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

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

Parity influences the severity of ACPA-negative early rheumatoid arthritis : a cohort study based on the Swedish EIRA material

Background: In women with rheumatoid arthritis (RA) it has been observed that during pregnancy a majority of patients experience amelioration, but after delivery a relapse of the disease is common. However, there are few studies, with diverging results, addressing the effect of parity on the severity of RA over time. Our aim was to explore the impact of parity, with stratification for anti-citrullinated protein antibody (ACPA) status as well as for onset during reproductive age or not. Methods: Female RA cases aged 18-70 years were recruited for the Epidemiological Investigation of Rheumatoid Arthritis (EIRA). Information on disease severity (the health assessment questionnaire (HAQ) and the disease activity score 28 (DAS28)) was retrieved from the Swedish Rheumatology Quality Register at inclusion and 3, 6, 12 and 24 months after diagnosis. Mixed models were used to compare mean DAS28 and HAQ scores over time in parous and nulliparous women. Mean differences at individual follow-up visits were compared using analysis of covariance. The odds of having DAS28 or HAQ above the median in parous verus nulliparous women were estimated in logistic regression models. Results: A total of 1237 female cases (mean age 51 years, 65 % ACPA-positive) were included. ACPA-negative parous women, aged 18-44 years, had on average 1.17 units higher DAS28 (p < 0.001) and 0.43 units higher HAQ score (p < 0.001) compared to nulliparous women during the follow-up time, adjusted for age. In this subgroup, the average DAS28 and HAQ scores were significantly higher in parous women at all follow-up time points. Younger parous ACPA-negative women were significantly more likely to have DAS28 and HAQ values above the median compared to nulliparous women at all follow-up visits. No association between parity and severity of ACPA-positive disease was observed. Conclusions: Parity was a predictor of a more severe RA among ACPA-negative younger women, which might indicate that immunomodulatory changes during and after pregnancy affect RA severity, in particular for the ACPA-negative RA phenotype

Parity influences the severity of ACPA-negative early rheumatoid arthritis : a cohort study based on the Swedish EIRA material

Background: In women with rheumatoid arthritis (RA) it has been observed that during pregnancy a majority of patients experience amelioration, but after delivery a relapse of the disease is common. However, there are few studies, with diverging results, addressing the effect of parity on the severity of RA over time. Our aim was to explore the impact of parity, with stratification for anti-citrullinated protein antibody (ACPA) status as well as for onset during reproductive age or not. Methods: Female RA cases aged 18-70 years were recruited for the Epidemiological Investigation of Rheumatoid Arthritis (EIRA). Information on disease severity (the health assessment questionnaire (HAQ) and the disease activity score 28 (DAS28)) was retrieved from the Swedish Rheumatology Quality Register at inclusion and 3, 6, 12 and 24 months after diagnosis. Mixed models were used to compare mean DAS28 and HAQ scores over time in parous and nulliparous women. Mean differences at individual follow-up visits were compared using analysis of covariance. The odds of having DAS28 or HAQ above the median in parous verus nulliparous women were estimated in logistic regression models. Results: A total of 1237 female cases (mean age 51 years, 65 % ACPA-positive) were included. ACPA-negative parous women, aged 18-44 years, had on average 1.17 units higher DAS28 (p < 0.001) and 0.43 units higher HAQ score (p < 0.001) compared to nulliparous women during the follow-up time, adjusted for age. In this subgroup, the average DAS28 and HAQ scores were significantly higher in parous women at all follow-up time points. Younger parous ACPA-negative women were significantly more likely to have DAS28 and HAQ values above the median compared to nulliparous women at all follow-up visits. No association between parity and severity of ACPA-positive disease was observed. Conclusions: Parity was a predictor of a more severe RA among ACPA-negative younger women, which might indicate that immunomodulatory changes during and after pregnancy affect RA severity, in particular for the ACPA-negative RA phenotype

High serum cholesterol predicts rheumatoid arthritis in women, but not in men: a prospective study.

Environmental exposures, including smoking, hormone-related factors, and metabolic factors, have been implicated in the etiology of rheumatoid arthritis (RA). A previous study has indicated that blood lipid levels may influence the development of RA. The objective of this study was to investigate the impact of serum total cholesterol and triglycerides on the risk of RA in a prospective study

Early menopause is an independent predictor of rheumatoid arthritis.

BACKGROUND: As rheumatoid arthritis (RA) occurs more often in women than in men, it has been suggested that reproductive hormones may play an important role in the pathogenesis.METHODS: Between 1991 and 1996, 30 447 subjects (18 326 women) were included in a community-based health survey. Information on female hormonal changes and stress-related factors was obtained using a self-administered questionnaire. This population was linked to four different local and national RA registers. The medical records for patients with a diagnosis of RA were subjected to a structured review and all women with incident RA according to the 1987 American College of Rheumatology criteria after inclusion in the health survey were included in a nested case-control study. Matched controls (1:4) were selected from the health survey population.RESULTS: Early age at menopause (≤45 years) was associated with the subsequent development of RA (OR 2.42, 95% CI 1.32 to 4.45). The effect of early menopause remained significant after adjusting for smoking, level of education and length of breastfeeding (OR 1.92, 95% CI 1.02 to 3.64)CONCLUSION: RA was predicted by an early age at menopause. This implicates an influence of hormonal changes during the fertile period on the development of RA in postmenopausal women

A high body mass index is associated with reduced risk of rheumatoid arthritis in men, but not in women.

To investigate the impact of overweight and obesity on the risk of RA

Association between testosterone levels and risk of future rheumatoid arthritis in men: a population-based case-control study.

OBJECTIVES: Rheumatoid arthritis (RA) is less common among men than women, and sex hormones have been suggested to play a part in the pathogenesis. Lower levels of testosterone have been demonstrated in men with RA, but it is not known if these changes precede the disease. METHODS: In a nested case-control study, using information and blood samples from a population-based health survey, we identified incident cases of RA by linking the cohort to local and national RA registers. Two controls for each validated case, matched for age, sex and year of screening, were selected from the health survey. Using stored blood samples, collected between 08:00 and 10:00 am after an overnight fast, we analysed levels of testosterone and other reproductive hormones. RESULTS: Serum was available from 104 cases (median time from screening to RA diagnosis 12.7 years (range 1-28); 73% rheumatoid factor (RF) positive at diagnosis or later) and 174 matched controls. In conditional logistic regression models, adjusted for smoking and body mass index, lower levels of testosterone were associated with subsequent development of RF-negative RA (OR 0.31 per SD, 95% CI 0.12 to 0.85), with a weaker association with RF-positive RA (OR 0.87 per SD; 95% CI 0.53 to 1.43). Levels of follicle-stimulating hormone were significantly increased in pre-RF-negative RA (p=0.02), but decreased in pre-RF-positive RA (p=0.02). CONCLUSIONS: Lower levels of testosterone were predictive of RF-negative RA, suggesting that hormonal changes precede the onset of RA and affect the disease phenotype