Dimethyl Fumarate Delays Multiple Sclerosis in Radiologically Isolated Syndrome

Abstract

Objective The radiologically isolated syndrome (RIS) represents the earliest detectable pre‐clinical phase of multiple sclerosis (MS). This study evaluated the impact of therapeutic intervention in preventing first symptom manifestation at this stage in the disease spectrum. Methods We conducted a multi‐center, randomized, double‐blinded, placebo‐controlled study involving people with RIS. Individuals without clinical symptoms typical of MS but with incidental brain MRI anomalies consistent with central nervous system (CNS) demyelination were included. Within 12 MS centers in the United States, participants were randomly assigned 1:1 to oral dimethyl fumarate (DMF) 240 mg twice daily or placebo. The primary endpoint was the time to onset of clinical symptoms attributable to a CNS demyelinating event within a follow‐up period of 96 weeks. An intention‐to‐treat analysis was applied to all participating individuals in the primary and safety investigations. The study is registered at http://clinicaltrials.gov, NCT02739542 (ARISE). Results Participants from 12 centers were recruited from March 9, 2016, to October 31, 2019, with 44 people randomized to dimethyl fumarate and 43 to placebo. Following DMF treatment, the risk of a first clinical demyelinating event during the 96‐week study period was highly reduced in the unadjusted Cox proportional‐hazards regression model (hazard ratio [HR] = 0.18, 95% confidence interval [CI] = 0.05–0.63, p = 0.007). More moderate adverse reactions were present in the DMF (34 [32%]) than placebo groups (19 [21%]) but severe events were similar (DMF, 3 [5%]; placebo, 4 [9%]). Interpretation This is the first randomized clinical trial demonstrating the benefit of a disease‐modifying therapy in preventing a first acute clinical event in people with RIS. ANN NEUROL 2023;93:604–614

Imaging of Central Nervous System Demyelinating Disorders

“…case 11-1 reviews some of the characteristic RIS findings, workup, and follow-up. Treatment of RIS is generally recommended to be provided by neurologists with expertise in MS. To date, no specific evidence-based recommendations for treatment exist, but ongoing clinical trials are investigating the use of disease-modifying therapy 10 …”

How a pioneering diabetes drug offers hope for preventing autoimmune disorders

“…Rheumatologists have had some success with preventing disease using a T-cell-blocking agent called abatacept, with a preliminary study 10 showing that the drug reduces joint inflammation and delays the development of RA in at-risk individuals. And for MS, clinicians have identified a drug that, in preliminary testing, wards off neurological symptoms in people who have early signs of nerve damage in the brain 11 .…”

“…Late last year, a team led by Darin Okuda, a neurologist at the University of Texas Southwestern Medical Center in Dallas, reported results for an anti-inflammatory drug called dimethyl fumarate. When given to people with a distinct type of anomalous brain scan, the drug helped to reduce the risk of MS by more than 80% compared with a placebo 11 . Over the course of 22 months, 3 of 44 people who received the drug progressed to MS, compared with 14 of 43 placebo-treated individuals.…”

Risk Factors and Time to Clinical Symptoms of Multiple Sclerosis Among Patients With Radiologically Isolated Syndrome

“…Despite this homology with MS, the association of early treatment with decreased conversion to MS is unknown. Two multicenter, randomized, double-blinded clinical trials evaluated the efficacy of dimethyl fumarate (NCT02739542) 14 and teriflunomide (NCT03122652) 15 vs placebo in delaying time to the first clinical event. In this study, we evaluated the 2-year risk of a first clinical event suggestive of MS and estimated sample sizes needed for 24-month prospective clinical trials based on the primary outcome of a first clinical event and critical risk factors that may enrich cohorts studied.…”