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Review

An update on combination therapies for multiple sclerosis: where are we now?

ORCID Icon, &
Pages 1173-1187 | Received 10 Mar 2023, Accepted 27 Nov 2023, Published online: 06 Dec 2023

References

  • Comi G, Radaelli M, Soelberg Sorensen P. Evolving concepts in the treatment of relapsing multiple sclerosis. Lancet. 2017;389(10076):1347–1356. doi:10.1016/S0140-6736(16)32388-1
  • Duquette P, Girard M, Despault L, et al. Interferon beta-1B is effective in relapsing-remitting multiple-sclerosis - clinical-results of a multicenter, randomized, double-blind, placebo-controlled trial. Neurology. 1993;43(4):655–661.
  • Jacobs LD, Cookfair DL, Rudick RA, et al. Intramuscular interferon beta-1a for disease progression in relapsing multiple sclerosis. The MUltiple Sclerosis Collaborative Research Group (MSCRG). Ann Neurol. 1996;39(3):285–294. doi: 10.1002/ana.410390304
  • PRISMS Study Group. Randomised double-blind placebo-controlled study of interferon beta-1a in relapsing/remitting multiple sclerosis. Lancet. 1998;352(9139):1498–1504. doi: 10.1016/S0140-6736(98)03334-0
  • 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. The copolymer 1 multiple sclerosis study group [see comments]. Neurology. 1995;45(7):1268–1276.
  • Yong VW, Chabot S, Stuve O, et al. Interferon beta in the treatment of multiple sclerosis: mechanisms of action. Neurology. 1998;51(3):682–689. doi:10.1212/WNL.51.3.682
  • Gran B, Tranquill LR, Chen M, et al. Mechanisms of immunomodulation by glatiramer acetate. Neurology. 2000;55(11):1704–1714. doi: 10.1212/WNL.55.11.1704
  • Hauser SL, Dawson DM, Lehrich JR, et al. Intensive immunosuppression in progressive multiple sclerosis. A randomized, three-arm study of high-dose intravenous cyclophosphamide, plasma exchange, and ACTH. N Engl J Med. 1983;308(4):173–180.
  • Patzold U, Pocklington P. Azathioprine in multiple sclerosis–a 3 year controlled study of its effectiveness. J Neurol. 1980;223(2):97–117. doi:10.1007/BF00313173
  • Hartung HP, Gonsette R, Konig N, et al. Mitoxantrone in progressive multiple sclerosis: a placebo-controlled, double-blind, randomised, multicentre trial. Lancet. 2002;360(9350):2018–2025. doi: 10.1016/S0140-6736(02)12023-X
  • Martinelli V, Radaelli M, Straffi L, et al. Mitoxantrone: benefits and risks in multiple sclerosis patients. Neurol Sci. 2009;Suppl 30(S2):S167–S170. doi: 10.1007/s10072-009-0142-7
  • Miller AE. Oral teriflunomide in the treatment of relapsing forms of multiple sclerosis: clinical evidence and long-term experience. Ther Adv Neurol Disord. 2017;10(12):381–396. doi:10.1177/1756285617722500
  • Sorensen PS. New management algorithms in multiple sclerosis. Curr Opin Neurol. 2014;27(3):246–259. doi:10.1097/WCO.0000000000000096
  • Najjar E, Staun-Ram E, Volkowich A, et al. Dimethyl fumarate promotes B cell-mediated anti-inflammatory cytokine profile in B and T cells, and inhibits immune cell migration in patients with MS. J Neuroimmunol. 2020;343:577230. doi:10.1016/j.jneuroim.2020.577230
  • 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. doi: 10.1056/NEJMoa044397
