CHAPTER 272 RHEUMATOID ARTHRITIS

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272
RHEUMATOID ARTHRITIS
JAMES R. ODELL

DEFINITION

Rheumatoid arthritis (RA) is a chronic systemic inflammatory disease of

unknown etiology that primarily targets synovial tissues. It is relatively
common, with a prevalence of slightly less than 1% in adults all over the
world. RA shortens survival and significantly affects quality of life in most
patients. Essentially all patients exhibit some systemic features such as fatigue,
low-grade fevers, anemia, and elevations of acute phase reactants (erythrocyte sedimentation rate [ESR] or C-reactive protein [CRP]). The primary
target of RA is the synovium, and this is responsible for most of the protean
clinical features. Synovial tissues proliferate in an uncontrolled fashion,
resulting in excess fluid production, destruction of cartilage, erosion of marginal bone, and stretching and damage of the tendons and ligaments.
In the past decade, the landscape of treatment of RA has changed dramatically. Current therapies result in substantial clinical benefit for most patients,
particularly with early diagnosis, and 50% of patients can achieve remissions

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CHAPTER 272 RHEUMATOID ARTHRITIS

with treatment with an appropriate disease-modifying antirheumatic drug

(DMARD).

EPIDEMIOLOGY

RA is present all over the world, with a remarkably consistent prevalence of

0.5 to 1% of adults, and with some differences in certain population groups.
For reasons that are still unclear, the prevalence in women is two or three
times greater than that in men. RA can occur at any age, but onset before the
age of 45 years in men is uncommon. The relatively few well-done inception
cohorts that are available suggest that the yearly incidence of RA is approximately 40 per 100,000 for women, and about half that for men. These figures
vary significantly based on the age of the cohort. The best available data
suggest that the incidence of RA in women increases with age until approximately 50 years of age and then reaches a plateau. The incidence rate is much
lower in young men, approximately one third that in women, but increases
steadily with age and approaches that of women older than 65 years. Because
the incidence of RA increases or is stable with age and RA is a lifelong disease,
the prevalence of RA increases with each decade. Recent data suggest that
the incidence of RA, particularly rheumatoid factor (RF)-negative RA, may
be decreasing. The reasons for this are unclear, but, if elucidated, they could
provide valuable insights into the etiology and pathogenesis of RA and might
allow the implementation of strategies to prevent clinical disease.
RA has a significant genetic component; therefore, it is not surprising that
RA is reportedly very unusual in certain populations and more common in
others. Most notably, cohorts have been described in rural Nigeria in which
no individuals are affected with RA; in contrast, a prevalence of RA of 5% has
been found in some studies of Chippewa, Yakima, and Inuit Native American
tribes.

PATHOBIOLOGY

Genetics

Genetics plays a significant role in determining both the risk of developing

RA and the severity of the disease. Twin studies reveal a concordance rate for
RA that averages 15% for monozygotic twins and approximately 5% for dizygotic twins. These data in monozygotic twins simultaneously reveal both the
significance of genetic factors and the fact that they are clearly not the only
important factor, or else the concordance rate would approach unity.
It has now been clearly shown that RA is a multigene disease with important contributions from both human leukocyte antigen (HLA) and non-HLA
genes. The association of certain HLA alleles, specifically HLA-DR4, with an
increased risk of developing RA and of having more severe disease has long
been recognized. This association is explained by a particular amino acid
sequence in the third hypervariable region on the DR1 chain. HLA-DR
molecules are present on the surface of antigen-presenting cells and allow T
cells to recognize antigen in the context of DR. Hypervariable regions on the
DR molecule are particularly important for antigen recognition. Table 272-1

details the amino acid sequence of several DR1 chains that are associated
with RA and some that are not. The amino acid sequence associated with RA
has been called the shared epitope or the at-risk allele. It has been shown
by a number of investigators that patients with the shared epitope have more
severe RA and more extra-articular manifestations than those who are negative for the shared epitope. Furthermore, individuals with two copies of the
shared epitope, particularly those with HLA-DR4, have a further increased
risk for the development of severe RA. This association with a particular
antigen recognition site may ultimately aid understanding of the antigen or
antigens that are important for triggering RA. Recently, proteins in which
arginine has been converted to citrulline were shown to be bound with
greater avidity by the shared epitope. The importance of certain DR1 alleles
in RA supports the concept that T cells are integrally involved in the
pathogenesis.
Population-based studies have suggested that only about one third of the
genetic risk for RA is explained by genes located in the HLA region. A functional polymorphism for the gene that encodes intracellular protein tyrosine
phosphatase nonreceptor 22 (PTPN22) has been reproducibly associated
with RA and with a number of other autoimmune diseases, including type 1
diabetes, systemic lupus erythematosus, Graves disease, and Hashimotos
thyroiditis. Recent genome-wide association studies (GWAS) have identified
at least 20 other candidate genes that are associated with RA, including polymorphisms for signal transducer and activator of transcription (STAT4),
tumor necrosis factor receptorassociated factor 1 (TRAF-1), and CD40.
The shared epitope is present in approximately 25 to 35% of the white
population, but the chance of developing RA among individuals who carry
this allele is only about 1 in 25. Therefore, despite identifying the most important genetic risk factor for RA, this test has little or no clinical utility. In addition to genetics, a number of other factors have been associated with the
incidence, and in some cases the severity, of RA, including estrogen use
(protective), smoking, and silica exposure.

ETIOLOGY

Clearly, other factors, in addition to genetics, are active in precipitating or

triggering RA. RA appears to require the complex interaction of genetic and
environmental factors with the immune system, and ultimately in the synovial tissues throughout the body (Fig. 272-1). Serum collected before the
development of clinical RA show that immunologic changes predate clinical
manifestations by years. Autoantibodies, particularly anticitrullinated
peptide antigen (ACPA) antibodies and RF, are present in the sera of many
individuals 5 to 10 years before the clinical onset of disease. By following
cohorts of people at high risk for RA, investigators are learning much about
these early immunologic changes and ultimately about the triggers for the
disease.
The use of oral contraceptives has been associated with a decrease in the
incidence of RA; because the effect appears to be strongest for oral contra
ceptives that have high estrogen content, it is postulated that estrogen is

TABLE 272-1 HUMAN LEUKOCYTE ANTIGEN ASSOCIATIONS WITH RHEUMATOID ARTHRITIS

HLA Types (Alleles) and Methods of Detection
ALLOANTISERA (DR)

MLC (Dw)

Third Hypervariable Region Amino Acid Sequences

DNA (DR1)

70

71

72

73

74

MOST COMMON
ETHNIC GROUPS

ASSOCIATED WITH RA
DR4

Dw4

*0401

DR4

Dw14

*0404

Whites (Western Europe)

Whites (Western Europe)

DR4

Dw15

*0405

Japanese, Chinese

DR1

Dw1

*0101

Asian Indians, Israelis

DR6 (14)

Dw16

*1402

Yakima Native Americans

DR10

*1001

Spanish, Greeks, Israelis

DR4

Dw10

*0402

DR4

Dw13

*0403

DR2

Dw2

*1501

DR3

Dw3

*0301

NOT ASSOCIATED WITH RA

E

Whites (Eastern Europe)

R
D

Polynesians
Whites

Whites

A = alanine; D = aspartic acid; E = glutamic acid; HLA = human leukocyte antigen; K = lysine; MLC = mixed leukocyte cultures; Q = glutamine; R = arginine; = the same amino acid in that position as for
DRB1*0401.

