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Immunomodulators and immunosuppressants for multiple sclerosis: a network meta-analysis

  1. Graziella Filippini1,*,
  2. Cinzia Del Giovane2,
  3. Laura Vacchi3,
  4. Roberto D'Amico2,
  5. Carlo Di Pietrantonj4,
  6. Deirdre Beecher5,
  7. Georgia Salanti6

Editorial Group: Cochrane Multiple Sclerosis and Rare Diseases of the Central Nervous System Group

Published Online: 6 JUN 2013

Assessed as up-to-date: 10 FEB 2012

DOI: 10.1002/14651858.CD008933.pub2

How to Cite

Filippini G, Del Giovane C, Vacchi L, D'Amico R, Di Pietrantonj C, Beecher D, Salanti G. Immunomodulators and immunosuppressants for multiple sclerosis: a network meta-analysis. Cochrane Database of Systematic Reviews 2013, Issue 6. Art. No.: CD008933. DOI: 10.1002/14651858.CD008933.pub2.

Author Information

  1. 1

    Fondazione I.R.C.C.S. Istituto Neurologico Carlo Besta, Neuroepidemiology Unit, Milano, Italy

  2. 2

    University of Modena and Reggio Emilia, Statistics Unit, Department of Clinical and Diagnostic Medicine and Public Health, Modena, Italy

  3. 3

    Scientific Institute and University Ospedale San Raffaele, Institute of Experimental Neurology (INSPE), Milano, Italy

  4. 4

    Azienda Sanitaria Locale ASL AL, Servizio Regionale di Riferimento per l'Epidemiologia, SSEpi-SeREMI - Cochrane Vaccines Field, Alessandria, Piemonte, Italy

  5. 5

    London School of Hygiene & Tropical Medicine, Cochrane Injuries Group, London, UK

  6. 6

    University of Ioannina School of Medicine, Department of Hygiene and Epidemiology, Ioannina, Greece

*Graziella Filippini, Neuroepidemiology Unit, Fondazione I.R.C.C.S. Istituto Neurologico Carlo Besta, via Celoria, 11, Milano, 20133, Italy.

