Skip to main content

Advertisement

SpringerLink
Log in

A comprehensive review on the treatment approaches of multiple sclerosis: currently and in the future

  • Review
  • Published:
Inflammation Research Aims and scope Submit manuscript

Abstract

Background

Multiple sclerosis (MS) is a chronic and autoimmune disease of the central nervous system (CNS), mainly characterized by inflammatory demyelination, which manifests as relapses and diffuse damage and brain volume loss, both accounting for neurodegeneration, and therefore, physical disability. MS typically affects young adults and is commonly diagnosed in the early years by acute relapses, which then followed through partial or complete remission period. The clinical course of MS is characterized as four major classifications, including relapsing–remitting (RRMS), primary progressive (PPMS), progressive relapsing (PRMS), and secondary progressive (SPMS).

Purpose

This review provides comprehensive overview of the current treatments and future innovative approaches in the treatment of MS.

Results

Currently, there is no definite cure for MS. The treatment of MS has mainly been based on the prescription of immunosuppressive and immune-modulating agents. However, a number of disease-modifying treatments (DMTs) have been designed that reduce the attack rate and delay progression and mainly target inflammation settings in these patients. Although remarkable advancements have occurred in the therapy of MS, the rate of progressive disability and early mortality is still worrisome. Recently, a monoclonal antibody (ocrelizumab) was demonstrated to be beneficial in a clinical trial of primary progressive MS. Furthermore, novel treatment strategies concentrating on the remyelination or neuroprotection are under evaluation.

Conclusions

In spite of prosperous experiences in MS therapy, the future research, hopefully, will bring substantial improvements in the understanding and approaches of MS therapy.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

  1. Coclitu C, Constantinescu CS, Tanasescu R. The future of multiple sclerosis treatments. Expert Rev Neurother. 2016;16(12):1341–56.

    Article  CAS  PubMed  Google Scholar 

  2. Javan M-R, Seyfizadeh N, Aslani S, Farhoodi M, Babaloo Z. Molecular analysis of interleukin-25 exons 1 and 2 and its serum levels in Iranian patients with multiple sclerosis. Am J Clin Exp Immunol. 2014;3(2):91.

    PubMed  PubMed Central  Google Scholar 

  3. Javan MR, Shahraki S, Safa A, Zamani MR, Salmaninejad A, Aslani S. An interleukin 12 B single nucleotide polymorphism increases IL-12p40 production and is associated with increased disease susceptibility in patients with relapsing-remitting multiple sclerosis. Neurol Res. 2017;39(5):435–41.

    Article  CAS  PubMed  Google Scholar 

  4. Javan MR, Aslani S, Zamani MR, Rostamnejad J, Asadi M, Farhoodi M, et al. Downregulation of immunosuppressive molecules, PD-1 and PD-L1 but not PD-L2, in the patients with multiple sclerosis. Iran J Allerg Asthma Immunol. 2016;15(4):296.

    Google Scholar 

  5. Azimi M, Ghabaee M, Moghadasi AN, Noorbakhsh F, Izad M. Immunomodulatory function of Treg-derived exosomes is impaired in patients with relapsing-remitting multiple sclerosis. Immunol Res. 2018. 1–8.

  6. Dendrou CA, Fugger L, Friese MA. Immunopathology of multiple sclerosis. Nat Rev Immunol. 2015;15(9):545–58.

    Article  CAS  PubMed  Google Scholar 

  7. Lublin FD, Reingold SC, Cohen JA, Cutter GR, Sørensen PS, Thompson AJ, et al. Defining the clinical course of multiple sclerosis The 2013 revisions. Neurology. 2014;83(3):278–86.

    Article  PubMed  PubMed Central  Google Scholar 

  8. Tanasescu R, Ionete C, Chou I-J, Constantinescu C. Advances in the treatment of relapsing-remitting multiple sclerosis. Biomed J. 2014;37(2):41.

    Article  PubMed  Google Scholar 

  9. Thomas RH, Wakefield RA. Oral disease-modifying therapies for relapsing-remitting multiple sclerosis. Am J Health Syst Pharm. 2015;72(1).

  10. Ali R, Nicholas RSJ, Muraro PA. Drugs in development for relapsing multiple sclerosis. Drugs. 2013;73(7):625–50.

    Article  CAS  PubMed  Google Scholar 

  11. Boster AL, Ford CC, Neudorfer O, Gilgun-Sherki Y. Glatiramer acetate: long-term safety and efficacy in relapsing-remitting multiple sclerosis. Expert Rev Neurother. 2015;15(6):575–86.

    Article  CAS  PubMed  Google Scholar 

  12. Johnson KP, Brooks B, Cohen J, Ford C, Goldstein J, Lisak R, 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. Neurology. 1995;45(7):1268–76.

    Article  CAS  PubMed  Google Scholar 

  13. Lugaresi A, Di Ioia M, Travaglini D, Pietrolongo E, Pucci E, Onofrj M. Risk–benefit considerations in the treatment of relapsing-remitting multiple sclerosis. Neuropsychiatr Dis Treat. 2013;9:893.

