Balancing the benefits and risks of disease-modifying therapy in patients with multiple sclerosis

  • Per Soelberg Sørensen
    Correspondence: Prof. Per Soelberg Sorensen, MD, DMSci, Danish Multiple Sclerosis Center, Department of Neurology, Copenhagen University Hospital Rigshospitalet, DK-2100 Copenhagen, Denmark
    Danish Multiple Sclerosis Research Centre, Copenhagen University and Rigshospitalet, Copenhagen, Denmark
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      Balancing efficacy versus burden of therapy is essential for the choice of disease-modifying therapy in every MS patient. The first-line therapies, interferon–? and glatiramer acetate, have well-established efficacy and present no major safety concerns. Certain second-line therapies, such as natalizumab, offer potentially greater efficacy, but are associated with an increased level of risk. Over the last year, the first two oral treatments of relapsing–remitting multiple sclerosis, cladribine and fingolimod, have been marketed in certain countries, although cladribine was subsequently withdrawn. In the Phase III clinical development programme, both drugs appeared effective and reasonably safe. However, there were cases of serious adverse events (malignancies and fatal infections) whose relationship with treatment was unclear. Specific postmarketing studies will be necessary to assess the risks of these new oral therapies. Indeed, both natalizumab and mitoxantrone are known today to be associated with rare adverse drug reactions (progressive multifocal leukoencephalopathy for natalizumab and treatment-related leukaemia for mitoxantrone), which were not identified before the treatments were approved. The use of therapies carrying potential serious risks is justified in patients who cannot be treated effectively with safe first-line therapies, but probably not in the average relapsing–remitting multiple sclerosis or clinical isolated syndrome patient. Pivotal Phase III clinical trials, on which basis drug approval is generally granted, are designed to demonstrate clinical efficacy and reveal frequently occurring adverse effects of a new drug. However, post-approval trials with extensive patient exposure are needed to generate knowledge of more patient-specific clinical effectiveness and long-term safety, in particular with respect to rare adverse reactions. Other post-approval measures, such as risk management programmes, pharmacovigilance studies, or phased launch of the drug, may be useful to ensure that risks associated with new treatments are identified and minimised. The final evaluation of the benefits to risks balance of a drug should be made in every patient by weighing benefits in disease activity and progression, quality of life and health economy against both commonly occurring mild side-effects and rare potentially life-threatening adverse drug effects. This decision should be shared between the physician and patient, who may not share the same perceptions of acceptable risk.


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        • Markowitz CE
        Interferon-beta: mechanism of action and dosing issues.
        Neurology. 2007; 68: S8-11
        • Neuhaus O
        • Farina C
        • Wekerle H
        • Hohlfeld R
        Mechanisms of action of glatiramer acetate in multiple sclerosis.
        Neurology. 2001; 56: 702-708
        • Ziemssen T
        • Schrempf W
        Glatiramer acetate: mechanisms of action in multiple sclerosis.
        Int Rev Neurobiol. 2007; 79: 537-570
        • Jacobs LD
        • Cookfair DL
        • Rudick RA
        • Herndon RM
        • Richert JR
        • Salazar AM
        • et al.
        Intramuscular interferon beta-1a for disease progression in relapsing multiple sclerosis. The Multiple Sclerosis Collaborative Research Group (MSCRG).
        Ann Neurol. 1996; 39: 285-294
        • Johnson KP
        • Brooks BR
        • Cohen JA
        • Ford CC
        • Goldstein J
        • Lisak RP
        • 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: 1268-1276
        • PRISMS (Prevention of Relapses and Disability by Interferon beta-1a Subcutaneously in Multiple Sclerosis) Study Group
        Randomised double-blind placebo-controlled study of interferon beta-1a in relapsing/remitting multiple sclerosis.
        Lancet. 1998; 352: 1498-1504
        • The IFNB Multiple Sclerosis Study Group and The University of British Columbia MS/MRI Analysis Group
        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: 655-661
        • Cadavid D
        • Wolansky LJ
        • Skurnick J
        • Lincoln J
        • Cheriyan J
        • Szczepanowski K
        • et al.
