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Mark J. Tullman, MD
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A Review of Current and Emerging Therapeutic Strategies in Multiple Sclerosis
Mark J. Tullman, MD
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Improving Clinical and Economic Outcomes in Multiple Sclerosis

A Review of Current and Emerging Therapeutic Strategies in Multiple Sclerosis

Mark J. Tullman, MD
Multiple sclerosis (MS) is a chronic immune-mediated disease that potentially requires symptomatic and disease-modifying therapies. Numerous symptoms (eg, fatigue, spasticity, depression, bowel and bladder dysfunction, pain, and impaired mobility) are associated with the neurologic damage that results from MS. Several therapies (eg, modafinil, dalfampridine, baclofen, diazepam, gabapentin, opioids) are used for symptomatic treatment of disability and symptoms, but these do not improve disease outcome. Intravenous corticosteroids (with or without an oral corticosteroid taper) are used in the management of MS exacerbations, but do not appear to affect the degree of improvement from acute exacerbations. A more definitive therapy for MS should reduce relapse rate, prolong remission, limit the onset of new MS lesions, and postpone the development of long-term disability. The currently available MS disease-modifying therapies have been shown to reduce relapse rate, have beneficial effects on magnetic resonance imaging measures, and delay accumulation of disability. In addition, a number of agents are in development, but thus far no beneficial agent has been established in primary-progressive MS.

(Am J Manag Care. 2013;19:S21-S27)
Management of Acute Multiple Sclerosis Exacerbations

High-dose intravenous corticosteroids hasten recovery from, but do not appear to affect the degree of improvement from, acute multiple sclerosis (MS) exacerbations. A typical regimen consists of a 3- to 5-day course of 1000 mg of intravenous methylprednisolone with or without an oral prednisone taper. Because treatment does not appear to affect long-term outcome, not every MS exacerbation (eg, mild sensory symptoms) requires treatment. Based on the results of the Optic Neuritis Treatment Trial (ONTT), low-dose oral corticosteroids have no role as a treatment for MS exacerbations. In the ONTT, prednisone 1 mg/kg/day for 14 days had no effect on the rate of recovery from optic neuritis and was associated with an increased risk of subsequent optic neuritis.1,2 Corticosteroids are well tolerated by most MS patients. Side effects of short pulsed doses include insomnia, behavioral disturbances, elevated blood glucose, risk of infection, and aseptic necrosis of bone. Plasma exchange may be considered for the treatment of exacerbations that result in significant disability despite high-dose intravenous corticosteroid therapy.2

Symptomatic Therapies

Most patients with MS experience symptoms on a daily basis. Many of these symptoms can be disabling and socially distressing, and they often interfere with personal relationships and impact quality of life (QOL).3 Common symptoms include fatigue, spasticity, depression, bowel and bladder dysfunction, pain, weakness, impaired mobility, cognitive problems, and sexual dysfunction. Disease-modifying drugs (DMDs) have no effect on preexisting symptoms, so therapies to alleviate the daily symptoms of MS are an integral part of patient care. Successful treatment often requires a combination of pharmacotherapy with nonpharmacologic measures, such as rehabilitation, exercise, and/or lifestyle and environmental modifications.

There are many therapies available for the symptoms of MS; several are described below.1-3 Fatigue is one of the most common and disabling MS symptoms. Modafinil and amantadine are the most commonly used medications to treat MS-related fatigue.1,3 Walking impairment has been reported in up to approximately 60% to 85% of patients with MS. Dalfampridine (previously referred to as fampridine) is a broad-spectrum potassium channel blocker that enhances conduction across demyelinated axons and improves walking in some MS patients.4-7 Spasticity occurs in up to 75% of patients with MS. Treatment should begin with, or at least include, physical therapy and stretching exercises. Medication, which is often necessary for optimal management, commonly includes baclofen and tizanidine, alone or in combination.1,3 Other agents that may also be effective include onabotulinum toxin (especially for focal spasticity), diazepam, or gabapentin. Pain is reported in more than 80% of patients with MS at some point during the course of the disease and it is usually ameliorated with anticonvulsants and/or antidepressants. Opioids may be necessary for some patients.1,3 Cognitive impairment affects approximately 40% to 60% of patients. Attention concentration, short-term memory, information processing, verbal intelligence, and visuospatial skills are the domains most commonly affected.8 To date, there is no clearly effective treatment for MS-related cognitive impairment. Some patients may benefit from cognitive remediation and strategies to compensate for deficits. Donepezil improved memory in 1 small controlled trial in patients with MS and mild to moderate cognitive impairment. However, the results could not be duplicated in a larger multicenter study. DMDs that minimize lesion development, tissue destruction, or brain atrophy may limit cognitive decline.

