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From the Centro Riferimento Regionale Sclerosi Multipla and Neurobiologia Clinica, ASO S. Luigi Gonzaga, Orbassano, Torino, Italy.
Address correspondence and reprint requests to Dr. Antonio Bertolotto, Centro di Riferimento Regionale Sclerosi Multipla and Neurobiologia Clinica, ASO S. Luigi Gonzaga, Regione Gonzole 10, I-10043 Orbassano, Torino, Italy sclerosi.multipla{at}sanluigi.piemonte.it
Background: Prolonged therapy with interferon β (IFNβ) often leads to the development of anti-IFNβ binding antibodies (BAbs). A subset of the BAbs is of a neutralizing nature (neutralizing antibodies, NAbs) and is associated with reduced clinical efficacy of therapy. Myxovirus-resistance-protein A (MxA) has proven to be a reliable biomarker of IFNβ bioactivity. We analyzed the prognostic value of MxA mRNA, NAbs, and BAbs on the risk of having a new relapse in IFNβ-treated patients.
Methods: A 3-year study was conducted in 137 IFNβ-treated patients. Blood samples for BAbs, NAbs, and MxA mRNA measurements were taken after 12 ± 3 months of therapy. Analysis of relapse-free survival (RFS) was performed for all measures by using known thresholds, generating "positive" and "negative" groups. Also, time between sampling and following relapse and risk of new relapses were calculated.
Results: The MxA-negative group showed poorer RFS rates than the MxA-positive group [p < 0.0001, hazard ratio (HR) = 2.87]. Likewise, the NAb-positive group showed poorer RFS rates than the NAb-negative group (p =0.0013; HR = 2.49). On the contrary, BAb measurement did not show a clear clinical significance.
Conclusions: Findings indicate that measurements of both myxovirus-resistance-protein A (MxA) and neutralizing antibodies (NAbs) predict the risk of new relapses; however, the slightly stronger prognostic significance of MxA mRNA and the easier method for it measurement make MxA mRNA the preferred biomarker for monitoring interferon β (IFNβ)-treated patients. This information can be used to better tailor treatment to the individual patient with MS.
GLOSSARY: BAb = binding antibody; CPE = cytopathic effect; EDSS = Expanded Disability Status Scale; GAPDH = glyceraldehyde phosphate dehydrogenase; HR = hazard ratio; IFN = interferon; MxA = myxovirus-resistance-protein A; NAb = neutralizing antibody; RFS = relapse-free survival; ROC = receiver operating characteristic; TRU = 10-fold reduction units.
Supplemental data at www.neurology.org
Editorial, page 1069
e-Pub ahead of print on February 13, 2008, at www.neurology.org.
*These authors contributed equally to this work.
Supported in part by a grant from the European Community under its 6th Framework, for a specific project on neutralizing antibodies in MS (NABINMS Project, Contract 018926). Also supported by the Fondazione per la Ricerca Biomedica ONLUS and the S. Luigi Gonzaga ONLUS. Funding sources had no role in data collection, data analysis, data interpretation, or writing of this paper.
Disclosure: The authors report no conflicts of interest.
Received June 15, 2007. Accepted in final form October 22, 2007.
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  R. A. Rudick and R. M. Ransohoff Biomarkers for interferon response in MS: Are we there yet? Neurology, March 25, 2008; 70(13_Part_2): 1069 - 1070. [Full Text] [PDF]
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