Long-term disability after initiation of platform versus high-efficacy disease-modifying therapy in relapsing-onset multiple sclerosis

BACKGROUND: Several observational studies have compared high-efficacy and platform disease-modifying therapies (DMTs) with respect to long-term disability in relapsing-onset multiple sclerosis (MS), yet it remains unclear whether observed differences reflect relapse-associated worsening (RAW), progression independent of relapse activity (PIRA), or both. METHODS: We included 2,563 DMT-naïve individuals with relapsing-onset MS enrolled in a population-based study linked to the Swedish MS registry (40 clinics, 2005-2019). The exposure was initial DMT efficacy class (platform versus high-efficacy therapy), with platform as the reference. Cox models estimated hazard ratios (HRs) with 95% confidence intervals (CIs) for RAW, PIRA, and time to EDSS 3 and 4. EDSS trajectories were modeled using mixed-effects models. Follow-up started at DMT initiation and was censored at treatment switch, discontinuation, death, drop-out, or study end. RESULTS: At treatment initiation, 1,987 participants started a platform DMT and 576 a high-efficacy DMT. High-efficacy therapy was associated with a lower risk of RAW (HR 0.60, 95% CI 0.38-0.92), while the risk of PIRA did not differ between treatment groups (HR 1.05, 95% CI 0.79-1.39). Risks of reaching EDSS 3 and EDSS 4 were also lower with high-efficacy DMT (EDSS 3: HR 0.26, 95% CI 0.17-0.38; EDSS 4: HR 0.32, 95% CI 0.18-0.54). EDSS trajectories increased more steeply among platform-treated participants, with partial convergence toward the high-efficacy group over time. CONCLUSIONS: Our findings suggest that inflammatory and relapse-independent components of MS disability respond differently to current therapies and highlight the need for complementary neuroprotective strategies.