Disability patterns in multiple sclerosis: a meta-analysis on PIRA and RAW in the real world context

Abstract

ABSTRACTBackgroundThe confirmed disability accrual (CDA) due to multiple sclerosis (MS) is driven by two factors: relapse-associated worsening (RAW) and progression independent of relapse activity (PIRA). However, accurate estimations of these phenomena in the real-world setting are lacking. This study aims at summarizing current evidence on RAW and PIRA, including associated factors, through a quantitative synthesis of real-world studies.MethodsScientific databases were searched to identify real-world studies published until December 31, 2023, reporting how many patients experienced RAW and PIRA (events of interest). Random-effects meta-analyses, subgroup analyses and meta-regression models were ran to provide pooled estimates of RAW and PIRA events, and to identify their potential moderators (PROSPERO registration: CRD42024503895).ResultsEighteen articles met the eligibility criteria, with a pooled sample size of 52,667 patients followed for 2.4 to 12.1 years (415,825 patient-years). Pooled event rates for RAW and PIRA were 1.6 and 3.1 per 100 patient-years, respectively. Less RAW events were found in patient cohorts under high-efficacy disease-modifying treatments (β=–0.031, p=0.007), while PIRA events were directly related to older age (β=0.397, p=0.027), predicting ≥6 PIRA events per 100 patient-years at an age ≥54 years. Additionally, we found significant differences in PIRA event rates according to the criteria adopted to define CDA.DiscussionPIRA accounts for most CDA events in the real-world setting, even at the earlier disease stages, whereas RAW represents a less frequent phenomenon, likely due to effective treatments. However, the detection and statistical analysis of PIRA outcomes pose challenges, raising the risk of biased interpretation.What is already known on this topicIrreversible accumulation of disability in multiple sclerosis stems from two distinct yet not mutually exclusive phenomena: relapse-associated worsening (RAW) and progression independent of relapse activity (PIRA).What this study addsIn this meta-analysis including data of 52,667 patients followed for 2.4 to 12.1 years, the pooled event rates were 1.6 and 3.1 per 100 patient-years for RAW and PIRA, respectively. High-efficacy treatment strongly suppresses RAW but not PIRA, which is instead associated with age and definition criteria.How this study might affect research, practice or policyAlthough PIRA accounts for most disability events in MS, its detection in real-world setting is necessarily inaccurate and its statistical analysis is challenging.