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Age-related macular degeneration (AMD) is a complex neurodegenerative disease and is the leading cause of blindness in the aging population. Early AMD is characterized by drusen in the macula and causes minimal changes in visual function. The later stages are responsible for the majority of visual impairment and blindness and can be either manifest as geographic atrophy (dry) or neovascular disease (wet). Available medicines are directed against the wet form and do not cure vision loss. Therefore, it is imperative to identify preventive and therapeutic targets. As the mechanism for AMD is unclear, we aim to interrogate the disease-affected tissue - the macular neural retina and macular retina pigment epithelium (RPE)/choroid. We investigated differentially expressed genes expression (DEG) across the clinical stages of AMD in meticulously dissected and phenotyped eyes using a standardized published protocol (Owen et al., 2019). Donor eyes (n=27) were obtained from Caucasian individuals with an age range of 60-94 and 63% were male, and tissue from the macula RPE/choroid and macula neural retina were taken from the same eye. Donor eyes were recovered within 6 hours post mortem interval time to ensure maximal preservation of RNA quality and accuracy of diagnosis. Eyes were then phenotyped by retina experts using multi modal imaging (fundus photos and SD-OCT). Utilizing DESeq2, followed PCA, Benjamini Hochberg adjustment to control for the false discovery rate, and Bonferonni correction for the number of paired comparisons: a total of 26,650 genes were expressed in the macula RPE/choroid and/or macula retina among which significant differential expression was found for 1,204 genes between neovascular AMD and normal eyes, 40 genes between intermediate AMD and normal eyes, and 1,194 genes between intermediate AMD and neovascular AMD. A comparison of intermediate AMD versus normal eyes includedTCN2, PON1, IFI6,GPR123, andTIMD4as being some of the most significant DEGs in the macula RPE/choroid. A comparison of neovascular AMD versus normal eyes includedSLC1A2, SLC24A1, SCAMP5, PTPRN, and SEMA7A asbeing some of the most significant DEGs in the macula RPE/choroid. Top pathways of DEGs in the macular RPE/choroid identified through Ingenuity Pathway Analysis (IPA) for the comparison of intermediate AMD with normal eyes were interferon signaling and Th1 and Th2 activation, while those for the comparison of neovascular AMD with normal eyes were the phototransduction and SNARE signaling pathways. Allele-specific expression (ASE) in coding regions of previously reported AMD risk loci identified by GWAS (Fritsche et al, 2016) revealed significant ASEs for C3 rs2230199 and CFH rs1061170 in the macula RPE/choroid for normal eyes and intermediate AMD, and for CFH rs1061147 in the macula RPE/choroid for normal eyes and intermediate and neovascular AMD. An investigation of the 34 established AMD risk loci revealed that 75% of them were significantly differentially expressed between normal macular RPE/choroid and macular neural retina, with 75% of these loci showing higher expression in the RPE. Similarly, disease state differences for the GWAS loci were only found to be statistically differentially expressed in the macular RPE/choroid. Moreover, the known coding variants in the previously identified GWAS loci including,CFH,C3,CFB, demonstrated ASE across AMD clinical stages in the macular RPE/choroid and not in the neural retina. These data at the bulk level underscore the importance of the RPE/choroid to AMD pathophysiology. While many bulk RNASeq data sets are publicly available, to the best of our knowledge this is one of the first publicly available datasets with both maculae RPE/choroid and macula neural retina from the same well phenotyped donor eye(s) where the macula is separated from the periphery. Our findings also underscore the importance of studying both macular tissue types to gain a full understanding of mechanisms leading to AMD. Our results provide insights into underlying biological mechanisms that may differentiate the disease subtypes and into the tissues affected by the disease.

To evaluate changes in health-related and vision-related quality of life (VRQoL) among patients with noninfectious uveitis who were treated with antimetabolites.Secondary analysis of a randomized controlled trial.Patients with noninfectious uveitis from India, the United States, Australia, Saudi Arabia, and Mexico.From 2013 through 2017, 216 participants were randomized to receive 25 mg weekly oral methotrexate or 1.5 g twice daily oral mycophenolate mofetil. Median changes in quality of life (QoL) were measured using Wilcoxon signed-rank tests, and differences between treatment groups were measured using linear mixed models, adjusting for baseline QoL score, age, gender, and site. Among Indian patients, VRQoL scores from a general scale (the National Eye Institute Visual Function Questionnaire [NEI-VFQ]) and a culturally specific scale (the Indian Visual Function Questionnaire [IND-VFQ]) were compared using Pearson correlation tests.Vision-related QoL (NEI-VFQ and IND-VFQ) and health-related QoL (HRQoL; physical component score [PCS] and mental component score [MCS] of the Medical Outcomes Study 36-Item Short Form Survey [SF-36v2]) were measured at baseline, the primary end point (6 months or treatment failure before 6 months), and the secondary end point (12 months or treatment failure between 6 and 12 months).Among 193 participants who reached the primary end point, VRQoL increased from baseline by a median of 12.0 points (interquartile range [IQR], 1.0-26.1, NEI-VFQ scale), physical HRQoL increased by a median of 3.6 points (IQR, -1.4 to 14.9, PCS SF-36v2), and mental HRQoL increased by a median of 3.0 points (IQR, -3.7 to 11.9, MCS SF-36v2). These improvements in NEI-VFQ, SF-36v2 PCS, and SF-36v2 MCS scores all were significant (P0.01). The linear mixed models showed that QoL did not differ between treatment groups for each QoL assessment (NEI-VFQ, IND-VFQ, PCS SF-36v2, and MCS SF-36v2; P0.05 for all). The NEI-VFQ and IND-VFQ scores for Indian participants were correlated highly at baseline and the primary and secondary end points (correlation coefficients, 0.87, 0.80, and 0.90, respectively).Among patients treated with methotrexate or mycophenolate mofetil for uveitis, VRQoL and HRQoL improved significantly over the course of 1 year and did not differ by treatment allocation. These findings suggest that antimetabolites could improve overall patient well-being and daily functioning.

Purpose To determine classification criteria for multifocal choroiditis with panuveitis (MFCPU) DESIGN: : Machine learning of cases with MFCPU and 8 other posterior uveitides. Methods Cases of posterior uveitides were collected in an informatics-designed preliminary database, and a final database was constructed of cases achieving supermajority agreement on diagnosis, using formal consensus techniques. Cases were split into a training set and a validation set. Machine learning using multinomial logistic regression was used on the training set to determine a parsimonious set of criteria that minimized the misclassification rate among the posterior uveitides. The resulting criteria were evaluated on the validation set. Results One thousand sixty-eight cases of posterior uveitides, including 138 cases of MFCPU, were evaluated by machine learning. Key criteria for MFCPU included: 1) multifocal choroiditis with the predominant lesions size >125 µm in diameter; 2) lesions outside the posterior pole (with or without posterior involvement); and either 3) punched-out atrophic chorioretinal scars or 4) more than minimal mild anterior chamber and/or vitreous inflammation. Overall accuracy for posterior uveitides was 93.9% in the training set and 98.0% (95% confidence interval 94.3, 99.3) in the validation set. The misclassification rates for MFCPU were 15% in the training set and 0% in the validation set. Conclusions The criteria for MFCPU had a reasonably low misclassification rate and appeared to perform sufficiently well for use in clinical and translational research.

