The 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. The relationship between HLA class II polymorphisms and RA-specific IgG anti-cyclic citrullinated peptide (CCP) antibodies was investigated.

High-resolution HLA-DR and DQ typing and anti-CCP2 antibody testing was performed in 279 RA patients from the Leiden Early Arthritis cohort. 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 hands and feet using the Sharp/Van der Heijde method.

Carriers of DQ-DR genotypes containing proposed RA susceptibility alleles were significantly more frequently anti-CCP antibody positive. Carriership of one or two HLA-DRB1 shared epitope (SE) alleles was significantly associated with production of anti-CCP antibodies (OR 2.9, 95% CI 1.6–5.2 and OR 10.2, 95% CI 3.8–28.5, respectively). In SE carrying, anti-CCP antibody positive patients an increased rate of joint destruction was observed (mean Sharp score 7.6 points/year) compared with non-SE carrying, anti-CCP positive (2.4 points; P = 0.03), SE carrying, anti-CCP-negative patients (1.6 points; P < 0.001) and non-SE carrying, anti-CCP negative patients (1.6 points; P < 0.001).

Anti-CCP antibodies are associated with HLA class II RA susceptibility alleles and presence of both factors is indicative of a severe disease course. As the principal role of HLA class II molecules is antigen presentation to T cells, these data point toward a pivotal role of citrulline-directed T cells in the production of anti-CCP antibodies.