Elena Gambicorti

Aflibercept in wet AMD: specific role and optimal use

Background Vascular endothelial growth factor (VEGF) is a naturally occurring glycoprotein in the body that acts as a growth factor for endothelial cells. It regulates angiogenesis, enhances vascular permeability, and plays a major role in wet age-related macular degeneration. The consistent association between choroidal neovascularization and increased VEGF expression provides a strong reason for exploring the therapeutic potential of anti-VEGF agents in the treatment of this disorder. Blockade of VEGF activity is currently the most effective strategy for arresting choroidal angiogenesis and reducing vascular permeability, which is frequently the main cause of visual acuity deterioration. In recent years, a number of other molecules have been developed to increase the efficacy and to prolong the durability of the anti-VEGF effect. Aflibercept (EYLEA®; Regeneron Pharmaceutical Inc and Bayer), also named VEGF Trap-eye, is the most recent member of the anti-VEGF armamentarium that was approved by the US Food and Drug Administration in November 2011. Because of its high binding affinity and long duration of action, this drug is considered to be a promising clinically proven anti-VEGF agent for the treatment of wet maculopathy. Objective This article reviews the current literature and clinical trial data regarding the efficacy and the pharmacological properties of VEGF-Trap eye and describes the possible advantages of its use over the currently used “older” anti-VEGF drugs. Methods For this review, a search of PubMed from January 1989 to May 2013 was performed using the following terms (or combination of terms): vascular endothelial growth factors, VEGF, age-related macular degeneration, VEGF-Trap eye in wet AMD, VEGF-Trap eye in diabetic retinopathy, VEGF-Trap eye in retinal vein occlusions, aflibercept. Studies were limited to those published in English. Results and conclusion Two Phase III clinical trials, VEGF Trap-eye Investigation of Efficacy and Safety in Wet AMD (VIEW) 1 and 2, comparing VEGF Trap-eye to ranibizumab demonstrated the noninferiority of this novel compound. The clinical equivalence of this compound against ranibizumab is maintained even when the injections are administered at 8-week intervals, which indicates the potential to reduce the risk of monthly intravitreal injections and the burden of monthly monitoring.

Proliferative Vitreoretinopathy after Eye Injuries: An Overexpression of Growth Factors and Cytokines Leading to a Retinal Keloid

Eye injury is a significant disabling worldwide health problem. Proliferative Vitreoretinopathy (PVR) is a common complication that develops in up to 40–60% of patients with an open-globe injury. Our knowledge about the pathogenesis of PVR has improved in the last decades. It seems that the introduction of immune cells into the vitreous, like in penetrating ocular trauma, triggers the production of growth factors and cytokines that come in contact with intra-retinal cells, like Müller cells and RPE cells. Growth factors and cytokines drive the cellular responses leading to PVRs development. Knowledge of the pathobiological and pathophysiological mechanisms involved in posttraumatic PVR is increasing the possibilities of management, and it is hoped that in the future our treatment strategies will evolve, in particular adopting a multidrug approach, and become even more effective in vision recovery. This paper reviews the current literature and clinical trial data on the pathogenesis of PVR and its correlation with ocular trauma and describes the biochemical/molecular events that will be fundamental for the development of novel treatment strategies. This literature review included PubMed articles published from 1979 through 2013. Only studies written in English were included.

Systemic thromboembolic adverse events in patients treated with intravitreal anti-VEGF drugs for neovascular age-related macular degeneration: An overview

Introduction: Anti-VEGF therapy improved the quality of life for millions of patients suffering from wet age-related macular degeneration (wet-AMD); unfortunately, this therapy involves multiple injections over many years. The administration of anti-VEGF can overcome the blood-retinal barrier with agents entering the systemic circulation and causing a significant decrease in VEGF serum concentration. Although circulating VEGF protects the integrity and patency of vessels, prolonged anti-VEGF treatment has the potential to increase the risk of thromboembolic events. Areas covered: In this review, we discuss the safety data from recent trials involving available anti-VEGF drugs. Expert opinion: During the 2 years of follow-up in the relevant clinical trials, the rates of serious adverse events such as stroke, heart attack and death were similar for patients treated with different anti-VEGF drugs. Moreover the arterial thrombotic risk appears sufficiently low when compared with the natural incidence of arterial thrombotic events in this category of elderly patients and acceptably balanced against the advantage of improved vision. Since the use of these drugs is likely to become increasingly widespread and prolonged, it is desirable that the scientific community improves the pharmacovigilance program on all anti-VEGF drugs, expanding knowledge with studies that compares head to head all four compounds belonging to anti-VEGF armamentarium.

