A novel stratification framework based on vascular-fibrotic complications identifies distinct risk endotypes in...

Systemic sclerosis (SSc) is highly heterogeneous, and the traditional skin-based classification inadequately guides organ-specific management or predicts prognosis.

To develop and validate a novel stratification framework based on dominant vascular and fibrotic complications to identify distinct risk endotypes.

This retrospective cohort study included 281 SSc patients categorized at baseline into 4 subgroups: Vascular-dominant, Fibrotic-dominant, Mixed (both), and Limited (neither). Clinical, serological, and immunophenotypic data were compared. Longitudinal progression was analyzed using Kaplan-Meier and Cox regression.

Four distinct endotypes were identified. The Mixed subgroup (n = 47) was characterized by cytopenias, Th17/Treg imbalance, elevated IL-6, and specific autoantibodies. It demonstrated the shortest median progression-free survival (36 months) and the highest independent risk of disease progression (adjusted hazard ratio = 3.194, 95% confidence interval: 1.219-8.369). Biomarker combinations showed moderate predictive value for subgroup identification.

This single-center study has a moderate sample size, an incomplete biomarker panel, and a relatively short follow-up duration, which may limit generalizability and comprehensive progression assessment.

We establish a novel complication-based framework that identifies a high-risk. Mixed vascular-fibrotic endotype, providing a pragmatic tool for early risk stratification and personalized management in SSc.