Clinical Challenges: Determining When to Stop MS Therapy as Patients Age

Stopping multiple sclerosis (MS) treatment as patients age can be a fraught decision, but there are some signposts to help guide the way.

This neurological disease of inflammatory damage to the brain most commonly starts in the second or third decade of life, and then by the fifth decade patients see declines in the frequency of new lesions on imaging and clinical relapse.

At the same time disease activity is declining, the risks of treatment with immune-modulating therapies increase, such as infection and malignancy.

After the first MS disease-modifying therapy was approved in 1993, “we probably began seeing shot fatigue as early as 1995,” noted John Corboy, MD, of the University of Colorado in Aurora. “That was the earliest sign that there was going to be likely some pushback from patients that they were not going to necessarily want to take these drugs for up to 10, 20, 30 years.”

Along with daily self-injections, some drugs had flu-like side effects and others had injection-site reactions. As individuals started “voting with their feet” to stop medication, observational studies emerged. The evidence was fairly inconclusive until recently, when the DISCOMS trial was published in the Lancet Neurology.

In that trial of 259 patients ages 55 years and older, with no relapse within the past 5 years or new MRI lesion in the past 3 years while continuously taking disease-modifying therapy, discontinuation of those medications didn’t prove non-inferior to continuation for the primary composite outcome of relapse or new or expanding brain MRI lesion within 2 years, with rates of 12.2% versus 4.7%.

This finding was driven by radiological activity, without any definite differences between groups in hard outcomes. Progression of disability as measured by Expanded Disability Status Scale was similar between the discontinue- and continue-medication groups (mean change -0.1 vs +0.1, P=0.39). In a post-hoc analysis, relapse with new disease activity occurred in only three of the 131 discontinue-therapy patients (2%) and one of the 128 continue-therapy patients (<1%), for an event rate difference of 1.5% (95% CI -2.3 to 6.0, P=0.0051). “Thus, we could reject the null hypothesis of inferiority and conclude that discontinuing disease-modifying therapy was non-inferior,” the researchers wrote.

“It was remarkable that there were so few events on or off drug,” said Corboy, the lead author of the study. “Although we don’t have a definitive answer, the reality is that we have a significant amount of data.”

Having that data is a huge advance that helps with discussions in the clinic, said co-author Robert Fox, MD, of the Cleveland Clinic Mellen Center for MS, in an interview monitored by media relations.

“Right now, it’s a conversation more likely brought up by the clinician, because these patients have been on these therapies for 5, 10, 15, sometimes 20 years,” he said. “They sort of assume they’re on it for life. And we say, ‘You know what, you may not need this for life. You may be at a point where we can think about stopping.’ And they’re usually surprised, pleasantly surprised, and then we get into the conversation.”

While the trial enrollment criteria were somewhat empirically chosen, Fox said he roughly follows them in clinical practice as well, initiating a conversation typically when patients reach around age 55.

“What it comes down to is whether patients are tolerating the therapy, whether they’re having complications from the therapy like recurrent infections, whether they’re affording the therapy — out-of-pocket co-pays and things like that, that’s what usually ends up driving things — and their fear of a relapse,” Fox noted.

For those who don’t want to “fix what isn’t broken,” he recommends only bringing it up again if clinical circumstances provide another decision point.

“My job is not to stop them on therapy. My job is to inform them of their choices, and help make sure they have the right information to make the right choice for themselves,” he said. “But if they’ve had some struggles with respiratory infections, or they had a bad influenza even though they got the flu shot, I may say, ‘Alright, well, we’ll kind of revisit this next year. Let’s see how you go through this flu season.'”

In DISCOMS, the number of upper respiratory infections and SARS-CoV-2 infections did not differ between groups, “despite the reasons for considering discontinuation in clinical practice being generally related to safety or tolerability issues,” Kristen Krysko, MD, of the University of Toronto and St. Michael’s Hospital in Toronto, wrote in an editorial accompanying the paper in the Lancet Neurology.

Her concern was that the trial’s relatively short follow-up “does not allow for conclusions about the long-term effects of discontinuation or the effects of short-term MRI activity on longer-term outcomes. This limitation is important because, with the availability of high-efficacy therapies in clinical practice, clinicians and patients often aim to reach a state in which there is no evidence of disease activity, as this has been associated with lower odds of long-term disability progression.”

An extension study of DISCOMS is underway to answer some of those questions, Corboy noted, which so far has “simply found very little disease activity” in longer-term follow-up.

There’s no data on whether it would be better to just de-escalate to lower-risk therapies rather than discontinuing altogether, Krysko noted. “Most participants in [the DISCOMS] study discontinued interferon beta or glatiramer acetate and the results probably do not apply for individuals who are discontinuing higher-efficacy therapies — especially drugs known to have risks of rebound disease activity on discontinuation, such as natalizumab [Tysabri] and the sphingosine-1-phosphate receptor modulators.” She cited an observational study in adults 45 years and older showing higher probability of relapse after stopping natalizumab than after stopping first-line disease-modifying therapies.

The “consequences of breakthrough activity can be clinically significant, especially because individuals later in the disease course can have poorer recovery from relapses than those at an earlier stage of disease,” she added. She agreed with Fox that the decision must be based on an individualized risk-benefit discussion.

In the absence of any guidelines on follow-up after stopping therapy, most clinicians have opted for an MRI every 6 to 12 months.

“We’re still figuring this out in the field,” Fox noted. “The more-worried patient, we may do 6; the less-worried patient, we may do 12.”

When a new spot on MRI does show up after treatment discontinuation, it prompts another discussion, Fox said: how many, how big, and how typical of MS versus nonspecific small vessel ischemia that is typical with aging in healthy populations?

“Just as we make changes in MS therapy, in the earlier stages, just based on MRI disease activity, we’ll do that here as well,” he said. It’s also an opportunity to revisit which treatment they might take.

If older patients continue to do well off drug for a couple of years, they may get at least annual office visits with MRI scans at least every 2 to 3 years, Corboy added. “We don’t know everything about what all the risks are, and so continually monitoring does matter.”