Cerebrospinal Fluid sCD27 as a Biomarker of Neuroinflammatory Disease: A Systematic Review and Meta‐Analysis

ABSTRACT Neuroinflammatory diseases of the central nervous system (CNS) present considerable diagnostic challenges due to overlapping clinical features and the lack of specific biomarkers capable of reliably detecting CNS inflammation. Soluble CD27 (sCD27) is a marker of adaptive immune activation, released upon CD27–CD70 interaction. sCD27 has emerged as a promising cerebrospinal fluid (CSF) biomarker, but its clinical utility remains unclear. This systematic review and meta‐analysis aimed to clarify the diagnostic value of CSF sCD27 across neuroinflammatory conditions. We systematically searched PubMed, Embase, and Scopus for studies reporting CSF sCD27 levels in neuroinflammatory disorders versus controls, including demyelinating diseases, autoimmune encephalitis, neuroinfectious diseases, and primary CNS lymphoma, following PRISMA 2020 guidelines. Nineteen studies met the inclusion criteria for qualitative synthesis, and ten provided sufficient quantitative data for meta‐analysis, encompassing 685 neuroinflammatory and 751 control participants. Using multivariate and random‐effects models, we found significantly elevated levels of CSF sCD27 in neuroinflammatory diseases compared to controls (standardized mean difference [SMD] = 1.24, 95% CI 0.98–1.51, p  < 0.0001), with consistent results in sensitivity and subgroup analysis restricted to multiple sclerosis. Despite between‐study heterogeneity, largely driven by variation in assay methods, reporting units, and study populations, effect sizes remained large and robust. Most studies also reported excellent diagnostic accuracy, with area under the curve (AUC) values above 0.85, supporting the discriminatory potential of CSF sCD27 for neuroinflammatory diseases versus controls. Collectively, these findings strongly support that CSF sCD27 is a robust biomarker of adaptive immune‐mediated neuroinflammation across a spectrum of neuroinflammatory diseases. Future research should focus on assay standardization and consistent reporting practices using well‐characterized prospective cohorts of a broader spectrum of neuroinflammatory disorders to define clinical thresholds and facilitate the integration of CSF sCD27 into diagnostic protocols. This study provides a comprehensive synthesis and substantiates CSF sCD27 as a promising biomarker for detecting adaptive immune‐mediated neuroinflammation in clinical practice. image