Pharmacokinetic and Pharmacodynamic Properties of Anti-VEGF Drugs After Intravitreal Injection

Subretinal neovascularization and pathologic ocular angiogenesis are common causes of progressive, irreversible impairment of central vision, and dramatically affect quality of life. Anti-vascular endothelial growth factor (anti-VEGF) therapy has improved the quality of life for many patients with age-related macular degeneration, diabetic retinopathy, and other ocular diseases involving neovascularization and edema. In these pathologies, the inhibition of intraocular VEGF is the only therapy that can preserve vision. Four anti-VEGF drugs are currently used to treat ocular neovascularization; pegaptanib, ranibizumab, and aflibercept have been approved for this condition, while bevacizumab can be used off-label. Anti-VEGF therapy is administered regularly for many months or years because its suspension or discontinuation may cause recurrence of neovascularization. On the other hand, VEGF is necessary for the survival of retinal and choroidal endothelial cells. Experimental studies in animal models have shown that local inhibition of VEGF causes thinning and atrophy of the choriocapillaris and degeneration of photoreceptors, primarily cones. These studies combined with clinical experience indicated that prolonged VEGF inhibition could impair retinal function. Moreover, anti-VEGF compounds can cross the blood-retina barrier, enter the systemic circulation, and inhibit serum VEGF. Since circulating VEGF protects blood vessel integrity, prolonged anti-VEGF treatment could induce thromboembolic adverse events from vascular causes such as heart attack and stroke, and even death. The ocular dosing regimen and systemic toxicity of anti-VEGF compounds are therefore central concerns. A better understanding of this topic requires knowledge of the metabolism, tissue distribution, and clearance of anti-VEGF compounds. This manuscript reviews the properties of anti-VEGF compounds following intravitreal administration.

Current Trends about Inner Limiting Membrane Peeling in Surgery for Epiretinal Membranes

The inner limiting membrane (ILM) is the basement membrane of the Müller cells and can act as a scaffold for cellular proliferation in the pathophysiology of disorders affecting the vitreomacular interface. The atraumatic removal of the macular ILM has been proposed for treating various forms of tractional maculopathy in particular for macular pucker. In the last decade, the removal of ILM has become a routine practice in the surgery of the epiretinal membranes (ERMs), with good anatomical results. However many recent studies showed that ILM peeling is a procedure that can cause immediate traumatic effects and progressive modification on the underlying inner retinal layers. Moreover, it is unclear whether ILM peeling is helpful to improve vision after surgery for ERM. In this review, we describe the current understanding about ILM peeling and highlight the beneficial and adverse effects associated with this surgical procedure.

Heavy Silicone Oil and Intraocular Inflammation

In the past two decades, many advances have been made in vitrectomy instrumentation, surgical techniques, and the use of different tamponade agents. These agents serve close retinal breaks, confine eventual retinal redetachment, and prevent proliferative vitreoretinopathy (PVR). Long-acting gases and silicone oil are effective internal tamponade agents; however, because their specific gravity is lower than that of the vitreous fluid, they may provide adequate support for the superior retina but lack efficacy for the inferior retina, especially when the fill is subtotal. Thus, a specific role may exist for an internal tamponade agent with a higher specific gravity, such as heavy silicone oils (HSOs), Densiron 68, Oxane HD, HWS 45-300, HWS 46-3000, and HeavySil. Some clinical evidence seems to presume that heavy tamponades are more prone to intraocular inflammation than standard silicone if they remain in the eye for several months. In this review, we discuss the fundamental clinical and biochemical/molecular mechanisms involved in the inflammatory response after the use of heavy tamponade: toxicity due to impurities or instability of the agent, direct toxicity and immunogenicity, oil emulsification, and mechanical injury due to gravity. The physical and chemical properties of various HSOs and their efficacy and safety profiles are also described.

