The future of multiple sclerosis treatments

References

• Federation MSI. Atlas of MS 2013: mapping multiple sclerosis around the world, Eds. London; 2013. Available from: http://www.msif.org/wp-content/uploads/2014/09/Atlas-of-MS.pdf
   Google Scholar
• Compston A, Coles A. Multiple sclerosis. Lancet. 2008;372(9648):1502–1517.
   PubMed Web of Science ®Google Scholar
• Lublin FD, Reingold SC, Cohen JA, et al. Defining the clinical course of multiple sclerosis: the 2013 revisions. Neurology. 2014;83(3):278–286.
   PubMed Web of Science ®Google Scholar
• Tanasescu R, Ionete C, Chou IJ, et al. Advances in the treatment of relapsing-remitting multiple sclerosis. Biomed J. 2014;37(2):41–49.
   PubMedGoogle Scholar
• Thomas RH, Wakefield RA. Oral disease-modifying therapies for relapsing-remitting multiple sclerosis. Am J Health Syst Pharm. 2015;72(1):25–38.
   PubMed Web of Science ®Google Scholar
• Ali R, Nicholas RS, Muraro PA. Drugs in development for relapsing multiple sclerosis. Drugs. 2013;73(7):625–650.
   PubMed Web of Science ®Google Scholar
• Boster AL, Ford CC, Neudorfer O, et al. Glatiramer acetate: long-term safety and efficacy in relapsing-remitting multiple sclerosis. Expert Rev Neurother. 2015;15(6):575–586.
   PubMed Web of Science ®Google Scholar
• Johnson KP, Brooks BR, Cohen JA, et al. Copolymer 1 reduces relapse rate and improves disability in relapsing-remitting multiple sclerosis: results of a phase III multicenter, double-blind, placebo-controlled trial. 1995. Neurology. 2001;57(12Suppl 5):S16–24.
   PubMed Web of Science ®Google Scholar
• Lugaresi A, Di Ioia M, Travaglini D, et al. Risk-benefit considerations in the treatment of relapsing-remitting multiple sclerosis. Neuropsychiatr Dis Treat. 2013;9:893–914.
   PubMed Web of Science ®Google Scholar
• Palace J, Duddy M, Bregenzer T, et al. Effectiveness and cost-effectiveness of interferon beta and glatiramer acetate in the UK multiple sclerosis risk sharing scheme at 6 years: a clinical cohort study with natural history comparator. Lancet Neurol. 2015;14(5):497–505.
   PubMed Web of Science ®Google Scholar
• Ford C, Goodman AD, Johnson K, et al. Continuous long-term immunomodulatory therapy in relapsing multiple sclerosis: results from the 15-year analysis of the US prospective open-label study of glatiramer acetate. Mult Scler. 2010;16(3):342–350.
   PubMed Web of Science ®Google Scholar
• Giovannoni G, Southam E, Waubant E. Systematic review of disease-modifying therapies to assess unmet needs in multiple sclerosis: tolerability and adherence. Mult Scler. 2012;18(7):932–946.
   PubMed Web of Science ®Google Scholar
• Craddock J, Markovic-Plese S. Immunomodulatory therapies for relapsing-remitting multiple sclerosis: monoclonal antibodies, currently approved and in testing. Expert Rev Clin Pharmacol. 2015;8(3):283–296.
   PubMed Web of Science ®Google Scholar
• 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(9):899–910.
   PubMed Web of Science ®Google Scholar
• Rudick RA, Stuart WH, Calabresi PA, et al. Natalizumab plus interferon beta-1a for relapsing multiple sclerosis. N Engl J Med. 2006;354(9):911–923.
   PubMed Web of Science ®Google Scholar
• Miller DH, Soon D, Fernando KT, et al. MRI outcomes in a placebo-controlled trial of natalizumab in relapsing MS. Neurology. 2007;68(17):1390–1401.
   PubMed Web of Science ®Google Scholar
• Rommer PS, Zettl UK, Kieseier B, et al. Requirement for safety monitoring for approved multiple sclerosis therapies: an overview. Clin Exp Immunol. 2014;175(3):397–407.
   PubMed Web of Science ®Google Scholar
• McGuigan C, Craner M, Guadagno J, et al. Stratification and monitoring of natalizumab-associated progressive multifocal leukoencephalopathy risk: recommendations from an expert group. J Neurol Neurosurg Psychiatry. 2016;87(2):117–125.
   PubMed Web of Science ®Google Scholar
• Bloomgren G, Richman S, Hotermans C, et al. Risk of natalizumab-associated progressive multifocal leukoencephalopathy. N Engl J Med. 1870-1880;366(20):2012.
   Google Scholar
• Plavina T, Subramanyam M, Bloomgren G, et al. Anti-JC virus antibody levels in serum or plasma further define risk of natalizumab-associated progressive multifocal leukoencephalopathy. Ann Neurol. 2014;76(6):802–812.
   PubMed Web of Science ®Google Scholar
• Torkildsen O, Myhr KM, Bo L. Disease-modifying treatments for multiple sclerosis – a review of approved medications. Eur J Neurol. 2016;23(Suppl 1):18–27.
   PubMed Web of Science ®Google Scholar
• Jones JL, Coles AJ. Mode of action and clinical studies with alemtuzumab. Exp Neurol. 2014;262(Pt A):37–43.
   PubMed Web of Science ®Google Scholar
• Singer BA. Parenteral treatment of multiple sclerosis: the advent of monoclonal antibodies. Semin Neurol. 2016;36(2):140–147.
   PubMed Web of Science ®Google Scholar
• Cohen JA, Arnold DL, Comi G, et al. Safety and efficacy of the selective sphingosine 1-phosphate receptor modulator ozanimod in relapsing multiple sclerosis (RADIANCE): a randomised, placebo-controlled, phase 2 trial. Lancet Neurol. 2016;15(4):373–381.
   PubMed Web of Science ®Google Scholar
• Coles AJ, Twyman CL, Arnold DL, et al. Alemtuzumab for patients with relapsing multiple sclerosis after disease-modifying therapy: a randomised controlled phase 3 trial. Lancet. 2012;380(9856):1829–1839.
   PubMed Web of Science ®Google Scholar
• Cohen JA, Coles AJ, Arnold DL, et al. Alemtuzumab versus interferon beta 1a as first-line treatment for patients with relapsing-remitting multiple sclerosis: a randomised controlled phase 3 trial. Lancet. 2012;380(9856):1819–1828.
   PubMed Web of Science ®Google Scholar
• Cossburn M, Pace AA, Jones J, et al. Autoimmune disease after alemtuzumab treatment for multiple sclerosis in a multicenter cohort. Neurology. 2011;77(6):573–579.
   PubMed Web of Science ®Google Scholar
• Tuohy O, Costelloe L, Hill-Cawthorne G, et al. Alemtuzumab treatment of multiple sclerosis: long-term safety and efficacy. J Neurol Neurosurg Psychiatry. 2015;86(2):208–215.
