雷珠单抗治疗湿性AMD的研究进展

湿性年龄相关性黄斑变性(age-related macular degeneration,AMD)是老年人群视力丧失的主要原因之一,目前其发病原因尚不明确.研究已证实血管内皮生长因子与湿性AMD有明确相关性,已有多种抗血管内皮生长因子的药物应用于其治疗.玻璃体腔注射雷珠单抗能抑制血管内皮生长因子,阻断新生血管生长及渗漏而发挥治疗作用,其在湿性AMD的治疗中已显示出确切疗效.本文对雷珠单抗治疗湿性AMD的进展作一综述,包括雷珠单抗治疗湿性AMD的方案及疗效,影响其疗效的因素,联合治疗,以及雷珠单抗治疗湿性AMD的不良反应等几个方面.     

Current status of anti-vascular endothelial growth factor therapy in Europe

Vascular endothelial growth factor (VEGF) is an important modulator of angiogenesis, and has been implicated in the pathology of a number of conditions, including age-related macular degeneration (AMD), diabetic retinopathy, and cancer. AMD is a progressive disease of the macula and the third major cause of blindness worldwide. If not treated appropriately, AMD can progress rapidly, causing legal blindness within months of the second eye becoming affected. Until recently, the treatment options for AMD have been limited, with photodynamic therapy (PDT) the mainstay treatment. Although PDT is effective at slowing disease progression, it rarely results in improved vision. Pegaptanib and ranibizumab are both anti-VEGF therapies licensed for the treatment of neovascular AMD in Europe; however, these drugs are not yet available in Japan. This article reviews the available clinical data on anti-VEGF therapies for the treatment of neovascular AMD in Europe, and considers the future of this exciting therapy.     

Ranibizumab治疗湿性AMD的相关研究

脉络膜新生血管(choroidal neovascularization,CNV)形成是湿性AMD导致视力丧失的重要因素。大量证据表明,血管内皮生长因子-A(vascular endothelial growth factor A,VEGF-A)是湿性AMD新生血管生成和血管渗漏的重要调质。VEGF的抑制剂已在临床中应用,其中,ranibizumab是一种重组的人源化抗VEGF单克隆抗体片段,能够结合并抑制VEGF,阻止血管渗漏和新生血管的形成,抑制CNV的发生。III期临床试验结果表明,ranibizumab不仅可以延缓患者视力的降低,同时相当一部分患者出现临床有意义视力提高。而且,在治疗过程中严重不良事件发生率低。ranibizumab很有可能首次使多数AMD患者获得良好而稳定的视力。2006-06-30ranibizumab经美国食品药物管理局批准应用于湿性AMD的治疗。本文简要回顾VEGF的生物学特点,临床应用的途径,同时对ranibizum-ab临床研究结果进行总结。     

Serum vascular endothelial growth factor receptor-2 and adropin levels in age-related macular degeneration

AIM: To investigate the serum levels of vascular endothelial growth factor receptor-2 (VEGFR-2) and adropin in age-related macular degeneration (AMD) patients. METHODS: Ninety-eight AMD patients were included in the study. Seventy-eight age- and sex-matched healthy volunteers were recruited as the control group. Fundus florescein angiography and optical coherence tomography were performed to assess the posterior segment details. Serum VEGFR-2 and adropin levels were measured using enzyme-linked immunosorbent assays and compared between the study groups. RESULTS: AMD group had significantly increased foveal retinal thickness, serum LDL and HDL levels and significantly decreased subfoveal choroidal thickness (P =0.01, 0.047, 0.025 and <0.001, respectively). Serum VEGFR-2 level revealed a significant decrease in AMD patients compared to controls (26.48±6.44 vs 30.42±7.92 ng/mL, P<0.001). There was an insignificant increase in serum adropin level in AMD patients (6.17±3.19 vs 5.79±2.71 ng/mL, P=0.4) . Serum level of VEGFR-2 in AMD patients had a significant negative correlation with foveal retinal thickness (r=-0.226, P=0.025) and a significant positive correlation with subfoveal choroidal thickness (r=0.2, P=0.048). CONCLUSION: The current study demonstrated that the decreased serum VEGFR-2 level may be considered in the development of AMD. Adropin does not seem to play a role in the pathogenesis of AMD.     

