Sex differences in systemic sclerosis: from pathogenesis to clinical manifestations and treatment.

Systemic sclerosis (SSc) exhibits sex-related disparities in prevalence, clinical features, and outcomes. While women are more frequently affected, men often experience a more severe disease course, including diffuse cutaneous involvement, interstitial lung disease, and reduced survival. These differences are shaped by biological factors such as sex hormones and genetic influences. Estrogens and androgens differentially influence immune and fibrotic pathways, while life stages such as menopause further modulate disease expression. Genetic mechanisms, including X chromosome inactivation, regulation of immune-related genes, and cell signaling pathways, vary between sexes and also play an important role in the sex bias seen in SSc. In addition to these biological aspects, gender, as a sociocultural factor involving roles, behaviors, and access to care, may further modify disease perception, healthcare engagement, and outcomes, though it remains underexplored in SSc research. Treatment responses may also vary by sex, as suggested by emerging studies, but sex-specific clinical recommendations are still lacking. This review aims to summarize current knowledge on sex-related differences in SSc and highlight implications for clinical management and future research.