Rheumatoid Arthritis

2751CHAPTER 358

an international normalized ratio (INR) ranging from 2.0 to 3.0 in

case of an unprovoked venous thrombosis. For patients with arterial thrombosis, the corresponding INR target should be 3.0–4.0

or 2.0–3.0 along with low-dose aspirin (LDA, 75–100 mg daily),

depending on the thrombotic/hemorrhagic patient profile. Administration of direct oral thrombin inhibitors recently has been shown

to increase the risk of arterial events, especially in patients with triple

positivity or previous arterial thrombosis. However, they could be

considered with extreme caution in cases in which contraindications

to VKAs or inability to achieve a target INR despite adherence to the

treatment are present. In pregnant women with a history of obstetric

APS, combination treatment with LDA and prophylactic dose of lowmolecular-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, increasing the LMWH dose (from prophylactic to therapeutic) or administering oral hydroxychloroquine

400 mg/d or IV immunoglobulin (IVIg) 400 mg/kg every day for

5 days are alternative options.

For asymptomatic individuals or SLE patients with a high-risk

anti-PL profile and no evidence of a previous thrombotic event

or pregnancy morbidity, prophylactic treatment with LDA is recommended. In nonpregnant women with a history of APS-related

obstetric complications, independently of the presence of underlying SLE diagnosis, treatment with LDA seems to reduce the risk of

a subsequent thrombotic event.

Patients with CAPS should be treated with combination therapy with glucocorticoids, heparin, and plasma exchange or IVIG

together with appropriate management 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

Sciascia S et al: Diagnosing antiphospholipid syndrome: “Extra-criteria” manifestations and technical advances. Nat Rev Rheumatol

13:548, 2017.

Tebo AE: Laboratory evaluation of antiphospholipid syndrome: An

update on autoantibody testing. Clin Lab Med 39:553, 2019.

Tektonidou MG et al: EULAR recommendations for the management

of antiphospholipid syndrome in adults. Ann Rheum Dis 78:1296,

2019.

INTRODUCTION

Rheumatoid arthritis (RA) is a chronic inflammatory disease of

unknown etiology characterized by a symmetric polyarthritis and 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 aggressively before damage ensues. RA, a systemic

disease, may also lead to a variety of extraarticular manifestations,

including fatigue, subcutaneous nodules, lung involvement, pericarditis, peripheral neuropathy, vasculitis, and hematologic abnormalities,

which must be managed accordingly.

358 Rheumatoid Arthritis

Ankoor Shah, E. William St. Clair

Insights gained by a wealth of basic and clinical research 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 diagnostic evaluation of patients with

suspected RA, and these antibodies serve as biomarkers of prognostic

significance. Advances in imaging modalities assist clinical decisionmaking 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 molecular components and pathways of

disease pathogenesis in even more detail. The relative contribution of

these cellular and inflammatory mediators in disease pathogenesis has

been further brought to light by the observed benefits of an expanded

pipeline of biologic and targeted synthetic disease-modifying therapies.

Despite this progress, incomplete understanding of the initiating events

of RA and the factors perpetuating the chronic inflammatory response

remains a barrier to its cure and prevention.

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 adoption of early

treatment intervention. The shift in treatment strategy dictates a new

mindset for primary care practitioners—namely, one that demands

early referral of patients with inflammatory arthritis to a rheumatologist for prompt diagnosis and initiation of therapy. Only then will

patients achieve their best outcomes.

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 of RA typically result from inflammation of the joints,

tendons, and bursae. Patients often complain of early morning joint

stiffness lasting >1 hour that eases with physical activity. The earliest

involved joints are typically 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 inflammatory 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.

Once the disease process of RA is established, the wrists and metacarpophalangeal (MCP) and proximal interphalangeal (PIP) joints

stand out as the most frequently involved joints (Fig. 358-1). Distal

FIGURE 358-1 Metacarpophalangeal joint swelling and subluxation. (RP Usatine,

MA Smith, EJ Mayeaux: The Color Atlas and Synopsis of Family Medicine, 3rd ed.

New York, McGraw Hill, 2019; Fig. 97.5.)

