Rheumatoid Arthritis

Rheumatoid arthritis (RA) is a chronic multisystem disease of unknown cause. Although there are a variety of systemic manifestations, the characteristic feature of RA is persistent inflammatory synovitis, usually involving peripheral joints in a symmetric distribution. The potential of the synovial inflammation to cause cartilage destruction and bone erosions and subsequent changes in joint integrity is the hallmark of the disease. Despite its destructive potential, the course of RA can be quite variable. Some patients may experience only a mild oligoarticular illness of brief duration with minimal joint damage, whereas others will have a relentless progressive polyarthritis with marked functional impairment.

Epidemiology and Genetics

The prevalence of RA is approximately 0.8% of the population (range 0.3 to 2.1%); women are affected approximately three times more often than men. The prevalence increases with age, and sex differences diminish in the older age group. RA is seen throughout the world and affects all races. However, the incidence and severity seem to be less in rural sub-Saharan Africa and in Caribbean blacks. The onset is most frequent during the fourth and fifth decades of life, with 80% of all patients developing the disease between the ages of 35 and 50. The incidence of RA is more than six times as great in 60- to 64-year-old women compared to 18- to 29-year-old women.

Family studies indicate a genetic predisposition. For example, severe RA is found at approximately four times the expected rate in first-degree relatives of individuals with disease associated with the presence of the autoantibody, rheumatoid factor; approximately 10% of patients with RA will have an affected first-degree relative. Moreover, monozygotic twins are at least four times more likely to be concordant for RA than dizygotic twins, who have a similar risk of developing RA as nontwin siblings. Only 15 to 20% of monozygotic twins are concordant for RA, however, implying that factors other than genetics play an important etiopathogenic role. Of note, the highest risk for concordance of RA is noted in twins who have two HLA-DRB1 alleles known to be associated with RA. The class II major histocompatibility complex allele HLA-DR4. (DRB1*0401) and related alleles are known to be major genetic risk factors for RA. Early studies showed that as many as 70% of patients with classic or definite RA express HLA-DR4 compared with 28% of control individuals. An association with HLA-DR4 has been noted in many populations, including North American and European whites, Chippewa Indians, Japanese, and native populations in India, Mexico, South America, and southern China. In a number of groups, including Israeli Jews, Asian Indians, and Yakima Indians of North America, however, there is no association between the development of RA and HLA-DR4. In these individuals, there is an association between RA and HLA-DR1 in the former two groups and HLA-Dw16 in the latter. Molecular analysis of HLA-DR antigens has provided insight into these apparently disparate findings. The HLA-DR molecule is composed of two chains, a nonpolymorphic 0x0003b1chain and a highly polymorphic 0x0003b2chain. Allelic variations in the HLA-DR molecule reflect differences in the amino acids of the 0x0003b2chain, with the major amino acid changes occurring in the three hypervariable regions of the molecule. Each of the HLA-DR molecules that is associated with RA has the same or a very similar sequence of amino acids in the third hypervariable region of the 0x0003b2chain of the molecule. Thus the 0x0003b2chains of the HLA-DR molecules associated with RA, including HLA-Dw4 (DR0x0003b21*0401), HLA-Dw14 (DR0x0003b21*0404), HLA-Dw15 (DR0x0003b21*0405), HLA-DR1 (DR0x0003b21*0101), and HLA-Dw16 (DR0x0003b21*1402), contain the same amino acids at positions 67 through 74, with the exception of a single change of one basic amino acid for another (arginine 0x002192lysine) in position 71 of HLA-Dw4. All other HLA-DR 0x0003b2chains have amino acid changes in this region that alter either their charge or hydrophobicity. These results indicate that a particular amino acid sequence in the third hypervariable region of the HLA-DR molecule is a major genetic element conveying susceptibility to RA, regardless of whether it occurs in HLA-DR4, HLA-Dw16, or HLA-DR1. It has been estimated that the risk of developing RA in a person with HLA-Dw4 (DR0x0003b21*0401) or HLA-Dw14 (DR0x0003b21*0404) is 1 in 35 and 1 in 20, respectively, whereas the presence of both alleles puts persons at an even greater risk. The lack of association of HLA-DR4 and RA in certain populations is explained by the major member of the DR4 family found in that population. HLA-DR4 is a family of closely related, serologically defined molecules, including HLA-Dw4, -Dw10, -Dw13, and -Dw15. Different members of the HLA-DR family of molecules are found to predominate in different ethnic groups. Thus, in HLA-DR4-positive North American whites, HLA-Dw4 and -Dw14 are the most frequent, whereas HLA-Dw15 is most frequent in Japanese and southern Chinese. Each of these is associated with RA. By contrast, HLA-Dw10, which is not associated with RA and contains nonconservative amino acid changes in positions 70 and 71 of the 0x0003b2chain, is most common in Israeli Jews. Therefore, HLA-DR4 is not associated with RA in this population. In certain groups of patients, there does not appear to be a clear association between HLA-DR4-related epitopes and RA. Thus, nearly 75% of African American RA patients do not have this genetic element. Moreover, there is an association with HLA-DR10 (DRB1*1001) in Spanish and Italian patients, with HLA-DR9 (DRB1*0901) in Chileans, and with HLA-DR3 (DRB1*0301) in Arab populations.

Additional genes in the HLA-D complex may also convey altered susceptibility to RA. Certain HLA-DR alleles, including HLA-DR5 (DRB1*1101), HLA-DR2 (DRB1*1501), HLA-DR3 (DRB1*0301), and HLA-DR7 (DRB1*0701), may protect against the development of RA in that they tend to be found at lower frequency in RA patients than in controls. Moreover, the HLA-DQ alleles, DQB1*0301 and DQB1*0302, that are in linkage disequilibrium with HLA-DR4 and DQB1*0501, have also been associated with RA. This has raised the possibility that HLA-DQ alleles may represent the actual RA susceptibility genes, whereas specific HLA-DR alleles may convey protection. In this model, the complement of HLA-DR and DQ alleles determines RA susceptibility. Disease manifestations have also been associated with HLA phenotype. Thus, early aggressive disease and extraarticular manifestations are more frequent in patients with DRB1*0401 or DRB1*0404, and more slowly progressive disease in those with DRB1*0101. The presence of both DRB1*0401 and DRB1*0404 appears to increase the risk for both aggressive articular and extraarticular disease. It has been estimated that HLA genes contribute only a portion of the genetic susceptibility to RA. Thus genes outside the HLA complex also contribute. These include genes controlling the expression of the antigen receptor on T cells and both immunoglobulin heavy and light chains. Moreover, polymorphisms in the tumor necrosis factor (TNF) 0x0003b1and the interleukin (IL) 10 genes are also associated with RA, as is a region on chromosome 3 (3q13).

Genetic risk factors do not fully account for the incidence of RA, suggesting that environmental factors also play a role in the etiology of the disease. This is emphasized by epidemiologic studies in Africa that have indicated that climate and urbanization have a major impact on the incidence and severity of RA in groups of similar genetic background.


