without
quadriceps strengthening first. Exercise programmes for individuals
with significant muscle weakness should begin with low-​impact ex-
ercises such as cycling on exercise bikes and walking laps in a swim-
ming pool. Depending upon each individuals capability, the ‘dose’ of
exercise should be titrated up.
Overweight or obese individuals should be offered a dietician’s re-
view or dietary advice because weight loss is associated with reduc-
tion in pain and better function (though there is little evidence for
benefits on structural progression). Aids and devices (e.g. splints for
base of thumb osteoarthritis and devices for opening jars) help with
everyday activities. Recommended footwear for individuals with
Table 19.9.4  Summary of evidenced-​based guidelines for osteoarthritis treatments
Guideline
NICE 2014
OARSI 2014
OARSI 2014
EULAR 2013
ACR 2012
ACR 2012
ACR 2012
Site of osteoarthritis
all sites
knee
multijoint
knee and hip
hand
knee
hip
Exercise/​physiotherapy (water-​ and land-​based)
+
+
+
+
NE
+
+
Education, self-​management
+
+
+
+
(+)
(+)
(+)
Weight loss in obesity
+
+
+
+
NE
+
+
Thermotherapy (eg hot packs/​spa)
+
NR
(+)
NE
(+)
(+)
(+)
Acupuncture
–​
NR
NR
NE
NE
(+)
NE
Transcutaneous electrical nerve stimulation
+
NR
–​
NE
NE
(+)
NE
Aids, adaptations, braces, footwear (site specific)
+
(+)
(+)
+
(+)
(+)
(+)
Paracetamol
+
(+)
+
NE
NE
(+)
(+)
Topical NSAIDs
+
+
NR
NE
(+)
(+)
NR
Oral NSAIDs (lowest possible dose)
+
(+)
(+)
NE
(+)
(+)
(+)
Topical capsaicin
+a
(+)
NR
NE
(+)
–​
NE
Opioids (for refractory pain)
(+)
NR
NR
NE
–​
(+)
NR
Glucosamine and chondroitin sulphate
–​
NR
NR
NE
NE
–​
–​
Duloxetine
NE
NR
+
NE
NE
(+)
NR
Risedronate
NE
–​
–​
NE
NE
NE
NE
Strontium
–​
NE
NE
NE
NE
NE
NE
Intra-​articular corticosteroids
+
(+)
+
NE
–​
(+)
(+)
Intra-​articular hyaluronans
–​
NR
–​
NE
–​
(+)
NR
Surgery—​lavage/​debridement
–​b
NE
NE
NE
NE
NE
NE
Surgery—​TJR/​arthroplasty (site specific)
(+)
+
NE
NE
NE
NE
NE
This is not a head-​to-​head comparison of the guidelines but a summary of the recommendations; each guideline addresses different anatomical sites
treatment is unconditionally recommended; (+) treatment is conditionally recommended; -​ treatment is not recommended; a excluding hip osteoarthritis; b unless there is a clear
history of mechanical knee locking; NR = no recommendation for treatment despite reviewing the evidence; NE = treatment not evaluated; TJR = total joint replacement
Reprinted with permission from Barr A and Conaghan P (2014). Osteoarthritis: recent advances in diagnosis and management. Prescriber, 51(21), 26–​33.
section 19  Rheumatological disorders
4480
osteoarthritis includes shoes with no heel elevation, thick shock-​
absorbing soles, and adequate plantar arch support.
In summary, the multidisciplinary patient-​centred combination
of exercise self-​management and education should set realistic goals
with regular reassessment and encouragement to maintain the re-
quired lifestyle changes.
Pharmacological interventions
Before prescribing pharmacological treatments for osteoarthritis,
practitioners should holistically consider, the individual’s existing
pharmacotherapy, age, risk of cardiovascular and gastrointestinal
comorbidity, and probability of treatment adherence. When pre-
scribing analgesia, the practitioner should also consider the drug
half-​life, dose-​regimen, and the route of administration.
The first-​line pharmacological treatments are topical NSAIDs and
oral paracetamol due to their favourable risk:benefit ratio. However
recent evidence suggests that paracetamol, may have greater tox-
icity than is generally appreciated, and be a less effective analgesic in
osteoarthritis than previously thought (Table 19.9.5). In one study,
after 13 weeks of regularly taking either ibuprofen or paracetamol
three times a day for knee osteoarthritis, one in five participants lost
more than 1 g per decilitre of haemoglobin. A systematic review
identified a dose-​response effect on cardiovascular, gastrointestinal,
and renal adverse events. Topical capsaicin is a chilli pepper extract
that depletes neurotransmitters in sensory terminals and attenuates
the central transmission of peripheral pain impulses from the joint.
It is generally recommended as supplementary analgesic for hand
and knee osteoarthritis and is again safe.
Should further analgesia be required, practitioners should con-
sider oral non​steroidal anti-​inflammatory drugs (NSAIDS), selective
COX-​2 inhibitors, and then opiates, acknowledging the greater risk
of toxicity, particularly with increasing age and comorbidities.
Nutraceuticals, including glucosamine sulphate and chondroitin
sulphate products, are natural compounds consisting of glycosa-
minoglycan unit components and glycosaminoglycans respectively.
Despite the substantial volume of published evidence, they are often
not recommended due to the lack of certainty of clinically important
analgesic or structural benefits. However nutraceuticals have been re-
ported to afford small benefits in pain relief in low quality trials.
The intra-​articular injection of corticosteroids is a useful short-​
term adjunct in the treatment of moderate to severe osteoarth-
ritis pain, which may facilitate muscle strengthening and exercise.
Hyaluronan (HA, or hyaluronic acid) is a high molecular-​weight gly-
cosaminoglycan, a naturally occurring synovial fluid and cartilage
component. It provides the visco-​elastic properties of synovial fluid
that may provide lubricating and shock-​absorbing properties. Intra-​
articular HA is not recommended for osteoarthritis by the NICE
guideline; in contrast the ACR guideline conditionally recommends
its use in individuals older than 74 years with knee osteoarthritis
pain that is refractory to conventional pharmacological therapies.
Duloxetine is a selective serotonin and norepinephrine reuptake
inhibitor and has demonstrated efficacy in reducing musculoskel-
etal pain with a favourable adverse event profile. The analgesic ef-
fects of duloxetine in osteoarthritis are thought to be mediated by
enhancement of serotonergic and noradrenergic activity which at-
tenuates nociceptive impulse transmission in the central nervous
system. The evidence-​base for the use of duloxetine is limited to
knee osteoarthritis. It is a licensed treatment for chronic musculo-
skeletal osteoarthritic pain in the United States and the OARSI and
ACR guidelines recommend its use in multijoint osteoarthritis and
knee osteoarthritis, respectively.
Joint surgery
Surgical intervention in osteoarthritis may include arthroscopic sur-
gery or partial or complete joint replacement. Arthroscopic debride-
ment and lavage are not recommended as treatment for osteoarthritis,
except when there is a clear history of true mechanical locking of an
osteoarthritic knee. True locking may represent displaced meniscal
material but in the absence of true locking arthroscopic procedures
do not confer better clinical outcomes than sham surgery, even with
symptoms of ‘giving way’ (frequently a symptom of muscle weakness)
or radiographic evidence of loose bodies. However joint surgery
should be considered if a patient with osteoarthritis suffers persistent
symptoms, despite adequate use of the non​pharmacological and
pharmacological interventions described here. In this circumstance
clinicians should consider an orthopaedic referral to primarily con-
sider joint replacement. The patient should be provided with infor-
mation to understand the risks and benefits of pursuing nonsurgical
and surgical treatments, including the postsurgical rehabilitation
implications. This ensures the patient can make informed autono-
mous decisions and their preferences and opinions are respected.
Referrals to an orthopaedic surgeon should not be precluded by age,
comorbidity, obesity, smoking, or gender. The referring practitioner
should make a timely referral before severe pain and an established
functional limitation occur. In younger patients with advanced
osteoarthritis, the discussion on advantages of primary arthroplasty
must be tempered by awareness of the increased likelihood of revi-
sion arthroplasty with less favourable outcomes.
Conclusions
Clinical osteoarthritis represents a process of joint failure with a
great variety of risk factors and complex pathogenic pathways. It
Table 19.9.5  Relationship between effect size for pain relief and
quality of randomized controlled trial
All trials ES (95% CI)
High-​quality trials
(Jaded = 5), ES (95% CI)
Acupuncture
0.35 (0.15, 0.55)
0.22 (0.01, 0.44)
Acetaminophen
0.14 (0.05, 0.23)
0.10 (−0.03, 0.23)
NSAIDs
0.29 (0.22, 0.35)
0.39 (0.24, 0.55)
Topical NSAIDs
0.44 (0.27, 0.62)
0.42 (0.19, 0.65)
IAHA
0.60 (0.37, 0.83)
0.22 (−0.11, 0.54)
GS
0.58 (0.30, 0.87)
0.29 (0.003, 0.57)
CS
0.75 (0.50, 1.01)
0.005 (−0.11, 0.12)
ASU
0.38 (0.01, 0.76)
0.22 (−0.06, 0.51)
Lavage/​debridement
0.21 (−0.12, 0.54)
−0.11 (−0.30, 0.08)
ES, effect size; NSAIDs, non-​steroidal anti-​inflammatory drugs; IAHA, intra-​articular
hyaluronic acid; GS, glucosamine; CS, chondroitin sulphate; ASU, avocado soybean
unsponifiables
Reprinted from Zhang W et al. (2010). OARSI recommendations for the management of
hip and knee osteoarthritis Part III: changes in evidence following systematic cumulative
update of research published through January 2009. Osteoarthritis and Cartilage, 18(4),
476–​499. Copyright 2010, with permission from Elsevier.
19.9  Osteoarthritis
4481
confers a huge burden on individuals and health economies alike
which is expected to increase in ageing and increasingly obese
populations. Current treatments consist of moderately effective
non​pharmacological and pharmacological pain-​relieving therapies.
There are currently no licensed structure-​modifying therapies. Joint
replacement reduces pain but joint prostheses have a finite life ex-
pectancy and revision surgery offers less favourable outcomes.
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19.12 Miscellaneous conditions presenting to rheum
19.12 Miscellaneous conditions presenting to rheumatologist 4598

19.2 Clinical presentation and diagnosis of rheuma
19.2 Clinical presentation and diagnosis of rheumatological disorders 4386 Christopher Deighton and Fiona Pearce
ESSENTIALS
Most rheumatological diagnoses are made through effective history
taking and physical examination rather than investigation.
Systemic symptoms, such as weight loss, anorexia, and fever,
point to systemic diseases such as rheumatoid arthritis, other
polyarthritides, systemic lupus erythematosus, polymyalgia, and
vasculitides. Swelling of joints is a symptom commonly reported
by patients with no objective evidence of this on examination.
Inflammatory arthropathies should not be diagnosed unless the
physician is able to identify objective swelling, if necessary by arran-
ging a prompt review during an active episode. Diagnostic criteria
for the systemic rheumatic diseases are useful in directing the history
taking to verify a suspected diagnosis.
Investigations are best used to confirm a strongly suspected diag-
nosis, already made on the basis of history and examination, not as a
screening tool for rheumatic disease.
What are rheumatological disorders?
Rheumatological disorders include arthritis and other conditions
where musculoskeletal symptoms and signs are prominent. They
include inflammatory arthritis and other systemic autoimmune dis-
orders (connective tissue diseases and vasculitis) as well as soft tissue
conditions, osteoarthritis, and spinal pain. Many rheumatology de-
partments also provide expertise in metabolic bone disease. All to-
gether rheumatological disorders incorporate over 200 conditions
affecting joints, bones, muscles, and soft tissues. A significant pro-
portion of these also affect other organ systems directly (e.g. glom-
erulonephritis in vasculitis) or indirectly (e.g. cardiovascular disease
in rheumatoid arthritis).
How do rheumatological disorders
present?
Most patients presenting with rheumatological disorders present
with pain, but occasionally other symptoms suggest underlying auto-
immune rheumatic disorders (e.g. Raynaud’s phenomenon). A chief
task in the history is to determine whether the pain that the person
presents with is inflammatory, mechanical, or sinister. To deal with
the latter category first, it is important that patients with significant
systemic symptoms and musculoskeletal pain have a history taken
carefully, thorough general medical examination, and appropriate
investigations. Life-​threatening disease such as infection and malig-
nancy can present with musculoskeletal symptoms, and this needs
to be considered primarily. A good example is back pain, where ‘red
flag’ signs should alert the clinician to the possibility of infection
or malignancy until proven otherwise (Table 19.2.1). Similar prin-
ciples can be applied to limb musculoskeletal symptoms.
Once sinister disease has been considered and seems unlikely or
preferably excluded, the authors consider it is helpful to categorize
19.2
Clinical presentation and diagnosis
of rheumatological disorders
Christopher Deighton and Fiona Pearce
Table 19.2.1  Red flags for back pain
Features
• Previous history of malignancy (however long ago)
• Age <16 or >50 with NEW onset pain
• Weight loss (unexplained)
• Previous or current longstanding steroid use
• Recent serious illness
• Recent significant infection
Signs
• Saddle anaesthesia
• Reduced anal tone
• Hip or knee weakness
• Generalized neurological deficit
• Progressive spinal deformity
• Urinary retention
Symptoms
• Non​mechanical pain (worse at rest)
• Thoracic pain
• Fevers/​rigors
• General malaise
• Urinary retention
19.2  Clinical presentation and diagnosis of rheumatological disorders
4387
rheumatological disorders into four main groups: inflamma-
tory arthritis; autoimmune rheumatic diseases and vasculitis;
non​inflammatory musculoskeletal pain and pain syndromes; and
bone disease (Table 19.2.2).
A general approach in the history
Key considerations in the history of a patient with musculoskeletal
pain that influence the differential diagnosis are:
• How many joints or regions are affected? Is it a monoarthritis,
oligoarthritis (two to four joints), or a polyarthritis? Is it
periarticular (structures around joints but not in them)? Are
there any axial symptoms?
• How quickly did it come on? Was it acute, or insidious, or waxing
and waning?
• Is there anything to suggest
■	 Any sinister features?
■	 Inflammatory features?
■	 Multisystem autoimmune disease (Table 19.2.3)?
■	 Other local or general musculoskeletal disorders?
■	 Bone disease?
• Are there any other clues on systematic enquiry (e.g. recent
gastroenteritis, psoriasis, iritis, and so on?) (Table 19.2.3)
Table 19.2.2  A clinical classification of rheumatological disorders
Inflammatory arthritis
—	 Rheumatoid arthritis
—	 Spondyloarthropathies: ankylosing spondylitis, psoriatic arthritis, reactive
arthritis, enteropathic arthritis
—	 Juvenile idiopathic arthritis (JIA)
—	 Crystal arthropathies: gout, pseudogout
—	 Septic arthritis
Multisystem autoimmune rheumatic disease
—	 Systemic lupus erythematosus
—	 Sjögren’s syndrome
—	 Scleroderma (systemic sclerosis)
—	 Polymyositis
—	 Dermatomyositis
—	 Polymyalgia rheumatica
—	 Mixed connective tissue disease
—	 Polychondritis
—	 Sarcoidosis
—	 Vasculitis: Granulomatosis with polyangiitis (GPA, formerly known as
Wegener’s granulomatosis), Microscopic Polyangiitis, Eosinophilic
granulomatosis with polyangiitis (EGPA, formerly known as Churg-Strauss
syndrome), Polyarteritis nodosa, IgA nephropathy (formerly known as
Henoch–Schönlein purpura), Takayasu’s arteritis, Behçet’s syndrome,
Kawasaki’s disease (mucocutaneous lymph node syndrome), Buerger’s
disease (thromboangiitis obliterans)
Non​inflammatory musculoskeletal pain and pain syndromes
—	 Local (diseases affecting the joints and structures around the joints
including tendons, ligaments capsules, bursae, stress fractures, muscles,
nerve entrapment, vascular lesions, and ganglia). For example:
—	 Low back pain
—	 Tennis elbow
—	 Plantar fasciitis
—	 Olecranon bursitis
—	 General
—	 Osteoarthritis
—	 Fibromyalgia and regional pain syndromes
Bone disease
—	 Osteoporosis
—	 Osteomalacia
—	 Paget’s disease
—	 Rare metabolic bone disorders
Table 19.2.3  Extra-​articular manifestations of rheumatological
disorders
Clinical feature
Causes
Mucocutaneous
Photosensitivity
Raynaud’s phenomenon
Mouth ulcers
Subcutaneous nodules
Erythema nodosum
Nail dystrophy
Cutaneous vasculitis
Systemic lupus erythematosus (SLE),
dermatomyositis, Sjögren’s syndrome
SLE, scleroderma, dermatomyositis
SLE, Behçet’s syndrome, spondyloarthropathies
(particularly reactive arthritis and IBD-related)
Rheumatoid arthritis (RA), tophaceous gout,
acute rheumatic fever
Sarcoidosis, Behçet’s syndrome,
spondyloarthropathies, SLE
Spondyloarthropathies (particularly psoriatic
arthritis, and reactive arthritis)
Systemic vasculitis, SLE, RA, dermatomyositis,
Behçet’s syndrome
Ocular
Keratoconjunctivitis sicca
Conjunctivitis
Scleritis
Uveitis
Retinal vasculitis
Primary: Sjögren’s syndrome. Secondary: RA, SLE,
scleroderma
Spondyloarthropathies (particularly reactive
arthritis)
RA, Granulomatosis with polyangiitis
Spondyloarthropathies (particularly ankylosing
spondylitis and IBD-related), juvenile idiopathic
arthritis, Behçet’s syndrome, sarcoidosis
SLE, Behçet’s syndrome
Renal
Acute kidney injury
Glomerulonephritis
Renal calculi
Scleroderma (renal crisis), SLE, systemic vasculitis
SLE, ANCA-​associated vasculitis
Gout
Pulmonary
Serositis (pleuritis,
pericarditis, peritonitis)
Interstitial lung disease
Nodules
Pulmonary hypertension
SLE, systemic juvenile arthritis (Still’s disease),
rheumatoid arthritis, acute rheumatic fever
Scleroderma, antisynthetase syndrome
(myositis), SLE, RA
Sarcoidosis, RA, granulomatosis with polyangiitis
Scleroderma, SLE
Cardiac
Valvular heart disease
(mitral regurgitation,
aortic regurgitation)
Myocarditis
Acute rheumatic fever, Ankylosing spondylitis,
RA, SLE, reactive arthritis, systemic vasculitis,
scleroderma, sarcoidosis
SLE, mixed connective tissue disease,
scleroderma
Neurological
Mononeuritis multiplex
Stroke
Systemic vasculitis, RA, SLE
Antiphospholipid syndrome, Behçet’s syndrome,
Takayasu’s arteritis
ANCA, antineutrophil cytoplasmic antibody; IBD, inflammatory bowel disease; RA,
rheumatoid arthritis; SLE, systemic lupus erythematosus;
section 19  Rheumatological disorders
4388
There are some typical patterns that suggest a likely diagnosis; for
example, acute monoarthritis in a systemically unwell 17-​year-​
old woman with a vaginal discharge returning from a holiday in
Majorca (gonococcal septic arthritis); a 54-​year-​old publican with
a red hot swollen big toe (gout); insidious onset of symmetrical
peripheral joint inflammation in a 63-​year-​old woman (rheuma-
toid arthritis); recent onset of severe Raynaud’s phenomenon with
arthralgias, myalgias, pleurisy, and a rash on sun exposure (sys-
temic lupus erythematosus). However, most patients do not fit
into straightforward caricatures, and the diagnosis is determined
by using traditional medical skills in history and examination
findings, and may then be confirmed on blood tests, aspirates,
imaging, or biopsies. Suggested initial screening tests and some
diagnostic tips are included in Tables 19.2.4 and 19.2.5.
Inflammatory arthritis
A common challenge in a patient with arthralgias is whether the
patient has inflammatory or non​inflammatory joint symptoms.
Features of inflammatory versus noninflammatory symptoms
(e.g. osteoarthritis) are listed in Table 19.2.6. The examination
finding of synovitis may be difficult to elicit, and may not be present
in all types of inflammatory arthritis (e.g. enthesitis-​related arth-
ritis) and ultrasound or MRI imaging can be helpful in equivocal
cases. Once an inflammatory arthritis is suspected, the number
and pattern of joint involvement, along with presence or absence of
extra-articular features, suggests likely diagnoses (see Figs. 19.2.1
and 19.2.2). These are considered next.
Monoarthritis
Monoarthritis is septic arthritis until proven otherwise. A history
and examination must be followed by joint aspiration, and certainly
before commencing empirical antibiotics. Analysis of the joint fluid
suggests likely causes (Table 19.2.7), but these are a guide only and
septic arthritis may occur with ‘normal’ or ‘inflammatory’-​looking
Table 19.2.4  Screening tests
In all cases
consider
Acute
polyarthritis
Chronic
polyarthritis
Diffuse arthralgias/​
myalgias
FBC, ESR
Blood cultures
TSH
CRP
ASOT
Uric acid
Creatinine kinase
Rheumatoid
factor (RF)
Parvovirus B-​
19 IgG & IgM
Urinalysis
U&E, calcium,
phosphate, glucose,
Anti-​CCP (if RF
negative)
Hepatitis B
TSH
Vitamin D
ANA, HIV
Serum and
urine protein
electrophoresis
Rubella
ACE, CXR
ANCA
ANA, antinuclear antibody; Anti-​CCP, anticitrullinated peptide; ASOT, antistreptolysin O
titre; ACE, angiotensin converting enzyme; ANCA, antineutrophil cytoplasmic antibody;
TSH, thyroid-​stimulating hormone
Table 19.2.5  What to look for: diagnostic tips
Rheumatoid
arthritis (RA)
Spondyloarthropathies
(e.g. reactive and
psoriatic arthritis)
Gout
Connective
tissue disease
Osteoarthritis
(OA)
Fibromyalgia
Polymyalgia
rheumatica
Onset
Usually subacute
or acute
Acute/​subacute/​ chronic
Usually Acute
Subacute
Chronic
Chronic
Usually within a
few weeks
Typical age
and gender
Female: male 3:1
Any age
Any age
Female: male
1:3 Very rare in pre-​
menopausal women
Female: male
10:1
Typically pre-
menopausal
Hand OA more
common in
females Usually
age ≥45
Female:male 7:1
Age 30–​50
Female:male 2:1
Pattern
of joint
involvement
Usually
symmetrical
hands and feet
Can be monoarthritis
or asymmetrical oligo/​
polyarthritis
Monoarthritis most
commonly—1st
metatarsophalangeal
joints, ankle, or knee
Can be symmetrical
Any, may be
flitting
Hands, knees,
hip, and feet most
common
Widespread
Usually shoulder
and pelvic girdle
Other clues
15–​30% of
patients are
rheumatoid factor
negative—​this
does not exclude
the diagnosis
May be associated with
inflammatory back pain,
Psoriasis, Inflammatory
bowel disease or Uveitis
Risk factors: diuretic
treatment, obesity,
alcohol
Raynaud’s
phenomenon,
mouth ulcers,
rashes (butterfly
or vasculitic),
Systemic
features,
Pleuritic chest
pain
Heberden’s or
Bouchard’s nodes
Crepitus
Poor quality of
sleep Tender
soft-​ tissue
‘trigger points’
on examination
Multiple
symptoms
Overlap with
temporal
arteritis—​ask
about headache,
visual symptoms
and jaw
claudication
Table 19.2.6  Features of inflammatory versus noninflammatory
arthralgias
Favours noninflammatory
disease
Favours inflammatory disease
Pain after activity/​at end of
day
Pain worse after rest and on waking in the
morning
Morning stiffness for <30
minutes
Morning stiffness for >30 minutes
No night-​time pain
Night-​time paina
No systemic symptoms
Systemic symptoms presenta
Chronic symptoms
Acute/​subacute presentation
a Night pain and systemic symptoms indicate other serious pathology including cancer,
or infection (see above).
19.2  Clinical presentation and diagnosis of rheumatological disorders
4389
joint fluid, and gram stain and culture are essential. For example,
patients who are on steroids or who are immunocompromized may
not mount an inflammatory response and have synovial fluid that
looks benign but is infected.
It is common for those with a septic joint to have fever, neutrophilia,
and raised inflammatory markers. But as with joint fluid that appears
unremarkable, it is also possible for these features to be completely
normal in patients who are on steroids or immunocompromized,
or on biological therapies such as anti-​TNF or tocilizumab. Septic
arthritis is more common in abnormal joints, and is usually spread
haematologically. Bear in mind that prosthetic joints may have no
signs (only symptoms), and are more prone to infection than native
joints. Staphylococcus and Streptococcus are the most common or-
ganisms, but atypical organisms should be covered in certain groups
(e.g. sickle cell—​salmonella; intravenous drug abusers—​gram nega-
tive or fungal organisms).
Gout typically has an acute onset over hours, and a natural history
of resolution over three to four days in early attacks. Pyrophosphate
can come on more insidiously and last longer. The joint may be very
erythematous and hot, as well as swollen, and the appearance may be
confused with cellulitis. The key differentiator between intra-​articular
inflammation and cellulitis is the global painful loss of movement in
the affected joint. Joint fluid viewed under polarized light microscopy
shows needle shaped negatively birefringent monosodium urate
crystals in gout, and rhomboid weakly positively birefringent crys-
tals in pseudogout (acute calcium pyrophosphate arthritis).
Oligoarthritis (2–​4 joints) and spondyloarthritis
An oligoarthritis is most commonly one of the spondyloarthro­
pathies (SpA) which include ankylosing spondylitis and psoriatic
arthritis. These conditions (Table 19.2.8) share several common
features which are set out in Table 19.2.9. Clinically, SpA should
be suspected whenever a young patient (<40 years) presents, with
inflammatory low back pain, and/​or asymmetrical involvement
of knees or ankles. These may be associated with psoriasis, uve-
itis, inflammatory bowel disease, and recent gastroenteritis or
urethritis.
Polyarthritis (five or more joints)
Rheumatoid arthritis
Rheumatoid arthritis (RA) should be considered in patients pre-
senting with symmetrical, inflammatory, polyarthritis affecting the
hand joints. The longer the duration of symptoms, the more likely it
is to be rheumatoid arthritis. Key points are as follows:
• Rheumatoid arthritis is a diagnosis that can confidently be
made on clinical grounds. Only 70–​85% of patients are rheuma-
toid factor seropositive. Rheumatoid arthritis is typically sym-
metrical:  asymmetrical or unilateral involvement should
arouse suspicion of other arthritides such as psoriatic or other
spondyloarthropathy.
• Do not diagnose rheumatoid arthritis unless hands are involved.
Distal interphalangeal joint involvement is uncommon in rheuma-
toid arthritis. If distal interphalangeal joints are involved, suspect
psoriatic arthropathy, scleroderma, or osteoarthritis.
• The lumbar spine is not involved in rheumatoid arthritis. The pres-
ence of inflammatory low backache with mono or oligoarticular
involvement, especially in lower limbs, should arouse suspicion of
a spondyloarthropathy.
Table 19.2.7  Analysis of joint fluid
Normal Non-​
inflammatory
Inflammatory Septic
Haemorrhagic
Colour
Clear
Yellow
Yellow to
opalescent
Yellow-​
green
Red
White
blood
cells/​mm3
<200
200–​2000
2000–​75 000
50 000
Similar to
blood level
Neutrophils
(%)
<25
<25
50–​70
70
Similar to
blood level
Viscosity
Normal Normal
Decreased
Decreased Decreased
Table 19.2.8  Spondyloarthropathies (SpA)
• Ankylosing spondylitis
• Reactive arthritis
• Psoriatic arthritis
• Inflammatory bowel disease related (Enteropathic spondyloarthropathy)
Joint pain
Noninflammatory
Inflammatory
Monoarthritis
Oliogoarthritis
Polyarthritis
Septic arthritis
Crystal arthritis
Haemarthrosis
Spondyloarthritis
Psoriatic arthritis
Enteropathy arthritis
Crystal arthritis
Acute sarcoid
Rheumatoid arthritis
Psoriatic arthritis
SLE or other CTD
Fig. 19.2.1  Patterns of inflammatory joint pain, and likely diagnoses.
Fig. 19.2.2  Symmetrical swelling of the metacarophalangeal joints and
proximal iinterphalangeal joints characteristic of rheumatoid arthritis,
with some nodal osteoarthritis in the distal interphalangeal joints and
possible nail dystrophy in the left ring finger nail.
Reproduced with permission from Chapel H, et al. (2014). Essentials of Clinical
Immunology, 6th edn. Blackwell Publishing, Oxford. © John Wiley and Sons 2014.
section 19  Rheumatological disorders
4390
• Mere presence of rheumatoid factor in blood is not enough to make
a diagnosis of rheumatoid arthritis. It is also seen in 5% of elderly
people who are well, and in other conditions see Table 19.2.10.
• The presence of extra-​articular features like fever, oral ulcers,
malar rash, and alopecia, should alert the clinician to the pres-
ence of lupus or other multisystem autoimmune rheumatic dis-
ease (see ‘Autoimmune rheumatic diseases and vasculitis’, next).
The presence of prominent Raynaud’s phenomenon in a patient
with joint pains should alert the physician to the possibility of
scleroderma. A history of bloody diarrhoea may be a pointer
towards enteropathic arthritis.
Autoimmune rheumatic diseases and
vasculitis
Autoimmune rheumatic diseases and vasculitis range from mild
presentations of fatigue and arthralgias, to severe, rapidly progres-
sive organ-​ or life-​threatening diseases. Diagnosis requires a full his-
tory and a high level of suspicion, as presenting symptoms are often
non​specific, and the key to not missing a diagnosis is considering it
whenever multiple organ systems are affected. The assumption must
always be that the patient has a sinister disease (such as infection or
malignancy) or life-​threatening autoimmune disease until fully as-
sessed and proven otherwise. Onset is usually subacute or chronic,
patients usually feel unwell, and inflammatory markers are often
raised. Presenting symptoms are very variable, such as fatigue, joint
pain, shortness of breath, rash, abdominal pain, and paraesthesia.
Systemic symptoms such as weight loss, fever, fatigue, and lymph-
adenopathy are common. More specific are new onset or worsening
Raynaud’s phenomenon (Fig. 19.2.3) or typical rashes which are
strongly suggestive of a connective tissue disease (see Table 19.2.2
for extra-​articular manifestations of rheumatic diseases and Table
Table 19.2.10  Diseases associated with a positive
rheumatoid factor
Condition
Prevalence (%)
Rheumatoid arthritis
70–​85
Elderly people
5
Other rheumatological disorders
—	Mixed cryoglobulinaemia
90–​100
—	Primary Sjögren’s syndrome
75–​90
—	Mixed connective tissue disease
50–​60
—	Systemic lupus erythematosus
20–​30
—	Systemic sclerosis
20–​30
Chronic bacterial infections
—	Subacute bacterial endocarditis
25–​50
Miscellaneous conditions
—	Interstitial pulmonary fibrosis
10–​50
—	Chronic active hepatitis
25–​40
—	Sarcoidosis
5–​30
Table 19.2.9  Key features of spondyloarthropathies
• Usual age <40 years
• Male preponderance
• Involvement of sacroiliac joints is a cardinal feature
• Affects the axial skeleton; inflammatory low back pain is common
• Peripheral joint involvement is usually asymmetrical, oligoarticular,
below waist
• Enthesopathy (pain along soft tissue insertion sites into bone (e.g. tendons,
ligaments, fascia) is characteristic)
• Seronegative for rheumatoid factor
• Usually associated with HLA-​B27
Fig. 19.2.3  Persistent acrocyanosis suggesting secondary Raynaud’s.
Reproduced with permission from Ball GV, et al. (eds) (2014). Oxford Textbook of
Vasculitis, 3rd edn. Oxford University Press, Oxford. © Oxford University Press 2014.
Table 19.2.11  Typical skin manifestations of connective tissue
diseases and vasculitis
SLE
Photosensitive (often malar or ‘butterfly’) rash
Diffuse alopecia
Mouth ulcers
Antiphospholipid syndrome
Livedo reticularis
Scleroderma
Sclerodactyly and Raynaud’s
Digital pitting/​ulceration
Telangiectasia
Calcinosis
Dermatomyositis
Facial rash (‘heliotrope’) with periorbital oedema
Gottron’s papules
Periungal erythema
Vasculitis
Splinter haemorrhages and nailfold infarcts
Purpuric rash (often ‘palpable purpura’)
Oral and genital ulcers in Behçet’s syndrome
Cutaneous ulcers
19.2  Clinical presentation and diagnosis of rheumatological disorders
4391
19.2.11 for typical skin manifestations). If an autoimmune connective
tissue disease or vasculitis is a possibility, urinalysis, blood pressure,
and urea and electrolytes must be performed, as renal disease may
be silent. Persistent symptoms in other organ systems (e.g. shortness
of breath or cough, blocked nose/​epistaxis/​hearing loss, skin rashes/​
photosensitivity) require assessment by the appropriate specialty.
Autoimmune rheumatic diseases are often associated with specific
autoantibodies that can assist with diagnosis, see Table 19.2.12.
Autoimmune rheumatic diseases
Systemic lupus erythematosus typically affects women in their
childbearing years, and is more common in those of Afro-​
Caribbean, Asian, or Chinese origin. It covers a spectrum of disease
from mild rashes, mouth ulcers, and flitting joint aches to severe
life-​threatening multiorgan disease including immune-​complex
glomerulonephritis, serositis (pleural effusion, pericarditis, or
abdominal pain), and cytopaenias. Renal disease when present
is usually silent, and urinalysis must be performed. Occasionally
inflammation of the brain can cause epilepsy, headaches, and mi-
graines, but usually neurological symptoms are caused by an as-
sociated antiphospholipid syndrome causing arterial or venous
thrombosis. The presence of antinuclear antibodes is almost uni-
versally positive and often typical extractable nuclear antigens are
seen (Table 19.2.12). ESR is raised but C-​reactive protein usu-
ally normal unless there is serositis or superimposed infection.
Appearances of severe disease are often similar to infection and
specialist management is required.
Scleroderma (systemic sclerosis) is characterized by hardening
of the skin caused by increased deposition of collagen in skin and
to a variable extent in internal organs. It is subdivided into limited
(skin thickening limited to distal to the elbow and face) and diffuse
(skin thickening proximal to the elbow) with typical antibody as-
sociations (Table 19.2.12), and association of limited disease with
pulmonary arterial hypertension, and diffuse with interstitial lung
disease. Scleroderma renal crisis causing severe hypertension and
renal dysfunction may be precipitated by steroids:  diagnosis de-
pends on urinalysis, blood pressure, and renal function.
Other connective tissue diseases are briefly described in Table
19.2.13. All of the connective tissue diseases can overlap, and mani-
festations can include inflammatory arthritis, myositis, interstitial
lung disease, or glomerulonephritis.
Vasculitis
The vasculitides cover a collection of disorders caused by inflam-
mation within blood vessels. The commonest vasculitis is giant cell
arteritis (temporal arteritis) which causes temporal headaches and
tenderness, and can cause blindness due to anterior ischaemic optic
neuropathy. Risk of blindness is increased in patients with symp-
toms of tongue or jaw claudication. It affects people aged above 50,
and diagnosis is supported by a typical history, tender temporal ar-
teries on palpation, and an abnormal temporal artery biopsy. Less
invasive imaging techniques (e.g. ultrasound) are entering clinical
use, having recently completed clinical trials.
The vasculitides were classified by the Chapel Hill consensus con-
ference in 2012 according to the vessel size predominantly affected
(Table 19.2.14).
Non​inflammatory musculoskeletal pain
and pain syndromes
Most self-​limiting non​inflammatory disorders and exacerbations of
chronic degenerative disease such as osteoarthritis and back pain
are managed in primary care and physiotherapy, with more severe
conditions referred to orthopaedics. While most back pain does
not reflect serious underlying pathology, the suspicion of fracture,
infection, or malignancy are raised by the ‘red flags’ discussed pre-
viously (Table 19.2.1).
Fibromyalgia syndrome
Fibromyalgia and other chronic pain syndromes are also mainly
managed in the community, but patients often attend rheumatology
clinics if there is diagnostic uncertainty, significantly uncontrolled
symptoms, or patient request for specialist opinion.
Fibromyalgia syndrome is the presence of chronic widespread
pain, often combined with other multiple symptoms, in the absence
of any demonstrable explanatory pathology. Symptom clusters asso-
ciated with fibromyalgia syndrome include irritable bowel syndrome,
dysmenorrhoea, premenstrual syndrome, headaches, atypical facial
pain, non​cardiac chest pain, and chronic fatigue syndrome.
While there are diagnostic criteria for fibromyalgia syndrome,
it is essential to rule out other causes of widespread musculoskel-
etal pain, such as those listed in Table 19.2.15. Serious illness such
Table 19.2.12  Autoimmune rheumatic diseases associated
with specific autoantibodies that can assist with diagnosis
Disease
Antibody
Frequency
Systemic lupus
erythematosus
Anti-​DsDNA)
Anti-​Sm
Anti-​RNP
Anti-​Ro
Anti-​La
70%
10–​25%
30%
40%
15%
Drug induced Lupus
Antihistone
Drugs associated are: isoniazid,
phenytoin, hydralazine,
methyldopa, chlorpromazine,
penicillamine, and minocycline
Sjögren’s syndrome
Anti-​RNP
Anti-​Ro
Anti-​La
15%
60–​90%
35–​85%
Scleroderma
Centromere
pattern ANA
Anti-​Scl-​70
20–​30%
40% of diffuse, 10% of limited
Dermato/​polymyositis
Anti-​Jo-​1 &
other
antisynthetases
Anti-​SRP
Anti-​Mi2
myositis, fevers, interstitial lung
disease and ‘mechanic’s hands’
Severe myositis
Dermatomyositis
Mixed connective
tissue disease
Anti-RNP
100%
Table 19.2.13  Other connective tissue diseases
Sjögren’s syndrome
Dry eyes and a dry mouth predominate
(keratoconjunctivitis sicca)
Polymyositis
Inflammation of muscles, causing
weakness which may include bulbar and
respiratory muscles
Dermatomyositis
Muscle inflammation and a typical rash
Mixed connective tissue disease
Overlapping clinical features of SLE,
scleroderma and myositis
section 19  Rheumatological disorders
4392
as connective tissue diseases and vasculitis can also present with
non​specific widespread aches and pain and fatigue. The ACR 2010
diagnostic criteria for fibromyalgia syndrome require a combination of
widespread pain and symptoms such as fatigue, waking unrefreshed,
cognitive symptoms, and somatic symptoms for ≥3 months, with no
alternative explanation for the pain. A suggested list of initial blood
tests is given in Table 19.2.16.
Regional pain syndromes
Complex regional pain syndrome, formerly termed reflex sympa-
thetic dystrophy, ‘causalgia’, or reflex neurovascular dystrophy, is
a debilitating painful condition in a limb, associated with sensory,
motor, and autonomic skin and bone abnormalities. It commonly
arises after injury to a limb, but there is no relationship to severity
of injury and in some cases no injury at all. The diagnosis is one
of exclusion and made according to the ‘Budapest criteria’, which
require (1) continuing pain disproportionate to the inciting event;
(2)  the patient has signs in two or more of the following four
categories—​sensory (heightened pain to a stimulus—​allodynia
or hyperalgaesia), vasomotor (symptoms of skin temperature or
colour changes or asymmetry), ‘sudomotor/​oedema’ (asymmetry of
sweating or oedema), motor/​trophic changes (weakness, tremor, or
dystonia or trophic changes to hair, skin, or nails); (3) the patient re-
ports at least one symptom in three or more of these four categories;
(4) no other diagnosis provides better explanation for the patient’s
symptoms and signs.
Table 19.2.14  Chapel Hill consensus conference classification of vasculitides
Vessel size
Previous name
Typical presentation
Associated infection
or autoantibody
Small,
ANCA-​associated
Granulomatosis with Polyangiitis
(GPA)
Wegener’s
granulomatosis
50s, nasal crusting, deafness, SOB, and positive
urinalysis
PR3 (c-​ANCA)
Microscopic polyangiitis (MPA)
N/​A
60s, fatigue, arthralgia, myalgia, mononeuritis
multiplex, and renal failure
MPO (p-​ANCA)
Eosinophilic polyangiitis with
Granulomatosis (EGPA)
Churg-​Strauss
syndrome
50s, asthma, nasal polyps, lung infiltrates,
mononeuritis multiplex, or cardiac involvement
Often ANCA negative
MPO (p-​ANCA)
Small, immune
complex
IgA vasculitis
Henoch Schonlein
purpura
Children, purpuric rash on legs, can include
abdominal pain, arthritis, and renal involvement
IgA deposition
Medium
Polyarteritis nodosa (PAN)
N/​A
Constitutional symptoms, deranged LFTs, aneurysms
on renal angiogram
Hepatitis B
Kawasaki disease
N/​A
Childhood disease, uncommonly affects 20s. Fever,
conjunctivitis, lymphadenopathy, desquamation, risk
of coronary artery aneurysms
None
Large
Giant cell arteritis
Temporal arteritis
70s, headache, temporal tenderness, possible jaw
claudication, and sudden blindness
None
Takayasu’s
Women 20s–​30s
Constitutional then claudicant symptoms
Pulseless in later stages
None
N/​A
Behçet’s syndrome
N/​A
Oral and genital ulceration, thrombosis, and vasculitis
None
N/​A
Thromboangiitis obliterans
Buerger’s disease
Ischaemia of extremities in a heavy smoker
Angiogram may show ‘corkscrew’ arteries
Smoking
Table 19.2.15  Causes of diffuse or widespread musculoskeletal
pain (differential diagnosis of fibromyalgia syndrome)
•	 Inflammatory arthritis (including rheumatoid arthritis and
spondyloarthropathies)
•	 Hypermobility syndromes
•	 Polymyalgia rheumatica
•	 Polymyositis/​dermatomyositis
•	 Vasculitis
•	 Hypo-​/​hyperthyroidism
•	 Multiple sclerosis
•	 Neuropathies
•	 Osteomalacia
•	 Chronic fatigue syndrome/​myalgic encephalomyelitis
•	 Statin-induced myopathy
Table 19.2.16  List of suggested blood tests in suspected
fibromyalgia syndromeor other chronic pain syndrome
Full blood count
Erythrocyte sedimentation rate
C-​reactive protein
Creatinine kinase
Calcium and phosphate
Alkaline phosphatase
Blood glucose
Thyroid-​stimulating hormone
Antinuclear antibody/​rheumatoid factor
Urinalysis for protein, blood, and glucose
19.2  Clinical presentation and diagnosis of rheumatological disorders
4393
Patients are often referred to rheumatology (among other spe-
cialties) for exclusion of other conditions. Management is by a
multidisciplinary pain management approach.
Bone disease
Bone disease includes malignant, metabolic, and genetic disorders
of bone.
Osteosarcoma is rare, usually presenting as bone pain in chil-
dren. Leukaemia can also present with bone pain due to pressure
within the bone marrow. In adults, cancer of bone is usually sec-
ondary cancer. Red flags for bone cancer are listed in Table 19.2.17.
Diagnosis is initially made on plain X-​ray.
Metabolic bone diseases are disorders of bone strength, usually
caused by abnormalities of bone mass, bone mineralization, or bone
structure. The most common metabolic bone disorders are osteo-
porosis, osteomalacia, and Paget’s disease, the pathologies of which
are briefly characterized in Table 19.2.18.
Rare genetic disorders are managed by metabolic bone specialists
in tertiary centres (e.g. osteogenesis imperfect, x-linked hypopho­
sphataemic rickets or autosomal recessive hypophosphataemic
rickets).
Osteoporosis
Osteoporosis is characterized by a decrease in bone mass and density
which can lead to an increased risk of fracture, especially of wrist,
hip, and vertebrae. Those at high risk for osteoporosis include pa-
tients with older age, low BMI, personal or family history of fractures,
steroid use, intestinal diseases, and kidney disorders. As it is asymp-
tomatic, it must be suspected in at-​risk individuals and investigated.
Osteoporosis is defined by the World Health Organization (WHO)
as a bone mineral density of 2.5 standard deviations or more below
the mean peak bone mass (average of young, healthy adults) as meas-
ured by dual-​energy X-​ray absorptiometry (T-​score ≤–​2.5); the term
‘established osteoporosis’ includes the presence of a fragility fracture.
Osteomalacia/​Rickets
Osteomalacia is softening of the bones, due to defective mineraliza-
tion. It is typically caused by deficiency of vitamin D (normally de-
rived from sunlight exposure and, to a lesser extent, from the diet).
More rarely it may be due to deficiency of phosphate or calcium, or
overactive resorption of calcium from the bone secondary to hyper-
parathyroidism or cancer. It causes the bones to become soft and
weak. In children it is called Rickets, and can cause deformities in
growing bones.
Signs and symptoms of both can include diffuse body pains,
muscle weakness, and fragility of the bones (Table 19.2.19). If meta-
bolic derangement is very severe, it can be associated with hypocal-
caemia and tetany.
The most specific screening test for vitamin D deficiency in other-
wise healthy individuals is a serum 25(OH)D level. Other investi-
gations should include calcium, phosphate, alkaline phosphatase,
parathyroid hormone, and x-rays of painful bones or joints.
Paget’s disease
Paget’s disease is a disorder of chronic, disorganized bone remod-
elling. This causes affected bone to weaken, resulting in pain, mis-
shapen bones, fractures, and arthritis in the joints near the affected
bones. It most commonly affects the pelvis, femur, and lower lumbar
vertebrae, and is often localized to a few bones. It can cause compli-
cations such as uni/bilateral deafness or blindness from neural com-
pression from bone overgrowth, and rarely it can undergo malignant
transformation into Paget’s sarcoma.
Onset is usually over the age of 55 years, men are more commonly
affected than women, and incidence is decreasing. An elevated level
of alkaline phosphatase in the blood, in combination with normal
Table 19.2.17  Red flags for bone cancer
•	 History of malignancy
•	 Weight loss
•	 Night sweats
•	 Reduction in appetite
•	 Night pain
•	 Pain that is progressive or persistent
•	 Pain in children
Table 19.2.18  Comparison of bone pathology in common metabolic bone disorders
Condition
Calcium
Phosphate
Alkaline phosphatase
Parathyroid hormone
Comments
Osteomalacia and rickets
Decreased
Decreased
Elevated
Elevated
Soft bones
Osteoporosis
Unaffected
Unaffected
Normal
Unaffected
Decreased bone mass
Paget’s disease of bone
Unaffected
Unaffected
Variable (depending on
stage of disease)
Unaffected
Abnormal bone architecture
Table 19.2.19  Signs and radiographic findings in osteomalacia
and rickets
Osteomalacia
Rickets
Proximal weakness
Costochondral swelling (aka ‘rickety rosary’)
Waddling gait
Greenstick fractures
Looser’s zones
(pseudofractures)
Toddlers: genu varum (bow legs)
Older children: genu valgum (knock knees)
Skull bossing or delayed fontanelle closure
Pelvic deformity
kyphoscoliosis or lumbar lordosis
Harrison’s sulcus (groove at costal insertion of
diaphragm)
Widening of wrist or double malleoli sign (due to
metaphyseal hyperplasia)
section 19  Rheumatological disorders
4394
calcium, phosphate, and aminotransferase levels are suggestive of
Paget’s disease, as are ‘hot spots’ in typical locations on a bone scan.
X-​rays have a characteristic appearance, and a skeletal survey to as-
sess extent is therefore indicated.
FURTHER READING
Arthritis Research UK (2012). The Approach to the Patient
Presenting with Multiple Joint Pain. ‘Hands on’ series. http://​www.
arthritisresearchuk.org/​shop/​products/​publications/​information-​
for-​medical-​professionals/​hands-​on/​ho1-​series-​7.aspx
British Society for Rheumatology. Guidelines. https://​www.
Rheumatology.org.uk
Coakley G, et  al. (2006). BSR & BHPR, BOA, RCGP and BSAC
guidelines for management of the hot swollen joint in adults.
Rheumatology, 45, 1039–​41.
NICE guidance (CG79). Management of Rheumatoid Arthritis in
Adults. https://​www.nice.org.uk/​guidance/​cg79
Ntatsaki E., et al. (2014). BSR and BHPR guidelines for the manage-
ment of adults with ANCA-​associated vasculitis. Rheumatology, 53,
2306–​9.
Woolf AD, Pfleger B (2003). Burden of major musculoskeletal dis-
orders. Bull World Health Organ, 81, 646–​56.

19.3 Clinical investigation 4395 Michael Doherty a
19.3 Clinical investigation 4395 Michael Doherty and Peter C. Lanyon
ESSENTIALS
Laboratory and imaging markers are an adjunct to competent clin-
ical assessment and should not be used as a substitute. Tests should
only be ordered if the results will alter diagnosis, prognosis, or clinical
management.
Synovial fluid examination—​this is the key investigation to confirm
the diagnosis of either acute crystal or septic arthritis. Fluid can usu-
ally be obtained by direct aspiration from any peripheral joint, or
alternatively under ultrasound guidance. The identification of crystals
requires compensated polarized light microscopy.
Plain radiographs—​these remain the single most useful imaging
technique, enabling the detection of soft-​tissue swelling, changes in
bone density, and cartilage and bone erosion or remodelling, which
in conjunction with the pattern of joint sites involved can aid con-
firmation of diagnosis and assessment of disease extent. The car-
dinal radiological features of rheumatoid arthritis are osteopenia and
cartilage/​bone erosion: the features of osteoarthritis are preserved
bone density, joint-​space narrowing, osteophyte formation, and
bone cysts.
