Interventions for the Treatment of Multiple Sclerosis

Abstract

Multiple sclerosis (MS) is an inflammatory disease, involving autoimmune-mediated damage to the central nervous system (CNS). This results in impairment of communication between the brain and the rest of the body, with relapses and remissions of neurological symptoms, leading to a progressive loss of functional ability. A treatment to resolve this condition is currently unavailable, and the management of MS requires a comprehensive approach, which includes pharmacological and non-pharmacological therapies, rehabilitation, specialty care and lifestyle management interventions. The available treatments for MS can help reduce the frequency of relapses and delay the progression of disability. Optimising the existing treatments and developing new ones is essential for combatting and preventing MS.

Introduction

MS is a chronic inflammatory, demyelinating disease that involves immune-mediated lesions in both white and grey matter in the CNS. MS is characterised by relapses and remissions of neurological symptoms and progression of functional disability over time.1 A single neurological event consistent with one or more white matter lesions in the CNS, is the earliest sign or symptom of MS.2 A single treatment to cure MS is currently not available, and a multidisciplinary approach is generally implemented for the management of this condition.

Interventions for Multiple Sclerosis

The findings from a clinical trial have shown that two dosing frequencies of subcutaneous interferon (IFN) β-1a in patients with a first clinical demyelinating event, resulted in delayed clinical relapses and subclinical disease activity.3 The design of the clinical trial has been described in detail elsewhere.3 Briefly, eligible patients were randomly assigned into 3 groups in a 1:1:1 ratio, and were administered IFN β-1a, 44μg subcutaneously three times a week or once a week, or placebo three times a week for up to 24 months. MRI scans were performed at intervals of 3 months, or every 6 months if the patient developed clinically definite multiple sclerosis (CDMS). End points analysed included: number of combined unique active (CUA) lesions per patient per scan; numbers and volumes of new T2, T1 hypointense and gadolinium-enhancing (Gd+) lesions per patient per scan; and brain volume.

Detailed MRI results of the clinical trial have been described elsewhere.2 Briefly, the results showed that the treatment with subcutaneous IFN β-1a at the dosing frequency of three times or once a week, resulted in a significant decrease in the number of CUA lesions compared with placebo. Moreover, the reduction in the number of CUA lesions was greater in the three times a week dose regimen compared with the once a week dose regimen, indicating a clear dose effect. Analogous positive effects were observed for the numbers and volumes of new T2, T1 hypointense and Gd+ lesions per patient per scan.

These results are in accordance with those of previous studies, which indicated that the treatment with IFN β-1b and IFN β-1a in patients with clinically isolated syndromes (CIS) improves MRI outcomes, and this effect is maintained for two years4 and five years.5 De Stefano, and co-workers observed that in patients treated with subcutaneous IFN β-1a, the number of CUA lesions seemed to be higher at 24 months than at 12 months. However, this can be attributed to a small number of patients with large numbers of lesions at month 24 and the decreased number of patients still in the double blind (DB) analysis compared with baseline.2

Investigations into the demographic characteristics that could potentially affect the efficacy of the therapy intended to delay MS, provided mixed results. For instance, in one trial female patients appeared to have a more pronounced IFN β treatment effect compared with male patients.3

These results are in contrasts with the findings of a previous trial, which suggested a greater treatment effect in male patients.6 Also, the effect of IFN β treatment on percentage of brain volume loss appeared to produce mixed results. Some have reported a greater percentage of brain volume loss at a higher dose of IFN β treatment.3 Whereas, others have found that lower dose of IFN β treatment resulted in a reduction in the loss of brain volume.7 However, a reduction in brain volume does not necessary indicate atrophy, because it can occur due to the resolution of inflammation, mediated by IFN β treatment.8 Collectively, the findings from these studies highlight the advantages of early IFN β treatment in patients with CIS2 4 5 also suggesting a clear dose effect.2

IFN β was the first disease-modifying intervention available to treat MS, and it is capable of reducing relapse rates and delays in the onset of disability. Four IFNβ drugs are currently available to treat MS, and these are subcutaneous IFN β-1b, IFN β-1a and peginterferon β-1a, and intramuscular IFN β-1a. Various clinical trials provided evidence for the effectiveness of interferons in treating relapsing MS.8 Injection site reactions and flu-like symptoms are the most frequent adverse events associated with IFN β treatment. Mitigation strategies and patient education are important factors for the management of these adverse events, as well as for supporting treatment adherence. Peginterferon β-1a is the most recently developed interferon treatment, requiring fewer injections and causing less frequent discomfort, and this may improve adherence, which is a key factor for treatment efficacy.8 In addition to IFN β treatment, there are various other therapies for MS, including oral drugs.

