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IgG4-Related Disease: Beyond Glucocorticoids

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Abstract

IgG4-related disease is a heterogeneous immune-mediated fibroinflammatory condition that can affect every single organ. This disease is more prevalent in the elderly (the mean age of patients is above 60 years) and the prevalence rate is estimated to be over 4.6 per 100,000 population. Before making a diagnosis, the exclusion of malignancies, lymphoma, anti-neutrophil cytoplasmic antibody-associated vasculitis, multicentric Castleman disease, and other mimickers is crucial for appropriate treatment. Broad management guidelines have been published emphasizing the need for prompt treatment and the use of glucocorticoids as first-line drug therapy for induction of remission. However, the toxic effects of glucocorticoids are problematic because IgG4-related disease is more prevalent in patients above 60 years of age, a population with frequent comorbid conditions and polypharmacy. Immunosuppressants (cyclophosphamide, methotrexate, leflunomide, and tacrolimus) and targeted immunomodulators (rituximab, XmAb5871, and abatacept) are appealing to overcome potential toxic effects of glucocorticoids and as emerging glucocorticoid-sparing and/or maintenance treatments. In this review, we provide an overview of our understanding of the pathophysiology of the disease (T follicular helper cells, CD4+ cytotoxic T cells, plasmablasts, and alternatively activated M2 macrophages) and clinical characteristics, and highlight the potential targets for treatment intervention.

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References

  1. Stone JH, Zen Y, Deshpande V. IgG4-related disease. N Engl J Med. 2012;366:539–51.

    Article  CAS  PubMed  Google Scholar 

  2. Kanno A, Masamune A, Okazaki K, Kamisawa T, Kawa S, Nishimori I, et al. Nationwide epidemiological survey of autoimmune pancreatitis in Japan in 2011. Pancreas. 2015;44:535–9.

    Article  PubMed  Google Scholar 

  3. Zen Y, Nakanuma Y. IgG4-related disease: a cross-sectional study of 114 cases. Am J Surg Pathol. 2010;34:1812–9.

    Article  PubMed  Google Scholar 

  4. Kawa S, Ota M, Yoshizawa K, Horiuchi A, Hamano H, Ochi Y, et al. HLA DRB10405-DQB10401 haplotype is associated with autoimmune pancreatitis in the Japanese population. Gastroenterology. 2002;122:1264–9.

    Article  PubMed  Google Scholar 

  5. Umemura T, Ota M, Hamano H, Katsuyama Y, Kiyosawa K, Kawa S. Genetic association of Fc receptor-like 3 polymorphisms with autoimmune pancreatitis in Japanese patients. Gut. 2006;55:1367–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Umemura T, Ota M, Hamano H, Katsuyama Y, Muraki T, Arakura N, et al. Association of autoimmune pancreatitis with cytotoxic T-lymphocyte antigen 4 gene polymorphisms in Japanese patients. Am J Gastroenterol. 2008;103:588–94.

    Article  CAS  PubMed  Google Scholar 

  7. Ota M, Ito T, Umemura T, Katsuyama Y, Yoshizawa K, Hamano H, et al. Polymorphism in the KCNA3 gene is associated with susceptibility to autoimmune pancreatitis in the Japanese population. Dis Markers. 2011;31:223–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Terao C, Ota M, Shiokawa M, Kuriyama K, Kodama Y, Uchida K, et al. OP0238 Fcgr2b and multiple HLA loci are associated with susceptibility to IGG4-related disease. Ann Rheum Dis. 2016;75:148.

    Article  Google Scholar 

  9. Buechter M, Manka P, Heinemann FM, Lindemann M, Juntermanns B, Canbay A, et al. Outcome and genetic factors in IgG4-associated autoimmune pancreatitis and cholangitis: a single center experience. Gastroenterol Res Pract. 2017;2017:6126707.

    Article  PubMed  PubMed Central  Google Scholar 

  10. Wallace ZS, Wallace CJ, Lu N, Choi HK, Stone JH. Association of IgG4-related disease with history of malignancy. Arthritis Rheumatol. 2016;68:2283–9.

