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 membran