Therapies for Multiple Sclerosis
Multiple sclerosis (MS) is a chronic inflammatory disease of unknown cause, affecting the central nervous system (CNS). It affects more than 2 million people worldwide and 85% of patients experience at least 1 relapse, followed by partial or complete recovery (Neuhaus, Kieseier & Hartung 2006). Hence MS is often referred to as a relapsing - remitting disease. Without adequate therapeutic intervention over half of all MS patients will enter a second disease phase, involving a progressively worsening disability, often in conjunction with superimposed relapses.
The pathogenesis of MS
Figure 1 below indicates the hypothetical pathogensis of MS, although it should be recognised that it is only hypothetical.
1. The hypothetical pathogenesis of multiple sclerosis, indicating the
potential role of immune cells (Neuhaus, Kieseier & Hartung 2006)
Ordinarily Th1 cells release pro-inflammatory cytokines, including
Interferon-γ and interleukin-2, but are reciprocally modulated by the
Th2 mediated anti-inflammatory response, leading to an appropriate
inflammatory response. Unlike the normal immune response,
unfortunately patients with MS show over activity in Th1 cells, leading
to an excessive production of Th1 pro-inflammatory cytokines (Javed,
Reder 2006), which is not balanced by the Th2 response, which is
MS is associated with axonal transection leading to neurological
deficits (Khan et al. 2005). Indeed it is believed that it is this
axonal degeneration that underlies the worsening neurological deficits
and brain atrophy and chronic disability observed as the disease
progresses (Kreitman, Blanchette 2004).
Drug interventions in the treatment of MS - an initial cautionary point
It is sometimes difficult to assess the relative effects of therapies
for MS as patients who do not experience the expected benefit in
clinical trials, perhaps due to placebo administration, will often drop
out of the trial in order to obtain a better therapeutic effect
elsewhere (Rudick et al. 2005). Thus results will be biased towards
the more successful therapy, as individuals on that therapy will feel
its benefit and wish to continue with the trial. It is therefore
necessary to view highly successful clinical trail results with some
scepticism, unless full data on drop out rate and reason for drop out
is taken into account.
Another problem with trials is that MS takes an average of 14 years for
a patient to reach a point that they require assistance due to
increasing disability (Javed, Reder 2006). In practise this means
that, unless all trials only involve those who have already reached the
disability stage, it is not clear whether the drug effects are halting
symptoms or reversing them. MS follows a different disease course in
all patients, so even comparing drug treated patients with those on
placebo will not accurately give a measure of how effective the
treatment has been. This has been referred to as “at best [a]
speculation of the long term efficacy of agents” (Javed, Reder 2006).
An alternative to a double blind study is to use an open label study.
Whilst this does mean that patients are aware of the therapy being
taken, there is the benefit that they can make an informed choice about
what treatment they actually wish to undergo. In a recently completed
6 year open label trail of glatiramer acetate it was found that the
majority of patients chose to remain on the trial and showed a lower
relapse rate than those on some other therapies (Johnson et al. 2003).
Interferons are naturally occurring signalling
molecules that are involved in the ordinary innate immune response to
antigens. They act by binding to receptors on the cell surface and
causing enzymatic activity and cross-phosphorylation of receptor
subunits to result (Javed, Reder 2006). Blood borne transcription
factors are then activated by these altered receptors, and can go on to
stimulate gene expression. MS patients have low levels of interferon
stimulated gene products so therapy can aim to replace the gene
products or reverse the signalling defects.
Therapy with IFN-β acts by inhibiting the initial Th cell activation, but also by decreasing inflammatory cytokine release.
Betaseron (IFN-β 1b) has been shown to have therapeutic efficacy in
MS. In a 2 year phase III placebo-controlled, double blind trial
betaseron was found to reduce relapse rates from an annualised average
of 1.27 (placebo) to 0.84 (250μg active drug) (Javed, Reder 2006). In
addition those receiving the highest dose (250μg) of betaseron
experienced less disability worsening than either those on placebo or
on those receiving the lower dose (50μg) of betaseron.
Avonex (IFN-β 1a) showed similarly good results as betaseron, with a
37% reduction in disability progression and a 32% reduction in relapse
rates, when compared to placebo in a 2 year trial (Javed, Reder
2006). Similar results were found for a different preparation of
IFN-β 1b - Rebif.
Side effects for interferons include local site injection reactions as
well as possible spasticity on the day of injection, and other flu like
symptoms, all of which generally clear up within 12 hours of drug
administration (Javed, Reder 2006). It has also been indicated that up
to ¼ of patients receiving interferons will develop neutralising
antibodies which greatly reduce the efficacy of the drugs (Murray
2006). In these instances the subsequent treatment of choice is
glatiramer acetate (discussed below). However, interferons are still
suggested to be the first line treatment for relapsing-remitting MS
(Polman, Uitdehaag 2000).
Glatiramer acetate works in a similar way to
interferons, in that it aids the generation of Th2 biased T cells,
which are then able to migrate across the blood brain barrier and
secrete Th2 cytokines which will then help to reduce inflammation (Khan
et al. 2005). Specifically glatiramer acetate induces specific
regulatory T cells formed close to the site of action, which are then
reactivated by myelin basic protein and other myelin antigens in order
to secrete anti-inflammatory cytokines (Filippi, Wolinsky & Comi
2006). These include interleukin 4, 5 and 6 as well as transforming
growth factor (TGF) and brain-derived growth factor (BDNF).
