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1. Serum profiling identifies CCL8, CXCL13, and IL-1RA as markers of active disease in patients with systemic lupus erythematosus

Author

Julius Lindblom, Lorenzo Beretta, Maria Orietta Borghi, PRECISESADS Clinical Consortium, Marta E. Alarcón-Riquelme, Ioannis Parodis, Barbara Vigone, Jacques-Olivier Pers, Alain Saraux, Valérie Devauchelle-Pensec, Divi Cornec, Sandrine Jousse-Joulin, Bernard Lauwerys, Julie Ducreux, Anne-Lise Maudoux, Carlos Vasconcelos, Ana Tavares, Esmeralda Neves, Raquel Faria, Mariana Brandão, Ana Campar, António Marinho, Farinha Fátima, Isabel Almeida, Angel Gonzalez-Gay Mantecón, Ricardo Blanco Alonso, Alfonso Corrales Martínez, Ricard Cervera, Ignasi Rodríguez-Pintó, Gerard Espinosa, Rik Lories, Ellen De Langhe, Nicolas Hunzelmann, Doreen Belz, Torsten Witte, Niklas Baerlecken, Georg Stummvoll, Michael Zauner, Michaela Lehner, Eduardo Collantes, Rafaela Ortega-Castro, MaAngeles Aguirre-Zamorano, Alejandro Escudero-Contreras, MaCarmen Castro-Villegas, Norberto Ortego, María Concepción Fernández Roldán, Enrique Raya, Inmaculada Jiménez Moleón, Enrique de Ramon, Isabel Díaz Quintero, Pier Luigi Meroni, Maria Gerosa, Tommaso Schioppo, Carolina Artusi, Carlo Chizzolini, Aleksandra Zuber, Donatienne Wynar, Laszló Kovács, Attila Balog, Magdolna Deák, Márta Bocskai, Sonja Dulic, Gabriella Kádár, Falk Hiepe, Velia Gerl, Silvia Thiel, Manuel Rodriguez Maresca, Antonio López-Berrio, Rocío Aguilar-Quesada, and Héctor Navarro-Linares.

Subjects
autoimmunity, systemic lupus erythematosus, antiphospholipid syndrome, diagnosis, biomarkers, cytokines, Immunologic diseases. Allergy, RC581-607
Abstract

IntroductionSystemic lupus erythematosus (SLE) is a clinically heterogeneous disease that presents a challenge for clinicians. To identify potential biomarkers for diagnosis and disease activity in SLE, we investigated a selected yet broad panel of cytokines and autoantibodies in patients with SLE, healthy controls (HC), and patients with other autoimmune diseases (AIDs).MethodsSerum samples from 422 SLE patients, 546 HC, and 1223 other AIDs were analysed within the frame of the European PRECISESADS project (NTC02890121). Cytokine levels were determined using Luminex panels, and autoantibodies using different immunoassays.ResultsOf the 83 cytokines analysed, 29 differed significantly between patients with SLE and HC. Specifically, CCL8, CXCL13, and IL-1RA levels were elevated in patients with active, but not inactive, SLE versus HC, as well as in patients with SLE versus other AIDs. The levels of these cytokines also correlated with SLE Disease Activity Index 2000 (SLEDAI-2K) scores, among five other cytokines. Overall, the occurrence of autoantibodies was similar across SLEDAI-2K organ domains, and the correlations between autoantibodies and activity in different organ domains were weak.DiscussionOur findings suggest that, upon validation, CCL8, CXCL13, and IL-1RA could serve as promising serum biomarkers of activity in SLE.

Published
2023
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2. Integrative Analysis Reveals a Molecular Stratification of Systemic Autoimmune Diseases

