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Multiple Sclerosis Update

An expanding landscape of treatments.

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Multiple sclerosis (MS) is a chronic and often progressive disease that affects the central nervous system (CNS). It is characterized by relapses and remissions of neurologic symptoms as well as progressive functional loss with variable severity over time.1-3 The estimated prevalence of MS in the United States ranges from 47.2 to 109.5 per 100,000 people. It is most common in women, people between the ages of 40 and 59, and non-Hispanic people.1

The pathologic mechanisms of MS have not been completely elucidated, but experts believe that the disease occurs as a result of autoimmune-mediated inflammatory changes, demyelination and axonal loss.2,3 The current theory of immunopathology points toward a peripheral activation of the immune system, dysregulation that allows self-recognition of CNS antigens, migration of lymphocytes into the CNS, and reactivation by CNS self-antigens that produces an inflammatory and destructive process.

Although no cure for MS has been identified, currently available FDA-approved treatment options can modify the disease process. In recent years, the field has expanded to 10 medications with varying mechanisms of action.

Clinical Presentation and Diagnosis

Since the demyelination and axonal damage of MS can occur throughout the CNS (cerebrum, cerebellum, spinal cord), presenting symptoms may vary widely from patient to patient and even in the same patient over time. Patients may experience the following: visual disturbance, most commonly optic neuritis4; sensory disturbance; muscle weakness; gait and balance difficulty; depression; cognitive dysfunction; and/or elimination dysfunction. Any of these may worsen with heat exposure.5

No single test can confirm the diagnosis of MS. In most cases, a revised version of the McDonald Criteria for MS is used. This tool combines clinical and magnetic resonance imaging (MRI) findings to evaluate neurologic lesions that must be disseminated in both space and time.6

The fundamental criteria for an MS diagnosis are at least two episodes of neurologic symptoms that are referable to the CNS and disseminated in space and time. The revised McDonald criteria use MRI and other paraclinical evidence to establish the dissemination in the absence of adequate clinical events. One of the most important aspects of diagnosis is the exclusion of other conditions that may mimic MS.

The most common disease course of MS is relapsing-remitting MS (RRMS), in which patients experience symptoms that last a minimum of 24 hours, followed by a full or partial recovery for some time.7 Patients with RRMS often transition years after onset to a more progressive disease course with fewer relapses but more progressive functional loss over time. This is known as secondary-progressive MS (SPMS).

A small percentage (10% to 15%) of patients never experience characteristic relapses, but they have progressive functional loss from onset. This disease course is known as primary-progressive MS (PPMS). Patients who present with an initial symptom or constellation of symptoms consistent with a demyelinating process, but without evidence to support dissemination in space and/or time, have clinically isolated syndrome or CIS.

Disease-Modifying Treatments

MS is best managed using a comprehensive approach that combines pharmacologic and nonpharmacologic strategies for optimal symptom and disease management. Throughout a patient's lifetime, multiple disciplines may need to be involved in care, including psychology, urology, physical therapy, occupational therapy and speech pathology.

Pharmacologic treatments for MS are known as disease-modifying treatments (DMTs). Once the diagnosis of MS has been made, treatment should begin as soon as possible after a thorough discussion with the patient about all available treatments, their risks, benefits and alternatives. The first DMTs were approved in the 1990s, and today 10 agents are indicated for MS. DMTs are used to modify the disease process and in doing so reduce the occurrence of CNS inflammation, clinical relapses and disease progression.

The DMTs have various mechanisms of action, routes of administration, side effects and risks. Five of these treatments are self-injected medications: four interferon beta preparations and a non-interferon, glatiramer acetate. Oral treatments for MS are fingolimod, teriflunomide and dimethyl fumarate. Intravenously administered treatments are natalizumab and mitoxantrone.

The interferons, glatiramer acetate, natalizumab, teriflunomide, fingolimod and dimethyl fumarate, are indicated for relapsing MS. Mitoxantrone is indicated for secondary progressive MS, worsening relapsing MS, and progressive relapsing MS. The interferon preparations and glatiramer acetate have also been shown to delay the conversion of CIS to MS.8-11

Injectable Treatments

Interferon beta 1a and 1b preparations for MS differ in their route/frequency of administration (weekly IM, three times weekly or every other day subcutaneously) and in how they are produced. Interferon betas work similarly to reduce T cell activation in the periphery and downregulate adhesion molecules necessary for the migration of T cells into the CNS.

Interferons are naturally occurring proteins in humans and have a role in immune response. They have antiviral properties and are anti-inflammatory. Interferons are likely to produce a mild elevation in body temperature. This increase, while mild, may cause flu-like symptoms, including fever, chills, malaise, achiness and fatigue. In addition, injection site reactions are common in the subcutaneous interferon preparations. Interferons may provoke mild transaminitis and less frequently, lymphopenia. Interferons may provoke or worsen a depressed mood. Interferons are pregnancy category C.