A recent study using glatiramer acetate indicated that it could
actually be neuroprotective by minimising the damage to neurons that
had undergone sublethal injury (Khan et al. 2005). This has obvious
benefits in MS, where the use of the drug to reduce the inflammatory
effects would also prevent further damage to existing neurons, thus
halting the progression of the disease. However, another recent
clinical trial found that there was no difference in the relapse rate
of MS in those administered oral glatiramer acetate in milligram doses
and those who received placebo, leading the authors to state that
glatiramer acetate could not be recommended at such doses in that
preparation (Filippi, Wolinsky & Comi 2006).
Side effects for glatiramer acetate are associated with its method of
administration (injection) and include local site reactions similar to
those observed with interferons.
Mitoxantrone is a DNA intercalator that exhibits
immunosuppressive effects (Neuhaus, Kieseier & Hartung 2006).
Mitoxantrone acts to inhibit the proliferation of T cells, B cells and
macrophages, all part of the possible pathogenesis of MS, as indicated
in figure 1. Placebo controlled trials indicated that mitoxantrone
reduced relapse rate by 2/3 and also reduced the generation of new
pathology. In fact the largest trial (194 patients) showed such a
reduction in relapse rates that the majority of patients treated with
mitoxantrone did not actually relapse during the 2 year trial (Neuhaus,
Kieseier & Hartung 2006). Unfortunately mitoxantrone is associated
with cardiotoxicity at higher doses so its use in MS is questionable
and it has also been noted that its long term effects are not yet
proven and any effects are mainly in the short term (Murray 2006).
Corticosteroids are used to treat the relapses
common in MS. Indeed they were the only useful treatment until the
arrival of the interferons in the mid 1990s (Neuhaus, Kieseier &
Hartung 2006) and methyprednisolone remains the treatment of choice and
most widely used option to treat acute attacks (Murray 2006).
Corticosteroids work by reducing the inflammatory response but have no
effect on reducing the agents causing the inflammatory response. Thus
they are effectively a palliative option only, dealing with the
symptoms but not the cause. In addition, as corticosteroids reduce the
whole immune response, they leave patients open to infection, which can
greatly impair recovery from MS relapses.
Natalizumab is a novel immunoregulatory agent which was believed to
offer hope in the treatment of MS. Natalizumab is a monoclonal antibody
that acts against α2-integrin, a adhesion molecule involved in T-cell
migration through the blood brain barrier (Senior 2005). Unfortunately
it has been found to be associated with progressive multifocal
leucoencephalopathy, which can be fatal. Indeed, in one trial of
natalizumab one patient did die as a result of the development of
multifocal leucoencephalopathy, but it was found that she did not in
fact have MS. It was more likely that she suffered from serious
migraines that brought on similar clinical symptoms to MS. Nonetheless
it has resulted in natalizumab undergoing a safety update, which
includes all previous patients who have received the drug (Senior
2005). However this case has highlighted the need for stricter
diagnoses prior to enrolment onto clinical trials for new MS agents
(Langer-Gould, Steinman 2006).
Cannabis and the cannabinoid family of drugs are
believed to have a therapeutic potential in MS, due to the effects of
endocannabinoids on reducing inflammation in vivo. Up to 4% of UK MS
patients are believed to use cannabis for symptom relief (Zajicek et
A review of trials to date indicated that whilst earlier trials showed
a greater effect on spasticity and tremor, as well as in improving the
subjective feelings associated with MS; the more recent trials have not
replicated these results (Ben Amar 2006). One example is the three
year cannabis in MS (CAMS) trial of more than 600 patients, which found
that there was no clear benefit to using cannabis to treat MS,
specifically the spasticity symptoms often anecdotally benefiting from
cannabis use (Zajicek et al. 2003). Although the trial was supposed to
be blinded and results did appear to show an improvement when patients
were asked face to ace; it was actually believed that the majority of
those taking the active drug had guessed as much and their answers were
correspondingly biased (Dyer 2003).
It has been noted that ¾ of MS patients do use at least one form of
alternative therapy, often in conjunction with traditional medicine
(Murray 2006). In a recent study in Germany it was found that
physiotherapy, vitamins and mineral supplements, phytotherapy and
massage were all used to improve symptoms. Over 60% of the patients
surveyed used at least one form of complementary medicine, with an
average of 2.4 forms being used each (Apel, Greim & Zettl 2005).
The majority of users reported a benefit to their use of complementary
Due to the fact that multiple sclerosis (MS) has no
definitive cause, and no cure, therapies should ideally involve a dual
function of addressing the symptoms as well as halting the disease
progression. Traditionally therapies have solely aimed to restore the
remission period of the disease, reducing the overactive immune
response characterising the relapse period. Drugs such as
methyprednisolone still remain an effective option in these instances.
However, up until 10 years ago there were no real options in terms of
halting disease progression, but recent research has elucidated the
interferons, as well as other immunsuppressant drugs including
mitoxantrone. Drug therapy aims to stop the detrimental effects of the
over active immune response experienced in MS, and the interferons
appear to do this reasonably well to begin with, acting to reduce the
inflammatory response and save further neuronal damage. Unfortunately
the interferons can suffer from a limited span of use, due to the
development of neutralising antibodies, which can occur in ¼ of
patients. However glatiramer acetate provides an alternative in such
Finally consideration must be given to the use of complementary
therapies in the treatment of MS. Whilst the anecdotally successful
cannabis is not experimentally successful, the fact that ¾ of all MS
patients use some form of complementary therapy suggests that it does
have a use, albeit possibly merely in improving mood.
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with multiple sclerosis use complementary and alternative medicine?",
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