Keywords
retroperitoneal fibrosis
biomarker
DMARDs
Categories
How to Cite
Abstract
IgG4-related disease (IgG4-RD) has evolved from a series of organ-specific clusters into a recognized systemic fibroinflammatory disorder defined by a unique B-T cell axis. This review provides a comprehensive analysis of current diagnostic and therapeutic paradigms, emphasizing the pathogenic roles of CD4+ cytotoxic T lymphocytes and follicular helper T cells in driving storiform fibrosis. Despite the utility of the 2019 ACR/EULAR classification criteria, diagnostic challenges persist; notably, serum IgG4 remains a fallible biomarker, with a significant amount of patients maintaining normal concentrations during active disease. While glucocorticoids are the traditional first-line treatment, their long-term toxicity and high relapse rates have catalyzed a shift toward targeted B-cell depletion. Emerging evidence suggests that early intervention with biological agents can arrest and even reverse established fibrotic lesions, highlighting the dynamic nature of the immune-fibroblast interface. However, the current reliance on retrospective data and the lack of sensitive biomarkers for diagnosis and monitoring disease activity remain significant hurdles. This review underscores the necessity for precision-driven management and large-scale randomized trials to optimize long-term outcomes and minimize organ damage in this complex multi-organ condition.
References
1. Stone JH, Zen Y, Deshpande V. IgG4-related disease. N Engl J Med [Internet]. 2012 Feb 9;366(6):539–51. Available from: http://dx.doi.org/10.1056/nejmra1104650
2. Karadeniz H, Vaglio A. IgG4-related disease: a contemporary review. Turk J Med Sci [Internet]. 2020 Nov 3;50(SI-2):1616–31. Available from: http://dx.doi.org/10.3906/sag-2006-375
3. Kamisawa T, Zen Y, Pillai S, Stone JH. IgG4-related disease. Lancet [Internet]. 2015 Apr;385(9976):1460–71. Available from: http://dx.doi.org/10.1016/s0140-6736(14)60720-0
4. Dimov D. Rheumatological aspects of IgG4-related disease (IgG4-RD). Ревматология [Internet]. 2023 Mar 6;30(4):41–56. Available from: https://doi.org/10.35465/30.4.2022.pp41-56
5. Deshpande V, Zen Y, Chan JK, Yi EE, Sato Y, Yoshino T, et al. Consensus statement on the pathology of IgG4-related disease. Mod Pathol [Internet]. 2012 Sep;25(9):1181–92. Available from: https://doi.org/10.1038/modpathol.2012.72
6. Lee C, To CH. IgG4-related disease: A concise review. Journal of Clinical Rheumatology and Immunology [Internet]. 2023 Jul;23(01):25–34. Available from: http://dx.doi.org/10.1142/s2661341723300033
7. Wallace ZS, Miles G, Smolkina E, Petruski-Ivleva N, Madziva D, Cook C, et al. Incidence, prevalence and mortality of IgG4-related disease in the USA: a claims-based analysis of commercially insured adults. Ann Rheum Dis [Internet]. 2023 Jul;82(7):957–62. Available from: http://dx.doi.org/10.1136/ard-2023-223950
8. Parums DV. IgG4-related disease: A review of persistent challenges in the pathogenesis, diagnosis, and approaches to treatment. Med Sci Monit [Internet]. 2025 Jun 18;31:e950212. Available from: http://dx.doi.org/10.12659/MSM.950212
9. Gasparyan AY, Ayvazyan L, Blackmore H, Kitas GD. Writing a narrative biomedical review: considerations for authors, peer reviewers, and editors. Rheumatol Int [Internet]. 2011 Nov;31(11):1409–17. Available from: https://doi.org/10.1007/s00296-011-1999-3
10. Perugino CA, Stone JH. IgG4-related disease: an update on pathophysiology and implications for clinical care. Nat Rev Rheumatol [Internet]. 2020 Dec;16(12):702–14. Available from: https://doi.org/10.1038/s41584-020-0500-7