   PubMed Web of Science ®Google Scholar
• http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/003718/WC500150521.pdf).
   Google Scholar
• Bielekova B, Catalfamo M, Reichert-Scrivner S, et al. Regulatory CD56(bright) natural killer cells mediate immunomodulatory effects of IL-2Ralpha-targeted therapy (daclizumab) in multiple sclerosis. Proc Natl Acad Sci U S A. 2006;103(15):5941–5946.
   PubMed Web of Science ®Google Scholar
• Wynn D, Kaufman M, Montalban X, et al. Daclizumab in active relapsing multiple sclerosis (CHOICE study): a phase 2, randomised, double-blind, placebo-controlled, add-on trial with interferon beta. Lancet Neurol. 2010;9(4):381–390.
   PubMed Web of Science ®Google Scholar
• Gold R, Giovannoni G, Selmaj K, et al. Daclizumab high-yield process in relapsing-remitting multiple sclerosis (SELECT): a randomised, double-blind, placebo-controlled trial. Lancet. 2013;381(9884):2167–2175.
   PubMed Web of Science ®Google Scholar
• Giovannoni G, Gold R, Selmaj K, et al. Daclizumab high-yield process in relapsing-remitting multiple sclerosis (SELECTION): a multicentre, randomised, double-blind extension trial. Lancet Neurol. 2014;13(5):472–481.
   PubMed Web of Science ®Google Scholar
• Krueger JG, Kircik L, Hougeir F, et al. Cutaneous adverse events in the randomized, double-blind, active-comparator DECIDE study of daclizumab high-yield process versus intramuscular interferon beta-1a in relapsing-remitting multiple sclerosis. Adv Ther. 2016;33(7):1231–1245.
   PubMed Web of Science ®Google Scholar
• Cortese I, Ohayon J, Fenton K, et al. Cutaneous adverse events in multiple sclerosis patients treated with daclizumab. Neurology. 2016;86(9):847–855.
   PubMed Web of Science ®Google Scholar
• http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm504000.htm).
   Google Scholar
• Millefiorini E, Gasperini C, Pozzilli C, et al. Randomized placebo-controlled trial of mitoxantrone in relapsing-remitting multiple sclerosis: 24-month clinical and MRI outcome. J Neurol. 1997;244(3):153–159.
   PubMed Web of Science ®Google Scholar
• Hartung HP, Gonsette R, Konig N, et al. Mitoxantrone in progressive multiple sclerosis: a placebo-controlled, double-blind, randomised, multicentre trial. Lancet. 2018-2025;360(9350):2002.
   Google Scholar
• Li JM, Yang Y, Zhu P, et al. Mitoxantrone exerts both cytotoxic and immunoregulatory effects on activated microglial cells. Immunopharmacol Immunotoxicol. 2012;34(1):36–41.
   PubMed Web of Science ®Google Scholar
• Tanasescu R, Debouverie M, Pittion S, et al. Acute myeloid leukaemia induced by mitoxantrone in a multiple sclerosis patient. J Neurol. 2004;251(6):762–763.
   PubMed Web of Science ®Google Scholar
• Tanasescu R, Evangelou N, Constantinescu CS. Role of oral teriflunomide in the management of multiple sclerosis. Neuropsychiatr Dis Treat. 2013;9:539–553.
   PubMed Web of Science ®Google Scholar
• Li L, Liu J, Delohery T, et al. The effects of teriflunomide on lymphocyte subpopulations in human peripheral blood mononuclear cells in vitro. J Neuroimmunol. 2013;265(1–2):82–90.
   PubMed Web of Science ®Google Scholar
• O’Connor P, Wolinsky JS, Confavreux C, et al. Randomized trial of oral teriflunomide for relapsing multiple sclerosis. N Engl J Med. 2011;365(14):1293–1303.
   PubMed Web of Science ®Google Scholar
• Confavreux C, O’Connor P, Comi G, et al. Oral teriflunomide for patients with relapsing multiple sclerosis (TOWER): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Neurol. 2014;13(3):247–256.
   PubMed Web of Science ®Google Scholar
• Vermersch P, Czlonkowska A, Grimaldi LM, et al. Teriflunomide versus subcutaneous interferon beta-1a in patients with relapsing multiple sclerosis: a randomised, controlled phase 3 trial. Mult Scler. 2014;20(6):705–716.
   PubMed Web of Science ®Google Scholar
• Miller AE, Wolinsky JS, Kappos L, et al. Oral teriflunomide for patients with a first clinical episode suggestive of multiple sclerosis (TOPIC): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Neurol. 2014;13(10):977–986.
   PubMed Web of Science ®Google Scholar
• Comi G, Freedman MS, Kappos L, et al. Pooled safety and tolerability data from four placebo-controlled teriflunomide studies and extensions. Mult Scler Relat Disord. 2016;5:97–104.
   PubMed Web of Science ®Google Scholar
• Linker RA, Gold R. Dimethyl fumarate for treatment of multiple sclerosis: mechanism of action, effectiveness, and side effects. Curr Neurol Neurosci Rep. 2013;13(11):394.
   PubMed Web of Science ®Google Scholar
• Gold R, Kappos L, Arnold DL, et al. Placebo-controlled phase 3 study of oral BG-12 for relapsing multiple sclerosis. N Engl J Med. 2012;367(12):1098–1107.
   PubMed Web of Science ®Google Scholar
• Fox RJ, Miller DH, Phillips JT, et al. Placebo-controlled phase 3 study of oral BG-12 or glatiramer in multiple sclerosis. N Engl J Med. 2012;367(12):1087–1097.
   PubMed Web of Science ®Google Scholar
• Havrdova E, Hutchinson M, Kurukulasuriya NC, et al. Oral BG-12 (dimethyl fumarate) for relapsing-remitting multiple sclerosis: a review of DEFINE and CONFIRM. Evaluation of: Gold R, Kappos L, Arnold D, et al. Placebo-controlled phase 3 study of oral BG-12 for relapsing multiple sclerosis. N Engl J Med 2012;367:1098-107;and Fox RJ, Miller DH, Phillips JT, et al. Placebo-controlled phase 3 study of oral BG-12 or glatiramer in multiple sclerosis. N Engl J Med 2012;367:1087-97. Expert Opin Pharmacother. 2013;14(15):2145–2156.
   PubMed Web of Science ®Google Scholar
• Gold R, Arnold DL, Bar-Or A, et al. Long-term effects of delayed-release dimethyl fumarate in multiple sclerosis: interim analysis of ENDORSE, a randomized extension study. Mult Scler. 2016. doi:10.1177/1352458516649037
   Google Scholar
• Prosperini L, Pontecorvo S. Dimethyl fumarate in the management of multiple sclerosis: appropriate patient selection and special considerations. Ther Clin Risk Manag. 2016;12:339–350.
