Silent progression in an Italian CIS and Relapsing-Remitting MS cohort
Objectives. To analyze, in a big Italian multicentric cohort of CIS and RRMS patients, data regarding the silent disease progression independent from relapse activity and MRI data, comparing treated - with "platform" and "highly active" therapies - and untreated patients.Methods. Patients with: age >18 years; a CIS or RRMS diagnosis made using the 2010 McDonald's criteria and followed with a clinical evaluation with an EDSS score and a brain MRI every 12 months; treated and untreated and that have at least a 10-years follow-up. A disability worsening will be defined as an EDSS worsening of 1.5 points if the previous EDSS was 0; 1.0 point if the previous EDSS was between 1.0 and 5.0 points; 0.5 points if the previous EDSS was of 5.5 points or above, registered at first clinical evaluation and confirmed 12 months later. This worsening will be defined as "relapse-related" if a relapse was recorded in the previous 12 months, or "silent-progression" if no relapses were recorded. This worsening will be defined as "confirmed disability worsening" if confirmed at the following clinical evaluation, and as a "long-term worsening" if confirmed at five years (±1 year) (the mid-point of the follow-up) and at ten years (±1 year). Therapies will be classified as: "platform" therapies (interferon in its various formulations; glatiramer acetate), "high-efficacy" therapies Dimethilfumarate;Fingolimod;Natalizumab;Ocrelizumab;Rituximab;Alemtuzumab;Cladribine;Mithoxantrone;Cyclophosphamide; HSCT). In this cohort, we will evaluate the impact of relapses on short and long-term disability worsening; the proportion of patients with a prevalent silent progression, the effect of treatments on silent progression and time to secondary progression, as defined either by the clinician judgment or the Lorscheider's definition of SPMS. The aim of this project is, therefore, to replicate, on a multicentric independent Italian cohort, the data published on the EPIC cohort regarding the silent progression in RRMS patients and to compare two treatment cohorts and untreated patients. These data could aid the clinician in the patients' prognostic evaluation and treatment choices.
Introduction and aims Disability accrual in multiple sclerosis may occur as relapse-associated worsening (RAW) or progression independent of relapse activity (PIRA). The role of PIRA in early MS is yet to be established. The objective of this multicentre, observational, retrospective cohort study was to investigate the contribution of RAW and PIRA to confirmed disability accumulation in patients with clinically isolated syndrome and early relapsing-remitting multiple sclerosis, assessed within one year from onset and with follow-up >/= 5 years. ResultsData were extracted from the Italian Multiple Sclerosis Register. Confirmed disability accumulation was defined by an increase in Expanded Disability Status Scale score confirmed at 6 months, and classified per temporal association with relapses. Factors associated with progression independent of relapse activity and relapse-associated worsening were assessed using multivariable Cox regression models. A total of 5169 patients were recruited. Over a follow-up period of 11.5 + 5.5 years, PIRA occurred in 1.427 (27.6%) and RAW in 922 (17.8%) patients. PIRA was associated with older age at baseline (HR=1.19; 95CI 1.13-1.25, p<0.001), having a relapsing-remitting course at baseline (HR=1.44; 95CI 1.28-1.61, p<0.001), longer disease duration at baseline (HR=1.56; 95%CI 1.28-1.90, p<0.001), lower Expanded Disability Status Scale at baseline (HR=0.92; 95CI 0.88-0.96, p<0.001), lower number of relapses before the event (HR=0.76; 95CI 0.73-0.80, p<0.001). RAW was associated with younger age at baseline (HR=0.87; 95CI 0.81-0.93, p<0.001), having a relapsing-remitting course at baseline (HR=1.55; 95CI 1.35-1.79, p<0.001), lower Expanded Disability Status Scale at baseline (HR=0.94; 95CI 0.89-0.99, p=0.017), higher number of relapses before the event (HR=1.04; 95CI 1.01-1.07, p<0.001). Longer exposure to disease modifying drugs was associated with a lower risk of both PIRA and RAW (p<0.001). Over the follow-up period, 840 (16.3%) patients fulfilled the algorithmic definition of secondary progressive MS (27.0% of RAW and 41.4% of PIRA subjects). Focusing on patients with one or more confirmed disability accrual, secondary progressive course was associated with older age at baseline (HR=1.28-1.31; 95CI 1.15-1.49, p<0.001), higher expanded disability status scale at baseline (HR=1.38-48; 95CI 1.26-1.55, p<0.001) lower number of relapses before transition (HR=0.91; 95CI 0.85-0.96, p<0.001) and a higher proportion of PIRA events before transition (HR=3.35; 95%CI 2.67-4.22, p<0.001).ConclusionsThis study provides evidence that in early relapsing-onset multiple sclerosis cohort, PIRA was an important contributor to confirmed disability accumulation. Our findings indicate that insidious progression appears even in the earliest phases of the disease, suggesting that inflammation and neurodegeneration can represent a single disease continuum, in which age is one of the main determinants of disease phenomenology.Pubblicazioni e Comunicazioni a Congressi/ Publications and Congress Presentations Portaccio E, et al. Progression independent of relapse activity in early multiple sclerosis patients. WCN 2021Portaccio E, et al. Progression independent of relapse activity in early multiple sclerosis patients and risk of secondary progression: an Italian multicentre study. ECTRIMS 2021Bellinvia A, et al. Progression independent of relapse activity in paediatric, adult and late-onset multiple sclerosis patients. ECTRIMS 2021 Fonderico M, et al. Relapse-associated worsening and progression independent of relapse activity in an Italian multicentre cohort of early multiple sclerosis patients. ECTRIMS 2021Portaccio E, et al. Progression is independent of relapse activity in early multiple sclerosis: a real-life cohort study. Brain, under revisions
Portaccio E, Bellinvia A, Fonderico M, Pastò L, Razzolini L, Totaro R, Spitaleri D, Lugaresi A, Cocco E, Onofrj M, Di Palma F, Patti F, Maimone D, Valentino P, Confalonieri P, Protti A, Sola P, Lus G, Maniscalco GT, Brescia Morra V, Salemi G, Granella F, Pesci I, Bergamaschi R, Aguglia U, Vianello M, Simone M, Lepore V, Iaffaldano P, Filippi M, Trojano M, Amato MP. Progression is independent of relapse activity in early multiple sclerosis: a real-life cohort study. Brain. 2022 Aug 27;145(8):2796-2805. doi: 10.1093/brain/awac111.
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