Current and Emerging Treatment of Multiple Sclerosis

The treatment of multiple sclerosis (MS) falls into 3 categories: treatment of exacerbations, slowing disease progression with disease-modifying therapies (DMTs), and symptomatic therapies. The management of MS is becoming increasingly complex with the development of additional DMTs that, like the older DMTs, reduce the frequency and severity of relapses, and the accumulation of lesions detected by magnetic resonance imaging. Initiating treatment to slow or reverse inflammatory lesion formation early in the course of the disease is advocated as a way to prevent accumulation of disability. Nevertheless, there is a lack of comparative efficacy data and few clinical guidelines to aid healthcare providers in the optimal selection of DMTs. Given that some of the newer agents are associated with potentially serious, but rare, adverse events, careful consideration of the risk-benefit profile is necessary to minimize the risk to patients. This article provides an overview of the existing treatments for MS with an emphasis on DMTs and emerging therapies.

Am J Manag Care. 2016;22:S159-S170

over the course of the disease. Also, interventions exist to address acute and chronic symptoms, and modify the disease course. Depending on the clinical situation, different interventions may be prescribed. Comprehensive treatment encompasses 3 areas: relapse management, disease modification, and symptom management.

Relapse Management

One component of comprehensive MS treatment is the management of relapses, which are defined as spontaneous episodes of new or recurrent neurologic dysfunction; they must be differentiated from unrelated neurologic symptoms due to infection, fever, or other stresses (which are termed pseudo-relapses). By definition, true relapses usually last at least 24 hours (although the average total duration is approximately 3 months) and are associated with the emergence of new symptoms not previously experienced by the patient; however, in some cases, old symptoms may reemerge.² In contrast, pseudo-relapse symptoms, which may fluctuate in severity with a rise or drop in a person’s body temperature, or as a consequence of physical or emotional stress, are not considered to be relapses; instead, they are referred to as a pseudo-relapse or pseudo-exacerbation, unless the symptoms are more severe and of a greater duration than usual.² Determining whether a person is having a true relapse or a pseudo-relapse or pseudo-exacerbation can be challenging. Fatigue, overexertion, and exposure to heat and humidity can cause fluctuations or worsening of symptoms in the absence of a true relapse (Uhthoff’s phenomenon).² Treatment of acute relapses aims to: (1) speed functional recovery from the neurologic deficits

sustained as a result of inflammatory demyelination, (2) alleviate the severity of the attack, and (3) lessen or eliminate potentially persistent residual deficits.² The treatment of MS exacerbations with short-term courses of anti-inflammatory agents, such as high-dose intravenous or oral corticosteroids, represents an established practice among neurologists.^2,3 Although steroids do not affect the course of MS, over time, they have been shown to reduce symptoms, improve motor function, and shorten time to recovery from acute attacks.² Corticosteroids may be administered orally or parenterally,² and their effect on the immune system is presumed to be dependent on dose and duration. Although longterm use of low corticosteroid doses has been found to be effective and relatively safe, shorter courses of high-dose corticosteroids are generally preferred to treat acute exacerbations of inflammatory disorders. With regard to MS,

high-dose, short-term intravenous corticosteroids provide symptomatic relief, improve motor function, and shorten the recovery phase of acute disease-related attacks.² The Optic Neuritis Trial established the efficacy of intravenous corticosteroids for the management of MS relapses.⁴ In this trial, intravenous methylprednisolone 1g/day for 3 days, followed by oral prednisone for 11 days, accelerated the recovery of visual loss due to optic neuritis and resulted in slightly better vision at 6 months compared with placebo.

For pregnant women who experience relapses, intravenous immunoglobulin, which can be used safely during pregnancy,⁵ should be considered; however, relapses during pregnancy are very uncommon. Through an unknown mechanism, MS disease activity generally subsides during pregnancy and breast-feeding.

Infrequently, adrenocorticotropic hormone may be prescribed for individuals with poor venous access, those who prefer self-injection, or those who respond poorly to corticosteroids.⁵ Additionally, plasmapheresis should be reserved for patients who have not responded to corticosteroids and are still experiencing severe attacks.⁶

Disease-Modifying Therapies The mechanism of action of disease-modifying therapies (DMTs) is linked to the pathophysiology of MS, which is a central nervous system (CNS) disease that consists of damage to the myelin sheath and axonial destruction. The damage is associated with inflammation caused by a perivenular infiltrate consisting of T and B lymphocytes, macrophages, antibodies, and complement.⁷ Until

recently, it was largely thought that the autoimmune disease was primarily mediated by T cells; however, it is now understood that B cells within the immune system also play a pivotal role in MS disease pathology. It is this new understanding that has led to the advent of new DMTs targeting B-cell involvement within the disease.

