Publications by authors named "Glenn J Jaffe"

192 Publications

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Ophthalmology 2021 Feb 4. Epub 2021 Feb 4.

IVERIC bio, Inc, New York, New York. Electronic address:

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http://dx.doi.org/10.1016/j.ophtha.2020.12.031DOI Listing
February 2021

Complement-mediated release of fibroblast growth factor 2 from human RPE cells.

Exp Eye Res 2021 Jan 28;204:108471. Epub 2021 Jan 28.

Department of Ophthalmology, Duke University Medical Center, Durham, NC, 27710, USA. Electronic address:

Purpose: Complement activation is associated with choroidal neovascularization (CNV) in age-related macular degeneration (AMD). Fibroblast growth factor 2 (FGF2) and membrane attack complex (MAC) are present in eyes of patients with CNV. Herein, we investigated the effect of complement activation on FGF2 release in human retinal pigment epithelial (RPE) cells.

Methods: Cultured human RPE cells were primed with an anti-RPE antibody and then treated with C1q-depleted human serum in the presence or absence of Tec kinases inhibitor (LFM-A13). 38 cytokines/chemokines levels were measured by Luminex technology. Secretion of FGF2 and interleukin (IL)-6 was assessed by ELISA. Tec protein was measured by Western blot. mRNA expression of FGF2, chemokine (C-X-C motif) ligand 1 (CXCL-1), and family members of Tec kinases was evaluated by qPCR. Cell viability and MAC deposition were determined by WST-1 assay and flow cytometry, respectively.

Results: Complement activation caused increased FGF2 and IL-6 release. FGF2 was released when C6-depleted human serum was reconstituted with C6. Anti-C5 antibody significantly attenuated complement-mediated FGF2 release, but not IL-6. FGF2 mRNA levels were not affected, while CXCL-1 mRNA levels were increased by complement activation. FGF2-containing extracellular vesicles were detected in response to complement challenge. Tec mRNA and protein were expressed in RPE cells. In the presence of LFM-A13, secretion of FGF2, but not IL-6, and MAC deposition were significantly decreased and cell viability was significantly increased in complement-treated cells when compared to controls.

Conclusions: Complement plays an important role to release FGF2 from RPE cells. Tec kinase is involved in MAC formation and complement-mediated FGF2 release. This information suggests a role for complement activation to mediate neovascularization in conditions such as AMD, and may elucidate potential therapeutic targets.
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http://dx.doi.org/10.1016/j.exer.2021.108471DOI Listing
January 2021

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Retina 2021 Mar;41(3):e39

Department of Ophthalmology, Duke University, Durham, North Carolina.

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http://dx.doi.org/10.1097/IAE.0000000000003121DOI Listing
March 2021

COMPARISON OF SINGLE DRUSEN SIZE ON COLOR FUNDUS PHOTOGRAPHY AND SPECTRAL-DOMAIN OPTICAL COHERENCE TOMOGRAPHY.

Retina 2021 Jan 2. Epub 2021 Jan 2.

Department of Ophthalmology, Chungbuk National University Hospital, College of Medicine, Chungbuk National University, Cheongju, Korea Department of Ophthalmology, Duke University, Durham, North Carolina, United States. Department of Biomedical Engineering, Duke University, Durham, North Carolina, United States.

Purpose: To determine the relationship of drusen size as determined by spectral domain optical coherence tomography (SD-OCT), with that measured on registered Color fundus photography (CFP) images, to derive an OCT-based classification system that was comparable to that determined by CFP.

Methods: Custom software was developed to register CFP images to the scanning laser ophthalmoscopy fundus images obtained simultaneously with the corresponding SD-OCT images, so that individual drusen observed on CFP could be matched with those seen on SD-OCT. Single druse size (diameter, area, volume, height) on CFP and SD-OCT images from a phase 2 clinical trial was determined with the Duke OCT Retinal Analysis Program.

Results: The sizes of 213 individual drusen were measured on CFP and SD-OCT. The drusen diameter measured on CFP was significantly correlated with those determined on SD-OCT(R:0.879,p<0.001). Based on the corresponding formula:drusen diameter on SD-OCT=0.77*(drusen diameter on CFP)+50.67µm, large drusen defined as ≥125µm on CFP had a diameter ≥145µm on OCT, medium drusen defined as 63-124µm on CFP had diameters 100-144µm on OCT, and small drusen defined as <63µm on CFP had diameters <100µm on OCT.

Conclusion: With our registration software and imaging processing algorithms, we were able to correlate individual druse sizes measured on CFP with those determined on SD-OCT. These data can be used to develop an SD-OCT-based grading scale, analogous to the CFP AREDS drusen scale, that may be useful in the clinic and in clinical trials.
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http://dx.doi.org/10.1097/IAE.0000000000003099DOI Listing
January 2021

Imaging Features Associated with Progression to Geographic Atrophy in Age-Related Macular Degeneration: CAM Report 5.

Ophthalmol Retina 2020 Dec 18. Epub 2020 Dec 18.

Department of Ophthalmology and Visual Sciences, School of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA.

Purpose: To provide an image-based description of retinal features associated with risk for development of geographic atrophy (GA) in eyes with age-related macular degeneration (AMD), as visualized with multimodal imaging anchored by structural optical coherence tomography.

Design: Consensus meeting METHODS: As part of the Classification of Atrophy Meeting program, an international group of experts analyzed and discussed retinal multimodal imaging features in eyes with AMD associated with GA and/or risk of progression to GA. Attendees undertook pre-meeting grading exercises that were reviewed during the meeting sessions. Meeting presentations illustrated established and investigational multimodal imaging features and associated histology. These different features were then each discussed openly by the entire group to arrive at consensus definitions. These definitions were applied to 40 additional images that were graded independently by attendees, to further refine the consensus definitions and descriptions.

Results: Consensus was reached on images with descriptors for 12 features. These features included components of outer retinal atrophy (e.g., ellipsoid zone disruption), components of complete retinal pigment epithelium (RPE) and outer retinal atrophy (e.g., RPE perturbation with associated hypo- or hyper-transmission), features frequently seen in eyes with atrophy (e.g., refractile drusen) and features conferring risk for atrophy development (e.g., hyperreflective foci, drusen, and subretinal drusenoid deposits).

Conclusions: An International consensus on terms and descriptions was reached on multimodal imaging features associated GA and with risk for GA progression in eyes with AMD. We believe this information will be useful to clinicians who manage patients with AMD, researchers who study AMD disease interventions and pathogenesis, and those who design clinical trials for therapies targeting earlier AMD stages than GA expansion.
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http://dx.doi.org/10.1016/j.oret.2020.12.009DOI Listing
December 2020

Deep learning-based classification and segmentation of retinal cavitations on optical coherence tomography images of macular telangiectasia type 2.

Br J Ophthalmol 2020 Nov 23. Epub 2020 Nov 23.

Biomedical Engineering, Duke University, Durham, North Carolina, USA.

Aim: To develop a fully automatic algorithm to segment retinal cavitations on optical coherence tomography (OCT) images of macular telangiectasia type 2 (MacTel2).

Methods: The dataset consisted of 99 eyes from 67 participants enrolled in an international, multicentre, phase 2 MacTel2 clinical trial (NCT01949324). Each eye was imaged with spectral-domain OCT at three time points over 2 years. Retinal cavitations were manually segmented by a trained Reader and the retinal cavitation volume was calculated. Two convolutional neural networks (CNNs) were developed that operated in sequential stages. In the first stage, CNN1 classified whether a B-scan contained any retinal cavitations. In the second stage, CNN2 segmented the retinal cavitations in a B-scan. We evaluated the performance of the proposed method against alternative methods using several performance metrics and manual segmentations as the gold standard.

Results: The proposed method was computationally efficient and accurately classified and segmented retinal cavitations on OCT images, with a sensitivity of 0.94, specificity of 0.80 and average Dice similarity coefficient of 0.94±0.07 across all time points. The proposed method produced measurements that were highly correlated with the manual measurements of retinal cavitation volume and change in retinal cavitation volume over time.

