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  • Review Article
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IgG4-related disease and other fibro-inflammatory conditions

Nature Reviews Rheumatology volume 21, pages 275–290 (2025)Cite this article

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Abstract

IgG4-related disease (IgG4-RD) is a fibro-inflammatory disorder usually characterized by multi-organ involvement. Its pathogenesis is complex and involves genetic and environmental factors, while immune responses usually mediate organ damage and promote fibrosis, which is a key feature of the disease. IgG4 responses, however, are not exclusive to IgG4-RD and can be encountered in other diseases with phenotypes that partially overlap that of IgG4-RD. Although IgG4-RD has clinical and histological hallmarks, the lack of validated diagnostic criteria often makes the diagnosis challenging, requiring a multi-dimensional approach that integrates clinical, radiological and serological data. The present Review covers recent advances in the understanding of disease drivers and its clinical phenotypes, mainly focusing on the differential diagnosis with potential IgG4-RD mimickers, namely histiocytoses, lymphoproliferative disorders, systemic vasculitides and other immune-mediated conditions. The Review also provides a schematic approach to IgG4-RD treatment, including a brief overview of glucocorticoid-sparing agents and emerging therapies, from B cell-depleting monoclonal antibodies to cytokine-targeting drugs, the majority of which are currently under investigation in randomized clinical trials.

Key points

  • IgG4-related disease (IgG4-RD) is a fibro-inflammatory disease characterized by slow-growing and often pseudotumoural lesions that can be solitary or occur in multiple organs.

  • The diagnosis of IgG4-RD requires the exclusion of a wide array of neoplastic, infectious and autoimmune disorders as well as of rare proliferative conditions such as histiocytoses and Castleman disease.

  • The different subphenotypes of IgG4-RD (Mikulicz, head-and-neck limited, pancreato-hepato-biliary, retroperitoneal and/or aortic disease) differ in terms of patients’ demographic features, clinical manifestations and serum IgG4 levels.

  • Treatment of IgG4-RD is based on the use of glucocorticoids, but B cell-depleting therapies (for example, rituximab or inebilizumab) are being incorporated into the standard therapeutic regimens.

  • IgG4-RD is a chronic–relapsing disorder and therefore requires careful and long-term follow-up.

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Fig. 1: Main histological findings in IgG4-related disease.
Fig. 2: Radiological findings in IgG4-related disease.
Fig. 3: Immunopathogenesis of IgG4-related disease.
Fig. 4: Classification and diagnostic criteria for IgG4-RD.
Fig. 5: Radiological and histopathological findings in histiocytoses mimicking IgG4-related disease.
Fig. 6: Treatment algorithm for IgG4-related disease.

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References

  1. Hamano, H. et al. High serum IgG4 concentrations in patients with sclerosing pancreatitis. N. Engl. J. Med. 344, 732–738 (2001).

    Article  CAS  PubMed  Google Scholar 

  2. Hamano, H. et al. Hydronephrosis associated with retroperitoneal fibrosis and sclerosing pancreatitis. Lancet 359, 1403–1404 (2002).

    Article  PubMed  Google Scholar 

  3. Kamisawa, T. et al. A new clinicopathological entity of IgG4-related autoimmune disease. J. Gastroenterol. 38, 982–984 (2003).

    Article  CAS  PubMed  Google Scholar 

  4. Stone, J. H., Zen, Y. & Deshpande, V. IgG4-related disease. N. Engl. J. Med. 366, 539–551 (2012).

    Article  CAS  PubMed  Google Scholar 

  5. Maritati, F. et al. Clinical and prognostic significance of serum IgG4 in chronic periaortitis. An analysis of 113 patients. Front. Immunol. 10, 693 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Nishikori, A. et al. Diagnostic challenges of the idiopathic plasmacytic lymphadenopathy (IPL) subtype of idiopathic multicentric Castleman disease (iMCD): factors to differentiate from IgG4-related disease. J. Clin. Pathol. https://doi.org/10.1136/jcp-2023-209280 (2024).

  7. Chazal, T. et al. Clinical phenotypes and long-term outcome of kidney involvement in Erdheim-Chester histiocytosis. Kidney Int. 103, 177–186 (2023).

    Article  PubMed  Google Scholar 

  8. Mazzariol, M. et al. Kidney involvement in Rosai-Dorfman disease. Kidney Int. 103, 231–232 (2023).

    Article  PubMed  Google Scholar 

  9. Jha, I. et al. Sex as a predictor of clinical phenotype and determinant of immune response in IgG4-related disease: a retrospective study of patients fulfilling the American College of Rheumatology-European League Against Rheumatism classification criteria. Lancet Rheumatol. 6, e460–e468 (2024).

    Article  CAS  PubMed  Google Scholar 

  10. Perugino, C. A. & Stone, J. H. IgG4-related disease: an update on pathophysiology and implications for clinical care. Nat. Rev. Rheumatol. 16, 702–714 (2020).

    Article  CAS  PubMed  Google Scholar 

  11. Vaglio, A., Pipitone, N. & Salvarani, C. Chronic periaortitis: a large-vessel vasculitis? Curr. Opin. Rheumatol. 23, 1–6 (2011).

