Smoking is a risk factor for anti-CCP antibodies only in RA patients that carry HLA-DRB1 Shared Epitope alleles

Suzanne P. Linn-Rasker ¹, Annette H.M. van der Helm - van Mil ^2*, Floris A. Van Gaalen ³, Margreet Kloppenburg ³, Rene de Vries ³, Saskia le Cessie ³, Ferdinand C. Breedveld ³, Rene E.M. Toes ³ and Tom W.J. Huizinga ³

¹ Leiden University Medical Center, Netherlands
² Leiden Univerisity Medical Center, Netherlands
³ Leiden Univeristy Medical Center, Netherlands

^* To whom correspondence should be addressed. E-mail: avdhelm{at}lumc.nl.

Accepted 3 July 2005

Abstract

Objectives: To study the gene-environment interaction of tobacco-exposure (TE) and shared-epitope (SE) on autoantibodies in Rheumatoid Arthritis (RA) and Undifferentiated Arthritis (UA).

Methods: From incident cases of arthritis (n=1305), patients that did not fulfil any classification criteria at the two weeks visit, UA (n=486) , as well as patients that fulfilled the ACR criteria for RA (n=407) were identified. IgM Rheumatoid Factor (RF), anti-cyclic-citrullinated peptide (CCP) antibodies and HLA-DRB1 alleles were determined.

Results: In RA an interaction was found between TE and SE for the presence of anti-CCP antibodies, as the odds ratio (OR) for anti-CCP antibodies of patients having both TE and SE was higher than the summed OR's of patients having only TE or SE (OR TE+SE- 1.07, TE-SE+ 2.49, and TE+SE+ 5.27, all relative to TE-SE-). A similar effect was found for RF, but stratification revealed that the interaction primarily associates with the anti-CCP antibody response. In patients with UA at two weeks or with persistent UA after one year no interaction between TE and SE was observed for the presence of autoantibodies.

Conclusions: TE increases the risk factor for anti-CCP antibodies only in SE-positive RA-patients. The gene-environment interaction between smoking and SE leading to autoantibodies is specific for RA and is not observed in UA.

Keywords: anti-CCP antibodies, rheumatoid arthritis, rheumatoid factor, shared epitope HLA-DRB1 alleles, smoking

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