Doctors Urged to Consider Newer Agents to Gain Maximal Efficacy in Initiating Treatment for Multiple Sclerosis


Session at the 2014 AAN annual meeting contrasts a "tiered" treatment strategy that focuses on safety with a "maximal efficacy" approach and offers an in-depth review of the clinical benefits and potential side effects of the current array of treatments for multiple sclerosis.

Although there are a host of options available for treating multiple sclerosis (MS), the practicing clinician will find relatively little guidance to help optimize treatment for individual patients, according to the University of California-San Francisco’s Bruce Cree, MD, PhD. He presented a review of treatment choices and strategies at the American Academy of Neurology annual conference on April 30, 2014, in Philadelphia, PA

In framing choices for clinicians, Cree noted that strategies for initiating treatment may vary; further, there is a dearth of good “switch” studies, which would give guidance about changing MS treatment when a patient is not tolerating a medication or not responding to treatment. However, a thorough understanding of the efficacy and safety profiles of some of the newer choices among MS drugs can help with logical and patient-centered decision making.

Cree began the discussion by proposing that initial treatment planning could be guided by one of two strategies. The first would involve a tiered strategy, beginning with medications generally accepted as safer, but which may be less efficacious. Treatment response can be assessed by relapse incidence, disability progression, and changes in imaging findings. An alternate strategy, reviewed below, would try for maximal efficacy from the initial time of treatment forward.

Medications generally considered to be “first-tier” would be the interferons, along with glatiramer acetate (Copaxone), according to Cree. Some clinicians might also place fingolimod (Gilenya), teriflunomide (Aubagio), and dimethyl fumarate (Tecfidera) in the first-line category. The common side effects associated with interferon therapy are significant but well known, and clinicians can be vigilant for worsening or serious effects. Similarly, glatiramer acetate can cause post-injection site reactions, flushing, and chest pain, all of which can be anticipated and monitored.

For some clinicians and some patients, fingolimod’s safety profile might place it in the second-line column. Mitoxantrone (Novantrone) and natalizumab (Tysabri), also generally considered less safe, would similarly be considered second-line therapy. This tiered approach has the advantage of being easily understood by patients and families, and uses proven agents with well-known safety and side effect profiles. On the other hand, Cree said this tiered treatment strategy does not take individual patient needs into account.

For many patients, natalizumab will be considered: it has been proven effective, with a 68-70% reduction in relative risk (RR) of relapse and a 42-54% reduction in hazard ratio (HR) for disability progression. However, individuals who are positive for the John Cunningham virus (JCV) antibody are at increased risk for progressive multifocal leukoencephalopathy (PML), a potentially devastating complication. About 50% of individuals carry the JCV antibody, and their risk for PML may be particularly high if they have had prior immunosuppression.

Fingolimod, another effective treatment, yields an overall 54% reduction in RR of relapse and a 30% reduced HR for disability progression. There is no clear risk of PML associated with this treatment, so it can be used in JCV seropositive individuals. However, bradyarrhythmias can result, so a baseline EKG, along with vital sign monitoring and an EKG at dosing and six hours after administration are recommended. The risk of undetected macular edema can be mitigated by obtaining a baseline ophthalmologic exam with follow-up exams every 3-4 months. Spirometry at similar intervals can monitor lung function. The risk of infection can be reduced by providing varicella zoster immunization before treatment initiation, avoiding concurrent steroid use when possible, and avoiding administration of live attenuated vaccines.

Among the oral agents, teriflunomide is an option for many patients. It carries an overall 32% reduction in RR of relapse and a 30% decrease in HR for disability progression. Hepatic and renal function must be monitored, and patients should be counseled about risk for neuropathy, alopecia, and hypertension. Blood pressure should be monitored regularly. Teriflunomide is pregnancy category X, with teratogenicity shown in animal models (though available human data do not show elevated risk of adverse pregnancy outcomes). Clinicians should provide pretreatment counseling to avoid pregnancy; if pregnancy should occur, the drug should be eliminated immediately with cholestyramine or activated charcoal.

Dimethyl fumarate is taken as a twice-daily capsule, and shows an overall 53% decrease in RR of relapse and a 38% reduction in HR for disability progression. There is a theoretic risk of PML with this medication, so checking JCV serology before starting treatment is recommended. Baseline and follow-up CBC and liver function testing can monitor for the risk of elevated liver enzymes and lymphopenia. GI side effects are common; flushing can be minimized with the co-administration of aspirin.

Returning to treatment strategies, Cree proposed considering a “maximal efficacy” rather than a tiered approach. In this model, the most efficacious treatment should be the first one considered, if patient characteristics allow. Natalizumab might then be the first drug considered for JCV-negative individuals. Fingolimod would also be an initial choice, with efficacy arguably superior to the interferons. Cree also made the point that oral medications are better tolerated and may result in better adherence than self-injectibles, another important consideration.

The maximal efficacy approach may allow for early disease modification, reducing inflammation initially, with later transition to a “maintenance” phase with what are now considered first-line treatments. This treatment strategy, with initial use of potentially cytotoxic medications to modify disease course, borrows from oncology. Cree encouraged industry and academia to conduct more long-term observational studies comparing the two approaches; in this way, clinicians can be guided to help patients reach the best outcomes.

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