Even in former users. But oral contraceptives seem to lower the risk.
Menopausal hormone therapy could increase the risk of late onset rheumatoid arthritis, and there’s more evidence that oral contraceptives have a protective effect in younger people.
Sex hormones are known to have a role in the development of rheumatoid arthritis and patients are routinely advised to use oral contraceptives. Meanwhile, late onset RA (diagnosed at 60 or over) is becoming more prevalent as the population ages.
Fewer studies have targeted this cohort, and they have pointed to a positive association between MHT and late onset rheumatoid arthritis. But important time-variable covariates have mostly not been taken into account, said the authors of the latest study, published in Rheumatology.
This Swedish study used data from the UK Biobank from over 250,000 women, with information about their use of oral contraceptives or MHT from 2006-2010 and RA diagnoses up to 2020. To get a homogeneous sample, analysis was initially carried out on the largest group represented in the UK Biobank – white British women (88% of the cohort) – and then repeated across the entire group of all ethnicities for generalisability.
There were just over 100,000 British white women aged 60 or over who had not been diagnosed with RA before the age of 60, and these were the ones analysed for MHT use and late onset rheumatoid arthritis risk. In this group, 2320 were diagnosed with late onset rheumatoid arthritis. Around 45% of women had never used MHT and 55% had, with a mean duration of MHT use of just over seven years.
Women who had ever used MHT had a 16% higher risk of developing late onset rheumatoid arthritis (19% for current users in the core group and 17% in the all-ethnicities group; 13% for former white British users and 12% in the total group). Having PCOS did not affect the risk.
The results for oral contraception confirmed early studies, where oral contraceptives were found to lower the risk of rheumatoid arthritis by 11% for white British women who had ever taken them, and 8% for all ethnicities, compared to never users. Age and BMI did not significantly affect these figures.
British white women who were still taking the pill at the time of the study had a 19% lower risk of rheumatoid arthritis (14% lower for all ethnicities) than never-users. But after stopping oral contraception, the association was not significant.
“The observed presence of two distinct effects of exposure to exogenous hormones on risk of RA could be related to differences in the hormones’ functions in the body, variations in the response to hormones in different reproductive statuses, or heterogeneity between early-onset RA and late onset rheumatoid arthritis,” the authors wrote.
There were several mechanisms proposed to explain the connection between female sex hormones and RA, they noted.
“Estrogen could directly modulate the immune system and can, therefore, in a receptor- and dosage-dependent manner, contribute to development of RA. Moreover, estrogen may have the capacity of influencing the production of antibodies by changing their glycosylation process,” the authors said.
“B-cell activating factor (BAFF) is a ligand that is necessary for the survival and homeostasis of peripheral B cells. It has been shown that the presence of estrogen is associated with a 5-fold higher expression of BAFF and a higher concentration of BAFF has been detected in the serum of RA patients compared with controls.”
Estrone, one of three estrogens produced before menopause, promotes inflammation, and, with TNF-?, activates the NF-?B signalling pathway, they explained.
Additionally, ageing changes the immune system, and in menopause estrone becomes the most prominent estrogen left, tipping the balance in favour of pro-inflammatory function.
“One explanation for the present observation could be that women with the lowest natural levels of estrogen more often use MHT due to stronger symptoms,” they said.
Another was that the synthetic ethinylestradiol in oral contraceptives doesn’t convert into and even suppresses the body’s production of estrone, while oral MHT estradiol generates a large amount of circulating estrone, they suggested.
There were limitations to the study’s generalisability, the authors warned. There’s an inherent selection bias in the UK Biobank, with participants being, on the whole, healthier than the general population. First occurrence of RA was self-reported, and there wasn’t detailed information about the formulation of hormones and routes of administration, the majority of women in the all-ethnicities group were still mainly white European women, and PCOS is most probably under-reported.