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MS information for health and social care professionals Drug therapies

Significant advances have been made in the last ten years in developing drug therapies that offer real benefit to people who have MS. It is therefore important that whether a person is newly diagnosed, or has more advanced MS, they are actively managed by a neurologist with special interest in MS.

The aim of effective therapy is to reduce frequency and severity of relapses, prevent disability directly attributable to relapses, relieve symptoms, prevent disability arising from disease progression and promote tissue repair to treat established progression. Drugs used in the treatment of MS can therefore be considered in three categories[1]:

Treatment of relapse

Steroids

A relapse can be defined as the recurrence of old symptoms or the appearance of new symptoms lasting for more than 24 hours, followed by partial or complete recovery, that cannot be attributed to any other cause[2]. They are acute, unpredictable events of varying severity and duration and often present with a wide array of symptoms.

Steroids are the standard treatment for a relapse in MS and have been in use for about 50 years. Many studies have shown that steroids are effective in speeding up recovery from relapse but make no difference either to the degree of recovery or to the long-term progression of the disease[3]. It is still unclear exactly how steroids work but they probably act by partly suppressing the immune system and / or by reducing fluid accumulation around the site of nervous damage.

People who are offered steroid therapy should be aware that this will neither alter the course of the disease, nor the outcome of the relapse, in order to enable them to make an informed treatment choice. Treatment may be in hospital or at home and given orally or intravenously[4]. It has been shown that combining steroid therapy with planned multidisciplinary team care is superior to administering drug therapy in a standard neurology or day ward setting[5]. It has also been shown that intravenous steroid therapy can be administered as safely and effectively at home as in an outpatient setting[6].

The NICE guidelines state that any individual who experiences an acute episode (including optic neuritis) sufficient to cause distressing symptoms or an increased limitation on activities should be offered a course of high dose steroids to be started as soon as possible after the onset of the relapse[7]. This should be either:

  • IV methylprednisolone 500mg-1g daily for 3-5 days
  • high dose oral methylprednisolone 500mg-2g daily for 3-5 days.

Long-term treatment (of more than three weeks' duration) should normally be avoided and NICE guidelines recommend that practitioners limit use to three times a year. Steroids have a number of undesirable long-term side effects but in the short-term side effects are usually minor and transient.

Disease modification

Disease modifying therapies licensed to treat MS

In the UK there are five licensed treatments for relapsing remitting MS:

  • beta interferon 1a - two forms are available : Avonex, Rebif
  • beta interferon 1b - Betaferon
  • glatiramer acetate - Copaxone
  • natalizumab - Tysabri - only available for highly active relapsing remitting MS

Beta interferon 1b (Betaferon) and beta interferon 1a (Rebif) are licensed to treat secondary progressive MS where relapses are still a major feature. Natalizumab is only available for people with highly active relapsing remitting MS, characterised by two or more disabling relapses a year.

Beta interferons and glatiramer acetate

Glatiramer acetate and the beta interferons are different drugs with different modes of action[8] though all have been shown in large multicentre randomised, double blind, placebo controlled trials to result in reducing the number and severity of relapses by approximately 30%. There is some evidence that this effect is dose related[9-13]. These effects have been shown to translate to routine clinical practice[14].

Glatiramer acetate is a synthetic combination of four amino acids, resembling the myelin protein surrounding nerve fibres, thought to lessen the immune reaction involved in demyelination. Interferons are cytokines, small basic proteins produced in cells as a response to a variety of agents, in particular viruses. There are three types of interferon in the body alpha, beta and gamma. Alpha interferons are used in cancer treatments and gamma interferons have been found to increase exacerbations. Two different forms of beta interferon, 1a and 1b are available for treatment of MS, the difference resulting from the manufacturing process.

The Association of British Neurologists (ABN) has set out prescribing criteria for the beta interferons and glatiramer acetate for both relapsing remitting and where appropriate secondary progressive MS (Read the ABN prescribing criteria). The criteria reflect clinical experience that treatment soon after the onset of multiple sclerosis is more effective in the long-term than treatment at a later stage of MS.

As both the interferons and glatiramer acetate are proteins and would be broken down in the digestive tract, they are given by either subcutaneous or intra muscular injection. Trials of oral preparations have been unsuccessful.

