Secondary progressive multiple sclerosis (SPMS) is a form of MS characterized by
continuously worsening disability with or without superimposed relapses that occurs
after a variable period of relapsing remitting disease and results in limited
ambulation for almost all patients. The use of interferon beta (IFN b) for
immunomodulation in patients with SPMS has been evaluated in four recent clinical
trials: The European multicentre trial on IFN b-1b in SPMS (EUSPMS), the Secondary
Progressive Efficacy Trial of Rebif (IFN b-1a) in MS (SPEC TRIMS), the North A
merican Study of IFN b-1b in SPMS (NA SPMS), and the Internatio nal MS Secondary
Progressive Avonex C linical Trial (IMPAC T). EUSPMS was the only trial to
demonstrate a significant positive effect of therapy on disease progression as
measured by the expanded disability status scale (EDSS). However, results from all
studies demonstrated significant positive effects of treatment on relapse, T2 lesion
load, and gadolinium enhancement. Immunomodulation with IFN b has the potential to
significantly slow disease progression and improve quality of life for patients with
SPMS. While results with monthly IV Ig were disappointing, positive effects on
disease progression have been reported with the applicatio n of immunosuppressants,
especially Mitoxantrone. The risk-benefit ratio of these cytostatic agents remains
controversial. New strategies addressing the important neurodegenerative aspects of
the disease are urgently needed.
National Multiple Sclerosis Society. Sourcebook. 2003. Available at:
http://www.nationalmssociety.org/Sourcebook Last accessed April 2004.
2.
Pozzilli C, Romano S, Cannoni S.Epidemiology and current treatment of multiple sclerosis in Europe today. J Rehabil Res Dev2002; 39: 175-185.
3.
Pugliatti M, Sotgiu S, Rosati G.The worldwide prevalence of multiple sclerosis. Clin Neurol Neurosurg2002; 104: 182-191.
4.
Lublin FD, Reingold SC.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. Neurology1996; 46: 907-911.
5.
Minderhoud JM, van der Hoeven JH, Prange AJA.Course and prognosis of chronic progressive multiple sclerosis. Results of
an epidemiological study. Acta Neurol Scand1988; 78: 10-15.
6.
Keegan BM, Noseworthy JH.Multiple sclerosis. Annu Rev Med2002; 53: 285-302.
7.
Thompson AJ, Kermode AG, Wicks D, et al.Major differences in the dynamics of primary and secondary progressive
multiple sclerosis. Ann Neurol1991; 29: 53-62.
8.
Herndon RM.Medical hypothesis. Why secondary progressive multiple sclerosis is a
relentlessly progressive illness. Arch Neurol2002; 59: 301-304.
9.
Prineas JW, Kwon EE, Cho ES, et al.Immunopathology of secondary-progressive multiple sclerosis. Ann Neurol2001; 50: 646-657.
10.
Kurtzke JF.Rating neurologic impairment in multiple sclerosis: an expanded disability
status scale (EDSS). Neurology1983; 33: 1444-1452.
11.
Rudick RA, Cutter G, Reingold S.The multiple sclerosis functional composite: a new clinical outcome measure
for multiple sclerosis trials. Mult Scler2002; 8: 359-365.
12.
Cutter GR, Baier ML, Rudick RA, et al.Development of a multiple sclerosis functional composite as a clinical
trial outcome measure. Brain1999; 122: 871-882.
13.
Weinshenker BG, Ebers GC.The natural history of multiple sclerosis. Can J Neurol Sci1987; 14: 255-261.
14.
Confavreux C, Vukusic S, Adeleine P.Early clinical predictors and progression of irreversible disability in
multiple sclerosis: an amnesic process. Brain2003; 126: 770-782.
15.
McDonald WI, Ron MA.Multiple sclerosis: the disease and its manifestations. Phil Trans R Soc Lond1999; 354: 1615-1622.
16.
Racke MK.Multiple sclerosis and magnetic resonance imaging. Advancement in linking
the pictures with the progression. Arch Neurol2001; 58: 35-36.
17.
Giovannoni G, Miller DH, Losseff NA, et al.Serum inflammatory markers and clinical/MRI markers of disease progression
in multiple sclerosis. J Neurol2001; 248: 487-495.
18.
Eikelenboom MJ, Petzold A, Lazeron RH, Silber E, Sharief M, Thompson EJ, Barkhof F, Giovannoni G, Polman CH, Uitdehaag BM.sclerosis: Neurofilament light chain antibodies are correlated to cerebral atrophy. Neurol2003; 60: 219-223.
19.
Polman CH, Thompson AJ, Murray GJ, McDonald IW.Multiple Sclerosis - The Guide to Treatment and Management. Demos Medical Publishing Inc, New York2001; 5th Edition.
20.
Weinstock-Guttman B, Jacobs LD.What is new in the treatment of multiple sclerosis?Drugs2000; 59: 401-410.
21.
Dhib-Jalbut S.Mechanisms of action of interferons and glatiramer acetate in multiple sclerosis. Neurology2002; 58(Suppl 4): S3-S9.
22.
Yong VW, Chabot S, Stuve O, Williams G.Interferon beta in the treatment of multiple sclerosis: mechanisms of action. Neurology1998; 51: 682-689.
23.
Goebel M, Baase J, Pithan V, et al.Acute interferon b-1b administration alters hypothalamic-pituitary-adrenal
axis activity, plasma cytokines and leukocyte distribution in healthy subjects. Psychoneuroendocrinology2002; 27: 881-892.
24.
