Preserved in vivo response to interferon-alpha in multiple sclerosis patients with neutralising antibodies against interferon-beta (REPAIR study)

Melinda Magyari; Helle Bach Søndergaard; Finn Sellebjerg; Per Soelberg Sørensen

doi:10.1016/j.msard.2012.10.001

Preserved in vivo response to interferon-alpha in multiple sclerosis patients with neutralising antibodies against interferon-beta (REPAIR study)

Mult Scler Relat Disord. 2013 Apr;2(2):141-6. doi: 10.1016/j.msard.2012.10.001. Epub 2012 Dec 11.

Authors

Melinda Magyari¹, Helle Bach Søndergaard², Finn Sellebjerg², Per Soelberg Sørensen²

Affiliations

¹ Danish Multiple Sclerosis Center, Department of Neurology, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark. Electronic address: melinda_magyari@dadlnet.dk.
² Danish Multiple Sclerosis Center, Department of Neurology, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark.

PMID: 25877635
DOI: 10.1016/j.msard.2012.10.001

Abstract

Background: A major problem in the treatment of multiple sclerosis (MS) patients with interferon-beta (IFN-β) is the development of neutralising antibodies (NAbs). High levels of NAbs block the induction of IFN-β-inducible markers, including Myxovirus Resistance Protein A (encoded by the MX1 gene), resulting in a loss of bioactivity and therapeutic benefit.

Objective: The primary objective of this study is to investigate the in vivo biological response to interferon-alpha (IFN-α) in MS patients, who have developed neutralising antibodies (NAbs) against IFN-β.

Design/methods: The study was an open-label phase II study in 10 patients with relapsing-remitting MS with persisting NAbs against IFN-β and absent in vivo mRNA MxA response. We used in vivo induction of MX1 mRNA and other IFN-inducible genes as measure of the biological response. The primary endpoint was the in vivo mRNA MX1 response after an injection of IFN-α compared with the response after an injection of IFN-β.

Results: In all 10 patients we found high MX1 expression after injection of IFN-α 6 MIU, indicating a preserved in vivo response to IFN-α. We measured the gene expression index of immune system genes in blood cells from the 10 NAb-positive patients after IFN-α treatment and 10 NAb-negative patients after injection of IFN-β. We found a significantly increased expression of a number of genes, including MX1, IFI27, IL10 and TNFSF10 (encoding TRAIL) in the NAb-positive patients treated with IFN-α.

Interpretation: IFN-α could be a therapeutic option in patients, who have lost the biological response to IFN-β because of NAbs against IFN-β. ClinicalTrials gov. Identifier: NCT01171209.

Keywords: Beta-interferon; Biomarkers; Disease modifying therapies; Immunology; Multiple Sclerosis; Neutralising antibodies.

Associated data

ClinicalTrials.gov/NCT01171209