DMTs are a component of the long-term management of patients with MS. The goal of disease modification is to reduce the early clinical and subclinical disease activity that is thought to contribute to long-term disability.⁸ Treatment is highly variable and differs based on disease severity, cost, adverse effect (AE) profiles, and patient and prescriber preference.

that efficacy, tolerability, and safety profiles vary greatly among agents. Newer DMTs are more efficacious than their counterparts, but many have uncommon, but serious potential AEs, and some carry significant risks that result in somewhat restricted distribution utilizing a Risk Evaluation and Mitigation Strategy (REMS) program, such as the TOUCH Prescribing Program associated with

natalizumab use.^9,10 In addition, some DMTs require frequent monitoring of a patient’s John Cunningham (JC) virus infection status, which has been associated with the development of progressive multifocal leukoencephalopathy (PML), a rare viral brain infection that is often severely disabling or fatal.

Because few head-to-head trials have been conducted with DMTs, there is a paucity of data on the comparative efficacy of these treatments. Likewise, few clinical guidelines exist to guide healthcare providers in the use of these agents. The most recent treatment guidelines come from a consensus paper released by the Multiple Sclerosis Coalition in March 2015, and clinical guidelines

from the Association of British Neurologists published in May 2015.^9,10 Thus, DMTs often are prescribed on a trialand-error and case-by-case basis, attempting to achieve a balance between efficacy, patient tolerability, and safety. For eligible patients, treatment should begin as early as possible after diagnosis and continue indefinitely. The initial and/or subsequent treatments may be modified

if the individual has a suboptimal treatment response, develops intolerable AEs, or does not adhere to the treatment regimen. All patients with MS should avoid live attenuated virus vaccinations, if possible, no matter which DMT they are on; pharmacists should review the National Multiple Sclerosis Society recommendations for more information on vaccinations.⁸ Table 1^11-25 identifies the DMTs approved by the FDA that have been found to slow or reverse inflammatory lesion formation in patients with MS.^11-25 In addition, oral dalfampridine (Amprya) is a potassium channel blocker that, while not a DMT, is indicated to improve walking in patients with MS (see symptomatic therapy in Ampyra prescribing information).²⁶ The generic (compounded) version, 4-aminopyridine, has also shown benefit in treating other MS symptoms, such as fatigue, poor coordination, and strength.

Self-Injected DMTs: Interferon Beta-1a, Interferon Beta-1b, Peginterferon Beta-1a, and Glatiramer Acetate

All of the approved DMTs for MS reduce the frequency and severity of relapses, and the accumulation of lesions detected by magnetic resonance imaging (MRI) in relapsing-remitting MS (RRMS). DMTs also appear to impede the accumulation of disability.⁸ Unfortunately, they have little, if any, demonstrated benefit in progressive forms of MS.⁹ Moreover, it is important to recognize

products vary based on dose and frequency of administration. IFN products that contain higher dosages, and are administered more frequently, are more effective; however, patients are more likely to develop antibodies that render the IFN less effective.^28,29 Betaseron, Extavia, and Rebif are considered high-potency IFNs, whereas Avonex is considered a low-potency IFN.