    Article  PubMed  PubMed Central  Google Scholar 

  14. Palace J, Duddy M, Bregenzer T, Lawton M, Zhu F, Boggild M, 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.

    Article  PubMed  Google Scholar 

  15. Ford C, Goodman A, Johnson K, Kachuck N, Lindsey J, Lisak R, 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 J. 2010;16(3):342–50.

    Article  CAS  Google Scholar 

  16. 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):283–96.

    Article  CAS  PubMed  Google Scholar 

  17. Polman CH, O’connor PW, Havrdova E, Hutchinson M, Kappos L, Miller DH, et al. A randomized, placebo-controlled trial of natalizumab for relapsing multiple sclerosis. N Engl J Med. 2006;354(9):899–910.

    Article  CAS  PubMed  Google Scholar 

  18. Miller D, Soon D, Fernando K, MacManus D, Barker G, Yousry T, et al. MRI outcomes in a placebo-controlled trial of natalizumab in relapsing MS. Neurology. 2007;68(17):1390–401.

    Article  CAS  PubMed  Google Scholar 

  19. Rommer P, Zettl U, Kieseier B, Hartung HP, Menge T, Frohman E, et al. Requirement for safety monitoring for approved multiple sclerosis therapies: an overview. Clin Exp Immunol. 2014;175(3):397–407.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. McGuigan C, Craner M, Guadagno J, Kapoor R, Mazibrada G, Molyneux P, et al. Stratification and monitoring of natalizumab-associated progressive multifocal leukoencephalopathy risk: recommendations from an expert group. J Neurol Neurosurg Psychiatry. 2015: jnnp-2015-311100.

  21. Bloomgren G, Richman S, Hotermans C, Subramanyam M, Goelz S, Natarajan A, et al. Risk of natalizumab-associated progressive multifocal leukoencephalopathy. N Engl J Med. 2012;366(20):1870–80.

    Article  CAS  PubMed  Google Scholar 

  22. Plavina T, Subramanyam M, Bloomgren G, Richman S, Pace A, Lee S, 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):802–12.

    Article  CAS  PubMed  Google Scholar 

  23. Torkildsen Ø, Myhr KM, Bø L. Disease-modifying treatments for multiple sclerosis—a review of approved medications. Eur J Neurol. 2016;23(S1):18–27.

    Article  PubMed  Google Scholar 

  24. Jones JL, Coles AJ. Mode of action and clinical studies with alemtuzumab. Exp Neurol. 2014;262:37–43.

    Article  CAS  PubMed  Google Scholar 

  25. Singer BA, editor. Parenteral treatment of multiple sclerosis: the advent of monoclonal antibodies. Seminars in neurology; 2016. Thieme Medical Publishers.

  26. Cohen JA, Arnold DL, Comi G, Bar-Or A, Gujrathi S, Hartung JP, 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):373–81.

    Article  CAS  PubMed  Google Scholar 

  27. Coles AJ, Twyman CL, Arnold DL, Cohen JA, Confavreux C, Fox EJ, et al. Alemtuzumab for patients with relapsing multiple sclerosis after disease-modifying therapy: a randomised controlled phase 3 trial. Lancet. 2012;380(9856):1829–39.

    Article  CAS  PubMed  Google Scholar 

  28. Cohen JA, Coles AJ, Arnold DL, Confavreux C, Fox EJ, Hartung H-P, 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):1819–28.

    Article  CAS  PubMed  Google Scholar 

  29. Bielekova B, Catalfamo M, Reichert-Scrivner S, Packer A, Cerna M, Waldmann TA, et al. Regulatory CD56bright natural killer cells mediate immunomodulatory effects of IL-2Rα-targeted therapy (daclizumab) in multiple sclerosis. Proc Natl Acad Sci. 2006;103(15):5941–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Wynn D, Kaufman M, Montalban X, Vollmer T, Simon J, Elkins J, 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):381–90.

    Article  CAS  PubMed  Google Scholar 

  31. Gold R, Giovannoni G, Selmaj K, Havrdova E, Montalban X, Radue E-W, et al. Daclizumab high-yield process in relapsing-remitting multiple sclerosis (SELECT): a randomised, double-blind, placebo-controlled trial. The Lancet. 2013;381(9884):2167–75.

    Article  CAS  Google Scholar 

  32. Giovannoni G, Gold R, Selmaj K, Havrdova E, Montalban X, Radue E-W, et al. Daclizumab high-yield process in relapsing-remitting multiple sclerosis (SELECTION): a multicentre, randomised, double-blind extension trial. Lancet Neurol. 2014;13(5):472–81.

