Effect of HLA-DRB1 alleles and genetic variants on the development of neutralizing antibodies to interferon beta in the BEYOND and BENEFIT trials

Dorothea Buck, Till Fm Andlauer, Wilmar Igl, Eva-Maria Wicklein, Mark Mühlau, Frank Weber, Karl Köchert, Christoph Pohl, Barry Arnason, Giancarlo Comi, Stuart Cook, Massimo Filippi, Hans-Peter Hartung, Douglas Jeffery, Ludwig Kappos, Frederik Barkhof, Gilles Edan, Mark S Freedman, Xavier Montalbán, Bertram Müller-Myhsok & 2 others Bernhard Hemmer, BEYOND and BENEFIT Study Groups

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

BACKGROUND: Treatment of multiple sclerosis (MS) with interferon β can lead to the development of antibodies directed against interferon β that interfere with treatment efficacy. Several observational studies have proposed different HLA alleles and genetic variants associated with the development of antibodies against interferon β.

OBJECTIVE: To validate the proposed genetic markers and to identify new markers.

METHODS: Associations of genetic candidate markers with antibody presence and development were examined in a post hoc analysis in 941 patients treated with interferon β-1b in the Betaferon® Efficacy Yielding Outcomes of a New Dose (BEYOND) and BEtaseron®/BEtaferon® in Newly Emerging multiple sclerosis For Initial Treatment (BENEFIT) prospective phase III trials. All patients were treated with interferon β-1b for at least 6 months. In addition, a genome-wide association study was conducted to identify new genetic variants.

RESULTS: We confirmed an increased risk for carriers of HLA-DRB1*04:01 (odds ratio (OR) = 3.3, p = 6.9 × 10-4) and HLA-DRB1*07:01 (OR = 1.8, p = 3.5 × 10-3) for developing neutralizing antibodies (NAbs). Several additional, previously proposed HLA alleles and genetic variants showed nominally significant associations. In the exploratory analysis, variants in the HLA region were associated with NAb development at genome-wide significance (OR = 2.6, p = 2.30 × 10-15).

CONCLUSION: The contribution of HLA alleles and HLA-associated single-nucleotide polymorphisms (SNPs) to the development and titer of antibodies against interferon β was confirmed in the combined analysis of two multi-national, multi-center studies.

Original languageEnglish
Pages (from-to)565-573
JournalMultiple Sclerosis
Volume25
Issue number4
DOIs
Publication statusPublished - 1 Apr 2019

