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 Table of Contents  
Year : 2022  |  Volume : 10  |  Issue : 1  |  Page : 78-80

Immunoglobulin G4-related ophthalmic disease and aortitis

1 Department of Geriatric Medicine, Hunter New England Health, New Lambton Heights, NSW, Australia
2 Hunter Imaging Group, Adamstown, NSW, Australia
3 School of Medicine and Public Health, University of Newcastle, Australia

Date of Submission03-Apr-2022
Date of Decision15-May-2022
Date of Acceptance18-May-2022
Date of Web Publication23-Jun-2022

Correspondence Address:
Dr. Mingshu Cai
Department of Geriatric Medicine, Hunter New England Health, 2 Lookout Road, New Lambton Heights, 2305, NSW
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/amhs.amhs_71_22

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Immunoglobulin G4-related disease (IgG4-RD) is an immune-mediated inflammatory condition which is a relatively new clinical entity that can have various clinical manifestations. Our understanding of its pathogenesis is rapidly evolving and many theories have been proposed. The determinants of clinical phenotypes in various populations remain unclear. We report a case of IgG4-RD involving the extraocular muscles and aorta in an elderly male who improved with oral prednisolone. We also provided an overview of the current literature on the disease.

Keywords: Aortitis, Immunoglobulin G4, Immunoglobulin G4-related ophthalmic disease

How to cite this article:
Cai M, Voutnis D, Nair BR. Immunoglobulin G4-related ophthalmic disease and aortitis. Arch Med Health Sci 2022;10:78-80

How to cite this URL:
Cai M, Voutnis D, Nair BR. Immunoglobulin G4-related ophthalmic disease and aortitis. Arch Med Health Sci [serial online] 2022 [cited 2023 Feb 9];10:78-80. Available from: https://www.amhsjournal.org/text.asp?2022/10/1/78/347975

  Introduction Top

Immunoglobulin G4-related disease (IgG4-RD) is an immune-mediated inflammatory condition that can affect various organs. The diagnosis can be challenging and we are only starting to gain insight into this complex disease. We report a case of IgG4-RD with concurrent involvement of the extraocular muscles and aorta which responded well to oral prednisolone.

  Case Report Top

An 83-year-old male of Chinese descent from Hong Kong was referred for a 4-month history of lethargy, fatigue, and decreased mobility on a background of Mikulicz syndrome (IgG4-RD involving the lacrimal and parotid glands) requiring multiple treatment courses with prednisolone. When seen in the clinic, in Australia, where he had been residing for a few years, he reported intermittent peri-orbital swelling. He did not complain of any cardiorespiratory symptoms. His past medical history was significant for mild asthma which required only salbutamol pro re nata. Clinical examination revealed restrictions in horizontal and vertical gaze without proptosis or peri-orbital swelling. There were no signs of hyperthyroidism. No aortic regurgitation was heard on auscultation. Abdominal examination did not reveal any hepatosplenomegaly and there was no palpable lymphadenopathy. He was not on prednisolone during this presentation.

Initial blood tests showed raised erythrocyte sedimentation rate (ESR 119 mm/h, normal: <30 mm/h) and immunoglobulin G (IgG 35.92 g/L, normal: 6.50–16.00 g/L), specifically in the IgG4 subclass (5.70 g/L, normal: 0.04–0.86 g/L). Full blood count was essentially normal. Antinuclear antibodies were negative (<1:80) and thyroid-stimulating hormone was within the reference range (3.6 mIU/L, normal: 0.5–4.0 mIU/L). Thyroid-stimulating immunoglobulin was undetectable (<0.01 IU/L). Syphilis serology was negative. Magnetic resonance imaging showed diffuse inflammation and enhancement of the extraocular muscles and infraorbital nerves as well as inflammatory change in the lacrimal glands [Figure 1].
Figure 1: Axial and sagittal views on magnetic resonance imaging which showed diffuse inflammation of the extraocular muscles

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Positron emission tomography (PET) demonstrated prominent linear fluorodeoxyglucose uptake in the aorta suggestive of aortitis and hypermetabolic lymphadenopathy at the left main bronchus [Figure 2].
Figure 2: Positron emission tomography pre and post treatment. (a) Initial scan which showed prominent linear fluorodeoxyglucose uptake in the aorta, (b) Three months posttreatment with prednisolone which showed improved generalised aortic wall activity

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There was also low avidity in the para-aortic lymph nodes. His imaging findings were discussed with the radiology team who felt that there was significant risk associated with biopsy of the lymph nodes, and therefore, histopathological confirmation was not pursued.