    Article  CAS  PubMed  Google Scholar 

  33. Cortese I, Ohayon J, Fenton K, Lee C-C, Raffeld M, Cowen EW, et al. Cutaneous adverse events in multiple sclerosis patients treated with daclizumab. Neurology. 2016;86(9):847–55.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Baldassari LE, Rose JW. Daclizumab: development, clinical trials, and practical aspects of use in multiple sclerosis. Neurotherapeutics. 2017:1–17.

  35. Li J-M, Yang Y, Zhu P, Zheng F, Gong F-L, Mei Y-W. Mitoxantrone exerts both cytotoxic and immunoregulatory effects on activated microglial cells. Immunopharmacol Immunotoxicol. 2012;34(1):36–41.

    Article  CAS  PubMed  Google Scholar 

  36. Millefiorini E, Gasperini C, Pozzilli C, D’andrea F, Bastianello S, Trojano M, et al. Randomized placebo-controlled trial of mitoxantrone in relapsing-remitting multiple sclerosis: 24-month clinical and MRI outcome. J Neurol. 1997;244(3):153–9.

    Article  CAS  PubMed  Google Scholar 

  37. Hartung H-P, Gonsette R, Konig N, Kwiecinski H, Guseo A, Morrissey SP, et al. Mitoxantrone in progressive multiple sclerosis: a placebo-controlled, double-blind, randomised, multicentre trial. Lancet. 2002;360(9350):2018–25.

    Article  PubMed  Google Scholar 

  38. Tanasescu R, Debouverie M, Pittion S, Anxionnat R, Vespignani H. Acute myeloid leukaemia induced by mitoxantrone in a multiple sclerosis patient. J Neurol. 2004;251(6):762–3.

    Article  PubMed  Google Scholar 

  39. Tanasescu R, Evangelou N, Constantinescu CS. Role of oral teriflunomide in the management of multiple sclerosis. Neuropsychiatr Dis Treat. 2013;9:539.

    CAS  PubMed  PubMed Central  Google Scholar 

  40. O’connor P, Wolinsky JS, Confavreux C, Comi G, Kappos L, Olsson TP, et al. Randomized trial of oral teriflunomide for relapsing multiple sclerosis. N Engl J Med. 2011;365(14):1293–303.

    Article  PubMed  Google Scholar 

  41. Confavreux C, O’Connor P, Comi G, Freedman MS, Miller AE, Olsson TP, 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):247–56.

    Article  CAS  PubMed  Google Scholar 

  42. Vermersch P, Czlonkowska A, Grimaldi LM, Confavreux C, Comi G, Kappos L, et al. Teriflunomide versus subcutaneous interferon beta-1a in patients with relapsing multiple sclerosis: a randomised, controlled phase 3 trial. Mult Scler J. 2014;20(6):705–16.

    Article  CAS  Google Scholar 

  43. Miller AE, Wolinsky JS, Kappos L, Comi G, Freedman MS, Olsson TP, 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):977–86.

    Article  CAS  PubMed  Google Scholar 

  44. Comi G, Freedman MS, Kappos L, Olsson TP, Miller AE, Wolinsky JS, et al. Pooled safety and tolerability data from four placebo-controlled teriflunomide studies and extensions. Mult Scler Relat Disord. 2016;5:97–104.

    Article  PubMed  Google Scholar 

  45. 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.

    Article  CAS  PubMed  Google Scholar 

  46. Gold R, Kappos L, Arnold DL, Bar-Or A, Giovannoni G, Selmaj K, et al. Placebo-controlled phase 3 study of oral BG-12 for relapsing multiple sclerosis. N Engl J Med. 2012;367(12):1098–107.

    Article  CAS  PubMed  Google Scholar 

  47. Havrdova E, Hutchinson M, Kurukulasuriya NC, Raghupathi K, Sweetser MT, Dawson KT 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):2145–56.

    Article  CAS  PubMed  Google Scholar 

  48. Gold R, Arnold DL, Bar-Or A, Hutchinson M, Kappos L, Havrdova E, et al. Long-term effects of delayed-release dimethyl fumarate in multiple sclerosis: Interim analysis of ENDORSE, a randomized extension study. Mult Scler J. 2017;23(2):253–65.

    Article  CAS  Google Scholar 

  49. Brinkmann V, Davis MD, Heise CE, Albert R, Cottens S, Hof R, et al. The immune modulator FTY720 targets sphingosine 1-phosphate receptors. J Biol Chem. 2002;277(24):21453–7.

    Article  CAS  PubMed  Google Scholar 

  50. Tanasescu R, Constantinescu CS. Pharmacokinetic evaluation of fingolimod for the treatment of multiple sclerosis. Expert Opin Drug Metab Toxicol. 2014;10(4):621–30.

    Article  CAS  PubMed  Google Scholar 

  51. 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):9–18.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Kappos L, Radue E-W, O’connor P, Polman C, Hohlfeld R, Calabresi P, et al. A placebo-controlled trial of oral fingolimod in relapsing multiple sclerosis. N Engl J Med. 2010;362(5):387–401.