Choroidal endothelial cells transmigrate across the retinal pigment epithelium but do not proliferate in response to soluble vascular endothelial growth factor

The purpose of this study was to investigate the effects of soluble VEGF on human choroidal endothelial cell (CEC) transmigration across an RPE monolayer as it relates to choroidal neovascularization in AMD. In coculture assays, ARPE-19 (ARPE) was plated on the undersides of Transwell inserts having 0.4 microm pores. Primary human CECs were then plated into the insert. CECs in the Transwell inserts were counted after 72 hr of growth. CEC proliferation was also measured after culturing CECs in ARPE-CEC coculture-conditioned media or in media with exogenous VEGF121 and/or VEGF165 added. Transmigration assays were performed on Transwells with 8.0 microm pores: green-labelled CECs were plated in Transwell inserts with or without red-labelled ARPE plated on the undersides of the insert. In some transmigration assays, ARPE was plated into the wells to provide a chemotactic gradient for CEC transmigration. After 72 hr CECs were plated, green cells were counted either within the well media as CECs that transmigrated the epithelial monolayer, or on the underside of the insert as CECs that transmigrated the Transwell insert to but not beyond the ARPE monolayer. A neutralizing antibody to VEGF was added to the wells of Transwells at the time the CECs were plated in the insert and transmigrated CECs were counted. VEGF protein was measured in the conditioned media of ARPE and CEC coculture and in transmigration assays. Compared to control, CEC proliferation significantly increased when CECs were cultured in coculture conditioned media (p=0.001) or in coculture assays (p<0.001). However, there was no effect on CEC proliferation when VEGF121, VEGF165, or both were added to solo CECs. Antibody to VEGF did not reduce the proliferative effects of coculture conditioned media on CEC. ARPE plated in the well significantly increased CEC transmigration (p<0.001) compared to transmigration assays without ARPE in the well. VEGF protein measured in the well media of transmigration assays having ARPE within the well was significantly greater than in the assays without ARPE within the well (p<0.004). Exogenous neutralizing antibody to VEGF significantly reduced transmigration, and this effect was dose-dependent. VEGF provides a chemotactic gradient for human CECs to transmigrate across a monolayer of ARPE. Neutralization of VEGF in the media partially reduces transmigration. Whereas soluble VEGF does not increase proliferation of solo CECs, coculture conditioned media enhances proliferation, suggesting that growth factors other than VEGF cause CEC proliferation. These findings may have relevance to the transformation of occult CNV into CNV within the neurosensory retina in AMD.     

Antivascular endothelial growth factor therapies for neovascular age-related macular degeneration: Search for the optimized treatment regimen

Age-related macular degeneration is the leading cause of irreversible visual loss in elderly patients. After photodynamic therapy, therapy targeting vascular endothelial growth factor (VEGF) therapy has become the gold standard for treating neovascular age-related macular degeneration. Although monthly intravitreal injections of anti-VEGF agents are the most promising treatment to improve and sustain vision, as-needed treatments were administered based on the monthly examinations mainly because of cost-effectiveness. However, as-needed treatments are considered reactive treatments that burden patients and doctors with required monthly examinations and potentially decrease the improved vision. To address this, the treat-and-extend regimen, a proactive treatment, has been advocated as individualized medicine. This article reviews the characteristics of currently available anti-VEGF agents and treatment strategies.     

Vascular endothelial growth factor and its inhibitor in age-related macular degeneration

Intraocular angiogenesis is considered the leading cause for severe loss of vision, and contributes to many ocular diseases such as neovascular age-related macular degeneration, diabetic retinopathy, and retinopathy of prematurity, the main causes of blindness in developed countries.¹ An enormous body of work has demonstrated that vascular endothelial growth factor (VEGF) plays a prominent role as mediator in the procedure of pathological angiogenesis. This makes VEGF a potential target for the medical therapies of retinal angiogenesis and some clinical trials have proved the efficacy of anti-VEGF strategies. This review evaluates the role of VEGF in the pathogenesis of age-related macular degeneration and provides an overview of recent developments in therapeutic modalities.     

