Ocular Changes. About 30% patients with rheumatoid arthritis have features of Sjögren syndrome, called secondary Sjögren syndrome. Keratoconjunctivitis is commonly associated with rheumatoid arthritis. Granulomatous scleritis occurs less often but may lead to scleromalacia perforans (see Plate 5-6).

Nervous System Involvement. The dura mater is another site of rheumatoid nodules. A more frequent clinical manifestation, however, is peripheral neuropathy due to inflammation in the arterioles supplying the nerve. Peripheral nerve compression from localized articular or nonarticular inflammation surrounding the nerve (e.g., compression of the median nerve in carpal tunnel syndrome) is also common. Ulnar neuropathy and radial nerve palsy are seen less often.

Periarticular Fibrous Tissue Manifestations. In many cases, the inflammation affects specialized periarticular fibrous tissue structures, most commonly, tendons, tendon sheaths, and bursae (see Plate 5-7). The periarticular inflammation has the same proliferative and invasive characteristics as synovitis. Tendonitis and tenosynovitis may cause the tendon to rupture; and in some patients, the periarticular inflammation causes as much pain, stiffness, and disability as the arthritis. Muscle weakness and atrophy occur in late stages of rheumatoid arthritis.

Rheumatoid Vasculitis. Now recognized as a major manifestation of rheumatoid arthritis, vasculitis is classified by pathologic changes into three main categories: (1) intimal proliferation of digital arteries causing ischemic areas in the nail fold, nail edge, or digital pulp; (2) subacute lesions in small vessels of muscles, nerves, heart, and other tissues; and (3) widespread fulminant necrotizing arteritis of medium-sized and large vessels. Leukocytosis, scleritis, neuropathy, mesenteric infarction, and ischemic skin ulceration or gangrene are commonly associated with occlusive or necrotizing arteritis.

Rheumatoid arthritis complicated by vasculitis is associated with severe and long-standing joint inflammation, elevated serum titers of rheumatoid factor, diminished serum complement levels, rheumatoid nodules and other extra-articular manifestations, and a poor prognosis. The detection of IgG, IgM, and complement components in the inflamed arterial wall supports the hypothesis that rheumatoid vasculitis is due to the deposition of soluble immune complexes in the vessel wall (see Plate 5-8).

Other Manifestations. Mild-to-moderate anemia is typical of active disease, with the exception of mild cases, and is largely due to a relative failure of bone marrow production because of increased uptake and abnormal storage of iron by the reticuloendothelial system and the phagocytic cells of the inflamed, hyperplastic synovial membrane. Unless an iron deficiency supervenes, the erythrocytes are normocytic and only slightly hypochromic. Impaired absorption of iron from the gastrointestinal tract and, in some cases, bleeding into the gastrointestinal tract caused by nonsteroidal anti-inflammatory agents or other therapeutic drugs also contribute to the development of anemia.

Osteoporosis in the metaphyses of bones adjacent to inflamed joints begins early and is termed periarticular osteopenia. This manifestation is caused by inflammatory cells and cytokines in the bone marrow that result in decreased bone formation. In advanced disease, especially when weight-bearing activity is curtailed, the osteoporosis becomes generalized and often severe.

Although generalized lymphadenopathy is a frequent finding, splenomegaly occurs in only about 5% of patients. When accompanied by leukopenia, the disorder is known as Felty syndrome. Leukopenia, if severe, may lead to serious infection. Other manifestations of Felty syndrome include rheumatoid nodules, chronic leg ulcers, peripheral neuropathy, thrombocytopenia, anemia (often severe), keratoconjunctivitis sicca, as well as increased myeloid activity and very high titers of rheumatoid factor. Felty syndrome should be differentiated from large granular lymphocyte syndrome. In the latter, peripheral blood analysis and bone marrow biopsy demonstrate typical large granular cells. T-cell receptor recombination studies can provide additional diagnostic evidence.