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Since the onset of COVID-19 pandemic, parallel opportunistic infections have also been emerging as another disease spectrum. Among all these opportunistic infection, mucormycosis has become a matter of concern with its rapid increase of cases with rapid spread as compared to pre-COVID-19 era. Cases have been reported in post-COVID-19-related immune suppression along with the presence of comorbidity which adds on the deadly outcome. There is no systematic review addressing the issue of COVID-19-associated mucormycosis. This is the first systematic review of published studies of mucormycosis associated with COVID-19. The aim was to analyze the real scenario of the disease statement including all the published studies from first November 2019 to 30th June to analyze the contemporary epidemiology, clinical manifestations, risk factor, prognosis, and treatment outcome of COVID-19 associated rhino-orbito-cerebral-mucormycosis. A comprehensive literature search was done in following databases, namely, PubMed, Google Scholar, Scopus, and EMBASE using keywords mucormycosis, rhino orbital cerebral mucormycosis, COVID-19, and SARS-CoV-2 (from November 01, 2019 to June 30, 2021). Our study shows that, while corticosteroids have proved to be lifesaving in severe to critical COVID-19 patients, its indiscriminate use has come with its price of rhino-orbito-cerebral mucormycosis epidemic, especially in India especially in patients with preexisting diabetes mellitus with higher mortality. Corticosteroid use should be monitored and all COVID-19 patients should be closely evaluated/monitored for sequelae of immunosuppression following treatment., Competing Interests: None

Background: Idiopathic orbital inflammation (IOI) is a disfiguring and vision-threatening fibroinflammatory disorder. The pathogenesis of IOI has not been elucidated. We sought to clarify the regulatory T cell (Treg) distribution and function in patients with IOI., Methods: The frequency, phenotype and function of Tregs were identified by multicolor flow cytometry and in vitro cell functional assays. Plasma and tissue samples were obtained to investigate cytokines, chemokines and their receptors of interest by relative real-time polymerase chain reaction (PCR) and Luminex assays., Results: Compared with healthy subjects, patients with IOI exhibited obvious increases of Tregs in peripheral blood and affected orbital tissues. Circulating Tregs from patients with IOI were significantly more polarized to a Th17-like phenotype with defective regulatory function, whereas orbit-derived Tregs were polarized to a Th2-like phenotype. Furthermore, ST2 expression levels in circulating Tregs and interleukin (IL)-33 mRNA levels in orbital tissues were decreased in IOI. IL-33 restored the suppressive function of Tregs, reduced interferon (IFN)-γ production by Tregs and decreased the activation of orbital fibroblasts (OFs) cocultured with Tregs in IOI., Conclusion: Increased Tregs with proinflammatory and profibrotic polarization were first identified in IOI, suggesting that Treg plasticity and heterogeneity plays an essential role in IOI pathogenesis. Additionally, our study identified a regulatory effect of IL-33 on inflammation and fibrosis in IOI. Reversing the plastic Tregs via IL-33 might be a potential option for IOI patients., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Chen, Ye, Xiao, Mao, Ai, Chen, Lian, Shi, Wang, Bi, Yang, Ji, Zhang and Yang.)

IgG4-related ophthalmic disease (IgG4-ROD) is a rare inflammatory disorder often refractory to corticosteroids and prone to recurrence. IgG4-ROD may frequently lack the characteristic histopathological features seen in other organs. Thus, the criteria for diagnosis of IgG4-ROD relies on elevated IgG4 cells seen on biopsied tissue. Proposed threshold levels of IgG4 to diagnose IgG4-ROD are currently based on a limited understanding of this cell type's presence in the orbit. This study seeks to describe the population of IgG4 in inflammatory and noninflammatory orbital tissues. A tertiary care center's pathology database was searched with keywords "orbit" or "orbital" from 1995 to 2013. Specimens meeting the selection criteria were evaluated, and regions of highest inflammation were identified and immunostained with IgG4 and CD138 antibodies. Immunohistochemical quantification proceeded as previously established by the international consensus criteria. Eighteen cases without a history of orbital inflammation were included as controls and were evaluated as above. Specimens from 68 inflammatory and 18 noninflammatory orbits met the selection criteria. Pathologist interreader correlation coefficient on quantification was >0.70 (P<0.001). The mean IgG4+/high powered field (HPF) and IgG4+/CD138 was 10.3 and 0.1 in inflammatory tissues and 0.5 and 0.01 in noninflammatory tissues, respectively. The spearman rho correlation coefficient between IgG4/HPF and IgG4+/CD138+ was >0.95 (P<0.0001). The mean IgG4/HPF in our study reached previously proposed threshold values for diagnosis of IgG4-ROD, illustrating the need for further discussion regarding diagnostic criteria of IgG4-ROD.

Purpose : To explore the pathogenesis that TIMP-1 mediated in adult orbital xanthogranulomatous disease (AOXGD), a rare type of non-Langerhans histiocytosis that damages the appearance and quality of life of patients Methods : We reviewed 22 patients diagnosed with AOXGD based on clinical manifestations and histological analysis, and then investigated the expression of TIMP-1 and IL-6 with q-PCR and IHC in AOXGD tissues and the possible mechanism involved in the induction of TIMP-1 by IL-6. Results: IL-6 and TIMP-1 were significantly increased in AOXGD tissues. IL-6 promoted TIMP-1 production by M1 macrophages by stimulating the phosphorylation of JAK2 and STAT3. Moreover, IL-17 and IFN-γ, the classical markers of Th1 and Th17 cells, were increased in AOXGD. Conclusion: These data implied that the IL6~JAK2/STAT3-TIMP-1 signalling pathway is activated in AOXGD and that adaptive Th1 and Th17 responses are involved in the development of AOXGD.

