Integrated transcriptomic and epigenomic profiling reveals conserved molecular subtypes across systemic autoimmune diseases.

Rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), and primary Sjögren's syndrome (pSS) frequently share overlapping clinical features, yet exhibit substantial intradisease heterogeneity in organ involvement and severity. This study aimed to define conserved molecular subtypes across these systemic autoimmune diseases (SADs) and delineate their transcriptional and epigenetic underpinnings. We profiled 262 treatment-naïve Chinese Han patients (RA: n = 109; SLE: n = 69; pSS: n = 84), predominantly female (83.2%), who were divided into discovery (n = 119) and validation (n = 143) cohorts. Bulk RNA sequencing defined molecular subtypes, which were correlated with clinical phenotypes. Chromatin accessibility and super-enhancer landscapes were mapped by Assay for Transposase-Accessible Chromatin with high-throughput sequencing and cleavage under targets and tagmentation, and single-cell RNA sequencing (scRNA-seq) was performed to delineate subtype-specific cellular compositions. Integrative analyses uncovered 2 robust and reproducible molecular subtypes, megakaryocyte-enriched and B-cell-enriched, which were consistent across all 3 SADs and both cohorts. The megakaryocyte-enriched subtype was associated with higher platelet counts, greater disease activity, and broader organ involvement. Epigenomic profiling identified distinct chromatin accessibility and regulatory architectures, with megakaryocyte-associated genes (eg, ZFP36L1 and RAD51B) linked to active superenhancers in the megakaryocyte-enriched subtype, and B-cell-associated genes (eg, MAF and PRDM1) in the B-cell-enriched subtype. scRNA-seq confirmed expansion of platelet-producing megakaryocytes and enhanced B-cell-activation signatures in their respective subtypes. Integrative multiomics profiling defines 2 conserved molecular subtypes across RA, SLE, and pSS with distinct cellular and regulatory programmes. This cross-disease taxonomy may inform precision stratification and the development of lineage-targeted therapies in SADs. Further multicentre validation and investigation of the epigenetic mechanisms underlying molecular subtypes are warranted.