    Article  CAS  PubMed  Google Scholar 

  53. Cohen JA, Barkhof F, Comi G, Hartung H-P, Khatri BO, Montalban X, et al. Oral fingolimod or intramuscular interferon for relapsing multiple sclerosis. N Engl J Med. 2010;362(5):402–15.

    Article  CAS  PubMed  Google Scholar 

  54. Lublin F, Miller DH, Freedman MS, Cree BA, Wolinsky JS, Weiner H, et al. Oral fingolimod in primary progressive multiple sclerosis (INFORMS): a phase 3, randomised, double-blind, placebo-controlled trial. Lancet. 2016;387(10023):1075–84.

    Article  CAS  PubMed  Google Scholar 

  55. 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.

    CAS  PubMed  PubMed Central  Google Scholar 

  56. Hauser SL, Waubant E, Arnold DL, Vollmer T, Antel J, Fox RJ, et al. B-cell depletion with rituximab in relapsing–remitting multiple sclerosis. N Engl J Med. 2008;358(7):676–88.

    Article  CAS  PubMed  Google Scholar 

  57. Komori M, Lin YC, Cortese I, Blake A, Ohayon J, Cherup J, et al. Insufficient disease inhibition by intrathecal rituximab in progressive multiple sclerosis. Ann Clin Transl Neurol. 2016;3(3):166–79.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Berenguer-Ruiz L, Sempere AP, Gimenez-Martinez J, Gabaldon-Torres L, Tahoces L, Sanchez-Perez R, et al. Rescue therapy using rituximab for multiple sclerosis. Clin Neuropharmacol. 2016;39(4):178–81.

    Article  CAS  PubMed  Google Scholar 

  59. Alping P, Frisell T, Novakova L, Islam-Jakobsson P, Salzer J, Björck A, et al. Rituximab versus fingolimod after natalizumab in multiple sclerosis patients. Ann Neurol. 2016;79(6):950–8.

    Article  CAS  PubMed  Google Scholar 

  60. Kappos L, Li D, Calabresi PA, O’Connor P, Bar-Or A, Barkhof F, et al. Ocrelizumab in relapsing-remitting multiple sclerosis: a phase 2, randomised, placebo-controlled, multicentre trial. Lancet. 2011;378(9805):1779–87.

    Article  CAS  PubMed  Google Scholar 

  61. Hauser S, Comi G, Hartung H, Selmaj K, Traboulsee A, Bar-Or A. 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 ECTRIMS Online Libr. 2015;116634.

  62. Traboulsee A, Arnold D, Bar-Or A, Comi G, Hartung H-P, Kappos L, 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 (PL02. 004). Neurology. 2016;86(16 Supplement):PL02.004.

    Google Scholar 

  63. Montalban X, Hemmer B, Rammohan K, Giovannoni G, De Seze J, Bar-Or A. Efficacy and safety of ocrelizumab in primary progressive multiple sclerosis-results of the placebo-controlled, double-blind, Phase III ORATORIO study. Mult Scler. 2015;21(S1):781–2.

    Google Scholar 

  64. Sorensen PS, Lisby S, Grove R, Derosier F, Shackelford S, Havrdova E, et al. Safety and efficacy of ofatumumab in relapsing-remitting multiple sclerosis A phase 2 study. Neurology. 2014;82(7):573–81.

    Article  CAS  PubMed  Google Scholar 

  65. Bar-Or A, Grove R, Austin D, Tolson J, Vanmeter S, Lewis E, 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)(I7-1.007). Neurology. 2014;82(10 Supplement):I7-1.007.

    Google Scholar 

  66. Brück W, Wegner C. Insight into the mechanism of laquinimod action. J Neurol Sci. 2011;306(1):173–9.

    Article  CAS  PubMed  Google Scholar 

  67. Kim W, Zandoná ME, Kim S-H, Kim HJ. Oral disease-modifying therapies for multiple sclerosis. J Clin Neurol. 2015;11(1):9–19.

    Article  PubMed  PubMed Central  Google Scholar 

  68. Yang J-S, Xu L-Y, Xiao B-G, Hedlund G, Link H. Laquinimod (ABR-215062) suppresses the development of experimental autoimmune encephalomyelitis, modulates the Th1/Th2 balance and induces the Th3 cytokine TGF-β in Lewis rats. J Neuroimmunol. 2004;156(1):3–9.

    Article  CAS  PubMed  Google Scholar 

  69. Thöne J, Gold R. Laquinimod: a promising oral medication for the treatment of relapsing-remitting multiple sclerosis. Expert Opin Drug Metab Toxicol. 2011;7(3):365–70.

    Article  CAS  PubMed  Google Scholar 

  70. Filippi M, Rocca MA, Pagani E, De Stefano N, Jeffery D, Kappos L, et al. Placebo-controlled trial of oral laquinimod in multiple sclerosis: MRI evidence of an effect on brain tissue damage. J Neurol Neurosurg Psychiatry. 2013:jnnp-2013-306132.

