Neurotherapeutics

, Volume 10, Issue 1, pp 77–88 | Cite as

Role of Immunosuppressive Therapy for the Treatment of Multiple Sclerosis

  • James M. Stankiewicz
  • Hadar Kolb
  • Arnon Karni
  • Howard L. Weiner
Review

Abstract

Immunosuppressives have been used in multiple sclerosis (MS) since 1966. Today, we have many treatments for the relapsing forms of the disease, including 8 US Food and Drug Administration-approved therapies, with more soon to be introduced. Given the current treatment landscape what place do immunosuppressants have in combating MS? Trial work and our experience suggest that immunosuppressives still have an important role in treating MS. Cyclophosphamide finds use in treating patients with severe, inflammatory relapsing remitting MS or those suffering from a fulminant attack. We tend to employ mycophenolate mofetil as an add-on to injectable therapy for patients experiencing breakthrough activity. Some progressive (primary progressive multiple sclerosis or secondary progressive multiple sclerosis) patients may stabilize after treatment with either cyclophosphamide or mycophenolate. We rarely employ mitoxantrone because of potential cardiac or carcinogenic effects. We prefer to use cyclophosphamide or mycophenolate mofetil in preference to methotrexate because evidence of efficacy is limited for this drug. We have less experience with azathioprine, but it may be an alternative for patients with limited options who are unable to tolerate conventional therapies.

Keywords

Cyclophosphamide Mycophenolate mofetil Azathioprine Mitoxantrone Methotrexate 

Supplementary material

13311_2012_172_MOESM1_ESM.pdf (511 kb)
ESM 1(PDF 510 kb)

