Müller Jannis, Sharmin Sifat, Lorscheider Johannes, Ozakbas Serkan, Karabudak Rana, Horakova Dana, Weinstock-Guttman Bianca, Shaygannejad Vahid, Etemadifar Masoud, Alroughani Raed, Patti Francesco, Eichau Sara, Prat Alexandre, Lugaresi Alessandra, Tomassini Valentina, Kermode Allan G, Amato Maria Pia, Turkoglu Recai, Altintas Ayse, Buzzard Katherine, Soysal Aysun, van der Walt Anneke, Butzkueven Helmut, Blanco Yolanda, Gerlach Oliver, Khoury Samia J, Barnett Michael, John Nevin, Lechner-Scott Jeannette, Foschi Matteo, Surcinelli Andrea, van Pesch Vincent, Prevost Julie, Sa Maria Jose, Maimone Davide, D'hooghe Marie, Hughes Stella, Hodgkinson Suzanne, McGuigan Chris, Cartechini Elisabetta, Taylor Bruce, Spitaleri Daniele, Slee Mark, McCombe Pamela, Yamout Bassem, Benkert Pascal, Kuhle Jens, Kappos Ludwig, Roos Izanne, Kalincik Tomas, Havrdova Eva Kubala, Girard Marc, Duquette Pierre, Fabis-Pedrini Marzena, Carroll William M, Skibina Olga, Gouider Riadh, Mrabet Saloua, Ramo-Tello Cristina, Solaro Claudio, Habek Mario, Van Wijmeersch Bart, Ampapa Radek, Macdonell Richard, Oreja-Guevara Celia, de Gans Koen, Laureys Guy, Oh Jiwon, Garber Justin, Gray Orla, Agüera-Morales Eduardo, Sanchez-Menoyo Jose Luis, Castillo-Triviño Tamara, Grigoriadis Nikolaos, Petersen Thor, Hardy Todd A, Vucic Steve, Reddel Stephen, Ramanathan Sudarshini, Al-Asmi Abdullah, Simu Mihaela, Baghbanian Seyed Mohammad, Poehlau Dieter, Al-Harbi Talal, Rojas Juan Ignacio, Deri Norma, Lalive Patrice, Cambron Melissa, Csepany Tunde, Shuey Neil, Willekens Barbara, Shaw Cameron, Decoo Danny, Massey Jennifer, Yaldizli Özgür, Derfuss Tobias, Granziera Cristina
CORe, Department of Medicine, University of Melbourne, Melbourne, Victoria, Australia.
Neuroimmunology Centre, Department of Neurology, Royal Melbourne Hospital, Melbourne, Victoria, Australia.
JAMA Neurol. 2025 Apr 14. doi: 10.1001/jamaneurol.2025.0495.
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.
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.
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).
For each definition, we quantified PIRA incidence and persistence (ie, absence of a 3-month confirmed EDSS improvement over ≥5 years).
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.
Incidence and persistence of PIRA are determined by the definition used. The proposed standardized definition aims to enhance comparability among studies.
与复发活动无关的疾病进展（PIRA）是复发缓解型多发性硬化症（MS）长期残疾积累的重要因素。先前的研究使用了不同的PIRA定义，这妨碍了研究结果的可比性。
比较PIRA的各种定义。
设计、设置和参与者：这项队列研究对2004年7月至2023年7月从MSBase注册中心前瞻性收集的数据进行了回顾性分析。参与者是来自43个国家186个中心的MS患者，他们患有临床确诊的复发缓解型MS，拥有完整的最小数据集，并且有3次或更多次记录在案的扩展残疾状态量表（EDSS）评估。
360种PIRA定义，这些定义是以下标准的组合：基线残疾（固定基线，PIRA后重新设定基线，或复发后加重新设定基线，或改善后加重新设定基线）、最小确认期（6、12或24个月）、确认幅度（EDSS评分达到或高于恶化评分，或与基线相比达到或高于阈值）、EDSS评分恶化时无复发（恶化前90天、恶化前90天及恶化后30天、恶化前180天及恶化后、自上次EDSS评估以来、或自基线以来）、确认时无复发（确认前30天、确认前90天、确认前30天及确认后、或在恶化与确认之间）。
对于每种定义，我们量化了PIRA的发病率和持续时间（即≥5年内无3个月确认的EDSS改善）。
在87239例MS患者中，33303例患者符合纳入标准；24152例（72.5%）为女性，9151例（27.5%）为男性。首次就诊时，平均（标准差）年龄为36.4（10.9）岁；28052例患者（84.2%）患有复发缓解型MS，EDSS评分中位数（四分位间距）为2.0（1.0 - 3.0）。参与者在8.9（5.2）年中平均（标准差）就诊15.1（11.9）次。根据定义，PIRA发病率每十年从0.141至0.658事件不等，持续时间从0.753至0.919不等。特别是，基线和确认期影响PIRA的检测。以下定义产生了平衡的发病率和持续时间：与基线相比显著残疾恶化（每次PIRA事件、复发和EDSS评分改善后重新设定基线），自上次EDSS评估以来无复发，通过EDSS评分确认（30天内无复发），且至少12个月保持在恶化阈值以上。
PIRA的发病率和持续时间由所使用的定义决定。提议的标准化定义旨在提高研究之间的可比性。
