Functional Improvement and Symptom Management in Multiple Sclerosis: Clinical Efficacy of Current Therapies

Abstract

Disease-modifying treatments (DMTs), which are the foundation of multiple sclerosis (MS) care, reduce clinical exacerbations (relapses) and slow disease progression; however, improving quality of life (QOL) is an unmet need for many individuals with MS. DMTs, including interferon-beta, glatiramer acetate, natalizumab, mitoxantrone, and fingolimod, reduce the rate and severity of relapses, the accumulation of brain and spinal cord lesions as shown on magnetic resonance imaging (MRI), and disability progression. Many studies link diminished QOL with specific MS symptoms (fatigue, impaired mobility, spasticity, etc). Even in patients already receiving DMTs, symptoms and QOL may improve with additional agents that treat specific symptoms, thereby improving patient function and ability to perform activities of daily living (ADLs). Patients have reported that mobility impairment is one of the worst aspects of MS. Almost half of patients treated with DMTs reported no improvement in mobility. However, blocking the voltage-dependent potassium channels on the surface of demyelinated nerve fibers may improve signal conduction. Dalfampridine, a potassium channel blocker, received Food and Drug Administration (FDA) approval for all forms of MS specifically to improve walking, which was demonstrated by increased walking speed. By improving walking in some patients with MS, the effects of dalfampridine may complement those of DMTs and address the stated priorities of many patients.

(Am J Manag Care. 2011;17:S146-S153)

MS Treatment and QOL

Improving quality of life (QOL) is an unmet need for many individuals with multiple sclerosis (MS). Disease-modifying treatments (DMTs), which are the foundation of MS care,¹ reduce clinical exacerbations (relapses) and slow disease progression.² QOL improvement, although assumed with fewer relapses, has not always been well documented.

Treatment individualization can include additional agents that treat specific symptoms, improving patient function and ability to perform activities of daily living (ADLs).³ Because many symptom-specific treatments are available, MS treatment should address QOL at every stage of disease progression.

Actions and Safety of DMTs

DMTs reduce the rate and severity of relapses, the accumulation of brain and spinal cord lesions as shown on magnetic resonance imaging (MRI), and disability progression as measured by Expanded Disability Status Scale (EDSS).² Controlled clinical trials demonstrated relapse rate reductions of 28% to 68%.² However, relatively few DMT trials documented QOL improvement with QOL metrics. The National Multiple Sclerosis Society (NMSS) stated that DMTs “can be looked upon as an investment in the future,” rather than treatment that makes patients feel better now.² Thus, clinicians may appreciate the effects of DMTs while some patients on DMT therapy continue to suffer treatable symptoms, poor QOL, and sometimes, adverse effects (AEs).

Interferon-beta (IFNB) is a cytokine primarily secreted by fibroblasts as part of immune response⁴; recombinant DNA technology produces therapeutic IFNB agents.⁵ In MS, the IFNB mechanism seems to involve immunomodulatory effects mediated through interactions with specific cell-surface receptors.⁴ Whereas IFNB-1b is injected subcutaneously every other day, IFNB-1a is available in forms for intramuscular (weekly) and subcutaneous (3 times/week) injection.² Four IFNB agents have received Food and Drug Administration (FDA) approval for relapsing forms of MS: interferon beta-1b (Betaseron) in 1993, interferon beta-1a (Avonex) in 1996, interferon beta-1a (Rebif) in 2002, and interferon beta-1b (Extavia) in 2009.² Numerous randomized multicenter trials have demonstrated reduced rate and severity of relapses, delayed EDSS progression, and fewer MRI lesions with IFNB.^4,5,6 Some patients develop neutralizing antibodies, potentially lessening efficacy over time.^2,5

