18 - PART 11 Immune-Mediated, Inflammatory, and Rheumatologic Disorders

02 - 360 Introduction to the Immune System
360 Introduction to the Immune System
Immune-Mediated, Inflammatory, and Rheumatologic Disorders
PART 11
Section 1	 The Immune System in Health
and Disease
Barton F. Haynes, Kelly A. Cuttle,
Anthony S. Fauci
Introduction to the
Immune System
■
■DEFINITIONS
• Adaptive immune system—recently evolved system of immune
responses mediated by T and B lymphocytes. Immune responses by
these cells are based on specific antigen recognition by clonotypic
receptors that are products of genes that rearrange during devel­
opment and throughout the life of the organism. Additional cells
of the adaptive immune system include various types of antigenpresenting cells (APCs).
• Antibody—B cell–produced molecules encoded by genes that rear­
range during B-cell development consisting of immunoglobulin
heavy and light chains that together form the central component
of the B-cell receptor (BCR) for antigen. Antibody can exist as B cell–
surface antigen-recognition molecules or as secreted molecules in
plasma and other body fluids.
• Antigens—foreign or self-molecules that are recognized by the adap­
tive and innate immune systems resulting in immune cell triggering,
T-cell activation, and/or B-cell antibody production.
• Antigen-presenting cells (APCs)—a group of immune cells that
process antigens to mediate both adaptive immune responses and
the maintenance of peripheral tolerance. Classical APCs include
dendritic cells, macrophages, and B cells.
• Apoptosis—the process of programmed cell death whereby signal­
ing through “death receptors” on the surface of cells (e.g., tumor
necrosis factor [TNF] receptors, CD95) leads to signaling cascades
that involve activation of the caspase family of molecules and leads
to DNA cleavage and cell death. Apoptosis, which does not lead to
induction of inordinate inflammation, is to be contrasted with cell
necrosis, which does lead to induction of inflammatory responses.
• Autoimmune diseases—diseases such as systemic lupus erythemato­
sus and rheumatoid arthritis in which cells of the adaptive immune
system such as autoreactive T and B cells become overreactive and
produce pathogenic T-cell and antibody responses.
• Autoinflammatory diseases—hereditary disorders such as heredi­
tary periodic fevers (HPFs) characterized by recurrent episodes of
severe inflammation and fever due to mutations in controls of the
innate inflammatory response, i.e., the inflammasome (see below
and Table 360-5). Patients with HPFs also have rashes and serosal
and joint inflammation, and some can have neurologic symptoms.
Autoinflammatory diseases are different from autoimmune diseases
in that evidence for activation of adaptive immune cells such as
autoreactive B cells is not present.
• Autophagy—lysosomal degradation pathway mechanism of cells to
dispose of intracellular debris and damaged organelles. Autophagy
by cells of the innate immune system is used to control intracel­
lular infectious agents such as mycobacteria, in part by initiation
of phagosome maturation and enhancing major histocompatibility
complex (MHC) class II antigen presentation to CD4 T cells.
• B-cell receptor (BCR) for antigen—complex of surface molecules that
rearrange during postnatal B-cell development, made up of surface
immunoglobulin (Ig) and associated Ig αβ chain molecules that
recognize nominal antigen via Ig heavy- and light-chain variable
regions, and signal the B cell to terminally differentiate to make
antigen-specific antibody.
• B lymphocytes—bone marrow–derived lymphocytes that express
surface immunoglobulin (the BCR for antigen) and secrete specific
antibody after interaction with antigen.
• B regulatory cells—a population of suppressive B cells that aid in the
inhibition of inflammation through the release of cytokines such as
interleukin-(IL) 10.
• CD classification of human lymphocyte differentiation antigens—the
development of monoclonal antibody technology led to the discov­
ery of a large number of new leukocyte surface molecules. From
a series of International Workshop on Leukocyte Differentiation
Antigens has come the cluster of differentiation (CD) classification
of leukocyte antigens.
• CD4 T cell—T lymphocyte subset that participates in adaptive
immunity and helps B cells make antibody.
• CD8 T cell—cytotoxic T lymphocyte subset that kills tumor cells and
cells infected with pathogens.
• Chemokines—soluble molecules that direct and determine immune
cell movement and circulation pathways.
• Complement—cascading series of plasma enzymes and effector
proteins that function to lyse pathogens and/or target them to be
phagocytized by neutrophils and monocyte/macrophage lineage
cells of the reticuloendothelial system.
• Co-stimulatory molecules—molecules of APCs (such as B7-1, B7-2,
or CD40) that lead to T-cell activation when bound by ligands on
activated T cells (such as CD28 or CD40 ligand).
• Crystallopathies—nanoparticle- or microparticle-sized deposits of
crystals, misfolded proteins, or airborne particulate matter that can
stimulate the inflammasome and initiate inflammation and tissue
damage.
• Cytokines—soluble proteins that interact with specific cellular recep­
tors that are involved in the regulation of the growth and activation
of immune cells and mediate normal or pathologic inflammatory
and immune responses.
• Dendritic cells—myeloid and/or lymphoid lineage APCs of the
adaptive immune system. Immature dendritic cells (DCs), or DC
precursors, are key components of the innate immune system by
responding to infections with production of high levels of cytokines.
DCs are key initiators of innate immune responses via cytokine pro­
duction and mediators of adaptive immune responses via presenta­
tion of antigen to T lymphocytes.
• Ig fragment crystallizable (Fc) receptors (Rs)—receptors found on
the surface of certain cells including B cells, natural killer (NK)
cells, macrophages, neutrophils, and mast cells. Fc receptors bind
to the Fc domains of antibodies that have attached to invading
pathogen-infected cells. FcRs stimulate cytotoxic cells to destroy
microbe-infected cells through antibody-dependent cell-mediated
cytotoxicity (ADCC). Examples of important FcRs include CD16
(FcγRIIIa), CD23 (FcεR), CD32 (FcγRII), CD64 (FcγRI), and CD89
(FcαR).
• Inflammasome—large cytoplasmic complexes of intracellular pro­
teins that link the sensing of microbial products and cellular stress
to the proteolytic activation of IL-1β and IL-18 inflammatory
cytokines. Activation of molecules in the inflammasome is a key
step in the response of the innate immune system for intracellular
recognition of microbial and other danger signals in both health and
pathologic states.
• Innate immune system—ancient immune recognition system of
host cells bearing germline-encoded pattern recognition receptors
(PRRs) that recognize pathogens and trigger a variety of mecha­
nisms of pathogen elimination. Cells of the innate immune system
include NK cell lymphocytes, monocytes/macrophages, DCs, neu­
trophils, basophils, eosinophils, tissue mast cells, and epithelial cells.
• Innate lymphoid cells (ILCs)—lymphocytes that do not express the
type of diversified antigen receptors on T cell and B cells. ILC1s,
ILC2s, and ILC3s are tissue resident cells and functionally may be
analogous to CD4 TH1, TH2, and TH17 cells, respectively.
• Natural killer (NK) cells—a type of ILC that kills target cells express­
ing few or no human leukocyte antigen (HLA) class I molecules,
such as malignantly transformed cells and virally infected cells.
NK cells express receptors that inhibit killer cell function when
self-MHC class I is present. Innate NK cells mirror the cytolytic
functions of CD8 cytotoxic T cells of the adaptive immune system.
• NK T cells—innate-like lymphocytes that use an invariant T-cell
PART 11
Immune-Mediated, Inflammatory, and Rheumatologic Disorders
receptor (TCR)-α chain combined with a limited set of TCR-β
chains and coexpress receptors commonly found on NK cells. NK T
cells recognize lipid antigens of bacterial, viral, fungal, and protozoal
infectious agents.
• Pathogen-associated molecular patterns (PAMPs)—invariant molec­
ular structures expressed by large groups of microorganisms that
are recognized by host cellular PRRs in the mediation of innate
immunity.
• Pattern recognition receptors (PRR)—germline-encoded receptors
expressed by cells of the innate immune system that recognize PAMPs.
• T lymphocytes—thymus-derived lymphocytes that mediate adaptive
cellular immune responses including T helper, T regulatory, and
cytotoxic T lymphocyte effector cell functions.
• T-cell exhaustion—state of T cells when the persistence of antigen
disrupts memory T-cell function, resulting in defects in memory
T-cell responses. Most frequently occurs in malignancies and in
chronic viral infections such as HIV-1 and hepatitis C.
• TCR for antigen—complex of surface molecules that rearrange
during postnatal T-cell development made up of clonotypic TCR-α
and -β chains that are associated with the CD3 complex composed
of invariant γ, δ, ε, ζ, and η chains. TCR-α and -β chains recognize
peptide fragments of protein antigen physically bound in APC
MHC class I or II molecules, leading to signaling via the CD3
complex to mediate effector functions.
• T follicular helper T cells (TFH)—CD4 T cells regulated by bcl-6
in B-cell follicle germinal centers that produce IL-4 and IL-21 and
drive B-cell differentiation and affinity maturation in peripheral
lymphoid tissues such as lymph node and spleen.
• TH1 T cells—CD4 helper T-cell subset regulated by transcription
factor T-bet that produces interferon (IFN)-γ, IL-2, and TNF-β and
participates in cell-mediated immunity.
• TH2 T cells—CD4 helper T-cell subset regulated by transcription fac­
tors STAT6 and GATA3 that produces IL-4, IL-5, IL-6, IL-9, IL-10,
and IL-13 and regulates antibody and eosinophil responses.
• T regulatory cells (Treg)—CD4 or CD8 T cells regulated by the tran­
scription factor forkhead box P3 (FOXP3) that play roles in modulat­
ing immune responses to prevent harmful immune activation. Treg
cells that prevent autoimmunity can arise in the thymus (thymic
Tregs) after exposure to self-antigens on thymic epithelial cells or can
arise outside the thymus and are called peripheral Tregs. Intestinal
Tregs are essential to preventing pathogenic immune responses to the
gut microbiome, thus preventing intestinal inflammation.
• TH9 T cells—CD4 T cells regulated by the transcription factor PU.1
that secrete IL-9 and enhance inflammation in atopic disease and
inflammatory bowel disease as well as mediate antitumor immunity.
• TH13 T cells—T follicular helper cells (TFH) regulated by the
GATA3 transcription factor that produce IL-4, IL-5, and IL-13. TH13
TFH induce high-affinity IgE antibody responses that cause anaphy­
lactic reactions to allergens.
• TH17 T cells—CD4 T cells regulated by the transcription factor
RORγt that secrete IL-17, IL-22, and IL-26 and play roles in autoim­
mune inflammatory disorders as well as defend against bacterial and
fungal pathogens.
• Tolerance—B- and T-cell nonresponsiveness to antigens that results
from encounter with foreign or self-antigens by B and T lympho­
cytes in the absence of expression of APC co-stimulatory molecules.
Tolerance to antigens may be induced and maintained by multiple
mechanisms either centrally (B-cell deletion in the thymus for T cells or
bone marrow for B cells) or peripherally (by cell deletion or anergy
at sites throughout the peripheral immune system).
• Trained immunity—the epigenetic, transcriptional, and functional
reprogramming of innate immune cells to adapt to previous encoun­
ters with pathogens and respond to a second challenge in an altered
manner.
■
■INTRODUCTION
The human immune system has evolved over millions of years from
both invertebrate and vertebrate organisms to develop sophisticated
defense mechanisms that protect the host from microbes and their
virulence factors. The normal immune system has three key properties:
a highly diverse repertoire of antigen receptors that enables recognition
of a nearly infinite range of pathogens; immune memory, to mount
rapid recall immune responses; and immunologic tolerance, to avoid
immune damage to self-tissues.
From invertebrates, humans have inherited the innate immune sys­
tem, an ancient defense system that uses germline-encoded proteins
to recognize pathogens. Cells of the innate immune system, such as
macrophages, DCs, and NK lymphocytes, recognize PAMPs that are
highly conserved among many microbes and use a diverse set of PRR
molecules. Important components of the recognition of microbes by
the innate immune system include recognition by germline-encoded
host molecules, recognition of key microbe virulence factors but not
recognition of self-molecules, and nonrecognition of benign foreign
molecules or microbes such as are found in mucosal or other bar­
rier microbiomes. Upon contact with pathogens, cells of the innate
immune system may kill pathogens directly or, in concert with DCs,
activate a series of events that both slow the infection and recruit the
more recently evolved arm of the human immune system, the adaptive
immune system. In addition, innate immune cells undergo epigenetic,
transcriptional, and functional changes that allow adapted (either
enhanced or reduced) innate cell responses to repeat encounters with
pathogens, called trained immunity.
Adaptive immunity is found only in vertebrates and is based on the
generation of antigen receptors on T and B lymphocytes by gene rear­
rangements, such that individual T or B cells express unique antigen
receptors on their surface capable of specifically recognizing diverse
antigens of infectious agents in the environment. Coupled with specific
recognition mechanisms that maintain tolerance (nonreactivity) to selfantigens or nonpathogenic microbes (Chap. 361), T and B lymphocytes
bring both specificity and immune memory to vertebrate host defenses.
This chapter describes the cellular components, key molecules
(Table 360-1), and mechanisms that make up the innate and adaptive
immune systems and describes how adaptive immunity is recruited to
the defense of the host by innate immune responses. An appreciation
of the cellular and molecular bases of innate and adaptive immune
responses is critical to understanding the pathogenesis of inflam­
matory, autoimmune, infectious, and immunodeficiency diseases, as
well as a wide range of diseases associated with inflammation such as
atherosclerotic cardiovascular disease and neurodegenerative diseases.
■
■THE INNATE IMMUNE SYSTEM
All multicellular organisms, including humans, have developed the use
of surface and intracellular germline-encoded molecules that recognize
pathogens. Because of the myriad of human pathogens, host molecules
of the human innate immune system sense “danger signals” and either
recognize PAMPs, the common molecular structures shared by many
pathogens, or recognize host cell molecules produced in response to
infection such as heat shock proteins and fragments of the extracel­
lular matrix. PAMPs must be conserved structures vital to pathogen
virulence and survival, such as bacterial endotoxin, so that pathogens
cannot mutate molecules of PAMPs to evade human innate immune
responses. PRRs are host proteins of the innate immune system that
recognize PAMPs as host danger signal molecules (Tables 360-2 and
360-3). Thus, recognition of pathogen molecules by hematopoietic
and nonhematopoietic cell types leads to activation/production of the
complement cascade, cytokines, or antimicrobial peptides as effector
molecules. In addition, pathogen PAMPs as host danger signal mol­
ecules activate DCs to mature and to express molecules on the DC sur­
face that optimize antigen presentation to respond to foreign antigens.
TABLE 360-1  Human Leukocyte Surface Antigens—The CD Classification of Leukocyte Differentiation Antigens
SURFACE ANTIGEN
(OTHER NAMES)
FAMILY
MOLECULAR
MASS, kDa
DISTRIBUTION
LIGAND(S)
FUNCTION
CD1a (T6, HTA-1)
Ig
CD, cortical thymocytes,
Langerhans type of DCs
CD1b
Ig
CD, cortical thymocytes,
Langerhans type of DCs
CD1c
Ig
DC, cortical thymocytes,
subset of B cells,
Langerhans type of DCs
CD1d
Ig
Cortical thymocytes,
intestinal epithelium,
Langerhans type of DCs
CD2 (T12, LFA-2)
Ig
T, NK
CD58, CD48, CD59,
CD15
CD3 (T3, Leu-4)
Ig
γ:25–28, δ:21–
28, ε:20–25,
η:21–22, ζ:16
T, NK T
Associates with the
TCR
CD4 (T4, Leu-3)
Ig
T, myeloid
MHC-II, HIV gp120,
IL-16, SABP
CD7 (3A1, Leu-9)
Ig
T, NK
K-12 (CD7L)
T- and NK-cell signal transduction and regulation of IFN-γ,
TNF-α production
CD8 (T8, Leu-2)
Ig
T, subset of NK
MHC-I
T-cell selection, T-cell activation, signal transduction with
p56lck
CD14 (LPS-receptor)
LRG
53–55
M, G (weak), not by
myeloid progenitors
CD16a (FcγRIIIa)
Ig
50–80
NK, macrophages,
neutrophils
CD19 B4
Ig
B (except plasma cells),
FDC
CD20 (B1)
Unassigned
33–37
B (except plasma cells)
Not known
Cell signaling, may be important for B-cell activation and
proliferation
CD21 (B2, CR2, EBV-R,
C3dR)
RCA
Mature B, FDC, subset of
thymocytes
CD22 (BL-CAM)
Ig
130–140
Mature B
CDw75
Cell adhesion, signaling through association with p72sky,
p53/56lyn, PI3 kinase, SHP1, fLCγ
C-type lectin 45
B, M, FDC
IgE, CD21, CD11b,
CD11c
CD23 (FcεRII, B6,
Leu-20, BLAST-2)
CD28
Ig
T, plasma cells
CD80, CD86
Co-stimulatory for T-cell activation; involved in the
decision between T-cell activation and anergy
CD32a (FcγRIIa)
Ig
NK, macrophages,
neutrophils
CD40
TNFR
48–50
B, DC, EC, thymic
epithelium, MP, cancers
CD45 (LCA, T200,
B220)
PTP
180, 200, 210,
All leukocytes
Galectin-1, CD2, CD3,
CD4
CD45RA
PTP
210, 220
Subset T, medullary
thymocytes, “naive” T
CD45RB
PTP
200, 210, 220
All leukocytes
Galectin-1, CD2, CD3,
CD4
CD45RC
PTP
210, 220
Subset T, medullary
thymocytes, “naive” T
CD45RO
PTP
Subset T, cortical
thymocytes, “memory” T
CD64 (FcγRI)
Ig
45–55
Macrophages and
monocytes
CD80 (B7-1, BB1)
Ig
Activated B and T, MP, DC
CD28, CD152 (CTLA-4)
Co-regulator of T-cell activation; signaling through CD28
stimulates and through CD152 inhibits T-cell activation
CD86 (B7-2, B70)
Ig
Subset B, DC, EC,
activated T, thymic
epithelium
CD89 (FCαR)
Ig
55–100
Neutrophils, eosinophils,
monocytes, and MP
CD1 molecules present lipid antigens of intracellular
bacteria such as Mycobacterium leprae and
M. tuberculosis to TCRγδT cells or NK T cells
TCRγδ T cells,
NK T cells
CHAPTER 360
 
TCRγδ T cells,
NK T cells
 
TCRγδ T cells,
NK T cells
Introduction to the Immune System
 
TCRγδ T cells,
NK T cells
Alternative T-cell activation, T-cell anergy, T-cell cytokine
production, T- or NK-mediated cytolysis, T-cell apoptosis,
cell adhesion
T-cell activation and function; ζ is the signal transduction
component of the CD3 complex
T-cell selection, T-cell activation, signal transduction with
p56lck, primary receptor for HIV-1
Endotoxin
(lipopolysaccharide),
lipoteichoic acid, PI
TLR4 mediates with LPS and other PAMP activation of
innate immunity
Fc portion of IgG
Mediates phagocytosis and ADCC
Not known
Associates with CD21 and CD81 to form a complex
involved in signal transduction in B-cell development,
activation, and differentiation
C3d, C3dg, iC3b, CD23,
EBV
Associates with CD19 and CD81 to form a complex
involved in signal transduction in B-cell development,
activation, and differentiation; Epstein-Barr virus receptor
Regulates IgE synthesis, cytokine release by monocytes
Fc portion of IgG
Mediates phagocytosis and ADCC
CD154 (CD40L)
B-cell activation, proliferation, and differentiation;
formation of GCs; isotype switching; rescue from apoptosis
T and B activation, thymocyte development, signal
transduction, apoptosis
Galectin-1, CD2, CD3,
CD4
Isoforms of CD45 containing exon 4 (A), restricted to a
subset of T cells
Isoforms of CD45 containing exon 5 (B)
Galectin-1, CD2, CD3,
CD4
Isoforms of CD45 containing exon 6 (C), restricted to a
subset of T cells
Galectin-1, CD2, CD3,
CD4
Isoforms of CD45 containing no differentially spliced
exons, restricted to a subset of T cells
Fc portion of IgG
Mediates phagocytosis and ADCC
CD28, CD152 (CTLA-4)
Co-regulator of T-cell activation; signaling through CD28
stimulates and through CD152 inhibits T-cell activation
Fc portion of IgG
Mediates phagocytosis and ADCC of IgA-coated
pathogens
(Continued)
TABLE 360-1  Human Leukocyte Surface Antigens—The CD Classification of Leukocyte Differentiation Antigens
SURFACE ANTIGEN
(OTHER NAMES)
FAMILY
MOLECULAR
MASS, kDa
DISTRIBUTION
LIGAND(S)
FUNCTION
CD95 (APO-1, Fas)
TNFR
Activated T and B
Fas ligand
Mediates apoptosis
CD112 (nekton-2,
PVRL2)
Ig
Epithelial cells,
endothelial cells, other
tissues
PART 11
Immune-Mediated, Inflammatory, and Rheumatologic Disorders
CD134 (OX40)
TNFR
Activated T
OX40L (CD252)
T-cell survival, cytokine stimulation
CD137 (4-1BB)
TNFR
Activated T, DCs, B, NK
CD137L (41BBL)
T-cell co-stimulation
CD155 (PVR)
Ig
50–65
DCs, NK, epithelial cells
TIGIT, CD96, DNAM-1
T-cell inhibition (TIGIT, CD96), T-cell activation (DNAM-1)
CD223 (LAG-3)
Ig
NK, B, activated T
MHC class II
T-cell inhibition
CD226 (DNAM-1)
Ig
NK, monocytes, T
CD112, CD155
T-cell activation (CD112), T-cell activation (CD155)
CD252 (OX40L)
TNFR
16–25
Antigen-presenting cells,
endothelial cells
CD272 (BTLA)
Ig
Activated T
HVEM
T-cell inhibition
CD274 (PD-L1)
Ig
T, NK, myeloid, B, tumor
cells
CD278 (ICOS)
Ig
55–60
Activated T
ICOSL
T-cell activation
CD357 (GTTR)
TNFR
Activated T, Tregs
GITRL
T-cell activation
CD152 (CTLA-4)
Ig
30–33
Activated T
CD80, CD86
Inhibits T-cell proliferation
CD154 (CD40L)
TNF
Activated CD4+ T, subset
CD8+ T, NK, M, basophil
CD279 (PD-1)
Ig
50–55
B, T, TFH
PD-L1 (CD274), PD-L2
(CD273)
Abbreviations: ADCC, antibody-dependent cell-mediated cytotoxicity; BTLA, band T lymphocyte attenuators; CTLA, cytotoxic T lymphocyte–associated protein; DC, dendritic
cells; DNAM-1, DNAX accessory molecule-1; EBV, Epstein-Barr virus; EC, endothelial cells; ECM, extracellular matrix; Fcγ RIII, low-affinity IgG receptor isoform A; FDC, follicular
dendritic cells; G, granulocytes; GC, germinal center; GITR, glucocorticoid-induced TNFR-related protein; GPI, glycosyl phosphatidylinositol; HTA, human thymocyte antigen;
HVEM, herpesvirus entry mediator; ICOS, inducible T-cell co-stimulator; Ig, immunoglobulin; IgG, immunoglobulin G; LAG-3, lymphocyte-activation gene 3; LCA, leukocyte
common antigen; LPS, lipopolysaccharide; MHC-I, major histocompatibility complex class I; MP, macrophages; Mr, relative molecular mass; NK, natural killer cells; P,
platelets; PBT, peripheral blood T cells; PD-1, programmed cell death-1; PI, phosphatidylinositol; PI3K, phosphatidylinositol 3-kinase; PLC, phospholipase C; PTP, protein
tyrosine phosphatase; PVR, polio virus receptor; PVRL2, polio virus receptor-related 2; RCA, regulators of complement activation; SABP, seminal actin binding protein; TCR,
T-cell receptor; TFH, T follicular helper cells; TIGIT, T-cell immunoreceptor with Ig and ITIM domains; TNF, tumor necrosis factor; TNFR, tumor necrosis factor receptor.
Note: For an expanded list of cluster of differentiation (CD) human antigens, see Harrison’s Online at accessmedicine.com; and for a full list of CD human antigens from
the most recent Human Workshop on Leukocyte Differentiation Antigens (VII), D Mason, P Andre, A Bensussan, et al (eds): Leucocyte Typing VII. Oxford: Oxford University
Press, 2002.
Source: Compiled from T Kishimoto et al (eds): Leukocyte Typing VI. New York: Garland Publishing, 1997; R Brines et al: Immunol Today 18S:1, 1997; and D Mason et al:
CD antigens 2002. Blood 99:3877, 2002.
■
■PATTERN RECOGNITION
Major PRR families of proteins include transmembrane proteins, such
as the Toll-like receptors (TLRs) and C-type lectin receptors (CLRs),
and cytoplasmic proteins, such as the retinoic acid–inducible gene (RIG)-
1-like receptors (RLRs) and NOD-like receptors (NLRs) (Table 360-4).
A major group of PRR collagenous glycoproteins with C-type lectin
domains are termed collectins and include the serum protein mannosebinding lectin (MBL). MBL and other collectins, as well as two other
protein families—the pentraxins (such as C-reactive protein and serum
amyloid P) and macrophage scavenger receptors—all have the property
of opsonizing (coating) bacteria for phagocytosis by macrophages and
TABLE 360-2  Major Components of the Innate Immune System
Pattern recognition
receptors (PRRs)
Toll-like receptors (TLRs), C-type lectin receptors (CLRs),
retinoic acid–inducible gene (RIG)-1-like receptors (RLRs),
and NOD-like receptors (NLRs)
Antimicrobial
peptides
α-Defensins, β-defensins, cathelin, protegrin, granulysin,
histatin, secretory leukoprotease inhibitor, and probiotics
Cells
Macrophages, dendritic cells, innate lymphoid cells
(ILC1, ILC2, ILC3, NK cells, lymphoid tissue inducer [LTi]
cells), mucosal-associated invariant T (MAIT) cells, NK-T
cells, neutrophils, eosinophils, mast cells, basophils, and
epithelial cells
Complement
components
Classic and alternative complement pathway, and proteins
that bind complement components
Cytokines
Autocrine, paracrine, endocrine cytokines that mediate
host defense and inflammation, as well as recruit, direct,
and regulate adaptive immune responses
Abbreviation: NK, natural killer.
(Continued)
DNAM-1 (CD226),
TIGIT
T-cell activation (DNAM-1), T-cell inhibition (TIGIT)
OX40
T-cell survival, cytokine stimulation
PD-1 (CD279)
Inhibit TCR activation
CD40
Co-stimulatory for T-cell activation, B-cell proliferation and
differentiation
Inhibits T-cell proliferation
can also activate the complement cascade to lyse bacteria. Integrins
are cell-surface adhesion molecules that affect attachment between
cells and the extracellular matrix and mediate signal transduction
that reflects the chemical composition of the cell environment. For
example, integrins signal after cells bind bacterial lipopolysaccharide
(LPS) and activate phagocytic cells to ingest pathogens.
There are multiple connections between the innate and adaptive
immune systems; these include (1) a plasma protein, LPS-binding
protein, that binds and transfers LPS to the macrophage LPS recep­
tor, CD14; (2) the human family of proteins called Toll-like receptor
proteins (TLRs), some of which are associated with CD14, bind LPS,
and signal epithelial cells, DCs, and macrophages to produce cytokines
and upregulate cell-surface molecules that signal the initiation of
adaptive immune responses (Fig. 360-1, Table 360-3); and (3) families
of intracellular microbial sensors called NLRs and RLRs. Proteins in
the Toll family can be expressed on macrophages, DCs, and B cells as
well as on a variety of nonhematopoietic cell types, including respira­
tory epithelial cells. Eleven TLRs have been identified in humans (Table
360-3). Upon ligation, TLRs activate a series of intracellular events
that lead to the killing of bacteria- and viral-infected cells as well as
to the recruitment and ultimate activation of antigen-specific T and
B lymphocytes (Fig. 360-1). Importantly, signaling by massive amounts
of LPS through TLR4 leads to the release of high levels of cytokines that
mediate LPS-induced shock. Mutations in TLR4 proteins in mice pro­
tect from LPS shock, and TLR mutations in humans can protect from
LPS-induced inflammatory diseases such as LPS-induced asthma.
Table 360-4 lists diseases caused by gene variants in nucleic acid–sensing
Toll family and related receptors.
Two other families of cytoplasmic PRRs are the NLRs and the RLRs.
These families, unlike the TLRs, are composed primarily of soluble
TABLE 360-3  Pattern Recognition Receptors (PRRs) and Their Ligands
PRR
LOCALIZATION
LIGAND
ORIGIN OF THE LIGAND
TLR
 
 
 
  TLR1
Plasma membrane
Triacyl lipoprotein
Bacteria
  TLR2
Plasma membrane
Lipoprotein
Bacteria, viruses, parasite, self
  TLR3
Endolysosome
dsRNA
Virus
  TLR4
Plasma membrane
LPS
Bacteria, viruses, self
  TLR5
Plasma membrane
Flagellin
Bacteria
  TLR6
Plasma membrane
Diacyl lipoprotein
Bacteria, viruses
  TLR7 (human TLR8)
Endolysosome
ssRNA
Virus, bacteria, self
  TLR9
Endolysosome
CpG-DNA
Virus, bacteria, protozoa, self
  TLR10
Endolysosome
Unknown
Unknown
  TLR11
Plasma membrane
Profilin-like molecule
Protozoa
RLR
 
 
 
  RIG-I
Cytoplasm
Short dsRNA, triphosphate dsRNA
RNA viruses, DNA virus
  MDA5
Cytoplasm
Long dsRNA
RNA viruses (Picornaviridae)
  LGP2
Cytoplasm
Unknown
RNA viruses
NLR
 
 
 
  NOD1
Cytoplasm
iE-DAP
Bacteria
  NOD2
Cytoplasm
MDP
Bacteria
CLR
 
 
 
  Dectin-1
Plasma membrane
β2-Glucan
Fungi
  Dectin-2
Plasma membrane
β2-Glucan
Fungi
  MINCLE
Plasma membrane
SAP130
Self, fungi
Abbreviations: CLR, C-type lectin receptors; dsRNA, double-strand RNA; iE-DAP, D-glutamyl-meso-diaminopimelic acid moiety; LGP2, Laboratory of Genetics and Physiology
2 protein encoded by the gene DHX58; MDA5, melanoma differentiation-associated protein 5; MDP, MurNAc-L-Ala-D-isoGln, also known as muramyl dipeptide; MINCLE,
macrophage-inducible C-type lectin; NLR, NOD-like receptor; NOD, NOTCH protein domain; RIG, retinoic acid–inducible gene; RLR, RIG-like receptors; SAP130, Sin-3
associated protein 130; TLR, Toll-like receptor.
Source: Reproduced with permission from O Takeuchi: Pattern recognition receptors and inflammation. Cell 140:805, 2010.
Triacylated
lipopeptides
Diacylated
lipopeptides
Flagellin
Unknown
LPS
CD14
TLR4
TLR2
TLR1
TLR2
TLR6
TLR5
TLR10
MYD88
MYD88
TIRAP
TRIF
TRAM
TRIF
IRF3
TLR3
dsRNA
Endosome
IRF3
Inflammatory
cytokines and/
or chemokines
Nucleus
IFN-β
FIGURE 360-1  Overview of major TLR signaling pathways. All TLRs signal through MYD88, with the exception of TLR3. TLR4 and the TLR2 subfamily (TLR1, TLR2, TLR6) also
engage TIRAP (Toll-interleukin 1 receptor domain-containing adapter protein). TLR3 signals through TRIF (Toll-interleukin 1 receptor domain-containing adapter-inducing
interferon-β). TRIF is also used in conjunction with TRAM (TRIF-related adaptor molecule) in the TLR4-MYD88-independent pathway. Dashed arrows indicate translocation
into the nucleus. dsRNA, double-strand RNA; IFN, interferon; IRF3, interferon regulatory factor 3; LPS, lipopolysaccharide; MAPK, mitogen-activated protein kinases; NF-κB,
nuclear factor-κB; ssRNA, single-strand RNA; TLR, Toll-like receptor. (Reproduced with permission from D Van Duin et al: Triggering TLR signaling in vaccination. Trends
Immunol 27:49, 2006.)
CHAPTER 360
Introduction to the Immune System
Flagellin
TLR11
Plasma membrane
MYD88
TLR9
CpG
IRAK
ssRNA
Endosome
TLR7
or TLR8
TRAF-6
NF-κB
MAPK
NF-κB
TABLE 360-4  Diseases Caused by Gene Variants in Nucleic Acid-Sensing Receptors and Related Proteins
CHANGE IN
FUNCTION
LOCATION
LIGAND OR PARTNER
GENE
PROTEIN
DNASE1
DNASE1
LOF
Extracellular
dsDNA (NETs)
SLE
Yes
PART 11
Immune-Mediated, Inflammatory, and Rheumatologic Disorders
DNASE1L3
DNASE1L3
LOF
Extracellular
Nucleosomes exposed on
microparticles or apoptotic bodies
TLR7
TLR7
GOF
Endosomal
ssRNA, 2’3’cGMP
SLE 17
Yes
TLR9
TLR9
–
Endosomal
CpG dsDNA
N/A
–
No
MyD88
MyD88
–
Endosomal
TLRs
N/A (GOF)
–
No
ADA2
ADA2
LOF
Endolysosomal
Adenosine,
Sneddon syndrome
No
 
 
 
 
2’-deoxyadenosine
Vasculitis, autoinflammation,
immunodeficiency, and
hematologic defects syndrome
(DADA2)
DNASE2
DNASE2
LOF
Lysosomal
Exogenous DNA
Autoinflammatory-pancytopenia
syndrome
TREX1
TREX1
LOF
Cytoplasmic
DNA (retroviral/retrotransposon)
AGS 1
Yes
 
 
 
 
Chilblain lupus
Vasculopathy, retinal, with
cerebral leukoencephalopathy
and systemic manifestations
 
 
 
 
 
Susceptibility to SLE
TMEM173
STING
LOF
Cytoplasmic
cGAMP and excess DNA
STING-associated vasculopathy,
infantile-onset
CGAS
cGAS
–
Cytoplasmic
Cytosolic DNA
N/A (GOF)
–
No
SAMHD1
SAMHD1
LOF
Cytoplasmic
dNTPs
Chilblain lupus?
Yes
 
 
 
 
 
AGS 5
RNASEH2A
RNASEH2A
LOF
Cytoplasmic
RNA in RNA-DNA hybrids
AGS 4
Yes
RNASEH2B
RNASEH2B
LOF
Cytoplasmic
RNA in RNA-DNA hybrids
AGS 2
Yes
RNASEH2C
RNASEH2C
LOF
Cytoplasmic
RNA in RNA-DNA hybrids
AGS 3
Yes
IFIH1
MDA5
GOF
Cytoplasmic
Long dsRNA
AGS 7
Yes
RIGI
DDX58
GOF
Cytoplasmic
Short dsRNA
Singleton-Merten syndrome 2
No
MAVS
MAVS
–
Cytoplasmic
–
N/A (GOF)
–
No
AIM2
AIM2
–
Cytoplasmic
Cytosolic dsDNA
N/A
–
No
IFI16
IFI16
–
Nuclear
Viral DNA or damaged self-DNA
N/A (GOF)
–
No
Note: See the online catalogue of human genes and genetic disorders (OMIM) at https://omim.org.
Abbreviations: GOF, gain of function; LOF, loss of function; N/A, not applicable; SLE, systemic lupus erythematosus.
Source: Reproduced with permission from CG Vinuesa CG et al: Innate virus-sensing pathways in B cell systemic autoimmunity. Science 380:478, 2023.
intracellular proteins that scan host cell cytoplasm for intracellular
pathogens (Tables 360-2 and 360-3).
The intracellular microbial sensors, NLRs, after triggering, form
large cytoplasmic complexes termed inflammasomes, which are aggre­
gates of molecules including NOD-like receptor pyrin (NLRP) proteins
(Table 360-5). Inflammasomes activate inflammatory caspases and
IL-1β in the presence of nonbacterial danger signals (cell stress) and
bacterial PAMPs. Mutations in inflammasome proteins can lead to
chronic inflammation in a group of periodic febrile diseases called
autoinflammatory syndromes. Polymorphisms in inflammasome com­
ponents can either protect or enhance risk of infections or autoimmune/
autoinflammatory diseases (Table 60-4). Inflammasomes are activated
upon sensing of PAMPs. Crystallopathies are diseases caused by tissue
crystal deposition such as monosodium urate that can activate the
inflammasome and, in the case of urate deposition, can lead to gout
with arthritis or renal disease.
■
■EFFECTOR CELLS OF INNATE IMMUNITY
Cells of the innate immune system and their roles in the first line
of host defense are listed in Table 360-6. Equally important as their
roles in the mediation of innate immune responses are the roles that
each cell type plays in recruiting T and B lymphocytes of the adaptive
immune system to engage in specific pathogen responses.
Monocytes-Macrophages 
Monocytes arise from precursor cells
within bone marrow (Fig. 360-2) and circulate with a half-life ranging
AUTOIMMUNE OR
AUTOINFLAMMATORY
DISEASE IN OMIM
LUPUS
SUSCEPTIBILITY
ALLELES
OMIM
NUMBER
SLE16
Yes
No
Yes
Singleton-Merten syndrome 1
from 1 to 3 days. Monocytes leave the peripheral circulation via capil­
laries and migration into a vast extravascular cellular pool. Tissue
macrophages arise from monocytes that have migrated out of the
circulation and by in situ proliferation of macrophage precursors in tis­
sue. Common locations where tissue macrophages (and certain of their
specialized forms) are found are lymph node, spleen, bone marrow,
perivascular connective tissue, serous cavities such as the peritoneum,
pleura, skin connective tissue, lung (alveolar macrophages), liver
(Kupffer cells), bone (osteoclasts), central nervous system (microglia
cells), and synovium (type A lining cells).
In general, monocytes-macrophages are on the first line of defense
associated with innate immunity and ingest and destroy microorgan­
isms through the release of toxic products such as hydrogen peroxide
(H2O2) and nitric oxide (NO). Inflammatory mediators produced by
macrophages attract additional effector cells such as neutrophils to
the site of infection. Macrophage mediators include prostaglandins;
leukotrienes; platelet activating factor; cytokines such as IL-1, TNF-α,
IL-6, and IL-12; and chemokines (Tables 360-7 and 360-8).
Although monocytes-macrophages were originally thought to be
the major APCs of the immune system, it is now clear that cell types
called dendritic cells are the most potent and effective classical APCs
in the body (see below). Monocytes-macrophages mediate innate
immune effector functions such as destruction of antibody-coated bac­
teria, tumor cells, or even normal hematopoietic cells in certain types
of autoimmune cytopenias. Monocytes-macrophages ingest bacteria
TABLE 360-5  Mutations in Innate Inflammasome Molecules Associated with Clinical Disease
Inherited Inflammasomopathies
INHERITED PATTERN
AND EFFECT
PHENOTYPE
MUTATED GENE
DISEASE
NLRP1
NLRP1-associated
autoinflammation with arthritis
and dyskeratosis
Autosomal dominant GoF
Hyperkeratotic ulcerative skin
lesions, fever, arthritis, ANA
NLRP3
Cryopyrin-associated periodic
syndromes (CAPS)
Autosomal dominant GoF
Spectrum from cold-induced
urticaria and fever to CNS
inflammation and bone
overgrowth
NLRC4
Autoinflammatory infantile
fever with enterocolitis (AIFEC)
Autosomal dominant GoF
Recurrent MAS, enterocolitis,
cold-induced fever and
urticaria, CNS inflammation
MEFV
Familial Mediterranean fever
(FMF)
Autosomal recessive LoF
or gene-dosage-dependent
autosomal dominant GoF
Genetic Polymorphisms in Inflammasome Components and Human Infectious Diseases
INFECTIOUS AGENT/DISEASE
GENE
VARIANT ID
Candida albicans (recurrent
vulvovaginal candidiasis)
NLRP3
rs74163773
Increased
Risk
Chlamydia trachomatis
NLRP3
rs12065526
Unknown
Risk
HCV
NLRP3
rs1539019; rs35829419
Unknown; increased
Protection
HIV-1
NLRP3
rs10754558
Increased
Protection
 
IFI16
rs1417806
Increased
Protection
HPV
NLRP1
rs11651270
Increased
Protection
 
NLRP3
rs10754558
Increased
Protection
HSV-2
IFI16
rs2276404
Increased
Protection
HTLV
NLRP3
rs10754558
Increased
Protection
Microbial infection in lungs
NLRC4
rs212704
Decreased
Risk
Mycobacterium leprae
NLRP1
rs2670660, rs12150220
Increased
Protection
 
 
rs2137722
(Haplotype)
 
Mycobacterium tuberculosis
NLRP3
rs10754558
Increased
Protection
 
 
rs10754558
Increased
Risk
 
CARD8
rs6509365
Unknown
Risk
 
NLRC4
rs385076
Decreased
Protection
Plasmodium vivax
NLRP1
rs12150220
Increased
Risk
Renal parenchymal infections
NLRP3
rs4612666
Increased
Protection
Streptococcus pneumoniae
NLRP1
rs11651270
Increased
Risk
 
CARD8
rs2043211
Increased
 
Trypanosoma cruzi
NLRP1
rs11691270
Increased
Risk
 
CASP1
rs501192
Unknown
Risk
Genetic Polymorphisms in Inflammasome Components and Autoimmune in Polygenic Autoinflammatory Diseases
Addison disease
NLRP1
rs12150220
Increased
Risk
Ankylosing spondylitis
NLRP3
rs4612666
Increased
Risk
 
MEFV
rs224204
Unknown
Risk
 
CARD8
rs2043211
Increased
Protection
Autoimmune thyroiditis
NLRP1
rs12150220, rs2670660
Increased
Risk
 
AIM2
rs855873
Unknown
Risk
Behçet disease
AIM2
rs855873
Unknown
Risk
 
IFI16
rs6940
Decreased
 
Celiac disease
NLRP3
rs35829419
Increased
Protection; risk
IBD: Crohn’s disease (CD) and
ulcerative colitis (UC)
NLRP3
rs35829419
Increased
Risk (men)
 
 
Increased
Protection
 
 
rs10754558
Increased
Risk
 
 
rs10925019
Unknown
Risk
 
 
rs4925648
Unknown
Risk
 
 
rs4353135, rs55646866;
rs4266924, rs6672995,
rs10733113
PREDOMINANT
EFFECTOR CELLS
CHAPTER 360
Keratinocytes
Monocytes, granulocytes
(neutrophils), chondrocytes
Introduction to the Immune System
Monocytes/macrophages
Fever, serositis, rash, SAA
amyloidosis
Neutrophils, monocytes,
serosal and synovial fibroblasts
EFFECT ON INFLAMMASOME
ACTIVATION
ASSOCIATION
Decreased; unknown
Risk
(Continued)
TABLE 360-5  Mutations in Innate Inflammasome Molecules Associated with Clinical Disease
INFECTIOUS AGENT/DISEASE
GENE
VARIANT ID
IBD: Crohn’s disease (CD) and
ulcerative colitis (UC) (Cont.)
MEFV
rs182674, rs224217, rs224225,
rs224224, rs224223, rs224222
PART 11
Immune-Mediated, Inflammatory, and Rheumatologic Disorders
 
CARD8
rs2043211
Increased
Risk
 
 
 
 
Protection
 
 
rs1972619
Unknown
Risk
HS purpura
MEFV
rs3743930
Unknown
Risk
Kawasaki disease
NLRP1
rs11651270, rs8079034,
rs3744717, rs11078571,
rs16954813, rs8079727
Multiple sclerosis
NLRP3
rs3806265, rs10754557
Unknown
Risk
 
 
rs35829419
Increased
Risk
 
NLRC4
rs479333
Decreased
Protection
PFAPA
CARD8
rs140826611
Unknown
Risk
Psoriasis
NLRP1
rs8079034
Unknown
Risk
 
NLRP3
rs3806265, rs10754557
Unknown
Risk
 
 
rs10733113
Unknown
Risk
 
CARD8
rs2043211
Increased
Risk
 
AIM2
rs2276405
Unknown
Protection
Psoriatic JIA
NLRP3
rs4353135
Decreased
Risk
 
 
rs3806265
Unknown
Risk
 
MEFV
rs224204
Unknown
Risk
Rheumatoid arthritis
NLRP1
rs878329
Unknown
Risk
 
NLRP3
rs35829419
Increased
Risk
 
 
rs10754558
Increased
Risk
 
 
rs10159239, rs4925648,
rs4925659
 
CASP5
rs9651713
Unknown
Risk
SLE
NLRP1
rs12150220, rs2670660
Increased
Risk
Systemic sclerosis
NLRP1
rs8182352
Unknown
Risk
Type 1 diabetes
NLRP1
rs12150220
Increased
Risk
 
 
rs2670660, rs11651270
Increased
Protection
 
NLRP3
rs10754558
Increased
Protection
Vitiligo
NLRP1
rs12150220
Increased
Risk
 
 
rs2670660
Increased
Risk
 
 
rs8182352
Unknown
Risk
 
 
rs6502867
Unknown
Risk
 
 
rs1008588
Unknown
Risk
Note: Mutated gene and respective syndrome name are reported for inflammasomopathies, as well as inheritance pattern and effect of mutations, clinical phenotype, and
predominant disease effector cells. Inflammasome variants previously associated with infectious agents and/or diseases are briefly resumed from literature (https://www
.ncbi.nlm.nih.gov/pubmed). Significantly associated polymorphisms were grouped according to the infectious agent/disease. Infectious agent or disease (in alphabetical
order), gene name (gene), identification number of polymorphism (ID), resulting effect on inflammasome activation (“increased,” “decreased,” or “unknown”), cohort origin
(cohort) and eventually specifications (severity, etc.), sample size (n), and type (case/control or cases only), association result (“risk” or “protection”), and respective
reference are reported.
Abbreviations: ANA, antinuclear antibodies; CNS, central nervous system; GoF, gain-of-function; HCV, hepatitis C virus; HIV, human immunodeficiency virus; HPV, human
papillomavirus; HS, Henoch-Schönlein; HSV, herpes simplex virus; HTLV, human T-lymphotropic virus; IBD, inflammatory bowel disease; JIA, juvenile idiopathic arthritis;
LoF, loss-of-function; MAS, macrophage activation syndrome; PFAPA, periodic fever with aphthous stomatitis, pharyngitis, and cervical adenitis; SAA, serum amyloid A; SLE,
systemic lupus erythematosus.
Source: Reproduced with permission from FP Fernandes et al: Inflammasome genetics and complex diseases: A comprehensive review. Eur J Hum Genet 28:1307, 2020.
or are infected by viruses, and in doing so, they frequently undergo
programmed cell death or apoptosis. Macrophages that are infected by
intracellular infectious agents are recognized by DCs as infected and
apoptotic cells and are phagocytosed by DCs. In this manner, DCs
“cross-present” infectious agent antigens of macrophages to T cells.
Activated macrophages can also mediate antigen-nonspecific lytic
activity and eliminate cell types such as tumor cells in the absence of
antibody. This activity is largely mediated by cytokines (i.e., TNF-α
and IL-1). Monocytes-macrophages express lineage-specific molecules
(e.g., the cell-surface LPS receptor, CD14) as well as surface receptors
for a number of molecules, including the Fc region of IgG, activated
complement components, and various cytokines (Table 360-7).
(Continued)
EFFECT ON INFLAMMASOME
ACTIVATION
ASSOCIATION
Unknown
Risk
Increased (haplotype)
Risk
Unknown
Risk
Dendritic Cells 
Human DCs contain several subsets, including
myeloid DCs and plasmacytoid DCs. Myeloid DCs can differentiate
into either macrophages-monocytes or tissue-specific DCs. In contrast
to myeloid DCs, plasmacytoid DCs are potent producers of TLR-7
dependent type I IFN (e.g., IFN-α) in response to free virus and virusinfected cells. The maturation of DCs is regulated through cell-to-cell
contact and soluble factors, and DCs attract immune effectors through
secretion of chemokines. When DCs come in contact with bacterial
products, viral proteins, or host proteins released as danger signals
from distressed host cells (Fig. 360-2), infectious agent molecules bind
to various TLRs and activate DCs to release cytokines and chemokines
that drive cells of the innate immune system to become activated to
TABLE 360-6  Cells of the Innate Immune System and Their Major Roles in Triggering Adaptive Immunity
CELL TYPE
MAJOR ROLE IN INNATE IMMUNITY
MAJOR ROLE IN ADAPTIVE IMMUNITY
Macrophages
Phagocytose and kill bacteria; produce antimicrobial peptides;
bind LPS; produce inflammatory cytokines
Plasmacytoid dendritic
cells (DCs) of lymphoid
lineage
Produce large amounts of interferon-α (IFN-α), which has
antitumor and antiviral activity, and are found in T-cell zones of
lymphoid organs; they circulate in blood
Myeloid DCs are of two
types: interstitial and
Langerhans-derived
Interstitial DCs are strong producers of IL-12 and IL-10 and are
located in T-cell zones of lymphoid organs, circulate in blood,
and are present in the interstices of the lung, heart, and kidney;
Langerhans DCs are strong producers of IL-12; are located in
T-cell zones of lymph nodes, skin epithelia, and the thymic medulla;
and circulate in blood
ILC1 cells
Weakly cytotoxic, dependent on T-bet transcription factor, first line
of defense against viruses and bacteria
ILC2 cells
Mediate innate responses to parasites/helminths, repair damaged
tissues by producing amphiregulin
ILC3 cells
Innate immune response to extracellular bacteria and gut
microbiome
Lymphoid tissue inducer
(LTi) cells
Critical for formation of secondary lymphoid tissue during
embryogenesis
Natural killer (NK) cells
Kill foreign and host cells that have low levels of MHC+ selfpeptides. Express NK receptors that inhibit NK function in the
presence of high expression of self-MHC.
NK-T cells
Lymphocytes with both T-cell and NK surface markers that
recognize lipid antigens of intracellular bacteria such as
Mycobacterium tuberculosis by CD1 molecules and kill host cells
infected with intracellular bacteria
Neutrophils
Phagocytose and kill bacteria, produce antimicrobial peptides
Produce nitric oxide synthase and nitric oxide, which inhibit apoptosis
in lymphocytes and can prolong adaptive immune responses
Eosinophils
Kill invading parasites
Produce IL-5, which recruits Ig-specific antibody responses
Mast cells and basophils
Release TNF-α, IL-6, and IFN-γ in response to a variety of bacterial
PAMPs
Epithelial cells
Produce antimicrobial peptides; tissue-specific epithelia produce
mediator of local innate immunity; e.g., lung epithelial cells
produce surfactant proteins (proteins within the collectin family)
that bind and promote clearance of lung-invading microbes
Abbreviations: GM-CSF, granulocyte-macrophage colony-stimulating factor; IL-4, IL-5, IL-6, IL-10, and IL-12, interleukin 4, 5, 6, 10, and 12, respectively; ILC, innate lymphoid
cell; MHC, major histocompatibility complex: LPS, lipopolysaccharide; PAMP, pathogen-associated molecular patterns; TGF, transforming growth factor; TH, helper T cell;
TNF-α, tumor necrosis factor-alpha.
Source: Reproduced with permission from R Medzhitov, CA Janeway: Curr Opinion Immunol 9:4-9; 1997.
respond to invading organisms, and recruit T and B cells of the adap­
tive immune system to respond. Plasmacytoid DCs produce antiviral
IFN-α that activates NK cell killing of pathogen-infected cells; IFN-α
also activates CD8 T cells to mature into antipathogen cytotoxic (killer)
T cells. Following contact with pathogens, both plasmacytoid and
myeloid DCs produce chemokines that attract helper and cytotoxic T
cells, B cells, polymorphonuclear cells, and naïve and memory T cells
as well as regulatory T cells to ultimately dampen the immune response
once the pathogen is controlled. TLR engagement on DCs upregulates
MHC class II, B7-1 (CD80), and B7-2 (CD86), which enhance DCspecific antigen presentation and induce cytokine production. Thus,
DCs are important bridges between early (innate) and later (adaptive)
immunity. DCs also modulate and determine the types of immune
responses induced by pathogens via the TLRs expressed on DCs
(TLR7–9 in plasmacytoid DCs, TLR4 on monocytoid DCs) and via
the TLR adapter proteins that are induced to associate with TLRs
(Fig. 360-1, Table 360-1). In addition, other PRRs, such as C-type lectins,
NLRs, and mannose receptors, upon ligation by pathogen products,
activate cells of the adaptive immune system and, like TLR stimulation,
by a variety of factors, determine the type and quality of the adaptive
immune response that is triggered.
Produce IL-1 and TNF-α to upregulate lymphocyte adhesion molecules
and chemokines to attract antigen-specific lymphocyte. Produce
IL-12 to recruit TH1 T helper cell responses; upregulate co-stimulatory
and MHC molecules to facilitate T and B lymphocyte recognition and
activation. Macrophages and dendritic cells, after LPS signaling,
upregulate co-stimulatory molecules B7-1 (CD80) and B7-2 (CD86) that
are required for activation of pathogen-specific T cells. There are also
Toll-like proteins on B cells and dendritic cells that, after LPS ligation,
induce CD80 and CD86 on these cells for T-cell antigen presentation.
CHAPTER 360
Introduction to the Immune System
IFN-α is a potent activator of macrophage and mature DCs to
phagocytose invading pathogens and present pathogen antigens to
T and B cells.
Interstitial DCs are potent activators of macrophage and mature DCs
to phagocytose invading pathogens and present pathogen antigens to
T and B cells.
Produce IFN-γ to recruit CD4 TH1 T cells
Produce IL-4, IL-5, IL-13; recruit CD4 TH2 T cells
Produce IL-22, IL-17, GM-CSF, lymphotoxin; recruit CD4 TH17 T cells
Produce lymphotoxin for lymph node and Peyer’s patch development in
which adaptive immune responses occur
Produce TNF-α and IFN-γ, which recruit TH1 helper T-cell responses
Produce IL-4 to recruit TH2 helper T-cell responses, IgG1 and IgE
production
Produce IL-4, which recruits TH2 helper T cell responses, and recruit
IgG1- and IgE-specific antibody responses
Produces TGF-β, which triggers IgA-specific antibody responses
Innate Lymphoid Cells 
ILCs are comprised of ILC1, ILC2, ILC3,
lymphoid tissue inducer (LTi), and NK cells. ILC1, ILC2, ILC3, and
LTi are primarily tissue resident cells. ILCs develop from a common
lymphoid precursor in the bone marrow and then differentiate into
one of five ILC types—ILC1, ILC2, ILC3, LTi, or NK cells—based on
their development (Fig. 360-3A) and function (Fig. 360-3B). NK cells
and ILC1s depend on T-bet transcription factor for their development
and function and produce IFN-γ. NK cells are innate analogues to CD8
cytotoxic T cells in that they both mediate granzyme and perforinbased cytotoxic cell activity. ILC1s mirror CD4 TH1 lymphocytes and
react to intracellular pathogens such as viruses and to tumors. ILC2s
are the analogues of TH2 CD4 T cells and are dependent on GATA3 and
RORα factors and produce type 2 cytokines, such as IL-5 and IL-13.
ILC2s respond to extracellular parasites and allergens. ILC3s and LTi
cells are dependent on transcription factor retinoic acid receptor-related
orphan receptor γt (RORγt) and produce IL-17. ILC3s are analogues of
CD4 TH17 lymphocytes and attack extracellular pathogens such as bacte­
ria and fungi. LTi cells are critical for the formation of lymph nodes and
Peyer’s patches in gut during fetal development (Fig. 360-3B).
In the intestine, a critical function of the immune system is not
only to quickly respond to pathogens but also to ignore benign
Stem cell
PART 11
Immune-Mediated, Inflammatory, and Rheumatologic Disorders
B cell
Plasmacytoid
dendritic cell
Natural
killer cell
Monocyte/
macrophage
Dendritic
cell
Neutrophilic,
eosinophilic,
or basophilic
granulocyte
Antibodies
antigen
presentation
IL-12 antigen
presentation
IL-1, IL-6
phagocytosis
of microbes
IFN-α
antigen
presentation
GATA3
GATA3
RORγt
PU 1
Fox3p
Tbet
Bcl6
TFH13
cell
TH1
cell
TH2
cell
TH17
cell
TH9
cell
T regulatory
cell
T follicular
helper cell (TFH)
IL-13
IFN-γ
IL-4
IL-5
IL-13
IL-17
IL-22
IL-9
IL-10
TGF-β
IL-21
Cytotoxic
T-cell
responses
B-cell affinity
maturation
in germinal
centers
IgE
allergic
reaction
FIGURE 360-2  Model of immune effector cell development. Hematopoietic stem cells differentiate into T cells, antigen-presenting dendritic cells, natural killer cells,
macrophages, granulocytes, or B cells. Foreign antigen is processed by dendritic cells, macrophages, and B cells, and peptide fragments of foreign antigen are presented
to CD4+ and/or CD8+ T cells. CD8+ T-cell activation leads to induction of cytotoxic T lymphocyte (CTL) or killer T-cell generation, as well as induction of cytokine-producing
CD8+ cytotoxic T cells. Granulocytes (neutrophils, eosinophils, or basophils) are effector cells of the innate immune system and mediate anti-infectious agent activity by
cytokine production, infectious agent killing, or both. TH1 CD4+ T cells play an important role in defense against intracellular microbes and help in the generation of CD8+
cytotoxic T cells. TH2 CD4+ T cells producing interferon (IFN) γ or interleukin (IL) 4, IL-5, or IL-13 regulate Ig class switching and determine the type of antibody produced.
TH17 cells secrete IL-17 and IL-22, TH9 cells secrete IL-9, and TFH13 cells secrete IL-4, IL-5, and IL-13. TH17 and TH9 CD4 T cells are linked to mediation of autoimmune disease,
and TFH13 cells are linked to IgE-mediated anaphylaxis. CD4+ T regulatory cells produce IL-10 and transforming growth factor (TGF)-β and downregulate T- and B-cell
responses once the microbe has been eliminated. Each of the types of CD4+ T cells are regulated by different transcription factors, and the key transcription factors are
shown in the circles above each CD4+ T-cell type.
Lymphoid precursor
T cell
IFN-α
antigen
presenting
Antibodydependent
cellular
cytotoxicity
tumor cell
killing
CD4+
T cell
CD8+ cytotoxic
T cell
Kill pathogeninfected cells
Differentiation/
activation
Kill tumor cells
Linked to
autoimmune
disease
mediation
T-cell function
downregulation;
prevent autoimmune
disease
Antibody
responses;
stimulate
eosinophils
TABLE 360-7  Cytokines and Cytokine Receptors
CYTOKINE
RECEPTOR
CELL SOURCE
CELL TARGET
BIOLOGIC ACTIVITY
IL-1α, β
Type I IL-1r, type
II IL-1r
Monocytes/macrophages,
B cells, fibroblasts, most epithelial
cells including thymic epithelium,
endothelial cells
IL-2
IL-2r α, β,
common γ
T cells
T cells, B cells, NK cells,
monocytes-macrophages
IL-3
IL-3r, common β
T cells, NK cells, mast cells
Monocytes-macrophages, mast
cells, eosinophils, bone marrow
progenitors
IL-4
IL-4r α, common γ T cells, mast cells, basophils
T cells, B cells, NK cells,
monocytes-macrophages,
neutrophils, eosinophils,
endothelial cells, fibroblasts
IL-5
IL-5r α, common γ T cells, mast cells, eosinophils
Eosinophils, basophils, murine
B cells
IL-6
IL-6r, gp130
Monocytes-macrophages,
B cells, fibroblasts, most epithelium
including thymic epithelium,
endothelial cells
IL-7
IL-7r α, common γ Bone marrow, thymic epithelial
cells
IL-8
CXCR1, CXCR2
Monocytes-macrophages, T cells,
neutrophils, fibroblasts, endothelial
cells, epithelial cells
IL-9
IL-9r α, common γ T cells
Bone marrow progenitors,
B cells, T cells, mast cells
IL-10
IL-10r
Monocytes-macrophages, T cells,
B cells, keratinocytes, mast cells
IL-11
IL-11r α, gp130
Bone marrow stromal cells
Megakaryocytes, B cells,
hepatocytes
IL-12 (35-kDa and
40-kDa subunits)
IL-12r
Activated macrophages, dendritic
cells, neutrophils
IL-13
IL-13r/IL-4r α
T cells (TH2)
Monocytes-macrophages,
B cells, endothelial cells,
keratinocytes
IL-14
Unknown
T cells
Normal and malignant B cells
Induces B-cell proliferation, inhibits antibody secretion,
and expands selected B-cell subgroups
IL-15
IL-15r α, common
γ, IL2r β
Monocytes-macrophages,
epithelial cells, fibroblasts
IL-16
CD4
Mast cells, eosinophils, CD8+
T cells, respiratory epithelium
IL-17
IL-17r
CD4+ T cells
Fibroblasts, endothelium,
epithelium, macrophages
IL-18
IL-18r (IL-1Rrelated protein)
Keratinocytes, macrophages
T cells, B cells, NK cells
Upregulates IFN-γ production, enhances NK cell
cytotoxicity
IL-21
IL-δγ chain/IL-21R CD4 T cells
NK cells
Downregulates NK cell–activating molecules, NKG2D/
DAP10; produced by T follicular helper cells in B-cell
germinal centers that stimulate B-cell maturation
IL-22
IL-22 R1/IL-10R2
DC, T cells
Epithelial cells
Innate responses against bacterial pathogens; promotes
hepatocyte survival
IL-23
IL-12Rb1/IL23R
Macrophages, other cell types
T cells
Opposite effects of IL-12 (↑IL-17, ↑IFN-γ)
IL-24
IL-20R1/IL-20R2
IL-22R1/IL-20R2
Macrophages,
TH2 cells
All cells
Upregulates adhesion molecule expression, neutrophil
and macrophage emigration, mimics shock, fever,
upregulates hepatic acute-phase protein production,
facilitates hematopoiesis
CHAPTER 360
Promotes T-cell activation and proliferation, B-cell
growth, NK-cell proliferation and activation, enhanced
monocyte/macrophage cytolytic activity
Stimulates hematopoietic progenitors
Introduction to the Immune System
Stimulates TH2 helper T-cell differentiation and
proliferation; stimulates B-cell Ig class switch to IgG1
and IgE anti-inflammatory action on T cells, monocytes;
produced by T follicular helper cells in B-cell germinal
centers that stimulate B-cell maturation
Regulates eosinophil migration and activation
T cells, B cells, epithelial
cells, hepatocytes,
monocytes-macrophages
Induces acute-phase protein production, T- and B-cell
differentiation and growth, myeloma cell growth, and
osteoclast growth and activation
T cells, B cells, bone marrow
cells
Differentiates B-, T-, and NK-cell precursors, activates
T and NK cells
Neutrophils, T cells,
monocytes-macrophages,
endothelial cells, basophils
Induces neutrophil, monocyte, and T-cell migration,
induces neutrophil adherence to endothelial cells
and histamine release from basophils, and stimulates
angiogenesis; suppresses proliferation of hepatic
precursors
Induces mast cell proliferation and function, synergizes
with IL-4 in IgG and IgE production and T-cell growth,
activation, and differentiation
Monocytes-macrophages,
T cells, B cells, NK cells, mast
cells
Inhibits macrophage proinflammatory cytokine
production, downregulates cytokine class II antigen and
B7-1 and B7-2 expression, inhibits differentiation of TH1
helper T cells, inhibits NK cell function, stimulates mast
cell proliferation and function, B-cell activation, and
differentiation
Induces megakaryocyte colony formation and
maturation, enhances antibody responses, stimulates
acute-phase protein production
T cells, NK cells
Induces TH1 T helper cell formation and lymphokineactivated killer cell formation; increases CD8+ CTL
cytolytic activity; ↓IL-17, ↑IFN-γ
Upregulates VCAM-1 and C-C chemokine expression on
endothelial cells and B-cell activation and differentiation,
and inhibits macrophage proinflammatory cytokine
production
T cells, NK cells
Promotes T-cell activation and proliferation,
angiogenesis, and NK cells
CD4+ T cells, monocytes-
macrophages, eosinophils
Promotes chemoattraction of CD4+ T cells, monocytes,
and eosinophils; inhibits HIV-1 replication; inhibits T-cell
activation through CD3/T-cell receptor
Enhances cytokine/chemokine secretion; promotes
delayed-type reactions
Nonhematopoietic cells such
as fibroblasts
Promotes wound healing
(Continued)
TABLE 360-7  Cytokines and Cytokine Receptors
(Continued)
CYTOKINE
RECEPTOR
CELL SOURCE
CELL TARGET
BIOLOGIC ACTIVITY
IL-25 (also called
IL-17E)
IL-17RB
CD4 T cells, mast cells
Fibroblasts, endothelium,
epithelium, macrophages
IL-26
IL-20R1/IL-10R2
TH1, TH17 T cells, synovial cells
Epithelial cells
Proinflammatory; induces cytokine production
PART 11
Immune-Mediated, Inflammatory, and Rheumatologic Disorders
IL-27
gp130t
wsx-1
Myeloid cells such as
macrophages and DCs
Myeloid lineage cells; epithelial
cells
IL-28A (IFN-λ2)
IFN-λ receptor 1,
IL-28Rα, IL-10Rβ
Myeloid lineage cells; epithelial
cells
IL-28B (IFN-λ3)
IFN-λ receptor 1,
IL-28Rα, IL-10Rβ
Myeloid lineage cells; epithelial
cells
IL-29 (IFN-λ1)
IFN-λ receptor 1,
IL-28Rα, IL-10Rβ
IL-30 (p28 of
IL-27)
Activated macrophages and
DCs; epithelial malignancies
IL-27Rα;
gp130+wsx-1
IL-31
IL-31RA/
oncostatin MRβ
Eosinophils, CD4 T cells
Epithelial cells, monocytes
Pruritis, proinflammatory
IL-32 (NK4)
?
Monocytes, T cells, NK cells,
epithelial cells
IL-33 (NF-HEV;
IL-1 F11)
ST-2
Endothelial cells, epithelial cells,
fibroblasts, mucosal epithelium
IL-34 (C16of77)
CSF-1R, PTP-E,
CD138
Neurons, Treg, myeloid cells
 
Anti-inflammatory myeloid cell proliferation
IL-35
IL-12Rβ2/
IL-12Rβ2, gp130/
gp130, IL-12Rb2/
gp130
Tregs, Bregs
Macrophages, T cells
Prevents TH1 and TH17 proliferation; induced Treg/Breg
proliferation/anti-inflammatory
IL-36R
Keratocytes
Mucosal epithelial cells
Monocytes-macrophages
Langerhans cells
CD4 T cells
IL-36α
IL36β
IL36γ
IL36RA
(IL-1 F5)
IL-38
IL-10 F10
IL-1R, IL-36R,
IL-1RA PL1
Epithelial cells, B cells
Epithelial cells, macrophages,
DCs, T cells, B cells, plasma
cells
IL-39
?
Macrophages, DCs, B cells
Neutrophils
Proinflammatory
IL-40
?
B cells, bone marrow/stroma
B cells
Involved in IgA production, B-cell homeostasis and
development
IFN-α
Type I interferon
receptor
All cells
All cells
Promotes antiviral activity; stimulates T-cell,
macrophage, and NK-cell activity; direct antitumor
effects; upregulates MHC class I antigen expression;
used therapeutically in viral and autoimmune conditions
IFN-β
Type I interferon
receptor
All cells
All cells
Antiviral activity; stimulates T-cell, macrophage, and
NK-cell activity; direct antitumor effects; upregulates
MHC class I antigen expression; used therapeutically in
viral and autoimmune conditions
IFN-γ
Type II interferon
receptor
T cells, NK cells
All cells
Regulates macrophage and NK-cell activations;
stimulates immunoglobulin secretion by B cells;
induction of class II histocompatibility antigens; TH1
T-cell differentiation
TNF-α
TNFrI, TNFrII
Monocytes-macrophages, mast
cells, basophils, eosinophils, NK
cells, B cells, T cells, keratinocytes,
fibroblasts, thymic epithelial cells
TNF-β
TNFrI, TNFrII
T cells, B cells
All cells except erythrocytes
Cell cytotoxicity, lymph node and spleen development
LT-β
LTβR
T cells
All cells except erythrocytes
Cell cytotoxicity, normal lymph node development
G-CSF
G-CSFr; gp130
Monocytes-macrophages,
fibroblasts, endothelial cells,
thymic epithelial cells, stromal
cells
GM-CSF
GM-CSFr,
common β
T cells, monocytes-macrophages,
fibroblasts, endothelial cells,
thymic epithelial cells
Proinflammatory; induces cytokine production
T cells
Collaborates with other cytokines to activate T-cell
differentiation
Epithelial cells
Enhanced clearance of viral infections
Epithelial cells
Enhanced clearance of viral infections
Epithelial cells
Enhanced clearance of viral infections
Monocytes
Anti-inflammatory cytokines; upregulation of breast and
prostate cancer metastasis
Monocytes, macrophages,
bone marrow stroma
Angiogenesis, IL-2 production in bone marrow,
proinflammatory
T cells, mast cells eosinophils,
basophils, ILC2s
Alarmin cytokine, proinflammatory
Epithelial cells, macrophages,
DCs, T cells, B cells, plasma
cells
TH responses, proinflammatory
Blocks IL-36; anti-inflammatory
All cells except erythrocytes
Fever, anorexia, shock, capillary leak syndrome,
enhanced leukocyte cytotoxicity, enhanced NK-cell
function, acute phase protein synthesis, proinflammatory
cytokine induction
Myeloid cells, endothelial cells
Regulates myelopoiesis; enhances survival and function
of neutrophils; clinical use in reversing neutropenia after
cytotoxic chemotherapy
Monocytes-macrophages,
neutrophils, eosinophils,
fibroblasts, endothelial cells
Regulates myelopoiesis; enhances macrophage
bactericidal and tumoricidal activity; mediator of
dendritic cell maturation and function; upregulates
NK-cell function; clinical use in reversing neutropenia
after cytotoxic chemotherapy
(Continued)
(Continued)
TABLE 360-7  Cytokines and Cytokine Receptors
CYTOKINE
RECEPTOR
CELL SOURCE
CELL TARGET
BIOLOGIC ACTIVITY
M-CSF
M-CSFr (c-fms
protooncogene)
Fibroblasts, endothelial cells,
monocytes-macrophages, T cells,
B cells, epithelial cells including
thymic epithelium
LIF
LIFr-α; gp130
Activated T cells, bone marrow
stromal cells, thymic epithelium
OSM
OSMr; LIFr; gp130
Activated monocytesmacrophages and T cells, bone
marrow stromal cells, some breast
carcinoma cell lines, myeloma
cells
SCF
SCFr (c-kit
protooncogene)
Bone marrow stromal cells and
fibroblasts
Type I, II, III
TGF-β receptor
Most cell types
Most cell types
Downregulates T-cell, macrophage, and granulocyte
responses; stimulates synthesis of matrix proteins;
stimulates angiogenesis
TGF-β
(3 isoforms)
Lymphotactin/
SCM-1
XCR1
NK cells, mast cells, doublenegative thymocytes, activated
CD8+ T cells
MCP-1
CCR2
Fibroblasts, smooth-muscle cells,
activated PBMCs
MCP-2
CCR1, CCR2
Fibroblasts, activated PBMCs
Monocytes-macrophages,
T cells, eosinophils, basophils,
NK cells
MCP-3
CCR1, CCR2
Fibroblasts, activated PBMCs
Monocytes-macrophages,
T cells, eosinophils, basophils,
NK cells, dendritic cells
MCP-4
CCR2, CCR3
Lung, colon, small intestinal
epithelial cells, activated
endothelial cells
Eotaxin
CCR3
Pulmonary epithelial cells, heart
Eosinophils, basophils
Potent chemoattractant for eosinophils and basophils;
induces allergic airways disease; acts in concert with
IL-5 to activate eosinophils; antibodies to eotaxin inhibit
airway inflammation
TARC
CCR4
Thymus, dendritic cells, activated
T cells
MDC
CCR4
Monocytes-macrophages,
dendritic cells, thymus
MIP-1α
CCR1, CCR5
Monocytes-macrophages, T cells
Monocytes-macrophages,
T cells, dendritic cells, NK cells,
eosinophils, basophils
MIP-1β
CCR5
Monocytes-macrophages, T cells
Monocytes-macrophages,
T cells, NK cells, dendritic cells
RANTES
CCR1, CCR2, CCR5 Monocytes-macrophages, T cells,
fibroblasts, eosinophils
CCR6
Dendritic cells, fetal liver cells,
activated T cells
LARC/MIP-3α/
Exodus-1
ELC/MIP-3β
CCR7
Thymus, lymph node, appendix
Activated T cells and B cells
Chemoattractant for B and T cells; receptor upregulated
on EBV-infected B cells and HSV-infected T cells
I-309/TCA-3
CCR8
Activated T cells
Monocytes-macrophages,
T cells
SLC/TCA-4/
Exodus-2
CCR7
Thymic epithelial cells, lymph node,
appendix, and spleen
DC-CK1/PARC
Unknown
Dendritic cells in secondary
lymphoid tissues
Monocytes-macrophages
Regulates monocyte-macrophage production
and function
CHAPTER 360
Megakaryocytes, monocytes,
hepatocytes, possibly
lymphocyte subpopulations
Induces hepatic acute-phase protein production;
stimulates macrophage differentiation; promotes
growth of myeloma cells and hematopoietic progenitors;
stimulates thrombopoiesis
Introduction to the Immune System
Neurons, hepatocytes,
monocytes-macrophages,
adipocytes, alveolar epithelial
cells, embryonic stem cells,
melanocytes, endothelial cells,
fibroblasts, myeloma cells
Induces hepatic acute-phase protein production;
stimulates macrophage differentiation; promotes
growth of myeloma cells and hematopoietic progenitors;
stimulates thrombopoiesis; stimulates growth of Kaposi’s
sarcoma cells
Embryonic stem cells, myeloid
and lymphoid precursors, mast
cells
Stimulates hematopoietic progenitor cell growth, mast
cell growth; promotes embryonic stem cell migration
T cells, NK cells
Chemoattractant for lymphocytes; only known
chemokine of C class
Monocytes-macrophages, NK
cells, memory T cells, basophils
Chemoattractant for monocytes, activated memory
T cells, and NK cells; induces granule release from CD8+
T cells and NK cells; potent histamine-releasing factor
for basophils; suppresses proliferation of hematopoietic
precursors; regulates monocyte protease production
Chemoattractant for monocytes, memory and naïve
T cells, eosinophils,? NK cells; activates basophils and
eosinophils; regulates monocyte protease production
Chemoattractant for monocytes, memory and naïve
T cells, dendritic cells, eosinophils,? NK cells; activates
basophils and eosinophils; regulates monocyte protease
production
Monocytes-macrophages,
T cells, eosinophils, basophils
Chemoattractant for monocytes, T cells, eosinophils, and
basophils
T cells, NK cells
Chemoattractant for T and NK cells
Activated T cells
Chemoattractant for activated T cells; inhibits infection
with T-cell tropic HIV-1
Chemoattractant for monocytes, T cells, dendritic cells,
and NK cells, and weak chemoattractant for eosinophils
and basophils; activates NK-cell function; suppresses
proliferation of hematopoietic precursors; necessary for
myocarditis associated with coxsackievirus infection;
inhibits infection with monocytotropic HIV-1
Chemoattractant for monocytes, T cells, and NK cells;
activates NK-cell function; inhibits infection with
monocytotropic HIV-1
Monocytes-macrophages,
T cells, NK cells, dendritic cells,
eosinophils, basophils
Chemoattractant for monocytes-macrophages, CD4+,
CD45Ro+ T cells, CD8+ T cells, NK cells, eosinophils, and
basophils; induces histamine release from basophils;
inhibits infections with monocytotropic HIV-1
T cells, B cells
Chemoattractant for lymphocytes
Chemoattractant for monocytes; prevents
glucocorticoid-induced apoptosis in some T-cell lines
T cells
Chemoattractant for T lymphocytes; inhibits
hematopoiesis
Naïve T cells
May have a role in induction of immune responses
(Continued)
TABLE 360-7  Cytokines and Cytokine Receptors
(Continued)
CYTOKINE
RECEPTOR
CELL SOURCE
CELL TARGET
BIOLOGIC ACTIVITY
TECK
CCR9
Dendritic cells, thymus, liver, small
intestine
GRO-α/MGSA
CXCR2
Activated granulocytes, monocytemacrophages, and epithelial cells
PART 11
Immune-Mediated, Inflammatory, and Rheumatologic Disorders
GRO-β/MIP-2α
CXCR2
Activated granulocytes and
monocyte-macrophages
NAP-2
CXCR2
Platelets
Neutrophils, basophils
Derived from platelet basic protein; neutrophil
chemoattractant and activator
IP-10
CXCR3
Monocytes-macrophages, T cells,
fibroblasts, endothelial cells,
epithelial cells
MIG
CXCR3
Monocytes-macrophages, T cells,
fibroblasts
SDF-1
CXCR4
Fibroblasts
T cells, dendritic cells,?
basophils,? endothelial cells
Fractalkine
CX3CR1
Activated endothelial cells
NK cells, T cells,
monocytes-macrophages
PF-4
Unknown
Platelets, megakaryocytes
Fibroblasts, endothelial cells
Chemoattractant for fibroblasts; suppresses proliferation
of hematopoietic precursors; inhibits endothelial cell
proliferation and angiogenesis
Abbreviations: B7-1, CD80; B7-2, CD86; Breg, regulatory B cells; CCR, CC-type chemokine receptor; CXCR, CXC-type chemokine receptor; DC, dendritic cell; DC-CK,
dendritic cell chemokine; EBV, Epstein-Barr virus; ELC, EB11 ligand chemokine (MIP-1b); G-CSF, granulocyte colony-stimulating factor; GM-CSF, granulocyte-macrophage
colony-stimulating factor; GRP, growth-related peptide; HSV, herpes simplex virus; IFN, interferon; Ig, immunoglobulin; IL, interleukin; IP-10, IFN-γ-inducible protein-10;
LARC, liver- and activation-regulated chemokine; LIF, leukemia inhibitory factor; MCP, monocyte chemotactic protein; M-CSF, macrophage colony-stimulating factor; MDC,
macrophage-derived chemokine; MGSA, melanoma growth-stimulating activity; MHC, major histocompatibility complex; MIG, monokine induced by IFN-γ; MIP, macrophage
inflammatory protein; NAP, neutrophil-activating protein; NK, natural killer; OSM, oncostatin M; PARC, pulmonary- and activation-regulated chemokine; PBMC, peripheral
blood mononuclear cells; PF, platelet factor; RANTES, regulated on activation, normally T cell–expressed and –secreted; SCF, stem cell factor; SDF, stromal cell–derived
factor; SLC, secondary lymphoid tissue chemokine; TARC, thymus- and activation-regulated chemokine; TCA, T-cell activation protein; TECK, thymus-expressed chemokine;
TGF, transforming growth factor; TH1 and TH2, helper T cell subsets; TNF, tumor necrosis factor; Treg, regulatory T cells; VCAM, vascular cell adhesion molecule.
Sources: Data from JS Sundy et al: Appendix B, in Inflammation, Basic Principles and Clinical Correlates, 3rd ed. J Gallin, R Snyderman (eds). Philadelphia, Lippincott
Williams and Wilkins, 1999; J Ye et al: Frontiers in Pharmacology 11; HM Lazear et al: Immunity 43:15, 2015; J Catalan-Dibene et al: J Interferon and Cytokine Research
38:423, 2018.
microorganisms or environmental antigens. Inability to prevent
immune responses to the gut microbiome can be a factor in the cause
of inflammatory bowel diseases (Chap. 337). In healthy individuals, a
subset of RORγt+ ILCs, possibly ILC3s, stimulate naïve CD4 T cells to
differentiate into peripheral Tregs that suppress immune responses to
microbiome organisms.
NK cells express surface receptors for the Fc portion of IgG (FcR)
(CD16) and for NCAM-I (CD56), and many NK cells express T lineage
markers, particularly CD2, CD7, and CD8, and proliferate in response
to IL-2. NK cells arise in both bone marrow and thymic microenviron­
ments. In addition to mediating cytotoxicity to foreign or malignant
cells, NK cells also mediate ADCC. ADCC is the binding of an opso­
nized (antibody-coated) target cell to an Fc receptor-bearing effector
cell via the Fc region of antibody, resulting in target cell lysis. NK cell
cytotoxicity is the MHC-unrestricted, non-antibody-mediated killing
of target cells, which are usually malignant cell types, transplanted for­
eign cells, or virus-infected cells. Thus, NK cell cytotoxicity may play
an important role in immune surveillance and destruction of malig­
nant and virus-infected host cells. NK cell hyporesponsiveness is also
observed in patients with Chédiak-Higashi syndrome, an autosomal
recessive disease associated with fusion of cytoplasmic granules and
defective degranulation of neutrophil lysosomes.
NK cells have a variety of surface receptors that have inhibitory or
activating functions (Table 360-9). NK immunoglobulin superfamily
receptors include the killer cell immunoglobulin-like activating or
inhibitory receptors (KIRs), many of which have been shown to have
HLA class I ligands. The KIRs are made up proteins with either two
(KIR2D) or three (KIR3D) extracellular immunoglobulin domains
(D). Moreover, their nomenclature designates their function as either
inhibitory KIRs with a long (L) cytoplasmic tail and immunoreceptor
tyrosine-based inhibitory motif (ITIM) (KIRDL) or activating KIRs
T cells, monocytesmacrophages, dendritic cells
Thymic dendritic cell–derived cytokine, possibly involved
in T-cell development
Neutrophils, epithelial cells,?
endothelial cells
Neutrophil chemoattractant and activator; mitogenic for
some melanoma cell lines; suppresses proliferation of
hematopoietic precursors; angiogenic activity
Neutrophils and? endothelial
cells
Neutrophil chemoattractant and activator; angiogenic
activity
Activated T cells, tumorinfiltrating lymphocytes,?
endothelial cells,? NK cells
IFN-γ-inducible protein that is a chemoattractant for
T cells; suppresses proliferation of hematopoietic
precursors
Activated T cells, tumorinfiltrating lymphocytes
IFN-γ-inducible protein that is a chemoattractant for
T cells; suppresses proliferation of hematopoietic
precursors
Low-potency, high-efficacy T-cell chemoattractant;
required for B lymphocyte development; prevents
infection of CD4+, CXCR4+ cells by T-cell tropic HIV-1
Cell-surface chemokine/mucin hybrid molecule that
functions as a chemoattractant, leukocyte activator, and
cell adhesion molecule
with a short (S) cytoplasmic tail (KIRDS). NK cell inactivation by
KIRs is a central mechanism to prevent damage to normal host cells.
Genetic studies have demonstrated the association of KIRs with viral
infection outcome, or to outcomes in autoimmune or malignant diseases
(Table 360-10).
In addition to the KIRs, a second set of immunoglobulin superfam­
ily receptors includes the natural cytotoxicity receptors (NCRs), which
include NKp46, NKp30, and NKp44. These receptors help to mediate
NK cell activation against target cells. The ligands to which NCRs bind
on target cells have been recently recognized to be comprised of mol­
ecules of pathogens such as influenza, cytomegalovirus, and malaria,
as well as host molecules expressed on tumor cells. Signaling lym­
phocytic activating molecule (SLAM) family receptors are expressed
on hematopoietic cells, with SLAMF2 (CD48), SLAMF4 (2B4), and
SLAMF7/CD2-like receptor activating cytotoxic cells (CRACCs) the
most prominent on NK cells (Table 360-9).
NK cell signaling is, therefore, a highly coordinated series of inhibit­
ing and activating signals that prevent NK cells from responding to
uninfected, nonmalignant self-cells; however, they are activated to
attack malignant and virally infected cells (Fig. 360-4). Recent evidence
suggests that NK cells, although not possessing rearranging immune
recognition genes, may be able to mediate recall for NK cell responses
to viruses and for immune responses such as contact hypersensitivity.
Some NK cells express CD3 and invariant TCR-α chains and are
termed NK T cells. TCRs of NK T cells recognize lipid molecules of
intracellular bacteria when presented in the context of CD1 molecules
on APCs. Upon activation, NK T cells secrete effector cytokines such
as IL-4 and IFN-γ. This mode of recognition of intracellular bacteria
such as Listeria monocytogenes and Mycobacterium tuberculosis by NK
T cells leads to induction of activation of DCs and is thought to be an
important innate defense mechanism against these organisms.
TABLE 360-8  CC, CXC1, CX3, C1, and XC Families of Chemokines and Chemokine Receptors
CHEMOKINE
RECEPTOR
CHEMOKINE LIGANDS
CELL TYPES
DISEASE CONNECTION
CCR1
CCL3 (MIP-1α), CCL5 (RANTES), CCL7
(MCP-3), CCL14 (HCC1)
T cells, monocytes, eosinophils,
basophils
CCR2
CCL2 (MCP-1), CCL8 (MCP-2), CCL7
(MCP-3), CCL13 (MCP-4), CCL16 (HCC4)
Monocytes, dendritic cells (immature),
memory T cells
CCR3
CCL11 (eotaxin), CCL13 (eotaxin-2), CCL7
(MCP-3), CCL5 (RANTES), CCL8 (MCP-2),
CCL13 (MCP-4)
Eosinophils, basophils, mast cells, TH2,
platelets
CCR4
CCL17 (TARC), CCL22 (MDC)
T cells (TH2), dendritic cells (mature),
basophils, macrophages, platelets
CCR5
CCL3 (MIP-1α), CCL4 (MIP-1α), CCL5
(RANTES), CCL11 (eotaxin), CCL14
(HCC1), CCL16 (HCC4)
T cells, monocytes
HIV-1 co-receptor (T cell–tropic strains), transplant rejection
CCR6
CCL20 (MIP-3α, LARC)
T cells (T regulatory and memory),
B cells, dendritic cells
CCR7
CCL19 (ELC), CCL21 (SLC)
T cells, dendritic cells (mature)
Transport of T cells and dendritic cells to lymph nodes, antigen
presentation, and cellular immunity
CCR8
CCL1 (1309)
T cells (TH2), monocytes, dendritic cells
Dendritic cell migration to lymph node, type 2 cellular immunity,
granuloma formation
CCR9
CCL25 (TECK)
T cells, IgA+ plasma cells
Homing of T cells and IgA+ plasma cells to the intestine,
inflammatory bowel disease
CCR10
CCL27 (CTACK), CCL28 (MEC)
T cells
T-cell homing to intestine and skin
CXCR1
CXCL8 (interleukin-8), CXCL6 (GCP2)
Neutrophils, monocytes
Inflammatory lung disease, COPD
CXCR2
CXCL8, CXCL1 (GROα), CXCL2 (GROα),
CXCL3 (GROα), CXCL5 (ENA-78), CXCL6
Neutrophils, monocytes, microvascular
endothelial cells
CXCR3-A
CXCL9 (MIG), CXCL10 (IP-10), CXCL11
(I-TAC)
Type 1 helper cells, mast cells,
mesangial cells
CXCR3-B
CXCL4 (PF4), CXCL9 (MIG), CXCL10
(IP-10), CXCL11 (I-TAC)
Microvascular endothelial cells,
neoplastic cells
CXCR4
CXCL12 (SDF-1)
Widely expressed
HIV-1 co-receptor (T cell–tropic), tumor metastases,
hematopoiesis
CXCR5
CXCL13 (BCA-1)
B cells, follicular helper T cells
Formation of B-cell follicles
CXCR6
CXCL16 (SR-PSOX)
CD8+ T cells, natural killer cells, and
memory CD4+ T cells
CX3CR1
CX3CL1 (fractalkine)
Macrophages, endothelial cells,
smooth-muscle cells
XCR1
XCL1 (lymphotactin), XCL2
T cells, natural killer cells
Rheumatoid arthritis, IgA nephropathy, tumor response
Abbreviations: BCA-1, B-cell chemoattractant 1; COPD, chronic obstructive pulmonary disease; CTACK, cutaneous T cell–attracting chemokine; ELC, Epstein-Barr I1-ligand
chemokine; ENA, epithelial cell–derived neutrophil-activating peptide; GCP, granulocyte chemotactic protein; GRO, growth-regulated oncogene; HCC, hemofiltrate
chemokine; IP-10, interferon inducible 10; I-TAC, interferon-inducible T-cell alpha chemoattractant; LARC, liver- and activation-regulated chemokine; MCP, monocyte
chemoattractant protein; MDC, macrophage-derived chemokine; MEC, mammary-enriched chemokine; MIG, monokine induced by interferon-γ; MIP, macrophage
inflammatory protein; PF, platelet factor; SDF, stromal cell–derived factor; SLC, secondary lymphoid-tissue chemokine; SR-PSOX, scavenger receptor for phosphatidylserinecontaining oxidized lipids; TARC, thymus- and activation-regulated chemokine; TECK, thymus-expressed chemokine; TH2, type 2 helper T cells.
Source: From IF Charo, RM Ranshohoff: The many roles of chemokines and chemokine receptors in inflammation. N Engl J Med 354:610, 2006. Copyright © (2006)
Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society.
The receptors for the Fc portion of IgG (FcγRs) are present on NK
cells, B cells, macrophages, neutrophils, and mast cells and mediate
interactions of IgG with antibody-coated target cells, such as virally
infected cells. Antibody-NK interaction via antibody Fc and NK cell
FcR links the adaptive and innate immune systems and regulates the
mediation of IgG antibody effector functions such as ADCC. There are
both activation and inhibitory FcγRs. Activation FcRs, such as FcγRI
(CD64), FcγRIIa (CD32a), and FcγRIIIa (CD16a), are characterized
by the presence of an immunoreceptor tyrosine-based activating motif
(ITAM) sequence, whereas inhibitory FcRs, such as FcγRIIb (CD32b),
contain an ITIM sequence. There is evidence that dysregulation in
IgG-FcγR interactions plays roles in arthritis, multiple sclerosis, and
systemic lupus erythematosus.
Neutrophils, Eosinophils, and Basophils 
Granulocytes are
present in nearly all forms of inflammation and are amplifiers and
effectors of innate immune responses (Fig. 360-2). Unchecked accu­
mulation and activation of granulocytes can lead to host tissue damage,
as seen in neutrophil- and eosinophil-mediated systemic necrotizing
vasculitis. Granulocytes are derived from stem cells in bone marrow.
Rheumatoid arthritis, multiple sclerosis
CHAPTER 360
Atherosclerosis, rheumatoid arthritis, multiple sclerosis,
resistance to intracellular pathogens, type 2 diabetes mellitus
Allergic asthma and rhinitis
Introduction to the Immune System
Parasitic infection, graft rejection, T-cell homing to skin
Mucosal humoral immunity, allergic asthma, intestinal T-cell
homing
Inflammatory lung disease, COPD, angiogenic for tumor growth
Inflammatory skin disease, multiple sclerosis, transplant rejection
Angiostatic for tumor growth
Inflammatory liver disease, atherosclerosis (CXCL16)
Atherosclerosis
Each type of granulocyte (neutrophil, eosinophil, or basophil) is
derived from a different subclass of progenitor cell that is stimulated to
proliferate by colony-stimulating factors (Table 360-6). During termi­
nal maturation of granulocytes, class-specific nuclear morphology and
cytoplasmic granules appear that allow for histologic identification of
granulocyte type.
Neutrophils express Fc receptor IIIa for IgG (CD16a) as well as
receptors for activated complement components (C3b or CD35). Upon
interaction of neutrophils with antibody-coated (opsonized) bacteria
or immune complexes, azurophilic granules (containing myeloper­
oxidase, lysozyme, elastase, and other enzymes) and specific granules
(containing lactoferrin, lysozyme, collagenase, and other enzymes) are
released, and microbicidal superoxide radicals (O2
–) are generated at
the neutrophil surface. The generation of superoxide leads to inflam­
mation by direct injury to tissue and by alteration of macromolecules
such as collagen and DNA.
Eosinophils are potent cytotoxic effector cells for various para­
sitic organisms. In Nippostrongylus brasiliensis helminth infection,
eosinophils are important cytotoxic effector cells for removal of these
parasites. Key to regulation of eosinophil cytotoxicity to N. brasiliensis
worms are antigen-specific T helper cells that produce IL-4, thus pro­
viding an example of regulation of innate immune responses by adap­
tive immunity antigen-specific T cells. Intracytoplasmic contents of
eosinophils, such as major basic protein, eosinophil cationic protein,
and eosinophil-derived neurotoxin, are capable of directly damaging
tissues and may be responsible in part for the organ system dysfunction
in the hypereosinophilic syndromes (Chap. 67). Because the eosinophil
granule contains anti-inflammatory types of enzymes (histaminase,
arylsulfatase, phospholipase D), eosinophils may also downregulate or
terminate ongoing inflammatory responses.
PART 11
Immune-Mediated, Inflammatory, and Rheumatologic Disorders
TOX
NFIL3
ID2
ETS1
NKP
T-BET
EOMES
T-BET
NFIL3
RUNX3
NK
A
ILC1
ILC2
FIGURE 360-3  Development and function of innate lymphoid cells (ILCs). A. ILC development, mainly based on mouse ILC differentiation paths, is schematized. ILCs develop
from common innate lymphoid progenitors (CILPs), which themselves differentiate from common lymphoid progenitors (CLPs). CILPs can differentiate into natural killer (NK)
cell precursor (NKP) cells or into common helper innate lymphoid progenitors (CHILPs), which themselves give rise to lymphoid tissue inducer progenitors (LTiPs) and innate
lymphoid cell precursors (ILCPs). LTiPs differentiate into lymphoid tissue inducers (LTis) and ILCPs into ILC1, ILC2, or ILC3. Each stage of differentiation is dependent on the
expression of the indicated transcription factors: NFIL3 (nuclear factor IL-3 induced), Id2 (inhibitor of DNA binding 2), TOX (thymocyte selection-associated high mobility
group box protein), TCF-1 (T-cell factor 1), ETS1 (avian erythroblastosis virus E26 homolog-1), GATA3 (GATA binding protein 3), PLZF (promyelocytic leukemia zinc finger),
T-bet (T-box transcription factor), Eomes (eomesodermin), RUNX3 (runt-related transcription factor 3), RORα (RAR-related orphan receptor α), Bcl11b (B cell lymphoma/
leukemia 11B), RORγt (RAR-related orphan receptor γt), and AHR (Aryl hydrocarbon receptor). It has been shown in humans that ILC1 subsets may originate from precursors
other than ILCPs, but the identity of these precursors remains unknown at this time. B. Some of the most well-known immune functions of each ILC subset are shown: NK
cells and ILC1s react to intracellular pathogens, such as viruses, and to tumors; ILC2s respond to large extracellular parasites and allergens; ILC3s combat extracellular
microbes, such as bacteria and fungi; and Lutes are involved in the formation of secondary lymphoid structures. For each ILC subset, effector molecules that can be
produced upon activation are indicated AREG, amphiregulin; RANK, receptor activation of nuclear factor kB; RANK-L, RANK-ligand. (Reproduced with permission from
E Vivier et al: Innate lymphoid cells: 10 years on. Cell 174:1054, 2018.)
Basophils and tissue mast cells are potent reservoirs of cytokines
such as IL-4 and can respond to bacteria and viruses with cytokine
production through multiple TLRs expressed on their surface. Mast
cells and basophils can also mediate antipathogen immunity through
the binding of antibodies. This is a particularly important host defense
mechanism against parasitic diseases. Basophils express high-affinity
surface receptors for IgE (FcεRII) (CD23) and, upon cross-linking
of basophil-bound IgE by antigen, can release histamine, eosinophil
chemotactic factor of anaphylaxis, and neutral proteases—all media­
tors of allergic immediate (anaphylaxis) hypersensitivity responses.
CLP
NFIL3
ID2
TOX
TCF-1
ETS1
CILP
GATA3
CHILP
LTiP
PLZF
ROR γT
TOX
ID2
ILCP
ROR γT
AHR
ID2
ROR α
Bci11B
GATA3
ILC3
LTi
Stimuli
Mediators
Immune function
Tumors, intracellular
microbes (virus, bacteria,
parasites)
NK
Large extracellular
parasites and allergens
Mesenchymal
organizer cells
(retinoic acid,
CXCL13, RANK-L)
Extracellular microbes
(bacteria, fungi)
B
FIGURE 360-3  (Continued)
In addition, basophils express surface receptors for activated comple­
ment components (C3a, C5a), through which mediator release can be
directly effected. Thus, basophils, like most cells of the immune sys­
tem, can be activated in the service of host defense against pathogens,
or they can be activated for mediator release and cause pathogenic
responses in allergic and inflammatory diseases. For further discus­
sion of tissue mast cells, see Chap. 366.
The Complement System 
The complement system, an impor­
tant soluble component of the innate immune system, is a series of
plasma enzymes, regulatory proteins, and proteins that are activated
in a cascading fashion, resulting in cell lysis. There are four pathways
of the complement system: the classic activation pathway activated by
antigen/antibody immune complexes, the MBL (a serum collectin)
activation pathway activated by microbes with terminal mannose
groups, the alternative activation pathway activated by microbes or
tumor cells, and the terminal pathway that is common to the first
three pathways and leads to the membrane attack complex that lyses
cells (Fig. 360-5). The series of enzymes of the complement system
are serine proteases.
Activation of the classic complement pathway via immune complex
binding to C1q links the innate and adaptive immune systems via
specific antibody in the immune complex. The alternative complement
activation pathway is antibody-independent and is activated by bind­
ing of C3 directly to pathogens and “altered self” such as tumor cells.
In the renal glomerular inflammatory disease IgA nephropathy, IgA
activates the alternative complement pathway and causes glomerular
damage and decreased renal function. Activation of the classic comple­
ment pathway via C1, C4, and C2 and activation of the alternative path­
way via factor D, C3, and factor B both lead to cleavage and activation
of C3. C3 activation fragments, when bound to target surfaces such as
bacteria and other foreign antigens, are critical for opsonization (coat­
ing by antibody and complement) in preparation for phagocytosis. The
MBL pathway substitutes MBL-associated serine proteases (MASPs) 1
and 2 for C1q, C1r, and C1s to activate C4. The MBL activation path­
way is activated by mannose on the surface of bacteria and viruses.
CHAPTER 360
IFN-γ
Granzymes
Perforin
Type 1 immunity
(macrophage activation,
cytotoxicity)
ILC1
Introduction to the Immune System
Type 2 immunity
(alternative macrophage
activation)
IL-4
IL-5
IL-13
IL-9
AREG
ILC2
RANK
Lymphotoxin
TNF
IL-17
IL-22
Formation of secondary
lymphoid structures
LTi
Type 3 immunity
(phagocytosis,
antimicrobial peptides)
IL-22
IL-17
GM-CSF
Lymphotoxin
ILC3
The three pathways of complement activation all converge on the
final common terminal pathway. C3 cleavage by each pathway results
in activation of C5, C6, C7, C8, and C9, resulting in the membrane
attack complex that physically inserts into the membranes of target
cells or bacteria and lyses them.
Thus, complement activation is a critical component of innate
immunity for responding to microbial infection. The functional conse­
quences of complement activation by the three initiating pathways and
the terminal pathway are shown in Fig. 360-5. In general, the cleavage
products of complement components facilitate microbe or damaged
cell clearance (C1q, C4, C3), promote activation and enhancement of
inflammation (anaphylatoxins, C3a, C5a), and promote microbe or
opsonized cell lysis (membrane attack complex).
■
■CYTOKINES
Cytokines are soluble proteins produced by a wide variety of cell types
(Tables 360-7 and 360-8). They are critical for both normal innate and
adaptive immune responses, and their expression may be perturbed in
most immune, inflammatory, and infectious disease states.
Cytokines are involved in the regulation of the growth, develop­
ment, and activation of immune system cells and in the mediation of
the inflammatory response. In general, cytokines are characterized
by considerable redundancy in that different cytokines have similar
functions. In addition, many cytokines are pleiotropic in that they are
capable of acting on many different cell types. This pleiotropism results
from the expression on multiple cell types of receptors for the same
cytokine (see below), leading to the formation of “cytokine networks.”
The action of cytokines may be (1) autocrine when the target cell is
the same cell that secretes the cytokine, (2) paracrine when the target
cell is nearby, and (3) endocrine when the cytokine is secreted into the
circulation and acts distal to the source.
Cytokines have been named based on presumed targets or based on
presumed functions. Those cytokines that are thought to primarily target
leukocytes have been named IL-1, -2, -3, etc. Many cytokines that were
originally described as having a certain function have retained those
names (e.g., granulocyte colony-stimulating factor [G-CSF]). Cytokines
TABLE 360-9  NK-Cell Receptors, Cognate Ligands, and Their Known Signaling Domains/Proximal Adapters
SIGNALING DOMAINS AND
PROXIMAL ADAPTERS
Inhibitory KIR
 
Conserved epitopes on HLA I (“KIR ligands”)
ITIM, Src phosphatases
KIR2DL1
KIR2DL1
HLA-C2 alleles (Lys80)
 
KIR2DL2
KIR2DL2
HLA-C1 alleles (Asp80); HLA-C2 alleles (Lys80)
 
KIR2DL3
KIR2DL3
HLA-C1 alleles (Asp80)
 
KIR3DL1
KIR3DL1
HLA-B alleles carrying the Bw4 motif; HLA-A alleles
carrying the Bw4 motif
RECEPTOR
GENE
LIGAND
PART 11
Immune-Mediated, Inflammatory, and Rheumatologic Disorders
KIR3DL2
KIR3DL2
HLA-A03, HLA-A11 carrying specific peptides
 
KIR2DL4
KIR2DL4
HLA-G
 
KIR2DL5
 
CD155
 
Activating KIR
 
HLA-C2, HLA-C1, HLA-F, certain configurations of HLApeptide combinations
KIR2DS1
KIR2DS1
HLA-C2 alleles (Lys80) carrying specific peptides
KIR2DS2
KIR2DS2
HLA-C1 (Asp80) HLA-A11
KIR2DS3
KIR2DS3
Unknown
KIR3DS1
 
HLA-F
KIR2DS5
 
Unknown
Natural cytotoxicity receptors (NCRs)
 
NKp30
NCR3
B7-H6, BAT-3, heparan sulfates
 
NKp44
NCR2
PDGF, heparan sulfates, PCNA
 
NKp46
NCR1
Viral hemagglutinins, heparan sulfates, vimentin,
ecto-calreticulin
SLAM family receptors
ITSM, SAP, EAT
SLAMF1 (SLAM, CD150, IPO-3)
SLAMF1
SLAMF1
 
SLAMF2 (CD48, BLAST-1)
CD48
SLAMF4, CD2
 
SLAMF3 (CD229, Ly9)
LY9
SLAMF3
 
SLAMF4 (CD244, 2B4, ERT)
CD244
SLAMF2
 
SLAMF6 (NTB-A, Ly108, CD352)
SLAMF6
SLAMF6
 
SLAMF7 (CRACC, CD319)
SLAMF7
SLAMF7
 
SLAMF8 (BLAME, CD353)
SLAMF8
Unknown
 
Abbreviations: BAT-3, human leukocyte antigen-B-associated transcript 3; EAT, Ewing sarcoma associated transcript; HLA, human leukocyte antigens; ITAM, immunoreceptor
tyrosine-based activation motif; ITIM, immunoreceptor tyrosine-based inhibitory motif; ITSM, immunoreceptor tyrosine-based switch motif; KIR, killer cell immunoglobulin-like
receptor; NCRs, natural cytotoxicity receptors; NK, natural killer cell; SAP, SLAM-associated protein; SFK, Src family kinase; SLAM, signalling lymphocyte activating molecule.
Source: Reproduced from S Nersesian et al: Killer instincts: Natural killer cells as multifactorial cancer immunotherapy. Front Immunol. 2023; 14:1269614.
TABLE 360-10  Association of KIRS with Disease
DISEASE
KIR ASSOCIATION
OBSERVATION
Psoriatic arthritis
KIR2DS1/KIR2DS2; HLA-Cw group homozygosity
Susceptibility
Spondylarthritides
Increased KIR3DL2 expression
Interaction of HLA-B27 homodimers with KIR3DL1/KIR3DL2;
independent of peptide
Ankylosing spondylitis
KIR3DL1/3DS1; HLA-B27 genotypes
Susceptibility
Rheumatoid vasculitis
KIR2DS2; HLA-Cw03
Increased KIR2L2/2DS2 in patients with extraarticular
manifestations
Susceptibility
Clinical manifestations may have different genetic backgrounds
with respect to KIR genotype
Rheumatoid arthritis
Decreased KIR2DS1/3DS1 in patients without bone erosions
KIR2DS4; HLA-Cw4
Susceptibility 
Susceptibility
Scleroderma
KIR2DS2+/KIR2DL2–
Susceptibility
Behçet’s disease
Altered KIR3DL1 expression
Associated with severe eye disease
Psoriasis vulgaris
2DS1; HLA-Cw*06
2DS1; 2DL5; haplotype B
Susceptibility
Susceptibility
IDDM
KIR2DS2; HLA-C1
Susceptibility
Type 1 diabetes
KIR2DS2; HLA-C1 and no HLA-C2, no HLA-Bw4
Increased disease progression
Preeclampsia
KIR2DL1 with fewer KIR2DS (mother); HLA-C2 (fetus)
Increased disease progression
AIDS
KIR3DS1; HLA-Bw4Ile80
KIR3DS1 homozygous; no HLA-Bw4Ile80
Decreased disease progression
Increased disease progression
HCV infection
KIR2DL3 homozygous; HLA-C1 homozygous
Decreased disease progression
Cervical neoplasia (HPV induced)
KIR3DS1; HLA-C1 homozygous and no HLA-Bw4
Increased disease progression
Malignant melanoma
KIR2DL2 and/or KIR2DL3; HLA-C1
Increased disease progression
Abbreviations: HCV, hepatitis C virus; HLA, human leukocyte antigen; HPV, human papillomavirus; IDDM, insulin-dependent diabetes mellitus; KIR, killer cell immunoglobulin-like receptor.
Source: Reproduced with permission from R Diaz-Pena et al: KIR genes and their role in spondyloarthropathies. Adv Exp Med Biol 649:286, 2009.
 