  71. Vollmer T, Sorensen P, Selmaj K, Zipp F, Havrdova E, Cohen J, et al. A randomized placebo-controlled phase III trial of oral laquinimod for multiple sclerosis. J Neurol. 2014;261(4):773–83.

    Article  CAS  PubMed  Google Scholar 

  72. Varrin-Doyer M, Zamvil SS, Schulze-Topphoff U. Laquinimod, an up-and-coming immunomodulatory agent for treatment of multiple sclerosis. Exp Neurol. 2014;262:66–71.

    Article  CAS  PubMed  Google Scholar 

  73. Huynh E, Sigal D, Saven A. Cladribine in the treatment of hairy cell leukemia: initial and subsequent results. Leuk Lymphoma. 2009;50(sup1):12–7.

    Article  CAS  PubMed  Google Scholar 

  74. Beutler E. Cladribine (2-chlorodeoxyadenosine). Lancet. 1992;340(8825):952–6.

    Article  CAS  PubMed  Google Scholar 

  75. Thöne 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Beutler E, Sipe J, Romine J, Koziol J, McMillan R, Zyroff J. The treatment of chronic progressive multiple sclerosis with cladribine. Proc Natl Acad Sci. 1996;93(4):1716–20.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Sipe J, Romine J, Koziol J, McMillan R, Beutler E, Zyroff J. Cladribine in treatment of chronic progressive multiple sclerosis. Lancet. 1994;344(8914):9–13.

    Article  CAS  PubMed  Google Scholar 

  78. Cook S, Vermersch P, Comi G, Giovannoni G, Rammohan K, Rieckmann P, et al. Safety and tolerability of cladribine tablets in multiple sclerosis: the CLARITY (CLAdRIbine tablets treating multiple sclerosis orallY) study. Mult Scler Jo. 2011;17(5):578–93.

    Article  CAS  Google Scholar 

  79. Giovannoni G, Comi G, Cook S, Rieckmann P, Rammohan K, Soelberg-Soerensenn 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 (P3. 028). Neurology. 2016;86(16 Supplement):P3.028.

    Google Scholar 

  80. Comi G, Cook S, Giovannoni G, Rammohan K, Rieckmann P, Soelberg-Sorensen P et al, editors. Magnetic resonance imaging (MRI) outcomes in patients with relapsing-remitting multiple sclerosis (RRMS) treated with cladribine tablets: results from the CLARITY study, a 96-week, phase III, double-blind, placebo-controlled trial. J Neurol; 2009 (Dr Dietrich Steinkopff Verlag).

  81. Montalban X, Cohen B, Leist T, Moses H, Hicking C, Dangond F. 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 (P3. 029). Neurology. 2016;86(16 Supplement):P3.029.

    Google Scholar 

  82. Leist TP, Comi G, Cree BA, Coyle PK, Freedman MS, Hartung H-P, 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):257–67.

    Article  CAS  PubMed  Google Scholar 

  83. Freedman M, Leist T, Comi G, Cree B, Coyle P, Hartung H-P, et al. Efficacy of cladribine tablets in ORACLE study patients who retrospectively met 2010 McDonald multiple sclerosis (MS) criteria at baseline (P3. 035). Neurology. 2016;86(16 Supplement):P3.035.

    Google Scholar 

  84. Pakpoor J, Disanto G, Altmann DR, Pavitt S, Turner BP, Marta M, et al. No evidence for higher risk of cancer in patients with multiple sclerosis taking cladribine. Neurol Neuroimmunol Neuroinflamm. 2015;2(6):e158.

    Article  PubMed  PubMed Central  Google Scholar 

  85. Gonzalez-Cabrera PJ, Brown S, Studer SM, Rosen H. S1P signaling: new therapies and opportunities. F1000 prime reports. 2014;6.

  86. Selmaj K, Li DK, Hartung H-P, Hemmer B, Kappos L, Freedman MS, et al. Siponimod for patients with relapsing-remitting multiple sclerosis (BOLD): an adaptive, dose-ranging, randomised, phase 2 study. Lancet Neurol. 2013;12(8):756–67.

    Article  CAS  PubMed  Google Scholar 

  87. Karussis D, Vourka-Karussis U, Mizrachi-Koll R, Abramsky O. Acute/relapsing experimental autoimmune encephalomyelitis: induction of long lasting, antigen-specific tolerance by syngeneic bone marrow transplantation. Mult Scler J. 1999;5(1):017–21.

    Article  CAS  Google Scholar 

  88. Radaelli M, Merlini A, Greco R, Sangalli F, Comi G, Ciceri F, et al. Autologous bone marrow transplantation for the treatment of multiple sclerosis. Curr Neurol Neurosci Rep. 2014;14(9):478.

    Article  CAS  PubMed  Google Scholar 

  89. Muraro PA, Douek DC. Renewing the T cell repertoire to arrest autoimmune aggression. Trends Immunol. 2006;27(2):61–7.