References

  1. 1.
    Calne DB, Leibowitz S. Suppression of experimental allergic encephalomyelitis by cytotoxic drugs. Nature 1963;197:1309–1310.PubMedCrossRefGoogle Scholar
  2. 2.
    Aimard G, Girard PF, Raveau J. Multiple sclerosis and the autoimmunization process. Treatment by antimitotics. Lyon Med 1966;215:345–352.PubMedGoogle Scholar
  3. 3.
    ten Berge RJ, van Walbeek HK, Schellekens PT. Evaluation of the immunosuppressive effects of cyclophosphamide in patients with multiple sclerosis. Clin Exp Immunol 1982;50:495–502.PubMedGoogle Scholar
  4. 4.
    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;29:341–348.PubMedCrossRefGoogle Scholar
  5. 5.
    Hommes OR, Aerts F, Bahr U, Schulten HR. Cyclophosphamide levels in serum and spinal fluid of multiple sclerosis patients treated with immunosuppression. J Neurol Sci 1983;58:297–303.PubMedCrossRefGoogle Scholar
  6. 6.
    Hafler DA, Orav J, Gertz R, Stazzone L, Weiner HL. Immunologic effects of cyclophosphamide/ACTH in patients with chronic progressive multiple sclerosis. J Neuroimmunol 1991;32:149–158.PubMedCrossRefGoogle Scholar
  7. 7.
    Mickey MR, Ellison GW, Fahey JL, Moody DJ, Myers LW. Correlation of clinical and immunologic states in multiple sclerosis. Arch Neurol 1987;44:371–375.PubMedCrossRefGoogle Scholar
  8. 8.
    Takashima H, Smith DR, Fukaura H, et al. Pulse cyclophosphamide plus methylprednisolone induces myelin-antigen-specific IL-4-secreting T cells in multiple sclerosis patients. Clin Immunol Immunopathol 1998;88:28–34.PubMedCrossRefGoogle Scholar
  9. 9.
    Comabella M, Balashov K, Issazadeh S, et al. Elevated interleukin-12 in progressive multiple sclerosis correlates with disease activity and is normalized by pulse cyclophosphamide therapy. J Clin Invest 1998;102:671–678.PubMedCrossRefGoogle Scholar
  10. 10.
    Karni A, Balashov K, Hancock WW, et al. Cyclophosphamide modulates CD4+ T cells into a T helper type 2 phenotype and reverses increased IFN-gamma production of CD8+ T cells in secondary progressive multiple sclerosis. J Neuroimmunol 2004;146:189–198.PubMedCrossRefGoogle Scholar
  11. 11.
    Hommers OR, Lamers KJ, Reekers P. Effect of intensive immunosuppression on the course of chronic progressive multiple sclerosis. J Neurol 1980;223:177–190.PubMedCrossRefGoogle Scholar
  12. 12.
    Gonsette RE, Demonty L, Delmotte P. Intensive immunosuppression with cyclophosphamide in multiple sclerosis. Follow up of 110 patients for 2–6 years. J Neurol 1977;214:173–181.PubMedCrossRefGoogle Scholar
  13. 13.
    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;308:173–180.PubMedCrossRefGoogle Scholar
  14. 14.
    The Canadian Cooperative Multiple Sclerosis Study Group. The Canadian cooperative trial of cyclophosphamide and plasma exchange in progressive multiple sclerosis. Lancet 1991;337:441–446.Google Scholar
  15. 15.
    Likosky WH, Fireman B, Elmore R, et al. Intense immunosuppression in chronic progressive multiple sclerosis: the Kaiser study. J Neurol Neurosurg Psychiatry 1991;54:1055–1060.PubMedCrossRefGoogle Scholar
  16. 16.
    Manova MG, Kostadinova, II, Rangelov AA. Clinico-laboratory study of methylprednisolone and cyclophosphamide treatment in patients with multiple sclerosis relapse. Folia Med (Plovdiv) 2000;42:20–25.Google Scholar
  17. 17.
    D'Andrea F, D'Aurizio C, Marini C, Prencipe M. Cyclophosphamide in relapsing remitting multiple sclerosis. Ital J Neurol Sci 1990;11:271–274.PubMedCrossRefGoogle Scholar
  18. 18.
    Killian JM, Bressler RB, Armstrong RM, Huston DP. Controlled pilot trial of monthly intravenous cyclophosphamide in multiple sclerosis. Arch Neurol 1988;45:27–30.PubMedCrossRefGoogle Scholar
  19. 19.
    Khan OA, Zvartau-Hind M, Caon C, et al. Effect of monthly intravenous cyclophosphamide in rapidly deteriorating multiple sclerosis patients resistant to conventional therapy. Mult Scler 2001;7:185–188.PubMedGoogle Scholar
  20. 20.
    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;11:573–582.PubMedCrossRefGoogle Scholar
