Diabetic Retinopathy Severity Scale Research Articles

Predictors of Early Diabetic Retinopathy Regression with Ranibizumab in the RIDE and RISE Clinical Trials.

PurposeTo investigate the predictors of early diabetic retinopathy (DR) improvement in the RIDE/RISE (NCT00473382/NCT00473330) clinical trials.Patients and MethodsIn RIDE/RISE, adult patients with vision loss due to diabetic macular edema (DME) were randomized to monthly intravitreal ranibizumab 0.3 or 0.5 mg (n=502 total) or sham (n=257). DR severity was graded (using the Early Treatment Diabetic Retinopathy Study Diabetic Retinopathy Severity Scale). In this post hoc analysis of RIDE/RISE, eyes with baseline DR score ≥35 were evaluated for ≥2-step improvements, and eyes with baseline DR score ≥43 were evaluated for ≥3-step improvements. The characteristics associated with ≥2- or ≥3-step DR improvement at months 3 or 6 were assessed using univariate and/or multivariable analyses.ResultsThe percentage of eyes with a ≥2- or ≥3-step DR improvement was 20.1% and 3.7% at month 3 and 31.2% and 5.8% at month 6. Odds of ≥2-step DR improvement at months 3 or 6 were significantly greater in eyes with moderately severe to severe nonproliferative DR (NPDR) at baseline versus less severe or more severe DR (both P<0.0001). At month 6, odds of ≥2-step DR improvement were significantly greater in eyes with no DME at month 3 (P=0.008). Most patients with ≥3-step DR improvement at months 3 or 6 had proliferative DR (PDR) at baseline (83.3% and 66.7%).ConclusionThe strongest predictors of DR response to ranibizumab at month 6 were baseline DR severity and DME quiescence at month 3. Eyes with the most robust early improvements had moderately severe or severe NPDR or PDR at baseline.

Impact of Systemic Dipeptidyl Peptidase-4 Inhibitor Use in Diabetic Macular Edema

To evaluate impact of baseline systemic dipeptidyl peptidase-4 (DPP-4) inhibitor use in diabetic macular edema (DME). This was a post hoc exploratory analysis of previously completed randomized, controlled clinical trials (VISTA and VIVID) in patients with DME evaluating intravitreal aflibercept injection (IAI) every 4 weeks (2q4) or every 8 weeks (2q8) or macular laser photocoagulation. Overall, a small number of patients (12.2% [n = 35], 9.7% [n = 28], and 15.4% [n = 44]) in the laser control, 2q4, and 2q8 groups reported baseline DPP-4 inhibitor use. There were no differences in changes from baseline in best-corrected visual acuity, central subfield thickness, or rates of 2-or-greater-step improvement in Diabetic Retinopathy Severity Scale score based on DPP-4 inhibitor use within each treatment group. DPP-4 inhibitor use at baseline did not influence the magnitude of visual and anatomic benefit in patients with DME being treated with IAI or laser. [Ophthalmic Surg Lasers Imaging Retina. 2020;51:226-234.].

Functional correlation between choroidal and retinal vascularity in low-grade diabetic retinopathy.

To perform an automated functional assessment of retinal and choroidal microvasculature in eyes with low-grade diabetic retinopathy (DR) using optical coherence tomography angiography (OCT-A) and to identify potential perfusion changes in case of early vascular damage. This is an observational, case-control study of consecutive diabetic patients with level 20 DR severity scale score and age-matched healthy subjects. A prototypal OCT-angiography was used to obtain the OCT-angiograms of the superficial capillary plexus (SCP), deep capillary plexus (DCP) and choriocapillaris (CC) layer. A validated automated microstructural analysis provided data on SCP, DCP and CC vascular perfusion density (VPD). A comparative assessment between different vascular layers and different groups was performed. Twenty-nine diabetic patients (7 females, 24%) and 20 healthy controls were enrolled. VPD values were significantly lower in the DCP (25.1% vs. 26.5%; p = 0.04) and CC (71.2% vs. 86.6%; p = 0.0001) of diabetic patients compared with controls. A statistically significant negative linear correlation was reported between CC VPD and DCP VPD in diabetic patients; at the reverse, a positive linear correlation between the same parameters was noticed in controls. Retinal and choroidal vascular networks, although distinct entities, seem functionally interconnected: varying the degree of perfusion may be a mutual compensatory mechanism in response to an ischemic injury.

Characterization of Disease Progression in the Initial Stages of Retinopathy in Type 2 Diabetes: A 2-Year Longitudinal Study.

