Background: The identification of reliable diagnostic biomarkers for systemic lupus erythematosus (SLE) remains challenging due to disease heterogeneity and its molecular and clinical overlap with other systemic autoimmune diseases. Robust diagnostic biomarkers should discriminate SLE not only from healthy individuals but also from related autoimmune conditions.

Objectives: To identify and validate serum protein biomarkers capable of discriminating SLE from healthy donors (HD) and patients with rheumatoid arthritis (RA) using large-scale proteomics and independent cohort validation.

Methods: A total of 459 individuals were analyzed, including 275 HD, 94 RA patients, and 90 SLE patients. Serum levels of 184 proteins were measured using Proximity Extension Assay (PEA) across the Olink Target Inflammation and Cardiovascular panels, generating more than 80,000 protein measurements. To strengthen diagnostic robustness, all SLE patients presented low disease activity, whereas RA patients were selected with high disease activity. Differential protein expression was assessed with multiple testing correction, and diagnostic performance was evaluated using ROC curve analysis. Independent validation was performed in the multicenter European PRECISESADS cohort, including 100 SLE patients and 20 healthy controls.

Results: IL12B emerged as the most robust diagnostic biomarker. Serum IL12B levels were significantly higher in SLE compared with both RA and HD (FDR = 2.18 × 10 ⁻¹⁸ ). IL12B showed strong discriminative capacity between SLE and HD, with a ROC AUC >0.80. Notably, elevated IL12B levels were observed in SLE patients with low disease activity when compared with highly active RA patients, supporting its diagnostic relevance across distinct inflammatory contexts. Validation in the PRECISESADS cohort confirmed significantly higher IL12B levels in SLE compared with healthy controls (FDR <0.05), with consistent diagnostic performance (ROC AUC >0.75). These findings are biologically supported by the central role of IL12B in Th1/Th17 immune responses and interferon-related pathways involved in SLE pathophysiology. Moreover, multiple genetic studies have consistently associated IL12B polymorphisms with SLE susceptibility (PMID: 15941730, 20658240, 21278068, 27059274, 35086377, 37543802).

Conclusions: IL12B is a robust, biologically and genetically supported serum biomarker with strong diagnostic potential for systemic lupus erythematosus, capable of discriminating SLE from both healthy individuals and rheumatoid arthritis. These results support IL12B as a promising component of diagnostic biomarker panels for systemic autoimmune diseases.

REFERENCES: NIL.

Acknowledgments: NIL.

Disclosure of Interests: None declared.