The cause of RA remains unknown. It has been suggested that RA might be a manifestation of the response to an infectious agent in a genetically susceptible host. Because of the worldwide distribution of RA, it has been hypothesized that if an infectious agent is involved, the organism must be ubiquitous. A number of possible causative agents have been suggested, including Mycoplasma, Epstein-Barr virus (EBV), cytomegalovirus, parvovirus, and rubella virus, but convincing evidence that these or other infectious agents cause RA has not emerged. The process by which an infectious agent might cause chronic inflammatory arthritis with a characteristic distribution also remains a matter of controversy. One possibility is that there is persistent infection of articular structures or retention of microbial products in the synovial tissues which generates a chronic inflammatory response. Alternatively, the microorganism or response to the microorganism might induce an immune response to components of the joint by altering its integrity and revealing antigenic peptides. In this regard, reactivity to type II collagen and heat shock proteins has been demonstrated. Another possibility is that the infecting microorganism might prime the host to cross-reactive determinants expressed within the joint as a result of "molecular mimicry." Recent evidence of similarity between products of certain gram-negative bacteria and EBV and the HLA-DR4 molecule itself has supported this possibility. Finally, products of infecting microorganisms might induce the disease. Recent work has focused on the possible role of "superantigens" produced by a number of microorganisms, including staphylococci, streptococci and M. arthritidis. Superantigens are proteins with the capacity to bind to HLA-DR molecules and particular V0x0003b2 segments of the heterodimeric T cell receptor and stimulate specific T cells expressing the V0x0003b2 gene products (Chap. 305). The role of superantigens in the etiology of RA remains speculative. Of all the potential environmental triggers, the only one clearly associated with the development of RA is cigarette smoking

Pathology and Pathogenesis

Microvascular injury and an increase in the number of synovial lining cells appear to be the earliest lesions in rheumatoid synovitis. The nature of the insult causing this response is not known. Subsequently, an increased number of synovial lining cells is seen along with perivascular infiltration with mononuclear cells. Before the onset of clinical symptoms, the perivascular infiltrate is predominantly composed of myeloid cells, whereas in symptomatic arthritis, T cells can also be found, although their number does not appear to correlate with symptoms. As the process continues, the synovium becomes edematous and protrudes into the joint cavity as villous projections.

Light-microscopic examination discloses a characteristic constellation of features, which include hyperplasia and hypertrophy of the synovial lining cells; focal or segmental vascular changes, including microvascular injury, thrombosis, and neovascularization; edema; and infiltration with mononuclear cells, often collected into aggregates around small blood vessels (Fig. 312-1). The endothelial cells of the rheumatoid synovium have the appearance of high endothelial venules of lymphoid organs and have been altered by cytokine exposure to facilitate entry of cells into tissue. Rheumatoid synovial endothelial cells express increased amounts of various adhesion molecules involved in this process. Although this pathologic picture is typical of RA, it can also be seen in a variety of other chronic inflammatory arthritides. The mononuclear cell collections are variable in composition and size. The predominant infiltrating cell is the T lymphocyte. CD4+ T cells predominate over CD8+ T cells and are frequently found in close proximity to HLA-DR+ macrophages and dendritic cells. Increased numbers of a separate population of T cells expressing the 0x0003b30x0003b4form of the T cell receptor have also been found in the synovium, although they remain a minor population there and their role in RA has not been delineated. The major population of T cells in the rheumatoid synovium is composed of CD4+ memory T cells that form the majority of cells aggregated around postcapillary venules. Scattered throughout the tissue are CD8+ T cells. Both populations express the early activation antigen, CD69. Besides the accumulation of T cells, rheumatoid synovitis is also characterized by the infiltration of variable numbers of B cells and antibody-producing plasma cells. In advanced disease, structures similar to germinal centers of secondary lymphoid organs may be observed in the synovium. Both polyclonal immunoglobulin and the autoantibody rheumatoid factor are produced within the synovial tissue, which leads to the local formation of immune complexes. Finally, the synovial fibroblasts in RA manifest evidence of activation in that they produce a number of enzymes such as collagenase and cathepsins that can degrade components of the articular matrix. These activated fibroblasts are particularly prominent in the lining layer and at the interface with bone and cartilage. Osteoclasts are also prominent at sites of bone erosion.


Figure 312-1

Figure 312-1: Histology of rheumatoid synovitis. A. The characteristic features of rheumatoid inflammation with hyperplasia of the lining layer (arrow) and mononuclear infiltrates in the sublining layer (double arrow). B. A higher magnification of the largely CD4+ T cell infiltrate around postcapillary venules (arrow).

The rheumatoid synovium is characterized by the presence of a number of secreted products of activated lymphocytes, macrophages, and fibroblasts. The local production of these cytokines and chemokines appears to account for many of the pathologic and clinical manifestations of RA. These effector molecules include those that are derived from T lymphocytes such as interleukin IL-2, interferon (IFN) 0x0003b3, IL-6, IL-10, granulocyte-macrophage colony stimulating factor (GM-CSF), TNF-0x0003b1, transforming growth factor 0x0003b2(TGF-0x0003b2); IL-13, IL-16, and IL-17; those originating from activated myeloid cells, including IL-1, TNF-0x0003b1, IL-6, IL-8, IL-10, IL-12, GM-CSF, macrophage CSF, platelet-derived growth factor, insulin-like growth factor, and TGF-0x0003b2; as well as those secreted by other cell types in the synovium, such as fibroblasts and endothelial cells, including IL-1, IL-6, IL-8, GM-CSF, IL-15, IL-16, IL-18, and macrophage CSF. The activity of these chemokines and cytokines appears to account for many of the features of rheumatoid synovitis, including the synovial tissue inflammation, synovial fluid inflammation, synovial proliferation, and cartilage and bone damage, as well as the systemic manifestations of RA. In addition to the production of effector molecules that propagate the inflammatory process, local factors are produced that tend to slow the inflammation, including specific inhibitors of cytokine action and additional cytokines, such as TGF-0x0003b2, which inhibits many of the features of rheumatoid synovitis including T cell activation and proliferation, B cell differentiation, and migration of cells into the inflammatory site.