PurposeTo characterize 2-year changes occurring in neurodegeneration, edema, and capillary dropout in nonproliferative diabetic retinopathy.MethodsTwo-year prospective longitudinal observational cohort of eyes/patients with type 2 diabetes using spectral domain optical coherence tomography (SD-OCT) and optical coherence tomography angiography (OCTA). Eyes were examined three times with intervals of 1 year. Thickness of the full retina and layer-by-layer measurements were used to identify edema or neurodegeneration. OCTA vessel density maps of the retina were used to identify capillary dropout. Early Treatment Diabetic Retinopathy Study (ETDRS) classification was performed using the seven-field ETDRS protocol.ResultsA total of 62 eyes from 62 patients with diabetes were followed for 2 years. After verification for image quality, a total of 44 eyes from 44 patients (30% women) aged 52 to 80 years were retained for data analysis. There were 18 eyes with ETDRS grades 10 to 20, 17 eyes with ETDRS grade 35, and 9 eyes with ETDRS grades 43 to 47. During the 2-year follow-up period, there was a progressive increase in capillary dropout, whereas edema and neurodegeneration remained stable. In multivariate analysis, considering a model adjusted for age, sex, hemoglobin A1C, visual acuity, and diabetes duration, vessel density remained significantly different between Diabetic Retinopathy Severity Scale groups (Wilks’ λ = 0.707; P = 0.015) showing association with disease progression.ConclusionsCapillary dropout increased in a period of 2 years in eyes with minimal, mild, and moderate diabetic retinopathy, whereas the presence of edema and neurodegeneration remained stable.

Profile of non-responder and late responder patients treated for diabetic macular edema: systemic and ocular factors.

Diabetic macular edema (DME) treatment represents a challenge for the ophthalmologists, and several aspects of real treatment expectancy are still being discussed and not yet fully elucidated. A univocal definition of responsiveness to treatment has not been reached. How the clinicians can evaluate the therapeutic success? The evaluation of systemic and ocular factors should help in this complex management. The age influences the long-term outcomes, and the role of glycemic control is confounded by contrasting correlations between hemoglobin glycated A1c and DME. Long-term treatment success is influenced by baseline best-corrected visual acuity (BCVA), central macular thickness (CMT) and early BCVA response. Also baseline diabetic retinopathy severity scale score is useful to evaluate the chances of improvement before and during treatments. The time-switching was influenced by early BCVA response, however considering a delayed response in a percentage of patients. Several structural optical coherence tomography (OCT) findings could predict long-term success, as the presence of serous retinal detachment, hyperreflective retinal spots, the disruption of external limiting membrane and ellipsoid zone, the disorganization of inner retinal layers and continued increase in CMT were considered predictors of poor response to treatment. Foveal avascular zone enlargement, high number of microaneurysms (Mas), lower vessel density (VD) in deep capillary plexus and lower parafoveal VD in superficial capillary plexus were considered as OCT angiography biomarkers of poor responsiveness. The aim of this review is to report the factors that could influence the response to treatment of DME patients.

A study on the severity of diabetic retinopathy and macular edema in diabetes mellitus patients on hemodialysis

Introduction: Diabetes Mellitus (DM) refers to a group of common metabolic disorders that share the phenotype of hyperglycemia. Microvascular abnormalities of DM include both nephropathy and retinopathy. Diabetic retinopathy (DR) tends to deteriorate with failing renal function. Diabetic nephropathy constitutes the most common cause of End Stage Renal Disease (ESRD). ESRD patients require Renal Replacement Therapy (RRT) for survival. Hemodialysis is one of the major methods of RRT. Aim: Aim of the study is to study the prevalence and severity of DR and Diabetic Macular Edema (DME) in diabetic patients on hemodialysis. Study Design: A cross sectional observational study. Methodology:105 diabetic patients undergoing hemodialysis for ESRD were subjected to detailed ophthalmic examination with a special emphasis on fundus examination for DR and macularedema. The severity of diabetic retinopathy and macular edema were graded according to International Clinical Diabetic Retinopathy Severity Scale and International Clinical Diabetic Macular Edema Severity Scale respectively. Results: In the present study prevalence of DR was 89.8% and prevalence of DME was 23%. Prevalence of Non-Proliferative Diabetic Retinopathy (NPDR) 61.4% was more than Proliferative Diabetic Retinopathy (PDR) 38.6 percent. Conclusion: The visual morbidity due to PDR and DME was high among the diabetic patients undergoing hemodialysis.

