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Multicenter Study
. 2025 Jun 1;82(6):614-625.
doi: 10.1001/jamaneurol.2025.0495.

Standardized Definition of Progression Independent of Relapse Activity (PIRA) in Relapsing-Remitting Multiple Sclerosis

Jannis Müller  1   2   3 Sifat Sharmin  1   2 Johannes Lorscheider  3 Serkan Ozakbas  4   5 Rana Karabudak  6 Dana Horakova  7 Bianca Weinstock-Guttman  8 Vahid Shaygannejad  9 Masoud Etemadifar  10 Raed Alroughani  11 Francesco Patti  12   13 Sara Eichau  14 Alexandre Prat  15 Alessandra Lugaresi  16   17 Valentina Tomassini  18 Allan G Kermode  19 Maria Pia Amato  20   21 Recai Turkoglu  22 Ayse Altintas  23 Katherine Buzzard  24   25 Aysun Soysal  26 Anneke van der Walt  27 Helmut Butzkueven  27 Yolanda Blanco  28 Oliver Gerlach  29   30 Samia J Khoury  31 Michael Barnett  32 Nevin John  33   34 Jeannette Lechner-Scott  35 Matteo Foschi  36 Andrea Surcinelli  37 Vincent van Pesch  38 Julie Prevost  39 Maria Jose Sa  40 Davide Maimone  41 Marie D'hooghe  42 Stella Hughes  43 Suzanne Hodgkinson  44 Chris McGuigan  45 Elisabetta Cartechini  46 Bruce Taylor  47 Daniele Spitaleri  48 Mark Slee  49 Pamela McCombe  50 Bassem Yamout  51 Pascal Benkert  3 Jens Kuhle  3 Ludwig Kappos  3 Izanne Roos  1   2 Tomas Kalincik  1   2 MSBase Study GroupEva Kubala Havrdova  7 Marc Girard  15 Pierre Duquette  15 Marzena Fabis-Pedrini  19 William M Carroll  19 Olga Skibina  24 Riadh Gouider  52 Saloua Mrabet  53 Cristina Ramo-Tello  53 Claudio Solaro  54 Mario Habek  55 Bart Van Wijmeersch  56 Radek Ampapa  57 Richard Macdonell  58 Celia Oreja-Guevara  59 Koen de Gans  60 Guy Laureys  61 Jiwon Oh  62 Justin Garber  63 Orla Gray  64 Eduardo Agüera-Morales  65 Jose Luis Sanchez-Menoyo  66 Tamara Castillo-Triviño  67 Nikolaos Grigoriadis  68 Thor Petersen  69 Todd A Hardy  70 Steve Vucic  70 Stephen Reddel  70 Sudarshini Ramanathan  71   72 Abdullah Al-Asmi  73 Mihaela Simu  74 Seyed Mohammad Baghbanian  75 Dieter Poehlau  76 Talal Al-Harbi  77 Juan Ignacio Rojas  78 Norma Deri  79 Patrice Lalive  80 Melissa Cambron  81 Tunde Csepany  82 Neil Shuey  83 Barbara Willekens  84   85 Cameron Shaw  86 Danny Decoo  87 Jennifer Massey  88 Özgür Yaldizli  3 Tobias Derfuss  3 Cristina Granziera  3
Affiliations
Multicenter Study

Standardized Definition of Progression Independent of Relapse Activity (PIRA) in Relapsing-Remitting Multiple Sclerosis

Jannis Müller et al. JAMA Neurol. .

Abstract

Importance: Progression independent of relapse activity (PIRA) is a significant contributor to long-term disability accumulation in relapsing-remitting multiple sclerosis (MS). Prior studies have used varying PIRA definitions, hampering the comparability of study results.

Objective: To compare various definitions of PIRA.

Design, setting, and participants: This cohort study involved a retrospective analysis of prospectively collected data from the MSBase registry from July 2004 to July 2023. The participants were patients with MS from 186 centers across 43 countries who had clinically definite relapsing-remitting MS, a complete minimal dataset, and 3 or more documented Expanded Disability Status Scale (EDSS) assessments.

Exposure: Three-hundred sixty definitions of PIRA as combinations of the following criteria: baseline disability (fixed baseline with re-baselining after PIRA, or plus re-baselining after relapses, or plus re-baselining after improvements), minimum confirmation period (6, 12, or 24 months), confirmation magnitude (EDSS score at/above worsening score or at/above threshold compared with baseline), freedom from relapse at EDSS score worsening (90 days prior, 90 days prior and 30 days after, 180 days prior and after, since previous EDSS assessment, or since baseline), and freedom from relapse at confirmation (30 days prior, 90 days prior, 30 days before and after, or between worsening and confirmation).

