artritis reumatoide

CHAPTER 272 RHEUMATOIDARTHRITIS 1681

272RHEUMATOID ARTHRITIS JAMES R. ODELL

DEFINITIONRheumatoid 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 (erythro-cyte 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 mar-ginal bone, and stretching and damage of the tendons and ligaments.In the past decade, the landscape of treatment of RA has changed dramati-

cally. Current therapies result in substantial clinical benefit for most patients, particularly with early diagnosis, and 50% of patients can achieve remissions

CHAPTER 272 RHEUMATOIDARTHRITIS1682

with treatment with an appropriate disease-modifying antirheumatic drug (DMARD).

EPIDEMIOLOGYRA 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 approxi-mately 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 approxi-mately 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.

PATHOBIOLOGYGeneticsGenetics 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 dizy-gotic 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 impor-

tant 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 nega-tive 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 func-tional 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 poly-morphisms 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 impor-tant genetic risk factor for RA, this test has little or no clinical utility. In addi-tion 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.

ETIOLOGYClearly, 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 syno-vial 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 HUMANLEUKOCYTEANTIGENASSOCIATIONSWITHRHEUMATOIDARTHRITISHLA Types (Alleles) and Methods of Detection Third Hypervariable Region Amino Acid Sequences MOSTCOMMON

ETHNICGROUPSALLOANTISERA(DR) MLC(Dw) DNA(DR1) 70 71 72 73 74ASSOCIATEDWITHRADR4 Dw4 *0401 Q K R A A Whites (Western Europe)DR4 Dw14 *0404 R Whites (Western Europe)DR4 Dw15 *0405 R Japanese, ChineseDR1 Dw1 *0101 R Asian Indians, IsraelisDR6 (14) Dw16 *1402 R Yakima Native AmericansDR10 *1001 R R Spanish, Greeks, Israelis

NOTASSOCIATEDWITHRADR4 Dw10 *0402 D E Whites (Eastern Europe)DR4 Dw13 *0403 R E PolynesiansDR2 Dw2 *1501 D A WhitesDR3 Dw3 *0301 G R WhitesA = 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.


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 ACPA-positive patients and is not associated with ACPA-negative disease. Further-more, 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.

PATHOGENESISThe 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,

RAinitiated

Ongoingautoimmuneresponse

Genetic backgroundSome HLA-DRBI

allelesOther HLA allelesNon-HLA alleles

Trigger? Bacterial antigens? Viral antigens? Smoking? Others

Synovial proliferation andjoint destruction

FIGURE 272-1. Initiationofrheumatoidarthritis(RA).HLA=humanleukocyteantigen.

including syndromes induced by mycobacteria and streptococci. Reactive arthritis has clearly been shown to occur when any one of a myriad of differ-ent 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 elu-cidated 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 involv-ing 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, particu-larly 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 cyto-kines 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, includ-ing 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 anti-bodies 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.

PATHOLOGYThe 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 inter-action of T cells, B cells, macrophages, and synovial cells (Fig. 272-2). The resultant proliferation of the synovial tissues (synovitis) causes the produc-tion of excessive amounts of synovial fluid and the infiltration of pannus into adjacent bone and cartilage. Synovitis results in the destruction of cartilage

Bone

Inhibition ofproteoglycansynthesis (IL-1)

Bone resorption (IL-1)Collagenase andPGE2 secretedby synoviocytes(induced by IL-1and TNF-)

Rheumatoid pannus

Neutrophilsattracted andactivated (GM-CSF,IL-8, TNF-, TGF-)

Jointcapsule

Normalsynovium

Cartilage

Synoviocytehyperplasia

Initiation Immune ResponsesCellularHumoral

Inflammation Destruction

M

CytokinesTNF-, IL-1, IL-6,

IL-8, GM-CSFC

IgGCellularreactivation andproliferationby cytokines

ProstaglandinIysosomalenzymes

Phagocytosisof immunecomplex

O2 radicals

T

B PIgM=RF

Vascular injuryInflux of immune cells and plasma

FIGURE 272-2. Eventsinvolvedinthepathogenesisofrheumatoidsyno-vitis (progressing from left to right). B= B lymphocyte; C= complement;GM-CSF = granulocyte-macrophage colony-stimulating factor; IgG, IgM =immunoglobulinG,M;IL=interleukin;M=macrophage;P=plasmacell;PGE2=prostaglandinE2;RF=rheumatoidfactor;T=Tlymphocyte;TGF-=trans-forminggrowthfactor-;TNF-=tumornecrosisfactor-.


