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Treatment Options in Multiple Sclerosis

Emmanuelle Waubant, MD, PhD

Department of Neurology, University of California San Francisco Multiple Sclerosis Center, San Francisco

Multiple sclerosis (MS) is an autoimmune disorder in which lymphocytes cross the blood-brain barrier and invade tissues in the central nervous system, resulting in inflammation, demyelination, and axonal and neuronal loss. The earliest clinical stage of MS is termed a clinically isolated syndrome (CIS), which is diagnosed when a patient has neurologic symptoms—such as optic neuritis or partial transverse myelitis—and MRI of the brain or spinal cord identifies abnormal ovoid T2-bright lesions in the deep white matter. Although most patients will fully recover from an initial CIS, the diagnosis means that the patient has a high probability of converting to clinically definite multiple sclerosis (CDMS). Four subtypes of MS have been identified: relapsing-remitting (the most common form at diagnosis), secondary progressive, primary progressive, and progressive relapsing. The typical course of MS is characterized by periods of symptom exacerbation followed by periods of remission; patients will eventually accrue disability from the inflammation and demyelination. For more information on the symptoms and course of MS, see “Early Recognition and Diagnosis of Multiple Sclerosis.”

Current treatments for MS are anti-inflammatory agents designed to treat specific immune dysfunction in an effort to prevent exacerbations, rather than to help the patient recover once a relapse has occurred. Beginning treatment early after a first neurologic event, if deemed appropriate, is an effective strategy for slowing the patient’s conversion to CDMS (AV 1).1,2

AV 1. Long-Term Effect of Early MS Treatment (0:26)

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Medications Approved for MS

The FDA has approved 6 anti-inflammatory medications to treat adults with relapsing forms of MS, all of which are intended to prevent symptom exacerbations. These treatments have little or unknown impact on the primary progressive or chronic progressive forms of MS, which appear to have less inflammation overall but more neurodegenerative changes than the relapsing forms.3

First-line treatments. First-line therapies for MS are the immune modulating agents interferon beta (IFNβ-1a and IFNβ-1b) and glatiramer acetate. These drugs have overall similar efficacy in the outcome measures of risk of relapse, time to relapse, and lesion volume on monthly MRI scans.1One study4 found that 67% of patients taking IFNβ-1a and 65% of patients taking glatiramer acetate remained relapse-free over a trial period of 96 weeks.

Although generally well tolerated and safe, treatment with these medications is complicated by the fact that they must be administered by either intramuscular or subcutaneous injection, sometimes daily. Inflammation at the injection site is a common reaction for interferon beta, and more serious reactions, including necrosis, are possible. The most common adverse effect associated with interferon beta is flu-like symptoms, including myalgia, fever, fatigue, headaches, and chills. Liver toxicity has been reported, and liver enzyme levels should be monitored every 3 to 6 months. Depression has also been reported as a side effect, but this may be related to the patient’s pretreatment level of depression.5 Glatiramer acetate does not have flu-like side effects, but injection site reactions are common. A small number of patients also experience symptoms similar to those of a panic attack, including chest tightness, shortness of breath, and anxiety that lasts for seconds or minutes.

Second-line treatments. Natalizumab, fingolimod, and mitoxantrone are considered second-line treatments for MS due to their limited safety data and/or association with severe outcomes. Natalizumab is administered by IV injection once a month and prevents T-cells from migrating across the blood-brain barrier. The medication has been shown to reduce rates of clinical relapse by about 70%, number of gadolinium-enhancing lesions by about 90%, and disability progression by about 40% at 2 years when compared with placebo (AV 2).6,7 Natalizumab has been linked to rare occurrences of PML, a slow infection of the brain caused by the JC virus. This complication occurs in approximately 1 in 1000 patients and happens only after receiving more than 1 treatment. Currently, different methods of determining an individual patient’s risk for developing PML, including JC virus serology, are being investigated, along with risk management strategies for those with PML.8,9

AV 2. Patients Without Disease Activity Over 2 Years With Natalizumab Vs Placebo (0:24)

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Approved by the FDA in late 2010, fingolimod is the first oral therapy for relapsing-remitting MS. Through its mechanism of action, lymphocytes lose their ability to migrate outside of lymph nodes, which reduces the number of lymphocytes circulating in the bloodstream and prevents them from migrating to the central nervous system. Fingolimod is generally well tolerated and has been shown to reduce relapse rates by more than 50% and disability progression by 30% over 2 years versus placebo.10 When compared with IFNβ-1a in a 12-month double-blind study,11 annualized relapse rates were significantly lower for patients receiving fingolimod (P < .001). Some patients may experience elevated liver enzyme levels and have a higher risk of developing potentially fatal viral infections. Patients should also be monitored for bradycardia for the first 6 hours following their initial dose and monitored for the small risk of macular edema on a regular basis with optical coherence tomography.

