Sonoma 2018


Perioperative Use of Prostaglandin Analogues During Cataract Extraction

Stephanie Midtling, Adam Jacobson, Raymond J Clifford, Thaddeus L Wandel Purpose: Surgeons differ in opinion whether to stop prostaglandin analogue (PGA) medication after cataract surgery. Some stop them due to the theoretical risk of increased inflammation. Our study aimed to investigate the effect of prior PGA use on post-operative inflammation and visual outcomes and to determine if post-operative cessation improves these measures. Methods: A retrospective review was performed of 128 patients who underwent uncomplicated cataract extraction between September 2011 and August 2013 at Metropolitan Hospital in Manhattan, NY. Patients were grouped based on prior PGA status and post-operative use. Inflammation was measured and compared post-operatively using Standardized Uveitis Nomenclature (SUN). Visual acuity (VA) was measured and compared both pre- and post-operatively using logarithm of the minimum angle of resolution (logMAR). Results: PGA use prior to cataract extraction was associated with increased inflammation and decreased VA at post-operative day 1 (SUN 2.4 vs 1.8; P=0.002, logMAR 0.9 v 0.5; P=0.006) and week 1 (SUN 1.0 v 0.6; P=0.004, logMAR 0.5 v 0.3; P=0.009). This result was unaffected by cessation of PGA post-operatively. Conclusions: PGA use prior to cataract extraction is correlated with early increased inflammation and decreased VA. This result was not significant after 1 month.

Scleral Vessel Density Using Novel Optical Coherence Tomography Angiography Methodology

Muhammad Sohail Halim, Muhammad Hassan, Rubbia Afridi, Nam V. Nguyen, Arash Maleki, Sean C. Baluyot, Yasir Jamal Sepah Purpose: To develop and assess the reliability of a novel acquisition protocol to image scleral vasculature and measure scleral vessel density in eyes with no known pathology. Methods: Sclera from Twenty (20) eyes of 10 subjects were scanned with the Optovue AngioVue Imaging System (Optovue, Inc., Fremont, CA). Two (2) eyes were excluded from the analysis due to motion artifacts in the optical coherence tomography angiography (OCTA). With the anterior segment lens mounted, the retina map 3.0 scan was selected. Follow-up was turned off while tracking was kept on. Internal illumination light was turned off. The Z value was increased to maximum while focus was lowered to minimum. External fixation light was used to fixate the eye at approximately 45o from the primary gaze. The red external light was shined on the anterior portion of the eye to get a better-quality IR image. OCTA images were captured of the temporal portion of sclera near the edge of limbus. Each eye was imaged by two independent operators after adequate training of the methodology was provided. Paired sample t-test was applied to compare the difference of vessel density between graders. The limits of agreement were plotted against difference between operators. The Stanford’s institutional review board (IRB) had approved the study. Results: The mean age of the study population was 35.66 ± 13.42 years. 50% (9) eyes were of female subjects. The mean scleral vessel density was 54.62 ± 3.69%. There was no statistical difference in the vessel densities for gender (p-value:0.29). The mean scleral vessel density for operator 1 and operator 2 was 55.05 ± 3.34% and 54.20 ± 4.06% respectively. There was no statistical difference in the scleral vessel density measurements between the graders (p-value: 0.17). Bland-Altman plot showed that all, but one vessel densities were within the limits of agreement. Conclusion: Our methodology can be reliably utilized to image scleral vessels and assess scleral vessel densities.