Publication History

  1. Publication Status: New
  2. Published Online: 6 JUN 2013



References to studies included in this review

  1. References to studies included in this review
  2. References to studies excluded from this review
  3. Additional references
Achiron 1998 {published data only}
  • Achiron A, Gabbay U, Gilad R, Hassin B, Barak Y, Gornish M, et al. Intravenous immunoglobulin treatment in multiple sclerosis. Effect on relapses. Neurology 1998;50(2):398-402.
AFFIRM 2006 {published data only}
  • Polman CH, O'Connor PW, Havrdova E, Hutchinson M, Kappos L, Miller DH, et al. A randomized, placebo-controlled trial of natalizumab for relapsing multiple sclerosis. The New England Journal of Medicine 2006;354(9):899-910.
Andersen 2004 {published data only}
  • Andersen O, Elovaara I, Farkkila M, Hansen HJ, Mellgren SI, Myhr KM, et al. Multicentre, randomised, double blind, placebo controlled, phase III study of weekly, low dose, subcutaneous interferon beta-1a in secondary progressive multiple sclerosis. Journal of Neurology, Neurosurgery, and Psychiatry 2004;75(5):706-10. [PUBMED: 15090564]
BEYOND 2009 {published data only}
  • O'Connor P, Filippi M, Arnason B, Comi G, Cook S, Goodin D, et al. 250 microg or 500 microg interferon beta-1b versus 20 mg glatiramer acetate in relapsing-remitting multiple sclerosis: a prospective, randomised, multicentre study. Lancet Neurology 2009;8(10):889-97.
Bornstein 1987 {published data only}
  • Bornstein MB, Miller A, Slagle, S, Weitzman M, Crystal, et al. A pilot trial of Cop 1 in exacerbating-remitting multiple sclerosis. The New England Journal of Medicine 1987; Vol. 317, issue 7:408-14.
Bornstein 1991 {published data only}
  • Bornstein MB, Miller A, Slagle S, Weitzman M, Drexler E, Keilson Metal. A placebo-controlled, double-blind, randomised, two-center, pilot trial of Cop 1 in chronic progressive multiple sclerosis. Neurology 1991;41:533-9. [: DOI]
BPSM 1995 {published data only}
British and Dutch 1988 {published data only}
  • The British, Dutch MSATG. Double-masked trial of azathioprine in multiple sclerosis. Lancet 1988; Vol. 2, issue 8604:179-83.
CCMSSG 1991 {published data only}
  • CCMSSG. The Canadian cooperative trial of cyclophosphamide and plasma exchange in progressive multiple sclerosis. Lancet 1991;337(8739):441-6.
Comi 2001 {published data only}
  • Comi G, Filippi M, Wolinsky JS. 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. European/Canadian Glatiramer Acetate Study Group. Annals of Neurology 2001;49(3):290-7. [PUBMED: 11261502]
Edan 1997 {published data only}
  • Edan G, Miller D, Clanet M, Confavreux C, Lyon-Caen O, Lubetzki C, et al. Therapeutic effect of mitoxantrone combined with methylprednisolone in multiple sclerosis: a randomised multicentre study of active disease using MRI and clinical criteria. Journal of Neurology, Neurosurgery, and Psychiatry 1997;62(2):112-8. [: DOI]
Ellison 1989 {published data only}
  • Ellison G, Myers L, Mickey M, Graves M, Tourtellotte W, Syndulko K, 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.
Etemadifar 2006 {published data only}
European Study Group 1998 {published data only}
  • European Study Group. 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. [PUBMED: 9820296]
EVIDENCE 2007 {published data only}
  • Schwid S, Panitch H. Full results of the Evidence of Interferon Dose-Response-European North American Comparative Efficacy (EVIDENCE) study: a multicenter, randomized, assessor-blinded comparison of low-dose weekly versus high-dose, high-frequency interferon beta-1a for relapsing multiple sclerosis. Clinical Therapeutics 2007;29(9):2031-48. [PUBMED: 18035202]
Fazekas 1997 {published data only}
  • Fazekas F, Deisenhammer F, Strasser-Fuchs S, Nahler G, Mamoli B. Randomised placebo-controlled trial of monthly intravenous immunoglobulin therapy in relapsing-remitting multiple sclerosis. Lancet 1997;349(9052):589-93.
Fazekas 2008 {published data only}
  • Fazekas F, Lublin F, Li D, Freedman M, Hartung H, Rieckmann P, et al. Intravenous immunoglobulin in relapsing-remitting multiple sclerosis: a dose-finding trial. Neurology 2008;71(4):265-71.
Ghezzi 1989 {published data only}
  • Ghezzi A, Di Falco M, Locatelli C. In: Consette RE, Delmotte P editor(s). Clinical controlled randomized trial of azathioprine in multiple sclerosis. Elsevier, 1989.
Goodkin 1991 {published data only}
  • Goodkin D, Bailly R, Teetzen M, Hertsgaard D, Beatty W. The efficacy of azathioprine in relapsing-remitting multiple sclerosis. Neurology 1991;41:20-5. [: DOI]
Goodkin 1995 {published data only}
Hartung 2002 {published data only}
  • Hartung H, Gonsette R, Konig N, Kwiecinski H, Guseo A, Morrissey S, et al. Mitoxantrone in progressive multiple sclerosis: a placebo-controlled, double-blind, randomised, multicentre trial. Lancet 2002;360(9350):2018-25. [PUBMED: 12504397]
