Clinical phenotypes of immunoglobulin G4-related disease and their metabolic and immunologic characteristics: a latent class analysis_West China Medical Journal

Authors：

ZHANG Sijun ^1,2 , MA Ling ¹ ^馬 , JI Xing ¹ , Lü Hanqiu ¹ , WU Yinlan ¹ , HUANG Yuxia ¹ ,  LUO Yubin ^1,2 ,  TAN Chunyu ¹

1. Department of Rheumatology and Immunology, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P. R. China;
2. Frontier Science Center for Molecular Networks of Diseases, Sichuan University, Chengdu, Sichuan 610041, P. R. China;

Corresponding?author：

LUO Yubin, Email: luoyubin2016@163.com; TAN Chunyu, Email: annaquintessence@163.com

Keywords：

IgG4-related disease; latent class analysis; disease classification; metabolic disorders

DOI：

10.7507/1002-0179.202511225

Video：

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Objective To identify potential clinical phenotypes in immunoglobulin G4-related disease (IgG4-RD) and to characterize differences in immune and metabolic profiles across distinct phenotypic subgroups. Methods A total of 125 patients diagnosed with IgG4-RD at West China Hospital, Sichuan University between January 2020 and December 2024 were retrospectively selected, and data regarding 12 organs (including the prostate) were collected. The prostate data were utilized solely for descriptive statistical purposes. Latent class analysis (LCA) was conducted using 11 organ variables, excluding the prostate, to perform a data-driven unsupervised classification of multiple organ involvement patterns. The optimal model was selected by comprehensively considering model fit indices, class size distribution, and clinical interpretability. Serum levels of immunoglobulin (Ig)G4, IgE, and uric acid were compared across different phenotypes. Results Among 125 patients with IgG4-RD, 89 were male (71.2%) and 36 were female (28.8%). Involvement of the pancreas was observed in 25 cases (20.0%), lymph nodes in 23 cases (18.4%), biliary system in 18 cases (14.4%), lungs in 16 cases (12.8%), lacrimal glands in 13 cases (10.4%), salivary glands and retroperitoneal fibrosis in 11 cases each (8.8%), eyes and pituitary glands in 7 cases each (5.6%), kidneys and aorta in 6 cases each (4.8%). LCA supported a three-class solution as optimal. Three distinct clinical phenotypes were identified: Class 1 (pulmonary-involvement type, n=26), characterized by frequent lung and lymph node involvement; Class 2 (mild systemic involvement type, n=89), showing limited multi-organ engagement; and Class 3 (glandular-lymphatic type, n=10), defined by predominant involvement of salivary glands, lacrimal glands, and lymph nodes, features resembling Mikulicz’s disease. Immunological and metabolic analysis revealed that the serum IgG4 level in Group 3 was higher than that in Group 1 and Group 2, but there was no statistically significant difference between the three groups (P>0.05). Spearman’s rank correlation analysis indicated a positive correlation between uric acid and IgG4 levels (r=0.2454, P=0.0067) as well as between IgE and IgG4 levels (r=0.4169, P<0.001). Conclusions Three distinct intrinsic clinical phenotypes of IgG4-RD were identified by LCA. Each phenotype exhibits characteristic patterns of organ involvement, along with specific immune and metabolic profiles. This suggests that interactions between metabolic and immune pathways may contribute to phenotypic differentiation and disease progression.

Citation： ZHANG Sijun, MA Ling, JI Xing, Lü Hanqiu, WU Yinlan, HUANG Yuxia, LUO Yubin, TAN Chunyu. Clinical phenotypes of immunoglobulin G4-related disease and their metabolic and immunologic characteristics: a latent class analysis. West China Medical Journal, 2026, 41(6): 927-932. doi: 10.7507/1002-0179.202511225 Copy

