Primary Progressive Multiple Sclerosis Current and Future Treatment Options
Siobhan M. Leary Alan J. Thompson Leading Article First Online: 29 August 2012 DOI :
10.2165/00023210-200519050-00001
Cite this article as: Leary, S.M. & Thompson, A.J. CNS Drugs (2005) 19: 369. doi:10.2165/00023210-200519050-00001 Abstract Approximately 10% of patients with multiple sclerosis (MS) run a primary progressive course characterised by an accumulation of neurological deficits without relapse or remission. Designing therapeutic trials in primary progressive MS (PPMS) has presented several problems. Patient recruitment may be difficult because of the relative rarity of PPMS and historically has been hindered by the lack of specific diagnostic criteria. There has been a limited choice of validated outcome measures, although, in recent studies, the MS functional composite measure and magnetic resonance imaging measures of lesion load and atrophy have been widely used.
Despite these problems, several trials have been designed specifically for PPMS, including exploratory randomised controlled trials of interferon-β-1a and interferon-β-1b and mitoxantrone, a phase III trial of glatiramer acetate, and an open-label study of riluzole. Patients with PPMS have also been included in randomised controlled trials of azathioprine, methotrexate, cladribine, intravenous immunoglobulin and cyclophosphamide, and open-label studies of haematopoietic stem cell transplantation and pirfenidone in progressive MS. However, no treatment has been proven definitively to modify the course of the disease. Looking to the future, therapeutic agents should aim to target the underlying pathogenic mechanisms in PPMS. As a result of the relative lack of inflammation in PPMS, neuroprotective agents that target neuronal loss directly, rather than inflammation, may be more worthwhile. However, further investigation into the pathogenic mechanisms in PPMS is required to guide the development of future therapeutic agents.
References 1.
Lublin FD, Reingold SC. Defining the clinical course of multiple sclerosis: results of an international survey. Neurology 1996; 46: 907–11
PubMed CrossRef Google Scholar 2.
Thompson AJ, Polman CH, Miller DH, et al. Primary progressive multiple sclerosis. Brain 1997; 120: 1085–96
PubMed CrossRef Google Scholar 3.
Stevenson VL, Miller DH, Rovaris M, et al. Primary and transitional progressive multiple sclerosis: a clinical and MRI cross sectional study. Neurology 1999; 52: 839–45
PubMed CrossRef Google Scholar 4.
Confavreux C, Aimard G, Devic M. Course and prognosis of multiple sclerosis assessed by the computerized data processing of 349 patients. Brain 1980; 103: 281–300
PubMed CrossRef Google Scholar 5.
Cottrell DA, Kremenchutzky M, Rice GPA, et al. The natural history of multiple sclerosis: a geographically based study: 5. the clinical features and natural history of primary progressive multiple sclerosis. Brain 1999; 122: 625–39
Google Scholar 6.
McDonnell GV, Hawkins SA. Clinical study of primary progressive multiple sclerosis in Northern Ireland, UK. J Neurol Neurosurg Psychiatry 1998; 64: 451–4
PubMed CrossRef Google Scholar 7.
Runmarker B, Andersen O. Prognostic factors in a multiple sclerosis incidence cohort with twenty-five years of follow-up. Brain 1993; 116: 117–34
PubMed CrossRef Google Scholar 8.
Weinshenker BG, Bass B, Rice GPA, et al. The natural history of multiple sclerosis: a geographically based study: 1. clinical course and disability. Brain 1989; 112: 133–46
Google Scholar 9.
Confavreux C, Vukusoc S, Moreau T, et al. Relapses and progression of disability in multiple sclerosis. N Engl J Med 2000; 343: 1430–8
PubMed CrossRef Google Scholar 10.
Minderhoud JM, van der Hoeven JH, Prange AJ. Course and prognosis of chronic progressive multiple sclerosis: results of an epidemiological study. Acta Neurol Scand 1988; 78: 10–5
PubMed CrossRef Google Scholar 11.
Thompson AJ, Kermode AG, MacManus DG, et al. Patterns of disease activity in multiple sclerosis: clinical and magnetic resonance imaging study. BMJ 1990; 300: 631–4
PubMed CrossRef Google Scholar 12.
Thompson AJ, Kermode AG, Wicks D, et al. Major differences in the dynamics of primary and secondary progressive multiple sclerosis. Ann Neurol 1991; 29: 53–62
PubMed CrossRef Google Scholar 13.
Revesz T, Kidd D, Thompson AJ, et al. A comparison of the pathology of primary and secondary progressive multiple sclerosis. Brain 1994; 117: 759–65
PubMed CrossRef Google Scholar 14.
