Semin Neurol 2013; 33(01): 013-025
DOI: 10.1055/s-0033-1343792
Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

The Use of Interferon Beta and Glatiramer Acetate in Multiple Sclerosis

Douglas S. Goodin
1   Department of Neurology, University of California, San Francisco, California
› Author Affiliations
Further Information

Publication History

Publication Date:
25 May 2013 (online)

Abstract

The modern era of the therapy for multiple sclerosis began in the 1990s with introduction of interferon beta and glatiramer acetate. Now 20 years since the introduction of these disease modifying therapies, several alternatives have become available. Although, in many cases, these new agents seem especially effective, there is little head-to-head trial data to actually compare the efficacy of the newer agents to that of the older. Moreover, there is no doubt that these older agents are both effective and very safe - something which has not always proven true about the newer therapies. Consequently, there will continue to be a place for these injectable treatments, even as we move into an era where physicians are confronted with many treatment possibilities.

 
  • References

  • 1 Weinshenker BG, Bass B, Rice GPA , et al. The natural history of multiple sclerosis: a geographically based study. I. Clinical course and disability. Brain 1989; 112 (Pt 1) 133-146
  • 2 Weinshenker BG, Bass B, Rice GP , et al. The natural history of multiple sclerosis: a geographically based study. 2. Predictive value of the early clinical course. Brain 1989; 112 (Pt 6) 1419-1428
  • 3 Weinshenker BG. Epidemiology of multiple sclerosis. Neurol Clin 1996; 14 (2) 291-308
  • 4 Tremlett H, Paty D, Devonshire V. Disability progression in multiple sclerosis is slower than previously reported. Neurology 2006; 66 (2) 172-177
  • 5 Compston A, Confavreux C, Lassmann H , et al. McAlpine's Multiple Sclerosis. 4 th ed. London: Churchill Livingston; 2006
  • 6 Conlon P, Oksenberg JR, Zhang J, Steinman L. The immunobiology of multiple sclerosis: an autoimmune disease of the central nervous system. Neurobiol Dis 1999; 6 (3) 149-166
  • 7 Ferguson B, Matyszak MK, Esiri MM, Perry VH. Axonal damage in acute multiple sclerosis lesions. Brain 1997; 120 (Pt 3) 393-399
  • 8 Trapp BD, Peterson JP, Ransohoff RM, Rudick R, Mörk S, Bö L. Axonal transection in the lesions of multiple sclerosis. N Engl J Med 1998; 338 (5) 278-285
  • 9 Bar-Or A, Oliveira EM, Anderson DE, Hafler DA. Molecular pathogenesis of multiple sclerosis. J Neuroimmunol 1999; 100 (1-2) 252-259
  • 10 Lublin FD, Reingold SC. National Multiple Sclerosis Society (USA) Advisory Committee on Clinical Trials of New Agents in Multiple Sclerosis. Defining the clinical course of multiple sclerosis: results of an international survey. Neurology 1996; 46 (4) 907-911
  • 11 Kurtzke JF. A new scale for evaluating disability in multiple sclerosis. Neurology 1955; 5 (8) 580-583
  • 12 Kurtzke JF. Rating neurologic impairment in multiple sclerosis: an expanded disability status scale (EDSS). Neurology 1983; 33 (11) 1444-1452
  • 13 Goodin DS. Magnetic resonance imaging as a surrogate outcome measure of disability in multiple sclerosis: have we been overly harsh in our assessment?. Ann Neurol 2006; 59 (4) 597-605
  • 14 Goodin DS, Traboulsee A, Knappertz V , et al; 16-Year Long Term Follow-up Study Investigators. Relationship between early clinical characteristics and long term disability outcomes: 16.  year cohort study (follow-up) of the pivotal interferon β-1b trial in multiple sclerosis. J Neurol Neurosurg Psychiatry 2012; 83 (3) 282-287