Main outcome and measure: For each definition, we quantified PIRA incidence and persistence (ie, absence of a 3-month confirmed EDSS improvement over ≥5 years).

Results: Among 87 239 patients with MS, 33 303 patients fulfilled the inclusion criteria; 24 152 (72.5%) were female and 9151 (27.5%) were male. At the first visits, the mean (SD) age was 36.4 (10.9) years; 28 052 patients (84.2%) had relapsing-remitting MS, and the median (IQR) EDSS score was 2.0 (1.0-3.0). Participants had a mean (SD) 15.1 (11.9) visits over 8.9 (5.2) years. PIRA incidence ranged from 0.141 to 0.658 events per decade and persistence from 0.753 to 0.919, depending on the definition. In particular, the baseline and confirmation period influenced PIRA detection. The following definition yielded balanced incidence and persistence: a significant disability worsening compared with a baseline (reset after each PIRA event, relapse, and EDSS score improvement), in absence of relapses since the last EDSS assessment, confirmed with EDSS scores (not preceded by relapses within 30 days) that remained above the worsening threshold for at least 12 months.

Conclusion and relevance: Incidence and persistence of PIRA are determined by the definition used. The proposed standardized definition aims to enhance comparability among studies.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Müller reported travel support from Novartis outside the submitted work. Dr Sharmin reported grants from MS Australia outside the submitted work. Dr Lorscheider reported grants paid to their institution from Innosuisse–Swiss Innovation agency, MSBase Foundation, Novartis, and Biogen and fees paid to their institution from Novartis, Roche, Teva, and Bristol Myers Squibb outside the submitted work. Dr Ozakbas reported grants from Merck and Novartis during the conduct of the study. Dr Karabudak had received honoraria for giving educational lectures, consultancy fees for participating advisory boards, and travel grants for attending scientific congresses or symposia from Roche, Sanofi-Genzyme, Merck-Serono, Novartis, Teva, Biogen Idec/Gen Pharma of Turkey, Sanovel, Abdi İbrahim İlaç. Dr Horakova reported grants from the Charles University Cooperation Program in Neuroscience, European Union–Next Generation EU Programme EXCELES (ID Project No. LX22NPO5107), and General University Hospital in Prague (MH CZ-DRO-VFN64165) during the conduct of the study and compensation for travel, speaker honoraria, and consultant fees from Biogen Idec, Novartis, Merck, Sanofi Genzyme, Roche, and Teva. Dr Weinstock-Guttman reported grants from Novartis, AstraZeneca, and Horizon and personal fees from EMD Serono, SANA, and Immunic outside the submitted work. Dr Alroughani reported fees for scientific advisory board and speaking services from Novartis, Roche, Merck, Biogen, Sanofi, and AstraZeneca outside the submitted work. Dr Patti reported grants from Alexion, Almirall, Biogen, Merc Serono, Novartis, and Sanofi and personal fees from Bristol outside the submitted work. Dr Lugaresi reported personal fees from Alexion, Amgen/Horizon, Biogen, Celgene/Bristol Myers Squibb, Merck Serono, Novartis, Roche, Sanofi/Genzyme, Janssen/Johnson & Johnson, Coloplast, and Fondazione Italiana ed Associazione Italiana Sclerosi Multipla and grants from Novartis and Sanofi/Genzyme from outside the submitted work. Dr Tomassini reported personal fees from Roche, Almirall, Lundbeck, Novartis, Bristol Myers Squibb, Biogen, Janssen, Viatris, Alexion, and Horizon outside the submitted work. Dr Amato reported grants from Roche, Merck, and Novartis and advisory board and speaker fees from Roche, Sanofi, Celgene, Bristol Myers Squibb, Merck, Novartis, Biogen, Sandoz, and Amgen speaker during the conduct of the study; and grants from Roche, Merck, and Novartis and advisory board and speaker fees from Roche, Merck, Novartis, Biogen, Sandoz, and Amgen outside the submitted work. Dr Buzzard reported personal fees for presentations and education support and/or advisory board activities from Biogen, Merck, Novartis, Sanofi-Genzyme, and Teva outside the submitted work. Dr Van der Walt reported grants and/or unrestricted research funding from Merck, Roche, and Novartis; travel support, speaking honoraria, and/or advisory board fees from