Two determinants of late disability progression in multiple sclerosis: early inflammatory disease and old age in damaged brain.

Background: Natural history studies have suggested that the disability progression due to multiple sclerosis (MS) is a 'two-stage' process, i.e. in the earlier stage inflammation and disability progression are associated, while in the later stage these two phenomena are independents. Nonetheless, the relationship between relapses and disability is still debated. Objective: To investigate the influence of relapses and paraclinical signs of inflammation detected at magnetic resonance imaging (MRI) on disability progression from an Expanded Disability Status Scale (EDSS) score of 3.5 (+/-0.5) to 6.0 or more. Methods: Data of patients regularly attending three tertiary MS centres in Italy (Rome, Ancones and Turin) were analyzed. A Cox proportional hazard model was built to assess the influence of some covariates on the risk of progression to an EDSS score of 6.0 or more (main outcome). These covariates included gender; age, MS duration, relapse rate and MRI activity at EDSS 3.5 (+/-0.5); onset symptom; time to first relapse; exposure to disease-modifying treatments (time-dependent covariate). The follow-up period was calculated as time elapsed from EDSS 3.5 (+/-0.5) to the main outcome, or the last available visit, whichever came first. Results: Data from 611 patients (409 F, 202 M) with mean age of 42.5 years and mean MS duration of 12.2 years at EDSS of 3.5 (+/-0.5) were collected. During a median follow-up time of 5 years (range 2-23), 361 patients reached an EDSS score of 6.0 or more. Out of these, 232 (64%) patients developed disability with superimposed relapses or paraclinical (i.e. gd-enhancement) signs of inflammation, while129 (36%) patients did not show any disease activity. Those patients presenting superimposed clinical/MRI activity were younger, had shorter MS duration and higher relapse rate at EDSS 3.5 (+/-0.5) than those without activity (p-values< 0.001). The Cox regression model showed that the risk of disability progression was associated with older age (HR=1.03, p< 0.001) and shorter MS duration (HR=0.97, p=0.001) at EDSS 3.5 (+/-0.5). Discussion: Our findings suggest that the occurrence of inflammation may lead to disability progression in approximately two third of patients, especially in those ones who are younger, with shorter disease duration and higher relapse rate. Old age is an independent risk factor for disability progression and it is the only determinant for reaching an EDSS of 6.0 or more in patients without inflammatory disease.