  • 15 Goodin DS, Jones J, Li D , et al; 16-Year Long-Term Follow-up Study Investigators. Establishing long-term efficacy in chronic disease: use of recursive partitioning and propensity score adjustment to estimate outcome in MS. PLoS ONE 2011; 6 (11) e22444
  • 16 Trojano M, Pellegrini F, Fuiani A , et al. New natural history of interferon-beta-treated relapsing multiple sclerosis. Ann Neurol 2007; 61 (4) 300-306
  • 17 Renoux C, Suissa S. Immortal time bias in the study of effectiveness of interferon-β in multiple sclerosis. Ann Neurol 2008; 64 (1) 109-110 , author reply 110
  • 18 Shirani A, Zhao Y, Karim ME , et al. Association between use of interferon beta and progression of disability in patients with relapsing-remitting multiple sclerosis. JAMA 2012; 308 (3) 247-256
  • 19 Suissa S. Immortal time bias in observational studies of drug effects. Pharmacoepidemiol Drug Saf 2007; 16 (3) 241-249
  • 20 Rosenbaum PR, Rubin DB. The central role of the propensity score in observational studies for causal effects. Biometrica 1983; 70: 41-55
  • 21 Trojano M, Pellegrini F. Reply (to Renoux & Suissa). Ann Neurol 2008; 64: 110
  • 22 Goodin DS, Reder AT, Cutter G. Treatment with interferon beta for multiple sclerosis. JAMA 2012; 308 (16) 1627 , author reply 1627–1628
  • 23 Came PE, Carter WA , eds. Interferons and Their Applications. Berlin: Springer-Verlag; 1984
  • 24 Der SD, Zhou A, Williams BRG, Silverman RH. Identification of genes differentially regulated by interferon α, β, or γ using oligonucleotide arrays. Proc Natl Acad Sci U S A 1998; 95 (26) 15623-15628
  • 25 Reder AT , ed. Interferon therapy of multiple sclerosis. New York: Marcel Dekker, Inc.; 2000
  • 26 Goodbourn S, Didcock L, Randall RE. Interferons: cell signalling, immune modulation, antiviral response and virus countermeasures. J Gen Virol 2000; 81 (Pt 10) 2341-2364
  • 27 de Veer MJ, Holko M, Frevel M , et al. Functional classification of interferon-stimulated genes identified using microarrays. J Leukoc Biol 2001; 69 (6) 912-920
  • 28 Servant MJ, Tenoever B, Lin R. Overlapping and distinct mechanisms regulating IRF-3 and IRF-7 function. J Interferon Cytokine Res 2002; 22 (1) 49-58
  • 29 Kerr IM, Costa-Pereira AP, Lillemeier BF, Strobl B. Of JAKs, STATs, blind watchmakers, jeeps and trains. FEBS Lett 2003; 546 (1) 1-5
  • 30 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 (4) 655-661
  • 31 Paty DW, Li DK. UBC MS/MRI Study Group and the IFNB Multiple Sclerosis Study Group. Interferon beta-1b is effective in relapsing-remitting multiple sclerosis. II. MRI analysis results of a multicenter, randomized, double-blind, placebo-controlled trial. Neurology 1993; 43 (4) 662-667
  • 32 The IFNB Multiple Sclerosis Study Group and The University of British Columbia MS/MRI Analysis Group. Interferon beta-1b in the treatment of multiple sclerosis: final outcome of the randomized controlled trial. Neurology 1995; 45 (7) 1277-1285
  • 33 Jacobs LD, Cookfair DL, Rudick RA , et al. The Multiple Sclerosis Collaborative Research Group (MSCRG). Intramuscular interferon beta-1a for disease progression in relapsing multiple sclerosis. Ann Neurol 1996; 39 (3) 285-294
  • 34 Rudick RA, Goodkin DE, Jacobs LD , et al; The Multiple Sclerosis Collaborative Research Group (MSCRG). Impact of interferon beta-1a on neurologic disability in relapsing multiple sclerosis. Neurology 1997; 49 (2) 358-363