Beta interferons and glatiramer acetate
Drug name Brand name Administration Dosage
Beta interferon 1a Avonex intra muscular once weekly 30μg
Beta interferon 1a Rebif subcutaneous 3 times per week 22μg or 44μg
Beta interferon 1b Betaferon subcutaneous alternate days 250μg
Glatiramer acetate Copaxone subcutaneous daily 20mg

Dosage regimes for all the products vary and it is possible that patient adherence, efficacy and tolerability are affected by the dosage regime used. However, as each product is licensed it is not ethical to conduct randomised, double blind, placebo controlled trials that directly compare efficacy and safety of each of these formulations. Therefore no direct comparison between the drugs is possible. Over the years, there have been a number of comparative studies between different types of beta interferon, and between beta interferon and glatiramer acetate, none of which have proved significant difference in efficacy[15-18].

Neutralising antibodies

The immune system can react to treatment with interferons and neutralising antibodies (NAbs) can develop in patients treated with beta interferons. Studies have shown that antibodies develop in up to 30% of people on Betaferon, 25% on Rebif and 5% on Avonex[19]. A recent review by the European Forum of Neurological Sciences has recommended that people receiving the beta interferon drugs should be tested for neutralising antibodies at 12 months and two years after starting treatment. If neutralising antibodies continue to be present at two years, are present in high levels, and an individual is beginning to experience more MS-related symptoms, then there is a case for stopping or switching treatment. However, the presence of neutralising antibodies alone is not a reason to stop or to change drugs unless there is other evidence that the treatment is not working[20].

Natalizumab (Tysabri)

Natalizumab is a recombinant monoclonal antibody against alpha 4 integrins. This is the first in a new class of drugs known as selective adhesion molecule inhibitors. They act in MS by preventing the migration of immune cells across the blood brain barrier, which would result in inflammation and myelin destruction.

Two large scale trials have been carried out. The AFFIRM trial was a two year, randomised, multicentre, placebo controlled, double blind study of 942 people. Participants received either an infusion of natalizumab or placebo every four weeks. The proportion of people who remained relapse free was 76% in the treatment group as opposed to 41% in the placebo group. Natalizumab also showed significant benefits on the risk of progression of disability - 29% of the placebo group progressed compared with 17% of the natalizumab group - and on quality of life. Persistent binding antibodies were present in 6% of people receiving active treatment, who also experienced a higher level of infusion-related adverse events and a loss of efficacy of the drug[21].

The SENTINEL trial has examined natalizumab 3 or 6 mg/kg IV in combination with beta interferon 1a (Avonex) 30μg intramuscularly to determine if this treatment was more effective than interferon treatment alone. Statistically significant reductions in relapse rate were seen over the two year period[22].

During this combination trial, two patients died of a rare complication directly related to treatment. As a result, natalizumab is approved by NICE only for people with highly active severe relapsing remitting MS. This is defined as having two or more disabling relapses in one year and with evidence of one or more gadolinium enhancing lesion on a brain MRI scan or significant increase in T2 lesion load compared with a previous MRI.

Drugs currently used in MS - licensed for other indications

Current thinking surrounding the aetiology of MS is that it has an autoimmune component. Immunoregulators have been proven effective in treatment of other diseases with an autoimmune element such as psoriasis and rheumatoid arthritis and this rationale has led to their use in multiple sclerosis. Immunoregulators commonly work by inhibiting the division and proliferation of immune cells.

Azathioprine and mitoxantrone

NICE guidelines recommend that the following two drugs should not be used except in specific circumstances by an expert in use of the drugs and with close monitoring of adverse events. Each centre that prescribes these agents will therefore have its own protocols and clinical guidelines for their use.

Azathioprine (Imuran)

Like steroids, azathioprine has an immunosuppressive effect. It is used in the treatment of moderate to severe rheumatoid arthritis.

Studies suggest that azathioprine reduces relapse rate in people with relapsing remitting MS and slows down disability progression[23]. A metaanalysis[24] suggested that efficacy could be similar to that of interferons although because of its side effect profile it is usually reserved for patients with moderately aggressive disease. Side effects include haematological and hepatic abnormalities; infections; gastrointestinal disturbance; and a possibly higher risk of developing cancer - the results are inconclusive.

Azathioprine has been studied in combination with beta interferon 1a in patients with relapsing remitting MS. A recent small scale study of people unresponsive to either monotherapy found the combination therapy was well tolerated after two years of treatment with no serious side effects reported[25]. Mean number of relapses over the trial period was significantly lower than that before combined treatment. Further larger studies are required.

