Induction of vascular endothelial growth factor receptor expression in human umbilical vein endothelial cells after repeated bevacizumab treatment in vitro

AIM: To investigate the mechanism underlying the loss of responsiveness to anti-vascular endothelial growth factor (VEGF) treatment after repeated injections for choroidal neovascularization, VEGF and VEGF receptor (VEGFR) expressions were evaluated following repeated bevacizumab treatments in hypoxic human umbilical vein endothelial cells (HUVECs) in vitro. METHODS: HUVECs were incubated under hypoxic conditions in two media of different bevacizumab concentrations (1.0 or 2.5 mg/mL) for 17h, and then in a new medium without bevacizumab for 7h. This procedure was repeated twice more. A culture with an identical volume of excipients served as the control. Cytotoxicity and cell proliferation were assessed using 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl tetrazolium bromide and Ki-67 assays, respectively. Levels of VEGF and VEGFR were assessed using enzyme-linked immunosorbent assay and Western blot respectively. RESULTS: Cytotoxic effects were not reported for either bevacizumab concentration. Cell proliferation was not reduced after anti-VEGF treatments. VEGF level after single treatment was significantly higher than that of the control and after repeated treatments. Phosphorylated VEGFR-2 expression increased significantly after single and repeated bevacizumab treatments compared with the control. The 1.0 mg/mL bevacizumab induced significantly higher expressions of VEGFR-2 than the 2.5 mg/mL in single and repeated treatment groups. CONCLUSION: Bevacizumab treatment of HUVECs elevated VEGFR expression in both single and repeated treatments, indicating a mechanism for the reduced efficacy of anti-VEGF therapy in ocular neovascular disorders.     

VEGF164(165) as the pathological isoform: differential leukocyte and endothelial responses through VEGFR1 and VEGFR2

PURPOSE: Vascular endothelial growth factor (VEGF) induces angiogenesis and vascular permeability and is thought to be operative in several ocular vascular diseases. The VEGF isoforms are highly conserved among species; however, little is known about their differential biological functions in adult tissue. In the current study, the inflammatory potential of two prevalent VEGF isoform splice variants, VEGF(120(121)) and VEGF(164(165)), was studied in the transparent and avascular adult mouse cornea. METHODS: Controlled-release pellets containing equimolar amounts of VEGF(120) and VEGF(164) were implanted in corneas. The mechanisms underlying this differential response of VEGF isoforms were explored. The response of VEGF in cultured endothelial cells was determined by Western blot analysis. The response of VEGF isoforms in leukocytes was also investigated. RESULTS: VEGF(164) was found to be significantly more potent at inducing inflammation. In vivo blockade of VEGF receptor (VEGFR)-1 significantly suppressed VEGF(164)-induced corneal inflammation. In vitro, VEGF(165) more potently stimulated intracellular adhesion molecule (ICAM)-1 expression on endothelial cells, an effect that was mediated by VEGFR2. VEGF(164) was also more potent at inducing the chemotaxis of monocytes, an effect that was mediated by VEGFR1. In an immortalized human leukocyte cell line, VEGF(165) was found to induce tyrosine phosphorylation of VEGFR1 more efficiently. CONCLUSIONS: Taken together, these data identify VEGF(164(165)) as a proinflammatory isoform and identify multiple mechanisms underlying its proinflammatory biology.     

In vitro studies on the mechanism of action of VEGF and its inhibitors

VEGF expression and signalling are deregulated in diabetic retinopathy. Cellular processes like migration and proliferation as well as control of the permeability of the endothelium by VEGF are regulated as a consequence of its binding to the VEGF receptor 2. Proteins forming tight junctions between microvascular endothelial cells of the retina are delocated to the cytoplasm after treatment with VEGF(165), likely leading to the breakdown of the blood-retina barrier. VEGF-inhibitors such as a VEGF-aptamer (modified RNA-oligonucleotide; pegaptanib) or specific antibodies/antibody fragments (bevacizumab, ranibzumab) which directly interfere with the interaction of VEGF with its receptors are considered to be promising novel therapeutics to treat diabetic retinopathy and age-related macular degeneration. In vitro studies using microvascular endothelial cells will help to clarify the mechanisms of action of VEGF and its inhibitors. In particular, the influence of VEGF isoforms and the inhibitor ranibizumab on the proliferation and migration of bovine retinal microvascular endothelial cells was studied, as well as the rearrangement of tight-junction proteins after treatment of the cells with VEGF(165) and specific inhibitors. In addition to a review of recent publications in the field, primary data from our own studies are presented in this article.     

