Shorter reproductive time span and early menopause increase the risk of ACPA-negative inflammatory arthritis in postmenopausal women with clinically suspect arthralgia.

Abstract

Objectives: The drop in oestrogen levels during menopause coincides with the peak incidence of rheumatoid arthritis(RA) in women, suggesting a role of oestrogens in its pathophysiology. However, the timing of the effect of oestrogens during RA-development is unknown. Studies in the final phase of RA-development, from clinically suspect arthralgia(CSA) towards clinically apparent arthritis, are lacking. We hypothesized that shorter lifetime oestrogen exposure might be associated with a higher risk of inflammatory arthritis(IA)-development in women with CSA and studied this in two cohorts.

Methods: Consecutively included women from two independent CSA cohorts, including a total of 433 patients, were prospectively studied. Time to inflammatory arthritis(IA) and RA-development was compared for pre- vs postmenopausal women and, in postmenopausal women, for three measures of lifetime duration of oestrogen exposure: number of reproductive years, number of ovulatory years and early menopause. Analyses were stratified for ACPA-status.

Results: Postmenopausal women, compared with premenopausal women, had an increased risk for ACPA-negative IA (HR 2.9, 95%CI 1.05-8.0) but not for ACPA-positive IA (HR 0.8, 95%CI 0.4-1.9). Results were similar for RA-development. Furthermore, early onset of menopause (HR 11.1, 95%CI 2.4-51.1), lower number of reproductive years (HR per 1 year increase 0.88, 95%CI 0.78-0.99), and lower number of ovulatory years (HR per 1 year increase 0.88, 95%CI 0.78-0.99) increased the risk of ACPA-negative IA, but not ACPA-positive IA.

Conclusion: In patients with arthralgia at-risk for RA, lifetime exposure to oestrogens and/or the drop in oestrogen levels after menopause might play a role in the pathophysiology of ACPA-negative RA.