, Volume 77, Issue 8, pp 885–910 | Cite as

Pharmacological Approaches to the Management of Secondary Progressive Multiple Sclerosis

  • A. Nandoskar
  • J. Raffel
  • A. S. Scalfari
  • T. Friede
  • R. S. Nicholas
Review Article


It is well recognised that the majority of the impact of multiple sclerosis (MS), both personal and societal, arises in the progressive phase where disability accumulates inexorably. As such, progressive MS (PMS) has been the target of pharmacological therapies for many years. However, there are no current licensed treatments for PMS. This stands in marked contrast to relapsing remitting MS (RRMS) where trials have resulted in numerous licensed therapies. PMS has proven to be a more difficult challenge compared to RRMS and this review focuses on secondary progressive MS (SPMS), where relapses occur before the onset of gradual, irreversible disability, and not primary progressive MS where disability accumulation occurs without prior relapses. Although there are similarities between the two forms, in both cases pinpointing when PMS starts is difficult in a condition in which disability can vary from day to day. There is also an overlap between the pathology of relapsing and progressive MS and this has contributed to the lack of well-defined outcomes, both surrogates and clinically relevant outcomes in PMS. In this review, we used the search term ‘randomised controlled clinical drug trials in secondary progressive MS’ in publications since 1988 together with recently completed trials where results were available. We found 34 trials involving 21 different molecules, of which 38% were successful in reaching their primary outcome. In general, the trials were well designed (e.g. double blind) with sample sizes ranging from 35 to 1949 subjects. The majority were parallel group, but there were also multi-arm and multidose trials as well as the more recent use of adaptive designs. The disability outcome most commonly used was the Expanded Disability Status Scale (EDSS) in all phases, but also magnetic resonance imaging (MRI)-measured brain atrophy has been utilised as a surrogate endpoint in phase II studies. The majority of the treatments tested in SPMS over the years were initially successful in RRMS. This has a number of implications in terms of targeting SPMS, but principally implies that the optimal strategy to target SPMS is to utilise the prodrome of relapses to initiate a therapy that will aim to both prevent progression and slow its accumulation. This approach is in agreement with the early targeting of MS but requires treatments that are both effective and safe if it is to be used before disability is a major problem. Recent successes will hopefully result in the first licensed therapy for PMS and enable us to test this approach.


  1. 1.
    Olesen J, Gustavsson A, Svensson M, Wittchen HU, et al. The economic cost of brain disorders in Europe. Eur J Neurol. 2012;19(1):155–62.PubMedCrossRefGoogle Scholar
  2. 2.
    Adelman G, Rane SG, Villa KF. The cost burden of multiple sclerosis in the United States: a systematic review of the literature. J Med Econ. 2013;16(5):639–47.PubMedCrossRefGoogle Scholar
  3. 3.
    Jones E, Pike J, Marshall T, Ye X. Quantifying the relationship between increased disability and health care resource utilization, quality of life, work productivity, health care costs in patients with multiple sclerosis in the US. BMC Health Serv Res. 2016;22(16):294.CrossRefGoogle Scholar
  4. 4.
    Reynolds R, Roncaroli F, Nicholas R, Radotra B, et al. The neuropathological basis of clinical progression in multiple sclerosis. Acta Neuropathol. 2011;122(2):155–70.PubMedCrossRefGoogle Scholar
  5. 5.
    Tramacere I, Del Giovane C, Salanti G, D’Amico R, et al. Immunomodulators and immunosuppressants for relapsing-remitting multiple sclerosis: a network meta-analysis. Cochrane Database Syst Rev. 2015:CD011381.Google Scholar
  6. 6.
    Montalban X HB, Rammohan K, Giovannoni G, On behalf of the ORATORIO Clinical Investigators, et al. Ocrelizumab versus placebo in in primary progressive multiple sclerosis. N Engl J Med. 2017;376(3):209–220.Google Scholar
  7. 7.
    Sedel F, Papeix C, Bellanger A, Touitou V, et al. High doses of biotin in chronic progressive multiple sclerosis: a pilot study. Mult Scler Relat Disord. 2015;4(2):159–69.PubMedCrossRefGoogle Scholar
  8. 8.
    Tourbah AL-FC, Edan G, Clanet M, et al. MD1003 (high doses of biotin) in progressive multiple sclerosis: subgroup analyses of the MS-SPI trial. ECTRIMS Online Library; 2015. p. 116698.Google Scholar
  9. 9.
    Chataway J, Schuerer N, Alsanousi A, Chan D, 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):2213–21.PubMedCrossRefGoogle Scholar
  10. 10.
    Scalfari A, Neuhaus A, Daumer M, Muraro PA, et al. Onset of secondary progressive phase and long-term evolution of multiple sclerosis. J Neurol Neurosurg Psychiatry. 2014;85(1):67–75.PubMedCrossRefGoogle Scholar
  11. 11.
    Novotna M, Paz Soldan MM, Abou Zeid N, Kale N, et al. Poor early relapse recovery affects onset of progressive disease course in multiple sclerosis. Neurology. 2015;85(8):722–9.PubMedPubMedCentralCrossRefGoogle Scholar
  12. 12.
    Lublin FD, Reingold SC, Cohen JA, Cutter GR, et al. Defining the clinical course of multiple sclerosis: the 2013 revisions. Neurology. 2014;83(3):278–86.PubMedPubMedCentralCrossRefGoogle Scholar
  13. 13.
    Kremenchutzky M, Rice GP, Baskerville J, Wingerchuk DM, et al. The natural history of multiple sclerosis: a geographically based study 9: observations on the progressive phase of the disease. Brain. 2006;129(pt 3):584–94.PubMedCrossRefGoogle Scholar
  14. 14.
    Katz Sand I, Krieger S, Farrell C, Miller AE. Diagnostic uncertainty during the transition to secondary progressive multiple sclerosis. Mult Scler. 2014;20(12):1654–7.PubMedCrossRefGoogle Scholar
  15. 15.
