Multiple Sclerosis
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Disease-modifying Agents Make Multiple Sclerosis a Treatable Disease

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Published Online: Jun 4th 2011
Authors: Nancy J Holland
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Until the 1990s, multiple sclerosis (MS) was considered to be an essentially untreatable disease leading to progressive disability. Therapies were largely symptomatic and there were no medications available that actually altered the disease course. With the introduction of several disease-modifying agents (DMAs) in the last decade, patients with MS can now look forward to a more promising future.


Overview of Multiple Sclerosis


MS is widely regarded as an autoimmune disease, generally characterized by periodic relapses or exacerbations and progressive neurological deterioration. The disease usually follows one of four courses (see Figures 1–4). Most patients usually present with a relapsing-remitting pattern, and according to a Mayo Clinic study, enter the secondary progressive phase five to 25 years later. Age at onset and gender are statistically related to the long-term course of the disease – female gender and younger age at onset often confer a more favorable prognosis. It is important to note that a patient living with MS for 20 or 30 years may experience substantial disability even if the progress is slow, and in the first 10 or 15 years he or she is relatively mildly affected. Late onset, i.e. over 55 years, particularly among males, is associated with a progressive course of the disease.

Relapsing-remitting MS (RRMS) is the most common form of the disease. It is characterized by clearly defined acute attacks with full recovery (see Figure 1a) or with residual deficit upon recovery (see Figure 1b). Periods between disease relapses are characterized by a lack of disease progression. Approximately 85% of people with MS begin with a relapsing-remitting course.

Secondary progressive MS (SPMS) begins with an initial relapsing-remitting disease course, followed by progression of disability (see Figure 2a) that may include occasional relapses and minor remissions and plateaus (see Figure 2b).Typically, SPMS is characterized by less recovery following attacks, persistently worsening functioning during and between attacks, and/or fewer and fewer attacks – or none at all – accompanied by progressive disability. Of the 85% who start with RRMS, more than 50% will develop SPMS within 10 years. Ninety per cent of those with RRMS will develop SPMS within 25 years.

Primary progressive MS (PPMS) is characterized by progression of disability from onset, without plateaus or remissions (see Figure 3a) or with occasional plateaus and temporary minor improvements (see Figure 3b). Ten per cent of people with MS are diagnosed with PPMS, although the diagnosis usually needs to be made after the fact – when the person has been living for a period of time with progressive disability, but not acute attacks.

Progressive relapsing MS (PRMS), which is the least common disease course, shows progression of disability from onset but with clear acute relapses, with (see Figure 4a) or without (see Figure 4b) full recovery. Approximately 5% of people with MS appear to have PRMS at diagnosis.Symptoms
Symptoms of MS vary in severity and duration, and manifest in differing combinations, depending on the area of the nervous system affected. Complete or partial remission, especially in the early stages of the disease, occurs in approximately 70% of MS patients. Patients often present with visual changes indicative of optic neuritis, sensory disturbances or focal muscle weakness.

Symptoms of MS include:

  • visual changes;
  • focal muscle weakness;
  • fatigue;
  • lidepression;
  • bowel/bladder/sexual dysfunction;
  • gait problems/spasticity;
  • paresthesias;
  • heat intolerance;
  • dysarthria/scanning speech/dysphagia;
  • Lhermitte’s sign;
  • neuritic pain;
  • vertigo/ataxia;
  • cognitive dysfunction; and
  • tremor/incoordination.

Figures 1–4: Courses of Multiple Sclerosis

Magnetic resonance imaging (MRI) can help locate central nervous system (CNS) lesions (inflammation, demyelinization, and axonal loss).The administration of gadolinium permits the visualization of hyperintense areas indicating recent disease activity, while older lesions appear hypointense. However, since these lesions can also occur in other neurological disorders, they do not provide a definitive diagnosis of MS.These changes support the clinician’s impression based on history, neurologic examination and patient characteristics, e.g. age and gender. Evoked potential testing, especially visual evoked potentials, may show delayed response time, and can sometimes support the MS diagnosis as well. However, as with MRI, the results of these tests are not conclusive.

Table 1: Approved Disease-modifying Agents and their Indications
IM = intramuscular, SC = subcutaneous.

