|SYMPOSIUM - DIABETIC RETINOPATHY UPDATE
|Year : 2014 | Volume
| Issue : 1 | Page : 35-40
Proliferative diabetic retinopathy and the use of anti-vascular endothelial growth factors agents
Emily C Fletcher, Fadi Alkherdhaji
Department of Ophthalmology, Gloucester Retinal Research Group, Gloucester NHS Foundation Trust, Gloucester GL1 3NN, United Kingdom
|Date of Web Publication||3-Mar-2015|
Dr. Emily C Fletcher
Gloucester Royal Hospital, Great Western Way, Gloucester GL1 3NN
Source of Support: None, Conflict of Interest: None
Current gold standard treatment for proliferative diabetic retinopathy (PDR) is panretinal photocoagulation (PRP) aimed at reducing the drive for new vessel proliferation. The focus is now changing to include the use of anti-vascular endothelial growth factor (VEGF) agents in conjunction with the gold standard in order to improve efficacy and reduce known side-effects associated with PRP, thus providing better outcomes for this group of advanced retinopathy. This paper aims to summarize our current knowledge behind the development of PDR, with review of treatment with anti-VEGF agents. Systematic search of both PubMed and the Cochrane Central Register of Controlled Trials was performed to identify relevant articles. Only articles in the English-language were selected for review. The use of anti-VEGF agents in conjunction with PRP has been shown to be beneficial in the regression of new vessels, reduction of macular edema as well as reduced duration of vitreous hemorrhage. In addition, its use during surgical intervention for PDR can reduce the duration of surgery and early postoperative complications. Despite the lack of large randomized controlled trials in this area there is significant evidence from case series showing the beneficial as well as the adverse effects of this treatment modality. The need for a large randomized controlled trial is an important development for diabetic retinopathy management.
Keywords: Bevacizumab, panretinal photocoagulation, proliferative diabetic retinopathy, ranibizumab, scatter laser, tractional retinal detachment, vascular endothelial growth factor, vitreous hemorrhage
|How to cite this article:|
Fletcher EC, Alkherdhaji F. Proliferative diabetic retinopathy and the use of anti-vascular endothelial growth factors agents. Egypt Retina J 2014;2:35-40
|How to cite this URL:|
Fletcher EC, Alkherdhaji F. Proliferative diabetic retinopathy and the use of anti-vascular endothelial growth factors agents. Egypt Retina J [serial online] 2014 [cited 2021 Jun 21];2:35-40. Available from: https://www.egyptretinaj.com/text.asp?2014/2/1/35/152486
| Introduction|| |
Proliferative diabetic retinopathy (PDR) is a major cause of blindness despite significant improvements worldwide in both screening and treatment protocols for systemic diabetic control and retinopathy alike. The prevalence of PDR is related to the type of diabetes (Type I or II), the duration and the age at diagnosis. This accounts for a range of prevalence as high as 62% in Type I to 5% of Type II patients who were diagnosed before the age of 30 with at least 20 years of diabetes. , Other major risk factors in addition to the duration of diabetes, include glycemic control, blood pressure and lipid levels. PDR is characterized by the development of new vessels from either the venous or arterial circulation in response to increased retinal ischemia. The development of neovascularization can lead to sudden, profound and permanent visual loss and therefore remains a serious end-stage development and an important public health issue. Panretinal photocoagulation (PRP) treatment was introduced in 1976 following the Diabetic Retinopathy Study, which showed treatment reduced the 2 years risk of severe visual loss by 50% in patients with high risk characteristics (HRC). , These HRC are defined as:
- The presence of vitreous hemorrhage,
- New vessels at the disc which are ≥ 1/4-1/3 disc area in size
- New vessels elsewhere (NVE) ≥1/2 disc area in size if associated with vitreous hemorrhage.
In addition, the Early Treatment Diabetic Retinopathy Study showed that although the development of HRC was reduced by 50% with early treatment with PRP, that is, in patients with severe non-PDR, or PDR without HRC, but did not show a parallel reduction in the rate of severe vision loss across the two groups. Therefore, it is recommended that treatment be initiated once HRC were present.  Laser however is not without its issues; such as loss of peripheral visual field, loss of visual acuity, in addition to its lack of efficacy despite good PRP coverage in a small percentage of patients. In light of this, adjuvant treatment with anti-vascular endothelial growth factor (VEGF) agents has been the subject of more recent investigation in order to enhance the treatment of new vessel regression. This paper looks at the pathogenesis behind the development of PDR and reviews current literature in relation to PDR and anti-VEGF treatment.