Two forms of GA have been approved by the FDA for RRMS. Copaxone is a synthetic form of myelin basic protein called copolymer 1; it is available in 2 dosage forms: 20 mg/mL daily or 40 mg/mL 3 times weekly.²¹ Glatopa is a generic version of the Copaxone 20-mg dose.²³ Evidence supporting the effectiveness of GA comes from 5 placebocontrolled trials; 4 used a 20-mg/mL daily dose, and 1 examined the 40-mg/mL 3 times weekly dose. Both GA doses had a beneficial effect on relapse rate, delaying the time to second exacerbation and reducing the number of new or enlarging MRI lesions compared with placebo. GA has few AEs, and does not require any monitoring of liver function. An immediate postinjection reaction exists that consists of various symptoms, including flushing, chest pain, palpitations, anxiety, dyspnea, constriction of the throat, and urticaria.^21,23 These symptoms are transient and self-limiting, not requiring any specific treatment. The more recent advent of the 40-mg/mL 3-times—weekly dose may improve tolerability and adherence because it requires less frequent administration.³⁰ Although none of the DMTs eliminate all risk of relapse, the IFNs and GA were studied in combination to evaluate whether there is an increased benefit. The 3-year, randomized CombiRx trial investigated whether the combined use of IFN beta-1a intramuscular once weekly and GA weekly was more efficacious than either agent alone in 1008 patients with RRMS.³¹ The primary end point was annualized relapse rate; secondary end points were disability progression and MRI outcomes. At 36 months, combination therapy was not superior to GA monotherapy, and GA monotherapy was significantly better than IFN monotherapy, reducing the risk of exacerbation by 31% (P = .027). The combination IFN and GA was significantly betterthan IFN alone, reducing the risk of exacerbation by 25% (P = .022). There were no significant differences with regard to disability progression between the combined treatment group and either agent alone. At 7 years, annualized relapse rates were similar to the 3-year data. The combination was not better at reducing disability than GA monotherapy.³²

Oral DMTs: Dimethyl Fumarate, Fingolimod, and Teriflunomide Dimethyl fumarate is a second-generation fumaric acid ester.²⁴ Although its exact mechanism of action in MS is not known, dimethyl fumarate and its metabolite, monomethyl fumarate, have been shown to activate the nuclear factor (erythroid-derived 2)-like 2 (Nrf2) pathway in vitro and in vivo in animals and humans. The Nrf2 pathway is associated with the cellular response to oxidative

stress. In 2 placebo-controlled trials that used doses of 240 mg twice daily or 3 times daily, dimethyl fumarate significantly reduced relapse rate (P <.0001) and the number of new or enlarging MRI lesions (P <.0001) in patients with RRMS. The relative risk reduction in the proportion of patients relapsing was 49% in the first study, and 44% in the second study for the 240-mg twice-daily dose

compared with with placebo. Safety issues with dimethyl fumarate include angioedema and anaphylaxis, lymphopenia, and the very rare PML.

Fingolimod, a sphingosine-1-phosphate (S1P) agonist, binds and activates S1P receptors.²² As a functional antagonist, fingolimod prevents lymphocytes from exiting lymph nodes, thereby reducing the number of lymphocytes in peripheral blood. This results in lymphopenia within hours of administration, reducing the number of naïve T cells and memory T cells available to enter the CNS, and mediates the MS disease process.³³ Fingolimod may also independently act on CNS sphingosine receptors with potential neuroprotective and remyelinating effects, although to what effect is unclear.³⁴ Fingolimod is the first DMT on the market where drugdrug interactions have become a concern. It is highly protein-bound, and utilizes the hepatic cytochrome P450 (CYP450) 4F2 enzyme as a primary route of metabolism. It is also a substrate of CYP2D6, CYP2E1, and CYP3A4, so medications that induce or inhibit CYP450 enzymes have the potential to substantially affect fingolimod

serum concentrations. Fingolimod causes bradycardia and can cause atrioventricular conduction block, so special consideration and additional monitoring should occur when used in combination with other drugs known to cause the same cardiac effects (eg, beta-blockers, diltiazem, verapamil, digoxin). Concurrent use with drugs that cause an increased risk of torsades de pointes via QT prolongation (eg, citalopram, chlorpromazine, haloperidol, methadone, erythromycin) should warrant extra caution, with continuous electrocardiogram (ECG) monitoring overnight after administration of the first dose of fingolimod. Additionally, the concomitant use of class Ia and class III antiarrhythmics is contraindicated with fingolimod therapy.²²

Treatment with fingolimod is associated with an increased risk for bradyarrhythmia and atrioventricular blocks during treatment initiation, elevated liver function tests, and an increased risk of infections, including herpes simplex, cryptococcal, and varicella zoster viral infections.²² Prior to initiating therapy with fingolimod, documentation of a confirmed history of chickenpox or a full course of vaccinations against varicella zoster virus by a healthcare professional is required. If this information is unavailable, patients should be tested for antibodies to varicella zoster virus, and an antibody-positive status is required to be eligible for treatment with fingolimod. When initiating treatment with fingolimod, patients should have hourly pulse and blood pressure measurements

for the first 6 hours after the first dose to monitor for bradycardia. They should also obtain an ECG prior to the first dose and at the end of the 6-hour monitoring period. First-dose monitoring should be repeated in anyone who has discontinued fingolimod for longer than 14 days. Individuals taking fingolimod should also be monitored for signs and symptoms associated with PML, along with periodic JC virus blood titers.

