Background Previous natural history studies highlighted a consistent heterogeneity of disability trajectories among individuals with primary or secondary progressive multiple sclerosis (MS). However, evidence on disability progression in relapsing onset MS is scarce.

The aim of this study was to investigate heterogeneity in disability accumulation over 10 years following a first clinical diagnosis of central nervous system demyelination (FCD) and identify genetic, demographic, environmental and clinical factors associated with these trajectories.

Methods We used group-based trajectory models to measure heterogeneity in disability trajectories based on the Expanded Disability Status Scale (EDSS) in a prospectively assessed cohort of 263 participants. To capture sustained neurological impairments and avoid issues related to significant changes in EDSS associated with relapse, we did not consider EDSS points recorded within 3 months of a relapse.

Results We identified three distinct and clinically meaningful disability trajectories: No/minimal, moderate and severe. Those in the no/minimal disability trajectory showed no appreciable progression of disability (median EDSS∼1 at 10-year review) while those in the moderate and severe disability trajectories experienced disability worsening (median time to reach EDSS 4 was 9 and 7 years, respectively). Compared with the no/minimal disability trajectory, those with older age, a higher number of relapses within the first 5 years post-FCD, and a higher number of comorbidities at baseline were more likely to be in the worse disability trajectory. Surprisingly, baseline MRI and anatomical site of initial symptoms did not influence long-term outcomes.

Conclusions Those at higher risk of faster MS disability progression can be identified based on their early clinical characteristics with potential therapeutic implications for early intervention and treatment escalation.