Objective The primary outcome was to identify the prognostic factors of Progression Independent of Relapse Activity (PIRA) in patients with Relapsing-Remitting Multiple Sclerosis (RRMS) treated with Natalizumab (NAT). Materials and methods We performed a single-center, retrospective, cohort study on patients with RRMS who started NAT from July 2007 to February 2017 at the Multiple Sclerosis Centre of Padua. Clinical and radiological data were collected every 6 months. We calculated the survival estimates for clinical relapses, radiological relapses, and PIRA, defined as in the 2023 harmonized criteria (Müller at al, JAMA Neurology) and in absence of any clinical and radiological disease activity in the previous 12 months. Multiple logistic regression models were used to analyse the probability of developing PIRA according to several factors, including sex, age of onset, disease duration, age at baseline, previous other disease modifying therapies and Expanded Disability Status Scale (EDSS) at baseline. Results We included 288 patients (197 F; 91 M) with an age at baseline of 34.3 ± 10.6 years and followed for 66.1 ± 51.6 months (from first to last NAT dose). Among these, 153 (53.1%) discontinued NAT for safety reasons. PIRA occurred in 80 patients (27.8%) after a mean time of 34.5 months of NAT (SD ± 30.6), of these 85% had sustained PIRA. The probability of PIRA-free condition was 84.3% at 24 months, 75% at 48 months, and 69.7% at 62 months. Multivariate analysis (AUC 0.7525, p < 0.0001) identified EDSS (β: 0.57, p < 0.0001) and age (β: 0.03, p = 0.02) as independent factors associated with an increased probability of developing PIRA. We repeated the analysis subgrouping patients according to different cohorts based on age (cut-off value: 42.5 years) and EDSS value at baseline (cut-off value: 4.0). Survival analysis identified three risk categories for PIRA: low (EDSS < 4.0 and age < 42.5 years), intermediate (EDSS < 4.0 and age ≥ 42.5, Hazard Ratio 2.2, 95%CI 0.92 - 5.26, p < 0.0239) and high risk (EDSS ≥ 4.0, Hazard Ratio 4.98, 95%CI 2.86 - 8.67, p < 0.0001). Discussion Our single center data confirm PIRA being the main driver of disability progression in RRMS on NAT. The percentage developing PIRA are in line with real-world data on NAT reported. Additionally, we identified older age and higher EDSS at baseline predicting PIRA occurrence, suggesting three categories of risk. Therefore, younger patients with lower EDSS are the ideal candidate for early intervention with NAT to prevent clinical/radiological relapse and PIRA.
Scopo dello Studio Lo scopo primario è stato quello di identificare i fattori prognostici di Progressione Indipendente da Ricaduta (PIRA) in pazienti con sclerosi multipla recidivante-remittente (RRMS) trattati con Natalizumab (NAT). Materiali e Metodi Abbiamo eseguito uno studio di coorte, retrospettivo, monocentrico, su pazienti con RRMS che hanno iniziato NAT tra luglio 2007 e febbraio 2017 presso il Centro Sclerosi Multipla di Padova. I dati clinici e radiologici sono stati raccolti ogni 6 mesi. Abbiamo calcolato le curve di sopravvivenza per ricadute cliniche, ricadute radiologiche e PIRA, definita come nei criteri armonizzati del 2023 (Müller at al, JAMA Neurology) e in assenza di qualsiasi attività clinica e radiologica nei precedenti 12 mesi. Più modelli di regressione logistica sono stati utilizzati per analizzare la probabilità di sviluppare PIRA in base a diversi fattori, tra cui genere, età di esordio, durata della malattia, età al basale, precedenti altre Terapie Modificanti la Malattia e Expanded Disability Status Scale (EDSS) basale. Risultati Abbiamo incluso 288 pazienti (197 F; 91 M) con un'età media di 34,3 ± 10,6 anni e seguiti per 66,1 ± 51,6 mesi (dalla prima all'ultima infusione di NAT). Tra questi, 153 (53,1%) hanno interrotto NAT per motivi di sicurezza. Il PIRA si è verificato in 80 pazienti (27,8%) dopo un tempo medio di 34,5 mesi di NAT (SD 30,6), di questi 85% aveva PIRA sostenuto. La probabilità di sopravvivenza liberi da PIRA è stata 84,3% a 24 mesi, 75% a 48 mesi, e 69,7% a 62 