A comprehensive and systematic literature search was performed by the authors for published studies on PubMed database and the Cochrane Central Register of Controlled Trials using the following search terms: PDR; PRP; scatter laser; anti-VEGF; ranibizumab; lucentis; bevacizumab; avastin; vitreous hemorrhage and tractional retinal detachment (TRD) in various combinations. We also searched the clinicaltrials.gov network. There were no date restrictions; however, we restricted our publication search to articles written in the English-language.
The abstracts were reviewed to identify relevance to the review followed by full article selection.
| Development of Proliferative Diabetic Retinopathy|| |
Retinal new vessel growth at the vitreo-retinal interface is the hallmark of PDR. They are defined by location; either at the optic disc (new vessels on the disc [NVD]) defined as: "At or within one disc diameter of the optic disc," NVE in the retina or new vessels in the anterior chamber angle or iris resulting in neovascular glaucoma.
The development of PDR includes several complex mechanisms many of which are related to hyperglycemia induced pathways such as increased oxidative stress, metabolic abnormalities and increased retinal blood flow. , Resultant damage to the endothelial cell lining of the retinal vessels, along with alterations in the platelet function and thrombocytic pathway can produce a shift in local blood flow to the retina. This regional closure of the retinal capillaries results in retinal hypoxia, which has two effects; first, it induces increased expression of several genes  with corresponding increased production of VEGF,  and erythropoietin (EPO). Second, stimulation of increased production of cytokines , producing a low grade inflammatory response within the retinal vessels. Activation of these potent signaling pathways promotes endothelial cell growth, migration, and differentiation resulting in a combination of both inflammation and angiogenesis. Diffusion of these growth factors and cytokines into and throughout the vitreous and anterior chamber allows promotion of neovascularization either at the edge of the ischemic retina, or at distant sites such as the optic disc and anterior chamber.  Investigation of vitreous and aqueous samples has shown an increased level of not only VEGF in comparison to normal controls, but also other cytokines. There have been 16 inflammatory cytokines identified that are independent of the VEGF levels.  VEGF concentrations have been shown to be increased by inflammatory mediators.  This supports the hypothesis that both inflammation and hypoxia are causative mechanisms, which need to be targeted in a treatment protocol. EPO is known to be increased in the vitreous of PDR in comparison to controls independent of VEGF.  The levels of EPO and VEGF have been linked to the hemoglobin A1c. 
The resultant developing new vessels use the vitreous as a scaffold on which to proliferate. Contraction of these fibrocellular membranes causes traction on the new vessels with subsequent loss of vision due to vitreous hemorrhage or TRD.
Vascular endothelial growth factor is made up of a family of growth factors and although there are several members of the VEGF group the only one that remains relevant in diabetic retinopathy is VEGF-A which is a 45 kDa glycosylated protein. These signaling proteins are responsible for both the de novo formation of the vascular system in the embryo - vasculogenesis, as well as the subsequent process of angiogenesis, which is the reorganization of the established endothelial cells in order to form the vascular network. The development of new vessels follows complex and sequential activation of a number of receptors of which VEGF is shown to be the rate limiting step. VEGF is also responsible for endothelial cell survival by preventing apoptosis of these cells. Once VEGF is blocked there is widespread apoptosis in the neovascular vessels. The VEGF signaling however, only influences the newly developed endothelial cells, having little effect on the established vessels. It is thought that once the pericytes cover the vessel, the influence of VEGF is diminished.  In addition to its effect on the development and survival of endothelial cells, VEGF also influences the vascular permeability with a role for the extravasation of fibrin which possibly provides a scaffold for the angiogenic vessels. This area of its role however is not yet fully established. Regulation of the VEGF gene expression is influenced by low oxygen tensions, that is, hypoxia. This environment stimulates the production of a protein called hypoxia inducible factor-1 (HIF-1). This in turn binds to the VEGF gene and initiates transcription of intracellular VEGF-A. The VEGF-A binds to one of two tyrosine kinase receptors on the endothelial cell surface - VEGF receptor-1 (VEGFR-1) also called Flt-1 and VEGF receptor-2 (VEGFR-2) also called kinase domain region. VEGFR-1 expression is upregulated by HIF-1. Binding of the VEGF to the receptor initiates an intracellular signaling pathway, by activating the mitogen-activated protein, which in turn stimulates endothelial cell proliferation. Cell migration is enabled through the VEGF-A stimulation of the endothelial cells to release matrix metallo-proteinases, which activates the degradation of basement membranes enabling migration.  Cell migration through this matrix is regulated by integrins released by the activated endothelial cells.  The newly formed vessels are then stabilized with the formation of basement membranes, a pathway regulated by platelet-derived growth factors.
