Abstract
BACKGROUND: Multiple sclerosis (MS) is a chronic neuroinflammatory and neurodegenerative disease. Emerging evidence suggests that chronic disease processes within the central nervous system are important drivers of the ongoing disability accumulation in people with MS (pwMS). Chronic lesion activity driven by smoldering neuroinflammation is considered one of the neuropathological hallmarks of disease progression in worsening disability. Our understanding of the role of chronic active lesions (CALs) in MS pathology has expanded with improvements in imaging technology. Three in vivo imaging biomarkers of CALs are available to detect CALs: paramagnetic rim lesions (PRLs), 18 kDa translocator protein (TSPO)-positron emission tomography rim-positive lesions, and the magnetic resonance imaging (MRI)-defined slowly expanding lesions (SELs). OBJECTIVE: To evaluate associations between CALs and measures of worsening disability in pwMS. METHODS: A systematic literature search was conducted following Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines using PubMed, Embase, and the Cochrane Library on April 21, 2023. The review included randomized controlled trials, retrospective studies, and prospective cross-sectional and longitudinal studies conducted during 2010-2023 reporting the outcomes of interest. Studies evaluating people with any MS phenotype were included if they reported any associative analysis between CALs and clinical outcomes. RESULTS: A total of 30 of 149 unique studies identified in the literature met the inclusion criteria. Of these 30 publications, 18 were based on PRLs, 9 on MRI-defined SELs, 1 on PRLs and MRI-defined SELs simultaneously, and 2 on TSPO-positive lesions. PRLs were associated with disability worsening in 17 studies, as measured by clinical disability scales. MRI-defined SELs were associated with worsening disability in 10 studies. CONCLUSIONS: CALs are frequently associated with disease progression and disability accumulation. CALs may provide an indicator of disease severity and may assist with the assessment of treatment efficacy.