Comparative antiproliferative and cytotoxic profile of bevacizumab (Avastin), pegaptanib (Macugen) and ranibizumab (Lucentis) on different ocular cells

Aim To compare the antiproliferative and cytotoxic properties of bevacizumab (Avastin), pegaptanib (Macugen) and ranibizumab (Lucentis) on human retinal pigment epithelium (ARPE19) cells, rat retinal ganglion cells (RGC5) and pig choroidal endothelial cells (CEC). Methods Monolayer cultures of ARPE19, RGC5 and CEC were used. Bevacizumab (0.1–0.3 mg/ml), pegaptanib (0.025–0.08 mg/ml) or ranibizumab (0.04–0.125 mg/ml) diluted in culture medium were added to the cells. Expression of VEGF-receptors (VEGFR1 and VEGFR2) and von Willebrand factor (a marker for endothelial cells) were analysed by immunohistochemistry. CEC cells were stimulated with VEGF. Cellular proliferative activity was monitored by BrdU-incorporation into cellular DNA. For cytotoxicity assays cells were grown to confluence and then cultured in a serum-depleted medium to ensure a static milieu. MTT-test was performed after one day. Results CEC and ARPE19 cells stained positively for VEGFR1 and VEGFR2. More than 95% of the CEC cells were positive for von Willebrand factor. Ranibizumab reduced CEC cell proliferation by 44.1%, bevacizumab by 38.2% and pegaptanib by 35.1% when the drugs were used at their established clinical doses. The differences, however, between the three drugs in respect to cell growth inhibition were not statistically significant. Only a mild antiproliferative effect of bevacizumab or pegaptanib on ARPE19 cells could be observed. Ranibizumab did not alter ARPE19 cell proliferation. No cytotoxicity on RGC5, CEC and ARPE19 cells could be seen. Conclusions Bevacizumab, pegaptanib and ranibizumab significantly suppress choroidal endothelial cell proliferation. However, when used at the currently established doses none of the drugs was superior over the others in respect to endothelial cell growth inhibition. The biocompatibility of all three drugs — including the off-label bevacizumab — seems to be excellent when used at the currently recommended intravitreal dose. This work is presented on behalf of the Tuebingen Bevacizumab Study Group.     

Systemic and ocular safety of intravitreal anti-VEGF therapies for ocular neovascular disease

The treatment of ocular neovascular diseases is being revolutionized by intravitreal therapies targeting vascular endothelial growth factor (VEGF). Two agents are approved for treating neovascular age-related macular degeneration and are being evaluated for other retinal conditions: the RNA aptamer pegaptanib and the monoclonal antibody antigen-binding fragment ranibizumab. Bevacizumab, a related antibody, is being used similarly, although its use is off-label. Pegaptanib selectively binds to a VEGF isoform identified as being especially pathogenic in the eye and spares other isoforms, whereas the other two agents nonselectively bind all VEGF isoforms. Because VEGF is involved in a wide variety of physiologic processes, the ocular and systemic safety of anti-VEGF agents is of paramount concern. I provide an overview of safety data for intravitreal anti-VEGF therapies, focusing primarily on randomized, controlled trials. For pegaptanib, an accumulation of data from pivotal trials and a dedicated systemic safety study have revealed no ocular or systemic safety concerns. For ranibizumab, the principal ocular adverse event detected in clinical trials was a low frequency of ocular inflammation, and systemic adverse events included a slightly elevated risk of nonocular hemorrhage and stroke. Safety data from properly designed randomized controlled trials for bevacizumab are not available.     