American Society of Retina Specialists Clinical Practice Guidelines on the Management of Nonproliferative and Proliferative Diabetic Retinopathy without Diabetic Macular Edema.

Nonproliferative (NPDR) and proliferative diabetic retinopathy (PDR) without diabetic macular edema (DME) affect millions of individuals living with diabetes throughout the world. There is increasing data on various management strategies for such patients, but there is limited consensus on how the data should be adopted into clinical practice. This literature review and editorial presents and synthesizes the current evidence for various management paradigms for NPDR and PDR without DME. Retina specialists are an integral member of the diabetes management team, and should encourage patients on the importance of glycemic and cardiovascular optimization for both systemic and retinopathy risk factor reduction. The diabetic retinopathy severity scale (DRSS) is now an approvable endpoint for clinical trials in the United States, therefore becoming more clinically relevant. For PDR without DME, the Diabetic Retinopathy Study (DRS) and the Early Treatment Diabetic Retinopathy Study (ETDRS) established the standard of care with panretinal photocoagulation (PRP). Laser parameters have since evolved to include less intense and earlier intervention. Studies have recently demonstrated that anti-vascular endothelial growth factor (VEGF) treatment of PDR is effective at regressing neovascularization and improving DRSS levels in many patients. Further evidence is required to determine optimal treatment frequency, duration, and retreatment criteria, in the real world. There are concerns for adverse events in patients being lost to follow up during anti-VEGF treatment. For NPDR without DME, the standard of care has been a wait-and-watch approach. Data within the DRS and the ETDRS suggest that PRP for severe NPDR can be an option for select patients as well. Multiple clinical trials have now demonstrated that anti-VEGF treatment can improve the DRSS score in NPDR. Further studies are required to assess whether this positively affects long-term visual outcomes, and whether the benefits outweigh the risks in the real world for routine use. There is cumulative evidence demonstrating the efficacy of various treatment options for NPDR and PDR without DME. Currently, patients would most likely benefit from thoughtful management strategies that are tailored to the individual patient.

Prospective Clinical Trial of Intravitreal Aflibercept Treat-and-extend Regimen for Diabetic Macular Edema: 1-Year Outcomes.

PurposeTo investigate the efficacy of aflibercept for the treatment of diabetic macular edema via a treat-and-extend regimen.MethodsThis prospective, single-center, open-label, interventional study involved 30 patients with a best-corrected visual acuity (BCVA) ≤0.6 and a central retinal thickness (CRT) ≥300 µm. The enrolled eyes each received a monthly intravitreal aflibercept injection until the CRT decreased below 300 µm, upon which the administration interval was extended for 1 month until the CRT once again increased to ≥300 µm. Main outcome measures were median BCVA and CRT at 6 and 12 months after initiation of treatment via last observation carried forward analysis, the median number of injections over the 12 months, and the effects on the diabetic retinopathy severity scale (DRSS) score of the patients who completed the 12-month follow-up period.ResultsOf the 30 enrolled patients, 29 and 25 respectively completed the 6- and 12-month follow-up examinations. From baseline to 6 and 12 months after treatment initiation, the median BCVA (logarithm of the minimum angle of resolution) significantly improved from 0.52 to 0.30 and 0.35, respectively, and the median CRT significantly decreased from 439.5 to 268.5 and 249.0 µm, respectively. The median number of injections over the 12-month follow-up period was 6.0. Compared to baseline, the DRSS score at 12 months was improved by 2 steps in 16% of patients; in no cases did the DRSS score worsen or improve by three steps or more.ConclusionsWhen administered in a treat-and-extend regimen, aflibercept is an effective treatment option for diabetic macular edema.

Trends in Diabetic Retinopathy, Visual Acuity, and Treatment Outcomes for Patients Living With Diabetes in a Fundus Photograph–Based Diabetic Retinopathy Screening Program in Bangladesh

