Supplementary Material for: Life and death with Multiple Sclerosis: 20 years reappraisal of Verona prevalence cohort.

Introduction: Multiple sclerosis (MS) is a debilitating condition which results in increased mortality rates in people with MS compared to general population (GP). Recent data suggest a potential rise in survival over the past 20 years. Objectives: Evaluate the 20-year (2001-2021) survival rate and assess clinical factors associated with mortality among people with MS in Verona, Italy. Methods: We evaluated all the prevalent cases of MS residing in Verona, Italy at 31/12/2001. We retrospectively investigated the survival state of each patient at 31/12/2021 through the consultation of medical records to assess if patients were still on follow-up; for those with no records, we surveyed the death certificates from Verona municipality to verify death notification and date. The groups of survived and deceased patients were compared by sex, variables related to disease onset (age, clinical phenotype, number and type of functional systems involved, oligoclonal bands) or collected at prevalence date (clinical phenotype, disease duration, exposure to disease-modifying treatment, EDSS, annual relapse rate). Results: Of the 273 prevalent MS cases (189 females) as of 31/12/2001, 73 patients (48 females) had died by 31/12/2021. Mean life expectancy deviation of deceased MS patients was – 17.0±12.4 years compared to the GP. Deceased patients had a higher mean age at onset (36.4±12.5 vs 30.5±10.0 years; p<0.001) and a higher median EDSS score at prevalence date compared to survived patients (6.5, range 1.0-9.5 vs 2.0, range 0-8.0; p<0.001). The relapsing-remitting phenotype was more prevalent in survived patients both at onset (92.2%, p<0.001) and prevalence date (76.2%, p<0.001). Visual or sensory impairments were more common in survivors (82.5%; p=0.023). The survival rate was significantly lower in patients with primary progressive MS (PPMS) or an EDSS score greater than 3 at prevalence date. Multivariate Cox regression analysis revealed that a progressive disease type at prevalence date (PPMS or secondary progressive MS), longer disease duration at prevalence date and older age at onset were independently associated with lower survival. Conclusions: After 20 years from initial observation, the 2001 Verona cohort of MS prevalent cases showed a lower life expectancy compared to the GP. Higher age at disease onset, longer disease duration, and a progressive clinical course were independent risk factors of shorter survival of patients with MS.