Fingolimod was compared in a head-to-head trial with intramuscular IFN beta-1a weekly and showed superior efficacy with respect to relapse rates and MRI outcomes.³⁴ The adjusted annualized relapse rate was 16% with fingolimod 0.5 mg, 20% with fingolimod 1.25 mg, and 33% with IFN beta-1a (P <.001). Fingolimod also was more effective than IFN beta-1a at reducing MRI lesion activity and loss of brain volume. Serious AEs that led to discontinuation of treatment occurred more frequently in patients receiving fingolimod 1.25 mg than in those receiving fingolimod 0.5 mg or IFN beta-1a.

imipramine, naproxen, duloxetine, cyclobenzaprine), and due to teriflunomide’s inhibition of CYP2C8, serum concentrations of pioglitazone would likely increase.²⁵ Teriflunomide was compared with placebo in 4 clinical trials in patients with RRMS. In the largest trial of 1185 patients, the annualized relapse rate was 39% with teriflunomide 7 mg, 32% with teriflunomide 14 mg, and 50% with placebo. The relative risk reduction in annualized relapse rate was 22% with teriflunomide 7 mg, and 36% with teriflunomide 14 mg, compared with placebo.

Teriflunomide undergoes extensive enterohepatic recirculation, which exposes the liver to high drug concentrations that may lead to hepatotoxicity.²⁵ Moreover, the extended 18-day half-life of teriflunomide may have clinical implications in cases of pregnancy or serious AEs, when rapid elimination of the drug is required.

Intravenous Agents: Alemtuzumab, Natalizumab, and Mitoxantrone The monoclonal antibodies alemtuzumab and natalizumab are the most effective DMTs currently available for the treatment of MS.⁸ However, both agents are associated with possible significant risks.^16,18 Alemtuzumab is a humanized monoclonal antibody that depletes immune cells.¹⁶ Although its exact mechanism of action in MS is unclear, it presumably binds to CD52 on several mature leukocyte subpopulations, resulting in rapid lysis of CD4 and CD8 T cells, B cells, natural killer cells, eosinophils, macrophages, and monocytes. Alemtuzumab is associated with possible AEs, including frequent development of secondary autoimmune thyroid diseases, autoimmune cytopenias, and increased risk of infection. It is recommended that patients receiving alemtuzumab be premedicated with high-dose corticosteroids, such as 1000 mg of methylprednisolone.

Alemtuzumab was compared in 2 head-to-head trials with IFN beta-1a 44 mcg 3 times weekly, and showed superior efficacy in both trials.¹⁶ In one trial, the annualized relapse rate was 52% for patients receiving IFN beta-1a and 26% for alemtuzumab. In a second trial, annualized relapse rates were 39% in the IFN beta-1a group and 18% in the alemtuzumab group. MRI outcomes were not significantly different.

Natalizumab, a recombinant humanized monoclonal antibody, is another monoclonal antibody approved for use in RRMS.¹⁸ In MS, lesions presumably develop when activated immune cells responsible for inflammation, including T-lymphocytes, cross the blood-brain barrier. Natalizumab prevents the transmigration of these immune cells across the blood-brain barrier by blocking the alpha-4 subunit of integrin molecules that are involved in the adhesion and migration of cells from the vasculature into inflamed tissues. Since natalizumab strictly blocks migration of these cells and does not deplete them, there is a risk of rebound disease activity once the drug is stopped. The primary safety concern associated with the use of natalizumab is the increased risk of PML, for which it carries a black box warning.