Cite this

Buck, D., Andlauer, T. F., Igl, W., Wicklein, E-M., Mühlau, M., Weber, F., ... BEYOND and BENEFIT Study Groups (2019). Effect of HLA-DRB1 alleles and genetic variants on the development of neutralizing antibodies to interferon beta in the BEYOND and BENEFIT trials. Multiple Sclerosis, 25(4), 565-573. https://doi.org/10.1177/1352458518763089
Buck, Dorothea ; Andlauer, Till Fm ; Igl, Wilmar ; Wicklein, Eva-Maria ; Mühlau, Mark ; Weber, Frank ; Köchert, Karl ; Pohl, Christoph ; Arnason, Barry ; Comi, Giancarlo ; Cook, Stuart ; Filippi, Massimo ; Hartung, Hans-Peter ; Jeffery, Douglas ; Kappos, Ludwig ; Barkhof, Frederik ; Edan, Gilles ; Freedman, Mark S ; Montalbán, Xavier ; Müller-Myhsok, Bertram ; Hemmer, Bernhard ; BEYOND and BENEFIT Study Groups. / Effect of HLA-DRB1 alleles and genetic variants on the development of neutralizing antibodies to interferon beta in the BEYOND and BENEFIT trials. In: Multiple Sclerosis. 2019 ; Vol. 25, No. 4. pp. 565-573.
@article{d0c909a260dd4956a3e0f79a1e9775fe,
title = "Effect of HLA-DRB1 alleles and genetic variants on the development of neutralizing antibodies to interferon beta in the BEYOND and BENEFIT trials",
abstract = "BACKGROUND: Treatment of multiple sclerosis (MS) with interferon β can lead to the development of antibodies directed against interferon β that interfere with treatment efficacy. Several observational studies have proposed different HLA alleles and genetic variants associated with the development of antibodies against interferon β.OBJECTIVE: To validate the proposed genetic markers and to identify new markers.METHODS: Associations of genetic candidate markers with antibody presence and development were examined in a post hoc analysis in 941 patients treated with interferon β-1b in the Betaferon{\circledR} Efficacy Yielding Outcomes of a New Dose (BEYOND) and BEtaseron{\circledR}/BEtaferon{\circledR} in Newly Emerging multiple sclerosis For Initial Treatment (BENEFIT) prospective phase III trials. All patients were treated with interferon β-1b for at least 6 months. In addition, a genome-wide association study was conducted to identify new genetic variants.RESULTS: We confirmed an increased risk for carriers of HLA-DRB1*04:01 (odds ratio (OR) = 3.3, p = 6.9 × 10-4) and HLA-DRB1*07:01 (OR = 1.8, p = 3.5 × 10-3) for developing neutralizing antibodies (NAbs). Several additional, previously proposed HLA alleles and genetic variants showed nominally significant associations. In the exploratory analysis, variants in the HLA region were associated with NAb development at genome-wide significance (OR = 2.6, p = 2.30 × 10-15).CONCLUSION: The contribution of HLA alleles and HLA-associated single-nucleotide polymorphisms (SNPs) to the development and titer of antibodies against interferon β was confirmed in the combined analysis of two multi-national, multi-center studies.",
author = "Dorothea Buck and Andlauer, {Till Fm} and Wilmar Igl and Eva-Maria Wicklein and Mark M{\"u}hlau and Frank Weber and Karl K{\"o}chert and Christoph Pohl and Barry Arnason and Giancarlo Comi and Stuart Cook and Massimo Filippi and Hans-Peter Hartung and Douglas Jeffery and Ludwig Kappos and Frederik Barkhof and Gilles Edan and Freedman, {Mark S} and Xavier Montalb{\'a}n and Bertram M{\"u}ller-Myhsok and Bernhard Hemmer and {BEYOND and BENEFIT Study Groups}",
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journal = "Multiple Sclerosis",
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Buck, D, Andlauer, TF, Igl, W, Wicklein, E-M, Mühlau, M, Weber, F, Köchert, K, Pohl, C, Arnason, B, Comi, G, Cook, S, Filippi, M, Hartung, H-P, Jeffery, D, Kappos, L, Barkhof, F, Edan, G, Freedman, MS, Montalbán, X, Müller-Myhsok, B, Hemmer, B & BEYOND and BENEFIT Study Groups 2019, 'Effect of HLA-DRB1 alleles and genetic variants on the development of neutralizing antibodies to interferon beta in the BEYOND and BENEFIT trials' Multiple Sclerosis, vol. 25, no. 4, pp. 565-573. https://doi.org/10.1177/1352458518763089

Effect of HLA-DRB1 alleles and genetic variants on the development of neutralizing antibodies to interferon beta in the BEYOND and BENEFIT trials. / Buck, Dorothea; Andlauer, Till Fm; Igl, Wilmar; Wicklein, Eva-Maria; Mühlau, Mark; Weber, Frank; Köchert, Karl; Pohl, Christoph; Arnason, Barry; Comi, Giancarlo; Cook, Stuart; Filippi, Massimo; Hartung, Hans-Peter; Jeffery, Douglas; Kappos, Ludwig; Barkhof, Frederik; Edan, Gilles; Freedman, Mark S; Montalbán, Xavier; Müller-Myhsok, Bertram; Hemmer, Bernhard; BEYOND and BENEFIT Study Groups.

In: Multiple Sclerosis, Vol. 25, No. 4, 01.04.2019, p. 565-573.

