Background It is unclear if all patients with RRMS ultimately develop progressive MS. Onset of progressive disease course seems to be age- rather than disease duration dependent. Some forms of progressive MS (e.g. PPMS) are uncommon in population-based studies. Ascertainment of patients with PPMS from clinic-based populations can facilitate a powerful comparison of age-of-progression-onset between SPMS and PPMS but may introduce unclear biases. Objective To confirm that onset of progressive disease course is more relevant to patient's age than the presence or duration of a pre-progression relapsing disease course in MS. Methods We studied a population-based MS cohort (n=210, relapsing-remitting MS n=109, progressive MS n=101) and a clinic-based progressive MS cohort (n=754). Progressive course was classified as primary- (PPMS; n=322), single attack- (SAPMS; n=112) and secondary-progressive (SPMS; n=421). We studied demographics (chi2 or t-test), age-of-progression-onset (t-test) and time-to-EDSS6 (Kaplan-Meier analyses). Results Sex-ratio (p=0.58), age-of-progression-onset (p=0.37) and time-to-EDSS6 (p=0.16) did not differ between the cohorts. Progression had developed before age 75 in 99% of patients with known progressive disease course; 38% with RRMS did not develop progression by age 75. Age-of-progression-onset did not differ between SPMS (44.9±9.6), SAPMS (45.5±9.6) and PPMS (45.7±10.8). In either cohort, only 2% of patients had reached EDSS6 before onset of progression. Conclusions Patients with RRMS do not inevitably develop progressive disease course. Onset of progression is more dependent on age than the presence or duration of a pre-progression symptomatic disease course. Moderate disability is sustained predominantly after the onset of a progressive disease course in MS.

Objective: We examined the effect of relapses-before and after progression onset-on the rate of postprogression disability accrual in a progressive multiple sclerosis (MS) cohort. Methods:We studied patients with primary progressive MS (n 5 322) and bout-onset progressive MS (BOPMS) including single-attack progressive MS (n 5 112) and secondary progressive MS (n 5 421). The effect of relapses on time to Expanded Disability Status Scale (EDSS) score of 6 was studied using multivariate Cox regression analysis (sex, age at progression, and immunomodulation modeled as covariates). Kaplan-Meier analysis was performed using EDSS 6 as endpoint. Conclusions: Pre-and postprogression relapses accelerate time to severe disability in progressive MS. Continuing immunomodulation for 5 years after the onset of progressive disease or until 55 years of age may be reasonable to consider in patients with BOPMS who have ongoing relapses. Results: Preprogression relapses (hazard ratioNeurology ® 2015;84:81-88 GLOSSARY BOPMS 5 bout-onset progressive multiple sclerosis; CI 5 confidence interval; EDSS 5 Expanded Disability Status Scale; HR 5 hazard ratio; MS 5 multiple sclerosis; PPMS 5 primary progressive multiple sclerosis; RRMS 5 relapsing-remitting multiple sclerosis; SAPMS 5 single-attack progressive multiple sclerosis; SPMS 5 secondary progressive multiple sclerosis.