Journal of Neurology

, Volume 252, Supplement 3, pp iii3–iii9 | Cite as

History of modern multiple sclerosis therapy



Although the earliest recorded description of multiple sclerosis (MS) dates back to the 14th century, it was not until the latter years of the 20th that treatments for this disabling condition were found. However, the “road to success” has not been without hurdles. Trials with both interferon alpha and gamma proved unsuccessful, as did treatment with oral myelin, cladribine, sulfasalazine and inhibitors of tumour necrosis factor. In 1993, interferon beta-1b (IFNβ-1b) became the first therapy proven to be effective in altering the natural history of relapsing-remitting MS (RRMS). This was followed by successful trials with IFNβ-1a and glatiramer acetate. In 1998, a European trial showed IFNβ-1b to be also beneficial in the treatment of secondary progressive MS (SPMS). A similar trial in North America failed to reach its primary endpoint but was effective across secondary endpoints, highlighting how different methodology and patient populations can lead to inconsistent results and, thus, making comparisons across trials difficult. The trend for early intervention in MS with IFNβ was recently supported by the CHAMPS (Controlled High-risk Avonex MultiPle Sclerosis) and ETOMS (Early Treatment of Multiple Sclerosis) studies using once-weekly IFNβ-1a. Both trials demonstrated delayed conversion to clinically definite MS in patients with a clinically isolated syndrome and magnetic resonance imaging (MRI) findings suggestive of MS. Two directly comparative trials of high- (250 µg IFNβ-1b or 44 µg IFNβ-1a) and low-dose (30 µg IFNβ-1a) IFNβ (INCOMIN [INdependent COMparison of INterferons] and EVIDENCE [EVidence of Interferon Dose-response: European North American Comparative Efficacy]) support the superior efficacy of the higher dose and/or more frequent administration for treating RRMS. Since MS entered the treatment era in 1993, therapies for RRMS, SPMS and, more recently, progressive- relapsing MS have been developed. There is now a much better understanding of the pathogenesis of the disease, but new and improved therapeutic approaches are still needed.

