IL-6 but Not TNFα Levels Are Associated With Time to Pregnancy in Female Rheumatoid Arthritis Patients With a Wish to Conceive

Fertility issues are common amongst women with rheumatoid arthritis (RA). Interleukin 6 (IL-6) and tumor necrosis factor alpha (TNF alpha), known key players in RA pathogenesis, have been associated with reproductive disorders. This study investigates the role of these cytokines in decreased fertility in women with active RA. Preconception cytokine measurements of 61 patients from the PARA-cohort, a prospective study on RA and pregnancy, were studied in relation to time to pregnancy as a measure for fertility. IL-6 levels were higher in patients with a time to pregnancy longer than 1 year (p = 0.016). Survival analysis of patients stratified by high or low serum IL-6 levels, shows a prolonged time to pregnancy in the high IL-6 group (p = 0.045). Univariate cox regression analysis of IL-6 in relation to time to pregnancy as well as multivariate cox regression analysis correcting for age, disease activity, nulliparity, NSAID use and prednisone use were performed, with hazards ratios for log transformed IL-6 of 0.68 (95% CI: 0.51-0.93, p = 0.015) and 0.66 (95% CI: 0.43-0.99, p = 0.044), respectively. For TNF alpha, no association with time to pregnancy was found. This study shows that high IL-6, but not TNF alpha, is associated with decreased fertility in women with RA. This finding provides a rationale to therapeutically target the IL-6 pathway in the time period before pregnancy. More research in the form of large cohort studies on drug safety and the effect of bDMARDS on fertility is needed for implementation of treatment strategies directed at fertility issues in women with RA.