Hommes 2004 {published data only}
  • Hommes O, Sorensen P, Fazekas F, Enriquez M, Koelmel H, Fernandez O, et al. Intravenous immunoglobulin in secondary progressive multiple sclerosis: randomised placebo-controlled trial. Lancet 2004;364(9440):1149-56.
IFNB MS Group 1993 {published data only}
  • IFNB MSG. Interferon beta-1b is effective in relapsing-remitting multiple sclerosis. I. Clinical results of a multicenter, randomized, double-blind, placebo-controlled trial. The IFNB Multiple Sclerosis Study Group. Neurology 1993;43(4):655-61. [PUBMED: 8469318]
IMPACT 2002 {published data only}
  • Cohen J, Cutter G, Fischer J, Goodman A, Heidenreich F, Kooijmans M, et al. Benefit of interferon beta-1a on MSFC progression in secondary progressive MS. Neurology 2002;59(5):679-87. [PUBMED: 12221157]
INCOMIN 2002 {published data only}
  • Durelli L, Verdun E, Barbero P, Bergui M, Versino E, Ghezzi A, 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;359:1453-60.
Johnson 1995 {published data only}
  • Johnson K, Brooks B, Cohen J, Ford C, Goldstein J, Lisak R, 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):1268-76. [PUBMED: 7617181]
Knobler 1993 {published data only}
  • Knobler R, Greenstein J, Johnson K, Lublin F, Panitch H, Conway K, et al. Systemic recombinant human interferon-beta treatment of relapsing-remitting multiple sclerosis: pilot study analysis and six-year follow-up. Journal of Interferon Research 1993;13:333-40. [PUBMED: 8301153]
Koch-Henriksen 2006 {published data only}
  • Koch-Henriksen N, Sørensen P, Christensen T, Frederiksen J, Ravnborg M, Jensen K, et al. A randomised study of two interferon-beta treatments in relapsing-remitting multiple sclerosis. Neurology 2006;66(7):1056-60.
Leary 2003 {published data only}
  • Leary S, Miller D, Stevenson V, Brex P, Chard D, Thompson A. Interferon beta-1a in primary progressive MS: an exploratory, randomized, controlled trial. Neurology 2003;60(1):44-51. [PUBMED: 12525716]
Lewanska 2002 {published data only}
Likosky 1991 {published data only}
  • Likosky W, Fireman B, Elmore R, Eno G, Gale K, Goode G, et al. Intense immunosuppression in chronic progressive multiple sclerosis: the Kaiser study. Journal of Neurology, Neurosurgery, and Psychiatry 1991; Vol. 54, issue 12:1055-60.
Milanese 1993 {published data only}
Millefiorini 1997 {published data only}
  • Millefiorini E, Gasperini C, Pozzilli C, D'Andrea F, Bastianello S, Trojano M, et al. Randomized placebo-controlled trial of mitoxantrone in relapsing-remitting multiple sclerosis: 24-month clinical and MRI outcome. Journal of Neurology 1997;244(3):153-9. [PUBMED: 9050955]
Miller 1961 {published data only}
  • Miller H, Newell D, Ridley A. Multiple sclerosis. Trials of maintenance treatment with prednisolone and soluble aspirin. Lancet 1961; Vol. 1, issue 7169:127-9.
Montalban 2009 {published data only}
  • Montalban X, Sastre-Garriga J, Tintore M, Brieva L, Aymerich F, Rio J, et al. A single-center, randomized, double-blind, placebo-controlled study of interferon beta-1b on primary progressive and transitional multiple sclerosis. Multiple Sclerosis 2009;15(10):1195-205. [PUBMED: 19797261]
MSCRG 1996 {published data only}
NASP 2004 {published data only}
  • Panitch H, Miller A, Paty D, Weinshenker B. Interferon beta-1b in secondary progressive MS: results from a 3-year controlled study. Neurology 2004;63(10):1788-95. [PUBMED: 15557491]
OWIMS 1999 {published data only}
  • OWIMS. Evidence of interferon beta-1a dose response in relapsing-remitting MS: the OWIMS Study. The Once Weekly Interferon for MS Study Group. Neurology 1999;53(4):679-86. [PUBMED: 10489026]
Pohlau 2007 {published data only}
  • Pohlau D, Przuntek H, Sailer M, Bethke F, Koehler J, Konig N, et al. Intravenous immunoglobulin in primary and secondary chronic progressive multiple sclerosis: a randomized placebo controlled multicentre study. Multiple Sclerosis 2007;13(9):1107-17. [PUBMED: 17623736]
PRISMS 1998 {published data only}
  • PRISMS. Randomised double-blind placebo-controlled study of interferon beta-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):1498-504. [PUBMED: 9820297]
REGARD 2008 {published data only}
  • Mikol D, Barkhof F, Chang P, Coyle P, Jeffery D, Schwid S, et al. 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 Neurology 2008;7(10):903-14.
SENTINEL 2006 {published data only}
  • Rudick R, Stuart W Calabresi P, Confavreux C, Galetta S, Radue E, et al. Natalizumab plus interferon beta-1a for relapsing multiple sclerosis. The New England Journal of Medicine 2006;354(9):911-23.
SPECTRIMS 2001 {published data only}
  • SPECTRIMS. Randomized controlled trial of interferon- beta-1a in secondary progressive MS: Clinical results. Neurology 2001;56(11):1496-504. [PUBMED: 11402106]
Wolinsky 2007 {published data only}

