1. Clinicogenomic factors of biotherapy immunogenicity in autoimmune disease: A prospective multicohort study of the ABIRISK consortium
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Caroline Trang, Salima Hacein-Bey Abina, Malin Ryner, Florian Deisenhammer, Manuel Comabella, Abiba Doukani, Philippe Broët, Anna Fogdell-Hahn, Julianne Duhaze, Hans-Peter Hartung, Clemens Warnke, Natacha Szely, Delphine Bachelet, Alessandra Vultaggio, Bernd C. Kieseier, Sebastian Spindeldreher, Olivier Brocq, Poul Erik Hyldgaard-Jensen, Michael Auer, Marc Pallardy, Matthieu Allez, Mary Birchler, Tom W J Huizinga, Yehuda Chowers, Yoram Bouhnik, Dorothea Buck-Martin, Elizabeth C. Jury, Amy Loercher, Dan Sikkema, Aude Gleizes, Tobias Derfuss, Jessica J Manson, Guillaume Cadiot, Claudia Sievers, Michael Khalil, Naoimh Donnellan, Raija L.P. Lindberg, Agnès Hincelin Mery, Badreddine Mohand Oumoussa, Enrico Maggi, Martin Soubrier, Kathleen Ingenhoven, Orhan Aktas, Sophie Tourdot, Xavier Montalban, Maria Nachury, Niek de Vries, Timothy P. Hickling, Christophe Richez, Bernhard Hemmer, Franck Carbonnel, Finn Sellebjerg, Jérôme Avouac, Petra Nytrova, Xavier Mariette, Anna Lauren, Signe Hässler, Pierre Dönnes, Eva Havrdova, Michael Guger, Claudia Mauri, BRUNEL, Nadège, Centre de recherche en épidémiologie et santé des populations (CESP), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Immunologie - Immunopathologie - Immunothérapie [CHU Pitié Salpêtrière] (I3), CHU Charles Foix [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Institut de médecine et d'épidémiologie appliquée [AP-HP Hôpital Bichat-Claude Bernard] (IMEA), AP-HP - Hôpital Bichat - Claude Bernard [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), CHU Sainte Justine [Montréal], Université Paris-Saclay, AP-HP Hôpital Bicêtre (Le Kremlin-Bicêtre), Unité de Technologies Chimiques et Biologiques pour la Santé (UTCBS - UM 4 (UMR 8258 / U1022)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Heinrich Heine Universität Düsseldorf = Heinrich Heine University [Düsseldorf], Innsbruck Medical University = Medizinische Universität Innsbruck (IMU), Université Paris Cité - UFR Médecine [Santé] (UPCité UFR Médecine), Université Paris Cité (UPCité), GlaxoSmithKline, Glaxo Smith Kline, Hôpital Beaujon, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Hôpital Princesse Grace [Monaco], Technische Universität Munchen - Université Technique de Munich [Munich, Allemagne] (TUM), Hôpital universitaire Robert Debré [Reims], University of Haifa [Haifa], Universitat Autònoma de Barcelona (UAB), University Hospital Basel [Basel], VU University Medical Center [Amsterdam], Royal Berkshire Hospital, Plateforme Post-génomique de la Pitié-Salpêtrière (PASS-P3S), Unité Mixte de Service Production et Analyse de données en Sciences de la vie et en Santé (PASS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Kepler University Hospital, University Hospital Düsseldorf, Charles University [Prague] (CU), Leiden University Medical Center (LUMC), Rigshospitalet [Copenhagen], Copenhagen University Hospital, University College of London [London] (UCL), Karl-Franzens-Universität Graz, Malmö Högskola = Malmö University, University of Basel (Unibas), Università degli Studi di Firenze = University of Florence (UniFI), University College London Hospitals (UCLH), Service des Maladies de l'Appareil Digestif et de la Nutrition [CHRU Lille], Hôpital Claude Huriez [Lille], CHU Lille-CHU Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), CHU de Bordeaux Pellegrin [Bordeaux], Karolinska Institutet [Stockholm], CHU Clermont-Ferrand, Université de Florence, Fachhochschule Köln, University of Skövde [Sweden], Pfizer, SANOFI Recherche, Hopital Saint-Louis [AP-HP] (AP-HP), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut de Chimie du CNRS (INC)-Université de Paris (UP)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), University of Dusseldorf, Innsbruck Medical University [Austria] (IMU), Université de Paris - UFR Médecine Paris Centre [Santé] (UP Médecine Paris Centre), Université de Paris (UP), Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Karl-Franzens-Universität [Graz, Autriche], Malmø University, Università degli Studi di Firenze = University of Florence [Firenze] (UNIFI), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), University of Graz, AII - Inflammatory diseases, and Clinical Immunology and Rheumatology
