新生血管性眼病的治療進(jìn)展

陳澤麗，祝麗娜，余梓逵，柳 林

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新生血管性眼病的治療進(jìn)展

陳澤麗，祝麗娜，余梓逵，柳 林*

（上海交通大學(xué)醫(yī)學(xué)院附屬仁濟(jì)醫(yī)院眼科，上海 200127）

隨著人口老齡化和生活質(zhì)量的提高，以年齡相關(guān)性黃斑變性及糖尿病性視網(wǎng)膜病變?yōu)橹鞯男律苄匝鄄≌找娉蔀橛绊懟颊呱钯|(zhì)量的主要因素。新生血管性眼病以新生血管形成為主要病理表現(xiàn)，病因復(fù)雜、機(jī)制多樣、預(yù)后不佳是其主要特征。近年來激光、抗VEGF藥物及手術(shù)等多種藥物和治療方法的不斷涌現(xiàn)與改進(jìn)，為該類疾病的治療帶來更多更好的療法。本文就這一系列新生血管性眼病的治療進(jìn)展予以綜述。

新生血管性眼病；抗VEGF；激光；光動(dòng)力療法

新生血管性眼病以新生血管形成為主要病理表現(xiàn)，病理性新生血管不同于正常血管，其內(nèi)皮不完整導(dǎo)致易滲出、出血，進(jìn)而出現(xiàn)多種并發(fā)癥，嚴(yán)重影響患者的視覺質(zhì)量[1]。常見的新生血管性眼病包括新生血管性年齡相關(guān)性黃斑變性（neovascular age-related macular degeneration，nAMD）、增殖性糖尿病性視網(wǎng)膜病變（proliferative diabetic retinopathy，PDR）、早產(chǎn)兒視網(wǎng)膜病變（retinopathy of premature children，ROP）、視網(wǎng)膜靜脈阻塞（retinal vein occlusion，RVO）、新生血管性青光眼（neovascular glaucoma，NVG）、新生血管性角膜?。╟orneal neovascularization）等。隨著人口老齡化的日益加劇，年齡相關(guān)性黃斑變性及糖尿病性視網(wǎng)膜病變已成為致盲性眼疾的重要組成部分[2,3]。近年來激光、抗血管內(nèi)皮生長(zhǎng)因子（vascular endothelial growth factors，VEGF）藥物及手術(shù)等多種方法的不斷涌現(xiàn)與改進(jìn)，為該類疾病的治療帶來更多更好的療法。本文就這一系列新生血管性眼病的治療進(jìn)展予以綜述。

1 目前對(duì)于新生血管性眼病的主要治療方法

1.1 激光光凝

激光治療應(yīng)用于眼科疾病始于上世紀(jì)40年代[4]，其封閉血管、減少氧耗的功能可達(dá)到減少新生血管及滲漏的作用[5]。早期糖尿病視網(wǎng)膜病變治療研究（Early Treatment Diabetic Retinopathy Study，ETDRS）證明，對(duì)于有臨床意義的黃斑水腫局部光凝可治療微血管瘤引起的局部滲漏，而格柵樣光凝則用于彌漫性或囊樣黃斑水腫。光凝對(duì)輕中度黃斑水腫的患者效果明顯，可延緩其視功能的損害，并且黃斑水腫早治療的療效要好于延期激光治療[6]。而ETDRS視力表成為了評(píng)價(jià)糖尿病性黃斑水腫療效中視力指標(biāo)的金標(biāo)準(zhǔn)。盡管抗VEGF藥物已逐漸成為治療新生血管性眼病的主流[7]，現(xiàn)如今導(dǎo)航激光用于全視網(wǎng)膜光凝（panretinal photocoagulation，PRP）[4]較傳統(tǒng)光凝術(shù)定位更加準(zhǔn)確，具有治療時(shí)間縮短、治療疼痛減輕以及光斑更為規(guī)則等優(yōu)勢(shì)，還可與其他方法伍用[8,9]，是治療新生血管性眼病不可或缺的方法之一。