  • Sellebjerg F, Cadavid D, Steiner D, et al. Exploring potential mechanisms of action of natalizumab in secondary progressive multiple sclerosis. Ther Adv Neurol Disord. 2016;9(1):31–43. doi:10.1177/1756285615615257
  • Cohen JA, Chun J. Mechanisms of fingolimod’s efficacy and adverse effects in multiple sclerosis. Ann Neurol. 2011;69(5):759–777. doi:10.1002/ana.22426
  • 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. doi: 10.1056/NEJMoa0909494
  • Comi G, Kappos L, Selmaj KW, et al. Safety and efficacy of ozanimod versus interferon beta-1a in relapsing multiple sclerosis (SUNBEAM): a multicentre, randomised, minimum 12-month, phase 3 trial. Lancet Neurol. 2019;18(11):1009–1020. doi: 10.1016/S1474-4422(19)30239-X
  • Kappos L, Bar-Or A, Cree BAC, et al. Siponimod versus placebo in secondary progressive multiple sclerosis (EXPAND): a double-blind, randomised, phase 3 study. Lancet. 2018;391(10127):1263–1273. doi: 10.1016/S0140-6736(18)30475-6
  • Kappos L, Fox RJ, Burcklen M, et al. Ponesimod compared with teriflunomide in patients with relapsing multiple sclerosis in the active-comparator phase 3 OPTIMUM study: a randomized clinical trial. JAMA Neurol. 2021;78(5):558–567. doi: 10.1001/jamaneurol.2021.0405
  • Giovannoni G, Comi G, Cook S, et al. A placebo-controlled trial of oral cladribine for relapsing multiple sclerosis. N Engl J Med. 2010;362(5):416–426. doi: 10.1056/NEJMoa0902533
  • Leist TP, Weissert R. Cladribine: mode of action and implications for treatment of multiple sclerosis. Clin Neuropharmacol. 2011;34(1):28–35. doi:10.1097/WNF.0b013e318204cd90
  • Hauser SL, Bar-Or A, Comi G, et al. Ocrelizumab versus Interferon Beta-1a in Relapsing Multiple Sclerosis. N Engl J Med. 2017;376(3):221–234. doi: 10.1056/NEJMoa1601277
  • 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. doi: 10.1056/NEJMoa0706383
  • Hauser SL, Bar-Or A, Cohen JA, et al. Ofatumumab versus teriflunomide in multiple sclerosis. N Engl J Med. 2020;383(6):546–557. doi: 10.1056/NEJMoa1917246
  • Sellebjerg F, Blinkenberg M, Sorensen PS. Anti-CD20 monoclonal antibodies for relapsing and progressive multiple sclerosis. CNS Drugs. 2020;34(3):269–280. doi:10.1007/s40263-020-00704-w
  • 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. doi: 10.1016/S0140-6736(12)61768-1
  • Hartung HP, Aktas O, Boyko AN. Alemtuzumab: a new therapy for active relapsing-remitting multiple sclerosis. Mult Scler. 2015;21(1):22–34. doi:10.1177/1352458514549398
  • Stuart WH. Combination therapy for the treatment of multiple sclerosis: challenges and opportunities. Curr Med Res Opin. 2007;23(6):1199–1208. doi:10.1185/030079907X187838
  • Rutherford GW, Sangani PR, Kennedy GE, Three- or four- versus two-drug antiretroviral maintenance regimens for HIV infection. Cochrane Database Syst Rev. 2003;4: CD002037. doi:10.1002/14651858.CD002037.
  • Greco A, Safi D, Swami U, et al. Efficacy and adverse events in metastatic melanoma patients treated with combination BRAF plus MEK inhibitors versus BRAF inhibitors: a systematic review. Cancers (Basel). 2019;11(12):1950.
