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.

AP HP Hôpital Beaujon Paris France

AP HP Hôpital Pitié Salpêtrière Biotherapy Paris France

AP HP Paris Sud University Hospitals Paul Brousse Hospital Villejuif France

BioMedicine Design Pfizer Inc Andover Massachusetts United States of America

Center for Multiple Sclerosis St Michael's Hospital University of Toronto Toronto Canada

Centre for Immunology of Viral Infections and Autoimmune Diseases INSERM UMR 1184 Université Paris Saclay AP HP Université Paris Saclay Le Kremlin Bicêtre France

Centre for Rheumatology Research University College London London United Kingdom

CESP INSERM UMR 1018 Faculty of Medicine Paris Sud University UVSQ Paris Saclay University Villejuif France

CHU Ste Justine Research Center Montreal Canada

Clinic for Neurology 2 Med Campus 3 Kepler University Hospital GmbH Linz Austria

Clinical Immunology Laboratory AP HP Le Kremlin Bicêtre Hospital Paris Sud University Hospitals Le Kremlin Bicêtre France

Current address Quanterix Corporation Billerica Massachusetts United States of America

Danish Multiple Sclerosis Center Department of Neurology Rigshospitalet University of Copenhagen Copenhagen Denmark

Department of Biostatistical Epidemiology and Clinical Research Hôpital Bichat Assistance Publique Hôpitaux de Paris AP HP Nord INSERM CIC EC 1425 Paris France

Department of Clinical Neuroscience Karolinska Institutet Stockholm Sweden

Department of Gastroenterology AP HP Hôpital Kremlin Bicêtre France

Department of Gastroenterology Hôpital Saint Louis AP HP Université Paris Diderot Paris France

Department of Gastroenterology Rambam Health Care Campus Haifa Israel; Bruce Rappaport School of Medicine Technion Israel Institute of Technology Haifa Israel; Clinical Research Institute Rambam Health Care Campus Haifa Israel

Department of Neurology and Center of Clinical Neuroscience 1st Faculty of Medicine Charles University and General University Hospital Prague Czech Republic

Department of Neurology Medical University of Graz Austria

Department of Neurology Technische Universität München Munich Germany

Department of Neurology University Hospital Köln Köln Germany

Department of Rheumatology Leiden University Medical Center Leiden the Netherlands

Department of Rheumatology University College London Hospital London United Kingdom

Departments of Biomedicine and Neurology University Hospital Basel and University of Basel Basel Switzerland

Dipartimento di Medicina Sperimentale e Clínica Università di Firenze Firenze Italy

Drug Metabolism Pharmacokinetics Biologics Novartis Institutes for Biomedical Research Basel Switzerland

GETAID Paris France

GlaxoSmithKline Clinical Immunology Biopharm Collegeville Pennsylvania United States of America

Immunology Area of Bambino Gesù Pediatric Hospital IRCCS Rome Italy

Innsbruck Medical University Department of Neurology Innsbruck Austria

INSERM UMR 996 Faculty of Pharmacy Paris Sud University Paris Saclay University Châtenay Malabry France

Institut des maladies de l'Appareil Digestif University Hospital of Nantes Nantes France

Integrated Biologix GmbH Basel Switzerland

Ipsen Biopharm Ltd Berkshire United Kingdom

Munich Cluster for Systems Neurology Munich Germany

Paris University Paris Descartes University INSERM U1016 Paris France

Princess Grace Hospital Rheumatology Monaco

Rheumatology and Clinical Immunology Amsterdam UMC | AMC University of Amsterdam Amsterdam the Netherlands

Rheumatology Department CHU de Bordeaux GH Pellegrin Bordeaux France

Rheumatology department Cochin Hospital AP HP CUP Paris France

Rheumatology University Hospital of Clermont Ferrand Clermont Ferrand France

Sanofi Chilly Mazarin France

SciCross AB Skövde Sweden

Servei de Neurologia Neuroimmunologia Centre d'Esclerosi Múltiple de Catalunya Hospital Universitari Vall d'Hebron Universitat Autònoma de Barcelona Barcelona Spain

Service d'hépato gastroentérologie University Hospital of Reims Reims France

Sorbonne Université INSERM UMR 959 Immunology Immunopathology Immunotherapy Paris France

Sorbonne Université Inserm UMS Production et Analyse des données en Sciences de la vie et en Santé UMS 37 PASS Plateforme Post génomique de la Pitié Salpêtrière P3S Paris France

Svar Life Science Malmö Sweden

UMR CNRS 5164 Bordeaux University Bordeaux France

University hospital of Lille Maladies de l'appareil digestif Lille France

University of Düsseldorf Medical Faculty Department of Neurology Düsseldorf Germany

UTCBS CNRS UMR 8258 INSERM U1022 Faculty of Pharmacy Paris Descartes Sorbonne Cite University Paris France

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