    Lublin F, Miller DH, Freedman MS, Cree BA, et al. Oral fingolimod in primary progressive multiple sclerosis (INFORMS): a phase III, randomised, double-blind, placebo-controlled trial. Lancet. 2016;387(10023):1075–84.PubMedCrossRefGoogle Scholar
  16. 16.
    Rovaris M, Confavreux C, Furlan R, Kappos L, et al. Secondary progressive multiple sclerosis: current knowledge and future challenges. Lancet Neurol. 2006;5(4):343–54.PubMedCrossRefGoogle Scholar
  17. 17.
    Polman CH, Reingold SC, Banwell B, Clanet M, et al. Diagnostic criteria for multiple sclerosis: 2010 revisions to the McDonald criteria. Ann Neurol. 2011;69(2):292–302.PubMedPubMedCentralCrossRefGoogle Scholar
  18. 18.
    Kalincik T, Cutter G, Spelman T, Jokubaitis V, et al. Defining reliable disability outcomes in multiple sclerosis. Brain. 2015;138(Pt 11):3287–98.PubMedCrossRefGoogle Scholar
  19. 19.
    Rover C, Nicholas R, Straube S, Friede T. Changing EDSS progression in placebo cohorts in relapsing MS: a systematic review and meta-regression. PLoS One. 2015;10(9):e0137052.PubMedPubMedCentralCrossRefGoogle Scholar
  20. 20.
    Lorscheider J, Buzzard K, Jokubaitis V, Spelman T, et al. Defining secondary progressive multiple sclerosis. Brain. 2016;139(pt 9):2395–405PubMedCrossRefGoogle Scholar
  21. 21.
    European Medicines agency: Guideline on clinical investigation of medicinal products for the treatment of Multiple Sclerosis Committee for Medicinal Products for Human Use. EMA/CHMP/771815/2011, Rev. 2; 2015.Google Scholar
  22. 22.
    Schaffler N, Schonberg P, Stephan J, Stellmann JP, et al. Comparison of patient-reported outcome measures in multiple sclerosis. Acta Neurol Scand. 2013;128(2):114–21.PubMedCrossRefGoogle Scholar
  23. 23.
    Kurtzke JF. Rating neurologic impairment in multiple sclerosis: an expanded disability status scale (EDSS). Neurology. 1983;33(11):1444–52.PubMedCrossRefGoogle Scholar
  24. 24.
    Chataway J, Nicholas R, Todd S, Miller DH, et al. A novel adaptive design strategy increases the efficiency of clinical trials in secondary progressive multiple sclerosis. Mult Scler. 2011;17(1):81–8.PubMedCrossRefGoogle Scholar
  25. 25.
    Meyer-Moock S, Feng YS, Maeurer M, Dippel FW, et al. Systematic literature review and validity evaluation of the Expanded Disability Status Scale (EDSS) and the Multiple Sclerosis Functional Composite (MSFC) in patients with multiple sclerosis. BMC Neurol. 2014;14:58.PubMedPubMedCentralCrossRefGoogle Scholar
  26. 26.
    Korn T. Pathophysiology of multiple sclerosis. J Neurol. 2008;255(Suppl 6):2–6.PubMedCrossRefGoogle Scholar
  27. 27.
    van der Valk P, De Groot CJ. Staging of multiple sclerosis (MS) lesions: pathology of the time frame of MS. Neuropathol Appl Neurobiol. 2000;26(1):2–10.PubMedCrossRefGoogle Scholar
  28. 28.
    Lassmann H. Multiple sclerosis: is there neurodegeneration independent from inflammation? J Neurol Sci. 2007;259(1–2):3–6.PubMedCrossRefGoogle Scholar
  29. 29.
    Fu L, Matthews PM, De Stefano N, Worsley KJ, et al. Imaging axonal damage of normal-appearing white matter in multiple sclerosis. Brain. 1998;121(pt 1):103–13.PubMedCrossRefGoogle Scholar
  30. 30.
    Rovaris M, Bozzali M, Santuccio G, Ghezzi A, et al. In vivo assessment of the brain and cervical cord pathology of patients with primary progressive multiple sclerosis. Brain. 2001;124(pt 12):2540–9.PubMedCrossRefGoogle Scholar
  31. 31.
    De Stefano N, Matthews PM, Filippi M, Agosta F, et al. Evidence of early cortical atrophy in MS: relevance to white matter changes and disability. Neurology. 2003;60(7):1157–62.PubMedCrossRefGoogle Scholar
  32. 32.
    Meinl E, Krumbholz M, Derfuss T, Junker A, et al. Compartmentalization of inflammation in the CNS: a major mechanism driving progressive multiple sclerosis. J Neurol Sci. 2008;274(1–2):42–4.PubMedCrossRefGoogle Scholar
  33. 33.
    Howell OW, Reeves CA, Nicholas R, Carassiti D, et al. Meningeal inflammation is widespread and linked to cortical pathology in multiple sclerosis. Brain. 2011;134(pt 9):2755–71.PubMedCrossRefGoogle Scholar
  34. 34.
    Magliozzi R, Howell O, Vora A, Serafini B, et al. Meningeal B-cell follicles in secondary progressive multiple sclerosis associate with early onset of disease and severe cortical pathology. Brain. 2007;130(pt 4):1089–104.PubMedGoogle Scholar
  35. 35.
    Calabrese M, Rocca MA, Atzori M, Mattisi I, et al. A 3-year magnetic resonance imaging study of cortical lesions in relapse-onset multiple sclerosis. Ann Neurol. 2010;67(3):376–83.PubMedGoogle Scholar
  36. 36.
    Waxman SG. Ion channels and neuronal dysfunction in multiple sclerosis. Arch Neurol. 2002;59(9):1377–80.PubMedCrossRefGoogle Scholar
  37. 37.
    Campbell GR, Ziabreva I, Reeve AK, Krishnan KJ, et al. Mitochondrial DNA deletions and neurodegeneration in multiple sclerosis. Ann Neurol. 2011;69(3):481–92.PubMedCrossRefGoogle Scholar
  38. 38.