  • Breedveld FC, Weisman MH, Kavanaugh AF, et al. The PREMIER study: a multicenter, randomized, double-blind clinical trial of combination therapy with adalimumab plus methotrexate versus methotrexate alone or adalimumab alone in patients with early, aggressive rheumatoid arthritis who had not had previous methotrexate treatment. Arthritis Rheum. 2006;54(1):26–37. doi: 10.1002/art.21519
  • Lublin FD, Cofield SS, Cutter GR, et al. Randomized study combining interferon and glatiramer acetate in multiple sclerosis. Ann Neurol. 2013;73(3):327–340. doi: 10.1002/ana.23863
  • Lublin FD, Cofield SS, Cutter GR, et al. Long-term follow-up of a randomized study of combination interferon and glatiramer acetate in multiple sclerosis: efficacy and safety results up to 7 years. Multi Sclerosis Relat Disord. 2017;18:95–102. doi: 10.1016/j.msard.2017.09.012
  • Lublin FD, Reingold SC. Combination therapy for treatment of multiple sclerosis. Ann Neurol. 1998;44(1):7–9. doi:10.1002/ana.410440106
  • Ozakbas S, Cinar BP, Kosehasanogullari G, et al. Monthly methylprednisolone in combination with interferon beta or glatiramer acetate for relapsing-remitting multiple sclerosis: a multicentre, single-blind, prospective trial. Clin Neurol Neurosur. 2017;160:69–72. doi:10.1016/j.clineuro.2017.06.016
  • Sorensen PS, Mellgren SI, Svenningsson A, et al. Nordic trial of oral methylprednisolone as add-on therapy to interferon beta-1a for treatment of relapsing-remitting multiple sclerosis (NORMIMS study): a randomised, placebo-controlled trial. Lancet Neurol. 2009;8(6):519–529. doi: 10.1016/S1474-4422(09)70085-7
  • Pozzilli C, Antonini G, Bagnato F, et al. Monthly corticosteroids decrease neutralizing antibodies to IFNβ1b: a randomized trial in multiple sclerosis. J Neurol. 2002;249(1):50–56. doi: 10.1007/PL00007847
  • Sorensen PS, Haas J, Sellebjerg F, et al. IV immunoglobulins as add-on treatment to methylprednisolone for acute relapses in MS. Neurology. 2004;63(11):2028–2033. doi:10.1212/01.WNL.0000145798.61383.39
  • Green AJ, Gelfand JM, Cree BA, et al. Clemastine fumarate as a remyelinating therapy for multiple sclerosis (ReBUILD): a randomised, controlled, double-blind, crossover trial. Lancet. 2017;390(10111):2481–2489. doi: 10.1016/S0140-6736(17)32346-2
  • Le Page E, Edan G. Induction or escalation therapy for patients with multiple sclerosis? Rev Neurol (Paris). 2018;174(6):449–457. doi:10.1016/j.neurol.2018.04.004
  • Comi G. Induction vs. escalating therapy in multiple sclerosis: practical implications. Neurol Sci. 2008;29 Suppl 2:S253–255. doi:10.1007/s10072-008-0954-x
  • Edan G, Miller D, Clanet M, et al. Therapeutic effect of mitoxantrone combined with methylprednisolone in multiple sclerosis: a randomised multicentre study of active disease using MRI and clinical criteria. J Neurol Neurosurg Psychiatry. 1997;62(2):112–118. doi: 10.1136/jnnp.62.2.112
  • Vollmer T, Panitch H, Bar-Or A, et al. Glatiramer acetate after induction therapy with mitoxantrone in relapsing multiple sclerosis. Mult Scler. 2008;14(5):663–670. doi: 10.1177/1352458507085759
  • Edan G, Comi G, Le PE, et al. Mitoxantrone prior to interferon beta-1b in aggressive relapsing multiple sclerosis: a 3-year randomised trial. J Neurol Neurosurg Psychiatry. 2011;82(12):1344–1350. doi: 10.1136/jnnp.2010.229724
  • 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. doi: 10.1056/NEJMoa044396
  • Goodman AD, Rossman H, Bar-Or A, et al. GLANCE: results of a phase 2, randomized, double-blind, placebo-controlled study. Neurology. 2009;72(9):806–812. doi: 10.1212/01.wnl.0000343880.13764.69
  • Togha M, Karvigh SA, Nabavi M, et al. Simvastatin treatment in patients with relapsing-remitting multiple sclerosis receiving interferon beta 1a: a double-blind randomized controlled trial. Mult Scler. 2010;16(7):848–854. doi: 10.1177/1352458510369147
  • Lanzillo R, Orefice G, Quarantelli M, et al. Atorvastatin combined to interferon to verify the efficacy (ACTIVE) in relapsing— remitting active multiple sclerosis patients: a longitudinal controlled trial of combination therapy. Mult Scler. 2010;16(4):450–454. doi: 10.1177/1352458509358909
  • Sorensen PS, Lycke J, Eralinna JP, et al. Simvastatin as add-on therapy to interferon beta-1a for relapsing-remitting multiple sclerosis (SIMCOMBIN study): a placebo-controlled randomised phase 4 trial. Lancet Neurol. 2011;10(8):691–701. doi: 10.1016/S1474-4422(11)70144-2
  • Kamm CP, El-Koussy M, Humpert S, et al. Atorvastatin added to interferon beta for relapsing multiple sclerosis: a randomized controlled trial. J Neurol. 2012;259(11):2401–2413. doi: 10.1007/s00415-012-6513-7
  • Lanzillo R, Quarantelli M, Pozzilli C, et al. No evidence for an effect on brain atrophy rate of atorvastatin add-on to interferon beta1b therapy in relapsing-remitting multiple sclerosis (the ARIANNA study). Mult Scler. 2016;22(9):1163–1173. doi: 10.1177/1352458515611222
  • Metz LM, Li D, Traboulsee A, et al. Glatiramer acetate in combination with minocycline in patients with relapsing—remitting multiple sclerosis: results of a Canadian, multicenter, double-blind, placebo-controlled trial. Mult Scler. 2009;15(10):1183–1194.