- Subjects
Male ,Physiology ,[SDV]Life Sciences [q-bio] ,Single Nucleotide Polymorphisms ,Autoimmune Diseases/drug therapy ,Biological Therapy/methods ,Arthritis ,030204 cardiovascular system & hematology ,Biochemistry ,Inflammatory bowel disease ,Etanercept ,Arthritis, Rheumatoid ,Cohort Studies ,chemistry.chemical_compound ,Medical Conditions ,0302 clinical medicine ,Crohn Disease ,Antibiotics ,Immune Physiology ,Medicine and Health Sciences ,Prospective Studies ,030212 general & internal medicine ,ComputingMilieux_MISCELLANEOUS ,Immune System Proteins ,Antimicrobials ,Drugs ,Neurodegenerative Diseases ,General Medicine ,Middle Aged ,3. Good health ,[SDV] Life Sciences [q-bio] ,Biological Therapy ,Antibodies, Monoclonal, Humanized/therapeutic use ,Neurology ,Arthritis, Rheumatoid/drug therapy ,Rheumatoid arthritis ,Genome-Wide Association Study/methods ,Medicine ,[SDV.IMM]Life Sciences [q-bio]/Immunology ,Female ,Rituximab ,Immunosuppressive Agents ,Interferon beta-1a ,Research Article ,medicine.drug ,Adult ,Multiple Sclerosis ,[SDV.IMM] Life Sciences [q-bio]/Immunology ,Immunology ,Rheumatoid Arthritis ,Gastroenterology and Hepatology ,Antibodies, Monoclonal, Humanized ,Microbiology ,Antibodies ,HLA-DQ alpha-Chains ,Autoimmune Diseases ,03 medical and health sciences ,Tocilizumab ,Rheumatology ,Adalimumab/therapeutic use ,Microbial Control ,HLA-DQ alpha-Chains/genetics ,Rituximab/therapeutic use ,Genetics ,medicine ,Adalimumab ,Humans ,Antigens ,Biological Products/immunology ,Pharmacology ,Biological Products ,Interferon beta-1a/therapeutic use ,business.industry ,Inflammatory Bowel Disease ,Biology and Life Sciences ,Proteins ,medicine.disease ,Demyelinating Disorders ,Infliximab ,Minor allele frequency ,Infliximab/therapeutic use ,chemistry ,Crohn Disease/drug therapy ,Immunosuppressive Agents/therapeutic use ,Multiple Sclerosis/drug therapy ,Clinical Immunology ,Colitis, Ulcerative ,Clinical Medicine ,Colitis, Ulcerative/drug therapy ,business ,Genome-Wide Association Study - Abstract
Background Biopharmaceutical products (BPs) are widely used to treat autoimmune diseases, but immunogenicity limits their efficacy for an important proportion of patients. Our knowledge of patient-related factors influencing the occurrence of antidrug antibodies (ADAs) is still limited. Methods and findings The European consortium ABIRISK (Anti-Biopharmaceutical Immunization: prediction and analysis of clinical relevance to minimize the RISK) conducted a clinical and genomic multicohort prospective study of 560 patients with multiple sclerosis (MS, n = 147), rheumatoid arthritis (RA, n = 229), Crohn’s disease (n = 148), or ulcerative colitis (n = 36) treated with 8 different biopharmaceuticals (etanercept, n = 84; infliximab, n = 101; adalimumab, n = 153; interferon [IFN]-beta-1a intramuscularly [IM], n = 38; IFN-beta-1a subcutaneously [SC], n = 68; IFN-beta-1b SC, n = 41; rituximab, n = 31; tocilizumab, n = 44) and followed during the first 12 months of therapy for time to ADA development. From the bioclinical data collected, we explored the relationships between patient-related factors and the occurrence of ADAs. Both baseline and time-dependent factors such as concomitant medications were analyzed using Cox proportional hazard regression models. Mean age and disease duration were 35.1 and 0.85 years, respectively, for MS; 54.2 and 3.17 years for RA; and 36.9 and 3.69 years for inflammatory bowel diseases (IBDs). In a multivariate Cox regression model including each of the clinical and genetic factors mentioned hereafter, among the clinical factors, immunosuppressants (adjusted hazard ratio [aHR] = 0.408 [95% confidence interval (CI) 0.253–0.657], p < 0.001) and antibiotics (aHR = 0.121 [0.0437–0.333], p < 0.0001) were independently negatively associated with time to ADA development, whereas infections during the study (aHR = 2.757 [1.616–4.704], p < 0.001) and tobacco smoking (aHR = 2.150 [1.319–3.503], p < 0.01) were positively associated. 