ITAM, SFK
 
May contribute to disease pathology
May contribute to disease pathogenesis
Inhibitory receptor
A
No response
No HLA
class I
No activating
ligands
Target
NK
Activating receptor
B
No response
HLA
class I
No activating
ligands
NK
Target
C
NK attacks
target cells
No HLA
class I
Activating
ligands
NK
Target
D
Outcome
determined by
balance of signals
HLA
class I
Activating
ligands
NK
Target
FIGURE 360-4  Encounters between natural killer (NK) cells: Potential targets
and possible outcomes. The amount of activating and inhibitory receptors on the
NK cells and the amount of ligands on the target cell, as well as the qualitative
differences in the signals transduced, determine the extent of the NK response.
A. When target cells have no HLA class I or activating ligands, NK cells cannot
kill target cells. B. When target cells bear self-HLA, NK cells cannot kill targets.
C. When target cells are pathogen-infected and have downregulated HLA and
express activating ligands, NK cells kill target cells. D. When NK cells encounter
targets with both self-HLA and activating receptors, then the level of target killing
is determined by the balance of inhibitory and activating signals to the NK cell.
HLA, human leukocyte antigen. (Republished with permission of Annual Review of
Immunology, from NK Cell Recognition, L Lanier 23:225,2005: permission conveyed
through Copyright Clearance Center, Inc.)
belong in general to three major structural families: the hematopoietin
family; the TNF, IL-1, platelet-derived growth factor (PDGF), and trans­
forming growth factor (TGF) β families; and the CXC and C-C chemo­
kine families. Chemokines are cytokines that regulate cell movement
and trafficking; they act through G protein–coupled receptors and have
a distinctive three-dimensional structure (Table 360-7).
In general, cytokines exert their effects by influencing gene activa­
tion that results in cellular activation, growth, differentiation, functional
cell-surface molecule expression, and cellular effector function. In this
regard, cytokines can have dramatic effects on the regulation of immune
responses and the pathogenesis of a variety of diseases. Indeed, T cells
have been categorized on the basis of the pattern of cytokines that they
secrete, which results in either humoral immune response (TH2) or cellmediated immune response (TH1). A third type of T helper cell is the
TH17 cell that contributes to host defense against extracellular bacteria
and fungi, particularly at mucosal sites (Fig. 360-2).
Cytokine receptors can be grouped into five general families based on
similarities in their extracellular amino acid sequences and conserved
structural domains. The immunoglobulin (Ig) superfamily represents a
large number of cell-surface and secreted proteins. The IL-1 receptors
(type 1, type 2) are examples of cytokine receptors with extracellular
Ig domains.
The hallmark of the hematopoietic growth factor (type 1) receptor
family is that the extracellular regions of each receptor contain two
conserved motifs. One motif, located at the N terminus, is rich in
Mannose-binding
Classic
activation
pathway
Bacteria, fungi, virus,
or tumor cells
Alternative
lectin
activation pathway
activation
pathway
Microbes with terminal
mannose groups
Antigen/antibody
immune complex
CHAPTER 360
C3 (H2O)
MBL-MASP1-MASP2
C1q-C1r-C1s
C4
B
C4
D
C2
C2
Introduction to the Immune System
P
Anaphylatoxin
C3
Opsonin
Immune complex
modification
Lymphocyte
activation
C3b
Clearance of
apoptotic cells
C5
C6
Anaphylatoxin
C7
Terminal
pathway
C8
Lysis
poly-C9
Membrane perturbation
FIGURE 360-5  The four pathways and the effector mechanisms of the complement
system. Dashed arrows indicate the functions of pathway components. (Reproduced
with permission from BJ Morley, MJ Walport: The Complement Facts Books.
London, Academic Press, 2000.)
cysteine residues. The other motif is located at the C terminus proximal
to the transmembrane region and comprises five amino acid residues,
tryptophan-serine-X-tryptophan-serine (WSXWS). This family can be
grouped on the basis of the number of receptor subunits they have and
on the utilization of shared subunits. A number of cytokine receptors,
i.e., IL-6, IL-11, IL-12, and leukemia inhibitory factor, are paired with
gp130. There is also a common 150-kDa subunit shared by IL-3, IL-5,
and granulocyte-macrophage colony-stimulating factor (GM-CSF)
receptors. The gamma chain (γc) of the IL-2 receptor is common to the
IL-2, IL-4, IL-7, IL-9, and IL-15 receptors. Thus, the specific cytokine
receptor is responsible for ligand-specific binding, whereas the sub­
units such as gp130, the 150-kDa subunit, and γc are important in sig­
nal transduction. The γc gene is on the X chromosome, and mutations
in the γc protein result in the X-linked form of severe combined immune
deficiency syndrome (X-SCID) (Chap. 362).
The members of the interferon (type II) receptor family include the
receptors for IFN-γ and -β, which share a similar 210-amino-acid
binding domain with conserved cysteine pairs at both the amino and
carboxy termini. The members of the TNF (type III) receptor family
share a common binding domain composed of repeated cysteine-rich
regions. Members of this family include the p55 and p75 receptors for
TNF (TNF-R1 and TNF-R2, respectively); CD40 antigen, which is an
important B-cell surface marker involved in immunoglobulin isotype
switching; fas/Apo-1, whose triggering induces apoptosis; CD27 and
CD30, which are found on activated T cells and B cells; and nerve
growth factor receptor.
The common motif for the seven transmembrane helix family was
originally found in receptors linked to GTP-binding proteins. This
family includes receptors for chemokines (Table 360-8), β-adrenergic
receptors, and retinal rhodopsin. It is important to note that two mem­
bers of the chemokine receptor family, CXC chemokine receptor type
4 (CXCR4) and β chemokine receptor type 5 (CCR5), have been found
to serve as the two major co-receptors for binding and entry of HIV-1
into CD4-expressing host cells (Chap. 208).
Significant advances have been made in defining the signaling
pathways through which cytokines exert their intracellular effects.
The Janus family of protein tyrosine kinases (JAK) is a critical ele­
ment involved in signaling via the hematopoietin receptors. Four JAK
kinases, JAK1, JAK2, JAK3, and Tyk2, preferentially bind different
cytokine receptor subunits. Cytokine binding to its receptor brings
the cytokine receptor subunits into apposition and allows a pair of
JAKs to transphosphorylate and activate one another. The JAKs then
phosphorylate the receptor on the tyrosine residues and allow signal­
ing molecules to bind to the receptor, whereby the signaling mol­
ecules become phosphorylated. Signaling molecules bind the receptor
because they have domains (SH2, or src homology 2 domains) that
can bind phosphorylated tyrosine residues. There are a number of
these important signaling molecules that bind the receptor, such as
the adapter molecule SHC, which can couple the receptor to the acti­
vation of the mitogen-activated protein kinase pathway. In addition,
an important class of substrate of the JAKs is the signal transducers
and activators of transcription (STAT) family of transcription factors.
STATs have SH2 domains that enable them to bind to phosphorylated
receptors, where they are then phosphorylated by the JAKs. It appears
that different STATs have specificity for different receptor subunits.
The STATs then dissociate from the receptor and translocate to the
nucleus, bind to DNA motifs that they recognize, and regulate gene
expression. The STATs preferentially bind DNA motifs that are slightly
different from one another and thereby control transcription of specific
genes. The importance of this pathway is particularly relevant to lym­
phoid development. Mutations of JAK3 itself also result in a disorder
identical to X-SCID; however, because JAK3 is found on chromosome
19 and not on the X chromosome, JAK3 deficiency occurs in boys
and girls (Chap. 362). A new class of immunosuppressive drugs of
JAK inhibitors has been developed that are approved to treat chronic
inflammatory diseases such as rheumatoid arthritis (Chap. 370),
psoriatic arthritis (Chap. 374), ulcerative colitis (Chap. 337), atopic
dermatitis (Chap. 59), and alopecia areata (Chap. 61).
PART 11
Immune-Mediated, Inflammatory, and Rheumatologic Disorders
■
■THE ADAPTIVE IMMUNE SYSTEM
Adaptive immunity is characterized by antigen-specific responses to
a foreign antigen or pathogen. A key feature of adaptive immunity is
that following the initial contact with antigen (immunologic priming),
subsequent antigen exposure leads to more rapid and vigorous immune
responses (immunologic memory). The adaptive immune system con­
sists of dual limbs of cellular and humoral immunity. The principal
effectors of cellular immunity are T lymphocytes, whereas the principal
effectors of humoral immunity are B lymphocytes. Both B and T lym­
phocytes derive from a common stem cell (Fig. 360-6).
The proportion and distribution of immunocompetent cells in
various tissues reflect cell traffic, homing patterns, and functional
capabilities. Bone marrow is the major site of maturation of B cells,
monocytes-macrophages, DCs, and granulocytes and contains pluripo­
tent stem cells that, under the influence of various colony-stimulating
factors, can give rise to all hematopoietic cell types. T-cell precursors
also arise from hematopoietic stem cells and home to the thymus for
maturation. Mature T lymphocytes, B lymphocytes, monocytes, and
DCs enter the circulation and home to peripheral lymphoid organs
(lymph nodes, spleen) and mucosal surface-associated lymphoid tis­
sue (gut, genitourinary, and respiratory tracts) as well as the skin and
mucous membranes and await activation by foreign antigen.
T Cells 
The pool of effector T cells is established in the thymus early
in life and is maintained throughout life both by new T-cell production
in the thymus and by antigen-driven expansion of virgin peripheral T
cells into “memory” T cells that reside in peripheral lymphoid organs.
The thymus exports ~2% of the total number of thymocytes per day
throughout life, with the total number of daily thymic emigrants
decreasing by ~3% per year during the first four decades of life.
Mature T lymphocytes constitute 70–80% of normal peripheral
blood lymphocytes (only 2% of the total-body lymphocytes are
contained in peripheral blood), 90% of thoracic duct lymphocytes,
30–40% of lymph node cells, and 20–30% of spleen lymphoid cells.
In lymph nodes, T cells occupy deep paracortical areas around B-cell
germinal centers, and in the spleen, they are located in periarteriolar
areas of white pulp (Chap. 70). T cells are the primary effectors of
cell-mediated immunity, with subsets of T cells maturing into CD8+
cytotoxic T cells capable of lysis of virus-infected or foreign cells
(short-lived effector T cells) and CD4+ T cells capable of T-cell help
for CD8+ T-cell and B-cell development. Two populations of long-lived
memory T cells are triggered by infections: effector memory and cen­
tral memory T cells. Effector memory T cells reside in nonlymphoid
organs and respond rapidly to repeated pathogenic infections with
cytokine production and cytotoxic functions to kill virus-infected cells.
Central memory T cells home to lymphoid organs where they replenish
long- and short-lived and effector memory T cells as needed.
In general, CD4+ T cells are the primary regulatory cells of T and B
lymphocyte and monocyte function by the production of cytokines and
by direct cell contact (Fig. 360-2). In addition, T cells regulate erythroid
cell maturation in bone marrow and, through cell contact (CD40
ligand), have an important role in activation of B cells and induc­
tion of Ig isotype switching. Considerable evidence now exists that
colonization of the gut by commensal bacteria (the gut microbiome) is
responsible for expansion of the peripheral CD4+ T-cell compartment
in normal children and adults.
Human T cells express cell-surface proteins that mark stages of
intrathymic T-cell maturation or identify specific functional subpopu­
lations of mature T cells. Many of these molecules mediate or partici­
pate in important T-cell functions (Table 360-1, Fig. 360-6, Chap. 361).
The earliest identifiable T-cell precursors in bone marrow are
CD34+ pro-T cells (i.e., cells in which TCR genes are neither rear­
ranged nor expressed). In the thymus, CD34+ T-cell precursors begin
cytoplasmic (c) synthesis of components of the CD3 complex of TCRassociated molecules (Fig. 360-6). Within T-cell precursors, TCR for
antigen gene rearrangement yields two T-cell lineages, expressing
either TCR-αβ chains or TCR-γδ chains. T cells expressing the TCR-αβ
chains constitute the majority of peripheral T cells in blood, lymph
node, and spleen and terminally differentiate into either CD4+ or
CD8+ cells. Cells expressing TCR-γδ chains circulate as a minor popu­
lation in blood; their functions have been postulated to be those of
immune surveillance at epithelial surfaces and cellular defenses against
mycobacterial organisms and other intracellular bacteria through rec­
ognition of bacterial lipids.
In the thymus, the recognition of self-peptides on thymic epithelial
cells, thymic macrophages, and DCs plays an important role in shap­
ing T-cell repertoire. As immature cortical thymocytes begin to express
surface TCR for antigen, thymocytes with TCRs capable of interacting
with self-peptides in the context of self-MHC antigens with low affinity
are activated and survive (positive selection). Thymocytes with TCRs
that are incapable of binding to self-MHC antigens or bind with high
affinity die of attrition (no selection) or by apoptosis (negative selec­
tion). Thymocytes that are positively selected undergo maturation into
CD4 or CD8 single positive T cells, and then migrate to the thymus
medulla where they interact with self-peptide–self-MHC molecules,
where they can again undergo selection. The purpose of negative and
positive thymocyte selection is to eliminate potential pathogenic auto­
reactive T cells, and at the same time, select a repertoire of mature T cells
capable of recognizing foreign antigens.
Mature TCRab thymocytes that are positively selected are func­
tional MHC class II–restricted CD4+ T cells (Fig. 360-2), or they
are CD8+ T cells destined to become CD8+ MHC class I–restricted
cytotoxic T cells. MHC class I or class II restriction means that T cells
recognize antigen peptide fragments only when they are presented
in the antigen-recognition site of a class I or class II MHC molecule,
respectively. After thymocyte maturation and selection, CD4 and CD8
thymocytes leave the thymus and migrate to the peripheral immune
system. The thymus can continue to be a contributor to the periph­
eral immune system well into adult life, both normally and when the
peripheral T-cell pool is damaged, such as occurs in AIDS and cancer
chemotherapy.
MOLECULAR BASIS OF T-CELL RECOGNITION OF ANTIGEN  The TCR
for antigen is a complex of molecules consisting of an antigen-binding
heterodimer of either αβ or γδ chains noncovalently linked with
five CD3 subunits (γ, δ, ε, ζ, and η) (Fig. 360-7). The CD3 ζ chains
are either disulfide-linked homodimers (CD3-ζ2) or disulfide-linked
Pro-T
Pro-T
Pro-T
Immature T
Mature T
CD34+
CD7lo+ or -
α,β Germline
CD34+
Hematopoietic
α,β Germline
CD7
CD2
CD3
α-Germline
β-VDJ Rearranged
Hematopoietic
stem cell
CD34+
Early
pro-B cell
Late
pro-B cell
Large
pre-B cell
Small
pre-B cell
Immature
B cell
Mature
B cell
Heavy-chain
genes
VDJ
rearranging
D-J
rearranging
Light-chain
genes
Germline
Germline
Surface Ig
Absent
Absent
Surface
marker
proteins
CD34
CD10
CD38
CD10
CD19
CD38
CD40
FIGURE 360-6  Development stages of T and B cells. Elements of the developing T- and B-cell receptor for antigen are shown schematically. The classification into the
various stages of B-cell development is primarily defined by rearrangement of the immunoglobulin (Ig) heavy (H) and light (L) chain genes and by the absence or presence
of specific surface markers. The classification of stages of T-cell development is primarily defined by cell-surface marker protein expression (sCD3, surface CD3 expression;
cCD3, cytoplasmic CD3 expression; TCR, T-cell receptor). For B-cell development, the pre-B-cell receptor is shown as a blue-orange B-cell receptor. (Adapted
from Janeway’s Immunobiology, 9th ed by Kenneth Murphy and Casey Weaver. Copyright © 2017 by Garland Science, Taylor & Francis Group, LLC. Used by permission of
W. W. Norton & Company, Inc.)
heterodimers composed of one ζ chain and one η chain. TCR-αβ
or TCR-γδ molecules must be associated with CD3 molecules to be
inserted into the T-cell surface membrane, TCR-α being paired with
TCR-β and TCR-γ being paired with TCR-δ. Molecules of the CD3
complex mediate transduction of T-cell activation signals via TCRs,
whereas TCR-α and -β or -γ and -δ molecules combine to form the
TCR antigen-binding site.
The α, β, γ, and δ TCR for antigen molecules have amino acid
sequence homology and structural similarities to immunoglobulin
heavy and light chains and are members of the immunoglobulin gene
superfamily of molecules. The genes encoding TCR molecules are
encoded as clusters of gene segments that rearrange during T-cell mat­
uration. This creates an efficient and compact mechanism for housing
the diversity requirements of antigen receptor molecules. The TCR-α
chain is on chromosome 14 and consists of a series of V (variable), J
(joining), and C (constant) regions. The TCR-β chain is on chromo­
some 7 and consists of multiple V, D (diversity), J, and C TCR-β loci.
The TCR-γ chain is on chromosome 7, and the TCR-δ chain is in the
middle of the TCR-α locus on chromosome 14. Thus, molecules of the
TCR for antigen have constant (framework) and variable regions, and
Thymus medulla
and peripheral
T-cell pools
CHAPTER 360
CD7
CD2
cCD3, TCRαβ
CD1
CD4, CD8
α-VJ Rearranged
β-VDJ Rearranged
CD7
CD2
CD3, TCRαβ
CD4
Mature T
Introduction to the Immune System
CD7
CD2
CD3, TCRαβ
CD8
Mature T
CD7
CD2
CD3, TCRγδ
CD8
IgM
IgD
VDJ
rearranged
VDJ
rearranged
VDJ
rearranged
VDJ
rearranged
VJ
rearranged
VJ
rearranged
VJ
rearranging
Germline
µ H-chain in
cytoplasm
µ H-chain at
surface as
part of the pre-B
receptor (orange)
containing
surrogate light
chain (SLC).
Receptor is
mainly intracellular
IgM expressed
on cell surface
IgD and IgM
made from
alternatively
spliced
H-chain
transcripts
CD19
CD20
CD19
CD20
CD21
CD19
CD20
CD38
CD19
CD20
CD38
the gene segments encoding the α, β, γ, and δ chains of these molecules
are recombined and selected in the thymus, culminating in synthesis of
the completed molecule. In both T- and B-cell precursors (see below),
DNA rearrangements of antigen receptor genes involve the same
enzymes, recombinase activating gene RAG1 and RAG2, both DNAdependent protein kinases.
TCR diversity is created by the different V, D, and J segments that
are possible for each receptor chain by the many permutations of
V, D, and J segment combinations, by “N-region diversification” due
to the addition of nucleotides at the junction of rearranged gene seg­
ments, and by the pairing of individual chains to form a TCR dimer. As
T cells mature in the thymus, the repertoire of antigen-reactive T cells
is modified by selection processes that eliminate many autoreactive
T cells, enhance the proliferation of cells that function appropriately
with self-MHC molecules and antigen, and allow T cells with nonpro­
ductive TCR rearrangements to die.
TCR-αβ cells do not recognize native protein or carbohydrate anti­
gens. Instead, T cells recognize only short (~9–13 amino acids) peptide
fragments derived from protein antigens taken up or produced in
APCs. Foreign antigens may be taken up by endocytosis into acidified
PART 11
Immune-Mediated, Inflammatory, and Rheumatologic Disorders
PtdIns (4,5)P3
Lipid raft
InsP3
Release of Ca2+
Translocation
of NFAT to the nucleus
DAG
PKC
RASGRP
Activation of downstream
effectors such as NFkB, AP1,
and NFAT to induce specific
gene transcription leading to
cell proliferation and differentiation
MAPK activation
FIGURE 360-7  Signaling through the T-cell receptor. Activation signals are mediated via immunoreceptor tyrosine-based activation (ITAM) sequences in LAT and CD3
chains (blue bars) that bind to enzymes and transduce activation signals to the nucleus via the indicated intracellular activation pathways. Ligation of the T-cell receptor
(TCR) by MHC complexed with antigen results in sequential activation of LCK and γ-chain-associated protein kinase of 70 kDa (ZAP70). ZAP70 phosphorylates several
downstream targets, including LAT (linker for activation of T cells) and SLP76 (SCR homology 2 [SH2] domain-containing leukocyte protein of 76 kDa). SLP76 is recruited
to membrane-bound LAT through its constitutive interaction with GADS (GRB2-related adaptor protein). Together, SLP76 and LAT nucleate a multimolecular signaling
complex, which induces a host of downstream responses, including calcium flux, mitogen-activated protein kinase (MAPK) activation, integrin activation, and cytoskeletal
reorganization. APC, antigen-presenting cell; NFAT, nuclear factor of activated T cells. (Reproduced with permission from GA Koretzky, F Abtahian, MA Silverman. SLP76
and SLP65: Complex regulation of signalling in lymphocytes and beyond. Nat Rev Immunol 6:67, 2006.)
intracellular vesicles or by phagocytosis and degraded into small pep­
tides that associate with MHC class II molecules (exogenous antigenpresentation pathway). Other foreign antigens arise endogenously in
the cytosol (such as from replicating viruses) and are broken down into
small peptides that associate with MHC class I molecules (endogenous
antigen-presenting pathway). Thus, APCs proteolytically degrade for­
eign proteins and display peptide fragments embedded in the MHC
class I or II antigen-recognition site on the MHC molecule surface,
where foreign peptide fragments are available to bind to TCR-αβ or
TCR-γδ chains of reactive T cells. CD4 molecules act as adhesives and,
by direct binding to MHC class II (DR, DQ, or DP) molecules, stabilize
the interaction of TCR with peptide antigen (Fig. 360-7). Similarly,
CD8 molecules also act as adhesives to stabilize the TCR-antigen inter­
action by direct CD8 molecule binding to MHC class Ia (HLA A, B, or
C) molecules or to MHC class Ib (HLA E).
Antigens that arise in the cytosol and are processed via the endog­
enous antigen-presentation pathway are cleaved into small peptides by
a complex of proteases called the proteasome. From the proteasome,
antigen peptide fragments are transported from the cytosol into the
lumen of the endoplasmic reticulum by a heterodimeric complex
termed transporters associated with antigen processing or TAP proteins.
There, MHC class I molecules in the endoplasmic reticulum mem­
brane physically associate with processed cytosolic peptides. Following
peptide association with class I molecules, peptide–class I complexes
are exported to the Golgi apparatus, and then to the cell surface, for
recognition by CD8+ T cells.
Antigens taken up from the extracellular space via endocytosis
into intracellular acidified vesicles are degraded by vesicle proteases
into peptide fragments. Intracellular vesicles containing MHC class II
molecules fuse with peptide-containing vesicles, thus allowing peptide
fragments to physically bind to MHC class II molecules. Peptide–MHC
APC
ICAM-1
LFA-3
CD28
B7-1
β
α
CD3
TCR
LFA-1
CD2
RAS
LCK
Cytoskeletal
reorganization
ZAP70
LAT
GRB2
SOS
ITK
VAV1
PLCγ
NCK
GADS
HPK1
ADAP
Integrin activation
class II complexes are then transported to the cell surface for recogni­
tion by CD4+ T cells.
Whereas it is generally agreed that the TCR-αβ receptor recognizes
peptide antigens in the context of MHC class I or class II molecules,
lipids in the cell wall of intracellular bacteria such as M. tuberculosis
can also be presented to a wide variety of T cells, including subsets of
TCR-γδ T cells, and a subset of CD8+ TCR-αβ T cells. Importantly,
bacterial lipid antigens are not presented in the context of MHC class I
or II molecules, but rather are presented in the context of MHC-related
CD1 molecules. Some γδ T cells that recognize lipid antigens via CD1
molecules have very restricted TCR usage, do not need antigen prim­
ing to respond to bacterial lipids, and may be a form of innate rather
than acquired immunity to intracellular bacteria.
Just as foreign antigens are degraded and their peptide fragments
presented in the context of MHC class I or class II molecules on APCs,
endogenous self-proteins also are degraded, and self-peptide frag­
ments are presented to T cells in the context of MHC class I or class II
molecules on APCs. In peripheral lymphoid organs, there are T cells
that are capable of recognizing self-protein fragments but normally are
anergic or tolerant, i.e., nonresponsive to self-antigenic stimulation, due
to lack of self-antigen upregulating APC co-stimulatory molecules such
as B7-1 (CD80) and B7-2 (CD86) (see below and Chap. 361).
Once engagement of mature T-cell TCR by foreign peptide occurs
in the context of self-MHC class Ia (A, B, or C), class 1b (E), or class II
molecules, binding of non-antigen-specific adhesion ligand pairs such
as CD54-CD11/CD18 and CD58-CD2 stabilizes MHC peptide-TCR
binding, and the expression of these adhesion molecules is upregu­
lated. Once antigen ligation of the TCR occurs, the T-cell membrane
is partitioned into lipid membrane microdomains, or lipid rafts, that
coalesce the key signaling molecules TCR/CD3 complex, CD28,
CD2, LAT (linker for activation of T cells), intracellular activated
(dephosphorylated) src family protein tyrosine kinases (PTKs), and the
key CD3ζ-associated protein-70 (ZAP-70) PTK (Fig. 360-7). Impor­
tantly, during T-cell activation, the CD45 molecule, with protein tyro­
sine phosphatase activity, is partitioned away from the TCR complex
to allow activating phosphorylation events to occur. The coalescence
of signaling molecules of activated T lymphocytes in microdomains has
suggested that T cell–APC interactions can be considered immunologic
synapses, analogous in function to neuronal synapses.
After TCR-MHC binding is stabilized, activation signals are trans­
mitted through the cell to the nucleus and lead to the expression of
gene products important in mediating the wide diversity of T-cell func­
tions such as the secretion of IL-2. The TCR does not have intrinsic
signaling activity but is linked to a variety of signaling pathways via
ITAMs expressed on the various CD3 chains that bind to proteins that
mediate signal transduction. Each of the pathways results in the activa­
tion of particular transcription factors that control the expression of
cytokine and cytokine receptor genes. Thus, antigen-MHC binding to
the TCR induces the activation of the src family of PTKs, Fyn and Lck
(Lck is associated with CD4 or CD8 co-stimulatory molecules); phos­
phorylation of CD3ζ chain; activation of the related tyrosine kinases
ZAP-70 and Syk; and downstream activation of the calcium-dependent
calcineurin pathway, the ras pathway, and the protein kinase C path­
way. Each of these pathways leads to activation of specific families of
transcription factors (including NF-AT, fos and jun, and rel/NF-κB)
that form heteromultimers capable of inducing expression of IL-2, IL-2
receptor, IL-4, TNF-α, and other T-cell mediators.
In addition to the signals delivered to the T cell from the TCR
complex and CD4 and CD8, molecules on the T cell, such as CD28
and inducible co-stimulator (ICOS), and molecules on DCs, such as
B7-1 (CD80) and B7-2 (CD86), also deliver important co-stimulatory
signals that upregulate T-cell cytokine production and are essential for
T-cell activation. If signaling through CD28 or ICOS does not occur,
or if CD28 is blocked, the T cell becomes anergic rather than activated
(see “Immune Tolerance and Autoimmunity” below and Chap. 361).
CTLA-4 (CD152) is similar to CD28 in its ability to bind CD80 and
CD86. Unlike CD28, CTLA-4 transmits an inhibitory signal to T cells,
acting as an off switch.
T-CELL EXHAUSTION IN VIRAL INFECTIONS AND CANCER  In chronic
viral infections such as HIV-1, hepatitis C virus, and hepatitis B virus
and in chronic malignancies, the persistence of antigen disrupts mem­
ory T-cell function, resulting in defects in memory T-cell responses.
This has been defined as T-cell exhaustion and is associated with
T-cell programmed cell death protein 1 (PD-1) (CD279) expression.
Exhausted T cells have compromised proliferation and lose the ability
to produce effector molecules, like IL-2, TNF-α, and IFN-γ. PD-1 and
CTLA-4 activation downregulates T-cell responses and is associated
with T-cell exhaustion and tumor progression. Inhibition of T-cell
PD-1 or CTLA-4 activity to enhance effector T-cell killing of tumor
cells has become a critical component of therapy for certain malignan­
cies (Chap. 361).
T-CELL SUPERANTIGENS  Conventional antigens bind to MHC class
I or II molecules in the groove of the αβ heterodimer and bind
to T cells via the V regions of the TCR-α and -β chains. In contrast,
superantigens bind directly to the lateral portion of the TCR-β chain
and MHC class II β chain and stimulate T cells based solely on the Vβ
gene segment used independent of the D, J, and Vα sequences present.
Superantigens are protein molecules capable of activating up to 20% of
the peripheral T-cell pool, whereas conventional antigens activate <1 in
10,000 T cells. T-cell superantigens include staphylococcal enterotox­
ins and other bacterial products. Superantigen stimulation of human
peripheral T cells occurs in the clinical setting of staphylococcal toxic
shock syndrome, leading to massive overproduction of T-cell cytokines
that leads to hypotension and shock (Chap. 152).
B CELLS  Mature B cells constitute 5–10% of human peripheral blood
lymphocytes, 20–30% of lymph node cells, 50% of splenic lympho­
cytes, and ~10% of bone marrow lymphocytes. B cells express on their
surface intramembrane immunoglobulin (Ig) molecules that function
as BCRs for antigen in a complex of Ig-associated α and β signaling
molecules with properties similar to those described in T cells
(Fig. 360-8). Unlike T cells, which recognize only processed peptide
fragments of conventional antigens embedded in the notches of MHC
class I and class II antigens of APCs, B cells are capable of recognizing
and proliferating to whole unprocessed native antigens via antigen
binding to B-cell surface Ig (sIg) receptors. B cells also express surface
receptors for the Fc region of IgG molecules (CD32) as well as receptors
for activated complement components (C3d or CD21, C3b or CD35).
The primary function of B cells is to produce antibodies. B cells also
serve as APCs and are highly efficient at antigen processing. Their
antigen-presenting function is enhanced by a variety of cytokines.
Mature B cells are derived from bone marrow precursor cells that arise
continuously throughout life (Fig. 360-6).
CHAPTER 360
Introduction to the Immune System
B lymphocyte development can be separated into antigen-inde­
pendent and antigen-dependent phases. Antigen-independent B-cell
development occurs in primary lymphoid organs and includes all
stages of B-cell maturation up to the sIg+ mature B cell. Antigendependent B-cell maturation is driven by the interaction of antigen
with the mature B-cell sIg, leading to memory B-cell induction, Ig
class switching, and plasma cell formation. Antigen-dependent stages
of B-cell maturation occur in secondary lymphoid organs, including
lymph node, spleen, and gut Peyer’s patches. In contrast to the T-cell
repertoire that is generated intrathymically before contact with foreign
antigen, the repertoire of B cells expressing diverse antigen-reactive
sites is modified by further alteration of Ig genes by the enzyme acti­
vation-induced cytidine deaminase after stimulation by antigen—a
process called somatic hypermutation—that occurs in lymph node
germinal centers.
During B-cell development, diversity of the antigen-binding variable
region of Ig is generated by an ordered set of Ig gene rearrangements
that are similar to the rearrangements undergone by TCR α, β, γ, and δ
genes. For the heavy chain, there is first a rearrangement of D segments
to J segments, followed by a second rearrangement between a V gene
segment and the newly formed D-J sequence; the C segment is aligned
to the V-D-J complex to yield a functional Ig heavy chain gene (V-D-JC). During later stages, a functional κ or γ light chain gene is generated
by rearrangement of a V segment to a J segment, ultimately yielding an
intact Ig molecule composed of heavy and light chains.
The process of Ig gene rearrangement is regulated and results in
a single antibody specificity produced by each B cell, with each Ig
molecule comprising one type of heavy chain and one type of light
chain. Although each B cell contains two copies of Ig light and heavy
chain genes, only one gene of each type is productively rearranged and
expressed in each B cell, a process termed allelic exclusion.
There are ~300 Vκ genes and 5 Jκ genes, resulting in the pairing of Vκ
and Jκ genes to create >1500 different kappa light chain combinations.
There are ~70 Vλ genes and 4 Jλ genes for >280 different lambda light
chain combinations. The number of distinct light chains that can be
generated is increased by somatic mutations within the V and J genes,
thus creating large numbers of possible specificities from a limited
amount of germline genetic information. As noted above, in heavy
chain Ig gene rearrangement, the VH domain is created by the joining
of three types of germline genes called VH, DH, and JH, thus allowing
for even greater diversity in the variable region of heavy chains than of
light chains.
The most immature B-cell precursors (early pro-B cells) lack cyto­
plasmic Ig (cIg) and sIg (Fig. 360-6). The large pre-B cell is marked by
the acquisition of the surface pre-BCR composed of μ heavy (H) chains
and a pre-B light chain, termed V pre-B. V pre-B is a surrogate light
chain receptor encoded by the non-rearranged V pre-B and the γ5 light
chain locus (the pre-BCR). Pro- and pre-B cells are driven to proliferate
and mature by signals from bone marrow stroma—in particular, IL-7.
Light chain rearrangement occurs in the small pre-B-cell stage such
that the full BCR is expressed at the immature B-cell stage. Imma­
ture B cells have rearranged Ig light chain genes and express sIgM.
As immature B cells develop into mature B cells, sIgD is expressed as
well as sIgM. At this point, B lineage development in bone marrow is
complete, and B cells exit into the peripheral circulation and migrate to
secondary lymphoid organs to encounter specific antigens.
Heavy chain
Fab region
PART 11
Immune-Mediated, Inflammatory, and Rheumatologic Disorders
BCR
RAS
LYN
Igβ
MAPK
activation
Cytoskeletal
reorganization
a
VAV1
PLCγ
NCK
SOS
FIGURE 360-8  B-cell receptor (BCR) activation results in the sequential activation of protein tyrosine kinases, which results in the formation of a signaling complex and
activation of downstream pathways as shown. Whereas SLP76 is recruited to the membrane through GADS and LAT, the mechanism of SLP65 recruitment is unclear.
Studies have indicated two mechanisms: (a) direct binding by the SH2 domain of SLP65 to immunoglobulin (Ig) of the BCR complex or (b) membrane recruitment through a
leucine zipper in the amino terminus of SLP65 and an unknown binding partner. ADAP, adhesion- and degranulation-promoting adaptor protein; AP1, activator protein 1; BTK,
Bruton’s tyrosine kinase; DAG, diacylglycerol; GRB2, growth factor receptor-bound protein 2; HPK1, hematopoietic progenitor kinase 1; InsP3, inositol-1,4,5-trisphosphate;
ITK, interleukin-2-inducible T-cell kinase; NCK, noncatalytic region of tyrosine kinase; NF-B, nuclear factor B; PKC, protein kinase C; PLC, phospholipase C; PtdIns(4,5)P2,
phosphatidylinositol-4,5-bisphosphate; RASGRP, RAS guanyl-releasing protein; SOS, son of sevenless homologue; SYK, spleen tyrosine kinase. (Reproduced with permission
from GA Koretzky et al: SLP76 and SLP65: Complex regulation of signalling in lymphocytes and beyond. Nat Rev Immunol 6:67, 2006.)
Random rearrangements of Ig genes occasionally generate selfreactive antibodies, and mechanisms must be in place to correct these
mistakes. One such mechanism is BCR editing, whereby autoreactive
BCRs are mutated to not react with self-antigens. If receptor editing
is unsuccessful in eliminating autoreactive B cells, then autoreactive
B cells may undergo negative selection in the bone marrow through
induction of apoptosis after BCR engagement of self-antigen.
After leaving the bone marrow, B cells populate peripheral B-cell
sites, such as lymph node and spleen, and await contact with foreign
antigens that react with each BCR. Antigen-driven B-cell activation
occurs through the BCR, and somatic hypermutation takes place
whereby point mutations in rearranged H- and L-genes give rise to
mutant sIg molecules, some of which bind antigen better than the
original sIg molecules. Somatic hypermutation, therefore, is a process
whereby memory B cells in peripheral lymph organs have the best
binding or the highest-affinity antibodies. This overall process of
generating the best antibodies is called affinity maturation of antibody.
Lymphocytes that synthesize IgG, IgA, and IgE are derived from
sIgM+, sIgD+ mature B cells. Ig class switching occurs in lymph node
and other peripheral lymphoid tissue germinal centers. CD40 on B cells
and CD40 ligand on T cells constitute a critical co-stimulatory receptorligand pair of immune-stimulatory molecules. Pairs of CD40+ B cells
and CD40 ligand+ T cells bind and drive B-cell Ig class switching via
T cell–produced cytokines such as IL-4 and TGF-β. IL-1, -2, -4, -5,
and -6 synergize to drive mature B cells to proliferate and differentiate
into Ig-secreting cells.
Humoral Mediators of Adaptive Immunity: Immunoglobulins 
Immunoglobulins are the products of differentiated B cells and mediate
Light chain
Igα
PtdIns(4,S)P3
SYK
b
InsP3
Release
of Ca2+
DAG
BTK
SLP65
PKCβ
RASGRP
GRB2
Activation of
downstream
effectors
the humoral arm of the immune response. The primary functions of
antibodies are to bind specifically to antigen and bring about the inac­
tivation or removal of the offending toxin, microbe, parasite, or other
foreign substance from the body. The structural basis of Ig molecule
function and Ig gene organization has provided insight into the role
of antibodies in normal protective immunity, pathologic immunemediated damage by immune complexes, and autoantibody formation
against host determinants.
All immunoglobulins have the basic structure of two heavy and two
light chains (Fig. 360-8). Immunoglobulin isotype (i.e., G, M, A, D, E)
is determined by the type of Ig heavy chain present. IgG and IgA iso­
types can be divided further into subclasses (G1, G2, G3, G4, and A1,
A2) based on specific antigenic determinants on Ig heavy chains. The
characteristics of human immunoglobulins are outlined in Table 360-11.
The four chains are covalently linked by disulfide bonds. Each chain is
made up of a V region and C regions (also called domains), themselves
made up of units of ~110 amino acids. Light chains have one variable
(VL) and one constant (CL) unit; heavy chains have one variable unit
(VH) and three or four constant (CH) units, depending on isotype. As
the name suggests, the constant, or C, regions of Ig molecules are made
up of homologous sequences and share the same primary structure as
all other Ig chains of the same isotype and subclass. Constant regions
are involved in biologic functions of Ig molecules. The CH2 domain
of IgG and the CH4 units of IgM are involved with the binding of the
C1q portion of C1 during complement activation. The CH region at
the carboxy-terminal end of the IgG molecule, the Fc region, binds to
surface Fc receptors (CD16, CD32, CD64) of macrophages, DCs, NK
cells, B cells, neutrophils, and eosinophils. The Fc of IgA binds to FcαR
(CD89), and the Fc of IgE binds to FcεR (CD23).
TABLE 360-11  Physical, Chemical, and Biologic Properties of Human Immunoglobulins
PROPERTY
IgG
IgA
IgM
IgD
IgE
Usual molecular form
Monomer
Monomer, dimer
Pentamer, hexamer
Monomer
Monomer
Other chains
None
J chain, SC
J chain
None
None
Subclasses
G1, G2, G3, G4
A1, A2
None
None
None
Heavy chain allotypes
Gm (=30)
No A1, A2m (2)
None
None
None
Molecular mass, kDa
160, 400
950, 1150
Serum level in average adult, mg/mL
9.5–12.5
1.5–2.6
0.7–1.7
0.04
0.0003
Percentage of total serum Ig
75–85
7–15
5–10
0.3
0.019
Serum half-life, days
2.5
Synthesis rate, mg/kg per day
0.4
0.016
Antibody valence
2, 4
10, 12
Classical complement activation
+(G1, 2?, 3)
–
++
–
–
Alternate complement activation
+(G4)
+
–
+
–
Binding cells via Fc
Macrophages, neutrophils, large
granular lymphocytes
Biologic properties
Placental transfer, secondary
antibody for most antipathogen
responses
Source: Reproduced with permission from L Carayannopoulos, JD Capra, in WE Paul (ed): Fundamental Immunology, 3rd ed. New York, Raven, 1993.
Variable regions (VL and VH) constitute the antibody-binding (Fab)
region of the molecule. Within the VL and VH regions are hypervari­
able regions (extreme sequence variability) that constitute the antigenbinding site unique to each Ig molecule. The idiotype is defined as the
specific region of the Fab portion of the Ig molecule to which antigen
binds. Antibodies against the idiotype portion of an antibody molecule
are called anti-idiotype antibodies. The formation of such antibodies in
vivo during a normal B-cell antibody response may generate a negative
(or “off”) signal to B cells to terminate antibody production.
IgG constitutes ~75–85% of total serum immunoglobulin. The four
IgG subclasses are numbered in order of their level in serum, IgG1
being found in greatest amounts and IgG4 the least. IgG subclasses
have clinical relevance in their varying ability to bind macrophage and
neutrophil Fc receptors and to activate complement (Table 360-11).
Moreover, selective deficiencies of certain IgG subclasses give rise to
clinical syndromes in which the patient is inordinately susceptible to
bacterial infections. IgG antibodies are frequently the predominant
antibody made after rechallenge of the host with antigen (secondary
antibody response).
IgM antibodies normally circulate as a 950-kDa pentamer with
160-kDa bivalent monomers joined by a molecule called the J chain, a
15-kDa nonimmunoglobulin molecule that also effects polymerization
of IgA molecules. IgM is the first immunoglobulin to appear in the
immune response (primary antibody response) and is the initial type
of antibody made by neonates. Membrane IgM in the monomeric form
also functions as a major antigen receptor on the surface of mature B
cells (Table 360-11). IgM is an important component of immune com­
plexes in autoimmune diseases. For example, IgM antibodies against
IgG molecules (rheumatoid factors) are present in high titers in rheu­
matoid arthritis, other collagen diseases, and some infectious diseases
(subacute bacterial endocarditis).
IgA constitutes only 7–15% of total serum immunoglobulin but
is the predominant class of immunoglobulin in secretions. IgA in
secretions (tears, saliva, nasal secretions, gastrointestinal tract fluid,
and human milk) is in the form of secretory IgA (sIgA), a polymer
consisting of two IgA monomers, a joining molecule, again termed
the J chain, and a glycoprotein called the secretory protein. Of the two
IgA subclasses, IgA1 is primarily found in serum, whereas IgA2 is
more prevalent in secretions. IgA fixes complement via the alternative
complement pathway and has potent antiviral activity in humans by
prevention of virus binding to respiratory and gastrointestinal epithe­
lial cells.
IgD is found in minute quantities in serum and, together with IgM,
is a major receptor for antigen on the naïve B-cell surface. IgE, which
is present in serum in very low concentrations, is the major class of
CHAPTER 360
Introduction to the Immune System
Lymphocytes
Lymphocytes
None
Mast cells, basophils,
B cells
Secretory
immunoglobulin
Primary antibody
responses
Marker for mature
B cells
Allergy, antiparasite
responses
immunoglobulin involved in arming mast cells and basophils by bind­
ing to these cells via the Fc region. Antigen cross-linking of IgE mol­
ecules on basophil and mast cell surfaces results in release of mediators
of the immediate hypersensitivity (allergic) response (Table 360-11).
■
■CELLULAR INTERACTIONS IN REGULATION OF
NORMAL IMMUNE RESPONSES
The net result of activation of the humoral (B-cell) and cellular (T-cell)
arms of the adaptive immune system by foreign antigen is the elimina­
tion of antigen directly by specific effector T cells or in concert with
specific antibody.
The expression of adaptive immune cell function is the result of
a complex series of immunoregulatory events that occur in phases.
Both T and B lymphocytes mediate immune functions, and each of
these cell types, when given appropriate signals, passes through stages,
from activation and induction through proliferation, differentiation,
and ultimately effector functions. The effector function expressed may
be at the end point of a response, such as secretion of antibody by a
differentiated plasma cell, or it might serve a regulatory function that
modulates other functions, such as is seen with CD4 and CD8 T lym­
phocytes that modulate both differentiation of B cells and activation of
CD8 cytotoxic T cells.
TH1 CD4+ T cells, through elaboration of IFN-γ, have a central
role in mediating intracellular killing by a variety of pathogens. TH1
CD4+ T cells also provide T-cell help for generation of cytotoxic T cells
and some types of opsonizing antibody, and they generally respond
to antigens that lead to delayed hypersensitivity types of immune
responses for many intracellular viruses and bacteria (such as HIV-1 or
M. tuberculosis). In contrast, TH2 cells have a primary role in regula­
tory humoral immunity and isotype switching. TH2 cells, through
production of IL-4 and IL-10, have a regulatory role in limiting proin­
flammatory responses mediated by TH1 cells (Fig. 360-2). In addition,
TH2 CD4+ T cells provide help to B cells for specific Ig production
and respond to antigens that require high antibody levels for foreign
antigen elimination (extracellular encapsulated bacteria such as Strep­
tococcus pneumoniae and certain parasite infections). TH17 cells secrete
cytokines IL-17, -22, and -26 and have been shown to play a role in
autoimmune inflammatory disorders in addition to defense against
extracellular bacteria and fungi, particularly at mucosal surfaces. TH9
cells are defined by their secretion of IL-9 and have been shown to play
a role in atopic disease, inflammatory bowel disease, and antitumor
immunity. Moreover, the TFH subset of helper T cells secrete IL-21
and is crucial for providing the necessary signals to B cells in germinal
centers to undergo affinity maturation. TFH13 cells secrete IL-4, IL-5,
and IL-13 in response to allergens and and have been postulated to
mediate anaphylaxis reactions (Fig. 360-2). In summary, the type of
T-cell response generated in an immune response is determined by
the microbe PAMPs presented to the DCs, the TLRs on the DCs that
become activated, the types of DCs that are activated, and the cytokines
that are produced (Table 360-7). Commonly, myeloid DCs produce IL-12
and activate TH1 T-cell responses that result in IFN-γ and cytotoxic
T-cell induction, and plasmacytoid DCs produce IFN-α and lead to
TH2 responses that result in IL-4 production and enhanced antibody
responses.
PART 11
Immune-Mediated, Inflammatory, and Rheumatologic Disorders
As shown in Fig. 360-2, upon activation by DCs, T-cell subsets that
produce IL-2, IL-3, IFN-γ, and/or IL-4, -5, -6, -10, and -13 are gener­
ated and exert positive and negative influences on effector T and B
cells. For B cells, trophic effects are mediated by a variety of cytokines,
particularly T cell–derived IL-3, -4, -5, and -6, that act at sequential
stages of B-cell maturation, resulting in B-cell proliferation, differentia­
tion, and ultimately antibody secretion. For cytotoxic T cells, trophic
factors include inducer T-cell secretion of IL-2, IFN-γ, and IL-12.
Important types of immunomodulatory T cells that control immune
responses are CD4 and CD8 Treg cells. These cells express the α chain
of the IL-2 receptor (CD25), produce IL-10, and suppress both T- and
B-cell responses. T regulatory cells (Tregs) are induced by immature
DCs and play key roles in maintaining tolerance to self-antigens. Loss
of Treg cells is the cause of organ-specific autoimmune disease in mice
such as autoimmune thyroiditis, adrenalitis, and oophoritis and plays a
role in inflammatory bowel disease (see “Immune Tolerance and Auto­
immunity” below, Chap. 361). Tregs also play key roles in controlling
the magnitude and duration of immune responses to microbes. Nor­
mally, after the initial immune response to a microbe has eliminated
the invader, Tregs are activated to suppress the antimicrobe response
and prevent host injury. Some microbes have adapted to induce Treg
activation at the site of infection to promote parasite infection and sur­
vival. In Leishmania infection, the parasite induces Treg accumulation
at skin infection sites that dampens anti-Leishmania T-cell responses
and prevents parasite elimination. Although B cells recognize native
antigen via B-cell surface Ig receptors, B cells require T-cell help to
produce high-affinity antibody of multiple isotypes that are the most
effective in eliminating foreign antigen. In B-cell germinal centers,
CD4 T cells that promote B-cell maturation and affinity maturation
are termed T follicular helper (TFH) cells. T cell–B cell interactions
that lead to high-affinity antibody production require (1) processing
of native antigen by B cells and expression of peptide fragments on the
B-cell surface for presentation to TH cells, (2) the ligation of B cells by
both the TCR complex and the CD40 ligand, (3) induction of the pro­
cess termed antibody isotype switching in antigen-specific B-cell clones,
and (4) induction of the process of affinity maturation of antibody in
the germinal centers of B-cell follicles of lymph node and spleen.
Naïve B cells express cell-surface IgD and IgM, and initial contact
of naïve B cells with antigen is via binding of native antigen to B-cell
surface IgM. T-cell cytokines, released following TH2 cell contact with
B cells or by a “bystander” effect, induce changes in Ig gene conforma­
tion that promote recombination of Ig genes. These events then result
in the switching of expression of heavy chain exons in a triggered B
cell, leading to the secretion of IgG, IgA, or, in some cases, IgE antibody
with the same V region antigen specificity as the original IgM antibody,
for response to a wide variety of extracellular bacteria, protozoa, and
helminths. CD40 ligand expression by activated T cells is critical for
induction of B-cell antibody isotype switching and for B-cell respon­
siveness to cytokines. Patients with mutations in T-cell CD40 ligand
have B cells that are unable to undergo isotype switching, resulting
in lack of memory B-cell generation and the immunodeficiency syn­
drome of X-linked hyper-IgM syndrome (Chaps. 361 and 362).
■
■IMMUNE TOLERANCE AND AUTOIMMUNITY
Immune tolerance is defined as the absence of activation of pathogenic
autoreactivity to self-antigens. Mechanisms of immune tolerance can
be classified as cell intrinsic or cell extrinsic. Cell intrinsic mechanisms
of tolerance include apoptosis and induction of cell unresponsiveness
(anergy). Mechanisms of cell extrinsic tolerance include suppression
of immune responses by immunomodulatory cells such as Tregs.
Autoimmune diseases are syndromes caused by the activation of T or
B cells or both, with no evidence of other causes such as infections or
malignancies (Chaps. 361 and 367). Low levels of autoreactivity of T
and B cells with self-antigens in the periphery are critical to T- and
B-cell survival. Similarly, low levels of autoreactivity and thymocyte
recognition of self-antigens in the thymus are the mechanisms whereby
normal T cells are positively selected to survive and leave the thymus to
respond to foreign microbes in the periphery and T cells highly reac­
tive to self-antigens are negatively selected and die to prevent overly
self-reactive T cells from migrating to the periphery (central toler­
ance). Unlike the presentation of microbial antigens by mature DCs,
the presentation of self-antigens by immature DCs neither activates
nor matures the DCs to express high levels of co-stimulatory molecules
such as B7-1 (CD80) or B7-2 (CD86). When peripheral T cells are
stimulated by DCs expressing self-antigens in the context of HLA mol­
ecules, sufficient stimulation of T cells occurs to keep them alive, but
otherwise, they remain anergic, or nonresponsive, until T cells contact
a DC with high levels of co-stimulatory molecules expressing microbial
antigens and become activated to respond to the microbe. If B cells
have high self-reactive BCRs, they normally undergo either deletion
in the bone marrow or receptor editing to express a less autoreactive
receptor. Although many autoimmune diseases are characterized by
abnormal or pathogenic autoantibody production (see Chap. 361,
Table 361-4), most autoimmune diseases are caused by a combination
of excess T- and B-cell reactivity.
Multiple factors contribute to the genesis of autoimmune disease
syndromes, including genetic susceptibility (e.g., HLA-B27 with anky­
losing spondylitis), environmental immune stimulants such as drugs
(e.g., procainamide and phenytoin [Dilantin] with drug-induced
systemic lupus erythematosus), infectious agent triggers (e.g., EpsteinBarr virus and autoantibody production against red blood cells and
platelets), and loss of Treg cells (leading to thyroiditis, adrenalitis, and
oophoritis).
Immunity at Mucosal Surfaces 
Mucosa covering the respiratory,
digestive, and urogenital tracts; the eye conjunctiva; the inner ear; and
the ducts of all exocrine glands contain cells of the innate and adaptive
mucosal immune system that protect these surfaces against pathogens.
In the healthy adult, mucosa-associated lymphoid tissue (MALT)
contains 80% of all immune cells within the body and constitutes the
largest mammalian lymphoid organ system.
MALT has three main functions: (1) to protect the mucous mem­
branes from invasive pathogens; (2) to prevent uptake of foreign anti­
gens from food, commensal organisms, and airborne pathogens and
particulate matter; and (3) to prevent pathologic immune responses
from foreign antigens if they do cross the mucosal barriers of the body.
MALT is a compartmentalized system of immune cells that func­
tions independently from systemic immune organs. Whereas the
systemic immune organs are essentially sterile under normal condi­
tions and respond vigorously to pathogens, MALT immune cells are
continuously bathed in foreign proteins and commensal bacteria, and
they must select those pathogenic antigens that must be eliminated.
MALT contains anatomically defined foci of immune cells in the
intestine, tonsil, appendix, and peribronchial areas that are inductive
sites for mucosal immune responses. From these sites, immune T and
B cells migrate to effector sites in mucosal parenchyma and exocrine
glands where mucosal immune cells eliminate pathogen-infected cells.
In addition to mucosal immune responses, all mucosal sites have
strong mechanical and chemical barriers and cleansing functions to
repel pathogens.
Key components of MALT include specialized epithelial cells called
“membrane” or “M” cells that take up antigens and deliver them to DCs
or other APCs. Regulatory cells that maintain gut homeostasis include
ILC APCs, likely ILC3, that drive the development of CD4 Tregs that
suppress pathogenic immune responses to benign commensal micro­
biota. Effector cells in MALT include B cells producing antipathogen
neutralizing antibodies of secretory IgA as well as IgG isotype, T cells
producing similar cytokines as in systemic immune responses, and T
helper and cytotoxic T cells that respond to pathogen-infected cells.
Secretory IgA is produced in amounts of >50 mg/kg of body weight
per 24 h and functions to inhibit bacterial adhesion, inhibit macromol­
ecule absorption in the gut, neutralize viruses, and enhance antigen
elimination in tissue through binding to IgA and receptor-mediated
transport of immune complexes through epithelial cells.
Recent studies have demonstrated the importance of commensal
gut and other mucosal bacteria to the health of the human immune
system. Normal commensal flora induces anti-inflammatory events
in the gut and protects epithelial cells from pathogens through TLRs
and other PRR signaling. When the gut is depleted of normal com­
mensal flora, the immune system becomes abnormal, with loss of TH1
T-cell function. Restoration of the normal gut flora can reestablish the
balance in Treg and T helper cell ratios characteristic of the normal
immune system. Diet also has an impact on the gut microbiome.
Altered microbiome composition has been etiologically related to
obesity, insulin resistance, inflammatory bowel disease, and diabetes.
When the gut barrier is intact, either antigens do not transverse the
gut epithelium or, when pathogens are present, a self-limited, protec­
tive MALT immune response eliminates the pathogen. However, when
the gut barrier breaks down, immune responses to commensal flora
antigens can contribute to Crohn’s disease and, perhaps, ulcerative colitis
(Chap. 337). Uncontrolled MALT immune responses to food antigens,
such as gluten, can cause celiac disease (Chap. 337).
■
■THE CELLULAR AND MOLECULAR CONTROL OF
PROGRAMMED CELL DEATH
The process of apoptosis (programmed cell death) plays a crucial
role in regulating normal immune responses to antigen. In general,
a wide variety of stimuli trigger one of several apoptotic pathways to
eliminate microbe-infected cells, eliminate cells with damaged DNA,
or eliminate activated immune cells that are no longer needed. The
largest known family of “death receptors” is the TNF receptor (TNF-R)
family (TNF-R1, TNF-R2, Fas [CD95], death receptor 3 [DR3], death
receptor 4 [DR4; TNF-related apoptosis-including ligand receptor 1,
or TRAIL-R1], and death receptor 5 [DR5, TRAIL-R2]); their ligands
are all in the TNF-α family. Binding of ligands to these death recep­
tors leads to a signaling cascade that involves activation of the caspase
family of molecules that leads to DNA cleavage and cell death. Two
other pathways of programmed cell death involve nuclear p53 in the
elimination of cells with abnormal DNA and mitochondrial cytochrome
c to induce cell death in damaged cells. A number of human diseases
have now been described that result from, or are associated with,
mutated apoptosis genes. These include mutations in the Fas and Fas
ligand genes in autoimmune and lymphoproliferation syndromes, and
multiple associations of mutations in genes in the apoptotic pathway
with malignant syndromes (Chap. 361).
■
■MECHANISMS OF IMMUNE-MEDIATED DAMAGE
TO MICROBES OR HOST TISSUES
Several responses by the host innate and adaptive immune systems
to foreign microbes culminate in rapid and efficient elimination of
microbes. In these scenarios, the classic weapons of the adaptive
immune system (T cells, B cells) interface with cells (macrophages,
DCs, NK cells, neutrophils, eosinophils, basophils) and soluble prod­
ucts (microbial peptides, pentraxins, complement and coagulation
systems) of the innate immune system (Chaps. 67 and 363).
There are five general phases of host defenses: (1) migration of
leukocytes to sites of antigen localization; (2) antigen-nonspecific rec­
ognition of pathogens by macrophages and other cells and systems of
the innate immune system; (3) specific recognition of foreign antigens
mediated by T and B lymphocytes; (4) amplification of the inflamma­
tory response with recruitment of specific and nonspecific effector
cells by complement components, cytokines, kinins, arachidonic acid
metabolites, and mast cell–basophil products; and (5) macrophage,
neutrophil, and lymphocyte participation in destruction of antigen
with ultimate removal of antigen particles by phagocytosis (by macro­
phages or neutrophils) or by direct cytotoxic mechanisms (involving
macrophages, neutrophils, DCs, or lymphocytes). Under normal cir­
cumstances, orderly progression of host defenses through these phases
results in a well-controlled immune and inflammatory response that
protects the host from the offending antigen. However, dysfunction of
any of the host defense systems can damage host tissue and produce
clinical disease. Furthermore, for certain pathogens or antigens, the nor­
mal immune response itself might contribute substantially to the tissue
damage. For example, the immune and inflammatory response in the
brain to certain pathogens such as M. tuberculosis may be responsible
for much of the morbidity rate of this disease in that organ system
(Chap. 183). In addition, the morbidity rate associated with certain
pneumonias such as that caused by Pneumocystis jirovecii may be
associated more with inflammatory infiltrates than with the tissuedestructive effects of the microorganism itself (Chap. 227).
CHAPTER 360
Introduction to the Immune System
Molecular Basis of Lymphocyte–Endothelial Cell Interac­
tions 
The control of lymphocyte circulatory patterns between the
bloodstream and peripheral lymphoid organs operates at the level of
lymphocyte–endothelial cell interactions to control the specificity of
lymphocyte subset entry into organs. Similarly, lymphocyte–endothelial
cell interactions regulate the entry of lymphocytes into inflamed tissue.
Adhesion molecule expression on lymphocytes and endothelial cells
regulates the retention and subsequent egress of lymphocytes within
tissue sites of antigenic stimulation, delaying cell exit from tissue and
preventing reentry into the circulating lymphocyte pool (Fig. 360-9). All
types of lymphocyte migration begin with lymphocyte attachment to
specialized regions of vessels, termed high endothelial venules (HEVs).
An important concept is that adhesion molecules do not generally bind
their ligand until a conformational change (ligand activation) occurs
in the adhesion molecule that allows ligand binding. Induction of a
conformation-dependent determinant on an adhesion molecule can be
accomplished by cytokines or via ligation of other adhesion molecules
on the cell.
The first stage of lymphocyte–endothelial cell interactions, attach­
ment and rolling, occurs when lymphocytes leave the stream of flowing
blood cells in a postcapillary venule and roll along venule endothelial
cells (Fig. 360-9). Lymphocyte rolling is mediated by the l-selectin
molecule (LECAM-1, LAM-1, CD62L) and slows cell transit time
through venules, allowing time for activation of adherent cells.
The second stage of lymphocyte–endothelial cell interactions, firm
adhesion with activation-dependent stable arrest, requires stimulation
of lymphocytes by chemoattractants or by endothelial cell–derived
cytokines. Cytokines thought to participate in adherent cell activa­
tion include members of the IL-8 family, platelet-activation factor,
leukotriene B4, and C5a. In addition, HEVs express chemokines, SLC
(CCL21) and ELC (CCL19), which participate in this process. Fol­
lowing activation by chemoattractants, lymphocytes shed l-selectin
from the cell surface and upregulate cell CD11b/18 (MAC-1) or
CD11a/18 (LFA-1) molecules, resulting in firm attachment of lym­
phocytes to HEVs.
Lymphocyte homing to peripheral lymph nodes involves adhesion
of l-selectin to glycoprotein HEV ligands collectively referred to as
peripheral node addressin (PNAd), whereas homing of lymphocytes
to intestine Peyer’s patches primarily involves adhesion of the a4β7
integrin to mucosal addressin cell adhesion molecule-1 (MAdCAM-1)
on the Peyer’s patch HEVs. However, for migration to mucosal Peyer’s
patch lymphoid aggregates, naïve lymphocytes primarily use l-selectin,
whereas memory lymphocytes use α4β7 integrin. α4β1 integrin
(CD49d/CD29, VLA-4)–VCAM-1 interactions are important in the
initial interaction of memory lymphocytes with HEVs of multiple
organs in sites of inflammation.
The third stage of leukocyte emigration in HEVs is sticking and
arrest. Sticking of the lymphocyte to endothelial cells and arrest at
the site of sticking are mediated predominantly by ligation of a1β2
integrin LFA-1 to the integrin ligand ICAM-1 on HEVs. Whereas the
first three stages of lymphocyte attachment to HEVs take only a few
seconds, the fourth stage of lymphocyte emigration, transendothelial
migration, takes ~10 min. Although the molecular mechanisms that
control lymphocyte transendothelial migration are not fully character­
ized, the HEV CD44 molecule and molecules of the HEV glycocalyx
(extracellular matrix) are thought to play important regulatory roles in
Blood vessel lumen
Tethering
and rolling
Chemokine
signal
Arrest
Polarization and
diapedesis
PART 11
Immune-Mediated, Inflammatory, and Rheumatologic Disorders
Basement
membrane
DC
Lymph vessel
DC migration
to draining LN
Inflammatory
chemoattractants
Selectin
sialomucin
Resting
actve
integrins
Collagen
FIGURE 360-9  Key migration steps of immune cells at sites of inflammation. Inflammation due to tissue damage or infection induces the release of cytokines (not shown)
and inflammatory chemoattractants (red arrowheads) from distressed stromal cells and “professional” sentinels, such as mast cells and macrophages (not shown). The
inflammatory signals induce upregulation of endothelial selectins and immunoglobulin “superfamily” members, particularly ICAM-1 and/or VCAM-1. Chemoattractants,
particularly chemokines, are produced by or translocated across venular endothelial cells (red arrow) and are displayed in the lumen to rolling leukocytes. Those leukocytes
that express the appropriate set of trafficking molecules undergo a multistep adhesion cascade (steps 1–3) and then polarize and move by diapedesis across the venular
wall (steps 4 and 5). Diapedesis involves transient disassembly of endothelial junctions and penetration through the underlying basement membrane (step 6). Once in the
extravascular (interstitial) space, the migrating cell uses different integrins to gain “footholds” on collagen fibers and other ECM molecules, such as laminin and fibronectin,
and on inflammation-induced ICAM-1 on the surface of parenchymal cells (step 7). The migrating cell receives guidance cues from distinct sets of chemoattractants,
particularly chemokines, which may be immobilized on glycosaminoglycans (GAG) that “decorate” many ECM molecules and stromal cells. Inflammatory signals also
induce tissue dendritic cells (DCs) to undergo maturation. Once DCs process material from damaged tissues and invading pathogens, they upregulate CCR7, which allows
them to enter draining lymph vessels that express the CCR7 ligand CCL21 (and CCL19). In lymph nodes (LNs), these antigen-loaded mature DCs activate naïve T cells and
expand pools of effector lymphocytes, which enter the blood and migrate back to the site of inflammation. T cells in tissue also use this CCR7-dependent route to migrate
from peripheral sites to draining lymph nodes through afferent lymphatics. (Reproduced with permission from AD Luster et al: Immune cell migration in inflammation: present
and future therapeutic targets. Nat Immunol 6:1182, 2005.)
this process (Fig. 360-10). Finally, expression of matrix metalloprote­
ases capable of digesting the subendothelial basement membrane, rich
in nonfibrillar collagen, appears to be required for the penetration of
lymphoid cells into the extravascular sites.
Abnormal induction of HEV formation and use of the molecules
discussed above have been implicated in the induction and mainte­
nance of inflammation in a number of chronic inflammatory diseases.
In animal models of type 1 diabetes mellitus, MAdCAM-1 and GlyCAM-1
have been shown to be highly expressed on HEVs in inflamed pancre­
atic islets, and treatment of these animals with inhibitors of l-selectin
and a4 integrin function blocked the development of type 1 diabetes
mellitus (Chap. 415). A similar role for abnormal induction of the
adhesion molecules of lymphocyte emigration has been suggested in
rheumatoid arthritis (Chap. 370), Hashimoto’s thyroiditis (Chap. 394),
Graves’ disease (Chap. 394), multiple sclerosis (Chap. 455), Crohn’s disease
(Chap. 337), and ulcerative colitis (Chap. 337).
Immune-Complex Formation 
Clearance of antigen by immunecomplex formation between antigen, complement, and antibody is
a highly effective mechanism of host defense. However, depending
Junctional
rearrangement
Proteolysis
Cytokinestimulated
parenchymal
cell
Damaged
or inflamed
tissue
Interstitial
migration
ECM with GAG
GPCR
CCL19
CCL21
CCR7
ICAM-1
or
VCAM-1
on the level of immune complexes formed and their physicochemi­
cal properties, immune complexes may or may not result in host and
foreign cell damage. After antigen exposure, certain types of soluble
antigen-antibody complexes freely circulate and, if not cleared by the
reticuloendothelial system, can be deposited in blood vessel walls
and in other tissues such as renal glomeruli and cause vasculitis or
glomerulonephritis syndromes (Chaps. 326 and 375). Deficiencies of
early complement components are associated with inefficient clearance
of immune complexes and immune complex–mediated autoimmune
syndromes or encapsulated bacterial infections such as S. pneumoniae,
whereas deficiencies of the later complement components are associ­
ated with susceptibility to recurrent Neisseria infections (Table 360-12).
Immediate-Type Hypersensitivity 
Helper T cells that drive
antiallergen IgE responses are usually TH2-type inducer T cells that
secrete IL-4, IL-5, IL-6, and IL-10. A subset of TFH, TFH13, cells
have been identified that produce IL-4, IL-5, and IL-13, which play
a key role in responses to allergens that induce IgE and mediate ana­
phylaxis. Mast cells and basophils have high-affinity receptors for the
Fc portion of IgE (FcRI), and cell-bound antiallergen IgE effectively
TABLE 360-12  Complement Deficiencies and Associated Diseases
COMPONENT
ASSOCIATED DISEASES
Classic Pathway
Clq, Clr, Cls, C4
Immune-complex syndromes,a pyogenic infections
C2
Immune-complex syndromes,a few with pyogenic infections
C1 inhibitor
Rare immune-complex disease, few with pyogenic infections
C3 and Alternative Pathway C3
C3
Immune-complex syndromes,a pyogenic infections
D
Pyogenic infections
Properdin
Neisseria infections
I
Pyogenic infections
H
Hemolytic-uremic syndrome
Membrane Attack Complex
C5, C6, C7, C8
Recurrent Neisseria infections, immune-complex disease
C9
Rare Neisseria infections
aImmune-complex syndromes include systemic lupus erythematosus (SLE) and
SLE-like syndromes, glomerulonephritis, and vasculitis syndromes.
Source: After JA Schifferli, DK Peters: Lancet 322:957, 1983. Copyright 1983.
“arms” basophils and mast cells. Mediator release is triggered by
antigen (allergen) interaction with Fc receptor-bound IgE, and the
mediators released are responsible for the pathophysiologic changes of
allergic diseases. Mediators released from mast cells and basophils can
be divided into three broad functional types: (1) those that increase
vascular permeability and contract smooth muscle (histamine, plateletactivating factor, SRS-A, BK-A), (2) those that are chemotactic for or
activate other inflammatory cells (ECF-A, NCF, leukotriene B4), and
(3) those that modulate the release of other mediators (BK-A, plateletactivating factor) (Chap. 363).
Cytotoxic Reactions of Antibody 
In this type of immunologic
injury, complement-fixing (C1-binding) antibodies against normal or
foreign cells or tissues (IgM, IgG1, IgG2, IgG3) bind complement via the
classic pathway and initiate a sequence of events similar to that initiated
by immune-complex deposition, resulting in cell lysis or tissue injury.
Examples of antibody-mediated cytotoxic reactions include red cell lysis
in transfusion reactions, Goodpasture’s syndrome with anti–glomerular
basement membrane antibody formation, and pemphigus vulgaris with
anti-epidermal antibodies inducing blistering skin disease.
Delayed-Type Hypersensitivity Reactions 
Inflammatory
reactions initiated by mononuclear leukocytes and not by antibody
alone have been termed delayed-type hypersensitivity reactions. The
term delayed has been used to contrast a secondary cellular response
that appears 48–72 h after antigen exposure with an immediate hyper­
sensitivity response generally seen within 12 h of antigen challenge
and initiated by basophil mediator release or preformed antibody.
For example, in an individual previously infected with M. tuberculo­
sis organisms, intradermal placement of tuberculin purified protein
derivative as a skin test challenge results in an indurated area of skin at
48–72 h, indicating previous exposure to tuberculosis.
The cellular events that result in classic delayed-type hypersensitiv­
ity responses are centered on T cells (predominantly, although not
exclusively, IFN-γ, IL-2, and TNF-α-secreting TH1-type helper T cells)
and macrophages. Recently, NK cells have been suggested to play a
major role in the form of delayed hypersensitivity that occurs follow­
ing skin contact with immunogens. First, local immune and inflam­
matory responses at the site of foreign antigen upregulate endothelial
cell adhesion molecule expression, promoting the accumulation of
lymphocytes at the tissue site. In the scheme outlined in Fig. 360-2,
antigen is processed by DCs and presented to small numbers of CD4+
T cells expressing a TCR specific for the antigen. IL-12 produced by
APCs induces T cells to produce IFN-γ (TH1 response). Macrophages
frequently undergo epithelioid cell transformation and fuse to form
multinucleated giant cells in response to IFN-γ. This type of mono­
nuclear cell infiltrate is termed granulomatous inflammation. Examples
of diseases in which delayed-type hypersensitivity plays a major role
are fungal infections (histoplasmosis; Chap. 218), mycobacterial infec­
tions (tuberculosis, leprosy; Chaps. 183 and 184), chlamydial infections
(lymphogranuloma venereum; Chap. 194), helminth infections (schis­
tosomiasis; Chap. 241), reactions to toxins (berylliosis; Chap. 300), and
hypersensitivity reactions to organic dusts (hypersensitivity pneumoni­
tis; Chap. 299). In addition, delayed-type hypersensitivity responses
play important roles in tissue damage in autoimmune diseases such as
rheumatoid arthritis, temporal arteritis, and granulomatosis with poly­
angiitis (Chaps. 370 and 375).
CHAPTER 360
Introduction to the Immune System
Autophagy 
Autophagy is a process that involves a lysosomal deg­
radation pathway mechanism of cells to dispose of intracellular debris
and damaged organelles. Autophagy by cells of the innate immune sys­
tem is used to control intracellular infectious agents such as M. tuber­
culosis, in part by initiation of phagosome maturation and enhancing
MHC class II antigen presentation to CD4 T cells.
■
■CLINICAL EVALUATION OF IMMUNE FUNCTION
Clinical assessment of immunity requires investigation of the four
major components of the immune system that participate in host
defense and in the pathogenesis of autoimmune diseases: (1) humoral
immunity (B cells); (2) cell-mediated immunity (T cells, monocytes);
(3) phagocytic cells of the reticuloendothelial system (macrophages),
as well as polymorphonuclear leukocytes; and (4) complement. Clini­
cal problems that require an evaluation of immunity include chronic
infections, recurrent infections, unusual infecting agents, and certain
autoimmune syndromes. The type of clinical syndrome under evalu­
ation can provide information regarding possible immune defects
(Chap. 362). Defects in cellular immunity generally result in viral,
mycobacterial, and fungal infections. An extreme example of defi­
ciency in cellular immunity is AIDS (Chap. 208). Antibody deficien­
cies result in recurrent bacterial infections, frequently with organisms
such as S. pneumoniae and Haemophilus influenzae (Chap. 362). Dis­
orders of phagocyte function are frequently manifested by recurrent
skin infections, often due to Staphylococcus aureus (Chap. 67). Finally,
deficiencies of early and late complement components are associated
with autoimmune phenomena and recurrent Neisseria infections
(Table 360-12). Artificial intelligence/machine learning algorithms are
now being tested for improving the diagnosis of infectious, immune
deficiency, and autoimmune diseases. For further discussion of useful
initial screening tests of immune function, see Chap. 362.
■
■IMMUNOTHERAPY
Many therapies for autoimmune and inflammatory diseases involve the
use of nonspecific immune-modulating or immunosuppressive agents
such as glucocorticoids or cytotoxic drugs. The goal of development
of new treatments for immune-mediated diseases is to design ways to
specifically interrupt pathologic immune responses, leaving nonpatho­
logic immune responses intact (Chap. 361). Novel ways to interrupt
pathologic immune responses that are under investigation include the
use of anti-inflammatory cytokines or specific cytokine inhibitors as
anti-inflammatory agents, the use of monoclonal antibodies against T
or B lymphocytes as therapeutic agents, the use of intravenous Ig for
certain infections and immune complex–mediated diseases, the use of
specific cytokines to reconstitute components of the immune system,
and bone marrow transplantation to replace the pathogenic immune
system with a more normal immune system (Chaps. 67, 208, 361,
and 362). CTLA-4 inhibitors such as ipilimumab and tremelimumab
and anti-PD-1 antibodies such as nivolumab are termed checkpoint
inhibitors and have been shown to reverse CD8 T-cell exhaustion in
melanoma and other solid tumors and induce immune cell control of
tumor growth (Chap. 361). A technique that engineers autologous T
cells to express antibody receptors that target leukemic cells, termed
chimeric antigen receptor T cells (CAR T cells), has been approved by
the U.S. Food and Drug Administration (FDA) for the treatment of
certain types of leukemias and lymphomas (Chap. 361).
Cell-based therapies have been studied for many years, includ­
ing ex vivo activation of NK cells for reinfusion into patients with

07 - 364 Anaphylaxis
364 Anaphylaxis
PART 11
Immune-Mediated, Inflammatory, and Rheumatologic Disorders
Anaphylaxis
David Hong, Joshua A. Boyce
■
■BACKGROUND
Anaphylaxis is a potentially life-threatening systemic allergic reac­
tion involving one or more organ systems that typically occurs within
seconds to minutes of exposure to the anaphylactic trigger, most often
a drug, food, or Hymenoptera sting. The term anaphylaxis was first
described in 1902 by Charles Richet and Paul Portier who attempted
to immunize dogs against sea anemone toxin in the same way Pasteur
was able to vaccinate individuals against the smallpox virus. To their
surprise, repeated administration of small, sublethal doses of sea anem­
one toxin reliably induced acute-onset death when readministered
2–3 weeks after initial “vaccination” to the toxin. The phenomenon
was termed ana (anti)-phylaxis (“protection or guarding”) because
vaccination with anemone toxin resulted in the opposite intended
immune effect. Charles Richet was awarded the Nobel Prize in Physiol­
ogy or Medicine in 1913 for this work which led to further insights into
hypersensitivity and mast cell biology.
■
■CLINICAL MANIFESTATIONS
While 80–90% of anaphylactic episodes are uniphasic, about 10–20%
of cases are biphasic, in which anaphylactic symptoms return about
an hour or longer after resolution of initial symptoms. Anaphylactic
reactions are particularly dangerous when hypotension or hypoxia
occurs, leading potentially to cardiovascular collapse or respiratory
failure, respectively. There may be upper or lower airway obstruc­
tion or both. Laryngeal edema may be experienced as a “lump” in the
throat, hoarseness, or stridor, whereas bronchial obstruction is associ­
ated with a feeling of tightness in the chest and/or audible wheezing.
Patients with underlying asthma are predisposed to severe involvement
of the lower airways and increased mortality associated with anaphy­
laxis. In fatal cases with clinical bronchial obstruction, the lungs show
marked hyperinflation on gross and microscopic examination. The
microscopic findings in the bronchi, however, are limited to luminal
secretions, peribronchial congestion, submucosal edema, and eosino­
philic infiltration, and the acute emphysema is attributed to intractable
bronchospasm that subsides with death. Angioedema resulting in
death by mechanical obstruction occurs in the epiglottis and larynx.
This process can also be evident in the hypopharynx and trachea.
On microscopic examination, there is wide separation of the collagen
fibers and the glandular elements. Vascular congestion and eosino­
philic infiltration may also be present. Patients dying of vascular col­
lapse without antecedent hypoxia from respiratory insufficiency have
visceral congestion with a presumed loss of intravascular fluid volume.
The associated electrocardiographic abnormalities in some patients,
with or without infarction, may reflect a primary cardiac event medi­
ated by mast cells (which are prominent near the coronary vessels) or
may be secondary to a critical reduction in intravascular volume.
Gastrointestinal manifestations represent another severe presenta­
tion of anaphylaxis and include nausea, vomiting, crampy abdominal
pain, and/or fecal incontinence. Angioedema of the bowel wall may
also cause sufficient intravascular volume depletion to precipitate car­
diovascular collapse.
Cutaneous manifestations are among the most common presenta­
tions of anaphylaxis (>90% of cases). Symptoms include urticarial
eruptions, flushing with diffuse erythema, and/or a feeling of general­
ized warmth. Urticarial eruptions are intensely pruritic and may be
localized or disseminated. They may coalesce to form large urticarial
plaques but seldom persist beyond 48 h.
■
■PATHOPHYSIOLOGY
Many of the important early mediators of anaphylaxis are derived from
mast cells, basophils, and eosinophils. Mast cells contain preformed
granules comprised of histamine, proteases (tryptase, chymase), pro­
teoglycans (heparin, chondroitin sulfate), and tumor necrosis factor-α,
which are rapidly released into surrounding tissue upon cell activation,
a process known as degranulation. Basophils, like mast cells, contain
and release histamine. Mast cells, basophils, and eosinophils are also
sources of arachidonic acid–derived products, which include cysteinyl
leukotrienes, prostaglandins, and platelet-activating factor (PAF).
Histamine release results in flushing, urticaria, pruritus, and, in high
concentrations, hypotension and tachycardia. Cysteinyl leukotrienes
and prostaglandin D2 cause bronchoconstriction and increased micro­
vascular permeability. Prostaglandin D2 causes cutaneous flushing and
attracts eosinophils and basophils to the site of mast cell activation.
Serum PAF levels correlate with anaphylaxis severity and are inversely
proportional to the constitutive level of PAF acetylhydrolase, which
is necessary for PAF inactivation. Tryptase and chymase can activate
complement and coagulation pathways. Activation of these pathways
results in production of the anaphylatoxins, C3a and C5a, and activa­
tion of the kallikrein-kinin system, which regulates blood pressure and
vascular permeability. The actions of these anaphylactic mediators are
likely additive or synergistic at the target tissues.
■
■PREDISPOSING FACTORS AND MECHANISMS
Because the most dangerous manifestations of anaphylaxis involve
the cardiovascular and/or respiratory systems, preexisting asthma and
underlying cardiovascular disease could lead to more rapid decompen­
sation from anaphylaxis. Atopy is not generally thought to be a risk fac­
tor for anaphylaxis from drug reactions or Hymenoptera stings, but it is
associated with radiocontrast sensitivity, exercise-induced anaphylaxis,
idiopathic anaphylaxis, and allergy to foods or latex. Severe Hyme­
noptera-induced anaphylaxis (generally with prominent hypotension)
is the most common initial presentation for patients with underlying
systemic mastocytosis. For this reason, it is important to check a base­
line tryptase (a reflection of mast cell burden) in patients who present
with sting-induced anaphylaxis to screen for this condition. Hyme­
noptera allergy is also more likely in patients whose occupations (i.e.,
beekeepers, trash haulers, and landscape workers) place them in regu­
lar proximity to stinging insects. Most commonly, allergen-induced
cross-linking of IgE-bound FcεRI receptors on mast cells and basophils
initiates the signal transduction events leading to hypersensitivity
syndromes, including anaphylaxis. The generation of allergen-specific
IgE is the end result of sensitization via the adaptive immune system.
While the mechanisms underlying sensitization are beyond the scope
of this chapter, environmental factors, innate immune responses, and
cytokines are among the many variables leading to antigen-specific IgE
production by B cells and plasma cells. IgE-mediated drug allergies
are most common with antibiotics and certain chemotherapy drugs,
though theoretically, they can occur with almost any medication. As
is the case with environmental allergies, repeated exposure to the
allergy-causing antigen is an important risk factor to keep in mind
when evaluating patients with anaphylaxis. In the case of allergy to
carboplatin, the incidence of hypersensitivity is 27% in patients who
have had ≥7 lifetime infusions and as high as 46% in patients who
have had ≥15 lifetime infusions. Similarly, patients with cystic fibrosis
have a relatively high incidence of allergic reactions to IV antibiotics,
particularly beta-lactams, that they receive periodically for intermittent
“clean-outs” to maintain airway clearance. Drugs can also function as
haptens that form immunogenic conjugates with host proteins. The
conjugating hapten may be the parent compound, a nonenzymatically
derived storage product, or a metabolite formed in the host. Recom­
binant biologics in some cases can also induce the formation of IgE
against the proteins or against glycosylated structures that serve as
immunogens. Outbreaks of anaphylaxis to the epidermal growth factor
receptor (EGFR) antibody, cetuximab, have been reported in associa­
tion with elevated titers of serum IgE to alpha-1,3-galactose (alphagal), an oligosaccharide found in nonprimate mammals. Cetuximab
is derived from a mouse cell line expressing a transferase that tags the
Fab′ portion of the cetuximab heavy chain with alpha-gal. Interestingly,
patients with a history of multiple bites from Amblyomma americanum
ticks commonly found in the Carolinas, Arkansas, and Tennessee are
more likely to have anti-alpha-gal IgE as compared to patients living
outside those states. A subset of individuals with anti-alpha-gal IgE
can develop episodes of delayed-onset anaphylaxis about 3–6 h after
consuming mammalian meat (beef, lamb, or pork) in a condition now
known as alpha-gal syndrome (AGS). The mechanisms behind AGS
are not yet well understood.
It is also important to remember that allergic reactions caused by the
effector cells and mediators described previously can be triggered by a
variety of mechanisms that may not require the presence of sensitizing
IgE. Non-IgE-mediated mast cell activation secondary to certain drugs
is clinically indistinguishable from classical IgE-mediated hypersensi­
tivity reactions but can occur with first known exposure since there
is no prior need for mast cell sensitization by IgE. MRGPRX2, a G
protein–coupled receptor that is highly expressed in skin mast cells,
has been shown in mouse models and in vitro studies using human
cells to induce mast cell activation and mediator release secondary to
neuromuscular blocking drugs (NMBDs), quinolones, and icatibant.
These findings are clinically significant since NMBDs are needed for
procedures done under general anesthesia while quinolones are a
commonly used antibiotic family. Icatibant, a bradykinin-2 receptor
antagonist administered by subcutaneous injection for the treatment of
acute attacks of hereditary angioedema, is known to frequently result
in local injection site reactions. Another example of non-IgE-mediated
anaphylaxis is demonstrated with paclitaxel, a chemotherapy agent
most commonly used in combination with carboplatin to treat ovar­
ian cancer. It is derived from yew tree bark and needles that require
polyethoxylated castor oil (Cremophor) to be solubilized into aqueous
solution. Cremophor has been shown in vitro to activate the comple­
ment cascade, resulting in complement-dependent histamine release
from mast cells and basophils. A version of paclitaxel that is solubilized
by being bound to albumin nanoparticles, Abraxane, has a far lower
rate of hypersensitivity, especially for patients who have had infusion
reactions to Cremophor-solubilized paclitaxel. Reactions such as flush­
ing, hives, angioedema, and/or anaphylaxis to radiocontrast, opiates,
vancomycin, and nonsteroidal anti-inflammatory drugs (NSAIDs) are
other examples of non-IgE-mediated hypersensitivity.
An example of non-IgE-mediated food anaphylaxis is scombroid
poisoning, caused by the ingestion of a pharmacologically significant
dose of histamine from contaminated fish. This is most commonly
associated with fish that are rich in histidine, such as mahi-mahi,
mackerel, and tuna. If improperly stored, surface contaminant bacteria
expressing histidine decarboxylase convert histidine into histamine,
which is not broken down by baking or broiling. Scombroid poison­
ing leads to symptoms including flushing, oropharyngeal pruritis/
angioedema, nausea/vomiting, and lightheadedness. Symptoms are
often self-limited but still treatable with antihistamines and, if needed,
epinephrine. Because the source of histamine is exogenous, tryptase
levels are not elevated.
A final example of non-IgE-mediated anaphylaxis occurred in
clustered cases of anaphylaxis to IV unfractionated heparin in Europe
and North America in 2008. Cases were attributable to specific lots of
heparin found to be enriched in a contaminant, oversulfated chon­
droitin sulfate (OSCS). OSCS is able to activate the contact activation
system, leading to the generation of bradykinin and the anaphylatoxins
C3a and C5a, which led to the anaphylactic symptoms. Heparin is now
routinely screened for this contaminant to prevent further outbreaks.
■
■DIAGNOSIS
The diagnosis of an anaphylactic reaction depends primarily on a his­
tory revealing the onset of symptoms and signs within seconds to min­
utes after the putative trigger is encountered. An exception is delayed
anaphylaxis to mammalian meats in patients with AGS. Table 364-1
lists other possibilities to consider on the differential for IgE-mediated
anaphylaxis. Every attempt to identify the specific cause or causes
should be made to minimize the risk of recurrent anaphylaxis. If a
particular drug or food is suspected, skin or serum-specific IgE testing
can be useful to confirm clinical suspicions. If a specific trigger cannot
be identified by history or testing, a workup of underlying baseline
atopic diatheses may be useful to identify risk factors that could play
potential contributory roles alone or in concert. In the acute setting,
laboratory biomarkers of mast cell degranulation may be useful to
TABLE 364-1  Differential Diagnoses for IgE-Mediated Anaphylaxis
CONDITION
DISTINGUISHED BY
Mastocytosis
Elevated baseline tryptase, spindleshaped mast cells (MCs) on bone marrow
CHAPTER 364
Pheochromocytoma
Elevated urine metanephrines
Carcinoid syndrome
Elevated urine 5-hydroxyindoleacetic
acid
Hereditary angioedema
Decreased C4 during attacks
Acquired angioedema
Decreased C1q
Anaphylaxis
Systemic capillary leak syndrome
Severe hypotension on presentation
with lack of response to firstline hypersensitivity medications
(epinephrine, antihistamines)
Scombroid poisoning
Tryptase not elevated; negative skin test
and oral challenge to fish
Drugs (opiates, neuromuscular
blocking agents, vancomycin),
computed tomography radiocontrast
Direct MC degranulation triggered
through MRGPRX2 receptor or other
as-yet-undetermined mechanism
document the severity of an anaphylactic episode. The most obvious
serum biomarker to assay, histamine, has an extremely short serum
half-life with a measurable time-window that expires <1 h from the
onset of anaphylaxis. A more practical and reliable biomarker is serum
tryptase, which is released from mast cells, peaks 60–90 min after the
onset of anaphylaxis, and can be measured as long as 5 h after the onset
of anaphylaxis. It may be useful to follow up an elevated tryptase mea­
surement in the acute setting with another measurement when the
patient is clinically stable to establish a baseline reference since there
is considerable variability of baseline serum tryptase (BST) within
the general population. For example, ~6% of Western populations
have hereditary alpha-tryptasemia (HAT), a mostly benign condition
featuring elevated BST due to expression of an extra allele of TPSAB1,
the gene that encodes alpha-tryptase. Some studies suggest that HAT
may be a risk factor for severe anaphylaxis and is also overrepresented
in patients with indolent mastocytosis. Another cause for temporarily
elevated BST is high environmental allergen exposure, something that
can occur, for example, in regions with distinct pollen seasons. A work­
ing group on mast cell disorders in 2010 came up with a formula to
better interpret tryptase levels since (1) the range of “normal” BST is
wide within the general population and (2) an acutely elevated tryptase
for a given patient may still fall within normal parameters if their BST
is low. The “20% + 2” rule stipulates that a tryptase level drawn in the
setting of possible anaphylaxis that is 20% above the patient’s baseline
plus 2 ng/mL is diagnostic for an acute event involving a clinically
significant degree of mast cell activation.
■
■TREATMENT
Early recognition of an anaphylactic reaction and appropriate interven­
tion are critically important because severe, even fatal, complications
can occur within minutes after symptoms first appear. The treatment
of first choice is intramuscular administration of 0.3–0.5 mL of 1:1000
(1 mg/mL) epinephrine, with repeated doses at 5- to 20-min intervals
as needed for a severe reaction. The failure to use epinephrine within
the first 20 min of symptoms is a risk factor for poor clinical outcomes
in various studies of anaphylaxis. IV fluids and vasopressor agents may
be administered in the acute medical setting if intractable hypoten­
sion occurs. Epinephrine provides both α- and β-adrenergic effects,
resulting in vasoconstriction, bronchial smooth-muscle relaxation,
and attenuation of enhanced venular permeability. Beta blockers may
attenuate this response; therefore, an alternative antihypertensive may
be considered in patients at high risk of needing emergency epineph­
rine. Oxygen alone via a nasal catheter or with nebulized albuterol may
be helpful; however, either endotracheal intubation or a tracheostomy
is mandatory for oxygen delivery if progressive hypoxia develops.
Ancillary agents such as antihistamines, glucocorticoids, and broncho­
dilators are also useful therapeutics to treat urticaria/angioedema and
bronchospasm once the patient is hemodynamically stable.

08 - 365 Desensitization
365 Desensitization
■
■PREVENTION
Avoidance 
The simplest and most straightforward approach to the
long-term management of a patient with a history of anaphylaxis is
strict avoidance of known anaphylactic triggers and education on acute
management, specifically, instructing the patient on proper use and
indications for use of self-administered epinephrine. Lifelong avoid­
ance is not easy if the trigger is an occupational exposure, Hymenop­
tera sting, a common food (i.e., peanut), or a drug representing the sole
or best therapeutic option for the patient. Special management options
may exist for these patients.
PART 11
Immune-Mediated, Inflammatory, and Rheumatologic Disorders
Venom Immunotherapy 
Patients of any age who have had docu­
mented anaphylaxis from Hymenoptera sting should be formally eval­
uated and started on venom immunotherapy (VIT) if skin or serologic
IgE testing confirms the history. Immunotherapy is a means of “toler­
izing” patients to allergen by means of serial subcutaneous administra­
tion of escalating doses of extract containing relevant allergen until
a target maintenance dose is achieved. Anaphylaxis can sometimes
occur during the course of administering immunotherapy extracts, so
formulating extracts and administering them is typically done under
the care of a specialist familiar with this type of treatment. In the
case of Hymenoptera allergy, patients receive VIT extracts containing
actual Hymenoptera venom with a maintenance dose equivalent to 2–5
stings. The recommended duration of treatment is 3–5 years; however,
some patients who have experienced severe respiratory or cardiovascu­
lar anaphylaxis are put on lifelong therapy. Patients with mastocytosis
may also require such lifelong treatment.
Preventative Tolerance Induction to Peanuts 
IgE sensitiza­
tion to foods occurs most frequently in infants and young children,
especially those with atopic dermatitis, and is a risk factor for anaphy­
laxis (although detection of specific IgE through skin or serum testing
has relatively poor predictive value). While most allergy to egg, milk,
soy, and/or wheat resolves spontaneously during childhood, ~80% of
children with peanut allergy remain sensitive for life. A sharp rise in
the prevalence of peanut allergy was also observed in the late 1990s to
early 2000s, especially in countries with Western diets where the aver­
age age of peanut introduction was age ≥3 years. Curiously, in cultures
where peanut was introduced much earlier into children’s diets, the
prevalence of peanut allergy remained low. The landmark Learning
Early About Peanut Allergy (LEAP) study demonstrated that early
introduction of peanut protein to the diet of high-risk infants (4–11
months of age with atopic dermatitis and/or egg allergy) prevented
the development of most (80% or more) peanut allergy compared with
children who did not consume peanuts (avoidance group), even when
IgE sensitization (based on positive skin test) had already developed at
the time of study entry. While the induction of tolerance at an early age
seems to be key to preventing clinical reactivity later in life, it is not yet
clear if this principle holds true for other foods commonly associated
with hypersensitivity reactions.
A relatively new treatment for patients who already suffer from
severe peanut allergy is peanut oral immunotherapy (OIT) in which
patients receive a titrating regimen of precisely dosed peanut protein in
the form of an oral capsule. The goal of peanut OIT is to raise a patient’s
threshold tolerance for accidental peanut exposure before anaphylaxis
occurs, and it is not a cure for peanut allergy. At the current time, pea­
nut is the only food for which a U.S. Food and Drug Administration
(FDA)-approved treatment exists, but research on developing OIT for
other foods, such as milk and egg, remains ongoing.
Desensitization 
For patients who have experienced anaphylaxis
from drug allergy and whose treatment regimen requires the admin­
istration of the offending drug, desensitization may be a short-term
treatment option to prevent reactions. Desensitization elicits a tem­
porary state of tolerance to the drug in sensitized, clinically reactive
patients. While it has been a proven technique for penicillin-allergic
patients for decades, desensitization has more recently been proven to
be effective for certain chemotherapy agents, especially platin-based
chemotherapy agents that can induce IgE-mediated sensitization with
repeated exposures. The exact mechanisms underlying desensitiza­
tion are not fully understood; however, temporary tolerance can be
achieved through the serial administration of gradually escalating
doses of drug, starting from extremely low doses, over the course of
hours. As long as the patient continues to receive the drug in question
at regular intervals based on drug half-life, a “desensitized” state can
also be maintained until the drug is no longer needed. While drug
desensitization certainly works for IgE-mediated reactions, it has been
performed in cases of non-IgE-mediated anaphylaxis from Cremophor-
solubilized paclitaxel as described earlier in this chapter. Drug
desensitization has also been shown by multiple groups to work for
non-IgE-mediated reactions from a variety of biologic agents, various
chemotherapy drugs, and NSAIDs. Given the complexity and variety
of possible drug reactions, the decision to desensitize, challenge, or
avoid should be made in conjunction with an allergy specialist for
complete evaluation and proper risk stratification of the different pos­
sible approaches to take.
■
■FURTHER READING
Brennan PJ et al: Hypersensitivity reactions to mAbs: 105 desensiti­
zations in 23 patients, from evaluation to treatment. J Allergy Clin
Immunol 124:1259, 2009.
Castells MC et al: Hypersensitivity reactions to chemotherapy: Out­
comes and safety of rapid desensitization in 413 cases. J Allergy Clin
Immunol 122:574, 2008.
Chung CH et al: Cetuximab-induced anaphylaxis and IgE specific for
galactose-alpha-1,3-galactose. N Engl J Med 358:1109, 2008.
Du Toit G et al: LEAP Study Team. Randomized trial of peanut con­
sumption in infants at risk for peanut allergy. N Engl J Med 373:803,
2015.
Du Toit G et al: Immune Tolerance Network LEAP-On Study Team.
Effect of avoidance on peanut allergy after early peanut consumption.
N Engl J Med 374:1435, 2016.
Lieberman P et al: Anaphylaxis—A practice parameter update 2015.
Ann Allergy Asthma Immunol 115:341, 2015.
McNeil BD et al: Identification of a mast cell-specific receptor crucial
for pseudoallergic drug reactions. Nature 519:237, 2015.
Valent P et al: Why the 20% + 2 tryptase formula is a diagnostic gold
standard for severe systemic mast cell activation and mast cell activa­
tion syndrome. Int Arch Allergy Immunol 180:44, 2019.
Mariana Castells
Desensitization
DRUG ALLERGY AND THE NEED FOR DRUG
DESENSITIZATION
Drug allergy is a rising problem, paralleling the worldwide increased
use of medications, the plethora of new targeted therapies, and the
greater longevity of patients. Allergic drug reactions decrease patients’
quality of life, limit treatment options, and can lead to vaccine hesi­
tancy, as seen for the COVID-19 mRNA vaccines. The first cases of
reported drug-induced anaphylaxis occurred shortly after the dis­
covery and therapeutic applications of penicillin in 1945, and today,
10–20% of the world’s population engaged in health care claims to
have a penicillin allergy. Truly allergic patients cannot use penicillin
and are negatively impacted by the decreased efficacy, increased costs,
and limited availability of second-line antibiotics. Similarly, the need to
avoid the offending medications in allergic patients with malignancies
and chronic inflammatory diseases can increase morbidity and impact
life expectancy.
To address the needs of drug-allergic patients, a novel modality of
drug delivery aimed at curtailing allergic symptoms has culminated
in drug desensitization (DD), a treatment option that takes advantage
of immune inhibitory mechanisms. Rapid multistep protocols that
deliver sequential small doses of drug until the target therapeutic dose
is reached in a few hours have shown outstanding safety, efficacy, and
wide applicability in thousands of patients with infections, chronic
inflammatory diseases, malignancies, and other conditions.
■
■DRUG ALLERGY DEFINITIONS AND RISK
FACTORS
Drug allergy and drug hypersensitivity are interchangeable terms
that refer to acute and delayed symptoms occurring after exposure
to medications. While there is a need to address drug-allergic
patients, those with unconfirmed allergy labels should be dela­
beled, and single-dose oral challenges have been shown to be safe
in children and adults at low risk for penicillin allergy. Drug allergy
is multifactorial and associated with female gender, specific human
leukocyte antigen (HLA) haplotypes, atopy, polypharmacy, older
age, chronic diseases, microbiome changes, and drug-dependent
factors such as the route of administration, repeated and high doses,
excipients, and glycosylation.
■
■CLASSIFYING HYPERSENSITIVITY REACTIONS
The modern classification of reactions has incorporated timing, sever­
ity, biomarkers, and new presentations to the classical Gell and Coombs
definitions. Acute or immediate reactions occur during or within 1–6 h
of drug exposure, while delayed reactions occur 6 h to several days or
weeks after drug exposure. Reactions can be mild (affecting one organ;
grade 1), moderate (affecting two or more organs; grade 2), or severe
(associated with changes in vital signs; grade 3).
■
■PHENOTYPES, ENDOTYPES, AND BIOMARKERS
The symptom presentation (phenotype) depends on the mechanisms
of the reactions (endotype). Acute reactions include infusion reactions,
type I IgE-dependent and -independent reactions, cytokine release
reactions (CRRs), and mixed reactions (type I and CRR symptoms).
Delayed reactions include type II antibody-mediated cytotoxicity; type
III immune complex–mediated reactions; and type IV reactions, which
include benign reactions, typically skin limited, and severe cutaneous
reactions with systemic symptoms (SCARS) such as Stevens-Johnson
syndrome (SJS), toxic epidermal necrolysis (TEN), drug reaction with
eosinophilia and systemic symptoms (DRESS), and acute generalized
eosinophilic pustulosis (AGEP) (Fig. 365-1). Symptoms are drug
specific, and acute musculoskeletal pain is common in reactions to
taxanes, oxaliplatin, doxorubicin, and rituximab.
Type I Reactions 
Type I reactions result from the activation of
mast cells and basophils through IgE-dependent and -independent
mechanisms. While IgE sensitization requires repeated exposures
and is typical for antibiotics, chemotherapy, and some biologicals,
IgE-independent reactions typically occur at first exposure through
either complement activation, inhibition of COX-1, or activation of the
MRGPRX2 receptor by quinolones, vancomycin, icatibant, and general
anesthetics with THIQ binding motif and by basic compounds. Symp­
toms of type I reactions include itching, flushing, hives, angioedema,
dyspnea, wheezing, oxygen desaturation, throat tightening, nausea,
vomiting, and hypotension with cardiovascular collapse and are associ­
ated with elevated serum tryptase, a specific biomarker of anaphylaxis
released from mast cells and basophils granules. Tryptase levels above
the normal range (11.4 ng/mL) or above a patient’s baseline (× 1.6)
obtained within 30 min to 4 h of initial symptoms are diagnostic of
type I and mixed reactions. Patients with baseline levels of 7.5 ng/mL
or higher may have duplications of the TPSAB1 tryptase gene located
on chromosome 16, known as hereditary alpha tryptasemia (HαT),
a familial autosomal dominant trait present in 4–6% of Caucasian
populations, which modulates anaphylaxis severity. Other mast cell–
derived mediators include urine N-methylhistamine, prostaglandins,
and leukotrienes.
Cytokine Release Reactions 
CRRs can occur at first exposure or
after several exposures and are thought to be due to activation of T cells
and other immune cells. Patients present with fever; chills; back, chest,
or pelvic pain; headache; oxygen desaturation; and hyper- or hypoten­
sion; these reactions are associated with a transient serum elevation of
interleukin (IL) 6.
CHAPTER 365
Mixed Reactions 
Mixed reactions present with symptoms of type I
and CRR reactions and are associated with tryptase and IL-6 elevations
(Fig. 365-1).
Desensitization
Delayed Type IV Reactions 
Delayed type IV reactions amenable
to DD present as benign maculopapular rashes without associated
systemic symptoms, whereas SCARS, type II, type III, vasculitis, and
single-organ toxic reactions are contraindications for DD because min­
ute amounts of medication can trigger severe reactions.
DIAGNOSTIC TESTING
Skin testing (ST) elicits a local wheal-and-flare reaction upon epicuta­
neous or intradermal injection of drugs inducing IgE-mediated reac­
tions. Its use is limited by the availability of drug components including
excipients, skin toxicity, costs, and the time elapsed since the patient’s
initial reaction (the longer the time, the lower the likelihood that an ST
will be positive) and the severity of the reaction (anaphylactic reactions
can deplete mediators inducing false-negative ST). Positive and nega­
tive predictive values are drug specific, and anaphylaxis to penicillin or
carboplatin has not been reported in ST-negative patients.
The basophil activation test (BAT) provides evidence of IgE sensi­
tization by challenging the patient’s basophils in vitro with the culprit
drug, eliminating the need for direct ST, which has a small risk for
anaphylaxis. Serum-specific IgE antibodies to penicillin and platins
are found in allergic patients with low sensitivity. Skin patch testing
is helpful to evaluate β-lactams, anticonvulsants, corticosteroids, and
other drugs that cause delayed type IV reactions with high specific but
low sensitivity. Lymphocyte transformation tests (LTTs) measure the
activation and/or cytokine release of lymphocytes exposed to culprit
drugs and can be used to identify drugs inducing SCARS. Certain HLA
haplotypes place patients at risk for SCARS when exposed to abacavir,
anticonvulsants, allopurinol, vancomycin, and other drugs, and geno­
typing is available.
DRUG DESENSITIZATION
■
■DEFINITIONS AND MECHANISMS
DD is a temporary immunotherapy modality, delivered through multi­
step protocols to safely and timely reintroduce a drug that has induced
an acute or delayed allergic reaction. IgE-mediated desensitization
takes advantage of inhibitory mast cell/basophil pathways, which are
activated by low doses of drug antigens. Rapid delivery of incremental
doses recruit phosphatases to IgE receptors, blocking signal transduc­
tion and the release of mediators when reaching the target dose and
protecting against anaphylaxis. Desensitized patients have transient
conversion from positive to negative ST.
■
■PROTOCOLS
Based on inhibitory pathways in mast cell models, human protocols
have been generated for type I phenotypes with low starting doses and
multiple steps that progress by doubling the dose administered in the
previous step at constant time intervals. The first standardized and
most used protocol contains three bags of 1/100, 1/10, and undiluted
concentrations of the target dose and 12 doubling steps delivered every
15 min so that the target dose is reached in 5.7 h (Fig. 365-2), which
has been adapted for IV, PO, SC, IM, intraperitoneal, intraocular,
and intrathecal use. Protocols with four bags (starting with a 1/1000
dilution bag) are used for patients with severe initial reactions and
associated comorbidities. The recent use of one-bag protocols for
type I reactions has produced mixed outcomes, with an increased use
of epinephrine during breakthrough reactions (BTRs) and inability to
complete treatments in highly sensitized patients.
Cytokine
Release
Phenotype
Infusion
Reaction
Type I
IgE/non-IgE
Type II
Type III
Mixed
Mast cell
T cell
NK cell
Lymphocyte
PART 11
Immune-Mediated, Inflammatory, and Rheumatologic Disorders
Endotype
Opsonization
Both
TNF-α,
IL-6, IL-1β
TNF-α,
IL-6, IL-1β
IL-6, IL-1β
Histamine,
tryptase
Biomarkers
Both
Flushing
Pruritus
Rash
Urticaria
Throat tightness
Shortness of
breath
Nausea and/or
vomiting
Anaphylaxis and
cardiovascular
collapse
Fever,
Chills/rigors
Nausea
Pain
Headache
Dyspnea
Hyper/
hypotension
Back pain
Fever
Chills/rigors
Nausea
Pain
Headache
Both
Symptoms
Indicated
Indicated
Indicated
Indicated
Non indicated,
regular infusion
Desensitization
Type IV Severe Cutaneous Adverse Reactions (SCARS); Not Indicated, Avoid Medication
Eosinophils
Antigen presenting cell
Interferon-γ
Granzyme B
Granulysin
Perforin
HLA-1
Penicillin
hapten-carrier
complex
TCR
Neutrophils
CD4+ or CD8+ cell
FIGURE 365-1  Drug allergy phenotypes, endotypes, and biomarkers and indications for desensitization. AGEP, acute generalized eosinophilic pustulosis; DRESS, drug
reaction with eosinophilia and systemic symptoms; IL, interleukin; SJS-TEN, Stevens-Johnson syndrome–toxic epidermal necrolysis; TNF, tumor necrosis factor. (From The
New England Journal of Medicine, Penicillin Allergy, M Castells, DA Khan et al: 381: 2338. Copyright @2019 Massachusetts Medical Society. Reprinted with permission from
Massachusetts Medical Society.)
The mechanisms of desensitization for other phenotypes are poorly
understood, and CRRs have been successfully treated with multistep
one-bag protocols, whereas multiple doses over several days have been
used for delayed reactions (see specific drugs). Premedications are
tailored to the initial symptoms, and steroids do not protect against
anaphylaxis. Omalizumab, a monoclonal anti-IgE antibody, has been
used as an adjuvant in highly sensitized patients with type I severe
IgE-mediated reactions, including life-threatening anaphylaxis. Desensitization is a temporary phenomenon that does not lead to sustained
tolerance and must be repeated with each exposure or if there has
been a pause between doses equal to two or more half-lives of the
drug. However, the desensitized state can be maintained by continued
drug exposure as with antibiotics and aspirin/COX-1 inhibitors. Some
Type IV
T cell
Neutrophil
MΦ
C3a
Antibody
dependent
cell cytotoxicity
C3a
C3a
Antigen/
antibody
complexes
T cell
Specific antibody
or antibody/antigen
complex deposition
IFN-γ, IL-4, IL-5
Autoimmune
Thrombocytopenia
Anemia
Neutropenia
Serum sickness
Urticaria vasculitis
Arthus reaction
Nephritis
Fever
Delayed
maculopapular
rash
Not indicated,
avoid medication
Not indicated,
avoid medication
Clinical Phenotype
Interleukin-4
Interleukin-5
Eotaxin
DRESS, 2- to 8-week delay:
Epidermal edema, fever, lymphadenopathy,
eosinophilia, atypical lymphocytosis, and
infiltration of skin and internal organs
Keratinocyte death
SJS–TEN, 4- to 28-day delay:
Epidermal necrosis, subepidermal bullae,
and involvement of multiple mucous
membranes
AGEP, 24- to 48-hour delay
Fever, neutrophilic leukocytosis, sterile
pustules in stratum corneum and epidermis,
dermal edema, and infiltration of neutrophils,
CD4+ T cells, CD8+ T cells, and some
eosinophils
Neutrophils
home to
the skin
Interferon-γ
CXCL8
GM-CSF
patients reactive to taxanes and certain biologicals with uneventful DD
protocols may eventually return to regular infusions.
INDICATIONS, BREAKTHROUGH
REACTIONS, AND OUTCOMES
■
■INDICATIONS (FIG. 365-2)
Qualifications for DD depend on the need of the medication as firstline therapy, the initial reaction phenotype, and its severity. Infusion
reactions, mild CRRs, and mild delayed reactions can be addressed
by symptoms targeting adjuvant medications. DD is indicated
for type I IgE-dependent and IgE-independent, CRR, mixed, and
nonsevere delayed type IV phenotypes. Type I and mixed reactions
BWH desensitization
1/1000
Rate (Ml/h)
2.5 X 15min
5 X 15min
10 X 15min
20 X 15min
A
Clinical Vignette 1: Rituximab
Rituximab
Carboplatin
59–year old, ovarian cancer, six courses of
carboplatin and paclitaxel with remission
61-year old, male
Marginal zone lymphoma
Reaction on 8th lifetime exposure
Immediate sweating, flushing, chest pain
Infusion stopped and resumed after
10 minutes but symptoms recurred
Treated with steroids and infusion discontinued
Allergy
evaluation for
desensitization
Change for a
second-line
treatment?
Skin test
positive
(ID 1 mg/mL)
Grade 2
Mixed
reaction
3-bag
12-step
protocol
Premedication:
Certirizine 10 mg
Aspirin 325 mg
Methylprednisolone 40 mg
Famotidine 20 mg
Acetaminophen 650 mg
Montelukast 10 mg
Tryptase 10.2 ng/mL
(baseline 6.1 ng/mL)
Desens # 1: step 12: Flushing, chills,
restlessness
Fluids (nl saline 250 mL/h)
Fever of 102.4F: Acetaminophen 650 mg
: Meperidine 25 mg IV
: Diphenhydramine 25 mg
: Famotidine 20 mg
Complete rest of steps
IL-6 >3000 pg/mL
(normal, <17.4 pg/mL;
baseline <2.9 pg/mL)
B
FIGURE 365-2  Desensitization: protocols and applications. A. Multibag, multistep intravenous desensitization protocols. B. Rituximab allergic reaction with mixed
phenotype, positive skin test, and elevated tryptase and interleukin (IL) 6 biomarkers and successful treatment with a three-bag 12-step protocol. C. Carboplatin allergic
reaction with type I phenotype, positive skin test, and elevated tryptase biomarker and successful treatment with a three-bag 12-step protocol. (Reproduced with permission
from L Campos et al: Curr Treat Options Allergy 6:519, 2019.)
4-bag 16-step protcol (6.7h)
3-bag 12-step protcol (5.7h)
CHAPTER 365
2-bag, 8-step protocol and
1-bag, 4-step protocol
Rate (Ml/h)
1/100
Rate (Ml/h)
1/10
Rate (Ml/h)
Full dose
Desensitization
2.5 X 15min
5 X 15min
10 X 15min
20 X 15min
5 X 15min
10 X 15min
20 X 15min
40 X 15min
10 X 15min
20 X 15min
40 X 15min
80 X 2.9h
Clinical Vignette 2: Carboplatin
Two years later, CA125 increase, mass
in abdomen, stage 4, restart carboplatin
and paclitaxel
Second carboplatin:
(8th exposure)
Itchy hands
Third carboplatin:
(9th exposure)
Flushing
Generalized pruritus
Shortness of breath
Dizziness
Hypotension
O2 desaturation with
syncopal episode
Fluids
Antihistamines
Steroids
Epinephrine IM:
Tryptase 52 ng/mL (normal level 11.4 ng/mL)
Change
chemotherapy
for a second-line
treatment?
Allergy
evaluation for
desensitization
ANAPHYLAXIS
Positive skin
test to
carboplatin
Epinephrine
3-bag
12-step
protocol
Grade 3
Type
reaction
Tryptase
Completed rest
of treatment cycle
via desensitization
to carboplatin
C
in patients with multiple exposures to antibiotics, chemotherapeutic
drugs, and biologicals indicate IgE sensitization. ST-positive patients
require DD for reexposure since the risk for anaphylaxis is high. In
patients with mild reactions and negative biomarkers, controlled drug
challenges are indicated to assess tolerance. Large clinical series sup­
port outpatient settings for the majority of DD, which decreases the
starting treatment time and costs and improves patients’ experiences.
PART 11
Immune-Mediated, Inflammatory, and Rheumatologic Disorders
■
■DD BREAKTHROUGH REACTIONS
AND OUTCOMES
BTRs are typically mild with symptoms similar to the initial reaction.
They occur in 10–30% of protocols and require symptom-specific
management including epinephrine for severe reactions. BTRs do
not preclude the completion of the DD protocols in 99% of cases,
and no deaths due to DD have been reported. Comorbidities such as
pregnancy, cystic fibrosis, decreased lung function, cardiac diseases,
advanced cancer, beta blocker and/or angiotensin-converting enzyme
inhibitor use, and prior severe reactions increase the risk during BTRs
(Fig. 365-3). The administration of antibiotics, monoclonal antibod­
ies, and chemotherapy drugs through DD has shown equal efficacy
as for standard administration, with the expected clearance of infec­
tions, decreased inflammation, and similar cancer responses. Kounis
syndrome and takotsubo cardiomyopathy resulting from drug-induced
anaphylaxis are contraindications for DD (Fig. 365-3).
APPROACH TO SPECIFIC DRUGS
■
■ANTIBIOTICS
Antibiotics can induce all the reactions in Fig. 365-1, but the most
common are type I IgE-dependent and type IV non-SCARS reactions,
both of which can be addressed by DD.
β-Lactams 
The first description of penicillin desensitization was
in a World War II allergic soldier who presented with wheezing and
hypotension after penicillin injection and received oral incremental
Principles of Drug Desensitization
No desensitization;
avoid culprit drug
Indications/Phenotypes
Contraindications
Risk Factors
• SCARS*
(SJS/TEN/DRESS/AGEP)
• Organ specific toxicity
• Cytopenias
• Serum sickness
• Vasculitis
• Kounis and Tako Tsubo
• Severe reactions
• Pregnancy
• Pulmonary diseases
• Acute cardiac diseases
• β-blockers
• ACE inhibitors
• Atopy
• HLA haplotypes
• Female gender
• Polypharmacy
• Advanced age
• Alpha-Gal syndrome
• Type 1 lgE/non-lgE
• Cytokine release reaction
(CRR)
• Mixed reaction
• Type IV
+Severe cutaneous adverse reaction
‡‡Non-steroidal anti-inflammatory drugs
^Cystic fibrosis transmembrane conductance regulator potentiator
FIGURE 365-3  Principles of drug desensitization: Indications, contraindications, risk factors, and drugs with successful desensitizations. ACE, angiotensin-converting
enzyme; AGEP, acute generalized eosinophilic pustulosis; DRESS, drug reaction with eosinophilia and systemic symptoms; HLA, human leukocyte antigen; SJS-TEN,
Stevens-Johnson syndrome–toxic epidermal necrolysis.
doses over 30 days until he was able to tolerate a treatment course. The
initial success led to shorter protocols to treat patients with bacterial
endocarditis and pregnant women with syphilis who had a history of
penicillin-induced anaphylaxis and positive ST. Safe rapid PO and IV
desensitization protocols are currently available for all antibiotic classes
and can treat high-risk patients, including cystic fibrosis patients with
low pulmonary function.
Sulfonamides 
Delayed type IV rashes to trimethoprim-
sulfamethoxazole occurred in up to 40% of patients with <100
total CD4 T cells/µL during the early 1990s HIV/AIDS epidemic,
and DD included incremental doses over multiple days. Reactions
have decreased since retroviral treatments, and shorter protocols have
evolved. One-day PO and IV multidose protocols have shown consis­
tent safety and efficacy for delayed reactions in non-HIV patients.
■
■CHEMOTHERAPY
Taxanes 
Over 40% of patients exposed to paclitaxel and docetaxel
presented with acute reactions, which have been reduced to 1% by
antihistamine and corticosteroid premedication. Moderate to severe
reactions attributed to lipid excipients (Cremophor and polysorbate
80) and to IgE sensitization through cross-reactive foods and envi­
ronmental allergens occur typically at first or second exposure with
type I, mixed, and delayed phenotypes. Patients with delayed rashes
can convert to acute reactions including anaphylaxis upon subsequent
exposures. The first DD to paclitaxel was reported in 2002, and an early
study of 940 DDs to paclitaxel and docetaxel in 138 patients described
BTRs in 20% of cases, and 22% of desensitized patients returning to
standard infusions. A review of 25 studies with 976 patients and 2396
DDs to paclitaxel and docetaxel, completed in 95–100% of cases, the
majority with three-bag 12-step protocols, showed 32% paclitaxel and
20% docetaxel mild BTRs and no deaths.
Platinums 
Platinum drug (carboplatin, cisplatin, and oxaliplatin)
IgE sensitization requires multiple exposures (typically six or more;
Desensitization
Drug Formulation
• Platins: carboplatin, cisplatin, oxaliplatin
• Taxanes: paclitaxel, docetaxel, cabazitaxel, nab-paclitaxel
• Monoclonals: rituximab, cetuximab, tocilizumab, bevacizumab,
ofatumumab, alemtuzumab, pertuzumab, nivolumab; sacituzumab,
etanercept, adalimumab, infliximab, ustekinumab, vedolizumab,
tezepelumab, golimumab, daratumumab, ocrelizumab,
obinutuzumab, trastuzumab, margetuximab, pembrolizumab
• Antibiotics: β-lactams, cephalosporins, sulfonamides, quinolones,
macrolides, vancomycin, aminoglycosides, doxycycline, rifampin,
metronidazole
• CFTCRP^: elexacaftor/tezacaftor/ivacaftor
• Enzymes: laronidase, elosulfase alfa, galsulfase, alglucosidease alfa,
imiglucerase, taliglucerase alfa, sebelipase alfa, idursulfase
• Iron: sodium ferric gluconate, ferumoxytol, iron sucrose, iron dextran
• NSAIDS‡‡: aspirin, naproxen
• Hormones: progesterone, aromatase inhibitor, letrozole
• Small molecules: lenalidomide, imatinib, osimertinib, olaparib

