Age-dependent response to initial highly effective treatment in relapsing multiple sclerosis

Objectives: To assess the impact of age on the superiority of highly effective (HE) disease-modifying treatments (DMTs) compared to platform DMTs in a real-world population of relapsing MS patients (pwMS). Methods: A total of 20,984 pwMS were extracted from the Italian Multiple Sclerosis Register with a diagnosis of Clinically Isolated Syndrome or Relapsing-Remitting MS, at least four Expanded Disability Status Scale (EDSS) evaluations and 2 years follow-up, starting DMT. The baseline was the nearest visit to the first DMT starting date. The risk of first 24-week confirmed disability accumulation (CDA) on EDSS in HE versus platform DMTs after 2 years and the entire follow-up was assessed through Cox regression models. Results: After 1:1 propensity score matching, we evaluated 1698 pwMS initiating HE-DMTs and 1698 initiating platforms. After 2 years follow-up, the proportion of CDA events was lower in patients on HE-DMTs (12.2%) than those on platform DMTs (15%), as confirmed by Cox regression analysis (hazard ratio (HR) = 0.22, 95% confidence interval (CI) = 0.10-0.47; p < 0.001). HE-DMTs were more effective in patients under 45 years of age (HR = 0.49, 95% CI = 0.39-0.63; p < 0.001), but not in patients over 45 (HR = 0.77, 95% CI = 0.54-1.08, p = 0.125). Notably, prolonged exposure to any DMT during follow-up reduced disability accumulation even in patients over 45 (HR = 0.13, 95% CI = 0.02-0.99; p = 0.050). Conclusion: This real-world study of relapsing pwMS demonstrates that the benefit of initial HE treatment diminishes with age. However, even in older patients, DMT exposure, regardless of the efficacy level, appears to reduce disability accumulation, and so, on an individual level, initial HE treatment could still be more effective.