Background The role of hormonal/reproductive factors has been hypothesized to contribute to the risk of Rheumatoid arthritis (RA), but the literature is somewhat contradictory. Postmenopausal hormone (PMH) use has previously been observed to provide increased , decreased , as well as no association  with the risk of RA.
Objectives The aim of the present work was to study the association between PMH use and the risk of developing RA in postmenopausal women (aged 50-70), stratifying the cases according to presence/absence of antibodies to citrullinated peptides (ACPA).
Methods Data from a subset of the Swedish population-based EIRA (Epidemiological Investigation of RA) case-control study was analyzed. In total, 467 incident postmenopausal female cases, and 935 randomly selected controls (matched by age and residential area) were included between 2006-2011. Of the cases, 303 (64.9%) were ACPA-positive. An extensive questionnaire was answered by the participating cases and controls, including questions regarding PMH use (type of medication, duration) and potential confounders (education, smoking, BMI, oral contraceptive use, reproductive factors). Current and past users of PMH were compared with never users to obtain odds ratios (ORs) with 95% confidence intervals (CI) by means of unconditional logistic regression models, adjusting for age, residential area and smoking.
Results Current users of PMH had a decreased risk of ACPA-positive RA compared with never users (OR=0.6, 95% CI 0.4-0.9). The decreased risk was observed mainly in the age-group 50-59 years (OR=0.3, 95% CI 0.1-0.8) but not in the age-group 60-70 years (OR=0.8, 95% CI 0.4-1.4). Among current users of a combined therapy (estrogen plus progestogens) an OR of 0.3 (95% CI 0.1-0.7) of ACPA-positive RA was observed, while no significant association was found among women who used estrogen only (OR=0.8, 95% CI 0.5-1.6). No association between PMH use and ACPA-negative RA was found.
Conclusions Our results indicate that current use of PMH reduces the risk of ACPA-positive RA in postmenopausal women over 50 years of age, but has no association with the risk of ACPA-negative RA. Further research is needed in order to explore the biological mechanisms behind our findings but our results contribute to the knowledge of environmental risk factors such as PMH use and their different impact on the subgroups of RA.
Merlino LA, Cerhan JR, Criswell LA et al. (2003) Estrogen and other female reproductive risk factors are not strongly associated with the development of rheumatoid arthritis in elderly women. Semin Arthritis Rheum 33, 72-82.
Vandenbroucke JP, Witteman JC, Valkenburg HA et al. (1986) Noncontraceptive hormones and rheumatoid arthritis in perimenopausal and postmenopausal women. JAMA 255, 1299-1303.
Walitt B, Pettinger M, Weinstein A et al. (2008) Effects of postmenopausal hormone therapy on rheumatoid arthritis: the women's health initiative randomized controlled trials. Arthritis Rheum 59, 302-310.
Acknowledgements We want to thank Marie-Louise Serra and Lena Nise for excellent assistance in collection of data. We also thank all the cases and controls who participated in the study as well as clinicians and nurses part of the Epidemiological Investigation of Rheumatoid Arthritis study group: Göran Lindahl, Danderyd Hospital; Berit Sverdrup, Eskilstuna Hospital; Helena Hellström, Falu lasarett; Tomas Weitoft, Gävle Hospital; Bengt Lindell, Kalmar Hospital; Birgitta Nordmark, Johan Bratt and Ingiäld Hafström, Karolinska University Hospital; Ido Leden, Kristianstad Hospital; Björn Löfström, Katrineholm Hospital; Ann Bengtsson and Thomas Skogh, Linköping Hospital; Elisabeth Lindqvist, Lund University Hospital; Lennart Jacobsson, Malmö University Hospital; Kjell Huddénius, Rheumatology Clinic in Stockholm City; Christin Lindström, Sophiahemmet; Annika Teleman, Spenshult Hospital; Eva Baecklund and Ann Knight, Uppsala University Hospital; Olle Svernell, Västervik Hospital; Patrik Stolt, Västerås Hospital.
Funding This study was supported by grants from the Swedish Medical Research Council, the Swedish Council for Working Life and Social Research, King Gustav V's 80-year foundation, the Swedish Rheumatic Foundation, the Stockholm County Council, the Insurance Company AFA, the Innovative Medicines Initiative-supported BTCure project, the Controlling Chronic Inflammatory Diseases with Combined Efforts project and the National Institutes of Health (NIH, AR047782).
Disclosure of Interest : None declared
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