Zhu Chao, Zhou Zhen, Kalincik Tomas, Roos Izanne, Buzzard Katherine, Skibina Olga, Alroughani Raed, Kuhle Jens, Girard Marc, Grammond Pierre, Lechner-Scott Jeannette, Gerlach Oliver, John Nevin, McCombe Pamela, Macdonell Richard, van Pesch Vincent, Laureys Guy, Prevost Julie, Horakova Dana, Kubala Havrdova Eva, Castillo-Triviño Tamara, Ramo-Tello Cristina, Blanco Yolanda, Meca-Lallana Jose E, Lugaresi Alessandra, Tomassini Valentina, Cartechini Elisabetta, Amato Maria Pia, Spitaleri Daniele, Patti Francesco, Maimone Davide, Foschi Matteo, Surcinelli Andrea, D'Amico Emanuele, Yamout Bassem, Khoury Samia J, Jose Sa Maria, Boz Cavit, Ozakbas Serkan, Weinstock-Guttman Bianca, Merlo Daniel, Monif Mastura, Jokubaitis Vilija G, van der Walt Anneke, Butzkueven Helmut
Department of Neuroscience, School of Translational Medicine, Monash University, Melbourne, VIC 3004, Australia.
School of Public Health and Preventive Medicine, Monash University, Melbourne, VIC 3004, Australia.
Brain Commun. 2025 Aug 21;7(5):fcaf306. doi: 10.1093/braincomms/fcaf306. eCollection 2025.
Patients with relapsing-remitting multiple sclerosis (RRMS) may experience disability progression independent of relapse activity (PIRA), which can be an early sign of secondary progressive MS (SPMS). We defined persistent PIRA as ongoing sustained disability over the entire available follow-up period. However, PIRA events can regress over time. Identifying factors that predict PIRA persistence is of great interest as they can refine the definition of RRMS to SPMS transition. Equally, factors associated with the non-persistence of PIRA have potential treatment implications for patients suffering from a PIRA event. We conducted a study to examine risk factors for PIRA persistence and risk differences in long-term disability progression between persistent and non-persistent PIRA. In this cohort study, we included only patients who had already experienced a PIRA event and investigated the persistence of disability progression following their first PIRA event. Therefore, PIRA occurrence time was set as the baseline. Data were collected from the MSBase registry between April 1995 and January 2024, with a median follow-up of 8.7 years. The primary outcome was time to 6-month confirmed non-persistence of PIRA. Secondary outcomes comprised time to 6-month confirmed Expanded Disability Status Scale (EDSS) 6 and time to SPMS. A stratified Cox regression model was used to identify risk factors associated with non-persistent PIRA. We then matched persistent PIRA patients with non-persistent PIRA patients in a 1:1 ratio using propensity scores, and compared their risk of reaching EDSS 6 using the Cox regression model. We re-matched patients with complete Kurtzke Functional Systems Scores to compare their risks of reaching SPMS. We included 4713 RRMS patients with PIRA, of whom around one-third experienced a post-PIRA disability improvement, over a relatively long period (median of 2.6 years to improvement). Use of high-efficacy disease-modifying therapies (DMT) at baseline [hazard ratio, 1.22; 95% confidence interval, (1.08-1.38); = 0.0015], lower baseline EDSS [hazard ratio, 0.73 (0.69-0.78); < 0.0001] and younger age [per 10 years; hazard ratio, 0.84 (0.80-0.89); < 0.0001] were associated with non-persistent PIRA. Patients with non-persistent PIRA had a hazard ratio of 0.19 [95% confidence interval, (0.15-0.25); < 0.0001] for reaching EDSS 6 and 0.18 [(0.11-0.29); < 0.0001] for reaching SPMS compared to patients with persistent PIRA. PIRA events slowly regress in one-third of patients. Patients with persistent PIRA had a substantially higher risk of reaching EDSS 6 and SPMS than those with non-persistent PIRA. Younger age, lower baseline EDSS, and use of high-efficacy DMT during PIRA events were associated with PIRA regression.
复发缓解型多发性硬化症（RRMS）患者可能会出现与复发活动无关的残疾进展（PIRA），这可能是继发进展型MS（SPMS）的早期迹象。我们将持续性PIRA定义为在整个可用随访期内持续存在的残疾。然而，PIRA事件可能会随时间消退。确定预测PIRA持续性的因素非常重要，因为它们可以完善RRMS向SPMS转变的定义。同样，与PIRA非持续性相关的因素对经历PIRA事件的患者具有潜在的治疗意义。我们进行了一项研究，以检查PIRA持续性的危险因素以及持续性和非持续性PIRA之间长期残疾进展的风险差异。在这项队列研究中，我们仅纳入已经经历过PIRA事件的患者，并调查他们首次PIRA事件后残疾进展的持续性。因此，将PIRA发生时间设定为基线。数据收集自1995年4月至2024年1月的MSBase注册库，中位随访时间为8.7年。主要结局是6个月确认的PIRA非持续性时间。次要结局包括6个月确认的扩展残疾状态量表（EDSS）达到6分的时间和达到SPMS的时间。使用分层Cox回归模型来确定与非持续性PIRA相关的危险因素。然后，我们使用倾向评分以1:1的比例将持续性PIRA患者与非持续性PIRA患者进行匹配，并使用Cox回归模型比较他们达到EDSS 6分的风险。我们对具有完整Kurtzke功能系统评分的患者进行重新匹配，以比较他们达到SPMS的风险。我们纳入了4713例患有PIRA的RRMS患者，其中约三分之一在相对较长的时间内（改善的中位时间为[具体数值缺失]）经历了PIRA后残疾改善。基线时使用高效疾病修饰疗法（DMT）[风险比，1.22；95%置信区间，（1.08 - 1.38）；P值 = 0.0015]、较低的基线EDSS[风险比，0.73（0.69 - 0.78）；P值 < 0.0001]和较年轻的年龄[每10岁；风险比，0.84（0.80 - 0.89）；P值 < 0.0001]与PIRA非持续性相关。与持续性PIRA患者相比。非持续性PIRA患者达到EDSS 6分的风险比为0.19[95%置信区间，（0.15 - 0.25）；P值 < 0.0001]，达到SPMS的风险比为0.18[（0.11 - 0.29）；P值 < 0.0001]。三分之一的患者PIRA事件会缓慢消退。与非持续性PIRA患者相比，持续性PIRA患者达到EDSS 6分和SPMS的风险要高得多。较年轻的年龄、较低的基线EDSS以及在PIRA事件期间使用高效DMT与PIRA消退相关。
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