Clinical Manifestations
Onset
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 ~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 some patients, a symmetric pattern is more typical.
FIGURE 5-2
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 and other autoantibody production and enhanced capacity to mediate tissue damage.
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 >1-h duration is an almost invariable feature of inflammatory arthritis. 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 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. Initially, impairment in physical function is caused by pain and inflammation, and disability owing to this is a frequent early feature of aggressive RA. 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 j 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 interpha-langeal 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. Later in the disease, disability is more related to structural damage to articular structures.
Extraarticular Manifestations
RA is a systemic disease with a variety of extraarticular manifestations. It is estimated that as many as 40% of patients may have extraarticular manifestations, and in ~15% these are severe. On occasion, extraarticular manifestations 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) or with antibodies to CCP. Although the frequency of patients with severe extraarticular manifestations appears to be declining, these patients have an increased mortality compared to other persons with RA or age-matched normal controls.
Rheumatoid nodules may develop in 20-30% 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, 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 was thought previously to be 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. More recently, an increased incidence of congestive heart failure and death from cardiovascular disease has been associated with RA. This relates to the level of disease activity and can be mitigated with appropriate antiinflammatory therapy.
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 <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 (sclero-malacia perforans). From 15-20% 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^L and sometimes <1000 cell^L. 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 ofthe causes ofleukopenia,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 PMNLs 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 is associated with an increased incidence of lymphoma, especially large B cell lymphoma. Notably, this is particularly observed in those with persistent inflammatory 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 and have classically been used to evaluate patients with RA. Widely utilized tests largely detect IgM rheumatoid factors. The presence of rheumatoid factor is not specific for RA, as rheumatoid factor is found in 5% of healthy persons.The frequency of rheumatoid factor in the general population increases with age, and 10-20% of individuals >65 years 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 less 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.
Antibodies to CCP (designated anti-CCP) can also be used to evaluate patients with RA. Although these antibodies are most commonly found in rheumatoid factorpositive patients, on occasion they can be detected in the absence of rheumatoid factor. In addition, the anti-CCP test has a similar sensitivity and a better specificity for RA than does rheumatoid factor, and, therefore, some have advocated its use to evaluate RA patients instead of rheumatoid factor. This is particularly the case in individuals with early RA, in whom assessment of anti-CCP may be the most useful to confirm the diagnosis and establish a likely prognosis. The presence of anti-CCP is most common in persons with aggressive disease, with a tendency for developing bone erosions. The development of anti-CCP is most frequent in individuals with an RA associated HLA-ß1 allele and in those who smoke cigarettes, and may occur before the development of clinical manifestations of RA. However, as with rheumatoid factor, the presence of anti-CCP is not useful to predict the future development of RA because it can be found in ~1.5% of normal individuals, most of whom will not develop RA, and occasionally in persons with other rheumatic diseases. However, it is a useful test to confirm a diagnosis of RA and to estimate prognosis.
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 (ESR) 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 are 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^L; PMNLs predominate.A synovial fluid white blood cell count >2000^L with >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, radiographic evaluations 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 attempting to estimate the aggressive nature of the disease, monitoring the impact of therapy with disease-modifying drugs, or determining the need for surgical intervention. Other means of imaging bones and joints, including 99mTc bisphosphonate bone scanning and MRI, 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.
