Sex and reproductive stage modify the effect of endogenous oestrogens on coronary atherosclerosis in rheumatoid arthritis

Objective We explored associations between endogenous oestrogens, coronary atherosclerosis and cardiovascular risk in rheumatoid arthritis (RA). We interrogated whether these relationships varied by sex and menopause and reflected differences in inflammation and lipoprotein functions influencing cell cholesterol homeostasis.Methods CT angiography evaluated atherosclerosis in 140 patients without cardiovascular disease from a single-centre observational cohort. Serum estrone and 17-b-oestradiol were measured with Elisa. Serum cholesterol loading capacity (CLC) on macrophages, which enhances atherosclerosis, was measured in THP-1 monocyte-derived macrophages. High-density lipoprotein cholesterol efflux capacity from macrophages via ATP-binding-cassette-A1 (ABCA1-CEC) and G1 transporters (ABCG1-CEC), which attenuates atherogenesis, was assessed in J774 macrophages and Chinese hamster ovary cells.Results Estrone and estradiol associated with higher coronary artery calcium score (p-for-interaction <= 0.023) and estradiol with more coronary plaques (p-for-interaction=0.048) in males but not females. Estrone was linked to fewer plaques in premenopausal women (p-for-interaction=0.043), while both estrone and estradiol were associated with more plaques in postmenopausal women. Estrone is associated with higher proatherogenic cytokine levels in males and in postmenopausal women, but lower levels in premenopausal women. Moreover, estrone was inversely associated with ABCA1-CEC (p-for-interaction=0.008) and ABCG1-CEC (p-for-interaction=0.040) in males, while estradiol was positively associated with CLC (p-for-interaction=0.044) and inversely with ABCA1-CEC (p-for-interaction=0.010) in males. Estrone, but not estradiol, was inversely associated with cardiovascular risk (adjusted HR 0.43 (95% CI 0.21 to 0.86) per SD increase), particularly among premenopausal women (p-for-interaction=0.015).Conclusion Sex and reproductive status modified the effect of endogenous oestrogens on atherosclerosis in RA and their associations with inflammation and lipoprotein functions impacting on cholesterol homeostasis.