CHAPTER 272 RHEUMATOID ARTHRITIS

responsible for this protective effect. Studies that have tried to address the
question of postmenopausal estrogen use and its effect on RA have yielded
conflicting results.
Smoking has long been associated with a significant increase in the risk of
developing RA but recently it has been shown that this is true only for ACPApositive patients and is not associated with ACPA-negative disease. Furthermore, smoking appears to be a risk factor for RA only in those patients who
are shared-epitope positive. Smoking has also been associated with poor
responses to treatment. Purported triggers in addition to smoking have
included bacteria (Mycobacteria, Streptococcus, Mycoplasma, Escherichia coli,
Helicobacter pylori), viruses (rubella, Epstein-Barr virus, parvovirus), super
antigens, and other undefined factors.

PATHOGENESIS

The pathogenesis of RA is complex, and there are almost certainly multiple

triggering mechanisms including but not limited to smoking, infection,
molecular mimicry, immune complexes, altered T-cell repertoire, and T-cell
reactivity. Furthermore, it is likely that the triggers may be different based on
the genetic background. As mentioned previously, smoking is a well-known
trigger for some individuals but appears to be a risk factor only in those
patients who possess the shared epitope.
Rheumatic fever, reactive arthritis (formerly known as Reiters syndrome),
and, more recently, Lyme arthritis are examples of arthritic syndromes for
which infectious triggers have clearly been demonstrated, but these triggering
agents are often difficult or impossible to isolate at the time when the arthritic
syndromes occur. Many other examples exist in animal models of arthritis,

Genetic background
Some HLA-DRBI
alleles
Other HLA alleles
Non-HLA alleles

RA
initiated

Trigger
? Bacterial antigens
? Viral antigens
? Smoking
? Others

Ongoing
autoimmune
response

FIGURE272-1. Initiation of rheumatoid arthritis (RA). HLA = human leukocyte antigen.

Joint
capsule

Bone resorption (IL-1)

Cartilage
Normal
synovium

Initiation

The synovial tissues are the primary target of the autoimmune inflammatory
process that is RA; the reason for this remains elusive. Once RA is initiated,
the synovial tissues throughout the body become the site of a complex interaction of T cells, B cells, macrophages, and synovial cells (Fig. 272-2). The
resultant proliferation of the synovial tissues (synovitis) causes the production of excessive amounts of synovial fluid and the infiltration of pannus into
adjacent bone and cartilage. Synovitis results in the destruction of cartilage

Inhibition of
proteoglycan
synthesis (IL-1)

Bone

Vascular injury
Influx of immune
cells and plasma

including syndromes induced by mycobacteria and streptococci. Reactive

arthritis has clearly been shown to occur when any one of a myriad of different but specific infectious triggers is presented to a specific location in the
body (the gastrointestinal or genitourinary tract) of individuals with a certain
genetic background, in most cases HLA-B27. Additionally, in this syndrome,
the age and gender of the individual and hence the maturity of the immune
system may be critical in the development of clinical disease, which occurs
primarily between the ages of 15 and 40 years in males. Once unraveled, the
pathophysiology of RA is likely to be similarly complex.
Despite the absence of clear evidence linking any infectious agent to RA,
it is widely believed that ultimately an important triggering role will be elucidated for infectious or other environmental agents. Once triggers for RA
are identified, strategies for prevention can be addressed, but this information
may not help individuals with established disease. Possibly infections involving the innate immune system are causative in an early subclinical phase of
the rheumatoid disease process, with the agents being absent once clinical
disease develops.
The relative roles of the cellular versus the humoral immune system in the
initiation and perpetuation of RA are much debated; both appear to be
important. Most likely, the mechanisms of initiation of the disease process
are different from those that perpetuate the chronic disease. T cells, particularly of the activated TH1 and TH17 types, appear to predominate in
synovial tissues. These T cells, presumably activated by some as yet unknown
antigen presented by macrophages, B cells, or synoviocytes in the context of
HLA-DR, secrete cytokines that drive further synovial proliferation. It is
believed by many that, although RA may initially be triggered by exogenous
antigens, the process, once initiated, may be perpetuated by autoantigens.
Macrophage-derived cytokines, particularly interleukin-1 (IL-1) and tumor
necrosis factor- (TNF-), play central roles in this ongoing inflammatory
process. As definitive proof, biologic products directed against these cytokines have shown significant efficacy in the treatment of RA.
The humoral immune system also plays a role. RF has long been a serologic
marker of RA and is well known to correlate with more severe disease, including erosions of bone, and with the presence of extra-articular features. The
reason that RF is produced in excess and the exact role that it plays remains
elusive. RF production may increase complement activation and result in the
release of lysosomal enzymes, kinins, and oxygen free radicals. ACPA antibodies exhibit a high specificity (95 to 99%) for RA, although their sensitivity
for RA with currently available assays is only about 70%. Even though both
RF and ACPA antibodies also correlate with more aggressive erosive disease,
this link is strongest for ACPA antibodies.

PATHOLOGY

Synovial proliferation and

joint destruction

Synoviocyte
hyperplasia

1683

Cytokines
C
T TNF-, IL-1, IL-6,
IL-8, GM-CSF
B P

Prostaglandin
Iysosomal
enzymes
O2 radicals

IgM=RF IgG
Cellular
Phagocytosis
reactivation and
of immune
proliferation
complex
by cytokines

Immune Responses
Cellular
Humoral

Inflammation

Collagenase and
PGE2 secreted
by synoviocytes
(induced by IL-1
and TNF-)
Rheumatoid pannus
Neutrophils
attracted and
activated (GM-CSF,
IL-8, TNF-, TGF-)
Destruction

FIGURE272-2. Events involved in the pathogenesis of rheumatoid synovitis (progressing from left to right). B = B lymphocyte; C = complement;
GM-CSF = granulocyte-macrophage colony-stimulating factor; IgG, IgM =
immunoglobulin G, M; IL = interleukin; M = macrophage; P = plasma cell; PGE2
= prostaglandin E2; RF = rheumatoid factor; T = T lymphocyte; TGF- = transforming growth factor-; TNF- = tumor necrosis factor-.

