Current Evidence and Therapeutic Strategies for Multiple Sclerosis

ABSTRACT

In the previous two decades several immunomodulatory and immunosuppressive therapies have been shown to favorably impact the inflammatory activity and course of multiple sclerosis. There are now six approved therapies for the disease. Clinical decision-making has become more complex because of the increasing number of available drugs, the lack of head-to-head comparisons that allow direct comparisons of efficacy, and special factors that may influence efficacy such as neutralizing antibodies against β-interferon preparations. Furthermore, all current therapies are partially effective; therefore, most patients experience breakthrough disease activity while using them, and there are no validated treatment failure definitions or management algorithms. This review outlines current evidence supporting efficacy of available drugs and scenarios for which more studies are required, and highlights the need for emerging therapies and strategies for multiple sclerosis management, including investigative oral and parenteral agents and combination therapy approaches.

KEYWORDS

Multiple sclerosis - drug therapy - β-interferon - glatiramer acetate - natalizumab - mitoxantrone - immunosuppression

REFERENCES

• 1 Miller D, Barkhof F, Montalban X, Thompson A, Filippi M. Clinically isolated syndromes suggestive of multiple sclerosis, part I: natural history, pathogenesis, diagnosis, and prognosis.  Lancet Neurol. 2005;  4 281-288
• 2 Miller D, Barkhof F, Montalban X, Thompson A, Filippi M. Clinically isolated syndromes suggestive of multiple sclerosis, part 2: non-conventional MRI, recovery processes, and management.  Lancet Neurol. 2005;  4 341-348
• 3 McDonald W I, Compston A, Edan G et al.. Recommended diagnostic criteria for multiple sclerosis: Guidelines from the international panel on the diagnosis of multiple sclerosis.  Ann Neurol. 2001;  50 121-127
• 4 Polman C H, Reingold S C, Edan G et al.. Diagnostic criteria for multiple sclerosis: 2005 revisions to the “McDonald Criteria..”  Ann Neurol. 2005;  58 840-846
• 5 Brex P A, Ciccarelli O, O'Riordan J I, Sailer M, Thompson A J, Miller D H. A longitudinal study of abnormalities on MRI and disability from multiple sclerosis.  N Engl J Med. 2002;  346 158-164
• 6 O'Riordan J I, Thompson A J, Kingsley D PE et al.. The prognostic value of brain MRI in clinically isolated syndromes of the CNS. A 10-year follow-up.  Brain. 1998;  121 495-503
• 7 Sailer M, O'Riordan J I, Thompson A J et al.. Quantitative MRI in patients with clinically isolated syndromes suggestive of demyelination.  Neurology. 1999;  52 599-606
• 8 CHAMPS Study Group . MRI predictors of early conversion to clinically definite MS in the CHAMPS placebo group.  Neurology. 2002;  59 998-1005
• 9 Jacobs L D, Beck R W, Simon J H et al.. Intramuscular interferon beta-1a therapy initiated during a first demyelinating event in multiple sclerosis.  N Engl J Med. 2000;  343 898-904
• 10 Comi G, Filippi M, Barkhof F et al.. Effect of early interferon treatment on conversion to definite multiple sclerosis: a randomised study.  Lancet. 2001;  357 1576-1582
• 11 Filippi M, Rovaris M, Inglese M et al.. Interferon beta-1a for brain tissue loss in patients at presentation with syndromes suggestive of multiple sclerosis: a randomised, double-blind, placebo-controlled trial.  Lancet. 2004;  364 1489-1496
• 12 Kappos L, Polman C, Freedman M S et al.. Treatment with interferon beta-1b delays conversion to clinically definite and McDonald MS in patients with clinically isolated syndromes.  Neurology. 2006;  67 1242-1249