Treatment with 1 mg/kg of prednisolone daily was commenced and tapered as guided by clinical response.[1] Repeat blood tests a month later showed improvement in ESR (53 mm/h) and IgG (18.99 g/L). This improvement was sustained 3 months down the track whilst being maintained on prednisolone 10 mg daily. A repeat PET scan at that point in time also demonstrated radiological improvement with reduced activity in the aorta and lymph nodes.

  Discussion Top

IgG4-RD is a relatively new clinical entity which was proposed by Kamisawa et al., as a systemic disease that laid the foundation for better understanding into conditions such as Riedel's thyroiditis and Mikulicz syndrome which were initially thought to be separate disease entities,[2] now believed to be part of the same disease spectrum.[3],[4] Epidemiological studies are limited and the incidence of IgG4-RD has been estimated to be between 0.28 and 1.08 per 100,000 in the Japanese population.[5] It tends to affect middle aged men, with Asians more likely to develop head and neck disease in keeping with Mikulicz syndrome as well as systemic involvement.[6] Many factors have been implicated to explain the differences in disease manifestation between races, gender, young, and old.

Interaction between B- and T-lymphocytes appears to be central to the pathogenesis of IgG4-RD. Current theories focus on CD4+ cytotoxic T-lymphocytes (CTL) as the main driver of tissue damage through the release of molecules such as granzyme B, perforin, interferon gamma, interleukin 1 beta, and transforming growth factors which promote cell death and fibrosis.[7] These CD4 + CTL also express signalling lymphocytic activation molecule family member 7 which has been found to super-activate macrophages.[8] Follicular helper T-cells are also thought to play a role in B-cell proliferation in IgG4-RD, contributing to the fibrosis and increased IgG4 production.[9] More recently, T peripheral helper-like cells expressing CX3CR1 have been implicated in tissue destruction in IgG4-RD through secretion of cytotoxic molecules.[10] The exact role of IgG4 in the disease process has also been questioned as its molecular structure is believed to be weak in generating or sustaining immune activation.[11]

A genome-wide association study has also been conducted in Japan which identified the Fc fragment of IgG receptor IIb (FCGR2B) and human leukocyte antigen DR beta 1 as susceptibility loci that could underpin the genetic basis of IgG4-RD, although other genes have also been implicated in smaller studies.[12] The concept of inflamm-aging has also been proposed to possibly explain the clinical differences between the young and old as well as the response to treatment.[13]

More recently, there have been attempts to classify IgG4-RD based on clinical phenotypes.[6],[14] The exact mechanisms responsible for the differences in clinical manifestations remain unclear but genetic and environmental factors are believed to play a part.[6] In a study published by Wallace and colleagues looking at two international cross-sectional cohorts, concurrent involvement of the extraocular muscles and thoracic aorta is less common across the phenotypic groups.[6]

The American College of Rheumatology and European League Against Rheumatism have developed a classification criteria to serve as a framework for clinicians when encountering patients with potential IgG4-RD by taking into consideration the clinical, serological, radiological, and pathological findings.[15] It also helps to highlight other conditions which could mimic IgG4-RD. Some of the features which increase the likelihood of a patient having IgG4-RD include characteristic tissue or organ involvement, significantly raised IgG4 level and lymphoplasmacytic infiltration with fibrosis in a storiform pattern.[15]

Glucocorticoid remains the first-line treatment for IgG4-RD with a recommended daily dose of 30–40 mg to induce remission.[16] Rituximab has also demonstrated efficacy in remission induction.[17] Combination therapy with glucocorticoid and a steroid-sparing agent for initial treatment continues to be an area of debate. Monoclonal antibodies targeting different receptors and therefore attenuating the process of inflammation in the pathogenesis IgG4-RD have been scrutinized in recent years, but they remain in the early stages.[18],[19]

  Conclusion Top

Our patient highlights the diversity in which IgG4-related disease can manifest and the need for ongoing vigilance for case finding and research in this relatively new entity to improve our understanding of determinants of clinical phenotypes. It also shares our findings and experience in managing an elderly gentleman with concurrent aortic and ophthalmic disease who responded well to oral glucocorticoid treatment. It is important to consider potential mimics of IgG4-RD and adopt a holistic approach in the diagnostic workup.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form, the patient has given his consent for his images and other clinical information to be reported in the journal. The patient understands that his name and initials will not be published and due efforts will be made to conceal identity, but anonymity cannot be guaranteed.