Kappos L.Multiple Sclerosis Therapeutics, 2nd Edition, ed by Rudick R and Cohen J. Chapter 20, Interferons. Martin Dunitz, London, 2003; pp 325-346
25.
Bayas A, Rieckmann P.Managing the adverse effects of interferon-b therapy in multiple sclerosis. Drug Saf2000; 22: 149-159.
26.
Walther EU, Hohlfeld R.Multiple sclerosis: side effects of interferon beta therapy and their management. Neurology1999; 53: 1622-1627.
27.
Polman C, Kappos L, Petkau J, Thompson A.Neutralising antibodies to interferon-beta during the treatment of multiple sclerosis. Neurology2003; 57: 1967-1975.
28.
Wolinsky JS, Toyka KV, Kappos L, Grossberg SE.Interferon-beta antibodies: implications for the treatment of MS. Lancet Neurol2003; 2: 528-528.
29.
European Study Group on interferon b-1b in secondary progressive MS.Placebo-controlled multicentre randomised trial of interferon beta-1b in
treatment of secondary progressive multiple sclerosis. European Study Group
on interferon b-1b in secondary progressive MS. Lancet1998; 352: 1491-1497.
30.
Kappos L, Polman C, Pozzilli C, Thompson A, Beckmann K, Dahlke F.Final analysis of the European multicenter trial on IFNb-1b in
secondary-progressive MS. Neurology2001; 57: 1969-1975.
31.
Freeman JA, Thompson AJ, Fitzpatrick R, et al.Interferon-b1b in the treatment of secondary progressive MS: impact on
quality of life. Neurology2001; 57: 1870-1875.
32.
Molyneux PD, Kappos L, Polman C, et al.The effect of interferon beta-1b treatment on MRI measures of cerebral
atrophy in secondary progressive multiple sclerosis. European Study Group on
Interferon beta-1b in secondary progressive multiple sclerosis. Brain2000; 123: 2256-2263.
33.
Barkhof F, van Waesberghe JH, Filippi M, et al.T1hypointense lesions in secondary progressive multiple sclerosis: effect
of interferon beta-1b treatment. Brain2001; 124: 1396-1402.
34.
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. Neurology2001; 56: 1496-1504.
35.
Li DK, Zhao GJ, Paty DW.Randomized controlled trial of interferon-beta-1a in secondary progressive
MS: MRI results. Neurology2001; 56: 1505-1513.
36.
Panitch H.Clinical trials in secondary progressive MS. Assessing response to therapy. Int J MS Care2000; Sept: (Suppl): 5-5.
37.
Cohen JA, Cutter GR, Fischer JS, et al.benefit of interferon beta-1a on MSFC progression in secondary progressive MS. Neurology2002; 59: 679-687.
Sorensen PS, Fazekas F, Lee M.Intravenous immunoglobulin G for the treatment of relapsing-remitting
multiple sclerosis: a meta-analysis. Eur J Neurol2002; 9: 557-563.
40.
Hommes OR, Maas-Enriquez M.ESIMS-an ongoing clinical trial in secondary progressive multiple sclerosis. Mult Scler2000; 6 (Suppl 2): S27-S32.
41.
Goodkin DE, Kinkel RP, Weinstock-Guttman B, et al.A phase II study of i.v. methylprednisolone in secondary-progressive
multiple sclerosis. Neurology1998; 51: 239-245.
42.
Lugaresi A, Caporale C, Farina D, et al.Low-dose oral methotrexate treatment in chronic progressive multiple sclerosis. Neurol Sci2001; 22: 209-210.
43.
La Mantia L, Eoli M, Salmaggi A, Torri V, Milanese C.cyclophosphamide in chronic progressive multiple sclerosis: a comparative study. Ital J Neurol Sci1998; 19: 32-36.
44.
Currier RD, Haerer AF, Meydrech EF.Low-dose methotrexate treatment of multiple sclerosis: a pilot study. J Neurol Neurosurg Psychiatry1993; 56: 1217-1218.
45.
Goodkin DE, Rudick RA, Vanderburg-Medendorp S, Daughtry MM, Schwetz KM, Fischer JSet al.Low-dose (7.5 mg) oral methotrexate reduces the rate of progression in
chronic progressive multiple sclerosis. Ann Neurol1995; 37: 30-40.
46.
Smith DR, Weiner HL.Cyclophosophamide treatment of multiple sclerosis. In: Cohen JA, Rudick RA (Eds): Multiple Sclerosis Therapeutics 2003; 2nd Edition, Martin Dunitz, London: 483-500.
47.
The Canadian Cooperative Multiple Sclerosis Study Group. The Canadian cooperative trial of cyclophosphamide and plasma exchange in
progressive multiple sclerosis. Lancet1991; 337: 441-446.
48.
Hartung HP, Gonsette R, Konig N, et al.Mitoxantrone in progressive multiple sclerosis: a placebo-controlled,
double-blind, randomised, multicentre trial. Lancet2002; 360: 2018-2025.
49.
Mancardi GL, Saccardi R, Filippi M, et al.Autologous hematopoietic stem cell transplantation suppresses Gd-enhanced
MRI activity in MS. Neurology2001; 57: 62-68.
50.
Fassas A, Passweg JR, Anagnostopoulos A, et al.Hematopoietic stem cell transplantation for multiple sclerosis. A
retrospective multicenter study. J Neurol2002; 249: 1088-1097.
51.
Stangel M, Hartung HP.Remyelinating strategies for the treatment of multiple sclerosis. Prog Neurobiol2002; 68: 361-376.