Natalizumab was evaluated in 2 placebo-controlled trials.¹⁸ One trial enrolled patients who had not received any IFN or GA for at least the previous 6 months; approximately 94% of patients were treatment-naïve to these agents. A second trial enrolled individuals who experienced 1 or more relapses while taking IFN beta-1a 30 mcg once weekly during the year prior to study entry; however, the efficacy of natalizumab monotherapy was not compared with the efficacy of natalizumab plus IFN beta-1a. Natalizumab reduced relapse rates and progression to disability and improved MRI outcomes in both trials. The annualized relapse rate was 22% with natalizumab monotherapy and 67% with placebo. In the second trial, the annualized relapse rate was 33% with natalizumab plus IFN beta-1a, and 75% with placebo plus IFN beta-1a.

treatment with mitoxantrone is associated with dosedependent cardiomyopathy and acute leukemia, and use of this agent has fallen out of favor.³⁵

Mitoxantrone is a synthetic antineoplastic anthracenedione that targets immune cell replication.³⁵ As an inhibitor of topoisomerase II-Hsp90 (heat shock protein 90) complex, mitoxantrone onselectively affects all proliferating cells, inhibiting B cells more than T cells. It is used as an antineoplastic agent in the treatment of metastatic breast cancer, acute myeloid leukemia, and non-Hodgkin lymphoma. Mitoxantrone is approved for use in secondary-progressive (chronic), progressive-relapsing, or worsening RRMS.¹⁷ However, postmarketing surveillance has shown that longterm

Off-Label Medications

Rituximab is a chimeric CD20-directed cytolytic monoclonal antibody indicated for non-Hodgkin lymphoma, chronic lymphocytic leukemia, rheumatoid arthritis, and granulomatosis with polyangiitis.³⁶ In patients with RRMS, rituximab reduced relapse rates and inflammatory MRI lesions compared with placebo, but its effect on disability progression was marginal. Most AEs are infusion-or infection-related reactions.^37,38 Severe infections have been observed in patients receiving rituximab, and a few rituximab-treated patients with hematologic malignancies or autoimmune disease have developed PML.³⁶ A phase 2/3 study of rituximab in primary-progressive MS (PPMS) and a phase 2 study in RRMS have been completed, but results have yet to be reported.^39,40 Azathioprine, a generic immunosuppressant, has been used off-label to treat all types of MS for decades, but with marginal efficacy. With the introduction of IFN beta, use of azathioprine declined. Azathioprine was associated with a 23% relative risk reduction in the frequency of relapses over 2 years, but its effect on disability progression was not demonstrated.^3,41 AEs include gastrointestinal symptoms, photosensitivity, menstrual irregularity, and reduced fertility. Safety issues include myelotoxicity, hepatotoxicity, lymphopenia, infections, acute pancreatitis, increased toxicity in patients with thiopurine methyltransferase deficiency, and malignancies with cumulative doses above 600 g.⁹

Teriflunomide, a pyrimidine synthesis inhibitor, targets DNA immune cell replication by inhibiting mitochondrial dihydroorotate dehydrogenase, an enzyme involved in de novo synthesis of pyrimidine nucleotides in proliferating cells.³⁵ Although the exact mechanism by which teriflunomide exerts its therapeutic effect is not known, it is presumed to involve a reduction in the number of activated lymphocytes in the CNS.²⁵ Teriflunomide is another DMT that has introduced the possibility of drug-drug interactions. It is a breast cancer resistance protein (BCRP) substrate that is hydrolyzed to minor metabolites and is highly protein-bound. It is also an inducer of CYP1A2 and an inhibitor of BCRP, CYP2C8, and organic anion-transporting polypeptide (OATP) 1B1. Teriflunomide’s ability to induce CYP1A2 causes clinically significant drug-drug interactions with several other medications (eg, warfarin, clozapine, olanzapine, tizanidine, fluvoxamine, haloperidol, Cyclophosphamide has been used for progressive forms of MS; however, it is used less often because of its severe toxicity.^9,42 Results from a meta-analysis showed that cyclophosphamide has no significant effect on disability progression at 12, 18, and 24 months.⁴³ AEs include nausea, vomiting, amenorrhea, infertility, and alopecia. Safety concerns include myelotoxicity, hepatotoxicity, infections, hemorrhagic cystitis, and bladder cancer.⁹ Methotrexate has been evaluated in patients with progressive types of MS, and intravenous immunoglobulins have been used for all types of MS.⁴² However, the evidence supporting the use of these agents is of poor quality, and neither agent has been shown to prevent disability progression. Both methotrexate and intravenous immunoglobulins are associated with severe toxicity.