These findings have suggested that the propagation of RA is an immunologically mediated event, although the original initiating stimulus has not been characterized. One view is that the inflammatory process in the tissue is driven by the CD4+ T cells infiltrating the synovium. Evidence for this includes (1) the predominance of CD4+ T cells in the synovium; (2) the increase in soluble IL-2 receptors, a product of activated T cells, in blood and synovial fluid of patients with active RA; and (3) amelioration of the disease by removal of T cells by thoracic duct drainage or peripheral lymphapheresis or suppression of their function by drugs, such as cyclosporine or nondepleting monoclonal antibodies to CD4. In addition, the association of RA with certain HLA-DR or -DQ alleles, whose only known functions are to shape the repertoire of CD4+ T cells during ontogeny in the thymus and bind and present antigenic peptides to CD4+ T cells in the periphery, strongly implies a role for CD4+ T cells in the pathogenesis of the disease. Finally, patients with established RA who become infected with HIV also have been noted to improve, although this has not been a uniform finding. Within the rheumatoid synovium, the CD4+ T cells differentiate predominantly into Th1-like effector cells producing the proinflammatory cytokine IFN-0x0003b3 and appear to be deficient in differentiation into Th2-like effector cells capable of producing the anti-inflammatory cytokine IL-4. As a result of the ongoing secretion of IFN-0x0003b3 without the regulatory influences of IL-4, macrophages are activated to produce the proinflammatory cytokines IL-1 and TNF-0x0003b1 and also increase expression of HLA molecules. Moreover, T lymphocytes express surface molecules such as CD154 (CD40 ligand) and also produce a variety of cytokines that promote B cell proliferation and differentiation into antibody-forming cells and therefore also may promote local B cell stimulation. The resultant production of immunoglobulin and rheumatoid factor can lead to immune-complex formation with consequent complement activation and exacerbation of the inflammatory process by the production of the anaphylatoxins, C3a and C5a, and the chemotactic factor C5a. The tissue inflammation is reminiscent of delayed type hypersensitivity reactions occurring in response to soluble antigens or microorganisms, although it has become clear that the number of T cells producing cytokines such as IFN-0x0003b3 is less than is found in typical delayed type hypersensitivity reactions, perhaps owing to the large amount of reactive oxygen species produced locally in the synovium that can dampen T cell function. It remains unclear whether the persistent T cell activity represents a response to a persistent exogenous antigen or to altered autoantigens such as collagen, immunoglobulin, or one of the heat shock proteins, or perhaps both. Alternatively, it could represent persistent responsiveness to activated autologous cells such as might occur as a result of EBV infection or persistent response to a foreign antigen or superantigen in the synovial tissue. Finally, rheumatoid inflammation could reflect persistent stimulation of T cells by synovial-derived antigens that cross-react with determinants introduced during antecedent exposure to foreign antigens or infectious microorganisms.

Overriding the chronic inflammation in the synovial tissue is an acute inflammatory process in the synovial fluid. The exudative synovial fluid contains more polymorphonuclear leukocytes than mononuclear cells. A number of mechanisms play a role in stimulating the exudation of synovial fluid. Locally produced immune complexes can activate complement and generate anaphylatoxins and chemotactic factors. Local production, by a variety of cells, of chemokines and cytokines with chemotactic activity as well as inflammatory mediators such as leukotriene B4 and products of complement activation can attract neutrophils. Moreover, many of these same agents can also stimulate the endothelial cells of postcapillary venules to become more efficient at binding circulating cells. The net result is the enhanced migration of polymorphonuclear leukocytes into the synovial site. In addition, vasoactive mediators such as histamine produced by the mast cells that infiltrate the rheumatoid synovium may also facilitate the exudation of inflammatory cells into the synovial fluid. Finally, the vasodilatory effects of locally produced prostaglandin E2 may also facilitate entry of inflammatory cells into the inflammatory site. Once in the synovial fluid, the polymorphonuclear leukocytes can ingest immune complexes, with the resultant production of reactive oxygen metabolites and other inflammatory mediators, further adding to the inflammatory milieu. Locally produced cytokines and chemokines can additionally stimulate polymorphonuclear leukocytes. The production of large amounts of cyclooxygenase and lipoxygenase pathway products of arachidonic acid metabolism by cells in the synovial fluid and tissue further accentuates the signs and symptoms of inflammation.

The precise mechanism by which bone and cartilage destruction occurs has not been completely resolved. Although the synovial fluid contains a number of enzymes potentially able to degrade cartilage, the majority of destruction occurs in juxtaposition to the inflamed synovium, or pannus, that spreads to cover the articular cartilage. This vascular granulation tissue is composed of proliferating fibroblasts, small blood vessels, and a variable number of mononuclear cells and produces a large amount of degradative enzymes, including collagenase and stromelysin, that may facilitate tissue damage. The cytokines IL-1 and TNF-0x0003b1 play an important role by stimulating the cells of the pannus to produce collagenase and other neutral proteases. These same two cytokines also activate chondrocytes in situ, stimulating them to produce proteolytic enzymes that can degrade cartilage locally and also inhibiting synthesis of new matrix molecules. Finally, these two cytokines may contribute to the local demineralization of bone by activating osteoclasts that accumulate at the site of local bone resorption. Prostaglandin E2 produced by fibroblasts and macrophages may also contribute to bone demineralization. The common final pathway of bone erosion is likely to involve the activation of osteoclasts that are present in large numbers at these sites. Systemic manifestations of RA can be accounted for by release of inflammatory effector molecules from the synovium. These include IL-1, TNF-0x0003b1, and IL-6, which account for many of the manifestations of active RA, including malaise, fatigue, and elevated levels of serum acute-phase reactants. The importance of TNF-0x0003b1 in producing these manifestations is emphasized by the prompt amelioration of symptoms following administration of a monoclonal antibody to TNF-0x0003b1 or a soluble TNF-0x0003b1 receptor Ig construct to patients with RA. In addition, immune complexes produced within the synovium and entering the circulation may account for other features of the disease, such as systemic vasculitis.

As shown in Fig. 312-2, the pathology of RA evolves over the duration of this chronic disease. The earliest event appears to be a nonspecific inflammatory response initiated by an unknown stimulus and characterized by accumulation of macrophages and other mononuclear cells within the sublining layer of the synovium. The activity of these cells is demonstrated by the increased appearance of macrophage-derived cytokines, including TNF-0x0003b1, IL-10x0003b2, and IL-6. Subsequently, activation of CD4+ T cells is induced, presumably in response to antigenic peptides displayed by a variety of antigen-presenting cells in the synovial tissue. The activated T cells are capable of producing cytokines, especially IFN-0x0003b3, which amplify and perpetuate the inflammation. The presence of activated T cells expressing CD154 (CD40 ligand) can induce polyclonal B cell stimulation and the local production of rheumatoid factor. The cascade of cytokines produced in the synovium activates a variety of cells in the synovium, bone, and cartilage to produce effector molecules that can cause tissue damage characteristic of chronic inflammation. It is important to emphasize that there is no current way to predict the progress from one stage of inflammation to the next, and once established, each can influence the other. Important features of this model include the following: (1) the major pathologic events vary with time in this chronic disease; (2) the time required to progress from one step to the next may vary in different patients and the events, once established, may persist simultaneously; (3) once established, the major pathogenic events operative in an individual patient may vary at different times; and (4) the process is chronic and reiterative, with successive events stimulating progressive amplification of inflammation. These considerations have important implications with regard to appropriate treatment.

Figure 312-2

Figure 312-2: The progression of rheumatoid synovitis. This figure depicts the evolution of the pathogenic mechanisms and ultimate pathologic changes involved in the development of rheumatoid synovitis. The stages of rheumatoid arthritis are proposed to be an initiation phase of nonspecific inflammation, followed by an amplification phase resulting from T cell activation, and finally a stage of chronic inflammation with tissue injury. A variety of stimuli may initiate the initial phase of nonspecific inflammation, which may last for a protracted period of time with no or moderate symptoms. When activation of memory T cells in response to a variety of peptides presented by antigen-presenting cells occurs in genetically susceptible individuals, amplification of inflammation occurs with the promotion of local rheumatoid factor production and enhanced capacity to mediate tissue damage.