2752 PART 11 Immune-Mediated, Inflammatory, and Rheumatologic Disorders

interphalangeal (DIP) joint involvement may occur in RA, but it

usually is a manifestation of coexistent osteoarthritis. Flexor tendon

tenosynovitis is a frequent hallmark of RA and leads to decreased range

of motion, reduced grip strength, and “trigger” fingers. Flexor tendon

involvement may also lead to tendon rupture, with the flexor pollicis

longest the most common flexor tendon to be affected by RA. Progressive destruction of the joints and soft tissues may lead to chronic,

irreversible deformities. Ulnar deviation results from 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 hyperextension 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 in these small joints. 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 involvement in the feet

is an early feature of disease, chronic inflammation of the ankle and

midtarsal regions usually comes later and may lead to pes planovalgus (“flat feet”). Large joints, including the knees and shoulders, are

often affected in established disease, although these joints may remain

asymptomatic for many years after onset.

Atlantoaxial involvement of the cervical spine is clinically noteworthy because of its potential to cause compressive myelopathy and

Ocular: Keratoconjunctivitis sicca,

Neurologic: Ce episcleritis, scleritis rvical myelopathy

Hematologic: Anemia of

chronic disease, neutropenia,

splenomegaly, Felty’s syndrome,

large granular lymphocyte

leukemia, lymphoma

GI: Vasculitis

Skeletal: Osteoporosis

Oral: Xerostomia, periodontitis

Endocrine: Hypoandrogenism

Skin: Rheumatoid nodules, purpura,

pyoderma gangrenosum

Pulmonary: Pleural effusions,

pulmonary nodules, interstitial

lung disease, pulmonary vasculitis,

organizing pneumonia

Cardiac: Pericarditis, ischemic

heart disease, myocarditis,

cardiomyopathy, arrhythmia,

mitral regurgitation

Renal: Membranous

nephropathy, secondary

amyloidosis

FIGURE 358-2 Extraarticular manifestations of rheumatoid arthritis.

neurologic dysfunction. Neurologic manifestations are rarely a presenting sign or symptom of atlantoaxial disease, but they may 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. 362),

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. 358-2). Patients most likely to develop extraarticular disease

have a history of cigarette smoking, have early onset of significant

physical disability, and test positive for serum RF or ACPA. Subcutaneous nodules, secondary Sjögren’s syndrome, interstitial lung disease

(ILD), pulmonary nodules, and anemia are among the most frequently

observed extraarticular 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.

Rheumatoid Arthritis

2753CHAPTER 358

■ 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, the disease-related shared epitope (SE) (see below), a

positive test for serum RF, and radiographic evidence of joint erosions.

However, more recent cohort studies suggest 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, pericardium, 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 phenomenon is

unclear.

■ SJÖGREN’S SYNDROME

Secondary Sjögren’s syndrome (Chap. 361) is defined by the presence

of either keratoconjunctivitis sicca (dry eyes) or xerostomia (dry mouth)

in association with another connective tissue 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

produce pleuritic chest pain and dyspnea, as well as a pleural friction

rub and effusion. Pleural effusions tend to be exudative with increased

numbers of monocytes and neutrophils. ILD may also occur in patients

with RA and is heralded 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 CT scan, which shows infiltrative opacification, or ground-glass

opacities, in the periphery of both lungs. Usual interstitial 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 honeycomb 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, with

volume loss and traction bronchiectasis. In both cases, pulmonary

function testing shows a restrictive pattern (e.g., reduced total lung

capacity) with a reduced diffusing capacity for carbon monoxide

(DlCO). The presence of ILD confers a poor prognosis. The prognosis

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. 293). 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 characterized

by the development of nodules and pneumoconiosis following silica

exposure. Respiratory bronchiolitis and bronchiectasis are pulmonary

disorders less commonly associated with RA.

■ CARDIAC

The most frequent site of cardiac involvement in RA is the pericardium. However, clinical manifestations of pericarditis occur in <10%

of patients with RA despite the fact that pericardial involvement is

detectable in nearly one-half of cases by echocardiogram or autopsy

studies. 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 involvement too may be subclinical and only identified by echocardiography or cardiac MRI. Rarely, the heart muscle

may contain rheumatoid nodules or be infiltrated with amyloid. Mitral

regurgitation is the most common valvular abnormality in RA, occurring at a higher frequency than in the general population.