• 13 CHAMPIONS Study Group . Interferon beta-1a delays definite multiple sclerosis 5 years after a first demyelinating event.  Neurology. 2006;  66 678-684
• 14 Achiron A, Kishner I, Sarova-Pinhas I et al.. Intravenous immunoglobulin treatment following the first demyelinating event suggestive of multiple sclerosis: a randomized, double-blind, placebo-controlled trial.  Arch Neurol. 2004;  61 1515-1520
• 15 The IFNB Multiple Sclerosis Study Group . Interferon beta-1b is effective in relapsing remitting multiple sclerosis. I. Clinical results of a multicenter, randomized, double-blind, placebo-controlled trial.  Neurology. 1993;  43 655-661
• 16 The IFNB Multiple Sclerosis Study Group and the University of British Columbia MS/MRI Analysis Group . Interferon beta-1b in the treatment of MS: Final outcome of the randomized controlled trial.  Neurology. 1995;  45 1277-1285
• 17 Jacobs L D, Cookfair D L, Rudick R A et al.. Intramuscular interferon beta-1a for disease progression in relapsing multiple sclerosis.  Ann Neurol. 1996;  39 285-294
• 18 PRISMS. (Prevention of Relapses and Disability by Interferon -1a Subcutaneously in Multiple Sclerosis) Study Group . Randomized double-blind placebo-controlled study of interferon beta-1a in relapsing/remitting multiple sclerosis.  Lancet. 1998;  352 1498-1504
• 19 PRISMS Study Group, and the University of British Columbia MS/MRI Analysis Group . PRISMS-4: long-term efficacy of interferon-β-1a in relapsing MS.  Neurology. 2001;  56 1628-1636
• 20 Goodin D S, Frohman E M, Garmany G P et al.. Disease modifying therapies in multiple sclerosis. Report of the Therapeutic and Technology Assessment Subcommittee of the American Academy of Neurology and the MS Council for Clinical Practice Guidelines.  Neurology. 2002;  58 169-178
• 21 Filippini G, Munari L, Incorvaia B et al.. Interferons in relapsing remitting multiple sclerosis: a systematic review.  Lancet. 2003;  361 545-552
• 22 Freedman M, King J, Oger J et al.. Interferons in relapsing remitting multiple sclerosis.  Lancet. 2003;  361 1822-1823 , Letter
• 23 Durelli L, Verdun E, Barbero P et al.. 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. 2002;  359 1453-1460
• 24 Panitch H, Goodin D S, Francis G et al.. Randomized, comparative study of interferon beta-1a treatment regimens in MS: the EVIDENCE trial.  Neurology. 2002;  59 1496-1506
• 25 Clanet M, Radue E W, Kappos L et al.. A randomized, double-blind, dose-comparison study of weekly interferon beta-1a in relapsing MS.  Neurology. 2002;  59 1507-1517
• 26 Kappos L, Traboulsee A, Constantinescu C et al.. Long-term subcutaneous interferon beta-1a therapy in patients with relapsing-remitting MS.  Neurology. 2006;  67 944-953
• 27 Noseworthy J H. How much can we learn from long-term extension trials in multiple sclerosis?.  Neurology. 2006;  67 930-931
• 28 Sorensen P S, Koch-Henrisken N, Ravnborg M et al.. Immunomodulatory treatment of multiple sclerosis in Denmark: a prospective nationwide survey.  Mult Scler. 2006;  12 253-264
• 29 Ebers G, Traboulsee A, Li D et al.. Final results from the interferon beta-1b 16-year long-term follow-up study. 22nd Congress of the European Committee for Treatment and Research in Multiple Sclerosis Madrid, Spain; September 2006: P666
• 30 Martinelli Boneschi F, Rovaris M, Johnson K P et al.. Effects of glatiramer acetate on relapse rate and accumulated disability in multiple sclerosis: meta-analysis of three double-blind, randomized, placebo-controlled clinical trials.  Mult Scler. 2003;  9 349-355
