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New Study Makes the Case for Early Aggressive Treatment for Multiple Sclerosis

Article In Brief


The graph compares the cumulative hazard of conversion to SPMS by timing of treatment.

In a large cohort study of MS patients based on real-world data, early treatment with natalizumab, fingolimod, or alemtuzumab was associated with a lower risk of conversion to secondary progressive MS compared with interferon beta or glatiramer acetate.

Aggressive treatment of relapsing-remitting multiple sclerosis (RRMS) can reduce the risk of conversion to secondary progressive MS (SPMS), particularly when it is started early after disease onset, according to a new study that compared differing approaches to disease-modifying therapy.

The study, published January 15 in the JournaloftheAmericanMedicalAssociation (JAMA), found that patients with RRMS who were treated initially with fingolimod, alemtuzumab, or natalizumab had a lower risk of developing SPMS compared with patients who began treatment with glatiramer acetate or interferon beta.

The study also found that no matter what type of disease-modifying therapy was used in patients with early signs of MS, treatment was better than no treatment, and the earlier the treatment, the better the outcomes.

The study, which relied on observational data, is not definitive, but the results could be helpful to doctors who must weigh the pros and cons of moving right to high-potency, though higher-risk, disease-modifying MS drugs compared with starting patients on interferon-beta or glatiramer acetate, older injectable drugs that are considered to have a lower-risk profile for side effects, the study authors said. The newer MS agents are also costly, they noted.

“This study shows us how important it is to treat relapsing MS early and proactively,” said one of the study's lead authors, Tomas Kalincik, PhD, who is head of the Clinical Outcome Research Unit at the University of Melbourne and head of MS and Neuroimmunology at The Royal Melbourne Hospital in Australia.

Dr. Kalincik said in an email to NeurologyToday that the “capability to delay progression of disability represents an important outcome for people living with multiple sclerosis.”

An editorial published online on January 15 in JAMA Neurology noted that “mounting evidence suggests that intervention with immunomodulatory or other immunotherapeutic agents actually bends the arc on the long-term progression of MS.” The editorial, by Ari Green, MD, chief of the division of neuroinflammation and glial biology at University of California, San Francisco (UCSF), urged doctors to stop equivocating over whether to start with heavier-hitting drugs. “Waiting on the sidelines does not appear justified,” he wrote.

The study authors pointed out that prior research has shown that 80 percent of patients with RRMS convert within two decades to SPMS.

“This phase is responsible for much of the disease's negative physical, psychological and societal effects,” they wrote.

The researchers noted that studies have shown that fingolimod, alemtuzumab, and natalizumab “confer greater reduction in relapse rate[s] than glatiramer acetate or interferon beta,” but it is unclear whether they are associated with a lower risk of conversion to SPMS.

Study Design

The new study drew on data from several cohorts of patients with RRMS, many of whom (1,272) were included in MSBase, an observational cohort study that collects real-world data on MS patients at 105 centers in 29 countries. The study also included a cohort of 230 patients from the University Hospital at Wales, who had not received any disease-modifying therapies, and 53 patients who were treated with alemtuzumab in Europe before the drug was licensed.

All patients in the study had been classified as having RRMS and had at least one Expanded Disability Status Scale (EDSS) score within six months before baseline and at least two EDSS scores after baseline. The patients had a minimum of four years of follow-up. An objective definition of SPMS was used to determine conversion.

At five years, 7 percent of patients who started on fingolimod, alemtuzumab, or natalizumab had converted to SPMS compared with 12 percent of those who were initially treated with glatiramer acetate or interferon beta; 27 percent of matched untreated patients converted to SPMS.

Treatment with either glatiramer acetate or interferon beta had the largest benefit when it was started within five years of disease onset (3 percent versus 6 percent conversion with later initiation).

When patients were escalated to fingolimod, alemtuzumab, or natalizumab within five years of disease onset the rate of conversion was lower (8 percent) compared to those who made the switch to these therapies later (14 percent).

Dr. Kalincik said that study shows “that treating aggressively, using higher-efficacy therapies early in the disease, may provide the most long-term benefits for delaying the onset of progressive disease,” but he said that doesn't mean that all patients with RRMS should be on aggressive therapy.” He said a question that still needs to be addressed through research is how to “select the right patients who will benefit from early aggressive treatment.”

“As is always the case [in everyday practice], a variety of factors need to be taken into consideration when deciding on the most appropriate treatment for a patient living with multiple sclerosis,” said Dr. Kalincik. Physicians and patients need to consider “the desires of the individual, their current life situation (for example, employment, family planning, etc.) and the side-effects and risk profile that they are comfortable with.”

The study had limitations, the study authors pointed out. For one, the authors noted that “given its observational design, the study is unable to ascribe causality and cannot distinguish between prevention and delay or conversion to secondary progressive MS.”

The method of matching treated patients to untreated patents likely also had some shortcomings. The study spanned a number of years (1988-2012) but MS care, including medications, changed over that time period, which could have also affected outcomes measured in the study.

Expert Commentary

Benjamin Segal, MD, professor of neurology and director of the Multiple Sclerosis Center at University of Michigan, said the study merits attention because it provides added insight into one of the most hotly debated questions in MS care.

