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To identify the risk factors associated with myopic macular neovascularization (mMNV)-related complications in patients treated with intravitreal anti-VEGF agents.Longitudinal cohort study.Myopic eyes (n = 313) with active mMNV and median (interquartile range) follow-up of 42 months (interquartile range, 18-68 months) after initiation of anti-VEGF treatment.Data regarding patients' clinical and mMNV-related characteristics were collected at baseline. Subsequent OCT scans were inspected for mMNV-related complications. Best-measured visual acuity (BMVA) values were retrieved from each visit.Incidence rate and hazard ratio (HR, with 95% confidence interval [CI]) of risk factors for fibrosis and macular atrophy calculated with Kaplan-Meier curves and Cox regression models. Crude incidence of macular hole (MH). Longitudinal BMVA changes.Five-year incidence of fibrosis, atrophy, and MH were 34%, 26%, and 8%, respectively. The rate of fibrosis was 10.3 (95% CI, 8.25-12.6) per 100 person-years. Risk factors were subfoveal mMNV location (HR [95% CI] = 12.7 [2.70-56.7] vs. extrafoveal, P = 0.001) and intraretinal fluid at baseline (HR [95% CI] = 1.75 [1.05-2.98], P = 0.03). The rate of macular atrophy was 6.5 (95% CI, 5-8.3) per 100 person-years. Risk factors were diffuse (HR, 2.20 vs. tessellated fundus; 95% CI, 1.13-5.45; P = 0.02) or patchy chorioretinal atrophy (HR, 3.17 vs. tessellated fundus; 95% CI, 1.32-7.64; P = 0.01) at baseline and more numerous anti-VEGF injections before baseline (HR, 1.21; 95% CI, 1.06-1.38 for each treatment; P = 0.005). Eyes with fibrosis and macular atrophy had faster BMVA decay over follow-up. Twenty eyes (6%) developed MH. Two subtypes of MH were identified: "atrophic" and "tractional."Myopic MNV-related complications are common in the long term despite initially successful treatment and have detrimental effects on visual acuity. Insights into their incidence and risk factors may help for future treatments to mitigate sight-threatening outcomes.

To investigate the suitability of 6 rod- or cone-mediated dark adaptation (DA) parameters as outcome measures for clinical trials in age-related macular degeneration (AMD), including their retest reliability, association with age and disease severity, and measurable longitudinal change over time.Prospective, longitudinal study (Clinicaltrials.gov: NCT01352975).A total of 191 patients with AMD and older participants followed longitudinally over 5 years.Dark adaptation testing was performed using the AdaptDx dark adaptometer with a maximum test time of 40 minutes. A 2-part exponential-linear curve was fitted to obtain values for cone decay, cone plateau, time to rod-cone break, rod intercept time (RIT), rod adaptation rate (S2), and area under the curve. Intersession retest reliability was assessed in tests performed within 2 weeks using the Bland-Altman analysis. The relationship of DA parameters with age, AMD severity, and reticular pseudodrusen (RPD) presence was evaluated using linear mixed models.Retest reliability, association with disease severity, and longitudinal change of 6 DA parameters.A total of 1329 DA curves were analyzed. Rod intercept time was the parameter that showed the greatest reliability (intraclass correlation coefficient of 0.88) and greatest association with age, AMD severity, and RPD (marginal RAge-related macular degeneration severity and RPD presence are each associated with large differences in multiple DA curve parameters. In addition, substantial differences in some parameters occur with age, even accounting for AMD severity and RPD status. This supports the 2-hit hypothesis of age and disease status on DA (and perhaps AMD pathophysiology itself). Of the DA parameters, RIT has the highest retest reliability, closest correlation with AMD severity and RPD, and largest longitudinal changes. This underscores the suitability of RIT as an outcome measure in clinical trials. The cone plateau increases only in advanced stages of kinetic rod dysfunction, indicating rod dysfunction preceding cone dysfunction and degeneration in the temporal sequence of pathology in AMD.

To determine prevalence of probable polypoidal choroidal vasculopathy (PCV) among White patients with neovascular age-related macular degeneration (nAMD) using non-indocyanine green angiography (ICGA) criteria DESIGN: Multicenter, multinational, retrospective, cross-sectional study.A total of 208 treatment-naive eyes from Hispanic and non-Hispanic White individuals diagnosed with nAMD were included. All underwent color fundus photography (CFP), optical coherence tomography (OCT), and fluorescein angiography (FFA). De-identified images of study eyes were sent to 2 groups of graders. Group 1 reviewed CFP, OCT, and FFA to confirm nAMD diagnosis. Group 2 reviewed CFP and OCT to determine highly suggestive features for PCV. Probable PCV diagnosis defined as the presence of ≥2 of 4 highly suggestive features for PCV: notched or fibrovascular pigment epithelial detachment (PED) on CFP, sharply-peaked PED, notched PED, and hyperreflective ring on OCT.Eleven eyes were excluded because of poor image quality (6) or non-nAMD diagnosis (5). Of 197 eligible eyes (197 patients), the mean age (SD) was 78.8 years (8.9), 44.2% were men, 26.4% were Hispanic, and 73.6% were non-Hispanic White individuals; 41.1%, 23.4%, 9.1%, and 2.5% had ≥1, ≥2, ≥3, and 4 highly suggestive features. Results showed that 23.4% (95% CI, 17.6%-29.9%) had probable PCV diagnosis. Predominantly occult CNV was more frequently found in probable PCV than nAMD subgroup (84.8% vs 64.9%, P = .01). Hispanic White individuals had a lower prevalence of probable PCV than non-Hispanic White individuals (9.6% vs 28.2%, P = .006) CONCLUSIONS: These findings suggest that probable PCV occurs between 17.6% and 29.9% in White individuals with nAMD, and more commonly in non-Hispanic than in Hispanic White individuals.

Neovascular age-related macular degeneration (nAMD) often requires intensive therapy with anti-VEGF injections. In prior post hoc studies, early residual fluid (ERF) after the loading phase was associated with poorer treatment outcomes. This retrospective study examined the impact of ERF on vision using machine learning (ML) methods in routine clinical practice.Retrospective cohort.This study included treatment-naïve patients with nAMD who were initiated on anti-VEGF between 2012 and 2018, with at least 1 year of follow-up.Overall, 286 patients with nAMD were included. An ML algorithm quantified intraretinal fluid (IRF), subretinal fluid (SRF), and total retinal fluid from OCTs. The ERF group included those with fluid at week 12 and was further stratified by fluid subtype. Paired t tests and analysis of variance compared best visual acuity (BVA) and fluid among subgroups, and a quartile analysis correlated fluid volumes to week 52 BVA. The risk of ERF was predicted from baseline factors using 3 ML methods: Ridge logistic regression, k nearest neighbors classification, and support vector classification.Mean change in BVA from baseline to week 52 according to week 12 fluid status.At week 12, 58.4% of patients had ERF. The breakdown of those in the ERF group included SRF-only (45.5%), IRF-only (21.6%), and IRF and SRF (32.9%). The ERF and ERF-free groups had similar BVA gains from baseline to week 52 (+5.7 ± 15.4 vs. +4.9 ± 18; P = 0.69). Examining specific ERF subgroups revealed no significant differences among the IRF-only (+4.6 ± 16.4), SRF-only (+5.6 ± 12.5), and IRF and SRF (+6.6 ± 18.5, P = 0.93) groups. Quartile analysis of week 12 fluid revealed no predictive pattern for BVA gains. Three ML methods were developed to predict those at risk for ERF achieved equivalent performance, with F1 score of 0.73 to 0.76.These results diverge from prior post hoc studies, in that there was no significant difference in long-term BVA gains between ERF and ERF-free cohorts, as well as between the week 12 fluid subgroups.

Myopic traction maculopathy (MTM), one of the complications of pathologic myopia, is a spectrum of pathological conditions that are attributed to tractional changes in the eye characterized by retinoschisis, lamellar or full thickness macular hole, and foveal retinal detachment. Considering the global public health burden of MTM and pathologic myopia, it is important to understand these sight-threatening complications and their associations. We conducted an evidence-based review of the prevalence and natural history of MTM and associated risk factors. The prevalence of MTM in the general population is low, but is increased among high myopes. MTM is associated with preretinal tractional structures, myopic refractive error and axial elongation, posterior staphyloma, dome-shaped macula, chorioretinal atrophy, and myopic macular degeneration. The clinical course of MTM tends to be stable; however, MTM may progress, resulting in visual acuity deterioration, although spontaneous improvement also occurs. The associations of MTM progression include vitreous traction, location, and extent of MTM, and lamellar macular hole-specific factors. More high-quality population-based studies that assess MTM prevalence and natural history are needed.