    Article  CAS  PubMed  Google Scholar 

  90. Karussis D, Petrou P, Vourka-Karussis U, Kassis I. Hematopoietic stem cell transplantation in multiple sclerosis. Expert Rev Neurother. 2013;13(5):567–78.

    Article  CAS  PubMed  Google Scholar 

  91. Mancardi GL, Sormani MP, Gualandi F, Saiz A, Carreras E, Merelli E, et al. Autologous hematopoietic stem cell transplantation in multiple sclerosis A phase II trial. Neurology. 2015;84(10):981–8.

    Article  CAS  PubMed  Google Scholar 

  92. Atkins HL, Bowman M, Allan D, Anstee G, Arnold DL, Bar-Or A, et al. Immunoablation and autologous haemopoietic stem-cell transplantation for aggressive multiple sclerosis: a multicentre single-group phase 2 trial. Lancet. 2016;388(10044):576–85.

    Article  PubMed  Google Scholar 

  93. Freedman M, Atkins HL. Haematopoietic stem cell transplants should be a second-line therapy for highly active MS–YES. Mult Scler J. 2016:1352458516654311.

  94. Soelberg Sorensen P. Haematopoietic stem cell transplants should be a second-line therapy for highly active MS–NO. Mult Scler J. 2016;22(10):1260–3.

    Article  Google Scholar 

  95. Franklin RJ, Kotter MR. The biology of CNS remyelination. J Neurol. 2008;255:19–25.

    Article  CAS  PubMed  Google Scholar 

  96. Peferoen L, Kipp M, Valk P, Noort JM, Amor S. Oligodendrocyte-microglia cross-talk in the central nervous system. Immunology. 2014;141(3):302–13.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Foote A, Blakemore W. Inflammation stimulates remyelination in areas of chronic demyelination. Brain. 2005;128(3):528–39.

    Article  CAS  PubMed  Google Scholar 

  98. Münzel EJ, Williams A. Promoting remyelination in multiple sclerosis—recent advances. Drugs. 2013;73(18):2017–29.

    Article  CAS  PubMed  Google Scholar 

  99. Zendedel A, Beyer C, Kipp M. Cuprizone-induced demyelination as a tool to study remyelination and axonal protection. J Mol Neurosci. 2013;51(2):567–72.

    Article  CAS  PubMed  Google Scholar 

  100. Blanchard B, Heurtaux T, Garcia C, Moll NM, Caillava C, Grandbarbe L, et al. Tocopherol derivative TFA-12 promotes myelin repair in experimental models of multiple sclerosis. J Neurosci. 2013;33(28):11633–42.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Meffre D, Massaad C, Grenier J. Lithium chloride stimulates PLP and MBP expression in oligodendrocytes via Wnt/β-catenin and Akt/CREB pathways. Neuroscience. 2015;284:962–71.

    Article  CAS  PubMed  Google Scholar 

  102. Preisner A, Albrecht S, Cui Q-L, Hucke S, Ghelman J, Hartmann C, et al. Non-steroidal anti-inflammatory drug indometacin enhances endogenous remyelination. Acta Neuropathol. 2015;130(2):247–61.

    Article  CAS  PubMed  Google Scholar 

  103. Huang JK, Jarjour AA, Oumesmar BN, Kerninon C, Williams A, Krezel W, et al. Retinoid X receptor gamma signaling accelerates CNS remyelination. Nat Neurosci. 2011;14(1):45–53.

    Article  CAS  PubMed  Google Scholar 

  104. de la Fuente AG, Errea O, van Wijngaarden P, Gonzalez GA, Kerninon C, Jarjour AA, et al. Vitamin D receptor–retinoid X receptor heterodimer signaling regulates oligodendrocyte progenitor cell differentiation. J Cell Biol. 2015;211(5):975–85.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Najm FJ, Madhavan M, Zaremba A, Shick E, Karl RT, Factor DC, et al. Drug-based modulation of endogenous stem cells promotes functional remyelination in vivo. Nature. 2015;522(7555):216–20.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Trifunovski A, Josephson A, Ringman A, Brené S, Spenger C, Olson L. Neuronal activity-induced regulation of Lingo-1. Neuroreport. 2004;15(15):2397–400.

    Article  CAS  PubMed  Google Scholar 

  107. Mi S, Lee X, Shao Z, Thill G, Ji B, Relton J, et al. LINGO-1 is a component of the Nogo-66 receptor/p75 signaling complex. Nat Neurosci. 2004;7(3):221–8.

    Article  CAS  PubMed  Google Scholar 

  108. 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):1561–70.

    Article  CAS  PubMed  Google Scholar 

  109. Wang CJ, Qu CQ, Zhang J, Fu PC, Guo SG, Tang RH. Lingo-1 inhibited by RNA interference promotes functional recovery of experimental autoimmune encephalomyelitis. Anat Record. 2014;297(12):2356–63.