Key words

multiple sclerosis therapy interferon beta-1b 


  1. 1.
    Bielekova B, Goodwin B, Richert N, Cortese I, Kondo T, Afshar G, Gran B, Eaton J, Antel J, Frank JA, McFarland HF, Martin R (2000) Encephalitogenic potential of the myelin basic protein peptide (amino acids 83–99) in multiple sclerosis: results of a phase II clinical trial with an altered peptide ligand. Nat Med 6:1167–1175CrossRefPubMedGoogle Scholar
  2. 2.
    Bornstein MB, Miller A, Slagle S, Weitzman M, Crystal H, Drexler E,Keilson M, Merriam A, Wassertheil-Smoller S, Spada V, et al. (1987) A pilot trial of Cop 1 in exacerbating-remitting multiple sclerosis. New Engl J Med 317:408–414PubMedGoogle Scholar
  3. 3.
    Clanet M, Radue EW, Kappos L, Hartung HP, Hohlfeld R, Sandberg-Wollheim M, Kooijmans-Coutinho MF, Tsao EC, Sandrock AW; European IFNbeta-1a (Avonex®) Dose-Comparison Study Investigators (2002) A randomized, double-blind, dose-comparison study of weekly interferon beta-1a in relapsing MS. Neurology 59:1507–1517PubMedGoogle Scholar
  4. 4.
    Comi G (2000) Why treat early multiple sclerosis patients? Curr Opin Neurol 13:235–240CrossRefPubMedGoogle Scholar
  5. 5.
    Comi G, Filippi M, Barkhof F,Durelli L, Edan G, Fernandez O, Hartung H, Seeldrayers P, Sorensen PS, Rovaris M, Martinelli V, Hommes OR; Early Treatment of Multiple Sclerosis Study Group (2001) Effect of early interferon treatment on conversion to definite multiple sclerosis: a randomised study. Lancet 357:1576–1582CrossRefPubMedGoogle Scholar
  6. 6.
    Durelli L, Verdun E, Barbero P, Bergui M, Versino E, Ghezzi A, Montanari E, Zaffaroni M; Independent Comparison of Interferon (INCOMIN) Trial Study Group (2002) Every-other-day interferon beta-1b versus once-weekly interferon beta-1a for multiple sclerosis: results of a 2-year prospective randomised multicentre study (INCOMIN). Lancet 359:1453–1460CrossRefPubMedGoogle Scholar
  7. 7.
    European Study Group on Interferon β-1b in Secondary Progressive MS (1998) Placebo controlled multicentre randomised trial of interferon β-1b in treatment of secondary progressive multiple sclerosis. Lancet 352:1491–1497CrossRefPubMedGoogle Scholar
  8. 8.
    Grossman RI, Gonzalez-Scarano F, Atlas SW, Galetta S, Silberberg DH (1986) Multiple sclerosis: gadolinium enhancement in MR imaging. Radiology 161:721–725PubMedGoogle Scholar
  9. 9.
    Hartung HP, Gonsette R, Konig N, Kwiecinski H, Guseo A, Morrissey SP, Krapf H, Zwingers T; Mitoxantrone in Multiple Sclerosis Study Group (MIMS) (2002) Mitoxantrone in progressive multiple sclerosis: a placebo-controlled, double-blind, randomized, multicentre trial. Lancet 360:2018–2025CrossRefPubMedGoogle Scholar
  10. 10.
    Iannucci G, Tonorella C, Rovaris M, Sormani MP, Comi G, Filippi M (2000) The prognostic value of MR and MTI findings at presentation in patients with clinically isolated syndromes suggestive of MS. Am J Neuroradiol 21:1034–1038PubMedGoogle Scholar
  11. 11.
    The IFNB Multiple Sclerosis Study Group. Interferon beta-1b is effective in relapsing-remitting multiple sclerosis (1993) I Clinical results of a multicenter, randomized, double-blind, placebo-controlled trial. Neurology 43:655–661PubMedGoogle Scholar
  12. 12.
    The IFNB Multiple Sclerosis Study Group and the University of British Columbia MS/MRI Analysis Group (1995) Interferon beta-1b in the treatment of multiple sclerosis: final outcome of the randomised controlled trial. Neurology 45:1277–1285PubMedGoogle Scholar
  13. 13.
    Jacobs LD, Cookfair DL, Rudick RA, Herndon RM, Richert JR, Salazar AM, Fischer JS, Goodkin DE, Granger CV, Simon JH, Alam JJ, Bartoszak DM, Bourdette DN, Braiman J, Brownscheidle CM, Coats ME, Cohan SL, Dougherty DS, Kinkel RP, Mass MK, Munschauer FE 3rd, Priore RL, Pullicino PM, Scherokman BJ, Whitham RH, et al. (1996) Intramuscular interferon beta-1a for disease progression in relapsing multiple sclerosis. The Multiple Sclerosis Collaborative Research Group (MSCRG). Ann Neurol 39:285–294CrossRefPubMedGoogle Scholar
  14. 14.
    Jacobs LD, Beck RW, Simon JH, Kinkel RP, Brownscheidle CM, Murray TJ, Simonian NA, Slasor PJ, Sandrock AW (2000) Intramuscular interferon beta-1a therapy initiated during a first demyelinating event in multiple sclerosis. CHAMPS Study Group. N Eng J Med 343:898–904CrossRefGoogle Scholar
  15. 15.
    Johnson KP, Brooks BR, Cohen JA, Ford CC, Goldstein J, Lisak RP, Myers LW, Panitch HS, Rose JW, Schiffer RB (1995) Copolymer 1 reduces relapse rate and improves disability in relapsing remitting multiple sclerosis: results of a phase III multicentre double-blind placebo-controlled trial. The Copolymer I Multiple Sclerosis Study Group. Neurology 45:1268–1276PubMedGoogle Scholar
