Caroline Helwick

May 29, 2017

NEW ORLEANS — Can some patients with multiple sclerosis (MS) discontinue disease-modifying therapy (DMT) without harm? The evidence is limited, but results of a literature review suggest it may be a reasonable option to discuss with certain patients, researchers say.

"DMTs are known to modify relapse rates and progression of disability early in relapsing-remitting MS (RRMS); however, it remains unknown whether they continue to be effective late in the course of RRMS, older patients, and secondary progressive MS (SPMS)," said Devyn Parsons, a medical student at the University of British Columbia (UBC), Vancouver, who led a study to address this question. The senior investigator was Anthony Traboulsee, MD, also at UBC.

In a literature review conducted through 2017, researchers found no randomized controlled trials but identified six observational studies that addressed the issue. Altogether, the findings suggested some patients may be candidates for stopping DMT, Parsons told attendees here at the Consortium of Multiple Sclerosis Centers (CMSC) 2017 Annual Meeting.

While the researchers called their work "an evidence-based review with expert recommendations," Parsons acknowledged that the existing literature is "poor quality" and their review offers "just a sense of what's out there."

Generally, the data suggest that patients with SPMS who lack evidence of disease activity for at least 1 year, and those with RRMS who are 65 years of age and older without active disease for at least 1 year, could be candidates.

But Parsons cautioned, "It would be a mistake at this point to tell a patient, 'You can come off your DMT and you'll be fine.' There is no evidence to support that."

A "Dangerous" Idea?

The findings were met with skepticism and even alarm by some attendees, however. Samuel F. Hunter, MD, PhD, for one, said he considers stopping DMT "dangerous."

"When we treat with a DMT, we do it because we know 20% of patients are destined to get worse. You're saying we should stop the drug and let those people who are going to progress do so, and we'll treat them again," he told Parsons.

Dr Hunter also suggested that this practice would "give license to payers to deny people therapy that physicians think they need. This is a very dangerous thing to put in the MS literature. It will only be used for harm to MS patients."

For the analysis, researchers found three observational studies to be informative.

A prospective study in 2013 included 40 patients who discontinued DMT after at least 5 years of continuous use of one agent and no new disease activity (Arq Neuropsiquiatr. 2013;71:516-520). After 46 months of follow-up, 90% remained free of clinical attacks and 85% had stable magnetic resonance imaging (MRI).

In 2015, Kister et al evaluated 303 patients (age ≥ 40 years) who discontinued DMT after at least 3 years and no clinical relapses in the last 5 years (ECTRIMS Online Library. 2015;8:82). They found that most patients resumed DMT use because of increased disease activity after stopping; however, there was a 25% reduction in the rate of restarting DMT for every 10-year increase in age.

In 2016, the same group evaluated 485 patients who stopped DMT and 854 propensity-matched controls who continued DMT (J Neurol Neurosurg Psychiatry. 2016;87:1133-1137). Mean annualized relapse rates and time to first relapse were similar for those who discontinued (0.27, 1.8 years) or continued treatment (0.25, 2.0 years), but time to confirmed disability progression was shorter among those who stopped.

Another study looked for independent predictors of remaining relapse-free after stopping DMT, which were found to be age 45 and older, lack of relapse in the prior 4 years, and absence of contrast-enhancing lesions.

Other studies have shown that risk of relapse was greater for patients who stopped natalizumab than those who stopped platform DMTs, and increased age was associated with decreased likelihood of relapse among SPMS patients. Several investigators have reported a risk for rebound syndromes following discontinuation of natalizumab and fingolimod, Parsons said.

The researchers also considered what is known about the natural history of MS — that disease activity decreases with increasing patient age, with fewer clinical relapses and fewer new MRI lesions, and that relapses have less impact on disease progression with greater time from disease onset.

Potential Candidates

Putting the findings together, the researchers suggest that a conversation about discontinuing DMT could be "reasonable" for the following patient subsets:

  • Patients with SPMS who have ongoing progression and no new brain or spinal cord MRI lesions in the prior 12 to 24 months.

  • Stable RRMS patients, aged 65 or older, with no brain or spinal cord MRI lesions in the prior 12 to 24 months.

  • Stable RRMS patients, aged 55 to 65, with no new brain or spinal cord lesions during the prior 5 years.

  • Patients who are pregnant, trying to conceive, or breastfeeding (because of safety concerns).

Issue Debated at CMSC

Whether DMT can be safety discontinued in older patients or SPMS was the topic of a debate at another CMSC session

"We've all had middle-aged patients in whom we stop treatment, and they relapse," Olaf Stuve, MD, PhD, professor of neurology and neurotherapeutics at UT Southwestern Medical Center, Dallas, Texas, commented. "We should not use age and duration of treatment as the main factors in determining stopping.... Is the patient really clinically stable or are they responding to treatment? We might consider being relapse-free for 5 years to be an adequate response to the drug."

Mitchell T. Wallin, MD, MPH, of the Washington DC VA Medical Center, agreed that one runs the risk of breakthrough disease when DMT is withdrawn, "but you can be pretty confident that taking an older patient off platform drugs is relatively safe." The key is to follow patients very closely to monitor for new lesions, he said.

To study this question in a more formal way, John Corboy, MD, of the University of Colorado in Denver, is leading a multicenter randomized controlled trial of DMT discontinuation in MS patients aged ≥ 55 who have had no relapses or brain MRI changes for at least 5 years on continuous DMT.

The study was supported by Sanofi Genzyme. Drs Parsons, Hunter, Stuve, and Wallin have reported no relevant financial relationships.

Consortium of Multiple Sclerosis Centers (CMSC) 2017 Annual Meeting. Abstract DX03. Presented May 26, 2017.

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