Other imaging techniques—​(1) magnetic resonance imaging pro-
vides additional benefit with plain radiographs in the assessment
of the anatomy and biochemistry of soft tissues as well as bone;
(2)  ultrasound is emerging as an effective bedside technique for
detecting joint effusions (particularly at clinically occult sites), crystal
deposits and tophi, and to assess joint erosions and neovascularity.
Blood tests—​(1) inflammatory markers:  C-​reactive protein is the
single most useful measure of the acute phase response, having
greater reproducibility and greater sensitivity to change than the
erythrocyte sedimentation rate; (2) specific antibodies: antibodies to
cyclic citrullinated peptides are a marker associated with rheuma-
toid arthritis, with similar sensitivity to rheumatoid factor but higher
specificity for distinguishing between rheumatoid arthritis and other
rheumatic diseases; antibodies detected against nuclear components
have high sensitivity for connective tissue diseases (e.g. systemic
lupus erythematosus) but low specificity, and hence a positive result
does not confirm the diagnosis unless appropriate clinical features
are present. Compared with antinuclear antibodies, antibodies to ex-
tractable nuclear antigens have higher specificity and associate with
different patterns of system involvement within the same disease.
Introduction
Disease markers are pathological or physiological characteris-
tics of an individual that assist in determining the diagnosis, the
current activity of disease, or the expected prognosis of the
condition in that individual (Fig. 19.3.1). Some markers relate to
just one of these elements; others may relate to two, or occasion-
ally all three.
Clinical markers are derived from enquiry and examination
of the patient. For many common rheumatic disorders, clinical
assessment alone gives sufficient information for patient diag-
nosis and management. In some situations, however, particularly
with inflammatory, metabolic, or multisystem disease, a search
for additional investigational markers may be warranted. It is im-
portant to emphasize that the requirement for and selection of
investigations, as well as their subsequent interpretation, is prin-
cipally determined by the clinical assessment. Investigations are
an adjunct, never a substitute, for competent clinical assessment.
There is no place for a battery of screening tests. Investigational
markers may include:
•	 Laboratory markers (biochemical, haematological, microbio-
logical, histological) sought through investigation of body fluids
and tissues.
19.3
Clinical investigation
Michael Doherty and Peter C. Lanyon
Diagnosis
Disease
markers
Clinical
Laboratory (e.g. biochemical, histological)
Structural, physiological (imaging)
Genetic
Prognosis
Activity
Fig. 19.3.1  Markers may be used for diagnosis, assessment of disease
activity, or prognosis.
section 19  Rheumatological disorders
4396
•	 Structural and physiological markers, mainly assessed by imaging
(radiography, scintigraphy, magnetic resonance imaging (MRI),
ultrasonography).
•	 Genetic disease susceptibility and prognostic markers—​these
hold promise for the future but at present have clinical application
only to rare monogenic disorders
When considering any investigation, the following deliberations
are pertinent.
•	 ‘Is this the most appropriate investigation to answer the clinical
question?’ This may depend on various factors, for example, the
sensitivity and specificity of the marker being sought, its predictive
value (which takes into account disease prevalence as well as the
sensitivity and specificity), the cost and availability of the investi-
gation, and the pros and cons of invasive versus non​invasive tests.
•	 ‘Will the result of this test alter the diagnosis or clinical manage-
ment of the patient?’ It is easy to initiate more investigations than
are really required.
•	 ‘Will I be able to interpret and act on the results of this test?’ Tests
should only be ordered if the implications of either a normal or
abnormal result are understood.
In common rheumatological practice, the investigations that are
of most use in diagnosis are synovial fluid analysis and the plain
radiograph. Confirmation of clinically assessed inflammatory dis-
ease activity and its response to treatment is mainly by full blood
count and either direct or indirect measures of the acute phase re-
sponse. These investigations are therefore given special prominence
in this chapter: the usefulness of other investigations will be dis-
cussed in the context of specific clinical scenarios.
Synovial fluid analysis
This is the key investigation to confirm the diagnosis of the two
curable rheumatic diseases: septic arthritis and gout. Other crystal-​
associated arthropathies and intra-​articular bleeding are also
diagnosed in this way. Synovial fluid analysis is thus the pivotal
investigation for an acute monoarthritis, especially with overlying
erythema.
Synovial fluid can be obtained from almost any peripheral
joint, with only a small volume required for diagnostic purposes.
Aspiration of large joints should be no more uncomfortable than
venepuncture. The patient should be informed of the purpose and
nature of the procedure and positioned on a couch in a comfortable
and relaxed position, with full exposure of the relevant joint. The risk
of introducing sepsis is negligible, as long as sterile equipment and
the same sensible precautions used for venepuncture are employed.
Macroscopic appearance
Normal synovial fluid is present in small volume, contains very
few cells, is clear, colourless to pale yellow, and has high viscosity
due to macromolecular hyaluronan (Fig. 19.3.2). In general, with
increasing joint inflammation the volume increases, the total cell
count and proportion of neutrophils rises (causing turbidity), and
the viscosity lowers (due to degradation of hyaluronan by pro-
tease). However, there is such overlap between arthropathies that
these features are of little diagnostic value. Frank pus or pyarthrosis
due to very high neutrophil counts should always lead to exclu-
sion of sepsis, but can occur with any florid synovitis such as acute
crystal synovitis or rheumatoid. High concentrations of urate or
cholesterol crystals may result in white synovial fluid, known as
joint ‘milk’.
Non​uniform bloodstaining of synovial fluid is common and re-
flects inconsequential needle trauma to synovial vessels. Uniform
bloodstaining (haemarthrosis) most commonly occurs in associ-
ation with florid synovitis but may also result from a bleeding di-
athesis, trauma, or pigmented villonodular synovitis. A lipid layer
floating above bloodstained fluid is diagnostic of intra-​articular
fracture.
Gram stain and culture
Synovial fluid should be sent for urgent Gram stain and culture if
sepsis is suspected. Placement in blood culture bottles in addition to
a sterile universal container may be indicated if there is likely to be a
delay in processing the sample.
If gonococcal sepsis or uncommon organisms are suspected, es-
pecially in immunocompromized patients, it is advisable to discuss
this with the microbiologist so that the optimal cultures can be estab-
lished and molecular techniques of antigen detection used if appro-
priate. Although a positive result on Gram staining is found in over
50% of cases of adult septic arthritis (predominantly Staphylococcus
aureus), a negative result does not exclude infection. If there is a
strong clinical suspicion of sepsis, the patient should be given intra-
venous antibiotics pending the results of synovial fluid, blood, and
other culture results.
Crystal identification
Accurate identification of common synovial fluid crystals requires
a compensated polarized light microscope and an experienced ob-
server. Monosodium urate and calcium pyrophosphate crystals
may be seen by ordinary light microscopy, but confident identifi-
cation resides in their light characteristics as well as their morph-
ology. Analysis is best performed on fresh unrefrigerated synovial
fluid taken into a plain container to avoid problems of crystal
Fig. 19.3.2  Different macroscopic appearances of synovial fluids:
(a) on the left, clear straw-​coloured fluid from an osteoarthritic knee
(easy to read writing behind it); (b) less viscous, turbid (high cell
count) ‘inflammatory’ fluid from a rheumatoid knee; and (c) uniform
bloodstaining (haemarthrosis) due to acute pseudogout.
19.3  Clinical investigation
4397
dissolution, post-​aspiration crystallization, and artefacts from tube
additives. If only a few drops are obtained, these should be placed
straight onto a clean microscope slide and a second slide or cover-
slip placed on top. Even with an apparently ‘dry tap’, it is worth ex-
pelling the contents of the needle on to a slide: a very small amount
of fluid is sometimes obtained and may be diagnostic. Urate crys-
tals are long and needle-​shaped and show a strong intensity with
negative birefringence (Fig. 19.3.3). Pyrophosphate crystals are
smaller, rhomboid in shape, usually less numerous than urate, are
often non​birefringent but can also show weak intensity and posi-
tive birefringence (Fig. 19.3.4).
Although usually identified in the setting of acute synovitis,
crystals are also often present in fluid aspirated from the joint
after the attack has settled. Aspiration of an asymptomatic first
metatarsophalangeal joint (gout) or knee (gout, pseudogout) may
therefore permit confirmation of a suspected diagnosis. This is par-
ticularly important in gout because of the possible implications of
lifelong urate-​lowering therapy. The diagnosis can also be made by
analysis of a tophus aspirate.
Plain radiography
In conjunction with a full history and examination, plain radiog-
raphy remains the single most useful and widely available imaging
technique for assessment of rheumatic disease. Although a radio-
graph is a static record of predominantly past events, it can dem-
onstrate visually alterations that reflect the underlying pathological
processes of rheumatic disease (e.g. cartilage and bone erosion, bone
remodelling, calcification). The abnormalities that may be seen on a
plain film include:
•	 soft-​tissue swelling—​seen as altered skin contours and displaced
fat planes and intracapsular fat pads (fat appears dark on a
radiograph)
•	 decreased or increased bone density (localized or generalized)
(Table 19.3.1)
•	 joint erosion (non​proliferative or proliferative marginal erosion,
central erosion)
•	joint-​space narrowing (osteoarthritis—​focal; inflammatory
arthritis—​generalized)
•	 new bone formation (osteophyte, enthesophyte, syndesmophyte)
•	 periosteal reaction (Table 19.3.2)
•	 calcification (cartilage (chondrocalcinosis), synovium, capsule,
ligament, tendon, muscle, fat, vascular, skin)
•	 bone cysts and radiolucent lesions (Box 19.3.1)
•	 intra-​articular osteochondral bodies
•	 deformity
Fig. 19.3.3  Monosodium urate crystals viewed by compensated
polarized light microscopy (×400) showing bright birefringence (negative
sign) and needle-​shaped morphology.
Fig. 19.3.4  Calcium pyrophosphate crystals viewed by polarized light
microscopy (×400) showing weak birefringence (positive sign), scant
numbers, and a predominantly rhomboid morphology. These are clearly
more difficult to detect than urate crystals.
Table 19.3.1  Some causes of changes in bone density
Causes of increased bone density
Causes of decreased bone density
Generalized/​multiple regional
Myelofibrosis
Osteoporosis
Osteopetrosis
Myeloma, leukaemia
Osteomalacia, rickets
Hyperparathyroidism
Vitamin C deficiency
Osteogenesis imperfecta
Localized
Paget’s disease (with altered trabecular
pattern and radiolucent areas)
Inflammatory arthritis
(juxta-​articular)
Metastases (especially prostate, breast)
Infection
Osteoid osteoma (sometimes with a
central radiolucency)
Complex regional pain syndrome
(algodystrophy)
Extreme disuse
Bone islands
Table 19.3.2  Some causes of periosteal reaction
Localized
Infection
Trauma
Tumour
Multiple sites
Hypertrophic osteoarthropathy
Seronegative spondyloarthropathy
Scurvy
section 19  Rheumatological disorders
4398
Although most of these abnormalities taken individually have
low specificity, various combinations of some of these features, to-
gether with their targeting of certain joint sites (Fig. 19.3.5), result
in characteristic patterns of abnormality and distribution that have
high diagnostic specificity. The distribution of joint involvement, of
course, is usually apparent following clinical assessment of the pa-
tient, and joints to be investigated by radiography will usually be
selected on this basis. However, an important exception is seronega-
tive spondyloarthropathy, in which sacroiliac involvement is often
asymptomatic and is difficult to detect clinically. When this condi-
tion is suspected, an anteroposterior view of the pelvis and a lateral
thoracolumbar spine view (i.e. two films) are usually sufficient to
show sacroiliitis and syndesmophytes if these are present.
Radiographs should be selected to answer specific questions. For
example, to address the question of whether a patient with chronic
inflammatory polyarthritis affecting hands, elbows, neck, knees, and
ankles has erosive disease typical of rheumatoid, posteroanterior
views of hands and feet (i.e. two films), but not radiographs of all
symptomatic joints, are appropriate. This is because rheumatoid ero-
sions appear first in wrists and the small joints of hands and feet, and
may first affect the metatarsophalangeal joints, even if they are rela-
tively asymptomatic. However, if the degree of structural damage in
one large joint is a principal cause for concern, then a radiograph
of that particular joint should obviously be taken. For most joints,
a single (two-​dimensional) view is sufficient (e.g. anteroposterior
view of pelvis, posteroanterior view of both hands, posteroanterior
view of both feet), although two views are required for some (e.g.
posteroanterior weight-​bearing (semi-​flexed) view of both knees,
plus individual lateral or bilateral skyline patello-​femoral view).
Thus selection of radiographs will often differ for purposes of diag-
nosis or disease assessment.
Erosions
An important hallmark of inflammatory arthropathies is cartilage
and bone erosion. Intracapsular bone erosion first occurs at the
‘bare areas’ of the joint margin (marginal erosion) where bone is ex-
posed directly to inflammatory synovium without the protection of
overlying cartilage. Loss of the sharp cortical line, the ‘dot-​dash’ ap-
pearance, is the first radiographic sign that precedes more definite
scalloping of the bony contour (Fig. 19.3.6). Cartilage erosion also
commences at the joint margin and slowly works centrally, resulting
in relatively late loss of interosseous distance or ‘joint space’.
Both rheumatoid disease and the seronegative spondyloar­
thropathies (especially psoriatic and chronic reactive arthritis)
cause marginal erosions. In rheumatoid disease, however, the ag-
gressive synovitis overwhelms any reparative response, presenting
a very atrophic appearance (‘non​proliferative erosions’) (Figs.
19.3.6 and 19.3.7) with no new bone or periosteal reaction and
Box 19.3.1  Some causes of radiolucent lesions
•	 Bone cysts (isolated or in association with osteoarthritis)
•	 Inflammatory arthritis (erosions)
•	 Infection
•	 Metastases (especially breast, lung, kidney, thyroid)
•	 Myeloma
•	 Osteochondromata
•	 Osteogenic sarcoma
•	 Histiocytosis X
(a)
(b)
(c)
Fig. 19.3.5  Diagram to show different target sites of involvement
in the forefoot for (a) rheumatoid arthritis, (b) psoriatic arthritis, and
(c) osteoarthritis.
(d)
(c)
(b)
(a)
Fig. 19.3.6  Diagram of metacarpophalangeal joint showing (a) early
dot-​dash erosion, (b) the later definite nonproliferative erosion of
rheumatoid arthritis, (c) the proliferative erosion of psoriatic arthritis, and
(d) the intra and extracapsular pressure erosions of gout.
Fig. 19.3.7  Radiograph of metacarpophalangeal joint showing late
non​proliferative marginal erosions of rheumatoid arthritis, more obvious
proximally than distally (reflecting the more proximal than distal distribution
of synovium in small finger joints) and eventual global loss of cartilage.
19.3  Clinical investigation
4399
only juxta-​articular osteopenia (a sign of inflammation) and soft-​
tissue swelling as accompanying early radiographic features. By con-
trast, the seronegative spondyloarthropathies are characterized by
a degree of low-​grade inflammation that permits some reparative
response. Such inflammation results in a tendency to fibrosis, calci-
fication, and ossification. Marginal erosions in these arthropathies
are therefore commonly accompanied by fluffy new bone forma-
tion (‘proliferative erosions’) (Figs. 19.3.6 and 19.3.8) with normal
or increased periosteal and bone density rather than osteopenia.
The fact that different joints are targeted in these conditions, and
the common accompanying involvement of entheses—​fibrous in-
sertions of tendons, ligaments, or capsule into bone—​further assists
differentiation in most cases.
In early septic arthritis the radiograph is often normal, apart
from osteopenia and soft-​tissue swelling, for one to two weeks.
However, erosion proceeds rapidly and results in generalized loss of
joint space with loss of cortical integrity centrally (central erosion)
as well as marginally. In chronic gout, bony defects develop slowly
as massive crystal concretions (tophi) causing pressure necrosis to
surrounding bone; such pressure erosions (Fig. 19.3.6) occur at
extracapsular as well as intracapsular sites and are unaccompanied
by osteopenia.
Osteoarthritis
The features of osteoarthritis, by far the most common joint disease,
are highly characteristic and contrast with those of inflammatory
arthropathy. The two cardinal features are narrowing of the joint
space and osteophytes. By contrast to inflammatory arthropathies,
joint-​space narrowing is focal rather than widespread within
the joint, mainly targeting the maximum load-​bearing region
(Fig. 19.3.9). Bony osteophyte is most noticeable at the margins
of the joint but also occurs centrally and as periosteal osteophyte
(‘buttressing’) at sites such as the femoral neck. Subchondral scler-
osis, or increased density of bone is also common, principally
below the site of maximal narrowing. Additional features include
subchondral ‘cysts’, osteochondral (‘loose’) bodies within the
synovium, and an increased association with chondrocalcinosis. In
contrast to inflammatory arthritis, the bone density is normal or in-
creased and marginal erosions are not a feature.
Calcification
Calcification can affect any locomotor tissue. Calcification of fibro
and hyaline cartilage (chondrocalcinosis) is most commonly due to
calcium pyrophosphate crystals, less commonly to apatite or other
basic calcium phosphates. This can occur as an isolated phenom-
enon (mainly age associated, rarely as a result of metabolic or fa-
milial disease predisposition) or in association with structural
changes of osteoarthritis (chronic pyrophosphate arthropathy). Less
commonly, pyrophosphate crystals also cause calcification of the
synovium and capsule, and linear tendon calcification (mainly hip
adductors, Achilles, triceps).
Periarticular calcification is usually apatite. Isolated periarticular
calcification mainly affects central sites such as the shoulder
(supraspinatus tendons) or hip (abductor tendons), appearing as
single dense concretions with rounded contours, as opposed to
the linear calcification of pyrophosphate. Shedding of these crystal
deposits can result in severe, self-​limiting inflammation (acute
calcific periarthritis) with reduction or loss of the radiographic
calcification.
Spotty, multiple calcification of soft tissues (calcinosis) mainly
targets peripheral and intermediate sites such as the finger pulps,
wrists, and forearms and is a feature of connective tissue disease,
most commonly CREST syndrome (calcinosis, Raynaud’s, oesopha-
geal dysmotility, sclerodactyly, telangiectasia). Calcinosis requires
distinction from small blood vessel calcification, which has a thin,
meandering tramline appearance (and is increased in diabetes
and chronic renal failure), sesamoids, and solitary dense calcified
phleboliths. Myositis ossificans is rare and appears as dense sheets of
calcification mainly at proximal sites such as the hip. Fine reticular
or linear calcification of subcutaneous fat and muscle may follow
young onset dermatomyositis.
Fig. 19.3.8  Radiograph of the hallux showing proliferative erosions and
cartilage loss of the interphalangeal joint, and associated increased bone
density (ivory phalanx) typical of psoriatic arthropathy.
Fig. 19.3.9  Radiograph of the hip to show changes of osteoarthritis,
specifically superior joint-​space narrowing, subchondral sclerosis,
marginal osteophyte, and cysts.
section 19  Rheumatological disorders
4400
Other imaging
Scintigraphy
Scintigraphy is a cheap, readily available technique that delivers
only a very small amount of radiation. It involves gamma camera
imaging following an intravenous injection of radioisotope, usually
technetium-​99m diphosphonate. Early ‘flow’ images obtained im-
mediately post-​injection, or a little later when the isotope is in the
soft tissues (‘blood pool’ phase), reflect vascularity and will show,
for example, the increased perfusion of inflamed synovium, Pagetic
bone, or hypervascular primary or secondary bone tumour (Fig.
19.3.10). ‘Delayed’ images, taken a few hours after injection, indicate
bone remodelling due to localization of the diphosphonate to sites of
active bone turnover. Although non​specific and lacking high spatial
resolution, the major advantage of scintigraphy is its high sensitivity
for detecting important bone and joint pathology that may not be
apparent on plain radiographs. However, although this technique
has predominately been superseded by MRI in the assessment of a
single region, it can still be used to detect:
•	 bone metastases at clinically occult sites
•	 bone or joint sepsis at clinically occult sites
•	 early osteonecrosis at the presenting site and at clinically occult
sites
•	 The extent and current activity of Paget’s disease of bone
•	 complex regional pain syndrome (reflex sympathetic dystrophy,
algodystrophy)
•	 hypertrophic osteoarthropathy
Computed tomography (CT)
This can give detailed information on anatomy, especially of bone,
allowing three-​dimensional visualization of structures such as the
spinal canal and facet joints. Its principal use is therefore in assessing
areas of complex anatomy such as the spine or pelvis, where plain
radiographs may be inadequate (e.g. to investigate stenosis of the
spinal canal). Drawbacks, however, include limited soft-​tissue reso-
lution and exposure to a considerable radiation dose; in many situ-
ations it is has now been superseded by MRI. It still has advantages
to MRI in specific situations; for example, visualization of complex
fractures including detection of osseous fragments, anatomical
mapping prior to complex bone surgery, and visualizing joints in the
the thorax where MRI would be degraded by respiration artefacts
(costovertebral and sternoclavicular).
Magnetic resonance imaging (MRI)
The ability of MRI to image the anatomy and biochemistry of soft
tissue as well as bone means that it provides detailed information not
only on structure but also on the pathophysiology of all locomotor
tissues. Further advantages include its capacity for multiplanar
imaging (e.g. coronal, axial, sagittal, oblique) and its safety, without
radiation exposure. The physics of MRI is complex. When a pa-
tient is placed in the magnetic field of the scanner, the protons in
the body align along the central axis of the field. Application of a
radiofrequency pulse, or sequence, causes the protons to spin in
phase with each other. When the pulse is stopped, the protons re-
turn to random spinning and dephase. As they do so, they emit a
signal that is converted to an image by computer manipulation.
In general, T1-​weighted short sequences are useful for defining
anatomy, and T2-​weighted long sequences are useful for assessing
pathology. Other sequences are selected for special purposes (e.g.
the short tau inversion recovery sequence is used to image marrow
as it suppresses fat and makes the marrow appear dark). MRI, with
or without enhancement with gadolinium, is particularly useful in
detecting and assessing the following:
• early osteonecrosis at the presenting site and the contralateral
clinically occult site
• intervertebral disc disease, root entrapment, and spinal cord
compression
• osteoarticular and soft-​tissue sepsis
• osteoarticular and soft-​tissue malignancy
• internal mechanical derangement of joints (particularly the knee)
• assessment of soft-​tissue and periarticular pathology (e.g. early
synovitis, rotator cuff tears bursitis, tenosynovitis)
• stress fracture
• complex regional pain syndrome (reflex sympathetic dystrophy,
algodystrophy)
The choice between three-​phase scintigraphy and MRI for de-
tection of conditions such as early osteonecrosis, where both have
excellent sensitivity (scintigraphy 90%, MRI 100%), will depend on
practical issues such as ease of access, musculoskeletal reporting ex-
pertise, radiation risk, and local cost.
Ultrasonography
This is a safe, accessible technique that can be used at the bedside
and is increasingly used to detect synovitis/​effusions at both clin-
ically occult joints (e.g. hip) and small peripheral joints (e.g. prox-
imal interphalyngeal joints) when there is clinical uncertainty. It can
also be used to assess for neovascularity (a positive Doppler signal
Fig. 19.3.10  Bone scan demonstrating secondary deposits of prostate
cancer. The presenting painful lesion was in the right hemipelvis and the
plain pelvic radiograph was normal. The spinal lesion (and two others not
shown on this photograph) were asymptomatic.
19.3  Clinical investigation
4401
indicates increased blood perfusion) and erosions, and hence is im-
portant in assessing response to treatment. Crystal deposits in car-
tilage (urate at the surface, pyrophosphate in the mid-​zone) may also
show as a specific hyperechoic double contour sign, and tophi (often
mobile on pressure) may be evident in synovium and extracapsular
sites. Ultrasound examination is also very useful to assess soft-​tissue
changes such as popliteal cysts, or Achilles tendon pathology, and
can also be used to guide synovial fluid aspiration and intra-​articular
and soft-​tissue injection.
Arthrography
The main use of this technique, which requires injection of positive
(iodinated) or negative (air) contrast, or a combination of both, is
in addition to MRI to delineate labral tears within the shoulder or
hip capsule.
Blood tests for inflammation and
systemic disease
The full blood count, erythrocyte sedimentation rate (ESR), and
C-​reactive protein may show changes that indicate the presence of
inflammation somewhere in the body. These changes are very sensi-
tive but are non​specific: they are mainly used as a semiquantitative
measure to complement the clinical assessment of inflammatory
disease and its response to treatment.
Detection of an acute phase response
The systemic response to injury that results in these changes is
summarized in Fig. 19.3.11. At any site of injury or inflammation,
macrophages and monocytes release soluble intercellular signalling
polypeptides (cytokines) including interleukin 1, interleukin 6, and
tumour necrosis factor-​α. Some of these enter the systemic circula-
tion and exert effects on the hypothalamus, bone marrow, and liver.
These combined systemic effects are called the acute phase response,
even though they accompany chronic as well as acute inflammation.
Interleukin 6 is the main cytokine to influence the liver, causing
increased production of certain acute phase proteins (including fi-
brinogen and C-​reactive protein) and decreased production of other
negative acute phase reactants (such as albumin and transferrin).
Much of the acute phase response is beneficial for body defence
and adaptation to injury, especially for dealing with the two major
complications of injury that threaten life: haemorrhage and sepsis.
For example, the thrombocytosis and increased serum levels of clot-
ting factors facilitate haemostasis; neutrophilia and the increased
serum levels of complement, immunoglobulin, and C-​reactive pro-
tein (an opsonin) combat infection; and the anaemia and low serum
transferrin levels result in diminished delivery of iron to bacteria
and parasites.
C-​reactive protein
Of all the acute phase proteins, C-​reactive protein shows the greatest
shift from very low to very high levels, varying over a several-​
hundredfold range in concentration. C-​reactive protein also closely
mirrors the current degree of inflammation, rising rapidly at its
onset and falling as inflammation subsides, such that it is therefore
the single most useful direct measure of the acute phase response.
Interestingly, some rheumatic diseases—​specifically lupus, sys-
temic sclerosis, and dermatomyositis—​associate with only modest
or no elevation of C-​reactive protein, despite unequivocal patho-
logical evidence of inflammation and tissue damage. The reason for
this remains unclear, but patients with such disease are capable of
mounting a typical acute phase response (e.g. in response to infec-
tion). In a patient with lupus or scleroderma, gross elevation of C-​
reactive protein should therefore suggest an incidental cause such as
sepsis. Some clinical features of active systemic lupus and infection
overlap; hence, in this situation the C-​reactive protein can prove a
useful test.
Erythrocyte sedimentation rate
The ESR is a long-​established indirect measure of the acute phase re-
sponse. It mainly reflects the degree of rouleaux formation. Normally
our circulating erythrocytes do not clump together because of the
net balance of three electrical forces (Fig. 19.3.12), namely weak at-
tractant van der Waal’s forces resulting from red cells being bodies;
a strong repellent net negative surface charge, or zeta potential, due
mainly to membrane sialic acid residues; and an attractant dielec-
tric constant resulting from the charge characteristics of the plasma
constituents.
In health the zeta potential far exceeds the sum of the two at-
tractant forces, so that erythrocytes electrostatically repel each other
and remain single. However, during the acute phase response the
change in plasma protein concentrations leads to an increase in
dielectric constant. Fibrinogen is particularly important in this re-
spect. Although its increase in concentration is relatively modest,
fibrinogen is a very asymmetric molecule that exerts a major elec-
trical charge effect. The resulting increase in dielectric constant is
sufficient to overcome the zeta potential, so that rouleaux form more
readily. Rouleaux have a higher ratio of mass per surface area and
(Rise in ESR)
Liver
Brain
IL-1, IL-6
IL-1, TNF
Acute phase reactants, e.g. CRP
Reduced albumin synthesis
Fibrinogen
Fever
Slow wave sleep
Reduced appetite
Inflamed joint
IL-8, IL-1
TNF
Bone marrow
Muscle
Wasting
IL-1,    TNF
Neutrophilia
Reduced red blood cell
production (anaemia)
Thrombocytosis
Immune system
Lymphocyte
adherence
Platelet activation
B,T-cell activation
Fig. 19.3.11  Diagram to show the important elements of the acute
phase response.
section 19  Rheumatological disorders
4402
so sediment faster than single red cells, which is the property meas-
ured in the ESR. In the Westergren test system a 200 mm capillary
tube is filled with the patient’s blood. After 1 h, the clearance of red
cells from the top is measured. If there is little rouleaux formation,
the discrete red cells sediment only slowly and the clearance is small
(<5–​10 mm). However, if there is significant rouleaux formation,
the clearance is greater and the ESR in the first hour is elevated.
Therefore, in a patient with an acute phase response, the ESR and
C-​reactive protein are both elevated, with the ESR lagging behind
the C-​reactive protein in terms of speed of change.
It is important to recognize, however, that the ESR may be elevated
for reasons other than the acute phase response. Immunoglobulins
are very symmetrical molecules, and their modest increase in con-
centration during the acute phase response has relatively little ef-
fect, compared with fibrinogen, on the dielectric constant. However,
large increases in immunoglobulin concentration (e.g. in multiple
myeloma or associated with autoimmune diseases such as Sjögren’s
syndrome) will increase the dielectric constant and lead to rouleaux
formation. In this situation, the patient may have a high ESR but
normal or relatively low C-​reactive protein. Such discordance be-
tween the ESR and C-​reactive protein should lead to consideration
of hypergammaglobulinaemia and myeloproliferative disease and
to direct measurement of serum immunoglobulins and paraprotein
electrophoresis.
In addition to the changes reflecting an acute phase response, the
full blood count may show other alterations that are nonspecific in
themselves but which, taken in the context of the clinical features,
may be characteristic of certain rheumatic diseases or their com-
plications (Fig. 19.3.13). For example, neutrophilia may be seen in
systemic vasculitis and neutropenia in lupus. Furthermore, many of
the slow-​acting drugs used to control chronic inflammation have
toxicity on the bone marrow, such that the full blood count is often
included in the routine monitoring of such treatment.
Taken together, therefore, the full blood count, ESR, and
C-​reactive protein can be a useful complement of tests in the
major rheumatic diseases, to:
• assess inflammatory disease activity
• assess response to disease-​suppressing treatment
• detect certain disease complications
• screen for drug toxicity
Van der Waal’s forces
Zeta potential
Dielectric constant
Rouleaux
Mass/surface.area
Fig. 19.3.12  Diagram showing the balance of three electrical forces
that influence clumping of erythrocytes. Rouleaux sediment faster than
individual erythrocytes.
Erythrocytes
Chronic inflammation
Lupus (haemolysis)
Drugs
Neutrophils
Eosinophils
Monocytes
Lymphocytes
Platelets
Lupus
Felty’s syndrome
Drugs
Infection
Lupus
Steroid therapy
Drugs
Infection
Steroid therapy
Vasculitis
Drugs
Psoriatic arthropathy
Adult onset Still’s disease
Polyarteritis nodosa
Sepsis
Steroid therapy
Felty’s syndrome
Lupus
Drugs
Steroid therapy
Infection
Inflammation
Fig. 19.3.13  Diagram showing some of the nonspecific changes that may occur in
individual elements of the full blood count in patients with systemic rheumatic disease.
19.3  Clinical investigation
4403
However, it is important to appreciate that although an elevated
acute phase response is consistent with inflammatory rheumatic
disease, it is non​specific; also that the degree of elevation is often
proportional to the amount or ‘burden’ of inflammatory tissue (e.g.
isolated small joint synovitis in rheumatoid arthritis may not be suf-
ficient to cause a detectable acute phase response, but this does not
mean that inflammatory disease is not present).
Immunological tests
There are an increasing variety of autoantibodies that can be detected
in a serum sample by clinical laboratory services. Production of some
of these is a common, age-​related phenomenon that may be exagger-
ated by the presence of chronic inflammation. The isolated presence of
some autoantibodies therefore has low diagnostic specificity and may
not imply the presence of any disease at all. If present in high concen-
trations, however, their disease specificity usually increases; hence it is
always important to know how much antibody is present (the titre or
concentration in units), rather than just whether it is detectable. The
titre of some autoantibodies (e.g. antineutrophil cytoplasmic antibody
(ANCA)) can reflect the activity of the associated disease and predict
relapse risk after treatment; only a few antibodies (e.g. anti-​dsDNA)
have high diagnostic specificity. Again, the correct choice and inter-
pretation of tests will depend on detailed knowledge of the patient.
There are different detection and assay systems for many of these auto-
antibodies: close liaison with the local immunology service is required.
Rheumatoid factor
The definition of a rheumatoid factor is an antibody directed against
a specific region of the Fc (crystallizable) fragment of human IgG.
The antibody itself may be of any immunoglobulin class, although
IgM anti-​IgG is the rheumatoid factor that is most commonly meas-
ured in the first instance. One of the traditional methods used to
detect IgM rheumatoid factor is to coat latex beads with human IgG.
If the patient’s serum is then added to the test system the penta-
meric IgM antibody binds to the IgG, causing the latex particles to
flocculate, producing a positive latex fixation test. The amount the
patient’s serum must be diluted before this flocculation is lost is then
determined; the higher this ‘titre’, the higher the concentration of
antibody present. Although ‘rheumatoid factor’ was so named be-
cause it was first detected in the sera of patients with rheumatoid
arthritis, it also occurs in association with a variety of other condi-
tions, as well as in some normal adults (Box 19.3.2). It thus has low
diagnostic specificity, particularly in older people, and is not a ‘test
for rheumatoid arthritis’. In terms of sensitivity, it is present in most
patients with erosive rheumatoid disease but may only appear after
many months or years of disease, once the diagnosis is beyond dis-
pute. It is therefore of little value in making a diagnosis of rheuma-
toid arthritis, being neither sufficient nor necessary:  rheumatoid
arthritis is predominately a clinical diagnosis, based on detecting
the presence of synovitis (capsular swelling, joint line tenderness,
stress pain). However, if present in high titre at the onset of rheuma-
toid arthritis it associates with a poorer prognosis. IgG rheumatoid
factor has greater specificity for major rheumatic disease, but these
caveats still remain. One situation in which a negative rheumatoid
factor is of diagnostic significance is in a patient with arthritis and
nodules. As a general rule all patients with nodular rheumatoid arth-
ritis are seropositive (as are those patients who have extra-​articular
disease manifestations), so that in this situation, other causes of
‘arthritis plus nodules’ must be considered (e.g. tophaceous gout or
hypercholesterolaemia).
Anti-​ cyclic citrullinated peptide antibodies
A highly specific autoantibody system has been described in rheuma-
toid arthritis in which antibodies are detected against modified
(citrullinated) arginine residues. The detection of antibodies to cyclic
citrullinated peptides (anti-​CCPs) is a relatively new test, with similiar
sensitivity for rheumatoid factor (65–​80%) but higher specificity (89–​
98%). It can also be positive in patients who are negative for rheuma-
toid factor, and this is one of the clinical scenarios in which the test
is most useful. Anti-​CCP positivity in the setting of a patient with
possible early inflammatory arthritis has prognostic significance as it
is strongly associated with progression to persistent rheumatoid dis-
ease, higher inflammatory markers, and greater erosive change. Unlike
rheumatoid factor, anti-​CCP status is unlikely to be influenced by age,
the presence of other autoimmune diseases, infection or smoking, and
it therefore has a much lower false positivity rate.
Antinuclear antibody
An antinuclear antibody (ANA) is any autoantibody directed against
one or more components of the nucleus. The standard method of
detection is immunofluorescence microscopy after serum has been
applied to a nucleated tissue substrate, usually either rodent liver,
kidney, or a human cell line (e.g. HEp-​2). Four main patterns of
staining are reported. As with rheumatoid factor, the higher the titre
of antinuclear antibody, the greater its significance, but a high titre
does not necessarily imply more severe disease. The specificity and
sensitivity also vary according to the antigen preparation used in the
test system, but tests are not universally standardized and (again)
liaison with the laboratory is important in order to determine the
cut-​off titre that is considered to be ‘abnormal’. The many causes of a
positive ANA are outlined in Box 19.3.3.
The commonest reason to undertake an antinuclear antibody test
is in a patient with suspected lupus. For lupus, the antinuclear anti-
body has high sensitivity (97–​100%), but because the specificity is
very low (10–​40%), a positive result does not make the diagnosis; by
contrast, a negative antinuclear antibody virtually excludes it, par-
ticularly if the extractable nuclear antigen (ENA) test is negative.
If a screening serum antinuclear antibody test is positive, most la-
boratories will then attempt to determine the specific antigenic deter-
minants. Some of these determinants are soluble and can be extracted
Box 19.3.2  Associations with a positive rheumatoid factor
• Rheumatoid arthritis (about 75%)
• Lupus, scleroderma, Sjögren’s syndrome, dermatomyositis
• Chronic infection:
—​	Bacterial endocarditis
—	Viruses (rubella, cytomegalovirus, infectious mononucleosis)
• Parasites
• Neoplasms—​after irradiation or chemotherapy
• Hyperglobulinaemic states:
—	Hypergammaglobulinaemic purpura
—	Cryoglobulinaemia
—	Chronic liver disease
Note that normal subjects can be seropositive.
section 19  Rheumatological disorders
4404
from the nucleus, hence ‘extractable nuclear antigens’, although many
of the antigen–​antibody specificities in human disease remain to be
discovered. Compared with the antinuclear antibodies, antibodies
against specific nuclear antigens have higher specificity for certain
diagnoses or for certain patterns of system involvement within the
same disease. For example, antinuclear antibodies directed against
double-​stranded DNA are highly specific for lupus, but present in only
a minority of patients, usually those who have more severe disease
with a greater likelihood of renal involvement, in whom the diagnosis
is usually already clear. Antibodies to Sm antigen occur almost exclu-
sively in lupus and are associated with a higher risk of renal disease.
Antitopoisomerase 1 and anticentromere antibodies are found in dif-
fuse cutaneous and limited cutaneous systemic sclerosis, respectively.
Antibodies to Ro antigen occur predominantly in Sjögren’s syndrome
(often in combination with anti-​La) and in lupus and are associated
with a high frequency of photosensitive rashes and a risk of neo-
natal heart block. Antibodies to ribonucleoprotein (RNP) are found
in lupus but are often associated with the presence of overlapping
connective tissue disorders that may have features of scleroderma,
myositis, and rheumatoid arthritis. Antisynthetase autoantibodies
(e.g. Jo-​1) are associated with myositis (see Chapter 19.11.5).
The antiphospholipid syndrome, defined by the occurrence of ar-
terial and venous thromboses, recurrent fetal losses, and thrombo-
cytopenia in the presence of antiphospholipid antibodies, occurs
in lupus (secondary antiphospholipid syndrome (APS)) and other
autoimmune diseases, and also in subjects with no other underlying
disease (primary antiphospholipid syndrome). Antiphospholipid
antibodies can be detected in assays for anticardiolipin and anti-​β-2
glycoprotein 1 antibodies and in phospholipid-​dependent coagu-
lation studies to detect lupus anticoagulants (prolonged activated
partial thromboplastin time (APTT) which fails to correct with the
addition of normal serum). Antiphospholipid antibodies also occur
in a wide variety of rheumatic, infectious (bacterial, viral, proto-
zoal) and malignant conditions, and can also be drug induced, but
in these situations they are not usually associated with thromboses.
Further information on these tests can be found in Chapters 14.14
and 19.11.2.
Tests for specific clinical situations
Chronic inflammatory disease at a single site
Patients with unexplained inflammatory disease at a single loco-
motor site (monoarthritis, bursitis, tenosynovitis, osteitis) should be
considered for biopsy. The timing for this will vary according to how
florid the lesion appears, but in general this should be undertaken
for any undiagnosed lesion that has persisted for six months. The
reason is to determine or exclude specific disease that can only be
diagnosed by this means (Box 19.3.4). Although these conditions
are uncommon or rare, they require a specific treatment approach,
rather than a continuing empirical symptomatic one. The com-
monest site for unexplained inflammatory monoarthritis is the knee,
followed by the wrist and small hand joints. Arthroscopic biopsy is
ideally used for larger joints (for additional information from direct
visualization and guided biopsy), open biopsy for smaller joints, and
periarticular lesions. Tissue should be examined histologically and
sent for culture, including mycobacteria. Apart from the specific
conditions in Box 19.3.4, histopathology has no role in the diagnosis
or management of most common rheumatic disease.
Investigation of suspected muscle disease
There are five principal investigations for the diagnosis and moni-
toring of muscle disease: serum creatine kinase, myositis-​specific
autoantibodies, electromyography, MRI, and muscle histology.
None are 100% sensitive, hence each may be normal despite ab-
normality detected by one or both of the others. Although creatine
kinase is the most indirect measure, it is readily available and com-
monly measured in the first instance, alongside autoantibodies if
the test result is raised. It is important to realize that elevation of the
creatine kinase may result from a variety of causes (Box 19.3.5), and
certain racial groups (e.g. Afro-​Caribbean) have higher ‘normal
range’ values. MRI is usually performed next as it is non​invasive
and useful for demonstrating soft tissue and muscle changes,
including oedema within and around muscles (which although not
specific for myositis, is a typical finding in the acute phase), muscle
calcification and fatty infiltration/​atrophy (often seen in the chronic
phase). Muscle involvement can also be patchy and asymmetric;
hence MRI can be used to select muscle groups for electromyog-
raphy (EMG) or biopsy.
Box 19.3.4  Causes of chronic single-​site synovitis
• Foreign body (e.g. plant thorn)
• Infection, including tuberculosis, fungi
• Sarcoidosis
• Amyloidosis
• Pigmented villonodular synovitis
• Synovial chondromatosis
• Synovial sarcoma
Box 19.3.5  Causes of elevation of serum creatine kinase
• Inflammatory myositis ± vasculitis
• Inclusion body myositis
• Muscular dystrophy
• Motor neuron disease
• Alcohol, drugs
• Trauma, strenuous exercise
• Myocardial infarction
• Hypothyroidism, metabolic myopathy
Note that rhabdomyolysis is associated with massive elevation of serum creatine
kinase.
Box 19.3.3  Associations with a positive antinuclear antibody
• Systemic lupus erythematosus
• Rheumatoid arthritis
• Sjögren’s syndrome
• Polymyositis
• Polyarteritis nodosa
• Juvenile idiopathic arthritis
• Chronic active hepatitis
• Autoimmune thyroid disease
• Myaesthenia gravis
• Extensive burns
Note that normal subjects may be antinuclear antibody positive.
19.3  Clinical investigation
4405
Electromyography or muscle biopsy will be undertaken next, the
choice depending on local availability and expertise. How much in-
formation on diagnosis and disease activity has been gained from
the first of these tests will then often determine whether the second
is also undertaken.
Electromyography measures the action potentials produced at
rest and during voluntary contraction. Normal muscle is electric-
ally silent at rest. On slight contraction, motor-​unit potentials of
500–​1000 µV in amplitude and 4–​8 ms in duration are recorded. On
maximal contraction, as many motor units as possible are recruited
and an interference pattern develops. With inflammatory polymyo-
sitis the electromyography may show a diagnostic triad of spontan-
eous fibrillation, short-​duration action potentials in a polyphasic
disorganized outline, and repetitive bouts of high-​voltage oscilla-
tions produced by contact of diseased muscle with the needle.
Muscle histology can readily be obtained from a needle muscle
biopsy sample. This is a relatively simple procedure requiring a local
anaesthetic, small skin incision (no stitches required), an appropriate
muscle biopsy needle, and no subsequent limitation of activity: it can
easily be repeated serially for subsequent monitoring of response to
treatment. The quadriceps is usually chosen, although the deltoid
or other muscles can also be biopsied this way. The two or more
small cores of tissue obtained need to be transported rapidly to the
laboratory and correctly orientated before freezing and sectioning.
Immunohistochemical staining in conjunction with plain histology
gives considerable information concerning primary and secondary
muscle and neuromuscular disease. Although open biopsy will yield
more tissue than needle biopsy, only a small amount of muscle is ac-
tually required and serial open biopsy is clearly problematic.
Investigation of suspected vasculitis
The presenting features of vasculitis are usually those of vessel wall
inflammation leading to ischaemia in the affected organ (e.g. upper
airway, kidney, peripheral nerve, abdomen, skin), in combination
with the non​specific systemic effects of inflammation (malaise,
weight loss, night sweats). These symptoms can also be produced
both by severe infection and by malignancy, and in view of this—​
and the potential toxicity of appropriate treatment—​further in-
vestigation is always required. In terms of laboratory tests, simple
measures such as a urine dipstick test and microscopy should not be
overlooked, as the prognosis of many of these diseases is dictated by
renal involvement.
Antineutrophil cytoplasmic antibodies, initially detected in pa-
tients with glomerulonephritis, are antibodies directed against
enzymes present in neutrophil granules. Two main patterns of im-
munofluorescence are detected: cytoplasmic and perinuclear. Most
c-​ANCAs and p-​ANCAs are specific for the neutrophil enzymes
proteinase 3 (PR3) and myeloperoxidase (MPO), respectively. These
two antibodies associate with particular vasculitis subtypes, for ex-
ample, anti-​PR3 with granulomatosis with polyangiitis (Wegener’s),
and anti-​MPO with microscopic polyangiitis. However, positive
antineutrophil cytoplasmic antibodies occur in a variety of other
settings, including malignancy and infections (bacterial and HIV)
as well as other autoimmune diseases (inflammatory bowel disease,
rheumatoid arthritis, thyroid disease, pulmonary fibrosis). Equally,
some patients with definite systemic vasculitis are antineutrophil
cytoplasmic antibody negative, and thus diagnosis of these con-
ditions should not be made or refuted on the antineutrophil
cytoplasmic antibody test alone. Other supporting evidence should
be obtained whenever possible by biopsy of an appropriate organ
(nose, kidney, muscle, skin).
For further information, see Chapter 19.11.9.
Investigation of multiple regional pain
In most patients who present with widespread musculoskeletal pain,
the diagnosis is made from clinical examination alone (e.g. wide-
spread rheumatoid disease). In some cases, however, there may be
little to detect on clinical examination to explain the widespread
pain. In most cases the diagnosis will be fibromyalgia. This is con-
firmed clinically by the appropriate symptoms (e.g. widespread pain,
non​restorative sleep, marked fatigue, tension headache, irritable
bowel symptoms, anxiety and depression, poor memory and concen-
tration, urinary frequency) and the presence of widespread hyper-
algesic tender sites and negative control sites (see Chapters 19.2,
26.3.3, and 26.5.12). However, several other conditions may present
similarly with multiple regional symptoms and few, if any, physical
findings, hence a limited screen (Table 19.3.3) is justified to detect
conditions for which there are specific treatments, either as the pri-
mary cause or as a comorbidity in people with fibromyalgia.
FURTHER READING
Berden A, et al. (2012). Diagnosis and management of ANCA associ-
ated vasculitis. BMJ, 344, e26.
Catrina A, et al. (2014). Lungs, joints and immunity against citrullinated
proteins in rheumatoid arthritis. Nat Rev Rheumatol, 10, 645–​53.
Lisnevskaia L, Murphy G, Isenberg D (2014). Systemic lupus
erythematosus. Lancet, 384, 1878–​88.
Marinos C, Dalakas MD (2015). Inflammatory muscle diseases. N Engl
J Med, 372, 1734–​47.
Mariz HA, et al. (2011). Pattern on the antinuclear antibody–​HEp-​2
test is a critical parameter for discriminating antinuclear antibody–​
positive healthy individuals and patients with autoimmune rheum-
atic diseases. Arthritis Rheum, 63, 191–​200.
McQueen FM, Doyle A, Dalbeth N (2011). Imaging in gout—​what can
we learn from MRI, CT, DECT and US? Arthritis Res Ther, 13, 246.
Rowbotham EL, Grainger AJ (2011). Rheumatoid arthritis: ultrasound
versus MRI. AJR Am J Roentgenol, 197, 541–​6.
Ten Cate DF, Luime JJ, Swen N (2013). Role of ultrasonography in
diagnosing early rheumatoid arthritis and remission of rheumatoid
arthritis—​a systematic review of the literature. Arthritis Res Ther,
15, R4.
van Venrooij WJ1, van Beers JJ, Pruijn GJ (2011). Anti-​CCP anti-
bodies: the past, the present and the future. Nat Rev Rheumatol,
7, 391–​8.
Table 19.3.3  Investigations to perform in multiple regional pain
Investigation
Condition
ESR/​CRP
Systemic inflammation
Creatine kinase
Myositis
Antinuclear antibody
Lupus
Calcium
Parathyroid disease, osteomalacia
Thyroid function tests
Thyroid disease
CRP, C-​reactive protein; ESR, erythrocyte sedimentation rate.

19.4 Back pain and regional disorders 4406 Carlo A
19.4 Back pain and regional disorders 4406 Carlo Ammendolia and Danielle Southerst
ESSENTIALS
Low back pain
Over 70% of people in industrialized countries suffer from low back
pain at some time, and it is one of the main reasons for visits to phys-
icians. Risk factors include heavy physical work, smoking, stress,
depression, and job dissatisfaction. In more than 90% of cases the
exact anatomical source of back pain cannot be determined, and
the preferred diagnostic label is ‘non​specific low back pain’.
‘Red flags’ is the term used for the presence on history of any of the
following: age over 50; fever; weight loss; significant trauma; previous
history of neoplasia; use of corticosteroids; drug or alcohol abuse;
neurological symptoms and signs; night pain; morning stiffness; and
the persistence of pain after one month of conservative therapy. Such
red flags may suggest the possibility of serious disorders (e.g. neo-
plasia, infection, fracture, or inflammatory spinal disease).
Investigation should be restricted to patients with red flags and
clinical suspicion of serious disease, with magnetic resonance
imaging the best imaging modality for the diagnosis of lumbar dis-
orders. In the absence of red flags, patients with acute low back pain
should receive non pharmacological care as first treatment option
including reassurance, advise to remain active, massage and spinal
manipulation followed by non steroidal anti-inflammatory drugs
and muscle relaxants if necessary.
