Absence of MxA induction by interferon beta 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) beta reduce or in high concentrations abolish bioactivity and therapeutic efficacy. In vivo MxA induction by IFNbeta is used as a marker of biologic response to IFNbeta. 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 IFNbeta 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 IFNbeta-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 IFNbeta-regulated genes at a 5% level in NAb-negative patients. The corresponding number of IFNbeta-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) beta-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 IFNbeta, with no indication of residual bioactivity.