Purpose To determine classification criteria for sarcoidosis-associated uveitis DESIGN: Machine learning of cases with sarcoid uveitis and 15 other uveitides. Methods Cases of anterior, intermediate, and panuveitides were collected in an informatics-designed preliminary database, and a final database was constructed of cases achieving supermajority agreement on the diagnosis, using formal consensus techniques. Cases were analyzed by anatomic class, and each class was split into a training set and a validation set. Machine learning using multinomial logistic regression was used on the training sets to determine a parsimonious set of criteria that minimized the misclassification rate among the intermediate uveitides. The resulting criteria were evaluated on the validation sets. Results One thousand eighty-three anterior uveitides, 589 intermediate uveitides, and 1012 panuveitides, including 278 cases of sarcoidosis-associated uveitis, were evaluated by machine learning. Key criteria for sarcoidosis-associated uveitis included a compatible uveitic syndrome of any anatomic class and evidence of sarcoidosis, either 1) a tissue biopsy demonstrating non-caseating granulomata or 2) bilateral hilar adenopathy on chest imaging. The overall accuracy of the diagnosis of sarcoidosis-associated uveitis in the validation set was 99.7% (95% confidence interval 98.8, 99.9).The misclassification rates for sarcoidosis-associated uveitis in the training sets were: anterior uveitis 3.2%, intermediate uveitis 2.6%, and panuveitis 1.2%; in the validation sets the misclassification rates were: anterior uveitis 0%, intermediate uveitis 0%, and panuveitis 0%, respectively. Conclusions The criteria for sarcoidosis-associated uveitis had a low misclassification rate and appeared to perform sufficiently well for use in clinical and translational research.

Purpose To determine classification criteria for birdshot chorioretinitis. Design Machine learning of cases with birdshot chorioretinitis and 8 other posterior uveitides. Methods Cases of posterior uveitides were collected in an informatics-designed preliminary database, and a final database was constructed of cases achieving supermajority agreement on diagnosis, using formal consensus techniques. Cases were split into a training set and a validation set. Machine learning using multinomial logistic regression was used on the training set to determine a parsimonious set of criteria that minimized the misclassification rate among the infectious posterior/panuveitides. The resulting criteria were evaluated on the validation set. Results One thousand sixty-eight cases of posterior uveitides, including 207 cases of birdshot chorioretinitis, were evaluated by machine learning. Key criteria for birdshot chorioretinitis included a multifocal choroiditis with: 1) the characteristic appearance a bilateral multifocal choroiditis with cream-colored or yellow-orange, oval or round choroidal spots ("birdshot" spots); 2) absent to mild anterior chamber inflammation; and 3) absent to moderate vitreous inflammation; or multifocal choroiditis with positive HLA-A29 testing and either: 1) classic "birdshot spots" or 2) characteristic imaging on indocyanine green angiography. Overall accuracy for posterior uveitides was 93.9% in the training set and 98.0% (95% confidence interval 94.3, 99.3) in the validation set. The misclassification rates for birdshot chorioretinitis were 10% in the training set and 0% in the validation set. Conclusions The criteria for birdshot chorioretinitis had a low misclassification rate and appeared to perform sufficiently well for use in clinical and translational research.

PURPOSE: To evaluate long-term efficacy and safety of extended treatment with adalimumab in patients with noninfectious intermediate, posterior, or panuveitis.DESIGN: Open-label, multicenter, phase 3 extension study (VISUAL III).PARTICIPANTS: Adults who had completed a randomized, placebo-controlled phase 3 parent trial (VISUAL I or II) without treatment failure (inactive uveitis) or discontinued after meeting treatment failure criteria (active uveitis).METHODS: Patients received subcutaneous adalimumab 40 mg every other week. Data were collected for ≤362 weeks. Adverse events (AEs) were recorded until 70 days after the last dose of study drug.MAIN OUTCOME MEASURES: Main outcome measures were long-term safety and quiescence; other efficacy variables included inflammatory lesions, anterior chamber cell and vitreous haze grade, macular edema, visual acuity, and dose of uveitis-related corticosteroids.RESULTS: Of 424 patients enrolled, 67% (283/424) had active uveitis and 33% (141/424) had inactive uveitis at study entry; 60 patients subsequently met exclusion criteria, and 364 patients were included in the intent-to-treat analysis. Efficacy variables were analyzed through week 150 when approximately 50% of patients (214/424) remained in the study. The percentage of patients in quiescence increased from 34% (122/364) at week 0 to 85% (153/180) at week 150. Corticosteroid-free quiescence was achieved by 54% (66/123) and 89% (51/57) of patients with active or inactive uveitis at study entry, respectively, by week 150. Mean daily dose of corticosteroids was reduced from 9.4±17.1 mg/day at week 0 (n=359) to 1.5±3.9 mg/day at week 150 (n=181). The percentage of patients who achieved other efficacy variables increased over time for those with active uveitis at study entry and was maintained for those with inactive uveitis. The most frequently reported treatment-emergent AEs of special interest for adalimumab were infections (n=275; 78.7 events/100 patient-years); AEs and serious AEs occurred at a rate of 396 events/100 patient-years and 15 events/100 patient-years, respectively.CONCLUSIONS: Long-term treatment with adalimumab led to quiescence and reduced corticosteroid use for patients who entered VISUAL III with active uveitis and maintenance of quiescence for those with inactive uveitis. AEs were comparable to those reported in the parent trials and consistent with the known safety profile of adalimumab.

Uveitis is a heterogeneous collection of diseases. We tested the hypothesis that despite the diversity of uveitides, there could be common mechanisms shared by multiple subtypes, and that evidence of these common mechanisms may be detected as gene expression profiles in whole blood.Cohort study.Ninety subjects with uveitis including axial spondyloarthritis (n = 17), sarcoidosis (n = 13), inflammatory bowel disease (n = 12), tubulointerstitial nephritis with uveitis (n = 10), or idiopathic uveitis (n = 38) as well as 18 healthy controls were enrolled, predominantly at Oregon HealthScience University. RNA-Seq data generated from peripheral, whole blood identified 19,859 unique transcripts. We analyzed gene expression pathways via Kyoto Encyclopedia of Genes and Genomes and Gene Ontology (GO). We validated our list of upregulated genes by comparison to a previously published study on peripheral blood gene expression among 50 subjects with diverse forms of uveitis.Both the Kyoto Encyclopedia of Genes and Genomes and GO analysis identified multiple shared pathways or GO terms with a P value of.0001. Almost all pathways related to the immune response and/or response to an infection. A total of 119 individual transcripts were upregulated by at least 1.5-fold and false discovery rate.05, and 61 were downregulated by similar criteria. Comparing mRNA from our study with a false discovery rate.05 and the prior report, we identified 10 common gene transcripts: ICAM1, IL15RA, IL15, IRF1, IL10RB, GSK3A, TYK2, MEF2A, MEF2B, and MEF2D.Many forms of uveitis share overlapping mechanisms. These data support the concept that a single therapeutic approach could benefit diverse forms of this disease.

PURPOSE: To test the hypothesis that idiopathic uveitis can be categorized into subtypes based on gene expression from blood. DESIGN: Case control study METHODS: We applied RNA-Seq to peripheral blood from patients with uveitis associated with one of four systemic diseases, including axial spondyloarthritis (n=17), sarcoidosis (n=13), inflammatory bowel disease (n=12), tubulo-interstitial nephritis with uveitis (n=10), or idiopathic uveitis (n=38) as well as 18 healthy controls evaluated predominantly at Oregon Health & Science University. A high dimensional negative binomial regression model implemented in the edgeR R package compared each disease group against the controls. The 20 most distinctive genes for each diagnosis were extracted. Out of 80 genes, there were 75 unique genes. A classification algorithm was developed by fitting a gradient boosting tree with 5-fold cross-validation. mRNA from subjects with idiopathic uveitis was analyzed to see if any fit clinically and by gene expression pattern with one of the diagnosable entities. RESULTS: For uveitis associated with a diagnosable systemic disease, gene expression profiling achieved an overall accuracy of 85% (balanced average of sensitivity plus specificity, p-value < 0.001). Although the majority of patients with idiopathic uveitis presumably have none of these four associated systemic diseases, gene expression profiles helped to reclassify 11 of 38 subjects. CONCLUSIONS: Peripheral blood gene expression profiling is a potential adjunct in accurate differential diagnosis of the cause of uveitis. Validation of these results and characterization of the gene expression profile from additional discrete diagnoses could enhance the value of these observations.

