Association between serum immunoglobulin G4 levels and Graves' ophthalmopathy: a meta-analysis

Graves' ophthalmopathy (GO) is a severe extrathyroidal manifestation of Graves' disease (GD) lacking simple and specific biomarkers. Immunoglobulin G4 (IgG4) has attracted increasing attention in autoimmune and fibrotic diseases. This study systematically evaluates the association of serum IgG4 levels with GO and clarifies the altered characteristics of serum IgG4 levels among GO individuals, as well as their association with GO risk and activity.

Embase, Cochrane Library, PubMed, and Web of Science were searched from inception to December 2025. Two researchers independently performed literature screening, data extraction, and quality assessment using the Newcastle-Ottawa Scale. Statistical analysis used Stata 18.0. Effect sizes were standardized mean difference (SMD) for continuous variables and odds ratio (OR) for dichotomous variables, both with 95% confidence intervals (CI). Either random- or fixed-effects models were applied based on heterogeneity (I² statistic). Sensitivity and subgroup analyses explored heterogeneity sources. Publication bias was evaluated via funnel plots and Egger's test using R.

Ten studies with 1, 221 subjects (patients with GO, those with GD without ophthalmopathy, and healthy controls) were included. Meta-analysis showed significantly elevated serum IgG4 levels in patients with GO, especially those with active GO, compared to healthy controls (SMD = 1.260, 95%CI:0.681-1.839) and GD patients without ophthalmopathy (SMD = 1.018, 95%CI:0.278-1.758). High IgG4 levels were associated with increased GO risk (OR = 2.808, 95%CI:1.150-6.859). Univariable analysis confirmed IgG4 as a potential risk factor for GO (ES = 4.735, 95%CI:1.582-14.171), but this association was not statistically significant in multivariable analysis after adjusting for confounders. Subgroup analyses showed higher serum IgG4 levels in active versus inactive GO (SMD = 0.911, 95%CI:0.363-1.460, p=0.001).

Serum IgG4 levels are elevated in individuals with GO and closely associated with disease activity. High serum IgG4 levels represent a significant factor associated with increased GO risk. These findings suggest IgG4 may be involved in specific immunopathological processes underlying GO and could serve as a potential biomarker for auxiliary diagnosis, activity assessment, and risk identification. However, the influence of IgG4 on GO may be modulated by other factors, requiring further validation of its role as an independent risk factor.

https://www.crd.york.ac.uk/PROSPERO/view/CRD420251078723, identifier CRD420251078723.