Glatiramer acetate is a daily subcutaneous injection that works by shifting the immune response to one that it less inflammatory. Side effects include injection site reactions usually consisting of erythema, itching, discomfort and possibly lipoatrophy over time. Much less frequently, a postinjection reaction is possible that occurs immediately after the injection and includes symptoms of tachycardia, flushing, dyspnea and achiness. Glatiramer acetate is a pregnancy category B drug.

Oral Treatments

Fingloimod is a daily dosed 0.5-mg capsule that modulates the sphingosine 1 phosphate receptor, thereby inhibiting T cell migration out of lymph nodes. Clinical trials demonstrated statistically significant effects on relapse rate, disability progression and MRI outcomes.12 Because the S1P receptor is located on various cells throughout the body, side effects to the drug may occur.

Fingolimod produces a first-dose bradycardia with the potential for heart block; therefore 6 hours of first-dose monitoring is required. Caution must be used in patients with conduction abnormalities or those taking certain antiarrythmic or antipsychotic medications. Ongoing monitoring of complete blood count and hepatic function is needed because lymphopenia is likely and transaminitis is possible. Herpes infections including varicella zoster may occur, and all patients should have a VZV titer prior to the initiation of treatment and vaccination prior to fingolimod treatment, if needed. Macular edema has also been observed, therefore ophthalmologic evaluation at baseline and several months after treatment initiation are indicated. Fingolimod is a pregnancy category C drug.

Teriflunomide is a daily treatment administered once daily as 7 mg or 14 mg. This agent works by inhibiting dihydroorotate dehydrogenase, which is necessary for DNA replication. It therefore reduces T-cell and B-cell activation and proliferation. Clinical trials demonstrated a modest effect on annualized relapse rate, disability progression and MRI outcomes. Adverse events reported with teriflunomide include gastrointestinal upset, transient hair thinning, hepatic enzyme elevation, mild neutropenia, and mild blood pressure elevations.13 Teriflunimide is a pregnancy category X drug.

Dimethyl fumarate is a 240-mg capsule administered twice daily. It works via several potential mechanisms, including activation of the Nrf2 pathway, which may reduce oxidative stress. In addition, it may induce a less inflammatory immune response and may inhibit adhesion molecules necessary for T-cell trafficking into the CNS.14-16 Side effects may include episodes of flushing, GI symptoms, transaminitis and possible lymphopenia. Dimethyl fumarate is a pregnancy category C drug.

Intravenous Treatments

Natalizumab is a monoclonal antibody administered in a 300-mg dose once every 28 days. Natalizumab blocks VLA-4, an adhesion molecule on activated lymphocytes that is necessary for T-cell trafficking. In patients treated with this drug, fewer activated lymphocytes are able to enter the CNS. Clinical trials of natalizumab demonstrated a significant relapse reduction (67%), disability reduction (42%) and fewer new areas of CNS inflammation.17 Due to risks associated with its use, natalizumab is recommended as a second-line agent when a patient has experienced a suboptimal response or intolerability to other DMTs. Infusion reactions can occur, but generally natalizumab is well tolerated with mild side effects including headache, achiness, fatigue and, less often, GI side effects.

A risk associated with natalizumab is the reactivation of an otherwise dormant virus, the John Cunningham (JC) virus. Reactivation of JC virus may provoke progressive multifocal leukoencephalopathy (PML), a potentially fatal CNS infection that causes widespread white matter destruction. Recent research indicates that the risk of PML exists in patients who have antibodies to the JC virus. A serum JC virus antibody test is available to determine previous exposure and thus risk for the development of PML. Approximately 50% of the general population has previous exposure to the JCvirus.18,19 Natalizumab is in pregnancy category C.

Mitoxantrone is an immunosuppressant treatment approved for the treatment of secondary progressive MS, worsening relapsing MS or progressive relapsing MS. It is used infrequently due to the high risk for long-term complications. Clinical trials demonstrated a reduction in relapse rate, reduction in disability progression and favorable MRI outcomes. Currently, mitoxantrone is used infrequently due to numerous and significant risks. Mitoxantrone suppresses the immune system; therefore careful post-dose complete blood count monitoring is necessary. Due to known cardiotoxicity, mitoxantrone is generally administered every 3 months for a lifetime maximum dose of 140 mg/kg. Testing of left ventricular ejection fraction is necessary prior to and during treatment and is recommended annually following completion of treatment. In addition, an increased risk of acute myelogenous leukemia develops after mitoxantrone treatment. Mitoxantrone is a pregnancy category D drug.