Depression occurs in 50% to 75% of patients with MS; patients respond well to psychotherapy and antidepressants, either alone or in combination. Pseudobulbar affect, involuntary and uncontrollable episodes of laughing and/or crying, may respond to dextromethorphan with quinidine sulfate.1,3 Other MS symptoms that should be identified and treated as appropriate include bladder, bowel, and sexual dysfunction, paroxysmal symptoms, and tremor.9-12

Disease-Modifying Drugs

There are currently 9 DMDs approved by the US Food and Drug Administration (FDA) for MS. All of these agents reduce relapse rate and have a beneficial effect on a variety of magnetic resonance imaging (MRI) measures, and most have been shown to delay the accumulation of disability in short-term clinical trials. Current and some potential MS therapies for relapsing-remitting or relapsing forms of MS are described in the Table. The treatment of progressive forms of MS is challenging, with no proven therapy for the primary-progressive form of the disease, and discussion of this is beyond the scope of this article.13-15

The beta interferons and glatiramer acetate are considered first-line therapies for relapsing-remitting MS (RRMS). Studies have also shown these agents to be effective (and possibly even more so) when initiated at the time of a clinically isolated syndrome (CIS) in patients with at least several asymptomatic MRI brain lesions. Delaying treatment results in irreversible neurologic deficit. The interferons and glatiramer acetate clearly alter the short-term course of MS. Anecdotes, along with retrospective and prospective open-label studies, suggest a long-term treatment effect, but controlled studies are lacking.14-17

The therapeutic effects of interferon may be due to its anti-proliferative action, down-regulation of co-stimulatory molecules, or decrease of pro-inflammatory cytokines, or may occur through effects on matrix metalloproteinases and adhesion molecules, which reduce the permeability of the blood-brain barrier and limit trafficking of T lymphocytes into the central nervous system. The beneficial effects of glatiramer acetate, a synthetic polypeptide composed of the 4 amino acids L-alanine, L-glutamic acid, L-lysine, and L-tyrosine, may result from reactive Th2 cells that cross the blood-brain barrier and increase the secretion of suppressor-type cytokines and down-regulate inflammatory activity within the CNS, a process known as bystander suppression.14-17

Interferon beta-1a is administered at a dosage of 30 mcg intramuscularly once weekly or usually 44 mcg subcutaneously 3 times a week. The standard dose of interferon beta-1b is 250 mcg subcutaneously every other day. Glatiramer acetate is given as a daily 20-mg subcutaneous injection. Most evidence suggests an interferon dose/frequency effect; however, the results of a recent large double-blind study that compared a double dose of interferon beta-1b with the standard dose were disappointing and indicated a ceiling dose effect.18,19

In head-to-head studies, the clinical effectiveness of glatiramer acetate was similar to that of high-dose interferons (ie, interferon beta-1b 250 mcg administered subcutaneously every other day or interferon beta-1a 44 mcg administered subcutaneously 3 times weekly) in patients with RRMS.20-32 Effects on MRI measures of disease were inconsistent. In a recently completed randomized, double-blind, placebocontrolled, multicenter study, the combination of interferon beta-1a 30 mcg once weekly and glatiramer acetate was no better than either agent alone.

However, the annualized relapse rate was approximately 30% lower in patients who received glatiramer acetate monotherapy compared with patients who received interferon beta alone. There were no significant differences on any other clinical or MRI outcome measures between the glatiramer acetate– and interferon-treated groups.

The main interferon-related side effects include flu-like symptoms, injection site reactions, and laboratory abnormalities. Injection site reactions, which include local redness and swelling, are less common when interferon is given intramuscularly. Interferon is frequently given at night to limit flu-like symptoms during wakefulness, which may be worse in the first few weeks after starting treatment.20-25 Flu-like symptoms can often be managed with nonsteroidal anti-inflammatory medications or acetaminophen, and typically lessen after 2 to 3 months of therapy. However, the flu-like symptoms are occasionally severe enough to warrant discontinuation of treatment and commencement of an alternative therapy. Skin necrosis is a rare side effect associated with subcutaneously administered interferons. Thrombocytopenia, anemia, leukopenia, or an increase in liver enzymes may develop at any time during therapy. Reports of liver damage are rare. Thyroid dysfunction, which is usually subclinical, may also occur. Interferons may cause or worsen depression, and it is probably best to avoid their use in patients with a history of severe depression.20-25

Neutralizing antibodies (NAbs) develop in 15% to 25% of patients treated with subcutaneous interferon beta-1a (44 mcg 3 times a week), and in 25% to 40% of those treated with interferon beta-1b. Intramuscular interferon beta-1a (30 mcg) is clearly less immunogenic, with NAbs occurring in only 2% of patients. NAbs typically develop between 6 and 18 months after the initiation of treatment, and only rarely after more than 2 years of therapy. Although potentially transient, persistent high-titer NAbs (>100 NU/ml) are associated with a reduced therapeutic effect.22

The most common adverse effects related to glatiramer acetate include injection site reactions, which typically consist of itching, redness, or induration. Lipoatrophy occurs less frequently. A systemic reaction characterized by a combination of chest tightness, flushing, shortness of breath, palpitations, and anxiety occurs in a small percentage of patients within seconds to a few minutes after an injection. The reaction is self-limited, lasts for several minutes, resolves without sequelae, and rarely recurs.26-32

Mitoxantrone is an anthracendione with immunosuppressive and immunomodulatory properties that is effective in aggressive MS. However, it is no longer widely used because of safety concerns (mainly irreversible cardiotoxicity and treatment-associated leukemia) and the availability of newer agents (eg, natalizumab, fingolimod).33-43

 
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