Conclusion: The proposed method will be useful to help clinicians quantify retinal cavitations, assess changes over time and further investigate the clinical significance of these early structural changes observed in MacTel2.
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http://dx.doi.org/10.1136/bjophthalmol-2020-317131DOI Listing
November 2020

Localized Optical Coherence Tomography Precursors of Macular Atrophy and Fibrotic Scar in the Comparison of Age-Related Macular Degeneration Treatments Trials.

Am J Ophthalmol 2020 Nov 19;223:338-347. Epub 2020 Nov 19.

Department of Ophthalmology, Duke University, Durham, North Carolina, USA; Department of Biomedical Engineering, Duke University, Durham, North Carolina, USA. Electronic address:

Purpose: To identify precursors of macular atrophy (MA) and of fibrotic scar (FS) in eyes treated with anti-vascular endothelial growth factor through pixel-mapping analysis of baseline optical coherence tomography (OCT).

Methods: Design: Cross-sectional analysis.

Setting: Multicenter clinical trial.

Patient Population: 68 eyes from the Comparison of Age-Related Macular Degeneration Treatments Trials.

Intervention: Treatment with anti-vascular endothelial growth factor agents.

Main Outcome Measure: The percentage of MA or FS pixels with each OCT feature at baseline, and the odds ratio for baseline pixels with an OCT feature to develop MA or FS.

Results: Retinal pigment epithelium atrophy and photoreceptor loss on OCT were highly predictive of MA at that location at years 2 and 5 (P < .0001), but accounted for only 22.5% of the ensuing atrophy at year 2 and less at year 5. Among pixels of MA at year 2, 78% were preceded by thick drusen, 54% by subretinal macular neovascularization (MNV), and 22.5% by no detectable OCT features. MNV, subretinal hyperreflective material, pigment epithelial detachment, intraretinal fluid, and sub-retinal pigment epithelium fluid were predictive of FS at that location (P values <.05). More than 75% of the pixels of FS at years 2 and 5 were preceded by pixels of baseline MNV.

Conclusions: Most pixels of FS were preceded by components of neovascularization. Although one-quarter of MA was accounted for by pre-existing evidence of atrophy on OCT alone, the development of MA in areas of thick drusen, areas with and without subretinal MNV lesion, and areas without detectable OCT precursors argues that the development of MA is multifactorial and may follow, in part, a non-neovascular pathway.
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http://dx.doi.org/10.1016/j.ajo.2020.11.002DOI Listing
November 2020

Development, Validation, and Innovation in Ophthalmic Laser-Based Imaging: Report From a US Food and Drug Administration-Cosponsored Forum.

JAMA Ophthalmol 2021 Jan;139(1):113-118

Cornea Society, Fairfax, Virginia.

In April 2019, the US Food and Drug Administration, in conjunction with 11 professional ophthalmic, vision science, and optometric societies, convened a forum on laser-based imaging. The forum brought together the Food and Drug Administration, clinicians, researchers, industry members, and other stakeholders to stimulate innovation and ensure that patients in the US are the first in the world to have access to high-quality, safe, and effective medical devices. This conference focused on the technology, clinical applications, regulatory issues, and reimbursement issues surrounding innovative ocular imaging modalities. Furthermore, the emerging role of artificial intelligence in ophthalmic imaging was reviewed. This article summarizes the presentations, discussion, and future directions.
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http://dx.doi.org/10.1001/jamaophthalmol.2020.4994DOI Listing
January 2021

Risk of Inflammation, Retinal Vasculitis, and Retinal Occlusion-Related Events with Brolucizumab: Post Hoc Review of HAWK and HARRIER.

Ophthalmology 2020 Nov 15. Epub 2020 Nov 15.

Ophthalmic Consultants of Boston, Boston, Massachusetts. Electronic address:

Purpose: An independent Safety Review Committee (SRC), supported by Novartis Pharma AG, analyzed investigator-reported cases of intraocular inflammation (IOI), endophthalmitis, and retinal arterial occlusion in the phase 3 HAWK and HARRIER trials of brolucizumab versus aflibercept in neovascular age-related macular degeneration (nAMD).

Design: A post hoc analysis of a subset of data from two 2-year, double-masked, multicenter, active-controlled randomized phase 3 trials (NCT02307682, NCT02434328).

Participants: Patients (N = 1817) with untreated, active choroidal neovascularization due to age-related macular degeneration in the study eye were randomized and treated in HAWK/HARRIER. The SRC reviewed data from cases of investigator-reported IOI (60/1088 brolucizumab-treated eyes; 8/729 aflibercept-treated eyes).

Methods: The SRC received details and images (color fundus photography, fluorescein angiography, and OCT) for all investigator-determined cases of IOI, retinal arterial occlusion, and endophthalmitis. Cases were reviewed in detail by ≥2 readers, then adjudicated by the SRC as a group.

Main Outcome Measures: Within this patient subset: incidence of IOI, signs and incidence of retinal vasculitis and/or retinal vascular occlusion, and visual acuity loss; time since first brolucizumab injection to IOI event onset; and frequency of visual acuity loss after brolucizumab injection by time of first IOI event onset.

Results: Fifty brolucizumab-treated eyes were considered to have definite/probable drug-related events within the spectrum of IOI, retinal vasculitis, and/or vascular occlusion. On the basis of these cases, incidence of definite/probable IOI was 4.6% (IOI + vasculitis, 3.3%; IOI + vasculitis + occlusion, 2.1%). There were 8 cases (incidence 0.74%) of at least moderate visual acuity loss (≥15 ETDRS letters) in eyes with IOI (7 in eyes with IOI + vasculitis + occlusion). Of the 8 cases, 5 experienced their first IOI-related event within 3 months of the first brolucizumab injection (increasing to 7/8 within 6 months). Incidence of IOI in aflibercept-treated eyes was 1.1%, with at least moderate visual acuity loss in 0.14%.

Conclusions: This analysis of IOI cases after brolucizumab injection identified signs of retinal vasculitis with or without retinal vascular occlusion and an associated risk of visual acuity loss. The findings will help physicians to evaluate the risks and benefits of brolucizumab treatment for nAMD.
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http://dx.doi.org/10.1016/j.ophtha.2020.11.011DOI Listing
November 2020

Long-Term Safety and Efficacy of Adalimumab in Patients with Noninfectious Intermediate Uveitis, Posterior Uveitis, or Panuveitis.

Ophthalmology 2020 Nov 3. Epub 2020 Nov 3.

Departments of Ophthalmology and Medicine, Oregon Health & Science University and Legacy Devers Eye Institute, Portland, Oregon.

Purpose: To evaluate long-term efficacy and safety of extended treatment with adalimumab in patients with noninfectious intermediate, posterior, or panuveitis.

Design: Open-label, multicenter, phase 3 extension study (VISUAL III).

Participants: Adults who had completed a randomized, placebo-controlled phase 3 parent trial (VISUAL I or II) without treatment failure (inactive uveitis) or who discontinued the study after meeting treatment failure criteria (active uveitis).

Methods: Patients received subcutaneous adalimumab 40 mg every other week. Data were collected for ≤ 362 weeks. Adverse events (AEs) were recorded until 70 days after the last dose.

Main Outcome Measures: Long-term safety and quiescence; other efficacy variables included inflammatory lesions, anterior chamber cell and vitreous haze grade, macular edema, visual acuity, and dose of uveitis-related systemic corticosteroids.

