Skip to main content
SpringerLink
Log in

Inflammatory features, including symptoms, increased serum interleukin-6, and C-reactive protein, in IgG4-related vascular diseases

  • Original Article
  • Published:
Heart and Vessels Aims and scope Submit manuscript

Abstract

Immunoglobulin (IgG) 4-related diseases (IgG4-RDs) are fibro-inflammatory conditions characterized by tumorous swelling and serum IgG4 levels. Intrapelvic IgG4-RD has been subclassified according to the localization site and aortic shape as IgG4-related aortic aneurysms (IgG4-AAs), periaortitis (IgG4-PA), and retroperitoneal fibrosis (IgG4-RF). The IgG4-AA pathogenesis would involve interleukin (IL)-6 upregulation, and Th2-predominant and Treg-activated immune conditions. We characterized the features of intrapelvic IgG4-RD lesions, including presence of vascular lesions. The clinical, serological, and pathological features, including cytokines concerning Th1/2 and Treg (IL-4, IL-6, IL-10, IL-13, and interferon-gamma) of patients with IgG4-AAs (n = 24), IgG4-PA (n = 8), and IgG4-RF (n = 10) were retrospectively compared. Clinical symptoms, such as low-grade fever, abdominal/lumber pain, and anemia, were frequently detected in IgG4-AAs but rarely in IgG4-RF. Serum IL-6 and C-reactive protein (CRP) were significantly higher in IgG4-AAs and IgG4-PA than in IgG4-RF. Pathologically, IL-6+ cells were more frequently detected in IgG4-PA and IgG4-AAs than in IgG4-RF. There were no noteworthy differences in the clinical complications, white blood cell counts, serum IgE, and serum and immunopositive cells of other cytokines between the subgroups. Among IgG4-AAs and IgG4-PA, serum IL-6 and IL-6+ cells correlated with CRP, aortic diameter, and periaortic fibrosis. IgG4-AA and IgG4-PA, but not IgG4-RF, were characterized by “inflammatory” features, such as increased CRP and serum/pathological IL-6, and clinical inflammatory symptoms; thus, IgG4-AA and IgG4-PA belong to the same group as IgG4-related vascular disease. High levels of CRP and IL-6 would be hallmarks of IgG4-related vascular disease.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  1. Ormond JK (1948) Bilateral ureteral obstruction due to envelopment and compression by inflammatory process. J Urol 59:1072–1079

    Article  CAS  Google Scholar 

  2. Vaglio A, Salvarani C, Buzio C (2006) Retroperitoneal fibrosis. Lancet 367(9506):241–251

    Article  Google Scholar 

  3. Walker DI, Bloor K, Williams G, Gillie I (1972) Inflammatory aneurysm of the abdominal aorta. Br J Surg 59(8):609–614

    Article  CAS  Google Scholar 

  4. Mitchinson MJ (1984) Chronic periaortitis and periarteritis. Histopathology 8(4):589–600

    Article  CAS  Google Scholar 

  5. Inoue D, Zen Y, Abo H, Gabata T, Demachi H, Yoshikawa J, Miyayama S, Nakanuma Y, Matsui O (2011) Immunoglobulin G4-related periaortitis and periarteritis: CT findings in 17 patients. Radiology 261(2):625–633

    Article  Google Scholar 

  6. Vaglio A, Greco P, Gerradi D (2006) Autoimmune aspects of chronic periaortitis. Autoimmune Rev 5(7):458–464

    Article  Google Scholar 

  7. Runowska M, Majewski D, Puszczewicz M (2016) Retroperitoneal fibrosis—the state-of-the-art. Reumatologia 54(5):256–263

    Article  Google Scholar 

  8. Perungino CO, Wallance ZS, Meyersohn N, Oliveria G, Stone JR, Stone JH (2016) Large vessel involvement by IgG4-related disease. Medicine (Baltimore) 95(28):e3344

    Article  Google Scholar 

  9. Zen Y, Onodera M, Inoue D, Kitao A, Matsui O, Nohara T, Namiki M, Kasashima S, Kawashima A, Matsumoto Y, Katayanagi K, Murata T, Ishizawa S, Hosaka N, Kuriki K, Nakanuma Y (2009) Retroperitoneal fibrosis: a clinicopathologic study with respect to immunoglobulin G4. Am J Surg Pathol 33(12):1833–1839