mesi. L'analisi multivariata (AUC 0.7525, p < 0.0001) ha identificato EDSS (β: 0.57, p < 0.0001) e età al basale (β: 0.03, p = 0.02) come fattori indipendenti associati ad una maggiore probabilità di sviluppare PIRA. Abbiamo ripetuto l'analisi dei sottogruppi di pazienti stratificati in diverse coorti in base all'età (valore cut-off: 42,5 anni) e al valore EDSS basale (valore cut-off: 4.0). L'analisi di sopravvivenza ha identificato tre categorie di rischio per PIRA: basso (EDSS < 4,0 e età < 42,5 anni), intermedio (EDSS < 4,0 e ≥ 42,5 anni, rapporto di rischio 2,2, 95%CI 0,92 - 5,26, p < 0,0239) e ad alto rischio (EDSS ≥ 4,0, rapporto di rischio 4,98, 95%CI 2,86 - 8,67, p < 0,0001). Discussione I nostri dati confermano che PIRA è il principale driver di progressione della disabilità nelle RRMS in NAT. Le percentuali di pazienti che hanno sviluppato PIRA sono in linea con i dati reali sul NAT riportati in letteratura. Inoltre, abbiamo identificato un'età più avanzata e un EDSS più elevato al basale come predittori dell'insorgenza di PIRA, suggerendo tre categorie di rischio. Pertanto, i pazienti più giovani con EDSS inferiore sono i candidati ideale per un intervento precoce con NAT per prevenire la ricaduta clinica, radiologica e PIRA.
Marcatori prognostici di Progressione Indipendente da ricaduta clinica di malattia nei pazienti affetti da Sclerosi Multipla
ROZZI, MARTINA
2023/2024
Abstract
Objective The primary outcome was to identify the prognostic factors of Progression Independent of Relapse Activity (PIRA) in patients with Relapsing-Remitting Multiple Sclerosis (RRMS) treated with Natalizumab (NAT). Materials and methods We performed a single-center, retrospective, cohort study on patients with RRMS who started NAT from July 2007 to February 2017 at the Multiple Sclerosis Centre of Padua. Clinical and radiological data were collected every 6 months. We calculated the survival estimates for clinical relapses, radiological relapses, and PIRA, defined as in the 2023 harmonized criteria (Müller at al, JAMA Neurology) and in absence of any clinical and radiological disease activity in the previous 12 months. Multiple logistic regression models were used to analyse the probability of developing PIRA according to several factors, including sex, age of onset, disease duration, age at baseline, previous other disease modifying therapies and Expanded Disability Status Scale (EDSS) at baseline. Results We included 288 patients (197 F; 91 M) with an age at baseline of 34.3 ± 10.6 years and followed for 66.1 ± 51.6 months (from first to last NAT dose). Among these, 153 (53.1%) discontinued NAT for safety reasons. PIRA occurred in 80 patients (27.8%) after a mean time of 34.5 months of NAT (SD ± 30.6), of these 85% had sustained PIRA. The probability of PIRA-free condition was 84.3% at 24 months, 75% at 48 months, and 69.7% at 62 months. Multivariate analysis (AUC 0.7525, p < 0.0001) identified EDSS (β: 0.57, p < 0.0001) and age (β: 0.03, p = 0.02) as independent factors associated with an increased probability of developing PIRA. We repeated the analysis subgrouping patients according to different cohorts based on age (cut-off value: 42.5 years) and EDSS value at baseline (cut-off value: 4.0). Survival analysis identified three risk categories for PIRA: low (EDSS < 4.0 and age < 42.5 years), intermediate (EDSS < 4.0 and age ≥ 42.5, Hazard Ratio 2.2, 95%CI 0.92 - 5.26, p < 0.0239) and high risk (EDSS ≥ 4.0, Hazard Ratio 4.98, 95%CI 2.86 - 8.67, p < 0.0001). Discussion Our single center data confirm PIRA being the main driver of disability progression in RRMS on NAT. The percentage developing PIRA are in line with real-world data on NAT reported. Additionally, we identified older age and higher EDSS at baseline predicting PIRA occurrence, suggesting three categories of risk. Therefore, younger patients with lower EDSS are the ideal candidate for early intervention with NAT to prevent clinical/radiological relapse and PIRA.File | Dimensione | Formato | |
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https://hdl.handle.net/20.500.12608/65805