   PubMed Web of Science ®Google Scholar
• Longbrake EE, Naismith RT, Parks BJ, et al. Dimethyl fumarate-associated lymphopenia: risk factors and clinical significance. Mult Scler J Exp Transl Clin. 2015;1. doi:10.1177/2055217315596994
   PubMedGoogle Scholar
• Rosenkranz T, Novas M, Terborg C. PML in a patient with lymphocytopenia treated with dimethyl fumarate. N Engl J Med. 2015;372(15):1476–1478.
   PubMed Web of Science ®Google Scholar
• Sweetser MT, Dawson KT, Bozic C. Manufacturer’s response to case reports of PML. N Engl J Med. 1659-1661;368(17):2013.
   Google Scholar
• Reich K, Hartung HP, Lebwohl M. More on PML in patients treated with dimethyl fumarate. N Engl J Med. 2016;374(3):294–295.
   PubMed Web of Science ®Google Scholar
• Brinkmann V, Davis MD, Heise CE, et al. The immune modulator FTY720 targets sphingosine 1-phosphate receptors. J Biol Chem. 2002;277(24):21453–21457.
   PubMed Web of Science ®Google Scholar
• Tanasescu R, Constantinescu CS. Pharmacokinetic evaluation of fingolimod for the treatment of multiple sclerosis. Expert Opin Drug Metab Toxicol. 2014;10(4):621–630.
   PubMed Web of Science ®Google Scholar
• Groves A, Kihara Y, Chun J. Fingolimod: direct CNS effects of sphingosine 1-phosphate (S1P) receptor modulation and implications in multiple sclerosis therapy. J Neurol Sci. 2013;328(1–2):9–18.
   PubMed Web of Science ®Google Scholar
• 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(5):387–401.
   PubMed Web of Science ®Google Scholar
• Cohen JA, Barkhof F, Comi G, et al. Oral fingolimod or intramuscular interferon for relapsing multiple sclerosis. N Engl J Med. 2010;362(5):402–415.
   PubMed Web of Science ®Google Scholar
• Lublin F, Miller DH, Freedman MS, et al. Oral fingolimod in primary progressive multiple sclerosis (INFORMS): a phase 3, randomised, double-blind, placebo-controlled trial. Lancet. 2016;387(10023):1075–1084.
   PubMed Web of Science ®Google Scholar
• Ayzenberg I, Hoepner R, Kleiter I. Fingolimod for multiple sclerosis and emerging indications: appropriate patient selection, safety precautions, and special considerations. Ther Clin Risk Manag. 2016;12:261–272.
   PubMed Web of Science ®Google Scholar
• http://www.fda.gov/Drugs/DrugSafety/ucm303192.htm
   Google Scholar
• Cohen JA, Barkhof F, Comi G, et al. Oral fingolimod or intramuscular interferon for relapsing multiple sclerosis. New England J Med. 2010;362(5):402–415.
   PubMed Web of Science ®Google Scholar
• Khatri BO. Fingolimod in the treatment of relapsing-remitting multiple sclerosis: long-term experience and an update on the clinical evidence. Ther Adv Neurol Disord. 2016;9(2):130–147.
   PubMed Web of Science ®Google Scholar
• Hauser SL, Waubant E, Arnold DL, et al. B-cell depletion with rituximab in relapsing-remitting multiple sclerosis. N Engl J Med. 2008;358(7):676–688.
   PubMed Web of Science ®Google Scholar
• Hawker K, O’Connor P, Freedman MS, et al. Rituximab in patients with primary progressive multiple sclerosis: results of a randomized double-blind placebo-controlled multicenter trial. Ann Neurol. 2009;66(4):460–471.
   PubMed Web of Science ®Google Scholar
• Clifford DB, Ances B, Costello C, et al. Rituximab-associated progressive multifocal leukoencephalopathy in rheumatoid arthritis. Arch Neurol. 2011;68(9):1156–1164.
   PubMed Web of Science ®Google Scholar
• Topping J, Dobson R, Lapin S, et al. The effects of intrathecal rituximab on biomarkers in multiple sclerosis. Mult Scler Relat Disord. 2016;6:49–53.
   PubMed Web of Science ®Google Scholar
• Komori M, Lin YC, Cortese I, et al. Insufficient disease inhibition by intrathecal rituximab in progressive multiple sclerosis. Ann Clin Transl Neurol. 2016;3(3):166–179.
   PubMed Web of Science ®Google Scholar
• Berenguer-Ruiz L, Sempere AP, Gimenez-Martinez J, et al. Rescue therapy using rituximab for multiple sclerosis. Clin Neuropharmacol. 2016;39:178–181.
   PubMed Web of Science ®Google Scholar
• Alping P, Frisell T, Novakova L, et al. Rituximab versus fingolimod after natalizumab in multiple sclerosis patients. Ann Neurol. 2016;79(6):950–958.
   PubMed Web of Science ®Google Scholar
• Kappos L, Li D, Calabresi PA, et al. Ocrelizumab in relapsing-remitting multiple sclerosis: a phase 2, randomised, placebo-controlled, multicentre trial. Lancet. 2011;378(9805):1779–1787.
   PubMed Web of Science ®Google Scholar
• Hauser SCG, Hartung H-P, Selmaj K, et al. on behalf of the OPERA I and II clinical investigators. Efficacy and safety of ocrelizumab in relapsing multiple sclerosis – results of the interferon-beta-1a-controlled, double-blind, phase III OPERA I and II studies. In: ECTRIMS. Eds, Barcelona, Spain; 2015;116634. Available from: http://onlinelibrary.ectrims-congress.eu/ectrims/2015/31st/116634/stephen.hauser.efficacy.and.safety.of.ocrelizumab.in.relapsing.multiple.html?f=m3
   Google Scholar
• Traboulsee AL, Arnold D., Bar-Or A, et al. Ocrelizumab no evidence of disease activity (NEDA) status at 96 weeks in patients with relapsing multiple sclerosis: analysis of the phase III double-blind, double-dummy, interferon beta-1a-controlled OPERA I and OPERA II studies. In: the 68th Annual Meeting of the American Academy of Neurology. (Ed. (Eds) (Vancouver, British Columbia, 2016)
   Google Scholar
• Montalban XHB, Rammohan K, Giovannoni G et al. Efficacy and safety of ocrelizumab in primary progressive multiple sclerosis: results of the phase III double-blind, placebo-controlled ORATORIO study In: the 68th Annual Meeting of the American Academy of Neurology. (Ed. (Eds) (Vancouver, British Columbia, Canada, 2016)
   Google Scholar
• Sorensen PS, Lisby S, Grove R, et al. Safety and efficacy of ofatumumab in relapsing-remitting multiple sclerosis: a phase 2 study. Neurology. 2014;82(7):573–581.
   PubMed Web of Science ®Google Scholar
• Bar-Or A, Groves R, Austin D et al. The MIRROR study: a randomized, double-blind, placebo-controlled, parallel-group, dose-ranging study to investigate the safety and MRI efficacy of subcutaneous ofatumumab in subjects with relapsing-remitting multiple sclerosis (RRMS). In: the 66th Annual Meeting of the American Academy of Neurology(Ed.(Eds) (2014)
   Google Scholar
• Huynh E, Sigal D, Saven A. Cladribine in the treatment of hairy cell leukemia: initial and subsequent results. Leuk Lymphoma. 2009;50(Suppl 1):12–17.