    Article  PubMed  Google Scholar 

  12. Katz, G. et al. IgG4-related disease as a variable-vessel vasculitis: a case series of 13 patients with medium-sized coronary artery involvement. Semin. Arthritis Rheum. 60, 152184 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Palmisano, A. et al. Chronic periaortitis with thoracic aorta and epiaortic artery involvement: a systemic large vessel vasculitis? Rheumatology 54, 2004–2009 (2015).

    Article  CAS  PubMed  Google Scholar 

  14. Corradi, D., Nicastro, M. & Vaglio, A. Immunoglobulin G4-related disease: some missing pieces in a still unsolved complex puzzle. Cardiovasc. Pathol. 25, 90–92 (2016).

    Article  PubMed  Google Scholar 

  15. Accorsi Buttini, E., Maritati, F. & Vaglio, A. [18F]-fluorodeoxyglucose positron emission tomography and response to therapy in idiopathic retroperitoneal fibrosis. Eur. Urol. 73, 145–146 (2018).

    Article  PubMed  Google Scholar 

  16. Kamisawa, T., Zen, Y., Nakazawa, T. & Okazaki, K. Advances in IgG4-related pancreatobiliary diseases. Lancet Gastroenterol. Hepatol. 3, 575–585 (2018).

    Article  PubMed  Google Scholar 

  17. Yamamoto, M. et al. A new conceptualization for Mikulicz’s disease as an IgG4-related plasmacytic disease. Mod. Rheumatol. 16, 335–340 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Dahlgren, M., Khosroshahi, A., Nielsen, G. P., Deshpande, V. & Stone, J. H. Riedel’s thyroiditis and multifocal fibrosclerosis are part of the IgG4-related systemic disease spectrum. Arthritis Care Res. 62, 1312–1318 (2010).

    Article  Google Scholar 

  19. Zhang, X. et al. Novel advances in the study of IgG4-related disease in the eye and ocular adnexa. Ophthalmic Res. 65, 605–614 (2022).

    Article  CAS  PubMed  Google Scholar 

  20. Marinelli, J. P. et al. Manifestations of skull base IgG4-related disease: a multi-institutional study. Laryngoscope 130, 2574–2580 (2020).

    Article  CAS  PubMed  Google Scholar 

  21. Vaglio, A. & Maritati, F. Idiopathic retroperitoneal fibrosis. J. Am. Soc. Nephrol. 27, 1880–1889 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Chaba, A. et al. Clinical and prognostic factors in patients with IgG4-related kidney disease. Clin. J. Am. Soc. Nephrol. 18, 1031–1040 (2023).

    PubMed  PubMed Central  Google Scholar 

  23. Peyronel, F. & Vaglio, A. IgG4-related kidney disease. Clin. J. Am. Soc. Nephrol. 18, 994–996 (2023).

    Article  PubMed  PubMed Central  Google Scholar 

  24. Wallace, Z. S. et al. Clinical phenotypes of IgG4-related disease: an analysis of two international cross-sectional cohorts. Ann. Rheum. Dis. 78, 406–412 (2019).

    Article  CAS  PubMed  Google Scholar 

  25. Wallace, Z. S. et al. IgG4-related disease: clinical and laboratory features in one hundred twenty-five patients. Arthritis Rheumatol. 67, 2466–2475 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Katz, G. et al. Proliferative features of IgG4-related disease. Lancet Rheumatol. 6, e481–e492 (2024).

    Article  CAS  PubMed  Google Scholar 

  27. Lanzillotta, M. et al. Fibrotic phenotype of IgG4-related disease. Lancet Rheumatol. 6, e469–e480 (2024).

    Article  CAS  PubMed  Google Scholar 

  28. Chang, M. C. et al. T-cell regulatory gene CTLA-4 polymorphism/haplotype association with autoimmune pancreatitis. Clin. Chem. 53, 1700–1705 (2007).

    Article  CAS  PubMed  Google Scholar 

  29. Park, D. H. et al. Substitution of aspartic acid at position 57 of the DQβ1 affects relapse of autoimmune pancreatitis. Gastroenterology 134, 440–446 (2008).

    Article  CAS  PubMed  Google Scholar 

  30. Ota, UmemuraT., Hamano, M., Katsuyama, H., Kiyosawa, Y. & Kawa, K. S. Genetic association of Fc receptor-like 3 polymorphisms with autoimmune pancreatitis in Japanese patients. Gut 55, 1367–1368 (2006).

    Article  PubMed  PubMed Central  Google Scholar 

  31. Umemura, T. et al. Association of autoimmune pancreatitis with cytotoxic T-lymphocyte antigen 4 gene polymorphisms in Japanese patients. Am. J. Gastroenterol. 103, 588–594 (2008).

    Article  CAS  PubMed  Google Scholar 

  32. Chang, M. C. et al. Human cationic trypsinogen but not serine peptidase inhibitor, Kazal type 1 variants increase the risk of type 1 autoimmune pancreatitis. J. Gastroenterol. Hepatol. 29, 2038–2042 (2014).

    Article  CAS  PubMed  Google Scholar 

  33. Liu, Q. et al. IKZF1 and UBR4 gene variants drive autoimmunity and Th2 polarization in IgG4-related disease. J. Clin. Invest. 134, e178692 (2024).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Terao, C. et al. IgG4-related disease in the Japanese population: a genome-wide association study. Lancet Rheumatol. 1, e14–e22 (2019).

