Occurrence of Anti-Drug Antibodies against Interferon-Beta and Natalizumab in Multiple Sclerosis: A Collaborative Cohort Analysis.
Immunogenicity of biopharmaceutical products in multiple sclerosis is a frequent side effect which has a multifactorial etiology. Here we study associations between anti-drug antibody (ADA) occurrence and demographic and clinical factors. Retrospective data from routine ADA test laboratories in Sweden, Denmark, Austria and Germany (Dusseldorf group) and from one research study in Germany (Munich group) were gathered to build a collaborative multi-cohort dataset within the framework of the ABIRISK project. A subset of 5638 interferon-beta (IFNβ)-treated and 3440 natalizumab-treated patients having data on at least the first two years of treatment were eligible for interval-censored time-to-event analysis. In multivariate Cox regression, IFNβ-1a subcutaneous and IFNβ-1b subcutaneous treated patients were at higher risk of ADA occurrence compared to IFNβ-1a intramuscular-treated patients (pooled HR = 6.4, 95% CI 4.9-8.4 and pooled HR = 8.7, 95% CI 6.6-11.4 respectively). Patients older than 50 years at start of IFNβ therapy developed ADA more frequently than adult patients younger than 30 (pooled HR = 1.8, 95% CI 1.4-2.3). Men developed ADA more frequently than women (pooled HR = 1.3, 95% CI 1.1-1.6). Interestingly we observed that in Sweden and Germany, patients who started IFNβ in April were at higher risk of developing ADA (HR = 1.6, 95% CI 1.1-2.4 and HR = 2.4, 95% CI 1.5-3.9 respectively). This result is not confirmed in the other cohorts and warrants further investigations. Concerning natalizumab, patients older than 45 years had a higher ADA rate (pooled HR = 1.4, 95% CI 1.0-1.8) and women developed ADA more frequently than men (pooled HR = 1.4, 95% CI 1.0-2.0). We confirmed previously reported differences in immunogenicity of the different types of IFNβ. Differences in ADA occurrence by sex and age are reported here for the first time. These findings should be further investigated taking into account other exposures and biomarkers.
CESP, Université Pa ris-Sud, UVSQ, INSERM, Université Paris-Saclay, Villejuif, France.
Delphine
D
Bachelet
CESP, Université Pa ris-Sud, UVSQ, INSERM, Université Paris-Saclay, Villejuif, France.
Signe
http://orcid.org/0000-0003-4263-3079
S
Hässler
CESP, Université Pa ris-Sud, UVSQ, INSERM, Université Paris-Saclay, Villejuif, France.
Cyprien
C
Mbogning
Karolinska Institutet, Department of Clinical Neuroscience, Clinical Neuroimmunology, Stockholm, Sweden.
Jenny
J
Link
Karolinska Institutet, Department of Clinical Neuroscience, Clinical Neuroimmunology, Stockholm, Sweden.
Malin
M
Ryner
Karolinska Institutet, Department of Clinical Neuroscience, Clinical Neuroimmunology, Stockholm, Sweden.|KTH-Royal Institute of Technology, Stockholm, Sweden.
Ryan
R
Ramanujam
Department of Neurology, Innsbruck Medical University, Innsbruck, Austria.
Michael
M
Auer
Danish MS Center, Department of Neurology, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark.
Poul Erik
PE
Hyldgaard Jensen
Danish Multiple Sclerosis Registry, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark.|Department of Clinical Epidemiology, University of Aarhus, Aarhus, Denmark.
Nils
N
Koch-Henriksen
University of Düsseldorf, Medical Faculty, Department of Neurology, Düsseldorf, Germany.
Clemens
C
Warnke
University of Düsseldorf, Medical Faculty, Department of Neurology, Düsseldorf, Germany.
Kathleen
K
Ingenhoven
Department of Neurology, Technische Universität München, Munich, Germany.
Dorothea
D
Buck
Department of Neurology, Technische Universität München, Munich, Germany.
Verena
V
Grummel
GlaxoSmithKline, Uxbridge, Middlesex, United Kingdom.
Andy
A
Lawton
IPSEN, Slough, Berkshire, United Kingdom.
Naoimh
N
Donnellan
Sanofi, Chilly-Mazarin, France.
Agnès
A
Hincelin-Mery
GlaxoSmithKline, Uxbridge, Middlesex, United Kingdom.
Dan
D
Sikkema
INSERM UMR 996, Univ. Paris-Sud, Faculty of Pharmacy, Université Paris-Saclay, Châtenay-Malabry, France.
Marc
M
Pallardy
University of Düsseldorf, Medical Faculty, Department of Neurology, Düsseldorf, Germany.
Bernd
B
Kieseier
Department of Neurology, Technische Universität München, Munich, Germany.|Munich Cluster for Systems Neurology (SyNergy), Munich, Germany.
Bernard
B
Hemmer
University of Düsseldorf, Medical Faculty, Department of Neurology, Düsseldorf, Germany.
Hans Peter
HP
Hartung
Danish MS Center, Department of Neurology, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark.
Per
P
Soelberg Sorensen
Department of Neurology, Innsbruck Medical University, Innsbruck, Austria.
Florian
F
Deisenhammer
SciCross AB, Skövde, Sweden.
Pierre
P
Dönnes
GlaxoSmithKline, Uxbridge, Middlesex, United Kingdom.
Julie
J
Davidson
Karolinska Institutet, Department of Clinical Neuroscience, Clinical Neuroimmunology, Stockholm, Sweden.
Anna
A
Fogdell-Hahn
CESP, Université Pa ris-Sud, UVSQ, INSERM, Université Paris-Saclay, Villejuif, France.|Assistance Publique-Hôpitaux de Paris, Hôpital Paul Brousse, Villejuif, France.
Philippe
P
Broët
D000328:Adult; D000368:Aged; D000906:Antibodies / Q000097:blood / Q000276:immunology*; D000888:Antibodies, Anti-Idiotypic / Q000097:blood / Q000276:immunology*; D015331:Cohort Studies; D016208:Databases, Factual; D005060:Europe / Q000453:epidemiology; D005260:Female; D006801:Humans; D016899:Interferon-beta / Q000009:adverse effects* / Q000276:immunology* / Q000627:therapeutic use; D008297:Male; D008875:Middle Aged; D009103:Multiple Sclerosis / Q000150:complications* / Q000188:drug therapy / Q000453:epidemiology / Q000401:mortality; D000069442:Natalizumab / Q000009:adverse effects* / Q000276:immunology* / Q000627:therapeutic use; D063868:Patient Outcome Assessment; D011159:Population Surveillance; D016016:Proportional Hazards Models; D012307:Risk Factors
D000906:Antibodies; D000888:Antibodies, Anti-Idiotypic; D000069442:Natalizumab; D016899:Interferon-beta