Background: Cognitive impairment is a common feature of multiple sclerosis (MS), affecting daily functioning and quality of life. We aimed to investigate how disease-modifying therapies (DMTs) of varying efficacy are associated with long-term cognitive trajectories in MS, as measured by the Symbol Digit Modalities Test (SDMT).
Methods: Using the data from Swedish population-based MS cohorts linked to the Swedish MS registry, we included individuals with relapsing-onset MS receiving DMT to evaluate longitudinal SDMT trajectories. From a cohort of 5467 treated individuals, several analytic subsets were defined for specific trajectory analyses. Mixed-effects models were used to examine changes in cognitive performance across treatment categories, including platform therapies, high-efficacy therapies overall, and specific high-efficacy agents.
Results: SDMT scores increased during the first years of follow-up among individuals initiating high-efficacy DMT and subsequently declined, whereas changes in the platform group were smaller over time. Differences between groups were observed at years 3 and 4, with an estimated difference of approximately 2 points, which were not sustained at later follow-up. When compared with anti-CD20 therapies, natalizumab-treated individuals showed a greater early increase (β - 0.77, 95% CI - 1.26, - 0.27) and a more pronounced subsequent decline (β 0.38, 95% CI 0.21-0.55), with trajectories converging over time. Adjustment for repeated testing attenuated early increases in SDMT scores.
Conclusions: There was limited evidence for a sustained or clinically relevant short-term effect of high-efficacy DMTs on cognitive trajectories in MS. Differences between groups and changes over time are likely influenced by underlying patient characteristics and practice effects related to repeated testing.
Keywords: Multiple sclerosis; cognitive function; disease-modifying therapy; longitudinal study; processing speed.
© 2026. The Author(s).