Current therapies are therefore directed at not only the control of the systemic features of diabetes in order to modify the hyperglycemic environment, but also local treatment in the eye to reduce the hypoxic drive from the retina via PRP. It does therefore not seem unreasonable that combination of systemic control, local treatment and reduction of both the VEGF and inflammatory drive may result in improved visual outcomes.
Reduction of hypoxic drive via PRP treatment by destroying the retinal cells reduces the oxidative demand, is as discussed above, very effective however, associated unwanted side effects from PRP such as pain during the procedure, loss of central vision due to macular edema, , peripheral visual field constriction (influencing driving visual fields), , reduced dark adaption, reduced accommodation, inadvertent central macular laser burn and loss of color vision  has led to the need for adjuvant therapy to be considered. In addition, despite optimal medical management, and full laser photocoagulation a proportion of patients , (5-8%) have persistent neovascularization or even progression, requiring further laser or vitrectomy in order to prevent visual loss. Pattern scan laser (PASCAL) has been developed in order to reduce some of the adverse effects of the more traditional argon laser. Conventional argon laser produces a thermal burn of the retinal pigment epithelium. The PASCAL however produces mechanical disruption of the cells and is therefore less painful.  In addition, the ability for multispot application has allowed reduced treatment times by employing shorter single session application, with no additional effect on central retinal thickness, and equal effectiveness in NV regression in comparison to conventional single spot sessions. 
Subset analysis of the RIDE and RISE trials show that the cumulative probability of clinical progression of diabetic retinopathy at 2 years was 33.8% in the sham treated group versus 11.5% in the ranibizumab treated eyes.  This identified that anti-VEGF not only treated the maculopathy, but also potentially reduced rate of progression of retinopathy. Furthermore, its longstanding use in neovascular glaucoma  with dramatic resolution of anterior segment neovascularization, and the successful treatment of retinopathy of prematurity,  has provided the basis for this agent to be considered.
Initially, the use of anti-VEGF was used only for the treatment of vitreous hemorrhage under the rational that if the vitreous hemorrhage clears quickly it provides an adequate fundal view enabling retinal laser to be performed, detection of tractional detachment and reduces the need for vitrectomy. However, treatment with intravitreal ranibizumab in the Diabetic Retinopathy Clinical Research Network (DRCR.net) trial in this instance did not show any benefit over sham saline injections with regard vitrectomy rate in the treatment versus the sham group. 
The use of anti-VEGF agents as an adjunct to surgical treatment for PDR with meta-analysis results of randomized controlled trials showing a shorter duration of surgery, a shorter time for the resolution of vitreous hemorrhage, as well as less intra and early postoperative bleeding in comparison to vitrectomy alone.  A review of prevention of postoperative vitreous cavity hemorrhage after vitrectomy, found the use of preoperative anti-VEGF agents to reduce the rate of early onset of postoperative vitreous hemorrhage (within 3 weeks).  The timing of the administration of the anti-VEGF agent, that is, pre- or per-operatively was significant only in the rate of early recurrence of vitreous hemorrhage, that is, within 4 weeks of surgery, with simultaneous intravitreal anti-VEGF and vitrectomy showing best results. This is likely related to the duration of action of the anti-VEGF agent. 
| Evidence for Effect in Proliferative Diabetic Retinopathy|| |
Initial studies examining the effect of anti-VEGF with PDR included patients unresponsive to conventional laser treatment with several trials addressing the treatment of persistent new vessels despite adequate PRP.
Studies have shown resolution of the NV in 78.8%, 63.6% and 45.4% regression at 1, 3 and 6 months, respectively, following single intravitreal treatment with bevacizumab. This increased to 60.6% at 6 months for those who had a second injection after 3 months.  A prospective interventional case series  in which 17 patients (20 eyes) with HR-PDR were treated with a combination of bevacizumab and PRP showed all patients to have regression of new vessels by 3 months with mean regression time of NVD at 10.8 ± 3.4 weeks. However, 30% showed recurrence 3 months after the initial injection leading to an average of 1.4 injections required over an average follow-up time of 7.5 months.
