The HLA–DRB1 shared epitope alleles differ in the interaction with smoking and predisposition to antibodies to cyclic citrullinated peptide

Objective

The HLA shared epitope (SE) alleles are primarily a risk factor for the presence of antibodies to cyclic citrullinated peptide (anti‐CCP antibodies) rather than for the development of rheumatoid arthritis (RA). The SE alleles interact with the environmental risk factor tobacco exposure (TE) for predisposition to anti‐CCP+ RA. The objectives of this study were to determine 1) whether different SE subtypes contribute differently to the presence of anti‐CCP antibodies, 2) whether different SE subtypes all interact with TE for the development of anti‐CCP antibodies, and 3) the effect of TE in relation to the SE alleles and anti‐CCP antibodies on the risk of progression from undifferentiated arthritis (UA) to RA.

Methods

We assessed the effect of SE subtypes and TE on the presence and level of anti‐CCP antibodies and on the risk of progression from UA to RA in 977 patients with early arthritis who were included in the Leiden Early Arthritis Clinic.

Results

The HLA–DRB1*0401, *0404, *0405, or *0408 SE alleles conferred the highest risk of developing anti‐CCP antibodies (odds ratio [OR] 5.0, compared with an OR of 2.0 for the HLA–DRB1*0101 or *0102 SE alleles and an OR of 1.7 for the HLA–DRB1*1001 SE allele). Conversely, the TE–SE allele interaction was the strongest for the HLA–DRB1*0101 or *0102 SE alleles and the HLA–DRB1*1001 SE allele. TE in SE+, anti‐CCP+ patients correlated with higher levels of anti‐CCP antibodies and with progression from UA to RA. In logistic regression analysis, only the presence and level of anti‐CCP antibodies were associated independently with RA development.

Conclusion

The HLA–DRB1 SE subtypes differ in their interaction with smoking and in their predisposition to anti‐CCP antibodies. TE contributes to the development of RA in SE+, anti‐CCP+ patients, which is explained by its effect on the level of anti‐CCP antibodies.