To examine the risk, prevalence, and progression of glaucoma development in age-related macular degeneration (AMD) eyes receiving intravitreal anti-vascular endothelial growth factor (anti-VEGF) injections compared to controls.Retrospective clinical cohort study.Retrospective review of eyes receiving intravitreal anti-VEGF injections from January 1, 2004, to December 31, 2013, for exudative AMD. Age- and sex-matched control groups of eyes included eyes with nonexudative AMD (NEAMD) and no AMD. Eyes with a diagnosis of glaucoma or glaucoma suspect were reviewed for injection details, type and date of glaucoma diagnosis, glaucoma treatments, standard automated perimetry (SAP), and spectral domain optical coherence tomography (SD-OCT). Qualitative progression was determined by indication of glaucoma progression in provider notes. Quantitative progression was assessed based on change in mean deviation (MD) on SAP, retinal nerve fiber layer thickness on SD-OCT, and intraocular pressure (IOP).There were 707 eyes of 504 patients treated with anti-VEGF injections and 1008 eyes in the NEAMD and no-AMD cohorts. There was no difference in glaucoma or suspect prevalence at initial presentation between eyes treated with injections and NEAMD (6.9% vs 9.7%, P = .22) or no-AMD controls (vs 8.5%, P = .55). There was no difference in cumulative 5-year probability of new glaucoma diagnosis after anti-VEGF injections compared to NEAMD (1.9% vs 1.0%, P = .69) or no-AMD controls (vs 1.6%, P = .88). There was no difference in qualitative progression of glaucoma in the injection cohort vs NEAMD (P = .19) or no-AMD controls (P = .61). The rate of MD change in injection eyes was similar to NEAMD eyes (P = .74) but greater than no-AMD eyes (P = .02). Eyes receiving injections required more topical glaucoma medications compared with NEAMD (P = .03) and more glaucoma laser treatments compared with no-AMD controls (P = .009). Eyes receiving injections did not require more frequent incisional glaucoma surgery compared with NEAMD (21.0% vs 15.0%, P = .95) or no-AMD controls (vs 10.0%, P = .10).Eyes treated with intravitreal anti-VEGF injections for exudative AMD did not have increased risk of developing glaucoma compared with controls. Of those with a glaucoma diagnosis, exudative AMD eyes receiving injections required a greater number of topical glaucoma medications compared with NEAMD eyes and had a greater rate of MD loss than no-AMD controls.

Age-related macular degeneration (AMD) is the leading cause of central vision loss in the elderly. Oxidative stress-induced retinal pigment epithelium (RPE) cell apoptosis is a crucial pathogenic hallmark in AMD. Chemoattractant receptor-homologous molecule expressed on T helper type 2 cells (CRTH2), a prostaglandin (PG) D2 receptor, has been implicated in various pathophysiological events, especially inflammation and stress-induced cell apoptosis. However, its specific role in AMD is not fully understood. Here we studied the effect of CRTH2 on AMD. Our results showed that when stimulated by H

The RENOWNED study investigated the treatment patterns, real-world effectiveness and safety of ranibizumab in Taiwanese patients with neovascular age-related macular degeneration (nAMD) treated with ranibizumab 0.5 mg in accordance with the first reimbursement scheme effective from 2012 to 2014.This study was a Phase IV, 12-month, open-label, prospective, observational study conducted in Taiwan. Patients with visual impairment due to nAMD initiating treatment with ranibizumab 0.5 mg were included. The primary endpoint was mean change in best-corrected visual acuity (BCVA) from Baseline at Month 3.Overall, 202 patients with nAMD were included. Mean (standard deviation [SD]) BCVA Early Treatment Diabetic Retinopathy Study letters improved from Baseline (49.6 [21.5] letters) at Month 3 (+4.9 [11.8], P 0.0001), and at Month 12 (+3.5 [14.1], P = 0.0043). The proportion of patients with nAMD who lost ≥5 letters at Months 3 and 12 was 13.6% (n = 27) and 26.6% (n = 37), respectively. Mean (SD) central retinal thickness decreased from Baseline (320.1 [127.2] μm) with a mean reduction of 49.1 (107.3) μm at Month 3 (P 0.0001), but was not significant at Month 12 with a mean reduction of 11.6 (115.6) μm (P = 0.2861). Mean (SD) number of ranibizumab injections over 12 months was 3.1 (1.0). A mean treatment interval of 109.5 days was observed between the third and fourth injections. After limited reimbursed ranibizumab injections, 43.8% patients received other treatments. The safety findings are consistent with previous studies.Ranibizumab 0.5 mg treatment for 12 months under real-world settings improved visual outcomes in Taiwanese patients with nAMD.

Intravitreal anti-vascular endothelial growth factor (anti-VEGF) injections are the gold standard treatment for wet age-related macular degeneration (wet AMD). Coronavirus disease 2019 (COVID-19) has led to the cancellation of many scheduled intravitreal anti-VEGF injection visits. We compared the functional and structural visual outcomes of wet AMD patients who did not adhere to their planned intervals (group 1) with those who did (group 2).Wet AMD patients of Swiss Visio Montchoisi and RétinElysée were included. Best-corrected visual acuity (BCVA) and optical coherence tomography (OCT) changes between their first visit after the end of the first national lockdown in Switzerland (27 April 2020, first post-lockdown visit) and their last visit before the beginning of the first national lockdown in Switzerland (13 March 2020, last pre-lockdown visit) were assessed. The BCVA outcome was defined as unfavorable when there was a loss of≥5 ETDRS letters in the first post-lockdown visit compared to the BCVA at last pre-lockdown visit. The OCT outcome was defined as unfavorable when there was an increase in at least one of the parameters, intraretinal fluid (IRF), subretinal fluid (SRF), or pigment epithelial detachment (PED), at the first post-lockdown visit compared to the last pre-lockdown visit.Group 1 (89 patients, 109 eyes) had a 13.41% greater rate of unfavorable BCVA outcomes and a 38.27% greater rate of unfavorable OCT outcomes than group 2 (96 patients, 122 eyes) (P=0.04, P0.0001, respectively). Multivariate analysis showed that the more the patients deviated from their programmed injections and the higher the BCVA pre-lockdown, the higher the rate of unfavorable BCVA outcomes (P=0.03 and P=0.02, respectively). OCT outcomes were not a predictive factor for an unfavorable BCVA outcome.The cancellation of many intravitreal anti-VEGF injection appointments resulted in worse functional and structural outcomes in wet AMD patients. The COVID-19 pandemic led many patients to refrain from their routine intravitreal anti-VEGF injection appointments, allowing us to analyze the role of designated intervals in the treatment of wet AMD. During any future lockdown due to COVID-19 or similar circumstances, continuity of care for wet AMD patients should be maintained.

To compare the enlargement rates of geographic atrophy (GA) over 5 years of follow-up with those of macular atrophy (MA) associated with macular neovascularization (MNV).Retrospective, longitudinal, comparative case series.Consecutive series of patients with age-related macular degeneration and GA (dry) or with MA and MNV.Atrophic regions detected on serial registered fundus autofluorescence images were semiautomatically delineated, and the measurements of these areas were recorded every 6 ± 3 months for the first 2 years of follow-up and at yearly intervals for up to 5 years.Annual raw and square root-transformed rates of atrophy growth.The study included 117 eyes of 95 patients (61 in the GA cohort and 56 in the MA cohort); 100% and 38.5% of the eyes completed 2 and 5 years of follow-up, respectively. The mean size of lesions at baseline was similar between the 2 groups (raw: 1.74 vs. 1.53 mmThe presence of MNV was associated with a slower rate of expansion, resulting in overall smaller areas of atrophy over time. These findings support the hypothesis that MNV may protect against the progression of atrophy.

To assess the association between treatment interval and likelihood of anti-vascular endothelial growth factor (anti-VEGF) discontinuation among patients with neovascular age-related macular degeneration (nAMD) in a real-world setting in the United States.Retrospective clinical cohort study.Health insurance claims data from the IBM MarketScan Commercial and Medicare Supplemental databases were retrospectively reviewed to identify adults with nAMD who received anti-VEGF for the first time between July 1, 2011, and June 30, 2017. The proportion of discontinued patients was analyzed using Kaplan-Meier curves. Cox proportional hazards models were used to examine the association between treatment intervals at 24 months and anti-VEGF discontinuation.The analysis included 8167 patients on continuous, unilateral anti-VEGF treatment for at least 24 months. Baseline demographics and clinical characteristics were well balanced between treatment interval groups. The overall rate of discontinuation from 24 months until 60 months after treatment initiation was 30.4%. At 60 months, patients on shorter treatment intervals were more likely to remain on treatment than those on longer intervals, ranging from 76.8% (4-week interval group) to 60.6% (12-week interval group) and corresponding to a 28% lower likelihood (HR [SE] 0.72 [0.12], P.01) and 55% higher likelihood of discontinuing treatment (HR [SE] 1.55 [0.07], P.01), respectively, compared with the 8-week group.nAMD patients on longer anti-VEGF treatment intervals at 24 months had consistently higher discontinuation rates than patients on shorter intervals in the following years. This highlights the need to support and educate patients on long treatment intervals to continue with their treatment.

The retinal pigment epithelium (RPE) plays a crucial part in sight-threatening diseases. In this review, we shed light on the pivotal implication of the RPE in age-related macular degeneration, diabetic retinopathy and retinopathy of prematurity; and explain why a paradigm shift toward targeted RPE therapy is needed to efficiently fight these retinal diseases. We provide guidance for the development of RPE-specific nanotherapeutics by giving a comprehensive overview of the possibilities and challenges of drug delivery to the RPE and highlight successful nanotherapeutic approaches targeting the RPE.

To determine whether the rates of macular atrophy (MA) differ between eyes with neovascular age-related macular degeneration (nAMD) treated continuously with the Port Delivery System with ranibizumab (PDS) and those treated with ranibizumab given as a bolus intravitreal injection.A preplanned exploratory analysis of a phase 2, multicenter, randomized, active treatment-controlled, dose-ranging study.Patients diagnosed with nAMD within 9 months of screening who had received at least 2 previous intravitreal anti-vascular endothelial growth factor injections of any agent and were responsive to the treatment.Eyes were randomized (3:3:3:2) to treatment with either the PDS (filled with a customized formulation of ranibizumab at 10, 40, or 100 mg/ml and refilled pro re nata) or monthly intravitreal ranibizumab 0.5-mg injections.The prevalence, incidence, and progression of MA.The analysis population consisted of 220 eyes (58, 62, 59, and 41 eyes in the PDS 10-mg/ml, 40-mg/ml, 100-mg/ml, and monthly intravitreal ranibizumab 0.5-mg injection arms, respectively). At study baseline, MA was observed in 14.5% (PDS 10-mg/ml), 11.5% (PDS 40-mg/ml), 13.6% (PDS 100-mg/ml), and 7.6% (monthly ranibizumab) of eyes. At the last assessment (mean, 22.1 months), the prevalence of MA had increased to 38.6% (PDS 10-mg/ml), 40.0% (PDS 40-mg/ml), 40.4% (PDS 100-mg/ml), and 45.7% (monthly ranibizumab). In patients without MA at baseline, a higher proportion of eyes in the monthly ranibizumab arm (40.6%) developed MA than in those in the PDS arms (28.6%, 32.1%, and 30.6% of eyes in the PDS 10-, 40-, and 100-mg/ml arms, respectively). The mean change in the area of MA from baseline to the last assessment for the PDS 10-mg/ml, 40-mg/ml, 100-mg/ml, and monthly ranibizumab arms was +2.46, +1.61, +1.09, and +1.15 mmIn the phase 2 Ladder trial, there was no evidence of worse MA with the PDS compared with that with monthly intravitreal ranibizumab 0.5-mg injections. Larger trials focusing on MA are needed to confirm this finding.

