Treatment escalation after clinically silent MRI lesions in relapsing-remitting multiple sclerosis

Clinically silent MRI lesions occur frequently in people with relapsing-remitting multiple sclerosis (RRMS) despite disease modifying therapy (DMT). Guidelines only routinely recommend DMT escalation after multiple silent lesions, and adherence is variable. We explored outcomes and the effect of treatment escalation following single and multiple on-treatment silent lesions. This cohort study and emulated target trial used MSBase registry data from 99 clinics in 26 countries between 2007 and 2025. Clinically stable participants receiving any DMT for RRMS with silent lesions versus without silent lesions were compared. Among participants with silent lesions while taking platform or moderate-efficacy DMTs, outcomes following treatment escalation within 6 months versus no treatment escalation (unless a post-MRI clinical event occurred) were compared. The primary outcome was an MS relapse, and the secondary outcome was 6-month confirmed disability worsening. A total of 10,232 participants met inclusion criteria (71.7% female, mean age 41 [SD 11]). The 2-year cumulative incidence of relapse was 27.8% (95% CI: 25.7%-29.9%) in participants with silent lesions versus 14.3% (95% CI: 13.5%-15.2%) without (adjusted hazard ratio [aHR] 1.76 [95% CI: 1.57-1.97]). The 2-year cumulative incidence of disability worsening was 13.8% (95% CI: 12.2%-15.5%) in participants with silent lesions versus 11.4% (95% CI: 10.7%-12.2%) without (aHR 1.38 [95% CI: 1.18-1.62]). Rates of relapse and disability worsening were higher following single and multiple silent lesions versus no silent lesions. The emulated trial included 2,264 participants with ≥1 silent lesion on platform or moderate efficacy DMTs, 286 of whom escalated DMT within 6 months following silent lesions. The 4-year cumulative incidence of relapse was lower following treatment escalation (16.8% [95% CI: 12.4%-23.4%]) versus continuation (38.9% [95% CI: 35.8%-42.1%]), aHR 0.34 (95% CI: 0.23-0.47), with similar aHRs following single and multiple silent lesions. The 4-year cumulative incidence of disability worsening was similar following treatment escalation (16.0% [95% CI: 10.8%-22.2%]) versus continuation (17.7% [95% CI: 15.3%-20.1%]), aHR 0.89 (95% CI: 0.56-1.33). People with RRMS with single or multiple on-treatment silent MRI lesions have higher subsequent risks of relapse and disability worsening than people without silent lesions. DMT escalation mitigates the relapse risk, though disability worsening continues at a similar rate over 4 years. Contrary to guidelines, DMT escalation should be considered after single or multiple silent lesions.