Association between HLA class II genes and autoantibodies to cyclic citrullinated peptides (CCPs) influences the severity of rheumatoid arthritis

Objective The functional role of HLA class II molecules in the pathogenesis of rheumatoid arthritis (RA) is unclear. HLA class II molecules are involved in the interaction between T and B lymphocytes required for long‐lived B cell responses and generation of high‐affinity IgG antibodies. We undertook this study to investigate the relationship between HLA class II gene polymorphisms and RA‐specific IgG antibodies against cyclic citrullinated peptides (anti‐CCP antibodies). Methods High‐resolution HLA–DR and DQ typing and anti–CCP‐2 antibody testing were performed on 268 RA patients from the Early Arthritis Clinic cohort at the Department of Rheumatology of the Leiden University Medical Center. The presence of anti‐CCP antibodies was analyzed in carriers of the different DR and DQ alleles. Disease progression was measured over a period of 4 years by scoring radiographs of the hands and feet using the Sharp/van der Heijde method. Results Carriership of the individual alleles HLA–DRB1*0401, DRB1*1001, DQB1*0302, and DQB1*0501 was associated with the presence of anti‐CCP antibodies. Carriers of DQ–DR genotypes containing proposed RA susceptibility alleles were significantly more often anti‐CCP antibody positive. Carriership of one or two HLA–DRB1 shared epitope (SE) alleles was significantly associated with production of anti‐CCP antibodies (odds ratio [OR] 3.3, 95% confidence interval [95% CI] 1.8–6.0 and OR 13.3, 95% CI 4.6–40.4, respectively). An increased rate of joint destruction was observed in SE+, anti‐CCP+ patients (mean Sharp score 7.6 points per year) compared with that in SE−, anti‐CCP+ patients (2.4 points per year) (P = 0.04), SE+, anti‐CCP− patients (1.6 points per year) (P < 0.001), and SE−, anti‐CCP− patients (1.6 points per year) (P < 0.001). Conclusion HLA class II RA susceptibility alleles are associated with production of anti‐CCP antibodies. Moreover, more severe disease progression is found in RA patients with both anti‐CCP antibodies and SE alleles.