BACKGROUND. —: A major cause of blindness in older persons is age-related macular degeneration (AMD). Cigarette smoking is one of the major risk factors for AMD. In the present study, we analyzed UK Biobank data to determine whether smoking cannabis, like cigarettes, might be related to AMD. METHODS. —: Our UK Biobank application was approved as UKB project 57245 (S.L., P.H.R.). Our analysis included all subjects with AMD and cannabis smoking information. The diagnosis of AMD was ascertained based on the 10th Revision of the International Classification of Diseases (ICD10), H35.3. Age at time of diagnosis of AMD was obtained from data field 5923. Cannabis information was recorded in UKB category 143, data field 20453, ever taken cannabis. A touch screen posed the question, “Have you taken CANNABIS (cannabis, grass, hash, ganja, blow, draw, skunk, weed, spliff, dope), even if it was a long time ago?” Possible answers were no, yes, 1–2 times, yes 3–10 times, yes, 11–100 times, yes, more than 100 times. RESULTS. —: Subjects who had used marijuana more than 100 times had a significantly reduced risk of AMD, compared to subjects who had never used marijuana, and use of marijuana every day was associated with less AMD than use of marijuana less than once a month. But subjects who used cannabis 100 times or more were significantly younger (8 years) when they developed AMD than subjects who never used cannabis. CONCLUSION. —: Drusen, deposits of lipids, proteins, and cellular debris, accumulate in Bruch’s membrane, limiting transport between the retinal pigment epithelium and the vasculature, triggering an inflammatory reaction. Marijuana can retard the inflammatory process because it is a powerful anti-inflammatory agent. Therefore, marijuana could reduce the risk of AMD. At the same time, blood vessels in the choriocapillaris below Bruch’s membrane become more sparse with age. This phenomenon is believed to be a starting point for AMD. Marijuana can accelerate the loss of blood vessels due to its anti-angiogenic properties. Therefore, marijuana use might cause AMD to develop sooner in younger people.

To evaluate the transancestry portability of current myopia polygenic risk scores (PRSs) to predict high myopia (HM) and myopic macular degeneration (MMD) in an Asian population.Population-based study.A total of 5894 adults (2141 Chinese, 1913 Indian, and 1840 Malay) from the Singapore Epidemiology of Eye Diseases study were included in the analysis. The mean ± standard deviation age was 57.05 ± 9.31 years. A total of 361 adults had a diagnosis of HM (spherical equivalent [SE]-5.00 diopters [D]) from refraction measurements, 240 individuals had a diagnosis of MMD graded by the International Photographic Classification and Grading System for Myopic Maculopathy criteria from fundus photographs, and 3774 individuals were control participants without myopia (SE-0.5 D).The PRS, derived from 687 289 HapMap3 single nucleotide polymorphisms (SNPs) from the largest genome-wide association study of myopia in Europeans to date (n = 260 974), was assessed on its ability to predict patients with HM and MMD versus control participants.The primary outcomes were the area under the receiver operating characteristic curve (AUC) to predict HM and MMD.The PRS had an AUC of 0.73 (95% confidence interval [CI], 0.70-0.75) for HM and 0.66 (95% CI, 0.63-0.70) for MMD versus no myopia. The inclusion of the PRS with other predictors (age, sex, educational attainment [EA], and ancestry; age-by-ancestry, sex-by-ancestry, and EA-by-ancestry interactions; and 20 genotypic principal components) increased the AUC to 0.84 (95% CI, 0.82-0.86) for HM and 0.79 (95% CI, 0.76-0.82) for MMD. Individuals with a PRS in the top 5% showed up to a 4.66 (95% CI, 3.34-6.42) times higher risk of HM developing and up to a 3.43 (95% CI, 2.27-5.05) times higher risk of MMD developing compared with the remaining 95% of individuals.The PRS is a good predictor for HM and facilitates the identification of high-risk children to prevent myopia progression to HM. In addition, the PRS also predicts MMD and helps to identify high-risk adults with myopia who require closer monitoring for myopia-related complications.

Thioredoxin (Trx) family proteins are key players in redox signaling. Here, we have analyzed glutaredoxin (Grx) 1 and Grx2 in age-related macular degeneration (AMD) and in retinal pigment epithelial (ARPE-19) cells. We hypothesized that these redoxins regulate cellular functions and signaling circuits such as cell proliferation, Wnt signaling and VEGF release that have been correlated to the pathophysiology of AMD. ARPE-19 cells were transfected with specific siRNAs to silence the expression of Grx1 and Grx2 and were analyzed for proliferation/viability, migration capacity, β-catenin activation, and VEGF release. An active site-mutated C-X-X-S Grx1 was utilized to trap interacting proteins present in ARPE-19 cell extracts. In both, AMD retinas and in ARPE-19 cells incubated under hypoxia/reoxygenation conditions, Grx1 showed an increased nuclear localization. Grx1-silenced ARPE-19 cells showed a significantly reduced proliferation and migration rate. Our trapping approach showed that Grx1 interacts with β-catenin in a dithiol-disulfide exchange reaction. Knock-down of Grx1 led to a reduction in both total and active β-catenin levels. These findings add redox control to the regulatory mechanisms of β-catenin signaling in the retinal pigment epithelium and open the door to novel therapeutic approaches in AMD that is currently treated with VEGF-inhibitors.

West African crystalline maculopathy (WACM) is characterized by the presence of macular hyperrefractile crystal-like deposits. Although the underlying pathophysiology has not been elucidated, a few biologic drivers have been proposed. We analyzed a large WACM case series to gain a more robust understanding of its features and etiology.Prospective, cross-sectional cohort study.Participants with WACM were selected from the large cohort recruited in the Ghana Age-Related Macular Degeneration Study.Demographic and detailed medical histories, full ophthalmic examinations, digital color fundus photographs, and OCT images were obtained. All cases with WACM were evaluated by 3 retina experts. Crystal numbers, location, and distribution were determined. Associations between WACM and White age-related macular degeneration (AMD) risk variants were assessed using Firth's bias-reduced logistic regression, including age and sex as covariates.Phenotypic features of, and genetic associations with, WACM.West African crystalline maculopathy was identified in 106 eyes of 53 participants: 22 were bilateral and 24 were unilateral. Grading for AMD was not possible in 1 eye in 7 participants with WACM; therefore, laterality was not assessed in these subjects. Thirty-eight participants were women and were 14 men; sex was unrecorded for 1 participant. The mean age was 68.4 years (range, 45-101 years). Typical WACM crystals were demonstrated on OCT, which were more easily identified at high contrast and predominantly located at the inner limiting membrane. In eyes with copathology, crystals localized deeper in the inner retina, with wider retinal distribution over copathology lesions. There was no association with age or sex. A significant association was observed between the complement factor H (CFH) 402H risk variant and WACM.This study confirms the localization of crystals adjacent to the inner limiting membrane and distribution over lesions in eyes with copathology. The evaluation of OCT images under high contrast allows improved identification. West African crystalline maculopathy may be associated with the CFH-CFHR5 AMD risk locus identified among Whites; however, it is also possible that the combination of crystals and the CFH 402H allele increases the risk for developing late AMD. Further analyses using larger sample sizes are warranted to identify causalities between genotype and WACM phenotype.

To evaluate the correlation between fundus autofluorescence (FAF) and en face spectral-domain OCT (SD-OCT) measurements of geographic atrophy (GA) area associated with age-related macular degeneration.Retrospective, cross-sectional study.Two hundred seventy eyes from 172 subjects with GA associated with age-related macular degeneration.Subjects with atrophic age-related macular degeneration who underwent both FAF (Heidelberg HRA + Spectralis) and dense volume (128 B-scans over 6 × 6 mmCorrelation between the SD-OCT and FAF measurements of the GA area.The mean GA area measured from the FAF images was 8.1 ± 5.04 mmSpectral-domain OCT-derived measurements of GA correlate well with areas of DDAF obtained from FAF images. The manual correction of SD-OCT segmentation errors can further improve this correlation. These observations may support the use of SD-OCT-based measurements of the GA area in clinical research and clinical trials.

