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Published on 1 September 2001

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Pharmacotherapeutic choice in multiple sclerosis

Cris Constantinescu
MD PhD
Senior Lecturer
Consultant Neurologist
Queen’s Medical Centre
Nottingham, UK
E:cris.constantinescu@nottingham.ac.uk

Multiple sclerosis (MS) is an immune-mediated CNS disease characterised clinically by neurological deficits and pathologically by demyelination, inflammation and axonal loss.(1) Most patients (about 85%) initially exhibit a relapsing–remitting (RR) course marked by attacks, followed in some 50% by progressive neurological deterioration termed secondary progressive (SP) MS. About 10–15% have primary progressive (PP) MS, a progressive dysfunction without relapses. Of these, 6% have progressive relapsing (PR) MS, relapses superimposed on a progressive course from the onset. Immunological/inflammatory mechanisms are prominent in RRMS, where treatments that modulate immune responses are more effective. Axonal loss, which may start early, may explain long-term disabilities.

Symptomatic treatment is an important component of MS therapy. Examples include baclofen or tizanidine for spasticity, amantadine for fatigue, or antiepileptics such as carbamazepine or gabapentin for pain syndromes such as trigeminal neuralgia. Symptomatic treatment is not reviewed here.

Treatment of relapses
Significant relapses are shortened by high-dose intravenous glucocorticoids (eg, methylprednisolone 1g daily for three days).(2) Equivalent doses of oral steroids are equally effective.(3) Steroids can also delay development of MS for two years after the first attack of optic ­neuritis.

Relapsing–remitting MS

Interferon beta
Pivotal multicentre, placebo-controlled studies conducted in the last decade have made a major impact and changed MS management, introducing the first disease-modifying agents for this disease. Interferon beta, a recombinant immunomodulatory drug, was shown to decrease the frequency of relapses and slow the progression of disease by about 30%. It also significantly reduces the activity of disease detected by magnetic resonance imaging (MRI).(2)

There are three interferon beta preparations. Interferon beta-1b (Betaferon [Schering Healthcare, Betaseron [Berlex Laboratories]) is subcutaneous, given at 8 million international units (MIU) every other day. Interferon beta-1a is subcutaneous (Rebif [Serono], 12 MIU high dose or 6 MIU low dose) or intramuscular (Avonex [Biogen], 6 MIU). Efficacy and side-effects (flu-like symptoms, injection site reactions, blood count and liver enzyme changes, and increased muscle tone) are comparable.(2) There is evidence for a dose-dependent effect, mainly from the Rebif studies. Trials of interferon alpha, an immunomodulatory substance with significant homology with interferon beta, have also shown benefit.

Recent trials demonstrate that early interferon treatment is important. Interferon after the first demyelinating attack reduces the risk of MS development.(4) Importantly, patients receiving Rebif for four consecutive years did much better that those given placebo in the first two years and then switched to active drug.

Glatiramer acetate (Copaxone [Teva])
This synthetic copolymer of four myelin amino acids is administered subcutaneously daily at 20mg/day. It reduces relapse rate and decreases the worsening of disability. MRI activity is also reduced under treatment with glatiramer acetate, and the effect is sustained for a long time.(5) Skin and flu-like side-effects are less common. Glatiramer acetate rarely induces a benign systemic reaction with palpitations and chest tightness.

Intravenous immunoglobulin (IVIG)
IVIG reduced relapse rate and disability scores in some trials. Larger studies are planned. IVIG also reduces the risk of postpartum relapses. A multicentre study is planned for confirmation of these important findings. Side-effects are nausea and headaches.(6)

Azathioprine
This immunosuppressant may benefit RRMS patients failing interferon or glatiramer. It reduces relapse rate and slows progression after 2–3 years of treatment, at the expense of side-effects and requirements for blood monitoring.

Secondary progressive MS

Interferon beta
A large multicentre trial of interferon beta-1b showed that it slows progression and reduces superimposed relapses in SPMS.(2) Preliminary results from an American trial also suggest a positive effect of intramuscular weekly interferon beta-1a. Other studies showed no clinical benefit.(2) The subgroup of SPMS patients with super­imposed relapses may benefit the most.

Immunosuppressive treatment
Immunosuppressives were the main form of treatment before introduction of interferons, and they still play a role in SPMS and RRMS with frequent disabling relapses and/or unresponsiveness or intolerance of immunomodulation. Azathioprine slows progression after 2–3 years of treatment. Methotrexate is of moderate benefit and has a more acceptable toxicity than other immunosuppressants. Cyclophosphamide showed benefit in PPMS but its toxicity can be significant.

