IgG4-related disease (IgG4-RD) exhibits marked clinical heterogeneity. We hypothesized that an acquired low immunoglobulin M state defines a distinct clinical subtype within IgG4-RD and investigated its associations with disease features, including organ involvement patterns and specific immune profiles.

In this retrospective cohort study, 309 treatment-naïve patients fulfilling the 2019 ACR/EULAR classification criteria were enrolled. Based on the institutional lower limit of normal (40 mg/dL), patients were stratified into a hypo-IgM group (serum IgM <40 mg/dL, n=66) and a normal-IgM group (n=243). Clinical phenotypes, laboratory parameters and disease activity (IgG4-RD Responder Index (RI)) were compared. Logistic regression and formal causal mediation analyses were performed to identify independent associates of hypo-IgM and to elucidate potential mechanistic pathways.

The hypo-IgM group exhibited a unique organ tropism, with significantly higher frequencies of lung (45.3% vs 22.7%, P<0.001), kidney (35.9% vs 20.2%, P=0.008) and submandibular glands (76.6% vs 58.4%, P=0.008) involvement compared to the normal-IgM group, which more commonly involved the liver, pancreas, and retroperitoneum. Hypo-IgM was associated with a more active immune profile, including higher serum IgG, IgG4, IgG3, eosinophil counts, and lower complement C3/C4 levels. Serum IgM levels correlated inversely with IgG4-RD RI, number of involved organs, and IgG4 levels (all P<0.05). Multivariable analysis identified elevated IgG4 (OR 1.07, 95% CI 1.01 to 1.12) eosinophil (OR 3.59, 95% CI 1.01 to 12.77), and lung involvement (OR 2.64, 95% CI 1.13 to 6.15) as independent factors associated with hypo-IgM. Critically, mediation analyses revealed that reductions in C3 and C4 significantly mediated the pathways from hypo-IgM to kidney (36.1% and 36.3% of total effect mediated, respectively) and lung involvement (17.3% and 18.8%). The combined presence of hypo-IgM and hypocomplementemia identified a patient subgroup with the highest risk of lung/kidney involvement (74.2%), highlighting the synergistic value of combined assessment.

We define a novel, clinically distinct IgG4-RD subtype characterized by an acquired hypo-IgM state, pulmonary-renal-submandibular glands tropism, elevated IgG4 levels, and complement consumption. This complement consumption mechanistically links the low IgM state to disease in target organs. The combined assessment of serum IgM and complement identifies a high-risk phenotype for pulmonary-renal involvement, offering a simple tool for risk stratification.