The early recognition of psychosocial risk factors, or ‘yellow flags’,
is important to identify patients who are at higher risk of progressing
towards chronic low back pain. Cognitive behavioural therapy,
supervised exercise therapy, brief educational interventions, multi-
disciplinary treatment, and short courses of manipulation/​mobiliza-
tion can each be recommended in patients with non​specific chronic
low back pain, but the condition is often refractory.
Other regional disorders
Neck pain—​the clinical approach should follow the same principles
as described for low back pain.
Regional musculoskeletal pain disorders—​painful conditions af-
fecting a specific region of the body are extremely common. Various
pains have been described affecting the shoulder, elbow, wrist and
hand, hip, knee, ankle, and foot regions. The majority can usually
be identified by a careful history and directed physical examination.
The principles of management include temporary rest, analgesics or
non​steroidal anti-​inflammatory drugs, local corticosteroid injections,
thermal modalities, orthotics, and graded flexibility and strength-
ening exercises.
Low back pain
Low back pain is one of the commonest symptoms and a leading
reason for all visits to physicians in the United States. Between 60 and
80% of adults suffer from at least one episode of back pain during their
lifetime. The vast majority of those who develop an episode of low
back pain improve quickly with or without professional care. However,
recurrences are common with 24–​80% of individuals experiencing
further episodes within a year. Low back pain is best viewed as a re-
current disorder that can occur anytime in a person’s life and fluctu-
ates between no or mild pain to disabling pain. In the United States
1–​2% of the population are disabled due to back pain and worldwide
back pain is the leading cause of years lived with disability. Those with
persistent and disabling low back pain are a difficult therapeutic chal-
lenge, owing to the influence of psychological and social factors on
the continuation of pain. In terms of costs, persistent back pain and
related disability is responsible for more than 75% of the total costs of
low back pain to society, estimated to be between 1 and 2% of the gross
national product in most industrialized countries.
Significant risk factors for the occurrence of back pain include
older age, heavy labour (in particular jobs requiring lifting in an
awkward position), lower education and income, smoking, high
birth weight (in males), and obesity. Twin studies suggest that
genetic factors have an important influence on the lifetime preva-
lence of back pain, with heritability ranging from 52 to 68%. Long-​
distance driving and whole-​body vibration such as experienced
by truck drivers are well-​known risk factors for disc herniation.
Previous episodes of back pain are strong predictors of recurrence.
Several psychosocial risk factors, or so-​called ‘yellow flags’, predict
poor outcomes (Box 19.4.1). These include beliefs that back pain is
harmful or potentially severely disabling, resulting in fear/​avoid-
ance behaviour and reduced activity levels, excessive reliance on
aids and appliances, depressed mood, withdrawal from social inter-
action, and job dissatisfaction.
19.4
Back pain and regional disorders
Carlo Ammendolia and Danielle Southerst
19.4  Back pain and regional disorders
4407
Many structures of the back, including the muscles, ligaments,
discs, bones, and zygapophyseal and sacroiliac joints are innervated
and can therefore be a source of pain. However, in more than 90%
of patients presenting with low back pain it is extremely difficult—​if
not impossible—​to identify precisely the anatomical source of the
pain on the basis of history and physical examination. These pa-
tients should be diagnosed as suffering from ‘non​specific low back
pain’. A host of clinical entities such as muscle strain, degenerative
disc disease, facet syndrome, myofascial pain syndrome, segmental
instability, piriformis syndrome, and so on, have been described
within this broad category based on the localization of pain and ten-
derness, reproduction of symptoms by specific manoeuvres, radio-
logical features, or pathophysiological hypotheses. Unfortunately,
the signs and manoeuvres described for each of these clinical syn-
dromes lack sensitivity and specificity and are not reproducible,
even by experienced clinicians. Moreover, the claim that any of these
entities is responsible for the pain in a given patient can very rarely
be validated. For example, it is hazardous to ascribe pain to degen-
erative disc disease or zygapophyseal joint osteoarthritis when it has
been shown that individuals with similar radiological changes can
be completely asymptomatic. The only way to determine if the discs
or zygapophyseal or sacroiliac joints are the source of pain in a given
patient is through injection studies done under stringent, controlled
conditions (see next).
Clinical approach to the diagnosis of low
back pain
In evaluating a patient presenting with low back pain, the physician
should not try to differentiate between the various elusive entities
responsible for non​specific back pain, but rather should focus on
determining if the patient needs emergency surgery, has sciatica
(radiculopathy) with signs of nerve root compression, or has an
underlying pathological cause of back pain (infectious, inflamma-
tory, metabolic, tumoural, or visceral) (Table 19.4.1). Back pain with
an identifiable cause is referred to as specific low back pain.
Is this a surgical emergency?
Cauda equina syndrome and an expanding vascular aneurysm are
two extremely rare but important conditions to recognize, because
both are surgical emergencies. In the first instance, the patient will
usually present with low back and/​or buttock pain, associated with
bilateral sciatica, neurological symptoms in the lower extremities,
and urinary and/​or bowel incontinence. Physical examination may
show bilateral weakness, sensory losses, saddle anaesthesia, de-
creased reflexes in the legs, and decreased rectal tone. Diagnostic
procedures (MRI or CT) should be performed on an emergency
basis if bowel and bladder control are to be preserved. Central disc
herniation is the most common cause of the syndrome, followed by
tumours and epidural abscesses.
An aortic aneurysm can be responsible for a dull, gnawing back
pain due to direct compression of the aneurysm on the lumbar ver-
tebrae. They are typically seen in elderly patients, especially white
men, and physical examination may reveal a pulsating abdom-
inal mass and decreased pulses in the legs. Diagnosis is most im-
portant because rupture or dissection of the aneurysm is often fatal.
Dissection should be suspected in patients presenting with sudden,
excruciating, tearing abdominal or back pain radiating to the groin,
buttocks, or thighs along with haemodynamic compromise (hypo-
tension, tachycardia, and shock). Up to 30% of ruptured aneurysms
are initially misdiagnosed. Preventive surgery (before rupture or
dissection) is the optimal treatment.
Box 19.4.1  Yellow flags predicting poor outcome in back pain
• Belief that pain is harmful or disabling resulting in fear; avoidance
behaviour
• Belief that all pain must be abolished before attempting to return to
work or normal activity
• Catastrophizing, thinking the worst, misinterpreting bodily symptoms
• Passive attitude to rehabilitation
• Report of extremely high intensity of pain (e.g. above 10, on a 0–​10
visual analogue scale)
• Excessive reliance on use of aids or appliances
• Depression (long-​term low mood), loss of sense of enjoyment
• Lack of social support and interaction
• Job dissatisfaction
Table 19.4.1  Causes of back pain
Surgical
emergencies
Cauda equina syndrome (disc, tumour mass, abscess)
Aortic aneurysm (ruptured, dissected)
Radiculopathy
with neurological
signs
Ruptured intervertebral disc
Spinal stenosis (the neurological examination is often
normal)
Spinal cord tumours (extradural, intradural—​
extramedullary/​intramedullary)
Pathological conditions
Neoplastic
Benign: osteoid osteoma
Malignant: primary (multiple myeloma), secondary
(metastasis)
Infectious
Acute: pyogenic discitis, osteomyelitis
Chronic: tuberculosis
Inflammatory
Ankylosing spondylitis
Psoriatic arthritis
Reactive arthritis
Inflammatory bowel diseases
Metabolic
Osteoporosis (with fractures)
Osteomalacia
Paget’s disease of bone
Visceral
Pelvic organs (endometriosis, prostatitis)
Renal disease (pyelonephritis, renal colic)
Gastrointestinal (pancreatitis)
Aortic aneurysm
Non​specific
low back pain
Muscle
Ligaments
Discs
Zygapophyseal joints
Spondylolisthesis
Sacroiliac joints
section 19  Rheumatological disorders
4408
Does the patient have lumbar radiculopathy (sciatica)
and/​or neurological signs?
Lumbar radiculopathy refers to pain in the back or buttock that ra-
diates down the leg in a dermatomal distribution. It is usually asso-
ciated with an identifiable aetiology, typically a herniated disc giving
rise to compression and/​or irritation of the spinal nerves most com-
monly originating between L4 and L5 (L5 nerve root) and/​or L5 and
S1 (S1 nerve root). About 4% of back pain patients have a lumbar
herniated disc causing radiculopathy.
Lumbar radiculopathy can also be caused by spinal stenosis, which
is a narrowing of the central and/​or lateral spinal canals, usually due
to degenerative thinning and bulging of discs and thickening of
bone and ligaments. Tumours, infections, or epidural haemorrhage
can very rarely produce similar symptoms and signs. The pain in a
patient with a herniated disc tends to be aggravated by prolonged
sitting, forward bending, and manoeuvres that increase intrathecal
pressure, such as sneezing, coughing, or defecation. It is often as-
sociated with paraesthesias and weakness in the distribution of the
involved nerve.
Patients with spinal stenosis are usually older and typically com-
plain of pain and/​or paraesthesias in one or both buttocks, thighs,
and/​or legs that develop on standing or walking and are relieved by
sitting (neurogenic claudication). These patients often walk with the
trunk flexed, as extension aggravates their symptoms by worsening
nerve impingement. The neurological examination is often normal
or shows non​specific abnormalities such as reduced or absent ankle
reflexes. Differentiating neurological from vascular claudication can
be difficult as both problems occur in the same age category, but
changing trunk posture does not typically influence pain from vas-
cular claudication.
Does the patient have an underlying pathological cause
for their back pain?
The patient history is by far the most important diagnostic step in
the search for potential pathological causes of low back pain. Certain
clues or ‘red flags’ should be looked for systematically (Table 19.4.2).
These include the presence of fever, chills, night sweats, weight loss,
and nocturnal pain, which should direct the clinician towards the
possibility of neoplasia or infection. An insidious onset of back pain
accompanied by significant early morning stiffness in a young patient
suggests a spondyloarthropathy and should prompt the clinician to
enquire about the family history and undertake a detailed review of
the ocular (conjunctivitis, iritis), cutaneous (psoriasis, mouth ul-
cers, balanitis, keratoderma blennorrhagica), gastrointestinal (diar-
rhoea, haematochezia, abdominal pain), genitourinary (urethritis),
and musculoskeletal (peripheral arthritis, dactylitis, enthesitis, heel
pain) systems. Risk factors for neoplasia (previous or current history
of malignancy), infection (history of tuberculosis, AIDS, intravenous
drug abuse, or recent genitourinary procedures), and metabolic bone
diseases (previous fractures, menopause, corticosteroid intake, his-
tory of anorexia nervosa) should also be sought in patients suspected
of having a pathological problem underlying their back pain.
What are the key signs to look for in the physical
examination?
A  good examination of the lumbar spine and relevant nerves
can be accomplished in less than three minutes if it is done
systematically (Table 19.4.3). A full physical examination must
be completed in patients suspected of having a pathological cause
for their back pain. The diagnostic utility of the many physical
manoeuvres described to identify zygapophyseal and sacroiliac
joint pain has been refuted when validated against diagnostic
blocks with local anaesthetic. Waddell has described several
non​organic physical signs (Box 19.4.2):  psychological factors
or secondary gains may be involved when a patient has three or
more of these.
Who should be investigated and how?
There is a general agreement that the initial assessment should focus
on the detection of ‘red flags’ suggestive of a pathological aetiology,
and that the vast majority of patients with back pain do not need any
investigations.
Recommendations for ordering imaging in a patient presenting
with back pain include those with red flags combined with clinical
suspicion of underlying cancer, fracture, infection, inflammatory or
Table 19.4.2  Red flags for possible pathological cause of back paina
Pathology
Red flags
Cancer
History of cancer in past 10 years
Unexplained weight loss >10 kg within 6 months
Age over 50 or under 18 years old
Failure to improve with therapy
Activity-​limiting pain >4 weeks
Night pain or pain at rest
Infection
Persistent fever (temperature >38oC)
History of IV drug abuse
Indwelling intravascular catheters (e.g. dialysis lines)
Recent bacterial infection
(i)	 urinary tract infection or pyelonephritis
(ii)	 cellulitis
(iii)	 pneumonia
Immunocompromised States
(i)	 therapeutic (e.g. corticosteroids or other
immunosuppressants)
(ii)	 diabetes mellitus
(iii)	 HIV
Pain at rest
Fracture
Prolonged corticosteroid use
Mild trauma age over 70 years of age
Major trauma any age
History of osteoporosis
Abdominal
aneurysm
Abdominal palpating mass
Atherosclerotic vascular disease
Pain at rest or night pain
Age greater than 60 years
Inflammatory
disease
Age of onset <40 years of age
Morning back stiffness improved with exercise
Three months duration or greater
Iritis and/​or conjunctivitis
Psoriasis, mouth ulcer, or other skin lesions
Gastrointestinal disturbance
Peripheral arthritis, dactylitis, enthesitis, heel pain
a Presence of one red flag alone may not necessary increase risk of underlying pathology
causing back pain but rather a combination of red flags may increase risk.
19.4  Back pain and regional disorders
4409
visceral disease; those with progressive neurological signs including
cauda equina syndrome. Magnetic resonance imaging (MRI) is the
imaging method of choice for the detection of most pathological
causes of low back pain, although plain film radiography can be used
for the initial work up of suspected sacroiliitis or vertebral fractures.
All other tests should be restricted to patients in whom a patho-
logical aetiology is suspected from the history and physical exam-
ination, and patients with significant abnormalities on neurological
examination. Ordering blood tests and imaging in any other
situation cannot be justified. Abnormalities on computed tom-
ography (CT) and MRI such as disc herniation can be seen in
25–50% of asymptomatic individuals. In back pain patients, these
nonspecific findings may lead to unnecessary interventions. In add-
ition to being unhelpful, excessive testing also contributes signifi-
cantly to healthcare costs.
The erythrocyte sedimentation rate (ESR) is the most useful blood
test in patients suspected of having spinal infection, as it is elevated
in up to 80% of cases. Neutrophilia and anaemia are also commonly
seen in patients with neoplasia and infection. Laboratory evaluation
of patients with osteoporosis and/​or pathological fractures should
include serum calcium, phosphate and alkaline phosphatase, as well
as serum and urine immunoelectrophoresis (to detect myeloma),
particularly if the ESR is elevated.
MRI is also the imaging modality of choice for the diagnosis
of lumbar disorders. It provides a unique non​invasive means of
studying the spine and is unsurpassed for imaging soft tissues. It
is particularly helpful in the evaluation of spinal cord tumours, as
well as infections of the spine, including discitis and epidural and
paraspinal abscesses. CT is a recommended imaging modality for
the evaluation of bony structures and therefore is a good choice
for spinal stenosis. The diagnostic accuracy of MRI and plain CT
is comparable for the assessment of nerve root compression due to
disc herniation. Although MRI is non​invasive and involves no ra-
diation to the patient, the much lower cost of plain CT makes it an
excellent choice in this context. CT-​guided percutaneous biopsy can
be used to obtain histological material from patients with tumour
mass or infection.
As mentioned previously, injection studies done under fluoro-
scopic guidance are the only means of diagnosing back pain of
discal, zygapophyseal, or sacroiliac joint origin. However, the impact
of this approach on patient management is unclear, as no specific
treatment has yet been demonstrated to be significantly effective for
these conditions.
Radionuclide bone scintigraphy with technetium-​99m is helpful
in conditions characterized by increased bone turnover. These in-
clude bone metastases, fracture, Paget’s disease, and infections.
Gallium-​67 binds to polymorphonuclear leucocytes and can be
helpful in the evaluation of vertebral osteomyelitis and sacroiliac
septic arthritis. Typically, bone scans are negative in patients with
multiple myeloma, which is characterized by lytic lesions.
Neurophysiological studies are rarely indicated, except in pa-
tients in whom it is difficult to distinguish between a neuropathy,
radiculopathy, or plexopathy. Fibrillations in the paraspinous
muscles are the most common and earliest findings seen in
radiculopathy. Their presence indicates a lesion proximal to the
vertebral foramen and excludes a plexopathy.
How are patients with low back pain best managed?
Surgical emergencies
As mentioned earlier, cauda equina syndrome and a ruptured vas-
cular aneurysm are the only two conditions that must be managed
surgically on an emergency basis.
Radiculopathy and neurological deficits
More than 90% of patients with radiculopathy will improve sig-
nificantly with conservative treatment including education,
Table 19.4.3  Physical examination of the patient with back pain
Patient standing
Posture (protruding abdomen, hyperlordosis, loss
of lordosis, scoliosis)
Spinal motion (flexion–​extension–​lateral flexion)
Walking on heels (L4–​L5) and toes (S1)
Squatting (L2–​L3–​L4)
Patient sitting
Straight leg-​raising test (tripod sign)
Knee (L4) and ankle (S1) reflexes
Patient supine
Abdominal examination (mass, bruit)
Vascular examination
Sensory examination:
L4: anteromedial knee and leg
L5: lateral leg, web space between first and
second toes
S1: lateral aspect of the foot, heel
Motor examination (if abnormalities are noted in
the standing position):
L4: quadriceps
L5: dorsiflexion of first toe
S1: plantar flexion of foot and toes
Hip examination
Patient prone
Palpation (spinous processes, paraspinal muscles)
Sensory examination:
S2–​S4: saddle anaesthesia
Motor examination:
S1: contraction of gluteus maximus
Femoral stretch test (L2 to L4)
Sphincter tone
Box 19.4.2  Waddel’s tests for non​organic back pain
• Tenderness to superficial touch
• Simulation testsa
— Axial loading
— Spinal rotation in one plane
• Distraction tests
— Inconsistent results on confirmatory testing
• Regional disturbances
— Abnormalities not following neuroanatomical structures
•	 Overreaction
— Disproportionate verbalization
a A positive test results in aggravation of low back pain.
section 19  Rheumatological disorders
4410
reassurance, advise to keep active, manual therapy and anti-
inflammatory drugs. The role of epidural steroids remains un-
clear: they may afford short-​term improvement in leg pain, but
they do not reduce the need for surgery. Indications for surgery
include persistent disabling buttock and/​or leg pain despite two
to three months of conservative management, and/​or severe or
progressive worsening neurological deficit while on treatment.
Surgical outcomes for herniated lumbar disc are superior to con-
servative management in the first three to six months but out-
comes are similar at 12 months or longer. Surgery may also be
indicated in patients with neurological claudication due to spinal
stenosis, but only after all attempts with conservative manage-
ment have failed. However, what conservative treatments are
most effective in neurogenic claudication remains unknown. The
positive benefits of surgery for neurological claudication tend to
diminish after two to four years. Patients with spinal stenosis who
are more incapacitated by back pain than by neurogenic claudica-
tion should probably not be operated on, because surgery is rarely
effective and may worsen back pain.
Specific (pathological) back pain
Primary and secondary tumours of the spine can be treated by sur-
gery, radiotherapy, or chemotherapy, whereas antibiotics with or
without surgical drainage are the treatments for discitis and osteo-
myelitis. Postural exercises and non​steroidal anti-​inflammatory
drugs (NSAIDs) remain the cornerstone of treatment for patients
with spondyloarthropathies. Sulphasalazine and methotrexate are
helpful for the peripheral arthritis associated with these condi-
tions, but they have no role in the treatment of the spinal disease.
Biological agents including etanercept, infliximab, adalimumab,
golimumab, and certolizumab are the drugs of choice in patients
with spinal disease associated with spondyloarthropathies who fail
NSAIDs. The treatment of metabolic bone diseases is discussed in
Chapters 20.1 and 20.4.
Non​specific low back pain
Several systematic reviews of randomized controlled trials of
the most common interventions have been published and form
the basis of the recommendations found in the over 15 national
guidelines published in the past two decades. These national
guidelines were developed with the main objectives of improving
prevention and management of acute and chronic non​specific low
back pain.
Patients with acute back pain should receive non pharmaco-
logical care as a first treatment option including reassurance, ad-
vise to stay active and continue with normal activities, including
work if possible. Referral for spinal manipulation or massage
therapy, and if necessary, non steroidal anti-inflammatory drugs
and muscle relaxants should be considered in patients failing
to return to normal activities. Exercise therapy is ineffective in
the acute phase but should be recommended for prevention of
recurrence.
An important objective in managing acute low back pain is to re-
duce the likelihood of patients progressing to chronicity, not least
because there are only a few modalities that have been shown to
be beneficial in chronic back pain. The early identification of psy-
chosocial risk factors, or ‘yellow flags’ (Box 19.4.1), should lead to
appropriate cognitive and behavioural management in an attempt
to influence positively some of these factors.
In patients with chronic low back pain, non pharmacological
care should initially be considered including cognitive behavioural
therapy, supervised exercise therapy, yoga, spinal manipulation,
educational interventions including instruction in self-​management
and multidisciplinary (biopsychosocial) treatment. In patients who
fail to respond, non steroidal anti-inflammatory drugs followed
by tramadol or duloxetine may be considered. Invasive treatments
including epidural corticosteroids, intra-​articular steroid injec-
tions, and local facet nerve blocks, radiofrequency facet joint de-
nervation, intradiscal injections, and prolotherapy (injection of an
irritant solution into a joint space, ligament, or tendon insertion)
are generally not recommended. Surgery is rarely indicated for
nonspecific low back pain.
Neck pain
Neck pain is a very common symptom: in the general population,
its 12-​month prevalence among adults ranges between 30% and
50% and one-​month prevalence between 15% and 45%. As for low
back pain, neck pain can rarely be attributed to a specific anatom-
ical source, and most patients presenting with this symptom should
be diagnosed as suffering from ‘non​specific neck pain’ or ‘cervical
spinal pain of unknown origin’, rather than applying non​validated
diagnostic labels. Trauma, in particular acceleration–​deceleration
(whiplash) injuries, younger age, female gender, and previous his-
tory of neck pain are the most common risk factors associated with
seeking care for neck pain.
The clinical approach to the patient with neck pain should
follow the same principles as described for low back pain. Signs
of nerve root and/​or spinal cord compression should always be
looked for, particularly in patients complaining of associated
pain, numbness, or weakness in their arms or legs. Older pa-
tients with cervical spinal stenosis due to severe osteoarthritis
may present with wasting and lower motor neuron weakness in
the arms or hands, and spastic weakness and sensory disturbance
in the legs.
Certain diseases of the pharynx (pharyngitis, retropharyngeal
abscess), larynx (laryngitis), trachea (tracheitis), thyroid (acute
thyroiditis), lymph nodes (lymphadenitis), carotids (carotidynia),
lungs (Pancoast tumour), heart (myocardial infarction), pericar-
dium (pericarditis), aorta (dissecting aneurysm), and diaphragm
(subphrenic abscess) can refer pain to the neck and should be
considered. These conditions will usually have other clinical
manifestations to alert the physician to the proper diagnosis. The
neoplastic, infectious, inflammatory, and metabolic conditions
enumerated in Table 19.4.1 can also affect the cervical spine.
In addition, rheumatoid arthritis and diffuse idiopathic skeletal
hyperostosis should be considered in the differential diagnosis,
as both can involve the cervical spine and cause spinal cord
compression.
A special task force proposed a classification of neck pain and
associated disorders that takes into account presenting signs and
symptoms and impact on activities of daily living (Table 19.4.4).
This can be very useful in guiding management.
19.4  Back pain and regional disorders
4411
Investigation of patients with neck pain—​who
and how?
Patients with grade I  or grade II neck pain (non​specific neck
pain) do not usually require radiographic evaluation. Those
with grade III and grade IV neck pain and associated disorders
may require a baseline radiological examination, particularly if
there is associated trauma. This should consist of plain films with
anteroposterior, lateral, and open-​mouth views. Degenerative
changes in the discs and zygapophyseal joints increase with age
and do not correlate with symptoms of neck pain. CT is helpful
for evaluating the bony structures of the neck. MRI is therefore
preferred in most cases with spinal cord or nerve root com-
promise. Fifty per cent (50%) of patients with chronic neck pain
after motor vehicle collisions respond to diagnostic zygapophyseal
joint injection, suggesting that these joints are responsible for
their pain.
Management of patients with neck pain
Most treatments recommended for the management of patients
with neck pain have not been evaluated in a scientifically rigorous
manner. Those that have been have shown very little, if any, evidence
of efficacy. These include soft cervical collars, zygapophyseal joint
injections, and acupuncture. Patients with acute neck pain should
be encouraged to maintain their usual level of activity. There is
evidence that NSAIDs, exercise, mobilization, and manipulation
are effective, whereas the promotion of rest and soft collars tends
to prolong disability. Surgery is indicated only for patients with se-
vere radiculopathy not responsive to 6–​12 weeks of conservative
management.
Regional pain disorders
Regional musculoskeletal pain disorders, defined as painful condi-
tions in a specific region of the body, are extremely common. Several
clinical entities have been described for the shoulder, elbow, wrist
and hand, hip, knee, ankle, and foot regions (Table 19.4.5). The ma-
jority can be identified by a careful history and directed physical
examination, although recent research indicates that interobserver
diagnostic agreement is only moderate for the conditions related to
the shoulder and knee regions, particularly in patients complaining
of severe or chronic pain, and those with bilateral involvement.
Investigations are not usually required for the diagnosis of most re-
gional pain disorders.
In a patient presenting with regional pain, one should aim to de-
termine whether the pain has its origin in the bones and joints, peri-
articular soft tissues (tendons, bursa, and fascia), nerve roots and
peripheral nerves, or blood vessels, or if it is referred from distant
musculoskeletal or visceral structures. Lesions of the periarticular
soft tissues account for most causes of regional pain disorders.
Plain radiographs are helpful in delineating soft tissue calcifica-
tion that may or may not be relevant to the patient’s presentation.
Ultrasonography and MRI are of equal value in confirming a diag-
nosis of tendon rupture in the shoulder, knee, or ankle regions.
The principles of management include temporary or relative rest,
analgesics or NSAIDs, local corticosteroid injections, thermal or
electrical modalities, orthotics or supportive devices, and graded
flexibility and/​or strengthening exercises.
Diffuse musculoskeletal pain
Between 8 and 10% of adults report suffering from chronic dif-
fuse musculoskeletal pain and a large proportion of these satisfy
the classification criteria for fibromyalgia. Fibromyalgia has a
female:male ratio of 2:1 and it can develop at any age, including
childhood. In addition to widespread pain, coexisting symptoms
include sleep disturbance, negative mood, cognitive dysfunction,
and fatigue, which together give rise to high levels of disability.
The aetiology of fibromyalgia is unknown, but appears to result
from central nervous system changes that lead to amplification of
pain (central sensitization). Underlying genetic and environmental
risk factors appear equally important. Common environmental
triggers include acute pain episode(s), infections, and psycho-
logical stress.
The diagnosis of fibromyalgia is made clinically and should be
suspected in patients having multifocal pain not fully explained by
injury or inflammation and who display central sensitization and
the coexisting symptoms described here.
Fibromyalgia is challenging and best managed by integrating
pharmacological and non​pharmacological treatments while engaging
patients as active participants in the process. Patient education,
regular aerobic exercise, and cognitive behavioural therapy with the
goal of adopting self-​management strategies are likely important
non​pharmacological treatments. Potentially effective pharmacological
treatments include low-​dose tricyclic agents, gabapentinoids, sero-
tonin norephinephrine reuptake inhibitors, and y-​hydroxybutyrate.
For further discussion see Chapters 19.2, 26.3.3, and 26.5.12.
Table 19.4.4  Classification of neck pain and associated
disorders
Grade
Clinical presentation
I
Neck pain and associated disorders with no signs or symptoms
suggestive of
major structural pathologya and no or minor interference with
activities of daily
living
II
Neck pain and associated disorders with no signs or symptoms
of major structural
pathology, but major interference with activities of
daily living
III
Neck pain and associated disorders with no signs or symptoms
of major structural
pathology, but presence of neurological signsb
IV
Neck pain and associated disorders with signs and symptoms
suggestive of major
structural pathology
Symptoms and disorders that can manifest in all grades include deafness,
dizziness, tinnitus, headache, memory loss, dysphagia, and temporomandibular
joint pain.
a Major structural pathology include (but not limited to) fracture, vertebral dislocation,
injury to spinal cord, infection, neoplasm, or systemic disease including the
inflammatory arthropathies.
b Neurological signs include decreased or absent deep tendon reflexes, weakness, and
sensory deficits.
Adapted from Haldeman et al. A best evidence synthesis on Neck Pain:
Findings from the Bone and Joint Decade 2000–​2010 Task Force on Neck Pain and Its
Associated Disorders. Spine 2008, 33 (supp) pS1–​220, with permission from Lippincott
Williams and Wilkins.
section 19  Rheumatological disorders
4412
Table 19.4.5  Common musculoskeletal disorders by body region
Diagnosis
Epi-​demiology
Clinical symptoms
Physical examination
Associations
Investigations
Treatment
Shoulder region
Rotator cuff
tendinopathy
Any age; although
more common
among 40–​50
Pain over the deltoid
region; increased at night
and by specific movements
depending on involved
tendon
Painful arc of abduction 60–​120
degrees; full passive range; pain
aggravated by resisted contraction
of the involved tendon; positive
impingement signs
DM, repetitive movements
(sports, occupational), may
precede tendon tears
Radiograph in
chronic cases may
show cysts and
sclerosis of greater
tuberosity
NSAIDs, exercise, activity modification,
steroid injections
Calcific
tendinpathy
Age 20–​60
Acute severe pain over the
tip of the shoulder
Limitation of both active and
passive movements due to pain;
occasional swelling when bursa
involved
Calcification on
radiograph
NSAIDs, exercise, activity modification,
electrical modalities (shockwave
therapy), steroid injection
Adhesive
capsulitis
Age 40–​65, more
common in females
Diffuse pain in the shoulder;
progressive capsular
restriction of movement
Limitation of both active and
passive movements in all directions
(external rotation-​abduction
internal rotation)
DM, prior history of
adhesive capsulitis in
opposite shoulder; Note:
MI, stroke, thyroid and
pulmonary diseases may
also present at diffuse
shoulder pain
Arthrography
NSAIDs, steroid injection, shoulder
mobility, and stretching exercises,
passive mobilizations, arthrographic
distension, suprascapular nerve block
Bicipital tendinitis
Very rare in isolation
Pain in anterior aspect of
the shoulder and over the
deltoid region
Speed’sa and Yerganson’sb
manoeuvres non​specific
Rotator cuff tendinitis
NSAIDs, exercise, activity modification,
steroid injection
Rotator cuff tear
Age >40; incidence
increases with age
Sudden pain over
the deltoid area; high
prevalence of asymptomatic
rotator cuff tears
Weakness of abduction if full
thickness
May be preceded by
tendinopathy
US, arthrography,
MRI
Surgery if acute/​traumatic,
symptomatic and patient
<65; NSAIDs, exercise, activity
modification otherwise
Elbow region
Lateral
epicondylitis
Age 40–​55
Pain over the lateral
epicondyle; may radiate
proximally or distally
Tenderness lateral epicondyle;
increased by resisted extension of
the wrist or middle finger
Overuse or repetitive
strain injury (sport or
occupational), smoking,
obesity, DM
NSAIDs, forearm bracing/​taping,
exercise, activity modification,
modalities (shockwave therapy, laser,
ultrasound), steroid injection
Medial
epicondyltiis
15 times more
rare than lateral
epicondylitis
Pain over the medial
epicondyle
Tenderness medial epicondyle;
increased by resisted flexion of the
wrist or fingers
Overuse or repetitive
strain injury (sports or
occupational)
NSAIDs, forearm bracing/​taping,
exercise, activity modification,
modalities (shockwave therapy, laser,
ultrasound), steroid injection
Olecranon
bursitis
Swelling ± pain over the
olecranon bursa
Swelling ± erythema ± tenderness
Trauma, RA, gout
Bursal aspiration: cell
count, Gram stain,
culture, crystals
NSAIDs, compression, ice, steroid
injection, antibiotics if septic
Wrist and hand region
DeQuervain
tenosynovitis
Age 30–​50, more
common in females
Pain radial aspect of wrist
and base of the thumb;
exacerbated by pinching
Tenderness ± swelling surround
abductor pollicis longus tendon;
Finkelstein manoeuvre c, pain
with resisted thumb abduction/​
extension
Overuse or repetitive strain
injury (manual handling
activities)
NSAIDs, splinting, activity
modification, steroid injection
19.4  Back pain and regional disorders
4413
Trigger finger
Any age
Pain over palm of hand;
snapping finger
Tenderness ± swelling ± nodule in
flexor tendon
Diabetes, RA
NSAIDs, steroid injection, manual
release
Dupuytren’s
contracture
Males, age 40–​80
Flexion contracture of 4th
and 5th fingers
Thickening palmar aponeurosis
Alcohol, liver disease, DM
Steroid injection
Hip region
Trochanteric
bursitis
Women, age 40–​70
Pain lateral aspect of
hip and thigh; worse at
night; increased by lateral
decubitus
Tenderness greater trochanter
Hip OA, obesity
NSAIDs, exercise, modalities
(shockwave therapy) steroid injection
Knee region
Prepatellar
bursitis
Women
Swelling ± pain anterior
aspect of knee
Tenderness in prepatellar region
Kneeling
Synovial fluid
aspiration
NSAIDs, compression, ice, steroid
injection
Patello-​femoral
syndrome
Age 15–​40
Pain in the anterior knee,
aggravated with stairs, and
squatting
Tenderness patella ± patellofemoral
crepitus
NSAIDs, exercise, activity modification
Anserine bursitis
Women, age 40–​60
Pain over the medial aspect
upper tibia
Tenderness medial aspect of tibia
Knee OA, obesity
NSAIDs, compression, ice, steroid
injection
Popliteal cyst
Any age
Pain, stiffness, swelling
posterior knee
Swelling posterior knee; leg swelling
with rupture
Inflammatory arthritis
Steroid injection
Ankle and foot region
Achilles
tendinopathy
Age 20–​50
Pain over Achilles tendon
Tenderness ± swelling ± crepitus
over Achilles tendon
Spondyloarthropathies
Relative rest, NSAIDs, exercise
(eccentric over concentric), splinting/​
bracing, modalities (shockwave
therapy laser therapy)
Plantar fasciitis
Pain plantar aspect foot,
especially with first step
upon waking or after
prolonged inactivity
Tenderness medial calcaneus,
pain with passive extension of the
toes, decreased range of motion
in ankle
Spondyloarthropathies,
obesity, work-​related
weight-​bearing, runners,
recent increase in
weight-​bearing activity
Orthotics (prefabricated or custom),
night splinting, stretching exercises,
weight loss, modalities (shockwave
therapy), steroid injection
Morton’s
neuroma
Women, age 40–​60
Burning pain in interdigital
clefts increased by walking
Tenderness interdigital cleft
exacerbated by squeezing the
forfoot; rarely sensory alteration;
cleft 4th toe
Pes planus, pes cavus, tight
shoes
Proper shoes, surgery, injections
DM, diabetes mellitus; NSAIDs, non​steroidal anti-​inflammatory drugs; MI, myocardial infarction; US, ultrasonography; MRI, magnetic resonance imaging; RA, rheumatoid arthritis; OA, osteoarthritis.
a Speed’s test: the examiner resists shoulder forward flexion while the patient’s arm is held in flexion and supination. Pain over the biceps tendon within the bicipital groove indicates a positive test.
b Yergason’s test: the patient’s elbow is flexed to 90 degrees and the forearm pronated. The examiner resists the patient’s attempts to flex the elbow and supinate the forearm. Pain over the biceps tendon within the bicipital groove
indicates a positive test.
c Finkelestein’s test: the patient’s thumb is flexed inside the fingers and the wrist is passively deviated in an ulnar direction. Pain over the abductor pollicis longus and extensor pollicis brevis tendons at the wrist indicates a positive test.
section 19  Rheumatological disorders
4414
FURTHER READING
Accident Compensation Corporation (2009). Distal upper limb: guide-
lines for management of some common musculoskeletal disorders.
Accident Compensation Corporation, New Zealand.
American Academy of Orthopaedic Surgeons (2010). Optimizing the
management of rotator cuff problems: guideline and evidence report.
American Academy of Orthopaedic Surgeons, Rosemont.
Ammendolia C, et  al. (2013). Nonoperative treatment for lumbar
spinal stenosis with neurogenic claudication. Cochrane Database
Syst Rev, 30, CD010712.
Baumbach SF, et  al. (2014). Prepatellar and olecranon bursitis:  lit-
erature review and development of a treatment algorithm. Arch
Orthopaedic Trauma Surg, 134, 359–​70.
Carette S, Fehlings MG (2005). Cervical radiculopathy. New Engl J
Med, 353, 392–​9.
Chou R, et al. (2017). Nonpharmacologic Therapies for Low Back Pain:
A Systematic Review for an American College of Physicians Clinical
Practice Guideline. Ann Intern Med, 166, 493–505.
Chou R, et al. (2017). Systemic Pharmacologic Therapies for Low Back
Pain: A Systematic Review for an American College of Physicians
Clinical Practice Guideline. Ann Intern Med, 166, 480–92.
Côté P, et al. (2016). Management of neck pain and associated dis-
orders: A clinical practice guideline from the Ontario Protocol for
Traffic Injury Management (OPTIMa) Collaboration. Eur Spine J,
25, 2000–22.
Clauw DJ (2014). Fibromyalgia: a clinical review. JAMA, 311, 1547–​55.
Haldeman S, et al. (2008). Best evidence synthesis on neck pain: find-
ings from the bone and joint decade 2000–​2010 task force on neck
pain and its associated disorders. Spine, 33, S1–​220.
Hill JC, et al. (2011). Comparison of stratified primary care manage-
ment for low back pain with current best practice (STarT Back): a
randomised controlled trial. Lancet, 378, 1560–​71.
Hoy D, et al. (2010). The epidemiology of low back pain. Best Pract Res
Clin Rheumatol, 24, 769–​81.
Kelley MJ, et al. (2013). Shoulder pain and mobility deficits: adhesive
capsulitis. Clinical practice guidelines linked to the International
Classification of Functioning, Disability, and Health from the
Orthopaedic Section of the American Physical Therapy Association.
J Orthop Sports Phys Ther, 43, A1–​31.
Kent P, Kjaer P (2012). The efficacy of targeted interventions for modi-
fiable psychosocial risk factors of persistent nonspecific low back
pain—​a systematic review. Man Ther, 17, 385–​401.
Lawry G, et al. (2010). Fam’s musculoskeletal examination and joint in-
jection techniques, 2nd edition, Mosby Elsevier, Maryland.
Martin RL, et al. (2014). Heel pain—​plantar fasciitis: revision 2014.
Clinical practice guideline linked to the International Classification
of Functioning, Disability, and Health from the Orthopaedic Section
of the American Physical Therapy Association. J Orthop Sports Phys
Ther, 44, A1–​23.
Qaseem A, Wilt TJ, McLean RM, Forciea MA (2017). Clinical
Guidelines Committee of the American College of Physicians.
Noninvasive Treatments for Acute, Subacute, and Chronic Low Back
Pain: A Clinical Practice Guideline From the American College of
Physicians. Ann Intern Med, 166, 514–30.
Schwarzer AC, et al. (1994). The relative contributions of the disc and
zygapophyseal joint in chronic low back pain. Spine, 19, 801–​6.
Scottish Intercollegiate Guidelines Network (SIGN) (2013). Manage­ment
of Chronic Pain: A National Clinical Guideline. Scottish Intercollegiate
Guidelines Network (SIGN), Edinburgh (Scotland); December 2013.
http://​www.sign.ac.uk/​guidelines/​fulltext/​136/​index.html
Winters ME, Kluetz P, Zilberstein J (2006). Back pain emergencies.
Med Clin North Am, 90, 505–​23.
Woitzik E, et al. (2015). The effectiveness of exercise on recovery
and clinical outcomes of soft tissue injuries of the leg, ankle, and
foot: a systematic review by the Ontario Protocol for Traffic Injury
Management (OPTIMa) Collaboration. Man Ther, 20, 633–​45.
Yu H, et al. (2015). Effectiveness of passive physical modalities for
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injury management collaboration. Phys Ther, 95, 306–​18.

19.5 Rheumatoid arthritis 4415 Kenneth F. Baker an
19.5 Rheumatoid arthritis 4415 Kenneth F. Baker and John D. Isaacs
ESSENTIALS
Rheumatoid arthritis is a common, painful, and disabling auto-
immune disease affecting 0.5 to 1.0% of adults, with a female:male
ratio of 2.5:1.
Clinical features
Rheumatoid arthritis is characterized by both synovial and systemic
inflammation. Synovitis classically presents as a symmetrical destruc-
tive polyarthritis affecting the hands and feet typified by episodic pain,
stiffness, and swelling. Systemic inflammation commonly leads to fa-
tigue, weight loss, and depression. Other extra-​articular manifestations
include accelerated atherosclerosis, interstitial lung disease, nerve and
spinal cord compression, scleritis, vasculitis, rheumatoid nodules, and
haematological abnormalities such as anaemia and Felty’s syndrome.
If left untreated, patients can rapidly develop irreversible joint damage
leading to chronic pain, deformity, disability, and premature mortality.
Aetiology, pathogenesis, and diagnosis
Rheumatoid arthritis is best conceptualized as a syndrome of
dysregulated chronic inflammation in which the causal pathogenic
pathways vary between patients but ultimately lead to a common
disease phenotype. The aetiology is multifactorial and involves an
interplay between genetic factors and environmental insults such as
tobacco smoking, with immune dysregulation developing over sev-
eral years prior to the onset of clinical disease.
The defining macroscopic feature of chronic synovitis is rheuma-
toid pannus, a potent inflammatory infiltrate which causes cartilage
destruction and bone erosion. Most immune cells have been impli-
cated in pathogenesis, with CD4+ T cells and B lymphocytes having
central roles. Furthermore, joint stromal cells are likely to actively
contribute towards and perpetuate the disease.
Rheumatoid arthritis is a clinical diagnosis based largely upon
history and examination, supported by a limited range of investiga-
tion findings including elevated levels of acute-​phase reactants (e.g.
C-​reactive protein), the presence of autoantibodies (e.g. rheuma-
toid factor and anti-​citrullinated peptide antibody), and the visu-
alization of synovitis on imaging (e.g. musculoskeletal ultrasound).
International consensus classification criteria have been developed
to aid in the standardization of research, but these are only valid after
exclusion of the broad range of differential diagnoses.
Prognosis and management
The past two decades have witnessed a revolution in rheumatoid
arthritis outcomes, from a disease in which progressive deformity
and disability were inevitable to one where remission is a realistic
and achievable aim for many patients. This has been achieved by the
rapid initiation of disease-​modifying anti-​rheumatic drug (DMARD)
therapy at initial clinical presentation, with a treat-​to-​target ap-
proach delivered holistically via a multidisciplinary team in which the
rheumatologist plays a central coordinating role.
Conventional synthetic DMARDs (csDMARDs) are the anchor of
rheumatoid arthritis therapy, with methotrexate the recommended
first-​choice DMARD. Alternative agents include sulfasalazine,
hydroxychloroquine, and leflunomide. Multiple csDMARDs are often
used together in combination therapy when required to achieve ad-
equate disease control. Many of these drugs carry the risk of poten-
tially serious adverse effects such as bone marrow suppression and
hepatitis, hence regular blood monitoring is generally required.
Biological drugs (monoclonal antibodies and soluble receptors) are
usually reserved for those who fail to achieve adequate disease control
with csDMARD therapy, which is usually continued alongside biologic
therapy to both maximize therapeutic response and retard the devel-
opment of anti-​drug antibodies. A wide range of biologic approaches
are available, including:  (a) TNF inhibition (infliximab, etanercept,
adalimumab, golimumab and certolizumab pegol); (b) B-cell deple-
tion (rituximab); (c) IL-​6 receptor blockade (tocilizumab, sarilumab);
and (d) co-stimulation blockade (abatacept). All of these agents carry
a risk of serious infection, for example mycobacterial infections, with
TNF inhibition. There are no biomarkers that reliably predict response
to biologic therapy, and the sequence of biologic use is largely dic-
tated by clinician experience. The high cost of biologic therapy is
falling with the introduction of biosimilar agents.
Targeted synthetic DMARDs (tsDMARDs—tofacitinib and bariciti­
nib) inhibit the Janus kinases (JAKs), and block signalling through various
cytokine and haematopoietic growth factor receptors, dependent on
their precise selectivity. They are also used after the failure of csDMARD
therapy, though not in combination with biologics. They have been
introduced relatively recently but their adverse effects appear similar
to biologics except for an enhanced risk of herpes zoster reactivation.
Glucocorticoids are helpful as bridging therapy to provide tem-
porary control of arthritis flares until DMARD therapy has taken
19.5
Rheumatoid arthritis
Kenneth F. Baker and John D. Isaacs
section 19  Rheumatological disorders
4416
effect. They can be administered locally by intra-​articular or tendon
sheath injection, or systemically by oral or intramuscular routes.
However, their considerable side effect profile restricts their use as
maintenance therapy in all but those patients who fail to respond
to maximal DMARD and biologic therapy, or those in whom these
are contraindicated. Non​steroidal anti-​inflammatory drugs (NSAIDs)
are effective in relieving arthritis pain, but long-​term use is limited
by their potential cardiovascular, renal, and gastrointestinal toxicities.
With optimal care patients can achieve and retain disease re-
mission with maintenance of employment and quality of life.
Nevertheless, rheumatoid arthritis is a life-​long autoimmune disease,
requiring long-term treatment. The ultimate goal of restoration of
immune self-​tolerance remains elusive.
Introduction
Rheumatoid arthritis (RA) is an autoimmune disease characterized
by synovial and systemic inflammation. The hallmark of rheumatoid
arthritis is inflammation of the synovium (synovitis), which classic-
ally presents as a symmetrical polyarthritis principally affecting the
small joints of the hands and feet. If left untreated, irreversible joint
destruction can rapidly ensue with consequent permanent deformity
and disability. For this reason, arthritis is the most visible and hence
well-​recognized consequence of the disease. Nevertheless, rheumatoid
arthritis is a systemic disorder with significant inflammation occurring
outside of the joints. These extra-​articular features include accelerated
atherosclerosis, pulmonary disease, and neurological sequelae, all of
which contribute to excess morbidity and mortality. Thus, as with
all multisystem rheumatologic disorders, it is vital that the physician
adopts a holistic approach to the patient with rheumatoid arthritis.
Historically, most patients diagnosed with rheumatoid arthritis
suffered relentless joint destruction, progressive disability, and
poor quality of life. The past two decades, however, have witnessed
a revolution in rheumatoid arthritis management, with vastly im-
proved outcomes. The treatment paradigm has shifted to one of
early intervention and the aggressive targeting of inflammation
using drug combinations as well as biological and synthetic drugs
targeted to key pathways in rheumatoid arthritis pathogenesis.
With these advances have come remarkable improvements in mor-
bidity and mortality, with disease remission now a realistic and
achievable target for many patients.
Aetiology
The precise mechanisms by which self-​tolerance is breached in
rheumatoid arthritis remain elusive. Most experts now agree that
rheumatoid arthritis is not a single disease entity but rather a syn-
drome of dysregulated chronic inflammation in which the causal
pathogenic pathways vary between patients. Increasing evidence
supports critical roles for both genetic and environmental aetio-
logical factors. A  disease model has emerged whereby environ-
mental insults act upon a genetically predisposed individual to
cause breach of tolerance, immune dysregulation and, ultimately,
clinical rheumatoid arthritis. It is important to recognize that
autoreactivity, the propensity to generate immune responses against
self, is common in the healthy population, but in autoimmunity this
process has become dysregulated and pathological.
Genetic factors
Evidence to support the importance of genetic factors in rheumatoid
arthritis susceptibility first emerged from twin studies. Probandwise
concordance (i.e. the probability of a twin developing rheumatoid
arthritis conditional upon their cotwin having already developed
the disease) is 22–​35% for monozygotic twins and approximately 7%
for dizygotic twins. Nevertheless, monozygotic twin concordance in
rheumatoid arthritis is much lower compared with other common
autoimmune disorders (Table 19.5.1), emphasizing the significant
aetiological contribution of environmental factors.
HLA-​DRB1 and the ‘shared epitope’ hypothesis
The major histocompatibility complex (MHC) is a cluster of genes lo-
cated on the short arm of chromosome 6 which play important roles
in the immune response. Most of the MHC comprises the highly
polymorphic human leukocyte antigen (HLA) genes which encode
for MHC class I (HLA-​A, HLA-​B and HLA-​C) and class II (HLA-​DP,
HLA-​DQ and HLA-​DR), that are critical antigen-​presenting mol-
ecules. There are hundreds of different HLA alleles and therefore a
multitude of combinations. However, certain groups of alleles tend
to be inherited together in blocks known as haplotypes, with marked
variation between geographically and ethnically distinct populations.
Of particular importance to the aetiology of rheumatoid arth-
ritis are the MHC-​II molecules, which comprise an invariant α and
polymorphic β chain. MHC-​II is constitutively expressed at the sur-
face of professional antigen-​presenting cells (APCs) such as den-
dritic cells, B cells, and macrophages. In the extracellular region of
the molecule a highly variable region of the β-​chain forms part of a
groove which binds short antigenic peptides. The MHC-​II-​peptide
complex is then recognized by CD4+ helper T cells as the first crit-
ical stage of the adaptive immune response.
Early studies identified a link between specific HLA-​DR alleles (for
example, HLA-​DRB1*0101, *0401, and *0404) and the presence of
rheumatoid arthritis. These alleles share specific amino acids within
the peptide binding groove, known as the ‘shared epitope’. The most
favoured explanation for this association is that autoantigens im-
portant in the initiation of rheumatoid arthritis bind to shared epitope-​
containing HLA-​DR molecules with high affinity. Although the precise
autoantigens in rheumatoid arthritis remain elusive, there is now good
evidence for a role for citrullinated peptides (see next section).