Lassman H, Brack W, Lucchinetti C, et al. Remyelination in multiple sclerosis. Mult Scler 1997; 3: 133–6
CrossRef Google Scholar 15.
Lucchinetti C, Bruck W, Parisi J, et al. A quantitative analysis of oligodendrocytes in multiple sclerosis lesions: a study of 113 cases. Brain 1999; 122: 2279–95
PubMed CrossRef Google Scholar 16.
Neuhaus O, Hartung HP. In search of a disease marker: the cytokine profile of primary progressive multiple sclerosis. Mult Scler 2001; 7: 143–4
PubMed Google Scholar 17.
Hillert J. Genetics of primary progressive MS [abstract]. Rev Neurol 2000; 156 Suppl. 3: S14
Google Scholar 18.
Poser CM, Paty DW, Scheinberg L, et al. New diagnostic criteria for multiple sclerosis: guidelines for research protocols. Ann Neurol 1983; 13: 227–31
PubMed CrossRef Google Scholar 19.
Leary SM, Stevenson VL, Miller DH, et al. Problems in designing and recruiting to therapeutic trials in primary progressive multiple sclerosis. J Neurol 1999; 246: 562–8
PubMed CrossRef Google Scholar 20.
Thompson AJ, Montalban X, Barkhof F, et al. Diagnostic criteria for primary progressive multiple sclerosis: a position paper. Ann Neurol 2000; 47: 831–5
PubMed CrossRef Google Scholar 21.
McDonald WI, 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: 121–7
PubMed CrossRef Google Scholar 22.
Cottrell DA, Kremenchutzky M, Rice GPA, et al. The natural history of multiple sclerosis: a geographically based study: 6. applications to planning and interpretation of clinical therapeutic trials in primary progressive multiple sclerosis. Brain 1999; 122: 641–7
Google Scholar 23.
Wolinsky JS, on behalf of the PROMiSe trial Study Group. The diagnosis of primary progressive multiple sclerosis. J Neurol Sci 2003; 206: 145–52
PubMed CrossRef Google Scholar 24.
Whitaker JN, McFarland HF, Rudge P, et al. Outcomes assessment in multiple sclerosis clinical trials: a critical analysis. Mult Scler 1995; 1: 37–47
PubMed Google Scholar 25.
Kurtzke JF. Rating neurologic impairment in multiple sclerosis: an Expanded Disability Status Scale (EDSS). Neurology 1983; 33: 1444–52
PubMed CrossRef Google Scholar 26.
Willoughby EW, Paty DW. Scales for rating impairment in multiple sclerosis: a critique. Neurology 1988; 38: 1793–8
PubMed CrossRef Google Scholar 27.
Noseworthy JH, Vandervoort MK, Wong CJ, et al. Interrater variability with the expanded disability status scale (EDSS) and functional systems (FS) in a multiple sclerosis clinical trial. Neurology 1990; 40: 971–5
PubMed CrossRef Google Scholar 28.
Hobart J, Freeman J, Thompson A. Kurtzke scales revisited: the application of psychometric methods to clinical intuition. Brain 2000; 123: 1027–40
PubMed CrossRef Google Scholar 29.
Cutter GR, Baier ML, Rudick RA, et al. Development of a multiple sclerosis composite as a clinical trial outcome measure. Brain 1999; 122: 871–82
PubMed CrossRef Google Scholar 30.
Kalkers NF, de Groot V, Lazeron RHC, et al. MS functional composite: relation to disease phenotype and disability strata. Neurology 2000; 54: 1233–9
PubMed CrossRef Google Scholar 31.
Cohen JA, Cutter GR, Fischer JS, et al. Use of the multiple sclerosis functional composite as an outcome measure in a phase 3 clinical trial. Arch Neurol 2001; 58: 961–7
PubMed CrossRef Google Scholar 32.
Ciccarelli O, Brex PA, Thompson AJ, et al. Disability and lesion load in MS: a reassessment with MS functional composite score and 3D fast FLAIR. J Neurol 2002; 249: 18–24
PubMed CrossRef Google Scholar 33.
Miller DH, Albert PS, Barkhof F, et al. Guidelines for the use of magnetic resonance techniques in monitoring the treatment of multiple sclerosis. Ann Neurol 1996; 39: 6–16
PubMed CrossRef Google Scholar 34.
Ingle GT, Stevenson VL, Miller DH, et al. Primary progressive multiple sclerosis: a 5-year clinical and MR study. Brain 2003; 126: 2528–36
PubMed CrossRef Google Scholar 35.