“I tend to be more aggressive in my approach to MS [cases] that present with poor prognostic factors because I have seen the damage that can occur with suboptimal treatment,” said Dr. Segal, “However, treatment strategies should be informed by the patient's clinical course, degree of disability, and modifying factors.”

“The therapeutic approach should be personalized. You have to take into account patients' vulnerability to side effects, how side-effect adverse they are, and what their lifestyle is,” Dr. Segal said. While many side effects of disease-modifying therapies are manageable, he said there is potential for dangerous side effects with particular medications. For instance, natalizumab has been tied to an elevated risk of progressive multifocal leukoencephalopathy and fingolimod may elevate the risk for herpes zoster infection, he said.

On the other hand, holding off on potent drugs until MS worsens is problematic because the disease course is diverse, and there is no reliable way to predict when an exacerbation will occur that causes long- term disability, he said.

“There is no good evidence that initiation of disease-modifying drugs when an individual is already in the progressive stage will curtail the accumulation of disability,” Dr. Segal said.

Elias S. Sotirchos, MD, a clinical and research fellow in multiple sclerosis at Johns Hopkins Hospital, said the new findings “provide important additional evidence that halting inflammation early on in the disease course prevents long-term disability in MS,” adding: “Aggressive therapy from the start should be especially considered in MS patients with poor prognostic factors, including incomplete recovery from prior attacks, non-sensory symptoms, spinal cord involvement, and high MRI lesion load.”

“There are many factors that should be taken into account when selecting the initial therapy, and the patient's preference and risk tolerance are extremely important in guiding this discussion in the clinic,” said Dr. Sotirchos, whose fellowship is supported by the National Multiple Sclerosis Society. He said no matter which therapy is picked, “it has to be revisited frequently.”


“I tend to be more aggressive in my approach to MS [cases] that present with poor prognostic factors because I have seen the damage that can occur with suboptimal treatment. However, treatment strategies should be informed by the patients clinical course, degree of disability, and modifying factors.”—DR. BENJAMIN SEGAL


“This study shows us how important it is to treat relapsing MS early and proactively.”—DR. TOMAS KALINCIK


The graph compared the cumulative hazard of conversion to SPMS with initial treatment with glatiramer acetate or interferon beta compared with fingolimod, alemtuzumab, or natalizumab.

Dr. Sotirchos said more insight into the impact of initial therapy selection in MS is likely to come from ongoing multicenter randomized-controlled trials, including the TREAT-MS and DELIVER-MS studies, which are comparing clinical and imaging outcomes between an “early aggressive” and a traditional “escalation” therapeutic approach.

While the study did not address costs, one element in the debate over which MS drugs to use and when has been cost, with the newer MS drugs carrying big price tags.

Dr. Green, medical director of the UCSF Multiple Sclerosis and Neuroinflammation Center, told Neurology Today, “There are logistical challenges to changing clinical practice because physicians can be prevented by payers from getting patients the most efficacious drugs.” He said some “payers enact step edits and argue that they are curtailing cost in the public interest.”

Dr. Green said that while newer MS medications are very expensive, “disabled patients are way costlier to society than most of these medicines. A high cost for medicines that prevent disability may be justified.”

Jack Antel, MD, professor of neurology and neurosurgery at McGill University, said the new study does not provide a definitive answer to the question of whether stopping the early inflammation in MS will have an effect on long-term outcomes. Still, he said, the current study is noteworthy because it was based on “real-world data and very large numbers.”

He said the challenge for doctors is to “try and make some judgment on what is the safest, most effective medicine” for any given patient based on their clinical symptoms and MRI, as well as their tolerance for side effects and acceptance of long-term risks.

“What we are trying to predict is ‘How difficult is it going to be to control their disease?” he said, which isn't necessarily easy to do. For instance “people can get progressively worse even if there are no new apparent lesions.”

Also, Dr. Antel said the line between RRMS and SPMS is not always clear because people have relapses become worse from them. “Relapses do matter,” he said, adding: “The issue of progressive MS is a complicated one in that it really means a person is not doing as well now [as he or she did] two or three years ago.”


Dr. Kalincik reported receiving travel expenses, advisory board fees, and speaking honoraria from WebMD Global, Roche, Sanofi-Genzyme, Novartis, Teva, BioCSL, Merck; he received grant support from the Australian National Health and Medical Research Council, the Faculty of Medicine, Dentistry, and Health Sciences of the University of Melbourne Foundation d'Aide pour la Recherche sur la Sclerose en Plaques, and Biogen. Dr. Sotirchos reported no disclosures. Dr. Antel received compensations for serving on safety monitoring or advisory committees from WAVE Life Sciences, Biogen IDEC, Medday, and Sanofi Aventis. He has received grant support to McGill University from Novartis, Roche, and Medday.

Link Up for More Information

• Brown JW, Coles A, Horakova D, et al; for the MSBase Study Group. Association of initial disease-modifying therapy with later conversion to secondary progressive multiple sclerosis JAMA 2019; 321(2): 175–187.
• Green AJ. Potential benefits of early aggressive treatment in multiple sclerosis JAMA Neurol 2019; Epub 2019 Jan 15.