■ VASCULITIS

Rheumatoid vasculitis (Chap. 363) typically occurs in patients with

long-standing disease, a positive test for serum RF or anti–cyclic citrullinated peptide (CCP) antibodies, and hypocomplementemia. 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. Vasculitic ulcers, which may be

difficult to distinguish from those caused by venous insufficiency,

may be treated successfully with immunosuppressive agents (requiring

cytotoxic treatment in severe cases) as well as skin grafting. Sensorimotor polyneuropathies, such as mononeuritis multiplex, may occur in

association with systemic rheumatoid vasculitis and usually clinically

present with a new onset of numbness, tingling, or focal muscle weakness depending on its severity.

■ 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 in this disease.

Felty’s syndrome is defined by the clinical triad of neutropenia, splenomegaly, 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, leading 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 associated 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, hypercholesterolemia,

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 population. The

presence of elevated serum inflammatory markers appears to confer

an increased risk of cardiovascular disease in this disease population.

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 probably spills over into

the rest of the body and promotes generalized bone loss by activating osteoclasts. Both trabecular and cortical bone are affected by the

2754 PART 11 Immune-Mediated, Inflammatory, and Rheumatologic Disorders

inflammatory response, with cortical sites more susceptible to bone

loss. Chronic use of glucocorticoids and disability-related 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. 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. 358-3). For example, the Native

American 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

response, respectively. However, estrogens have both stimulatory and

inhibitory effects on the immune system, and the hormonal mechanisms, if any, influencing the development of RA are unknown

GENETIC CONSIDERATIONS

It has been recognized for >30 years that genetic factors contribute

to the occurrence of RA as well as to its severity. The likelihood 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 estimatesrange from 40 to 50%

and are approximately the same for autoantibody-positive and -negative

individuals. The estimate of genetic influence may vary across studies

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, MHC class II molecules. MHC class II molecules are typically

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. These amino acids are

located in the antigen-binding grove with the hypervariable regions of

the HLA-DRβ1 molecule. Hypervariable regions within DR molecules

are particularly important for determining antigen recognition and

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 shared epitope, providing a potential mechanism

for increased disease risk at a molecular level.

Carriership of the SE alleles is associated with production of antiACPA and worse disease outcomes. Some of these 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, HLADRB1*

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,

where RA tends to be milder than in western European countries, RA

susceptibility has been associated with the *

0101 SE allele. By comparison, 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. GWAS are based on the detection of single nucleotide

polymorphisms (SNPs), which allow for examination of the genetic

architecture of complex diseases such as RA. There are ~10 million

common SNPs within a human genome consisting of 3 billion base

pairs. As a rule, GWAS identify only common variants, namely, those

with a frequency of >5% in the general population.

US:

0.7–1.3%

Brazil:

0.4–1.4%

Jamaica:

1.9–2.2%

European ancestry:

Asian ancestry:

HLA-DRB1:

HLA-DRB1:

PTPN22: European

PADI4

CD244

STAT4: North American

TNFAIP3: North American

TRAFI/CF: North American

CTLA4: European

Other:

CD40

*0401

*0404

*0301

*0101

*0401 (East Asian)

*0405

*0901 (Japanese, Malaysian, Korean)

UK:

0.8–1.1%

South Africa:

2.5–3.6%

Lesotho:

1.7–4.5%

Saudi Arabia:

0.1–0.2%

Java:

0.1–0.2%

Liberia:

2–3%

Norway: 0.4%

Spain:

0.2–0.8%

Greece:

0.3–1%

Bulgaria:

0.2–0.6%

Iraq:

0.4–1.5% India:

0.1–0.4% Japan:

0.2–0.3%

Hong Kong:

0.1–0.5%

FIGURE 358-3 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.

Rheumatoid Arthritis

2755CHAPTER 358

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 ACPA-positive disease, there are several risk loci that are

unique to ACPA-negative 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

non-receptor 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 ACPA-positive 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 development 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 apolipoprotein M (APOM) have been demonstrated

in an East Asian population to confer an increased risk for RA as well

as risk for dyslipidemia, independent of RA disease activity.

In addition to PTPN22, other genes associated with B-cell function

and/or antigen presentation such as BTLA (B- and T-lymphocyte

attenuator), Fc receptors, and CD40 have been identified. Signal

transduction genes and pathways that regulate immune function (e.g.,

TRAF1-C5 and STAT4), cell migration (ELMO1) and fetal development (LBH) have also been discovered to be linked to RA. Other risk

alleles affect cytokine signaling, such as tumor necrosis factor (TNF)

promoter polymorphisms that can potentially modulate TNF gene

expression and an interleukin (IL) 6 receptor polymorphism that is

functionally implicated in the strength of IL-6 signaling. Thus, the

genetic clues implicate both adaptive and innate immune mechanisms

in disease pathogenesis.

