Extra-articular Manifestations in Rheumatoid Arthritis

SKIN MANIFESTATIONS

Rheumatoid nodules are the most frequent skin manifestations (20%) in RA. They occur mainly in rheumatoid factor positive RA patients and in early RA give risk to severe extra-articular manifestations. Histologically focal central fibrinoid necrosis with surrounding fibroblasts is observed: it is believed to occur as a result of small vessel vasculitis. Other manifestations of rheumatoid small vessel vasculitis affecting the skin are splinter haemorrhages, periungual infarcts, leg ulcers, digital gangrene and sharply demarcated painful ulcerations. They appear mostly at the lower extremities or where skin is exposed to pressure.

Skin manifestations are frequently associated with episcleritis, pleural and pericardial effusions. Early lesions show fibrinoid necrosis of the vessel wall, with an inflammatory cell infiltrate. Later on, artery wall fibrosis with occlusion can appear. Subcutaneous nodules commonly occur on extensor surfaces subject to extenal pressure, for example, the upper forearm and elbow. Occasionally, they arise within the lungs or heart. Nodules are rare in seronegative RA (1-4,25-27). Pyoderma gangrenosum is a rare disease characterized by chronic, recurrent ulceration of non-infective origin and usually associated with rheumatoid arthritis. Pyoderma gangrenosum is a circumscribed necrotizing vasculitis of unknown etiology. Lesions associated with arthritis are often ulcerative. Although these lesions typically affect the lower limbs, they can also affect the entire body (28,29). ❑

OCULAR MANIFESTATIONS

The most frequent is keratoconjunctivitis sicca, which affects at least 10% of patients. It is frequently observed together with xerostomia in a secondary Sjögren's syndrome (3). Episcleritis, inflammation of the layer superficial to the sclera, occurs in less than 1% of patients with RA and is generally a self-limiting condition. Scleritis is a more aggressive process, characterized by an intensely painful inflammation of the sclera itself. Peripheral ulcerative keratitis develops as an extension of scleral inflammation with involvement of the peripheral cornea and can lead to corneal melt (1,2,4,30,31). ❑

ORAL MANIFESTATIONS

Oral dryness and salivary gland swelling can also be found in patients with RA. These patients can also develop secondary Sjögren's syndrome (3). ❑

GASTROINTESTINAL SYSTEM

Gastrointestinal complications in RA are mostly iatrogenic and caused by medications. Primary involvement of the gastrointestinal tract, caused by mesenteric vasculitis leading to intestinal infarction, is very rare (3). This condition causes acute abdominal pain, and can lead to intestinal bleeding and perforation. There is no direct relation with arthritis activity, but as with other vasculitis, it is mostly observed in RA patients with high rheumatoid factor and subcutaneous nodules. Prognosis is poor and outcome frequently fatal (1,2,4). ❑

PULMONARY MANIFESTATIONS

Pulmonary involvement in RA is frequent although not always clinically recognized. Pleural disease is common but usually asymptomatic; autopsy studies reported pleural involvement in 50% of cases, with only 10% clinically detected (5,32-35). Pleural effusions are usually exudates with mixed cell counts and high protein concentration. Multinucleated giant cells are highly specific but seen in fewer than 50% of the cases (6,36-38). The disease is frequently associated with exsudative pericarditis, and with interstitial lung disease. Parenchimal pulmonary nodules generally are asymptomatic and found in RF-positive patients with nodules elsewhere (7,8,39). They can cavitate and cause pleural effusions. Pathological examination of the nodules reveals a central necrotic zone surrounded by a cellular area of proliferating fibroblasts (40). As with classical subcutaneous nodules, the underlying process appears to be a vasculitis. Interstitial lung disease is associated with RA; however, the prevalence and natural history are undefined. Diffuse interstitial pulmonary fibrosis in RA tends to occur more often in RF-positive male patients with longstanding nodular disease (9,10,41-43). ❑