1.	Morales AT, Cignarella AG, Jabeen IS, et al. An update on IgG4-related lung disease. Eur J Intern Med, 2019, 66: 18-24.
2.	伍思沁, 金珍婧, 邱晨, 等. IgG4 相關性疾病的診療研究現狀. 國際老年醫學雜志, 2025, 46(6): 746-751.
3.	Katz G, Hernandez-Barco Y, Palumbo D, et al. Proliferative featuresof IgG4-related disease. Lancet Rheumatol, 2024, 6(7): e481-e492.
4.	Lanzillotta M, Culver E, Sharma A, et al. Fibrotic phenotype of IgG4-related disease. Lancet Rheumatol, 2024, 6(7): e469-e480.
5.	Wallace ZS, Zhang Y, Perugino CA, et al. Clinical phenotypes of IgG4-related disease: an analysis of two international cross-sectional cohorts. Ann Rheum Dis, 2019, 78(3): 406-412.
6.	Sinha P, Calfee CS, Delucchi KL. Practitioner's guide to latent class analysis: methodological considerations and common pitfalls. Crit Care Med, 2021, 49(1): e63-e79.
7.	Li Q, Wen Y, Wang L, et al. Hyperglycemia-induced accumulation of advanced glycosylation end products in fibroblast-like synoviocytes promotes knee osteoarthritis. Exp Mol Med, 2021, 53(11): 1735-1747.
8.	Dawson M, Pye D, Mahon R, et al. Metabolic and vascular inflammation in alopecia areata: linking uric acid, lipid imbalance and ICAM-1 upregulation. Exp Dermatol, 2025, 34(12): e70186.
9.	Ohradanova-Repic A, Machacek C, Charvet C, et al. Extracellular purine metabolism is the switchboard of immunosuppressive macrophages and a novel target to treat diseases with macrophage imbalances. Front Immunol, 2018, 9: 852.
10.	Yang Y, Wang H, Kouadir M, et al. Recent advances in the mechanisms of NLRP3 inflammasome activation and its inhibitors. Cell Death Dis, 2019, 10(2): 128.
11.	Wallace ZS, Naden RP, Chari S, et al. The 2019 American College of Rheumatology/European League Against Rheumatism Classification Criteria for IgG4-Related Disease. Arthritis Rheumatol, 2020, 72(1): 7-19.
12.	Yang Q, Zhao A, Lee C, et al. Latent profile/class analysis identifying differentiated intervention effects. Nurs Res, 2022, 71(5): 394-403.
13.	葛可, 杜瑩, 張東東, 等. 系統性紅斑狼瘡與類風濕關節炎患者血清代謝譜的比較研究. 南京醫科大學學報 (自然科學版), 2023, 43(3): 371-379.
14.	Elnady B, Almalki A, Abdel-Fattah MM, et al. Serum uric acid as a sensitive concordant marker with lupus nephritis and new onset of renal damage: a prospective cohort study. Clin Rheumatol, 2021, 40(5): 1827-1834.
15.	Zhang J, Sun N, Zhang W, et al. The impact of uric acid on musculoskeletal diseases: clinical associations and underlying mechanisms. Front Endocrinol (Lausanne), 2025, 16: 1515176.
16.	Lee J, Kim TH, Murray F, et al. Cyclic AMP concentrations in dendritic cells induce and regulate Th2 immunity and allergic asthma. Proc Natl Acad Sci U S A, 2015, 112(5): 1529-1534.
17.	Zen Y, Fujii T, Harada K, et al. Th2 and regulatory immune reactions are increased in immunoglobin G4-related sclerosing pancreatitis and cholangitis. Hepatology, 2007, 45(6): 1538-1546.
18.	Fonseca W, Malinczak CA, Schuler CF, et al. Uric acid pathway activation during respiratory virus infection promotes Th2 immune response via innate cytokine production and ILC2 accumulation. Mucosal Immunol, 2020, 13(4): 691-701.
19.	Fan KQ, Li YY, Wang HL, et al. Stress-induced metabolic disorder in peripheral CD4⁺ T cells leads to anxiety-like behavior. Cell, 2019, 179(4): 864-79. e19.
20.	Weiler M, Schmetzer H, Braeu M, et al. Inhibitory effect of extracellular purine nucleotide and nucleoside concentrations on T cell proliferation. Exp Cell Res, 2016, 349(1): 1-14.
21.	Cai S, Chen Y, Hu Z, et al. The landscape of T and B lymphocytes interaction and synergistic effects of Th1 and Th2 type response in the involved tissue of IgG4-RD revealed by single cell transcriptome analysis. J Autoimmun, 2022, 133: 102944.
22.	Gilani SI, Buglioni A, Cornell LD. IgG4-related kidney disease: clinicopathologic features, differential diagnosis, and mimics. Semin Diagn Pathol, 2024, 41(2): 88-94.
23.	Balakumar P, Alqahtani A, Khan NA, et al. Mechanistic insights into hyperuricemia-associated renal abnormalities with special emphasis on epithelial-to-mesenchymal transition: pathologic implications and putative pharmacologic targets. Pharmacol Res, 2020, 161: 105209.
24.	Xie C, Xu W, Rao S, et al. The role of Th17/Treg imbalance, FeNO, eosinophils, IgE and their correlation with lung function parameters with asthma-chronic obstructive pulmonary disease. Iran J Allergy Asthma Immunol, 2024, 23(6): 625-640.
25.	Xie T, Xu N, Zhao H, et al. Pulmonary features and stage of disease in adult patients with hyper-IgE syndrome: a single-centre clinical study and literature review. Orphanet J Rare Dis, 2025, 20(1): 270.
26.	Pa?gan K. Mast cells and basophils in IgE-independent anaphylaxis. Int J Mol Sci, 2023, 24(16): 12802.
27.	Aalberse RC, Platts-Mills TA, Rispens T. The developmental history of IgE and IgG4 antibodies in relation to atopy, eosinophilic esophagitis, and the modified TH2 response. Curr Allergy Asthma Rep, 2016, 16(6): 45.
28.	Zhou J, Peng Y, Peng L, et al. Serum IgE in the clinical features and disease outcomes of IgG4-related disease: a large retrospective cohort study. Arthritis Res Ther, 2020, 22(1): 255.

