pericarditis in necropsy studies [55, 56]. Patients with pericarditis in RA usually show a high incidence of subcutaneous nodules (up to 47%), anemia, and high sedimentation rates [57, 58]. The presence of pericarditis does not correlate with the duration of the arthritis; in fact, it can precede the onset of arthritis [58]. Pericardial rheumatoid nodules are rarely found. The majority of patients are asymptomatic, but pain and congestive heart failure may occur. Signs consist of pericardial friction or paradoxical pulse. Pericardial ßuid is an exudate containing leukocytes, rheumatoid factor titers equal to or greater than those in serum, high lactate dehydrogenase, low complement, low glucose, immune complexes, lymphokines (migration inhibition factor), and cholesterol crystals. Symptomatic patients usually respond to salicylates or nonsteroidal anti-inßammatory drugs, but if pain is refractory or systemic vasculitis is present steroids should be used. In case of severe systemic vasculitis, cytotoxic agents are recommended.

Myocarditis in RA can be interstitial or granulomatous. Interstitial myocarditis, occurring in 4Ð30% of RA patients at autopsy, is usually a focal inßammation of the myocardium, although occasionally a diffuse necrotizing process may occur [49, 50, 59Ð61]. It is characterized microscopically by focal or diffuse inßammatory inÞltration of plasma cells, lymphocytes, and histiocytes. Focal interstitial myocarditis is clinically silent, but diffuse intertitial myocarditis may show congestive heart failure, conduction abnormalities, and pulmonic and systemic embolizations.

Granulomatous myocarditis, occurring in 5% of RA patients at autopsy, is characterized by the presence of grayish yellow nodules that histologically resemble subcutaneous rheumatoid nodules [50, 62]. Patients are usually asymptomatic unless the nodules are located in critical areas, such as the conduction system, where they can cause conduction abnormalities [63].

Endocarditis (valvular) is found in 30Ð40% of RA patients at autopsy [64Ð66]. The mitral, aortic, tricuspid, and pulmonic valves are affected, in decreasing order of frequency [67]. The entire valve may be involved by a nonspeciÞc inßammation, resulting in either stenosis or insufÞciency. In a speciÞc granulomatous inßammation, inßammatory nodules involve the central core

of the leaßet, leaving a small rim of uninvolved tissue in the periphery. The nodules can spread to involve the base of the aorta in severe cases [68]. These nodules, seen in 5Ð15% of cases, are histologically identical to subcutaneous nodules [69].

Coronary arteritis is found in 15Ð20% of patients with RA at autopsy [27]. It is usually clinically silent, but anginal chest pain or myocardial infarction may occasionally occur, particularly in patients with severe systemic vasculitis or in young patients without atherosclerotic coronary artery disease [70Ð72].

Nervous System

Although both the central and peripheral nervous system can be damaged in RA, peripheral neurologic involvement is much more common. The major causes of peripheral neuropathy in RA include (1) compression neuropathy (carpal tunnel syndrome) and (2) angiopathic neuropathy (distal sensory neuropathy and distal sensorimotor neuropathy).

Compression neuropathy, speciÞcally a carpal tunnel syndrome, may be the presenting feature of RA or may occur at any time during the clinical course. The proliferative synovitis compresses the nerve within a bony canal. The diagnosis is suggested by the characteristic symptoms, such as paresthesias in the area of the median nerve distribution and nocturnal pain in the arm or hand, and is conÞrmed by nerve conduction studies. However, electrodiagnostic abnormalities showing compression of the median nerve are relatively common in asymptomatic patients with RA. Ulnar, radial, sciatic, or posterior tibial (tarsal tunnel syndrome) nerve entrapments also may occur in RA. Although entrapment neuropathies usually are related to the severity of arthritis, they do not correlate with the duration of RA, rheumatoid factor, sex, acute-phase reactant levels, or other extraarticular features.