09 - 366 Mastocytosis
366 Mastocytosis
less for BRCA mutation carriers), and sensitized patients typically have
type I symptoms with pruritus, flushing, urticaria, throat tightening, and
hypotension with elevated tryptase (Fig. 365-2). ST is positive in >85%
of patients with recent reactions. In a prospective study of 126 women
who received six or more carboplatin treatments, repeat ST before each
exposure identified reactors, with seven anaphylactic reactions in seven
patients who agreed to be reexposed to carboplatin despite positive
ST. Oxaliplatin reaction phenotypes include CRR and mixed reactions
with conversion from type I to CRR and mixed phenotypes during DD.
Oxaliplatin-induced immune-mediated thrombocytopenia (OIIT) with
bleeding is a rare complication that precludes further DD.
Carboplatin DD started in early 2000 and a large study in 2016
with 370 patients (212 carboplatin-allergic and 13 cisplatin-allergic
patients), who underwent 2177 DDs, mostly in the outpatient setting
with three- or four-bag protocols, showed 20% mild BTRs, non­
superior costs compared to regular infusions, and a life expectancy
advantage at 5 years in ovarian cancer patients compared to nonallergic
patients. A study of 272 patients allergic to platins, taxanes, and mono­
clonals who underwent 1471 DDs with three-bag 12-step protocols
reported similar safety. Oxaliplatin DD poses challenges due to the
heterogeneity of phenotypes and phenotype switching. A study of 48
patients with 200 DDs who underwent three-bag 12-step protocols
showed mild to moderate BTRs in 18 patients, 1 patient with OIIT, and
2 patients with hemolytic anemia. A study of patients with type I, CRR,
and mixed reactions who underwent 273 DDs indicated a switch from
type I to CRR and mixed reactions during DD, with elevated IL-6, and
two patients developed OIIT. The survival of platinum-desensitized
patients is noninferior to nonallergic patients.
Doxorubicin and Other Chemotherapy Drugs 
Doxorubicin
reactions are rare, occurring at first exposure, and a study of 30 patients
and 128 DDs, mostly with three-bag 12-step protocols, showed 16%
mild BTRs, and one patient required epinephrine. DDs for etoposide,
cyclophosphamide, methotrexate, gemcitabine, and other chemother­
apy drugs have shown similar safety.
■
■MONOCLONALS/BIOLOGICALS
Infusion reactions of the type I IgE/non-IgE mediated, CRR, mixed,
and delayed-reaction phenotypes have been reported for monoclonal
antibodies (MoAbs). Hypersensitivity reactions can occur on first
exposure or after multiple exposures (Fig. 365-2). Reactions are more
frequent with chimeric MoAbs but also occur with humanized and
fully humanized MoAbs. Skin testing is limited by cost. Patients with
cetuximab-induced anaphylaxis react to galactose-alpha-1-3-galactose,
a nonhuman carbohydrate in the Fab chain of cetuximab, due to pre­
existing IgE acquired through tick bite sensitization. DDs have been
reported for most IV and SC available MoAbs (Fig. 365-3). The first
series of MoAb desensitizations included 23 patients with moderate to
severe type I and mixed reactions to trastuzumab, infliximab, and ritux­
imab who underwent 105 DDs with three bags and 12 steps and had
29% mild BTRs. A study of 104 patients who reacted to 16 MoAbs with
type I, CRR, mixed, and delayed reactions and received 526 DDs, mostly
with three bags and 12 steps in the outpatient setting, presented with
23% mild BTRs. Tryptase was elevated in type I and IL-6 in CRR BTRs.
■
■SMALL MOLECULES
Epidermal growth factor receptor and tyrosine kinase inhibitors such as
imatinib, osimertinib, and olaparib can induce type I and type IV reac­
tion phenotypes, and successful DDs with multiple oral doubling doses
have been reported, allowing for continued long-term maintenance.
■
■NONSTEROIDAL ANTINFLAMMATORY
DRUGS (NSAIDS)
Aspirin (ASA) and other NSAIDs can induce type I reactions with
urticaria and anaphylaxis thought to be IgE-mediated and, in patients
with asthma and dysregulated lipid metabolism, a syndrome termed
aspirin-exacerbated respiratory disease (AERD) with bronchospasm.
Patients with AERD have universal intolerance to COX-1 inhibitors
but tolerate COX-2 inhibitors. The American Academy of Allergy,
Asthma, and Immunology Work Group Report in 2020 reviewed 14
series of ASA DDs with intranasal ketorolac or oral aspirin in >900
AERD patients. More than 70% of patients reported improvement of
asthma, lack of polyp recurrence, recovery of sense of smell, and less
steroid usage, with cross-desensitization and tolerance to all COX-1
inhibitors while maintained on daily ASA. For type I reactions in car­
diac and neurologic patients, DD with rapid doubling doses has been
proven safe and effective.
CHAPTER 366
■
■OTHER DRUGS
Symptoms of progestogen hypersensitivity (PH) are cyclical and
include type I and delayed phenotypes. PH can lead to miscarriage,
and oral and vaginal DD protocols have resulted in viable pregnancies.
Reactions to iron formulations include type I, CRR, mixed, and delayed
phenotypes that are responsive to DD. Allopurinol-induced delayed
rashes respond to PO and IV DD protocols. Corticosteroids, glatiramer
acetate, vaccines, and other medication DDs have been reported with
doubling multistep PO, IV, and SC protocols.
Mastocytosis
IMPACT
Discontinuing drugs inducing allergic symptoms affects patients for
whom second-line therapies may not be available, are more expensive,
or do not provide similar therapeutic benefits. DD protocols allow for
the safe reintroduction of first-line therapies, and their use should be
extended to all patients in need.
■
■FURTHER READING
Adnan A, Acharya S: Multistep IgE mast cell desensitization is a
dose- and time-dependent process partially regulated by SHIP-1. J
Immunol 210:709, 2023.
Castells M et al: Penicillin allergy. N Engl J Med 381:2338, 2019.
Dhopeshwarkar N: Drug-induced anaphylaxis documented in elec­
tronic health records. J Allergy Clin Immunol Pract 7:103, 2019.
Isabwe GAC: Hypersensitivity reactions to therapeutic monoclonal
antibodies: Phenotypes and endotypes. J Allergy Clin Immunol
142:159, 2018.
Sloane D: Safety, costs, and efficacy of rapid drug desensitizations to
chemotherapy and monoclonal antibodies. J Allergy Clin Immunol
Pract 4:497, 2016.
Matthew P. Giannetti, Joshua A. Boyce
Mastocytosis
■
■DEFINITION AND EPIDEMIOLOGY
Mastocytosis is defined by accumulation of clonally expanded mast
cells in tissues such as skin, bone marrow, liver, spleen, and gut. Diag­
nostically, mast cell expansion is most readily identified in skin and/
or bone marrow. Mastocytosis occurs at any age, although it is most
commonly diagnosed in infancy and young adulthood. The prevalence
of mastocytosis is estimated at ~1 in 10,000 people. Most forms of the
disease are characterized by somatic gain-of-function mutations in
the stem cell factor receptor (KIT) gene, and >90% of patients carry the
KIT D816V mutation. Familial occurrence is rare, and atopy is not
increased compared with the general population.
■
■CLASSIFICATION AND PATHOPHYSIOLOGY
A consensus classification for mastocytosis recognizes cutaneous mas­
tocytosis with variants, systemic mastocytosis with five variants, and
mast cell sarcoma (Table 366-1).
Cutaneous mastocytosis is the most common diagnosis in children
and indicates disease limited to skin with absence of pathologic infil­
trates in internal organs. It is usually diagnosed within the first year
TABLE 366-1  Classification of Mastocytosis
Cutaneous mastocytosis (CM)
  Maculopapular cutaneous mastocytosis (MPCM)
  Solitary mastocytoma of skin
  Diffuse cutaneous mastocytosis
Systemic mastocytosis
  Indolent systemic mastocytosis (ISM)
  Smoldering systemic mastocytosis
  Systemic mastocytosis with associated clonal hematologic non–mast cell
PART 11
Immune-Mediated, Inflammatory, and Rheumatologic Disorders
lineage disease (SM-AHNMD)
  Aggressive systemic mastocytosis (ASM)
  Mast cell leukemia (MCL)
Mast cell sarcoma (MCS)
Source: Modified from DA Arber et al: International consensus classification of
myeloid neoplasms and acute leukemias: integrating morphologic, clinical, and
genomic data. Blood 140:1200, 2022.
of life with demonstration of fixed, maculopapular, polymorphic, and
hyperpigmented lesions (known as maculopapular cutaneous mas­
tocytosis [MPCM]), solitary mastocytoma(s), or diffuse cutaneous
mastocytosis. Although mast cell accumulation is limited to the skin,
children often have systemic symptoms. Systemic mastocytosis (SM)
refers to involvement of an extracutaneous site (most often bone mar­
row). There are five distinct variants of SM. Indolent systemic mastocy­
tosis (ISM) accounts for >70% of adult patients. ISM is diagnosed when
there is no evidence of organ dysfunction due to mast cell infiltration,
an associated hematologic disorder, or mast cell leukemia. ISM is asso­
ciated with a normal life expectancy. Smoldering systemic mastocytosis
(SSM) is characterized by high mast cell burden including bone mar­
row infiltration of >30% and a baseline serum tryptase >200 ng/mL (B
findings), but absence of systemic mastocytosis associated with clonal
hematologic non–mast cell lineage disease (SM-AHNMD) or aggressive
systemic mastocytosis (ASM) (Table 366-2). In SM-AHNMD, the prog­
nosis is determined by the nature of the associated disorder, which can
range from dysmyelopoiesis to leukemia. In ASM, mast cell infiltration
may occur in multiple organs such as liver, spleen, gut, bone, and bone
marrow resulting in one or more C findings and a poor prognosis
(Table 366-2). Mast cell leukemia (MCL) is the rarest form of SM and
is invariably fatal at present; the peripheral blood contains circulating,
metachromatically staining, atypical mast cells. An aleukemic form of
MCL is recognized without circulating mast cells when the percentage
of high-grade immature mast cells in bone marrow smears exceeds
20% in a nonspicular area. Mast cell sarcoma is a rare solid mast cell
tumor with malignant invasive features.
TABLE 366-2  B and C Findings for Diagnosis of SSM and ASM
B Findings (2 or more in the absence of any C findings are required for a
diagnosis of SSM):
High MC burden: MC infiltration in bone marrow of >30%, basal serum
tryptase level >200 ng/mL, and/or KIT D816V >10% VAF in bone marrow
Hypercellular bone marrow with signs of dysmyelopoiesis but without
cytopenias meeting C criteria or WHO criteria for an MDS or MPN
Palpable hepatomegaly, palpable splenomegaly, or lymphadenopathy (on CT
or ultrasound: >2 cm) without impaired liver function or hypersplenism
C Findings (1 or more required for a diagnosis of ASM). C findings should be
reasonably attributable to high tissue MC infiltration:
Cytopenia(s): ANC <1000/μL or Hb <10 g/dL or PLT <100,000/μL
Hepatomegaly with ascites and impaired liver function
Palpable splenomegaly with associated hypersplenism
Malabsorption with hypoalbuminemia and weight loss
Skeletal lesions: large area(s) of osteolysis with pathologic fractures
(presence of osteoporosis alone without osteolytic lesions does not satisfy
this criterion)
Abbreviations: ANC, absolute neutrophil count; ASM, aggressive systemic
mastocytosis; CT, computed tomography; Hb, hemoglobin; MC, mast cells; MDS,
myelodysplastic syndromes; MPN, myeloproliferative disorders; PLT, platelets;
SSM, smoldering systemic mastocytosis; VAF, variant allele frequency; WHO, World
Health Organization.
Somatic activating mutations in the KIT gene are characteristic of
mastocytosis. KIT D816V is most common, although other mutations
have been reported. KIT mutations are found in mast cells and some­
times in other cell lineages in patients with mastocytosis. KIT muta­
tions are observed in patients with all forms of SM but are also present
in some children with cutaneous mastocytosis in lesional skin. Addi­
tional mutations in genes such as TET2, SRSF2, ASLX1, and RUNX1
known to be associated with other hematologic neoplastic disorders
can be detected in patients, usually with advanced variants of SM.
The life expectancy for patients with cutaneous mastocytosis and for
most patients with ISM is normal, whereas that for patients with SMAHNMD is determined by the non–mast cell component. ASM and
MCL have a poor prognosis, while patients with SSM have an inter­
mediate prognosis. Progression from ISM to a more advanced form is
uncommon (~5% lifetime risk); however, patients should be monitored
for emergence of hematologic disease and end-organ manifestations of
ASM. In infants and children with cutaneous manifestations, namely,
maculopapular cutaneous mastocytosis, mastocytoma(s), or bullous
lesions, visceral involvement is usually lacking, and spontaneous reso­
lution is common prior to adolescence. Polymorphic maculopapular
cutaneous mastocytosis usually resolves spontaneously. Progression
from cutaneous mastocytosis (CM) to ISM may occur in ~10% of chil­
dren, especially in those with high mast cell burden (diffuse cutaneous
mastocytosis) or hematologic abnormalities and those who present
with smaller uniform lesions with diameters measuring <2 cm (mono­
morphic MPCM).
■
■CLINICAL MANIFESTATIONS
The clinical manifestations of SM are due to the release of bioactive
substances acting at both local and distal sites, tissue infiltration by
mast cells, and the tissue response to the cellular infiltrate. Clinical
manifestations include intermittent urticaria, flushing, tachycardia and
vascular collapse, gastric acid hypersecretion, crampy lower abdominal
pain, and diarrhea. The increased local mast cell burden in the skin
(MPCM), bone marrow, and gastrointestinal tract may be a direct
cause of pruritus, bone pain, and malabsorption, respectively. Mast
cell–mediated fibrotic changes may occur in liver, spleen, and bone
marrow but not in gastrointestinal tissue or skin.
The cutaneous lesions of MPCM are reddish-brown macules, pap­
ules, or plaques that respond to trauma with urtication and erythema
(Darier’s sign). Two distinct forms of MPCM are recognized: poly­
morphic MPCM and monomorphic MPCM. Children with CM may
present with MPCM, mastocytomas, or diffuse cutaneous mastocyto­
sis (DCM). Mastocytomas are generally solitary elevated lesions that
are yellow, brown, or red in color. Their size may vary from a few
millimeters to several centimeters. Rubbing or irritation of a masto­
cytoma lesion may lead to systemic symptoms such as flushing and
urticaria. Children with DCM present without distinct lesions, but
rather a generalized thickening of skin and “peau d’orange” appear­
ance due to diffuse mast cell infiltration. DCM is associated with bul­
lae formation and more severe systemic symptoms, including upper
gastrointestinal irritation and vascular collapse in the first few years
of life. Maculopapular skin lesions of mastocytosis may be present in
patients with adult-onset systemic disease. The apparent incidence of
cutaneous lesions is ≥80% in patients with ISM and <50% in those
with SM-AHNMD or ASM. In the upper gastrointestinal tract, gas­
tritis and peptic ulcer are significant problems. In the lower intestinal
tract, the occurrence of diarrhea and abdominal pain is attributed to
increased motility due to mast cell mediators. The periportal fibrosis
associated with mast cell infiltration may lead to portal hypertension
and ascites. In some patients, anaphylaxis may occur with rapid and
life-threatening vascular collapse. Anaphylaxis is most commonly
induced by Hymenoptera stings and nonsteroidal anti-inflammatory
drugs (NSAIDs). The neuropsychiatric disturbances are clinically
most evident as impaired recent memory, decreased attention span,
and “migraine-like” headaches. Patients may experience exacerbation
of a specific clinical sign or symptom variably with alcohol ingestion,
temperature changes, stress, use of mast cell–interactive opioids, or
ingestion of NSAIDs.

11 - 368 Systemic Lupus Erythematosus
368 Systemic Lupus Erythematosus
thyroiditis. Cancers commonly associated with autoimmunity include
melanoma, thyroid cancer, and non-small-cell lung cancer. One spe­
cific example is the development of encephalitis through generation
of Abs to N-methyl-d-aspartate glutamate receptor in women affected
by ovarian cancer. In some cases, these events may be associated with
favorable disease outcomes that may suggest a beneficial effect from
the autoimmune response. The autoimmune manifestations can be
severe, and management of these patients is difficult given the coexis­
tent malignancy.
■
■IATROGENIC AUTOIMMUNITY
Checkpoint Inhibitors 
Immune checkpoint inhibitors (ICIs) have
revolutionized cancer treatment. They act by blocking inhibitory mole­
cules involved in regulating T lymphocytes, promoting the destruction
of tumors by the adaptive immune system. Immune-related adverse
events (irAEs) have been described as toxic complications related to
tissue-specific autoimmunity from the use of ICIs, and they can persist
after withholding therapy and using immunomodulatory therapy to
control them. Among these complications, DM, arthritis, thyroiditis,
and colitis are prevalent. Up to 85% of individuals treated with an ICI
may develop irAEs. Most of these are mild, and overall survival and
time to malignancy progression are not influenced by the development
of these immune complications.
Drug-Induced Autoimmunity 
In addition to ICIs, many drugs
have been linked to the development of autoimmunity. These include
antibiotics, antihypertensives, antiarrhythmics, TNF inhibitors, and
antiseizure medications, among many others. Drug-induced lupus is
a well-described entity, and patients developing this condition have
characteristic detection of antihistone Abs. In many cases, discontinu­
ation of the drug may be sufficient for symptoms to be abrogated or
decreased.
■
■PREVENTION AND TREATMENT OF
AUTOIMMUNITY
The hope is that better understanding of the pathophysiology of overt
development of ADs and their associated organ damage will lead
to primary or secondary prevention strategies in conditions such as
T1DM, RA, and SLE. One promising example is where infants at risk
of developing multiple T1DM autoAbs and clinical disease are being
studied to determine if certain interventions (oral insulin) can delay or
stop progression to overt disease. Studies have also been performed on
people considered at risk for RA to assess delayed disease progression,
but more studies are needed to better characterize the utility of these
preventive strategies. Overall, opportunities to initiate early therapy
depend on the availability of serologic tests that can predict disease, to
initiate treatments that have a good efficacy-to-safety ratio.
Specific treatments for ADs are included in chapters focusing on
individual diseases and include a variety of immunomodulatory agents
(e.g., antimalarials) and immunosuppressive drugs (spanning those
drugs with broad effects on the immune system, such as corticosteroids
or cyclophosphamide, to highly specific biologic agents targeting spe­
cific cytokines or immune cells). It is the hope that the development of
personalized medicine approaches will lead in the future to the specific
targeting of dysregulated immune cell components while sparing other
critical cells and functions of the immune system.
■
■FURTHER READING
Enhancing NIH Research on Autoimmune Diseases. Consensus
Study Report. The National Academies of Sciences, Engineering,
Medicine, 2022.
Gupta  S, Kaplan  MJ: Bite of the wolf: Innate immune responses
propagate autoimmunity in lupus. J Clin Immunol 131:e144918, 2021.
Johnson  D, Jang W: Infectious diseases, autoantibodies and autoim­
munity. J Autoimm 137:102962, 2023.
Singh  N et al: Immune-related adverse events after immune check
point inhibitors: Understanding the intersection with autoimmunity.
Immunol Rev 318:81, 2023.
Chelsey J.F. Smith, Paul J. Hoover,
Kenneth Kalunian
Systemic Lupus
Erythematosus
CHAPTER 368
DEFINITION, PREVALENCE,
AND EPIDEMIOLOGY
Systemic lupus erythematosus (SLE) is an autoimmune disease in
which overactive innate and adaptive immune systems cause tissue
damage through the effects of autoantibodies and immune complexes.
Many organ systems can be affected, with cutaneous, musculoskeletal,
and renal systems most involved, followed by pulmonary, hematologic,
cardiovascular, serosal, and central nervous system involvement. Con­
stitutional symptoms are often present. Autoantibodies can be detected
years prior to a clinical diagnosis. Approximately 90% of affected indi­
viduals are women, most of childbearing age; however, the disease can
also affect neonates and older children, men, and elderly individuals.
Certain ethnic and racial groups are at higher risk for more prevalent
disease and more severe disease. The Centers for Disease Control and
Prevention (CDC) National Lupus Registry estimates the prevalence
in the United States to be 204,295 cases, with overall prevalence being
nine times higher in women compared to men. The highest prevalence
is seen in Black women, followed by Hispanic, White, and Asian/
Pacific Islander women. Among men with SLE, Black men have the
highest prevalence and White men have the lowest. Prognosis and
survival from SLE can vary widely by geographic region, race, ethnicity,
and access to both care and medications.
Systemic Lupus Erythematosus
DIAGNOSIS AND CLASSIFICATION
For the diagnosis of SLE, an individualized approach should be taken
based on available clinical data and excluding other disease entities.
Classification criteria for SLE have been developed for the purposes
of enrollment of patients into clinical trials rather than criteria for
diagnosis. Currently, the 2019 European League Against Rheumatism
(EULAR)/American College of Rheumatology (ACR) classification
criteria for SLE and the 2012 Systemic Lupus International Collabo­
rating Clinics (SLICC) SLE classification criteria are both utilized for
enrollment of patients into clinical trials. For the EULAR/ACR criteria,
an antinuclear antibody (ANA) titer of at least 1:80 is required. Clinical
criteria are then weighed by points within several clinical domains, and
a patient requires at least 10 points to meet criteria. No single clinical or
laboratory value leads to 10 points except for a renal biopsy revealing
class III or IV lupus nephritis.
Certain subsets of patients with SLE are currently not included in
clinical trials, including patients with incomplete lupus or features
of SLE without an established diagnosis and the ~5% of SLE patients
who are ANA negative. Researchers have suggested that if predictive
or diagnostic biomarkers for progression are developed, then early
treatment for patients with incomplete lupus could prevent progression
to SLE. Furthermore, because the EULAR/ACR criteria exclude ANAnegative patients from participating in clinical trials, the opportunity
to understand whether new drugs have a role in this disease subset is
also underserved.
SLE has been classified into two broad categories based on symp­
toms. Those with predominant classic findings of SLE that have a clear
relationship to immune dysregulation, such as nephritis, arthritis, and
vasculitis, have been categorized as having type 1 lupus, whereas those
with predominant symptoms of fatigue, diffuse body pain, depres­
sion, cognitive dysfunction, sleep disturbances, anxiety, and/or brain
fog have been categorized as having type 2 lupus. Type 1 symptoms
arise from autoimmune inflammation and/or organ damage and often
respond to standard immunosuppression, whereas type 2 patients are
less responsive to immunosuppressive therapy. This categorization
presents an opportunity to explore the genetic and immune association
of each category as well as develop biomarkers and treatments for the
distinct types.
PATHOGENESIS
■
■OVERVIEW
SLE reflects multiple immunoregulatory defects and is characterized
by the production of autoantibodies to cellular components, especially
nucleic acids and nuclear proteins, that promote inflammation and tis­
sue damage. The interaction of environmental factors with the stochas­
tic dysregulation of genes controlled by common genetic variations
underpins the development of SLE (Fig. 368-1).
PART 11
Immune-Mediated, Inflammatory, and Rheumatologic Disorders
■
■GENETICS
SLE has a strong genetic component as evidenced by familial cluster­
ing, a greater incidence in monozygotic twins versus dizygotic (24% vs
2%), and the identification of >150 susceptibility loci from genomewide association studies (GWAS). Genetic studies have identified
groups of immunoregulatory genes associated with SLE, reflecting
common pathways that may contribute to pathogenesis. It is pos­
sible that each pathway differentially contributes to the expression
of disease, accounting for clinical heterogeneity. The most common
genetic association is within the major histocompatibility complex
that contains genes for antigen presentation molecules (class I and
class II), several complement components, and cytokines. Nearly half
of the susceptibility loci are associated with type 1 interferon (IFN)
production or its downstream signaling. For example, some suscep­
tibility genes lead to increased IFN through defects in nucleic acid
sensing and metabolism (TLR7, ADAR, IFIH1, SAMHD1, RNASEH2B,
TREX1) or nucleic acid degradation (DNASE1, DNASE1L3), whereas
other IFN-related susceptibility genes amplify the IFN response (IRF5,
IRF7, IRF8, STAT4). Many predisposing genes are immune cell type
specific, affecting activation and survival of T cells (OX40L) or B cells
(BANK1, BACH2). The complement cascade (C1Q, C1r, C1s, C2, C4),
Neutrophils and dying
cells release debris
NETosis
Predisposing Factors
Environmental triggers and potential
mechanism
UV light - induces apoptosis and
autoantigen release.
Crystalline silica - induces inflammation.
Smoking - causes autoantigen release.
Sex hormones - regulate development
and function of adaptive immune cells.
Microbes (EBV, microbiome) - induce
nucleic acid response, increase gut
permeability.
Toxins (i.e., mercury, diet) - induce cell
death, inflammation, epigenetic changes.
Cell death
Key immunologic SLE pathways and
selected susceptibility genes
Antigen presentation (MHC) - HLA-DR,
HLA-DQ
IFN induction - IRAK1, SLC15A4, SPP1,
TNIP1, UBE2L3
Nucleic acid sensing - TLR7, ADAR,
IFIH1, SAMHD1, RNASEH2B, TREX1
Nucleic acid degradation - DNASE1,
DNASE1L3
Response to IFN - IRF5, IRF7, IRF8,
STAT4, TYK2
Phagocytosis - FCGR2A, C1Q, C1r,
C1s, C2, C4
T-cell activation ETS1, IL21, IKZF1,
IKZF2, PTPN22, STAT4, TCF7, OX40L
B-cell activation - ARID5B, BANK1,
BACH2, BLK, CD40, CSK, IKZF3, IRF5
Monocytes infiltrate tissue and
are activated by immune
complexes binding to FcGR,
inducing tissue inflammation
FcGR
Classic
monocyte
Non-classical
monocyte
anti-dsDNA: Anti double-stranded DNA
anti-Sm: anti-Smith
FcGR: Fc gamma receptor
IFN: Type 1 interferon
MHC: Major histocompatibility complex
Epigenetic changes DNA methylation
and histone acetylation can affect the IFN
response of T, B, and myeloid subsets.
FIGURE 368-1  Pathogenesis of systemic lupus erythematosus (SLE). Autoantigens from neutrophil NETosis and cellular turnover overwhelm clearance mechanisms
regulated by the innate immune system in SLE. Consequently, these autoantigens accumulate and induce an immune response. Nucleic acid activates TLR signaling in
plasmacytoid dendritic cells (DCs), producing type 1 IFN, sensitizing the innate and adaptive immune responses. DCs present autoantigens to autoreactive T cells, leading
to B-cell stimulation and the production of immune complexes against these autoantigens. Immune complexes deposit in tissue and induce local immune responses that
lead to inflammation and repair and, eventually, fibrosis after recurrent SLE flares. EBV, Epstein-Barr virus.
which is essential for clearance of apoptotic cellular debris and immune
complexes, is often affected in monogenic cases, leading to severe SLE.
■
■ENVIRONMENT
About a quarter of monozygotic twins are clinically concordant for
SLE, implicating environmental factors in disease expression. Low
socioeconomic status is associated with the development of SLE and
may include exposures to environmental toxins, including mercury,
pesticides, and diet. Viral infections such as Epstein-Barr virus likely
contribute to disease development by inducing the IFN response dur­
ing an acute infection or by expressing viral proteins that activate SLE
susceptibility genes. Ultraviolet light can impact DNA methylation,
generate self-stimulatory nucleic acids, activate keratinocyte immune
responses, and produce autoreactive T cells. Finally, emerging evidence
suggests that the gut microbiome may increase gut permeability, pro­
moting the translocation of certain gut microbes into the blood with
the development of lupus-specific autoantibodies contributing to SLE
pathogenesis.
■
■INNATE IMMUNITY
Multiple innate immune cell defects contribute to increased cellular
breakdown and reduced cell debris clearance, culminating in the pro­
duction of autoantibodies. Neutrophils are typically short-lived and
abundant immune cells, representing a large burden of cellular debris
that is usually cleared without inducing an immune response. Patients
with SLE, however, have neutrophils with higher turnover, delivering
a large load of stimulatory nucleic acids and autoantigens. Cellular
debris and immune complexes are typically cleared by macrophages
and dendritic cells through complement-mediated phagocytosis and
nucleic acid digestion; these mechanisms are dysregulated in SLE. In
turn, the burden of cellular debris exceeds that which can be cleared
in SLE, triggering nucleic acid sensors and toll-like receptors (TLRs)
in plasmacytoid dendritic cells to express type 1 IFN. Consequently,
IFN primes neutrophils for further turnover and sensitizes the adaptive
Cellular debris induces IFN
response that sensitizes the
immune response
The innate immune system
processes debris
FcGR
TLR
Endosome
Macrophage
phagocytosis
Dendritic cell
antigen presentation
(MHC) to T-cells
IFN
Plasmacytoid DC
Autoreactive B cells produce
autoantibody with activation
signals from T-helper cells.
Autoreactive
T cell
Autoreactive
B cell
Autoantibodies
Immune complexes
deposit in tissue
Autoantibodies (i.e., anti-dsDNA, anti-Sm
autoantibodies) against cellular debris
form immune complexes
Legend
NETosis: Program for formation of neutrophil
extracellular traps (NETs)
Plasmacytoid DC: Plasmacytoid dendritic cell
TLR: Toll-like receptor
immune system. Other innate immune cells with aberrant function in
SLE include classical monocytes that infiltrate and repair injured tissue
due to immune complex deposition and nonclassical monocytes that
patrol the vascular lumen for injury. Sustained activation of these sub­
sets from SLE leads to tissue inflammation and scarring.
■
■ADAPTIVE IMMUNITY
B cells play a central role in the SLE pathogenesis based on the production
of autoantibodies due to their loss of tolerance. Autoantibodies, especially
those complexed with nucleic acid, are pathogenic mediators of tissue
inflammation and damage in SLE. These autoantibodies induce type 1
IFN and other inflammatory mediators and activate patrolling monocytes
in tissue. A subset of circulating age-associated B cells (ABCs) expands in
SLE patients and eventually matures into autoantibody-secreting plasma
cells, indicating that SLE patients have an increased population of B cells
primed to generate pathogenic autoantibodies. Similar to B cells, T cells
lose tolerance and play a central role in the autoimmune response. In
particular, both T follicular and T peripheral helper cells promote B-cell
differentiation into pathogenic, high-affinity, autoantibody-secreting
plasma cells. T regulatory cells meant to maintain tolerance in both T and
B cells are defective in SLE.
CLINICAL MANIFESTATIONS
■
■OVERVIEW AND SYSTEMIC MANIFESTATIONS
The initial presentation of SLE is variable and may present as nonspe­
cific constitutional symptoms with or without single-organ or mul­
tiorgan involvement. Autoantibody presence is helpful in attributing
nonspecific symptoms to SLE. Symptoms can be mild to severe at any
time over the course of the disease, including at initial presentation.
Patients with severe disease often have systemic symptoms such as
fever, anorexia, and unintentional weight loss. Approximately 15% of
patients have relatively mild disease, which may or may not be accom­
panied by fatigue, brain fog, and/or mild arthralgia. The majority of
SLE patients have active disease despite therapy or have frequent flares
of their disease requiring treatment adjustment. Goals for SLE treat­
ment are low-level disease activity or remission on ongoing therapy.
(See “Outcomes” section for more details.)
■
■MUSCULOSKELETAL MANIFESTATIONS
Nonspecific arthralgia and myalgia are common in SLE. Lupus arthritis
is characterized by a polyarthritis most commonly involving the wrists,
the metacarpal-phalangeal and proximal interphalangeal joints of the
hands, and the knees. In some cases, damage of the periarticular liga­
ments may lead to Jaccoud-like changes (Fig. 368-2A). Rheumatoid
arthritis and SLE can occur simultaneously, and this overlap is denoted
by the term rhupus. While radiographs rarely demonstrate erosive
changes in lupus arthritis, emerging studies with magnetic resonance
imaging (MRI) and ultrasound imaging suggest a possible erosive pat­
tern that is less severe than that seen with rheumatoid arthritis. Pain in
a single hip, shoulder, or knee out of proportion to other joints should
prompt consideration of avascular necrosis of bone, particularly with
history of corticosteroid usage. Inflammatory muscle disease is also
seen in lupus, characterized by symmetrical proximal weakness, ele­
vated creatine kinase and aldolase levels, and inflammatory changes on
muscle biopsy. Corticosteroids used to treat SLE may cause myopathy,
as can antimalarials, although this is rare.
■
■CUTANEOUS MANIFESTATIONS
Three major categories of SLE skin manifestations include acute cuta­
neous lupus erythematosus (ACLE), subacute cutaneous lupus erythe­
matosus (SCLE), and chronic cutaneous lupus (Fig. 368-2B-F). ACLE
occurs with SLE disease activity, whereas SCLE and certain forms of
chronic cutaneous lupus may be seen in the absence of systemic dis­
ease. The most classic form of ACLE is the malar rash, which appears in
a “butterfly” distribution across the cheeks of the face with nasolabial
sparing. Due to its photosensitive nature, slightly raised lesions, and
location on the face, this may be confused with rosacea, which involves
the nasolabial folds. ACLE may also present as a generalized macu­
lopapular rash in sun-exposed areas of the body, bullous lupus, toxic
epidermal necrolysis variant, and generalized photosensitivity. SCLE
is a photosensitive rash associated with anti-Ro or SSA antibodies that
is characterized by flat, red-rimmed annular or psoriasiform lesions.
Discoid lesions are rough, circular lesions that are slightly raised,
scaly, and hyperpigmented with depigmented, atrophic centers and
erythematous rims, and are the most common chronic dermatitis seen
in SLE. Other chronic forms of cutaneous lupus include hypertrophic
or verrucous lupus, lupus panniculitis, tumid lupus, chilblains lupus,
and discoid lupus/lichen planus overlap. Nonspecific cutaneous mani­
festations that may be seen in SLE include nonscarring alopecia, oral
and nasal painful or nonpainful mucosal ulcers, and the less common
leukocytoclastic and urticarial vasculitides. Approximately one-third
of SLE patients also experience Raynaud’s phenomenon, a condition
in which small blood vessels undergo vasospasm with exposure to cold
environment or stress, causing a classically triphasic color change of the
fingers and/or toes, inducing white (blanching), blue (cyanosis), and
red (hyperemia) coloring of the extremities.
CHAPTER 368
Systemic Lupus Erythematosus
■
■RENAL MANIFESTATIONS
Nephritis occurs in ~35% of patients with SLE and is more severe in
non-White patients, more frequently leading to end-stage renal dis­
ease (ESRD) despite therapy. Nephritis can be seen with or without
extrarenal SLE disease and may be present in an asymptomatic patient.
Patients should therefore be screened at regular 3-month intervals with
a random urine protein-to-creatinine ratio (UPCr) or a 24-h urine pro­
tein and creatinine determination. Usually, nephritis is seen in patients
with elevated serum anti–double-stranded DNA (dsDNA) antibody
titers and decreased serum levels of C3 and/or C4, and trends of these
biomarkers over time may serve as warning signs of impending active
nephritis. Renal biopsy is generally prompted by a UPCr of >0.5 and/
or declining kidney function. Classification is based on renal pathol­
ogy from a renal biopsy and is defined by the International Society of
Nephrology/Renal Pathology Society criteria. Aggressive therapy is
generally reserved for patients with class III (focal proliferative glo­
merulonephritis), class IV (diffuse proliferative glomerulonephritis),
or a combination of class III or IV with class V disease (membranous)
(Fig. 368-3, Chap. A4). Approximately 20% of lupus nephritis patients
with significant proteinuria tend to have class V disease and more often
have nephrotic syndrome. Patients with class V lupus nephritis have a
better overall prognosis than patients with class III or IV lupus nephri­
tis and are treated in the same manner as class III and IV. Patients who
do not respond to treatment may require a repeat biopsy to evaluate
for a change in class. In the United States, ~20% of SLE patients with
class IV lupus nephritis die or develop ESRD within 10 years. Newer
approaches are being developed to both increase renal survival and
spare patients from accelerated atherosclerosis, hypertension, hyper­
glycemia, and hyperlipidemia, all of which can be accelerated by renal
disease and corticosteroid usage.
■
■NERVOUS SYSTEM MANIFESTATIONS
Lupus patients experience neuropsychiatric manifestations of disease
that are characterized by diffuse or focal symptoms. The most com­
mon diffuse symptom is “brain fog,” a cognitive dysfunction or slow­
ing of thought. The etiology is not well understood but may be related
to autoantibodies crossing the blood-brain barrier, leading to local
inflammation and neuronal damage. Headache is common and often
severe, although it may be difficult to distinguish from migraine or
tension headache. Seizures of any type may be seen in neuropsychiat­
ric lupus. Acute psychosis and confusional states are uncommon but
can occur in SLE without any structural abnormalities. In these cases,
glucocorticoid-induced psychosis and infectious encephalitis should
be ruled out. Transverse myelitis is a rare SLE complication that mani­
fests as bilateral neurologic deficits such as symmetric motor weakness
and decreased sensation due to spinal cord inflammation.
■
■VASCULAR OCCLUSION: MYOCARDIAL
INFARCTIONS AND STROKE
Coronary heart disease from accelerated atherosclerosis in SLE is a
significant cause of morbidity and premature death, especially in young
patients without other risk factors. Vascular injury due to excessive
PART 11
Immune-Mediated, Inflammatory, and Rheumatologic Disorders
A
B
C
D
E
F
FIGURE 368-2  Characteristic musculoskeletal and cutaneous manifestations seen in systemic lupus erythematosus (SLE). A. Jaccoud arthropathy, characterized by
chronic, nonerosive, and reversible deviations caused by joint capsule inflammation with subsequent fibrotic retraction and metacarpophalangeal joint subluxation. B.
Patchy, nonscarring alopecia. C. Patchy scarring alopecia. D. Patchy alopecia associated with chronic, scarring discoid lupus changes. E. Classic photosensitive malar
rash. F. Subacute cutaneous lupus erythematosus (SCLE) with widespread, nonscarring photosensitive features. (Panels B–E reproduced with permission from Victoria
Werth, MD. Panels A and F reproduced with permission from DoQuyen Huynh, MD.)
type 1 IFN and cellular death may predispose to atherosclerosis. The
risk of coronary artery disease and vascular thrombosis is further
increased in SLE patients with antiphospholipid syndrome (APS), an
autoimmune syndrome that commonly occurs in SLE and is character­
ized by arterial, venous, or small vessel thromboembolic events in the
presence of antiphospholipid antibodies with prothrombotic proper­
ties (Chap. 369). Stroke has been reported in up to 19% of patients
with SLE, a result of atherosclerosis and increased risk from APS. In
addition to stroke, APS appears to be a significant risk factor for other
focal central nervous system manifestations including seizures and
transverse myelitis.
■
■PULMONARY MANIFESTATIONS
The most common pulmonary manifestation of SLE is pleuritis,
which can occur with or without exudative pleural effusions. Acute
pneumonitis may present in active SLE, with pulmonary infiltrates
often appearing indistinguishable from infection on imaging. Diffuse
alveolar hemorrhage with capillaritis and interstitial lung disease may
also be seen. Restrictive lung defect from reduced lung volumes, also
known as shrinking lung syndrome, is uncommon but may occur.
Pulmonary arterial hypertension and pulmonary embolism may be
present with or without APS.
■
■CARDIAC MANIFESTATIONS
All layers of the heart may be involved in SLE, with pericardial involvement
being the most frequent. Pericarditis can typically be managed with
anti-inflammatory medications, colchicine, and anti-IL-1–directed
therapies, or without glucocorticoids, and rarely leads to tamponade
physiology. Myocarditis is rarer and may lead to left-sided heart failure
and/or arrhythmia. Libman-Sacks endocarditis, a fibrinous sterile form
of endocarditis that may be associated with antiphospholipid antibod­
ies, may increase the risk for embolic events. Right-sided heart failure
may be present with pulmonary arterial hypertension or chronic lung
disease.
■
■HEMATOLOGIC MANIFESTATIONS
Cytopenias in SLE are often multifactorial and may be associated
with disease activity, medication use, or infection. Anemia is the most
common hematologic manifestation of SLE and is present in >50% of
SLE cases, with anemia of chronic disease representing approximately
Class I
Class II
Class III/IV
Class V
Class III/IV + V
FIGURE 368-3  Ultrastructural features of lupus glomerulonephritis. Class I: Mesangial immune deposits (black) without mesangial cell (red) hypercellularity or leukocyte
infiltration. Class II: Mesangial immune deposits with mesangial cell hypercellularity, no leukocyte infiltration. Class III/IV: Subendothelial immune deposits visible by light
microscopy, with infiltration of mesangial and capillary leukocytes (dark green neutrophils and light green monocytes/macrophages). Class III/IV + V: Leukocyte infiltration
with subepithelial and subendothelial immune deposits. Class V: Subepithelial immune deposits, no leukocyte infiltration. (Reproduced with permission from IM Bajema et
al: Revision of the International Society of Nephrology/Renal Pathology Society classification for lupus nephritis: Clarification of definitions, and modified National Institutes
of Health activity and chronicity indices. Kidney Int 93:789, 2018, Figure 2.)
one-third of cases; other causes for anemia in SLE include iron
deficiency, autoimmune hemolytic anemia, aplastic anemia, micro­
angiopathic hemolytic anemia, and medication effect. Leukopenia
(<4000/µL) is common, occurring in about half of SLE patients, and
usually consists of lymphopenia (<1500/µL), rather than neutropenia.
Thrombocytopenia (<150,000/µL) is usually mild but can also be
severe (<50,000/µL) and pose significant bleeding risk. It is most com­
monly due to immune mechanisms and may be associated with APS
or antiphospholipid antibodies against platelet antigens. Splenomegaly,
splenic atrophy, and asplenism may all be seen in SLE. Depending
on severity of the abnormal blood counts, treatment considerations
include glucocorticoids, anti-CD20 biologic agents, platelet growth
factors, intravenous immunoglobulin, and/or splenectomy in resistant
cases. Rarely, atypical hemolytic-uremic syndrome (formerly des­
ignated as thrombotic thrombocytopenic purpura or the syndrome
of microvascular thrombotic crisis) may occur. This is a condition
that presents with hemolysis, thrombocytopenia, and microvascular
thrombosis, as well as brain and other tissue involvement. Laboratory
testing shows schistocytes in the peripheral blood smear, low levels of
ADAMTS13 activity, and elevated serum lactate dehydrogenase levels.
■
■GASTROINTESTINAL MANIFESTATIONS
Lupus can involve any part of the gastrointestinal tract. Flaring SLE
activity has been associated with nonspecific gastrointestinal symptoms
including nausea, vomiting, and diarrhea. Abdominal pain may be
caused by lupus peritonitis, enteritis, pancreatitis, or vasculitis. Mesen­
teric vasculitis can lead to intestinal perforation, bleeding, and ischemia
and requires high doses of glucocorticoids for treatment. Impaired
intestinal motility and protein-losing enteropathy may also occur.
CHAPTER 368
Systemic Lupus Erythematosus
Elevated liver enzymes are common and may be associated with flaring
disease activity, medications, and/or coexisting autoimmune hepato­
biliary disease. Mesenteric thrombosis, Budd-Chiari syndrome, and
hepatic venoocclusive disease can be observed with concomitant APS.
■
■OCULAR MANIFESTATIONS
Keratoconjunctivitis sicca is common in SLE, even in the absence of
secondary Sjögren’s syndrome. Retinal vasculitis, optic neuritis, uveitis,
scleritis, peripheral ulcerative keratitis, episcleritis, and nonspecific
conjunctivitis may all be seen. Retinal vasculitis is rare but, when
present, requires aggressive immunosuppression to prevent blindness.
Adverse ocular effects from medications include cataracts and glau­
coma from glucocorticoid treatment and hydroxychloroquine (HCQ)-
induced maculopathy (Table 368-1).
LABORATORY TESTS
■
■AUTOANTIBODIES
An elevated titer of ANA reflects the underlying immune dysregulation
in SLE. Measuring ANA presence and titer is the best screening test for
SLE because ANAs are seen in almost all SLE patients. Repeated nega­
tive tests by immunofluorescence make a diagnosis unlikely, but rare
cases of ANA-negative SLE do occur. Classification of SLE by current
EULAR/ACR criteria requires the presence of an ANA titer of 1:80 for
enrollment of patients into SLE clinical trials; however, the diagnosis
is based on clinical and laboratory features and ultimately, clinical
judgement (see “Diagnosis and Classification” section). Numerous
ANAs have been identified that target nuclear antigens; in particu­
lar, components of the nucleosome (DNA wrapped around a histone
TABLE 368-1  Clinical Manifestations of Systemic Lupus Erythematosus
Constitutional
Fatigue, malaise, fever, weight loss, anorexia
Cutaneous 
  Generalized
Photosensitivity, oral and nasal ulcers, alopecia
  Acute cutaneous
Malar rash, maculopapular rash, bullous lupus, toxic
epidermal necrolysis variant
PART 11
Immune-Mediated, Inflammatory, and Rheumatologic Disorders
lupus
  Subacute cutaneous
 
lupus
  Chronic forms of
Discoid rash, panniculitis, tumid lupus, chilblains,
verrucous lupus, cutaneous vasculitis
cutaneous lupus
Musculoskeletal
Arthralgia, myalgia, polyarthritis, Jaccoud hand
deformity, inflammatory myopathy, avascular necrosis
of bone
Hematologic
Anemia, leukopenia, lymphopenia, thrombocytopenia,
lymphadenopathy, splenomegaly, venous or arterial
thrombosis, atypical hemolytic-uremic syndrome
Cardiopulmonary
Pleurisy, pericarditis, pleural and pericardial effusions,
myocarditis, endocarditis, pneumonitis, coronary artery
disease, interstitial fibrosis, pulmonary hypertension,
diffuse alveolar hemorrhage, shrinking lung syndrome
Vascular
Pulmonary hypertension, stroke, myocardial infarction,
peripheral arterial disease, pulmonary embolism, deep
vein thrombosis, Raynaud’s phenomenon
Neurologic
Cognitive dysfunction, mood disorder, depression,
headache, seizures, mononeuropathy, polyneuropathy,
stroke, transient ischemic attack, psychosis, aseptic
meningitis, transverse myelitis
Renal
Proteinuria ≥500 mg/24 h, cellular casts, nephrotic
syndrome, end-stage renal disease
Gastrointestinal
Nausea, abdominal pain, diarrhea, elevated liver
enzymes, lupus peritonitis or enteritis, vasculitis,
pancreatitis
Ocular
Sicca syndrome, conjunctivitis, episcleritis, scleritis,
uveitis, retinal vasculitis
octamer) or RNA-binding proteins (RBPs). In SLE, the most common
antinucleosome antibodies are anti-dsDNA antibodies that are pres­
ent in ~40–60% of patients and highly specific (75–99%). Anti-Smith
(anti-Sm) antibodies are the most common anti-RBP, present in ~30%
of patients, and are highly specific for SLE (55–100%). Given their
high specificity, both anti-dsDNA and anti-Sm antibodies are the only
ANA subtypes that are included in the current EULAR/ACR criteria.
Anti-Ro (SS-A) antibodies, which recognize a protein complexed pri­
marily to 60-kDa and 52-kDa RNAs, are often seen in ANA-negative
SLE patients and are associated with risk for neonatal lupus, sicca
symptoms, photosensitivity, and SCLE. Antihistone antibodies may
be associated with drug-induced lupus (see “Drug-Induced Lupus”
section). Antiphospholipid antibodies, as measured by IgG, IgM, and
IgA isotypes of anticardiolipin and anti–beta-2 glycoprotein-1 antibod­
ies (anti-β2GP-1), and the lupus anticoagulant usually obtained using
the dilute Russell venom viper time (dRVVT) are present in ~50% of
SLE patients. These antibodies, especially the IgG and IgA isotypes of
cardiolipin and β2GP-1, and the lupus anticoagulant are associated with
arterial and venous thrombosis, thrombocytopenia, and recurrent fetal
loss (Table 368-2). Many ANA subtypes can be present in SLE and
other systemic autoimmune diseases including myositis, rheumatoid
arthritis, Sjögren’s syndrome, and systemic scleroderma, as well as
organ-specific autoimmune diseases such as autoimmune hepatitis,
Hashimoto’s thyroiditis, and primary biliary cholangitis.
■
■STANDARD DIAGNOSTIC TESTS
Immunologic, renal, and hematologic domains make up the laboratory
testing for the diagnosis of SLE. Among the immunologic domain,
elevated titers of ANA confer a high likelihood of SLE. Although ANAs
are present at low levels in healthy patients, the threshold for a positive
test of 1:80 or higher favors SLE. In the setting of ANA negativity with
a clinical presentation highly suggestive of SLE, anti-Ro (SSA) confers
a high likelihood of SLE. Further immunologic testing for anti-dsDNA
TABLE 368-2  Autoantibodies in Systemic Lupus Erythematosus
PREVALENCE,
%
CLINICAL ASSOCIATIONS
ANTIBODY
ANA
Titers of 1:80 or higher are considered
positive and are sensitive for SLE but
not specific.
Anti-dsDNA
Higher titers are more specific for
SLE.
Levels correlate with disease activity
and nephritis.
Anti-Sm
Most specific autoantibody for SLE
and more common in black and
Asian patients. May correlate with
CNS manifestations and incidence of
nephritis.
Anti-RNP
Not SLE-specific. Associated with
overlap syndromes and increased
risk for pulmonary hypertension.
Correlates with high interferon gene
signature.
Anti-Ro (SS-A)
Not SLE-specific. Associated with
sicca syndrome, neonatal lupus and
congenital heart block, and subacute
cutaneous lupus.
Anti-La (SS-B)
Associated with anti-Ro.
Antiribosomal P
May be associated with CNS
involvement. Specific for SLE but not
sensitive.
Antihistone
Associated with drug-induced lupus.
Anti–U1-RNP
Associated with musculoskeletal and
lung impairment.
Antiphospholipid
  Anticardiolipin
  Anti–b2-glycoprotein
  Lupus anticoagulant
Arterial or venous thrombosis,
pregnancy morbidity and fetal loss,
thrombocytopenia. Associated
with CNS manifestations, LibmanSacks endocarditis, hypertension,
pulmonary hypertension.
Abbreviations: ANA, antinuclear antibody; CNS, central nervous system; dsDNA,
double-stranded DNA; RNP, ribonucleoprotein; SLE, systemic lupus erythematosus;
Sm, Smith.
and anti-Sm autoantibodies confers specificity. Anti-dsDNA antibod­
ies and reduced levels of complement components C3 and C4 suggest
a propensity for lupus nephritis, as these tests indirectly reflect the
pathogenic production of autoantibodies and the high load of cellular
debris. Laboratory testing is required at initial presentation to screen
for hematologic abnormalities including leukopenia, lymphopenia,
thrombocytopenia and anemia of chronic inflammation, hemolytic
anemia, and atypical hemolytic-uremic syndrome. Initial testing for
renal abnormalities is necessary to determine an estimated glomerular
filtration rate (eGFR), serum creatinine, and either a random or 24-h
UPCr. When commercially available, consideration should be given
to measuring urinary biomarkers recently noted to be associated with
renal inflammatory and fibrotic disease, including urinary interleukin
16, CD163, type 1 IFN, and transforming growth factor-beta (TGF-β).
■
■TESTS FOR FOLLOWING DISEASE COURSE
Clinical manifestations of SLE vary over time, likely in response to
the aberrant immunologic mechanisms that are driving disease. In
particular, anti-dsDNA antibody titers are important to track disease
activity. These autoantibodies are produced by a short-lived population
of B-cell plasmablasts that turn over rapidly, reflecting the presence
or absence of immunologic activity. Levels of the complement factors
C3 and C4 can drop during episodes of high disease activity, as these
are affected by the formation of autoimmune immune complexes and
apoptotic cells. In lupus nephritis, the extent of proteinuria and the
eGFR are also frequently monitored. Quarterly testing is suggested
in asymptomatic patients because hematologic and renal manifesta­
tions can be present in the absence of symptoms. Testing should be
performed to consider the presence of leukopenia, lymphopenia,
thrombocytopenia, anemia (both anemia of chronic inflammation and
hemolytic anemia), and rarely, atypical hemolytic-uremic syndrome.
Testing for eGFR, serum creatinine, and a random or 24-h UPCr level
is essential for routine follow-up care with consideration of a renal
biopsy when urinary protein exceeds a new level of UPCr of 0.5 to rule
out active lupus nephritis. Consideration should be given to measuring
urinary biomarkers on a quarterly basis when available.
MANAGEMENT
EULAR recently updated recommendations for the management of
SLE and lupus nephritis. Goals for SLE treatment include improved
disease activity with minimal symptoms, prevention of damage, and
improved quality of life (Figs. 368-4 and 368-5). Adherence to treat­
ment plans is essential. Achieving these goals with safe treatments and
minimal corticosteroids is an integral aspect of achieving low levels of
disease activity and remission. If corticosteroids are utilized for active
or flaring disease, the goal should be to utilize the lowest possible dos­
age to suppress disease activity. Aggressive therapy should be reserved
for life-threatening manifestations or those that could lead to damage.
Consideration should be given to minimize both the effects of active
disease and complications from treatment. Renal treatment goals based
on EULAR recommendations include (1) a goal that all patients should
at least achieve a state of low disease activity, defined by a Systemic
Lupus Erythematosus Disease Activity Index (SLEDAI) score of 0–4;
or (2) remission, defined as a SLEDAI score of 0, both with stable use
of HCQ, immunosuppressives or biologics, and a daily dose of 5 mg
of prednisone (or glucocorticoid equivalent) or less (see “Outcomes”
section).
Treatment of Non-Renal Systemic Lupus Erythematosus
Mild*
Moderate*
Severe*
1st line
2nd line
1st line
2nd line
1st line
2nd line
General measures
HCQ (all patients unless contraindicated)
Sun protection
Exercise
No smoking
Balanced diet
Vaccinations
Normal body weight
Blood pressure, lipid,
glucose control
GC PO/IV (if needed, short-term use to control active disease; taper to ≤5 mg/day
as quickly as possible and discontinue, if possible)
MTX
AZA
MMF
MMF
Acetylsalicylic acid,
VKA
(in aPL+/APS)
Immunosuppressive
or biological agents
at stable, tolerated
dose
Assess adherence
to treatment
Grade A
Grade B
Grade C
Grade D
FIGURE 368-4  Treatment of nonrenal systemic lupus erythematosus (SLE). Notes: Top-to-bottom sequence does not imply order of preference (e.g., MTX, AZA, and MMF
are equal options for second-line therapy in mild disease or first-line therapy in moderate disease). *Mild disease: constitutional symptoms; mild arthritis; rash ≤9% body
surface area; platelet count (PLTs) 50–100 × 109/L; SLEDAI ≤6; BILAG C or ≤1 BILAG B manifestation. *Moderate disease: moderate-to-severe arthritis (“rheumatoid
arthritis–like”; rash 9–18% body surface area [BSA]; PLTs 20–50 × 109/L; serositis; SLEDAI 7–12; ≥2 BILAG B manifestations). *Severe disease: major organ-threatening
disease (e.g., cerebritis, myelitis, pneumonitis, mesenteric vasculitis); thrombocytopenia with platelets <20 × 109/L; thrombotic thrombocytopenic purpura–like disease
or acute hemophagocytic syndrome; rash >18% BSA; SLEDAI >12; ≥1 BILAG A manifestation. †Recommendation of belimumab and anifrolumab as first-line therapy in
severe disease refers to cases of extrarenal SLE with nonmajor organ involvement but extensive disease from skin, joints, and so on. The use of anifrolumab as add-on
therapy in severe disease refers mainly to severe skin disease. For patients with severe neuropsychiatric disease, anifrolumab and belimumab are not recommended. ANI,
anifrolumab; aPL, antiphospholipid antibodies; APS, antiphospholipid syndrome; AZA, azathioprine; BEL, belimumab; BILAG, British Isles Lupus Assessment Group; CNI,
calcineurin inhibitor; CYC, cyclophosphamide; GC, glucocorticoids; HCQ, hydroxychloroquine; IV, intravenous; MMF, mycophenolate mofetil; MTX, methotrexate; PO, per os;
RTX, rituximab; SLEDAI, SLE Disease Activity Index; VKA, vitamin K antagonists. (Reproduced with permission from A Fanouriakis et al: Ann Rheum Dis 83:15, 2024.)
■
■ESSENTIAL LUPUS THERAPEUTIC APPROACHES
AND ANTIMALARIALS
All SLE patients should use daily sunscreen on sun-exposed areas,
maintain a healthy diet and weight, avoid smoking, exercise regularly,
maintain compliance with vaccination recommendations, and regu­
larly monitor and achieve control of their blood pressure, lipid, and
glucose levels. Antimalarials should be used in all patients unless con­
traindicated, as they have been shown to prevent flares, increase overall
survival, and decrease the risk of developing renal disease and acceler­
ated atherosclerosis, among other benefits. HCQ, one of the first drugs
approved by the U.S. Food and Drug Administration (FDA) for use in
SLE, is the most common antimalarial used and is first-line therapy
for patients with skin manifestations and arthritis. It is the most use­
ful drug to improve fatigue in SLE. Use during pregnancy and during
breastfeeding has been demonstrated to be safe. Appropriate dosing of
HCQ is under investigation, as higher doses may be associated with
better disease control. Current recommendations are for dosing up
to 5 mg/kg per day (actual body weight) with performance of retinal
evaluations at baseline and at yearly intervals to monitor for macular
effects, which are associated with prolonged usage. Risk factors for
retinal toxicity from HCQ include higher dose and longer duration
of use; however, higher doses may also confer better disease control,
and overall risk for maculopathy remains low. The most appropri­
ate dose of HCQ for SLE treatment thus remains unclear. Other side
effects of HCQ may include rash, nausea, vomiting and diarrhea, and
skin dyspigmentation. Tobacco use may interfere with the efficacy of
antimalarials. Alternative antimalarials include chloroquine, which
has a higher risk of retinal toxicity, and quinacrine, which has a higher
CHAPTER 368
Systemic Lupus Erythematosus
Target
Remission
Clinical SLEDAI = 0
HCQ
GC ≤5 mg/day
or
Low disease
activity
SLEDAI ≤4
HCQ
GC ≤5 mg/day
BEL†
ANI†
CNI
CNI
CYC
RTX
RTX
Treatment of Lupus Nephritis
Initial
Subsequent
HCQ (all patients unless contraindicated)
Adjunct treatment
for kidney
protection#
PART 11
Immune-Mediated, Inflammatory, and Rheumatologic Disorders
GC PO/IV (consider pulse IV MP, then 0.3–0.5 mg/kg/day depending
on severity; taper to ≤5 mg/day as quickly as possible)
ACEi/ARBs
Consider SGLT2i
(if decreased eGFR)
Low-dose CYC
VKA, heparin
(if concomitant APS
nephropathy)
MMF/AZA + BEL§
MMF/low-dose CYC + BEL§
MMF + CNI (esp. VOC, TAC)^
High-dose CYC *,¶
Any of the above–
mentioned unless
contraindicated^
RTX†
Assess adherence
to treatment
Grade A
Grade B
Grade C
Grade D
FIGURE 368-5  Treatment of lupus nephritis. Notes: Top-to-bottom sequence does not imply order of preference. #In addition to general protective measures, as outlined
in Figure 368-3. §BEL should always be given in combination with MMF or low-dose CYC as initial therapy and with MMF or AZA as maintenance therapy. ˆCNIs should be
given in combination with MMF. *Particularly recommended in the presence of poor prognostic factors: reduced eGFR, histologic presence of cellular crescents or fibrinoid
necrosis, or severe interstitial inflammation. ¶Extension of high-dose CYC to subsequent phase refers to severe lupus nephritis cases, in which bimonthly or quarterly CYC
pulses may be given following 6 monthly pulses. †In relapsing/refractory disease, especially after failure of CYC-based regimens. ACEi, angiotensin-converting enzyme
inhibitors; APS, antiphospholipid syndrome; ARB, angiotensin receptor blockers; AZA, azathioprine; BEL, belimumab; CNI, calcineurin inhibitor; CYC, cyclophosphamide;
eGFR, estimated glomerular filtration rate; GC, glucocorticoids; HCQ, hydroxychloroquine; IV, intravenous; MMF, mycophenolate mofetil; MP, methylprednisolone; PO, per
os; RTX, rituximab; SGLT2i, sodium-glucose cotransporter 2 inhibitors; TAC, tacrolimus; Upr, urine protein; VKA, vitamin K antagonists; VOC, voclosporin. (Reproduced with
permission from A Fanouriakis et al: Ann Rheum Dis 83:15, 2024.)
risk of skin dyspigmentation. Quinacrine can be used as alternative
therapy in cases of toxic retinopathy or as add-on therapy to HCQ for
patients with inadequate response. For arthritis and arthralgia, non­
steroidal anti-inflammatory drugs (NSAIDs) can be useful but should
be used with caution in SLE patients due to increased risk for aseptic
meningitis, hypertension, renal dysfunction, elevated serum transami­
nases, and increased myocardial infarction risk with cyclooxygenase-2
inhibition.
■
■GLUCOCORTICOIDS
Glucocorticoid dosing is based on the organ-specific needs and sever­
ity of disease. While effective at reducing inflammation quickly, their
use is associated with dose-dependent side effects including cushin­
goid metabolic effects, hyperglycemia, hypertension, osteoporosis,
and avascular necrosis. If needed, corticosteroids should be tapered as
quickly as possible to maintenance doses of 5 mg or less of daily predni­
sone or its equivalent, and withdrawn as soon as feasible. Use of intra­
venous methylprednisolone (usually 125–1000 mg daily for 1–3 days)
is limited to emergent needs such as active nephritis, severe central
nervous system or vascular involvement, and hematologic manifesta­
tions such as life-threatening hemolytic anemia or thrombocytopenia.
A major goal of novel SLE therapies is the ability to develop treatment
algorithms that are less dependent on chronic glucocorticoid use.
■
■SKIN AND MUSCULOSKELETAL
MANIFESTATIONS: IMMUNOMODULATING AND
IMMUNOSUPPRESSANT DRUGS
All SLE patients and especially those with skin manifestations of
disease should be treated with topical sunscreens and antimalarials.
If unresponsive to these approaches, topical glucocorticoids and/
or calcineurin inhibitors can be utilized. Persistent mucocutane­
ous disease and/or arthritis may prompt consideration of additional
oral immunomodulating drugs such as azathioprine (6-thioguanine
purine analogue), leflunomide (lymphocyte-specific pyrimidine syn­
thesis inhibitor), mycophenolate mofetil (MMF), or mycophenolic
acid (purine synthesis inhibitors). Biological drugs such as belimumab
Targets
3 months
≥25% reduction in
UPr
MMF
6 months
≥50% reduction in
UPr to <3 gr/day
AZA/MMF
12 to 24 months
UPr <0.5–0.7 gr/day
(all with eGFR within
10% from baseline)
(anti-BAFF, administered intravenously or subcutaneously) and ani­
frolumab (anti–type 1 IFN receptor, administered intravenously) are
FDA-approved approaches shown to improve outcomes in these clini­
cal domains, with better ability to taper glucocorticoids. Thalidomide
and lenalidomide may be used for some cutaneous subtypes but with
caution due to risk for polyneuropathy and teratogenicity. Methotrex­
ate (a folinic acid antagonist) is another option for arthritis associated
with SLE.
■
■RENAL DISEASE: SUCCESSES WITH
COMBINATION THERAPIES
Treatment approaches have been recommended by EULAR for
class III and IV lupus nephritis, as well as combination of class V lupus
nephritis with either class III or IV (Fig. 368-5). The recommended
targets are a 3-month target of 25% or more reduction in UPCr level,
a 6-month target of 50% or more reduction in UPCr to <3 g/d,
and a 12- to 24-month target in UPCr to <0.5–0.7 g/d, with each of
these targets associated with an eGFR within 10% from baseline. All
patients with class III, IV, or V nephritis should receive an angiotensinconverting enzyme (ACE) inhibiting agent or an angiotensin receptor
blocking (ARB) agent to decrease proteinuria and reduce systemic
and glomerular hypertension. With a baseline decreased eGFR, use
of a sodium-glucose cotransporter 2 (SGLT2) inhibitor should be
considered to reduce glomerular hyperfiltration, lower blood pressure,
and decrease proteinuria. Patients with active lupus nephritis with
concomitant antiphospholipid nephropathy as noted by biopsy should
receive a vitamin K antagonist or heparin.
Current initial regimens include either cyclophosphamide (an
alkylating agent administered intravenously) or MMF (administered
orally) plus glucocorticoids to reduce progression to ESRD and death.
Rates of infection and death are similar in both treatment approaches.
Induction in Black or Hispanic patients with MMF 2–3 g daily is appro­
priate given better response to MMF in these ethnic groups, while use
of either MMF or cyclophosphamide may be an option for White and
Asian patients. Low doses of cyclophosphamide (500 mg every 2 weeks
for six doses) followed by either azathioprine or MMF maintenance are
as effective as standard high doses of cyclophosphamide with improved
tolerability. High-dose cyclophosphamide monthly for 6 months fol­
lowed by azathioprine or MMF may be more appropriate for patients
with crescentic proliferative glomerulonephritis or rapidly progressive
glomerulonephritis. Ovarian failure is a potential consequence of
high-dose cyclophosphamide, and therefore, a gonadotropin-releasing
hormone agonist may be given prior to each cyclophosphamide dose.
Dosing of glucocorticoids as part of the initial therapeutic approach is
controversial, with more recent data suggesting the use of intermediate
doses for shorter periods of time with more rapid dose reduction. For
subsequent therapy, MMF is superior to azathioprine in maintaining
renal function and survival, but both may be used, and azathioprine
is the preferred agent for lupus nephritis in pregnancy. Patients using
azathioprine should be screened for homozygous deficiency of the
thiopurine S-methyltransferase (TMPT) gene, which increases the risk
for severe bone marrow suppression, as this gene is responsible for the
TPMT enzyme necessary for metabolizing thiopurine drugs. Calcineu­
rin inhibitors such as tacrolimus and cyclosporine may be beneficial
for decreasing proteinuria, and tacrolimus can be used in pregnancy.
Two immunomodulating therapies have recently been approved by
the FDA for use in lupus nephritis for patients on standard therapy for
active nephritis: belimumab, approved in 2020, and the cyclosporine
analogue voclosporin, approved in 2021. The randomized controlled
trials for these medications demonstrate favorable outcomes without the
use of high-dose steroids. Voclosporin-based triple immunotherapy
(with MMF and glucocorticoids) or belimumab-based triple therapy
(with either low-dose cyclophosphamide or MMF and glucocorticoids)
can be considered as an initial approach in active lupus nephritis.
Patients with active lupus nephritis and inadequate response to con­
ventional therapies may also consider alternative biologics targeting B
cells such as rituximab. While rituximab studies in lupus nephritis did
not demonstrate efficacy compared to standard therapies, issues with
the trial designs may have hampered the demonstration of an effect.
Treatment approaches for patients with pure class V membranous
glomerulonephritis have not been well studied, and commonly patients
with this presentation are treated only in the setting of significant
proteinuria. All patients with class III, IV, or V nephritis, including
combinations of class III or IV with class V, should be considered for
treatment with ARB or ACE inhibition to reduce proteinuria.
■
■THERAPIES FOR OTHER ORGAN-BASED SYSTEMS
Few studies have focused on central and peripheral nervous system,
cardiac, pulmonary, serosal, gastrointestinal, or hematologic manifes­
tations of SLE. Anti-CD20 agents such as rituximab are used for lupusrelated hemolytic anemia and severe thrombocytopenia. Colchicine
can be used to treat pleural, pericardial, or peritoneal inflammatory
symptoms. MMF, cyclophosphamide, and rituximab plus corticoste­
roids are the mainstay of treatment for serious central and peripheral
inflammatory nervous system presentations including psychosis, vas­
culitis, and transverse myelitis. Plasmapheresis and high levels of glu­
cocorticoids can be lifesaving in atypical hemolytic-uremic syndrome.
In refractory patients, rituximab and a C5 inhibitor, eculizumab, are
used. Concomitant APS should be treated with warfarin for long-term
anticoagulation rather than direct oral anticoagulants (Chap. 369).
■
■EMERGING THERAPIES AND TREATMENT
APPROACHES
SGLT2 inhibitors are being studied in lupus nephritis for their effects
on preserving function through tubular protection with effects on
inflammation and fibrosis. Obinutuzumab, a CD20-targeted mono­
clonal antibody that is commercially available for oncologic indi­
cations, has recently demonstrated efficacy in a phase 3 study for
lupus nephritis, and is also being investigated for use in SLE without
nephritis. Anecdotal experience with obinutuzumab by rheumatolo­
gists in treating SLE patients off-label suggests that this drug may be
more clinically effective than rituximab due to improved CD20 tissue
depletion. Deucravacitinib, an oral Tyk2 inhibitor, is in phase 3 study
for SLE. Telitacicept, a TACI-Fc fusion protein that targets BLyS and
APRIL growth factors for B cells, has been approved in China for use in
patients with SLE, and global phase 3 studies are underway. Litifilimab,
a drug in late-stage development with initial promising results, is a
monoclonal antibody targeting BDCA2, a protein expressed on plas­
macytoid dendritic cells, that suppresses activation of type I interferons
and other proinflammatory cytokines. Initial results show achievement
of remission, according to the Definition of Remission in Systemic
Lupus Erythematosus (DORIS), from nonrandomized CD19-directed
chimeric antigen receptor T-cell treatment, which has prompted inter­
est in further study of this approach. Other cell-based therapeutic
programs under investigation include both allogenic and autologous
natural killer cell–based programs and mesenchymal embryonic stem
cell transplantation for severe SLE.
CHAPTER 368
Systemic Lupus Erythematosus
■
■GUIDELINES
Besides the recent EULAR (2013) and Pan-American League of
Associations for Rheumatology (2018) guidelines for SLE and lupus
nephritis, the ACR (2012) and the Kidney Disease Improving Global
Outcomes (KDIGO) organization (2021) have published guidelines
specifically for lupus nephritis. These guidelines address medicationbased, lifestyle, and nonpharmacologic approaches, as well as infection
screening and vaccination recommendations. The KDIGO guidelines
include recommendations prior to the approval of belimumab and
voclosporin. An important concept that the KDIGO group emphasizes
is the unsettled question of duration of immunosuppression. The
group notes that the risk of lupus relapse should be balanced with
risk of adverse events secondary to immunosuppressive drugs. They
suggest that for patients who have achieved a complete renal response
and have no ongoing extrarenal SLE manifestations, the total duration
of immunosuppression (initial plus maintenance) should not be <36
months. The EULAR guidelines provide consensus guidance for SLE
management that combines evidence and expert opinion concerning
the use of HCQ, glucocorticoids, immunosuppressive drugs, calcineu­
rin inhibitors, and biologics, with suggestions for treatment strategies,
response assessment, combination approaches, and therapy tapering
(see Figures 368-4 and 368-5). Most of the concepts and strategies pre­
sented in these guidelines are described in the sections above.
DRUG-INDUCED LUPUS
Drug-induced lupus (DIL) is an autoimmune phenomenon in which a
positive ANA and clinical features of SLE arise from a drug exposure.
DIL accounts for ~6–12% of all lupus cases. Symptoms may include
fever, rash, arthralgia, myalgia, and serositis. Antihistone antibodies
are commonly associated with DIL, with dsDNA antibodies occurring
less frequently. DIL tends to be less severe than SLE, rarely involving
kidneys or brain, and symptoms typically resolve within several weeks
after discontinuation of the offending agent.
The first agent identified to cause lupus symptoms was hydralazine
in 1954. Over the years, >100 drugs have been identified as potential
triggers for DIL. The highest incidence of DIL occurs with the anti­
arrhythmic procainamide, with risk reported to be as high as 30%.
Other substances associated with DIL include the antihypertensives
hydralazine and methyldopa; other antiarrhythmics; antibiotics includ­
ing minocycline, isoniazid, rifampin, and nitrofurantoin; the anti­
rheumatic drug sulfasalazine; anticonvulsants such as phenytoin and
carbamazepine; antipsychotics including chlorpromazine and lithium;
several ACE inhibitors and beta blockers; the diuretic hydrochloro­
thiazide; the antithyroid propylthiouracil; proton pump inhibitors;
NSAIDs; and oral contraceptives. Biologic agents include antitumor
necrosis factor α medications, particularly infliximab and etanercept,
and IFN-α.
Diagnosis can be difficult, as DIL symptoms may start weeks to
several months after drug initiation. Furthermore, skin biopsy may be
indistinguishable from SLE, and laboratory characteristics including
histone antibody may be seen in the majority of SLE cases. In DIL, the
ANA pattern is most commonly homogeneous, and histone is posi­
tive in 75% of DIL cases. Cytopenias may be present but are typically
mild. The presence of other autoantibodies may help to distinguish
SLE from DIL, as these are rarely seen in DIL. The ANA test typically
appears before symptoms, although many of the same medications will
induce a positive ANA in patients who never develop symptoms. If DIL
is suspected, these laboratory tests should help to inform the clinical
picture to decide if medication discontinuation is appropriate. If symp­
toms resolve after medication discontinuation, this helps to confirm a
diagnosis of DIL.
PART 11
Immune-Mediated, Inflammatory, and Rheumatologic Disorders
PREGNANCY AND REPRODUCTIVE
HEALTH
■
■FERTILITY
Lupus activity can affect the menstrual and ovulation cycle. Lower
measures of ovarian reserve are seen in SLE patients compared to
healthy controls. Women with SLE have a higher risk for infertility if
they have active disease, comorbidities such as APS or nephritis, and
prior exposure to treatments such as cyclophosphamide. Cyclophos­
phamide use may lead to amenorrhea, ovarian insufficiency, and early
menopause.
■
■CONTRACEPTION/HORMONE REPLACEMENT
Contraception and family planning should be discussed with all women
of reproductive age with SLE. SLE patients with antiphospholipid anti­
bodies and those with moderate-to-severe or active lupus should avoid
estrogen compounds due to increased risk for thromboembolism.
Progestin-only contraceptive options such as the levonorgestrel intra­
uterine device or etonogestrel implant, as well as emergency contracep­
tion, may be used safely in women with SLE. Estrogen compounds as a
part of postmenopausal hormone replacement therapy should similarly
be avoided in the presence of antiphospholipid antibodies.
■
■PREGNANCY
SLE pregnancies are high risk. Disease activity in pregnancy is unpre­
dictable, and the disease can flare during any trimester. Active disease
at time of conception is associated with more flares during pregnancy.
HCQ reduces the risk of flares during pregnancy and postpartum.
Women with SLE are at a higher risk for adverse pregnancy outcomes
including pregnancy loss, preterm birth, preeclampsia and pregnancyinduced hypertension, intrauterine growth restriction, cesarean sec­
tion, and maternal death. Flaring or active disease increases the risk for
these adverse outcomes. The presence of maternal hypertension, use of
glucocorticoids during pregnancy, maternal renal disease, discontinu­
ation of HCQ, non-White ethnicity, and lupus anticoagulant positivity
are all associated with worse pregnancy outcomes. SLE patients at
the highest risk for maternal death are those with pulmonary arterial
hypertension, prior arterial thrombosis, and severe end-organ damage,
and these patients should strongly consider avoiding pregnancy.
Outcomes are generally favorable for women with SLE with mildto-moderate disease activity on pregnancy-compatible medications.
Low-dose aspirin is used during pregnancy for preeclampsia preven­
tion. HCQ is safe and the standard of care for all SLE pregnancies.
Azathioprine and tacrolimus may be used safely in pregnancy for more
severe disease and/or renal disease. MMF and methotrexate are terato­
genic and should be avoided. Belimumab, anifrolumab, and voclospo­
rin should currently be avoided due to lack of safety data. Patients who
get pregnant on these medications may be switched to azathioprine
or tacrolimus. Rituximab should be discontinued at conception but
may be used during pregnancy in organ-threatening disease. Predni­
sone may be used for disease flares and can suppress disease activity,
but the dose should be tapered to the lowest effective dose by adding
pregnancy-compatible immunosuppressant medications. Warfarin is
teratogenic; low-molecular-weight heparin is used in SLE pregnancies
with APS or prior pregnancy morbidity.
■
■NEONATAL LUPUS
SS-A (Ro) antibodies may cross the placenta into the fetal circulation
and put the infant at risk for neonatal lupus. Neonatal lupus can consist
of a transient cutaneous rash or lab abnormalities that present after
birth or, less commonly, congenital heart block that presents in utero.
The presence of Ro antibodies, particularly in high titer, should prompt
referral to high-risk obstetricians who can perform fetal echocardiog­
raphy to screen for congenital heart block. The use of fluorinated
steroids may be considered if first- or second-degree heart block is
detected. The use of HCQ in pregnancy significantly reduces the risk
of congenital heart block in women who have had a prior fetus with
congenital heart block.
OUTCOMES
Measuring SLE outcomes both in clinical trials and in clinical practice is
complex given the multisystem nature of the disease. Various aspects of
disease require unique treatment approaches and often at differing rates,
which makes measuring response challenging. Modern SLE treatment
outcomes include improvement in inflammatory type 1 and chronic type
2 symptoms, quality of life, and the prevention of frailty and damage.
New drugs and interventions are constantly being explored as
potential treatments for SLE in clinical trials. Goals of clinical trials for
novel therapies include improved disease activity and acceptable safety.
Long-term extension studies focus on long-term safety and mainte­
nance of improved disease activity. The Systemic Lupus Erythematosus
Responder Index (SRI) and the British Isles Lupus Assessment Group
(BILAG)-based Composite Lupus Assessment (BICLA) are validated
instruments for use in clinical trials. The Cutaneous Lupus Disease Area
and Severity Index (CLASI) is also utilized specifically for trials involv­
ing cutaneous lupus. Several instruments are utilized in clinical trials to
assess quality of life and fatigue, although few are specific to SLE.
■
■TREAT-TO-TARGET APPROACHES
Treat-to-target goals for clinical trials and clinical practice have been
developed and validated, including the definition of a lupus low dis­
ease activity state (LLDAS) and remission (DORIS). Both LLDAS and
DORIS remission scoring utilize the SLEDAI-2K instrument, a vali­
dated instrument that measures SLE disease activity. Achievement of
remission by these measures is defined by low disease activity (LLDAS)
or no disease activity (DORIS), with minimal use of steroids and stable
use of antimalarials, immunosuppressants, and/or biologics and by low
levels (LLDAS) or no evidence of disease activity (DORIS) as assessed
by the evaluating physician. LLDAS has been shown to be attainable in
up to 80% of patients, and the achievement of sustained LLDAS for 2
more years is associated with significantly less overall damage.
■
■DAMAGE
Organ or structural damage occurs in SLE due to the use of medica­
tions to treat the disease or because of persistent disease activity. Use
of glucocorticoids is associated with the development of irrevers­
ible organ damage that is independent of disease activity. Cataracts,
osteoporosis-associated fractures, avascular necrosis, and diabetes
mellitus are the complications from glucocorticoid treatment that
are most commonly observed. Development of damage accrues in a
dose-dependent manner, but even low doses of 5 mg of prednisone or
equivalent appear to be associated with damage accrual. Accelerated
atherosclerosis is a major cause of death after 5 years of SLE disease
duration. Increased myocardial infarction and cerebrovascular event
rates are due to both traditional cardiovascular risk factors and non­
traditional factors including presence of antiphospholipid antibodies,
increased disease activity, low C3 levels, high glucocorticoid dose, and
high homocysteine and leptin levels. Statin use has been demonstrated
to reduce all-cause mortality in SLE patients with renal transplantation.
Studies of malignancy rates in SLE have been inconsistent; however,
recent meta-analyses suggest an increased risk of overall cancer and
cancer-related death in SLE patients. Seventeen site-specific cancers
noted include digestive cancers (esophagus, colon, anus, hepatobiliary,
liver, and pancreas), hematologic cancers (lymphoma, Hodgkin’s lym­
phoma, non-Hodgkin’s lymphoma, leukemia, and multiple myeloma),
and cancer involving lung, larynx, cervix, vagina/vulva, kidney, blad­
der, skin, and thyroid.
■
■FURTHER READING
Aringer M et al: 2019 European League Against Rheumatism/Ameri­
can College of Rheumatology classification for systemic lupus erythe­
matosus. Ann Rheum Dis 78:1151, 2019.
Aringer M et al: A glimpse into the future of systemic lupus erythe­
matosus. Ther Adv Musculoskelet Dis 14:1759720X221086719, 2022.

12 - 369 Antiphospholipid Syndrome
369 Antiphospholipid Syndrome
Barber MRW et al: Global epidemiology of systemic lupus erythema­
tosus. Nat Rev Rheumatol 17: 515, 2021.
Fanouriakis A et al: EULAR recommendations for the management
of systemic lupus erythematosus: 2023 update. Ann Rheum Dis
83:15, 2024.
Izmirly PM et al: Prevalence of systemic lupus erythematosus in
the United States: Estimates from a meta-analysis of the centers for
Disease Control and Prevention National Lupus Registries. Arthritis
Rheumatol 73:991, 2021.
Morand EF et al: Advances in the management of systemic lupus ery­
thematosus. BMJ 383:e073980, 2023.
Petri M et al: Derivation and validation of Systemic Lupus Interna­
tional Collaborating Clinics classification criteria for systemic lupus
erythematosus. Arthritis Rheum 64:2677, 2012.
Pisetsky DS et al: A novel system to categorize the symptoms of systemic
lupus erythematosus. Arthritis Care Res (Hoboken) 71:735, 2019.
Shumilova A, Vital EM: Musculoskeletal manifestations of systemic
lupus erythematosus. Best Pract Res Clin Rheumatol 22:101859, 2023.
Vale ECSD, Garcia LC: Cutaneous lupus erythematosus: A review of
etiopathogenic, clinical, diagnostic and therapeutic aspects. An Bras
Dermatol 98:355, 2023.
Haralampos M. Moutsopoulos,
Maria G. Tektonidou
Antiphospholipid
Syndrome
■
■DEFINITIONS
Antiphospholipid syndrome (APS) is an autoantibody-mediated
acquired thrombophilia characterized by recurrent arterial or venous
thrombosis, microvascular manifestations, and/or pregnancy morbid­
ity. It affects primarily young females. APS may occur alone (primary)
or in association with other autoimmune diseases, mainly systemic
lupus erythematosus (SLE). Catastrophic APS (CAPS) is a rare, lifethreatening, rapidly progressive thromboembolic disease involving
simultaneously three or more organs.
The major autoantibodies detected in APS patients are directed
against phospholipid-binding plasma proteins such as β2-glycoprotein
I (β2GPI) and prothrombin. The plasma protein β2GPI is a 43-kDa
plasma apolipoprotein, which consists of 326 amino acids arranged
in five domains (I through V). The presence of anti–domain I IgG
antibodies has been associated with increased thrombotic risk. Recent
evidence from animal studies has shown that the antithrombotic func­
tion of β2GPI is dependent on its fifth domain (domain V). Another
group of antibodies against phospholipid-binding proteins, termed
lupus anticoagulant (LA), prolongs clotting time in vitro, which is not
corrected by adding normal plasma.
Anticardiolipin and anti-β2GPI IgG/IgM antibodies are measured by
standardized enzyme-linked immunosorbent assays (ELISA); β2GPI in
combination with cardiolipin or β2GPI in the absence of cardiolipin
serve as target antigens, respectively. LA testing includes a threestep procedure: (1) screening including testing with activated partial
thromboplastin time (aPTT) and dilute Russel viper venom test
(DRVVT); (2) mixing study; and (3) confirmation. In patients receiv­
ing anticoagulation treatment, LA test positivity should be interpreted
with caution. In patients with features highly reminiscent of APS in
the absence of classical antiphospholipid antibodies (aPL), testing for
antiphosphatidylserine/prothrombin antibodies may have a valuable
diagnostic role.
■
■EPIDEMIOLOGY
The incidence of APS is estimated to be 1–2 cases per 100,000 persons
per year. The prevalence of APS in the general population is estimated
to be 40–50 per 100,000. APL antibodies occur in 1–5% of the general
population. Their prevalence increases with age; however, it is ques­
tionable whether they are able to induce thrombotic events in elderly
individuals. Moreover, one-third of patients with SLE (Chap. 368) pos­
sess these antibodies and 10–15% of them develop APS.
CHAPTER 369
■
■PATHOGENESIS
The initiating events for the induction of antibodies to phospholipidbinding proteins seem to be endothelial injury induced by infections,
oxidative stress, and major physical stresses such as surgery or trauma in
an appropriate genetic background, given the previously demonstrated
associations with alleles within the human leukocyte antigen (HLA)
locus. These contributors seem to induce increased apoptosis of the ves­
sel endothelial cells, autoantigen presentation, and subsequent initiation
of autoimmune response. The binding of aPL to the disrupted endothe­
lial cells leads to a proinflammatory and prothrombotic state involving
monocytes and platelets activation, adhesion molecules and proinflam­
matory cytokines production, complement and neutrophil activation,
neutrophil extracellular trap (NET) formation, and thrombus formation.
Recently, type I interferon pathway activation and an imbalance between
type I and III interferons have been proposed as potential mechanisms of
thrombotic events and APS-related obstetric complications.
Antiphospholipid Syndrome
■
■CLINICAL MANIFESTATIONS AND
LABORATORY FINDINGS
Clinical manifestations include venous or arterial thrombosis, micro­
vascular events, and/or pregnancy morbidity (Table 369-1). Deep
venous thrombosis occurs primarily in the lower extremities and often
causes pulmonary emboli. Thrombosis of the pulmonary arteries leads
to pulmonary hypertension and thrombosis of hepatic veins to BuddChiari syndrome. Cerebral venous thrombosis presents with signs and
symptoms of intracranial hypertension and focal neurologic deficits.
Other venous thrombosis manifestations include retinal vein throm­
bosis and renal, mesenteric, or splanchnic vein thrombosis. Arterial
thrombosis affects more commonly the arteries of the brain and is
manifested as transient ischemic attack, stroke, migraines, or cognitive
dysfunction. Peripheral artery thrombosis presents with acute limb
ischemia, ischemic leg ulcers, or digital gangrene. Thrombosis of other
arteries leads to myocardial infarction, retinal artery occlusion, renal
artery stenosis, and infarcts of spleen, liver, and adrenals.
Microvascular manifestations include livedo reticularis, which con­
sists of a mottled reticular vascular pattern that appears as a lace-like,
purplish discoloration of the skin; livedo racemosa, characterized by a
broken, irregular, and asymmetric pattern; and livedoid vasculopathy,
which presents with painful papules or lower limb ulcers. Another
microvascular feature of APS is the so-called aPL-nephropathy, mani­
fested with hypertension, proteinuria (mild to nephrotic range),
hematuria, and mild renal insufficiency. Histologically, the acute
phase is characterized by thrombotic microangiopathy lesions in the
glomerular capillaries and/or arterioles. In a chronic phase, fibrous
intima hyperplasia, fibrous and/or fibrocellular arteriolar occlusions,
and focal cortical atrophy are present (Table 369-1). Additional rare
microvascular manifestations are pulmonary hemorrhage, myocardial
disease confirmed by magnetic resonance imaging or histologically,
and adrenal hemorrhage.
Pregnancy morbidity manifests with prefetal (<10 weeks of gesta­
tion) or fetal death, preeclampsia, eclampsia, and placental insuffi­
ciency with intrauterine fetal growth restriction, abnormal umbilical
arterial Doppler, and/or infarctions of the placenta
Cardiac valve manifestations include valve thickening or veg­
etations. Libman-Sacks endocarditis consists of small (usually <1 cm)
valve vegetations, histologically characterized by organized plateletfibrin microthrombi surrounded by growing fibroblasts and mac­
rophages. Premature atherosclerosis has been also recognized as a
feature of APS. Thrombocytopenia and autoimmune hemolytic anemia
are the main hematologic manifestations of APS. Musculoskeletal
TABLE 369-1  Clinical Features of Antiphospholipid Syndrome
MANIFESTATION
%
Venous Thrombosis and Skin Manifestations
Deep-vein thrombosis
Livedo reticularis
Pulmonary embolism
Superficial thrombophlebitis
Thrombosis in various other sites
PART 11
Immune-Mediated, Inflammatory, and Rheumatologic Disorders
Arterial Thrombosis and Cardiac Manifestations
Stroke
Cardiac valve thickening/dysfunction and/or Libman-Sacks
vegetations
Transient ischemic attack
Myocardial ischemia (infarction or angina) and coronary bypass
graft thrombosis
Leg ulcers and/or digital gangrene
Arterial thrombosis in the extremities
Retinal artery thrombosis/amaurosis fugax
Ischemia of visceral organs or avascular necrosis of bone
Multi-infarct dementia
Neurologic Manifestations of Uncertain Etiology
Migraine
Epilepsy
Chorea
Cerebellar ataxia
Transverse myelopathy
0.5
Renal Manifestations Due to Various Reasons
(Renal Artery/Renal Vein/Glomerular Thrombosis,
Fibrous Intima Hyperplasia)
Musculoskeletal Manifestations
Arthralgias
Arthritis
Obstetric Manifestations (Referred to the Number of Pregnancies)
Preeclampsia
Eclampsia
Fetal Manifestations (Referred to the Number of Pregnancies)
Early fetal loss (<10 weeks)
Late fetal loss (≥10 weeks)
Premature birth among the live births
Hematologic Manifestations
Thrombocytopenia
Autoimmune hemolytic anemia
Source: Adapted from R Cervera et al: Arthritis Rheum 46:1019, 2002.
manifestations may also occur in APS including arthralgias/arthritis,
avascular bone necrosis, bone marrow necrosis, nontraumatic frac­
tures, and osteoporosis.
■
■DIAGNOSIS AND DIFFERENTIAL DIAGNOSIS
The diagnosis of APS should be seriously considered in cases of throm­
bosis, cerebral vascular accidents in individuals <55 years of age, or
pregnancy morbidity, in the presence of livedo reticularis or thrombo­
cytopenia. In these cases, aPL antibodies should be measured. Accord­
ing to the 2023 American College of Rheumatology/European Alliance
of Associations for Rheumatology (ACR/EULAR) classification criteria
for APS, the presence of at least 3 points from clinical domains and 3
points from laboratory domains is required to classify APS. Clinical
manifestations with other equally or more likely explanations than
APS will not be counted. Clinical domains include (1) venous throm­
boembolism; (2) arterial thrombosis; (3) microvascular events; (4)
obstetric complications; (5) cardiac valve disease; and (6) hematologic
manifestations, as shown in Table 369-2. Laboratory domains include
(1) LA, (2) anticardiolipin (aCL), and/or (3) anti-β2GPI antibodies, at
moderate (40-79 units) or high titers (≥ 80 units) on two occasions
12 weeks apart.
Differential diagnosis is based on the exclusion of other inherited
or acquired causes of thrombophilia (Chap. 121), Coombs-positive
hemolytic anemia (Chap. 105), and thrombocytopenia (Chap. 120).
Livedo reticularis with or without a painful ulceration on the lower
extremities may be also a manifestation of disorders affecting (1)
the vascular wall, such as atherosclerosis, polyarteritis nodosa, SLE,
cryoglobulinemia, and lymphomas; or (2) the vascular lumen, such as
TABLE 369-2  2023 American College of Rheumatology/European
Alliance of Associations for Rheumatology (ACR/EULAR)
Classification Criteria for Antiphospholipid Syndrome
Clinical Domains 
DOMAINS/CRITERIA
POINTS
Venous thromboembolism (VTE)
• With high-risk VTE profile
• Without a high-risk VTE profile
Microvascular events
Suspected (any of below)
• Livedo racemosa (exam)
• Livedoid vasculopathy lesions (exam)
• Acute/chronic aPL-nephropathy (exam or lab)
• Pulmonary hemorrhage (symptoms and imaging) 
Established (any of below)
• Livedoid vasculopathy (pathology)
• Acute/chronic aPL-nephropathy (pathology)
• Pulmonary hemorrhage (BAL or pathology)
• Myocardial disease (imaging or pathology)
• Adrenal hemorrhage (imaging or pathology)
Cardiac valve disease
• Thickening
• Vegetation
Arterial thrombosis
• With high-risk CVD profile
• Without high-risk CVD profile
Obstetric complications
• >3 consecutive prefetal (<10 w) and/or early fetal deaths
(10w0d–15w6d)
• Fetal death (16w0d–33w6d) in the absence of preeclampsia (PEC)
with severe features or placental insufficiency (PI) with severe
features
• PEC with severe features (<34w0d) or PI with severe features
(<34w0d) with/without fetal death
• PEC with severe features (<34w0d) and PI with severe features
(<34w0d) with/without fetal death
Hematologic manifestations
• Thrombocytopenia (otherwise unexplained lowest platelet count
ever between 20 and 130 × 109/L)
Laboratory Domains (aPL)
DOMAINS/CRITERIA
POINTS
Lupus anticoagulant (LA) test
• One time positive
• Persistent
Anticardiolipin (aCL) and/or anti-β2GPI antibodies (persistent)
• Moderate (40–79 units) or high (≥80 units) IgM aCL and/or
 
anti-β2GPI
• Moderate (40–79 units) IgG aCL and/or anti-β2GPI
• High (≥80 units) positive IgG aCL or anti-β2GPI
• High (≥80 units) IgG aCL and anti-β2GPI
Abbreviations: aPL, antiphospholipid antibody; anti-β2GPI, anti-β2-glycoprotein
I; BAL, bronchoalveolar lavage; CVD, cardiovascular disease; Exam, physical
examination; Lab, laboratory tests.
Source: Modified with permission from R Zuo et al: The 2023 ACR/EULAR
Antiphospholipid Syndrome Classification Criteria. Arthritis Rheumatol 75:1687, 2023.