1. Morales AT, Cignarella AG, Jabeen IS, et al. An update on IgG4-related lung disease. Eur J Intern Med, 2019, 66: 18-24.
2. 伍思沁, 金珍婧, 邱晨, 等. IgG4 相關性疾病的診療研究現狀. 國際老年醫學雜志, 2025, 46(6): 746-751.
3. Katz G, Hernandez-Barco Y, Palumbo D, et al. Proliferative featuresof IgG4-related disease. Lancet Rheumatol, 2024, 6(7): e481-e492.
4. Lanzillotta M, Culver E, Sharma A, et al. Fibrotic phenotype of IgG4-related disease. Lancet Rheumatol, 2024, 6(7): e469-e480.
5. Wallace ZS, Zhang Y, Perugino CA, et al. Clinical phenotypes of IgG4-related disease: an analysis of two international cross-sectional cohorts. Ann Rheum Dis, 2019, 78(3): 406-412.
6. Sinha P, Calfee CS, Delucchi KL. Practitioner's guide to latent class analysis: methodological considerations and common pitfalls. Crit Care Med, 2021, 49(1): e63-e79.
7. Li Q, Wen Y, Wang L, et al. Hyperglycemia-induced accumulation of advanced glycosylation end products in fibroblast-like synoviocytes promotes knee osteoarthritis. Exp Mol Med, 2021, 53(11): 1735-1747.
8. Dawson M, Pye D, Mahon R, et al. Metabolic and vascular inflammation in alopecia areata: linking uric acid, lipid imbalance and ICAM-1 upregulation. Exp Dermatol, 2025, 34(12): e70186.
9. Ohradanova-Repic A, Machacek C, Charvet C, et al. Extracellular purine metabolism is the switchboard of immunosuppressive macrophages and a novel target to treat diseases with macrophage imbalances. Front Immunol, 2018, 9: 852.
10. Yang Y, Wang H, Kouadir M, et al. Recent advances in the mechanisms of NLRP3 inflammasome activation and its inhibitors. Cell Death Dis, 2019, 10(2): 128.
11. Wallace ZS, Naden RP, Chari S, et al. The 2019 American College of Rheumatology/European League Against Rheumatism Classification Criteria for IgG4-Related Disease. Arthritis Rheumatol, 2020, 72(1): 7-19.
12. Yang Q, Zhao A, Lee C, et al. Latent profile/class analysis identifying differentiated intervention effects. Nurs Res, 2022, 71(5): 394-403.
13. 葛可, 杜瑩, 張東東, 等. 系統性紅斑狼瘡與類風濕關節炎患者血清代謝譜的比較研究. 南京醫科大學學報 (自然科學版), 2023, 43(3): 371-379.
14. Elnady B, Almalki A, Abdel-Fattah MM, et al. Serum uric acid as a sensitive concordant marker with lupus nephritis and new onset of renal damage: a prospective cohort study. Clin Rheumatol, 2021, 40(5): 1827-1834.
15. Zhang J, Sun N, Zhang W, et al. The impact of uric acid on musculoskeletal diseases: clinical associations and underlying mechanisms. Front Endocrinol (Lausanne), 2025, 16: 1515176.
16. Lee J, Kim TH, Murray F, et al. Cyclic AMP concentrations in dendritic cells induce and regulate Th2 immunity and allergic asthma. Proc Natl Acad Sci U S A, 2015, 112(5): 1529-1534.