    Article  PubMed  Google Scholar 

  35. Martorana, D. et al. A large-scale genetic analysis reveals an autoimmune origin of idiopathic retroperitoneal fibrosis. J. Allergy Clin. Immunol. 142, 1662–1665 (2018).

    Article  PubMed  Google Scholar 

  36. de Buy Wenniger, L. J., Culver, E. L. & Beuers, U. Exposure to occupational antigens might predispose to IgG4-related disease. Hepatology 60, 1453–1454 (2014).

    Article  PubMed  Google Scholar 

  37. Wallwork, R. et al. The association of smoking with immunoglobulin G4-related disease: a case-control study. Rheumatology 60, 5310–5317 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Goldoni, M. et al. Asbestos and smoking as risk factors for idiopathic retroperitoneal fibrosis: a case-control study. Ann. Intern. Med. 161, 181–188 (2014).

    Article  PubMed  Google Scholar 

  39. Uibu, T. et al. Asbestos exposure as a risk factor for retroperitoneal fibrosis. Lancet 363, 1422–1426 (2004).

    Article  CAS  PubMed  Google Scholar 

  40. Maillette de Buy Wenniger, L. J. et al. Immunoglobulin G4+ clones identified by next-generation sequencing dominate the B cell receptor repertoire in immunoglobulin G4 associated cholangitis. Hepatology 57, 2390–2398 (2013).

    Article  CAS  PubMed  Google Scholar 

  41. Mattoo, H. et al. De novo oligoclonal expansions of circulating plasmablasts in active and relapsing IgG4-related disease. J. Allergy Clin. Immunol. 134, 679–687 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Hubers, L. M. et al. Annexin A11 is targeted by IgG4 and IgG1 autoantibodies in IgG4-related disease. Gut 67, 728–735 (2018).

    CAS  PubMed  Google Scholar 

  43. Perugino, C. A. et al. Identification of galectin-3 as an autoantigen in patients with IgG4-related disease. J. Allergy Clin. Immunol. 143, 736–745.e6 (2019).

    Article  CAS  PubMed  Google Scholar 

  44. Shiokawa, M. et al. Laminin 511 is a target antigen in autoimmune pancreatitis. Sci Transl Med 10, eaaq0997 (2018).

    Article  PubMed  Google Scholar 

  45. Liu, H. et al. Disease severity linked to increase in autoantibody diversity in IgG4-related disease. Arthritis Rheumatol. 72, 687–693 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Trampert, D. C., Hubers, L. M., van de Graaf, S. F. J. & Beuers, U. On the role of IgG4 in inflammatory conditions: lessons for IgG4-related disease. Biochim. Biophys. Acta Mol. Basis Dis. 1864, 1401–1409 (2018).

    Article  CAS  PubMed  Google Scholar 

  47. van der Neut Kolfschoten, M. et al. Anti-inflammatory activity of human IgG4 antibodies by dynamic Fab arm exchange. Science 317, 1554–1557 (2007).

    Article  PubMed  Google Scholar 

  48. Della-Torre, E., Lanzillotta, M. & Doglioni, C. Immunology of IgG4-related disease. Clin. Exp. Immunol. 181, 191–206 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Shiokawa, M. et al. Pathogenicity of IgG in patients with IgG4-related disease. Gut 65, 1322–1332 (2016).

    Article  CAS  PubMed  Google Scholar 

  50. Campochiaro, C. et al. Long-term efficacy of maintenance therapy with rituximab for IgG4-related disease. Eur. J. Intern. Med. 74, 92–98 (2020).

    Article  CAS  PubMed  Google Scholar 

  51. Della-Torre, E. et al. Efficacy and safety of rituximab biosimilar (CT-P10) in IgG4-related disease: an observational prospective open-label cohort study. Eur. J. Intern. Med. 84, 63–67 (2021).

    Article  CAS  PubMed  Google Scholar 

  52. Lanzillotta, M. et al. Effects of glucocorticoids on B-cell subpopulations in patients with IgG4-related disease. Clin. Exp. Rheumatol. 37, 159–166 (2019).

    PubMed  Google Scholar 

  53. Allard-Chamard, H. et al. Extrafollicular IgD−CD27−CXCR5−CD11c− DN3 B cells infiltrate inflamed tissues in autoimmune fibrosis and in severe COVID-19. Cell Rep. 42, 112630 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Della-Torre, E. et al. B lymphocytes directly contribute to tissue fibrosis in patients with IgG4-related disease. J. Allergy Clin. Immunol. 145, 968–981.e14 (2020).

    Article  CAS  PubMed  Google Scholar 

  55. Della-Torre, E. et al. A CD8α− subset of CD4+SLAMF7+ cytotoxic T cells is expanded in patients with IgG4-related disease and decreases following glucocorticoid treatment. Arthritis Rheumatol. 70, 1133–1143 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Heeringa, J. J. et al. Expansion of blood IgG4+ B, TH2, and regulatory T cells in patients with IgG4-related disease. J. Allergy Clin. Immunol. 141, 1831–1843.e10 (2018).

