Destructive arthritis, rheumatoid factor, and HLA–DR4. Susceptibility versus severity, a case–control study

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Abstract
In response to the continuing debate as to whether seronegative rheumatoid arthritis (RA) and seropositive RA are part of the same disease spectrum or are distinct disorders, we evaluated 720 patients with definite and classic RA, of whom 53 subjects had definite persistently seronegative destructive disease. For all but 1 seronegative RA patient, a seropositive RA case control was identified and matched for age, disease duration, degree of destruction on hand radiographs, and disease‐modifying drug therapy. DR typing was undertaken on these 105 patients, together with scoring of hand radiographs. The frequency of DR4 was 69% in seropositive RA patients and 60% in seronegative RA patients (P = 0.22), versus 36% in 318 healthy controls (P = 0.008 and P = 0.007 versus seropositive and seronegative RA, respectively). Patients were matched and rematched with different controls in a series of subanalyses in order to make comparisons of hand radiograph scores. We found that HLA–DR4 was associated with destructive RA in both seropositive and seronegative RA patients. In general, DR4+ patients had more severe disease by radiologic criteria than did DR4– patients. Thus, HLA–DR4 may be an additive factor to the serologic status and may be more closely related to disease severity than to disease susceptibility.