Question 1

Intraocular Pressure Elevation in The Fellow Eye After Ahmed Valve Implantation in Uveitic Patients

Accepted Answer

Ying Han, Kelsey Liu, Eugene A. Lowry, Yen Hsia, Gabriel Lazcano, Travis Porco
Purpose: To determine if patients with and without uveitic glaucoma are differently susceptible to IOP changes in the fellow eye during the early post-operative period after Ahmed valve implantation.
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Methods: Sixty-five patients with glaucoma undergoing Ahmed valve surgery by a single surgeon at University of California, San Francisco between May 2015 and August 2016 were prospectively followed. Data was collected at pre-operative visits and at 1-2, 4, 6, 8 and 12 weeks post-operatively. Post-operative changes in IOP of the fellow eye were analyzed using Wilcoxon signed rank test and longitudinal analysis with linear mixed effects regression. Subgroup analysis was performed on the basis of uveitic glaucoma.
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Results: Post-operatively, patients with uveitic glaucoma had a pronounced IOP increase in the fellow eye from its baseline value compared to patients without uveitic glaucoma at 1-2 weeks (4.5±5.8 mmHg vs. 0.2±3.2 mmHg; P = 8.0×10-3). The peak of difference was at 1-2 weeks, and remained elevated up to week 6 (1.5±5.0 mmHg, P = 5.6×10-3), at which point IOP in the fellow eye fell back to baseline. In contrast to the increase in fellow eye IOP, no significant changes in visual acuity or the number of glaucoma medications used were observed for the fellow eye during the follow-up period.
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Conclusion: There is a transient but significant elevation of IOP in the fellow eye in patients with uveitic glaucoma in the immediate post-operative period after Ahmed valve placement. Thus, in this population especially, IOP should be monitored in both eyes after Ahmed valve surgery.

Question 2

The Role of The Intestinal Microbiome in Ocular Inflammatory Diseases

Accepted Answer

Phoebe Lin
 
Purpose of Review: The intestinal commensal microbiota is important in shaping immune cell repertoire and is influenced by host genetics. Because of this intricate interaction, an intestinal dysbiosis has been associated with multiple immune-mediated polygenic diseases. This talk will summarize the literature on how alterations in the intestinal microbiota contribute to immune-mediated ocular disease, and how to potentially target the gut microbiome for therapeutic benefit.
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Recent Findings: Several groups have demonstrated the importance of the intestinal microbiome in uveitis pathogenesis. Two groups showed that altering the microbiota with oral antibiotics results in reduced uveitis severity, and another group demonstrated that a commensal bacterial antigen activates retina-specific autoreactive T cells, potentially indicating a commensal trigger for uveitis. We have found that commensal bacterial metabolites, short chain fatty acids, can suppress autoimmune uveitis. Age-related macular degeneration is associated with an intestinal dysbiosis, which can be influenced by genetic risk alleles and AREDS supplementation. Strategies that might be effective for targeting the intestinal microbiota might involve several approaches, including the use of antibiotics, drugs that supplement beneficial bacterial components or target inflammatory bacterial strains, dietary strategies, or microbial transplantation.
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Summary: The intestinal microbiota is potentially crucial in propagating inflammatory diseases of the eye, and can be targeted for therapeutic benefit.

Question 3

Pharmacokinetics of Intravitreal Sirolimus in a Subset of Subjects with Non-infectious Uveitis of the Posterior Segment: SAKURA Program Results