Mitoxantrone is an IV-administered chemotherapy agent that inhibits T-cell, B-cell, and macrophage proliferation. Mitoxantrone is indicated for reducing neurologic disability and/or the frequency of clinical relapses for patients with worsening MS, but duration of treatment with mitoxantrone is limited to about 2 years due to cardiotoxicity.12

Additional treatments. Low vitamin D levels are a risk factor for MS and may be associated with an increased relapse rate for patients with MS; conversely, every 10 ng/mL increase in seasonally adjusted vitamin D levels has been associated with a 34% decrease in MS exacerbations.13 For patients with low vitamin D levels, supplementation may be used to bring levels up to normal limits. A clinical trial is currently being conducted to confirm whether such supplementation limits disease activity.

The approved agent natalizumab is a monoclonal antibody, and other monoclonal antibodies such as daclizumab, alemtuzumab, and rituximab are sometimes used for MS, although they are not FDA–approved for that purpose. Four new oral medications that show promise for treating MS—laquinomod, fumaric acid, teriflunomide, and cladribine—are in phase III trials or have shown a beneficial effect in phase III trials.3

Treatment Strategies

Preventive therapy. A first-line medication should be initiated for patients who have had several exacerbations over a relatively short period of time or for those whose onset of symptoms was accompanied by a substantial number of T2-bright lesions. When choosing among therapies, physicians should consider dosing frequency, ease of administration, and side effects—along with the patient’s emotional status concerning his or her treatment and diagnosis in general—to optimize tolerability and enhance patient compliance. Preventive treatment should be provided in the context of symptomatic treatment (eg, spasticity, fatigue, depression).

Switching medications. Although first-line medications have similar overall treatment outcomes, individual patients may have a greater response to one medication over another. Therefore, switching first-line medications is an option for patients with breakthrough symptoms or with suboptimal response to a first medication. Relapse frequency, disability progression, and a combination of relapse frequency and MRI activity (lesion development) are the most common reasons for switching medications.

Switching from an interferon agent to glatiramer acetate, from glatiramer acetate to an interferon agent, and from one interferon to another (mostly from a lower to higher dose) due to suboptimal response have all been effective strategies in lowering relapse rates.14 Patients receiving interferons, particularly those that must be injected more than once a week, may develop antibodies to the medication, which reduces efficacy. Physicians should measure these antibodies before switching a nonresponsive patient from one interferon to another.

Another strategy for managing patients with breakthrough disease is switching to a second-line medication. Relapse rates have been decreased by 70% in first-line breakthrough patients who switched to natalizumab or to an immunosuppressant.15 Patients who switched from weekly IFNβ-1a to fingolimod experienced a reduction in annualized relapse rates (AV 3).16

AV 3. Relapse Rates Over 2 Years With Interferon Switched to Fingolimod Vs Continuous Fingolimod (0:34)

av3 small

Symptomatic treatment. Several psychiatric drugs are often used off-label for treating the symptoms caused by MS. Amitriptyline or clonazepam are sometimes prescribed for neuropathic pain, which is a relatively common symptom of MS. Benzodiazepines (and baclofen) may be helpful in treating spasticity. Bladder urgency may be treated with tricyclic antidepressants, such as amitriptyline, if other medications have not provided relief. For fatigue, some clinicians may prescribe an SSRI or, occasionally, stimulants such as methylphenidate; however, methylphenidate is usually avoided because of possible side effects.

Conclusion

Several treatment options with comparable efficacy but different side effect profiles are available for patients with MS. When choosing among medications, physicians should tailor treatment to the individual patient to address predominant symptoms and enhance treatment compliance. To evaluate treatment efficacy, patients should be monitored for relapse and have periodic MRI scans to assess for new lesion development. If patients experience a suboptimal response to a first-line medication, switching to another first-line or to a second-line medication with a different mechanism of action can be an effective treatment strategy. With early diagnosis and treatment, most patients with MS can maintain active social and professional lives.

