Research progress of NLRP3 inflammasome in the treatment of uveitis / 国际眼科杂志(Guoji Yanke Zazhi)

The NLRP3 inflammasome is a cellular multimeric protein complex that plays a crucial role in inflammation and immune responses. It consists of three main components: Nod-like receptor protein 3(NLRP3), apoptosis-associated speck-like protein containing(ASC)and cysteine protease 1(caspase-1). Uveitis is a broad term encompassing a range of inflammatory diseases that primarily affect the iris, ciliary body, vitreous, retina and choroid. It is considered a major cause of blindness globally. Numerous studies have demonstrated the involvement of NLRP3 inflammasome in the onset and progression of uveitis, indicating its potential as a significant therapeutic target for uveitis in the future. This article provides an overview of the structure, biological functions and activation pathways of the NLRP3 inflammasome, as well as the current research progress on its association with different types of uveitis. Additionally, it discusses the application potential of the NLRP3 inflammasome in the treatment of uveitis.

Surgical management for treatment-resistant cases of inflammatory exudative retinal detachment: Mission impossible?

Purpose: To report the outcome of surgical intervention for inflammatory, exudative retinal detachment (ERD). Methods: A retrospective analysis of eyes with ERD that underwent vitrectomy. Results: Twelve eyes (10 patients) with ERD, non?responsive to medical therapy, underwent vitrectomy. The mean age was 35.7 ± 17.7 years. Five eyes (42%) had Vogt–Koyanagi–Harada disease, three (25%) had presumed tuberculosis (TB), two (17%) pars planitis, and one (8%) had sympathetic ophthalmia. The mean time of vitrectomy was 6.76 ± 4.1 months after onset. Six (50%) eyes had a recurrence, two settled with medical treatment, and four underwent re?surgery. The mean follow?up was 2.7 years. At the last visit, 10 (83.3%) eyes had attached retina; the best?corrected visual acuity (BCVA) had reduced to 1.6 ± 0.7 logarithms of the minimum angle of resolution (logMAR) from 1.3 ± 0.7 at baseline. Conclusion: Vitrectomy in ERD can act as an adjuvant to conventional medical therapy and help maintain structural integrity. Early vitrectomy may help preserve visual function.

Síndrome de Vogt-Koyanagi-Harada / Vogt-Koyanagi-Harada Syndrome

El síndrome de Vogt-Koyanagi-Harada es una enfermedad autoinmune multisistémica crónica, caracterizada por panuveítis difusa granulomatosa bilateral con desprendimiento exudativo de retina y papilitis. Compromete el sistema nervioso central (meninges, disacusia neurosensorial) así como piel y mucosas. A pesar de ser una enfermedad compleja y poco frecuente, se hace necesario comprender la importancia del diagnóstico rápido y el tratamiento oportuno con seguimiento especializado. Es por ello que se decidió realizar una revisión de la literatura con el objetivo de actualizar los conocimientos existentes sobre este tema. La búsqueda se realizó en diferentes publicaciones y textos básicos de la especialidad. Las fuentes consultadas fueron las bases de datos PubMed y Google Scholar. El diagnóstico de la enfermedad es esencialmente clínico y son los oftalmólogos quienes más lo sospechan por ser los síntomas oculares los más frecuentes y dramáticos. El pronóstico visual de los pacientes es generalmente bueno si el diagnóstico es precoz y se indica un tratamiento adecuado. Los corticosteroides sistémicos a altas dosis asociados a inmunosupresores y agentes biológicos tienen gran impacto en la evolución de la enfermedad, sobre todo estos últimos a nivel mundial, previniendo complicaciones y permitiendo resultados visuales satisfactorios para una mejor calidad de vida del paciente(AU)

Vogt-Koyanagi-Harada syndrome is a chronic multisystem autoimmune disease characterized by bilateral diffuse granulomatous panuveitis with exudative retinal detachment and papillitis. It involves the central nervous system (meninges, sensorineural dysacusis) as well as skin and mucous membranes. In spite of being a complex and infrequent disease, it is necessary to understand the importance of rapid diagnosis and timely treatment with specialized follow-up. For this reason, it was decided to carry out a review of the literature with the aim of updating the existing knowledge on this subject. The search was carried out in different publications and basic texts of the specialty. The sources consulted were the PubMed and Google Scholar databases. The diagnosis of the disease is essentially clinical and it is the ophthalmologists who suspect it the most because the ocular symptoms are the most frequent and dramatic. The visual prognosis of patients is generally good if the diagnosis is early and adequate treatment is indicated. Systemic corticosteroids at high doses associated with immunosuppressants and biological agents have a great impact on the evolution of the disease, especially the latter worldwide, preventing complications and allowing satisfactory visual results for a better quality of life of the patient(AU)