    Fischer MT, Sharma R, Lim JL, Haider L, et al. NADPH oxidase expression in active multiple sclerosis lesions in relation to oxidative tissue damage and mitochondrial injury. Brain. 2012;135(pt 3):886–99.PubMedPubMedCentralCrossRefGoogle Scholar
  39. 39.
    Fischer MT, Wimmer I, Hoftberger R, Gerlach S, et al. Disease-specific molecular events in cortical multiple sclerosis lesions. Brain. 2013;136(Pt 6):1799–815.PubMedPubMedCentralCrossRefGoogle Scholar
  40. 40.
    Holland CM, Charil A, Csapo I, Liptak Z, et al. The relationship between normal cerebral perfusion patterns and white matter lesion distribution in 1,249 patients with multiple sclerosis. J Neuroimaging. 2012;22(2):129–36.PubMedCrossRefGoogle Scholar
  41. 41.
    Davies AL, Desai RA, Bloomfield PS, McIntosh PR, et al. Neurological deficits caused by tissue hypoxia in neuroinflammatory disease. Ann Neurol. 2013;74(6):815–25.Google Scholar
  42. 42.
    Lansley J, Mataix-Cols D, Grau M, Radua J, et al. Localized grey matter atrophy in multiple sclerosis: a meta-analysis of voxel-based morphometry studies and associations with functional disability. Neurosci Biobehav Rev. 2013;37(5):819–30.PubMedCrossRefGoogle Scholar
  43. 43.
    Hauser SL, Oksenberg JR. The neurobiology of multiple sclerosis: genes, inflammation, and neurodegeneration. Neuron. 2006;52(1):61–76.PubMedCrossRefGoogle Scholar
  44. 44.
    Strimbu K, Tavel JA. What are biomarkers? Curr Opin HIV AIDS. 2010;5(6):463–6.PubMedPubMedCentralCrossRefGoogle Scholar
  45. 45.
    Prentice RL. Surrogate endpoints in clinical trials: definition and operational criteria. Stat Med. 1989;8(4):431–40.PubMedCrossRefGoogle Scholar
  46. 46.
    Narayanan D, Cheng H, Bonem KN, Saenz R, et al. Tracking changes over time in retinal nerve fiber layer and ganglion cell-inner plexiform layer thickness in multiple sclerosis. Mult Scler. 2014;20(10):1331–41.PubMedPubMedCentralCrossRefGoogle Scholar
  47. 47.
    Raftopoulos R, Hickman SJ, Toosy A, Sharrack B, et al. Phenytoin for neuroprotection in patients with acute optic neuritis: a randomised, placebo-controlled, phase 2 trial. Lancet Neurol. 2016;15(3):259–69.PubMedCrossRefGoogle Scholar
  48. 48.
    Kearney H, Miller DH, Ciccarelli O. Spinal cord MRI in multiple sclerosis–diagnostic, prognostic and clinical value. Nat Rev Neurol. 2015;11(6):327–38.PubMedCrossRefGoogle Scholar
  49. 49.
    Ciccarelli O, Barkhof F, Bodini B, De Stefano N, et al. Pathogenesis of multiple sclerosis: insights from molecular and metabolic imaging. Lancet Neurol. 2014;13(8):807–22.PubMedCrossRefGoogle Scholar
  50. 50.
    Barkhof F, Calabresi PA, Miller DH, Reingold SC. Imaging outcomes for neuroprotection and repair in multiple sclerosis trials. Nat Rev Neurol. 2009;5(5):256–66.PubMedCrossRefGoogle Scholar
  51. 51.
    Fisniku LK, Brex PA, Altmann DR, Miszkiel KA, et al. Disability and T2 MRI lesions: a 20-year follow-up of patients with relapse onset of multiple sclerosis. Brain. 2008;131(Pt 3):808–17.PubMedCrossRefGoogle Scholar
  52. 52.
    Ontaneda D, Fox RJ, Chataway J. Clinical trials in progressive multiple sclerosis: lessons learned and future perspectives. Lancet Neurol. 2015;14(2):208–23.PubMedPubMedCentralCrossRefGoogle Scholar
  53. 53.
    Teleshova N, Bao W, Kivisakk P, Ozenci V, et al. Elevated CD40 ligand expressing blood T-cell levels in multiple sclerosis are reversed by interferon-beta treatment. Scand J Immunol. 2000;51(3):312–20.PubMedCrossRefGoogle Scholar
  54. 54.
    Genc K, Dona DL, Reder AT. Increased CD80(+) B cells in active multiple sclerosis and reversal by interferon beta-1b therapy. J Clin Invest. 1997;99(11):2664–71.PubMedPubMedCentralCrossRefGoogle Scholar
  55. 55.
    Jiang H, Milo R, Swoveland P, Johnson KP, et al. Interferon beta-1b reduces interferon gamma-induced antigen-presenting capacity of human glial and B cells. J Neuroimmunol. 1995;61(1):17–25.PubMedCrossRefGoogle Scholar
  56. 56.
    Hallal-Longo DE, Mirandola SR, Oliveira EC, Farias AS, et al. Diminished myelin-specific T cell activation associated with increase in CTLA4 and Fas molecules in multiple sclerosis patients treated with IFN-beta. J Interferon Cytokine Res. 2007;27(10):865–73.PubMedCrossRefGoogle Scholar
  57. 57.
    Muraro PA, Leist T, Bielekova B, McFarland HF. VLA-4/CD49d downregulated on primed T lymphocytes during interferon-beta therapy in multiple sclerosis. J Neuroimmunol. 2000;111(1–2):186–94.Google Scholar
  58. 58.
    Dhib-Jalbut S, Marks S. Interferon-beta mechanisms of action in multiple sclerosis. Neurology. 2010;5(74 Suppl 1):S17–24.CrossRefGoogle Scholar
  59. 59.
    La Mantia L, Vacchi L, Di Pietrantonj C, Ebers G, et al. Interferon beta for secondary progressive multiple sclerosis. Cochrane Database Syst Rev. 2012;1:CD005181.Google Scholar
  60. 60.