Non-Hodgkin orbital lymphoma (NHOL) and idiopathic orbital inflammation (IOI) are common orbital conditions with largely unknown pathophysiology that can be difficult to diagnose. In this study we aim to identify serum miRNAs associated with NHOL and IOI. We performed OpenArray ® miRNA profiling in 33 patients and controls. Differentially expressed miRNAs were technically validated across technology platforms and replicated in an additional cohort of 32 patients and controls. We identified and independently validated a serum miRNA profile of NHOL that was remarkably similar to IOI and characterized by an increased expression of a cluster of eight miRNAs. Pathway enrichment analysis indicated that the miRNA-cluster is associated with immune-mediated pathways, which we supported by demonstrating the elevated expression of this cluster in serum of patients with other inflammatory conditions. The cluster contained miR-148a, a key driver of B-cell tolerance, and miR-365 that correlated with serum IgG and IgM concentrations. In addition, miR-29a and miR-223 were associated with blood lymphocyte and neutrophil populations, respectively. NHOL and IOI are characterized by an abnormal serum miRNA-cluster associated with immune pathway activation and linked to B cell and neutrophil dysfunction., (© 2019 The Authors. European Journal of Immunology published by Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Competing Interests: Competing interests: None declared.

IgG4-related disease (IgG4-RD) is an immune-mediated systemic fibro inflammatory disease. Treatment of IgG4-related orbital disease (IgG4-ROD) is often indicated to relieve the symptoms and to prevent complications. For IgG4-ROD, no international formal treatment guidelines are available and the optimal treatment strategy is uncertain. In this systematic review, we describe the efficacy of conventional and biologic disease-modifying antirheumatic drugs (DMARDs) in IgG4-ROD. A systematic search of Embase, Medline, Web-of-Science, PubMed publisher, Cochrane and Google Scholar was performed for treatment outcomes in IgG4-ROD. Relevant articles on treatment of IgG4-ROD were retrieved to last date of inclusion 3 January 2018. The following inclusion criteria were used: articles in English or English translation, studies evaluating the use of DMARDs (conventional and biologic) in the treatment of IgG4-ROD. Meta-analysis and review articles were excluded. A final selection after full-text evaluation was made by independent reviewers, based on treatment of IgG4-ROD with DMARDs and the availability of treatment outcomes. With this systematic review, we identified 35 studies and case reports/series on IgG4-ROD, describing 95 patients, treated with conventional and/or biologic DMARDs. The success of conventional DMARDs varies between 36% and 75% in patients with IgG4-ROD, while rituximab is successful in the majority (93%) of the patients. Based on this systematic review, rituximab is the most effective DMARD in IgG4-ROD, while the efficacy of conventional DMARDs is limited. We propose early initiation of rituximab in case of refractory and organ- or life-threatening disease., (© 2019 Acta Ophthalmologica Scandinavica Foundation. Published by John Wiley & Sons Ltd.)

Purpose: To report a case of IgG4-related ophthalmic disease (IgG4-ROD) which presented as choroidal and orbital lesions., Methods: Case report., Results: A 64-year-old man presented with left eye photopsias and a history of IgG4-related perirenal fibrosis. Fundoscopic examination showed multiple bilateral yellow choroidal lesions, and optical coherence tomography showed multiple choroidal lesions. Magnetic resonance imaging of the orbits showed an enhancing lesion present circumferential to the optic nerve, but greater medially, abutting the posterior surface of the left globe. Workup for infectious, autoimmune, and malignant etiologies was negative, and the patient has responded well to treatment with rituximab., Conclusion: IgG4-related disease is a systemic fibroinflammatory disease, which often presents in another location, as in our patient. In cases of uncertain choroidal and orbital lesions, a thorough workup for other etiologies is indicated, and lymphoma must be ruled out. Steroids are the mainstay of treatment for IgG4-ROD, however, small case series and our patient responded well to rituximab. To our knowledge, this is the first reported case of choroidal and orbital lesions secondary to IgG4-ROD.

Case Report: The case is presented of a 64-year-old woman with bilateral palpebral swelling and dacryoadenitis, exophthalmos, and a history of chronic rhinitis and asthma. An increase in serum IgG4 was observed, and an incisional biopsy of lacrimal glands was performed, which showed fibrosis and a lymphoplasmacytic infiltrate with IgG4 producing cells., Discussion: Orbital involvement in IgG4-related disease is frequent. Bilateral dacryoadenitis is the most common manifestation. Histopathology is essential for the diagnosis and to exclude malignancy., (Copyright © 2018 Sociedad Española de Oftalmología. Publicado por Elsevier España, S.L.U. All rights reserved.)

A 40 year-old male presented after one year of unilateral, progressive, steroid-responsive, orbital inflammatory disease causing proptosis, extraocular muscle (EOM) restriction, and compressive optic neuropathy. The development of anti-thyroidal antibodies prompted the diagnosis of thyroid eye disease (TED); however, the prolonged active phase, remarkable reversibility of ophthalmic features with high-dose corticosteroids, unilaterally of disease, uncharacteristic EOM involvement (including both obliques), and the absence of autoimmune thyroid disease provoked consideration of alternative diagnoses. Inferior oblique biopsy stained positive for IgG4 with histologic features atypical of TED. The patient received rituximab for presumed IgG4-related orbital disease (IgG4-ROD) with subsequent reversal of compressive optic neuropathy, near complete resolution of EOM restriction, and improved proptosis, the latter two of which are not routinely anticipated in advanced TED. The possible role for B-cell depletion in both TED and IgG4-ROD suggests a degree of overlap in the underlying immune-related pathophysiology that is yet to be defined.

