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+/SE2, 1.07; TE2/SE+, 2.49; and TE+/SE+, 5.27-all relative to TE2/SE2). 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.

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Objective: To investigate whether there is an association between HLA class II and distal interphalangeal osteoarthritis (DIP OA). Methods: The study group consisted of consecutive patients with and without DIP OA aged between 40 and 70 years. DIP OA was diagnosed by radiology. These patients were referred to an "Early Arthritis Clinic" (EAC) with different types of arthritis at an early stage. Patients with rheumatoid arthritis, systemic lupus erythematosus, spondyloarthropathies, and psoriatic arthritis were excluded for the purpose of this study. DNA typing for HLA-DR and x ray examination of the hands were performed at enrolment in the EAC. To establish whether the study group was representative of the Dutch population, a population based study in Zoetermeer (n=3243) for the prevalence of DIP OA and blood donors in the Leiden area (n=2400) for the HLA-DR antigen frequencies were used as references. Results: Fifty five patients (33%) of the total study group (n=166) had DIP OA. The prevalence of DIP OA and frequency of the HLA-DR alleles were similar to those of the two reference groups. Within the study group an association between DIP OA and HLA-DR2 and DR4 with respectively odds ratios of 2.4 (95% confidence interval (CI) 1.1 to 5.0) and 0.3 (95% CI 0.1 to 0.7) was found. No association was found between other HLA-DR alleles and DIP OA. Conclusion:The study group is a representative sample of the Dutch population. The HLA-DR2 allele was more common in patients with DIP OA. Furthermore, an inverse relation was observed between DIP OA and HLA-DR4. The results confirm findings from other investigations implicating HLA-DR2 as a risk factor in the development of DIP OA.

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