Examination of the cerebrospinal fluid for abnormalities often associated with MS can also be helpful. These include oligoclonal bands, increased white blood cells, and elevated protein, especially myelin basic protein and immunoglobulin (Ig)G. Symptomatic Management There are a variety of pharmacological and non-pharmacological therapies available to treat the symptoms of MS. Although it is beyond the scope of this article to review these therapies, information can be found on the National Multiple Sclerosis Society (NMSS) website directed at both patients and clinicians. Physicians may receive consultation from an MS expert on the NMSS Medical Advisory Board by telephoning or emailing the NMSS.

FDA-approved Disease-modifying Therapies
There are now five disease-modifying therapies approved by the US Food and Drug Administration (FDA) for the treatment of MS. The beta interferons (INF-?) are approved for relapsing forms of MS, glatiramer acetate for RRMS and mitoxantrone for worsening RRMS,PRMS, and SPMS courses (see Table 1). None of these agents is a cure, nor do they impact symptoms.

The interferons and glatiramer acetate for injection modulate the immune system and are intended for longterm use via self-injection. Mitoxantrone, originally developed for use in cancer, is an immunosuppressive agent administered by intravenous (IV) infusion. The total lifetime dose is limited to 140mg/m2 in order to avoid cardiac damage. Patients taking this drug require regular cardiac evaluation with multiple-gated acquisition scans. It cannot be used in people with pre-existing cardiac or liver disease, and certain blood disorders. In placebo-controlled clinical trials, the four agents approved for RRMS or relapsing forms of MS reduced the frequency of relapses by approximately 30%, and decreased the severity as well. In addition, they can reduce the number and size of new lesions – the disease burden of MS – as visualized by MRI.In general, the DMAs have also been shown to slow the rate of progression of disability. As axonal damage and brain atrophy can occur early in MS and lead to increasing disability, MS specialists, including the Medical Advisory Board of the NMSS, advise that initiation of one of the DMAs be considered soon after the diagnosis of a relapsing form of MS.

Mechanism of Action
The mechanism of action of the interferons differs from glatiramer acetate. INF-? inhibits T-cell proliferation, reduces the production of pro-inflammatory cytokines, and decreases cellular adhesion, among other functions. The anti-inflammatory properties most likely contribute to the significant reduction in new brain MRI lesions in patients treated with these agents.

On the other hand, glatiramer acetate is believed to exert its effects by crossing the blood–brain barrier into the CNS and exerting a bystander suppression on inflammation, also reducing brain lesion load. It is also thought to alter the pro-inflammatory cascade of damaging cells to a neuroprotective environment within the CNS.

Table 2: Potential Side Effects of Disease-modifying Agents

Potential Side Effects
All of the available agents can produce unwanted side effects, as shown in Table 2.

Women with MS are generally advised not to become pregnant when taking a DMA.

The flu-like symptoms experienced with the interferons can be managed in most cases by pre- and postadministration of agents such as acetaminophen or a non-steroidal anti-inflammatory drug (NSAID). The incidence and severity of injection site reactions and pain can be reduced by use of an auto-injector device, briefly pre-treating the site with ice or a topical anesthetic, and rotating sites meticulously.

Adherence Issues with Injectable DMAS
Many patients have been using injectable DMAs for up to 12 years, but others precipitously discontinue medication for a variety of reasons. Obviously, mitoxantrone, as an infusible agent, does not encounter the same risk of non-adherence since it is usually administered at a healthcare facility. Issues that cause problems include disease symptoms such as tremor, which may make it increasingly challenging for patients to self-inject, or patients sometimes being wrongly told that the disease burns out over time and that therapy is no longer needed. In some cases, patients may face financial challenges to remaining on therapy. However, one of the most common impediments identified is unrealistic expectations. Patients often expect the relapses to stop altogether, or even that they will feel better, and so managing patient expectations is crucial. Frequent reminders of the goals of therapy are warranted.

Initial education about MS and its treatment continues to be crucial for newly diagnosed patients. It also becomes the foundation for adherence over the long term, with a sustained need for reinforcement.

The introduction of DMAs for the treatment of MS has expanded the horizons for people with MS and their families. When prescribing these drugs, it is essential to emphasize that although not a cure, they can reduce the frequency and severity of exacerbations and slow progression.As long-term adherence is an issue, clinicians must strive to develop an open, trusting therapeutic relationship with patients to forestall non-adherence and loss of benefit.

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