    Placebo-controlled multicentre randomised trial of interferon beta-1b in treatment of secondary progressive multiple sclerosis. European Study Group on interferon beta-1b in secondary progressive MS. Lancet. 1998;352(9139):1491–7.Google Scholar
  61. 61.
    Cohen JA, Cutter GR, Fischer JS, Goodman AD, et al. Benefit of interferon beta-1a on MSFC progression in secondary progressive MS. Neurology. 2002;59(5):679–87.PubMedCrossRefGoogle Scholar
  62. 62.
    Andersen O, Elovaara I, Farkkila M, Hansen HJ, et al. Multicentre, randomised, double blind, placebo controlled, phase III study of weekly, low dose, subcutaneous interferon beta-1a in secondary progressive multiple sclerosis. J Neurol Neurosurg Psychiatry. 2004;75(5):706–10.PubMedPubMedCentralCrossRefGoogle Scholar
  63. 63.
    Panitch H, Miller A, Paty D, Weinshenker B, et al. Interferon beta-1b in secondary progressive MS: results from a 3-year controlled study. Neurology. 2004;63(10):1788–95.PubMedCrossRefGoogle Scholar
  64. 64.
    Secondary Progressive Efficacy Clinical Trial of Recombinant Interferon-Beta-1a in MSSG. Randomized controlled trial of interferon-beta-1a in secondary progressive MS: clinical results. Neurology. 2001;56(11):1496–504.Google Scholar
  65. 65.
    Kala M, Miravalle A, Vollmer T. Recent insights into the mechanism of action of glatiramer acetate. J Neuroimmunol. 2011;235(1–2):9–17.PubMedCrossRefGoogle Scholar
  66. 66.
    Dhib-Jalbut S. Glatiramer acetate (Copaxone) therapy for multiple sclerosis. Pharmacol Ther. 2003;98(2):245–55.PubMedCrossRefGoogle Scholar
  67. 67.
    Neuhaus O, Farina C, Wekerle H, Hohlfeld R. Mechanisms of action of glatiramer acetate in multiple sclerosis. Neurology. 2001;56(6):702–8.PubMedCrossRefGoogle Scholar
  68. 68.
    Chen C, Liu X, Wan B, Zhang JZ. Regulatory properties of copolymer I in Th17 differentiation by altering STAT3 phosphorylation. J Immunol. 2009;183(1):246–53.PubMedCrossRefGoogle Scholar
  69. 69.
    La Mantia L, Munari LM, Lovati R. Glatiramer acetate for multiple sclerosis. Cochrane Database Syst Rev. 2010;(5):CD004678.Google Scholar
  70. 70.
    Bornstein MB, Miller A, Slagle S, Weitzman M, et al. A placebo-controlled, double-blind, randomized, two-center, pilot trial of Cop 1 in chronic progressive multiple sclerosis. Neurology. 1991;41(4):533–9.PubMedCrossRefGoogle Scholar
  71. 71.
    Wolinsky JS, Narayana PA, O’Connor P, Coyle PK, et al. Glatiramer acetate in primary progressive multiple sclerosis: results of a multinational, multicenter, double-blind, placebo-controlled trial. Ann Neurol. 2007;61(1):14–24.PubMedCrossRefGoogle Scholar
  72. 72.
    Martinelli V, Radaelli M, Straffi L, Rodegher M, et al. Mitoxantrone: benefits and risks in multiple sclerosis patients. Neurol Sci. 2009;30(Suppl 2):S167–70.PubMedCrossRefGoogle Scholar
  73. 73.
    Watson CM, Davison AN, Baker D, O’Neill JK, et al. Suppression of demyelination by mitoxantrone. Int J Immunopharmacol. 1991;13(7):923–30.PubMedCrossRefGoogle Scholar
  74. 74.
    Vollmer T, Stewart T, Baxter N. Mitoxantrone and cytotoxic drugs’ mechanisms of action. Neurology. 2010;5(74 Suppl 1):S41–6.CrossRefGoogle Scholar
  75. 75.
    Millefiorini E, Gasperini C, Pozzilli C, D’Andrea F, 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.PubMedCrossRefGoogle Scholar
  76. 76.
    Li JM, Yang Y, Zhu P, Zheng F, et al. Mitoxantrone exerts both cytotoxic and immunoregulatory effects on activated microglial cells. Immunopharmacol Immunotoxicol. 2012;34(1):36–41.PubMedCrossRefGoogle Scholar
  77. 77.
    Hartung HP, Gonsette R, Konig N, Kwiecinski H, et al. Mitoxantrone in progressive multiple sclerosis: a placebo-controlled, double-blind, randomised, multicentre trial. Lancet. 2002;360(9350):2018–25.Google Scholar
  78. 78.
    Martinelli Boneschi F, Vacchi L, Rovaris M, Capra R, et al. Mitoxantrone for multiple sclerosis. Cochrane Database Syst Rev. 2013;(5):CD002127.Google Scholar
  79. 79.
    Patel AA, Swerlick RA, McCall CO. Azathioprine in dermatology: the past, the present, and the future. J Am Acad Dermatol. 2006;55(3):369–89.Google Scholar
  80. 80.
    Tiede I, Fritz G, Strand S, Poppe D, et al. CD28-dependent Rac1 activation is the molecular target of azathioprine in primary human CD4+ T lymphocytes. J Clin Invest. 2003;111(8):1133–45.PubMedPubMedCentralCrossRefGoogle Scholar
  81. 81.
    Casetta I, Iuliano G, Filippini G. Azathioprine for multiple sclerosis. Cochrane Database Syst Rev. 2007;(4):CD003982.Google Scholar
  82. 82.
    Goodkin DE, Bailly RC, Teetzen ML, Hertsgaard D, et al. The efficacy of azathioprine in relapsing-remitting multiple sclerosis. Neurology. 1991;41(1):20–5.PubMedCrossRefGoogle Scholar
  83. 83.
