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Developing a Therapeutic Plan for MS: Evidence for New Treatments

Michael C. Levin, MD

Department of Neurology and the MS Clinic and Laboratory of Viral and Demyelinating Disease, University of Tennessee Health Science Center, Memphis

W. Clay Jackson, MD, DipTh

Departments of Family Medicine and Psychiatry, University of Tennessee College of Medicine, Memphis

The course of multiple sclerosis (MS) is highly varied and unpredictable, with each patient experiencing different symptoms and varying levels of disability. For patients who are diagnosed with MS, the chronic, incurable nature of the disease can create fear and depression regarding the future. However, clinicians can offer hope to patients by providing education on the disease and available support networks, as well as by creating individualized treatment plans. To do this, clinicians should discuss disease-modifying therapies with each patient and prescribe the best personalized option, try to delay relapses and treat them in a timely manner, and offer complementary and alternative medicines (CAMs) when appropriate.

Disease-Modifying Therapies

Disease-modifying therapies are designed to shorten the duration and frequency of relapses and to reduce disease activity and progression. Ten agents are currently FDA-approved to treat relapsing forms of MS, with 1 agent also approved for secondary progressive MS. Table 1 provides a quick reference on the recommended dosages, adverse events, and relapse rate reductions for each medication.

β Interferons. Four β interferon drugs are approved for delaying physical disability and reducing relapses in patients with relapsing forms of MS—2 interferon β-1a and 2 interferon β-1b formulations, administered by either intramuscular or subcutaneous injection from daily to weekly dosages. The β interferons are cytokines that help regulate inflammatory responses to pathogens and injury. Although their exact mechanisms of action are unknown, these agents have anti-inflammatory properties that are associated with their therapeutic benefits in MS.1 The interferons have been shown to reduce MS relapses by about 30% and to reduce radiographically visible lesions by 50% to 80%.1 The most common side effects associated with interferons are flu-like symptoms (eg, fever, chills, headache), injection-site reactions, depression, and liver damage.1,2 Patients taking interferons require liver function tests as well as ongoing monitoring for liver injury, decreased white blood cell counts, and cardiac symptoms.1

Glatiramer acetate. Glatiramer acetate is a copolymer polypeptide administered by subcutaneous injection at 20 mg/d or 40 mg/tiw.3 Its mechanism of action is not fully known, but it is believed to modify immune processes implicated in MS. Unlike interferons, this agent induces and activates suppressor T-cells in the periphery.3 Similar to interferons, glatiramer acetate reduces relapse rates by about one-third in clinical trials.4 Common side effects are rash, lipoatrophy, and post-injection reactions (eg, flushing, chest tightness, anxiety), which are typically transient but should be monitored carefully.2,3

Mitoxantrone. As a synthetic antineoplastic drug used in cancer treatment, mitoxantrone suppresses the activity of T-cells, B-cells, and macrophages, which are associated with attacking the myelin sheath.1,5 Administered by IV every 3 months at recommended doses of 5 to 12 mg/m2, mitoxantrone also inhibits topoisomerase II, an enzyme involved in repairing damaged DNA.1 Clinicians should be aware that the lifetime cumulative dose must be limited to 140 mg/m2 or 2 to 3 years of treatment.1 Indicated for worsening relapsing-remitting, progressive relapsing, and secondary progressive forms of MS, mitoxantrone significantly reduced relapse rates by 66% (P = .0001) and reduced the progression of disability compared with placebo in pivotal trials.6 Mitoxantrone carries boxed warnings for cardiotoxicity and secondary leukemia, so patients should be vigilantly monitored for these conditions. Common side effects include nausea, alopecia, menstrual disorders, and urinary tract infection.5

AV 1. PML Risk Estimates for Anti-JCV Antibodies in Patients With No Prior Immunosuppressant Use (0:40)

AV 1. PML Risk Estimates for Anti-JCV Antibodies in Patients With No Prior Immunosuppressant Use