Background: Cytomegalovirus retinitis (CMVR) is the primary cause of AIDS-related blindness and remains a substantial cause of blindness in resource-limited settings. Retinal detachment (RD) occurs in approximately 1/3 of patients with CMV retinitis. There is limited capacity to treat retinal detachment in resource-limited settings, and retinal detachment commonly results in permanent profound vision loss. Prophylactic argon laser demarcation was widely used in the pre-HAART era in high income countries, and we here describe our experience with this safe, low-cost intervention to prevent blindness from CMV retinitis-related retinal detachment in a resource-limited setting, in the current era where effective antiretroviral therapy is available. Methods: A non-randomized retrospective observational cohort study was conducted over 4 years in patients on cART (combined antiretroviral therapy) and with inactive AIDS-related CMVR involving at least 25% of the retina, and who were treated with prophylactic argon laser demarcation (LD). The main outcomes were retinal detachment and loss of vision.Results: In a 45 eyes from 38 patients with inactive CMVR on cART for HIV/AIDS who underwent prophylactic laser demarcation, there were no retinal detachments and no loss of vision.Conclusion: In this series of patients at risk for CMVR-related retinal detachment who were treated with prophylactic laser demarcation, retinal detachment was prevented and visual acuity was maintained. Prophylactic argon laser demarcation is a safe, effective, and a realistically affordable intervention to reduce blindness in patients with AIDS-related CMV retinitis.

Purpose: This work evaluates the role of combined phacoemulsification and vitrectomy surgery in the management of cataract associated with noninfectious uveitis. Methods: A retrospective chart review was conducted of all patients aged 7 years or older who underwent a combined surgical approach from 2005 to 2018. Results: Eighty-five eyes of 67 patients were included in the study; 10.7% of eyes had a best-corrected visual acuity (BCVA) of 20/40 or better at time of surgery. At 1-year follow-up, 63.4% of eyes had a BCVA 20/40 or better and 7.6% had a BCVA of 20/200 or worse. There was an overall decrease in cystoid macular edema after surgery compared with preoperatively (47.6% vs 34.5% presurgery and postsurgery, respectively). Complete inflammatory disease remission off immunomodulatory therapy and systemic steroids was achieved in 21.1% of patients. Conclusions: A combined surgical approach is effective in visual rehabilitation in patients with uveitic cataracts and may promote inflammatory disease remission specifically in intermediate uveitis.

Purpose To describe a patient who developed concurrent acute posterior multifocal placoid pigment epitheliopathy (APMPPE) and posterior scleritis. Observations We describe a middle-aged woman that developed eye pain and photopsia. She was found to have a “T-sign” on ultrasound of the right eye and multiple, nearly confluent, ill-defined subretinal whitish lesions in both eyes. After an extensive laboratory evaluation and neuroimaging, her photopsia, pain with eye movements, and subretinal lesions began to regress on high dose systemic corticosteroids. Conclusions and Importance This is the first reported case of bilateral APMPPE and concurrent posterior scleritis. Our case highlights the importance of performing a full review of systems, specifically eliciting neurological changes, and dilated eye examination in all new uveitis cases.

PURPOSE: To determine classification criteria for serpiginous choroiditis. DESIGN: Machine learning of cases with serpiginous choroiditis and 8 other posterior uveitides. METHODS: Cases of posterior uveitides were collected in an informatics-designed preliminary database, and a final database was constructed of cases achieving supermajority agreement on diagnosis, using formal consensus techniques. Cases were split into a training set and a validation set. Machine learning using multinomial logistic regression was used on the training set to determine a parsimonious set of criteria that minimized the misclassification rate among the infectious posterior uveitides / panuveitides. The resulting criteria were evaluated on the validation set. RESULTS: One thousand sixty-eight cases of posterior uveitides, including 122 cases of serpiginous choroiditis, were evaluated by machine learning. Key criteria for serpiginous choroiditis included (1) choroiditis with an ameboid or serpentine shape; (2) characteristic imaging on fluorescein angiography or fundus autofluorescence; (3) absent to mild anterior chamber and vitreous inflammation; and (4) the exclusion of tuberculosis. Overall accuracy for posterior uveitides was 93.9% in the training set and 98.0% (95% confidence interval 94.3, 99.3) in the validation set. The misclassification rates for serpiginous choroiditis were 0% in both the training set and the validation set. CONCLUSIONS: The criteria for serpiginous choroiditis had a low misclassification rate and seemed to perform sufficiently well for use in clinical and translational research.

Purpose To determine classification criteria for acute posterior multifocal placoid pigment epitheliopathy (APMPPE). Design Machine learning of cases with APMPPE and 8 other posterior uveitides. Methods Cases of posterior uveitides were collected in an informatics-designed preliminary database, and a final database was constructed of cases achieving supermajority agreement on diagnosis, using formal consensus techniques. Cases were split into a training set and a validation set. Machine learning using multinomial logistic regression was used on the training set to determine a parsimonious set of criteria that minimized the misclassification rate among the infectious posterior/panuveitides. The resulting criteria were evaluated on the validation set. Results One thousand sixty-eight cases of posterior uveitides, including 82 cases of APMPPE, were evaluated by machine learning. Key criteria for APMPPE included: 1) choroidal lesions with a plaque-like or placoid appearance and 2) characteristic imaging on fluorescein angiography (lesions "block early and stain late diffusely"). Overall accuracy for posterior uveitides was 92.7% in the training set and 98.0% (95% confidence interval 94.3, 99.3) in the validation set. The misclassification rates for APMPPE were 5% in the training set and 0% in the validation set. Conclusions The criteria for APMPPE had a low misclassification rate and appeared to perform sufficiently well for use in clinical and translational research.

A woman presented with bilateral visual disturbances that had been diagnosed as visual snow. Dilated ophthalmic examination and multimodal imaging were strongly suggestive of birdshot chorioretinopathy, meriting initiation of systemic immunomodulatory therapy. Visual snow requires a thorough ophthalmologic exam to exclude other ocular diseases.

Purpose To evaluate the comparative effectiveness of 3 regional corticosteroid injections for uveitic macular edema (ME): periocular triamcinolone acetonide (PTA), intravitreal triamcinolone acetonide (ITA), and the intravitreal dexamethasone implant (IDI). Design Multicenter, randomized clinical trial. Participants Patients with uveitic ME. Methods Patients were randomized 1:1:1 to receive 1 of the 3 therapies. Patients with bilateral ME were assigned the same treatment for both eyes. Main Outcome Measures The primary outcome was the proportion of baseline (PropBL) central subfield thickness (CST) at 8 weeks (CST at 8 weeks/CST at baseline) assessed with OCT by masked readers. Secondary outcomes included ≥20% improvement and resolution of ME, best-corrected visual acuity (BCVA), and intraocular pressure (IOP) events over 24 weeks. Results All treatment groups demonstrated improved CST during follow-up. At 8 weeks, each group had clinically meaningful reductions in CST relative to baseline (PropBL: 0.77, 0.61, and 0.54, respectively, which translates to reductions of 23%, 39%, and 46% for PTA, ITA, and IDI, respectively). Intravitreal triamcinolone acetonide (PropBL ITA/PropBL PTA, hazard ratio [HR], 0.79; 99.87% confidence interval [CI], 0.65–0.96) and IDI (PropBL IDI/PropBL PTA, HR, 0.69; 99.87% CI, 0.56–0.86) had larger reductions in CST than PTA (P Conclusions Intravitreal triamcinolone acetonide and the IDI were superior to PTA for treating uveitic ME with modest increases in the risk of IOP elevation. This risk did not differ significantly between intravitreal treatments.