  21. 21.
    Gobbini MI, Smith ME, Richert ND, Frank JA, McFarland HF. Effect of open label pulse cyclophosphamide therapy on MRI measures of disease activity in five patients with refractory relapsing-remitting multiple sclerosis. J Neuroimmunol 1999 ;99:142–149.PubMedCrossRefGoogle Scholar
  22. 22.
    Patti F, Reggio E, Palermo F, et al. Stabilization of rapidly worsening multiple sclerosis for 36 months in patients treated with interferon beta plus cyclophosphamide followed by interferon beta. J Neurol 2004;251:1502–1506.PubMedCrossRefGoogle Scholar
  23. 23.
    Patti F, Cataldi ML, Nicoletti F, et al. Combination of cyclophosphamide and interferon-beta halts progression in patients with rapidly transitional multiple sclerosis. J Neurol Neurosurg Psychiatry 2001;71:404–407.PubMedCrossRefGoogle Scholar
  24. 24.
    Reggio E, Nicoletti A, Fiorilla T, et al. The combination of cyclophosphamide plus interferon beta as rescue therapy could be used to treat relapsing-remitting multiple sclerosis patients—twenty-four months follow-up. J Neurol 2005;252:1255–1261.PubMedCrossRefGoogle Scholar
  25. 25.
    Weiner HL, Mackin GA, Orav EJ, et al. Intermittent cyclophosphamide pulse therapy in progressive multiple sclerosis: final report of the Northeast Cooperative Multiple Sclerosis Treatment Group. Neurology 1993;43:910–918.PubMedCrossRefGoogle Scholar
  26. 26.
    Zephir H, de Seze J, Duhamel A, et al. Treatment of progressive forms of multiple sclerosis by cyclophosphamide: a cohort study of 490 patients. J Neurol Sci 2004;218:73–77.PubMedCrossRefGoogle Scholar
  27. 27.
    Makhani N, Gorman MP, Branson HM, et al. Cyclophosphamide therapy in pediatric multiple sclerosis. Neurology 2009;72:2076–2082.PubMedCrossRefGoogle Scholar
  28. 28.
    Yeh EA, Weinstock-Guttman B. Moving on to second-line therapies in pediatric MS: Immunosuppression with cyclophosphamide. Neurology 2009;72:2064–2065.PubMedCrossRefGoogle Scholar
  29. 29.
    Hohol MJ, Olek MJ, Orav EJ, et al. Treatment of progressive multiple sclerosis with pulse cyclophosphamide/methylprednisolone: response to therapy is linked to the duration of progressive disease. Mult Scler 1999;5:403–409.PubMedGoogle Scholar
  30. 30.
    Zipoli V, Portaccio E, Hakiki B, et al. Intravenous mitoxantrone and cyclophosphamide as second-line therapy in multiple sclerosis: an open-label comparative study of efficacy and safety. J Neurol Sci 2008;266:25–30.PubMedCrossRefGoogle Scholar
  31. 31.
    Myers LW, Fahey JL, Moody DJ, et al. Cyclophosphamide 'pulses' in chronic progressive multiple sclerosis. A preliminary clinical trial. Arch Neurol 1987 ;44:828–832.PubMedCrossRefGoogle Scholar
  32. 32.
    Carter JL, Hafler DA, Dawson DM, Orav J, Weiner HL. Immunosuppression with high-dose i.v. cyclophosphamide and ACTH in progressive multiple sclerosis: cumulative 6-year experience in 164 patients. Neurology 1988;38:9–14.PubMedCrossRefGoogle Scholar
  33. 33.
    Krishnan C, Kaplin AI, Brodsky RA, et al. Reduction of disease activity and disability with high-dose cyclophosphamide in patients with aggressive multiple sclerosis. Arch Neurol 2008;65:1044–1051.PubMedCrossRefGoogle Scholar
  34. 34.
    Harrison DM, Gladstone DE, Hammond E, et al. Treatment of relapsing-remitting multiple sclerosis with high-dose cyclophosphamide induction followed by glatiramer acetate maintenance. Mult Scler 2012;18:202–209.PubMedCrossRefGoogle Scholar
  35. 35.
    Gourley MF, Austin HA, Scott D, et al. Methylprednisolone and cyclophosphamide, alone or in combination, in patients with lupus nephritis. A randomized, controlled trial. Ann Intern Med 1996;125:549–557.PubMedGoogle Scholar
  36. 36.
    Portaccio E, Zipoli V, Siracusa G, et al. Safety and tolerability of cyclophosphamide 'pulses' in multiple sclerosis: a prospective study in a clinical cohort. Mult Scler 2003;9:446–450.PubMedCrossRefGoogle Scholar
  37. 37.
