Changes in Aqueous and Vitreous Inflammatory Cytokine Levels in Retinal Vein Occlusion: A Systematic Review and Meta-analysis

Purpose: Evidence suggests that inflammatory cytokines not only play a role in the pathogenesis of retinal vein occlusion (RVO) but also may be useful as biomarkers to predict disease severity and response to treatment. We aimed to quantitatively summarize data on inflammatory cytokines associated with RVO. Methods: A systematic search of peer-reviewed English-language articles was performed without year limitation up to August 19, 2019. Studies were included if they provided data on aqueous or vitreous cytokine concentrations in patients with RVO. Data were extracted from 116 studies that encompassed 3242 study eyes with RVO and 1402 control eyes. Effect sizes were generated as standardized mean differences (SMDs) of cytokine concentrations between patients with RVO vs controls. Results: Among the 4644 eyes in 116 studies, aqueous and vitreous concentrations (SMD, 95% CI, and P value) of interleukin (IL)-6 (aqueous: 1.23, 0.65 to 1.81, P <.001 vitreous: 0.70, 0.49 to 0.90, P <.001), IL-8 (aqueous: 1.11, 0.73 to 1.49, P <.001; vitreous: 1.19, 0.73 to 1.65, P <.001), monocyte chemoattractant protein 1(aqueous: 1.22, 0.72 to 1.72, P <.001; vitreous 1.42, 0.92 to 1.91, P <.001), vascular endothelial growth factor (VEGF) (aqueous: 1.52, 1.09 to 1.94, P <.001; vitreous: 0.99, 0.78 to 1.21, P <.001) were significantly higher in patients with RVO than in healthy controls. Only aqueous concentrations of IL-10 (0.81, 0.45 to 1.18, P <.001), angiopoietin 4 (1.96, 0.92 to 3.00, P <.001), and platelet-derived growth factor (PDGF)-AA (0.82, 0.35 to 1.30, P <.001) were significantly higher in patients with RVO than in healthy controls. Only the vitreous concentration of soluble intercellular adhesion molecule-1 (sICAM-1) (1.23, 0.83 to 1.63, P <.001) was significantly higher in patients with RVO. No differences, failed sensitivity analyses, or insufficient data were found between patients with RVO and healthy controls for the concentrations of the remaining cytokines. Conclusions: Several cytokines in addition to VEGF have the potential to be useful biomarkers and therapeutic targets in RVO.