The role of different VEGF isoforms in scar formation after glaucoma filtration surgery

Vascular endothelial growth factor (VEGF) plays an important role in both physiological and pathological angiogenesis. Our previous studies showed a differential role of VEGF isoforms in retinal physiological angiogenesis. We also demonstrated that non-selective inhibition of VEGF by bevacizumab had a beneficial effect on surgical outcome after glaucoma filtration surgery by reducing angiogenesis as well as fibrosis. However, the function of the VEGF isoforms in pathological angiogenesis and wound healing in the eye still remains unidentified. This study was designed to elucidate the differential roles of VEGF isoforms in scar formation after trabeculectomy. Furthermore, we also investigated whether pegaptanib (Macugen™, Pfizer), an aptamer which specifically blocks VEGF₁₆₅, could improve surgical outcome by reducing postoperative scarring. VEGF-R2 and neuropilin-1 (NRP-1) expression was analyzed in vitro by RT-PCR, and were found to be expressed at higher levels in human umbilical vein endothelial cells (HUVEC) as compared to Tenon fibroblasts (TF). The effect of the different VEGF isoforms (VEGF₁₂₁, VEGF₁₆₅ and VEGF₁₈₉) and pegaptanib on cell proliferation was determined via WST-1 assay. Endothelial cell proliferation was stimulated after addition of VEGF₁₂₁ and VEGF₁₆₅, whereas VEGF₁₂₁ and VEGF₁₈₉ increased fibroblast growth. These effects on proliferation were associated with an activation of the ERK pathway, as revealed using the TransAM c-Myc assay. Inhibition of the ERK pathway, by PD98059 administration, significantly reduced VEGF isoform induced cell growth. A dose-dependent reduction of endothelial cell proliferation was observed after pegaptanib administration, while only the highest dose was able to inhibit fibroblast growth. Next, the in vivo effect of pegaptanib was investigated in a rabbit model of trabeculectomy. The surgical outcome was evaluated by performing clinical investigations (IOP, bleb area, height and survival), as well as histomorphometric analyses of angiogenesis (CD31), inflammation (CD45) and fibrosis (Sirius Red). A single postoperative application of pegaptanib had a beneficial impact on surgical outcome, mainly by reducing angiogenesis, but not inflammation or collagen deposition. Repeated injections slightly improved surgical outcome, but again solely by reducing angiogenesis. In summary, our results revealed that the VEGF isoforms play a differential role in ocular wound healing: VEGF₁₆₅ and VEGF₁₂₁ predominantly affect blood vessel growth, whereas VEGF₁₈₉ is rather involved in fibrosis, an important process in wound healing.     

Ranibizumab efficiently blocks migration but not proliferation induced by growth factor combinations including VEGF in retinal endothelial cells

Background

Proliferation and migration of retinal endothelial cells (REC) are associated with the development of proliferative diabetic retinopathy. REC proliferation is stimulated by isoforms of vascular endothelial growth factor-A (i.e., VEGF₁₂₁ and VEGF₁₆₅), basic fibroblast growth factor (bFGF), and insulin-like growth factor (IGF-1) of which VEGF₁₆₅ also enhances migration of REC. Effects induced by VEGF-A can be blocked with ranibizumab, a VEGF-binding Fab fragment used in therapy of diabetic macular edema. In this study, we investigated potential angiogenic effects of placental growth factors (PlGF-1, PlGF-2) as other members of the VEGF family and whether the primary action of VEGF₁₆₅ is modulated in the presence of bFGF, IGF-1 and PlGF-1/-2. We also studied how effects of growth factor combinations can be attenuated with ranibizumab.

Methods

Effects of single growth factors or their combinations on proliferation and migration of immortalized bovine retinal endothelial cells (iBREC) were studied with or without ranibizumab or the inhibitor of VEGF receptors KRN951.

Results

Proliferation of iBREC was significantly stimulated by 1–100 ng/ml PlGF-1 or PlGF-2, but additive effects were not observed with various combinations of the tested growth factors. Ranibizumab neutralized VEGF’s effect on proliferation but was not effective when the other growth factors were used in combination with VEGF. bFGF and IGF-1 but not PlGF-1 or PlGF-2 stimulated iBREC migration as single agents, and they further enhanced VEGF-induced migration. The effects of such growth factor combinations including VEGF on migration were efficiently blocked by targeting only VEGF with ranibizumab. Migration induced by VEGF plus bFGF and IGF-1 was also almost completely inhibited by KRN951 interfering with VEGF receptor signalling.

Conclusions

Migration but not proliferation of iBREC induced by combinations of bFGF, IGF-1, PlGF-1 or PlGF-2 together with VEGF is efficiently suppressed by ranibizumab. VEGF-mediated signalling through VEGFR2 seems to control REC migration dominantly in the presence of other growth factors.     

