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.

[Recurrent chronic Vogt-Koyanagi-Harada syndrome or sarcoidosis? A Gloomy diagnosis]. / ¿Síndrome de Vogt-Koyanagi-Harada crónico o sarcoidosis? Un diagnóstico sombrío.

Background: Vogt-Koyanagi-Harada syndrome (VKH) is a systemic disease that affects organs profuse in melanocytes, presenting with a chronic and diffuse bilateral granulomatous panuveitis, as well as neurological, auditory, and cutaneous manifestations. In this article, a systematic approach is presented for the diagnostic management of VKH syndrome, considering relevant diagnostic possibilities to rule out other entities that manifest similar symptoms. Clinical case: 71-year-old man with a long-standing history of vitiligo, who experienced visual loss in his right eye 6 months before his admission, along with bilateral hearing loss predominantly in the right ear. During his hospitalization, he presented with chronic headache, fever, and significant involuntary weight loss. Ophthalmological examination revealed that his right eye only perceived light and had hyperemic bulbar conjunctiva, while the left eye had a visual acuity of 20/200. The right fundus had scattered pigmentation, while the left had an edematous optic disc and right optic atrophy. Conclusions: The diagnosis of VKH syndrome is established by the presence of the 5 diagnostic criteria for complete disease, including retinal depigmentation, neurological alterations, and dermatological manifestations. Since patients can present with a wide variety of symptoms, initial differential diagnosis should be considered, which represents a diagnostic challenge.

Introducción: el síndrome de Vogt-Koyanagi-Harada (VKH) es una enfermedad sistémica que afecta a órganos ricos en melanocitos y se manifiesta con una panuveítis granulomatosa bilateral, crónica y difusa, así como con manifestaciones neurológicas, auditivas y cutáneas. En este artículo se presenta un enfoque sistemático para el abordaje diagnóstico del síndrome de VKH y se consideran las posibilidades diagnósticas relevantes para descartar otras entidades que se presentan con síntomas similares. Caso clínico: hombre de 71 años con antecedentes de vitiligo de larga data, quien experimentó una pérdida visual en su ojo derecho seis meses antes de su ingreso, junto con hipoacusia bilateral, predominantemente en el oído derecho. Durante su hospitalización, presentó cefalea crónica, fiebre y una significativa pérdida involuntaria de peso. En la exploración oftalmológica, el ojo derecho solo percibía luz y presentaba conjuntiva bulbar hiperémica, mientras que el ojo izquierdo tenía una agudeza visual de 20/200. El fondo del ojo derecho presentaba pigmentación dispersa, mientras que el izquierdo tenía una papila edematosa y atrofia óptica derecha. Conclusiones: el diagnóstico del síndrome de VKH se establece mediante la presencia de los 5 criterios diagnósticos para la enfermedad completa, incluida la hipopigmentación retiniana, las alteraciones neurológicas y las manifestaciones dermatológicas. Dado que los pacientes pueden presentar una amplia variedad de síntomas, el diagnóstico diferencial debe considerarse inicialmente, lo que representa un desafío diagnóstico.

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

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.

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.

Ocular syphilis mimicking Vogt-Koyanagi-Harada syndrome: a diagnostic dilemma.

This case demonstrates the dilemma in the diagnosis of ocular syphilis, as it can mimic many other ocular conditions where initial steroid therapy might complicate the disease course and can worsen the infection. Also, it represents an example of anchoring bias, where a provisional diagnosis resulted in unnecessary treatment that would have worsened her clinical outcomes.

Rare Association Between Lichen Planus and Vogt-Koyanagi-Harada Syndrome: A Case Report.

Vogt-Koyanagi-Harada syndrome (VKHS) is a rare inflammatory autoimmune condition that affects tissues with high melanocyte concentrations such as the skin, inner ears, eyes, and central nervous system. VKHS has previously been reported to be associated with various autoimmune diseases, but we have observed the first known co-occurrence of VKHS and lichen planus (LP). In this report, we examine the similarities between these two diseases and discuss how they relate to each other.

Systemic lymphoma masquerading as Vogt-Koyanagi-Harada syndrome: Report of a case with multimodal imaging and histopathology.

