Post-Menopause, Early Post-Menopause Associated With Increased Risk of RA

In women at an increased risk for rheumatoid arthritis (RA), characteristic systemic autoimmunity was associated with menopause. This suggests that acute decline in ovarian function might contribute to the autoimmunity associated with RA and might increase the risk for RA in women, according to research published in Rheumatology.¹

“The increased prevalence of RA in women suggests a potential role for female hormonal and reproductive factors,” wrote Deshiré Alpizar-Rodriguez, MD, from University Hospitals of Geneva in Switzerland and colleagues.

Studies have found associations between the development of RA and high estrogen exposure such as hormonal replacement therapy or oral contraceptives, as well as with low estrogen exposure such as early menopause onset or anti-estrogen agents. RA has also been associated with conditions involving endocrine changes such as polycystic ovary syndrome, pre-eclampsia, and the postpartum period.

“Overall, female hormonal factor associations with RA development have been inconsistent in epidemiologic studies,” the researchers noted.

Dr Alpizar-Rodriguez and colleagues analyzed 768 women from an ongoing study of first-degree relatives of patients with RA (RA-FDRs). The main outcome was anti-citrullinated protein antibodies (ACPA) positivity. The researchers also gathered information on predictors of interest such as oral contraceptives, breastfeeding, post-menopausal status, early post-menopausal period, and total number of ovulatory years.

Of the 768 women, 42 (5%) developed ACPA positivity, and this 5% of women were older than women with ACPA negativity (52 vs 44, P =.001).

The hormonal factors significantly and independently associated with ACPA positivity were post-menopausal (P <.001) and early post-menopausal periods (P =.040).

Summary & Clinical Applicability

“In summary, we demonstrated that, in women at increased risk of RA, the presence of ACPA is associated with menopause and with the early post-menopausal period. These results suggest that the acute decline in ovarian function and estrogen bioavailability contributes to the development of autoimmunity associated with RA and potentially with an increased risk of RA in women,” the researchers wrote.

As preventive interventions are being developed for RA, it will be important to determine which groups of people should be screened.² “Post-menopausal FDR [first-degree relatives]-RA women, and particularly those women in the early post-menopausal period, could be one of the high-risk groups warranting screening for RA,” the researchers concluded.

Limitations

• Female hormonal factors were self-reported
• Summarizing lifetime estrogen exposure in a single measurement was challenging due to the lack of well-validated scores
• The limited follow-up may limit statistical power due to the possibility of ACPA-negative RA-FDRs to eventually develop systemic autoimmunity or RA
• Participants with very early presentations of RA were excluded from this study due to the possibility that this could lead to overestimation of prevalent ACPA positivity

References

1. Alpizar-Rodriguez D, Mueller RB, Möller B, et al. Female hormonal factors and the development of anti-citrullinated protein antibodies in women at risk of rheumatoid arthritis [published online June 25, 2017]. Rheumatology. doi:10.1093/rheumatology/kex239
2. Sparks JA, Iversen MD, Miller Kroouze R, et al. Personalized Risk Estimator for Rheumatoid Arthritis (PRE-RA) Family Study: rationale and design for a randomized controlled trial evaluating rheumatoid arthritis risk education to first-degree relatives. Contemp Clin Trials. 2014;39:14557.