Epigenetics is the study of heritable traits that affect gene expression

but do not modify DNA sequence. It may provide a link between environmental exposure and predisposition to disease. 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 methylation. DNA methylation patterns have been shown

to differ between RA patients and healthy controls, as well as from

patients with osteoarthritis. MicroRNAs, which are noncoding RNAs

that function as posttranscriptional regulators of gene expression,

represent an additional epigenetic mechanism that may potentially

influence cellular responses. Many microRNAs have been identified as

contributing to the activated phenotype of synovial fibroblasts, such as

miR146a or miR155.

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

shared epitope alleles alone modestly 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 his or her 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, improves disease activity. Inhalant-related occupations and silica inhalants also

may increase RA risk. These observations have led to the theory that

lung disease may play a critical early role in the initial development

of autoreactive immune cells, as well as to the known occurrence of

autoantibodies more than a decade prior to the clinical development

of joint disease.

Researchers began to aggressively seek an infectious etiology for

RA after the discovery in 1931 that sera from patients with this disease 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 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 is that microbial dysbiosis of the oral or gut

microbiome may predispose to the development of RA. Recent studies

suggest 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 Porphyromonas gingivalis. It has been

hypothesized that the immune response to P. gingivalis may trigger the

development of RA and that induction of ACPA results from citrullination of arginine residues in human tissues by the bacterial enzyme peptidyl arginine deiminase (PAD). Interestingly, P. gingivalis is the only

oral bacterial species known to harbor this enzyme. Some studies have

shown a relationship between circulating antibodies to P. gingivalis and

RA, as well as these antibodies and 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, and results from

other studies argue against a causal link between periodontitis and the

development of RA.

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 particular, Prevotella copri was reported to be enriched in early

untreated RA as well as 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 direct immune-modulating

mechanisms.

PATHOLOGY

RA affects the synovial tissue primarily of the diarthrodial joints and

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

2756 PART 11 Immune-Mediated, Inflammatory, and Rheumatologic Disorders

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 containing multiple layers of fibroblast-like synoviocytes and granulation-reactive

fibrovascular tissue that invades the underlying cartilage 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.

The structural damage to the mineralized cartilage and subchondral

bone is mediated by the osteoclast. Osteoclasts are multinucleated

giant cells that can be identified by their expression of CD68, tartrateresistant acid phosphatase, cathepsin K, and the calcitonin receptor.

They 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 bones 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 juxtaposed

to the insertion sites of the tendons, collateral ligaments, and synovial

membrane. Another form of bone loss is periarticular osteopenia that

occurs in joints with active inflammation. It is associated with substantial thinning of the bony trabeculae along the metaphyses of bones,

and likely results 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

characteristics 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 relatively thin and susceptible to penetration by the

inflamed synovium. The bone marrow lesions seen 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.

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 cartilage zones)—chondrocytes constitute the unique cellular component

in these layers. Originally, cartilage was considered to be an inert

tissue, 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 perichondrocytic zone and in regions adjacent to the subchondral bone.

PATHOGENESIS

The pathogenic mechanisms of synovial inflammation are likely to

result from a complex interplay of genetic, environmental, and immunologic factors that produces dysregulation of the immune system and

a breakdown in self-tolerance (Fig. 358-4). Precisely what triggers

these initiating events and what genetic and environmental factors

disrupt the immune system remain a mystery. However, a detailed

molecular picture is emerging of the mechanisms underlying the

chronic inflammatory response and the destruction of the articular

cartilage and bone.

In RA, the preclinical stage appears to be characterized by a breakdown in self-tolerance. This idea is supported by the finding that autoantibodies, such as RF and ACPA, may be found in sera from patients

many years before onset of clinical disease. However, the antigenic

targets of ACPA and RF are not restricted to the joint, and their role

in disease pathogenesis remains speculative. ACPA are directed against

deaminated peptides, which result from posttranslational modification

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. Other autoantibodies have been found in a

minority of patients with RA, but they also occur in the setting of other

types of arthritis. They bind to a diverse array of autoantigens, including type II collagen, human cartilage gp-39, aggrecan, calpastatin,

immunoglobulin binding protein (BiP), and glucose-6-phosphate

isomerase.