Other studies from Arevalo et al.  repo rted on the location of the NV and the regression rates with intravitreal bevacizumab and PRP. Results from this retrospective study of 43 eyes in 39 patients showing 39.5% total regression (34.9% of eyes with NVE, 30.2% of eyes with NVD), 34.9% partial regression (23.3% of eyes with NVE, 32.5% of eyes with NVD) and 25.6% showed no regression (27.9% of eyes with NVE, 37.2% eyes with NVD). In addition, it again identified the duration of effect was limited suggesting that anti-VEGF alone is not sufficient as a treatment modality. Ranibizumab is shown to block the migration of retinal endothelial cells, but not the proliferation suggesting that anti-VEGF agents are not sufficient alone to prevent the progression of PDR,  and therefore should always be considered as an adjunctive treatment option.
Increased duration of effect has been shown in variable dose regimens with one study hypothesizing that higher doses may have longer duration of effect.  Higher dose injections (2.5 mg) of bevacizumab, however, have been associated with an increased risk of TRD  making more frequent injections more desirable than higher dose in order to provide a sustained effect.
In combination studies prospective comparison of PRP alone compared with PRP with ranibizumab in patients with HR-PDR showed patients receiving combination treatment had a significant reduction in area (mm 2 ) of fluorescein leakage in comparison to PRP alone. , The latter study identified that if the ranibizumab was given 1 week before the panretinal laser then the best corrected visual acuity at 3 months was worse in the PRP alone group with increased risk of vitreous hemorrhage (P = 0.023).
| Adverse Effects|| |
Anti-VEGF agents affect the rate of apoptosis in the new endothelial cells producing contraction of the fibrous tissue with resultant traction on the retina and new vessels which can cause both TRD and vitreous hemorrhage. The mechanical displacement effects on the vitreous via the introduction of fluid into the vitreous cavity are also thought to disturb the vitreous face and this in turn also produces a tractional element. Reports of increased risk of TRD following intravitreal anti-VEGF range can be as high as 18% with the majority occurring within 5 days of intravitreal injection. , As a result vitrectomy is recommended within 4 days of intravitreal injection. In comparison no increased incidence of TRD was found in the anti VEGF treated group in the DRCR net. 
The association of macular edema following PRP is a well-known complication and has often been attributed to extensive laser in a single session. In patients with a combination of both macular edema and PDR, injection of ranibizumab 1 week before the PRP helped to reduce the degree of postlaser diabetic macular edema. ,
| Conclusions|| |
Proliferative diabetic retinopathy results from both ischemic and inflammatory conditions in the retina as a result of poor hyperglycemic control in addition to duration of diabetes, and systemic control of lipids and blood pressure. This results in an increase in the VEGF levels in both the vitreous and the anterior chamber leading to proliferation of new vessels. Control of systemic risk factors as well as treatment with PRP has shown regression and stability in the majority of patients. However, a small number of patients continue to progress and are therefore nonresponsive, or show further signs of proliferation following initial but un-sustained response. In addition, PRP can produce side-effects resulting in the reduction of vision from loss of field, or macular edema among other complications. Adjuvant therapy from intravitreal treatment with an anti-VEGF agent has shown significant advances in both the reduction in the number of nonresponders as well as reducing some of the side-effects of treatment. However, in order to ascertain the correct timing of treatment (before or after PRP), dosage (increased dose with may provide longer duration of action, but possible increased side-effects), and frequency of administration a well-designed randomized control trial is required. Such a trial is currently underway in Europe to address some of these questions (PROTEUS trial). Treatment as a replacement for laser is not recommended due to the transient nature of its effect. More evidence is available for the surgical treatment of PDR. Meta-analysis data on the use of anti-VEGF treatment in conjunction with vitrectomy for resistant cases have shown to produce reduced surgical time and reduced early re-bleed rate in cases treated pre or during surgery. The risk of TRD can be addressed with the timing of administration in relation to the vitrectomy.
Interestingly, moving forward from here there is the evidence that VEGF alone is not the only aggravating factor. It may well be that in addition to anti-VEGF treatment we need to address the inflammatory pathway in order to fully control this advanced stage of disease.
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