Bevacizumab Injection in Patients with Neovascular Age-Related Macular Degeneration Increases Angiogenic Biomarkers

Abstract

Purpose To evaluate the expression of 19 angiogenic biomarkers in the aqueous humor before and after intravitreal bevacizumab injection (IVB) in eyes with neovascular age-related macular degeneration (AMD). Design Prospective, noncomparative, interventional case series. Participants Twenty-three eyes of 23 treatment-naïve patients with choroidal neovascularization (CNV) secondary to neovascular AMD. Methods Eyes were diagnosed with CNV secondary to neovascular AMD and were treated with 3 monthly IVBs. Aqueous humor samples were obtained by anterior chamber paracentesis at baseline and immediately before each intravitreal bevacizumab injection. Main Outcome Measures Aqueous humor levels of 19 angiogenic biomarkers (angiopoietin 2, bone morphogenetic protein 9 [BMP-9], epidermal growth factor [EGF], endoglin, endothelin 1, fibroblast growth factor [FGF]-1 and FGF-2, follistatin, granulocyte colony-stimulating factor [GCSF], heparin-binding EGF-like growth factor [HB-EGF], hepatocyte growth factor [HGF], interleukin 8, leptin, placental growth factor [PLGF], vascular endothelial growth factor [VEGF]-A, VEGF-C, VEGF-D, and tissue inhibitor of metalloproteinases [TIMP]-1 and TIMP-2) were measured. Best-corrected visual acuity (BCVA), spectral-domain OCT parameters, and intraocular pressure also were evaluated. Results Baseline aqueous VEGF-A expression was elevated in all study eyes before treatment initiation. A statistically significant decrease of VEGF-A was observed at the 1- and 2-month follow-ups. A statistically significant increased concentration was observed in 7 biomarkers: VEGF-C, angiopoietin 2, endothelin 1, follistatin, HB-EGF, HGF, and interleukin 8. The other 11 study biomarker levels (VEGF-D, BMP-9, EGF, endoglin, FGF-1, FGF-2, GCSF, leptin, PLGF, TIMP-1, and TIMP-2) did not show any significant difference during follow-up. The BCVA statistically improved significantly at 2 months. Spectral-domain OCT parameters improved significantly at all follow-ups. Mean intraocular pressure values were not statistically different during the study period. Conclusions Despite a decrease in VEGF-A, the aqueous levels of VEGF-C, angiopoietin 2, endothelin 1, follistatin, HB-EGF, HGF, and interleukin 8 increased significantly after intravitreal injection of bevacizumab. These upregulated angiogenic biomarkers may represent new therapeutic targets in exudative AMD.

CCL1, IL-22, and IL-36β Have Higher Expression Levels in Aqueous Humor of Neovascular Age-Related Macular Degeneration Patients in Comparison to Cataract Patients

“…33 In a previous study, there was no significant difference in the aqueous concentration of FGF-α between nAMD group and control group, but FGF-α concentration increased significantly after intravitreal injection of bevacizumab. 35 In our study, FGF-α concentration was significantly higher in nAMD patients before and after two consecutive monthly ranibizumab injections, in comparison to cataract patients, which deserves further study.…”

“…In a previous study, BMP-9 did not show any significant difference between nAMD and cataract group, and there was no difference after intravitreal injection of bevacizumab in nAMD patients. 35 Our study found higher expression of BMP-9 in the aqueous humor of nAMD patients, compared with cataract patients, which needs further research in the future.…”

A Combination Therapy Targeting Endoglin and VEGF-A Prevents Subretinal Fibro-Neovascularization Caused by Induced Müller Cell Disruption

“…53 Our observation indicates that the potential neurotoxic side effects of anti-VEGF therapy should not be overlooked because patients with nAMD and diabetic macular edema require a significant number of anti-VEGF injections in clinical practice. 30,[33][34][35] We acknowledge that our transgenic model may not recapitulate the full features of nAMD in humans. In our transgenic mice, subretinal new vessels actually originate from the retinal vasculature, 25 which is different from the choroidal origin of new vessels in nAMD.…”

“…endothelin 1, follistatin, heparin-binding epidermal growth factor (HB-EGF), hepatocyte growth factor (HGF), and IL8. 35,36 TGFb signaling plays an important role in fibrosis and neovascularization in multiple organs, but there is limited information about how it contributes to subretinal fibroneovascularization. TGFb signaling begins with the binding of TGFb superfamily ligands to the TGFb type II receptor, leading to activation of the TGFb type I receptor and phosphorylation of Smad proteins.…”

Apratoxin S4 Inspired by a Marine Natural Product, a New Treatment Option for Ocular Angiogenic Diseases

“…4 Despite its efficacy, a substantial number of patients (15%-20%) are intrinsically refractory to anti-VEGF treatment or may develop resistance over time, which is likely due to the compensatory activation of alternative angiogenic pathways. Indeed, hepatocyte growth factor (HGF) 5 and erythropoietin 6 were reported to be upregulated in eyes treated with anti-VEGF agents. Besides its role in angiogenesis, VEGF exerts a potent neuroprotective effect 7 and mediates vascular 8 and organ 9 homeostasis.…”