    Article  CAS  PubMed  Google Scholar 

  57. Maehara, T. et al. Lesional CD4+ IFN-γ+ cytotoxic T lymphocytes in IgG4-related dacryoadenitis and sialoadenitis. Ann. Rheum. Dis. 76, 377–385 (2017).

    Article  CAS  PubMed  Google Scholar 

  58. Munemura, R. et al. Distinct disease-specific Tfh cell populations in 2 different fibrotic diseases: IgG4-related disease and Kimura disease. J. Allergy Clin. Immunol. 150, 440–455.e17 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Perugino, C. A. et al. CD4+ and CD8+ cytotoxic T lymphocytes may induce mesenchymal cell apoptosis in IgG4-related disease. J. Allergy Clin. Immunol. 147, 368–382 (2021).

    Article  CAS  PubMed  Google Scholar 

  60. Mattoo, H. et al. Clonal expansion of CD4+ cytotoxic T lymphocytes in patients with IgG4-related disease. J. Allergy Clin. Immunol. 138, 825–838 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Rovati, L. et al. Mer tyrosine kinase as a possible link between resolution of inflammation and tissue fibrosis in IgG4-related disease. Rheumatology 60, 4929–4941 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Katz, G. & Stone, J. H. Clinical perspectives on IgG4-related disease and its classification. Annu. Rev. Med. 73, 545–562 (2022).

    Article  CAS  PubMed  Google Scholar 

  63. Gianfreda, D. et al. Erdheim-Chester disease as a mimic of IgG4-related disease: a case report and a review of a single-center cohort. Medicine 95, e3625 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  64. Vaglio, A. et al. IgG4 immune response in Churg-Strauss syndrome. Ann. Rheum. Dis. 71, 390–393 (2012).

    Article  CAS  PubMed  Google Scholar 

  65. Wallace, Z. S. et al. The 2019 American College of Rheumatology/European League Against Rheumatism Classification Criteria for IgG4-Related Disease. Arthritis Rheumatol. 72, 7–19 (2020).

    Article  PubMed  Google Scholar 

  66. Liu, Z. et al. The external validation of the 2019 ACR/EULAR classification criteria for IgG4-related disease in a large cohort from China. Semin. Arthritis Rheum. 61, 152202 (2023).

    Article  CAS  PubMed  Google Scholar 

  67. Writing Group of the Histiocyte Society. Histiocytosis syndromes in children. Lancet 1, 208–209 (1987).

    Google Scholar 

  68. Okada, F. et al. A suspected case of IgG4-related bilateral arthritis of the knee. J. Orthop. Sci. 21, 100–104 (2016).

    Article  PubMed  Google Scholar 

  69. Wheeler, S., Andeen, N. & Reddy, R. Isolated IgG4 related disease of the trachea. Respir. Med. Case Rep. 49, 102031 (2024).

    PubMed  PubMed Central  Google Scholar 

  70. Danlos, F. X. et al. Antineutrophil cytoplasmic antibody-associated vasculitides and IgG4-related disease: a new overlap syndrome. Autoimmun. Rev. 16, 1036–1043 (2017).

    Article  CAS  PubMed  Google Scholar 

  71. Yamamoto, M. et al. A case with good response to belimumab for lupus nephritis complicated by IgG4-related disease. Lupus 28, 786–789 (2019).

    Article  CAS  PubMed  Google Scholar 

  72. Batani, V. et al. Association of IgG4-related disease and systemic rheumatic disorders. Eur. J. Intern. Med. 111, 63–68 (2023).

    Article  PubMed  Google Scholar 

  73. Abad, S. et al. IgG4-related disease in patients with idiopathic orbital inflammation syndrome: data from the French SIOI prospective cohort. Acta Ophthalmol. 97, e648–e656 (2019).

    Article  CAS  PubMed  Google Scholar 

  74. Rossi, G. M. et al. Idiopathic mediastinal fibrosis: a systemic immune-mediated disorder. a case series and a review of the literature. Clin. Rev. Allergy Immunol. 52, 446–459 (2017).

    Article  CAS  PubMed  Google Scholar 

  75. Trivioli, G., Bond, M., Emmi, G. & Vaglio, A. IgG4-related disease: not just a matter of IgG4. Rheumatology 60, iii35–iii38 (2021).

    Article  PubMed  Google Scholar 

  76. Umehara, H. et al. The 2020 revised comprehensive diagnostic (RCD) criteria for IgG4-RD. Mod. Rheumatol. 31, 529–533 (2021).

    Article  CAS  PubMed  Google Scholar 

  77. Umehara, H. et al. Comprehensive diagnostic criteria for IgG4-related disease (IgG4-RD), 2011. Mod. Rheumatol. 22, 21–30 (2012).

    Article  CAS  PubMed  Google Scholar 

  78. Kogami, M. et al. Performance of classification and diagnostic criteria for IgG4-related disease and comparison of patients with and without IgG4-related disease. Sci. Rep. 13, 2509 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Seth, A., Ansari, M. S., Trikha, V. & Mittal, R. Retroperitoneal fibrosis: a rare complication of Pott’s disease. J. Urol. 166, 622–623 (2001).

