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PLoS One. 2016 Nov 2;11(11):e0162752. doi: 10.1371/journal.pone.0162752. eCollection 2016.

Occurrence of Anti-Drug Antibodies against Interferon-Beta and Natalizumab in Multiple Sclerosis: A Collaborative Cohort Analysis.

Author information

CESP, Université Pa ris-Sud, UVSQ, INSERM, Université Paris-Saclay, Villejuif, France.
Karolinska Institutet, Department of Clinical Neuroscience, Clinical Neuroimmunology, Stockholm, Sweden.
KTH-Royal Institute of Technology, Stockholm, Sweden.
Department of Neurology, Innsbruck Medical University, Innsbruck, Austria.
Danish MS Center, Department of Neurology, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark.
Danish Multiple Sclerosis Registry, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark.
Department of Clinical Epidemiology, University of Aarhus, Aarhus, Denmark.
University of Düsseldorf, Medical Faculty, Department of Neurology, Düsseldorf, Germany.
Department of Neurology, Technische Universität München, Munich, Germany.
GlaxoSmithKline, Uxbridge, Middlesex, United Kingdom.
IPSEN, Slough, Berkshire, United Kingdom.
Sanofi, Chilly-Mazarin, France.
INSERM UMR 996, Univ. Paris-Sud, Faculty of Pharmacy, Université Paris-Saclay, Châtenay-Malabry, France.
Munich Cluster for Systems Neurology (SyNergy), Munich, Germany.
SciCross AB, Skövde, Sweden.
Assistance Publique-Hôpitaux de Paris, Hôpital Paul Brousse, Villejuif, France.


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.

[Indexed for MEDLINE]
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Conflict of interest statement

D. Bachelet, S. Hässler, C. Mbogning, J. Link, R. Ramanujam, M. Auer, P.E. Hyldgaard Jensen, K. Ingenhoven, D. Buck, V. Grummel, M. Pallardy, P. Dönnes, P. Broët: have nothing to declare. N. Koch-Henriksen has received honoraria for lecturing and participation in advisory councils, travel expenses for attending congresses and meetings, and financial support for monitoring the Danish Multiple Sclerosis Treatment Register from Bayer-Schering, MerckSerono, Biogen Idec, Teva, Sanofi-Aventis and Novartis. A. Fogdell-Hahn has received funding speaking honoraria from Biogen Idec and Pfizer. F. Deisenhammer participated in meetings sponsored by or received honoraria for acting as an advisor/speaker for Bayer Healthcare, Biogen Idec, Genzyme-Sanofi, Merck, Novartis Pharma, and Roche. C. Warnke participated in meetings sponsored by, or received honoraria for acting as an advisor/speaker for Bayer, Biogen, Novartis, and Teva. D. Buck has received compensation for activities with Bayer HealthCare, BiogenIdec, MerckSerono, and Novartis and she is supported by the Abirisk Consortium. H. Hartung has received honoraria for consulting, serving on steering committees and speaking from Biogen, GeNeuro, Genzyme, Merck, Novartis, Opexa, Receptos, Roche, Sanofi, Teva with approval by the president of Heinrich-Heine University. B. Kieseier has received honoraria for lecturing, travel expenses for attending meetings, and financial support for research from Bayer Health Care, Biogen Idec, Genzyme/Sanofi Aventis, Grifols, Merck Serono, Mitsubishi Europe, Novartis, Roche, Talecris, and TEVA. B. Hemmer has served on scientific advisory boards for Roche, Novartis, Bayer Schering, Merck Serono, Biogen Idec, GSK, Chugai Pharmaceuticals, Micromet, Genentech and Genzyme Corporation; serves on the international advisory board of Archives of Neurology and Experimental Neurology; has received speaker honoraria from Bayer Schering, Novartis, Biogen Idec, Merck Serono, Roche, and Teva Pharmaceutical Industries Ltd; and has received research support from Biogen Idec, Bayer Schering, Merck Serono, Five prime, Metanomics, Chugai Pharmaceuticals and Novartis. He has been filed a patent for the detection of antibodies and T cells against KIR4.1 in a subpopulation of MS patients and genetic determinants of neutralizing antibodies to interferon-beta. P.S. Sørensen has served on scientific advisory boards for Biogen Idec, Merck Serono, Novartis, Genzyme, Teva Pharmaceutical Industries Ltd., GlaxoSmithKline, medDay Pharmaceuticals and Forward Pharma; has been on steering committees or independent data monitoring boards in clinical trials sponsored by Merck Serono, Teva Pharmaceutical Industries Ltd., and GlaxoSmithKline; and has received speaker honoraria from Biogen Idec, Merck Serono, Teva Pharmaceutical Industries Ltd., Genzyme, and Novartis. His department has received research support from Biogen Idec, Bayer Schering, Merck Serono, TEVA, Baxter, Sanofi-Aventis, BioMS, Novartis, Bayer, RoFAR, Roche, Genzyme, from the Danish Multiple Sclerosis Society, the Danish Medical Research Council, and the European Union Sixth Framework Programme: Life sciences, Genomics and Biotechnology for health. M. Ryner has received research support from Biogen Idec and Sanofi-Aventis, and received speaker honoraria from Biogen Idec. Andy Lawton and Dan Sikkema are employed by GlaxoSmithKline. At the time of writing Julie Davidson was employed by and held stocks/shares in GlaxoSmithKline. Naoimh Donnellan is employed by IPSEN. Agnès Hincelin-Mery is employed by Sanofi. Pierre Dönnes is an employee of SciCross AB and has received support from the Innovative Medicines Initiative Joint Undertaking under grant agreement No. [115303], resources of which are composed of financial contribution from the European Union's Seventh Framework Program (FP7/2007–2013) and EFPIA companies' in kind contribution. All the company-employed authors declare that this does not alter their adherence to PLOS ONE policies on sharing data and materials.

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