%0 Journal Article
%T Human Leukocyte Antigen Genes and Interferon Beta Preparations Influence Risk of Developing Neutralizing Anti-Drug Antibodies in Multiple Sclerosis
%A Jenny Link
%A Malin Lundkvist Ryner
%A Katharina Fink
%A Christina Hermanrud
%A Izaura Lima
%A Boel Brynedal
%A Ingrid Kockum
%A Jan Hillert
%A Anna Fogdell-Hahn
%J PLOS ONE
%D 2014
%I Public Library of Science (PLoS)
%R 10.1371/journal.pone.0090479
%X A significant proportion of patients with multiple sclerosis who receive interferon beta (IFN¦Â) 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 IFN¦Â 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 IFN¦Â-1a, subcutaneous IFN¦Â-1a or subcutaneous IFN¦Â-1b. Carriage of HLA-DRB1*15 was associated with increased risk of developing NAbs and high NAb titers. After stratification based on type of IFN¦Â 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 IFN¦Â-1a. Furthermore, in patients receiving subcutaneous IFN¦Â-1a carriage of HLA-DQA1*05 decreased the risk for high NAb titers. In IFN¦Â-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 IFN¦Â high enough to be clinically relevant in treatment decisions for patients with multiple sclerosis if confirmed in future studies. However, choice of IFN¦Â preparation still remains the single most significant determinant for the risk of developing NAbs.
%U http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0090479