• 31 Munari L, Lovati R, Boiko A. Therapy with glatiramer acetate for multiple sclerosis (Cochrane Review). In: The Cochrane Library, Issue 4. Chichester, United Kingdom; John Wiley and Sons Ltd 2004
• 32 Cohen J, Rovaris M, Goodman A et al.. Randomised, double-blind, parallel-group, dose-comparison study of glatiramer acetate in relapsing-remitting multiple sclerosis. 22nd Congress of the European Committee for Treatment and Research in Multiple Sclerosis Madrid, Spain; September 2006
• 33 Ford C C, Johnson K P, Lisak R P et al.. A prospective open-label study of glatiramer acetate: over a decade of continuous use in multiple sclerosis patients.  Mult Scler. 2006;  12 309-320
• 34 Rice G P, Hartung H P, Calabresi P A. Anti-alpha4 integrin therapy for multiple sclerosis: mechanisms and rationale.  Neurology. 2005;  64 1336-1342
• 35 Miller D H, Khan O A, Sheremata W A et al.. A controlled trial of natalizumab for relapsing multiple sclerosis.  N Engl J Med. 2003;  348 15-23
• 36 Van Assche G, Van Ranst M, Sciot R et al.. Progressive multifocal leukoencephalopathy after natalizumab therapy for Crohn's disease.  N Engl J Med. 2005;  353(4) 362-368
• 37 Kleinschmidt-DeMasters B K, Tyler K L. Progressive multifocal leukoencephalopathy complicating treatment with natalizumab and interferon beta-1a for multiple sclerosis.  N Engl J Med. 2005;  353(4) 369-374
• 38 Langer-Gould A, Atlas S W, Green A J, Bollen A W, Pelletier D. Progressive multifocal leukoencephalopathy in a patient treated with natalizumab.  N Engl J Med. 2005;  353(4) 375-381
• 39 Berger J R, Koralnik I J. Progressive multifocal leukoencephalopathy and natalizumab-unforeseen consequences.  N Engl J Med. 2005;  353(4) 414-416
• 40 Polman C H, O'Connor P W, Havrdova E et al.. A randomized, placebo-controlled trial of natalizumab for relapsing multiple sclerosis.  N Engl J Med. 2006;  354 899-910
• 41 Rudick R A, Stuart W H, Calabresi P A et al.. A randomized, placebo-controlled trial of natalizumab plus interferon beta-1a for relapsing multiple sclerosis.  N Engl J Med. 2006;  354 911-923
• 42 Yousry T A, Major E O, Ryschkewitsch C et al.. Evaluation of patients treated with natalizumab for progressive multifocal leukoencephalopathy.  N Engl J Med. 2006;  354 924-933
• 43 Stüve O, Marra C M, Jerome K R et al.. Immune surveillance in multiple sclerosis patients treated with natalizumab.  Ann Neurol. 2006;  59 743-747
• 44 Niino M, Bodner C, Simard M L et al.. Natalizumab effects on immune cell responses in multiple sclerosis.  Ann Neurol. 2006;  59 748-754
• 45 Kappos L, Bates D, Hartung H P et al.. Natalizumab treatment for multiple sclerosis: recommendations for patient selection and monitoring.  Lancet Neurol. 2007;  6 431-441
• 46 Hartung H-P, Gonsette R, Konig N et al.. Mitoxantrone in progressive multiple sclerosis: a placebo-controlled, double-blind, randomised, muticentre trial.  Lancet. 2002;  360 2018-2025
• 47 Goodin D S, Arnason B G, Coyle P K et al.. The use of mitoxantrone (Novantrone) for the treatment of multiple sclerosis.  Neurology. 2003;  61 1332-1338
• 48 Novantrone [package insert]. Rockland, MA; Serono Inc 2005
• 49 Ghalie R G, Edan G, Laurent M et al.. Cardiac adverse effects associated with mitoxantrone (Novantrone) therapy in patients with MS.  Neurology. 2002;  59 909-913
• 50 Avasarala J R, Cross A H, Clifford D B, Singer B A, Siegel B A, Abbey E E. Rapid onset mitoxantrone-induced cardiotoxicity in secondary progressive multiple sclerosis.  Mult Scler. 2003;  9(1) 59-62
