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Comment
. 2022 Oct 1;140(10):936-945.
doi: 10.1001/jamaophthalmol.2022.3130.

Association of Ultra-Widefield Fluorescein Angiography-Identified Retinal Nonperfusion and the Risk of Diabetic Retinopathy Worsening Over Time

Paolo S Silva  1   2 , Dennis M Marcus  3   4 , Danni Liu  5 , Lloyd Paul Aiello  1   2 , Andrew Antoszyk  6 , Michael Elman  7 , Scott Friedman  8 , Adam R Glassman  5 , Joseph M Googe  9 , Lee Merrill Jampol  10 , Daniel F Martin  11 , Michele Melia  5 , Carin M Preston  5 , Charles C Wykoff  12 , Jennifer K Sun  1   2 ; DRCR Retina Network
Collaborators, Affiliations
Comment

Association of Ultra-Widefield Fluorescein Angiography-Identified Retinal Nonperfusion and the Risk of Diabetic Retinopathy Worsening Over Time

Paolo S Silva et al. JAMA Ophthalmol. .

Erratum in

Abstract

Importance: Presence of predominantly peripheral diabetic retinopathy (DR) lesions on ultra-widefield fluorescein angiography (UWF-FA) was associated with greater risk of DR worsening or treatment over 4 years. Whether baseline retinal nonperfusion assessment is additionally predictive of DR disease worsening is unclear.

Objective: To assess whether the extent and location of retinal nonperfusion identified on UWF-FA are associated with worsening in Diabetic Retinopathy Severity Scale (DRSS) score or DR treatment over time.

Design, setting, and participants: This cohort study was a prospective, multicenter, longitudinal observational study with data for 508 eyes with nonproliferative DR and gradable nonperfusion on UWF-FA at baseline. All images were graded at a centralized reading center; 200° ultra-widefield (UWF) color images were graded for DR at baseline and annually for 4 years. Baseline 200° UWF-FA images were graded for nonperfused area, nonperfusion index (NPI), and presence of predominantly peripheral lesions on UWF-FA (FA PPL).

Interventions: Treatment of DR or diabetic macular edema was at investigator discretion.

Main outcomes and measures: Association of baseline UWF-FA nonperfusion extent with disease worsening, defined as either 2 or more steps of DRSS worsening within Early Treatment Diabetic Retinopathy Study fields on UWF-color images or receipt of DR treatment.

Results: After adjusting for baseline DRSS, the risk of disease worsening over 4 years was higher in eyes with greater overall NPI (hazard ratio [HR] for 0.1-unit increase, 1.11; 95% CI, 1.02-1.21; P = .02) and NPI within the posterior pole (HR for 0.1-unit increase, 1.35; 95% CI, 1.17-1.56; P < .001) and midperiphery (HR for 0.1-unit increase, 1.08; 95% CI, 1.00-1.16; P = .04). In a multivariable analysis adjusting for baseline DRSS score and baseline systemic risk factors, greater NPI (HR, 1.11; 95% CI, 1.02-1.22; P = .02) and presence of FA PPL (HR, 1.89; 95% CI, 1.35-2.65; P < .001) remained associated with disease worsening.