Clinical Usage Patterns of OCT Angiography

M. Pekelis, M. Durbin, B. Ge Purpose: To determine usage patterns of OCT Angiography among US optometrists, US ophthalmologists and ophthalmologists worldwide. Different priorities and clinical goals may exist depending on the doctors’ occupation and geographic location. Methods: Four surveys were conducted within ZEISS AngioPlex™ OCT Angiography (ZEISS, Dublin, CA) users by independent third parties. The survey questions that were common in all the four surveys were combined to represent the entire pool of answers. Results: Majority of respondents currently use OCTA for AMD (90%), DR (88%) and Vasculature diseases (85%). 40% currently use OCTA for a baseline exam on new patients and 27% consider adopting this strategy. More doctors in Europe (43%) vs. the US (21%) use OCTA for a baseline exam. 51% currently scan or plan to scan with OCTA at least half of all their diabetic patients. 33% of retina specialists would do OCTA for ¾ of diabetic patients, 45% of optometrists have the same approach. 40% of doctors who perform surgeries use OCTA for pre surgery assessment at least occasionally. 77% of doctors who manage anti-VEGF patients use OCTA for managing treatments. For another 17% management with OCTA is a good future strategy. Only 5% prefer other techniques to OCTA for assessing effectiveness of anti-VEGF treatments. 77% confirmed that OCT-A has allowed detecting early indicators of disease that could not be detected with a structural OCT scan alone. 64% of US specialists and 100% of US optometrists agree with this statement. Conclusions: A majority of respondents found advantages of OCTA in diagnosing and monitoring retina pathology (AMD, DR and vasculature diseases). At the same time, using OCTA in pre-surgery assessment has not become a common practice. The survey indicated that OCTA can be useful for detecting early disease indicators that otherwise could have been missed by structural OCT scan alone.

Effects of Vitreomacular Adhesion on Treatment Outcomes in the Study of Safety and Bioactivity of TOcilizumab in Patients with Non-Infectious UVEITIS: The STOP-UVEITIS Study

Nam V. Nguyen, Muhammad Hassan, Muhammad Sohail Halim, Rubbia Afridi, Sean Baluyot, Yasir J. Sepah Purpose: To evaluate the role of VMA in visual and anatomic outcomes in patients with non-infectious uveitis (NIU) treated with intravenous (IV) infusion of tocilizumab (TCZ)
Methods: In the STOP-Uveitis study, patients with NIU received monthly IV infusions of either 4mg/kg or 8mg/kg TCZ until month 6 (primary endpoint). Spectral domain optical coherence tomography (SD-OCT) images of patients that completed primary endpoint of the study, were analyzed at the baseline visit to identify the presence (VMA+) and absence (VMA-) of VMA. Patients with any degree of vitreomacular traction (VMT) or epiretinal membrane causing structural abnormalities within center-1mm were excluded. All images were graded by two independent graders. VMA was classified by size of adhesion into either focal (<1500 µm) or broad (≥1500 µm). Main outcome measures were mean change in visual acuity (VA), central retinal thickness (CRT), and vitreous haze (VH) at month 6. Student t-test was performed; statistical significance was set at p<0.05.
Results: A total of 37 patients were randomized in the STOP-Uveitis study. 47 eyes (27 patients) were included in the analysis. At baseline, 15 eyes were classified as VMA (+), and 32 eyes were classified as VMA(-). At month 6, the VMA(+) showed a mean improvement of 2.07±3.63 letters, whereas the VMA (-) group showed a mean improvement of 6.94 ± 9.49 letters. The difference between the two groups was considered statistically significant (p=0.016). The mean improvement in CRT was 23.9±54.2 µm and 80.4±157.2 µm in the VMA(+) and VMA(-) groups, respectively (p=0.081). The mean change in VH was -0.63±0.38 and -0.76±0.71 in VMA(+) and VMA(-) groups, respectively (p=0.420). Out of 15 eyes, 2 eyes showed complete resolution of VMA at month 6, and one eye the VMA grade was reduced from broad to focal. Conclusion: The presence of VMA seems to contribute to suboptimal improvement in vision in subjects receiving treatment for uveitis, even though the changes in CRT and VH did not differ due the presence of VMA.