Intravitreal Ranibizumab and Bevacizumab: A Review of Risk

Ranibizumab (Lucentis®), a recombinant monoclonal antibody, blocks all active forms of vascular endothelial growth factor A and was the first treatment for age-related macular degeneration shown to improve visual acuity in a substantial percentage of patients rather than slowing visual loss. Bevacizumab (Avastin®) has a similar action, is related to the ranibizumab compound with respect to its structure, but has not been approved by the FDA for intravitreal use and therefore must be utilized only in an off-label setting. While ranibizumab was approved by the FDA at a dose of 0.5 mg per intravitreal injection, the manufacturer recently issued a letter to physicians warning of the increased risk of stroke at the FDA-approved dose as compared to a lower studied dose of 0.3 mg. An interim analysis of the ongoing SAILOR study revealed a 1.2% risk of stroke in the 0.5 mg arm versus 0.3% in the 0.3 mg arm (p = 0.02). It is unclear whether the trend toward a higher risk of stroke in patients receiving 0.5 mg dose of ranibizumab would persist in the final analysis, but details such as causality, topography, and severity of stroke in the SAILOR study should also be delineated. The risks of intraocular use of bevacizumab remain largely unknown at this time.     

Vascular endothelial growth factor gene polymorphisms in age-related macular degeneration in a Turkish population

AIM:To assess the association between age-related macular degeneration (AMD) and three single nucleotide polymorphisms (SNPs) related to the vascular endothelial growth factor (VEGF) gene.METHODS: The patients who were diagnosed with AMD were included in this prospective study. Three SNPs (rs1413711, rs2146323, and rs3025033) of the VEGF gene were genotyped by real-time polymerase chain reaction in the genomic DNA isolated from peripheral blood samples of the 82 patients and 80 controls.RESULTS: The genotype frequencies of rs1413711 and rs2146323 were not significantly different between the study group and the control group (P=0.072 and P=0.058). However, there was a significant difference in the genotype frequencies of these SNPs between the wet type AMD and dry type AMD (P=0.005 and P=0.010, respectively). One of the SNPs (rs1413711) was also found to be associated with the severity of AMD (P=0.001) with significant genotype distribution between early, intermediate, and advanced stages of the disease. The ancestral alleles were protective for both SNPs while the polymorphic alleles increased the risk for dry AMD.CONCLUSION: VEGF SNPs rs1413711 and rs2146323 polymorphisms are significantly associated with AMD subtypes in our population.     

CFH基因多态性与玻璃体液VEGF对年龄相关性黄斑变性患者抗VEGF疗效影响的交互作用

目的 探讨补体因子H(CFH)基因多态性与玻璃体液血管内皮生长因子(VEGF)对年龄相关性黄斑变性(AMD)患者抗VEGF疗效影响的交互作用。方法 选取2020年5月～2022年1月广州医科大学附属第三医院眼科149例(149眼)AMD患者为研究对象,根据抗VEGF治疗是否有应答,分为应答组(111例)、无应答组(38例)。比较两组患者CFH基因多态性、玻璃体液VEGF表达水平,比较CFH位点rs1061170不同基因型患者玻璃体液VEGF表达水平,采用Logistic分析抗VEGF疗效的相关影响因素,采用交互作用系数γ分析CFH基因多态性、玻璃体液VEGF的交互作用是否存在及其作用类型。结果 无应答组患者CFH位点rs1061170基因型分布与应答组比较,差异有统计学意义(P<0.05)。无应答组患者玻璃体液VEGF高于应答组(P<0.05)。在全部AMD患者中,玻璃体液VEGF高水平患者CFH位点rs1061170基因型分布与低水平患者比较,差异有统计学意义(P<0.05)。在全部AMD患者中,玻璃体液VEGF、CFH位点rs1061170 CC基因型均是抗VEG...     