  • 35 Simon JH, Jacobs LD, Campion M , et al; The Multiple Sclerosis Collaborative Research Group. Magnetic resonance studies of intramuscular interferon β-1a for relapsing multiple sclerosis. Ann Neurol 1998; 43 (1) 79-87
  • 36 Khatri BO, McQuillen MP. Disease modifying therapies in multiple sclerosis. Neurology 2002; 59 (3) 472-473 , author reply 472–473
  • 37 Biogen Inc. Summary Basis of Approval. FDA Official Document for License of Interferon Beta-1a (Avonex). Cambridge, MA: Biogen Inc; 1995
  • 38 Rudick RA, Fisher E, Lee JC, Simon J, Jacobs L. Multiple Sclerosis Collaborative Research Group. Use of the brain parenchymal fraction to measure whole brain atrophy in relapsing-remitting MS. Neurology 1999; 53 (8) 1698-1704
  • 39 Fischer JS, Priore RL, Jacobs LD , et al; Multiple Sclerosis Collaborative Research Group. Neuropsychological effects of interferon beta-1a in relapsing multiple sclerosis. Ann Neurol 2000; 48 (6) 885-892
  • 40 Miller DM, Weinstock-Guttman B, Bourdette D, You X, Foulds P, Rudick RA. Change in quality of life in patients with relapsing-remitting multiple sclerosis over 2 years in relation to other clinical parameters: results from a trial of intramuscular interferon beta-1a. Mult Scler 2011; 17 (6) 734-742
  • 41 Bermel RA, Weinstock-Guttman B, Bourdette D, Foulds P, You X, Rudick RA. Intramuscular interferon beta-1a therapy in patients with relapsing-remitting multiple sclerosis: a 15-year follow-up study. Mult Scler 2010; 16 (5) 588-596
  • 42 PRISMS Study Group. Randomized double-blind placebo-controlled study of interferon β-1a in relapsing-remitting multiple sclerosis. PRISMS (Prevention of Relapses and Disability by Interferon beta-1a Subcutaneously in Multiple Sclerosis) Study Group. Lancet 1998; 352 (9139) 1498-1504
  • 43 Li DK, Paty DW. UBC MS/MRI Analysis Research Group, PRISMS Study Group. Magnetic resonance imaging results of the PRISMS trial: a randomized, double-blind, placebo-controlled study of interferon-beta1a in relapsing-remitting multiple sclerosis. Prevention of Relapses and Disability by Interferon-beta1a Subcutaneously in Multiple Sclerosis. Ann Neurol 1999; 46 (2) 197-206
  • 44 European Study Group on Interferon beta-1b in secondary progressive MS. Placebo-controlled multicentre randomized trial of interferon β-1b in treatment of secondary progressive multiple sclerosis. Lancet 1998; 352 (9139) 1491-1497
  • 45 Panitch H, Miller A, Paty D, Weinshenker B. 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 (10) 1788-1795
  • 46 Kappos L, Weinshenker B, Pozzilli C , et al; European (EU-SPMS) Interferon beta-1b in Secondary Progressive Multiple Sclerosis Trial Steering Committee and Independent Advisory Board; North American (NA-SPMS) Interferon beta-1b in Secondary Progressive Multiple Sclerosis Trial Steering Committee and Independent Advisory Board. Interferon beta-1b in secondary progressive MS: a combined analysis of the two trials. Neurology 2004; 63 (10) 1779-1787
  • 47 Secondary Progressive Efficacy Clinical Trial of Recombinant Interferon-Beta-1a in MS (SPECTRIMS) Study Group. Randomized controlled trial of interferon- beta-1a in secondary progressive MS: Clinical results. Neurology 2001; 56 (11) 1496-1504
  • 48 Li DK, Zhao GJ, Paty DW. University of British Columbia MS/MRI Analysis Research Group. The SPECTRIMS Study Group. Randomized controlled trial of interferon-beta-1a in secondary progressive MS: MRI results. Neurology 2001; 56 (11) 1505-1513