Emerging Treatments for MS

Ocrelizumab Ocrelizumab is a humanized anti-CD20 monoclonal antibody in phase 3 clinical development for both RRMS and progressive forms of MS.⁴⁴ Ocrelizumab selectively targets CD20-positive B cells, key contributors to myelin and axonal damage. Its effect in MS has been attributed to loss of B-cell-mediated cellular immunity.³⁶ In 2 phase 3, randomized, double-blind, global multicenter trials in 1656 patients with RRMS, OPERA I and OPERA II, ocrelizumab (600 mg intravenously every 6 months) significantly reduced the annualized relapse rate by almost 50% over a 2-year period compared with IFN beta 1-a 44 mcg 3 times weekly.⁴⁴ Progression of clinical disability also was delayed. Ocrelizumab was associated

with a significant reduction in the number of MRI detected lesions compared with IFN beta-1a (P <.0001).

Overall incidence of AEs was 83.3% in both groups⁴⁴; however, serious AEs occurred in 6.9% of patients given ocrelizumab and 8.7% of patients given IFN beta-1a. Infusion-related reactions were the most common AEs in patients treated with ocrelizumab; 34.3% of patients receiving ocrelizumab had at least 1 infusion-related reaction.

In the ORATORIO study in patients with PPMS,compared with placebo, ocrelizumab (600 mg intravenously every 6 months given as two 300-mg doses 2 weeks apart) significantly reduced the risk of progression of clinical disability for at least 12 weeks by 24% (P = .0321) and for at least 24 weeks by 25% (P = .0365).⁴⁴ Overall incidence of AEs was 95% in the ocrelizumab group and 90%

in the placebo group. Serious AEs developed in 20.4% of patients given ocrelizumab and 22.2% of patients given placebo. Infusion-related reactions developed in 39.9% of patients in the ocrelizumab group compared with 25.5% in the placebo group.

Daclizumab

Daclizumab is a humanized non-depleting immunoglobulin G1 monoclonal antibody directed against the CD25 receptor expressed on active T cells.³⁶ It targets immune cell function by preventing formation of highaffinity interleukin-2 receptors, but does not prevent proliferation of T cells. Daclizumab has been associated with expansion and activation of regulatory CD56^bright natural killer cells, which potentially go on to kill activated autologous T cells. In a randomized, double-blind, active-controlled study in RRMS, subcutaneous daclizumab high-yield process 150 mg once every 4 weeks

demonstrated superior efficacy compared with intramuscular IFN beta-1a 30 mcg once weekly.⁴⁵ Daclizumab was associated with a 45% reduction in the annualized relapse rate (P <.001) and a 41% reduction in the proportion of patients who relapsed. The number of new or enlarging MRI lesions also was significantly reduced. AEs, including infections, cutaneous events, and hepatic events, were more frequent in the daclizumab group.

Laquinimod Laquinimod is an oral quinolone-3-carboxamide derived from linomide.⁴⁶ Although its exact mechanism of action is not clear, it is presumed to reduce leukocyte migration into the CNS by downregulation of verylate-antigen-4—mediated adhesiveness. Laquinimod is in clinical development for RRMS and PPMS. However, in January 2016, the trial sponsors announced that 2 ongoing

studies in MS involving higher doses of laquinimod were being discontinued due to cardiovascular events.⁴⁶ Seven cardiovascular events developed in patients with RRMS who received laquinimod 1.2 mg daily; no events occurred in the 0.6-mg or placebo groups, and 1 event was observed in a patient with PPMS who received laquinimod 1.5 mg daily. Both trials will continue using the lower laquinimod dose (0.6 mg daily).

Masitinib

Masitinib, a selective tyrosine kinase inhibitor, was found to control the survival, migration, and degranulation of mast cells through the inhibition of certain growth and activation signaling pathways.⁴⁷ Masitinib is currently being investigated in progressive forms of MS in a phase 3, double-blind, randomized, placebocontrolled study.

Autologous Hematopoietic Stem Cell Transplantation

In a multicenter, phase 2 trial in patients with secondary-progressive MS or RRMS, autologous stem cell transplantation reduced annualized relapse rate and decreased the number of new MRI lesions by 79% compared with mitoxantrone (P = .00016).⁴⁸ However, there was no difference in the progression of disability.