To evaluate hypotheses about the role of acquired vitelliform lesion (AVL) in age-related macular degeneration pathophysiology.Laboratory histology study; retrospective, observational case series.Two donor eyes in a research archive with AVL and age-related macular degeneration were analyzed with light and electron microscopy for AVL content at locations matched to ex vivo B-scans. A retrospective, observational clinical cohort study of 42 eyes of 30 patients at 2 referral clinics determined the frequency of optical coherence tomography features stratified by AVL fate.Histologic and clinical cases showed subretinal drusenoid deposit and drusen. Ultrastructural AVL components in 2 donor eyes included retinal pigment epithelium (RPE) organelles (3%-22% of volume), outer segments (2%-10%), lipid droplets (0.2%-12%), and a flocculent material (57%-59%). Of 48 AVLs (mean follow-up 46 ± 39 months), 50% collapsed to complete RPE and outer retinal atrophy, 38% were stable, 10% resorbed, and 2% developed neovascularization. The Early Treatment Diabetic Retinopathy Study grid central subfield contained 77% of AVLs. Hyperreflective foci, ellipsoid zone disruption, and hyperreflective thickening of the RPE-basal lamina-Bruch membrane band were common at maximum AVL expansion. Collapsing and noncollapsing AVLs had different growth rates (rapid vs slow, respectively).AVL deposits contain unexpectedly low levels of RPE organelles and outer segments. Subfoveal predilection, reflectivity on optical coherence tomography, hyperautofluorescence, yellow color, and growth-regression phases suggest dysregulation of lipid transfer pathways specific to cone photoreceptors and supporting cells in formation of AVL deposit, analogous to drusen and subretinal drusenoid deposit. Prediction of AVL outcomes via growth rates should be confirmed in larger clinical studies.

To perform a nationwide analysis of trends in the incidence of etiologies for legal blindness in Israel during 2009-2020, and to compare the results with those of the previous decade.Descriptive, retrospective population-based trend study.Data were retrieved from the Israeli National Registry of the Blind during 2009-2020. Data obtained included demographics, years of registration, and causes. Primary and secondary outcomes were the incidence of new certified blindness cases and its comparison with that of the previous decade, respectively.The age-standardized incidence rate of blindness in Israel decreased from 15.76 per 100,000 residents in 2009 to 11.83 in 2020, a 24.9% drop. The mean annual decline was evident until 2013 (P.001, 6.15%), but subsequently flattened (P = .71, 0.42%). Age-related macular degeneration (AMD), glaucoma, optic atrophy, and cataract decreased until 2014, and reached a plateau that was maintained until the end of the study period. Diabetic retinopathy (DR) incidence rates diminished throughout the decade (P.001, 9.2%), with attenuation of the rate of decline after 2014.The impact of efforts to reduce the incidence of preventable causes of blindness may have nearly reached saturation for most of the leading causes of blindness in Israel, namely, AMD, glaucoma and cataract. The incidence of DR has been maintained; however, attenuation has been observed. New modalities to detect and treat these causes may have to emerge before a resurgence of improvement can occur.

Age-related macular degeneration (AMD) is a leading cause of severe, irreversible vision impairment in developed countries, and its prevalence is rising all over the world, increasing sharply with age. AMD represents an acquired degeneration of the retina that causes significant central visual impairment through a combination of non-neovascular and neovascular derangement. The main risk factors for the development of advanced AMD are increasing age, genetic factors, and cigarette smoking; however, the exact pathophysiology of AMD is yet relatively poorly understood. In recent years, the gut microbiota has been intensively studied and linked to several pathologic processes, including ocular diseases. In this sense, the aim of this review is to gather published evidence about the relationship between gut microbiota and AMD.

Macular hemorrhages are a severe complication of other retinal pathologies, such as age-related macular degeneration (AMD) or macroaneurysms. Their therapeutic approach is not standardized, and can vary from observation to surgical treatment.Retrospective analysis of 22 cases of macular hemorrhage, treated with vitrectomy associated to subretinal rTPA and intravitreal anti-VEGF over a period of 5 years.22 eyes of 22 patients were included, of which 12 (52%) were women. The mean age at diagnosis was 84.4 years. 13 patients were pseudophakic (54.1%) and 19 (86.36%) had previous ophthalmological comorbidities. The etiology of the macular hemorrhage was AMD in 19 patients (86.36%). The mean of best VA corrected at diagnosis was 24.55 (Early Treatment Diabetic Retinopathy Study score -ETDRS), with a statistically significant improvement to 36.78 3 months after surgery (p = 0.011). With an average of 23.5 months of follow-up, no differences in prognosis associated with the etiology or size of the hemorrhage were observed.The treatment of macular hemorrhages by vitrectomy, subretinal rTPA and antiVEGF improves the visual prognosis of affected patients.

To validate the performance of the Notal Vision Home OCT (NVHO) system for daily self-imaging at home and characterize the retinal fluid dynamics of patients with neovascular age-related macular degeneration (nAMD).Prospective observational study.Fifteen participants who had at least 1 eye with nAMD and underwent anti-VEGF treatments.The participants performed daily self-imaging at home using NVHO for 3 months. The scans were uploaded to the cloud, analyzed using the Notal OCT Analyzer (NOA), evaluated by human experts for fluid presence, and compared with in-office OCT scans.Weekly self-scan rate, image quality, scan duration, agreement between NOA and human expert grading for fluid presence, agreement between NVHO and in-office OCT scans for fluid presence, central subfield thickness (CST) and retinal fluid volume, and the characteristics of fluid dynamics during the study and in response to treatments.The mean weekly scan frequency was 5.7 ± 0.9 scans per week, and 93% of the scans were eligible for NOA analyses. The median scan time was 42 seconds. The NOA and human experts agreed on the fluid status in 83% of the scans, and discrepancies were limited to trace amounts of fluid. The NVHO scans analyzed using NOA and the in-office OCT scans graded by human experts agreed on the fluid status in 96% of the cases. The CST and retinal fluid volume measurements using the home OCT and in-office OCT scans demonstrated a Pearson correlation coefficient of r = 0.90 and r = 0.92, respectively. Novel parameters, such as retinal fluid volume and area under the curve (AUC) of retinal fluid volume, demonstrated wide variations in fluid exudation and fluid load over time among the patients. Parameters such as the rate of reduction in fluid volume in the first week after treatment and AUC between treatments captured the speed and duration of the response to anti-VEGF agents.Daily home OCT imaging is feasible among patients with nAMD. It demonstrated good agreement with human expert grading for retinal fluid identification and excellent agreement with the in-clinic OCT scans. Home OCT allows for detailed graphical and mathematical analyses of retinal fluid volume trajectories, including novel parameters to inform clinical decision making.

To determine whether causal association lies between thyroid function and age-related macular degeneration (AMD) risk in human beings.Two-sample Mendelian randomization (MR) study.The single-nucleotide polymorphisms associated with free thyroxine (FT4) and thyroid-stimulating hormone (TSH) were selected from a genome-wide association study (GWAS) of 72,167 individuals of European descent. Summary-level data for AMD were obtained from a GWAS published by the International Age-related Macular Degeneration Genomics Consortium of 33,526 individuals (16,144 cases and 17,832 controls). An inverse-variance-weighted (IVW) method was the main MR analysis. Maximum likelihood, weighted median, MR-Egger, MR-pleiotropy residual sum outlier methods were used for the sensitivity analysis.An increase of 1 SD in genetically predicted FT4 levels was found to be significantly associated with an 18.9 % increase in the overall AMD risk (P = .005). In the multivariable MR analysis controlling for TSH level, the causal effect of FT4 level on the risk of AMD remained (odds ratio [OR] = 1.207, P = .004). A 1-SD increase in TSH levels was nominally associated with a 10.0% decrease in the overall AMD risk (P = .032). After adjusting for FT4 level by multivariable MR analysis, no direct causal relationship was found between TSH level and AMD risk (95% CI = 0.810, 1.125, P = .582).Genetic variants predisposing to higher FT4 levels within the normal range were associated with higher AMD risk. Further studies are required to understand the mechanism underlying this putative causal relationship.

To identify baseline OCT predictors of the 3-year visual outcome for type 3 (T3) macular neovascularization (MNV) secondary to age-related macular degeneration (AMD) treated by anti-vascular endothelial growth factor (VEGF) therapy.Retrospective longitudinal study.Forty eyes of 30 patients affected by exudative treatment-naive T3 MNV were enrolled.Baseline best-corrected visual acuity (BCVA) and several baseline OCT features were assessed and included in the analysis. Univariate and multivariate analyses served to identify risk factors associated with the 3-year BCVA.Baseline OCT features that are associated with bad or good visual outcomes of T3 MNV treated by anti-VEGF injections.Mean baseline BCVA was 0.34 ± 0.28 logarithm of the minimum angle of resolution (LogMAR), which significantly decreased to 0.52 ± 0.37 LogMAR at the end of the 3-year follow-up (P = 0.002). In the univariate analysis, the following baseline features were associated with the 3-year BCVA outcome: baseline BCVA (P = 0.004), foveal involvement of exudation (P = 0.004), and presence of subretinal fluid (SRF; P = 0.004). In the multivariate model, baseline BCVA (P = 0.032), central macular thickness (P = 0.036), number of active T3 lesions (P = 0.034), and presence of SRF (P = 0.008) were associated with the 3-year BCVA outcome. Interestingly, 3-year BCVA was significantly lower in 19 eyes with SRF at the baseline (0.69 ± 0.42 LogMAR) than 21 eyes without SRF (0.37 ± 0.24 LogMAR; P = 0.004).We identified structural OCT features associated with BCVA outcome after 3-year treatment with anti-VEGF injections. In contrast to previous studies on neovascular AMD, in our series, the presence of SRF at baseline was the most significant independent negative predictor of functional outcomes. Current findings may be employed to identify less favorable T3 patterns potentially deserving a more intensive treatment.

