Association between HLA-DRB1*15 and secondary Sjogren's syndrome in patients with rheumatoid arthritis

Objective. To examine the relationship between HLA-DRB1 alleles and the clinical expression of the secondary form of Sjogren's syndrome (SS) in patients with rheumatoid arthritis (RA). Methods. Typing of HLA-DRB1 alleles was carried out by molecular based techniques on DNA obtained from a population of patients with RA from Lugo in northwestern Spain. Patients were diagnosed according to the 1987 American College of Rheumatology criteria for RA, and comprised 137 seropositive and 42 seronegative individuals. Secondary SS was defined by xerostomia and keratoconjunctivitis sicca, supported by ophthalmologic examination. Patients were compared with 145 ethnically matched controls. Results. Twenty-two (12.3%) of the patients with RA also had secondary SS. The majority of these (19/22) were rheumatoid factor positive. Eleven (57.9%) of the seropositive patients with secondary SS carried an HLA-DRB1*15 allele compared with 28 (23.7%) seropositive patients without secondary SS (OR 4.4, 95% CI 1.5-13.6, P(c) = 0.014). In contrast, the frequency of DRB1*04 was reduced in seropositive patients with secondary SS compared to those without secondary SS, although this did not achieve significance after correction for multiple testing (OR 0.28, 95% CI 0.09-0.88, P(c) = 0.08). Of note, in individuals lacking the RA shared epitope (SE), DRB1*15 was found to be associated (OR 2.3, 95% CI 1.0-5.1, P(c) = 0.03) with RA in the absence of secondary SS. No differences were found between DRB1*15 positive and negative patients in terms of erosive disease, nodules, or rheumatoid factor positivity. Conclusion. Secondary SS is associated with an increased frequency of HLA-DRB1*15 in seropositive patients with RA from northwestern Spain. HLA-DRB1*15 is also associated with RA in SE negative individuals without secondary SS, although the possibility that such patients will later develop SS cannot be ruled out. Further studies are needed to confirm whether the HLA-DRB1*15 association with secondary SS in RA is common to Spanish and other ethnic populations.