Orbital Inflammation in IgG4-related Sclerosing Disease

IgG4-related sclerosing disease is a recently described systemic inflammatory disease that should be considered when evaluating patients with nonspecific orbital inflammation (pseudotumor). Orbital biopsy is necessary to establish a diagnosis and demonstrates lymphoplasmacytic infiltration, fibrosis, obliterative phlebitis of medium and small veins, and variable degrees of eosinophilia. We report the clinical and histopathological findings of 2 patients who developed chronic orbital inflammation as a manifestation of IgG4-related sclerosing disease. The 2 cases illustrate the widely varying clinical characteristics of this elusive disease.     

Orbital Manifestations of Immunoglobulin G4–Related Disease in Bilateral Lacrimal Glands,Optic Nerves,Trigeminal Nerves,and Maxillary Sinuses

Immunoglobulin G4 (IgG4)-related disease is characterised by numerous aggregates of IgG4-positive plasma cells in multiple organs. We report two patients who had bilateral proptosis associated with extensive inflammation bilaterally in lacrimal glands, optic nerves, trigeminal nerves, and maxillary sinuses. The patients were treated as idiopathic orbital inflammation syndrome with corticosteroid pulse therapy. As symptoms relapsed upon tapering, a reassessment of immunohistochemical stains of the lacrimal glands confirmed the diagnosis of IgG4-related disease. During 2 years of follow-up, the inflammation regressed spontaneously without any medical treatment in the first patient; however, inflammation in the other patient progressed, and he lost his vision. The extensive orbital involvement, characteristic pathological findings, and slowly progressive clinical course might help practitioners differentiate orbital IgG4-related disease from presumed idiopathic orbital inflammation syndrome.     

A case of non-lacrimal immunoglobulin G4 (IgG4)-related orbital disease with mastitis

IgG4-related orbital disease is a recognised cause for orbital inflammation. As its awareness increases and diagnostic accuracy improves there will be an increased number of cases being identified. This unique case demonstrates for the first time, with histological evidence, a case of a non-lacrimal IgG4-related orbital disease with concurrent IgG4-related mastitis. We describe a 47 year old who presented with a supraorbital swelling and mass. This was initially successfully treated with oral steroids and was later excised on recurrence. Immunohistochemical and blood serum analysis confirmed IgG4-related orbital disease. On systemic enquiry she was found to have a mass of the breast, which was shown to be IgG4-related mastitis. She is currently asymptomatic with no sign of recurrence and is under long-term surveillance. This case highlights the importance of systemic work up in patients presenting with orbital foci of IgG4 disease.     

免疫球蛋白G4相关性眼眶病的临床研究进展

近年来,免疫球蛋白G4( IgG4)相关性疾病作为一种新的自身免疫性疾病,受到国内外医学界的的广泛关注。IgG4相关性疾病以IgG4+浆细胞浸润和血清IgG4浓度升高为特征,同时伴有因全身多器官的纤维化而发生肿大、结节性或增生性病变的自身免疫性疾病。当累及眼眶时称为IgG4相关性眼眶病。目前提出了IgG4相关性眼眶病的相对完善的诊断标准,然而治疗方面还没有公认有效的手段,目前首选激素治疗。本文就IgG4相关性眼眶病的临床特征、诊断和治疗的研究进展进行综述。     

A prevalence study of IgG4-related ophthalmic disease in Japan

Purpose

Immunoglobulin (Ig)G4-related ophthalmic disease belongs to a category of ocular adnexal lymphoproliferative disorders, the most frequent group of orbital tumors and simulating lesions. The aim of this study was to elucidate the number of IgG4-related diseases of orbital lymphoproliferative disorders and correlate ages and sex of such patients from 18 centers in Japan.

Methods

One thousand and fourteen patients with orbital lymphoproliferative disorders were enrolled in this study. All had pathologically diagnosed lymphoproliferative disorders with surgical samples of ocular adnexal tissue. Patients with conjunctival lesions and intraocular lymphoma were excluded.