To evaluate whether topical acrizanib (LHA510), a small-molecule vascular endothelial growth factor receptor inhibitor, could suppress the need for anti-vascular endothelial growth factor therapy over a 12-week period in patients with neovascular age-related macular degeneration.A phase 2 multicenter randomized double-masked, vehicle-controlled proof-of-concept study.Trial includes n = 90 patients with active choroidal neovascularization due to neovascular age-related macular degeneration and under anti-vascular endothelial growth factor treatment. All patients received an intravitreal injection of ranibizumab at baseline and were retreated when there was evidence of disease recurrence (rescue). Patients were randomized 1:1 to receive topical LHA510 or vehicle for 12 weeks. Drops were administered twice a day for 8 weeks and then 3 times a day for the last 4 weeks.The primary outcome was the number of patients requiring rescue over 84 days of topical dosing. Key secondary outcome measures were time to first rescue, total number of ranibizumab injections, changes in central subfield thickness, and changes of visual acuity from baseline to day 84.The extended per protocol set included 70 patients of whom 25 of 33 patients in the LHA510 group (75.8%) and 25 of 37 patients in the placebo group (67.6%) required rescue by day 84 (P = .8466). Secondary and subgroup analysis did not support evidence of efficacy. Twenty-one of 46 patients administered LHA510 developed a reversible corneal haze that resolved with cessation of treatment and did not recur in patients restarted at once daily frequency.In spite of extensive optimization for topical efficacy, LHA510 failed to demonstrate clinical efficacy.

Clustered regularly interspaced short palindromic repeats (CRISPR)-based genomic disruption of vascular endothelial growth factor A (Vegfa) with a single gRNA suppresses choroidal neovascularization (CNV) in preclinical studies, offering the prospect of long-term anti-angiogenesis therapy for neovascular age-related macular degeneration (AMD). Genome editing using CRISPR-CRISPR-associated endonucleases (Cas9) with multiple guide RNAs (gRNAs) can enhance gene-ablation efficacy by augmenting insertion-deletion (indel) mutations with gene truncations but may also increase the risk of off-target effects. In this study, we compare the effectiveness of adeno-associated virus (AAV)-mediated CRISPR-Cas9 systems using single versus paired gRNAs to target two different loci in the Vegfa gene that are conserved in human, rhesus macaque, and mouse. Paired gRNAs increased Vegfa gene-ablation rates in human cells invitro but did not enhance VEGF suppression in mouse eyes invivo. Genome editing using paired gRNAs also showed a similar degree of CNV suppression compared with single-gRNA systems. Unbiased genome-wide analysis using genome-wide unbiased identification of double-stranded breaks (DSBs) enabled by sequencing (GUIDE-seq) revealed weak off-target activity arising from the second gRNA. These findings suggest that invivo CRISPR-Cas9 genome editing using two gRNAs may increase gene ablation but also the potential risk of off-target mutations, while the functional benefit of targeting an additional locus in the Vegfa gene as treatment for neovascular retinal conditions is unclear.

OK Publisher Copyright: © 2023 American Academy of Ophthalmology Purpose: To investigate intraretinal neovascularization and microvascular anomalies by correlating in vivo multimodal imaging with corresponding ex vivo histology in a single patient. Design: A case study comprising clinical imaging from a community-based practice, and histologic analysis at a university-based research laboratory (clinicopathologic correlation). Participants: A White woman in her 90s treated with numerous intravitreal anti-VEGF injections for bilateral type 3 macular neovascularization (MNV) secondary to age-related macular degeneration (AMD). Methods: Clinical imaging comprised serial infrared reflectance, eye-tracked spectral-domain OCT, OCT angiography, and fluorescein angiography. Eye tracking, applied to the 2 preserved donor eyes, enabled the correlation of clinical imaging signatures with high-resolution histology and transmission electron microscopy. Main Outcome Measures: Histologic/ultrastructural descriptions and diameters of vessels seen in clinical imaging. Results: Six vascular lesions were histologically confirmed (type 3 MNV, n = 3; deep retinal age-related microvascular anomalies [DRAMAs], n = 3). Pyramidal (n = 2) or tangled (n = 1) morphologies of type 3 MNV originated at the deep capillary plexus (DCP) and extended posteriorly to approach without penetrating persistent basal laminar deposit. They did not enter the subretinal pigment epithelium (RPE)–basal laminar space or cross the Bruch membrane. Choroidal contributions were not found. The neovascular complexes included pericytes and nonfenestrated endothelial cells, within a collagenous sheath covered by dysmorphic RPE cells. Deep retinal age-related microvascular anomaly lesions extended posteriorly from the DCP into the Henle fiber and the outer nuclear layers without evidence of atrophy, exudation, or anti-VEGF responsiveness. Two DRAMAs lacked collagenous sheaths. External and internal diameters of type 3 MNV and DRAMA vessels were larger than comparison vessels in the index eyes and in aged normal and intermediate AMD eyes. Conclusions: Type 3 MNV vessels reflect specializations of source capillaries and persist during anti-VEGF therapy. The collagenous sheath of type 3 MNV lesions may provide structural stabilization. If so, vascular characteristics may be useful in disease monitoring in addition to fluid and flow signal detection. Further investigation with longitudinal imaging before exudation onset will help determine if DRAMAs are part of the type 3 MNV progression sequence. Financial Disclosure(s): Proprietary or commercial disclosure may be found after the references. publishersversion published

Retinal pigment epithelial (RPE) is primarily impaired in age-related macular degeneration (AMD), leading to progressive loss of photoreceptors and sometimes choroidal neovascularization (CNV). mTOR has been proposed as a promising therapeutic target, while the usage of its specific inhibitor, rapamycin, was greatly limited. To mediate the mTOR pathway in the retina by a noninvasive approach, we developed novel biomimetic nanocomplexes where rapamycin-loaded nanoparticles were coated with cell membrane derived from macrophages (termed as MRaNPs). Taking advantage of the macrophage-inherited property, intravenous injection of MRaNPs exhibited significantly enhanced accumulation in the CNV lesions, thereby increasing the local concentration of rapamycin. Consequently, MRaNPs effectively downregulated the mTOR pathway and attenuate angiogenesis in the eye. Particularly, MRaNPs also efficiently activated autophagy in the RPE, which was acknowledged to rescue RPE in response to deleterious stimuli. Overall, we design and prepare macrophage-disguised rapamycin nanocarriers and demonstrate the therapeutic advantages of employing biomimetic cell membrane materials for treatment of AMD.

Purpose To investigate the association between the presence of a cilioretinal artery (CRA) and advanced age-related macular degeneration (AMD), including the prevalence of choroidal neovascularization (CNV) and geographic atrophy (GA). Design Retrospective cross-sectional study. Methods Setting: Single center Patient population: A total of 738 patients with AMD who underwent optical coherence tomography angiography (OCTA) were included in the study. Fundus photographs were reviewed to determine the presence of the CRA. Intervention/observation procedures: In patients with a unilateral CRA, paired tests were performed between eyes with and without the CRA to compare AMD severity and prevalence of CNV and GA. Main outcomes: AMD stage, and prevalence of CNV and GA. Macular vasculature, including vessel density, perfusion density, and foveal avascular zone, examined using OCTA. Results A total of 27.8% and 8.1% of patients had a CRA in one and both eyes, respectively. A total of 174 eyes from 87 patients with a unilateral CRA were examined. Eyes with a CRA showed lower AMD stage (4-step AREDS category; P = 0.037) and a lower prevalence of CNV (23.0% vs. 41.4%; P = 0.024) than those without a CRA. The prevalence of GA and macular vessel density, perfusion density, and foveal avascular zone measured by OCTA were similar in both groups. Conclusions In the eyes with a CRA, AMD stage and prevalence of CNV were lower than those in the eyes without a CRA. However, the effect of the CRA on the macular vascular system remains unclear.

PURPOSE: A training exercise was performed to study the ability of graders to reliably identify precursor lesions to geographic atrophy (GA), known as persistent choroidal hyper-transmission defects (hyperTDs), using en face optical coherence tomography (OCT) images from eyes with non-exudative age-related macular degeneration (AMD). DESIGN: Intergrader agreement study PARTICIPANTS: Eleven graders participated in this exercise. METHODS: Formal training on how to identify persistent hyperTDs on en face OCT images was provided to the graders. Persistent hyperTDs were defined as bright lesions having a greatest linear dimension (GLD) of at least 250 μm. Training consisted of a tutorial session followed by the grading of three pretest exercises, each consisting of three cases. After all the graders scored 100% on the pretest exercises, they performed a final exercise consisting of 30 en face OCT images from 29 eyes with non-exudative AMD containing 107 hyperTDs that each grader needed to evaluate. The cases contained a variety of AMD-related atrophic lesions. MAIN OUTCOME MEASURES: The sensitivity, positive predictive value (PPV), and modified accuracy were assessed for each grader. RESULTS: A total of 1177 hyperTDs from 30 en face OCT images were reviewed by the graders. The mean sensitivity, PPV, and modified accuracy for all the graders were calculated to be 99.0%, 99.2%, and 98.2%, respectively. There was a 97% agreement observed between all the graders (AC(1) = 0.97). Internal graders from the Bascom Palmer Eye Institute (BPEI) had a slightly higher agreement compared with the external graders (AC(1) = 0.98 vs. 0.96). The hyperTDs most often incorrectly identified included the following features: (1) hyperTDs containing a hypo-transmission defect (hypoTD) core, (2) single hyperTDs that were incorrectly graded as two separate lesions, and (3) hyperTDs with a borderline GLD that was close to 250 μm. CONCLUSION: The accurate detection of persistent hyperTDs on en face OCT images by graders demonstrates the feasibility of using this OCT biomarker to identify disease progression in eyes with non-exudative AMD, especially when used as a clinical trial endpoint in studies designed to test new therapies that may slow disease progression from intermediate AMD (iAMD) to GA.