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CHAPTER 272 RHEUMATOID ARTHRITIS

Median nerve
in carpal tunnel

FIGURE272-3. Severe advanced rheumatoid arthritis of the hands. There is massive

tendon swelling over the dorsal surface of both wrists, severe muscle wasting, ulnar deviation of the metacarpophalangeal joints, and swan-neck deformity of the fingers. (From
Forbes CD, Jackson WF. Color Atlas and Text of Clinical Medicine, 3rd ed. London: Mosby;
2003.)

Rheumatoid Arthritis

Osteoarthritis

Tapping produces
paresthesias in
the shaded area
(Tinels sign)
FIGURE272-5. Carpal tunnel syndrome. Distribution of pain and/or paresthesias
(shaded area) when the median nerve is compressed by swelling in the wrist (carpal tunnel).

Hands

The hands are a major site of involvement, and a significant portion of the
disability that RA causes is because of damage and dysfunction of the hands.
Typical early disease starts with swelling of the PIPs and MCPs. The distal
interphalangeal (DIP) joints are rarely involved; significant involvement of
the DIP joints should suggest the possibility of a different diagnosis (i.e.,
osteoarthritis or psoriatic arthritis). Figure 272-3 illustrates the classic ulnar
deviation of the MCP joints and swan-neck deformities (hyperextension of
the PIP joints) that are commonly seen in late, more established disease.
Boutonniere (or buttonhole) deformities also occur as a result of hyperflexion of the PIP joints. If the clinical disease remains active, hand function
deteriorates. Sudden loss of function of individual fingers may occur as a
result of tendon rupture, which requires the expertise of a carefully selected
hand surgeon to repair.

Feet

FIGURE272-4. Distribution of involved joints in the two most common forms of

arthritis: rheumatoid arthritis and osteoarthritis. Shaded circles are shown over the
involved joint areas.

and marginal bone and in the stretching or rupture of the joint capsule as well
as tendons and ligaments. In patients, these effects are manifested by the
deformities (Fig. 272-3 and E-Fig. 272-1) and disabilities that make up the
clinical picture of RA.

CLINICAL MANIFESTATIONS

Articular Manifestations

RA can affect any of the synovial (diarthrodial) joints (Fig. 272-4). Most
commonly, the disease starts in the metacarpophalangeal (MCP), proximal
interphalangeal (PIP), and metatarsophalangeal (MTP) joints, followed by
the wrists, knees, elbows, ankles, hips, and shoulders, in roughly that order.
Early treatment helps limit the number of joints involved. Less commonly,
and usually later, RA may involve the temporomandibular, cricoarytenoid,
and sternoclavicular joints. RA may involve the upper part of the cervical
spine, particularly the C1-C2 articulation, but, unlike the spondyloarthropathies, it does not involve the rest of the spine. However, RA patients are at an
increased risk for osteoporosis, and this risk should be considered and dealt
with early.

Feet, particularly the MTP joints, are involved early in most patients with RA.
Radiographic erosions occur at least as early in the feet as in the hands. Subluxation of the toes is common and leads to the dual problem of breakdown
of the skin and ulcers on the top of the toes. Painful ambulation may also
develop owing to loss of the cushioning pads that usually protect the heads
of the MTP joints.

Wrists

The wrist joints are involved in most patients with RA; radial deviation is the
rule, and patients with severe involvement may progress to volar subluxation.
Even early in the course of the disease, synovial proliferation in and around
the wrists may compress the median nerve, causing carpal tunnel syndrome
(Fig. 272-5). Later, this synovial proliferation may invade tendons and lead
to rupture of some extensor tendons.

Large Joints

Involvement of knees, ankles, elbows, hips, and shoulders is common. Characteristically, the whole joint surface is involved in a symmetrical fashion.
Therefore, RA is symmetrical not only from one side of the body to the other
but also within the individual joint. In the case of the knee (Fig. 272-6A), the
medial and lateral compartments are both severely narrowed in RA; in contrast, in patients with osteoarthritis (see Fig. 272-6B), only one compartment
of the knee may be involved.
Synovial cysts may occur around any of the joints (large or small), and they
occasionally manifest as soft, fluctuant masses that present diagnostic challenges. Synovial cysts from the knee are perhaps the best examples of this
phenomenon. When the knee produces excess synovial fluid, it may accumulate in the popliteal space (popliteal or Bakers cyst) (E-Fig. 272-2). These
cysts can cause problems by pressing on the popliteal nerve, artery, or veins.

CHAPTER 272 RHEUMATOID ARTHRITIS

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FIGURE272-7. Rheumatoid nodules. Large rheumatoid nodules are seen in a classic

location along the extensor surface of the forearm and in the olecranon bursa.

FIGURE272-6. Radiographs of the knees in the two most common forms of arthritis:

rheumatoid arthritis and osteoarthritis. A, Severe involvement in rheumatoid arthritis,

with almost complete symmetrical loss of joint space in both the medial and the lateral
compartment, but with little subchondral sclerosis or osteophyte formation. B, Typical
osteoarthritis, with severe, near-total loss of joint space of one compartment and a normal
or actually increased joint space of the other compartment. Note also the significant subchondral sclerosis in the involved area, typical of osteoarthritis.

Bakers cysts may dissect into the tissues of the calf (usually posteriorly), or
they may rupture into the upper calf. Dissection may produce only minor
symptoms, such as a feeling of fullness; rupture of the cyst with extravasation
of the inflammatory content produces significant pain and swelling and may
be confused with thrombophlebitis, the so-called pseudothrombophlebitis
syndrome. Ultrasonography of the popliteal fossa and calf is useful to establish the correct diagnosis and to rule out thrombophlebitis, which may be
precipitated by popliteal cysts. Treatment of popliteal (Bakers) cysts should
be directed at interrupting the inflammatory process through an intraarticular injection of corticosteroid into the knee.

Neck

Although most of the axial skeleton is spared in RA, the cervical spine is
commonly involved, particularly the C1-C2 articulation. Bony erosions and
ligament damage can occur in this area and may lead to subluxation (see
E-Fig. 272-1). Most often, subluxation at C1-C2 is minor and without
accompanying symptoms; patients and caregivers need only be cautious and
avoid forcing the neck into positions of flexion. Occasionally, subluxation at
C1-C2 is severe and leads to compromise of the cervical cord with symptoms
and in some cases death.

Other Joints

Wherever synovial tissue exists, RA can cause problems. The temporomandibular, cricoarytenoid, and sternoclavicular joints are examples of other
joints that may be involved in RA. The cricoarytenoid joint is responsible for
abduction and adduction of the vocal cords. Involvement of this joint may
lead to a feeling of fullness in the throat, to hoarseness, and, rarely, when the
cords are essentially fused in a closed position, to a syndrome of acute respiratory distress with or without stridor. In this latter situation, emergent tracheotomy may be life-saving.