  • Sorensen PS, Sellebjerg F, Lycke J, et al. Minocycline added to subcutaneous interferon beta-1a in multiple sclerosis: randomized RECYCLINE study. Eur J Neurol. 2016;23(5):861–870. doi: 10.1111/ene.12953
  • Cohen JA, Imrey PB, Calabresi PA, et al. Results of the Avonex combination trial (ACT) in relapsing-remitting MS. Neurology. 2009;72(6):535–541. doi: 10.1212/01.wnl.0000341934.12142.74
  • Ravnborg M, Sorensen PS, Andersson M, et al. Methylprednisolone in combination with interferon beta-1a for relapsing-remitting multiple sclerosis (MECOMBIN study): a multicentre, double-blind, randomised, placebo-controlled, parallel-group trial. Lancet Neurol. 2010;9(7):672–680. doi: 10.1016/S1474-4422(10)70132-0
  • Havrdova E, Zivadinov R, Krasensky J, et al. Randomized study of interferon beta-1a, low-dose azathioprine, and low-dose corticosteroids in multiple sclerosis. Mult Scler. 2009;15(8):965–976. doi: 10.1177/1352458509105229
  • Voskuhl RR, Wang H, Wu TC, et al. Estriol combined with glatiramer acetate for women with relapsing-remitting multiple sclerosis: a randomised, placebo-controlled, phase 2 trial. Lancet Neurol. 2016;15(1):35–46. doi: 10.1016/S1474-4422(15)00322-1
  • Khoury SJ, Healy BC, Kivisakk P, et al. A randomized controlled double-masked trial of albuterol add-on therapy in patients with multiple sclerosis. Arch Neurol. 2010;67(9):1055–1061. doi: 10.1001/archneurol.2010.222
  • Kaiser CC, Shukla DK, Stebbins GT, et al. A pilot test of pioglitazone as an add-on in patients with relapsing remitting multiple sclerosis. J Neuroimmunol. 2009;211(1–2):124–130. doi: 10.1016/j.jneuroim.2009.04.011
  • Gonsette RE, Sindic C, D’Hooghe MB, et al. Boosting endogenous neuroprotection in multiple sclerosis: the ASsociation of Inosine and interferon β in relapsing- remitting multiple sclerosis (ASIIMS) trial. Mult Scler. 2010;16(4):455–462. doi: 10.1177/1352458509360547
  • Munoz Garcia D, Midaglia L, Martinez Vilela J, et al. Associated Inosine to interferon: results of a clinical trial in multiple sclerosis. Acta Neurol Scand. 2015;131(6):405–410. doi: 10.1111/ane.12333
  • Sorensen PS, Bertolotto A, Edan G, et al. Risk stratification for progressive multifocal leukoencephalopathy in patients treated with natalizumab. Mult Scler. 2012;18(2):143–152. doi: 10.1177/1352458511435105
  • Freedman MS, Wolinsky JS, Wamil B, et al. Teriflunomide added to interferon-beta in relapsing multiple sclerosis: a randomized phase II trial. Neurology. 2012;78(23):1877–1885. doi: 10.1212/WNL.0b013e318258f7d4
  • Ytterberg C, Johansson S, Andersson M, et al. Combination therapy with interferon-beta and glatiramer acetate in multiple sclerosis. Acta Neurol Scand. 2007;116(2):96–99. doi: 10.1111/j.1600-0404.2007.00801.x
  • 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.