In April 2019, the US Food and Drug Administration, in conjunction with 11 professional ophthalmic, vision science, and optometric societies, convened a forum on laser-based imaging. The forum brought together the Food and Drug Administration, clinicians, researchers, industry members, and other stakeholders to stimulate innovation and ensure that patients in the US are the first in the world to have access to high-quality, safe, and effective medical devices. This conference focused on the technology, clinical applications, regulatory issues, and reimbursement issues surrounding innovative ocular imaging modalities. Furthermore, the emerging role of artificial intelligence in ophthalmic imaging was reviewed. This article summarizes the presentations, discussion, and future directions.

Acute retinal pigment epitheliitis is a rare, idiopathic, self-limited inflammatory condition of the outer retina and retinal pigment epithelium of unknown etiology. It is also known as Krill’s disease.

Background: The American Indian Navajo and Goshute peoples are underserved patient populations residing in the Four Corners area of the United States and Ibupah, Utah, respectively. Methods: We conducted a cross-sectional study of epidemiological factors and lipid biomarkers that may be associated with type II diabetes, hypertension and retinal manifestations in tribal and non-tribal members in the study areas (n = 146 participants). We performed multivariate analyses to determine which, if any, risk factors were unique at the tribal level. Fundus photos and epidemiological data through standardized questionnaires were collected. Blood samples were collected to analyze lipid biomarkers. Univariate analyses were conducted and statistically significant factors at p &lt, 0.10 were entered into a multivariate regression. Results: Of 51 participants for whom phenotyping was available, from the Four Corners region, 31 had type II diabetes (DM), 26 had hypertension and 6 had diabetic retinopathy (DR). Of the 64 participants from Ibupah with phenotyping available, 20 had diabetes, 19 had hypertension and 6 had DR. Navajo participants were less likely to have any type of retinopathy as compared to Goshute participants (odds ratio (OR) = 0.059, 95% confidence interval (CI) = 0.016&ndash, 0.223, p &lt, 0.001). Associations were found between diabetes and hypertension in both populations. Older age was associated with hypertension in the Four Corners, and the Navajo that reside there on the reservation, but not within the Goshute and Ibupah populations. Combining both the Ibupah, Utah and Four Corners study populations, being American Indian (p = 0.022), residing in the Four Corners (p = 0.027) and having hypertension (p &lt, 0.001) increased the risk of DM. DM (p &lt, 0.001) and age (p = 0.002) were significantly associated with hypertension in both populations examined. When retinopathy was evaluated for both populations combined, hypertension (p = 0.037) and living in Ibupah (p &lt, 0.001) were associated with greater risk of retinopathy. When combining both American Indian populations from the Four Corners and Ibupah, those with hypertension were more likely to have DM (p &lt, 0.001). No lipid biomarkers were found to be significantly associated with any disease state. Conclusions: We found different comorbid factors with retinal disease outcome between the two tribes that reside within the Intermountain West. This is indicated by the association of tribe and with the type of retinopathy outcome when we combined the populations of American Indians. Overall, the Navajo peoples and the Four Corners had a higher prevalence of chronic disease that included diabetes and hypertension than the Goshutes and Ibupah. To the best of our knowledge, this is the first study to conduct an analysis for disease outcomes exclusively including the Navajo and Goshute tribe of the Intermountain West.

Purpose: We report a presumptive case of bilateral placoid choroiditis secondary to disseminated Cryptococcus neoformans infection and review the literature on choroidal involvement of C neoformans. Methods: A case report is presented. Results: A 35-year-old HIV-positive man presented with disseminated cryptococcal infection. Cryptococcal meningitis was confirmed by lumbar puncture, and skin involvement was confirmed by microscopy of scrapings from a papular, umbilicated, ulcerated lesion. Ophthalmologic examination revealed intact visual acuity, clear vitreous, and multiple yellowish, placoid-appearing choroidal lesions in the posterior pole bilaterally. Conclusions: Multifocal choroiditis caused by C neoformans is an uncommon manifestation of disseminated infection, and placoid yellowish choroidal lesions are an unusual variant. These findings must be differentiated from choroidal tuberculosis and other infections. Multifocal choroiditis typically occurs in AIDS patients and may precede the presentation of meningitis. In such patients, choroidal lesions warrant investigation for systemic, life-threatening opportunistic infections.

PURPOSE: To determine classification criteria for multiple evanescent white dot syndrome (MEWDS).DESIGN: Machine learning of cases with MEWDS and 8 other posterior uveitides.METHODS: Cases of posterior uveitides were collected in an informatics-designed preliminary database, and a final database was constructed of cases achieving supermajority agreement on diagnosis, using formal consensus techniques. Cases were split into a training set and a validation set. Machine learning using multinomial logistic regression was used on the training set to determine a parsimonious set of criteria that minimized the misclassification rate among the infectious posterior/panuveitides. The resulting criteria were evaluated on the validation set.RESULTS: One thousand sixty-eight cases of posterior uveitides, including 51 cases of MEWDS, were evaluated by machine learning. Key criteria for MEWDS included: 1) multifocal gray white chorioretinal spots with foveal granularity; 2) characteristic imaging on fluorescein angiography ("wreath-like" hyperfluorescent lesions) and/or optical coherence tomography (hyper-reflective lesions extending from retinal pigment epithelium through ellipsoid zone into the retinal outer nuclear layer); and 3) absent to mild anterior chamber and vitreous inflammation. Overall accuracy for posterior uveitides was 93.9% in the training set and 98.0% (95% confidence interval 94.3, 99.3) in the validation set. The misclassification rates for MEWDS were 7% in the training set and 0% in the validation set.CONCLUSIONS: The criteria for MEWDS had a low misclassification rate and appeared to perform sufficiently well for use in clinical and translational research.

Purpose: Placoid-pigment-epitheliopathies like Acute-Posterior-Multifocal-Placoid-Pigment Epitheliopathy (APMPPE) and Relentless-Placoid-Choroidopathy (RPC) usually show bilateral involvement. This retrospective case series describes the clinical features with unilateral disease onset. Methods: 21 patients from 9 tertiary referring institutions were collected and evaluated. Results: Seventeen patients were included: 11 (65%) had unilateral placoid-pigment-epitheliopathy consistent with APMPPE, 6 (35%) with RPC (mean age: 28.82 ± 9.1 years). Mean follow-up time was 45 ± 48 months. Forty-one percent fellow-eyes had initial inflammatory signs including vitreous-cells, vascular-sheathing, and ONH swelling. Thirty-five percent developed chorioretinal lesions during follow-up after 19.5 ± 16.9 months. Initial inflammation in fellow-eye was not associated with fellow-eye involvement (p =.5). However, subfoveal choroidal-thickness (SCT) at baseline was significantly thicker in fellow-eyes who developed chorioretinal lesion compared to fellow-eyes who did not (400 ± 70 µm versus 283 ± 127 µm,p =.047). Conclusion: Unaffected fellow-eyes may have inflammatory signs at initial disease-onset and may develop lesions over time. They should be carefully monitored, particularly if they present with an increased SCT.