The evidence for IFNB using QOL metrics is mixed. An early IFNB study incorporating several QOL domains and patient preferences demonstrated similar QOL between patients and controls.⁷ In another early study, patients with EDSS less than 3.0 were given IFNB-1b and had higher SF-36 QOL than historical controls in role-physical, general health, physical function, and social function domains.⁸ However, differences between groups with higher EDSS disability were not significant.⁸ In the IMPACT study of secondary progressive MS (SPMS), 8 of 11 subscales on the MS QOL Inventory improved with IFNB-1a.⁹ Another IFNB-1a trial found no significant changes in SF-36 scores except for a decrease in physical function (P = .03).¹⁰ Two-year studies have shown both significant increases¹¹ and decreases¹² in MSQOL-54 scores. Interferon adverse events (AEs) include flu-like symptoms, injection site reactions, depression, allergic reactions, liver abnormalities, anemia, and neutropenia.²

Glatiramer acetate (GA) is a synthetic analog of myelin basic protein, the MS-associated antigen.¹³ GA is thought to act by inducing a shift in cytokine production toward secretion of anti-inflammatory cytokines.¹³ GA, which received FDA approval for relapsing-remitting MS (RRMS) in 1996,² is injected subcutaneously every day.² Randomized, double-blind, multicenter GA trials have shown significant reductions in relapse rate and number of lesions on MRI, with relapse rate reduction sustained to 15 years (open-label extension).¹³ In open-label multicenter trials, GA showed similar efficacy to subcutaneous IFNB-1a and IFNB-1b in time to first relapse, risk of relapse, and number of active lesions.¹³

Regarding QOL, in a recent multicenter prospective observational study, patients with and without previous immunomodulatory treatment received GA.¹⁴ At 12 months, Leeds MS QOL and Fatigue Impact Scale scores improved significantly (P <.001 and P <.01, respectively) in treatment-naïve but not pre-treated patients.¹⁴ Beck Depression Inventory scores did not change in either group.¹⁴ AEs of GA include injection site reactions, chest pain, and a combined reaction of chest pain, palpitations, shortness of breath, anxiety, and flushing.²

Natalizumab, a monoclonal antibody, blocks lymphocyte entry into the central nervous system.¹⁵ Natalizumab received FDA approval for relapsing forms of MS in 2004.² The Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology (AAN) reviewed 6 natalizumab studies with Class 1 evidence and found significant benefits in reduced disease activity and severity on clinical and MRI measures.¹⁶ In the double-blind, multicenter AFFIRM trial, natalizumab reduced the relapse rate by 68%, the risk of sustained EDSS progression by 42%, and new or enlarging brain lesions by 83%.¹⁷ In the similarly designed SENTINEL trial, adding natalizumab to IFNB-1a further reduced relapse rate and disability progression compared with IFNB-1a alone.¹⁸ In 2113 AFFIRM and SENTINEL patients, those given natalizumab were more likely to experience clinically important improvement on SF-36 Physical Component Summary and Mental Component Summary.¹⁹ Natalizumab was associated with improved scores on the MSQOL-54 (German version),²⁰ Multiple Sclerosis Impact Scale-29,²¹ and a QOL visual analog scale.²²

In 2005, the manufacturer of natalizumab voluntarily suspended marketing following reports of progressive multifocal leukoencephalopathy (PML).²³ The FDA reapproved natalizumab in 2006, but with restricted distribution; administration is by intravenous infusion every 4 weeks at a registered center with close monitoring for PML.^2,23,24 In the postmarketing setting, the estimated incidence of PML is 0.3 per 1000 patients who received up to 24 infusions, 1.5 per 1000 patients who received 25 to 36 infusions, and 0.9 per 1000 patients who received 37 to 48 infusions.²⁴ Other AEs include headache, fatigue, urinary tract infections (UTIs), depression, lower respiratory tract infections, joint pain, chest discomfort, hypersensitivity reactions, and liver abnormalities.²