References to studies excluded from this review

  1. References to studies included in this review
  2. References to studies excluded from this review
  3. Additional references
Arnason 1999 {published data only}
  • Arnason, BGW, Jacobs G, Hanlon M, Harding B, Noronha ABC, Auty A, et al. TNF neutralization in MS: Results of a randomized, placebo-controlled multicenter study. Neurology 1999;53(3):457-65.
Barkhof 2003 {published data only}
Baum 2006 {published data only}
  • Baum K, Mannitol Formulation Study Group. Safety and tolerability of a 'refrigeration-free' formulation of interferon beta-1b--results of a double-blind, multicentre, comparative study in patients with relapsing-remitting or secondary progressive multiple sclerosis. The Journal of International Medical Research 2006;34(1):1-12.
BENEFIT 2006 {published data only}
  • Kappos L, Polman C, Freedman M, Edan G, Hartung H, Miller D, et al. Treatment with interferon beta-1b delays conversion to clinically definite and McDonald MS in patients with clinically isolated syndromes. Neurology 2006;67(7):1242-9.
Boiko 2001 {published data only}
  • Boiko A, Skurkovich S, Buglak A, Alekseeva, T, Smirnova N, Skurkovich B, et al. Randomized, placebo-controlled trial comparing short course of anti-IFN? And anti-TNFa showed only anti-IFN? Effective in secondary progressive MS. Journal of Neurosurgery 2001;187 Suppl 1:S456.
Burton 2009 {published data only}
CHAMPS 2000 {published data only}
  • Jacobs L, Beck R, Simon J, Kinkel R, Brownscheidle C, Murray T, et al. Intramuscular interferon beta-1a therapy initiated during a first demyelinating event in multiple sclerosis. CHAMPS Study Group. The New England Journal of Medicine 2000;343(13):898-904. [PUBMED: 11006365]
Christodoulou 2006 {published data only}
  • Christodoulou C, Melville P, Scherl WF, MacAllister WS, Elkins LE, Krupp LB. Effects of donepezil on memory and cognition in multiple sclerosis. Journal of the Neurological Sciences 2006;245(1-2):127-36.
Clanet 2002 {published data only}
  • Clanet M, Radue E, Kappos L, Hartung H, Hohlfeld R, Sandberg-Wollheim M, et al. A randomized, double-blind, dose-comparison study of weekly interferon beta-1a in relapsing MS. Neurology 2002;59(10):1507-17. [PUBMED: 12451189]
Durelli 1994 {published data only}
  • Durelli L, Bongioanni M, Cavallo R, Ferrero B, Ferri R, Ferrio M, et al. Chronic systemic high-dose recombinant interferon alfa-2a reduces exacerbation rate, MRI signs of disease activity, and lymphocyte interferon gamma production in relapsing-remitting multiple sclerosis. Neurology 1994;44(3 (Pt 1)):406-13.
ETOMS 2001 {published data only}
  • Comi G, Filippi M, Barkhof F, Durelli L, Edan G, Fernández O, et al. Effect of early interferon treatment on conversion to definite multiple sclerosis: a randomised study. Lancet 2001;357(9268):1576-82.
Fernandez 2002 {published data only}
  • Fernandez O, Guerrero M, Mayorga C, Munoz L, Lean A, Luque G, et al. Combination therapy with interferon beta-1b and azathioprine in secondary progressive multiple sclerosis. A two-year pilot study. Journal of Neurology 2002;249(8):1058-62.
Filippi 2004 {published data only}
  • Filippi M, Rovaris M, Inglese M, Barkhof F, De Stefano N, Smith S, 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(9444):1489-96.
Filippi 2006 {published data only}
  • Filippi M, Wolinsky J, Comi G. Effects of oral glatiramer acetate on clinical and MRI-monitored disease activity in patients with relapsing multiple sclerosis: a multicentre, double-blind, randomised, placebo-controlled study. Lancet Neurology 2006;5:213-20.
GLANCE 2009 {published data only}
  • Goodman A, Rossman H, Bar-Or A, Miller A, Miller D, Schmierer K, et al. GLANCE: Results of a phase 2, randomized, double-blind, placebo-controlled study. Neurology 2009;72:806-12.
Goodkin 2000 {published data only}