    Article  CAS  PubMed  Google Scholar 

  80. Greco, P. et al. Tuberculosis as a trigger of retroperitoneal fibrosis. Clin. Infect. Dis. 41, e72–e75 (2005).

    Article  PubMed  Google Scholar 

  81. Keller-Sarmiento, L. et al. Increased prevalence of malignancies in patients with IgG4-related disease: implications for clinical care. Rheumatology 64, 1326–1332 (2025).

    Article  PubMed  Google Scholar 

  82. Garcia-Solis, B. et al. IgG4-related disease and B-cell malignancy due to an IKZF1 gain-of-function variant. J. Allergy Clin. Immunol. 154, 819–826 (2024).

    Article  CAS  PubMed  Google Scholar 

  83. Wallace, Z. S., Wallace, C. J., Lu, N., Choi, H. K. & Stone, J. H. Association of IgG4-related disease with history of malignancy. Arthritis Rheumatol. 68, 2283–2289 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Inoue, D. et al. IgG4-related disease: dataset of 235 consecutive patients. Medicine 94, e680 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Matsui, S. et al. Immunoglobulin G4-related lung disease: clinicoradiological and pathological features. Respirology 18, 480–487 (2013).

    Article  PubMed  Google Scholar 

  86. Hua, T. et al. Coronary periarteritis and pericarditis are rare but distinct manifestations of heart involvement in IgG4-related disease: a retrospective cohort study. Orphanet J. Rare Dis. 19, 266 (2024).

    Article  PubMed  PubMed Central  Google Scholar 

  87. Estrada-Veras, J. I. et al. The clinical spectrum of Erdheim-Chester disease: an observational cohort study. Blood Adv. 1, 357–366 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Cohen-Aubart, F. et al. Phenotypes and survival in Erdheim-Chester disease: results from a 165-patient cohort. Am. J. Hematol. 93, E114–E117 (2018).

    Article  PubMed  Google Scholar 

  89. Arnaud, L. et al. CNS involvement and treatment with interferon-alpha are independent prognostic factors in Erdheim-Chester disease: a multicenter survival analysis of 53 patients. Blood 117, 2778–2782 (2011).

    Article  CAS  PubMed  Google Scholar 

  90. Arnaud, L. et al. Pulmonary involvement in Erdheim-Chester disease: a single-center study of thirty-four patients and a review of the literature. Arthritis Rheum. 62, 3504–3512 (2010).

    Article  PubMed  Google Scholar 

  91. Nikpanah, M. et al. Abdominal involvement in Erdheim-Chester disease (ECD): MRI and CT imaging findings and their association with BRAF(V600E) mutation. Eur. Radiol. 28, 3751–3759 (2018).

    Article  PubMed  Google Scholar 

  92. Mirmomen, S. M. et al. Thoracic involvement in Erdheim-Chester disease: computed tomography imaging findings and their association with the BRAF(V600E) mutation. Eur. Radiol. 28, 4635–4642 (2018).

    Article  PubMed  Google Scholar 

  93. Robinson, D. Jr. et al. Clinical epidemiology and treatment patterns of patients with multicentric Castleman disease: results from two US treatment centres. Br. J. Haematol. 165, 39–48 (2014).

    Article  CAS  PubMed  Google Scholar 

  94. Yu, L. et al. Clinical and pathological characteristics of HIV- and HHV-8-negative Castleman disease. Blood 129, 1658–1668 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Liu, A. Y. et al. Idiopathic multicentric Castleman’s disease: a systematic literature review. Lancet Haematol. 3, e163–e175 (2016).

    Article  PubMed  Google Scholar 

  96. Dispenzieri, A. et al. The clinical spectrum of Castleman’s disease. Am. J. Hematol. 87, 997–1002 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  97. Dispenzieri, A. POEMS syndrome: 2019 update on diagnosis, risk-stratification, and management. Am. J. Hematol. 94, 812–827 (2019).

    Article  PubMed  Google Scholar 

  98. Schupp, J. C. et al. Phenotypes of organ involvement in sarcoidosis. Eur. Respir. J. 51, 1700991 (2018).

    Article  PubMed  Google Scholar 

  99. Baughman, R. P. et al. Clinical characteristics of patients in a case control study of sarcoidosis. Am. J. Respir. Crit. Care Med. 164, 1885–1889 (2001).

    Article  CAS  PubMed  Google Scholar 

  100. Rastelli, F. et al. Renal involvement in sarcoidosis: histological patterns and prognosis, an Italian survey. Sarcoidosis Vasc. Diffus. Lung Dis. 38, e2021017 (2021).

    Google Scholar 

  101. Danda, D. et al. Clinical course of 602 patients with Takayasu’s arteritis: comparison between childhood-onset versus adult onset disease. Rheumatology 60, 2246–2255 (2021).

    Article  CAS  PubMed  Google Scholar 

  102. Schmidt, J. et al. Diagnostic features, treatment, and outcomes of Takayasu arteritis in a US cohort of 126 patients. Mayo Clin. Proc. 88, 822–830 (2013).

    Article  PubMed  Google Scholar 

  103. Comarmond, C. et al. Long-term outcomes and prognostic factors of complications in Takayasu arteritis: a multicenter study of 318 patients. Circulation 136, 1114–1122 (2017).

    Article  PubMed  Google Scholar 

  104. Adams, T. N., Zhang, D., Batra, K. & Fitzgerald, J. E. Pulmonary manifestations of large, medium, and variable vessel vasculitis. Respir. Med. 145, 182–191 (2018).