Objective: To discuss the clinical features, imaging features, pathological patterns, treatment principles and prognosis of the orbital nonspecific inflammatory response diseases patients whose CT or MR images show enlargement of the infraorbital nerves. Methods: A retrospective case series study. Seven orbital disease patients who were treated at Tianjin Medical University Eye Hospital between March 2013 and May 2017 were included. All patients, imaging pictures showed enlargement of the infraorbital nerve. The medical histories, clinical featuers, imaging features, pathologies, serological examinations, therapeutic processes and prognosis were collected and analyzed. Results: The 7 patients included 4 males and 3 females aged from 55 to 68 years (the average age was 60). Bilateral involvement was present in 5 of 7 patients. The main clinical manifestations include proptosis, increasing of orbital pressure, impairment of visual functions, reduction in ocular motility, facial sensation, periocular ache, involvement of lymph node and salivary gland, etc. CT results showed enlargement of infraorbital nerve, accompanied with or without the destruction of bone. The inflammatory response may involve with extraocular muscles and lacrimal glands, or were shown as lesions with irregular shape and blurred borders. The MR images generally showed equal T(1) and equal T(2) signal, accompanied with evident enlargement of the infraorbital nerve. Of all the 7 patients, 6 underwent operation, and the pathology confirmed that 2 of the 6 were involved with inflammatory pseudotumors and the rest 4 were involved with IgG4-related ophthalmic disease (IgG4-ROD). The level of IgG4 in the serum were detected for 4 patients, the results of 3 were high and the other was normal. Of all the 7 patients,1 patient underwent conservative treatment, but disease recurred for several times, and the serum IgG4 level for the patient was higher than normal;1 inflammatory pseudotumor patient was cured completely only by surgery, and has a favourable prognosis; 1 IgG4-ROD patient accepted glucocorticoid, surgery, radiotherapy and chemotherapy, but disease recurred several times; The rest of the patients accepted glucocorticoid and operation, 2 were sensitive to glucocorticoid, 2 were not sensitive, and 1 involved with recurrence. Conclusions: If orbital nonspecific inflammation response was accompanied with enlargement of infraorbital nerve, it is suggested that patient is more likely to be involved with IgG4-ROD;Pathology and serological tests can be used for the diagnosis of IgG4-ROD, however treatment effect appears to be poor for most patients, and patients prone to relapse. (Chin J Ophthalmol, 2018, 54: 515-519) .

Introduction: There are limited data on the natural history of untreated myasthenia gravis (MG) with ocular presentation., Methods: We analyzed 93 patients from symptom onset who presented to the Birmingham Midlands Eye Centre (BMEC) between January 2004 and July 2015. We used multiple stepwise logistic regression to identify predictive factors of generalization and Kaplan-Meier analysis on time to generalization., Results: Forty-six percent of patients developed generalized symptoms during the study period. Median time to generalization was 7 months. Time to generalization was earlier in patients seropositive for acetylcholine receptor (AChR) antibody (median 5 months vs. 21 months, P < 0.0001) and bilateral ptosis at onset (P = 0.015). Multivariate analysis identified AChR seropositivity [hazard ratio (HR) 5.03; 95% confidence interval (CI) 1.48-17.14; P = 0.001] and disease onset < 50 years (HR 3.58; 95% CI 1.18-10.90; P = 0.035) as risk factors for generalization., Discussion: As patients were steroid-naive before generalization, our cohort approximated the natural history of the condition. Muscle Nerve 57: 622-627, 2018., (© 2017 Wiley Periodicals, Inc.)

The authors describe a 9-year-old female who presented with swelling, proptosis, and tenderness of the right upper eyelid and MRI imaging demonstrating right lacrimal gland enlargement. After failing treatment with corticosteroids, the patient underwent a biopsy that was consistent with IgG4-related orbital disease. She was subsequently successfully treated with adalimumab (TNF-α inhibitor). This is the first case report of the successful use of a TNF-α inhibitor for the treatment of IgG4-related orbital disease in a child.

Objective: To characterize the clinical correlates and outcome of inflammatory ocular disease (IOD) among patients with ANCA-associated vasculitides (AAV)., Methods: Medical records of potential cases of AAV seen at Mayo Clinic from 2003 to 2013, inclusive, were reviewed to identify confirmed cases meeting the diagnosis of AAV using the Chapel Hill Consensus Conference 2012 descriptors. Records of confirmed cases of AAV were then further reviewed for IOD, and clinical characteristics, treatment and outcomes abstracted., Results: A total of 1171 confirmed cases of AAV were identified of which 183 patients (mean age 49.0 years; 51% female; 95% Caucasian) had IOD. The most common manifestation of IOD was injection of the eye (57%) followed by eye pain (46%) and visual acuity loss (18%). Scleritis was the most common type of IOD (22%) followed by episcleritis (21%), orbital inflammation (18%), lacrimal duct stenosis (10%) and uveitis (9%). Oral glucocorticoids were used to treat IOD in the majority of patients (96%). CYC and rituximab were the most frequently used immunosuppressive agents (54 and 36%, respectively). Of those with orbital inflammation, 52% underwent therapeutic surgical intervention. Clinical remission of IOD was achieved in 91% of patients but relapses were seen in 23%. Significant visual acuity loss was observed in only six patients., Conclusion: IOD is a common manifestation of AAV and seen in about 16% of patients with AAV. Scleritis, episcleritis and orbital inflammation are the most common subtypes. Most patients respond well to glucocorticoids and immunosuppression, but relapse of IOD is common., (© The Author 2017. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oup.com)

Background/aim: Although flow cytometry (FCM) is used to evaluate cell surface markers of various leucocyte populations quantitatively, little is known about the usefulness of FCM in lymphoproliferative disorders of the ocular adnexa. The aim of this study was to disclose results of FCM, which were compared among IgG4-related ophthalmic disease (IgG4-ROD), idiopathic orbital inflammation (IOI), and extranodal marginal zone B-cell lymphoma (EMZL)., Materials and Methods: This is a retrospective observational study. Sixty-nine tumors comprising of 16 IgG4-ROD, 24 IOI, and 29 EMZL were enrolled in the study. All tumors, surgically excised, were diagnosed based on histopathology, immunoglobulin (Ig) heavy chain gene rearrangement, and FCM. In FCM, the percentage of T-cell markers (CD2, CD3, CD4, CD5, CD7, CD8), B-cell markers (CD10, CD19, CD20, CD23), NK cell marker (CD56) and cell surface kappa/lambda was searched based on medical records. Ig light chain restriction was evaluated from results in kappa/lambda deviation by FCM., Results: The percentage of CD2, CD3, CD4, CD7, and CD10 was significantly higher in IgG4-ROD/IOI than EMZL (p<0.05 in every factor). In contrast, CD19 and CD20 percentages were significantly greater in EMZL than IgG4-ROD/IOI (p<0.01). There was no significant difference in any marker between IgG4-ROD and IOI. Kappa-positive cells were significantly greater in EMZL than IgG4-ROD/IOI (p<0.05). In kappa/lambda deviation, false-positive was noted in 3 (7.5%) benign IgG4-ROD/IOI and false-negative was observed in 10 (34.5%) EMZL cases. Sensitivity and specificity of Ig light chain restriction were 65.5 and 92.5%, respectively., Conclusion: Analyses of cell surface markers using FCM were useful in differentiating EMZL from IgG4-ROD/IOI. Sensitivity of Ig light chain restriction was relatively low in diagnosis of EMZL using FCM., (Copyright© 2017, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