Roche and Novartis outside the submitted work; and being chief operating officer of the MSBase Foundation. Dr Butzkueven reported and Investigator Grant level A from National Health and Medical Research Council (NHMRC); institutional grants and study funding from Roche, Biogen, UCB, Novartis, and Merck; and travel support from Merck and Novartis outside the submitted work. Dr Gerlach reported grants from the National MS Foundation and MS Research Foundation outside the submitted work. Dr Khoury reported personal fees from Biogen for serving on IDMC outside the submitted work. Dr Barnett reported grants from Genzyme-Sanofi, Novartis, Merck, Bristol Myers Squibb, and Alexion and personal fees from Novartis and Alexion outside the submitted work and being the honorary research director and co-founder of Sydney Neuroimaging Analysis Centre (SNAC). Dr John reported being a PI on MS studies funded by Novartis, Roche, and Sanofi; receiving speaking honoraria and consulting fees from Merck and congress travel and registration reimbursement and consulting fees from Novartis. Dr Lechner-Scott reported grants from Merck and advisory board fees from Merck and Novartis outside the submitted work. Dr Foschi reported personal fees from Roche, Novartis, Merck, Bristol Myers Squibb, Biogen, and Sanofi outside the submitted work. Dr Van Pesch reported consultant and/or lecture fees paid to their institution from Biogen, Novartis, Merck, Sanofi, Alexion, Neuraxpharm, Roche, Eisai, Bristol Myers Squibb, Janssen, and Almirall outside the submitted work. Dr Maimone reported personal fees from Alexion, Biogen, Merck, Novartis, Roche, Bristol Myers Squibb, Sanofi, and Janssen outside the submitted work. Dr Hughes reported personal fees from Roche, Sanofi, Biogen, and Merck outside the submitted work. Dr Hodgkinson reported honoraria for advisory boards from Merck, Bayer, Sanofi, Biogen, Novartis, Atara, and CSL. Dr Havrdova reported advisory board fees and/or speaker honoraria from Merck, Sanofi, Teva, Novartis, Bristol Myers Squibb, and Johnson & Johnson and grants from the Czech Ministry of Education research outside the submitted work. Dr Gouider reported advisory board fees from Biogen, Hikma, Merck, Sanofi, and Roche outside the submitted work. Dr Mrabet reported grants from MENACTRIMS for a clinical fellowship in 2020 outside the submitted work. Dr Habek reported grants from Croatian Science Foundation and personal fees from Roche, Novartis, Merck, AstraZeneca, Amgen, Zentiva, and Siemens Healthcare outside the submitted work. Dr Van Wijmeersch reported personal fees from Amgen, Bristol Myers Squibb, Merck, Sanofi, Novartis, Janssen, Imcyse, Biogen, and Roche and grants from Merck, Roche, Viatris, and Roche outside the submitted work. Dr Ampapa reported personal fees from Roche, Merck, Novartis, Bristol Myers Squibb, and Sanofi during the conduct of the study. Dr Oreja-Guevara reported speaker, advisor, and/or consultant fees from Merck, Biogen, Sanofi, Novartis, Roche, Sandoz, Viatris, Neuraxpharm, Alexion, and Amgen outside the submitted work. Dr de Gans reported financial support for ECTRIMS 2023 from Merck and financial support for a Dutch neurological conference 2024 from Novartis outside the submitted work. Dr Laureys reported research or travel grants and/or advisory board and lecture fees paid to their institution from Roche, Merck, Bristol Myers Squibb, Novartis, Celgene, Sanofi, and Biogen outside the submitted work. Dr Oh reported grants from Biogen-Idec and Roche and personal fees from Biogen-Idec, Roche, Novartis, and Sanofi outside the submitted work. Dr Gray reported grants to their trust from Biogen and personal fees from Novartis, Roche, Biogen, and Merck outside the submitted work. Dr Agüera reported speaker fees from Sanofi, Merck, and Biogen outside the submitted work. Dr Sanchez-Menoyo reported travel and/or speaker fees from Roche, Novartis, Merck, Biogen, Novartis, and Sanofi and clinical trial funds from Merck and Roche outside the submitted work. Dr Castillo-Trivino reported travel support and/or personal fees from Almirall, Biogen, Bristol Myers Squibb, Janssen, Merck, Novartis, Roche, and Sanofi-Genzyme outside the submitted work. Dr Hardy reported grants from MS Australia and NHMRC Medical Research Future Fund (MRFF) and personal fees from Novartis, Merck, Roche, and Biogen outside the submitted work. Dr Reddel reported travel support, honoraria, trial payments, and/or research and clinical support to the neurology department or academic projects from NHMRC, MRFF, NBA, Myasthenia Alliance Australia, Beeren Foundation, Alexion, Argenx, Biogen, CSL, Genzyme, Grifols, Jannsen, Merck, Novartis, Roche, Sandoz, Sanofi, and UCB; and reported being and/or serving and/or receiving a co-founder/shareholder of RxPx Health, National IVIG Governance Advisory Council & Specialist Working Group Australia (Neurology) (paid), Australian Medical Services Advisory Committee ad hoc subcommittee on IVIG (paid), Australian Technical Advisory Group on Immunisation Varicella Zoster working party (unpaid), public salary as a staff specialist neurologist from Concord Hospital Sydney Local Health District (paid), private billings from patients and Medicare Australia reimbursement as a private practice neurologist (paid), and medical advisor (unpaid) to various patient and advocacy groups. Dr Ramanathan reported grants from NHMRC (Investigator Grant and research funding) and University of Sydney (research funding) outside the submitted work; receiving research funding from NHMRC, Petre Foundation, Brain Foundation, Royal Australasian College of Physicians, and University of Sydney; serving as a consultant on an advisory board for UCB and Limbic Neurology; having been an invited speaker for educational/research sessions coordinated by Biogen, Alexion, Novartis, Excemed, and Limbic Neurology; and serving on the medical advisory boards (nonremunerated positions) of The MOG Project and the Sumaira Foundation. Dr Al-Asmi reported a grant paid to their institution from MENACTRIMS during the conduct of the study and speaker/moderator fees from Roche, Novartis, Biogen, and Merck outside the submitted work. Dr Simu reported personal fees from AbbVie, Novartis, Roche, Bristol Myers Squibb, Merck, Johnson & Johnson, Sanofi, and Teva outside the submitted work. Dr Lalive reported grants from Novartis and travel support and/or advisory board fees from Merck, Roche, and Novartis outside the submitted work. Dr Shuey reported personal fees from Roche and Novartis during the conduct of the study. Dr Willekens reported grants from Janssen, Novartis, FWO, NMSS USA, Roche, Queen Elisabeth Medical Foundation, Start 2 Cure Foundation, UZA Foundation, and Belgian Charcot Foundation; fees paid to their institution from Janssen, Alexion, Horizon, Merck, Novartis, Roche, Sanofi, Bristol Myers Squibb, Celgene, Biogen, Galapagos, and Immunic; and nonfinancial support from Merck, Novartis, Roche, EAN, and ECTRIMS outside the submitted work. Dr Yaldizli reported having received grants from ECTRIMS/MAGNIMS, University of Basel, Pro Patient Stiftung University Hospital Basel, Free Academy Basel, Swiss Multiple Sclerosis Society, and Swiss National Science Foundation and advisory board/lecture and consultancy fees from Roche, Sanofi Genzyme, Almirall, Biogen, and Novartis. Dr Derfuss reported grants from Alexion, Roche, and Biogen and serving as a member of advisory boards/steering committees/data safety monitoring boards from Alexion, Roche, Biogen, Merck, Sanofi, and Novartis outside the submitted work. Dr Kuhle reported grants from Roche, Novartis, Merck, Swiss National Science Foundation, and Progressive MS Alliance and personal fees from Quanterix, Immunic, Stata DX, Merck, NeuroGenesis, and Roche outside the submitted work. Dr Roos reported grants from the NHMRC and MS Australia during the conduct of the study and; personal fees from Merck, Roche, Biogen, and Novartis outside the submitted work. Dr Kalincik reported scientific advisory boards or consultancy fees from MS International Federation, World Health Organisation, Therapeutic Goods Administration, Bristol Myers Squibb, Roche, Janssen, Genzyme, Novartis, Merck, and Biogen; conference travel support or speaker honoraria from WebMD Global, Merck, Sandoz, Novartis, Biogen, Roche, Eisai, Genzyme, Teva, and BioCSL; and research or educational event support from Biogen, Novartis, Genzyme, Roche, Celgene, and Merck outside the submitted work. No other disclosures were reported.

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