The Effect of Suturing of 23-Gauge Pars Plana Vitrectomy on Ocular Discomfort And Tear Film Dynamics

Mee Yon Lee, Kyung Seek Choi

Purpose: To evaluate the effect of suturing of 23-gauge pars plana vitrectomy on ocular discomfort and tear film dynamics.

Methods: This retrospective chart review involved 50 cases from 50 patients who underwent 23-gauge pars plana vitrectomy from January to November 2016. The eyes were divided into two groups by the presence of suture; 35 eyes underwent sutureless vitrectomy (Group 1) and 15 eyes underwent vitrectomy with at least one sclerotomy site suture (Group 2). In each group, we evaluated objective methods including tear film break-up time (TBUT), Schirmer test I, corneal surface grading with Oxford system and quantitative method evaluating subjective dry eye symptom using ocular surface disease index (OSDI) questionnaire preopeatively and 1 week, 1 and 3 months after surgery.

Results: TBUT showed significant difference at 3 months follow-up (TBUT: P=0.026). Schirmer test I and Corneal surface staining score showed no statistically significant differences between two groups at any postoperative follow up. OSDI score was significantly lower in Group 1 than Group 2 at 1 week, 1 month and 3 months after surgery (P=0.032, P=0.026, P=0.041, respectively).

Conclusion: Sclerotomy suturing had influence on ocular discomfort and tear film dynamics. Suturing had negative effect on ocular discomfort during all postoperative period. However, suturing had negative effect on TBUT test only in late postoperative period. We can conclude that sclerotomy without suturing is better than suturing to prevent dry eye.

Longitudinal Evaluation of Retinal Structure in Epiretinal Membrane Using Optical Coherence Tomography

Mee Yon Lee, Kyung Seek Choi

Purpose: To evaluate the change of visual acuity (VA), central foveal thickness (CFT), disruption of external limiting membrane (ELM), disruption of inner/outer Segment junction (IS/OS junction), growth of ectopic inner retinal tissue for idiopathic epiretinal membrane (iERM) without surgery.

Methods: We tracted 49 patients(49 eyes) with iERM without surgical treatment, retrospectively for over 6 months from January 2016 to January 2018. VA, CFT, disruption of ELM, disruption of IS/OS junction, growth of ectopic inner retinal was reviewed.

Results: The average follow-up duration was 13 months(range 6-21 months). From first visit to final visit, VA(LogMAR) changed from 0.18±0.23 to 0.19±0.18, CFT changed from 350.34μm to 354.52μm not showing clinically significant changes(p = 0.565, p = 0.065). Disruption of ELM, growth of ectopic inner retinal tissue did not show clinically significant changes(p = 0.083, p = 0.317). Disruption of IS/OS junction showed significantly difference at follow-up period(p = 0.008).

Conclusions: Clinically significant change of the disruption of IS/OS junction was observed during the average follow-up duration of 13 months. It is known that damage of inner retina is more sensitive indicator than outer retina to surgical results. However, due to the change of outer retina during average of 13 months, early surgical approaches would be recommended for relatively good prognosis.

Reliability of Conjunctival Biopsy for Diagnosis of Ocular Cicatricial Pemphigoid

Stephen D. Anesi, Laura Eggenschwiler, Mariantonia Ferrara, and C. Stephen Foster

Purpose: Ocular cicatricial pemphigoid (OCP), a subset of mucous membrane pemphigoid, is a potentially blinding chronic conjunctivitis. Initial symptoms are usually non-specific, which may delay diagnosis. Chronic disease may eventually cause corneal keratinization, responsible for most blindness. Direct immunofluorescence (DIF) microscopy is the current gold standard for diagnosis, involving the integrin β4-subunit, with linear depostition of immunoglobulin (Ig) and/or complement at the basement membrane zone (BMZ). Use of avidin-biotin complex technique (ABC) increases sensitivity, but is rarely performed. This retrospective study aims to demonstrate the reliability of conjunctival biopsy analyzed by DIF, and ABC as needed, and the corresponding response to immunomodulatory therapy (IMT) in OCP positive patients.