This chapter will focus on techniques for the repair of dislocated intraocular lenses (IOLs) and placement of secondary IOLs in patients with uveitis. Secondary IOL placement in uveitic eyes introduces risk for the development of chronic uveitis from a variety of mechanisms including anatomic chaffing of uveal tissues. This chapter will review the anatomic and IOL design options for secondary IOL placement in uveitic eyes with a focus on minimizing the induction of inflammation. An additional focus of this chapter is on the apparent increased risk for dislocation of primary IOLs as a result of enhanced risk for capsule contraction syndrome and zonulopathy in eyes with uveitis

Single-cell RNA-seq is a powerful tool in decoding the heterogeneity in complex tissues by generating transcriptomic profiles of the individual cell. Here, we report a single-nuclei RNA-seq (snRNA-seq) transcriptomic study on human retinal tissue, which is composed of multiple cell types with distinct functions. Six samples from three healthy donors are profiled and high-quality RNA-seq data is obtained for 5873 single nuclei. All major retinal cell types are observed and marker genes for each cell type are identified. The gene expression of the macular and peripheral retina is compared to each other at cell-type level. Furthermore, our dataset shows an improved power for prioritizing genes associated with human retinal diseases compared to both mouse single-cell RNA-seq and human bulk RNA-seq results. In conclusion, we demonstrate that obtaining single cell transcriptomes from human frozen tissues can provide insight missed by either human bulk RNA-seq or animal models., The retina is a heterogeneous tissue composed of multiple cell types. Via single-nuclei RNA sequencing on human neural retinal tissue, the authors characterise the transcriptome profile for individual cell types in the human retina.

Ocular inflammation is a leading cause of vision loss around the world. The presentation can be variable and ophthalmologists have developed a standardized nomenclature to help categorize the numer...

To review a case of bilateral diffuse chorioretinopathy as a presenting sign of juvenile dermatomyositis (JDM) and review the literature regarding retinal manifestations associated with this disease.Review of case record and literature regarding retinal manifestations related to juvenile dermatomyositis.A 13-year-old girl presented with bilateral diffuse chorioretinopathy as the presenting sign of juvenile dermatomyositis. A review of the literature suggests that retinopathy associated with JDM is a rare finding that is symptomatic to patients and often responds to systemic treatment of juvenile dermatomyositis. This is also the first documented case of paracentral acute middle maculopathy in the setting of juvenile dermatomyositis.Chorioretinopathy is a rare finding in juvenile dermatomyositis. While all patients with JDM likely do not warrant screening ophthalmologic examinations, any patient who has visual symptoms should have a careful dilated examination to evaluate for retinopathy or steroid-induced cataracts.

Purpose: To describe the treatment and outcomes of a cohort of pediatric intermediate uveitis (IU) patients, with a particular focus on the use of immunomodulatory therapy (IMT).Methods: The disease course, treatment, and outcomes of 39 pediatric IU patients treated in the Uveitis Clinic at the University of Utah from 1999 to 2012 were reviewed, retrospectively.Results: Mean age at presentation was 7.7 years (SD 3.1). In total, 95% had bilateral involvement. Out of 77 total eyes involved, the most frequent disease complications were ocular hypertension (0.71 events per person year, PPY), cataracts (events PPY = 0.39), and cystoid macular edema (events PPY = 0.33). A total of 20 patients received IMT; 19/20 were tapered off systemic corticosteroids without a uveitis recurrence; 75% of eyes had inactive disease at final follow-up (mean 37 months).Conclusions: The use of IMT, including biologic therapies, may effectively manage disease inflammation and reduce steroid dosages in pediatric IU patients.

Surgery is required in the care of many patients with posterior uveitis: both diagnostically, when noninvasive studies have failed to guide appropriate treatment, and therapeutically, in eyes that have developed sight-threatening structural complications of intraocular inflammation. Recent advances in microsurgical instrumentation, conventional and molecular diagnostic laboratory techniques, multimodal imaging, and novel drug delivery systems have expanded both the diagnostic and therapeutic scope of vitreoretinal surgery in patients with posterior uveitis.

Purpose To identify the molecular cause in five unrelated families with a distinct autosomal dominant ocular systemic disorder we called ROSAH syndrome due to clinical features of retinal dystrophy, optic nerve edema, splenomegaly, anhidrosis, and migraine headache. Methods Independent discovery exome and genome sequencing in families 1, 2, and 3, and confirmation in families 4 and 5. Expression of wild-type messenger RNA and protein in human and mouse tissues and cell lines. Ciliary assays in fibroblasts from affected and unaffected family members. Results We found the heterozygous missense variant in the ɑ-kinase gene, ALPK1, (c.710C>T, [p.Thr237Met]), segregated with disease in all five families. All patients shared the ROSAH phenotype with additional low-grade ocular inflammation, pancytopenia, recurrent infections, and mild renal impairment in some. ALPK1 was notably expressed in retina, retinal pigment epithelium, and optic nerve, with immunofluorescence indicating localization to the basal body of the connecting cilium of the photoreceptors, and presence in the sweat glands. Immunocytofluorescence revealed expression at the centrioles and spindle poles during metaphase, and at the base of the primary cilium. Affected family member fibroblasts demonstrated defective ciliogenesis. Conclusion Heterozygosity for ALPK1, p.Thr237Met leads to ROSAH syndrome, an autosomal dominant ocular systemic disorder.

Vitreoretinal surgical intervention is an indispensable tool in the management of uveitis and its structural complications. Pars plana vitrectomy may attenuate the inflammatory response in eyes by both reducing antigen load and reducing the levels of inflammatory mediators. Structural complications such as epiretinal membranes, tractional retinal detachment, and cyclitic membranes leading to ciliary body failure and hypotony may also be addressed by PPV and adjunctive interventions such as membrane dissection and silicone oil tamponade. The surgical implantation of sustained-release drug delivery devices may be a viable alternative or adjunct to conventional regional or systemic immunomodulatory therapy.

The retina is the innermost layer of tissue in the eyes of human and most other vertebrates. It receives the information of the visual images like the film of a camera, translates the images into neural signals, and transduces the signal to the brain. Three layers of neural cells (photoreceptor cells, bipolar cells, and ganglion cells) within the retina are comprised of seven major cell types; rod, cone, Muller glia cell, amacrine cell, horizontal cell, bipolar cell, and retinal ganglion cells, which create visual perception through functional cooperation. In all retinal diseases, it is the ultimate degeneration of the photoreceptors, the rods and cones, which results in blindness. Understanding all the individual cell types and how they contribute the basic neural circuitry in both the human and mouse retina will be key to elucidating mechanism of retinal degenerations. Here, we report to the best of our knowledge the first single-nuclei RNA-seq based transcriptomic study on human neural retinal tissue. We sequenced 6544 nuclei from six samples, and 4730 nuclei passed the quality filtering steps. The donor samples came from both the macular and peripheral regions, respectively, from three donors’ retina. None of the donors had any evidence of any ocular disease including retinal diseases as evidenced by medical record and post mortem imaging and phenotyping (Owen et al., IOVS in press). Unsupervised clustering was able to identify all seven cell populations. Known markers of neural retinal cell types were used to assign the clusters to these seven major retinal cell types, and thus, gene expression profiles for each cell type were obtained. With this dataset, the similarities and differences in cell proportion and gene expression between human and mouse were assessed. We highlighted the genes that demonstrated statistically significant differential distribution between human and mouse photoreceptors. In addition, the gene expression profiles of the same cell types between the macular and peripheral regions between human and mouse were compared. Specifically, as a means of validation the highly expressed genes in photoreceptor cells were found to be significantly enriched in known inherited retinal disease genes. Thus, we propose that this cell-specific gene list would serve as a prioritization during not only novel disease gene discovery, but cell-specific pathway gene analysis. This should facilitate a better understanding of retinal cell biology with the goal of cell-specific therapeutic interventions for retinal degenerations, as therapies are limited.