Symptom Management

An additional component of the comprehensive treatment of patients with MS is management of MS-related symptoms. MS is associated with a wide range of symptoms that can affect an individual’s ability to carry out routine activities of daily living, and the symptoms are classified as primary, secondary, or tertiary. Primary symptoms are those that are a direct consequence of the

nerve damage caused by the disease, such as spasticity, paresthesia, and optic neuritis. Common primary symptoms include¹:

• Fatigue
• Mood changes
• Cognitive impairment
• Visual difficulties, such as diplopia or blurred vision
• Motor deficits such as impaired balance and coordination, muscle weakness, spasticity, and gait dysfunction
• Sensory deficits such as numbness, pain, paresthesia, and heat intolerance
• Bowel and bladder dysfunction

Secondary symptoms arise from complications of primary symptoms, such as recurrent urinary tract infections caused by bladder dysfunction. Tertiary symptoms include social, vocational, and psychological complications that manifest as individuals with MS acquire disability (ie, they no longer have the ability to walk without assistance due to the effects of MS).

Symptom management aims to ameliorate or eliminate symptoms that affect a patient’s ability to participate in and perform daily activities, and reduce quality of life.⁴⁹ Ongoing management of symptoms is a key to preventing secondary impairment or disability, such as contractures due to severe spasticity or urinary tract infections that develop as a consequence of impaired bladder function.

alter the treatment approach.⁴⁹ Ongoing management of MS symptoms involves both nonpharmacologic and pharmacologic interventions.^1,49 Physical and occupational therapy may be recommended to ameliorate pain and spasticity, to reduce fatigue, and improve overall health and physical strength.⁴⁹ Mobility aids, such as canes, braces, and walkers, may enable patients to remain mobile and independent.¹

Symptomatic management is based on the individual needs of the person with MS and begins with the identification of issues and symptoms that are affecting the patients functionally, emotionally, socially, and vocationally.¹ Proper classification of symptoms is essential, as certain MS-related symptoms, such as pain, can arise from different presumed pathogenic mechanisms and Pharmacologic treatment can be beneficial for some MS-related symptoms.¹ However, many prescription medications and interventions used for symptomatic management of MS remain off label. In addition, because few of these agents have been investigated in formal clinical trials in patients with MS, high-quality evidence of their efficacy in this population is lacking.⁴⁹ Pemoline and amantadine may reduce fatigue in some people with MS.¹ Table 2^1,49 provides a list of medications commonly used for MS-related symptoms.^1,49

Numerous other symptomatic treatments may also be utilized based on studies and the personal experience of prescribers and patients.

nonadherence can be significant, considering that the average cost per relapse for patients requiring the most care is estimated at $13,000.⁵¹ Patients who adhere to a DMT regimen use fewer medical resources and have lower disease-related medical costs.⁵⁰ In 1 analysis, people with MS who had higher rates of adherence also had 39% fewer emergency department visits and saved 31% annually on medical expenses than those with lower adherence.⁵² Despite the benefits of therapy, adherence to DMTs is often suboptimal, ranging from 41% to 88%, depending on the study and the definition of adherence.⁵¹ There are many barriers to adherence, including⁵³:

• AEs
• Needle phobia and burdensome injection processes
• Real or perceived lack of treatment efficacy
• Limited understanding of the benefits of treatment
• Out-of-pocket treatment costs
• MS-associated comorbidity

Although there is no cure for multiple sclerosis (MS), appropriate management strategies can slow disease progression, improve symptoms, and help maintain quality of life. MS is a complex and unpredictable disease with similarly complex management that calls for a coordinated, multidisciplinary approach to care.¹ Comprehensive care requires a team of professionals with experience in treating MS, including consulting neurologists, MS nurses, MS pharmacists, physical and occupational therapists, speech-language pathologists, psychologists/neuro-psychologists, dieticians, other medical subspecialists (eg, urologists), and social workers. Treatment of MS is an ongoing process that begins with the management of the first symptoms and subsequent relapses, and it continues The interferons (IFNs) and glatiramer acetate (GA) were the first-approved DMTs for MS.²⁷ For both IFN and GA, the reduction in relapse frequency and severity is about 30%; however, this may be slightly lower in patients treated with low-potency IFNs.¹ To date, 5 forms of IFN beta (Avonex, Betaseron [or Extavia], Rebif, and Plegridy) have been approved by the FDA for RRMS.^11-15 IFN beta has been shown to reduce the number of exacerbations and may slow the progression of physical disability. The mechanism behind the efficacy of IFNs in MS is poorly understood; however, it is believed that the efficacy is mediated by the immunomodulating properties of IFNs.³ The safety of IFNs has been established over 2 decades of use; most AEs are minor or benign. These include flu-like symptoms for up to 24 hours post injection, reversible decreases in white blood cell count, and elevated liver enzymes. IFNs are also associated with rare allergic reactions such as anaphylaxis, seizures, and a decrease in peripheral blood counts. Because of the risk of uncommon hepatic injury, periodic liver function testing is required during treatment. The efficacy and AE profiles of IFNImpact of Adherence on the Management of MS Even with effective treatment options, adherence to therapy is necessary for optimal disease management. Because early and successful control of disease activity is one factor in preventing accumulation of disability, poorer outcomes, including higher rates of relapse and disease progression, are more likely in those who do not adhere to treatment regimens.8,50 Costs associated with Current treatments require regular administration; however, memory or cognitive dysfunction may limit an individual’s ability to follow the prescribed regimen.⁵³ Similarly, cognitive impairment may impede a person’s ability to recall proper injection technique.