        Efficacy of treatment of MS with IFNb-1b or glatiramer acetate by monthly brain MRI in the BECOME study.
        Neurology. 2009; 72: 1976-1983
        • Mikol DD
        • Barkhof F
        • Chang P
        • Coyle PK
        • Jeffery DR
        • Schwid SR
        • 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 Neurol. 2008; 7: 903-914
        • O'Connor P
        • Filippi M
        • Arnason B
        • Comi G
        • Cook S
        • Goodin D
        • et al.
        250mug or 500mug interferon beta-1b versus 20mg glatiramer acetate in relapsing–remitting multiple sclerosis: a prospective, randomised, multicentre study.
        Lancet Neurol. 2009; 8: 889-897
        • Sorensen PS
        • Mellgren SI
        • Svenningsson A
        • Elovaara I
        • Frederiksen JL
        • Beiske AG
        • et al.
        NORdic trial of oral Methylprednisolone as add-on therapy to Interferon beta-1a for treatment of relapsing–remitting Multiple Sclerosis (NORMIMS study): a randomised, placebo-controlled trial.
        Lancet Neurol. 2009; 8: 519-529
        • 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.
        N Engl J Med. 2006; 354: 899-910
        • Hartung HP
        • Gonsette R
        • Konig N
        • Kwiecinski H
        • Guseo A
        • Morrissey SP
        • et al.
        Mitoxantrone in progressive multiple sclerosis: a placebo-controlled, double-blind, randomised, multicentre trial.
        Lancet. 2002; 360: 2018-2025
        • Rudick RA
        • Stuart WH
        • Calabresi PA
        • Confavreux C
        • Galetta SL
        • Radue EW
        • et al.
        Natalizumab plus interferon beta-1a for relapsing multiple sclerosis.
        N Engl J Med. 2006; 354: 911-923
        • Kleinschmidt-DeMasters BK
        • Tyler KL
        Progressive multifocal leukoencephalopathy complicating treatment with natalizumab and interferon beta-1a for multiple sclerosis.
        N Engl J Med. 2005; 353: 369-374
        • Langer-Gould A
        • Atlas SW
        • Green AJ
        • Bollen AW
        • Pelletier D
        Progressive multifocal leukoencephalopathy in a patient treated with natalizumab.
        N Engl J Med. 2005; 353: 375-381
        • Hartung HP
        New cases of progressive multifocal leukoencephalopathy after treatment with natalizumab.
        Lancet Neurol. 2009; 8: 28-31
        • Kappos L
        • Bates D
        • Edan G
        • Eraksoy M
        • Garcia-Merino A
        • Grigoriadis N
        • et al.
        Natalizumab treatment for multiple sclerosis: updated recommendations for patient selection and monitoring.
        Lancet Neurol. 2011; 10: 745-758
        • Iaffaldano P
        • D'Onghia M
        • Trojano M
        Safety profile of Tysabri: international risk management plan.
        Neurol Sci. 2009; 30: S159-S162
        • Pratt RG
        • Boehm GA
        • Kortepeter CM
        • Racoosin JA
        Mitoxantrone treatment of multiple sclerosis: safety considerations.
        Neurology. 2005; 65: 1997
        • Martinelli V
        • Radaelli M
        • Straffi L
        • Rodegher M
        • Comi G
        Mitoxantrone: benefits and risks in multiple sclerosis patients.
        Neurol Sci. 2009; 30: S167-S170
        • Marriott JJ
        • Miyasaki JM
        • Gronseth G
        • O'Connor PW
        Evidence Report: The efficacy and safety of mitoxantrone (Novantrone) in the treatment of multiple sclerosis: Report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology.
        Neurology. 2010; 74: 1463-1470
        • Kappos L
        • Radue EW
        • O'Connor P
        • Polman C
        • Hohlfeld R
        • Calabresi P
        • et al.
        A placebo-controlled trial of oral fingolimod in relapsing multiple sclerosis.
