Elevated serum IgG1, complement activation, and clinical severity in IgG4-related disease: a comprehensive subgroup...

OBJECTIVES: To evaluate the clinical associations of elevated serum IgG1 and to assess the utility of integrating IgG1 with IgG4 for patient stratification in IgG4-related disease (IgG4-RD).

This retrospective study included 344 treatment-naïve IgG4-RD patients. Patients were first classified into elevated and non-elevated IgG1 groups based on the institutional laboratory upper limit of normal (ULN) (cutoff: 10.11 g/L). Subsequently, to explore distinct immunopathological phenotypes, patients were further stratified into four groups by integrating this IgG1 cutoff with an IgG1/IgG4 ratio cutoff of 1.0. Subgroup analyses were performed based on gender and the presence of lung, kidney, or liver involvement.

Patients with elevated IgG1 (> 10.11 g/L, n = 137) were older, more frequently male, and had higher disease activity, more organ involvement, and increased lung, kidney, and liver involvement (all P < 0.05). They exhibited profound hypocomplementemia, with serum IgG1 levels showing strong negative correlations with both C3 (r = -0.43, P < 0.001) and C4 (r = -0.48, P < 0.001). Crucially, the most severe phenotype was defined by the "Elevated IgG1, non-IgG1-dominant" signature (IgG1 > 10.11 g/L and IgG1/IgG4 < 1.0). Subgroup analyses revealed exceptionally strong IgG1-complement correlations in males and in patients with kidney or liver involvement.

Elevated serum IgG1 marks a severe IgG4-RD phenotype. The "Elevated IgG1, non-IgG1-dominant" serological signature specifically identifies a more severe phenotype, characterized by complement consumption and multi-organ injury. This composite marker may serve as a useful tool for risk stratification. Keypoints • Elevated serum IgG1 (>10.11 g/L) defines a severe IgG4-RD phenotype with higher disease activity, multi-organ involvement, and profound complement consumption. • A novel serological signature, "Elevated IgG1, non-IgG1-dominant" (IgG1>10.11 g/L and IgG1/IgG 4<1.0), identifies a more severe phenotype of IgG4-RD patients. • Serum IgG1 correlates strongly with hypocomplementemia, with exceptionally strong correlations in male patients and those with kidney or liver involvement.