Research output: Contribution to journalArticleAcademicpeer-review

TY - JOUR

T1 - Effect of HLA-DRB1 alleles and genetic variants on the development of neutralizing antibodies to interferon beta in the BEYOND and BENEFIT trials

AU - Buck, Dorothea

AU - Andlauer, Till Fm

AU - Igl, Wilmar

AU - Wicklein, Eva-Maria

AU - Mühlau, Mark

AU - Weber, Frank

AU - Köchert, Karl

AU - Pohl, Christoph

AU - Arnason, Barry

AU - Comi, Giancarlo

AU - Cook, Stuart

AU - Filippi, Massimo

AU - Hartung, Hans-Peter

AU - Jeffery, Douglas

AU - Kappos, Ludwig

AU - Barkhof, Frederik

AU - Edan, Gilles

AU - Freedman, Mark S

AU - Montalbán, Xavier

AU - Müller-Myhsok, Bertram

AU - Hemmer, Bernhard

AU - BEYOND and BENEFIT Study Groups

PY - 2019/4/1

Y1 - 2019/4/1

N2 - BACKGROUND: Treatment of multiple sclerosis (MS) with interferon β can lead to the development of antibodies directed against interferon β that interfere with treatment efficacy. Several observational studies have proposed different HLA alleles and genetic variants associated with the development of antibodies against interferon β.OBJECTIVE: To validate the proposed genetic markers and to identify new markers.METHODS: Associations of genetic candidate markers with antibody presence and development were examined in a post hoc analysis in 941 patients treated with interferon β-1b in the Betaferon® Efficacy Yielding Outcomes of a New Dose (BEYOND) and BEtaseron®/BEtaferon® in Newly Emerging multiple sclerosis For Initial Treatment (BENEFIT) prospective phase III trials. All patients were treated with interferon β-1b for at least 6 months. In addition, a genome-wide association study was conducted to identify new genetic variants.RESULTS: We confirmed an increased risk for carriers of HLA-DRB1*04:01 (odds ratio (OR) = 3.3, p = 6.9 × 10-4) and HLA-DRB1*07:01 (OR = 1.8, p = 3.5 × 10-3) for developing neutralizing antibodies (NAbs). Several additional, previously proposed HLA alleles and genetic variants showed nominally significant associations. In the exploratory analysis, variants in the HLA region were associated with NAb development at genome-wide significance (OR = 2.6, p = 2.30 × 10-15).CONCLUSION: The contribution of HLA alleles and HLA-associated single-nucleotide polymorphisms (SNPs) to the development and titer of antibodies against interferon β was confirmed in the combined analysis of two multi-national, multi-center studies.

AB - BACKGROUND: Treatment of multiple sclerosis (MS) with interferon β can lead to the development of antibodies directed against interferon β that interfere with treatment efficacy. Several observational studies have proposed different HLA alleles and genetic variants associated with the development of antibodies against interferon β.OBJECTIVE: To validate the proposed genetic markers and to identify new markers.METHODS: Associations of genetic candidate markers with antibody presence and development were examined in a post hoc analysis in 941 patients treated with interferon β-1b in the Betaferon® Efficacy Yielding Outcomes of a New Dose (BEYOND) and BEtaseron®/BEtaferon® in Newly Emerging multiple sclerosis For Initial Treatment (BENEFIT) prospective phase III trials. All patients were treated with interferon β-1b for at least 6 months. In addition, a genome-wide association study was conducted to identify new genetic variants.RESULTS: We confirmed an increased risk for carriers of HLA-DRB1*04:01 (odds ratio (OR) = 3.3, p = 6.9 × 10-4) and HLA-DRB1*07:01 (OR = 1.8, p = 3.5 × 10-3) for developing neutralizing antibodies (NAbs). Several additional, previously proposed HLA alleles and genetic variants showed nominally significant associations. In the exploratory analysis, variants in the HLA region were associated with NAb development at genome-wide significance (OR = 2.6, p = 2.30 × 10-15).CONCLUSION: The contribution of HLA alleles and HLA-associated single-nucleotide polymorphisms (SNPs) to the development and titer of antibodies against interferon β was confirmed in the combined analysis of two multi-national, multi-center studies.

U2 - 10.1177/1352458518763089

DO - 10.1177/1352458518763089

M3 - Article

VL - 25

SP - 565

EP - 573

JO - Multiple Sclerosis

JF - Multiple Sclerosis

SN - 1352-4585

IS - 4

ER -