Hormonal factors in rheumatoid arthritis – Their impact on disease risk and severity

Abstract: Rheumatoid arthritis (RA) is 4-6 times more common in women than men during the fertile years. For women, the incidence peaks shortly after menopause, and for men the risk is greater with higher age, when androgen levels drops. Sex hormones have been suggested to play a part in the pathogenesis, since low testosterone levels have been noted in men with RA and pregnancy has an ameliorating effect of the disease in women. Breastfeeding and use of exogenous hormones have been suggested to protect against the disease as well as being associated with a milder phenotype. Our aim was to further investigate associations between hormonal factors and RA. Two large community based cohorts were established in Malmö between 1974 and 1992 (Malmö preventive medicine programme, (MPMP)) and 1991-1996 (Malmö diet and cancer study (MDCS), respectively). Participants answered a questionnaire and blood samples were collected. We identified incident cases of RA by linking the cohorts to four different RA registers. In nested case-control studies, we studied hormonal predictors in women from the MDCS cohort, and analysed androgens in males from the MPMP. By a structured review of female incident cases in the MDCS, clinical outcomes were collected, with the purpose of classifying the severity of the disease. Three clusters were identified; severe RA, mild/moderate RF negative RA and mild/moderate RF positive RA. Longer duration of breastfeeding was associated with a reduced risk of RA (Odds ratio (OR)=0.46, 95% Confidence Interval (CI)=0.24-0.91), and menopause at 45 years of age or earlier was associated with an increased risk of RA (OR=2.42, 95% CI=1.32-4.45), in particular with a mild/moderate Rheumatoid factor (RF) negative phenotype. In multivariate analysis, there was a negative association between levels of testosterone and future development of RF negative RA in men (OR=0.31, CI=0.12-0.85). These results may improve our understanding about the impact hormones have in the complex pathogenesis of RA.