   PubMed Web of Science ®Google Scholar
• Liliemark J. The clinical pharmacokinetics of cladribine. Clin Pharmacokinet. 1997;32(2):120–131.
   PubMed Web of Science ®Google Scholar
• Cladribine BE. (2-chlorodeoxyadenosine). Lancet. 1992;340(8825):952–956.
   PubMed Web of Science ®Google Scholar
• Thone J, Ellrichmann G. Oral available agents in the treatment of relapsing remitting multiple sclerosis: an overview of merits and culprits. Drug Healthc Patient Saf. 2013;5:37–47.
   PubMedGoogle Scholar
• Beutler E, Sipe JC, Romine JS, et al. The treatment of chronic progressive multiple sclerosis with cladribine. Proc Natl Acad Sci U S A. 1716-1720;93(4):1996.
   Google Scholar
• Sipe JC, Romine JS, Koziol JA, et al. Cladribine in treatment of chronic progressive multiple sclerosis. Lancet. 1994;344(8914):9–13.
   PubMed Web of Science ®Google Scholar
• Cook S, Vermersch P, Comi G, et al. Safety and tolerability of cladribine tablets in multiple sclerosis: the CLARITY (CLAdRIbine tablets treating multiple sclerosis orallY) study. Mult Scler. 2011;17(5):578–593.
   PubMed Web of Science ®Google Scholar
• Giovannoni GCG, Cook S, Rieckmann P et al. Clinical efficacy of cladribine tablets in patients with relapsing-remitting multiple sclerosis (RRMS): final results from the 120-week phase IIIb extension trial to the CLARITY study. In: the 68th Annual Meeting of the American Academy of Neurology. (Ed. (Eds) (Vancouver, British Columbia., 2016)
   Google Scholar
• Giancarlo C., Giovannoni G., Cook S. et al. Magnetic resonance imaging (MRI) outcomes in patients with relapsing-remitting multiple sclerosis (RRMS) treated with cladribine tablets: results from the 120-week phase IIIb extension of the CLARITY. In: the 68th Annual Meeting of the American Academy of Neurology. (Ed. (Eds) (Vancouver, British Columbia, 2016)
   Google Scholar
• Montalban XCB, Leist T, Moses H et al. Efficacy of cladribine tablets as add-on to IFN-beta therapy in patients with active relapsing MS: final results from the phase II ONWARD study In: the 68th Annual Meeting of the American Academy of Neurology(Ed.(Eds) (Vancouver, British Columbia, 2016)
   Google Scholar
• Leist TP, Comi G, Cree BA, et al. Effect of oral cladribine on time to conversion to clinically definite multiple sclerosis in patients with a first demyelinating event (ORACLE MS): a phase 3 randomised trial. Lancet Neurol. 2014;13(3):257–267.
   PubMed Web of Science ®Google Scholar
• Freedman MLT, Comi G, Cree B et al. Efficacy of cladribine tablets in ORACLE study patients who retrospectively met 2010 McDonald multiple sclerosis (MS) criteria at baseline. In: the 68th Annual Meeting of the American Academy of Neurology. (Ed. (Eds) (Vancouver, British Columbia., 2016)
   Google Scholar
• Agency EM. Refusal of the marketing authorization for Movectro (cladribine): outcome of re-examination, Eds. 2011 Jan 20. Available from: http://www.ema.europa.eu/docs/en_GB/document_library/Summary_of_opinion_-_Initial_authorisation/human/001197/WC500101072.pdf
   Google Scholar
• Pakpoor J, Disanto G, Altmann DR, et al. No evidence for higher risk of cancer in patients with multiple sclerosis taking cladribine. Neurol Neuroimmunol Neuroinflamm. 2015;2(6):e158.
   PubMed Web of Science ®Google Scholar
• Brueck W, Wegner C. Insight into the mechanism of laquinimod action. J Neurol Sci. 2011;306(1–2):173–179.
   PubMed Web of Science ®Google Scholar
• Kim W, Zandona ME, Kim SH, et al. Oral disease-modifying therapies for multiple sclerosis. J Clin Neurol. 2015;11(1):9–19.
   PubMed Web of Science ®Google Scholar
• Yang HS, Xu LY, Xiao BG, et al. Laquinimod (ABR-215062) suppresses the development of experimental autoimmune encephalomyelitis, modulates the Th1/Th2 balance and induces the Th3 cytokine TGF-beta in Lewis rats. J Neuroimmunol. 2004;156(1–2):3–9.
   PubMed Web of Science ®Google Scholar
• Thone J, Gold R. Laquinimod: a promising oral medication for the treatment of relapsing-remitting multiple sclerosis. Expert Opin Drug Metab Toxicol. 2011;7(3):365–370.
   PubMed Web of Science ®Google Scholar
• Filippi M, Rocca MA, Pagani E, et al. Placebo-controlled trial of oral laquinimod in multiple sclerosis: MRI evidence of an effect on brain tissue damage. J Neurol Neurosurg Psyc. 2014 Aug;85(8):851–858.
   Google Scholar
• Vollmer TL, Sorensen PS, Selmaj K, et al. A randomized placebo-controlled phase III trial of oral laquinimod for multiple sclerosis. J Neurol. 2014;261(4):773–783.
   PubMed Web of Science ®Google Scholar
• Varrin-Doyer M, Zamvil SS, Schulze-Topphoff U. Laquinimod an up-and-coming immunomodulatory agent for treatment of multiple sclerosis. Exp Neurol. 2014;262(Pt A):66–71.
   PubMed Web of Science ®Google Scholar
• Teva and active biotech announce discontinuation of higher doses of laquinimod in two multiple sclerosis trials. CONCERTO and ARPEGGIO Trials Continue Study of Lower-dose Laquinimod. (Ed. (Eds) (2016)
   Google Scholar
• Gonzalez-Cabrera PJ, Brown S, Studer SM, et al. S1P signaling: new therapies and opportunities. F1000Prime Rep. 2014;6:109.
   PubMedGoogle Scholar
• Selmaj K, Li DK, Hartung HP, et al. Siponimod for patients with relapsing-remitting multiple sclerosis (BOLD): an adaptive, dose-ranging, randomised, phase 2 study. Lancet Neurol. 2013;12(8):756–767.
   PubMed Web of Science ®Google Scholar
• Shirani A, Okuda DT, Stuve O. Therapeutic advances and future prospects in progressive forms of multiple sclerosis. Neurotherapeutics. 2016;13(1):58–69.
   PubMed Web of Science ®Google Scholar
• Ontaneda D, Fox RJ, Chataway J. Clinical trials in progressive multiple sclerosis: lessons learned and future perspectives. Lancet Neurol. 2015;14(2):208–223.