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 MANIFESTATIONSArticular ManifestationsRA 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 spondyloarthropa-thies, 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.

HandsThe 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 hyperflex-ion 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.

FeetFeet, 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. Sub-luxation 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.

WristsThe 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 JointsInvolvement of knees, ankles, elbows, hips, and shoulders is common. Char-acteristically, 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 con-trast, 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 chal-lenges. Synovial cysts from the knee are perhaps the best examples of this phenomenon. When the knee produces excess synovial fluid, it may accumu-late 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.

FIGURE 272-3. Severeadvanced rheumatoidarthritisof thehands.There ismassivetendonswellingoverthedorsalsurfaceofbothwrists,severemusclewasting,ulnardevia-tion of themetacarpophalangeal joints, and swan-neck deformity of the fingers. (FromForbes CD, JacksonWF.Color Atlas and Text of Clinical Medicine, 3rd ed. London:Mosby;2003.)

Rheumatoid Arthritis Osteoarthritis

FIGURE 272-4. Distribution of involved joints in the two most common forms ofarthritis: rheumatoid arthritis and osteoarthritis. Shaded circles are shown over theinvolvedjointareas.

Median nervein carpal tunnel

Tapping produces paresthesias in

the shaded area (Tinels sign)

FIGURE 272-5. Carpal tunnel syndrome. Distribution of pain and/or paresthesias(shaded area)whenthemediannerveiscompressedbyswellinginthewrist(carpaltunnel).


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

A BFIGURE 272-6. Radiographsofthekneesinthetwomostcommonformsofarthritis:rheumatoid arthritis and osteoarthritis.A, Severe involvement in rheumatoid arthritis,withalmost complete symmetrical lossof joint space inboth themedial and the lateralcompartment, but with little subchondral sclerosis or osteophyte formation. B, Typicalosteoarthritis,withsevere,near-totallossofjointspaceofonecompartmentandanormaloractuallyincreasedjointspaceoftheothercompartment.Notealsothesignificantsub-chondralsclerosisintheinvolvedarea,typicalofosteoarthritis.

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 estab-lish 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 intra-articular injection of corticosteroid into the knee.

NeckAlthough 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 JointsWherever synovial tissue exists, RA can cause problems. The temporoman-dibular, 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 respira-tory distress with or without stridor. In this latter situation, emergent trache-otomy may be life-saving.

Extra-articular ManifestationsSystemic 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).

SkinSubcutaneous 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

TABLE 272-2 EXTRA-ARTICULARMANIFESTATIONSOFRHEUMATOIDARTHRITIS

Skin Nodules, fragility, vasculitis, pyoderma gangrenosumHeart Pericarditis, premature atherosclerosis, vasculitis, valve disease, and

valve ring nodulesLung Pleural effusions, interstitial lung disease, bronchiolitis obliterans,

rheumatoid nodules, vasculitisEye Keratoconjunctivitis sicca, episcleritis, scleritis, scleromalacia

perforans, peripheral ulcerative keratopathyNeurologic Entrapment neuropathy, cervical myelopathy, mononeuritis

multiplex (vasculitis), peripheral neuropathyHematopoietic Anemia, thrombocytosis, lymphadenopathy, Feltys syndromeKidney Amyloidosis, vasculitisBone Osteopenia

FIGURE 272-7. Rheumatoid nodules. Large rheumatoid nodules are seen in a classiclocationalongtheextensorsurfaceoftheforearmandintheolecranonbursa.