    Article  CAS  PubMed  Google Scholar 

  11. de Buy Wenniger LJ, Culver EL, Beuers U. Exposure to occupational antigens might predispose to IgG4-related disease. Hepatology. 2014;60:1453–4.

    Article  PubMed  PubMed Central  Google Scholar 

  12. Goldoni M, Bonini S, Urban ML, Palmisano A, De Palma G, Galletti E, et al. Asbestos and smoking as risk factors for idiopathic retroperitoneal fibrosis: a case–control study. Ann Intern Med. 2014;161:181–8.

    Article  PubMed  Google Scholar 

  13. Culver EL, Vermeulen E, Makuch M, van Leeuwen A, Sadler R, Cargill T, et al. Increased IgG4 responses to multiple food and animal antigens indicate a polyclonal expansion and differentiation of pre-existing B cells in IgG4-related disease. Ann Rheum Dis. 2015;74:944–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Hubers LM, Vos H, Schuurman AR, et al. Annexin A11 is targeted by IgG4 and IgG1 autoantibodies in IgG4-related disease. Gut. 2017. https://doi.org/10.1136/gutjnl-2017-314548.

    PubMed  Google Scholar 

  15. van der Neut Kolfschoten M, Schuurman J, Losen M, Bleeker WK, Martínez-Martínez P, Vermeulen E, et al. Anti-inflammatory activity of human IgG4 antibodies by dynamic Fab arm exchange. Science. 2007;317:1554–7.

    Article  Google Scholar 

  16. Trampert DC, Hubers LM, van de Graaf SFJ, Beuers U. On the role of IgG4 in inflammatory conditions: lessons for IgG4-related disease. Biochim Biophys Acta. 2017. https://doi.org/10.1016/j.bbadis.2017.07.038.

    PubMed  Google Scholar 

  17. Shiokawa M, Kodama Y, Kuriyama K, Yoshimura K, Tomono T, Morita T, et al. Pathogenicity of IgG in patients with IgG4-related disease. Gut. 2016;65:1322–32.

    Article  CAS  PubMed  Google Scholar 

  18. Fukui Y, Uchida K, Sakaguchi Y, Fukui T, Nishio A, Shikata N, et al. Possible involvement of Toll-like receptor 7 in the development of type 1 autoimmune pancreatitis. J Gastroenterol. 2015;50:435–44.

    Article  CAS  PubMed  Google Scholar 

  19. Ohta M, Moriyama M, Maehara T, Gion Y, Furukawa S, Tanaka A, et al. DNA microarray analysis of submandibular glands in IgG4-related disease indicates a role for MARCO and other innate immune-related proteins. Medicine (Baltimore). 2016;95:e2853.

    Article  CAS  Google Scholar 

  20. Furukawa S, Moriyama M, Miyake K, Nakashima H, Tanaka A, Maehara T, et al. Interleukin-33 produced by M2 macrophages and other immune cells contributes to Th2 immune reaction of IgG4-related disease. Sci Rep. 2017;7:42413.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Furukawa S, Moriyama M, Tanaka A, Maehara T, Tsuboi H, Iizuka M, et al. Preferential M2 macrophages contribute to fibrosis in IgG4-related dacryoadenitis and sialoadenitis, so-called Mikulicz’s disease. Clin Immunol. 2015;156:9–18.

    Article  CAS  PubMed  Google Scholar 

  22. Tsuboi H, Nakai Y, Iizuka M, Asashima H, Hagiya C, Tsuzuki S, et al. DNA microarray analysis of labial salivary glands in IgG4-related disease: comparison with Sjögren’s syndrome. Arthritis Rheumatol. 2014;66:2892–9.

    Article  CAS  PubMed  Google Scholar 

  23. Akiyama M, Yasuoka H, Yoshimoto K, Takeuchi T. CC-chemokine ligand 18 is a useful biomarker associated with disease activity in IgG4-related disease. Ann Rheum Dis. 2017. https://doi.org/10.1136/annrheumdis-2017-212110.