Angiopathic neuropathy is the result of axonal degeneration of nerve Þbers caused by occlusion of vasa nervorum and resultant ischemia of the peripheral nerve. The milder form is distal sensory neuropathy, which may precede the onset of arthritis, although it more often appears many years after the joint disease [73]. The clinical picture is characterized by symmetrical burning,

numbness, or tingling of lower limbs with distal loss of vibration sense and proprioception; occasionally, the upper limbs are involved in a stocking-glove distribution [74, 75]. There is usually a concomitant motor deÞcit that can be detected by electromyogram, but this is often not clinically demonstrable, particularly in patients with joint pain or deformity [76]. Muscle wasting, weakness, and loss of tendon reßexes are frequently present. Distal sensory neuropathy is a manifestation seen in vasculitis that may occur alone, without widespread vascular involvement. The prognosis is good with effective treatment of RA, although in a small number of cases the disorder progresses to the more ominous sensorimotor neuropathy.

Less common but more severe is distal sensorimotor neuropathy, which may present as an abrupt painful asymmetric multiple mononeuropathy (mononeuritis multiplex) characterized initially by severe pain and paresthesias of individual peripheral nerves followed hours to days later by a wristdrop, a footdrop, or motor weakness in another involved peripheral nerve. Asymmetric multiple mononeuropathy may progress to symmetric polyneuropathy. Electromyogram abnormalities corroborate the clinical Þndings, and in questionable cases biopsy of an involved sural nerve conÞrms the diagnosis. This type of neuropathy is seen in patients with long-standing RA (average duration, 10 years), severe joint deformities, rheumatoid nodules, anemia, anorexia, fever, high titers of rheumatoid factor, and low serum complement levels. Males are afßicted as commonly as females, unlike uncomplicated RA, in which there is a female preponderance. Patients with sensorimotor neuropathy frequently have skin vasculitic lesions, such as nailfold infarcts, leg ulcers, and digital gangrene, and widespread underlying vasculitis that may extend to involve mesenteric, coronary, or cerebral arteries. Prognosis is poor, with a 42% mortality rate for patients with a sensorimotor neuropathy involving three or four extremities [35]. Treatment must include systemic immunosuppression.

Lymph Nodes

Asymptomatic enlarged, Þrm, and mobile lymph nodes are often found in patients with active

synovitis [77Ð79]. The nodes most commonly involved are axillary, epitrochlear, and inguinal, and their presence does not correlate with erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), anemia, or disease severity. Effective treatment of proliferative synovitis may improve or correct lymphadenopathy. Development of lymphoma occurs with greater frequency in RA patients who also have SjšgrenÕs syndrome [80], a disorder associated with increased risk for this neoplasm [81].

Larynx

Laryngeal manifestations in RA include (1) cricoarytenoid joint involvement, (2) vocal cord paralysis, and (3) vocal cord nodules.

Cricoarytenoid joint involvement may be found in nearly 50% of RA cases at autopsy and approximately 25% of living patients with RA. Signs and symptoms may be subtle and include tenderness on palpation, hoarseness, tightness of the throat, difÞculty in swallowing, and mild dyspnea. Laryngoscopy may show, in severe cases, edema of the cricoarytenoid joint and the vocal cords.

Vocal cord paralysis in patients with RA is secondary to neuropathy affecting intrinsic laryngeal muscles.

Vocal cord nodules may also appear in patients with RA. Signs and symptoms may resemble those of a tumor.

Felty’s Syndrome

FeltyÕs syndrome consists of RA, splenomegaly, and leukopenia [82]. It is most common in the fourth through the sixth decades of life and usually occurs after 10 years of arthritis. Patients with FeltyÕs syndrome have more erosive and deforming articular disease, a more elevated ESR, higher rheumatoid factor titers, and more extraarticular manifestations than do other patients with RA [83, 84].

Extraarticular manifestations include subcutaneous nodules, leg ulcers, lymphadenopathy, pleuritis, and neuropathy. Patients with FeltyÕs syndrome are more susceptible to infection than are other patients with RA [85Ð88]. Splenectomy and effective control of RA are the treatments of choice [89, 90].