Purpose To report the results of a first-in-human study using a robotic device to assist subretinal drug delivery in patients undergoing vitreoretinal surgery for macular haemorrhage. Design Double armed, randomized controlled surgical trial (ClinicalTrials.gov identifier: NCT03052881). Methods Setting Oxford Eye Hospital, Oxford University Hospitals NHS Foundation Trust, Oxford, United Kingdom. Participants In total, 12 participants were recruited: 6 in the robot-assisted and 6 in the control manual surgery arm according to the pre-specified inclusion and exclusion criteria. All subjects presented with acute loss of vision due to a sub-foveal haemorrhage secondary to neovascular age-related macular degeneration. Intervention After standard vitrectomy, intraoperative OCT-guided subretinal injection of tissue plasminogen activator (TPA) was performed either by robot-assisted or conventional manual technique under local anaesthesia. The robotic part of the procedure involved advancement of a cannula through the retina and stabilizing it during foot-controlled injection of up to 100µl of TPA solution. Main Outcome Measures We assessed surgical success, duration of surgery, adverse events, and tolerability of surgery under local anaesthesia. Results The procedure was well tolerated by all participants and safely performed in all cases. Total duration of surgery, time taken to complete the injection and retinal microtrauma were similar between the groups and not clinically significant. Subretinal haemorrhage was successfully displaced at 1-month post-intervention, except for one control subject, and the median gain in visual acuity was similar in both arms. Conclusions This first-in-human study demonstrates the feasibility and safety of high precision robot-assisted subretinal drug delivery as part of the surgical management of sub-macular haemorrhage, simulating its potential future application in gene or cell therapy.

To investigate the 5-year cumulative incidence and progression of myopic maculopathy in the general population in Germany and to analyze potential risk factors.The Gutenberg Health Study (GHS) is a population-based cohort study including 15 010 participants aged 35 to 74 years at baseline.A total of 494 eyes of 323 participants (mean age, 50.2 ± 9.2 years; median, -7.25 diopters [D] myopic refractive error) without myopic maculopathy at baseline and 34 eyes of 27 subjects (mean age, 56.7 ± 9.1 years; median, -8.75 D myopic refractive error) with myopic maculopathy met the inclusion conditions, phakic eyes with spherical equivalent ≤-6 D (baseline), and had gradable fundus photographs at baseline and 5-year follow-up.Myopic maculopathy incidence and progression were assessed by grading of fundus photographs according to a recent international photographic classification system (META-PM). Multivariable logistic regression analysis was used to assess risk factors for progression of myopic maculopathy.Estimates for incidence and progression of myopic maculopathy.The 5-year cumulative incidence of myopic maculopathy was 0.3% (95% confidence interval [CI], 0.02-1.99; n = 1). Progression occurred in 17 of 34 eyes (50%) with prior myopic maculopathy over 5 years with 4 changes in category. The most common types of progression were enlargement of diffuse and patchy chorioretinal atrophy; a new pathology was present in 8 eyes. Higher intraocular pressure (IOP) (odds ratio [OR], 1.62; 95% CI, 1.51-1.59; P = 0.035) was associated with progression of myopic maculopathy. Female gender (OR, 5.54; 95% CI, 0.93-32.92; P = 0.060) and higher myopic refractive error (OR, 1.62 per diopter; 95% CI, 0.99-1.49; P = 0.063) showed a tendency toward progression.Incidence of myopic maculopathy is rare in highly myopic eyes in the general population aged 35 to 74 years in Germany. Progression of myopic maculopathy in the German population occurred in 50% of highly myopic eyes. We presented population-based 5-year follow-up data on incidence and progression of myopic maculopathy in Europe.

Purpose To evaluate the risk of developing late age-related macular degeneration (AMD) following incident cataract surgery. Design A prospective cohort study within a randomized controlled clinical trial of oral supplementation for the treatment of AMD - the Age-Related Eye Disease Study 2 (AREDS2). Participants AREDS2 participants aged 50 to 85 years with either bilateral large drusen or unilateral late AMD. Methods In eyes that were free of cataract surgery and late AMD at baseline, two groups were compared for incident late AMD: 1) eyes that received cataract surgery after the baseline visit and before any evidence of late AMD and 2) eyes that remained phakic until the study completion. Eyes that had at least 2 years of follow-up after cataract surgery were included in the analysis. We used Cox regression models, matched-pairs analysis, and logistic regression models that were adjusted for baseline age, sex, smoking, education, study treatment group, and AMD severity. Main outcome measures Late AMD was defined as the presence of geographic atrophy or neovascular AMD detected on annual stereoscopic fundus photographs or as documented by medical records, including intravitreous injections of anti-vascular endothelial growth factor medication. Results A total of 1767 eligible eyes (1195 participants) received cataract surgery and 1981 eyes (1524 participants) developed late AMD during a mean (range) follow-up of 9 (1 - 12) years. The Cox regression model showed no increased risk of developing late AMD after cataract surgery: hazard ratios (Confidence Interval [CI]): 0.96 (0.8,1.13; p = 0.60) for the right eye and 1.05 (0.89,1.25; p = 0.56) for the left eye. Of the matched pairs, late AMD was identified in 412 eyes that received cataract surgery and in 433 phakic controls, resulting in an odds ratio (95% CI) of 0.92 (0.77,1.10; p = 0.34). The risk of late AMD after cataract surgery from the logistic regression model was not statistically significant (risk ratio [95%CI]: 0.92 [0.56,1.49], p = 0.73). Conclusions Cataract surgery did not increase the risk of developing late AMD among the AREDS2 participants with up to 10 years of follow-up. This study provides data for counselling AMD patients who might benefit from cataract surgery.

PURPOSE: To estimate and compare cross-sectional scotopic versus mesopic macular sensitivity losses measured by microperimetry, and to report and compare the longitudinal rates of scotopic and mesopic macular sensitivity losses in ABCA4 gene associated Stargardt Disease (STGD1). DESIGN: Multicenter prospective cohort study. METHODS: PARTICIPANTS: 127 molecular confirmed STGD1 patients enrolled from 6 centers in the USA and Europe and followed every 6 months for up to 2 years. OBSERVATION PROCEDURES: The Nidek MP-1S device was used to measure macular sensitivities of the central 20° under mesopic and scotopic conditions. The mean deviations (MD) from normal for mesopic macular sensitivity for the fovea (within 2° eccentricity) and extrafovea (4°−10° eccentricity), and the MD for scotopic sensitivity for the extrafovea were calculated. Linear mixed effects models were used to estimate mesopic and scotopic changes. MAIN OUTCOME MEASURES: Baseline mesopic mean deviation (mMD) and scotopic MD (sMD) and rates of longitudinal changes in the mMDs and sMD. RESULTS: At baseline, all eyes had larger sMD, and the difference between extrafoveal sMD and mMD was 10.7 dB (p

The prognosis of age-related macular degeneration (AMD) has improved significantly since the advent of antiangiogenic treatments. However, several «real life» studies have shown lower number of injections and a markedly worse visual prognosis than pivotal clinical trials.To assess the effectiveness and safety of the treatment of neovascular AMD and analyse clinical factors related to the functional and structural prognosis in routine clinical practice.Retrospective, observational, single-centre study that included 143 eyes of 122 patients diagnosed with neovascular AMD between the years 2015 and 2016, who received treatment with antiangiogenic drugs and were followed up for two or more years.Visual acuity improved in 45% of patients after two years of treatment. The mean decrease in central macular thickness was 85 μm (p 0.001) and the mean number of injections was 13. Retinal pigment epithelium rupture was present in 3.5%. Ranibizumab was the drug most used as a first option, although 79 patients (55.2%) required a change in treatment, most being switched to aflibercept. A greater number of visits (p 0.001) and a lower number of injections (p 0.01) were predictors of worse structural outcome. The number of visits was associated with better visual acuity (p 0.001).The treatment has demonstrated its efficacy by improving visual acuity and central macular thickness. However, the number of injections performed has generally been higher than in other real-life studies.

Objective To find the best cost-effective NVAMD treatment to improve vision while avoiding complications. The model is based on a cost-risk tradeoff analysis from policymakers’ perspective. Design A powerful and flexible simulation models outcomes of 2 years of treatment with the four commonly used anti-VEGF drugs (bevacizumab, ranibizumab, aflibercept, and brolucizumab) across three injection protocols, building on prior findings that these drugs are non-inferior. The model incorporates blinding complications, their management, and associated cost to society. Each option and several “what-if” scenarios were simulated 1,000 times with 100,000 hypothetical patients. Participants 100,000 simulated patients using data from published clinical trials. Method Case- and eye-specific cost-risk economic analysis. Main Outcome Measures Costs of NVAMD treatment per patient and number of eyes that become blind due to treatment over 2 years. Results Using published prices and fees, the injection protocol that follows published clinical studies, results showed that the mean (SD) cost per patient were $16,859 (3.65), $32,949 (3.27), $39,831 (3.80), and $53,056 (2.99) for bevacizumab, brolucizumab, aflibercept, and ranibizumab. The numbers of treated eyes that became blind were 108 (10.18), 694 (26.66), 168 (12.83), and 108 (10.52) respectively. We further provide a lower bound (when all patients are maximally extended) and upper bound (when no patient is extended) to these numbers. For brolucizumab the upper bound is the 2-month interval injection protocol. Conclusions Taking a policymaking perspective, this study suggests that bevacizumab is the preferred first-line therapy. Recommendation for second-line therapy depends on the extent of the policymaker’s risk-aversion because of the tradeoff between cost and risk of blindness due to treatment. If risk-neutral, the least expensive option (brolucizumab) is preferred. But if moderate to high, then aflibercept or ranibizumab are preferred. Since medical advances and different costs may change our findings, we provide a free application ( https://eye-inj.shinyapps.io/calc/ ) for readers who wish to use different cost structures. Simulating outcomes is an innovative approach, unique in ophthalmology, and presents significant opportunity as it can be easily adapted to different settings (using different costs, risks, and protocols), and to other diseases (e.g., DME), to ultimately improve wide-scale decision-making and use of funds.

