High antibody levels linked to multi-organ risk in IgG4-RD
Very high IgG4 could be red flag to test for organ involvement, study shows
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People with IgG4-related disease (IgG4-RD) who have very high levels of the antibody immunoglobulin G4 (IgG4) are more likely to have multi-organ involvement, a study showed.
The findings suggest that extremely high antibody levels — at or above five times the upper limit of normal (ULN) — might be a useful red flag to prompt careful evaluation for signs of multi-organ involvement in IgG4-RD, scientists said.
“For patients with [blood] IgG4 levels [at least five times the ULN], a more proactive multisystem evaluation strategy should be adopted in clinical practice to facilitate the early identification of potential organ involvement and reduce the risk of missed diagnoses,” the researchers wrote.
The study, “Clinical characteristics of IgG4-related disease patients with different serum IgG4 levels: A single-center retrospective study,” was published in the Journal of International Medical Research.
IgG4-RD is a rare immune-mediated inflammatory disease characterized by abnormal clumps of immune cells, primarily plasma cells that produce IgG4. IgG4 antibody levels can vary substantially among patients, but it’s unclear whether, or how, these variations are associated with differences in the clinical manifestations of IgG4-RD.
Exploring variability
“Currently, there is a lack of comprehensive analyses of the clinical characteristics of patients with IgG4-RD according to different [blood] IgG4 levels,” wrote the team of researchers, in China. “Therefore, a deeper exploration of the clinical [variability] of patients across different [blood] IgG4 levels will improve our understanding of the diverse manifestations of IgG4-RD.”
With this in mind, they retrospectively analyzed data from 77 people diagnosed with IgG4-RD at a single center in the country from January 2019 to April 2025. Patients’ mean age was 60.31, and 80.52% were men.
The researchers divided the patients into four groups based on IgG4levels. Thirteen patients (16.88%) had IgG4 levels up to the ULN. Another 19 people (24.68%) had antibody levels above the ULN, but less than double the ULN. A third group of 25 patients (32.47%) had levels higher than twice the ULN, but less than five times the ULN. The fourth group consisted of 20 people (25.97%) with IgG4 levels of at least five times the ULN.
Using mathematical analyses, the researchers looked for statistically significant differences in clinical and biomarker features among the groups.
Results showed that the frequency of multi-organ involvement was significantly higher in the group with the highest antibody levels (85%) than in the group with levels up to the UNL (30.77%) and the group with levels higher than twice the ULN but less than five times the ULN (44%).
While less than half of patients in the group with IgG4 levels above the ULN but less than double the ULN had disease involvement of several organs (47.37%), the difference relative to the highest level group was not statistically significant.
“Patients with [blood] IgG4 [levels of at least five times the] ULN were more likely to have multiorgan involvement than patients with” lower IgG4 levels, the researchers wrote.
Higher antibody levels “may enhance autoimmune responses, leading to increased accumulation of immune cells and inflammatory mediators in multiple organs, thereby promoting multiorgan involvement,” the team wrote. “[Blood] IgG4 levels may serve as a useful adjunctive marker for assessing the risk of organ involvement in patients with IgG4-RD.”
Involvement of the lymph nodes (immune structures throughout the body) was significantly more frequent in the group with the highest levels than in the other three groups (66.67% vs. 0%-30%).
“Because lymph nodes are key immune organs that are rich in immune cells, these plasma cells may preferentially infiltrate the lymph nodes, resulting in a substantially increased incidence of lymph node involvement,” the researchers wrote, adding that this finding “underscores the need for heightened vigilance regarding potential lymph node involvement” in patients with very high IgG4 levels.
Further analyses showed that patients with higher IgG4 levels also had significantly higher levels of IgG (the broader antibody class that IgG4 belongs to) relative to the other groups, as well as significantly lower levels of the C3 protein, reflecting more inflammation. Both IgG and C3 “are important biomarkers for IgG4-RD,” the researchers wrote.
“These findings suggest that the combined assessment of IgG, IgG4, and C3 may provide a more comprehensive evaluation of immune status in patients with IgG4-RD, offering valuable information for assessing disease activity, guiding treatment decisions, and monitoring therapeutic efficacy,” the scientists wrote.
The researchers stressed that their study was limited to a relatively small number of patients at one center. “Future research should conduct multicenter, large-scale investigations to … enhance the generalizability and credibility of the findings,” they concluded.
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