IgG4-related disease (IgG4-RD) is a rare, chronic inflammatory condition that may involve nearly every organ system. Originally identified as a cause of autoimmune pancreatitis, its characteristic histological and clinical features have been found in a wide variety of inflammatory presentations, including the eye and orbit. Here we describe an example of a case of IgG4-RD initially presenting as scleritis and vitritis, with further progression to multifocal bilateral orbital involvement. Tissue biopsy of an orbital mass was highly characteristic of IgG4-RD histology and a rapid clinical response to corticosteroids was observed. This case highlights IgG4-RD as a rare cause of intraocular inflammation that may progress to involve the orbit., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Ltd (unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Various approaches have been used to model human Graves' disease in mice, including transfected fibroblasts, and plasmid or adenoviral immunisations with the extracellular A subunit of the human thyrotropin receptor (TSHR). Some of these models were only observed for a short time period or were self-limiting. A long-term model for human Graves' disease was established in mice using continuing immunisations (4-weekly injections) with recombinant adenovirus expressing TSHR. Generation of TSHR binding cAMP-stimulatory antibodies, thyroid enlargement and alterations, elevated serum thyroxin levels, tachycardia and cardiac hypertrophy were maintained for at least 9 months in all Ad-TSHR-immunised mice. Here, we show that these mice suffer from orbitopathy, which was detected by serial orbital sectioning and histomorphometry. Attempts to treat established Graves' disease in preclinical mouse model studies have included small molecule allosteric antagonists and specific antagonist antibodies which were isolated from hypothyroid patients. In addition, novel peptides have been conceived which mimic the cylindrical loops of the TSHR leucine-rich repeat domain, in order to re-establish tolerance toward the antigen. Here, we show preliminary results that one set of these peptides improves or even cures all signs and symptoms of Graves' disease in mice after six consecutive monthly injections. First beneficial effects were observed 3-4 months after starting these therapies. In immunologically naïve mice, administration of the peptides did not induce any immune response.

Thyroid eye disease (TED) is a degenerative disease that manifests with detrimental tissue remodeling, myofibroblast accumulation, and scarring in the orbit of affected individuals. Currently, there are no effective therapies for TED that target or prevent the excessive tissue remodeling caused by myofibroblast formation and activation. The canonical cytokine that induces myofibroblast formation is transforming growth factor (TGF)-β. The TGF-β signaling pathway is influenced by aryl hydrocarbon receptor (AHR) signaling pathways. We hypothesized that AHR agonists can prevent myofibroblast formation in fibroblasts from patients with TED, and thus AHR ligands are potential therapeutics for the disease. Orbital fibroblasts explanted from patients with TED were treated with TGF-β to induce myofibroblast formation, contraction, and proliferation. We found that AHR ligands prevent TGF-β-dependent myofibroblast formation, and this ability is dependent on AHR expression. The AHR and AHR ligands block profibrotic Wnt signaling by inhibiting the phosphorylation of GSK3β to prevent myofibroblast formation. These results provide new insight into the molecular pathways underlying orbital scarring in TED. These novel studies highlight the potential of the AHR and AHR ligands as future therapeutic options for eye diseases and possibly also for other scarring conditions., (Copyright © 2016 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

Purpose: To evaluate ophthalmic involvement of systemic immunoglobulin-G4-related disease (IgG4-RD) and describe the changes in both ocular surface parameters and corneal subbasal nerve plexus., Materials and Methods: Twenty eyes of 10 patients with systemic IgG4-RD and 20 eyes of 10 control subjects were enrolled in this study. Demographic information, medical history, serum IgG4 levels, orbital imaging, and follow-up data of subjects were recorded. Ocular surface tests were carried out in the order of tear break-up time (BUT), lissamine green (LG) staining, Schirmer I test with anesthesia, and ocular surface disease index (OSDI) questionnaire for all participants. Corneal subbasal nerves and basal epithelial cell layer were evaluated using in vivo confocal microscopy., Results: Among the 10 patients with IgG4-RD, 11 eyes of 7 patients had orbital involvement. Among these 7 patients with IgG4-related ophthalmic disease, 4 presented with painless eyelid or periorbital swelling, 2 with diplopia and restricted ocular motility, and 1 with proptosis. Patients with IgG4-RD had higher OSDI (5.9 ± 6.6 vs. 1.7 ± 2.4, P < 0.001) and LG staining scores (0.7 ± 1.0 vs. 0.0 ± 0.0, P = 0.011) and lower BUT (5.6 ± 1.4 vs. 10.2 ± 1.0, P < 0.001) and Schirmer values (11.9 ± 10.3 vs. 18.3 ± 4.4, P = 0.021) as compared with those of control subjects. Total nerve density and nerve fiber length were found to be significantly lower in patients with IgG4-RD., Conclusions: The orbit is frequently involved during the course of IgG4-RD. These patients should be evaluated in terms of ocular surface disease and dry eye, which may be associated with lacrimal gland and/or orbital nerve involvement.

Purpose of Review: Checkpoint inhibitors have been increasingly considered as new targets for cancer therapies. Patients receiving checkpoint inhibitors develop many immune-related adverse events (IRAEs). However, ophthalmic IRAEs are rare and have been reported in less than 1% of patients. To date, few case reports evaluating the ophthalmological side-effects of checkpoint inhibitors have been published. In this review, we plan to report the different ocular and orbital side-effects of the checkpoint inhibitors, and to help guide ophthalmologists and oncologists in their management., Recent Findings: Ocular side-effects of checkpoint inhibitors include peripheral ulcerative keratitis, uveitis, Vogt-Koyanagi-Harada syndrome, choroidal neovascularization and melanoma-associated retinopathy. Both thyroid-associated orbitopathy and idiopathic orbital inflammation have also been reported in association with checkpoint inhibitors. Mild IRAE can be treated with topical steroids, whereas systemic corticosteroids and discontinuation of checkpoint inhibitors are indicated in more severe ocular and orbital inflammation., Summary: Physicians involved in the care of oncologic patients should be aware of the ocular and orbital IRAEs that may develop with checkpoint inhibitors. A strong cooperation between oncologists and ophthalmologists is required in the diagnosis and prompt management of these IRAEs.