Diabetic retinopathy (DR) is the leading cause of low vision among working-age adults. An estimated 6.9 million people in Bangladesh were living with diabetes in 2017, which is projected to increase to more than 10 million people in 2025. Currently, no standardized and/or large-scale DR screening program exists in Bangladesh. To develop a novel fundus photograph-based eye screening model for early detection of DR to prevent vision loss in Bangladeshi individuals with diabetes. In this cross-sectional study, 49 264 patients with diabetes underwent opportunistic eye screening at 2 eye hospitals and 1 diabetic hospital in Bangladesh between June 1, 2010, and September 30, 2017. The data set was analyzed from April 8 to December 30, 2018. Technicians were trained to obtain 2-field digital fundus photographs and to grade each according to a standardized DR severity scale. Each patient was counseled and triaged for treatment using defined DR referral criteria. Primary DR grading outcomes, visual acuity, and treatment outcomes. A total of 49 264 patients (54.3% male; mean [SD] age, 50.8 [12.3] years) underwent DR screening during a 7-year period. The DR prevalence rate across all 3 sites was 33% (95% CI, 33%-33%). Prevalence rates varied by center (Chittagong, 64.6% [95% CI, 64.0%-65.0%]; Dhaka, 39.8% [95% CI, 39.0%-41.0%]; and Feni, 13.0% [95% CI, 13.0%-14.0%]). Across all age groups, male patients were at higher risk of prevalent DR than female patients (odds ratio, 1.99; 95% CI, 1.90-2.07). The prevalence was 3.9% for preproliferative DR, 7.8% for proliferative DR, and 19.2% for maculopathy. Individuals with DR had significantly worse visual acuity than those with no DR (best-corrected visual acuity, 0.35 vs 0.21 logMAR; P < .001). The rate of moderate visual impairment was 12.2%, and the rate of blindness was 2.5%. Primary treatments included laser photocoagulation (n = 1637), intravitreal injection (n = 1440), and vitrectomy (n = 309). Screening Bangladeshi individuals known to have diabetes using fundus photography identified large numbers of patients with sight-threatening proliferative DR, maculopathy, and visual impairment or blindness. Expansion of eye screening services in Bangladesh is warranted as part of a national government eye care and diabetes health policy.

Automatic Detection of Diabetic Retinopathy in Retinal Fundus Photographs Based on Deep Learning Algorithm.

PurposeTo achieve automatic diabetic retinopathy (DR) detection in retinal fundus photographs through the use of a deep transfer learning approach using the Inception-v3 network.MethodsA total of 19,233 eye fundus color numerical images were retrospectively obtained from 5278 adult patients presenting for DR screening. The 8816 images passed image-quality review and were graded as no apparent DR (1374 images), mild nonproliferative DR (NPDR) (2152 images), moderate NPDR (2370 images), severe NPDR (1984 images), and proliferative DR (PDR) (936 images) by eight retinal experts according to the International Clinical Diabetic Retinopathy severity scale. After image preprocessing, 7935 DR images were selected from the above categories as a training dataset, while the rest of the images were used as validation dataset. We introduced a 10-fold cross-validation strategy to assess and optimize our model. We also selected the publicly independent Messidor-2 dataset to test the performance of our model. For discrimination between no referral (no apparent DR and mild NPDR) and referral (moderate NPDR, severe NPDR, and PDR), we also computed prediction accuracy, sensitivity, specificity, area under the receiver operating characteristic curve (AUC), and κ value.ResultsThe proposed approach achieved a high classification accuracy of 93.49% (95% confidence interval [CI], 93.13%–93.85%), with a 96.93% sensitivity (95% CI, 96.35%–97.51%) and a 93.45% specificity (95% CI, 93.12%–93.79%), while the AUC was up to 0.9905 (95% CI, 0.9887–0.9923) on the independent test dataset. The κ value of our best model was 0.919, while the three experts had κ values of 0.906, 0.931, and 0.914, independently.ConclusionsThis approach could automatically detect DR with excellent sensitivity, accuracy, and specificity and could aid in making a referral recommendation for further evaluation and treatment with high reliability.Translational RelevanceThis approach has great value in early DR screening using retinal fundus photographs.

Deep learning algorithm predicts diabetic retinopathy progression in individual patients

The global burden of diabetic retinopathy (DR) continues to worsen and DR remains a leading cause of vision loss worldwide. Here, we describe an algorithm to predict DR progression by means of deep learning (DL), using as input color fundus photographs (CFPs) acquired at a single visit from a patient with DR. The proposed DL models were designed to predict future DR progression, defined as 2-step worsening on the Early Treatment Diabetic Retinopathy Diabetic Retinopathy Severity Scale, and were trained against DR severity scores assessed after 6, 12, and 24 months from the baseline visit by masked, well-trained, human reading center graders. The performance of one of these models (prediction at month 12) resulted in an area under the curve equal to 0.79. Interestingly, our results highlight the importance of the predictive signal located in the peripheral retinal fields, not routinely collected for DR assessments, and the importance of microvascular abnormalities. Our findings show the feasibility of predicting future DR progression by leveraging CFPs of a patient acquired at a single visit. Upon further development on larger and more diverse datasets, such an algorithm could enable early diagnosis and referral to a retina specialist for more frequent monitoring and even consideration of early intervention. Moreover, it could also improve patient recruitment for clinical trials targeting DR.

