Bsteh Gabriel, Dal-Bianco Assunta, Krajnc Nik, Berger Thomas
Department of Neurology, Medical University of Vienna, 1090 Wien, Austria.
Comprehensive Center for Clinical Neurosciences and Mental Health, Medical University of Vienna, 1090 Wien, Austria.
Int J Mol Sci. 2025 May 14;26(10):4704. doi: 10.3390/ijms26104704.
Progression independent of relapse activity (PIRA) is increasingly recognized as a key driver of disability in multiple sclerosis (MS). However, the concept of PIRA remains elusive, with uncertainty surrounding its definition, underlying mechanisms, and methods of quantification. This review examines the current landscape of biomarkers used to predict and measure PIRA, focusing on clinical, imaging, and body fluid biomarkers. Clinical disability scores such as the Expanded Disability Status Scale (EDSS) are widely used, but may lack sensitivity in capturing subtle relapse-independent progression. Imaging biomarkers, including MRI-derived metrics (brain and spinal cord volume loss, chronic active lesions) and optical coherence tomography (OCT) parameters (retinal nerve fiber layer and ganglion cell-inner plexiform layer thinning), offer valuable insights, but often reflect both inflammatory and neurodegenerative processes. Body fluid biomarkers, such as neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP), are promising indicators of axonal damage and glial activation, but their specificity for PIRA remains limited. This review emphasizes the distinction between predicting PIRA-identifying individuals at risk of future progression-and measuring ongoing PIRA-related disability in real time. We highlight the limitations of current biomarkers in differentiating PIRA from relapse-associated activity and call for a clearer conceptual framework to guide future research. Advancing the precision and utility of PIRA biomarkers will require multimodal approaches, longitudinal studies, and standardized protocols to enable their clinical integration and to improve personalized MS management.
独立于复发活动的疾病进展（PIRA）日益被认为是多发性硬化症（MS）导致残疾的关键驱动因素。然而，PIRA的概念仍然难以捉摸，其定义、潜在机制和量化方法都存在不确定性。本综述探讨了用于预测和测量PIRA的生物标志物的现状，重点关注临床、影像学和体液生物标志物。临床残疾评分，如扩展残疾状态量表（EDSS）被广泛使用，但在捕捉细微的与复发无关的疾病进展方面可能缺乏敏感性。影像学生物标志物，包括磁共振成像衍生指标（脑和脊髓体积损失、慢性活动性病变）和光学相干断层扫描（OCT）参数（视网膜神经纤维层和神经节细胞-内丛状层变薄）提供了有价值的见解，但往往反映了炎症和神经退行性过程。体液生物标志物，如神经丝轻链（NfL）和胶质纤维酸性蛋白（GFAP），是轴突损伤和胶质细胞活化的有前景的指标，但它们对PIRA的特异性仍然有限。本综述强调了预测PIRA（识别未来有疾病进展风险的个体）和实时测量正在进行的与PIRA相关的残疾之间的区别。我们强调了当前生物标志物在区分PIRA和复发相关活动方面的局限性，并呼吁建立一个更清晰的概念框架来指导未来的研究。提高PIRA生物标志物的精度和实用性将需要多模态方法、纵向研究和标准化方案，以实现其临床整合并改善个性化的MS管理。
