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 Table of Contents  
Year : 2020  |  Volume : 15  |  Issue : 3  |  Page : 229-233

An unusual presentation of IgG4-related disease

1 Department of Internal Medicine, Command Hospital, Pune, Maharashtra, India
2 Department of Rheumatology, Command Hospital, Pune, Maharashtra, India
3 Department of Pathology, Command Hospital, Pune, Maharashtra, India
4 Department of Otolaryngorhinology, Command Hospital, Pune, Maharashtra, India
5 Department of Nuclear Medicine, Command Hospital, Pune, Maharashtra, India
6 Department of Radiology, AFMC, Pune, Maharashtra, India

Date of Submission23-Jan-2020
Date of Acceptance08-May-2020
Date of Web Publication3-Sep-2020

Correspondence Address:
Dr. Hegde Arun
Department of Rheumatology, Command Hospital, Pune - 410 040, Maharashtra
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/injr.injr_12_20

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IgG4-related disease (IgG4-RD) is an emerging disease concept that was first recognized in the 21st century. It has since then been attracting substantial attention in many fields of medicine as it tends to involve either synchronously or metachronously, various organs, including the pancreas, bile duct, lacrimal gland, salivary gland, and many others. This umbrella diagnosis now successfully explains a substantial number of disorders, which were previously regarded as “idiopathic.” Reports of the manifestations of IgG4-RD in the head and neck are extremely rare. Otologic manifestations have been reported, but only a handful of cases are available in literature that have been confirmed by immunohistopathology. We, herein, present a case of IgG4-RD of the middle ear, which manifested as a growth in the left mastoid and middle ear cavity, and became symptomatic with symptoms of chronic otitis media in the left ear, and was subsequently diagnosed to have IgG4-RD.

Keywords: IgG4, IgG4-related disease, middle ear disease, lymphoplasmacytic infiltrate, storiform fibrosis

How to cite this article:
Rohit U, Arun H, Prashant S, Vikas G, Anurag J, Bhanu KU. An unusual presentation of IgG4-related disease. Indian J Rheumatol 2020;15:229-33

How to cite this URL:
Rohit U, Arun H, Prashant S, Vikas G, Anurag J, Bhanu KU. An unusual presentation of IgG4-related disease. Indian J Rheumatol [serial online] 2020 [cited 2021 Jul 25];15:229-33. Available from:

  Introduction Top

IgG4-related disease (IgG4-RD) is a rare systemic fibro-inflammatory and immune-mediated condition which can involve multiple organs. The condition has been recently described, and the unified term IgG4-RD was chosen at the first international symposium on IgG4-RD held in Boston, in 2011.[1] In addition, the organizing committee endorsed the preferred nomenclature for individual organ manifestation of IgG4-RD. For instance, Mikulicz disease has now been replaced with IgG4-related dacryoadenitis and sialadenitis.[2] Its description has enabled the inclusion and connection of unspecific symptoms/disorders within its spectrum and has placed a number of pathologies within its spectrum, linking symptoms, and conditions formerly considered isolated. Type 1 autoimmune pancreatitis is the most common presentation of IgG4 RD and has been most classically described. However, with increasing awareness, cases involving various other systems including the head and neck are being increasingly diagnosed.[3] Recent studies have enabled a clear clinical and histopathological description of IgG4-RD. Typically, lymphoplasmacytic inflammation, storiform fibrosis, and obliterative phlebitis are found in IgG4-RD biopsies, and the tissue-invading plasma cells largely produce IgG4. Consequently, diagnostic criteria for IgG4-RD were proposed in 2012 by Umehara et al., which clearly define the IgG4 RD diagnosis as definite, probable, or possible based on clinical features, serology, and histopathological findings [Table 1].[4] The typical patient with IgG4-RD is a middle-aged to elderly man. For autoimmune pancreatitis, the mean age at diagnosis is 67 years, and the male-to-female ratio is 3:1.[5] The male predilection contrasts strikingly with classic autoimmune diseases, for which female patients can outnumber male cases by 9:1. The condition has an equal sexual preponderance for the head and neck; however, there is a significant predominance among the middle-aged male population when abdominal and retroperitoneal organs are affected. The reasons for differential organ expression in the two sexes are unclear.[6]
Table 1: Diagnostic criteria for the diagnosis of IgG4-related disease