Extra-articular Manifestations

Systemic features of RA such as fatigue, weight loss, and low-grade fevers

occur frequently. As with all the other extra-articular features, they are more
common in those patients who possess RF or ACPA antibodies, or both
(Table 272-2).

Skin

Subcutaneous nodules are seen in approximately one fourth of patients with

RA, almost exclusively in those who are RF positive. Patients with nodules
who are RF negative should be carefully scrutinized for a different diagnosis,
such as chronic tophaceous gout. Nodules may occur almost anywhere (e.g.,
lungs, heart, eye), but most commonly they occur subcutaneously on

FIGURE272-8. Rheumatoid nodulosis. In this patient, multiple rheumatoid nodules are

present over joints. In some cases, nodules may dominate the clinical picture. Rarely, this
may be seen as a side effect of methotrexate therapy.

TABLE 272-2 EXTRA-ARTICULAR MANIFESTATIONS OF

RHEUMATOID ARTHRITIS
Skin

Nodules, fragility, vasculitis, pyoderma gangrenosum

Heart

Pericarditis, premature atherosclerosis, vasculitis, valve disease, and

valve ring nodules

Lung

Pleural effusions, interstitial lung disease, bronchiolitis obliterans,

rheumatoid nodules, vasculitis

Eye

Keratoconjunctivitis sicca, episcleritis, scleritis, scleromalacia

perforans, peripheral ulcerative keratopathy

Neurologic

Entrapment neuropathy, cervical myelopathy, mononeuritis

multiplex (vasculitis), peripheral neuropathy

Hematopoietic

Anemia, thrombocytosis, lymphadenopathy, Feltys syndrome

Kidney

Amyloidosis, vasculitis

Bone

Osteopenia

extensor surfaces (particularly the forearms) (Fig. 272-7), over joints, or over
pressure points. Rheumatoid nodules are firm on examination, usually are not
tender, have a characteristic histologic picture, and are thought to be initiated
by small vessel vasculitis. A syndrome of increased nodulosis, despite good
control of the joint disease, has been described with methotrexate therapy
(Fig. 272-8).
Small vessel vasculitis, manifested as digital infarcts or leukocytoclastic
vasculitis, may occur in RA (Fig. 272-9) and should prompt more aggressive

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CHAPTER 272 RHEUMATOID ARTHRITIS

FIGURE272-9. Small vessel vasculitis. A and B, Rheumatoid vasculitis with small brown
infarcts of palms and fingers in chronic rheumatoid arthritis. (Courtesy of Dr. Martin Lidsky,
Houston, TX.)

DMARD treatment. A vasculitis of small and medium arteries that is indistinguishable from polyarteritis nodosa also can be seen with RA and requires
aggressive systemic therapy. Finally, pyoderma gangrenosum occurs with
increased frequency in association with RA.

Cardiac Involvement

Cardiac involvement directly related to RA is uncommon; however, patients

with RA have a significantly increased morbidity and mortality from coronary artery disease. The reasons are not clear, but chronic inflammation may
be the major cause. Some of the medications used to treat RA and a sedentary
lifestyle may be additional risk factors for the development of coronary artery
disease. Pericardial effusions are common in RA (50% by echocardiography)
but usually are asymptomatic. Rarely, long-standing pericardial disease may
result in a fibrinous pericarditis, and patients may present clinically with
constrictive pericarditis (Chapter 77). Uncommonly, rheumatoid nodules
occur in the conduction system and cause heart block.

Pulmonary Manifestations

Pulmonary manifestations of RA include pleural effusions, rheumatoid

nodules, and parenchymal lung disease (Chapters 84 and 92). Pleural effusions occur more commonly in men and are usually small and asymptomatic.
Of interest, pleural fluid in RA is characterized by low levels of glucose and
low pH and, therefore, may at times be confused with empyema. Rheumatoid
nodules may occur in the lung, especially in men (Fig. 272-10); these are
usually solid but may calcify, cavitate, or become infected. Rarely, pulmonary
nodules rupture and produce a pneumothorax. If RA patients are exposed to
coal dust, diffuse nodular densities may occur (Caplans syndrome). Differentiating rheumatoid nodules from lung cancer can be problematic, particularly if the lesion is solitary. Therefore, the presence of pulmonary nodules in
a patient with RA should precipitate an aggressive diagnostic evaluation.
Diffuse interstitial fibrosis occurs in RA and may progress to a honeycomb
appearance on radiography with increasing dyspnea. Rarely, bronchiolitis
obliterans can be seen with or without organizing pneumonia. Bronchiolitis
obliterans carries a poor prognosis and may occur more often in association
with d-penicillamine or gold therapy.

Ophthalmologic Manifestations

The most common manifestation of RA in the eye is keratoconjunctivitis

sicca (dry eyes) from secondary Sjgrens syndrome. Patients may have associated xerostomia (dry mouth), parotid gland swelling, or, occasionally,
lymphadenopathy. Scleritis can also occur and may be painful, with progression to thinning of the sclera (with deep pigment showing through on physical examination). Scleritis may progress to perforation of the orbit
(scleromalacia perforans). Rarely, tendonitis of the superior oblique muscles
can result in double vision (Browns syndrome).

Neurologic Manifestations

Peripheral nerve entrapment syndromes, including carpal tunnel syndrome

(median nerve at the wrist), and tarsal tunnel syndrome (anterior tibial nerve
at the ankle), are common in RA. Vasculitis can lead to mononeuritis multiplex and a host of additional neurologic problems. Subluxations at C1-C2
may produce myelopathy (see E-Fig. 272-1). Rheumatoid nodules in the
central nervous system have been described but are rare and usually
asymptomatic.

Feltys Syndrome

Feltys syndrome is the triad of RA, splenomegaly, and neutropenia. This

complication is seen in patients with severe, RF-positive disease and may be

FIGURE272-10. Rheumatoid nodules in the lung. Chest radiograph demonstrates discrete rheumatoid nodules in both right and left lower lobes. (Courtesy of Dr. Martin Lidsky,
Houston, TX.)

accompanied by hepatomegaly, thrombocytopenia, lymphadenopathy, and

fevers. Most patients with Feltys syndrome do not require special therapy;
instead, treatment should be directed toward their severe RA. If severe neutropenia (Chapter 170) exists (<500 cells/L) and is accompanied by recurrent bacterial infections or chronic, nonhealing leg ulcers, splenectomy may
be indicated.
Some patients with RA, who were previously thought to have Feltys syndrome, have peripheral white blood cell counts dominated by large granular
lymphocytes with almost complete absence of neutrophils. This condition
is known as the large granular lymphocyte syndrome and is thought to be
a variant of T-cell leukemia. In the setting of RA, this syndrome has a
good prognosis, with the neutropenia often responding dramatically to
methotrexate therapy.