  16. 16.
    The Lenercept Multiple Sclerosis Study Group and The University of British Columbia MS/MRI Analysis Group (1999) TNF neutralization in MS: results of a randomized, placebo-controlled multicenter study. Neurology 53:457–465PubMedGoogle Scholar
  17. 17.
    Lublin FD, Reingold SC (1996) Defining the clinical course of multiple sclerosis: results of an international survey. National Multiple Sclerosis Society (USA) Advisory Committee on Clinical Trials of New Agents in Multiple Sclerosis. Neurology 46:907–911PubMedGoogle Scholar
  18. 18.
    Noseworthy JH, O’Brien P, Erickson BJ, Lee D, Sneve D, Ebers GC, Rice GP, Auty A, Hader WJ, Kirk A, Duquette P, Carter J, Francis G, Metz L, Shuster E (1998) The Mayo Clinic-Canadian Cooperative trial of sulfasalazine in active multiple sclerosis. Neurology 51:1342–1352PubMedGoogle Scholar
  19. 19.
    Noseworthy JH, Wolinsky JS, Lublin FD, Whitaker JN, Linde A, Gjorstrup P, Sullivan HC (2000) Linomide in relapsing and secondary progressive MS: part I: trial design and clinical results. North American Linomide Investigators. Neurology 54:1726–1733PubMedGoogle Scholar
  20. 20.
    van Oosten BW, Barkhof F, Truyen L, Boringa JB, Bertelsmann FW, von Blomberg BM, Woody JN, Hartung HP, Polman CH (1996) Increased MRI activity and immune activation in two multiple sclerosis patients treated with the monoclonal anti-tumor necrosis factor antibody cA2. Neurology 47:1531–1534PubMedGoogle Scholar
  21. 21.
    Panitch H, Goodin DS, Francis G, Chang P, Coyle PK, O’Connor P, Monaghan E, Li D, Weinshenker B; EVIDENCE Study Group. EVidence of Interferon Dose-response: European North American Comparative Efficacy; University of British Columbia MS/MRI Research Group (2002) Randomized, comparative study of interferon beta-1a treatment regimens in MS: The EVIDENCE Trial. Neurology 59:1496–1506PubMedGoogle Scholar
  22. 22.
    Panitch H, Miller A, Paty D, Weinshenker B, North American Study Group on Interferon beta-1b in Secondary Progressive MS (2004) Interferon beta-1b in secondary progressive MS: results from a 3-year controlled study. Neurology 63:1788–1795PubMedGoogle Scholar
  23. 23.
    PRISMS (Prevention of Relapses and Disability by Interferon β-1a Subcutaneously in Multiple Sclerosis) Study Group (1998) Randomized double-blind placebo-controlled study of interferon β-1a in relapsing/remitting multiple sclerosis. Lancet 352:1498–1504CrossRefPubMedGoogle Scholar
  24. 24.
    Rice GP, Filippi M, Comi G (2000) Cladribine and progressive MS: clinical and MRI outcomes of a multicenter controlled trial. Cladribine MRI Study Group. Neurology 54:1145–1155PubMedGoogle Scholar
  25. 25.
    Secondary Progressive Efficacy Clinical Trial of Recombinant Interferonbeta-1 a (Serono) in MS (SPECTRIMS) Study Group. Randomized controlled trial of interferon-beta-la in secondary progressive MS: clinical results. Neurology (in press)Google Scholar
  26. 26.
    Stone LA, Frank JA, Albert PS, Bash C, Smith ME, Maloni H, McFarland HF (1995) The effects of interferon beta on blood-brain barrier disruptions demonstrated by contrast-enhanced magnetic resonance imaging in relapsing-remitting multiple sclerosis. Ann Neurol 37:611–619CrossRefPubMedGoogle Scholar
  27. 27.
    Trapp BD, Peterson J, Ransohoff RM, Rudick R, Mork S, Bo L (1998) Axonal transection in the lesions of multiple sclerosis. N Engl J Med 338:278–285CrossRefPubMedGoogle Scholar
  28. 28.
    Trapp BD, Ransohoff R, Rudick R (1999) Axonal pathology in multiple sclerosis: relationship to neurologic disability. Curr Opin Neurol 12:295–302CrossRefPubMedGoogle Scholar
  29. 29.
    UBC MS/MRI Study Group and the IFNB Multiple Sclerosis Study Group (1993) Interferon beta-1b is effective in relapsing-remitting multiple sclerosis. II. MRI analysis results of a multicenter, randomized, double-blind, placebo-controlled trial. Neurology 43:662–667PubMedGoogle Scholar
  30. 30.
    Wolinsky S, Narayana PA, Johnson KP (2001) United States open-label glatiramer acetate trial for relapsing multiple sclerosis: MRI and clinical correlates. Multiple Sclerosis Study Group and MRI analysis Group. Mutl Scler 7:33–41CrossRefGoogle Scholar
  31. 31.
    Young IR, Hall AS, Pallis CA, Legg NJ, Bydder GM, Steiner RE (1981) Nuclear magnetic resonance imaging of the brain in multiple sclerosis. Lancet 2:1063–1066CrossRefPubMedGoogle Scholar

Copyright information

© Steinkopff-Verlag 2005

Authors and Affiliations

  1. 1.Corinne Goldsmith Dickinson Center for Multiple SclerosisMount Sinai Medical CenterNew York, NY 10029-6574USA

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