Menopausal hormone therapy linked to increased risk of SLE and SSc

Menopausal hormone therapy linked to increased risk of SLE and SSc | Image Credit: © Graphicroyalty - © Graphicroyalty - stock.adobe.com.

Menopausal hormone therapy (MHT) is linked to immune-mediated diseases systemic lupus erythematosus (SLE) and systemic sclerosis (SSc), according to a recent study published in Rheumatology.¹

Over 80% of patients with SLE and SSc are women, highlighting the role of female sex hormones in immune-mediated diseases. Data has also linked exogenous estrogens to increased risk of SLE, including MHT.²

According to investigators, “an influence of sex hormones has been suggested, but only a few studies have directly assessed the impact of sex hormones on SSc pathogenesis.”¹ Therefore, a study was conducted to address this research gap.

Data was obtained from the National Patient Register, Prescribed Drug Register (PDR), and Total Population Register. These databases contained information about hospitalization and outpatient visits, dispensed medications from Swedish pharmacies, and longitudinal demographic information, respectively.

The Longitudinal Integration Database for Health Insurance and labour Market Studies was also assessed for data about sick leave, income and educational attainment. Investigators identified disease cases in the Swedish population and matched each to 10 controls.

Participants included women aged at least 40 years with a first-ever visit indicating SLE or SSc as main diagnosis from January 1, 2009, to December 31, 2019. Exclusion criteria included having a contributory SLE/SSc diagnosis before the first-ever main diagnosis.

MHT exposure before the index date was determined through codes in the PDR. These included codes for estrogen, progestogen, combined estrogen-progestogen, and tibolone, and were classified as either systemic or local.

Women with MHT dispensed at any point were classified as ever users. Associations were also assessed based on MHT, route of administration, and duration of use. Covariates included date of birth, country of residence, education level, gross income, and sick leave.

There were 943 SLE cases and 8381 controls included in the SLE analysis. Women with SLE had an increased rate of extended sick leave compared to controls.

A statistically significant link was reported between having ever taken MHT and presenting with SLE, with an odds ratio (OR) of 1.3. For systemic estrogen and progestogen, local estrogen, and systemic estrogen, the ORs were 1.5, 1.3, and 1.0, respectively.

Dispensing local MHT drug was linked to a 20% increase in SLE risk, and no association was reported for systemic MHT. The highest odds were reported in women using both local and systemic MHT, with an OR of 1.9. These odds remained relatively stable for up to 7 years before SLE diagnosis.

In the SSc analysis, there were 733 SSc cases matched to 6571 controls. A lower disposable income and increased odds of sick leave were reported in women with SSc. These patients were also more likely to use MHT, at 34% vs 29% of controls.

The risk of SSc was increased 1.4-fold among MHT users. Additionally, the odds were increased by 70% from systemic estrogen-progestogen combination treatment. This was followed by a 30% increase from local estrogen. Systemic estrogen on its own was not linked to increased SSc risk.

An OR of 1.4 for SSc was reported for systemic only treatments vs 1.30 for local only treatments. Women dispensing both types of treatments had the highest risk of SSc, with an OR of 1.8.

These results indicated an increased risk of SLE/SSc from the use of MHT. “Future research should focus on the validation and functional interpretation of these results,” concluded investigators.

References

1. Patasova K, Dehara M, Mantel A, Bixo M, Arkema EV, Holmqvist M. Menopausal hormone therapy and the risk of systemic lupus erythematosus and systemic sclerosis: a population-based nested case-control study. Rheumatology. 2025. doi:10.1093/rheumatology/keaf004
2. Rojas-Villarraga A, Torres-Gonzalez JV, Ruiz-Sternberg ÁM.Safety of hormonal replacement therapy and oral contraceptives in systemic lupus erythematosus: a systematic review and meta-analysis. PLoS One.2014;9:e104303. doi:10.1371/journal.pone.0104303