Late‐onset multiple sclerosis (MS) has a prevalence of about 10–20% in natural history MS studies. Few data have been published about the long‐term disease trajectory in the cohort of late‐onset relapsing‐remitting MS (LORRMS). The aim of this study was to identify the risk factors for reaching an Expanded Disability Status Scale (EDSS) score of 6.0 in LORRMS (onset at >40 years of age) and young‐onset relapsing‐remitting MS (YORRMS) (onset between 18 and 40 years of age).

Clinical and radiological [magnetic resonance imaging (MRI) of the brain] follow‐up data were collected. Disability was assessed by EDSS score. A Cox proportional hazards model was used to evaluate the demographic and clinical predictors of reaching an EDSS score of 6.0 in the two cohorts.

A total of 671 patients with relapsing‐remitting MS were enrolled, 143 (21.3%) with LORRMS and 528 (78.7%) with YORRMS. In LORRMS, age at onset was 47.8 ± 5.3 (mean ± SD) years and duration of follow‐up was 120.7 ± 52.7 months. In YORRMS, age at onset was 27 ± 2.7 years and duration of follow‐up was 149.9 ± 92.7 months. The survival curve analyses showed a higher probability of reaching an EDSS score of 6.0 for LORRMS in a shorter time (months) than for YORRMS (94.2 vs. 103.2 months; log‐rank 8.8; P < 0.05). On MRI, YORRMS showed more brain inflammatory features than LORRMS. In the multivariate Cox model, age at onset [Exp(B) value, 6.5; 95% confidence interval, 1.9–22.6; P < 0.001] and male gender [Exp(B) value, 1.7; 95% confidence interval, 1.0–2.8; P < 0.05] were the strongest predictors of reaching an EDSS score of 6.0.

The male population with LORRMS reached severe disability faster than those with YORRMS, even when YORRMS showed more brain inflammatory features on MRI.