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. 2026 Jan 29:e255658.
doi: 10.1001/jamaophthalmol.2025.5658. Online ahead of print.

Ultra-Widefield Fluorescein Angiographic Quantitative Leakage Parameters and Clinical Outcomes in Nonproliferative Diabetic Retinopathy

Justis P Ehlers  1 , Kristin Josic  2 , Lloyd P Aiello  3 , Reem Amine  1 , Asmita Indurkar  1 , Alison A Martin  4 , Karen Matar  1 , Paolo S Silva  3 , Jennifer K Sun  3   5 ; DRCR Retina Network
Collaborators, Affiliations

Ultra-Widefield Fluorescein Angiographic Quantitative Leakage Parameters and Clinical Outcomes in Nonproliferative Diabetic Retinopathy

Justis P Ehlers et al. JAMA Ophthalmol. .

Abstract

Importance: This study could facilitate the generation of automated quantitative assessments, providing clinicians and clinical trials with a continuous severity scale of retinal leakage to improve the prediction of future diabetic retinopathy (DR) worsening.

Objective: To examine ultra-widefield fluorescein angiography (UWF-FA) retinal leakage associated with DR progression and complications.

Design, setting, and participants: This cohort study was a post hoc analysis of the DRCR Retina Network Protocol AA clinical trial. Participants were adults with nonproliferative diabetic retinopathy (NPDR). Data was collected from February 2015 to March 2020. Analysis was performed June 2023 to April 2024.

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

Main outcomes and measures: Time to Diabetic Retinopathy Severity Scale (DRSS) worsening of 2 or more steps, vitreous hemorrhage (VH), and proliferative diabetic retinopathy (PDR) over 4 years. Baseline and 1-year leakage index, calculated as the area with leakage divided by the total area in the analyzable retina on UWF-FA, were evaluated as risk factors.

Results: Among 537 eyes (363 participants; mean [SD] age, 61 [12] years; 183 [50%] male, 180 [50%] female), the baseline leakage index (mean [SD], 3.5% [3.9%]) was associated with DRSS worsening over 4 years (hazard ratio [HR] for 1% increase, 1.09; 95% CI, 1.05-1.13; P < .001). At 1 year, 114 of 453 eyes (25%) had an absolute leakage increase 1% or greater from baseline, which was associated with a higher risk of DRSS worsening over 4 years (61% vs 33%; HR, 2.63; 95% CI, 1.90-3.64; P < .001). Baseline leakage and a 1% or greater increase at 1 year were also associated with development of VH and PDR.

Conclusions and relevance: In eyes with NPDR, higher leakage at baseline and an increase from baseline to 1 year were associated with greater risk of DRSS worsening and vision-threatening complications, including VH and PDR. These findings support quantitative leakage assessment at baseline and over time as a promising biomarker for predicting the severity and progression of diabetic retinopathy.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Ehlers reported grants and personal fees from Regeneron, Novartis, Boehringer Ingelheim, Stealth, RegenxBIO, Aviceda, Astellas, Iveric Bio, Opthea, and Roche and personal fees from Perfuse, ONL Therapeutics, and Osanni outside the submitted work; and having had patents issued for “Analysis of angiographic imaging biomarkers in posterior segment ophthalmic diseases” and “Automated clinical evaluation of the eye: integrative imaging biomarker analysis with correlated phenotypic features and outcomes.” Dr Josic reported grants from Breakthrough T1D and some equipment for the study provided by Optos during the conduct of the study. Dr Aiello reported executive committee fees from the DRCR Retina Network to their institution during the conduct of the study. Dr Silva reported personal fees from Eyepoint, Bayer, AbbVie, and Optos and nonfinancial support from Optos outside the submitted work. Dr Sun reported grants from Jaeb Center for Health Research/National Eye Institute during the conduct of the study; grants from Boehringer Ingelheim, Roche, Genentech, Novo Nordisk, Physical Sciences, Breakthrough T1D, Massachusetts Lions Eye Research Fund, and Mary Tyler Moore Vision Initiative (through Mary Tyler Moore and S. Robert Levine, MD, Charitable Foundation); food at meetings, travel, and/or nonfinancial support from Alcon, Boehringer Ingelheim, Novo Nordisk, Adaptive Sensory Technology, Optovue, Konan, and LKC Technologies; and personal fees for serving as an editor for the American Diabetes and American Medical Association outside the submitted work. No other disclosures were reported.

References

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