Relationship between serum IgG4 levels and clinical activity of ophthalmopathy in Graves’ disease

The aim of this study was to evaluate the association between serum IgG4 levels and the presence, activity, and severity of thyroid eye disease (TED) within a single cohort of patients with Graves’ disease, and to assess the potential role of IgG4 as a complementary biomarker across the clinical spectrum of the disease. This cross-sectional study included 46 patients diagnosed with Graves’ disease, comprising 23 patients with TED and 23 without TED. All participants underwent a comprehensive ophthalmological and biochemical evaluation, including thyroid function testing, autoantibody profiling, and measurement of serum total IgG, IgG4, and the IgG4/IgG ratio. Disease activity was assessed using the Clinical Activity Score (CAS ≥ 3), and disease severity was classified according to the European Group on Graves’ Orbitopathy (EUGOGO) criteria. Serum IgG4 levels were significantly higher in TED patients than in those without TED (97.7 ± 92.6 vs. 52.9 ± 42.9 mg/dL; p = 0.041). The IgG4/IgG ratio was also increased (8.05 ± 6.75% vs. 4.44 ± 3.42%; p = 0.027). Moderate-to-severe TED showed higher IgG4 and IgG4/IgG values than mild disease ( p = 0.042 and p = 0.041). Active TED had greater IgG4 levels than inactive cases (132.0 ± 112.1 vs. 60.2 ± 45.4 mg/dL; p = 0.049). IgG4 correlated positively with activity and severity. The proportion of patients with IgG4 ≥ 135 mg/dL was 8.7% in patients without TED and 21.7% in those with TED, with higher proportions particularly observed in active and moderate-to-severe cases. Elevated serum IgG4 levels in TED were associated with the presence, activity, and severity of the disease. These findings suggest that serum IgG4 may reflect underlying immunological activity across the TED spectrum. Measurement of serum IgG4 may serve as a complementary biomarker to conventional clinical scoring systems in the assessment of disease activity and severity. To clarify the clinical significance and temporal dynamics of these associations, large-scale prospective and longitudinal studies incorporating imaging and tissue-based evaluations are warranted.