13 - 370 Rheumatoid Arthritis
370 Rheumatoid Arthritis
myeloproliferative disorders, hypercholesterolemia, or other causes of
thrombophilia.
Diagnosis of CAPS should be considered in patients with mainly
microvascular thrombotic disease involving multiple organs in a short
time period. A patient is classified as definite CAPS if all four of the
following criteria are fulfilled and as probable CAPS when a combina­
tion of these criteria is present: (1) thrombosis in three or more organs/
systems; (2) development in less than a week; (3) histologic evidence
of small-vessel thrombosis in at least one organ; and (4) aPL presence.
Because thrombotic microangiopathy (microangiopathic hemolytic
anemia and severe thrombocytopenia) is a typical finding in CAPS, the
differential diagnosis includes thrombotic thrombocytopenic purpura,
hemolytic-uremic syndrome, disseminated intravascular coagulation,
and heparin-induced thrombocytopenia.
TREATMENT
Antiphospholipid Syndrome
It has been increasingly appreciated that the risk of thrombotic and
obstetric events is closely related to the underlying aPL profile. The
latter depends on the type of autoantibodies (IgG high risk vs IgM
low risk), the number of aPL antibodies (simultaneous presence of
two or three classical autoantibodies vs a single antibody denotes a
higher risk profile), their titer (moderate-high titer vs low), and the
persistence of aPL positivity in repeated measurements.
Following the first thrombotic event, APS patients should be
placed on vitamin K antagonists (VKAs) for life, aiming to achieve
an international normalized ratio (INR) ranging from 2.0 to 3.0 in
case of an unprovoked venous thrombosis. For patients with arte­
rial thrombosis, the corresponding INR target should be 3.0–4.0
or 2.0–3.0 with or without low-dose aspirin (LDA, 75–100 mg
daily), depending on the thrombotic/hemorrhagic patient profile.
Administration of direct oral anticoagulants (DOACs) recently
has been shown to increase the risk of arterial events, especially
in patients with triple positivity or previous arterial thrombosis.
A recent meta-analysis of four open-label randomized controlled
trials showed that prior thrombosis type (arterial vs venous) did
not affect the increased odds of arterial thrombosis associated with
DOACs compared to VKAs in APS. In pregnant women with a
history of obstetric APS, combination treatment with LDA and
prophylactic dose of low-molecular-weight heparin (LMWH) is
recommended, whereas in cases of thrombotic APS, LDA plus
therapeutic LMWH dose should be administered. When recurrent
obstetric complications occur despite standard treatment, increas­
ing the LMWH dose (from prophylactic to therapeutic) or adminis­
tering oral hydroxychloroquine 400 mg/d or low-dose prednisolone
in the first trimester are alternative options.
For asymptomatic individuals or SLE patients with a high-risk
aPL profile and no evidence of a previous thrombotic event or
pregnancy morbidity, prophylactic treatment with LDA is recom­
mended. In nonpregnant women with a history of APS-related
obstetric complications, independently of the presence of underly­
ing SLE diagnosis, treatment with LDA seems to reduce the risk of
a subsequent thrombotic event.
Patients with CAPS should be treated with combination therapy
including glucocorticoids, heparin, and plasma exchange or intra­
venous immunoglobulin (IVIG) together with appropriate manage­
ment of triggering events such as infections. For refractory CAPS,
B-cell depletion (e.g., with rituximab) or complement inhibition
(e.g., with eculizumab) therapies are alternative options.
■
■FURTHER READING
Barbhaiya  M et al: 2023 ACR/EULAR antiphospholipid syndrome
classification criteria. Arthritis Rheumatol 75:1687, 2023.
Knight  JS et al: Antiphospholipid syndrome: Advances in diagnosis,
pathogenesis, and management. BMJ 380:e069717, 2023.
Tektonidou  MG et al: EULAR recommendations for the management
of antiphospholipid syndrome in adults. Ann Rheum Dis 78:1296, 2019.
Ankoor Shah, E. William St. Clair
Rheumatoid Arthritis
CHAPTER 370
INTRODUCTION
Rheumatoid arthritis (RA) is a chronic inflammatory disease charac­
terized by a symmetric, erosive polyarthritis. It is the most common
form of chronic inflammatory arthritis. Since persistently active RA
often results in articular cartilage and bone destruction and functional
disability, it is vital to diagnose and treat this disease early and aggres­
sively before damage ensues. Although predominately affecting joints,
RA is a systemic disease that may lead to a variety of extraarticular
manifestations, including fatigue, subcutaneous nodules, lung involve­
ment, pericarditis, peripheral neuropathy, vasculitis, and hematologic
abnormalities.
Rheumatoid Arthritis
Insights gained over the past two decades have revolutionized the
contemporary paradigms for the diagnosis and management of RA.
Testing for serum antibodies to anti-citrullinated protein antibodies
(ACPA) and rheumatoid factor continues to be valuable in the diagnos­
tic evaluation of patients with suspected RA, and these autoantibodies
serve as biomarkers of prognostic significance. Advances in imaging
modalities assist clinical decision-making by improving the detection
of joint inflammation and monitoring the progression of damage.
The science of RA has taken major leaps forward by illuminating new
disease-related genes, environmental interactions, and the molecu­
lar components and pathways of disease pathogenesis. The relative
contribution of these cellular and inflammatory mediators in disease
pathogenesis has been further brought to light by the efficacy of the
approved biologic and targeted synthetic disease-modifying therapies.
Despite these major strides, incomplete understanding of the initiating
events of RA and the factors perpetuating the chronic inflammatory
response remains a barrier to finding a cure.
The past 20 years have witnessed a remarkable improvement in the
outcomes of RA. The crippling arthritis of years past is encountered
much less frequently today. Much of this progress can be traced to
the expanded therapeutic armamentarium and the renewed sense of
urgency to identify patients earlier in the disease process, enabling
prompt treatment intervention. This shift in treatment strategy dic­
tates a new mindset for primary care practitioners—namely, one that
demands early referral of patients with inflammatory arthritis to a
rheumatologist for confirmation of the diagnosis and initiation of dis­
ease-modifying therapy, since delays in starting effective treatment are
associated with worse outcomes. Reaching a clinical state of low disease
activity and remission is now an achievable goal for most patients.
CLINICAL FEATURES
The incidence of RA increases between 25 and 55 years of age, after
which it plateaus until the age of 75 and then decreases. The presenting
symptoms are typically related to inflammation of the joints, tendons,
and bursae. Patients often complain of early morning joint stiffness
lasting >1 h that eases with physical activity. The earliest involved joints
are mostly the small joints of the hands and feet. The initial pattern of
joint involvement may be monoarticular, oligoarticular (≤4 joints), or
polyarticular (>5 joints), usually in a symmetric distribution. Some
patients with inflammatory arthritis will present with too few affected
joints to be classified as having RA—so-called undifferentiated inflam­
matory arthritis. Those with an undifferentiated arthritis who are most
likely to be diagnosed later with RA have a higher number of tender
and swollen joints, test positive for serum rheumatoid factor (RF) or
ACPA, and have higher scores for physical disability.
In established RA, the most frequently involved joints are the wrists
and metacarpophalangeal (MCP) and proximal interphalangeal (PIP)
joints (Fig. 370-1). Distal interphalangeal (DIP) joint involvement
may occur in patients with RA, but it is usually due to coexistent
osteoarthritis. Flexor tendon tenosynovitis is a frequent hallmark of
RA and leads to decreased range of motion, reduced grip strength,
PART 11
Immune-Mediated, Inflammatory, and Rheumatologic Disorders
FIGURE 370-1  Metacarpophalangeal joint swelling and subluxation. (Reproduced
with permission from RP Usatine, MA Smith, EJ Mayeaux: The Color Atlas and
Synopsis of Family Medicine, 3rd ed. New York, McGraw Hill, 2019; Fig. 97.5.)
and “trigger” fingers. Flexor tendon involvement may also lead to
tendon rupture, most commonly the flexor pollicis longus. Progres­
sive destruction of the joints and soft tissues may result in chronic,
irreversible deformities. Ulnar deviation is a common deformity of
long-standing RA that is caused by subluxation of the MCP joints, with
subluxation, or partial dislocation, of the proximal phalanx to the volar
side of the hand. Hyperextension of the PIP joint with flexion of the
DIP joint (“swan-neck deformity”), flexion of the PIP joint with hyper­
extension of the DIP joint (“boutonnière deformity”), and subluxation
of the first MCP joint with hyperextension of the first interphalangeal
(IP) joint (“Z-line deformity”) also may result from damage to the
tendons, joint capsule, and other soft tissues. Inflammation about the
ulnar styloid and tenosynovitis of the extensor carpi ulnaris may cause
subluxation of the distal ulna, resulting in a “piano-key movement” of
the ulnar styloid. Although metatarsophalangeal (MTP) joint involve­
ment is an early feature of disease, chronic inflammation of the ankle
and midtarsal regions usually comes later and may lead to pes pla­
novalgus (“flat feet”). Large joints, including the knees and shoulders,
are often affected in established disease and may remain asymptomatic
for many years after onset.
Atlantoaxial involvement of the cervical spine is clinically note­
worthy because of its potential to cause compressive myelopathy and
neurologic dysfunction. Neurologic manifestations are rarely a present­
ing sign or symptom of atlantoaxial disease, but they may slowly evolve
over time with progressive instability of C1 on C2. The prevalence of
atlantoaxial subluxation has been declining in recent years and occurs
now in <10% of patients. Unlike the spondyloarthritides (Chap. 374),
RA rarely affects the thoracic and lumbar spine.
Extraarticular manifestations may develop during the clinical course
of RA in up to 40% of patients, even prior to the onset of arthritis
(Fig. 370-2). Patients most likely to develop extraarticular disease have
a history of cigarette smoking, have early onset of significant physi­
cal disability, and test positive for serum RF or ACPA. Subcutaneous
nodules, Sjögren’s disease, interstitial lung disease (ILD), pulmonary
nodules, and anemia are among the most frequently observed extraar­
ticular manifestations. Recent studies have shown a decrease in the
incidence and severity of at least some extraarticular manifestations,
particularly Felty’s syndrome and vasculitis.
The most common systemic and extraarticular features of RA are
described in more detail in the sections below.
■
■CONSTITUTIONAL
These signs and symptoms include weight loss, fever, fatigue, malaise,
depression, and in the most severe cases, cachexia; they generally
reflect a high degree of inflammation and may even precede the onset
of joint symptoms. In general, the presence of a fever of >38.3°C
(101°F) at any time during the clinical course should raise suspicion of
systemic vasculitis (see below) or infection.
■
■NODULES
Subcutaneous nodules have been reported to occur in 30–40% of
patients and more commonly in those with the highest levels of disease
activity, who carry the disease-related shared epitope (SE) (see below),
who have a positive test for serum RF, and who show radiographic
evidence of joint erosions. However, more recent cohort studies sug­
gest a declining prevalence of subcutaneous nodules, perhaps related to
early and more aggressive disease-modifying therapy. When palpated,
the nodules are generally firm; nontender; and adherent to periosteum,
tendons, or bursae; they develop in areas of the skeleton subject to
repeated trauma or irritation such as the forearm, sacral prominences,
and Achilles tendon. They may also occur in the lungs, pleura, peri­
cardium, and peritoneum. Nodules are typically benign, although they
can be associated with infection, ulceration, and gangrene. Accelerated
growth of smaller nodules may occur in up to 10% of patients taking
long-term methotrexate, although the mechanisms behind this phe­
nomenon are unclear.
■
■SJÖGREN’S SYNDROME
Secondary Sjögren’s syndrome, or Sjögren’s disease (Chap. 373), is
defined by the presence of either keratoconjunctivitis sicca (dry eyes)
or xerostomia (dry mouth) in association with another connective tis­
sue disease, such as RA. Approximately 10% of patients with RA have
secondary Sjögren’s syndrome.
■
■PULMONARY
Pleuritis, the most common pulmonary manifestation of RA, may
result in pleuritic chest pain and dyspnea, as well as a finding of a pleu­
ral friction rub and radiographic evidence of a pleural effusion. Pleural
effusions tend to be exudative with increased numbers of monocytes
and neutrophils. ILD may also occur in patients with RA and is her­
alded by symptoms of dry cough and progressive shortness of breath.
ILD can be associated with cigarette smoking and is generally found
in patients with higher disease activity, although it may be diagnosed
in up to 3.5% of patients prior to the onset of joint symptoms. Recent
studies have shown the overall prevalence of ILD in RA to be as high
as 12%. Diagnosis is readily made by high-resolution chest computed
tomography (CT) scan, which shows infiltrative opacification, or
ground-glass opacities, in the periphery of both lungs. Usual intersti­
tial pneumonia (UIP) and nonspecific interstitial pneumonia (NSIP)
are the main histologic and radiologic patterns of ILD. UIP causes
progressive scarring of the lungs that, on chest CT scan, produces hon­
eycomb changes in the periphery and lower portions of the lungs. In
contrast, the most common radiographic changes in NSIP are relatively
symmetric and bilateral ground-glass opacities with associated fine
reticulations, volume loss, and traction bronchiectasis. In both cases,
pulmonary function testing shows a restrictive pattern (e.g., reduced
total lung capacity) and a reduced diffusing capacity for carbon mon­
oxide (DLCO). The presence of ILD confers a poor prognosis. The prog­
nosis of ILD in RA, however, is not quite as poor as that of idiopathic
pulmonary fibrosis (e.g., usual interstitial pneumonitis) and responds
better to immunosuppressive therapy (Chap. 304). Pulmonary nodules
are also common in patients with RA and may be solitary or multiple.
Caplan’s syndrome is a rare subset of pulmonary nodulosis character­
ized by the development of nodules and pneumoconiosis following
silica exposure. Less commonly, RA may be associated with respiratory
bronchiolitis and bronchiectasis.
■
■CARDIAC
The most frequent site of cardiac involvement in RA is the pericar­
dium. However, clinical manifestations of pericarditis occur in <10%
of patients with RA despite pericardial involvement being detectable
in nearly one-half of cases by echocardiogram or at autopsy. Up to
20% of patients with RA may have asymptomatic pericardial effusions
on echocardiography. Cardiomyopathy, another clinically important
manifestation of RA, may result from necrotizing or granulomatous
myocarditis, coronary artery disease, or diastolic dysfunction. This
Ocular: Keratoconjunctivitis sicca,
episcleritis, scleritis
Neurologic: Cervical myelopathy
Hematologic: Anemia of
chronic disease, neutropenia,
splenomegaly, Felty’s syndrome,
large granular lymphocyte
leukemia, lymphoma
GI: Vasculitis
Skeletal: Osteoporosis
FIGURE 370-2  Extraarticular manifestations of rheumatoid arthritis.
involvement, too, may be subclinical and only identified by echocar­
diography or cardiac magnetic resonance imaging (MRI). Rarely, the
heart muscle may contain rheumatoid nodules or be infiltrated with
amyloid.
■
■VASCULITIS
Rheumatoid vasculitis (Chap. 375) typically occurs in patients with
long-standing disease, a positive test for serum RF or ACPA, and hypo­
complementemia. The overall incidence has decreased significantly
in the past decade to <1% of patients. The cutaneous signs vary and
include petechiae, purpura, digital infarcts, gangrene, livedo reticularis,
and in severe cases large, painful lower extremity ulcerations. Vascu­
litic ulcers, which may be difficult to distinguish from those caused
by venous insufficiency, may be treated successfully with immuno­
suppressive agents including cytotoxic treatment and skin grafting in
severe cases. Sensorimotor polyneuropathies, such as mononeuritis
multiplex, may occur in association with systemic rheumatoid vasculi­
tis; they usually present with new onset of numbness, tingling, or focal
muscle weakness.
■
■HEMATOLOGIC
A normochromic, normocytic anemia often develops in patients with
RA and is the most common hematologic abnormality. The degree of
anemia parallels the degree of inflammation, correlating with the levels
of serum C-reactive protein (CRP) and erythrocyte sedimentation rate
(ESR). Platelet counts may also be elevated in RA as an acute-phase
reactant; immune-mediated thrombocytopenia is rare.
CHAPTER 370
Oral: Xerostomia, periodontitis
Pulmonary: Pleural effusions,
pulmonary nodules, interstitial
lung disease, pulmonary vasculitis,
organizing pneumonia
Rheumatoid Arthritis
Cardiac: Pericarditis, ischemic
heart disease, myocarditis,
cardiomyopathy, arrhythmia,
mitral regurgitation
Renal: Membranous
nephropathy, secondary
amyloidosis
Endocrine: Hypoandrogenism
Skin: Rheumatoid nodules, purpura,
pyoderma gangrenosum
Felty’s syndrome is defined by the clinical triad of neutropenia, sple­
nomegaly, and nodular RA and is seen in <1% of patients, although
its incidence appears to be declining in the face of more aggressive
treatment of the joint disease. It typically occurs in the late stages of
severe RA and is more common in whites than other racial groups.
T-cell large granular lymphocyte leukemia (T-LGL) may have a similar
clinical presentation and often occurs in association with RA. T-LGL is
characterized by a chronic, indolent clonal growth of LGL cells, lead­
ing to neutropenia and splenomegaly. As opposed to Felty’s syndrome,
T-LGL may develop early in the course of RA. Leukopenia apart from
these disorders is uncommon and most often a side effect of drug
therapy.
■
■LYMPHOMA
Large cohort studies have shown a two- to fourfold increased risk of
lymphoma in RA patients compared with the general population. The
most common histopathologic type of lymphoma is a diffuse large
B-cell lymphoma. The risk of developing lymphoma increases if the
patient has high levels of disease activity or Felty’s syndrome.
■
■ASSOCIATED CONDITIONS
In addition to extraarticular manifestations, several conditions asso­
ciated with RA contribute to disease morbidity and mortality rates.
They are worthy of mention because they affect chronic disease
management.
Cardiovascular Disease 
The most common cause of death in
patients with RA is cardiovascular disease. The incidence of coronary
artery disease and carotid atherosclerosis is higher in RA patients
than in the general population even when controlling for traditional
cardiac risk factors, such as hypertension, obesity, hypercholesterol­
emia, diabetes, and cigarette smoking. Furthermore, congestive heart
failure (including both systolic and diastolic dysfunction) occurs at an
approximately twofold higher rate in RA than in the general popula­
tion. The presence of elevated serum inflammatory markers appears to
confer an increased risk of cardiovascular disease.
PART 11
Immune-Mediated, Inflammatory, and Rheumatologic Disorders
Osteoporosis 
Osteoporosis is more common in patients with
RA than an age- and sex-matched population, with an incidence rate
of nearly double that of the healthy population and a prevalence of
approximately one-third in postmenopausal women with RA. There
is also an increased risk of fragility fracture, with a greater risk among
women. The inflammatory milieu of the joint promotes generalized
bone loss by activating osteoclasts. Both trabecular and cortical bone
are affected by the inflammatory response, with cortical sites more
susceptible to bone loss. Chronic use of glucocorticoids and disabilityrelated immobility also contribute to osteoporosis. Hip fractures are
more likely to occur in patients with RA and are significant predictors
of increased disability and mortality rate in this disease.
EPIDEMIOLOGY
RA affects ~0.5–1% of the adult population worldwide, although the
majority of epidemiologic studies have been done in Western coun­
tries. There is evidence that the overall incidence of RA has been
decreasing in recent decades, whereas the prevalence has remained
the same because individuals with RA are living longer. The incidence
and prevalence of RA vary based on geographic location, both globally
and among certain ethnic groups within a country (Fig. 370-3). For
example, the indigenous Yakima, Pima, and Chippewa tribes of North
America have reported prevalence rates in some studies of nearly 7%.
In contrast, many population studies from Africa and Asia show lower
prevalence rates for RA in the range of 0.2–0.4%.
Like many other autoimmune diseases, RA occurs more commonly
in females than in males, with a 2–3:1 ratio. Interestingly, studies of RA
from some of the Latin American and African countries show an even
greater predominance of disease in females compared to males, with
ratios of 6–8:1. Given this preponderance of females, various theories
have been proposed to explain the possible role of estrogen in disease
pathogenesis. Broadly speaking, most of the theories center on the role
of estrogens and androgens in enhancing and suppressing the immune
European ancestry:
HLA-DRB1:
*0401
*0404
*0301
*0101
PTPN22:  European
US:
0.7–1.3%
STAT4: North American
TNFAIP3:  North American
TRAFI/CF:  North American
CTLA4:  European
Asian ancestry:
HLA-DRB1:
Brazil:
0.4–1.4%
*0401 (East Asian)
*0405
*0901 (Japanese, Malaysian, Korean)
PADI4
CD244
Other:
CD40
FIGURE 370-3  Global prevalence rates of rheumatoid arthritis (RA) with genetic associations. Listed are the major genetic alleles associated with RA. Although human
leukocyte antigen (HLA)-DRB1 mutations are found globally, some alleles have been associated with RA in only certain ethnic groups.
response, respectively. However, estrogens have both stimulatory and
inhibitory effects on the immune system, and their role, if any, on the
development of RA is unknown.
GENETIC CONSIDERATIONS
It has been recognized for >30 years that genetic factors contrib­
ute to the occurrence of RA as well as to its severity. The likeli­
hood that a first-degree relative of a patient will share the
diagnosis of RA is 2–10 times greater than in the general population.
There remains, however, some uncertainty in the extent to which
genetics plays a role in the causative mechanisms of RA. Heritability
estimates range from 40 to 60%, although this may be higher in ACPApositive patients compared to those without ACPA. The estimate of
genetic influence has varied across studies, probably due to gene–
environment interactions.
The alleles known to confer the greatest risk of RA are located within
the major histocompatibility complex (MHC) and, in particular, those
encoding the MHC class II molecules. MHC class II molecules are typi­
cally expressed on antigen-presenting cells and are comprised of α and
β chains. Most, but probably not all, of this risk is associated with allelic
variation in the HLA-DRB1 gene, which encodes the MHC II β-chain
molecule. The disease-associated HLA-DRB1 alleles share an amino
acid sequence at positions 70–74 in the third hypervariable regions
of the HLA-DR β-chain, termed the shared epitope (SE). These amino
acids are located in the antigen-binding grove within the hypervariable
regions of the HLA-DRβ1 molecule. These hypervariable regions are
important not only for determining antigen recognition but also for
binding of the MHC-peptide complex to the T-cell receptor (TCR).
Peptides derived from posttranslationally modified proteins (via
citrullination, acetylation, or carbamylation, for example) may bind
with greater avidity to the SE, providing a potential explanation for
increased disease risk at a molecular level. The risk of RA is four times
higher in persons carrying a single SE allele and eight times higher in
those carrying two alleles compared to SE-negative individuals.
Carriership of the SE alleles is associated with production of ACPAs
and worse disease outcomes. Some HLA-DRB1 alleles bestow a high risk
of disease (∗0401), whereas others confer a more moderate risk (∗0101,
0404, 1001, and 0901). Over 90% of patients with RA express at least one
of these variants. Interestingly, HLA-DRB1∗1301 and to a lesser extent
HLA-DRB1∗1302 confer protection from ACPA-positive RA.
Additionally, there is geographic variation in disease susceptibility
and the identity of the HLA-DRB1 risk alleles. In Greece, for example,
Norway: 0.4%
Bulgaria:
0.2–0.6%
UK:
0.8–1.1%
Iraq:
0.4–1.5% India:
0.1–0.4%
Japan:
0.2–0.3%
Spain:
0.2–0.8%
Greece:
0.3–1%
Jamaica:
1.9–2.2%
Hong Kong:
0.1–0.5%
Saudi Arabia:
0.1–0.2%
Liberia:
2–3%
Java:
0.1–0.2%
Lesotho:
1.7–4.5%
South Africa:
2.5–3.6%
where RA tends to be milder than in western European countries, RA
susceptibility has been associated with the ∗0101 SE allele. By com­
parison, the ∗0401 or ∗0404 alleles are found in ~50–70% of northern
Europeans and are the predominant risk alleles in this group. The
most common disease susceptibility SE alleles in Asians, namely the
Japanese, Koreans, and Chinese, are ∗0405 and ∗0901. Lastly, disease
susceptibility of Native American populations such as the Pima and
Tlingit Indians, where the prevalence of RA can be as high as 7%, is
associated with the SE allele ∗1042. The risk of RA conferred by these
SE alleles is less in African and Hispanic Americans than in individuals
of European ancestry.
Genome-wide association studies (GWAS) have made possible the
identification of several non-MHC-related genes that contribute to RA
susceptibility. GWASs are based on the detection of single nucleotide
polymorphisms (SNPs), which allow for examination of the genetic
architecture of complex diseases such as RA. Overall, several themes
have emerged from GWAS in RA. First, among the >100 non-MHC
loci identified as risk alleles for RA, they individually have only a
modest effect on risk; they also contribute to the risk for developing
other autoimmune diseases, such as type 1 diabetes mellitus, systemic
lupus erythematosus, and multiple sclerosis. Second, although most
of the non-HLA associations are described in patients with ACPApositive disease, there are several risk loci that are unique to ACPAnegative disease. Third, risk alleles vary among ethnic groups. And
fourth, the risk loci mostly reside in genes encoding proteins involved
in the regulation of the immune response. However, the risk alleles
identified by GWAS only account at present for ~5% of the genetic risk,
suggesting that rare variants or other classes of DNA variants, such as
variants in copy number, may be yet found that significantly contribute
to the overall risk model.
Among the best examples of the non-MHC genes contributing to
the risk of RA is the gene encoding protein tyrosine phosphatase nonreceptor 22 (PTPN22). This gene varies in frequency among patients
from different parts of Europe (e.g., 3–10%) but is absent in patients of
East Asian ancestry. PTPN22 encodes lymphoid tyrosine phosphatase,
a protein that regulates T- and B-cell function. Inheritance of the risk
allele for PTPN22 produces a gain-of-function in the protein that is
hypothesized to result in the abnormal thymic selection of autoreactive
T and B cells and appears to be associated exclusively with ACPApositive disease. The peptidyl arginine deiminase type IV (PADI4) gene
is another risk allele that encodes an enzyme involved in the conversion
of arginine to citrulline and is postulated to play a role in the develop­
ment of antibodies to citrullinated antigens. A polymorphism in PADI4
has been associated with a twofold increase in the risk of RA, primarily
in those of East Asian descent. Recently, polymorphisms in apolipo­
protein M (APOM) in an East Asian population were found confer an
increased risk for RA as well as risk for dyslipidemia, independent of
RA disease activity.
Epigenetics is the study of heritable traits that affect gene expres­
sion but do not modify DNA sequence. Epigenetic mechanisms are
theoretically involved in three important aspects of RA: contribution
to disease etiology, perpetuation of chronic inflammatory responses,
and disease severity. The best-studied epigenetic mechanisms are those
regulating posttranslational histone modifications and DNA methyla­
tion. DNA methylation patterns have been shown to differ between RA
patients and healthy controls, including monozygotic twins, as well as
from patients with osteoarthritis. Epigenetics may also offer a mecha­
nistic explanation for how cigarette smoking confers an increased risk
for ACPA-positive RA (see below) as those patients with the SE have
higher levels of DNA methylation compared to nonsmokers. MicroR­
NAs, which are noncoding RNAs that function as posttranscriptional
regulators of gene expression, represent an additional epigenetic
mechanism that may potentially influence cellular responses.
ENVIRONMENTAL FACTORS
In addition to genetic predisposition, a host of environmental factors
have been implicated in the pathogenesis of RA. The most reproducible
of these environmental links is cigarette smoking. Numerous cohort
and case-control studies have demonstrated that smoking confers a
relative risk for developing RA of 1.5–3.5 times. Smoking-related risk
interacts in a synergistic manner with MHC risk alleles. The classic
SE alleles alone increase the likelihood of developing RA by four- to
sixfold; however, this risk increases to 20- to 40-fold when combined
with smoking. In particular, women who smoke cigarettes have a
nearly 2.5 times greater risk of RA, a risk that persists even 15 years
after smoking cessation. A twin who smokes will have a significantly
higher risk for RA than their monozygotic co-twin, theoretically with
the same genetic risk, who does not smoke. Interestingly, the risk
from smoking is almost exclusively related to RF and ACPA-positive
disease. However, it has not been shown that smoking cessation, while
having many health benefits, reduces the severity or extent of joint
inflammation. Inhalant-related occupations and silica inhalants also
may increase RA risk. These observations have led to the theory that
subclinical lung disease may play a critical early role in the initial devel­
opment of autoreactive immune cells and account for the occurrence
of autoantibodies more than a decade prior to the clinical development
of joint disease.
CHAPTER 370
Rheumatoid Arthritis
Researchers began to aggressively seek an infectious etiology for
RA after the discovery in 1931 that sera from patients with this dis­
ease could agglutinate strains of streptococci. Certain viruses such as
Epstein-Barr virus (EBV) have garnered the most interest over the past
30 years given their ubiquity, ability to persist for many years in the
host, and frequent association with arthritic complaints. For example,
titers of IgG antibodies against EBV antigens in the peripheral blood
and saliva are significantly higher in patients with RA than in the
general population. EBV DNA has also been found in synovial fluid
and synovial cells of RA patients. Because the evidence for these links
is largely circumstantial, it has not been possible to directly implicate
infection as a causative factor in RA.
An attractive hypothesis raised by newer studies is that microbial
dysbiosis of the oral or gut microbiome may predispose to the devel­
opment of RA. Recent work suggests that periodontitis in the oral
cavity may play a role in disease mechanisms. Multiple studies provide
evidence for a link between ACPA-positive RA and cigarette smoking,
periodontal disease, and the oral microbiome, specifically Porphyromo­
nas gingivalis. It has been hypothesized that the immune response to
P. gingivalis may trigger the development of RA and the bacterial
enzyme peptidyl arginine deiminase (PAD) induces ACPA by catalyzing
the citrullination of arginine residues on the stimulating autoantigens.
Interestingly, P. gingivalis is the only oral bacterial species known to
harbor this enzyme. Some studies have shown a relationship between
the presence of circulating antibodies to P. gingivalis and RA, as well as
with first-degree relatives at risk for this disease. However, it remains
unproven whether the observed dysbiosis in the oral cavity precedes
the development of disease.
There are also limited data suggesting a role for the gut microbiome
in the etiology of RA. Some studies have found that the gut microbiome
is different in patients with early RA compared with controls. In par­
ticular, Prevotella copri was reported to be enriched in early untreated
RA as well as in an “at-risk” population. On the other hand, a common
dysbiotic signature does not seem to predominate in patients with RA,
and evidence is lacking for a direct immune-modulating effect.
PATHOLOGY
RA affects the synovial lining tissue of the diarthrodial joints and the
underlying cartilage and bone. The synovial membrane, which covers
most articular surfaces, tendon sheaths, and bursae, normally is a thin
layer of connective tissue. In joints, it faces the bone and cartilage,
bridging the opposing bony surfaces and inserting at periosteal regions
close to the articular cartilage. It consists primarily of two cell types—
type A synoviocytes (macrophage-derived) and type B synoviocytes
(fibroblast-derived). The synovial fibroblasts are the most abundant
and produce the structural components of joints, including collagen,
fibronectin, and laminin, as well as other extracellular constituents
of the synovial matrix. The sublining layer consists of blood vessels
and a sparse population of mononuclear cells within a loose network
of connective tissue. Synovial fluid, an ultrafiltrate of blood, diffuses
through the subsynovial lining tissue across the synovial membrane
and into the joint cavity. Its main constituents are hyaluronan and
lubricin. Hyaluronan is a glycosaminoglycan that contributes to the
viscous nature of synovial fluid, which, along with lubricin, lubricates
the surface of the articular cartilage.
The pathologic hallmarks of RA are synovial inflammation and
proliferation, focal bone erosions, and thinning of articular cartilage.
Chronic inflammation leads to synovial lining hyperplasia and the
formation of pannus, a thickened cellular membrane consisting of
multiple layers of fibroblast-like synoviocytes and granulation-reactive
fibrovascular tissue that has a propensity for invading underlying car­
tilage and bone. The inflammatory infiltrate is made up of no less than
six cell types: T cells, B cells, plasma cells, dendritic cells, mast cells,
and, to a lesser extent, granulocytes. The T cells compose 30–50% of
the infiltrate, with the other cells accounting for the remainder. The
topographical organization of these cells is complex and may vary
among individuals with RA. Most often, the lymphocytes are diffusely
organized among the tissue resident cells; however, in some cases, the B
cells, T cells, and dendritic cells may form higher levels of organization,
such as lymphoid follicles and germinal center–like structures. Growth
factors secreted by synovial fibroblasts and macrophages promote the
formation of new blood vessels in the synovial sublining that supply
the increasing demands for oxygenation and nutrition required by the
infiltrating leukocytes and expanding synovial tissue.
PART 11
Immune-Mediated, Inflammatory, and Rheumatologic Disorders
The structural damage to the mineralized cartilage and subchondral
bone is mediated by the osteoclast. Osteoclasts are multinucleated giant
cells that appear at the pannus-bone interface where they eventually
form resorption lacunae. These lesions typically localize where the
synovial membrane inserts into the periosteal surface at the edges of
bone close to the rim of articular cartilage and at the attachment sites
of ligaments and tendon sheaths. This process most likely explains why
bone erosions usually develop at the radial sites of the MCP joints jux­
taposed to the insertion sites of the tendons, collateral ligaments, and
synovial membrane. Periarticular osteopenia, another form of bone
loss, occurs in joints with active inflammation. It is associated with
substantial thinning of the bony trabeculae along the metaphyses of
bones from inflammation of the bone marrow cavity. These lesions can
be visualized on MRI scans, where they appear as signal alterations in
the bone marrow adjacent to inflamed joints. Their signal characteris­
tics show they are water-rich with a low-fat content and are consistent
with highly vascularized inflammatory tissue. These bone marrow
lesions are often the forerunner of bone erosions. The cortical bone
layer that separates the bone marrow from the invading pannus is rela­
tively thin and susceptible to penetration by the inflamed synovium.
The bone marrow lesions visualized on MRI scans are associated with
an endosteal bone response characterized by the accumulation of
osteoblasts and deposition of osteoid. Finally, generalized osteoporosis,
which results in the thinning of trabecular bone throughout the body,
is a third form of bone loss found in patients with RA and can lead to
fragility fractures.
Articular cartilage is an avascular tissue comprised of a specialized
matrix of collagens, proteoglycans, and other proteins. It is organized
in four distinct regions (superficial, middle, deep, and calcified carti­
lage zones)—chondrocytes constitute the unique cellular component
in these layers. Originally, cartilage was considered to be an inert tis­
sue, but it is now known to be a highly responsive tissue that reacts to
inflammatory mediators and mechanical factors, which, in turn, alter
the balance between cartilage anabolism and catabolism. In RA, the
initial areas of cartilage degradation are juxtaposed to the synovial
pannus. The cartilage matrix is characterized by a generalized loss
of proteoglycan, most evident in the superficial zones adjacent to the
synovial fluid. Degradation of cartilage may also take place in the peri­
chondrocytic zone and in regions adjacent to the subchondral bone.
PATHOGENESIS
The pathogenic mechanisms of synovial inflammation are likely the
result of a complex interplay of genetic, environmental, and immuno­
logic factors that cause immune system dysregulation and a breakdown
in self-tolerance (Fig. 370-4). Precisely what triggers these initiating
events and what genetic and environmental factors disrupt the immune
system remains a mystery. However, a detailed molecular picture is
emerging of the mechanisms underlying the chronic inflammatory
response and the resulting destruction of the articular cartilage and
bone.
In RA, the preclinical stage appears to be characterized by a break­
down in self-tolerance. This idea is supported by the finding that auto­
antibodies, such as RF and ACPA, may be found in sera from patients
many years before onset of clinical disease. However, the antigenic tar­
gets of ACPA and RF are not restricted to the joint. ACPAs are directed
against deaminated peptides, which result from posttranslational mod­
ification by the enzyme PADI4. They recognize citrulline-containing
regions of several different matrix proteins, including filaggrin, keratin,
fibrinogen, and vimentin, and are present at higher levels in the joint
fluid compared to the serum. Antibodies binding to carbamylated pep­
tides and mutant citrullinated vimentin, as well as the 14-3-3 family of
proteins, have also been detected in a minority of RA patients.
In theory, environmental triggers may synergize with other factors
to bring about inflammation in RA. People who smoke display higher
citrullination of proteins in bronchoalveolar fluid than those who
do not smoke. Thus, it has been speculated that long-term exposure
to tobacco smoke might induce citrullination of cellular proteins via
increased PADI expression in the lung and generate a neoepitope
capable of inducing self-reactivity, which in turns, leads to formation of
immune complexes that trigger joint inflammation and joint damage.
Microbiota may also be involved in the initiating events of RA. The
immune system is alerted to the presence of microbial infections when
pathogen-associated molecular patterns (PAMPs) on their surface
bind to Toll-like receptors (TLRs) on host cells. There are 10 TLRs
in humans that recognize a variety of microbial products, including
bacterial cell-surface lipopolysaccharides and heat-shock proteins
(TLR4), lipoproteins (TLR2), double-strand RNA viruses (TLR3), and
unmethylated CpG DNA from bacteria (TLR9). TLR2, 3, and 4 are
abundantly expressed by synovial fibroblasts in early RA and, when
bound by their ligands, upregulate the cell’s production of proinflam­
matory cytokines. Although TLR ligands may theoretically amplify
inflammatory pathways in RA, their specific role in disease pathogen­
esis remains uncertain.
The pathogenesis of RA is built upon the concept that self-reactive
T cells drive the chronic inflammatory response. In theory, self-reactive
T cells might arise in RA from abnormal central (thymic) selection
or intrinsic defects lowering the threshold in the periphery for T-cell
activation. Either mechanism might result in abnormal expansion of
a self-reactive T-cell repertoire and a breakdown in T-cell tolerance.
The support for these ideas comes mainly from studies of arthritis
in mouse models. It has not been shown that patients with RA have
abnormal thymic selection of T cells or defective apoptotic pathways
regulating cell death. At least some antigen stimulation inside the joint
seems likely, owing to the fact that T cells in the synovium express a
cell-surface phenotype indicating prior antigen exposure and show
evidence of clonal expansion.
There is substantial evidence of a role for CD4+ T cells in the patho­
genesis of RA. First, the co-receptor CD4 on the surface of T cells binds
to invariant sites on MHC class II molecules, stabilizing the MHCpeptide–T-cell receptor complex during T-cell activation. Because the
SE on MHC class II molecules is a risk factor for RA, it follows that
CD4+ T-cell activation plays a role in the pathogenesis of this disease.
Second, CD4+ memory T cells are enriched in the synovial tissue
from patients with RA and therefore are implicated through “guilt by
association.” Third, CD4+ T cells have been shown to be important in
the initiation of arthritis in animal models. Fourth, some, but not all,
T cell–directed therapies have shown clinical efficacy in this disease.
Taken together, these lines of evidence suggest that CD4+ T cells play
an important role in orchestrating the chronic inflammatory response
in RA. However, other cell types, such as CD8+ T cells, natural killer
(NK) cells, and B cells are present in synovial tissue and may also influ­
ence pathogenic responses.
In the rheumatoid joint, by mechanisms of cell-cell contact and
release of soluble mediators, activated T cells stimulate macro­
phages and fibroblast-like synoviocytes to generate proinflammatory
Genetics
Environment
TLR
APC
MHC II
TCR
TH1
IFN-γ, TNF-α
lymphotoxin-β
TH
CD40L
CD40
IFN-γ,
IL17
IL15, GM-CSF,
TNF-α
B
M
RF,
Anti-CCP Ab
Pre-OB
OB
FIGURE 370-4  Pathophysiologic mechanisms of inflammation and joint destruction. Genetic predisposition along with environmental factors may trigger the development
of rheumatoid arthritis (RA), with subsequent synovial T-cell activation. CD4+ T cells become activated by antigen-presenting cells (APCs) through interactions between
the T-cell receptor and class II MHC-peptide antigen (signal 1) with co-stimulation through the CD28-CD80/86 pathway, as well as other pathways (signal 2). In theory,
ligands binding Toll-like receptors (TLRs) may further stimulate activation of APCs inside the joint. Synovial CD4+ T cells differentiate into TH1 and TH17 cells, each with their
distinctive cytokine profile. CD4+ TH cells in turn activate B cells, some of which are destined to differentiate into autoantibody-producing plasma cells. Immune complexes,
possibly comprised of rheumatoid factors (RFs) and anti–cyclic citrullinated peptides (CCP) antibodies, may form inside the joint, activating the complement pathway and
amplifying inflammation. T effector cells stimulate synovial macrophages (M) and fibroblasts (SF) to secrete proinflammatory mediators, among which is tumor necrosis
factor α (TNF-α). TNF-α upregulates adhesion molecules on endothelial cells, promoting leukocyte influx into the joint. It also stimulates the production of other inflammatory
mediators, such as interleukin 1 (IL-1), IL-6, and granulocyte-macrophage colony-stimulating factor (GM-CSF). TNF-α has a critically important function in regulating the
balance between bone destruction and formation. It upregulates the expression of dickkopf-1 (DKK-1), which can then internalize Wnt receptors on osteoblast precursors.
Wnt is a soluble mediator that promotes osteoblastogenesis and bone formation. In RA, bone formation is inhibited through the Wnt pathway, presumably due to the action
of elevated levels of DKK-1. In addition to inhibiting bone formation, TNF-α stimulates osteoclastogenesis. However, it is not sufficient by itself to induce the differentiation
of osteoclast precursors (Pre-OC) into activated osteoclasts capable of eroding bone. Osteoclast differentiation requires the presence of macrophage colony-stimulating
factor (M-CSF) and receptor activator of nuclear factor-κB (RANK) ligand (RANKL), which binds to RANK on the surface of Pre-OC. Inside the joint, RANKL is mainly derived
from stromal cells, synovial fibroblasts, and T cells. Osteoprotegerin (OPG) acts as a decoy receptor for RANKL, thereby inhibiting osteoclastogenesis and bone loss. FGF,
fibroblast growth factor; IFN, interferon; MMP, matrix metalloproteinase; TGF, transforming growth factor.
CHAPTER 370
Rheumatoid Arthritis
CD80
CD28
T
TH17
IL-17A, IL-17F,
TNF-α, IL-6,
GM-CSF
Teff
Teff
SF
IL-6, IL-8
FGF,
TGF-β
IL-1, IL-6, IL-18
TNF-`
MMP
+
Wnt
TH
+
St
Dkk-1
OPG
RANK-L
+
RANK
OC
Pre-OC
Cathepsin K
mediators and proteases that drive the synovial inflammatory response
and destroy the cartilage and bone. CD4+ T-cell activation is depen­
dent on two signals: (1) T-cell receptor binding to peptide-MHC
on antigen-presenting cells; and (2) CD28 binding to CD80/86 on
antigen-presenting cells. This interaction then leads to downstream
signals that differentiate CD4+ T cells into effector and memory
cell populations, as well as activate CD8+ T cells. Certain subsets of
CD4+ T cells, called T helper cells, enable B cells to differentiate into
antibody-secreting cells. An earlier T cell–centric model for the patho­
genesis of RA was based on a TH1-driven paradigm, which came from
studies indicating that CD4+ T helper (TH) cells differentiated into TH1
and TH2 subsets, each with their distinctive cytokine profiles. TH1 cells
were found to mainly produce interferon γ (IFN-γ), lymphotoxin β,
and tumor necrosis factor (TNF)-α, whereas TH2 cells predominately
secreted interleukin (IL)-4, IL-5, IL-6, IL-10, and IL-13. In humans,
naïve T cells may also be induced to differentiate into TH17 cells by
exposure to transforming growth factor β (TGF-β), IL-1, IL-6, and
IL-23. Upon activation, TH17 cells secrete a variety of proinflamma­
tory mediators such as IL-17, IL-21, IL-22, TNF-α, IL-26, IL-6, and
granulocyte-macrophage colony-stimulating factor (GM-CSF). Sub­
stantial evidence now exists from studies in both animal models and
humans that IL-17 plays an important role not only in promoting joint
inflammation but also in destroying cartilage and subchondral bone.
However, therapeutic antibodies that interfere with the IL-17/IL-17
receptor pathway were not particularly effective in clinical trials for
reducing joint inflammation in RA.
PART 11
Immune-Mediated, Inflammatory, and Rheumatologic Disorders
The immune system has evolved mechanisms to counterbalance
the potentially harmful immune-mediated inflammatory responses
provoked by infectious agents and other triggers. Among these nega­
tive regulators are regulatory T (Treg) cells, which are produced in the
thymus and induced in the periphery to suppress immune-mediated
inflammation. They are characterized by the surface expression of
CD25 and the expression of the transcription factor forkhead box
P3 (FOXP3). Tregs orchestrate dominant tolerance through contact
with other immune cells and secretion of inhibitory cytokines, such
as TGF-β, IL-10, and IL-35. They are heterogeneous and capable of
suppressing distinct classes (TH1, TH2, TH17) of the immune response,
although data supporting their role in suppressing inflammation in RA
are inconclusive.
Cytokines, chemokines, antibodies, and endogenous danger sig­
nals bind to receptors on the surface of immune cells and stimulate a
cascade of intracellular signaling events that can amplify the inflam­
matory response. Examples of signaling molecules in these critical
inflammatory pathways include Janus kinase (JAK)/signal transducers
and activators of transcription (STAT), spleen tyrosine kinase (Syk),
mitogen-activated protein kinases (MAPKs), and nuclear factor-κB
(NF-κB). These pathways exhibit significant crosstalk and are found
in many cell types. Some signal transducers, such as the JAKs, are
expressed in hematopoietic cells and play an important role in the
inflammatory response in RA.
Activated, autoreactive B cells are also important players in the
chronic inflammatory process. B cells give rise to plasma cells, which,
in turn, produce antibodies, including RF and ACPA. RFs may form
large immune complexes inside the joint that contribute to the patho­
genic process by fixing complement and promoting the release of pro­
inflammatory cytokines and chemokines. In mouse models of arthritis,
RF-containing immune complexes and ACPA-containing immune
complexes synergize with other mechanisms to exacerbate the synovial
inflammatory response.
RA is often considered to be a macrophage-driven disease because
this cell type is the predominant source of proinflammatory cyto­
kines inside the joint. Key proinflammatory cytokines released by
macrophage-like synoviocytes include TNF-α, IL-1, IL-6, IL-12, IL-15,
IL-18, and IL-23. Synovial fibroblasts, the other major cell type in this
microenvironment, produce the cytokines IL-1 and IL-6 as well as
TNF-α. TNF-α is a pivotal cytokine in the pathobiology of synovial
inflammation and has many proinflammatory effects. It upregulates
adhesion molecules on endothelial cells, promoting the influx of
leukocytes into the synovial microenvironment; activates synovial
fibroblasts; stimulates angiogenesis; promotes pain receptor sensitiz­
ing pathways; and drives osteoclastogenesis. Fibroblasts secrete matrix
metalloproteinases (MMPs) as well as other proteases that are chiefly
responsible for the breakdown of articular cartilage; they also promote
inflammation and synovial proliferation by secreting cytokines such as
IL-6, IL-1, IL-18, and GM-CSF, chemokines, and vascular endothelial
growth factor.
Recent studies of synovial tissue samples from patients with RA have
combined histology and single-cell RNA expression data to identify
distinct cell populations that drive joint inflammation. These studies
reveal that synovial tissue samples can be distinguished among patients
with RA by the relative abundance of myeloid cells, T cells, B cells,
synovial fibroblasts, and endothelial cells and hence can be divided
into different subsets. Thus far, these data highlight the importance of
IFN-γ-secreting granzyme K+ CD8+ T cells, peripheral helper CD4+
T cells, activated sublining fibroblasts, and proinflammatory mono­
cytes as key mediators of joint inflammation. In these studies, most
of the synovial tissue samples were found to be populated by T cells,
fibroblasts, and myeloid cells and had cellular phenotypes classified as
predominately myeloid, T and B cell, and T cell and myeloid, while oth­
ers had a paucity of immune cells and were dominated by endothelial
cells and fibroblasts. Further research along these lines will enrich our
understanding of the active immune pathways in RA and may help to
determine in the future if knowledge of these cellular phenotypes can
be used to guide a personalized treatment approach.
Osteoclast activation at the site of the pannus is closely tied to the
presence of focal bone erosion. Receptor activator of nuclear factor-κB
ligand (RANKL) is expressed by stromal cells, synovial fibroblasts, and
T cells. Upon binding to its receptor RANK on osteoclast progenitors,
RANKL stimulates osteoclast differentiation and bone resorption.
RANKL activity is regulated by osteoprotegerin (OPG), a decoy recep­
tor of RANKL that blocks osteoclast formation. Monocytic cells in the
synovium serve as the precursors of osteoclasts and, when exposed to
macrophage colony-stimulating factor (M-CSF) and RANKL, fuse to
form polykaryons termed preosteoclasts. These precursor cells undergo
further differentiation into osteoclasts with a characteristic ruffled
membrane. Cytokines such as TNF-α, IL-1, IL-6, and IL-17 can pro­
mote osteoclastogenesis by increasing the expression of RANKL inside
the joint. Osteoclasts also secrete cathepsin K, a cysteine protease that
degrades the bone matrix by cleaving collagen and thus contributes to
generalized bone loss and osteoporosis.
Increased bone loss is only part of the story in RA, as decreased bone
formation plays a crucial role in bone remodeling at sites of inflam­
mation. Recent evidence shows that inflammation suppresses bone
formation. TNF-α plays a key role in actively suppressing bone forma­
tion by enhancing the expression of dickkopf-1 (DKK-1). DKK-1 is an
important inhibitor of the Wnt pathway, which acts to promote osteo­
blast differentiation and bone formation. The Wnt system is a family
of soluble glycoproteins that binds to cell-surface receptors known
as frizzled (fz) and low-density lipoprotein (LDL) receptor–related
proteins (LRPs) and promotes cell growth. In animal models, increased
levels of DKK-1 are associated with decreased bone formation, whereas
inhibition of DKK-1 protects against structural damage in the joint.
Wnt proteins also induce the formation of OPG and thereby shut down
bone resorption, emphasizing their key role in tightly regulating the
balance between bone resorption and formation.
DIAGNOSIS
The clinical diagnosis of RA is largely made by recognizing the signs
and symptoms of a chronic inflammatory arthritis and the typical
pattern of joint involvement, with laboratory and radiographic results
providing important corroborating information. In 2010, a collab­
orative effort between the American College of Rheumatology (ACR)
and the European League Against Rheumatism (EULAR) revised the
1987 ACR classification criteria for RA in an effort to improve early
diagnosis with the goal of identifying patients who would benefit from
early introduction of disease-modifying therapy (Table 370-1). The
items in the newly revised criteria yield a score of 0–10, with a score of
≥6 fulfilling the requirements for definite RA. The new classification
TABLE 370-1  Classification Criteria for Rheumatoid Arthritis
 
 
SCORE
Joint
involvement
1 large joint (shoulder, elbow, hip, knee, ankle)
2–10 large joints
1–3 small joints (MCP, PIP, thumb IP, MTP, wrists)
4–10 small joints
10 joints (at least 1 small joint)
Serology
Negative RF and negative ACPA
Low-positive RF or low-positive anti-CCP antibodies
(≤3 times ULN)
High-positive RF or high-positive anti-CCP
antibodies (>3 times ULN)
Acute-phase
reactants
Normal CRP and normal ESR
Abnormal CRP or abnormal ESR
Duration of
symptoms
<6 weeks
≥6 weeks
Note: These criteria are aimed at classification of newly presenting patients who
have at least one joint with definite clinical synovitis that is not better explained by
another disease. A score of ≥6 fulfills requirements for definite RA.
Abbreviations: ACPA, anti-citrullinated peptide antibodies; CCP, cyclic citrullinated
peptides; CRP, C-reactive protein; ESR, erythrocyte sedimentation rate; IP,
interphalangeal joint; MCP, metacarpophalangeal joint; MTP, metatarsophalangeal
joint; PIP, proximal interphalangeal joint; RF, rheumatoid factor; ULN, upper limit of
normal.
Source: Reproduced with permission from D Aletaha et al: 2010 Rheumatoid arthritis
classification criteria: An American College of Rheumatology/European League
Against Rheumatism collaborative initiative. Arthritis Rheum 62:2569, 2010.
criteria differ in several ways from the older criteria sets. Previous
classification schemes required symptoms to be present for >6 weeks.
There are several conditions, including virus-related syndromes, that
may cause a polyarthritis mimicking RA and be associated with tran­
sient production of RF. Such conditions usually last only 2–3 weeks.
The 2010 criteria, however, do not mandate symptoms be present
for >6 weeks. They also include as an item a positive test for serum
ACPA, which carries greater specificity for the diagnosis of RA than
a positive test for RF. About three-fourths of patients with the clini­
cal and radiographic features of RA test positive for RF and/or ACPA
(seropositive), while the remaining one-fourth of patients with RA test
negative for RF and/or ACPA (seronegative). The presence of rheuma­
toid nodules or radiographic joint damage as items were not included
as they occur only rarely in early RA. It is important to emphasize that
the 2010 ACR-EULAR criteria are “classification criteria” as opposed
to “diagnostic criteria” and serve to distinguish patients at the onset of
disease who have a high likelihood of evolution to chronic disease with
persistent synovitis and joint damage. The presence of radiographic
joint erosions or subcutaneous nodules may inform the diagnosis in
the later stages of the disease.
The differential diagnosis for RA includes all types of acute and
chronic inflammatory arthritides, many of which may be differentiated
from RA based on the clinical course, pattern of joint involvement, the
presence of disease in other organ systems, and ancillary laboratory
studies. Patients with primary Sjögren’s syndrome whose predominate
clinical manifestations are dry eyes and dry mouth often also have
symptoms of polyarthralgia and may show a mild inflammatory syno­
vitis similar to RA. Moreover, 50% of patients with primary Sjögren’s
syndrome test positive for RF and, therefore, may be confused with
early RA. However, most patients with primary Sjögren’s syndrome
test positive for ANA and approximately two-thirds have detectable
anti-Ro/SSA antibodies. Spondyloarthropathies, such as psoriatic
arthritis or enteropathy-associated arthritis, may present similarly
to RA and may be distinguished by the presence of sacroiliitis, other
enthesopathic features, and the presence of psoriasis or inflammatory
bowel disease, respectively. In elderly patients, seronegative RA may be
difficult at times to distinguish from polymyalgia rheumatica (PMR), a
chronic inflammatory condition of the elderly characterized by neck/
shoulder girdle and lower back/hip girdle pain and stiffness (Chap. 375).
While PMR may occasionally feature distal limb involvement, RA
predominately affects the wrists/hands and ankles/feet, especially at
disease onset. Similarly, the relatively rare condition called remitting
seronegative symmetrical synovitis with pitting edema (RS3PE) and
paraneoplastic syndromes may also be confused with early RA. RS3PE
is typically characterized by prominent distal limb pitting edema,
which is unusual in RA, and responds promptly to treatment with low
doses of prednisone. Chronic tophaceous gout may mimic severe RA
in some cases, and tophi may be confused with rheumatoid nodules.
Hepatitis C–related arthropathy often involves the small joints of
the hands and is associated in half the cases with a positive RF, but
generally not ACPA.
CHAPTER 370
Rheumatoid Arthritis
LABORATORY FEATURES
Patients with systemic inflammatory diseases such as RA will often
present with elevated nonspecific inflammatory markers such as an
ESR or CRP. Testing for serum RF and anti-cyclic citrullinated peptide
(CCP) antibodies is important in differentiating RA from other poly­
articular diseases, although RF lacks diagnostic specificity and may
be found in association with other chronic inflammatory diseases in
which arthritis figures in the clinical manifestations.
IgM, IgG, and IgA isotypes of RF occur in sera from patients with
RA, although the IgM isotype is the one most frequently measured
by commercial laboratories. Serum IgM RF has been found in 75% of
patients with RA; therefore, a negative result does not exclude the pres­
ence of this disease. It is also found in other connective tissue diseases,
such as primary Sjögren’s syndrome, systemic lupus erythematosus,
and type II mixed essential cryoglobulinemia, as well as chronic infec­
tions such as subacute bacterial endocarditis and hepatitis B and C.
Serum RF, mostly at low levels, may also be detected in 1–5% of the
healthy population.
The presence of serum anti-CCP antibodies has about the same
sensitivity as serum RF for the diagnosis of RA. However, its diagnostic
specificity approaches 95%, so a positive test for anti-CCP antibodies in
the setting of an early inflammatory arthritis is useful for distinguish­
ing RA from other forms of arthritis. There is some incremental value
in testing for the presence of both RF and anti-CCP, as some patients
with RA are positive for RF but negative for anti-CCP and vice versa.
The presence of RF or anti-CCP antibodies also has prognostic signifi­
cance, with anti-CCP antibodies showing the most value for predicting
worse outcomes.
Patients with RA may also have other antibodies associated with
autoimmune disease. Approximately 30% of patients with RA test
positive for antinuclear antibodies (ANAs), and some sera from some
patients contain antineutrophil cytoplasmic antibodies (ANCAs; par­
ticularly p-ANCAs). However, patients with RA would not be expected
to test positive for anti-MPO or anti-PR3 antibodies as they would if
they had an ANCA-associated vasculitis.
■
■SYNOVIAL FLUID ANALYSIS
Typically, the cellular composition of synovial fluid from patients with
RA reflects an acute inflammatory state. Synovial fluid white blood cell
(WBC) counts can vary widely but generally range between 5000 and
50,000 WBC/μL, compared with <2000 WBC/μL for a noninflamma­
tory condition such as osteoarthritis. In contrast to the synovial tissue,
the overwhelming cell type in the synovial fluid is the neutrophil.
Clinically, the analysis of synovial fluid is most useful for confirming
an inflammatory arthritis (as opposed to osteoarthritis), while at the
same time excluding infection or a crystal-induced arthritis such as
gout or pseudogout (Chap. 384).
■
■JOINT IMAGING
Joint imaging is a valuable tool not only for diagnosing RA but also
for tracking progression of any joint damage. Plain x-ray is the most
common imaging modality, but it is limited to visualization of the
bony structures and inferences about the state of the articular carti­
lage based on the amount of joint space narrowing. MRI and ultra­
sound techniques offer the added value of detecting changes in the
soft tissues such as synovitis, tenosynovitis, and effusions, as well as
providing greater sensitivity for identifying bony abnormalities. Plain
PART 11
Immune-Mediated, Inflammatory, and Rheumatologic Disorders
FIGURE 370-5  X-ray of the right hand demonstrating features of advanced
rheumatoid arthritis. This x-ray is notable for carpal crowding of the wrist (yellow
arrow), loss of joint space and subluxation of the fifth metacarpophalangeal joint
(green arrow), and an erosion of the fourth proximal interphalangeal joint (red
arrow).
radiographs are usually relied upon in clinical practice for the purpose
of diagnosis and monitoring affected joints. However, in selected cases,
MRI and ultrasound can provide additional diagnostic information
that may guide clinical decision-making. Musculoskeletal ultrasound
with power Doppler is increasingly used in rheumatology clinical prac­
tice for detecting synovitis and bone erosion.
Plain Radiography 
Classically in RA, the initial radiographic
finding is periarticular osteopenia. Practically speaking, however, this
finding is difficult to appreciate on plain films and particularly their
digitalized images. Other findings on plain radiographs include soft
tissue swelling, symmetric joint space loss, and juxtaarticular and
subchondral erosions, most frequently in the wrists and hands (MCPs
and PIPs) and the feet (MTPs). In the feet, the lateral aspect of the fifth
MTP is often targeted first, but other MTP joints may be involved at the
same time. X-ray imaging of advanced RA may reveal signs of severe
destruction, including joint subluxation and collapse (Fig. 370-5).
MRI 
MRI offers the greatest sensitivity for detecting synovitis and
joint effusions, as well as early bone and bone marrow changes. These
soft tissue abnormalities often occur before osseous changes are noted
on x-ray. Presence of bone marrow edema has been recognized to be an
early sign of inflammatory joint disease and can predict the subsequent
development of erosions on plain radiographs as well as MRI scans.
Cost and availability of MRI are the main factors limiting its routine
clinical use.
Ultrasound 
Ultrasound, including power color Doppler, can detect
more erosions than plain radiography, especially in easily accessible
joints. It can also reliably detect synovitis, including increased joint
vascularity indicative of inflammation. The usefulness of ultrasound is
dependent on the experience of the sonographer; however, it does offer
the advantages of portability, lack of radiation, and low expense relative
to MRI, factors that make it attractive as a clinical tool (Fig. 370-6).
See Videos 370-1, 370-2, and 370-3.
CLINICAL COURSE
The natural history of RA is complex and affected by a number of fac­
tors including age of onset, gender, genotype, phenotype (i.e., extraar­
ticular manifestations or variants of RA), and comorbid conditions,
which make for a truly heterogeneous disease. It is important to realize
FIGURE 370-6  Ultrasound demonstrating an effusion (arrow) within the
metacarpophalangeal joint. (Courtesy of Dr. Ryan Jessee.)
that as many as 10% of patients with inflammatory arthritis fulfilling
ACR classification criteria for RA will undergo a spontaneous remis­
sion within 6 months (particularly seronegative patients). However,
the vast majority of patients will exhibit a pattern of persistent and
progressive disease activity that waxes and wanes in intensity over time.
A minority of patients will show intermittent and recurrent explosive
attacks of inflammatory arthritis interspersed with periods of disease
quiescence. Finally, an aggressive form of RA may occur in an unfor­
tunate few with inexorable progression of severe erosive joint disease,
although this highly destructive course is less common in the modern
treatment era.
Disability, as measured by the Health Assessment Questionnaire
(HAQ), shows gradual worsening over time in the face of poorly con­
trolled disease activity and disease progression. Disability may result
from both a disease activity–related component that is potentially
reversible with therapy and a joint damage–related component owing
to the cumulative and largely irreversible effects of soft tissue, cartilage,
and bone breakdown. Early in the course of disease, the extent of joint
inflammation is the primary determinant of disability, while in the later
stages of disease, the amount of joint damage is the dominant contrib­
uting factor. Previous studies have shown that more than one-half of
patients with RA are unable to work 10 years after the onset of their
disease; however, increased employability and less work absenteeism
have been reported recently with the use of newer therapies and earlier
treatment intervention.
The overall mortality rate in RA is two times greater than in the
general population. In particular, patients are at significantly increased
risk for death due to respiratory illness, cardiovascular disease, and
infection. Median life expectancy is shortened by an average of 7 years
for men and 3 years for women compared with control populations.
Patients at higher risk for shortened survival are those with systemic
extraarticular involvement, low functional capacity, low socioeco­
nomic status, low education, and chronic prednisone use.
TREATMENT
Rheumatoid Arthritis
The amount of clinical disease activity in patients with RA reflects
the overall burden of inflammation and is the variable that most
influences treatment decisions. Joint inflammation is the main
driver of joint damage and is the most important cause of functional
disability in the early stages of disease. Several composite indices
have been developed to assess clinical disease activity. The ACR
20, 50, and 70 improvement criteria (which correspond to a 20,
50, and 70% improvement, respectively, in joint counts, physician/
patient assessment of disease severity, pain scale, serum levels of
acute-phase reactants [ESR or CRP], and a functional assessment
of disability using a self-administered patient questionnaire) are a
composite index with a dichotomous response variable. The ACR
improvement criteria are commonly used in clinical trials as an
endpoint for comparing the proportion of responders between
treatment groups. In contrast, the Disease Activity Score (DAS),
Simplified Disease Activity Index (SDAI), the Clinical Disease
Activity Index (CDAI), and the Routine Assessment of Patient
Index Data 3 (RAPID3) are continuous measures of disease activ­
ity that are used in clinical practice for tracking disease status and
documenting treatment response.
The identification of genetic and environmental risk factors as
well as the presence of autoantibodies creates a phenotype of a per­
son who may be at higher risk for development of RA, or “preclini­
cal RA.” Several trials have enrolled patients meeting a definition
of preclinical RA in an attempt to prevent development of disease
with disease-modifying therapies approved for the treatment of RA.
While some of these disease-modifying therapies may delay the
development of RA compared to a placebo, no strategy has yet been
successful in preventing disease.
Several developments during the past two decades have changed
the therapeutic landscape in RA. They include (1) the emer­
gence of methotrexate as the disease-modifying antirheumatic
drug (DMARD) of first choice for the treatment of early RA; (2)
the development of novel highly efficacious biologicals that can
be used alone or in combination with methotrexate; and (3) the
proven superiority of combination DMARD regimens over metho­
trexate alone. The medications used for the treatment of RA may
be divided into broad categories: nonsteroidal anti-inflammatory
drugs (NSAIDs); glucocorticoids, such as prednisone and meth­
ylprednisolone; conventional DMARDs; and biologic DMARDs
(Table 370-2). Although disease for some patients with RA is man­
aged adequately with a single DMARD, such as methotrexate, it
calls in most cases for the use of a combination DMARD regimen
that may vary in its components over the treatment course depend­
ing on fluctuations in disease activity, loss of treatment efficacy, and
emergence of drug-related toxicities and comorbidities.
NSAIDS
NSAIDs were formerly viewed as the core of RA therapy, but they
are now considered to be adjunctive agents for management of
symptoms uncontrolled by other measures. NSAIDs exhibit both
analgesic and anti-inflammatory properties. The anti-inflammatory
effects of NSAIDs derive from their ability to nonselectively inhibit
cyclooxygenase (COX)-1 and COX-2. Although the results of clini­
cal trials suggest that NSAIDs are roughly equivalent in their effi­
cacy, experience suggests that some individuals may preferentially
respond to a particular NSAID. Chronic use should be minimized
due to the possibility of side effects, particularly gastritis and peptic
ulcer disease and kidney injury.
GLUCOCORTICOIDS
Glucocorticoids may serve in several ways to control disease activ­
ity in RA. First, they may be administered in low to moderate doses
to achieve rapid disease control before the onset of fully effective
DMARD therapy, which often takes several weeks or even months.
Second, a 1- to 2-week burst of glucocorticoids may be prescribed
for the management of acute disease flares, with dose and duration
guided by the severity of the exacerbation. Chronic administra­
tion of low doses (5–10 mg/d) of prednisone (or its equivalent)
may also be warranted to control disease activity in patients with
an inadequate response to DMARD therapy. As much as possible,
chronic glucocorticoid therapy should be avoided in favor of find­
ing an effective DMARD regimen that adequately controls the
disease. Best practices minimize chronic use of low-dose predni­
sone therapy owing to the risk of osteoporosis and other long-term
complications; however, the use of chronic prednisone therapy
is unavoidable in some cases. High-dose glucocorticoids may be
necessary for the treatment of severe extraarticular manifestations
of RA, such as ILD. Finally, if a patient exhibits one or a few actively
inflamed joints, the clinician may consider intraarticular injection
of an intermediate-acting glucocorticoid such as triamcinolone ace­
tonide. This approach may allow for rapid control of inflammation
in a limited number of affected joints. Caution must be exercised to
appropriately exclude joint infection as it often mimics a monoar­
ticular RA flare.
CHAPTER 370
Osteoporosis ranks as an important long-term complication of
chronic prednisone use. Based on a patient’s risk factors, including
total prednisone dosage, length of treatment, gender, race, and bone
density, treatment with an oral (e.g., alendronate, risedronate) or
parenteral (e.g., zoledronic acid) bisphosphonate may be appropri­
ate for primary prevention of glucocorticoid-induced osteoporosis.
Other agents, including denosumab and teriparatide, have also
been approved for the treatment of steroid-induced osteoporosis
and may be indicated in certain cases. Although prednisone use is
known to increase the risk of peptic ulcer disease, especially with
concomitant NSAIDs, no evidence-based guidelines recommend
routine co-administration of proton pump inhibitors for gastroin­
testinal ulcer prophylaxis.
DMARDS
DMARDs are so named because of their ability to slow or prevent
structural progression of RA. The conventional DMARDs include
hydroxychloroquine, sulfasalazine, methotrexate, and leflunomide;
they exhibit a delayed onset of action of ~6–12 weeks or longer.
Methotrexate is the DMARD of choice for the treatment of RA
and is the anchor drug for most combination therapies. It was
approved for the treatment of RA in 1988 and remains a benchmark
for comparison with the newer disease-modifying therapies. At
the dosages used for the treatment of RA, methotrexate has been
shown to stimulate adenosine release from cells, producing an
anti-inflammatory effect. Methotrexate is administered weekly by
the oral or subcutaneous route. Folic acid is taken as co-therapy to
mitigate some of methotrexate’s side effects. The clinical efficacy of
leflunomide, an inhibitor of pyrimidine synthesis, appears similar
to that of methotrexate; it has been shown in well-designed trials to
be effective for the treatment of RA as monotherapy or in combina­
tion with methotrexate and other DMARDs.
Rheumatoid Arthritis
Although similar to the other DMARDs in its slow onset of
action, hydroxychloroquine has not been shown to delay radio­
graphic progression of disease and thus is not considered to be a
true DMARD. In clinical practice, hydroxychloroquine is generally
used for treatment of early, mild disease or as adjunctive therapy
in combination with other DMARDs. It is prescribed at a dosage
of 5 mg/kg of body weight or less to decrease the risk of retinal
toxicity. Sulfasalazine has been shown in randomized, controlled
trials to reduce joint inflammation and radiographic progression of
disease. A regimen termed oral triple therapy, which is comprised
of hydroxychloroquine, sulfasalazine, and methotrexate, is an effec­
tive combination regimen often used in patients with an inadequate
response to treatment with methotrexate alone.
BIOLOGICALS
Biologic DMARDs have revolutionized the treatment of RA over
the past two decades (Table 370-2). They are protein therapeutics
designed to target cytokines and cell-surface molecules. The TNF
inhibitors were the first biologicals approved for the treatment of
RA, but several others have come to market since their introduc­
tion in 1999. Additionally, biosimilars are agents that have been
designed with the same active properties as the licensed biophar­
maceutical product. Several of these biosimilars have been studied
for the treatment of RA and demonstrate a similar efficacy and
side-effect profile to the reference biological.
Anti-TNF Agents  The development of TNF inhibitors was origi­
nally spurred by the experimental finding that TNF-α is a critical
upstream mediator of joint inflammation. Five original “innovator”
TNF inhibitors with various molecular designs have been approved
for the treatment of RA. Three of these products are anti-TNF
TABLE 370-2  DMARDs Used for the Treatment of Rheumatoid Arthritis
DRUG
DOSAGE
SERIOUS TOXICITIES
Hydroxychloroquine
200–400 mg/d orally (≤5 mg/kg)
Irreversible retinal damage
Cardiotoxicity
Blood dyscrasia
PART 11
Immune-Mediated, Inflammatory, and Rheumatologic Disorders
Sulfasalazine
Initial: 500 mg orally twice daily
Maintenance: 1000–1500 mg twice
daily
Granulocytopenia
Hemolytic anemia (with G6PD
deficiency)
Methotrexate
10–25 mg/week orally or SQ
Folic acid 1 mg/d to reduce toxicities
Hepatotoxicity
Myelosuppression
Infection
Interstitial pneumonitis
Pregnancy category X
Leflunomide
10–20 mg/d
Hepatotoxicity
Myelosuppression
Infection
Pregnancy category X
TNF-α inhibitors
Infliximab: 3 mg/kg IV at weeks 0, 2,
6, then every 8 weeks. May increase
dose up to 10 mg/kg every 4 weeks
↑ Risk bacterial, fungal
infections
Reactivation of latent
tuberculosis
↑ Lymphoma risk
(controversial)
Drug-induced lupus
Neurologic deficits
 
Etanercept: 50 mg SQ weekly, or
25 mg SQ biweekly
As above
Injection site reaction
Tuberculosis
screening
 
Adalimumab: 40 mg SQ every other
week
As above
Injection site reaction
Tuberculosis
screening
 
Golimumab: 50 mg SQ monthly
As above
Injection site reaction
Tuberculosis
screening
 
Certolizumab: 400 mg SQ weeks
0, 2, 4, then 200 mg every other week
As above
Injection site reaction
Tuberculosis
screening
Abatacept
Weight based:
<60 kg: 500 mg
60–100 kg: 750 mg
100 kg: 1000 mg
IV dose at weeks 0, 2, and 4, and then
every 4 weeks
OR
125 mg SQ weekly
↑ Risk bacterial, viral
infections
Anakinra
100 mg SQ daily
↑ Risk bacterial, viral
infections
Reactivation of latent
tuberculosis
Neutropenia
Rituximab
1000 mg IV × 2, days 0 and 14
May repeat course every 24 weeks
or more
Premedicate with methylprednisolone
100 mg to decrease infusion reaction
↑ Risk bacterial, viral
infections
Infusion reaction
Cytopenia
Hepatitis B reactivation
Interleukin-6
inhibitors
Tocilizumab:
4–8 mg/kg IV monthly
OR
162 mg SQ every other week
(<100 kg weight)
162 mg SQ every week
(≥100 kg weight)
Sarilumab:
200 mg SQ every other week
Risk of infection
Infusion reaction
LFT elevation
Dyslipidemia
Cytopenias
OTHER COMMON SIDE
EFFECTS
INITIAL
EVALUATION
MONITORING
Nausea
Diarrhea
Headache
Rash
Eye examination
if >40 years old
or prior ocular
disease
Optical coherence
tomography and visual
field testing every
12 months
Nausea
Diarrhea
Headache
CBC, LFTs
G6PD level
CBC every 2–4 weeks
for first 3 months, then
every 3 months
Nausea
Diarrhea
Stomatitis/mouth ulcers
Alopecia
Fatigue
CBC, LFTs
Viral hepatitis
panela
CBC, creatinine,
LFTs every 2–3 months
Chest x-ray
Alopecia
Diarrhea
CBC, LFTs
Viral hepatitis
panela
CBC, creatinine, LFTs
every 2–3 months
Infusion reaction
↑ LFTs
Tuberculosis
screeningb
LFTs periodically
Monitor for injection
site reactions
Monitor for injection
site reactions
Monitor for injection
site reactions
Monitor for injection
site reactions
Headache
Nausea
Tuberculosis
screening
Monitor for infusion
reactions
Injection site reaction
Headache
Tuberculosis
screening
CBC with
differential
CBC every month
for 3 months, then every
4 months for 1 year
Monitor for injection
site reactions
Rash
Fever
CBC
Viral hepatitis
panela
CBC at regular intervals
 
Tuberculosis
screening
CBC and LFTs at regular
intervals
(Continued)
TABLE 370-2  DMARDs Used for the Treatment of Rheumatoid Arthritis
DRUG
DOSAGE
SERIOUS TOXICITIES
JAK inhibitors
Tofacitinib:
5 mg orally twice daily
OR
11 mg orally daily
Upadacitinib:
15 mg orally daily
Baricitinib:
2 mg orally daily
Risk of infection
LFT elevation
Dyslipidemia
Neutropenia
Thrombosis
aViral hepatitis panel: hepatitis B surface antigen, hepatitis C viral antibody. bTuberculosis screening can be performed using a Mantoux tuberculin skin test or blood
interferon-gamma release assay.
Abbreviations: CBC, complete blood count; DMARDs, disease-modifying antirheumatic drugs; G6PD, glucose-6-phosphate dehydrogenase; IV, intravenous; LFTs, liver
function tests; JAK, Janus kinase; SQ, subcutaneous.
monoclonal antibodies: infliximab, a chimeric (part mouse and
human) monoclonal antibody; and adalimumab and golimumab,
humanized monoclonal antibodies. Certolizumab pegol, a fourth
product, is a pegylated Fab′ fragment of a humanized monoclonal
antibody, while the other, etanercept, is a soluble fusion protein
consisting of the TNF receptor 2 in covalent linkage with the Fc
portion of IgG1. All of these TNF inhibitors have been shown
in randomized controlled clinical trials to reduce the signs and
symptoms of RA, slow radiographic progression of joint damage,
and improve physical function and quality of life. Anti-TNF drugs
may be used alone or in combination with background methotrex­
ate therapy. Patients with RA who have an inadequate response to
methotrexate therapy are often treated with a TNF inhibitor, usually
in combination with methotrexate.
Anti-TNF agents should be avoided in patients with active infec­
tion or a history of hypersensitivity to these agents and are contra­
indicated in patients with chronic hepatitis B infection or class III/
IV congestive heart failure. A major concern is the increased risk
for infection, including serious bacterial infections, opportunistic
fungal infection, and reactivation of latent tuberculosis infection
(LTBI). For this reason, all patients are screened for LTBI accord­
ing to national guidelines with either an intradermal injection of
purified protein derivative (PPD) or an IFN-γ release assay prior
to starting anti-TNF therapy (Chap. 183). If positive, treatment for
LTBI is given for at least 1 month prior to starting anti-TNF therapy.
Anakinra  Anakinra is the recombinant form of the naturally
occurring IL-1 receptor antagonist. Anakinra has seen limited use
for the treatment of RA because other biologic DMARDs have seen
greater efficacy in practice.
Abatacept  Abatacept is a soluble fusion protein consisting of the
extracellular domain of human CTLA-4 linked to the modified
portion of human IgG. It inhibits the co-stimulation of T cells by
blocking CD28-CD80/86 interactions and may also inhibit the
function of antigen-presenting cells by reverse signaling through
CD80 and CD86. Abatacept has been shown in clinical trials to
reduce disease activity, slow radiographic progression of damage,
and improve functional disability. Most patients receive abatacept
in combination with a conventional DMARD. Abatacept therapy
has been associated with an increased risk of infection and can
inhibit a vaccine response.
Rituximab  Rituximab is a chimeric monoclonal antibody directed
against CD20, a cell-surface molecule expressed by most mature B
lymphocytes. It works by depleting B cells, which, in turn, leads to a
reduction in the inflammatory response by unknown mechanisms.
These mechanisms may include a reduction in autoantibodies, inhi­
bition of T-cell activation, and alteration of cytokine production.
Rituximab has been approved for the treatment of refractory RA
(failure of treatment with a TNF-α inhibitor) in combination with
methotrexate and has been shown to be more effective for patients
with seropositive than seronegative disease. Its administration has
(Continued)
OTHER COMMON SIDE
EFFECTS
INITIAL
EVALUATION
MONITORING
Upper respiratory tract
infections
Diarrhea
Headache
Nasopharyngitis
Tuberculosis
screening
CBC, LFTs, and lipids at
regular intervals
CHAPTER 370
Rheumatoid Arthritis
been associated with mild to moderate infusion reactions, as well as
an increased risk of infection. Notably, there have been rare isolated
reports of a potentially lethal brain disorder, progressive multifocal
leukoencephalopathy (PML), in association with rituximab therapy,
although the absolute risk of this complication appears to be very
low in patients with RA (~1:25,000). Most of these cases have
occurred on a background of previous or current exposure to other
potent immunosuppressive drugs. Studies in recent years have
also demonstrated that rituximab significantly inhibits a vaccine
response (e.g., response to SARS-CoV-2 vaccination).
Anti-IL-6 Receptor Agents  IL-6 is a proinflammatory cytokine
implicated in the pathogenesis of RA, with effects on both joint
inflammation and damage. IL-6 binding to its receptor acti­
vates intracellular signaling pathways that affect the acute-phase
response, cytokine production, and osteoclast activation. Tocili­
zumab and sarilumab are both monoclonal antibodies directed
against the membrane and soluble forms of the IL-6 receptor.
Clinical trials attest to the clinical efficacy of these therapies for
RA, both as monotherapy and in combination with methotrexate
and other conventional DMARDs. Anti-IL-6 receptor agents have
been associated with an increased risk of infection, neutropenia,
and thrombocytopenia; the hematologic abnormalities appear to
be reversible upon stopping the drug. In addition, this agent has
been shown to increase LDL cholesterol. However, it is not known
if this effect on lipid levels increases the risk for atherosclerotic
disease. Anti-IL-6 receptor agents have also been associated with an
increased rate of gastrointestinal perforation and should be avoided
if possible in patients with a history of diverticulitis and a recent
gastric or duodenal ulcer.
TARGETED SYNTHETIC DMARDs
Because treatment with conventional DMARDs and/or biologic
therapies may not result in optimal disease control, other therapeu­
tic strategies have been investigated to fill this gap. The so-called
targeted synthetic DMARDs have been designed to target intracel­
lular signaling pathways, which transduce the positive signals from
cell-surface receptors activated by cytokines and other inflamma­
tory mediators. They have an advantage over biologics in their oral
formulation.
JAK Inhibitors  Although several different kinases have been
evaluated as potential treatment targets, only inhibitors of the JAKs
have demonstrated safety and efficacy for the treatment of RA.
The JAK family comprises four members (JAK1, JAK2, JAK3, and
tyrosine kinase 2 [Tyk2]) and link a host of extracellular cytokine
receptors with their intracellular signaling domains. They form
homodimeric and heterodimeric duplexes that mediate signaling of
the receptors for the common γ-chain-related cytokines IL-2, -4, -7,
-9, -15, and -21, as well as IFN-γ, IL-6, IL-12, IL-23, IL-10, the type
I IFNs, and the hemopoietic cytokines and growth factors. Many of
these cytokines play critical roles in promoting T- and B-cell activa­
tion as well as chronic inflammation in RA.
Tofacitinib is a potent JAK1 and JAK3 inhibitor with minor
inhibitory effects on JAK2 and Tyk2; baricitinib is a JAK1 and JAK2
inhibitor with moderate inhibition of Tyk2 and minimal inhibition
of JAK3; and upadacitinib is a predominately selective inhibitor of
JAK1. Each of the JAK inhibitors can be used as monotherapy or in
combination with methotrexate. However, they are associated with
an increased risk of infections, including bacterial infections and
herpes zoster. Other possible side effects of these agents include
elevated liver transaminases, neutropenia, increased cholesterol
levels, hypertension, and elevations in serum creatinine. Recent
studies have also found an increased risk of thrombosis, major
adverse cardiovascular events, and malignancies in patients taking
tofacitinib compared with TNF inhibitors, with the highest of these
risks in the elderly.
TREATMENT OF EXTRAARTICULAR MANIFESTATIONS
In general, treatment of the underlying RA favorably modifies its
extraarticular manifestations, and observational studies suggest
aggressive management of early disease can potentially prevent
their occurrence in established disease. The treatment of patients
with RA-ILD, however, can be particularly challenging because
some of the DMARDs used for the treatment of RA are also associ­
ated with pulmonary toxicity, such as methotrexate and lefluno­
mide. RA-ILD is often treated with high doses of corticosteroids
and adjunctive immunosuppressive agents, such as azathioprine,
mycophenolate mofetil, or rituximab.
PART 11
Immune-Mediated, Inflammatory, and Rheumatologic Disorders
APPROACH TO THE PATIENT
Rheumatoid Arthritis
The treatment of RA adheres to the following principles and goals:
(1) early, aggressive therapy to prevent joint damage and disability;
(2) frequent modification of DMARD therapy to achieve treatment
goals with utilization of combination therapy where appropriate; (3)
individualization of DMARD therapy in an attempt to maximize
response and minimize side effects; (4) minimal use of long-term
glucocorticoid therapy; and (5) achieving, whenever possible, low
disease activity or clinical remission. A considerable amount of
evidence supports this intensive treatment approach and has been
termed “treat to target,” with a target of achieving low disease activ­
ity or remission.
As mentioned earlier, methotrexate is the DMARD of first choice
for initial treatment of moderate to severe RA. Failure to achieve
adequate improvement with methotrexate therapy calls for a change
in DMARD therapy, usually a transition to an effective combination
regimen. Effective combinations include methotrexate, sulfasala­
zine, and hydroxychloroquine (oral triple therapy); methotrexate
and leflunomide; and methotrexate plus a biological. The combina­
tion of methotrexate and an anti-TNF agent, for example, has been
shown in randomized controlled trials to be superior to methotrex­
ate alone, not only for reducing signs and symptoms of disease but
also for retarding the progression of structural joint damage. Pre­
dicting which patients are at higher risk for developing radiologic
joint damage is imprecise at best, although some factors such as an
elevated serum level of acute-phase reactants, high burden of joint
inflammation, and the presence of erosive disease are associated
with increased likelihood of developing structural injury.
In 2021, the ACR updated their guidelines for the treatment of
RA. These recommendations do not make a distinction between
the treatment of patients with early (<6 months of disease dura­
tion) or established disease and highlight the use of a treat-to-target
approach and the need to switch or add therapies for worsening or
persistent moderate/high disease activity. For example, in patients
with early RA who have persistent moderate/high disease activity
despite DMARD monotherapy, providers should consider escala­
tion to combination DMARD therapy or switching to an antiTNF +/– methotrexate or a non-TNF biologic +/– methotrexate.
Since a more intensive initial approach (e.g., combination DMARD
therapy) has been shown to produce superior long-term outcomes
compared with starting methotrexate alone, the usual approach
is to begin with methotrexate and, in the absence of an adequate
therapeutic response, rapidly step up (e.g., after 3–6 months) to a
combination of conventional DMARDs or add an anti-TNF or nonTNF biological agent.
Some patients may not respond to an anti-TNF drug or may be
intolerant of its side effects. Initial responders to an anti-TNF agent
who later experience worsening of their condition may benefit from
switching to another anti-TNF agent or an alternative biological
with a different mechanism of action. Indeed, some studies suggest
that switching to an alternative biological such as abatacept is more
effective than switching to another anti-TNF drug. Unacceptable
toxicity from an anti-TNF agent may also call for switching to
another biological or targeted synthetic DMARD with a different
mechanism of action or a conventional DMARD regimen.
Studies have also shown that oral triple therapy (hydroxychloro­
quine, methotrexate, and sulfasalazine) may be used effectively for
the treatment of early RA. Treatment may be initiated with metho­
trexate alone and, lacking an adequate treatment response, followed
within 6 months by a step-up to oral triple therapy.
A clinical state defined as low disease activity or remission is the
optimal goal of therapy, although most patients never achieve com­
plete remission despite every effort to achieve it. Composite indices,
such as the Disease Activity Score-28 (DAS-28), are useful for clas­
sifying states of low disease activity and remission; however, they
are imperfect tools due to the limitations of the clinical joint exami­
nation in which low-grade synovitis may escape detection. Com­
plete remission has been stringently defined as the total absence
of all articular and extraarticular inflammation and immunologic
activity related to RA. However, evidence for this state can be dif­
ficult to demonstrate in clinical practice. In an effort to standardize
and simplify the definition of remission for clinical trials, the ACR
and EULAR developed two provisional operational definitions of
remission in RA (Table 370-3). A patient may be considered in
remission if the patient (1) meets all the clinical and laboratory
criteria listed in Table 370-3 or (2) has a composite SDAI score of
<3.3. The SDAI is calculated by taking the sum of a tender joint
and swollen joint count (using 28 joints), patient global assessment
(0–10 scale), physician global assessment (0–10 scale), and CRP (in
mg/dL). This definition of remission does not consider the pos­
sibility of subclinical synovitis or that damage alone may produce a
tender or swollen joint. Ignoring the semantics of these definitions,
the aforementioned remission criteria are nonetheless useful for
setting a level of disease control that will likely result in minimal or
no progression of structural damage and disability. With an early,
aggressive approach to treatment, a significant number of patients
who reach remission may have a reduction in treatment without
an increased risk of flare or loss of remission. However, complete
withdrawal of DMARD therapy during established disease almost
invariably leads to a relapse.
TABLE 370-3  ACR/EULAR Provisional Definition of Remission in
Rheumatoid Arthritis
At any time point, patient must satisfy all of the following:
  Tender joint count ≤1
  Swollen joint count ≤1
  C-reactive protein ≤1 mg/dL
  Patient global assessment ≤1 (on a 0–10 scale)
OR
At any time point, patient must have a Simplified Disease Activity Index score of
≤3.3
Abbreviations: ACR, American College of Rheumatology; EULAR, European League
Against Rheumatism.
Source: Reproduced with permission from DT Felson et al; American College of
Rheumatology/European League Against Rheumatism provisional definition of
remission in rheumatoid arthritis for clinical trials. Arthritis Rheum 63:573, 2011.
PHYSICAL ACTIVITY AND ASSISTIVE DEVICES
In principle, all patients with RA should receive a prescription for
exercise and physical activity. The ACR has developed guidelines for
integrative interventions to accompany disease-modifying therapy
and includes evidence-based recommendations for diet and exercise.
Dynamic strength training, community-based comprehensive phys­
ical therapy, and physical-activity coaching (emphasizing achieving
150 min of moderate-to-vigorous physical activity per week) have all
been shown to improve muscle strength and perceived health status,
as well as improve DAS-28 scores and inflammatory markers. Foot
orthotics for painful valgus deformity decrease foot pain and may
reduce disability and functional limitations. Judicious use of wrist
splints can also decrease pain; however, their benefits may be offset
by decreased dexterity and variably curb grip strength.
SURGERY
Surgical procedures may improve pain and disability in RA with
varying degrees of reported long-term success—most notably for the
hands, wrists, and feet. For large joints, such as the knee, hip, shoul­
der, or elbow, the preferred option for advanced joint disease may
be total joint arthroplasty. A few surgical options exist for dealing
with the smaller hand joints. Silicone implants are the most com­
mon prosthetic for MCP arthroplasty and are generally implanted in
patients with severe decreased arc of motion, marked flexion contrac­
tures, MCP joint pain with radiographic abnormalities, and severe
ulnar drift. Arthrodesis and total wrist arthroplasty are reserved for
patients with severe disease who have substantial pain and functional
impairment. Numerous surgical options exist for correction of hallux
valgus in the forefoot, including arthrodesis and arthroplasty, as well
as primarily arthrodesis for refractory hindfoot pain.
OTHER MANAGEMENT CONSIDERATIONS
Pregnancy  Up to 75% of female RA patients will note overall
improvement in symptoms during pregnancy but they will often
flare shortly after delivery. Flares during pregnancy are gener­
ally treated with low doses of prednisone. Hydroxychloroquine
and sulfasalazine are probably the safest DMARDs to use during
pregnancy, although anti-TNF agents are generally accepted to be
safe in this setting. However, current guidelines call for anti-TNF
drugs to be discontinued during the third trimester of pregnancy.
Methotrexate and leflunomide therapy are contraindicated during
pregnancy due to their teratogenicity in animals and humans. The
experience with other biologic agents, such as abatacept, anti-IL-6
receptor antibodies, rituximab, and JAK inhibitors has been insuf­
ficient to make specific recommendations for their use during
pregnancy and are discontinued at conception. Active inflamma­
tory disease is associated with worse pregnancy outcomes, and thus,
controlling disease activity remains a priority.
Elderly Patients  RA presents in up to one-third of patients after
the age of 60; however, older individuals may receive less aggressive
treatment due to concerns about increased risks of drug toxicity.
Studies suggest that conventional DMARDs and biological agents
are equally effective and safe in younger and older patients (with the
possible exception of JAK inhibitors). Due to comorbidities, many
elderly patients have an increased risk of infection. Aging also leads
to a gradual decline in renal function that may raise the risk for side
effects from NSAIDs and some DMARDS, such as methotrexate.
Renal function must be taken into consideration before prescribing
methotrexate, which is mostly cleared by the kidneys. To reduce the
risks of side effects, methotrexate doses may need to be adjusted
downward for the drop in renal function that usually comes with
the seventh and eighth decades of life.
GLOBAL CHALLENGES
Developing countries are finding an increase in the incidence of non­
communicable, chronic diseases such as diabetes, cardiovascular dis­
ease, and RA in the face of ongoing poverty, rampant infectious disease,
and poor access to modern health care facilities. In these areas, patients
tend to have a greater delay in diagnosis and limited access to special­
ists and, thus, greater disease activity and disability at presentation. In
addition, infection risk remains a significant issue for the treatment of
RA in developing countries because of the immunosuppression associ­
ated with the use of glucocorticoids and most DMARDs. For example,
in some developing countries, patients undergoing treatment for RA
have a substantial increase in the incidence of tuberculosis, which
demands the implementation of far more comprehensive screening
practices and liberal use of isoniazid prophylaxis than in developed
countries. The increased prevalence of hepatitis B and C, as well as
human immunodeficiency virus (HIV), in these developing countries
also poses challenges. Reactivation of viral hepatitis has been observed
in association with some of the DMARDs, such as rituximab. Also,
reduced access to antiretroviral therapy may limit the control of HIV
infection and therefore the choice of DMARD therapies.
CHAPTER 370
Rheumatoid Arthritis
Despite these challenges, one should attempt to initiate early treat­
ment of RA in the developing countries with the resources at hand.
Hydroxychloroquine, sulfasalazine, and methotrexate are all reason­
ably accessible throughout the world where they can be used as both
monotherapy and in combination with other drugs. The availability
of biological agents is increasing in the developed countries as well as
in other areas around the world, although their use is limited by high
cost; national protocols restrict their use, and concerns remain about
the risk for opportunistic infections.
SUMMARY
Improved understanding of the pathogenesis of RA and its treat­
ment has dramatically revolutionized the management of this disease.
The outcomes of patients with RA are vastly superior to those of the
prebiologic modifier era; more patients than in years past are able to
avoid significant disability and continue working, albeit with some job
modifications. The need for early and aggressive treatment of RA as
well as frequent follow-up visits for monitoring of drug therapy has
implications for our health care system. Primary care physicians and
rheumatologists must be prepared to work together as a team to imple­
ment a treat-to-target approach with the goal of reaching remission
or low disease activity. In many settings, rheumatologists have reengi­
neered their practice in a way that places high priority on consultations
for any new patient with early inflammatory arthritis.
The therapeutic regimens for RA are becoming increasingly com­
plex with the rapidly expanding armamentarium. Patients receiving
these therapies must be carefully monitored by both the primary care
physician and the rheumatologist to minimize the risk of side effects
and identify quickly any complications of chronic immunosuppression.
Also, prevention and treatment of RA-associated conditions such as
ischemic heart disease and osteoporosis will likely benefit from a team
approach owing to the value of multidisciplinary care.
Research will continue to search for new therapies with superior
efficacy and safety profiles and investigate treatment strategies that
can bring the disease under control more rapidly and nearer to remis­
sion. However, prevention and cure of RA will likely require new
breakthroughs in our understanding of disease pathogenesis. Several
prevention trials in RA are currently underway and focus on a variety
of prevention strategies in individuals who have serologic and/or clini­
cal features at higher risk than the general population for developing
RA. Equally important is the identification of predictive biomarkers
in RA that will enable a personalized approach to DMARD therapy, a
foreseeable goal in the future that will take advantage of the advances
in technology and scientific understanding of the disease.
■
■FURTHER READING
Aletaha D, Smolen JS: Diagnosis and management of rheumatoid
arthritis: A review. JAMA 320:1360, 2018.
Catrina  AI et al: Mechanisms leading from systemic autoimmunity
to joint-specific disease in rheumatoid arthritis. Nat Rev Rheumatol
13:79, 2017.
Erickson AR et al: Clinical features of rheumatoid arthritis, in Kelley
and Firestein’s Textbook of Rheumatology, 10th ed. Firestein GS et al
(eds). Philadelphia, Elsevier, 2017, pp 1167–1186.

