Biomarkers of Progression Independent of Relapse Activity—Can We Actually Measure It Yet?

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.