Purpose To provide an update on the hemodynamic model of age-related macular degeneration (AMD). Design Evidence-based perspective. Methods Review of literature and experience of authors. Results Choroidal hemodynamics are not the primary cause of AMD as proposed by Ephraim Friedman in 1997. However, evidence is accumulating to suggest that choroidal perfusion is an important environmental influence that contributes to our understanding disease progression in this complex genetic disease. While early and intermediate AMD appear to be influenced to a large extent by the underlying genetics, the asymmetry of disease progression to the later stages of AMD cannot be explained by genetics alone. The progression of disease and the asymmetry of this progression appear to correlate with abnormalities in choroidal perfusion that can be documented by optical coherence tomography. These perfusion abnormalities in the setting of a thickened Bruch's membrane are thought to exacerbate the impaired nutritional exchange between the retinal pigment epithelium and the choriocapillaris. We propose that the genetic susceptibility to develop AMD combined with age-related changes in macular choroidal hemodynamics, such as increasing choriocapillaris perfusion deficits and decreasing choroidal vascular densities, play an important role in disease progression and may help explain the asymmetry between eyes, particularly in the later stages of AMD. Conclusions This updated hemodynamic model of AMD focuses on disease progression and highlights the importance of age-related changes in the choroidal circulation as a major environmental influence on disease severity in eyes that are genetically susceptible to develop AMD.

Purpose To evaluate the safety and tolerability of single and multiple intravitreal injections of NGM621 in patients with geographic atrophy (GA) and to characterize the pharmacokinetics and immunogenic potential. Design Multicenter, open-label, single- and multiple-dose phase 1 study. Methods Fifteen patients enrolled at 4 sites in the United States. Participants had GA secondary to age-related macular degeneration, lesion size ≥2.5 mm2 and best-corrected visual acuity of 4 to 54 letters (20/80 to 20/800 Snellen equivalent) in the study eye and no history of choroidal neovascularization in either eye. Patients who met eligibility criteria were treated in a single ascending-dose phase (2 mg, 7.5 mg, 15 mg) or received 2 doses NGM621 15 mg 4 weeks apart in the multidose phase and were followed for 12 weeks (85 days). Assessments included adverse events, best-corrected visual acuity, low luminance visual acuity, vital signs, clinical laboratory evaluations, GA lesion area as measured by fundus autofluorescence, spectral domain optical coherence tomography, and pharmacokinetic, immunogenicity, and pharmacodynamic assessments. Results All 15 participants completed the 12-week study. There were no serious adverse events and no drug-related adverse events, and no choroidal neovascularization developed in either eye. Mean visual acuity and GA lesion area appeared stable through week 12 for all cohorts. Pharmacokinetic analyses indicated that NGM621 serum exposures appeared to be dose proportional, and no antidrug antibodies were identified at any of the evaluated time points. Conclusions In this small, open-labelled, 12-week phase 1 study, NGM621 was safe and tolerable when administered intravitreally up to 15 mg.

PURPOSE To study the time course to macular atrophy (MA) and associated risk factors in eyes with acquired vitelliform lesions (AVLs) as they vary between patients and between eyes of an individual. DESIGN Single-center, retrospective, observational cohort study. PARTICIPANTS Consecutive patients registered between January 2009 and January 2014 with first diagnosis of AVL confirmed by multimodal imaging were included. Eyes with baseline MA or choroidal neovascularization were excluded. METHODS Patient demographics were collected. Serial OCT scans and fundus autofluorescence (FAF) scans were graded and analyzed. Turnbull's estimator was used, and time was censored at 5 years. Multivariable Weibull parametric proportional hazard models were used to assess the association of risk factors with MA after adjustment for age and gender. Hazard ratios (HRs) are reported with 95% confidence interval (CI). MAIN OUTCOME MEASURES Time to the first OCT evidence of MA stratified by presenting visual acuity (VA) and AVL lesion subtypes. Secondary outcome included risk factors for incident MA. RESULTS A total of 237 eyes (132 patients) met the inclusion criteria. Incident MA was detected in 52 of 237 eyes (21.9%) by 5 years. Stratified by baseline VA, 40.3% of eyes with VA ≤70 letters developed atrophy within 5 years of first diagnosis in contrast to 10.3% eyes with VA >70 letters (P < 0.001). Based on lesion type only, 12.9% of eyes with vitelliform lesion at baseline developed MA versus 39.8% and 44.2% of eyes with pseudohypopyon or vitelliruptive lesion type, respectively. In adjusted analysis, baseline factors associated with increased risk of MA included VA ≤70 letters (hazard ratio [HR], 5.54; 95% confidence interval [CI], 2.30-13.34), base width (HR, 1.22; 95% CI, 1.16-1.28), maximum height (HR, 2.61; 95% CI, 1.82-3.74), presence of subretinal drusenoid deposits (SDDs) (HR, 2.83; 95% CI, 1.34-5.96), and disrupted external limiting membrane (ELM) (HR, 2.81; 95% CI, 1.34-5.86). CONCLUSIONS Baseline VA of ≤70 letters (Snellen ≤20/40) and pseudohypopyon or vitelliruptive lesion type attribute the highest risk for MA. Other prognostic indicators for MA include baseline presence of SDD, disrupted ELM, and larger lesion area.

The aim of this study was to determine the short-term compliance with regular home monitoring of macular retinal sensitivity (RS) in intermediate age-related macular degeneration (iAMD). Home-based outcomes were compared with in-clinic outcomes determined using (1) the same tablet device under supervision, and (2) the Macular Integrity Assessment (MaIA) microperimeter.Single-center longitudinal compliance and reliability study.A total of 73 participants with iAMD were trained to perform macular field testing with the Melbourne Rapid Fields-macular (MRF-m) iPad application. Volunteers were asked to return 6 weekly tests from home, guided by audio instructions. We determined compliance with weekly testing and surveyed for factors that limited compliance. Test reliability (false positive, false negative) and RS were compared to in-clinic assays (MaIA). Data are given as mean ± SD or as median [quartile 1-3 range]. Group comparisons were achieved with bootstrap to define the 95% confidence limits.A total of 59 participants submitted 6 home examinations with a median intertest interval of 8.0 [7.0-17] days. Compliance with weekly testing (7 days ±24 hours) was 55%. The main barrier to compliance was information technology (IT) logistic reasons. Of 694 home examinations submitted, 96% were reliable (false-positive results25%). The mean RS returned by the tablet was significantly higher (+3.2 dB, P.05) compared to the MaIA.Home monitoring produces reliable results that differ from in-clinic tests because of test design. This should not affect self-monitoring once an at-home baseline is established, but these differences will affect comparisons with in-clinic outcomes. Reasonable compliance with weekly testing was achieved. Improved IT support might lead to better compliance.

Accumulation of lipofuscin in the retinal pigment epithelium (RPE) is a hallmark of aging and is associated with retinal degeneration encountered in age-related macular degeneration (AMD) and Stargardt disease (SD). Currently, treatment for lipofuscin-induced retinal degeneration is unavailable. Here, we report that Remofuscin (INN: soraprazan, a tetrahydropyridoether small molecule) reverses lipofuscin accumulation in aged primary human RPE cells and is non-cytotoxic in aged SD mouse RPE cells in vitro. In addition, we show that the removal of lipofuscin after a single intravitreal injection of Remofuscin results in a rescue from retinal degeneration in a mouse model of advanced SD which is even accompanied by an amelioration of the retinal dysfunction. Finally, we demonstrate that the mechanism causing lipofuscinolysis may involve the reactive oxygen species generated via the presence of Remofuscin. These data suggest a possible therapeutic approach to untreatable lipofuscin-mediated diseases like AMD, SD and lipofuscinopathies in neurodegenerative diseases.

N-acetylcysteine (NAC) was first discovered as a mucolytic agent in 1960. We investigate the role of topical NAC in ocular therapeutics, including its mechanism of action, current applications, and adverse effects. A systematic search of peer-reviewed articles identified 106 references including in vitro, in vivo and clinical studies on the use of NAC in the treatment of ocular diseases. NAC can be synthetically manufactured, and its mechanisms of action include mucolysis, scavenging hydroxyl radicals, and modulation of inflammatory cascades. These unique properties contribute to the diverse applications of NAC, including its steroid-sparing potential. NAC has been used topically in the treatment of corneal wounds, chemical injuries, keratitis, dry eye disease and meibomian gland dysfunction. The clinical benefits of NAC are evident over a wide range of concentrations, the most common being 5-10% topical NAC applied four times daily. Adverse effects such as corneal necrosis are rare, but have been reported with higher doses. NAC also has potential applications in laser epithelial keratomileusis, diabetic eye disease, retinitis pigmentosa, senile nuclear cataracts, macular degeneration, and cigarette smoke-induced corneal damage. Recently, chitosan-NAC has been used as a nanocarrier for the topical administration of medications to the ocular surface. Owing to its potent antioxidant, anti-inflammatory and mucolytic properties, topical NAC has had extensive use in the treatment of ocular pathology.