Losseff NA, Webb SL, O’Riordan JI, et al. Spinal cord atrophy and disability in multiple sclerosis: a new reproducible and sensitive MRI method with potential to monitor disease progression. Brain 1996; 119: 701–8
PubMed CrossRef Google Scholar 36.
Losseff NA, Wang L, Lai HM, et al. Progressive cerebral atrophy in multiple sclerosis: a serial MRI study. Brain 1999; 119: 2009–19
CrossRef Google Scholar 37.
Rovaris M, Bozzali M, Santuccio G, et al. In vivo assessment of the brain and cervical cord pathology of patients with primary progressive multiple sclerosis. Brain 2001; 124: 2540–9
PubMed CrossRef Google Scholar 38.
Miller DH, Grossman RI, Reingold SC, et al. The role of magnetic resonance techniques in understanding and managing multiple sclerosis. Brain 1998; 121: 3–24
PubMed CrossRef Google Scholar 39.
Thompson AJ. Symptomatic management and rehabilitation in multiple sclerosis. J Neurol Neurosurg Psychiatry 2001; 71 Suppl. 2: 22–7
Google Scholar 40.
Trapp BD, Peterson J, Ransohoff RM, et al. Axonal transection in the lesions of multiple sclerosis. N Engl J Med 1998; 338: 278–85
PubMed CrossRef Google Scholar 41.
Ferguson B, Matysak MK, Esiri MM, et al. Axonal damage in acute multiple sclerosis lesions. Brain 1997; 120: 393–9
PubMed CrossRef Google Scholar 42.
Nijeholt GJ, van Walderveen AA, Castelijns JA, et al. Brain and spinal cord abnormalities in multiple sclerosis: correlation between MRI parameters, clinical subtypes and symptoms. Brain 1998; 121: 687–97
PubMed CrossRef Google Scholar 43.
Weinstock-Guttman B, Ransohoff RM, Kinkel RP, et al. The interferons: biological effects, mechanisms of action, and use in multiple sclerosis. Ann Neurol 1995; 37: 7–15
PubMed CrossRef Google Scholar 44.
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: 655–61
Google Scholar 45.
Jacobs LD, Cookfair DL, Rudick RA, et al. Intramuscular interferon beta-1a for disease progression in relapsing multiple sclerosis. Ann Neurol 1996; 39: 285–94
PubMed CrossRef Google Scholar 46.
PRISMS (Prevention of Relapses and Disability by Interferon beta-la Subcutaneously in Multiple Sclerosis) Study Group. Randomised double-blind placebo-controlled study of interferon β-1a in relapsing/remitting multiple sclerosis. Lancet 1998; 352: 1498–504
CrossRef Google Scholar 47.
European Study Group on Interferon β-1b in Secondary Progressive Multiple Sclerosis. Placebo-controlled multicentre randomised trial of interferon β-1b in treatment of secondary progressive multiple sclerosis. Lancet 1998; 352: 1491–7
CrossRef Google Scholar 48.
Secondary Progressive Efficacy Clinical Trial of Recombinant Interferon-beta-1a in MS (SPECTRIMS) Study Group. Randomized controlled trial of recombinant interferon-beta-1a in secondary progressive MS: clinical results. Neurology 2001; 56: 1496–504
CrossRef Google Scholar 49.
Cohen JA, Cutter GR, Fischer JS, et al. Benefit of interferon beta-la on MSFC progression in secondary progressive MS. Neurology 2002; 59: 679–87
PubMed CrossRef Google Scholar 50.
Paty DW. MRI data from the North American Study of interferon beta 1b in secondary progressive multiple sclerosis [abstract]. Rev Neurol 2000; 156Suppl. 3: S39
Google Scholar 51.
Leary SM, Miller DH, Stevenson VL, et al. Interferon beta-1a in primary progressive MS: an exploratory randomized controlled trial. Neurology 2003; 60: 44–51
PubMed CrossRef Google Scholar 52.
Montalban X. Overview of European pilot study of interferon beta-1b in primary progressive multiple sclerosis. Mult Scler 2004; 10Suppl. 1: S62
PubMed CrossRef Google Scholar 53.
Aharoni R, Teitelbaum D, Arnon R, et al. Copolymer 1 acts against the immunodominant epitope 82–100 of myelin basic protein by T cell receptor antagonism in addition to major histocompatibility complex blocking. Proc Natl Acad Sci U S A 1999; 96: 634–9
PubMed CrossRef Google Scholar 54.