1.2 光動(dòng)力療法

光動(dòng)力療法（photodynamic therapy，PDT）最初用于治療腫瘤。第二代光敏劑維替泊芬問世后，采用冷激光照射破壞異常的新生血管內(nèi)皮細(xì)胞[10]的療法于2000年獲批用于典型性脈絡(luò)膜新生血管（choroidal neovascularization，CNV），曾作為AMD的一線治療方法。而隨著培加他尼鈉（pegaptanib，Macugen）、雷尼珠單抗（諾適得，ranibizumab Lucentis）等抗VEGF藥物的相繼問世，這種單一療法在穩(wěn)定視力、保護(hù)視野等方面不如抗VEGF治療[11,12]，而且實(shí)驗(yàn)證實(shí)，PDT治療AMD可產(chǎn)生急性網(wǎng)膜下積液[12]。采用光學(xué)相干斷層掃描（optical coherence tomography，OCT）評(píng)估視網(wǎng)膜厚度及網(wǎng)膜下積液，是評(píng)估眼底新生血管性疾病病情的又一重要指標(biāo)。因維替泊芬組織特異性不高，常需多次注射，其高昂的費(fèi)用使得冷激光照射破壞異常的新生血管內(nèi)皮細(xì)胞技術(shù)的推廣受限。現(xiàn)在更多的是采取PDT伍用抗VEGF藥物治療新生血管性眼病[13,14]，兩者的結(jié)合能減少急性血管反應(yīng)，更為有效地封閉新生血管，減少?gòu)?fù)發(fā)以及治療次數(shù)。

1.3 抗VEGF

相對(duì)于激光治療，抗VEGF藥物針對(duì)新生血管的關(guān)鍵因子——VEGF，具有抗新生血管內(nèi)皮細(xì)胞增生、減少血管滲漏等作用，因此倍受青睞。VEGF是1989年Ferrara等[15]從牛垂體濾泡星狀細(xì)胞體外培養(yǎng)液中首先提純出來的，根據(jù)其具有促血管內(nèi)皮細(xì)胞有絲分裂的作用而命名。它是一種可溶性二聚體糖蛋白，其家族包含有VEGF-A、VEGF-B、VEGF-C、VEGF-D、VEGF-E和胎盤誘發(fā)生長(zhǎng)因子（placenta-induced growth factor，PIGF）[2]，目前研究的靶點(diǎn)主要是VEGF-A，在未做特殊說明的情況下通常將VEGF視作VEGF-A。由于外顯子剪切的不同，VEGF（-A）有VEGF121，VEGF165，VEGF189，VEGF206四個(gè)同分異構(gòu)體形式[1,16]。

1.3.1 培加他尼鈉 由美國(guó)Eyetech和Pfizer公司聯(lián)合開發(fā)的人工合成寡核苷酸序列，對(duì)VEGF165異構(gòu)體具有高親和力，2004年12月美國(guó)食品藥物管理局（Food and Drug Administration，F(xiàn)DA）批準(zhǔn)用于AMD[17]。有學(xué)者[18]對(duì)PDR患者行培加他尼鈉與全視網(wǎng)膜光凝術(shù)治療進(jìn)行比較，發(fā)現(xiàn)培加他尼鈉能迅速有效地消退糖尿病性視網(wǎng)膜病變的新生血管。Rinaldi等[17]對(duì)20名病理性近視患者行玻璃體腔內(nèi)注射培加他尼鈉后，隨訪最佳矯正視力、中心網(wǎng)膜厚度、微視野，結(jié)果證實(shí)培加他尼鈉能有效地改善上述指標(biāo)。在兒童眼疾研究中，培加他尼鈉在ROP中的應(yīng)用同樣獲得了良好的療效[19]。但由于其只能結(jié)合完整的VEGF165，而不會(huì)與其他VEGF異構(gòu)體或仍有生物活性的VEGF165裂解片段結(jié)合，且貝伐珠單抗（bevacizumab，Avastin）和雷尼珠單抗相繼問世，治斑劑已逐漸淡出眼科的應(yīng)用。

1.3.2 貝伐珠單抗 由Genentech公司研制的全長(zhǎng)人源化單克隆抗體，可與所有VEGF異構(gòu)體結(jié)合并使其失活，美國(guó)FDA批準(zhǔn)其用于治療結(jié)腸癌，然而許多臨床經(jīng)驗(yàn)表明，貝伐珠單抗能有效地應(yīng)對(duì)眼部新生血管、減輕黃斑水腫、減少出血、穩(wěn)定甚至提高視力[11,20,21]。相對(duì)于雷尼珠單抗，其價(jià)格低廉且療效顯著，但未獲準(zhǔn)用于眼病，目前在眼科使用仍屬于標(biāo)簽外用藥[22,23]。

