Association of HLA-DR4/Dw4 with rheumatoid arthritis (RA) is well established, but conflicting data exist on a possible association with the severity of the disease, including its extra-articular manifestations. In order to investigate whether a subgroup of RA is preferentially associated with DR4, HLA typing was performed in two groups of patients with severe extra-articular manifestations (Felty's syndrome and histologically proved leucocytoclastic vasculitis), patients with severe joint destruction (seropositive and seronegative), a group with only mild joint destruction, and in healthy controls. The frequency of HLA-DR4 was significantly raised in all patient groups compared with that in healthy controls. The two groups with severe extra-articular manifestations, however, both had a DR4 frequency of 92%, which was significantly (p = 0.002) higher than the 62.7% found in the remaining patients. No significant differences were observed between severe or mild joint destruction and seropositivity or seronegativity in the groups without the above-mentioned extra-articular manifestations. From these data we concluded that DR4 is preferentially associated with severe extra-articular disease manifestations of RA. This observation provides an immunogenetic basis for the disease heterogeneity and for the immunological analogy between RA and leprosy.
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