Communication Is Essential

MS is a chronic disease with a complex pathophysiology. Once diagnosis is made, patients should initiate a disease-modifying treatment to reduce relapses and the likelihood of additional disability. The 10 available FDA-approved DMTs for the treatment of relapsing forms of MS have varying mechanisms of action, differing side effect profiles, and differing risk-benefit profiles. These medications have positive effects on relapse rate and disability progression. Several more DMTs are in the development pipeline.

Most patients will take more than one DMT over the course of their disease. NPs and PAs must be cognizant of the effects of all MS medications on the immune system as well as other systems and be mindful that, in some cases, a switch from one medication to another must be well planned.

While the DMTs are important in the overall management of MS, a comprehensive approach that incorporates expertise from other disciplines is usually necessary for optimal lifetime management. NPs and PAs should maintain open lines of communication with their MS patients to ensure adherence as well as the safety and efficacy of their treatment plans. 

References:

1. Noonan CW, et al. The prevalence of multiple sclerosis in 3 US communities. Prev Chronic Dis. 2010;7(1):A12.

2. Compston A, Coles A. Multiple sclerosis. Lancet. 2008;372(9648):1502-1517.

3. Roach ES. Is multiple sclerosis an autoimmune disorder? Arch Neurol. 2004;61(10):1615-1616.

4. Balcer LJ. Clinical practice. Optic neuritis. N Engl J Med. 2006;354(12):1273-1280.

5. Saul RF, et al. Visual evoked potentials during hyperthermia. J Neuroophthalmol. 1995;15(2):70-78.

6. Polman CH, et al. Diagnostic criteria for multiple sclerosis: 2010 revisions to the McDonald criteria. Ann Neurol. 2011;69(2):292-302.

7. Lublin FD, Reingold SC. Defining the clinical course of multiple sclerosis: results of an international survey. National Multiple Sclerosis Society (USA) Advisory Committee on Clinical Trials of New Agents in Multiple Sclerosis. Neurology. 1996;46(4):907-911.

8. Jacobs LD, et al. Intramuscular interferon beta-1a therapy initiated during a first demyelinating event in multiple sclerosis. N Engl J Med. 2000;343(13):898-904.

9. Kappos L, et al. Treatment with interferon beta-1b delays conversion to clinically definite and McDonald MS in patients with clinically isolated syndromes. Neurology. 2006;67(7):1242-1249.

10. Comi G, et al. Effect of glatiramer acetate on conversion to clinically definite multiple sclerosis in patients with clinically isolated syndrome (PreCISe study): a randomised, double-blind, placebo-controlled trial. Lancet. 2009;374(9700):1503-1511.

11. Comi G, et al. Comparison of two dosing frequencies of subcutaneous interferon beta-1a in patients with a first clinical demyelinating event suggestive of multiple sclerosis (REFLEX): a phase 3 randomised controlled trial. Lancet Neurol. 2012;11(1):33-41.

12. Kappos L, et al. A placebo-controlled trial of oral fingolimod in relapsing multiple sclerosis. N Engl J Med. 2010;362(5):387-401.

13. O'Connor P, et al. Randomized trial of oral teriflunomide for relapsing multiple sclerosis. N Engl J Med. 2011;365(14):1293-1303.

14. Kappos L, et al. Efficacy and safety of oral fumarate in patients with relapsing-remitting multiple sclerosis: a multicentre, randomised, double-blind, placebo-controlled phase IIb study. Lancet. 2008;372(9648):1463-1472.

15. Gold R. Oral therapies for multiple sclerosis: a review of agents in phase III development or recently approved. CNS Drugs. 2011;25(1):37-52.

16. Killestein J, et al. Oral treatment for multiple sclerosis. Lancet Neurol. 2011;10(11):1026-1034.

17. Polman CH, et al. A randomized, placebo-controlled trial of natalizumab for relapsing multiple sclerosis. N Engl J Med. 2006;354(9):899-910.

18. Monaco MC, Major EO. The link between VLA-4 and JC virus reactivation. Expert Rev Clin Immunol. 2012;8(1):63-72.

19. Fox RJ, Ruddick RA. Risk stratification and patient counseling for natalizumab in multiple sclerosis. Neurology. 2012;78(6):436-437.

Bryan Walker is a physician assistant who is an assistant professor in the Department of Physician Assistant Studies at The George Washington University School of Medicine and Health Science in Washington, D.C. Kathleen Costello is an adult nurse practitioner at the Johns Hopkins Multiple Sclerosis Center in Baltimore, and an assistant professor at the Johns Hopkins School of Medicine. The authors have completed disclosure statements and report the following: Walker holds a limited number of stock options in Biogen Idec. Costello has served on scientific advisory boards for Teva Neuroscience, Genzyme, Sanofi, Aventis, Biogen Idec, EMDSerono, Questcor and Novartis.




     

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