Relapse Risk Higher in Nonactive MS With High-Efficacy Therapy Discontinuation

Older adults with nonactive multiple sclerosis (MS) who discontinue high-efficacy therapies (HET), such as fingolimod or natalizumab, without a relay therapy, may have a higher risk for relapse, according to study findings published in JAMA Neurology.

Typically, HET is initiated early in relapsing-remitting MS, especially in patients at high risk. However, there is a lack of data on discontinuing HET in older patients with nonactive disease, although studies suggest a possible age-dependent decrease in relapse rates and magnetic resonance imaging (MRI) activity.

Researchers conducted an observational cohort study to compare the risk for relapse in older patients with nonactive MS who discontinued HET vs those who continued it.

The researchers analyzed follow-up visit data extracted in June 2022 from 38 referral centers in the French MS registry (Observatoire Français de la Sclérose en Plaques [OFSEP] database). They identified 1620 patients aged 50 years and older (average age, 54.7; women, 72.5%) from a database of 84,704 individuals with relapsing-remitting MS. These patients were initiated on HET (rituximab, ocrelizumab, natalizumab, or fingolimod) and had no relapse or MRI activity for a minimum of 2 years and were followed for an average of 5.1 years.

The primary outcome was the time until the initial relapse, characterized as the onset, recurrence, or worsening of neurological symptoms lasting at least 24 hours without fever. Secondary outcomes included the time until the first occurrence of inflammatory activity and the time until confirmed disability progression.

Of the 1620 patients, 1452 continued HET while 168 discontinued HET.

Participants were paired 1:1 using propensity score matching, resulting in 154 patients being analyzed in both the HET continuation and HET discontinuation groups. Among the 154 patients continuing HET, 51 (33%) received fingolimod treatment, 45 (29%) were treated with natalizumab, and 58 (38%) received anti-CD20 therapy. In 92 out of 154 patients, treatment discontinuation reasons were primarily due to disability progression without relapse (22%), adverse effects (22%), and scheduled discontinuation (35%).

When compared to individuals continuing HET, those who discontinued HET experienced a significantly reduced time to first relapse with a hazard ratio (HR) of 4.1 (95% CI, 2.0 to 8.5; P <.001). This decrease in time varied across different HETs, showing HRs of 7.2 (95% CI, 2.1 to 24.5; P =.001) for natalizumab, 4.5 (95% CI, 1.3-15.5; P =.02) for fingolimod, and 1.1 (95% CI, 0.3-4.8; P =.85) for anti-CD20 therapies, highlighting the differences in effectiveness among the treatments.

Additionally, the researchers found a significant correlation between patient age and the likelihood of relapse after treatment discontinuation, with the nature of the discontinued treatment influencing the resurgence of inflammatory activity.

Out of 154 patients who stopped treatment, 69 (44.8%) resumed within 1.8 years, primarily with HET; 32 (46.3%) resumed anti-CD20 therapy, 19 (27.5%) resumed fingolimod, and 3 (4.3%) resumed natalizumab.

The primary limitations of the study included challenges in verifying treatment discontinuation without treatment switches in a registry-based setting and the lower level of evidence compared to randomized clinical trials despite propensity score matching.

“…[A]fter discontinuing natalizumab, a treatment that transiently blocks migration of lymphocytes to the central nervous system, the effects on immune cells start weeks after the last natalizumab dose and the risk of disease recurrence or rebound increases,” the researchers wrote. They concluded, “Our study confirmed these risks in an older population, suggesting that the mechanism of action of the interrupted treatment is an important factor, independent of patient age.”

Disclosure: Some study authors declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of disclosures.