Background: Central neuropsychiatric systemic lupus erythematosus (cNPSLE) represents a major cause of mortality in systemic lupus erythematosus (SLE). However, its clinical manifestations frequently overlap with those of central nervous system (CNS) infections, creating critical diagnostic and therapeutic dilemmas in clinical practice.

Objectives: To address this diagnostic challenge by conducting a large-scale cerebrospinal fluid (CSF) proteomic investigation to identify and validate specific biomarkers capable of distinguishing cNPSLE from CNS infections.

Methods: We applied high-throughput data-independent acquisition mass spectrometry (DIA-MS) to profile 2,175 CSF proteins in a discovery cohort comprising 20 cNPSLE patients, 8 CNS infection controls (cNIC), and 11 non-diseased controls (NDC). Candidate biomarkers were subsequently validated using enzyme-linked immunosorbent assay (ELISA) in an independent internal cohort (46 cNPSLE vs. 29 cNIC) and an external validation cohort (40 cNPSLE vs. 13 cNIC).

Results: Differentially expressed proteins were significantly enriched in immune and metabolic pathways, reflecting the multifactorial pathophysiology of cNPSLE. Five proteins were consistently upregulated in cNPSLE compared with both control groups. Validation confirmed the robust diagnostic value of three candidates: matrilin-3 (MATN3; AUC = 0.875 and 0.868 in the internal and external cohorts, respectively), tyrosine-protein kinase Mer (MERTK; AUC = 0.801 and 0.775), and V-set and immunoglobulin domain-containing 4 (VSIG4; AUC = 0.724 and 0.752). Notably, a composite three-protein panel achieved superior discriminatory performance, yielding AUCs of 0.921 and 0.911 in the respective cohorts.

Conclusions: These findings establish MATN3, MERTK, and VSIG4 as a validated, high-performance CSF biomarker panel. This signature holds strong potential to improve the precision of differential diagnosis between cNPSLE and CNS infections, thereby facilitating timely and appropriate therapeutic interventions.

REFERENCES: NIL.

Acknowledgments: NIL.

Disclosure of Interests: None declared.