Accepted Answer

Quan Dong Nguyen, MD, MSc for the SAKURA Study Group
 
Purpose: The SAKURA Program consisted of two Phase III, randomized, multinational, active-control studies assessing the efficacy and safety of intravitreal (IVT) sirolimus in the treatment of active non-infectious uveitis of the posterior segment (NIU-PS). We describe the whole-blood pharmacokinetics (PK) of IVT sirolimus in the subset of subjects randomized at Japan sites in the SAKURA Program (n=18).
Methods: Subjects received IVT sirolimus 44 (n=4), 440 (n=8), or 880 (n=6) μg at Months 0, 2, and 4. Blood samples were taken at baseline and on Days 1, 3, 14, 30, 60 (before and after the second injection), 62, 73, 90, 120 (after the third injection), 122, 133, and 150, and at Month 6. Blood sirolimus concentrations were determined by liquid chromatography/tandem mass spectrometry.
Results: Blood sirolimus concentrations increased after the first injection, reaching a mean Cmax of 0.42 ng/mL, 2.05 ng/mL, and 2.70 ng/mL for the 44, 440, and 880 µg doses, respectively. Mean AUC0-60d after the first injection was 1.79, 16.24, and 29.13 ng∙day/mL for 44, 440, and 880 µg, respectively. The mean AUC0-60d and the mean Cmax did not change between the first and the third administration with any dose (Cmax were 0.3225, 1.507, 3.057 ng/mL and AUC were 1.27, 13.45, 28.27 ng.day/mL for 44, 440, and 880 µg, respectively), suggesting no change in systemic exposure after repeated IVT injections. The mean systemic sirolimus concentrations in all dose groups were below the trough level of immunosuppression (5-15 ng/mL).
Conclusion: In this subset of Japanese subjects enrolled in the SAKURA Program, mean sirolimus concentrations remained below the 5-15 ng/mL considered necessary for systemic immunosuppression throughout the 6-month study period. Together with the low incidence of systemic adverse events reported, this indicates that the effects of IVT sirolimus are confined to the eye.

Question 4

Heterochromatin Protects Retinal Pigment Epithelial Cells from Oxidative Stress-Induced Damage

Accepted Answer

David W. Li, Lili Gong, Fang-Yuan Liu, Ruili Qi, Qian Sun, Zhong-Wen Luo, Qian Nie, Xiao-Dong Gong, Yun-Fei Liu, Lan Zhang, Xiangcheng Tang, Ling Wang, Quan Dong Nguyen, Yizhi Liu
Purpose: Oxidative stress (OS)-induced retinal pigment epithelium (RPE) cell apoptosis is critically implicated in the pathogenesis of age-related macular degeneration (AMD), one of the leading causes for blindness in the elderly. The highly condensed, repressive heterochromatin is recently found to play critical roles in mediating diverse stress response. How RPE heterochromatin is regulated upon OS exposure is largely unknown. In the present study, we used both mouse model and cultured human RPE cells to investigate heterochromatin function upon OS exposure.
Methods: The heterochromatin status was assessed by micrococcal nuclease digestion, immunofluorescence microscopy, western blot, quantitative RT-PCR and chromatin immunoprecipitation analysis. To determine the biological functions of heterochromatin in OS, both pharmaceutical and genetic approaches were applied. MTT assay, flow cytometry and permeability measurement were employed to determine the RPE cell viability, apoptosis and barrier functions, respectively.  
Results: Our results showed that OS led to increase heterochromatin formation, as indicated by upregulation of trimethylation at histone3 lyscine9 (H3K9me3) and suppression of heterochromatin satellite genes. Disruption of heterochromatin by chaetocin, a selective inhibitor of H3K9 methyltransferases SUV39H1, led to increased cell apoptosis and degeneration of RPE upon OS exposure. OS-induced heterochromatin selectively accumulates at p53-regulated proapoptotic target promoters and inhibits their transcription.  Furthermore, OS-induced desumoylation of p53 promotes p53-heterchromatin interaction and regulates p53 promoter selection, resulting in the locus-specific recruitment of heterochromatin and transcription repression. On the other hand, enhanced heterochromatin formation by resveratrol treatment or overexpression of SUV39H1 increased cell viability in oxidative injury.
Conclusion: Heterochromatin protects RPE cells from OS-induced cell damage via p53 functional status which is regulated by sumoylation, and targeting heterochromatin may provide a potential strategy for AMD treatment.
(Supported by grants from National Natural Science Foundation of China, 81570824, 81770910, 81500738, 81500707, and 81700821 as well as the Fundamental Funds from the State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen Univiersity).

