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

Delphine Bachelet; Signe Hässler; Cyprien Mbogning; Jenny Link; Malin Ryner; Ryan Ramanujam; Michael Auer; Poul Erik Hyldgaard Jensen; Nils Koch-Henriksen; Clemens Warnke; Kathleen Ingenhoven; Dorothea Buck; Verena Grummel; Andy Lawton; Naoimh Donnellan; Agnès Hincelin-Mery; Dan Sikkema; Marc Pallardy; Bernd Kieseier; Bernard Hemmer; Hans Peter Hartung; Per Soelberg Sorensen; Florian Deisenhammer; Pierre Dönnes; Julie Davidson; Anna Fogdell-Hahn; Philippe Broët; ABIRISK Consortium

doi:10.1371/journal.pone.0162752

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

Delphine Bachelet, Signe Hässler, Cyprien Mbogning, Jenny Link, Malin Ryner, Ryan Ramanujam, Michael Auer, Poul Erik Hyldgaard Jensen, Nils Koch-Henriksen, Clemens Warnke, Kathleen Ingenhoven, Dorothea Buck, Verena Grummel, Andy Lawton, Naoimh Donnellan, Agnès Hincelin-Mery, Dan Sikkema, Marc Pallardy, Bernd Kieseier, Bernard HemmerHans Peter Hartung, Per Soelberg Sorensen, Florian Deisenhammer, Pierre Dönnes, Julie Davidson, Anna Fogdell-Hahn, Philippe Broët, ABIRISK Consortium

Department of Clinical Medicine

24 Citations (Scopus)

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Abstract

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.

Original language	English
Article number	e0162752
Journal	P L o S One
Volume	11
Issue number	11
Pages (from-to)	1-19
Number of pages	19
ISSN	1932-6203
DOIs	https://doi.org/10.1371/journal.pone.0162752
Publication status	Published - Nov 2016

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Occurrence of Anti-Drug Antibodies against Interferon-Beta and Natalizumab in Multiple Sclerosis: A Collaborative Cohort AnalysisFinal published version, 2.34 MBLicence: CC BY

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Bachelet, D., Hässler, S., Mbogning, C., Link, J., Ryner, M., Ramanujam, R., Auer, M., Jensen, P. E. H., Koch-Henriksen, N., Warnke, C., Ingenhoven, K., Buck, D., Grummel, V., Lawton, A., Donnellan, N., Hincelin-Mery, A., Sikkema, D., Pallardy, M., Kieseier, B., ... ABIRISK Consortium (2016). Occurrence of Anti-Drug Antibodies against Interferon-Beta and Natalizumab in Multiple Sclerosis: A Collaborative Cohort Analysis. P L o S One, 11(11), 1-19. [e0162752]. https://doi.org/10.1371/journal.pone.0162752

Bachelet, D, Hässler, S, Mbogning, C, Link, J, Ryner, M, Ramanujam, R, Auer, M, Jensen, PEH, Koch-Henriksen, N, Warnke, C, Ingenhoven, K, Buck, D, Grummel, V, Lawton, A, Donnellan, N, Hincelin-Mery, A, Sikkema, D, Pallardy, M, Kieseier, B, Hemmer, B, Hartung, HP, Soelberg Sorensen, P, Deisenhammer, F, Dönnes, P, Davidson, J, Fogdell-Hahn, A, Broët, P & ABIRISK Consortium 2016, 'Occurrence of Anti-Drug Antibodies against Interferon-Beta and Natalizumab in Multiple Sclerosis: A Collaborative Cohort Analysis', P L o S One, vol. 11, no. 11, e0162752, pp. 1-19. https://doi.org/10.1371/journal.pone.0162752

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abstract = "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.",

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T2 - A Collaborative Cohort Analysis

AU - Bachelet, Delphine

AU - Hässler, Signe

AU - Mbogning, Cyprien

AU - Link, Jenny

AU - Ryner, Malin

AU - Ramanujam, Ryan

AU - Auer, Michael

AU - Jensen, Poul Erik Hyldgaard

AU - Koch-Henriksen, Nils

AU - Warnke, Clemens

AU - Ingenhoven, Kathleen

AU - Buck, Dorothea

AU - Grummel, Verena

AU - Lawton, Andy

AU - Donnellan, Naoimh

AU - Hincelin-Mery, Agnès

AU - Sikkema, Dan

AU - Pallardy, Marc

AU - Kieseier, Bernd

AU - Hemmer, Bernard

AU - Hartung, Hans Peter

AU - Soelberg Sorensen, Per

AU - Deisenhammer, Florian

AU - Dönnes, Pierre

AU - Davidson, Julie

AU - Fogdell-Hahn, Anna

AU - Broët, Philippe

AU - ABIRISK Consortium

PY - 2016/11

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N2 - 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.

AB - 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.

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M1 - e0162752

ER -

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

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