54:974 early multiple sclerosis: CHAMPS trial subgroup analyses. Ann Neurol 2002;51:481-490. 2) Kappos L, Freedman MS, Polman CH, et al. Effect of early versus delayed interferon beta-1b treatment on disability after a first clinical event suggestive of multiple sclerosis: a 3-year follow-up analysis of the BENEFIT study. Lancet 2007;370: 389-397. 3) Kinkel RP, Dontchev M, Kollman C, et al. Association between immediate initiation of intramuscular interferon beta-1a at the time of a clinically

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... solated syndrome and long-term outcomes:a 10-year follow-up of the Controlled High-Risk Avonex Multiple Sclerosis Prevention Study in Ongoing Neurological Surveillance. Arch Neurol 2012;69:183-190. 4) Leray E, Yaouanq J, Le Page E, et al. Evidence for a two-stage disability progression in multiple sclerosis. Brain 2010;133: 1900-1913. 5) Kuhlmann T, Lingfeld G, Bitsch A, et al. Acute axonal damage in multiple sclerosis is most extensive in early disease stages and decreases over time. Brain 2002;125:2202-2212. 6) Kappos L, Radue EW, O'Connor P, et al. A placebo-controlled trial of oral fingolimod in relapsing multiple sclerosis. N Engl J Med 2010;362:387-401. 7) Polman CH, O'Connor PW, Havrdova E, et al. A randomized, placebo-controlled trial of natalizumab for relapsing multiple sclerosis. N Engl J Med 2006;354:899-910. 8) Rio J, Nos C, Tintore M, et al. Defining the response to interferon-beta in relapsing-remitting multiple sclerosis patients. Ann Neurol 2006;59:344-352. 9) Nakatsuji Y, Okuno T, Moriya M, et al. Elevation of Sema4A implicates Th cell skewing and the efficacy of IFN-beta therapy in multiple sclerosis. J Immunol 2012;188:4858-4865. 10) Koda T, Okuno T, Takata K, et al. Sema4A inhibits the therapeutic effect of IFN-beta in EAE. J Neuro immunol 2014; 268:43-49. Abstract Sema4A as a biomarker predicting responsiveness to IFN b treatment Approximately one-third of patients with multiple sclerosis (MS) exhibit markedly high-level-expression of Sema4A. The expression of Sema4A is increased on DCs in MS patients and shed from these cells in a metalloproteinasedependent manner. DC-derived Sema4A is critical for Th17 cell differentiation, and MS patients with high Sema4A levels exhibit Th17 skewing. Furthermore, patients with high Sema4A levels have more severe disabilities and are unresponsive to IFN-b treatment. We investigated whether recombinant Sema4A abrogates the efficacy of IFN-b in mice with experimental autoimmune encephalomyelitis (EAE), an animal model of MS. Administration of Sema4A concurrently with IFN-b abrogated the efficacy of IFN-b. These effects of Sema4A were attributed to promote Th1 and Th17 differentiation and to increase adhesive activation of T cells to endothelial cells, even in the presence of IFN-b. Thus unresponsiveness to IFN-b treatment of MS patients with high Sema4A was also confirmed by model mice EAE. We recommend assaying Sema4A first, and then selecting DMD other than IFN-b for patients with high Sema4A. (Clin Neurol 2014;54:972-974)