Methods: We reviewed conjunctival biopsies from 136 consecutive OCP suspect patients (2008-2014) at MERSI analyzed in a CLIA certified immunopathology laboratory (by CSF) using histopathology and DIF, supplemented by ABC in high suspect DIF negative or inconclusive cases. Diagnosis of OCP was made with linear IgG, IgA, or complement (C3, C4) deposition at BMZ, via DIF or ABC. Primary outcome was diagnosis of OCP. Secondary outcome was response to IMT in terms of durable remission (> 3 months) and Foster stage progression after 2 years of follow-up.

Results: Addition of ABC to DIF increased sensitivity from 79.6% with DIF alone to 95.6%. In 49 patients with previous biopsy, sensitivity increased from 5% (previous biopsy alone) to 57.5% (DIF at MERSI) to 97.5% (DIF with ABC at MERSI). With follow-up > 2 years, 54 of 57 (94.7%) biopsy-positive patients achieved steroid-free remission, 51 required IMT.

Conclusions: OCP often goes unrecognized during assessment. We feel this shows the need for a new standard in diagnosis of OCP to necessarily include DIF supplemented by ABC with uncertainty or high clinical suspicion and negative DIF. In addition, we propose surgical technique and tissue handling play an important role, and that a full thickness sample and “one-touch” technique are key. The high percentage of biopsy-positive patients attaining steroid-free remission with IMT emphasizes the importance of improving biopsy sensitivity with this technique.

Phase 1b Study of AK002, a Humanized anti-Siglec-8 Antibody, in Allergic Conjunctival Diseases: a Novel Approach to Treatment (KRONOS)

Quan Dong Nguyen, Andrea Kantor, Henrik S. Rasmussen, David S. Chu, Joseph Tauber Purpose: Atopic keratoconjunctivitis (AKC), vernal keratoconjunctivitis (VKC), and perennial allergic conjunctivitis (PAC) are types of severe allergic conjunctivitis (AC) primarily caused by IgE-mediated degranulation of mast cells (MC), which release histamine and other inflammatory mediators, resulting in the recruitment of eosinophils and other inflammatory cells. MC-driven ocular surface inflammation and conjunctival eosinophils (releasing cytotoxic proteins) contribute to the debilitating symptoms and poor outcome (vision loss) characteristic of chronic, severe AC.
Siglec-8 is an inhibitory receptor that is selectively expressed on eosinophils and MCs. Preclinical experiments have demonstrated that anti-Siglec-8 antibodies directly deplete eosinophils and inhibit mast cells. AK002 is a humanized, non-fucosylated IgG1 monoclonal anti-Siglec-8 antibody. Studies in healthy volunteers and indolent systemic mastocytosis patients evaluated ascending single and multiple doses of AK002. All AK002 dose groups reported complete depletion of blood eosinophils by 1 hr. The PK, pharmacodynamic (PD), and tolerability of AK002 suggest an acceptable profile for chronic administration. Current treatment options for AC have limited efficacy and are often inappropriate for chronic use. AK002 targets the end effector cells involved in AC (eosinophils and MCs) by a mechanism not previously explored. KRONOS represents the first evaluation of this novel therapeutic approach in AC. Methods: AK002-005 (KRONOS) is an open-label, phase 1b study enrolling 30 adults with AC. Subjects will receive monthly 1 mg/kg infusions for 6 months. Inclusion criteria include AKC, VKC, or PAC diagnosis, an average single symptom score of ≥3 from daily ACS questionnaires, and a history of topical and/or systemic corticosteroid treatment. The primary objective is to evaluate safety and tolerability. Secondary objectives are PD and preliminary efficacy as measured by daily ACS questionnaires, Ocular Symptom Score assessment, NEI VFQ 25, slit lamp photography, and blood eosinophils. Results: KRONOS study updates will be presented. Conclusion: AK002 is a first-in-class drug that represents a novel approach to the treatment of AC. Given the insufficient efficacy and risks associated with long-term use of FDA-approved therapies, results of KRONOS may have important clinical impact.