Natalizumab. Natalizumab is a humanized monoclonal antibody and α4-integrin selective adhesion molecule inhibitor designed to hinder potentially damaging immune cells from entering the brain and spinal cord. Administered at 300 mg by IV infusion over 1 hour every 4 weeks, natalizumab has proven efficacy over placebo for reducing relapses (67%)7 and gadolinium-enhanced lesions (92%).7,8 However, because it increases the risk of PML, an often fatal viral disease, natalizumab is recommended for patients who have not responded to or cannot tolerate an alternate MS treatment and is available only through the TOUCH Prescribing Program. The ability to test patients’ serum for the presence of JCV antibodies, which are a risk factor for PML, enables clinicians and patients to better evaluate the risks and benefits of starting or continuing treatment with natalizumab (AV 1).9,10 Patients who have anti-JCV antibodies, have taken natalizumab for 2 years or more, or were treated with another immunosuppressant are at increased risk for PML. Besides PML, side effects of natalizumab include infusion reactions, liver damage, infections, headache, and fatigue.7

Fingolimod. Fingolimod is a sphingosine-1-phosphate receptor modulator and the first oral treatment approved by the FDA for relapsing forms of MS.11 Fingolimod blocks white blood cells from leaving lymph nodes, thereby hindering them from entering the bloodstream or brain.1 The recommended dose is 0.5 mg/d, taken with or without food.11 Therapeutic effects of fingolimod include a 54% relapse reduction rate, fewer new or enlarged lesions on MRI (P = .001), and significant disability reduction at 24 months compared with placebo (P = .02).12 Comparing the annualized relapse rate of fingolimod with interferon β-1a resulted in a relative reduction of 38% in favor of fingolimod.13 First-dose monitoring is required for 6 hours due to the risk of bradycardia, and other warnings include the risk of infections, macular edema, liver injury, blood pressure effects, respiratory effects, and fetal harm. Common side effects are headache, influenza, infections, diarrhea, back pain, liver problems, and cough.11

Teriflunomide. Teriflunomide is a pyrimidine synthesis inhibitor with anti-inflammatory properties.14 Although its exact mechanism of therapeutic effect in MS is not clear, it may be associated with reducing the number of activated white blood cells in the CNS.14 Taken orally at doses of 7 mg/d or 14 mg/d with or without food, teriflunomide lowered relapse rates by 31% compared with placebo (for either dose) and reduced disability progression by 24% to 30%.14 Boxed warnings for teriflunomide include hepatotoxicity and teratogenicity, and common adverse events include immunosuppression, infections, peripheral neuropathy, renal failure, liver problems, diarrhea, nausea, alopecia, influenza, and paresthesia. Some patients may require cholestyramine or activated charcoal to remove teriflunomide from the body after discontinuation.14

Dimethyl fumarate. As an anti-inflammatory and antioxidant, dimethyl fumarate may inhibit immune cells and molecules and protect against damage to the brain and spinal cord. As a twice-daily oral medication, dimethyl fumarate has a starting dose of 120 mg for 7 days followed by a maintenance dose of 240 mg, taken with or without food.15 It is approved as monotherapy for the treatment of relapsing forms of MS and has shown relative reduction rates of 48% and 53% (twice-daily and thrice-daily 240 mg doses, respectively) versus placebo.16 Dimethyl fumarate may cause lymphopenia, flushing, abdominal pain, diarrhea, and nausea.15

Relapse Treatments

In addition to disease-modifying therapy, patients with MS may require treatment for neurologic deficits (optic neuritis, spinal cord syndromes) that affect functioning and do not spontaneously resolve. Around one-third of relapses resolve with no intervention, and some relapses may be caused or lengthened by infections.17 Although not FDA-approved, common practice is to treat acute relapses with short-term corticosteroid therapy,1 such as high-dose methylprednisolone (via oral or IV formulations), to reduce CNS inflammation.17,18 Both formulations appear to have similar efficacy and tolerability, so clinicians may consider other factors such as patient preference and cost.17,19 Using a strategy like short-term, high-dose IV corticosteroids may also require tapering down the medication with oral steroids.17 Adverse events that commonly occur with steroid use include infections, adrenocortical insufficiency, psychic derangement, elevated blood pressure, and gastrointestinal and musculoskeletal abnormalities.20,21

