HLA markers and prediction of clinical course and outcome in rheumatoid arthritis

Objective. To evaluate HLA markers as early prognostic factors for disease severity in rheumatoid arthritis (RA). Methods. HLA genotyping was carried out in a retrospective analysis of 66 RA patients and in a prospective study of 55 RA patients and 87 healthy controls using polymerase chain reaction-based methods for HLA-DRB1 specificities, DR4 alleles, and their linked DQB1 alleles, as well as HLA-B27. The clinical course of RA was assessed by clinical and radiologic scores. The impact of HLA markers was evaluated by epidemiologic means in addition to modeling using multiple logistic regression analysis. Results. Shared epitope-positive (HVR3+) DR4 alleles and the HVR3 amino acid cassette QKRAA were associated with RA in both longstanding (relative risk [RR] 3.34 and 3.19) and recent-onset (RR 2.1 and 2.37) RA. In longstanding RA, radiologic evidence of severe joint destruction (Larsen score > 1.62) was seen more often in HVR3 shared epitope-positive patients than in epitope-negative patients (odds ratio [OR] = 25.67, X² = 13.59, P = 0.0003). Moreover, rank sum analysis of Larsen indices indicated significantly higher ranking for the presence of the RA-associated HVR3 cassettes (QKRAA, QRRAA) when expressed on a DR4 allele (P < 0.0001). In the prospective study, DR4-positive patients had a significantly increased risk (OR = 13.75, P = 0.00083) of developing bony erosions. In addition, HVR3 epitope-positive DR4-positive individuals had significantly higher Larsen indices than did epitope-negative patients (P = 0.0083). In particular, the presence of the HVR3 epitope on DR4 resulted in an increased a posteriori likelihood (0.91) of developing early erosive disease compared with an a priori risk of 0.62. Conversely, the likelihood decreased to a minimum of 0.35 when the HVR3 epitope was absent. Conclusion. While the contribution of HLA typing to establishing the diagnosis of RA is limited, HLA-DR genotyping and DR4 subtype determination provide valuable markers for the prognosis of joint destruction in RA.