Results: At study entry, 67% of patients (283/424) showed active uveitis and 33% (141/424) showed inactive uveitis; 60 patients subsequently met exclusion criteria, and 364 were included in the intention-to-treat analysis. Efficacy variables were analyzed through week 150, when approximately 50% of patients (214/424) remained in the study. Patients showing quiescence increased from 34% (122/364) at week 0 to 85% (153/180) at week 150. Corticosteroid-free quiescence was achieved by 54% (66/123) and 89% (51/57) of patients with active or inactive uveitis at study entry. Mean daily dose of systemic corticosteroids was reduced from 9.4 ± 17.1 mg/day at week 0 (n = 359) to 1.5 ± 3.9 mg/day at week 150 (n = 181). The percentage of patients who achieved other efficacy variables increased over time for those with active uveitis at study entry and was maintained for those with inactive uveitis. The most frequently reported treatment-emergent AEs of special interest were infections (n = 275; 79 events/100 patient-years [PY]); AEs and serious AEs occurred at a rate of 396 events/100 PY and 15 events/100 PY, respectively.

Conclusions: Long-term treatment with adalimumab led to quiescence and reduced corticosteroid use for patients who entered VISUAL III with active uveitis and led to maintenance of quiescence for those with inactive uveitis. AEs were comparable with those reported in the parent trials and consistent with the known safety profile of adalimumab.
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http://dx.doi.org/10.1016/j.ophtha.2020.10.036DOI Listing
November 2020

Seven-Year Outcomes of Uveitic Macular Edema: The Multicenter Uveitis Steroid Treatment Trial and Follow-up Study Results.

Ophthalmology 2020 Sep 10. Epub 2020 Sep 10.

Center for Clinical Trials and Evidence Synthesis, Department of Epidemiology, The Johns Hopkins University Bloomberg School of Public Health, Baltimore, Maryland; Department of Ophthalmology, the Wilmer Eye Institute, the Johns Hopkins University School of Medicine, Baltimore, Maryland. Electronic address:

Purpose: To evaluate the long-term outcomes of uveitic macular edema (ME).

Design: Longitudinal follow-up of a cohort of participants in a randomized clinical trial.

Participants: A total of 248 eyes of 177 participants with uveitic ME enrolled in the Multicenter Uveitis Steroid Treatment (MUST) Trial and Follow-up Study.

Methods: OCT measurements, taken at baseline and annually, were graded by reading center graders masked to clinical data. Macular edema was defined as a center macular thickness (CMT) ≥240 μm on time-domain OCT or time-domain OCT equivalent. Resolution of ME was defined as normalization of macular thickness on OCT. Relapse of ME was defined as increase in macular thickness to ≥240 μm in an eye that previously had resolution. Visual acuity was measured at each visit with logarithmic visual acuity charts.

Main Outcome Measures: Resolution and relapse of ME. Visual acuity.

Results: Among 227 eyes with ME followed ≥1 year, the cumulative percent of eyes with ME resolving at any point during 7 years was 94% (95% confidence interval [CI], 89-97). Epiretinal membranes on OCT were associated with a lower likelihood of ME resolution (hazard ratio [HR], 0.74; 95% CI, 0.55-1.01; P = 0.05). Among 177 eyes with resolved ME, the cumulative percent with relapse within 7 years was 43% (95% CI, 32-51). Eyes in which ME resolved gained a mean of 6.24 letters (95% CI, 4.40-8.09; P < 0.001) compared with eyes that remained free from ME during the 1-year follow-up intervals, whereas eyes in which ME did not resolve experienced no gain in vision (mean change -1.30 letters; 95% CI, -2.70 to 0.09; P = 0.065), and eyes that developed ME during the year (incident or relapsed) experienced a mean loss of -8.65 letters (95% CI, -11.5 to -5.84, P < 0.001).

Conclusions: Given sufficient time and treatment, nearly all uveitic ME resolves, but episodes of relapse were common. Visual acuity results were better among eyes with resolved ME, suggesting that control of inflammation and resolution of ME might be visually relevant treatment targets.
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http://dx.doi.org/10.1016/j.ophtha.2020.08.035DOI Listing
September 2020

C5 Inhibitor Avacincaptad Pegol for Geographic Atrophy Due to Age-Related Macular Degeneration: A Randomized Pivotal Phase 2/3 Trial.

Ophthalmology 2020 Sep 1. Epub 2020 Sep 1.

IVERIC bio, Inc., New York, New York. Electronic address:

Purpose: The complement pathway may play a key role in the pathogenesis of age-related macular degeneration (AMD). The safety and efficacy of avacincaptad pegol (Zimura, IVERIC bio Inc, New York, NY), a C5 inhibitor, were assessed in participants with geographic atrophy (GA) secondary to AMD (GATHER1 Study).

Design: International, prospective, randomized, double-masked, sham-controlled, pivotal phase 2/3 clinical trial.

Participants: A total of 286 participants with GA secondary to AMD.

Main Outcome Measures: The primary efficacy endpoint was the mean rate of change in GA over 12 months measured by fundus autofluorescence (FAF) at 3 timepoints: baseline, month 6, and month 12.

Results: The reduction in the mean rate of GA growth (square root transformation) over 12 months was 27.4% (P = 0.0072) for the avacincaptad pegol 2 mg cohort and 27.8% (P = 0.0051) for the avacincaptad pegol 4 mg cohort compared with their corresponding sham cohorts. The results for both dose groups were statistically significant. Avacincaptad pegol was generally well tolerated after monthly administration over 12 months. There were no avacincaptad pegol-related adverse events (AEs) or inflammation. Further, there were no ocular serious AEs (SAEs) and no cases of endophthalmitis. The most frequent ocular AEs were related to the injection procedure.

Conclusions: Intravitreal administration of avacincaptad pegol 2 mg and 4 mg led to a significant reduction of GA growth in eyes with AMD over a 12-month period. Because C5 inhibition theoretically preserves C3 activity, it may offer additional safety advantages. A second confirmatory pivotal clinical trial is underway to confirm the efficacy and safety of avacincaptad pegol in slowing the GA growth (GATHER2 Study).
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http://dx.doi.org/10.1016/j.ophtha.2020.08.027DOI Listing
September 2020

Risuteganib Protects against Hydroquinone-induced Injury in Human RPE Cells.

Invest Ophthalmol Vis Sci 2020 08;61(10):35

Department of Ophthalmology, Duke University Eye Center, Durham, North Carolina, United States.

Purpose: Cigarette smoking has been implicated in the pathogenesis of AMD. Integrin dysfunctions have been associated with AMD. Herein, we investigate the effect of risuteganib (RSG), an integrin regulator, on RPE cell injury induced by hydroquinone (HQ), an important oxidant in cigarette smoke.

Methods: Cultured human RPE cells were treated with HQ in the presence or absence of RSG. Cell death, mitochondrial respiration, reactive oxygen species production, and mitochondrial membrane potential were measured by flow cytometry, XFe24 analyzer, and fluorescence plate reader, respectively. Whole transcriptome analysis and gene expression were analyzed by Illumina RNA sequencing and quantitative PCR, respectively. F-actin aggregation was visualized with phalloidin. Levels of heme oxygenase-1, P38, and heat shock protein 27 proteins were measured by Western blot.

Results: HQ induced necrosis and apoptosis, decreased mitochondrial bioenergetics, increased reactive oxygen species levels, decreased mitochondrial membrane potential, increased F-actin aggregates, and induced phosphorylation of P38 and heat shock protein 27. HQ, but not RSG alone, induced substantial transcriptome changes that were regulated by RSG cotreatment. RSG cotreatment significantly protected against HQ-induced necrosis and apoptosis, prevented HQ-reduced mitochondrial bioenergetics, decreased HQ-induced reactive oxygen species production, improved HQ-disrupted mitochondrial membrane potential, reduced F-actin aggregates, decreased phosphorylation of P38 and heat shock protein 27, and further upregulated HQ-induced heme oxygenase-1 protein levels.

Conclusions: RSG has no detectable adverse effects on healthy RPE cells, whereas RSG cotreatment protects against HQ-induced injury, mitochondrial dysfunction, and actin reorganization, suggesting a potential role for RSG therapy to treat retinal diseases such as AMD.
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http://dx.doi.org/10.1167/iovs.61.10.35DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7443126PMC
August 2020

Effect of a Fluocinolone Acetonide Insert on Recurrence Rates in Noninfectious Intermediate, Posterior, or Panuveitis: Three-Year Results.