Purpose This analysis of the pivotal phase 3 HAWK and HARRIER trials aimed to provide insights on the timing of presentation, management, and outcomes of intraocular inflammation (IOI)-related adverse events (AEs), as reported by investigators in these trials. Design Post hoc analysis of investigator-reported IOI-related AEs in HAWK and HARRIER. Participants Of 1088 brolucizumab-treated eyes (3 or 6 mg), 49 eyes demonstrated at least 1 IOI-related AE and were included in this analysis. Methods Reports of IOI-related AEs were analyzed and descriptive statistics were provided for outcome measures. Main Outcome Measures Incidence and description of eyes with IOI-related AEs, timing of presentation, management, clinical outcomes, and brolucizumab treatment after the first IOI-related AE. Results Seventy IOI-related AEs were reported in 49 eyes. Before the onset of first IOI-related AE, eyes received a mean ± standard deviation (SD) of 3.9 ± 2.2 brolucizumab injections. Median time to first IOI-related AE from the last administered brolucizumab injection was 18.0 days (interquartile range, 4.0–29.0 days). Of the 70 AEs, 61 (87.1%) were treated, most with topical corticosteroids; systemic and intraocular corticosteroids were used for 3 AEs each. Overall, inflammation resolved completely in 39 eyes (79.6%), resolved with sequelae in 5 eyes (10.2%), and did not resolve in 5 eyes (10.2%) by end-of-study (EOS). Overall, the mean ± SD best-corrected visual acuity (BCVA) change from baseline to EOS, before AE to the lowest BCVA in 3 months after AE, and from before AE to EOS were −0.84 ± 20.6 , −16.31 ± 17.6, and −0.22 ± 18.9 Early Treatment Diabetic Retinopathy Study (ETDRS) letters, respectively. Of the 36 eyes (73.5%) that continued with brolucizumab therapy after the first IOI-related AE, 24 completed the trials and 12 discontinued; mean ± SD BCVA change in these eyes was 2.6 ± 17.6, 7.8 ± 13.2, and −7.7 ± 21.3 ETDRS letters, respectively, from baseline to EOS. The remaining 13 eyes (26.5%) were not treated with brolucizumab after first IOI-related AE and showed a mean ± SD BCVA change of −10.4 ± 25.5 ETDRS letters from baseline to EOS. Conclusions Findings of this analysis highlight the need for continued vigilance and monitoring for any signs of IOI-related events in patients receiving brolucizumab.

OBJECTIVE To evaluate whether pentosan polysulfate maculopathy manifests distinctive imaging features that can be differentiated from those found in age-related macular degeneration (AMD). METHODS Local databases were queried to identify patients with a diagnosis of interstitial cystitis who were seen at the Emory Eye Center between May 2014 and January 2019 and who had fundus imaging available for review. Ninety patients met the eligibility criteria. Masked graders categorized patients based on imaging characteristics as follows: category 1: pentosan polysulfate maculopathy; category 2: AMD or drusen; category 3: neither; and category 4: unsure. Pentosan polysulfate exposure characteristics were compared among groups. RESULTS Of the 90 subjects evaluated, 79 (88%) were female and the median age was 61.5 years (range, 30-89). Seventeen patients were placed in category 1; 25 in category 2; 47 in category 3, and; 1 in category 4. Among categories 1 to 4, respectively, 17 (100%), 15 (60%), 28 (60%), and 0 patients had exposure to pentosan polysulfate (p = 0.007). Mean cumulative exposure to pentosan polysulfate across the four categories was 2.1, 0.36, 0.34, and 0 kg, respectively (p < 0.00001). Eyes with pentosan polysulfate maculopathy did not have typical drusen in the macula. CONCLUSION Although pentosan polysulfate maculopathy resembles some aspects of AMD, the 2 conditions can be differentiated with the use of multimodal fundus imaging.

A common clinical phenotype of several neurodegenerative and systemic disorders including Alzheimer’s disease and atherosclerosis is the abnormal accumulation of extracellular material, which interferes with routine cellular functions. Similarly, patients with age-related macular degeneration (AMD), the leading cause of vision loss among the aged population, present with extracellular lipid- and protein-filled basal deposits in the back of the eye. While the exact mechanism of growth and formation of these deposits is poorly understood, much has been learned from investigating their composition, providing critical insights into AMD pathogenesis, prevention, and therapeutics. We identified human osteopontin (OPN), a phosphoprotein expressed in a variety of tissues in the body, as a newly discovered component of basal deposits in AMD patients, with a distinctive punctate staining pattern. OPN expression within these lesions, which are associated with AMD disease progression, were found to co-localize with abnormal calcium deposition. Additionally, OPN puncta colocalized with an AMD risk-associated complement pathway protein, but not with apolipoprotein E or vitronectin, two other well-established basal deposit components. Mechanistically, we found that retinal pigment epithelial cells, cells vulnerable in AMD, will secrete OPN into the extracellular space, under oxidative stress conditions, supporting OPN biosynthesis locally within the outer retina. Finally, we report that OPN levels in plasma of aged (non-AMD) human donors were significantly higher than levels in young (non-AMD) donors, but were not significantly different from donors with the different clinical subtypes of AMD. Collectively, our study defines the expression pattern of OPN in the posterior pole as a function of disease, and its local expression as a potential histopathologic biomarker of AMD.

Purpose To present select cases of paracentral acute middle maculopathy (PAMM) demonstrating progressive vascular occlusion and the ischemic cascade, and illustrate scenarios in which therapeutic intervention may be considered. Design Perspective. Methods Review and interpretation of selected literature, with perspective on the evaluation and management of patients with PAMM lesions. Multimodal imaging, including cross sectional and en face optical coherence tomography (OCT), of three illustrative cases of PAMM are presented, with progressive vascular occlusion and evidence of the ischemic cascade noted in two of the cases. Results All three cases showed evidence of PAMM at baseline, including perivenular PAMM in two of the cases. Progression from a mild central retinal vein occlusion (CRVO) to a more severe CRVO was noted in the first case, while the second case progressed from an incomplete to complete central retinal artery occlusion. In the third case, there was resolution of PAMM lesions associated with partial CRAO after the patient was started on aspirin. Conclusions Perivenular PAMM can be the only presenting sign of retinal vascular occlusion. In such cases it is important to differentiate between partial CRVO and incomplete CRAO as the underlying cause. This Perspective provides guidance on making this important distinction, which plays a critical role in directing the nature and urgency of the systemic work up. In patients with PAMM caused by partial retinal arterial occlusion, a benign empirical approach such as low-dose aspirin (81 mg) may be reasonable to reduce the likelihood of subsequent vision loss from progression to complete arterial occlusion. A clinical trial, however, is necessary to support such a strategy.

Purpose To evaluate early predictive factors of visual loss in patients treated with anti–vascular endothelial growth factor (VEGF) injections under an as-needed regimen for neovascular age-related macular degeneration (AMD). Design Post hoc analysis from the randomized controlled trial Groupe d’Evaluation Francais Avastin versus Lucentis (GEFAL). Participants A total of 393 patients with neovascular AMD. Methods The present analysis is based on 1-year data from patients included in the study. Patients were separately categorized according to the best-corrected visual acuity (BCVA) change at 3 months and 1 year into 3 trajectories: (1) patients with no vision loss ≥5 letters at 3 months and 1 year (absence of loss ≥5 letters); (2) patients with no vision loss ≥5 letters at 3 months but loss ≥5 letters at 1 year (secondary loss ≥5 letters); and (3) patients with vision loss ≥5 letters at 3 months and 1 year (initial loss ≥5 letters). Main Outcome Measures The following factors were evaluated at baseline and 3 months: age, sex, BCVA, presence of fluid, central macular thickness, angiographic choroidal neovascularization (CNV) subtype, CNV area measured in disc area on fluorescein angiography, and number of intravitreal injections. Results An absence of loss ≥5 letters was found in 225 patients (57.3%), a secondary loss ≥5 letters after 3 months was found in 109 patients (27.7%), and an initial loss ≥5 letters was found in 59 patients (15%). Baseline characteristics were comparable among the 3 groups except for the total CNV area, which was larger in the initial and secondary loss groups (P = 0.0412). At 3 months, a significant association was found between presence of subretinal fluid (SRF) (P = 0.0318) and vision loss ≥5 letters, and an even stronger significant association between the presence of intraretinal fluid (IRF) (P = 0.0066) and vision loss ≥5 letters. Conclusions In the present study, we found that a large CNV area at baseline was significantly associated with initial or secondary loss of visual acuity ≥5 letters despite anti-VEGF injection. The presence of fluid, both SRF and IRF, at 3 months was found in patients with poorer trajectories.

Faricimab is a bispecific antibody that acts through dual inhibition of both angiopoietin-2 and vascular endothelial growth factor A. We report primary results of two phase 3 trials evaluating intravitreal faricimab with extension up to every 16 weeks for neovascular age-related macular degeneration (nAMD).TENAYA and LUCERNE were randomised, double-masked, non-inferiority trials across 271 sites worldwide. Treatment-naive patients with nAMD aged 50 years or older were randomly assigned (1:1) to intravitreal faricimab 6·0 mg up to every 16 weeks, based on protocol-defined disease activity assessments at weeks 20 and 24, or aflibercept 2·0 mg every 8 weeks. Randomisation was performed through an interactive voice or web-based response system using a stratified permuted block randomisation method. Patients, investigators, those assessing outcomes, and the funder were masked to group assignments. The primary endpoint was mean change in best-corrected visual acuity (BCVA) from baseline averaged over weeks 40, 44, and 48 (prespecified non-inferiority margin of four letters), in the intention-to-treat population. Safety analyses included patients who received at least one dose of study treatment. These trials are registered with ClinicalTrials.gov (TENAYA NCT03823287 and LUCERNE NCT03823300).Across the two trials, 1329 patients were randomly assigned between Feb 19 and Nov 19, 2019 (TENAYA n=334 faricimab and n=337 aflibercept), and between March 11 and Nov 1, 2019 (LUCERNE n=331 faricimab and n=327 aflibercept). BCVA change from baseline with faricimab was non-inferior to aflibercept in both TENAYA (adjusted mean change 5·8 letters [95% CI 4·6 to 7·1] and 5·1 letters [3·9 to 6·4]; treatment difference 0·7 letters [-1·1 to 2·5]) and LUCERNE (6·6 letters [5·3 to 7·8] and 6·6 letters [5·3 to 7·8]; treatment difference 0·0 letters [-1·7 to 1·8]). Rates of ocular adverse events were comparable between faricimab and aflibercept (TENAYA n=121 [36·3%] vs n=128 [38·1%], and LUCERNE n=133 [40·2%] vs n=118 [36·2%]).Visual benefits with faricimab given at up to 16-week intervals demonstrates its potential to meaningfully extend the time between treatments with sustained efficacy, thereby reducing treatment burden in patients with nAMD.F Hoffmann-La Roche.