Question 5

Validation Of 3-Dimensional Analysis of CNV as a Surrogate Marker for Response to Therapy

Accepted Answer

Rubbia Afridi, Alex Mckeown, Nam Nguyen, Sohail Halim, Muhammad Hassan, Sean Baluyot, Yasir Sepah
 
Purpose: To assess changes in 3-dimensional (Volumetric) analysis of CNV in eyes treated with ranibizumab using a novel algorithm and evaluate correlation between changes in volume of CNV, changes in area of CNV using Fluorescein angiography (FA) and changes in central retinal thickness (CRT). 
Methods: Algorithm validation was performed using 10 eyes with 30° macular OCT scans (25 B-scans). Each B-scan was segmented at internal limiting membrane (ILM) and Bruch’s membrane (BM) by Heidelberg Eye Explorer software (Heyex). Volume of the central 3-mm region in Heyex software was noted. All B-scans for each subject were exported and a custom generated algorithm was used to project a 3-mm circle on the en-face OCT image (1B). A boundary identification tool was used to manually identify points on B-scans corresponding to 3-mm circle and its volume was measured. Results from the algorithm were compared with results from Heyex. After validation, OCT scans of 8 eyes with CNV from two visits 6 months apart were processed using our algorithm to obtain volumes of the CNV lesion.Fluorescein angiography (FA) images of the same subjects from the same visits were evaluated for Area of CNV was also calculated for these eyes using FA images from the corresponding visits using Image J. Changes in central retinal thickness (CRT) on OCT, CNV area on FA and volume on custom algorithm were compared using t-test and linear regression.
Results: The mean volume (n=10 eyes) calculated for validation analysis using the custom algorithm was within 0.05 mm3 (p>0.05). In the diseased eyes, the percent change in the area of CNV lesion on FA, volumetric change on MATLAB and change in CRT demonstrated a 4.11%, 19.31%, 10.07% reduction respectively. Mean change in area measured on FA, and volume on MATLAB from baseline to month 7 was not statistically significant (-0.44mm2 and -0.50 mm3, respectively; p>0.05). Linear Regression demonstrated a statistically significant linear relationship between change volume with the change in CRT (r:0.01; p=0.03). A non-significant relationship was seen between the change in area and change in CRT (r: 0.005; p=0.60).
Conclusions: CNV lesions are 3-dimensional and volumetric analysis of such lesions using OCT may be more sensitive to detecting smaller changes with response to therapy.

Question 6

Short-Term effects of Ranibizumab on Diabetic Retinopathy Severity and Progression in the Ranibizumab for Edema of the Macula in Diabetes – Protocol 3 with High Dose (READ-3) Study

