Intraocular Inflammatory Disease Research Articles

Artificial intelligence derived large language model in decision-making process in uveitis

BackgroundUveitis is the ophthalmic subfield dealing with a broad range of intraocular inflammatory diseases. With the raising importance of LLM such as ChatGPT and their potential use in the medical field, this research explores the strengths and weaknesses of its applicability in the subfield of uveitis.MethodsA series of highly clinically relevant questions were asked three consecutive times (attempts 1, 2 and 3) of the LLM regarding current uveitis cases. The answers were classified on whether they were accurate and sufficient, partially accurate and sufficient or inaccurate and insufficient. Statistical analysis included descriptive analysis, normality distribution, non-parametric test and reliability tests. References were checked for their correctness in different medical databases.ResultsThe data showed non-normal distribution. Data between subgroups (attempts 1, 2 and 3) was comparable (Kruskal-Wallis H test, p-value = 0.7338). There was a moderate agreement between attempt 1 and attempt 2 (Cohen’s kappa, ĸ = 0.5172) as well as between attempt 2 and attempt 3 (Cohen’s kappa, ĸ = 0.4913). There was a fair agreement between attempt 1 and attempt 3 (Cohen’s kappa, ĸ = 0.3647). The average agreement was moderate (Cohen’s kappa, ĸ = 0.4577). Between the three attempts together, there was a moderate agreement (Fleiss’ kappa, ĸ = 0.4534). A total of 52 references were generated by the LLM. 22 references (42.3%) were found to be accurate and correctly cited. Another 22 references (42.3%) could not be located in any of the searched databases. The remaining 8 references (15.4%) were found to exist, but were either misinterpreted or incorrectly cited by the LLM.ConclusionOur results demonstrate the significant potential of LLMs in uveitis. However, their implementation requires rigorous training and comprehensive testing for specific medical tasks. We also found out that the references made by ChatGPT 4.o were in most cases incorrect. LLMs are likely to become invaluable tools in shaping the future of ophthalmology, enhancing clinical decision-making and patient care.

10 common mistakes in uveitis. A guide to escape disasters

Intraocular inflammatory diseases are relatively rare, involving predominantly younger patients and are usually characterized by rapid progression. Consequently, effective management of uveitis requires prompt diagnosis and initiation of the correct treatment regimen without delay, an occasionally challenging task for the non‐specialist ophthalmologist. Despite the frequent overlap of clinical features in uveitis patients, certain disease characteristics should be recognized to facilitate efficacy and avoidance of pitfalls. We provide a survival guide of 10 crucial key points, essential to ensure the optimum outcome and safe management in inflammatory conditions.

MiR-223-3p attenuates M1 macrophage polarization via suppressing the Notch signaling pathway and NLRP3-mediated pyroptosis in experimental autoimmune uveitis

Autoimmune uveitis is an intraocular inflammatory disease with a high blindness rate in developed countries such as the United States. It is pressing to comprehend the pathogenesis of autoimmune uveitis and develop novel schemes for its treatment. In the present research, we demonstrated that the Notch signaling pathway was activated, and the level of miR-223-3p was significantly reduced in rats with experimental autoimmune uveitis (EAU) compared with the level of normal rats. To investigate the relationship between miR-223-3p and Notch signaling, EAU rats received miR-223-3p-carrying lentivirus, miR-223-3p vector-carrying lentivirus (miR-223-3p-N), and γ-secretase inhibitor (DAPT), respectively. The results of Q-PCR, immunological experiments, and flow cytometry analysis all support the hypothesis that both miR-223-3p and DAPT, a Notch signaling pathway inhibitor, had similar inhibitory effects on the EAU pathological process. That is to say, they could both inhibit the activation of the Notch signaling pathway via modulating recombination signal binding protein-Jκ (RBPJ) to restore the polarization imbalance of M/M2 macrophages in EAU rats. In addition, miR-223-3p could also inhibit NLRP3 inflammasome activation and inflammasome-induced pyroptosis in ocular tissues. Taken together, our findings indicate that miR-223-3p serves as an important regulator in M1 macrophage polarization and pyroptosis, thereby alleviating the inflammatory response in uveitis.