Purpose: To report a case of systemic diffuse large B cell lymphoma presenting with ocular manifestations and neurologic findings resembling Vogt-Koyanagi-Harada syndrome. Observations: A 51-year-old Caucasian man presented with headache, ear pain, and blurry vision in both eyes. He was found to have bilateral exudative retinal detachments. After a short period of initial improvement with high dose systemic corticosteroid, his condition significantly worsened. An extensive work-up, including a kidney biopsy, led to a diagnosis of systemic diffuse large B cell lymphoma. He had excellent recovery following treatment with appropriate chemotherapy. Conclusions and Importance: Systemic malignancy may present with ocular manifestations and may masquerade as another diagnosis. An unexpected clinical course may suggest an alternative diagnosis. A broad systemic work-up including an evaluation for malignancy should be considered for patients presenting with unexplained exam or systemic findings.

Reflections on a case of Vogt-Koyanagi-Harada syndrome first diagnosed in internal medicine: a case report.

BACKGROUND: A case of Vogt-Koyanagi-Harada syndrome (VKH) first diagnosed with encephalitis was reported and it bring us the clinical reflection. CASE DESCRIPTION: A 73-year-old Chinese woman was first diagnosed in the department of neurology with headache, nausea, vomiting, and elevated body temperature. Cerebrospinal fluid (CSF) assays showed significant increases in leukocytes and Cerebrospinal fluid total protein (CS-TP). Gradually, symptoms appeared in the eyes including decreased vision, keratic precipitates (KP) (+++), iris local posterior adhesion, vitreous opacity, and optic disc congestion edema. The fundus fluorescence examination showed optic disc hyperfluorescence with both eyes exudative retinal detachment. Type-B ultrasonography of obit showed a large number of flocculent opacities in the vitreous and retinal edema. Optical coherence tomography (OCT) showed that significant edema was evident in the macular area and papillary, and there were wavy changes in the retinal pigment epithelium layer. Review of the clinical, photographic, fundus fluorescence angiography (FFA) data of the patient suggested a clinical diagnosis of VKH. CONCLUSIONS: VKH is an autoimmune disease involving many systems. It has specific systemic symptoms, such as tinnitus, dizziness, headache, nausea, skin injury and so on. But Neurological and auditory manifestations usually precede the involvement of other sites especially in the neurological manifestations. So we should pay attention to the diversity of clinical manifestations, so as to avoid delaying treatment or even misdiagnosis in clinical diagnosis and treatment.

Vogt-Koyanagi-Harada syndrome-like uveitis after nivolumab administration as a treatment for ovarian cancer.

PURPOSE: To report a case of Vogt-Koyanagi-Harada (VKH) syndrome-like posterior uveitis after nivolumab administration to treat an ovarian cancer with an electrophysiological finding. A 61-year-old woman with ovarian cancer (stage 3A) and salpingo-oophorectomy surgery history visited the clinic complaining of blurred vision in both eyes. She had been enrolled a clinical trial using nivolumab in patients with ovarian cancer. She received four cycles of nivolumab administration and experienced blurred vision one week before the initial visit. There was no remarkable finding in the anterior segment and the vitreous body. Multiple subretinal fluid accumulations and serous retinal detachment were identified on the posterior pole. Subretinal fluid with choroidal folding was noted in optical coherence tomography, and multiple leakage points were also observed in wide-field fundus fluorescein angiography. Therefore, intravenous high-dose steroid pulse therapy was applied under the diagnosis of VKH syndrome-like posterior uveitis induced by an immunotherapy agent. After steroid therapy, the subretinal fluid was absorbed completely, and the patient's visual acuity was recovered to the normal range. The amplitudes in the multifocal electroretinogram were also restored after the treatment. CONCLUSION: Nivolumab is a human IgG4 monoclonal antibody and an immune checkpoint inhibitor. It is associated with the upregulation of T-cell activity by interfering with the interaction between the programmed death-1 (PD-1) receptor and the PD-ligand. Targeted therapy using immunotherapy agents has been widely used for malignant melanoma, lung cancer, renal cell carcinoma, and other cancers. However, immunotherapy agents such as nivolumab can induce autoimmune-related adverse events including uveitis. This report suggests that VKH syndrome-like posterior uveitis could be induced by nivolumab administration for an ovarian cancer treatment, which was resolved by steroid pulse therapy.

The emerging role of epigenetics and gut microbiota in Vogt-Koyanagi-Harada syndrome.

