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O31 Integrative analysis reveals a molecular stratification of systemic autoimmune diseases
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  1. Guillermo Barturen1,
  2. Sepideh Babaei2,
  3. Francesc Català-Moll3,
  4. Manuel Martínez-Bueno1,
  5. Zuzanna Makowska2,
  6. Jordi Martorell-Marugán4,
  7. Pedro Carmona-Sáez4,
  8. Daniel Toro-Domínguez1,
  9. Elena Carnero-Montoro1,
  10. Martin Kerick5,
  11. Marialbert Acosta-Herrera5,
  12. Lucas Le Lann6,
  13. Christophe Jamin6,
  14. Javier Rodríguez-Ubreva3,
  15. Antonio García-Gómez3,
  16. Jorge Kageyama2,
  17. Anne Buttgereit2,
  18. Sikander Hayat2,
  19. Joerg Mueller2,
  20. Ralf Lesche2,
  21. Maria Hernandez-Fuentes7,
  22. Maria Juarez7,
  23. Tania Rowley7,
  24. Ian White7,
  25. Concepción Marañón1,
  26. Tania Gomes Anjos1,
  27. Nieves Varela1,
  28. Rocío Aguilar-Quesada8,
  29. Francisco Javier Garrancho8,
  30. Antonio López-Berrio8,
  31. Manuel Rodriguez Maresca8,
  32. Héctor Navarro-Linares8,
  33. Isabel Almeida9,
  34. Nancy Azevedo10,
  35. Mariana Brandão9,
  36. Ana Campar9,
  37. Raquel Faria9,
  38. Fátima Farinha9,
  39. António Marinho9,
  40. Esmeralda Neves10,
  41. Ana Tavares9,
  42. Carlos Vasconcelos9,
  43. Elena Trombetta11,
  44. Gaia Montanelli12,
  45. Barbara Vigone12,
  46. Damiana Alvarez-Errico3,
  47. Tianlu Li3,
  48. Ricardo Blanco Alonso13,
  49. Alfonso Corrales Martínez13,
  50. Fernanda Genre13,
  51. Raquel López Mejías13,
  52. Miguel A Gonzalez-Gay13,
  53. Sara Remuzgo13,
  54. Begoña Ubilla Garcia13,
  55. Ricard Cervera14,
  56. Gerard Espinosa14,
  57. Ignasi Rodríguez-Pintó14,
  58. Ellen De Langhe15,
  59. Jonathan Cremer15,
  60. Rik Lories15,
  61. Doreen Belz16,
  62. Nicolas Hunzelmann16,
  63. Niklas Baerlecken17,
  64. Katja Kniesch17,
  65. Torsten Witte17,
  66. Michaela Lehner18,
  67. Georg Stummvoll18,
  68. Michael Zauner18,
  69. Maria Angeles Aguirre-Zamorano19,
  70. Nuria Barbarroja19,
  71. Maria Carmen Castro-Villegas19,
  72. Eduardo Collantes-Estevez19,
  73. Enrique de Ramon20,
  74. Isabel Díaz Quintero20,
  75. Alejandro Escudero-Contreras19,
  76. María Concepción Fernández Roldán21,
  77. Yolanda Jiménez Gómez19,
  78. Inmaculada Jiménez Moleón22,
  79. Rosario Lopez-Pedrera19,
  80. Rafaela Ortega-Castro19,
  81. Norberto Ortego21,
  82. Enrique Raya22,
  83. Carolina Artusi23,
  84. Maria Gerosa23,
  85. Pier Luigi Meroni23,
  86. Tommaso Schioppo23,
  87. Aurélie De Groof24,
  88. Julie Ducreux24,
  89. Bernard Lauwerys24,
  90. Anne-Lise Maudoux24,
  91. Divi Cornec6,
  92. Valérie Devauchelle-Pensec6,
  93. Sandrine Jousse-Joulin6,
  94. Pierre-Emmanuel Jouve25,
  95. Bénédicte Rouvière6,
  96. Alain Saraux6,
  97. Quentin Simon6,
  98. Montserrat Alvarez26,
  99. Carlo Chizzolini26,
  100. Aleksandra Dufour26,
  101. Donatienne Wynar26,
  102. Attila Balog27,
  103. Márta Bocskai27,
  104. Magdolna Deák27,
  105. Sonja Dulic27,
  106. Gabriella Kádár27,
  107. László Kovács27,
  108. Qingyu Cheng28,
  109. Velia Gerl28,
  110. Falk Hiepe28,
  111. Laleh Khodadadi28,
  112. Silvia Thiel28,
  113. Emanuele de Rinaldis29,
  114. Sambasiva Rao30,
  115. Robert J Benschop31,
  116. Chris Chamberlain7,
  117. Ernst R Dow31,
  118. Yiannis Ioannou7,
  119. Laurence Laigle32,
  120. Jacqueline Marovac7,
  121. Jerome Wojcik33,
  122. Yves Renaudineau6,
  123. Maria Orietta Borghi23,34,