Slit2 suppresses endotoxin-induced uveitis by inhibiting the PI3K/Akt/IKK/NF-κB pathway.

Uveitis is a devastating intraocular inflammatory disease. The secreted leucine-rich repeat protein slit homologue 2 (Slit2) has been found to be an essential regulator of inflammation. This study aimed to analyse the anti-inflammatory effects and the underlying mechanisms of Slit2 in an endotoxin-induced uveitis (EIU) rat model. In this study, rats with EIU pretreated recombinant human Slit2 (rhSlit2) or a control vehicle by intravitreal injection. The clinical scores were graded under a slit lamp. The protein concentrations and total number of cells in the aqueous humour (AqH) were examined, and the retinal expression of various inflammatory mediators was detected. The levels of nuclear factor-kappa B (NF-κB), phosphorylated NF-κB, IkappaB-a (IκB-a), phosphorylated IκB-a, IKK, phosphorylated IKK, PI3Kp85, phosphorylated PI3Kp85, Akt and phosphorylated Akt were evaluated by western blotting. Treatment with rhSlit2 dramatically diminished the clinical scores of EIU, with significant decreases in inflammatory cell infiltration, protein concentrations, cellulose-like exudates, the production of ICAM-1, MCP-1, TNF-α and IL-6 in the AqH; and adhesion of leucocytes. The PI3K/Akt/IKK/NF-κB pathway was found to be activated in EIU. However, the pre-treatment of rhSlit2 significantly inhibited the production of ICAM-1, MCP-1, TNF-α, and IL-6, and inhibited leucocyte adhesion by modulating the PI3K/Akt/IKK/NF-κB pathway. In conclusion, the intravitreal injection of rhSlit2 alleviated EIU-related inflammation in Sprague-Dawley rats by reducing the proinflammatory cytokines and leucocyte adhesion; in particular, rhSlit2 may inhibit LPS-induced inflammation by inhibiting the activation of PI3K/Akt/IKK/NF-κB signalling pathway. Therefore, rhSlit2 shows significant potential for effectively alleviating immune inflammatory responses in vivo.

Corticosteroid implants for chronic non-infectious uveitis.

Corticosteroid implants for chronic non-infectious uveitis.

Exposure of autoimmune uveitis-prone germ-free mice to commensal microbiota promotes development of ocular inflammation

Abstract Autoimmune uveitis is a group of intraocular inflammatory diseases driven by retina-specific T cells that target the neuroretina and is one of the leading causes of blindness. Using a spontaneous mouse model of autoimmune uveitis (R161H), in which CD4 T cells express a transgenic retina-specific T cell receptor, we have shown that gut commensal microbiota are involved in activating retina-specific T cells and promoting uveitis. To study how a germ-free (GF) host responds to de novo microbiota exposure, R161H TCRa −/−mice, rederived into GF conditions and developing much milder disease than their SPF counterparts, were cohoused with SPF mice for 4 wks (exGF). Fecal samples were collected weekly to examine changes in the gut microbiome by 16S amplicon sequencing. Disease progression was monitored twice weekly by fundus examination. At the endpoint, eyes were collected for histopathology, and T cells from lymph nodes, eyes, and intestinal lamina propria were analyzed by flow cytometry and RNAseq for immunophenotype and gene expression. Exposure to commensal microbiota strongly promoted disease development. After 2 wks of cohousing, exGF disease scores reached the severity of age-matched SPF mice and were significantly higher than those of control GF mice. Flow cytometry analyses revealed an increased percentage of CD4 T cells expressing the proinflammatory cytokines IL-17A and IFN-g in exGF mice. 16S analyses showed that by 1 wk of cohousing exGF mice had acquired gut microbiota of SPF mice, which we hypothesize to include microbes affecting disease outcomes. RNAseq data will provide insights into phenotypic differences among retina-specific T cells in different tissues and may uncover novel pathways involved in uveitis development.

Corticosteroid implants for chronic non-infectious uveitis.

Corticosteroid implants for chronic non-infectious uveitis.

Association Between Atherosclerosis-Related Cardiovascular Disease and Uveitis: A Systematic Review and Meta-Analysis.

