expert roundtables

Treatment Strategies for Reducing Active Symptoms and Delaying Disability in Patients With Multiple Sclerosis

by David A. Hafler, MD, Staley Brod, MD, Dean Wingerchuk, MD, FRCP(C)

Overview

Many adults with multiple sclerosis (MS) are no longer able to work as early as 5 years after diagnosis, and this is most commonly because of disability. This is a major concern for patients who may live for 30 to 40 years with the disease. Disease-modifying therapies improve the physical disability for some patients with MS, but improving the cognitive disability remains an unmet need of this patient population. Results of randomized, placebo-controlled trials have shown that the rate of reduction in disability progression ranges from 12% to 42% among patients with relapsing-remitting MS treated with disease-modifying therapies compared with placebo. Treatment strategies depend on the individual patient and his or her prognostic factors. Some physicians may start with more aggressive therapies, especially if multiple poor prognostic factors are present, or they may decide that a step-wise approach to treatment may better suit the patient who presents with favorable prognostic factors. The risk of ongoing disease versus the risks of therapy need to be considered for each patient. Drugs that more effectively control the disease process and prevent disability progression may lead to decreased immune surveillance. On the other hand, the step-wise approach may lead to more treatment failures, with each failure contributing to disability progression for the patient. The disadvantage of this approach is that each time a patient fails a treatment, he or she accumulates brain or spinal cord damage. Our featured experts in the field discuss treatment strategies for reducing active symptoms and delaying disability in patients with MS.

Q: What is the most effective treatment strategy for reducing active symptoms and delaying disability in patients with MS?

David A. Hafler, MD

Chairman, Department of Neurology
Professor of Immunobiology
Yale School of Medicine
New Haven, CT

“Early B-cell depletion appears to have a major effect on stopping the inflammatory process associated with early MS, and may be the most effective drugs for stopping flare-ups with minimal side effects.”

David A. Hafler, MD

Although there have not been head-to-head comparisons of ocrelizumab (B-cell depletion), natalizumab (T-cell traffic blocking), or alemtuzumab (anti-CD52) with fingolimod or dimethyl fumarate, I think that most of us agree, and the literature strongly suggests, that the former drugs are most effective and should be used as a first line. Specifically, early B-cell depletion appears to have a major effect on stopping the inflammatory process associated with early MS, and may be the most effective drugs for stopping flare-ups with minimal side effects. Alemtuzumab is similarly a highly effective way of stopping relapses, but there is the issue of drug-induced autoimmunity. Approximately 35% of patients develop autoimmune thyroid disease, 1% to 2% of patients develop idiopathic thrombocytopenic purpura, and there have been a few reported cases of Goodpasture syndrome. This suggests that ocrelizumab may be the most cost-effective in terms of therapeutic index. Still, those 2 drugs are clearly the most effective. An additional issue with natalizumab is progressive multifocal leukoencephalopathy, with approximately half of the patients being positive for the JC virus. Also, some patients will have a flare-up when they discontinue taking natalizumab. However, while the most effective method of stopping the disease may be with ocrelizumab and alemtuzumab, the major question is whether these drugs stop the disease from entering the progressive phase later on. We do not know the answer to that question.

Staley Brod, MD

Professor of Neurology
Director, Division of MS/Neuro-immunology
Department of Neurology
Medical College of Wisconsin
Milwaukee, WI

“There are individuals I see clinically and I would like to start them on a drug such as alemtuzumab. Alemtuzumab, unlike ocrelizumab or natalizumab, provides 55% relapse-free activity at 7 years, without re-treatment.”

Staley Brod, MD

Despite some thoughts on platform therapies that I have expressed previously, and that most people do not need these kinds of aggressive treatments, I think that alemtuzumab is a unique kind of medicine because it does 2 things at once. The drug is immunosuppressive, for at least the first 2 years or longer, but it is also immune-reconstitutive, meaning that it does not affect the bone marrow directly, and it recruits more regulatory populations into the blood and into the immune system after several years. There are issues with the drugs, particularly as they affect the thyroid, and the autoimmune problems in the early return of B cells, but when you examine the evidence, you can superimpose the relapse-free 5-year data of alemtuzumab upon that of autologous bone marrow transplants, (There were a number of meta-analyses published last year, including 1 in JAMA Neurology [formerly Archives of Neurology] and 1 in Neurology.) Dr Hafler had mentioned that, throughout the world, alemtuzumab can be used as a first-line agent; however, in this country we are not allowed to use it until the patient “fails” 2 other therapies. There are individuals I see clinically and I would like to start them on a drug such as alemtuzumab. Alemtuzumab, unlike ocrelizumab or natalizumab, provides 55% relapse-free activity at 7 years, without re-treatment. This would be my approach to aggressive therapy, currently limited by our ability to get it through the insurers, the payers.

Dean Wingerchuk, MD, FRCP(C), MSc

Professor and Chair
Department of Neurology
Mayo Clinic
Phoenix, AZ

“The outcomes we are really looking for are prevention or delay of transition from relapsing MS to a more disabling progressive form of the disease.” 

Dean Wingerchuk, MD, FRCP(C)

That remains an open question and an area of active debate. There is no question that currently available therapies are beneficial, but in what order or sequence they should be used and which therapy should be used first remain a major challenge. In general, many clinicians have used, at least up until recently, a so-called step-wise approach where the clinician might start with a platform therapy such as a self-injectable interferon or glatiramer acetate, see how the patient does, and then escalate to a more effective therapy if there is breakthrough disease. More recently, there has been emphasis on considering the use of the more highly effective therapies earlier in the disease, even as a first-line therapy, for the reason that more successful suppression of all or the vast majority of inflammatory activity right from the beginning might translate into better intermediate and long-term success. The outcomes we are really looking for are prevention or delay of transition from relapsing MS to a more disabling progressive form of the disease. And there are some data now suggesting that, perhaps, highly effective early therapy may be more likely to achieve that. Some studies now are starting to directly address that issue.

References

Fernández Ó. Is there a change of paradigm towards more effective treatment early in the course of apparent high-risk MS? Mult Scler Relat Disord. 2017;17:75-83.

Mehr SR, Zimmerman MP. Reviewing the unmet needs of patients with multiple sclerosis. Am Health Drug Benefits. 2015;8(6):426-431.

Strober LB, Christodoulou C, Benedict RH, et al. Unemployment in multiple sclerosis: the contribution of personality and disease. Mult Scler. 2012;18(5):647-653.

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