Intravitreal Aflibercept for Retinal Nonperfusion in Proliferative Diabetic Retinopathy: Outcomes from the Randomized RECOVERY Trial

Evaluate the impact of intravitreal aflibercept (Eylea; Regeneron, Tarrytown, NY) on retinal nonperfusion (RNP) in eyes with proliferative diabetic retinopathy (PDR). Prospective, randomized clinical trial. Eyes with treatment-naïve PDR and extensive RNP without diabetic macular edema. Patients were randomized 1:1 to intravitreal 2 mg aflibercept every 4 weeks (monthly) or every 12 weeks (quarterly). The primary outcome measure was change in total RNP area (in square millimeters) from baseline to year 1. Secondary outcomes included ischemic index (ISI), diabetic retinopathy severity scale (DRSS) scores, visual acuity, central retinal thickness, and adverse events. The mean and 95% confidence interval were calculated for each outcome. Through 1 year, the monthly (n= 20) and quarterly (n= 20) cohorts received 11.0 and 3.95 mean aflibercept injections, and DRSS scores improved 2 steps or more in 74% and 67% of patients, respectively. Among all patients through 1 year, mean total area of RNP increased from 235 mm2 to 266 mm2 (P= 0.18) and ISI increased from 25.8% to 31.9% (P= 0.004). Retinal nonperfusion outcomes favored monthly dosing. Mean total RNP increased from 207 mm2 at baseline to 268 mm2 (P= 0.01) at 1 year in the quarterly cohort and remained stable at 264 mm2 at baseline and 1 year (P= 0.70) in the monthly cohort (P= 0.05, monthly vs. quarterly cohorts). Although many eyes demonstrated increased areas of RNP longitudinally (n= 24 [66.7%]), this was more common with quarterly dosing (n= 14 [77.8%]), and a proportion of eyes (n= 12 [33.3%]) demonstrated localized areas of apparent reperfusion of nonperfused retina, more commonly in the monthly cohort (n= 8 [44.4%]). Widespread evidence of retinal reperfusion with aflibercept dosing of PDR eyes with extensive RNP was not identified, and therefore the primary outcome of the current study was not met. Nevertheless, zones of apparent reperfusion were detected in some patients, and a dose response was identified with a reduction of RNP progression with monthly compared to quarterly dosing.

606-P: Point-of-Care Retinal Photography Is Effective in Identifying Diabetic Retinopathy in Patients Not Routinely Followed by Ophthalmology in the Intermountain West

Early detection and treatment of diabetic retinopathy (DR) can reduce blindness risk by &amp;gt;90%. Due to limitations in access to specialized eye care, the majority of people with diabetes (PWD) are not screened routinely. This project aims to determine if implementation of a point-of-care retinal screening program for PWD not routinely followed by ophthalmology would be effective in detecting DR in the Intermountain West region of the U.S. PWD who had not had a dilated eye exam within the last year underwent fundus photography during a regularly scheduled diabetes visit at the University of Utah Diabetes and Endocrinology Center. Non-mydriatic retinal images were classified by a vitreoretinal specialist as to DR severity based on the International Clinical Diabetic Retinopathy and Macular Edema Severity Scale. Abnormal findings were present in 49% of 116 patients imaged: Mild-moderate non-proliferative diabetic retinopathy (NPDR) in 16%, moderate-severe NPDR in 13%, proliferative retinopathy in 4% and hypertensive retinopathy in 13%. Point-of-care retinal imaging effectively identified DR and other retinal conditions in the Intermountain West. The finding of serious eye conditions in PWD not routinely followed by ophthalmologists supports the importance of improving ease of access for eye screening in diabetes care. Disclosure M. Wahl: None. A. Haynes: None. M.L. Litchman: None. A. Fagerlin: None. R.K. Delaney: None. J. Neuberger: None. G.S. Adjei-Poku: None. M. Serrato: None. M. Hartnett: None. S. Fisher: None.

