Sex Hormone Therapy May be Linked to Remission in Female Patients With RA

The use of sex hormones in female patients with rheumatoid arthritis (RA) was independently associated with more frequent remission, especially for women who were perimenopausal, a group less likely to achieve remission compared with premenopausal, and early postmenopausal, according to a study published in Rheumatology.¹

Dala N Daraghmeh, PhD

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As previous studies reported, exogenous estrogen may improve treatment outcomes in RA, although it may not reduce the risk of developing the condition.² Further, sex hormone replacement in postmenopausal women improved disease activity, decreased inflammation, and improved bone mineral density.

“Sex is well known to influence risk, severity, and treatment outcomes of RA, although the underlying causes are uncertain,” wrote Dala N Daraghmeh, PhD, associated with Health and Biomedical Innovation, UniSA: Clinical and Health Sciences at the University of South Australia, and a team of investigators. “The aim of this research was to examine whether factors influencing female sex hormones (reproductive status and exogenous sex hormone use) are associated with the efficacy of disease-modifying antirheumatic drugs (DMARDs).”

Patients with moderate-to-severe active RA treated with tocilizumab (4 or 8 mg/kg once every 4 weeks) and/or conventional synthetic DMARDs (csDMARDs), mainly methotrexate, were pooled from 5 phase 3 clinical trials. The primary outcome was the time to first remission based on the Simplified Disease Activity Index (SDAI) criteria. Patients with an inadequate response to at least 1 DMARD were included in 4 out of the 5 studies. A Cox proportional analysis examined the relationship between menopausal status or the use of exogenous sex hormones and first remission.

Data of interest included baseline menopausal status, defined as premenopausal, perimenopausal, early postmenopausal, and postmenopausal, as well as sex, age, body mass index (BMI), race, baseline disease activity, and the number of previous DMARDs.

Of the 4474 patients, 62.9% (n=2817) were postmenopausal, 22.8% (n=1021) were premenopausal, 9.2% (n=414) were perimenopausal, and 4.5% (n=202) were early postmenopausal. Among these groups, 7.8% (n=221), 25% (n=225), 11.4% (n=47), and 6.4% (n=13), respectively, were being treated with exogenous sex hormones. Most (75%, n=3347) were treated with tocilizumab ± csDMARDs.

According to the pooled analysis, perimenopause was linked to reduced remission when compared with patients with premenopausal status (adjusted hazard ratio [HR] 0.78 [95% confidence interval (CI) 0.61, 0.99]). Reproductive status was not associated with SDAI remission, although it was significantly associated using the Clinical Disease Activity Index (CDAI) and the Disease Activity Score-28 for Rheumatoid Arthritis with ESR (DAS28-ESR).

Sex hormone use was linked to significantly higher remission (adjusted HR 1.20 [95% CI 1.01, 1.43]). An exploratory analysis of the perimenopausal subgroup indicated that patients receiving exogenous sex hormones more frequently achieved SDAI- and CDAI-defined remission (SDAI: HR 2.18 [95% CI 1.27, 3.72], P = 0.004; CDAI: HR 1.86 [95% CI 1.09, 3.15], P = 0.022).

The 5 clinical trials studied were not designed to evaluate the association between sex hormone use, reproductive status, and remission. Therefore, information regarding sex hormone use, menopausal classification criteria, and age at the initiation of menopause could not be analyzed. Further, the number of patients using exogenous sex hormones was comparatively low, particularly after categorizing patients into 4 reproductive subgroups.

However, the large number of patients included in the study allowed for high-powered analysis and adjustment for confounders. Using SDAI, CDAI, and DAS28-ESR to evaluate the consistency of results increased robustness and strengthened the analysis. Future research is necessary to better understand and confirm these findings.

References

1. ^{Daraghmeh DN, Hopkins AM, King C, et al. Female reproductive status and exogenous sex hormone use in rheumatoid arthritis patients treated with tocilizumab and csDMARDs. Rheumatology (Oxford). 2023;62(2):583-595. doi:10.1093/rheumatology/keac357}
2. ^{Qi S, Xin R, Guo W, Liu Y. Meta-analysis of oral contraceptives and rheumatoid arthritis risk in women. Ther Clin Risk Manag 2014;10:915–23.}