Mitoxantrone, an immunosuppressant, reduces lymphocyte proliferation via several mechanisms.²⁵ In 2000 the FDA approved this chemotherapeutic agent for use in RRMS, SPMS, and progressive relapsing MS (PRMS).^2,25 Mitoxantrone is administered by infusion 4 times per year.² Three randomized trials produced Class II and III evidence that mitoxantrone reduces relapse rate, EDSS progression, and MRI lesions.^25,26 In the 2-year, double-blind, multicenter MIMS trial, a significant treatment effect was found for the primary outcome (P <.0001 versus placebo), which combined measures of relapse and disability, and all 5 component measures.²⁷ In patients with annual brain MRI, significantly fewer treated with mitoxantrone had enhancing lesions at 24 months (0% versus 15%, P = .02).²⁷ A more recent trial showed decreased lesions with mitoxantrone, but no discernible effect on EDSS progression or relapses.²⁵ In the MIMS study, mean QOL index scores on the Stanford health assessment increased significantly with mitoxantrone (P = .024 versus placebo); differences in Zung self-rated depression scores were not significant.²⁷

A boxed warning was added to mitoxantrone prescribing information in 2005 because of postmarketing reports of decreased systolic function, heart failure, and treatment-related acute leukemia.²⁵ Comprehensive postmarketing data are lacking, but the AAN therapeutics subcommittee concluded that mitoxantrone treatment resulted in systolic dysfunction in 12% of treated patients, heart failure in 0.4%, and leukemia in 0.8%, and noted that 2002 MIMS efficacy results have not been reproduced.²⁵ Other AEs include urine discoloration, infections, bone marrow suppression, nausea, hair loss, bladder infections, and mouth sores.² Monitoring for liver and cardiac damage is necessary.² Mitoxantrone has a lifetime cumulative limit of 8 to 12 doses over 2 to 3 years.²

Fingolimod, a fungus-derived immunomodulator originally used in organ transplantation,²⁸ was approved by the FDA for relapsing forms of MS in 2010.² Fingolimod is an oral DMT taken once daily.² In multicenter clinical trials (FREEDOMS and TRANSFORMS) fingolimod reduced the relapse rate and the number of new or enlarging lesions on MRI; comparisons were significant versus placebo and IFNB-1a.^29,30 Data with QOL metrics are lacking. An oral DMT would have apparent QOL advantages over injected therapies, especially for newly diagnosed patients who could benefit from early intervention to delay progression. If it were proved safe and effective over very long terms, it might prevent the need for injected therapies in some patients. However, because of safety concerns, fingolimod may not turn out to be the oral therapy that replaces injected agents. In clinical trials, AEs included infections (2 fatal), bradycardia and atrioventricular block, hypertension, macular edema, and elevation of liver enzymes.^29,30 FDA approval included a Risk Evaluation and Mitigation Strategy with written guides for providers and patients; a 5-year postmarketing safety study is under way.³¹ Other AEs include headache, flu-like symptoms, diarrhea, back pain, and cough.²

Corticosteroids in MS

Corticosteroids have anti-inflammatory effects that reduce severity and duration of acute relapses, but do not affect the disease course.^23,32 They have been shown to speed relapse recovery in several trials,³³ and the AAN and NMSS recommend them for relapse treatment.^33,34 Corticosteroids can be used safely in patients receiving DMTs, but long-term daily use is not recommended.³³ An MRI is suggested in any patient experiencing a relapse on natalizumab before initiating corticosteroids, to exclude the possibility of PML.³³ Corticosteroid treatment commonly begins with intravenous methylprednisolone, followed by tapering oral prednisone; high-dose oral steroids have also been used.³³ QOL scores on MSQOL-54 and MS Functional Composite have improved with methylprednisolone treatment of relapses.³⁵

Corticosteroid AEs include stomach irritation, elevated blood glucose, water retention, restlessness, insomnia, and mood swings.³² The NMSS recommends close monitoring for patients taking warfarin or with comorbid hypertension, diabetes, peptic ulcer, or psychiatric disorders.³³

Supportive Drug Therapies

Many studies link diminished QOL with specific MS symptoms (fatigue, impaired mobility, spasticity, etc).³⁶ Even in patients already receiving DMTs, symptoms and QOL may improve with symptom-specific medications (Table), most of which are oral.