    Article  CAS  Google Scholar 

  110. Pepinsky RB, Shao Z, Ji B, Wang Q, Walus L, Lee X, 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):519–29.

    Article  CAS  PubMed  Google Scholar 

  111. Tran JQ, Rana J, Barkhof F, Melamed I, Gevorkyan H, Wattjes MP, et al. Randomized phase I trials of the safety/tolerability of anti-LINGO-1 monoclonal antibody BIIB033. Neurol Neuroimmunol Neuroinflamm. 2014;1(2):e18.

    Article  PubMed  PubMed Central  Google Scholar 

  112. Wang S, Bates J, Li X, Schanz S, Chandler-Militello D, Levine C, et al. Human iPSC-derived oligodendrocyte progenitor cells can myelinate and rescue a mouse model of congenital hypomyelination. Cell stem cell. 2013;12(2):252–64.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. 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):841–59.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Abramowski P, Krasemann S, Ernst T, Lange C, Ittrich H, Schweizer M, 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(15):1134–48.

    Article  CAS  PubMed  Google Scholar 

  115. Meamar R, Nematollahi S, Dehghani L, Mirmosayyeb O, Shayegannejad V, Basiri K, 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.

  116. Karussis D, Karageorgiou C, Vaknin-Dembinsky A, Gowda-Kurkalli B, Gomori JM, Kassis I, 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):1187–94.

    Article  PubMed  PubMed Central  Google Scholar 

  117. Amor S, Groome N, Linington C, Morris MM, Dornmair K, Gardinier MV, 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):4349–56.

    CAS  PubMed  Google Scholar 

  118. Fritz R, Chou C, McFarlin D. Relapsing murine experimental allergic encephalomyelitis induced by myelin basic protein. J Immunol. 1983;130(3):1024–6.

    CAS  PubMed  Google Scholar 

  119. Tuohy V, Sobel R, Lees M. Myelin proteolipid protein-induced experimental allergic encephalomyelitis. Variations of disease expression in different strains of mice. J Immunol. 1988;140(6):1868–73.

    CAS  PubMed  Google Scholar 

  120. Johns TG, de Rosbo NK, Menon KK, Abo S, Gonzales MF, Bernard C. Myelin oligodendrocyte glycoprotein induces a demyelinating encephalomyelitis resembling multiple sclerosis. J Immunol. 1995;154(10):5536–41.

    CAS  PubMed  Google Scholar 

  121. Fissolo N, Montalban X, Comabella M. DNA-based vaccines for multiple sclerosis: current status and future directions. Clin Immunol. 2012;142(1):76–83.

    Article  CAS  PubMed  Google Scholar 

  122. Billetta R, Ghahramani N, Morrow O, Prakken B, de Jong H, Meschter C, et al. Epitope-specific immune tolerization ameliorates experimental autoimmune encephalomyelitis. Clin Immunol. 2012;145(2):94–101.

    Article  CAS  PubMed  Google Scholar 

  123. Spence A, Klementowicz JE, Bluestone JA, Tang Q. Targeting Treg signaling for the treatment of autoimmune diseases. Curr Opin Immunol. 2015;37:11–20.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Lutterotti A, Yousef S, Sputtek A, Stürner KH, Stellmann J-P, Breiden P, et al. Antigen-specific tolerance by autologous myelin peptide–coupled cells: a phase 1 trial in multiple sclerosis. Sci Transl Med. 2013;5(188):188ra75-ra75.

    Article  CAS  Google Scholar 

  125. 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):267–75.

    Article  PubMed  Google Scholar 

  126. Vandenbark AA, Abulafia-Lapid R. Autologous T-cell vaccination for multiple sclerosis. Biodrugs. 2008;22(4):265–73.

    Article  PubMed  PubMed Central  Google Scholar 

  127. Fox E, Wynn D, Cohan S, Rill D, McGuire D, Markowitz C. A randomized clinical trial of autologous T-cell therapy in multiple sclerosis: subset analysis and implications for trial design. Mult Scler J. 2012;18(6):843–52.

    Article  CAS  Google Scholar 

  128. Karussis D, Shor H, Yachnin J, Lanxner N, Amiel M, Baruch K, et al. T cell vaccination benefits relapsing progressive multiple sclerosis patients: a randomized, double-blind clinical trial. PLoS One. 2012;7(12):e50478.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Aslani S, Mahmoudi M, Garshasbi M, Jamshidi AR, Karami J, Nicknam MH. Evaluation of DNMT1 gene expression profile and methylation of its promoter region in patients with ankylosing spondylitis. Clin Rheumatol. 2016;35(11):2723–31.

    Article  PubMed  Google Scholar 

  130. Rezaei R, Mahmoudi M, Gharibdoost F, Kavosi H, Dashti N, Imeni V, et al. IRF7 gene expression profile and methylation of its promoter region in patients with systemic sclerosis. Int J Rheum Dis. 2017;20(10):1551–61.

