Prospective Study in High-Risk Individuals Supports Primary Prevention Trials in MS

As disease-modifying therapies continue to demonstrate the greatest benefit when initiated early in multiple sclerosis (MS), researchers are increasingly asking whether intervention before clinical onset could alter the trajectory of the disease or prevent it altogether. A new prospective analysis is highlighting the potential of this step forward, showing both an elevated risk facing first-degree relatives of patients with MS and the growing readiness of this population to engage in prevention-focused research.¹

Published in Annals of Clinical and Translational Neurology, the analysis comes as clinical evidence and diagnostic criteria evolve in their recognition of asymptomatic disease states such as radiologically isolated syndrome (RIS),^2,3 suggesting that the ability to identify and intervene in high-risk individuals before clinical onset may represent a critical step forward.

“The inclusion of asymptomatic MS is likely to broaden access to treatment worldwide, providing an opportunity to target individuals at high risk before the onset of clinical symptoms,” explained the researchers of the analysis. “This aligns with our goal of intervening early to prevent or delay the biological progression of MS, including any tissue damage seen in the CNS by MRI.”

The researchers followed 1,903 first-degree relatives of patients with MS over an 11-year period as part of the nationwide Genes and Environment in Multiple Sclerosis (GEMS) project. Among the participants, 141 (8%) had an existing MS diagnosis at enrollment, 18 (0.9%) were diagnosed with MS during follow-up, and 1744 (91%) remained asymptomatic throughout 8526 person-years of observation.

Among participants who were initially free of MS, the incidence rate of new diagnoses was estimated at 211 cases per 100,000 first-degree relatives per year, approximately 100 times greater than the reported incidence of sporadic MS in the general population. The median time to conversion was 2 years, with a median age at diagnosis of 37.

The researchers explored the predictive utility of an integrated Genetic and Environmental Risk Score (GERS), which combines established MS-associated genetic variants with known environmental risk factors such as female sex, smoking status, and a history of infectious mononucleosis. The group found that participants with MS at enrollment had significantly higher GERS values than asymptomatic relatives.

An updated genetic risk score incorporating 224 susceptibility loci demonstrated strong correlation with earlier versions of the score, with Spearman correlation coefficients ranging from 0.80 to 0.85 (P < .001). These findings, wrote the researchers, support the continued use of combined genetic and environmental risk stratification tools to identify individuals at highest risk of developing MS.

Importantly, risk stratification may have practical implications for trial design, they noted. Investigators estimate that targeting high-risk subsets, such as those in the top quartile of GERS distribution, could double the likelihood of conversion compared with the average first-degree relative, potentially enabling adequately powered prevention studies with smaller sample sizes.

The study also assessed participant interest in future prevention trials. Among asymptomatic respondents, nearly half (48%) expressed willingness to enroll in a study testing a preventive intervention based on their baseline familial risk. However, when presented with a hypothetical scenario in which genetic testing indicated a 20% lifetime risk of developing MS, willingness to participate increased to 75%.

Enthusiasm for participation was highest for interventions involving existing or approved treatments. Nearly 90% of respondents were willing to consider a known vaccine under baseline risk assumptions, with interest increasing further when elevated risk was assumed. Similar trends were observed for approved oral therapies.

References

1. Laitinen AW, Tozlu C, Roostaei T, et al. A prospective study of individuals at risk of multiple sclerosis informs the design of primary prevention studies. Ann Clin Transl Neurol. Published online February 17, 2026. doi:10.1002/acn3.70340

2. Lebrun-Frénay C, Siva A, Sormani MP, et al. Teriflunomide and time to clinical multiple sclerosis in patients with radiologically isolated syndrome: the TERIS randomized clinical trial. JAMA Neurol. 2-23;80(10):1080-1088. doi:10.1001/jamaneurol.2023.2815

3. Lebrun-Frénay C, Okuda DT, Siva A, et al. The radiologically isolated syndrome: revised diagnostic criteria. 2023;146(8):3431-3443. doi:10.1093/brain/awad073