1. Integrative Analysis Reveals a Molecular Stratification of Systemic Autoimmune Diseases.
- Author
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Barturen G, Babaei S, Català-Moll F, Martínez-Bueno M, Makowska Z, Martorell-Marugán J, Carmona-Sáez P, Toro-Domínguez D, Carnero-Montoro E, Teruel M, Kerick M, Acosta-Herrera M, Le Lann L, Jamin C, Rodríguez-Ubreva J, García-Gómez A, Kageyama J, Buttgereit A, Hayat S, Mueller J, Lesche R, Hernandez-Fuentes M, Juarez M, Rowley T, White I, Marañón C, Gomes Anjos T, Varela N, Aguilar-Quesada R, Garrancho FJ, López-Berrio A, Rodriguez Maresca M, Navarro-Linares H, Almeida I, Azevedo N, Brandão M, Campar A, Faria R, Farinha F, Marinho A, Neves E, Tavares A, Vasconcelos C, Trombetta E, Montanelli G, Vigone B, Alvarez-Errico D, Li T, Thiagaran D, Blanco Alonso R, Corrales Martínez A, Genre F, López Mejías R, Gonzalez-Gay MA, Remuzgo S, Ubilla Garcia B, Cervera R, Espinosa G, Rodríguez-Pintó I, De Langhe E, Cremer J, Lories R, Belz D, Hunzelmann N, Baerlecken N, Kniesch K, Witte T, Lehner M, Stummvoll G, Zauner M, Aguirre-Zamorano MA, Barbarroja N, Castro-Villegas MC, Collantes-Estevez E, de Ramon E, Díaz Quintero I, Escudero-Contreras A, Fernández Roldán MC, Jiménez Gómez Y, Jiménez Moleón I, Lopez-Pedrera R, Ortega-Castro R, Ortego N, Raya E, Artusi C, Gerosa M, Meroni PL, Schioppo T, De Groof A, Ducreux J, Lauwerys B, Maudoux AL, Cornec D, Devauchelle-Pensec V, Jousse-Joulin S, Jouve PE, Rouvière B, Saraux A, Simon Q, Alvarez M, Chizzolini C, Dufour A, Wynar D, Balog A, Bocskai M, Deák M, Dulic S, Kádár G, Kovács L, Cheng Q, Gerl V, Hiepe F, Khodadadi L, Thiel S, de Rinaldis E, Rao S, Benschop RJ, Chamberlain C, Dow ER, Ioannou Y, Laigle L, Marovac J, Wojcik J, Renaudineau Y, Borghi MO, Frostegård J, Martín J, Beretta L, Ballestar E, McDonald F, Pers JO, and Alarcón-Riquelme ME
- Subjects
- Adult, Aged, Antiphospholipid Syndrome genetics, Antiphospholipid Syndrome immunology, Arthritis, Rheumatoid genetics, Arthritis, Rheumatoid immunology, Autoimmune Diseases immunology, Case-Control Studies, Cluster Analysis, Cross-Sectional Studies, Epigenomics, Female, Humans, Inflammation immunology, Interferons immunology, Lupus Erythematosus, Systemic genetics, Lupus Erythematosus, Systemic immunology, Male, Middle Aged, Mixed Connective Tissue Disease genetics, Mixed Connective Tissue Disease immunology, Scleroderma, Systemic genetics, Scleroderma, Systemic immunology, Sjogren's Syndrome genetics, Sjogren's Syndrome immunology, Undifferentiated Connective Tissue Diseases genetics, Undifferentiated Connective Tissue Diseases immunology, Autoimmune Diseases classification, Autoimmune Diseases genetics, Epigenome, Gene Expression Profiling
- Abstract
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., (© 2020, American College of Rheumatology.)
- Published
- 2021
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