Early menopause and late menarche may increase risk of rheumatoid arthritis

Some hormonal and reproductive factors are associated with a higher risk of rheumatoid arthritis, according to a large UK Biobank study.

The study, published in RMD Open, found that women who experienced their first occurrence of menstruation (menarche) after the age of 14 were found to have a greater risk of rheumatoid arthritis compared with menarche at 13.

Having more than four children, early menopause, history of hysterectomy and oophorectomy, and the use of HRT were also observed to be associated with a higher risk of rheumatoid arthritis.

Ling-Qiong Jiang et al say the findings indicate that hormonal and reproductive factors should be considered in risk assessment and formulating management plans in female patients with RA.

Data linking reproductive factors with rheumatoid arthritis “inconsistent”

Rheumatoid arthritis (RA) is one of the most common autoimmune rheumatic diseases, however, the study’s authors say available epidemiological data on the role of hormonal and reproductive factors in the pathogenesis of RA are “inconsistent and uncertain”.

To fill this knowledge gap, researchers collected data from 223,526 Biobank participants and analysed whether reproductive factors were associated with RA risk. The hormonal and reproductive factors studied included:

• age at menarche
• pregnancy history
• number of live children
• age at menopause
• reproductive years
• history of hysterectomy and oophorectomy
• contraceptive pill (and duration where applicable)
• HRT (and duration where applicable).

During a media follow up period of around 12 years, 3,313 women with RA were identified. They used restricted cubic spline to analyse the associations and Cox proportional hazard regressions to estimate hazard ratios.

HRT use may increase risk of RA

According to the researchers, women who had their menarche at the age of 14 or older were at increased risk of RA. Having an early period (before the age of 12) was also associated with increased risk, but this associated was weakened after adjusting for confounding factors.

There was also an increased risk of RA for women who had more than four children and for those who had less than 33 reproductive years.

Postmenopausal women and women who had their menopause before the age of 45 years were also found to be an increased risk of RA, while the same was true for women who reported a history of hysterectomy or oophorectomy.

There was no clear evidence that the use of oral contraceptives increased the risk of RA, however, HRT use was associated with an increased risk.

The authors highlight that results of the subgroup analysis indicated that the association between RA and pregnancy was not altered by overweight and obesity in the BMI. These results contradict previous studies that reported a high prevalence of RA in the overweight or obese population.

Healthcare professionals should ‘carefully evaluate’ link between hormonal factors and RA

Ling-Qiong Jiang et al noted some limitations to the study, including that the cohort predominantly comprised of relatively healthy and affluent people of white ethnic background. They say it is therefore unlikely this study will produce reliable estimates of either the prevalence of female reproductive factors or the risk of RA in the UK population at large.

They also note that some of the demographic and clinical information was self-reported, which might be subject to possible measurement error, and that other unadjusted confounders might still exist.

The authors therefore warn that conclusions drawn from this study need to be handled with caution. However, they concluded that healthcare professionals should “carefully evaluate” hormonal and reproductive aspects when diagnosing and managing women with RA.

They said: “The findings of this study are significant and form a basis on which novel and target specific intervention measures to curb the risk of RA in women may be developed. Furthermore, future studies should investigate the involvement of female hormones in the pathophysiology of RA.”