Table 6.2 Extraarticular clinical features of rheumatoid arthritis

Rheumatoid nodules

Vasculitis

Digital arteritis

Cutaneous ulceration

Peripheral neuropathy

Organ infarction

Pulmonary involvement

Pleural disease

Rheumatoid nodules

Diffuse interstitial Þbrosis

Pneumoconiosis

Infection

Arteritis

Cardiac involvement

Pericarditis

Myocarditis

Endocarditis

Coronary arteritis

Neurologic involvement

Compression neuropathy

Distal sensory neuropathy

Distal sensorimotor neuropathy

Lymphadenopathy

Laryngeal involvement

Cricoarytenoid joint involvement

Vocal cord paralysis

Vocal cord nodules

FeltyÕs syndrome

Amyloidosis

Miscellaneous

Gastrointestinal involvement

Kidney involvement

Bone involvement

Ocular involvement

Extraarticular Systemic Manifestations

Rheumatoid arthritis is a systemic disease rather than a localized inßammatory disorder of the joints. In general, patients with either high titers of rheumatoid factor (RF) or severe joint disease have a higher incidence of extraarticular manifestations than do patients without these Þndings [4, 5]. Extraarticular manifestations in RA are listed in Table 6.2 and are brießy described here.

There is strong evidence to suggest that RA has a genetic basis; a high degree of association exists between HLA-DR4 (subtypes Dw4 and Dw14) and Caucasian RA patients, predominantly seropositive for rheumatoid factor (70% compared with 28% of control individuals); sub-

Fig. 6.5 Keratoconjunctivitis sicca. Rose bengal dye (1%) has been instilled into the cul-de-sac. Note the punctate staining of the conjunctival epithelium in the interpalpebral Þssure

types Dw4 and Dw14 are present in 50 and 35% of the patients, respectively [6]. Thus, HLA-Dw4 is the major HLA gene accounting for susceptibility to RA.

6.1.1.2 Systemic Manifestations

Onset

In 55Ð70% of patients, RA begins with the insidious development of malaise, anorexia, fatigue, weakness, weight loss, and diffuse musculoskeletal pain [7, 8]. Although asymmetrical involvement of peripheral joints may then appear, it gradually becomes symmetrical. In 8Ð15% of patients, RA begins with an acute onset of symptoms. A rapid development of polyarthritis may appear, accompanied by fever, splenomegaly, and lymphadenopathy. In 15Ð20% of patients, RA begins with an intermediate onset over a period of several weeks.

Tegument

Subcutaneous rheumatoid nodules occur in about 20Ð30% of patients with deÞnite or classic RA. They also may (rarely) appear prior to the onset of the arthritis. They almost always occur in patients with rheumatoid factor, although without correlation with the titer [9, 10]. Subcutaneous rheumatoid nodules are usually seen on the extensor surface of the forearms, olecranon, AchillesÕ tendons, buttock, Þngertip pads, and other areas subjected to mechanical trauma and soft tissue stress (Fig. 6.5). Nodules vary in consistency

from a soft, completely mobile mass to a Þrm rubbery lesion attached to the subjacent periosteum. They also vary in size from a few millimeters up to 3 cm in diameter. Examination of early nodules has suggested that the initial event may be a focal vasculitis. Although nodules in patients with RA are almost always of rheumatoid etiology, other possible causes are trauma, tophi (gout) [11], xanthomatosis (type II hyperlipoproteinemia) [12], multiple myeloma (amyloidosis) [13, 14], basal cell carcinoma [15], granuloma annulare [16], SLE [17, 18], rheumatic fever, and reticulohistiocytosis [19]. Nodules are asymptomatic, requiring no treatment, unless they are constantly subject to pressure (feet, hands) in which case erosion and ulceration may occur and may cause local, articular, or systemic infections. Excision of these nodules is at least of temporary beneÞt, but recurrence is common. Nodules may dissappear or new nodule formation may cease in the course of gold salts or penicillamine therapy.

The presence of subcutaneous nodules has been associated with rheumatoid factor seropositivity and more severe erosive articular disease [9, 10, 20], and with the extraarticular manifestations of RA, particularly rheumatoid vasculitis [9, 10, 20Ð23]. Patients with subcutaneous nodules have a poorer prognosis than do RA patients without rheumatoid nodules [9, 24, 25].

