The potential of tear proteomics for diagnosis and management of orbital inflammatory disorders including Graves' ophthalmopathy.

BACKGROUND: Orbital compartments harbor a variety of tissues that can be independently targeted in a plethora of disorders resulting in sight-threatening risks. Orbital inflammatory disorders (OID) including Graves' ophthalmopathy, sarcoidosis, IgG4 disease, granulomatosis with polyangiitis, and nonspecific orbital inflammation constitute an important cause of pain, diplopia and vision loss. Physical examination, laboratory tests, imaging, and even biopsy are not always adequate to classify orbital inflammation which is frequently deemed "nonspecific". Tear sampling and testing provide a potential "window" to the orbital disease process through a non-invasive technique that allows longitudinal sampling as the disease evolves. Using PubMed/Medline, we identified potentially relevant articles on tear proteomics published in the English language between 1988 and 2021. Of 303 citations obtained, 225 contained empirical data on tear proteins, including 33 publications on inflammatory conditions, 15 in glaucoma, 15 in thyroid eye disease, 1 in sarcoidosis (75) and 2 in uveitis (77,78). Review articles were used to identify an additional 56 relevant articles through citation search. In this review, we provide a short introduction to the potential use of tears as a diagnostic fluid and tool to investigate the mechanism of ocular diseases. A general review of previous tear proteomics studies is also provided, with a focus on Graves' ophthalmopathy (GO), and a discussion of unmet needs in the diagnosis and treatment of orbital inflammatory disease (OID). The review concludes by pointing out current limitations of mass spectrometric analysis of tear proteins and summarizes future needs in the field.

Serum IgG2 and tissue IgG2 plasma cell elevation in orbital IgG4-related disease (IgG4-RD): Potential use in IgG4-RD assessment.

AIMS: To determine the role of serum and tissue IgG2 in orbital biopsies with the histological features of IgG4-related disease (IgG4-RD) in comparison with non-IgG4-related orbital inflammatory disorders (OID), including autoimmune disorders. METHODS: This is an international (Sheffield, UK, and Singapore) collaborative, retrospective case review of 69 patients (38 from Singapore National Eye Centre and 31 from Royal Hallamshire Hospital, Sheffield) with orbital inflammatory biopsies between 2002 and 2016. Clinical information and histology were reviewed and cases were classified into three groups: Group 1: IgG4-RD orbital inflammation (n=43); Group 2: idiopathic OID (n=12) and Group 3: autoimmune OID (n=14). Serum IgG1, IgG2, IgG3 and IgG4 levels were collated where available and immunohistochemistry (IHC) for tissue IgG2 plasma cells was performed. RESULTS: Dual IHC showed IgG2 plasma cells as a distinct population from IgG4 plasma cells. Significant (twofold) serum IgG2 elevation was noted among IgG4-RD (group 1), idiopathic (group 2) and autoimmune OID (group 3). Similarly, significant elevation of tissue IgG2 plasma cells was also seen among IgG4-RD (group 1), idiopathic and autoimmune OID (groups 2 and 3). CONCLUSIONS: Significant elevations of serum IgG2 and tissue IgG2 plasma cells are present in orbital IgG4-RD in comparison with non-IgG4 orbital inflammation (idiopathic and autoimmune OID), suggesting that IgG2 may play a role in IgG4-RD. A serum IgG2 cut-off >5.3 g/L was found to be 80% sensitive and 91.7% specific for orbital IgG4-RD, with an accuracy of 0.90. Tissue IgG2 and IgG4 subclass reporting may provide additional insight regarding the 'IgG4-RD' pathogenesis.

Spontaneous regression of inflammatory myofibroblastic tumor of the orbit: A case report and review of literature.

Inflammatory myofibroblastic tumor is a rare entity characterized by the presence of myofibroblasts and inflammatory cells within a fibrous stroma. It typically occurs in the pediatric population. The most common site of occurrence is the lung though it has been reported throughout the body. Although rare, it has been reported in the orbit. The clinical course is ill defined in the literature; here we report a case of pediatric IMT with delayed spontaneous regression.

Inflammatory myofibroblastic tumor of the orbit: a case report.

Inflammatory myofibroblastic tumor (IMT) is a neoplasm most commonly found in the abdominal-pelvic region, lung, and retroperitoneum. The tumor tends to affect soft tissues of children and young adults and can locally recur but rarely metastasizes. Histologically, the appearance is one of bland spindle cell proliferation with a prominent, chronic inflammatory infiltrate. This article describes 1 case of IMT found in the orbit that is presented with rapidly progressive painless proptosis. In the authors' review of the literature, they have only found 2 other case reports involving the orbit.

Nitrogen bisphosphonate-induced orbital inflammatory disease: gamma delta T cells--a report and review of 2 cases.