    Montanari E ML, Pesci I, et al. ASPIRE (azathioprine secondary progressive interferon treated patients randomised evaluation) study: 2-year double-blind and 1-year open, randomised, multicentre, pilot study. Multiple sclerosis functional composite (MSFC) and magnetic resonance data. Mult Scler. 2009;250(suppl):822.Google Scholar
  84. 84.
    Double-masked trial of azathioprine in multiple sclerosis. British and Dutch Multiple Sclerosis Azathioprine Trial Group. Lancet. 1988;2(8604):179–83.Google Scholar
  85. 85.
    Ellison GW, Myers LW, Mickey MR, Graves MC, et al. A placebo-controlled, randomized, double-masked, variable dosage, clinical trial of azathioprine with and without methylprednisolone in multiple sclerosis. Neurology. 1989;39(8):1018–26.PubMedCrossRefGoogle Scholar
  86. 86.
    Ghezzi A, Di Falco M, Locatelli C, et al. Clinical controlled randomized trial of azathioprine in multiple sclerosis. In: Consette RE, Delmotte P, editors. Recent advances in multiple sclerosis therapy. Elsevier; 1989.Google Scholar
  87. 87.
    Milanese CLML, Salmaggi A, Eoli M. A double blind study on azathioprine efficacy in multiple sclerosis: final report. J Neurol. 1993;240:295–8.PubMedCrossRefGoogle Scholar
  88. 88.
    Borel JF, Feurer C, Magnee C, Stahelin H. Effects of the new anti-lymphocytic peptide cyclosporin A in animals. Immunology. 1977;32(6):1017–25.PubMedPubMedCentralGoogle Scholar
  89. 89.
    Granelli-Piperno A. In situ hybridization for interleukin 2 and interleukin 2 receptor mRNA in T cells activated in the presence or absence of cyclosporin A. J Exp Med. 1988;168(5):1649–58.PubMedCrossRefGoogle Scholar
  90. 90.
    Matsuda S, Koyasu S. Mechanisms of action of cyclosporine. Immunopharmacology. 2000;47(2–3):119–25.PubMedCrossRefGoogle Scholar
  91. 91.
    Efficacy and toxicity of cyclosporine in chronic progressive multiple sclerosis: a randomized, double-blinded, placebo-controlled clinical trial. The Multiple Sclerosis Study Group. Ann Neurol. 1990;27(6):591–605.Google Scholar
  92. 92.
    Calabresi P, Chabner BA. Chemotheraphy of neoplastic diseases. In: S GL, Gilman A, Rall T, Nies AS, Taylor P, editors. The Pharmacological Basis of Therapeutics. New York: Pergamon Press; 1990. p. 1202–1208.  Google Scholar
  93. 93.
    Gray O, McDonnell GV, Forbes RB. Methotrexate for multiple sclerosis. Cochrane Database Syst Rev. 2004;(2):CD003208.Google Scholar
  94. 94.
    Goodkin DE, Rudick RA, VanderBrug Medendorp S, Daughtry MM, et al. Low-dose (7.5 mg) oral methotrexate reduces the rate of progression in chronic progressive multiple sclerosis. Ann Neurol. 1995;37(1):30–40.PubMedCrossRefGoogle Scholar
  95. 95.
    Kovarsky J. Clinical pharmacology and toxicology of cyclophosphamide: emphasis on use in rheumatic diseases. Semin Arthritis Rheum. 1983;12(4):359–72.PubMedCrossRefGoogle Scholar
  96. 96.
    Brinkman CJ, Nillesen WM, Hommes OR. T-cell subpopulations in blood and cerebrospinal fluid of multiple sclerosis patients: effect of cyclophosphamide. Clin Immunol Immunopathol. 1983;29(3):341–8.PubMedCrossRefGoogle Scholar
  97. 97.
    Comabella M, Balashov K, Issazadeh S, Smith D, et al. Elevated interleukin-12 in progressive multiple sclerosis correlates with disease activity and is normalized by pulse cyclophosphamide therapy. J Clin Invest. 1998;102(4):671–8.PubMedPubMedCentralCrossRefGoogle Scholar
  98. 98.
    Smith DR, Balashov KE, Hafler DA, Khoury SJ, et al. Immune deviation following pulse cyclophosphamide/methylprednisolone treatment of multiple sclerosis: increased interleukin-4 production and associated eosinophilia. Ann Neurol. 1997;42(3):313–8.PubMedCrossRefGoogle Scholar
  99. 99.
    The Canadian cooperative trial of cyclophosphamide and plasma exchange in progressive multiple sclerosis. The Canadian Cooperative Multiple Sclerosis Study Group. Lancet. 1991;337(8739):441–6.Google Scholar
  100. 100.
    Brochet B, Deloire MS, Perez P, et al. Double-blind, randomized, controlled study of cyclophosphamide versus methylprednisolone in secondary progressive multiple sclerosis. PLoS One. 2017;12(e0168834):2017.Google Scholar
  101. 101.
    Abramsky O, Lehmann D, Karussis D. Immunomodulation with linomide: possible novel therapy for multiple sclerosis. Mult Scler. 1996;2(4):206–10.PubMedGoogle Scholar
  102. 102.
    Lehmann D, Karussis DM, Fluresco D, Mizrachi-Koll R, et al. Immunomodulation of autoimmunity by linomide: inhibition of antigen presentation through down regulation of macrophage activity in the model of experimental autoimmune encephalomyelitis. J Neuroimmunol. 1997;74(1–2):102–10.PubMedCrossRefGoogle Scholar
  103. 103.
    Karussis DM, Meiner Z, Lehmann D, Gomori JM, et al. Treatment of secondary progressive multiple sclerosis with the immunomodulator linomide: a double-blind, placebo-controlled pilot study with monthly magnetic resonance imaging evaluation. Neurology. 1996;47(2):341–6.PubMedCrossRefGoogle Scholar
  104. 104.
    Noseworthy JH, Wolinsky JS, Lublin FD, Whitaker JN, et al. Linomide in relapsing and secondary progressive MS: part I: trial design and clinical results. North American Linomide Investigators. Neurology. 2000;54(9):1726–33.PubMedCrossRefGoogle Scholar
  105. 105.