Fingolimod, a sphingosine 1-phosphate (S1P) receptor modulator, was the first approved oral disease-modifying treatment (DMT). Fingolimod, was a major advancement because of the improved efficacy and new route of administration. Subsequently, a variety of oral options have been approved, including Siponimod and Ozanimod that are also selective S1P receptor modulators. Other approved oral drugs include Teriflunomide that acts primarily as a pyrimidine synthesis inhibitor, and dimethyl fumarate that is in a class of medications called Nrf2 activators. Diroximel fumarate is a recently approved fumarate, with the same mechanism of action as dimethyl fumarate, but has improved tolerability. Cladribine is another oral medication that appears to have the highest efficacy.1 Overall, the oral medications are more efficacious than the IFN β injectable therapies, except for teriflunomide, which is similar in efficacy to injectables, and cladribine that is the most efficacious. Generally, oral drugs are well tolerated, and their side effect profile varies. The use of some oral drugs may be limited because of risks of side effects, such as lymphopenia, and also the risk of infections is greater compared with the IFN β injectable therapies.1

Other MS interventions include infusions of monoclonal antibodies, stem cell transplant, re-myelination therapies and neuroprotective treatments, with varying dosing schedule, routes of administration, mechanisms of action, efficacy and side-effect profiles.1

Until a treatment that resolves MS becomes available, the optimization of existing treatments remains a crucial factor. However, the prevention of this diseases should be the ultimate goal. In this context, it is vital to identify and reduce the risk factors of MS. For instance, it appears that the active form of vitamin D has immunomodulatory effects on cells of the immune system, especially T lymphocytes, as well as on the production and action of several cytokines. Moreover, vitamin D deficiency is associated with a number of autoimmune diseases, including MS, inflammatory bowel disease, rheumatoid arthritis and systemic lupus erythematosus.9 Research has revealed that vitamin D has a role to play in reducing MS relapse rates, as well as in the prevention of the disease.9

Besides, it is important to reduce/eliminate toxic chemicals, such as pesticides, dioxin, mercury, aluminum, asbestos, trichlorethylene, and many other industrial and environmental toxins, because are associated with autoimmunity. These toxic chemicals can impair immune function and lead to autoimmunity in various ways, including binding to gamma aryl hydrocarbon and peroxisome proliferator-activated receptors resulting in abnormal antigen-presenting responses and lymphocyte dysregulation. Also, they can bind to nucleic acids and promote the activation of anti-nuclear antibodies, or bind to circulating proteins found throughout the body and induce protein misfolding, thereby configuring proteins into neo-antigens. Toxic chemicals can also bind to oestrogen and pituitary receptors, resulting in immune dysfunction.10

In conclusion, optimising the existing treatments and developing new ones, as well as ensuring optimal intake of nutrients that affect immune function, such as vitamin D, and reduce/eliminate toxic chemicals and other risk factors, are critical interventions for combatting and preventing MS.

References

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2. De Stefano N, Comi G, Kappos L, et al. Efficacy of subcutaneous interferon β-1a on MRI outcomes in a randomised controlled trial of patients with clinically isolated syndromes. J Neurol Neurosurg Psychiatry 2014; 85(6):647-53.

3. Comi G, De Stefano N, Freedman MS, et al. Comparison of two dosing frequencies of subcutaneous interferon beta-1a in patients with a first clinical demyelinating event suggestive of multiple sclerosis (REFLEX): a phase 3 randomised controlled trial. Lancet Neurol 2012;11:33–41.

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