Soluble CD14 and Lipopolysaccharide-Binding Protein Are Not Superior to Soluble CD25 as Biomarkers for Sarcoidosis

Background/Objectives: Sarcoidosis is a granulomatous disease with no widely accepted circulating biomarkers for routine diagnostics. Soluble CD14 (sCD14) and lipopolysaccharide-binding protein (LBP), identified through extracellular vesicle proteomics, have been proposed as candidates. We aimed to compare the diagnostic accuracy of serum sCD14 and LBP with the established biomarker soluble interleukin-2 receptor alpha chain (sCD25). Methods: A matched case–control study included 46 newly diagnosed, untreated sarcoidosis patients and 46 age- and sex-matched healthy controls. Serum sCD14, sCD25, and LBP were quantified by ELISA. BMI was included as a covariate in multivariable logistic regression. Diagnostic performance was evaluated by ROC analysis and stepwise AIC model selection. Longitudinal biomarker dynamics were assessed in 32 patients under treatment. Results: sCD25 demonstrated superior diagnostic discrimination (AUC 0.92, 95% CI 0.87–0.98), compared with LBP (AUC 0.71, 95% CI 0.60–0.82) and sCD14 (AUC 0.61, 95% CI 0.49–0.73). In multivariate analysis, only sCD25 (OR per +100 pg/mL: 1.53; p < 0.001) remained an independent predictor of sarcoidosis. Neither LBP nor sCD14 improved model fit. All biomarkers significantly decreased following therapy. Conclusions: Among routinely measurable serum markers, sCD25 outperformed sCD14 and LBP in sarcoidosis diagnosis. Further studies should explore immunometabolic interactions to refine diagnostic algorithms.