Azathioprine is given orally as tablets.

Mitoxantrone (Novantrone)

In the UK mitoxantrone is licensed as a chemotherapy agent and acts by inhibition of DNA repair. In the US this has a licence for use in treatment of relapsing remitting and secondary progressive MS.

A randomised placebo controlled observer blinded trial has shown mitoxantrone to be effective in reducing progression of disability in clinical exacerbations in patients with worsening relapsing remitting or secondary progressive MS[26]. Studies have suggested that mitoxantrone should be reserved for patients with rapid accumulation of disability over a short time where disease progression cannot be controlled by other immunomodulatory drugs.

Mitoxantrone is given by intravenous infusion and dose is weightdependent. Regimes vary and may be every three months or monthly for three months then once every three months. Treatment is in hospital and all units using this drug have specific policies and protocols. Some hospital trusts require administration by chemotherapy rather than neurology staff.

Cardiotoxicity is the main side effect and as such this sets the limit for the amount of treatment a person can have. Practically this allows 8-12 doses over 2-3 years. Electrocardiograms are performed on patients prior to, during and after receiving the drug.

A recent study has examined using mitoxantrone as a first-line treatment, followed by glatiramer acetate over a longer period of time, in 60 people with relapsing remitting MS who experienced frequent, severe relapses. Results have been promising and a larger trial is currently underway[27].

Disease modifying drugs still in clinical trials for MS

Campath (alemtuzumab)

Campath is a humanised monoclonal antibody that acts by killing T-cells, which in MS recognise myelin as a foreign body. It is hoped that the T-cells regenerated following treatment with Campath will not include those that destroy myelin. Alemtuzumab is already licensed for use in B-cell chronic lymphocytic leukaemia, a type of cancer.

Interim results from an international Phase II clinical trial have recently been reported. The trial looked at 334 people with early, aggressive relapsing remitting MS who had a first relapse less than three years ago, had more than two attacks in the last two years and remained ambulatory when starting on treatment. This trial CAMM223 was a randomised single blind trial comparing the efficacy of two doses of Campath 1 and interferon beta 1a (Rebif) in treatment of drug naïve patients, which began in 2002. Results showed that alemtuzumab-treated patients on the lower dose experienced a 87% reduction in the risk of relapses, and a 65% reduction in the risk for progression of clinically significant disability compared with interferon beta 1a. Those receiving the higher dose experienced a 72% reduction in the risk of relapse and 88% reduction in the risk of progression to disability.

However, the trial was voluntarily suspended in September 2004 following one fatal case of immune thrombocytopenic purpura(ITP), although results could be collated as most patients had received their full dose of alemtuzumab by this time.

Side effects can be significant. To date, six trial participants (3%) have developed ITP, and 16.2% of participants developed thyroid-related side effects. Flu-like symptoms after infusion are also reported[28,29].

Alemtuzumab is administered as an annual infusion. Dosage regime is intravenous once a day for five days, repeated 12 months later.

It is unclear how easily this drug will progress to licensing for MS, however, Phase III trials are planned.

Fingolimod

Fingolimod (FTY720) works by binding to the surface of immune cells and preventing them from attacking cells in the central nervous system.

A six month, phase II controlled clinical trial of fingolimod involving 255 people with relapsing remitting MS found inflammation measured on MRI scans was significantly reduced in treatment groups when compared to people on placebo. More people in the treatment group stayed relapse free. Two doses of fingolimod were tried, 1.25mg and 5mg. Results between the two treatment groups were similar, with relapses of 0.35 and 0.36 respectively, compared with 0.77 in the placebo group.

A six month extension of the original study, in which those previously taking a placebo started treatment, confirmed these results, with up to 77% of those taking fingolimod remaining free of relapses over one year. Better results were seen in those who had been on active treatment for twelve months, with those around 65-67% of those who had been on placebo followed by fingolimod remaining relapse free.

Although the trials so far have shown fingolimod to be well tolerated, the side effects that have occurred include upper respiratory tract infections, shortness of breath, diarrhoea and nausea[30].

Fingolimod is taken orally as tablets.