Ophthalmology 2020 10 17;127(10):1395-1404. Epub 2020 Apr 17.

Moorfields Eye Hospital, London, United Kingdom.

Purpose: To examine the 36-month efficacy and safety of a 0.2 μg/day fluocinolone acetonide insert (FAi) to treat noninfectious uveitis of the posterior segment (NIU-PS).

Design: Phase 3, prospective, double-masked, multicenter study (clinicaltrials.gov, NCT01694186).

Participants: Adults (≥18 years old) with a diagnosis of NIU-PS in ≥1 eye for ≥1 year and ≥2 recurrences of uveitis requiring systemic corticosteroid, immunosuppressive treatment, or intraocular corticosteroids.

Methods: Participants were randomized 2:1 to FAi or sham (injection plus standard of care) treatment.

Main Outcome Measures: The primary outcome was the difference between the proportion of FAi-treated and sham-treated patients who had a uveitis recurrence. Secondary outcomes included time to first recurrence, number of recurrences, best-corrected visual acuity (BCVA) change from baseline, resolution of macular edema, and number of adjunctive treatments.

Results: One hundred twenty-nine participants (n = 87 FAi-treated; n = 42 sham-treated) were enrolled. Over 36 months of treatment, cumulative uveitis recurrences were significantly reduced with FAi compared with sham (65.5% vs. 97.6%, respectively; P < 0.001); time to first recurrence was commensurately longer (median 657.0 and 70.5 days, respectively; P < 0.001). The number of recurrences per eye was significantly lower in the FAi-treated compared with the sham-treated group (mean 1.7 vs. 5.3, respectively, P < 0.001). At 36 months, more FAi-treated eyes had a ≥15-letter increase in BCVA from baseline and fewer FAi-treated eyes had investigator-determined macular edema at month 36 compared with sham-treated eyes (33.3% vs. 14.7% and 13.0% vs. 27.3% for BCVA and macular edema, respectively). Fewer FAi compared with sham-treated participants required adjunctive treatments (57.5% vs. 97.6%, respectively). Intraocular pressure (IOP) was similar for both study groups at month 36 (mean ± standard deviation 14.5±5.1 and 14.8±5.3, respectively), and approximately half as many eyes in the FAi-treated group when compared with the sham-treated group underwent IOP-lowering surgery (5.7% vs. 11.9%). Cataract surgery was required more frequently over 36 months in the FAi-treated compared with the sham-treated group (73.8% vs. 23.8% of eyes, respectively).

Conclusions: Fluocinolone acetonide insert-treated eyes had significantly reduced uveitis recurrence rates throughout the study duration, significantly increased recurrence-free durations, fewer recurrence episodes among those with recurrences, less adjunctive therapy, and an acceptable side-effect profile compared with sham-treated eyes.
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http://dx.doi.org/10.1016/j.ophtha.2020.04.001DOI Listing
October 2020

HAWK and HARRIER: Ninety-Six-Week Outcomes from the Phase 3 Trials of Brolucizumab for Neovascular Age-Related Macular Degeneration.

Ophthalmology 2021 Jan 20;128(1):89-99. Epub 2020 Jun 20.

University of Bonn, Bonn, Germany.

Purpose: To report the 96-week outcomes from HAWK and HARRIER.

Design: Phase 3, prospective, randomized, double-masked, multicenter studies comparing efficacy and safety of brolucizumab 3 mg (HAWK only) and 6 mg with aflibercept 2 mg in eyes with neovascular age-related macular degeneration (nAMD).

Participants: Treatment-naïve eyes with nAMD were randomized 1:1:1 to brolucizumab 3 mg (n = 358), brolucizumab 6 mg (n = 360), aflibercept 2 mg (n = 360; HAWK) or 1:1 to brolucizumab 6 mg (n = 370), aflibercept 2 mg (n = 369; HARRIER).

Methods: After 3 monthly loading doses, brolucizumab patients received every (q)-12-week (w) dosing, possibly adjusting to q8w dosing if disease activity was present at predefined disease activity assessment (DAA) visits. Aflibercept was dosed in a fixed q8w regimen. Visual and anatomic parameters were assessed throughout. Primary end point was at week 48 (48w), confirmed at 96w.

Main Outcome Measures: Mean best-corrected visual acuity (BCVA) change from baseline, proportion of patients on an q12w regimen, retinal thickness, retinal fluid changes, and safety, all to 96w.

Results: Mean change (least squares [LS] mean ± standard error) in BCVA from baseline to 96w in HAWK was 5.6±0.79 Early Treatment Diabetic Retinopathy Study (ETDRS) letters for brolucizumab 3 mg, 5.90±0.78 letters for brolucizumab 6 mg, and 5.3±0.78 letters for aflibercept and in HARRIER was 6.1±0.73 letters for brolucizumab 6 mg and 6.6 ± 0.73 letters for aflibercept. Greater central subfield thickness reductions were observed with brolucizumab 6 mg versus aflibercept in HAWK (LS mean, -174.8 μm vs. -148.7 μm; 95% confidence interval for treatment difference, -46.2 to -5.9 μm; P = 0.0115) and HARRIER (LS mean, -197.7 μm vs. -155.1 μm; 95% confidence interval for treatment difference, -62.0 to -23.3 μm; P < 0.0001). The proportions of eyes with intraretinal fluid and/or subretinal fluid (IRF/SRF) at 96w in HAWK were 31% (P = 0.0688) and 24% (P = 0.0002) for brolucizumab 3 mg and 6 mg and 37% for aflibercept, whereas in HARRIER, they were 24% for brolucizumab 6 mg (P < 0.0001) and 39% for aflibercept. At 92w (last DAA), a 45.4% and 38.6% probability was observed for brolucizumab 6 mg patients of maintaining an q12w treatment regimen in HAWK and HARRIER, respectively. Brolucizumab exhibited an overall well-tolerated safety profile.

Conclusions: Visual outcomes from 48w to 96w confirm the efficacy achieved at 48w. Brolucizumab demonstrated greater fluid resolution compared with aflibercept. The q12w potential for brolucizumab observed at 48w was maintained to 96w.
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http://dx.doi.org/10.1016/j.ophtha.2020.06.028DOI Listing
January 2021

Baseline Visual Field Findings in the RUSH2A Study: Associated Factors and Correlation With Other Measures of Disease Severity.

Am J Ophthalmol 2020 11 22;219:87-100. Epub 2020 May 22.

Institut de la Vision, Sorbonne Université, INSERM, CNRS, Paris, France; Centre Hospitalier National d'Ophtalmologie des Quinze-Vingts, INSERM-DGOS CIC1423, Paris, France; Department of Ophthalmology, The University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.

Purpose: To report baseline visual fields in the Rate of Progression in USH2A-related Retinal Degeneration (RUSH2A) study.

Design: Cross-sectional study within a natural history study.

Methods: Setting: multicenter, international.

Study Population: Usher syndrome type 2 (USH2) (n = 80) or autosomal recessive nonsyndromic retinitis pigmentosa (ARRP) (n = 47) associated with biallelic disease-causing sequence variants in USH2A.

Observation Procedures: Repeatability of full-field static perimetry (SP) and between-eye symmetry of kinetic perimetry (KP) were evaluated with intraclass correlation coefficients (ICCs). The association of demographic and clinical characteristics with total hill of vision (V) was assessed with general linear models. Associations between V and other functional and morphologic measures were assessed using Spearman correlation coefficients and t tests.

Main Outcome Measures: V (SP) and III4e isopter area (KP).

