Barturen, Guillermo ORCID: 0000-0003-2103-1028, Babaei, Sepideh, Catala-Moll, Francesc, Martinez-Bueno, Manuel, Makowska, Zuzanna, Martorell-Marugan, Jordi ORCID: 0000-0002-5186-0735, Carmona-Saez, Pedro ORCID: 0000-0002-6173-7255, Toro-Dominguez, Daniel, Carnero-Montoro, Elena ORCID: 0000-0002-1947-9627, Teruel, Maria, Kerick, Martin ORCID: 0000-0002-6298-4514, Acosta-Herrera, Marialbert, Le Lann, Lucas, Jamin, Christophe, Rodriguez-Ubreva, Javier, Garcia-Gomez, Antonio, Kageyama, Jorge, Buttgereit, Anne, Hayat, Sikander ORCID: 0000-0001-5919-8371, Mueller, Joerg, Lesche, Ralf, Hernandez-Fuentes, Maria, Juarez, Maria, Rowley, Tania, White, Ian, Maranon, Concepcion, Gomes Anjos, Tania, Varela, Nieves, Aguilar-Quesada, Rocio, Garrancho, Francisco Javier, Lopez-Berrio, Antonio, Rodriguez Maresca, Manuel, Navarro-Linares, Hector, Almeida, Isabel, Azevedo, Nancy, Brandao, Mariana, Campar, Ana, Faria, Raquel ORCID: 0000-0002-2956-1966, Farinha, Fatima, Marinho, Antonio, Neves, Esmeralda ORCID: 0000-0002-7754-8109, Tavares, Ana, Vasconcelos, Carlos ORCID: 0000-0002-8073-5028, Trombetta, Elena ORCID: 0000-0002-1933-6415, Montanelli, Gaia, Vigone, Barbara, Alvarez-Errico, Damiana, Li, Tianlu ORCID: 0000-0001-7152-4870, Thiagaran, Divya, Blanco Alonso, Ricardo, Corrales Martinez, Alfonso, Genre, Fernanda, Lopez Mejias, Raquel, Gonzalez-Gay, Miguel A., Remuzgo, Sara, Ubilla Garcia, Begona, Cervera, Ricard, Espinosa, Gerard ORCID: 0000-0003-1336-0163, Rodriguez-Pinto, Ignasi ORCID: 0000-0001-6193-6396, De Langhe, Ellen, Cremer, Jonathan, Lories, Rik ORCID: 0000-0002-5986-3092, Belz, Doreen, Hunzelmann, Nicolas, Baerlecken, Niklas, Kniesch, Katja, Witte, Torsten, Lehner, Michaela, Stummvoll, Georg, Zauner, Michael, Aguirre-Zamorano, Maria Angeles, Barbarroja, Nuria ORCID: 0000-0002-0962-6072, Castro-Villegas, Maria Carmen, Collantes-Estevez, Eduardo, de Ramon, Enrique, Diaz Quintero, Isabel, Escudero-Contreras, Alejandro, Fernandez Roldan, Maria Concepcion, Jimenez Gomez, Yolanda, Jimenez Moleon, Inmaculada, Lopez-Pedrera, Rosario, Ortega-Castro, Rafaela, Ortego, Norberto, Raya, Enrique, Artusi, Carolina, Gerosa, Maria, Meroni, Pier Luigi, Schioppo, Tommaso, De Groof, Aurelie, Ducreux, Julie, Lauwerys, Bernard, Maudoux, Anne-Lise, Cornec, Divi, Devauchelle-Pensec, Valerie, Jousse-Joulin, Sandrine, Jouve, Pierre-Emmanuel, Rouviere, Benedicte, Saraux, Alain, Simon, Quentin ORCID: 0000-0002-2383-2809, Alvarez, Montserrat, Chizzolini, Carlo, Dufour, Aleksandra, Wynar, Donatienne, Balog, Attila, Bocskai, Marta, Deak, Magdolna, Dulic, Sonja, Kadar, Gabriella, Kovacs, Laszlo, Cheng, Qingyu, Gerl, Velia, Hiepe, Falk ORCID: 0000-0003-3584-5292, Khodadadi, Laleh, Thiel, Silvia, de Rinaldis, Emanuele, Rao, Sambasiva, Benschop, Robert J., Chamberlain, Chris, Dow, Ernst R., Ioannou, Yiannis, Laigle, Laurence, Marovac, Jacqueline, Wojcik, Jerome, Renaudineau, Yves ORCID: 0000-0001-5098-5002, Borghi, Maria Orietta, Frostegard, Johan, Martin, Javier ORCID: 0000-0002-2202-0622, Beretta, Lorenzo, Ballestar, Esteban, McDonald, Fiona, Pers, Jacques-Olivier and Alarcon-Riquelme, Marta E. (2021). Integrative Analysis Reveals a Molecular Stratification of Systemic Autoimmune Diseases. Arthritis Rheumatol., 73 (6). S. 1073 - 1086. HOBOKEN: WILEY. ISSN 2326-5205

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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.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Barturen, GuillermoUNSPECIFIEDorcid.org/0000-0003-2103-1028UNSPECIFIED
Babaei, SepidehUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Catala-Moll, FrancescUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Martinez-Bueno, ManuelUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Makowska, ZuzannaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Martorell-Marugan, JordiUNSPECIFIEDorcid.org/0000-0002-5186-0735UNSPECIFIED
Carmona-Saez, PedroUNSPECIFIEDorcid.org/0000-0002-6173-7255UNSPECIFIED
Toro-Dominguez, DanielUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Carnero-Montoro, ElenaUNSPECIFIEDorcid.org/0000-0002-1947-9627UNSPECIFIED
Teruel, MariaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kerick, MartinUNSPECIFIEDorcid.org/0000-0002-6298-4514UNSPECIFIED
Acosta-Herrera, MarialbertUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Le Lann, LucasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Jamin, ChristopheUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Rodriguez-Ubreva, JavierUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Garcia-Gomez, AntonioUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kageyama, JorgeUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Buttgereit, AnneUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hayat, SikanderUNSPECIFIEDorcid.org/0000-0001-5919-8371UNSPECIFIED
Mueller, JoergUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lesche, RalfUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hernandez-Fuentes, MariaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Juarez, MariaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Rowley, TaniaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
White, IanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Maranon, ConcepcionUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Gomes Anjos, TaniaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Varela, NievesUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Aguilar-Quesada, RocioUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Garrancho, Francisco JavierUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lopez-Berrio, AntonioUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Rodriguez Maresca, ManuelUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Navarro-Linares, HectorUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Almeida, IsabelUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Azevedo, NancyUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Brandao, MarianaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Campar, AnaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Faria, RaquelUNSPECIFIEDorcid.org/0000-0002-2956-1966UNSPECIFIED
Farinha, FatimaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Marinho, AntonioUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Neves, EsmeraldaUNSPECIFIEDorcid.org/0000-0002-7754-8109UNSPECIFIED
Tavares, AnaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Vasconcelos, CarlosUNSPECIFIEDorcid.org/0000-0002-8073-5028UNSPECIFIED
Trombetta, ElenaUNSPECIFIEDorcid.org/0000-0002-1933-6415UNSPECIFIED