  • Goodkin DE, Shulman M, Winkelhake J, Waubant E, Andersson P, Stewart T, et al. A phase I trial of solubilized DR2:MBP84-102 (AG284) in multiple sclerosis. Neurology 2000;54(7):1414.
Hauser 1983 {published data only}
  • Hauser S, Dawson D, Lehrich J, Beal M, Kevy S, Propper R, et al. Intensive immunosuppression in progressive multiple sclerosis. A randomized, three-arm study of high-dose intravenous cyclophosphamide, plasma exchange and ACTH [comment in: N Engl J Med 1983;309:239-40; comment in: N Engl J Med 1983;309:241; comment in: Lancet 1991;337:1540-1]. The New England Journal of Medicine 1983;308(4):173-80.
Hoogervorst 2002 {published data only}
Labetouelle 2001 {published data only}
  • Labetouelle M. [About the article: " Intramuscular interferon beta-1a therapy initiated during a first demyelinating event in multiple sclerosis" by Jacobs LD et al]. Journal Francais of Ophthalmology 2001;24(2):222.
Liu 2010 {published data only}
Myhr 1999 {published data only}
  • Myhr K, Riise T, Green L, Beiske T, Celius E, Edland A, et al. Interferon-alpha2a reduces MRI disease activity in relapsing-remitting multiple sclerosis. Norwegian Study Group on Interferon-alpha in Multiple Sclerosis. Neurology 1999;52(5):1049-56. [MEDLINE: 99200550]
Patti 1999 {published data only}
  • Patti F, L'Episcopo MR, Cataldi ML, Reggio A. Natural interferon-beta treatment of relapsing-remitting and secondary-progressive multiple sclerosis patients. A two-year study. Acta Neurologica Scandinavica 1999;100(5):283-9.
Rio 2007 {published data only}
  • Río J, Tintoré M, Nos C, Téllez N, Galán I, Pelayo R, et al. Interferon beta in secondary progressive multiple sclerosis. Daily clinical practice. Journal of Neurology 2007;254:849–53.
Skurkovich 2001 {published data only}
  • Skurkovich S, Boiko A, Beliaeva I, Buglak A, Alekseeva T, Smirnova N, et al. Randomized study of antibodies to IFN-gamma and TNF-alpha in secondary progressive multiple sclerosis. Multiple Sclerosis 2001;7(5):277-84.
Steultjens 2003 {published data only}
  • Steultjens E, Dekker J, Bouter L, Cardol M, Van den Ende E, van de Nes J. Occupational therapy for multiple sclerosis. Cochrane Database of Systematic Reviews 2003, Issue 3. [DOI: 10.1002/14651858.CD003608; : CD003608]
Tejani 2010 {published data only}
Tubridy 1999 {published data only}
  • Tubridy N, Behan PO, Capildeo R, Chaudhuri A, Forbes R, Hawkins CP, et al. The effect of anti-[alpha]4 integrin antibody on brain lesion activity in MS. Neurology 1999;53(3):466-72.
Van de Wyngaert 2001 {published data only}
  • van de Wyngaert F, Beguin C, D'Hooghe M, Dooms G, Lissoir F, Carton H, et al. A double-blind clinical trial of mitoxantrone versus methylprednisolone in relapsing, secondary progressive multiple sclerosis. Acta Neurologica Belgica 2001;101(4):210-6.
Wender 1988 {published data only}
  • Wender M, Tokarz-Kupczyk E, Mularek O. Early results of the treatment of chronic progressive forms of multiple sclerosis with cyclophosphamide and ACTH [Wczesne wyniki leczenia postaci przewlekle postepujacych stwardnienia rozsianego cyklofosfamidem i ACTH]. Neurologia i Neurochirurgia Polska 1988;22(5):399-403.
Zavalishin 2003 {published data only}
  • Zavalishin IA, Gusev EI, Iakhno NN, Skoromets AA, Ko AN, Demina TL, et al. Results of a multicenter study of Rebif-22 mcg administration in Russia. Zhurnal Nevrologii i Psikhiatrii Imeni S.S. Korsakova / Ministerstvo zdravookhraneniia i meditsinskoi promyshlennosti Rossiiskoi Federatsii, Vserossiiskoe obshchestvo nevrologov [i] Vserossiiskoe obshchestvo psikhiatrov 2003;Spec No 2:S73-8.
Zivadinov 2001 {published data only}
  • Zivadinov R, Rudick R, De Masi R, Nasuelli D, Ukmar M, et al. Effects of IV methylprednisolone on brain atrophy in relapsing-remitting MS. Neurology 2001;57(7):1239-47.

Additional references

  1. References to studies included in this review
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