    Article  Google Scholar 

  10. Kasashima S, Zen Y (2011) IgG4-related inflammatory abdominal aortic aneurysm. Curr Opin Rhumatol 23(1):18–23

    Article  CAS  Google Scholar 

  11. Stone JH, Zen Y, Deshpande V (2012) IgG4-related disease. N Engl J Med 366:539–551

    Article  CAS  Google Scholar 

  12. Inoue D, Yoshida K, Yoneda N, Ozaki K, Matsubara T, Nagai K, Okumura K, Toshima F, Toyama J, Minami T, Matsui O, Gabata T, Zen Y (2015) IgG4-related disease: Dataset of 235 consecutive patients. Medicine 94(15):e680

    Article  CAS  Google Scholar 

  13. Ozawa M, Fujinaga Y, Asano J, Nakamura A, Watanabe T, Ito T, Muraki T, Hamano H, Kawa S (2017) Clinical features of IgG4-related perioartitis/periarteritis based on the analysis of 179 patients with IgG4-relatded disease; a case–control study. Arthritis Res Ther 19(1):223

    Article  Google Scholar 

  14. Mizushima I, Inoue D, Yamamoto M, Yamada K, Saeki T, Ubara Y, Matsui S, Masaki Y, Wada T, Kasashima S, Harada K, Takahashi H, Notohara K, Nakanuma Y, Umehara H, Yamagishi M, Kawano M (2014) Clinical course after corticosteroid therapy in IgG4-related aortitis/periaortitis and periarteritis: a retrospective multicenter study. Arthritis Res Ther 16(4):R156

    Article  Google Scholar 

  15. Sneed TB, Stanley DJ, Young LA, Sanderson RD (1994) Interleukin-6 regulates expression of syndecan-1 proteoglycan on B lymphoid cells. Cell Immunol 153(2):456–467

    Article  CAS  Google Scholar 

  16. Kasashima S, Kawashima A, Zen Y, Ozaki S, Kasashima F, Endo M, Matsumoto Y, Kawakami K (2017) Upregulated interleukins (IL-6, IL-10, and IL-13) in immunoglobulin G4-related aortic aneurysm patients. J Vasc Surg. https://doi.org/10.1016/j.jvs.2016.12.140

    Article  PubMed  Google Scholar 

  17. Deshpande V, Zen Y, Chan JK, Yi EE, Sato Y, Yoshino T, Klöppel G, Heathcote JG, Khosroshahi A, Ferry JA, Aalberse RC, Bloch DB, Brugge WR, Bateman AC, Carruthers MN, Chari ST, Cheuk W, Cornell LD, Fernandez-Del Castillo C, Forcione DG, Hamilos DL, Kamisawa T, Kasashima S, Kawa S, Kawano M, Lauwers GY, Masaki Y, Nakanuma Y, Notohara K, Okazaki K, Ryu JK, Saeki T, Sahani DV, Smyrk TC, Stone JR, Takahira M, Webster GJ, Yamamoto M, Zamboni G, Umehara H, Stone JH (2012) Consensus statement on the pathology of IgG4-related disease. Consensus statement on the pathology of IgG4-related disease. Mod Pathol 25(90):1181–1192

    Article  Google Scholar 

  18. Shimosegawa T (2012) The amendment of the clinical diagnostic criteria in Japan (JPS2011) in response to the proposal of the international consensus of diagnostic criteria (ICDC) for autoimmune pancreatitis. Pancreas 41(8):1341–1342

    Article  Google Scholar 

  19. JCS Joint Working Group (2013) Guidelines for diagnosis and treatment of aortic aneurysm and aortic dissection (JCS 2011): digest version. Circ J 77(3):789–823

    Article  Google Scholar 

  20. Palmisano A, Urban ML, Corradi D, Cobelli R, Alberici F, Maritati F, Versari A, Pipitone N, Salvarani C, Buzio C, Vaglio A (2015) Chronic periaortitis with thoracic aorta and epiaortic artery involvement: a systemic large vessel vasculitis? Rheumatology 54(11):2004–2009

    Article  CAS  Google Scholar 

  21. Kasashima S, Kasashima F, Kawashima A, Endo M, Matsumoto Y, Kawakami K (2017) Clinical outcomes after endovascular repair and open surgery to treat Immunoglobulin G4-related and nonrelated inflammatory abdominal aortic aneurysms. J Endovasc Ther 24(6):833–845

    Article  Google Scholar 

  22. Yamamoto H, Sugiyama E, Serikawa M, Tatsugami F, Yokozaki M, Kitagawa T, Senoo A, Nakamoto YK, Awai K, Chayama K, Kihara Y (2017) Clinical features and predictive value of serum inflammatory markers of perivascular involvement in immunoglobulin G4-related disease. Heart Vessels 32(10):1176–1185