Montanelli, GaiaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Vigone, BarbaraUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Alvarez-Errico, DamianaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Li, TianluUNSPECIFIEDorcid.org/0000-0001-7152-4870UNSPECIFIED
Thiagaran, DivyaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Blanco Alonso, RicardoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Corrales Martinez, AlfonsoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Genre, FernandaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lopez Mejias, RaquelUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Gonzalez-Gay, Miguel A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Remuzgo, SaraUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ubilla Garcia, BegonaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Cervera, RicardUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Espinosa, GerardUNSPECIFIEDorcid.org/0000-0003-1336-0163UNSPECIFIED
Rodriguez-Pinto, IgnasiUNSPECIFIEDorcid.org/0000-0001-6193-6396UNSPECIFIED
De Langhe, EllenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Cremer, JonathanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lories, RikUNSPECIFIEDorcid.org/0000-0002-5986-3092UNSPECIFIED
Belz, DoreenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hunzelmann, NicolasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Baerlecken, NiklasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kniesch, KatjaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Witte, TorstenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lehner, MichaelaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Stummvoll, GeorgUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Zauner, MichaelUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Aguirre-Zamorano, Maria AngelesUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Barbarroja, NuriaUNSPECIFIEDorcid.org/0000-0002-0962-6072UNSPECIFIED
Castro-Villegas, Maria CarmenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Collantes-Estevez, EduardoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
de Ramon, EnriqueUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Diaz Quintero, IsabelUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Escudero-Contreras, AlejandroUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Fernandez Roldan, Maria ConcepcionUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Jimenez Gomez, YolandaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Jimenez Moleon, InmaculadaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lopez-Pedrera, RosarioUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ortega-Castro, RafaelaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ortego, NorbertoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Raya, EnriqueUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Artusi, CarolinaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Gerosa, MariaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Meroni, Pier LuigiUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schioppo, TommasoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
De Groof, AurelieUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ducreux, JulieUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lauwerys, BernardUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Maudoux, Anne-LiseUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Cornec, DiviUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Devauchelle-Pensec, ValerieUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Jousse-Joulin, SandrineUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Jouve, Pierre-EmmanuelUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Rouviere, BenedicteUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Saraux, AlainUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Simon, QuentinUNSPECIFIEDorcid.org/0000-0002-2383-2809UNSPECIFIED
Alvarez, MontserratUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Chizzolini, CarloUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Dufour, AleksandraUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wynar, DonatienneUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Balog, AttilaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bocskai, MartaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Deak, MagdolnaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Dulic, SonjaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kadar, GabriellaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kovacs, LaszloUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Cheng, QingyuUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Gerl, VeliaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hiepe, FalkUNSPECIFIEDorcid.org/0000-0003-3584-5292UNSPECIFIED
Khodadadi, LalehUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Thiel, SilviaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
de Rinaldis, EmanueleUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Rao, SambasivaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Benschop, Robert J.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Chamberlain, ChrisUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Dow, Ernst R.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ioannou, YiannisUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Laigle, LaurenceUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Marovac, JacquelineUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wojcik, JeromeUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Renaudineau, YvesUNSPECIFIEDorcid.org/0000-0001-5098-5002UNSPECIFIED
Borghi, Maria OriettaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Frostegard, JohanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Martin, JavierUNSPECIFIEDorcid.org/0000-0002-2202-0622UNSPECIFIED
Beretta, LorenzoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ballestar, EstebanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
McDonald, FionaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Pers, Jacques-OlivierUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Alarcon-Riquelme, Marta E.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-607601
DOI: 10.1002/art.41610
Journal or Publication Title: Arthritis Rheumatol.
Volume: 73
Number: 6
Page Range: S. 1073 - 1086
Date: 2021
Publisher: WILEY
Place of Publication: HOBOKEN
ISSN: 2326-5205
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
CONNECTIVE-TISSUE DISEASE; RHEUMATIC-DISEASE; I INTERFERON; CLASSIFICATION; HETEROGENEITY; SIGNATURES; PROFILESMultiple languages
RheumatologyMultiple languages
URI: http://kups.ub.uni-koeln.de/id/eprint/60760

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