FIGURE 272-8. Rheumatoidnodulosis.Inthispatient,multiplerheumatoidnodulesarepresentover joints. Insomecases,nodulesmaydominatetheclinicalpicture.Rarely,thismaybeseenasasideeffectofmethotrexatetherapy.


DMARD treatment. A vasculitis of small and medium arteries that is indis-tinguishable 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 InvolvementCardiac involvement directly related to RA is uncommon; however, patients with RA have a significantly increased morbidity and mortality from coro-nary 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 ManifestationsPulmonary manifestations of RA include pleural effusions, rheumatoid nodules, and parenchymal lung disease (Chapters 84 and 92). Pleural effu-sions 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). Differ-entiating rheumatoid nodules from lung cancer can be problematic, particu-larly 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 ManifestationsThe most common manifestation of RA in the eye is keratoconjunctivitis sicca (dry eyes) from secondary Sjgrens syndrome. Patients may have asso-ciated xerostomia (dry mouth), parotid gland swelling, or, occasionally, lymphadenopathy. Scleritis can also occur and may be painful, with progres-sion to thinning of the sclera (with deep pigment showing through on physi-cal 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 ManifestationsPeripheral 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 multi-plex 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 SyndromeFeltys syndrome is the triad of RA, splenomegaly, and neutropenia. This complication is seen in patients with severe, RF-positive disease and may be

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 neu-tropenia (Chapter 170) exists (


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 hepa-titis B and C, parvovirus, rubella (infection or vaccination), and Epstein-Barr virus. At any time, systemic lupus erythematosus, psoriatic arthritis, and reac-tive arthritis may present diagnostic challenges. In the case of these three mimics, a targeted history and examination to elucidate their associated clini-cal 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.

TABLE 272-3 CLASSIFICATIONCRITERIAFORRHEUMATOIDARTHRITIS*

Morning stiffness (1 hr)Swelling (soft tissue) of three or more jointsSwelling (soft tissue) of hand joints (PIP, MCP, or wrist)Symmetrical swelling (soft tissue)Subcutaneous nodulesSerum rheumatoid factorErosions and/or periarticular osteopenia in hand or wrist joints seen on radiograph*Criteria 1 through 4 must have been continuously present for 6 wk 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.

ClassificationTable 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 condi-tions 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 aggres-sive RA. New classification criteria for RA have been developed and, once validated, may prove more useful in diagnosis.

Laboratory FindingsHistorically, 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 associ-ated with more severe articular disease as well as with essentially all the extra-articular features previously discussed. Importantly, RF is seen in asso-ciation 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 diag-nosed, 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 destruc-tion 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 DiagnosisThe accurate diagnosis of RA early in its course, although challenging, is criti-cal if patients are to benefit maximally from therapeutic intervention. Once disease has been present and active for years and the characteristic deformi-ties and radiographic changes have occurred, the diagnosis is all too obvious.

TABLE 272-4 DIFFERENTIALDIAGNOSISOFRHEUMATOIDARTHRITIS

DISORDERSUBCUTANEOUS

NODULESRHEUMATOID

FACTORViral arthritis (hepatitis B and C,

parvovirus, rubella, others)

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

General MeasuresRA is a lifelongdiseaseprocess thathasnoknowncure; thediagnosis is

madebasedonclinicalcriteria,andmanydifferentoptionsexistfortreatment.Allthesefactorsmagnifytheimportanceofthepatient-physicianrelationshipandplaceapremiumontheartratherthanthescienceofmedicine.Optimalcare for patients with RA requires effective ongoing interactions betweenprimary care physicians and rheumatologists, and, in some cases, physicaltherapists,occupationaltherapists,andorthopedicsurgeons.Becauseoftheseriousnatureofthedisease,therapid introductionofnewtreatments,andthe need for expertise in monitoring these therapies, all patients with RAshouldbeevaluatedearlybyarheumatologistandfollowedclosely.