Vogt-Koyanagi-Harada (VKH) syndrome is an autoimmune disorder characterized often by acute diffuse uveitis, also known as idiopathic uveoencephalitis. The associated complications can potentially affect multiple systems throughout the body, including eyes, ears, skin and nervous system. Although the pathogenesis of VKH syndrome remains unclear, it has been established that the various genetic factors, epigenetic factors and the imbalance in immune regulation can significantly contribute to the development of this disease. In addition, the experimental autoimmune uveitis (EAU) has been commonly used to further explore the pathogenesis of the disease. Herein, in this review article, we discuss about the major research advances made in understanding of the different epigenetic factors and gut microbes involved in the pathogenesis of VKH syndrome as well as EAU. The information discussed can help to better understand the pathogenesis of VKH syndrome, and thereby might provide a basis for finding novel molecular targets and innovative treatment strategies in the future.

Ponatinib Inducing a Panuveitis with Choroidal Effusions and Neurosensory Retinal Detachment in a Patient with Chronic Myeloid Leukaemia.

CASE SUMMARY: We present the case of a 50 year old male patient being treated for chronic myeloid leukemia by the tyrosine kinase inhibitor, Ponatinib. After 3 months of treatment, he developed a sight-threatening granulomatous panuveitis in both eyes, with choroidal effusions and neurosensory retinal detachments. Except for a positive interferon-gamma release assay suggesting previous Tuberculosis exposure, all uveitis investigations were normal. Discontinuation of the suspected causative drug led to resolution of signs and a consequent improvement in visual acuity. CONCLUSION: Ponatinib use may be associated with with a uveitic phenotype that is reminiscent of Harada's disease. We compare and contrast this rare ocular phenomenon with Vogt-Koyanagi-Harada syndrome and discuss a possible immunological basis.

Association Between Interleukin 35 Gene Single Nucleotide Polymorphisms and the Uveitis Immune Status in a Chinese Han Population.

Autoimmune uveitis is characterized by immune disorders of the eyes and the whole body and is often recurrent in young adults, but its pathogenesis is still unclear. IL-35 is an essential regulatory factor in many autoimmune diseases, which is produced by Breg cells and can induce Breg cells to regulate the immune response. The relationship between the expression and gene polymorphism of IL-35 and the immune status of patients with autoimmune uveitis has not been reported. The peripheral blood of the subjects was collected from patients with Behçet's Disease (BD) and those with Vogt-Koyanagi-Harada (VKH) syndrome. The percentage of immune cell subsets including B cells, DC, and T cells, and the expression of IL-35 in serum of these two kinds of disease were analyzed. And then, the associations between seven IL-35 single nucleotide polymorphism (SNP) sites and disease susceptibility, the immune status, the clinical characteristics, and the serum IL-35 levels were analyzed. Our results showed that the percentage of Breg cells was significantly decreased in the blood of patients with VKH syndrome compared to that of healthy controls. The levels of IL-35 in the serum of patients with VKH syndrome or BD patients were not changed significantly, compared to that of healthy controls. Furthermore, the associations between two subunits of IL-35 (IL-12p35 and EBI3) and BD or VKH patients were analyzed. We found that there was an association between the EBI3 rs428253 and the occurrence of BD. There was an association between the IL-12p35 rs2243131 and the low level of Breg cell of VKH patients. In addition, there were associations between the polymorphisms of EBI3 rs4740 and the occurrence of headache and tinnitus of VKH patients, respectively. And the genotype frequency of IL-12p35 rs2243115 was related to the concentration of serum IL-35 in patients with VKH syndrome. Thus, the specific SNP sites change of IL-35 were correlated to the immune disorders in uveitis. And they may also play a guiding role in the occurrence of clinical symptoms in patients with uveitis, especially for VKH syndrome.

A fingerprint hidden inside the eye. A unique pattern of outer retina splitting as seen on en-face OCT and OCT-angiography.

A splitting of the outer plexiform retinal layer in a saw-like hyporeflective pattern in addition to partially formed concentric circles centred at the foveola were observed using en-face OCT and OCT-angiography in a 27-year-old female patient with rhegmatogenous retinal detachment and a 50-year-old female patient with Vogt-Koyanagi-Harada chorioretinopathy.

Vogt-Koyanagi-Harada Syndrome - A Neurologist's Perspective.