11. Kubo S, Nakayamada S, Tanaka Y. Immunophenotype involved in IgG4-related disease. Mod Rheumatol [Internet]. 2019 Mar;29(2):226–30. Available from: https://doi.org/10.1080/14397595.2018.1537962
12. Bozzalla Cassione E, Stone JH. IgG4-related disease. Curr Opin Rheumatol [Internet]. 2017 May;29(3):223–7. Available from: http://dx.doi.org/10.1097/BOR.0000000000000383
13. Yoshikawa T, Watanabe T, Minaga K, Kamata K, Kudo M. Cytokines produced by innate immune cells in IgG4-related disease. Mod Rheumatol [Internet]. 2019 Mar;29(2):219–25. Available from: https://doi.org/10.1080/14397595.2018.1536364
14. Pillai S, Perugino C, Kaneko N. Immune mechanisms of fibrosis and inflammation in IgG4-related disease. Curr Opin Rheumatol [Internet]. 2020 Mar;32(2):146–51. Available from: http://dx.doi.org/10.1097/bor.0000000000000686
15. Michailidou D, Schwartz DM, Mustelin T, Hughes GC. Allergic aspects of IgG4-related disease: Implications for pathogenesis and therapy. Front Immunol [Internet]. 2021 Jul 7;12:693192. Available from: http://dx.doi.org/10.3389/fimmu.2021.693192
16. Touzani F, Pozdzik A. New insights into immune cells cross-talk during IgG4-related disease. Clin Immunol [Internet]. 2019 Jan;198:1–10. Available from: https://doi.org/10.1016/j.clim.2018.11.004
17. Akiyama M, Alshehri W, Ishigaki S, Saito K, Kaneko Y. The immunological pathogenesis of IgG4-related disease categorized by clinical characteristics. Immunol Med [Internet]. 2025 Mar;48(1):11–23. Available from: https://doi.org/10.1080/25785826.2024.2407224
18. Kamekura R, Takahashi H, Ichimiya S. New insights into IgG4-related disease: emerging new CD4+ T-cell subsets. Curr Opin Rheumatol [Internet]. 2019 Jan;31(1):9–15. Available from: http://dx.doi.org/10.1097/bor.0000000000000558
19. Liu C, Zhang P, Zhang W. Immunological mechanism of IgG4-related disease. J Transl Autoimmun [Internet]. 2020 Mar 19;3(100047):100047. Available from: https://doi.org/10.1016/j.jtauto.2020.100047
20. Liu J, Yin W, Westerberg LS, Lee P, Gong Q, Chen Y, et al. Immune dysregulation in IgG4-related disease. Front Immunol [Internet]. 2021 Sep 1;12:738540. Available from: http://dx.doi.org/10.3389/fimmu.2021.738540
21. Avincsal MO, Zen Y. The histopathology of IgG4-related disease. Curr Top Microbiol Immunol [Internet]. 2017;401:45–60. Available from: http://dx.doi.org/10.1007/82_2016_38
22. Obiorah IE, Henao Velasquez A, Özdemirli M. The clinicopathologic spectrum of IgG4-related disease. Balkan Med J [Internet]. 2018 Jul 24;35(4):292–300. Available from: http://dx.doi.org/10.4274/balkanmedj.2018.0809
23. Hara A, Watanabe T, Minaga K, Yoshikawa T, Kurimoto M, Sekai I, et al. A positive cytokine/chemokine feedback loop establishes plasmacytoid DC–driven autoimmune pancreatitis in IgG4-related disease. JCI Insight [Internet]. 2024 Oct 22;9(20). Available from: http://dx.doi.org/10.1172/jci.insight.167910
24. Ishikawa Y, Terao C. Genetic analysis of IgG4-related disease. Mod Rheumatol [Internet]. 2020 Jan;30(1):17–23. Available from: https://doi.org/10.1080/14397595.2019.1621000
25. Lanzillotta M, Mancuso G, Della-Torre E. Advances in the diagnosis and management of IgG4 related disease. BMJ [Internet]. 2020 Jun 16;m1067. Available from: http://dx.doi.org/10.1136/bmj.m1067
26. Wallace ZS, Zhang Y, Perugino CA, Naden R, Choi HK, Stone JH. Clinical phenotypes of IgG4-related disease: an analysis of two international cross-sectional cohorts. Ann Rheum Dis [Internet]. 2019 Mar;78(3):406–12. Available from: http://dx.doi.org/10.1136/annrheumdis-2018-214603