   PubMed Web of Science ®Google Scholar
• Peyro Saint Paul L, Debruyne D, Bernard D, et al. Pharmacokinetics and pharmacodynamics of MD1003 (high-dose biotin) in the treatment of progressive multiple sclerosis. Expert Opin Drug Metab Toxicol. 2016;12(3):327–344.
   PubMed Web of Science ®Google Scholar
• Sedel F, Papeix C, Bellanger A, et al. High doses of biotin in chronic progressive multiple sclerosis: a pilot study. Mult Scler Relat Disord. 2015;4(2):159–169.
   PubMed Web of Science ®Google Scholar
• Tourbah A, Lebrun-Frenay C, Edan G, et al. MD1003 (high doses of biotin) in progressive multiple sclerosis: subgroup analyses of the MS-SPI trial. In Eds. ECTRIMS. Barcelona, Spain; 2015 Oct 10;116698. Available from: http://onlinelibrary.ectrims-congress.eu/ectrims/2015/31st/116698/tourbah.ayman.md1003.(high.doses.of.biotin).in.progressive.multiple.sclerosis.html?f=m3
   Google Scholar
• Kummer S, Hermsen D, Distelmaier F. Biotin treatment mimicking Graves’ disease. N Engl J Med. 2016;375(7):704–706.
   PubMed Web of Science ®Google Scholar
• Elston MS, Sehgal S, Du Toit S, et al. Factitious Graves’ disease due to biotin immunoassay interference – a case and review of the literature. J Clin Endocrinol Metab. 2016 Sep;101(9):3251–3255.
   Google Scholar
• Karussis D, Petrou P, Vourka-Karussis U, et al. Hematopoietic stem cell transplantation in multiple sclerosis. Expert Rev Neurother. 2013;13(5):567–578.
   PubMed Web of Science ®Google Scholar
• Bakhuraysah MM, Siatskas C, Petratos S. Hematopoietic stem cell transplantation for multiple sclerosis: is it a clinical reality? Stem Cell Res Ther. 2016;7:12.
   PubMed Web of Science ®Google Scholar
• Reston JT, Uhl S, Treadwell JR, et al. Autologous hematopoietic cell transplantation for multiple sclerosis: a systematic review. Mult Scler. 2011;17(2):204–213.
   PubMed Web of Science ®Google Scholar
• Pfender N, Saccardi R, Martin R. Autologous hematopoietic stem cell transplantation as a treatment option for aggressive multiple sclerosis. Curr Treat Options Neurol. 2013;15(3):270–280.
   PubMed Web of Science ®Google Scholar
• Radaelli M, Merlini A, Greco R, et al. Autologous bone marrow transplantation for the treatment of multiple sclerosis. Curr Neurol Neurosci Rep. 2014;14(9):478.
   PubMed Web of Science ®Google Scholar
• Karussis D, Vourka-Karussis U, Mizrachi-Koll R, et al. Acute/relapsing experimental autoimmune encephalomyelitis: induction of long lasting, antigen-specific tolerance by syngeneic bone marrow transplantation. Mult Scler. 1999;5(1):17–21.
   PubMed Web of Science ®Google Scholar
• Muraro PA, Douek DC. Renewing the T cell repertoire to arrest autoimmune aggression. Trends Immunol. 2006;27(2):61–67.
   PubMed Web of Science ®Google Scholar
• Mancardi GL, Sormani MP, Gualandi F, et al. Autologous hematopoietic stem cell transplantation in multiple sclerosis: a phase II trial. Neurology. 2015;84(10):981–988.
   PubMed Web of Science ®Google Scholar
• Atkins HL, Bowman M, Allan D, et al. Immunoablation and autologous haemopoietic stem-cell transplantation for aggressive multiple sclerosis: a multicentre single-group phase 2 trial. Lancet. 2016;388(10044):576–585.
   PubMed Web of Science ®Google Scholar
• Freedman M, Atkins HL. Haematopoietic stem cell transplants should be a second-line therapy for highly active MS – YES. Mult Scler. 2016 Sep;22(10):1258–1259.
   Google Scholar
• Sorensen PS. Haematopoietic stem cell transplants should be a second-line therapy for highly active MS – NO. Mult Scler. 2016 Sep;22(10):1260–1263.
   Google Scholar
• Mowry EM. Haematopoietic stem cell transplants should be a second-line therapy for highly active MS – commentary. Mult Scler. 2016 Sep;22(10):1263–1265.
   Google Scholar
• Atkins HL, Freedman MS. Hematopoietic stem cell therapy for multiple sclerosis: top 10 lessons learned. Neurotherapeutics. 2013;10(1):68–76.
   PubMed Web of Science ®Google Scholar
• Lee H, Narayanan S, Brown RA, et al. Brain atrophy after bone marrow transplantation for treatment of multiple sclerosis. Mult Scler. 2016. doi:10.1177/1352458516650992
   Google Scholar
• Franklin RJ, Kotter MR. The biology of CNS remyelination: the key to therapeutic advances. J Neurol. 2008;255(Suppl 1):19–25.
   PubMed Web of Science ®Google Scholar
• Chari DM. Remyelination in multiple sclerosis. Int Rev Neurobiol. 2007;79:589–620.
   PubMed Web of Science ®Google Scholar
• Harlow DE, Macklin WB. Inhibitors of myelination: ECM changes, CSPGs and PTPs. Exp Neurol. 2014;251:39–46.
   PubMed Web of Science ®Google Scholar
• Lau LW, Cua R, Keough MB, et al. Pathophysiology of the brain extracellular matrix: a new target for remyelination. Nat Rev Neurosci. 2013;14(10):722–729.
   PubMed Web of Science ®Google Scholar
• Harlow DE, Honce JM, Miravalle AA. Remyelination therapy in multiple sclerosis. Front Neurol. 2015;6:257.
   PubMed Web of Science ®Google Scholar
• Peferoen L, Kipp M, van der Valk P, et al. Oligodendrocyte-microglia cross-talk in the central nervous system. Immunology. 2014;141(3):302–313.
   PubMed Web of Science ®Google Scholar
• Foote AK, Blakemore WF. Inflammation stimulates remyelination in areas of chronic demyelination. Brain. 2005;128(Pt 3):528–539.
   PubMed Web of Science ®Google Scholar
• Ruckh JM, Zhao JW, Shadrach JL, et al. Rejuvenation of regeneration in the aging central nervous system. Cell Stem Cell. 2012;10(1):96–103.
   PubMed Web of Science ®Google Scholar
• Munzel EJ, Williams A. Promoting remyelination in multiple sclerosis-recent advances. Drugs. 2017-2029;73(18):2013.
   Google Scholar
• Zendedel A, Beyer C, Kipp M. Cuprizone-induced demyelination as a tool to study remyelination and axonal protection. J Mol Neurosci. 2013;51(2):567–572.