Vogt-Koyanagi-Harada syndrome: a discussion about resistance to corticotherapy / Vogt-Koyanagi-Harada: uma discussão sobre resistência à corticoterapia

ABSTRACT Vogt-Koyanagi-Harada (VKH) syndrome is an inflammatory condition of unknown etiology that can affect the eye. The most common ocular manifestation related to VKH is bilateral diffuse uveitis associated to exudative retinal detachment. Although these patients respond well to steroid pulse therapy, we report a case of a 44-year-old female patient presenting bilateral exudative retinal detachment and clinical diagnosis of VKH, who did not respond to the first cycle of 3-day pulse therapy with methylprednisolone. The exudation was reabsorbed only after a second cycle of steroid therapy.

RESUMO A doença de Vogt-Koyanagi-Harada é inflamatória e de etiologia desconhecida, podendo afetar o olho. A manifestação ocular mais comum relacionada à doença de Vogt-Koyanagi-Harada é a uveíte difusa bilateral associada ao descolamento exsudativo da retina. Embora esses pacientes respondam bem à pulsoterapia com esteroides, relatamos um caso de paciente de 44 anos que apresentou descolamento exsudativo bilateral da retina com diagnóstico clínico de doença de Vogt-Koyanagi-Harada que não respondeu ao primeiro ciclo de pulsoterapia de 3 dias com metilprednisolona. A exsudação apenas reabsorveu após uma segunda rodada de terapia com esteroides.

Notch signaling pathway regulates IL-22 secretion by CD4+T cells in patients with Vogt-Koyanagi-Harada syndrome / 国际眼科杂志(Guoji Yanke Zazhi)

@#AIM:To investigate the changes of Notch receptors and interleukin(IL)-22 expression in patients with Vogt-Koyanagi-Harada(VKH)syndrome, and to assess the regulatory activity of Notch signaling to IL-22 production by CD4+ T cells in patients with VKH syndrome.<p>METHODS: Thirty-five patients with VKH syndrome(including fifteen active VKH and twenty inactive VKH)and twelve healthy controls were enrolled. Plasma was isolated, and CD4+T cells were purified. Notch receptors were investigated by qRT-PCR and Western blot. Plasma IL-22 expression was measured by ELISA. The percentage of Th17 and Th22 cells was investigated by flow cytometry. CD4+T cells, which were purified from active VKH patients, were stimulated with Notch signaling inhibitor DAPT. mRNA expression of transcription factor in CD4+T cells as well as IL-22 secretion by CD4+T cells was investigated.<p>RESULTS: Notch1-Notch3 in CD4+T cells from active VKH syndrome patients was significantly elevated in comparison with inactive VKH and healthy controls. Plasma IL-22 expression and percentage of Th17 and Th22 was notably increased in active VKH syndrome in comparison with inactive VKH and controls. DAPT stimulation inhibited Notch signaling pathway in CD4+T cells, leading to the down-regulation of AhR mRNA and IL-22 secretion.<p>CONCLUSION:Notch-AhR-IL-22 signaling pathway might take part in the pathogenesis of VKH syndrome.

Virus infection and limbic encephalitis: Clinical analysis of 5 cases of anti-N-methyl-D-aspartic receptor encephalitis and literature review / 中华实验和临床病毒学杂志