For patients whose relapses are unresponsive to steroids, clinicians may consider plasma exchange (plasmapheresis) or IV immunoglobulin (IVIG).17,18 IVIG may also be appropriate for women who are pregnant, since they should generally avoid steroid use. Complications related to plasma exchange include excessive bleeding or hypotension, and complications for IVIG include kidney problems, injection site reaction, hypersensitivity, thrombosis, and hemolysis.22

Clinicians must monitor side effects carefully throughout relapse treatment, make necessary dose adjustments, or stop or switch medications that are intolerable or ineffective.

Complementary and Alternative Medicines

Patients with MS may want to explore natural therapeutic options such as CAMs, as evidenced by about 30% to 70% of MS patients having tried a CAM treatment.23 Randomized, controlled trials are rare for CAMs in MS, but supplements with at least theoretical appeal include vitamin D, antioxidants, and omega-3 fatty acids.23

Vitamin D. The risk for MS increases as the distance from the equator increases, which is thought to be related to sunlight exposure,24 and patients with higher levels of vitamin D have lower prevalence rates of MS.25 In addition, research indicates that patients with MS in relapse have lower levels of vitamin D than those in remission.23 While vitamin D may play a role in preventing MS and some research suggests that vitamin D may have beneficial effects in MS, more evidence is needed on the efficacy of vitamin D supplementation for this disorder.23,25 When administering vitamin D, moderate doses (1,000 IU/d) may be more appropriate than high doses (13,000 IU/d) for patients with MS.25

Antioxidants. Antioxidants such as lipoic acid show some promise for reducing inflammation in MS patients. A 2-week pilot study26 suggested that lipoic acid may be a well-tolerated anti-inflammatory treatment that reduces MMP-9 and sICAM-1 levels and interferes with T-cell migration into the CNS for patients with MS.

Omega-3 fatty acids. Omega-3 fatty acids are involved in brain function, such as neurotransmission and inflammation response, and their deficiency may increase the possibility of myelin damage.25 One randomized, double-blind, 2-year trial27 showed a nonsignificant trend, favoring 10 g/d of fish oil over olive oil on the outcomes of deterioration, frequency, duration, and severity of relapses in patients with MS.23

Conclusion

Patients with MS require an individualized treatment plan with disease-modifying therapies to slow disease progression and resolve relapses. In general, these agents can substantially reduce relapses, but clinicians must help patients select a therapy based on disease course, benefit, risk, and preferred administration method. When a patient experiences an exacerbation or a relapse, clinicians can use short-term corticosteroids, either IV or oral. Other methods, such as plasma exchange and IVIG, are reserved for patients who cannot tolerate or who are contraindicated to use steroid treatment. Patients may want to try natural supplement treatments such as CAMs, but more research is needed to establish the benefits in MS. Finally, a critical component of treatment for patients with MS is simply offering education and resources for further information and support.

Drug Names

dimethyl fumarate (Tecfidera), fingolimod (Gilenya), glatiramer acetate (Copaxone), interferon β-1a (Avonex and Rebif), interferon β-1b (Betaseron and Extavia), methylprednisolone (Medrol, Solu-Medrol, and others), natalizumab (Tysabri), teriflunomide (Aubagio)