599-P: Diabetic Retinopathy (DR) Screening Performance of General Ophthalmologists, Retina Specialists, and Artificial Intelligence (AI): Analysis from a Pivotal Multicenter Prospective Clinical Trial

A prospective study (NCT03112005) evaluated DR screening using the EyeArt AI eye screening system and dilated ophthalmoscopy by board-certified ophthalmologists against the ETDRS clinical reference standard (CRS) of adjudicated expert grading of 4-wide field stereoscopic fundus photographs. A total of 497 subjects with diabetes from 10 U.S. clinical centers underwent undilated 2-field fundus photography for analysis by the EyeArt system, dilated ophthalmoscopy, and dilated 4-wide field stereo fundus photography for the CRS. Performance (Table) of dilated ophthalmoscopy against CRS for identifying referable DR [moderate non-proliferative or higher on the International Clinical Diabetic Retinopathy severity scale or clinically significant macular edema] indicates significant variability across retina specialists and general ophthalmologists. In a previous study, this AI system has been shown to achieve sensitivity 89.0% [95% CI: 87.7-90.2%] and specificity 91.6% [95% CI: 91.0-92.2%] against 7-field ETDRS reference standard. We await the results of the EyeArt system in this multicenter study to verify its ability to provide a more consistent performance for detection of referable DR to facilitate DR screening in primary care and endocrinology clinics. Disclosure E. Ipp: Research Support; Self; Eyenuk Inc., Novartis Pharmaceuticals Corporation. V.N. Shah: Advisory Panel; Self; Sanofi US. Consultant; Self; Dexcom, Inc. B.W. Bode: Consultant; Self; ADOCIA, Lexicon Pharmaceuticals, Inc., Novo Nordisk Inc. Research Support; Self; Becton, Dickinson and Company, Dexcom, Inc., Diasome Pharmaceuticals, Inc., Eli Lilly and Company, Eyenuk Inc., Insulet Corporation, National Institutes of Health, Novo Nordisk Inc., Sanofi Research &amp; Development, Senseonics, Xeris Pharmaceuticals, Inc. Speaker's Bureau; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Janssen Pharmaceuticals, Inc., Novo Nordisk Inc., Sanofi US, Senseonics. Stock/Shareholder; Self; AgaMatrix, Glytec, LLC. S.R. Sadda: Consultant; Self; Carl Zeiss Meditec, Centervue, Heidelberg Engineering, Optos. Other Relationship; Self; Nidek. Other Relationship; Spouse/Partner; Topcon. Funding Eyenuk Inc.

Optos wide-field imaging versus conventional camera imaging in Danish patients with type 2 diabetes.

Diabetic retinopathy (DR) screening methods are costly, requiring specialized personnel and patient mydriasis. The Optos apparatus can be operated by nonspecialists and provides ultra-wide-field imaging, with 200° views of the retina in a single image. We compared DR grading obtained from Optos imaging with DR grading from conventional Topcon imaging. We conducted a cross-sectional study of 101 persons with diabetes who participated in the Addition-DK 10-year follow-up study. Retina fundus photos using both Optos and Topcon imaging were taken for both eyes. All photos were graded by specialist ophthalmologic nurses, using a modified version of the 'Proposed International Clinical DR severity scale'. We constructed frequency tables and assessed levels of agreement between Optos and Topcon gradings using weighted Kappa statistics, separately for peripheral and macular grading. We tested if the agreements between the two cameras were significantly different using a stratified Wilcoxon test. Significantly, more lesions in the periphery were identified by Optos compared with Topcon (p<0.01), resulting in a fair Kappa agreement of 0.21. We saw no significant differences in the grading of the macula region (p=0.97) between the two cameras. Although only 7% of the macula image gradings differed between the cameras, the Kappa agreement of macula grading was only moderate (Kappa=0.52). The inter-camera agreement was acceptable for macula image grading, but only fair for peripheral grading, with Optos identifying more microvascular changes in the periphery. The clinical significance and impact on screening modality and frequency remain to be explored.

Simultaneous Inhibition of Angiopoietin-2 and Vascular Endothelial Growth Factor-A with Faricimab in Diabetic Macular Edema: BOULEVARD Phase 2 Randomized Trial

