Association of Aqueous Cytokine Expression with Quantitative Leakage Patterns on Ultra-widefield Angiography in the PRIME Study

Abstract

Purpose : To investigate the link between aqueous cytokine expression and quantitative leakage phenotypes on ultra-widefield fluorescein angiography (UWFA) in diabetic retinopathy (DR).

Methods : Patients with DR enrolled in the prospective randomized PRIME trial were included in this study. Baseline aqueous samples were analyzed for cytokine expression using a multi-plex ELISA assay for 54 cytokines. UWFA scans from the same visit were utilized for automated machine learning-enhanced quantitative analysis to obtain perivascular leakage index (PLI) and general leakage index (GLI) with manual correction, as needed. Perivascular leakage was denoted by hyperfluorescence within 5 pixels of the segmented vascular tree. Generalized leakage was all other leakage beyond the specified distance from the vessel. Pearson’s correlation was used to study the correlation between leakage metrics obtained from UWFA and 16 high expression cytokines found in >80% of the samples.

Results : Thirty-seven DR eyes without edema were included in this study. Significant correlations of panretinal PLI with ANGPTL4 (r=0.36, p=0.028) and angiostatin (r=0.37, p=0.025) were identified. Additionally, panretinal GLI significantly correlated with ANGPTL4 (r=0.40, p=0.015), IFNg (r=0.35, p=0.035), and CXCL16 (r=0.33, p=0.047). Foveal PLI significantly correlated with TNFa (r=0.40, p=0.015). Foveal GLI significantly correlated with VEGF-D (r=0.33, p=0.043), IL12p70 (r=0.34, p=0.039), and IL-17 (r=0.43, p=0.007). PlGF correlated significantly with foveal PLI/GLI ratio (r=0.48, p=0.002) and ANG-2 correlated significantly with panretinal PLI/GLI ratio (r=0.58, p=0.002).
Additional correlation trends were identified with panretinal PLI with HB-EGF (r=0.32, p=0.051) and follistatin (r=0.28, p=0.097). Panretinal GLI trended towards significant correlation with VEGF-A (r=0.28, p=0.091), HGF (r=0.28, p=0.097), IL-17 (r=0.28, p=0.090), and TNFb (r=0.28, p=0.092. Foveal PLI/GLI ratio showed correlation trend for ANG-2 (r=0.28, p=0.097).

Conclusions : In this analysis, PLI and GLI on UWFA demonstrate differential significant correlations with aqueous cytokine expression in eyes with DR. Further investigation with larger datasets is warranted to substantiate these associations and evaluate the potential role for these signals for treatment response.

This abstract was presented at the 2022 ARVO Annual Meeting, held in Denver, CO, May 1-4, 2022, and virtually.