Changes in aqueous and vitreous inflammatory cytokine levels in nonproliferative diabetic retinopathy: systematic review and meta-analysis

Objective: Diabetic retinopathy is a complication of diabetes mellitus with the potential for significant patient morbidity. Although changes to intraocular inflammatory cytokines are integral to disease pathogenesis, studies have been inconsistent about which exact cytokines are associated with diabetic retinopathy. We aimed to quantitatively summarize proangiogenic and proinflammatory cytokines in nonproliferative diabetic retinopathy (NPDR), given its frequency among those with diabetes mellitus. Methods: A systematic literature search without year limitation to February 21, 2022, identified 59 studies assessing vitreous or aqueous cytokine levels in NPDR, encompassing 1378 eyes with NPDR and 1288 eyes from nondiabetic controls. Effect sizes were generated as standardized mean differences (SMD) of cytokine concentrations between patients with NPDR and controls. Results: Concentrations (SMD, 95% confidence interval, and p value) of aqueous interleukin-6 (IL-6) (2.58, 1.17-3.99; p = 0.0003), IL-8 (1.56, 0.39-2.74; p = 0.009), IL-17 (13.55, 7.50-19.59; p < 0.001), transforming growth factor beta (TGF-beta) (2.44, 1.02-3.85; p = 0.0007) and vascular endothelial growth factor (VEGF) (1.35, 0.76-1.93; p < 0.00001), and vitreous VEGF (1.49, 0.60-2.37; p = 0.001) were significantly higher in patients with NPDR when compared with those of healthy controls. Conclusions: These cytokines may serve as disease markers of the biochemical alterations seen in NPDR and may guide interventions, as we move into an era of more targeted therapeutics.