  • Rudick RA, Pace A, Rani MR, et al. Effect of statins on clinical and molecular responses to intramuscular interferon beta-1a. Neurology. 2009;72(23):1989–1993. doi: 10.1212/WNL.0b013e3181a92b96
  • Birnbaum G, Cree B, Altafullah I, et al. Combining beta interferon and atorvastatin may increase disease activity in multiple sclerosis. Neurology. 2008;71(18):1390–1395. doi: 10.1212/01.wnl.0000319698.40024.1c
  • Ghasami K, Faraji F, Fazeli M, et al. Interferon beta-1a and atorvastatin in the treatment of multiple sclerosis. Iran J Immunol. 2016;13(1):16–26.
  • Maier K, Merkler D, Gerber J, et al. Multiple neuroprotective mechanisms of minocycline in autoimmune CNS inflammation. Neurobiol Dis. 2007;25(3):514–525. doi: 10.1016/j.nbd.2006.10.022
  • Metz LM, DKB L, Traboulsee AL, et al. Trial of minocycline in a clinically isolated syndrome of multiple sclerosis. N Engl J Med. 2017;376(22):2122–2133. doi: 10.1056/NEJMoa1608889
  • Beck RW, Cleary PA, Anderson MMJ, et al. A randomized, controlled trial of corticosteroids in the treatment of acute optic neuritis. The Optic Neuritis Study Group [see comments]. N Engl J Med. 1992;326(9):581–588.
  • Zivadinov R, Rudick RA, De Masi R, et al. Effects of IV methylprednisolone on brain atrophy in relapsing- remitting MS. Neurology. 2001;57(7):1239–1247. doi: 10.1212/WNL.57.7.1239
  • Smith DR, Weinstock-Guttman B, Cohen JA, et al. A randomized blinded trial of combination therapy with cyclophosphamide in patients-with active multiple sclerosis on interferon beta. Mult Scler. 2005;11(5):573–582. doi: 10.1191/1352458505ms1210oa
  • Kalincik T, Horakova D, Dolezal O, et al. Interferon, azathioprine and corticosteroids in multiple sclerosis: 6-year follow-up of the ASA cohort. Clin Neurol Neurosurg. 2012;114(7):940–946.
  • Milligan NM, Miller DH, Compston DA. A placebo-controlled trial of isoprinosine in patients with multiple sclerosis. J Neurol Neurosurg Psychiatry. 1994;57(2):164–168. doi: 10.1136/jnnp.57.2.164
  • Amato MP, Derfuss T, Hemmer B, et al. Environmental modifiable risk factors for multiple sclerosis: report from the 2016 ECTRIMS focused workshop. Mult Scler. 2018;1352458516686847(5):590–603.
  • Fitzgerald KC, Munger KL, Kochert K, et al. Association of vitamin D levels with multiple sclerosis activity and progression in patients receiving interferon beta-1b. JAMA Neurol. 2015;72(12):1458–1465. doi: 10.1001/jamaneurol.2015.2742
  • Müller T, Lohse L, Blodau A, et al. Vitamin D and Blood Parameters. Biomolecules. 2021 Jul 12;11(7):1017. doi: 10.3390/biom11071017
  • Soilu-Hanninen M, Aivo J, Lindstrom BM, et al. A randomised, double blind, placebo controlled trial with vitamin D3 as an add on treatment to interferon beta-1b in patients with multiple sclerosis. J Neurol Neurosurg Psychiatry. 2012;83(5):565–571. doi: 10.1136/jnnp-2011-301876
  • Shaygannejad V, Janghorbani M, Ashtari F, et al. Effects of adjunct low-dose vitamin d on relapsing-remitting multiple sclerosis progression: preliminary findings of a randomized placebo-controlled trial. Mult Scler Int. 2012;2012:452541. doi: 10.1155/2012/452541
  • Hupperts R, Smolders J, Vieth R, et al. Randomized trial of daily high-dose vitamin D3 in patients with RRMS receiving subcutaneous interferon beta-1a. Neurology. 2019;93(20):e1906–e1916. doi: 10.1212/WNL.0000000000008445
  • Jagannath VA, Filippini G, Di Pietrantonj C, et al. Vitamin D for the management of multiple sclerosis. Cochrane Database Syst Rev. 2018;9(6):CD008422.
