Genetic aspects of rheumatoid arthritis.

Studies on the population of patients with rheumatoid arthritis and families with multiple cases of rheumatoid arthritis have provided definite evidence that susceptibility to the disease is determined both by genetic factors associated with alleles of the major histocompatibility complex as well as environmental factors. The development of seropositive, but not seronegative rheumatoid arthritis is associated with the presence in an individual of the Ia alloantigen HLA-DR4. This association is common to all major ethnic groups. Some evidence exists that this association is stronger in patients that have more severe disease but this fact requires further study. The fraction of the seropositive patients with rheumatoid arthritis that lack HLA-DR4 has not been well characterized. The occurrence of certain untoward side effects of therapy is influenced by the presence of HLA-DR2 or HLA-DR3. Family studies emphasize the association with HLA-DR4, and indicate that the disease has a dominant mode of inheritance with partial penetrance. The inheritance of susceptibility appeared, at least in some families, to be primarily associated with the inheritance of HLA-DR4 itself and not well explained by a hypothetical disease susceptibility gene present at low frequency and associated in linkage disequilibrium with a HLA-DR4 marker. However, in others different mechanisms appeared more likely. A model of two MHC genes involved in influencing disease susceptibility is postulated. Speculations concerning the primary disease mechanism are presented involving abnormalities of IR genes, general immune regulation, and factors outside of the immune system.