Other approaches to disease modification

It is now recognised that immunomodulatory drugs are of maximum benefit before axonal damage has occurred and clinical progression has been established. The aim of therapies therefore must be not only to reduce frequency of relapses[31] but also to prevent transition to a secondary progressive course, and repair tissue damage. The last decade has seen development of therapies that moderately affect the course of the disease where inflammation predominates over degeneration. The challenge to repair and prevent damage caused by MS remains.

Stem Cells

Experimental and clinical observations have suggested that high dose immunosuppression followed by autologous stem cell transplantation (ASCT) can induce remission in people with rapidly evolving relapsing remitting and secondary progressive MS.

The rationale of this treatment is based on immunosuppressive and imunomodulatory effects of ASCT. A number of studies conducted worldwide since 1995 and analysis of 85 patients by the European Group for Blood and Marrow Transplantation (EBMT) have shown the feasibility of this. However results in terms of disease stabilisation and prevention of disability need validation. The treatment also carries a transplant related mortality risk. A randomised controlled trial by the EBMT is now underway to compare ASCT to mitoxantrone[32].

In December 2005, an Italian study involving 21 participants who were beginning to have difficulty walking and were rapidly deteriorating reported. Participants received stem cells harvested from their own blood. 20 of the 21 improved and had been followed up at report for 66 months[33].

In January 2006, a group in Holland reported results from 14 people with MS treated with autologous bone marrow stem cell transplants. In the 36 months follow-up post transplant, three patients stabilised, two improved but nine patients deteriorated[34].

Cannabis

To date, no medicine derived from the cannabis plant is licensed for use for any condition in the UK. There are two main cannabis-based products being used in cannabis trials which are based on plant extracts; in some of the trials these are also compared with synthetic versions of cannabis.

Cannabis trials have examined both symptomatic relief of MS and the hope of neuroprotection. Results have been mixed, with patient-reported improvements on clinical trials receiving only limited support from clinician-administered outcome measures.

The largest trial of cannabis-based medicine was CAMS, which looked at cannabis-based medicine as a possible treatment for spasticity. The outcomes were not statistically significant but many participants reported substantial benefit[35]. An extension trial suggested that both plant-based cannabis-based medicine and a synthetic equivalent might lessen some people's increase in disability over time, and have a neuroprotective effect[36].

The CUPID trial is now in place which will test this hypothesis, and hopes to recruit 500 people with MS to a three-year study. It will look at whether cannabis can slow the increase of disability in people with progressive MS. Other outcome measures include symptomatic relief for spasticity, and an assessment of the long-term safety of cannabisbased medicines, particularly given concerns about the effects of cannabis on cognitive function and mental health. Participants need to have primary or secondary MS, their MS must have got worse over the past year, and they must still be able to walk 20 metres, with or without a walking aid.

References

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    8. DMTs

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    19. Neutralising antibodies

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    21. Natalizumab

  21. Polman CH, O'Connor PW, Havrdova E, et al. A randomized, placebo-controlled trial of natalizumab for relapsing multiple sclerosis. New England Journal of Medicine 2006; 354(9): 899-910.
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    23. Azathioprine

  23. Yudkin PL, Ellison GW, Ghezzi A, et al. Overview of azathioprine treatment in multiple sclerosis. Lancet 1991;3338:1051-1055.
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    26. Mitoxantrone

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    28. Campath

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    30. Fingolimod

  30. Kappos L, Antel J, Comi G, et al. Oral fingolimod (FTY720) for relapsing multiple sclerosis. NEJM 2006;355(11):1124-1140.

    31. Stem cells

  31. Lublin FD. Effects of relapses on residual deficit in MS. Neurology 2003;61(11):1528-1532.
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  34. Samijn JP, te Boekhorst PA, Mondria T, et al. Intense T cell depletion followed by autologous bone marrow transplantation for severe multiple sclerosis. J Neurol Neurosurg Psych 2006; 77: 46-50.

    35. Cannabis

  35. Zajicek J, Fox P, Sanders H, et al. Cannabinoird for treatment of spasticity and other symptoms related to multiple sclerosis (CAMS study): multicentre randomised placebo-controlled trial. Lancet 2003;362(9395):1517-1526.
  36. Zajicek J, Sanders H, Wright DE, et al. Cannabinoids in multiple sclerosis (CAMS) study: safety and efficacy data for 12 months follow up. J Neurol Neurosurg Psych 2005; 76(12): 1664-1669.