Stopping High-Efficacy MS Drugs Raises Relapse Risk for Older Patients

Patients ages 50 or older with non-active multiple sclerosis (MS) who discontinued high-efficacy therapy (HET) had a higher risk of relapse compared with those who continued HET, a matched observational cohort study found.

Time to first relapse in the HET discontinuation group was significantly shortened compared with the continuation group (hazard ratio [HR] 4.1, 95% CI 2.0-8.5, P<0.001), especially for natalizumab (Tysabri) and fingolimod (Gilenya), according to Anne Kerbrat, MD, PhD, of the University Hospital of Rennes in France, and colleagues.

The increase in relapse risk was highest for older patients who stopped natalizumab (HR 7.2, 95% CI 2.1-24.5, P=0.001) or fingolimod (HR 4.5, 95% CI 1.3-15.5, P=0.02), the researchers reported in JAMA Neurology.

For anti-CD20 therapies included in the study -- rituximab and ocrelizumab (Ocrevus) -- the increase in relapse risk was not significant (HR 1.1, 95% CI 0.3-4.8, P=0.85).

"In particular, the risk was much higher after discontinuation of HETs that impact immune cell trafficking (natalizumab and fingolimod) than after discontinuation of treatments that deplete B-cells (anti-CD20 therapy), as illustrated by the probability of relapse at 1 year in each HET subgroup," Kerbrat and colleagues wrote.

Several studies have confirmed a decrease in MS relapse rate and MRI activity as age increases, the researchers noted. Treatment effectiveness also may decline with age, while the risk of side effects may increase, they added.

This study shows "a relatively surprising amount of new disease activity in a relatively older population with high levels of disability -- which may well reflect not only going off the drug, but that these individuals had relatively high activity prior to going on the highly effective therapy," said John Corboy, MD, of the Rocky Mountain MS Center at the University of Colorado in Aurora, who wasn't involved with the study. "We know that is a major risk for occurrence of disease activity," he told MedPage Today.

The recent randomized DISCOMS trial, led by Corboy, reported a much lower percentage of relapses after treatment discontinuation, but DISCOMS participants were older on average -- their mean age was 63 -- and they tended to have lower levels of disability, he said. Most DISCOMS participants also used older, injectable MS drugs at baseline.

"I think this work is complementary to the work performed by John Corboy because [the DISCOMS study included] less than 10% of patients with MS with high-efficacy therapies," Kerbrat said in a JAMA Neurology podcast interview.

Kerbrat and colleagues analyzed data from the Observatoire Français de la Sclérose en Plaques (OFSEP) French MS registry. Of 1,620 registry patients ages 50 or older on HET from 2008 through 2021, the mean age was about 55 and 72.5% were women.

All participants had relapsing-remitting MS or secondary progressive MS, no evidence of relapse or MRI activity in 2 years or more, and an HET duration of 1 year or more. Patients were propensity-scored matched into two groups depending on whether they had stopped or continued HET.

High-efficacy treatment included natalizumab, fingolimod, rituximab, and ocrelizumab. First relapse was defined as appearance, recurrence, or aggravation of neurologic symptoms for a period of at least 24 hours without fever, validated by a neurologist.

Most patients (75.7%) had relapsing-remitting MS, and mean delay since last inflammatory activity was 5.6 years. Mean follow-up duration after propensity score matching was 2.5 years, and 154 patients were selected for each treatment group after matching -- 51 treated with fingolimod, 45 with natalizumab, and 58 with anti-CD20 therapy.

For those who discontinued therapy, the probability of a first relapse at 1 year was 33.6% for natalizumab, 16.3% for fingolimod, and 0% for anti-CD20 therapy. Relapse risk in the secondary progressive MS subgroup was not significantly higher with HET discontinuation compared with continuation.

MRI data showed that time to first focal inflammatory activity was significantly reduced in the discontinuation group compared with the continuation group, and the probability of inflammatory activity varied by HET.

Potential limitations of the registry-based study were ensuring that HET discontinuation didn't reflect a switch in treatment, along with limited available MRI data. The lower age limit of 50 years, the authors acknowledged, was "young in view of the available data on immunoscience." Though risk of relapse decreased with age, the study could not reliably estimate risks for stopping HETs after age 60, they added.

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