In theory, environmental stimulants 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.

How might microbes or their products be involved in the initiating

events of RA? The immune system is alerted to the presence of microbial infections through the binding of pathogen-associated molecular

patterns (PAMPs) to Toll-like receptors (TLRs). 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 production of proinflammatory

cytokines. Although TLR ligands may theoretically amplify inflammatory pathways in RA, their specific role in disease pathogenesis 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

the self-reactive T-cell repertoire and a breakdown in T-cell tolerance.

The support for these theories 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. Of interest, peripheral blood T cells from

patients with RA have been shown to display a fingerprint of premature

aging that mostly affects inexperienced naïve T cells. In these studies,

the most glaring findings have been the loss of telomeric sequences and

a decrease in the thymic output of new T cells. Although intriguing,

it is not clear how generalized T-cell abnormalities might provoke a

systemic disease with a predominance of synovitis.

There is substantial evidence of a role for CD4+ T cells in the pathogenesis 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 may play a role in the pathogenesis of this

disease. Second, CD4+ memory T cells are enriched in the synovial

tissue from patients with RA and can be 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,

Rheumatoid Arthritis

2757CHAPTER 358

+

+

+

St

Genetics Environment

APC

TLR

CD80

CD28

CD40L

CD40

TCR

MHC II

T

TH1

Pre-OB

Wnt

Dkk-1

Pre-OC

IFN-γ, TNF-α

lymphotoxin-β

IFN-γ,

IL17 IL15, GM-CSF,

TNF-α

RF,

Anti-CCP Ab

IL-6, IL-8

IL-1, IL-6, IL-18

MMP

OPG

RANK-L

RANK

FGF,

TGF-β

IL-17A, IL-17F,

TNF-α, IL-6,

GM-CSF

TH

TH

OC

OB

B

M

SF

Teff

Teff

TH17

Cathepsin K

FIGURE 358-4 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.

2758 PART 11 Immune-Mediated, Inflammatory, and Rheumatologic Disorders

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 influence pathogenic responses.

In the rheumatoid joint, by mechanisms of cell-cell contact and

release of soluble mediators, activated T cells stimulate macrophages

and fibroblast-like synoviocytes to generate proinflammatory mediators and proteases that drive the synovial inflammatory response

and destroy the cartilage and bone. CD4+ T-cell activation is dependent 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 pathogenesis 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 TNF-α, whereas TH2 cells predominately secreted IL-4, IL-5,

IL-6, IL-10, and IL-13. In humans, naïve T cells may 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 proinflammatory mediators such as IL-17, IL-21, IL-22,

TNF-α, IL-26, IL-6, and granulocyte-macrophage colony-stimulating

factor (GM-CSF). Substantial 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, in a phase 2 clinical trial, treatment

with secukinumab, an anti-IL-17 receptor antibody, failed to produce

significant clinical benefit in patients with RA.

The immune system has evolved mechanisms to counterbalance

the potential harmful immune-mediated inflammatory responses provoked by infectious agents and other triggers. Among these negative

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) and the absence of CD127, the IL-7 receptor. 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. In RA, the data that Treg

numbers and suppressive capacity are deficient compared with normal

healthy controls are contradictory and inconclusive. Some experimental

evidence suggests that Treg suppressive activity is lost due to dysfunctional expression of cytotoxic T lymphocyte antigen 4 (CTLA-4). The

nature of Treg defects in RA and their role in disease mechanisms

remain unclear.

Cytokines, chemokines, antibodies, and endogenous danger signals

bind to receptors on the surface of immune cells and stimulate a cascade of intracellular signaling events that can amplify the inflammatory

response. Signaling molecules and their binding partners in these pathways are the target of small-molecule drugs designed to interfere with

signal transduction and, in turn, block these reinforcing inflammatory

loops. Examples of signaling molecules in these critical inflammatory

pathways include Janus kinase (JAK)/signal transducers and activators of transcription (STAT), spleen tyrosine kinase (Syk), mitogenactivated 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 response. 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

pathogenic process by fixing complement and promoting the release

of proinflammatory 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 cytokines

inside the joint. Key proinflammatory cytokines released by synovial

macrophages 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. It

upregulates adhesion molecules on endothelial cells, promoting the

influx of leukocytes into the synovial microenvironment; activates

synovial fibroblasts; stimulates angiogenesis; promotes pain receptor

sensitizing 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.