Vessels

Rheumatoid vasculitis presents classically as (1) digital arteritis, a noninßammatory obliterative endarteritis ranging from splinter infarcts in the nailbeds to gangrene of the Þngertips (Fig. 6.6) [26]; (2) cutaneous ulceration, an inßammatory inÞltration with Þbrinoid necrosis of the cutaneous venule walls on the lower legs, which clinically appears as palpable purpura or urticaria (Fig. 6.7); (3) peripheral neuropathy, a mild distal sensory neuropathy or a severe sensorimotor neuropathy (mononeuritis multiplex), the latter characterized by severe arterial damage on nerve biopsy specimens [27]; or (4) organ infarction, an arteritis with marked inßammatory inÞltration, Þbrinoid necrosis, and thrombosis of both smalland medium-sized arteries of different organs, such as lungs, heart, bowel, spleen, liver, pancreas,

Fig. 6.6 Necrotizing scleritis and peripheral ulcerative keratitis in a patient with rheumatoid arthritis. Surgical correction of the problem has been attempted, with the predictable result of destruction of the inlay ÒtectonicÓ scleral graft that the surgeon has used

Fig. 6.7 Typical butterßy rash in a patient with systemic lupus erythematosus

lymph nodes, and testis [28, 29]; the kidney is rarely involved by vasculitis but often is compromised by amyloidosis or toxicity from therapy. An inßammatory microangiopathy is also the cause of some ocular diseases, such as scleritis (Fig. 6.8) and peripheral ulcerative keratitis

Fig. 6.8 Hands of a patient with systemic lupus erythematosus and RaynaudÕs phenomenon. The patientÕs hands had been exposed to the cold just prior to her arriving in the clinic, and they were markedly blanched during the exposure to the cold. They were painful then and were still painful at the time that this photograph was taken, with venous dilatation producing the dramatic, bluish color of the Þngers, particularly those of the right hand

(PUK), and rheumatologists are beginning to recognize that the eye is an especially sensitive barometer for potentially lethal but occult rheumatoid vasculitis [30].

Rheumatoid vasculitis usually occurs in patients whose RA has existed for more than 10 years and who have signiÞcant joint destruction and erosion, rheumatoid nodules, high levels of rheumatoid factor, antinuclear antibodies (ANAs), CICs, and depressed complement levels [31Ð33]. It has been suggested that patients with rheumatoid vasculitis may have a genetic susceptibility because 88% of them are HLA-DRw4 positive [31]. The occurrence of vasculitis in a patient with RA should be cause for great concern because it is often a sign of life-threatening lesions. The rapid rate of appearance of new areas of involvement indicates widespread vasculitic disease. Palpable purpura tends to subside most quickly. Digital arteritis is also self-limited, although these necrotic lesions last longer. Motor neuropathy, visceral infarctions, weight loss, renal impairment, and histological evidence of vasculitis on rectal biopsy contribute to a poor prognosis [34, 35]. Patients with RA may develop widespread necrotizing lesions involving medium-sized arteries in a variety of sites, producing a condition

Fig. 6.9 Lateral chest X ray of patient with ankylosing spondylitis. Note the kyphosis, the soft tissue calciÞcations in the Þbers of the annulus of the disk, and the anterior and lateral vertebral ligaments, creating the so-called Òbamboo spine.Ó New bone formation (syndesmophyte) bridges the disk space and fuses the spine

similar to PAN. Some of the clinical features of rheumatoid vasculitis are more extensively described as the involved organs are reviewed.

Lung

Pleuropulmonary manifestations (Fig. 6.9) include (1) pleural disease, (2) rheumatoid nodules, (3) diffuse interstitial Þbrosis, (4) pneumoconiosis (CaplanÕs syndrome), (5) infections, and

(6) arteritis.