Results

Of the 1,014 cases of orbital lymphoproliferative disorders 404 (39.8 %) had extranodal mucosa-associated lymphoid tissue (MALT) lymphoma, 156 (15.4 %) had other malignant lymphomas, 191 (18.8 %) had non-IgG4 orbital inflammation, 219 (21.6 %) had IgG4-related orbital inflammation, and 44 (4.3 %) had IgG4-positive MALT lymphoma. Median age of the IgG4-related orbital inflammation group was 62 years, which is significantly lower than that of the MALT lymphoma group (median 66 years) and higher than the non-IgG4 orbital inflammation group (median 57 years). The male/female ratio was 105/114 in the IgG4-related orbital inflammation group.

Conclusions

Nearly a quarter of orbital lymphoproliferative disorders in Japan are related to IgG4.     

Unusual involvement of IgG4-related sclerosing disease in lacrimal and submandibular glands and extraocular muscles

Chronic sclerosing sialadenitis, also known as Kuttner tumor, is a chronic inflammatory disease of the salivary glands that is reported in a few cases in medical literature. Recent reports suggest that certain aspects of sclerosing diseases, including chronic sclerosing sialadenitis or dacryoadenitis, should be classified under immunoglobulin G4 (IgG4)-related sclerosing disease based on immunohistochemical studies. This study reports an unusual case of IgG4-related sclerosing disease appearing simultaneously in the lacrimal glands, submandibular glands, and extraocular muscles. A 56-year-old male presented with complaints of bilateral eyelid swelling and proptosis that began two years ago. Computed tomography confirmed that bilateral submandibular enlargements also existed five years ago in the subject. Orbital computed tomography and magnetic resonance imaging revealed bilateral lacrimal gland enlargement and thickening of extraocular muscles. Typical findings of chronic sclerosing dacryoadenitis were revealed upon pathologic exam of the right lacrimal gland. Immunostaining revealed numerous IgG4-positive plasma cells. Through these clinical features, we make a diagnosis of IgG4-relataed sclerosing disease in the subject.     

Systemic immunoglobulin G4 (IgG4) disease and idiopathic orbital inflammation; removing ‘idiopathic' from the nomenclature?

The discovery of systemic disease related to raised tissue and serum immunoglobulin G4 (IgG4) is changing diagnostic and therapeutic practice in many medical specialties. Orbital inflammation remains a diverse and heterogeneous group of disorders that can pose a diagnostic and therapeutic challenge, but with improved understanding and corresponding diagnostic advances the previously expansive group of idiopathies is reducing. The recent discovery that IgG4 has a causative role in a subtype of, what is currently termed, idiopathic orbital inflammation is encouraging. The term 'idiopathic' can now be removed from the nomenclature for another subtype of orbital inflammation. IgG4 disease should be especially considered in patients with a bilateral dacryoadenitis and systemic features (eg, lung and gastrointestinal involvement). However, reports are emerging suggesting that IgG4 may be responsible for more diverse disease subtypes. The relationship between IgG4-related disease and lymphoma remains unknown but vigilance is required.     

免疫球蛋白G4相关性眼眶病的研究进展

近年来,免疫球蛋白G4（IgG4）相关性疾病作为一种新的临床疾病正逐渐受到医学界的广泛关注。尽管该病临床表现多种多样,但是血清IgG4质量浓度增高和组织中IgG4阳性浆细胞的大量浸润是其共有的特征。该病可累及全身多个器官,最常见的是胰腺,其次为腮腺、胆管、肝脏、肺脏和淋巴结等,累及眼眶者较为少见。目前研究初步显示,良性淋巴上皮病变、特发性眼眶炎性假瘤、Castleman病、黄色肉芽肿、Rosai—Dofman病等几种眼眶病具有IgG4相关性疾病的特征。就IgG4相关性眼眶病的研究进展进行综述。     

IgG4相关性眼病研究进展

IgG4相关性疾病是一种近几年才被认识的疾病,病因尚不明确。以同时或逐步出现的一种或多种组织和器官中大量IgG4阳性淋巴浆细胞浸润、席纹状纤维化、闭塞性静脉炎为特征,可伴有血清IgG4水平升高。当累及眼部时称为IgG4相关性眼病。任何眼附属器均可受累,多见于泪腺、眼眶脂肪、眶下神经、眼外肌和眼睑。本文将对近年来IgG4相关性眼病的流行病学特点、病理特点、临床表现、影像特点、诊断和治疗方面的最新进展作一综述。     

The impact of IgG-4-ROD on the diagnosis of orbital tumors: A retrospective analysis