    Boumpas DT, Austin HA, Vaughan EM, et al. Risk for sustained amenorrhea in patients with systemic lupus erythematosus receiving intermittent pulse cyclophosphamide therapy. Ann Intern Med 1993;119:366–369.PubMedGoogle Scholar
  38. 38.
    Slater CA, Liang MH, McCune JW, Christman GM, Laufer MR. Preserving ovarian function in patients receiving cyclophosphamide. Lupus 1999;8:3–10.PubMedCrossRefGoogle Scholar
  39. 39.
    Patti F, Lo Fermo S. Lights and shadows of cyclophosphamide in the treatment of multiple sclerosis. Autoimmune Dis 2011;2011:961702.PubMedGoogle Scholar
  40. 40.
    Martin F, Lauwerys B, Lefebvre C, Devogelaer JP, Houssiau FA. Side-effects of intravenous cyclophosphamide pulse therapy. Lupus 1997;6:254–257.PubMedCrossRefGoogle Scholar
  41. 41.
    Morgenstern LB, Pardo CA. Progressive multifocal leukoencephalopathy complicating treatment for Wegener's granulomatosis. J Rheumatol 1995;22:1593–1595.PubMedGoogle Scholar
  42. 42.
    Yokoyama H, Watanabe T, Maruyama D, et al. Progressive multifocal leukoencephalopathy in a patient with B-cell lymphoma during rituximab-containing chemotherapy: case report and review of the literature. Int J Hematol 2008 ;88:443–447.PubMedCrossRefGoogle Scholar
  43. 43.
    Bloomgren G, Richman S, Hotermans C, et al. Risk of natalizumab-associated progressive multifocal leukoencephalopathy. N Engl J Med 2012;366:1870–1880.PubMedCrossRefGoogle Scholar
  44. 44.
    Radis CD, Kahl LE, Baker GL, et al. Effects of cyclophosphamide on the development of malignancy and on long-term survival of patients with rheumatoid arthritis. A 20-year followup study. Arthritis Rheum 1995;38:1120–1127.PubMedCrossRefGoogle Scholar
  45. 45.
    Talar-Williams C, Hijazi YM, Walther MM, et al. Cyclophosphamide-induced cystitis and bladder cancer in patients with Wegener granulomatosis. Ann Intern Med 1996;124:477–484.PubMedGoogle Scholar
  46. 46.
    Moore MJ. Clinical pharmacokinetics of cyclophosphamide. Clin Pharmacokinet 1991;20:194–208.PubMedCrossRefGoogle Scholar
  47. 47.
    Kinlen LJ, Sheil AG, Peto J, Doll R. Collaborative United Kingdom-Australasian study of cancer in patients treated with immunosuppressive drugs. BMJ 1979;2:1461–1466.PubMedCrossRefGoogle Scholar
  48. 48.
    Illei GG, Austin HA, Crane M, et al. Combination therapy with pulse cyclophosphamide plus pulse methylprednisolone improves long-term renal outcome without adding toxicity in patients with lupus nephritis. Ann Intern Med 2001;135:248–257.PubMedGoogle Scholar
  49. 49.
    Ahrens N, Salama A, Haas J. Mycophenolate-mofetil in the treatment of refractory multiple sclerosis. J Neurol 2001;248:713–714.PubMedCrossRefGoogle Scholar
  50. 50.
    Frohman EM, Brannon K, Racke MK, Hawker K. Mycophenolate mofetil in multiple sclerosis. Clin Neuropharmacol 2004;27:80–83.PubMedCrossRefGoogle Scholar
  51. 51.
    Vermersch P, Waucquier N, Michelin E, et al. Combination of IFN beta-1a (Avonex) and mycophenolate mofetil (Cellcept) in multiple sclerosis. Eur J Neurol 2007;14:85–89.PubMedCrossRefGoogle Scholar
  52. 52.
    Frohman EM, Cutter G, Remington G, et al. A randomized, blinded, parallel-group, pilot trial of mycophenolate mofetil (CellCept) compared with interferon beta-1a (Avonex) in patients with relapsing-remitting multiple sclerosis. Ther Adv Neurol Disord 2010;3:15–28.PubMedCrossRefGoogle Scholar
  53. 53.
    Jacob A, Matiello M, Weinshenker BG, et al. Treatment of neuromyelitis optica with mycophenolate mofetil: retrospective analysis of 24 patients. Arch Neurol 2009;66:1128–1133.PubMedCrossRefGoogle Scholar
  54. 54.
    Berger JR. Progressive multifocal leukoencephalopathy and newer biological agents. Drug Saf 2010;33:969–983.PubMedCrossRefGoogle Scholar
  55. 55.
    Neuhaus O, Kieseier BC, Hartung HP. Immunosuppressive agents in multiple sclerosis. Neurotherapeutics 2007;4:654–660.PubMedCrossRefGoogle Scholar
  56. 56.
    Casetta I, Iuliano G, Filippini G. Azathioprine for multiple sclerosis. Cochrane Database Syst Rev 2007:CD003982.Google Scholar