Thegoaloftherapyisdiseaseremission(Table272-5).WhenRAistreatedearly, remission is possible in 40 to 50% of patients. However, remissionsrequiretheongoinguseofDMARDsand,eventhen,arenotalwaysdurable.EssentiallyallRApatientsshouldbetreatedwithDMARDs.Somecombinationof nonsteroidal anti-inflammatory drugs (NSAIDs), steroids, and DMARDs isnecessaryinmostpatients.Inmany,orperhapsmost,patientswithRA,com-binationsofdifferentDMARDs(conventionalandbiologic)arenecessaryforoptimalcontrol.Therapyshouldbeescalatedrapidlytoensuremaximalsup-pressionofdiseasewhileminimizing toxicityandexpense.PatientswithRAshould be educated about their disease and its treatment. In most cases,patients shouldhaveanopportunity to spend timewithphysical therapistsand occupational therapists to learn about range-of-motion exercises, jointprotection,andassistivedevices.

Medical TherapyInthetreatmentofRA,threetypesofmedicaltherapiesareused:NSAIDs,

glucocorticoids,andDMARDs(bothconventionalandbiologic).InitialtherapyshouldincludeatleastoneDMARD,whereascombinationsofthethreetypesofmedicationsistherule.1

TREATMENT


TABLE 272-5 KEYSTOOPTIMIZEOUTCOMEOFTREATMENTOFRHEUMATOIDARTHRITIS

Early, accurate diagnosisEarly DMARD therapyStrive for remission in all patientsMonitor carefully for treatment toxicitiesConsider and treat comorbid conditions**Important comorbid conditions include cardiovascular disease, increased susceptibility to infections, and osteoporosis.DMARD = disease-modifying antirheumatic drug.

NonsteroidalAnti-inflammatoryDrugsNSAIDsareimportantforthesymptomaticrelieftheyprovidetoRApatients;

however,theyplayonlyaminorroleinalteringtheunderlyingdiseaseprocess(Chapter 36). Therefore, NSAIDs should rarely, if ever, be used to treat RAwithouttheconcomitantuseofDMARDs.ManyclinicianswastevaluabletimeswitchingfromoneNSAIDtoanotherbeforestartingDMARDtherapy.

Muchhasbeenwrittenaboutthegastrointestinal toxicityofNSAIDs,andtheseconcernsareparticularlyrelevanttoRApatientswhooftenhavesignifi-cant risk factors, including age and concomitant steroid use. Therefore,cyclooxygenase-2 (COX2)selective agents have been a popular choice forpatientswithRA.Therecentevidence linkingtheseagentsto increasedcar-diovasculartoxicityhasbeenparticularlytroublingforpatientswithRA,whoarealreadyathighriskformyocardialinfarction.Therefore,ifCOX2-selectiveagentsareused,theyshouldbekeptatalowdose.Considerationshouldbegiventolow-doseaspirinprophylaxisinRA,butthismayincreasethegastro-intestinal toxicity ofNSAIDs.The use of concomitantmisoprostol or protonpumpinhibitorsshouldbeconsideredinallpatientswithRAwhoaretakingNSAIDs.Additionally, thepotential forNSAIDs todecrease renal blood flowandtoincreasebloodpressureshouldbekeptinmind.

GlucocorticoidsGlucocorticoidshavehadasignificantroleinthetreatmentofRAformore

thanhalfacentury(Chapter34).Indeed,RAwaschosenasthefirstdiseasetobetreatedwiththisnewtherapy,partlybecauseitwasthoughtthatRAwasadiseaseofglucocorticoiddeficiency(an issuethatremainsunresolved).Aswasthecasewiththefirstpatienttreatedin1948,glucocorticoidsaredramati-cally and rapidly effective in patientswith RA.Not only are glucocorticoidsusefulforsymptomaticimprovement,buttheyalsosignificantlydecreasetheradiographicprogressionofRA.However,thetoxicitiesoflong-termtherapyareextensiveandpotentiallydevastating.Therefore,theoptimaluseofthesedrugsrequiresanunderstandingofseveralprinciples(Table272-6).