    PubMed  Google Scholar 

  24. Tanaka A, Moriyama M, Nakashima H, Miyake K, Hayashida JN, Maehara T, et al. Th2 and regulatory immune reactions contribute to IgG4 production and the initiation of Mikulicz disease. Arthritis Rheum. 2012;64:254–63.

    Article  CAS  PubMed  Google Scholar 

  25. Akiyama M, Suzuki K, Kassai Y, Miyazaki T, Morita R, Yoshimura A, et al. Resolution of elevated circulating regulatory T cells by corticosteroids in patients with IgG4-related dacryoadenitis and sialoadenitis. Int J Rheum Dis. 2016;19:430–2.

    Article  PubMed  Google Scholar 

  26. Akiyama M. The call for considering follicular helper T cells in IgG4-related disease. J Allergy Clin Immunol. 2018. https://doi.org/10.1016/j.jaci.2017.11.017.

    Google Scholar 

  27. Akiyama M, Suzuki K, Yasuoka H, Kaneko Y, Yamaoka K, Takeuchi T. Follicular helper T cells in the pathogenesis of IgG4-related disease. Rheumatology (Oxford). 2018;57:236–45.

    Article  Google Scholar 

  28. Mattoo H, Mahajan VS, Della-Torre E, Sekigami Y, Carruthers M, Wallace ZS, et al. De novo oligoclonal expansions of circulating plasmablasts in active and relapsing IgG4-related disease. J Allergy Clin Immunol. 2014;134:679–87.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Doorenspleet ME, Hubers LM, Culver EL, de Buy Maillette, Wenniger LJ, Klarenbeek PL, Chapman RW, et al. Immunoglobulin G4(+) B-cell receptor clones distinguish immunoglobulin G 4-related disease from primary sclerosing cholangitis and biliary/pancreatic malignancies. Hepatology. 2016;64:501–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Akiyama M, Suzuki K, Yamaoka K, Yasuoka H, Takeshita M, Kaneko Y, et al. Number of circulating follicular helper 2 T cells correlates with IgG4 and interleukin-4 levels and plasmablast numbers in IgG4-related disease. Arthritis Rheumatol. 2015;67:2476–81.

    Article  CAS  PubMed  Google Scholar 

  31. Akiyama M, Kaneko Y, Yamaoka K, Hayashi Y, Yasuoka H, Suzuki K, et al. Subclinical labial salivary gland involvement in IgG4-related disease affected with vital organs. Clin Exp Rheumatol. 2015;33:949–50.

    CAS  PubMed  Google Scholar 

  32. Akiyama M, Yasuoka H, Yamaoka K, Suzuki K, Kaneko Y, Kondo H, et al. Enhanced IgG4 production by follicular helper 2 T cells and the involvement of follicular helper 1 T cells in the pathogenesis of IgG4-related disease. Arthritis Res Ther. 2016;18:167.

    Article  PubMed  PubMed Central  Google Scholar 

  33. Maehara T, Moriyama M, Nakashima H, Miyake K, Hayashida JN, Tanaka A, et al. Interleukin-21 contributes to germinal centre formation and immunoglobulin G4 production in IgG4-related dacryoadenitis and sialoadenitis, so-called Mikulicz’s disease. Ann Rheum Dis. 2012;71:2011–9.

    Article  CAS  PubMed  Google Scholar 

  34. Akiyama M, Yasuoka H, Yoshimoto K, Takeuchi T. FRI0361 Interleukin-4 induces class-switching to IGG4 and synergistically contributes to plasmablasts differentiation with interleukin-21 through CD40 dependent manner in IGG4-related disease. Ann Rheum Dis. 2017;76(Suppl. 2):623. https://doi.org/10.1136/annrheumdis-2017-eular.3040.