Uveitis is not only an intraocular inflammatory disease, but also an indicator of systemic inflammation. It is unclear whether uveitis can increase the risk of cardiovascular disease (CVD) through the atherosclerotic pathway. PubMed and Embase databases were searched until 5 September, 2022. Original studies investigating uveitis and cardiovascular events were selected. The random-effects model was used to calculate the difference of groups in pooled estimates. A total of six observational studies that included mainly ankylosing spondylitis (AS) patients were included. Of these, three studies reported data on carotid plaques and carotid intima-media thickness (cIMT) and the other three studies provided data on atherosclerosis-related CVD. No significant difference was found in cIMT between uveitis and controls (MD = 0.01, 95% CI = -0.03-0.04, p = 0.66), consistent with the findings of carotid plaque incidence (OR = 1.30, 95% CI = 0.71-2.41, p = 0.39). However, uveitis was associated with a 1.49-fold increase in atherosclerosis-related CVD (HR = 1.49, 95% CI = 1.20-1.84, p = 0.0002). Uveitis is a predictor of atherosclerosis-related CVD in AS patients. For autoimmune disease patients with uveitis, earlier screening of cardiovascular risk factors and the implementation of corresponding prevention strategies may be associated with a better prognosis.

A new small molecule DHODH-inhibitor [KIO-100 (PP-001)] targeting activated T cells for intraocular treatment of uveitis - A phase I clinical trial.

[https://www.clinicaltrials.gov/ct2/show/NCT03634475], identifier [NCT03634475].

Heritability of insidious uveitis in Appaloosa horses.

Equine recurrent uveitis (ERU) is a blinding ocular disorder among horses, and the Appaloosa horse breed is disproportionally affected by a chronic form of this intraocular inflammatory disease known as insidious uveitis. Strong breed predisposition and previous investigations suggest that there is a genetic component to the pathology of insidious uveitis among Appaloosa horses; however, no estimates of the heritability of the disease have previously been determined. This study aimed to characterize the genetic underpinning of the disease by estimating the heritability for insidious uveitis among Appaloosas. After combining two genotyping array datasets from the Illumina Equine SNP70 BeadChip and the Axiom Equine 670 K Genotyping Array, heritability was estimated for 59 affected and 83 unaffected horses using both restricted maximum likelihood (REML) and phenotype correlation - genotype correlation solvers from the linkage disequilibrium adjusted kinship software. Based on previous research, age and sex were used as covariates, and the locus responsible for the characteristic Appaloosa coat pattern (LP), previously associated with ERU risk, was included as a fixed effect ('top predictor'). Using prevalence values from 0.05 to 0.42, the heritability estimate for insidious uveitis ranged from 0.95 (SE=0.14) to 1.74 (SE=0.25) with LP contributing 0.16-0.33 to the estimate. This study suggests that insidious uveitis is highly heritable (REML 95% CI, h2 =0.68-1.0) and additional loci outside of LP are contributing to the genetic risk for insidious uveitis for Appaloosas. Once identified, these other genetic factors may lead to new disease mitigation efforts in veterinary care and breeding practices.

N6-methyladenosine demethylase FTO regulates inflammatory cytokine secretion and tight junctions in retinal pigment epithelium cells

ObjectiveUveitis is an intraocular inflammatory disease. Epigenetics has been associated with its pathogenesis. However, the role of N6-methyladenosine (m6A) in uveitis has not been reported. We aimed to examine the role of m6A and its regulatory mechanism in experimental autoimmune uveitis (EAU). MethodsThe mRNA expression of m6A-related methylase and demethylase of retinal pigment epithelium (RPE) between mice with EAU and control mice was detected by RT-qPCR. The overall m6A level of ARPE-19 cells was detected by an m6A quantitative detection kit. Cell proliferation was observed by CCK-8 assays, and ELISA was used to test the secretion of inflammatory factors. The expression of tight junction proteins and the target genes of FTO were examined by western blotting and MeRIP-PCR. ResultsA decreased expression of FTO in RPE cells was found in mice with EAU. Increased overall m6A%, proliferation of cells and secretion of IL-6, IL-8 and MCP-1 were found after FTO knockdown in ARPE-19 cells. However, ZO-1 and occludin protein expression was decreased. ATF4 protein expression was decreased in the FTO knockdown (shFTO) group as compared with the control (shNC) group. In contrast, the m6A level of ATF4 was elevated, as shown by MeRIP-PCR. Functional analysis showed that p-STAT3 expression was increased in the shFTO group, and the change in occludin expression was reversed in ATF4 rescue experiment. ConclusionFTO may affect the translation of ATF4 by regulating its m6A level, resulting in the increased expression of p-STAT3 and inflammatory factors, and leading to uveitis.

