Elevated tumor necrosis factor alpha and vascular endothelial growth factor in intermediate age-related macular degeneration and geographic atrophy

Introduction: Tumor necrosis factor alpha (TNF-alpha) is an inflammatory cytokine implicated in pathological changes to the retinal pigment epithelium that are similar to changes in geographic atrophy (GA), an advanced form of age related macular degeneration (AMD). TNF-alpha also modulates expression of other cytokines including vascular endothelial growth factor (VEGF), leading to choroidal atrophy in models of AMD. The purpose of this study was to investigate systemic TNF-alpha and VEGF in patients with GA and intermediate AMD (iAMD) compared to controls without AMD. Methods: We examined plasma levels of TNF-alpha and VEGF in patients with GA, iAMD, and controls without AMD from the University of Colorado AMD registry (2014 to 2021). Cases and controls were characterized by multimodal imaging. TNF-alpha and VEGF were measured via multiplex immunoassay and data were analyzed using a non-parametric rank based linear regression model fit to plasma biomarkers. Results: There were 97 GA, 199 iAMD patients and 139 controls. TNF-alpha was significantly increased in GA (Median:9.9pg/ml, IQR:7.3-11.8) compared to iAMD (Median:7.4, IQR:5.3-9.1) and in both GA and iAMD compared to controls (Median:6.4, IQR:5.3-7.8), p<0.01 for all comparisons. VEGF was significantly increased in iAMD (Median:8.9, IQR:4.8-14.3) compared to controls (Median:7.7, IQR:4.6-11.1), p<0.01. There was a significant positive correlation between TNF-alpha and VEGF in GA (0.46, p<0.01), and iAMD (0.20, p=0.01) with no significant interaction between TNF-alpha and VEGF in any group. Discussion: These findings suggest TNF-alpha and VEGF may contribute to systemic inflammatory processes associated with iAMD and GA. TNF-alpha and VEGF may function as systemic biomarkers for disease development.