Ziemssen T, Kumpfel T, Klinkert WE, et al. Glatiramer acetate-specific T-helper 1- and 2-type cell lines produce BDNF: implications for multiple sclerosis therapy. Brain-derived neurotrophic factor. Brain 2002; 125: 2381–91
Google Scholar 55.
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. Neurology 1995; 45: 1268–76
PubMed CrossRef Google Scholar 56.
Wolinsky JS. New insights in primary progressive multiple sclerosis [abstract]. Mult Scler 2004; 10Suppl. 2: SI 10
Google Scholar 57.
Hartung HP, Gonsette R, Konig N, et al. Mitoxantrone in progressive multiple sclerosis: a placebo-controlled, double-blind, randomized, multicentre trial. Lancet 2002; 360: 2018–25
PubMed CrossRef Google Scholar 58.
Kita M, Cohen JA, Fox RJ, et al. A phase II trial of mitoxantrone in patients with primary progressive multiple sclerosis [abstract]. Neurology 2004; 62 Suppl. 5: A99
Google Scholar 59.
Pitt D, Werner P, Raine CS. Glutamate excitotoxicity in a model of multiple sclerosis. Nat Med 2000; 6: 67–70
PubMed CrossRef Google Scholar 60.
Kalkers NF, Barkhof F, Bergers E, et al. The effect of the neuroprotective agent riluzole on MRI parameters in primary progressive multiple sclerosis: a pilot study. Mult Scler 2002; 8: 532–3
PubMed CrossRef Google Scholar 61.
British and Dutch Multiple Sclerosis Azathioprine Trial Group. Double-masked trial of azathioprine in multiple sclerosis. Lancet 1988; II: 179–83
Google Scholar 62.
Goodkin DE, Rudick RA, Vander Brug Medendorp S, et al. Low dose (7.5mg) oral methotrexate reduces the rate of progression in chronic progressive multiple sclerosis. Ann Neurol 1995; 37: 30–40
PubMed CrossRef Google Scholar 63.
Rice GPA, Filippi M, Comi G, et al. Cladribine and progressive MS: clinical and MRI outcomes of a multicenter controlled trial. Neurology 2000; 54: 1145–55
PubMed CrossRef Google Scholar 64.
Poehlau D, Federlein J, Postert T, et al. Intravenous immunoglobulin (IVIG) treatment for patients with primary or secondary progressive multiple sclerosis: outline of a double-blind randomized, placebo-controlled trial. Mult Scler 1997; 3: 149–52
PubMed CrossRef Google Scholar 65.
Hommes OR, Sorensen PS, Fazekas F, et al. Intravenous immunoglobulin in secondary progressive multiple sclerosis: randomized placebo-controlled trial. Lancet 2004; 364: 1149–56
PubMed CrossRef Google Scholar 66.
Zephir H, de Seze J, Duhamel A, et al. Treatment of progressive forms of multiple sclerosis by cyclophosphamide: a cohort study of 490 patients. J Neurol Sci 2004; 218: 73–7
PubMed CrossRef Google Scholar 67.
Weiner HL, Cohen JA. Treatment of multiple sclerosis with cyclophosphamide: critical review of clinical and immunologic effects. Mult Scler 2002; 8: 142–54
PubMed CrossRef Google Scholar 68.
Fassas A, Passweg JR, Anagnostopoulos A, et al. Hematopoietic stem cell transplantation for multiple sclerosis: a retrospective multicenter study. J Neurol 2002; 249: 1088–97
PubMed CrossRef Google Scholar 69.
Bowen JD, Maravilla K, Margolin SB. Open-label study of pirfenidone in patients with progressive forms of multiple sclerosis. Mult Scler 2003; 9: 280–3
PubMed CrossRef Google Scholar 70.
Noseworthy JH. Management of multiple sclerosis: current trials and future options. Curr Opin Neurol 2003; 16: 289–97
PubMed CrossRef Google Scholar 71.
Miller DH, Khan OA, Sheremata WA, et al. A controlled trial of natalizumab for relapsing multiple sclerosis. N Engl J Med 2003; 348: 15–23
PubMed CrossRef Google Scholar 72.
Coles AJ, Wing MG, Molyneux P, et al. Monoclonal antibody treatment exposes three mechanisms underlying the clinical course of multiple sclerosis. Ann Neurol 1999; 46: 296–304
PubMed CrossRef Google Scholar 73.
Stangel M, Hartung HP. Despair of repair. J Neurol Neurosurg Psychiatry 2002; 72: 1–4
PubMed CrossRef Google Scholar © Adis Data Information BV 2005
Authors and Affiliations Siobhan M. Leary Alan J. Thompson 1. Institute of Neurology University College London London UK