27. Wallace ZS, Katz G, Hernandez-Barco YG, Baker MC. Current and future advances in practice: IgG4-related disease. Rheumatol Adv Pract [Internet]. 2024 Apr 10;8(2):rkae020. Available from: https://doi.org/10.1093/rap/rkae020
28. Katz G, Stone JH. Clinical perspectives on IgG4-related disease and its classification. Annu Rev Med [Internet]. 2022 Jan 27;73(1):545–62. Available from: http://dx.doi.org/10.1146/annurev-med-050219-034449
29. Wallace ZS, Naden RP, Chari S, Choi H, Della-Torre E, Dicaire JF, et al. The 2019 American College of Rheumatology/European League Against Rheumatism classification criteria for IgG4-related disease. Arthritis Rheumatol [Internet]. 2020 Jan;72(1):7–19. Available from: http://dx.doi.org/10.1002/art.41120
30. Umehara H, Okazaki K, Kawa S, Takahashi H, Goto H, Matsui S, et al. The 2020 revised comprehensive diagnostic (RCD) criteria for IgG4-RD. Mod Rheumatol [Internet]. 2021 May;31(3):529–33. Available from: https://doi.org/10.1080/14397595.2020.1859710
31. Arias-Intriago M, Gomolin T, Jaramillo F, Cruz-Enríquez AC, Lara-Arteaga AL, Tello-De-la-Torre A, et al. IgG4-related disease: Current and future insights into pathological diagnosis. Int J Mol Sci [Internet]. 2025 Jun 1;26(11):5325. Available from: https://doi.org/10.3390/ijms26115325
32. Treglia G, Mattoli MV, Bertagna F, Giubbini R, Giordano A. Emerging role of Fluorine-18-fluorodeoxyglucose positron emission tomography in patients with retroperitoneal fibrosis: a systematic review. Rheumatol Int [Internet]. 2013 Mar;33(3):549–55. Available from: http://dx.doi.org/10.1007/s00296-012-2576-0
33. Jansen I, Hendriksz TR, Han SH, Huiskes AWLC, van Bommel EFH. (18)F-fluorodeoxyglucose position emission tomography (FDG-PET) for monitoring disease activity and treatment response in idiopathic retroperitoneal fibrosis. Eur J Intern Med [Internet]. 2010 Jun;21(3):216–21. Available from: http://dx.doi.org/10.1016/j.ejim.2010.02.008
34. Kamper L, Brandt AS, Ekamp H, Abanador-Kamper N, Piroth W, Roth S, et al. Diffusion-weighted MRI findings of treated and untreated retroperitoneal fibrosis. Diagn Interv Radiol [Internet]. 2014 Nov;20(6):459–63. Available from: http://dx.doi.org/10.5152/dir.2014.14027
35. Culver EL, Sadler R, Simpson D, Cargill T, Makuch M, Bateman AC, et al. Elevated serum IgG4 levels in diagnosis, treatment response, organ involvement, and relapse in a prospective IgG4-related disease UK cohort. Am J Gastroenterol [Internet]. 2016 May;111(5):733–43. Available from: http://dx.doi.org/10.1038/ajg.2016.40
36. Xu WL, Ling YC, Wang ZK, Deng F. Diagnostic performance of serum IgG4 level for IgG4-related disease: a meta-analysis. Sci Rep [Internet]. 2016 Aug 25;6(1). Available from: http://dx.doi.org/10.1038/srep32035
37. Carruthers MN, Khosroshahi A, Augustin T, Deshpande V, Stone JH. The diagnostic utility of serum IgG4 concentrations in IgG4-related disease. Ann Rheum Dis [Internet]. 2015 Jan;74(1):14–8. Available from: http://dx.doi.org/10.1136/annrheumdis-2013-204907
38. Boonstra K, Culver EL, de Buy Wenniger LM, van Heerde MJ, van Erpecum KJ, Poen AC, et al. Serum immunoglobulin G4 and immunoglobulin G1 for distinguishing immunoglobulin G4-associated cholangitis from primary sclerosing cholangitis. Hepatology [Internet]. 2014 May;59(5):1954–63. Available from: http://dx.doi.org/10.1002/hep.26977
39. Sah RP, Chari ST. Serologic issues in IgG4-related systemic disease and autoimmune pancreatitis. Curr Opin Rheumatol [Internet]. 2011 Jan;23(1):108–13. Available from: http://dx.doi.org/10.1097/BOR.0b013e3283413469
