Immunological Biomarkers to Assess Activity and Treatment Response in IgG4-Related Disease

<i>Background and Objectives</i>: IgG4-related disease is a chronic fibro-inflammatory condition. Despite the development of classification and responder indexes, reliable biomarkers for disease activity and therapeutic monitoring remain limited. We evaluate the performance of a panel of biomarkers, including cytokine profiles, plasmablasts and conventional markers. <i>Materials and Methods</i>: We conducted a cross-sectional, single-center study, involving 35 patients diagnosed with IgG4-RD. Disease activity was evaluated using the IgG4-RD Responder Index (RI), Damage Index (DI) and clinical assessment. Laboratory evaluation included serum IgG4, total IgG, CRP, ESR, eosinophils, IgE, complement levels, and cytokine profiling via multiplex immunoassay. B cell subpopulations were analyzed by flow cytometry. Statistical analyses were performed using STATA/BE 17.0. <i>Results</i>: Patients with active disease (RI > 4 or clinical judgment) exhibited significantly higher levels of total IgG (<i>p</i> = 0.02), IgG4 (<i>p</i> = 0.01), and IL-5 (<i>p</i> = 0.03). PET-positive patients showed a Th1-skewed immune profile, with elevated IFN-γ/IL-4 (<i>p</i> < 0.001), reduced IL-21/IFN-γ (<i>p</i> = 0.03), and increased eosinophils (<i>p</i> = 0.03). Clinician-assessed active disease was associated with higher total IgG levels (<i>p</i> = 0.01). Treatment-specific effects were observed: prednisone was associated with lower IgG4 and C3 levels. Notably, plasmablasts did not consistently correlate with clinical or imaging activity scores, possibly reflecting treatment status or B cell dynamics. <i>Conclusions</i>: This study demonstrates that cytokine ratios, particularly those involving IL-5, IL-13, IL-21, and IFN-γ, offer complementary information to traditional serological markers for IgG4-RD activity. While PET/CT-defined activity was best reflected by biomarkers of an IFN-γ-mediated pathway, the IgG4-RD RI demonstrated a stronger association with conventional humoral markers like serum IgG4 and total IgG. None of these biomarkers correlated with organ damage.