Rethinking multiple sclerosis across the lifespan: Lessons from adult disease

First, the field has moved from “Epstein–Barr virus (EBV) is associated with MS” to “EBV is a dominant causal driver in most cases.” This shift is supported by large longitudinal datasets demonstrating that EBV seroconversion precedes MS onset and is followed by biomarker evidence of neuroaxonal injury. As a result, prevention can now be considered a realistic goal, for example through EBV vaccination or antiviral strategies, rather than a purely theoretical one.

Second, MS “risk” is increasingly measurable. Machine-learning approaches are now able to identify subtypes and stages with distinct disease trajectories, while scalable biomarkers, such as paramagnetic rim lesions and serum neurofilament light chain, help bridge the continuum from susceptibility to progression.

Q. How has our understanding of progression in adult MS evolved, and what lessons from adult disease trajectories should inform earlier intervention strategies in younger patients or at-risk populations?

Our understanding of progression in adult MS has shifted from the view that progression occurs only later in the disease course to the recognition that progressive biology can begin early and run in parallel with inflammatory activity. Analyses of pooled adult trial datasets show that a substantial proportion of disability accumulation occurs independent of relapses, referred to as progression independent of relapse activity (PIRA). This challenges the assumption that relapse suppression alone is an adequate surrogate for long-term outcomes.

Mechanistic insights from adult imaging and pathology studies have also strengthened links between disability worsening and smouldering, compartmentalized inflammation. Chronic active lesions, often paramagnetic rim lesion-positive, and slowly expanding lesions help explain why progression may continue even when relapses and conventional magnetic resonance imaging activity appear controlled.

Q. In clinical practice, how should insights from adult MS reshape decisions around the timing, intensity and goals of treatment at different stages of life?

In younger patients and in early disease, the implication is not simply to treat earlier, but to treat earlier using endpoints that reflect long-term biology. Relapse control remains necessary but is insufficient on its own. Monitoring should incorporate objective measures of tissue injury, including lesion biology on magnetic resonance imaging, optical coherence tomography where feasible, and blood biomarkers such as neurofilament light chain and glial fibrillary acidic protein, to detect neuroaxonal injury before it becomes clinically apparent.

In mid-life patients with stable disease, adult experience supports de-risking strategies rather than default indefinite maximal immunosuppression, particularly with anti-CD20 therapies. Finite-course approaches, extended-interval dosing and biomarker-guided retreatment or switching are all reasonable options, with the explicit goal of reducing cumulative risk while maintaining disease control.

Q. If you could highlight one key lesson from adult MS that HCPs should apply more consistently when managing patients across the lifespan, what would it be and why does it matter now?

Neuroaxonal loss appears to be steepest in younger patients, meaning the window for preserving long-term neurological reserve may be widest early in the disease course. At the same time, younger patients tend to have the lowest risk of immunosuppressive side effects. Using highly effective therapies in paediatric and young adult patients, followed by later de-escalation, may therefore offer the most effective balance between disease control and long-term safety.

Q. What were the most important therapeutic and treatment updates presented at ACTRIMS 2026?

Beyond my presentation, two Phase III trials of oral, brain-penetrant Bruton’s tyrosine kinase inhibitors in primary progressive multiple sclerosis reported divergent outcomes at ACTRIMS 2026. In the FENtrepid trial (n=985), fenebrutinib met its primary endpoint of non-inferiority to ocrelizumab on 12-week composite confirmed disability progression, with a numerical 12% risk reduction (hazard ratio 0.88; 95% confidence interval 0.75–1.03).

By contrast, tolebrutinib failed to meet its primary endpoint in the PERSEUS trial, demonstrating only a 14% reduction in disability progression versus placebo and no significant delay in 6-month composite confirmed disability progression. Together, these results raise important questions regarding class effects among Bruton’s tyrosine kinase inhibitors, trial design choices, including active comparator versus placebo and non-inferiority versus superiority frameworks, and patient selection in progressive MS trials.