Integrative Analysis Reveals a Molecular Stratification of Systemic Autoimmune Diseases
Authors: Barturen Guillermo , Babaei Sepideh , Català-Moll Francesc , Martínez-Bueno Manuel , Makowska Zuzanna , Martorell-Marugán Jordi , Carmona-Sáez Pedro , Toro-Domínguez Daniel , Carnero-Montoro Elena , Teruel María , Kerick Martin , Acosta-Herrera Marialbert , Lann Lucas Le , Jamin Christophe , Rodríguez-Ubreva Javier , García-Gómez Antonio , Kageyama Jorge , Buttgereit Anne , Hayat Sikander , Mueller Joerg , Lesche Ralf , Hernandez-Fuentes Maria , Juarez Maria , Rowley Tania , White Ian , Marañón Concepción , Anjos Tania Gomes , Varela Nieves , Aguilar-Quesada Rocío , Garrancho Francisco Javier , López-Berrio Antonio , Maresca Manuel Rodriguez , Navarro-Linares Héctor , Almeida Isabel , Azevedo Nancy , Brandão Mariana , Campar Ana , Faria Raquel , Farinha Fátima , Marinho António , Neves Esmeralda , Tavares Ana , Vasconcelos Carlos , Trombetta Elena , Montanelli Gaia , Vigone Barbara , Alvarez-Errico Damiana , Li Tianlu , Alonso Ricardo Blanco , Martínez Alfonso Corrales , Genre Fernanda , López Mejías Raquel , Gonzalez-Gay Miguel A. , Remuzgo Sara , Garcia Begoña Ubilla , Cervera Ricard , Espinosa Gerard , Rodríguez-Pintó Ignasi , De Langhe Ellen , Cremer Jonathan , Lories Rik , Belz Doreen , Hunzelmann Nicolas , Baerlecken Niklas , Kniesch Katja , Witte Torsten , Lehner Michaela , Stummvoll Georg , Zauner Michael , Aguirre-Zamorano Maria Angeles , Barbarroja Nuria , Castro-Villegas Maria Carmen , Collantes-Estevez Eduardo , de Ramon Enrique , Díaz Quintero Isabel , Escudero-Contreras Alejandro , Fernández Roldán María Concepción , Jiménez Gómez Yolanda , Jiménez Moleón Inmaculada , Lopez-Pedrera Rosario , Ortega-Castro Rafaela , Ortego Norberto , Raya Enrique , Artusi Carolina , Gerosa Maria , Meroni Pier Luigi , Schioppo Tommaso , De Groof Aurélie , Ducreux Julie , Lauwerys Bernard , Maudoux Anne-Lise , Cornec Divi , Devauchelle-Pensec Valérie , Jousse-Joulin Sandrine , Jouve Pierre-Emmanuel , Rouvière Bénédicte , Saraux Alain , Simon Quentin , Alvarez Montserrat , Chizzolini Carlo , Dufour Aleksandra , Wynar Donatienne , Balog Attila , Bocskai Márta , Deák Magdolna , Dulic Sonja , Kádár Gabriella , Kovács László , Cheng Qingyu , Gerl Velia , Hiepe Falk , Khodadadi Laleh , Thiel Silvia , de Rinaldis Emanuele , Rao Sambasiva , J.Benschop Robert , Chamberlain Chris , Dow Ernst R. , Ioannou Yiannis , Laigle Laurence , Marovac Jacqueline , Wojcik Jerome , Renaudineau Yves , Borghi Maria Orietta , Frostegård Johan , Martín Javier , Beretta Lorenzo , Ballestar Esteban , McDonald Fiona , Pers Jacques-Olivier , Alarcón-Riquelme Marta E. 
Published: February 2020

Background

Clinical heterogeneity, a hallmark of systemic autoimmune diseases (SADs) impedes early diagnosis and effective treatment, issues that may be addressed if patients could be grouped into a molecular defined stratification.

Methods

With the aim of reclassifying SADs independently of the clinical diagnoses, unsupervised clustering of integrated whole blood transcriptome and methylome cross-sectional data of 918 patients with 7 SADs and 263 healthy controls was undertaken. In addition, an inception cohort was prospectively followed for 6 and 14 months to validate the results and analyze if cluster assignment changed or not with time.

Results

Four clusters were identified. Three clusters were aberrant, representing ‘inflammatory’, ‘lymphoid’, and ‘interferon’ patterns each including all diagnoses and defined by genetic, clinical, serological and cellular features. A fourth cluster showed no specific molecular pattern and accumulated also healthy controls. An independent inception cohort showed that with time, the molecular clusters remain stable, showing that single aberrant molecular signatures characterize each individual patient.

Conclusions

Patients with SADs can be jointly stratified into three 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 therapy non-responsiveness marking a paradigm shift in the view of SADs.