Targeting angiogenesis, the underlying disorder in neovascular age-related macular degeneration

Angiogenesis has a causal role in many diseases, including neovascular age-related macular degeneration (AMD). Identification of key regulators of angiogenesis, including vascular endothelial growth factor (VEGF), fibroblast growth factor 2, pigment epithelium-derived growth factor, angiopoietins and extracellular matrix molecules, has facilitated the development of novel therapeutic agents that target the underlying pathological angiogenic process. Among these, VEGF serves as a "master switch" for many ocular neovascular conditions through its promotion of endothelial cell proliferation and survival, vascular permeability and ocular inflammation. Two anti-VEGF agents are now clinically available: bevacizumab, an antibody for metastatic colorectal cancer, and pegaptanib sodium, an aptamer for neovascular AMD. Unlike bevacizumab, which binds all VEGF isoforms, pegaptanib targets only VEGF165, the isoform responsible for pathological ocular neovascularization and thus an ideal target for treatment of AMD. Although other therapies targeting angiogenesis in AMD are in clinical development, to date, pegaptanib is the only therapy approved by the Food and Drug Administration of the United States for the treatment of all neovascular AMD and represents a valuable addition to the hitherto limited options available for patients.     

Ranibizumab inhibits multiple forms of biologically active vascular endothelial growth factor in vitro and in vivo

Neovascular age-related macular degeneration (AMD) is the leading cause of blindness in older adults in the Western world. Ranibizumab (Lucentis), a humanized antibody fragment directed against vascular endothelial growth factor (VEGF-A), was recently approved by the US Food and Drug Administration (FDA) for the treatment of neovascular AMD. The objective of this study was to characterize the binding affinity and pharmacological activity of ranibizumab for 3 biologically active forms of VEGF-A: VEGF165, VEGF121, and VEGF110. The apparent equilibrium binding affinity of ranibizumab for VEGF-A molecules was determined by Biacore analysis; the biological activity of VEGF-A was demonstrated in a human umbilical vein endothelial cell (HUVEC) proliferation-inhibition assay. Inhibition of VEGF-A-induced vascular permeability by ranibizumab was assessed in vivo using hairless guinea pigs and a modified Miles assay. Ranibizumab was capable of binding to recombinant human VEGF165, VEGF121, and VEGF110 (KD < or = 192 pM), inhibiting VEGF-A-induced HUVEC proliferation in a concentration-dependent manner. Ranibizumab also exerted potent dose-dependent inhibition (IC(50) of 0.4-1.2 nM) of the vascular permeability-enhancing activity of VEGF165, VEGF121, and VEGF110 in the Miles assay. In conclusion, these results show that ranibizumab is capable of binding to and specifically inhibiting the activities of 3 biologically active forms of VEGF-A. As VEGF-A plays a pivotal role in the pathogenesis of neovascular AMD, ranibizumab activity, as demonstrated in this study, supports its clinical utility in the treatment of this disease.     

抗VEGF药物在视网膜血管性疾病围手术期的应用

血管内皮生长因子（VEGF）与新生血管性眼病密切相关,是有效的治疗靶点.抗VEGF药物能减少新生血管形成,降低血管通透性,为新生血管性眼病的治疗带来重大变革.目前雷珠单抗在国内已被批准用于湿性年龄相关性黄斑变性的治疗,在美国被批准用于糖尿病性黄斑水肿和视网膜静脉阻塞后黄斑水肿的治疗.抗VEGF药物也作为适应证外治疗药物用于其他新生血管性眼病的治疗,如增生性糖尿病视网膜病变、其他视网膜血管性疾病和新生血管性青光眼等.抗VEGF药物辅助手术治疗显示出明显的疗效,可减少术中、术后的并发症和疾病的复发率.就贝伐单抗和雷珠单抗等抗VEGF药物在视网膜血管性疾病围手术期的应用情况进行综述.     

Replacing ranibizumab with bevacizumab on the Pharmaceutical Benefits Scheme: where does the current evidence leave us?

The battle between two anti-vascular endothelial growth factor (VEGF) treatment options (ranibizumab and bevacizumab) for neovascular macular degeneration is a topic of particular significance to eye health professionals with an interest in cost-effective treatment. Being the first of its kind directly comparing the two anti-VEGF, a recent large multicentre clinical trial has shown that bevacizumab is not inferior when compared with ranibizumab in regards to efficacy of visual acuity outcomes; the evidence at this stage is inconclusive for safety outcomes. Before bevacizumab can be considered a justifiable replacement for the much more expensive ranibizumab on the Pharmaceutical Benefits Scheme (PBS), its safety in treatment needs further supporting evidence.     