Results: USH2 participants had more severe visual field loss than ARRP participants (P < .001, adjusting for disease duration, age of enrollment). Mean V measures among 3 repeat tests were 32.7 ± 24.1, 31.2 ± 23.4, and 31.7 ± 23.9 decibel-steradians (intraclass correlation coefficient [ICC] = 0.96). Better VA, greater photopic ERG 30-Hz flicker amplitudes, higher mean microperimetry sensitivity, higher central subfield thickness, absence of macular cysts, and higher III4e seeing area were associated with higher V (all r > .48; P < .05). Mean III4e isopter areas for left (4561 ± 4426 squared degrees) and right eyes (4215 ± 4300 squared degrees) were concordant (ICC = 0.94).

Conclusions: USH2 participants had more visual field loss than participants with USH2A-related ARRP, adjusting for duration of disease and age of enrollment. V was repeatable and correlated with other functional and structural metrics, suggesting it may be a good summary measure of disease severity in patients with USH2A-related retinal degeneration.
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http://dx.doi.org/10.1016/j.ajo.2020.05.024DOI Listing
November 2020

Resveratrol Protects Against Hydroquinone-Induced Oxidative Threat in Retinal Pigment Epithelial Cells.

Invest Ophthalmol Vis Sci 2020 04;61(4):32

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Purpose: Oxidative stress in retinal pigment epithelial (RPE) cells is associated with age-related macular degeneration (AMD). Resveratrol exerts a range of protective biologic effects, but its mechanism(s) are not well understood. The aim of this study was to investigate how resveratrol could affect biologic pathways in oxidatively stressed RPE cells.

Methods: Cultured human RPE cells were treated with hydroquinone (HQ) in the presence or absence of resveratrol. Cell viability was determined with WST-1 reagent and trypan blue exclusion. Mitochondrial function was measured with the XFe24 Extracellular Flux Analyzer. Expression of heme oxygenase-1 (HO-1) and glutamate cysteine ligase catalytic subunit was evaluated by qPCR. Endoplasmic reticulum stress protein expression was measured by Western blot. Potential reactions between HQ and resveratrol were investigated using high-performance liquid chromatography mass spectrometry with resveratrol and additional oxidants for comparison.

Results: RPE cells treated with the combination of resveratrol and HQ had significantly increased cell viability and improved mitochondrial function when compared with HQ-treated cells alone. Resveratrol in combination with HQ significantly upregulated HO-1 mRNA expression above that of HQ-treated cells alone. Resveratrol in combination with HQ upregulated C/EBP homologous protein and spliced X-box binding protein 1. Additionally, new compounds were formed from resveratrol and HQ coincubation.

Conclusions: Resveratrol can ameliorate HQ-induced toxicity in RPE cells through improved mitochondrial bioenergetics, upregulated antioxidant genes, stimulated unfolded protein response, and direct oxidant interaction. This study provides insight into pathways through which resveratrol can protect RPE cells from oxidative damage, a factor thought to contribute to AMD pathogenesis.
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http://dx.doi.org/10.1167/iovs.61.4.32DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7401947PMC
April 2020

Ranibizumab and Bevacizumab for Treatment of Neovascular Age-related Macular Degeneration: Two-Year Results.

Ophthalmology 2020 04;127(4S):S135-S145

National Eye Institute, National Institutes of Health, Bethesda, Maryland.

Objective: To describe effects of ranibizumab and bevacizumab when administered monthly or as needed for 2 years and to describe the impact of switching to as-needed treatment after 1 year of monthly treatment.

Design: Multicenter, randomized clinical trial.

Participants: Patients (n = 1107) who were followed up during year 2 among 1185 patients with neovascular age-related macular degeneration who were enrolled in the clinical trial.

Interventions: At enrollment, patients were assigned to 4 treatment groups defined by drug (ranibizumab or bevacizumab) and dosing regimen (monthly or as needed). At 1 year, patients initially assigned to monthly treatment were reassigned randomly to monthly or as-needed treatment, without changing the drug assignment.

Main Outcome Measures: Mean change in visual acuity.

Results: Among patients following the same regimen for 2 years, mean gain in visual acuity was similar for both drugs (bevacizumab-ranibizumab difference, -1.4 letters; 95% confidence interval [CI], -3.7 to 0.8; P = 0.21). Mean gain was greater for monthly than for as-needed treatment (difference, -2.4 letters; 95% CI, -4.8 to -0.1; P = 0.046). The proportion without fluid ranged from 13.9% in the bevacizumab-as-needed group to 45.5% in the ranibizumab monthly group (drug, P = 0.0003; regimen, P < 0.0001). Switching from monthly to as-needed treatment resulted in greater mean decrease in vision during year 2 (-2.2 letters; P = 0.03) and a lower proportion without fluid (-19%; P < 0.0001). Rates of death and arteriothrombotic events were similar for both drugs (P > 0.60). The proportion of patients with 1 or more systemic serious adverse events was higher with bevacizumab than ranibizumab (39.9% vs. 31.7%; adjusted risk ratio, 1.30; 95% CI, 1.07-1.57; P = 0.009). Most of the excess events have not been associated previously with systemic therapy targeting vascular endothelial growth factor (VEGF).

Conclusions: Ranibizumab and bevacizumab had similar effects on visual acuity over a 2-year period. Treatment as needed resulted in less gain in visual acuity, whether instituted at enrollment or after 1 year of monthly treatment. There were no differences between drugs in rates of death or arteriothrombotic events. The interpretation of the persistence of higher rates of serious adverse events with bevacizumab is uncertain because of the lack of specificity to conditions associated with inhibition of VEGF.

Financial Disclosure(s): Proprietary or commercial disclosure may be found after the references.
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http://dx.doi.org/10.1016/j.ophtha.2020.01.029DOI Listing
April 2020

Incidence and Progression of Nongeographic Atrophy in the Comparison of Age-Related Macular Degeneration Treatments Trials (CATT) Clinical Trial.

JAMA Ophthalmol 2020 05;138(5):510-518

Department of Ophthalmology, University of Pennsylvania, Philadelphia.

Importance: Retinal hypopigmentation and hyperpigmentation are precursors of geographic atrophy (GA). Incidence and progression to GA in eyes treated with anti-vascular endothelial growth factor for neovascular age-related macular degeneration (nAMD) have not been investigated.

Objective: To determine the incidence and progression of non-GA (NGA) and associated risk factors.

Design, Setting, And Participants: This study is a post hoc analysis of a cohort study within the Comparison of Age-Related Treatments Trials (CATT) clinical trial. Participants were recruited February 20, 2008, through December 9, 2009; released from protocol follow-up and treatment after 2 years; and recalled from March 14, 2014, through March 31, 2015. Data analyses were conducted from January 11, 2019, through November 27, 2019.

Interventions: Participants were randomized to ranibizumab or bevacizumab for (1) 2 years of monthly or as-needed injections or (2) monthly injections for 1 year and as-needed injections the following year. Participants were treated according to best medical judgement thereafter.

Main Outcomes And Measures: Incidence of nAMD-associated NGA (hypopigmentation and hyperpigmentation in color images) and progression; adjusted risk ratios (aRR) for baseline characteristics.

Results: Among 1107 participants, risk of NGA was 35% (391 eyes), 59% (246 eyes), and 81% (122 eyes) at 1, 2, and 5 years, respectively. Risk factors for NGA included worse visual acuity (20/200-20/320: aRR, 1.74 [95% CI, 1.24-2.43], compared with ≤20/40; P = .006), larger neovascularization area (>4 disc areas: aRR, 1.31 [95% CI, 1.01-1.71], compared with ≤1 disc areas; P = .007), switched drug regimen (aRR, 1.28 [95% CI, 1.06-1.54], compared with as-needed injections; P = .02), and single-nucleotide variants Age-Related Maculopathy Susceptibility 2 (ARMS2) (TT variant: relative risk [RR], 1.53 [95% CI, 1.22-1.93]; P = .001) and HtrA Serine Peptidase 1 (HTRA1) (AG variant: RR, 1.23 [95% CI, 1.01-1.48]; AA variant: RR, 1.51 [95% CI, 1.20-1.91]; P = .002). Sub-retinal pigment epithelium thickness was protective (>275 μm: aRR, 0.59 [95% CI, 0.46-0.75], compared with ≤75 μm; P < .001). Among 389 eyes with NGA by 2 years and subsequent color images, risk of progression to GA was 29%, 43%, and 50% at 1, 3, and 4 years, respectively. Risk factors for progression to GA included worse visual acuity (20/200-20/320: aRR, 2.75 [95% CI, 1.54-4.93], compared with ≤20/40; P < .001), worse fellow-eye visual acuity (<20/40: aRR, 1.77 [95% CI, 1.12-2.79], compared with ≥20/40; P = .01), fellow-eye GA (aRR, 1.71 [95% CI, 1.06-2.75]; P = .03), and pseudodrusen in either eye (aRR, 1.65 [95% CI, 1.17-2.34]; P = .005). Subretinal fluid was associated with a decreased risk of progression (aRR, 0.42 [95% CI, 0.28-0.63]; P < .001).