Aim: To review the efficacy of intraorbital corticosteroid injection for the treatment of IgG4-related ophthalmic disease (IgG4-ROD)., Methods: This study was a retrospective twin-centre histopathology review and observational case series. A chart review was undertaken for 10 cases of biopsy-confirmed IgG4-ROD treated with intraorbital corticosteroid injection. The main outcome measures were the magnitude, onset and duration of the clinical response., Results: All cases received intraorbital injection(s) of 20 or 40 mg doses of triamcinolone acetonide suspension (Kenacort-A 40, Bristol-Myers Squibb, Australia). Intraorbital corticosteroid injection was associated with a swift positive response in all cases. 50% of cases achieved complete and sustained clinical remission during mean follow-up of 41 months. This was achieved with a single injection in three cases and with repeat injections in two cases. Peak clinical improvement was reached in ≤7 days following 61% of injections. 60% of cases suffered relapse and 56% of relapses occurred during weeks 3 or 4 following injection. Sclerosing histology was associated with a clinical response that was gradual in onset (p=0.01) and that tended to be incomplete (p=0.4). There were no complications of injection other than brief discomfort., Conclusions: Intraorbital injection of corticosteroid may be a useful treatment option for IgG4-ROD. It may have a role as a first-line therapy in selected cases of IgG4-ROD centred in the anterior orbit. However, most cases require repeat injections due to incomplete response and relapse., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/)

Orbital changes in thyroid orbitopathy (TO) result from de novo adipogenesis, hyaluronan synthesis, interstitial oedema and enlargement of extraocular muscles. Cellular immunity, with predominantly CD4+ T cells expressing Th1 cytokines, and overexpression of macrophage-derived cytokines, perpetuate orbital inflammation. Orbital fibroblasts appear to be the major effector cells. Orbital fibroblasts express both thyrotropin receptor (TSHR) and insulin-like growth factor-1 receptor (IGF-1R) at higher levels than normal fibroblasts. TSHR expression increases in adipogenesis; TSHR agonism enhances hyaluronan production. IGF-1R stimulation leads to adipogenesis, hyaluronan synthesis and production of the chemokines, interleukin (IL)-16 and Regulated on Activation, Normal T Cell Expression and Secreted, which facilitate lymphocyte trafficking into the orbit. Immune activation uses a specific CD40:CD154 molecular bridge to activate orbital fibroblasts, which secrete pro-inflammatory cytokines including IL-1β, IL-1α, IL-6, IL-8, macrophage chemoattractant protein-1 and transforming growth factor-β, to perpetuate orbital inflammation. Molecular pathways including adenylyl cyclase/cyclic adenosine monophosphate, phophoinositide 3 kinase/AKT/mammalian target of rapamycin, mitogen-activated protein kinase are involved in TO. The emergence of a TO animal model and a new generation of TSHR antibody assays increasingly point towards TSHR as the primary autoantigen for extrathyroidal orbital involvement. Oxidative stress in TO resulting from imbalances of the oxidation-reduction state provides a framework of understanding for smoking prevention, achieving euthyroidism and the use of antioxidants such as selenium. Progress has been made in the understanding of the pathogenesis of TO, which should advance development of novel therapies targeting cellular immunity, specifically the CD40:CD40 ligand interaction, antibody-producing B cells, cytokines, TSHR and IGF-1R and its signalling pathways. Further studies in signalling networks and molecular triggers leading to burnout of TO will further our understanding of TO., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/)

Langerhans cell histiocytosis (LCH) is a proliferation of Langerhans cells intermixed with inflammatory cells, in particular eosinophils, that may manifest as a unisystem (unifocal or multifocal) or multisystem disease. We describe the clinical and histologic spectrum of LCH of the orbit and skull in our two cases. Both cases had unifocal erosive skull lesions with a history of trauma. Typical histologic features included numerous histiocytes with varying degrees of giant cell formation and scattered eosinophilic granulocytes. The presence of Langerhans cells was confirmed by CD1a and S100 immunohistochemistry. LCH has an excellent prognosis when treated with surgical resection, steroids and radiotherapy or chemotherapy. One of our patients is disease free at 7 year follow-up and one patient had regression of lesion on follow-up.

Objective: Descriptive and comparative study of patients with orbital IgG4-related disease., Material and Methods: A review and analysis of the cases diagnosed with inflammatory orbital lesion related to IgG4 by the Ophthalmic Pathology Service in the Dr. Luis Sánchez Bulnes Hospital., Results: A total of 9 cases were found, in which 66% were women, and with a mean age of 48 years and time to diagnosis of 2 years. Unilateral involvement was observed in 56% of cases. All the females experienced pain, and there was an optimal response to corticosteroid treatment in 100% of patients who required medical treatment (one case showed spontaneous resolution). In bilateral cases (44%), only 25% were female, and none had pain as a presenting symptom. Furthermore, 25% of these patients required a combination with immunosuppressants to control inflammation., Conclusions: Clinical presentation of patients with unilateral orbital IgG4-related disease differs from those with bilateral involvement., (Copyright © 2014 Sociedad Española de Oftalmología. Published by Elsevier España, S.L.U. All rights reserved.)

IgG4-related disease is a systemic fibro-inflammatory disorder mainly affecting the middle-aged and elderly population. IgG4-related orbital disease is very rare in childhood. We present here two children with IgG4-related orbital disease, one of whom responded well to prednisolone treatment while the other one was refractory to most immunosuppressive agents. It is important to treat patients at the early active stage of disease before fibrotic changes predominate. Thus, although rare, increased awareness of IgG4-related orbital disease in childhood may avoid delays in diagnosis and treatment.

