RA appears to be an "autoimmune" disease, similar to other MHC class II-associated disorders (see Chapter 278) . Autoantibodies to the Fc portion of IgG molecules, or rheumatoid factors are present in the blood and synovial tissues of 80% of RA patients. Such cases are termed "seropositive." High titers of serum rheumatoid factor typically of the IgM isotype, are associated with more severe joint disease and with extra-articular manifestations, especially subcutaneous nodules.

Despite the extremely strong association of rheumatoid factors with RA, they clearly do not cause the disease. Production of rheumatoid factor commonly occurs in other disorders characterized by chronic antigenic stimulation, such as bacterial endocarditis, tuberculosis, syphilis, kala-azar, viral infections, intravenous drug abuse, and cirrhosis. Normal individuals occassionally produce rheumatoid factor, especially with increasing age.

An infectious origin for RA has been a continuing hypothesis. A variety of bacterial and viral candidates have been proposed and later discarded because of lack of definitive evidence. Viral infections such as rubella, Ross River virus, and parvovirus B19 have been shown to produce an acute polyarthritis, but no evidence exists that they initiate chronic RA. Epstein-Barr virus (EBV) remains a viable but unproven candidate for a pathogenetic role because several unusual immune responses to it are found in patients with RA. An EBV protein has also been shown to share the same five amino acids as the HLA-DR4 (Dw14) and HLA-DR1 molecules, which are implicated in susceptibility to RA, thus raising the possibility of "molecular mimicry" as a mechanism. A similar homology with an Escherichia coli heat shock protein has also been found.

PATHOLOGY AND PATHOGENESIS.

The pathologic hallmark of RA is synovial membrane proliferation and outgrowth associated with erosion of articular cartilage and subchondral bone. Often likened to a malignant tumor, proliferating inflammatory tissue (pannus) may subsequently lead to destruction of intra-articular and periarticular structures and result in the joint deformities and dysfunction seen clinically.

The events initiating the process are unknown (Fig. 286-1) . The earliest findings include microvascular injury and proliferation of synovial cells, accompanied by interstitial edema and perivascular infiltration by mononuclear cells, predominantly T lymphocytes. Continuation of the process leads to further hyperplasia of lining cells, both DR-positive type A (macrophage-like) and DR-negative type B (fibroblast-like), and the normally acellular subsynovial stroma becomes engorged with mononuclear inflammatory cells, which may collect into aggregates or follicles, especially around post-capillary venules. The composition of cellular infiltrates varies, with some being predominantly T cells, usually CD4+ (helper/inducer), and others having a mixed population of lymphocytes (often CD8+ cytotoxic T cells), plasma cells, macrophages, and interdigitating (dendritic) cells. Occasionally, germinal centers rich in B lymphocytes can be seen. The proliferating synovium (pannus) becomes villous and is vascularized by arterioles, capillaries, and venules.

Roles for both cellular and humoral immune mechanisms in the rheumatoid synovium are supported by molecular and immunopathologic findings. T lymphocytes, chiefly of the T_H 1 type, appear to be activated, presumably by some unknown antigen(s) presented by DR-positive cells (type A synoviocytes, macrophages, dendritic cells, B lymphocytes). Studies of TCR gene expression suggest restricted Vbeta usage and oligoclonality, but this area is controversial. Collectively, these interacting immune cells produce a variety of cytokines that promote further synovial proliferation and inflammation, as well as bone and cartilage destruction. Important pro-inflammatory cytokines appear to be linked in a cascade, with tumor necrosis factor alpha (TNF-alpha) at the apex promoting the subsequent elaboration of interleukin-1 (IL-1), IL-6, IL-8, and granulocyte-macrophage colony-stimulating factor (GM-CSF). IL-1 induces the production of metalloproteinases (collagenase and stromelysin) and prostaglandin E₂ by synoviocytes. This cytokine also promotes the degradation and inhibits the synthesis of proteoglycan by chondrocytes, as well as enhances resorption of calcium from bone. At the same time, there appears to be an attempt by unregulated anti-inflammatory cytokines, such as soluble TNF receptor, transforming-growth factor beta (TGF-beta), IL-10, and IL-1 receptor antagonist, to counterbalance these destructive effects.

z36