• 51 Edan G, Brochet B, Clanet M et al.. Safety profile of mitoxantrone in a cohort of 802 multiple sclerosis patients: a 4 year mean follow-up study.  Neurology. 2004;  62(suppl 5) A493
• 52 Brassat D, Recher C, Waubant E et al.. Therapy-related acute myeloblastic leukemia after mitoxantrone treatment in a patient with MS.  Neurology. 2002;  59 954-955
• 53 Bernitsas E, Wei W, Mikol D D. Suppression of mitoxantrone cardiotoxicity in multiple sclerosis patients by dexrazoxane.  Ann Neurol. 2006;  59 206-209
• 54 European Study Group on Interferon β-1b in Secondary Progressive MS . Placebo-controlled multicentre randomised trial of interferon β-1b in treatment of secondary progressive multiple sclerosis.  Lancet. 1998;  352 1491-1497
• 55 Cohen J A, Cutter G R, Fischer J S for the IMPACT Investigators et al. Benefit of interferon β-1a on MSFC progression in secondary progressive MS.  Neurology. 2002;  59 679-687
• 56 Secondary Progressive Efficacy Trial of Recombinant Interferon-beta-1a in MS (SPECTRIMS) Study Group . Randomized controlled trial of interferon-beta-1a in secondary progressive MS.  Neurology. 2001;  56 1496-1504
• 57 Li D K, Zhao G J, Paty D W. University of British Columbia MS/MRI Analysis Research Group, and the SPECTRIMS Study Group . Randomized controlled trial of interferon beta-1a in secondary progressive MS. MRI results.  Neurology. 2001;  56 1505-1518
• 58 Panitch H, Miller A, Paty D, Weinshenker B. for the North American Study Group on Interferon beta-1b in Secondary. Progressive MS. Interferon beta-1b in secondary progressive MS: results from a 3-year controlled study.  Neurology. 2004;  63 1788-1795
• 59 Hommes O R, Sorenson P S, Fazekas F et al.. Intravenous immune globulin in secondary progressive multiple sclerosis: randomised placebo-controlled trial.  Lancet. 2004;  364 1149-1156
• 60 Kappos L, Weinshenker B, Pozzilli C et al.. Interferon beta-1b in secondary progressive MS: a combined analysis of the two trials.  Neurology. 2004;  63 1779-1787
• 61 Cohen J A, Antel J P. Does interferon beta help in secondary progressive MS?.  Neurology. 2004;  63 1768-1769
• 62 Wolinsky J S, Narayana P A, O'Connor P et al.. Glatiramer acetate in primary progressive multiple sclerosis: results of a multinational, multicenter, double-blind, placebo-controlled trial.  Ann Neurol. 2007;  61 14-24
• 63 Freedman M S, Patry D G, Grand'Maison F, Myles M L, Paty D W, Selchen D H. Canadian MS Working Group . Treatment optimization in multiple sclerosis.  Can J Neurol Sci. 2004;  31 157-168
• 64 Rudick R A, Lee J C, Simon J et al.. Defining interferon beta response status in multiple sclerosis patients.  Ann Neurol. 2004;  56 548-555
• 65 Rio J, Nos V, Tintore M et al.. Defining the response to interferon-beta in relapsing-remitting multiple sclerosis patients.  Ann Neurol. 2006;  59 344-352
• 66 Giovannoni G, Munschauer III F E, Deisenhammer F. Neutralising antibodies to interferon beta during the treatment of multiple sclerosis.  J Neurol Neurosurg Psychiatry. 2002;  73 465-469
• 67 Bertolotto A, Malucchi S, Sala A et al.. Differential effects of three interferon betas on neutralizing antibodies in patients with multiple sclerosis: a follow up study in an independent laboratory.  J Neurol Neurosurg Psychiatry. 2002;  73 148-153
• 68 Sorensen P S, Ross C, Clemmesen K M et al.. Clinical importance of neutralizing antibodies against interferon beta in patients with relapsing-remitting multiple sclerosis.  Lancet. 2003;  362 1184-1191