Accepted Answer

Muhammad Hassan, Mohammad A. Sadiq, Muhammad Sohail Halim, Rubbia Afridi, Nam Nguyen, MD, Yasir J. Sepah
Purpose: To evaluate the short-term effects of two doses of Ranibizumab (0.5mg and 2.0mg) on diabetic retinopathy (DR) severity in patients with diabetic macular edema (DME).
Methods: In the READ-3 study, patients with DME were stratified into two groups to receive either 0.5mg or 2.0mg monthly intravitreal ranibizumab until month 6, followed by pro-re-nata dosing until month 24. Seven field fundus photographs were evaluated utilizing a 9-step ETDRS diabetic retinopathy (DR) severity scale, to assess DR severity at baseline, month 3 and month 6 by a centralized reading center. Chi-sqaure and logistic regression was utilized to assess differences in proportion of subjects demonstrating change in DR severity at month 3 and month 6.
Results: Out of 152 eyes (152 patients) randomized in the READ-3 study, 91 eyes (91 patients) fulfilled the inclusion criteria for the index study. Thirty-nine eyes in the 0.5mg group and 24 eyes in 2.0mg group with the potential for improvement in the DR severity score were analyzed. Twenty-eight eyes (44.4%; 18 in 0.5mg and 10 in 2.0mg) had a prior history of PRP with baseline DR severity score 60. The median ETDRS DR severity score improved from 4 (moderate NPDR) to 3 (mild NPDR) at month 3 and was maintained at month 6 in both study groups. The proportion of patients with DR severity score of mild or better increased at month 3 (0.5mg:32.4% and 2.0mg:36.4%) and month 6 (0.5mg:41% and 2.0mg:50%) from baseline (0.5mg: 12.8% and 2.0mg: 4.2%) (Figure 1). 22.9% of eyes (groups combined) demonstrated a ≥2-step reduction in the ETDRS DR severity scale (0.5mg: 33.3% and 2.0mg:7.1%), at month 6 (Figure 2). The difference between the groups was not significant (p=0.071). Worsening of the DR severity was not demonstrated by any of the study subjects.
Conclusions: Intravitreal ranibizumab has a role in stopping the progression of DR severity in patient with DME starting as early as 3 to 6 months. 2.0 mg ranibizumab did not demonstrate any additional benefit over 0.5mg ranibizumab in improving DR severity.

Question 7

Drop Size – Is it an issue or not?

Accepted Answer

Gary D. Novack
Most pharmacotherapies for ophthalmic inflammatory disease are given as eyedrops, even though these are less than optimum as a delivery method – requiring both patient adherence and performance.  Over the past 40 years, drop size has been a scientific, clinical and financial issue. Most recently, ProPublica published an article the role of drop size in therapeutics and pricing (https://www.propublica.org/article/drug-companies-make-eyedrops-too-big-and-you-pay-for-the-waste, October 2017).  A recent bill in the U.S. Senate included reference to drop size. The author will present two sides of the ProPublica position, including supportive data.

Question 8

History of Uveitis Therapy

Accepted Answer

C. Stephen Foster
 
Purpose: To review the history of therapy for uveitis
Methods: Review of the literature
Results: Eye inflammation and remedies for such date as far back in history as written records exist, including in documents from ancient Egyptian physicians in 1700 BC. And in 1806 Scarpa described a female with uveitis and debilitating photophobia Therapy was with expurgation and blood letting, along with poltices of herbs. Cycloplegia was added by McKenzie in 1830, and in 1950 Kendall and Hench’s corticosteroid preparation employed the previous year at the Mayo Clinic for patients with rheumatoid arthritis was used by Dan Gordon of Cornell in New York City in drop form for patients with uveitis.This revolutionized the care of patients with uveitis, and it took about one year for Gordon to realize that open ended topical corticosteroid therapy was accompanied by cataract development and sometimes by glaucoma development. Others were exploring non-steroid therapies for treating uveitis, and writings from Spanish pioneers in 1950 languished in Spanish ophthalmic literature as Vernon Wong at the National Institutes of Health, un aware of the Spanish work with nitrogen mustard therapy for uveitis independently reasoned that immunosuppressive medication might help put ocular inflammation into remission. Thus, he treated patients who had uveitis with intravenous methotrexate, successfully abolishing the uveitis. Others followed (some of the pioneers included Frank Newell and James Gills), and today most uveitis experts agree that many patients with uveitis are best served with immunomodulatory therapy, which, in many instances, is curative.
Conclusions: Treatment of eye inflammation has evolved over the past 3000 years. It continues to evolve. We cannot know what physicians 100 years from now will think of our current efforts to save vision in patients with vision-threatening uveitis. Nevermind. We’re doing just fine, saving sight as never before, and causing precious little mischief in doing so.

ABSTRACTS

Sonoma 2018