Identification of candidate biomarkers for diagnosis, disease activity, and relapse prediction in IgG4-related disease

IgG4-related disease (IgG4-RD) is an immune-mediated condition with diagnostic challenges in clinical practice. Sensitive biomarkers are needed for diagnosis, disease activity and disease progression assessment. This study aimed to identify and validate novel serum protein biomarkers of IgG4-RD to improve clinical management. Using Olink proteomics, we analyzed the expression of 92 serum immuno-oncology-related proteins in 11 treatment-naïve IgG4-RD patients and 11 healthy controls (HCs). Candidate biomarkers capable of distinguishing IgG4-RD patients from HC were subsequently validated by enzyme-linked immunosorbent assay in a large independent cohort (n = 220). Diagnostic performance was assessed via 5-fold cross-validation. Correlations between biomarkers and clinical characteristics were also investigated, as well as predictive value for disease relapse. Olink proteomic analysis identified 27 differentially expressed proteins between IgG4-RD and HCs. Through longitudinal follow-up, serum PD1, OX40, CCL19, and MMP12 were significantly upregulated in IgG4-RD patients and closely associated with disease progression, serum IgG4 levels and inflammatory indicators. A comprehensive diagnostic model incorporating the four biomarkers was developed and showed high discriminatory capacity. Elevated baseline PD1 level served as an independent risk factor to predict clinical relapse of IgG4-RD patients. This study identifies four novel serum biomarkers that effectively assist diagnosis, assess disease activity, and one capable for clinical relapse prediction. These findings provide a practical approach for large-scale clinical screening and monitoring of IgG4-RD patients. Furthermore, the identified proteins may offer new insights into disease pathogenesis and represent potential therapeutic targets for this challenging condition.