Clinical Course

Although the presentation is variable, most patients with RA have an insidious onset of pain, stiffness, or swelling, or a combination of these, in multiple
joints over the course of weeks to months. Systemic features such as fatigue,
low-grade fevers, and weight loss may accompany the joint manifestations of
RA. Less commonly, the onset can be fulminant, occurring almost overnight,
or patients may exhibit persistent monoarthritis or oligoarthritis for prolonged periods before manifesting the more typical pattern of joint involvement. Rarely, some patients, particularly men, develop extra-articular features
of RA before the joint problems appear.
The distribution of involved joints is a critical clue to the underlying diagnosis. The joints that are involved in patients with RA at presentation are also
variable; typically, the symptoms start in the small joints of the hands (PIP
and MCP joints) and in the toes (MTP joints). Importantly, RA usually
spares the DIP joints and the small joints of the toes (see Fig. 272-4). Later,
RA moves, or some would say metastasizes, to larger joints: wrists, knees,
elbows, ankles, hips, and shoulders (roughly in that order). Although the
patients history of joint symptoms (arthralgia) is important, the diagnosis of
RA requires the presence of inflammation (swelling, warmth, or both) on
examination of the joints.
Morning stiffness is a hallmark of inflammatory arthritis and is a
prominent feature of RA. Patients with RA are characteristically at their
worst in the morning or after prolonged periods of rest (called gel phe
nomenon). This stiffness in and around joints often lasts for hours, and quantifying it is one way to measure improvement. Stiffness is relieved by warmth
and activity, and reducing or eliminating joint stiffness is a clear goal of
therapy.

DIAGNOSIS

All current treatment paradigms for RA stress the early and aggressive use of
DMARDs. Therefore, the importance of accurate early diagnosis of RA
cannot be overemphasized. However, there is no one single finding on physical examination or laboratory testing that is pathognomonic of RA. Instead,
the diagnosis of RA requires a collection of historical and physical features as
well as an alert and informed clinician.

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CHAPTER 272 RHEUMATOID ARTHRITIS

TABLE 272-3 CLASSIFICATION CRITERIA FOR

RHEUMATOID ARTHRITIS*
Morning stiffness (1hr)
Swelling (soft tissue) of three or more joints
Swelling (soft tissue) of hand joints (PIP, MCP, or wrist)
Symmetrical swelling (soft tissue)
Subcutaneous nodules
Serum rheumatoid factor
Erosions and/or periarticular osteopenia in hand or wrist joints seen on radiograph
*Criteria 1 through 4 must have been continuously present for 6wk or longer, and criteria 2 through
5 must be observed by a physician. A classification of rheumatoid arthritis requires that four of the
seven criteria be fulfilled.
MCP = metacarpophalangeal; PIP = proximal interphalangeal.

Classification

Table 272-3 lists the current classification criteria for RA; although they are
not designed specifically for the purpose of diagnosis, these criteria are
widely used as a diagnostic aid. The first five criteria are all clinical; in other
words, they are established by physical examination or by talking with the
patient. Only the last two criteria require laboratory tests or radiographs. The
first four criteria must be present for at least 6 weeks before a diagnosis of RA
can be made. This caveat is necessary because a host of conditions, including
many virus-related syndromes, can cause self-limited polyarthritis syndromes
that look identical to RA, including at times the presence of RF. Such conditions usually last only 2 to 3 weeks. Therefore, inflammatory arthritis that is
present for at least 6 weeks should not be considered a postviral condition,
except for parvovirus arthritis, and the diagnosis of RA should be strongly
considered, with the early initiation of appropriate treatment. The goal for
most RA patients should be to establish a diagnosis and to start DMARD
therapy within 3 months of disease onset. The presence of ACPA antibodies,
even in the first few weeks of disease, is strongly suggestive of ongoing aggressive RA. New classification criteria for RA have been developed and, once
validated, may prove more useful in diagnosis.

Laboratory Findings

Historically, the most characteristic laboratory abnormality in RA is the

presence of RF, which is found in approximately 80% of patients. RF was
first described in the 1930s and is an antibody that recognizes the Fc portion
of immunoglobulin G as its antigen. The presence of RF is strongly associated with more severe articular disease as well as with essentially all the
extra-articular features previously discussed. Importantly, RF is seen in association with many diseases other than RA, particularly in disease processes
that provide chronic stimulation of the immune system (Table 272-4).
ACPA antibodies, found in approximately 70% of patients with RA, have a
high specificity (93 to 98%), are often present before clinical disease is diagnosed, and are associated with aggressive erosive disease. RA is associated
with many other autoantibodies, including antinuclear antibodies (~30%)
and antineutrophil cytoplasmic antibodies, particularly of the perinuclear
type (~30%).
Most patients with RA have an anemia of chronic disease. The degree of
anemia is proportional to the activity of the disease, and therapy that controls
the disease will normalize the hemoglobin levels. Other causes of anemia
should also be considered in RA, particularly iron deficiency anemia from
gastrointestinal blood loss. Thrombocytosis is common, with platelet counts
returning to normal as the inflammation is controlled. Acute phase reactants
and ESR and CRP levels also parallel the activity of the disease, and their
persistent elevation portends a poor prognosis in terms of both joint destruction and mortality. White blood cell counts may be elevated, normal, or, in
the case of Feltys syndrome, profoundly depressed. Eosinophilia is present
in some patients with RA.
Synovial fluid in RA is characterized by white blood cell counts in the range
of 5000 to 100,000/mm3, with approximately two thirds of the cells being
polymorphonuclear leukocytes. There are no synovial fluid findings that are
pathognomonic of RA.

Differential Diagnosis

The accurate diagnosis of RA early in its course, although challenging, is critical if patients are to benefit maximally from therapeutic intervention. Once
disease has been present and active for years and the characteristic deformities and radiographic changes have occurred, the diagnosis is all too obvious.

TABLE 272-4 DIFFERENTIAL DIAGNOSIS OF

RHEUMATOID ARTHRITIS
SUBCUTANEOUS
NODULES

RHEUMATOID
FACTOR

Bacterial endocarditis

Rheumatic fever

Sarcoidosis

Reactive arthritis

Psoriatic arthritis

Systemic lupus erythematosus

Primary Sjgrens syndrome

Chronic tophus gout

Calcium pyrophosphate disease

Polymyalgia rheumatica

Osteoarthritis (erosive)

DISORDER
Viral arthritis (hepatitis B and C,
parvovirus, rubella, others)

= Not present; + = frequently present; = occasionally present.