Clinical Manifestations


Characteristically, RA is a chronic polyarthritis. In approximately two-thirds of patients, it begins insidiously with fatigue, anorexia, generalized weakness, and vague musculoskeletal symptoms until the appearance of synovitis becomes apparent. This prodrome may persist for weeks or months and defy diagnosis. Specific symptoms usually appear gradually as several joints, especially those of the hands, wrists, knees, and feet, become affected in a symmetric fashion. In approximately 10% of individuals, the onset is more acute, with a rapid development of polyarthritis, often accompanied by constitutional symptoms, including fever, lymphadenopathy, and splenomegaly. In approximately one-third of patients, symptoms may initially be confined to one or a few joints. Although the pattern of joint involvement may remain asymmetric in a few patients, a symmetric pattern is more typical.

Signs and Symptoms of Articular Disease

Pain, swelling, and tenderness may initially be poorly localized to the joints. Pain in affected joints, aggravated by movement, is the most common manifestation of established RA. It corresponds in pattern to the joint involvement but does not always correlate with the degree of apparent inflammation. Generalized stiffness is frequent and is usually greatest after periods of inactivity. Morning stiffness of greater than 1-h duration is an almost invariable feature of inflammatory arthritis and may serve to distinguish it from various noninflammatory joint disorders. Notably, however, the presence of morning stiffness may not reliably distinguish between chronic inflammatory and noninflammatory arthritides, as it is also found frequently in the latter. The majority of patients will experience constitutional symptoms such as weakness, easy fatigability, anorexia, and weight loss. Although fever to 40°C occurs on occasion, temperature elevation in excess of 38°C is unusual and suggests the presence of an intercurrent problem such as infection.

Clinically, synovial inflammation causes swelling, tenderness, and limitation of motion. Warmth is usually evident on examination, especially of large joints such as the knee, but erythema is infrequent. Pain originates predominantly from the joint capsule, which is abundantly supplied with pain fibers and is markedly sensitive to stretching or distention. Joint swelling results from accumulation of synovial fluid, hypertrophy of the synovium, and thickening of the joint capsule. Initially, motion is limited by pain. The inflamed joint is usually held in flexion to maximize joint volume and minimize distention of the capsule. Later, fibrous or bony ankylosis or soft tissue contractures lead to fixed deformities.

Although inflammation can affect any diarthrodial joint, RA most often causes symmetric arthritis with characteristic involvement of certain specific joints such as the proximal interphalangeal and metacarpophalangeal joints. The distal interphalangeal joints are rarely involved. Synovitis of the wrist joints is a nearly uniform feature of RA and may lead to limitation of motion, deformity, and median nerve entrapment (carpal tunnel syndrome). Synovitis of the elbow joint often leads to flexion contractures that may develop early in the disease. The knee joint is commonly involved with synovial hypertrophy, chronic effusion, and frequently ligamentous laxity. Pain and swelling behind the knee may be caused by extension of inflamed synovium into the popliteal space (Baker's cyst). Arthritis in the forefoot, ankles, and subtalar joints can produce severe pain with ambulation as well as a number of deformities. Axial involvement is usually limited to the upper cervical spine. Involvement of the lumbar spine is not seen, and lower back pain cannot be ascribed to rheumatoid inflammation. On occasion, inflammation from the synovial joints and bursae of the upper cervical spine leads to atlantoaxial subluxation. This usually presents as pain in the occiput but on rare occasions may lead to compression of the spinal cord.

With persistent inflammation, a variety of characteristic joint changes develop. These can be attributed to a number of pathologic events, including laxity of supporting soft tissue structures; damage or weakening of ligaments, tendons, and the joint capsule; cartilage degradation; muscle imbalance; and unopposed physical forces associated with the use of affected joints. Characteristic changes of the hand include (1) radial deviation at the wrist with ulnar deviation of the digits, often with palmar subluxation of the proximal phalanges ("Z" deformity); (2) hyperextension of the proximal interphalangeal joints, with compensatory flexion of the distal interphalangeal joints (swan-neck deformity); (3) flexion contracture of the proximal interphalangeal joints and extension of the distal interphalangeal joints (boutonnière deformity); and (4) hyperextension of the first interphalangeal joint and flexion of the first metacarpophalangeal joint with a consequent loss of thumb mobility and pinch. Typical joint changes may also develop in the feet, including eversion at the hindfoot (subtalar joint), plantar subluxation of the metatarsal heads, widening of the forefoot, hallux valgus, and lateral deviation and dorsal subluxation of the toes.

Extraarticular Manifestations

RA is a systemic disease with a variety of extraarticular manifestations. Although these occur frequently, not all of them have clinical significance. However, on occasion, they may be the major evidence of disease activity and source of morbidity and require management per se. As a rule, these manifestations occur in individuals with high titers of autoantibodies to the Fc component of immunoglobulin G (rheumatoid factors).

Rheumatoid nodules develop in 20 to 30% of persons with RA. They are usually found on periarticular structures, extensor surfaces, or other areas subjected to mechanical pressure, but they can develop elsewhere, including the pleura and meninges. Common locations include the olecranon bursa, the proximal ulna, the Achilles tendon, and the occiput. Nodules vary in size and consistency and are rarely symptomatic, but on occasion they break down as a result of trauma or become infected. They are found almost invariably in individuals with circulating rheumatoid factor. Histologically, rheumatoid nodules consist of a central zone of necrotic material including collagen fibrils, noncollagenous filaments, and cellular debris; a midzone of palisading macrophages that express HLA-DR antigens; and an outer zone of granulation tissue. Examination of early nodules has suggested that the initial event may be a focal vasculitis. In some patients, treatment with methotrexate can increase the number of nodules dramatically.

Clinical weakness and atrophy of skeletal muscle are common. Muscle atrophy may be evident within weeks of the onset of RA and is usually most apparent in musculature approximating affected joints. Muscle biopsy may show type II fiber atrophy and muscle fiber necrosis with or without a mononuclear cell infiltrate.

Rheumatoid vasculitis (Chap. 317), which can affect nearly any organ system, is seen in patients with severe RA and high titers of circulating rheumatoid factor. Rheumatoid vasculitis is very uncommon in African Americans. In its most aggressive form, rheumatoid vasculitis can cause polyneuropathy and mononeuritis multiplex, cutaneous ulceration and dermal necrosis, digital gangrene, and visceral infarction. While such widespread vasculitis is very rare, more limited forms are not uncommon, especially in white patients with high titers of rheumatoid factor. Neurovascular disease presenting either as a mild distal sensory neuropathy or as mononeuritis multiplex may be the only sign of vasculitis. Cutaneous vasculitis usually presents as crops of small brown spots in the nail beds, nail folds, and digital pulp. Larger ischemic ulcers, especially in the lower extremity, may also develop. Myocardial infarction secondary to rheumatoid vasculitis has been reported, as has vasculitic involvement of lungs, bowel, liver, spleen, pancreas, lymph nodes, and testes. Renal vasculitis is rare.

