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Review
. 2025 Oct 14:17:1759720X251384602.
doi: 10.1177/1759720X251384602. eCollection 2025.

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

Melpomeni Toitou  1 , Maria Iacovantuono  2   3 , Gesa Sauer  2 , Carina Mihai  2 , Maria Sole Chimenti  3 , Oliver Distler  2 , Cosimo Bruni  2 , Muriel Elhai  2
Affiliations
Review

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

Melpomeni Toitou et al. Ther Adv Musculoskelet Dis. .

Abstract

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.

Keywords: epidemiology; gender; pathogenesis; prognosis; sex; sex differences; systemic sclerosis; treatment response.

Plain language summary

Understanding how sex influences Systemic Sclerosis: From underlying causes to symptoms and treatment Systemic sclerosis (SSc) is a complex autoimmune disease that affects the skin and internal organs. It is more common in women than in men, but men often experience a more severe disease course. This includes greater organ involvement and poorer overall outcomes. Biological factors, such as sex hormones and genetic differences, are thought to play a central role in these disparities. Estrogens and androgens affect immune responses and the development of fibrosis in different ways. Changes in hormone levels across life stages, such as during menopause, can also influence how the disease appears. Genetic mechanisms, including how genes on the X chromosome are expressed, contribute further to the differences seen between men and women. In addition to these biological influences, gender-related factors, such as differences in social roles, health behaviors, and access to care, may also affect how people experience the disease and respond to treatment. However, these aspects are still poorly studied in SSc. This review outlines the current understanding of how sex shapes the development, clinical presentation, and treatment responses in SSc, and emphasizes the need for more personalized approaches in both research and clinical care.

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Conflict of interest statement

M.T., M.I., and G.S.: none; C.M.: Consultancy relationship and/or research funding and/or speaker fees from: Boehringer Ingelheim, Janssen Cilag AG, Medbase, MED Talks Switzerland, Mepha, Medtrix, Novartis, PlayToKnow AG. M.S.C.: none. O.D.: Scleroderma associated Disclosures (2 years backwards, 2023–2025): O.D. has/had consultancy relationship with and/or has received research funding from or has served as a speaker for the following companies in the area of potential treatments for systemic sclerosis and its complications in the last 2 years: 4P-Pharma, Abbvie, Acepodia, Aera, AnaMar, Anaveon AG, Argenx, Avalyn, Boehringer Ingelheim, BMS, Calluna, Cantargia AB, Citus AG, CSL Behring, EMD Serono, Galderma, Galapagos, Hemetron AG, (Innovaderm), Lilly, Mediar, MSD Merck, Nkarta Inc., Novartis, Oorja Bio, Orion, Pilan, Prometheus, Quell, Scleroderma Research Foundation, Topadur, and UCB in the area of potential treatments of scleroderma and its complications. Patent issued “mir-29 for the treatment of systemic sclerosis” (US8247389, EP2331143). Co-founder of CITUS AG. Research Grants: Kymera, Mitsubishi Tanabe, UCB. C.B.: Consultant for Boehringer Ingelheim; Grant/research support from: Gruppo Italiano Lotta alla Sclerodermia (GILS), European Scleroderma Trials and Research Group (EUSTAR), Foundation for research in Rheumatology (FOREUM), Scleroderma Clinical Trials Consortium (SCTC), Scleroderma Research Foundation (SRF), Novartis Foundation for Bio-Medical Research, EMDO Foundation. Educational grants from AbbVie and Wellcome Trust. Congress Support from Boehringer Ingelheim. M.E.: Last 3 years: Grant/research support from Pfizer, Novartis Foundation for Bio-Medical Research, Iten Kohaut foundation, Kurt und Senta Herrmann foundation, Foundation for research in Rheumatology (FOREUM), University Zurich, Walter and Gertrud Siegenthaler Foundation, Theodor und Ida Herzog-Egli – Stiftung and Association des Sclérodermiques de France (ASF). Congress Support from Janssen. Speaker fees from Boehringer Ingelheim.

Figures

Sex bias in systemic sickness.
Figure 1.
Sex bias in systemic sclerosis. Source: Figure created in Biorender. ILD, interstitial lung disease; LVEF, left ventricular ejection fraction.
See this image and copyright information in PMC

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