Conclusions And Relevance: In this study, after 2 years of protocol-guided anti-vascular endothelial growth factor treatment for nAMD, more than half of the eyes in the study developed NGA in the location of nAMD. After 3 additional years of regular care, half of them progressed to GA.

Trial Registration: ClinicalTrials.gov Identifier: NCT00593450.
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http://dx.doi.org/10.1001/jamaophthalmol.2020.0437DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7082767PMC
May 2020

Retinal cavitations in macular telangiectasia type 2 (MacTel): longitudinal structure-function correlations.

Br J Ophthalmol 2021 Jan 9;105(1):109-112. Epub 2020 Mar 9.

Department of Ophthalmology, Duke Medicine, Durham, North Carolina, USA

Background/aims: To quantify retinal cavitation size over time in macular telangiectasia type 2 (MacTel) and to correlate changes with visual acuity and area of ellipsoid zone loss.

Methods: Optical coherence tomography (OCT) macula volume scans from sham eyes included in a prospective, phase II clinical trial of human ciliary neutrophic factor for MacTel at baseline, 1 year and 2 years of follow-up were analysed. Cavitations were segmented by two independent readers. Total cavitation volume was compared with area of ellipsoid zone loss and best-corrected visual acuity (BCVA).

Results: Fifty-one eyes from 51 unique patients (mean age 62 years, range 45-79 years) were included. Intraclass correlation between readers for cavitation volume was excellent (>0.99). Average cavitation volume was 0.0109 mm, 0.0113 mm and 0.0124 mm at baseline, 1 year and 2 years, respectively. The average rate of cavitation volume change was +0.0039 mm/year. 10 eyes (20%) had a significant change in cavitation volume during the study (3 decreased, 7 increased). Eyes with increased cavitation volume had worse BCVA compared with eyes with no change/decreased cavitation volume (71.5 vs 76.1 ETDRS letters, respectively). Cavitation volume was negatively correlated to BCVA (r=-0.37) but not to area of ellipsoid zone loss. Cavitation volume was negatively predictive of BCVA in both univariate and multivariate mixed-effects modelling with ellipsoid zone loss.

Conclusions: Retinal cavitations and their rate of change in MacTel can be reliably quantified using OCT. Cavitations are negatively correlated with visual acuity and may be a useful OCT-based biomarker for disease progression and visual function in MacTel.
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http://dx.doi.org/10.1136/bjophthalmol-2019-315416DOI Listing
January 2021

Time to disease recurrence in noninfectious uveitis following long-acting injectable fluocinolone acetonide implant.

Graefes Arch Clin Exp Ophthalmol 2020 May 29;258(5):1023-1030. Epub 2020 Feb 29.

Department of Ophthalmology, Duke University Medical Center, Durham, NC, USA.

Purpose: To determine the time to disease recurrence with long-acting injectable fluocinolone acetonide implant (FAi) for noninfectious intermediate, posterior, and panuveitis.

Methods: This was a retrospective study of patients with at least 12 months of follow-up who had completed a 2-year prospective, investigational new drug study with 0.18-mg FAi. Time to uveitis recurrence or cystoid macular edema (CME) occurrence was recorded.

Results: Twelve eyes from 12 participants (mean age 43 years, range 25-64 years) were included. Patients were followed for a mean of 34.2 months (range, 12.0-56.9 months) after completion of the prospective trial. Five eyes (42%) did not have a documented uveitis recurrence or CME occurrence. Five eyes (42%) had a uveitis recurrence with the mean time to recurrence 36.1 months (range, 22.8-61.1 months) after FAi implantation. Two eyes (16%) had CME alone, the mean time to occurrence 36.9 months (range 36.1-42.1 months). On Kaplan-Meier analysis, the estimated probability of remaining recurrence-free 36 months after FAi implantation was 0.67 (95% confidence interval, 0.34-0.86).

Conclusions: Data of study participants after completing a clinical trial suggest that the injectable FAi for noninfectious uveitis can provide control for 3 years on average. These long-term data support the use of FAi to control noninfectious uveitis.
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http://dx.doi.org/10.1007/s00417-020-04614-xDOI Listing
May 2020

Anti-Vascular Endothelial Growth Factor Use and Atrophy in Neovascular Age-Related Macular Degeneration: Systematic Literature Review and Expert Opinion.

Ophthalmology 2020 05 22;127(5):648-659. Epub 2019 Nov 22.

Department of Ophthalmology, Duke University, Durham, North Carolina.

Topic: To summarize the rates of atrophy, risk factors, and atrophy-associated visual outcomes in patients with neovascular age-related macular degeneration (nAMD) who received anti-vascular endothelial growth factor (VEGF) treatment for macular neovascularization (MNV).

Clinical Relevance: Age-related macular degeneration is a leading cause of vision loss worldwide, and VEGF inhibitors are the primary treatment for nAMD. However, atrophy is observed frequently in eyes treated with anti-VEGF therapy, prompting questions regarding a causative role for these therapies in atrophy development.

Methods: PubMed was searched for articles published in the past 5 years (January 1, 2014, through January 10, 2019). Studies including atrophy outcome(s) in patients with age-related macular degeneration who received anti-VEGF treatment were included. Review articles, retrospective studies, case reports or studies, preclinical studies, prevalence data reports, and non-English studies were excluded. Randomization was not required.

Results: Overall, 145 studies were identified; 29 publications were included, with cohorts ranging from 8 to 1185 eyes. Imaging methods used to assess atrophy varied across studies. All studies confirmed the occurrence of atrophy, and when available, longitudinal data from the included studies demonstrated an increase in atrophy incidence over time. Key risk factors or phenotypes associated with atrophy were fellow eye atrophy, reticular pseudodrusen, increased injections, and type 3 lesion. In addition, visual acuity loss was noted with foveal atrophy.

Discussion: All studies demonstrated that atrophy occurs in the context of MNV treated with anti-VEGF therapy; however, it is not clear whether anti-VEGF treatment is causative of atrophy versus being associated with atrophy development. The included studies were not designed or powered to assess atrophy as a primary outcome. In addition, it is difficult to determine whether prognostic factors directly affect atrophy. Furthermore, patient populations in clinical trials do not necessarily represent real-world patients. Although phenotypes and risk factors may help to identify those at greater risk of atrophy developing, it is important to recognize that adequately treating exudative MNV remains the best option to optimize vision outcomes in patients with nAMD, particularly given the risk of vision loss with undertreatment observed in the real world.
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http://dx.doi.org/10.1016/j.ophtha.2019.11.010DOI Listing
May 2020

Beyond Performance Metrics: Automatic Deep Learning Retinal OCT Analysis Reproduces Clinical Trial Outcome.

Ophthalmology 2020 06 23;127(6):793-801. Epub 2019 Dec 23.

Department of Biomedical Engineering, Duke University, Durham, North Carolina; Department of Ophthalmology, Duke University Medical Center, Durham, North Carolina. Electronic address:

Purpose: To validate the efficacy of a fully automatic, deep learning-based segmentation algorithm beyond conventional performance metrics by measuring the primary outcome of a clinical trial for macular telangiectasia type 2 (MacTel2).