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  Case Report Top

A 31-year-old male presented in 2011 with complaints of hearing loss and pain in the left ear of a 3-month duration, which was insidious at onset and gradually progressive in nature. He was diagnosed by an otorhinolaryngologist as a case of left otitis media with effusion, and the patient underwent myringotomy along with grommet insertion in the left ear with symptomatic relief. The patient again became symptomatic in 2018 with history of worsening of symptoms of the left ear of 1.5-year duration, in the form of difficulty in hearing conversational voice and associated tinnitus. Examination revealed a bulging tympanic membrane on the left side along with a posterosuperior bulge in the external auditory canal of the left ear. The patient underwent high-resolution computed tomography of the temporal bone for the same, which revealed tegmen plate erosion, erosion of bone over the sigmoid sinus, and posterior meatal wall erosion [Figure 1]a. In view of the above findings, the patient underwent an magnetic resonance imaging (MRI) of the brain which revealed well-defined lesion measuring 35 mm × 25 mm × 27 mm in the left mastoid air cells with attico-antral involvement of the left ear causing focal bony defect of both the dural and sinus plates without any evidence of dural or intracranial extension [Figure 1]b. Laboratory investigations revealed normal renal and liver functions and elevated C-reactive protein (16 mg/L, normal – 10 mg/L). Investigations for autoimmune etiology revealed normal levels of rheumatoid factor and anticitrullinated protein antibodies, negative antineutrophil cytoplasmic antibodies, and antinuclear antibodies by immunofluorescence and normal serum immunoglobulin E levels. He underwent surgical management in the form of tympanomastoid exploration (left) which revealed extensive bony erosions and dense fibrotic tissue completely filling the mastoid antrum, aditus, and attic. Histopathological examination revealed chronic inflammatory tissue with storiform fibrosis and lymphoplasmacytic infiltrate, along with eosinophils and histiocytes. Immunohistochemistry (IHC) was suggestive of IgG4-RD with positivity for CD 138 and IgG4 [Figure 2]a, [Figure 2]b, [Figure 2]c, [Figure 2]d. The patient also underwent whole-body fluorodeoxyglucose positron-emission tomography which revealed metabolically active erosive lesions with maximum standardized uptake values of 4.26 with soft-tissue component at the mastoid antrum region of the left temporal bone [Figure 1]c.[6] He was managed with oral glucocorticoids in the form of prednisolone at 0.6 mg/kg body weight along with a steroid-sparing agent in the form of mycophenolate mofetil (MMF) at a dose of 1 g twice daily. On review at 3 months, the patient had only modest improvement in symptoms. Repeat MRI of the brain showed an increase in the posterolateral component of the enhancing lesion in the left mastoid region with no significant change in the overall size as compared to the previous MRI. In view of the above, the patient was exhibited B-cell depletion therapy with rituximab (1000 mg × 2 doses) and was continued on MMF, along with steroids in tapering doses. At 6 month review, he reported significant relief in symptoms in the form of improvement in hearing and resolution of tinnitus. A repeat MRI of the brain showed a significant reduction in the size of the mass in the left mastoid region.
Figure 1: Radioimaging and positron-emission tomography scan. (a) High-resolution computed tomography of the temporal bone showing tegmen plate erosion and erosion of the bone over the sigmoid sinus and posterior meatal wall erosion suggestive of chronic otitis media. (b) T1-weighted magnetic resonance imaging showing slightly hyperintense lesion in the left mastoid air cells with attico-antral involvement. (c) 18F fluorodeoxyglucose whole-body positron-emission tomography showing metabolically active erosive lesions (maximum standardized uptake values 4.26) with a soft-tissue component at the mastoid antrum region of the left temporal bone

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Figure 2: Histopathology and immunohistochemistry. (a) (IHC, ×100) with CD 138-positive plasma cells. (b) (IHC, ×100) with plasma cells showing IgG positivity. (c) (IHC, ×100) with plasma cells showing IgG4 positivity. (d) (H and E, ×100) stain showing inflammatory infiltrates comprising plasma cells and lymphocytes with storiform fibrosis

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  Discussion Top

IgG4-RD can mimic a number of systemic illnesses depending on the pattern of organ involvement. The Japanese IgG4 team in 2012 proposed a comprehensive diagnostic criterion for IgG4-RD, for practical use.[4] It takes into account two major characteristics of IgG4 RD: increased serum concentrations of IgG4 and infiltration by IgG4 positive cells. Cutoff value for serum IgG4 concentration is 135 mg/dl.[4] Histologically, lymphoplasmacytic infiltration, storiform or swirling fibrosis (centrifugally arranged collagen fibers, fibroblasts, and inflammatory cells), and obliterative phlebitis (affects medium-sized veins) are characteristic and important findings along with eosinophilic infiltration which is commonly seen in addition to IgG4-positive cells. Histopathologic findings of marked IgG4-positive cell infiltration (>10 cells/hpf) and an IgG4-to-IgG cell ratio >40% are diagnostic of IgG4-RD.[4] The pathophysiology of IgG4 RD involves two parallel processes. One is the induction of a polarized CD4-positive T-cell population, which activates innate immune cells, including macrophages, myofibroblasts, and fibroblasts to drive fibrosis.[1],[7] The second is a feedback negative regulatory process, which might involve the generation of IgG4-secreting plasmablasts, plasma cells, and IgG4 antibodies.[8] It is believed that the function of IgG4 may be related to the regulation of the response to allergens and pathogens. IgG4 antibodies can swap a heavy chain and attached light chain and hence can form bi-specific antibodies. There is a blockade of Fc-mediated effector functions of IgG1 because of weaker interaction of IgG4 with Fc gamma receptor and C1q as compared to other IgG classes.[9] This inhibits the formation of large immune complexes and decreased interleukin-8 excretion from neutrophils. These properties of IgG4 mediate impaired adaptive immunity. T-cells are implicated in the disease pathogenesis because of the observation that many CD4-positive T-cells are present at the sites of inflammation in IgG4-RD.[10]

