Menopause May Influence Risk for Seronegative RA

Action Points

  • Note that this large observational study based on administrative data suggests an increased risk of seronegative rheumatoid arthritis (RA) among women after menopause.
  • The effect of menopause on seropositive RA was much less pronounced.

Postmenopausal women have more than double the risk of seronegative rheumatoid arthritis (RA) compared with premenopausal women, with the highest risk found among those experiencing early natural menopause, a new analysis from the Nurses’ Health Studies (NHS) reveals.

The pooled hazard ratio for developing RA among postmenopausal women enrolled in the NHS and NHS II was 2.1 (95% CI 1.4-3), according to Camilla Bengtsson, PhD, of the Karolinska Institute in Stockholm, Sweden, and colleagues.

And for those who had natural menopause at age 44 or younger, the pooled hazard ratio was 2.4 (95% CI 1.5-4), the team reported online in Arthritis Care & Research.

The study also found that postmenopausal women had only a marginally increased risk of seropositive RA.

Along with other recent research, the results of this new study “suggest that menopausal transition may influence the development of seronegative RA,” the authors wrote.

“Our findings add to the growing literature supporting the idea that seronegative and seropositive RA may have different epidemiological risk factors.”

Although environmental factors such as smoking and genetic factors such as HLA-DRB shared epitope alleles have been associated with seropositive RA, the risk factors for seronegative RA are less clear.

For the study, the researchers used data from two large U.S. cohorts: the NHS, which began in 1976 with female nurses born between 1921 and 1946; and NHS II, which was launched in 1989 and includes women born between 1947 and 1964. Since the start of both cohorts, participants have answered questionnaires biennially.

The new analysis included 109,443 women from the NHS and 112,523 from the NHS II. Women were excluded if they had RA at baseline.

In total, 1,096 incident RA cases were included in the analysis, with 401 patients found to be seronegative for both rheumatoid factor and anti-citrullinated protein antibodies and 695 seropositive for one or both of the autoantibodies.

The researchers determined the menopausal status of the women and categorized those who were menopausal as natural and surgical. Women with a hysterectomy and bilateral oophorectomy were categorized as menopausal at the time of the surgery.

Women age 45 and older had an increased risk of RA compared with younger women, with peak hazard ratios for both seropositive and seronegative RA at ages 55 to 59. The authors pointed out that this age is after the menopausal transition in most women.

The risk for seronegative RA was increased in both NHS (HR 1.8, 95% CI 1.1-3) and NHS II (HR 2.4, 95% CI 1.4-3.9) when considered separately, after adjusting for age, questionnaire cycle, median household income, body mass index (BMI), pack-years of smoking, breastfeeding, and parity.

Any age at menopause was associated with an increased risk of seronegative RA.

The researchers also looked at other covariates, including alcohol consumption, oral contraceptive use, age at menarche, and irregular menses. But since these did not substantially alter the estimates, these were not included in the final model.

In addition, they gathered information on postmenopausal hormone therapy (PMH) use. As the authors explained, if increased RA risk at the time of menopause is due to hormonal fluctuations, then PMH could theoretically reduce RA risk.

However, neither current nor long-term (8 or more years) use of PMH was associated with risk of seronegative RA.

As for seropositive RA, current PMH use had an increased risk in the NHS (HR 1.4, 95% CI 1.1-1.9) but not in NHS II. Long duration of PMH use was significantly associated with risk of seropositive RA, but age at initiation of PMH was not associated with either type of RA.

A potential limitation of the study was that RA cases could have been misclassified as non-cases since the authors relied on medical records rather than physical examination. Self-reported exposure data might have led to misclassification of menopausal factors.

And, the team said, since less is known about risk factors for seronegative RA, unidentified confounders contributing to the association may have been missed.

The study was supported by the National Institutes of Health, the Swedish Council for Working Life and Social Research, the Swedish Rheumatism Association, and the Borje Dahlin fund.

The authors reported no competing interests.

  • Reviewed by
    F. Perry Wilson, MD, MSCE Assistant Professor, Section of Nephrology, Yale School of Medicine and Dorothy Caputo, MA, BSN, RN, Nurse Planner


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