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

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.