老年性黄斑变性治疗方法试验比较的启示

老年性黄斑变性(AMD)治疗方法试验比较(CATT)结果显示,倍伐单抗(商品名Avastin)和雷珠单抗按照相同的给药计划给药,临床观察12个月,患者视力效果等同.雷珠单抗按需求给药组在视力上与每一个月给药组等同.倍伐单抗是一个对抗血管内皮生长因子(VEGF)的全长单克隆抗体(MAb),能够对抗VEGF所有有生物活性的亚型,阻止VEGF和受体结合;雷珠单抗是把倍伐单抗和抗原结合部的片段分离出来,在临床上完成了4期Ⅰ/Ⅱ观察的制剂.二者在价格上悬殊巨大,倍伐单抗50美元/支,而雷珠单抗2000美元/支.在如此价格差距下,如果倍伐单抗能够改善视力和黄斑解剖,其临床应用的性价比会优于雷珠单抗.CATT研究结果支持全球继续使用玻璃体腔入路的给药途径使用倍伐单抗作为对雷珠单抗的一种廉价选择.

Abstract：

Comparison of age-related macular degeneration treatments trials(CATT)reported the results of the first year:At 1 year,bevacizumab and ranibizumab had equivalent effects on visual acuity when administered according to the same schedule.Ranibizumab given as needed with monthly evaluation had effects on vision that were equivalent to those of ranibizumab administered monthly.Bevacizumab is a monoclonal antibody(MAb)and full-length anti-VEGF antibody that successfully prevents binding of all the biologically active isoforms of VEGF to the receptor.Ranibizumab is a isolated antigen-binding fragment (Fab)from bevacizumab using recombinant genetic techniques.Ranibizumab has been clinically evaluated in 4 Phase Ⅰ/Ⅱ studies.The cost of Avastin is ＄50 per dose compared with ＄ 2000 per dose for Ranibizumab.If Avastin could improve vision and macular anatomy,then it would not only be clinically superior to Ranibizumab.The CATT data support the continued global use of intravitreal bevacizumab as an effective.low-cost alternative to ranibizumab,particularly for patients paying all costs out of pocket.     

Bevacizumab(Avastin)抑制角膜新生血管的应用新进展

诱发角膜新生血管的因素涉及各种生长因子。研究表明:在角膜新生血管中广泛存在的血管内皮生长因子(vascular endothelial growth factor,VEGF)起着主要作用。一种可行的治疗角膜新生血管策略是:通过特异性的中和抗VEGF抗体竞争性的结合VEGF,从而抑制VEGF活性。近年来,利用抗VEGF治疗策略,抑制脉络膜新生血管获得了很好的效果。靶向VEGF治疗药物的疗效和安全性已经证明。因此我们设想,局部应用新的抗VEGF药物,如贝伐单抗、兰尼单抗等可以有效地抑制角膜新生血管,恢复角膜透明和视力。     

Tears of the retinal pigment epithelium: an old problem in a new era

BACKGROUND/PURPOSE: Recent attention has focused upon several reports of retinal pigment epithelium (RPE) tears following vascular endothelial growth factor (VEGF)-modulating therapy. The authors review the clinical features, etiologies, imaging characteristics, and pathogenesis of RPE tears and their relationship with intravitreal anti-VEGF treatments. METHODS: The authors conducted a comprehensive literature search of RPE tears or rips of any etiology using the PubMed database. They have also included a retrospective analysis of an additional five cases of RPE tears following anti-VEGF therapy, four after bevacizumab and one after ranibizumab. RESULTS: Thirty-three cases of RPE tear after treatment with pegaptanib, bevacizumab, or ranibizumab have been previously reported in the literature. The authors have collected and analyzed the clinical features for 25 of these cases for which this information was available. The authors have also included analysis of an additional five cases. Common features of each of these 30 cases included advanced age of the patient, the presence of fibrovascular pigment epithelial detachment (PED) or PED associated with choroidal neovascularization (CNV), and diagnosis of the tear within 4 to 8 weeks of the first or second injection. CONCLUSIONS: RPE tears may develop during the course of anti-VEGF therapy for age-related macular degeneration-related PED. Patients with high-risk lesions, especially large irregular PED associated with CNV, should be counseled and monitored for this complication, which may limit visual prognosis.     