Objective@#To have a profound understanding of anti-N-methyl-D-aspartic receptor (anti-NMDAR) encephalitis, through the clinical analysis of 5 cases of anti-NMDAR encephalitis, and literature review.@*Methods@#This is a retrospective analysis. Five cases of anti-NMDA receptor encephalitis treated from May 2010 to June 2015, in the Department of Neurology, Beijing Friendship Hospital affiliated to Capital Medical University, were included in this study. The clinical data, including clinical manifestation, past history, radiological features, serum and cerebral spinal fluid examinations, treatment and prognosis, were analyzed.@*Results@#Among the 5 cases, 3 young female and 2 middle-to old-aged male. The clinical features of the onset was mental and behavior disorder, as well as seizure and extrapyramidal features, like facial and limbic involuntary movements or tremor. Coma and hypopnea was severe in 3 young female cases, needing assistance of mechanical ventilator, while the manifestation of 2 male patients was much mild, need not assisted respiration. 1 case had teratoma of ovary, 1 case had Vogt-Koyanagi-Harada syndrome. The anti-NMDA receptor antibody was positive in cerebraospinal fluid of all 5 cases, but in serum of 3 cases, serum and CSF Epstein-Barr virus (EBV) IgM antibody was positive in 1 case, while herpes simplex I virus (HSV-1) IgM antibody positive in another case, and anti-myelin oligodendrocyte glycoprotein (MOG) antibody was seen in serum and CSF in 1 case. The time interval from the onset to treatment was 10-37 d (18.8±9.8 d). IVIG was used in all of the 5 cases, glucocoticoid in 4 cases, and plasma exchange in 3 cases. One case with Vogt-Koyanagi-Harada syndrome, having a long time before diagnosis and treatment, died, while the other 4 cases had good prognosis, and had no relapse.@*Conclusions@#Mental and behavior disturbance is common at onset of anti-NMDAR encephalitis. The radiological and lab examination may be normal. It may be accompanied with HSV-1 or EBV infection, anti-MOG antibody may be positive in this disease. Active treatment is important.

Advances in treatment of Vogt-Koyanagi-Harada syndrome / 国际眼科杂志(Guoji Yanke Zazhi)

Vogt-Koyanagi-Harada (VKH)syndrome is an autoimmune disease attacking against pigmented cells, resulting in blindness and usually affecting multiple organs including ears, meninges, hair and skin.Correct diagnosis and immediate treatment in the early stage is vital to visual prognosis.Currently, corticosteroids is first-line drug.In addition, VKH patients refractory to corticosteroids can choose other treatment such as immunosuppressive agents and biological agents.

Sympathetic Ophthalmia as a Major Sight-threatening Disorder.

SO Iris and eyeball inflammatory condition affecting both eyes that occurs after a penetrating injury as a delayed autoimmune reaction to eye injury. Patients present with pain, photophobia, paresis of accommodation, metamorphopsia and mild to significant visual loss. The granulomatous anterior uveitis is accompanied by posterior segment findings including moderate to severe vitritis, choroiditis, papillitis, perivasculitis, and yellow-white lesions of the retinal pigment epithelium (Dalen-Fuchs nodules). The inflammation can lead to serious retinal detachment and macular edema. Extraocular symptoms include headache, meningitis or cerebrospinal fluid pleocytosis, hearing loss, poliosis and vitiligo. The inflammation is caused by a cell-mediated immune mechanism and autoimmune inflammatory response directed against ocular self-antigens released after the initial injury. SO may occur after ocular trauma (47 to 65% of patients) or contusions. Wounds involving the ciliary body are associated with the highest risk. Surgical interventions may also trigger SO, with posterior segment surgery carrying a higher risk than anterior segment surgery. Diagnosis of SO is mainly based on patient history and clinical presentation. Imaging studies (fluorescein or indocyanine green angiography, B-scan ultrasonography and optical coherence tomography) may be useful to confirm the diagnosis.

Paying attention to the differential diagnosis of central serous chorioretinopathy / 中华实验眼科杂志

Central serous chorioretinopathy (CSC)is a common eye disease characterized by macular serous retinal detachment.However,sometimes there are some atypical features,such as diffuse retinal pigment epitheliopathy,choroidal neovascularization (CNV),acute bullous retinal detachment,subretinal fibrosis,etc.Atypical CSC often is misdiagnosed because of its similar manifestations to polypoidal choroidal vasculopathy (PCV),inflammatory diseases such as Vogt-Koyanagi-Harada syndrome (VKH),et al.Furthermore,there are some other ophthalmic and systematic diseases which can cause serous retinal detachment and other atypical features.Nevertheless,the therapeutic regimens of these diseases are in great variation.In view of this,oculist should pay more attention to the differential diagnosis of CSC by fully understanding its clinical findings and concerning the general history including gluococorticoid administration.In this way,a precise diagnosis and correct management can be done.