Table 19.5.1  Probandwise concordance rates for common
autoimmune diseases in monozygotic (MZ) and dizygotic (DZ)
twin studies. Higher concordance in MZ compared to DZ twins
suggests a relatively greater contribution of genetic factors
to the aetiology of the disease
Disease
Percentage MZ
probandwise
concordance
Percentage DZ
probandwise
concordance
Rheumatoid arthritis
22–​35.3
0–​6.9
Ankylosing spondylitis
40
4.3
Systemic lupus erythematosus
20–​39.3
0–​3.2
Type I diabetes mellitus
23–​64.3
3–​20.8
Coeliac disease
83.3–​91
16.7–​20
Psoriasis
72
17
Crohn’s disease
58.3–​62.5
0–​3.8
Adapted from Journal of Autoimmunity, volume 38, Bogdanos et al, Twin studies
in autoimmune disease: Genetics, gender and environment, pages J156–​J169.
Copyright 2012, with permission from Elsevier.
19.5  Rheumatoid arthritis
4417
Non-​MHC susceptibility genes
The advent of high-​throughput genomic sequencing has fuelled
a surge of genome-​wide association studies (GWAS). In these
studies, entire genomes of many thousands of patients with a par-
ticular disease are compared with healthy controls at hundreds
of thousands of common sequence variants known as single nu-
cleotide polymorphisms (SNPs). SNPs that are more commonly
inherited by rheumatoid arthritis patients are assumed to be in,
or close to, predisposing genes. Multiple GWAS have identified
an increasing number of SNPs associated with rheumatoid arth-
ritis (Fig. 19.5.1). Several of these fall within genes involved in
pathways that are already incriminated in rheumatoid arthritis
pathogenesis, whereas others highlight novel potential pathways.
Many disease-​associated SNPs lie within intergenic regions, prob-
ably highlighting regulatory genetic elements with effects on both
nearby and distant genes.
Protein tyrosine phosphatase non​receptor type 22 (PTPN22, also
known as Lyp), is an intracellular protein important in the regula-
tion of lymphocyte responses. A SNP in the PTPN22 gene (1858C
to T) results in a single amino acid change at position 620 (arginine
to tryptophan). This R620W mutation has been associated with a
range of autoimmune diseases including rheumatoid arthritis, sys-
temic lupus erythematosus (SLE) and myasthenia gravis. It has the
strongest non-​MHC genetic association with rheumatoid arthritis
and, while its precise pathogenic contribution has not been defined,
highlights the fact that many rheumatoid arthritis-​associated genes
are immuno-​regulatory.
Epigenetic factors
Epigenetics refers to heritable differences in gene expression that do
not reflect the primary DNA base-​pair sequence. Epigenetic mechan-
isms include DNA methylation, histone methylation and acetylation,
non​coding RNAs such as microRNAs, and small ubiquitin-​related
modifier (SUMO) proteins, all of which can modify gene expres-
sion. Epigenetic changes can be triggered by environmental influ-
ences and several studies have identified epigenetic ‘signatures’ in
rheumatoid arthritis. For example, increased expression of specific
microRNAs, such as miR155, has been observed in rheumatoid
arthritis synovial tissue. Although the net effect of epigenetic modi-
fication is complex and currently poorly understood, the epigenetic
regulation of predisposing genes is likely to play an important role in
the aetiology of rheumatoid arthritis.
Environmental factors
Smoking
Smoking is a potent epigenetic modifier and strong evidence links
cigarette smoking to both an increased risk of developing rheuma-
toid arthritis and increased disease severity. Furthermore, epi-
demiological studies demonstrate a multiplicative interaction
between smoking, shared epitope, and the PTPN22 R620W muta-
tion. Consequently, an individual with all three risk factors is more
than 20 times more likely to develop anti-​citrullinated peptide
autoantibody (ACPA) positive rheumatoid arthritis compared to
an individual with none (Fig. 19.5.2). Exposure to cigarette smoke
is known to induce peptidyl-​arginase deiminase (PADI) enzymes,
which post-​translationally modify arginine to citrulline residues in
a process known as citrullination or deimination. Combined with
the observation that citrullinated peptides bind more readily to
shared epitope-​containing HLA-​DR molecules, this helps to build
a model linking smoking, genetic predisposition, and the develop-
ment of rheumatoid arthritis.
Fig. 19.5.1  Relative contributions of single nucleotide polymorphisms (SNPs) to the risk (odds ratio) of developing rheumatoid arthritis. Aside from a
few strongly associated mutations, most SNPs confer only a small increased risk.
Reprinted from Journal of Autoimmunity, volume 64, Messemaker et al, Immunogenetics of rheumatoid arthritis: understanding functional implications, pages 74-​81.
Copyright (2015), with permission from Elsevier.
Any R620W, smoking
No R620W, smoking
REF
Any R620W, no smoking
No R620W, no smoking
Double SE
Single SE
No SE
25
Anti–CCP–positive RA
20
10
5
0
15
Odds ratio of developing ACPA+ RA
Fig. 19.5.2  Interaction between smoking, shared epitope (SE) and
PTPN22 R620W allele upon the risk of developing anti-​citrullinated
peptide antibody (ACPA)-​positive rheumatoid arthritis. REF, reference.
Reprinted from The American Journal of Human Genetics, volume 80, Källberg et al,
Gene-​gene and gene-​environment interactions involving HLA-​DRB1, PTPN22, and
smoking in two subsets of rheumatoid arthritis, pages 867-​875, copyright 2007 by
the American Society of Human Genetics, with permission from Elsevier.
section 19  Rheumatological disorders
4418
Infection
Many pathogens contain proteins that are similar or identical to human
proteins. An immune response against the pathogen could thus theor-
etically trigger autoimmunity in a process termed molecular mimicry.
Indeed, infection is a recognized trigger of autoreactivity in conditions
such as rheumatic heart disease, post-​streptococcal glomeruloneph-
ritis, and reactive arthritis. These observations have led to inevitable
speculation that infections may play a causative role in rheumatoid
arthritis. Indeed certain chronic infective conditions are associated
with rheumatoid arthritis, such as chronic periodontitis and bronchi-
ectasis, although not necessarily via molecular mimicry. For example,
Porphyromonas gingivalis, which is present in dental caries, expresses
PADI enzymes which could citrullinate host proteins and trigger
autoreactivity and, in a genetically predisposed host, autoimmunity.
Microbiome
There has been a surge of recent interest in the role of the human com-
mensal microflora, or ‘microbiome’, in the aetiology of autoimmune
disease. It is estimated that the human gut alone contains 10 times
more microbes than the number of cells in the body, with additional
complexity in the oral and pulmonary mucosae. With an average of
65% genetic variation between the microbiome of different individ-
uals, and the delicate symbiotic relationship that exists at mucosal
surfaces, the microbiome is an attractive and potentially powerful
environmental trigger for autoimmune disease. Evidence from mice
reared in germ-​free environments provides proof of principle for the
role of the microbiome both in the initiation and regulation of auto-
immunity. Although the exact mechanisms remain unclear, it appears
that both beneficial and potentially pathogenic immune responses
can be triggered by intestinal bacteria. Therapeutic manipulation of
the microbiome is possible by dietary modification, antibiotics or
even the adoptive transfer of faecal matter from healthy individuals
in a process termed ‘faecal transplantation’. The effectiveness of these
approaches in the prevention or treatment of rheumatoid arthritis
remains to be established but could prove to be particularly attractive
in predisposed but healthy individuals.
Hormonal
The excess female prevalence of rheumatoid arthritis, and a height-
ened incidence post-​partum and peri-​menopausally, suggest a likely
role for sex hormones in disease aetiology. Breast feeding and age
at menarche may also have an influence but studies are conflicting.
Several studies have suggested that the oral contraceptive pill may
be protective against rheumatoid arthritis but data on hormone
replacement therapy are inconclusive. Many patients attribute
the onset of rheumatoid arthritis and flares in disease activity to
periods of emotional or physical stress. Although there is evidence
for dysregulation of the hypothalamo-​pituitary-​adrenal (HPA) axis
in established rheumatoid arthritis, there is limited evidence for an
aetiological role.
 Diet
Patients often report that diet influences the activity of their arth-
ritis, although there is a lack of robust supportive evidence from ran-
domized controlled trials. Nevertheless vegetarian, and particularly
Mediterranean, diets appear to protect against rheumatoid arthritis
as well as reducing rheumatoid arthritis pain, possibly due to the
high levels of anti-​oxidants they contain. Dietary supplements such
as fish oils rich in omega-​3 polyunsaturated fatty acids may also have
anti-​inflammatory effects in rheumatoid arthritis. A  recent meta-​
analysis demonstrated a negative relationship between alcohol in-
take and ACPA+ RA suggesting a possible protective role of alcohol
consumption in moderation. In contrast, red meat may increase the
risk of inflammatory arthritis. Recent interest has focused on the
role of vitamin D, with the suggestion that low levels could explain
the higher prevalence of rheumatoid arthritis in Northern latitudes.
Observational studies suggest that vitamin D may also reduce disease
activity in rheumatoid arthritis and have cardio-​protective effects,
although contradictory studies also exist.
Environmental toxins
Occupational exposure to silica dust has been associated with an
increased risk of rheumatoid arthritis in case-​control and cross-​
sectional studies, particularly in male smokers. Organic solvents and
mineral oils have also been incriminated. Furthermore, rheumatoid
arthritis incidence is higher in urbanized areas, suggesting a poten-
tial role for other airborne pollutants.
‘Pre-​RA’ and a model of rheumatoid arthritis aetiology
Intriguing insights into rheumatoid arthritis aetiology have
arisen from the retrospective analysis of stored serum samples
from individuals who subsequently developed rheumatoid arth-
ritis. The results of these studies are remarkable in demonstrating
that autoantibodies such as ACPA can appear up to two decades
before rheumatoid arthritis manifests clinically (Fig. 19.5.3).
Furthermore, affinity maturation and class-​switching of these
autoantibodies develops in the years immediately prior to disease
onset. During the same period, pro-​inflammatory cytokines and
chemokines start to appear in peripheral blood, and C-​reactive
protein (CRP) levels rise. This prodromal period of serological
abnormality has been termed ‘pre-​RA’.
These observations have led to a model of rheumatoid arthritis
aetiology, endorsed by the European League Against Rheumatism
lgM–RF or anti–CCP
anti–CCP
lgM–RF
60
50
40
30
20
10
0
15 14 13 12 11 10
9
8
7
6
5
4
3
2
1
0
Year before the start of symptoms
Percentage of positive patients
27.8%
40.5%
49.4%
Fig. 19.5.3  Development of rheumatoid factor (RhF) and ACPA can
precede the clinical onset of rheumatoid arthritis by many years.
Reprinted from Arthritis & Rheumatism, volume 50, Nielen et al, pages 380–​386.
Copyright 2004 by the American College of Rheumatology, with permission
from Wiley.
19.5  Rheumatoid arthritis
4419
(EULAR), whereby genetic and environmental risk factors com-
bine to trigger a state of immune dysregulation termed ‘systemic
autoimmunity associated with rheumatoid arthritis’. After several
years, and possibly additional triggers, a threshold is crossed after
which the individual manifests symptoms and signs of rheumatoid
arthritis. This may initially be symptoms without clinical arthritis,
subsequently developing into unclassified arthritis and finally
fulfilment of rheumatoid arthritis clinical classification criteria
(Fig. 19.5.4). In this model distinct genetic and environmental
factors, potentially influencing different immunopathological
pathways, culminate in a final common clinical presentation of
rheumatoid arthritis.
The study of pre-​rheumatoid arthritis is also revealing other rele-
vant insights. For example, there is a high incidence of subclinical
lung disease of varying types in these individuals. Combined with
emerging microbiome data, and periodontitis as a risk factor, this
highlights the likely importance of the mucosae as sites of tolerance
breach in rheumatoid arthritis. Importantly this model is based
largely upon studies of ACPA+ RA. Seronegative rheumatoid arth-
ritis has a distinct and less well defined genetic and environmental
predisposition, suggesting these to be different diseases with a
common phenotype.
Epidemiology
Rheumatoid arthritis has a global prevalence of approximately 1 in
400 and is around 2.5 times more common in women than men. The
reported incidence varies widely between studies, and lies approxi-
mately between 20 and 50 per 100 000 per year in North America
and Northern Europe and increases with advancing age. There is
geographical variation in rheumatoid arthritis prevalence and in-
cidence rates, although there is a paucity of data from developing
countries. Rheumatoid arthritis is a significant cause of disability,
mortality, and work-​related absence, all of which contribute to the
high economic impact of the disease.
Prevalence
The most recent and comprehensive rheumatoid arthritis preva-
lence data come from the 2010 Global Burden of Disease study,
which found a global prevalence of 0.35% in females and 0.13% in
males. Considerable geographic variation was found (Table 19.5.2),
with notably lower prevalence in African regions. However, a lack
of epidemiological data from developing countries, combined with
underdiagnosis due to limited healthcare resources, is likely to have
contributed to an underestimated prevalence in these regions. In
contrast, several studies in developed Western countries estimate a
prevalence of rheumatoid arthritis between 0.5 and 1% of the adult
population. Several studies have also explored ethnic differences in
rheumatoid arthritis prevalence; for example, a very high preva-
lence (5.3%) has been reported for the Pima and Papago Indians of
Arizona, whereas lower rates have been observed in rural Chinese,
Japanese, and African populations. These observed differences likely
reflect a combination of both genetic and environmental risk factors.
Incidence
Of the few studies which have explored the incidence of rheumatoid
arthritis, most have been conducted in retrospective cohorts in the
United States and Europe. These studies suggest an annual incidence
of between 20 and 50 per 100 000 adults—​the wide range in part re-
flecting methodological variation (Table 19.5.3).
Although the prevalence of rheumatoid arthritis has remained
relatively stable, there is some evidence from longitudinal cohort
studies for a decline in incidence over the past few decades. For ex-
ample, an inception cohort study based in Rochester (USA) demon-
strated a halving of annual incidence in women from 83 per 100 000
in in 1955–​1964 to 40 per 100 000 in 1985–​1994. Several theories
have been proposed to explain this observation, including a poten-
tial protective effect of the oral contraceptive pill.
Gender and age
In keeping with most autoimmune diseases, rheumatoid arthritis is
more common in women with a female:male ratio of around 2.5:1.
Although this finding is consistent in all populations, the underlying
mechanisms remain unclear and could reflect hormonal factors
and/​or neoantigen exposure during pregnancy and breastfeeding.
The onset of inflammatory arthritis in a child under the age of
16 years is, by definition, diagnosed as juvenile idiopathic arthritis.
Notwithstanding this semantic limitation, the onset of rheumatoid
arthritis can occur at any age, leading to an increasing prevalence
with advancing age (Fig. 19.5.5). The peak age of onset is around
the sixth decade for women and seventh decade for men. There is
Genotype
HLADRB1
PTPN22
CTLA4
STAT4
TRAF1–C5
PADI4
FCRL3
OLIG3–AIP3
TNF–AIP3
Tolerance
breakdown
Biomarkers:
ACPA and
rheumatoid factor
Subclinical inflammation
Biomarkers: ↑CRP,
circulating cytokines and
chemokines
Additional
environmental factors:
Infection?
Trauma?
Stress?
Inevitable
progression?
≤ 5 years
May take up to 15 years
Mediterranean diet
Anti–oxidants
Alcohol?
Oestrogens?
Synovitis in single or
multiple joints
Biomarkers: subclinical
synovitis in other joints
(arthroscopy and imaging)
Smoking
Caffeine?
Obesity?
Fig. 19.5.4  Proposed model of rheumatoid arthritis aetiology. Individuals who are genetically predisposed towards developing rheumatoid arthritis
encounter environmental insults which result in a loss of self-​tolerance. The ensuing immune dysregulation leads to the production of autoantibodies
and chronic subclinical inflammation which, after several years and in combination with possible further environmental insults, leads to the evolution
of clinical disease.
Reprinted by permission from Macmillan Publishers Ltd: Nature Reviews Immunology, volume 10, Isaacs JD, The changing face of rheumatoid arthritis: sustained remission
for all?, copyright 2010.
section 19  Rheumatological disorders
4420
Table 19.5.2  Global prevalence and DALYs for rheumatoid arthritis in the age range 5–​100 years, by region and sex, GBD 2010 study
Age (standardized)
All ages (thousands)
Prevalence
LCL
UCL
Region
Sex
%
%
%
DALYs
LCL
UCL
Global
Male
0.13
0.12
0.13
1201
927
1538
Female
0.35
0.34
0.37
3618
2721
4602
Asia, central
Male
0.16
0.12
0.21
17
12
23
Female
0.39
0.30
0.53
47
32
65
Asia, east
Male
0.08
0.08
0.09
222
167
297
Female
0.24
0.22
0.27
601
446
779
Asia Pacific, high income
Male
0.22
0.18
0.26
62
45
84
Female
0.57
0.48
0.69
229
162
307
Asia, south
Male
0.08
0.07
0.09
212
130
291
Female
0.26
0.24
0.29
445
317
583
Asia, southeast
Male
0.08
0.07
0.09
68
51
87
Female
0.23
0.21
0.26
186
136
242
Australasia
Male
0.26
0.15
0.46
9
5
16
Female
0.66
0.37
1.11
31
18
53
Caribbean
Male
0.15
0.12
0.18
7
5
9
Female
0.39
0.32
0.49
24
17
33
Europe, central
Male
0.15
0.11
0.19
24
16
33
Female
0.41
0.31
0.52
95
63
133
Europe, eastern
Male
0.14
0.08
0.22
43
28
64
Female
0.38
0.24
0.57
177
113
265
Europe, western
Male
0.24
0.21
0.28
148
107
197
Female
0.63
0.55
0.75
548
382
734
Latin America., Andean
Male
0.15
0.10
0.22
8
5
12
Female
0.39
0.25
0.59
27
18
42
Latin America, central
Male
0.14
0.12
0.17
38
28
52
Female
0.40
0.34
0.49
138
101
180
Latin America, southern
Male
0.20
0.13
0.30
14
9
21
Female
0.51
0.33
0.78
51
31
83
Latin America, tropical
Male
0.14
0.13
0.15
27
20
36
Female
0.38
0.35
0.41
105
76
135
North Africa Middle East
Male
0.09
0.08
0.11
42
30
55
Female
0.24
0.20
0.28
121
86
163
North America, high income
Male
0.24
0.22
0.27
107
78
141
Female
0.63
0.58
0.70
388
285
503
Oceania
Male
0.09
0.05
0.14
0.9
0.6
1
Female
0.25
0.15
0.41
2
1
4
Sub-​Saharan Africa, central
Male
0.12
0.07
0.18
12
6
22
Female
0.30
0.19
0.47
30
17
50
Sub-​ Saharan Africa, east
Male
0.11
0.08
0.14
92
46
209
Female
0.29
0.23
0.37
232
152
433
Sub-​Saharan Africa, south
Male
0.10
0.09
0.12
9
7
12
Female
0.30
0.26
0.34
28
21
36
Sub-​Saharan Africa., west
Male
0.10
0.09
0.12
38
24
67
Female
0.28
0.25
0.32
112
81
164
DALYs, disabilitv adjusted life years; GBD, Global Burden of Disease; LCL, lower confidence limit; UCL, upper confidence limit.
Data from the 2010 Global Burden of Disease study, reproduced from: Annals of the Rheumatic Diseases, Cross et al, volume 73, pages 1316–​22, copyright 2014 with permission from
BMJ Publishing Group Ltd.
4421
Prevalence
0.030
0.025
0.020
0.015
0.010
0.005
0.000
0
20
40
60
80
100
Posterior rheumatoid arthritis prevalence female 2010
Age
Posterior rheumatoid arthritis prevalence male 2010
Prevalence
0.030
0.025
0.020
0.015
0.010
0.005
0.0000
20
40
60
80
100
Age
Sub-Saharan Africa, West
Sub-Saharan Africa, Southern
Sub-Saharan Africa, East
Sub-Saharan Africa, Central
North America, High Income
North Africa/Middle East
Oceania
Asia, East
Asia, Central
Asia Pacific, High income
Australasia
Asia, South
Caribbean
Asia, Southeast
Europe, Western
Europe, Eastern
Europe, Central
Latin America, Southern
Latin America, Tropical
Latin America, Central
Latin America, Andean
Fig. 19.5.5  Worldwide prevalence of rheumatoid arthritis according to age.
Reproduced from: Annals of the Rheumatic Diseases, Cross et al, volume 73, pages 1316–​1322, copyright 2014 with permission from
BMJ Publishing Group Ltd.
Table 19.5.3  Estimates of annual incidence of rheumatoid arthritis by several studies
Publication
Country
Type of study
Incidence (cases/​103 inhabitants)
Population Age
(years) 
Total
Male
Female
Doran 2002
USA
Retrospective
0.5
0.3
0.6
≥​18
Savolainen 2003
Finland
Prospective
0.4a
0.3
0.5
≥​16
Chan 1993
USA
Retrospective
0.3
0.2
0.5
≥​18
Kaipiainen-​Seppanen 2000
Finland
Retrospective
0.3a
0.2
0.4
≥16
Riise 2000
Norway
Retrospective
0.3a
0.2
0.4
≥​20
Uhlig 1998
Norway
Retrospective
0.3
0.1
0.4
20–​79
Kaipiainen-​Seppanen 2001
Finland
Retrospective
0.3
0.2
0.4
≥​16
Drosos 1997
Greece
Retrospective
0.2
0.1
0.4
≥16
Symmons 1994
England
Prospective
0.2
0.1
0.3
≥16
Soderlin 2002
Sweden
Prospective
0.2
0.2
0.3
≥​16
Guillemin 1994
France
Retrospective
0.1
0.1
0.1
20–​70
a Crude rates.
Reprinted from Seminars in Arthritis and Rheumatism, volume 36, Alamanos et al, Incidence and prevalence of rheumatoid arthritis, based on the 1987 American College of
Rheumatology criteria: a systematic review, pages 182–​188. Copyright (2006), with permission from Elsevier.
section 19  Rheumatological disorders
4422
some evidence to suggest a modern trend towards an advancing age
of onset.
Disability
The capacity for rheumatoid arthritis to erode joints, alongside sys-
temic features such as fatigue, makes rheumatoid arthritis an im-
portant cause of disability. In the 2010 Global Burden of Disease
study, rheumatoid arthritis was the forty-​second highest cause of
disability of 291 conditions (falling between malaria and iodine de-
ficiency) and was the cause of an estimated 3.7 million years lived
with disability worldwide in 2010. Recent decades have witnessed a
steady fall in the rates of joint damage, orthopaedic interventions,
and long-​term disability, consistent with improved treatment
strategies implemented earlier in the disease course. Nevertheless,
there remains an inverse relationship between average rheumatoid
arthritis disease activity and national gross domestic product, sug-
gesting the highest burden of disease among those patients with
rheumatoid arthritis living in poorer countries (Fig. 19.5.6).
Mortality
Numerous studies have found a substantial increase in standard-
ized mortality rates of around 1.2-​ to 3-​fold in rheumatoid arth-
ritis patients. Whereas mortality within the general population of
developed countries has fallen sharply over the past six decades,
the mortality of rheumatoid arthritis patients has only modestly
reduced, leading to a further widening of this ‘mortality gap’
(Fig. 19.5.7). Life expectancy is reduced in severe rheumatoid
arthritis by between 6 and 10 years although there is evidence to
suggest a modest improvement over the past decade, consistent
with reductions in joint damage and disability.
The commonest causes of death in patients with rheumatoid
arthritis reflect those in the general population, namely cardiovas-
cular disease (especially myocardial infarction and heart failure),
pulmonary disease (especially chronic obstructive pulmonary
disease), infection, and cancer. The first three of these occur at a
greater frequency in patients with rheumatoid arthritis, often with
unusual presentations or greater severity. For example, patients
with rheumatoid arthritis are more likely to suffer a sudden cardiac
death or silent myocardial infarction compared with the general
population. Overall cancer rates are similar between rheumatoid
arthritis patients and the general population, but this statistic masks
important differences. The risk of lymphoma, particularly non-​
Hodgkin B-​cell subtypes, is significantly increased in patients with
rheumatoid arthritis. Lung cancer is also around twice as common,
potentially explained by the presence of smoking as a rheumatoid
arthritis risk factor. In contrast the incidence of colorectal cancer is
modestly reduced in patients with rheumatoid arthritis, which has
7.0
Ko
Se
Li
La Hu
Es
It Ge
UKSw
USA
De
Ir
Ne
Fi
Fr
Sp
Gr
Po
6.5
6.0
5.5
5.0
4.5
4.0
3.5
3.0
2.5
2.0
0
5
10
15
20
25
30
GDP per capita, 1000€
DAS28
35
40
45
50
55
Fig. 19.5.6  Association between gross domestic product per capita
(GDP) and disease activity score in 28 joints (DAS28) in 18 European
countries and the United States in the QUEST–​RA study. The correlation
of GDP with DAS28 is r = 20.85 (95% CI 20.63–​20.94); indicated with
colour. The area of the disc is proportional to the total national health
expenditure of each country in 2004. De, Denmark; Es, Estonia; Fi,
Finland; Fr, France; Ge, Germany; Gr, Greece; Hu, Hungary; Ir, Ireland;
It, Italy; Ko, Kosovo; La, Latvia; Li, Lithuania; Ne, The Netherlands; Po,
Poland; Se, Serbia; Sp, Spain; Sw, Sweden.
Reproduced from Annals of the Rheumatic Diseases, Sokka et al, volume 68, pages
1666–​1672, copyright 2009 with permission from BMJ Publishing Group Ltd.
5
4
3
2
1
0
1970
1980
Calendar year
1990
2000
Mortality rate (per 100 py)
1970
1980
Calendar year
1990
2000
5
4
3
2
1
0
Mortality rate (per 100 py)
Fig. 19.5.7  The mortality gap in rheumatoid arthritis. Observed mortality
rates (solid line) in female patients with rheumatoid arthritis (top) and
male patients with rheumatoid arthritis (bottom) and expected mortality
rates (broken line) from the Minnesota white population, over the last
4–​5 decades. Shaded areas indicate the 95% confidence limits for the
observed mortality. Values are expressed per 100 person-​years (py).
Reprinted from Arthritis & Rheumatism, volume 56, Gonzalez et al, pages 3583–358​7.
Copyright 2007 by the American College of Rheumatology, with permission
from Wiley.
19.5  Rheumatoid arthritis
4423
been attributed to the use of NSAIDs. Prostatic and female genital
cancer may also be lower in rheumatoid arthritis, potentially for
similar reasons.
Economic impact
Rheumatoid arthritis poses substantial direct costs to healthcare sys-
tems in terms of investigation, drug treatment, safety monitoring,
and both outpatient and inpatient episodes. However, rheumatoid
arthritis also carries very significant indirect costs including lost and
reduced productivity due to sick leave and disability, welfare support,
and the cost of providing social care. Poorly controlled rheumatoid
arthritis substantially reduces quality of life, and also has a profound
effect upon the lives of family members, friends, and carers.
The economic impact of rheumatoid arthritis is therefore consid-
erably greater than the direct healthcare costs alone. For example,
in 2009 the United Kingdom National Audit Office estimated that
the national direct healthcare cost of rheumatoid arthritis was
£560 million; in the same year, the National Institute for Health
and Care Excellence (NICE) estimated that the combined direct
and indirect costs of rheumatoid arthritis were between £3.8 and
£4.75 billion. Nevertheless, the wider economic impact of rheuma-
toid arthritis varies between countries dependent on different
healthcare and social factors (Fig. 19.5.8). Thus evaluations of the
cost-​effectiveness of treatment strategies must take into account
both direct and indirect costs specific to the healthcare system in
which they will be delivered.
Pathogenesis
The complex immune dysregulation present in the years before
onset of symptoms makes it difficult to disentangle the order and
relative importance of pathogenic events in the development of
rheumatoid arthritis. Most immune cells have been implicated in
rheumatoid arthritis pathogenesis, ranging from T and B lympho-
cytes of the adaptive immune system through to macrophages
and dendritic cells of the innate immune system. Furthermore,
resident cells within the joint including macrophages (type
A synoviocytes), fibroblasts (type B synoviocytes), and osteoclasts
each play important roles in articular damage and perpetuation
of inflammation. Although some aspects of rheumatoid arthritis
pathogenesis are relatively well understood, less is known about
seronegative disease and less still about extra-​articular inflam-
mation. Indeed, it is becoming clear that rheumatoid arthritis is
a heterogeneous condition, with various pathological pathways
that may vary both between individuals as well as over time in the
same patient.
The rheumatoid joint
The defining macroscopic feature of active rheumatoid arthritis
within the joint is the pannus—​a potent mix of inflammatory
cells, fibroblasts, and granulation tissue that destructively spreads
throughout and beyond the joint. Macroscopically, the normally
thin and translucent synovial membrane becomes extensively thick-
ened and hypervascular, with undulating villous folds protruding
into the joint space (Fig. 19.5.9). Accompanying this is an increased
production of synovial fluid, leading to the characteristic joint ef-
fusion observed clinically. Beneath the pannus, destruction of car-
tilage and subchondral bone leads to radiological joint erosions, and
invasion of pannus into surrounding structures causes tendon and
ligament weakening and rupture. Synovium lining tendon sheaths
can undergo similar changes.
Microscopically within the pannus, there is hyperplasia of type
B synoviocytes mixed with an inflammatory infiltrate that includes
USA
25 000
20 000
15 000
10 000
5000
0
Annual cost in (€)
France
Germany
Italy
Spain
UK
3842
3422
7425
2974
4431
7224
4450
3031
1931
1138
1989
2506
806
352
4900
4130
6114
2166
2230
1160
6041
3463
6476
702
6417
11 424
5127
1484
4411
2029
Indirect costs
Informal care
Nonmedical costs
Other medical costs
Drug costs
Fig. 19.5.8  Annual per-patient direct and indirect costs of rheumatoid arthritis to the
economies of five European countries and the United States.
Reproduced from Furneri et al (2012). Clinical and Experimental Rheumatology; 30 (Suppl 73): S72–​S84.
section 19  Rheumatological disorders
4424
macrophages, B and T lymphocytes, plasma cells, and dendritic
cells. In contrast, the synovial fluid contains an abundance of neu-
trophils. Sometimes the infiltrate is organized into lymphoid fol-
licles, akin to those found in lymph nodes—​so-​called ectopic or
tertiary lymphoid follicles. The extracellular matrix of articular car-
tilage is digested by secreted lysosomal acid and enzymes such as
the matrix metalloproteinases, with chondrocyte apoptosis and loss
of cartilage architecture progressing to wholescale cartilage break-
down. At the ‘leading edge’ of pannus, activation of osteoclasts
results in peri-​articular thinning of osteoid matrix and increased
resorption of subchondral bone, with the development of ‘erosions’
visible on X-​rays.
The diverse mixture of cells within the pannus contributes to
its potent destructive power. Although the precise order of events
is difficult to identify, the key factors underpinning rheumatoid
arthritis pathogenesis can be pragmatically divided into those of
the adaptive and innate immune systems, and of the joint stroma.
Adaptive immunity and rheumatoid
arthritis pathogenesis
CD4+ T lymphocytes
Central to the pathogenesis of rheumatoid arthritis is the CD4+ T
lymphocyte. These cells initiate and orchestrate adaptive immune
responses via recognition of (auto)antigen on the surface of APCs.
The importance of CD4+ T cells in rheumatoid arthritis patho-
genesis is underscored by the strong association between rheuma-
toid arthritis and the shared epitope, and by the high number of
rheumatoid arthritis-​associated SNPs within genes important for
CD4+ T-​cell function. Furthermore, many of these overlap with
regions of epigenetic modification in CD4+ T cells, implying gene
activation.
CD4+ T cells release cytokines which determine the nature of
the ensuing immune response. IL-​17, produced by Th17 T cells, is
a potent pro-​inflammatory cytokine which can activate endothelial
cells to enhance leucocyte recruitment, as well as activating syn-
ovial fibroblasts and osteoclasts. Th17 cells are thought to play an
important role in rheumatoid arthritis pathogenesis, counterbal-
anced by regulatory T cells (Tregs). There are several types of regu-
latory T cell which develop either in the thymus or, in the presence
of anti-​inflammatory cytokines such as IL-​10 and transforming
growth factor β (TGF​β), in non​inflamed peripheral tissues and the
gut. Tregs suppress immune responses and play an important role
in the maintenance of self-​tolerance. The balance of Tregs and pro-​
inflammatory T cell subsets is disrupted in several autoimmune dis-
eases; in rheumatoid arthritis, there is evidence for both qualitative
and quantitative Treg defects.
CD4+ T cells also play a crucial role in the activation and mat-
uration of B cells. So-​called T follicular helper (TFH) cells are
characterized by their expression of high levels of CXCR5 and
production of IL-​21. They are found in lymphoid follicles, and in
synovial tissue and peripheral blood of rheumatoid arthritis pa-
tients. T follicular regulatory (TFR) cells have also been recently
characterized and may be important in the maintenance of per-
ipheral tolerance.
B lymphocytes and plasma cells
The presence of autoantibodies in the serum of many rheumatoid
arthritis patients suggests a role for B lymphocytes and plasma
cells in rheumatoid arthritis pathogenesis. Indeed, the presence of
rheumatoid factor (RhF) and ACPA many years prior to the symp-
tomatic onset of rheumatoid arthritis suggests a possible role for
these cells at an early disease stage. Furthermore, depletion of B
cells has therapeutic efficacy in established rheumatoid arthritis,
suggesting the continued importance of this cell type in driving
the autoinflammatory process. However, up to 30% of rheumatoid
arthritis patients are seronegative and a pathogenic role for auto-
antibodies has not been conclusively demonstrated. In addition to
autoantibody production, B cells are potent APCs and, like T cells,
secrete cytokines to drive and polarize the immune response. Recent
(a)
(b)
Fig. 19.5.9  Macroscopic appearance of normal (a) and inflamed
(b) synovium. Normal synovium is translucent, revealing underlying
blood vessels; the inflamed synovium shows villus formation, increased
vascularity, and fibrin deposition.
Images courtesy of Dr. R Reece and Dr. J. Canete. Reproduced with permission from
Isaacs JD, Moreland LW. Fast Facts: Rheumatoid Arthritis, 2nd edn. Oxford: Health
Press Limited, 2011, fastfacts.com.
19.5  Rheumatoid arthritis
4425
interest has focused on regulatory B cells which, analogous to Tregs,
have immunoregulatory functions.
Innate immunity and rheumatoid arthritis pathogenesis
Macrophages
Macrophages are cells of the innate immune system and are acti-
vated through pathogen-​ and damage-​associated molecular patterns
(PAMPs and DAMPs) via intracellular and cell-​surface receptors
such as the Toll-​like receptor (TLR) family. Macrophages can release
large amounts of lysosomal enzymes, pro-​inflammatory cytokines,
and vasoactive compounds. Furthermore, they efficiently present
antigen to CD4+ T cells, which in turn provide reciprocal stimula-
tion to macrophages through direct cell contact and cytokines such
as IL-​1, IL-​15, and TNF​α. Macrophages are one of the first cells to
enter a rheumatoid joint and their number provides a good correlate
of rheumatoid arthritis disease activity, presumably in part via secre-
tion of TNF​α and IL-​6.
Although macrophages are thought to play a key role in rheuma-
toid arthritis pathogenesis, other innate immune cells are also
present in the pannus. These include mast cells, which release vaso-
active compounds that further enhance inflammatory cell recruit-
ment, and natural killer cells.
Dendritic cells
Dendritic cells (DCs) are often described as the sentinels of the
immune system. They circulate through peripheral tissues and
sample (auto)antigens while receiving environmental cues before
entering lymph nodes, where they initiate either an activating or
tolerogenic immune response. Furthermore the cytokines they
secrete, such as IL-​12 (pro-​TH1) and IL-​23 (pro-​TH17), further
polarize the ensuing immune response. Thus DCs have the po-
tential to play a critical role in rheumatoid arthritis pathogenesis.
They are present in synovial fluid and synovium of rheumatoid
arthritis patients, and DCs isolated from rheumatoid arthritis
joints activate CD4+ T cells in vitro. Costimulation blockade acts
by inhibiting the interaction between APCs and T cells, and pro-
vides an effective biological treatment approach for rheumatoid
arthritis.
Cytokines
Numerous cytokines are produced by innate and adaptive immune
cells within the rheumatoid arthritis synovium. Pro-​inflammatory
cytokines activate effector cells such as macrophages and osteoclasts,
as well as upregulating vascular adhesion molecule expression. In
concert with chemokines, which are essentially chemo-​attractive
cytokines, this increases cellular traffic into the joint. Cytokines
also have important systemic effects such as induction of fatigue,
upregulation of the acute-​phase response and the anaemia of
chronic disease. In health, pro-​inflammatory cytokines are held in
check by anti-​inflammatory cytokines such as IL-​10, as well as by
soluble cytokine receptors and molecules such as the IL-​1 receptor
antagonist.
Several pro-​inflammatory cytokines including TNFα, IL-​1, IL-​6,
and IL-​17 have been therapeutically targeted by biological drugs in
rheumatoid arthritis. While both TNFα and IL-​6 blockade are highly
efficacious, IL-​1 blockade is less so. Similarly, despite the apparent
importance of IL-​17 in rheumatoid arthritis pathogenesis, blockade
of this cytokine provides relatively modest benefits. Within one in-
dividual it is possible to observe a dramatic response to the blockade
of one cytokine pathway, whereas blockade of another is ineffective.
Furthermore the benefits of cytokine blockade often wane over time,
highlighting both redundancy and plasticity within the pathogenic
cytokine pathways in rheumatoid arthritis.
Joint stromal cells in rheumatoid arthritis pathogenesis
Synoviocytes
In rheumatoid arthritis pannus type B synoviocytes, also known
as fibroblast-​like synoviocytes (FLS), lose their normal physio-
logical characteristics and produce pro-​inflammatory cytokines
and chemokines, as well as large amounts of destructive enzymes.
Furthermore, increased cell turnover and a resistance to apop-
tosis confer quasi-​malignant properties upon RA FLS, which dir-
ectly invade and destroy adjacent joint tissues. They upregulate
oncogenes, and experimental grafting of rheumatoid arthritis
pannus into immune-​deficient mice has demonstrated their
ability to migrate via the vasculature, potentially ‘spreading’
synovitis from joint to joint, although whether this occurs in
rheumatoid arthritis is unknown. While the events that lead to
this transformation of FLS phenotype remain unclear, epigenetic
modification likely plays an important role. Thus FLS maintain
their pro-​inflammatory phenotype ex vivo even after several cell
cycles, supported by altered DNA methylation and microRNA
regulatory networks. Such observations suggest that FLS help to
perpetuate a state of chronic synovitis and represent an important
therapeutic target.
Osteoclasts
Osteoclast activation is increased in the inflamed rheumatoid
arthritis joint, secondary to up-​regulated RANK-​L expression by
osteoblasts, FLS, and some inflammatory cells such as Th17 cells.
Osteoclast differentiation from haematopoietic progenitors is also
driven directly by cytokines such as TNF​α. Increased osteoclast
activity leads to peri-​articular osteoporosis and bone resorption at
the osteochondral junction. Impaired osteocyte function may also
contribute to bone destruction.
Pathogenesis of extra-​articular manifestations
of rheumatoid arthritis
Rheumatoid arthritis is a systemic autoimmune disorder and sub-
stantial levels of inflammation occur outside of the joints. This
causes organ damage and the multiple extra-​articular manifest-
ations discussed in the next section. One of the most characteristic
features of extra-​articular rheumatoid arthritis is the rheumatoid
nodule, which usually occurs under the skin overlying bony prom-
inences, or in viscera such as the lungs and heart. At the centre of
a rheumatoid nodule is a focus of fibrinoid necrosis, which is sur-
rounded by macrophages.
Generalized and profound fatigue is a very common and dis­
abling symptom of rheumatoid arthritis. In addition to psycho-
logical and social contributing factors, biological mechanisms also
contribute. Activation of the HPA axis is a physiological adaptation
to acute stresses such as infection or physical injury. In rheuma-
toid arthritis, however, chronic inflammation and sustained high
levels of circulating inflammatory cytokines can cause dysfunction
section 19  Rheumatological disorders
4426
of both the HPA and hypothalamo-​pituitary-​gonadal (HPG) axes,
which may in turn contribute to development of chronic fatigue and
mood disorders. Circulating cytokines such as TNFα and IL-​6 also
undoubtedly contribute, but in some patients fatigue persists even
when their joint disease is in remission.
Clinical features
Rheumatoid arthritis typically presents insidiously, although less
common variants include acute, palindromic, polymyalgic, and
systemic onsets. The principal feature of rheumatoid arthritis is
an inflammatory arthritis which can affect any synovial joint, but
typically involves the small joints of the hands, wrists, and feet in
a symmetrical pattern. Patients describe episodic pain, stiffness,
and swelling in affected joints, with joint stiffness usually worse in
the mornings and after resting. There are also many extra-​articular
manifestations, which tend to be more common in patients with
seropositive disease.
Onset
In most cases rheumatoid arthritis presents as a slowly progres-
sive symmetrical arthritis affecting the small joints of the hands
and feet. The insidious onset often results in delayed presenta-
tion to a family doctor or rheumatologist. In contrast, in some
patients the onset can be dramatic over just a few days, although
this is less common. A smaller number of patients experience
arthritis limited to just a few joints, which can be asymmetrical
and transient, moving from joint to joint in a pattern termed
‘palindromic rheumatism’. Patients with palindromic rheuma-
tism are often asymptomatic between bouts of arthritis, although
with time can progress to a more classical rheumatoid arthritis
phenotype. Around 10% of patients present with a polymyalgic
onset of rheumatoid arthritis, where the onset of arthritis is ac-
companied or even preceded by proximal myalgia, stiffness,
and fatigue. Polymyalgic rheumatoid arthritis is rarely ob-
served in patients under the age of 60 years. Finally, rheumatoid
arthritis can occasionally present as a systemic illness with extra-​
articular features dominating. Such systemic presentations are
fortunately rare and warrant careful exclusion of alternative
diagnoses such as adult-​onset Still’s disease, other autoimmune
connective tissue diseases such as systemic lupus erythematosus,
and malignancy.
Articular features
Pattern of arthritis
Rheumatoid arthritis can affect any synovial joint, although most
frequently starts in the small joints of the hands and feet. The
metacarpophalangeal (MCP), proximal interphalangeal (PIP),
metatarsophalangeal (MTP) and wrist joints are commonly affected,
whereas distal interphalangeal joint arthritis is not characteristic and
should raise the suspicion of psoriatic arthritis or osteoarthritis. The
elbows, knees, ankles, and shoulders are also commonly involved,
whereas the temporomandibular and sternoclavicular joints are less
commonly affected. Whereas cervical spine involvement is relatively
common, thoracolumbar spine and hip joint inflammation is rare in
rheumatoid arthritis and their presence should prompt a consider-
ation of alternative diagnoses.
Symptoms of arthritis
Patients with rheumatoid arthritis typically describe a deep
‘toothache-​like’ pain in affected joints, which is accompanied by
a disabling stiffness that is worse in the mornings and after rest.
The duration of early morning stiffness after waking is a useful
measure of disease activity. Indeed, an important diagnostic fea-
ture of the pain and stiffness of rheumatoid arthritis is their relief
by activity and aggravation by rest, in contrast to osteoarthritis.
The activity of rheumatoid arthritis tends to wax and wane, with
flares of arthritis that develop over days but which can take weeks
to subside. Such flares are often unpredictable but can be triggered
by emotional distress and physiological insults such as infection
or surgery.
Physical signs of arthritis
The visible extent of arthritis depends both upon the duration of
disease and its severity. In most patients with early rheumatoid
arthritis, the only signs on examination are mild joint swelling and
tenderness on palpation. A slight erythema may be present in the
skin overlying the joint. Joint swelling in rheumatoid arthritis re-
sults from a combination of synovial thickening and synovial effu-
sion, and is typically described as ‘boggy’ to palpation in contrast to
the hard bony swelling of nodal osteoarthritis or the fluctuance of
a large effusion. Lateral squeeze pressure applied gently across the
MCP and MTP joints is a useful and sensitive screening technique
for synovitis in these commonly affected joints.
Only when synovitis has persisted for several months or longer
do the hallmark joint deformities of rheumatoid arthritis start
to develop. Typical deformities develop in the hands and feet
secondary to joint and tendon subluxation and dislocation
(Fig. 19.5.10 and Table 19.5.4). Tendon sheaths can also become
inflamed (tenosynovitis) leading to painful triggering and locking
of digits and, ultimately, tendon rupture. Destruction of articular
cartilage and erosion of subchondral bone also leads to physical
deformity and reduced range of movement at affected joints. The
prevention of bone and cartilage damage, and consequent de-
formities, is a key aim of modern rheumatoid arthritis treatment
strategies.
Extra-​articular features
Rheumatoid arthritis is associated with various extra-​articular
manifestations (Table 19.5.5), some common and others rare,
but all contributing to the burden of morbidity. Extra-​articular
features often cluster, such that a patient with one extra-​articular
manifestation is more likely to develop others. Several of the com-
monest extra-​articular features contribute to the excess mortality
of rheumatoid arthritis. The incidence of extra-​articular features is
greater in seropositive rheumatoid arthritis, as is joint destruction,
thus making autoantibodies useful as both diagnostic and prog-
nostic biomarkers.
Cardiovascular
Vasculitis occurs in around 3% of rheumatoid arthritis patients, an
incidence that appears to be falling. Rheumatoid arthritis vasculitis
19.5  Rheumatoid arthritis
4427
is more common in men and is strongly associated with smoking,
the presence of rheumatoid nodules and the presence of high titres
of RhF. It typically affects small-​ and medium-​sized vessels, and
usually presents as vasculitic infarcts in the distal extremities, es-
pecially in the nail folds. In more severe cases necrotic ulcers can
develop, usually on the lower legs, which are persistent and slow to
(a)
(b)
(c)
Fig. 19.5.10  Characteristic appearance of the hands and feet in long-
standing rheumatoid arthritis. (a, b) The hands demonstrate: swelling,
subluxation, and ulnar deviation at the metacarpophalangeal joints; flexion
deformities of the fingers and Z deformity of the thumb on the right; and
early swan neck deformities on the left. Multiple rheumatoid nodules are
also evident, as is (teno)synovitis at the right wrist. (c) The feet demonstrate
swelling and valgus deformities at the ankles, flattening of the longitudinal
arches with pes planus, and early clawing of the toes.
Reproduced with permission from Isaacs JD, Moreland LW. Fast Facts: Rheumatoid
Arthritis, 2nd edn. Oxford: Health Press Limited, 2011, fastfacts.com.
Table 19.5.4  Characteristic hand and wrist deformities
in rheumatoid arthritis
Region
Physical sign
Fingers
Boutonnière deformity (fixed flexion of PIPJ and hyperextension
of DIPJ)
Swan neck deformity (fixed hyperextension of PIPJ and flexion
of DIPJ)
Ulnar deviation
MCPJ palmar subluxation
Thumb
Z-​thumb deformity (fixed flexion of the first MCPJ and
hyperextension of the IPJ)
Palm
Wastage of intrinsic hand musculature (esp. thenar eminence
from median nerve compression in the carpal tunnel)
Palpable flexor tendon thickening and finger triggering
Wrist
Radial deviation
Prominent ulnar styloid process
DIPJ, distal interphalangeal joint; IPJ, interphalangeal joint; MCPJ, metacarpophalangeal
joint; PIPJ, proximal interphalangeal joint.
Table 19.5.5  The extra-​articular features of rheumatoid arthritis
Organ system
Extra-​articular manifestation
Cardiac
Pericarditis
Heart block
Circulatory
Vasculitis
Pulmonary
Inflammatory interstitial lung disease
Pulmonary fibrosis
Pulmonary nodules
Pleural effusion
Caplan’s syndrome
Neurological
Compression neuropathy (e.g. carpal tunnel
syndrome)
Cervical myelopathy (secondary to atlanto-​axial
subluxation or subaxial subluxation)
Peripheral neuropathy
Ocular
Keratoconjunctivitis sicca
Scleritis
Scleromalacia perforans
Episcleritis
Peripheral ulcerative keratitis
Corneal melt
Haematological
Anaemia
Thrombocytosis
Felty’s syndrome
Lymphoma
Dermatological
Rheumatoid nodules
Rheumatoid neutrophilic dermatosis
Cutaneous vasculitis and vasculitic ulcer
Pyoderma gangrenosum
Constitutional
Fatigue
Anorexia
Weight loss
Osteoporosis
Amyloidosis
section 19  Rheumatological disorders
4428
heal. In the worst cases, a full-​blown systemic vasculitis can occur
resembling polyarteritis nodosa, although without microaneurysm
formation.
The treatment of rheumatoid vasculitis depends on its severity,
although there is a poor evidence-​base. Mild vasculitis with per-
ipheral small infarcts often responds to optimization of traditional
immunosuppressive therapy plus low-​dose glucocorticoids,
whereas systemic vasculitis with end-​organ involvement may
require cytotoxic treatment and high-​dose glucocorticoids.
Biological drugs such as rituximab may also have a place in the
treatment of severe rheumatoid arthritis vasculitis. Rheumatoid
arthritis may also be associated with the development of pericar-
ditis and heart block (secondary to a rheumatoid nodule in the
conducting system).
