Menopause and Rheumatoid Arthritis Risk

RA and hormone replacement therapy
RA and hormone replacement therapy
Data from the Nurses' Health Studies were analyzed to determine if there is a link between seropositive and seronegative rheumatoid arthritis and age of menopause onset.

Early natural menopause has been linked to the development of seronegative rheumatoid arthritis (RA), according to research published in Arthritis Care & Research.

Camilla Bengtsson, PhD, of the Institute of Environmental Medicine at the Karolinska Institutet in Stockholm, Sweden, and colleagues assessed data collected from the Nurses’ Health Studies (NHS, 1976-2010; NHSII, 1989-2011). Data for more than 238,130 women between 25 and 55 years of age were included.

All women who self-reported a clinical diagnosis of RA filled out the Connective Tissue Disease Screening Questionnaire (CSQ), and records were reviewed by 2 board-certified rheumatologists. Seropositive RA was defined as either rheumatoid factor (RF)-positive (RF+) or antibodies to citrullinated peptides (ACPA)-positive (ACPA+) RA; seronegative RA was both RF- and ACPA-negative RA.

High-Yield Data Summary

  • Women who began natural menopause at ≤44 years had increased risk for seronegative rheumatoid arthritis; the reason has yet to be determined.

Ultimately, 109,443 women (2,498,323 person-years) from NHS and 112,523 women (1,987,756 person-years) from NHSII were included in the study. Researchers’ analyses included 1096 cases: 401 seronegative cases and 695 seropositive cases.

Dr Bengtsson and colleagues found that women aged 45 and older had an increased RA risk compared with those aged 25 to 44. Between ages 45 and 49, pooled hazard ratio [HR] was 1.5 (95% CI, 1.2-1.9), increasing to 2.0 at ages 50 to 54 and 2.3 at ages 55 to 59 (95% CI, 1.6-2.5 and 1.7-3.2, respectively). Patterns were similar among seronegative RA cases.

It was noted that after adjustments, postmenopausal women had an increased risk of seronegative RA vs premenopausal women (NHS HR: 1.8; 95% CI, 1.1-3.0; NHSII HR: 2.4; 95% CI, 1.4-3.9). Regardless of the age at menopause onset, menopause was associated with an increased seronegative RA risk, although the highest HR was found among women who began natural menopause at ≤44 years (NHS HR: 2.7; 95% CI, 1.4-5.3; NHSII HR, 2.6; 95% CI, 1.1-6.2).

Postmenopausal hormone (PMH) use was not linked to a seronegative RA risk (NHS HR: 1.3; 95% CI, 0.6-2.9; NHSII HR: 1.3; 95% CI, 0.6-2.69); similarly, PMH use for 8 or more years was also not associated with an elevated risk (NHS HR: 1.4; 95% CI, 0.9-2.0; NHSII: 1.8; 95% CI, 0.8-4.2). Only current PMH users in the NHS cohort were found to have an elevated risk of seropositive RA (HR: 1.4; 95% CI, 1.1-1.9). However, 8 or more years of PMH use was associated with a heightened risk of seropositive RA (NHS HR: 1.5; 95% CI, 1.1-2.0; NHSII HR: 1.2; 95% CI, 0.6-2.2).

Summary and Clinical Applicability

Dr Bengtsson and colleagues noted that the reason for the increased RA risk is still to be determined, as it is unclear if it is related to falling estrogen or progesterone levels. “However,” they wrote, “there is an immunomodulatory effect given by the natural hormone progesterone. [A]s progesterone might decrease RA disease activity in the pregnant state…progesterone might also be important during the menopausal phase.”

Study Limitations

  • There is a potential risk that RA cases may have been misclassified due to reliance on medical record review rather than physical examinations.
  • Self-reported exposure data may lead to misclassification of menopausal factors.
  • There is potential for ACPA+ RA cases to be misclassified as seronegative cases.


Bengtsson C, Malsepis S, Orellana C, Sparks JA, Costenbader KH, Karlson EW. Menopausal factors are associated with seronegative RA in large prospective cohorts: results from the Nurses’ Health Studies [published online January 13, 2017]. Arthrit Care Res. doi: 10.1002/acr.23194

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