40. Abraham M, Khosroshahi A. Diagnostic and treatment workup for IgG4-related disease. Expert Rev Clin Immunol [Internet]. 2017 Sep;13(9):867–75. Available from: http://dx.doi.org/10.1080/1744666X.2017.1354698
41. Kwon OC, Park MC, Kim YG. Correlation between serologic parameters and disease activity of IgG4-related disease: Differences between patients with normal and elevated serum IgG4 concentrations. Front Immunol [Internet]. 2022 Oct 12;13:1020459. Available from: https://doi.org/10.3389/fimmu.2022.1020459
42. Peng Y, Wang M, Sun R, Nie Y, Zhang N, He X, et al. Revealing the distinct clinical patterns and relapse risk factors in seronegative IgG4-RD patients: A retrospective cohort study over a decade. J Intern Med [Internet]. 2024 Aug;296(2):200–12. Available from: http://dx.doi.org/10.1111/joim.13814
43. Chang CT, Chan TM, Yu HH, Yu KH. Diagnostic utility of serum IgG4 level in IgG4-related diseases: a comprehensive systematic review and meta-analysis. RMD Open [Internet]. 2023 Dec;9(4):e003498. Available from: https://doi.org/10.1136/rmdopen-2023-003498
44. Wallace ZS, Mattoo H, Carruthers M, Mahajan VS, Della Torre E, Lee H, et al. Plasmablasts as a biomarker for IgG4-related disease, independent of serum IgG4 concentrations. Ann Rheum Dis [Internet]. 2015 Jan;74(1):190–5. Available from: http://dx.doi.org/10.1136/annrheumdis-2014-205233
45. Lanzillotta M, Stone JH, Della-Torre E. B-Cell depletion therapy in IgG4-related disease: State of the art and future perspectives. Mod Rheumatol [Internet]. 2023 Mar 2;33(2):258–65. Available from: https://doi.org/10.1093/mr/roac098
46. Cargill T, Makuch M, Sadler R, Lighaam LC, Peters R, van Ham M, et al. Activated T-follicular helper 2 cells are associated with disease activity in IgG4-related sclerosing cholangitis and pancreatitis. Clin Transl Gastroenterol [Internet]. 2019 Apr 26;10(4):e00020. Available from: https://ora.ox.ac.uk/objects/uuid:d854631f-dd91-4bac-aefa-2d88eb6f6f84/files/m4c6c522e4fbb56657ded9a82c5b8a4cd
47. Karim AF, Eurelings LEM, Bansie RD, van Hagen PM, van Laar JAM, Dik WA. Soluble interleukin-2 receptor: A potential marker for monitoring disease activity in IgG4-related disease. Mediators Inflamm [Internet]. 2018 Mar 1;2018:6103064. Available from: http://dx.doi.org/10.1155/2018/6103064
48. Kawashiri SY, Origuchi T, Umeda M, Nishino A, Shimizu T, Fukui S, et al. Association of serum levels of fibrosis-related biomarkers with disease activity in patients with IgG4-related disease. Arthritis Res Ther [Internet]. 2018 Dec 14;20(1):277. Available from: https://doi.org/10.1186/s13075-018-1777-7
49. Ohta N, Kurakami K, Ishida A, Furukawa T, Suzuki Y, Aoyagi M, et al. Roles of TGF-beta and periostin in fibrosclerosis in patients with IgG4-related diseases. Acta Otolaryngol [Internet]. 2013 Dec;133(12):1322–7. Available from: http://dx.doi.org/10.3109/00016489.2013.831187
50. Yoshifuji H, Umehara H. Glucocorticoids in the treatment of IgG4-related disease—Prospects for new international treatment guidelines. Mod Rheumatol [Internet]. 2023 Mar 2;33(2):252–7. Available from: http://dx.doi.org/10.1093/mr/roac097
51. Omar D, Chen Y, Cong Y, Dong L. Glucocorticoids and steroid sparing medications monotherapies or in combination for IgG4-RD: a systematic review and network meta-analysis. Rheumatology (Oxford) [Internet]. 2020 Apr 1;59(4):718–26. Available from: http://dx.doi.org/10.1093/rheumatology/kez380
52. Hammitzsch A, Ferraro N, Bachmann Q, Heemann U, Moog P. Long-term treatment patterns and outcomes in IgG4-related disease - a retrospective single-center cohort study focusing on rituximab. Rheumatol Int [Internet]. 2026 Jan 13;46(1):33. Available from: http://dx.doi.org/10.1007/s00296-025-06065-1