Pulmonary
The pulmonary manifestations of rheumatoid arthritis have
not reduced with modern management and make an important
contribution to excess mortality. Subclinical abnormalities can
be demonstrated by appropriate imaging in more than 50%
of patients in some studies. Interstitial lung disease can be an
extra-​articular manifestation of rheumatoid arthritis as well
as an adverse effect of medications such as methotrexate and
leflunomide (Fig. 19.5.11). A variety of patterns of interstitial
lung disease can be observed in rheumatoid arthritis, the most
common of which is usual interstitial pneumonia (UIP) followed
by nonspecific interstitial pneumonia (NSIP), although mixed
disease and other patterns also occur. Rheumatoid nodules
also occur in the lung, although these are usually asymptomatic
and of clinical importance only due to the need to exclude ma-
lignancy. A  particularly florid form of pulmonary rheumatoid
nodulosis known as Caplan’s syndrome is observed in the setting
of pneumoconiosis, especially in male coal-​miners. The inci-
dence of this complication has fallen in recent decades, possibly
due to better occupational health measures. Pleural inflamma-
tion can result in chronic pleural effusions, which are classically
exudative and often recur after drainage unless systemic disease
activity is adequately controlled.
Neurological
The most common neurological deficits in rheumatoid arthritis
are secondary to compressive neuropathies as a consequence of
synovitis and bony deformities. Particularly vulnerable to com-
pression are the median nerve as it traverses the carpal tunnel
at the wrist, and the ulnar nerve as it passes around the lateral
epicondyle of the elbow and through Guyon’s canal at the wrist.
Nerve palsies may occasionally be seen as a result of mononeuritis
multiplex in patients with rheumatoid vasculitis.
Persistent inflammation within the cervical spine can lead to in-
stability, subluxation, and spinal cord compression. While subaxial
disease is more common, instability of the atlanto-​axial joint due
to erosion or dislocation of the odontoid peg is a classical extra-​
articular manifestation of rheumatoid arthritis. If subluxation
occurs, compression of the spinal cord can ensue (Fig. 19.5.12).
Detection of cervical instability may require dynamic imaging, and
surgical fixation is essential before the onset of neurological symp-
toms. Cervical subluxation tends to be observed in patients with es-
tablished rheumatoid arthritis that has been poorly controlled and
should always be considered prior to a general anaesthetic, with
modification to intubation procedures as necessary for high risk
patients.
 Ocular
Keratoconjunctivitis sicca (dryness of the eyes) is a commonly ob-
served feature of rheumatoid arthritis and may occur as part of a
secondary Sjogren’s syndrome. Ocular inflammation in rheuma-
toid arthritis tends to manifest as episcleritis, scleritis, and periph-
eral ulcerative keratitis. Episcleritis typically presents as a painless
‘gritty’ red eye. In contrast, scleritis presents as a painful red eye
which, if left untreated, can result in thinning of the sclera and
perforation (Fig. 19.5.13). Dependent on the location of scleral
involvement, its detection may require retraction of the eyelid
and deviated gaze. Occasionally scleral necrosis develops in the
absence of pain or apparent inflammation, a condition called
scleromalacia perforans. Peripheral ulcerative keratitis is charac-
terized by ulceration around the corneal limbus, which in severe
cases results in ‘corneal melt’. Scleritis and peripheral ulcerative
keratitis are potentially sight-​threatening and warrant urgent
ophthalmological assessment and aggressive topical and systemic
immunosuppression.
Haematological
Anaemia is a common finding in established rheumatoid arthritis
and can be caused by a variety of factors (Table 19.5.6). The com-
monest is anaemia of chronic disease secondary to chronic sys-
temic inflammation, which can also drive a thrombocytosis. An
important mediator in both processes is IL-​6, which stimulates
megakaryocyte differentiation as well as stimulating hepatocytes to
release hepcidin, which leads to iron sequestration and reduced
Fig. 19.5.11  High-​resolution computed tomography (HRCT) of
interstitial lung disease in rheumatoid arthritis. A usual interstitial
pneumonia (UIP) pattern is more prevalent in rheumatoid arthritis, with
basal subpleural honeycombing on CT.
Reproduced from Watts RA et al (eds) Oxford Textbook of Rheumatology, 4th edn.
Oxford University Press, 2013. By permission of Oxford University Press.
19.5  Rheumatoid arthritis
4429
absorption. Autoimmune haemolytic anaemia also occurs in
rheumatoid arthritis, as do autoimmune thrombocytopenia
and neutropenia. Felty’s syndrome is the combination of rheuma-
toid arthritis, neutropenia and splenomegaly, and affects less
than 1% of patients. The mechanisms underlying neutro-
penia are incompletely understood, but may include both re-
duced production and immune-​mediated increased peripheral
(a)
(b)
(c)
Fig. 19.5.12  (a, b) Plain cervical spine radiographs of a patient with
rheumatoid arthritis, demonstrating anterior subluxation of the atlas (C1)
on flexion, with increased distance between the odontoid peg and anterior
arch of the atlas. (c, d) The eroded and posteriorly migrated dens is clearly
visible on sagittal and transverse CT scans. (e, f) Sagittal and transverse MRI
scans demonstrate indentation of the spinal canal by inflammatory tissue
at C1, as well as additional damage at the lower cervical levels.
Images courtesy of Dr. G. Hide. Reproduced with permission from Isaacs JD, Moreland LW.
Fast Facts: Rheumatoid Arthritis, 2nd edn. Oxford: Health Press Limited, 2011, fastfacts.com.
(d)
(e)
(f)
Fig. 19.5.12  Continued
section 19  Rheumatological disorders
4430
consumption. The neutropenia of Felty’s syndrome can reach
clinically significant levels with bacterial infection. Rheumatoid
arthritis patients are more likely to develop haematological
malignancies, particularly B-​cell non-​Hodgkin’s lymphoma and,
to a lesser extent, multiple myeloma. Chronic inflammation may
drive malignant transformation in lymphocytes, and the risk of
lymphoma is greater in those patients with more active disease
(Fig. 19.5.14).
Dermatological
There are several cutaneous manifestations of rheumatoid arth-
ritis (Table 19.5.5). The best-​known are rheumatoid nodules—​
firm and usually painless subcutaneous nodules which develop
principally over the extensor surfaces of the elbows and fingers
(Fig. 19.5.15).
Rheumatoid nodules are almost exclusively found in patients
with seropositive rheumatoid arthritis, and may occur alongside
other extra-​articular disease. They sometimes develop in the vis-
cera, notably the lung (see previous section on the pulmonary
system). Rheumatoid nodules are usually asymptomatic unless
they become infected or cause mass-​occupying effects, in which
case they can be surgically excised. A nodule in the conducting
system of the heart, however, can cause heart block. Adequate
control of systemic inflammation usually reduces nodulosis al-
though rapid acceleration has been observed upon treatment
with methotrexate. In contrast, hydroxychloroquine may reduce
nodulosis.
Rheumatoid neutrophilic dermatosis (RND) is an uncommon
condition characterized by erythematous papules, nodules,
or plaques secondary to lymphocyte and neutrophil infiltra-
tion of the dermis. RND usually occurs in patients with estab-
lished rheumatoid arthritis and principally affects the trunk and
extensor aspects of the extremities such as the forearms and
hands.
Fig. 19.5.13  Scleromalacia perforans. A 50-​year-​old woman with
severe rheumatoid arthritis has suffered from relapsing scleritis for over
20 years. She now has a very thin superior sclera with underlying choroid
bulging through.
Reproduced from Watts RA et al (eds). Oxford Textbook of Rheumatology, 4th edn.
Oxford University Press, 2013. By permission of Oxford University Press.
Table 19.5.6  Common causes of anaemia in rheumatoid arthritis.
G6PD: glucose-6-phosphate dehydrogenase
•	 Anaemia of chronic disease
•	 Iatrogenic
—	Bone marrow suppression (e.g. methotrexate)
—	Haemolysis (e.g. sulfasalazine in G6PD deficiency)
—	Peptic ulcer disease and NSAID therapy
•	 Autoimmune
—	Autoimmune haemolytic anaemia
—	Co-incidental pernicious anaemia
•	 Haematinic deficiency (iron, folate, vitamin B12)
Cases/Controls
0
5
1st
2nd
3rd
4th
5th
6th
7th
8th
9th
10th
10
15
20
OR (95% c.i.)
Cumulative disease activity decile
25
30
35
40
45
50
55
60
65
181
9/41
11/41
7/38
14/36
16/39
9/36
18/38
27/36
35/37
226/37
Fig. 19.5.14  Risk of lymphoma in relation to cumulative disease activity, assessed in 372 patients with lymphoma and rheumatoid arthritis, and
in matched cancer-free rheumatoid arthritis controls. Symbols show unadjusted odds ratios (ORs); bars show 95% confidence intervals (95% CIs).
Deciles of the area under the curve for cumulative disease activity are shown above each symbol; ORs were calculated using the first decile as the
reference. A line is included where OR 1.
Reprinted from Arthritis & Rheumatism, volume 54, Baecklund et al, pages 692–​701. Copyright 2006 by the American College of Rheumatology, with permission
from Wiley.
19.5  Rheumatoid arthritis
4431
Systemic features
As a result of chronic, systemic inflammation patients with se-
vere active rheumatoid arthritis may develop cachexia with an-
orexia, weight loss, profound fatigue, and depression. Systemic
inflammation, in addition to glucocorticoids, is also associated
with osteoporosis in rheumatoid arthritis patients. Many years
of uncontrolled systemic inflammation can provoke amyloid-
osis with renal and cardiovascular pathology although this is now
extremely rare.
Diagnosis
Rheumatoid arthritis classification criteria
Several rheumatoid arthritis classification criteria have been pro-
posed over the past few decades. Historically these placed em-
phasis upon the development of features of established rheumatoid
arthritis, such as joint erosions and rheumatoid nodules. These
therefore performed poorly in the early disease stages, precisely
when diagnosis is most important yet challenging. To address this
paradox, the 2010 American College of Rheumatology (ACR)
and EULAR classification criteria remove features of established
rheumatoid arthritis and instead focus upon the number and
nature of involved joints, serology, acute-​phase reactants and
symptom duration (Table 19.5.7). These criteria can be fulfilled
cumulatively over time and generally have greater discrimination
for early rheumatoid arthritis than previous classification systems.
Nevertheless diagnosis can still be challenging, particularly in
seronegative disease.
While rheumatoid arthritis classification criteria have been in-
valuable for standardization in research there are no pathogno-
monic features, and all classification criteria require that there must
not be a more likely alternative diagnosis for the patient’s presen-
tation. In practice therefore, rheumatoid arthritis remains firmly
a clinical diagnosis based upon history, examination, and relevant
investigations.
Differential diagnosis
The differential diagnosis of rheumatoid arthritis is broad, owing to
the many causes of arthralgia and arthritis. The onset, pattern, and
nature of joint involvement can each provide useful clues towards
the diagnosis, which may only manifest with the passage of time.
The differential diagnosis of inflammatory arthritis according to
clinical presentation is listed in Table 19.5.8.
Overlap syndromes
Rheumatoid arthritis is associated with an increased risk of
developing other autoimmune disorders. In some patients this
results in an evolution of clinical phenotype with time. Thus
rheumatoid arthritis patients may occasionally develop auto-
antibodies against nuclear antigens, followed by features of other
connective tissue diseases such as Sjogren’s syndrome or systemic
lupus erythematosus. Similarly, patients with systemic lupus
erythematosus can develop RhF and ACPA concurrent with
onset of a rheumatoid arthritis pattern of synovitis, colloquially
known as ‘rhupus’. These observations highlight the dynamic na-
ture of autoimmunity in rheumatoid arthritis and the need for the
Fig. 19.5.15  Patient with rheumatoid arthritis presenting with
involvement of the elbow accompanied by effusion in the olecranon
fossa and bursitis, plus a rheumatoid nodule distal to olecranon bursitis.
Reproduced from Watts RA et al (eds). Oxford Textbook of Rheumatology, 4th edn.
Oxford University Press, 2013. By permission of Oxford University Press.
Table 19.5.7  The 2010 American College of Rheumatology (ACR)
and European League Against Rheumatism (EULAR) classification
criteria for rheumatoid arthritis. Patients should have at least one
joint with definite synovitis which is not better explained by
another disease
Criterion
Score
A. Joint involvement a
–​ 1 large joint
–​ 2–​10 large joints
– 1–​3 small joints (with or without involvement of large joints)
– 4–​10 small joints (with or without involvement of large joints)
– >10 joints (at least one small joint)
1
2
3
4
5
B. Serologyb
–​ Negative RhF and negative ACPA
– Low-​positive RhF or low-​positive ACPA
– High-​positive RhF or high-​positive ACPA
0
2
3
C. Acute-​phase reactants
–​ Normal CRP and normal ESR
– Abnormal CRP or abnormal ESR
0
1
D. Duration of symptoms
–​ <6 weeks
– ≥6 weeks
0
1
ACPA, anti-​citrullinated peptide antibody; CRP, C-reactive protein; ESR, Erythrocyte
sedimentation rate; RhF, rheumatoid factor.
A score of ≥6/​10 is required for classification of a patient as having definite rheumatoid
arthritis (criteria can be cumulatively fulfilled over time)
a ‘Large joints’ refers to shoulders, elbows, hips, knees, and ankles. ‘Small joints’ refers
to the metacarpophalangeal joints, proximal interphalangeal joints, second through
fifth metatarsophalangeal joints, thumb interphalangeal joints, and wrists. The distal
interphalangeal joints, first carpometacarpal joints, and first metatarsophalangeal joints
are excluded from assessment
b Negative refers to international unit (IU) values that are less than or equal to the upper
limit of normal (ULN) for the laboratory and assay; low-​positive refers to IU values
that are higher than the ULN but ≤3 times the ULN for the laboratory and assay; high-​
positive refers to IU values that are >3 times the ULN for the laboratory and assay. Where
RhF information is only available as positive or negative, a positive result should be
scored as low-​positive for RhF.
Reproduced from: Annals of the Rheumatic Diseases, Aletaha et al, volume 69, pages
1580–​8, copyright 2010 with permission from BMJ Publishing Group Ltd.
section 19  Rheumatological disorders
4432
clinician to remain vigilant to change and prepared to revise the
diagnosis and treatment approach where necessary.
Clinical investigations
The clinical investigations for a patient presenting with potential
rheumatoid arthritis are presented in Table 19.5.9. Several investi-
gations are included at baseline to aid the subsequent detection of
extra-​articular features or medication-​related side effects, such as a
chest radiograph and pulmonary function tests. Similarly, as athero-
sclerosis is accelerated in rheumatoid arthritis, cardiovascular risk
profiling including blood pressure measurement, electrocardio-
gram, and lipid profile are also appropriate.
Autoantibodies
The first autoantibody to be characterized in rheumatoid arth-
ritis was RhF, an autoantibody directed against the Fc portion of
the immunoglobulin (Ig) G molecule. Although RhF can exist
in any isotope, it is the IgM isotype which is most well-​known
and clinically utilized. IgM RhF forms pentameric complexes
with IgG, and is a potent activator of complement. More recently,
several other classes of autoantibody have been discovered in
rheumatoid arthritis, of which ACPA testing is now in wide-
spread clinical use. Together with the recently characterized
anti-​carbamylated peptide autoantibodies, these emphasize the
importance of post-​translationally modified peptides as poten-
tial autoantigens in rheumatoid arthritis.
Testing for the presence of RhF and ACPA can be useful diag-
nostically, mainly where there is an intermediate clinical suspicion
of rheumatoid arthritis. Where there is a high pre-​test probability,
autoantibody testing has limited diagnostic value as up to 35% of
patients who satisfy rheumatoid arthritis classification criteria are
seronegative for both RhF and ACPA. Furthermore, RhF has poor
specificity for rheumatoid arthritis and can be elevated in a variety
of circumstances, including other autoimmune conditions, chronic
infections, as well as in otherwise healthy individuals. It is there-
fore of little diagnostic use in settings where the clinical suspicion
of rheumatoid arthritis is low. In contrast the specificity of ACPA
is high at around 95%, and hence a positive finding is usually in-
dicative of rheumatoid arthritis in the appropriate clinical setting.
Autoantibodies also carry prognostic value in rheumatoid arth-
ritis. Thus patients who are seropositive for RhF and (particularly)
ACPA are at increased risk of developing joint damage and extra-​
articular complications.
Table 19.5.8  The differential diagnosis of rheumatoid arthritis
according to typical clinical presentation, although overlap
between presentations can exist
Clinical
presentation
Differential diagnosis
Polyarthritis/​
arthralgia
Polyarticular psoriatic arthritis
Polyarticular osteoarthritis
Haemochromatosis
Remitting Seronegative Symmetrical Synovitis with Pitting
(o)edema (RS3PE)
Connective tissue diseases (e.g. systemic lupus
erythematosus)
Sarcoidosis
Fibromyalgia
Systemic onset
Adult-​onset Still’s disease
Polymyalgia rheumatica
Paraneoplastic syndrome
Numerous systemic infections, including:
–​ Parvovirus
–​ Lyme disease
–​ Human immunodeficiency virus seroconversion illness
–​ Chikungunya fever
–​ Dengue fever
–​ Whipple’s disease
–​ Disseminated gonococcal infection
Mono-​ or
oligo-​arthritis/​
arthralgia
Septic arthritis
Crystal arthropathy (gout, pseudogout)
Haemarthrosis
Seronegative spondyloarthropathy
–​ Psoriatic arthritis
–​ Enteropathic arthritis
–​ Reactive arthritis
–​ Ankylosing spondylitis with peripheral joint involvement
Osteoarthritis
Pigmented villonodular synovitis (PVNS)
Table 19.5.9  Typical investigations for a patient presenting
with possible rheumatoid arthritis. Not all of these investigations
would need to be performed in every case, and should be tailored
to the history and examination
Category
Investigation
Biochemistry
C-​reactive protein
Renal and liver function tests (baseline prior to drug
therapy)
Ferritin
Uric acid
Thyroid function tests
Calcium, phosphate
Angiotensin converting enzyme
Vitamin D
Haematology
Full blood count
Erythrocyte sedimentation rate
Serology
Rheumatoid factor
Anti-​citrullinated peptide antibodies
Other autoantibodies as dictated by clinical picture
(e.g. ANA, ENAs, ANCA, anti-​cardiolipin antibody)
Infectious agent serology tests (if appropriate, e.g. ASO
titre, parvovirus, hepatitis B and C, HIV, Lyme disease)
Immunoglobulins and serum protein electrophoresis
Synovial fluid
analysis
Synovial fluid microscopy and culture (if septic arthritis
suspected)
Polarizing light microscopy (if crystal arthropathy
suspected)
Imaging
Plain radiographs of hands and feet
Musculoskeletal ultrasonography (if available)
Other tests
Pulmonary function tests (baseline prior to e.g.
methotrexate therapy)
Chest X-​ray
Cardiovascular risk profiling
–​ Electrocardiography
– Fasting lipid profile
Investigation of
extra-​articular
features (when
indicated)
Nerve conduction studies
HRCT of chest
Echocardiogram
ANA, anti-​nuclear antibody; ANCA, anti-​neutrophil cytoplasmic antibody; ASO, anti-​
streptolysin O; ENAs, extractable nuclear antigens; HIV, human immunodeficiency virus;
HRCT, high-​resolution computed tomography.
19.5  Rheumatoid arthritis
4433
Musculoskeletal imaging
Plain radiographs remain a useful tool for the detection of joint
erosions, particularly in the hands and feet. As well as providing
prognostic information they can also help distinguish rheumatoid
arthritis from other differential diagnoses such as psoriatic arth-
ritis and crystal arthropathies. Nevertheless, apart from providing a
baseline, plain radiographs have limited utility in early rheumatoid
arthritis, before joint damage has developed. Magnetic resonance
imaging (MRI) is significantly more sensitive and can detect both
synovial inflammation and the bone oedema that precedes erosions.
While potentially of use in early rheumatoid arthritis, however,
its cost and inconvenience due to slow scan times restricts its use
largely to research studies.
Musculoskeletal ultrasound has gained popularity in recent
years, and is regarded by many as the imaging modality of choice in
rheumatoid arthritis. The relatively low cost and size of ultrasound
equipment make it ideal for use in the clinic and at the bedside,
and real-​time imaging allows for dynamic assessment of joint and
tendon movement. Ultrasound can detect both synovial thickening
and hypervascularity, together with joint effusions and articular ero-
sions. It is of particular use as an addition to clinical examination in
the detection of synovitis in early rheumatoid arthritis, but is also
useful in the assessment of treatment response and in the guiding
of articular injections. A further useful setting is the patient who
is refractory to multiple medications, where ultrasound can help
to distinguish active synovitis and joint damage from superadded
fibromyalgia. Nevertheless, musculoskeletal ultrasound is operator-​
dependent and relies upon appropriate training and standardization
of equipment.
Synovial fluid analysis
The aspiration of synovial fluid from inflamed joints can pro-
vide both symptomatic relief and the opportunity to inject gluco-
corticoid. Although there are no features of synovial fluid which
are specific for rheumatoid arthritis, synovial fluid analysis can be
invaluable in the exclusion of differential diagnoses. This includes
microbial culture in suspected septic arthritis, and polarizing light
microscopy for the diagnosis of crystal arthropathies.
Composite clinical disease activity scores
Measurement of disease activity in rheumatoid arthritis has im-
proved outcomes by enabling objective assessment of response to
treatment. No single measurement adequately captures all aspects
of disease activity and consequently several composite scoring sys-
tems have been developed that encompass a range of different do-
mains. The most well-​known is the disease activity score in 28 joints
(DAS28), a composite measure including joint examination, patient
subjective assessment and erythrocyte sedimentation rate (ESR)
(Table 19.5.10). The DAS28 was derived from the original DAS,
which assessed 44 joints, but DAS28 is similarly discriminative and
much quicker to score in daily practice. An alternative version of
DAS28 uses CRP instead of ESR. Other composite scores include
the simple disease activity index (SDAI), which is similar to DAS28
but easier to calculate and includes a physician global assessment,
and the clinical disease activity index (CDAI), which does not re-
quire ESR or CRP and can therefore be calculated without labora-
tory results.
There is increasing interest in the use of patient-​reported outcome
measures (PROMs) in rheumatoid arthritis, both for the measure-
ment of disease activity but also for other aspects of disease such as
functional ability, fatigue, and quality of life. Use of such instruments
can therefore provide a more global assessment of disease status.
The Stanford Health Assessment Questionnaire (HAQ) measures
functional ability and EuroQol 5 Dimensions (EQ-​5D) is a quality
of life instrument, both of which are used in health economic as-
sessments by bodies such as the National Institute for Health and
Care Excellence (NICE). In contrast, the Nottingham Short Form 36
(SF36) combines several features in physical and mental health do-
mains and is commonly used to assess quality of life in clinical trials.
The optimal disease state for a rheumatoid arthritis patient is re-
mission. As with diagnostic criteria and disease activity measures,
various definitions of remission have existed over recent decades
and coexist today. A commonly used definition in daily practice is a
DAS28 of less than 2.6, although this does not exclude the potential to
have residual synovitis, for example in the feet. Recently, EULAR and
the ACR developed new remission criteria (the 2011 ACR/​EULAR
remission criteria). These are more stringent than previous criteria
and require a patient to have no more than one tender or swollen
joint, a CRP ≤10 mg/​litre, and a patient global assessment of 10 or less
on a 100 point scale (Table 19.5.11). These are the so-​called Boolean
criteria but, as an alternative, an index-​based definition of SDAI ≤ 3.3
was also proposed and accepted.
Table 19.5.10  The disease activity score in 28 joints (DAS28). The
28 joints assessed include the bilateral proximal interphalangeal,
thumb interphalangeal, metacarpophalangeal, wrist, elbow, shoulder,
and knee joints. The DAS28 score can be used to define thresholds
of disease activity, though it is widely recognized that DAS28 can
underestimate disease activity at and close to remission levels
DAS28 score
Interpretation
DAS28 <2.6
Remission
2.6 ≤DAS28 ≤3.2
Low disease activity
3.2 <DAS28 ≤5.1
Moderate disease activity
DAS 28 >5.1
High disease activity
ESR, erythrocyte sedimentation rate in mm/​hour; SJC, swollen joint count; TJC,
tender joint count; VASpatient, patient visual analogue score of general health ranging
from zero (best) to 100 (worst).
DAS
TJC
SJC
ESR
VAS
28
0.56
28
0.28
28
0.70
ln
0.014
patient
×
+
×
+
×
Table 19.5.11  The American College of Rheumatology (ACR)/​
EULAR 2011 Boolean remission criteria for rheumatoid arthritis.
For patient global assessment the following anchor statement is
used: ‘Considering all of the ways your arthritis has affected you, how
do you feel your arthritis is today?’ (anchors: very well–​very poor)
At any single time point, the patient must satisfy all of the following:
Tender joint count ≤1
Swollen joint count ≤1
Patient global assessment ≤10 (on a 100-​point scale)
C-​reactive protein ≤10 mg/​litre
Reproduced from: Annals of the Rheumatic Diseases, Felson et al, volume 70, pages 404–​413,
copyright 2011 with permission from BMJ Publishing Group Ltd.
section 19  Rheumatological disorders
4434
Treatment
The past two decades have witnessed a revolution in rheumatoid
arthritis outcomes, from a disease in which progressive deformity
and disability were almost inevitable to one where remission is a real-
istic aim for many patients. This revolution has been underpinned
by a paradigm shift in treatment, including the importance of early
intervention before irreversible joint damage occurs; ‘treatment-​to-​
target’, whereby therapy is escalated until a treatment target (such
as DAS28 remission) is achieved; and the advent of several classes
of potent, targeted biological and synthetic drugs. Nonetheless, it
is also important to remember that a systemic immune disorder
such as rheumatoid arthritis demands a holistic approach in which a
multidisciplinary model remains central to patient care.
The therapeutic ‘window of opportunity’ and
treatment-​to-​target
There is now considerable evidence that successful suppression
of synovitis at an early stage results in better long-​term rheuma-
toid arthritis outcomes. For example, data from the Leiden Early
Arthritis Clinic show that patients treated within 12 weeks of
symptom onset achieve better outcomes, regardless of the specific
therapy. Outcomes measured included joint damage, disability, the
cumulative likelihood of achieving remission and even mortality.
Other studies have shown that HAQ score, even during the first year
of disease, reflects subsequent mortality. The reason why early treat-
ment has such a dramatic effect on long-​term outcomes is currently
uncertain, but may reflect epigenetic consequences of inflamma-
tion, for example, in FLS and the cardiovascular system. The con-
cept of a ‘window of opportunity’ has led to a paradigm shift in the
treatment of rheumatoid arthritis. Historically, disease-​modifying
medications were introduced late and slowly escalated, often only
after damage had appeared on X-​rays. In contrast, current treatment
strategies focus on the early initiation of medications, often in com-
bination with local and systemic glucocorticoids, in order to rapidly
and completely suppress synovitis. Many healthcare systems have
introduced mechanisms of rapid access to rheumatologists, such
as early arthritis clinics, to deal with these previously unrecognized
medical emergencies.
Alongside early intervention has arisen the treatment-​to-​target
concept. Studies such as the Combinatietherapie Bij Reumatoide
Artritis (COBRA) trial demonstrated the long-​term benefits of
a step-​down approach in which initial aggressive treatment with
glucocorticoids and combination DMARDs led to rapid disease
control followed by tapering of therapy. In contrast, the Tight
Control for RA (TICORA) trial illustrated the importance of a treat-
ment target, which was achieved by regular (e.g. monthly) assess-
ments and escalation of treatment (step-​up therapy), which again
might ultimately involve combination DMARD therapy along-
side local and systemic glucocorticoids. Joint damage, long-​term
functional disability, and mortality have all been shown to benefit
from such targeted approaches to disease activity. Many profes-
sional societies and regulatory agencies, including EULAR, ACR,
and NICE publish and regularly update guidelines for rheumatoid
arthritis management. In the United Kingdom, NICE has also pub-
lished quality standards which incorporate early treatment and
treatment-​to-​target.
Early and aggressive intervention means that up to half of
rheumatoid arthritis patients can now achieve disease remission
early in the disease course. Indeed, remission should be the target
of disease control for most patients. In others the disease is more
difficult to control, reflecting both undefined prognostic factors
and, probably, treatment delay. Such patients may cycle through
various conventional synthetic anti-​rheumatic drugs, often in
combination, and subsequently receive biological and targeted
synthetic therapies. Nevertheless, even if remission proves un-
achievable, tight arthritis control to low activity levels affords
better long-​term outcomes compared to those patients with
poorly controlled disease.
Conventional synthetic disease-​modifying
anti-​rheumatic drugs
Although most conventional synthetic disease-​modifying anti-​
rheumatic drugs (csDMARDs) have been available for several
decades, they remain the anchor of modern rheumatoid arthritis
therapy (Table 19.5.12). When csDMARDs are used early, and in
combination where necessary, they can be as effective as the newer
targeted therapies. Nonetheless, most also have the potential to
cause serious side effects including hepatitis and bone marrow
suppression. These drugs tend to be slow-​acting, taking several
weeks or months to exert their full therapeutic effect. The modes of
action for most csDMARDs remain unknown.
Methotrexate
Methotrexate is recommended as the first-​choice DMARD by most
if not all rheumatoid arthritis treatment guidelines (Fig. 19.5.16).
It inhibits the enzyme dihydrofolate reductase, although how this
translates into therapeutic efficacy is unknown. It is usually titrated
upwards from a starting dose of 7.5–​10 mg once weekly, according
to tolerability and efficacy. Most patients require 15–​25 mg per week
for therapeutic benefit, which can take six to eight weeks to develop.
Oral folic acid (at least 24 hours after methotrexate administration) is
coprescribed to reduce the incidence of gastrointestinal side effects.
Methotrexate is available in both oral and parenteral preparations;
the latter route of delivery has greater bioavailability and causes fewer
gastrointestinal side effects. It should not be coprescribed with other
folate antagonists such as trimethoprim, to minimize the serious ad-
verse effect of bone marrow suppression. Intravenous folinic acid is
the antidote to methotrexate and can be life-​saving in cases of acute
toxicity. Methotrexate is potently teratogenic, and women of repro-
ductive age must ensure they use adequate contraception during and
for 6 months after receiving the drug.
The development of breathlessness or cough in a patient taking
methotrexate should raise the suspicion of pneumonitis, a rare
idiosyncratic reaction which can occur at any time during therapy.
A baseline chest radiograph and pulmonary function tests (PFTs)
are recommended, and some rheumatologists recommend repeat
PFTs at regular intervals during therapy. Methotrexate is also asso-
ciated with hepatitis and, rarely, cirrhosis, and should be avoided
in patients with pre-​existing liver disease or those who drink al-
cohol to excess. It is renally excreted and should be avoided or used
with extreme caution in patients with renal failure. All patients
receiving methotrexate should receive regular monitoring of full
blood count (FBC) and liver function tests (LFTs) as an early signal
of impending toxicity.
19.5  Rheumatoid arthritis
4435
Sulfasalazine
Sulfasalazine is a conjugate of 5-​aminosalicylate with sulfapyridine and
a common first-​choice csDMARD in those patients for whom metho-
trexate is contraindicated:  it can also be used in combination with
methotrexate. Most patients receive 2–​3 g daily in two divided doses
which, like methotrexate, can take several weeks to work. Sulfasalazine
is considered safe in pregnancy although does have a reversible adverse
effect upon spermatogenesis. Side effects tend to occur in the first few
months of therapy and close monitoring of FBC (neutropenia) and
LFTs in this period is required. Orange discolouration of urine and tears
is a frequent though harmless side effect of the medication, and head-
aches can occasionally be troublesome. Sulfasalazine can rarely provoke
skin reactions and even a drug-​induced lupus syndrome. The mode of
action of sulfasalazine is poorly understood.
Antimalarials
Hydroxychloroquine is used as a csDMARD in the treatment of
rheumatoid arthritis although has only modest efficacy compared
to methotrexate and sulfasalazine, and is similarly slow-​acting. It
lacks significant toxicity, however, and regular blood monitoring
is not required. Rare hypersensitivity reactions, including Stevens–​
Johnson syndrome, can nonetheless occur. Hydroxychloroquine
is often coprescribed with methotrexate, or as triple therapy with
sulfasalazine. There is a small risk of visual disturbance via drug de-
position in the cornea (reversible) or retina (irreversible), but the
risk is much greater with chloroquine, which is rarely prescribed
for rheumatoid arthritis in the United Kingdom or United States.
Nonetheless, all patients taking hydroxychloroquine should have
a baseline visual assessment and annual ophthalmological review
thereafter. Hydroxychloroquine is generally considered safe in preg-
nancy although there are isolated reports of fetal ototoxicity with
doses above 200 mg daily.
Leflunomide
Leflunomide is an inhibitor of pyrimidine synthesis and was intro-
duced as a csDMARD in the late 1990s. Its efficacy and side effect
profile are similar to that of methotrexate, although with a lower
risk of pneumonitis. It can also cause hypertension and hence blood
pressure monitoring is required during therapy, particularly in the
initial weeks. Leflunomide is teratogenic and should be avoided in
women and men of reproductive age. The drug undergoes entero-
hepatic recirculation and hence can persist in the body for up to two
years after cessation. Where rapid reversal is required, washout with
oral cholestyramine or activated charcoal is required.
Table 19.5.12  Commonly used conventional synthetic disease-​modifying anti-​rheumatic drug (csDMARD) therapy in rheumatoid arthritis.
For full information please refer to the current prescribing information provided by the manufacturer
Drug
Route
Maintenance dose
Cautions
Notable side effects
Monitoring requirements
Methotrexatea
Oral,
intramuscular or
subcutaneous
15–​25 mg once
weeklyb
Contraindicated
in pregnancy and
breastfeeding, pre-​existing
liver disease, and bone
marrow suppression.
Should be used with
caution in renal impairment
and with pre-existing lung
disease.
Nausea, fatigue, bone
marrow suppression,
hepatotoxicity, pneumonitis
Routine FBC, LFTs and
U&Es for duration of
therapy
Baseline CXR and PFTs
Sulfasalazine
Oral
1–​1.5 g twice daily
Allergy to salicylates or
sulphonamides, G6PD
deficiency, impaired renal
or hepatic function, bone
marrow suppression,
pregnancyc
Nausea, bone marrow
suppression, hepatotoxicity,
yellow/​orange
discolouration of urine and
tears
Routine FBC and LFTs
at least for first year of
therapy
Hydroxychloroquine
Oral
200 mg once to
twice daily
(should not exceed
6.5 mg/​kg/​day)
Pre-​existing maculopathy,
renal impairment, liver
impairment, psoriasis (can
worsen), epilepsy (reduced
seizure threshold)
Nausea, vomiting, skin
eruption including Steven-​
Johnson syndrome,
maculopathy
Baseline and annual
ophthalmological
examination for duration
of therapy
Leflunomide
Oral
10–​20 mg once
dailyd
Contraindicated
in pregnancy and
breastfeeding, renal
impairment, liver
impairment, severe
hypoproteinaemia, bone
marrow suppression
Nausea, diarrhoea,
hepatotoxicity, bone
marrow suppression,
hypertension, weight loss,
pneumonitis (rare)
Routine FBC, LFTs, blood
pressure and weight for
duration of therapy
CXR, chest X-​ray; FBC, full blood count; G6PD, glucose-​6-​phosphate dehydrogenase; LFTs, liver function tests; PFTs, pulmonary function tests; U&Es, urea and electrolytes.
a Methotrexate should be coprescribed with oral folic acid, at a minimal dose of 5 mg once weekly to be taken at least 24 hours after the dose of methotrexate.
b Methotrexate is only ever given once weekly in the treatment of rheumatoid arthritis. Greater sensitivity to methotrexate is seen in Japanese populations where doses prescribed
usually do not exceed 10 mg per week.
c Sulfasalazine may be prescribed in pregnancy where the benefits are felt to outweigh the risks–​the daily dose should not exceed 2 g/​day and folic acid supplement should be
prescribed. Sulfasalazine is generally considered safe in breastfeeding.
d A loading dose of leflunomide 100 mg once daily for three days may be given when starting the drug, though this can cause gastrointestinal upset and is often omitted in clinical
practice.
Based upon recommendations within the 2017 British Society of Rheumatology/British Health Professionals in Rheumatology guideline for the prescription and monitoring of non-
biologic DMARDs (Ledingham et al. (2017). Rheumatology; 56(6):865–8), and the Summary of Product Characteristics of the individual drugs.
section 19  Rheumatological disorders
4436
Fig. 19.5.16  Algorithm based on the 2016 European League Against Rheumatism (EULAR) recommendations on
rheumatoid arthritis (RA) management. ACPA, anticitrullinated protein antibody; ACR, American College of Rheumatology;
bDMARD, biological DMARD; bsDMARD, biosimilar DMARDs; csDMARDs, conventional synthetic DMARDs; DMARDs,
disease-modifying antirheumatic drugs; EMA, European Medicines Agency; FDA, Food and Drug Administration; IL,
interleukin; MTX, methotrexate; RF, rheumatoid factor; TNF, tumour necrosis factor; tsDMARDs, targeted synthetic DMARDs.
Reproduced from Annals of the Rheumatic Diseases, Smolen et al, volume 76, pages 960–77, copyright 2017 with permission from BMJ Publishing
Group Ltd.
19.5  Rheumatoid arthritis
4437
Other csDMARDs
Parenteral gold was a popular csDMARD in the 1970s and 80s,
though is now infrequently used due to its side effect profile. Its use
in modern practice tends to be reserved for patients in whom al-
ternative DMARD therapy is either ineffective or contraindicated.
Other older csDMARDs such as D-​penicillamine, ciclosporin, and
azathioprine are now very rarely used in the treatment of rheuma-
toid arthritis.
Biological DMARDs
Advances in understanding of the molecular pathogenesis of
rheumatoid arthritis coupled with developments in pharmaceut-
ical bioengineering have led to an explosion of biological DMARDs
(bDMARDs) over the past two decades. These are highly specific
therapies, characterized by potent and selective targeting of a single
molecule. Owing to their protein structure, bDMARDs are admin-
istered parenterally. Commonly used bDMARDs in rheumatoid
arthritis are listed in Table 19.5.13. In brief, there are four classes
of bDMARD currently licensed for rheumatoid arthritis treatment,
which neutralize TNF, deplete B cells, prevent T-​cell costimulation
by APCs, or block IL-6 signalling.
When bDMARDs were first introduced there was significant con-
cern regarding the potential for long-​term side effects. These con-
cerns have abated somewhat with increasingly reassuring data from
biologic registries. Nonetheless, compared with csDMARDs, their
use is associated with an approximately 20% increased risk of serious
infection, which is similar across the drug classes. The risk is not uni-
form across all patients, however, and factors such as previous severe
infection, current glucocorticoid use, chronic lung or renal disease,
and age each impact upon infection risk. Specific infections are in-
creased with the use of particular therapeutic classes, most notably
mycobacterial infections and anti-​TNF therapy; patients should be
screened for latent tuberculosis and, if positive, receive prophylactic
anti-​tuberculous therapy before commencing treatment. Compared
to csDMARDs there does not appear to be an enhanced risk of solid
organ malignancy, nonmelanoma skin cancer or lymphoma with
bDMARD use, although the risk of malignant melanoma is increased
for anti-​TNF therapy, particularly in patients with a previous history
of this malignancy. Nonetheless, caution is still recommended in the
use of bDMARDs in patients with a prior history of malignancy.
bDMARDs are expensive agents and have been the subject of
intense health economic scrutiny. In the United Kingdom, guide-
lines on their use have been introduced by NICE, restricting their
prescription to patients with highly active disease that is resistant
to at least two csDMARD therapies and requiring documentation
of improved disease activity with treatment. As with csDMARDs,
there is response heterogeneity for bDMARDs among rheumatoid
arthritis patients—​good responses to one therapy are not predictive
of similarly good responses to another. No biomarkers have yet
been identified that predict bDMARD efficacy, with the sequence
of bDMARD use dictated largely by financial cost and clinician ex-
perience. The recent introduction of biosimilar bDMARDs should
significantly reduce the cost of therapy and could potentially change
the future availability of these treatments.
Targeted synthetic DMARDs
Targeted synthetic DMARDs (tsDMARDs) comprise a new category
of orally bioavailable drugs for rheumatoid arthritis. Janus kinase
inhibitors (JAKi) comprise the first class of tsDMARDs. JAKs are a
family of four membrane-associated protein tyrosine kinases that are
required for the signalling of several cytokines and haematopoietic
growth factors. The selectivity of the JAKi, and hence their potential
therapeutic profile, varies. Tofacitinib is most selective for JAK 3 and
JAK 1, baricitinib for JAK 1 and JAK 2. JAKi with different selectivities
are in development. Tofacitinib and baricitinib have a rapid onset of
action and can be prescribed as monotherapy or in combination with
other csDMARDs for patients with rheumatoid arthritis who do not
respond to or are intolerant of methotrexate. As with bDMARDs, their
use is subject to guidelines from bodies such as NICE. To date, the ad-
verse event profile of JAKi appears similar to bDMARDs with the ex-
ception of a higher incidence of herpes zoster reactivation. JAKi must
not be prescribed in combination with biological DMARDs or potent
immunosuppressants such as azathioprine and cyclophosphamide.
Glucocorticoids
Glucocorticoids are highly potent anti-​inflammatory drugs, which
can deliver a rapid and profound suppression of synovitis. When
first introduced in the 1950s, they were seen as a miraculous ‘cure’
for rheumatoid arthritis; unfortunately, the now familiar spectrum
of serious long-​term side effects limits their use as maintenance
therapy. Nonetheless, glucocorticoids still play an important role in
rheumatoid arthritis management, particularly in the initial stages
of disease, or when switching therapy, as a ‘bridging measure’ to con-
trol inflammation while waiting for DMARDs to act. Similarly, they
provide rapid symptomatic relief during an arthritis flare.
When using glucocorticoids in rheumatoid arthritis, the central
aim is to use as low a dose as possible for the shortest possible dur-
ation. Tapering courses of oral prednisolone can be used, or alter-
natively deep intramuscular depot injections such as depomedrone
Table 19.5.13  The mechanism of action of biological DMARDs
commonly used in the treatment of rheumatoid arthritis (see
Chapter 2.7 for further details)
Biologic agent
Nature
Mechanism of action
Infliximab
Chimeric human/​mouse anti-​
TNFα antibody
Bind to and neutralise
TNFα
Etanercept
Fusion protein of extracellular
domain of p75 TNFα
receptor with human IgG1 Fc
Adalimumab
Human IgG1 anti-​TNFα
antibody
Certolizumab
pegol
PEGylated humanized
anti-​TNFα Fab’ fragment
Golimumab
Human IgG1 anti-​TNFα
antibody
Sarilumab
Human IgG1 anti-IL6
receptor antibody
Prevent IL6 binding to
its receptor
Tocilizumab
Humanized anti-​IL6 receptor
antibody
Abatacept
Fusion protein of extracellular
domain of CTLA-​4 with
human IgG1 Fc
Blocks costimulation of
T cells via CD28
Rituximab
Chimeric human/​mouse
anti-​CD20 antibody
Depletes CD20 positive
B cells
CTLA-​4, cytotoxic T-​lymphocyte-​associated antigen 4; Ig, immunoglobulin; IL,
interleukin; TNFα, tumour necrosis factor alpha.
section 19  Rheumatological disorders
4438
(80–​120 mg) or triamcinolone acetonide (40–​80 mg). Single or mul-
tiple joints can also be injected with glucocorticoid to provide symp-
tomatic relief while minimizing systemic adverse effects, and this is
the preferred route when just a few joints are inflamed. With repeated
or prolonged courses of glucocorticoid therapy come increasing risks
of adverse effects. Gastro-​protection with a proton-​pump inhibitor or
H2-​receptor antagonist should be offered under these circumstances.
Prophylaxis against the development of osteoporosis, such as vitamin
D replacement, calcium supplements, and anti-​resorptive therapies
should also be provided. Periodic screening for the development of
steroid-​induced diabetes mellitus is recommended, as is tight con-
trol of other cardiovascular risk factors. Finally, it is important to re-
member that glucocorticoids carry a dose-​related infection risk, the
highest of all rheumatoid arthritis therapies. Enhanced vigilance is
thus required, especially because glucocorticoids can mask the typ-
ical clinical and laboratory features of sepsis.
Non​steroidal anti-​inflammatory drugs
NSAIDs play a useful role in the relief of the pain and stiffness of
rheumatoid arthritis and, until recently, were prescribed chronically
to many patients. However, they do not prevent joint damage, and the
recognition that they predispose to cardiovascular disease in addition
to their long-​recognized renal and gastric toxicity now limits their
long-​term use. When NSAIDs are used, it is preferable to prescribe
agents with lower cardiovascular risk such as naproxen and ibuprofen.
Specific cyclooxygenase-​2 (COX-​2) inhibitors afford reduced gastric
toxicity, although concerns regarding their cardiovascular toxicity
profile have limited their more widespread use in clinical practice.
Non​pharmacological management
Non​pharmacological management is crucial for the effective and
holistic treatment of rheumatoid arthritis. Basic medical care should
not be overlooked such as blood pressure and cholesterol control,
smoking cessation and immunization with appropriate (non​live)
vaccines such as influenza and pneumococcus. Patient education via
leaflets, websites, and support groups are important to help patients
understand the nature of their disease, the importance of effective
treatment and to offer guidance on the practicalities of living with a
chronic illness such as rheumatoid arthritis. Although the rheuma-
tologist plays a central role in the provision of care, the support of
and cooperation with other health professionals within a multi-
disciplinary team is paramount to successful rheumatoid arthritis
management (Table 19.5.14). Rheumatoid arthritis is now viewed
as a partnership between the patient and the multidisciplinary team,
with the best outcomes arising when an empowered patient enters
an effective partnership with a broadly skilled team.
With less joint damage as a result of improved medical man-
agement, there is now a reduced role for surgery in the treatment
of rheumatoid arthritis. Nevertheless surgical intervention in the
form of nerve decompression, synovectomy for refractory syno-
vitis, and tendon reconstruction is sometimes required. Joint re-
placements are also occasionally required to improve pain and
function of damaged joints but a partnership is equally important
here, such that the patient understands the likely results of surgery.
Prognosis
Many clinical factors have been associated with increased radio-
graphic progression and poor functional outcomes in observa-
tional cohort studies of rheumatoid arthritis (Table 19.5.15).
Not all factors have been replicated in all studies, and their in-
dependence from each other is debatable. Arguably the greatest
Table 19.5.14  The multidisciplinary team management
of rheumatoid arthritis
Professional
Team role
Rheumatologist
Diagnoses rheumatoid arthritis, monitors disease
activity, prescribes DMARDs, monitors for
complications of disease and therapy
Rheumatology
specialist nurse
Supports role of rheumatologist, provides patient
support and education, acts as coordinator of care
General
practitioner
Makes initial referral to rheumatologist, assists with
DMARD prescription and monitoring, vaccination,
assists with cardiovascular risk modification
Orthopaedic
surgeon
Synovectomy, joint fusion, nerve decompression,
spinal fixation, joint replacement
Pharmacist
Dispensing DMARDs, may assist with DMARD
monitoring
Physiotherapist
Exercise and joint strengthening
Occupational
therapist
Joint protection (behavioural, splints and education),
modifications to home and work environments
Podiatrist
Fits orthotic devices and provides foot care
Social worker
Advises on employment opportunities, coordinates
welfare benefits and home care arrangements
Psychologist
Counselling, cognitive behavioural therapy (e.g. for
depression and fatigue)
Table 19.5.15  Poor prognostic factors for increased joint damage
in rheumatoid arthritis. Note that not all factors have been
replicated in all studies, and the independence of each factor is
debatable
• Older age at onset
• Female gender
• Longer duration of disease at diagnosis
• Delay in treatment initiation
• Erosions at presentation
• Raised BMI
• Cigarette smoking
• Socioeconomic deprivation
• Low educational attainment
• Extra-​articular features
• Anaemia of chronic disease
• High cumulative levels of inflammation (clinical and biochemical
measures)
• Rheumatoid factor positive (particularly IgA subtype)
• ACPA positive
• Shared epitope positive
• Baseline serum matrix metalloproteinase-​3 (MMP-​3) level
• Bone oedema on MRI
• Bone mineral density loss in first year measured by bone densitometry
• Power Doppler synovitis on ultrasound (in some studies)
Adapted from Markatseli et al 2010 Clin Exp Rheumatol; 28: 114–​123.
19.5  Rheumatoid arthritis
4439
single factor governing long-​term prognosis in rheumatoid arthritis
is the adequacy of disease control at an early stage. Long duration of
symptoms at diagnosis, delay in initiation of DMARD therapy and
high disease activity in the first year after diagnosis are all strongly
associated with poor long-​term outcomes, including joint damage,
disability, cardiovascular comorbidity, and increased mortality.
Some investigations carry prognostic value, most notably sero-
positivity for RhF and especially ACPA, which are both associ-
ated with more aggressive arthritis and increased incidence of
erosive disease and extra-​articular manifestations. A persistently
elevated acute-​phase response also portends a poor outcome.
Musculoskeletal imaging may also have a role in prognostication,
with some studies suggesting that patients in clinical remission but
with active power Doppler synovitis on ultrasound scans are more
likely to experience future arthritis flares and joint erosions com-
pared to patients without this finding. Nevertheless, recent trials
exploring the escalation of therapy to achieve ultrasound-defined
targets of disease control have failed to show superiority when com-
pared to clinical disease activity targets alone.
Complications of rheumatoid arthritis
Accelerated atherosclerosis
The cardiovascular (CV) complications of rheumatoid arthritis
make the largest contribution to excess mortality. Accelerated ath-
erosclerosis is a key comorbidity of rheumatoid arthritis, and is sec-
ondary to the effects of chronic inflammation and medications (e.g.
glucocorticoids and NSAIDs) in addition to traditional CV risk fac-
tors such as reduced physical activity. Whereas CV mortality has
fallen sharply over past decades in the general population, there has
been very little change in rheumatoid arthritis, suggesting that con-
trol of traditional CV risk factors alone is not sufficient. However,
recent epidemiological evidence suggests a reduction of CV risk
with improved disease control, although these observations remain
to be confirmed in long-​term prospective trials.
