Molecular Biomarkers of Neovascular Age-Related Macular Degeneration With Incomplete Response to Anti-Vascular Endothelial Growth Factor Treatment

Abstract

The standard treatment for neovascular age-related macular degeneration (nAMD) consists of intravitreal anti-vascular endothelial growth factors (VEGF). However, for some patients, even maximal anti-VEGF treatment does not entirely suppress exudative activity. The goal of this study was to identify molecular biomarkers in nAMD with incomplete response to anti-VEGF treatment. Aqueous humor (AH) samples were collected from three groups of patients: 17 patients with nAMD responding incompletely to anti-VEGF (18 eyes), 17 patients affected by nAMD with normal treatment response (21 eyes), and 16 control patients without any retinopathy (16 eyes). Proteomic and multiplex analyses were performed on these samples. Proteomic analyses showed that nAMD patients with incomplete anti-VEGF response displayed an increased inflammatory response, complement activation, cytolysis, protein-lipid complex, and vasculature development pathways. Multiplex analyses revealed a significant increase of soluble vascular cell adhesion molecule-1 (sVCAM-1) [ p = 0.001], interleukin-6 (IL-6) [ p = 0.009], bioactive interleukin-12 (IL-12p40) [ p = 0.03], plasminogen activator inhibitor type 1 (PAI-1) [ p = 0.004], and hepatocyte growth factor (HGF) [ p = 0.004] levels in incomplete responders in comparison to normal responders. Interestingly, the same biomarkers showed a high intercorrelation with r2 values between 0.58 and 0.94. In addition, we confirmed by AlphaLISA the increase of sVCAM-1 [ p < 0.0001] and IL-6 [ p = 0.043] in the incomplete responder group. Incomplete responders in nAMD are associated with activated angiogenic and inflammatory pathways. The residual exudative activity of nAMD despite maximal anti-VEGF treatment may be related to both angiogenic and inflammatory responses requiring specific adjuvant therapy. Data are available via ProteomeXchange with identifier PXD02247

Fluid dynamics between injections in incomplete anti-VEGF responders within neovascular age-related macular degeneration: a prospective observational study

“…AMD is a complex disease and its pathophysiology combines many different pathways, including among others, inflammatory molecules, the complement system, and lipoprotein metabolism, in addition to the influence of genetic susceptibility and environmental factors [38]. On that matter, we have previously reported an increase in inflammatory and vasoproliferative biomarkers in the aqueous humor of patients with incomplete response to anti-VEGF (some of them being included in this study as well), compared to a control group of standard nAMD patients [7] supporting the idea that other (anti-VEGF independent) mechanisms may be implicated. These findings may justify future studies about adjuvant antiinflammatory treatment in this selective set of patients.…”

“…Some masquerading pathologies could be the origin of unresponsive fluid on OCT, such as central serous chorioretinopathy (CSC), epiretinal membranes, vitreomacular traction syndrome, or inflammatory causes [7,25]. Therefore, we carefully analyzed the baseline multimodal imaging in order to detect any signs related to these pathologies.…”

“…Despite good efficacy of anti-VEGF treatments in nAMD, some cases remain poor responders. Several terms have been used to qualify a suboptimal response to treatment, such as "incomplete anti-VEGF response", "unresponsive", "refractory to anti-VEGF", or "resistant to anti-VEGF" to name a few [6,7]. Although no consensus exists on the definition of this condition, "refractory nAMD" has been proposed to comprise cases with evidence of exudative activity after 6 or more monthly IVI [6,8].…”

“…In case of complete absorption and rapid recurrence, VEGF might be the main mediator. However, in case of nonresolution even under intensive anti-VEGF treatment the remaining fluid might be related to VEGF-independent pathogenic pathways [7].…”

Caffeine Inhibits Choroidal Neovascularization Through Mitigation of Inflammatory and Angiogenesis Activities

“…Thus, in patients receiving anti-VEGF therapy for nAMD, the amount of VEGF needs to be reduced to prevent vascular inflammation, excessive permeability, and pathologic neovascularization but not so low to cause RPE atrophy. Clinically, this is challenging to establish and maintain, which may also explain, at least in part, the incomplete response to anti-VEGF noted in 30% of patients with nAMD ( Mantel et al, 2020 ; Maroñas et al, 2020 ).…”