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The disease affects mostly the female sex. In this review, we highlight sex bias in clinical manifestations in SSc, and the pathophysiological changes underlying this bias. Male sex is associated with the diffuse cutaneous form of the disease, digital ulcers, interstitial lung disease, and worse prognosis. These clinical differences can be attributed to sex hormones and sex chromosomes, as females differ from males in sex hormones (estrogens in females, androgens in males) and sex chromosomes (XX in females, XY in males). Estrogens in females generally have immunostimulatory and profibrotic effects, and androgens have immunosuppressive effects. The X-chromosome contains many immunity-related genes, but the double dose of X-linked genes in females is avoided by random inactivation of one X-chromosome (XCI). However, many X-linked immunity-related genes, including toll-like receptor (TLR)7, TLR8 and Bruton\u2019s tyrosine kinase (BTK), escape XCI resulting in a biallelic expression with pathophysiological implications. Also, autosomal genes are differentially expressed between sexes. Therefore, sex should be included in future studies on SSc to aid in forming predictive algorithms and helping therapeutic decisions in this difficult-to-treat disease.<\/jats:p>","DOI":"10.1007\/s12016-025-09062-1","type":"journal-article","created":{"date-parts":[[2025,5,27]],"date-time":"2025-05-27T08:54:28Z","timestamp":1748336068000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["Sex Bias in Systemic Sclerosis: from Clinical to Immunological Differences"],"prefix":"10.1007","volume":"68","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7670-3314","authenticated-orcid":false,"given":"Lazaros I.","family":"Sakkas","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9697-7902","authenticated-orcid":false,"given":"Dimitrios P.","family":"Bogdanos","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8602-0958","authenticated-orcid":false,"given":"Ian C.","family":"Chikanza","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,5,27]]},"reference":[{"issue":"10373","key":"9062_CR1","doi-asserted-by":"publisher","first-page":"304","DOI":"10.1016\/S0140-6736(22)01692-0","volume":"401","author":"ER Volkmann","year":"2023","unstructured":"Volkmann ER, Andr\u00e9asson K, Smith V (2023) Systemic sclerosis. 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