With the increased use of nitrogen bisphosphonate therapy for osteoporosis, multiple myeloma, metastatic prostate carcinoma, and Paget disease, it is now recognized that orbital inflammation is a potential sequelae of treatment. To date, 15 isolated cases of orbital inflammation exist in the literature with additional 2 cases reported herein. While the precise triggering mechanism for orbital inflammation is not definitively understood, it appears that a regulatory response from gamma delta T cells is the most likely causative factor. Nitrogen bisphosphonates are a causative agent of orbital inflammatory disease. These case reports adhered to the principles of Helsinki and the Health Insurance Portability and Accountability Act.

Inflammatory pseudotumor in head and neck.

BACKGROUND: Inflammatory pseudotumor (IPT) is a tumefactive lesion characterized by fibroblastic proliferations and a prominent inflammatory component. It behaves as a locally benign or aggressive lesion, clinically and radiologically mimicking a neoplastic process. Numerous entities can be diagnosed as IPT, from reactive lesions to true neoplasms. The diagnosis of IPT requires further elaboration, and IPT should be distinguished from other similar entities such as inflammatory myofibroblastic tumor and IgG4-related sclerosing disease. CASE SUMMARY: We report two cases of IPT arising from the head and neck region. One occurred at the orbit and the other at the parapharyngeal space. Histologically, they showed aggregates of myofibroblasts and inflammatory cells. Immunohistochemically, the number of IgG4-positive cells was less than 40% of the number of IgG positive cells, and the myofibroblastic cells were negative for anaplastic lymphoma kinase. The diagnosis was IPT/not otherwise specified. One patient was treated by systemic administration of corticosteroid and had good response. The other, who was treated by local administration of corticosteroid, partially responded and is currently stable with limited disease. DISCUSSION: IPT has been reported to occur in various anatomical sites, most commonly in the lungs. The incidence in the head and neck area is extremely rare. Treatment of IPT is controversial and may involve corticosteroids or surgical resection, or both. Other chemotherapeutic agents and radiotherapy may be considered in steroid-resistant patients. The pathological subtype, safety of resection, and safety of corticosteroid use must be included in the decision-making process for treatment.

Toll-like receptors in idiopathic orbital inflammation.

PURPOSE: A prior investigation has demonstrated that innate immune-specific cytokines are enriched in idiopathic orbital inflammation (IOI). To further document the role of innate immunity in IOI, the authors sought to determine whether toll-like receptors (TLRs) are present in biopsy specimens of this disorder. METHODS: Immunohistochemical staining for TLR2, TLR3, and TLR4 was performed on biopsy specimens taken from patients with IOI, and the number of TLR-positive cells was counted across five 40× light microscopic fields. These results were compared with an isotype control and with orbital adipose tissue taken from patients without evidence of inflammation. RESULTS: All IOI specimens demonstrated positivity for all 3 TLRs, and sections stained for isotype controls did not demonstrate any positivity. Furthermore, orbital adipose tissue did not demonstrate any significant signal. The mean number of positive cells was 24.4 cells/high power field (hpf; standard deviation = 11.6 cells/hpf), 7.23 cells/hpf (standard deviation = 5.59 cells/hpf), and 11.7 cells/hpf for TLR2, TLR3, and TLR4, respectively. CONCLUSIONS: This study provides the first documentation of TLRs in orbital disease. Toll-like receptors are present in IOI, and IOI may represent an aberrant innate immune response. Interference with TLRs may represent an additional potential therapeutic mechanism in the management of IOI.

Characterization of the molecular biologic milieu of idiopathic orbital inflammation.

PURPOSE: To identify the cytokines that are expressed in elevated concentrations in idiopathic orbital inflammation (IOI). DESIGN: Experimental study. PARTICIPANTS AND CONTROLS: Biopsy specimens from 8 patients with biopsy-proven IOI and negative serologic and radiographic examinations, versus orbital biopsy samples taken from 8 control patients without clinical evidence or subjective complaint of orbital inflammation. METHODS: Quantitative cytokine assays were performed to assess the levels of 9 different molecules for IOI and control patients. Statistical analyses were performed to compare the cytokine concentrations between the 2 groups. MAIN OUTCOME MEASURES: Cytokine concentrations. RESULTS: Six cytokines were statistically significantly elevated in IOI (interleukin-2, -8, -10, -12, gamma interferon, and tumor necrosis factor alpha) (p < 0.05). Gamma interferon and interleukin-12 were expressed at concentrations greater than 10 times higher in patients with IOI. CONCLUSIONS: IOI involves discrete elevations of specific cytokines, and individual molecules are clearly implicated in the pathogenesis of this disease. Specifically, gamma interferon and interleukin-12 concentrations are markedly elevated in IOI. These cytokines represent novel therapeutic targets in the management of this inflammatory process. Agents that affect these molecules could be used as potential therapies to control this disease in a more effective fashion with fewer side effects.