The phase 2 BOULEVARD trial compared safety and efficacy of faricimab, a novel bispecific antibody targeting angiopoietin-2 and vascular endothelial growth factor-A (VEGF-A), with ranibizumab in patients with diabetic macular edema (DME). The BOULEVARD trial (ClinicalTrials.gov identifier, NCT02699450) was a prospective, randomized, active comparator-controlled, double-masked, multicenter, phase 2 study conducted at 59 sites in the United States. The trial enrolled patients 18 years of age or older with center-involving DME, best-corrected visual acuity (BCVA) of 73 to 24 Early Treatment Diabetic Retinopathy Study (ETDRS) letters, and central subfield thickness (CST) of 325 μm or more. Anti-VEGF treatment-naïve patients were randomized 1:1:1 to intravitreal 6.0 mg faricimab, 1.5 mg faricimab, or 0.3 mg ranibizumab, and patients previously treated with anti-VEGF were randomized 1:1 to 6.0 mg faricimab or 0.3 mg ranibizumab. Patients were dosed monthly for 20 weeks, followed by an observation period up to week 36 to assess durability. The prespecified primary outcome measure was mean change in BCVA from baseline at week 24 for faricimab versus ranibizumab in treatment-naïve patients. Key secondary and exploratory outcome measures included CST, Diabetic Retinopathy Severity Scale (DRSS) score, and durability as assessed by time to re-treatment. The trial enrolled 229 patients (168 treatment-naïve and 61 previously treated with anti-VEGF). In treatment-naïve patients, 6.0 mg faricimab, 1.5 mg faricimab, and 0.3 mg ranibizumab resulted in mean improvements of 13.9, 11.7, and 10.3 ETDRS letters from baseline, respectively. The 6.0-mg faricimab dose demonstrated a statistically significant gain of 3.6 letters over ranibizumab (P= 0.03). In both patient populations, faricimab resulted in dose-dependent reductions in CST, improvements in DRSS score, and longer time to re-treatment during the observation period compared with ranibizumab. Faricimab showed no new or unexpected safety signals. The BOULEVARD trial met its primary end point; faricimab demonstrated statistically superior visual acuity gains versus ranibizumab at week 24 in treatment-naïve patients. Central subfield thickness reduction, DRSS score improvement, and extended durability outcomes support the primary outcome. These findings suggest the benefit of simultaneous inhibition of angiopoietin-2 and VEGF-A with faricimab for patients with DME.

Combined Multimodal Analysis of Peripheral Retinal and Macular Circulation in Diabetic Retinopathy (COPRA Study)

To systematically examine the relationships between the microvascular indices that are measured on OCT angiography (OCTA) and the presence and extent of peripheral nonperfusion in persons with diabetic retinopathy. A retrospective cross-sectional study of patients who had varying degrees of diabetic retinopathy. The study sample was recruited from 2 large tertiary referral retina clinics. In total, 82 eyes of 45 patients with varying degrees of diabetic retinopathy were enrolled and analyzed. Relationships between peripheral ischemia measured on fluorescein angiography (FA) and OCTA metrics, including foveal avascular zone (FAZ) and vessel density measurements. A significant decrease in mean signal index in both the superficial and deep plexus and binarized flow index in the superficial plexus were found with increasing duration of diabetes mellitus. OCT and OCTA grading showed increasing central macular thickness and prevalence of microvascular abnormalities in the superficial and deep capillary bed with worse retinopathy as measured on the Diabetic Retinopathy Severity Scale. FAZ area and major axis and minor axis length were strongly associated with diabetic retinopathy severity. On classifying eyes into tertiles of peripheral ischemia measured on FA, significant increases in various FAZ metrics, including FAZ area and minor axis length, were noted. Statistically worsening of FAZ OCTA metrics was only seen between tertiles 2 and 3, indicating a non-linear relationship. The presence of neovascularization of the disc, neovascularization elsewhere, or intraretinal microvascular abnormality was associated with a significant increase in FAZ major axis length in the superficial plexus and a significant decrease in binarized flow index in the deep plexus. OCTA metrics are indicators of the severity of peripheral retinal nonperfusion. However, the central ischemic index did not exhibit a linear relationship with peripheral capillary nonperfusion. Our findings suggest that a rise in intraocular vascular endothelial growth factor as a consequence of mild peripheral capillary nonperfusion may play a compensatory role in maintaining the central macular microcirculation. Further investigations with studies employing longitudinal design will improve our understanding of the relationship between macular microcirculation and peripheral ischemia.

Vascular endothelial growth factor inhibition and proliferative diabetic retinopathy, a changing treatment paradigm?

Prior to the development of panretinal photocoagulation (PRP) in the 1970s, proliferative diabetic retinopathy (PDR) was the most common cause of blindness in diabetic patients. The diabetic retinopathy study demonstrated that PRP could decrease severe visual loss from PDR by 50%. Since then and for the past four decades, PRP has been the treatment of choice for eyes with PDR. In the past decade, vascular endothelial growth factor (VEGF) inhibition has become the treatment of choice for diabetic macular edema (DME). When treated intensively with anti-VEGF drugs, about one-third of eyes with DME experience an improvement in their diabetic retinopathy severity scale. Randomized clinical trials comparing ranibizumab to PRP and aflibercept to PRP have shown that VEGF inhibitors cause regression of intraocular neovascularization but need to be given on a fairly regular basis. Despite these promising results, concerns about treatment adherence have surfaced. Patients with PDR that are treated solely with anti-VEGF drugs and somehow interrupt their treatment are at a high risk of developing irreversible blindness. Combination treatment of PRP plus an anti-VEGF drug may be the treatment of choice for PDR.