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 receptor 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 the characteristic ruffled

membrane. Cytokines such as TNF-α, IL-1, IL-6, and IL-17 increase

the expression of RANKL in the joint and thus promote osteoclastogenesis. Osteoclasts also secrete cathepsin K, a cysteine protease that

degrades the bone matrix by cleaving collagen and 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

inflammation. Recent evidence shows that inflammation suppresses

bone formation. TNF-α plays a key role in actively suppressing bone

formation by enhancing the expression of dickkopf-1 (DKK-1).

DKK-1 is an important inhibitor of the Wnt pathway, which acts to

promote osteoblast 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 based on signs and symptoms

of a chronic inflammatory arthritis, with laboratory and radiographic

results providing important corroborating information. In 2010, a

collaborative 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 358-1). Application of the newly revised criteria yields a score

of 0–10, with a score of ≥6 fulfilling the requirements for definite RA.

The new classification criteria differ in several ways from the older

criteria set. Early clinical classifications for RA required symptoms

to be present for >6 weeks. There are several conditions, including

virus-related syndromes, that can cause a polyarthritis mimicking

Rheumatoid Arthritis

2759CHAPTER 358

TABLE 358-1 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)

0

1

2

3

5

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)

0

2

3

Acute-phase

reactants

Normal CRP and normal ESR

Abnormal CRP or abnormal ESR

0

1

Duration of

symptoms

<6 weeks

≥6 weeks

0

1

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.

RA and stimulate the transient production of RF. Such conditions

usually last only 2–3 weeks. The newer criteria, however, do not mandate symptoms be present for >6 weeks. The new criteria 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. The newer

classification criteria also do not take into account whether the patient

has rheumatoid nodules or radiographic joint damage because these

findings occur 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. About three-fourths of patients with the

clinical 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 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, and

the presence of disease in other organ systems. 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 synovitis similar to RA. Moreover,

50% of patients with primary Sjögren’s syndrome test positive for RF

and therefore, may be confused with early RA. Spondyloarthropathies

such as psoriatic arthritis or enteropathy-associated arthritis may

present similarly to RA. However, they may be distinguished by the

presence of sacroiliitis and other enthesopathic features and are generally accompanied by signs of psoriasis or inflammatory bowel disease,

respectively. In elderly patients, seronegative RA may be difficult at

times to distinguish from polymyalgia rheumatica (PMR). While PMR

has been associated in a minority with distal limb involvement, RA

may be distinguished by predominant involvement of the wrists/hands

and ankles/feet in most cases. Similarly, the relatively rare condition

called remitting seronegative symmetrical synovitis with pitting edema

(the so-called RS3PE syndrome) 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 particular responsive 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 with a

positive RF in about half the cases, but generally not ACPA.

LABORATORY FEATURES

Patients with systemic inflammatory diseases such as RA will often

present with elevated nonspecific inflammatory markers such as an

ESR or CRP. Detection of serum RF and anti-CCP antibodies is important in differentiating RA from other polyarticular 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

presence 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

infections such as subacute bacterial endocarditis and hepatitis B and

C. Serum RF 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 distinguishing 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 significance, 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; particularly p-ANCAs). However, patients with RA would not be expected

to test positive for anti-MPO or anti-PR3 antibodies.

■ SYNOVIAL FLUID ANALYSIS

Typically, the cellular composition of synovial fluid from patients with RA

reflects an acute inflammatory state. Synovial fluidwhite blood cell(WBC)

counts can varywidely but generally range between 5000 and 50,000WBC/

μL, compared with <2000 WBC/μL for a noninflammatory 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. 372).

■ 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 cartilage

based on the amount of joint space narrowing. MRI and ultrasound

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 radiographs are usually relied upon in clinical practice for the purpose of

diagnosis and monitoring of 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 practice 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 on the newer

digitalized x-rays. Other findings on plain radiographs include soft

tissue swelling, symmetric joint space loss, and subchondral erosions,

2760 PART 11 Immune-Mediated, Inflammatory, and Rheumatologic Disorders

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. 358-5).

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. 358-6).