Increased serum levels of soluble CD146 and vascular endothelial growth factor receptor 2 in patients with exudative age-related macular degeneration

AIM: To investigate serum levels of soluble CD146 (sCD146) and vascular endothelial growth factor receptor 2 (VEGFR2) in patients with age-related macular degeneration (AMD). METHODS: Eighty-eight patients with exudative AMD and 45 sex- and age-matched healthy controls were enrolled in this study conducted in China. Serum samples was obtained from the patients with exudative AMD and from the controls. Serum sCD146 and VEGFR2 protein levels were measured using an enzyme-linked immunosorbent assay. RESULTS: We found that serum sCD146 and VEGFR2 protein levels were significantly higher in the patients with exudative AMD group than in the controls (t=3.859, P<0.001 and t=3.829, P<0.001, respectively). Serum sCD146 levels were significantly higher in patients with classic choroidal neovascularization (CNV) than in those with occult CNV (t=9.899, P<0.001). There was a significant difference in the trend for exudative AMD in the highest versus lowest quartile of circulating sCD146 levels (χ2=10.29, P=0.001). The receiver operating characteristic curve analysis showed that the area under the curve was 0.696 for sCD146 (95%CI: 0.601-0.791) with an optimum diagnostic cut-off value of 157.16 ng/mL, a sensitivity of 55.7%, and a specificity of 82.2%. CONCLUSION: The serum sCD146 level increases and may be a biomarker for exudative AMD.     

Pigment epithelium-derived factor (PEDF) and vascular endothelial growth factor (VEGF) in aged human choroid and eyes with age-related macular degeneration

The purpose of this study was to examine the localization and relative levels of vascular endothelial growth factor (VEGF; an angiogenic factor) and pigment epithelium-derived factor (PEDF; an antiangiogenic factor) in aged human choroid and to determine if the localization or their relative levels changed in age-related macular degeneration (AMD). Ocular tissues were obtained from eight aged control donors (age range, 75-86 years; mean age, 79.8 years) with no evidence or history of chorioretinal disease and from 12 donors diagnosed with AMD (age range, 61-105 years; mean age, 83.9 years). Tissues were cryopreserved and streptavidin alkaline phosphatase immunohistochemistry was performed with rabbit polyclonal anti-human VEGF and rabbit polyclonal anti-human PEDF antibodies. Binding of the antibodies was blocked by preincubation of the antibody with an excess of recombinant human PEDF or VEGF peptide. Choroidal blood vessels were identified with mouse anti-human CD-34 antibody in adjacent tissue sections. Three independent observers graded the immunohistochemical reaction product. The most prominent sites of VEGF and PEDF localization in aged control choroid were RPE-Bruch's membrane-choriocapillaris complex including RPE basal lamina, intercapillary septa, and choroidal stroma. There was no significant difference in immunostaining intensity and localization of VEGF and PEDF in aged control choroids. The most intense VEGF immunoreactivity was observed in leukocytes within blood vessels. AMD choroid had a similar pattern and intensity of VEGF immunostaining to that observed in aged controls. However, PEDF immunoreactivity was significantly lower in RPE cells (p=0.0073), RPE basal lamina (p=0.0141), Bruch's membrane (p<0.0001), and choroidal stroma (p=0.0161) of AMD choroids. The most intense PEDF immunoreactivity was observed in disciform scars. Drusen and basal laminar deposits (BLDs) were positive for VEGF and PEDF. In aged control subjects, VEGF and PEDF immunostaining was the most intense in RPE-Bruch's membrane-choriocapillaris complex. In AMD, PEDF was significantly lower in RPE cells, RPE basal lamina, Bruch's membrane and choroidal stroma. These data suggest that a critical balance exists between PEDF and VEGF, and PEDF may counteract the angiogenic potential of VEGF. The decrease in PEDF may disrupt the balance and be permissive for the formation of choroidal neovascularization (CNV) in AMD.     

