Towards precision medicine: Systemic Sclerosis research in light of sex- differences

Systemic sclerosis (SSc) is a chronic autoimmune disease that primarily affects connective tissues, leading to fibrosis, vascular abnormalities, and autoimmune response in many organs. Interestingly, SSc exhibits a higher prevalence in females than men, however affected males often present a more severe phenotype. This gender-based difference in disease manifestation suggests the potential influence of sex-related factors not only in SSc development and progression. Our aim is to study this sexual dimorphism in disease manifestation and identify the role of sex hormones in SSc. Using Fra-2 transgenic mouse model; an established model for SSc studies, we conducted a comprehensive investigation into the role of sex hormones on disease phenotype and performed castration experiments. Our results show that ovariectomy did not exacerbate the disease in females, while orchiectomy worsened the phenotype in males. Further experimentation involved testosterone replacement in castrated mice, resulting in a notable amelioration of the phenotype in males. This improvement was evidenced by enhanced lung function, reduced fibrosis, reduce immune infiltration and a more favourable vascular phenotype in the lungs. However, testosterone replacement showed no significant phenotypic improvement in females. These findings suggest a potential role of testosterone levels in disease severity in male Fra-2 mice, highlighting the importance of sex hormones in SSc pathology. It also paves the way for further investigations into hormonal levels in SSc patients and potentially personalised hormonal therapies in some patients, with the ultimate goal of improving the outcome of the disease. GK and BV have contributed equally