For Clinical Use
  • Become familiar with first- and second-line treatments for MS, and tailor prescriptions to the patient on the basis of tolerability and method of administration
  • Begin first-line treatment early to prevent relapse in patients with MS
  • Treat symptoms related to MS with adjunctive medications
  • Monitor patients for relapse and new lesion development, and adjust treatment as necessary
Drug Names

alemtuzumab (Campath), baclofen (Gablofen, Lioresal, and others), cladribine (Leusatin and others), clonazepam (Klonopin and others), daclizumab (Zenapax), fingolimod (Gilenya), glatiramer acetate (Copaxone), interferon beta-1a (Rebif and Avonex), interferon beta-1b (Betaseron and Extavia), methylphenidate (Focalin, Daytrana, and others), mitoxantrone (Novantrone and others), natalizumab (Tysabri), rituximab (Rituxan)

Abbreviations

CDMS = clinically definite multiple sclerosis, CIS = clinically isolated syndrome, FDA = US Food and Drug Administration, IFNβ-1a = interferon beta-1a, IFNβ-1b = interferon beta-1b, IV = intravenous, JC virus = John Cunningham virus, MRI = magnetic resonance imaging, MS = multiple sclerosis, PML = progressive multifocal leukoencephalopathy, SSRI = selective serotonin reuptake inhibitor

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References
  1. Carter NJ, Keating GM. Glatiramer acetate: a review of its use in relapsing-remitting multiple sclerosis and in delaying the onset of clinically definite multiple sclerosis. Drugs. 2010;70(12):1545–1577. PubMed
  2. Kappos L, Freedman MS, Polman CH, et al, for the BENEFIT Study Group. Long-term effect of early treatment with interferon beta-1b after a first clinical event suggestive of multiple sclerosis: 5-year active treatment extension of the phase 3 BENEFIT trial. Lancet Neurol. 2009;8(11):987–997. PubMed
  3. Spain RI, Cameron MH, Bourdette D. Recent developments in multiple sclerosis therapeutics. BMC Med. 2009;7:74. PubMed
  4. Mikol DD, Barkhof F, Chang P, et al, for the REGARD Study Group. Comparison of subcutaneous interferon beta-1a with glatiramer acetate in patients with relapsing multiple sclerosis (the REbif vs Glatiramer Acetate in Relapsing MS Disease [REGARD] study): a multicentre, randomized, parallel, open-label trial. Lancet Neurol. 2008;7(10):903–914. PubMed
  5. Mohr DC, Likosky W, Dwyer P, et al. Course of depression during the initiation of interferon beta-1a treatment for multiple sclerosis. Arch Neurol. 1999;56(10):1263–1265. PubMed
  6. Polman CH, O'Connor PW, Havrdova E, et al, for the AFFIRM Investigators. A randomized, placebo-controlled trial of natalizumab for relapsing multiple sclerosis. N Engl J Med. 2006;354(9):899–910. PubMed
  7. Havrdova E, Galetta S, Hutchinson M, et al. Effect of natalizumab on clinical and radiological disease activity in multiple sclerosis: a retrospective analysis of the Natalizumab Safety and Efficacy in Relapsing-Remitting Multiple Sclerosis (AFFIRM) study. Lancet Neurol. 2009;8(3):254–260. PubMed
  8. Sadiq SA, Puccio LM, Brydon EW. JCV detection in multiple sclerosis patients treated with natalizumab. J Neurol. 2010;257(6):954–958. PubMed
  9. Warnke C, Adams O, Gold R, et al. Progressive multifocal leukoencephalopathy under natalizumab: initial possibilities for risk stratification [in German]? Nervenarzt. 2011;82(4):475–480. PubMed
  10. Singer B, Ross AP, Tobias K. Oral fingolimod for the treatment of patients with relapsing forms of multiple sclerosis [published online ahead of print June 16, 2011]. Int J Clin Pract. doi:10.1111/j.1742.2011.02721.x. PubMed
  11. Cohen JA, Barkhof F, Comi G, et al, for the TRANSFORMS Study Group. Oral fingolimod or intramuscular interferon for relapsing multiple sclerosis. N Engl J Med. 2010;362(5):402–415. PubMed
  12. Fox EJ. Management of worsening multiple sclerosis with mitoxantrone: a review. Clin Ther. 2006;28(4):461–474. PubMed
  13. Mowry EM, Krupp LB, Milazzo M, et al. Vitamin D status is associated with relapse rate in pediatric-onset multiple sclerosis. Ann Neurol. 2010;67(5):618–624. PubMed
  14. Gajofatto A, Bacchetti P, Grimes B, et al. Switching first-line disease-modifying therapy after failure: impact on the course of relapsing-remitting multiple sclerosis. Mult Scler. 2009;15(1):50–58. PubMed
  15. Castillo-Trivino T, Mowry EM, Gajofatto A, et al. Switching multiple sclerosis patients with breakthrough disease to second-line therapy. PLoS One. 2011;6(2):e16664. PubMed
  16. Khatri B, Barkhof F, Comi G, et al, for the TRANSFORMS Study Group. Comparison of fingolimod with interferon beta-1a in relapsing-remitting multiple sclerosis: a randomized extension of the TRANSFORMS study. Lancet Neurol. 2011;10(6):520–529. PubMed
From the Series:
Overview of Current Issues in the Management of Multiple Sclerosis