Inflammatory myofibroblastic tumor of the orbit presenting as a subconjunctival mass.

PURPOSE: To present a case of inflammatory myofibroblastic tumor in the anterior orbit and to describe its clinical features, diagnosis, and management. METHODS: Case report and literature review. RESULTS: A 10-year-old boy presented with diplopia and limited ocular motility in his right eye secondary to a subconjunctival mass in the right supranasal side. Incisional biopsy and debulking were performed. Histopathologic examination showed the proliferation of spindle-shaped myofibroblasts that were immunoreactive for smooth muscle actin and vimentin and infiltrate of inflammatory cells. CONCLUSIONS: We believe this is the first case of an inflammatory myofibroblastic tumor found localized in the orbit.

Immunohistochemical profile of lymphoid lesions of the orbit.

BACKGROUND: Orbital idiopathic inflammation, lymphoid hyperplasia, and lymphoma may all present clinically in the same manner. Histopathology and especially immunohistochemistry play a major role in the differential diagnosis. The purpose of this study was to determine the immunophenotypic features of these lesions. METHODS: Fifty-five orbital lymphoid lesions were retrieved from the ophthalmic pathology registries at McGill University, Montreal, Canada, and the Federal University of São Paulo, São Paulo, Brazil. Formalin-fixed, paraffin-embedded, histopathologic sections were stained with hematoxylin and eosin and periodic acid-Schiff. The sections were also immunostained for B-cell (CD20) and T-cell (CD43) markers and for immunoglobulin light chains kappa and lambda. Two pathologists determined the histopathologic and immunohistochemical pattern of each lesion in a masked fashion. RESULTS: Of the 55 lesions, 11 (20%) were idiopathic chronic inflammations, 22 (40%) were lymphoid hyperplasias and 22 (40%) were lymphomas. Idiopathic inflammation displayed a predominance of T cells and all lesions expressed polyclonal light chains. Lymphoid hyperplasia displayed a mixture of B cells and T cells, with a slight predominance of the former and all lesions expressed polyclonal light chains. Lymphoma showed a striking predominance of B cells and all lesions expressed monoclonal light chains, usually kappa (63.7%). The differences in the mean percentages of B cells among the orbital lymphoid lesions (inflammation, 35%; hyperplasia, 65.9%; lymphoma, 87.3%) were statistically significant (p < 0.001). INTERPRETATION: Orbital lymphoid lesions can be differentiated based on the percentages of B cells and T cells and the monoclonal or polyclonal expression of immunoglobulin light chains.

[Clinical and radiological features and clinical course of orbital myositis]. / Myosite orbitaire: étude clinique, radiologique et profil évolutif.

Orbital myositis is idiopathic inflammation of the extraocular muscles in the absence of thyroid orbitopathy and often is included under broad description pseudotumor. We report here a series of three cases. Data from literature, combined with our own results yield a distinguishing pattern of orbital myositis suggesting that the term "orbital pseudotumor" is no longer a useful concept. The diagnostic criteria purposed here are: acute orbital pain exacerbated on eye movement; enlargement of one or more extraocular muscles with the respect of other orbital structures on muscle CT scan; absence of clinical and biological thyroid dysfunction: absence of signs of anterior uveitis or scleritis or visual decrease; rapid response to immunomodulator treatment.

Idiopathic orbital inflammation: ocular mechanisms and clinicopathology.

Pathogenesis of idiopathic orbital inflammation remains elusive but several lines of evidence point to immune-mediated processes as the likely underlying ocular mechanism. The exact nature of the immunological process and possible role of infection need to be elucidated in greater depth. There is an obvious need for a more satisfactory animal model for orbital pseudotumor. Given the prevalence of recurrent and persistent orbital inflammation, therapeutic alternatives to corticosteroids need to be further explored and systematically investigated.

Immunohistology of eye muscle in idiopathic orbital inflammatory disease (pseudotumor), Graves' ophthalmopathy and healthy controls.

Inflammatory orbital disease can be triggered by a variety of causes. Two such diseases are pseudotumor orbitae and Graves' ophthalmopathy, and both involve extraocular muscles. Biopsies were obtained from ocular muscles during a quiet phase in these two diseases. Biopsies obtained from a previous pseudotumor orbitae showed complement deposits and increased expression of HLA class-I antigens in the intermuscular tissue. The biopsies from two out of four pseudotumor cases and two out of four Graves' ophthalmopathy cases contained increased numbers of intermuscular HLA class-II-expressing cells. In spite of clinical remission, the local condition in all four pseudotumor cases and in two out of four cases of Graves' ophthalmopathy still suggests active inflammatory disease.