To Report Our Experience of Treatment with Certolizumab Pegol in Refractory Non-Infectious Uveitis

Yael Sharon, David S. Chu

Purpose: To Report Our Experience of Treatment with Certolizumab Pegol In Refractory Non-Infectious Uveitis.

Methods: Retrospective case series of three patients with bilateral active non-infectious uveitis, treated with twice-monthly, subcutaneous certolizumab pegol. All patients had previously failed various immunomodulatory therapies and/or were intolerant to, including at least one tumor-necrosis-factor inhibitor (TNFi).

Results: All 3 patients showed reduction in ocular inflammation after certolizumab therapy was initiated. First patient, 21-year-old male, with idiopathic pars planitis, had favorable response to therapy, without side effects. In the second patient, 20-year-old female with recurrent iridocyclitis and juvenile idiopathic arthritis, therapy was well tolerated, however mild inflammation persisted. The third patient, 17-year-old male, with recurrent iridocyclitis and Crohn's disease, had long-term and adequate response to therapy. However his colitis flared and therapy was changed.

Conclusions: Certolizumab pegol treatment in patients with refractory uveitis appears to be effective. Patients that have failed another TNFi, may benefit from certolizumab.

Non-Viral Gene Therapy of Stargardt’s Disease with Smart Lipid ECO Plasmid DNA Nanoparticles

Purpose: Monogenic retinal dystrophies can be treated with gene replacement therapy (GRT) with local delivery of a normal gene into the retina. Adeno-associated virus (AAV)-mediated gene therapy is recently approved for treating LCA. However, AAVs have a limited loading capacity, restricting their applications in diseases that require delivery of large genes, such as Stargardt’s disease (STGD). We have developed a smart pH-sensitive lipid ECO as an efficient gene delivery platform, which has unlimited cargo capacity and has mediated effective gene transduction in the retina. In this study, we have established and evaluated a nanoparticle-based GRT for STGD using ECO and tissue-specific therapeutic ABCA4 plasmid.

Methods: Therapeutic ABCA4 plasmids with rod photoreceptor-specific RHO promoter and non-specific CMV promoter formed stable ECO/pDNA nanoparticles with ECO via self-assembly at an N/P ratio of 10/1. The formulations were subretinally injected into Abca4-/- mice (STGD model). ABCA4 expression was evaluated by IHC and qRT-PCR 7 days after injection. Treatment efficacy was evaluated by HPLC analysis of A2E levels (phenotype marker) in the retina after 6 months.

Results: ABCA4 expression was observed in the treated eyes for both RHO and CMV plasmids, demonstrating significantly higher expression at the protein and RNA levels compared with sham injections. Targeted ECO/pRHO-ABCA4 nanoparticles generated photoreceptor specific expression when compared with ECO/pCMV-ABCA4 nanoparticles. A2E levels were read as the peaks eluted at 10~11 minutes in the chromatograms. The treatments by both particles demonstrated a significant decrease in A2E levels compared with sham, indicating the slowing down of STGD progression.

Conclusions: Successful non-viral GRT of STGD using ECO and therapeutic ABCA4 plasmids was demonstrated by tissue specific expression of ABCA4 and slowing down of A2E accumulation and STGD progression. The non-viral ECO/therapeutic gene formulations are a promising GRT strategy for STGD and a broad range of visual dystrophies.


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

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. 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. 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. 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.

The Role of The Intestinal Microbiome in Ocular Inflammatory Diseases

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. 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. Summary: The intestinal microbiota is potentially crucial in propagating inflammatory diseases of the eye, and can be targeted for therapeutic benefit.

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

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.

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

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).

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

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.

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

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.

Drop Size – Is it an issue or not?

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.

History of Uveitis Therapy

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.

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