  124. Johan Frostegård35,
  125. Javier Martín5,
  126. Lorenzo Beretta12,
  127. Esteban Ballestar3,
  128. Fiona McDonald2,
  129. Jacques-Olivier Pers6 and
  130. Marta E Alarcón-Riquelme1,35
  1. 1Dept. of Medical Genomics, Center for Genomics and Oncological Research (GENYO), Granada, Spain
  2. 2Pharmaceuticals Division, Bayer Pharma Aktiengesellschaft, Berlin, Germany
  3. 3Cancer Epigenetics and Biology Program, Bellvitge Biomedical Research Institute (IDIBELL), Barcelona
  4. 4Dept. of Bioinformatics, Center for Genomics and Oncological Research (GENYO), Granada
  5. 5Institute of Parasitology and Biomedicine López Neyra, Spanish National Research Council, Granada, Spain
  6. 6Université de Brest, INSERM, Labex IGO, CHU de Brest, Brest, France
  7. 7UCB Pharma, Slough, UK
  8. 8Andalusian Public Health System Biobank, Granada, Spain
  9. 9Unidade de Imunologia Clínica, Centro Hospitalar do Porto
  10. 10Serviço de Imunologia EX-CICAP, Centro Hospitalar e Universitário do Porto, Porto, Portugal
  11. 11Laboratorio di Analisi Chimico Cliniche e Microbiologia – Servizio di Citofluorimetria, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico di Milano, Milano, Italy
  12. 12Scleroderma Unit, Referral Center for Systemic Autoimmune Diseases, Fondazione IRCCS Ca’Granda Ospedale Maggiore Policlinico di Milano, Milan, Italy
  13. 13Servicio Cántabro de Salud, Hospital Universitario Marqués de Valdecilla, IDIVAL, Santander
  14. 14Hospital Clinic, Institut d’Investigacions Biomèdiques August Pi i Sunyer, Barcelona, Spain
  15. 15Skeletal Biology and Engineering Research Center, KU Leuven and Division of Rheumatology, UZ Leuven, Leuven, Belgium
  16. 16Klinikum der Universitaet zu Koeln, Cologne
  17. 17Klinik für Immunologie und Rheumatologie, Medical University Hannover, Hannover, Germany
  18. 18Medical University Vienna, Vienna, Austria
  19. 19Rheumatology Service, Reina Sofia Hospital, Maimonides Institute for Research in Biomedicine of Cordoba (IMIBIC), University of Cordoba, Cordoba
  20. 20Servicio Andaluz de Salud, Hospital Regional Universitario de Málaga
  21. 21Servicio Andaluz de Salud, Complejo Hospitalario Universitario de Granada (Hospital Universitario San Cecilio)
  22. 22Servicio Andaluz de Salud, Complejo Hospitalario Universitario de Granada (Hospital Virgen de las Nieves), Granada, Spain
  23. 23Università degli studi di Milano, Milan
  24. 24Pôle de Pathologies Rhumatismales Inflammatoires et Systémiques, Institut de Recherche Expérimentale et Clinique, Université Catholique de Louvain, Brussels, Belgium
  25. 25AltraBio SAS, Lyon, France
  26. 26Immunology and Allergy, University Hospital and School of Medicine, Geneva, Switzerland
  27. 27University of Szeged, Szeged, Hungary
  28. 28Dept. of Rheumatology and Clinical Immunology, Charité University Hospital, Berlin, Germany
  29. 29Precision Immunology Cluster, Sanofi, Cambridge
  30. 30Sanofi Genzyme, Framingham
  31. 31Eli Lilly and Company, Indianapolis, USA
  32. 32Institut de Recherches Internationales Servier, Suresnes, France
  33. 33QuartzBIO, SA, Geneva, Switzerland
  34. 34Istituto Auxologico Italiano, Milan, Italy
  35. 35Unit for Chronic Inflammatory Diseases, Institute for Environmental Medicine, Karolinska Institutet, Stockholm, Sweden

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.

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.

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