    Comi G, Hartung HP, Kurukulasuriya NC, Greenberg SJ, et al. Cladribine tablets for the treatment of relapsing-remitting multiple sclerosis. Expert Opin Pharmacother. 2013;14(1):123–36.PubMedCrossRefGoogle Scholar
  106. 106.
    Beutler E, Sipe JC, Romine JS, Koziol JA, et al. The treatment of chronic progressive multiple sclerosis with cladribine. Proc Natl Acad Sci USA. 1996;93(4):1716–20.PubMedPubMedCentralCrossRefGoogle Scholar
  107. 107.
    Rice GP, Filippi M, Comi G. Cladribine and progressive MS: clinical and MRI outcomes of a multicenter controlled trial. Cladribine MRI Study Group. Neurology. 2000;54(5):1145–55.PubMedCrossRefGoogle Scholar
  108. 108.
    Sipe JC, Romine JS, Koziol JA, McMillan R, et al. Cladribine in treatment of chronic progressive multiple sclerosis. Lancet. 1994;344(8914):9–13.Google Scholar
  109. 109.
    Stangel M, Hartung HP. Intravenous immunoglobulins in multiple sclerosis. Studies and mechanisms of action–an update. Nervenarzt. 2002;73(2):119–24.PubMedCrossRefGoogle Scholar
  110. 110.
    Humle Jorgensen S, Sorensen PS. Intravenous immunoglobulin treatment of multiple sclerosis and its animal model, experimental autoimmune encephalomyelitis. J Neurol Sci. 2005;233(1–2):61–5.PubMedCrossRefGoogle Scholar
  111. 111.
    Hommes OR, Sorensen PS, Fazekas F, Enriquez MM, et al. Intravenous immunoglobulin in secondary progressive multiple sclerosis: randomised placebo-controlled trial. Lancet. 2004;364(9440):1149–56.Google Scholar
  112. 112.
    Pohlau D, Przuntek H, Sailer M, Bethke F, et al. Intravenous immunoglobulin in primary and secondary chronic progressive multiple sclerosis: a randomized placebo controlled multicentre study. Mult Scler. 2007;13(9):1107–17.PubMedCrossRefGoogle Scholar
  113. 113.
    Warren KG, Catz I, Ferenczi LZ, Krantz MJ. Intravenous synthetic peptide MBP8298 delayed disease progression in an HLA Class II-defined cohort of patients with progressive multiple sclerosis: results of a 24-month double-blind placebo-controlled clinical trial and 5 years of follow-up treatment. Eur J Neurol. 2006;13(8):887–95.PubMedCrossRefGoogle Scholar
  114. 114.
    Freedman MS, Bar-Or A, Oger J, Traboulsee A, et al. A phase III study evaluating the efficacy and safety of MBP8298 in secondary progressive MS. Neurology. 2011;77(16):1551–60.PubMedCrossRefGoogle Scholar
  115. 115.
    Cavallo MG, Pozzilli P, Thorpe R. Cytokines and autoimmunity. Clin Exp Immunol. 1994;96(1):1–7.PubMedPubMedCentralCrossRefGoogle Scholar
  116. 116.
    Skurkovich S, Boiko A, Beliaeva I, Buglak A, et al. Randomized study of antibodies to IFN-gamma and TNF-alpha in secondary progressive multiple sclerosis. Mult Scler. 2001;7(5):277–84.PubMedGoogle Scholar
  117. 117.
    Tong XK, Hamel E. Simvastatin restored vascular reactivity, endothelial function and reduced string vessel pathology in a mouse model of cerebrovascular disease. J Cereb Blood Flow Metab. 2015;35(3):512–20.PubMedPubMedCentralCrossRefGoogle Scholar
  118. 118.
    Malfitano AM, Marasco G, Proto MC, Laezza C, et al. Statins in neurological disorders: an overview and update. Pharmacol Res. 2014;88:74–83.PubMedCrossRefGoogle Scholar
  119. 119.
    Zhang X, Tao Y, Wang J, Garcia-Mata R, et al. Simvastatin inhibits secretion of Th17-polarizing cytokines and antigen presentation by DCs in patients with relapsing remitting multiple sclerosis. Eur J Immunol. 2013;43(1):281–9.PubMedCrossRefGoogle Scholar
  120. 120.
    Ketter TA, Manji HK, Post RM. Potential mechanisms of action of lamotrigine in the treatment of bipolar disorders. J Clin Psychopharmacol. 2003;23(5):484–95.PubMedCrossRefGoogle Scholar
  121. 121.
    Stys PK. General mechanisms of axonal damage and its prevention. J Neurol Sci. 2005;233(1–2):3–13.PubMedCrossRefGoogle Scholar
  122. 122.
    Frohman EM, Filippi M, Stuve O, Waxman SG, et al. Characterizing the mechanisms of progression in multiple sclerosis: evidence and new hypotheses for future directions. Arch Neurol. 2005;62(9):1345–56.PubMedCrossRefGoogle Scholar
  123. 123.
    Bechtold DA, Miller SJ, Dawson AC, Sun Y, et al. Axonal protection achieved in a model of multiple sclerosis using lamotrigine. J Neurol. 2006;253(12):1542–51.PubMedCrossRefGoogle Scholar
  124. 124.
    Kapoor R, Davies M, Blaker PA, Hall SM, et al. Blockers of sodium and calcium entry protect axons from nitric oxide-mediated degeneration. Ann Neurol. 2003;53(2):174–80.PubMedCrossRefGoogle Scholar
  125. 125.
    Kapoor R, Furby J, Hayton T, Smith KJ, et al. Lamotrigine for neuroprotection in secondary progressive multiple sclerosis: a randomised, double-blind, placebo-controlled, parallel-group trial. Lancet Neurol. 2010;9(7):681–8.PubMedCrossRefGoogle Scholar
  126. 126.
    Hampson AJ, Grimaldi M, Axelrod J, Wink D. Cannabidiol and (−)Delta9-tetrahydrocannabinol are neuroprotective antioxidants. Proc Natl Acad Sci USA. 1998;95(14):8268–73.PubMedPubMedCentralCrossRefGoogle Scholar
  127. 127.
