Objective To explore the clinical significance of decreased serum immunoglobulin (Ig) A levels in patients with IgG4-related disease (IgG4-RD).

Methods A retrospective analysis was performed on patients with IgG4-RD hospitalized at Beijing Friendship Hospital, Capital Medical University from January 2012 to December 2024. Patients were divided into three groups according to serum IgA levels: decreased IgA group (< 70 mg/dL), normal group (70-400 mg/dL), and elevated group (> 400 mg/dL), with the decreased IgA group set as the main research subject. Clinical data were collected to compare clinical characteristics and organ involvement among the three groups, and the correlations between IgA levels and various clinical indicators were analyzed. To further verify the robustness of the results, propensity score matching(PSM) with a 1∶2 matching ratio was performed between the decreased IgA group and the normal IgA group for sensitivity analysis. Meanwhile, principal component analysis (PCA) was used to evaluate the overall distribution differences in clinical characteristics among the three groups with different IgA levels.

Results A total of 330 patients with IgG4-RD were included, including 14 in the decreased IgA group, 297 in the normal IgA group, and 19 in the elevated IgA group. The decreased IgA group had a significantly longer median disease course than the normal IgA group and the elevated IgA group (all P < 0.017). The levels of IgG and IgG4 in the decreased IgA group were significantly higher than those in the other two groups (all P < 0.017). The IgG3 level in the decreased IgA group was only markedly higher than that in the normal IgA group (P < 0.017), with no significant difference compared with the elevated IgA group (P > 0.017). A significant overall difference in IgG1 levels was observed among the three groups(P=0.008), whereas no significant differences were found in post-hoc pairwise comparisons (all P > 0.017). Compared with the other two groups, the decreased IgA group presented significantly lower complement (C)3 and C4 levels and significantly higher eosinophil (EOS) counts (all P < 0.017). The submandibular gland involvement rate in the decreased IgA group was significantly higher than that in the elevated IgA group (P < 0.017), with no statistical difference versus the normal IgA group (P > 0.017). The pulmonary involvement rate in the decreased IgA group was significantly higher than that in the normal IgA group (P < 0.017), and no significant difference was found compared with the elevated IgA group (P > 0.017). After PSM, significant differences in IgG, IgG3, IgG4, C4 levels and EOS counts remained between the decreased IgA group and normal IgA group (all P < 0.05), confirming the robustness of the results. Spearman rank correlation analysis showed that serum IgA level was significantly negatively correlated with IgG4 (r=-0.363), EOS counts (r=-0.178), number of involved organs(r=-0.216), and IgG4-RD responder index score (r=-0.183)(all P < 0.05), and significantly positively correlated with C3 (r=0.256) and C4 (r=0.237) levels (all P < 0.001). PCA revealed that the elevated IgA group was distinctly separated from the other two groups, while partial distribution overlap existed between the decreased IgA group and the normal IgA group.

Conclusions Decreased IgA level represents a distinct immune subtype of IgG4-RD, with distinct immunological features (elevated IgG/IgG4 levels, reduced C4 level, and increased EOS count), independent of age, gender and disease course. These findings suggest that serum IgA level has potential value for immune typing of IgG4-RD.