  • Shaygannejad V, Janghorbani M, Savoj MR, et al. Effects of adjunct glucosamine sulfate on relapsing-remitting multiple sclerosis progression: preliminary findings of a randomized, placebo-controlled trial. Neurological res. 2010;32(9):981–985. doi:10.1179/016164110X12656393664964
  • Ramirez-Ramirez V, Macias-Islas MA, Ortiz GG, et al. Efficacy of fish oil on serum of TNF alpha, IL-1 beta, and IL-6 oxidative stress markers in multiple sclerosis treated with interferon beta-1b. Oxid Med Cell Longev. 2013;2013:709493. doi: 10.1155/2013/709493
  • Torkildsen O, Wergeland S, Bakke S, et al. ω-3 fatty acid treatment in multiple sclerosis (OFAMS study). Arch Neurol. 2012;69(8). doi: 10.1001/archneurol.2012.283
  • Lovera J, Ramos A, Devier D, et al. Polyphenon E, non-futile at neuroprotection in multiple sclerosis but unpredictably hepatotoxic: phase I single group and phase II randomized placebo-controlled studies. J Neurol Sci. 2015;358(1–2):46–52. doi: 10.1016/j.jns.2015.08.006
  • Koulinska I, Riester K, Chalkias S, et al. Effect of bismuth subsalicylate on gastrointestinal tolerability in healthy volunteers receiving oral delayed-release dimethyl fumarate: PREVENT, a randomized, multicenter, double-blind, placebo-controlled study. Clin Ther. 2018;40(12):2021–2030.e1. doi:10.1016/j.clinthera.2018.10.013
  • Sorensen PS. Antidrug Antibodies Against Biological Treatments for Multiple Sclerosis. CNS Drugs. 2022;36(6):569–589. doi:10.1007/s40263-022-00920-6
  • Sorensen PS, Koch-Henriksen N, Ross C, et al. Appearance and disappearance of neutralizing antibodies during interferon-beta therapy. Neurology. 2005;65(1):33–39. doi:10.1212/01.WNL.0000166049.51502.6A
  • Sorensen PS, Ross C, Clemmesen KM, et al. Clinical importance of neutralising antibodies against interferon beta in patients with relapsing-remitting multiple sclerosis. Lancet. 2003;362(9391):1184–1191. doi: 10.1016/S0140-6736(03)14541-2
  • Hesse D, Frederiksen JL, Koch-Henriksen N, et al. Methylprednisolone does not restore biological response in multiple sclerosis patients with neutralizing antibodies against interferon-β. Euro J Of Neurology. 2009;16(1):43–47. doi: 10.1111/j.1468-1331.2008.02336.x
  • Ravnborg M, Bendtzen K, Christensen O, et al. Treatment with azathioprine and cyclic methylprednisolone has little or no effect on bioactivity in anti-interferon beta antibody-positive patients with multiple sclerosis. Mult Scler. 2009;15(3):323–328. doi: 10.1177/1352458508099476
  • Visser LH, Beekman R, Tijssen CC, et al. A randomized, double-blind, placebo-controlled pilot study of i.V. immune globulins in combination with i.V. methylprednisolone in the treatment of relapses in patients with MS. Mult Scler. 2004;10(1):89–91. doi: 10.1191/1352458504ms978sr
  • Najmi Varzaneh F, Najmi Varzaneh F, Azimi AR, et al. Efficacy of combination therapy with erythropoietin and methylprednisolone in clinical recovery of severe relapse in multiple sclerosis. Acta Neurol Belg. 2014;114(4):273–278. doi:10.1007/s13760-014-0286-y
  • Borhani-Haghighi A, Ghodsi M, Razeghinejad MR, et al. Erythropoietin for acute multiple sclerosis in patients with optic neuritis as a first demyelination event. Neurosciences (Riyadh). 2012;17(2):151–155.