Design: Evaluation of diagnostic test or technology.

Participants: A total of 92 eyes from 62 participants with MacTel2 from a phase 2 clinical trial (NCT01949324) randomized to 1 of 2 treatment groups METHODS: The ellipsoid zone (EZ) defect areas were measured on spectral domain OCT images of each eye at 2 time points (baseline and month 24) by a fully automatic, deep learning-based segmentation algorithm. The change in EZ defect area from baseline to month 24 was calculated and analyzed according to the clinical trial protocol.

Main Outcome Measure: Difference in the change in EZ defect area from baseline to month 24 between the 2 treatment groups.

Results: The difference in the change in EZ defect area from baseline to month 24 between the 2 treatment groups measured by the fully automatic segmentation algorithm was 0.072±0.035 mm (P = 0.021). This was comparable to the outcome of the clinical trial using semiautomatic measurements by expert readers, 0.065±0.033 mm (P = 0.025).

Conclusions: The fully automatic segmentation algorithm was as accurate as semiautomatic expert segmentation to assess EZ defect areas and was able to reliably reproduce the statistically significant primary outcome measure of the clinical trial. This approach, to validate the performance of an automatic segmentation algorithm on the primary clinical trial end point, provides a robust gauge of its clinical applicability.
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http://dx.doi.org/10.1016/j.ophtha.2019.12.015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7246171PMC
June 2020

Characteristics of Eyes With Good Visual Acuity at 5 Years After Initiation of Treatment for Age-Related Macular Degeneration but Not Receiving Treatment From Years 3 to 5: Post Hoc Analysis of the CATT Randomized Clinical Trial.

JAMA Ophthalmol 2020 03;138(3):276-284

Department of Ophthalmology, Perelman School of Medicine, University of Pennsylvania, Philadelphia.

Importance: Identifying the characteristics of eyes with neovascular age-related macular degeneration (nAMD) that maintain good vision without anti-vascular endothelial growth factor treatment for at least 3 years after management, as occurred in the Comparison of Age-Related Macular Degeneration Treatments Trials (CATT), may have prognostic importance and help in understanding the disease and its treatment.

Objectives: To ascertain the characteristics of eyes in the CATT that retained good vision despite receiving no therapy for 3 years after release from the 2-year CATT treatment protocol.

Design, Setting And Participants: This case-control study analyzed the baseline and follow-up characteristics of eyes with nAMD that were enrolled in the CATT from 43 US clinical centers between February 20, 2008, and December 9, 2009. After initial randomization to 1 of 4 treatment groups (ranibizumab monthly, bevacizumab monthly, ranibizumab as needed, or bevacizumab as needed), at year 1, participants in the monthly groups were rerandomized to continue monthly treatment or to switch to as-needed treatment using the same drug as originally assigned. At year 2, participants were released from the protocol to treatment at the discretion of their ophthalmologist. At year 5, participants were recalled for examination. This present analysis, conducted from December 1, 2018, to September 30, 2019, compared the eyes of 40 participants (referred to as the cessation of treatment with good visual acuity, or CTGVA, group) with the eyes of the remainder of the CATT Follow-up Study (referred to as the other group).

Main Outcomes And Measures: Visual acuity, morphologic characteristics, and number of treatments over 5 years.

Results: Among 625 eyes with nAMD at baseline and a visual acuity measurement at year 5, 40 (6.4%; 95% CI, 4.7%-8.7%) were included in the analysis. These 40 participants, compared with the other group (n = 585), had a lower mean (SD) age of 74.7 (7.3) years (vs 77.7 [7.3] years; P = .01) and included 26 women (65.0%). Baseline characteristics were similar between eyes in the CTGVA and other groups, except for better visual acuity letter score in the study eye (68.8 vs 61.8; P = .001) and the fellow eye (78.4 vs 68.0; P = .01) as well as the presence of blocked fluorescence seen more often in participants in the CTGVA vs the other group (27.5% vs 13.8%; P = .02). Eyes in the CTGVA group with as-needed treatment received fewer mean (SD) injections in year 1 (5.8 [4.0] vs 8.1 [3.5]) and year 2 (7.7 [5.7] vs 13.8 [6.8]) than eyes in the other as-needed group. Mean (SD) visual acuity letter score at 5 years was 79.0 (5.5; Snellen 20/25) in the CTGVA group and 57.5 (24.2; Snellen 20/80) in the other group.

Conclusions And Relevance: These findings suggest that a small proportion of eyes with nAMD can retain good visual acuity with no treatment for at least 3 years after the initial 2 years of treatment. Unique characteristics of eyes that could discontinue treatment while maintaining good visual acuity could not be identified at baseline, but data suggest that not all eyes with this disease may need treatment forever.

Trial Registration: ClinicalTrials.gov Identifier: NCT00593450.
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http://dx.doi.org/10.1001/jamaophthalmol.2019.5831DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7042910PMC
March 2020

Consensus Nomenclature for Reporting Neovascular Age-Related Macular Degeneration Data: Consensus on Neovascular Age-Related Macular Degeneration Nomenclature Study Group.

Ophthalmology 2020 05 14;127(5):616-636. Epub 2019 Nov 14.

Department of Electrical Engineering and Computer Science, Massachusetts Institute of Technology, Cambridge, Massachusetts.

Purpose: To establish a process to evaluate and standardize a state-of-the-art nomenclature for reporting neovascular age-related macular degeneration (AMD) data.

Design: Consensus meeting.

Participants: An international panel of retina specialists, imaging and image reading center experts, and ocular pathologists.

Methods: During several meetings organized under the auspices of the Macula Society, an international study group discussed and codified a set nomenclature framework for classifying the subtypes of neovascular AMD and associated lesion components.

Main Outcome Measures: A consensus classification of neovascular AMD.

Results: The study group created a standardized working definition of AMD. The components of neovascular AMD were defined and subclassified. Disease consequences of macular neovascularization were delineated.

Conclusions: The framework of a consensus nomenclature system, a definition of AMD, and a delineation of the subtypes of neovascular AMD were developed. Establishing a uniform set of definitions will facilitate comparison of diverse patient groups and different studies. The framework presented is modified and updated readily, processes that are anticipated to occur on a periodic basis. The study group suggests that the consensus standards outlined in this article be used in future reported studies of neovascular AMD and clinical practice.
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http://dx.doi.org/10.1016/j.ophtha.2019.11.004DOI Listing
May 2020

Reply.

Ophthalmology 2019 12;126(12):e96-e97

University of Bonn, Bonn, Germany.

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http://dx.doi.org/10.1016/j.ophtha.2019.08.016DOI Listing
December 2019

Incomplete Retinal Pigment Epithelial and Outer Retinal Atrophy in Age-Related Macular Degeneration: Classification of Atrophy Meeting Report 4.

Ophthalmology 2020 03 30;127(3):394-409. Epub 2019 Sep 30.

Doheny Eye Institute, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California.

Purpose: To describe the defining features of incomplete retinal pigment epithelium (RPE) and outer retinal atrophy (iRORA), a consensus term referring to the OCT-based anatomic changes often identified before the development of complete RPE and outer retinal atrophy (cRORA) in age-related macular degeneration (AMD). We provide descriptive OCT and histologic examples of disease progression.

Design: Consensus meeting.

Participants: Panel of retina specialists, including retinal imaging experts, reading center leaders, and retinal histologists.

Methods: As part of the Classification of Atrophy Meeting (CAM) program, an international group of experts analyzed and discussed longitudinal multimodal imaging of eyes with AMD. Consensus was reached on a classification system for OCT-based structural alterations that occurred before the development of atrophy secondary to AMD. New terms of iRORA and cRORA were defined. This report describes in detail the CAM consensus on iRORA.

Main Outcome Measures: Defining the term iRORA through OCT imaging and longitudinal cases showing progression of atrophy, with histologic correlates.