    Zajicek JP, Sanders HP, Wright DE, Vickery PJ, et al. Cannabinoids in multiple sclerosis (CAMS) study: safety and efficacy data for 12 months follow up. J Neurol Neurosurg Psychiatry. 2005;76(12):1664–9.PubMedPubMedCentralCrossRefGoogle Scholar
  128. 128.
    Zajicek J, Ball S, Wright D, Vickery J, et al. Effect of dronabinol on progression in progressive multiple sclerosis (CUPID): a randomised, placebo-controlled trial. Lancet Neurol. 2013;12(9):857–65.PubMedPubMedCentralCrossRefGoogle Scholar
  129. 129.
    Theoharides TC, Kempuraj D, Kourelis T, Manola A. Human mast cells stimulate activated T cells: implications for multiple sclerosis. Ann N Y Acad Sci. 2008;1144:74–82.PubMedCrossRefGoogle Scholar
  130. 130.
    Dubreuil P, Letard S, Ciufolini M, Gros L, et al. Masitinib (AB1010), a potent and selective tyrosine kinase inhibitor targeting KIT. PLoS One. 2009;4(9):e7258.PubMedPubMedCentralCrossRefGoogle Scholar
  131. 131.
    Vermersch P, Benrabah R, Schmidt N, Zephir H, et al. Masitinib treatment in patients with progressive multiple sclerosis: a randomized pilot study. BMC Neurol. 2012;12:36.PubMedPubMedCentralCrossRefGoogle Scholar
  132. 132.
    Klotz L, Wiendl H. Monoclonal antibodies in neuroinflammatory diseases. Expert Opin Biol Ther. 2013;13(6):831–46.PubMedCrossRefGoogle Scholar
  133. 133.
    Sedel F, Bernard D, Mock DM, Tourbah A. Targeting demyelination and virtual hypoxia with high-dose biotin as a treatment for progressive multiple sclerosis. Neuropharmacol. 2016;110(pt B):644–53.CrossRefGoogle Scholar
  134. 134.
    Maloney DG, Grillo-Lopez AJ, White CA, Bodkin D, et al. IDEC-C2B8 (Rituximab) anti-CD20 monoclonal antibody therapy in patients with relapsed low-grade non-Hodgkin’s lymphoma. Blood. 1997;90(6):2188–95.PubMedGoogle Scholar
  135. 135.
    Browning JL. B cells move to centre stage: novel opportunities for autoimmune disease treatment. Nat Rev Drug Discov. 2006;5(7):564–76.PubMedCrossRefGoogle Scholar
  136. 136.
    Dalakas MC. B cells as therapeutic targets in autoimmune neurological disorders. Nat Clin Pract Neurol. 2008;4(10):557–67.Google Scholar
  137. 137.
    Hawker K, O’Connor P, Freedman MS, Calabresi PA, 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):460–71.PubMedCrossRefGoogle Scholar
  138. 138.
    Marracci GH, Jones RE, McKeon GP, Bourdette DN. Alpha lipoic acid inhibits T cell migration into the spinal cord and suppresses and treats experimental autoimmune encephalomyelitis. J Neuroimmunol. 2002;131(1–2):104–14.Google Scholar
  139. 139.
    Morini M, Roccatagliata L, Dell’Eva R, Pedemonte E, et al. Alpha-lipoic acid is effective in prevention and treatment of experimental autoimmune encephalomyelitis. J Neuroimmunol. 2004;148(1–2):146–53.PubMedCrossRefGoogle Scholar
  140. 140.
    Chaudhary P, Marracci G, Yu X, Galipeau D, et al. Lipoic acid decreases inflammation and confers neuroprotection in experimental autoimmune optic neuritis. J Neuroimmunol. 2011;233(1–2):90–6.PubMedPubMedCentralCrossRefGoogle Scholar
  141. 141.
    Khalili M, Azimi A, Izadi V, Eghtesadi S, et al. Does lipoic acid consumption affect the cytokine profile in multiple sclerosis patients: a double-blind, placebo-controlled, randomized clinical trial. NeuroImmunoModulation. 2014;21(6):291–6.PubMedCrossRefGoogle Scholar
  142. 142.
    Spain RI MC, Horak F, Simon J, et al. P1.373—lipoic acid for neuroprotection in secondary progressive multiple sclerosis. In: 68th Annual meeting of the American academy of neurology, Vancouver; 2016.Google Scholar
  143. 143.
    Pan S, Gray NS, Gao W, Mi Y, et al. Discovery of BAF312 (Siponimod), a potent and selective S1P Receptor modulator. ACS Med Chem Lett. 2013;4(3):333–7.PubMedPubMedCentralCrossRefGoogle Scholar
  144. 144.
    Selmaj K, Li DK, Hartung HP, Hemmer B, 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.PubMedCrossRefGoogle Scholar
  145. 145.
    Kappos L, Li DK, Stuve O, Hartung HP, et al. Safety and efficacy of siponimod (BAF312) in patients with relapsing-remitting multiple sclerosis: dose-blinded, randomized extension of the phase 2 BOLD study. JAMA Neurol. 2016;73(9):1089-98.Google Scholar
  146. 146.
    Kappos L B-OA, Cree B, Fox R, et al. Baseline subgroup characteristics of EXPAND: a phase 3 study of siponimod (BAF312) for the Treatment of Secondary progressive multiple sclerosis (P3.084). Neurology. 2016;86(16):suppl. P3.084.Google Scholar
  147. 147.
    Kappos L B-OA, Cree B, et al. Efficacy and safety of siponimod in secondary progressive multiple sclerosis—results of the placebo controlled, double-blind, phase III EXPAND study. ECTRIMS 2016. London: ECTRIMS Online Library; 2016.Google Scholar
  148. 148.
    Barkhof F, Hulst HE, Drulovic J, Uitdehaag BM, et al. Ibudilast in relapsing-remitting multiple sclerosis: a neuroprotectant? Neurology. 2010;74(13):1033–40.PubMedCrossRefGoogle Scholar
  149. 149.