14 - 371 Acute Rheumatic Fever
371 Acute Rheumatic Fever
Fraenkel  L et al: 2021 American College of Rheumatology guide­
line for the treatment of rheumatoid arthritis. Arthritis Rheumatol
73:1108, 2021.
Gravallese  EM, Firestein  GS: Rheumatoid arthritis: Common ori­
gins, divergent mechanisms. N Engl J Med 388:529, 2023.
Karimi J et al: Genetic implications in the pathogenesis of rheumatoid
PART 11
Immune-Mediated, Inflammatory, and Rheumatologic Disorders
arthritis; an updated review. Gene 702:8, 2019.
Moreland LW et al: A randomized comparative effectiveness study
of oral triple therapy versus methotrexate plus etanercept in early
aggressive rheumatoid arthritis: The Treatment of Early Aggressive
Rheumatoid Arthritis Trial. Arthritis Rheum 64:2824, 2012.
VIDEO 370-1  Transverse view of 2nd MCP demonstrating synovial hypertrophy
with abnormal power doppler signal (yellow) consistent with synovitis. Synovial
proliferation is displacing the overlying extensor tendon of the digit above the
joint space. This view demonstrates small erosions of the dorsal metacarpal head.
(Courtesy of Dr. Philip Chu.)
VIDEO 370-2  Longitudinal dorsal view of the 2nd MCP demonstrating synovial
hypertrophy with abnormal power doppler signal (yellow) consistent with synovitis.
(Courtesy of Dr. Philip Chu)
VIDEO 370-3  Transverse view of 2nd MCP demonstrating synovial hypertrophy and
intrasynovial effusion with abnormal power doppler signal (yellow) consistent with
synovitis. Fluid and synovial proliferation is displacing the overlying extensor tendon
of the digit above the joint space. (Courtesy of Dr. Philip Chu.)
Joseph Kado, Jonathan Carapetis
Acute Rheumatic Fever
Acute rheumatic fever (ARF) is a multisystem disease resulting from
an autoimmune reaction to infection with group A Streptococcus.
Although many parts of the body may be affected, almost all of the
manifestations resolve completely. The major exception is cardiac
valvular damage (rheumatic heart disease [RHD]), which may persist
after the other features have disappeared.
GLOBAL CONSIDERATIONS
ARF and RHD are diseases of poverty. They were common in all coun­
tries until the early twentieth century, when their incidence began to
decline in industrialized nations. This decline was largely attributable
to improved living conditions—particularly less crowded housing and
better hygiene—which resulted in reduced transmission of group A
streptococci. The introduction of antibiotics and improved systems of
medical care had a supplemental effect.
The virtual disappearance of ARF and reduction in the incidence of
RHD in high-income countries during the first half of the twentieth
century unfortunately was not replicated in low- and middle-income
countries (LMICs), where these diseases continue unabated. RHD is
the most common cause of acquired heart disease in children in LMICs
and is a major cause of mortality and morbidity in adults as well. It
is estimated that >40 million people worldwide are affected by RHD,
with >300,000 deaths occurring each year. Some 95% of ARF cases and
RHD deaths now occur in developing countries, with particularly high
burdens in sub-Saharan Africa, Pacific nations, Australasia, China,
and South and Central Asia. The pathogenetic pathway from exposure
to group A Streptococcus followed by pharyngeal or superficial skin
infection and subsequent development of ARF, ARF recurrences, and
development of RHD and its complications is associated with a range
of risk factors and, therefore, potential interventions at each point
(Fig. 371-1). In affluent countries, many of these risk factors are well
controlled, and where needed, interventions are in place. Unfortu­
nately, the greatest burden of disease is found in LMICs, most of which
do not have the resources, capacity, and/or interest to tackle this multi­
faceted disease. In particular, few of these countries have coordinated,
register-based RHD control programs, which have been proven to be
cost-effective in reducing the burden of RHD. Enhancing awareness
of RHD and mobilizing resources for its control in LMICs are issues
requiring international attention. In 2018, member states of the World
Health Organization (WHO) unanimously adopted a Global Resolu­
tion on Rheumatic Fever and Rheumatic Heart Disease, calling on all
states as well as international stakeholders and the WHO itself to take
practical actions to control these diseases.
EPIDEMIOLOGY
ARF is mainly a disease of children aged 5–14 years. Initial episodes
become less common in older adolescents and young adults and are rare
in persons aged >30 years. By contrast, recurrent episodes of ARF remain
relatively common in adolescents and young adults. This pattern con­
trasts with the prevalence of RHD, which peaks between 25 and 40 years.
There is no clear gender association for ARF, but RHD more commonly
affects females, sometimes up to twice as frequently as males.
PATHOGENESIS
■
■ORGANISM FACTORS
Conventional teaching has it that ARF is exclusively caused by infection
of the upper respiratory tract with group A streptococci (Chap. 153).
Although classically, certain M-serotypes (particularly types 1, 3, 5, 6,
14, 18, 19, 24, 27, and 29) were associated with ARF, recent evidence
demonstrates that many more M-serotypes are rheumatogenic and
that so-called “rheumatogenic motifs” are found in only a minority of
serotypes associated with rheumatic fever. This epidemiologic evidence
also points to a clear role of skin infection in the pathogenesis of ARF.
The potential role of groups C and G streptococci is unclear at this time.
■
■HOST FACTORS
Based on epidemiologic evidence, ~3–6% of any population may be sus­
ceptible to ARF, and this proportion does not vary dramatically between
populations. Findings of familial clustering of cases and concordance
in monozygotic twins—particularly for chorea—confirm that suscep­
tibility to ARF is an inherited characteristic, with 44% concordance in
monozygotic twins compared to 12% in dizygotic twins and heritability
more recently estimated at 60%. Most evidence for host factors focuses
on immunologic determinants. Initial studies found associations with
human leukocyte antigen (HLA) class II alleles, some protective and
some associated with increased susceptibility, as well as polymorphisms
in tumor necrosis factor and mannose binding lectin. Recent genomewide association studies and genomic sequencing analyses have identi­
fied associations with a range of genes including the immunoglobulin
heavy chain (IGH) locus (specifically the IGHV4-61*02 allele), comple­
ment factor H, and some HLA class II (a range of HLA-DQ A and B
alleles) and III loci. The associations are often population dependent,
although increasing consistency is being found across populations in
meta-analyses of genomic studies. Over coming years, further genomic
analyses are expected to provide additional insights into ARF and RHD
pathogenesis, as well as host protective and susceptibility factors.
■
■THE IMMUNE RESPONSE
The most widely accepted theory of rheumatic fever pathogenesis
is based on the concept of molecular mimicry, whereby an immune
response targeted at streptococcal antigens (mainly thought to be on
the M protein) also recognizes human tissues. In this model, antigen
processing cells of the innate immune system present streptococcal
antigens after throat (and possibly skin) group A streptococcal infec­
tion to T cells, which then lead to activation of both humoral and cellu­
lar immunity. Cross-reactive antibodies bind to endothelial cells on the
heart valve, leading to activation of the adhesion molecule VCAM-1,
with resulting recruitment of activated lymphocytes and lysis of endo­
thelial cells in the presence of complement. The latter leads to release
of peptides including laminin, keratin, and tropomyosin, which, in
turn, activates cross-reactive T cells that invade the heart, amplifying
the damage and causing epitope spreading. An alternative hypothesis
proposes that the initial damage is due to streptococcal invasion of
epithelial surfaces, with binding of M protein to type IV collagen
Asymptomatic infection
Overcrowded living
conditions
Failure to seek health care
for sore throat
Risk
factors
Poverty
Inadequate diagnosis and
treatment of streptococcal
pharyngitis
Rural residence
Urban slum residence
Treatment failure
Exposure to
group A
streptococcus
Group A streptococcal
upper respiratory tract
infection*
Better diagnosis and
treatment of sore throat in
primary care
Better primary care
Economic
development
Good
evidence
base
Better living
conditions
Opportunities
for
Intervention
Systematic sore throat
screening and treatment
programs
Unproven/
Hypothesized/
Future
(Vaccine)
(Skin infection
control programs)
*Increasing evidence of the role of streptococcal skin infection
FIGURE 371-1  Pathogenetic pathway for acute rheumatic fever and rheumatic heart disease (RHD), with associated risk factors and opportunities for intervention at each
step. Interventions in parentheses are either unproven or currently unavailable.
allowing it to become immunogenic, but not through the mechanism
of molecular mimicry.
CLINICAL FEATURES
There is a latent period of ~3 weeks (1–5 weeks) between the precipitat­
ing group A streptococcal infection and the appearance of the clinical
features of ARF. The exceptions are chorea and indolent carditis, which
may follow prolonged latent periods lasting up to 6 months. Although
many patients report a prior sore throat, the preceding group A strep­
tococcal infection is commonly subclinical; in these cases, it can only
be confirmed using streptococcal antibody testing. The most common
clinical features are polyarthritis (present in 60–75% of cases) and car­
ditis (50–75%). The prevalence of chorea in ARF varies substantially
between populations, ranging from <2 to 30%. Erythema marginatum
and subcutaneous nodules are now rare, being found in <5% of cases.
■
■HEART INVOLVEMENT
Up to 75% of patients with ARF progress to RHD. The endocardium,
pericardium, or myocardium may be affected. Valvular damage is
the hallmark of rheumatic carditis. The mitral valve is almost always
affected, sometimes together with the aortic valve; isolated aortic valve
involvement is rare. Damage to the pulmonary or tricuspid valves is
usually secondary to increased pulmonary pressures resulting from
left-sided valvular disease. Early valvular damage leads to regurgita­
tion. Over ensuing years, usually as a result of recurrent episodes, leaf­
let thickening, scarring, calcification, and valvular stenosis may develop
(Fig. 371-2). See Videos 371-1 and 371-2. Therefore, the characteristic
manifestation of carditis in previously unaffected individuals is mitral
Poor access to health care
Poor access to health care
Inherited susceptibility
Lack of medication
Poor delivery of secondary
prophylaxis
Female gender (chorea)
CHAPTER 371
Lack of cardiac surgical
facilities
Poor access to health care
Asymptomatic or
undiagnosed acute
rheumatic fever
Acute Rheumatic Fever
Recurrent
acute rheumatic
fever
Heart
failure
Rheumatic
heart
disease (RHD)
Surgery
Disability
Death
Acute rheumatic
fever
Stroke
Endocarditis
Improved access
to health care
Secondary prophylaxis
Register-based programs
Register-based control programs
Integration of RHD control
into primary care, childhealth,
and noncommunicable
disease programs
Specialist services
• Cardiology
• Cardiac surgery
Echocardiographic screening
(Immunotherapies)
regurgitation, sometimes accompanied by aortic regurgitation. Myo­
cardial inflammation may affect electrical conduction pathways, lead­
ing to P-R interval prolongation (first-degree atrioventricular block or
rarely higher-level block) and softening of the first heart sound.
People with RHD are often asymptomatic for many years before their
valvular disease progresses to cause cardiac failure. Moreover, particularly
in resource-poor settings, the diagnosis of ARF is often not made, so
children, adolescents, and young adults may have RHD but not know it.
These cases can be diagnosed using echocardiography; auscultation is
poorly sensitive and specific for RHD diagnosis in asymptomatic patients.
Echocardiographic screening of school-aged children in populations with
high rates of RHD is becoming more widespread and has been facilitated
by improving technologies in portable echocardiography and the avail­
ability of consensus guidelines for the diagnosis of RHD on echocardiog­
raphy (Table 371-1). These guidelines replace the previous “definite,”
“borderline,” and “latent” diagnostic category terms with a classification
based on the risk of progression to more advanced valvular heart disease
and provide recommendations on secondary prophylaxis for each group.
■
■JOINT INVOLVEMENT
The most common form of joint involvement in ARF is arthritis, i.e.,
objective evidence of inflammation, with hot, swollen, red, and/or ten­
der joints, and involvement of more than one joint (i.e., polyarthritis).
Polyarthritis is typically migratory, moving from one joint to another
over a period of hours. ARF almost always affects the large joints—
most commonly the knees, ankles, hips, and elbows—and is asymmet­
ric. The pain is severe and usually disabling until anti-inflammatory
medication is commenced.
RV
PART 11
Immune-Mediated, Inflammatory, and Rheumatologic Disorders
LV
AV
MV
LA
FIGURE 371-2  Transthoracic echocardiographic image from a 5-year-old boy
with chronic rheumatic heart disease. This diastolic image demonstrates leaflet
thickening, restriction of the anterior mitral valve leaflet tip, and doming of the body
of the leaflet toward the interventricular septum. This appearance (marked by the
arrowhead) is commonly described as a “hockey stick” or an “elbow” deformity.
AV, aortic valve; LA, left atrium; LV, left ventricle; MV, mitral valve; RV, right ventricle.
(Courtesy of Dr. Bo Remenyi, Department of Paediatric and Congenital Cardiac
Services, Starship Children’s Hospital, Auckland, New Zealand.)
Less severe joint involvement is also relatively common and has
been recognized as a potential major manifestation in high-risk
populations in the most recent revision of the Jones criteria. Arthralgia
without objective joint inflammation usually affects large joints in the
same migratory pattern as polyarthritis. In some populations, aseptic
monoarthritis may be a presenting feature of ARF, which may, in turn,
result from early commencement of anti-inflammatory medication
before the typical migratory pattern is established.
The joint manifestations of ARF are highly responsive to salicylates
and other nonsteroidal anti-inflammatory drugs (NSAIDs).
■
■CHOREA
Sydenham’s chorea commonly occurs in the absence of other manifes­
tations, follows a prolonged latent period after group A streptococcal
infection, and is found mainly in females. The choreiform movements
affect particularly the head (causing characteristic darting movements
of the tongue) and the upper limbs (Chap. 447). They may be gen­
eralized or restricted to one side of the body (hemi-chorea). In mild
cases, chorea may be evident only on careful examination, whereas in
the most severe cases, the affected individuals are unable to perform
activities of daily living. There is often associated emotional lability
or obsessive-compulsive traits, which may last longer than the chorei­
form movements (which usually resolve within 6 weeks but sometimes
may take up to 6 months). More than 50% of patients presenting with
chorea will have carditis, for which reason echocardiography should be
part of the workup.
■
■SKIN MANIFESTATIONS
The classic rash of ARF is erythema marginatum (Chap. 21), which
begins as pink macules that clear centrally, leaving a serpiginous,
spreading edge. The rash is evanescent, appearing and disappearing
before the examiner’s eyes. It occurs usually on the trunk, sometimes
on the limbs, but almost never on the face.
Subcutaneous nodules occur as painless, small (0.5–2 cm), mobile
lumps beneath the skin overlying bony prominences, particularly of the
hands, feet, elbows, occiput, and occasionally the vertebrae. They are a
delayed manifestation, appearing 2–3 weeks after the onset of disease,
last for just a few days up to 3 weeks, and are commonly associated
with carditis.
TABLE 371-1  Staging of Rheumatic Heart Disease Detected by
Echocardiographya,b
Stage A: Minimal Echocardiographic Criteria for RHD
Applies only to individuals aged ≤20 years old
• Clinical risk: might be at risk of valvular heart disease progression
• Echocardiographic features: the presence of mildc MR or AR without
morphologic features
Stage B: Mild RHD
Can apply to any age
• Clinical risk: at moderate or high risk of progression and at risk of developing
symptoms of valvular heart disease
• Echocardiographic features: evidence of mildc valvular regurgitation plus at
least one morphologic feature in individuals aged ≤20 years and at least two
morphologic features in individuals aged >20 yearsd; or mild regurgitation in
both mitral and aortic valves
Stage C: Advanced RHD at Risk of Clinical Complications
Can apply to any age
• Clinical risk: at high risk of developing clinical complications that require
medical or surgical intervention
• Echocardiographic features: moderate or severe MR, moderate or severe AR,
any MS or ASe, pulmonary hypertension, and decreased LV systolic function
Stage D: Advanced RHD with Clinical Complications
Can apply to any age
• Clinical risk: established clinical complications include cardiac surgery, heart
failure, arrhythmia, stroke, and infective endocarditis
• Echocardiographic features: moderate or severe MR, moderate or severe AR,
any MS or ASe, pulmonary hypertension, and decreased LV systolic function
aTo be applied in high-risk settings and requires other causes of valvular heart
disease to have been excluded. bAfter the application of the confirmatory
echocardiographic criteria, diagnostic categories might include “normal” and
“other,” which encompasses other diseases such as congenital heart disease,
cardiomyopathies, and pericardial effusion. cFulfilling the confirmatory criteria for
pathologic regurgitation (see Source). dThis cutoff value is derived from expert
consensus. eAortic stenosis is defined in accordance with international guidelines on
valvular heart disease. A diagnosis of rheumatic aortic stenosis requires the exclusion
of other causes, including bicuspid aortic valve and degenerative calcific AS.
Abbreviations: AR, aortic regurgitation; AS, aortic stenosis; LV, left ventricular; MR,
mitral regurgitation; MS, mitral stenosis, RHD, rheumatic heart disease.
Source: Reproduced with permission from J Rwebembera et al: 2023 World Heart
Federation guidelines for the echocardiographic diagnosis of rheumatic heart
disease. Nat Rev Cardiol 21:250; 2023.
■
■OTHER FEATURES
Fever occurs in most cases of ARF, although rarely in cases of pure
chorea. Although high-grade fever (≥39°C) is the rule, lower grade
temperature elevations are not uncommon. Elevated acute-phase reac­
tants are also present in most cases.
■
■EVIDENCE OF A PRECEDING GROUP A
STREPTOCOCCAL INFECTION
With the exception of chorea and low-grade carditis, both of which
may become manifest many months later, evidence of a preceding
group A streptococcal infection is essential in making the diagnosis of
ARF. Because most cases do not have a positive throat swab culture or
rapid antigen test, serologic evidence is usually needed. The most com­
mon serologic tests are the anti-streptolysin O (ASO) and anti-DNase
B (ADB) titers. Where possible, age-specific reference ranges should
be determined in a local population of healthy people without a recent
group A streptococcal infection.
■
■CONFIRMING THE DIAGNOSIS
Because there is no definitive test, the diagnosis of ARF relies on the
presence of a combination of typical clinical features together with
evidence of the precipitating group A streptococcal infection, and the
exclusion of other diagnoses. This uncertainty led Dr. T. Duckett Jones
in 1944 to develop a set of criteria (subsequently known as the Jones
criteria) to aid in the diagnosis. The most recent revision of the Jones
criteria (Table 371-2) requires the clinician to determine if the patient
is from a setting or population known to experience low rates of ARF.
TABLE 371-2  Jones Criteria
A. For All Patient Populations with Evidence of Preceding Group A
Streptococcal Infection
Diagnosis: initial ARF
2 major manifestations or 1 major plus
2 minor manifestations
Diagnosis: recurrent ARF
2 major or 1 major and 2 minor or
3 minor
B. Major Criteria
Low-risk populationsa
Moderate- and high-risk populations
  Carditisb
  Carditis
• Clinical and/or subclinical
• Clinical and/or subclinical
Arthritis
Arthritis
• Polyarthritis only
• Monoarthritis or polyarthritis
• Polyarthralgiac
  Chorea
Chorea
  Erythema marginatum
Erythema marginatum
  SC nodules
SC nodules
C. Minor Criteria
Low-risk populationsa
Moderate- and high-risk populations
  Polyarthralgia
  Monoarthralgia
  Fever (≥38.5°C)
  Fever (≥38°C)
  ESR ≥60 mm in the first hour and/or
CRP ≥3.0 mg/dLd
  ESR ≥30 mm/h and/or CRP ≥3.0 mg/dLd
  Prolonged PR intervale, after
  Prolonged PR intervale, after
accounting for age variability (unless
carditis is a major criterion)
accounting for age variability (unless
carditis is a major criterion)
aLow-risk populations are those with ARF incidence ≤2 per 100,000 school-age
children or all-age rheumatic heart disease prevalence of ≤1 per 1000 population
per year. bSubclinical carditis indicates echocardiographic valvulitis. (See source
document.) cPolyarthralgia should only be considered as a major manifestation
in moderate- to high-risk populations after exclusion of other causes. As in past
versions of the criteria, erythema marginatum and SC nodules are rarely “standalone” major criteria. Additionally, joint manifestations can only be considered in
either the major or minor categories but not both in the same patient. (See source
document for more information.) dCRP value must be greater than upper limit of
normal for laboratory. Also, because ESR may evolve during the course of ARF, peak
ESR values should be used. eProlonged PR interval can only be considered in the
absence of carditis as a major criterion.
Abbreviations: ARF, acute rheumatic fever; CRP, C-reactive protein; ESR, erythrocyte
sedimentation rate; SC, subcutaneous.
Source: Reproduced with permission from MH Gewitz et al: Revision of the
Jones criteria for the diagnosis of acute rheumatic fever in the era of Doppler
echocardiography: A scientific statement from the American Heart Association.
Circulation 131(20):1806, 2015. https://www.ahajournals.org/doi/full/10.1161/
CIR.0000000000000205.
For this group, there is a set of “low-risk” criteria; for all others, there is
a set of more sensitive criteria.
TREATMENT
Acute Rheumatic Fever
Patients with possible ARF should be followed closely to ensure
that the diagnosis is confirmed, treatment of heart failure and other
symptoms is undertaken, and preventive measures including com­
mencement of secondary prophylaxis, inclusion on an ARF registry,
and health education are commenced. Echocardiography should be
performed on all possible cases to aid in making the diagnosis and
to determine the severity at baseline of any carditis. Other tests that
should be performed are listed in Table 371-3.
There is no treatment for ARF that has been proven to alter the
likelihood of developing, or the severity of, RHD. With the excep­
tion of treatment of heart failure, which may be lifesaving in cases
of severe carditis, the treatment of ARF is symptomatic.
ANTIBIOTICS
All patients with ARF should receive antibiotics sufficient to treat the
precipitating group A streptococcal infection (Chap. 153). Penicil­
lin is the drug of choice and can be given orally (as phenoxymethyl
TABLE 371-3  Testing and Monitoring of ARF in the Acute Setting
Investigations
Always request:
• Electrocardiogram (ECG)
• Echocardiogram
• Complete blood count (CBC)
• C-reactive protein (CRP)
• Streptococcal serology (antistreptolysin and anti-DNase B)
In relevant situations:
• Throat swab
• Skin sore swab
• Blood cultures
• Synovial fluid aspirate
CHAPTER 371
Acute Rheumatic Fever
• Ensure sample does not clot by using correct tubes that have been well
mixed and transported promptly to the laboratory
• Include request for cell count, microscopy, culture, and gonococcal
polymerase chain reaction (PCR)
• Pregnancy test
• Creatinine test (UEC [urea, electrolytes, creatinine]) since nonsteroidal
anti-inflammatory drugs can affect renal function
Tests to exclude alternative diagnoses, depending on clinical presentation
and locally endemic infections:
• Autoantibodies, double-stranded DNA, anti–cyclic citrullinated peptide
(anti-CCP) antibodies
• Urine for Neisseria gonorrhoeae molecular test
• Urine for Chlamydia trachomatis molecular test
• Serologic or other testing for viral hepatitis, Yersinia spp., cytomegalovirus
(CMV), parvovirus B19, respiratory viruses, Ross River virus, Barmah Forest
virus
Source: Reproduced with permission from RDHAustralia, Menzies School of Health
Research. RHDAustralia (ARF/RHD writing group). The 2020 Australian guideline
for prevention, diagnosis and management of acute rheumatic fever and rheumatic
heart disease (3rd edition); 2020. Available at https://www.rhdaustralia.org.au/
arf-rhd-guideline.
penicillin, 500 mg [250 mg for children ≤27 kg] PO twice daily, or
amoxicillin, 50 mg/kg [maximum, 1 g] daily, for 10 days) or as a
single dose of 1.2 million units (600,000 units for children ≤27 kg)
IM benzathine penicillin G.
SALICYLATES AND NSAIDS
These may be used for the treatment of arthritis, arthralgia, and
fever once the diagnosis is confirmed. They are of no proven value
in the treatment of carditis or chorea. Aspirin has traditionally
been the first-line choice, delivered at a dose of 50–60 mg/kg per
day, up to a maximum of 80–100 mg/kg per day (4–8 g/d in
adults) in 4–5 divided doses. At higher doses, the patient should
be monitored for symptoms of salicylate toxicity such as nausea,
vomiting, or tinnitus; if symptoms appear, lower doses should be
used. Owing to the frequency of gastrointestinal side effects and
the potential of more severe adverse effects of aspirin, many clini­
cians now prefer to use naproxen at a dose of 10–20 mg/kg per day
because it may be safer than aspirin and has the advantage of twicedaily dosing. When the acute symptoms are substantially resolved,
usually within the first 2 weeks, patients on higher doses of antiinflammatory medications can have the dose reduced for a further
2–4 weeks. Fever, joint manifestations, and elevated acute-phase
reactants sometimes recur up to 3 weeks after the medication is
discontinued. This does not indicate a recurrence and can be man­
aged by recommencing anti-inflammatory agents for a brief period.
CONGESTIVE HEART FAILURE
Glucocorticoids  The use of glucocorticoids in ARF remains con­
troversial. Two meta-analyses have failed to demonstrate a benefit
of glucocorticoids compared to placebo or salicylates in improving
the short- or longer-term outcome of carditis. However, the studies
included in these meta-analyses all took place >40 years ago and did
not use medications in common usage today. There are some recent
data that suggest corticosteroids improve laboratory, radiologic,
and echocardiographic parameters in carditis. Many clinicians treat
cases of severe carditis (causing heart failure) with glucocorticoids
in the belief that they may reduce the acute inflammation and result
in more rapid resolution of failure. However, the potential benefits
of this treatment should be balanced against the possible adverse
effects. If used, prednisone or prednisolone is recommended at a
dose of 1–2 mg/kg per day (maximum, 80 mg), usually for a few
days or up to a maximum of 3 weeks.
MANAGEMENT OF HEART FAILURE
See Chap. 265.
BED REST
Traditional recommendations for long-term bed rest, once the cor­
nerstone of management, are no longer widely practiced. Instead,
bed rest should be prescribed as needed while arthritis and arthral­
gia are present and for patients with heart failure. Once symptoms
are well controlled, gradual mobilization can commence as tolerated.
CHOREA
Medications to control the abnormal movements do not alter the
duration or outcome of chorea. Milder cases can usually be man­
aged by providing a calm environment. In patients with severe cho­
rea, carbamazepine or sodium valproate is preferred to haloperidol.
A response may not be seen for 1–2 weeks, and medication should
be continued for 1–2 weeks after symptoms subside. There is recent
evidence that corticosteroids are effective and lead to more rapid
symptom reduction in chorea. They should be considered in severe
or refractory cases. Prednisone or prednisolone may be commenced
at 0.5 mg/kg daily, with weaning as early as possible, preferably
after 1 week if symptoms are reduced, although slower weaning or
temporary dose escalation may be required if symptoms worsen.
INTRAVENOUS IMMUNOGLOBULIN (IVIG)
Small studies have suggested that IVIg may lead to more rapid reso­
lution of chorea but have shown no benefit on the short- or longterm outcome of carditis in ARF without chorea. In the absence
of better data, IVIg is not recommended except in cases of severe
chorea refractory to other treatments.
PART 11
Immune-Mediated, Inflammatory, and Rheumatologic Disorders
PROGNOSIS
Untreated, ARF lasts on average 12 weeks. With treatment, patients
are usually discharged from hospital within 1–2 weeks. Inflammatory
markers should be monitored every 1–2 weeks until they have normal­
ized (usually within 4–6 weeks), and an echocardiogram should be
performed after 1 month to determine if there has been progression of
carditis. Cases with more severe carditis need close clinical and echo­
cardiographic monitoring in the longer term.
Once the acute episode has resolved, the priority in management is
to ensure long-term clinical follow-up and adherence to a regimen of
secondary prophylaxis. Patients should be entered onto the local ARF
registry (if present) and contact made with primary care practitioners
to ensure a plan for follow-up and administration of secondary prophy­
laxis before the patient is discharged. Patients and their families should
also be educated about their disease, emphasizing the importance of
adherence to secondary prophylaxis.
PREVENTION
■
■PRIMARY PREVENTION
Ideally, primary prevention would entail elimination of the major risk
factors for streptococcal infection, particularly overcrowded housing.
This is difficult to achieve in most places where ARF is common but
must remain a priority in ongoing efforts to achieve global control of
ARF and RHD.
Concerted international efforts are underway to develop a vaccine
against group A Streptococcus that would prevent infection of the throat
or skin and consequently prevent ARF in the absence of a suitable vac­
cine; however, the mainstay of primary prevention for ARF remains
primary prophylaxis (i.e., the timely and complete treatment of group
A streptococcal sore throat with antibiotics). If commenced within 9
days of sore throat onset, a course of penicillin (as outlined above for
treatment of ARF) will prevent almost all cases of ARF that would oth­
erwise have developed. In settings where ARF and RHD are common
but microbiologic diagnosis of group A streptococcal pharyngitis is not
available, such as in resource-poor countries, primary care guidelines
sometimes recommend that all patients with sore throat be treated with
penicillin (an approach that has the potential drawbacks that come
from antibiotic overuse, including side effects and increasing pres­
sure on antimicrobial resistance in group A Streptococcus or bystander
pathogens) or, alternatively, that a clinical algorithm be used to identify
patients with a higher likelihood of group A streptococcal pharyngitis.
Although imperfect, such approaches recognize the importance of ARF
prevention at the expense of overtreating many cases of sore throat that
are not caused by group A Streptococcus. Although there is no proof
that antibiotic treatment of group A streptococcal skin infections can
prevent ARF, the increasing evidence that impetigo is strongly associ­
ated with ARF in some populations argues for a focus on treatment
and prevention of group A streptococcal skin infections as part of a
comprehensive ARF control strategy in regions with endemic impetigo.
■
■SECONDARY PREVENTION
The mainstay of controlling ARF and RHD is secondary prevention.
Because patients with ARF are at dramatically higher risk than the gen­
eral population of developing a further episode of ARF after a group
A streptococcal infection, they should receive long-term penicillin
prophylaxis to prevent recurrences. The best antibiotic for secondary
prophylaxis is benzathine penicillin G (1.2 million units, or 600,000
units if ≤27 kg) delivered intramuscularly every 4 weeks. It can be given
every 3 weeks, or even every 2 weeks, to persons considered to be at
particularly high risk, although in settings where good compliance
with an every-4-week dosing schedule can be achieved, more frequent
dosing is rarely needed. Evidence has emerged recently that subcutane­
ous delivery of benzathine penicillin G provides more optimal pharma­
cokinetics than intramuscular delivery and may have added advantages
of reducing pain and allowing for larger doses to be delivered less
frequently, although this approach is yet to be recommended in clinical
guidelines. Oral penicillin V (250 mg) can be given twice daily instead
but is less effective than benzathine penicillin G. Penicillin-allergic
patients can receive erythromycin (250 mg) twice daily.
The duration of secondary prophylaxis is determined by many fac­
tors, in particular the duration since the last episode of ARF (recur­
rences become less likely with increasing time), age (recurrences are
less likely with increasing age), and the severity of RHD (if severe, it
may be prudent to avoid even a very small risk of recurrence because
of the potentially serious consequences) (Table 371-4). Secondary
prophylaxis is best delivered as part of a coordinated RHD control pro­
gram, based around a registry of patients. Registries improve the ability
to follow patients and identify those who default from prophylaxis and
to institute strategies to improve adherence.
TABLE 371-4  American Heart Association Recommendations for
Duration of Secondary Prophylaxisa
CATEGORY OF PATIENT
DURATION OF PROPHYLAXIS
Rheumatic fever without carditis
For 5 years after the last attack or 21
years of age (whichever is longer)
Rheumatic fever with carditis but no
residual valvular disease
For 10 years after the last attack, or 21
years of age (whichever is longer)
Rheumatic fever with persistent
valvular disease, evident clinically or
on echocardiography
For 10 years after the last attack, or
40 years of age (whichever is longer);
sometimes lifelong prophylaxis
aThese are only recommendations and must be modified by individual
circumstances as warranted. Note that some organizations recommend a minimum
of 10 years of prophylaxis after the most recent episode, or until 21 years of age
(whichever is longer), regardless of the presence of carditis with the initial episode.
Source: Reproduced with permission from MA Gerber et al: Prevention
of rheumatic fever and diagnosis and treatment of acute streptococcal
pharyngitis. Circulation 119:1541, 2009. https://www.ahajournals.org/doi/10.1161/
CIRCULATIONAHA.109.191959?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.
org&rfr_dat=cr_pub%20%200pubmed.

16 - 373 Sjögren’s Disease
373 Sjögren’s Disease
dermatomyositis (heliotrope rash on the eyelids, erythematous rash
on knuckles) may occur. Arthralgia is common, and some patients
develop erosive polyarthritis. Pulmonary fibrosis and isolated or sec­
ondary PAH may develop. Other manifestations include esophageal
dysmotility, pericarditis, Sjögren’s syndrome, and renal disease, espe­
cially membranous glomerulonephritis. Laboratory evaluation shows
elevated ESR and hypergammaglobulinemia. In contrast to SSc, MCTD
often responds to glucocorticoids, and the long-term prognosis is bet­
ter than that of SSc. Whether MCTD is truly a distinct entity or is a
subset of SLE or SSc remains controversial.
PART 11
Immune-Mediated, Inflammatory, and Rheumatologic Disorders
EOSINOPHILIC FASCIITIS (DIFFUSE
FASCIITIS WITH EOSINOPHILIA)
Eosinophilic fasciitis is a rare idiopathic disorder of adults associated
with abrupt skin induration. The skin characteristically shows a coarse
cobblestone “peau d’orange” appearance. In contrast to SSc, Raynaud’s
phenomenon and SSc-associated internal organ involvement and
autoantibodies are absent. Furthermore, skin involvement spares the
fingers. Full-thickness biopsy of the lesional skin reveals fibrosis of the
subcutaneous fascia, with variable inflammation and eosinophil infil­
tration. In the acute phase of the illness, peripheral blood eosinophilia
may be prominent. MRI appears to be a sensitive tool for the diagnosis
of eosinophilic fasciitis. Eosinophilic fasciitis can occur in association
with, or preceding, various myelodysplastic syndromes or multiple
myeloma. Although glucocorticoids cause prompt resolution of eosin­
ophilia, the skin shows slow and variable improvement. The prognosis
of patients with eosinophilic fasciitis is generally good.
■
■FURTHER READING
Allanore Y et al: Systemic sclerosis. Nat Rev Dis Primers 1:15002,
2015.
Herzog EL et al: Interstitial lung disease associated with systemic
sclerosis and idiopathic pulmonary fibrosis: How similar or distinct?
Arthritis Rheum 66:1967, 2014.
Joseph CG et al: Association of the autoimmune disease scleroderma
with an immunologic response to cancer. Science 343:152, 2014.
Martyanov V, Whitfield ML: Molecular stratification and precision
medicine in systemic sclerosis from genomic and proteomic data.
Curr Opin Rheumatol 28:83, 2016.
Tashkin DP et al: Mycophenolate mofetil versus oral cyclophospha­
mide in scleroderma-related interstitial lung disease (SLS II): A ran­
domised controlled, double-blind, parallel group trial. Lancet Respir
Med 4:708, 2016.
Haralampos M. Moutsopoulos,
Clio P. Mavragani
Sjögren’s Disease
■
■DEFINITION, INCIDENCE, AND PREVALENCE
Sjögren’s disease is a prototype autoimmune disease characterized by
lymphocytic infiltration of the exocrine glands resulting in xerostomia,
dry eyes (keratoconjunctivitis sicca), and profound B-cell hyperactivity.
The disease has unique features since it presents with a wide clinical
spectrum from organ-specific to systemic disease; can occur alone
or in association with other systemic rheumatic diseases, more com­
monly rheumatoid arthritis, limited scleroderma, and systemic lupus
erythematosus; and displays high probability of the development of
lymphoma. Because of all these characteristics, it is an ideal model to
study not only autoimmunity but also lymphoid malignancy.
Middle-aged women (female-to-male ratio 10–20:1) are primarily
affected, although Sjögren’s disease may occur at any age, including
childhood. Patients with earlier disease onset express a more aggres­
sive disease phenotype manifested by a high occurrence of systemic
manifestations and serum autoantibodies. The prevalence of Sjögren’s
disease is ~0.5–1%, while 5–20% of patients with other autoimmune
diseases can express sicca manifestations.
■
■PATHOGENESIS
The autoimmune phenomena observed in Sjögren’s disease include
lymphocytic infiltration of the exocrine glands (primarily salivary
and lachrymal glands) and B lymphocyte hyperreactivity. The latter
is mainly manifested by hypergammaglobulinemia and the pres­
ence of serum autoantibodies toward non-organ-specific antigens
such as immunoglobulins (rheumatoid factors) and extractable cel­
lular antigens (Ro52, Ro60, and La). The major infiltrating cells in
the affected exocrine glands are activated T lymphocytes. In labial
minor salivary gland tissues with extensive lymphocytic infiltrations,
B-cell populations prevail. Other cellular subsets detected in the
labial minor salivary gland histopathologic lesion of Sjogren’s disease
include follicular, myeloid, and plasmacytoid dendritic cells, as well
as macrophages. The latter along with inflammasome activation
have been shown to be associated with increased risk for lymphoma
development.
The interplay of endogenous (e.g., intracellular stress, inappropriate
overexpression of endogenous nucleic acids) and exogenous triggers
(e.g., viruses, hormonal triggers, stressful life events) in a background
of a genetically determined hyperactive immune response seems to be
crucial for the initiation and perpetuation of the disease. Ductal and
acinar epithelial cells appear to play a significant role in the initiation
and perpetuation of autoimmune injury. These cells (1) express inap­
propriately costimulatory molecules and the intracellular autoantigens
Ro and La on their cell surfaces, acquiring the capacity to provide sig­
nals essential for lymphocytic activation; (2) produce proinflammatory
cytokines and lymphocyte-attracting chemokines necessary for sus­
taining the autoimmune lesion and allowing the formation of ectopic
germinal centers; (3) express functional receptors of innate immunity,
particularly Toll-like receptors (TLRs) 3, 7, and 9 molecules, which
may account for the initiation of the autoimmune reactivity; and (4)
display immunoregulatory molecules such as ICAM and CD40. Glan­
dular epithelial cells also seem to have an active role in the production
of B cell–activating factor (BAFF), which is induced after stimulation
with type I and II interferons. Circulating BAFF has been found to be
elevated also in the serum of Sjögren’s disease patients, especially those
with hypergammaglobulinemia and serum autoantibodies, and prob­
ably accounts for the antiapoptotic effect on B lymphocytes.
In contrast to B and T lymphocytes, glandular epithelial cells dis­
play increased rates of apoptotic death. Established risk genetic loci
implicated in Sjögren’s disease include the human leukocyte antigen
DQA1∗0501 allele, variations involved in the interferon/BAFF axis
(IRF5, STAT4, BAFF) and B-cell function (EBF1, BLK), as well as com­
bined genetic deficiencies in the classical complement pathway.
CLINICAL MANIFESTATIONS
Most patients with Sjögren’s disease have symptoms related to impaired
exocrine gland, particularly lacrimal and salivary gland, function. The
disease evolution is slow and, in the majority of patients, runs a benign
course. Studies have shown that prior to disease onset, patients with
Sjögren’s disease experience major stressful life events with which they
cannot cope adequately.
The principal oral symptom of Sjögren’s disease is dryness (xero­
stomia). Patients report difficulty in swallowing dry food, a burning
mouth sensation, an increase in dental caries, and problems in wearing
complete dentures. Physical examination shows a dry, erythematous
sticky oral mucosa. In patients with severe oral dryness, the filiform
papillae on the tongue dorsum are atrophic, and the tongue is deeply
fissured (Fig. 373-1). Furthermore, saliva from the major glands is
either not expressible or cloudy. Intermittent or persistent enlargement
of the parotid or other major salivary glands occurs in two-thirds of
patients with Sjögren’s disease. Diagnostic tests include sialometry and
several imaging techniques, including ultrasound, magnetic resonance
FIGURE 373-1  A dry deeply fissured tongue from a patient with Sjögren’s disease.
imaging (MRI), and magnetic resonance sialography of the major
salivary glands. In particular, salivary gland ultrasound is an emerg­
ing tool of both diagnostic and prognostic utility. Biopsy of the labial
minor salivary gland allows histopathologic confirmation of focal
lymphocytic infiltrates.
Ocular involvement is the other major manifestation of Sjögren’s
disease. Patients usually report a sandy or gritty feeling under the eye­
lids. Other ocular symptoms include burning, accumulation of secre­
tions in thick strands at the inner canthi, decreased tearing, redness,
itching, eye fatigue, and increased photosensitivity. These symptoms
are attributed to the destruction of corneal and bulbar conjunctival
epithelium, a pathology termed keratoconjunctivitis sicca. Diagnostic
evaluation of keratoconjunctivitis sicca includes measurement of tear
flow by Schirmer’s I test, determination of tear composition by tear
breakup time or tear lysozyme content, and slit-lamp examination of
the cornea and conjunctiva after lissamine green or Rose Bengal stain­
ing that reveals punctuate corneal and bulbar conjunctival ulcerations
and attached filaments.
Involvement of other exocrine glands, which occurs less frequently,
includes a decrease in mucous gland secretions of the upper and lower
respiratory tree, resulting in dry nose, throat, and trachea (xerotra­
chea). In addition, diminished secretion of the exocrine glands of the
gastrointestinal tract leads to esophageal mucosal dysmotility and atro­
phic gastritis. Dyspareunia, in premenopausal women, due to dryness
of the external genitalia and dry skin also may occur.
Extraglandular (systemic) manifestations are seen in one-third of
patients with Sjögren’s disease (Table 373-1) and can be classified as
follows: nonspecific, periepithelial (surrounding of epithelial tissues by
lymphocytes), immune complex–mediated, and lymphoma. Nonspecific
manifestations include fatigability, low-grade fever, Raynaud’s phe­
nomenon, myalgias, arthralgias, and arthritis. Arthritis in patients
with primary Sjögren’s disease is nonerosive. Periepithelial pathology
due to periepithelial accumulation of lymphocytes results from the
involvement of parenchymal organs such as the lungs, kidneys, and
liver. On the basis of this observation, one of the authors (H.M.M.) has
coined the term autoimmune epithelitis. Lung involvement is usually
manifested with dry cough and rarely with dyspnea. The underlying
lung pathology includes peribronchial infiltrates (bronchitis sicca)
and interstitial pneumonitis. Renal involvement includes interstitial
TABLE 373-1  Prevalence of Extraglandular Manifestations in Primary
Sjögren’s disease
CLINICAL MANIFESTATION
PERCENT
REMARKS
Nonspecific
CHAPTER 373
Fatigability/myalgias
Fibromyalgia
Arthralgias/arthritis
Usually nonerosive, leading to
Jaccoud’s arthropathy
Raynaud’s phenomenon
In one-third of patients, precedes
sicca manifestations
Sjögren’s Disease
Periepithelial
Lung involvement
Small airway disease/lymphocyte
interstitial pneumonitis
Kidney involvement
Interstitial kidney disease is usually
asymptomatic
Liver involvement
Primary biliary cirrhosis stage I
Immune complex–mediated
Small vessel vasculitis
Purpura, urticarial lesions
Peripheral neuropathy
Polyneuropathy, either sensory or
sensorimotor
Glomerulonephritis
Membranoproliferative
Lymphoma
Lymphoma
Glandular MALTa lymphoma is most
common
aMucosa-associated lymphoid tissue.
nephritis, clinically manifested by hyposthenuria and renal tubular
dysfunction with or without acidosis. Untreated acidosis may lead to
nephrocalcinosis. Immune complex–mediated disease is expressed with
vasculitis affecting primarily small-sized vessels, mainly manifested
with purpura and rarely with urticarial rash, skin ulcerations, mono­
neuritis multiplex, and membranoproliferative glomerulonephritis
associated with mixed type II or III cryoglobulinemia. Central nervous
system involvement is rarely recognized. A few cases of myelitis associ­
ated with antibodies to aquaporin 4 have been described.
Sjögren’s disease is characterized by the highest risk for lymphoma
development among all autoimmune diseases with clinical, labora­
tory, and histopathologic features being designated as risk factors
(Fig. 373-2). Despite that the pathogenesis of lymphoma in the set­
ting of Sjögren’s disease remains to be elucidated, genetic alterations
involved in chronic inflammatory, B-cell activation, and the type I and
II interferon pathways, as well as epigenetic abnormalities, have been
shown to be significant contributors. Of interest, B cells producing
cryoglobulins were shown to harbor mutations in genes recurrently
mutated in B-cell malignancies. Most lymphomas are extranodal,
low-grade, marginal zone B-cell lymphomas and are usually detected
incidentally during evaluation of the labial minor salivary gland biopsy.
The affected lymph nodes are usually peripheral. Survival rates are
decreased in patients with B symptoms, lymph node mass >7 cm in
diameter, and high or intermediate histologic grade. Fluorodeoxyglu­
cose positron emission tomography (FDG-PET)/computed tomogra­
phy (CT) can be a useful tool to exclude lymphoma when suspected.
In line with observations in rheumatoid arthritis and systemic lupus
erythematosus, patients with Sjögren’s disease also display an increased
risk of cardiovascular disease.
Routine laboratory tests in Sjögren’s disease can reveal leukopenia
and infrequently lymphopenia. In two-thirds of patients, elevated
erythrocyte sedimentation rate, hypergammaglobulinemia, antinuclear
antibodies, rheumatoid factors, and antibodies against Ro52/Ro60 and
La autoantigens are detected. Anticentromere autoantibodies are pres­
ent in Sjögren’s patients with a clinical picture similar to that of limited
scleroderma (Chap. 372), while the presence of antimitochondrial
antibodies may connote liver involvement in the form of autoim­
mune cholangitis (Chap. 357). Autoantibodies to 21-hydroxylase
are found in patients with a blunted adrenal response, while autoan­
tibodies to citrullinated peptides are seen in Sjögren’s patients with
Hematologic/Serologic
Leukopenia
Autoantibodies
(Rheumatoid factor, against
Ro/SSA and La/SSB autoantigens)
PART 11
Immune-Mediated, Inflammatory, and Rheumatologic Disorders
Low C4 complement levels
Monoclonal gammopathy
Cryoglobulins
Clinical
Parotid gland enlargement
Severe tongue atrophy
Palpable purpura
FIGURE 373-2  Sjögren’s disease risk factors for lymphoma development.
arthritis. Anticalponin-3 antibodies have been recently associated with
the occurrence of peripheral neuropathies.
■
■DIAGNOSIS AND DIFFERENTIAL DIAGNOSIS
Sjögren’s disease should be suspected if a patient presents with eye
and/or mouth dryness, major salivary gland enlargement, or systemic
manifestations such as Raynaud’s phenomenon, palpable purpura, or
symptomatology of renal tubular acidosis. A careful history of medica­
tions causing dryness should be obtained. Recently, cases of Sjögren’s
disease were triggered by PD-1/PD-L1 checkpoint inhibitors.
The workup should include eye tests that might reveal keratocon­
junctivitis sicca, salivary flow tests or ultrasonography, and serum
TABLE 373-2  Differential Diagnosis of Sicca Symptoms
BILATERAL PAROTID
GLAND ENLARGEMENT
XEROSTOMIA
DRY EYE
Viral infections (HCV, HIV)
Drugs
  Psychotherapeutic
  Parasympatholytic
  Antihypertensive
Psychogenic origin
Irradiation
Diabetes mellitus
Trauma
Sjögren’s disease
Amyloidosis
Autoimmune thyroid
disease
 
Inflammation
  Stevens-Johnson
Viral infections
  Mumps
  Influenza
  Epstein-Barr virus
  Coxsackievirus A
  Cytomegalovirus
  HIV, HCV
Sarcoidosis, tuberculosis
IgG4-related disease
Sjögren’s disease
Metabolic disorders
  Diabetes mellitus
  Hyperlipoproteinemias
syndrome
  Pemphigoid
  Chronic conjunctivitis
  Chronic blepharitis
  Sjögren’s Disease
Toxicity
  Burns
  Drugs
Neurologic conditions
  Impaired lacrimal
gland function
  Impaired eyelid
(types IV and V)
  Chronic pancreatitis
  Hepatic cirrhosis
Endocrine
  Acromegaly
  Gonadal hypofunction
Eosinophilic sialodochitis
Lymphoma
function
Miscellaneous
  Trauma
  Hypovitaminosis A
  Blink abnormality
  Anesthetic cornea
  Lid scarring
  Epithelial irregularity
  Autoimmune thyroid
disease
Abbreviation: HCV, hepatitis C virus.
Histopathologic
(salivary gland tissues)
Germinal center formation
Heavy focal lymphocytic
infiltrates
Lymphoma
related to
Sjögren’s
disease
evaluation for specific autoantibodies. Testing for chronic viral infec­
tions (hepatitis C virus, HIV), chest x-ray to rule out sarcoidosis,
protein electrophoresis, IgG4 serum levels, and autoantibodies to
thyroid antigens can be also offered. Labial biopsy is valuable to rule
out conditions that may cause dry mouth, dry eyes, or parotid gland
enlargement (Tables 373-2 and 373-3). A diagnostic algorithm based on
recent classification criteria (2016 American College of Rheumatology–
European League Against Rheumatism [EULAR] Classification Crite­
ria) is presented in Fig. 373-3.
TREATMENT
Sjögren’s Disease
Treatment of Sjögren’s disease aims to relieve symptoms and limit
the damage from chronic xerostomia and keratoconjunctivitis sicca
through substitution or stimulation of impaired secretions.
To replace deficient tears, several ophthalmic preparations are
readily available (hydroxypropyl methylcellulose; polyvinyl alcohol;
0.5% methylcellulose; Hypo Tears). If corneal ulcerations are
present, eye patching and boric acid ointments are recommended,
as well as cyclosporine eye drops. Certain drugs that may decrease
lacrimal and salivary secretions, such as diuretics, antihypertensive
drugs, anticholinergics, and antidepressants, should be avoided.
For xerostomia, the best replacement is water. Propionic acid gels
may be used to treat vaginal dryness. To stimulate secretions, orally
administered pilocarpine (5 mg thrice daily) or cevimeline (30 mg
TABLE 373-3  Differential Diagnosis of Sjögren’s disease
HIV INFECTION AND
SICCA SYNDROME
SJÖGREN’S DISEASE
SARCOIDOSIS
Predominant in young
males
Predominant in middleaged women
No age or sex preference
Lack of autoantibodies to
Ro and/or La
Presence of
autoantibodies
Lack of autoantibodies to
Ro and/or La
Lymphoid infiltrates of
salivary glands by CD8+ T
lymphocytes
Lymphoid infiltrates of
salivary glands by CD4+ T
lymphocytes
Granulomas in salivary
glands
Association with
HLA-DR5
Association with
HLA-DR3 and DRw52
Unknown
Positive serologic tests
for HIV
Negative serologic tests
for HIV
Negative serologic tests
for HIV

17 - 374 Spondyloarthritis
374 Spondyloarthritis
Dry eyes and/or dry mouth1
And/or
Major salivary gland enlargement, fatigue, Raynaud’s phenomenon, arthralgias/arthritis
(particularly small hand joints), palpable purpura/urticarial lesions, renal
tubular acidosis/membranoproliferative glomerulonephritis, ILD/small airways
disease, autoimmune cholangitis, peripheral neuropathy, MS-like lesions
Ocular staining
score ≥5 (or van
Bijsterveld’s
score ≥4) on at
least one eye2
Unstimulated
whole saliva flow
rate ≤0.1 mL/min
Schirmer’s test
≤5 mm/5 min on
at least one eye
If any of those present
If any of those present
+
Sjögren’s disease
FIGURE 373-3  Diagnostic algorithm for Sjögren’s disease. 1Defined as a positive response to at least one of the following questions: (a) Have you had daily, persistent,
troublesome dry eyes for more than 3 months? (b) Do you have a recurrent sensation of sand or gravel in the eyes? (c) Do you use tear substitutes more than three times a
day? (d) Have you had a daily feeling of dry mouth for more than 3 months? (e) Do you frequently drink liquids to aid in swallowing dry food? 2Ocular staining score described
in Whitcher et al. van Bijsterveld score described in van Bijsterveld et al. 3Focus score count ≥1 (based on the number of foci per 4 mm2 of salivary gland tissue) following a
protocol described in Daniels et al. ILD, interstitial lung disease; MS, multiple sclerosis.
thrice daily) appears to improve sicca manifestations, and both are
well tolerated. Hydroxychloroquine (200 to 400 mg daily) and/or
methotrexate (0.2–0.3 mg/kg body weight/weekly) are helpful for
arthralgias and mild arthritis.
Patients with renal tubular acidosis should receive sodium bicar­
bonate by mouth (0.5–2 mmol/kg in four divided doses). Gluco­
corticoids and monoclonal antibody to CD20 (rituximab) appear to
be effective in patients with systemic disease, particularly in those
with purpura and persistent arthritis. Novel monoclonal antibodies
targeting the CD40L/CD40 costimulatory pathway or the BAFF
receptor or sequential treatment of belimumab and rituximab seem
to be promising therapeutic strategies. Data for a beneficial role of
other conventional immunosuppressants are limited. Treatment of
lymphoma in the setting of Sjögren’s disease follows the general
guidelines for lymphoma management in the general population.
Detailed recommendations on Sjögren’s disease management have
been issued by EULAR and British Society of Rheumatology.
■
■FURTHER READING
Daniels TE et al: Associations between salivary gland histopathologic
diagnoses and phenotypic features of Sjögren’s syndrome among
1,726 registry participants. Arthritis Rheum 63:2021, 2011.
Fragkioudaki  S  et al: Predicting the risk for lymphoma develop­
ment in Sjogren syndrome: An easy tool for clinical use. Medicine
(Baltimore) 95:e3766, 2016.
Mavragani CP, Moutsopoulos HM: Sjögren’s syndrome. CMAJ
186:579, 2014.
Mavragani CP, Moutsopoulos HM: Sjogren’s syndrome: Old and
new therapeutic targets. J Autoimmun 110:102364, 2020.
Moutsopoulos HM: Sjögren’s syndrome: A forty-year scientific jour­
ney. J Autoimmun 51:1, 2014.
Nocturne  G, Mariette  X: Expert perspective: Challenges in
Sjögren’s disease. Arthritis Rheumatol 75:2078, 2023.
Price EJ et al: British Society for Rheumatology guideline on man­
agement of adult and juvenile onset Sjögren disease. Rheumatology
(Oxford)16:keae152, 2024.
Shiboski CH et al: 2016 American College of Rheumatology/European
League Against Rheumatism Classification Criteria for Primary
CHAPTER 374
Exclude
History of head and neck radiation
treatment
Active hepatitis C infection
Acquired immunodeficiency
syndrome
Sarcoidosis
Amyloidosis
Graft-versus-host disease
IgG4-related disease
Spondyloarthritis
Serum
antibodies
against Ro
antigen
Minor salivary
gland biopsy3
Sjögren’s Syndrome: A consensus and data-driven methodology
involving three international patient cohorts. Arthritis Rheumatol
69:35, 2017.
van Bijsterveld OP: Diagnostic tests in the Sicca syndrome. Arch
Ophthalmol 82:10, 1969.
Whitcher JP et al: A simplified quantitative method for assessing
keratoconjunctivitis sicca from the Sjögren’s Syndrome International
Registry. Am J Ophthalmol 149:405, 2010.
Atul Deodhar, Dirk Elewaut
Spondyloarthritis
Spondyloarthritis (SpA) refers to a family of immune-mediated
inflammatory arthritis disorders that share many clinical, genetic, and
pathologic characteristics. Moll and Wright are credited in recogniz­
ing these diseases in 1974 as distinct from rheumatoid arthritis (RA),
a well-recognized inflammatory arthritis at that time. While axial
skeletal involvement is hinted at in the word “spondyloarthritis,” it is
not mandatory. The musculoskeletal manifestations of SpA include
sacroiliitis, inflammatory spinal lesions, peripheral inflammatory
arthritis, enthesitis (inflammation at the attachment of tendons and
ligaments to the bones), tendonitis, tenosynovitis, and dactylitis (“sau­
sage digits”). Other clinical manifestations include uveitis, skin pso­
riasis, inflammatory bowel disease (IBD, Crohn’s, or ulcerative colitis),
absence of rheumatoid factor (RF) and nodules (to differentiate from
RA), familial correlation, and association with the gene human leuko­
cyte antigen (HLA)-B27. The 2009 Assessment of Spondyloarthritis
International Society (ASAS) classification criteria divided SpA under
“axial” (axSpA) and “peripheral” (pSpA). “Peripheral” SpA may seem
a misnomer, but it simply indicates that peripheral musculoskeletal
TABLE 374-1  Spectrum of Spondyloarthritis
SPONDYLOARTHRITIS (SPA)
AXIAL SPONDYLOARTHRITIS (axSpA)
PERIPHERAL SPONDYLOARTHRITIS (pSpA)
CONDITION
CLINICAL FEATURES
CONDITION
CLINICAL FEATURES
 
 
Conditions commonly included under pSpA
PART 11
Immune-Mediated, Inflammatory, and Rheumatologic Disorders
Radiographic axSpA
(r-axSpA, also called
ankylosing spondylitis [AS])
Sacroiliitis grade 2 (bilateral),
grade 3 or 4 (unilateral or
bilateral)
Psoriatic arthritis
Skin psoriasis and nail involvement usually preceding
arthritis, enthesitis, dactylitis
Nonradiographic axSpA
(nr-axSpA)
Sacroiliitis grade 1 (unilateral or
bilateral) or grade 2 (unilateral)
Inflammatory bowel disease–associated
arthritis
 
 
Reactive arthritis
Urethritis, history of preceding infection with
Salmonella, Shigella, Yersinia, Campylobacter, and
Chlamydia, mucosal ulcers, conjunctivitis, keratoderma
blennorrhagica
 
 
Undifferentiated peripheral SpA
Enthesitis, dactylitis, family history of SpA, HLA-B27,
acute anterior uveitis, and not fitting in any of the other
conditions mentioned above
 
 
Conditions sometimes included under pSpA
 
 
SAPHO syndrome
Synovitis, acne, pustulosis, hyperostosis, and osteitis;
typical involvement of anterior chest wall joints
 
 
Acne-associated arthritis
Acne conglobata, peripheral arthritis
 
 
Hidradenitis suppurativa–associated
arthritis
manifestations are predominant and more troublesome to the patient
than the spinal involvement.
AxSpA is further divided into radiographic (r-axSpA, also known
as ankylosing spondylitis [AS]), and nonradiographic (nr-axSpA). The
conditions included under pSpA are psoriatic arthritis (PsA), reactive
arthritis (ReA), arthritis associated with IBD, and undifferentiated
SpA, where patients cannot be classified under any known categories.
Patients with axSpA can have peripheral musculoskeletal manifes­
tations, and patients with pSpA may have additional axial skeletal
involvement at presentation or may develop it later in the course of
their disease. Other conditions sometimes included under pSpA are
SAPHO (synovitis, acne, pustulosis, hyperostosis, and osteitis) syn­
drome, acne-associated arthritis, and arthritis associated with hidrad­
enitis suppurativa. Table 374-1 shows the full spectrum of conditions
included under “spondyloarthritis.”
Pattern recognition is important for the diagnosis of SpA. Typical
patterns include asymmetric, mono- or oligoarticular (four or less
joints) inflammatory arthritis of large joints in the lower limb (usu­
ally knee), with enthesitis, tendonitis, and dactylitis. This contrasts
with RA, where polyarticular symmetric involvement of metacarpo­
phalangeal (MCP)/proximal interphalangeal (PIP) joints predomi­
nates. The cumulative prevalence of all conditions under SpA is 2–3%
of the population, much more common than RA.
PATHOLOGY OF SPONDYLOARTHRITIS
SpA is a prototypic chronic immune-mediated inflammatory disease
that couples inflammation to structural damage. A unique feature of
SpA is that inflammation-induced bone loss coexists with pathologic
new bone formation, which occurs at specific sites in the skeleton.
These sites include not only the sacroiliac joint but also the anterior
spinal ligaments or at entheses in the peripheral skeleton. If uncon­
trolled, axSpA may ultimately lead to a complete ankylosis of the
sacroiliac joints and the spine, termed “bamboo spine.” With increas­
ing awareness of SpA resulting from early diagnosis and treatment,
there has been a steady decrease in the amount of structural damage
observed over the past decades with a gradual shift of higher preva­
lence from r-AxSpA to nr-AxSpA.
While histopathologic studies have led to an increased under­
standing of local inflammatory and structural changes, the acces­
sibility to target tissue particularly in the axial skeleton and tendons/
entheses has been hampered by technical issues. Most of the informa­
tion to date comes from surgically derived specimens from patients
with longstanding disease. Accordingly, many of the described
Crohn’s disease or ulcerative colitis with inflammatory
arthritis
Hidradenitis suppurativa, peripheral arthritis, rarely
asymmetric sacroiliitis
features represent disease under treatment, which inevitably impacts
histopathology. Obtaining synovial tissue from an array of joints
such as knees, wrists, and small joints in fingers has become much
more readily accessible through ultrasound-guided synovial tissue
biopsy, which permits study of synovial tissue alterations in an early
treatment-naïve stage.
PATHOGENESIS OF SPONDYLOARTHRITIS
Although the exact mechanisms that initiate the disease are not fully
delineated, genetic and environmental risk factors and molecular and
cellular alterations at key disease sites have been implicated in the
pathophysiology of SpA (Fig. 374-1). At these sites, which include the
axial and peripheral joints, entheses, skin, and gut, variation is seen in
the disease mechanisms and perturbations of the key cytokine path­
ways. These tissue-based variations are most likely associated with the
dissimilar clinical responses observed between the spine, peripheral
joints, and gut during treatment with cytokine inhibitors.
■
■GENETIC ASSOCIATIONS IN AXIAL
SPONDYLOARTHRITIS AND OTHER
SPONDYLOARTHRITIS: HLA-B27 AND BEYOND
HLA-B27 is a major histocompatibility complex (MHC) class I allele
that forms the strongest genetic risk factor for SpA and specifically
axSpA. MHC class I molecules are expressed on the surface of nucle­
ate cells and can present peptides to CD8+ T cells. HLA-B27 is present
in 85–90% of the patients with r-axSpA and 50–90% in nr-axSpA, in
contrast to about 5% of the healthy Caucasian population.
Besides HLA-B27, other MHC class I genes and non-MHC coding
genes have been identified in large genome-wide association stud­
ies (GWAS) in axSpA. Within the group of non-MHC coding genes,
genes linked to innate immune processes, interleukin (IL)-23/IL-17
immunity, joint and bone remodeling, epithelial function, and antigen
presentation are seen, which are processes relevant in the immuno­
pathogenesis of axSpA. Whether all of these represent independent risk
factors is still not clear, although some appear to be interconnected.
For example, genetic epistatic interaction has been suggested between
ERAP1, a peptide-trimming enzyme, of which single nucleotide poly­
morphisms (SNPs) are associated with AS and HLA-B27. How HLAB27 fosters development of SpA remains unclear despite the discovery
of this strong genetic association 50 years ago. At present, several
theories exist with limitations to each of them.
The “arthritogenic peptide” theory proposes that HLA-B27 pres­
ents pathological microbial peptides to CD8+ cytotoxic T cells that
Genetic predisposition
e.g., HLA-B27
Gut
Gut
iNKT
MAIT
Urogenital
system
Tc17
Th17
γδT
ILC3
Joint
Skin
IL-17
Axial SpA
IBD
PsA
PsO
Fibroblast
Fibroblast
Fibroblast
Fibroblast
MAIT
ILC3
T17
T17
T17
T17
ILC3
γδT
γδT
Mø
Mø
Mø
Neutrophil
Neutrophil
Neutrophil
Neutrophil
DC
AntiIL-17
AntiIL-17
Anti-IL-17
JAKi
JAKi
JAKi
JAKi
AntiIL-23
AntiIL-23
Anti-IL-23
Anti-TNF
Anti-TNF
Anti-TNF
AntiTNF
FIGURE 374-1  Pathogenesis and signature cytokines across different disease domains in spondyloarthritis (SpA). In genetically predisposed individuals, SpA may arise
from mechanical stress, a well-known disease precipitator in psoriatic arthritis and axial SpA, or by altered host-microbial interplay at inner (gut, urogenital tract) or outer
(skin) surfaces culminating in a cytokine crosstalk characterized by both tumor necrosis factor (TNF)- and interleukin (IL)-17-driven immune responses. Drivers of disease
include cells of both innate and adaptive immune system, along with tissue-resident stromal cells. Different disease domains (gut, spin, peripheral joints, and skin) harbor
overlapping (e.g., TNF-α) but also distinct (e.g., IL-17, IL-23) signature cytokines, which has major therapeutic implications. Janus kinase (JAK) inhibitors, which interfere
with signaling of several cytokines, are effective across all domains.
then target cross-reactive human peptides leading to inflammation
and resulting in molecular mimicry. Presumably, this first antigenic
exposure could take place in the gut or at the urogenital tract. Several
allotypes of HLA-B27 exist, but not all of them represent risk factors for
axSpA. For example, HLA-B2704 and HLA-B2705 subtypes confer a
genetic risk, whereas the HLA-B2706 and HLA-B2709 allotypes are
not associated with axSpA even though they only differ in one peptide
Mechanical strain
Barrier integrity loss
CHAPTER 374
Urogenital
system
Spondyloarthritis
Skin
Neutrophil
Mø
T cell
Joint
TNF-α
Disease domains
ILC3
γδT
Mø
γδT
residue or amino acid. This would suggest that there could be spe­
cific peptides that can only be presented by the pathogenic HLA-B27
subtypes to induce the “arthritogenic” response. In the arthritogenic
peptide hypothesis, inflammation is driven by antigen presentation
to CD8+ T cells. Existence of HLA-B27-restricted CD8+ T cells in the
synovial fluid of AS patients was shown three decades ago, whereas
more recent next-generation sequencing T-cell receptor (TCR) studies
showed expansion of both CD4+ and CD8+ TCR clonotypes in blood
and synovium of HLA-B27-positive SpA. Expansion of CD8+ TCR
clonotypes with the CAS **STDTQYF CDR3 motif were found in AS
patients versus HLA-B27-positive controls in blood and synovium,
which was recently suggested as a target for therapeutic intervention.
The second theory relates to the ability of HLA-B27 to homodimer­
ize. These HLA-B27 homodimers can be expressed at the cell surface
and interact with innate immune receptors, such as the KIR3DL2
receptor, on T and natural killer (NK) cells resulting in IL-17 produc­
tion, one of the key pathogenic cytokines in axSpA. However, there is
still some controversy regarding whether various allotypes of HLA-B27
differ in their ability to form homodimers.
PART 11
Immune-Mediated, Inflammatory, and Rheumatologic Disorders
A third theory links HLA-B27 to unfolded protein responses
(UPR) and autophagy, which may promote type 17 immune responses
through release of IL-23. Support comes from the HLA-B27 transgenic
rat model, while no evidence for an increase in UPR in synovial tissue
or blood of HLA-B27-positive AS patients was found in steady state,
which questions its role in humans.
Although HLA-B27 has the strongest genetic link, other MHC
class I associations have also been found, for example (HLA-Cw6) in
PsA. IL-23R gene polymorphisms are shared across most forms of SpA.
This suggests overlapping yet distinct features across different disease
domains.
■
■FACTORS INSTIGATING THE ONSET OF
SPONDYLOARTHRITIS IN GENETICALLY
PREDISPOSED INDIVIDUALS
Despite the strong genetic association between HLA-B27 and AS, only
a minority of HLA-B27-positive subjects develop disease. In addition,
the risk of developing AS in HLA-B27-positive first-degree relatives
of AS patients is only 20%. This indicates that additional factors are
needed to induce disease. Because SpA affects seemingly distinct tis­
sues (spine, peripheral joints, enthesis, anterior eye chamber, intestine,
skin), it has been a challenge to seek a common denominator between
these different organs. Two main mechanisms are currently under con­
sideration: the role of intestinal microbiota following a loss of barrier
integrity and an aberrant response to mechanical stress.
Barrier Integrity Loss and the Intestinal Microbiota in
SpA 
In view of the link between gut inflammation and SpA, much
attention has been focused on barrier integrity loss in the intestine and
the role of the intestinal microbiota. Evidence supporting this mecha­
nism has been the development of ReA following an infectious gas­
troenteritis with Salmonella typhimurium, Shigella enteritidis, Yersinia
enterocolitica, or Campylobacter enteritidis. Studies have highlighted
the loss of barrier integrity, which may facilitate translocation of bac­
teria and microbial peptides that can elicit an immune response. The
human microbiome is shaped by genetic and environmental factors.
Changes in diversity and composition of the gut microbiome have been
identified in SpA, pinpointing an intestinal dysbiosis that is similar to
patients with IBD. While most information on host-microbial interplay
in SpA relates to the intestine, other mucosal surfaces and particularly
the urogenital tract (e.g., Chlamydia) may serve as an entry route for
pathogens to instigate the onset of SpA.
Germ-free HLA-B27 transgenic rats fail to develop SpA, suggest­
ing a crucial pathogenic role for intestinal microbiota. In humans,
microbiome profiling in stool and biopsy samples of HLA-B27–positive
individuals found that HLA-B27 affects the gut microbiome even in
the absence of disease. This supports the concept that in HLA-B27–
positive individuals, intestinal dysbiosis occurs prior to the onset
of clinical manifestations and may contribute to the risk of disease.
Earlier research suggested that HLA-B27 may promote intracellular
survival and persistence of pathogens such as Chlamydia trachomatis in
monocytes, which could travel to joints and promote synovial inflam­
mation. More recent studies indicate that not all preclinical models
of combined gut and joint disease mimicking SpA impact these sites
similarly: in a tumor necrosis factor (TNF) cytokine-dependent model
with Crohn’s-like ileitis and peripheral arthritis, gut inflammation was
found to be microbiota dependent but not joint inflammation. This
suggests that intestinal microbiota may play a role in some, but not all,
SpA patients or disease features.
The skin, as the outer barrier of the body, is also vulnerable to the
development of immune-mediated inflammatory disease. Like the inner
barriers of the intestines and joints, the skin plays a key role in preserving
tissue homeostasis at a site exposed to microbial, chemical, and mechani­
cal challenges. Alterations in the cutaneous microbiome of patients with
psoriasis and PsA have been described with striking similarities between
nonlesional and lesional skin. However, the functional impact of skin
microbiota on the disease trajectory is still ill defined.
Mechanical Stress as Gateway to Joint Disease in SpA 
The
entheses in SpA and PsA are key inflammatory target tissues, and
patients can present with both axial and peripheral entheseal inflam­
mation. In both SpA patients and in individuals without inflammatory
conditions, mechanical stress in entheses may lead to microdamage
that leads to immune activation and tissue repair. The importance
of mechanical strain in the pathophysiology of enthesitis in SpA is
supported by observations in patients and animal models. Enthesitis
occurs more often in the lower limbs, which are subject to higher
mechanical strain. In patients with AS, exposure to physical labor was
related to more structural damage. In mouse models, mechanical strain
was shown to be causally related to development of enthesitis and
SpA-related new bone formation through mechanisms that support
chronicity of inflammation.
Responses to mechanical stress are physiologic and self-limited,
but they appear to be enhanced and prolonged in SpA. The reason for
this is unclear, but this may be influenced by genetic factors and/or
impaired intestinal barrier function.
Chronic entheseal inflammation in axSpA also leads to excessive
local bone responses. This is associated with osteoblast differentia­
tion initiated by prostaglandin E2, IL-17-A and -F, and IL-22 followed
by activation of downstream bone morphogenic proteins and Wnt
proteins, which are thought to play a role in pathological new bone
formation. This culminates in the generation of bony spurs at vertebral
bodies and sacroiliac joints, eventually leading to ankylosis.
Common Versus Private Cytokine Hubs in Disease Domains
in SpA 
Regardless of the route of disease initiation, several common
effector pathways have emerged, with TNF and IL-17 representing sig­
nature cytokines in the immunologic basis of axSpA.
The impact of TNF-α as a common effector pathway that acts down­
stream in the inflammatory process has been long recognized given its
broad therapeutic efficacy across all disease domains (gut, enthesis,
skin, eye, spine, and joints). TNF-α is an important activator and prod­
uct of macrophages that stimulates cytokine production in immune
cells and activates fibroblasts. TNF-α can also be made by neutrophils
and activated T cells in the inflamed synovium, enthesis, and intestine.
By activating osteoclasts, it promotes inflammation-induced bone loss
and bone erosions in SpA.
Even though axSpA and IBD share a similar genetic predisposi­
tion in IL-23R polymorphisms, the two disorders differ substantially
in their cytokine dependency. IL-17A blockade is effective in axSpA,
whereas IL-23 inhibition does not provide benefit. Conversely, IL-23
blockers are approved in IBD, but agents targeting IL-17A are contra­
indicated in active IBD, due to the barrier protective roles of IL-17. In
PsA, IL-23 and IL-17 inhibitors both appear to be effective.
These observations instigated a search into cellular sources of IL-17
in SpA and their dependency on IL-23. Several IL-17A–producing cell
types, including T17 cells (consisting of both CD4+ TH17 and CD8+
cytotoxic T17 [Tc17] cells), γ/δ T cells, and ILC3, are present at enthe­
seal sites in steady-state conditions. In synovial fluid of SpA patients,
innate-like T cells such as γδ T cells were found to be the major T-cell
source of IL-17 in the presence or absence of IL-23. This is of particu­
lar interest as these γδ T cells also survey epithelial sites such as skin
or intestine. Thus, entheses, synovium, and mucosal sites appear to
harbor cells that may boost IL-17A responses in the absence of IL-23.
Janus kinase (JAK) inhibitors, which block signaling of several
cytokines, are effective in a wide range of SpA including all clinical
domains (Fig. 374-1).
AXIAL SPONDYLOARTHRITIS
AxSpA is a chronic, immune-mediated inflammatory disorder pre­
dominantly involving the axial skeleton (sacroiliac joints and the spine)
and also the peripheral skeleton. The axial skeleton is always involved,
and involvement of the peripheral joints occurs in ~30–40% of patients.
The hips, historically considered “root joints,” are the most common
nonspinal joints affected. Enthesitis in the axial and peripheral skel­
eton is a common feature, but dactylitis is relatively rare. Extraarticular
manifestations include psoriasis, acute anterior uveitis, and IBD. Some
patients with axSpA experience gradual spinal bony fusion over several
years, which leads to reduced spine and neck flexibility. Despite these
osteoproliferative changes in the skeleton, osteoporosis is a common
morbidity. AxSpA significantly affects patients’ well-being, function,
productivity, and health-related quality of life.
■
■DEFINITIONS AND NOMENCLATURE
AxSpA is divided into r-axSpA (also called AS) and nr-axSpA, the dif­
ference based on the presence or absence of definitive sacroiliitis on
plain radiographs. “Definitive sacroiliitis” is defined by the modified
New York criteria (Table 374-2) as grade 2 bilateral or grade 3 or 4
unilateral or bilateral (Table 374-3). Patients with sacroiliitis of lower
grade are classified as nr-axSpA. Since the differentiation between
r-axSpA and nr-axSpA is based on the degree of sacroiliitis, it is open
to disagreements even between trained musculoskeletal radiologists.
The interreader reliability as measured by the kappa statistic is between
0.35 and 0.45. nr-axSpA and r-axSpA have the same clinical features
and share similar disease burden, though in late-stage r-axSpA, fusion
of spine and hip involvement can add to functional loss.
■
■EPIDEMIOLOGY
The male-to-female ratio is 2:1 for r-axSpA and 1:1 for nr-axSpA. The
population prevalence of axSpA depends on the prevalence of HLAB27 in that geographic region. In Europe, HLA-B27 frequency in the
population increases from south to north, and so does the prevalence
of axSpA. For example, the prevalence of HLA-B27 in Spain and Nor­
way is 7 and 9%, respectively, and the prevalence of AS and axSpA in
these two countries is 0.1 and 0.56%. The 2009–2010 National Health
and Nutritional Examination Survey (NHANES) estimated that in the
United States, the population prevalence of HLA-B27 is 6% and that of
axSpA is between 0.9 and 1.4%, of which 0.5% were reported to have
AS. The population prevalence of axSpA in the rest of the world is not
well studied and is believed to be between 0.02 and 1.5%. Diagnostic
prevalence of axSpA in the United States, which includes only the diag­
nosed cases in a population, is one-tenth that of population prevalence,
suggesting a large undiagnosed population. Based on insurance claims
databases in the United States, the diagnostic prevalence of axSpA
increased between 2006 to 2019, which could be attributed to increased
disease awareness. The incidence rates of AS are 0.005–0.01 per 100
patient-years globally and are not available for nr-axSpA.
The risk of axSpA is 5% in HLA-B27-positive people but increases to
20% in HLA-B27-positive first-degree relatives of affected individuals
with axSpA.
TABLE 374-2  Modified New York Classification Criteria for Ankylosing
Spondylitis (AS)
Clinical Criteria
Low back pain >3 months
  Improved with exercise
  Not relieved by rest
Limited lumbar motion in fontal and lateral planes
Reduced chest expansion 
Radiographic Criteria
Bilateral grade >2 sacroiliitis on x-ray
Unilateral or bilateral grade 3 or 4 on x-ray 
Definite AS requires ≥1 clinical criterion plus 1 radiographic criterion
Source: Adapted from S van der Linden et al: Arthritis Rheum 27:361, 1984.
TABLE 374-3  Grading of Sacroiliitis
GRADE
DESCRIPTION
Grade 0
Normal
Grade 1
Suspicious change
CHAPTER 374
Grade 2
Minimum abnormality (small, localized areas with erosions or
sclerosis, without alterations in the joint width)
Grade 3
Unequivocal abnormality (moderate or advanced sacroiliitis with
erosions, evidence of sclerosis, widening, narrowing, or partial ankylosis)
Grade 4
Severe abnormality (total ankylosis)
Spondyloarthritis
Source: Reproduced with permission from S van der Linden et al: Evaluation of
diagnostic criteria for ankylosing spondylitis. Arthritis Rheum 27:361, 1984.
■
■CLINICAL MANIFESTATIONS
The most common first manifestation of axSpA is low back, hip, or
buttock pain, which starts before the age of 40–45 years, usually in
the 20s to 30s. The typical characteristics of this back pain include any
combination of the following: insidious onset, chronicity (>3 months’
duration), age of onset <45 years, improvement with exercise or activ­
ity and no improvement with rest, worse back pain in the second half
of the night with improvement after getting out of bed and walking
around, and prolonged (>30 min) morning stiffness. Back pain with
these characteristics is termed “inflammatory back pain” (IBP) to dif­
ferentiate it from the common “mechanical back pain” (Table 374-4),
but the term is a misnomer because only 15% of patients with IBP have
demonstrable inflammation in their axial skeleton. Rarely, thoracic or
neck pain can be a presenting feature, and when present, it is more
commonly seen in women. Fatigue and stiffness are the two most both­
ersome symptoms after back pain in axSpA. Fatigue is multifactorial,
secondary to sleep disturbance, active inflammation, and anemia, and
may also indicate underlying depression and anxiety of chronic disease.
Peripheral arthritis is seen in 30–40% of patients with axSpA. Typi­
cally, this is an asymmetric, oligoarticular inflammatory arthritis involv­
ing the large joints of the lower extremities and rarely the small joints of
hands and feet. Hip involvement, presenting as pain in the groin with
radiation to medial thigh or the knee, is common and is associated with
significant functional impairment. Enthesitis is a common manifesta­
tion of axSpA. Enthesitis may present as heel pain (plantar fasciitis,
Achilles tendon insertion pain), chest wall pain, intercostal muscle
insertions, medial or lateral epicondylitis, quadriceps or patellar tendon
insertion pain around knees, or pelvic rim pain. Dactylitis is an uncom­
mon manifestation of axSpA. Persistent axial inflammation may lead to
bony fusion of sacroiliac joints, apophyseal joints, and development of
syndesmophytes by osteoproliferation in the outer fibers of the annulus
fibrosus of the intervertebral disks. These bony changes lead to limitation
of spinal, including neck, mobility in all directions and are a major cause
of significant functional impairment in late stages of the disease.
Extramusculoskeletal manifestations of axSpA, such as psoriasis,
IBD, and acute anterior uveitis, can also be the presenting symptom of
axSpA in some patients, and such patients may first present to a der­
matologist, gastroenterologist, or an ophthalmologist. Uveitis, the most
TABLE 374-4  Clinical Features of Inflammatory Versus Mechanical
Back Pain
MECHANICAL
BACK PAIN
FEATURE
INFLAMMATORY BACK PAIN
Age at onset
Before 40–45 years
20–65 years
Onset
Insidious
Acute or insidious
Morning stiffness
Prolonged (more than 30 min)
Less than 30 min
Pain at night
Yes, usually after midnight
No, usually late in the day
Exercise/activity
Improves pain and stiffness
Worsens pain
Rest/inactivity
Worsens pain and stiffness
Improves pain
Duration
Chronic
Acute or chronic
Response to fulldose NSAIDs
More than 50% relief in 48 hours
Limited relief
Note: Not all features are required for diagnosis of inflammatory back pain, nor are
they present in every patient.
Abbreviation: NSAIDs: nonsteroidal anti-inflammatory drugs.
common extramusculoskeletal manifestation, is seen in 40% of patients
with axSpA and presents as eye discomfort followed by redness, pain,
photophobia, and miosis. The typical phenotype of uveitis associated
with axSpA is acute, anterior, unilateral, and episodic. While frank IBD
is seen in 10%, histologic evidence of subclinical gut inflammation is
seen in up to 50% of patients. Psoriasis is seen in 10%, and osteoporosis
can be present in 40%.
PART 11
Immune-Mediated, Inflammatory, and Rheumatologic Disorders
AxSpA can affect multiple organ systems. The two renal manifesta­
tions of axSpA are IgA nephropathy, which can present at any time in
the disease course as microscopic hematuria, and nephrotic syndrome
secondary to renal (AA) amyloidosis, which is a late complication only
seen after prolonged uncontrolled inflammation. Conduction abnor­
malities (heart blocks) can be seen at any stage of the disease, whereas
aortic valve insufficiency and cauda equina syndrome presenting as
urinary hesitancy and/or saddle anesthesia are late complications.
Pulmonary manifestations of axSpA include apical fibrosis, cavitary
lung lesion, or fibrotic parenchymal lesions. Sleep apnea syndrome and
restrictive lung disease seen in late-stage axSpA are mostly related to
osteoproliferative structural changes of the cervical spine and rib cage.
The course of axSpA can be variable, with close to 50% of patients
progressing from nonradiographic to radiographic stage over 20 years
and <10% progressing to significant spinal involvement with bamboo
spine. Risk factors for osteoproliferation include male sex, persistent
inflammation (seen on magnetic resonance imaging [MRI] of sacro­
iliac joints and spine, high C-reactive protein [CRP]), syndesmophytes,
presence of HLA-B27, and smoking.
■
■DIAGNOSIS
A diagnostic delay of 5–14 years from symptom onset of axSpA
reported in various parts of the world is mostly related to the common­
ality of mechanical back pain in the general population. Traditionally,
Chronic back pain >3 months,
Insidious onset <45 years, common causes such
as mechanical back pain, fibromyalgia ruled out
SI joint x-ray positive for definite sacroiliitis
Yes
No
Presence of SpA features: IBP, inflammatory arthritis,
uveitis, dactylitis, enthesitis, psoriasis, IBD,
family history, good response to NSAIDs, high CRP
AS (R-axSpA)
≥ 4 SpA Features
Compelling clinical
picture
Yes
Nr-axial SpA
Nr-axSpA
FIGURE 374-2  Schema for the diagnosis of axial spondyloarthritis in a patient complaining of chronic back pain (back pain lasting >3 months).
AS is thought to be a disease of males, and back pain and enthesitis
in women are commonly mistaken for fibromyalgia. This delays the
diagnosis in females even further. Lower prevalence of HLA-B27 in
nonwhite populations also adds to the delay in diagnosis.
The diagnosis of axSpA is based on pattern recognition, ruling out
common causes for the symptoms, and clinical reasoning. Figure 374-2
shows a schema for the diagnosis of axSpA in a patient complaining of
chronic (>3 months) back pain. While elevated inflammatory mark­
ers, erythrocyte sedimentation rate (ESR), and CRP help in making
the diagnosis of axSpA, these tests are neither sensitive (seen in only
30–40% of patients with active axSpA) nor specific for axSpA.
Imaging plays a very important role in the diagnosis of axSpA. A
single anteroposterior (AP) view or a Ferguson view x-ray of the pelvis
is sufficient to image sacroiliac joints. Multiple views (e.g., oblique) of
the sacroiliac joints add little in making the diagnosis; in addition, they
increase radiation risk to gonads. Radiographic features of sacroiliitis
include marginal sclerosis, erosions, narrowing and widening of the
joints, and in late stages, fusion (Fig. 374-3A and Table 374-3). As a gen­
eral rule, plain radiographs of the spine should be avoided in patients
with chronic back pain. However, there are some characteristic changes
of axSpA seen in the lateral radiograph of the spine, and they include
Romanus lesions or the shiny corner sign and squaring of the vertebral
body seen as a result of erosions at the attachments of the spinal liga­
ments at the vertebral corners. Andersson lesion is an uncommon find­
ing and is characterized by vertebral body erosion and sclerosis at the
intervertebral disk level. In the late stages, ossification of the outer layer
of annulus fibrosus leads to syndesmophyte formation (Fig. 374-3B).
Typical syndesmophyte orientation is vertical, differentiating it from
the horizontal orientation of osteophytes, which is commonly seen
with osteoarthritis (OA) of the spine. Bamboo spine, or ankylosis of the
entire spine, is seen in a very small percentage of late-stage AS patients.
<4 SpA Features
MRI SI Joints positive
for sacroiliitis
Yes
No
Compelling clinical
picture plus
HLA-B27 positive
Clinical picture not
compelling and/or
HLA-B27 negative
Nr-axSpA
Not axSpA
A
B
FIGURE 374-3  Radiographic axial spondyloarthritis. A. Bilateral sacroiliitis
(modified New York grade 3) with sclerosis and erosions. B. Lateral view
cervical spine in advanced radiographic axial spondyloarthritis showing anterior
syndesmophytes and fused facet joints.
Low-dose computed tomography (CT) of the sacroiliac joints and spine
in the diagnosis of axSpA is emerging as an alternative to plain radiog­
raphy for diagnosis and assessing progression (Fig. 374-4).
Magnetic resonance imaging (MRI) of the sacroiliac joints and spine
has evolved as an important tool in making the diagnosis of axSpA.
During the early stage of disease, MRI of the sacroiliac joints may show
evidence of active inflammation, or “osteitis,” and that may be the only
abnormality. As time passes, the active inflammatory changes transition
to fatty metaplasia, and this may further transform to new bone forma­
tion. The structural changes of sclerosis, fat metaplasia, erosions, fat
metaplasia in an erosion cavity (backfill), and new bone formation, in
addition to the inflammatory changes seen on MRI, aid in making the
diagnosis of axSpA (Fig. 374-5). Sole presence of inflammatory lesions
in early stages or sole presence of ankylosis in very late stage may be
enough for the diagnosis of axSpA, but as a general rule, multiple types
of inflammatory and structural lesions increase the suspicion of axSpA.
In the spine, multiple corner inflammatory lesions and/or multiple cor­
ner fatty lesions increase the confidence of axSpA diagnosis.
MRI is a very sensitive imaging technique, and mechanical stress on
the sacroiliac joints in professional athletes, postpartum women, and
even in normal individuals, especially above the age of 40, may show
changes of osteitis. Fat metaplasia-type changes in the sacroiliac joints
are also seen in degenerative arthritis as well as in normal individuals.
Inappropriate utilization of MRI can lead to overdiagnosis.
CHAPTER 374
Spondyloarthritis
FIGURE 374-4  Computed tomography of the thoracic spine sagittal view in
radiographic axial spondyloarthritis showing anterior and posterior syndesmophytes.
■
■DIFFERENTIAL DIAGNOSIS
Chronic nonspecific “mechanical” back pain is common in the general
population, and axSpA is the etiology in only 4–5% of such patients.
Mechanical causes of back pain therefore should be considered first in
a patient presenting with chronic back pain. The so-called “red flag”
A
B
FIGURE 374-5  Magnetic resonance images of spondyloarthritis. A. T1-weighted
image of sacroiliac joints with bilateral erosions (left-sided erosions marked by **),
left fatty metaplasia (single *), and right bone marrow edema (marked with white
arrows). B. Short tau inversion recovery (STIR) image with bilateral bone marrow
edema suggestive of joint space inflammation (shown by *) and anterior capsulitis
(shown by a white arrow).
signs of fever, weight loss, advanced age, and past history of malig­
nancy should alert the examiner to look for osteomyelitis, osteoporotic
fracture, or metastatic disease. In young patients with generalized body
pain, fibromyalgia, central sensitization, hypermobility, hypothyroid­
ism, and hypovitaminosis D may be considered.
Abnormalities on incidental imaging in a patient with or even
without chronic back pain lead to other differential diagnoses such
as diffuse idiopathic skeletal hyperostosis (DISH) or osteitis conden­
sans ilii (OCI). DISH is a noninflammatory, degenerative condition
affecting the spine, with exuberant new bone formation in the form of
anterior and posterior longitudinal ligament ossification of at least four
contiguous vertebral bodies and bulky “flowing” osteophytes typically
on the right side of the thoracic spine, but normal sacroiliac joints. It
is generally seen in obese, diabetic males, often older than 50 years
of age. DISH is sometimes mistaken for bamboo spine of AS. OCI is
usually an asymptomatic condition of multiparous women character­
ized by radiographic findings of a triangular area of dense sclerosis
on the lower and inferior part of the iliac side of the sacroiliac joints.
This can be mistaken for sacroiliitis, and in early stages, MRI of the
sacroiliac joints may be indistinguishable from that of axSpA. Lack of
erosions should help distinguish OCI from axSpA. OCI can be seen in
nulliparous women and even men. While DISH and OCI are generally
asymptomatic, some patients with either condition may present with
chronic back pain.
PART 11
Immune-Mediated, Inflammatory, and Rheumatologic Disorders
Inflammatory back pain with sclerotic changes on sacroiliac joint
radiographs can also be seen in conditions such as postpartum insuf­
ficiency fracture of the sacrum; septic sacroiliitis from tuberculosis,
brucellosis, fungi, and other infectious agents; and rarely, malignancies
such as acute lymphoblastic leukemia.
■
■MONITORING
AxSpA patients should be monitored at every visit for disease activ­
ity, function, and medication safety. The frequency of monitoring is
individualized. Assessment of disease activity can be performed by
using the Bath Ankylosing Spondylitis Disease Activity Index (BAS­
DAI) or the Ankylosing Spondylitis Disease Activity Score (ASDAS).
Functional impairment can be measured by the Bath Ankylosing
Spondylitis Functional Index (BASFI). This is a patient-administered
questionnaire that includes 10 activities of daily living. The Bath
Ankylosing Spondylitis Metrology Index is an index of spinal and hip
mobility in patients with AS.
The ESR and CRP may be useful in monitoring disease activity.
MRI of the sacroiliac joints or spine is expensive and is not indicated
to monitor disease activity of AxSpA. Spine radiographs and MRI are
not used for monitoring purposes in daily practice, although they may
be used if back pain persists or relapses to rule out active inflammation
despite therapy or complications such as spinal fractures.
TREATMENT
Axial Spondyloarthritis
Principles of treatment of nr-axSpA and r-axSpA are identical and
are described as one disease. Some agents are approved to treat only
AS (r-axSpA) and are mentioned below.
The targets for treatment include low disease activity or remis­
sion. Traditionally, the treatment of axSpA was limited to exer­
cise, physical therapy, and nonsteroidal anti-inflammatory drugs
(NSAIDs), but with the advent of biologics and targeted synthetic
disease-modifying antirheumatic drugs (tsDMARDs), great strides
have been made in in the last two decades. Shared decision-making
regarding all modes of therapy is the key to success.
Treatment of axSpA can be divided into nonpharmacologic,
pharmacologic, and surgical.
NONPHARMACOLOGIC INTERVENTIONS
Physical exercise in the form of active physical therapy (on land
or aquatic) and self-directed physical exercise are strongly recom­
mended by all international guidelines and should be promoted.
Physical therapy improves fatigue, mobility, and posture. Smoking
cessation is encouraged in all patients.
PHARMACOLOGIC INTERVENTIONS
The American College of Rheumatology (ACR), Spondylitis Associ­
ation of America (SAA), Spondyloarthritis Research and Treatment
Network (SPARTAN) treatment guidelines, and ASAS-EULAR
(European Alliance of Associations for Rheumatology) treatment
recommendations have many commonalities regarding the order of
treatments, choices of agents, and precautions. Table 374-5 outlines
pharmacologic interventions for the treatment of axSpA.
The use of immunosuppressive biologics and tsDMARDs has
been associated with an increased risk of serious infections. While
bacterial infections are seen in both classes, herpes zoster is mostly
seen with JAK inhibitors (JAKis), and reactivation of latent tubercu­
losis is mostly seen with TNF inhibitors (TNFis). Mucosal and skin
Candida infections are associated with IL-17 inhibitor (IL-17i) use.
Other side effects of biologic therapy include injection-site reac­
tions with subcutaneous injections or infusion reactions with intra­
venous (IV) medication. TNFi adverse effects include development
of demyelinating disease, worsening of congestive heart failure, and
paradoxical development of psoriasis-like skin lesions. Adverse
events associated with IL-17i therapy include leukopenia and devel­
opment or worsening of IBD. JAKis have a higher risk of major
cardiovascular adverse events and cancers (lymphoma and lung
cancers), especially in patients aged 65 years or older and in those
with current or past history of smoking, with history of cardiovas­
cular disease, or with malignancy. As a result, the U.S. Food and
Drug Administration (FDA) suggests reserving these medicines for
patients who have had an inadequate response or intolerance to one
or more TNFi.
SURGICAL INTERVENTIONS
Hip involvement in axSpA leads to significant functional impair­
ment, and total hip arthroplasty should be considered in patients
with refractory hip pain or functional decline in the presence
of radiographic evidence of structural damage. Spinal osteoto­
mies should be reserved for severe fixed kyphotic deformities in
advanced AS that affect horizontal vision and should be performed
in centers of expertise.
■
■COMPLICATIONS
The prevalence of osteoporosis is ~25% after 10 years of axSpA. Verte­
bral fractures are seen in ~10% of patients with AS. The lower cervical
spine is the most commonly involved area, where there is often also
neurologic compromise. One should consider vertebral fractures in
patients with neck and back pain that has changed in intensity or
character from baseline. Another rare complication is the cauda equina
syndrome from long-standing AS resulting from inflammation of the
lumbosacral nerve roots caused by arachnoiditis. Cardiac manifesta­
tions include aortic valve insufficiency and conduction abnormali­
ties. Pulmonary manifestations are rare and include chest expansion
restriction from ossification of costovertebral joints and upper lobe–
predominant interstitial lung disease. Patients with AS can have IgA
nephropathy or, in late stages, renal amyloidosis if the disease is left
untreated. Cardiovascular disease is being recognized as a common
comorbidity in patients with AS and is linked to chronic inflammation.
All patients with AS should be counseled about the traditional risk
factors for cardiovascular disease, and appropriate treatment should be
instituted if necessary.
PSORIATIC ARTHRITIS
PsA is a relatively common immune-mediated inflammatory condition
that may lead to progressive joint damage. If left untreated, it is associ­
ated with poor quality of life, loss of function, and increased morbid­
ity and mortality. PsA, associated with cutaneous and nail psoriasis,
involves peripheral joints, axial skeleton (sacroiliac joints and spine),
entheses, and tendon sheaths. In addition, uveitis and inflammatory
bowel disease may coexist with PsA. Common comorbidities of PsA
TABLE 374-5  Pharmacologic Management of Axial Spondyloarthritis (axSpA)
• Nonsteroidal anti-inflammatory drugs (NSAIDs) should be used in highest tolerable doses continuously in active disease and on an as-needed basis if the disease
is stable. No particular NSAID is preferred over any other. Side effects to monitor are gastric ulcer disease, hypertension, renal insufficiency, and cardiovascular
disease.
• Conventional synthetic DMARDs like sulfasalazine, up to 3 g/d, and methotrexate, up to 25 mg/wk, are useful for the treatment of peripheral joint and entheses
involvement, but not for axial disease in axSpA.
• If the disease remains active despite a 4-week trial of full-dose NSAIDs, treatment should be escalated to start a biologic from either the TNFi or IL-17i class.
• Before initiating therapy with biologics or JAKi, screening for latent tuberculosis, hepatitis B, and hepatitis C should be performed.
• All five TNFi agents are approved for the treatment of AS, while selective TNFis are approved for nr-axSpA in various countries.
• Soluble receptor of TNF–etanercept 50 mg subcutaneous (SC) injection once weekly.
• TNFi monoclonal antibodies:
• Adalimumab 40 mg SC every 2 weeks.
• Certolizumab pegol 200 mg SC twice a month or 400 mg SC once a month.
• Golimumab 50 mg SC once a month or golimumab 2 mg/kg intravenous (IV) at weeks 0, 4, and then every 8 weeks thereafter.
• Infliximab 5 mg/kg IV infusion at weeks 0, 2, 6, and then every 6 weeks.
• No TNFi is preferred, except in patients with concomitant uveitis or IBD in whom TNF monoclonal antibodies are preferred over soluble receptor TNFi therapy.
• In the case of primary failure of TNFi, treatment can be switched to IL-17i or JAKi. In the case of secondary failure of TNFi therapy (failing after initial benefit), an
alternative TNFi can be used.
• Two IL-17Ais are approved for the treatment of nr-axSpA and AS.
• Secukinumab 150 mg SC at weeks 0, 1, 2, 3, and 4, followed by 150 or 300 mg every 4 weeks.
• Ixekizumab 160 mg SC once, followed by 80 mg every 4 weeks.
• In case of primary failure of IL-17Ai, treatment can be switched to TNFi or JAKi. In the case of secondary failure of IL-17Ai therapy, an alternative IL-17i can be used.
• Two JAKis are approved for the treatment of AS, while only one is approved for nr-axSpA. JAKi should be used in patients who have failed TNFi.
• Tofacitinib 5 mg orally two times a day is approved for the treatment of AS only.
• Upadacitinib 15 mg once a day is approved for the treatment of AS and nr-axSpA.
• One IL-17A and IL-17F inhibitor is approved in certain parts of the world to treat both nr-axSpA and radiographic axSpA.
• Bimekizumab 160 mg SC every 4 weeks.
• Local glucocorticoid injections for upper extremity enthesitis or intraarticular injections for peripheral arthritis are indicated. Injections around lower limb weightbearing entheses are not recommended because of the risk of rupture.
• Systemic glucocorticoids do not have any efficacy in axSpA and should be avoided. 
Abbreviations: AS, ankylosing spondylitis; DMARDs, disease-modifying antirheumatic drugs; IBD, inflammatory bowel disease; IL-17i, interleukin 17 inhibitor; JAKi, Janus
kinase inhibitor; nr-axSpA, nonradiographic axial spondyloarthritis; TNFi, tumor necrosis factor inhibitor.
include depression, metabolic syndrome, diabetes mellitus, and car­
diovascular disease. Sometimes the term “psoriatic disease” is used to
emphasize these varied manifestations.
In 1973 Moll and Wright defined PsA as an inflammatory arthritis
(peripheral arthritis and/or sacroiliitis or spondylitis), with presence
of cutaneous psoriasis and absence of RF. They demonstrated the
association between PsA and the gene HLA-B*27 and described five
phenotypes of PsA, namely asymmetric oligoarticular inflammatory
arthritis, symmetric polyarticular arthritis, distal interphalangeal joint
arthritis, spondylitis, and arthritis mutilans. Over the years, enthesitis
and dactylitis have been added to these musculoskeletal manifesta­
tions. It is important to remember that these clinical phenotypes are
not exclusive and frequently coexist.
■
■EPIDEMIOLOGY
With a prevalence of 2–3%, skin psoriasis is one of the most common
immune-mediated diseases. The prevalence of PsA in patients with
psoriasis is 30% (range, 6–42%). The incidence of PsA in patients with
psoriasis is 3 per 100 patient-years (range 2–10) and depends on the
severity of skin psoriasis. The likelihood of developing PsA in psoriasis
patients does not change over time.
■
■CLINICAL FEATURES
Clinical features of PsA include peripheral arthritis, axial arthritis
(spondylitis), enthesitis, dactylitis, and tenosynovitis. Inflammatory
arthritis presents with joint pain, swelling, prolonged stiffness, and
reduced mobility. Typically, early PsA is oligoarticular (<4 joints) and
often asymmetric, and as the number of affected joints increases, the
disease becomes polyarticular and the distribution becomes more sym­
metric. Distal interphalangeal joint involvement is typical of PsA and
is associated with psoriatic nail changes since the nail bed is closely
linked to the distal interphalangeal (DIP) joints.
Inflammatory arthritis of the axial skeleton occurs in 5% of PsA
patients in early stage and can be seen in 50% of patients after 20 years
CHAPTER 374
Spondyloarthritis
of disease. Axial inflammatory arthritis presents with inflammatory
back and/or neck pain and stiffness, which is typically worse after peri­
ods of prolonged inactivity and improves with activity. However, axial
arthritis can be asymptomatic or overshadowed by patients’ peripheral
arthritis symptoms. Most patients with axial involvement have sacroi­
liitis, although axial involvement without sacroiliitis may distinguish
axial PsA from axial SpA. While many of the radiographic features
may resemble AS, presence of asymmetric sacroiliitis, nonmarginal
and asymmetric bulky syndesmophytes, and frequent involvement of
cervical spine have been more often assigned to axial PsA then AS.
These phenotypic differences have led to the suggestion that this may
reflect potential pathogenic distinctions. Whether axial PsA pathogen­
esis differs substantially from axSpA and especially whether this has
therapeutic consequences are the subjects of investigations by several
international consortia.
Other important musculoskeletal manifestations of PsA include
dactylitis, enthesitis, and tenosynovitis. Dactylitis is defined as inflam­
matory swelling of an entire finger or toe. Dactylitis is due to inflam­
mation of the joints, tendons, bones, and soft tissues within the digit.
Dactylitis is a marker of severity of PsA, and persistent dactylitis leads
to structural damage to the joints within that digit. Arthritis mutilans
is an end manifestation of a severe arthritis process.
Enthesitis is another important manifestation of PsA. The most
common sites affected by enthesitis are the plantar fascia and Achil­
les tendon insertion on the calcaneum (plantar fasciitis and Achilles
enthesitis). Other common sites for enthesitis include quadriceps
tendon insertion on the patella, patellar tendon insertion on tibia,
medial and lateral epicondyle, pelvic rim, spinous processes, and
intercostal muscle insertion on ribs. Tenosynovitis, or inflammation
of the tendon sheath, may affect tendons in the hands, wrists, and
around the ankles.
Most patients with PsA have psoriasis vulgaris. In ~80% of people
with PsA, psoriasis develops first, and the musculoskeletal mani­
festations develop after a variable duration. In ~10%, both arthritis
and psoriasis develop simultaneously. While patients with PsA have
psoriasis by definition, in 10% of patients, the arthritis develops first
and cutaneous psoriasis manifests a few years later. Diagnosis of PsA
is challenging in such patients, and family history of psoriasis, with
typical musculoskeletal involvement, can help make the diagnosis.
Although 40% of patients with psoriasis without PsA have nail lesions,
nail involvement is much more frequent in patients with PsA, affect­
ing close to 90% of patients. Psoriatic nail manifestations may be
classified into nail matrix disease and nail bed disease. Nail pitting,
leukonychia, crumbling, and red spots in the lunula are manifestations
of nail matrix disease, whereas onycholysis, subungual hyperkeratosis,
oil drop change, and splinter hemorrhages are manifestations of nail
bed disease.
PART 11
Immune-Mediated, Inflammatory, and Rheumatologic Disorders
Patients with PsA may also have involvement of the eye and gastro­
intestinal tract. Uveitis may occur in 5% of patients, and conjunctivitis
is rarely seen. While unilateral acute anterior uveitis is the commonest
form, posterior uveitis and bilateral eye involvement are also reported.
IBD (Crohn’s disease or rarely ulcerative colitis) may coexist in patients
with PsA. Mucous membrane inflammation presents with painful
mouth ulcers and rarely urethritis.
The disease course of PsA is variable. Whereas some patients
do well with few joints involved and no significant damage, others
progress very quickly to develop marked joint damage within a few
months. Patients with PsA have a worse quality of life and function
compared with the general population as well as to patients with
psoriasis without PsA.
Patients with psoriasis and PsA have an increased risk of cardiovas­
cular disease, as high as the risk in people with diabetes mellitus. The
increased risk is independent of cardiovascular risk factors and cor­
relates with more severe skin disease, disease duration, and increased
inflammatory markers. Patients with PsA have more severe subclinical
atherosclerosis compared with psoriasis patients without PsA. The
prevalence of hypertension, type 2 diabetes, obesity, metabolic syn­
drome, fatty liver disease, angina, and myocardial infarction is higher
among patients with PsA compared with the general population.
Obesity has an additional adverse impact on PsA disease activity and
treatment response. Patients with psoriasis and PsA have increased
rates of depression and suicidality compared to the general population.
The prevalence of malignancy in PsA is not increased, and mortality
studies have shown conflicting results.
■
■DIAGNOSIS
The diagnosis of PsA is based on clinical features of cutaneous psoriasis
with inflammatory musculoskeletal disease such as arthritis, dactylitis,
enthesitis, or spondylitis. Presence of dactylitis is an important sign,
and careful examination of feet is important since dactylitis of a single
toe or enthesitis around the heel may be the only musculoskeletal man­
ifestation of PsA in a patient with psoriasis. Psoriasis may be hidden in
areas such as the scalp, umbilicus, below breasts, or in the natal cleft,
or it may be present in the nail only and should be looked for carefully.
Typical involvement of the joints of the fingers or toes is in a “ray” dis­
tribution (involvement of all joints in a finger or toe), with one finger
showing dactylitis, another with bony ankylosis, and the neighboring
finger showing arthritis mutilans. The pattern of involvement in PsA is
often asymmetric compared with RA, in which the pattern tends to be
symmetric. The presence of spondylitis with asymmetric oligoarticular
peripheral arthritis would virtually rule out RA and would make the
diagnosis of PsA more likely. The diagnosis of PsA may sometimes
be made even in the absence of psoriasis if the above characteristic
features are present and if there is a family history of psoriasis or PsA.
Laboratory tests only play a minor role in the diagnosis of PsA.
Tests for acute-phase reactants such as ESR or CRP are abnormal in
~50% of patients despite clinically active disease. High levels of ESR or
CRP are markers of severe disease and are predictors of radiographic
damage and mortality. RF is typically negative, but low titer RF or
low titer anticyclic citrullinated peptide antibody may be positive in
<10% of patients. HLA-B27 is positive in 20% of all patients with PsA
and 50% of patients with axial PsA. A patient with PsA may present
with monoarticular arthritis of knee or ankle, and in this situation,
synovial fluid analysis will differentiate between infection (“septic
arthritis”), crystal-induced arthritis, OA, or immune-mediated inflam­
matory arthritis such as PsA. White blood cell counts of >2000/mL of
synovial fluid with no crystals and negative Gram stain and culture
are diagnostic of inflammatory arthritis and, in this clinical scenario,
should raise the suspicion of SpA such as PsA, reactive arthritis, or
IBD-associated arthritis. Routine laboratory tests such as complete
blood counts or kidney or liver function tests do not help in making
the diagnosis of PsA but can be useful for monitoring treatment or
assessing comorbidities.
■
■IMAGING FEATURES
Imaging is an important modality in the assessment of PsA and may
help in confirming the diagnosis and determining disease severity.
Radiographs of the hands, feet, pelvis, spine, and other affected joints
should be performed to look for changes suggestive of PsA. In early
disease, x-rays of the hands and feet show soft tissue swelling around
the involved joints. Periarticular osteopenia is generally absent. Mar­
ginal erosions are markers of disease severity and predict further radio­
graphic progression, deformity, and disability. In PsA, erosions are often
accompanied by “fluffy” new bone formation. The combination of ero­
sions at joint margins with new bone formation is characteristic of PsA
(Fig. 374-6). New bone formation may also cause ankylosis of the joints.
There also may be joint space narrowing, “pencil-in-cup” deformity, and
in late stages, such as arthritis mutilans, total joint destruction or joint
lysis and acro-osteolysis (resorption of the terminal phalanx) are seen.
Certain characteristic radiographic features such as “pencil-in-cup”
deformity, bony ankylosis in a ray distribution, or “fluffy” new bone
formation close to sites of erosions can be pathognomonic of PsA.
X-ray of the pelvis (anteroposterior view) may show changes of sac­
roiliitis. Sacroiliitis in PsA is more likely to be unilateral compared to
axSpA, where it is usually bilateral. Axial involvement in PsA may show
changes of shiny vertebral corners, erosions, squaring of vertebrae, and
syndesmophyte formation on the lateral view of the spine. While this
may mimic radiographic axSpA, often in PsA, the syndesmophytes
are chunky and “nonmarginal” and develop from sites away from the
vertebral corners (Fig. 374-7). The presence of such syndesmophytes
is characteristic of PsA. Cervical and lumbar vertebrae are frequently
involved. Rarely, atlantoaxial subluxation develops with potentially
serious consequences.
Ultrasound combined with Doppler evaluation can help in differ­
entiating enthesitis from fibromyalgia tender points or in differenti­
ating mechanical versus inflammatory etiology. Ultrasound can also
detect erosions before they appear on x-rays, especially in the hand
joints. Some of the findings in inflammatory enthesitis in PsA include
thickening of the tendon with loss of the regular fibrillar architecture,
hypoechoic lesion, and neovascularization around insertions of ten­
dons, ligaments, and joint capsules at the bone. Bony irregularities and
erosions would distinguish inflammatory from mechanical enthesitis.
Ultrasound, however, is highly operator dependent and is useful in
expert hands only, which remains a limitation. MRI with IV contrast
of the peripheral joints can detect synovitis, and MRI without contrast
in axial joints may show bone marrow edema (on the short tau inver­
sion recovery [STIR] image) suggestive of active inflammation before
any abnormality is visualized on x-rays. MRI can also show erosions in
the joints even before they are seen on plain x-rays. MRI is also very
useful in visualizing enthesitis. CT scans are useful when an MRI is
unavailable or contraindicated, although the risk of considerable radia­
tion exposure needs to be balanced with the benefits. Nuclear medicine
bone scans are neither specific nor sensitive to diagnose PsA. Use of
fluorodeoxyglucose positron emission tomography scans to assess
inflammatory burden in PsA is experimental.
■
■CLASSIFICATION CRITERIA
The Classification of Psoriatic Arthritis (CASPAR) criteria (Table 374-6)
have a specificity of 98.7% and sensitivity of 91.4%. To meet the CASPAR
criteria for PsA, individuals must first have inflammatory articular dis­
ease (joint, spine, or entheseal) and must have at least three points from
the five categories described in Table 374-6.
A
 