Proteome Analysis of Urinary Biomarkers in a Bovine IRBP-Induced Uveitis Rat Model via Data-Independent Acquisition and Parallel Reaction Monitoring Proteomics.

Uveitis, a group of intraocular inflammatory diseases, is one of the major causes of severe visual impairment among the working-age population. This study aimed to screen potential urinary biomarkers for uveitis based on proteome analysis. An experimental autoimmune uveitis (EAU) rat model induced by bovine interphotoreceptor retinoid-binding protein (IRBP) was used to mimic uveitis. In discovery phase, a total of 704 urinary proteins were identified via data-independent acquisition (DIA) proteomic technique, of which 76 were significantly changed (34, 36, and 37 on days 5, 8, and 12, respectively, after bovine IRBP immunization). Gene Ontology annotation of the differential proteins indicates that acute-phase response, innate immune response, neutrophil aggregation, and chronic inflammatory response were significantly enriched. Protein-protein interaction network indicates that these differential urinary proteins were biologically connected in EAU, as a group. In validation phase, 17 proteins having human orthologs were verified as the potential markers associated with uveitis by parallel reaction monitoring (PRM) targeted quantitative analysis. Twelve differential proteins changed even when there were no clinical manifestations or histopathological ocular damage. These 12 proteins are potential biomarkers for early diagnosis of uveitis to prevent the development of visual impairment. Five differential proteins changed at three time-points and showed progressive changes as the uveitis progressed, and another five differential proteins changed only on day 12 when EAU severity peaked. These 10 proteins may serve as potential biomarkers for prognostic evaluation of uveitis. Our findings revealed that the urinary proteome could sensitively reflect dynamic pathophysiological changes in EAU, and represent the first step towards the application of urinary protein biomarkers for uveitis.

Time to Uveitis Control with Methotrexate and Mycophenolate Mofetil

Uveitis is a group of sight-threatening intraocular inflammatory diseases responsible for 5% to 20% of legal blindness in developed countries. 1 Durrani O.M. Meads C.A. Murray P.I. Uveitis: a potentially blinding disease. Ophthalmologica. 2004; 218: 223-236 Crossref PubMed Scopus (211) Google Scholar Timely control of inflammation is essential to prevent serious complications, and corticosteroid therapy is the mainstay of treatment for noninfectious uveitis. However, long-term exposure to corticosteroids has undesirable ocular and systemic side effects. 2 Jabs D.A. Rosenbaum J.T. Foster C.S. et al. Guidelines for the use of immunosuppressive drugs in patients with ocular inflammatory disorders: recommendations of an expert panel. Am J Ophthalmol. 2000; 130: 492-513 Abstract Full Text Full Text PDF PubMed Scopus (717) Google Scholar Among the available corticosteroid-sparing treatment options, the antimetabolites methotrexate and mycophenolate mofetil (MMF) are used commonly.

Diagnosis and Treatment of Primary Inflammatory Choriocapillaropathies (PICCPs): A Comprehensive Overview.