Study and analysis of Vogt-Koyanagi-Harada syndrome by fundus fluorescein angiography / 国际眼科杂志(Guoji Yanke Zazhi)

AIM:To study cilncial features and significance of Vogt-Koyanagi - Harada syndrome ( VKHS ) by fundus fluorescein angiography ( FFA) . METHODS: All 16 cases ( 30 eyes ) of VKHS were underwent by detailed paysical examination. Then took colour photographs and examined by FFA. RESULTS:Uveitis stage of VKHS could be classified into three kinds of fundus appearances. The vision damage was mainly associated to exudation of choroidal vessel and exsudative retinal detachment rather than edema of optic disc which could achieve a better recovery. CONCLUSION: FFA is an important and valuable examination to diagnose the VKHS forepart.

Management of recurrent inflammatory choroidal neovascular membrane secondary to Vogt-Koyanagi-Harada syndrome, using combined intravitreal injection of bevacizumab and triamcinolone acetate.

The purpose of this report is to evaluate the efficacy and safety of combined intravitreal injection of bevacizumab and intravitreal triamcinolone acetonide (IVTA) for recurrent inflammatory choroidal neovascular membrane (CNVM). It was a prospective interventional study of a young female, who was a known case of Vogt-Koyanagi-Harada syndrome. She presented with an inflammatory choroidal neovascualar membrane and signs of panuveitis in the right eye. She underwent a complete ophthalmic examination. She was given intravitreal injection of bevacizumab and IVTA at different sites. There was complete regression of CNVM and ocular inflammation within a week. After six months, she had recurrence of CNVM in the same eye, which was treated similarly. There was a complete resolution of CNVM and ocular inflammation after the combination therapy and systemic steroids, until one year of follow-up. No serious systemic or ocular adverse events were noted. Combination therapy appears to be an effective and safe method in the management of recurrent inflammatory CNVM.

Vogt-Koyanagi-Harada Syndrome.

The Vogt-Koyanagi-Harada (VKH) syndrome is a rare systemic disorder of uveitis, dysacousia, vitiligo, premature graying of the hair, eyebrows and eyelashes, and meningoencephalitis. Although frequently unrecognised,VKH may affect children. We report a case of a 10 year old girl who presented with headache and dimness of vision and was diagnosed as papillitis on the basis of bilateral disc edema. However over the course of time developed skin changes(poliosis,vitiligo over lower back)and depigmented patches in inferior fundus suggesting diagnosis of VKH disease.Thus the diagnosis is difficult in the absence of extraocular manifestations.In such cases the diagnosis is based on clinical evolution of the disease.

Follow-up study on multifocal electroretinogram of acute and convalescence stage of Vogt-Koyanagi-Harada syndrome / 中华实验眼科杂志

Background Researches showed that multifocal electroretinogram (mfERG) is able to assess the retinal function in the eyes with acute Vogt-Koyanagi-Harada ( VKH ) syndrome. But the mfERG characteristics of convalescence stage of VKH are still below clear. Objective Present study was to compare and follow up the variation process of visual acuity and mfERG in acute and recovery stages of VKH syndrome. Methods This was a clinic-based retrospective study. Visual acuity, mfERG and fundus fluorescence angiography ( FFA ) were recorded from 35 eyes of 18 acute VKH cases. The period of follow-up in recovery stage lasted about 18 months with the repetitive recording results for 4 times. Results In this study, the visual acuity range in acute stage VKH was 0. 01 to 1.0, and 91.4% (32/35 eyes) was below 0.6. Compared with normal control group, the visual acuity was significantly decreased (P＜0.01). The response densities (amplitudes) of N1 ,P1 waves of the first-order kernel were significantly lowed in all the 6 rings,and the implicit times of 1-4 rings of both waves were significantly prolonged in acute VKH eyes(P＜0. 05). The abnormalities of retinal function showed a regional difference at the posterior pole retina with the dominant change in the first ring,showing a cutting off78% in the P1 amplitude. The abnormal degree of mfERG was more serious as the the increase of retinal eccentricity. In 2 months of convalescence after glucocorticosteroids therapy,the range of visual acuity were 0. 1-1.2 ,and the amplitudes of N1, P1 of 1-2 rings were greatly elevated in comparison with acute on-set (P＜0. 05 ). However, there was still a remarkable difference in the amplitudes of from 1 through 6 rings,comparing with normal. The response density of P1 wave from whole recording region was only 44% of normal. Though the visual acuity was stable during the follow-up duration, a decreasing tendency in N1 and P1 amplitudes were seen. The implicit times of both wave shortened only in 1-3 rings in recovery stages of VKH (P＜0.05). Conclusion VKH syndrome cause serious damage of posterior retinal function.Macular region is the site with greater retinal functional lesion and restore before and after medication. This hardly recovery of retinal function can last over one and half year,even satisfied visual acuity is stable after proper treatment.