抗VEGF药物在湿性年龄相关性黄斑变性中的应用进展

年龄相关性黄斑变性(ARMD)是导致老年人不可逆失明的主要原因之一,ARMD致失明患者中,以脉络膜新生血管(CNV)为特征的湿性ARMD比例达到90%。随着我国老年人口比例的不断上升,湿性ARMD已经成为一个日益严重的社会医学问题。目前,针对湿性ARMD的治疗方案主要是抗血管内皮生长因子(VEGF)药物的应用,这类药物抑制了CNV的发展,提高了患者视力,改善了预后,降低了致盲率。但是在治疗过程中的无反应、长期用药后的维持和用药后的耐受、不良反应以及用药的经济效益也是我们需要关注的。本文就近年来临床用于治疗湿性ARMD的药物进行综述。     

Pilot study to evaLuate the role of high-dose rAnibizumab 2.0 mg in the management of neovascular age-related macular degeneration in patients with perSistent/recurrenT macular fluid <30 days following treatment with intravitreal anti-VEGF therapy (the LAST Study)

Purpose

To determine the efficacy of intravitreal ranibizumab 2.0 mg in patients with recalcitrant neovascular age-related macular degeneration (AMD).

Methods

This single-masked, randomized, prospective, pilot study enrolled patients with subfoveal neovascular AMD. All study eyes had persistent subretinal (SRF) or intraretinal fluid (IRF) on spectral-domain optical coherence tomography (SD-OCT) <30 days following at least 6 monthly intravitreal injections of ranibizumab or bevacizumab. Patients were randomized 2 : 1 to receive either ranibizumab 2.0 or 0.5 mg. Following three-loading treatments 4-weeks apart, both groups were treated using a ‘treat and extend'' regimen guided by eye-tracked SD-OCT through month 12. The primary end point was the mean change in best-corrected visual acuity (BCVA) at month 6.

Results

Nine eyes of 9 patients (mean age±SD, 82.0±5.8 years) were enrolled. Seven eyes received ranibizumab 2.0 mg and two eyes received 0.5 mg. Owing to the small number of patients enrolled, no statistical comparison could be made between the two dosages. At month 6, the mean improvement in BCVA was +6.1±3.7 (W=0, P<0.001) ETDRS letters and +2.0 ETDRS letters in the 2.0 and 0.5 mg groups, respectively. In the 2.0 mg group, there was a statistically significant decline in central foveal thickness, SRF and maximum pigment epithelial detachment height at 6 months compared with baseline. No adverse events were reported in either group.

Conclusion

Ranibizumab 2.0 mg has the potential to maintain or improve BCVA in some patients with persistent or recurrent SRF or IRF secondary to neovascular AMD despite prior monthly intravitreal anti-vascular endothelial growth factor therapy with the standard dose.     

A comparative debate on the various anti-vascular endothelial growth factor drugs: pegaptanib sodium (Macugen), ranibizumab (Lucentis) and bevacizumab (Avastin)

Wet age-related macular degeneration and diabetic retinopathy are pathological consequences of vascular endothelial growth factor (VEGF) release as a reaction to deficiency of oxygen and nutrients in the macular cells. Conventional treatment modalities have been constrained by limited success. Convincing evidence exists that targeting VEGF signaling is a significant approach for the therapy of these ocular angiogenesis-dependent disorders. We have come a long way since the approval of the first angiogenesis inhibitors in medicine. The clinical use of these drugs has provided enormous tempo to clinical and pharmacological research. It has also significantly altered patient outcome and expectations. In the following brief, we will discuss the development and emergence of these drugs as well as the anticipated future course based on evidence.     

雷珠单抗联合光动力疗法治疗wAMD的效果

目的：探讨湿性年龄相关性黄斑变性(wAMD)患者采用雷珠单抗联合光动力疗法的临床效果及对患者血清新生血管调控因子的影响。

方法：回顾性分析。选取2014-01/2016-06我院治疗的wAMD患者68例68眼进行分析,其中采取光动力疗法治疗(对照组)34眼、采用雷珠单抗联合光动力疗法治疗(治疗组)34眼,对比两组患者治疗前后BCVA、视网膜平均厚度、黄斑中心凹视网膜厚度(CMT)值及血清新生血管调控因子情况。