FIGURE 374-6  A. X-ray of the feet in psoriatic arthritis. These images show erosions, loss of cartilage in bilateral first metatarsophalangeal (MTP) joints, bilateral
interphalangeal joint of great toes, and right fifth MTP joint. There are changes of secondary osteoarthritis with sclerosis and osteophyte formation in these joints and early
pencil-in-cup deformity in the left fifth MTP joint. B. X-ray of the hands in psoriatic arthritis. Left thumb interphalangeal joint showing early pencil-in-cup deformity (marked
with **). Right third finger has dactylitis and shows periosteal new bone formation in the third proximal phalanx (white arrow), along with erosions in the proximal (marked
with *) and distal interphalangeal joints (marked with *). This combination of periosteal new bone formation and erosions in “ray” distribution is typical of psoriatic arthritis.
■
■DIFFERENTIAL DIAGNOSIS
OA, the most common form of arthritis, occurs in ~5% of the popu­
lation, and it may coexist with psoriasis especially in the DIP joints.
Thus, the presence of Heberden nodules in the context of patients
with hand OA with concomitant psoriasis is an important differential
diagnosis to be made. Psoriatic nail involvement would differentiate
PsA from inflammatory OA of the DIP joints, along with imaging
abnormalities such as on ultrasonography. Patients with “seronegative
RA” should be carefully examined for presence of psoriasis in hidden
areas (scalp, umbilicus, gluteal cleft, genitals, below breasts, and nails)
and questioned about family history of psoriasis. Many patients with
seronegative RA may have pSpA such as PsA, ReA, or IBD-associated
arthritis. The high skin turnover in psoriasis can lead to hyperuri­
cemia, and gout can coexist with PsA. Flare of monoarticular PsA
should be assessed with synovial fluid analysis to rule out gout or
septic arthritis. PsA shares several clinical, laboratory, and imaging
features with other SpA conditions such as ReA, IBD-associated
FIGURE 374-7  X-ray of the lumbar spine anteroposterior view in psoriatic arthritis. The
images show nonmarginal “chunky” syndesmophytes (marked with white arrows).
CHAPTER 374
Spondyloarthritis
B
arthritis, and axSpA, and patients may fulfill classification criteria
of multiple SpAs simultaneously. Calcium pyrophosphate deposition
disease (CPPD) arthritis affecting the MCP joints may coexist in
the elderly with skin psoriasis. Chondrocalcinosis of the triangular
fibrocartilage in the wrist, “hook-like” osteophytes in the MCP joints,
and absence of erosions or fluffy new bone formation should rule out
PsA. Synovitis, acne, pustulosis, SAPHO, and rarely hidradenitis sup­
purativa may mimic palmer plantar psoriasis and PsA.
■
■ASSESSING DISEASE ACTIVITY IN
PSORIATIC ARTHRITIS
Disease Activity in Psoriatic Arthritis (DAPSA) and Minimal Disease
Activity (MDA) are the most common instruments used to assess dis­
ease activity in clinical practice. A simple scale used to assess plaque
psoriasis is to ask the patient, “How many palms will be covered by
the current psoriasis on your body?” With one palm of the patient
counted as 1% body surface area (BSA), the total BSA involved by
active psoriasis can be assessed. Nail psoriasis and dactylitis can be
TABLE 374-6  Classification Criteria for Psoriatic Arthritis (CASPAR)
Patients with Inflammatory Articular Disease (Joint, Spine, or Entheseal)
Plus ≥3 Points Meet CASPAR Criteria for Psoriatic Arthritis
CATEGORY
DESCRIPTION
POINT VALUE
Psoriasisa
Current psoriasis as determined by a
rheumatologist or dermatologist
Personal history of psoriasis obtained from
patient or qualified health care provider
A family history of psoriasis as reported
by patient in a first- or second-degree
relative
Nail changes
Typical psoriatic nail dystrophy
(onycholysis, pitting, and hyperkeratosis)
present at assessment
Rheumatoid factor
Rheumatoid factor negative
Dactylitis (swelling
of entire digit)
Current dactylitis or history of dactylitis
recorded by a rheumatologist
Radiographic
evidence
Juxtaarticular new bone formation
(excluding osteophyte formation) on plain
radiograph of hand or foot; appears as illdefined ossification near joint margins
aPsoriasis should account for only one of the three descriptors.
Source: Adapted from WJ Taylor et al: Arthritis Rheum 54: 2665, 2006.
assessed by simply counting the digits with affected fingernails or with
dactylitis. A number of enthesitis indices have been developed, such as
the Spondyloarthritis Research Consortium of Canada Index and the
Leeds Enthesitis Index. Axial arthritis is assessed using tools borrowed
from axSpA assessment.
PART 11
Immune-Mediated, Inflammatory, and Rheumatologic Disorders
TREATMENT
Psoriatic Arthritis
The treatment target is remission or low disease activity. This
is achieved by nonpharmacologic and pharmacologic interven­
tions including novel advanced therapies. A multidisciplinary team
consisting of rheumatologists, physical and occupational thera­
pists, dermatologists, and depending upon the domains involved,
gastroenterologists, ophthalmologists, psychologists/psychiatrists,
dieticians, endocrinologists, and cardiologists may be needed to
manage common comorbidities. All pharmacologic interventions
need to be based on shared decision-making between the patient
and their provider.
The four main classes of pharmacotherapy used in the man­
agement of PsA include NSAIDs, conventional synthetic diseasemodifying antirheumatic drugs (csDMARDs), biologic DMARDs,
and tsDMARDs. Biologic and tsDMARDs have revolutionized
the management of PsA by effectively controlling signs and
symptoms, decreasing joint damage progression, and improving
health-related quality of life. Biologic DMARDs used in the man­
agement of PsA include TNFi (etanercept, adalimumab, inflix­
imab, certolizumab, or golimumab), antibodies against IL-12/23
(ustekinumab), IL-17A (secukinumab, ixekizumab), IL-17A and
IL-17F (bimekizumab), IL-23 (guselkumab, risankizumab), and
costimulatory blockade agent (abatacept). tsDMARDs include the
phosphodiesterase-4 (PDE4) inhibitor apremilast; JAKis such as
tofacitinib, baricitinib, and upadacitinib; and the tyrosine kinase
2 (TYK2) inhibitor deucravacitinib. The IL-17A and IL-17A+F
inhibitor nanobodies izokibep and sonelokimab are currently
undergoing clinical trials.
TREATMENT RECOMMENDATIONS
The ACR along with National Psoriasis Foundation (ACR-NPF),
EULAR, and Group for the Research and Assessment of Psoriasis
and Psoriatic Arthritis (GRAPPA) have published separate recom­
mendations for the pharmacologic management of PsA, though
there are many similarities. They all recommend that the treat­
ment should be tailored according to the disease activity assessed
by level of symptoms and clinical findings in peripheral joints,
skin, nails, axial skeleton, entheses, and presence of dactylitis.
Individual clinical features (age, gender, concomitant medica­
tions, and psychosocial factors), comorbidities (especially IBD,
uveitis, metabolic syndrome, and heart disease), prognostic indi­
cators, and patient preferences, values, and cultural background
need to be considered in this shared decision-making process.
Patients should be monitored at regular intervals and treatment
adjusted as appropriate. Treatment is generally continued indefi­
nitely for this lifelong disease since there is high risk of flare once
treatment is discontinued.
Principles and recommendations for PsA management from
these recommendations are summarized in Table 374-7.
For musculoskeletal manifestations of PsA, TNFi and IL-17i
have demonstrated comparable efficacy, whereas IL-17i, IL-12/23i,
and IL-23i have shown superior efficacy in clearing skin psoriasis
compared to TNFi in head-to-head studies. JAKis have comparable
efficacy to TNFis for musculoskeletal manifestations of PsA. All
biologics except abatacept, and JAKis have shown efficacy in reduc­
ing radiographic progression in PsA, but none of the csDMARDs,
PDE-4 inhibitors, or TYK2 inhibitors have shown this. While there
are no comparative studies on safety, IL-17i, IL-12/23i, IL-23i,
PDE-4 inhibitors, and TYK2 inhibitors are perceived to be safer
than TNFis in clinical practice.
REACTIVE ARTHRITIS
The interrelation between infection and arthritic disease has been
established for many decades. ReA refers to the development of arthri­
tis following urogenital or gastrointestinal infection involving welldefined triggering microorganisms that are normally not cultivable
from the joints affected. Prototypical inducers of reactive arthritis
include Yersinia, Campylobacter, Salmonella, Shigella, and Chlamydia.
■
■CLINICAL FEATURES
A crucial factor in the diagnosis relates to recognition of the clinical pic­
ture and the identification of causative organisms. A hallmark feature is
the time delay between initial infection and onset of arthritis: the interval
ranges between 1 day and 4 weeks after infection. Inflammatory mus­
culoskeletal disease (joint, spine, or entheseal) is essential for the diag­
nosis of ReA. The clinical spectrum may include a typical asymmetrical
oligoarticular arthritis preferentially involving lower limbs, enthesitis,
tendonitis, bursitis, dactylitis, inflammatory back pain, and sacroiliitis.
Mucocutaneous lesions may also occur in addition to the musculoskel­
etal manifestations and include uveitis/conjunctivitis, erythema nodo­
sum, oral ulcers, circinate balanitis, and keratoderma blenorrhagica.
ReA is strongly associated with the presence of HLA-B27, with up to
50–80% of all reactive arthritis patients carrying HLA-B27. Accordingly,
prevalence of ReA matches the prevalence of HLA-B27, which has a clear
North-South gradient; e.g., the highest prevalence of HLA-B27 is observed
in the Northern Hemisphere, which was reflected by historical large out­
breaks of ReA in, for example, Scandinavian regions. However, over the
past decades, there has been a steady decline in the number of such out­
breaks with improved hygiene and changes in microbiota. Recent updates
on incidence of reactive arthritis point to an overall incidence rate estimate
of 3.4 cases per 100,000 person-years. Overall, the estimated percentage of
cases to develop ReA following an enteric infection with Campylobacter,
Salmonella, Shigella, or Yersinia is estimated around 2.6%.
Expert consensus refers to ReA only if clinical picture and causative
microbes are HLA-B27 and SpA related. Hence many other infections
that trigger onset of arthritis fall outside of the SpA construct. These
“infection-related arthritides” constitute all forms of arthritis associated
with infections except septic arthritis. They include, among others, acute
rheumatic fever, meningococcus, Mycoplasma genitalium, Ureaplasma
urealyticum, Chlamydia pneumoniae, beta-hemolytic streptococci, and
some live vaccines and COVID. These should not be described as ReA
since the clinical pattern does not fit the SpA spectrum and is unrelated
to HLA-B27. Thus, the term ReA should be restricted to an acute SpA
that is linked to an acute genitourinary or gastrointestinal infection. The
other forms should be referred to as postinfectious arthritides and will
not be discussed further in this chapter.
■
■DIAGNOSIS
ReA is diagnosed based on clinical features and identification of an
antecedent infection from medical history and laboratory tests and
exclusion of other different diagnosis. While diagnostic procedures are
focused around HLA-B27 and molecular testing for Chlamydia tracho­
matis infection, additional individualized diagnostic tests must also be
considered to rule out other causes (e.g., postinfectious arthritides).
Laboratory tests such as stool cultures to test for Salmonella, Shigella,
Campylobacter, and Yersinia can sometimes confirm a preceding or
concomitant infection with a causative pathogen, but since gastrointes­
tinal symptoms often have resolved when rheumatic features develop,
pathogens may no longer be retrievable. Serology for enteric pathogens
is used primarily in epidemiologic studies to test for preceding infec­
tions, but there are some questions on its utility in daily clinical prac­
tice given the overall low yield of positive results. All patients should be
offered screening for Chlamydia.
TREATMENT
Reactive Arthritis
Treatment of ReA is oriented to management of SpA features, but
treatment guidelines for ReA do not exist currently. While antibiot­
ics are not used in the routine care of ReA, one study demonstrated
TABLE 374-7  Pharmacologic Management of Psoriatic Arthritis (PsA)
 PRINCIPLES AND RECOMMENDATIONS
  1.  The primary goal of treating patients with PsA is to maximize long-term health-related quality of life through control of symptoms, abrogation of inflammation,
prevention of structural damage, normalization of function, and social participation.
  2.  PsA requires multidisciplinary treatment (rheumatologist, dermatologist, psychiatrist, gastroenterologist, ophthalmologist, dietician, endocrinologist, cardiologist,
and physical/occupational therapists), and it should be based on a shared decision-making between the patient and the rheumatologist.
  3.  “Treat to target” is recommended, with the target being minimal disease activity or remission. Patients should be regularly monitored, and treatment should be
adjusted appropriately to reach the target.
  4.  NSAIDs may be used as an initial short-term treatment to relieve symptoms related to peripheral arthritis, enthesitis, dactylitis, and axial disease. NSAIDs alone are
very rarely sufficient to treat PsA but can be combined with cs-, b-, or tsDMARDs.
  5.  Local injections of glucocorticoids should be considered for active arthritis, enthesitis, and/or dactylitis. Glucocorticoid injections around lower extremity weightbearing entheses should be avoided due to the risk of tendon rupture.
  6.  Systemic glucocorticoids should be avoided. In rare circumstances such as acute flares of arthritis, they may be used with caution at the lowest effective dose for
the shortest period.
  7.  In patients with active disease with peripheral arthritis, enthesitis, and/or dactylitis, treatment with csDMARDs, such as methotrexate, sulfasalazine, or leflunomide,
should be considered at an early stage. Methotrexate is preferred if clinically relevant psoriasis is present.
  8.  PDE-4 inhibitor or TYK-2 inhibitor may be considered as the initial treatment instead of csDMARD for active musculoskeletal disease (except axial disease) or active
skin disease.
  9.  In patients with predominant axial disease, csDMARDs should be avoided, and either bDMARDs or JAKi should be considered after inadequate response to
NSAIDs.
10.  In rare circumstances, in patients with very active musculoskeletal disease (multiple swollen joints, structural damage in the presence of active inflammation, and/
or clinically relevant extraarticular manifestations such as IBD or uveitis) or extensive skin involvement, treatment with bDMARDs can be started before csDMARDs
at the discretion of the treating provider.
11.  The choice of initial biologic for active musculoskeletal disease (TNF, IL-12/23, IL-17, or IL-23 inhibitors) should be based on pros and cons of each therapy class,
patients’ comorbidities, and their comfort with risks/benefit.
12.  For patients with predominant skin disease along with musculoskeletal disease, IL-12/23, IL-17, or IL-23 inhibitors are preferred over TNF inhibitors.
13.  For PsA patients with comorbid IBD, monoclonal antibodies against TNF, IL-12/23 inhibitors, IL-23 inhibitors, or JAKi therapy is preferred. IL-17 inhibitors should be
avoided in patients with active IBD but can be used in patients with history of IBD.
14.  For PsA patients with comorbid uveitis, therapy with monoclonal antibodies against TNF is preferred.
15.  JAKi should be used after failure of TNF inhibitors according to the black-box warning issued by regulatory authorities based on their CV risk. Comorbidities of
metabolic syndrome and CV disease should be considered before JAKi treatment.
16.  Combination of methotrexate with bDMARDs such as TNF inhibitors has not been shown to improve efficacy compared to bDMARDs alone.
17.  Abatacept has no efficacy against the disease domains of skin, nail, and the axial skeleton. Its efficacy against peripheral arthritis is modest.
18.  Agents that effectively treat skin and nail involvement (but with minimal efficacy on the musculoskeletal domains) include topical glucocorticoids such as
clobetasol, retinoic acid derivatives, PUVA, and cyclosporin.
19.  Biosimilars may be used in place of the original biologics.
20.  Tapering of DMARDs in a PsA patient with long-term minimal disease activity or remission should be a shared decision. Stopping DMARD therapy is not
recommended.
Abbreviations: bDMARDs, biologic disease-modifying antirheumatic drugs; csDMARDs, conventional synthetic disease-modifying antirheumatic drugs; CV, cardiovascular;
IBD, inflammatory bowel disease; IL, interleukin; JAKi, Janus kinase inhibitor; NSAIDs, nonsteroidal anti-inflammatory drugs; PUVA, psoralene plus ultraviolet light A;
TNF, tumor necrosis factor; tsDMARDs, targeted synthetic disease-modifying antirheumatic drugs.
that a 6-month course of combination antibiotics (doxycycline or
azithromycin, combined with rifampicin) yielded higher response
rates then placebo in chronic Chlamydia-induced ReA. However,
these results have not been replicated, and the routine use of longterm antibiotics to treat chronic ReA is not recommended.
In acute ReA, management of joint symptoms include NSAIDs,
intraarticular glucocorticoids for monoarthritis or oligoarthritis,
and short-term low-dose systemic glucocorticoids for polyarticular
joint involvement. While ReA is thought to be self-limiting and
resolving in a large proportion of patients, ReA may also evolve into
a chronic phase. The presence of HLA-B27 has been linked to the
evolution into chronicity in part because HLA-B27 has been sug­
gested to promote intracellular survival of causative microorgan­
isms in infected macrophages, providing a roadmap to chronicity.
In chronic forms of ReA (e.g., lasting longer than 6 months and
with inadequate response to management outline in acute ReA),
DMARDs such as sulfasalazine and methotrexate and even TNFis
can be considered. Overall, the management of chronic forms of
ReA follows treatment principles of peripheral SpA.
IBD-ASSOCIATED ARTHRITIS
An intriguing relationship between bowel and joint inflammation has
emanated for >50 years that points to a prominent role of barrier integ­
rity loss and dysbiosis in SpA, initially recognized by uncovering the
CHAPTER 374
Spondyloarthritis
occurrence of arthritis in IBD patients. The link between gut and joint
inflammation, however, is reciprocal. Hence, patients with a diagnosis
of SpA but without associated gastrointestinal symptoms were also
found to display histologic signs of inflammation in ileocolonoscopic
studies, primarily in the terminal ileum. Here, two types of lesions
were described: an acute type of inflammation resembling an infectious
enterocolitis and a chronic type of inflammation with many features of
Crohn’s disease. Overall, the frequency of microscopic inflammatory
lesions mounts up to 50% of new-onset treatment-naïve SpA patients
and is associated with higher degrees of bone marrow edema in MRI
of sacroiliac joints. Furthermore, the presence of chronic lesions rep­
resents a risk factor for evolution into full-blown Crohn’s disease and
progression to AS. These microscopic lesions are accompanied by
elevated fecal calprotectin and CRP levels.
Both ulcerative colitis and Crohn’s disease are associated with SpA.
AxSpA as well as pSpA commonly occur in both of them, with pSpA
being the most prevalent form. R-axSpA develops in up to 10% of IBD
patients, whereas prevalence of pSpA varies largely according to vari­
ous studies, ranging from 10 to 30%.
Conversely, patients with axSpA have a substantially higher risk of
developing IBD, with a prevalence varying between 5 and 10% and
with an observed increase with disease duration. This reciprocal rela­
tionship between IBD and AS is reflected by a considerable overlap in
the genetic predisposition between these diseases, including polymor­
phisms in genes linked to type 3 immunity (e.g., IL-23R, IL-12p40,
RORc), innate immunity (TNFAIP3, TLR4), and epithelial integrity
(GPR35, PTGER4). However, HLA-B27 is not a risk factor for IBD.
■
■CLINICAL FEATURES
Axial skeletal involvement associated with IBD is clinically similar to
idiopathic axSpA. There may be, however, a disconnect in time in the
occurrence of both. Thus, axSpA may develop after diagnosis of IBD
but, in other cases, precedes onset of IBD. Peripheral involvement
in IBD resembles the clinical picture of peripheral SpA, which may
include more acute forms of oligoarthritis that co-occur with relapses
of IBD. More chronic forms of SpA may also occur that may cause
substantial structural damage if not appropriately treated. A rare sym­
metric polyarticular arthritis that runs an independent course has also
been described.
PART 11
Immune-Mediated, Inflammatory, and Rheumatologic Disorders
In addition to IBD patients with a firm diagnosis of SpA, a compara­
ble fraction of IBD patients have arthralgias or fibromyalgia symptoms.
■
■DIAGNOSIS
IBD-related arthritis is diagnosed based on clinical and imaging fea­
tures in patients with a history of IBD and follows the same diagnostic
principles as other forms of SpA. It is important to note, however, that
most patients with IBD-related arthritis are seen while being treated for
IBD. Thus, special caution should be taken in interpretation of imag­
ing in patients treated with biologics, immune suppressive drugs, and
glucocorticoids.
TREATMENT
IBD-Associated Arthritis
Management of IBD-related arthritis follows the general prin­
ciples of axSpA and pSpA treatment with some special consid­
erations, given the observed disconnect that may occur between
gut and joint symptoms with some targeted therapies. Within
the targeted therapies, the monoclonal antibodies, but not the
soluble receptor, blocking TNF-α are effective in IBD as well as
in both axial and peripheral SpA. Other biologics with efficacy
in IBD that may have proven efficacy in peripheral SpA include
ustekinumab (anti-IL12/23p40), guselkumab, and risankizumab
(anti-IL23p19), but anti-IL17 therapy is contraindicated. The JAKi
tofacitinib and upadacitinib are approved in ulcerative colitis and
upadacitinib in Crohn’s disease and are also effective in axSpA and
pSpA. Other treatments for IBD include sulfasalazine and related
drugs as well as systemic and local glucocorticoids. NSAIDs,
especially COX2-selective formulations, are helpful for arthritis
and generally well tolerated but may induce IBD flares, so they
should be considered only for temporary use. Vedolizumab is a
gut-selective integrin inhibitor approved for both Crohn’s disease
and ulcerative colitis. However, up to 15% of IBD patients treated
with vedolizumab may develop new-onset disease or flare of
axSpA or pSpA.
UNDIFFERENTIATED PERIPHERAL
SPONDYLOARTHRITIS
The term “undifferentiated pSpA” is used to describe patients who do
not fit into any of the above well-defined conditions such as axSpA,
PsA, ReA, or IBD-associated arthritis but have the typical SpA phe­
notype (oligoarticular inflammatory arthritis, usually involving lower
limbs, asymmetric, or peripheral enthesitis or dactylitis). The ASAS
group developed classification criteria for pSpA in 2011 (Table 374-8).
These criteria allow the classification of a patient with peripheral
enthesitis or dactylitis but without peripheral arthritis. The prevalence
and incidence of undifferentiated pSpA are not known since there are
no epidemiologic studies available. Some of these patients are likely to
have ReA, where the inciting infection is silent, and in some patients,
features of psoriasis and/or IBD may develop later. Treatment of pSpA
TABLE 374-8  Assessment of Spondyloarthritis International Society
(ASAS) Criteria for Peripheral Spondyloarthritis (SpA)
Arthritis or enthesitis or dactylitis
Plus ≥1 of:
Psoriasis
Inflammatory bowel disease
Preceding infection
HLA-B27
Uveitis
Sacroiliitis on imaging (radiographs
Plus ≥2 of the remaining:
Arthritis
Enthesitis
Dactylitis
IBP in the past
Positive family history for SpA
 
or MRI) 
Note: Peripheral arthritis: usually lower limb, asymmetric arthritis; enthesitis:
clinically assessed; dactylitis: clinically assessed.
Abbreviations: IBP, Inflammatory back pain; MRI, magnetic resonance imaging.
should be individualized based on the predominant musculoskeletal
manifestation.
SPONDYLOARTHRITIS ASSOCIATED WITH
SAPHO SYNDROME AND HIDRADENITIS
SUPPURATIVA
SAPHO is a clinical entity that is sometimes associated with Propioni­
bacterium acne infection on bone biopsies. It is included under SpA
since some patients have asymmetric inflammatory arthritis (typi­
cally sternoclavicular joints and chest wall costochondral junctions),
sacroiliitis, and spinal hyperostosis. The skin manifestations include
acne conglobate and palmoplantar pustular lesions that are patho­
logically identical to psoriasis. Some consider SAPHO as the adult
phenotype of juvenile chronic recurrent multifocal osteomyelitis
(CRMO), where the osteomyelitis is sterile. Apart from TNFi, IL-17i,
and JAKi, there are case reports of pamidronate, a bisphosphonate,
being effective in treatment. Hidradenitis suppurativa patients may
develop a SpA phenotype of musculoskeletal involvement, including
asymmetric sacroiliitis.
■
■FURTHER READING
Coates  L et al: Group for Research and Assessment of Psoriasis and
Psoriatic Arthritis (GRAPPA): Updated treatment recommendations
for psoriatic arthritis 2021. Nat Rev Rheumatol 18:465, 2022.
Danve A et al: Treatment of axial spondyloarthritis: An update. Nat
Rev Rheumatol 18:205, 2022.
Gracey  E et al. Revisiting the gut-joint axis: Links between gut inflam­
mation and spondyloarthritis. Nat Rev Rheumatol 16:415, 2020.
Gracey  E et al: Tendon and ligament mechanical loading in the
pathogenesis of inflammatory arthritis. Nat Rev Rheumatol 16:193,
Maksymowych  WP et al: Data-driven definitions for active and
structural MRI lesions in the sacroiliac joint in spondyloarthritis and
their predictive utility. Rheumatology (Oxford) 60:4778, 2021.
Moll  JM et al: Psoriatic arthritis. Semin Arthritis Rheum 3:55,
Rudwaleit  M et al: The development of assessment of SpondyloAr­
thritis International Society classification criteria for axial spondy­
loarthritis (part II): Validation and final selection. Ann Rheum Dis
68:777, 2009.
Schett  G et al: Reframing immune-mediated inflammatory diseases
through signature cytokine hubs. N Engl J Med 385:628, 2021.
van der Linden  S et al: Evaluation of diagnostic criteria for ankylos­
ing spondylitis: A proposal for modification of the New York criteria.
Arthritis Rheum 27:361, 1984.
Ward  MM et al: 2019 update of the American College of Rheumatology/
Spondylitis Association of America/Spondyloarthritis Research and
Treatment Network recommendations for the treatment of ankylosing
spondylitis and non-radiographic axial spondyloarthritis. Arthritis
Rheumatol 71:1519, 2019.

18 - 375 The Vasculitis Syndromes
375 The Vasculitis Syndromes
Carol A. Langford, Anthony S. Fauci
The Vasculitis
Syndromes
DEFINITION
Vasculitis is a clinicopathologic process characterized by inflammation
of and damage to blood vessels. The vessel lumen is usually compro­
mised, and this is associated with ischemia of the tissues supplied by
the involved vessel. A broad and heterogeneous group of syndromes
may result from this process, since any type, size, and location of blood
vessel may be involved. Vasculitis and its consequences may be the
primary or sole manifestation of a disease; alternatively, vasculitis
may be a secondary component of another disease. Vasculitis may be
confined to a single organ, such as the skin, or it may simultaneously
involve several organ systems.
CLASSIFICATION
The vasculitic syndromes as a group have a great deal of heterogeneity
while also possessing a considerable degree of overlap. Table 375-1 lists
the major vasculitis syndromes. The distinguishing and overlapping
features of these syndromes are discussed below.
PATHOPHYSIOLOGY AND PATHOGENESIS
Generally, most of the vasculitic syndromes are assumed to be medi­
ated at least in part by immunopathogenic mechanisms that occur in
response to certain antigenic stimuli. However, evidence supporting
this hypothesis is for the most part indirect and may reflect epiphe­
nomena as opposed to true causality. Furthermore, it is unknown
why some individuals might develop vasculitis in response to certain
antigenic stimuli, whereas others do not. It is likely that a number of
factors are involved in the ultimate expression of a vasculitic syndrome.
These include the genetic predisposition, environmental exposures,
and the regulatory mechanisms associated with immune response to
certain antigens. Although immune complex formation, antineutro­
phil cytoplasmic antibodies (ANCA), and pathogenic T lymphocyte
responses (Table 375-2) have been among the prominent hypothesized
mechanisms, the pathogenesis of individual forms of vasculitis remains
complex and varied.
TABLE 375-1  Vasculitis Syndromes
SECONDARY VASCULITIS
SYNDROMES
PRIMARY VASCULITIS SYNDROMES
Granulomatosis with polyangiitis
Microscopic polyangiitis
Eosinophilic granulomatosis with
polyangiitis (Churg-Strauss)
IgA vasculitis (Henoch-Schönlein)
Cryoglobulinemic vasculitis
Polyarteritis nodosa
Kawasaki disease
Giant cell arteritis
Takayasu arteritis
Behçet’s disease
Cogan’s syndrome
Single-organ vasculitis
  Cutaneous leukocytoclastic angiitis
  Cutaneous arteritis
  Primary central nervous system
Vasculitis associated with probable
etiology
  Drug-induced vasculitis
  Hepatitis C virus–associated
cryoglobulinemic vasculitis
  Hepatitis B virus–associated
vasculitis
  Cancer-associated vasculitis
Vasculitis associated with systemic
disease
  Lupus vasculitis
  Rheumatoid vasculitis
  Sarcoid vasculitis
  Others
vasculitis
  Isolated aortitis
Source: Adapted from JC Jennette et al: Arthritis Rheum 65:1, 2013.
TABLE 375-2  Potential Mechanisms of Vessel Damage in
Vasculitis Syndromes
Pathogenic immune-complex formation and/or deposition
  IgA vasculitis (Henoch-Schönlein)
  Lupus vasculitis
  Serum sickness and cutaneous vasculitis syndromes
  Hepatitis C virus–associated cryoglobulinemic vasculitis
  Hepatitis B virus–associated vasculitis
Production of antineutrophilic cytoplasmic antibodies
  Granulomatosis with polyangiitis
  Microscopic polyangiitis
  Eosinophilic granulomatosis with polyangiitis (Churg-Strauss)
Pathogenic T lymphocyte responses and granuloma formation
  Giant cell arteritis
  Takayasu arteritis
  Granulomatosis with polyangiitis
  Eosinophilic granulomatosis with polyangiitis (Churg-Strauss)
CHAPTER 375
The Vasculitis Syndromes
Source: Reproduced with permission from MC Sneller, AS Fauci: Pathogenesis of
vasculitis syndromes. Med Clin North Am 81:221, 1997.
■
■PATHOGENIC IMMUNE-COMPLEX FORMATION
Deposition of immune complexes was the first and most widely
accepted pathogenic mechanism of vasculitis. However, the causal role
of immune complexes has not been clearly established in most of the
vasculitic syndromes. Circulating immune complexes need not result
in deposition of the complexes in blood vessels with ensuing vasculitis,
and many patients with active vasculitis do not have demonstrable
circulating or deposited immune complexes. The actual antigen con­
tained in the immune complex has only rarely been identified in vascu­
litic syndromes. In this regard, hepatitis B antigen has been identified
in both the circulating and deposited immune complexes in a subset
of patients who have features of a systemic vasculitis clinically similar
to polyarteritis nodosa (see “Polyarteritis Nodosa”). Cryoglobulinemic
vasculitis is strongly associated with hepatitis C virus infection; hepa­
titis C virions and hepatitis C virus antigen-antibody complexes have
been identified in the cryoprecipitates of these patients (see “Cryo­
globulinemic Vasculitis”).
The mechanisms of tissue damage in immune complex–mediated
vasculitis resemble those described for serum sickness. In this model,
antigen-antibody complexes are formed in antigen excess and are
deposited in vessel walls whose permeability has been increased by
vasoactive amines such as histamine, bradykinin, and leukotrienes
released from platelets or from mast cells as a result of IgE-triggered
mechanisms. The deposition of complexes results in activation of com­
plement components, particularly C5a, which is strongly chemotactic
for neutrophils. These cells then infiltrate the vessel wall, phagocytose
the immune complexes, and release their intracytoplasmic enzymes,
which damage the vessel wall. As the process becomes subacute or
chronic, mononuclear cells infiltrate the vessel wall resulting in com­
promise of the vessel lumen with ischemic changes in the tissues sup­
plied by the involved vessel. Several variables may explain why only
certain types of immune complexes cause vasculitis and why only cer­
tain vessels are affected in individual patients. These include the ability
of the reticuloendothelial system to clear circulating complexes from
the blood, the size and physicochemical properties of immune com­
plexes, the relative degree of turbulence of blood flow, the intravascular
hydrostatic pressure in different vessels, and the preexisting integrity of
the vessel endothelium.
■
■ANTINEUTROPHIL CYTOPLASMIC ANTIBODIES
ANCA are antibodies directed against certain proteins in the
cytoplasmic granules of neutrophils and monocytes. These auto­
antibodies are present in a high percentage of patients with active
granulomatosis with polyangiitis and microscopic polyangiitis and
in a lower percentage of patients with eosinophilic granulomatosis
with polyangiitis. Because these diseases share the presence of ANCA
and small-vessel vasculitis, they have been grouped collectively as
“ANCA-associated vasculitis.” However, since these diseases possess
unique clinical phenotypes, they should continue to be viewed as
separate entities.
There are two major categories of ANCA based on different targets
for the antibodies. The terminology of cytoplasmic ANCA (cANCA)
refers to the diffuse, granular cytoplasmic staining pattern observed
by immunofluorescence microscopy when serum antibodies bind to
indicator neutrophils. Proteinase-3, a 29-kDa neutral serine protein­
ase present in neutrophil azurophilic granules, is the major cANCA
antigen. More than 90% of patients with active granulomatosis with
polyangiitis have detectable antibodies to proteinase-3 (see below).
The terminology of perinuclear ANCA (pANCA) refers to the more
localized perinuclear or nuclear staining pattern of the indicator neu­
trophils. The major target for pANCA is the enzyme myeloperoxidase;
other targets that can produce a pANCA pattern include elastase,
cathepsin G, lactoferrin, lysozyme, and bactericidal/permeabilityincreasing protein. However, only antibodies to myeloperoxidase have
been convincingly associated with vasculitis. Antimyeloperoxidase
antibodies have been reported in a variable percentage of patients with
microscopic polyangiitis, eosinophilic granulomatosis with polyangi­
itis, isolated necrotizing crescentic glomerulonephritis, and granulo­
matosis with polyangiitis (see below). A pANCA pattern that is not
due to antimyeloperoxidase antibodies has been associated with non­
vasculitic entities such as rheumatic and nonrheumatic autoimmune
diseases, inflammatory bowel disease, certain drugs, and infections
such as endocarditis and bacterial airway infections in patients with
cystic fibrosis.
PART 11
Immune-Mediated, Inflammatory, and Rheumatologic Disorders
It is unclear why patients with these vasculitis syndromes develop
antibodies to myeloperoxidase or proteinase-3 or what role these
antibodies play in disease pathogenesis. There are a number of in vitro
observations that suggest possible mechanisms whereby these antibod­
ies can contribute to the pathogenesis of the vasculitis syndromes.
Proteinase-3 and myeloperoxidase reside in the azurophilic granules
and lysosomes of resting neutrophils and monocytes, where they are
apparently inaccessible to serum antibodies. However, when neutro­
phils or monocytes are primed by tumor necrosis factor α (TNF-α)
or interleukin 1 (IL-1), or activation of the alternative complement
cascade, proteinase-3 and myeloperoxidase translocate to the cell
membrane, where they can interact with extracellular ANCA. The neu­
trophils then degranulate and produce reactive oxygen species that can
cause tissue damage. Furthermore, ANCA-activated neutrophils can
adhere to and kill endothelial cells in vitro. Activation of neutrophils
and monocytes by ANCA also induces the release of proinflamma­
tory cytokines such as IL-1 and IL-8. Adoptive transfer experiments
in genetically engineered mice provide further evidence for a direct
pathogenic role of ANCA in vivo. In contradiction, however, a number
of clinical and laboratory observations argue against a primary patho­
genic role for ANCA. Patients may have active granulomatosis with
polyangiitis in the absence of ANCA; the absolute height of the anti­
body titers does not correlate well with disease activity; and patients
with granulomatosis with polyangiitis in remission may continue to
have high ANCA levels for years (see below).
■
■PATHOGENIC T LYMPHOCYTE RESPONSES
AND GRANULOMA FORMATION
The histopathologic feature of granulomatous vasculitis has provided
evidence to support a role of pathogenic T lymphocyte responses and
cell-mediated immune injury. Vascular endothelial cells can express
human leukocyte antigen (HLA) class II molecules following activa­
tion by cytokines such as interferon (IFN) γ. This allows these cells to
participate in immunologic reactions such as interaction with CD4+ T
lymphocytes in a manner similar to antigen-presenting macrophages.
Endothelial cells can secrete IL-1, which may activate T lymphocytes
and initiate or propagate in situ immunologic processes within the
blood vessel. In addition, IL-1 and TNF-α are potent inducers of
endothelial-leukocyte adhesion molecule 1 (ELAM-1) and vascular cell
adhesion molecule 1 (VCAM-1), which may enhance the adhesion of
leukocytes to endothelial cells in the blood vessel wall.
APPROACH TO THE PATIENT
General Principles of Diagnosis
The diagnosis of vasculitis should be considered in any patient
with an unexplained systemic illness. However, there are certain
clinical features that should suggest a diagnosis of vasculitis. These
include palpable purpura, pulmonary infiltrates and microscopic
hematuria, chronic sinusitis, mononeuritis multiplex, unexplained
ischemic events, and glomerulonephritis with evidence of multi­
system disease. As a number of nonvasculitic diseases may also
produce these abnormalities, the first step in the workup of a
patient with suspected vasculitis is to exclude other diseases that
can mimic vasculitis (Table 375-3). It is particularly important
to exclude infectious diseases with features that overlap those of
vasculitis, especially if the patient’s clinical condition is deteriorat­
ing rapidly and empirical immunosuppressive treatment is being
contemplated.
Once diseases that mimic vasculitis have been excluded, the
workup should follow a series of progressive steps that establish the
diagnosis of vasculitis and determine, where possible, the category
of the vasculitis syndrome (Fig. 375-1). This approach is of consid­
erable importance since several of the vasculitis syndromes require
aggressive therapy with glucocorticoids and other immunosuppres­
sive agents, whereas other syndromes usually resolve spontaneously
and require symptomatic treatment only. The definitive diagnosis
of vasculitis is usually made based on biopsy of involved tissue.
The yield of “blind” biopsies of organs with no subjective or objec­
tive evidence of involvement is very low and should be avoided.
TABLE 375-3  Conditions That Can Mimic Vasculitis
Infectious Diseases
  Bacterial endocarditis
  Disseminated gonococcal infection
  Pulmonary histoplasmosis
  Coccidioidomycosis
  Syphilis
  Lyme disease
  Rocky Mountain spotted fever
  Whipple’s disease
Coagulopathies/Thrombotic Microangiopathies
  Antiphospholipid syndrome
  Thrombotic thrombocytopenic purpura
Neoplasms
  Atrial myxoma
  Lymphoma
  Carcinomatosis
Drug Toxicity
  Cocaine
  Levamisole
  Amphetamines
  Ergot alkaloids
  Methysergide
  Arsenic
Other
  Sarcoidosis
  Atheroembolic disease
  Antiglomerular basement membrane disease (Goodpasture’s syndrome)
  Amyloidosis
  Migraine
  Fibromuscular dysplasia
  Heritable disorders of connective tissue
  Segmental arterial mediolysis (SAM)
  Reversible cerebral vasoconstrictive syndrome
Presentation of patient
with suspected vasculitis
Clinical findings
Biopsy
Establish diagnosis
Angiogram where
appropriate
Laboratory workup
Properly categorize to a
specific vasculitis syndrome
Determine pattern and
extent of disease
Look for
offending antigen
Look for
underlying disease
Characteristic
syndrome (i.e.,
granulomatosis
with polyangiitis
PAN, Takayasu
arteritis)
Yes
No
Yes
No
Treat underlying
disease
Remove antigen
Syndrome
resolves
Treat vasculitis
Yes
No
No further action
Treat vasculitis
FIGURE 375-1  Algorithm for the approach to a patient with suspected diagnosis of
vasculitis. PAN, polyarteritis nodosa.
When syndromes such as polyarteritis nodosa, Takayasu arteri­
tis, or primary central nervous system (CNS) vasculitis are sus­
pected, arteriogram of organs with suspected involvement should
be performed.
GENERAL PRINCIPLES OF TREATMENT
Once a diagnosis of vasculitis has been established, a decision
regarding therapeutic strategy must be made (Fig. 375-1). If an
offending antigen that precipitates the vasculitis is recognized,
the antigen should be removed where possible. If the vasculitis is
associated with an underlying disease such as an infection, neo­
plasm, or connective tissue disease, the underlying disease should
be treated. If the syndrome represents a primary vasculitic disease,
treatment should be initiated according to the category of the
vasculitis syndrome. Specific therapeutic regimens are discussed
below for the individual vasculitis syndromes; however, certain
general principles regarding therapy should be considered. Deci­
sions regarding treatment should be based on the use of regimens
for which there has been published literature supporting efficacy
for that particular vasculitic disease. Since the potential toxic side
effects of certain therapeutic regimens may be substantial, the riskversus-benefit ratio of any therapeutic approach should be weighed
carefully. Glucocorticoids and/or other immunosuppressive agents
should be instituted immediately in diseases where irreversible
organ system dysfunction and high morbidity and mortality rates
have been clearly established. Granulomatosis with polyangiitis
is the prototype of a severe systemic vasculitis requiring such a
therapeutic approach (see below). Conversely, aggressive therapy
should be avoided for vasculitic manifestations that rarely result in
irreversible organ system dysfunction such as isolated idiopathic
cutaneous vasculitis. Glucocorticoids should be initiated in those
systemic vasculitides that cannot be specifically categorized or for
which there is no established standard therapy, with other immu­
nosuppressive agents being added if an adequate response does not
result or if remission can only be achieved and maintained with an
unacceptably toxic regimen of glucocorticoids. Following improve­
ment, one should continually attempt to taper glucocorticoids and
discontinue when possible. When using other immunosuppressive
regimens, one should base the choice of agent upon the available
therapeutic data supporting efficacy in that disease, the site and
severity of organ involvement, and the toxicity profile of the drug.
CHAPTER 375
Most forms of vasculitis carry the potential for relapse such that
treatment planning needs to include assessment of relapse risk for
that vasculitis and the medication regimen being used.
Physicians should be thoroughly aware of the acute and longterm side effects associated with the agents that are commonly used
to treat different forms of vasculitis (Table 375-4).
The Vasculitis Syndromes
Morbidity and mortality can occur as a result of treatment, and
strategies to monitor for and prevent toxicity represent an essential
part of patient care.
Addressing the risk of bone loss is important in all patients
receiving glucocorticoids. Daily cyclophosphamide should be taken
all at once in the morning with a large amount of fluid throughout
the day to reduce the risk of bladder injury, and monitoring for
bladder cancer should continue indefinitely.
Maintaining the white blood cell (WBC) count at >3000/μL and
the neutrophil count at >1500/μL is essential to reduce the risk
of life-threatening infections. Monitoring of the complete blood
count every 1–2 weeks for as long as the patient receives cyclo­
phosphamide can effectively prevent cytopenias. Methotrexate,
azathioprine, and mycophenolate mofetil are also associated with
bone marrow suppression, and complete blood counts should be
obtained every 1–2 weeks for the first 1–2 months after their initia­
tion and once a month thereafter. To lessen toxicity, methotrexate
is often given together with folic acid, 1 mg daily, or folinic acid,
5–10 mg once a week 24 h following methotrexate. Methotrexate is
eliminated by the kidney and contraindicated in renal insufficiency
as this increases the risk for toxicity. Prior to initiation of azathio­
prine, thiopurine methyltransferase (TPMT), an enzyme involved
in the metabolism of azathioprine, should be assayed because inad­
equate levels may result in severe cytopenia.
Rituximab can be associated with infusion reactions. In addition
to administering this within a skilled infusion center, these reac­
tions can be lessened by the use of premedications. There is a risk of
hepatitis B reactivation with rituximab such that all patients should
be screened for this infection prior to its use. Immunoglobulins
should be monitored with rituximab use.
Tocilizumab and sarilumab are associated with cytopenias, hepa­
totoxicity, and hyperlipidemia. Laboratory monitoring for drug
toxicity should be performed 4–8 weeks after start of therapy and
every 3 months thereafter.
Infection represents a significant toxicity for all vasculitis patients
treated with immunosuppressive therapy. Infections with Pneumo­
cystis jirovecii and certain fungi can be seen even when the WBC
count is within normal limits, particularly in patients receiving
glucocorticoids. Use of prophylactic therapy to prevent P. jirovecii
infection should be based on the treatment regimen being used.
Patients with granulomatosis with polyangiitis or microscopic poly­
angiitis who are receiving induction treatment with glucocorticoids
in combination with another immunosuppressive agent should
receive trimethoprim-sulfamethoxazole (TMP-SMX) or a different
preventive medication. Continuation of Pneumocystis prophylaxis
during maintenance therapy should be strongly considered in most
patients, particularly for those receiving rituximab or who have
persistent lymphopenia.
In recent years, national and regional organizations have pub­
lished treatment guidelines that can provide additional direction to
clinicians. It should be emphasized that each patient is unique and
requires individual decision-making. Information from guidelines
as well as this chapter should serve as a framework for the applica­
tion of evidence-based approaches with incorporation of patientspecific goals to provide maximal therapeutic efficacy with minimal
toxic side effects.
TABLE 375-4  Major Toxic Side Effects of Drugs Used in the
Treatment of Vasculitisa
CONVENTIONAL IMMUNOSUPPRESSIVE AGENTS
Glucocorticoids
Osteoporosis
Cataracts
Glaucoma
Diabetes mellitus
Electrolyte abnormalities
Metabolic abnormalities
Severe and opportunistic infections
Cushingoid features
Growth suppression in children
Hypertension
Avascular necrosis of bone
Myopathy
Alterations in mood
Psychosis
Pseudotumor cerebri
Peptic ulcer diathesis
Pancreatitis
PART 11
Immune-Mediated, Inflammatory, and Rheumatologic Disorders
Cyclophosphamide
Bone marrow suppression
Cystitis
Bladder carcinoma
Gonadal suppression
Gastrointestinal intolerance
Hypogammaglobulinemia
Pulmonary fibrosis
Myelodysplasia
Oncogenesis
Teratogenicity
Severe and opportunistic infections
Methotrexate
Gastrointestinal intolerance
Stomatitis
Bone marrow suppression
Hepatotoxicity (may lead to fibrosis or
cirrhosis)
Pneumonitis
Teratogenicity
Severe and opportunistic infections
Azathioprine
Gastrointestinal intolerance
Bone marrow suppression
Hepatotoxicity
Severe and opportunistic infections
Hypersensitivity
Mycophenolate mofetil
Bone marrow suppression
Gastrointestinal intolerance
Severe and opportunistic infections
Teratogenicity
BIOLOGIC AGENTS AND SMALL-MOLECULE INHIBITORS
Rituximab (granulomatosis with polyangiitis and microscopic
polyangiitis)
Infusion reactions
Progressive multifocal
leukoencephalopathy
Mucocutaneous reactions
Hypogammaglobulinemia
Impaired vaccine response
Severe and opportunistic infections
Hepatitis B reactivation
Tumor lysis syndrome
Late-onset neutropenia
Tocilizumab (giant cell arteritis)
Sarilumab (polymyalgia rheumatica)
Bone marrow suppression
Hepatotoxicity
Hyperlipidemia
Severe and opportunistic infections
Gastrointestinal perforation
Hypersensitivity reactions
Mepolizumab (eosinophilic granulomatosis with polyangiitis
[Churg-Strauss])
Hypersensitivity reactions
Opportunistic infections: herpes zoster
Apremilast (Behçet’s syndrome; see Chap. 376)
Diarrhea, nausea, and vomiting
Depression
Weight decrease
Avacopan (severe granulomatosis with polyangiitis and microscopic
polyangiitis)
Hepatotoxicity
Hypersensitivity reactions
Hepatitis B reactivation
Serious infections
aConsult the drug package insert for a full listing of side effects.
FIGURE 375-2  Lung histology in granulomatosis with polyangiitis. This area
of geographic necrosis has a serpiginous border of histiocytes and giant cells
surrounding a central necrotic zone. Vasculitis is also present with neutrophils
and lymphocytes infiltrating the wall of a small arteriole (upper right). (Courtesy of
William D. Travis, MD; with permission.)
GRANULOMATOSIS WITH POLYANGIITIS
■
■DEFINITION
Granulomatosis with polyangiitis is a distinct clinicopathologic entity
characterized by granulomatous vasculitis of the upper and lower
respiratory tracts together with glomerulonephritis. In addition, vari­
able degrees of disseminated vasculitis involving both small arteries
and veins may occur.
■
■INCIDENCE AND PREVALENCE
Granulomatosis with polyangiitis has an estimated prevalence of 3
per 100,000. It is extremely rare in blacks compared with whites; the
male-to-female ratio is 1:1. The disease can be seen at any age; ~15%
of patients are <19 years of age, but only rarely does the disease occur
before adolescence; the mean age of onset is 40–60 years.
■
■PATHOLOGY AND PATHOGENESIS
The histopathologic hallmarks of granulomatosis with polyangiitis are
necrotizing vasculitis of small arteries and veins together with granu­
loma formation, which may be either intravascular or extravascular
(Fig. 375-2). Lung involvement typically appears as multiple, bilateral,
nodular or cavitary infiltrates (Fig. 375-3), which on biopsy can reveal
necrotizing granulomatous vasculitis. Upper airway lesions, particu­
larly those in the sinuses and nasopharynx, typically reveal inflamma­
tion, necrosis, and granuloma formation, with or without vasculitis.
In its earliest form, renal involvement is characterized by a focal and
segmental glomerulitis that may evolve into a rapidly progressive cres­
centic glomerulonephritis. Granuloma formation is only rarely seen on
FIGURE 375-3  Computed tomography scan of a patient with granulomatosis with
polyangiitis. The patient developed multiple, bilateral, and cavitary infiltrates.
renal biopsy. In contrast to other forms of glomerulonephritis, immune
complex deposition is not found in the renal lesion of granulomatosis
with polyangiitis (pauci-immune glomerulonephritis). In addition to
the classic triad of disease of the upper and lower respiratory tracts and
kidney, virtually any organ can be involved with vasculitis, granuloma,
or both.
The immunopathogenesis of this disease is unclear, although the
involvement of upper airways and lungs with granulomatous vasculitis
suggests an aberrant cell-mediated immune response to an exogenous
or even endogenous antigen that enters through or resides in the
upper airway. Chronic nasal carriage of Staphylococcus aureus has been
reported to be associated with a higher relapse rate of granulomatosis
with polyangiitis; however, there is no evidence for a role of this organ­
ism in the pathogenesis of the disease.
Peripheral blood mononuclear cells obtained from patients with
granulomatosis with polyangiitis manifest increased secretion of
IFN-γ but not of IL-4, IL-5, or IL-10 compared to healthy controls.
In addition, TNF-α production from peripheral blood mononuclear
cells and CD4+ T cells is elevated and monocytes from patients with
granulomatosis with polyangiitis produce increased amounts of IL-12.
These findings indicate an unbalanced TH1-type T-cell cytokine pat­
tern in this disease that may have pathogenic and perhaps therapeutic
implications.
A high percentage of patients with granulomatosis with polyangiitis
develop ANCA, and these autoantibodies may play a role in the patho­
genesis of this disease (see above).
■
■CLINICAL AND LABORATORY MANIFESTATIONS
Involvement of the upper airways occurs in 95% of patients with gran­
ulomatosis with polyangiitis. Patients often present with severe upper
respiratory tract findings such as paranasal sinus pain and drainage
and purulent or bloody nasal discharge, with or without nasal mucosal
ulceration (Table 375-5). Nasal septal perforation may follow, leading
to saddle nose deformity. Serous otitis media may occur as a result
of eustachian tube blockage. Subglottic stenosis resulting from active
disease or scarring occurs in ~16% of patients and may result in severe
airway obstruction.
Pulmonary involvement (85–90% of patients) may be clinically
expressed as cough, hemoptysis, dyspnea, and chest discomfort, or
active disease may be asymptomatic in up to 30% of cases. Endobron­
chial disease, either in its active form or as a result of fibrous scarring,
may lead to obstruction with atelectasis.
Eye involvement (52% of patients) may range from a mild conjunc­
tivitis to dacryocystitis, episcleritis, scleritis, granulomatous sclerou­
veitis, ciliary vessel vasculitis, and retroorbital mass lesions leading to
proptosis.
Skin lesions (46% of patients) appear as papules, vesicles, palpable
purpura, ulcers, or subcutaneous nodules; biopsy reveals vasculitis,
granuloma, or both. Cardiac involvement (8% of patients) mani­
fests as pericarditis, coronary vasculitis, or, rarely, cardiomyopathy.
Nervous system manifestations (23% of patients) include cranial
neuritis, mononeuritis multiplex, or, rarely, cerebral vasculitis and/
or granuloma.
Renal disease (77% of patients) generally dominates the clinical pic­
ture and, if left untreated, accounts directly or indirectly for most of the
mortality in this disease. Although it may smolder in some cases as a
mild glomerulitis with proteinuria, hematuria, and red blood cell casts,
once clinically detectable renal functional impairment occurs, rapidly
progressive renal failure usually ensues unless appropriate treatment
is instituted.
While the disease is active, most patients have nonspecific symp­
toms and signs such as malaise, weakness, arthralgias, anorexia, and
weight loss. Fever may indicate activity of the underlying disease but
more often reflects secondary infection, usually of the upper airway.
Characteristic laboratory findings include an elevated erythrocyte
sedimentation rate (ESR) and/or C-reactive protein (CRP), anemia
and leukocytosis, and mild hypergammaglobulinemia. Thrombocy­
tosis may be seen as an acute-phase reactant. Approximately 90% of
patients with active granulomatosis with polyangiitis have a positive
TABLE 375-5  Granulomatosis with Polyangiitis: Frequency of
Clinical Manifestations in 158 Patients Studied at the National
Institutes of Health
PERCENTAGE
THROUGHOUT COURSE
OF DISEASE
CHAPTER 375
PERCENTAGE AT
DISEASE ONSET
MANIFESTATION
Kidney
Glomerulonephritis
Ear/Nose/Throat
The Vasculitis Syndromes
Sinusitis
Nasal disease
Otitis media
Hearing loss
Subglottic stenosis
Ear pain
Oral lesions
Lung
Pulmonary infiltrates
Pulmonary nodules
Hemoptysis
Pleuritis
Eyes
Conjunctivitis
Dacryocystitis
Scleritis
Proptosis
Eye pain
Visual loss
Retinal lesions
Corneal lesions
Iritis
Othera
Arthralgias/arthritis
Fever
Cough
Skin abnormalities
Weight loss (>10% body weight)
Peripheral neuropathy
Central nervous system disease
Pericarditis
Hyperthyroidism
aFewer than 1% had parotid, pulmonary artery, breast, or lower genitourinary
(urethra, cervix, vagina, testicular) involvement.
Source: GS Hoffman et al: Ann Intern Med 116:488, 1992.
antiproteinase-3 ANCA. However, in the absence of active disease,
the sensitivity drops to ~60–70%. A small percentage of patients with
granulomatosis with polyangiitis may have antimyeloperoxidase rather
than antiproteinase-3 antibodies, and up to 20% may lack ANCA.
Patients with granulomatosis with polyangiitis have been found to
have an increased incidence of venous thrombotic events. Although
routine anticoagulation for all patients is not recommended, a height­
ened awareness for any clinical features suggestive of deep-vein throm­
bosis or pulmonary emboli is warranted.
■
■DIAGNOSIS
The diagnosis of granulomatosis with polyangiitis can be established
by the demonstration of necrotizing granulomatous vasculitis on tis­
sue biopsy in a patient with compatible clinical features. Pulmonary
tissue offers the highest diagnostic yield, almost invariably revealing
granulomatous vasculitis. Biopsy of upper airway tissue usually reveals
acute and chronic inflammation but can show granulomas and/or vas­
culitis. Renal biopsy can confirm a pauci-immune glomerulonephritis
(Chaps. A4 and A14), which differentiates this from other causes of
glomerular disease (Chap. 326).
The utility of ANCA in diagnosis varies based on the clinical pre­
sentation. The predictive value of a positive ANCA is 90% in patients
with active glomerulonephritis. However, in patients who present with
sinus and/or lung disease where renal disease is absent, this decreases
to 30–60%. Tissue biopsy is typically necessary in these settings to rule
out infection or malignancy, which can have a similar presentation and
be associated with a false-positive ANCA. Biopsy should also be pur­
sued when clinically inconsistent features are present or when ANCA
is absent.
PART 11
Immune-Mediated, Inflammatory, and Rheumatologic Disorders
In its typical presentation, the clinicopathologic complex of granu­
lomatosis with polyangiitis usually provides ready differentiation from
other disorders. However, if all the typical features are not present at
once, it needs to be differentiated from the other vasculitides, anti­
glomerular basement membrane disease (Goodpasture’s syndrome)
(Chap. 326), relapsing polychondritis (Chap. 378), tumors of the
upper airway or lung, and infectious diseases such as histoplasmosis
(Chap. 218), endocarditis (Chap. 133), mucocutaneous leishmaniasis
(Chap. 233), and rhinoscleroma (Chap. 166) as well as noninfectious
granulomatous diseases.
Of particular note is the differentiation from other midline destruc­
tive diseases. These diseases lead to extreme tissue destruction and
mutilation localized to the midline upper airway structures including
the sinuses; erosion through the skin of the face commonly occurs,
a feature that is extremely rare in granulomatosis with polyangiitis.
Although blood vessels may be involved in the intense inflammatory
reaction and necrosis, primary vasculitis is not seen. Upper airway neo­
plasms and specifically extranodal natural killer (NK)/T-cell lymphoma
(nasal type) are important causes of midline destructive disease. These
lesions are diagnosed based on histology, which reveals polymorphous
atypical lymphoid cells with an NK cell immunophenotype, typi­
cally Epstein-Barr virus (Chap. 199). Such cases are treated based on
their degree of dissemination, and localized lesions have responded
to irradiation. Upper airway lesions should never be irradiated in
granulomatosis with polyangiitis. Cocaine-induced tissue injury can
be another important mimic of granulomatosis with polyangiitis in
patients who present with isolated midline destructive disease. ANCA
that target human neutrophil elastase can be found in patients with
cocaine-induced midline destructive lesions and can complicate the
differentiation from granulomatosis with polyangiitis. This has been
further confounded by the high frequency of levamisole adulteration of
cocaine, which can result in cutaneous infarction and serologic changes
that may mimic vasculitis. Granulocytopenia is a common finding in
levamisole-induced disease that is not associated with granulomatosis
with polyangiitis.
Granulomatosis with polyangiitis must also be differentiated from
lymphomatoid granulomatosis, which is an Epstein-Barr virus–positive
B-cell proliferation that is associated with an exuberant T-cell reaction.
Lymphomatoid granulomatosis is characterized by lung, skin, CNS,
and kidney involvement in which atypical lymphocytoid and plasma­
cytoid cells infiltrate nonlymphoid tissue in an angioinvasive manner.
In this regard, it clearly differs from granulomatosis with polyangiitis
in that it is not an inflammatory vasculitis in the classic sense but an
angiocentric perivascular infiltration of atypical mononuclear cells. Up
to 50% of patients may develop a true malignant lymphoma.
TREATMENT
Granulomatosis with Polyangiitis
Prior to the introduction of effective therapy, granulomatosis with
polyangiitis was universally fatal within a few months of diagnosis.
Glucocorticoids alone led to some symptomatic improvement,
with little effect on the ultimate course of the disease. The develop­
ment of treatment with cyclophosphamide dramatically changed
patient outcome such that marked improvement was seen in >90%
of patients, complete remission was seen in 75% of patients, and
5-year patient survival was seen in >80%.
Despite the ability to successfully induce remission, 50–70%
of remissions are later associated with one or more relapses. The
determination of relapse should be based on objective evidence
of disease activity, taking care to rule out other features that may
have a similar appearance such as infection, medication toxicity,
or chronic disease sequelae. Many patients who achieve remission
continue to have a positive ANCA for years, and changes in ANCA
should not be used as a measure of disease activity. Results from
a large prospective study found that only 43% of patients relapsed
within 1 year of an increase in ANCA levels. Thus, a rise in ANCA
by itself is not a harbinger of immediate disease relapse and should
not lead to reinstitution or increase in immunosuppressive therapy.
Reinduction of remission after relapse is almost always achieved;
however, a high percentage of patients ultimately have some degree
of damage from irreversible features of their disease, such as vary­
ing degrees of renal insufficiency, neurologic impairment, hearing
loss, subglottic stenosis, saddle nose deformity, and chronic sinus
dysfunction. Patients who developed irreversible renal failure but
who achieved subsequent remission have undergone successful
renal transplantation.
Treatment of granulomatosis with polyangiitis is viewed as hav­
ing two phases: induction, where active disease is put into remis­
sion, followed by maintenance. Decisions regarding induction and
maintenance agents are guided by published data, individual patient
factors that include contraindications, relapse history, and comor­
bidities, and stratification based on disease severity. Severe disease
is associated with life- or organ-threatening manifestations and is
based not only on the degree of involvement but also the organ
affected. Pulmonary involvement can be nonsevere when present­
ing as nodular disease without respiratory compromise or severe in
the setting of alveolar hemorrhage. In contrast, active glomerulo­
nephritis is always considered to be severe disease even when renal
function remains normal.
REMISSION INDUCTION OF SEVERE DISEASE
Regimens to induce remission of severe active disease consist of either
cyclophosphamide or rituximab given in combination with glucocor­
ticoids and consideration of adjunctive avacopan. Glucocorticoids
were historically given as prednisone 1 mg/kg per day for the first
month, followed by tapering. In a randomized trial, use of a reduceddose glucocorticoid regimen was noninferior to a standard-dose regi­
men and was associated with a lower rate of serious infection.
Avacopan (a C5a receptor inhibitor) was investigated in a ran­
domized trial as an alternative to glucocorticoids in patients receiv­
ing induction with either cyclophosphamide or rituximab. At
52 weeks, sustained remission was higher in those who received
avacopan as compared to prednisone with a similar rate of serious
adverse events. Although glucocorticoids were given within the
first few weeks to most patients receiving avacopan, glucocorticoid
exposure in the avacopan group remained markedly less than those
randomized to the prednisone treatment arm. This supported that
glucocorticoids can be rapidly withdrawn in patients with severe
active disease receiving avacopan together with either rituximab or
cyclophosphamide.
In patients presenting with disease that is life-threatening, meth­
ylprednisolone 1000 mg daily for 3 days has been used. Adjunctive
plasma exchange was found to provide no added benefit in reduc­
ing the composite outcome of end-stage renal disease or death in a
large, randomized trial. Whether it may still play a role in selected
patients with the most fulminant disease remains controversial.
Although a low number of patients in this trial were enrolled with
alveolar hemorrhage requiring mechanical ventilation, a retrospec­
tive study also showed no benefit. From a meta-analysis, patients
with active glomerulonephritis and serum creatinine >5.7 mg/dL
who received plasma exchange had improvement in renal func­
tion but an increased risk of serious infection. Plasma exchange
should be used in patients with granulomatosis with polyangiitis or
microscopic polyangiitis who are also positive for antiglomerular
basement membrane autoantibody (Chap. 326). When plasma
exchange is used concurrently with rituximab, these treatments
must be separated by at least 48 h to avoid removal of rituximab.
CYCLOPHOSPHAMIDE INDUCTION FOR SEVERE DISEASE
Daily cyclophosphamide combined with glucocorticoids was the first
regimen proven to effectively induce remission and prolong survival.
Cyclophosphamide is given in doses of 2 mg/kg per day orally, but
because it is renally eliminated, dosage reduction should be consid­
ered in patients with renal insufficiency. Although we continue to
favor the use of daily cyclophosphamide, a randomized trial found
IV cyclophosphamide 15 mg/kg, three infusions given every 2 weeks,
then every 3 weeks thereafter, to have a similar rate of remission but
higher frequency of relapse compared to cyclophosphamide 2 mg/kg
daily given for 3 months followed by 1.5 mg/kg daily. Although leu­
kopenia occurred more often with daily cyclophosphamide, this was
likely related to a reduced frequency of blood count monitoring after
the first month.
RITUXIMAB INDUCTION FOR SEVERE DISEASE
Rituximab (anti-CD20) has been of proven effectiveness for the
treatment of granulomatosis with polyangiitis and microscopic poly­
angiitis. In two randomized trials that enrolled patients with severe
active granulomatosis with polyangiitis or microscopic polyangiitis,
rituximab 375 mg/m2 once a week for 4 weeks in combination with
glucocorticoids was found to be as effective as cyclophosphamide
with glucocorticoids for inducing disease remission. In the trial that
also enrolled patients with relapsing disease, rituximab was found to
be statistically superior to cyclophosphamide. Although rituximab
does not have the bladder toxicity or infertility risks of cyclophospha­
mide, in both randomized trials, the rate of adverse events was similar
in the rituximab and cyclophosphamide arms.
The decision about whether to utilize cyclophosphamide or
rituximab for remission induction must be individually based.
Factors to consider include disease severity, whether the patient
has newly diagnosed or relapsing disease, medication contraindica­
tions, and individual patient factors particularly fertility concerns
and risk factors for toxicity. In patients with rapidly progressive
glomerulonephritis with a creatinine >4.0 mg/dL or pulmonary
hemorrhage requiring mechanical ventilation, daily cyclophospha­
mide and glucocorticoids may be favored.
There has been no evidence to date that using cyclophosphamide
and rituximab together for induction is more efficacious, and com­
bined use raises concern for additive toxicity, particularly infection.
However, in instances of toxicity or rare occurrences of inefficacy,
there may be a need to switch from cyclophosphamide to rituximab
or vice versa.
REMISSION MAINTENANCE OF SEVERE DISEASE
When cyclophosphamide is given for induction, it should be
stopped after 3–6 months and switched to another agent for remis­
sion maintenance. Medications used in this setting with which
there has been published experience from randomized trials are
rituximab, azathioprine, methotrexate, and mycophenolate mofetil.
A lower rate of relapse was seen with rituximab given at 500 mg
for two doses followed by 500 mg every 6 months when compared
to azathioprine 2 mg/kg per day. In a randomized trial comparing
methotrexate to azathioprine for remission maintenance, similar
rates of toxicity and relapse were seen. Methotrexate is administered
orally or subcutaneously at a starting dose of 15 mg/week, which is
increased by 2.5 mg every 2 weeks up to a dosage of 20–25 mg/week.
In patients who are unable to receive methotrexate or azathioprine
or who have experienced relapse on such treatment, mycophenolate
mofetil 1000 mg twice a day may also sustain remission, but it is
associated with a higher rate of relapse compared to azathioprine.
For patients who receive rituximab for remission induction, a
randomized trial found that rituximab had a lower rate of relapse
compared to azathioprine. Although rituximab maintenance doses
have not been directly compared, use of 1000 mg every 4 months
in this trial was not found to be associated with a longer length of
sustained remission after discontinuation.
The optimal duration of maintenance therapy is uncertain. With
regard to glucocorticoids, it has been unclear whether maintaining
patients on prednisone 5 mg/d has greater risks or benefits. Main­
tenance therapy with azathioprine, methotrexate, or mycophenolate
mofetil is usually given for a minimum of 2 years. Because there is
evidence that the risk of relapse is higher once maintenance medi­
cation has been stopped, the decision is individualized regarding
whether to continue treatment or taper these agents over a 6- to
12-month period until discontinuation. Patients with significant
organ damage or a history of relapse may benefit from longer-term
maintenance therapy. Although rituximab has been found to have a
lower relapse rate, studies have similarly shown that relapses occur
once treatment is discontinued. Longer term use of rituximab can
be associated with hypogammaglobulinemia such that the decision
for how long to continue this agent beyond 2 years must be weighed
in each patient.
REMISSION INDUCTION AND MAINTENANCE OF
NONSEVERE DISEASE
For patients whose disease is not immediately organ- or life-threat­
ening, methotrexate or mycophenolate mofetil together with gluco­
corticoids, often initiated at a lower dose, may be given to induce
and then maintain remission. Rituximab can also be used in this
setting weighing the risks and benefits. Treatment with cyclophos­
phamide is rarely, if ever, justified for the treatment of nonsevere
granulomatosis with polyangiitis. There have been no published
studies to date with the use of avacopan in nonsevere disease.
OTHER BIOLOGIC AGENTS
Etanercept (TNF inhibitor) was not found to sustain remission
when used adjunctively to standard therapy and should not be
used in granulomatosis with polyangiitis. Belimumab (anti-B
lymphocyte stimulator) was examined as an adjunctive therapy
to azathioprine for remission maintenance but showed no added
benefit in reducing the risk of relapse. Abatacept (CTLA4-Ig) was
examined in a randomized trial in patients with nonsevere relaps­
ing disease where it did not reduce the risk of relapse, disease
worsening, or failure to achieve remission.
ORGAN-SPECIFIC TREATMENT
Not all manifestations of granulomatosis with polyangiitis require
or respond to immunosuppressive therapy, and differentiation of
active disease from damage is necessary. As sinus disease can dis­
rupt the mucociliary barrier, patients should be instructed on the
use of local care with moisturization and humidification. Although
certain reports have indicated that TMP-SMX may be of benefit
in the treatment of granulomatosis with polyangiitis isolated to
the sinonasal tissues, it should never be used alone to treat active
granulomatosis with polyangiitis involving other organs. Subglot­
tic stenosis can often scar and responds optimally to nonmedical
intervention with dilation and glucocorticoid injection.
CHAPTER 375
The Vasculitis Syndromes
MICROSCOPIC POLYANGIITIS
■
■DEFINITION
The term microscopic polyarteritis was introduced into the literature by
Davson in 1948 in recognition of the presence of glomerulonephritis
in patients with polyarteritis nodosa. In 1992, the Chapel Hill Consen­
sus Conference on the Nomenclature of Systemic Vasculitis adopted
the term microscopic polyangiitis to connote a necrotizing vasculitis
with few or no immune complexes affecting small vessels (capillar­
ies, venules, or arterioles). Glomerulonephritis is very common in
microscopic polyangiitis, and pulmonary capillaritis often occurs. The
absence of granulomatous inflammation in microscopic polyangiitis is
said to differentiate it from granulomatosis with polyangiitis.
■
■INCIDENCE AND PREVALENCE
The incidence of microscopic polyangiitis is estimated to be
3–5/100,000. The mean age of onset is ~57 years, and males are slightly
more frequently affected than females.
■
■PATHOLOGY AND PATHOGENESIS
Microscopic polyangiitis has a predilection to involve capillaries and
venules in addition to small- and medium-sized arteries. Immunohis­
tochemical staining reveals a paucity of immunoglobulin deposition
in the vascular lesion of microscopic polyangiitis, suggesting that
immune-complex formation does not play a role in the pathogenesis
of this syndrome. The renal lesion seen in microscopic polyangiitis is
histologically identical to that of granulomatosis with polyangiitis. Like
granulomatosis with polyangiitis, microscopic polyangiitis is highly
associated with ANCA, which may play a role in pathogenesis of this
syndrome (see above).
PART 11
Immune-Mediated, Inflammatory, and Rheumatologic Disorders
■
■CLINICAL AND LABORATORY MANIFESTATIONS
Because of its predilection to involve the small vessels, microscopic
polyangiitis and granulomatosis with polyangiitis share similar clinical
features. Disease onset may be gradual, with initial symptoms of fever,
weight loss, and musculoskeletal pain; however, it is often acute. Glo­
merulonephritis occurs in at least 79% of patients and can be rapidly
progressive, leading to renal failure. Hemoptysis may be the first symp­
tom of alveolar hemorrhage, which occurs in 12% of patients. Other
manifestations include mononeuritis multiplex and gastrointestinal
tract and cutaneous vasculitis. Upper airway disease and pulmonary
nodules are not typically found in microscopic polyangiitis and, if pres­
ent, suggest granulomatosis with polyangiitis.
Features of inflammation may be seen, including an elevated ESR
and/or CRP, anemia, leukocytosis, and thrombocytosis. ANCA are
present in 75% of patients with microscopic polyangiitis, with antimy­
eloperoxidase antibodies being the predominant antigen association.
■
■DIAGNOSIS
The diagnosis is based on histologic evidence of vasculitis or pauciimmune glomerulonephritis in a patient with compatible clinical
features of multisystem disease. Although microscopic polyangiitis is
strongly ANCA-associated, tissue biopsy should continue to be pur­
sued in patients who do not have a clinically compatible picture.
TREATMENT
Microscopic Polyangiitis
The 5-year survival rate for patients with treated microscopic poly­
angiitis is 74%, with disease-related mortality occurring from alveo­
lar hemorrhage or gastrointestinal, cardiac, or renal disease. Studies
on treatment have come from trials that have included patients
with granulomatosis with polyangiitis or microscopic polyangiitis.
Currently, the treatment approach for microscopic polyangiitis
is the same as is used for granulomatosis with polyangiitis (see
“Granulomatosis with Polyangiitis” for a detailed description of this
therapeutic regimen). Disease relapse has been observed in at least
34% of patients. Treatment for such relapses would be based on site
and severity of disease.
EOSINOPHILIC GRANULOMATOSIS WITH
POLYANGIITIS (CHURG-STRAUSS)
■
■DEFINITION
Eosinophilic granulomatosis with polyangiitis was described in 1951
by Churg and Strauss and is characterized by asthma, peripheral and
tissue eosinophilia, extravascular granuloma formation, and vasculitis
of multiple organ systems.
■
■INCIDENCE AND PREVALENCE
Eosinophilic granulomatosis with polyangiitis is an uncommon disease
with an estimated annual incidence of 1–3 per million. The disease can
occur at any age with the possible exception of infants. The mean age
of onset is 48 years, with a female-to-male ratio of 1.2:1.
■
■PATHOLOGY AND PATHOGENESIS
The necrotizing vasculitis of eosinophilic granulomatosis with polyan­
giitis involves small- and medium-sized muscular arteries, capillaries,
veins, and venules. A characteristic histopathologic feature of eosino­
philic granulomatosis with polyangiitis is granuloma that may be
present in the tissues or even within the walls of the vessels them­
selves. These are usually associated with infiltration of the tissues with
eosinophils. This process can occur in any organ in the body; lung
involvement is predominant, with skin, cardiovascular system, kidney,
peripheral nervous system, and gastrointestinal tract also commonly
involved. Although the precise pathogenesis of this disease is uncer­
tain, its strong association with asthma and its clinicopathologic mani­
festations, including eosinophilia, granuloma, and vasculitis, point to
aberrant immunologic phenomena.
■
■CLINICAL AND LABORATORY MANIFESTATIONS
Patients with eosinophilic granulomatosis with polyangiitis often
exhibit nonspecific manifestations such as fever, malaise, anorexia,
and weight loss, which are characteristic of a multisystem disease. The
pulmonary findings in eosinophilic granulomatosis with polyangiitis
dominate the clinical picture with asthmatic attacks and the presence
of pulmonary infiltrates. Mononeuritis multiplex is the second most
common manifestation and occurs in up to 72% of patients. Allergic
rhinitis and sinusitis develop in up to 61% of patients and are often
observed early in the course of disease. Clinically recognizable heart
disease with myocarditis, pericarditis, endocarditis, or coronary vascu­
litis occurs in ~14% of patients and is an important cause of mortality.
Skin lesions occur in ~51% of patients and include purpura in addition
to cutaneous and subcutaneous nodules. Renal disease in eosinophilic
granulomatosis with polyangiitis is less common than that of granulo­
matosis with polyangiitis and microscopic polyangiitis.
The characteristic laboratory finding in virtually all patients with
eosinophilic granulomatosis with polyangiitis is a striking eosinophilia,
which reaches levels >1000 cells/μL in >80% of patients. Evidence of
inflammation as evidenced by elevated ESR and/or CRP, fibrinogen,
or α2-globulins can be found in 81% of patients. The other laboratory
findings reflect the organ systems involved. Approximately 48% of
patients with eosinophilic granulomatosis with polyangiitis have circu­
lating ANCA that is usually antimyeloperoxidase.
■
■DIAGNOSIS
Although the diagnosis of eosinophilic granulomatosis with polyan­
giitis is optimally made by biopsy in a patient with the characteristic
clinical manifestations (see above), histologic confirmation can be
challenging because the pathognomonic features often do not occur
simultaneously. In order to be diagnosed with eosinophilic granulo­
matosis with polyangiitis, a patient should have evidence of asthma,
peripheral blood eosinophilia, and clinical features consistent with
vasculitis.
TREATMENT
Eosinophilic Granulomatosis with Polyangiitis
The prognosis of untreated eosinophilic granulomatosis with poly­
angiitis is poor, with a reported 5-year survival of 25%. With treat­
ment, prognosis is favorable, with one study finding a 78-month
actuarial survival rate of 72%. Myocardial involvement is the most
frequent cause of death and is responsible for 39% of patient mor­
tality. Echocardiography should be performed in all newly diag­
nosed patients because this may influence therapeutic decisions.
Glucocorticoids alone appear to be effective in many patients.
Dosage tapering is often limited by asthma, with asthma often
persisting after clinical recovery from vasculitis. In patients who
present with fulminant multisystem disease, particularly cardiac
involvement, the treatment of choice is daily cyclophosphamide
and prednisone followed by azathioprine or methotrexate (see
“Granulomatosis with Polyangiitis” for a detailed description of
this therapeutic regimen). Use of rituximab and prednisone can be
considered, particularly in ANCA-positive patients who have glo­
merulonephritis or other features of severe small-vessel vasculitis.
Mepolizumab (anti-IL-5 antibody) 300 mg given subcutane­
ously once a month was studied in a randomized trial and found
to be more effective than placebo, with a higher number of weeks
in remission (28% vs 3%) and a higher proportion of patients in
remission (32% vs 3%). Patients with life-threatening eosinophilic
granulomatosis with polyangiitis were excluded from this trial,
and mepolizumab should not be used for the treatment of severe
disease. Mepolizumab may have a particularly beneficial role in the
setting of relapsing or resistant asthma requiring glucocorticoids,
sinus disease, mild to moderate eosinophilic disease features, or
mild vasculitis. In a recent study, benralizumab, which also inhibits
IL-5, demonstrated noninferior rates of remission compared to
mepolizumab in patients with relapsing or refractory, non-lifethreatening eosinophilic granulomatosis with polyangiitis.
POLYARTERITIS NODOSA
■
■DEFINITION
Polyarteritis nodosa was described in 1866 by Kussmaul and Maier. It is
a multisystem, necrotizing vasculitis of small- and medium-sized mus­
cular arteries characteristically involving the renal and visceral arteries.
Polyarteritis nodosa does not involve pulmonary arteries, although
bronchial vessels may be involved; glomerulonephritis, granuloma, and
significant eosinophilia are not seen.
■
■INCIDENCE AND PREVALENCE
It is difficult to establish an accurate incidence of polyarteritis nodosa
because previous reports have included microscopic polyangiitis as
well as other related vasculitides. Polyarteritis nodosa, as currently
defined, is felt to be a very uncommon disease.
■
■PATHOLOGY AND PATHOGENESIS
The vascular lesion in polyarteritis nodosa is a necrotizing inflamma­
tion of small- and medium-sized muscular arteries. The lesions are
segmental and tend to involve bifurcations and branchings of arteries.
They may spread circumferentially to involve adjacent veins. However,
involvement of venules is not seen in polyarteritis nodosa and, if pres­
ent, suggests microscopic polyangiitis (see below). In the acute stages
of disease, polymorphonuclear neutrophils infiltrate all layers of the
vessel wall and perivascular areas, which results in intimal prolifera­
tion and degeneration of the vessel wall. Mononuclear cells infiltrate
the area as the lesions progress to the subacute and chronic stages.
Fibrinoid necrosis of the vessels ensues with compromise of the lumen,
thrombosis, infarction of the tissues supplied by the involved vessel,
and, in some cases, hemorrhage. As the lesions heal, there is collagen
deposition, which may lead to further occlusion of the vessel lumen.
Aneurysmal dilations up to 1 cm in size along the involved arteries are
characteristic.
Multiple organ systems are involved, and the clinicopathologic
findings reflect the degree and location of vessel involvement and the
resulting ischemic changes. As mentioned above, pulmonary arteries
are not involved, and bronchial artery involvement is uncommon. The
pathology in the kidney is that of arteritis without glomerulonephritis.
In patients with significant hypertension, typical pathologic features
of glomerulosclerosis may be seen. In addition, pathologic sequelae of
hypertension may be found elsewhere in the body.
The presence of a polyarteritis nodosa–like vasculitis in patients
with hepatitis B together with the isolation of circulating immune
complexes composed of hepatitis B antigen and immunoglobulin and
the demonstration by immunofluorescence of hepatitis B antigen,
IgM, and complement in the blood vessel walls strongly suggest the
role of immunologic phenomena in the pathogenesis of this disease.
A polyarteritis nodosa–like vasculitis has also been reported in
patients with hepatitis C. Hairy cell leukemia can be associated with
polyarteritis nodosa; the pathogenic mechanisms of this association
are unclear.
A polyarteritis nodosa–like vasculitis has been described in con­
junction with deficiency of adenosine deaminase type 2 (DADA2).
Patients with DADA2 usually present in childhood with a variable
pattern of clinical features and vascular pathology that is respon­
sive to TNF inhibitors. As this differs from the usual treatment for
TABLE 375-6  Clinical Manifestations Related to Organ System
Involvement in Polyarteritis Nodosa
PERCENT
INCIDENCE
CLINICAL MANIFESTATIONS
ORGAN SYSTEM
CHAPTER 375
Renal
Renal failure, hypertension
Musculoskeletal
Arthritis, arthralgia, myalgia
Peripheral nervous
system
Peripheral neuropathy, mononeuritis
multiplex
Gastrointestinal
tract
Abdominal pain, nausea and vomiting,
bleeding, bowel infarction and perforation,
cholecystitis, hepatic infarction, pancreatic
infarction
The Vasculitis Syndromes
Skin
Rash, purpura, nodules, cutaneous infarcts,
livedo reticularis, Raynaud’s phenomenon
Cardiac
Congestive heart failure, myocardial
infarction, pericarditis
Genitourinary
Testicular, ovarian, or epididymal pain
Central nervous
system
Cerebral vascular accident, altered mental
status, seizure
Source: Reproduced with permission from TR Cupps, AS Fauci: The vasculitides.
Major Probl Intern Med 21:1, 1981.
polyarteritis nodosa, DADA2 should be considered in patients with
suggestive clinical features, particularly those with early-onset disease.
■
■CLINICAL AND LABORATORY MANIFESTATIONS
Nonspecific signs and symptoms are the hallmarks of polyarteritis
nodosa. Fever, weight loss, and malaise are present in over one-half
of cases. Patients usually present with vague symptoms such as weak­
ness, malaise, headache, abdominal pain, and myalgias that can rapidly
progress to a fulminant illness. Specific complaints related to the vas­
cular involvement within a particular organ system may also dominate
the presenting clinical picture as well as the entire course of the illness
(Table 375-6). Renal involvement most commonly manifests as hyper­
tension, renal insufficiency, or hemorrhage due to microaneurysms.
There are no diagnostic serologic tests for polyarteritis nodosa. In
75% of patients, the leukocyte count is elevated with a predominance
of neutrophils. Eosinophilia is rare and, when present at high levels,
suggests the diagnosis of eosinophilic granulomatosis with polyangiitis.
The anemia of chronic disease may be seen, and an elevated ESR and/
or CRP is almost always present. Other laboratory findings reflect the
particular organ involved. Hypergammaglobulinemia may be present,
and all patients should be screened for hepatitis B and C. ANCA are
rarely found.
■
■DIAGNOSIS
The diagnosis of polyarteritis nodosa is based on the demonstration
of characteristic findings of vasculitis on biopsy material of involved
organs. Biopsy of symptomatic organs such as nodular skin lesions,
painful testes, and nerve/muscle provides the highest diagnostic yields.
In the absence of easily accessible tissue for biopsy, the arteriographic
demonstration of involved vessels, particularly in the form of aneu­
rysms of small- and medium-sized arteries in the renal, hepatic, and
visceral vasculature, is sufficient to make the diagnosis. This should
consist of a catheter-directed dye arteriogram because magnetic
resonance and computed tomography arteriograms do not have suf­
ficient resolution at the current time to visualize the affected vessels.
Aneurysms of vessels are not pathognomonic of polyarteritis nodosa;
furthermore, aneurysms may not always be present, and arteriographic
findings may be limited to stenotic segments and obliteration of vessels.
TREATMENT
Polyarteritis Nodosa
The prognosis of untreated polyarteritis nodosa is extremely poor,
with a reported 5-year survival rate between 10 and 20%. Death usu­
ally results from gastrointestinal complications, particularly bowel
infarcts and perforation, and cardiovascular causes. Intractable
hypertension often compounds dysfunction in other organ systems,
such as the kidneys, heart, and CNS, leading to additional late
morbidity and mortality. The combination of prednisone and cyclo­
phosphamide has been found to significantly improve the survival
rate (see “Granulomatosis with Polyangiitis” for a description of this
therapeutic regimen). In less severe cases, glucocorticoids alone have
resulted in disease remission. Treatment of hypertension can lessen
vascular complications. Following remission, relapse has been esti­
mated to occur in 10–20% of patients. In patients with hepatitis B or
C who have a polyarteritis nodosa–like vasculitis, antiviral therapy
is an essential part of management, with immunosuppression being
given concurrently for severe vasculitis and then withdrawn once
the vasculitis is controlled. Plasma exchange has been used in some
series of hepatitis virus-associated polyarteritis nodosa.
PART 11
Immune-Mediated, Inflammatory, and Rheumatologic Disorders
GIANT CELL ARTERITIS AND
POLYMYALGIA RHEUMATICA
■
■DEFINITION
Giant cell arteritis, historically referred to as temporal arteritis, is an
inflammation of medium- and large-sized arteries. It characteristically
involves one or more branches of the carotid artery, particularly the
temporal artery. However, it is a systemic disease that can involve arter­
ies in multiple locations, particularly the aorta and its main branches.
Giant cell arteritis is closely associated with polymyalgia rheumatica,
which is characterized by stiffness, aching, and pain in the muscles
of the neck, shoulders, lower back, hips, and thighs. Most commonly,
polymyalgia rheumatica occurs in isolation, but it may be seen in
40–50% of patients with giant cell arteritis. In addition, ~10–20% of
patients who initially present with features of isolated polymyalgia
rheumatica later go on to develop giant cell arteritis. A careful his­
tory and physical examination at initial and subsequent visits should
be performed in patients with polymyalgia rheumatica to look for
features suggestive of giant cell arteritis. This strong clinical associa­
tion together with data from pathophysiologic studies has supported
that giant cell arteritis and polymyalgia rheumatica represent differing
clinical spectrums of a single disease process.
■
■INCIDENCE AND PREVALENCE
Giant cell arteritis occurs almost exclusively in individuals aged
50 years. It is more common in women than in men and is rare in
blacks. The incidence of giant cell arteritis varies widely in different
studies and in different geographic regions. A high incidence has been
found in Scandinavia and in regions of the United States with large
Scandinavian populations, compared to a lower incidence in southern
Europe. The annual incidence rates in individuals aged ≥50 years range
from 6.9 to 32.8 per 100,000 population. Familial aggregation has been
reported, as has an association with HLA-DR4. In addition, genetic link­
age studies have demonstrated an association of giant cell arteritis with
alleles at the HLA-DRB1 locus, particularly HLA-DRB1∗04 variants.
In Olmsted County, Minnesota, the annual incidence of polymyalgia
rheumatica in individuals aged ≥50 years is 58.7 per 100,000 population.
■
■PATHOLOGY AND PATHOGENESIS
Although the temporal artery is most frequently involved in giant cell
arteritis, patients often have a systemic vasculitis of multiple medium-
and large-sized arteries, which may go undetected. Histopathologically,
the disease is a panarteritis with inflammatory mononuclear cell infil­
trates within the vessel wall with frequent giant cell formation. There
is proliferation of the intima and fragmentation of the internal elastic
lamina. Pathophysiologic findings in organs result from the ischemia
related to the involved vessels.
Experimental data support that giant cell arteritis is an antigendriven disease in which activated T lymphocytes, macrophages, and
dendritic cells play a critical role in pathogenesis. Sequence analysis of
the T-cell receptor of tissue-infiltrating T cells in lesions of giant cell
arteritis indicates restricted clonal expansion, suggesting the presence
of an antigen residing in the arterial wall. Giant cell arteritis is believed
to be initiated in the adventitia where CD4+ T cells enter through
the vasa vasorum, become activated, and orchestrate macrophage
differentiation. T cells recruited to vasculitic lesions in patients with
giant cell arteritis produce predominantly IL-2 and IFN-γ, and the
latter has been suggested to be involved in the progression to arteritis.
Laboratory-based data demonstrate that at least two separate lineages
of CD4 T cells—IFN-γ-producing TH1 cells and IL-17-producing TH17
cells—participate in vascular inflammation and may have differing
levels of responsiveness to glucocorticoids.
■
■CLINICAL AND LABORATORY MANIFESTATIONS
Giant cell arteritis is most commonly characterized clinically by the
complex of fever, anemia, high ESR and/or CRP, and headaches in a
patient aged >50 years. Four phenotypic manifestations can be seen
including cranial arteritis, polymyalgia rheumatica, large-vessel dis­
ease, and features of systemic inflammation. These can occur together,
in isolation, or at different times.
In patients with involvement of the cranial arteries, headache is the
predominant symptom and may be associated with a tender, thick­
ened, or nodular artery, which may pulsate early in the disease but
may become occluded later. Scalp pain and claudication of the jaw and
tongue may occur. A well-recognized and dreaded complication of
giant cell arteritis, particularly in untreated patients, is ischemic optic
neuropathy, which may lead to serious visual symptoms, including
sudden blindness in some patients. However, most patients have com­
plaints relating to the head or eyes before visual loss. Attention to such
symptoms with institution of appropriate therapy (see below) lessens
the risk of this complication. Other cranial ischemic complications
include strokes and scalp or tongue infarction.
Up to one-third of patients can have large-vessel disease that can
be the primary presentation of giant cell arteritis or can emerge at a
later point in patients who have had previous cranial arteritis features
or polymyalgia rheumatica. Manifestations of large-vessel disease can
include subclavian artery stenosis that can present as arm claudication
or aortic aneurysms involving the thoracic and to a lesser degree the
abdominal aorta, which carry risks of rupture or dissection.
Clinical features of systemic inflammation can include malaise,
fatigue, anorexia, weight loss, and sweats. Laboratory findings can
also support an inflammatory process. An elevated ESR and/or CRP
will be seen in most patients. Therapeutic blockade of IL-6 signaling
prevents the hepatic production of CRP and other acute-phase pro­
teins like ESR. These values will therefore normalize in patients who
are treated with an IL-6 inhibitor, eliminating the ability to utilize CRP
and ESR in monitoring disease activity or infection assessment in this
setting. Other laboratory features include a normochromic or slightly
hypochromic anemia. Liver function abnormalities are common, par­
ticularly increased alkaline phosphatase levels. Increased levels of IgG
and complement have been reported.
■
■DIAGNOSIS
The diagnosis of giant cell arteritis can often be suggested clinically
by the demonstration of the complex of fever, anemia, and high ESR
and/or CRP with or without symptoms of polymyalgia rheumatica
in a patient >50 years old. The diagnosis can be confirmed by biopsy
of the temporal artery but may not be positive in all patients due
to patchy histologic findings. Since involvement of the vessel may
be segmental, positive yield is increased by obtaining a biopsy seg­
ment of 3–5 cm together with serial sectioning of biopsy specimens.
Ultrasonography of the temporal arteries alone or in combination
with the axillary arteries demonstrating a noncompressible “halo”
sign has been used in supporting the diagnosis. Therapy should not
be delayed pending the performance of diagnostic studies. In this
regard, it has been reported that temporal artery biopsies may show
vasculitis even after ~14 days of glucocorticoid therapy. A dramatic
clinical response to a trial of glucocorticoid therapy can further sup­
port the diagnosis.
Large-vessel disease may be suggested by symptoms and findings
on physical examination such as diminished pulses or bruits. It is
confirmed by vascular imaging, most commonly through magnetic
resonance or computed tomography. Positron emission tomography
has become increasingly investigated, although its role in diagnosis and
monitoring remains unclear.
Isolated polymyalgia rheumatica is a clinical diagnosis made by
the presence of typical symptoms of stiffness, aching, and pain in the
muscles of the hip and shoulder girdle, an increased ESR and/or CRP,
the absence of clinical features suggestive of giant cell arteritis, and
a prompt therapeutic response to low-dose prednisone. Polymyalgia
rheumatica can be associated with a peripheral arthritis that can
mimic rheumatoid arthritis (Chap. 370). Rheumatoid factor and anti–
cyclic citrullinated peptide (CCP) should be negative. In patients who
develop a worsening pattern of peripheral arthritis, the potential for a
seronegative rheumatoid arthritis or other inflammatory arthropathy
should be considered. Levels of enzymes indicative of muscle damage
such as serum creatine kinase are not elevated.
TREATMENT
Giant Cell Arteritis
Acute disease–related mortality directly from giant cell arteritis is
uncommon, with fatalities occurring from cerebrovascular events
or myocardial infarction. However, patients are at risk of late mor­
tality from aortic aneurysm rupture or dissection as patients with
giant cell arteritis are 18 times more likely to develop thoracic aortic
aneurysms than the general population.
The goals of treatment in giant cell arteritis are to reduce symp­
toms and, most importantly, to prevent visual loss. The treatment
approach for cranial arteritis and large-vessel disease in giant cell
arteritis is currently the same.
Giant cell arteritis and its associated symptoms are responsive
to glucocorticoid therapy. Treatment should begin with predni­
sone 40–60 mg/d for ~1 month, followed by a gradual tapering.
When ocular signs and symptoms occur, consideration should
be given for the use of methylprednisolone 1000 mg daily for 3 days
to protect remaining vision. Although the optimal duration of
glucocorticoid therapy has not been established, most series have
found that patients require treatment for ≥2 years. Symptom
recurrence during prednisone tapering develops in 60–85% of
patients with giant cell arteritis, requiring a dosage increase. For
patients treated with prednisone alone, the ESR and/or CRP can
serve as an indicator of inflammatory disease activity in monitor­
ing and tapering therapy and can be used to guide the tapering
schedule. However, minor increases in the ESR and/or CRP can
occur as glucocorticoids are being tapered and do not necessar­
ily reflect an exacerbation of arteritis, particularly if the patient
remains symptom-free. Under these circumstances, the tapering
should continue with caution. An increase in ESR and/or CRP can
also occur for other reasons, including infection. Glucocorticoid
toxicity occurs in 35–65% of patients and represents an important
cause of patient morbidity.
Tocilizumab (anti-IL-6 receptor) 162 mg given subcutaneously
once every week or once every other week combined with a 26-week
prednisone taper was found to be superior to prednisone alone in
sustaining glucocorticoid-free remission in a randomized trial. The
decision about when to use tocilizumab in giant cell arteritis is indi­
vidually based, taking into account comorbidities, glucocorticoid
toxicity, and the side effects of tocilizumab. Pharmacokinetic stud­
ies supported that tocilizumab 6 mg/kg given intravenously every 4
weeks could also be used as a treatment option in giant cell arteritis.
The use of methotrexate as a glucocorticoid-sparing agent was
examined in two randomized placebo-controlled trials that reached
conflicting conclusions. It may be considered in select patients with
glucocorticoid toxicity who are unable to take or are intolerant of
tocilizumab.
Abatacept (CTLA4-Ig) was examined in a small randomized trial
in giant cell arteritis and demonstrated greater efficacy than gluco­
corticoids alone. Infliximab, a monoclonal antibody to TNF, was
studied in a randomized trial and was not found to provide benefit.
Aspirin 81 mg daily has been found in retrospective studies to
reduce the occurrence of cranial ischemic complications in giant
cell arteritis, and adjunctive use should be considered in patients
who do not have contraindications.
Polymyalgia Rheumatica
CHAPTER 375
Patients with isolated polymyalgia rheumatica respond promptly to
prednisone given at a dose of 10–20 mg/d. Similar to giant cell arte­
ritis, the ESR and/or CRP can serve as a useful indicator in moni­
toring prednisone reduction in those treated with glucocorticoids
alone. Recurrent polymyalgia symptoms develop in the majority of
patients during prednisone tapering.
The Vasculitis Syndromes
Sarilumab (anti-IL-6 receptor) was found to be effective in a
randomized trial of patients with glucocorticoid-resistant polymy­
algia rheumatica who relapsed on prednisone ≥7.5 mg/d. In this
trial, sarilumab 200 mg given subcutaneously every 2 weeks plus a
14-week glucocorticoid taper was associated with a higher rate of
sustained remission compared to glucocorticoids alone. As most
patients with polymyalgia rheumatica can be successfully treated
with glucocorticoids alone, use of sarilumab should be restricted to
those who have had an inadequate response to glucocorticoids or
who relapse with a glucocorticoid taper.
One study of methotrexate found that this reduced the prednisone
dose on average by only 1 mg and did not decrease prednisonerelated side effects. A randomized trial in polymyalgia rheumatica did
not find infliximab to lessen relapse or glucocorticoid requirements.
TAKAYASU ARTERITIS
■
■DEFINITION
Takayasu arteritis is an inflammatory disease of large-sized arteries char­
acterized by a strong predilection for the aortic arch and its branches.
■
■INCIDENCE AND PREVALENCE
Takayasu arteritis is an uncommon disease with an estimated annual
incidence rate of 1.2–2.6 cases per million. It is most prevalent in ado­
lescent girls and young women. Although it is more common in Asia,
it is neither racially nor geographically restricted.
■
■PATHOLOGY AND PATHOGENESIS
The disease involves large-sized arteries, with a strong predilection
for the aortic arch and its branches; the pulmonary artery may also be
involved. The most commonly affected arteries seen by arteriography
are listed in Table 375-7. The involvement of the major branches of
TABLE 375-7  Frequency of Arteriographic Abnormalities and Potential
Clinical Manifestations of Arterial Involvement in Takayasu Arteritis
PERCENTAGE OF
ARTERIOGRAPHIC
ABNORMALITIES
POTENTIAL CLINICAL
MANIFESTATIONS
ARTERY
Subclavian
Arm claudication, Raynaud’s
phenomenon
Common carotid
Visual changes, syncope,
transient ischemic attacks, stroke
Abdominal aortaa
Abdominal pain, nausea, vomiting
Renal
Hypertension, renal failure
Aortic arch or root
Aortic insufficiency, congestive
heart failure
Vertebral
Visual changes, dizziness
Coeliac axisa
Abdominal pain, nausea, vomiting
Superior mesenterica
Abdominal pain, nausea, vomiting
Iliac
Leg claudication
Pulmonary
10–40
Atypical chest pain, dyspnea
Coronary
<10
Chest pain, myocardial infarction
aArteriographic lesions at these locations are usually asymptomatic but may
potentially cause these symptoms.
Source: G Kerr et al: Ann Intern Med 120:919, 1994.
the aorta is much more marked at their origin than distally. The
disease is a panarteritis with inflammatory mononuclear cell infiltrates
and occasionally giant cells. There are marked intimal proliferation and
fibrosis, scarring and vascularization of the media, and disruption and
degeneration of the elastic lamina. The vasa vasorum are frequently
involved. Narrowing of the lumen occurs with or without thrombosis.
Pathologic changes in various organs typically reflect reduced blood
flow through these vascular stenoses. Aneurysms can also occur due
to weakening of the vessel wall.
PART 11
Immune-Mediated, Inflammatory, and Rheumatologic Disorders
Immunopathogenic mechanisms, the precise nature of which is
uncertain, are suspected in this disease. As with several of the vasculitis
syndromes, circulating immune complexes have been demonstrated,
but their pathogenic significance is unclear.
■
■CLINICAL AND LABORATORY MANIFESTATIONS
Takayasu arteritis is a systemic disease with generalized as well as
vascular symptoms. The generalized symptoms include malaise, fever,
night sweats, arthralgias, anorexia, and weight loss, which may occur
months before vessel involvement is apparent. These symptoms may
merge into those related to vascular compromise and organ ischemia.
Pulses are commonly absent in the involved vessels, particularly the
subclavian artery. The frequency of arteriographic abnormalities and
the potentially associated clinical manifestations are listed in Table 375-7.
Hypertension occurs in 32–93% of patients and contributes to renal,
cardiac, and cerebral injury.
Characteristic laboratory findings include an elevated ESR and/or
CRP, mild anemia, and elevated immunoglobulin levels.
■
■DIAGNOSIS
The diagnosis of Takayasu arteritis should be suspected strongly in a
young woman who develops a decrease or absence of peripheral pulses,
a discrepancy in blood pressure between arms, or arterial bruits. The
diagnosis is confirmed by the characteristic pattern on arteriography,
which includes irregular vessel walls, stenosis, poststenotic dilation,
aneurysm formation, occlusion, and evidence of increased collateral
circulation. Complete imaging of the aorta and its major branches by
magnetic resonance or computed tomography arteriography should
be obtained to fully delineate the distribution and degree of arterial
disease. Because of the involvement of the large vessels, tissue is rarely
available or necessary as a means of diagnosis and obtained only if
vascular surgery is necessary. IgG4-related disease (Chap. 380) is a
potential cause of aortitis and periaortitis that is histologically differen­
tiated from Takayasu arteritis by a dense lymphoplasmacytic infiltrate
rich in IgG4-positive plasma cells, a storiform pattern of fibrosis, and
obliterative phlebitis.
TREATMENT
Takayasu Arteritis
The long-term outcome of patients with Takayasu arteritis has var­
ied widely between studies. Although two North American reports
found overall survival to be ≥94%, the 5-year mortality rate from
other studies has ranged from 0 to 35%. Disease-related mortality
most often occurs from congestive heart failure, cerebrovascular
events, myocardial infarction, aneurysm rupture, or renal failure.
Even in the absence of life-threatening disease, Takayasu arteritis
can be associated with significant morbidity. The course of the dis­
ease is variable, and although spontaneous remissions may occur,
Takayasu arteritis is most often chronic and relapsing. Although
glucocorticoids, given as prednisone 40–60 mg/d followed by a
taper, alleviate symptoms, there are no convincing studies that indi­
cate that it increases survival. The combination of glucocorticoid
therapy for acute signs and symptoms and an aggressive surgical
and/or arterioplastic approach to stenosed vessels has markedly
improved outcome and decreased morbidity by lessening the risk
of stroke, correcting hypertension due to renal artery stenosis, and
improving blood flow to ischemic viscera and limbs. Unless it is
urgently required, surgical correction of stenosed arteries should
be undertaken only when the vascular inflammatory process is well
controlled with medical therapy.
In individuals who are refractory to or unable to taper glucocor­
ticoids, methotrexate in doses up to 25 mg per week has been used
with positive results. Retrospective series with anti-TNF therapies
have shown benefit, but these agents have not been studied through
randomized trials to determine efficacy.
Tocilizumab has been investigated in a randomized trial where it
did not reach its primary efficacy endpoint, although it was found
to be associated with glucocorticoid-sparing effects and improve­
ments in well-being. Encouraging results have also been seen in
retrospective studies such that the utility of this agent remains an
active question. Abatacept was examined in a randomized trial in
Takayasu arteritis but did not demonstrate efficacy beyond gluco­
corticoids alone.
IGA VASCULITIS (HENOCH-SCHÖNLEIN)
■
■DEFINITION
IgA vasculitis (Henoch-Schönlein) is a small-vessel vasculitis charac­
terized by palpable purpura (most commonly distributed over the
buttocks and lower extremities), arthralgias, gastrointestinal signs and
symptoms, and glomerulonephritis.
■
■INCIDENCE AND PREVALENCE
IgA vasculitis is usually seen in children ages 4–7 years; however, the
disease may also be seen in infants and adults. It is not a rare disease;
in one series, it accounted for between 5 and 24 admissions per year at
a pediatric hospital. The male-to-female ratio is 1.5:1. A seasonal varia­
tion with a peak incidence in spring has been noted.
■
■PATHOLOGY AND PATHOGENESIS
The presumptive pathogenic mechanism for IgA vasculitis is immunecomplex deposition. A number of inciting antigens have been sug­
gested including upper respiratory tract infections, various drugs,
foods, insect bites, and immunizations. IgA is the antibody class most
often seen in the immune complexes and has been demonstrated in the
renal biopsies of these patients.
■
■CLINICAL AND LABORATORY MANIFESTATIONS
In pediatric patients, palpable purpura is seen in virtually all patients;
most patients develop polyarthralgias in the absence of frank arthritis.
Gastrointestinal involvement, which is seen in almost 70% of pediatric
patients, is characterized by colicky abdominal pain usually associated
with nausea, vomiting, diarrhea, or constipation, and is frequently
accompanied by the passage of blood and mucus per rectum; bowel
intussusception may occur. Renal involvement occurs in 10–50% of
patients and is usually characterized by mild glomerulonephritis lead­
ing to proteinuria and microscopic hematuria, with red blood cell casts
in the majority of patients; it usually resolves spontaneously without
therapy. Progressive glomerulonephritis rarely develops. In adults,
presenting symptoms are most frequently related to the skin and joints,
while initial complaints related to the gut are less common. Although
certain studies have found that renal disease is more frequent and
more severe in adults, this has not been a consistent finding. However,
the course of renal disease in adults may be more insidious and thus
requires close follow-up. Myocardial involvement can occur in adults
but is rare in children.
Laboratory studies generally show a mild leukocytosis, a normal
platelet count, and occasionally eosinophilia. Serum complement
components are normal, and IgA levels are elevated in about one-half
of patients.
■
■DIAGNOSIS
The diagnosis of IgA vasculitis is based on clinical signs and symptoms.
Skin biopsy specimen can be useful in confirming leukocytoclastic
vasculitis with IgA and C3 deposition by immunofluorescence. Renal
biopsy is rarely needed for diagnosis but may provide prognostic infor­
mation in some patients.
TREATMENT
IgA Vasculitis
The prognosis of IgA vasculitis is excellent. Mortality is exceed­
ingly rare, and 1–5% of children progress to end-stage renal disease,
although renal failure may be more common in adults. Most patients
recover completely, and some do not require therapy. When glucocor­
ticoids are required, prednisone, 1 mg/kg per day and tapered accord­
ing to clinical response, has been shown to be useful in decreasing
tissue edema, arthralgias, and abdominal discomfort; however, it has
not proved beneficial in the treatment of skin or renal disease and
does not appear to shorten the duration of active disease or lessen the
chance of recurrence. Patients with rapidly progressive glomerulone­
phritis have been anecdotally reported to benefit from glucocorticoids
used in combination with another immunosuppressive agent. Disease
recurrences have been reported in 10–40% of patients.
CRYOGLOBULINEMIC VASCULITIS
■
■DEFINITION
Cryoglobulins are cold-precipitable monoclonal or polyclonal immu­
noglobulins. Cryoglobulinemia may be associated with a systemic
vasculitis characterized by palpable purpura, arthralgias, weakness,
neuropathy, and glomerulonephritis. The most common association
has been with hepatitis C, although cryoglobulinemia can be observed
in association with a variety of underlying disorders including multiple
myeloma, lymphoproliferative disorders, connective tissue diseases,
infection, and liver disease and can be idiopathic.
■
■INCIDENCE AND PREVALENCE
The incidence of cryoglobulinemic vasculitis has not been established.
It has been estimated that 5% of patients with chronic hepatitis C will
develop cryoglobulinemic vasculitis.
■
■PATHOLOGY AND PATHOGENESIS
Skin biopsies in cryoglobulinemic vasculitis reveal an inflammatory
infiltrate surrounding and involving blood vessel walls, with fibrinoid
necrosis, endothelial cell hyperplasia, and hemorrhage. Deposition
of immunoglobulin and complement is common. Abnormalities
of uninvolved skin including basement membrane alterations and
deposits in vessel walls may be found. Membranoproliferative glo­
merulonephritis is responsible for 80% of all renal lesions in cryo­
globulinemic vasculitis.
The association between hepatitis C and cryoglobulinemic vasculitis
has been supported by the high frequency of documented hepatitis C
infection, the presence of hepatitis C RNA and anti–hepatitis C anti­
bodies in serum cryoprecipitates, evidence of hepatitis C antigens in
vasculitic skin lesions, and the effectiveness of antiviral therapy. Cur­
rent evidence suggests that in the majority of cases, cryoglobulinemic
vasculitis occurs when an aberrant immune response to hepatitis C
infection leads to the formation of immune complexes consisting of
hepatitis C antigens, polyclonal hepatitis C–specific IgG, and monoclo­
nal IgM rheumatoid factor. The deposition of these immune complexes
in blood vessel walls triggers an inflammatory cascade that results in
cryoglobulinemic vasculitis.
■
■CLINICAL AND LABORATORY MANIFESTATIONS
The most common clinical manifestations of cryoglobulinemic vas­
culitis are cutaneous vasculitis, arthritis, peripheral neuropathy, and
glomerulonephritis. Renal disease develops in 10–30% of patients.
Life-threatening rapidly progressive glomerulonephritis or vasculitis of
the CNS, gastrointestinal tract, or heart occurs infrequently.
The presence of circulating cryoprecipitates is the fundamental find­
ing in cryoglobulinemic vasculitis. Rheumatoid factor is almost always
found and may be a useful clue to the disease when cryoglobulins are
not detected. Hypocomplementemia occurs in 90% of patients. An
elevated ESR and/or CRP and anemia occur frequently. Evidence for
hepatitis C infection must be sought in all patients by testing for hepa­
titis C antibodies and hepatitis C RNA.
TREATMENT
Cryoglobulinemic Vasculitis
Acute mortality directly from cryoglobulinemic vasculitis is uncom­
mon, but the presence of glomerulonephritis is a poor prognostic
sign for overall outcome. In such patients, 15% progress to endstage renal disease, with 40% later experiencing fatal cardiovascular
disease, infection, or liver failure. As indicated above, the majority
of cases are associated with hepatitis C infection. In such patients,
treatment with antiviral therapy (Chap. 352) is first-line therapy
for hepatitis C–associated cryoglobulinemic vasculitis, particularly
given the efficacy of current hepatitis C therapies. Clinical improve­
ment with antiviral therapy is dependent on the virologic response.
Patients who clear hepatitis C from the blood have objective
improvement in their vasculitis along with significant reductions
in levels of circulating cryoglobulins, IgM, and rheumatoid factor.
While transient improvement can be observed with glucocorti­
coids, a complete response is seen in only 7% of patients. Plasma
exchange and cytotoxic agents have been used in anecdotal reports.
These observations have not been confirmed, and such therapies
carry significant risks. Randomized trials with rituximab in hepa­
titis C–associated cryoglobulinemic vasculitis showed evidence of
benefit such that this should be considered in patients with active
vasculitis either in combination with antiviral therapy or alone in
patients who have relapsed through, are intolerant to, or have con­
traindications to antiviral agents.
CHAPTER 375
The Vasculitis Syndromes
SINGLE-ORGAN VASCULITIS
Single-organ vasculitis has been defined as vasculitis in arteries or veins
of any size in a single organ that has no features that indicate that it is
a limited expression of a systemic vasculitis. Examples include isolated
aortitis, testicular vasculitis, vasculitis of the breast, isolated cutaneous
vasculitis, and primary CNS vasculitis. In some instances, this may be
discovered at the time of surgery such as orchiectomy for a testicular
mass where there is concern for neoplasm that is found instead to be
vasculitis. Some patients originally diagnosed with single-organ vas­
culitis may later develop additional manifestations of a more systemic
disease. In instances where there is no evidence of systemic vasculitis and
the affected organ has been removed in its entirety, the patient may be
followed closely without immunosuppressive therapy. In other instances,
such as primary CNS vasculitis, medical intervention is necessary.
IDIOPATHIC CUTANEOUS VASCULITIS
■
■DEFINITION
The term cutaneous vasculitis is defined broadly as inflammation of
the blood vessels of the dermis. Because of its heterogeneity, cutaneous
vasculitis has been described by a variety of terms including hypersen­
sitivity vasculitis and cutaneous leukocytoclastic angiitis. However, cuta­
neous vasculitis is not one specific disease but a manifestation that can
be seen in a variety of settings. In >70% of cases, cutaneous vasculitis
occurs either as part of a primary systemic vasculitis or as a second­
ary vasculitis related to an inciting agent or an underlying disease (see
“Secondary Vasculitis,” below). In the remaining 30% of cases, cutane­
ous vasculitis occurs idiopathically.
■
■INCIDENCE AND PREVALENCE
Cutaneous vasculitis represents the most commonly encountered vas­
culitis in clinical practice. The exact incidence of idiopathic cutaneous
vasculitis has not been determined due to the predilection for cutane­
ous vasculitis to be associated with an underlying process and the vari­
ability of its clinical course.
■
■PATHOLOGY AND PATHOGENESIS
The typical histopathologic feature of cutaneous vasculitis is the pres­
ence of vasculitis of small vessels. Postcapillary venules are the most
commonly involved vessels; capillaries and arterioles may be involved
less frequently. This vasculitis is characterized by a leukocytoclasis, a
term that refers to the nuclear debris remaining from the neutrophils
that have infiltrated in and around the vessels during the acute stages.
In the subacute or chronic stages, mononuclear cells predominate; in
certain subgroups, eosinophilic infiltration is seen. Erythrocytes often
extravasate from the involved vessels, leading to palpable purpura.
Cutaneous arteritis can also occur, which involves slightly larger-sized
vessels within the dermis.
PART 11
Immune-Mediated, Inflammatory, and Rheumatologic Disorders
■
■CLINICAL AND LABORATORY MANIFESTATIONS
The hallmark of idiopathic cutaneous vasculitis is the predominance of
skin involvement. Skin lesions may appear typically as palpable purpura;
however, other cutaneous manifestations of the vasculitis may occur,
including macules, papules, vesicles, bullae, subcutaneous nodules,
ulcers, and recurrent or chronic urticaria. The skin lesions may be pru­
ritic or painful, with a burning or stinging sensation. Lesions most com­
monly occur in the lower extremities in ambulatory patients or in the
sacral area in bedridden patients due to the effects of hydrostatic forces
on the postcapillary venules. Edema may accompany certain lesions, and
hyperpigmentation often occurs in areas of recurrent or chronic lesions.
There are no specific laboratory tests diagnostic of idiopathic cuta­
neous vasculitis. A mild leukocytosis with or without eosinophilia is
characteristic, as is an elevated ESR and/or CRP. Laboratory studies
should be aimed toward ruling out features to suggest an underlying
disease or a systemic vasculitis.
■
■DIAGNOSIS
The diagnosis of cutaneous vasculitis is made by the demonstration of
vasculitis on biopsy. An important diagnostic principle in patients with
cutaneous vasculitis is to search for an etiology of the vasculitis—be it
an exogenous agent, such as a drug or an infection, or an endogenous
underlying disease (Fig. 375-1). In addition, a careful history, physical,
and laboratory examination should be performed to rule out the pos­
sibility of coexisting systemic vasculitis.
TREATMENT
Idiopathic Cutaneous Vasculitis
When an antigenic stimulus is recognized as the precipitating fac­
tor in the cutaneous vasculitis, it should be removed; if this is a
microbe, appropriate antimicrobial therapy should be instituted. If
the vasculitis is associated with another underlying disease, treat­
ment of the latter often results in resolution of the former. In situ­
ations where disease is apparently self-limited, no therapy, except
possibly symptomatic therapy, is indicated. When cutaneous vas­
culitis persists and when there is no evidence of an inciting agent,
an associated disease, or an underlying systemic vasculitis, the
decision to treat should be based on weighing the balance between
the degree of symptoms and the risk of treatment. Some cases of
idiopathic cutaneous vasculitis resolve spontaneously, whereas oth­
ers remit and relapse. In patients with persistent vasculitis, a variety
of therapeutic regimens have been tried with variable results. In
general, the treatment of idiopathic cutaneous vasculitis has not
been satisfactory. Fortunately, since the disease is generally limited
to the skin, this lack of consistent response to therapy usually does
not lead to a life-threatening situation. Agents with which there
have been anecdotal reports of success include dapsone, colchicine,
hydroxychloroquine, and nonsteroidal anti-inflammatory agents.
Glucocorticoids are often used in the treatment of idiopathic
cutaneous vasculitis. Therapy is usually instituted with the lowest
effective dose of prednisone with rapid tapering to discontinuation.
In cases that prove refractory to glucocorticoids, a trial of another
immunosuppressive agent may be indicated. Patients with chronic
vasculitis isolated to cutaneous venules rarely respond dramatically
to any therapeutic regimen, and other immunosuppressive agents
should be used only as a last resort in these patients. Methotrexate
and azathioprine have been used in such situations in anecdotal
reports. Cyclophosphamide should almost never be used for idio­
pathic cutaneous vasculitis because of the potential toxicity.
PRIMARY CENTRAL NERVOUS
SYSTEM VASCULITIS
Primary CNS vasculitis is an uncommon clinicopathologic entity
characterized by vasculitis restricted to the vessels of the CNS without
other apparent systemic vasculitis. The inflammatory process is usually
composed of mononuclear cell infiltrates with or without granuloma
formation.
Patients may present with headaches, altered mental function, and
focal neurologic defects. Systemic symptoms are generally absent.
Devastating neurologic abnormalities may occur depending on the
extent of vessel involvement. The diagnosis can be suggested by abnor­
mal magnetic resonance imaging of the brain, an abnormal lumbar
puncture, and/or demonstration of characteristic vessel abnormalities
on arteriography (Fig. 375-4), but it is confirmed by biopsy of the
brain parenchyma and leptomeninges. In the absence of a brain biopsy,
care should be taken not to misinterpret as true primary vasculitis
arteriographic abnormalities that might actually be related to another
cause. An important entity in the differential diagnosis is reversible
cerebral vasoconstrictive syndrome, which typically presents with
“thunderclap” headache and is associated with reversible arteriographic
abnormalities that mimic primary CNS vasculitis. Other diagnostic
considerations include infection, atherosclerosis, emboli, connective
tissue disease, sarcoidosis, malignancy, and drug-associated causes.
The prognosis of granulomatous primary CNS vasculitis is poor;
however, some reports indicate that glucocorticoid therapy, alone or
together with cyclophosphamide administered as described above, has
induced clinical remissions. Following disease remission, cyclophos­
phamide should be switched to azathioprine or mycophenolate mofetil
as these have good penetration into the CNS.
BEHÇET’S DISEASE
Behçet’s disease is a clinicopathologic entity characterized by recurrent
episodes of oral and genital ulcers, iritis, and cutaneous lesions. The
underlying pathologic process is a leukocytoclastic venulitis, although
vessels of any size and in any organ can be involved. This disorder is
described in detail in Chap. 376.
COGAN’S SYNDROME
Cogan’s syndrome is characterized by interstitial keratitis together with
vestibuloauditory symptoms. It may be associated with a systemic
vasculitis, particularly aortitis with involvement of the aortic valve.
FIGURE 375-4  Cerebral arteriogram from a 32-year-old man with primary central
nervous system vasculitis. Dramatic beading (arrow) typical of vasculitis is seen.
Glucocorticoids are the mainstay of treatment. Initiation of treatment
as early as possible after the onset of hearing loss improves the likeli­
hood of a favorable outcome.
KAWASAKI’S DISEASE
Kawasaki’s disease is an acute, febrile, multisystem disease of children.
Some 80% of cases occur prior to the age of 5, with the peak incidence
occurring at ≤2 years. It is characterized by nonsuppurative cervi­
cal adenitis and changes in the skin and mucous membranes such as
edema; congested conjunctivae; erythema of the oral cavity, lips, and
palms; and desquamation of the skin of the fingertips. Although the
disease is generally benign and self-limited, it is associated with coro­
nary artery aneurysms in ~25% of cases, with an overall case-fatality
rate of 0.5–2.8%. These complications usually occur between the third
and fourth weeks of illness during the convalescent stage. Vasculitis
of the coronary arteries is seen in almost all the fatal cases that have
been autopsied and can cause complications into adulthood. There
is typical intimal proliferation and infiltration of the vessel wall with
mononuclear cells. Beadlike aneurysms and thromboses may be seen
along the artery. Other manifestations include pericarditis, myocardi­
tis, myocardial ischemia and infarction, and cardiomegaly.
Apart from the up to 2.8% of patients who develop fatal complica­
tions, the prognosis of this disease for uneventful recovery is excellent.
High-dose IV γ-globulin (2 g/kg as a single infusion over 10 h) together
with aspirin (100 mg/kg per day for 14 days followed by 3–5 mg/kg per
day for several weeks) has been shown to be effective in reducing the
prevalence of coronary artery abnormalities when administered early
in the course of the disease. Surgery may be necessary for Kawasaki
disease patients who have giant coronary artery aneurysms or other
coronary complications. Surgical treatment most commonly includes
thromboendarterectomy, thrombus clearing, aneurysmal reconstruc­
tion, and coronary artery bypass grafting.
Multisystem inflammatory syndrome (MIS-C), a serious condition
that may resemble Kawasaki’s disease, has been observed with infections
due to SARS-CoV-2 (Chap. 205). Although clinical features consistent
with Kawasaki’s disease have been observed, these patients can also have
manifestations atypical for Kawasaki’s disease, including gastrointestinal
symptoms, myocarditis, neurocognitive symptoms, and shock. Any
patient who presents with a clinical picture suggestive of Kawasaki’s dis­
ease should be tested for SARS-CoV-2 to guide management.
POLYANGIITIS OVERLAP SYNDROMES
Some patients with systemic vasculitis manifest clinicopathologic
characteristics that do not fit into a specific disease but have overlap­
ping features of different vasculitides. The diagnostic and therapeutic
considerations as well as the prognosis for these patients depend on the
sites and severity of active vasculitis. Patients with vasculitis that could
cause irreversible damage to a major organ system should be treated as
described under “Granulomatosis with Polyangiitis.”
SECONDARY VASCULITIS
■
■DRUG-INDUCED VASCULITIS
Vasculitis associated with drug reactions usually presents as palpable
purpura that may be generalized or limited to the lower extremities or
other dependent areas; however, urticarial lesions, ulcers, and hemor­
rhagic blisters may also occur (Chap. 63). Signs and symptoms may
be limited to the skin, although systemic manifestations such as fever,
malaise, and polyarthralgias may occur. Although the skin is the pre­
dominant organ involved, systemic vasculitis may result from drug reac­
tions. Drugs that have been implicated in vasculitis include allopurinol,
thiazides, gold, sulfonamides, phenytoin, and penicillin (Chap. 63).
An increasing number of drugs have been reported to cause vas­
culitis associated with ANCA. Of these, the best evidence of causality
exists for hydralazine and propylthiouracil. The clinical manifestations
in ANCA-positive drug-induced vasculitis can range from cutaneous
lesions to glomerulonephritis and pulmonary hemorrhage. Outside
of drug discontinuation, treatment should be based on the severity of
the vasculitis. Patients with immediately life-threatening small-vessel
vasculitis should initially be treated with glucocorticoids and cyclo­
phosphamide as described for granulomatosis with polyangiitis. Fol­
lowing clinical improvement, consideration may be given for tapering
such agents along a more rapid schedule.
CHAPTER 375
■
■SERUM SICKNESS AND SERUM
SICKNESS–LIKE REACTIONS
These reactions are characterized by the occurrence of fever, urticaria,
polyarthralgias, and lymphadenopathy 7–10 days after primary expo­
sure and 2–4 days after secondary exposure to a heterologous protein
(classic serum sickness) or a nonprotein drug such as penicillin or
sulfa (serum sickness–like reaction). Most manifestations are not due
to vasculitis; however, occasional patients will have typical cutaneous
venulitis that may progress rarely to a systemic vasculitis.
The Vasculitis Syndromes
■
■VASCULITIS ASSOCIATED WITH OTHER
UNDERLYING DISEASES
Certain infections may directly trigger an inflammatory vasculitic
process. For example, rickettsias can invade and proliferate in the
endothelial cells of small blood vessels causing a vasculitis (Chap. 192).
In addition, the inflammatory response around blood vessels associ­
ated with certain systemic fungal diseases such as histoplasmosis
(Chap. 218) may mimic a primary vasculitic process. A cutaneous
leukocytoclastic vasculitis with occasional involvement of other organs
may be a component of some infections. These include subacute bac­
terial endocarditis, Epstein-Barr virus infection, HIV infection, and a
number of other infections.
Vasculitis can be associated with certain malignancies, particularly
leukemic, lymphoid, or reticuloendothelial neoplasms. Leukocytoclas­
tic venulitis confined to the skin is the most common finding; however,
systemic vasculitis may occur.
A number of connective tissue diseases have vasculitis as a second­
ary manifestation of the underlying primary process. Foremost among
these are systemic lupus erythematosus (Chap. 368), rheumatoid
arthritis (Chap. 370), inflammatory myositis (Chap. 377), relapsing
polychondritis (Chap. 378), and Sjögren’s syndrome (Chap. 373). The
most common form of vasculitis in these conditions is the small-vessel
venulitis isolated to the skin. However, certain patients may develop a
fulminant systemic necrotizing vasculitis.
Secondary vasculitis has also been observed in association with
ulcerative colitis, congenital deficiencies of various complement compo­
nents, sarcoidosis, primary biliary cirrhosis, α1-antitrypsin deficiency,
and intestinal bypass surgery.
■
■FURTHER READING
Finkielman JD et al: Antiproteinase 3 antineutrophil cytoplasmic
antibodies and disease activity in Wegener granulomatosis. Ann
Intern Med 147:611, 2007.
Jayne D et al: A randomized trial of maintenance therapy for vasculitis
associated with antineutrophil cytoplasmic autoantibodies. N Engl J
Med 349:36, 2003.
Jayne DRW et al: Avacopan for the treatment of ANCA-associated
vasculitis. N Engl J Med 18:599, 2021.
Jennette JC et al: 2012 revised International Chapel Hill Consensus
Conference Nomenclature of Vasculitides. Arthritis Rheum 65:1, 2013.
Smith RM et al: Rituximab versus azathioprine for maintenance of
remission for patients with ANCA-associated vasculitis and relapsing
disease: An international randomised controlled trial. Ann Rheum
Dis 82:937, 2023.
Spiera RF et al: Sarilumab for relapse of polymyalgia rheumatica dur­
ing glucocorticoid taper. N Engl J Med 389:1263, 2023.
Stone JH et al: Rituximab versus cyclophosphamide for ANCAassociated vasculitis. N Engl J Med 363:221, 2010.
Stone JH et al: Trial of tocilizumab in giant-cell arteritis. N Engl J Med
377:317, 2017.
Walsh M et al: Plasma exchange and glucocorticoids in severe ANCAassociated vasculitis. N Engl J Med 382:622, 2020.
Wechsler ME et al: Mepolizumab or placebo for eosinophilic granu­
lomatosis with polyangiitis. N Engl J Med 376:1921, 2017.

