Importance The mechanisms driving neurodegeneration and brain atrophy in relapsing multiple sclerosis (RMS) are not completely understood. Objective To determine whether disability progression independent of relapse activity (PIRA) in patients with RMS is associated with accelerated brain tissue loss. Design, Setting, and Participants In this observational, longitudinal cohort study with median (IQR) follow-up of 3.2 years (2.0-4.9), data were acquired from January 2012 to September 2019 in a consortium of tertiary university and nonuniversity referral hospitals. Patients were included if they had regular clinical follow-up and at least 2 brain magnetic resonance imaging (MRI) scans suitable for volumetric analysis. Data were analyzed between January 2020 and March 2021. Exposures According to the clinical evolution during the entire observation, patients were classified as those presenting (1) relapse activity only, (2) PIRA episodes only, (3) mixed activity, or (4) clinical stability. Main Outcomes and Measures Mean difference in annual percentage change (MD-APC) in brain volume/cortical thickness between groups, calculated after propensity score matching. Brain atrophy rates, and their association with the variables of interest, were explored with linear mixed-effect models. Results Included were 1904 brain MRI scans from 516 patients with RMS (67.4% female; mean [SD] age, 41.4 [11.1] years; median [IQR] Expanded Disability Status Scale score, 2.0 [1.5-3.0]). Scans with insufficient quality were excluded (n = 19). Radiological inflammatory activity was associated with increased atrophy rates in several brain compartments, while an increased annualized relapse rate was linked to accelerated deep gray matter (GM) volume loss. When compared with clinically stable patients, patients with PIRA had an increased rate of brain volume loss (MD-APC, -0.36; 95% CI, -0.60 to -0.12; P = .02), mainly driven by GM loss in the cerebral cortex. Patients who were relapsing presented increased whole brain atrophy (MD-APC, -0.18; 95% CI, -0.34 to -0.02; P = .04) with respect to clinically stable patients, with accelerated GM loss in both cerebral cortex and deep GM. No differences in brain atrophy rates were measured between patients with PIRA and those presenting relapse activity. Conclusions and Relevance Our study shows that patients with RMS and PIRA exhibit accelerated brain atrophy, especially in the cerebral cortex. These results point to the need to recognize the insidious manifestations of PIRA in clinical practice and to further evaluate treatment strategies for patients with PIRA in clinical trials.

中文翻译：

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与复发性多发性硬化症患者的复发活动无关的脑萎缩与疾病进展的关联。

重要性 在复发性多发性硬化症 (RMS) 中驱动神经退行性变和脑萎缩的机制尚不完全清楚。目的 确定 RMS 患者独立于复发活动的残疾进展 (PIRA) 是否与加速的脑组织丢失相关。设计、设置和参与者在这项观察性纵向队列研究中，中位 (IQR) 随访时间为 3.2 年 (2.0-4.9)，数据是从 2012 年 1 月至 2019 年 9 月在一个由高等教育大学和非大学转诊医院组成的联盟中获得的。如果患者有定期的临床随访和至少 2 次适合体积分析的脑磁共振成像 (MRI) 扫描，则他们被纳入研究。对 2020 年 1 月至 2021 年 3 月期间的数据进行了分析。暴露 根据整个观察期间的临床演变，患者被分类为（1）仅复发活动，（2）仅 PIRA 发作，（3）混合活动，或（4）临床稳定性。主要结果和测量 组间脑容量/皮质厚度的年变化百分比 (MD-APC) 的平均差异，在倾向得分匹配后计算。使用线性混合效应模型探索脑萎缩率及其与感兴趣变量的关联。结果 包括来自 516 名 RMS 患者的 1904 次脑部 MRI 扫描（67.4% 为女性；平均 [SD] 年龄，41.4 [11.1] 岁；中位数 [IQR] 扩展残疾状态量表评分，2.0 [1.5-3.0]）。排除了质量不足的扫描（n = 19）。放射炎症活动与几个脑区的萎缩率增加有关，而年复发率增加与深部灰质 (GM) 体积减少有关。与临床稳定的患者相比，PIRA 患者的脑容量减少率增加（MD-APC，-0.36；95% CI，-0.60 至 -0.12；P = .02），主要是由于脑部 GM 损失皮质。与临床稳定的患者相比，复发患者的全脑萎缩增加（MD-APC，-0.18；95% CI，-0.34 至 -0.02；P = .04），大脑皮层和深部 GM 的 GM 损失加速. 在 PIRA 患者和表现出复发活动的患者之间没有测量到脑萎缩率的差异。结论和相关性 我们的研究表明，患有 RMS 和 PIRA 的患者表现出加速的脑萎缩，尤其是在大脑皮层。这些结果表明需要认识到 PIRA 在临床实践中的隐匿表现，并在临床试验中进一步评估 PIRA 患者的治疗策略。