    Google Scholar 

  35. Grados A, Ebbo M, Piperoglou C, Groh M, Regent A, Samson M, et al. T cell polarization toward TH2/TFH2 and TH17/TFH17 in patients with IgG4-related disease. Front Immunol. 2017;8:235.

    Article  PubMed  PubMed Central  Google Scholar 

  36. Akiyama M, Kaneko Y, Hayashi Y, Takeuchi T. IgG4-related disease involving vital organs diagnosed with lip biopsy: a case report and literature review. Medicine (Baltimore). 2016;95:e3970.

    Article  Google Scholar 

  37. Yajima H, Yamamoto M, Shimizu Y, Sakurai N, Suzuki C, Naishiro Y, et al. Loss of interleukin-21 leads to atrophic germinal centers in multicentric Castleman’s disease. Ann Hematol. 2016;95:35–40.

    Article  CAS  PubMed  Google Scholar 

  38. Kamekura R, Takano K, Yamamoto M, Kawata K, Shigehara K, Jitsukawa S, et al. Cutting edge: a critical role of lesional T follicular helper cells in the pathogenesis of IgG4-related disease. J Immunol. 2017;199:2624–9.

    Article  CAS  PubMed  Google Scholar 

  39. Yang H, Wei R, Liu Q, Shi Y, Li J. Frequency and distribution of CD4+CXCR5+ follicular B helper T cells within involved tissues in IgG4-related ophthalmic disease. Mol Med Rep. 2017;16:9512–20.

    Article  PubMed  PubMed Central  Google Scholar 

  40. Maehara T. IgG4-related disease: mechanistic insights from both clinical and immunologic understanding of this condition. Nihon Rinsho Meneki Gakkai Kaishi. 2017;40:206–12.

    Article  PubMed  Google Scholar 

  41. Kubo S, Nakayamada S, Zhao J, Yoshikawa M, Miyazaki Y, Nawata A, et al. Correlation of T follicular helper cells and plasmablasts with the development of organ involvement in patients with IgG4-related disease. Rheumatology (Oxford). 2018;57(3):514–24.

    Article  Google Scholar 

  42. Mattoo H, Mahajan VS, Maehara T, Deshpande V, Della-Torre E, Wallace ZS, et al. Clonal expansion of CD4(+) cytotoxic T lymphocytes in patients with IgG4-related disease. J Allergy Clin Immunol. 2016;138:825–38.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Shimizu Y, Yamamoto M, Naishiro Y, Sudoh G, Ishigami K, Yajima H, et al. Necessity of early intervention for IgG4-related disease–delayed treatment induces fibrosis progression. Rheumatology (Oxford). 2013;52:679–83.

    Article  CAS  Google Scholar 

  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. 2015;74:190–5.

    Article  CAS  PubMed  Google Scholar 

  45. Lin W, Zhang P, Chen H, Chen Y, Yang H, Zheng W, et al. Circulating plasmablasts/plasma cells: a potential biomarker for IgG4-related disease. Arthritis Res Ther. 2017;19:25.

    Article  PubMed  PubMed Central  Google Scholar 

  46. Akiyama M, Sasaki T, Kaneko Y, Yasuoka H, Suzuki K, Yamaoka K, Takeuchi T. Serum soluble interleukin-2 receptor is a useful biomarker for disease activity but not for differential diagnosis in IgG4-related disease and primary Sjögren’s syndrome adults from a defined population. Clin Exp Rheumatol. 2018 (Epub ahead of print])

  47. Saeki T, Nishi S, Imai N, Ito T, Yamazaki H, Kawano M, et al. Clinicopathological characteristics of patients with IgG4-related tubulointerstitial nephritis. Kidney Int. 2010;78:1016–23.

    Article  CAS  PubMed  Google Scholar 

  48. Nakatsuka Y, Handa T, Nakamoto Y, Nobashi T, Yoshihuji H, Tanizawa K, et al. Total lesion glycolysis as an IgG4-related disease activity marker. Mod Rheumatol. 2015;25:579–84.