Pulmonary
Lung disease is common in rheumatoid arthritis and while some
manifestations are clearly extra-​articular features of active disease
others, such as bronchiectasis, are becoming incriminated in dis-
ease aetiology albeit via uncertain mechanisms. Because smoking
is a risk factor for rheumatoid arthritis, conditions such as chronic
obstructive pulmonary disease and bronchogenic carcinoma are
more common in rheumatoid arthritis populations. Furthermore,
pneumonitis is an idiosyncratic adverse effect of several DMARDs,
including methotrexate and leflunomide.
Infection
Patients with rheumatoid arthritis are at increased risk of infection,
both as a consequence of the immune dysregulation underlying
the disease and the immunosuppressive drugs used to control it.
Discriminating infection from the acute-​phase response and low
grade pyrexia associated with widespread synovitis can sometimes
pose a clinical challenge.
 Renal
Renal manifestations that are directly attributable to rheumatoid
arthritis are uncommon and largely confined to isolated cases of
systemic amyloidosis and glomerulonephritis. Nevertheless, renal
complications are frequently observed in patients with rheumatoid
arthritis secondary to nephrotoxic drug use, especially NSAIDs,
and were historically seen with older csDMARDs such as gold and
D-​penicillamine.
Other autoimmune diseases
The systemic autoimmunity at the heart of rheumatoid arthritis
pathogenesis leads to an increased risk of other autoimmune dis-
eases for which the clinician needs to be vigilant. For example,
the incidence of autoimmune hypothyroidism is increased in
rheumatoid arthritis, though can be mistakenly overlooked given
the chronic fatigue experienced by patients with active arthritis.
Type I diabetes mellitus is also more frequently encountered in
the rheumatoid arthritis population, the control of which may be
destabilized by glucocorticoid therapy.
Future developments
Stratified medicine
It is apparent that rheumatoid arthritis is a heterogeneous con-
dition, with multiple distinct immunopathological pathways
leading to a common clinical phenotype. Nevertheless, current
rheumatoid arthritis therapy adopts a ‘one size fits all’ approach,
with limited scope for individualization of treatment, and appro-
priate biomarkers are urgently required to underpin personalized
management of rheumatoid arthritis (Fig. 19.5.17). For example,
robust prognostic biomarkers would allow the early targeting of
aggressive therapy to those patients most likely to develop future
disability. Furthermore, biomarkers that predict response to drug
therapy would enable intelligent selection of DMARDs most likely
to benefit individual patients. Additional biomarkers could even
help guide the tapering of DMARD therapy in patients who have
achieved remission.
Recent advances in high-​throughput analytic techniques, collect-
ively referred to as the ‘omics’ technologies (e.g. transcriptomics,
proteomics, metabolomics), offer the potential to search for bio-
markers within literally hundreds of thousands of biological
parameters. However, considerable challenges remain in the as-
similation of the vast datasets generated and the translation of
these findings into diagnostic assays that are appropriate for rou-
tine clinical use. It is possible that such biomarkers will be found
in the synovium rather than in the blood, catalysing a significant
change in practice. In oncology, for example, tissue biomarkers
increasingly guide treatment choices. When these challenges are
Disease flare
Early diagnosis
Prognosis
Predictive RA
biomarkers
DMARD
response
DMARD-free
remission
Fig. 19.5.17  The categories of potential predictive biomarkers that
would be of clinical value in the management of rheumatoid arthritis.
section 19  Rheumatological disorders
4440
overcome, stratified medicine will not only improve long-​term
outcomes but also reduce the cost of therapy.
Preventative medicine
Given the prodromal period of immune dysregulation that precedes
the clinical onset of rheumatoid arthritis, recent interest has focused
on whether rheumatoid arthritis could be prevented by targeting
pre-​rheumatoid arthritis. It should be easier to correct dysfunctional
pathways of autoimmunity before they become fully established,
possibly requiring only short periods of relatively mild therapy.
Nonetheless, the potential benefits of such prophylactic interven-
tions would need to be carefully balanced against the potential side
effects, while considering the ultimate risk of developing rheumatoid
arthritis. However, even lifestyle modification measures such as at-
tending to dietary factors and smoking cessation, could be effective
in preventing rheumatoid arthritis in at-​risk individuals. Microbiome
modification could also halt progression to clinical disease.
New therapeutic targets
Despite recent therapeutic advances, a proportion of patients with
rheumatoid arthritis remain resistant to currently available ther-
apies and consequently there remains a demand for new therapies
with diverse modes of action. Current therapies target the known
immunopathology of rheumatoid arthritis, with little attention directed
towards the joint stroma. Given recent observations that FLS play an im-
portant role in the pathogenesis of rheumatoid arthritis, they provide an
attractive target for future therapeutic approaches. These include anti-​
proliferative drugs, pro-​apoptotic drugs, or even epigenetic modifiers;
potential compounds already exist in the oncology armamentarium.
Therapeutic tolerance
The ultimate therapy for rheumatoid arthritis would be an im-
mune manipulation that abrogates autoimmunity and restores self-​
tolerance, removing the need for long-​term immunosuppression.
Therapeutic tolerance to organ allografts and experimentally-​induced
autoimmunity is achievable in animal models. It has also recently been
demonstrated through haematopoietic chimerism in human renal
transplant recipients. In addition to targeting of the immune system in
vivo, tolerogenic conditioning of autologous or heterologous immune
cells ex vivo and their use as a cellular therapy is another route to po-
tentially achieving therapeutic tolerance. If effective, such tolerogenic
therapies would revolutionise the treatment of rheumatoid arthritis
by providing sustained benefit from a single short course of therapy,
probably delivered at an early stage of the disease.
FURTHER READING
Aletaha D, et al. (2010). Rheumatoid arthritis classification criteria: an
American College of Rheumatology/​European League Against
Rheumatism collaborative initiative. Ann Rheum Dis, 69, 1580–​8.
Bottini N, Firestein GS (2013). Duality of fibroblast-​like synoviocytes
in RA:  passive responders and imprinted aggressors. Nat Rev
Rheumatol, 9, 24–​33.
Bottini N, Firestein GS (2013). Epigenetics in rheumatoid arthritis: a
primer for rheumatologists. Curr Rheumatol Rep, 15, 372.
Ledingham, et al. (2017). BSR and BHPR guideline for the prescription
and monitoring of nonbiologic disease-modifying anti-rheumatic
drugs. Rheumatology, 56, 865–8.
Choudhary MM, Hajj-​Ali RA, Lowder CY (2014). Gender and ocular
manifestations of connective tissue diseases and systemic vasculit-
ides. J Ophthalmol, 2014, 403042.
Cross M, et al. (2014). The global burden of rheumatoid arthritis: es-
timates from the global burden of disease 2010 study. Ann Rheum
Dis, 73, 1316–​22.
Doran MF, et al. (2002). Trends in incidence and mortality in rheuma-
toid arthritis in Rochester, Minnesota, over a forty-​year period.
Arthritis Rheum, 46, 625–​31.
England BR, et al. (2016). Cause-​specific mortality in male US veterans
with rheumatoid arthritis. Arthritis Care Res, 68, 36–​45.
Felson DT, et al. (2011). American College of Rheumatology/​European
League against Rheumatism provisional definition of remission in
rheumatoid arthritis for clinical trials. Ann Rheum Dis, 70, 404–​13.
Fietta P, Delsante G, Quaini F (2009). Hematologic manifestations of
connective autoimmune diseases. Clin Exp Rheumatol, 27, 140–​54.
Gabriel SE (2008). Why do people with rheumatoid arthritis still die
prematurely? Ann Rheum Dis, 67 Suppl 3, iii30–​4.
Gerlag DM, et al. (2012). EULAR recommendations for terminology
and research in individuals at risk of rheumatoid arthritis: report
from the Study Group for Risk Factors for Rheumatoid Arthritis.
Ann Rheum Dis, 71, 638–​41.
Grigor C, et al. (2004). Effect of a treatment strategy of tight control for
rheumatoid arthritis (the TICORA study): a single-​blind random-
ised controlled trial. Lancet, 364, 263–​9.
Isaacs JD (2010). The changing face of rheumatoid arthritis: sustained
remission for all? Nat Rev Immunol, 10, 605–​11.
Karlson EW, Deane K (2012). Environmental and gene-​environment
interactions and risk of rheumatoid arthritis. Rheum Dis Clin North
Am, 38, 405–​26.
Landewé RB, et al. (2002). COBRA combination therapy in patients
with early rheumatoid arthritis: long-​term structural benefits of a
brief intervention. Arthritis Rheum, 46, 347–​56.
Malmström V, Catrina AI, Klareskog L (2017). The immunopatho­
genesis of seropositive rheumatoid arthritis: from triggering to
targeting. Nat Rev Immunol, 17, 60–75.
Markatseli TE, Papagoras C, Drosos AA (2010). Prognostic factors for
erosive rheumatoid arthritis. Clin Exp Rheumatol, 28, 114–​23.
Messemaker TC, Huizinga TW, Kurreeman F (2015). Immunogenetics
of rheumatoid arthritis:  understanding functional implications. J
Autoimmun, 64, 74–​81.
National Audit Office (2009). Services for people with rheumatoid ar-
thritis. The Stationary Office, London.
National Institute for Health and Care Excellence (2013). NICE clin-
ical guideline 79: the management of rheumatoid arthritis in adults.
NICE, Manchester.
Simon TA, et al. (2015). Incidence of malignancy in adult patients with
rheumatoid arthritis: a meta-​analysis. Arthritis Res Ther, 17, 212.
Singh JA, et al. (2016). American College of Rheumatology Guideline for
the Treatment of Rheumatoid Arthritis. Arthritis Rheumatol, 68, 1–​25.
Smolen JS, et al. (2017). EULAR recommendations for the management
of rheumatoid arthritis with synthetic and biological disease-modifying
antirheumatic drugs: 2016 update. Ann Rheum Dis, 76, 960–77.
Smolen JS, Aletaha D, McInnes IB (2016). Rheumatoid Arthritis.
Lancet, 388, 22–8.
Smolen JS, et al. (2016). Treating rheumatoid arthritis to target: 2014
update of the recommendations of an international task force. Ann
Rheum Dis, 75, 3–​15.
Yamamoto T (2009). Cutaneous manifestations associated with
rheumatoid arthritis. Rheumatol Int, 29, 979–​88.
Yunt ZX, Solomon JJ (2015). Lung disease in rheumatoid arthritis.
Rheum Dis Clin North Am, 41, 225–​36.

19.6 Spondyloarthritis and related conditions 4441
19.6 Spondyloarthritis and related conditions 4441 Jürgen Braun and Joachim Sieper
ESSENTIALS
The spondyloarthritides are a group of common inflammatory rheum-
atic diseases with predominant involvement of axial and peripheral
joints and entheses, together with other characteristic clinical fea-
tures, including inflammatory back pain, sacroiliitis, peripheral arth-
ritis (mainly in the legs), enthesitis, dactylitis, preceding infection of the
urogenital/​gastrointestinal tract, psoriatic skin lesions, Crohn-​like gut
lesions, anterior uveitis, and a family history of spondyloarthritis.
Five subsets can be distinguished on clinical grounds:  (1) axial
spondyloarthritis, including ankylosing spondylitis; (2)  reactive
(spondylo)arthritis/​Reiter’s syndrome (see Chapter 19.8); (3) psori-
atic (spondylo)arthritis; (4)  (spondylo)arthritis associated with in-
flammatory bowel diseases; and (5)  undifferentiated peripheral
spondyloarthritis. Prevalence in any population correlates roughly
with that of HLA B27, but the relevance of this to pathogenesis is
not known. Another more recent approach is to differentiate the
spondyloarthritis on the basis of the predominant clinical manifest-
ation: predominant axial and/​or peripheral spondyloarthritis.
Axial spondyloarthritis, including ankylosing spondylitis
There are no diagnostic criteria, only classification criteria: the 2009
Assessment of SpondyloArthritis International Society criteria for axial
and peripheral spondyloarthritis. Chronic back pain (>3  months)
that has started before the age of 45 years is mandatory; then there
should be either a positive imaging finding (conventional radiograph
or magnetic resonance imaging of the sacroiliac joints) or a positive
HLA B27 test; plus one (if imaging positive) or two (if HLA B27 posi-
tive) more characteristic features.
The historical modified New York classification criteria of 1984
required one of three clinical criteria—​(1) inflammatory back pain;
(2) limitation of spinal movement in three planes; or (3) deterioration
of chest expansion—​and radiological sacroiliac joint changes (bilat-
eral grade 2 or unilateral grade 3/​4). Sacroiliac radiographs may be
normal in early disease when dynamic magnetic resonance imaging
of the sacroiliac joints can be helpful in providing objective evidence
of sacroiliitis in clinically suspicious cases.
Age of onset of ankylosing spondylitis is commonly in the twenties,
with male:female ratio of 2:1. Early in the course of disease there may be
no limitation of spinal movement or chest expansion, but as it progresses
there is restriction of lateral flexion, forward flexion, and extension.
Treatment options include acute anti-​inflammatory therapy with
nonsteroidal anti-​inflammatory drugs and local corticosteroids,
disease-​modifying drugs (sulphasalazine and methotrexate) and
biologicals (antitumour necrosis factor), together with physiotherapy.
There is no cure.
Psoriatic arthritis
Psoriasis precedes joint disease in most cases, but there is poor cor-
relation between onset, severity, and activity of psoriatic skin lesions
and arthritis. More than 80% of patients with psoriatic arthritis have
nail dystrophy.
The most characteristic features are dactylitis and osteoproliferative
changes in radiographs of peripheral joints. The CASPAR classifica-
tion criteria, which are both sensitive and specific, require established
inflammatory articular disease with at least three points from the fol-
lowing features: (1) current psoriasis (score 2); (2) a history of psoriasis
(unless current psoriasis); (3) a family history of psoriasis (unless cur-
rent psoriasis or history of psoriasis); (4) dactylitis; (5) juxta-​articular
new bone formation; (6) rheumatoid factor negativity; and (7) nail
dystrophy.
Many patients improve with the use of non​steroidal anti-​
inflammtory drugs and intra-​articular steroids, especially in the case
of large joint involvement or flexor tenosynovitis. Those who do not
improve need to be treated with disease-​modifying drugs (sulpha-
salazine, methotrexate).
Arthritis associated with inflammatory bowel disease
Similar to the other spondyloarthritides, the arthritis is mostly asym-
metric and predominantly affects the legs. Flaring of gut symptoms
is often associated with arthritis. Treatment with non​steroidal anti-​
inflammtory drugs may be effective for arthritis and spondylitis
but can exacerbate bowel disease: there are few data on the use of
disease-​modifying drugs.
Peripheral, including undifferentiated peripheral
spondyloathritis
According to the above-​mentioned Assessment of SpondyloArthritis
International Society classification criteria, patients with predom-
inant peripheral spondyloarthritis have as a primary symptom ei-
ther (1) arthritis, (2) enthesitis or (3) dactylitis, and—​in addition—​at
least one of (a) anterior uveitis, (b) psoriasis, (c) inflammatory bowel
19.6
Spondyloarthritis and related conditions
Jürgen Braun and Joachim Sieper
section 19  Rheumatological disorders
4442
disease, (d) preceding infection, (e) HLA B27 and (f) sacroiliitis on
magnetic resonance imaging. In addition, they may also have at
least two of (a) arthritis, (b) enthesitis, (c) dactylitis, (d) inflamma-
tory back pain, and (e) positive family history for spondyloarthritis.
Classification of undifferentiated spondyloarthritis excludes the pres-
ence of psoriasis, inflammatory bowel disease, or a preceding in-
fection but includes the rest of the Assessment of SpondyloArthritis
International Society criteria for peripheral spondyloarthritis.
Non​specific therapy is as for other arthritides, with non​steroidal
anti-​inflammtory drugs and intraarticular and/​or systemic gluco-
corticoids. Sulfasalazine may be useful for peripheral and axial
symptoms, but very few therapeutic trials with disease-​modifying
drugs have been performed. Methotrexate is often used but data
are scarce.
SAPHO syndrome
There are no evaluated diagnostic criteria for the acronym of
SAPHO syndrome (synovitis, acne, pustulosis palmaris et plantaris,
hyperostosis, and osteitis). However, the combination of a classical
skin symptom (such as pustolosis or significant acne) with a charac-
teristic joint or bone lesion (such as arthritis of the sternoclavicular
joint, osteitis, or hyperostosis in the anterior chest wall) is clinic-
ally convincing. Analgesics, non​steroidal anti-​inflammtory drugs,
and intra-​articular steroids are usually effective. Anti-​TNF agents
and bisphosphonates have been shown to be efficacious in more
severe cases.
Spondyloarthritides
Introduction and definitions
The spondyloarthritides are a heterogenous group of inflam-
matory rheumatic diseases with predominant involvement of
axial and peripheral joints and entheses. In addition to these, the
spondyloarthritides share other characteristic clinical features
(e.g. anterior uveitis, psoriasis, and colitis with mostly asymp-
tomatic Crohn-​like gut lesions). Clinical symptoms in subsets of
spondyloarthritides can overlap, for example, with psoriatic skin
lesions in reactive arthritis (keratoderma blenorrhagicum), espe-
cially the subform formerly called ‘Reiter’s syndrome’ with the triad
arthritis, urethritis, conjunctivitis, and patients can move from one
subset to another, for example, from undifferentiated peripheral
spondyloarthritis (SpA) to axial spondyloarthritis and ankylosing
spondylitis (AS).
The various names that have been and are still used for the
spondyloarthritides include seronegative spondarthropathies,
spondarthritis,
spondylarthropathy,
and
spondyloarthritis.
Importantly, the term spondyloarthritis means a category of inter-
related rheumatic disease, it does not only mean axial involve-
ment, as the asymmetric pattern of involvement of mainly the
legs by oligoarthritis and enthesitis is also typical. The prefix sero-
negative, referring to the general absence of rheumatoid factors
in the spondyloarthritides, is historical and redundant. The term
spondyloarthritis is now generally preferred.
The spondyloarthritides are not ‘modern’ diseases, with anky-
losing spondylitis first having been described in 1649 (Table 19.6.1).
Epidemiology
The mean age at onset of patients with axial spondyloarthritis is 20
to 30 years, with a slight preponderance of men. Next to rheumatoid
arthritis, the spondyloarthritides are the most frequent inflamma-
tory rheumatic diseases (Table 19.6.2), with ankylosing spondyl-
itis, psoriatic spondyloarthritis, and undifferentiated peripheral
spondyloarthritis being the most common subsets. The overall
prevalence of spondyloarthritides in patients presenting with back
pain to general practitioners’ surgeries in the United Kingdom has
been estimated at 5%.
The spondyloarthritides are associated with the major histo­
compatability complex class I antigen HLA B27, and the prevalence
of spondyloarthritides in any population correlates roughly with
that of HLA B27. The magnitude of association differs between the
subsets (Table 19.6.3): it has been mainly shown for ankylosing
spondylitis, but in Inuit populations reactive arthritis is more
frequent.
Pathogenesis
The overall influence of genes in the pathogenesis of ankylosing
spondylitis has been estimated to be 80 to 90%, leaving only 10 to
20% to other causative factors such as environmental influences,
including infections. HLA B27 is responsible for less than one-​third
of the total genetic load: more than 150 subtypes are now recog-
nized by polymerase chain reaction technology, two of which are not
associated with ankylosing spondylitis: HLA B2706 (Thailand) and
HLA B2709 (Sardinia). There is a weaker association of ankylosing
Table 19.6.1  First historical descriptions of spondyloarthritis
Spondyloarthritis
Moll/​Wright 1974, ESSG 1991
Ankylosing spondylitis
Connors 1649, Brodie 1888
Reactive arthritis/​Reiter’s syndrome
Reiter 1916, Ahonen 1973
Psoriatic arthritis
Wright 1959
Arthritis associated with inflammatory
bowel diseases
Bargen 1930
Enthesitis
Niepel 1961
HLA B27 association
Brewerton, Schlosstein 1973
(Undifferentiated) Spondylarthropathy
ESSG 1991
(Non​radiographic) axial
spondyloarthritis
ASAS 2009
ASAS, Assessment of SpondyloArthritis international Society; ESSG, European
Spondylarthropathy Study Group.
Table 19.6.2  Prevalence of spondyloarthritis
Disease
Prevalence
Spondyloarthritis
0.6–​2.0%
Ankylosing spondylitis
0.2–​1.4%
Undifferentiated spondyloarthritis
0.2–​0.7%
Reactive arthritis
0.01%
Psoriasis
1.0–​3.0%
Psoriatic arthritis
0.3%
Arthritis associated with inflammatory bowel disease
0.001%
19.6  Spondyloarthritis and related conditions
4443
spondylitis with HLA B60 and HLA DR1, and the interleukin 1 (IL1)
gene cluster, while the association with tumour necrosis factor α
(TNFα) polymorphisms is weak. Recently, ERAP-​1, IL-​23R have
been identified as major genetic contributors to ankylosing spon-
dylitis: in the case of ERAP-​1 this works only together with HLA
B27. Gene–​gene interactions have now been demonstrated between
ERAP1 variants and HLA‑B 27 and HLA‑B 40 in ankylosing spon-
dylitis, HLA‑Cw6 in psoriasis, and HLA‑B 51 in Behçet’s disease.
Of note, the main genes responsible for psoriasis (Cw6) and IBD
(NOD2) are not associated with ankylosing spondylitis. Non-​
MHC genes have also been genetically associated with ankylosing
spondylitis.
The relevance of HLA B27 to disease pathogenesis is unknown:
several models have been proposed to explain tissue tropism,
including the new bone formation, and the genetic associations of
the spondyloarthritides (Table 19.6.4). The strongest argument in
favour of a central involvement of the cellular immune system is the
combined genetic association of the MHC class I molecule HLA B27
with ERAP-​1. Another convincing finding has been the demonstra-
tion of TNFα mRNA and protein in the sacroiliac joints of patients
with ankylosing spondylitis.
The classical arthritogenic peptide model is backed by the dem-
onstration of HLA B27-​restricted CD8+ T-​cell clones in the synovial
fluid of patients with reactive arthritis. Immunodominant peptide
motifs and peptides have been described, but their pathogenetic
relevance is not yet clear. Lipopolysaccharide and RNA of bacteria
associated with reactive arthritis and a CD4+ T-​cell response dir-
ected against bacterial antigens have been detected in reactive arth-
ritis, but it is not clear whether this immune response is beneficial
or arthritogenic. At the humoral and the cellular level, molecular
mimicry (partial sequence homologies at the protein and DNA
level) between bacterial antigens and self structures (mainly the
HLA B27 molecule) has been described. It also seems possible that
patients with HLA B27+ SpA have deficient immune reactivity, for
example, diminished ability to secrete TNFα, or a synovial Th2 re-
sponse (secretion of too little interferon-​γ, too much IL-​4, IL-​10),
making elimination of bacteria difficult. Presentation of HLA B27-​
derived peptides themselves by HLA class II molecules, or even by
HLA class I molecules, has been proposed as an explanation of the
association of HLA B27 with disease.
The ‘HLA-​B27 mis-​folding hypothesis’ suggests that HLA B27
has a tendency to mis-​fold in the endoplasmic reticulum, it being a
particular feature of HLA B27 that newly synthesized HLA B*2705
molecules fold and associate with β2-​microglobulin (β(2)m) more
slowly than other MHC class  I  molecules. As a consequence of
this mis-​folding, free HLA B27 heavy chains can form abnormal
homodimers, which—​as β(2)m-​free HLA B27 homodimers and
multimers—​are expressed at the cell surface of leucocytes, dendritic,
and other cells with the possible function of antigen presentation.
There is also an increasing tendency to incriminate mechanical
stress as an initiating factor in pathogenesis.
Clinical features
The characteristic clinical features of the spondyloarthritides (see
Figs. 19.6.1–​19.6.3) are listed in Table 19.6.5.
Diagnosis
Five subsets of spondyloarthritis can be distinguished on clinical
grounds:  axial spondyloarthritis including ankylosing spondyl-
itis; reactive (spondylo)arthritis/​; psoriatic (spondylo)arthritis;
(spondylo)arthritis associated with inflammatory bowel diseases;
and undifferentiated peripheral spondyloarthritis.
Classification criteria for spondyloarthritides are shown in
Box 19.6.1. Inflammatory back pain is one of the main clinical
findings on which a diagnosis of axial spondyloarthritis can be
based (Box 19.6.2 and Table 19.6.6). Patients younger than 45
with chronic back pain (defined as being present for more than
three months), initially located to the buttocks (sometimes alter-
nating), who have significant morning stiffness, who frequently
wake up in the second half of the night because of pain, and who
report relief by exercise but not by rest, are very likely to have
axial spondyloarthritis. Other features of possible relevance in-
clude other clinical signs of spondyloarthritis (enthesitis, arthritis,
Table 19.6.3  HLA B27 association of spondyloarthritis. Note that
the prevalence of spondyloarthritis (mainly of the first four listed
in Table 19.6.2) relates to the prevalence of HLA B27 in different
populations
Spondyloarthritis
HLA B27 prevalence
Ankylosing spondylitis
85–​95%
Reactive arthritis
30–​80%
Reiter’s syndrome
60–​90%
Psoriatic arthritis
Peripheral arthritis
10–​30%
Axial involvement
40–​60%
Arthritis associated with inflammatory bowel diseases
Peripheral arthritis
10–​30%
Axial involvement
40–​60%
Undifferentiated spondyloarthritis
50–​70%
Population
HLA B27 prevalence
Native Americans
6–​50%
Inuit
15–​25%
North Europeans
10–​25%
Middle Europeans
6–​9%
North Americans
6–​8%
South Europeans
4–​6%
Africans
1–​5%
Table 19.6.4  Spondyloarthritis—​pathogenetic models
Model
Mechanism
Arthritogenic peptide
model
Bacterial protein processed/​ presented by B27 to
CD8+ T cells
Deficient immune
response
Failure of B27+ cells to properly present and
eliminate bacteria
Molecular mimicry
Similarity of bacterial and self structures, possibly
resulting in autoimmunity
Autoimmunity
Self structures such as B27-​derived peptides
presented by class I or II molecules
section 19  Rheumatological disorders
4444
anterior uveitis, family history), elevated acute phase reactants
(C-​reactive protein, ESR), the presence of HLA B27, and a good
response to nonsteroidal anti-​inflammatory drugs (NSAIDs).
HLA B27 contributes much more to the diagnosis of axial
spondyloarthritis than do elevated acute phase reactants, but
note that HLA B27 alone can never make a diagnosis, although it
does increase the probability of an underlying spondyloarthritis
by more than tenfold. Likelihood ratios have also been calculated
for the other items. In combination with the leading symptom
of chronic back pain starting before the age of 45, buttock pain,
improvement by movement and psoriasis, HLA B27 is of value
for identification of patients with spondyloarthritis in a primary
care setting.
Differential diagnosis
The most important, because most frequent, differential diagnosis is
nonspecific low back pain, especially if it exceeds 3 months duration
in a patient younger than 45 years. The leading clinical symptom
of inflammatory back pain may be associated with pain radiating
from the lower back to the thighs. Hence an important initial dif-
ferential diagnosis is sciatica, but this usually has an acute onset.
Fig. 19.6.1  Enthesitis at the insertion of the Achilles tendon in a patient
with reactive arthritis.
Table 19.6.5  Characteristic clinical features of spondyloarthritides
Clinical feature
Details
Inflammatory back pain
See Box 19.6.2
Sacroiliitis
Imaging
Peripheral arthritis
Affects predominantly but not exclusively the
lower limbs; it is often asymmetric but may also
involve both knees or ankles
Enthesitis
Inflammation at the insertion sites of tendons
and ligaments to bone (00A0;19.6.1 and 19.6.2)
Dactylitis
Inflammatory involvement of a whole finger or
toe (Fig. 19.6.3) with tendovaginitis and arthritis
(sausage digit)
Preceding infection
In the urogenital/​enteral tract 1–​6 weeks before
the onset of arthritis
Psoriatic skin lesions
Confirmed by a dermatologist
Crohn-​like gut lesions
Confirmed by a gastroenterologist
Anterior uveitis
Confirmed by a ophthalmologist
Family history of
spondyloarthritis
First-​degree relatives
Fig. 19.6.2  MRI showing inflammation of the plantar fascia in a patient
with spondyloarthritis.
Fig. 19.6.3  Dactylitis of the third finger of the right hand in a patient
with undifferentiated spondyloarthritis.
19.6  Spondyloarthritis and related conditions
4445
In inflammatory back pain, radiation is more often bilateral than
unilateral, rarely extends below the knees, almost never into the foot,
and is not associated with paraesthesia, although cough impulse
pain may be present. Diagnostic procedures for the detection of
disc herniation by magnetic resonance imaging (MRI) or computed
tomography (CT) can be misleading, as disc prolapses are found in
as many as 30% of normal individuals.
Diffuse idiopathic skeletal hyperostosis (DISH) or Forestier’s dis-
ease, an often-​severe radiographic spondylosis, can be difficult to
distinguish from longstanding ankylosing spondylitis. The appear-
ance and localization of the spondylophytes helps to differentiate
DISH from syndesmophytes and ankylosing spondylitis. Scoliosis is
not usually a marked feature of ankylosing spondylitis.
Classification requires the presence of one major and one minor
criterion (Table 19.6.6). Note that dactylitis, uveitis, and HLA B27
are not included. The peripheral arthritis does not have to be asym-
metric, although it often is; both knees or ankles might well be in-
volved. Inflammatory back pain is mostly due to sacroiliitis but can
also be caused by enthesitis. For patients with axial spondyloarthritis
who do not fulfil the criteria the term non​radiographic axial
spondyloarthritis has been created, but at present this is only rele-
vant for the approval status of biologics, since some are only ap-
proved for ankylosing spondylitis. Since the threshold between
non​radiographic axial spondyloarthritis and ankylosing spondylitis
(‘definite radiographic changes in the sacroiliac joints’) is artificial
and methodologically unreliable, it is recommended that only the
term axial spondyloarthritis be used for this condition.
Sacroiliitis occurs in several other rheumatic and infectious
diseases, as shown in Table 19.6.7. The differential diagnosis of
peripheral arthritis of the legs includes Lyme disease, sarcoidosis
(Löfgren’s syndrome), gout, and undifferentiated oligoarthritis.
The differential diagnosis of enthesitis includes epicondylitis and
fibromyalgia, and that of dactylitis is erysipela and infection.
Prognosis
The following seem to be poor prognostic factors for the develop-
ment of new bone formation (more syndesmophytes, ankylosis) in
patients with ankylosing spondylitis: male gender, the presence of
syndesmophytes at presentation, elevated C-​reactive protein (CRP),
much inflammation on MRI, smoking, manual work and (perhaps)
medication.
Box 19.6.1  ASAS Classification Criteria for axial spondyloathritis
Patients must have ≥3 months back pain with age at onset less than
45 years PLUS
Sacroiliitis on imaging PLUS ≥1 spondyloarthritis feature, or HLA-​B27
PLUS ≥2 other spondyloarthritis features
Spondyloarthritis features:
• IBP
• arthritis
• enthesitis heel
• uveitis
• dactylitis
• psoriasis
• Crohn’s/​colitis
• good response to non​steroidal anti-​inflammatory drugs
• family history for spondyloarthritis
• HLA-​B27
• elevated C-​reactive protein
Box 19.6.2  Features of inflammatory back pain
• nature: chronic back pain for more than three months
• age at onset: less than 45 years
• location: buttocks
• time characteristics:
—	morning stiffness for more than 30 minutes
—	wakening up in the second half of the night
—	slow onset
• response to interventions:
—	improvement by movement, not by rest
—	improvement by non​steriodal ani-​inflammtory drugs within 48 hours
• other features of spondyloarthritis
Table 19.6.6  Diagnostic criteria for spondyloathritis (1991
European Spondylarthropathy Study Group criteria)
Major criteria
Inflammatory back pain
Oligoarthritis (asymmetric) of the lower limbs
Minor criteria
Enthesitis
Alternating buttock pain
Preceding symptomatic infection
Psoriasis
Crohn-​like gut lesions
Family history
Radiographic sacroiliitis
Table 19.6.7  Differential diagnosis of sacroiliitis
Axial spondyloarthritis
Reactive arthritis
Psoriatic arthritis
Arthritis associated with inflammatory bowel disease
SAPHO syndrome
Other rheumatic diseases (rare)
Rheumatoid arthritis
Systemic lupus erythematosus
Sjögren’s syndrome
Gout
Osteoarthritis
Paget’s disease
Hyper/​hypoparathyroidism
Infectious diseases and malignancies
Septic sacroiliitis
Acute (staphylococci, steptococci, others)
Chronic (tuberculosis, brucellosis)
Malignancies (lymphoma, metastasis)
section 19  Rheumatological disorders
4446
In reactive arthritis—​a disease with a relatively good prognosis—​
HLA B27 is a risk factor for chronicity.
Ankylosing spondylitis
Ankylosing spondylitis is a chronic inflammatory rheumatic disease
that mainly affects the axial skeleton, starting in the sacroiliac joints
and often progressing to the spine, but peripheral joints, enthesial
structures, the anterior uvea, and the aorta can also become affected.
The diagnosis is made on the basis of significant radiological
changes in the sacroiliac joints and the spine, the typical clinical his-
tory of inflammatory back pain and stiffness, and evidence of limited
spinal movement and/​or chest expansion on physical examination.
Epidemiology
The age of onset is commonly in the twenties, but ankylosing spon-
dylitis can begin in childhood, or considerably later (at age >50).
The male:female ratio is about 2:1. About 80–​90% of white patients
with ankylosing spondylitis are positive for HLA B27, the percentage
may be a bit lower in axial spondyloarthritis.
There is a strong tendency of ankylosing spondylitis to recur
within families, with its heritability formally calculated to be more
than 90%. The likelihood of getting ankylosing spondylitis in a
sibling or first-​degree relative of a patient with ankylosing spon-
dylitis, compared with the prevalence in the general population,
is 52–​94 (the relative recurrence risk ratio). The recurrence risk
ratio in ankylosing spondylitis drops rapidly with increasing dis-
tance of relationship. Recurrence risk is also 6–​16-​fold higher in
HLA-​B27-​positive first-​degree relatives of patients with ankylosing
spondylitis compared with the risk of HLA-​B27-​carriers in the gen-
eral population. The non-​MHC contribution has been more accur-
ately quantified in studies of twins that show a concordance rate in
monozygotic twins (about 63%) that is substantially higher than in
dizygotic twins (about 12.5%), even when dizygotic twins are con-
cordant for HLA-​B27_​ (about 27%). Disease activity (51%), func-
tional impairment (68%) and radiographic change (62%) are also
heritable in ankylosing spondylitis.
There is a strong cofamiliality of ankylosing spondylitis with in-
flammatory bowel disease and psoriasis. First-​degree relatives of
patients with ankylosing spondylitis are c.3-​fold more likely to de-
velop Crohn’s disease or ulcerative colitis than unrelated individ-
uals. Psoriasis is at least threefold more common in patients with
ankylosing spondylitis than in the general community. The dis-
covery of multiple genes shared between these conditions has con-
firmed that these diseases are closely related.
Immunopathology and pathogenesis
The leading features of ankylosing spondylitis are spinal inflamma-
tion and ankylosis, but their cause is unknown. The association of
ankylosing spondylitis with bacterial infections is unlike reactive
arthritis. However, antibodies to Klebsiella pneumoniae have been
more frequently detected in patients with ankylosing spondylitis
than in healthy controls, but similarly often in patients with Crohn’s
disease and first-​degree relatives of those with ankylosing spon-
dylitis. This finding is probably explained by increased gut perme-
ability, and its predominant clinical association is with peripheral
(not axial) arthritis.
The sacroiliac joint is the structure most frequently involved in the
initial phase of disease. If biopsy is performed, T cells and macrophages
are seen to be the predominant infiltrating cells, with CD4+ and CD8+
T cells both present. The reason for this tropism is unclear. The fact that
sacroiliac and spinal joints are affected in diseases caused by mycobac-
teria and other microbes may argue for a pathogen-​triggered patho-
genesis in ankylosing spondylitis, but bacteria associated with reactive
arthritis have not been detected in the sacroiliac joints.
Clinical features
The most common initial symptom is inflammatory back pain, com-
monly in the lower back and the buttocks. Early in the course of
disease there may be no limitation of spinal movement or chest ex-
pansion. As it progresses, there is restriction of lateral flexion, for-
ward flexion, and extension. There is often a flattening of the lumbar
lordosis, or an inability to reverse this on forward flexion. With
more advanced disease a thoracic kyphosis develops, with concomi-
tant restriction of thoracic rotation and chest expansion due to in-
flammation and ankylosis of the costovertebral and costotransverse
joints. In severe cases movements of the cervical spine are also re-
stricted in all planes, with dramatic limitation of lateral flexion. The
combination of cervical stiffness and severe thoracic kyphosis can
lead to difficulties with forward vision. An example of a young pa-
tient with severe progressive disease is shown in Fig. 19.6.4. Severe
Fig. 19.6.4  Thirty-​year-​old man with rapidly progressive ankylosing
spondylitis (disease of five years’ duration).
19.6  Spondyloarthritis and related conditions
4447
spinal disease is more frequent in men than in women. There is no
evidence that pregnancy has a significant impact on the course of
the disease.
Peripheral joint involvement occurs in 30 to 50% of cases at some
time, with about 20 to 30% of patients having acute peripheral
arthritis of the legs, often with joint effusions as the first symptom,
this being especially marked in children. This situation is difficult
to differentiate from reactive arthritis. Joint involvement is usu-
ally oligoarticular and often asymmetrical. The joints most often
involved are the knees, ankles, hips, shoulders, wrists, temporo-
mandibular joints, sternoclavicular joints, manubriosternal joints,
costovertebral joints, zygapophyseal joints, and symphysis pubis.
Small joints are rarely affected.
Enthesitis occurs at the heel at the insertion of the Achilles tendon
(Fig. 19.6.1) and the plantar fascia (Fig. 19.6.2), and at the iliac
crests, the ischial tuberosities, the greater trochanters, and other
sites. The diagnosis is often difficult if no swelling is apparent, in
which case ultrasound can be revealing. Dactylitis of fingers and toes
is uncommon in ankylosing spondylitis, being seen most often in
psoriatic arthritis.
Physical examination of the spine and thoracic cage
The physical examination is important in the evaluation of patients
with ankylosing spondylitis—​in particular to quantitate flexibility of
the spine and thoracic cage. The following measurements are useful,
but it should be stressed that the values expected of normal individ-
uals are dependent on age and physical training.
• Anterior and lateral spinal mobility (Schober test):
■ Ventral—​with the patient standing upright, a horizontal line
is drawn across the lumbar spine connecting the two posterior
superior iliac spines. Marks are made in the midline over the
spine 10 cm cranial (original version) and 5 cm caudal (modi-
fied version) to the horizontal line. The patient then bends
with legs straight and the distance is measured again. It nor-
mally increases by more than 3 cm, and in younger people by
more than 5 cm. The measure is age dependent.
■ Lateral—​the distance between the tip of the longest finger and
the floor is measured in the upright position. This is repeated
when the patient tries to flex laterally towards the ground as far
as possible, normally moving by more than 10 cm.
• Chest expansion—​the circumference of the thorax is measured
in the fourth intercostal space after maximal inspiration and ex-
piration. It normally alters by more than 3 cm, in younger people
by more than 5 cm: again the measure is age dependent. In pa-
tients with ankylosing spondylitis it indicates involvement of the
costovertebral joints.
• Occiput/​wall distance—​in the upright position the patient
leans backwards against a wall. The distance between occiput
and wall is measured: there is no gap (0 cm) in most young pa-
tients; in patients with ankylosing spondylitis it usually indicates
hyperkyphosis of the thoracic spine.
• Chin/​sternum distance—​the chin is maximally bent towards the
sternum, and should normally be able to touch it.
• Cervical rotation—​the head is rotated to the left and right sides,
with the angles of rotation measured (normally >50°).
• Intermalleolar distance—​the patient tries to stand with their feet
together and also to spread their legs maximally: the malleoli
should normally touch and the distance of the spread feet usually
exceeds 1 m. This measure is dependent on age, training, and the
degree of osteoarthritis of the hip.
Physical examination for extra-​articular organ involvement
Acute anterior uveitis can occur at any time in the course of disease
and is seen in 20 to 30% of patients. It is typically unilateral, but ei-
ther eye may be affected in separate episodes. Recurrent attacks are
common. Aortic regurgitation secondary to aortitis occurs in about
1 to 2% of patients with ankylosing spondylitis, most frequently in
advanced disease, and may be associated with atrioventricular block.
Probably on the basis of a restrictive pulmonary defect due to limited
chest expansion, apical pulmonary fibrosis occurs in no more than 1%
of patients, especially those with advanced disease. Cauda equina syn-
drome caused by arachnoid cysts may complicate severe longstanding
disease, with resultant disturbance of the bladder and bowel function.
Lumbar diverticulae may be demonstrated by MRI.
Diagnosis
The 1984 modified New  York criteria for ankylosing spondylitis
are shown in Table 19.6.8. There is a significant diagnostic delay in
women (8 years) and in men (5 years), the most probable reason
being that back pain is a very frequent complaint, and that primary
care and general physicians are often not trained to distinguish in-
flammatory from other causes of back pain such that referral for spe-
cialist opinion is delayed.
Laboratory and radiological features
The ESR and the C-​reactive protein are raised in 30 to 50% of patients,
with moderate correlation to overall disease activity. Less com-
monly, serum IgA levels are raised. Mild to severe normochromic
normocytic anaemia occurs in about 10 to 20% of patients.
Note that other Spondyloarthritis-​like symptoms and syndes­
mophytes are not part of these criteria. For a definite diagnosis of
ankylosing spondylitis, the radiological criterion is essential and one
clinical criterion required. If only clinical symptoms and findings
are present, a diagnosis of probable ankylosing spondylitis may
be made.
Sacroiliac radiography
Dependent on stage, severity, and duration of disease, there are sacro-
iliac joint abnormalities in almost all patients. The radiological changes
are graded from 0 (normal), to I (minimal changes), II (sclerosis,
some erosions), III (severe erosions, pseudodilatation of joint space,
limited ankylosis), and IV (ankylosis) (Fig. 19.6.5). They are crucial
Table 19.6.8  Diagnostic criteria for ankylosing spondylitis
Clinical parameters
Inflammatory back pain
Limitation of spinal movement in three planes
Deterioration of chest expansion
Radiological parameters
Sacroiliac joint changes of at least:
Bilateral grade 2
Unilateral grade 3 or 4
section 19  Rheumatological disorders
4448
for the diagnosis of ankylosing spondylitis and for the differentiation
from undifferentiated spondyloarthritis, but it must be noted that
significant inter-​ and intraobserver variability has been reported—​
particularly concerning grades I and II—​which creates diagnostic
problems and confusion. Sclerosis, joint space narrowing, and even
synchondrosis occur in healthy elderly individuals. Oblique and
other special views are generally not significantly better than normal
anteroposterior pelvic radiographs, but can be helpful in a few cases.
Sacroiliac magnetic resonance imaging and computed
tomography
Sacroiliac radiographs may be normal in early ankylosing spondyl-
itis, and in clinically suspicious cases dynamic magnetic resonance
imaging of the sacroiliac joints can be helpful in providing objective
evidence of sacroiliitis. Active inflammation can be demonstrated
by enhancement after application of a contrast agent (gadolinium
DTPA) or by special magnetic resonance sequences, such as short tau
inversion recovery (STIR) or other fat saturation techniques that op-
timize the visualization of oedematous areas (Fig. 19.6.6). CT of the
sacroiliac joints is superior to normal radiographs for documenting
bony changes such as erosions and ankylosis. The sacroiliac joint is
accessible to biopsy under CT guidance.
Spinal radiography
The characteristic spinal lesion, mostly occurring in more advanced
disease, is the syndesmophyte—​a bony proliferation originating
from an inflammatory area at the ligamentous/​discal attachment
to the vertebral edge. This early ankylotic structure predominantly
grows cranially to fuse with the next vertebral body and has to be
distinguished from the spondylophyte, which mainly grows laterally
and typically indicates degenerative vertebral disease.
In ankylosing spondylitis, the earliest spinal lesions are frequently
in the lower thoracic and upper lumbar spine, sometimes preceded
by squaring of the vertebrae seen on lateral films. The zygapophyseal
joints are frequently involved at all stages. Anterior spondylitis is in-
dicated by lateral spinal radiographs showing hypersclerotic corners
(Romanus lesion, Fig. 19.6.7). Spondylodiscitis (Anderson lesion)
is revealed by erosion of the disc and vertebra with a hypersclerotic
lining. In later stages new bone formation and calcification of liga-
ments occurs, eventually leading to bridging syndesmophytes and
the characteristic ‘bamboo spine’ (Fig. 19.6.8).
Spinal magnetic resonance imaging
Early spinal inflammation (spondylitis, spondylodiscitis) can be de-
tected by dynamic MRI, which can be useful for localizing inflam-
mation in the spine in the early stages when plain radiographs are
normal.
Treatment
Although there is no cure for ankylosing spondylitis, several treat-
ments are available. The main therapeutic options are:
• Acute anti-​inflammatory therapy—​NSAIDs and local cortico-
steroids; systemic corticosteroids are not recommended
Fig. 19.6.5  Radiographic sacroiliitis (stage IV in both joints) in a 28-​
year-​old man with ankylosing spondylitis.
Fig. 19.6.6  MRI showing right-​sided active sacroiliitis.
Fig. 19.6.7  Radiographic anterior spondylitis (arrow) in a 42-​year-​old
man with ankylosing spondylitis.
19.6  Spondyloarthritis and related conditions
4449
• Disease-​modifying therapy—​sulfasalazine for peripheral arth-
ritis and possibly in early disease stages; methotrexate has limited
value for peripheral arthritis but is clearly not useful for axial
conditions. There is no evidence for the use of leflunomide, gold,
or hydroxychloroquine
• Antiresorptive therapy—​bisphosphonates (disodium pamidronate)
may have some value in selected patients (only one controlled trial,
no approval)
• Biologicals—​anti-​TNF therapy (infliximab, adalimumab, etanercept,
certolizumab, golimumab) and anti-​IL17A (secukinumab)
Non​steroidal anti-​inflammtory drugs are better than analgesics and
can be used in combination with them. Diclofenac (50–​150 mg),
meloxicam (7.5–​15 mg), acemetacin and indometacin (50–​150 mg)
are frequently given. Thalidomide and phenylbutazone, which had
been reserved for severe cases when other agents have failed, are now
very rarely used (where available). The more novel COX-​2 selective
coxibs (celecoxib 100–​200 mg, etoricoxib 90–​120 mg) are also
useful. The main risk of NSAIDs is gastrointestinal side effects: 25%
of patients are affected, ranging from dyspepsia to peptic ulceration
and (rarely) bleeding or perforation. It is important to identify pa-
tients at risk and to provide them with proper information about
possible symptoms. Prophylactic therapy with proton pump inhibi-
tors is indicated in those at particularly high risk (older age, history
of ulcer, disability, comorbidity). As most NSAIDs may be associ-
ated with a slightly increased incidence of cardiovascular events over
time, the individual risk profile of the patient also has to be taken
into account. This might be of special clinical relevance, as patients
with ankylosing spondylitis may have increased cardiovascular risk
because of persistent inflammation.
Most patients with ankylosing spondylitis do not respond to small
doses of corticosteroids. Transient high-​dose steroid treatment has
been tried in extreme cases with additional symptoms of inflamma-
tory bowel disease, with temporary and limited success.
Sulfasalazine is given in a dosage of 2–​3 g/​day, when effects may
be seen after 2 to 4 months. An influence on peripheral joint disease
has been demonstrated, but not on axial symptoms, which may be
due to the preferential study of patients with longstanding disease.
It is therefore mainly indicated for patients with peripheral arthritis.
Methotrexate is also often used in the absence of convincing data.
The anti-​TNFα antibodies infliximab (in a dosage of 5 mg/​kg intra-
venously every 6 to 8 weeks after an initial induction phase at weeks
0, 2, and 6), which has also been found to be effective in Crohn’s
disease and rheumatoid arthritis, and adalimumab (40 mg subcuta-
neously every 2 weeks), golimumab (50 mg subcutaneously every
month) and certolizumab (200 mg subcutaneously every two weeks)
have been shown in randomized placebo-​controlled trials to have
significant clinical efficacy in patients with persistently active axial
spondyloarthritis, including non​radiographic axial spondyloarthritis
and ankylosing spondylitis, but regulatory approvals are complex and
changing in both Europe and the United States.
The TNF receptor antagonist etanercept (50 mg subcutaneously
weekly, given either in one or two dosages) has similar clinical ef-
ficacy for musculoskeletal symptoms, but is less or not effective
for gut, skin, and eye symptoms associated with spondyloarthritis.
Secukinumab (an anti-​interleukin 17A monoclonal) has been ap-
proved for patients with active ankylosing spondylitis by both the
European and US regulatory agencies. The dosage of 150 mg sub-
cutaneously every 4 weeks, after an initial saturation phase with
every week dosing, is lower than that approved for psoriasis (300 mg
subcutaneously every 4 weeks).
The aim of physiotherapy is to maintain and enhance function
by improving mobility and muscle strength. Patients affected by
spinal stiffness should have physiotherapy on a regular daily basis.