Unfortunately, once RA has progressed to that point, many of the deformities

no longer are amenable to medical therapy.
Many diseases can mimic RA (see Table 272-4). Early in the course of
disease, self-limited viral syndromes need to be considered, especially hepatitis B and C, parvovirus, rubella (infection or vaccination), and Epstein-Barr
virus. At any time, systemic lupus erythematosus, psoriatic arthritis, and reactive arthritis may present diagnostic challenges. In the case of these three
mimics, a targeted history and examination to elucidate their associated clinical features, such as rashes, oral ulcers, nail changes, dactylitis, urethritis, and
renal, pulmonary, gastrointestinal, or ophthalmologic problems, is critical.
Especially in elderly patients with fulminant-onset RA, remitting RF-negative
symmetrical synovitis with pitting edema (the so-called RS3PE syndrome)
and paraneoplastic syndromes should be considered. Chronic tophaceous
gout may also mimic severe nodular RA. Hypothyroidism not only causes
many rheumatic manifestations but also occurs commonly in conjunction
with RA and, therefore, should be kept in mind.

TREATMENT
General Measures

RA is a lifelong disease process that has no known cure; the diagnosis is

made based on clinical criteria, and many different options exist for treatment.
All these factors magnify the importance of the patient-physician relationship
and place a premium on the art rather than the science of medicine. Optimal
care for patients with RA requires effective ongoing interactions between
primary care physicians and rheumatologists, and, in some cases, physical
therapists, occupational therapists, and orthopedic surgeons. Because of the
serious nature of the disease, the rapid introduction of new treatments, and
the need for expertise in monitoring these therapies, all patients with RA
should be evaluated early by a rheumatologist and followed closely.
The goal of therapy is disease remission (Table 272-5). When RA is treated
early, remission is possible in 40 to 50% of patients. However, remissions
require the ongoing use of DMARDs and, even then, are not always durable.
Essentially all RA patients should be treated with DMARDs. Some combination
of nonsteroidal anti-inflammatory drugs (NSAIDs), steroids, and DMARDs is
necessary in most patients. In many, or perhaps most, patients with RA, combinations of different DMARDs (conventional and biologic) are necessary for
optimal control. Therapy should be escalated rapidly to ensure maximal suppression of disease while minimizing toxicity and expense. Patients with RA
should be educated about their disease and its treatment. In most cases,
patients should have an opportunity to spend time with physical therapists
and occupational therapists to learn about range-of-motion exercises, joint
protection, and assistive devices.

Medical Therapy

In the treatment of RA, three types of medical therapies are used: NSAIDs,
glucocorticoids, and DMARDs (both conventional and biologic). Initial therapy
should include at least one DMARD, whereas combinations of the three types
of medications is the rule.1

1688

CHAPTER 272 RHEUMATOID ARTHRITIS

TABLE 272-5 KEYS TO OPTIMIZE OUTCOME OF TREATMENT

OF RHEUMATOID ARTHRITIS
Early, accurate diagnosis
Early DMARD therapy
Strive for remission in all patients
Monitor carefully for treatment toxicities
Consider and treat comorbid conditions*

TABLE 272-6 GUIDELINES FOR USE OF GLUCOCORTICOIDS

Avoid use of glucocorticoids without DMARDs
Prednisone, >10mg/day, is rarely indicated for articular disease
Taper to the lowest effective dose
Use as bridge therapy until DMARD therapy is effective
Remember prophylaxis against osteoporosis
DMARD = disease-modifying antirheumatic drug.

*Important comorbid conditions include cardiovascular disease, increased susceptibility to

infections, and osteoporosis.
DMARD = disease-modifying antirheumatic drug.

Nonsteroidal Anti-inflammatory Drugs

NSAIDs are important for the symptomatic relief they provide to RA patients;
however, they play only a minor role in altering the underlying disease process
(Chapter 36). Therefore, NSAIDs should rarely, if ever, be used to treat RA
without the concomitant use of DMARDs. Many clinicians waste valuable time
switching from one NSAID to another before starting DMARD therapy.
Much has been written about the gastrointestinal toxicity of NSAIDs, and
these concerns are particularly relevant to RA patients who often have significant risk factors, including age and concomitant steroid use. Therefore,
cyclooxygenase-2 (COX2)selective agents have been a popular choice for
patients with RA. The recent evidence linking these agents to increased cardiovascular toxicity has been particularly troubling for patients with RA, who
are already at high risk for myocardial infarction. Therefore, if COX2-selective
agents are used, they should be kept at a low dose. Consideration should be
given to low-dose aspirin prophylaxis in RA, but this may increase the gastrointestinal toxicity of NSAIDs. The use of concomitant misoprostol or proton
pump inhibitors should be considered in all patients with RA who are taking
NSAIDs. Additionally, the potential for NSAIDs to decrease renal blood flow
and to increase blood pressure should be kept in mind.

Glucocorticoids

Glucocorticoids have had a significant role in the treatment of RA for more

than half a century (Chapter 34). Indeed, RA was chosen as the first disease to
be treated with this new therapy, partly because it was thought that RA was
a disease of glucocorticoid deficiency (an issue that remains unresolved). As
was the case with the first patient treated in 1948, glucocorticoids are dramatically and rapidly effective in patients with RA. Not only are glucocorticoids
useful for symptomatic improvement, but they also significantly decrease the
radiographic progression of RA. However, the toxicities of long-term therapy
are extensive and potentially devastating. Therefore, the optimal use of these
drugs requires an understanding of several principles (Table 272-6).
Glucocorticoids remain among the most potent anti-inflammatory treatments available; for this reason, and because of their rapid onset of action,
they are ideally suited to help control the inflammation in RA while the much
slower-acting DMARDs are starting to work. Prednisone, the most commonly
used glucocorticoid, should rarely be used in doses higher than 10mg/day to
treat the stiffness and articular manifestations of RA. This dose should be
slowly tapered to the lowest effective dose, and the concomitant DMARD
therapy should be adjusted to make this possible. Glucocorticoids should
rarely, if ever, be used to treat RA without concomitant DMARD therapy. The
paradigm is to shut off inflammation rapidly with glucocorticoids and then to
taper them as the DMARD is taking effect (bridge therapy). In all patients
receiving glucocorticoids, strong measure should be taken to prevent osteoporosis. Bisphosphonates have been shown to be particularly effective in this
regard. Higher doses of glucocorticoids may be necessary to treat extraarticular manifestations, especially vasculitis and scleritis.

Disease-Modifying Antirheumatic Drugs

DMARDs are a group of medications that have the ability to inhibit greatly
the disease process in the synovium and to modify or change the disabling
potential of RA. In most cases, these drugs have the ability to halt or slow the
radiographic progression of RA.