Purpose: Primary inflammatory choriocapillaropathies (PICCPs) belong to a group of intraocular inflammatory diseases with the common characteristic of inflammatory choriocapillaris hypo- or non-perfusion as the main clinicopathological mechanism. The purpose of our article is to describe clinical characteristics and multimodal imaging, that can help the diagnosis and treatment of PICCPs. Methods: Narrative review with multimodal imaging analysis. Results: Choriocapillaris non-perfusion can affect the end-choriocappilaries, at the benign end of the PICCP spectrum (MEWDS), to larger choriocapillaris vessels or precapillary vessels at the origin of more severe forms such as acute posterior multifocal placoid pigment epitheliopathy (APMPPE), idiopathic multifocal choroiditis (MFC) and Serpiginous Choroiditis (SC). Diagnosis is mostly based on multimodal imaging and especially on indocyanine green angiography (ICGA), fundus autofluorescence (FAF) and spectral-domain optical coherence tomography (SD-OCT)/OCT-angiography (OCT-A). ICGA shows the typical pattern of patchy lobular hypofluorescence reflecting hypo- or non-perfusion of the choriocapillaris that can also take the aspect of geographic areas in the more severe forms. Treatment depends on the severity of the disease and goes from observation in MEWDS and some mild cases of APMPPE, to oral corticosteroid and/or immunomodulator agents in the more severe conditions of APMPPE and MFC and SC cases. Close multimodal monitoring is crucial in order to introduce or adjust treatment. Conclusion: PICCPs are resulting from one common clinicopathological mechanism, inflammatory choriocapillaris hypo- or non-perfusion. ICGA findings are essential for the diagnosis and follow-up of PICCPs, but non-invasive methods such as FAF and SD-OCT/OCT-A also have their role especially in follow-up of the diseases. Treatment should be individualized according to the pathology and the evolution of lesions.

Experimental Autoimmune Uveitis: An Intraocular Inflammatory Mouse Model.

Experimental Autoimmune Uveitis (EAU) is driven by immune cells responding to self-antigens. Many features of this non-infectious, intraocular inflammatory disease model recapitulate the clinical phenotype of posterior uveitis affecting humans. EAU has been used reliably to study the efficacy of novel inflammatory therapeutics, their mode of action and to further investigate the mechanisms that underpin disease progression of intraocular disorders. Here, we provide a detailed protocol on EAU induction in the C57BL/6J mouse - the most widely used model organism with susceptibility to this disease. Clinical assessment of disease severity and progression will be demonstrated using fundoscopy, histological examination and fluorescein angiography. The induction procedure involves subcutaneousinjection of an emulsion containing a peptide (IRBP1-20) from the ocular protein interphotoreceptor retinoid binding protein (also known as retinol binding protein 3), Complete Freund's Adjuvant (CFA) and supplemented with killed Mycobacterium tuberculosis. Injection of this viscous emulsion on the back of the neck is followed by a single intraperitoneal injection of Bordetella pertussis toxin. At the onset of symptoms (day 12-14) and under general anesthesia, fundoscopic images are taken to assess disease progression through clinical examination. These data can be directly compared with those at later timepoints and peak disease (day 20-22) with differences analyzed. At the same time, this protocol allows the investigator to assess potential differences in vessel permeability and damage using fluorescein angiography. EAU can be induced in other mouse strains - both wildtype or genetically modified - and combined with novel therapies offering flexibility for studying drug efficacy and/or disease mechanisms.

Seasonal Hyperacute Panuveitis (SHAPU)

IntroductionSHAPU is a mysterious disease seen and reported only from Nepal since 1975. It is an important cause of unilateralchildhood blindness and is the most devastating intraocular inflammatory disease leading to loss of sight within a week. Although initially presented as a case report at a Nepal prevention of blindness meeting in 1978 and reported in national journal Malla O, editor Endophthalmitis probably caused by Tussock moth. Report of the preceding of the first National seminar on Prevention of Blindness: 1978.Upadhyan MP: Eye problems of Nepalese Children in 1979.Now there are more than 10 published articles available in the Website.

Management of Intraocular Inflammatory Disease

Background: Intra ocular inflammatory disease is a broad-spectrum eye inflammatory condition. Objective: To evaluate various management protocols for Intra ocular inflammatory disease. Study Design: Retrospective study Place and Duration of Study: Department of Ophthalmology, Lorallai Medical College, Loralai from 1st January 2020 to 31st March 2021. Methodology: One hundred and twenty medical files of patients with various intra ocular inflammatory diseases were recruited. Patients were managed by various pharmacological drugs including corticosteroids, second line agents, anti-metabolites as well as biologics (anti-TNF-alpha) therapy. Results: There were 45% females while 55% were males. The mean age of the patients was 45±4.4 years. Majority of the patients were within 41-50 years with 37.5% followed by those >50 years of age. Corticosteroids were efficient in 50% of patients with intra ocular inflammatory disease as a secondary condition while azathioprine in 75% patient and tacrolimus 93.4% patients. Conclusion: Second line agents and antimetabolites have higher prevalence of acceptance and efficacy in managing intra ocular inflammatory disease. Keywords: Management, Intraocular inflammatory disease, Broad spectrum

CAUSES AND CLINICAL MANIFESTATIONS OF MASQUERADE SYNDROMES IN INTRAOCULAR INFLAMMATORY DISEASES.