    Article  PubMed  Google Scholar 

  105. Iudici, M. et al. Granulomatosis with polyangiitis: study of 795 patients from the French Vasculitis Study Group registry. Semin. Arthritis Rheum. 51, 339–346 (2021).

    Article  PubMed  Google Scholar 

  106. Solans-Laque, R. et al. Clinical characteristics and outcome of Spanish patients with ANCA-associated vasculitides: impact of the vasculitis type, ANCA specificity, and treatment on mortality and morbidity. Medicine 96, e6083 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  107. Shimojima, Y. et al. Hypertrophic pachymeningitis in ANCA-associated vasculitis: a cross-sectional and multi-institutional study in Japan (J-CANVAS). Arthritis Res. Ther. 24, 204 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Junek, M. L. et al. Ocular manifestations of ANCA-associated vasculitis. Rheumatology 62, 2517–2524 (2023).

    Article  PubMed  Google Scholar 

  109. Gercik, O. et al. Splenic infarction is not rare in granulomatosis with polyangiitis. Clin. Rheumatol. 39, 1929–1934 (2020).

    Article  PubMed  Google Scholar 

  110. Zhou, J. et al. Clinical and radiologic differences in lung involvement between IgG4-related disease and plasma cell-type idiopathic multicentric Castleman disease. Lung 203, 20 (2025).

    Article  CAS  PubMed  Google Scholar 

  111. Pegoraro, F. et al. Erdheim-Chester disease: a rapidly evolving disease model. Leukemia 34, 2840–2857 (2020).

    Article  CAS  PubMed  Google Scholar 

  112. Pegoraro, F. et al. Childhood-onset Erdheim-Chester disease in the molecular era: clinical phenotypes and long-term outcomes of 21 patients. Blood 142, 1167–1171 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Cohen Aubart, F. et al. Central nervous system involvement in Erdheim-Chester disease: an observational cohort study. Neurology 95, e2746–e2754 (2020).

    Article  PubMed  Google Scholar 

  114. Gianfreda, D. et al. Cardiac involvement in Erdheim-Chester disease: an MRI study. Blood 128, 2468–2471 (2016).

    Article  CAS  PubMed  Google Scholar 

  115. Salvarani, C. et al. Vasculitis of the gastrointestinal tract in chronic periaortitis. Medicine 90, 28–39 (2011).

    Article  PubMed  Google Scholar 

  116. Emile, J. F., Vaglio, A., Cohen-Aubart, F. & Haroche, J. IgG4-related disease and Rosai-Dorfman-Destombes disease — authors’ reply. Lancet 398, 1214–1215 (2021).

    Article  CAS  PubMed  Google Scholar 

  117. Vaglio, A., Salvarani, C. & Buzio, C. Retroperitoneal fibrosis. Lancet 367, 241–251 (2006).

    Article  PubMed  Google Scholar 

  118. Haroche, J., Cohen-Aubart, F. & Amoura, Z. Erdheim-Chester disease. Blood 135, 1311–1318 (2020).

    Article  PubMed  Google Scholar 

  119. Haroche, J. et al. Reproducible and sustained efficacy of targeted therapy with vemurafenib in patients with BRAF(V600E)-mutated Erdheim-Chester disease. J. Clin. Oncol. 33, 411–418 (2015).

    Article  CAS  PubMed  Google Scholar 

  120. Goyal, G. et al. Erdheim-Chester disease: consensus recommendations for evaluation, diagnosis, and treatment in the molecular era. Blood 135, 1929–1945 (2020).

    Article  CAS  PubMed  Google Scholar 

  121. Ebbo, M. et al. Pathologies associated with serum IgG4 elevation. Int. J. Rheumatol. 2012, 602809 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  122. Razanamahery, J. et al. Erdheim-Chester disease with concomitant Rosai-Dorfman like lesions: a distinct entity mainly driven by MAP2K1. Haematologica 105, e5–e8 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  123. Abla, O. et al. Consensus recommendations for the diagnosis and clinical management of Rosai-Dorfman-Destombes disease. Blood 131, 2877–2890 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Shimizu, A., Noguchi-Shinohara, M., Komatsu, J. & Ono, K. Multifocal intracranial Rosai-Dorfman disease mimicking immunoglobulin G4-related pachymeningitis. Neurology 103, e209741 (2024).

    Article  PubMed  Google Scholar 

  125. Wang, L. et al. Rosai-Dorfman disease mimicking IgG4-related diseases: a single-center experience in China. Orphanet J. Rare Dis. 15, 285 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  126. Chen, L. Y. C., Huang, A. J., Stone, J. H. & Ferry, J. A. Case 30-2024: a 45-year-old woman with kidney lesions and lytic bone disease. N. Engl. J. Med. 391, 1140–1151 (2024).

    Article  PubMed  Google Scholar 

  127. Tomelleri, A. et al. Disease stratification in GCA and PMR: state of the art and future perspectives. Nat. Rev. Rheumatol. 19, 446–459 (2023).

    Article  CAS  PubMed  Google Scholar 

  128. van der Geest, K. S. M. et al. Large vessel giant cell arteritis. Lancet Rheumatol. 6, e397–e408 (2024).