351,824 Single-Nucleotide Polymorphisms (SNPs) and 38 imputed Human Leukocyte Antigen (HLA) alleles were analyzed through a genome-wide association study. We found that the HLA-DQA1*05 allele significantly increased the rate of immunogenicity (aHR = 3.9 [1.923–5.976], p < 0.0001 for the homozygotes). Among the 6 genetic variants selected at a 20% false discovery rate (FDR) threshold, the minor allele of rs10508884, which is situated in an intron of the CXCL12 gene, increased the rate of immunogenicity (aHR = 3.804 [2.139–6.764], p < 1 × 10−5 for patients homozygous for the minor allele) and was chosen for validation through a CXCL12 protein enzyme-linked immunosorbent assay (ELISA) on patient serum at baseline before therapy start. CXCL12 protein levels were higher for patients homozygous for the minor allele carrying higher ADA risk (mean: 2,693 pg/ml) than for the other genotypes (mean: 2,317 pg/ml; p = 0.014), and patients with CXCL12 levels above the median in serum were more prone to develop ADAs (aHR = 2.329 [1.106–4.90], p = 0.026). A limitation of the study is the lack of replication; therefore, other studies are required to confirm our findings. Conclusion In our study, we found that immunosuppressants and antibiotics were associated with decreased risk of ADA development, whereas tobacco smoking and infections during the study were associated with increased risk. We found that the HLA-DQA1*05 allele was associated with an increased rate of immunogenicity. Moreover, our results suggest a relationship between CXCL12 production and ADA development independent of the disease, which is consistent with its known function in affinity maturation of antibodies and plasma cell survival. Our findings may help physicians in the management of patients receiving biotherapies., In a multicohort prospective study of patients from 12 countries, Signe Hässler and colleagues investigate clinical and genetic factors associated with development of anti-biopharmaceutical drug antibodies in patients with autoimmune diseases., Author summary Why was this study done? Biopharmaceutical products such as monoclonal antibodies are widely used to treat autoimmune diseases. Biopharmaceutical products may induce the development of antidrug antibodies, which often lead to therapy failure. Patient-related factors that influence the development of antidrug antibodies need to be characterized. What did the researchers do and find? We set up a European multicohort prospective study on 4 autoimmune diseases (multiple sclerosis, rheumatoid arthritis, Crohn’s disease, and ulcerative colitis) treated with 8 different biopharmaceutical products. We collected demographic and clinical data and tested antidrug antibodies in longitudinal serum samples from 560 patients. For 457 patients who gave consent, we also collected genetic data. We identified antibiotics and immunosuppressants as negatively associated risk factors and heavy smoking, infections during the study, the HLA-DQA1*05 allele and a minor variant in the CXCL12 chemokine gene associated with increased protein expression as risk factors of antidrug antibody development. What do these findings mean? Our findings suggest that the combination of immunosuppressant and biopharmaceutical therapy could be associated with decreased risk of antidrug antibody occurrence, which has implications for rheumatoid arthritis and inflammatory bowel diseases, for which immunosuppressants are often, but not always, given together with biopharmaceuticals. Patients heterozygotes or homozygotes for the HLA-DQA1*05 allele may have an increased risk of antidrug antibody occurrence associated with biopharmaceutical therapy. The small study size warrants a validation through independent studies, in particular for the genetic findings.
- Published
- 2020
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