Conventional DMARDs

Included in this group of medications are methotrexate, sulfasalazine (Azulfidine), gold, antimalarials (Plaquenil and others), leflunomide (Arava), azathioprine (Imuran), and minocycline. It is critically important that clinicians and
patients understand that conventional DMARDs take 2 to 6 months to exert
their maximal effect, and all require some monitoring (Table 272-7). Therefore,
other measures, such as glucocorticoid therapy, may be needed to control the
disease while these medications are starting to work.
All these DMARDs have been shown to be effective in treating both early
and more advanced RA that remains active. Until additional research elucidates factors that allow selection of the best initial therapy for each patient,
the choice will depend on patient and physician concerns about toxicity and
monitoring issues, as well as the activity of disease and presence of comorbid
conditions. The critical factor is not which DMARD to start first but rather
getting the DMARD therapy started early in the disease process.

TABLE 272-7 CAVEATS FOR MONITORING

DISEASE-MODIFYING ANTIRHEUMATIC
DRUG THERAPIES*
MEDICATION
Prednisone

CAVEATS
Use as bridge to effective DMARD therapy. Prophylaxis for
osteoporosis? (see Table 272-6)

Hydroxychloroquine Keep dosage lower than 6.5mg/kg/day. Yearly eye checkup

by ophthalmologist
Sulfasalazine

CBC for neutropenia, initially every month, then every 6mo

Methotrexate

CBC and SGOT/SGPT every 8-12wk when dose is stable.

Many toxicities respond to folic acid or small dose
reduction. If pneumonitis, stop and do not restart.
Decreasing renal function may precipitate toxicities.
Absolute contraindication in pregnancy

Leflunomide

CBC and SGOT/SGPT every 4-8wk; long half-life may

require cholestyramine washout; absolute contraindication
in pregnancy

TNF inhibitors

If fevers or infectious symptoms of any kind, stop until

symptoms resolve; aggressively work up and treat possible
infections. May precipitate congestive heart failure,
demyelinating syndromes, or lupus-like syndromes

*Patients receiving DMARDs, both conventional and biologic, should be monitored by a

rheumatologist.
CBC = compete blood count; DMARD = disease-modifying antirheumatic drug; SGOT = serum
glutamate oxaloacetate transaminase (aspartate aminotransferase); SGPT = serum glutamate
pyruvate transaminase (alanine aminotransferase); TNF = tumor necrosis factor.

Methotrexate

Methotrexate is the preferred DMARD of most rheumatologists, in part

because patients have a more durable response, and because, with correct
monitoring, serious toxicities are rare. Methotrexate is dramatically effective in
slowing radiographic progression and is usually given orally in doses ranging
from 5 to 25mg/week as a single dose. This once-a-week administration is
worthy of emphasis; prior experience with daily therapy in psoriasis has demonstrated the importance of allowing the liver time to recover between doses.
Oral absorption of methotrexate is variable; subcutaneous injections of methotrexate may be effective if oral treatment is not. Side effects of methotrexate
include oral ulcers, nausea, hepatotoxicity, bone marrow suppression, and
pneumonitis. With the exception of pneumonitis, these toxicities respond to
dose adjustments. Monitoring of blood counts and liver blood tests (albumin
and aspartate aminotransaminase [SGOT] or alanine aminotransferase [SGPT])
should be done every 4 to 8 weeks initially and, when stable, every 3 months
thereafter, with adjustments in the dose of methotrexate as needed. Renal
function is critical for clearance of methotrexate; previously stable patients
may experience severe toxicities when renal function deteriorates. Pneumonitis, although rare, is less predictable and can be fatal, particularly if the methotrexate is not stopped or is restarted. Folic acid, 1 to 4mg/day, can significantly
decrease most methotrexate toxicities without apparent loss of efficacy. If
methotrexate alone does not sufficiently control disease, it is combined with
other DMARDs. Methotrexate in combination with virtually any of the other
DMARDs (conventional or biologic) has been shown to be more effective than
either drug alone.2

Leflunomide

Leflunomide, a pyrimidine antagonist, has a very long half-life and is most

commonly started at 10 to 20mg/day orally. Diarrhea is the most common
toxicity and responds to dose reduction, and doses of leflunomide of 10 to
20mg three to five times per week are frequently used. Also, because of the
long half-life and teratogenic potential of leflunomide, women wishing to
become pregnant who have previously received leflunomide, even if therapy
was stopped years ago, should have blood levels drawn. If toxicity occurs or if
pregnancy is being considered, leflunomide can be rapidly eliminated from

CHAPTER 272 RHEUMATOID ARTHRITIS

the body by treatment with cholestyramine. Laboratory monitoring for hematologic and hepatic toxicity should be done during treatment with leflunomide, as recommended for methotrexate.

Antimalarial Drugs

The antimalarial drugs hydroxychloroquine (Plaquenil) and chloroquine are

frequently used for the treatment of RA. They have the least toxicity of any of
the DMARDs and do not require monitoring of blood tests. Yearly monitoring
by an ophthalmologist is recommended to detect any signs of retinal toxicity
(rare). Hydroxychloroquine is the most commonly used preparation and is
given orally at 200 to 400mg/day. These drugs are frequently used in combination with other DMARDs, particularly methotrexate.2 Hydroxychloroquine
has recently been shown to decrease the incidence of diabetes in patients
with RA.

Sulfasalazine

Sulfasalazine is an effective treatment when given in doses of 1 to 3g/day.

Monitoring of blood counts, particularly white blood cell counts, in the first 6
months is recommended. Sulfasalazine and hydroxychloroquine are often
combined with methotrexate,; this is referred to as triple therapy.

Minocycline

Minocycline, 100mg twice daily, has been shown to be an effective treatment for RA, particularly when used in early, RF-positive disease. Chronic
therapy (>2 years) with minocycline may lead to cutaneous hyperpigmentation. Minocycline has been associated with drug-induced lupus.

Gold

Gold, the oldest DMARD, when given intramuscularly remains an extremely

effective therapy for a small percentage of patients. It is less commonly used
because of its slow onset of action, need for intramuscular administration,
frequent monitoring required (complete blood count and urinalysis), and frequent toxicities. Toxicities include skin rashes, bone marrow suppression, and
proteinuria.

