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

Yu Fan; Miaotong Su; Lijun Yu; Shaoqi Chen; Kedi Zheng; Jianqun Lin; Qisheng Lin; Weijin Zhang; Shaoyu Zheng; Zexuan Zhou; Shaohui Zhang; Xiaohan Yuan; Marco Matucci-Cerinic; Daniel E Furst; Guohong Zhang; Yukai Wang

doi:10.1016/j.ard.2026.05.008

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

Ann Rheum Dis. 2026 May 30:S0003-4967(26)00285-2. doi: 10.1016/j.ard.2026.05.008. Online ahead of print.

Authors

Affiliations

¹ Department of Pathology, Shantou University Medical College, Shantou, Guangdong, China.
² Department of Ultrasound, the First Affiliated Hospital of Shantou University Medical College, Shantou, Guangdong, China.
³ Department of Rheumatology and Immunology, Shantou Central Hospital, Shantou, Guangdong, China.
⁴ Unit of Immunology, Rheumatology, Allergy and Rare Diseases (UnIRAR), IRCCS (Istituto di Ricovero e Cura a Carattere Scientifico) San Raffaele Hospital, Milan, Italy; Vita Salute San Raffaele University, Milan, Italy.
⁵ Division of Rheumatology, Department of Medicine, University of California at Los Angeles, Los Angeles, CA, USA; University of Washington, Seattle, WA, USA; Department of Experimental and Clinical Medicine, Division of Rheumatology, Careggi University Hospital, University of Florence, Florence, Italy.
⁶ Department of Pathology, Shantou University Medical College, Shantou, Guangdong, China. Electronic address: g_ghzhang@stu.edu.cn.
⁷ Department of Rheumatology and Immunology, Shantou Central Hospital, Shantou, Guangdong, China. Electronic address: stzxyywyk@126.com.

PMID: 42218077
DOI: 10.1016/j.ard.2026.05.008

Abstract

Objectives: 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.

Methods: 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.

Results: 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.

Conclusions: 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.