Sex-dependent mechanisms in rheumatic diseases

Sex differences in the prevalence, clinical phenotypes and therapeutic responses of rheumatic diseases have been recognized for decades, but the underlying mechanisms remain largely unknown. Accumulating evidence highlights the critical roles of both immune and non-immune cells in disease pathogenesis and the influence of sex hormones on cellular function. In addition, factors such as sex chromosomes, hormonal regulation, antiviral immune response, the gut microbiome and genetic and epigenetic variation probably contribute to the divergent features of rheumatic diseases between women and men. A deeper understanding of these intersecting pathways might uncover novel therapeutic targets. Thus far, treatment strategies for rheumatic diseases largely focus on immunomodulation; however, elucidating the biological basis of sex differences could enable the development of preventative therapies that target hormonal pathways and the gut microbiome, with the potential to avert both the onset and progression of these debilitating diseases to improve health for all patients.