Biological sex and disease architecture in systemic sclerosis: a multilayer translational framework for precision...

Biological sex is routinely incorporated into systemic sclerosis (SSc) research as a demographic or stratification variable. Women are substantially more likely to develop SSc, whereas men experience a greater burden of severe organ involvement and adverse outcomes. Whether these observations represent parallel sex-associated differences or reflect differences in the relationships among disease components remains unresolved. Here, we propose the Systemic Sclerosis-Multilayer Architecture Framework (SSc-MAF) as a hypothesis-generating framework for addressing this distinction. We define a sex-dependent architectural difference not as an isolated difference in a molecule, cell population, pathway, or clinical phenotype, but as a reproducible sex-associated difference in relationships among disease components, including multicellular communication, fibrovascular coupling, spatial tissue organization, molecular co-activation, or longitudinal clinical-biological trajectories. SSc-MAF therefore distinguishes clinical disease trajectories from the biological architecture that may generate them and from the methodological strategies required for empirical validation. We critically evaluate current evidence across immune, fibrovascular, metabolic, and regulatory domains, while distinguishing direct sex-stratified SSc evidence from indirect mechanistic evidence and framework-level hypotheses. We further outline measurable predictions and conditions that would weaken or fail to support individual propositions of SSc-MAF. This framework is intended not to establish sex-dependent disease architecture as a proven feature of SSc, but to provide an operational strategy for testing whether biological sex contributes information beyond conventional component-level comparisons and additive covariate adjustment.