Treatment options for the wet form of age-related macular degeneration-a perspective

Treatment of the wet form of age-related macular degeneration (wet AMD) has been revolutionized a decade ago with the introduction of vascular endothelial growth factor (VEGF) blockers that reduce neovascularization and macular edema. Two approved drugs are marketed for the treatment of wet AMD—ranibizumab and alfibercept, but there is a third drug, bevacizumab, which is widely used off-label; a cancer drug that also blocks VEGF but was never tested in pivotal trials and never approved for ophthalmic indications including wet AMD. Similarity of bevacizumab to ranibizumab led to off-label use and even to government-sponsored studies comparison the approved ranibizumab head-to-head to the off-label cancer drug bevacizumab in wet AMD, like the Comparison of Age-related Macular Degeneration Treatments Trials (CATT) study, discussed in this perspective paper. Recent publication of 5-year follow-up from the initial 2-year CATT study provided the occasion to discuss the similarities and differences between these two drugs and the lessons learned from the last decade of anti-VEGF therapy for wet AMD. Clinical efifcacy is comparable, with an advantage for ranibizumab. Likewise, safety ifnding favor ranibizumab over bevacizumab in some aspects. The latest addition of approved anti-VEGF drugs for wet AMD, alfibercept, may provide even more beneift to patients. In this perspective we discuss results of CATT and other long-term follow-up and comparative studies. While all demonstrate clinical beneift of anti-VEGF, all reveal that most patients’ loose visual acuity (VA) in real-life situations over 5–7 years. This loss is based on—what we believe—significant under-treatment of wet AMD patients, due to economic or practical limitations and overestimation of perceived risks as geographic atrophy. We compare own data that showed more intensive treatment (more than twice the CATT-follow-up injections) with ranibizumab or alfibercept can maintain a sustained gain in VA in wet AMD patients after 6 years. We encourage retina specialists to treat wet AMD patients more aggressively and frequently in order to provide the maximum beneift for their patients.     

Are intravitreal bevacizumab and ranibizumab effective in a rat model of choroidal neovascularization?

Background  Vascular endothelial growth factor (VEGF) is an important stimulator of choroidal neovascularization (CNV). Bevacizumab (Avastin), ranibizumab (Lucentis) and pegaptanib sodium (Macugen) are anti-VEGF medications that have been used in the treatment of CNV. The purpose of our study is to evaluate the efficacy and safety of intravitreal injections of bevacizumab, ranibizumab and pegaptanib sodium in the treatment of CNV in a rat model. Methods  Multiple CNV lesions were induced by laser photocoagulation of the retina in Brown-Norway rats. After 3 weeks, 17 rats were divided into three groups and received intravitreal injections of bevacizumab, ranibizumab or pegaptanib sodium in different dosages. The lesions were evaluated by fluorescein angiography 1, 7, 14, and 28 days later to assess the efficacy of these medications. Results  Different doses of bevacizumab did not show any effect on stopping the leakage on fluorescein angiography on days 1, 7, 14, and 28. Ranibizumab and pegaptanib sodium did not stop the leakage of CNV either. No angiographic or histopathologic toxicity was observed. Conclusions  These three anti-VEGF agents did not show any therapeutic effect on stopping CNV leakage in rats. Previous experiments with ranibizumab in monkeys resulted in a significant decrease in leakage of CNV. The difference may be due to the fact that both ranibizumab and bevacizumab are humanized and species-specific. There are several studies evaluating the effect of bevacizumab in non-primates. Since bevacizumab is humanized, the results of studies on non-primates may not be similar to humans and non-human primates. Grant Support: Leir Foundation The authors have full control of the primary data and will provide it to Graefe’s Archive for Clinical and Experimental Ophthalmology at their request. Neither author has any conflict of interest, financial or otherwise, to report.     

