Integrative Analysis Reveals a Molecular Stratification of Systemic Autoimmune Diseases

Guillermo Barturen, Sepideh Babaei, Francesc Català-Moll, Manuel Martínez-Bueno, Zuzanna Makowska, Jordi Martorell-Marugán, Pedro Carmona-Sáez, Daniel Toro-Domínguez, Elena Carnero-Montoro, María Teruel, Martin Kerick, Marialbert Acosta-Herrera, Lucas Le Lann, Christophe Jamin, Javier Rodríguez-Ubreva, Antonio García-Gómez, Jorge Kageyama, Anne Buttgereit, Sikander Hayat, Joerg MuellerRalf Lesche, Maria Hernandez-Fuentes, Maria Juarez, Tania Rowley, Ian White, Concepción Marañón, Tania Gomes Anjos, Nieves Varela, Rocío Aguilar-Quesada, Francisco Javier Garrancho, Antonio López-Berrio, Manuel Rodriguez Maresca, Héctor Navarro-Linares, Isabel Almeida, Nancy Azevedo, Mariana Brandão, Ana Campar, Raquel Faria, Fátima Farinha, António Marinho, Esmeralda Neves, Ana Tavares, Carlos Vasconcelos, Elena Trombetta, Gaia Montanelli, Barbara Vigone, Damiana Alvarez-Errico, Pier Luigi Meroni, Maria Orietta Borghi, Lorenzo Beretta

Research output: Contribution to journalArticlepeer-review


Objective: Clinical heterogeneity, a hallmark of systemic autoimmune diseases, impedes early diagnosis and effective treatment, issues that may be addressed if patients could be classified into groups defined by molecular pattern. This study was undertaken to identify molecular clusters for reclassifying systemic autoimmune diseases independently of clinical diagnosis. Methods: Unsupervised clustering of integrated whole blood transcriptome and methylome cross-sectional data on 955 patients with 7 systemic autoimmune diseases and 267 healthy controls was undertaken. In addition, an inception cohort was prospectively followed up for 6 or 14 months to validate the results and analyze whether or not cluster assignment changed over time. Results: Four clusters were identified and validated. Three were pathologic, representing “inflammatory,” “lymphoid,” and “interferon” patterns. Each included all diagnoses and was defined by genetic, clinical, serologic, and cellular features. A fourth cluster with no specific molecular pattern was associated with low disease activity and included healthy controls. A longitudinal and independent inception cohort showed a relapse–remission pattern, where patients remained in their pathologic cluster, moving only to the healthy one, thus showing that the molecular clusters remained stable over time and that single pathogenic molecular signatures characterized each individual patient. Conclusion: Patients with systemic autoimmune diseases can be jointly stratified into 3 stable disease clusters with specific molecular patterns differentiating different molecular disease mechanisms. These results have important implications for future clinical trials and the study of nonresponse to therapy, marking a paradigm shift in our view of systemic autoimmune diseases.

Original languageEnglish
Pages (from-to)1073-1085
Number of pages13
JournalArthritis and Rheumatology
Issue number6
Publication statusPublished - Jun 2021

ASJC Scopus subject areas

  • Immunology and Allergy
  • Rheumatology
  • Immunology


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