Results: OCT was used in cases of early and intermediate AMD as the base imaging method to identify cases of iRORA. In the context of drusen, iRORA is defined on OCT as (1) a region of signal hypertransmission into the choroid, (2) a corresponding zone of attenuation or disruption of the RPE, and (3) evidence of overlying photoreceptor degeneration. The term iRORA should not be used when there is an RPE tear. Longitudinal studies confirmed the concept of progression from iRORA to cRORA.

Conclusions: An international consensus classification for OCT-defined anatomic features of iRORA are described and examples of longitudinal progression to cRORA are provided. The ability to identify these OCT changes reproducibly is essential to understand better the natural history of the disease, to identify high-risk signs of progression, and to study early interventions. Longitudinal data are required to quantify the implied risk of vision loss associated with these terms. The CAM classification provides initial definitions to enable these future endeavors, acknowledging that the classification will be refined as new data are generated.
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http://dx.doi.org/10.1016/j.ophtha.2019.09.035DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7218279PMC
March 2020

Assessment of Macular Microvasculature in Healthy Eyes of Infants and Children Using OCT Angiography.

Ophthalmology 2019 12 15;126(12):1703-1711. Epub 2019 Jul 15.

Department of Ophthalmology, Duke University School of Medicine, Durham, North Carolina. Electronic address:

Purpose: To assess macular vasculature in healthy infants and children using OCT angiography (OCTA).

Design: Prospective cross-sectional study.

Participants: One hundred thirty-five normal maculae of 89 healthy infants and children (mean age, 8.5±5.3 years; range, 9 weeks-17 years) treated at the Duke University Eye Center.

Methods: We imaged 135 maculae of 89 pediatric patients using the standard Spectralis tabletop and investigational Spectralis with Flex module devices, both equipped with investigational OCTA software (Heidelberg Engineering, Heidelberg, Germany). OCT angiography images of the superficial vascular complex (SVC) and deep vascular complex (DVC) were analyzed for foveal avascular zone (FAZ) area and superficial and deep vessel density. We assessed effects of age, gender, race, axial length (AL), and central subfield thickness on FAZ and vessel density. Patients with both eyes imaged were assessed for agreement between the FAZ and vessel densities of the left and right eyes.

Main Outcome Measures: The FAZ area, as well as vessel area density (VAD) and vessel length density (VLD) in the SVC and DVC.

Results: The FAZ varied significantly with race; white patients showed a significantly smaller FAZ than black patients (mean difference, 0.11 mm; P = 0.004). The FAZ did not vary with age, gender, or AL (P > 0.05). In the SVC, VAD and VLD varied significantly with age (P < 0.001) and AL (R = 0.46; P < 0.001) but not gender (P > 0.05). The SVC VLD was significantly different between races and ethnicities (P = 0.037), but VAD was not (P < 0.05). In the DVC, VAD and VLD also varied significantly with age (P < 0.001) and AL (R = 0.46; P < 0.001) but not gender or race (P > 0.05). There was excellent agreement between the right and left eyes for FAZ (intraclass correlation [ICC], 0.97), SVC VLD (ICC, 1.00), and DVC VLD (ICC, 1.00).

Conclusions: Quantitative studies of pediatric perifoveal vasculature should consider age, race, and AL. In eyes with unilateral disease, the perifoveal vasculature in the unaffected eye may be used as a control comparison because there is excellent agreement between eyes.
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http://dx.doi.org/10.1016/j.ophtha.2019.06.028DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6875602PMC
December 2019

The Evolution of Fibrosis and Atrophy and Their Relationship with Visual Outcomes in Asian Persons with Neovascular Age-Related Macular Degeneration.

Ophthalmol Retina 2019 12 12;3(12):1045-1055. Epub 2019 Jun 12.

Department of Ophthalmology, Duke University, Durham, North Carolina.

Purpose: To describe the rate of development and progression of fibrosis and macular atrophy (MA) and their relationship with 1-year visual outcomes in Asian participants with neovascular age-related macular degeneration (nAMD).

Design: Review of images collected from a prospectively recruited observational cohort.

Participants: Participants with treatment-naïve nAMD.

Methods: All participants underwent multimodality imaging at baseline and month 12 and were treated according to standard of care. Retinal specialists evaluated color fundus photographs fluorescein and indocyanine green angiography images to determine the subtypes according polypoidal choroidal vasculopathy (PCV) and non-PCV subtypes. An independent reading center graded qualitative and quantitative morphologic features on spectral-domain OCT. Fibrosis and MA were determined based on multimodal imaging.

Main Outcome Measures: Incidence of fibrosis and MA and their impact on visual outcome at 1 year.

Results: We included 93 eyes (48.4% PCV). Between baseline and month 12, visual acuity (VA) improved from 0.81±0.56 logarithm of the minimum angle of resolution (logMAR; Snellen equivalent, approximately 20/126) to 0.71±0.61 logMAR (Snellen equivalent, approximately 20/100; P = 0.007), and mean retinal thickness decreased from 471.1 μm to 343.4 μm (P < 0.001). Between baseline and month 12, prevalence of fibrosis and MA increased from 13.0% to 37.8% (P < 0.001) and 9.7% to 17.2% (P = 0.008), respectively. Worse baseline VA and presence of subretinal hyperreflective material (SHRM) at month 12 were associated with worse VA at month 12 after adjusting for multiple factors, whereas PCV subtype was associated with better VA at month 12. At month 12, the predominant composition of SHRM was fibrosis (82.5%).

Conclusions: We describe significant development of fibrosis and MA in Asian nAMD eyes and show that fibrosis is the most important predictor of outcomes. These results highlight the need for therapy beyond anti-vascular endothelial growth factor inhibition to address fibrosis in Asian nAMD.
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http://dx.doi.org/10.1016/j.oret.2019.06.002DOI Listing
December 2019

BASELINE CHARACTERISTICS OF VITREOMACULAR TRACTION PROGRESSING TO FULL-THICKNESS MACULAR OR LAMELLAR HOLES IN THE PHASE III TRIALS OF ENZYMATIC VITREOLYSIS.

Retina 2020 Aug;40(8):1579-1584

Department of Ophthalmology, Duke University Eye Center, Duke University, Durham, North Carolina.

Purpose: To identify characteristics associated with progression from vitreomacular traction (VMT) to a full-thickness macular hole (FTMH) or lamellar hole (LH).

Methods: Post-hoc analysis of the Phase III clinical trial comparing ocriplasmin with placebo for treatment of vitreomacular adhesion (MIVI-TRUST). Exact logistic regression analyses were used to identify baseline characteristics significantly associated with progression from vitreomacular traction to FTMH or LH over the 6-month study period.

Results: Twenty eyes (4.5%) developed an FTMH and 38 (9.7%) developed an LH during the study period. The rate of progression to FTMH or LH did not differ significantly between ocriplasmin- and saline-treated eyes (P = 0.090 for FTMH, P = 0.369 for LH). On univariate analysis, the presence of subretinal fluid (adjusted odds ratio 5.64, 95% confidence interval 2.02-17.17, P < 0.001) and mean subretinal fluid thickness (adjusted odds ratio 1.10, 95% confidence interval 1.04-1.16, P = 0.003) were associated with FTMH development. Both remained significantly associated with FTMH development on multivariate testing. On univariate analysis, the presence of macular schisis (adjusted odds ratio 2.26, 95% confidence interval 1.30-3.82, P = 0.004) and mean retinal thickness (adjusted odds ratio 1.06, 95% confidence interval 1.01-1.10, P = 0.010) were associated with LH development. Schisis remained a significant predictor of LH formation on multivariate testing.

Conclusion: Vitreomacular traction is more likely to progress to FTMH when associated with subretinal fluid, but when associated with intraretinal changes (such as schisis), vitreomacular traction appears more likely to progress to a LH after a single intravitreal injection of ocriplasmin or saline.
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http://dx.doi.org/10.1097/IAE.0000000000002634DOI Listing
August 2020