    Nicholas R Straube S, Schmidli H, Schneider S, et al. Trends in annualized relapse rates in relapsing remitting multiple sclerosis and consequences for clinical trial design. Mult Scler. 2011;17(10):1211–7.Google Scholar
  150. 150.
    Friede T, Pohlmann H, Schmidli H. Blinded sample size reestimation in event driven clinical trials: methods and an application in multiple sclerosis. 2017 (in preparation).Google Scholar
  151. 151.
    Friede T, Parsons N, Stallard N, Todd S, et al. Designing a seamless phase II/III clinical trial using early outcomes for treatment selection: an application in multiple sclerosis. Stat Med. 2011;30(13):1528-40.Google Scholar
  152. 152.
    Friede T, Nicholas R, Stallard N, Todd S, et al. Refinement of the Clinical Scenario Evaluation Framework for Assessment of Competing Development Strategies with an Application to Multiple Sclerosis. Drug Inf J. 2010;44(6):713–718.Google Scholar
  153. 153.
    Mahad DH, Trapp BD, Lassmann H. Pathological mechanisms in progressive multiple sclerosis. Lancet Neurol. 2015;14(2):183–93.PubMedCrossRefGoogle Scholar
  154. 154.
    Trapp BD, Peterson J, Ransohoff RM, Rudick R, et al. Axonal transection in the lesions of multiple sclerosis. N Engl J Med. 1998;338(5):278–85.PubMedCrossRefGoogle Scholar
  155. 155.
    Evangelou N, DeLuca GC, Owens T, Esiri MM. Pathological study of spinal cord atrophy in multiple sclerosis suggests limited role of local lesions. Brain. 2005;128(pt 1):29–34.PubMedGoogle Scholar
  156. 156.
    Giorgio A, Stromillo ML, Rossi F, Battaglini M, et al. Cortical lesions in radiologically isolated syndrome. Neurology. 2011;77(21):1896–9.PubMedCrossRefGoogle Scholar
  157. 157.
    Bjartmar C, Trapp BD. Axonal degeneration and progressive neurologic disability in multiple sclerosis. Neurotox Res. 2003;5(1–2):157–64.PubMedCrossRefGoogle Scholar
  158. 158.
    Fox RJ, Thompson A, Baker D, Baneke P, et al. Setting a research agenda for progressive multiple sclerosis: the International Collaborative on Progressive MS. Mult Scler. 2012;18(11):1534–40.PubMedPubMedCentralCrossRefGoogle Scholar
  159. 159.
    Confavreux C, Vukusic S, Adeleine P. Early clinical predictors and progression of irreversible disability in multiple sclerosis: an amnesic process. Brain. 2003;126(pt 4):770–82.PubMedCrossRefGoogle Scholar
  160. 160.
    Leray E, Yaouanq J, Le Page E, Coustans M, et al. Evidence for a two-stage disability progression in multiple sclerosis. Brain. 2010;133(pt 7):1900–13.PubMedPubMedCentralCrossRefGoogle Scholar
  161. 161.
    Scalfari A, Neuhaus A, Degenhardt A, Rice GP, et al. The natural history of multiple sclerosis: a geographically based study 10: relapses and long-term disability. Brain. 2010;133(pt 7):1914–29.PubMedPubMedCentralCrossRefGoogle Scholar
  162. 162.
    Tremlett H, Yousefi M, Devonshire V, Rieckmann P, et al. Impact of multiple sclerosis relapses on progression diminishes with time. Neurology. 2009;73(20):1616–23.PubMedPubMedCentralCrossRefGoogle Scholar
  163. 163.
    Coles AJ, Cox A, Le Page E, Jones J, et al. The window of therapeutic opportunity in multiple sclerosis: evidence from monoclonal antibody therapy. J Neurol. 2006;253(1):98–108.PubMedCrossRefGoogle Scholar
  164. 164.
    Jacobs LD, Beck RW, Simon JH, Kinkel RP, et al. Intramuscular interferon beta-1a therapy initiated during a first demyelinating event in multiple sclerosis. CHAMPS Study Group. N Engl J Med. 2000;343(13):898–904.PubMedCrossRefGoogle Scholar
  165. 165.
    Miller AE, Wolinsky JS, Kappos L, Comi G, 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.PubMedCrossRefGoogle Scholar
  166. 166.
    Comi G, Martinelli V, Rodegher M, Moiola L, et al. Effect of glatiramer acetate on conversion to clinically definite multiple sclerosis in patients with clinically isolated syndrome (PreCISe study): a randomised, double-blind, placebo-controlled trial. Lancet. 2009;374(9700):1503–11.PubMedCrossRefGoogle Scholar
  167. 167.
    Kappos L, Freedman MS, Polman CH, Edan G, 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):389–97.PubMedCrossRefGoogle Scholar
  168. 168.
    Comi G, Filippi M, Barkhof F, Durelli L, et al. Effect of early interferon treatment on conversion to definite multiple sclerosis: a randomised study. Lancet. 2001;357(9268):1576–82.PubMedCrossRefGoogle Scholar
  169. 169.
    Kinkel RP, Kollman C, O’Connor P, Murray TJ, et al. IM interferon beta-1a delays definite multiple sclerosis 5 years after a first demyelinating event. Neurology. 2006;66(5):678–84.PubMedCrossRefGoogle Scholar
  170. 170.
    Kappos L, Freedman MS, Polman CH, Edan G, 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):987–97.PubMedCrossRefGoogle Scholar

Copyright information

© Springer International Publishing Switzerland 2017

Authors and Affiliations

  • A. Nandoskar
    • 1
  • J. Raffel
    • 1
  • A. S. Scalfari
    • 1
  • T. Friede
    • 2
  • R. S. Nicholas
    • 1
  1. 1.Wolfson Neuroscience Laboratories, Faculty of MedicineImperial College LondonLondonUK
  2. 2.Department of Medical StatisticsUniversity Medical Center GöttingenGöttingenGermany

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