    Article  PubMed  Google Scholar 

  129. Kataoka, K. et al. IgG4-related periarteritis in the superficial temporal artery, clinically mimicking giant cell arthritis. Eur. J. Dermatol. 34, 198–200 (2024).

    Article  PubMed  Google Scholar 

  130. Mason, J. C. Takayasu arteritis — advances in diagnosis and management. Nat. Rev. Rheumatol. 6, 406–415 (2010).

    Article  PubMed  Google Scholar 

  131. Vaglio, A., Buzio, C. & Zwerina, J. Eosinophilic granulomatosis with polyangiitis (Churg-Strauss): state of the art. Allergy 68, 261–273 (2013).

    Article  CAS  PubMed  Google Scholar 

  132. Trivioli, G. et al. Genetics of ANCA-associated vasculitis: role in pathogenesis, classification and management. Nat. Rev. Rheumatol. 18, 559–574 (2022).

    Article  CAS  PubMed  Google Scholar 

  133. Vaglio, A. et al. ANCA-positive periaortic vasculitis: does it fall within the spectrum of vasculitis? J. Intern. Med. 251, 268–271 (2002).

    Article  CAS  PubMed  Google Scholar 

  134. Bennett, D. et al. Chitotriosidase: a biomarker of activity and severity in patients with sarcoidosis. Respir. Res. 21, 6 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  135. Deshpande, V. et al. Consensus statement on the pathology of IgG4-related disease. Mod. Pathol. 25, 1181–1192 (2012).

    Article  PubMed  Google Scholar 

  136. Emile, J. F. et al. Revised classification of histiocytoses and neoplasms of the macrophage-dendritic cell lineages. Blood 127, 2672–2681 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Emile, J. F. et al. Histiocytosis. Lancet 398, 157–170 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. Ebbo, M. et al. Usefulness of 2-[18F]-fluoro-2-deoxy-D-glucose-positron emission tomography/computed tomography for staging and evaluation of treatment response in IgG4-related disease: a retrospective multicenter study. Arthritis Care Res. 66, 86–96 (2014).

    Article  CAS  Google Scholar 

  139. Shimizu, M. et al. Effectiveness of imaging modalities for screening IgG4-related dacryoadenitis and sialadenitis (Mikulicz’s disease) and for differentiating it from Sjogren’s syndrome (SS), with an emphasis on sonography. Arthritis Res. Ther. 17, 223 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  140. Vaglio, A. et al. 18F-fluorodeoxyglucose positron emission tomography in the diagnosis and followup of idiopathic retroperitoneal fibrosis. Arthritis Rheum. 53, 122–125 (2005).

    Article  PubMed  Google Scholar 

  141. Carruthers, M. N., Khosroshahi, A., Augustin, T., Deshpande, V. & Stone, J. H. The diagnostic utility of serum IgG4 concentrations in IgG4-related disease. Ann. Rheum. Dis. 74, 14–18 (2015).

    Article  CAS  PubMed  Google Scholar 

  142. Zhao, E. J., Carruthers, M. N., Li, C. H., Mattman, A. & Chen, L. Y. C. Conditions associated with polyclonal hypergammaglobulinemia in the IgG4-related disease era: a retrospective study from a hematology tertiary care center. Haematologica 105, e121–e123 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  143. Katz, G. et al. Multiorgan involvement and circulating IgG1 predict hypocomplementaemia in IgG4-related disease. Ann. Rheum. Dis. 83, 1773–1780 (2024).

    Article  CAS  PubMed  Google Scholar 

  144. Khosroshahi, A. et al. International consensus guidance statement on the management and treatment of IgG4-related disease. Arthritis Rheumatol. 67, 1688–1699 (2015).

    Article  CAS  PubMed  Google Scholar 

  145. Masaki, Y. et al. A multicenter phase II prospective clinical trial of glucocorticoid for patients with untreated IgG4-related disease. Mod. Rheumatol. 27, 849–854 (2017).

    Article  CAS  PubMed  Google Scholar 

  146. Masamune, A. et al. Randomised controlled trial of long-term maintenance corticosteroid therapy in patients with autoimmune pancreatitis. Gut 66, 487–494 (2017).

    Article  CAS  PubMed  Google Scholar 

  147. Vaglio, A. et al. Prednisone versus tamoxifen in patients with idiopathic retroperitoneal fibrosis: an open-label randomised controlled trial. Lancet 378, 338–346 (2011).

    Article  CAS  PubMed  Google Scholar 

  148. Hart, P. A. et al. Treatment of relapsing autoimmune pancreatitis with immunomodulators and rituximab: the Mayo Clinic experience. Gut 62, 1607–1615 (2013).

    Article  CAS  PubMed  Google Scholar 

  149. Alberici, F. et al. Methotrexate plus prednisone in patients with relapsing idiopathic retroperitoneal fibrosis. Ann. Rheum. Dis. 72, 1584–1586 (2013).

    Article  CAS  PubMed  Google Scholar 

  150. Scheel, P. J. Jr, Feeley, N. & Sozio, S. M. Combined prednisone and mycophenolate mofetil treatment for retroperitoneal fibrosis: a case series. Ann. Intern. Med. 154, 31–36 (2011).

