Authors: Samuel A. Minaker, Ryan Mason, Motaz Bamakrid, Yung Lee, Rajeev Muni

Author Disclosure Block: S.A. Minaker: None. R. Mason: None. M. Bamakrid: None. Y. Lee: None. R. Muni: None.

Abstract Body:

Purpose: The role of inflammatory cytokines other than VEGF in RVO is increasingly recognized. Evidence suggests that inflammatory cytokines not only play a role in the pathogenesis of 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.
Study Design: Systematic review and meta-analysis.
Methods: A systematic search of peer-reviewed English-language articles from PubMed, Ovid MEDLINE, Ovid MEDLINE Epub (ahead of print) and EMBASE Classic plus EMBASE without year limitation was performed from March to December 2017. Data was extracted from the 97 studies that encompassed 2809 study eyes with RVO and 1187 control eyes by two independent investigators. Data was pooled using a random-effects model with the Comprehensive Meta-analysis software. Effect sizes were generated as standardized mean differences (SMD) of cytokine concentrations between patients with RVO and healthy controls and converted to the Hedges g statistic.
Results: Among the 3996 eyes in 97 studies, concentrations of IL-4 (SMD = 0.52, 95% confidence interval (CI) = 0.15 to 0.88, p = 0.006), IL-6 (SMD = 0.76, 95% CI = 0.40 to 1.11, p < 0.0001), IL-8 (SMD = 1.03, 95% CI = 0.77 to 1.29, p < 0.00001), IL-10 (SMD = 0.69, 95% CI = 0.43 to 0.95, p < 0.00001), IL-15 (SMD = 0.55, 95% CI = 0.22 to 0.88, p = 0.001), ANGPT (SMD = 1.99, 95% CI = 1.06 to 2.92, p < 0.0001), IFN-γ (SMD = 0.69, 95% CI = 0.25 to 1.13, p = 0.002), MCP-1 (SMD = 1.21, 95% CI = 0.82 to 1.59, p < 0.00001), PDGF-AA (SMD = 0.68, 95% CI = 0.25 to 1.10, p = 0.002), and VEGF (SMD = 1.17, 95% CI = 0.91 to 1.43, p = 0.001) were significantly higher in patients with RVO when compared to healthy controls. No differences or failed sensitivity analyses were found between patients with RVO and healthy controls for the concentrations of IL-1α (SMD = 0.53, 95% CI = 0.11 to 0.94, p = 0.01), IL-1β (SMD = 0.76, 95% CI = -0.10 to 1.63, p = 0.08), IL-2 (SMD = 0.55, 95% CI = 0.14 to 0.96, p = 0.009), IL-12 (SMD = 0.61, 95% CI = 0.09 to 1.12, p = 0.02), IL-13 (SMD = 0.39, 95% CI = -0.20 to 0.97, p = 0.20), b-FGF (SMD = 0.64, 95% CI = -0.44 to 1.73, p = 0.25), PEDF (SMD = 0.36, 95% CI = -1.64 to 2.36, p = 0.73), TGF-β (SMD = 2.22, 95% CI = 0.42 to 4.03, p = 0.02), and TNF-α (SMD = -0.14, 95% CI = -0.80 to 0.52, p = 0.67) cytokines. Too little data made the comparison impossible for CXCL9, CXCL12, EGF, eotaxin, FGF-6, G-CSF, GM-CSF, ICAM-1, IGFBP, IL-5, IL-7, IL-9, IL-17, IL-18, IL-23, MIP-1, MMP, PDGF-BB, PGF, RANTES, SAA, sICAM-1, sVEGFR, TIMP-4, or TSG-14.
Conclusions: Our meta-analysis demonstrated higher aqueous and vitreous concentrations of IL-4, IL-6, IL-8, IL-10, IL-15, ANGPT, IFN-γ, MCP-1, PDGF-AA, and VEGF in patients with RVO, strengthening the clinical evidence that RVO is accompanied by an inflammatory response and that cytokines in addition to VEGF have the potential to be useful biomarkers and therapeutic targets in RVO.