Author

Isabel Almeida, Divi Cornec, Torsten Witte, Tania F. Rowley, Tianlu Li, Elena Carnero-Montoro, Mariana Brandão, Antonio Garcia-Gomez, Nancy Azevedo, Esmeralda Neves, Ana Lisa Taylor Tavares, Ana Campar, Jacques-Olivier Pers, Nicolas Hunzelmann, Ellen De Langhe, Ernst R. Dow, Magdolna Deák, Jorge Kageyama, Francisco Javier Garrancho, Gerard Espinosa, Carlo Chizzolini, Laleh Khodadadi, Falk Hiepe, Maria Angeles Aguirre-Zamorano, Marta E. Alarcón-Riquelme, Rosario Lopez-Pedrera, Anne Buttgereit, Ricard Cervera, Javier Rodríguez-Ubreva, Fernanda Genre, Jerome Wojcik, Begoña Ubilla Garcia, Héctor Navarro-Linares, Maria Orietta Borghi, N.T. Baerlecken, Katja Kniesch, Yolanda Jiménez Gómez, Zuzanna Makowska, Martin Kerick, Elena Trombetta, Pierre-Emmanuel Jouve, Lorenzo Beretta, Ricardo Blanco Alonso, Bénédicte Rouvière, Isabel Díaz Quintero, Michael Zauner, Ralf Lesche, Daniel Toro-Domínguez, Manuel Rodriguez Maresca, Attila Balog, Pier Luigi Meroni, Qingyu Cheng, Georg Stummvoll, Johan Frostegård, Javier Martín, Márta Bocskai, Joerg Mueller, Tommaso Schioppo, Chris Chamberlain, Sonja Dulic, László Kovács, Raquel López Mejías, Velia Gerl, Francesc Català-Moll, Robert J. Benschop, Sara Remuzgo, Carolina Artusi, María Teruel, Eduardo Collantes-Estevez, Miguel A. González-Gay, Silvia Thiel, Bernard Lauwerys, Maria Gerosa, Yves Renaudineau, Pedro Carmona-Sáez, Raquel Faria, Rocío Aguilar-Quesada, Sepideh Babaei, Nuria Barbarroja, Maria Hernandez-Fuentes, María Concepción Fernández Roldán, Sambasiva P. Rao, Aurélie De Groof, Montserrat Alvarez, Anne-Lise Maudoux, Sikander Hayat, Guillermo Barturen, Maria Juarez, Damiana Álvarez-Errico, Alfonso Corrales Martínez, Julie Ducreux, Lucas Le Lann, Norberto Ortego, Jacqueline Marovac, Sandrine Jousse-Joulin, Enrique Raya, Laurence Laigle, Concepción Marañón, Esteban Ballestar, Manuel Martínez-Bueno, Barbara Vigone, Rik Lories, Doreen Belz, Gabriella Kádár, Gaia Montanelli, Fátima Farinha, Divya Thiagaran, M.C. Castro-Villegas, Christophe Jamin, Alain Saraux, Carlos Vasconcelos, Emanuele de Rinaldis, Donatienne Wynar, Enrique de Ramón, Antonio López-Berrio, Tania Anjos, Alejandro Escudero-Contreras, Ian White, Valérie Devauchelle-Pensec, Ignasi Rodríguez-Pintó, Nieves Varela, Quentin Simon, Michaela Lehner, Inmaculada Jiménez Moleón, Aleksandra Maria Dufour, Rafaela Ortega-Castro, Marialbert Acosta-Herrera, Mcdonald Fiona Mcdougall, Yiannis Ioannou, Jonathan Cremer, António Marinho, Jordi Martorell-Marugán, Centre for Genomics and Oncological Research (GENYO) Pfizer, University of Granada, Pharmaceuticals Division Bayer Pharma Aktiengesellschaft, Institut d'Investigació Biomèdica de Bellvitge (IDIBELL), University of Barcelona, Centro de Genomica e Investigacion Oncologica (GENYO), Department of Bioinformatics, Center for Genomics and Oncological Research (GENYO), Granada, Spain, Institute of Parasitology and Biomedicine (IPB - GRANADA), Spanish National Research Council (CSIC), LabEX IGO Immunothérapie Grand Ouest, Lymphocyte B et Auto-immunité (LBAI), Université de Brest (UBO)-Institut Brestois Santé Agro Matière (IBSAM), Université de Brest (UBO)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut d'Investigació Biomèdica de Bellvitge [Barcelone] (IDIBELL), UCB Pharma, Slough SL1 3WE, United Kingdom, Centre for Genomics and Oncological Reearch (GENYO), Andalusian Public Health System Biobank, Granada, Spain, Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP), Universidade do Porto, Servico de Immunologica EX-CICAP, Servico de Imunologica EX-CICAP, Unidade de Imunologia Clínica, Centro Hospitalar do Porto, Portugal, Istituto Clinico Humanitas [Milan] (IRCCS Milan), Humanitas University [Milan] (Hunimed), Scleroderma Unit, Referral Center for Systemic Autoimmune Diseases, Fondazione IRCCS Istituto Nazionale Tumori - National Cancer Institute [Milan], Bellvitge Biomedical Research Institute IDIBELL [Barcelona, Spain], Karolinska Institutet [Stockholm], Universidad de Cantabria [Santander], Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Universitat de Barcelona (UB), Catholic University of Leuven - Katholieke Universiteit Leuven (KU Leuven), Klinikum Leverkusen Teaching Hospital of the University of Cologne, Hannover Medical School [Hannover] (MHH), Medical University of Vienna, Vienna, Austria, Medical University of Vienna, General Hospital of Vienna, Hospital Reina Sofía, Hospital Regional Universitario de Málaga [Spain], Hospital Universitario San Cecilio, Hospital Universitario Virgen de las Nieves, Università degli Studi di Milano [Milano] (UNIMI), Université Catholique de Louvain = Catholic University of Louvain (UCL), AltraBio [Lyon], Geneva University Hospital (HUG), University of Szeged [Szeged], Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], Sanofi [Cambridge, MA, USA], Sanofi Genzyme, Eli Lilly, Indianapolis, USA, UCB Celltech [Slough, UK], Institut de Recherches Internationales Servier [Suresnes] (IRIS), Quartzbio, Geneva, Instituto de Parasitología y Biomedicina 'López-Neyra', Fondazione IRCCS Ca’ Granda – Ospedale Maggiore Policlinico [Milan, Italy], Bellvitge Institute for Biomedical Research, Bayer HealthCare, Berlin, Centre for Genomics and Oncological Research Pfizer [Granada, Spain], University of Granada [Granada]-Andalusian Regional Government [Granada, Spain], Michel, Geneviève, Universidad de Granada = University of Granada (UGR), Nantes Université (Nantes Univ), Lymphocytes B, Autoimmunité et Immunothérapies (LBAI), Université de Brest (UBO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-LabEX IGO Immunothérapie Grand Ouest, Nantes Université (Nantes Univ)-Nantes Université (Nantes Univ)-Institut Brestois Santé Agro Matière (IBSAM), Université de Brest (UBO), Universidade do Porto = University of Porto, University of Cologne, Hospital Regional Universitario de Málaga = Regional University Hospital of Malaga [Spain], Università degli Studi di Milano = University of Milan (UNIMI), Universidad de Granada = University of Granada (UGR)-Andalusian Regional Government [Granada, Spain], UCL - SSS/IREC/RUMA - Pôle de Pathologies rhumatismales, and UCL - (SLuc) Service de rhumatologie

