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| Item Type: | Article |
|---|---|
| Title: | Development and expert refinement of a stratified framework for progression independent of relapse activity (PIRA) in multiple sclerosis |
| Creators: |
Hamdy, Eman  ORCID: https://orcid.org/0000-0001-5004-7454, Talaat, Farouk, Ramadan, Ismail, Oertel, Frederike Cosima ORCID: https://orcid.org/0000-0003-4906-5983, Bennett, Jeffrey L., Abousteit, Alaa, Almashad, Salma S. ORCID: https://orcid.org/0000-0003-3486-4766, Zeineddine, Maya ORCID: https://orcid.org/0000-0002-6842-5609, Hassan, Amr, Said, Sameh M., Contentti, Edgar Carnero, Gaber, Dina, Zakaria, Magd, Ahmed, Sandra ORCID: https://orcid.org/0000-0002-9375-3110, Grigoriadis, Nikolaos ORCID: https://orcid.org/0000-0003-4706-4637, Fouda, Basem Hamdy, Shalaby, Nevin Mohieldin, Nasr, Nada, Paul, Friedemann, Zamzam, Dina, Krupp, Lauren, Sayed, Amira, Hassan, Shady Safwat, Naseer, Maged Abdel, Hegazy, Mohamed I., Galeel, Aya Abel, Elmesnshawy, Ibrahim and Salama, Sara ORCID: https://orcid.org/0000-0003-2380-8152
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| Abstract: | INTRODUCTION: Progression Independent of Relapse Activity (PIRA) is a critical measure of disability progression in multiple sclerosis (MS) independent of relapses but lacks a standardized definition. Current reliance on the Expanded Disability Status Scale (EDSS) limits sensitivity to non-motor domains, necessitating a stratified framework to enhance detection and guide management. OBJECTIVES: To develop a novel seven-level stratified PIRA definition and assess its validity, enhanced sensitivity, clinical relevance, and feasibility through expert consensus, and propose a simplified framework based on feedback. METHODS: A two-stage study: (1) A four-expert panel developed a seven-level PIRA framework (PIRA 1: EDSS-based; PIRA 2: EDSS-plus measures; PIRA 3: stress tests; PIRA 4: patient-reported outcomes [PROs]; PIRA 5: conventional MRI; PIRA 6: advanced MRI; PIRA 7: biomarkers) via literature synthesis. (2) A survey of 90 MS experts (26 responded, 28.9%) from nine countries evaluated each level's validity, sensitivity (vs. EDSS), relevance, and feasibility (1-5 scale), with open-ended comments on barriers and suggestions. High agreement was defined as a score ≥ 4. Qualitative feedback on barriers and improvement suggestions was thematically analyzed. RESULTS: Strong support (24/26; 92.3%) endorsed a stratified PIRA definition. Respondents included primarily clinician-researchers (22/26; 84.6%), with 11/26 (42.3%) reporting more than 20 years of MS experience. High agreement for validity ranged from 15/26 (57.7%) for PIRA 1-23/26 (88.5%) for PIRA 6. Agreement regarding enhanced sensitivity was highest for PIRA 2 (25/26; 96.2%), followed by PIRA 6 (22/26; 84.6%) and PIRA 5 (19/26; 73.1%). Clinical relevance was rated highly for PIRA 1, PIRA 2, and PIRA 6 (each 25/26; 96.2%). Feasibility was highest for PIRA 1 (24/26; 92.3%) and declined for higher levels, particularly PIRA 7. Barriers included inter-rater variability (PIRA 1, 30.8%), subjectivity (PIRA 4, 23.1%), and cost/expertise (PIRA 6-7, 26.9% each). Suggestions included digital tools (PIRA 2-3), AI for MRI (PIRA 5-6), biomarker validation (PIRA 7), and combining PIRA 5-6. PIRA 1-2 were preferred for clinical practice, PIRA 5-7 for research. A three-tier framework was proposed: Probable PIRA (clinical), Definite PIRA (clinical + MRI), and Definite PIRA Plus (clinical + MRI + biomarkers). CONCLUSIONS: The proposed seven-level PIRA framework demonstrates strong expert support for its conceptual validity and clinical relevance but highlights feasibility challenges for advanced assessments. A simplified three-tier model may provide a practical structure for standardized evaluation of relapse-independent progression in MS. Further empirical validation in diverse clinical cohorts is required. |
| Keywords: | Multiple Sclerosis, PIRA, Progression Independent of Relapse Activity, Definition |
| Source: | Clinical Neurology and Neurosurgery |
| ISSN: | 0303-8467 |
| Publisher: | Elsevier |
| Volume: | 267 |
| Page Range: | 109430 |
| Date: | August 2026 |
| Official Publication: | https://doi.org/10.1016/j.clineuro.2026.109430 |
| PubMed: | View item in PubMed |
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