  • 49 Cohen JA, Cutter GR, Fischer JS , et al; IMPACT Investigators. Benefit of interferon beta-1a on MSFC progression in secondary progressive MS. Neurology 2002; 59 (5) 679-687
  • 50 Jacobs LD, Beck RW, Simon JH , et al; CHAMPS Study Group. Intramuscular interferon beta-1a therapy initiated during a first demyelinating event in multiple sclerosis. N Engl J Med 2000; 343 (13) 898-904
  • 51 Comi G, Filippi M, Barkhof F , et al; Early Treatment of Multiple Sclerosis Study Group. Effect of early interferon treatment on conversion to definite multiple sclerosis: a randomised study. Lancet 2001; 357 (9268) 1576-1582
  • 52 Kappos L, Freedman MS, Polman CH , et al; BENEFIT Study Group. 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) 389-397
  • 53 Kappos L, Traboulsee A, Constantinescu C , et al. Long-term subcutaneous interferon beta-1a therapy in patients with relapsing-remitting MS. Neurology 2006; 67 (6) 944-953
  • 54 Goodin DS, Reder AT, Ebers GC , et al. Survival in MS patients 21 years after initiation of the interferon beta-1b pivotal trial. Neurology 2012; 78 (17) 1315-1322
  • 55 Goodin DS, Ebers GC, Cutter G , et al. Cause of death in MS: Long-term follow-up of a randomized cohort, 21-years after the start of the pivotal IFNB-1b study. BMJ Open 2012; 2 (6) . pii: e001972
  • 56 Panitch H, Goodin DS, Francis G , et al. EVIDENCE Study Group. Evidence of interferon dose-response: European North American Comparative Efficacy; University of British Columbia MS/MRI Research Group. Randomized, comparative study of interferon beta-1a treatment regimens in MS: the EVIDENCE trial. Neurology 2002; 59 (10) 1496-1506
  • 57 Durelli L, Verdun E, Barbero P , et al; Independent Comparison of Interferon (INCOMIN) Trial Study Group. 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 (9316) 1453-1460
  • 58 O'Connor P, Filippi M, Arnason B , et al; BEYOND Study Group. 250 microg or 500 microg interferon beta-1b versus 20.  mg glatiramer acetate in relapsing-remitting multiple sclerosis: a prospective, randomised, multicentre study. Lancet Neurol 2009; 8 (10) 889-897
  • 59 Deisenhammer F, Mayringer I, Harvey J , et al. A comparative study of the relative bioavailability of different interferon beta preparations. Neurology 2000; 54 (11) 2055-2060
  • 60 Stürzebecher S, Maibauer R, Heuner A, Beckmann K, Aufdembrinke B. Pharmacodynamic comparison of single doses of IFN-beta1a and IFN-beta1b in healthy volunteers. J Interferon Cytokine Res 1999; 19 (11) 1257-1264
  • 61 Salmon P, Le Cotonnec JY, Galazka A, Abdul-Ahad A, Darragh A. Pharmacokinetics and pharmacodynamics of recombinant human interferon-beta in healthy male volunteers. J Interferon Cytokine Res 1996; 16 (10) 759-764
  • 62 Munafo A, Trinchard-Lugan I, Nguyen TXQ, Buraglio M. Comparative pharmacokinetics and pharmacodynamics of recombinant human interferon beta-1a after intramuscular and subcutaneous administration. Eur J Neurol 1998; 5: 1-7
  • 63 Goodin DS, Frohman EM, 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 (13) 977-984
  • 64 Goodin DS, Hurwitz B, Noronha A. Neutralizing antibodies to interferon beta-1b are not associated with disease worsening in multiple sclerosis. J Int Med Res 2007; 35 (2) 173-187
  • 65 Goodin DS. Neutralizing antibodies to interferon beta-1b are not associated with disease worsening in multiple sclerosis. (Correspondence). J Int Med Res 2008; 36: 208-210
  • 66 Farrell R, Bendtzen K, Bertolotto A , et al. European NABINMS Consortium. Re: Neutralizing antibodies to interferon beta-1b are not associated with disease worsening in multiple sclerosis. J Int Med Res 2008; 36 (1) 204-208 , author reply 208–210
