The effect of systemic levels of TNF-alpha and complement pathway activity on outcomes of VEGF inhibition in neovascular AMD

Abstract

Background/Objectives Systemic levels of pro-inflammatory cytokines and activated complement components affect the risk and/or progression of neovascular age-related macular degeneration (AMD). This study investigated the effect of serum pro-inflammatory cytokine levels and complement pathway activity on the clinical response to vascular endothelial growth factor (VEGF) inhibition in neovascular AMD. Methods Sixty-five patients with a new diagnosis of neovascular AMD were observed over a six-month period in a single-centre, longitudinal cohort study. At each visit, the visual acuity score (VAS), central macular thickness (CMT), serum levels of CRP, pro-inflammatory cytokines (TNF-α, IL-1β, IL-2, IL-6 and IL-8), and complement pathway activity were measured. Participant DNA samples were sequenced for six complement pathway single nucleotide polymorphisms (SNPs) associated with AMD. Results A statistically significant difference in VAS was observed for serum levels of TNF-α only: there was a gain in VAS (from baseline) of 1.37 for participants below the 1st quartile of mean concentration compared to a reduction of 2.71 for those above the 3rd quartile. Statistical significance was maintained after Bonferroni correction (P value set at <0.006). No significant differences in CMT were observed. In addition, statistically significant differences, maintained after Bonferroni correction, were observed in serum complement activity for participants with the following SNPs: CFH region (rs1061170), SERPING1 (rs2511989) and CFB (rs641153). Serum complement pathway components did not significantly affect VAS. Conclusions Lower serum TNF-α levels were associated with an increase in visual acuity after anti-VEGF therapy. This suggests that targeting pro-inflammatory cytokines may augment treatment for neovascular AMD.

The Changes of Irisin and Inflammatory Cytokines in the Age-Related Macular Degeneration and Retinal Vein Occlusion

“…On the contrary, the levels of IL-6, IL-8, and IL-10 in the aqueous of the RVO group were significantly higher, which is consistent with previous studies ( 50 , 51 ). TNF-α also plays a very important role in the pathogenesis of AMD as lower serum TNF-α levels were associated with an increase in visual acuity after anti-VEGF therapy in AMD patients ( 52 ). Bevacizumab, an anti-VEGF drug, was found to reduce the expression of IL-8 and TNF-α in RPE cells ( 53 ).…”

Effect of Humanin G (HNG) on inflammation in age-related macular degeneration (AMD)

“…Next, we tested the protein levels of cytokines and chemokines and investigated the effects of Humanin G treatment on the expression of the pro-inflammatory markers. TNF-α (Tumor Necrosis Factor alpha) is a key player in the pathogenesis of AMD as reduced TNF-α levels in the serum are associated with higher visual acuity score in AMD patients [ 57 ]. The transcription of TNF-α is genetically regulated and in the promoter region of the TNF-α gene, three SNPs were detected: TNF-α-863 (rs1800630), TNF-α-308 (rs1800629) and TNF-α-238 (rs361525).…”

Neuroprotection for Age-Related Macular Degeneration

“…Since certain genetic mutations may be associated with a less robust response to anti-VEGF treatments or to antioxidant/vitamin supplementation 5,66 , it follows that patients with different underlying genetic mutations may have different underlying pathophysiology and thus might require different treatments for optimal management. Moreover, given a possible contribution of inflammation and immune dysregulation in AMD pathogenesis, others have J o u r n a l P r e -p r o o f focused on identifying inflammatory biomarkers, including both general serum markers of inflammation and markers of complement activation 57,67 . Finally, since dysregulation of lipid metabolism is also thought to contribute to AMD pathogenesis, others have investigated whether patients with AMD also have systemic perturbations in lipid homeostasis 68,69 .…”