Longitudinal Assessment of Intraocular Cytokine Expression in Retinal Venous Occlusive Disease Following Anti-VEGF Therapy

Abstract

Purpose : Vascular endothelial growth factor (VEGF) is well established in the pathogenesis of ischemia and macular edema (ME) associated with retinal vein occlusion (RVO), but clinical response to anti-VEGF therapy is not universal. This study evaluates the longitudinal alterations in intraocular cytokine expression during anti-VEGF therapy in a prospective clinical trial setting.

Methods : The IMAGINE study is a post-hoc analysis of cytokine expression and imaging features in retinal vascular disease that includes the WAVE study cohort. The WAVE study was a prospective randomized trial evaluating ranibizumab monotherapy versus a combination ranibizumab and targeted retinal photocoagulation (TRP) to nonperfusion in 30 eyes with central, hemi- or branch retinal vein occlusions (CRVO, HRVO, BRVO). Aqueous samples were obtained at baseline and with every injection. Fifty-four cytokines associated with inflammation and angiogenesis, including VEGF, ANG1, G-CSF, IL-6, and TGF-alpha were measured in quadruplicate using 2 multi-plex arrays. Cytokine levels were also compared between monotherapy and combination therapy.

Results : Of the 30 eyes, 27 (90%) had sufficient samples. The mean age was 64 years. Twenty-one of 27 eyes (78%) were in the combination therapy group. At baseline, VEGF, ANGPTL4, IL-6 and leptin, FGF-4 and G-CSF were elevated. Compared to baseline, VEGF concentrations were significantly lower at month 4 (p=0.007) and trended towards a significant decline by month 9 (p=0.08). At month 4, FGF-4 and G-CSF were significantly decreased (p=0.02 and 0.04). ANGPTL4 showed a significant decline at month 9 (p=0.05). Additionally, VEGF levels decreased threefold with combination treatment versus monotherapy. Eyes with BRVO demonstrated higher expression levels of angiogenin and TGF-alpha compared to eyes with CRVO.

Conclusions : As novel therapies are integrated into RVO management, precision medicine in therapeutic selection may be critical to optimize outcomes. In this study, multiple cytokines are demonstrated to be elevated in eyes with RVO with variable modulation following anti-VEGF therapy. Multi-modal therapy resulted in greater reduction in VEGF burden. Future research will include correlation of imaging features with underlying cytokine expression for the exploratory assessment of imaging biomarkers.

This is a 2020 ARVO Annual Meeting abstract.