Glucocorticoids remain among themost potent anti-inflammatory treat-ments available; for this reason, andbecauseof their rapidonsetof action,theyareideallysuitedtohelpcontroltheinflammationinRAwhilethemuchslower-actingDMARDsarestartingtowork.Prednisone,themostcommonlyusedglucocorticoid,shouldrarelybeusedindoseshigherthan10mg/daytotreat the stiffness and articular manifestations of RA. This dose should beslowly tapered to the lowest effective dose, and the concomitant DMARDtherapy should be adjusted to make this possible. Glucocorticoids shouldrarely, ifever,beusedtotreatRAwithoutconcomitantDMARDtherapy.Theparadigmistoshutoffinflammationrapidlywithglucocorticoidsandthentotaper themas theDMARD is takingeffect (bridge therapy). In allpatientsreceivingglucocorticoids,strongmeasureshouldbetakentopreventosteo-porosis.Bisphosphonateshavebeenshowntobeparticularlyeffectiveinthisregard. Higher doses of glucocorticoids may be necessary to treat extra-articularmanifestations,especiallyvasculitisandscleritis.

Disease-Modifying Antirheumatic DrugsDMARDsareagroupofmedicationsthathavetheabilitytoinhibitgreatly

thediseaseprocess in thesynoviumandtomodifyorchangethedisablingpotentialofRA.Inmostcases,thesedrugshavetheabilitytohaltorslowtheradiographicprogressionofRA.

ConventionalDMARDsIncludedinthisgroupofmedicationsaremethotrexate,sulfasalazine(Azul-

fidine),gold,antimalarials(Plaquenilandothers),leflunomide(Arava),azathio-prine (Imuran), andminocycline. It is critically important that clinicians andpatientsunderstandthatconventionalDMARDstake2to6monthstoexerttheirmaximaleffect,andallrequiresomemonitoring(Table272-7).Therefore,othermeasures,suchasglucocorticoidtherapy,maybeneededtocontrolthediseasewhilethesemedicationsarestartingtowork.

AlltheseDMARDshavebeenshowntobeeffectiveintreatingbothearlyandmore advanced RA that remains active. Until additional research eluci-datesfactorsthatallowselectionofthebest initialtherapyforeachpatient,thechoicewilldependonpatientandphysicianconcernsabouttoxicityandmonitoringissues,aswellastheactivityofdiseaseandpresenceofcomorbidconditions. The critical factor is not which DMARD to start first but rathergettingtheDMARDtherapystartedearlyinthediseaseprocess.

TABLE 272-6 GUIDELINESFORUSEOFGLUCOCORTICOIDSAvoid use of glucocorticoids without DMARDsPrednisone, >10 mg/day, is rarely indicated for articular diseaseTaper to the lowest effective doseUse as bridge therapy until DMARD therapy is effectiveRemember prophylaxis against osteoporosisDMARD = disease-modifying antirheumatic drug.

TABLE 272-7 CAVEATSFORMONITORINGDISEASE-MODIFYINGANTIRHEUMATICDRUGTHERAPIES*

MEDICATION CAVEATSPrednisone Use as bridge to effective DMARD therapy. Prophylaxis for

osteoporosis? (see Table 272-6)Hydroxychloroquine Keep dosage lower than 6.5 mg/kg/day. Yearly eye checkup

by ophthalmologistSulfasalazine CBC for neutropenia, initially every month, then every 6 moMethotrexate CBC and SGOT/SGPT every 8-12 wk 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 4-8 wk; 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.

