Integrative Analysis Reveals a Molecular Stratification of Systemic Autoimmune Diseases
Authors: 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 Mueller, Ralf 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, Tianlu Li, Divya Thiagaran, Ricardo Blanco Alonso, Alfonso Corrales Martínez, Fernanda Genre, Raquel López Mejías, Miguel A. Gonzalez‐Gay, Sara Remuzgo, Begoña Ubilla Garcia, Ricard Cervera, Gerard Espinosa, Ignasi Rodríguez‐Pintó, Ellen De Langhe, Jonathan Cremer, Rik Lories, Doreen Belz, Nicolas Hunzelmann, Niklas Baerlecken, Katja Kniesch, Torsten Witte, Michaela Lehner, Georg Stummvoll, Michael Zauner, Maria Angeles Aguirre‐Zamorano, Nuria Barbarroja, Maria Carmen Castro‐Villegas, Eduardo Collantes‐Estevez, Enrique de Ramon, Isabel Díaz Quintero, Alejandro Escudero‐Contreras, María Concepción Fernández Roldán, Yolanda Jiménez Gómez, Inmaculada Jiménez Moleón, Rosario Lopez‐Pedrera, Rafaela Ortega‐Castro, Norberto Ortego, Enrique Raya, Carolina Artusi, Maria Gerosa, Pier Luigi Meroni, Tommaso Schioppo, Aurélie De Groof, Julie Ducreux, Bernard Lauwerys, Anne‐Lise Maudoux, Divi Cornec, Valérie Devauchelle‐Pensec, Sandrine Jousse‐Joulin, Pierre‐Emmanuel Jouve, Bénédicte Rouvière, Alain Saraux, Quentin Simon, Montserrat Alvarez, Carlo Chizzolini, Aleksandra Dufour, Donatienne Wynar, Attila Balog, Márta Bocskai, Magdolna Deák, Sonja Dulic, Gabriella Kádár, László Kovács, Qingyu Cheng, Velia Gerl, Falk Hiepe, Laleh Khodadadi, Silvia Thiel, Emanuele de Rinaldis, Sambasiva Rao, Robert J. Benschop, Chris Chamberlain, Ernst R. Dow, Yiannis Ioannou, Laurence Laigle, Jacqueline Marovac, Jerome Wojcik, Yves Renaudineau, Maria Orietta Borghi, Johan Frostegård, Javier Martín, Lorenzo Beretta, Esteban Ballestar, Fiona McDonald, Jacques‐Olivier Pers, Marta E. Alarcón‐Riquelme
Journal: Arthritis & Rheumatology (2020)

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.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.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.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.