1.3.3 雷尼珠單抗 同樣由美國(guó)Genentech公司研發(fā)，是第二代人源化重組抗VEGF單克隆抗體，由于其不含F(xiàn)c段，相對(duì)分子質(zhì)量約為貝伐珠單抗的1/3，能結(jié)合所有檢測(cè)到的VEGF異構(gòu)體及其降解產(chǎn)物，是專用于眼內(nèi)的藥物[22]。年齡相關(guān)性黃斑變性治療比較試驗(yàn)（Comparison of Age-related Macular Degeneration Treatment Trial，CATT）、LUCIDATE、BRAVO、CRUISE等前瞻性隨機(jī)臨床試驗(yàn)均證實(shí)，雷尼珠單抗在新生血管性眼病中起到減少滲漏、改善視力、抑制新生血管生長(zhǎng)的作用[3,24,25]。同貝伐珠單抗一樣，重復(fù)注射仍然是新生血管性眼病患者所面臨的負(fù)擔(dān)[22,26]，而相伴注射次數(shù)增多所帶來的白內(nèi)障、眼壓升高、出血、眼內(nèi)炎、醫(yī)源性視網(wǎng)膜脫離、視網(wǎng)膜色素上皮層撕裂等并發(fā)癥[27]也是對(duì)眼科醫(yī)師的一種挑戰(zhàn)。

1.3.4 阿柏西普（aflifercept，Eylea，VEGF-Trap-eye） 此藥是由Regeneron Pharmaceuticals公司生產(chǎn)的一種包含有VEGFR-1和VEGFR-2細(xì)胞外區(qū)的融合蛋白，與單克隆抗體相比，對(duì)VEGF有更強(qiáng)的親和力，還能結(jié)合PIGF和VEGF-B，此外在眼內(nèi)半衰期為18d，是雷尼珠單抗的兩倍，但短于貝伐單抗（21d）[28]。同貝伐珠單抗一樣，此藥最初是為治療結(jié)腸癌研發(fā)，COPERNICUS和VIEW兩項(xiàng)臨床Ⅲ期隨機(jī)雙盲研究[29,30]證實(shí)了其在新生血管性眼病中的療效與安全性。美國(guó)FDA已批準(zhǔn)其用于治療nAMD和視網(wǎng)膜中央靜脈阻塞（central retinal vein occlusion，CRVO）[16,28]。

1.3.5 康柏西普（conbercept，KH902） 由我國(guó)康弘生物公司研制，也是VEGFR1和VEGFR2的融合蛋白[31]，同時(shí)也能與PIGF1、PIGF2和VEGF-B結(jié)合，除了阿柏西普包含的結(jié)構(gòu)域外，KH902還含有VEGFR-2的第4結(jié)構(gòu)域，這有助于減少藥物與細(xì)胞外基質(zhì)的黏附[2]。我國(guó)的隨機(jī)雙盲多中心2期臨床AURORA試驗(yàn)[32]證實(shí)了康柏西普對(duì)nAMD有效，并且1次/月，每次2mg，連續(xù)12次的治療在視力提高和中央網(wǎng)膜厚度減少程度均好于其他劑量。實(shí)驗(yàn)亦證實(shí)其在角膜、脈絡(luò)膜、視網(wǎng)膜新生血管性疾病中均有良好的抗新生血管的作用[2,31]。我國(guó)FDA已批準(zhǔn)其用于nAMD的治療，糖尿病性黃斑水腫的Ⅲ期臨床試驗(yàn)也正在進(jìn)行中。

1.4 玻璃體切除術(shù)

自1970年首次應(yīng)用玻璃體切除術(shù)（pars plana vitrectomy，PPV）治療糖尿病玻璃體出血以來[33]，已成為治療眼底新生血管引起的難治性黃斑水腫、玻璃體積血、黃斑前膜和視網(wǎng)膜脫離等并發(fā)癥的有效手段。研究顯示，對(duì)于難治性黃斑水腫PPV能有效減輕黃斑水腫[34]。Sakamoto等[35]回顧性地分析了58例DME患者采用PPV治療的69只眼，發(fā)現(xiàn)黃斑部沒有完整的IS/OS結(jié)構(gòu)的患眼術(shù)后視力較差。此外，虹膜新生血管引起的繼發(fā)性青光眼除了采用抗新生血管的治療外，還可行小梁切除術(shù)、Ahmed Express引流閥植入術(shù)等方式控制眼壓[21]。

2 難治性新生血管性眼病的治療措施

2.1 增加治療劑量

目前貝伐珠單抗常用劑量為1.25mg/次，雷尼珠單抗通常使用0.5mg/次的劑量。但是對(duì)于難治性新生血管性眼病，有研究表示可采用提高劑量的療法。Waisbourd等[36]局部應(yīng)用2.5mg貝伐珠單抗治療各種繼發(fā)性角膜新生血管形成，結(jié)果顯示，17例患眼中有11例眼角膜新生血管減退，甚至角膜乳化作用減退。但有研究表明，大劑量的貝伐單抗眼內(nèi)注射治療nAMD病變會(huì)產(chǎn)生速效對(duì)藥反應(yīng)[37]。而Fung等[38]和Wykoff等[39]報(bào)道了使用雷尼珠單抗2.0mg治療nAMD可獲得長(zhǎng)期的視力穩(wěn)定的效果。

