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There is an immunogenetic predisposition to the development of rheumatoid arthritis. Class II major histocompatibility complex molecules on the surface of antigen-presenting cells are responsible for initiating cellular immune responses and for stimulating the differentiation of B lymphocytes into plasma cells that produce antibody. Most white patients with rheumatoid arthritis have class II major histocompatibility complex type HLA-DR4 or HLA-DR1 or both. HLA-DR4 can be divided into 5 subtypes, 2 of which independently promote susceptibility to rheumatoid arthritis (“shared epitope”). The risk of rheumatoid arthritis is increased 3 to 5 times in white Americans with HLA-DR4. The concordance of rheumatoid factor-positive rheumatoid arthritis is increased 6 times among dizygotic twins. The risk of rheumatoid arthritis in a monozygotic twin is increased 30 times when a sibling has the disease.