CLINICAL COURSE

The natural history of RA is complex and affected by a number of factors including age of onset, gender, genotype, phenotype (i.e., extraarticular manifestations or variants of RA), and comorbid conditions,

which make for a truly heterogeneous disease. There is no simple way

to predict the clinical course. It is important to realize that as many

as 10% of patients with inflammatory arthritis fulfilling ACR classification criteria for RA will undergo a spontaneous remission 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 unfortunate 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 of disability over time in the face of

poorly controlled 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 contributing 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 the general

population, with ischemic heart disease being the most common cause

of death followed by 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 socioeconomic 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/

FIGURE 358-6 Ultrasound demonstrating an effusion (arrow) within the metacarpophalangeal joint. (Courtesy of Dr. Ryan Jessee.)

FIGURE 358-5 X-ray demonstrating joint space loss and erosions of carpi,

metacarpophalangeal and proximal interphlangeal joints. (K Kgoebane et al: The

role of imaging in rheumatoid arthritis. SA Journal of Radiology. S Afr J Radiology

(Online) 22 (1), 2018.)

Rheumatoid Arthritis

2761CHAPTER 358

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 activity

that are used in clinical practice for tracking disease status and documenting treatment response.

Several developments during the past two decades have changed

the therapeutic landscape in RA. They include (1) the emergence 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 methotrexate 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 methylprednisolone; conventional DMARDs; and biologic DMARDs

(Table 358-2). Although disease for some patients with RA is

managed adequately with a single DMARD, such as methotrexate,

it demands in most cases the use of a combination DMARD regimen that may vary in its components over the treatment course

depending on fluctuations in disease activity 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 clinical trials suggest that NSAIDs are roughly equivalent in their efficacy, experience suggests that some individuals may preferentially

respond to a particular NSAID. Chronic use should be minimized

due to the possibility of side effects, including gastritis and peptic

ulcer disease as well as impairment of renal function.

GLUCOCORTICOIDS

Glucocorticoids may serve in several ways to control disease activity

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 administration

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 finding an

effective DMARD that adequately controls the disease. Best practices minimize chronic use of low-dose prednisone 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 acetonide. 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 an RA flare.

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 a bisphosphonate may be appropriate for

primary prevention of glucocorticoid-induced osteoporosis. Other

agents, including teriparatide and denosumab, have been approved

for the treatment of osteoporosis and may be indicated in certain

cases. Although prednisone use is known to increase the risk of

peptic ulcer disease, especially with concomitant NSAID use, no

evidence-based guidelines have been published regarding the use

of gastrointestinal ulcer prophylaxis in this situation.

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. 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 the benchmark for the efficacy

and safety of new 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 combination with

methotrexate and other DMARDs.

Although similar to the other DMARDs in its slow onset of

action, hydroxychloroquine has not been shown to delay radiographic 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 a prescribed at a dosage of

5 mg/kg of body weight or less to decrease the risk of retinal toxicity.

Sulfasalazine is used in a similar manner and has been shown in

randomized, controlled trials to reduce radiographic progression

of disease. Minocycline, gold salts, penicillamine, azathioprine, and

cyclosporine have all been used for the treatment of RA with varying degrees of success; however, they are used sparingly now due

to their inconsistent clinical efficacy or unfavorable toxicity profile.

BIOLOGICALS

Biologic DMARDs have revolutionized the treatment of RA overthe

past decade (Table 358-2). They are protein therapeutics designed

mostly to target cytokines and cell-surface molecules. The TNF

inhibitors were the first biologicals approved for the treatment of

RA. Anakinra, an IL-1 receptor antagonist, was approved shortly

thereafter; however, its benefits have proved to be relatively modest

compared with the other biologicals, and therefore, this biological

is rarely used for the treatment of RA with the availability of other

more effective agents. Abatacept, rituximab, and tocilizumab are the

newest members of this class.

Anti-TNF Agents The development of TNF inhibitors was originally spurred by the experimental finding that TNF-α is a critical

upstream mediator of joint inflammation. Currently, five agents

that inhibit TNF-α are approved for the treatment of RA. There

are three different anti-TNF monoclonal antibodies. Infliximab

is a chimeric (part mouse and human) monoclonal antibody,

whereas adalimumab and golimumab are humanized monoclonal

antibodies. Certolizumab pegol is a pegylated Fab′ fragment of a

humanized monoclonal antibody to TNF-α. Lastly, etanercept is a

soluble fusion protein comprising the TNF receptor 2 in covalent

linkage with the Fc portion of IgG1. All of the 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. AntiTNF drugs are typically used in combination with background

methotrexate therapy. This combination regimen, which affords