A Case of Vogt-Koyanagi-Harada Syndrome with Vertigo and Hearing Loss / 대한이비인후과학회지

Vogt-Koyanagi-Harada (VKH) syndrome is an uncommon multisystem autoimmune disease affecting the melanocytes located in the uvea, inner ear, skin, hair, and meninges. The syndrome is frequently reported by ophthalmologists since the most consistent finding is uveitis. Hearing loss, tinnitus and vertigo are the symptoms of VKH syndrome. The authors report one case of VKH syndrome with hearing loss and vertigo with related literature.

Síndrome de Vogt-Koyanagi-Harada: relato de caso / Vogt-Koyanagi-Harada´s syndrome: case report

A síndrome de Vogt-Koyanagi-Harada é uma doença inflamatória, multissistêmica, rara e autoimune contra proteínas da membrana dos melanócitos, responsáveis pela produção de melanina. Afeta, portanto, estruturas pigmentares, como retina, meninges, ouvido interno, pele e sistema nervoso central. Acomete preferencialmente, mulheres de peleescura ou miscigenadas, na quarta década de vida, e caracteriza-se por uveíte bilateral, principalmente posterior, hipoacusia neurossensorial bilateral, meningismo e alterações de pele, como vitiligo. O diagnóstico é essencialmente clínico, apoiado em achados à retinografia, ultrassonografia ocular e angiografia ocular fluoresceínica. O tratamentobaseia-se em corticoterapia precoce e agressiva, seguida de imunomoduladores, como a ciclosporina, nos casos recidivantes ou refratários. O prognóstico apresenta relação com o tempo entre o diagnóstico e o início do tratamento. As principais complicações são as oculares, como catarata, glaucoma, membrana neovascular subretiniana e fibrose subretiniana.

Vogt-Koyanagi-Harada disease is an inflammatory, multisystemic, rare autoimmune disease against membrane proteins of melanocytes that are responsible for the production of melanin, and therefore affect pigmented structures such as retina, meninges, inner ear, skin and central nervous system. Mainly affects women of dark skin or blended, in the 4th decade of life, and is characterized by bilateral, mainly posterior, uveitis, bilateral sensorineural hearing loss, meningism and integumentary findings, such as vitiligo. The diagnostic is essencially clinical, supported byretinography, ultrasonography and fluorescein angiography. The therapy relies on early and aggressive treatment with systemic corticosteroids, followed by immunomodulatory therapy, such as cyclosporine, in relapsed or refractory cases. The prognosis is correlated with the time between diagnosis and initiation of treatment. The main complicationsare the ocular ones, such as cataract, glaucoma, subretinal neovascular membrane and subretinal fibrosis.

Síndrome de Vogt-Koyanagi-Harada: revisão de literatura / Vogt-Koyanagi-Harada's disease: literature review

Introdução: A síndrome de Vogt-Koyanagi-Harada é uma doença rara que atingem tecidos contendo melanócitos como nos olhos, sistema nervoso central, pele e ouvido interno. Apresenta predominância nos asiáticos, indianos e latinoamericanos e no sexo feminino. Objetivo: Realizar uma revisão de literatura sobre os diversos aspectos da Síndrome de Vogt-Koyanagi-Harada, enfatizando a sua etiopatogenia bem como as manifestações clínicas otorrinolaringológicas através dos bancos de dados on line Cochrane, LILACS, MEDLINE, OMIM e SciELO. Revisão de Literatura: A etiologia é incerta, mas há indícios de processo auto-imune contra antígenos na superfície dos melanócitos determinando uma resposta inflamatória imune com predomínio de linfócitos T. O alelo HLA-DRB1*0405 é o mais associado à doença. As manifestações clínicas são divididas em quatro estágios: prodrômico, uveítico, crônico e de recorrência. As manifestações otorrinolaringológicas se desenvolvem na fase uveítica. Há hipoacusia do tipo neurossensorial bilateral e rapidamente progressiva associada a zumbidos. O comprometimento do componente vestibular leva a vertigem, nistagmo horizontal e alteração do reflexo óculo-vestibular.