Midline Destructive Lesions (MDL) are well known to cause nasal problems. There is a long differential diagnosis of such lesions. However, in the pediatric population, the 2 main diseases to be aware of are Non-Hodgkin's T-cell lymphoma and granulomatosis with polyangiitis (previously known as Wegener's granulomatosis). The authors present the report of a 15-year-old boy who presented with epiphora, chemosis, and limitation of left abduction. CT scan of his orbits suggested a destructive lesion of the ethmoid sinuses. His laboratory investigations revealed a positive ANCA. The patient underwent endoscopic sinus surgery, and this was characteristic for granulomatosis with polyangiitis. He was treated with systemic steroids and then maintained on cyclophosphamide, which controlled his disease activity. This case highlights the need for ophthalmologists to have a high index of suspicion for MDL and concomitant orbital disease.

Aim: To determine the proportion of idiopathic orbital inflammation (IOI) and orbital benign lymphoid hyperplasia (OBLH) accounted for by immunoglobulin (Ig)G4-related orbital disease (IgG4-ROD) using the comprehensive diagnostic criteria for IgG4-related disease published by Umehara et al and the consensus diagnostic criteria published by Deshpande et al. Secondary aims were to compare the histological and clinical features of IgG4-ROD and non-IgG4-ROD cases, and to compare IgG4-ROD cases diagnosed using the comprehensive diagnostic criteria with those diagnosed using the consensus diagnostic criteria., Methods: A retrospective histopathological review and clinical case series. 55 cases of biopsy-confirmed non-granulomatous IOI and 10 cases of biopsy-confirmed OBLH were included. The intensity of sclerosis, lymphoplasmacytic infiltration and eosinophilic infiltration was graded from 0 to 3+ using a standardised and validated scoring system., Results: IgG4-ROD accounted for 50% and 40% of cases originally diagnosed as OBLH and 23.6% and 5.4% of cases originally diagnosed as IOI, using the comprehensive diagnostic criteria and the consensus diagnostic criteria, respectively. IgG4-ROD cases had numerous significant histological differences, but relatively few significant clinical differences, from non-IgG4-ROD cases. Compared with the comprehensive diagnostic criteria, the consensus diagnostic criteria identified a group of IgG4-ROD cases with a slightly higher ratio of IgG4+ to IgG+ (p=0.01) and a slightly longer duration of symptoms (p=0.02)., Conclusions: This is the largest review of IgG4 staining among biopsy-confirmed IOI and OBLH. IgG4-ROD accounted for a substantial proportion of OBLH. The prevalence among cases of IOI was considerably reduced when the consensus diagnostic criteria were used in place of the comprehensive diagnostic criteria., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.)

Background: Kimura's disease (KD) is a rare and benign chronic inflammatory soft tissue disorder of unknown origin, which predominantly inflicts young male adults in Asia. IgG4-related disease is a new disease concept, established this century and characterized by fibrosis and sclerosis of the involved organs, with infiltration of IgG4-positive plasma cells. These two kinds of diseases share similar characteristics, which may complicate their diagnosis., Case Presentation: A 47-year-old Chinese man presented to our Department of Ophthalmology with a 26-month history of painless swelling and redness left upper eyelid. Surgical excisions of the left lacrimal gland were performed. A histopathology examination showed follicular hyperplasia with reactive germinal centres and eosinophilic infiltration involving the interfollicular areas as well as proliferation of post capillary venules, all signs of Kimura disease. Immunohistochemical analysis of the cells demonstrated positive staining for CK, Vimentin, CD3, CD4, CD20, CD21, CD117, CD5, CD8, CD23, IgG and IgG4 (30 per high-power field) and negative staining for CD10 and CD34. Some ophthalmologists in our department questioned whether the histological and immunohistochemical findings were also compatible with features of IgG4-related diseases. There was no sign of recurrence during the twelve months of regular follow-up., Conclusion: Kimura's disease may present with high serum IgG4 levels, which may be an epiphenomenon related to chronic antigen exposure. As clinical doctors, especially ophthalmologists, we should recognize the possibility of the occurrence of increased serum levels of IgG4 in Kimura's disease to ensure correct diagnosis.

Orbital inflammation is a generic term encompassing inflammatory pathologies affecting all structures within the orbit : anterior (involvement up to the posterior aspect of the globe), diffuse (involvement of intra- and/or extraconal fat), apical (involvement of the posterior orbit), myositis (involvement of only the extraocular muscles), dacryoadenitis (involvement of the lacrimal gland). We distinguish between specific inflammation and non-specific inflammation, commonly referred to as idiopathic inflammation. Specific orbital inflammation corresponds to a secondary localization of a "generalized" disease (systemic or auto-immune). Idiopathic orbital inflammation corresponds to uniquely orbital inflammation without generalized disease, and thus an unknown etiology. At the top of the differential diagnosis for specific or idiopathic orbital inflammation are malignant tumors, represented most commonly in the adult by lympho-proliferative syndromes and metastases. Treatment of specific orbital inflammation begins with treatment of the underlying disease. For idiopathic orbital inflammation, treatment (most often corticosteroids) is indicated above all in cases of visual loss due to optic neuropathy, in the presence of pain or oculomotor palsy., (Copyright © 2014 Elsevier Masson SAS. All rights reserved.)

Objective: To study the clinicopathologic characteristics of IgG4-related disease in the orbital and periorbital tissue., Methods: The clinical manifestations and pathologic features of 17 cases of IgG4-related disease affecting the orbital and periorbital tissue encountered during the period from 2012 to 2013 were studied., Results: There were 9 male patients and 8 female patients. The age of patients ranged from 11 to 71 years (mean = 48.5 years). The main clinical manifestation was swelling of the eyelids: bilateral in 11 patients and unilateral in 6 patients. The duration of disease ranged from 5 months to 7 years (more than 2 years in 13 cases). Six patients had history of allergic disorders. In addition to orbital/periorbital involvement, the disease also affected salivary gland, lymph node, lung and kidney. The disease relapsed in 9 patients. Amongst the 8 patients treated with steroids, 5 of them achieved complete remission and the remaining 3 patients had partial remission. The IgG4 level of the 17 cases ranged from 1.49 to 14.88 g/L. Histologic examination showed pseudolymphoma pattern in 8 cases, mixed pattern in 8 cases and sclerotic pattern in 1 case. There were various degrees of lymphoplasmacytic infiltrates (with lymphoid follicle formation) and stromal fibrosis. Classical obliterative phlebitis was absent. Tissue eosinophilia was demonstrated in the 17 cases studied. Immunohistochemical study showed the presence of more than 50 IgG4-positive plasma cells per high-power field, with IgG4/IgG plasma cells ratio more than 40%., Conclusion: There are characteristic clinical manifestations, pathologic features and laboratory findings in orbital and periorbital IgG4-related disease. Thorough understanding is important in arriving at a correct diagnosis.