Frequent steroid drops represent a challenge in patient compliance. This study evaluated the safety and efficacy of 5 minute topical dexamethasone sodium phosphate-Visulex (DSP-Visulex) treatment regimen (two applications on the first week then weekly after) compared to daily prednisolone acetate 1% (PA) for noninfectious anterior uveitis.Forty-four patients were randomized to 8% DSP-Visulex with placebo eye drops (8% group, n = 14), 15% DSP-Visulex with placebo eye drops (15% group, n = 15), or Vehicle-Visulex with PA eye drops (PA group, n = 15). Patients received daily eye drops and Visulex treatments on days 1, 3, 8, and 15 with an optional treatment on day 22. Efficacy measures were change in anterior chamber cell (ACC) count from baseline and proportion of patients with zero ACC count at days 8, 15, and 29. Safety measures were adverse events (AEs), visual acuity, ocular symptoms, and intraocular pressure (IOP).ACC resolution over time was similar among the three groups. The percentage of patients with clear ACC was 18%, 22%, and 15% on day 8; 27%, 56%, and 54% on day 15; and 90%, 88%, and 77% on day 29 for the 8%, 15%, and PA groups, respectively. The numbers of reported AEs were 10, 36, and 12 for the 8%, 15%, and PA groups, respectively. Ten patients among all groups experienced treatment-related AEs, which included headache, eye pain, corneal abrasion, conjunctival/corneal staining, conjunctivitis, visual acuity reduction, and keratitis all of which were resolved during the timeframe of patients' participation in the study. IOP elevation was noted in the PA group throughout the study, whereas IOP elevation in the DSP-Visulex groups was observed at day 3 but not thereafter.The efficacy of the DSP-Visulex applications was comparable to the daily PA drops in the treatment of noninfectious anterior uveitis. Both 8% and 15% DSP-Visulex treatments were safe and well tolerated.

To describe fluocinolone acetonide implant dissociations in the Multicenter Uveitis Steroid Treatment (MUST) Trial.Randomized clinical trial with extended follow-up.Review of data collected on the first implant in the eye(s) of participants. Dissociation was defined as the drug pellet no longer being affixed to the strut and categorized as spontaneous or surgically related.A total of 250 eyes (146 patients) had at least 1 implant placed. Median follow-up time after implant placement was 6 years (range 0.5-9.2 years). Thirty-four dissociations were reported in 30 participants. There were 22 spontaneous events in 22 participants; 6-year cumulative risk of a spontaneous dissociation was 4.8% (95% confidence interval [CI]: 2.4%-9.1%). The earliest event occurred 4.8 years after placement. Nine of 22 eyes with data had a decline in visual acuity ≥5 letters temporally related to the dissociation. Thirty-nine implant removal surgeries were performed, 33 with replacement. Twelve dissociations were noted during implant removal surgeries in 10 participants (26%, 95% CI 15%-48%); 5 of these eyes had a decline in visual acuity ≥5 letters after surgery. The time from implant placement to removal surgery was longer for the surgeries at which dissociated implants were identified than for those without one (5.7 vs 3.7 years, P.001). Overall, visual acuity declined 15 or more letters from pre-implant values in 22% of affected eyes; declines were frequently associated with complications of uveitis or its treatment.There is an increasing risk of dissociation of Retisert implants during follow-up; the risk is greater with removal/exchange surgeries, but the risk of both spontaneous and surgically related events increases with longevity of the implants. In 22% of affected eyes visual acuity declined by 15 letters. In the context of eyes with moderate to severe uveitis for years, this rate is not unexpected.

Objectives To evaluate the long-term safety and efficacy of adalimumab in patients with non-infectious intermediate, posterior, or panuveitis, across different disease etiologies. Methods Adult patients in the Phase III VISUAL I/II trials, who met treatment failure (TF) criteria or who completed the study without TF, were eligible to enter the Phase III open-label extension study, VISUAL III, wherein patients received adalimumab 40 mg every other week. In this exploratory analysis, endpoints were analysed by six uveitis etiologies: i) idiopathic/other (IO), ii) birdshot chorioretinopathy (BCR), iii) multifocal choroiditis and panuveitis (MCP), iv) Vogt-Koyanagi-Harada syndrome (VKH), v) sarcoidosis, vi) Behcet’s disease (BD). Endpoints assessed through Week 78 of treatment were proportion of patients with: no active inflammatory lesions in both eyes; anterior chamber (AC) cell grade ≤0.5 +in both eyes; vitreous haze (VH) grade ≤0.5 +in both eyes; and quiescence (defined as no active inflammatory lesions AND AC cell grade ≤0.5 + AND VH grade ≤0.5+). Mean best corrected visual acuity (BCVA) was also assessed. Missing data were reported using non-responder imputation for categorical endpoints and last observation carried forward for continuous variables. Adverse events (AEs) were collected from first adalimumab dose in VISUAL III through the interim cut-off date of Oct 31, 2016. Results Of 371 patients included in the intent-to-treat analysis, disease etiology subgroups were (n[%]): IO (155 [41.8]); BCR (51 [13.7]); MCP (14 [3.8]); VKH (72 [19.4]); Sarcoidosis (52 [14.0]); BD (27 [7.3]). The proportion of patients achieving quiescence improved over time in all uveitis etiologic subgroups: IO 28.4%/63.9% (Week 0/Week 78), BCR 43.1%/64.7%, MCP 35.7%/50.0%, VKH 37.5%/63.9%, sarcoidosis 32.7%/69.2%, and BD 44.4%/74.1%. The proportions of patients with no active inflammatory lesions, AC cell grade ≤0.5+, or VH grade ≤0.5+, showed moderate increases or decreases between Weeks 0 and 78 within specific etiology subgroups; percentage ranges across all subgroups at Weeks 0/78, were 60.8–87.5/57.1–78.8% (no active inflammatory lesions), 47.2–92.2/50.0–77.8% (AC cell grade ≤0.5+), and 42.9–72.2/57.1–77.8% (VH grade ≤0.5+), respectively. Improvement or maintenance of mean BCVA was observed over time across the etiologic subgroups. AE rates were consistent with the VISUAL I and II trials. Conclusions Adalimumab increased the percentage of patients achieving quiescence and improved or maintained visual acuity at Week 78 of the VISUAL III study, with consistent results across uveitis etiologic subgroups. No new safety signals were detected with long-term adalimumab treatment. Acknowledgements AbbVie funded the study and provided medical writing support. All authors contributed to the development of the content. The authors and AbbVie reviewed and approved the abstract. The authors maintained control over the final content. Medical writing assistance was provided by Kevin Hudson PhD, of 2theNth, which was funded by AbbVie Inc. Disclosure of Interest P. T. Merrill Consultant for: Steering Committee for the VISUAL studies and has served as a consultant and on advisory boards for Santen, Allergan, Alimera and pSivida, A. Vitale Consultant for: AbbVie and Aciont, M. Zierhut Consultant for: Scientific advisory board for AbbVie, Gilead, and Santen, E. Fortin Consultant for: advisory boards and as a consultant for AbbVie, Alcon and Allergan, H. Goto Consultant for: advisory boards for AbbVie, M. Kron Shareholder of: AbbVie, Employee of: AbbVie, A. Song Shareholder of: AbbVie, Employee of: AbbVie, K. Douglas Shareholder of: AbbVie, Employee of: AbbVie, S. Pathai Shareholder of: AbbVie, Employee of: AbbVie

Fluorescein angiography (FA) is an indispensable imaging modality in the diagnosis and management of patients with intermediate, posterior, and panuveitis. The pattern and type of retinovascular and chorioretinal involvement may be useful diagnostically and in the assessment of structural abnormalities associated with visual loss. Moreover, FA may provide a sensitive index with respect to extent of active inflammation and influence the threshold for treatment as well as monitoring the response to therapy. Finally, FA in combination with multimodal imaging provides not only expanded diagnostic and management capabilities but also may shed new light on our basic understanding of posterior segment inflammatory diseases.