MethotrexateMethotrexate is the preferred DMARD of most rheumatologists, in part

becausepatients have amore durable response, andbecause,with correctmonitoring,serioustoxicitiesarerare.Methotrexateisdramaticallyeffectiveinslowingradiographicprogressionandisusuallygivenorallyindosesrangingfrom 5 to 25mg/week as a single dose.This once-a-week administration isworthyofemphasis;priorexperiencewithdailytherapyinpsoriasishasdem-onstratedtheimportanceofallowingthelivertimetorecoverbetweendoses.Oralabsorptionofmethotrexateisvariable;subcutaneousinjectionsofmeth-otrexatemaybeeffectiveiforaltreatmentisnot.Sideeffectsofmethotrexateinclude oral ulcers, nausea, hepatotoxicity, bone marrow suppression, andpneumonitis.Withtheexceptionofpneumonitis,thesetoxicitiesrespondtodoseadjustments.Monitoringofbloodcountsandliverbloodtests(albuminandaspartateaminotransaminase[SGOT]oralanineaminotransferase[SGPT])shouldbedoneevery4to8weeksinitiallyand,whenstable,every3monthsthereafter, with adjustments in the dose ofmethotrexate as needed. Renalfunction is critical for clearance ofmethotrexate; previously stable patientsmayexperienceseveretoxicitieswhenrenalfunctiondeteriorates.Pneumoni-tis,althoughrare,islesspredictableandcanbefatal,particularlyifthemetho-trexateisnotstoppedorisrestarted.Folicacid,1to4mg/day,cansignificantlydecrease most methotrexate toxicities without apparent loss of efficacy. Ifmethotrexatealonedoesnotsufficientlycontroldisease,itiscombinedwithotherDMARDs.Methotrexate incombinationwithvirtuallyanyof theotherDMARDs(conventionalorbiologic)hasbeenshowntobemoreeffectivethaneitherdrugalone.2

LeflunomideLeflunomide,apyrimidineantagonist,hasaverylonghalf-lifeandismost

commonly startedat 10 to20mg/dayorally.Diarrhea is themost commontoxicity and responds todose reduction, anddosesof leflunomideof10 to20mgthreetofivetimesperweekarefrequentlyused.Also,becauseofthelong half-life and teratogenic potential of leflunomide, women wishing tobecomepregnantwhohavepreviouslyreceivedleflunomide,eveniftherapywasstoppedyearsago,shouldhavebloodlevelsdrawn.Iftoxicityoccursorifpregnancy isbeingconsidered, leflunomidecanbe rapidlyeliminated from


thebodybytreatmentwithcholestyramine.Laboratorymonitoringforhema-tologic andhepatic toxicity shouldbedoneduring treatmentwith lefluno-mide,asrecommendedformethotrexate.

Antimalarial DrugsTheantimalarialdrugshydroxychloroquine(Plaquenil)andchloroquineare

frequentlyusedforthetreatmentofRA.TheyhavetheleasttoxicityofanyoftheDMARDsanddonotrequiremonitoringofbloodtests.Yearlymonitoringbyanophthalmologistisrecommendedtodetectanysignsofretinaltoxicity(rare). Hydroxychloroquine is the most commonly used preparation and isgivenorallyat200to400mg/day.Thesedrugsarefrequentlyusedincombi-nationwithotherDMARDs,particularlymethotrexate.2Hydroxychloroquinehas recently been shown to decrease the incidence of diabetes in patientswithRA.

SulfasalazineSulfasalazineisaneffectivetreatmentwhengivenindosesof1to3g/day.

Monitoringofbloodcounts,particularlywhitebloodcellcounts,inthefirst6months is recommended. Sulfasalazine and hydroxychloroquine are oftencombinedwithmethotrexate,;thisisreferredtoastripletherapy.

MinocyclineMinocycline,100mgtwicedaily,hasbeenshowntobeaneffectivetreat-

ment for RA, particularly when used in early, RF-positive disease. Chronictherapy(>2years)withminocyclinemay leadtocutaneoushyperpigmenta-tion.Minocyclinehasbeenassociatedwithdrug-inducedlupus.

GoldGold,theoldestDMARD,whengivenintramuscularlyremainsanextremely

effectivetherapyforasmallpercentageofpatients.Itislesscommonlyusedbecause of its slow onset of action, need for intramuscular administration,frequentmonitoringrequired(completebloodcountandurinalysis),andfre-quenttoxicities.Toxicitiesincludeskinrashes,bonemarrowsuppression,andproteinuria.

