Long-term disability progression data from Canadian multiple sclerosis (MS) populations remain limited. We examined disability progression patterns and prognostic factors in a large Canadian MS registry while assessing the robustness of findings across different analytical approaches.

We analyzed 2,769 patients from the CHUM MS registry (1976–2020) with relapsing-remitting, secondary-progressive MS (SPMS), or clinically isolated syndrome. Primary outcomes were time to EDSS milestones 3, 4, 6, 8, and to SPMS from disease onset. Cox hazards models examined associations with sex, age at onset, calendar period, relapse frequency, pregnancy, and treatment timing. Sensitivity analyses used additional severity adjustments and alternative time origins to distinguish robust biological associations from methodology-sensitive findings.

The cohort included 2,101 women and 668 men with median age at onset of 29.9 years and median follow-up of 24.6 years. Median time from disease onset to EDSS 3 was 21.3 years (95% CI: 20.1–22.4), to EDSS 4 was 26.1 years (24.7–27.8), to EDSS 6 was 34.1 years (31.8–35.8), and to SPMS was 36.4 years (35.5–38.1). Male sex consistently predicted faster progression across all milestones (HR 1.50–1.71, P < 0.001). Age ≥ 30 years at onset was associated with faster progression to earlier milestones. Pregnancy after disease onset was associated with slower progression (HR 0.70-0.86). High relapse frequency and treatment-timing effects varied markedly depending on analytical approach.

This cohort demonstrates progression times comparable to international registries. Male sex emerged as the most robust prognostic factor, while other associations showed varying methodological sensitivity, highlighting complexity in interpreting observational MS research.