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

Background The 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. Methods Scientific 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). Results Eighteen 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. Discussion PIRA 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 topic Irreversible 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 adds In 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 policy Although PIRA accounts for most disability events in MS, its detection in real-world setting is necessarily inaccurate and its statistical analysis is challenging. ### Competing Interest Statement LP: personal fees and non-financial support from Biogen, Bristol-Mayer Squibb, Merck, Novartis, Roche, Sanofi, Viatris. SR: personal fees and non-financial support from Biogen, Merck, Novartis, Sanofi and Teva. SH: travel funding and/or speaker honoraria from Biogen, CSL Behring, Novartis, Roche, Sanofi. CT: honoraria for speaking and travel grants from Almirall, Bayer, Biogen, Merck, Novartis, Roche, Sanofi, Teva. CG: honoraria for speaking and travel grants from Biogen, Merck, Novartis, Roche, Sanofi, Teva and Viatris. ### Funding Statement This study did not receive any funding. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes An Excel spreadsheet containing all data of included studies is available as an Appendix.