BiologicDMARDsRecentresearchhascontinuedtoelucidatethecentralrolethatcytokines,

mostnotablyTNF-andIL-1,playinthepathophysiologyofRA(Chapter35).Thishas leddirectly to thedevelopmentandclinicaluseofbiologicagentsdirectedagainstTNF-1(etanercept3[Enbrel],infliximab4[Remicade],adali-mumab5 [Humira], golimumab [Simponi], and certolizumab [Cimzia]) andIL-1(anakinra[Kineret]).ThreenewmonoclonalshavebeenapprovedforRA:ananti-CD20,rituximab(Rituxan);aT-cellagent,abatacept(Orencia);andanantiIL-6receptorantibody,tocilizumab(Actemra).6-8AllRApatientsreceiv-ing biologic therapies should bemonitored by a rheumatologist, and theirphysicians shouldbeawareof the risk for infections thatareoftenatypical.Essentiallyallthebiologicals,whencombinedwithmethotrexate,havebeenshowntodecreasediseaseactivityandslowradiographicprogression inRApatientswithactivediseasedespitemethotrexate.Currently,biologicagentsshouldnotbeusedincombinationwitheachotherbecauseallstudiestodatehave shown a significant increase in infections. See Chapter 35 for furtherdetailsontheuseofbiologicagentsinthetreatmentofRA.

Treatment of Underlying ConditionsOptimal care of patients with RA requires recognition of the associated

comorbid conditions, including an increased risk of cardiovascular death,osteoporosis,infections(especiallypneumonia),andcertaincancers.

CardiovascularDiseaseIncreasingly, cardiovascular disease is being recognized as the cause of

much of the excessmortality in RA. A number of factors contribute to thismortality, including sedentary lifestyle, glucocorticoid therapy, and treat-mentsthatincreasehomocysteinelevels,suchasmethotrexateandsulfasala-zine. However, recently a strong association between chronic inflammationandcardiovasculardiseasewasidentified,anditislikelythatthismaybethemost significant factor. Therapies that control RA earlier and better can beexpected to decrease cardiovascular morbidity and mortality. CliniciansshouldconsiderRAariskfactorforcardiovasculardiseaseandshouldaggres-sivelyaddressothercardiovascularriskfactors(Chapter51) intheirrheuma-toidpatients.

OtherAssociatedDiseasesOsteoporosisiscommoninpatientswithRA,andearlytreatmentresultsin

long-termdividends.PatientswithRAareatan increasedrisk for infections,and some forms of treatment further increase this risk. Patients should becautionedtoseekmedicalattentionearlyforevenminorsymptomssugges-tiveofinfection,especiallyifreceivinganti-TNFtherapy.AllpatientswithRAshould receive a pneumococcal vaccine at appropriate intervals and yearlyinfluenzavaccinations.Finally,patientswithRAhaveanincreasedriskoflym-phoma.Occasionally,B-celllymphomasareassociatedwithimmunosuppres-sionandregressafterimmunosuppressionisdiscontinued.RApatientshavesignificantlydecreasedrisk(oddsratio,0.2)ofdevelopingcoloncancer.ThisisthoughttobesecondarytochronicinhibitionofCOXbyNSAIDs.

PROGNOSISUntil 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 avail-able, the current information strongly suggests that patients have the oppor-tunity to benefit greatly if the newer principles of therapy are practiced.

FUTURE DIRECTIONSSignificant 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 develop-ment 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 anti-rheumatic drugs: the tocilizumab in combination with traditional disease-modifying antirheumatic drug therapy study. Arthritis Rheum. 2008;58:2968-2980.

SUGGESTEDREADINGS

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. Anti-citrullinated peptide antibodies are useful for the early diagnosis of rheumatoid arthritis.

272 Rheumatoid Arthritis ?DefinitionEpidemiologyPathobiologyGeneticsEtiologyPathogenesisPathology

Clinical ManifestationsArticular ManifestationsHandsFeetWristsLarge JointsNeckOther Joints

Extra-articular ManifestationsSkinCardiac InvolvementPulmonary ManifestationsOphthalmologic ManifestationsNeurologic ManifestationsFeltys Syndrome

Clinical CourseDiagnosisClassificationLaboratory FindingsDifferential DiagnosisPrognosisFuture Directions

Grade ASuggested ReadingsAdditional Suggested Readings

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