    Article  Google Scholar 

  23. Nishimoto N, Sasai M, Shima Y, Nakagawa M, Matsumoto T, Shirai T, Kishimoto T, Yoshizaki K (2000) Improvement in Castleman’s disease by humanized anti-interleukin-6 receptor antibody therapy. Blood 95(1):56–61

    CAS  PubMed  Google Scholar 

  24. Nishihara M, Aoki H, Ohno S, Furusho A, Hirakata S, Nishida N, Ito S, Hayashi M, Imaizumi T, Fukumoto Y (2017) The role of IL-6 in pathogenesis of abdominal aortic aneurysm in mice. PLoS One 12(10):e0185923

    Article  Google Scholar 

  25. Sato Y, Kojima M, Takata K, Morito T, Mizobuchi K, Tanaka T, Inoue D, Shiomi H, Iwao H, Yoshino T (2010) Multicentric Castleman’s disease with abundant IgG4-positive cells: a clinical and pathological analysis of six cases. J Clin Pathol 63(12):1084–1089

    Article  CAS  Google Scholar 

  26. Izumi Y, Takeshita H, Moriwaki Y, Hisatomi K, Matsuda M, Yamashita N, Kawahara C, Shigemitsu Y, Iwanaga N, Kawakami A, Kurohama H, Niino D, Ito M, Migita K (2017) Multicentric Castleman disease mimicking IgG4-related disease: a case report. Mod Rheumatol 27(1):174–177

    Article  Google Scholar 

  27. Takenaka K, Takada K, Kobayashi D, Moriguchi M, Harigai M, Miyasaka N (2011) A case of IgG4-related disease with features of Mikulicz’s disease, and retroperitoneal fibrosis and lymphadenopathy mimicking Castleman’s disease. Mod Rheumatol 21(4):410–414

    Article  Google Scholar 

  28. Nakamura M, Iwamoto O, Chino T, Todoroki K, Kusukawa J (2016) Diagnostic dilemma of IgG4-related primary localized cervical lymphadenopathy associated with aberrant IL-6 expression level. Diagn Pathol 11(1):43

    Article  Google Scholar 

  29. Ikeura T, Horitani S, Masuda M, Kasai T, Yanagawa M, Miyoshi H, Uchida K, Takaoka M, Miyasaka C, Uemura Y, Okazaki K (2016) IgG4-related disease involving multiple organs with elevated serum interleukin-6 levels. Intern Med 55(18):2623–2628

    Article  Google Scholar 

  30. Yamamoto M, Takahashi H, Hasebe K, Suzuki C, Naishiro Y, Hayashi T, Yamamoto H, Ishida T, Shinomura Y (2009) The analysis of Interleukin-6 in patients with systemic IgG4-related plasmacytic syndrome-expansion of SIPS to the territory of Castleman’s diseases. Rheumatology 48(7):860–862

    Article  CAS  Google Scholar 

  31. Thuermel K, Einspieler I, Wolfram S, Moog P, Meier R, Schwaiger M, Heemann U (2017) Disease activity and vascular involvement in retroperitoneal fibrosis: first experience with fully integrated 18F-fluorodeoxyglucose positron emission tomography/magnetic resonance imaging compared to clinical and laboratory parameters. Clin Exp Rheumatol 35(1):146–154

    PubMed  Google Scholar 

  32. Tajima M, Nagai R, Hiroi Y (2014) IgG4-related cardiovascular disorders. Int Heart J 55(4):287–295

    Article  CAS  Google Scholar 

  33. Kasashima S, Kawashima A, Kasashima F, Endo M, Matsumoto Y, Kawakami K, Kayahara M, Ohta H, Yano M, Marukawa Y (2014) Immunoglobulin G4-related periaortitis complicated by aortic rupture and aortoduodenal fistula after endovascular AAA repair. J Endovasc Ther 21(4):589–597

    Article  Google Scholar 

  34. Schulte S, Sukhova GK, Libby P (2008) Genetically programmed biases in Th1 and Th2 immune responses modulate atherogenesis. Am J Pathol 172(6):1500–1508

    Article  CAS  Google Scholar 

  35. Tieu BC, Lee C, Sun H, Lejeune W, Recinos A 3rd, Ju X, Spratt H, Guo DC, Milewicz D, Tilton RG, Brasier AR (2009) An adventitial IL-6/MCP1 amplification loop accelerates macrophage-mediated vascular inflammation leading to aortic dissection in mice. J Clin Invest 119:3637–3651