        N Engl J Med. 2010; 362: 387-401
        • Cohen JA
        • Barkhof F
        • Comi G
        • Hartung HP
        • Khatri BO
        • Montalban X
        • et al.
        Oral fingolimod or intramuscular interferon for relapsing multiple sclerosis.
        N Engl J Med. 2010; 362: 402-415
        • Giovannoni G
        • Comi G
        • Cook S
        • Rammohan K
        • Rieckmann P
        • Soelberg Sorensen P
        • et al.
        A placebo-controlled trial of oral cladribine for relapsing multiple sclerosis.
        N Engl J Med. 2010; 362: 416-426
        • Rio J
        • Comabella M
        • Montalban X
        Predicting responders to therapies for multiple sclerosis.
        Nat Rev Neurol. 2009; 5: 553-560
        • Hesse D
        • Krakauer M
        • Lund H
        • Sondergaard HB
        • Langkilde A
        • Ryder LP
        • et al.
        Breakthrough disease during interferon-b therapy in MS: No signs of impaired biologic response.
        Neurology. 2010; 74: 1455-1462
        • Lucchinetti C
        • Bruck W
        • Parisi J
        • Scheithauer B
        • Rodriguez M
        • Lassmann H
        Heterogeneity of multiple sclerosis lesions: implications for the pathogenesis of demyelination.
        Ann Neurol. 2000; 47: 707-717
        • Lassmann H
        • Bruck W
        • Lucchinetti CF
        The immunopathology of multiple sclerosis: an overview.
        Brain Pathol. 2007; 17: 210-218
        • 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: 1788-1795
        • European Study Group on interferon beta-1b in secondary progressive MS
        Placebo-controlled multicentre randomised trial of interferon beta-1b in treatment of secondary progressive multiple sclerosis.
        Lancet. 1998; 352: 1491-1497
        • Cohen JA
        • Cutter GR
        • Fischer JS
        • Goodman AD
        • Heidenreich FR
        • Kooijmans MF
        • et al.
        Benefit of interferon beta-1a on MSFC progression in secondary progressive MS.
        Neurology. 2002; 59: 679-687
        • 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.
        J Neurol Neurosurg Psychiatry. 2004; 75: 706-710
        • Sorensen PS
        • Ross C
        • Clemmesen KM
        • Bendtzen K
        • Frederiksen JL
        • Jensen K
        • et al.
        Clinical importance of neutralising antibodies against interferon beta in patients with relapsing–remitting multiple sclerosis.
        Lancet. 2003; 362: 1184-1191
        • The IFNB Multiple Sclerosis Study Group and The University of British Columbia MS/MRI Analysis Group
        Neutralizing antibodies during treatment of multiple sclerosis with interferon beta-1b: experience during the first three years.
        Neurology. 1996; 47: 889-894
        • PRISMS Study Group and the University of British Columbia MS/MRI Analysis Group
        PRISMS-4: Long-term efficacy of interferon-beta-1a in relapsing MS.
        Neurology. 2001; 56: 1628-1636
        • Kappos L
        • Clanet M
        • Sandberg-Wollheim M
        • Radue EW
        • Hartung HP
        • Hohlfeld R
        • et al.
        Neutralizing antibodies and efficacy of interferon beta-1a: a 4-year controlled study.
        Neurology. 2005; 65: 40-47
        • Tomassini V
        • Paolillo A
        • Russo P
        • Giugni E
        • Prosperini L
        • Gasperini C
        • et al.
        Predictors of long-term clinical response to interferon beta therapy in relapsing multiple sclerosis.
        J Neurol. 2006; 253: 287-293
        • Rio J
        • Castillo J
        • Rovira A
        • Tintore M
        • Sastre-Garriga J
        • Horga A
        • et al.
        Measures in the first year of therapy predict the response to interferon beta in MS.
        Mult Scler. 2009; 15: 848-853
        • Tintoré M
        Rationale for early intervention with immunomodulatory treatments.
        J Neurol. 2008; 255: 37-43