19 - 376 Behçet Syndrome
376 Behçet Syndrome
Yusuf Yazici
Behçet Syndrome
PART 11
Immune-Mediated, Inflammatory, and Rheumatologic Disorders
Behçet syndrome is a systemic vasculitis, first described by Hulusi
Behçet, a Turkish dermatologist. It can present with oral and genital
ulcers, skin lesions, uveitis, arthritis, major arterial and venous ves­
sel disease, and gastrointestinal and neurologic manifestations. These
manifestations can be present in various combinations and sequences
over time. Patients are most commonly from the Middle East, the
Mediterranean region, and the Far East; it is most prevalent in Turkey,
with a prevalence of 1 in 250 adults. It is relatively rare before the late
teens and after age 50. Males and females are equally affected; however,
males frequently have more severe disease and poorer outcomes. Some
manifestations may show regional differences; for example, gastroin­
testinal involvement, rare in Turkey, is more common in Japan and is
seen in ~30% of patients in the United States.
■
■DIAGNOSIS
Behçet syndrome is diagnosed clinically. There are no specific labora­
tory, imaging, or histologic features that can help in the diagnosis of a
patient with suggestive symptoms. However, these can be used in rul­
ing out conditions that may mimic Behçet syndrome and the diagnosis
is based on a combination of clinical features in the setting of ruling
out other potential causes. In this regard, some patients may require
months to years to develop the array of symptoms that would lead
to a definitive diagnosis, although a tentative diagnosis may be made
well before. The most commonly used and best performing diagnostic
criteria are the International Study Group (ISG) criteria (sensitivity
~95%, specificity ~96%); patients need to have recurrent oral ulcers
plus two of the following four clinical manifestations: recurrent genital
ulcers, skin lesions, eye lesions, or a positive pathergy test (Table 376-1).
Additional clinical manifestations may involve various organ systems,
including the gastrointestinal, vascular, pulmonary, and central ner­
vous systems. Up to 50–60% of patients, depending on where they
are from, can be positive for HLA B∗51; however, it is not used as a
diagnostic test because it is also found in around 20% of the normal
population.
■
■PATHOGENESIS
The pathogenesis and etiology of Behçet syndrome are unknown.
Family studies show a possible genetic predisposition, and increased
inflammation and immunologic mechanisms play a role. Both innate
and adaptive immune systems may be involved. Unlike other auto­
immune diseases, however, Behçet syndrome is not typically associated
with autoantibodies, Raynaud’s phenomenon, Sjögren’s syndrome,
thrombocytopenia, hemolytic anemia, sun hypersensitivity, serosal
involvement, or an increased risk for other autoimmune diseases.
On the other hand, features that separate it from autoinflammatory
conditions include tendency to abate with time, absence of mutations
TABLE 376-1  International Study Group Criteria for the Diagnosis of
Behçet Syndrome
CRITERIA
FREQUENCY
COMMENTS
Oral ulcers
~98%
At least 3 times in a 12-month period
Plus 2 out of 4 from below:
 
 
Recurrent genital ulcers
~80%
Usually scarring
Skin lesions
~80%
Erythema nodosum, pseudofolliculitis,
papulopastular or acneiform nodules
(postadolescent, not receiving
corticosteroids)
Eye lesions
~50%
Anterior or posterior uveitis, cells in
vitreous or retinal vasculitis
Pathergy
~50%
Evaluated in 24–48 h, after dermal
insertion of a 20-gauge needle
associated with autoinflammatory diseases, and higher prevalence
than typical autoinflammatory diseases such as familial Mediterranean
fever (Chap. 381). There is neutrophil hyperreactivity; however, it is
not clear whether this is primary or secondary to cytokine-directed
activation. There is also evidence from retrospective patient cohort
analyses that there may be different clusters of disease presentation;
for example, acne lesions are more commonly seen with arthritis and
associated with enthesitis, and each of these clusters may have a differ­
ent pathogenesis.
■
■CLINICAL PRESENTATION
The most common symptoms are associated with mucocutaneous tis­
sues. Oral ulcers are seen in virtually all patients and are commonly the
first manifestation (Fig. 376-1). Commonly, like ordinary canker sores,
they are usually multiple. They last around 10 days but recur unless
treated. Only the uncommon, major ulcers tend to scar. Beneficial
effects of dental and periodontal therapies suggest that decreased oral
health is associated with disease severity.
Genital ulcers are the most specific lesions, most commonly occur­
ring on the scrotum or labia (Fig. 376-1). They are larger and deeper
and take longer to heal than oral ulcers and tend to form scars.
Acne-like or papulopustular lesions are indistinguishable from acne
vulgaris in appearance and pathology. They are seen both at the usual
acne sites as well as at uncommon sites such as lower extremities. Other
skin findings are the nodular lesions, which are of two types: erythema
nodosum lesions due to panniculitis and superficial vein thromboses.
Superficial thrombophlebitis often occurs in men and is associated
with deep-vein thrombosis; it should trigger workup for other vascular
involvement, including pulmonary artery aneurysms.
Pathergy reaction is a nonspecific hyperreactivity of the skin
to trauma. Typically, a papule or pustule forms in 24–48 h after a
A
B
FIGURE 376-1  Clinical findings in Behçet syndrome. A. Behçet oral ulcer. B. Behçet
scrotal ulcer.

20 - 377 Inflammatory Myopathies
377 Inflammatory Myopathies
20–21-gauge needle prick. It is rather unique for Behçet syndrome and
is part of the ISG diagnostic criteria.
Arthralgia or arthritis is seen in about half of patients; it is usually
a mono- or oligoarthritis in the lower extremities and does not usually
cause erosions or deformity.
Eye involvement is seen in half of all patients and may be seen in
up to ~70% of males. It is most commonly a bilateral panuveitis. A
hypopyon, seen in ~10% of patients with eye disease, is an intense
inflammation in the anterior chamber and is quite specific for Behçet
syndrome. Ocular involvement develops usually in the first 2 years
after fulfillment of diagnostic criteria and is most severe during the first
few years and then tends to abate. Male gender, posterior involvement,
frequent attacks (>3 per year), strong vitreous opacity, and macular
edema are poor prognostic factors.
Vascular disease is seen in up to 40% of patients. It is associated
with intensive thrombosis and runs a relapsing course. Several welldefined venous vascular associations are seen; superficial and deepvein thrombosis, Budd-Chiari syndrome, inferior vena cava syndrome,
pulmonary artery involvement, intracardiac thrombosis, and cerebral
venous sinus thrombosis frequently cluster in various combinations.
Pulmonary artery aneurysms carry a 5-year mortality rate of 20–25%.
Prevalence of neurologic involvement is ~5%, with about threequarters of patients presenting with parenchymal involvement, while
the remaining cases present with cerebral venous sinus thrombosis.
These two forms rarely occur together. Parenchymal involvement usu­
ally affects the telencephalic-diencephalic junction, brainstem, and
spinal cord. Patients may present with a subacute onset of severe head­
ache, cranial nerve palsy, dysarthria, ataxia, and hemiparesis.
Prevalence of gastrointestinal involvement changes significantly
across different populations (up to 50% in the Far East but rare in the
Middle East). Clinical and endoscopic appearance of intestinal involve­
ment can be similar to, and thus cannot easily be differentiated from,
Crohn’s disease. Ulcers tend to be single or less than five, are usually
confined to the ileocecal area, are more likely to be deep and round,
and are prone to perforate; perianal and rectal area involvement are
rare. In practice, it is difficult to distinguish Behçet syndrome from
Crohn’s disease unless extraintestinal manifestations are present.
TREATMENT
Behçet Syndrome
Treatment is guided by type and severity of involvement, with the
goal of preventing long-term damage. Most new manifestations
tend to present within the first 5 years, and for most patients, the
natural course is one of diminishing symptoms culminating in
potential remission, frequently not requiring ongoing treatment
with medications. Patient characteristics, such as being young and
male, need to be kept in mind when making treatment decisions,
as these patients tend to have a worse prognosis. In most patients,
tapering and/or stopping their medications in 2–3 years after the
symptoms have improved should be attempted.
Oral ulcers can be managed with topical glucocorticoids and
on an as-needed basis if mild. Lesions resistant to local measures
may require systemic treatment with colchicine, oral glucocorti­
coids, immunosuppressants such as apremilast, azathioprine, or
a tumor necrosis factor (TNF)-α inhibitor such as infliximab. A
similar treatment approach can be used for genital ulcers and other
mucocutaneous manifestations. Patients may need a combination
of medications, at least initially, to control disease activity.
Eye involvement, given its frequency and potential morbid­
ity, requires early and aggressive treatment with brief courses of
glucocorticoids and longer-term treatment with an immunosup­
pressant. Azathioprine is usually the preferred agent in clinical
practice. TNF inhibitors infliximab or adalimumab can also be
used, either as first-line monotherapy or more commonly in com­
bination with systemic glucocorticoids and azathioprine, for control
of disease activity. Cyclosporine can also be considered in combi­
nation regimens; monotherapy with interferon is another option.
Glucocorticoids can be tapered in many patients after active disease
has been controlled, whereas immunosuppressants are generally
continued for at least 2 years with plans to potentially taper them
also based on treatment response and ongoing disease activity.
Gastrointestinal involvement is treated with glucocorticoids plus
an immunosuppressant such as azathioprine alone or in combina­
tion with infliximab.
CHAPTER 377
Venous thrombotic events are treated by controlling systemic
inflammation with immunosuppressive medications (usually azathio­
prine or, for more severe cases, cyclophosphamide), rather than
using anticoagulants. However, if venous thrombotic events occur,
standard anticoagulation treatment can be given, provided there is
a low risk of bleeding and there are no coexistent pulmonary artery
aneurysms. For central nervous system involvement, the combina­
tion of azathioprine and a TNF inhibitor is usually the first choice.
Inflammatory Myopathies
■
■FURTHER READING
Hatemi G et al: 2018 update of the EULAR recommendations for the
management of Behçet’s syndrome. Ann Rheum Dis 77:808, 2018.
Kural-Seyahi E et al: The long-term mortality and morbidity of
Behçet syndrome: A 2-decade outcome survey of 387 patients followed
at a dedicated center. Medicine (Baltimore) 82:60, 2003.
Yazici H et al: Behçet syndrome: A contemporary view. Nat Rev
Rheumatol 14:107, 2018.
Yazici Y et al: Behçet syndrome. Nat Rev Dis Primers 7:67, 2021.
Steven A. Greenberg, Anthony A. Amato
Inflammatory
Myopathies
This chapter focuses on the major types of inflammatory myopathies
(IMs), including dermatomyositis (DM), polymyositis (PM), immunemediated necrotizing myopathy (IMNM), antisynthetase syndrome
(ASyS), and inclusion body myositis (IBM) (Table 377-1). Other IMs
include those caused by infection, eosinophilic myositis, granuloma­
tous myositis, and myositis triggered by checkpoint inhibitors. Of note,
inflammatory cell infiltrates can also be occasionally seen in muscle
biopsies of hereditary myopathies (e.g., muscular dystrophies, meta­
bolic myopathies), sporadic late-onset nemaline myopathy (SLONM),
and toxic myopathies.
Epidemiologic studies suggest that the incidence of IM grouped
together is up to 16 cases per 100,000 with prevalence in the range of
14–32 per 100,000. Defining the actual incidence and prevalence of
the individual myositides is limited, however, by different diagnostic
criteria employed in various epidemiologic studies, an increasing rec­
ognition of ASyS and IMNM, as well as the frequent misdiagnosis of
IBM. Idiopathic PM without signs of an overlap syndrome is quite rare
compared to DM, ASyS, IBM, and IMNM that occur in roughly simi­
lar frequencies. DM can occur in children (juvenile DM), while IBM
always occurs in adults and is the most common cause of myopathy
in those aged >50. DM, PM, and ASyS are more common in women,
while IBM is more common in men.
DIAGNOSTIC APPROACH AND
DIFFERENTIAL DIAGNOSIS
The approach to patients with suspected myopathy is detailed in
Chap. 460. In any patient presenting with weakness, the first step is to
localize the site of the lesion by history and clinical findings (Chap. 26).
Weakness could be caused by a process in the cerebral hemispheres, spi­
nal cord (Chap. 453), anterior horn cell (Chap. 448), peripheral nerve
TABLE 377-1  Inflammatory Myopathies: Clinical and Laboratory Features
AGE OF
ONSET
RASH
PATTERN OF
WEAKNESS
LABORATORY
FEATURES
MUSCLE BIOPSY
DISORDER
SEX
DM
F > M
Childhood
and adult
Yes
Proximal >
distal
Normal or increased
CK (up to 50× normal
or higher); various
MSAs (anti-MDA5,
anti-TIF1, anti-Mi-2,
anti-NXP2)
PART 11
Immune-Mediated, Inflammatory, and Rheumatologic Disorders
PM
F > M
Adult
No
Proximal >
distal
Increased CK (up to
50× normal or higher)
IMNM
M = F
Children
and adults
No
Proximal >
distal
Elevated CK (>10×
normal or higher);
anti-HMGCR or antiSRP antibodies
ASyS
F > M
Children
and adults
Sometimes
Proximal >
distal
Elevated CK (>10×
normal or higher);
antisynthetase
antibodies
IBM
M > F
Older adults
(>50 years)
No
Proximal
and distal;
predilection
for: finger/
wrist
flexors, knee
extensors
Normal or mildly
increased CK (usually
<10× normal); anticN-1A antibodies;
large granular
lymphocytes on
flow cytometry and
reduced CD4/CD8
ratio with increased
CD8 count
Abbreviations: CK, creatine kinase; cN-1A, cytosolic 5′-nucleotidase 1A; CTDs, connective tissue diseases; COX, cytochrome oxidase; DM, dermatomyositis; F, female; g,
immunoglobulin; IBM, inclusion body myositis; IFN-1, type 1 interferon; ILD, interstitial lung disease; IS, immunosuppressive; M, male; MAC, membrane attack complex;
MDA5, melanoma differentiation antigen; MHC-1, major histocompatibility antigen 1; MSA, myositis-specific autoantibodies; NCP2, nuclear matrix protein 2 (NXP2); NM,
necrotizing myopathy; PM, polymyositis; TIF1, transcriptional intermediary factor 1.
Source: Reproduced with permission from AA Amato, JA Russell (eds): Neuromuscular Disorders. 2nd ed. New York: McGraw-Hill Education; 2016.
(Chaps. 457–458), neuromuscular junction (Chap. 459), or muscle
(Chap. 460). Past medical history, medication use, and family history,
combined with a detailed clinical examination and an appreciation for
the pattern of muscle involvement (e.g., what muscles are weak and
atrophic or hypertrophic as well as the presence of scapular winging,
early contractures, sensory abnormalities, fasciculations, or rash), help
differentiate myopathies from other neuromuscular disorders and the
different types of myopathies from each other (see Chap. 460). For
example, atrophy with fasciculations suggests a neurogenic process
such as amyotrophic lateral sclerosis, fatigable weakness on examination
points to a neuromuscular junction defect such as myasthenia gravis,
and concomitant sensory symptoms suggest a central process such
as a spinal cord disorder or a polyneuropathy. Scapular winging, calf
hypertrophy or atrophy, and early contractures before significant weak­
ness develops would strongly suggest a muscular dystrophy, particularly
if there is a positive family history. A heliotrope rash combined with
Gottron papules (below) and dilated nailfold capillaries is diagnostic
for DM. The presence of atrophy and weakness of the flexor forearm
muscles and quadriceps in a person aged >50 years is most likely IBM.
When the site of the lesion cannot be localized based on history
and clinical examination alone, laboratory testing is required. Serum
creatine kinase (CK) is the most sensitive laboratory marker of muscle
destruction. Not all myopathies are associated with elevated CK levels,
but a markedly elevated CK (e.g., >2000 U/L) is almost always due
to a myopathy. A slightly elevated CK can also be seen in neurogenic
RESPONSE
TO IS
THERAPY
COMMON
ASSOCIATED
CONDITIONS
CELLULAR
INFILTRATE
Perimysial and
perivascular inflammation;
IFN-1 regulated proteins
(MHC-1, MxA), MAC
deposition on capillaries
CD4+ dendritic
cells; B cells;
macrophages
Yes
Myocarditis,
ILD,
malignancy,
vasculitis,
other CTDs
Endomysial and
perivascular inflammation;
ubiquitous expression of
MHC-1
CD8+ T cells;
macrophages;
plasma cells
Yes
Myocarditis,
ILD, other
CTDs
Necrotic muscle fibers;
minimal inflammatory
infiltrate; MHC-I and MAC
deposition on sarcolemma
of scattered nonnecrotic
muscle fibers
Macrophages
in necrotic
fibers
undergoing
phagocytosis
Yes
Malignancy,
CTD, HMGCR
antibody
cases can be
triggered by
statin use
Perimysial and
perivascular inflammation;
perimysial fragmentation
with alkaline phosphatase
staining; perimysial muscle
damage with necrosis;
MHC-I, HLA-DR, and MAC
deposition on sarcolemma
of perifascicular muscle
fibers
CD4+ dendritic
cells; B cells;
macrophages
Yes
Nonerosive
arthritis, ILD,
Raynaud’s
phenomenon,
mechanic
hands, and
fever
Endomysial and
perivascular inflammation;
ubiquitous expression
of MHC-1 and HLA-DR;
rimmed vacuoles; p62, LC3,
TDP-43 aggregates; EM:
15–18 nm tubulofilaments;
ragged red and COXnegative fibers
CD8+ T cells;
macrophages;
plasma cells;
myeloid
dendritic cells;
large granular
lymphocytes
None or
minimal
Granular
lymphocytic
leukemia/
lymphocytosis,
sarcoidosis,
sicca or
Sjögren’s
syndrome
disorders, however. Myositis-associated and myositis-specific antibod­
ies (MSAs) help to distinguish subtypes of IM, as discussed below.
Electromyography (EMG) and nerve conductions studies (NCS) are
useful in localizing the site of the lesion but are less specific in helping
to determine the actual cause of a myopathy. EMG can be useful at
times in guiding what muscle to biopsy, especially if muscles typically
biopsied are normal on clinical examination. Imaging skeletal muscle
can be helpful in assessing muscle involvement and revealing fatty
replacement, atrophy, or edema within muscle or surrounding fascia.
A muscle biopsy is often required to definitively distinguish one
myopathy from another, if there is no characteristic dermatomyositis
rash or myositis specific autoantibody. However, a muscle biopsy
should be performed in every case of suspected PM to exclude IBM
(if not clinically apparent) and other causes of myopathy. Diagnosis of
IMNM is by definition based upon histologic findings but again is not
needed if a patient has clinical features and anti-3-hydroxy-3-methylglutaryl-coenzyme reductase (HMGCR) or anti–signal recognition
particle (SRP) antibodies. It is important to biopsy a muscle that is
clinically affected but not too weak (e.g., Medical Research Council
grade 4 out of 5 in strength); otherwise, one may just see end-stage
muscle. A biopsy should always be coordinated with an experienced
muscle histopathology laboratory.
Patients with severe muscle pain, subjective weakness, and fatigue
with normal strength and function on examination are not likely to
have an IM. Polymyalgia rheumatica should be considered in older
individuals with an elevated erythrocyte
sedimentation rate (ESR) or C-reactive
protein (CRP) but normal CK and EMG.
Fibromyalgia is likely in patients with a
normal laboratory workup. In general,
a muscle biopsy is not indicated unless
there is objective weakness, an abnormal
EMG, or elevated CK.
SPECIFIC DISORDERS
■
■DERMATOMYOSITIS
Clinical Features 
DM manifests with
symmetric, proximal greater than dis­
tal weakness along with a characteristic
rash that includes the heliotrope rash
(erythematous discoloration of eyelids
with periorbital edema), Gottron sign
(erythematous rash over the extensor
surfaces of joints such as the knuck­
les, elbows, knees, and ankles), Gottron
papules (raised erythematous rash over
knuckles) (Fig. 377-1), V-sign (rash on
the sun-exposed anterior neck and chest),
shawl sign over the back of the neck
and shoulders, nail bed telangiectasias,
and subcutaneous calcium deposits. The
weakness and rash usually accompany
one another but can be separated by sev­
eral months. Furthermore, beyond “clas­
sic DM” with prominent muscle and skin
manifestations, there is a spectrum of
involvement such that some patients have
skin-predominant disease (only with a
rash called amyopathic DM, or mini­
mal muscle disease called hypomyopathic
DM), while others may present mainly
with weakness and little or no visible skin changes. Patients may also
have myalgias, arthralgias, dysphagia, and dysarthria. Cutaneous dis­
ease activity is highly relevant in DM; in comparison to other debilitat­
ing skin diseases including cutaneous lupus erythematosus, psoriasis,
and atopic dermatitis, skin symptoms in DM patients are associated
with an overall reduction in life quality. Pruritus can be especially
debilitating. Dyspnea can occur from ventilatory muscle weakness or
intrinsic lung involvement including interstitial lung disease (ILD),
bronchopneumonia, and alveolitis. Pulmonary manifestations are
often associated with anti-MDA-5 antibodies or with antisynthetase
antibodies; myositis associated with the ASyS is now considered a dis­
tinct disorder (discussed below). DM can present in children (juvenile
DM) or in adults. There is a higher risk for malignancy in adult-onset
cases, ~15% within the first 2–3 years.
A
B
FIGURE 377-1  Cutaneous manifestations of dermatomyositis. A. Macular erythema plaques (Gottron sign) and
erythematous papules (Gottron papules) on extensor surface of fingers and B. elbow. C. Macular erythema plaques
over anterior neck and chest (V-sign) and D. the posterior neck, shoulder, and upper back (Shawl sign). E. Nail bed
changes with dilated capillaries.
Laboratory Features 
Serum CK levels are elevated in 70–80%
of patients; in 10% of those with normal CK, serum aldolase may be
increased. Antinuclear antibodies can be positive but are a nonspecific
finding. The myositis-specific antibodies (MSAs) that are specific for
DM include anti–complex nucleosome remodeling histone deacetylase
(anti-Mi-2), anti–transcription intermediary factor 1-γ (anti-TIF1-γ),
anti–melanoma differentiation-associated gene 5 (anti-MDA5), anti–
nuclear matrix protein 2 (anti-NXP-2), and anti–small ubiquitin-like
modifier activating enzyme (anti-SAE). These antibodies are usually
associated with characteristic clinical features, and recent studies sug­
gest that they are also directly involved in the pathogenesis of DM.
Mi-2 antibodies are found in 15–20% of patients with DM and are
typically associated with an acute onset, a florid rash, and prominent
weakness but a good response to therapy and a favorable prognosis.
Anti-MDA5 antibodies are found in 10–20% of DM patients and up
to 65% of patients with clinically amyopathic DM. This antibody is
associated with palmar rash, severe skin ulcerations from ischemia,
CHAPTER 377
Inflammatory Myopathies
C
D
E
and rapidly progressive ILD. Anti-TIF1-γ, also known as p155, anti­
bodies are found in adult cancer-associated DM with an 89% specificity
and 70% sensitivity. Thus, enhanced vigilance for underlying cancer
is especially important in these patients. Anti-NXP-2 antibodies are
found in as many as 17% of patients with DM and are also associated
with calcinosis, subcutaneous edema, distal weakness, and dysphagia,
as well as with cancer. Anti-SAE antibodies are present in 1.5–8%
of DM and are associated with an underlying cancer in 14–57% of
patients. Most manifest with a skin rash alone, and CK is often normal,
but approximately one-third of patients have elevated aldolase levels.
ILD can also be seen in anti-SAE DM, but unlike anti-MDA-5 amyo­
pathic DM, the ILD is usually mild.
EMG of weak muscles shows increased insertional and spontaneous
activity in the form of positive sharp waves and fibrillation potentials,
or complex repetitive discharges along with early recruitment of smallamplitude, short-duration, polyphasic motor units. These findings are
nonspecific and can also be seen in other myopathies. Skeletal muscle
magnetic resonance imaging (MRI muscle) reveals edema in affected
muscles and sometimes more specific findings of abnormalities of
fascia suggesting fasciitis.
Histopathology and Pathogenesis 
The characteristic histo­
pathologic abnormality on muscle biopsy is perifascicular atrophy
(Fig. 377-2A); however, this finding is present in perhaps only 50%
of patients. Immunohistochemical staining for myxovirus resistance
protein A (MxA) is diagnostically more sensitive and highly specific
(Fig. 377-2B). The inflammatory cell infiltrate is predominantly peri­
vascular and located in the perimysium and is composed primarily of
macrophages, B cells, and plasmacytoid dendritic cells. Recent studies
have highlighted some variability in histologic abnormalities associated
with different MSAs. Skin biopsies reveal cell-poor interface dermati­
tis, which is analogous to the perifascicular atrophy in that the basal
PART 11
Immune-Mediated, Inflammatory, and Rheumatologic Disorders
A
B
FIGURE 377-2  Perifascicular atrophy and myxovirus resistance protein A (MxA) expression in dermatomyositis. A.
Perifascicular myofibers (black arrows) bordering on disrupted perimysial connective tissue are atrophic and basophilic
on hematoxylin and eosin (H&E) stains. B. Perifascicular myofibers (white arrows) show intense staining for MxA protein
along a gradient from superficial to deep; all capillaries show intense MxA expression (white arrowheads).
layer of keratinocytes is most damaged; the inflammatory infiltrate is
typically absent or minimal and, when present, is located mainly at the
border zone of the dermis and epidermis.
The pathogenesis of DM was traditionally attributed to an
antibody-mediated attack on endothelial cells, followed by complementmediated destruction of capillaries and watershed ischemia of muscle
fibers. However, subsequent studies suggest that this is not likely the
case. Immunoglobulin deposition is largely absent on endothelial
cells, and complement deposition may be a secondary phenomenon.
There is increasing evidence that the microvasculopathy and skin
and muscle damage associated with DM are primarily due to toxicity
from type I interferon (IFN)–mediated pathways, most likely IFN-β.
As mentioned, there is increasing evidence that the MSAs are directly
pathogenic. For example, anti-Mi-2 antibodies appear to be capable of
entering myonuclei and inhibiting the CHD4/NuRD complex in the
nucleosome.
Prognosis 
In the absence of malignancy, prognosis is generally
favorable in patients with DM, with 5-year survival rates ranging from
70 to 93%. Poor prognostic features are increased age, associated ILD,
cardiac disease, and late or previous inadequate treatment.
■
■POLYMYOSITIS
Clinical Features 
PM is a heterogenous group of disorders that
usually presents with symmetric and proximal weakness that worsens
over several weeks to months. As with DM, there can be associated
heart, lung, and joint involvement as well as an increased risk of cancer.
Some epidemiologic studies suggest that the risk of cancer in PM is
less than that in DM, but these older series likely included patients with
IBM and dystrophies with inflammation
who were misdiagnosed as having PM.
Laboratory Features 
CK levels are
always elevated in uncontrolled PM. A
normal CK should alert clinicians to the
possibility of IBM. EMG and skeletal
muscle imaging can be abnormal, but
the findings are not specific (Fig. 377-3).
Histopathology and Pathogen­
esis 
Because PM is a heterogeneous
category, muscle pathology varies sub­
stantially. Most often, patients with
nonspecific inflammatory cells present
in perimysial more often than endo­
mysial locations have been categorized
as PM. A small minority of patients have
a mononuclear inflammatory infiltrate
that surrounds fibers with sarcolemmal
expression of major histocompatibility
complex (MHC-I) molecules (Fig. 377-4).
FIGURE 377-3  Skeletal muscle magnetic resonance imaging (MRI) with short T1 inversion recovery (STIR) imaging in
polymyositis. MRI of the thigh demonstrates bright signal indicative of edema/inflammation, particularly in the rectus
femoris muscle. This contrasts with MRI in inclusion body myositis in which there is more selective involvement of the
vastus lateralis and medialis with relative sparing of the rectus femoris (see Fig. 377-7F and G).
There is debate as to whether a true inva­
sion of myofibers occurs in PM or rather
always indicates IBM. The inflamma­
tory infiltrate predominantly consists of
CD8+ T cells and macrophages located
in the endomysial, perimysial, and peri­
vascular regions. PM is heterogeneous,
and its varied forms of pathogenesis are
poorly understood.
Prognosis 
Most patients with PM
improve with immunotherapies but
usually require lifelong treatment. Some
retrospective studies suggest that PM
does not respond as well as DM to these
therapies. However, many of these older
series of “PM” likely included patients
who actually had IMNM, IBM, or other
myopathies (including muscular dystro­
phies) that do not respond to immunotherapies. As in DM, poor prog­
nostic features are cancer, increased age, lung or cardiac involvement,
and late or previously inadequate treatment.
■
■OVERLAP SYNDROMES
The term overlap syndrome is applied when an inflammatory myopa­
thy is associated with other well-defined connective tissue diseases
(CTDs) such as scleroderma, mixed connective tissue disease (MCTD),
Sjögren’s syndrome, systemic lupus erythematosus (SLE), or rheuma­
toid arthritis. Overlap syndromes are usually responsive to immuno­
therapies. The exception is Sjogren’s syndrome with coexisting IBM.
■
■IMMUNE-MEDIATED NECROTIZING MYOPATHY
Clinical Features 
IMNM, or autoimmune necrotizing myopathy,
is characterized by the acute or insidious onset of symmetric, proximal
more than distal weakness. Dysphagia, dysarthria, or myalgia may
occur. Patients may have an underlying CTD (usually scleroderma
or MCTD) or cancer (paraneoplastic necrotizing myopathy), or the
condition may be idiopathic. There are at least two distinct forms of
IMNM associated with specific autoantibodies (anti-HMGCR and
anti-SRP). Anti-HMGCR myopathy can be seen in patients receiving
statins, inhibitors of HMGCR, particularly in those aged >50 years.
However, anti-HMGCR myopathy can develop in children and young
adults without a history of statin use and can mimic a limb girdle mus­
cular dystrophy. Unlike the more common “toxic” myopathy associated
with statin use, anti-HMGCR myopathy does not improve when statins
are discontinued. Anti-SRP myopathies are notable for the presence of
anti-SRP antibodies and a typically subacute, aggressive, and relatively
refractory course.
FIGURE 377-4  Pathology of polymyositis. Muscle biopsy demonstrates endomysial
infiltrates surrounding nonnecrotic muscle fibers.
Laboratory Features 
CK levels are markedly elevated (usually
10 × normal) in IMNM and are associated with titers of anti-HMGCR
or anti-SRP antibodies. EMG often shows increased insertional and
spontaneous activity, including myotonic discharges. Skeletal muscle
imaging findings are nonspecifically abnormal.
Histopathology and Pathogenesis 
Muscle biopsies reveal multi­
focal necrotic and regenerating muscle fibers with a paucity of inflam­
matory cells (Fig. 377-5). However, some patients with anti-HMGCR
myopathy have endomysial, macrophage-predominant infiltrates simi­
lar to what is seen in PM. Overexpression of MHC-I and membrane
attack complex (MAC) molecules may be evident on sarcolemma of
nonnecrotic fibers, and MAC deposition present on capillaries. The
pathogenesis of IMNM is not completely understood and likely varies
depending on subtype. A trial of a complement inhibitor in both antiHMGCR and anti-SRP myopathies failed to demonstrate any efficacy,
so IMNM in these subtypes does not appear to be primarily comple­
ment driven. Interestingly, pathogenic biallelic variants in the HMGCR
gene result in proximal weakness, myalgias, high CK, and dystrophic
changes on skeletal muscle MRI and biopsies. Recent studies suggest
that HMGCR antibodies may bind to the receptor on the sarcolemma
and lead to accumulation of acetyl-CoA and subsequently an increase
in lipids within muscle fibers. Recent studies also suggest that anti-SRP
antibodies are directly causal to the associated IMNM.
Prognosis 
Anti-HMGCR myopathy is often responsive to intra­
venous immunoglobulin (IVIG) monotherapy. However, anti-SRP
FIGURE 377-5  Pathology of immune-mediated necrotizing myopathy. Muscle
biopsy demonstrates scattered necrotic fibers with inflammatory infiltrate confined
to those fibers undergoing myophagocytosis along with a few regenerating fibers.
myopathy and seronegative IMNM are generally much more difficult
to treat, and aggressive immunotherapy is usually required. The pro­
gressive course despite immunotherapy and the marked weakness with
atrophy can lead to a misdiagnosis of a limb girdle muscular dystro­
phy. There may be an increased incidence of cancer in patients with
anti-HMGCR myopathy; thus, patients should undergo a malignancy
workup.
CHAPTER 377
■
■ANTISYNTHETASE SYNDROME
Clinical Features 
The presence of myositis, nonerosive arthritis,
ILD, Raynaud’s phenomenon, mechanic hands, and fever associated
with antibodies against aminoacyl-tRNA synthetase constitute the
ASyS. Some patients have an erythematous rash, and muscle biopsies
share histopathologic features of DM, which likely accounts for many
of these patients being classified as having DM.
Inflammatory Myopathies
Laboratory Features 
Antibodies against aminoacyl-tRNA syn­
thetases are the most common MSA, present in 25–35% of patients
with myositis. These include anti-Jo-1 (histidyl), anti-PL-7 (threo­
nyl), anti-PL-12 (alanyl), anti-EJ (glycyl), anti-OJ (isoleucyl), anti-KS
(asparaginyl), anti-Ha (tyrosyl), anti-Zo (phenylalanyl), and other
less common antibodies. The most common aminoacyl-tRNA syn­
thetase antibody is anti-Jo-1. CK is usually elevated in patients with
ASyS and myositis. Those with ILD demonstrate reduced forced vital
capacity and diffusion capacity on pulmonary function tests. Spiral
chest computed tomography (CT) scans are best at demonstrating
the honeycomb pattern of ILD. Skeletal muscle MRI and EMG show
abnormalities similar to DM, PM, and IMNM.
Histopathology and Pathogenesis 
Muscle biopsies demonstrate
a predilection for perimysial damage including perimysial fragmenta­
tion and staining with alkaline phosphatase (Fig. 377-6), plasmacytoid
dendritic cells and macrophages in the perimysium and around blood
vessels, and MAC deposition on capillaries. Also similar to DM, there
is perifascicular muscle fiber damage, but with ASyS, there is more
perifascicular muscle fiber necrosis compared to DM, in which peri­
fascicular atrophy is more prominent. MHC-I, MHC-II (HLA-DR),
and MAC deposits on muscle fibers may be seen on sarcolemma of
perifascicular muscle fibers. The HLA-DR expression on muscle fibers
suggests that ASyS is more driven by gamma-IFN than type 1 IFN.
Recent studies suggest that the various antibodies may be directly
pathogenic by binding to specific aminoacyl-tRNA synthetases thereby
impairing protein synthesis. More work needs to be done to confirm
these observations.
Prognosis 
Most patients respond to treatment, although ASyS
can be difficult to treat, in particular for patients with interstitial lung
disease. Aggressive treatment, often with early rituximab, is war­
ranted in such cases. There does not appear to be an increased risk of
malignancy.
■
■INCLUSION BODY MYOSITIS
Clinical Features 
IBM usually manifests in patients over the age
of 50 years and is slightly more common in men than women. It is
associated with slowly progressive weakness and muscle atrophy that
has a predilection for early involvement of the wrist and finger flexors
in the arms and quadriceps in the legs (Fig. 377-7). Weakness is often
asymmetric. Dysphagia is common and rarely can be the presenting
feature. These clinical features can help distinguish IBM from PM and
other forms of myopathy. The mean duration from onset of symptoms
to use of wheelchair or scooter is ~15 years. There is no known increase
in risk of malignancy.
Laboratory Features 
CK levels can be normal or only slightly
elevated (usually <10 times normal). Antibodies targeting cytosolic
5′-nucleotidase 1A (cN-1A) are detected in the blood in a third to
more than two-thirds of IBM patients and are a highly specific diag­
nostic biomarker for IBM among patients with myopathy. Other blood
biomarkers for IBM include the presence of an abnormal population of
large granular lymphocytes on flow cytometry and a reduced CD4/CD8
PART 11
Immune-Mediated, Inflammatory, and Rheumatologic Disorders
A
B
C
FIGURE 377-6  Pathology of myositis with anti-Jo-1 antibodies (antisynthetase syndrome). A. Perifascicular/perimysial muscle fiber atrophy and necrosis (thin arrow)
associated with perimysial connective tissue is edematous and fragmented in appearance (thick arrow), hematoxylin and eosin stain. B. The perimysial connective
tissue intensely stains red with alkaline phosphatase stain (arrowhead). C. Immunostaining demonstrates deposition of membrane attack complex (MAC) deposits on the
sarcolemma of nonnecrotic perifascicular muscle fibers (open arrow).
ratio with an increased CD8 count. Needle EMG may demonstrate
large-amplitude, long-duration motor unit potentials that can be mis­
interpreted as neurogenic but reflect the chronicity of the myopathy.
Muscle MRI may show a predilection for involvement of the flexor
digitorum profundus in the arms and the vastus medialis and lateralis
muscles with sparing of the rectus femoris muscle.
Histopathology and Pathogenesis 
Muscle biopsies demon­
strate endomysial inflammatory infiltrates predominantly composed
of highly differentiated CD8+ CD57+ T cells that express killer cell
lectin-like receptor G1 (KLRG1) molecules, plus macrophages, that
A
B
D
E
FIGURE 377-7  Muscle manifestations of inclusion body myositis (IBM; A–C). Finger flexor weakness can be (A) subtle and multifocal (black arrows), (B) moderate, or (C)
severe. Note that even with complete paralysis of deep and superficial finger flexors, metacarpophalangeal joint flexion (arrows) is often maintained due to preservation of
lumbricals. D. Ventral forearm atrophy (arrows). E. Atrophy of medial thighs due to loss of vastus medialis (arrows). F. Early IBM, with relatively preserved vastus medialis
(arrows), in contrast to (G) advanced IBM with marked fibrous replacement of vastus medialis (arrows).
100.00 µm
surround and invade nonnecrotic muscle fibers expressing MHC-I and
MHC-II on the sarcolemma, along with fibers with rimmed vacuoles,
cytochrome oxidase (COX)–negative fibers, and inclusions on light
or electron microscopy (Fig. 377-8). The inclusions contain betasheet misfolded proteins (amyloid) but are difficult to appreciate with
routine Congo red stain (they are seen on frozen but not paraffin sec­
tions). Immunostaining for p62 appears to be the most sensitive stain
for detection of these inclusions. Importantly, rimmed vacuoles may
not be seen in as many as 20–30% of muscle biopsies. In such cases,
the presence of mitochondrial abnormalities (ragged red and COXnegative fibers) and immunostaining demonstrating p62 inclusions are
C
F
G
A
C
FIGURE 377-8  Pathology of inclusion body myositis. A. Scattered muscle fibers with rimmed vacuoles and rare fibers with eosinophilic inclusions (arrow), hematoxylin and
eosin stain. B. Cytochrome oxidase stain demonstrates an increased number of pale-staining or COX-negative muscle fibers. C. Cytoplasmic inclusions stain positive with
p62 within a muscle fiber (thick arrow). D. Electromicroscopy reveals 15- to 21-nm tubulofilamentous inclusions within a myonucleus.
helpful in distinguishing IBM from PM (aside from the clinical pattern
of muscle weakness). Immunostaining also demonstrates that TAR
DNA-binding protein 43 (TDP-43), an intranuclear RNA/DNA-binding
protein involved in the regulation of RNA processing, is extruded from
the myonuclei in IBM. This is similar to what is found in neurons
of patients with neurodegenerative disorders such as frontotemporal
dementia (Chap. 443) and amyotrophic lateral sclerosis (Chap. 448).
The pathogenesis of IBM is poorly understood. The prominent
adaptive immune system abnormalities related to T-cell inflamma­
tion and the presence of a relatively specific autoantibody against a
muscle protein indicate an autoimmune attack on muscle. The chronic
and highly inflammatory environment within muscles in IBM may
alter protein synthesis and degradation pathways in part via aber­
rant immunoproteasome expression. Additional histologic features,
typically referred to as “degenerative,” include aggregation of various
proteins including markers of endoplasmic reticulum (ER) stress and
autophagy (e.g., p62 and LC3). Involvement of ER stress and autophagy
has also been observed in other autoimmune diseases, such as primary
biliary cholangitis (PBC), inflammatory bowel disease, and ankylosing
spondylitis, some of which can be highly refractory to immunotherapy.
As noted above, TDP-43, which is important for normal splicing of
messenger RNA, is extruded from myonuclei in IBM; loss of TDP43–mediated splicing repression likely leads to abnormal inclusion
of cryptic exons in skeletal muscle and aberrant translation of muscle
proteins. Whether this tissue damage results directly from a pathogenic
immune response or a secondary neurodegenerative process is unclear
at this time.
Prognosis 
The myopathy is slowly progressive and is not typically
responsive to immunotherapies. Most patients require a scooter or
wheelchair within 10–15 years of onset of symptoms.
TREATMENT OF INFLAMMATORY
MYOPATHIES (TABLE 377-2)
DM, PM, ASyS, and IMNM are typically responsive to immuno­
therapy. High-dose glucocorticoids are considered the first-line treat­
ment. There is uncertainty regarding when to start second-line
CHAPTER 377
Inflammatory Myopathies
B
D
agents (e.g., methotrexate, azathioprine, mycophenolate, immuno­
globulin, or rituximab). The clinician must weigh with the patient
the increased risks of immunosuppression versus possible benefits
(e.g., faster improvement, steroid-sparing effects, and/or avoidance of
morbidities associated with long-term glucocorticoid use). It is our
general practice to start a second-line agent (typically methotrexate)
with glucocorticoids in patients with severe weakness or other organ
system involvement (e.g., myocarditis, ILD), those with increased risk of
steroid complications (e.g., diabetics, osteoporosis, or postmenopausal
women), and patients with IMNM who are known to have difficultto-treat myositis. When treatment is initiated with prednisone alone, a
second-line agent is added in patients who fail to significantly improve
after 2–4 months of treatment or in those who cannot be tapered to a
low dose of prednisone. Many patients with IMNM do not respond to
prednisone alone or even prednisone plus a second-line agent in combi­
nation. Many require triple therapy with prednisone, methotrexate, and
IVIG and, if this fails, rituximab. In our experience and that of others,
anti-HMGCR myopathy often responds to monotherapy with IVIG.
Unfortunately, IBM does not typically respond to any known immu­
notherapy. The mainstay of treatment is physical and occupational
therapy to improve function, and swallowing therapy (and sometimes
esophageal dilation or cricopharyngeal myotomy) in those with
dysphagia.
■
■GENERAL GUIDELINES FOR USE OF
SPECIFIC IMMUNOTHERAPIES
Glucocorticoids 
Treatment is initiated with prednisone (0.75–1.5
mg/kg up to 100 mg) administered as a daily morning single dose (the
most common dose used in adults is 60 mg daily). In patients with
severe weakness or comorbidities (e.g., ILD, myocarditis), treatment
with a short course of intravenous methylprednisolone (1 g daily for 3
days) is recommended prior to starting oral glucocorticoids. Patients are
generally maintained on high-dose prednisone until strength normal­
izes or until improvement in strength has reached a plateau (usually 3–6
months). Subsequently, prednisone can be tapered by 5 mg every 2–4
weeks. Once the dose is reduced to 20 mg every day or every other day,
TABLE 377-2  Immunotherapies for Inflammatory Myopathies
THERAPY
ROUTE
DOSE
SIDE EFFECTS
MONITOR
Prednisone
Oral
0.75–1.5 mg/kg per day to start
Hypertension, fluid and weight gain,
hyperglycemia, hypokalemia, cataracts,
gastric irritation, osteoporosis, infection,
aseptic femoral necrosis
PART 11
Immune-Mediated, Inflammatory, and Rheumatologic Disorders
Methylprednisolone
Intravenous
1 g in 100 mL/normal saline over 1–2 h,
daily or every other day for 3–6 doses
Azathioprine
Oral
2–3 mg/kg per day; single a.m. dose
Flu-like illness, hepatotoxicity, pancreatitis,
leukopenia, macrocytosis, neoplasia,
infection, teratogenicity
Methotrexate
Oral
7.5–20 mg weekly, single or divided doses;
1 day a week dosing
 
Subcutaneously
20–50 mg weekly; 1 day a week dosing
Same as oral
Same as oral
Cyclophosphamide
Oral
Intravenous
1.5–2 mg/kg per day; single a.m. dose
0.5–1.0 g/m2 per month × 6–12 months
Cyclosporine
Oral
4–6 mg/kg per day, split into two daily
doses
Tacrolimus
Oral
0.1–0.2 mg/kg per day in two divided doses
Nephrotoxicity, hypertension, infection,
hepatotoxicity, hirsutism, tremor, gum
hyperplasia, teratogenicity
Mycophenolate
mofetil
Oral
Adults (1–1.5 g BID)
Children (600 mg/m2 per dose BID)
(no >1 g/d in patients with renal failure)
Intravenous
immunoglobulin
Intravenous
2 g/kg over 2–5 days; then 1 g/kg every 4–8
weeks as needed
Rituximab
Intravenous
A course is typically 750 mg/m2 (up to 1 g)
and repeated in 2 weeks
Courses are then repeated usually every
6–18 months
Abbreviations: BUN, blood urea nitrogen; IVIG, intravenous immunoglobulin.
Source: Reproduced with permission from AA Amato, JA Russell (eds): Neuromuscular Disorders. 2nd ed. New York: McGraw-Hill Education; 2016.
the taper is slowed to 2.5 mg every 2–4 weeks. The goal is to taper pred­
nisone to ≤10 mg daily. Although most patients improve, the response
may not be complete and many will require at least a small dose of pred­
nisone or a second-line agent to have a sustained remission. Serum CK
levels are monitored; however, dose adjustments of prednisone and other
immunotherapies are primarily based on the objective clinical examina­
tion and not the CK levels or the patients’ subjective response. When no
response is noted after an adequate trial of high-dose prednisone, alter­
native diagnoses (e.g., IBM or an inflammatory muscular dystrophy) and
a repeat muscle biopsy should be considered.
Relapse of the myositis needs to be distinguished from steroid
myopathy. Features suggesting a steroid myopathy include weakness
developing while on high dosage, a normal serum CK, clinical features
of steroid excess such as ecchymoses and “moon facies,” and absence
of muscle membrane irritability on EMG. By contrast, patients experi­
encing relapses of myositis may become weaker during the prednisone
taper, have increasing serum CK levels, and display abnormal sponta­
neous activity on EMG.
Intravenous Immunoglobulin 
IVIG is most often used in
patients refractory to prednisone and at least one second-line immuno­
suppressive agent. However, the ProDERM Trial Group found IVIG to
be effective in a randomized, controlled trial in patients with DM, lead­
ing to U.S. Food and Drug Administration (FDA) approval. Thus, IVIG
can be administered as first-line therapy in DM. In addition, IVIG is
effective as a monotherapy in anti-HMGCR myopathy and may be the
treatment of choice. A dose of 2 g/kg is divided over 2–5 days, and
repeat infusions are given at monthly intervals for at least 3 months.
Subsequently, intervals can be lengthened or dosage decreased: 2 g/kg
every 2 months or 1 g/kg per month.
Weight, blood pressure, serum
glucose/potassium, cataract
formation
Arrhythmia, flushing, dysgeusia,
anxiety, insomnia, fluid and weight gain,
hyperglycemia, hypokalemia, infection
Heart rate, blood pressure,
serum glucose/potassium
Blood count, liver enzymes
Hepatotoxicity, pulmonary fibrosis, infection,
neoplasia, infertility, leukopenia, alopecia,
gastric irritation, stomatitis, teratogenicity
Liver enzymes, blood count
Bone marrow suppression, infertility,
hemorrhagic cystitis, alopecia, infections,
neoplasia, teratogenicity
Blood count, urinalysis
Nephrotoxicity, hypertension, infection,
hepatotoxicity, hirsutism, tremor, gum
hyperplasia, teratogenicity
Blood pressure, creatinine/
BUN, liver enzymes,
cyclosporine levels
Blood pressure, creatinine/
BUN, liver enzymes, tacrolimus
levels
Bone marrow suppression, hypertension,
tremor, diarrhea, nausea, vomiting, headache,
sinusitis, confusion, amblyopia, cough,
teratogenicity, infection, neoplasia
Blood count
Hypotension, arrhythmia, diaphoresis,
flushing, nephrotoxicity, headache, aseptic
meningitis, anaphylaxis, stroke
Heart rate, blood pressure,
creatinine/BUN
Infusion reactions (as per IVIG), infection,
progressive multifocal leukoencephalopathy
Some check B-cell count prior
to subsequent courses (but this
may not be warranted)
■
■SECOND-LINE THERAPIES
Methotrexate 
Methotrexate is usually the second-line treatment
of choice because most authorities believe it works faster than other
agents. An oral dose of 5 or 7.5 mg/week is initiated and then gradually
increased as needed up to 25 mg/week. If there is no improvement after
1 month of 25 mg/week of oral methotrexate, a switch to weekly par­
enteral (usually subcutaneous) methotrexate is the next step, with dose
escalation by 5 mg weekly; only rarely is a dose >35 mg/week used. The
major side effects of methotrexate are alopecia, stomatitis, ILD, terato­
genicity, oncogenicity, risk of infection, and pulmonary fibrosis, along
with bone marrow, renal, and liver toxicity. Patients are concomitantly
treated with folate or folinic acid.
Azathioprine 
A recommended initial dose is 50 mg/d in adults,
which can be increased by 50 mg every 2 weeks up to 2–3 mg/kg per
day. Approximately 12% of patients develop a systemic reaction char­
acterized by fever, abdominal pain, nausea, vomiting, and anorexia that
requires discontinuation of the drug. The major practical limitation
of azathioprine is that 6–18 months of treatment are usually required
before benefit can be seen. Patients can be prescreened for thiopurine
methyltransferase (TPMT) deficiency that is associated with severe
bone marrow toxicity from this drug.
Mycophenolate Mofetil 
This drug inhibits the proliferation of T
and B lymphocytes by blocking purine synthesis. It appears to be effec­
tive in different forms of myositis and is the second-line treatment of
choice for myositis patients with ILD. The starting dose is 1.0 g twice
daily and can be increased to 3 g daily in divided doses, if necessary.
Mycophenolate is excreted through the kidneys; therefore, the dose
should be decreased in patients with renal insufficiency. An advantage

21 - 378 Relapsing Polychondritis
378 Relapsing Polychondritis
of mycophenolate compared to other immunosuppressive agents is the
lack of renal or hepatic toxicity.
Rituximab 
Rituximab is a monoclonal antibody directed against
CD20+ B cells. A large randomized controlled trial found no benefit,
but there were flaws in the study design. Most authorities feel that
rituximab can be beneficial in some patients who are refractory to
prednisone and at least one of the other second-line agents. The typi­
cal dosage is 750 mg/m2 (up to 1 g) IV with a second infusion 2 weeks
later and with repeat courses (375 mg/m2 as a single infusion or with a
second infusion 2 weeks apart) every 6–18 months as needed.
Drugs in Clinical Trials 
Trials of a monoclonal antibody to block
IFN-β and drugs to target downstream pathways (e.g., JAK-1) are
ongoing in DM and other forms of myositis. Studies targeting the neo­
natal Fc receptor (FcRn) to decrease myositis-specific antibodies are
underway in DM, ASyS, and IMNM, as are trials with chimeric antigen
receptor (CAR) T-cell therapy. Ongoing trials in IBM include rapamy­
cin as well as a trial of a monoclonal antibody binding to KLRG1 to
deplete highly differentiated muscle-invading T cells.
MYOSITIS ASSOCIATED WITH
CHECKPOINT INHIBITORS
Autoimmune neurologic complications, including inflammatory neu­
ropathy (Chap. 458), myasthenia gravis (Chap. 459), and myositis, can
occur with use of immune checkpoint inhibitors (anti-CTLA-4, antiPD-1, and anti-PD-L1) to treat various cancers. Patients with myosi­
tis often develop muscle pain and weakness (axial musculature and
proximal limbs) after one or two cycles. Myocarditis can also develop.
Additionally, diplopia with extraocular weakness along with dysphagia
and dysarthria suggesting the co-occurrence of myasthenia gravis
(MG) may be present. In such cases, an elevated CK level helps sup­
port the diagnosis of myositis, while acetylcholine receptor antibod­
ies or decremental response on slow repetitive nerve stimulation can
establish the diagnosis of MG. Endomysial inflammatory cell infiltrates
composed of macrophages expressing PD-L1 and CD8+ lymphocytes
expressing PD-1, overexpression of MHC-I on sarcolemma of muscle
fibers, and scattered necrotic and regenerating fibers can be found on
muscle biopsies.
The immune checkpoint inhibitor should be discontinued, but most
patients require concurrent treatment with glucocorticoids or IVIG.
Patients generally improve over several months, during which time
immunotherapy can be tapered. There are rare reports of patients
with mild myositis who were able to be successfully re-treated with an
immune checkpoint inhibitor.
MYOSITIS ASSOCIATED WITH COVID-19
INFECTION
Early series of patients hospitalized with COVID-19 report that as
many as 44% of patients experience muscle pain or fatigue and 33%
have elevated CK levels. Rare cases are complicated by myoglobinuria.
Histopathology can demonstrate inflammatory cell infiltration and
necrotic muscle fibers. In autopsy series, SARS-CoV-2 has not been
demonstrated in muscle fibers, and the myositis is felt in most, if not
all, to be due to cytokine storm. Whether COVID-19 infection can
induce a chronic autoimmune myositis is controversial; there have
been a number of reports of various types of IM, some with MSA, in
patients following COVID-19 infection, but temporal associations do
not equal causation.
GLOBAL ISSUES
There is a lack of epidemiologic data with regard to the incidence and
prevalence of various subtypes of IM throughout the world. Compli­
cating the issue is disease awareness and the inability to obtain and
process muscle biopsies and MSAs, particularly in less developed
countries. Nevertheless, each of these disorders occurs throughout the
world. The specific environmental triggers and genetic risk factors are
likely variable. Interestingly, a report from Japan found that 28% of
IBM patients had evidence of exposure to hepatitis C, which was much
higher than seen in the Western Hemisphere and also more common
than seen in PM and healthy population controls in Japan. HIV-associated
PM and IBM are more commonly encountered in areas endemic for
HIV, and recent studies suggest most of these “PM” patients turn out to
have IBM and can develop symptoms at an earlier age (e.g., in the 30s).
Interestingly, while most cases of anti-HMGCR myopathy in North
America and Europe are associated with prior statin use, the major­
ity of such cases in Asia are not. Pyomyositis and parasitic myositis
are clearly more common in the tropics. The prevalence of different
types of cancers varies in different parts of the world, an important
consideration with respect to paraneoplastic myositis. For example,
nasopharyngeal cancer is particularly common in Asia; thus, assess­
ment for this type of cancer should be considered in the workup of
patients from high-risk regions.
CHAPTER 378
Relapsing Polychondritis
■
■FURTHER READING
Aggarwal  R et al: ProDERM Trial Group. Trial of intravenous
immune globulin in dermatomyositis. N Engl J Med 387:1264, 2022.
Allenbach  Y et al: Immune-mediated necrotizing myopathy: Clinical
features and pathogenesis. Nat Rev Rheumatol 16:689, 2020.
Amato AA, Russell JA (eds): Neuromuscular Disorders, 2nd ed. New
York, McGraw-Hill Education, 2016, pp. 827–871.
Britson  KA et al: Loss of TDP-43 function and rimmed vacuoles persist
after T cell depletion in a xenograft model of sporadic inclusion body
myositis. Sci Transl Med 14:eabi9196, 2022.
Greenberg SA: Inclusion body myositis: clinical features and patho­
genesis. Nat Rev Rheumatol 15:257, 2019.
Julien  S et al: Immune-mediated necrotizing myopathy (IMNM): A
story of antibodies. Antibodies (Basel) 13:12, 2024.
Mariampillai  K et al: Development of a new classification system for
idiopathic inflammatory myopathies based on clinical manifestations
and myositis-specific autoantibodies. JAMA Neurol 75:1528, 2018.
Müller  F et al: CD19 CAR T-cell therapy in autoimmune disease: A
case series with follow-up. N Engl J Med 390:687, 2024.
Pinal-Fernandez  I et al: Pathogenic autoantibody internalization in
myositis. medRxiv [Preprint]. 17:2024.01.15.24301339, 2024.
Puwanant A et al: Clinical spectrum of neuromuscular complications
after immune checkpoint inhibition. Neuromuscul Disord 29:127,
2019.
Suh J et al: Skeletal muscle and peripheral nerve histopathology in
COVID-19. Neurology 97:e849, 2021.
Marcela A. Ferrada, Peter C. Grayson
Relapsing Polychondritis
Relapsing polychondritis (RP) is a rare systemic disease characterized
by recurrent inflammation in cartilaginous structures. Involvement of
the ears, nose, respiratory tract, and joints are hallmark features of the
disease; however, other organs can be affected including the eyes, inner
ear, nervous system, skin, and cardiovascular system. Some patients
with RP may be concomitantly diagnosed with other rheumatologic
diseases, such as Sjögren’s syndrome or systemic lupus erythematosus.
Recurrent chondritis of the ears and nose in older male patients with
severe systemic inflammation and progressive bone marrow failure is
associated with acquired hematologic mutations in UBA1, a condition
now known as the VEXAS (vacuoles, E1 enzyme, X-linked, autoin­
flammatory, somatic) syndrome. Prompt recognition and accurate
diagnosis of RP or VEXAS syndrome are essential to prevent lifethreatening complications of these diseases.
The epidemiology of RP is poorly characterized. The disease is
commonly reported to primarily affect middle-aged adults without a
strong sex predilection; some cohort studies report female predilection,
but large, population-based studies typically show equal sex distribu­
tion. Children can be affected; however, these data are limited to case
reports. Rare instances of familial aggregation have also been reported.
The estimated incidence rate of disease is 0.7–3.5 cases per million per
year, and prevalence estimates range from 4.5–25 cases per million.
Epidemiologic data in RP are limited to older studies, typically evalu­
ating population distributions more than three decades ago in cohorts
from Europe and North America. Given the diagnostic challenges
encountered in this condition, these data may underestimate the true
prevalence of disease. Although RP has been reported in many regions
of the world, whether racial or ethnic differences are associated with
variable clinical features or outcomes is not known.
PART 11
Immune-Mediated, Inflammatory, and Rheumatologic Disorders
■
■PATHOLOGY AND PATHOPHYSIOLOGY
Histologic findings from biopsy of affected cartilage are dependent on
the timing of tissue sampling. In acute disease, a mixed inflammatory
infiltrate of myeloid and lymphoid populations is observed at the car­
tilage interface. Over time, cartilage destruction is marked by lacunar
breakdown and loss of chondrocytes, replaced by fibrosis. Biopsy of
affected cartilage may cause morbidity, and there are no features on
histology that are specifically diagnostic for RP. Therefore, biopsy is
often reserved when there is a high suspicion of conditions that mimic
RP, particularly infectious diseases and malignancies.
Although genetic, environmental, and immunologic aspects of the
disease have been studied in humans and in animal models, the exact
mechanisms that drive the disease are unclear. Limited studies in animal
models support the concept that autoimmunity to cartilage components
may play a role in RP. Immunization of specific animals to type II col­
lagen, type IX collagen, or matrillin-1 can recapitulate various aspects
of the clinical phenotypes observed in patients with RP; however, the
performance characteristics of these antibodies in clinical practice are
poor to differentiate RP from other diseases. Autoantibodies to type II
collagen have been reported in small cohorts of patients with RP but
are neither sensitive nor specific to be considered as an acceptable diag­
nostic marker of disease. Observational cohort data suggest that B-cell–
depleting therapies are not particularly effective to treat the condition,
arguing against a strong primary role of antibody-mediated disease.
Acute phase reactants (e.g., erythrocyte sedimentation rate or
C-reactive protein) are not reliably elevated in patients with RP.
Proinflammatory cytokines and chemokines related to both innate
and adaptive immunity have been identified in association with RP;
A
 
FIGURE 378-1  Representation of ear involvement in relapsing polychondritis. A and B. Examples of typical ear chondritis, with significant inflammation of the pinnae.
C. Mild ear cartilage inflammation. D. Cartilage damage.
however, these findings are not consistent and, therefore, are not rou­
tinely measured to guide management in clinical practice.
■
■CLINICAL MANIFESTATIONS AND
ORGAN INVOLVEMENT
RP is associated with a wide range of clinical manifestations. In the
absence of a diagnostic blood test, a detailed medical history and
physical examination are the most essential tools for diagnosis and,
most importantly, further management. Because disease activity is
intermittent and patients may not exhibit clear signs of inflammation
during direct evaluation, it is crucial to consider the patient’s symptoms
over time and to review any provided photographic documentation of
disease features.
Ears, Nose, and Throat 
Ear involvement is one of the most
common clinical manifestations of relapsing polychondritis, affecting
80–90% of the patients. However, there are no clear definitions of ear
chondritis, and patient descriptions of pain and associated symptoms
are variable. The typical description includes involvement of only the
cartilaginous aspect of the ear (pinnae) (Fig. 378-1A and B). However,
a subset of patients may report pain in the ears with minimal associ­
ated findings visualized on physical examination, such as mild swell­
ing or erythema (Fig. 378-1C). Although damage to the cartilaginous
portion of the external ear (i.e., “cauliflower ear”) is observed in RP
(Fig. 378-1D), it is present only in a small number of patients, usually
in the setting of recurrent episodes of ear inflammation. Questions
that can be helpful to elicit the nature of ear pain include asking about
onset, duration, and triggers. Common triggers include minimal
trauma to the ear (such as from lying on the effected side or wearing
glasses) or temperature changes.
Patients usually describe a sensation of pressure at the bridge of the
nose that may not be accompanied by other associated symptoms. Some
patients may have overt redness and swelling of the bridge or tip of
nose, but this is less common (Fig. 378-2A). While a “saddle nose” has
been described as a typical clinical finding in RP, many patients will not
develop an obvious nasal deformity (Fig. 378-2B). The nasal septum and
nasal passages should always be evaluated in patients with suspected RP,
as many patients can have septal ulcers and mucosal inflammation. In
contrast to granulomatosis with polyangiitis (GPA) where a saddle nose
deformity is usually associated with a septal perforation (Chap. 375),
patients with RP who have a saddle nose deformity usually do not have
B
C
 
FIGURE 378-1  (Continued)
a septal perforation, as most of the nasal perforations in patients with RP
are located anteriorly.
Patients can have complaints of throat pain or a sensation of globus,
usually described as a “choking sensation.” Patients can also report
pain on the anterior aspect of the neck, in some cases associated with
erythema, usually located at the level of the thyroid cartilage.
Upper and Lower Airway 
Conditions like subglottic stenosis
may manifest acutely or subacutely, leading to cough, voice changes, or
breathlessness. Severe narrowing can result in stridor, requiring urgent
medical attention to avoid mortality (Fig. 378-3A). Often misdiag­
nosed as adult-onset asthma, timely recognition of airway involvement
is important to prevent chronic damage to the large airways, which
can result in tracheomalacia, bronchomalacia, or tracheal calcification
(Fig. 378-3B and C). Patients with intermittent episodes of wheezing
A
 
FIGURE 378-2  Nose involvement in relapsing polychondritis. A. Redness and swelling of the base and tip of the nose. B. Saddle nose deformity.
CHAPTER 378
Relapsing Polychondritis
D
and with a review of symptoms positive for possible RP should be fol­
lowed closely and further evaluated for lower airway involvement.
Musculoskeletal 
• 
JOINTS  RP is associated with a nonerosive
inflammatory arthritis that can affect small and large peripheral joints
and as well as the axial skeleton. Erosions have been described in the
sacroiliac joints but not in other joints. The most common large joint
affected is the knees, often presenting with effusions. The pattern of
small joint involvement emulates rheumatoid arthritis, without ero­
sions or deformities.
TENOSYNOVITIS  Different tendons can be affected including Achilles
and peroneal tendons.
COSTOCHONDRAL JOINTS  Located at the rib-sternum junction, these
joints are frequently inflamed in RP, producing constant pain that
B
PART 11
Immune-Mediated, Inflammatory, and Rheumatologic Disorders
A
 
B
C
FIGURE 378-3  Airway involvement in relapsing polychondritis. A. Subglottic
stenosis. B and C. Computed tomography demonstrating tracheal calcification and
tracheomalacia.
stands out due to its unique severe quality. Pain due to costochondritis
can be so severe that patients will seek evaluation in the emergency
room due to concerns for an acute coronary event. The pain is bilateral,
reproducible with palpation, and not associated with movement of the
affected rib.
Inner Ear 
All patients with RP should undergo hearing tests to
evaluate for conductive and sensorineural hearing loss. During the
physical exam, the ear canal should be evaluated as some patients can
have severe inflammation or eustachian tube dysfunction leading to
conductive hearing loss. The presence of dizziness necessitates further
evaluation through maneuvers like finger-to-nose, Romberg, and nys­
tagmus to rule out vestibular involvement.
Ocular Involvement 
Episcleritis is the most frequent type of ocu­
lar inflammation in RP. It might coincide with other flare symptoms or
occur independently. Although rare, features suggesting scleritis man­
date urgent ophthalmologic evaluation due to its potential catastrophic
outcomes, including vision loss, scleromalacia, or global rupture neces­
sitating enucleation (Fig. 378-5A).
Cardiovascular 
Patients with mouth and genital ulcers with
inflamed cartilage (MAGIC) syndrome may exhibit symptoms seen in
Behçet’s syndrome (Chap. 376), including pathergy and gastrointes­
tinal involvement. These patients can also have large-vessel vasculitis
involving the aorta.
Neurologic 
The diagnosis of neurologic involvement due to RP is
one of exclusion. All possible etiologies including infection and malig­
nancy should be ruled out before attributing the clinical findings to RP;
however, encephalitis and meningitis can be seen in RP.
■
■DIAGNOSIS
There are no circulating or tissue-based biomarkers with adequate
performance characteristics to function as a diagnostic test for RP.
As such, diagnosis is based primarily on clinical pattern recognition
informed by a comprehensive review of systems and physical examina­
tion. Several diagnostic criteria have been proposed; however, these
criteria were developed in small cohorts, are largely based on expert
opinion, and have not been formally validated. McAdam’s criteria
require presence of three of six symptoms, including bilateral auricular
chondritis, nonerosive seronegative inflammatory polyarthritis, nasal
chondritis, ocular inflammation, respiratory tract chondritis, or ves­
tibular/cochlear dysfunction. Damiani and Levine modified McAdam’s
criteria to include either three clinical features or one clinical feature
with histologic evidence of chondritis or two clinical features with
clinical response to glucocorticoids, dapsone, or both. Michet’s criteria
propose three major criteria (inflammation of ear, nose, or respira­
tory tract) and four minor criteria (ocular inflammation, hearing loss,
vestibular dysfunction, and seronegative inflammatory arthritis) and
require fulfillment of two major criteria or one major plus two minor
criteria to establish the diagnosis. Another important limitation of
these criteria is the lack of precise definitions of organ involvement.
The differential diagnosis for RP includes conditions that mimic
chondritis in specific cartilaginous organs and systemic diseases for
which chondritis may be a manifestation. Ear chondritis can be mim­
icked by infectious and cutaneous diseases of the external ear, trau­
matic otohematoma, or red ear syndrome. Various infectious diseases
and angiocentric centrofacial lymphoma can mimic nasal chondritis.
Asthma, traumatic airway stenosis, infectious diseases, and congenital
disorders involving the airway can mimic airway chondritis. Systemic
diseases that mimic RP include GPA (Chap. 375) and autoinflamma­
tory diseases (Chap. 381). GPA can be differentiated from RP in part
by the presence of antineutrophil cytoplasmic autoantibodies (ANCA)
and glomerulonephritis, which are not features of RP. Presence of
cytopenia, most notably macrocytosis and lymphopenia, in older male
patients should trigger consideration of genetic testing and bone mar­
row assessment for VEXAS.
Audiometry to assess hearing loss and dynamic expiratory phase
computed tomography of the chest to assess tracheobronchomalacia are
critical studies that should be performed in all patients with suspected

22 - 379 Sarcoidosis
379 Sarcoidosis
RP to define the extent of disease involvement. Direct laryngoscopy
can be useful to visualize cartilage damage and inflammation in the
upper airway; however, bronchoscopy to visualize the lower airway can
exacerbate disease and should be performed with caution. Echocardiog­
raphy can assess valvular heart disease. Fluorodeoxyglucose–positron
emission tomography may have utility to detect inflammation in the
large arteries and the larger airways. Biopsy of affected cartilage often
yields nonspecific findings and should be reserved to exclude mimick­
ing conditions.
TREATMENT
Relapsing Polychondritis
Patients with RP can present to diverse specialists prior to diagnosis
that can include multiple emergency room visits. Internal medicine
doctors are typically among the first to encounter patients who
present with the initial manifestations of RP and are instrumental
in starting the initial treatment regimen.
Because RP is a systemic and heterogeneous disease, clini­
cal management should typically involve multidisciplinary teams,
including otolaryngologists (ear, nose, and throat specialists) and
pulmonologists. Given the disease’s propensity to progressively
involve various organs, it is crucial to perform initial testing to
define organ damage. If possible, patients should be referred to a
rheumatologist for comprehensive evaluation, diagnosis confirma­
tion, and the establishment of a tailored treatment plan.
Glucocorticoids are the cornerstone of initial treatment for
inflammation in RP, with dosages tailored to the severity of the
disease and the specific organs involved. In cases where life-threat­
ening organ involvement, such as the airway, is present, high doses
of glucocorticoids (e.g., 1 mg/kg of prednisone or an equivalent
glucocorticoid) should be rapidly initiated. For patients with milder
disease, lower doses of glucocorticoids can be trialed. Different
disease-modifying agents can be used to treat the disease including
methotrexate, leflunomide, mycophenolate, anti-interleukin-6, or
tumor necrosis factor inhibitors. Due to the heterogeneity of the
disease, treatment strategies are often determined by the predomi­
nant clinical phenotype.
■
■FURTHER READING
Beck DB et al: Somatic mutations in UBA1 and severe adult-onset
autoinflammatory disease. N Engl J Med 383:2628, 2020.
Ferrada M et al: Defining clinical subgroups in relapsing polychon­
dritis: A prospective observational cohort study. Arthritis Rheum
72:1396, 2020.
Alicia K. Gerke
Sarcoidosis
Sarcoidosis is a systemic inflammatory disease of unknown cause char­
acterized by the formation of nonnecrotizing granulomatous inflam­
mation. Sarcoidosis affects the lung in >90% of cases but can afflict
almost any other organ system as well. The disease was first described
150 years ago by Dr. Jonathan Hutchinson of London, England, as a
skin malady of symmetrical purple plaques (later termed lupus pernio)
and raised red lesions (Mortimer’s malady). In 1899, the skin lesions
were noted to be “sarkoid” by Caeser Boeck, a Norwegian dermatolo­
gist, as they resembled sarcoma, albeit the lesions were largely benign
and granulomatous in their histology. The advent of imaging and
other clinical technology later unveiled the multiorgan involvement
associated with sarcoidosis. However, despite even modern advances
in immunology, genetics, and genomics, there is still considerable mys­
tery regarding the exact etiology of the inflammation and the factors
that contribute to variability of disease presentation and clinical course.
Because of this considerable heterogeneity and lack of large, random­
ized treatment trials, decisions regarding diagnosis and management
continue to be challenging.
CHAPTER 379
EPIDEMIOLOGY
Sarcoidosis occurs throughout the world, affecting all genders, races,
and ages. Epidemiologic studies regarding the incidence, prevalence,
and mortality rates of sarcoidosis are difficult to conduct and compare;
this is due to the potential for nonstandardized case definition, differ­
ing methods of case acquisition, and lack of known etiology. Regional
variabilities due to race and gender, as well as phenotypic variability,
further confound epidemiologic measurements. Taken as a whole, epi­
demiologic studies highlight the variation in disease globally.
Sarcoidosis
■
■INCIDENCE AND PREVALENCE
The incidence and prevalence of sarcoidosis vary by race, gender,
geographic region, ethnicity, and season. An increased familial risk
has been noted. The highest incidence in the world occurs in African
Americans (35.5 per 100,000) and Northern European populations
(24 per 100,000) as described by studies from the United States and
Sweden. A higher incidence occurring in women is consistent across
most studies, although the ratio does not usually exceed 2:1. The
U.S. Black Women’s Health Study cohort found a particularly high
annual incidence of 71 per 100,000 and a prevalence of 2%. Some
studies suggest an increase in incidence over time in the populations
of some countries such as the United States and Japan. Peak incidence
of the disease occurs between 35 and 45 years of age, but a significant
proportion of cases do happen after age 55, with men manifesting
disease earlier than women. The overall perceived incidence rate may
be underestimated, as identification of subclinical sarcoidosis may
only be possible in screening population studies or at autopsy. Certain
occupations and exposures and an elevated body mass index have been
identified as risk factors for development of sarcoidosis, whereas smok­
ing is associated with reduced odds of incident sarcoidosis. Seasonal
variation is also reported, with a predominance of diagnoses occurring
in the springtime.
Differences in presentation and severity are also seen among popu­
lations. Cardiac and ocular involvement are more commonly observed
in Japanese populations, whereas Europeans tend to develop erythema
nodosum, which is uncommon among Japanese and black populations.
Several studies suggest that overall severity is higher in black popula­
tions, with black patients presenting with more frequent involvement
of extrapulmonary disease and three times the likelihood of familial
disease. Women are at increased risk for developing erythema nodo­
sum and ocular, musculoskeletal, and neurologic disease, while men
are at higher risk for hypercalcemia. While most sarcoidosis patients
have lung involvement, black and female patients tend to have more
severe lung disease. Finally, lower income has also been associated with
severity of disease and potentially greater disability and impairment
(particularly increased dyspnea and onset of new organ involvement),
suggesting that socioeconomic status may impact disease course.
■
■MORTALITY
Mortality rates vary considerably based on the study setting, with popu­
lation screenings noting lower rates of mortality than those reported
from referral centers. These occurrences may reflect differences in
disease severity. Analysis of death certificates from the United States
shows an average age- and gender-adjusted mortality rate of 4.32 per
1,000,000. Mortality rates are higher in women and in African Ameri­
cans. Pulmonary fibrosis is the leading cause of death in this population.
Lower mortality rates are seen in Japan, with estimates at 0.1 per million
people. In Japan, mortality from sarcoidosis itself is usually attributed to
cardiac involvement, whereas in Europeans and Americans, respiratory
mortality predominates.
ETIOLOGY
The cause of sarcoidosis is unknown; however, current evidence
strongly indicates a heightened host immune response to an undeter­
mined environmental exposure in a genetically susceptible individual.
It is unknown if there are multiple different antigens that induce
the same disease process. The immunologic response in sarcoidosis
appears to be physiologic, although it is either exaggerated or is defi­
cient in its regulatory mechanisms. The transmissibility of the immune
response also supports the presence of an antigen. For example, the
Kveim-Siltzbach reagent (historically used to diagnose sarcoidosis) is
a homogenate of human splenic tissue from patients with sarcoidosis
that, when injected into the skin, induces a systemic granulomatous
response in patients with early sarcoidosis. In a similar fashion, trans­
plant recipients can develop a sarcoid-like inflammatory response after
receiving organ tissue from another person with sarcoidosis.
PART 11
Immune-Mediated, Inflammatory, and Rheumatologic Disorders
Histologic inflammatory responses like sarcoidosis occur in the
lungs of patients with known inorganic and organic exposures such
as beryllium, mycobacteria, or fungi, resulting in these antigens being
studied as potential causes. Mycobacterial proteins (e.g., mKatG, ESAT-6,
mycobacterial superoxide dismutase A, antigen 85A, heat shock pro­
teins) have been found disproportionately in sarcoidosis granulomas.
Heightened macrophage immune responses against these peptides
within blood and bronchoalveolar lavage (BAL) have also been noted
in patients with sarcoidosis. In a similar manner in other cohorts, Cuti­
bacterium acnes (formerly Propionibacterium acnes) has been impli­
cated. A genetic predisposition is also suspected, as antigen recognition
and presentation molecule polymorphisms have been associated with
sarcoidosis development and phenotype. Similarly, gene–environment
interactions have been identified, suggesting a complex interaction of a
susceptible host in a predisposing environment.
Epidemiologically, the role of antigens in pulmonary sarcoidosis is
further supported by case-cluster events and occupational association.
Whereas numerous familial case clusters support a genetic predisposi­
tion to sarcoidosis in at least a proportion of cases, spatial clustering
of nonrelated sarcoidosis cases suggests exposure to an inciting envi­
ronmental antigen. For example, a baseline higher incidence is noted
in U.S. firefighters, with an annual incidence of sarcoidosis occurring
in 13–15 per 100,000 individuals. Following the World Trade Center
event and building collapses, the rates of “sarcoid-like” disease were
86 per 100,000 in the first year and 22 per 100,000 over the next 4 years,
with the highest risk associated with working in the debris piles. Inter­
estingly, the cases included not only those with lung disease but also
those with multisystem involvement, which would not be expected
from a localized inhalational exposure. Additionally, employment in
agriculture, teaching, metalworking, radiation, cotton ginning, and
automobiles has also been associated with sarcoidosis.
Increased rates of sarcoidosis have been found in association with
environmental exposures. Musty or humid environments, mold and
mildew, insecticides, air conditioning, raising birds, and exposure
to wood stoves/burning and fireplaces have been associated with
increased risk of sarcoidosis. On the other hand, smoking is con­
sistently a negative predictor of disease; the mechanism of this is
unknown, although it is perhaps related to immunomodulatory effects
of nicotine and smoke. These epidemiologic studies would indicate
that the inciting exposure may be a bioaerosol or an inorganic agent,
which may explain some of the epidemiologic variability of clinical
presentation by race, age, gender, and ethnicity. Additionally, the incit­
ing antigen may not be a single agent; rather, differing antigens may
exist for each individual or population.
PATHOGENESIS
Like other granulomatous processes, granulomas of sarcoidosis are
presumably forming around a poorly degradable or insoluble material
that is identified and presented to lymphocytes by dendritic cells or
macrophages via the major histocompatibility complex (Fig. 379-1). The
initial innate immune response triggers the production of cytokines
and chemokines that begin the cascade of granulomatous inflamma­
tion, attracting cells of the adaptive immune response. Activated lym­
phocytes and mononuclear cells migrate to the site of granulomatous
Antigen Presentation
MHC
Unknown
antigen
TCR
CD4+
T cell
(activated)
T Cell Response
Th-1 response
TH17
cell
Granulomatous
Inflammation
Regulatory Response
Treg
Resolution
Fibrosis
FIGURE 379-1  Immunopathogenesis of sarcoidosis. Granulomatous inflammation
of sarcoidosis is presumed to be due to a heightened immune response to an
undetermined antigen in a genetically predisposed individual. The antigen
presentation via the major histocompatibility complex (MHC) activates CD4+ T
cells, leading to a polarized TH1 response. Activated lymphocytes, macrophages,
and monocytes migrate to sites of inflammation, leading to a cascade of tightly
formed noncaseating granulomas. Altered T-regulatory (Treg) and TH17 responses
are thought to be involved in lack of resolution of granulomatous inflammation or
progression to fibrosis in some cases.
inflammation in a process driven by amplification of oligoclonal T cells
of undefined antigenic specificity. Type 1 (TH1) immune polarization is
the immunopathogenic hallmark of sarcoidosis, characterized by highly
polarized CD4+ TH1 lymphocytes and less so by CD8+ lymphocytes,
producing interferon-gamma (IFN-γ). TH1-promoting immunoregula­
tory cytokines and chemokines (interleukin [IL]-1, IL-2, IL-15, IL-18,
CXCR3) are consistently upregulated at sites of inflammation, propa­
gating the immune response, activating macrophages, and forming
granulomas. The accumulation of inflammatory cells at granuloma
formation sites appears to be the result of both in situ proliferation and
redistribution of the peripheral blood to the lung. Alterations in regula­
tory T cells and TH17 cells may also play a role in the body’s inability
to control the inflammation. Although most patients with sarcoidosis
eventually recover, the critical step as to why some patients with sar­
coidosis transition to fibrosis is not understood.
CLINICAL PRESENTATION
The clinical presentation of patients varies considerably from asymp­
tomatic to progressive organ dysfunction. Acute-onset presentation
is seen in Löfgren syndrome in up to 10% of sarcoidosis cases (fever,
erythema nodosum, ankle arthralgias, bilateral hilar lymphadenopa­
thy) and, less commonly, Heerfordt syndrome (facial nerve palsy,
fever, anterior uveitis, and bilateral enlargement of the parotid glands).
These acute presentations typically have an excellent prognosis with
full spontaneous resolution. In subacute or chronic cases, symptoms
such as chronic cough, dyspnea, atypical chest pain, or intermittent
joint or muscle pain tend to have a more insidious onset. In rare cases,
presentation of sarcoidosis can be fatal, usually related to heart failure,
sudden cardiac death, or neurologic involvement.
Symptoms vary depending on organ involvement and intensity of
inflammatory response; therefore, patients can present to different
clinical specialists. Nonspecific symptoms of fevers, malaise, night
sweats, and weight loss are often present. More fulminant and organthreatening symptoms can include acute hypercalcemia, blindness,
arrhythmias, heart block, or neurologic demise, necessitating hospi­
talization. Cardiopulmonary symptoms such as cough, chest pain, or
shortness of breath can mimic more common diseases, contributing
to delays in diagnosis. In many cases, findings of sarcoidosis are found
incidentally on imaging, prompting further workup.
ESTABLISHING A DIAGNOSIS
The diagnosis of sarcoidosis is made using three main criteria: (1) a
compatible clinical presentation, (2) the presence of nonnecrotizing
granulomatous inflammation in one or more tissues, and (3) exclusion
of alternative causes of granulomatous inflammation. The diagnostic
workup for sarcoidosis should also include assessment of extent and
severity of organ involvement, a review of prognostic factors, and a
determination of whether therapy will benefit the patient.
If a compatible clinical picture or radiographic finding suggests
sarcoidosis, then biopsy should be considered as the next step. There
are no well-established, clinically useful diagnostic serum biomarkers
that can secure a diagnosis. Noninvasive sites for biopsy can include
A
B
C
FIGURE 379-2  Comparison of granulomas. (A) The sarcoidosis granuloma is tightly formed and nonnecrotizing. (B) The infectious granuloma as seen in tuberculosis or
fungal infections is tightly formed but with a necrotizing center. (C) The granuloma in hypersensitivity pneumonitis is loosely formed and without necrosis.
skin, conjunctiva, or superficial lymph nodes, but in cases where lung
involvement and mediastinal/hilar lymphadenopathy are the promi­
nent feature, bronchoscopy is the preferred method for diagnosis.
Endobronchial ultrasound-guided lymph node sampling has high
diagnostic yield and low procedural risk. BAL studies of lymphocyte
subpopulations can be performed and characteristically reveal an
elevated percentage of lymphocytes. A CD4:CD8 lymphocyte ratio
3.5 supports a diagnosis of sarcoidosis, particularly when combined
with consistent clinical and radiographic findings (albeit a normal
ratio does not exclude sarcoidosis). BAL is also important to exclude
infection. Granulomas can line all segments of airway walls, providing
the “cobblestone” appearance seen during bronchoscopy. If needed,
transbronchial lung tissue biopsies can also be done to confirm sar­
coidosis with lung infiltrates. Endoscopic ultrasound through the
esophagus can be considered as an alternative biopsy approach based
on clinical presentation and location of inflammation. Rarely, surgical
lung biopsy or mediastinoscopy may be indicated when less invasive
procedures have proven nondiagnostic and no other accessible sites for
biopsy have been identified. 18F-fluorodeoxyglucose (FDG) positron
emission tomography (PET)–computed tomography (CT) can also be
helpful to identify active tissue inflammation and a site to biopsy in
difficult cases.
CHAPTER 379
Sarcoidosis
In some cases, the clinical presentation can be so compelling that
lymph node sampling may not be necessary. For example, this can
occur in patients with classic Löfgren syndrome, Heerfordt syndrome,
or lupus pernio. Similarly, deferring biopsy in asymptomatic patients
with symmetrical bilateral hilar lymphadenopathy may be considered
based on patient-oriented discussions. In all cases, however, close clini­
cal follow-up is still recommended, as the diagnosis of sarcoidosis is
never fully secure.
PATHOLOGY
The sarcoidosis granuloma is an organized collection of macro­
phages, epithelioid cells, and multinucleated giant cells (which form
as the epithelioid cells fuse). These cells are surrounded by a wellcircumscribed rim of lymphocytes and fibroblasts. CD4+ T lympho­
cytes are also found interspersed within the granuloma center, while
CD8+ T lymphocytes and B lymphocytes reside at the periphery.
Sarcoidosis granulomas are nonnecrotizing; however, punctuate
necrosis may be present on rare occasions. More abundant necrosis
strongly indicates alternative causes of granulomatous inflammation
such as infection, and loosely formed nonnecrotizing granulomas
would suggest an alternative diagnosis such as hypersensitivity pneu­
monitis (Fig. 379-2). Additionally, inclusions occasionally appear in
sarcoidosis granulomas; these can include asteroid bodies, birefrin­
gent calcium carbonate or oxalate crystals, Schaumann bodies, and
Hamazaki-Wesenberg bodies (especially in lymph nodes). Although
most inflammatory granulomas tend to resolve, hyalinization and
fibrosis of the granulomas can occur.
TABLE 379-1  Common Exclusionary Causes of Granulomatous Disease
in the Diagnosis of Sarcoidosis
OTHER INFLAMMATORY
DISEASES
MALIGNANCY
RELATED
INFECTIONS
Mycobacterial infection
• Tuberculosis
• Atypical
Environmental exposure
• Hypersensitivity
Malignancy
• Local
PART 11
Immune-Mediated, Inflammatory, and Rheumatologic Disorders
pneumonitis
• Aspiration pneumonitis
• Chronic beryllium disease
• Silicosis
• Talc inhalation or injection
• Local or systemic reaction
granulomatous
reaction
surrounding tumor
• Systemic sarcoidmycobacteria
Fungal infection
• Histoplasmosis
• Coccidiomycosis
• Blastomycosis
• Aspergillosis
• Cryptococcus
Parasitic infection
• Toxoplasmosis
• Schistosomiasis
Other bacterial and viral
infection (less common)
• Herpes zoster
• Tularemia (Francisella
like reaction to
malignancy
Chemotherapy or
immunotherapy
• Sarcoid-like
to tattoo ink
Medication sarcoid-like
reaction
• Immune checkpoint
reaction
inhibitors
• Antiretroviral therapy
• Interferon
• TNF-α antagonist
Autoimmune/Inflammatory
• ANCA-associated vasculitis
• Granulomatous-lymphocytic
tularensis)
• Q fever (Coxiella
interstitial lung disease
(associated with common
variable immunodeficiency)
• IgG4-related disease
• Rheumatoid nodules
• Inflammatory bowel disease
• Bronchocentric
burnetii)
• Bartonella henselae
granulomatosis
Abbreviations: ANCA, antineutrophil cytoplasmic antibodies; TNF, tumor necrosis
factor.
A histopathologic examination of the involved organ tissue reveals
granulomas in sarcoidosis; however, diagnosis heavily relies on exclu­
sion of other causes of granulomas. The differential diagnosis can be
broad and must be considered in the clinical context (Table 379-1).
A careful history assessment for environmental exposures or other
inflammatory diseases is imperative to secure confidence in the diag­
nosis of sarcoidosis. Infections can be difficult to differentiate from
sarcoidosis and require special histologic stains and cultures. Necro­
tizing sarcoidosis granulomatosis, characterized by necrosis, is a rare
and less well-established entity that often involves vasculitis. Given the
numerous causes of granulomatous inflammation and disease mimics,
the diagnosis of sarcoidosis is never made with absolute certainty, and
new symptoms or signs that occur during the disease process should
be fully evaluated.
DIAGNOSTIC EVALUATION
The initial evaluation of sarcoidosis patients includes a complete his­
tory and physical exam, as well as assessment of organ involvement
and severity of disease. Once diagnosis is suspected, a full review of
symptoms is warranted to elucidate any potential pulmonary and
extrapulmonary involvement, as about half of patients will have
extrapulmonary involvement. Almost every organ system in the body
can be affected by sarcoidosis (Fig. 379-3). A baseline set of testing
(at minimum) should be done in all patients on initial evaluation,
including pulmonary function tests, chest imaging, a baseline oph­
thalmologic investigation to evaluate for clinically silent uveitis, and
an electrocardiogram (ECG) (Table 379-2). Serum tests for abnormal
calcium metabolism and any significant hepatic, renal, or hematologic
involvement should also be performed. Hematologic abnormalities are
frequent and can be attributed to redistribution of T cells to sites of
disease, splenic sequestration, granulomatous bone marrow involve­
ment, or immune mediation. Routine asymptomatic follow-up testing
is more controversial regarding its utility, but repeat testing should be
Neurologic: 5%
Eyes: 12%
Salivary/Parotid
Glands: 4%
Ear/Nose/Throat: 3%
ä Calcium: 4%
Peripheral Lymph
Nodes: 15%
Lungs: 95%
Heart: 2%
Liver: 12%
Spleen: 7%
Kidneys: 1%
Skin: 16%
Bones/Joints/
Muscles: 1%
FIGURE 379-3  Frequency of organ involvement in sarcoidosis. Organ involvement
upon presentation. (RP Baughman et al: Am J Respir Crit Care Med 164:1885, 2001.)
done to evaluate the onset of any new signs or symptoms as the disease
evolves. Abnormal initial testing may require further workup.
ORGAN INVOLVEMENT
■
■LUNGS
The lungs are involved in >90% of patients with sarcoidosis. Pulmo­
nary function tests are important to measure initial lung impairment
and to assess improvement or deterioration over time. Many patients
have normal lung function testing or a normal lung exam despite
the presence of granulomatous inflammation and abnormal imag­
ing findings. A restrictive pattern is often seen in those with more
TABLE 379-2  Baseline Testing upon Initial Diagnosis of Sarcoidosis
Full history, review of systems, physical exam
Pulmonary function testing
Chest imaging
Eye exam
Serum creatinine, alkaline phosphatase, calcium level, complete blood counts
25- and 1,25-hydroxyvitamin D levels if assessing vitamin D metabolism
Electrocardiogram
Note: Further testing is dependent upon signs or symptoms indicating potential
organ involvement.
advanced disease, and airflow obstruction can occur in up to one-third
of patients. Sarcoidosis tends to be upper-lobe predominant on lung
imaging. Chest x-rays are classically used to “stage,” or describe the
pattern of presentation in the lungs, known as Scadding stages (Fig. 379-4).
Although chest CT is not indicated in every patient, it is commonly
performed to determine extent of lung disease and to guide biopsies.
Sarcoidosis granulomas have a lymphangitic distribution in the lung
along the pleural and subpleural areas and interlobular septa and
around the bronchovascular bundles. Classic findings of sarcoidosis on
chest CT scans are widespread small nodules with a bronchovascular
and subpleural distribution (Fig. 379-5A, B), thickened interlobular
septa, mediastinal and hilar lymphadenopathy, and conglomerate
masses with architectural distortion (Fig. 379-5C). In advanced cases
of pulmonary involvement, CT findings include honeycombing, cyst
or cavity formation, and bronchiectasis. Nodular sarcoidosis or nec­
rotizing sarcoid granulomatosis can present with nodular masses.
Pleural effusions tend to be indirectly related (e.g., infections, heart
failure), but rarely, sarcoidosis can cause lymphocytic, exudative
STAGE 1:
Bilateral hilar
lymphadenopathy
without
parenchymal lung
involvement
STAGE 2:
Bilateral hilar
lymphadenopathy
and parenchymal
lung involvement
STAGE 3:
Parenchymal lung
involvement without
lymphadenopathy
STAGE 4:
Pulmonary fibrosis
with architectural
distortion and
volume loss
FIGURE 379-4  Scadding stages in sarcoidosis.  
pleural effusions. Upper respiratory tract involvement can also occur
rarely within the larynx, pharynx, and sinuses and is associated with
more chronic severe disease.
Progressive pulmonary fibrosis with irreversible scarring is a sig­
nificant cause of complications and death in patients with sarcoidosis.
Fibrosis can be complicated by cavitary lung disease, chronic pul­
monary aspergillosis or aspergillomas, and pulmonary hypertension.
Airflow obstruction is common in these patients due to central airway
scarring and distortion of the lung structure. Fibrosis can occur even
in the setting of anti-inflammatory therapy.
CHAPTER 379
Sarcoidosis
■
■HEART
Granulomas can infiltrate any part of the heart, causing rhythm abnor­
malities, heart failure, pericardial effusion, and even sudden death. In
the broader general population, cardiac sarcoidosis is the cause of a
significant proportion of cases of new-onset atrioventricular block,
cardiomyopathy, and ventricular dysrhythmias, particularly in younger
age groups. Clinical evidence of cardiac involvement in patients with
RESOLUTION RATE:
55–90%
40–70%
10–20%
0%
PART 11
Immune-Mediated, Inflammatory, and Rheumatologic Disorders
A
B
C
FIGURE 379-5  Imaging findings in sarcoidosis. (A and B) Chest computed tomography images of sarcoidosis show widespread small nodules in a perilymphatic and
subpleural distribution and prominent bronchovascular bundle thickening. (C) Large peribronchovascular mass-like consolidations extending along the hila along with
partially calcified mediastinal and hilar lymphadenopathy in a patient with sarcoidosis.
known sarcoidosis is found in <5% of U.S. sarcoidosis patients and 23%
of Japanese patients, although autopsy studies suggest a higher rate of
subclinical involvement. Severity of pulmonary involvement does not
appear to predict the presence of cardiac sarcoidosis, and therefore
every patient should be queried for potential cardiac symptoms, as
cardiac sarcoidosis can have life-threatening complications. Isolated
cardiac sarcoidosis can also rarely occur.
Sudden death is the most common cause of death among cardiac
sarcoidosis patients, and it can occur as the initial presentation of the
disease. Ventricular tachycardia is the most frequent tachyarrhythmia,
but atrial tachycardias are also found in relation to ventricular dysfunc­
tion, dilated atria, or severe pulmonary disease. Heart failure is most
often due to involvement of the myocardium but can also be caused by
infiltration of valves or papillary muscles. Predictors of sudden death
include severity of heart failure, left ventricular end-diastolic diameter,
and sustained ventricular tachycardia.
Diagnosis of cardiac sarcoidosis can be difficult, since gold-standard
biopsies lack sensitivity due to the patchy presence of granulomas in
cardiac tissue, predominant location at base of the heart, and the lack
of right ventricular involvement. ECG should be obtained on initial
evaluation of every patient with sarcoidosis to reveal the presence of
any conduction block, ST-T wave abnormalities, Q waves, frequent
premature ventricular complexes, or resting tachycardia. Symptoms
or unexpected abnormalities on ECG should prompt further cardiac
evaluation, which can include a Holter monitor, signal-averaged ECG,
or further cardiac imaging.
Several imaging tests are used for evaluating and diagnosing cardiac
sarcoidosis. Historically, thallium-201 scintigraphy or technetium-sestamibi
single-photon emission CT nuclear scans have been used to identify
segmental defects that correspond either to a granulomatous disease or a
fibrous scar. In contrast to coronary artery disease, patients with cardiac
sarcoidosis have perfusion defects that reverse with exercise or dipyri­
damole, termed reverse redistribution. More current imaging studies now
support the use of enhanced cardiac magnetic resonance imaging (MRI)
as a preferred diagnostic tool due to its superior resolution and ability to
detect early myocardial involvement with high sensitivity and specificity.
Cardiac PET/CT can also be used in some cases to detect the presence of
active inflammation in cases where cardiac MRI is unavailable, unable to
be done (noncompatible devices or claustrophobia), or inconclusive. The
use of these imaging techniques has largely obviated the need for myocar­
dial biopsy in the diagnosis of cardiac involvement.
In patients with rhythm disturbances, prompt referral to an electrophysi­
ologist is warranted for consideration of potential mapping or implantation
of cardiac devices. Echocardiography can help identify ventricular dysfunc­
tion, valve dysfunction, abnormal septal wall thickness, or wall motion
abnormalities that may also be contributing to the clinical picture.
Traditional treatments for cardiac arrhythmias and heart failure are
indicated depending on the presentation, as well as immunosuppres­
sive medications. The optimal amount of time dedicated to the course
of immunosuppressive therapy is unclear, although the presence of
cardiac sarcoidosis generally portends a more chronic and protracted
course. Serial imaging and response to therapy can help guide potential
therapy duration. Heart transplantation can be considered for refractory
severe cardiac sarcoidosis, resulting in better short- and intermediateterm survival rates as compared to other transplant recipients.
■
■PULMONARY ARTERY HYPERTENSION
Pulmonary hypertension (PH) in sarcoidosis, classified as a World
Health Organization group 5 cause of PH, can complicate the clinical
course and contribute significantly to morbidity and mortality. Pulmo­
nary hypertension in sarcoidosis may be due to granulomatous vascu­
litis, pulmonary arterial occlusion by lymphadenopathy, thrombosis,
pulmonary venous occlusion, destruction of the vascular bed, left heart
dysfunction due to myocardial involvement, portopulmonary hyper­
tension from associated liver cirrhosis, or hypoxic vasoconstriction
related to parenchymal abnormalities. In some cases, precapillary PH
can occur in the absence of other cardiopulmonary disease, resembling
idiopathic PH. Evaluation for PH should be sought in patients who
have symptoms that are disproportionate to the amount of parenchy­
mal disease, have extensive parenchymal abnormalities, desaturate on
6-min walk test, or have a low diffusing capacity.
Echocardiography is a useful noninvasive technique screening test
to evaluate pulmonary pressures, systolic or diastolic function, and val­
vular disease; however, right heart catheterization is the gold standard
for diagnosis. Treating granulomatous disease with corticosteroids may
result in the improvement of pulmonary pressures in some, but not
all, cases, and pulmonary vasodilator therapy can be considered on a
case-by-case basis.
■
■NERVOUS SYSTEM INVOLVEMENT
Sarcoidosis affecting the nervous system is highly associated with
systemic disease but also can occur in the absence of significant pul­
monary or systemic disease. Cranial nerve involvement, particularly
with the facial and optic nerves, is the most common manifestation
and can be a result of granulomatous basal meningitis or direct involve­
ment of the nerve. Facial nerve palsy is associated with good prognosis
compared to other neurologic findings. Neurosarcoidosis has a predi­
lection for the base of the brain. Inflammation of the hypothalamus
and pituitary gland can cause neuroendocrine abnormalities that can
persist even after immunosuppressive treatment. Other findings can
include space-occupying masses, acute or chronic meningitis, periph­
eral neuropathy, and neuromuscular or spinal cord involvement. Rare
presentations include seizures or neuropsychiatric symptoms.
Gadolinium-enhanced MRI is the preferred test for evaluating brain
parenchyma, meninges, dura, and the spinal cord. MRI findings of
leptomeningeal or parenchymal enhancement or multiple white matter
lesions in a periventricular distribution are the more common abnor­
malities and are sensitive diagnostic findings. However, the appearance
of sarcoidosis lesions is often nonspecific, mimicking malignancies
or infections. Chest imaging can be helpful in diagnosis since many
patients will have a pulmonary abnormality that can be biopsied.
Cerebrospinal fluid (CSF) analysis most often reveals mononuclear
cell pleocytosis and/or elevated proteins. Elevated CSF angiotensinconverting enzyme, high soluble IL-2 receptor, increased lysozyme,
decreased glucose, and oligoclonal bands can also be seen but are not
diagnostic. CSF analysis is important to help exclude infection. Histo­
logic confirmation of disease in the brain or spinal cord is occasionally
necessary when significant diagnostic uncertainty exists or a patient is
not responding to therapy. Otherwise, a diagnosis can be established
with an acceptable degree of certainty by biopsy of a nonneurologic
site, such as the lung, together with consistent clinical features and
imaging and exclusion of other causes.
Peripheral nerves can also be affected in sarcoidosis. Pain is a
common symptom among sarcoidosis patients and may be related to
neuropathic or fibromyalgia syndromes. Small-fiber neuropathy has
increasingly been noted to be a cause of pain and autonomic dysfunc­
tion. Large-fiber neuropathies can be evaluated by performing nerve
biopsy or nerve conduction studies. Unfortunately, pain syndromes,
regardless of their underlying cause, often do not respond well to
immunosuppressive medications.
■
■CUTANEOUS
Sarcoidosis causes many forms of skin lesions, with maculopapular,
nodular eruptions and plaques being the most common types involv­
ing granulomatous inflammation of the tissue itself. Other skin lesions
include infiltration of old scars or tattoos, hypo- and hyperpigmented
areas, scales, annular lesions, ulcerations, and subcutaneous nod­
ules or masses. Most of the time, lesions are not painful or pruritic.
Nonspecific, nongranulomatous lesions of erythema nodosum are
a well-established manifestation of sarcoidosis, commonly found
in Europeans and women. Lesions are raised, tender, erythematous
bumps or nodules found on the anterior legs and often a prominent
feature of Löfgren syndrome. Lupus pernio is a distinctive chronic
lesion and consists of indurated plaques and violaceous discoloration
of the nose, cheeks, lips, and ears, and frequently involves the nasal
mucosa (Fig. 379-6). This lesion appears most commonly among
members of the African-American female population. Lupus pernio is
often associated with more severe disease including bone cysts, pulmo­
nary fibrosis, and a prolonged clinical course. Overall, skin lesions can
be treated with topical or injected corticosteroids, although disfiguring
or symptomatic lesions may need systemic therapy.
■
■EYE INVOLVEMENT
Ocular sarcoidosis can affect any part of the eye or orbit, with clinical
manifestations ranging from asymptomatic to permanent vision loss.
Given the potential for permanent vision loss, ophthalmologic exami­
nation is recommended on initial exam in sarcoidosis patients and with
any change in visual symptoms. Uveitis (anterior, posterior, or panuve­
itis) is the most common manifestation and is often bilateral. Chronic
uveitis may lead to synechiae formation, glaucoma, cataracts, cystoid
macular edema, and blindness. Optic neuropathy can lead to sudden
permanent vision loss and should be treated as an emergency with
immediate initiation of immunosuppressive therapy. Other eye lesions
FIGURE 379-6  Cutaneous sarcoidosis. Extensive involvement of the nose and philtrum extending onto the cheeks is seen. The lesions include confluent papules and
plaques, some of which are vaguely annular on the philtrum. (Courtesy of Dr. Misha Rosenbach, MD.)
include conjunctival or eyelid granulomas, lacrimal gland enlarge­
ment, keratoconjunctivitis sicca, dacryocystitis, retinal vasculitis, and
periorbital swelling. If conjunctival nodules are present, biopsy can be
a relatively noninvasive way to obtain diagnostic tissue.
CHAPTER 379
■
■LIVER
Hepatic granulomas are found very frequently in patients with pulmo­
nary sarcoidosis (up to 80% in some autopsy studies) but are much less
often clinically significant (up to 15%). Conversely, hepatic sarcoidosis
can occur without involving the lungs. Liver function tests are abnor­
mal in up to one-third of sarcoidosis cases, with an elevated alkaline
phosphatase as the most common lab abnormality. Elevated trans­
aminases are also frequent, while elevated bilirubin levels are more
indicative of significant progressive sarcoidosis liver disease. Hepato­
megaly is commonly seen. Patients who do present with symptoms
experience abdominal pain, pruritus, fevers, weight loss, and jaundice.
Hepatic sarcoidosis can infrequently progress to chronic cholestasis,
hepatocellular disease, portal hypertension, Budd-Chiari syndrome,
or cirrhosis. The pattern of presentation depends on the extent and
location of granulomatous inflammation and fibrosis in the liver. Imag­
ing of the liver often shows hepatomegaly and/or small, innumerable
nodules of low attenuation. Extensive evaluation of alternative causes
should be performed when cases of isolated hepatic granulomas are
involved, because liver granulomas are associated with a large differ­
ential diagnosis. Immunosuppressives may be effective when a patient
experiences symptomatic liver dysfunction, but not in every case. Liver
transplantation remains a viable option when hepatic failure occurs.
Sarcoidosis
■
■MUSCULOSKELETAL
Acute arthritis (such as that seen in Löfgren syndrome) is common in
sarcoidosis, especially early in the course of disease. Pain is a potential
indication to treat. Chronic arthritis or synovitis is rarer than the acute
presentations. The most common joints affected by sarcoidosis are the
ankles, knees, elbows, wrists, and small joints of the hands and feet.
Bone lesions, characteristically identified as lacy, reticular osteolytic
lesions on radiographs, can be frequently asymptomatic but occasion­
ally cause pain. Bone marrow involvement can cause hematologic
abnormalities such as anemia and lymphopenia.
Cases of symptomatic muscle involvement present with pain, ten­
derness, or weakness and have physical findings that are consistent
with myositis, chronic myopathy, or muscle nodules. Myopathy is more
commonly found in women and can be the sole presentation of disease.
MRI or nuclear bone scans are useful to identify active inflammation in
patients with musculoskeletal symptoms or to differentiate nonsarcoid­
osis causes. Electromyogram studies and biopsy may also be helpful in
the diagnostic workup.
■
■HYPERCALCEMIA
Hypercalcemia occurs in only about 10–20% of patients with sarcoid­
osis, but hypercalciuria is much more frequent and is seen in up to 50%
of patients. High calcium levels are due to dysregulated production of
the active form of vitamin D (1,25-hydroxyvitamin D3 or calcitriol)
by activated macrophages and granulomas in the setting of abundant
cytokines such as IFN-γ. Normally, conversion of vitamin D to its
active form is a highly regulated process that occurs in the kidney via
the action of 1-alpha-hydroxylase (CYP27B1) controlled by parathy­
roid gland. The conversion of vitamin D to calcitriol by macrophages
occurs unregulated, causing increased intestinal absorption and bone
resorption and thereby raising serum calcium despite low parathyroid
hormone levels. Hypercalcemia, left untreated, leads to nephrocal­
cinosis and subsequent renal dysfunction. Patients with evidence
of hypercalcemia should monitor vitamin D intake, avoid excessive
sunlight, and maintain hydration. In severe acute symptomatic cases,
hypercalcemia is a cause of hospital admission requiring more urgent
corticosteroid therapy.
PART 11
Immune-Mediated, Inflammatory, and Rheumatologic Disorders
■
■KIDNEY
Renal dysfunction is mostly related to hypercalcemia and nephrocal­
cinosis associated with sarcoidosis, rather than direct granulomatous
infiltration. However, sarcoidosis can cause interstitial nephritis (with
and without granulomas), which is generally responsive to treatment.
Urinalysis usually reveals sterile pyuria, bland sediment, or mild
proteinuria.
■
■LYMPHOID SYSTEM
Peripheral lymphadenopathy can be the presenting sign of sarcoid­
osis in a minority of cases. The extrathoracic glands most frequently
involved are the cervical, axillary, epitrochlear, and inguinal glands.
Enlarged glands are discrete, movable, and nontender without ulcer­
ation or drainage. Splenomegaly in sarcoidosis is common but is
usually clinically silent. Hypodense nodules can be seen on imag­
ing. Infrequently, splenic involvement may cause pressure, pain,
constitutional symptoms, or hematologic abnormalities that require
splenectomy.
■
■PAROTID GLANDS
Parotid or salivary involvement occurs in 4% of sarcoidosis patients,
often associated with Heerfordt syndrome (parotitis, uveitis, fever,
facial palsy). Patients with parotid gland involvement can be asymp­
tomatic or present with painful, swollen glands or xerostomia. Parotid
enlargement is self-limiting in many cases and can present like
Sjögren’s syndrome.
■
■GASTROINTESTINAL TRACT
Gastrointestinal tract involvement is a rare manifestation of sarcoid­
osis and most commonly involves the stomach than any other parts.
Patients may present with dysphagia, bleeding, nausea or vomiting,
pain, weight loss, or obstructive symptoms.
■
■REPRODUCTIVE ORGANS
Granulomas may occur in the reproductive system, most commonly
appearing within the female uterus or the male epididymis. Given
the rarity of involvement, any new nodules or masses in these organs
require careful attention to exclude malignancy.
CLINICAL COURSE AND PROGNOSIS
In just over half of patients, the disease resolves spontaneously; how­
ever, a significant proportion (30–40%) of patients will have chronic
disease that threatens vital organs or causes debilitating symptoms,
necessitating treatment. Chronic symptoms can be progressive or
waxing and waning. Predicting clinical course on presentation in any
one individual is difficult, given lack of known prognostic biomarkers.
Research studies are often confounded by the variable clinical course
and the lack of correlation of serum and radiographic measures to the
intensity of granulomatous response. Most cases of sarcoidosis will
show improvement in chest radiography or spirometry after 2 years
of follow-up, including treated and untreated. Serious extrapulmonary
involvement (e.g., cardiac, central nervous system, hepatic) occurs in
4–7% of sarcoidosis patients at presentation and can develop as the
disease evolves. Relapses are common and are associated with shorter
treatment duration. Acute exacerbations of pulmonary sarcoidosis are
thought to occur in over one-third of patients, although they are not
well-defined.
Death related to sarcoidosis itself does occur in 1–5% patients
because of progressive respiratory insufficiency, complications of
pulmonary scarring (e.g., hemoptysis, infection, aspergilloma), central
nervous system involvement, liver failure, or myocardial involvement
(heart failure, cardiac block, sudden cardiac death, or arrhythmias).
Differing mortality rates reflect variances in disease severity, referral
bias, and diverse genetic and epidemiologic factors of the populations
studied. For instance, most deaths occurring in the United States and
Northern Europe are due to pulmonary complications, whereas a vast
majority of deaths due to sarcoidosis in Japanese patients are from
cardiac involvement. Complications of immunosuppressive therapies
can also contribute indirectly to mortality. Transplantation of the lungs,
heart, liver, or kidneys can be lifesaving in severe progressive cases.
■
■CLINICAL FACTORS OF PROGNOSTIC
SIGNIFICANCE
Overall, patients with a more robust initial immune response have a
better prognosis than those with more subacute or chronic presentation.
Patients that present with Löfgren or Heerfordt syndromes tend to have
an excellent prognosis with spontaneous remission in up to 80%. Löfgren
syndrome occurs in 20–30% of Caucasians with sarcoidosis, particularly
Northern Europeans, and <5% of Asians and African Americans. Ery­
thema nodosum and fever usually remit spontaneously within 6 weeks,
while resolution of lymphadenopathy may be delayed for over a year.
Immunosuppressive therapy is rarely necessary. On the other hand,
adverse clinical prognostic factors include lupus pernio, chronic uveitis,
older age, chronic hypercalcemia, nephrocalcinosis, African origins,
pulmonary hypertension, fibrotic pulmonary sarcoidosis, sinus involve­
ment, cystic bone lesions, neurosarcoidosis, and cardiac involvement.
Parenchymal infiltrates associated with Scadding radiographic stages
do not predict activity, progression of lung disease, or extrapulmonary
involvement but do reveal overall resolution rates (Fig. 379-4).
■
■PREDICTIVE VALUE OF SERUM,
BRONCHOALVEOLAR LAVAGE, AND GENETICS
There are no current clinically used biomarkers that can predict clinical
course in any one case. Serum angiotensin-converting enzyme (ACE)
levels, derived from macrophages, are not largely useful as a diagnostic
or prognostic tool due to low sensitivity. However, ACE levels have
been employed to monitor systemic disease activity, as they correlate
roughly with the granulomatous burden. Similarly, the T-cell–derived
soluble IL-2 receptor lacks sensitivity for diagnosis but correlates with
disease activity and may predict relapse rate. In BAL fluid, the high
CD4:CD8 ratio, although supporting a diagnosis, does not correlate
with disease progression or need for treatment, but higher values seem
to implicate a better overall prognosis. Increased percentages of BAL
neutrophils (or eosinophils) appear to be present in a higher propor­
tion of individuals with progression. In genetics, certain human leu­
kocyte antigen (HLA) haplotypes have been associated with acute and
chronic phenotypes. Similarly, variants of butyrophilin-like 2 (BTNL2),
tumor necrosis factor alpha (TNF-α), and annexin A11 (ANXA11)
genes have been associated with worse prognosis. Unfortunately, these
and multiple other serum and BAL markers lack generalizability and
utility in the clinical realm for any one individual.
FOLLOW-UP AND MONITORING
To assess prognosis and determine the need for therapy, longitudinal
surveillance of sarcoidosis should be most intensive during the 2-year
period following presentation with decreasing frequency as time goes
on. When therapy has started, follow-up of response and side effects
should be done in 1–3 months and, once stable on therapy, every
3–6 months. Once in full remission, patients should be followed for a
few years to assess for relapses; however, lengthier observation may be
necessary based on severity of disease or residual organ dysfunction.
Follow-up testing should include symptoms, a complete physical exam,
imaging of affected organs, periodic pulmonary function testing, and
markers of specific organ dysfunction. Choice of imaging depends on
clinical scenario and can include chest x-rays, CT scans, and in some
rarer cases, PET/CT or MRI. Any development of new symptoms over
time should prompt full evaluation of that organ system.
TREATMENT
Sarcoidosis
Treatment decisions in sarcoidosis are complex, and medication
options tend to be guided by expert opinion, uncontrolled trials,
and only a few larger randomized controlled trials. There is no
cure for sarcoidosis; the goal of treatment is to suppress granu­
lomatous inflammation, prevent irreversible organ fibrosis, and
alleviate debilitating symptoms as the disease evolves. With the
high side effect profile of corticosteroids and other immunosup­
pressive therapy, it is first important to identify those cases in which
therapy is indicated. For example, treatment is not indicated for
asymptomatic stage I disease, which has an inherent high rate of
spontaneous resolution. Mild symptoms may be closely monitored,
and topical immunosuppressive therapies are preferred for skin
disease if possible. Oral immunosuppressive therapy should be
reserved for those who have significant symptoms, disfigurement,
or dangerous impending organ damage. In pulmonary disease, this
may include worsening cough and shortness of breath, moderate
to severe parenchymal lung involvement, or a progressive decline
in pulmonary function. In each case of sarcoidosis, the risks and
toxicity of immunosuppression must be considered in comparison
to the potential benefit of treatment.
Corticosteroids remain the mainstay of first-line treatment,
although controversy exists regarding whether they alter the natural
history. Oral steroids have been shown to improve chest x-ray imag­
ing scores, symptoms, and spirometry in the short term. There are
limited data beyond 2 years to indicate whether oral steroids have
any modifying effect on long-term disease progression or mortal­
ity. In cases of intolerance or toxicity to corticosteroids, inability
to taper corticosteroids, or refractory disease, alternative steroidsparing immunosuppressives can be considered (Table 379-3). In
TABLE 379-3  Treatments for Sarcoidosis
DRUG NAME
DOSE RANGE
CONSIDERATIONS
Initial therapy
Corticosteroids
(prednisone,
prednisolone)
20–40 mg/d initial, tapered to 7.5–15 mg/d
Consider taper early based on clinical improvement
Monitor bone health
Consider implications of weight gain
Assess risk of diabetes
Monitor eye exams (glaucoma and cataracts)
Common second-line
therapies
Methotrexate
7.5–20 mg/wk orally or subcutaneously
Concurrent administration with folic acid
Monitor liver and renal function and blood counts
Contraindicated with significant alcohol use
Leflunomide
10–20 mg/d
Monitor liver and renal function and blood counts
In cases of toxicity, consider cholestyramine to accelerate clearance
Azathioprine
50–200 mg/d or
1–2 mg/kg/d
Mycophenolate
1000–3000 mg/d
Monitor blood counts
Enteric-coated option available (note: different dose range)
Hydroxychloroquine
200–400 mg/d
Periodic eye exams for retinopathy
Assess QT (monitor drug interactions)
Effective for skin or hypercalcemia, but not for pulmonary
Refractory disease
or inability to taper
corticosteroids
Infliximab
3–5 mg/kg intravenously at weeks 0 and 2,
and then every 4–8 weeks
Adalimumab
40 mg subcutaneous every 1–2 weeks
(exact dose unknown)
choosing a therapy, clinicians should take into consideration the
presence of comorbid conditions such as osteoporosis, diabetes,
cataracts, or glaucoma that may be aggravated by corticosteroids.
Organ transplantation is occasionally necessary in cases of progres­
sive organ damage including lungs, liver, heart, and kidney. Sarcoid­
osis can recur in transplanted organs but is rarely a cause of organ
failure after transplant.
CORTICOSTEROIDS
When it is determined that treatment is indicated, corticosteroids
are generally used as first-line therapy given efficacy and ease of
use. Generally, prednisone or an equivalent corticosteroid is started
at 0.5 mg/kg per day or ~20–40 mg/d for 4 weeks, and then reduced
to a maintenance dose that will control symptoms and disease
progression, ideally below 10 mg/d. Higher starting doses are not
largely effective in most cases of sarcoidosis and are associated
with increased morbidity. Lower induction doses can be considered
based on severity of presentation, side effect tolerance, and rate of
disease progression. More aggressive therapeutic approaches with
higher doses or in association with other immunosuppression can
be considered in life- or organ-threatening situations such as seen
in central nervous system involvement, ocular involvement leading
to vision loss, or extensive myocardial inflammation. In a subgroup
of cases with very mild pulmonary symptoms such as cough,
inhaled corticosteroids may be considered for symptom control
but have not been shown to be of benefit in the larger sarcoidosis
population.
CHAPTER 379
Sarcoidosis
STEROID-SPARING THERAPIES
As the landscape of drug development broadens, treatment options
have expanded beyond corticosteroids to include several antiinflammatories drawn from treatment of other rheumatologic con­
ditions (Table 379-3). The choice of steroid-sparing agent often
depends on several clinical factors (e.g., alcohol use, desire for
pregnancy, known pharmacogenetic profiles, comorbidities such
as liver or renal dysfunction), but methotrexate is the most recom­
mended second-line therapy due to its efficacy and favorable side
effect profile. Azathioprine appears to be equally effective, although
Monitor liver and renal function and blood counts
Consider thiopurine methyltransferase activity level
Tuberculosis screening prior to use
Avoid use in heart failure
Allergic reactions possible with infusion
Longer term association with demyelination syndrome and malignancy
Can induce sarcoid-like reactions
Similar precautions and adverse events as infliximab