Biologic DMARDs

Recent research has continued to elucidate the central role that cytokines,
most notably TNF- and IL-1, play in the pathophysiology of RA (Chapter 35).
This has led directly to the development and clinical use of biologic agents
directed against TNF-1 (etanercept3 [Enbrel], infliximab4 [Remicade], adalimumab5 [Humira], golimumab [Simponi], and certolizumab [Cimzia]) and
IL-1 (anakinra [Kineret]). Three new monoclonals have been approved for RA:
an anti-CD20, rituximab (Rituxan); a T-cell agent, abatacept (Orencia); and an
antiIL-6 receptor antibody, tocilizumab (Actemra).6-8 All RA patients receiving biologic therapies should be monitored by a rheumatologist, and their
physicians should be aware of the risk for infections that are often atypical.
Essentially all the biologicals, when combined with methotrexate, have been
shown to decrease disease activity and slow radiographic progression in RA
patients with active disease despite methotrexate. Currently, biologic agents
should not be used in combination with each other because all studies to date
have shown a significant increase in infections. See Chapter 35 for further
details on the use of biologic agents in the treatment of RA.

Treatment of Underlying Conditions

Optimal care of patients with RA requires recognition of the associated

comorbid conditions, including an increased risk of cardiovascular death,
osteoporosis, infections (especially pneumonia), and certain cancers.

Cardiovascular Disease

Increasingly, cardiovascular disease is being recognized as the cause of

much of the excess mortality in RA. A number of factors contribute to this
mortality, including sedentary lifestyle, glucocorticoid therapy, and treatments that increase homocysteine levels, such as methotrexate and sulfasalazine. However, recently a strong association between chronic inflammation
and cardiovascular disease was identified, and it is likely that this may be the
most significant factor. Therapies that control RA earlier and better can be
expected to decrease cardiovascular morbidity and mortality. Clinicians
should consider RA a risk factor for cardiovascular disease and should aggressively address other cardiovascular risk factors (Chapter 51) in their rheumatoid patients.

Other Associated Diseases

Osteoporosis is common in patients with RA, and early treatment results in

long-term dividends. Patients with RA are at an increased risk for infections,
and some forms of treatment further increase this risk. Patients should be
cautioned to seek medical attention early for even minor symptoms suggestive of infection, especially if receiving anti-TNF therapy. All patients with RA
should receive a pneumococcal vaccine at appropriate intervals and yearly
influenza vaccinations. Finally, patients with RA have an increased risk of lymphoma. Occasionally, B-cell lymphomas are associated with immunosuppression and regress after immunosuppression is discontinued. RA patients have
significantly decreased risk (odds ratio, 0.2) of developing colon cancer. This is
thought to be secondary to chronic inhibition of COX by NSAIDs.

1689

PROGNOSIS

Until recently, RA was thought to be a relatively benign disease. It is now clear

that, once established, RA is a lifelong progressive disease that produces
significant morbidity in most patients and premature mortality in many.
Long-term studies have found that 50% of patients with RA have had to stop
working after 10 years (approximately 10 times the average rate). Patients
who are RF or ACPA positive and those who are positive for the shared
epitope have a worse prognosis, with more erosions and more extra-articular
disease (see Table 272-2). Once deformities are found on examination or
erosions on radiography, the damage is largely irreversible. It has been clearly
shown that erosions occur in most patients in the first 1 to 2 years and that
the rate of radiographic damage can be affected by early therapy. Therefore,
early DMARD therapy is critical. Although limited long-term data are available, the current information strongly suggests that patients have the opportunity to benefit greatly if the newer principles of therapy are practiced.

FUTURE DIRECTIONS

Significant advances in the effective treatment of RA have come from an

understanding of the cytokine imbalance that accompanies this disease.
Much research is focused on the further development of biologic products
to modulate this balance. Biologic therapies that modulate B-cell and T-cell
function have been shown to be effective in the treatment of RA. There
remains a critical need for a cytokine thermostat that would allow titration
of the desired cytokine balance to control disease without altering critical
immune functions.
Even with existing therapies, there are many different effective options for
patients with RA. The challenge for the clinician is to pick the right option
for each patient. Few data are currently available to aid in this choice, and the
establishment of parameters, genetic or otherwise, that would allow selection
of the best initial option for each patient would be a major breakthrough.
Finally, elucidation of the trigger or triggers for RA may allow the development of strategies to prevent the onset of clinical disease.

1. Goekoop-Ruiterman YP, de Vries-Bouwstra JK, Allaart CF, et al. Comparison of treatment strategies
in early rheumatoid arthritis: a randomized trial. Ann Intern Med. 2007;146:406-415.
2. ODell JR, Haire CE, Erickson N, et al. Treatment of rheumatoid arthritis with methotrexate alone,
sulfasalazine and hydroxychloroquine, or a combination of all three medications. N Engl J Med.
1996;334:1287-1291.
3. Bathon JM, Martin RW, Fleischmann RM, et al. A comparison of etanercept and methotrexate in
patients with early rheumatoid arthritis. N Engl J Med. 2000;343:1586-1593.
4. Lipsky PE, Van der Heijde D, St. Clair EW, et al. Infliximab and methotrexate in the treatment of
rheumatoid arthritis. N Engl J Med. 2000;243:1594-1602.
5. Weinblatt ME, Keystone EC, Furst DE, et al. Adalimumab, a fully human anti-tumor necrosis factor
alpha monoclonal antibody, for the treatment of rheumatoid arthritis in patients taking concomitant
methotrexate: the ARMADA trial. Arthritis Rheum. 2003;38:35-45.
6. Lee YH, Bae SC, Song GG. The efficacy and safety of rituximab for the treatment of active rheumatoid
arthritis: a systematic review and meta-analysis of randomized controlled trials. Rheumatol Int. 2011.
[Epub ahead of print.]
7. Genovese MC, Becker JC, Schiff M, et al. Abatacept for rheumatoid arthritis refractory to tumor
necrosis factor inhibition. N Engl J Med. 2005;353:1114-1123.
8. Genovese MC, McKay JD, Nasonov EL, et al. Interleukin-6 receptor inhibition with tocilizumab
reduces disease activity in rheumatoid arthritis with inadequate response to disease-modifying antirheumatic drugs: the tocilizumab in combination with traditional disease-modifying antirheumatic
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SUGGESTED READINGS
McInnes IB, ODell JR. State-of-the-art: rheumatoid arthritis. Ann Rheum Dis. 2010;69:1898-1906.
Review of pathophysiology and treatment.
Scott DL, Wolf F, Huizinga TW. Rheumatoid arthritis. Lancet. 2010;376:1094-1108. Comprehensive
review.
Singh JA, Wells GA, Christensen R, et al. Adverse effects of biologics: a network meta-analysis and
Cochrane overview. Cochrane Database Syst Rev. 2011;2:CD008794. Biologics are associated with
significantly higher rates of adverse events and TB reactivation.
Whiting PF, Smidt N, Sterne JA, et al. Systematic review: accuracy of anti-citrullinated peptide anti
bodies for diagnosing rheumatoid arthritis. Ann Intern Med. 2010;152:456-464, W155-66. Anticitrullinated peptide antibodies are useful for the early diagnosis of rheumatoid arthritis.