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The HLA-DRB1 Shared Epitope Alleles Differ in the Interaction with Smoking and Predisposition to Antibodies to Cyclic Citrullinated Peptide.
van der Helm-van Mil, Annette H. M.; Verpoort, Kirsten N.; le Cessie, Saskia; Huizinga, Tom W. J.; de Vries, Rene R. P.; Toes, Rene E. M.
[Article] Arthritis & Rheumatism. 56(2):425-432, February 2007.

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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.