    Article  CAS  PubMed  Google Scholar 

  49. Ebbo M, Grados A, Guedj E, Gobert D, Colavolpe C, Zaidan 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. 2014;66:86–96.

    Article  CAS  Google Scholar 

  50. Umehara H, Okazaki K, Masaki Y, Kawano M, Yamamoto M, Saeki T, et al. Comprehensive diagnostic criteria for IgG4-related disease (IgG4-RD), 2011. Mod Rheumatol. 2012;22:21–30.

    Article  CAS  PubMed  Google Scholar 

  51. Umehara H, Okazaki K, Kawano M, Mimori T, Chiba T. How to diagnose IgG4-related disease. Ann Rheum Dis. 2017;76:e46.

    Article  PubMed  Google Scholar 

  52. Umehara H, Okazaki K, Nakamura T, Satoh-Nakamura T, Nakajima A, Kawano M, et al. Current approach to the diagnosis of IgG4-related disease: combination of comprehensive diagnostic and organ-specific criteria. Mod Rheumatol. 2017;27:381–91.

    Article  CAS  PubMed  Google Scholar 

  53. Anan R, Akiyama M, Kaneko Y, Kikuchi J, Suzuki K, Matsubara S, et al. Polymyositis with elevated serum IgG4 levels and abundant IgG4+ plasma cell infiltration: a case report and literature review. Medicine. 2017;96:e8710.

    Article  PubMed  PubMed Central  Google Scholar 

  54. Chang SY, Keogh KA, Lewis JE, Ryu JH, Cornell LD, Garrity JA, et al. IgG4-positive plasma cells in granulomatosis with polyangiitis (Wegener’s): a clinicopathologic and immunohistochemical study on 43 granulomatosis with polyangiitis and 20 control cases. Hum Pathol. 2013;44:2432–7.

    Article  CAS  PubMed  Google Scholar 

  55. Danlos FX, Rossi GM, Blockmans D, Emmi G, Kronbichler A, Durupt S, et al. Antineutrophil cytoplasmic antibody-associated vasculitides and IgG4-related disease: a new overlap syndrome. Autoimmun Rev. 2017;16:1036–43.

    Article  CAS  PubMed  Google Scholar 

  56. Sasaki T, Akiyama M, Kaneko Y, Mori T, Yasuoka H, Suzuki K, et al. Distinct features distinguishing IgG4-related disease from multicentric Castleman’s disease. RMD Open. 2017;3:e000432.

    Article  PubMed  PubMed Central  Google Scholar 

  57. de Roux-Serratrice C, Serratrice J, Granel B, Disdier P, Bartoli JM, Pache X, et al. Periaortitis heralding Wegener’s granulomatosis. J Rheumatol. 2002;29:392–4.

    Google Scholar 

  58. Nakabayashi K, Kamiya Y, Nagasawa T. Aortitis syndrome associated with positive perinuclear antineutrophil cytoplasmic antibody: report of three cases. Int J Cardiol. 2000;75(Suppl. 1):S89–94.

    Article  PubMed  Google Scholar 

  59. Blockmans D, Baeyens H, Van Loon R, Lauwers G, Bobbaers H. Periaortitis and aortic dissection due to Wegener’s granulomatosis. Clin Rheumatol. 2000;19:161–4.

    Article  CAS  PubMed  Google Scholar 

  60. Bijlsma WR, Hené RJ, Mourits MP, Kalmann R. Orbital mass as manifestation of Wegener’s granulomatosis: an ophthalmologic diagnostic approach. Clin Exp Rheumatol. 2011;29(1 Suppl. 64):S35–9.

    PubMed  Google Scholar 

  61. Nishimoto N, Kanakura Y, Aozasa K, Johkoh T, Nakamura M, Nakano S, et al. Humanized anti-interleukin-6 receptor antibody treatment of multicentric Castleman disease. Blood. 2005;106:2627–32.