Pleuropulmonary manifestations, which are more commonly observed in men, include pleural disease, interstitial fibrosis, pleuropulmonary nodules, pneumonitis, and arteritis. Evidence of pleuritis is found commonly at autopsy, but symptomatic disease during life is infrequent. Typically, the pleural fluid contains very low levels of glucose in the absence of infection. Pleural fluid complement is also low compared with the serum level when these are related to the total protein concentration. Pulmonary fibrosis can produce impairment of the diffusing capacity of the lung. Pulmonary nodules may appear singly or in clusters. When they appear in individuals with pneumoconiosis, a diffuse nodular fibrotic process (Caplan's syndrome) may develop. On occasion, pulmonary nodules may cavitate and produce a pneumothorax or bronchopleural fistula. Rarely, pulmonary hypertension secondary to obliteration of the pulmonary vasculature occurs. In addition to pleuropulmonary disease, upper airway obstruction from cricoarytenoid arthritis or laryngeal nodules may develop.

Clinically apparent heart disease attributed to the rheumatoid process is rare, but evidence of asymptomatic pericarditis is found at autopsy in 50% of cases. Pericardial fluid has a low glucose level and is frequently associated with the occurrence of pleural effusion. Although pericarditis is usually asymptomatic, on rare occasions death has occurred from tamponade. Chronic constrictive pericarditis may also occur.

RA tends to spare the central nervous system directly, although vasculitis can cause peripheral neuropathy. Neurologic manifestations may also result from atlantoaxial or midcervical spine subluxations. Nerve entrapment secondary to proliferative synovitis or joint deformities may produce neuropathies of median, ulnar, radial (interosseous branch), or anterior tibial nerves.

The rheumatoid process involves the eye in fewer than 1% of patients. Affected individuals usually have long-standing disease and nodules. The two principal manifestations are episcleritis, which is usually mild and transient, and scleritis, which involves the deeper layers of the eye and is a more serious inflammatory condition. Histologically, the lesion is similar to a rheumatoid nodule and may result in thinning and perforation of the globe (scleromalacia perforans). From 15 to 20% of persons with RA may develop Sjögren's syndrome with attendant keratoconjunctivitis sicca.

Felty's syndrome consists of chronic RA, splenomegaly, neutropenia, and, on occasion, anemia and thrombocytopenia. It is most common in individuals with long-standing disease. These patients frequently have high titers of rheumatoid factor, subcutaneous nodules, and other manifestations of systemic rheumatoid disease. Felty's syndrome is very uncommon in African Americans. It may develop after joint inflammation has regressed. Circulating immune complexes are often present, and evidence of complement consumption may be seen. The leukopenia is a selective neutropenia with polymorphonuclear leukocyte counts of <1500 cells per microliter and sometimes <1000 cells per microliter. Bone marrow examination usually reveals moderate hypercellularity with a paucity of mature neutrophils. However, the bone marrow may be normal, hyperactive, or hypoactive; maturation arrest may be seen. Hypersplenism has been proposed as one of the causes of leukopenia, but splenomegaly is not invariably found and splenectomy does not always correct the abnormality. Excessive margination of granulocytes caused by antibodies to these cells, complement activation, or binding of immune complexes may contribute to granulocytopenia. Patients with Felty's syndrome have increased frequency of infections usually associated with neutropenia. The cause of the increased susceptibility to infection is related to the defective function of polymorphonuclear leukocytes as well as the decreased number of cells.

Osteoporosis secondary to rheumatoid involvement is common and may be aggravated by glucocorticoid therapy. Glucocorticoid treatment may cause significant loss of bone mass, especially early in the course of therapy, even when low doses are employed. Osteopenia in RA involves both juxtaarticular bone and long bones distant from involved joints. RA is associated with a modest decrease in mean bone mass and a moderate increase in the risk of fracture. Bone mass appears to be adversely affected by functional impairment and active inflammation, especially early in the course of the disease.

RA in the Elderly

The incidence of RA continues to increase past age 60. It has been suggested that elderly-onset RA might have a poorer prognosis, as manifested by more persistent disease activity, more frequent radiographically evident deterioration, more frequent systemic involvement, and more rapid functional decline. Aggressive disease is largely restricted to those patients with high titers of rheumatoid factor. By contrast, elderly patients who develop RA without elevated titers of rheumatoid factor (seronegative disease) generally have less severe, often self-limited disease.

Laboratory Findings

No tests are specific for diagnosing RA. However, rheumatoid factors, which are autoantibodies reactive with the Fc portion of IgG, are found in more than two-thirds of adults with the disease. Widely utilized tests largely detect IgM rheumatoid factors. The presence of rheumatoid factor is not specific for RA. Rheumatoid factor is found in 5% of healthy persons. The frequency of rheumatoid factor in the general population increases with age, and 10 to 20% of individuals over 65 years old have a positive test. In addition, a number of conditions besides RA are associated with the presence of rheumatoid factor. These include systemic lupus erythematosus, Sjögren's syndrome, chronic liver disease, sarcoidosis, interstitial pulmonary fibrosis, infectious mononucleosis, hepatitis B, tuberculosis, leprosy, syphilis, subacute bacterial endocarditis, visceral leishmaniasis, schistosomiasis, and malaria. In addition, rheumatoid factor may appear transiently in normal individuals after vaccination or transfusion and may also be found in relatives of individuals with RA.

The presence of rheumatoid factor does not establish the diagnosis of RA as the predictive value of the presence of rheumatoid factor in determining a diagnosis of RA is poor. Thus fewer than one-third of unselected patients with a positive test for rheumatoid factor will be found to have RA. Therefore, the rheumatoid factor test is not useful as a screening procedure. However, the presence of rheumatoid factor can be of prognostic significance because patients with high titers tend to have more severe and progressive disease with extraarticular manifestations. Rheumatoid factor is uniformly found in patients with nodules or vasculitis. In summary, a test for the presence of rheumatoid factor can be employed to confirm a diagnosis in individuals with a suggestive clinical presentation and, if present in high titer, to designate patients at risk for severe systemic disease. A number of additional autoantibodies may be found in patients with RA, including antibodies to filaggrin, citrulline, calpastatin, components of the spliceosome (RA-33), and an unknown antigen, Sa. Some of these may be useful in diagnosis in that they may occur early in the disease before rheumatoid factor is present or may be associated with aggressive disease.

Normochromic, normocytic anemia is frequently present in active RA. It is thought to reflect ineffective erythropoiesis; large stores of iron are found in the bone marrow. In general, anemia and thrombocytosis correlate with disease activity. The white blood cell count is usually normal, but a mild leukocytosis may be present. Leukopenia may also exist without the full-blown picture of Felty's syndrome. Eosinophilia, when present, usually reflects severe systemic disease.

The erythrocyte sedimentation rate is increased in nearly all patients with active RA. The levels of a variety of other acute-phase reactants including ceruloplasmin and C-reactive protein are also elevated, and generally such elevations correlate with disease activity and the likelihood of progressive joint damage.

Synovial fluid analysis confirms the presence of inflammatory arthritis, although none of the findings is specific. The fluid is usually turbid, with reduced viscosity, increased protein content, and a slightly decreased or normal glucose concentration. The white cell count varies between 5 and 50,000/0x0003bcL; polymorphonuclear leukocytes predominate. A synovial fluid white blood cell count >2000/0x0003bcL with more than 75% polymorphonuclear leukocytes is highly characteristic of inflammatory arthritis, although not diagnostic of RA. Total hemolytic complement, C3, and C4 are markedly diminished in synovial fluid relative to total protein concentration as a result of activation of the classic complement pathway by locally produced immune complexes.