PURPOSE: To evaluate safety and efficacy of adalimumab in patients with noninfectious intermediate, posterior, or panuveitis. DESIGN: Phase 3, open-label, multicenter clinical trial extension (VISUAL III). PARTICIPANTS: Adults meeting treatment failure (TF) criteria or who completed VISUAL I or II (phase 3, randomized, double-masked, placebo-controlled) without TF. METHODS: Patients received adalimumab 40 mg every other week. Interim follow-up data were described from VISUAL III weeks 0 through 78. MAIN OUTCOME MEASURES: Disease quiescence, steroid-free quiescence, active inflammatory chorioretinal/retinal vascular lesions, anterior chamber cell grade, vitreous haze grade, best-corrected visual acuity (BCVA), and corticosteroid dose. Binary data were reported using nonresponder imputation (NRI), continuous data using last observation carried forward and as-observed analysis, and corticosteroid dose using observed-case analysis. Adverse events (AEs) were reported from first adalimumab dose in VISUAL III through interim cutoff. RESULTS: Of 424 patients enrolled, 371 were included in intent-to-treat analysis. At study entry, 242 of 371 (65%) patients had active uveitis; 60% (145/242, NRI) achieved quiescence at week 78, and 66% (95/143, as-observed) of those were corticosteroid free. At study entry, 129 of 371 (35%) patients had inactive uveitis; 74% (96/129, NRI) achieved quiescence at week 78, and 93% (89/96, as-observed) of those were corticosteroid free. Inflammatory lesions, anterior chamber grade, and vitreous haze grade showed initial improvement followed by decline in patients with active uveitis and remained stable in patients with inactive uveitis. BCVA improved in patients with active uveitis from weeks 0 to 78 (0.27 to 0.14 logMAR; left and right eyes; as-observed) and remained stable in patients with inactive uveitis. Mean corticosteroid dose decreased from 13.6 mg/day (week 0) to 2.6 mg/day (week 78) in patients with active uveitis and remained stable in those with inactive uveitis (1.5-1.2 mg/day). AEs (424 events/100 patient-years) and serious AEs (16.5 events/100 patient-years) were comparable with previous VISUAL trials. CONCLUSIONS: Patients with active uveitis at study entry who received adalimumab therapy were likely to achieve quiescence, improve visual acuity, and reduce their daily uveitis-related systemic corticosteroid use. Most patients with inactive uveitis at study entry sustained quiescence without a systemic corticosteroid dose increase. No new safety signals were identified. ispartof: OPHTHALMOLOGY vol:125 issue:7 pages:1075-1087 ispartof: location:United States status: published

Age-related macular degeneration (AMD) is a progressive blinding disease and represents the leading cause of visual impairment in the aging population. AMD affects central vision which impairs one's ability to drive, read and recognize faces. There is no cure for this disease and current treatment modalities for the exudative form of the disease require repeated intravitreal injections which may be painful, are incompletely efficacious, and represent a significant treatment burden for both the patient and physician. As such, AMD represents a significant and important clinical problem.It is anticipated that in three years' time, 196 million individuals will be affected with AMD. Over 250 billion dollars per year are spent on care for AMD patients in the US. Over half of the heritability is explained by two major loci, thus AMD is considered the most well genetically defined of the complex disorders. A recent GWAS on 43,566 subjects identified novel loci and pathways associated with AMD risk, which has provided an excellent platform for additional functional studies. Genetic variants have been investigated, particularly with respect to anti-VEGF treatment, however to date, no pharmacogenomic associations have been consistently identified across these studies. It may be that if the goal of personalized medicine is to be realized and biomarkers are to have predictive value for determining the magnitude of risk for AMD at the genetic level, one will need to examine the relationships between these pathways across disease state and relative to modifiable risk factors such as hypertension, smoking, body mass index, and hypercholesterolemia. Further studies investigating protective alleles in populations with low AMD prevalence may lead to this goal.

Background/purpose To report two novel cases of intermediate uveitis associated with Periodic Fever, Aphthous Stomatitis, Pharyngitis, and Cervical Adenitis syndrome. Methods Observational case reports and review of the literature. Results Both patients in this report had an established diagnosis of Periodic Fever, Aphthous Stomatitis, Pharyngitis, and Cervical Adenitis syndrome before the onset of ocular inflammation. Infectious and noninfectious systemic conditions known to be associated with intermediate uveitis were excluded. Intermediate uveitis was confirmed clinically in both patients by the presence of vitritis, snowballs, and peripheral snowbanks in the region of the pars plana. Both cases had a course characterized by recurrent inflammation; in which systemic steroid treatment, and in one case, immunomodulatory therapy was necessary. Conclusion Periodic Fever, Aphthous Stomatitis, Pharyngitis, and Cervical Adenitis syndrome is an auto-inflammatory fever disorder in childhood. Although other auto-inflammatory disorders such as, Blau syndrome, Muckle-Wells syndrome, and Behcets disease have been associated with various forms of uveitis, Periodic Fever, Aphthous Stomatitis, Pharyngitis, and Cervical Adenitis has never been reported to be associated with any type of ocular inflammation. We describe for the first time, two cases of Periodic Fever, Aphthous Stomatitis, Pharyngitis, and Cervical Adenitis syndrome presenting with intermediate uveitis.

Background There is increasing interest in understanding the efficacy of adalimumab across different etiologies of uveitis. No prospective analysis has been conducted to date to determine the efficacy of adalimumab among non-infectious uveitis patients with different etiologies. Objectives To assess adalimumab (ADA) efficacy in active and inactive, non-infectious uveitis across different etiologies in patients who were recruited as part of the VISUAL program. Methods Exploratory data analyses from two global phase 3, double-masked trials: VISUAL I (patients with active uveitis despite ≥2 weeks of prednisone 10–60 mg/day) and VISUAL II (patients with inactive disease dependent on 10–35 mg/day of prednisone to maintain inactivity) were performed. Patients received placebo (PBO) or ADA subcutaneously (80 mg week 0, followed by 40 mg every other week from week 1 up to 80 weeks). In VISUAL I, all patients received a prednisone burst followed by taper to 0 mg by week 15. In VISUAL II, prednisone taper to 0 mg was mandatory by week 19. The primary endpoint was time to treatment failure (TF) at or after week 6 for VISUAL I; and at or after week 2 for VISUAL II 1,2 . For this analysis, patients were categorized into different uveitis etiologies which they presented at study entry. Hazard ratios (HR) for time to TF were obtained for each uveitis etiology. Results The efficacy of ADA was significantly greater than PBO in the largest subgroup of patients with Idiopathic/other uveitis (VISUAL I: 103 and VISUAL II: 90) etiology in both VISUAL I 1 and VISUAL II trials. All other subgroups showed a trend in favor of ADA, except for Sarcoidosis subgroup in the VISUAL II trial (Figure). Overall safety for both trials has been previously reported 1,2 . Conclusions These exploratory analyses from the VISUAL I and VISUAL II trials show significantly higher efficacy in ADA-treated patients over PBO in “idiopathic/other” diagnoses of patients with both active and inactive non-infectious uveitis. Furthermore, across different uveitis etiologies, these analyses suggest that ADA-treated patients had a prolonged time to treatment failure compared to PBO. References Jaffe GJ, Dick AD, Brezin AP, et al. N Engl J Med (2016); 375:932–43. Nguyen QD, Merrill PT, Jaffe GJ, et al. The Lancet (2016); 388(10050): 1183–92. Acknowledgements AbbVie funded the VISUAL I and VISUAL II studies and provided writing support. All authors contributed to the development of the content. The authors and AbbVie reviewed and approved the abstract. The authors maintained control over the final content. Medical writing assistance was provided by Gaurav Patki, PhD of AbbVie Inc. Disclosure of Interest P. T. Merrill Consultant for: Santen, AbbVie, A. Vitale Consultant for: ACIONT, M. Zierhut Consultant for: AbbVie and Santen, E. Forton Consultant for: AbbVie, Alcon and Allergan, H. Goto Consultant for: AbbVie, M. Kron Shareholder of: AbbVie, Employee of: AbbVie, S. Tari Shareholder of: AbbVie, Employee of: AbbVie, S. Pathai Shareholder of: AbbVie, Employee of: AbbVie

