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.
Figure 1. The hypothetical pathogenesis of multiple sclerosis, indicating the potential role of immune cells (Neuhaus, Kieseier & Hartung 2006) Key
 
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 abnormally low. 
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

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

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

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

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
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). 

Cannabinoids

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 al. 2003). 
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).
Alternative therapies
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 therapies.

Commentary

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 cases.

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.

References

  • Apel, A., Greim, B. & Zettl, U.K. 2005, "How frequently do patients with multiple sclerosis use complementary and alternative medicine?", Complementary therapies in medicine, vol. 13, no. 4, pp. 258-263.
  • Ben Amar, M. 2006, "Cannabinoids in medicine: A review of their therapeutic potential", Journal of ethnopharmacology, vol. 105, no. 1-2, pp. 1-25.
  • Dyer, O. 2003, "Trial shows no clear benefit from cannabis for patients with MS", BMJ, vol. 327, no. 7424, pp. 1128.
  • Filippi, M., Wolinsky, J.S. & Comi, G. 2006, "Effects of oral glatiramer acetate on clinical and MRI-monitored disease activity in patients with relapsing multiple sclerosis: a multicentre, double-blind, randomised, placebo-controlled study", The Lancet Neurology, vol. 5, no. 3, pp. 213-220.
  • Javed, A. & Reder, A.T. 2006, "Therapeutic role of beta-interferons in multiple sclerosis", Pharmacology & therapeutics, vol. 110, no. 1, pp. 35-56.
  • Johnson, K., Brooks, B., Ford, C., Goodman, A., Lisak, R., Myers, L., Pruitt, A., Rizzo, M., Rose, J., Weiner, L. & Wolinsky, J. 2003, "Glatiramer acetate (Copaxone): comparison of continuous versus delayed therapy in a six-year organized multiple sclerosis trial", Multiple Sclerosis (Arnold Publishers), vol. 9, no. 6, pp. 585-591.
  • Khan, O., Yimin, S., Caon, C., Fen, B., Ching, W., Reznar, M., Buccheister, A., Jiani, H., Latif, Z., Tselis, A. & Lisak, R. 2005, "Axonal metabolic recovery and potential neuroprotective effect of glatiramer acetate in relapsing-remitting multiple sclerosis", Multiple Sclerosis (Arnold Publishers), vol. 11, no. 6, pp. 646-651.
  • Kreitman, R.R. & Blanchette, F. 2004, "On the horizon: possible neuroprotective role for glatiramer acetate", Multiple Sclerosis (Arnold Publishers), vol. 10, pp. 81-89.
  • Langer-Gould, A. & Steinman, L. 2006, "What went wrong in the natalizumab trials?", The Lancet, vol. 367, no. 9512, pp. 708-710.
  • Murray, T.J. 2006, "Diagnosis and treatment of multiple sclerosis", BMJ, vol. 332, no. 7540, pp. 525-527.
  • Neuhaus, O., Kieseier, B.C. & Hartung, H.-. 2006, "Therapeutic role of mitoxantrone in multiple sclerosis", Pharmacology & therapeutics, vol. 109, no. 1-2, pp. 198-209.
  • Polman, C.H. & Uitdehaag, B.M.J. 2000, "Regular review: Drug treatment of multiple sclerosis", BMJ, vol. 321, no. 7259, pp. 490-494.
  • Rudick, R.A., Cutter, G.R., Baier, M., Weinstock-Guttman, B., Mass, M.K., Fisher, E., Miller, D.M. & Sandrock, A.W. 2005, "Estimating long-term effects of disease-modifying drug therapy in multiple sclerosis patients", Multiple Sclerosis (Arnold Publishers), vol. 11, no. 6, pp. 626-634.
  • Senior, K. 2005, "Multiple sclerosis poses tough drug development challenges", Drug discovery today, vol. 10, no. 23-24, pp. 1583-1584.
  • Zajicek, J., Fox, P., Sanders, H., Wright, D., Vickery, J., Nunn, A. & Thompson, A. 2003, "Cannabinoids for treatment of spasticity and other symptoms related to multiple sclerosis (CAMS study): multicentre randomised placebo-controlled trial", The Lancet, vol. 362, no. 9395, pp. 1517-1526.

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