Radiographic Evaluation

Early in the disease, roentgenograms of the affected joints are usually not helpful in establishing a diagnosis. They reveal only that which is apparent from physical examination, namely, evidence of soft tissue swelling and joint effusion. As the disease progresses, abnormalities become more pronounced, but none of the radiographic findings is diagnostic of RA. The diagnosis, however, is supported by a characteristic pattern of abnormalities, including the tendency toward symmetric involvement. Juxtaarticular osteopenia may become apparent within weeks of onset. Loss of articular cartilage and bone erosions develop after months of sustained activity. The primary value of radiography is to determine the extent of cartilage destruction and bone erosion produced by the disease, particularly when one is monitoring the impact of therapy with disease-modifying drugs or surgical intervention. Other means of imaging bones and joints, including 99mTc bisphosphonate bone scanning and magnetic resonance imaging, may be capable of detecting early inflammatory changes that are not apparent from standard radiography but are rarely necessary in the routine evaluation of patients with RA.

Clinical Course and Prognosis

The course of RA is quite variable and difficult to predict in an individual patient. Most patients experience persistent but fluctuating disease activity, accompanied by a variable degree of joint abnormalities and functional impairment. After 10 to 12 years, fewer than 20% of patients will have no evidence of disability or joint abnormalities. Within 10 years, approximately 50% of patients will have work disability. A number of features are correlated with a greater likelihood of developing joint abnormalities or disabilities. These include the presence of more than 20 inflamed joints, a markedly elevated erythrocyte sedimentation rate, radiographic evidence of bone erosions, the presence of rheumatoid nodules, high titers of serum rheumatoid factor, the presence of functional disability, persistent inflammation, advanced age at onset, the presence of comorbid conditions, low socioeconomic status or educational level, or the presence of HLA-DRB1*0401 or -DRB*0404. The presence of one or more of these implies the presence of more aggressive disease with a greater likelihood of developing progressive joint abnormalities and disability. Persistent elevation of the erythrocyte sedimentation rate, disability, and pain on longitudinal follow-up are good predictors of work disability. Patients who lack these features have more indolent disease with a slower progression to joint abnormalities and disability. The pattern of disease onset does not appear to predict the development of disabilities. Approximately 15% of patients with RA will have a short-lived inflammatory process that remits without major disability. These individuals tend to lack the aforementioned features associated with more aggressive disease.

Several features of patients with RA appear to have prognostic significance. Remissions of disease activity are most likely to occur during the first year. White females tend to have more persistent synovitis and more progressively erosive disease than males. Persons who present with high titers of rheumatoid factor, C-reactive protein, and haptoglobin also have a worse prognosis, as do individuals with subcutaneous nodules or radiographic evidence of erosions at the time of initial evaluation. Sustained disease activity of more than 1 year's duration portends a poor outcome, and persistent elevation of acute-phase reactants appears to correlate strongly with radiographic progression. A large proportion of inflamed joints manifest erosions within 2 years, whereas the subsequent course of erosions is highly variable; however, in general, radiographic damage appears to progress at a constant rate in patients with RA. Foot joints are affected more frequently than hand joints. Despite the decrease in the rate of progressive joint damage with time, functional disability, which develops early in the course of the disease, continues to worsen at the same rate, although the most rapid rate of functional loss occurs within the first 2 years of disease.

The median life expectancy of persons with RA is shortened by 3 to 7 years. Of the 2.5-fold increase in mortality rate, RA itself is a contributing feature in 15 to 30%. The increased mortality rate seems to be limited to patients with more severe articular disease and can be attributed largely to infection and gastrointestinal bleeding. Drug therapy may also play a role in the increased mortality rate seen in these individuals. Factors correlated with early death include disability, disease duration or severity, glucocorticoid use, age at onset, and low socioeconomic or educational status.


The mean delay from disease onset to diagnosis is 9 months. This is often related to the nonspecific nature of initial symptoms. The diagnosis of RA is easily made in persons with typical established disease. In a majority of patients, the disease assumes its characteristic clinical features within 1 to 2 years of onset. The typical picture of bilateral symmetric inflammatory polyarthritis involving small and large joints in both the upper and lower extremities with sparing of the axial skeleton except the cervical spine suggests the diagnosis. Constitutional features indicative of the inflammatory nature of the disease, such as morning stiffness, support the diagnosis. Demonstration of subcutaneous nodules is a helpful diagnostic feature. Additionally, the presence of rheumatoid factor, inflammatory synovial fluid with increased numbers of polymorphonuclear leukocytes, and radiographic findings of juxtaarticular bone demineralization and erosions of the affected joints substantiate the diagnosis.

The diagnosis is somewhat more difficult early in the course when only constitutional symptoms or intermittent arthralgias or arthritis in an asymmetric distribution may be present. A period of observation may be necessary before the diagnosis can be established. A definitive diagnosis of RA depends predominantly on characteristic clinical features and the exclusion of other inflammatory processes. The isolated finding of a positive test for rheumatoid factor or an elevated erythrocyte sedimentation rate, especially in an older person with joint pains, should not itself be used as evidence of RA.

In 1987, the American College of Rheumatology developed revised criteria for the classification of RA (Table 312-1). These criteria demonstrate a sensitivity of 91 to 94% and a specificity of 89% when used to classify patients with RA compared with control subjects with rheumatic diseases other than RA. Although these criteria were developed as a means of disease classification for epidemiologic purposes, they can be useful as guidelines for establishing the diagnosis. Failure to meet these criteria, however, especially during the early stages of the disease, does not exclude the diagnosis. Moreover, in patients with early arthritis, the criteria do not discriminate effectively between patients who subsequently develop persistent, disabling, or erosive disease and those who do not.

Table 312-1: The 1987 Revised Criteria for the Classification of Rheumatoid Arthritis

    1. Guidelines for classification

a.       Four of seven criteria are required to classify a patient as having rheumatoid arthritis (RA).

b.      Patients with two or more clinical diagnoses are not excluded.

    1. Criteriaa

 .        Morning stiffness: Stiffness in and around the joints lasting 1 h before maximal improvement.

a.       Arthritis of three or more joint areas: At least three joint areas, observed by a physician simultaneously, have soft tissue swelling or joint effusions, not just bony overgrowth. The 14 possible joint areas involved are right or left proximal interphalangeal, metacarpophalangeal, wrist, elbow, knee, ankle, and metatarsophalangeal joints.

b.      Arthritis of hand joints: Arthritis of wrist, metacarpophalangeal joint, or proximal interphalangeal joint.

c.       Symmetric arthritis: Simultaneous involvement of the same joint areas on both sides of the body.

d.      Rheumatoid nodules: Subcutaneous nodules over bony prominences, extensor surfaces, or juxtaarticular regions observed by a physician.

e.       Serum rheumatoid factor: Demonstration of abnormal amounts of serum rheumatoid factor by any method for which the result has been positive in less than 5% of normal control subjects.

f.                    Radiographic changes: Typical changes of RA on posteroanterior hand and wrist radiographs that must include erosions or unequivocal bony decalcification localized in or most marked adjacent to the involved joints.

aCriteria a-d must be present for at least 6 weeks. Criteria b-e must be observed by a physician.