Vogt-Koyanagi-Harada (VKH) syndrome is an immune-mediated granulomatous disease which affects melanin-rich organs like eyes, skin, nervous system, and ears. Neurological and auditory manifestations usually precede the involvement of other sites. Patients may manifest with "complete" or "incomplete" syndrome. We report two patients who presented with acute headache and impaired vision. Fundus examination revealed optic disc hyperemia and exudative retinal detachment which provided a clue for the diagnosis at the bedside. Fundus fluorescein angiogram (FFA) revealed abnormal dye leakage, whereas B scan showed choroid thickening. Cerebrospinal fluid (CSF) pleocytosis contrasted with unremarkable brain magnetic resonance imaging and lack of meningeal signs. Melanophagocytosis was evidenced by melanin-laden macrophages in CSF and skin biopsy. This finding is specific for VKH syndrome and helps to clinch the diagnosis even when the complete syndrome is not present cross-sectionally. VKH syndrome should be suspected in patients with aseptic meningitis if tests for common infectious and immune-mediated diseases are negative.

Vogt Koyanagi Harada syndrome in a 15-year-old girl, steroids side effects and recurrences.

BACKGROUND: Vogt-Koyanagi-Harada Syndrome is rare in childhood and is usually seen between the 2nd and 5th decades. We present a 15-year-old girl with findings of incomplete Vogt-Koyanagi-Harada Syndrome. CASE: In the first visit, anterior chamber inflammation, vitritis, serous retinal detachment and papillitis were observed in her both eyes. She also had neurological symptoms such as a headache. During the systemic treatment period, some of the side effects related to steroids emerged. Additionally, the symptoms and findings of the disease relapsed while the steroid dose was reduced. CONCLUSION: Early diagnosis and selection of an individualized appropriate treatment provided good clinical and visual results without any serious complications in our case.

Proteomics Profiling of Plasma Exosomes in VKH Patients.

OBJECTIVES: Vogt-Koyanagi-Harada syndrome is common autoimmune uveitis that can cause blindness. Recent studies have shown that plasma exosomes carry disease-related proteins that may serve as biomarkers. Here, we aimed to find candidate biomarkers of Vogt-Koyanagi-Harada disease using proteomic analysis of plasma exosomes. METHODS: Exosomes were isolated from the plasma of normal controls and Vogt- Koyanagi-Harada patients in the following groups: a) initial inflammatory attack (active stage), b) remission after one month of treatment (unstable stage), and c) stationary phase after three months of treatment (stable stage). Groups were analyzed by mass spectrometry using isobaric tags for relative and absolute quantitation. After functional analysis, proteins of interest were verified by ELISA. RESULTS: 463 proteins were identified in the exosomes. Forty-three were upregulated at the active inflammation stage, including inflammation-associated proteins. Thirty-one were downregulated. Gene ontology and pathway analyses revealed differential proteins related to cell adhesion, cell phagocytosis, cytoskeleton movement, leukocyte migration across endothelial cells, and platelet activation. By ELISA, Carbonic anhydrase 2 and Ras-related protein Rap-1b were verified as more plentiful at the active stage compared to the normal control and stationary phase in exosomes, but not, however, in microvesicles or plasma. CONCLUSION: Plasma exosomes of Vogt-Koyanagi-Harada patients contain many proteins related to the degree of inflammation. The levels of Carbonic anhydrase 2 and Ras-related protein Rap-1b in exosomes can be used as biomarkers for active inflammation in Vogt-Koyanagi-Harada disease. Further investigation could help study the pathogenesis of Vogt-Koyanagi-Harada disease and identify therapeutic targets.

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.

Acute Lymphoblastic Leukemia Presenting as Acute Vogt-Koyanagi-Harada Syndrome.

We aimed to describe a case of acute lymphoblastic leukemia (ALL) that initially presented and was managed as Vogt-Koyanagi-Harada syndrome (VKH). A 62-year-old man was referred for vision loss starting 1 week ago. There was no prior systemic or ocular history. Visual acuity was 20/200 in both eyes. Anterior segment exam was also normal in both eyes. On funduscopy, foveal reflex was significantly reduced. On optical coherence tomography, subretinal fluid was evident in both eyes. Fluorescein angiography showed a hypofluorescent area compatible with subretinal fluid and multiple pinpoint hyper- and hypofluorescent dots surrounding the detached retina. After 4 days, we were informed that the patient had been admitted to a general hospital due to spontaneous ecchymosis and melena. On complete blood count, there was a high white cell count, thrombocytopenia, and low hemoglobin concentration with a probable diagnosis of leukemia. On bone marrow biopsy, ALL with B-cell precursor was confirmed. In conclusion, exudative retinal detachment can be a primary presentation of leukemia and/or lymphoma. In atypical VKH or acute central serous chorioretinopathy cases with multiple pinpoint leakages distributed mostly in the periphery of the subretinal fluid area (not randomly scattered throughout the subretinal fluid), we should consider leukemia.