# 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.