Inflammatory Activity Persists After Discontinuing Disease-Modifying Therapy in Stable Multiple Sclerosis

Eva Strijbis, MD, PhD

Recently published findings from the DOT-MS noninferiority randomized trial (NCT04260711) showed that discontinuation of first-line disease-modifying therapies (DMTs) in patients with stable multiple sclerosis (MS) for over 5 years can lead to recurrence of inflammatory disease activity. Investigators concluded that an attempt to discontinue first-line DMT in this patient population is still a viable option, but close clinical, radiological, and perhaps biomarker-based monitoring should be mandatory.¹

Led by Eva Strijbis, MD, PhD, a neuroinfection and inflammation affiliate at Amsterdam University Medical Center, the trial featured 89 participants with relapsing-onset MS who were assigned to either continue (n = 44) or discontinue (n = 45) their DMT after 5 years of previous treatment. In total, 8 of the 45 participants in the discontinue (17.8%) group vs 0 of 44 participants in the continue group reached the primary end point and had recurrent, mostly radiological inflammation. Notably, 2 of these patients had a clinical relapse.

Conducted between July 2020 and March 2023, the study was prematurely terminated because of the observed inflammatory disease activity recurrence above the predefined limit. The study, carried out at 14 centers in the Netherlands, featured adults with the disease who used first-line DMT, and had neither clinical relapses nor substantial radiological disease activity (defined as no new contrast-enhancing lesions and 1 or more new T2 lesions on MRI) for at least 5 years before inclusion. In case the last available MRI scan was conducted 10 or more years ago, no more than 3 new T2 lesions suggestive of demyelination in the last 10 years were accepted.

Within the discontinue group, 6 of the 45 participants (13.3%) had 3 or more new T2 lesions or 2 or more contrast-enhancing lesions without relapse. The other remaining 2 patients (4.4%) with primary outcome events had a relapse without inflammatory MRI activity. While those with significant disease activity had a younger median age (46.0 [IQR, 43.5-58.5] vs 54.0 [IQR, 50.0-59.0]) this difference was not significant (P = .19). Among those who had significant disease activity, the median time to reaching eh primary end point was 12.0 months (6.0-12.0).

Over the long-term period, linear mixed-effects models showed that absolute neurofilament light (NfL) levels were not different between the 2 groups (ß, 1.23; 95% CI, –1.50 to 3.92; P = .37) but in participants with significant disease activity, NfL levels were higher relative to those without (ß, 6.92; 95% CI, 2.55-11.29; P = .003). In contrast, there were no differences between either the continue or discontinue groups or those with or without disease activity in terms of glial fibrillary acidic protein (GFAP).

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Despite the early termination, DOT-MS continued as a observational study where those who discontinued their DMT were offered to restart and were followed up for 2 years. Until the end of the study, 35 of the 45 participants (77.8%) in the discontinue group remained off treatment. Among participants with MRI activity in the discontinue group, only one did not restart DMT, and within six months, 10 of the 12 participants with any MRI activity were clinically and MRI stable, although two showed persistent disease activity on MRI despite restarting DMT.

In the study, the risk of inflammation recurrence in younger patients, which was unknown prior to DOT-MS, was significantly higher compared with those discontinuing DMT in the previously published phase 4 DISCOMS trial that only included individuals aged 55 years or older. The DISCOMS trial reported a 12.2% recurrence rate after DMT discontinuation, compared with 24.4% (11 of 45) in the younger DOT-MS population using the criterium of any disease activity. Additionally, the median time to disease recurrence was shorter in the DOT-MS trial than the DISCOMS trial (6.0 months vs 16.3 months, respectively).²

A key distinction between the two trials is the difference in their study populations—DISCOMS included older participants, with a median age of 63.0 years compared to 54.0 years in the DOT-MS trial, and participants in DISCOMS had a longer duration since their last relapse (13.9 vs. 9.4 years). Additionally, the MRI protocols differed, particularly in the use of contrast enhancement, which may have led to a slight underestimation of disease activity in the DISCOMS cohort. In contrast, the DOT-MS trial did not include any participants who had contrast-enhancing lesions without corresponding new lesions on T2 or fluid-attenuated inversion recovery images.

"A key observation in both trials is the low occurrence of clinical relapses after discontinuation, with disease activity mostly detected through routine MRI scans," the study authors wrote. "Upon resuming DMT, most participants became clinically stable within 6 months. Ultimately, the decision to stop therapy should be individualized, and age and disease stability are critical factors. In addition to the DISCOMS and DOT-MS data, real-world data and the VIAADISC risk score suggest minimal risk of disease reactivation in patients aged 55 to 60 years and older, especially those with long-term disease stability (≥8 years). However, discontinuation of therapies like natalizumab or S1P modulators remains risky due to potential rebound activity."

REFERENCES
1. Coerver EM, Fung WH, Beukelaar J, et al. Discontinuation of first-line disease-modifying therapy in patients with stable multiple sclerosis: the DOT-MS randomized clinical trial. JAMA Neurol. Published December 9, 2024. doi:10.1001/jamaneurol.2024.4164
2. Corboy JR, Fox RJ, Kister I, et al. Risk of new disease activity in patients with multiple sclerosis who continue or discontinue disease-modifying therapies (DISCOMS): a multicenter, randomized, single-blind, phase 4, non-inferiority trial. Lancet Neurol. 2023;22(7):568-577. doi:10.1016/S1474-4422(23)00154-0