    Article  CAS  Google Scholar 

  36. Mitchinson MJ (1970) The pathology of idiopathic retroperitoneal fibrosis. J Clin Pathol 23(8):681–689

    Article  CAS  Google Scholar 

  37. Parums DV, Mitchinson MJ (1981) Demonstration of immunoglobulin in the neighborhood of advanced atherosclerotic plaque. Atherosclerosis 38(1–2):211–216

    Article  CAS  Google Scholar 

  38. Van Bommel EF, van Tits LJ, van den Berg EA, Prins J, Stalenhoef AF (2011) Autoantibodies against oxidized low-density lipoprotein and lipid profile in patients with chronic periaortitis: case–control study. Rheumatol Int 31(1–2):201–208

    Article  Google Scholar 

  39. Castelein T, Coudyzer W, Blockmans D (2015) IgG4-related periaortitis vs idiopathic periaortitis: in there a role for atherosclerotic plaque in the pathogenesis of IgG4-related periaortitis? Rheumatology 54(7):1250–1256

    Article  CAS  Google Scholar 

  40. Siddiquee Z, Smith RN, Stone JR (2015) An elevated IgG4 response in chronic infectious aortitis is associated with aortic atherosclerosis. Mod Pathol 28(11):1228–1233

    Article  Google Scholar 

  41. Weyand CM, Goronzy JJ (2013) Immune mechanisms in medium and large-vessel vasculitis. Nat Rev Rheumatol 9(12):731–740

    Article  CAS  Google Scholar 

  42. Unizony S, Stone JH, Stone JR (2013) New treatment strategies in large-vessel vasculitis. Curr Opin Rheumatol 25(1):3–9

    Article  CAS  Google Scholar 

  43. Vaglio A, Catanoso MG, Spaggiari L, Magnani L, Pipitone N, Macchioni P, Pulsatelli L, Nicastro M, Becchi G, Corradi D, Versari A, Boiardi L, Salvarani C (2013) Interleukin-6 as an inflammatory mediator and target of therapy in chronic periaortitis. Arthritis Rheum 65(9):2469–2475

    Article  CAS  Google Scholar 

  44. Ohta N, Makihara S, Okano M, Kurakami K, Ishida A, Furukawa T, Suzuki Y, Watanabe T, Kakehata S, Aoyagi M (2012) Roles of IL-17, Th1, and Tc1 cells in patients with IgG4-related sclerosing sialadenitis. Laryngoscope 122(10):2169–2174

    Article  CAS  Google Scholar 

  45. Ikeda A, Mitomi K, Konishi T, Matsuzaki K, Jikuya T, Hiramitsu Y (2015) Endovascular repair of a false aneurysm developing from IgG4-related periaortitis during corticosteroid therapy. Ann Vasc Surg 29(7):1452.e5–9

    Article  Google Scholar 

Download references

Acknowledgements

The authors would like to thank sincerely Mr. Yutaka Yamagishi, Ms. Mihoko Mizuno, Mr. Katsumasa Ishida, Ms. Aiko Matsuda, Ms. Youko Umehara, Mr. Keisuke Yonebayashi, and Mr. Rei Kasashima for their special technical assistance.

Funding

This work was supported by Grant-in AUC for Scientific Research (C) (JSPS KAKENHI) Grant number 26462119.

Author information

Authors and Affiliations

  1. Department of Clinical Laboratory Science, Kanazawa University, 5-11-80 Kodatsuno, Kanazawa, 920-0942, Japan

    Satomi Kasashima

  2. Department of Pathology, National Hospital Organization, Kanazawa Medical Center, Kanazawa, Japan

    Satomi Kasashima & Atsuhiro Kawashima

  3. Department of Clinical Laboratory, National Hospital Organization, Kanazawa Medical Center, Kanazawa, Japan

    Satomi Kasashima & Atsuhiro Kawashima

  4. Department of Cardiovascular Surgery, National Hospital Organization, Kanazawa Medical Center, Kanazawa, Japan

    Fuminori Kasashima, Masamitsu Endo, Yasushi Matsumoto & Kengo Kawakami

Authors
  1. Satomi Kasashima
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Atsuhiro Kawashima
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Fuminori Kasashima
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Masamitsu Endo
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Yasushi Matsumoto
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Kengo Kawakami
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Satomi Kasashima.

Ethics declarations

Conflict of interest

The authors declare that they have no conflicts of interest.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Kasashima, S., Kawashima, A., Kasashima, F. et al. Inflammatory features, including symptoms, increased serum interleukin-6, and C-reactive protein, in IgG4-related vascular diseases. Heart Vessels 33, 1471–1481 (2018). https://doi.org/10.1007/s00380-018-1203-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00380-018-1203-8

Keywords

Search

Navigation