Choroidal structural analysis in eyes with diabetic retinopathy and diabetic macular edema-A novel OCT based imaging biomarker.

PurposeTo evaluate structural changes in the choroid among patients with diabetic macular edema (DME), with varying grades of diabetic retinopathy (DR), using enhance depth imaging spectral domain optical coherence tomography (EDI SD-OCT) scans.MethodsA cross-sectional study was conducted on 82 eyes with DR and DME and 86 healthy control eyes. Eyes with DME were classified according to the severity of DR as per the international DR severity scale. Sub foveal choroidal thickness (SFCT)was obtained using EDI SD-OCT scans. These scans were binarized into luminal and stromal areas, to derive the choroidal vascularity index (CVI). CVI and SFCT were analyzed between the study and control group using paired-T test. Tukey’s test was used to correlate the differences in CVI and SFCT between different grades of DR. Further analysis was done to look for the effect of DR severity and type of DME on CVI as well as SFCT using correlation coefficient and linear regression analysis.ResultsSFCT was significantly increased in eyes with DME as compared to the controls (334.47±51.81μm vs 284.53±56.45μm, p<0.001), and showed an ascending trend with worsening of DR, though this difference was not statistically significant [mild non-proliferative diabetic retinopathy (NPDR) = 304.33±40.39μm, moderate NPDR = 327.81±47.39μm, severe NPDR = 357.72±62.65μm, proliferative DR (PDR) = 334.59±47.4μm, p-0.09]. CVI was significantly decreased in DME with DR eyes as compared to controls (63.89±1.89 vs 67.51±2.86, p<0.001). CVI was also significantly decreased with worsening DR (mild NPDR = 66.38±0.3, moderate NPDR = 65.28±0.37, severe NPDR = 63.50±0.47, PDR = 61.27±0.9, p<0.001).ConclusionSFCT and CVI are dynamic parameters that are affected by DME. Unlike CVI, SFCT is also affected by ocular and systemic factors like edema and hypertension. CVI may be a more accurate surrogate marker for DME and DR and can potentially be used to monitor the progression of DR.

Durability of Diabetic Retinopathy Improvement with As-Needed Ranibizumab: Open-Label Extension of RIDE and RISE Studies

To evaluate the durability of diabetic retinopathy (DR) improvements after a change in ranibizumab dosing from monthly to individualized pro re nata (PRN) therapy. Pooled analysis of the open-label extension (OLE) of RIDE and RISE (clinicaltrials.gov identifiers, NCT00473382 and NCT00473330) patients with DR and diabetic macular edema (DME). Patients who completed 36-month participation in RIDE and RISE and entered the OLE. In RIDE and RISE, patients (n= 759) were randomized 1:1:1 to ranibizumab 0.3 mg monthly, 0.5mg monthly, or monthly sham injections with rescue macular laser available after 6 months, per protocol-specified criteria. After 24 months, sham patients crossed over to ranibizumab 0.5 mg monthly. After 36 months in the core studies, patients in the OLE (n= 500) could receive ranibizumab 0.5 mg PRN based on predefined DME re-treatment criteria. Diabetic retinopathy severity was evaluated photographically using the Early Treatment Diabetic Retinopathy Study DR severity scale. Change in DR severity from months 36 to 48 by re-treatment status. Among patients who entered the OLE, 121 of 500 (24%) did not require additional ranibizumab injections. Overall, 367 patients had evaluable DR at months 36 and 48. Among patients not requiring ranibizumab re-treatment from months 36 to 48 (88/367), 57% to 78%, 0% to 7%, and 22% to 36% experienced DR severity stability, 2-step or more improvement, and 2-step or more worsening, respectively. Among patients requiring ranibizumab re-treatment (279/367), 84% to 94%, 2%, and 3% to 14% experienced DR severity stability, 2-step or more improvement, and 2-step or more worsening, respectively. On average, vision improvements were maintained during the OLE regardless of change in DR severity. Diabetic retinopathy severity improvements with ranibizumab were maintained in over 70% of OLE patients after switching from ranibizumab monthly to an individualized ranibizumab 0.5 mg PRN dosing regimen. Because approximately one third of OLE patients experienced DR worsening, careful monitoring should be part of the long-term management of patients with DR.