Human Leukocyte Antigen Genes and Interferon Beta Preparations Influence Risk of Developing Neutralizing Anti-Drug Antibodies in Multiple Sclerosis

Jenny Link,Katharina Fink,Christina Hermanrud,Izaura Lima,Jan Hillert,Malin Lundkvist Ryner,Ingrid Kockum,Anna Fogdell-Hahn,Boel Brynedal,Orhan Aktas

doi:10.1371/journal.pone.0090479

Abstract

A significant proportion of patients with multiple sclerosis who receive interferon beta (IFNβ) therapy develop neutralizing antibodies (NAbs) that reduce drug efficacy. To investigate if HLA class I and II alleles are associated with development of NAbs against IFNβ we analyzed whether NAb status and development of NAb titers high enough to be biologically relevant (>150 tenfold reduction units/ml) correlated with the HLA allele group carriage in a cohort of 903 Swedish patients with multiple sclerosis treated with either intramuscular IFNβ-1a, subcutaneous IFNβ-1a or subcutaneous IFNβ-1b. Carriage of HLA-DRB1*15 was associated with increased risk of developing NAbs and high NAb titers. After stratification based on type of IFNβ preparation, HLA-DRB1*15 carriage was observed to increase the risk of developing NAbs as well as high NAb titers against both subcutaneous and intramuscular IFNβ-1a. Furthermore, in patients receiving subcutaneous IFNβ-1a carriage of HLA-DQA1*05 decreased the risk for high NAb titers. In IFNβ-1b treated patients, HLA-DRB1*04 increased the risk of developing high NAb titers, and in a subgroup analysis of DRB1*04 alleles the risk for NAbs was increased in DRB1*04:01 carriers. In conclusion, there is a preparation-specific genetically determined risk to develop NAbs against IFNβ high enough to be clinically relevant in treatment decisions for patients with multiple sclerosis if confirmed in future studies. However, choice of IFNβ preparation still remains the single most significant determinant for the risk of developing NAbs.

Highlights

Recombinant interferon beta (IFNb) is a first-line therapy for relapsing-remitting multiple sclerosis (MS) and its therapeutic effect includes reduced frequency of clinical relapses and new lesions [1,2] and reduced accumulation of disability over time [3]
Carriage of human leukocyte antigen (HLA)-B*07 was associated with development of biologically relevant titers (Table 2)
Because of the high linkage disequilibrium (LD) within the HLA, a stratification on carriage of DRB1*15 was performed to assess whether B*07 was independently associated to the development of biologically relevant titers

Summary

Introduction

Recombinant interferon beta (IFNb) is a first-line therapy for relapsing-remitting multiple sclerosis (MS) and its therapeutic effect includes reduced frequency of clinical relapses and new lesions [1,2] and reduced accumulation of disability over time [3]. Two types of recombinant IFNb products are used for treatment of MS, IFNb-1a and IFNb-1b. A proportion of MS patients receiving IFNb treatment develop neutralizing anti-drug antibodies (NAbs), which at high titers block the biological response [4,5] and the therapeutic efficacy [6,7,8] of IFNb. The frequency of NAb positive patients differs depending on the IFNb preparations used with IFNb-1b inducing NAbs in 28%–47% of treated patients, s.c. IFNb-1a in 5%–28% and i.m. IFNb-1a in 2%–6% [9]. Among the NAb positive patients, the proportion with high NAb titers has been reported to be 19%–

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