This study was to determine the prevalence of immunoglobulin G4 (IgG4)-related orbital disease (IgG4-ROD) among patients who have previously undergone biopsy and were diagnosed to have idiopathic orbital inflammatory disease (IOID) or orbital lymphoproliferative disease (OLD), namely, lymphoma and benign reactive lymphoid hyperplasia (BRLH). This is a retrospective cross-sectional study. The charts and slides of all patients who underwent biopsies and were histopathologically diagnosed to have either IOID or OLD were reviewed. Demographics, clinical features, initial histopathological diagnoses, treatment received, and final outcome were noted. Using the diagnostic criteria for diagnosis for IgG4 disease, those cases that would classify as “possible IgG4-related disease (IgG4-RD)” were reviewed, reclassified, and reassigned a diagnosis of IgG4-ROD. We reviewed 105 patients’ clinical charts. Of these 105 patients, upon reviewing the histopathology, 18 (17.15%) patients were found to fit the diagnostic criteria for possible IgG4-ROD. Of these 18 patients who were now reassigned the diagnosis of IgG4-ROD, the most common previous histopathological diagnosis was found to be IOID, for eight patients (44%), then BRLH, which was noted in five patients (27.8%), followed by lymphoma, which was noted in two patients (11.1%). Previously diagnosed cases of IOID and OLD were found to fulfill the criteria for IgG4-ROD. Given the advent of recent diagnostic and histopathological techniques, all cases of suspected IOID and OLD should be screened for IgG4-ROD and all previously diagnosed cases must be closely followed up, given the systemic implication of IgG4-RD. Histopathological reassessment of previously diagnosed cases may be considered.     

Adjunctive Orbital Radiotherapy for Ocular Adnexal IgG4-related Disease: Preliminary Experience in Patients Refractory or Intolerant to Corticosteroid Therapy

Abstract

Purpose: To present the clinical outcomes of combined orbital radiotherapy and systemic corticosteroid for patients with refractory ocular adnexal IgG4-related disease.

Methods: We retrospectively reviewed 3 patients with histopathologically confirmed ocular adnexal IgG4-related disease who had been refractory or intolerant to corticosteroid therapy and treated with adjunctive orbital radiotherapy (2000 cGy; 10 fractions). Clinical improvement was assessed by monitoring the patient's ability to taper corticosteroid to discontinuation and by follow-up radiologic examination.

Results: All 3 patients had a favorable response to adjunctive radiotherapy with improvement of the clinical symptoms and radiologic abnormalities. Systemic corticosteroid was tapered and discontinued in all patients successfully. There were no adverse effects of treatment or recurrence after a mean follow-up of 19 months.

Conclusion: Adjunctive radiotherapy can help to achieve stable disease and cessation of systemic corticosteroid in patients with refractory ocular adnexal IgG4-related disease.     

IgG4-related ophthalmic disease

IgG4-related disease is a fibro-inflammatory condition with tendency to form tumors with inflammatory infiltrate with IgG4 rich plasma cells and elevation of IgG4 level in serum, which may affect virtually every organ and tissue in the organism. IgG4-related ophthalmic disease may present as dacryoadenitis, myositis, other orbital tissues, hypophysitis or pachymeningitis causing cranial neuropathies. The diagnosis of IgG4-related disease is based on a typical clinical scenario, supportive laboratory data, expected radiological characteristics and distinct histopathological and immunohistochemical features. Corticosteroid followed by the use of long-term immunosuppressive therapy is the most commonly attempted treatment.     

A Clinicopathologic Case Study of Two Patients with Pediatric Orbital IgG4-related Disease

Abstract

The purpose of this report is to describe the clinical, radiographica, and histopathologic findings in two pediatric patients with orbital IgG4-related disease.     

A unique case of IgG4 sclerosing dacryocystitis

IgG4-related ocular adnexal disease, a relatively recently described clinical entity, is important to diagnose because during the acute phase, it responds favorably to corticosteroid treatment. The diagnosis can be confirmed by simple blood tests and histology. IgG4-related dacryoadenitis and generalized orbital disease have been reported; however, this is the first report of IgG4-related disease of the lacrimal sac. We describe an 80-year-old female who presented with a painless erythematous indurated swelling in the right lacrimal sac area with complete obstruction of the right nasolacrimal system. A 9-mm lacrimal sac mass was noted on CT dacryocystogram. Blood tests revealed an elevated serum IgG4 level, and the lacrimal sac histology was characteristic of IgG4-related disease. Corticosteroid treatment was declined by the patient. She was kept under close observation for signs of progression, systemic involvement, and potential malignant transformation.     

