BACKGROUND: Multiple sclerosis (MS) patients treated with interferon beta (IFNβ) are at risk of a declining response to treatment because of the production of IFNβ-neutralizing antibodies (NAbs). The expression of Myxovirus resistance protein A (MxA) mRNA is regarded as a marker of IFNβ bioactivity. AIMS: The aim of this study was to analyze the kinetics of MxA mRNA expression during long-term IFNβ treatment and assess its relationship to NAb production. METHODS: A prospective, observational, open-label, non-randomized study was designed in multiple sclerosis patients starting IFNβ treatment. NAbs and MxA mRNA were monitored every six months. RESULTS: 119 patients were consecutively enrolled and 107 were included in the final analysis. Both the presence of NAbs and a decrease in MxA mRNA below the cut off were revealed in 15 patients, however, in six patients (40%) positivity for NAbs was preceded by the decrease in MxA mRNA. In addition, a further six patients showing a decline in MxA mRNA did not have detectable NAbs. CONCLUSION: Our data indicate that quantification of MxA mRNA is a more sensitive identifier of loss of IFNβ efficacy than the NAb positivity.

Department of Medical Microbiology Charles University 2nd Faculty of Medicine and Motol University Hospital Prague Czech Republic

Department of Neurology and Center of Clinical Neuroscience Charles University First Faculty of Medicine and General University Hospital Prague Czech Republic

Department of Neurology Charles University 2nd Faculty of Medicine and Motol University Hospital Prague Czech Republic

Laboratory of Molecular Diagnostics Na Homolce Hospital Prague Czech Republic

See more in PubMed

Bertolotto, A. (2015). Evaluation of the impact of neutralizing antibodies on IFNβ response. Clinica Chimica Acta, 449, 31–36. doi:10.1016/j.cca.2015.02.043. PubMed DOI

Bertolotto, A. , Gilli, F. , Sala, A. , Audano, L. , Castello, A. , Magliola, U. , … Giordana, M. T. (2001). Evaluation of bioavailability of three types of IFN beta in multiple sclerosis patients by a new quantitative‐competitive‐PCR method for MxA quantification. Journal of Immunological Methods, 256, 141–152. PubMed

Gilli, F. , Marnetto, F. , Caldano, M. , Valentino, P. , Granieri, L. , Di Sapio, A. , … Bertolotto, A. (2007). Anti‐interferon‐beta neutralising activity is not entirely mediated by antibodies. Journal of Neuroimmunology, 192, 198–205. PubMed

Hegen, H. , Millonig, A. , Bertolotto, A. , Comabella, M. , Giovanonni, G. , Guger, M. , … Deisenhammer, F. (2014). Early detection of neutralizing antibodies to interferon‐beta in multiple sclerosis patients: Binding antibodies predict neutralizing antibody development. Multiple Sclerosis, 20, 577–587. PubMed

Hesse, D. , Sellebjerg, F. , & Sørensen, P. S. (2009). Absence of MxA induction by interferon beta in patients with MS reflects complete loss of bioactivity. Neurology, 73, 372–377. PubMed

Kawade, Y. , Finter, N. , & Grossberg, S. E. (2003). Neutralization of the biological activity of cytokines and other protein effectors by antibody: Theoretical formulation of antibody titration curves in relation to antibody affinity. Journal of Immunological Methods, 278, 127–144. PubMed

Livak, K. J. , & Schmittgen, T. D. (2001). Analysis of relative gene expression data using real‐time quantitative PCR and the 2(‐Delta Delta C(T)) method. Methods, 25, 402–408. PubMed

Polman, C. H. , Bertolotto, A. , Deisenhammer, F. , Giovannoni, G. , Hartung, H. P. , Hemmer, B. , … Sørensen, P. S. (2010). Recommendations for clinical use of data on neutralizing antibodies to interferon‐beta therapy in multiple sclerosis. The Lancet Neurology, 9, 740–750. PubMed

Sørensen, P. S. , Deisenhammer, F. , Duda, P. , Hohlfeld, R. , Myhr, K. M. , Palace, J. , … Ross, C. (2005). EFNS Task Force on Anti‐IFN‐beta Antibodies in Multiple Sclerosis. Guidelineson use of anti‐IFN‐beta antibody measurements in multiple sclerosis: Report of an EFNS Task Force on IFN‐beta antibodies in multiple sclerosis. European Journal of Neurology, 12, 817–827. PubMed

van der Voort, L. F. , Visser, A. , Knol, D. L. , Oudejans, C. B. M. , Polman, C. H. , & Killestein, J. (2009). Lack of interferon‐beta bioactivity is associated with the occurrence of relapses in multiple sclerosis. European Journal of Neurology, 16, 1049–1052. PubMed