General Principles

The goals of therapy of RA are (1) relief of pain, (2) reduction of inflammation, (3) protection of articular structures, (4) maintenance of function, and (5) control of systemic involvement. Since the etiology of RA is unknown, the pathogenesis is not completely delineated, and the mechanisms of action of many of the therapeutic agents employed are uncertain, therapy remains largely empirical. None of the therapeutic interventions is curative, and therefore all must be viewed as palliative, aimed at relieving the signs and symptoms of the disease. The various therapies employed are directed at nonspecific suppression of the inflammatory or immunologic process in the hope of ameliorating symptoms and preventing progressive damage to articular structures.

Management of patients with RA involves an interdisciplinary approach, which attempts to deal with the various problems that these individuals encounter with functional as well as psychosocial interactions. A variety of physical therapy modalities may be useful in decreasing the symptoms of RA. Rest ameliorates symptoms and can be an important component of the total therapeutic program. In addition, splinting to reduce unwanted motion of inflamed joints may be useful. Exercise directed at maintaining muscle strength and joint mobility without exacerbating joint inflammation is also an important aspect of the therapeutic regimen. A variety of orthotic and assistive devices can be helpful in supporting and aligning deformed joints to reduce pain and improve function. Education of the patient and family is an important component of the therapeutic plan to help those involved become aware of the potential impact of the disease and make appropriate accommodations in life-style to maximize satisfaction and minimize stress on joints.

Medical management of RA involves five general approaches. The first is the use of aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs) and simple analgesics to control the symptoms and signs of the local inflammatory process. These agents are rapidly effective at mitigating signs and symptoms, but they appear to exert minimal effect on the progression of the disease. Recently, specific inhibitors of the isoform of cyclooxygenase (Cox) that is upregulated at inflammatory sites (Cox-2) have been developed. Cox-2-specific inhibitors (CSIs) have been shown to be as effective as classic NSAIDs, which inhibit both isoforms of Cox, but to cause significantly less gastroduodenal ulceration. The second line of therapy involves use of low-dose oral glucocorticoids. Although low-dose glucocorticoids have been widely used to suppress signs and symptoms of inflammation, recent evidence suggests that they may also retard the development and progression of bone erosions. Intraarticular glucocorticoids can often provide transient symptomatic relief when systemic medical therapy has failed to resolve inflammation. The third line of agents includes a variety of agents that have been classified as the disease-modifying or slow-acting antirheumatic drugs. These agents appear to have the capacity to decrease elevated levels of acute-phase reactants in treated patients and, therefore, are thought to modify the inflammatory component of RA and thus its destructive capacity. Recently, combinations of disease-modifying antirheumatic drugs (DMARDs) have shown promise in controlling the signs and symptoms of RA. A fourth group of agents are the TNF-0x0003b1 neutralizing agents, which have been shown to have a major impact on the signs and symptoms of RA. A fifth group of agents are the immunosuppressive and cytotoxic drugs that have been shown to ameliorate the disease process in some patients. Additional approaches have been employed in an attempt to control the signs and symptoms of RA. Substituting omega-3 fatty acids such as eicosapentaenoic acid found in certain fish oils for dietary omega-6 essential fatty acids found in meat has also been shown to provide symptomatic improvement in patients with RA. A variety of nontraditional approaches have also been claimed to be effective in treating RA, including diets, plant and animal extracts, vaccines, hormones, and topical preparations of various sorts. Many of these are costly, and none has been shown to be effective. However, belief in their efficacy ensures their continued use by some patients.


Nonsteroidal Anti-Inflammatory Drugs

Besides aspirin, many NSAIDs are available to treat RA. As a result of the capacity of these agents to block the activity of the Cox enzymes and therefore the production of prostaglandins, prostacyclin, and thromboxanes, they have analgesic, anti-inflammatory, and antipyretic properties. In addition, the agents may exert other anti-inflammatory effects. These agents are all associated with a wide spectrum of toxic side effects. Some, such as gastric irritation, azotemia, platelet dysfunction, and exacerbation of allergic rhinitis and asthma, are related to the inhibition of cyclooxygenase activity, whereas a variety of others, such as rash, liver function abnormalities, and bone marrow depression, may not be. None of the NSAIDs has been shown to be more effective than aspirin in the treatment of RA. However, these nonaspirin drugs are associated with a lower incidence of gastrointestinal intolerance. None of the newer NSAIDs appears to show significant therapeutic advantages over the other available agents. In addition, there is no consistent advantage of any of these newer agents over the others with respect to the incidence or severity of toxic manifestations. Recent evidence indicates that two separate enzymes, Cox-1 and -2, are responsible for the initial metabolism of arachidonic acid into various inflammatory mediators. The former is constitutively present in many cells and tissues, including the stomach and the platelet, whereas the latter is specifically induced in response to inflammatory stimuli. Inhibition of Cox-2 accounts for the anti-inflammatory effects of NSAIDs, whereas inhibition of Cox-1 induces much of the mechanism-based toxicity. As the currently available NSAIDs inhibit both enzymes, therapeutic benefit and toxicity are intertwined. CSIs have now been approved for the treatment of RA. Clinical trials have shown that CSIs suppress the signs and symptoms of RA as effectively as classic Cox-nonspecific NSAIDs but are associated with a significantly reduced incidence of gastroduodenal ulceration. This suggests that CSIs might be considered instead of classic Cox-nonspecific NSAIDs, especially in persons with increased risk of NSAID-induced major upper gastrointestinal side effects, including persons over 65, those with a history of peptic ulcer disease, persons receiving glucocorticoids or anticoagulants, or those requiring high doses of NSAIDs.

Disease-Modifying Antirheumatic Drugs

Clinical experience has delineated a number of agents that appear to have the capacity to alter the course of RA. This group of agents includes methotrexate, gold compounds, D-penicillamine, the antimalarials, and sulfasalazine. Despite having no chemical or pharmacologic similarities, in practice these agents share a number of characteristics. They exert minimal direct nonspecific anti-inflammatory or analgesic effects, and therefore NSAIDs must be continued during their administration, except in a few cases when true remissions are induced with them. The appearance of benefit from DMARD therapy is usually delayed for weeks or months. As many as two-thirds of patients develop some clinical improvement as a result of therapy with any of these agents, although the induction of true remissions is unusual. In addition to clinical improvement, there is frequently an improvement in serologic evidence of disease activity, and titers of rheumatoid factor and C-reactive protein and the erythrocyte sedimentation rate frequently decline. Moreover, emerging evidence suggests that DMARDs actually retard the development of bone erosions or facilitate their healing. Furthermore, developing evidence suggests that early aggressive treatment with DMARDs may be effective at slowing the appearance of bone erosions.

Which DMARD should be the drug of first choice remains controversial, and trials have failed to demonstrate a consistent advantage of one over the other. Despite this, methotrexate has emerged as the DMARD of choice because of its relatively rapid onset of action, its capacity to effect sustained improvement with ongoing therapy, and the high level of patient retention on therapy. Each of the DMARDs is associated with considerable toxicity, and therefore careful patient monitoring is necessary. Toxicity of the various agents also becomes important in determining the drug of first choice. Of note, failure to respond or development of toxicity to one DMARD does not preclude responsiveness to another. Thus, a similar percentage of RA patients who have failed to respond to one DMARD will respond to another when it is given as the second disease-modifying drug.