Fatigue can improve with various drugs including amantadine, methylphenidate, and modafinil.³⁷ Evidence has demonstrated amantadine produces significant reductions in fatigue in 20% to 40% of patients with mild to moderate disability.³⁷ AEs of amantadine include nausea, constipation, insomnia, and peripheral edema;³ of modafinil: insomnia, restlessness, headache, appetite suppression, and rarely, dyskinesia;³ of methylphenidate: dizziness, drowsiness, dyskinesia, nervousness, insomnia, hypersensitivity reactions, anorexia, and cardiovascular effects.³⁸

Spasticity is usually addressed with oral baclofen or tizanidine, which have demonstrated efficacy.³ Intrathecal (pump) baclofen is sometimes used when oral medications fail.³ AEs of baclofen include light-headedness and drowsiness; of tizanidine: sedation, hypotension, weakness, constipation, and rarely, hallucinations.³ In March 2010 the FDA approved onabotulinumtoxinA (Botox) for upper-limb spasticity in disorders including MS.³⁹ Botox had been used off-label for MS-related spasticity for years, but the approval followed 3 double-blind, placebo-controlled studies in which targeted intramuscular injections improved upper-limb spasticity after stroke.³⁹ AEs include difficulty swallowing, speaking, or breathing; spread beyond the injection site; fatigue and muscle weakness (particular concerns in MS); arm pain; nausea; and bronchitis.³⁹ Treatment should include close monitoring. Botox is generally considered second-line therapy for spasticity if oral agents fail.³⁹

Cognitive Dysfunction: Some clinicians prescribe cholinesterase inhibitors (eg, donepezil, galantamine, rivastigmine) for cognitive decline in MS, although evidence is sparse and mixed.⁴⁰ The NMSS emphasizes nonpharmacologic therapies for cognitive decline and notes that treating fatigue and depression can sometimes be associated with cognitive improvements.⁴⁰

Pseudobulbar Affect (PBA) (uncontrollable laughing or crying) is associated with brain atrophy and increased lesion load⁴¹ and may eventually develop in up to 10% of MS patients.⁴² In October 2010, the FDA approved dextromethorphan hydrobromide with quinidine sulfate (Nuedexta) for PBA in MS and other disorders.⁴² In clinical trials, this oral agent reduced the rate of PBA episodes by up to 49%.⁴² AEs include heart rhythm changes, influenza, gastrointestinal symptoms, cough, peripheral edema, elevated liver enzymes, UTI, dizziness, and weakness.⁴² Treatment should include close monitoring and additional measures to prevent falls.

Depression complicates MS because it diminishes QOL and may hinder adherence to medications, lifestyle recommendations, and medical and rehabilitation appointments. Selective serotonin reuptake inhibitors, tricyclic antidepressants, and other drugs are used in depressed patients with MS.³ Close monitoring is necessary because of safety concerns.⁴³

Pain in MS is addressed with various treatments, depending on its acute or chronic nature, origin, and other factors.³ Treatments may include anticonvulsants, antispasmatics, nonsteroidal anti-inflammatory drugs, opioids, nerve blocks, and antidepressants,³ each with its own safety profile and limitations on use with other medications and in specific populations.

Gait Impairment: The Role of Dalfampridine

Patients have reported that mobility impairment is one of the worst aspects of MS.⁴⁴ Almost half of patients treated with DMTs reported no improvement in mobility.³⁶ However, blocking the voltage-dependent potassium channels on the surface of demyelinated nerve fibers may improve signal conduction.⁴⁴ Ampyra (dalfampridine extended release tablets, hereafter “dalfampridine”), a potassium channel blocker, received FDA approval for all forms of MS specifically to improve walking, which was demonstrated by increased walking speed.⁴⁵ By improving walking in some patients with MS,^46,47 the effects of dalfampridine may complement those of DMTs and address the stated priorities of many patients.³⁶ Dalfampridine does not address disease modification, but can be used with DMTs and other medications; no drug interactions have been found.^45,46

The active ingredient in dalfampridine is 4-aminopyridine (4-AP).⁴⁵ The United States Adopted Name (USAN) for 4-AP was fampridine. At approval, the FDA required a name change to avoid potential confusion with an existing drug. The name dalfampridine was proposed and accepted by the USAN Council.⁴⁷ Outside the United States, the drug continues to be known by the International Nonproprietary Name fampridine.⁴⁸