Ear involvement has been scarcely reported till date. Takagi et al. performed a retrospective analysis of 39 patients with confirmed IgG4-RD in organs outside of the head and neck and found otologic symptoms in five of them.[11] The findings included serous otitis media, eosinophilic otitis media, and sensorineural hearing loss. However, unlike in our case, histopathological confirmation in the ear was not made, and thus, the findings could have been circumstantial. During the review of literature, we found four cases of IgG4-RD involving the mastoid and middle ear [Table 2].[12] They had presented with a wide range of symptoms including aural fullness, tinnitus, hearing loss, and multiple cranial nerve palsies. All the patients reported long-standing disease at this site with history of multiple surgical interventions and recurrences. The disease extended to the meninges and caused cerebritis in two cases. In both cases, the damage was significantly greater than that in our patient, involving bone erosion and damage to the facial nerve, presumably because the diagnosis was made at a later stage.
Table 2: Comparison of various cases of IgG4-related disease involving the middle ear

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In spite of the long-standing nature of the disease, therapy with steroids and/or rituximab in these cases resulted in the stabilization of the disease and resolution of symptoms. All the biopsies were characterized by lymphoplasmacytic infiltrate, elevated numbers of IgG4-positive plasma cells, and an elevated IgG4–IgG ratio.[13],[14] In our patient also, the histopathology report revealed lymphoplasmacytic infiltrates, and IHC revealed CD 138 and IgG4 positivity [Table 1]. He fit into probable IgG4-RD as per the currently accepted criteria originally proposed by Umehara et al.[4] (1) Positive localized organ involvement – this was evidenced in the otoscopic, intraoperative, and radiological findings, (2) serum IgG4 of >135 mg/dL, the case presented has a serum IgG4 of 109 mg/dL, and (3) histopathological findings of >10 IgG4 cells/HPF (our patient had 40). Hence, with (1) plus (3), he met the criteria for probable IgG4 disease.

At the time of writing this article, a new criterion was proposed: The 2019 American College of Rheumatology (ACR)/European League Against Rheumatism (EULAR) classification criteria for IgG4-RD proposed three-step approach for classifying a patient as a case of IgG4-RD.[15] If the patient meets the entry criteria and does not meet any exclusion criteria, then the patient is given certain points in the inclusion criteria. If the patient has >20 points, he can be classified as IgG4-RD. Our patient although did not meet the entry criteria, he did not have any exclusion criteria and had 27 points in the inclusion criteria (13 in the histopathology and 14 in the IHC). In the study also, since they included the involvement of only certain classically described organs as the entry criteria (and not middle ear disease and other atypical sites), they had some false negatives. Furthermore, these criteria are not intended for use in clinical practice as the basis of establishing the diagnosis of IgG4-RD. If the appropriate clinical diagnosis for a patient is IgG4-RD, then failure to fulfill the ACR/EULAR classification criteria should not prevent the management of that patient's condition accordingly.[16] Hence, our patient was managed as a case of IgG4-RD.

After the establishment of the diagnosis, our patient was started on oral steroids and MMF. In view of worsening of symptoms after the initial response to steroids wore off, he was exhibited rituximab. Rituximab offers targeted effect that lowers the levels of IgG4-producing cells specifically.[17] Response to an anti-CD20 antibody is an unexpected phenomenon, given that the disease is dominated by the presence of plasma cells. Nevertheless, it is believed that the IgG4-positive plasmablasts (short-lived cells) fuel the production of IgG4-positive plasma cells. These IgG4-positive plasmablasts bear CD20 and hence are responsive to rituximab.[18],[19],[20] However, in the absence of a randomized controlled trial, it is still considered an off-label use for rituximab. Similar to other reports of IgG4-RD, our patient's symptoms and imaging did improve with immunosuppression, and ours is the first case of IgG4-RD involving the middle ear being reported from our country.