   PubMed Web of Science ®Google Scholar
• Rodgers JM, Robinson AP, Miller SD. Strategies for protecting oligodendrocytes and enhancing remyelination in multiple sclerosis. Discov Med. 2013;16(86):53–63.
   PubMed Web of Science ®Google Scholar
• Keough MB, Yong VW. Remyelination therapy for multiple sclerosis. Neurotherapeutics. 2013;10(1):44–54.
   PubMed Web of Science ®Google Scholar
• Blanchard B, Heurtaux T, Garcia C, et al. Tocopherol derivative TFA-12 promotes myelin repair in experimental models of multiple sclerosis. J Neurosci. 2013;33(28):11633–11642.
   PubMed Web of Science ®Google Scholar
• Meffre D, Massaad C, Grenier J. Lithium chloride stimulates PLP and MBP expression in oligodendrocytes via Wnt/beta-catenin and Akt/CREB pathways. Neuroscience. 2015;284:962–971.
   PubMed Web of Science ®Google Scholar
• Preisner A, Albrecht S, Cui QL, et al. Non-steroidal anti-inflammatory drug indometacin enhances endogenous remyelination. Acta Neuropathol. 2015;130(2):247–261.
   PubMed Web of Science ®Google Scholar
• Huang JK, Jarjour AA, Nait Oumesmar B. et al. Retinoid X receptor gamma signaling accelerates CNS remyelination. Nat Neurosci. 2011;14(1):45–53.
   PubMed Web of Science ®Google Scholar
• de La Fuente AG, Errea O, van Wijngaarden P, et al. Vitamin D receptor-retinoid X receptor heterodimer signaling regulates oligodendrocyte progenitor cell differentiation. J Cell Biol. 2015;211(5):975–985.
   PubMed Web of Science ®Google Scholar
• Najm FJ, Madhavan M, Zaremba A, et al. Drug-based modulation of endogenous stem cells promotes functional remyelination in vivo. Nature. 2015;522(7555):216–220.
   PubMed Web of Science ®Google Scholar
• Trifunovski A, Josephson A, Ringman A, et al. Neuronal activity-induced regulation of Lingo-1. Neuroreport. 2004;15(15):2397–2400.
   PubMed Web of Science ®Google Scholar
• Mi S, Lee X, Shao Z, et al. LINGO-1 is a component of the Nogo-66 receptor/p75 signaling complex. Nat Neurosci. 2004;7(3):221–228.
   PubMed Web of Science ®Google Scholar
• Rudick RA, Mi S, Sandrock AW Jr. LINGO-1 antagonists as therapy for multiple sclerosis: in vitro and in vivo evidence. Expert Opin Biol Ther. 2008;8(10):1561–1570.
   PubMed Web of Science ®Google Scholar
• Wang CJ, Qu CQ, Zhang J, et al. Lingo-1 inhibited by RNA interference promotes functional recovery of experimental autoimmune encephalomyelitis. Anat Rec (Hoboken). 2014;297(12):2356–2363.
   PubMedGoogle Scholar
• Pepinsky RB, Shao Z, Ji B, et al. Exposure levels of anti-LINGO-1 Li81 antibody in the central nervous system and dose-efficacy relationships in rat spinal cord remyelination models after systemic administration. J Pharmacol Exp Ther. 2011;339(2):519–529.
   PubMed Web of Science ®Google Scholar
• Tran JQ, Rana J, Barkhof F, et al. Randomized phase I trials of the safety/tolerability of anti-LINGO-1 monoclonal antibody BIIB033. Neurol Neuroimmunol Neuroinflamm. 2014;1(2):e18.
   PubMedGoogle Scholar
• Cadavid D., KlistornerA., Chai Y., et al. on behalf of the RENEW Investigators. Evidence that the anti-LINGO-1 monoclonal antibody BIIB033 protects against multifocal visual evoked potential amplitude loss in the fellow eye of subjects with unilateral acute optic neuritis. In Eds. ECTRIMS. Barcelona, Spain; 2015 Oct 10;116697. Available from: http://onlinelibrary.ectrims-congress.eu/ectrims/2015/31st/116697/diego.cadavid.evidence.that.the.anti-lingo-1.monoclonal.antibody.biib033.html?f=m3
   Google Scholar
• Wang S, Bates J, Li X, et al. Human iPSC-derived oligodendrocyte progenitor cells can myelinate and rescue a mouse model of congenital hypomyelination. Cell Stem Cell. 2013;12(2):252–264.
   PubMed Web of Science ®Google Scholar
• Boyd A, Zhang H, Williams A. Insufficient OPC migration into demyelinated lesions is a cause of poor remyelination in MS and mouse models. Acta Neuropathol. 2013;125(6):841–859.
   PubMed Web of Science ®Google Scholar
• Arun T, Tomassini V, Sbardella E, et al. Targeting ASIC1 in primary progressive multiple sclerosis: evidence of neuroprotection with amiloride. Brain. 2013;136(Pt 1):106–115.
   PubMed Web of Science ®Google Scholar
• Yu XW, Hu ZL, Ni M, et al. Acid-sensing ion channels promote the inflammation and migration of cultured rat microglia. Glia. 2015;63(3):483–496.
   PubMed Web of Science ®Google Scholar
• Deshmukh VA, Tardif V, Lyssiotis CA, et al. A regenerative approach to the treatment of multiple sclerosis. Nature. 2013;502(7471):327–332.
   PubMed Web of Science ®Google Scholar
• Way SW, Podojil JR, Clayton BL, et al. Pharmaceutical integrated stress response enhancement protects oligodendrocytes and provides a potential multiple sclerosis therapeutic. Nat Commun. 2015;6:6532.
   PubMed Web of Science ®Google Scholar
• Bruck W, Pfortner R, Pham T, et al. Reduced astrocytic NF-kappaB activation by laquinimod protects from cuprizone-induced demyelination. Acta Neuropathol. 2012;124(3):411–424.
   PubMed Web of Science ®Google Scholar
• Comi G, Pulizzi A, Rovaris M, et al. Effect of laquinimod on MRI-monitored disease activity in patients with relapsing-remitting multiple sclerosis: a multicentre, randomised, double-blind, placebo-controlled phase IIb study. Lancet. 2008;371(9630):2085–2092.
   PubMed Web of Science ®Google Scholar
• Mishra MK, Wang J, Keough MB, et al. Laquinimod reduces neuroaxonal injury through inhibiting microglial activation. Ann Clin Transl Neurol. 2014;1(6):409–422.
   PubMed Web of Science ®Google Scholar
• Magalon K, Zimmer C, Cayre M, et al. Olesoxime accelerates myelination and promotes repair in models of demyelination. Ann Neurol. 2012;71(2):213–226.
   PubMed Web of Science ®Google Scholar
• Zhornitsky S, Wee Yong V, Koch MW, et al. Quetiapine fumarate for the treatment of multiple sclerosis: focus on myelin repair. CNS Neurosci Ther. 2013;19(10):737–744.