Clinical Points
  • Select a disease-modifying therapy based on disease course, efficacy, side effects, and the patient’s preferred method of administration
  • Treat acute relapses that do not spontaneously remit with steroids, plasma exchange, or IVIG when necessary
  • Understand the potential benefits of CAMs including vitamin D, antioxidants, and omega-3 fatty acids
Abbreviations
  • CAM = complementary and alternative medicine
  • CNS = central nervous system
  • FDA = US Food and Drug Administration
  • IV = intravenous
  • IVIG = intravenous immunoglobulin
  • JCV = John Cunningham virus
  • MMP = matrix metallopeptidase
  • MRI = magnetic resonance imaging
  • MS = multiple sclerosis
  • PML = progressive multifocal leukoencephalopathy
  • sICAM = soluble intercellular adhesion molecule
Take the CME posttest.
References
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  15. 15. Tecfidera (dimethyl fumarate)[package insert]. Cambridge, MA: Biogen Idec Inc; 2013. http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=665d7e74-036c-5f68-5b67-ab84b9b49151. Accessed May 19, 2014.
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  20. 20. Solu-Medrol (methylprednisolone)[package insert]. New York, NY: Pharmacia and Upjohn Company; 2013. http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=cd99be87-c8d9-48d6-a8e5-e081052e3f19. Accessed May 19, 2014.
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  27. 27. Bates D, Cartlidge NE, French JM, et al. A double-blind controlled trial of long chain n-3 polyunsaturated fatty acids in the treatment of multiple sclerosis. J Neurol Neurosurg Psychiatry. 1989;52(1):18–22. PubMed
From the Series:
Appropriate Management of Multiple Sclerosis in Primary Care: Focus on Rural Health

Supported by educational grants from EMD Serono and Genzyme, a Sanofi Company.

CME Background Information

Supported by educational grants from EMD Serono and Genzyme, a Sanofi Company.

Participants may receive credit by reading the activity, correctly answering 100% of the questions in the posttest, and completing the evaluation.

Objective

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

  • Prescribe an immunomodulatory agent or other medication to treat patients with MS as appropriate
  • Prescribe steroids to treat patients with MS who are having a relapse (off label)

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 Levin is a consultant for Merck and Gerson Lehrman, holds a patent titled Biomarker for Neurodegeneration in Neurologic Disease, and owns A1 Brain Diagnostics.

Dr Jackson is a consultant for DepoMed, Pamlab, and Sunovion; has received honoraria from Otsuka; and is a member of the speakers’ bureaus for Pamlab and Sunovion.

Accreditation Statement

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 claim only the 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 Neurology Report was published in July 2014 and is eligible for AMA PRA Category 1 Credit™ through July 31, 2017. The latest review of this material was May 2014.

Statement of Need and Purpose

Multiple sclerosis (MS) is a chronic autoimmune disorder characterized by diverse symptoms, an unpredictable course, and a highly variable prognosis. Functional disabilities are extremely common in MS, and some individuals may experience full or partial paralysis, cognitive disabilities, or impairments with vision, speech, or elimination. A diagnosis of MS is made based on the patient’s history, the presence of demyelinating lesions on brain or spinal cord MRI scans, and the exclusion of alternative diagnoses, yet many physicians, particularly those in primary care, still have difficulty diagnosing MS because of the heterogeneous nature of the disorder. Most patients who will develop MS initially present with a clinically isolated syndrome (CIS), but progression to clinically definite MS may be delayed or prevented if treatment with a disease-modifying agent (DMA) is initiated early. However, these agents are underused; evidence shows that less than half of patients with MS were prescribed DMAs. Because more than a quarter of patients with MS do not consult or have access to a neurologist, particularly those in rural areas, primary care physicians and other nonspecialists who are likely to provide care to patients with MS need more information on strategies for making an accurate and timely diagnosis of MS and on the importance of early treatment with DMAs. 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 Levin has determined that, to the best of his knowledge, no investigational information about pharmaceutical agents that is outside US Food and Drug Administration-approved labeling has been presented in this activity.

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 Neurology Report is derived from the planning teleconference and live meeting series “Appropriate Management of Multiple Sclerosis in Primary Care: Focus on Rural Health,” which was held from June 2013 to March 2014, and is supported by educational grants from EMD Serono and Genzyme, a Sanofi Company. The opinions expressed herein are those of the faculty and do not necessarily reflect the opinions of the CME provider and publisher or the commercial supporter.