Conclusions and relevance: This 4-year longitudinal study has demonstrated that both greater baseline retinal nonperfusion and FA PPL on UWF-FA are associated with higher risk of disease worsening, even after adjusting for baseline DRSS score and known systemic risk. These associations between disease worsening and retinal nonperfusion and FA PPL support the increased use of UWF-FA to complement color fundus photography in future efforts for DR prognosis, clinical care, and research.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Silva reported grants from Optos, the Massachusetts Lions Eye Research Foundation, the Medical Research Council (United Kingdom), and the Philippine Council of Health Research and Development; personal fees and nonfinancial research support from Optos during the conduct of the study; personal fees and nonfinancial support from Optomed outside the submitted work; and professional fees from the American Diabetes Association outside the submitted work. Dr Marcus reported fees from Jaeb Center for Health Research for serving as protocol chair during the conduct of the study; grants from Allergan, Amgen, Boehringer Ingelheim, Alcon, Kalvista, Ionis, Xplore, Mylan, Samsung, Novartis, Opthea, Chenghdu, Clearside, Ophthotech/Iveric, Outlook, Gemini, Genentech, Graybug, Topcon, Optos, Gyroscope, Stealth Spiam, Apellis, Roche, Novartis, Xplore, Regenxbio, Kodiak, Zeiss, Annexon, Oculis, Alexion, and Regeneron Pharmaceuticals; and serving as a consultant for Regenxbio, Genentech/Roche, Regeneron, Clearside, and Vial outside the submitted work. Ms Liu reported grants from the National Institutes of Health (NIH) and JDRF; loaner ophthalmic cameras to clinical sites from Optos, Zeiss, and Optovue; and additional funding or devices outside of the submitted work from Regeneron, Helmsley Charitable Trust, PhotoOptx, and Roche. Dr Aiello reported professional fees from Guidepoint Global, Japan Society of Ophthalmology and Diabetes, Johns Hopkins, Novo Nordisk, Perfuse Therapeutics, Samsung, System Analytic, and Valo Health and equity stock and professional fees from Kalvista. Dr Antoszyk reported research support from Apellis, Gemini Therapeutics, Genentech, Kodiak, NGM Biopharmaceutical, Novartis, Novo Nordisk, Amgen, Regeneron, Roche, and Notal and serving on an advisory board for Allergan. Dr Elman reported grants from the Jaeb Center for Health Research during the conduct of the study. Dr Friedman reported research support from Amgen, Boehringer Ingelheim, Chengdu Kang Hong, Opthea, and Regeneron. Mr Glassman reported grants from the NIH and JDRF; loaner ophthalmic cameras to clinical sites from Optos, Zeiss, and Optovue; and additional funding or devices outside of the submitted work from Regeneron, Helmsley Charitable Trust, PhotoOptx, and Roche. Dr Jampol reported professional fees from Alkahest. Ms Melia reported grants from the NIH and JDRF; loaner ophthalmic cameras to clinical sites from Optos, Zeiss, and Optovue; and additional funding or devices outside of the submitted work from Regeneron, Helmsley Charitable Trust, PhotoOptx, and Roche. Ms Preston reported grants from the NIH and JDRF; loaner ophthalmic cameras to clinical sites from Optos, Zeiss, and Optovue; and additional funding or devices outside of the submitted work from Regeneron, Helmsley Charitable Trust, PhotoOptx, and Roche. Dr Wykoff reported grants and other research or professional fees from AbbVie, Adverum, Aerie, AGTC, Aldeyra, Alexion, Alimera Sciences, Alkahest, Allergan, Amgen, Allgenesis, Alnylam, Annexon Biosciences, Apellis, Arrowhead, Asclepix, Bausch and Lomb, Bayer, Boehringer Ingelheim, Bionic Vision, Chengdu Kang Hong, Cholgene Therapeutics, Clearside Biomedical, Curacle, EyePoint, Frontera, Gemini Therapeutics, Genentech, Graybug, Gyroscope Therapeutics, IACTA, Ionis Pharmaceuticals, Irenix, Iveric Bio, Janssen Pharmaceuticals, Kato Pharmaceuticals, Kiora, Kodiak, Kriya, Lowy Medical Research Institute, Nanoscope Technologies, Neurotech, NGM Biopharmaceuticals, Novartis, Ocular Therapeutix, Ocuphire Phara, OccuRx, OliX, ONL Therapeutics, Opthea, Oxurion, Palatin, Perfuse, Polyphotonix, Ray, Recens Medical, Regeneron, RegenXBio, Roche, SamChunDang Pharm, Sandoz, Stealth, Surrozen, THEA, Taiwan Liposome Company, Tissue Gen, Unity Biotechnology, Unity Valo Health, Vitranu, and Xbrane Biopharma and equity or stock in ONL Therapeutics, Polyphotonix Tissue, Gen Visgenx, and Vitranu. Dr Sun reported grants from Jaeb Center for Health Research during the conduct of the study; grants from Optovue, JDRF, Kalvista, Novartis, Novo Nordisk, Boerhinger Ingelheim, Genentech/Roche, Physical Sciences, Janssen, and the Massachusetts Lions Eye Research Foundation outside the submitted work; nonfinancial support from Optovue, Merck, Novartis, Novo Nordisk, Genentech/Roche, Boston Micromachines, and Adaptive Sensory Technologies outside the submitted work; and professional fees from the American Medical Association and American Diabetes Association outside the submitted work. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. Examples of Eyes in the Low-, Medium-, and High-Nonperfusion Subgroups
Representative paired ultra-widefield color and fluorescein angiography (FA) images of eyes in the low, medium, and high tertile groups of retinal nonperfusion. White border on the color and yellow border on the FA represent the Early Treatment Diabetic Retinopathy Study (ETDRS) areas border. A and B, Eye with low nonperfusion. The baseline Diabetic Retinopathy Severity Scale (DRSS) level within the ETDRS area was moderate nonproliferative diabetic retinopathy (NPDR), and there was no progression at 4 years. Predominantly peripheral lesions on FA (FA PPL) were absent. C and D, Eye with medium nonperfusion. The baseline DRSS score was moderate NPDR with progression to very severe NPDR at year 2. Color PPL and FA PPL were present. E and F, Eye with high nonperfusion. The baseline DRSS score was moderate NPDR with progression to very severe NPDR at year 1. Color and FA PPL were present.
Figure 2.
Figure 2.. Cumulative Proportion of Disease Worsening Through 4 Years by Baseline Overall Nonperfusion Index (NPI) on Ultra-Widefield Fluorescein Angiography (UWF-FA)
Worsening was defined by either a worsening of 2 or more steps on the Diabetic Retinopathy Severity Scale (DRSS) within Early Treatment Diabetic Retinopathy Study (ETDRS) fields on masked ultra-widefield (UWF) color images or receipt of diabetic retinopathy (DR) treatment. Eyes receiving treatment with anti–vascular endothelial growth factor, steroid, or vitrectomy for conditions other than DR were censored after treatment initiation. The cumulative proportion for primary outcome of disease worsening was 26% (95% CI, 15%-43%) in the no-nonperfusion group, and 43% (95% CI, 34%-52%), 38% (95% CI, 30%-47%), and 46% (95% CI, 38%-55%) in eyes with low nonperfusion, medium nonperfusion, and high nonperfusion, respectively. Eyes that did not meet the primary outcome or that received non-DR treatment were censored at the last visit. The Cox proportional hazards model was adjusted for baseline DRSS score within the ETDRS fields on masked UWF-color images, percentage of total imaged area on UWF-FA, and the correlation between the 2 study eyes from the same participant.
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