Common autoimmune disorders tend to co-exist in the same subjects and cluster in families. The objective of this study was to determine the prevalence of autoimmune co-morbidity in patients with autoimmune thyroid disease (AITD) with and without thyroid-associated orbitopathy (TAO). This was a cross-sectional study conducted at an academic tertiary referral centre. Of 1310 patients with AITD [n = 777 or 59% with Graves' disease (GD) and n = 533, 41% with Hashimoto's thyroiditis (HT)] followed at a specialized joint thyroid-eye out-patient clinic, 176 (13·4%) had an adult type of the autoimmune polyglandular syndrome, 129 (9·8%) type 1 diabetes, 111 (8·5%) coeliac disease, 60 (4·6%) type A autoimmune gastritis, 57 (4·4%) vitiligo and 25 (1·9%) Addison's disease. Coeliac disease and autoimmune gastritis were associated positively with GD [odds ratio (OR) = 2·18; P = 0·002 and OR = 6·52; P < 0·001], whereas type 1 diabetes, Addison's disease, autoimmune primary hypogonadism, alopecia areata, rheumatoid arthritis and Sjögren's syndrome were 'protective' for GD and thus linked to HT, OR = 0·49 (P < 0·001), 0·06 (P < 0·001), 0·25 (P < 0·001), 0·50 (P = 0·090) and 0·32 (P = 0·003), respectively. Of 610 (46·6%) AITD patients with TAO, 584 (95·7%) and 26 (4·3%) had GD and HT, respectively (P < 0·001). TAO was most prevalent in GD patients with coeliac disease (94%, OR = 1·87, P < 0·001). Multivariate analysis showed high OR for coeliac disease and autoimmune gastritis (3·4 and 4·03, both P < 0·001) pertaining to the association with TAO while type 1 diabetes, Addison's disease and alopecia areata were protective for TAO. In patients with TAO, coeliac disease is the most prevalent co-morbid autoimmune condition and rates are increased compared to GD patients without TAO., (© 2014 British Society for Immunology.)

IgG4 related systemic disease (IgG4-RSD) has been recognised in the last few years. Orbital pseudotumor as a presentation of IgG4-RSD is one of the rare complaints encountered in pediatric population. It is an inflammatory condition of unknown etiology characterized by tumorous swelling of the organs, characteristic histopathologic changes and elevated IgG4: IgG plasma cells ratio. The disease is also characterized by involvement of varied organ systems. The authors describe a seven-year-old boy with orbital pseudotumor after two years of initial onset with waxing and waning course, steroid responsive lesion and biopsy suggestive of IgG4-RSD involving the extraocular soft tissue. Treatment with oral corticosteroids and Azathioprine produced a significant decline in the pseudotumor size. It is important for pediatricians to be aware of this condition as appropriate recognition and management is important to prevent long-term damage of the tissue involved. This is the first case of IgG4 related orbital pseudotumor reported from India.

Immunoglobulin-G4-related disease (IgG4-RD) is a distinct group of diseases characterized by elevated serum IgG4 titres and infiltration of affected organs by IgG4-positive plasma cells. IgG4-RD can involve any ocular adnexal tissue. They have a distinct prognosis and pattern of tissue involvement and hence need to be differentiated from orbital lesions with similar clinicopathological features. We report three cases of IgG4-RD and review the literature extensively discussing various aspects of this novel entity., (© 2013 Royal Australian and New Zealand College of Ophthalmologists.)

The pathology of granulomatosis with polyangiitis (GPA), formerly Wegener granulomatosis, typically features a granulomatous and sometimes necrotizing vasculitis targeting the respiratory tract and kidneys. However, orbital involvement occurs in up to 60% of patients and is frequently the first or only clinical presentation in patients with systemic or limited forms of GPA. Orbital GPA can cause significant morbidity and potentially lead to complete loss of vision and permanent facial deformity. Fortunately, GPA is highly responsive to medical treatment with corticosteroids combined with cyclophosphamide or, more recently, rituximab. Therefore, it is imperative for this disease to be accurately diagnosed on orbital biopsy and distinguished from other histologically similar orbital lesions. Herein, we review the clinical and pathologic findings of orbital GPA, focusing on the differentiation of this disease from other inflammatory orbital lesions.

Background and Purpose: Immunoglobulin G4-related disease is a systemic fibroinflammatory process of unknown etiology, characterized by tissue infiltration by immunoglobulin G4 plasma cells. The purpose of this study was to retrospectively identify the spectrum of imaging features seen in immunoglobulin G4-related disease of the orbit., Materials and Methods: This study included 27 patients with biopsy-proved immunoglobulin G4-related disease of the orbit and either a CT or MR imaging of the orbits. These CT or MR imaging examinations were evaluated for the following: extraocular muscle size, extraocular muscle tendon enlargement, lacrimal gland enlargement, infiltrative process in the orbital fat (increased attenuation on CT or abnormal signal on MR imaging), infraorbital nerve enlargement, mucosal thickening in the paranasal sinuses, and extension of orbital findings intracranially., Results: Extraocular muscles were enlarged in 24 of 27 (89%) patients, 21 (88%) bilaterally. In 32 of 45 (71%) affected orbits, the lateral rectus was the most enlarged muscle. In 26 (96%) patients, the tendons of the extraocular muscles were spared. Nineteen (70%) patients had lacrimal gland enlargement. Twelve (44%) patients had an infiltrative process within the orbital fat. Infraorbital nerve enlargement was seen in 8 (30%) patients. Twenty-four (89%) patients had sinus disease. Cavernous sinus or Meckel cave extension was seen in 3 (11%) patients., Conclusions: In patients with extraocular muscle enlargement, particularly when the tendons are spared and the lateral rectus is the most enlarged, and even more so when other noted findings are present, immunoglobulin G4-related disease should be a leading differential consideration, even over more commonly known etiologies of extraocular muscle enlargement., (© 2014 by American Journal of Neuroradiology.)