   PubMed Web of Science ®Google Scholar
• Warrington AE, Bieber AJ, Ciric B, et al. A recombinant human IgM promotes myelin repair after a single, very low dose. J Neurosci Res. 2007;85(5):967–976.
   PubMed Web of Science ®Google Scholar
• Pirko I, Ciric B, Gamez J, et al. A human antibody that promotes remyelination enters the CNS and decreases lesion load as detected by T2-weighted spinal cord MRI in a virus-induced murine model of MS. Faseb J. 2004;18(13):1577–1579.
   PubMed Web of Science ®Google Scholar
• Abramowski P, Krasemann S, Ernst T, et al. Mesenchymal stromal/stem cells do not ameliorate experimental autoimmune encephalomyelitis and are not detectable in the central nervous system of transplanted mice. Stem Cells Dev. 2016;25:1134–1148.
   PubMed Web of Science ®Google Scholar
• Meamar R, Nematollahi S, Dehghani L, et al. The role of stem cell therapy in multiple sclerosis: an overview of the current status of the clinical studies. Adv Biomed Res. 2016;5:46.
   PubMedGoogle Scholar
• Karussis D, Karageorgiou C, Vaknin-Dembinsky A, et al. Safety and immunological effects of mesenchymal stem cell transplantation in patients with multiple sclerosis and amyotrophic lateral sclerosis. Arch Neurol. 2010;67(10):1187–1194.
   PubMed Web of Science ®Google Scholar
• Amor S, Groome N, Linington C, et al. Identification of epitopes of myelin oligodendrocyte glycoprotein for the induction of experimental allergic encephalomyelitis in SJL and Biozzi AB/H mice. J Immunol. 1994;153(10):4349–4356.
   PubMed Web of Science ®Google Scholar
• Fritz RB, Chou CH, McFarlin DE. Relapsing murine experimental allergic encephalomyelitis induced by myelin basic protein. J Immunol. 1983;130(3):1024–1026.
   PubMed Web of Science ®Google Scholar
• Tuohy VK, Sobel RA, Lees MB. Myelin proteolipid protein-induced experimental allergic encephalomyelitis. Variations of disease expression in different strains of mice. J Immunol. 1988;140(6):1868–1873.
   PubMed Web of Science ®Google Scholar
• Johns TG, Kerlero de Rosbo N, Menon KK, et al. Myelin oligodendrocyte glycoprotein induces a demyelinating encephalomyelitis resembling multiple sclerosis. J Immunol. 1995;154(10):5536–5541.
   PubMed Web of Science ®Google Scholar
• Fissolo N, Montalban X, Comabella M. DNA-based vaccines for multiple sclerosis: current status and future directions. Clin Immunol. 2012;142(1):76–83.
   PubMed Web of Science ®Google Scholar
• Billetta R, Ghahramani N, Morrow O, et al. Epitope-specific immune tolerization ameliorates experimental autoimmune encephalomyelitis. Clin Immunol. 2012;145(2):94–101.
   PubMed Web of Science ®Google Scholar
• Spence A, Klementowicz JE, Bluestone JA, et al. Targeting Treg signaling for the treatment of autoimmune diseases. Curr Opin Immunol. 2015;37:11–20.
   PubMed Web of Science ®Google Scholar
• Lutterotti A, Martin R. Antigen-specific tolerization approaches in multiple sclerosis. Expert Opin Investig Drugs. 2014;23(1):9–20.
   PubMed Web of Science ®Google Scholar
• Bittner S, Wiendl H. Neuroimmunotherapies targeting T cells: from pathophysiology to therapeutic applications. Neurotherapeutics. 2016;13(1):4–19.
   PubMed Web of Science ®Google Scholar
• Lutterotti A, Yousef S, Sputtek A, et al. Antigen-specific tolerance by autologous myelin peptide-coupled cells: a phase 1 trial in multiple sclerosis. Sci Transl Med. 2013;5(188):188ra175.
   Web of Science ®Google Scholar
• Hellings N, Raus J, Stinissen P. T-cell vaccination in multiple sclerosis: update on clinical application and mode of action. Autoimmun Rev. 2004;3(4):267–275.
   PubMed Web of Science ®Google Scholar
• Vandenbark AA, Abulafia-Lapid R. Autologous T-cell vaccination for multiple sclerosis: a perspective on progress. BioDrugs. 2008;22(4):265–273.
   PubMed Web of Science ®Google Scholar
• Fox E, Wynn D, Cohan S, et al. A randomized clinical trial of autologous T-cell therapy in multiple sclerosis: subset analysis and implications for trial design. Mult Scler. 2012;18(6):843–852.
   PubMed Web of Science ®Google Scholar
• Karussis D, Shor H, Yachnin J, et al. T cell vaccination benefits relapsing progressive multiple sclerosis patients: a randomized, double-blind clinical trial. PLoS One. 2012;7(12):e50478.
   PubMed Web of Science ®Google Scholar
• Vesterinen HM, Connick P, Irvine CM, et al. Drug repurposing: a systematic approach to evaluate candidate oral neuroprotective interventions for secondary progressive multiple sclerosis. PLoS One. 2015;10(4):e0117705.
   PubMed Web of Science ®Google Scholar
• Chataway J, Schuerer N, Alsanousi A, et al. Effect of high-dose simvastatin on brain atrophy and disability in secondary progressive multiple sclerosis (MS-STAT): a randomised, placebo-controlled, phase 2 trial. Lancet. 2014;383(9936):2213–2221.
   PubMed Web of Science ®Google Scholar
• Raftopoulos R, Hickman SJ, Toosy A, et al. Phenytoin for neuroprotection in patients with acute optic neuritis: a randomised, placebo-controlled, phase 2 trial. Lancet Neurol. 2016;15(3):259–269.
   PubMed Web of Science ®Google Scholar
• Constantinescu CS, Goodman DB, Ventura ES. Captopril and lisinopril suppress production of interleukin-12 by human peripheral blood mononuclear cells. Immunol Lett. 1998;62(1):25–31.
   PubMed Web of Science ®Google Scholar
• Constantinescu CS, Ventura E, Hilliard B, et al. Effects of the angiotensin converting enzyme inhibitor captopril on experimental autoimmune encephalomyelitis. Immunopharmacol Immunotoxicol. 1995;17(3):471–491.
   PubMed Web of Science ®Google Scholar
• Abtahi Froushani SM, Delirezh N, Hobbenaghi R, et al. Synergistic effects of atorvastatin and all-trans retinoic acid in ameliorating animal model of multiple sclerosis. Immunol Invest. 2014;43(1):54–68.
   PubMed Web of Science ®Google Scholar
• Giovannoni G, Baker D, Schmierer K. The problem with repurposing: is there really an alternative to Big Pharma for developing new drugs for multiple sclerosis? Mult Scler Relat Disord. 2015;4(1):3–5.
   PubMed Web of Science ®Google Scholar
• Multiple Sclerosis Therapy Consensus G, Wiendl H, Toyka KV, et al. Basic and escalating immunomodulatory treatments in multiple sclerosis: current therapeutic recommendations. J Neurol 2008;255(10):1449–1463.