Subjects
0301 basic medicine, Adult, Epigenomics, Male, [SDV.IMM] Life Sciences [q-bio]/Immunology, Cross-sectional study, Immunology, Arthritis, Bioinformatics, Scleroderma, Autoimmune Diseases, Transcriptome, Arthritis, Rheumatoid, 03 medical and health sciences, Epigenome, 0302 clinical medicine, Rheumatology, medicine, Immunology and Allergy, Cluster Analysis, Humans, Lupus Erythematosus, Systemic, Undifferentiated Connective Tissue Diseases, Aged, Mixed Connective Tissue Disease, 030203 arthritis & rheumatology, Inflammation, Science & Technology, Lupus erythematosus, Scleroderma, Systemic, business.industry, Gene Expression Profiling, Case-control study, Middle Aged, medicine.disease, Antiphospholipid Syndrome, 3. Good health, Clinical trial, Gene expression profiling, 030104 developmental biology, Cross-Sectional Studies, Sjogren's Syndrome, Case-Control Studies, [SDV.IMM]Life Sciences [q-bio]/Immunology, Female, Interferons, business, Life Sciences & Biomedicine
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. ispartof: ARTHRITIS & RHEUMATOLOGY vol:73 issue:6 pages:1073-1085 ispartof: location:United States status: published

Published
2021
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3. O31 Integrative analysis reveals a molecular stratification of systemic autoimmune diseases

Author

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

Subjects
Oncology, medicine.medical_specialty, Disease clusters, business.industry, Disease progression, INCEPTION COHORT, Internal medicine, T cell immunity, medicine, Effective treatment, Christian ministry, Medical diagnosis, business, Unsupervised clustering
Abstract

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. An inception cohort prospectively followed for 6 and 14 months was studied to validate the results in early cases and analyze if cluster assignment was modified with time. Results Four clusters were identified Three aberrant clusters were ‘acute phase inflammatory’, ‘T cell immunity’, and ‘interferon’, each including all diagnoses, were defined by genetic, clinical, serological and cellular features. A fourth cluster showed no specific molecular pattern, to which 74% of healthy controls clustered with patients. The inception cohort showed that most patients were either assigned always to the same cluster or moved from the healthy-like cluster to a single aberrant cluster resembling the relapsing-remitting dynamic of these diseases, showing that single aberrant molecular signatures characterize each individual patient. Conclusions Patients with SADs share molecular signatures and can be therefore stratified into three disease clusters differentiating each patient into a specific molecular disease pathway. Such assignment is stable with time. These results have important implications for understanding disease progression and therapy design marking a paradigm shift in our view of SADs. Acknowledgment This work has been supported through a grant from the Innovative Medicines Initiative Joint Undertaking No. 115565 and in-kind and in-cash contributions from the EFPIA partners. G.B. is supported by the Instituto de Salud Carlos III (ISCIII, Spanish Health Ministry), through the Sara Borrell subprogram (CD18/00153). The authors would like to particularly express their gratitude to the patients, nurses and many others who helped directly or indirectly in the consecution of this study.

Published
2020
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4. Integrative Analysis Reveals a Molecular Stratification of Systemic Autoimmune Diseases

Author

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

Subjects
Oncology, medicine.medical_specialty, business.industry, Molecular Disease, INCEPTION COHORT, Clinical trial, Transcriptome, Internal medicine, Clinical heterogeneity, Medicine, Effective treatment, Medical diagnosis, business, Unsupervised clustering
Abstract

SUMMARYBackgroundClinical 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.MethodsWith 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.ResultsFour 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.ConclusionsPatients 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.

Published
2020
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