New Consensus Statement Aims to Refine PIRA Assessment in MS
Although Progression Independent of Relapse Activity (PIRA) is recognized as a key driver of disability accumulation in multiple sclerosis (MS), its clinical utility has been limited by a lack of consensus definition in the field and overreliance on the Expanded Disability Status Scale (EDSS). In a presentation given at the 41st Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS), researchers proposed a validated, stratified framework for PIRA aimed at enhancing sensitivity and standardization across clinical and research settings.
A panel of 4 MS experts first developed a 7-level framework through a synthesis of the literature, incorporating assessments ranging from traditional EDSS measures to biomarkers:
- PIRA 1: EDSS-identifiable PIRA
- PIRA 2: EDSS+ measures (Symbol Digits Modality Test, 9-Hole Peg Test, Timed 25-Foot Walk Test, Low-Contrast Letter Acuity)
- PIRA 3: Neurological stress tests
- PIRA 4: Patient-reported outcomes
- PIRA 5: Conventional MRI tests (PIRMA)
- PIRA 6: Advanced MRI tests (Advanced PIRMA)
- PIRA 7: Biomarkers (Biological/Pathobiological PIRA)
Subsequently, a pool of international MS experts were surveyed to evaluate each level’s validity, sensitivity (compared with EDSS), relevance, and feasibility (scale: 1-5), and to provide qualitative feedback about barriers. In all, 26 respondents completed the survey. Researchers calculated nonparametric medians and interquartile ranges and analyzed themes in the qualitative feedback.
- Across domains, validity ratings were high (median, 4 to 5 rank), with the strongest endorsement for advanced MRI (PIRA 6) and biomarker-based levels (PIRA 7).
- Enhanced sensitivity compared with EDSS was most notable for combined EDSS-plus measures (PIRA 2), conventional MRI (PIRA 5), and advanced MRI (PIRA 6).
- Clinical relevance was strongest for EDSS (PIRA 1) and EDSS+ (PIRA 2) measures, while feasibility declined for biomarker-based approaches (PIRA 7), reflecting concerns over cost, technical expertise, and inter-rater variability. Suggestions included use of digital tools for functional assessments, artificial intelligence evaluation of MRI interpretation, and further validation of biomarkers.
Based on these insights, investigators proposed a streamlined 3-tier framework:
- Probable PIRA (clinical measures)
- Definite PIRA (clinical measures + MRI)
- Advanced PIRA (clinical measures + MRI + biomarkers)
This model balances practicality with sensitivity, offering a path toward standardized monitoring of MS progression. Further validation of the 3-tier framework in diverse clinical and research settings is needed before widespread adoption.
This global initiative included researcher from the following institutions: Alexandria University Faculty of Medicine, Oslo University, Ain Shams University, University of Colorado Anschutz Medical Campus, Lebanese American University, Cairo University, Hospital Aleman/Buenos Aires, Dalhousie University, Aristotle University of Thessaloniki, Tanta University Faculty of Medicine, Assiut University, NYU Langone Health, and University College London.