• 69 Bertolotto A, Gilli F, Sala A et al.. Persistent neutralizing antibodies abolish the interferon β bioavailability in MS patients.  Neurology. 2003;  60 634-639
• 70 Pachner A. Anti-IFNβ antibodies in IFNβ-treated MS patients: summary.  Neurology. 2003;  61(suppl 5) S1-S5
• 71 Sorensen P S, Koch-Henriksen N, Ross C et al.. Appearance and disappearance of neutralizing antibodies during interferon-beta therapy.  Neurology. 2005;  65 33-39
• 72 Sorensen P S, Tscherning T, Mathiesen H K et al.. Neutralizing antibodies hamper IFNbeta bioactivity and treatment effect on MRI in patients with MS.  Neurology. 2006;  67 1681-1683
• 73 Francis G S, Rice G PA, Alsop J C et al.. Interferon β-1a in MS. Results following development of neutralizing antibodies in PRISMS.  Neurology. 2005;  65 48-55
• 74 Kappos L, Clanet M, Sandberg-Wollheim M et al.. Neutralizing antibodies and efficacy of interferon β-1a: a 4-year controlled study.  Neurology. 2005;  65 40-47
• 75 Giovannoni G, Goodman A. Neutralizing anti-IFN-β antibodies: how much more evidence do we need to use them in practice?.  Neurology. 2005;  65 6-8
• 76 Sorensen P S, Deisenhammer F, Duda P EFNS Task Force on Anti-IFN-beta Antibodies in Multiple Sclerosis et al. Guidelines on use of anti-IFN-beta antibody measurements in multiple sclerosis: report of an EFNS Task Force on IFN-beta antibodies in multiple sclerosis.  Eur J Neurol. 2005;  12 817-827
• 77 Goodin D S, Frohman E M, Hurwitz B et al.. Neutralizing antibodies to interferon beta-assessment of their clinical and radiographic impact: an evidence report. Report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology.  Neurology. 2007;  68 977-984
• 78 Petersen B, Bendtzen K, Koch-Henriksen N et al.. Persistence of neutralizing antibodies after discontinuation of IFNB therapy in patients with relapsing-remitting multiple sclerosis.  Mult Scler. 2006;  12 247-252
• 79 Tullman M J, Lublin F J. Combination therapy in multiple sclerosis.  Curr Neurol Neurosci Rep. 2005;  5 245-248
• 80 Pulicken M, Bash C N, Costello K et al.. Optimization of the safety and efficacy of interferon beta 1b and azathioprine combination therapy in multiple sclerosis.  Mult Scler. 2005;  11 169-174
• 81 Jeffery D R, Chepuri N, Durden N, Burdette J. A pilot trial of combination therapy with mitoxantrone and interferon beta-1b using monthly gadolinium-enhanced magnetic resonance imaging.  Mult Scler. 2005;  11 296-301
• 82 Smith D R, Weinstock-Guttman B, Cohen J A 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
• 83 Gladstone D E, Zamkoff K W, Krupp L et al.. High-dose cyclophosphamide for moderate to severe refractory multiple sclerosis.  Arch Neurol. 2006;  63 1388-1393
• 84 Ramtahal J, Jacob A, Das K, Boggild M. Sequential maintenance treatment with glatiramer acetate after mitoxantrone is safe and can limit exposure to immunosuppression in very active, relapsing remitting multiple sclerosis.  J Neurol. 2006;  253 1160-1164
• 85 Cree B. Emerging monoclonal antibody therapies for multiple sclerosis.  Neurologist. 2006;  12 171-178
• 86 U.S. Food and Drug Administration .Life-threatening brain infection in patients with systemic lupus erythematosus after rituxan (Rituximab) treatment. Available at: http://www.fda.gov/cder/drug/advisory/rituximab.htm Accessed May 10, 2007
• 87 Kappos L, Antel J, Comi G et al.. Oral fingolimod (FTY720) for relapsing multiple sclerosis.  N Engl J Med. 2006;  355 1124-1140
• 88 O'Connor P W, Li D, Freedman M S et al.. A Phase II study of the safety and efficacy of teriflunomide in multiple sclerosis with relapses.  Neurology. 2006;  66 894-900