Association of HLA–DR3 with anti–cyclic citrullinated peptide antibody–negative rheumatoid arthritis

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Abstract
Objective: Recent data have shown that the most prominent and longest known genetic risk factors for rheumatoid arthritis (RA), HLA–DRB1 shared epitope alleles, are only associated with RA that is characterized by the presence of antibodies against cyclic citrullinated peptide (anti‐CCP antibodies) and not with anti‐CCP–negative RA. We undertook this study to investigate whether anti‐CCP–negative RA is associated with other HLA–DRB1 alleles.Methods: HLA typing was performed for 377 patients from the Leiden Early Arthritis Clinic who were diagnosed as having RA within the first year of followup (206 anti‐CCP–positive patients and 171 anti‐CCP–negative patients), 235 patients who, after 1 year, had undifferentiated arthritis (UA) (28 anti‐CCP–positive patients and 207 anti‐CCP–negative patients), and 423 healthy control subjects. Odds ratios (ORs) with 95% confidence intervals (95% CIs) for HLA–DRB1 allele frequencies were determined for all patient groups compared with the healthy control group.Results: HLA–DR3 was more frequently present in the anti‐CCP–negative RA group than in the control group (OR 1.84, 95% CI 1.26–2.67). This was not the case for anti‐CCP–positive RA (OR 0.92, 95% CI 0.60–1.40). HLA–DR3 was also more frequently present in anti‐CCP–negative UA patients (OR 1.59, 95% CI 1.10–2.28), but not in anti‐CCP–positive UA patients (OR 0.68, 95% CI 0.17–1.92).Conclusion: HLA–DR3 is associated with anti‐CCP–negative arthritis and not with anti‐CCP–positive arthritis. These data show that distinct genetic risk factors are associated with the presence of anti‐CCP antibodies in RA and indicate that different pathogenetic mechanisms underlie anti‐CCP–positive and anti‐CCP–negative RA.

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