as safer, more efficacious DMTs become available. The results of the first study comparing the probability of increased disease activity in patients with stable MS after switching self-injected DMTs showed no evidence of increased relapse rate within the first 6 months.^54-56 Out-of-pocket treatment costs clearly impact adherence. People with MS who have high out-of-pocket costs more often forgo treatment or end treatment prematurely than others who have lower out-of-pocket expenses.⁵⁷ The issue of cost becomes a never-ending circle for people with MS who may have inadequate access to healthcare, with cost becoming a major reason for nonadherence, and nonadherence resulting in increased relapses and rising treatment costs.

Conclusion

Effective management of patients with MS involves addressing symptoms, treating acute exacerbations, and reducing long-term disability through disease modification. Current DMTs for MS include self-injected, oral, and intravenous agents, all of which reduce the frequency and severity of relapse and MRI lesion accumulation to varying degrees in RRMS, but with different safety profiles. Treatment of the person with MS should begin as soon as possible after diagnosis and continue indefinitely unless there is a suboptimal treatment response or the individual develops intolerable side effects or fails to adhere to the treatment regimen. Decreased adherence is associated with poorer outcomes including higher rates of relapse and disease progression.

Author affiliation: Department of Clinical Pharmacy, Skaggs School of Pharmacy and Pharmaceutical Sciences and Department of Neurology, School of Medicine, Anschutz Medical Campus, University of Colorado, Aurora, CO (JB); Department of Clinical Pharmacy, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado, Aurora, CO (FMH).

Funding source: This activity is supported by educational grants from Novartis Pharmaceuticals Corporation and Genzyme, a Sanofi Company.

Author disclosure: Dr Bainbridge and Dr Hart have no relevant financial relationships with commercial interests to disclose.

Authorship information: Analysis and interpretation of data (JB); drafting of the manuscript (JB, FMH); critical revision of the manuscript for important intellectual content (JB, FMH); and supervision (FMH).

Address correspondence to: Jacci.Bainbridge@ucdenver.edu.

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24. Tecfidera (dimethyl fumarate) [prescribing infromation]. Cambridge, MA: Biogen Idec, Inc; 2015.

25. Aubagio (teriflunomide) [prescribing information]. Cambridge, MA: Genzyme Corporation; 2014.

26. Ampyra (dalfampridine) [prescribing information]. Ardsley, NY: Acorda Therapeutics, Inc; 2014.

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55. Changing therapy in relapsing multiple sclerosis: considerations and recommendations of a task force of the National Multiple Sclerosis Society. National Multiple Sclerosis Society website. www.nationalmssociety.org/NationalMSSociety/media/MSNationalFiles/Brochures/Clinical_Bulletin_Changing-Therapyin-Relapsing-MS.pdf. Published 2004. Accessed May 10, 2016.

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57. Palmer L, Abouzaid S, Shi N, et al. Impact of patient cost sharing on multiple sclerosis treatment. Am J Pharm Benefits.2012;4(special issue):SP28-SP36.

Common reasons why patients with MS discontinue therapy are: a real or perceived lack of efficacy, AEs, and cost.⁵³ Given the variable disease process in MS, when the effects of treatment are not readily apparent, individuals may not understand or discern the true benefit they are receiving from treatment. AEs also affect treatment adherence, as the incidence of AEs is often highest when initiating a DMT and decreases as treatment continues. If patients are able to persist with treatment, long-term adherence is more likely. Conversely, patients who are unable to tolerate therapy due to persistent AEs, significant laboratory abnormalities, detection of antibodies, or unacceptable disease activity (increased clinical activity and/or MRI activity) should be able to switch therapies