No characteristic features of patients have emerged that predict responsiveness to a DMARD. Moreover, the indications for the initiation of therapy with one of these agents are not well defined, although recently the trend has been to begin DMARD therapy early in the course of the disease, and data have begun to emerge to support the conclusion that this approach may slow the development of bone erosions, although this remains controversial.

The folic acid antagonist methotrexate, given in an intermittent low dose (7.5 to 30 mg once weekly), is currently a frequently utilized DMARD. Most rheumatologists recommend use of methotrexate as the initial DMARD, especially in individuals with evidence of aggressive RA. Recent trials have documented the efficacy of methotrexate and have indicated that its onset of action is more rapid than other DMARDs, and patients tend to remain on therapy with methotrexate longer than they remain on other DMARDs because of better clinical responses and less toxicity. Long-term trials have indicated that methotrexate does not induce remission but rather suppresses symptoms while it is being administered. Maximal improvement is observed after 6 months of therapy, with little additional improvement thereafter. Major toxicity includes gastrointestinal upset, oral ulceration, and liver function abnormalities that appear to be dose-related and reversible and hepatic fibrosis that can be quite insidious, requiring liver biopsy for detection in its early stages. Drug-induced pneumonitis has also been reported. Liver biopsy is recommended for individuals with persistent or repetitive liver function abnormalities. Concurrent administration of folic acid or folinic acid may diminish the frequency of some side effects without diminishing effectiveness.

Glucocorticoid Therapy

Systemic glucocorticoid therapy can provide effective symptomatic therapy in patients with RA. Low-dose (<7.5 mg/d) prednisone has been advocated as useful additive therapy to control symptoms. Moreover, recent evidence suggests that low-dose glucocorticoid therapy may retard the progression of bone erosions. Monthly pulses with high-dose glucocorticoids may be useful in some patients and may hasten the response when therapy with a DMARD is initiated.

TNF-0x0003b1 neutralizing agents

Recently, biologic agents that bind and neutralize TNF-0x0003b1 have become available. One of these is a TNF-0x0003b1 type II receptor fused to IgG1 (etanercept), and the second is a chimeric mouse/human monoclonal antibody to TNF-0x0003b1 (infliximab). Clinical trials have shown that parenteral administration of either TNF-0x0003b1 neutralizing agent is remarkably effective at controlling signs and symptoms of RA in patients who have failed DMARD therapy. Repetitive therapy with these agents is effective with or without concomitant methotrexate. Although these agents are notably effective in persistently controlling signs and symptoms of RA in a majority of patients, their impact on the progression of bone erosions has not been proven. Side effects include the potential for an increased risk of serious infections and the development of anti-DNA antibodies, but with no associated evidence of signs and symptoms of systemic lupus erythematosus. Although these side effects are uncommon, their occurrence mandates that TNF-0x0003b1 neutralizing therapy be supervised by physicians with experience in their use.

Immunosuppressive Therapy

The immunosuppressive drugs azathioprine, leflunomide, cyclosporine, and cyclophosphamide have been shown to be effective in the treatment of RA and to exert therapeutic effects similar to those of the DMARDs. However, these agents appear to be no more effective than the DMARDs. Moreover, they cause a variety of toxic side effects, and cyclophosphamide appears to predispose the patient to the development of malignant neoplasms. Therefore, these drugs have been reserved for patients who have clearly failed therapy with DMARDs. On occasion, extraarticular disease such as rheumatoid vasculitis may require cytotoxic immunosuppressive therapy.


Surgery plays a role in the management of patients with severely damaged joints. Although arthroplasties and total joint replacements can be done on a number of joints, the most successful procedures are carried out on hips, knees, and shoulders. Realistic goals of these procedures are relief of pain and reduction of disability. Reconstructive hand surgery may lead to cosmetic improvement and some functional benefit. Open or arthroscopic synovectomy may be useful in some patients with persistent monarthritis, especially of the knee. Although synovectomy may offer short-term relief of symptoms, it does not appear to retard bone destruction or alter the natural history of the disease. In addition, early tenosynovectomy of the wrist may prevent tendon rupture.

Approach to the Patient

An approach to the medical management of patients with RA is depicted in Fig. 312-3. The principles underlying care of these patients reflect the variability of the disease, the frequent persistent nature of the inflammation and its potential to cause disability, the relationship between sustained inflammation and bone erosions, and the need to reevaluate the patient frequently for symptomatic response to therapy, progression of disability and joint damage, and side effects of treatment. At the onset of disease it is difficult to predict the natural history of an individual patient's illness. Therefore, the usual approach is to attempt to alleviate the patient's symptoms with NSAIDs or CSIs. Some patients may have mild disease that requires no additional therapy.

Figure 312-3

Figure 312-3: Algorithm for the medical management of rheumatoid arthritis. NSAID, nonsteroidal anti-inflammatory drug; CSI, Cox-2 specific inhibitor; DMARD, disease-modifying antirheumatic drug; TNF-0x0003b1, tumor necrosis factor 0x0003b1.

At some time during most patients' course, the possibility of initiating DMARD therapy and/or low-dose oral glucocorticoids is entertained. With aggressive disease this might occur sooner, often within 1 to 3 months of diagnosis, whereas in patients with more indolent disease, smoldering activity may not require such therapy for many years. The development of bone erosions or radiographic evidence of cartilage loss is clear-cut evidence of the destructive potential of the inflammatory process and indicates the need for DMARD therapy. The other indications as outlined above, including persistent pain, joint swelling, or functional impairment, are much more subjective, however. As persistent inflammation, involvement of multiple joints, elevated levels of acute-phase reactants, and rheumatoid factor titers correlate with the development of disability and/or bony erosions, some have advocated the use of these prognostic indicators of aggressive disease in the decision to employ DMARDs early in the course of RA. The decision to begin use of a DMARD and/or low-dose oral glucocorticoids requires experience and clinical judgment as well as the ability to assess joint swelling and functional activity and the patient's pain tolerance and expectation of therapy accurately. In this setting, the fully informed patient must play an active role in the decision to begin DMARD and/or low-dose oral glucocorticoid therapy, after careful review of the therapeutic and toxic potential of the various drugs.

If a patient responds to a DMARD, therapy is continued with careful monitoring to avoid toxicity. All DMARDs provide a suppressive effect and therefore require prolonged administration. Even with successful therapy, local injection of glucocorticoids may be necessary to diminish inflammation that may persist in a limited number of joints. In addition, NSAIDs or CSIs may be necessary to mitigate symptoms. Even after inflammation has totally resolved, symptoms from loss of cartilage and supervening degenerative joint disease or altered joint function may require additional treatment. Surgery may also be necessary to relieve pain or diminish the functional impairment secondary to alterations in joint function. Recently an alternative approach to treat patients with RA has been suggested. This involves the initiation of therapy with multiple agents early in the course of disease in an attempt to control inflammation, followed by maintenance on one or more agents as necessary to control disease activity. The effectiveness of this therapeutic alternative has not been proved.