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. 2014 Mar 7;9(3):e90479.
doi: 10.1371/journal.pone.0090479. eCollection 2014.

Human leukocyte antigen genes and interferon beta preparations influence risk of developing neutralizing anti-drug antibodies in multiple sclerosis

Jenny Link  1 , Malin Lundkvist Ryner  1 , Katharina Fink  1 , Christina Hermanrud  1 , Izaura Lima  1 , Boel Brynedal  2 , Ingrid Kockum  1 , Jan Hillert  1 , Anna Fogdell-Hahn  1
Affiliations

Human leukocyte antigen genes and interferon beta preparations influence risk of developing neutralizing anti-drug antibodies in multiple sclerosis

Jenny Link et al. PLoS One. .

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.

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Conflict of interest statement

Competing Interests: Malin Lundkvist Ryner has read the journal's policy and has the following conflicts: JL has received research support from the Swedish Association for Persons with Neurological Disabilities. She has received support from the Innovative Medicines Initiative Joint Undertaking under grant agreement n° [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. MLR has received research support from BiogenIdec, Sanofi-Aventis and the Swedish Association for Persons with Neurological Disabilities, as well as received honoraria for lectures by BiogenIdec. KF has received travel compensation for consultancy work from Novartis and Teva. CH, IL and BB report no conflicts of interest. IK has received research grants from Association for Persons with Neurological Disabilities. JH received honoraria for serving on advisory boards for BiogenIdec, Merck-Serono and Novartis and for speaker's fees from BiogenIdec, Merck-Serono, Bayer-Schering, Teva and Sanofi-Aventis. He has served as P.I. for and received projects supported by BiogenIdec, Merck-Serono, and Bayer-Schering. His MS research is funded by the Swedish Research Council, Bibbi and Nils Jensens Foundation and the European Commission. AFH has received research grants from Association for Persons with Neurological Disabilities and received unrestricted research grants from Merck-Serono, BiogenIdec; served as consultant for Johnson & Johnson; received honoraria for lectures by BiogenIdec and Sanofi-Aventis. She has received support from the Innovative Medicines Initiative Joint Undertaking under grant agreement n° [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. This does not alter the authors' adherence to all the PLOS ONE policies on sharing data and materials.

Figures

Figure 1
Figure 1. Absolute risk for development of NAbs and biologically relevant titers.
Calculation of the absolute risk was used to estimate how DRB1*04 and DRB1*15 carriage impacts the risk for the outcomes of NAb positivity (bars on grey floor) and biologically relevant titers (bars on white floor) when adjusted for the baseline risk. Baseline risk was the frequency of development of NAb (dark grey bars, grey floor) and biologically relevant titers (dark grey bars, white floor) for each IFNβ preparation in the Swedish NAb registry. Compared to the baseline risks, DRB1*15 carriage increased the absolute risk for both outcomes in s.c. IFNβ-1a treated patients (grey bars) and to a lesser extent in patients receiving i.m. IFNβ-1a (light grey bars), whereas DRB1*15 carriage lowered the risk for both outcomes in patients receiving IFNβ-1b (white bars). In DRB1*04 carriers the reversed relationship was observed, with an increased absolute risk for both outcomes in IFNβ-1b treated patients. Moreover, the absolute risk for NAb positivity and biologically relevant titers was constantly lower for i.m. IFNβ-1a than for the two s.c. IFNβ preparations, regardless of whether patients were positive or negative for DRB1*04 and DRB1*15.
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