Financial support and sponsorship


Conflicts of interest

There are no conflicts of interest.

  References Top

Kamisawa T, Zen Y, Pillai S, Stone JH. IgG4-related disease. Lancet 2015;385:1460-71.  Back to cited text no. 1
Kamisawa T, Funata N, Hayashi Y, Eishi Y, Koike M, Tsuruta K, et al. A new clinicopathological entity of IgG4-related autoimmune disease. J Gastroenterol 2003;38:982-4.  Back to cited text no. 2
Yamamoto M, Takahashi H, Ohara M, Suzuki C, Naishiro Y, Yamamoto H, et al. A new conceptualization for Mikulicz's disease as an IgG4-related plasmacytic disease. Mod Rheumatol 2006;16:335-40.  Back to cited text no. 3
Dahlgren M, Khosroshahi A, Nielsen GP, Deshpande V, Stone JH. Riedel's thyroiditis and multifocal fibrosclerosis are part of the IgG4-related systemic disease spectrum. Arthritis Care Res (Hoboken) 2010;62:1312-8.  Back to cited text no. 4
Umehara H, Okazaki K, Masaki Y, Kawano M, Yamamoto M, Saeki T, et al. A novel clinical entity, IgG4-related disease (IgG4RD): General concept and details. Mod Rheumatol 2012;22:1-14.  Back to cited text no. 5
Wallace ZS, Zhang Y, Perugino CA, Naden R, Choi HK, Stone JH, et al. Clinical phenotypes of IgG4-related disease: An analysis of two international cross-sectional cohorts. Ann Rheum Dis 2019;78:406-12.  Back to cited text no. 6
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.  Back to cited text no. 7
Simmons DP, Nguyen HN, Gomez-Rivas E, Jeong Y, Jonsson AH, Chen AF, et al. SLAMF7 engagement superactivates macrophages in acute and chronic inflammation. Science Immunology 2022;7:eabf2846.  Back to cited text no. 8
Chen Y, Lin W, Yang H, Wang M, Zhang P, Feng R, et al. Aberrant expansion and function of follicular helper T cell subsets in IgG4-related disease. Arthritis Rheumatol 2018;70:1853-65.  Back to cited text no. 9
Yabe H, Kamekura R, Yamamoto M, Murayama K, Kamiya S, Ikegami I, et al. Cytotoxic Tph-like cells are involved in persistent tissue damage in IgG4-related disease. Mod Rheumatol 2021;31:249-60.  Back to cited text no. 10
Della-Torre E, Lanzillotta M, Doglioni C. Immunology of IgG4-related disease. Clin Exp Immunol 2015;181:191-206.  Back to cited text no. 11
Terao C, Ota M, Iwasaki T, Shiokawa M, Kawaguchi S, Kuriyama K, et al. IgG4-related disease in the Japanese population: A genome-wide association study. Lancet Rheumatol 2019;1:e14-22.  Back to cited text no. 12
Yamamoto M, Takahashi H, Tanaka H. Differences in clinical features of immunoglobulin G4-related disease between older and younger patients. Geriatr Gerontol Int 2019;19:564-5.  Back to cited text no. 13
Niwamoto T, Handa T, Matsui S, Yamamoto H, Yoshifuji H, Abe H, et al. Phenotyping of IgG4-related diseases based on affected organ pattern: A multicenter cohort study using cluster analysis. Mod Rheumatol 2021;31:235-40.  Back to cited text no. 14
Wallace ZS, Naden RP, Chari S, Choi H, DellaDellahoi HDicaire JF, et al. The 2019 American College of Rheumatology/European League Against Rheumatism classification criteria for IgG4sm H, Della white mice follRheumatol 2020;72:7-19.  Back to cited text no. 15
Simpson RS, Lau SKC, Lee JK. Dupilumab as a novel steroid-sparing treatment for IgG4-related disease. Ann Rheum Dis 2020;79:549-50.  Back to cited text no. 16
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.  Back to cited text no. 17
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.  Back to cited text no. 18
Matza MA, Perugino CA, Harvey L, Fernandes AD, Wallace ZS, Liu H, et al. Abatacept in IgG4-related disease: A prospective, open-label, single-arm, single-centre, proof-of-concept study. Lancet Rheumatol 2022;4:e105-12.  Back to cited text no. 19


  [Figure 1], [Figure 2]


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