Pleural involvement is found at autopsy in more than 40% of patients with RA, but clinical disease during life is seen less frequently [36]. Although pleural disease in RA most commonly appears within 5 years after joint involvement (50%), it can, however, occur years prior to (5%) or simultaneous with (20%) the onset of clinical synovitis. The presence of pleural disease with or without effusion does not correlate with the severity of arthritis, but it does correlate with the presence of extraarticular lesions. Pleural effusion may be unilateral or bilateral and may be associated with nodules or Þbrosis. Respiratory

symptoms include dyspnea, chest pain, cough, and sometimes fever. The ßuid is an exudate containing leukocytes, predominantly lymphocytes, elevated lactate dehydrogenase levels, rheumatoid factor titers equal to or greater than those in serum, low complement levels, and low glucose concentrations. The latter, due to impaired transport of glucose into the pleural cavity [37], helps to differentiate this effusion from other nonpurulent effusions because the only other condition that usually has low glucose concentrations in pleural ßuid is sepsis, particularly tuberculosis. Tuberculosis may be excluded after a needle biopsy. Pleural disease usually improves spontaneously within a few months, although in some patients persistent effusion may lead to pleural thickening or empyema.

Parenchymal pulmonary rheumatoid nodules may occur at any time after the onset of arthritis and occasionally may antedate or appear simultaneous with joint involvement [38]. Patients with intrapulmonary nodules have more subcutaneous nodules and other extraarticular manifestations, particularly cardiac lesions. Whether single or in clusters, they are usually asymptomatic. Differential diagnosis with malignancy, tuberculosis, and fungal infection may require needle biopsy. Nodules may cavitate, leading to a bronchopleural Þstula [39]. Effective therapy of RA may clear or diminish the nodules.

Diffuse interstitial Þbrosis may follow (70%), precede (11%), or occur simultaneously (18%) with the onset of arthritis [40]. Although patients with diffuse interstitial Þbrosis have a high incidence of associated subcutaneous nodules, the arthritis does not seem to be more severe. The most common symptoms are dyspnea and cough, but chest pain, fever, and hemoptysis occur occasionally. Ten percent of patients are asymptomatic at the time of diagnosis. The most common signs are basal crepitations, Þnger clubbing, and, in severe cases, cyanosis. Differential diagnosis includes HammanÐRich syndrome, hypersensitivity pneumonitis, and sarcoidosis. The Þnding of intrapulmonary nodules or low glucose levels in pleural effusions helps to diagnose this Þbrosis as being part of RA. Radiographic changes show a bilateral reticular or

reticulonodular honeycomb-type pattern [41Ð43] and respiratory function tests demonstrate a restrictive defect with abnormal diffusing capacity [44]. Although pulmonary insufÞciency and even death may occur, diffuse pulmonary Þbrosis ascribed to RA is usually slowly progressive and has a better prognosis than idiopathic diffuse pulmonary Þbrosis. The treatment of choice is effective control of the rheumatoid synovitis.

Rheumatoid pneumoconiosis was initially described by Caplan as a nodular lung disease among coal miners with RA [45], but it can also appear in chalk, asbestos, gold, and silica workers [46, 47]. RA and pneumoconiosis are synergistic and may produce a violent Þbroblastic reaction to the dust, leading to multiple peripheral nodules greater than 1 cm in diameter, often with cavitation. Nodular lung disease appears in a small number of patients with RA and pneumoconiosis, usually after the onset of arthritis; the nodules rarely may antedate the articular disease [3]. The prognosis depends on the severity of the pneumoconiosis. Removal from exposure to inhalants and control of the arthritis are the treatments of choice.

Pulmonary infections, including bronchiectasis, acute bronchitis, chronic bronchitis, and pneumonia, are more common in patients with RA [48]. Interestingly, most of the pulmonary infections usually antedate the onset of arthritis by many years.

Pulmonary arteritis, although rare, may cause pulmonary hypertension. It is occasionally associated with digital arteritis.

Heart

Postmortem studies show that 30Ð50% of patients with classic RA have cardiac manifestations [49Ð 53]. Cardiac involvement can be classiÞed as follows: (1) pericarditis, (2) myocarditis, (3) endocarditis (valvular), and (4) coronary arteritis.

Pericarditis is the most common cardiac manifestation of RA. Although necropsy studies show that 40% of patients with RA have evidence of pericarditis, clinical disease is diagnosed only in 10% [54]. However, if echocardiographic studies are performed, the incidence of clinical pericarditis (15Ð40%) closely approximates the incidence of