Purpose Current understanding of local disease pathophysiology in AMD is limited. Analysis of the human disease-affected tissue is most informative, as gene expression, expressed quantitative trait loci, microenvironmental, and epigenetic changes can be tissue, cell type, and location specific. Development of a novel translational treatment and prevention strategies particularly for earlier forms of AMD are needed, although access to human ocular tissue analysis is challenging. We present a standardized protocol to study rapidly processed postmortem donor eyes for molecular biochemical and genomic studies. Methods We partnered with the Utah Lions Eye Bank to obtain donor human eyes, blood, and vitreous, within 6 hours postmortem. Phenotypic analysis was performed using spectral-domain optical coherence tomography (SD-OCT) and color fundus photography. Macular and extramacular tissues were immediately isolated, and the neural retina and retinal pigment epithelium/choroid from each specimen were separated and preserved. Ocular disease phenotype was analyzed using clinically relevant grading criteria by a group of four ophthalmologists incorporating data from SD-OCT retinal images, fundus photographs, and medical records. Results The use of multimodal imaging leads to greater resolution of retinal pathology, allowing greater phenotypic rigor for both interobserver phenotype and known clinical diagnoses. Further, our analysis resulted in excellent quality RNA, which demonstrated appropriate tissue segregation. Conclusions The Utah protocol is a standardized methodology for analysis of disease mechanisms in AMD. It uniquely allows for simultaneous rigorous phenotypic, molecular biochemical, and genomic analysis of both systemic and local tissues. This better enables the development of disease biomarkers and therapeutic interventions.

Aim: To describe the ophthalmologic findings in two patients with Muckle-Wells Syndrome, a phenotype of the Cryopyrin Associated Periodic Syndromes (CAPS) spectrum. There is currently sparse ophthalmic literature regarding the ocular manifestations of CAPS. We hope to increase awareness of this spectrum of diseases and the importance of proper treatment amongst eye care professionals.Methods: Interventional Case Series.Results: Patient 1 experienced resolution of aseptic meningitis, papilledema, and anterior uveitis following treatment with anikinra. Patient 2 experienced resolution of panuveitis following treatment with anikinra.Conclusions: The severe ocular manifestations of the most severe CAPS phenotype, Chronic Infantile Neurological Cutaneous and Articular Syndrome/Neonatal Onset Multisystem Inflammatory Disease Syndrome (CINCA/NOMID) have been previously described. There is increasing evidence that patients may experience similar ocular disease with the milder phenotype of Muckle-Wells Sydnrome. T...

Purpose:To report a case series of two cases of granulomatosis with polyangiitis, previously known as Wegener granulomatosis, which developed macular necrosis, not previously associated with granulomatosis with polyangiitis, healed with fibrosis, despite aggressive immune-modulating therapy and good control of systemic disease.Methods:Case series of two cases with observation of treatment progress.Results:The results reported the progress of response to treatment in the two cases, which resulted in the final outcome of fibrosis in the macula region, despite being on aggressive immune-modulating therapy and good systemic control.Conclusion:Granulomatosis with polyangiitis can be associated with macular necrosis leading to fibrosis, unresponsive to immune-modulating therapy.

Pregnancy is well known to have an ameliorating effect on a variety of autoimmune diseases, while its impact on the course of ocular inflammatory disease is less well established. The management of ocular inflammatory disease has been recently reviewed. This dynamic physiological state is orchestrated by a complex network of endocrine and immunologic factors that manifest both at the maternal-fetal interface and on a systemic level resulting in a shift away from cell-mediated immunity and toward humoral responses. Clinical and experimental evidence suggests that this immunologic bias is critical not only for successful pregnancy but also influences the course of coexistent systemic autoimmune disease including that of uveitis.

We describe a novel inherited disorder consisting of idiopathic massive splenomegaly, cytopenias, anhidrosis, chronic optic nerve edema, and vision loss. This disorder involves three affected patients in a single non-consanguineous Caucasian family, a mother and two daughters, who are half-sisters. All three patients have had splenectomies; histopathology revealed congestion of the red pulp, but otherwise no abnormalities. Electron microscopic studies of splenic tissue showed no evidence for a storage disorder or other ultrastructural abnormality. Two of the three patients had bone marrow examinations that were non-diagnostic. All three patients developed progressive vision loss such that the two oldest patients are now blind, possibly due to a cone-rod dystrophy. Characteristics of vision loss in this family include early chronic optic nerve edema, and progressive vision loss, particularly central and color vision. Despite numerous medical and ophthalmic evaluations, no diagnosis has been discovered.

PURPOSE To evaluate retinal function in patients on hydroxychloroquine using multifocal electroretinography. METHODS A retrospective chart review was performed for 23 patients (46 eyes) on hydroxychloroquine therapy and referred for multifocal electroretinogram (mfERG) testing. Duration of treatment, daily hydroxychloroquine dose, visual acuity, fundus examination, color vision testing, Amsler grid testing, visual field examination, and fluorescein angiography results were obtained when available. Multifocal electroretinogram response amplitudes were calculated for the central and paracentral regions and compared with previously published normal values. The central and paracentral regions of the mfERG color difference plot, which assigns colors to localized areas of the mfERG based on deviation from normal, were assessed using a novel Color Difference Plot Scoring System which relies on the color pattern observed within each region. RESULTS Ninety-two regions were assessed for response amplitudes, 31 of which showed a depressed response amplitude. Of the 17 eyes which had at least one region with a depressed response amplitude, clinical examination findings were relatively benign. Color difference plot scoring showed strong agreement with response amplitude, with a Color Difference Plot Scoring System score of 2 or 3 showing 93.55% sensitivity and 60% specificity for a depressed response amplitude. Interrater reliability of the scoring system as measured by Kendall's W coefficient of concordance was 0.6484 (P < 0.00001). CONCLUSION The mfERG appears to be able to detect decreased retinal function in hydroxychloroquine patients with normal clinical examinations, and may be useful in identifying patients that require close monitoring for the development of clinically relevant toxicity. The Color Difference Plot Scoring System may be used as a tool to aid in the interpretation of results of the mfERG in the clinic setting.