CARDIAC DISEASE

Rheumatoid arthritis patients are also more prone to heart conditions like the thickening of the artery walls (atherosclerosis) and heart attacks (44). Extra-articular manifestations of RA and the presence of traditional cardiovascular risk factors were also found. The risk for myocardial infarction in female RA patients is twice that of women without RA, and in long-standing disease of at least 10 years, the risk is 3 times higher. Pericaditis is the most common cardiac manifestation in RA (45-48). Although symptomatic pericarditis is relatively uncommon, autopsy studies revealed evidence of pericardial inflammation in 50% of the patients. It usually occurs in RF-positive patients with nodules and analysis of pericardial fluid reveals changes similar to those found in rheumatoid pleural effusions (49). Myocarditis (with presence of rheumatoid nodules) has been observed in autopsy studies, and myocardial fibrosis can lead to conduction abnormalities. Congestive heart failure may be more frequent than is clinically evident in RA (50). Endocarditis with formation of rheumatoid nodules in the aortic or mitral valves can lead to valvular dysfunction. Arterial stiffness is an important factor in cardiovascular comorbidity in patients with RA. Rheumatoid arthritis is associated with decreased distensibility of the abdominal aorta in females, and such changes seem to correlate with disease severity (1-4,51-53). ❑

RENAL DISEASE

Renal involvement in RA is rare, mesangial glomerulonephritis was the most common histopathological finding, whereas amyloidosis was the most common finding among patients with nephritic syndrome. Glomerulonephritis and interstitial renal disease are uncommon in the absence of vasculitis (3). Renal abnormalities are frequently iatrogenic (1,2,4). ❑

NEUROLOGICAL MANIFESTATIONS

Peripheral neuropathy, presenting as diffuse sensorimotor neuropathy or mononeuritis multiplex, occurs in a small subset of patients with RA. The underlying mechanism is small vessel vasculitis of the vasa vasorum of the nerves with ischemic neuropathy and demyelinisation. These manifestations are part of the rheumatoid vasculitis syndrome. Cervical myelopathy, caused by atlantoaxial subluxation or pannus formation, occurs frequently in RA patients with severe and longstanding disease (7,54,55). ❑

HAEMATOLOGIC MANIFESTATIONS

Patients with RA may present with haematological abnormalities either at the time of diagnosis, or during the course of their illness. Haematological manifestations in RA can be broadly categorized into areas of anaemia, neutropenia, thrombocytopenia, thrombocytosis, eosinophilia, and haematological malignancies (56). Anaemia is, by far, one of the most common extra-articular symptoms of RA. The cause of anaemia in RA is multifactorial-disease activity, drug-induced, nutritional, gastrointestinal bleed, bone marrow suppression, and ineffective erythopoesis (57). Anaemia of chronic disease is observed in RA, where it usually correlates with the disease activity, particular the degree of articular inflammation. It is normochromic and normocytic. Eosinophilia in RA reflects active disease or hypersensitivity to drugs (58). Thrombocytosis is a frequent finding in active RA and is correlated with the number of active inflamed joints (59). Lymphadenopathy is sometimes observed in active RA, usually presenting on biopsy as benign follicular hyperplasia (12-14,60). ❑

CONCLUSIONS

Rheumatoid arthritis is a chronic systemic disease of unknown etiology characterized by articular involvement, extra-articular involvement, and the presence of serum rheumatoid factor. In RA, there is a symmetric and persistent inflammation of the synovial tissue, usually involving the peripheral joints. Although considered a "joint disease" rheumatoid arthritis is associated with involvement of extra-articular manifestations. Prevalence of these manifestations is about 40% of patients at any time during the course of the disease; almost all manifestations are a consequence of longstanding active disease (vasculitis). Extra-articular RA is a serious condition, and RA patients with extra-articular manifestations should be aggressively treated and monitored. Currently, there are no reliable predictors for these features in early RA, although they are associated with men, smokers, more severe joint disease, and worse function. The longer the duration of the disease will be, the larger the number of extra-articular manifestations. Extra-articular manifestations in RA were present in a substantial proportion of patients, which lead to a worse disease outcome. Anaemia, thrombocytosis and respiratory system involvement were the commonest. They need to be recognised early and managed promptly. ❑