Absence of MxA induction by interferon β in patients with MS reflects complete loss of bioactivity

Background: In patients with multiple sclerosis (MS), neutralizing antibodies (NAbs) appearing during treatment with interferon (IFN) β reduce or in high concentrations abolish bioactivity and therapeutic efficacy. In vivo MxA induction by IFNβ is used as a marker of biologic response to IFNβ. It has been argued that despite absence of MxA induction measured by PCR, some bioactivity might be preserved. In a cohort study, we measured gene expression by gene chip analysis in NAb-negative and NAb-positive patients to test that hypothesis. Methods: The effect of IFNβ was studied by comparing samples collected before and 9–12 hours after an injection. The cohort consisted of 12 NAb-positive patients without MxA response and 12 NAb-negative patients with preserved response. MxA in vivo response was determined in whole blood using real-time PCR. Screening for IFNβ-regulated genes in mononuclear cells was done using gene chips. False discovery rate (FDR) analysis was used as statistical tool. Results: Of 8,793 genes, 5,593 were detectable in at least one patient in both groups. Of these, calculation of FDR revealed 1,077 IFNβ-regulated genes at a 5% level in NAb-negative patients. The corresponding number of IFNβ-regulated genes in NAb-positive patients was zero. Conclusion: In neutralizing antibody (NAb)–positive patients without an MxA response, we were not able to detect differential expression of any of the 1077 interferon (IFN) β-regulated genes identified in NAb-negative patients. Lack of MxA in vivo response in patients with multiple sclerosis with NAbs is a reliable marker of a completely blocked biologic response to IFNβ, with no indication of residual bioactivity.