IgG4 surge and relapse: determining the predictive threshold for IgG4 rising kinetics in IgG4-related disease

OBJECTIVES: To investigate longitudinal IgG4 dynamics in IgG4-related disease (IgG4-RD), identify the predictive value of IgG4 rising kinetics for relapse and evaluate outcomes of intensified treatment following IgG4 surge. METHODS: This cohort study was conducted at the Chinese PLA General Hospital from February 2016 to May 2023, including patients with >6 months of follow-up and ≥3 IgG4 measurements. Single-timepoint IgG4 level and IgG4-Ratio (sequential visit-to-visit fold-change) were dichotomized as binary indicators using variable thresholds to predict relapse assessed at a third consecutive visit in time-dependent Cox regression models. We used restricted cubic splines (RCS) to identify the optimal IgG4-Ratio threshold with adjustment for confounders. Subsequently, relapse-free survival after intensified treatment was analysed. RESULTS: Among 155 patients (median follow-up: 33 months; inter-visit interval: 3 months), 149 had baseline IgG4 positivity. IgG4 normalized in 63.8% (95/149) patients, of whom 61.1% (58/95) developed IgG4 re-positivity. Single-timepoint IgG4 level, whether as continuous or dichotomized variables, showed no significant predictive value for relapse. IgG4-Ratio thresholds >1.1-1.3 and ​>1.6-1.8 significantly predicted relapse (P < 0.05), with RCS confirming a nonlinear dose-response relationship (P = 0.008). IgG4-Ratio >1.6 was identified as the optimal threshold to predict relapses. Among 45 patients with IgG4-Ratio >1.6, intensified treatment reduced relapse risk by 68.3% (HR 0.317, 95% CI 0.102-0.988; P = 0.048). CONCLUSIONS: A paradigm shift from relying on static IgG4 levels to monitoring IgG4 dynamics is needed. The IgG4 surge defined as an IgG4-Ratio >1.6 (indicating a >60% increase in IgG4 levels between consecutive measurements taken at median 3-month intervals) predicts relapse in the majority of seropositive IgG4-RD patients. Intensified treatment in patients with IgG4 surge can reduce recurrence risk.