Introduction: Vogt-Koyanagi-Harada's disease is a rare syndrome that affects tissues with melanocytes like eyes, central nervous system, skin and inner ear. It affects primarily Asians, Indians and Latin Americans and also women.

Vogt-Koyanagi-Harada Syndrome Associated with Psoriasis Vulgaris / 대한피부과학회지

The Vogt-Koyanagi-Harada syndrome is an uncommon disorder characterized by uveitis and neurologic and cutaneous abnormalities including tinnitus, vertigo, headache, meningoencephalitis, vitiligo, alopecia, and poliosis. Although the cause of Vogt-Koyanagi-Harada syndrome remains unknown, it is believed to be the result of autoimmune mechanisms directed against the melanocytes in genetically susceptible individuals. The Vogt-Koyanagi-Harada syndrome has been reported to occur in association with other autoimmune disorders. We report a case of Vogt-Koyanagi-Harada syndrome associated with psoriasis vulgaris.

Bilateral Adrenal Gland Lymphoma Masquerading as Vogt-Koyanagi-Harada Syndrome

PURPOSE: To report a case of bilateral adrenal gland lymphoma mimicking symptoms of Vogt-Koyanagi-Harada syndrome. CASE SUMMARY: A 57-year-old woman complained of decreased visual acuity and metamorphopsia in both eyes. She had no prior medical history, but had experienced headaches in the past week. Fundus examination revealed multiple serous retinal detachment. Fluorescein angiography of the fundus revealed multiple pinpoint leaks in early stages and subretinal dye pooling in the retinal detachment area in late stages. The most likely diagnosis was therefore Vogt-Koyanagi-Harada syndrome. Two days later, mild fever developed and a systemic evaluation was performed. Computed tomography of chest and abdomen showed bilateral adrenal gland T-cell lymphoma. Through prompt combination chemotherapy, the patient's systemic condition recovered, and her fundus recovered with improved visual acuity. CONCLUSIONS: We experienced a rare case of bilateral adrenal lymphoma which masqueraded as Vogt-Koyanagi-Harada syndrome. When there are systemic symptoms such as mild fever and headaches, systemic evaluation should be done so as not to miss more serious systemic pathology.

Eficacia de la azatioprina en la enfermedad ocular inflamatoria no infecciosa resistente a tratamiento esteroidal sistémico / Role ofAzathioprine in steroid resistant non infectious ocular inflammatory diseases

Background: Topical and systemic steroids are the first line of treatment of non infectious inflammatory ocular disease. Immunosuppresants are reserved as a second line treatment. Aim: To evaluate the role ofAzathioprine (AZA) as a coadyuvant immunosuppressive treatment for non infectious ocular inflammatory diseases (OIDs) resistant to systemic steroid therapy in a retrospective, noncomparative interventional case series. Patients and methods: Patients using oral Prednisone due to an active or recurrent OID, without clinical response, and not receiving any other immunosuppressive treatment were studied. A standard protocol of oral Prednisone (0.5 mg/kg/ day) and oral AZA (2-3 mg/kg/day) during one year was used. Ocular and systemic monthly evaluations were done including relapse rate, steroid dosage, inflammatory score and visual acuity. Results: Thirty patients (10 male) aged 18-75 years (mean 44 years) were studied. Three had bilateral anterior uveitis, one had pars planitis, four had diffuse uveitis, eight Vogt-Koyanahi-Harada syndrome, three Behget's disease, three necrotizing scleritis and eight had retinochoroidopathy A complete initial response was observed in 26 patients (87 percent). The time of response was between 1 to 6 months (mean 2.65 months). Seventeen percent of these had a relapse 6 to 12 months after AZA was started. In 61 percent, visual acuity improved. The ocular inflammatory score decreased in 86.5 percent. Eleven patients had mild controlled side effects that did not require discontinuation of AZA. Conclusions: Combined systemic steroid and oral AZA therapy is safe and effective in controlling steroid resistant non infectious inflammatory ocular diseases.