   PubMed Web of Science ®Google Scholar
• Ziemssen T, Derfuss T, de Stefano N, et al. Optimizing treatment success in multiple sclerosis. J Neurol. 2016 Jun;263(6):1053–1065.
   Google Scholar
• Coles A. Newer therapies for multiple sclerosis. Ann Indian Acad Neurol. 2015;18(Suppl 1):S30–34.
   PubMed Web of Science ®Google Scholar
• Giovannoni G, Turner B, Gnanapavan S, et al. Is it time to target no evident disease activity (NEDA) in multiple sclerosis? Mult Scler Relat Disord. 2015;4(4):329–333.
   PubMed Web of Science ®Google Scholar
• Rotstein DL, Healy BC, Malik MT, et al. Evaluation of no evidence of disease activity in a 7-year longitudinal multiple sclerosis cohort. JAMA Neurol. 2015;72(2):152–158.
   PubMed Web of Science ®Google Scholar
• Stangel M, Penner IK, Kallmann BA, et al. Towards the implementation of ‘no evidence of disease activity’ in multiple sclerosis treatment: the multiple sclerosis decision model. Ther Adv Neurol Disord. 2015;8(1):3–13.
   PubMed Web of Science ®Google Scholar
• Kappos L, De Stefano N, Freedman MS, et al. Inclusion of brain volume loss in a revised measure of ‘no evidence of disease activity’ (NEDA-4) in relapsing-remitting multiple sclerosis. Mult Scler. 2016 Sep;22(10):1297–1305
   Google Scholar
• Sormani MP, Arnold DL, De Stefano N. Treatment effect on brain atrophy correlates with treatment effect on disability in multiple sclerosis. Ann Neurol. 2014;75(1):43–49.
   PubMed Web of Science ®Google Scholar
• Ziemssen T, De Stefano N, Pia Sormani M, et al. Optimizing therapy early in multiple sclerosis: an evidence-based view. Mult Scler Relat Disord. 2015;4(5):460–469.
   PubMed Web of Science ®Google Scholar
• 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(9585):389–397.
   PubMed Web of Science ®Google Scholar
• Kappos L, Freedman MS, Polman CH, et al. Long-term effect of early treatment with interferon beta-1b after a first clinical event suggestive of multiple sclerosis: 5-year active treatment extension of the phase 3 BENEFIT trial. Lancet Neurol. 2009;8(11):987–997.
   PubMed Web of Science ®Google Scholar
• Coles AJ, Cox A, Le Page E, et al. The window of therapeutic opportunity in multiple sclerosis: evidence from monoclonal antibody therapy. J Neurol. 2006;253(1):98–108.
   PubMed Web of Science ®Google Scholar
• Kappos L, Edan G, Freedman MS, et al. The 11-year long-term follow-up study from the randomized BENEFIT CIS trial. Neurology. 2016;87:978–987.
   PubMed Web of Science ®Google Scholar
• Kappos L, O’Connor P, Radue EW, et al. Long-term effects of fingolimod in multiple sclerosis: the randomized FREEDOMS extension trial. Neurology. 2015;84(15):1582–1591.
   PubMed Web of Science ®Google Scholar
• Goodin DS, Reder AT, Ebers GC, et al. Survival in MS: a randomized cohort study 21 years after the start of the pivotal IFNbeta-1b trial. Neurology. 2012;78(17):1315–1322.
   PubMed Web of Science ®Google Scholar
• Bermel RA, You X, Foulds P, et al. Predictors of long-term outcome in multiple sclerosis patients treated with interferon beta. Ann Neurol. 2013;73(1):95–103.
   PubMed Web of Science ®Google Scholar
• Dobson R, Rudick RA, Turner B, et al. Assessing treatment response to interferon-beta: is there a role for MRI? Neurology. 2014;82(3):248–254.
   PubMed Web of Science ®Google Scholar
• Prosperini L, Mancinelli CR, De Giglio L, et al. Interferon beta failure predicted by EMA criteria or isolated MRI activity in multiple sclerosis. Mult Scler. 2014;20(5):566–576.
   PubMed Web of Science ®Google Scholar
• Rio J, Rovira A, Tintore M, et al. Relationship between MRI lesion activity and response to IFN-beta in relapsing-remitting multiple sclerosis patients. Mult Scler. 2008;14(4):479–484.
   PubMed Web of Science ®Google Scholar
• Sormani MP, De Stefano N. Defining and scoring response to IFN-beta in multiple sclerosis. Nat Rev Neurol. 2013;9(9):504–512.
   PubMed Web of Science ®Google Scholar
• Sormani MP, Rio J, Tintore M, et al. Scoring treatment response in patients with relapsing multiple sclerosis. Mult Scler. 2013;19(5):605–612.
   PubMed Web of Science ®Google Scholar
• Comabella M, Sastre-Garriga J, Montalban X. Precision medicine in multiple sclerosis: biomarkers for diagnosis, prognosis, and treatment response. Curr Opin Neurol. 2016;29(3):254–262.
   PubMed Web of Science ®Google Scholar
• Mistry N, Abdel-Fahim R, Samaraweera A, et al. Imaging central veins in brain lesions with 3-T T2*-weighted magnetic resonance imaging differentiates multiple sclerosis from microangiopathic brain lesions. Mult Scler. 2016 Sep;22(10):1289–1296
   Google Scholar
• Fialova L, Bartos A, Svarcova J, et al. Serum and cerebrospinal fluid light neurofilaments and antibodies against them in clinically isolated syndrome and multiple sclerosis. J Neuroimmunol. 2013;262(1–2):113–120.
   PubMed Web of Science ®Google Scholar
• Mollgaard M, Degn M, Sellebjerg F, et al. Cerebrospinal fluid chitinase-3-like 2 and chitotriosidase are potential prognostic biomarkers in early multiple sclerosis. Eur J Neurol. 2016;23(5):898–905.
   PubMed Web of Science ®Google Scholar
• Villar LM, Costa-Frossard L, Masterman T, et al. Lipid-specific immunoglobulin M bands in cerebrospinal fluid are associated with a reduced risk of developing progressive multifocal leukoencephalopathy during treatment with natalizumab. Ann Neurol. 2015;77(3):447–457.
   PubMed Web of Science ®Google Scholar
• Schwab N, Schneider-Hohendorf T, Pignolet B, et al. PML risk stratification using anti-JCV antibody index and L-selectin. Mult Scler. 2016;22(8):1048–1060.
   PubMed Web of Science ®Google Scholar
• Ascherio A, Munger KL. Epidemiology of multiple sclerosis: from risk factors to prevention – an update. Semin Neurol. 2016;36(2):103–114.
   PubMed Web of Science ®Google Scholar
• Tanasescu R, Constantinescu CS. Helminth therapy for MS. Curr Top Behav Neurosci. 2015;26:195–220.
   PubMedGoogle Scholar