Encouraging results indicate that mitoxantrone, a synthetic anthracenedione, is beneficial in rapidly progressive MS or RRMS with frequent disabling relapses.(7) Mitoxantrone has cumulative cardiotoxicity which limits long-term use, but has a stabilising, probably sustained, effect. A recent randomised placebo-controlled study showed slowing of progression and reduction in relapse rates, and MRI activity in mitoxantrone-treated patients compared with placebo.(8)

In a recent SPMS trial cladribine suppressed MRI activity but had no clear clinical benefit.

Combination treatments
Combining immunosuppressant with immunomodulatory drugs or with periodic steroids has been investigated and may offer advantages. However, more studies are needed.

Improving conduction in demyelinating nerve fibres
Demyelinated nerve fibres in which impulse conduction has become ineffective or ceased may be more susceptible to immunologic damage and axonal loss. Improving conduction may not only improve symptoms, but also reduce long-term disability. 4-aminopyridine and 3,4-diaminopyridine are useful for symptomatic treatment of fatigue and motor symptoms in MS. They also reduce neurological disability in about 30% of patients.

Primary progressive MS
No proven disease-modifying treatment exists yet for PPMS. A trial with glatiramer acetate is underway.

Conclusion
MS is becoming a treatable disease. Recent studies examining the damage that occurs in early stages of MS and trials looking at the benefits of early treatment show that instituting disease-modifying treatment soon after diagnosis is very important. The US MS Society recommends initiating treatment with one of the immuno-modulatory ABC drugs (interferon beta-1A, beta-1B or Copaxone) soon after the diagnosis of clinically definite MS. The choice depends on tolerability, experience, route and frequency of administration, and patient preferences. No direct comparisons are available from blinded, controlled trials. Mitoxantrone and other immunosuppressants are used for aggressive disease where ABC drugs fail or are not tolerated.

References

  1. Noseworthy JH, Lucchinetti C, Rodriguez M, Weinshenker BG. Multiple sclerosis. New Engl J Med 2000;343:938-52.
  2. Weinstock-Guttman B, Jacobs LD. What is new in the treatment of multiple sclerosis? Drugs 2000;59:401-10.
  3. Sellebjerg F, Fredriksen JL, Nielsen PM, Olesen J. Double-blind, placebo controlled study of oral high-dose methylprednisolone in attacks of MS. Neurology 1998;51:529-34.
  4. Jacobs LD, Beck RW, Simon JH, et al. Intramuscular interferon beta-1a ­initiated during a first demyelinating event in multiple sclerosis. N Engl J Med 2000;343:898-904.
  5. Johnson KP, Brooks BR, Ford CC, et al. Sustained clinical benefits of glatiramer acetate in relapsing remitting multiple sclerosis patients observed for 6 years. Multiple Sclerosis 2000;6:255-66.
  6. Fasekas F, Diesenhammer F, Strasser-Fuchs S, Nahler G, Mamoli B. Randomized placebo-controlled trial of monthly intravenous immunoglobulin therapy in relapsing–remitting multiple sclerosis. Lancet 1997;349:589-93.
  7. Edan G, Morrisey S. Mitoxantrone. In: Hawkins CP, Wolinsky JS, editors. Principles of treatments in multiple ­sclerosis. Oxford: Butterworth Heinemann; 2000. p. 131-46.
  8. Millefiornini E, Gasperini C, Pozzilli C, et al. Randomized placebo-controlled trial of mitoxantrone in relapsing-remitting multiple sclerosis: 23-month clinical and MRI outcome. J Neurol 1997;244:153-9.

Resources
International Federation of MS Societies
10 Heddon Street
London W1R 7LE, UK
T:+44 (0)20 7724 9120
W:www.ifmss.org.uk
Sigma Health
MS societies list and MS information
W:www.sigmahealth.com/ms-societylist.html

Five-year ­forecast
Oral ­
immunomodulatory drugs (eg, the current trial with glatiramer acetate)
Expanding ­indications for immunomodulation (such as interferon after first ­demyelinating event)
Neuroprotective/remyelinating/neuroregenerative treatments
Identification of new treatment targets (such as cytokines and neurotoxic factors)
Combination treatments

Forthcoming events
12–15 Sept 2001
17th Annual Meeting of the European Committee for Treatment and Research in Multiple Sclerosis
Dublin, Ireland
Contact: ECTRIMS 2001 Secretariat T:+353 1 6769077
F:+353 1 6769088
E:info@ectrims2001.ie



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