Efficacy and vitreous levels of topical NSAIDs

Introduction: Nonsteroidal anti-inflammatory drugs (NSAIDs) are one of the most commonly prescribed medications and are routinely used for their analgesic, antipyretic, and anti-inflammatory properties. Because of their potent cyclooxygenase-inhibitory activity, they can inhibit pro-inflammatory prostaglandin synthesis, leading to complex inflammatory cascades. NSAIDs have been broadly used systemically for many decades and have recently become commercially available in the form of topical ophthalmic formulations. NSAIDs are weak acids with pKa values mostly between 3.5 and 4.5 and are poorly water-soluble. New, aqueous ophthalmic solutions of NSAIDs that afford better tissue penetration have recently been developed. In ophthalmological practice, topical NSAIDs are mostly used to stabilize pupillary dilation during intraocular surgery, manage postoperative pain and inflammation, and treat pseudophakic cystoid macular edema. Areas covered: This review focuses on the vitreous penetration of topical NSAIDs and their potential clinical applications in the treatment of retinal diseases. Expert opinion: A growing body of evidence suggests that NSAIDs may be beneficial in the treatment of age-related macular degeneration, diabetic retinopathy, and ocular tumors. Recent studies from our group and other authors have shown that the vitreous levels of NSAID exceed the median inhibitory concentration, which can significantly decrease vitreous PGE2 levels.

Heavy and standard silicone oil: intraocular inflammation

PurposeProliferative vitreoretinopathy in the inferior retina remains clinically challenging. Heavier-than-water intraocular tamponades have been developed to improve inferior tamponading properties, and their chemical compositions have been substantially improved over the years, in parallel with developments in vitrectomy instrumentation and surgical techniques. Herein we present an updated review of the clinical use of standard formulations and HSO, focusing on analysis of the intraocular inflammation associated with endotamponade agents, and comparison of the adverse effects of these agents on the physical and biological properties of the eye.MethodsA detailed literature search was conducted on PubMed, EMBASE, Cochrane Library, and Google Scholar using the key words. Fifty-eight articles matched our inclusion criteria that were included in this systematic review.ResultsPerfluorocarbon liquids and partially fluorinated alkanes are associated with tamponade emulsification, intraocular inflammation, and rises in intraocular pressure, but these associations are not as strong when these substances are mixed with a heavy silicone oil (HSO). Two recently approved heavy silicone oil tamponades, Oxane HD and Densiron 68, are now available for use in clinical practice. While the complication spectrum of the new generation of these HSOs seems to be similar to that of conventional silicone oil tamponades, they provide better support for the inferior retina and the posterior pole.ConclusionBoth regular and heavy silicone oils usually yield good success rates in cases of complicated retinal detachment. Decisions as to whether to utilize heavy or regular silicone oil should be made on a case-by-case basis.

Controversies over the role of internal limiting membrane peeling during vitrectomy in macular hole surgery.

Surgical management of an idiopathic macular hole consists of vitrectomy to release vitreofoveal traction and intraocular tamponade to flatten and reappose the holes edges. The intentional atraumatic removal of the internal limiting membrane has been proposed as cost-effective option in macular hole surgery. The internal limiting membrane contributes to tangential traction at the edges of the hole and acts as a platform on which glial cells proliferate. Removal of the internal limiting membrane increases the elasticity of the denuded macula and improves the anatomical success rate; however, the visual consequences of this surgical maneuver are still not fully known. We discuss the beneficial and adverse effects associated with internal limiting membrane peeling in macular hole surgery, highlighting the internal limiting membranes role in macular hole etiology and pathogenesis and the anatomical and functional findings after its removal.

ILM peeling in nontractional diabetic macular edema: review and metanalysis

PurposeTo evaluate the effect of internal limiting membrane (ILM) peeling during vitrectomy for nontractional diabetic macular edema.MethodsPUBMED, MEDLINE and CENTRAL were reviewed using the following terms (or combination of terms): diabetic macular edema, nontractional diabetic macular edema, internal limiting membrane peeling, vitrectomy, Müller cells. Randomized and nonrandomized studies were included. The eligible studies compared anatomical and functional outcomes of vitrectomy with or without ILM peeling for tractional and nontractional diabetic macular edema. Postoperative best-corrected visual acuity and central macular thickness were considered, respectively, the primary and secondary outcomes. Meta-analysis on mean differences between vitrectomy with and without ILM peeling was performed using inverse variance method in random effects.ResultsFour studies with 672 patients were eligible for analysis. No significant difference was found between postoperative best-corrected visual acuity or best-corrected visual acuity change of ILM peeling group compared with nonpeeling group. There was no significant difference in postoperative central macular thickness and central macular thickness reduction between the two groups.ConclusionsThe visual acuity outcomes in patients affected by nontractional diabetic macular edema using pars plana vitrectomy with ILM peeling versus no ILM peeling were not significantly different. A larger prospective and randomized study would be necessary.