17. Zen Y, Fujii T, Harada K, et al. Th2 and regulatory immune reactions are increased in immunoglobin G4-related sclerosing pancreatitis and cholangitis. Hepatology, 2007, 45(6): 1538-1546.
18. Fonseca W, Malinczak CA, Schuler CF, et al. Uric acid pathway activation during respiratory virus infection promotes Th2 immune response via innate cytokine production and ILC2 accumulation. Mucosal Immunol, 2020, 13(4): 691-701.
19. Fan KQ, Li YY, Wang HL, et al. Stress-induced metabolic disorder in peripheral CD4⁺ T cells leads to anxiety-like behavior. Cell, 2019, 179(4): 864-79. e19.
20. Weiler M, Schmetzer H, Braeu M, et al. Inhibitory effect of extracellular purine nucleotide and nucleoside concentrations on T cell proliferation. Exp Cell Res, 2016, 349(1): 1-14.
21. Cai S, Chen Y, Hu Z, et al. The landscape of T and B lymphocytes interaction and synergistic effects of Th1 and Th2 type response in the involved tissue of IgG4-RD revealed by single cell transcriptome analysis. J Autoimmun, 2022, 133: 102944.
22. Gilani SI, Buglioni A, Cornell LD. IgG4-related kidney disease: clinicopathologic features, differential diagnosis, and mimics. Semin Diagn Pathol, 2024, 41(2): 88-94.
23. Balakumar P, Alqahtani A, Khan NA, et al. Mechanistic insights into hyperuricemia-associated renal abnormalities with special emphasis on epithelial-to-mesenchymal transition: pathologic implications and putative pharmacologic targets. Pharmacol Res, 2020, 161: 105209.
24. Xie C, Xu W, Rao S, et al. The role of Th17/Treg imbalance, FeNO, eosinophils, IgE and their correlation with lung function parameters with asthma-chronic obstructive pulmonary disease. Iran J Allergy Asthma Immunol, 2024, 23(6): 625-640.
25. Xie T, Xu N, Zhao H, et al. Pulmonary features and stage of disease in adult patients with hyper-IgE syndrome: a single-centre clinical study and literature review. Orphanet J Rare Dis, 2025, 20(1): 270.
26. Pa?gan K. Mast cells and basophils in IgE-independent anaphylaxis. Int J Mol Sci, 2023, 24(16): 12802.
27. Aalberse RC, Platts-Mills TA, Rispens T. The developmental history of IgE and IgG4 antibodies in relation to atopy, eosinophilic esophagitis, and the modified TH2 response. Curr Allergy Asthma Rep, 2016, 16(6): 45.
28. Zhou J, Peng Y, Peng L, et al. Serum IgE in the clinical features and disease outcomes of IgG4-related disease: a large retrospective cohort study. Arthritis Res Ther, 2020, 22(1): 255.

West China Medical Journal

Clinical phenotypes of immunoglobulin G4-related disease and their metabolic and immunologic characteristics: a latent class analysis

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