To identify the clinical characteristics and prevalence of neoplastic and nonneoplastic inflammatory masquerade syndromes (IMSs) in a tertiary center and determine the useful diagnostic tests. A retrospective cohort study of consecutive 1906 patients diagnosed with intraocular inflammatory disease. Of all patients initially diagnosed with intraocular inflammatory disease, we identified 116 (6%) patients with noninflammatory causes (neoplastic IMSs in 36/116; 31% and nonneoplastic IMSs in 52/116; 45%). In addition, 26 patients (22%, 1.4% of all) had drug-induced uveitis and 2 (2%, 0.1% of all) had paraneoplastic uveitis. The large B-cell lymphoma was the most common neoplastic IMS (78%), and the major clinical features were presence of cells and floaters in the vitreous (69%) and chorioretinal lesions (33%). The causes of nonneoplastic IMSs included retinal vascular disorders (38%), hereditary retinal diseases (31%), and degenerative ocular disorders (19%). The common clinical manifestations consisted of chorioretinal scars (27%), small white-yellow retinal lesions (17%), and leaking vessels on fluorescein angiography (14%). Noninflammatory causes were determined in 6% of a large population with initial diagnosis of intraocular inflammatory disease. Although neoplastic IMS was commonly characterized by vitreous cells and opacities, most common definitive diagnoses in nonneoplastic IMS encompassed diverse retinal disorders.

The Usefulness of Diagnostic Vitrectomy in Neoplastic and Non-Neoplastic Masquerade Syndrome: An Observational Study

Introduction: Masquerade intraocular inflammation may be considered neoplastic or non- neoplastic masquerades such as primary intraocular lymphoma, leukemia, infectious and inflammatory diseases. These pathologies require a definitive diagnosis, as the treatment modalities are different. The aim of our study was to investigate the safety and usefulness of diagnostic vitrectomy with vitreous humor flow cytometry in eyes with intraocular inflammation of unknown etiology. Methods: A retrospective observational study included 35 eyes of 29 patients with atypical intraocular inflammation unresponsive to corticosteroid therapy. In all cases diagnostic vitrectomy with flow cytometry analysis of the vitreous specimen was performed. Results: Among 35 eyes, the result of diagnostic vitrectomy analysis showed unspecific inflammatory response in 7 (20.0%) eyes, confirmed neoplastic diseases in 5 (14.3%) eyes. All of them it was intraocular lymphoma but one of the eyes with primarily diagnosed lymphoma and one of the eyes with primarily diagnosed unspecific inflammatory response in flow cytometry has been diagnosed finally as a choroidal melanoma after enucleation of the eyeball. Diagnostic vitrectomy excluded neoplastic disease in 7 eyes (20.0%). In 3 eyes (8.6%) bacterial infection, in 4 eyes (11.4%) viral infection. In 2 eyes (5.7%) we excluded bacterial infection, in 7 cases (20.0%) no conclusive results were obtained. The most common adverse event was cataract in patients (12 eyes, 34.3%). Conclusion: Diagnostic vitrectomy with flow cytometry of vitreous humor is helpful in confirming the clinical suspected diagnosis of posterior segment inflammation. Flow cytometry need to be complemented with other diagnostic test including cytopathology, especially in cases suspected of intraocular lymphoma. Flow cytometry of the vitreous humor in choroidal melanoma is not a useful diagnostic tool.

Retrospective Study of the Frequency of TMP/SMX Prophylaxis Use and the Incidence of Pneumocystis Pneumonia Following Systemic Corticosteroid Therapy in Intraocular Inflammatory Disease Patients

Retrospective Study of the Frequency of TMP/SMX Prophylaxis Use and the Incidence of Pneumocystis Pneumonia Following Systemic Corticosteroid Therapy in Intraocular Inflammatory Disease Patients