    Article  CAS  PubMed  Google Scholar 

  131. Karami J, Mahmoudi M, Amirzargar A, Gharshasbi M, Jamshidi A, Aslani S, et al. Promoter hypermethylation of BCL11B gene correlates with downregulation of gene transcription in ankylosing spondylitis patients. Genes Immun. 2017;18(3):170–5.

    Article  CAS  PubMed  Google Scholar 

  132. Mahmoudi M, Aslani S, Nicknam MH, Karami J, Jamshidi AR. New insights toward the pathogenesis of ankylosing spondylitis; genetic variations and epigenetic modifications. Modern Rheumatol. 2017;27(2):198–209.

    Article  Google Scholar 

  133. Aslani S, Mahmoudi M, Karami J, Jamshidi AR, Malekshahi Z, Nicknam MH. Epigenetic alterations underlying autoimmune diseases. Autoimmunity. 2016;49(2):69–83.

    Article  CAS  PubMed  Google Scholar 

  134. Foma AM, Aslani S, Karami J, Jamshidi A, Mahmoudi M. Epigenetic involvement in etiopathogenesis and implications in treatment of systemic lupus erythematous. Inflamm Res. 2017:1–17.

  135. Camelo S, Iglesias AH, Hwang D, Due B, Ryu H, Smith K, et al. Transcriptional therapy with the histone deacetylase inhibitor trichostatin A ameliorates experimental autoimmune encephalomyelitis. J Neuroimmunol. 2005;164(1):10–21.

    Article  CAS  PubMed  Google Scholar 

  136. Ge Z, Da Y, Xue Z, Zhang K, Zhuang H, Peng M, et al. Vorinostat, a histone deacetylase inhibitor, suppresses dendritic cell function and ameliorates experimental autoimmune encephalomyelitis. Exp Neurol. 2013;241:56–66.

    Article  CAS  PubMed  Google Scholar 

  137. Zhang Z, Zhang Z-Y, Wu Y, Schluesener H. Valproic acid ameliorates inflammation in experimental autoimmune encephalomyelitis rats. Neuroscience. 2012;221:140–50.

    Article  CAS  PubMed  Google Scholar 

  138. Xie L, Li X-K, Funeshima-Fuji N, Kimura H, Matsumoto Y, Isaka Y, et al. Amelioration of experimental autoimmune encephalomyelitis by curcumin treatment through inhibition of IL-17 production. Int Immunopharmacol. 2009;9(5):575–81.

    Article  CAS  PubMed  Google Scholar 

  139. Shindler KS, Ventura E, Dutt M, Elliott P, Fitzgerald DC, Rostami A. Oral resveratrol reduces neuronal damage in a model of multiple sclerosis. J Neuroophthalmol. 2010;30(4):328.

    Article  PubMed  PubMed Central  Google Scholar 

  140. Chan MW, Chang C-B, Tung C-H, Sun J, Suen J-L, Wu S-F. Low-dose 5-aza-2′-deoxycytidine pretreatment inhibits experimental autoimmune encephalomyelitis by induction of regulatory T cells. Mol Med. 2014;20(1):248.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  141. Du C, Liu C, Kang J, Zhao G, Ye Z, Huang S, et al. MicroRNA miR-326 regulates TH-17 differentiation and is associated with the pathogenesis of multiple sclerosis. Nat Immunol. 2009;10(12):1252–9.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We are thankful of the Department of Microbiology and Immunology facilities at Islamic Azad University-Tehran Medical Branch.

Author information

Authors and Affiliations

  1. Department of Microbiology and Immunology, Faculty of Medicine, Tehran Medical Sciences, Islamic Azad University, Khaghani St., Shariati Ave., P.O Box: 19395/1495, Tehran, Iran

    Mehrdad Gholamzad & Zeinab Mahmodi

  2. Department of Immunology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran

    Masoumeh Ebtekar

  3. Department of Radiopharmacy, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran

    Mehdi Shafiee Ardestani

  4. Department of Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran

    Maryam Azimi, Mohammad Javad Mousavi & Saeed Aslani

  5. Department of Hematology, Faculty of Allied Medicine, Bushehr University of Medical Sciences, Bushehr, Iran

    Mohammad Javad Mousavi

  6. Rheumatology Research Center, Tehran University of Medical Sciences, Tehran, Iran

    Mohammad Javad Mousavi & Saeed Aslani

Authors
  1. Mehrdad Gholamzad
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Masoumeh Ebtekar
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Mehdi Shafiee Ardestani
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Maryam Azimi
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Zeinab Mahmodi
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Mohammad Javad Mousavi
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Saeed Aslani
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Mehrdad Gholamzad.

Ethics declarations

Conflict of interest

The authors declare that they have no competing interests.

Additional information

Responsible Editor: John Di Battista.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Gholamzad, M., Ebtekar, M., Ardestani, M.S. et al. A comprehensive review on the treatment approaches of multiple sclerosis: currently and in the future. Inflamm. Res. 68, 25–38 (2019). https://doi.org/10.1007/s00011-018-1185-0

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00011-018-1185-0

Keywords

Search

Navigation