Retinal pigment epithelial tear after ranibizumab therapy for subfoveal fibrovascular pigment epithelial detachment

PURPOSE: To describe the unusual complication of retinal pigment epithelial (RPE) tear after intravitreal ranibizumab (Lucentis) for subfoveal fibrovascular pigment epithelial detachment (PED) and its effective management. METHODS: Chart review for case report of RPE tear after ranibizumab. RESULTS: An inferior RPE tear was documented by fluorescein angiography, fundus photography, and optical coherence tomography (OCT) 1 month after receiving repeat ranibizumab injection in the right eye of a patient with bilateral subfoveal fibrovascular PED. He had undergone multiple bevacizumab followed by ranibizumab injections for neovascular age-related macular degeneration (AMD) in both eyes, starting 6 months previously. Subsequent antivascular endothelial growth factor (VEGF) therapy improved vision of right eye from 20/200 to 20/40, despite RPE tear. CONCLUSIONS: RPE tear may form after anti-VEGF therapy, including ranibizumab injection. Further anti-VEGF therapy may preserve or improve vision. To the authors' knowledge, this is first case report of effective suppression of neovascular activity with bevacizumab after an RPE tear following ranibizumab therapy.     

Anti-VEGF-refractory Exudative Age-related Macular Degeneration: Differential Response According to Features on Optical Coherence Tomography

Purpose

To describe optical coherence tomography (OCT) characteristics of neovascular age-related macular degeneration (AMD) patients refractory to intravitreal anti-vascular endothelial growth factor (VEGF) injections (ranibizumab, bevacizumab) and their responses to alternative anti-VEGF agents or photodynamic therapy (PDT).

Methods

A retrospective review of 267 neovascular AMD patients treated with intravitreal anti-VEGF injections.

Results

Twenty patients (7.5%) were refractory to anti-VEGF injections (stationary or increased retinal exudation despite three or more monthly injections). They were grouped into either the extensive intraretinal fluid group (IRF group, 9 patients) or the subretinal fluid only group (SRF group, 11 patients) according to OCT findings. In the IRF group, response rates to subsequent treatment were 0% (0 / 7) for bevacizumab, 50% (3 / 6) for ranibizumab and 50% (3 / 6) for PDT ± anti-VEGF. Three out of four bevacizumab-refractory patients showed response to ranibizumab as a secondary treatment. In the SRF group, response rates were lower with 0% (0 / 7) for bevacizumab, 22.2% (2 / 9) for ranibizumab and 28.6% (2 / 7) for PDT ± anti-VEGF. One out of four bevacizumab-refractory patients responded to ranibizumab. The visual outcome was worse in the IRF group (median 20 / 1,000) than in the SRF group (median 20 / 100).

Conclusions

In anti-VEGF-refractory neovascular AMD, patients with extensive IRF refractory to bevacizumab can be responsive to ranibizumab while patients with SRF may be refractory to both, suggesting a different pathophysiology and intraocular pharmacokinetics.     

The future implications and indications of anti-vascular endothelial growth factor therapy in ophthalmic practice

In the last few years anti-vascular endothelial growth factor (VEGF) therapy has changed the paradigm in the treatment of neovascular age-related macular degeneration (ARMD). Besides, its potential use in the treatment of diabetic retinopathy and other possible proliferative vascular disorders has also shown promise. Clinical trial results have shown tremendous beneficial effect of ranibizumab in ARMD. Off-label use of bevacizumab has also shown similar benefit but long-term and clinical trial results do not exist. Some of the potential questions in the use of anti-VEGF are recurring cost, possible long-term effect on physiological function of VEGF and determination of endpoint of treatment. Overall, the use of anti-VEGF therapy in ocular angiogenesis has proven to be beneficial at least now.     

Ranibizumab (Lucentis) versus Bevacizumab (Avastin) for the Treatment of Age-Related Macular Degeneration: An Economic Disparity of Eye Health

ABSTRACT

Age-related macular degeneration (AMD) is the leading cause of blindness in the elderly, and the advent of anti-vascular endothelial growth factor agents (VEGF) has revolutionized treatment for neovascular AMD. Two of the most popular anti-VEGF agents, ranibizumab (Lucentis; Genentech/Roche) and bevacizumab (Avastin; Genentech/Roche), effectively treat neovascular AMD but have a substantial difference in price. Multiple level 1 trials have demonstrated that bevacizumab is noninferior to ranibizumab in the treatment of neovascular AMD and that both have similar safety profiles. The decision to use one drug over the other is multifactorial with influences from industry as well as individual physician biases. However, the additional billions spent on ranibizumab result in a large economic disparity that is not rationalized by cost effectiveness models.