Independently developed by the CME Institute of Physicians Postgraduate Press, Inc.

CME Background Information

Independently developed by the CME Institute of Physicians Postgraduate Press, Inc.

Objective

After completing this educational activity, you should be able to:

  • Develop customized treatment plans for individual patients to optimize compliance and tolerability

Financial Disclosure

The faculty for this CME activity and the CME Institute staff were asked to complete a statement regarding all relevant personal and financial relationships between themselves or their spouse/partner and any commercial interest. The CME Institute has resolved any conflicts of interest that were identified. No member of the CME Institute staff reported any relevant personal financial relationships. Faculty financial disclosures are as follows:

Dr Waubant is a consultant for and has received honoraria from Roche, Actelion, and Sanofi-Aventis; has received grant/research support from the NIH, National MS Society, Nancy Davis Foundation, Biogen Idec, and Sanofi-Aventis; and is a member of the speakers/advisory board of Teva.

Accreditation Statements

The CME Institute of Physicians Postgraduate Press, Inc., is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.

Credit Designation

The CME Institute of Physicians Postgraduate Press, Inc., designates this enduring material for a maximum of 0.5 AMA PRA Category 1 Credit™. Physicians should only claim credit commensurate with the extent of their participation in the activity.

The American Academy of Physician Assistants (AAPA) accepts certificates of participation for educational activities certified for AMA PRA Category 1 Credit™ from organizations accredited by ACCME or a recognized state medical society. Physician assistants may receive a maximum of 0.5 hours of Category I credit for completing this program.

To obtain credit for this activity, study the material and complete the CME Posttest and Evaluation.

Release, Review, and Expiration Dates

This CME activity was published in November 2011 and is eligible for AMA PRA Category 1 Credit through November 30, 2014. The latest review of this material was August 2011.

Statement of Need and Purpose

A diagnosis of multiple sclerosis (MS) is generally made using the McDonald criteria, which require objective proof of lesions disseminated in both time and space and which provide guidelines on how to obtain this objective evidence. Although these criteria are accurate and sensitive, many clinicians still have difficulty diagnosing this disease. Patients may present with a variety of symptoms, such as subjective sensory complaints, or may have another condition commonly mistaken for MS, such as some infectious diseases and inflammatory disorders. Further, MS has a highly variable course of illness. Early recognition is critical because early treatment with disease-modifying drugs can slow the progression of MS. Additionally, recent advancements in disease-modifying drugs, such as approval of the first oral medications and the development of agents with possible neuroprotective effects, have the potential to revolutionize MS treatment. Clinicians need more information on the early detection and treatment of MS to optimize their patients’ overall outcomes. This activity was designed to meet the needs of participants in CME activities provided by the CME Institute of Physicians Postgraduate Press, Inc., who have requested information on MS.

Disclosure of Off-Label Usage

Dr Waubant has determined that, to the best of her knowledge, alemtuzumab, daclizumab, and rituximab are not approved by the US Food and Drug Administration for the treatment of multiple sclerosis; clonazepam is not approved for the treatment of neuropathic pain; methylphenidate is not approved for the treatment of fatigue; and amitriptyline is not approved for the treatment of neuropathic pain and bladder urgency.

Review Process

The entire faculty of the series discussed the content at a peer-reviewed planning session, the Chair reviewed the activity for accuracy and fair balance, and a member of the External Advisory CME Board who is without conflict of interest reviewed the activity to determine whether the material is evidence-based and objective.

Acknowledgment

This CME activity is derived from the planning teleconference “Overview of Current Issues in the Management of Multiple Sclerosis,” which was held on May 24, 2011. This activity is one in a series of independent projects undertaken by the CME Institute of Physicians Postgraduate Press, Inc., as a service to its members and the broader academic and clinical community.