Efficacy: In a 14-week, randomized, double-blind trial, 301 patients with any clinical presentation of MS were enrolled at 33 centers in the United States and Canada.⁴⁶ Participants received dalfampridine 10 mg twice daily or placebo in addition to their usual MS medications.⁴⁶ The modified intention-to-treat (ITT) population with efficacy data included 224 receiving dalfampridine and 72 receiving placebo.⁴⁶ Patients who did not complete any efficacy measurements during the double-blind period were excluded from the modified ITT population.⁴⁶ All participants had to be able to complete 2 trials of the timed 25-foot walk (T25FW) within prespecified limits.⁴⁶ The primary efficacy variable was timed walk responder status, which was defined as a faster walking speed for at least 3 of the 4 treatment period visits than the maximum speed for any of the first 5 off-drug visits (4 visits before double-blind treatment and 1 visit 2 weeks after the end of double-blind treatment).⁴⁶ Of patients given dalfampridine, 78 (35%) met responder criteria versus 6 (8%) of patients given placebo (odds ratio, 4.75; 95% confidence interval [CI], 2.08-10.86; P <.0001).⁴⁶ Walking speed in dalfampridine responders improved 25.2% (95% CI, 21.5%-28.8%) versus 7.5% (5.0%-10.0%) in dalfampridine nonresponders and 4.7% (1.0%-8.4%) in the placebo group (Figure).⁴⁶ The increase in dalfampridine responders’ walking speed was sustained for the 14 weeks of treatment and was reversed at 2-week and 4-week off-drug visits.⁴⁶ Leg strength on Lower Extremity Manual Muscle Test (LEMMT) score improved significantly in dalfamprindine responders (0.18) and dalfampridine nonresponders (0.11) versus placebo (0.04, P = .0002 and P = .046, respectively).⁴⁶

In the second randomized, double-blind trial, patients with any clinical presentation of MS received dalfampridine 10 mg twice daily (modified ITT n = 119) or placebo (n = 118) for 9 weeks.⁴⁷ The primary outcome was percentage of timed walk responders (defined as consistent improvement in T25FW; the same outcome as the first study).⁴⁷ In the dalfampridine group, 51 patients (42.9%) were responders, versus 11 (9.3%) in the placebo group (odds ratio, 8.14; 95% CI, 3.73-17.74; P <.0001).⁴⁷ Walking speed improved 24.7% from baseline (95% CI, 21.0%-28.4%) in dalfampridine responders versus 6.0% (2.2%-9.7%) in nonresponders and 7.7% (4.4%-11.0%) in the placebo group.⁴⁷ Mean speed improvements in responders at 9-10 hours, 10-11 hours, and 11-12 hours postdose at the last on-treatment visit were 25.5%, 25.3%, and 20.1%, respectively, which demonstrated sustained effect between doses.⁴⁷ After treatment discontinuation, drug effect was reversed.⁴⁷ LEMMT scores of dalfampridine responders improved an average of 0.145, compared with 0.042 in the placebo group (P = .028).⁴⁷

Patient-Reported Satisfaction: Even before the development of dalfampridine for MS, the active ingredient (4-AP) showed QOL and patient satisfaction benefits in other populations. A randomized, double-blind crossover trial of sustained release 4-AP in spinal cord—injured patients showed significant benefit on the 6-point Patient Satisfaction Questionnaire (P = .046) and QOL scores on the 7-point Terrible-Delighted Scale (P = .011).⁴⁹