  • 67 Pachner AR. Re: 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; 69: 1555-1556 , author reply 1565
  • 68 Polman CH, Deisenhammer F, Giovannoni G, Killestein J, Schellekens H. Re: 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; 69 (15) 1553-1555 , author reply 1555
  • 69 Sørensen PS, Bertolotto A. Re: 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; 69 (15) 1552-1553 , author reply 1553
  • 70 Pachner AR, Warth JD, Pace A, Goelz S. INSIGHT investigators. Effect of neutralizing antibodies on biomarker responses to interferon beta: the INSIGHT study. Neurology 2009; 73 (18) 1493-1500
  • 71 Pachner AR, Dail D, Pak E, Narayan K. The importance of measuring IFNbeta bioactivity: monitoring in MS patients and the effect of anti-IFNbeta antibodies. J Neuroimmunol 2005; 166 (1-2) 180-188
  • 72 Pachner AR, Narayan K, Pak E. Multiplex analysis of expression of three IFNbeta-induced genes in antibody-positive MS patients. Neurology 2006; 66 (3) 444-446
  • 73 Hesse D, Sellebjerg F, Sørensen PS. Absence of MxA induction by interferon beta in patients with MS reflects complete loss of bioactivity. Neurology 2009; 73 (5) 372-377
  • 74 Benjamini Y, Hochberg Y. Controlling the false discovery rate: a practical and powerful approach to multiple testing. J R Stat Soc, B 1995; 57: 289-300
  • 75 Hartung HP, Freedman MS, Polman CH , et al; BENEFIT Study Group. Interferon β-1b-neutralizing antibodies 5 years after clinically isolated syndrome. Neurology 2011; 77 (9) 835-843
  • 76 Goodin DS, Hartung HP, O'Connor P , et al; BEYOND Study Group. Neutralizing antibodies to interferon beta-1b multiple sclerosis: a clinico-radiographic paradox in the BEYOND trial. Mult Scler 2012; 18 (2) 181-195
  • 77 Sørensen PS, Koch-Henriksen N, Ross C, Clemmesen KM, Bendtzen K. Danish Multiple Sclerosis Study Group. Appearance and disappearance of neutralizing antibodies during interferon-beta therapy. Neurology 2005; 65 (1) 33-39
  • 78 Petkau AJ, White RA, Ebers GC , et al; IFNB Multiple Sclerosis Study Group. Longitudinal analyses of the effects of neutralizing antibodies on interferon beta-1b in relapsing-remitting multiple sclerosis. Mult Scler 2004; 10 (2) 126-138
  • 79 Rice GP, Paszner B, Oger J, Lesaux J, Paty D, Ebers G. The evolution of neutralizing antibodies in multiple sclerosis patients treated with interferon beta-1b. Neurology 1999; 52 (6) 1277-1279
  • 80 Bellomi F, Scagnolari C, Tomassini V , et al. Fate of neutralizing and binding antibodies to IFN beta in MS patients treated with IFN beta for 6 years. J Neurol Sci 2003; 215 (1-2) 3-8
  • 81 Reder AT, Ebers GC, Traboulsee A , et al; Investigators of the 16-Year Long-Term Follow-Up Study. Cross-sectional study assessing long-term safety of interferon-beta-1b for relapsing-remitting MS. Neurology 2010; 74 (23) 1877-1885
  • 82 Teitelbaum D, Aharoni R, Sela M, Arnon R. Cross-reactions and specificities of monoclonal antibodies against myelin basic protein and against the synthetic copolymer 1. Proc Natl Acad Sci U S A 1991; 88 (21) 9528-9532
  • 83 Teitelbaum D, Milo R, Arnon R, Sela M. Synthetic copolymer 1 inhibits human T-cell lines specific for myelin basic protein. Proc Natl Acad Sci U S A 1992; 89 (1) 137-141
  • 84 Lando Z, Teitelbaum D, Arnon R. Effect of cyclophosphamide on suppressor cell activity in mice unresponsive to EAE. J Immunol 1979; 123 (5) 2156-2160