23 - 380 IgG4-Related Disease
380 IgG4-Related Disease
potentially has higher rates of infectious complications. Other
medications that can be considered second-line treatment include
leflunomide or mycophenolate mofetil. Hydroxychloroquine can
also be an effective immunomodulator, particularly for skin disease
or hypercalcemia, but is not recommended for lung disease.
If all second-line therapies have been exhausted due to intoler­
ance, inefficacy, or inability to taper corticosteroids, tumor necrosis
factor (TNF) inhibitors can be considered. TNF-α is produced by
the activated macrophages of the granuloma and contributes to
propagation of inflammation in sarcoidosis. Infliximab and adali­
mumab are monoclonal antibodies that target TNF-α. Infliximab
has garnered the most supporting data, with randomized controlled
trials and larger case series showing positive effects on pulmonary
function, imaging, and inflammatory cytokine levels, particularly
in those with more severe disease. Adalimumab has shown efficacy
in smaller series, particularly in ocular sarcoidosis. Etanercept, on
the other hand, a TNF receptor antagonist, has been shown to be
ineffective for sarcoidosis and should not be used for treatment.
Other therapies targeting different aspects of the immune response
are also considered at times in refractory cases including anti-B-cell
therapy and antifibrotic medications.
IMMUNOSUPPRESSIVE MONITORING
While on immunosuppressive therapy, close attention to preven­
tion of toxicity is important in the care plan, and monitoring
should follow published rheumatologic guideline recommenda­
tions. Bisphosphonates should be considered to minimize steroidinduced osteoporosis, and regular eye exams should be obtained
with corticosteroid use and hydroxychloroquine. When assessing a
medication choice, it is also important to consider pregnancy risk,
as many second-line agents have adverse reproductive effects.
DURATION OF TREATMENT
The exact duration of treatment may differ between individuals
based on severity of disease but is ~1 year for most patients. Shorter
courses of therapy have been associated with higher relapse rates,
although they can be considered for particularly responsive cases.
For pulmonary involvement, the greatest amount of improvement
is seen within the first weeks to months of therapy; therefore,
tapering of corticosteroids to a lower maintenance dose should be
considered with early follow-up to minimize long-term toxicity.
Longer courses of treatment may be necessary for life-threatening
or refractory disease. Relapses are treated with the last known effec­
tive dosing regimen.
PART 11
Immune-Mediated, Inflammatory, and Rheumatologic Disorders
APPROACH TO THE PATIENT
Sarcoidosis
Comprehensive treatment of the patient with sarcoidosis includes
not only suppression of granulomatous inflammation but also
consideration of medication side effects and evaluation of fatigue,
psychological health, and pain. Up to 80% of patients with sarcoid­
osis experience multifactorial fatigue, which can persist even after
treatment and remission. Fatigue can be due to medications, sleep
disorders, pain, and the granulomatous inflammation itself. It is
associated with extrapulmonary involvement. Neuropathic pain
or autonomic dysfunction may require symptomatic care. Formal­
ized physical training has been shown to improve exercise capacity,
strength, and fatigue in patients with sarcoidosis. Depression is also
highly prevalent in chronic sarcoidosis, associated with female sex,
dyspnea, and poor access to care. Cognitive impairment contribut­
ing to decreased quality of life is well-noted but poorly understood.
Patient-centered care of the entire constellation of effects of sarcoid­
osis can include neuropsychiatric evaluation, sleep therapy, exercise
therapy, pain relief, and lifestyle modifications. An individualized
plan is necessary for every patient to address the benefits of antiinflammatory treatments, associated comorbidities, and mainte­
nance of quality of life while living with sarcoidosis.
■
■FURTHER READING
Baughman RP et al: Clinical characteristics of patients in a case con­
trol study of sarcoidosis. Am J Respir Crit Care Med 164:1885, 2001.
Baughman RP et al: European Respiratory Society clinical practice
guidelines on treatment of sarcoidosis. Eur Respir J 58: 2004079,
2021.
Crouser ED et al: Diagnosis and Detection of Sarcoidosis. An Official
American Thoracic Society Clinical Practice Guideline. Am J Respir
Crit Care Med 201:e26, 2020.
Drent M et al: Challenges of sarcoidosis and its management. N Engl
J Med 385:1018, 2021.
Judson MA: Environmental risk factors for sarcoidosis. Front Immu­
nol 11:1340, 2020.
John H. Stone
IgG4-Related Disease
IgG4-related disease (IgG4-RD) is a fibroinflammatory condition
characterized by a tendency to form tumefactive lesions. The clinical
manifestations of this disease, however, are protean, as IgG4-RD can
affect virtually any organ system. The disease has a particular predilec­
tion for targeting blood vessels of any size on either the venous or arte­
rial side of the circulation and is therefore regarded as a variable-vessel
vasculitis. Commonly affected organs are the pancreas, biliary tree,
major salivary glands (submandibular, parotid), periorbital tissues,
kidneys, lungs, lymph nodes, and retroperitoneum. In addition, IgG4RD involvement of the meninges, aorta, prostate, thyroid, pericardium,
skin, and other organs is well described. The disease affects the brain
parenchyma, the joints, the bone marrow, and the bowel mucosa only
rarely.
The pathologic findings are consistent across all affected organs.
These findings include a lymphoplasmacytic infiltrate with a high
percentage of IgG4-positive plasma cells; a characteristic pattern of
fibrosis termed “storiform” (from the Latin storea, for “woven mat”); a
tendency to target blood vessels, particularly veins, through an oblit­
erative process (“obliterative phlebitis”); and a mild to moderate tissue
eosinophilia. Although the pathology is consistent from organ to organ,
it is essentially never diagnostic in and of itself. Classification criteria
emphasize the importance of careful correlation among clinical, sero­
logic, radiologic, and pathologic findings in deciding whether a patient
should be classified as having IgG4-RD. Biopsy is not required in order
to establish the diagnosis in classic cases, but most patients undergo a
biopsy at some point in the evaluation in order to exclude malignancy.
IgG4-RD encompasses a number of conditions previously regarded
as separate, organ-specific entities. A condition once known as “lym­
phoplasmacytic sclerosing pancreatitis” became the paradigm of IgG4RD in 2000, when Japanese investigators recognized that these patients
had elevated serum concentrations of IgG4. This form of sclerosing
pancreatitis is now termed type 1 (IgG4-related) autoimmune pancre­
atitis (AIP). By 2003, extrapancreatic disease manifestations had been
identified in patients with type 1 AIP, and descriptions of IgG4-RD in
other organs followed. Mikulicz’s disease, once considered to be a subset
of Sjögren’s syndrome that affected the lacrimal, parotid, and subman­
dibular glands, is one of the most common presentations of IgG4-RD.
■
■CLINICAL FEATURES
The major organ lesions are summarized in Table 380-1. IgG4-RD
usually presents subacutely, and even in the setting of multiorgan dis­
ease, most patients do not have fevers or high elevations of C-reactive
protein levels. Some patients, however, experience substantial weight
loss over periods of months. This is generally because of exocrine
TABLE 380-1  Organ Manifestations of IgG4-Related Disease
ORGAN
MAJOR CLINICAL FEATURES
Orbits and periorbital
tissues
Painless eyelid or periocular tissue swelling; orbital pseudotumor; dacryoadenitis; dacryocystitis; orbital myositis; and mass lesions extending
into the pterygopalatine fossa and infiltrating along the trigeminal nerve
Ears, nose, and
sinuses
Allergic phenomena (nasal polyps, asthma, allergic rhinitis, peripheral eosinophilia); nasal obstruction, rhinorrhea, anosmia, chronic sinusitis;
occasional bone-destructive lesions
Salivary glands
Submandibular and/or parotid gland enlargement (isolated bilateral submandibular gland involvement more common); minor salivary glands
sometimes involved
Meninges
Headache, radiculopathy, cranial nerve palsies, or other symptoms resulting from spinal cord compression; tendency to form mass lesions;
magnetic resonance imaging (MRI) shows marked thickening and enhancement of dura
Hypothalamus and
pituitary
Clinical syndromes resulting from involvement of the hypothalamus and pituitary, e.g., anterior pituitary hormone deficiency, central diabetes
insipidus, or both; imaging reveals thickened pituitary stalk or mass formation on the stalk, swelling of the pituitary gland, or mass formation
within the pituitary
Lymph nodes
Generalized lymphadenopathy or localized disease adjacent to a specific affected organ; the lymph nodes involved are generally 1–2 cm in
diameter and nontender
Thyroid gland
Riedel’s thyroiditis; fibrosing variant of Hashimoto’s thyroiditis
Lungs
Asymptomatic finding on lung imaging; cough, hemoptysis, dyspnea, pleural effusion, or chest discomfort; associated with parenchymal lung
involvement, pleural disease, or both; four main clinical lung syndromes: inflammatory pseudotumor, paravertebral mass often extending over
several vertebrae, central airway disease, localized or diffuse interstitial pneumonia; pleural lesions have severe, nodular thickening of the
visceral or parietal pleura with diffuse sclerosing inflammation, sometimes associated with pleural effusion
Aorta
Asymptomatic finding on radiologic studies; surprise finding at elective aortic surgery; aortic dissection; clinicopathologic syndromes
described include lymphoplasmacytic aortitis of thoracic or abdominal aorta, aortic dissection, periaortitis and periarteritis, and inflammatory
abdominal aneurysm
Retroperitoneum
Backache, lower abdominal pain, lower extremity edema, hydronephrosis from ureteral involvement, asymptomatic finding on radiologic
studies. Classic radiologic appearance is periaortic inflammation extending caudally to involve the iliac vessels.
Kidneys
Tubulointerstitial nephritis; membranous glomerulonephritis in a small minority; asymptomatic tumoral lesions, typically multiple and bilateral,
are sometimes detected on radiologic studies; renal involvement strongly associated with hypocomplementemia
Pancreas
Type 1 autoimmune pancreatitis, presenting as mild abdominal pain; weight loss; acute, obstructive jaundice, mimicking adenocarcinoma of
the pancreas (including a pancreatic mass); between 20 and 50% of patients present with acute glucose intolerance; imaging shows diffuse
(termed “sausage-shaped pancreas”) or segmental pancreatic enlargement, with loss of normal lobularity; a mass often raises the suspicion
of malignancy
Biliary tree and liver
Obstructive jaundice associated with autoimmunity in most cases; weight loss; steatorrhea; abdominal pain; and new-onset diabetes mellitus;
mimicker of primary sclerosing cholangitis and cholangiocarcinoma
Other organs involved
Gallbladder, liver (mass), breast (pseudotumor), prostate (prostatism), pericardium (constrictive pericarditis), mesentery (sclerosing
mesenteritis), mediastinum (fibrosing mediastinitis), skin (erythematous or flesh-colored papules), peripheral nerve (perineural inflammation)
pancreatic failure and the resulting inability of the pancreas to produce
sufficient quantities of digestive enzymes. Failure of the endocrine
pancreas, resulting in diabetes mellitus, is also common. Clinically
apparent disease can evolve over months, years, or even decades before
the manifestations within a given organ become sufficiently severe
to bring the patient to medical attention. Some patients have disease
that is marked by the appearance and then resolution or temporary
improvement in symptoms within a particular organ. Other patients
accumulate new organ involvement as their disease persists in previ­
ously affected organs. Initial misdiagnosis, particularly of cancer, is
extremely common because of the disease’s tendency to cause mass
lesions in the organs it affects. IgG4-RD is also often identified inci­
dentally through radiologic findings.
Multiorgan disease may be evident at diagnosis but can also evolve
over months to years. Some patients, however, have disease that
appears to be confined to a single organ at the time of diagnosis. Others
have subclinical involvement of other organs when the major clini­
cal feature presents. For example, patients with type 1 AIP may have
their major disease focus in the pancreas, but thorough investigation
through the history and physical examination, blood tests, and crosssectional imaging may demonstrate disease in multiple other organs.
Two common characteristics of IgG4-RD are allergic disease and
the tendency to form tumefactive lesions that mimic malignancies
(Fig. 380-1). Many IgG4-RD patients have allergic features such as
atopy, eczema, asthma, nasal polyps, sinusitis, and modest peripheral
eosinophilia. IgG4-RD also appears to account for a significant propor­
tion of tumorous swellings—pseudotumors—in many organ systems
(Fig. 380-2). Some patients undergo major surgeries (e.g., modified
Whipple procedures or thyroidectomy) for the purpose of resecting
malignancies before the correct diagnosis is identified.
IgG4-RD often causes major morbidity and can lead to organ failure;
however, its general pattern is to cause damage in a subacute manner.
CHAPTER 380
IgG4-Related Disease
Destructive bone lesions in the sinuses, head, and middle ear spaces
that mimic granulomatosis with polyangiitis occur occasionally in
IgG4-RD, but less aggressive lesions are the rule in most organs. In
regions such as the retroperitoneum, substantial fibrosis often occurs
before the diagnosis is established, leading to ureteral entrapment,
hydronephrosis, postobstructive uropathy, and renal atrophy. Undiag­
nosed or undertreated IgG4-related sclerosing cholangitis can lead to
hepatic failure within months. Similarly, IgG4-related aortitis can cause
aneurysms and dissections. Substantial renal dysfunction and even
renal failure can ensue from IgG4-related tubulointerstitial nephritis,
and renal atrophy is a frequent sequel to this disease complication
even following apparently effective immunosuppressive therapy. IgG4related membranous glomerulonephropathy, a less common renal
manifestation than tubulointerstitial nephritis, must be distinguished
from idiopathic membranous glomerulonephropathy. As a variablevessel vasculitis, IgG4-RD can target small-, medium-, and large-sized
arteries and veins. Patients with longstanding IgG4-RD marked by
substantial elevations of serum IgG4 concentrations and other bio­
markers are at risk for developing coronary arteritis, marked by wall
thickening, periarterial soft tissue encasement, stenosis, calcification,
and aneurysms or ectasia.
■
■SEROLOGIC FINDINGS
The majority of patients with IgG4-RD have elevated serum IgG4 con­
centrations; however, the range of elevation varies widely. Serum con­
centrations of IgG4 as high as 30 or 40 times the upper limit of normal
sometimes occur, usually in patients with disease that affects multiple
organ systems simultaneously. Approximately 30% of patients have
normal serum IgG4 concentrations despite classic histopathologic and
immunohistochemical findings. Such patients tend to have disease that
affects fewer organs. Patients with IgG4-related retroperitoneal fibrosis
often have normal serum IgG4 concentrations, perhaps because the
PART 11
Immune-Mediated, Inflammatory, and Rheumatologic Disorders
A
B
FIGURE 380-1  A major clinical feature of IgG4-related disease is its tendency to
form tumefactive lesions. Shown here are mass lesions of the lacrimal glands,
causing supraorbital swelling (A) and the submandibular glands (B).
process has advanced to a fibrotic stage by the time the diagnosis is
considered.
Correlations between serum IgG4 concentrations, disease activity,
and the need for treatment are imperfect. Serum IgG4 concentrations
typically decline swiftly with the institution of therapy but often do not
normalize completely. Patients can achieve clinical remissions yet have
persistently elevated serum IgG4 concentrations. Following treatment
and a disease response, however, steadily rising serum IgG4 concentra­
tions are useful in identifying patients at risk for clinical flares who
should be considered for re-treatment. Clinical relapses occur in some
patients despite persistently normal IgG4 concentrations.
IgG4 concentrations in serum are usually measured by nephelome­
try assays. In the setting of extremely high serum IgG4 concentrations,
these assays can generate spuriously low IgG4 values because of the
prozone effect. Failure to identify dramatic serum IgG4 elevations can
have a substantial impact on patients, because that subset of patients is
at greatest risk for multiorgan disease and substantial end-organ injury.
The prozone effect should be considered when the results of serologic
testing for IgG4 concentrations are normal despite the presence of
clinical features that strongly suggest IgG4-RD. This effect can be cor­
rected by dilution of the serum sample in the laboratory.
■
■EPIDEMIOLOGY
The typical patient with IgG4-RD is a middle-aged to elderly man.
This epidemiology stands in stark contrast to that of many classic
autoimmune conditions, which tend to affect young women. Male
patients are approximately 5 years older at the time of diagnosis com­
pared to female patients and have higher degrees of serologic activity,
e.g., IgG4 hypergammaglobulinemia or hypocomplementemia. The
male-to-female ratio appears to be on the order of 2:1, with even more
striking male predominance reported in certain types of internal organ
A
B
FIGURE 380-2  Thickening of extraocular muscles and meninges. (A) Magnetic
resonance imaging study of the orbits, showing enhancement and enlargement of
extraocular muscles in a patient with IgG4-related orbital disease (orbit axial T1
postcontrast fat-saturated image). (B) Magnetic resonance imaging study of the
brain, showing thickening of the pachymeninges. There is nodular pachymeningeal
enhancement at the base of the brain (blue dot), anterior to the pons. There is
also abnormal enhancement and thickening of the tentorium cerebelli, interposed
between the superior cerebellum and the occipital lobes (sagittal MPRAGE
volumetric T1 postcontrast image).
involvement (e.g., the pancreas, kidneys, or retroperitoneum). Among
IgG4-RD manifestations that involve organs of the head and neck—the
orbits, lacrimal glands, and major salivary glands—the sex ratio may
be closer to 1:1.
■
■PATHOLOGY
The key histopathology characteristics of IgG4-RD are a dense lym­
phoplasmacytic infiltrate (Fig. 380-3) that is organized in a storiform
pattern, obliterative phlebitis, and a mild to moderate eosinophilic
infiltrate. Lymphoid follicles and germinal centers are frequently
observed. The infiltrate tends to aggregate around ductal structures
when it affects glands. The inflammatory lesion often aggregates into
tumefactive masses that destroy the involved tissue.
Obliterative arteritis is observed in some organs, particularly the lung;
however, venous involvement is more common (and is indeed a hall­
mark of IgG4-RD). Several histopathology features are uncommon in
IgG4-RD and, when detected, mitigate against the diagnosis of IgG4-RD.
These include intense neutrophilic infiltration, leukocytoclasis, granulo­
matous inflammation, multinucleated giant cells, and fibrinoid necrosis.
FIGURE 380-3  Hallmark histopathology characteristics of IgG4-related disease
(IgG4-RD) are a dense lymphoplasmacytic infiltrate and a mild to moderate
eosinophilic infiltrate. The cellular inflammation is often encased in a distinctive
type of fibrosis termed “storiform,” which often has a basket weave pattern.
Abundant fibroblasts and strands of fibrosis accompany the lymphoplasmacytic
infiltrate in this figure. Outlined by the arrowheads is a vein demonstrating
obliterative phlebitis, underscoring the vascular tropism of this disease, which is
classified as a variable-vessel vasculitis. This biopsy is from a patient with IgG4related hypertrophic pachymeningitis. However, the findings are identical to the
pathology found in the pancreas, kidneys, lungs, salivary glands, and other organs
affected by IgG4-RD.
The inflammatory infiltrate is composed of an admixture of B and T
lymphocytes. B cells are typically organized in germinal centers. Plasma
cells staining for CD19, CD138, and IgG4 appear to radiate from the
germinal centers. In contrast, the T cells, usually CD4+, are distributed
more diffusely throughout the lesion and generally represent the most
abundant cell type. Fibroblasts, histiocytes, and eosinophils can all be
observed in moderate numbers. Some biopsy samples are particularly
enriched with eosinophils. In other samples, particularly from longstanding cases, fibrosis predominates.
The histologic appearance of IgG4-RD, although characteristic,
should be supplemented by immunohistochemical stains for IgG4 and
IgG. IgG4-positive plasma cells predominate within the lesion, but
plasma cells containing immunoglobulins from each subclass can be
found. The number of IgG4-positive plasma cells can be quantified
by either counting the number of cells per high-power field (HPF) or
by calculating the ratio of IgG4- to IgG-bearing plasma cells. Tissue
fibrosis predominates in the latter phases of organ involvement, and
in this relatively acellular phase of inflammation, both the IgG4:total
IgG ratio and the pattern of tissue fibrosis are more important than the
number of IgG4-positive cells per HPF in establishing the diagnosis.
No matter how strongly the histopathology and immunohistochem­
istry studies favor a diagnosis of IgG4-RD, however, the pathology
findings must always be interpreted in the context of clinical, serologic,
and radiologic findings. Pathology findings alone are never sufficient
for the diagnosis.
■
■PATHOPHYSIOLOGY
Despite the emphasis of IgG4 in the name of this disease, the IgG4
molecule is not believed to play a direct role in the pathophysiology
of disease within most organs. The IgG4 molecule can undergo Fab
exchange, a phenomenon in which the two halves of the molecule dis­
sociate from each other and reassociate with hemi-molecules of differ­
ent antigen specificity that have originated from other dissociated IgG4
molecules. Partly as a result of this Fab exchange, IgG4 antibodies do
not bind antigen tightly. Moreover, the molecules have low affinities for
Fc receptors and C1q and are regarded generally as noninflammatory
immunoglobulins. The low affinities for Fc receptors and C1q impair
the ability of IgG4 antibodies to induce phagocyte activation, antibodydependent cellular cytotoxicity, and complement-mediated damage. It
is possible, therefore, that the role of IgG4 in this disease is actually as a
counterregulatory mechanism rather than part of the primary inflam­
matory process.
Next-generation sequencing studies of CD4+ effector T cells have
demonstrated a unique CD4+ cytotoxic T cell. This cell, also found in
abundance at tissue sites of disease, makes interferon gamma, T-cell
growth factor-beta, and interleukin-1, all of which may contribute to the
storiform fibrosis found in this condition. The cells also elaborate per­
forin, granzyme A and B, and granulysin, products capable of inducing
cytotoxicity. The pronounced oligoclonal expansion of this CD4+ cyto­
toxic T cell at tissue sites suggests that this cell is a major disease driver.
CHAPTER 380
IgG4-Related Disease
Oligoclonal expansions of plasmablasts are also present within the
blood of patients with IgG4-RD. Continuous antigen presentation by
B cells and plasmablasts may support CD4+ cytotoxic T cells, which
in turn produce profibrotic cytokines and other molecules, thereby
directly mediating tissue injury.
■
■TREATMENT
Vital organ involvement must be treated aggressively, because IgG4-RD
can lead to serious organ dysfunction and failure. Aggressive disease
can lead quickly to end-stage liver disease, permanent impairment of
pancreatic function, renal atrophy, aortic dissection or aneurysms, and
destructive lesions in the sinuses and nasopharynx. Not every disease
manifestation of IgG4-RD requires immediate treatment, however,
because the disease may take an indolent form in some patients. IgG4related lymphadenopathy, for example, can be asymptomatic for years,
without evolution to other disease manifestations. Watchful waiting
is prudent in some cases, but monitoring is essential because serious
organ involvement may evolve over time, particularly in the setting of
persistently rising serum IgG4 concentrations.
Glucocorticoids are the first line of therapy. Treatment regimens,
extrapolated from experience with the management of type 1 AIP,
generally begin with 40 mg/d of prednisone, with tapering to dis­
continuation or maintenance doses of 5 mg/d within 2 or 3 months.
Although the clinical response to glucocorticoids is usually swift and
striking, prolonged steroid-free remissions are uncommon and the risk
of steroid-induced morbidity in this middle-aged to elderly patient
population is high, particularly in those with baseline comorbidities
and pancreatic involvement by IgG4-RD. Few data exist to support the
utility of conventional glucocorticoid-sparing agents in this disease.
For patients with relapsing or glucocorticoid-resistant disease, B-cell
depletion with rituximab is an excellent second-line therapy. Ritux­
imab treatment (two doses of 1 g IV, separated by ~15 days) leads to a
swift decline in serum IgG4 concentrations, suggesting that rituximab
achieves its effects in part by preventing the repletion of short-lived
plasma cells that produce IgG4. More important than its effects on
IgG4 concentrations, however, may be the effect of B-cell depletion on
T-cell function. Specific effects of rituximab on the CD4+ cytotoxic T
cell described above have been documented in IgG4-RD. The rapidly
evolving understanding of the pathophysiology of IgG4-RD suggests
several novel targeted approaches to treating the disease, some of
which are in clinical trials. Phase 3 clinical trials of treatments target­
ing CD19+ B lymphocytes are now at advanced stages of recruitment.
B-cell–targeted treatment strategies may be appropriate first-line ther­
apy options for some patients following confirmation of their efficacy
in clinical trials, particularly for patients at high risk for glucocorticoid
toxicity and for those with immediately organ-threatening disease.
■
■FURTHER READING
Jha  I et al: Sex as a predictor of clinical phenotype and determinant
of immune response in IgG4-Related disease: A retrospective study
of 328 patients fulfilling the American College of Rheumatology/
European League Against Rheumatism classification criteria. Lancet
Rheumatol 6:E460, 2024.
Katz  G et al: IgG4-related disease as a variable-vessel vasculitis: A case
series of 13 patients with medium-sized coronary artery involvement.
Semin Arthritis Rheum 60:152184, 2023.
Katz  G et al: Proliferative features of IgG4-related disease. Lancet Rheu­
matol 6:e481, 2024.

27 - 383 Osteoarthritis
383 Osteoarthritis
David T. Felson, Tuhina Neogi
Osteoarthritis
Osteoarthritis (OA) is the most common type of arthritis. Its high
prevalence, especially in the elderly, and its negative impact on physi­
cal function make it a leading cause of disability in the elderly. Because
of the aging of Western populations and because obesity, a major risk
factor, is increasing in prevalence, the occurrence of OA is on the rise.
OA affects certain joints yet spares others (Fig. 383-1). Commonly
affected joints include the hip, knee, and first metatarsal phalangeal
joint (MTP) and cervical and lumbosacral spine. In the hands, the
distal and proximal interphalangeal joints and the base of the thumb
are often affected. Usually spared are the wrist, elbow, and ankle. Our
joints were designed, in an evolutionary sense, for brachiating apes,
animals that still walked on four limbs. We thus develop OA in joints
that were ill designed for human tasks such as pincer grip (OA in the
thumb base) and walking upright (OA in knees and hips). Some joints,
like the ankles, may be spared because their articular cartilage may be
uniquely resistant to loading stresses.
OA can be diagnosed based on structural abnormalities or on the
symptoms these abnormalities evoke. According to cadaveric studies,
by elderly years, structural changes of OA are nearly universal. These
include cartilage loss (seen as joint space loss on x-rays) and osteophytes.
Many persons with x-ray evidence of OA have no joint symptoms, and
although the prevalence of structural abnormalities is of interest in
understanding disease pathogenesis, what matters more from a clinical
perspective is the prevalence of symptomatic OA. Symptoms, usually
joint pain, determine disability, visits to clinicians, and disease costs.
Symptomatic OA of the knee (pain on most days of a recent month
plus x-ray evidence of OA in that knee) occurs in ~12% of persons age
≥60 in the United States and 6% of all adults age ≥30. Symptomatic hip
OA is roughly one-third as common as disease in the knee. Although
radiographic hand OA and the appearance of bony enlargement in
affected hand joints (Fig. 383-2) are extremely common in older
Distal and proximal
First
carpometacarpal
interphalangeal
Cervical
vertebrae
Lower
lumbar
vertebrae
Hip
Knee
First metatarsophalangeal
FIGURE 383-1  Joints commonly affected by osteoarthritis.  
CHAPTER 383
Osteoarthritis
FIGURE 383-2  Severe osteoarthritis of the hands affecting the distal interphalangeal
joints (Heberden’s nodes) and the proximal interphalangeal joints (Bouchard’s
nodes). There is no clear bony enlargement of the other common site in the hands,
the thumb base.
persons, most affected persons have no pain. Even so, painful hand OA
occurs in ~10% of elderly individuals and often produces measurable
limitation in function.
The prevalence of OA rises strikingly with age, being uncommon
in adults aged <40 and highly prevalent in those aged >60. It is also a
disease that, at least in middle-aged and elderly persons, is much more
common in women than in men.
X-ray evidence of OA is common in the lower back and neck, but
back pain and neck pain have not been tied to findings of OA on x-ray.
Thus, back pain and neck pain are treated separately (Chaps. 18 and 19).
■
■GLOBAL CONSIDERATIONS
With the aging of the populations, both the prevalence of OA and the
amount of disability worldwide related to OA have been increasing,
especially in developed countries where many are living into old age.
Hip OA is rare in China and in immigrants from China to the United States.
Anatomic differences between Chinese and white hips may account for
much of the difference in hip OA prevalence, with white hips having
a higher prevalence of anatomic predispositions to the development of
OA. However, OA in the knees is at least as common, if not more so, in
Chinese as in whites from the United States, and knee OA represents a
major cause of disability in China, especially in rural areas.
DEFINITION
OA is joint failure, a disease in which all structures of the joint have
undergone pathologic change, often in concert. The pathologic sine
qua non of disease is hyaline articular cartilage loss, present in a focal
and, initially, nonuniform manner. This is accompanied by increasing
thickness and sclerosis of the subchondral bony plate, by outgrowth of
osteophytes at the joint margin, by stretching of the articular capsule,
by variable degrees of synovitis, and by weakness of muscles bridging
the joint. In knees, meniscal degeneration is part of the disease. There
are numerous pathways that lead to joint failure, but the initial step is
often joint injury in the setting of a failure of protective mechanisms.
JOINT PROTECTIVE MECHANISMS
AND THEIR FAILURE
Joint protectors include joint capsule and ligaments, muscle, sensory
afferents, and underlying bone. Joint capsule and ligaments serve as
joint protectors by providing a limit to excursion, thereby fixing the
range of joint motion.
Synovial fluid reduces friction between articulating cartilage sur­
faces, thereby serving as a protector against friction-induced cartilage
wear. This lubrication function depends on hyaluronic acid and on
lubricin, a mucinous glycoprotein secreted by synovial fibroblasts whose
concentration diminishes after joint injury and in the face of synovial
inflammation.
The ligaments, along with overlying skin and tendons, contain
mechanoreceptor sensory nerves. These mechanoreceptors fire at
different frequencies throughout a joint’s range of motion, provid­
ing feedback by way of the spinal cord to muscles and tendons. As a
consequence, these muscles and tendons assume the right tension at
appropriate points in joint excursion to act as optimal joint protectors,
anticipating joint loading.
PART 11
Immune-Mediated, Inflammatory, and Rheumatologic Disorders
Muscles and tendons that bridge the joint are key joint protectors.
Focal stress across the joint is minimized by muscle contraction that
decelerates the joint before impact and assures that when joint impact
arrives, it is distributed broadly across the joint surface.
Failure of these joint protectors increases the risk of joint injury and
OA. For example, in animals, OA develops rapidly when a sensory nerve
to the joint is sectioned and joint injury induced. Similarly, in humans,
Charcot’s arthropathy, a severe and rapidly progressive OA, develops
when minor joint injury occurs in the presence of posterior column
peripheral neuropathy. Another example of joint protector failure is rup­
ture of ligaments, a well-known cause of the early development of OA.
■
■CARTILAGE AND ITS ROLE IN JOINT FAILURE
A thin rim of tissue at the ends of two opposing bones, cartilage is lubri­
cated by synovial fluid to provide an almost frictionless surface across
which these two bones move. The compressible stiffness of cartilage
compared to bone provides the joint with impact-absorbing capacity.
The earliest changes of OA may occur in cartilage, and abnormali­
ties there can accelerate disease development. The two major macro­
molecules in cartilage are type 2 collagen, which provides cartilage its
tensile strength, and aggrecan, a proteoglycan macromolecule linked
with hyaluronic acid, which consists of highly negatively charged gly­
cosaminoglycans. In normal cartilage, type 2 collagen is woven tightly,
constraining the aggrecan molecules in the interstices between collagen
strands, forcing these highly negatively charged molecules into close
proximity. The aggrecan molecule, through electrostatic repulsion of its
negative charges, gives cartilage its compressive stiffness. Chondrocytes,
the cells within this avascular tissue, synthesize all elements of the matrix
and produce enzymes that break it down (Fig. 383-3). Cartilage matrix
synthesis and catabolism are in a dynamic equilibrium influenced by
the cytokine and growth factor environment. Mechanical and osmotic
stress on chondrocytes induces these cells to alter gene expression and
Articular cartilage
Cartilage
degradation
Synovium
Macrophage
Neuropeptides
Neuron
Chondrocyte
Mechanoflammation
Apidokines
Adipose
tissue
Osteoblast
FIGURE 383-3  Selected factors involved in the osteoarthritic process including chondrocytes, bone, and synovium. Synovitis causes release of cytokines, alarmins,
damage-associated molecular pattern (DAMP) molecules, and complement, which activate chondrocytes through cell-surface receptors. Chondrocytes produce matrix
molecules (collagen type 2, aggrecan) and the enzymes responsible for the degradation of the matrix (e.g., ADAMTS-5 and matrix metalloproteinases [MMPs]). Bone
invasion occurs through the calcified cartilage, triggered by vascular endothelial growth factor (VEGF) and other growth factors. (Reproduced with permission from
De Roover A et al: Fundamentals of osteoarthritis: Inflammatory mediators in osteoarthritis. Osteoarthritis Cart 31:1303, 2023.)
increase production of inflammatory cytokines and matrix-degrading
enzymes. While chondrocytes synthesize numerous enzymes, matrix
metalloproteinases (MMPs; especially collagenases and ADAMTS-5)
are critical enzymes in the breakdown of cartilage matrix.
Local inflammation accelerates the development and progression of
osteoarthritis and increases the likelihood that an osteoarthritic joint
will be painful. Some of this inflammation may be induced by mechan­
ical stimuli, so called mechanoinflammation. The synovium, carti­
lage, and bone all influence disease development through cytokines,
chemokines, and even complement activation (Fig. 383-3). Matrix
fragments released from cartilage stimulate synovium, which releases
inflammatory cytokines, and they, in turn, induce chondrocytes to
synthesize other proinflammatory molecules. Ultimately, the combina­
tion of effects on chondrocytes triggers matrix degradation. Growth
factors are also part of this complex network, with bone morphogenetic
protein 2 (BMP-2) and transforming growth factor β (TGF-β) playing
prominent roles in stimulating the development of osteophytes. Trig­
gered by local vascular endothelial growth factor (VEGF) synthesis,
blood vessels invade cartilage and, with them, come nerves that may
bring nociceptive innervation.
With aging, articular chondrocytes develop a senescence-associated
secretory phenotype, exhibiting a decline in synthetic capacity and pro­
ducing proinflammatory mediators and matrix-degrading enzymes.
These chondrocytes are unable to maintain tissue homeostasis (such as
after insults of a mechanical or inflammatory nature). Thus, with age,
cartilage is easily damaged by minor sometimes unnoticed injuries,
including those that are part of daily activities.
OA cartilage is characterized by gradual depletion of aggrecan, an
unfurling of the tightly woven collagen matrix, and loss of type 2 col­
lagen. With these changes comes increasing vulnerability of cartilage,
which loses its compressive stiffness.
RISK FACTORS
Risk factors for OA can be understood in terms of their effect either on
joint vulnerability or joint loading. On the one hand, a vulnerable joint
whose protectors are dysfunctional can develop OA with minimal lev­
els of loading, perhaps even levels encountered during everyday activi­
ties. On the other hand, in a young joint with competent protectors, a
DAMPs
Cytokines
Synoviocyte
Osteophyte
Growth
factors
Subchondral
bone
Activated
osteoblast
Intrinsic joint
vulnerabilities (local
environment)
Previous damage (e.g.,
meniscectomy)
Bridging muscle weakness
Increasing bone density
Malalignment
Proprioceptive deficiences
Systemic factors
affecting joint
vulnerability
Use (loading) factors
acting on joints
Increased age
Female gender
Racial/ethnic factors
Genetic susceptibility
Nutritional factors
Obesity
Injurious physical
activities
Susceptibility
to OA
Osteoarthritis
or its
progression
FIGURE 383-4  Risk factors for osteoarthritis (OA) either contribute to the
susceptibility of the joint (systemic factors or factors in the local joint environment)
or increase risk by the load they put on the joint. Usually, a combination of loading
and susceptibility factors is required to cause disease or its progression.
major acute injury or long-term overloading is necessary to precipitate
disease (Fig. 383-4).
■
■SYSTEMIC RISK FACTORS THAT AFFECT
JOINT VULNERABILITY
Age is the most potent risk factor for OA. Radiographic evidence of
OA is rare in individuals aged <40; however, in some joints, such as
the hands, OA occurs in >50% of persons aged >70. Aging increases
joint vulnerability through several mechanisms. Whereas dynamic
loading of joints stimulates matrix synthesis by chondrocytes in young
cartilage, aged cartilage is less responsive to these stimuli. As a conse­
quence of this failure to synthesize matrix with loading, cartilage thins
with age, and thinner cartilage experiences higher shear stress and is at
greater risk of damage. Also, joint protectors fail more often with age.
Muscles that bridge the joint become weaker with age and respond
less quickly to oncoming impulses. Sensory nerve input slows with
age, retarding the feedback loop of mechanoreceptors to muscles and
tendons related to their tension and position. Ligaments stretch with
age, making them less able to absorb impulses. These factors work in
concert to increase the vulnerability of older joints to OA.
Older women are at high risk of OA in all joints, a risk that increases
as women reach their sixth decade. Although hormone loss with meno­
pause may contribute to this risk, there is little understanding of the
unique vulnerability of older women versus men.
■
■HERITABILITY AND GENETICS AND THEIR
RELATION TO JOINT VULNERABILITY
OA is a heritable disease, but its heritability is mostly joint specific.
Nearly 60–65% of OA in hips or hands may be attributed to shared
genetics within a family. However, heritability of knee OA is, at
most, 30%, with some studies suggesting no heritability at all. Knees are
susceptible to nongenetic factors like activities that affect joint loading
and risk of injury. On the other hand, many people with OA develop
“generalized OA” or multisite OA, but the involvement of multiple joints
with OA is usually a consequence of aging rather than genetics.
The best replicated genetic variant known to increase OA risk lies in
the locus for growth differentiation factor 5 (GDF5). It affects epigen­
etic regulation of GDF5 activity, resulting in reduction in GDF5 expres­
sion. GDF5 probably affects joint shape, a mechanism by which genes
increase disease risk. Minor abnormalities in joint shape can make a
joint vulnerable to damage if focal stresses across the joint increase.
■
■RISK FACTORS IN THE JOINT ENVIRONMENT
Some risk factors increase vulnerability of the joint through local
effects on the joint environment. With changes in joint anatomy, for
example, load across the joint is no longer distributed evenly across the
joint surface, but rather shows an increase in focal stress. In the hip,
three uncommon developmental abnormalities occurring in utero or
in childhood—congenital dysplasia, Legg-Perthes disease, and slipped
capital femoral epiphysis—leave a child with distortions of hip joint
anatomy that often lead to OA later in life. Girls are predominantly
affected by acetabular dysplasia, a mild form of congenital dysplasia,
whereas the other abnormalities more often affect boys. Depending
on the severity of the anatomic abnormalities, hip OA occurs either
in young adulthood (severe abnormalities) or middle age (mild
abnormalities). Femoroacetabular impingement can develop during
adolescence. It is a clinical syndrome in which an outgrowth of bone
at the femur’s head/neck junction thought to develop during closure of
the growth plate results in abnormal contact between the femur and
acetabulum, especially during hip flexion and rotation. This leads to
cartilage and labral damage, to hip pain, and ultimately in later life, to
an increased risk of hip OA.
CHAPTER 383
Osteoarthritis
Major injuries to a joint also can produce anatomic abnormalities
that leave the joint susceptible to OA. For example, a fracture through
the joint surface often causes OA in joints in which the disease is oth­
erwise rare such as the ankle and the wrist. Avascular necrosis can lead
to collapse of dead bone at the articular surface, producing anatomic
irregularities and subsequent OA.
Tears of ligamentous and fibrocartilaginous structures that protect
the joints, such as the anterior cruciate ligament or meniscus in the
knee and the labrum in the hip, can lead to premature OA. Meniscal
tears increase with age and, when chronic, are often asymptomatic but
lead to adjacent cartilage damage and accelerated OA. Even recalled
injuries in which the affected person never received a diagnosis may
increase risk of OA. For example, in the Framingham Study subjects,
men with a history of major knee injury, but no surgery, had a 3.5-fold
increased risk for subsequent knee OA.
Another source of anatomic abnormality is malalignment across
the joint (Fig. 383-5), a factor best studied in the knee. Varus (bow­
legged) knees with OA are at exceedingly high risk of cartilage loss in
the medial or inner compartment of the knee, whereas valgus (knockkneed) malalignment predisposes to rapid cartilage loss in the lateral
compartment. Malalignment causes this effect by increasing stress on
a focal area of cartilage, which then breaks down; it also causes dam­
age to bone underlying the cartilage, producing bone marrow lesions
seen on magnetic resonance imaging (MRI). Malalignment in the knee
often produces such a substantial increase in focal stress within the
knee (as evidenced by its destructive effects on subchondral bone) that
severely malaligned knees may be destined to progress regardless of the
status of other risk factors.
Weakness in the quadriceps muscles bridging the knee increases the
risk of the development of painful OA in the knee, especially in women.
Normal
Varus
Knock knees (valgus)
FIGURE 383-5  The two types of limb malalignment in the frontal plane: varus, in
which the stress is placed across the medial compartment of the knee joint, and
valgus, which places excess stress across the lateral compartment of the knee.
High bone density also increases OA risk, especially risk of a subtype
of OA characterized by large osteophytes.
■
■LOADING FACTORS
Obesity 
Three to six times body weight is transmitted across the knee
during single-leg stance. Any increase in weight may be multiplied by
this factor to reveal the excess force across the knee in overweight per­
sons during walking. Obesity is a potent risk factor for the development
of knee OA and, less so, for hip OA. It is a stronger risk factor for disease
in women than in men, and for women, the relationship of weight to the
risk of disease is linear, so that with each pound increase in weight, there
is a commensurate increase in risk. Not only is obesity a risk factor for
OA in weight-bearing joints, but obese persons have more pain from the
disease. Weight loss greater than 10% of body weight reduces cartilage
loss and, in most affected persons, alleviates pain.
PART 11
Immune-Mediated, Inflammatory, and Rheumatologic Disorders
Obesity’s effect on the development and progression of disease,
especially in knees, is mediated mostly through the increased loading
in weight-bearing joints that occurs in overweight persons. However,
high levels of leptin, an adipokine, are associated with increasing pain
severity in OA regardless of the joint affected.
Repeated Use of Joint and Exercise 
There are two categories of
repetitive joint use: occupational use and leisure time physical activities.
Workers who, over many years, perform repetitive tasks as part of their
occupations are at high risk of developing OA in joints they use repeatedly.
Workers whose jobs require regular knee bending or lifting or carrying
heavy loads have a high rate of knee OA. One reason why workers may
get disease is that during long days at work, their muscles may gradually
become exhausted, no longer serving as effective joint protectors.
It is widely recommended for people to adopt an exercise-filled life­
style, and long-term studies of exercise suggest no consistent associa­
tion of exercise with OA risk in most persons. However, persons who
already have injured joints may put themselves at greater risk by engag­
ing in certain types of exercise. For example, persons who have already
sustained major knee injuries are at increased risk of progressive knee
OA as a consequence of running. In addition, compared to nonrun­
ners, elite runners (professional runners and those on Olympic teams)
have high risks of both knee and hip OA. Lastly, although recreational
runners are not at increased risk of knee OA, studies suggest that they
have a modest increased risk of disease in the hip.
PATHOLOGY
The pathology of OA provides evidence of the involvement of many
joint structures in disease. Cartilage initially shows surface fibrillation
and irregularity. As disease progresses, focal erosions develop there,
and these eventually extend to the subjacent bone. With further pro­
gression, cartilage erosion down to bone expands to involve a larger
proportion of the joint surface, even though OA remains a focal disease
with nonuniform loss of cartilage.
After an injury to cartilage, chondrocytes undergo mitosis and clus­
tering. Although the metabolic activity of these chondrocyte clusters is
high, the net effect of this activity is to promote proteoglycan depletion in
the matrix surrounding the chondrocytes. This is because the catabolic
activity is greater than the synthetic activity. As disease develops, colla­
gen matrix becomes damaged, the negative charges of proteoglycans get
exposed, and cartilage swells from ionic attraction to water molecules.
Because in damaged cartilage proteoglycans are no longer forced into
close proximity, cartilage does not bounce back after loading as it did
when healthy, and cartilage becomes vulnerable to further injury.
With loss of cartilage comes alteration in subchondral bone. Stimu­
lated by growth factors and cytokines, osteoclasts and osteoblasts in the
bony plate just underneath cartilage become activated. Bone forma­
tion produces a thickening of the subchondral plate that occurs even
before cartilage ulcerates. Trauma to bone during joint loading may
be the primary factor driving this bone response, with healing from
injury (including microcracks) inducing remodeling. Small areas of
osteonecrosis usually exist in joints with advanced disease. Bone death
may also be caused by bone trauma with shearing of microvasculature,
leading to a cutoff of vascular supply to some bone areas.
At the margin of the joint, near areas of cartilage loss, osteophytes
form. These start as outgrowths of new cartilage, and with neurovas­
cular invasion from the bone, this cartilage ossifies. Osteophytes are an
important radiographic hallmark of OA.
The synovium produces lubricating fluids that minimize shear stress
during motion. In healthy joints, the synovium consists of a single dis­
continuous layer filled with fat and containing two types of cells, macro­
phages and fibroblasts, but in OA, it can sometimes become edematous
and inflamed. There is a migration of macrophages from the periphery
into the tissue, and cells lining the synovium proliferate. Inflammatory
cytokines and alarmins secreted by the synovium activate chondrocytes
to produce enzymes that accelerate destruction of matrix.
Additional pathologic changes occur in the capsule, which stretches,
becomes edematous, and can become fibrotic.
The pathology of OA is not identical across joints. In hand joints
with severe OA, for example, there are often cartilage erosions in the
center of the joint probably produced by bony pressure from the oppo­
site side of the joint.
Basic calcium phosphate and calcium pyrophosphate dihydrate
crystals are present microscopically in most joints with end-stage OA.
Their role in osteoarthritic cartilage is unclear, but their release from
cartilage into the joint space and joint fluid likely triggers synovial
inflammation, which can, in turn, produce release of cytokines and
trigger nociceptive stimulation.
SOURCES OF PAIN
Because healthy cartilage is aneural, cartilage loss alone is not accom­
panied by much pain. Thus, pain in OA likely arises from structures
outside the cartilage. Innervated structures in the joint include the
synovium, ligaments, joint capsule, muscles, and subchondral bone.
Most of these are not visualized by x-ray, and the severity of x-ray
changes in OA correlates poorly with pain severity. However, in later
stages of OA, loss of cartilage integrity accompanied by neurovascular
invasion may contribute more to pain.
Based on MRI studies in osteoarthritic knees comparing those with
and without pain and on studies mapping tenderness in unanesthetized
joints, likely sources of pain include synovial inflammation, joint effu­
sions, and bone marrow edema. Modest synovitis develops in many but
not all osteoarthritic joints. The presence of synovitis on MRI is cor­
related with the presence and severity of knee pain, and potentially with
pain sensitization. Capsular stretching from fluid in the joint stimulates
nociceptive fibers there, inducing pain. Increased focal loading as part
of the disease not only damages cartilage but probably also injures the
underlying bone. As a consequence, bone marrow edema appears on the
MRI; histologically, this edema signals the presence of microcracks and
scar, which are the consequences of trauma. These lesions may stimu­
late bone nociceptive fibers. Pain may arise from outside the joint also,
including bursae near the joints. Common sources of pain near the knee
are anserine bursitis and iliotibial band syndrome.
Much of the pain experienced in OA occurs when nociceptors in
the joint are stimulated during weight-bearing activities. However, the
pain may eventually become more constant and present at rest, and
this suggests other mechanisms contribute to the pain experience. The
pathologic changes of OA may lead to alterations in nervous system
signaling (Chap. 18). Specifically, peripheral nociceptors can become
more responsive to sensory input, known as peripheral sensitization,
and there can also be an increase in facilitated central ascending noci­
ceptive signaling, known as central sensitization. Individuals with OA
may also have insufficient descending inhibitory modulation. Some
individuals may be genetically predisposed to becoming sensitized;
however, regardless of the etiology, these nervous system alterations
are associated with more severe pain, contribute to the presence of
allodynia and hyperalgesia in patients with OA, and may predispose to
development of chronic pain.
CLINICAL FEATURES
Joint pain from OA is primarily activity-related in the early stages of
the disease. Pain comes on either during or just after joint use and then
gradually resolves. Examples include knee or hip pain with going up or
FIGURE 383-6  X-ray and magnetic resonance imaging (MRI) of knee with medial osteoarthritis. X-ray shows osteophytes at the medial and lateral tibia and femur and
joint space narrowing of the medial tibiofemoral joint. Coronal intermediate-weighted fat-suppressed MRI confirms the presence of medial and lateral osteophytes and the
medial tibiofemoral joint space narrowing. There is diffuse denuded area with no cartilage remaining at the weight-bearing medial tibiofemoral joint (arrows). There is also
a severe medial meniscus extrusion (arrowhead). Bone marrow lesions, which provide evidence of bone injury, are present at medial tibia, medial femur, and intraspinous
tibial region. Cartilage focal defects are also seen at the lateral weight-bearing femur and tibia.
down stairs, pain in weight-bearing joints when walking, and, for hand
OA, pain when cooking. Early in disease, pain is episodic, triggered
often by overactive use of a diseased joint, such as a person with knee
OA taking a long run and noticing a few days of pain thereafter. As
disease progresses, the pain becomes continuous and even begins to be
bothersome at night. Stiffness of the affected joint may be prominent,
but morning stiffness is usually brief (<30 min).
In knees, buckling may occur, in part, from weakness of muscles
crossing the joint. Mechanical symptoms, such as buckling, catching,
or locking, could also signify internal derangement, like an anterior
cruciate ligament or meniscal tear; however, these symptoms, which
are common in persons with knee OA, need to be further evaluated
only if they develop after an acute knee injury. In the knee, pain with
activities requiring knee flexion, such as stair climbing and arising
from a chair, often emanates from the patellofemoral compartment of
the knee, which does not actively articulate until the knee is bent ~35°.
OA is the most common cause of chronic knee pain in persons aged
45, but the differential diagnosis is long. Inflammatory arthritis is
likely if there is prolonged morning stiffness, and many other joints are
affected. Bursitis occurs commonly around knees and hips. A physical
examination should focus on whether tenderness is over the joint line
(at the junction of the two bones around which the joint is articulat­
ing) or outside of it. Anserine bursitis, medial and distal to the knee,
is an extremely common cause of chronic knee pain that may respond
to a glucocorticoid injection. Prominent nocturnal pain in the absence
of end-stage OA merits a distinct workup. For hip pain, OA can be
detected by loss of internal rotation on passive movement, and pain
isolated to an area lateral to the hip joint usually reflects the presence
of trochanteric bursitis.
No blood tests are routinely indicated for workup of patients with
OA unless symptoms and signs suggest inflammatory arthritis. Exami­
nation of the synovial fluid is often more helpful diagnostically than
CHAPTER 383
Osteoarthritis
an x-ray. If the synovial fluid white count is >1000/μL, inflammatory
arthritis or gout or pseudogout is likely, the latter two being also identi­
fied by the presence of crystals.
Radiographs are not indicated in the workup of OA. They should be
ordered only when joint pain and physical findings are not typical of
OA or if pain persists after inauguration of treatment effective for OA.
In OA, imaging findings (Fig. 383-6) correlate poorly with the pres­
ence and severity of pain. Further, in both knees and hips, radiographs
may be normal in early disease as they are insensitive to cartilage loss
and other early findings.
Although MRI may reveal the extent of pathology in an osteo­
arthritic joint, it is not indicated as part of the diagnostic workup.
Findings such as meniscal tears and cartilage and bone lesions occur
not only in most patients with OA in the knee but also in most older
persons without joint pain. MRI findings rarely warrant a change in
therapy.
TREATMENT
Osteoarthritis
The goals of the treatment of OA are to alleviate pain and minimize
loss of physical function. To the extent that pain and loss of function
are consequences of inflammation, of weakness across the joint, and
of laxity and instability, the treatment of OA involves addressing
each of these impairments. Comprehensive therapy consists of a
multimodality approach including physical modalities and phar­
macologic elements.
Foundational to OA management is patient education and
self-management strategies. Patients with mild and intermit­
tent symptoms may need only symptomatic management and/
or treatments aimed at weight loss, physical activity, exercise, and
self-management strategies. Patients with ongoing, disabling pain
are likely to need both physical modalities and pharmacotherapy.
Treatments for knee OA have been more completely evaluated
than those for hip and hand OA or for disease in other joints.
Thus, although the principles of treatment are identical for OA in
all joints, we shall focus below on the treatment of knee OA, not­
ing specific recommendations for disease in other joints, especially
when they differ from those for the knee.
PHYSICAL MANAGEMENT MODALITIES
Because OA is a mechanically driven disease, the mainstay of treat­
ment involves altering loading across the painful joint and improv­
ing the function of joint protectors, so they can better distribute
load across the joint. Ways of lessening focal load across the joint
include:
PART 11
Immune-Mediated, Inflammatory, and Rheumatologic Disorders
Avoiding painful activities as these are usually activities that
overload the joint
Improving the strength and conditioning of muscles that bridge
the joint to optimize their function
Unloading the joint, either by redistributing load within the joint
with a brace or a splint or by unloading the joint during weight
bearing with a cane or a crutch
The simplest treatment for many patients is to avoid activities
that precipitate pain. For example, for the middle-aged patient
whose long-distance running brings on symptoms of knee OA, a
less demanding form of weight-bearing activity may alleviate all
symptoms. For an older person whose daily walks up and down
hills bring on knee pain, routing these away from hills might elimi­
nate symptoms.
Weight loss is a central strategy for those who are overweight
or obese, particularly for knee OA. Each pound of weight loss has
a multiplier effect, unloading both knees and hips and probably
relieving pain in those joints. Depending on how much weight loss
occurs, bariatric surgery and drugs that cause weight loss such as
glucagon-like peptide 1 receptor agonists (GLP1R agonists) often
reduce pain and may slow structural disease progression.
In hand joints affected by OA, splinting, by limiting motion,
often minimizes pain for patients with involvement especially in
the base of the thumb. Weight-bearing joints such as knees and hips
can be unloaded by using a cane in the hand opposite the affected
joint for partial weight bearing. A physical therapist can help teach
the patient how to use the cane optimally, including ensuring that
its height is optimal for unloading. Crutches or walkers can serve a
similar beneficial function.
Exercise  Osteoarthritic pain in knees or hips during weight bear­
ing results in lack of activity and poor mobility, and because OA is
so common, the inactivity that results increases the risk of cardio­
vascular disease and obesity. Aerobic capacity is poor in most elders
with symptomatic knee OA, worse than others of the same age.
Weakness in muscles that bridge osteoarthritic joints is multi­
factorial in etiology. First, there is a decline in strength with age.
Second, with limited mobility comes disuse muscle atrophy. Third,
patients with painful knee or hip OA alter their gait to lessen load­
ing across the affected joint, and this further diminishes muscle
use. Fourth, “arthrogenous inhibition” may occur, whereby contrac­
tion of muscles bridging the joint is inhibited by a nerve afferent
feedback loop emanating in a swollen and stretched joint capsule;
this prevents attainment of voluntary maximal strength. Because
adequate muscle strength and conditioning are critical to joint pro­
tection, weakness in a muscle that bridges a diseased joint makes
the joint more susceptible to further damage and pain. The degree
of weakness correlates strongly with the severity of joint pain and
the degree of physical limitation. One of the cardinal elements of
the treatment of OA is to improve the functioning of muscles sur­
rounding the joint.
Trials in knee and hip OA have shown that exercise lessens pain
and improves physical function. Most effective exercise regimens
consist of aerobic and/or resistance training, the latter of which
focuses on strengthening muscles across the joint. Treatment guide­
lines strongly recommend exercise for knee and hip OA with no
hierarchy regarding type of exercise due to lack of sufficient headto-head data. Exercises are likely to be effective especially if they
train muscles for the activities a person performs daily. Activities
that increase pain in the joint should be avoided. Range-of-motion
exercises, which do not strengthen muscles, and isometric exer­
cises that strengthen muscles, but not through range of motion,
are unlikely to be effective by themselves. Low-impact exercises,
including water aerobics and water resistance training, are often
better tolerated by patients than exercises involving impact load­
ing, such as running or treadmill exercises. Evidence suggests that
high-intensity strengthening is no more effective in reducing knee
pain than less aggressive strengthening regimens. The exercise
regimen needs to be individualized to optimize effectiveness, and
patients should be referred to an exercise class or a therapist who
can create an individualized regimen. In addition to conventional
exercise regimens, tai chi may be effective for knee OA. However,
there is no strong evidence that patients with hand OA benefit from
therapeutic exercise.
Adherence over the long term is the major challenge to an exer­
cise prescription. In trials involving patients with knee OA who
were engaged in exercise treatment, from a third to over half of
patients stopped exercising by 6 months. Less than 50% continued
regular exercise at 1 year. The strongest predictor of a patient’s con­
tinued exercise is a previous personal history of successful exercise.
Physicians should reinforce the exercise prescription at each clinic
visit, help the patient recognize barriers to ongoing exercise, and
identify convenient times for exercise to be done routinely. Mobile
health and wearable technologies are increasingly being used to
encourage adherence to exercise. The combination of exercise with
calorie restriction and weight loss is especially effective in lessening
pain.
Correction of Malalignment  Malalignment in the frontal plane
(varus-valgus) markedly increases the stress across the joint, which
can lead to progression of disease and to pain and disability (Fig. 383-5).
Correcting varus-valgus malalignment, either surgically or with
bracing, may relieve pain in persons whose knees are malaligned.
However, correcting malalignment is often challenging. Fitted
braces that straighten varus knees by putting valgus stress across the
knee can be effective. Unfortunately, many patients are unwilling
to wear a realigning knee brace; in addition, in patients with obese
legs, braces may slip with usage and lose their realigning effect.
Braces are indicated for willing patients who can learn to put them
on correctly and on whom they do not slip. Shoes modified with
rubber hemispheres on the sole that alter alignment of the proximal
knee have shown efficacy in trials especially if worn for brief periods
daily over several months.
Pain from the patellofemoral compartment of the knee can be
caused by tilting of the patella or patellar malalignment with the
patella riding laterally in the femoral trochlear groove. Using a patel­
lar brace to realign the patella, or tape to pull the patella back into
the trochlear sulcus or reduce its tilt, can lessen patellofemoral pain.
However, patients may find it difficult to apply tape, with skin irrita­
tion common, and, like realigning braces, patellar braces may slip.
Although their effect on malalignment is questionable, neoprene
sleeves pulled up to cover the knee lessen pain and are easy to use
and popular among patients. The explanation for their therapeutic
effect on pain is unclear.
In patients with knee OA, acupuncture produces modest pain
relief compared to placebo needles and may be an adjunctive treat­
ment, though placebo effect is likely high. In patients with refrac­
tory joint pain from OA, radiofrequency ablation of the nerves
innervating the joint has been shown to provide prolonged pain
relief, although long-term safety is unknown.
PHARMACOTHERAPY
Although approaches involving physical modalities constitute its
mainstay, pharmacotherapy serves an important adjunctive role
in OA treatment for symptom management. Available drugs are
administered using oral, topical, and intraarticular routes. To date,
there are no available drugs that alter the disease process itself.
Acetaminophen, Nonsteroidal Anti-Inflammatory Drugs (NSAIDs),
and Cyclooxygenase-2 (COX-2) Inhibitors  The treatment effect of
acetaminophen (paracetamol) in OA is small and not considered
clinically meaningful (Table 383-1). However, for a minority of
patients, it is adequate to control symptoms, in which case more
toxic drugs such as oral NSAIDs can be avoided.
NSAIDs are the most popular drugs to treat osteoarthritic
pain. They can be administered either topically or orally. In
clinical trials, oral NSAIDs produce ~30% greater improvement in
pain than high-dose acetaminophen. Response to NSAIDs varies
greatly across patients. Occasional patients treated with NSAIDs
experience dramatic pain relief, whereas others experience little
improvement. Initially, NSAIDs should be administered topically
or taken orally on an “as-needed” basis because side effects are less
frequent with low intermittent doses. For those with mild symp­
toms, topical NSAIDs may be sufficient to reduce pain. If topicals
or occasional oral medication use is insufficiently effective, then
daily treatment may be indicated, with an anti-inflammatory dose
selected (Table 383-1).
Topical NSAIDs absorbed through the skin have plasma concen­
trations an order of magnitude lower than the same amount of drug
administered orally. However, when these drugs are administered
TABLE 383-1  Pharmacologic Treatment for Osteoarthritis
MAXIMAL
DOSAGE
COMMENTS
TREATMENT
Take with food. Increased risk of
myocardial infarction and stroke
for some NSAIDs. High rates of
gastrointestinal side effects, including
ulcers and bleeding. Patients at high
risk for gastrointestinal side effects
should also take either a proton pump
inhibitor or misoprostol.a There is
an increase in gastrointestinal side
effects or bleeding when taken with
acetylsalicylic acid. Can also cause
edema and renal insufficiency.
Oral NSAIDs and
COX-2 inhibitors
  Naproxen
  Salsalate
  Ibuprofen
  Celecoxib
375–500 mg bid
1500 mg bid
600–800 mg qid/tid
100–200 mg qd
Acetaminophen
Up to 2 g/d
Of limited efficacy; conditionally
recommended.
Opiates
Common side effects include dizziness,
sedation, nausea, vomiting, dry mouth,
constipation, urinary retention, and
pruritus. Addiction risk. Less efficacious
than oral NSAIDs.
Topical NSAIDs
Rub onto hands/knees. Few systemic
side effects.
Diclofenac Na
1% gel
4 g qid
Skin irritation common.
Capsaicin
0.025–0.075%
cream tid/qid
Can irritate mucous membranes.
Intraarticular
injections
  Steroids
Various
  Hyaluronans
Varies from 3 to 5
weekly injections
Mild to moderate pain at injection site.
Controversy exists regarding efficacy.
aPatients at high risk include those with previous gastrointestinal events, persons
≥60 years, and persons taking glucocorticoids. Trials have shown the efficacy
of proton pump inhibitors and misoprostol in the prevention of ulcers and
bleeding. Misoprostol is associated with a high rate of diarrhea and cramping;
therefore, proton pump inhibitors are more widely used to reduce NSAID-related
gastrointestinal symptoms.
Abbreviations: COX-2, cyclooxygenase-2; NSAIDs, nonsteroidal anti-inflammatory
drugs.
Source: From DT Felson: Osteoarthritis of the Knee. N Engl J Med 354:841, 2006.
Copyright © 2006 Massachusetts Medical Society. Reprinted with permission from
Massachusetts Medical Society.
topically over a superficial joint (knees, hands, but not hips), the
drug can be found in joint tissues such as the synovium and car­
tilage. Generally, topical NSAIDs are slightly less efficacious than
oral agents, but have far fewer gastrointestinal (GI) and systemic
side effects. Topical NSAIDs often cause local skin irritation where
the medication is applied, inducing redness, burning, or itching
(see Table 383-1).
CHAPTER 383
Oral NSAIDs are often effective in reducing moderate or severe
joint pain, but they have substantial and frequent side effects, the
most common of which is upper GI toxicity, including dyspepsia,
nausea, bloating, GI bleeding, and ulcer disease. Certain oral agents
including celecoxib and nabumetone are safer to the stomach than
others. Major NSAID-related GI side effects can occur in patients
who do not complain of upper GI symptoms. Patients should be
reminded to take low-dose aspirin and ibuprofen or naproxen at
different times during the day to avoid a drug interaction.
Osteoarthritis
Because of the increased rates of cardiovascular events associated
with conventional NSAIDs such as diclofenac, many of these drugs
are not appropriate long-term treatment choices for older persons
with OA, especially those at high risk of heart disease or stroke.
The American Heart Association has identified COX-2 inhibitors
as putting patients at high risk, although low doses of celecoxib
(≤200 mg/d) are not associated with an elevation of risk. Naproxen
is a safe NSAID from a cardiovascular perspective, but it does have
GI toxicity.
There are other common side effects of NSAIDs, including the
tendency to develop edema because of prostaglandin inhibition of
afferent blood supply to glomeruli in the kidneys and, for similar
reasons, a predilection toward reversible renal insufficiency. Blood
pressure may increase modestly in some NSAID-treated patients.
Oral NSAIDs should not be used in patients with stage 3, 4, or 5
renal disease.
Intraarticular Injections: Glucocorticoids, Hyaluronic Acid, and
Other Products  Because synovial inflammation is likely to be a
major cause of pain in patients with OA, local anti-inflammatory
treatments administered intraarticularly may be effective in ame­
liorating pain for up to 3 months. Glucocorticoid injections provide
such efficacy, but response is variable, with some patients having
little relief of pain, whereas most experience pain relief lasting up
to several months. Synovitis, a major cause of joint pain in OA,
may abate after an injection, and this correlates with the reduction
in knee pain severity. Glucocorticoid injections are useful to get
patients over acute flares of pain. Repeated injections may cause
minor amounts of cartilage loss, but these do not appear to increase
risk of disease progression, worsening pain, functional limitations,
or the need for surgery.
Hyaluronic acid injections can be given for treatment of symp­
toms in knee and hip OA, but most evidence suggests they have
little efficacy versus placebo (Table 383-1).
Few rigorous studies of intraarticular stem cell therapy and
platelet-rich plasma (PRP) have been conducted to date. Further,
the composition of the injected biologic materials reflecting stem
cells or PRP has not been standardized, making it challenging to
compare across studies due to variability in formulation.
Other Classes of Drugs and Nutraceuticals  Opioids have only
modest short-term efficacy in treating pain in hip or knee OA
without evidence of long-term benefit and, given concerns about
opioid dependency, should be avoided. If NSAIDs are ineffective,
one option is the use of duloxetine, which is U.S. Food and Drug
Administration approved for OA. Duloxetine may be particularly
efficacious when knee pain is part of a syndrome of widespread pain.
Biologic agents and disease-modifying agents used for rheuma­
toid arthritis have been tested for OA, but trials have mostly been
negative. Notable exceptions are two randomized trials for hand
OA, one of 6 weeks of prednisolone and the other of 6 months of
methotrexate. Both trials demonstrated reductions in hand pain
compared with placebo. In a large randomized trial, GLP1R ago­
nists reduced knee pain in obese patients.

29 - 385 Fibromyalgia
385 Fibromyalgia
Leslie J. Crofford
Fibromyalgia
■
■DEFINITION
Fibromyalgia (FM) is characterized by chronic widespread musculo­
skeletal pain and tenderness. Although FM is defined primarily as a
pain syndrome, patients also commonly report associated neuropsy­
chological symptoms of fatigue, unrefreshing sleep, cognitive dysfunc­
tion, anxiety, and depression. Patients with FM have an increased
prevalence of other syndromes associated with pain and fatigue,
including myalgic encephalitis/chronic fatigue syndrome (Chap. 461),
temporomandibular disorder, chronic headaches, irritable bowel syn­
drome, interstitial cystitis/painful bladder syndrome, and other pelvic
pain syndromes. These are collectively referred to as chronic primary
or chronic overlapping pain conditions. Available evidence implicates
the central nervous system as key to maintaining pain and other core
symptoms of FM and related conditions. The presence of FM is asso­
ciated with substantial negative consequences for physical and social
functioning.
■
■EPIDEMIOLOGY
Worldwide prevalence is ~2%, with a prevalence of ~4% in women and
<1% in men. There is some variability depending on the method of
ascertainment; however, the prevalence data are similar across world
regions and socioeconomic classes. Cultural factors may play a role in
determining whether patients with FM symptoms seek medical atten­
tion; however, even in cultures in which secondary gain is not expected
to play a significant role, the prevalence of FM remains in this range. In
clinical settings, a diagnosis of FM is far more common in women than
in men, with a ratio of ~8:1. In population studies, the ratio of women
to men is closer to 3:1. The prevalence of FM is much higher in patients
with rheumatic diseases such as rheumatoid arthritis or systemic lupus
erythematosus, where up to 30% have comorbid FM. Additional risk
factors include sleep disturbances, physical inactivity, and overweight
or obesity.
■
■CLINICAL MANIFESTATIONS
Pain and Tenderness 
At presentation, patients with FM most
commonly report “pain all over.” Widespread pain is operationalized
as being present both above and below the waist on both sides of the
body and involving the axial skeleton (neck, back, or chest). The pain
attributable to FM is poorly localized, difficult to ignore, severe in its
intensity, and associated with a reduced functional capacity. For a diag­
nosis of FM, pain should have been present most of the day on most
days for at least 3 months.
The pain of FM is associated with tenderness and increased evoked
pain sensitivity. In clinical practice, this elevated sensitivity may be
identified by pain induced by the pressure of a blood pressure cuff
or skin roll tenderness. More formally, an examiner may complete a
tender-point examination in which the examiner uses the thumbnail
to exert pressure of ~4 kg/m2 (or the amount of pressure leading to
blanching of the tip of the thumbnail) on well-defined musculoten­
dinous sites. Previously, the classification criteria of the American
College of Rheumatology required that 11 of 18 sites be perceived as
painful on exam for a diagnosis of FM. In practice, tenderness is a
continuous variable, and strict application of a categorical threshold for
diagnosis is not necessary. Newer criteria eliminate the need for identi­
fication of tender points and focus instead on patient-reported clinical
symptoms of widespread or multisite pain and neuropsychological
symptoms (Fig. 385-1). The newer criteria perform well in clinical set­
tings in comparison to the older, tender-point criteria. When subjective
criteria are applied to populations, the result is an increase in preva­
lence of FM and a change in the sex ratio (see “Epidemiology,” earlier).
Patients with FM often have peripheral pain generators that are
thought to serve as triggers for the more widespread pain attributed
to central nervous system factors. Potential pain generators such as
arthritis, bursitis, tendinitis, neuropathies, and other inflammatory or
degenerative conditions should be identified by history and physical
examination. More subtle pain generators may include joint hypermo­
bility and scoliosis. In addition, patients may have chronic myalgias
triggered by infectious, metabolic, or psychiatric conditions that can
serve as triggers for the development of FM. These conditions are often
identified in the differential diagnosis of patients with FM, and a major
challenge is to distinguish the ongoing pain of a triggering condition
from FM pain that is occurring as a consequence of a comorbid condi­
tion and that should itself be treated.
CHAPTER 385
Fibromyalgia
Neuropsychological Symptoms 
In addition to widespread pain,
FM patients typically report fatigue, stiffness, sleep disturbance, cogni­
tive dysfunction, anxiety, and depression. These symptoms are present
to varying degrees in most FM patients but are not present in every
patient or at all times in a given patient. Relative to pain, such symp­
toms may, however, have an equal or even greater impact on function
and quality of life. Fatigue is highly prevalent in patients in primary
care who ultimately are diagnosed with FM. Pain, stiffness, and fatigue
often are worsened by exercise or unaccustomed activity. The sleep
complaints include difficulty falling asleep, difficulty staying asleep,
and early-morning awakening. Regardless of the specific complaint,
patients awake feeling unrefreshed. Patients with FM may meet criteria
for restless legs syndrome and sleep-disordered breathing; frank sleep
apnea can also be documented. Cognitive issues are characterized
as difficulties with attention or concentration, problems with word
retrieval, and short-term memory loss. Studies have demonstrated
altered cognitive function in these domains in patients with FM,
although speed of processing is age appropriate. Symptoms of anxiety
and depression are common, and the lifetime prevalence of mood
disorders in patients with FM approaches 80%. Although depression is
neither necessary nor sufficient for the diagnosis of FM, it is important
to screen for major depressive disorders by querying for depressed
mood and anhedonia. Analysis of genetic factors that are likely to pre­
dispose to FM reveals shared neurobiologic pathways with mood dis­
orders, providing the basis for comorbidity (see later in this chapter).
Overlapping Syndromes 
FM is considered as part of a group of
conditions called chronic overlapping pain syndromes because of the
propensity to coexist with other syndromes that may share underlying
mechanisms. Review of systems often reveals headaches, facial/jaw
pain, regional myofascial pain particularly involving the neck or back,
and arthritis. Visceral pain involving the gastrointestinal tract, bladder,
and pelvic or perineal region is often present as well. It is important for
patients to understand that shared pathways may mediate symptoms
and treatment strategies effective for one condition may help with
global symptom management.
Comorbid Conditions 
FM is often comorbid with chronic mus­
culoskeletal, infectious, metabolic, or psychiatric conditions. Whereas
FM affects only ~2% of the general population, it occurs in ~10–30%
of patients with degenerative or inflammatory rheumatic disorders,
likely because these conditions serve as peripheral pain generators to
alter central pain-processing pathways. The proposition that there may
be an inflammatory or autoimmune etiology for FM in some patients
has not been rigorously tested to date. It is particularly important for
clinicians to be sensitive to pain management of these comorbid con­
ditions so that when FM emerges—characterized by pain outside the
boundaries of what could reasonably be explained by the triggering
condition, development of neuropsychological symptoms, or tender­
ness on physical examination—treatment of central pain processes
will be undertaken as opposed to a continued focus on treatment of
peripheral or inflammatory causes of pain.
Psychosocial Considerations 
Symptoms of FM often have their
onset and are exacerbated during periods of perceived stress. This
pattern may reflect an interaction among central stress physiol­
ogy, vigilance or anxiety, and central pain-processing pathways. An
understanding of current psychosocial stressors will aid in patient
Generalized pain - do not count jaws, chest, or abdomen
Widespread Pain Index (WPI score 0-19)
Pain and tenderness during the past week
Neck
Region 5
Right jaw
PART 11
Immune-Mediated, Inflammatory, and Rheumatologic Disorders
Left jaw
Right shoulder
Left shoulder
Upper back
Chest or
breast
Right upper arm
Left upper
arm
Lower back
Abdomen
Right lower arm
Left lower
arm
Left hip or
buttocks
Right hip or
buttocks
Right upper leg
Left upper leg
Left lower leg
Right lower leg
Widespread Pain Index (WPI) Total (maximum 19)
All of the following criteria must be met to make a diagnosis of fibromyalgia
= 3
= 3
= 3
No
No
= 0
WPI ≥ 7 and SSS ≥ 5 OR WPI 4 to 6 and SSS ≥ 9
Yes
Generalized pain: at least 4/5 regions
Yes
Have the symptoms in section 3 and pain been present at a similar clinical
level for at least 3 months?
No
Yes
Fulfills all diagnostic criteria for FM
No
Yes
FIGURE 385-1  Fibromyalgia (FM) 2016 diagnostic criteria. (Figure created using data from F Wolfe et al: Semin Arthritis Rheum 46:319, 2016.)
management, as many factors that exacerbate symptoms cannot be
addressed by pharmacologic approaches. Furthermore, there is a high
prevalence of exposure to previous interpersonal and other forms of
violence in patients with FM and related conditions. If posttraumatic
stress disorder is an issue, the clinician should be aware of it and con­
sider treatment options.
Functional Impairment 
It is crucial to evaluate the impact of FM
symptoms on function and role fulfillment. In defining the success of a
management strategy, improved function is a key measure. Functional
assessment should include physical, mental, and social domains. Rec­
ognition of the ways in which role functioning falls short will be helpful
in establishing treatment goals.
■
■DIFFERENTIAL DIAGNOSIS
Because musculoskeletal pain is such a common complaint, the dif­
ferential diagnosis of FM is broad. Table 385-1 lists some of the more
common conditions that should be considered. Patients with inflam­
matory causes for widespread pain should be identifiable on the basis
of specific history, physical findings, and laboratory or radiographic
tests.
■
■LABORATORY OR RADIOGRAPHIC TESTING
Routine laboratory and radiographic tests yield normal results in FM
without comorbidities. Thus, diagnostic testing is focused on iden­
tification of other diagnoses and evaluation for pain generators or
comorbid conditions (Table 385-2). Most patients with new chronic
widespread pain should be assessed for the most common entities in
the differential diagnosis. Radiographic testing should be used very
sparingly and only for diagnosis of inflammatory arthritis. After the
patient has been evaluated thoroughly, repeat testing is discouraged
Region 1
Region 2
Region 4
Region 3
Generalized Pain Total (maximum 5)
Sympton Severity Score (SSS range 0-12)
Over the past week:
No problem
Slight or mild problem: generally mild or intermittent
Moderate problem: considerable problems; often present and/or at a moderate level
Severe problem: continuous, life-disturbing
No problem Slight/mild Moderate Severe
• Fatigue
• Trouble thinking or remembering
• Waking up tired (unrefreshed)
= 1
= 1
= 1
= 2
= 2
= 2
= 0
= 0
During the past 6 months:
• Pain or cramps in the abdomen
• Depression
• Headache
No = 0
No = 0
No = 0
Yes = 1
Yes = 1
Yes = 1
Symptom Severity Score Total (maximum 12)
unless the symptom complex changes. Particularly to be discouraged
is magnetic resonance imaging (MRI) of the spine unless there are fea­
tures suggesting inflammatory spine disease or neurologic symptoms.
■
■GENETICS AND PHYSIOLOGY
As in most complex diseases, it is likely that a number of genes
contribute to vulnerability to the development of FM. To date,
these genes appear to be in pathways controlling pain and stress
responses. Some of the genetic underpinnings of FM are shared across
other chronic pain conditions. Genes associated with metabolism,
transport, and receptors of serotonin and other monoamines have been
implicated in FM and overlapping conditions. Genes associated with
other pathways involved in pain transmission have also been described
as vulnerability factors for FM. Taken together, the pathways in which
polymorphisms have been identified in FM patients further implicate
central factors in mediation of the physiology that leads to the clinical
manifestations of FM.
Psychophysical testing of patients with FM has demonstrated altered
sensory afferent pain processing and impaired descending noxious
inhibitory control leading to hyperalgesia and allodynia. Functional
MRI and other research imaging procedures clearly demonstrate
activation of the brain regions involved in the experience of pain in
response to stimuli that are innocuous in study participants without
FM. Pain perception in FM patients is influenced by the emotional
and cognitive dimensions, such as catastrophizing and perceptions of
control, providing a solid basis for recommendations for cognitive and
behavioral treatment strategies.
Studies have indicated that some patients meeting criteria for
FM may have a small fiber neuropathy. There have also been
early reports of a possible autoimmune etiology for changes in the
TABLE 385-1  Common Conditions in the Differential Diagnosis of
Fibromyalgia
Inflammatory
Polymyalgia rheumatica
Inflammatory arthritis: rheumatoid arthritis, spondyloarthritides
Connective tissue diseases: systemic lupus erythematosus, Sjögren’s syndrome
Infectious
Hepatitis C
HIV infection
Lyme disease
Parvovirus B19 infection
Epstein-Barr virus infection
Noninflammatory
Degenerative joint/spine/disk disease
Myofascial pain syndromes
Bursitis, tendinitis, repetitive strain injuries
Endocrine
Hypo- or hyperthyroidism
Hyperparathyroidism
Neurologic Diseases
Multiple sclerosis
Neuropathic pain syndromes
Psychiatric Disease
Major depressive disorder
Drugs
Statins
Aromatase inhibitors
peripheral nervous system in patients with FM. Other studies have
identified alterations in expressed gene or metabolic signatures in
peripheral blood. These studies raise the possibility that confirma­
tory diagnostic testing could be developed in the future to assist in
the diagnosis of FM.
APPROACH TO THE PATIENT
Fibromyalgia
FM is common and has an extraordinary impact on the patient’s
function and health-related quality of life. Optimal management
requires prompt diagnosis and assessment of pain, function, and
psychosocial context. Physicians and other health professionals
can be helpful in managing some of the symptoms and impact
TABLE 385-2  Laboratory and Radiographic Testing in Patients with
Fibromyalgia Symptoms
Routine
Erythrocyte sedimentation rate (ESR) or C-reactive protein (CRP)
Complete blood count (CBC)
Thyroid-stimulating hormone (TSH)
Guided by History and Physical Examination
Complete metabolic panel
Antinuclear antibody (ANA)
Anti-SSA (anti–Sjögren’s syndrome A) and anti-SSB
Rheumatoid factor and anti–cyclic citrullinated peptide (anti-CCP)
Creatine phosphokinase (CPK)
Viral (e.g., hepatitis C, HIV) and bacterial (e.g., Lyme) serologies
Spine and joint radiographs
Source: LM Arnold et al: J Women’s Health 21:231, 2012; MA Fitzcharles et al: J
Rheumatol 40:1388, 2013.
of FM. Developing a partnership with patients is essential for
improving the outcome of FM, with a goal of understanding
the factors involved, implementing a treatment strategy, and
choosing appropriate nonpharmacologic and pharmacologic
treatments.
CHAPTER 385
TREATMENT
Fibromyalgia
Fibromyalgia
NONPHARMACOLOGIC TREATMENT
Patients with chronic pain, fatigue, and other neuropsychological
symptoms require a framework for understanding the symptoms
that have such an important impact on their function and qual­
ity of life. Explaining the genetics, triggers, and physiology of FM
can be an important adjunct in relieving associated anxiety and
in reducing the overall cost of health care resources. In addition,
patients must be educated regarding expectations for treatment.
The physician should focus on improved function and quality of life
rather than elimination of pain. Illness behaviors, such as frequent
physician visits, should be discouraged and behaviors that focus on
improved function strongly encouraged.
Treatment strategies should include physical conditioning, with
encouragement to begin at low levels of aerobic exercise and to
proceed with slow but consistent advancement. Physical activity
and exercise are consistently found to be the most helpful strategies.
Exercise programs are helpful in reducing tenderness and enhanc­
ing self-efficacy. Patients who have been physically inactive may do
best in supervised or water-based programs at the start. Strength
training may be recommended after patients reach their aerobic
goals. The U.S. Food and Drug Administration has approved
devices including a laser therapy device and a transcutaneous
electric nerve stimulation (TENS) device. A large randomized,
placebo-controlled trial showed that TENS reduces movementevoked pain and fatigue. Meditative movement therapies, such as
qigong, yoga, or Tai Chi, may be helpful to manage symptoms.
Other defined physical therapies such as acupuncture or hydro­
therapy may also be considered. Cognitive-behavioral strategies
to improve sleep hygiene and reduce illness behaviors can also be
helpful in management.
PHARMACOLOGIC APPROACHES
It is essential for the clinician to treat any comorbid triggering condi­
tion and to clearly delineate for the patient the treatment goals for
each medication. For example, glucocorticoids or nonsteroidal antiinflammatory drugs may be useful for management of inflammatory
triggers but are not effective against FM-related symptoms. At present,
the treatment approaches that have proved most successful in FM
patients target afferent or descending pain pathways. Table 385-3 lists
the drugs with demonstrated effectiveness. It should be emphasized
that strong opioid analgesics are to be avoided in patients with
FM. These agents have no demonstrated efficacy in FM and are
associated with adverse effects that can worsen both symptoms and
function. Tramadol, an opioid with mild serotonin-noradrenaline
reuptake inhibitor activity, has been studied in this population
with indication of efficacy, however its use is generally discouraged
due to opioid-related adverse effects. Use of single agents to treat
multiple symptom domains is strongly encouraged. For example,
if a patient’s symptom complex is dominated by pain and sleep distur­
bance, use of an agent that exerts both analgesic and sleep-promoting
effects is desirable. These agents include cyclobenzaprine, sedating
antidepressants such as amitriptyline, and alpha-2-delta ligands
such as gabapentin and pregabalin. For patients whose pain is
associated with fatigue, anxiety, or depression, drugs that have both
analgesic and antidepressant/anxiolytic effects, such as duloxetine
or milnacipran, may be the best first choice.