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Insights into retinal vein occlusion: mechanisms of action of aflibercept

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Image: Julian Lovell

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Dr Aude Ambresin* MD

Professor Francine Behar Cohen*

* Jules Gonin University Eye Hospital, Lausane, Switzerland

 

Retinal vein occlusion (RVO) is a global health concern which may affect men and women equally at working age. It has been estimated to affect 16.4 million people worldwide14 and is the second most common cause of vision loss due to retinal vascular disease.

While age is an important risk factor for RVO, which is more common in elderly populations, people of working age still account for one in six of RVO patients.15 Its prevalence may also be higher in Asian and Hispanic populations.10

Vision loss in RVO is due to a combination of non-perfusion and macular oedema through several different mechanisms: first, vein occlusion occurs with impaired retinal blood flow leading to haemodynamic and vascular changes. The blockage also causes increased intraluminal pressure in the capillaries, with metabolic disturbance leading to increased oxidative stress and inflammation. With a reduction of retinal perfusion, non-perfusion may develop increasing the secretion of vascular endothelial grown factor (VEGF) and placental growth factor (PlGF). This results in vascular remodelling and blood-retinal barrier (BRB) breakdown which all ultimately lead to leakage and oedema.

Branch retinal vein occlusion (BRVO) can occur at different sites in the retinal vasculature but occlusions in the major superotemporal region are most common.17 Occlusions affect a large area and are associated with a range of complications.18 Significant BRVO is associated with visual complications: 50 per cent of patients with BRVO have macular oedema at presentation and 20 per cent of patients with BRVO develop retinal non-perfusion, usually within the first six to 12 months of occlusion.19

The role of non-perfusion

Non-perfusion is an important clinical feature of central retinal vein occlusion (CRVO). Non-perfusion has been historically defined as more that 10 disc areas of retinal non-perfusion on fluorescein angiography. However, this definition has not always been consistent across different clinical trials. Up to 75 per cent of CRVO cases are non-ischaemic20,21 and 34 per cent progress to non-perfusion within three years. Non-perfused CRVO is associated with worse visual acuity outcomes than the non-perfused type.22,23 BRVO has a lower risk of conversion to ischaemic disease that CRVO.24

Non-perfusion is an indication of severity in RVO, involving a complicated cascade that gives rise to free radical production with cell death, oxidative stress, intracellular oedema and inflammation. All of this will progressively increase the levels of VEGF, PlGF and soluble cytokines interleukin (IL) 6 and 8 which lead to rupture of haematoretinal barrier and subsequent oedema.25,26

This is why it is important to identify ischaemic disease with the development of novel imaging techniques such a wide-field angiography and optical coherence tomography angiography. Wide-field angiography allows for detailed visualisation of retinal changes. A recent study by Prasac et al used ultra wide-field angiography to show a correlation between macular oedema and peripheral ischemia in BRVO and hemi-retinal vein occlusion (HRVO) patients.27 Untreated non-perfusion at any location was significantly associated with macular oedema and untreated non-perfusion anterior to the globe equator was also significantly associated with macular oedema.

Peripheral non-perfusion is not the only consideration, however. Optical coherence tomography angiography can be used to show macular oedema due to perimacular capillary network remodelling with the superficial plexus showing zones of non-perfusion. Macular oedema can also be due to a decrease in macular perfusion and it is important to remember that macular perfusion also influences the visual prognosis.25,29

Macular oedema in RVO is also associated with other multiple factors, including increases in VEGF, PlGF and VEGF receptor 1 (VEGFR-1) levels which are expressed on endothelial cells, retinal pigment epithelium and pericytes.30,31 It is also associated with oxidative stress in which cytokine levels are elevated, leading to blood-retinal barrier breakdown and microglial activation and inflammation.32

VEGF Interactions

It is known that VEGF-A interacts with VEGFR-1 and VEGFR-2, whereas PlGF binds only to VEGFR-1. The altered expression plays an important role in non-perfusion mediated retinal neovascularisation. Excessive activation of VEGFR-1 and VEGFR-2 by VEGF-A can result in pathological neovascularisation and excessive vascular permeability leading to macular oedema.33

RVO leads to a breakdown of retinal vasculature through pericyte loss and endothelial cell apoptosis. Vein occlusion in animal models induces immediate apoptosis of endothelial cells in occluded vessels and upstream capillaries, and also massive and delayed VEGFR-1/PlGF dependent pericyte loss from upstream capillaries.34 This all leads to increased leakage.

One other mechanism of action in RVO is microglia activation which induces inflammatory factors L-6 that are mediated through the VEGFR-1 pathway. L-6 is strongly associated with retinal thickness in CRVO and BRVO35 and microglia are the first inflammatory cells activated in response to retinal stress. PlGF inhibition can attenuate this inflammation.37

This is the pathophysiological background against which aflibercept has been bio-engineered to demonstrate strong, broad and long-lasting activity in visual impairment due to macular oedema secondary to RVO.38 Aflibercept is the first fusion protein with innovative dual action against both VEGF and PlGF.

In summary, RVO has a complex patholophysiology with multiple contributing factors. Visual acuity decreases are mainly due to non-perfusion and macular oedema. PVO is associated with high levels of VEGF and PlGF which increase with the severity of non-perfusion. Macular oedema results from blood-retinal barrier breakdown inflammation and vascular remodelling. As a drug specifically designed to strongly bind both VEGF and PlGF, aflibercept addresses multiple factors that contribute to RVO pathogenesis.

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Reproduced from an original article sponsored by Bayer, with permission from Eurotimes. www.escrs.org.

References available on request. Email editor Jeff Megahan j.megahan@optometry.org.au.



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