Xanthogranulomatous variant of immunoglobulin G4 sclerosing disease presenting as ptosis,proptosis and eyelid skin plaques

A 70-year-old male was referred to the oculoplastic clinic with left-sided ptosis and floppy eyelids. During follow-up, bilateral upper lid xanthelasma developed with worsening ptosis and proptosis, which was worse on the left side. A left orbital biopsy showed xanthogranulomatous inflammation of the orbit. The patient was treated with a variety of immune modulator regimes but due to a variety of side-effects, treatment was discontinued. The left orbit was surgically debulked twice and histology revealed xanthogranulomatous inflammation, with the additional features of sclerosis, lymphoid aggregates and a prominent population of plasma cells. Around 80% of the plasma cells expressed immunoglobulin G4 (IgG4). This case report reveals an association between xanthogranulomatous inflammation of the orbit and a prominent population of IgG4-positive plasma cells. We propose that the overall disease is a novel variant of IgG4 sclerosing disease of the orbit and suggest that cases of histologically proven xanthogranulomatous inflammation should be stained for IgG4 if there is an accompanying plasma cell population.     

Bilateral Orbital IgG4-Related Disease with Systemic and Corneal Involvement Showing an Excellent Response to Steroid and Rituximab Therapy: Report of a Case with 11 Years Follow-Up

IgG4-related disease is a newly recognized fibro-inflammatory condition. The purpose of this report is to present a patient with 11 years of follow-up, who revealed characteristic features of IgG4-related disease with systemic, orbital and corneal involvement and showed a favorable response to steroids and rituximab treatment.     

Relationship between dacryoadenitis subtype of idiopathic orbital inflammatory pseudotumor and paranasal sinusitis

AIM: To determine the clinical features of the dacryoadenitis subtype of idiopathic orbital inflammatory pseudotumor and its relationship with paranasal sinusitis. METHODS: A retrospective analysis of 46 patients who received surgical treatment at the Department of Ophthalmology, Beijing Tongren Hospital, Capital Medical University for the dacryoadenitis subtype of idiopathic orbital inflammatory pseudotumor from October 2010 to December 2012. Each patient underwent magnetic resonance imaging (MRI) of the orbits and the 4 paranasal sinuses. Disease status and the level of serum immunoglobulin G4 (IgG4) was measured before and 6mo after surgery. RESULTS: The initial clinical feature of the idiopathic dacryoadenitis type of orbital inflammatory pseudotumor was redness or swelling of the eyelids. Masses were palpated in the area of the lacrimal gland in some patients. Of the 46 patients, 16 also suffered from sinusitis (34.8%), with 14 cases of ethmoid sinusitis, 8 cases of maxillary sinusitis, 9 cases of sphenoid sinusitis, and 8 cases of frontal sinusitis. Of the 16 patients with sinusitis, 4 patients had a medical history of rhinitis (range: 10mo to 15y previously), 10 patients had occasional nasal congestion, and 2 patients had no nasal congestion. Thirteen of the 46 patients had elevated serum IgG4 levels. Nine of these 13 patients had MRI signs of sinusitis. All patients (n=46) received oral glucocorticoid treatment for approximately 3mo after surgery. No sign of recurrence was found in the orbital MRI 6mo after surgery. Of the 16 patients with sinusitis, 9 cases of elevated serum IgG4 levels improved after treatment with decreased serum IgG4 level and 7 cases of normal serum IgG4 levels remained unchanged. CONCLUSION: Some patients with the dacryoadenitis subtype of idiopathic orbital inflammatory pseudotumor may also suffer from paranasal sinusitis. The incidence of paranasal sinusitis was much higher in patients with IgG4-elevated dacryoadenitis subtype orbital inflammatory pseudotumor than in those with normal IgG4 levels. Dacryoadenitis subtype orbital inflammatory pseudotumor and paranasal sinusitis may both the clinical manifestations of IgG4-related disease involved in different locations.     