Hip replacement is indicated for those with severe hip involve-
ment, and spinal osteotomy can be indicated in cases where visual
problems have occurred that are due to severe kyphosis.
Prognosis
The established myth is that ‘patients with ankylosing spondylitis
generally do well’. However, one-​third are severely disabled and ex-
perience intense pain and impairment of health comparable to those
with rheumatoid arthritis. ankylosing spondylitis does not burn
out: disease activity and pain are independent of its duration. As
the disease usually starts in the second or third decade of life, pa-
tients with ankylosing spondylitis typically suffer its effects for many
years. Mortality may be slightly increased, possible causes of prema-
ture death being amyloidosis, NSAID gastropathy (ulcers, bleeding),
vertebral fractures, and cardiac or respiratory complications.
Reactive arthritis/​Reiter’s syndrome
For further information see Chapter 19.8.
Undifferentiated spondyloarthritis
Definition
The term undifferentiated spondyloarthritis was introduced and
defined by the European Spondylarthropathy Study Group (ESSG)
Fig. 19.6.8  Spinal radiograph showing classical bamboo spine.
section 19  Rheumatological disorders
4450
in 1991. Terms such as incomplete Reiter’s syndrome, syndrome of
enthesopathy and arthritis, HLA B27-​positive oligoarthritis (and
others) had been used previously. The fact that patients with a clin-
ical picture of peripheral oligoarthritis but without spinal symp-
toms were also classified/​diagnosed as spondyloarthritis had indeed
been confusing for many rheumatologists. Now the terminology
has again changed and only patients with predominant peripheral
symptoms who do not have psoriasis, inflammatory bowel disease
or a preceding infection are named ‘undifferentiated’.
Patients with undifferentiated spondyloarthritis have the typ-
ical clinical features of predominant peripheral spondyloarthritis
but do not fit into any of the other defined categories as explained
here. The condition may represent an early form of another
spondyloarthritis subset (most often ankylosing spondylitis), or be
a genuine spondyloarthritis subset of its own. The new Assessment
of SpondyloArthritis International Society (ASAS) criteria for
spondyloarthritis cover axial and peripheral spondyloarthritis, es-
pecially axial spondyloarthritis is a possible predecessor of anky-
losing spondylitis, since at least 50% of patients go on to develop
this condition.
Epidemiology
The prevalence of peripheral undifferentiated spondyloarthritis
is not known precisely, but the frequency is not much less than
that of psoriatic arthritis, and it is more common in men. About
70% of patients are HLA B27-​positive. In some contrast to other
spondyloarthritides, late-​onset disease has been reported.
Clinical features
The main clinical features are asymmetric peripheral arthritis, pre-
dominantly of the lower limbs, enthesitis, dactylitis, anterior uveitis,
and some patients do also report inflammatory back pain.
Diagnosis
The term undifferentiated spondyloarthritis is no longer used for
patients with predominant axial symptoms but only for patients
with predominant peripheral symptoms. The diagnosis of periph-
eral undifferentiated spondyloarthritis requires peripheral arthritis
of the lower limbs and at least one other characteristic feature in
addition—​enthesitis, dactylitis, anterior uveitis, a positive family
history for spondyloarthritis, or HLA B27. The classification criteria
for peripheral spondyloarthritis have already been described. These
include psoriasis, inflammatory bowel disease, and a preceding
infection, but these features are now considered disease defining
and hence are not present in undifferentiated spondyloarthritis.
Radiographs are not essential for a diagnosis, but in clinically suspi-
cious cases MRI of the sacroiliac joints may be helpful in providing
objective evidence of sacroiliitis.
The differential diagnosis of asymmetric peripheral arthritis of
the lower limbs in spondyloarthritis comprises Lyme disease, sar-
coidosis, gout, osteoarthritis, atypical rheumatoid arthritis, and con-
nective tissue diseases and other rarer conditions.
Treatment
Non​specific therapy with NSAIDs, intra-​articular steroid injections,
transient immobilization, ice packs, and physiotherapy is similar to
that of other arthritides. Sulfasalazine may have some efficacy for
peripheral and axial symptoms, but very few therapeutic trials with
disease-​modifying agents have been performed in undifferentiated
spondyloarthritis. TNF blockers (so far mainly adalimumab) have
been shown to work for peripheral spondyloarthritis.
Prognosis
The long-​term prognosis of patients with peripheral undifferenti-
ated spondyloarthritis is uncertain: there are no data available at
present.
Psoriatic arthritis
Definition
All kinds of arthritis occurring in association with psoriasis can be
regarded as psoriatic arthritis, but it is clear that there can be con-
siderable variability in arthritic manifestation. Many patients can
be classified as having a spondyloarthritis, but some are affected in
a manner more closely resembling rheumatoid arthritis, and there
are other unique forms such as arthritis mutilans. Different forms of
psoriasis may be associated with different form of arthritis.
Epidemiology
Psoriasis is common, with prevalence between 1 and 3% of the
population. Arthritic symptoms occur in 20–​40% of these, with
the axial skeleton affected in 15–​25%, such that the overall preva-
lence of psoriatic arthritis is somewhere around 0.1–​0.3%. The peak
age of onset of psoriatic arthritis is between 20 and 40 years: ju-
venile disease is rare. Both sexes are equally affected, but women
more frequently get polyarthritis and men more often have spinal
involvement.
Pathogenesis
Familial aggregation and high concordance rates in monozygotic
(70%) compared with dizygotic twins (20%) suggest that there are
important genetic factors in psoriasis and psoriatic arthritis. About
30% of patients give a clear history of affected first-​degree rela-
tives. The genetic impact is thought to be multifactorial. Psoriasis
is associated with HLA B13, B17, B37, and HLA DR7, the strongest
association being with Cw6 (RR = 24). HLA associations of psori-
atic arthritis are with HLA B38 and B39 (peripheral arthritis), with
HLA DR4 (symmetric polyarthritis) and HLA B27 (spondylitis).
The importance of HLA genetic linkage may lie in determination
of the immunological response to particular antigens, and there has
been much interest in the possible role of streptococcal infection.
A proliferative response of skin and synovial T cells to streptococcal
antigens has been detected in psoriatic arthritis, but also in rheuma-
toid arthritis, and the (immuno)histology is similar in the two con-
ditions, although some differences have been described.
Koebner’s phenomenon is described in psoriasis, when plaques
arise at sites of skin injury, scratches, and scars, but the role of
trauma in psoriatic arthritis is not clear. Drugs can exacerbate and
trigger psoriasis: most well known are β-​blockers, antimalarials, and
lithium, and withdrawal of corticosteroids can induce a skin flare,
but the relevance of these factors to psoriatic arthritis is uncertain.
Clinical features
The most characteristic features of psoriatic arthritis are dactylitis
and osteoproliferative changes in radiographs of peripheral joints.
19.6  Spondyloarthritis and related conditions
4451
The pattern of axial involvement is somewhat different from that
in ankylosing spondylitis, and in contrast to rheumatoid arthritis,
patients with psoriatic arthritis may have involvement of the distal
interphalangeal joints. It is possible that psoriatic arthritis can occur
without skin involvement.
Psoriatic arthritis has been divided into five subgroups:  distal
interphalangeal (overlapping, most common); asymmetrical
(spondyloarthritis-​like); symmetrical (rheumatoid arthritis-​like);
mutilans (unique, rare; see Fig. 19.6.9); and spinal (ankylosing
spondylitis-​like). It must be stressed, however, that these subgroups
are not clearcut. In one study the initial classification pattern changed
when patients were evaluated over a period of eight years: finally
only two categories remained—​peripheral disease without axial in-
volvement (70%), and axial involvement with or without peripheral
arthritis (30%). The latter was correlated with duration of the disease
and magnitude of joint involvement. Erosions were found in 70% of
the patients.
Psoriasis precedes joint disease in most cases (70–​80%); both
occur simultaneously in 15%; and in about 10% arthritis comes first.
There is poor correlation between onset, severity, and activity of
psoriatic skin lesions and arthritis. More than 80% of patients with
psoriatic arthritis have nail dystrophy, whereas this is the case in
only 20% of those with uncomplicated skin disease. Nail dystrophy,
ranging from some to many nail pits and horizontal (not longitu-
dinal) ridging to onycholysis, occurs most often in those with distal
interphalangeal involvement. In some patients the involvement of
interphalangeal joints and nails is closely correlated, with both ap-
pearing on the same finger(s). Acute anterior uveitis occurs mainly
in those with radiological sacroiliitis and ankylosing spondylitis.
Different types of psoriatic skin involvement lead to different types
of arthropathy. Most frequent is the common psoriasis vulgaris, but
a type of skin disease that frequently affects the palms of the hands
and soles of the feet with many psoriatic plaques is also seen: pusto-
losis palmaris et plantaris. This type is associated with SAPHO syn-
drome, which is related to the spondyloarthritides but has unique
features that justify the designation as a separate subset of these
disorders.
A severe form of psoriatic arthritis can occur in HIV-​infected
patients, although is not clear whether HIV increases the overall
prevalence of psoriatic arthritis. Severe peripheral enthesitis
(predominantly of the heel) and dactylitis are characteristic. Knee
arthritis can be rapidly destructive. Axial inflammation is less
frequent.
There is an overlap between psoriatic arthritis and reactive arth-
ritis in the form of keratoderma blennorrhagica, a desquamating
psoriasis-​like lesion mostly occurring on the soles of the feet in pa-
tients with Reiter’s syndrome.
Psoriatic arthritis often improves during pregnancy. There is no
adverse effect of the disease on mother or child.
Diagnosis
Scaling erythematous papules and plaques on the scalp and ex-
tensor aspects of the extremities, often surmounted by a silvery
white micaceous scale that is easily removed, are suggestive of psor-
iasis. Elbows and knees are often affected. The diagnosis of psori-
atic arthritis is based on the presence of these characteristic skin
lesions, which are not always obvious. Less accessible areas such
as the navel, perineum, and scalp need to be examined carefully.
The patient should be asked whether they have a family history of
psoriasis or psoriatic arthritis.
As psoriasis is a frequent disease, it must be remembered that a
patient with psoriasis can have an attack of gout or another form of
arthritis. The diagnosis of psoriatic arthritis should be considered
in those without skin lesions if there is distal interphalangeal joint
involvement, dactylitis, the involvement of a whole finger or toe,
tendon sheaths and bone of an affected limb, and/​or typical radio-
graphic changes.
The CASPAR (Classification criteria for psoriatic arthritis) cri-
teria consist of established inflammatory articular disease with at
least three points from the following features:  current psoriasis
(assigned a score of 2; all other features are assigned a score of 1),
a history of psoriasis (unless current psoriasis is present), a family
history of psoriasis (unless current psoriasis is present or there is a
history of psoriasis), dactylitis, juxta-​articular new bone formation,
rheumatoid factor negativity, and nail dystrophy. These criteria are
sensitive (0.914) and specific (0.987).
Laboratory and radiological features
Acute phase reactants are often raised. HLA determinations
including HLA B27 do not provide diagnostic help in those with
psoriatic arthritis, but in HLA B27-​negative patients who appear to
have ankylosing spondylitis, psoriasis (and inflammatory bowel dis-
ease) should always be sought. The presence of rheumatoid factor
does not formally exclude a diagnosis of psoriatic arthritis, there
being a background prevalence of rheumatoid factor positivity, but a
positive result should always make the physician consider the diag-
nosis carefully.
The distribution of radiological changes reflects clinical involve-
ment, with the interphalangeal joints involved earlier than larger
joints. A  characteristic lesion in advanced cases is the so-​called
pencil-​in-​cup deformity (Fig. 19.6.10), which evolves by resorption
of the distal end of a phalanx or metacarpal with uniform deep ero-
sion of the end of the corresponding distal phalanx. In some cases the
joints can be completely destroyed and invisible on the radiograph.
Radiological grounds for thinking the diagnosis more likely to be
psoriatic arthritis than rheumatoid arthritis are distal interphalangeal
joint involvement, asymmetric joint involvement, marginal erosions
with adjacent bone proliferation (whiskering), osteolysis, periost-
itis, proliferative new bone formation, and ankylosis. Radiological
Fig. 19.6.9  Severe psoriatic arthritis (arthritis mutilans).
section 19  Rheumatological disorders
4452
sacroiliitis is a finding in 20 to 40% of patients. The axial disease in
psoriatic arthritis can be indistinguishable from that in primary an-
kylosing spondylitis, but in psoriatic arthritis the following are more
likely:  asymmetrical sacroiliitis; less zygapophyseal joint involve-
ment; fewer, coarser, and asymmetric syndesmophytes; and bony
bridging that is more often than not asymmetrical. Psoriatic arth-
ritis syndesmophytes can be indistinguishable from spondylophytes
typical of DISH (Forestier’s disease).
When scintigraphy is used to detect the extent and localization
of arthritis, an increased uptake of the isotope technetium-​99 can
frequently be detected in the sternoclavicular and manubriosternal
joints, but this is not necessarily associated with clinical symptoms.
Treatment
Many patients improve with the use of NSAIDs and intra-​articular
steroids, especially in the case of large joint involvement or flexor
tenosynovitis. However, 20 to 40% of patients will not improve
and need to be treated with conventional disease-​modifying
antirheumatic drugs or biologics. Sulfasalazine 2 to 3 g daily is often
effective against arthritis, especially in patients with limited skin
disease. Methotrexate 7.5 to 25 mg orally or subcutaneously weekly
is likely to also work for arthritis (limited data), and even better
for the skin. Intramuscular gold and azathioprine have been tried.
Antimalarials and penicillamine are not indicated; the former may
exacerbate psoriasis. Ciclosporin may be given in severe cases, es-
pecially with skin involvement. There is limited information on the
use of combination therapies. Systemic corticosteroids are limited
to extreme cases of arthritis: psoriasis usually flares when they are
withdrawn. Intra-​articular glucocorticoids are useful.
Local skin therapy has no effect on joint symptoms. Fumaric
acid is most frequently used as starting therapy in Northern
Europe. Etretinate is not clearly beneficial for arthritis and may
cause arthralgias and many other adverse reactions. Apremilast, a
phosphodiesterase-​4 inhibitor, has now been approved for psoriasis
and psoriatic arthritis. The safety profile is pretty good, no labora-
tory controls are necessary, and an effect on skin and joints has been
demonstrated, but the effect size in comparison to other biologics is
less impressive.
All anti-​TNF agents (see ankylosing spondylitis section) are ap-
proved for psoriasis and psoriatic arthritis, also an IL12/​IL-​23
inhibiting agent (these cytokines share the p40 receptor).
The role of physiotherapy is similar to that in other spondy­
loarthritides with predominant peripheral involvement, and there
are no special considerations for surgical intervention in psoriatic
arthritis, apart from the fact that the presence of florid skin lesions
close to a joint is a relative contraindication to surgery.
Prognosis
Severe psoriasis can lead to significant disability. There are only
limited data from long-​term studies in psoriatic arthritis, but in
cross-​sectional studies 10 to 20% of patients are in a poor functional
class, and the HLA antigens HLA B27, HLA B39, and DQw3 have
been associated with such an outcome.
Arthritis associated with inflammatory
bowel disease
Definition
An arthropathy with various clinical symptoms occurring in asso-
ciation with Crohn’s disease and ulcerative colitis is termed arth-
ritis associated with inflammatory bowel disease. Other forms of
arthropathy occurring in association with enteropathy are Whipple’s
disease, and arthritis after intestinal bypass surgery.
Epidemiology
A relationship between gut and joint disease was postulated in 1922
when Smith treated arthritis patients with segmental bowel surgery.
Bargen and Hench in 1929 and 1935 described arthritis in associ-
ation with ulcerative colitis and Crohn’s disease. Moll and Wright
included arthritis associated with inflammatory bowel disease in the
concept of spondyloarthritis in 1973. Mielants and Veys described
Crohn’s-​like gut lesions in all subsets of spondyloarthritis in 1984.
The prevalence of Crohn’s disease and ulcerative colitis is be-
tween 0.05 and 0.1% of the population, generally higher in white
and Jewish people. The peak occurrence of both diseases is between
15 and 35 years, but it may appear in every decade of life; both sexes
are equally involved. Arthritis associated with inflammatory bowel
disease occurs in 10 to 30% of patients with inflammatory bowel dis-
ease, in general more frequently in Crohn’s disease than in ulcerative
colitis, and more often in patients with colonic involvement and in
those with extensive bowel disease.
There is a genetic predisposition for inflammatory bowel disease
with documented familial aggregation for both Crohn’s disease and
ulcerative colitis. The association with HLA B16, HLA B18, and
HLA B62 is not strong. The peripheral arthritis of inflammatory
bowel disease is only weakly associated with HLA B27, but axial in-
flammation is more strongly associated with it (50%). The patient
with inflammatory bowel disease who is HLA B27-​positive is at high
risk of developing spondylitis. The relative frequency of sacroiliitis
and ankylosing spondylitis in inflammatory bowel diseases varies
Fig. 19.6.10  Radiograph of a hand showing destructive psoriatic arthritis.
19.6  Spondyloarthritis and related conditions
4453
between 2 and 20% or more, partly depending on the sensitivity of the
diagnostic imaging procedure. Only 4% of patients with ankylosing
spondylitis develop overt inflammatory bowel disease, whereas 60%
have microscopically detectable Crohn-​like gut lesions.
Pathogenesis
The pathogenesis of inflammatory bowel disease and arthritis as-
sociated with inflammatory bowel disease is not known. One hy-
pothesis is of an aberrant immune response to gut bacteria, with gut
inflammation leading to increased permeability, allowing bacteria
to cross the mucosal border and get access to joints. There is some
evidence from the HLA B27 transgenic rat model that gut and joints
are closely linked: susceptible rats get both colitis and arthritis once
they have left a germ-​free environment.
Clinical features
Patients with ulcerative colitis and Crohn’s disease typically pre-
sent with bloody diarrhoea and abdominal pain, and in severe
cases with fever, weight loss, and fatigue. For further details of
gastrointestinal and other non​rheumatological presentations, and
criteria for diagnosis, see Chapters 15.11 and 15.12.
As with the other spondyloarthritides, the arthritis is mostly
asymmetric and predominantly affects the legs. The arthritis is mi-
gratory, often transient, but tends to recur. It does not frequently
become chronic but may be associated with erosive disease in some
patients. Flaring of gut symptoms is often associated with arthritis,
especially in ulcerative colitis. Patients experience significantly
fewer joint symptoms after colectomy.
Two types of arthropathy were distinguished in a study of almost
1500 patients with inflammatory bowel disease, essentially on the
basis of how many joints are involved and (importantly) without
knowledge of spinal radiographs. Pauciarticular disease (type I,
fewer than five joints involved) affected 3.6% of patients with ulcera-
tive colitis and 6% of those with Crohn’s disease and was acute and
self-​limiting, with episodes lasting four to five weeks, in 83 and 79%
of the cases. Polyarticular disease (type II, five or more joints) af-
fected 2.5% of patients with ulcerative colitis and 4% of those with
Crohn’s disease and was associated with persistent symptoms in
87–​89% of the cases.
The onset of peripheral arthritis is associated with exacerbations
of colitis, but there is no link between enteric and spinal symptoms.
Acute anterior uveitis occurs in 10% of patients with inflamma-
tory bowel disease. It is associated with axial involvement and with
HLA B27. The type of uveitis is somewhat different in inflammatory
bowel diseases to that in other spondyloarthritides: posterior uveitis
and scleritis may occur. The most common skin lesion in arthritis
associated with inflammatory bowel disease is erythema nodosum,
occurring in association with exacerbation of enteritis.
Diagnosis
Most arthritic symptoms occurring in patients with inflammatory
bowel disease can generally be attributed to spondyloarthritides.
However, as in psoriasis, patients can have more than one dis-
ease (osteoarthritis, and so on). As many as 50–​60% of all patients
with ankylosing spondylitis have gut lesions resembling those in
Crohn’s disease, but most are asymptomatic. Clinically apparent
ankylosing spondylitis often precedes Crohn-​like symptoms. This
spectrum of diseases clearly and typically belongs to the spectrum
of spondyloarthritides. The differentiation (if needed) will rarely
cause problems, as one disease is usually predominant. Along with
psoriasis, inflammatory bowel disease should always be looked
for in HLA B27-​negative patients who appear to have ankylosing
spondylitis.
Treatment
Treatment of inflammatory bowel disease is always the first consid-
eration and will probably influence peripheral arthritis. Treatment
with NSAIDs may be effective for arthritis and spondylitis but
can exacerbate bowel disease. There are few data on the use of
DMARDs. Sulfasalazine is effective in ulcerative colitis and other
spondyloarthritides and may accordingly be used in arthritis asso-
ciated with inflammatory bowel disease. Azathioprine is effective in
Crohn’s disease and can be tried to treat severe and chronic joint
disease. Corticosteroids are the therapy of choice in acute inflamma-
tory bowel disease and will generally help arthritis, but they should
not be used for mild and transient joint symptoms. As previously
stated, NSAIDs tend to exacerbate gut symptoms, but etoricoxib did
not cause more flares than placebo (both c.10%) in one controlled
study. In more severe cases biologics are used to treat inflammatory
bowel disease and this will usually also have an effect on joint or axial
symptoms.
Prognosis
The prognosis of arthritis associated with inflammatory bowel dis-
ease is generally good. Joint destruction is a rare event. Patients may
have ankylosing spondylitis at presentation of inflammatory bowel
disease, or develop this later.
SAPHO syndrome
Definition
French workers proposed SAPHO (synovitis, acne, pustolosis
palmaris et plantaris, hyperostosis, and osteitis) as a unifying diag-
nosis for several idiopathic bone and skin diseases, thereby com-
bining over 50 different terms published in the literature (including
pustulotic arthro-​osteitis, chronic multifocal osteomyelitis, Tietze
syndrome (German), and acquired hyperostosis syndrome). Their
description of the common symptoms and overlapping features of
this heterogenous group of rheumatic joint, bone, and skin diseases
has led to better recognition of the relatively rare condition.
There is an argument that SAPHO simply represents a subset
of psoriatic arthropathy, also that it might not really belong to the
spondyloarthritides at all because only 43% of patients with SAPHO
fulfilled the European Spondylarthropathy Study Group criteria,
and only 1 in 19 was HLA B27-​positive in one follow-​up study.
However, there are some clear similarities.
Pathogenesis
The pathogenesis of SAPHO syndrome is unclear. Some authors
think that it is similar to that of reactive arthritis. Propionibacterium
acnes, which can induce arthritis in animals, has been detected
in acne lesions and grown from osteitic lesions in some cases.
However, cultures are negative in most cases, and antibiotics are
ineffective.
section 19  Rheumatological disorders
4454
Diagnosis
There are no evaluated diagnostic criteria for SAPHO. Most con-
vincing clinically is the combination of a classical skin symptom—​
such as pustolosis or significant acne (acne conglobata and acne
fulminans or hidradenitis suppurativa)—​with a characteristic joint
or bone lesion such as arthritis of the sternoclavicular joint, osteitis,
or hyperostosis in the anterior chest wall.
Diagnosis is important to avoid unnecessary biopsy procedures,
but can be very difficult, especially in those without typical skin le-
sions. The most important differential diagnoses are bacterial osteo-
myelitis and malignancy. The pattern of joints affected differs from
other rheumatic diseases: the sternoclavicular joint (Figs. 19.6.11
and 19.6.12), the clavicle, the ribs, and the mandible are frequently
involved by arthritis, osteitis, and/​or hyperostosis. Sacroiliitis,
mostly unilateral, occurs in one-​third of patients.
Treatment
Analgesics, NSAIDs, and intra-​articular steroids are usually ef-
fective. In severe cases systemic corticosteroids should be con-
sidered. Immunosuppressive agents can be added if the steroid
dose cannot be tapered to less than 10 mg/​day of prednisolone
(or equivalent). Sulfasalzine, azathioprine, and methotrexate have
been tried successfully in some cases. Radiation therapy can also
be effective in refractory cases. No controlled studies have been
performed. Patients with refractory disease might also respond to
treatment with TNF blockers. There are positive case reports also
for bisphosphonates.
Prognosis
The course of disease is very variable. Initially, occurrence of sev-
eral flares per year is common. Further progress is usually favour-
able, but complications such as axillary vein and C8 compression
can occur. Some patients may develop ankylosis and a few progress
to ankylosing spondylitis.
Other enteric arthropathies
Whipple’s disease
Whipple’s disease is a rare systemic disease that usually involves the
small intestine (see Chapter 15.10.6). The associated arthritis is often
symmetric and polyarticular, and may antedate the intestinal com-
plaints by years. It is not usually destructive. Axial involvement oc-
curs but is not typical.
Arthritis associated with coeliac disease
For a description of coeliac disease (gluten-​sensitive enteropathy)
see Chapter 15.10.3. The joint manifestations show a striking re-
sponse to a gluten-​free diet, which strongly suggests a causal rela-
tionship. The pattern of arthritis is very variable, and overt bowel
symptoms are absent in half of cases, making diagnosis difficult. The
lumbar spine, hips, knees, shoulders, elbows, wrists, and ankles are
most frequently affected, often symmetrically. The arthritis is not de-
structive. HLA B8 and DR3 are frequently found. The pathogenesis
is unclear.
Arthropathies associated with collagenous colitis
Collagenous colitis is a chronic diarrhoeal disease character-
ized by a normal or near-​normal mucosa endoscopically and a
thick subepithelial collagen layer. More than half of patients
with this disorder have some form of arthritis and use NSAIDs
regularly.
Arthropathies associated with intestinal bypass surgery
Arthritis has been reported in 5–​50% of patients in the first
three years after jejunoileal bypass surgery. A symmetric periph-
eral polyarthritis involves the knees, wrists, metacarpophalangeal
and metatarsophalangeal joints, elbows, proximal interphalangeal
joints, and ankles and is usually nondestructive. Almost half of
those affected also have vesicopustular skin lesions. No specific
HLA association has been found, but two previously healthy
HLA B27-​positive patients developed spondylitis. Bacterial over-
growth of the blind loop is critical for pathogenesis.
Fig. 19.6.11  Arthritis/​hyperostosis of the left sternoclavicular joint in a
52-​year-​old man with SAPHO syndrome.
Fig. 19.6.12  Computed tomography scan showing severe osteitis of the
left sternoclavicular joint in a 35-​year-​old woman with SAPHO syndrome.
19.6  Spondyloarthritis and related conditions
4455
FURTHER READING
General
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Brebam M, Hacquard-​Bouder C, Falgarone G (2004). Animal models
of HLA-​B27-​associated diseases. Curr Mol Med, 4, 31–​40.
Calin A, et al. (1977). Clinical history as a screening test for ankylosing
spondylitis. J Am Med Assoc, 237, 2613–​14.
Dougados M, et al. (1991). The European Spondylarthropathy Study
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Khan MA, van der Linden SM (1990). A wider spectrum of
spondyloarthropathies. Semin Arthritis Rheum, 20, 107–​13.
Moll JM, et al. (1974). Associations between ankylosing spondylitis,
psoriatic arthritis, Reiter’s disease, the intestinal arthropathies, and
Behçet’s syndrome. Medicine (Baltimore), 53, 343–​64.
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Ankylosing spondylitis
Braun J, Seiper J (2007). Ankylosing spondylitis. Lancet, 369, 1379–​90.
Brophy S, et al. (2002). The natural history of ankylosing spondylitis
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Undifferentiated spondyloarthritis
Olivieri I, et  al. (2001). Ankylosing spondylitis and undifferenti-
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disease subset with older age at onset. Curr Opin Rheumatol, 13,
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Zeidler H, Mau W, Khan A (1992). Undifferentiated spondyloar­
thropathies. Rheum Dis Clin North Am, 18, 187–​202.
Psoriatic arthritis
Gladman DD (1998). Psoriatic arthritis. Rheum Dis Clin North Am,
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Gossec L, et  al. (2016). European League Against Rheumatism
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Helliwell PS (2004). Relationship of psoriatic arthritis with the other
spondyloarthropathies. Curr Opin Rheumatol, 16, 344–​9.
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Marsal S, et al. (1999). Clinical, radiographic and HLA associations as
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Arthritis associated with inflammatory bowel disease
Leirisalo-​Repo M, et al. (1994). High frequency of silent inflamma-
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section 19  Rheumatological disorders
4456
Other enteric arthropathies
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19.7 Infection and arthritis 4457 Graham Raftery a
19.7 Infection and arthritis 4457 Graham Raftery and Muddassir Shaikh
ESSENTIALS
Bacterial causes of arthritis—​Septic arthritis is the most serious cause
of one or more hot swollen joints. A causative organism can be iden-
tified in about 80% of cases, with Staphylococcus aureus the most
common, followed by Streptococcus and gram-​negative organisms.
The key diagnostic investigation is microscopy and culture of aspir-
ated joint fluid. Management is with drainage of bacteria, pus, and
debris from the joint, along with antibiotics. Consensus is that these
should be given intravenously for up to two weeks, or until clinical
signs improve, followed by oral antibiotics for four weeks. Prosthetic
joint infection is a particular challenge requiring specialist care.
Viral causes of arthritis—​Arthralgia and/​or arthritis are common oc-
currences with many viral infections, particularly parvovirus, hepa-
titis B and C, rubella, human immunodeficiency virus, α-(including
chikungunya) and dengue viruses. Joint manifestations are usually
sudden in onset, correlate with the onset of clinical illness, and gen-
erally self-​limiting, but can persist following infection with chikun-
gunya and dengue.
Bacterial causes of arthritis
Introduction
There is a broad differential diagnosis for the patient presenting with
one or more hot swollen joints (Fig. 19.7.1). Septic arthritis is the
most serious of these; it is a medical emergency with a case fatality
rate of 11% for monoarticular disease and 30% for polyarticular dis-
ease. Considerable morbidity is also associated with the condition;
a poor functional outcome is seen in 24%, while osteomyelitis com-
plicates 8% of cases.
Epidemiology
The incidence of septic arthritis is 2–​10 per 100 000 and is thought to
be rising due to the combination of an ageing population, greater use
of immunosuppressive therapies and increased orthopaedic proced-
ures such as arthroscopies.
Septic arthritis typically occurs in the very old and very young.
Risk factors for septic arthritis are presented in Table 19.7.1. The
presence of pre-​existing joint pathology is an important risk
factor, with the risk greater in rheumatoid arthritis compared to
osteoarthritis. Rheumatoid arthritis is present in 15% of cases of
monoarticular and 50% of cases of polyarticular septic arthritis. The
increased risk with rheumatoid arthritis is likely to be multifactorial;
rheumatoid arthritis itself is a risk factor for infection, while therapy
for this condition also confers additional risk. UK national registry
data shows an increased risk of septic arthritis in rheumatoid arth-
ritis patients treated with anti-​TNF therapy when compared to
those treated with conventional disease-​modifying antirheumatic
19.7
Infection and arthritis
Graham Raftery and Muddassir Shaikh
Acute
monoarthritis
Gout
Calcium
pyrophosphate
Bacterial
Fungal
Mycobacterial
Osteoarthritis
Avascular necrosis
Spontaneous
haemarthrosis
Reactive
arthritis
Rheumatoid
arthritis
Trauma
Infection
Lyme disease
Inflammatory
arthritis
Psoriatic
arthritis
Other
causes
Crystals
Calcium oxalate
Hydroxyapatite
Pigmented villonodular
synovitis
Fig. 19.7.1  Causes of acute monoarthritis.
Table 19.7.1  Risk factors for septic arthritis
Rheumatoid arthritis
Joint prosthesis/​recent joint surgery
Diabetes
Alcoholism
Intravenous drug abuse
Leg ulceration
Low socioeconomic status
Pharmacological immunosuppression
section 19  Rheumatological disorders
4458
drug therapies; this increased risk is greatest in the early months
following initiation of this treatment. Local and distant risk fac-
tors for infection may be present. Local factors include hip or knee
prosthesis and recent arthroscopy. Septic arthritis is recognized
following intra-​articular injection, but the absolute risk associated
with this procedure is low (three infections per 7900 procedures).
Of the distant risk factors, skin infection is of particular importance.
Diagnostic criteria
Criteria for the diagnosis of septic arthritis proposed by Newman
have been widely accepted. The diagnosis of septic arthritis is made
when one of the following four points is met:
Organism is isolated from affected joint
Organism is isolated from elsewhere (in the context of clinical
suspicion of septic arthritis of one or more joints)
There is histological or radiological evidence of joint infection
There are clinical features of septic arthritis with turbid fluid as-
pirated from joint (usually in context of prior antibiotic therapy)
Pathogenesis
Study of human septic arthritis pathogenesis is challenging.
A  murine model of septic arthritis developed by Tarkowski has
been used to study bacterial virulence and host response with a
focus on Staphylococcus aureus-​induced disease. This mouse model
of septic arthritis has similarities to human arthritis; the arthritis
is induced by haematogenous spread while the rate of progression
and severity of joint damage also mirror human disease.
Bacterial virulence
The virulence of Staphylococcus aureus comes from several bacterial
factors. A capsule is expressed by many strains and acts as a phys-
ical barrier inhibiting phagocytosis. Adhesins are cell surface com-
ponents which facilitate bacterial colonization of host tissue; each
strain of Staph Aureus can express different adhesins. Inactivation
of adhesins by vaccination has a protective effect for mice exposed
to Staph Aureus. Staphylococcal protein A  (a cell wall anchored
protein) is another virulence factor. Strains expressing this pro-
tein are associated with more severe arthritis and increased mor-
tality. Staphylococcus aureus produces many toxins and enzymes.
A subset of ‘superantigen’ toxins stimulate T lymphocytes to release
pro-​inflammatory cytokines with systemic effects such as fever
and hypotension. Superantigen producing strains of Staphylococcus
aureus are more likely to induce septic arthritis of an increased
severity and associated with greater mortality when compared to
strains not producing superantigen toxins.
The host response
Neutrophils have an important role in the early response to
Staphylococcus aureus infection. Peptides produced by Staphylo­
coccus aureus act as a chemoattractant for neutrophils. A deficiency
in neutrophils increases the severity of disease, as does comple-
ment deficiency. Macrophage derived cytokines facilitate joint
damage but these cytokines also have a protective role. TNFα has
a role in bacterial clearance and is associated with reduced mor-
tality, while IL1 receptor signalling is involved in host protection
during Staphylococcus aureus infection. B lymphocytes are not sig-
nificantly involved in septic arthritis whereas T lymphocytes are
actively involved in the disease process. Cytokines expressed by T
lymphocytes have a mixed role: interferon-​γ is implicated in joint
destruction but is protective in early septic arthritis; IL-​10 acts as
an anti-​inflammatory molecule and a lack of IL-​10 causes enhanced
joint destruction; IL-​4 acts as an inhibitor to phagocytosis resulting
in decreased clearance of bacteria.
Causative organisms
The distribution and sensitivities of pathogens causing septic arth-
ritis has changed little over the last 20 years. A causative organism
is identified in 82% of cases. Staphylococcus aureus is the most com-
monly identified organism, followed by Streptococcus. Methicillin-​
resistant Staphylococcus aureus (MRSA) is responsible for around
10% of Staphylococcus aureus infections. While Staphylococci and
Streptococci are also the most prevalent organisms in all at risk sub-
groups, gram-​negative organisms are often seen in the very young
and very old, patients with diabetes, and intravenous drug users.
Intravenous drug users are prone to infections with an array of or-
ganisms, including pseudomonas, anaerobes, and fungi.
The role of immunosuppression is important. In patients treated
with anti-​TNF therapies developing septic arthritis, Staphylococcus
aureus is the most commonly reported organism, with MRSA re-
corded in 11% of cases. Organisms that rarely cause septic arthritis
in the immunocompetent can be seen in patients treated with anti-​
TNF therapies; cases of septic arthritis with intracellular organisms
such as salmonella and listeria have been documented.
Prosthetic joint infection is typically caused by Staphylococcus,
with coagulase negative Staphylococci and MRSA more prevalent
than in native joint infection.
Clinical features
The typical presenting symptoms are joint pain, redness, and
swelling, with restriction in range of movement of the affected joint.
Symptoms usually evolve over a few days up to three weeks, with a
median time to hospital admission of seven days. The knee is the
most frequently affected site. Polyarticular disease is present in
around 15% of patients with a mean of three joints involved. Pain
in a joint with known arthropathy is likely to be disproportionate to
the typical pain experienced in that joint. Symptoms suggestive of
infection (fever, sweats, and rigors) may not be present and raised
temperature on admission to hospital is only seen in around 60%
of patients.
Investigations
An algorithm for management of the hot swollen joint in adults is
shown in Fig. 19.7.2.
Tests of synovial fluid and blood
Synovial fluid should be aspirated from the affected joint and sent
for gram stain and culture prior to antibiotic therapy. Gram stain
is positive in around 50% of patients and culture is positive in 67%.
In addition to gram stain and culture, synovial fluid should also be
analysed for crystals by polarizing light microscopy. Suspected pros-
thetic joint infection should be referred to an orthopaedic surgeon
and aspirated in theatre under full aseptic technique.
Blood cultures should always be taken, and as with joint aspir-
ation this should be done prior to antibiotic therapy to increase the
likelihood of a positive microbiological diagnosis. Blood cultures
19.7  Infection and arthritis
4459
are positive in 33% to 46% of cases and can be so when the joint
aspirate is negative.
White cell count (WCC), C-​reactive protein (CRP), and
erythrocyte sedimentation rate (ESR) should all be checked
and are usually raised. However, each of these can be normal
in patients with septic arthritis and this finding does not refute
the diagnosis. Particular caution should be exercised in patients
taking immunosuppressive therapies; for example, Tocilizumab
profoundly suppresses C-​reactive protein production by the liver
via its inhibition of IL-​6.
Patient presents with acute increase in pain ± swelling in one or more joints
GP
History
examination
Clinical
impression
septic arthritis
No definite
alternative
diagnosis
Definite
alternative
diagnosis
Inflammatory
arthritis
Crystal arthritis
Haemarthrosis
Trauma
Bursitis/cellulitis
Treat as
appropriate
Refer for urgent A&E
or specialist
assessment
Self referral to
A&E
History
examination
MUST ASPIRATE
and other
investigations
NOT SEPTIC
Diagnosis SEPTIC ARTHRITIS
Empirical antibiotic treatment (as per local protocol)
Alter if necessary once results available
Management of septic arthritis in secondary care
Admit patient to hospital (rheumatology or
orthopaedics according to local custom)
Ensure synovial fluid sample is taken, with blood and any other relevant
culture samples prior to starting antibiotics
Commence antibiotics as per protocol
Joint should be aspirated to dryness as often
as required (either by needle aspiration or
arthroscopically)
Seek rheumatology or
orthopaedic advice if
in doubt
Further imaging e.g. MRI–osteomyelitis may require surgical intervention
If there is lack of resolution despite treatment consider the following:
Incorrect causative organism
Modification of antibiotic therapy
Seek specialist advice
Alternative foci of infection or systemic sepsis
Fig. 19.7.2  Algorithm for the management of hot swollen joint in adults.
Reproduced from Coakley G et al. (2006) BSR & BHPR, BOA, RCGP and BSAC guidelines for management of the hot
swollen joint in adults. Rheumatology (Oxford), 45(8), 1039–​1041, by permission of Oxford University Press.
section 19  Rheumatological disorders
4460
Renal and liver function should also be checked to assess end
organ damage, which may inform choice of antibiotic.
Investigations to identify a distant source for infection should be
tailored to the clinical presentation and may include chest X-​ray,
urine culture, wound and ulcer swab culture. Similarly, investiga-
tions to look for a haematogenous source of infection should be
considered (e.g. echocardiography). Endocarditis and discitis can
precede, coexist with, or complicate septic arthritis (especially due
to Staphylococcus aureus) in up to 5% of patients.
If gonococcal septic arthritis is suspected the microbiology labora-
tory should be informed before joint aspiration as delay in culturing the
joint aspirate can lower the yield for gonococcus growth. Gonorrhoea
nucleic acid amplification testing (NAAT) should be requested from
the following sites in those with possible gonococcal septic arthritis,
ensuring the correct swabs are used:  heterosexual men—​first pass
urine sample and throat swab; men who have sex with men—first
pass urine sample, throat swab and self taken rectal swab; women-self-
taken vaginal swab, self-taken rectal swab and throat swab​.
Molecular diagnostic techniques such as broad range polymerase
chain reaction targeting 16S ribosomal RNA will increasingly have a
role to play in culture negative septic arthritis. These are particularly
useful where patients have received antibiotic therapy prior to cul-
ture, and also in identifying anaerobes and other organisms such as
Kingella Kingae, where conventional culture yield is low.
White cell count, C-​reactive protein, and erythrocyte sedi-
mentation rate cannot reliably differentiate septic arthritis from
non​infective causes. Serum procalcitonin is an emerging biomarker
which may be useful in this regard; a small number of studies have
shown procalcitonin to be sensitive and specific in early septic arth-
ritis, and serum procalcitonin does not rise in acute crystal arthritis.
The main limitation of procalcitonin measurement is that it is likely
to be raised in any bacterial infection, and many patients with a hot
joint will have non​articular infection at presentation. In such pa-
tients procalcitonin has no discriminant function. Furthermore, the
limited evidence in suspected prosthetic joint infection has found
procalcitonin to be less sensitive than C-​reactive protein.
Imaging
Plain radiographs do not have a role in the diagnosis of septic arth-
ritis but may offer clues to an alternative diagnosis, such as the
presence of chondrocalcinosis caused by calcium pyrophosphate
deposition. Current imaging modalities cannot reliably differentiate
septic arthritis from other acute inflammatory joint pathology, but
MRI is useful in the assessment of osteomyelitis. Ultrasound can be
useful to guide joint aspiration, particularly from deep joints such
as the hip.
Management
Antibiotics
There is a paucity of high-​quality evidence on antibiotics for native
joint septic arthritis and no clear preferred antimicrobial strategy.
Consensus is that intravenous antibiotics should be given for up
to two weeks, or until clinical signs improve, followed by oral anti-
biotics for four weeks. An exception is gonococcal arthritis, which is
treated with a one-​week course of a third generation cephalosporin.
UK guidance on antimicrobial therapy for septic arthritis is shown
in Table 19.7.2. The choice of empiric treatment should adequately
treat Staphylococcus aureus and Streptococcus, as these are the most
likely pathogens in all patient groups; antibiotic choice should also
be informed by patient risk factors and local patterns of organism
prevalence and drug resistance.
Drainage
Bacteria, pus, and debris should be removed from the joint. The op-
tions for this include closed needle aspiration, or surgical drainage
by arthroscopy or open arthrotomy. There is a lack of evidence to
favour one approach over another, with little difference in mortality
or length of hospital stay. Whichever technique is chosen, it should
be repeated as required. In patients who have a suboptimal response
to needle aspiration, arthroscopic aspiration or open arthrotomy
should be used. Historically, open arthrotomy has been the preferred
technique for septic arthritis of the hip although there is evidence
that arthroscopy may be a safe and effective technique in this setting.
Prosthetic joint infection
Prosthetic joint infection is a particular challenge. The presence of
foreign material within the joint provides a platform for biofilm for-
mation, an organized bacterial colony that grows on the implant
surface. Bacteria within the biofilm may transiently have reduced
metabolic activity and become less susceptible to antibiotics reliant
on cellular replication for their mechanism of action. The biofilm is
difficult to eradicate.
Effective management of prosthetic joint infection requires a sur-
gical strategy combined with appropriate antibiotic therapy. Multiple
factors influence the choice of surgical strategy. In patients with a
well-​fixed prosthesis within 30 days of prosthesis implantation or
with less than three weeks of infectious symptoms, debridement,
antibiotics, and implant retention can be considered. For infections
that occur more than 30 days following arthroplasty, joint revision
is almost always required. Joint revision can be performed as a one-​
stage or two-​stage procedure, with the latter being more commonly
employed. A two-​stage procedure separates joint removal, debride-
ment and closure (the first-​stage) from subsequent re-​insertion by
weeks or months. A one-​stage exchange may be chosen if the patient
is not able to undergo multiple operations and providing there is
good soft tissue and good bone stock.
Novel therapeutics
Corticosteroids
Joint destruction in septic arthritis occurs as a consequence of the in-
flammatory response to infection. The suppression of the inflamma-
tory response with corticosteroids has been proposed as a potential
adjuvant treatment. Two randomized, placebo controlled studies have
looked at the administration of intravenous dexamethasone in add-
ition to antibiotics for management of septic arthritis in children. This
was found to be safe and led to a more rapid clinical improvement
than standard treatment. There was also significantly less residual
joint dysfunction at 6 and 12 months in the dexamethasone group.
However, at present there is insufficient evidence to advocate the use
of corticosteroids in the management of adult septic arthritis.
Bisphosphonates
Bisphosphonate therapy has been investigated in animal models of
Staphylococcus aureus septic arthritis. The addition of zoledronic
19.7  Infection and arthritis
4461
acid to antibiotics and corticosteroids led to less osteoclast activity
and less severe arthritis. While the authors propose this triple treat-
ment be considered in human septic arthritis, there is insufficient
evidence to support this approach at the present time.
Viral causes of arthritis
Introduction
Arthralgia and/​or arthritis are common occurrences with many
viral infections. Joints complaints are a common manifestation of
infections with parvovirus, hepatitis B and C, rubella, α- and dengue
virus, and joint symptoms are observed less commonly in associ-
ation with a wide variety of other viral infections (e.g. herpes viruses
including Epstein–​Barr virus, mumps, human immunodeficiency
virus, and enteroviruses).
Aetiology and pathogenesis
A  variety of different mechanisms have been described which
enable viruses to initiate rheumatic symptoms. Direct invasion
of the joint has been proposed as a mechanism utilized by ru-
bella and rubella vaccine virus, parvovirus, alphaviruses, and en-
teroviruses. Both rubella and rubella vaccine virus are thought
to grow preferentially in synovial tissues and have been cultured
from joint tissues. Formation and deposition of immune com-
plexes (containing viral particles as the antigen component) as
a result of humoral response to viral infection is thought to be
the mechanism behind arthritis seen with hepatitis B, hepatitis
C, and parvovirus. Molecular mimicry may also occur, whereby
antibodies directed against viral antigens cross react with tissue
antigens. The modes of transmission of viruses causing arthritis
are shown in Table 19.7.3.
Clinical features
Viral arthritides typically present with symmetric polyarticular dis-
ease which can be in the form of arthralgia or arthritis. These mani-
festations are usually sudden in onset, correlate with the onset of
clinical illness, and generally self-​limiting, although infections due
to rubella virus, parvovirus, and alphavirus can cause persistent
joint symptoms. However, even with persistent symptoms, viral
arthritis very rarely leads to deforming and destructive joint dis-
ease. Musculoskeletal manifestations of some of the common viral
arthritides are discussed next.
Hepatitis B virus
Up to 25% of patients with acute hepatitis B virus infection develop
joint symptoms in the prodromal phase. The arthritis most commonly
affects hands and knees, although other large joints can be affected as
well. The joint symptoms are usually self-​limiting and resolve with the
onset of jaundice, and there are no reports of resulting joint damage.
Polyarthritis in the setting of chronic hepatitis B virus infection is
less common, but can occur as part of clinical syndromes due to im-
mune complex mediated diseases such as hepatitis B virus-​associated
polyarteritis nodosa and essential mixed cryoglobulinemia.
Hepatitis C virus
About one-​fifth of patients with chronic hepatitis C virus infection
complain of arthralgia. Two-​thirds of these patients have symmet-
rical inflammatory arthritis involving small joints of the hands, re-
sembling rheumatoid arthritis but without erosions; the remaining
one-​third have oligoarthritis. The arthritis generally improves
with antiviral treatment. Symptomatic treatment is usually with
non​steroidal anti-​inflammtory drugs. Hydroxychloroquine has been
used, but other conventional disease-​modifying agents employed in
the treatment of rheumatoid arthritis (such as methotrexate) are of
limited value because of problems with hepatotoxicity. Biological
agents including etanercept have been used for the treatment of in-
flammatory arthritis in patients with chronic hepatitis C virus in-
fection. Arthritis can also be one of the manifestations of mixed
cryoglobulinemia seen with hepatitis C virus infection.
Parvovirus
Parvovirus B19 is the cause of fifth disease or erythema infectiosum.
Less than 10% of children with this syndrome have joints symptoms,
Table 19.7.2  Empirical antibiotic choice in suspected septic arthritis
Patient group
Antibiotic choice
No risk factors for atypical
organisms
Flucloxacillin 2 g qds iv. Local policy may be to
add gentamicin i.v.
If penicillin allergic, Clindamycin 450–​600 mg qds
i.v. or 2nd or 3rd generation cephalosporin i.v.
High risk of Gram-​
negative sepsis (elderly,
frail, recurrent UTI, recent
abdominal surgery)
2nd or 3rd generation cephalosporin, e.g.
cefuroxime 1.5 g tds i.v. Local policy may be
to add flucloxacillin i.v. to 3rd generation
cephalosporin. Discuss allergic patients with
Microbiology—​Gram stain may influence
antibiotic choice
MRSA risk (known MRSA,
recent inpatient, nursing
home resident, leg ulcers
or catheters, or other risk
factors determined locally)
Vancomycin i.v. plus 2nd or 3rd generation
cephalosporin i.v.
Suspected gonococcus or
meningococcus
Ceftriaxone i.v. or similar dependent on local
policy or resistance
i.v. drug users
Discuss with microbiologist
ITU patients, known
colonization of other
organs (e.g. cystic fibrosis)
Discuss with microbiologist
Reproduced from Coakley G et al. (2006) BSR & BHPR, BOA, RCGP and BSAC guidelines
for management of the hot swollen joint in adults. Rheumatology (Oxford), 45(8), 1039–​1041,
by permission of Oxford University Press.