53. Yue Z, Tong F, Chen Y, Shen Y, Li J, Zeng C, et al. Risk factors for IgG4 ‐related disease relapse: A systematic review and meta‐analysis. Scand J Immunol [Internet]. 2022 Sep;96(3). Available from: https://doi.org/10.1111/sji.13200
54. Pofi R, Caratti G, Ray DW, Tomlinson JW. Treating the side effects of exogenous glucocorticoids; Can we separate the good from the bad? Endocr Rev [Internet]. 2023 Nov 9;44(6):975–1011. Available from: https://doi.org/10.1210/endrev/bnad016
55. Kamisawa T, Okazaki K. Diagnosis and treatment of IgG4-related disease. Curr Top Microbiol Immunol [Internet]. 2017;401:19–33. Available from: http://dx.doi.org/10.1007/82_2016_36
56. Della-Torre E, Campochiaro C, Bozzolo EP, Dagna L, Scotti R, Nicoletti R, et al. Methotrexate for maintenance of remission in IgG4-related disease: Fig. 1. Rheumatology (Oxford) [Internet]. 2015 Oct;54(10):1934–6. Available from: http://dx.doi.org/10.1093/rheumatology/kev244
57. Boyadzhieva V, Doncheva - Dilova JS, Stoilov R, Milanov V, Lambova S, Stoilov N. IgG4-related disease - a clinical case. Ревматология [Internet]. 2023 Dec 14;31(3):64–78. Available from: https://doi.org/10.35465/31.3.2023.pp64-78
58. Tanaka Y, Stone JH. Perspectives on current and emerging therapies for immunoglobulin G4-related disease. Mod Rheumatol [Internet]. 2023 Mar 2;33(2):229–36. Available from: https://doi.org/10.1093/mr/roac141
59. González-García A, Starita-Fajardo G, Lucena López D, Iranzo Alcolea MP, López-Paraja M, Peña-Rodríguez M, et al. New developments in the treatment of IgG4-related disease: A comprehensive clinical approach. J Clin Med [Internet]. 2025 Sep 25;14(19):6774. Available from: http://dx.doi.org/10.3390/jcm14196774
60. Patel U, Saxena A, Patel D, Ayesha IE, Monson NR, Klair N, et al. Therapeutic uses of rituximab and clinical features in immunoglobulin G4-related disease: A systematic review. Cureus [Internet]. 2023 Sep;15(9):e45044. Available from: http://dx.doi.org/10.7759/cureus.45044
61. Stone JH, Khosroshahi A, Zhang W, Della Torre E, Okazaki K, Tanaka Y, et al. Inebilizumab for treatment of IgG4-related disease. N Engl J Med [Internet]. 2025 Mar 27;392(12):1168–77. Available from: http://dx.doi.org/10.1056/NEJMoa2409712
62. Golfinopoulou R, Giudicelli V, Manso T, Kossida S. Delving into molecular pathways: Analyzing the mechanisms of action of monoclonal antibodies integrated in IMGT/mAb-DB for myasthenia Gravis. Vaccines (Basel) [Internet]. 2023 Nov 26;11(12):1756. Available from: http://dx.doi.org/10.3390/vaccines11121756
63. Alexander T, Burmester GR. Obexelimab in IgG4-related disease: B-cell inhibition as a novel therapeutic approach. Lancet Rheumatol [Internet]. 2023 Aug;5(8):e428–9. Available from: http://dx.doi.org/10.1016/s2665-9913(23)00184-4
64. Kanda M, Kamekura R, Sugawara M, Nagahata K, Suzuki C, Takano K, et al. IgG4-related disease administered dupilumab: case series and review of the literature. RMD Open [Internet]. 2023 Mar;9(1):e003026. Available from: http://dx.doi.org/10.1136/rmdopen-2023-003026
65. Cao X, Li S, Wan J, Yu Z, Dong G, Zhou W. Effectiveness of tofacitinib monotherapy for patients with IgG4-RD or idiopathic retroperitoneal fibrosis. Clin Exp Rheumatol [Internet]. 2023 Dec 7; Available from: http://dx.doi.org/10.55563/clinexprheumatol/61mt03
This work is licensed under a Creative Commons Attribution 4.0 International License.
Copyright (c) 2026 Stoimen Dimitrov, Vassilia Terzieva, Georgi Kotov, Mariana Ivanova, Zlatimir Kolarov (Author)