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Smoking is a risk factor for anti-CCP antibodies only in rheumatoid arthritis patients who carry HLA-DRB1 shared epitope alleles
  1. S P Linn-Rasker1,
  2. A H M van der Helm-van Mil1,
  3. F A van Gaalen1,
  4. M Kloppenburg2,
  5. R R P de Vries3,
  6. S le Cessie4,
  7. F C Breedveld1,
  8. R E M Toes1,
  9. T W J Huizinga1
  1. 1Department of Rheumatology, Leiden University Medical Centre, Leiden, Netherlands
  2. 2Departments of Rheumatology and Epidemiology, Leiden University Medical Centre
  3. 3Department of Immunohaematology and Blood transfusion, Leiden University Medical Centre
  4. 4Department of Medical Statistics, Leiden University Medical Centre
  1. Correspondence to:
    Dr Annette H H van der Helm-van Mil
    Department of Rheumatology, Leiden University Medical Centre, PO Box 9600, 2300 RC Leiden, Netherlands; AvdHelm{at}


Objectives: To study the gene–environment interaction of tobacco exposure and shared epitope on autoantibodies in patients with rheumatoid arthritis and undifferentiated arthritis.

Methods: From incident cases of arthritis (n = 1305), patients who did not fulfil any classification criteria (undifferentiated arthritis (n = 486)) and those who fulfilled the American College of Rheumatology criteria for rheumatoid arthritis (n = 407) were identified. IgM rheumatoid factor (RF), anti-cyclic-citrullinated peptide (CCP) antibodies, and HLA-DRB1 alleles were determined.

Results: In rheumatoid arthritis, an interaction was found between tobacco exposure and shared epitope for the presence of anti-CCP antibodies, as the odds ratio for anti-CCP antibodies in patients having both tobacco exposure (TE) and shared epitope (SE) was higher than the summed odds ratios of patients having only tobacco exposure or shared epitope (odds ratios: 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 showed that the interaction primarily associated with the anti-CCP antibody response. In patients with undifferentiated arthritis at two weeks, or with persistent undifferentiated arthritis after one year, no interaction between tobacco exposure and shared epitope was observed for the presence of autoantibodies.

Conclusions: Tobacco exposure increases the risk factor for anti-CCP antibodies only in shared epitope positive patients with rheumatoid arthritis. The gene–environment interaction between smoking and shared epitope leading to autoantibodies is specific for rheumatoid arthritis and is not observed in undifferentiated arthritis.

  • ACR, American College of Rheumatology
  • CCP, cyclic citrullinated peptide
  • EAC, early arthritis clinic
  • RF, rheumatoid factor
  • SE+/−, shared epitope positive/negative
  • TE+/−, tobacco exposure positive/negative
  • rheumatoid arthritis
  • anti-CCP antibodies
  • rheumatoid factor
  • smoking
  • shared epitope

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  • Published Online First 13 July 2005