Document resource
Introduction Each autoantibody associated with systemic sclerosis (SSc) is linked to distinct clinical features, suggesting underlying molecular heterogeneity. While studies have characterized molecular signatures in anti-centromere (ACA), anti-topoisomerase (ATA), and anti-RNA polymerase III antibodies (ARA) positive patients, less frequent autoantibody groups remain unexplored. Our study employed multi-omics analysis to identify shared and unique molecular profiles across SSc-associated autoantibody subgroups.Material and Methods We enrolled 166 SSc patients stratified by antibody status (ACA=55, ATA=58, ARA=24, U1RNP=12, U3RNP=8, Ku=4, Th/To=5). We performed multi-omics profiling including plasma proteomics, peripheral blood mononuclear cells (PBMCs) transcriptomics, immune cell phenotyping, and plasma metabolomics to identify shared and distinct features across groups.Results All SSc subsets demonstrate common pathogenic features including endothelial injury, extracellular matrix deposition identified through plasma proteomics, as well as upregulated type I IFN signaling revealed by transcriptomic and decreased regulatory B cells observed with immune cell profiling. Meanwhile, each autoantibody subgroup exhibits unique disease mechanisms, such as calcinosis in ACA+ patients, metabolic oxidative stress in ATA+ patients, activation of oncogenic signaling in ARA+ patients, enhanced chromatin remodeling activity in U1RNP+ patients, muscle involvement in U3RNP/Ku groups, and unique metabolic signaling related to pulmonary arterial hypertension in Th/To+ cases.Conclusions This study provides the first multi-omics characterization of both common and rare SSc-associated autoantibody groups, revealing shared and distinct molecular signatures that correlate with clinical features. Our findings highlight the potential for autoantibody-based stratification to guide precision management of SSc, paving the way for biomarker-driven approaches in SSc care.Abstract P.038 Figure 1