Isolated sphenoid sinus disease is a rare entity with severe and potentially life threatening sequela. Because of the proximity of the sinus to the orbit, anatomical defects within the surrounding bony structures can facilitate communication with orbital content, predisposing the patient to substantial visual consequences. We report a case of a 51-year-old immunocompromised male who presented with headache and gradual unilateral decreases in vision. Computed tomography revealed opacification of the left sphenoid sinus accompanied by unusual bony dehiscence of the proximal optic canal. Early recognition and treatment of sphenoid sinusitis requires urgent surgical intervention with delay of treatment potentially leading to irreversible blindness or other devastating consequences. Bony dehiscence of the sphenoid sinus overlying the optic nerve has only been found in 4% of cadavers. It is associated with increased risk of orbital complications and predicts a poor prognosis. Immediate intervention is particularly important in immunocompromised individuals who are at greater risk of these severe complications.

Background: To describe a presumptive case of immunoglobulin G4-related ophthalmic disease (IgG4-ROD) with bilateral optic nerve involvement and to review the clinical features of this entity., Methods: Case report., Results: A 62-year-old man presented with bilateral blurred vision. He had a history of sinus surgery, and a biopsy specimen showed dense infiltration of IgG4-positive plasma cells. His visual acuity was 20/25, right eye, and 20/125, left eye. Serologies demonstrated elevated serum levels of IgG and IgG4, and computed tomography showed masses surrounding both optic nerves at the orbital apices and bilaterally enlarged infraorbital nerves. The patient underwent 2 cycles of intravenous pulse steroid therapy followed by a taper of oral steroids Three months later, vision was 20/20 in each eye and, while the serum level of IgG was within normal limits, the IgG4 level remained elevated., Conclusion: IgG4-ROD may involve the optic nerves resulting in vision loss. Although steroid administration is the primary treatment for this entity, slow tapering is essential to avoid relapse.

IgG4-related disease is an emerging disease entity characterized by elevated serum IgG4 concentration and tumefaction or tissue infiltration by IgG4-positive plasma cells. In IgG4-related disease, tumor-like lesions develop in multiple organs, such as the lacrimal gland, salivary gland, lung, pancreas, kidney, and lymph nodes. We report here three cases of IgG4-related orbital inflammation that presented as unilateral pseudotumors. The patients all were men, with an age range of 65-75 years. The patients had been pointed out unilateral intra-orbital masses, and histopathological examinations revealed marked accumulation of IgG4-positive plasma cells (IgG4/IgG ratio: 51.1-71.6%) with fibrosis. But storiform fibrosis was seen in only one case, and no obliterative phlebitis was seen. The serum levels of IgG4 were increased to 178-670 mg/dL. The masses had well-defined homogeneous signal intensities, and they were hypo-intense on T1-weighted MR images and iso-intense on T2-weighted MR images. Gadolinium enhanced mass lesions in two cases. All orbital mass lesions responded well to corticosteroid treatment.

Background: Immunoglobulin G4 (IgG4)-related sclerosing disease is a systemic disease characterized by extensive IgG4-positive plasma cells and T-lymphocyte infiltration of various organs. We present a case of a 69-year-old man with maxillary sinus IgG4 sclerosing disease, with orbital invasion treated with rituximab and dexamethasone pulse therapy. Surgery was used as well to debulk the disease and to obtain tissue for diagnosis., Methods: A PubMed search using the key phrase "IgG4-related Sclerosing Disease" was performed. There were 304 different articles regarding the disease for a multitude of different organ sites. Of the 304 articles, there were 3 articles that reported this disease in the paranasal sinuses., Conclusions: IgG4-related sclerosing disease is a rare entity in the head and neck. There are documented reports of steroid therapy for this disease, but the patient presented here demonstrated clinical progression of disease with steroids alone. The use of combination therapy of surgery, dexamethasone, and rituximab provided clinical improvement and stable disease determined by radiographic means., (Copyright © 2013 Wiley Periodicals, Inc.)

Graves' disease (GD) is a systemic autoimmune disease that is characterized by hyperthyroidism, orbitopathy and in rare cases dermopathy. Graves' orbitopathy (GO) is an inflammatory disease of eye and orbit which occurs in about 30-60% of patients. Hyperthyroidism occurs due to the presence of stimulating TSHR-autoantibodies (TRAbs) leading to increased serum levels of thyroid hormones. Attempts to induce Graves' disease in mice by immunization against the hTSHR or its variants have resulted in production of TRAbs that stimulate thyroid follicular cells to increase thyroid hormone secretion. Graves' like orbital changes, such as inflammation, adipogenesis and muscle fibrosis are more difficult to induce. In this review we summarize different methods used to induce murine Graves'-like disease and their impact on murine orbits., (© Georg Thieme Verlag KG Stuttgart · New York.)

Purpose: Immunoglobin G4 (IgG4)-related disease is a systemic condition characterized by lymphoplasmacytic infiltrates that can involve the orbit. The purpose of this study was to identify the various patterns of orbital IgG4-related disease on imaging., Methods: Retrospective review of radiologic examinations including CT, MRI, and positron emission tomography was performed in patients with proven cases of IgG4-related disease., Results: A total of 9 patients with orbital IgG4-related disease were identified, including 9 with CT, 4 with MRI, and 4 with 18-fluorodeoxyglucose positron emission tomography. Patterns of involvement included lacrimal gland enlargement, lacrimal sac involvement, extraocular muscle thickening, preseptal involvement, orbital fat involvement, and cranial nerve involvement, many of which occurred simultaneously. Associated demineralization of the orbital wall was evident on CT in 2 cases. On T2-weighted MRI, the lesions appeared as hypointense in 2 cases, heterogeneously hypointense to isointense in 1 case, and hyperintense in 1 case. Diffuse enhancement was present in all 3 cases in which postcontrast T1-weighted sequences were available. The lesions were hypermetabolic on positron emission tomography in 3 of 4 cases. There was definite extraorbital involvement by IgG4-related disease in 3 of the 9 patients and suspected involvement in another 3 of the 9 patients., Conclusions: IgG4-related disease displays a wide variety of imaging manifestations in the orbit. Extraorbital disease is often present and can help suggest the diagnosis.