    Article  CAS  PubMed  Google Scholar 

  62. Akiyama M, Yasuoka H, Takeuchi T. Interleukin-6 in idiopathic multicentric Castleman’s disease after long-term tocilizumab. Ann Hematol. 2017;96:2117–9.

    Article  CAS  PubMed  Google Scholar 

  63. Khosroshahi A, Wallace ZS, Crowe JL, Akamizu T, Azumi A, Carruthers MN, et al. International consensus guidance statement on the management and treatment of IgG4-related disease. Arthritis Rheumatol. 2015;67:1688–99.

    Article  CAS  PubMed  Google Scholar 

  64. Masaki Y, Matsui S, Saeki T, Tsuboi H, Hirata S, Izumi Y, et al. A multicenter phase II prospective clinical trial of glucocorticoid for patients with untreated IgG4-related disease. Mod Rheumatol. 2017;27:849–54.

    Article  CAS  PubMed  Google Scholar 

  65. Wu Q, Chang J, Chen H, Chen Y, Yang H, Fei Y, et al. Efficacy between high and medium doses of glucocorticoid therapy in remission induction of IgG4-related diseases: a preliminary randomized controlled trial. Int J Rheum Dis. 2017;20:639–46.

    Article  CAS  PubMed  Google Scholar 

  66. Masamune A, Nishimori I, Kikuta K, Tsuji I, Mizuno N, Iiyama T, et al. Randomised controlled trial of long-term maintenance corticosteroid therapy in patients with autoimmune pancreatitis. Gut. 2017;66:487–94.

    Article  CAS  PubMed  Google Scholar 

  67. Yamamoto M, Yajima H, Takahashi H, Yokoyama Y, Ishigami K, Shimizu Y, et al. Everyday clinical practice in IgG4-related dacryoadenitis and/or sialadenitis: results from the SMART database. Mod Rheumatol. 2015;25:199–204.

    Article  CAS  PubMed  Google Scholar 

  68. Yunyun F, Yu C, Panpan Z, Hua C, Di W, Lidan Z, et al. Efficacy of cyclophosphamide treatment for immunoglobulin G4-related disease with addition of glucocorticoids. Sci Rep. 2017;7:6195.

    Article  PubMed  PubMed Central  Google Scholar 

  69. Della-Torre E, Campochiaro C, Bozzolo EP, Dagna L, Scotti R, Nicoletti R, et al. Methotrexate for maintenance of remission in IgG4-related disease. Rheumatology (Oxford). 2015;54:1934–6.

    Article  Google Scholar 

  70. Wang Y, Li K, Gao D, Luo G, Zhao Y, Wang X, et al. Combination therapy of leflunomide and glucocorticoids for the maintenance of remission in patients with IgG4-related disease: a retrospective study and literature review. Intern Med J. 2017;47:680–9.

    Article  CAS  PubMed  Google Scholar 

  71. Hart PA, Topazian MD, Witzig TE, Clain JE, Gleeson FC, Klebig RR, et al. Treatment of relapsing autoimmune pancreatitis with immunomodulators and rituximab: the Mayo Clinic experience. Gut. 2013;62:1607–15.

    Article  CAS  PubMed  Google Scholar 

  72. Buechter M, Klein CG, Kloeters C, Schlaak JF, Canbay A, Gerken G, et al. Tacrolimus as a reasonable alternative in a patient with steroid-dependent and thiopurine-refractory autoimmune pancreatitis with IgG4-associated cholangitis. Z Gastroenterol. 2014;52:564–8.

    Article  CAS  PubMed  Google Scholar 

  73. Carruthers MN, Topazian MD, Khosroshahi A, Witzig TE, Wallace ZS, Hart PA, et al. Rituximab for IgG4-related disease: a prospective, open-label trial. Ann Rheum Dis. 2015;74:1171–7.

    Article  CAS  PubMed  Google Scholar 

  74. Ebbo M, Grados A, Samson M, Groh M, Loundou A, Rigolet A, 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. 2017;12:e0183844.

