Impact of age at onset on relapse-associated and relapse-independent disability accrual trajectories in multiple sclerosis.

OBJECTIVE: In multiple sclerosis (MS), older age at onset is linked to faster disability worsening and to increased frequency of progression independent of relapse activity (PIRA). In this study, we directly quantify the magnitude of relapse-associated and relapse-independent disability accrual as a function of age at onset. METHODS: We analysed the long-term course of Expanded Disability Status Scale (EDSS) in patients with relapsing-onset MS followed at the Centre of Montichiari (Italy) between 1980 and 2022. We assessed the effect of age at onset on the rate of relapse-associated, relapse-independent, and overall EDSS change from baseline using mixed-effects models adjusted for baseline characteristics and treatment exposure. RESULTS: 1488 patients were included in the study. Older age at onset was associated with a faster rate of EDSS worsening (p<0.0001). This acceleration was driven by an increased contribution of PIRA (p<0.0001), while the rate of relapse-associated EDSS change remained stable throughout the whole onset age range (p=0.2251). Patients who were 10 years older at onset accumulated on average 0.31 (0.22, 0.39) additional EDSS points per decade due to PIRA. CONCLUSION: Increasing age at onset selectively amplified the rate of relapse-independent disability accrual, while relapse-associated worsening remained stable across onset ages.