The IgG4-RD spectrum encompasses a multitude of disorders, some of which were previously deemed untreatable. With extensive research, the disease has been identified in nearly every organ system, and most of its clinical features have been clearly mapped.[21] Its description offers objective explanations and correlation between a number of rare disorders and symptoms, as well as new therapeutic options. Various pathological manifestations and effective treatments for IgG4 RD involving various organ systems have been identified, and the nomenclature has been standardized. At present, greater awareness in the medical community of this protean disease is needed to ensure earlier diagnoses, which can prevent severe organ damage, disabling tissue fibrosis, and death. The involvement of the middle ear within this spectrum has only been described in few occasions. The present report impresses on the fact that IgG4-RD can involve various organs of the body and with a high level of suspicion and on the basis of comprehensive diagnostic criteria, can be diagnosed and subsequently treated.

Informed consent

Written informed consent was obtained from the patient.

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 name and initials will not be published and due efforts will be made to conceal identity, but anonymity cannot be guaranteed.

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Conflicts of interest

There are no conflicts of interest.

  References Top

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 2012;25:1181-92.  Back to cited text no. 1
Himi T, Takano K, Yamamoto M, Naishiro Y, Takahashi H. A novel concept of Mikulicz's disease as IgG4-related disease. Auris Nasus Laryn×2012;39:9-17.  Back to cited text no. 2
Takano K, Yamamoto M, Takahashi H, Himi T. Recent advances in knowledge regarding the head and neck manifestations of IgG4-related disease. Auris Nasus Larynx 2017;44:7-17.  Back to cited text no. 3
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.  Back to cited text no. 4
Kanno A, Nishimori I, Masamune A, Kikuta K, Hirota M, Kuriyama S, et al. Nationwide epidemiological survey of autoimmune pancreatitis in Japan. Pancreas 2012;41:835-9.  Back to cited text no. 5
Zen Y, Nakanuma Y. IgG4-related disease: A cross-sectional study of 114 cases. Am J Surg Pathol 2010;34:1812-9.  Back to cited text no. 6
Tabata T, Kamisawa T, Takuma K, Anjiki H, Egawa N, Kurata M, et al. Serum IgG4 concentrations and IgG4-related sclerosing disease. Clin Chim Acta 2009;408:25-8.  Back to cited text no. 7
Tsuboi H, Matsuo N, Iizuka M, Tsuzuki S, Kondo Y, Tanaka A, et al. Analysis of IgG4 class switch-related molecules in IgG4-related disease. Arthritis Res Ther 2012;14:R171.  Back to cited text no. 8
Mattoo H, Della-Torre E, Mahajan VS, Stone JH, Pillai S. Circulating Th2 memory cells in IgG4-related disease are restricted to a defined subset of subjects with atopy. Allergy 2014;69:399-402.  Back to cited text no. 9
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.  Back to cited text no. 10
Takagi D, Nakamaru Y, Fukuda S. Otologic manifestations of immunoglobulin G4-related disease. Ann Otol Rhinol Laryngol 2014;123:420-4.  Back to cited text no. 11
Della Torre E, Mattoo H, Mahajan VS, Carruthers M, Pillai S, Stone JH. Prevalence of atopy, eosinophilia, and IgE elevation in IgG4-related disease. Allergy 2014;69:269-72.  Back to cited text no. 12
Deshpande V, Zane NA, Kraft S, Stone JH, Faquin WC. Recurrent Mastoiditis Mimics IgG4 Related Disease: A Potential Diagnostic Pitfall. Head Neck Pathol 2016;10:314-20.  Back to cited text no. 13
Wuesthoff C, Allende A, Patel N. IgG4 disease of the ear: Report and review. SAGE Open Med Case Rep 2018;6:2050313×18791428.  Back to cited text no. 14
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. 15
Aggarwal R, Ringold S, Khanna D, Neogi T, Johnson SR, Miller A, et al. Distinctions between diagnostic and classification criteria? Arthritis Care Res (Hoboken) 2015;67:891-7.  Back to cited text no. 16
Barnado AL, Cunningham MA. IgG4-related disease presenting as recurrent mastoiditis with central nervous system involvement. J Investig Med High Impact Case Rep 2014;2:2324709614553670.  Back to cited text no. 17
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.  Back to cited text no. 18
Stone JH, Zen Y, Deshpande V. IgG4-related disease. N Engl J Med 2012;366:539-51.  Back to cited text no. 19
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.  Back to cited text no. 20
Khosroshahi A, Bloch DB, Deshpande V, Stone JH. Rituximab therapy leads to rapid decline of serum IgG4 levels and prompt clinical improvement in IgG4-related systemic disease. Arthritis Rheum 2010;62:1755-62.  Back to cited text no. 21


  [Figure 1], [Figure 2]

  [Table 1], [Table 2]


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