The 2 major clinical trials of dalfampridine in MS also demonstrated patient satisfaction improvements in walking independent of treatment assignment.^46,47 In the 12-item MS Walking Scale (MSWS-12), a patient self-assessment, positive changes indicate worsening disability and negative changes indicate disability improvement.^46,47 In the first dalfampridine trial, average MSWS-12 scores changed —6.84 (–9.65 to –4.02) in timed walk responders and 0.05 (–1.48 to 1.57) in timed walk nonresponders (P = .0002), with improvement on all 12 items in timed walk responders.⁴⁶ In the second trial, average MSWS-12 scores changed —6.04 (–9.57 to –2.52) in responders and 0.85 (–0.72 to 2.43) in nonresponders, independent of treatment assignment (P <.001), and also showed a mean reduced disability score on all 12 items.⁴⁷ In both trials, patients rated effects of study medication on their physical well-being by Subject Global Impression (SGI).^46,47 Responders had more positive mean SGI scores than nonresponders (first trial: 4.88 versus 4.43, P = .001;⁴⁶ second trial: 4.76 versus 4.21, P <.001).⁴⁷

Safety: Dalfampridine can cause seizures; the risk increases with increasing doses.⁴⁵ Dalfampridine is contraindicated in patients with seizure history or moderate or severe renal impairment.⁴⁵ Seizure risk with mild renal impairment is unknown, but drug plasma levels may approach those seen at a dose that may be associated with increased risk.⁴⁵ AEs in at least 2% of patients and more often than with placebo included UTI, insomnia, dizziness, headache, nausea, asthenia, back pain, balance disorder, MS relapse, paresthesia, nasopharyngitis, constipation, dyspepsia, and pharyngolaryngeal pain.⁴⁵ In the first clinical trial, 17 of the original 228 patients given dalfampridine withdrew, 11 (5%) because of AEs.⁴⁶ In the dalfampridine group, 16 patients (7%) had serious AEs, but only 2 events were deemed possibly treatment-related: 1 case of severe anxiety and 1 focal seizure in a patient with sepsis associated with community-acquired pneumonia.⁴⁶ In the second trial, 7 of the original 120 patients given dalfampridine withdrew, 4 (3.3%) because of AEs.⁴⁷ In the dalfampridine group, 5 patients (4.2%) had the following serious AEs: pneumonia, cellulitis, pyelonephritis, patella fracture, coronary artery disease, and cholelithiasis combined with syncope.⁴⁷ Because the active ingredient is the same, dalfampridine should not be used with other forms of 4-AP.

Conclusions

Although DMTs have demonstrated efficacy at reducing relapses and slowing disease progression, they do not meet all treatment needs of MS patients. Corticosteroids reduce the severity and duration of relapses. Symptom-specific pharmacotherapies treat individual symptoms that diminish QOL.

Many studies link diminished QOL with specific MS symptoms (eg, fatigue, spasticity, cognitive dysfunction, PBA, depression, pain, and impaired mobility). Even in patients already receiving DMTs, symptoms and QOL may improve with symptom-specific medications. Fatigue can improve with various drugs including amantadine, methylphenidate, and modafinil. Spasticity is usually addressed with oral baclofen or tizanidine, which have demonstrated efficacy; spasticity may also be treated with onabotulinumtoxinA. To address cognitive dysfunction, some clinicians prescribe cholinesterase inhibitors (eg, donepezil, galantamine, rivastigmine), although evidence is sparse and mixed. For the treatment of PBA, dextromethorphan hydrobromide with quinidine sulfate (Nuedexta) may be prescribed. For depression, selective serotonin reuptake inhibitors, tricyclic antidepressants, and other drugs are used. Pain is addressed with various treatments, which may include anticonvulsants, antispasmatics, nonsteroidal anti-inflammatory drugs, opioids, nerve blocks, and antidepressants. Difficulty walking can be addressed with dalfampridine.

Author Affiliation: Department of Neurology, University of Kentucky College of Medicine, Lexington, KY.

Funding Source: This supplement was supported by Acorda Therapeutics, Inc.

Author Disclosure: Dr Berger reports serving as an advisory board member/consultant for Bayer, Biogen Idec, Eisai, Genentech, Millenium, Novartis, Perseid Therapeutics, and Pfizer; he reports receiving grants/honoraria from Bayer, Biogen Idec, and EMD Serono.

Authorship Information: Concept and design; analysis and interpretation of data; and supervision.

Address correspondence to: Joseph R. Berger, MD, University of Kentucky, 740 S Limestone St, Lexington, KY 40536. E-mail: jrbneuro@uky.edu.

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