Refining the complex rheumatoid arthritis phenotype based on specificity of the HLA–DRB1 shared epitope for antibodies to citrullinated proteins

Objective The main genetic risk factor for rheumatoid arthritis (RA), the HLA region, has been known for 25 years. Previous research has demonstrated, within the RA population, an association between HLA–DRB1 alleles carrying the shared epitope (SE) and antibodies directed against cyclic citrullinated peptides (anti‐CCP antibodies). We undertook this study to make the first comparison of SE allele frequencies in the healthy population with those in RA patients who do or do not harbor anti‐CCP antibodies. Methods HLA–DRB1 typing was performed in 408 RA patients from the Leiden Early Arthritis Clinic (the Leiden EAC; a Dutch population‐based inception cohort in which disease course was followed up over time), in 423 healthy Dutch controls, and in 720 affected members of 341 US multiplex (sibpair) families of Caucasian origin from the North American RA Consortium (NARAC) with well‐established disease and fulfilling the American College of Rheumatology classification criteria for RA. The presence of anti‐CCP antibodies was determined by enzyme‐linked immunosorbent assay. Results For the Leiden EAC, the odds ratio (OR) describing the association of 2 copies of the SE allele with anti‐CCP positivity (using no copies of the SE allele in the healthy control group as the referent) was 11.79 (P < 0.0001), while the OR for 1 SE allele was 4.37 (P < 0.0001). No association with the SE was observed in the Dutch anti‐CCP–negative RA patients. For the NARAC families, linkage and association analysis revealed the SE to be associated only with anti‐CCP–positive disease and not with anti‐CCP–negative disease. Stratified analyses indicated that anti‐CCP antibodies primarily mediated association of the SE with joint damage or disease persistence. Conclusion HLA–DRB1 alleles encoding the SE are specific for disease characterized by antibodies to citrullinated peptides, indicating that these alleles do not associate with RA as such, but rather with a particular phenotype.