IgG4相关性眼病的诊疗研究进展

免疫球蛋白G4(IgG4)相关性疾病(IgG4-RD)是近年来受关注度较高的一类慢性、系统性疾病。IgG4-RD可累及全身各个组织,主要表现为累及器官的肿胀及占位改变,当病变侵犯至眼部周围时称为IgG4相关性眼病(IgG4-ROD),主要侵犯泪腺、眼眶脂肪、眶下神经、眼外肌和眼睑等。目前,针对IgG4-ROD的主要治疗方式有药物治疗、手术、放射治疗等。随着近年对该病认识的不断提升,治疗有效率不断提高,本文就IgG4-ROD的流行病学特点、临床表现、影像特点、诊断和治疗的最新进展进行综述。     

Clinical features of IgG4-related dacryoadenitis

Background

To elucidate the clinical characteristics of IgG4-related dacryoadenitis.

Methods

Clinical features, laboratory findings, radiological findings, associated diseases, treatment, and prognosis were prospectively examined in 12 patients (seven men, five women; mean age, 60.9?±?15.1 years) with IgG4-related dacryoadenitis.

Results

In addition to eyelid swelling, other ophthalmologic symptoms were observed in seven patients, including diplopia (n?=?4), ptosis (n?=?2), visual field disturbance (n?=?2), eye pain (n?=?2), decrease of visual acuity (n?=?2), eye-movement disturbance (n?=?1), dry eye (n?=?1), corneal ulcer (n?=?1), and epiphora (n?=?1). Swelling of the lacrimal glands was bilateral in half of the patients. Other IgG4-related diseases were present in nine patients, including sialadenitis (n?=?5), autoimmune pancreatitis (n?=?4), retroperitoneal fibrosis (n?=?2), and lymphadenopathy (n?=?8). Serum IgG4 levels were significantly higher in patients with other IgG4-related disease (1070?±?813 mg/dl) than in those without (197?±?59 mg/dl, p?=?0.017). Allergic histories and elevated serum IgE levels were each detected in six patients. Eight patients showed inflammatory extension beyond the lacrimal gland, such as thickened rectus muscle (n?=?6), inflammation of the optic nerve (n?=?2), and retrobulbar inflammation (n?=?3). Steroid therapy was effective in seven patients, but dacryoadenitis relapsed in two patients with markedly higher serum IgG4 levels and autoimmune pancreatitis.

Conclusions

IgG4-related dacryoadenitis showed various ophthalmologic symptoms due to extensive inflammation beyond the lacrimal gland, frequent association with other IgG4-related disease or allergic phenomena, and steroid responsiveness.     

Location and frequency of lesions in patients with IgG4-related ophthalmic diseases

Background

It is well-known that the lacrimal gland (LG) may be affected in IgG4-related ophthalmic disease (IgG4ROD). Recently, IgG4-related ophthalmic lesions other than those of the lacrimal gland have been reported. However, no study to date has revealed the details of these lesions. This study was conducted to evaluate the location and frequency of lesions found in conjunction with IgG4ROD using radiological imaging.

Methods

Radiological images and clinical records of 65 patients collected from seven institutions in Japan were reviewed retrospectively. All patients had been pathologically diagnosed with IgG4ROD. Patients of mucosa-associated lymphoid tissue lymphoma associated with IgG4-related lesions were excluded. Orbital magnetic resonance imaging or computed tomography findings were evaluated.

Results

Of the 65 patients, 31 (47.7 %) had lesions involving the LG alone, whereas 34 (52.3 %) had lesions involving the areas other than LG, including eight patients who had lesions without any LG involvement. IgG4-related ophthalmic lesions included LG enlargement in 57 patients (87.7 %), trigeminal nerve branch enlargement in 25 (38.5 %), extraocular muscle enlargement in 16 (24.6 %), diffuse orbital fat lesions in 15 (23.1 %), orbital mass lesions in 11 (16.9 %), eyelid lesions in eight (12.3 %), and nasolacrimal duct lesion in one (1.5 %). Six patients (9.2 %) presented with visual disturbance due to optic nerve disturbance, eight (12.3 %) with a restriction of ocular movement, and 19 (29.2 %) with exophthalmos.

Conclusions

Thirty-four (52.3 %) of the 65 IgG4ROD patients had lesions in areas other than LG. Lesions were found in the trigeminal nerve branch including pterygopalatine fossa, extraocular muscles, orbital fat, eyelid, and nasolacrimal duct.