    Article  PubMed  PubMed Central  Google Scholar 

  75. Stone JH, Wallace ZS, Perugino CA, Fernandes AD, Patel P, Foster PA, Zack DJ. Final results of an open label phase 2 study of a reversible B cell inhibitor, Xmab®5871, in IgG4-related disease [abstract]. Arthritis Rheumatol. 2017;69(Suppl. 10).

  76. Carvajal Alegria G, Pochard P, Pers JO, Cornec D. Could abatacept directly target expanded plasmablasts in IgG4-related disease? Ann Rheum Dis. 2016;75:e73.

    Article  PubMed  Google Scholar 

  77. Yamamoto M, Takahashi H, Takano K, Shimizu Y, Sakurai N, Suzuki C, et al. Efficacy of abatacept for IgG4-related disease over 8 months. Ann Rheum Dis. 2016;75:1576–8.

    Article  PubMed  Google Scholar 

  78. Sasaki T, Akiyama M, Kaneko Y, et al. Risk factors for disease relapse in IGG4-related disease following glucocorticoids treatment. Ann Rheum Dis. 2017;76:712–3.

    Article  Google Scholar 

  79. Wallace ZS, Wallace CJ, Lu N, Choi HK, Stone JH. Association of IgG4-related disease with history of malignancy. Arthritis Rheumatol. 2016;68:2283–9.

    Article  CAS  PubMed  Google Scholar 

  80. Asano J, Watanabe T, Oguchi T, Kanai K, Maruyama M, Ito T, et al. Association between immunoglobulin G4-related disease and malignancy within 12 years after diagnosis: an analysis after longterm followup. J Rheumatol. 2015;42:2135–42.

    Article  CAS  PubMed  Google Scholar 

  81. Nishida K, Sogabe Y, Makihara A, Senoo A, Morimoto H, Takeuchi M, et al. Ocular adnexal marginal zone lymphoma arising in a patient with IgG4-related ophthalmic disease. Mod Rheumatol. 2016 (Epub ahead of print).

  82. Cheuk W, Yuen HK, Chan AC, Shih LY, Kuo TT, Ma MW, et al. Ocular adnexal lymphoma associated with IgG4+ chronic sclerosing dacryoadenitis: a previously undescribed complication of IgG4-related sclerosing disease. Am J Surg Pathol. 2008;32:1159–67.

    Article  PubMed  Google Scholar 

  83. Akiyama M. Regarding, “Upregulated interleukins (IL-6, IL-10, and IL-13) in immunoglobulin G4-related aortic aneurysm patients”. J Vasc Surg. 2017;66:1919.

    Article  PubMed  Google Scholar 

  84. Akiyama M. Trial of tocilizumab in giant-cell arteritis. N Engl J Med. 2017;377:1493–4.

    Article  PubMed  Google Scholar 

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  1. Division of Rheumatology, Department of Internal Medicine, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, Japan

    Mitsuhiro Akiyama & Tsutomu Takeuchi

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Mitsuhiro Akiyama has received consulting fees, speaking fees, and honoraria from Asahi Kasei Co., Cure Grades Co., and Eisai Co., Ltd, and a research grant from Mitsubishi Tanabe Pharma Co and Keio Medical Association. Tsutomu Takeuchi has received consulting fees, speaking fees and/or honoraria from Pfizer Japan, Mitsubishi Tanabe Pharma, Eisai, Astellas Pharma, and UCB (less than $10,000 each) and Chugai Pharmaceutical, Bristol-Myers K.K., Daiichi Sankyo, AbbVie, Janssen Pharmaceutical K.K., Pfizer Japan, Asahi Kasei Pharma, Takeda Pharmaceutical, AstraZeneca K.K., Eli Lilly Japan K.K., and Novartis Pharma K.K. (more than $10,000 each).

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Akiyama, M., Takeuchi, T. IgG4-Related Disease: Beyond Glucocorticoids. Drugs Aging 35, 275–287 (2018). https://doi.org/10.1007/s40266-018-0534-6

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