    Article  PubMed  Google Scholar 

  151. Lanzillotta, M. et al. Emerging therapy options for IgG4-related disease. Expert. Rev. Clin. Immunol. 17, 471–483 (2021).

    Article  CAS  PubMed  Google Scholar 

  152. Topazian, M. et al. Rituximab therapy for refractory biliary strictures in immunoglobulin G4-associated cholangitis. Clin. Gastroenterol. Hepatol. 6, 364–366 (2008).

    Article  CAS  PubMed  Google Scholar 

  153. Lanzillotta, M. et al. Efficacy and safety of rituximab for IgG4-related pancreato-biliary disease: a systematic review and meta-analysis. Pancreatology 21, 1395–1401 (2021).

    Article  CAS  PubMed  Google Scholar 

  154. Ebbo, M. et al. Long-term efficacy and safety of rituximab in IgG4-related disease: data from a French nationwide study of thirty-three patients. PLoS ONE 12, e0183844 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  155. Carruthers, M. N. et al. Rituximab for IgG4-related disease: a prospective, open-label trial. Ann. Rheum. Dis. 74, 1171–1177 (2015).

    Article  CAS  PubMed  Google Scholar 

  156. Maritati, F. et al. Rituximab therapy for chronic periaortitis. Ann. Rheum. Dis. 71, 1262–1264 (2012).

    Article  CAS  PubMed  Google Scholar 

  157. Urban, M. L. et al. Rituximab for chronic periaortitis without evidence of IgG4-related disease: a long-term follow-up study of 20 patients. Ann. Rheum. Dis. 79, 433–434 (2020).

    Article  PubMed  Google Scholar 

  158. Stone, J. H. et al. Inebilizumab for treatment of IgG4-related disease. N. Engl. J. Med. https://doi.org/10.1056/NEJMoa2409712 (2024).

    Article  PubMed  PubMed Central  Google Scholar 

  159. Perugino, C. A. et al. Evaluation of the safety, efficacy, and mechanism of action of obexelimab for the treatment of patients with IgG4-related disease: an open-label, single-arm, single centre, phase 2 pilot trial. Lancet Rheumatol. 5, e442–e450 (2023).

    Article  CAS  PubMed  Google Scholar 

  160. Cai, S. et al. BLyS/APRIL dual inhibition for IgG4-RD: a prospective single-arm clinical trial of telitacicept. Ann. Rheum. Dis. 82, 881–883 (2023).

    Article  PubMed  Google Scholar 

  161. Kiyama, K. et al. Serum BAFF and APRIL levels in patients with IgG4-related disease and their clinical significance. Arthritis Res. Ther. 14, R86 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  162. Matza, M. A. et al. Abatacept in IgG4-related disease: a prospective, open-label, single-arm, single-centre, proof-of-concept study. Lancet Rheumatol. 4, e105–e112 (2022).

    Article  CAS  PubMed  Google Scholar 

  163. Moussiegt, A. et al. IgG4-related disease and hypereosinophilic syndrome: overlapping phenotypes. Autoimmun. Rev. 20, 102889 (2021).

    Article  CAS  PubMed  Google Scholar 

  164. Simpson, R. S., Lau, S. K. C. & Lee, J. K. Dupilumab as a novel steroid-sparing treatment for IgG4-related disease. Ann. Rheum. Dis. 79, 549–550 (2020).

    Article  PubMed  Google Scholar 

  165. Ebbo, M. et al. Correspondence on: ‘Dupilumab as a novel steroid-sparing treatment for IgG4-related disease’ by Simpson et al. Ann. Rheum. Dis. 81, e26 (2022).

    Article  PubMed  Google Scholar 

  166. Cao, X. et al. Effectiveness of tofacitinib monotherapy for patients with IgG4-RD or idiopathic retroperitoneal fibrosis. Clin. Exp. Rheumatol. 42, 1736–1743 (2024).

    PubMed  Google Scholar 

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Authors and Affiliations

  1. Nephrology and Dialysis Unit, Meyer Children’s Hospital IRCCS, Florence, Italy

    Francesco Peyronel & Augusto Vaglio

  2. Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy

    Francesco Peyronel & Maria L. Urban

  3. University Vita-Salute San Raffaele, IRCCS San Raffaele Scientific Institute, Milan, Italy

    Emanuel Della-Torre

  4. Unit of Immunology, Rheumatology, Allergy and Rare Diseases (UnIRAR), IRCCS San Raffaele Scientific Institute, Milan, Italy

    Emanuel Della-Torre

  5. Nephrology, Dialysis and Kidney Transplant Unit, IRCCS-Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy

    Federica Maritati

  6. Department of Pathology and Medical Biology, University Medical Centre Groningen, Groningen, The Netherlands

    Ingeborg Bajema

  7. Assistance Publique-Hôpitaux de Marseille, Aix-Marseille Université, Department of Internal Medicine Hôpital Timone, Marseille, France

    Nicolas Schleinitz

  8. Department of Biomedical, Experimental and Clinical Sciences “Mario Serio”, University of Florence, Florence, Italy

    Augusto Vaglio

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Peyronel, F., Della-Torre, E., Maritati, F. et al. IgG4-related disease and other fibro-inflammatory conditions. Nat Rev Rheumatol 21, 275–290 (2025). https://doi.org/10.1038/s41584-025-01240-x

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