  • Mei F, Fancy SPJ, Shen YA, et al. Micropillar arrays as a high-throughput screening platform for therapeutics in multiple sclerosis. Nature Med. 2014;20(8):954–960. doi: 10.1038/nm.3618
  • Moghaddasi M, Nabovvati M, Koushki A, et al. Randomized control trial of evaluation of Clemastine effects on visual evoked potential, nerve fiber layer and ganglion cell layer complex in patients with optic neuritis. Clin Neurol Neurosur. 2020;193:105741. doi: 10.1016/j.clineuro.2020.105741
  • Schwartzbach CJ, Grove RA, Brown R, et al. Lesion remyelinating activity of GSK239512 versus placebo in patients with relapsing-remitting multiple sclerosis: a randomised, single-blind, phase II study. J Neurol. 2017;264(2):304–315. doi:10.1007/s00415-016-8341-7
  • Huang JK, Jarjour AA, Nait Oumesmar B, et al. Retinoid X receptor gamma signaling accelerates CNS remyelination. Nat Neurosci. 2011;14(1):45–53. doi: 10.1038/nn.2702
  • Brown JWL, Cunniffe NG, Prados F, et al. Safety and efficacy of bexarotene in patients with relapsing-remitting multiple sclerosis (CCMR one): a randomised, double-blind, placebo-controlled, parallel-group, phase 2a study. Lancet Neurol. 2021;20(9):709–720. doi: 10.1016/S1474-4422(21)00179-4
  • Mi S, Pepinsky RB, Cadavid D. Blocking LINGO-1 as a therapy to promote CNS repair: from concept to the clinic. CNS Drugs. 2013;27(7):493–503. doi:10.1007/s40263-013-0068-8
  • Tran JQ, Rana J, Barkhof F, et al. Randomized phase I trials of the safety/tolerability of anti-LINGO-1 monoclonal antibody BIIB033. Neurol(r) Neuroimmunol Neuroinflammation. 2014;1(2):e18. doi: 10.1212/NXI.0000000000000018
  • Cadavid D, Balcer L, Galetta S, et al. Safety and efficacy of opicinumab in acute optic neuritis (RENEW): a randomised, placebo-controlled, phase 2 trial. Lancet Neurol. 2017;16(3):189–199. doi: 10.1016/S1474-4422(16)30377-5
  • Cadavid D, Mellion M, Hupperts R, et al. Safety and efficacy of opicinumab in patients with relapsing multiple sclerosis (SYNERGY): a randomised, placebo-controlled, phase 2 trial. Lancet Neurol. 2019;18(9):845–856. doi: 10.1016/S1474-4422(19)30137-1
  • Brines M, Cerami A. Emerging biological roles for erythropoietin in the nervous system. Nat Rev Neurosci. 2005;6(6):484–494. doi:10.1038/nrn1687
  • Cervellini I, Ghezzi P, Mengozzi M. Therapeutic efficacy of erythropoietin in experimental autoimmune encephalomyelitis in mice, a model of multiple sclerosis. Methods Mol Biol. 2013;982:163–173.
  • Schreiber K, Magyari M, Sellebjerg F, et al. High-dose erythropoietin in patients with progressive multiple sclerosis: a randomized, placebo-controlled, phase 2 trial. Mult Scler. 2017;23(5):675–685. doi: 10.1177/1352458516661048
  • Lagreze WA, Kuchlin S, Ihorst G, et al. Safety and efficacy of erythropoietin for the treatment of patients with optic neuritis (TONE): a randomised, double-blind, multicentre, placebo-controlled study. Lancet Neurol. 2021;20(12):991–1000. doi: 10.1016/S1474-4422(21)00322-7
  • Chan D, Binks S, Nicholas JM, et al. Effect of high-dose simvastatin on cognitive, neuropsychiatric, and health-related quality-of-life measures in secondary progressive multiple sclerosis: secondary analyses from the MS-STAT randomised, placebo-controlled trial. Lancet Neurol. 2017;16(8):591–600. doi: 10.1016/S1474-4422(17)30113-8
  • Confavreux C, Saddier P, Grimaud J, et al. Risk of cancer from azathioprine therapy in multiple sclerosis: a case-control study. Neurology. 1996;46(6):1607–1612. doi:10.1212/WNL.46.6.1607
  • Correale J. BTK inhibitors as potential therapies for multiple sclerosis. Lancet Neurol. 2021;20(9):689–691. doi:10.1016/S1474-4422(21)00250-7
  • Schneider R, Oh J. Bruton’s tyrosine kinase inhibition in multiple sclerosis. Curr Neurol Neurosci Rep. 2022;22(11):721–734. doi:10.1007/s11910-022-01229-z

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