Table 19.7.3  Viral causes of arthritis according to mode of
transmission
Blood borne
Hepatitis B
Hepatitis C
HIV
Arthropod borne
α-viruses including (chikungunya virus)
Dengue
Respiratory acquired
Parvovirus
Rubella
section 19  Rheumatological disorders
4462
while more than half of adults complain of joint involvement, where
parvovirus is responsible for up to 15% of cases of acute arthritis.
In children joint involvement can be oligoarticular and asym-
metric, often involving the knees. The arthritis in adults is typically
of acute onset, symmetrical and polyarticular, commonly affecting
metacarpophalangeal and proximal interphalangeal joints, and it may
be mistaken for rheumatoid arthritis. Joint symptoms typically resolve
within a few weeks but can persist for several months in 20% of patients.
Rubella
Up to one-​third of patients with rubella or given rubella virus vac-
cine develop arthritis. Following administration of rubella vaccine
joints symptoms usually develop after two weeks. The onset of arth-
ritis due to rubella infection is seen within a few days before and
after the appearance of rash. Usually small joints of hands and wrists
are affected; aside from the knees, involvement of other joints is less
common. Tenosynovitis has also been described. Symptoms usually
resolve within a couple of weeks.
Alpha viruses
Alphaviruses (including chikungunya virus) are transmitted to verte-
brate hosts by arthropod vectors (usually mosquitoes). Joints involve-
ment is observed in almost all patients with symptomatic infections
with alphaviruses and is usually symmetrical and polyarticular, often
involving small joints of hand and feet. The onset of joint symptoms
in chikungunya is abrupt and severe. Symptoms usually resolve in
six months, although some patients with chikungunya can have per-
sistent symptoms lasting for several years. Chronic erosive inflamma-
tory arthritis has also been reported in patients with persistent joint
symptoms following chikungunya infection.
Dengue virus
Rheumatic manifestation are a major clinical feature of dengue virus
infection and up to three-​quarters of patients develop musculoskel-
etal manifestations, which can include involvement of muscles,
tendons, joints, and bone. Typically the patient complains of
marked muscle and joint pain (also described as bone-​break fever).
Symptoms usually resolve within a few weeks, but chronic arthritis
has been reported.
 HIV
Several disorders with musculoskeletal manifestations have been
described in HIV-​infected patients. HIV-​associated arthritis usually
involves lower limbs in an oligoarticular pattern, but involvement of
other joints can also occur in a mono or polyarticular distribution.
The illness is typically self-​limiting and resolves within six weeks.
Often no treatment other than non​steroidal anti-​inflammtory
drugs is required. However, a few patients can have a prolonged
course of arthritis, and disease-​modifying antirheumatic drugs
used in the treatment of rheumatoid arthritis such as sulfasalazine,
hydroxychloroquine, methotrexate and anti-​TNFα agents, have
been used in those not responding to symptomatic treatment and to
non​steroidal anti-​inflammtory drugs.
Other chronic arthritides such as spondyloarthropathies (reactive
arthritis, psoriatic arthritis and undifferentiated spondyloarthro­
pathy) and rheumatoid arthritis have also been described in patients
with HIV. Whether HIV infection plays a pathogenic role in causing
these disorders or is a coincidental finding remains unclear. They are
usually treated in the same way as in patients without HIV infection.
However, risk of infections with immunosuppression in HIV-​infected
patients has to be weighed up against the potential benefits. Agents
such as sulphasalazine and hydroxychloroquine, which are not con-
sidered to be particularly immunosuppressive, can be used. There is
a consensus that treatment with more potent immunosuppressive
agents such as methotrexate and anti-​TNFα therapies can also be con-
sidered in patients with well controlled HIV infection, such as those
with undetectable viral load and CD4 count of more than 200.
Diffuse infiltrative lymphocytosis syndrome (DILS) can mimic
Sjögren’s syndrome and presents with massive parotid gland swelling,
sicca symptoms, lymphadenopathy, and arthralgias. Lymphocytic
infiltration of other organs can lead to polymyositis, renal tubular
acidosis, hepatitis, interstitial pneumonitis, and peripheral neur-
opathy. DILS has been reported in up to 4% of HIV-​infected pa-
tients, although the introduction of highly active antiretroviral
therapy (HAART) has resulted in significant reduction in the in-
cidence. Autoantibodies (Ro, La, and Rheumatoid factor) typically
seen in patients with Sjögren’s syndrome are absent in patients with
DILS. Treatment is usually symptomatic and aimed at improving
sicca symptoms. Immunosuppressive treatment may be required for
those with pulmonary or renal involvement.
Following the initiation of highly active antiretroviral therapy in
HIV-​infected individuals about 10–​30% of patients develop para-
doxical deterioration of clinical status due to worsening of pre-​
existing infectious processes (the pre-​existing infections may have
been previously diagnosed and treated, or they may be subclinical).
This phenomenon is called immune reconstitution inflammatory
syndrome (IRIS), which is attributable to the rapid recovery of the
immune system following introduction of highly active antiretro-
viral therapy, resulting in the host regaining capacity to mount an
inflammatory response to a pre-​existing infection. In addition to
the inflammatory response to opportunistic infections affecting the
musculoskeletal system, IRIS can lead to the development of new
rheumatic autoimmune disorders and reactivation of pre-​existing
autoimmune disorders. The reported disorders include rheumatoid
arthritis, systemic lupus erythematosus, and sarcoidosis. Depending
on the severity of symptoms these autoimmune conditions, treat-
ment with corticosteroids may be warranted, especially in those
with severe and persistent disease.
Investigations
In a patient presenting with arthralgia/​arthritis there is no consensus
on routine testing for viral infections as the possible aetiology when
a specific viral infection is not suspected. Clinical clues, patient risk
factors and local epidemiology may suggest a possible viral aetiology
behind arthralgia/​arthritis and prompt further investigation.
Serologic testing using immunoassay for both IgM and IgG anti-
bodies to viral components is the commonly used method. The
testing must be directed against the specific viruses suspected to be
involved, based upon both epidemiologic data and clinical features.
Direct testing of serum for viral specific nucleic acid by polymerase
chain reaction (PCR) can also be performed.
Several viruses have been isolated from joint fluid or synovium
in individuals with clinical signs of arthritis, but viral isolation from
joint tissue has very little role in routine clinical practice due to cost,
difficulty in isolating the virus, and because only a small number of
viruses directly infect the joint.
19.7  Infection and arthritis
4463
Management
Since most viral arthritides are self-​limiting and of short duration,
treatment is primarily aimed at relieving symptoms with analgesic
agents (e.g. acetaminophen) and non​steroidal anti-​inflammtory
drugs. In general there is no need for specific antiviral therapy, al-
though the underlying condition may require specific treatment
(e.g. hepatitis B, hepatitis C, HIV). Immunosuppressants and gluco-
corticoids are of limited value and generally not required, other than
in those very few who develop chronic arthritis.
FURTHER READING
Coakley G, et  al. (2006). BSR & BHPR, BOA, RCGP and BSAC
guidelines for management of the hot swollen joint in adults.
Rheumatology (Oxford), 45, 1039–​41.
Couderc T, Lecuit M (2015). Chikungunya virus pathogenesis: from
bedside to bench. Antiviral Res, 121, 120–​31.
Fox C, Walker-​Bone K (2015). Evolving spectrum of HIV-​associated
rheumatic syndromes. Best Pract Res Clin Rheumatol, 29,
244–​58.
Herrero LJ, et al. (2015). Arthropod-​borne arthritides. Best Pract Res
Clin Rheumatol, 29, 259–​74.
Mathews CJ, et al. (2010). Bacterial septic arthritis in adults. Lancet,
375, 846–​55.
Osmon DR, et al. (2013). Executive summary: diagnosis and man-
agement of prosthetic joint infection: clinical practice guidelines
by the Infectious Diseases Society of America. Clin Infect Dis, 56,
1–​10.
Ryman KD, Klimstra WB (2014). Closing the gap between viral and
noninfectious arthritis. Proc Natl Acad Sci U S A, 111, 5767–​8.
Tarkowski A (2006). Infection and musculoskeletal conditions: infec-
tious arthritis. Best Pract Res Clin Rheumatol, 20, 1029–​44.

19.8 Reactive arthritis 4464 Carmel B. Stober and
19.8 Reactive arthritis 4464 Carmel B. Stober and Hill Gaston
ESSENTIALS
Reactive arthritis a subset of post-​infectious arthritis, and causative or-
ganisms are usually localized to the gastrointestinal or genitourinary
tracts. Following infection, organisms or their components find their
way to joints, where they provoke inflammatory immune responses.
Whether the responses cross-​react with self antigens is unclear; arth-
ritis may be maintained by persistent infection. The disease com-
monly has specific extra-​articular features not seen in other forms of
post-​infectious arthritis, and is genetically and pathologically a form
of spondyloarthritis.
Clinical presentation—​an acute oligoarthritis of weight-​bearing
joints is a common finding in secondary care, whereas community
cases show mild polyarthritis. In addition to synovitis, enthesopathy
is common, and extra-​articular features include conjunctivitis,
keratoderma, balanitis, and mouth ulcers. Urethritis can be reactive
and does not necessarily indicate genitourinary infection.
Diagnosis—​this depends on a careful history to determine whether
there has been preceding infection, followed by examination for
synovitis, enthesopathy, and extra-​articular features. Definitive proof
requires demonstration of recent infection by a triggering organism,
using stool culture, urine and genital swabs, nucleic acid amplifica-
tion techniques, and serology. In some cases, when the nature of the
triggering infection cannot be established, patients may be classified
as having undifferentiated arthritis.
Management—​treatment is with symptomatic measures—​
nonsteroidal anti-​inflammatory drugs, intra-​articular steroids, and
physiotherapy suffice in most cases. Severe, relapsing, or persistent
disease may require methotrexate or sulfasalazine, and occasionally
biologic drugs such as tumour necrosis factor inhibitors. Little evi-
dence supports prolonged treatment with antibiotics, although chla-
mydial infection requires conventional short-​term treatment.
Introduction and historical perspective
The term ‘reactive arthritis’ was introduced in 1969 by Aho in
Finland, where the combination of a high prevalence of HLA B27
and gastrointestinal yersinia infection afforded opportunities for
studying the disease. He defined the condition as ‘an arthritis which
develops soon after or during an infection elsewhere in the body, but
in which the microorganisms cannot be recovered from the joint’.
However, the condition was first recognized in the eighteenth and
nineteenth centuries as an arthritis that followed dysentery or ven-
ereal disease, and there were descriptions by Hans Reiter and other
contemporaries of the disease among troops affected by dysentery
in the trenches of the First World War. The term ‘Reiter’s disease’ has
been used extensively since that time, but should now be abandoned
for several reasons: Reiter was not the first to describe the disease; he
erroneously attributed it to spirochaetal infection; and the triad that
makes up Reiter’s disease—​arthritis, conjunctivitis, and urethritis/​
cervicitis—​is not a clinically meaningful subgroup within reactive
arthritis. The incorrect assumption that a patient with Reiter’s triad
has sexually acquired reactive arthritis is particularly unhelpful.
Definition
The term ‘reactive arthritis’ is sometimes used rather loosely to cover
any form of arthritis that follows infection, and then includes post-​
viral arthritides, rheumatic fever, Lyme disease, and other forms
of arthritis that do not generally share clinical features. This usage
is not appropriate, and the term ‘post-​infectious arthritis’ is much
preferred, with this all-​embracing term subdivided into different
clinical syndromes, one of which is reactive arthritis (Box 19.8.1).
Defined in this way, reactive arthritis is seen as one of the seronega-
tive spondyloarthritides (ankylosing spondylitis, psoriatic arthritis,
arthritis associated with inflammatory bowel disease, undiffer-
entiated spondyloarthritis), sharing clinical and immunogenetic
19.8
Reactive arthritis
Carmel B. Stober and Hill Gaston
Box 19.8.1  Post-​infectious arthritis
• Post-​viral arthritis (e.g. parvovirus)
• Post-​streptococcal arthritis
— Rheumatic fever
— Arthritis alone
• Post-​neisseria arthritis
• Lyme disease
• Whipple’s disease
• Reactive arthritis
19.8  Reactive arthritis
4465
features with those diseases. More recently, the Assessment of
Spondylarthritis Society (ASAS) has reclassified reactive arthritis as
a peripheral spondylarthritis. Other post-​infectious arthropathies
lack these common features.
In the absence of agreed and validated diagnostic or classification
criteria for reactive arthritis, Box 19.8.2 presents a useful working
classification of those patients who could reasonably be considered to
have reactive arthritis. This takes as its starting point the classical pat-
tern of arthritis and typical extra-​articular features (Box 19.8.3) that
are commonly seen after infection by five organisms—​salmonella,
yersinia, campylobacter, shigella, and Chlamydia trachomatis. The
same clinical syndrome (i.e. arthritis and extra-​articular signs) is
also seen, but more rarely, following various other infections, espe-
cially of the gastrointestinal tract (e.g. by Clostridium difficile); but
genitourinary infection with ureaplasma and respiratory infection
with Chlamydia pneumoniae can probably also act as triggers of re-
active arthritis. The other large group of patients is those who have
asymmetric oligoarthritis without extra-​articular features, but with
definite laboratory evidence of preceding infection by one of the five
major reactive arthritis-​associated bacteria.
Laboratory diagnosis of infection is given priority over symp-
toms as a classification criterion because infection may be clinic-
ally silent. Chlamydia is notorious for this, particularly in women,
while in yersinia infection arthritis is inversely correlated with the
severity of gastrointestinal symptoms. Positively identifying the trig-
gering infection often poses practical problems. Patients in whom
arthritis develops (with or without extra-​articular signs) after symp-
tomatic episodes of gastrointestinal or genitourinary infection are
therefore usually regarded as having reactive arthritis, even when
no triggering organism can be identified, although the diagnosis
is inevitably less secure in these cases. Improvement in methods
for diagnosing preceding infection should decrease the size of this
group, and may show reactive arthritis to be the commonest cause of
acute inflammatory oligo-​ or monoarthritis in young adults.
Epidemiology
Community studies in Scandinavia, where HLA B27 is present in
around 12% of the population (compared with 6–​7% elsewhere in
Europe), have suggested an incidence of 40 to 50 cases/​million for
each of the endemic organisms (chlamydia, campylobacter). The
lower figure of 1.3/​million for shigella probably represents a similar
incidence to other organisms, as almost all cases were acquired by
travellers. Incidence has also been studied in single outbreaks of food
poisoning, in which the proportion of infected patients developing
arthritis can be accurately assessed. However, in such studies the
proportion who develop reactive arthritis varies widely (0–​21%). By
contrast, careful population studies of campylobacter infection have
shown a high incidence (7–​16%) of musculoskeletal symptoms not
severe enough to require secondary care. The influence of HLA B27
on incidence is important: 60 to 80% of patients with reactive arth-
ritis presenting to rheumatology clinics are positive for HLA B27,
whereas among those with mild disease the figure drops to 30% or
lower. HLA B27 seems to be associated mainly with the severity and
persistence of arthritis, rather than its incidence.
Pathogenesis
There is considerable evidence that organisms reach the joints fol-
lowing infection of the gut or genitourinary tract. They may arrive
intact, when they can be detected using the polymerase chain reac-
tion (PCR), or as antigenic material (proteins, lipopolysaccharide)
that can be demonstrated in synovial macrophages and polymorphs
using organism-​specific antibodies. This process can continue for
months or even years, suggesting that some of the infections (e.g.
yersinia), persist such that antigens/​organisms continue to reach the
joint. Elevated and persistent titres of IgA antibody to these organ-
isms in reactive arthritis compared with uncomplicated infection
also favour the idea of persistence. A clear distinction between septic
and post-​infectious arthritis is no longer possible, as viable organ-
isms can be detected in the joint in various forms of post-​infectious
arthritis, including Lyme disease and reactive arthritis. However, an
important distinction is that in post-​infectious arthritis the organ-
isms in synovium or synovial fluid are noncultivatable (although
viable), and antibiotics generally do not influence the course of dis-
ease (see next).
Within the joint, cellular immune responses to the bacteria re-
sponsible for triggering reactive arthritis are readily detected, par-
ticularly responses by CD4+ helper T lymphocytes, but also CD8+
T cells. Interestingly, although the association with HLA B27 is often
taken to imply that CD8+ T cells are the principal effector cells in the
disease, HIV-​positive patients with reactive arthritis present during
Box 19.8.2  Working definition of reactive arthritis
Classical clinical features
• Asymmetric oligoarthritis, lower limbs predominate
•	 Enthesitis
• Extra-​articular signs (Box 19.8.3)
— Classical clinical features and proven infection by salmonella, cam-
pylobacter, yersinia, shigella, or Chlamydia trachomatis (whether
symptomatic or not)
— Classical clinical features and proven infection by other organisms
(e.g. Clostridium difficile, Mycobacterium bovis BCG)
— Any acute inflammatory arthritis (including monoarthritis) and
proven infection by reactive arthritis-​associated bacteria
— Classical clinical features and preceding diarrhoea or urethritis/​
cervicitis, infection not proven
Box 19.8.3  Extra-​articular features and their occurrence
in other forms of spondyloarthritis
•	 Eyes
—	Conjunctivitis
— Uveitis (ankylosing spondylitis and inflammatory bowel disease)
• Skin and mucous membranes
— Oral ulceration
— Circinate balanitis
— Keratoderma blennorrhagica (psoriasis)
— Nail dystrophy (psoriasis)
— Erythema nodosum (inflammatory bowel disease)
•	 Cardiac
— Aortitis (ankylosing spondylitis)
— Conduction defects (ankylosing spondylitis)
section 19  Rheumatological disorders
4466
stage I infection, when numbers of CD4+ T cells are less depressed.
By contrast, arthritis can be relatively quiescent in full-​blown AIDS.
Both CD4+ and CD8+ lymphocytes produce proinflammatory
cytokines such as interferon-​γ and interleukin 17 that can drive joint
inflammation by secondary effects on synoviocytes. Increased num-
bers of CD4+ IL-​17+ T cells have been detected in reactive arthritis
synovial fluid as compared to paired peripheral blood.
How does HLA B27 influence the course of reactive arthritis—​
particularly its severity and persistence? It has been proposed that
infection generates a B27-​restricted response by CD8+ T cells to
a bacterial peptide that cross-​reacts with a component of the joint
(i.e. infection triggers autoimmunity by ‘molecular mimicry’).
However, no such autoimmune response has yet been demon-
strated. Alternatively, HLA B27 may adversely affect the efficiency
with which the immune system clears the triggering organism. In
this case disease would not require autoimmunity but be primarily
driven by persistent bacterial antigens. Lastly, HLA B27 might affect
the immune response to the triggering organism qualitatively (e.g. by
allowing hyper-​responsiveness to particular antigens, or biasing the
immune response in favour of the production of proinflammatory
cytokines such as IL-​17 and IL-​22).
Clinical features
Preceding illness
A history of urethritis (dysuria or discharge) and diarrhoea must
be sought specifically, as patients do not automatically link these
occurrences with their arthritis. The interval between infection
and arthritis is variable but not usually more than 3 weeks. By the
time a rheumatologist is consulted, many weeks may have passed
and the triggering illness forgotten, particularly if symptoms were
mild. Note that urethritis may be triggered by gastrointestinal infec-
tion: minimally symptomatic gastrointestinal infection and prom-
inent urethritis may cause diagnostic confusion if this possibility is
forgotten.
Arthritis
The classical clinical picture in reactive arthritis is an asymmetric
oligoarthritis (generally fewer than six joints), predominantly af-
fecting the lower limbs (Box 19.8.4). However, any joint can be
affected, and some patients have monoarthritis only. Affected
joints are often hot and markedly swollen, with septic arthritis and
crystal-​induced arthritis being the most likely differential diagnoses.
Dactylitis, similar to that seen in psoriatic arthritis, also occurs.
Many patients describe low back or buttock pain, suggesting in-
volvement of the sacroiliac joint. Arthritis is usually at its worst early
in the course of the disease, but new sites can be affected after several
months and relapses are not uncommon, even in those in whom
disease eventually settles completely. The presence of enthesitis (in-
flammation of ligamentous and tendinous insertions) in addition to
arthritis is helpful diagnostically, with plantar fasciitis and involve-
ment of the Achilles tendon insertion the commonest sites.
The features described here are commonly seen in secondary care,
but the milder cases detected in community surveys commonly have
polyarthritis, whereas some have only inflammatory back pain or an
enthesopathy such as reactive tendonitis.
Extra-​articular features
In acute severe disease patients have constitutional symptoms of
malaise, fatigue, and fever. More useful diagnostically are the spe-
cific extra-​articular signs listed in Box 19.8.3 and illustrated in
Figs. 19.8.1, 19.8.2 and 19.8.3. The fact that these extra-​articular
features are common to other forms of spondyloarthritis greatly
strengthens the case for including reactive arthritis in this dis-
ease family, and for defining reactive arthritis as a distinct post-​
infectious syndrome.
Extra-​articular features are more common in those with severe
joint involvement. Conjunctivitis is often transient and no longer
present by the time the patient presents. More persistent eye inflam-
mation or painful eyes should raise the question of an acute anterior
uveitis rather than a simple conjunctivitis and prompt full ophthal-
mological assessment. Circinate balanitis is usually asymptomatic
and needs to be specifically sought in uncircumcized males. Oral
ulceration is usually asymptomatic. Keratoderma blennorrhagica
is histologically identical to psoriasis; it is most commonly seen on
the soles of the feet, but can also involve the hands or trunk, and
psoriaform nail changes are also seen. Erythema nodosum is associ-
ated with yersinia infection, but is otherwise uncommon in reactive
arthritis. Aortitis and cardiac conduction disorders are rare.
Box 19.8.4  Pattern of joint involvement in reactive arthritis
• Oligo-​ or monoarthritis
—	Asymmetric
— Predominantly lower limbs
• Coexisting enthesitis or reactive enthesopathy  alone
• Sacroiliac joint involvement
• Inflammatory back pain
• Polyarthritis (mild)
Fig. 19.8.1  Ulceration of the tongue in reactive arthritis.
Courtesy of Dr CJ Eastwood.
19.8  Reactive arthritis
4467
Differential diagnosis
The differential diagnosis of reactive arthritis is summarized in
Box 19.8.5. The principal concerns in acute disease are septic
arthritis, crystal arthropathies, and other forms of post-​infectious
arthritis such as Lyme disease, post-​streptococcal arthritis, or
gonococcal arthritis. In chronic disease it may be difficult to dis-
tinguish reactive arthritis from other forms of spondyloarthritis,
especially in those with inflammatory bowel disease, and many
patients in whom no infectious trigger can be implicated can be
classified as having an undifferentiated spondyloarthritis.
Laboratory features
General
The principal aims of investigation are to exclude important differen-
tial diagnoses and to identify the triggering organism. Abnormalities
in the early stages, when arthritis is most active, are those of a pro-
nounced acute inflammatory response—​raised ESR and C-​reactive
protein, the latter often very marked (>100 mg/​litre). Serum uric acid
should be checked. Rheumatoid factor and antinuclear antibodies
are absent. Positive antineutrophil cytoplasmic antibodies have been
described, but the antibodies are not directed against proteinase-​3
or myeloperoxidase and the test is not diagnostically useful. Septic
arthritis and crystal arthropathies are best excluded by aspiration
of synovial fluid followed by culture and microscopy. Findings in
synovial fluid are characteristic of an inflammatory arthritis, with
elevated white cell counts, which are predominantly neutrophils.
Blood, stool, and urine culture should be performed and genital
swabs taken if appropriate. Throat swab and antibodies to strepto-
coccal antigens may point to post-​streptoccocal arthritis, which
does not share extra-​articular features with reactive arthritis. In en-
demic areas, Lyme disease should be considered and antibodies to
Borrelia burgdorferi measured. A chest radiograph may reveal hilar
lymphadenopathy, suggesting the diagnosis of sarcoidosis, although
yersinia can cause both reactive arthritis and a sarcoid-​like illness.
Microbiological
Stool should be cultured for pathogens associated with reactive
arthritis, although cultures are often negative after gastrointestinal
symptoms have settled—​despite the recent evidence that persistent
infection contributes to pathogenesis. Chlamydia infection must
be sought in sexually active patients with new partners, particu-
larly when there is no history of gastroenteritis. Formal referral to
a department of genitourinary medicine is often helpful. Patients
are not infrequently infected with both chlamydia and gonococcus.
This can cause confusion, but gonococcal arthritis differs from re-
active arthritis with its characteristic rash and absence of classical
extra-​articular features. Chlamydia can be amplified from urethral
or cervical swabs, or from first-​catch urine. Nucleic acid amplifica-
tion techniques using amplification of C. trochomatis DNA or RNA
Fig. 19.8.2  Circinate balanitis in reactive arthritis.
Courtesy of Dr CJ Eastwood.
Fig. 19.8.3  Keratoderma blennorrhagica in reactive arthritis.
Courtesy of Dr CJ Eastwood.
Box 19.8.5  Differential diagnosis of reactive arthritis
• Septic arthritis
• Post-​infectious arthritis
— Lyme disease
— Post-​streptococcal or neisseria infection
— Viral arthritis
• Crystal arthropathies
• Other forms of spondyloarthritis
•	 Behçet’s
•	 Sarcoidosis
• Trauma, sports injury
section 19  Rheumatological disorders
4468
sequences are very sensitive and specific and are the preferred diag-
nostic method.
Spondyloarthritis in the context of HIV infection also needs to be
considered, although this is rare in developed countries. By contrast,
many cases of reactive arthritis, often related to dysentery, have re-
cently emerged among the HIV-​infected population in sub-​Saharan
Africa, where the disease was previously unknown. HIV testing
should be considered, particularly in patients with unusually severe
disease and relevant risk factors.
Immunological
When the triggering organism cannot be demonstrated directly,
infection can be inferred on the basis of immune responses.
However, this evidence needs to be interpreted cautiously, as in
many cases the findings simply imply immunological memory for
the organism in question and do not demonstrate a clear relation-
ship between infection and arthritis. Specific IgM antibodies may
indicate recent infection, whereas IgG may reflect remote infection
unless titres are increasing. However, when patients present sev-
eral months into their illness, IgM may no longer be evident and
IgG titres stable. In these circumstances high and persistent IgA
titres to organisms such as salmonella and yersinia may be useful.
Serological diagnosis of chlamydia infection is particularly difficult
because of high community levels of infection with Chlamydia pneu-
moniae, an organism that shares several highly conserved antigens
with Chlamydia trachomatis. Overall, serology is used less com-
monly for these infections.
Lastly, cellular immune responses to triggering organisms can be
demonstrated, particularly in the synovial fluid. Again, these dem-
onstrate only T-​cell memory for the organism and do not demon-
strate causality; patients with, for example, rheumatoid arthritis and
incidental salmonella infection will have salmonella-​specific T cells
in their synovial fluid. Such tests are currently used in research ra-
ther than diagnostically.
Radiological
Radiological investigations are not diagnostically helpful in the
acute stages of disease, with soft tissue swelling and occasionally
periarticular osteopaenia at affected joints being the only abnor-
malities. MRI using STIR sequences, or less commonly radionuclide
scintigraphy, can demonstrate acute sacroiliitis and may show the
full extent of acute synovitis and enthesitis, but is not usually re-
quired for clinical management. Radiological changes are confined
to the few patients with persistent disease (>1 year duration), with
the principal features being erosion of affected joints, including
the sacroiliac, and new bone formation manifested as periostitis
of metatarsal and metacarpal bones and ‘enthesophytes’, such as
plantar spurs. In the spine paravertebral ossification can be seen in
the lumbar region: this is asymmetric and differs from the classical
changes of ankylosing spondylitis. Erosive changes are also seen at
sites of enthesitis such as the calcaneum.
Treatment
Evidence-​based therapies for reactive arthritis are lacking, and con-
sensus opinion is the current guide. The management of reactive
arthritis can be divided into two stages: (a) acute reactive arthritis,
and (b) refractory (chronic) reactive arthritis, usually defined as dis-
ease of greater than six months duration. In the acute phase, affected
joints should be rested until they improve substantially. This often
needs emphasizing to young, active patients involved in sports, and
alternative forms of exercise should be considered. Physiotherapy
and advice on exercise is helpful, with quadriceps function needing
particular attention in view of the frequent involvement of the knees.
Non​steroidal anti-​inflammatory drugs (NSAIDs) are the first line
of treatment unless contraindicated, and an adequate trial should
be 2 weeks in duration. More than one NSAID could be tried, and
patients need to be counselled about side-​effects. Synovial effusions
should be aspirated and, when septic arthritis has been excluded,
will respond well to injection with long-​acting corticosteroids.
Systemic corticosteroids can be used if multiple joints are affected.
If chlamydia infection is established or thought likely, patients re-
quire conventional treatment with short-​term antibiotics, but there
is little evidence that this has any effect on the progress of reactive
arthritis. Enteric infections do not require antibiotics in their own
right, and the arthritis does not respond to antibiotics (see next).
Uveitis requires formal ophthalmological assessment and treatment
with local steroids.
There are two major unresolved treatment issues in chronic reactive
arthritis. Firstly, the place of disease-​modifying drugs: sulfasalazine
and methotrexate are useful in other forms of spondyloarthritis
and on this basis have been used in reactive arthritis, but without
controlled trials confined to this condition (because the disease is
often self-​limiting, controlled trials of second-​line agents are diffi-
cult to perform). There is one trial where sulfasalazine was used in a
36-​week randomized trial in patients not responding adequately to
NSAIDs, but the primary outcome measure was not met although
there was a trend towards benefit. The use of TNF inhibitors is not
supported by trial data although there are case series. The second
issue is whether long-​term antibiotics confer any benefit. In a con-
trolled trial in 1991, a subset of patients with evidence of chlamydia
infection benefited from prolonged lymecycline, but subsequent
trials using ciprofloxacin and azithromycin have been negative. It
may be that organisms in the joint, being in an uncultivatable state,
are also not susceptible to antibiotics, most of which affect bacterial
cell division. A trial in 2010 suggested that a combination of rifam-
picin and doxycycline or azithromycin may be useful in chronic
chlamydia-​induced reactive arthritis, resulting in affecting joints be-
coming PCR-​negative for chlamydia nucleic acids, but this has not
yet been confirmed.
Psychological and quality of life issues
Reactive arthritis commonly affects young fit adults who have not
previously experienced any form of prolonged illness or disability.
The danger is that the rheumatologist, all too used to the relatively
gloomy prognosis of rheumatoid arthritis, may treat reactive arth-
ritis, where there is a high likelihood of complete resolution of dis-
ease, too lightly. Patients need to be given a realistic prognosis (i.e.
that symptoms may well persist at some level for 6–​12 months, al-
though in the latter stages these are usually very mild compared with
those experienced in the first 4–​8 weeks). Exacerbations during this
time are not uncommon and do not imply that the disease will not
eventually resolve. The chances of the patient developing chronic
19.8  Reactive arthritis
4469
arthritis are less than 10%. Patients benefit from continuing psycho-
logical and clinical support throughout the course of their illness,
with rapid access to joint aspiration and intra-​articular steroid injec-
tion when there is recurrent joint swelling.
Areas of uncertainty
Current uncertainties concern classification criteria and manage-
ment strategies. Both may be resolved by developing more secure
diagnostic techniques for identifying the triggering infection.
Improved treatment is likely to come from either (1) additional
evidence about the importance of persistent infection and how to
eliminate it, or (2) discovery of the immune responses responsible
for maintaining joint inflammation, whether these are directed
against a bacterial antigen or an autoantigen. If a target antigen can
be identified, specific immunomodulation strategies would become
relevant.
Reactive arthritis differs from other forms of inflammatory arth-
ritis in having a clearly defined onset and being triggered by known
infectious agents. Genetic influences that result in a minority of in-
fected individuals developing arthritis are being investigated. These
include HLA B27, but it is likely that other genes are also involved.
Genome-​wide association studies in ankylosing spondylitis have
identified several genes which influence susceptibility to disease,
and many of these are concerned with the production of, and re-
sponse to, the cytokine IL-​23 and the generation of IL-​17-​producing
cells. Since increased numbers of IL-​17+ CD4+ T cells have been
noted in reactive arthritis synovial fluid, it seems likely that many
of the genes which have been implicated in ankylosing spondylitis
susceptibility play a similar role in reactive arthritis.
FURTHER READING
General review
Schmitt SK (2017). Reactive arthritis. Infect Dis Clin North Am, 31,
265–​77.
Reviews of pathogenesis
Gaston JSH (2000). Immunological basis of chlamydia induced re-
active arthritis. Sex Transm Infect, 76, 156–​61.
Sieper J, Braun J (1995). Pathogenesis of spondylarthropathies: per-
sistent bacterial antigen, autoimmunity, or both? Arthritis Rheum,
38, 1547–​54.
Incidence following enteric infection
Fendler C, et al. (2001). Frequency of triggering bacteria in patients
with reactive arthritis and undifferentiated oligoarthritis and the
relative importance of the tests used for diagnosis. Ann Rheum Dis,
60, 337–​43.
Gaston JSH (2005). Shigella induced reactive arthritis. Ann Rheum Dis,
64, 517–​8.
Hannu T, et al. (2002). Campylobacter-​triggered reactive arthritis: a
population-​based study. Rheumatology (Oxford) 41, 312–​8.
Hannu T, et al. (2005). Reactive arthritis attributable to Shigella infec-
tion: a clinical and epidemiological nation-​wide study. Ann Rheum
Dis, 64, 594–​8.
Evidence that bacteria or bacterial antigens reach the joint
in reactive arthritis
Gaston JSH, Cox C, Granfors K (1999). Clinical and experimental evi-
dence for persistent Yersinia infection in reactive arthritis. Arthritis
Rheum, 42, 2239–​42.
Gerard HC, et al. (1998). Synovial Chlamydia trachomatis in patients
with reactive arthritis/​Reiter’s syndrome are viable but show aber-
rant gene expression. J Rheumatol, 25, 734–​42.
Granfors K, et al. (1989). Yersinia antigens in synovial fluid cells from
patients with reactive arthritis. New Engl J Med, 320, 216–​21.
Granfors K, et al. (1990). Salmonella lipopolysaccharide in synovial
cells from patients with reactive arthritis. Lancet, 335, 685–​8.
Immune responses in reactive arthritis
Gaston JSH, et al. (1989). Synovial T lymphocyte recognition of organ-
isms that trigger reactive arthritis. Clin Exp Immunol, 76, 348–​53.
Granfors K, Toivanen A (1986). IgA-​anti-​yersinia antibodies in
yersinia-​triggered reactive arthritis. Ann Rheum Dis, 45, 561–​5.
Hermann E, et al. (1993). HLA-​B27-​restricted CD8 T-​cells derived
from synovial fluids of patients with reactive arthritis and anky-
losing spondylitis. Lancet, 342, 646–​50.
Reactive arthritis and other spondyloarthritis in HIV
infection
Njobvu P, McGill P (2005). Human immunodeficiency virus related
reactive arthritis in Zambia. J Rheumatol, 32, 1299–​304.
Treatment in reactive arthritis
Carter JD, et  al. (2010). Combination antibiotics as a treatment for
chronic chlamydia-​induced reactive arthritis:  a double-​blind,
placebo-​controlled, prospective trial. Arthritis Rheum, 62, 1298–​307.
Dougados M, et  al. (1995). Sulfasalazine in the treatment of
spondylarthropathy: a randomized, multicenter, double-​blind,
placebo-​controlled study. Arthritis Rheum, 38, 618–​27.
Kvien TK, et al. (2004). Three month treatment of reactive arthritis
with azithromycin: a EULAR double blind, placebo controlled study.
Ann Rheum Dis, 63, 1113–​9.
Lauhio A, et  al. (1991). Double-​blind, placebo-​controlled study of
three-​month treatment with lymecycline in reactive arthritis with
special reference to chlamydia arthritis. Arthritis Rheum, 34, 6–​14.
Sieper J, et al. (1999). No benefit of long-​term ciprofloxacin treatment in
patients with reactive arthritis and undifferentiated oligoarthritis—​
a three-​month, multicenter, double-​blind, randomized, placebo-​
controlled study. Arthritis Rheum, 42, 1386–​96.
Wakefield D, et  al. (1999). Ciprofloxacin treatment does not influ-
ence course or relapse rate of reactive arthritis and anterior uveitis.
Arthritis Rheum, 42, 1894–​7.
Yli-​Kerttula T, et  al. (2000). Effect of a three month course of
ciprofloxacin on the outcome of reactive arthritis. Ann Rheum Dis,
59, 565–​70.
Yli-​Kerttula T, et  al. (2003). Effect of a three month course of
ciprofloxacin on the late prognosis of reactive arthritis. Ann Rheum
Dis, 62, 880–​4.

19.9 Osteoarthritis 4470 Andrew J. Barr and Philip
19.9 Osteoarthritis 4470 Andrew J. Barr and Philip G. Conaghan
ESSENTIALS
Clinical osteoarthritis is a syndrome of joint pain associated with
structural deterioration of synovial joints that over time involves the
whole joint organ. It is the most common form of arthritis and a
leading cause of chronic pain, disability, and socioeconomic burden.
Affected individuals report pain (especially on weight bearing) and
joint stiffness leading to loss of muscle strength and poor joint func-
tion. This results in reduced participation in valued activities, low
mood, sleep disturbance, and poor quality of life.
Aetiology and pathogenesis
The aetiology of joint deterioration, pain, and the interaction of the
two remains unclear. Clinical osteoarthritis is associated with a variety
of both modifiable and non​modifiable risk factors including obesity,
age, gender, occupational injury, trauma, and genetic predisposition.
Obesity is the strongest potentially modifiable risk factor.
In early stages of pathogenesis individual tissues may be involved,
but typical clinical osteoarthritis involves a complex collection of
multitissue joint pathologies characterized by focal and progressive
loss of the hyaline articular cartilage with underlying bone changes and
secondary synovitis. Biomechanical factors are important in both inci-
dence and progression, and together with complex biochemical events
promote structural and nociceptive pathology within the synovium and
subchondral bone as well as the cartilage. All elements of pain path-
ways, including central processes, also play a role in pain perception.
Diagnosis
The syndrome typically manifests with joint symptoms after the age of
40 years, but the process of structural deterioration of the joint tissues
is likely to begin before this. A history of activity-​related pain with less
than 30 minutes of morning stiffness in the context of the patient’s age,
work history, prior injuries, and weight, is usually sufficient to confi-
dently diagnose osteoarthritis without need for investigations.
Management
A holistic assessment is essential to understand the patient’s con-
cerns and realistic treatment goals. Information on osteoarthritis
should be provided. Treatment consists of a combination of mod-
erately effective non​pharmacological (muscle strengthening, in-
creased activity and weight loss if needed) and pharmacological
(topical and oral non​steroidal anti-​inflammatory drugs (NSAIDs) and
opioids) pain-​relieving therapies. No agents are currently licensed
as structure-​modifying therapies. Joint replacements typically reduce
pain, though joint prostheses have a finite life expectancy and revi-
sion surgery offers less favourable outcomes.
Introduction
Osteoarthritis (OA) is the most common arthritis and is a leading
cause of global chronic pain, disability, and socioeconomic burden. It
affects 8.5 million people in the United Kingdom. In adults above the
age of 45 years, radiographic and symptomatic knee osteoarthritis
has a prevalence of 19–​28% and 7–​17%, respectively. The epidemi-
ology and natural history differ between joints and individuals. The
prevalence of clinical osteoarthritis increases with age and obesity,
and it represents a huge personal and health services burden.
Defining osteoarthritis and subtypes
Clinical osteoarthritis refers to structural deterioration of synovial
joints that in early stages may initially involve individual tissues,
which in the context of appropriate risk factors may evolve by a
complex cascade of biomechanical and biochemical pathologies,
into the typical whole joint multitissue pathologies seen in typical
painful clinical osteoarthritis. This includes changes to the hyaline
articular cartilage, the underlying subchondral bone, the meniscal
fibrocartilages (in the knee) and the synovium.
The problems with defining osteoarthritis
Definitions of osteoarthritis have derived from epidemiological
studies and clinical trials where osteoarthritis may be defined using
clinical findings (joint symptoms and examination findings) alone,
the presence of imaging-​assessed pathology, or a combination of the
two. Only 50% of knees with radiographic osteoarthritis have symp-
toms and activity-​related pain of osteoarthritis may occur in a pro-
dromal phase before the incidence of radiographic osteoarthritis.
Hence in research studies of osteoarthritis, a more specific defin-
ition can be achieved by any combination of joint imaging-​assessed
19.9
Osteoarthritis
Andrew J. Barr and Philip G. Conaghan
19.9  Osteoarthritis
4471
structural pathology (e.g. Kellgren Lawrence grade 2, a definite radio-
graphic osteophyte, Table 19.9.1) and clinical findings and laboratory
tests (e.g. American College of Rheumatology criteria, Table 19.9.2).
While conventional radiography is feasible, it is limited in its
utility by its relatively insensitive detection of structural path-
ology in tissues other than bone (Fig. 19.9.1). Among individ-
uals within the Framingham cohort, the age of 50 years, with no
pain and normal knee radiography, 88% of individuals had at least
one osteoarthritis tissue lesion in the knee on magnetic resonance
imaging (MRI). MRI can visualize the true three-​dimensional
multitissue joint pathology of osteoarthritis (Fig. 19.9.2) and these
MRI-​detected structural changes (Table 19.9.3) are more closely
associated with patient symptoms. Ultrasound also has the capacity
to acquire 3D images and, for example, has been shown to detect
many more osteophytes than conventional radiography in hand
osteoarthritis. These modern imaging studies highlight that many
of our concepts and definitions of osteoarthritis have been based on
an inaccurate imaging phenotype. Therefore there is currently no
generally agreed-​upon ‘gold standard’ for defining cases of osteo-
arthritis, and its epidemiology varies according to the definition of
clinical osteoarthritis for any specified joint.
Early osteoarthritis
The concept of early osteoarthritis is imprecisely defined. Incident
radiographic osteoarthritis has provided one operational concept
of early disease. However, both structural changes and symptoms
precede the incidence of radiographic osteoarthritis. As mentioned,
at least one structural lesion of knee osteoarthritis is present on
MRI of people over 50 years without radiographic osteoarthritis or
knee pain. By the time knee radiographic osteoarthritis is detect-
able, 10% of knee hyaline articular cartilage is lost. The incidence of
knee radiographic osteoarthritis is preceded by prodromal symp-
toms of pain on twisting or pivoting and pain on standing by 39 and
25 months respectively. Pain on stair climbing appears to be the first
mechanical symptom to manifest among knees with radiographic
osteoarthritis and at risk of this condition.
It is very likely that problems such as isolated cartilage de-
fects and meniscal tears are early structural lesions that progress
to clinical osteoarthritis, though these are not currently classi-
fied as early osteoarthritis. Compositional measures using special
Table 19.9.1  Kellgren Lawrence grade
Kellgren Lawrence grade
Features
Grade 0
No radiographic features of osteoarthritis
Grade 1
Doubtful joint space narrowing
Possible osteophytic lipping
Grade 2
Possible joint space narrowing
Definite osteophytes
Grade 3
Multiple osteophytes
Definite joint space narrowing
Some sclerosis
Possible deformity of bone contour
Grade 4
Large osteophytes
Marked joint space narrowing
Severe sclerosis
Definite bone deformity
Reprinted with permission from Demehri et al. (2015). Conventional and novel imaging
modalities in osteoarthritis: current state of the evidence. Curr Opin Rheumatol, 27(3),
295–​303.
Table 19.9.2  American College of Rheumatology radiological and
clinical criteria for osteoarthritis of the knee and hip and hand
Hand (clinical)
Osteoarthritis if 1, 2, 3, 4 or 1, 2, 3, 5 are present:
1
Hand pain, aching, or stiff ness for most days of previous month
2
Hard tissue enlargement of two or more of ten selected jointsa
3
Swelling in less than three metacarpophalangeal joints
4
Hard tissue enlargement of two or more distal interphalangeal joints
5
Deformity of two or more of ten selected hand jointsa
Hip (clinical and radiographic)
Osteoarthritis if 1, 2, 3 or 1, 2, 4 or 1, 3, 4 are present:
1
Hip pain for most days of previous month
2
Erythrocyte sedimentation rate of less than 20 mm in the first hour
3
Femoral or acetabular osteophytes on radiographs
4
Hip joint space narrowing on radiographs
Knee (clinical)
Osteoarthritis if 1, 2, 3, 4 or 1, 2, 5 or 1, 4, 5 are present:
1
Knee pain for most days of previous month
2
Crepitus on active joint motion
3
Morning stiffness lasting 30 min or less
4
Age 38 years or older
5
Bony enlargement of the knee on examination
Knee (clinical and radiographic)
Osteoarthritis if 1, 2 or 1, 3, 5, 6 or 1, 4, 5, 6 are present:
1
Knee pain for most days of previous month
2
Osteophytes at joint margins on radiographs
3
Synovial fluid typical of osteoarthritis (laboratory)
4
Age 40 years or older
5
Crepitus on active joint motion
6
Morning stiffness lasting 30 minutes or less
a Ten selected joints include bilateral second and third interphalangeal proximal joints,
second and third proximal interphalangeal joints, and first carpometacarpal joint.
Fig. 19.9.1  Radiograph of knee osteoarthritis.
section 19  Rheumatological disorders
4472
MRI sequences can demonstrate glycosaminoglycan loss before
‘standard’ MRI can detect morphological changes, so substantial
evolution of the concept and alternative definitions of ‘early’ osteo-
arthritis are required.
Inflammatory osteoarthritis
Clinical osteoarthritis is not considered to be a classical inflam-
matory arthritis because of features including a relative pau-
city of neutrophils in synovial fluid, a lack of subchondral bone
erosions, and no evidence of systemic inflammation or features
of autoimmunity; these features are used to distinguish osteo-
arthritis from the archetypal inflammatory arthritis, rheumatoid
arthritis (RA).
Clinicians may refer to inflammatory osteoarthritis as the discrete
very swollen joints seen in some patients with hand osteoarthritis,
but it is likely that there is much more widespread synovitis than
is appreciated clinically. Modern imaging with its more accurate
detection of synovial hypertrophy and effusion has changed our
understanding of the frequency of inflammation in osteoarthritic
joints. Using contrast-​enhanced MRI, extensive synovitis is preva-
lent in most knees (>85%) and hands (68%) with established osteo-
arthritis that meet the respective osteoarthritis joint criteria (Table
19.9.2).
Erosive osteoarthritis refers to a group of patients with radio-
graphic erosions, and the term is often used synonymously with
inflammatory osteoarthritis (though not all osteoarthritis inflam-
mation is associated with erosions). The overall prevalence of
erosive osteoarthritis is unclear, and the prevalence of erosions
varies somewhat according to their definition and the imaging
modality employed for detection. In two cohorts of women
selected for erosive hand radiographic osteoarthritis, erosions
were identified in 17–​18%, 35%, and 61% of small joints using
conventional radiography, ultrasonography, and MRI, respect-
ively. When defined radiographically, erosive hand osteoarthritis
appears to have a greater association with obesity, hypertension,
dyslipidaemia, and the metabolic syndrome relative to non​erosive
hand osteoarthritis.
Generalized osteoarthritis
An imprecisely defined phenotype is where multiple osteoarth-
ritis joints are present in an individual, which may be referred
to as generalized or polyarticular osteoarthritis. It is well recog-
nized that a history of hand osteoarthritis confers an increased
risk of hip and knee osteoarthritis, a history of knee osteoarth-
ritis confers a higher risk of hip osteoarthritis, and vice versa.
These associations are independent of confounding factors of
age, gender, and body mass index (BMI). Generalized clinical
osteoarthritis also confers a greater risk of knee osteoarthritis
structural progression.
Generalized osteoarthritis has been more frequently observed
in women than men and with increasing age, and is associated
with poorer function, disability, quality of life, and mortality than
osteoarthritis involving fewer joints. Whether generalized osteo-
arthritis reflects an accumulation of adverse biomechanical en-
vironments in adjacent joints, or load compensation from other
joints, or systemic factors such as genetic tendency or obesity, is
not well understood.
Fig. 19.9.2  MRI-​detected multitissue pathologies of knee osteoarthritis.
Reprinted by permission from Macmillan Publishers Ltd: Nature Reviews Rheumatology.
Wenham CYJ and Conaghan PG (2009). Imaging the painful osteoarthritic knee joint:
what have we learned? Volume 5, 149–​158, copyright 2009.
Table 19.9.3  The prevalence of MRI-​detected tissue lesions in knee osteoarthritis
General
MTF
LTF
PF
Presence of crepitus
180 (70.5%)
44 (17.3%)
48 (18.7%)
173 (67.9%)
Cartilage damage
221 (86.5%)
178 (69.8%)
151 (59.1%)
179 (70.1%)
Osteophytes
133 (52.0%)
95 (37.1%)
90 (35.3%)
102 (39.9%)
Medial meniscal damage
111 (43.7%)
95 (37.3%)
–​
–​
Lateral meniscal damage
–​
30 (11.9%)
–​
Cruciate pathology
23 (9.2%)
–​
–​
–​
MCL pathology
48 (18.7%)
48 (18.7%)
–​
–​
LCL pathology
0 (0%)
–​
0 (0%)
–​
MCL/​LCL, medial and lateral collateral ligaments of the knee; MTF/​LTF /​PF, medial tibiofemoral/​lateral tibiofemoral/​patellofemoral
Reprinted from Crema MD et al. (2011). The association of magnetic resonance imaging (MRI)-​detected structural pathology of the knee with crepitus in a population-​based cohort
with knee pain: the MoDEKO study. Osteoarthritis and Cartilage, 19(12), 1429–​1432. Copyright 2011, with permission from Elsevier.