This report deals with the question of whether or not the established association of HLA-DR4 with rheumatoid arthritis (RA) can also be detected in cases of RA as diagnosed in a population survey. For this purpose 6584 persons older than 19 years living in a single community in The Netherlands were investigated for the presence of rheumatoid arthritis and related abnormalities. After five years 83 patients with RA, 30 with only erosive abnormalities on radiological examination (Rad), and 48 with only rheumatoid factor (RF) were reinvestigated and typed for HLA and allotypes of immunoglobulin G heavy chain (GM). On the classification of the initial survey no significant association of HLA-DR4 or GM could be detected in any of the three categories. When the information of the follow-up investigation was taken into account, a reappraisal of the classification resulted in 53 cases with RA, 18 with Rad only, and 35 with RF only. The frequencies of HLA-DR4 and GM in the three categories were also about the same as those in normal controls. However, an increase in the frequency of HLA-DR4 was observed in cases of RA positive for Rad, RF, or both. We found no evidence for an interaction between HLA-DR4 and GM. Our results suggest that rheumatoid arthritis is a heterogeneous disorder, only a fraction of which is associated with HLA-DR4. At present no single determinant of RA such as Rad or RF can characterise the HLA-DR4-associated, and most probably more severe, type of RA.
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