结果：治疗前,两组患者的BCVA、视网膜平均厚度、CMT值比较差异无统计学意义(P>0.05); 治疗后3、6、12mo,两组患者的BCVA值、视网膜平均厚度、CMT值较本组治疗前均显著降低,差异有统计学意义(P<0.05); 治疗组患者的BCVA值、视网膜平均厚度、CMT值均显著低于对照组,差异有统计学意义(P<0.05)。治疗前,两组患者血清中VEGF、PDGF、TIMP-1、ES值差异无统计学意义(P>0.05); 治疗后3mo,两组患者血清中的VEGF、PDGF、ES值较本组治疗前均显著降低,差异有统计学意义(P<0.05); 治疗组患者的VEGF、PDGF、ES值均显著低于对照组,差异有统计学意义(P<0.05)。

结论：雷珠单抗联合光动力疗法治疗wAMD患者能取得更加显著的临床效果,更有效地降低血清中新生血管调控因子水平。     

Ranibizumab治疗脉络膜新生血管的研究现状

脉络膜新生血管(choroidal neovascularization,CNV)是引起多种眼底疾病、导致视力丧失的重要原因之一。CNV的发生机制尚不清楚,目前普遍认为血管生成因子与抑制因子之间平衡的破坏具有关键作用,而血管内皮生长因子(vascular endothelial growth factor,VEGF)是其重要的始动因素。Ranibizumab是一种重组的人源化抗VEGF单克隆抗体片段,能够结合并抑制VEGF,阻止血管渗漏和新生血管的形成,抑制CNV的发生,进而阻碍CNV相关疾病的病程进展。随着对CNV发生机制的深入研究,针对CNV发生过程进行治疗,有可能从根本上治愈CNV相关疾病。     

Intraocular pressure changes after repeated intravitreal antivascular endothelial growth factor injections in patients with neovascular age-related macular degeneration with or without glaucoma

PurposeTo investigate the long-term effects of multiple intravitreal injections on intraocular pressure (IOP) in patients with exudative age-related macular degeneration, and to determine whether this is related to a pre-existing diagnosis of glaucoma.MethodsA retrospective study was carried out on 209 eyes in 173 patients with neovascular age-related macular degeneration who received at least three intravitreal injections of bevacizumab or ranibizumab, or both, from January 2006 to December 2012 at Shin Kong Wu Ho-Su Memorial Hospital. Sequential changes in IOP following the intravitreal injections were documented and the incidence and characteristics of the patients diagnosed with glaucoma were recorded and analyzed.ResultsTwo hundred and nine eyes in 173 patients were included in this study. The mean number of injections was 10.1 (range 3–23). No significant change was found in IOP (p = 0.41, paired t test) and none of the patients experienced delayed ocular hypertension during the treatment course. No correlation was found between differences in IOP and the number of injections (correlation coefficient −0.086) and no significant change in IOP was found in patients with or without glaucoma (p = 0.42 and 0.37, respectively, paired t test). In addition, the use of drugs to lower IOP did not increase with repeated intravitreal injections in patients with glaucoma [single drug, 24 (63.2%) patients; two drugs 14 (36.8%) patients].ConclusionRepeated intravitreal antivascular endothelial growth factor injections of bevacizumab or ranibizumab, or both, did not increase the risk of increasing IOP in patients with exudative age-related macular degeneration, with or without glaucoma.     

Change of retinal pigment epithelial atrophy after anti-vascular endothelial growth factor treatment in exudative age-related macular degeneration

Purpose:The study aimed to investigate the quantitative changes of retinal pigment epithelial (RPE) atrophy during a 24-month follow-up period of anti-vascular endothelial growth factor (VEGF) for exudative age-related macular degeneration (AMD).Results:The mean number of anti-VEGF treatments was 9.18. RPE atrophic area was 1.293 ± 1.298 mm² at baseline and enlarged to 2.394 ± 1.940 mm² after 24 months, which differed significantly (P = 0.001). Multiple regression analysis revealed that larger areas of RPE atrophy at month 4 and larger numbers of anti-VEGF treatments were associated with increased RPE atrophic areas.Conclusions:RPE atrophy progresses in eyes with exudative AMD during anti-VEGF treatment. Larger areas of RPE atrophy at month 4 and larger numbers of anti-VEGF injections were associated with an increased risk of progression of RPE atrophy the following treatment. These findings may be useful to clinicians using intravitreal anti-VEGF for the treatment of exudative AMD, both for selecting an appropriate treatment plan and for predicting the progression of RPE atrophy.