  57. 57.
    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;15:965–976.PubMedCrossRefGoogle Scholar
  58. 58.
    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;114:940–6.PubMedCrossRefGoogle Scholar
  59. 59.
    Etemadifar M, Janghorbani M, Shaygannejad V. Comparison of interferon beta products and azathioprine in the treatment of relapsing-remitting multiple sclerosis. J Neurol 2007;254:1723–1728.PubMedCrossRefGoogle Scholar
  60. 60.
    Double-masked trial of azathioprine in multiple sclerosis. British and Dutch Multiple Sclerosis Azathioprine Trial Group. Lancet 1988;2:179–183.Google Scholar
  61. 61.
    Lhermitte F, Marteau R, Roullet E. Not so benign long-term immunosuppression in multiple sclerosis? Lancet 1984;1:276–277.PubMedCrossRefGoogle Scholar
  62. 62.
    Confavreux C, Saddier P, Grimaud J, et al. Risk of cancer from azathioprine therapy in multiple sclerosis: a case–control study. Neurology 1996;46:1607–1612.PubMedCrossRefGoogle Scholar
  63. 63.
    Amato MP, Pracucci G, Ponziani G, et al. Long-term safety of azathioprine therapy in multiple sclerosis. Neurology 1993;43:831–833.PubMedCrossRefGoogle Scholar
  64. 64.
    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;62:112–118.PubMedCrossRefGoogle Scholar
  65. 65.
    Hartung HP, Gonsette R, Konig N, et al. Mitoxantrone in progressive multiple sclerosis: a placebo-controlled, double-blind, randomised, multicentre trial. Lancet 2002;360:2018–2025.PubMedCrossRefGoogle Scholar
  66. 66.
    Marriott JJ, Miyasaki JM, Gronseth G, O'Connor PW. Evidence Report: The efficacy and safety of mitoxantrone (Novantrone) in the treatment of multiple sclerosis: Report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology. Neurology 2010;74:1463–1670.PubMedCrossRefGoogle Scholar
  67. 67.
    Neumann JW, Ziegler DK. Therapeutic trial of immunosuppressive agents in multiple sclerosis. Neurology 1972;22:1268–1271.PubMedCrossRefGoogle Scholar
  68. 68.
    Currier RD, Haerer AF, Meydrech EF. Low dose oral methotrexate treatment of multiple sclerosis: a pilot study. J Neurol Neurosurg Psychiatry 1993;56:1217–1218.PubMedCrossRefGoogle Scholar
  69. 69.
    Ashtari F, Savoj MR. Effects of low dose methotrexate on relapsing-remitting multiple sclerosis in comparison to Interferon beta-1alpha: A randomized controlled trial. J Res Med Sci 2011;16:457–462.PubMedGoogle Scholar
  70. 70.
    Calabresi PA, Wilterdink JL, Rogg JM, Mills P, Webb A, Whartenby KA. An open-label trial of combination therapy with interferon beta-1a and oral methotrexate in MS. Neurology 2002;58:314–317.PubMedCrossRefGoogle Scholar
  71. 71.
    Cohen JA, Imrey PB, Calabresi PA, et al. Results of the Avonex Combination Trial (ACT) in relapsing-remitting MS. Neurology 2009;72:535–541.PubMedCrossRefGoogle Scholar
  72. 72.
    Goodkin DE, Rudick RA, VanderBrug Medendorp S, et al. Low-dose (7.5 mg) oral methotrexate reduces the rate of progression in chronic progressive multiple sclerosis. Ann Neurol 1995;37:30–40.PubMedCrossRefGoogle Scholar
  73. 73.
    Goodkin DE, Rudick RA, VanderBrug Medendorp S, Daughtry MM, Van Dyke C. Low-dose oral methotrexate in chronic progressive multiple sclerosis: analyses of serial MRIs. Neurology 1996;47:1153–1157.PubMedCrossRefGoogle Scholar
  74. 74.
    Sadiq SA, Simon EV, Puccio LM. Intrathecal methotrexate treatment in multiple sclerosis. J Neurol 2010;257:1806–1811.PubMedCrossRefGoogle Scholar

Copyright information

© The American Society for Experimental NeuroTherapeutics, Inc. 2012

Authors and Affiliations

  • James M. Stankiewicz
    • 1
  • Hadar Kolb
    • 2
  • Arnon Karni
    • 2
  • Howard L. Weiner
    • 1
  1. 1.Department of Neurology, Brigham and Women’s Hospital, Center for Neurologic Disease and Partners MS CenterHarvard Medical SchoolBostonUSA
  2. 2.Department of Neurology, Tel Aviv Sourasky Medical Center, Sackler’s Medical SchoolTel Aviv UniversityTel AvivIsrael

Personalised recommendations