Defining progression independent of relapse activity (PIRA) in adult patients with relapsing multiple sclerosis: A systematic review

Background: Progression Independent of Relapse Activity (PIRA) is heterogeneously described in patients with multiple sclerosis (MS) regarding the frequency and nature of PIRA. This systematic review was conducted to characterise and define the elements of PIRA. Method: This systematic review was conducted and reported in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. A systematic search was conducted of the databases Embase, Medline, Cochrane Central Register of Controlled Trials, Scopus, Web of Science, ClinicalTrials.gov and Google Scholar. Results: 5,812 studies were identified by the initial search. 13 studies satisfied the inclusion criteria and were included in the systematic review. PIRA definitions varied considerably between studies. In the context of these variable definitions, along with other methodological differences relating to disease modifying therapy (DMT) use and follow-up duration, the reported proportion of patients experiencing PIRA varied from 4% to 24%. Conclusions: The currently available research supports the presence of PIRA in relapsing MS. Based on review of the existing literature, we propose a definition of PIRA that is clinically relevant and minimises confounding from inclusion of patients who have reached the secondary progressive phase of the disease.