  • 85 Teitelbaum D, Meshorer A, Hirshfeld T, Arnon R, Sela M. Suppression of experimental allergic encephalomyelitis by a synthetic polypeptide. Eur J Immunol 1971; 1 (4) 242-248
  • 86 Bornstein MB, Miller A, Slagle S , et al. A pilot trial of Cop 1 in exacerbating-remitting multiple sclerosis. N Engl J Med 1987; 317 (7) 408-414
  • 87 Johnson KP, Brooks BR, Cohen JA , 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. The Copolymer 1 Multiple Sclerosis Study Group. Neurology 1995; 45 (7) 1268-1276
  • 88 Johnson KP, Brooks BR, Cohen JA , et al. Extended use of glatiramer acetate (Copaxone) is well tolerated and maintains its clinical effect on multiple sclerosis relapse rate and degree of disability. Copolymer 1 Multiple Sclerosis Study Group. Neurology 1998; 50 (3) 701-708
  • 89 Comi G, Filippi M, Wolinsky JS. European/Canadian Glatiramer Acetate Study Group. European/Canadian multicenter, double-blind, randomized, placebo-controlled study of the effects of glatiramer acetate on magnetic resonance imaging—measured disease activity and burden in patients with relapsing multiple sclerosis. Ann Neurol 2001; 49 (3) 290-297
  • 90 Mikol DD, Barkhof F, Chang P , et al; REGARD study group. Comparison of subcutaneous interferon beta-1a with glatiramer acetate in patients with relapsing multiple sclerosis (the REbif vs Glatiramer Acetate in Relapsing MS Disease [REGARD] study): a multicentre, randomised, parallel, open-label trial. Lancet Neurol 2008; 7 (10) 903-914
  • 91 Bornstein MB, Miller A, Slagle S , et al. A placebo-controlled, double-blind, randomized, two-center, pilot trial of Cop 1 in chronic progressive multiple sclerosis. Neurology 1991; 41 (4) 533-539
  • 92 Wolinsky JS, Narayana PA, O'Connor P , et al; PROMiSe Trial Study Group. Glatiramer acetate in primary progressive multiple sclerosis: results of a multinational, multicenter, double-blind, placebo-controlled trial. Ann Neurol 2007; 61 (1) 14-24
  • 93 Comi G, Martinelli V, Rodegher M , et al; PreCISe study group. 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) 1503-1511
  • 94 Johnson KP, Brooks BR, Ford CC , et al. Sustained clinical benefits of glatiramer acetate in relapsing multiple sclerosis patients observed for 6 years. Copolymer 1 Multiple Sclerosis Study Group. Mult Scler 2000; 6 (4) 255-266
  • 95 Ford CC, Johnson KP, Lisak RP, Panitch HS, Shifronis G, Wolinsky JS. Copaxone Study Group. A prospective open-label study of glatiramer acetate: over a decade of continuous use in multiple sclerosis patients. Mult Scler 2006; 12 (3) 309-320
  • 96 Ford C, Goodman AD, Johnson K , 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 2010; 16 (3) 342-350
  • 97 Goodin DS. Disease-modifying therapy in MS: a critical review of the literature. Part I: Analysis of clinical trial errors. J Neurol 2004; 251 (Suppl. 05) v3-v11
  • 98 Edgar CM, Brunet DG, Fenton P, McBride EV, Green P. Lipoatrophy in patients with multiple sclerosis on glatiramer acetate. Can J Neurol Sci 2004; 31 (1) 58-63
  • 99 Polman CH, O'Connor PW, Havrdova E , et al; AFFIRM Investigators. A randomized, placebo-controlled trial of natalizumab for relapsing multiple sclerosis. N Engl J Med 2006; 354 (9) 899-910
  • 100 Kappos L, Radue EW, O'Connor P , et al; FREEDOMS Study Group. A placebo-controlled trial of oral fingolimod in relapsing multiple sclerosis. N Engl J Med 2010; 362 (5) 387-401
  • 101 O'Connor P, Wolinsky JS, Confavreux C , et al; TEMSO Trial Group. Randomized trial of oral teriflunomide for relapsing multiple sclerosis. N Engl J Med 2011; 365 (14) 1293-1303