2.2 改變藥物

從生物效應(yīng)上看，培加他尼鈉只能阻斷VEGF165，貝伐珠單抗和雷珠單抗可有效地阻斷所有VEGF-A異構(gòu)體，新近出現(xiàn)的融合蛋白阿柏西普除了能有效地與VEGFR-1和VEGFR-2結(jié)合外，還能阻斷PIGF，似乎更有優(yōu)勢(shì)。研究表明培加他尼納可以穩(wěn)定保持患者的現(xiàn)有視力，雷尼珠單抗和貝伐珠單抗可以使一定比例的患者視力得到提高[22]。新生血管往往退而復(fù)現(xiàn)，這可能與藥物耐受有關(guān)，更換藥物?？山鉀Q這一問題。如研究顯示，26名雷尼珠單抗和（或）貝伐珠單抗治療后仍活動(dòng)性滲出的AMD患者改用阿柏西普治療，6個(gè)月后中央網(wǎng)膜厚度下降平均38.6μm，最佳矯正視力平均增加了5.9個(gè)ETDRS視力表字母[28]。Bakall等[40]和Heussen等[41]的研究同樣顯示了換用阿柏西普對(duì)雷尼珠單抗和（或）貝伐珠單抗耐藥的AMD患者更為有益。病例報(bào)道中也顯示了阿柏西普對(duì)于雷珠單抗眼內(nèi)注射后并發(fā)癥治療的優(yōu)勢(shì)[42]。而Lazic等[43]對(duì)15名貝伐珠單抗耐藥的糖尿病性黃斑水腫患者改為地塞米松眼玻璃體植入劑Ozurdex治療，隨訪4個(gè)月的研究結(jié)果證明了激素的有效性。

2.3 聯(lián)合治療

2.3.1 抗VEGF藥物聯(lián)合激光或手術(shù) Di Lauro等[44]對(duì)68名PDR患者行術(shù)前注射1.25mg貝伐珠單抗的研究中，將患者隨機(jī)分為假注射組、術(shù)前7d注藥組、術(shù)前21d注藥組，結(jié)果顯示術(shù)前玻璃體腔內(nèi)注射有助于減少視網(wǎng)膜和虹膜新生血管，手術(shù)更快更安全，從而使患者獲得更佳的預(yù)后，并且該研究表明術(shù)前7d注藥為最佳時(shí)期。Diabetic Retinopathy Clinical Research Network[45]于2012年公布一項(xiàng)關(guān)于雷尼珠單抗治療聯(lián)合即時(shí)激光和延期激光治療DME隨訪3年的數(shù)據(jù)。結(jié)果顯示，在抗VEGF藥物治療后，延期激光組在視力改善程度好于即時(shí)激光療組，平均注藥次數(shù)延期激光組多于即時(shí)激光組，但54%延期激光組患者在后續(xù)試驗(yàn)中并未再接受激光治療，與之前的結(jié)果[46,47]一致。RESTORE[48]試驗(yàn)對(duì)隨訪雷尼珠單抗、激光、雷尼珠單抗伍用激光3種治療12個(gè)月的結(jié)果分析后，得出了伍用組相對(duì)于激光組的DME患者視力改善更佳的結(jié)論。Yang等[20]對(duì)20只PDR患眼實(shí)施貝伐珠單抗2.5mg聯(lián)合PRP治療后，患眼玻璃體內(nèi)出血和視網(wǎng)膜新生血管迅速改善，短期內(nèi)視力得到明顯提高。在糖尿病性黃斑水腫的治療中[9]，無(wú)灌注區(qū)的局部光凝對(duì)于貝伐珠單抗是一種有效的補(bǔ)充作用。

抗VEGF聯(lián)合其他療法在兒童新生血管性眼病中也同樣適用。Autrata等[19]比較培加他尼鈉伍用激光與激光聯(lián)合冷凍治療3期ROP療效，結(jié)果顯示，抗VEGF的應(yīng)用能有效地穩(wěn)定ROP網(wǎng)膜的解剖結(jié)構(gòu)，相比于激光在阻止新生血管的復(fù)發(fā)上也具有明顯優(yōu)勢(shì)。Gaillard等[49]關(guān)于玻璃體腔內(nèi)注射雷尼珠單抗聯(lián)合激光光凝、網(wǎng)膜冷凍術(shù)治療晚期Coat病的報(bào)道結(jié)果顯示，所有入組的9名患者在治療后2周虹膜新生血管消退，視網(wǎng)膜也在4個(gè)月后重新發(fā)揮作用，其中4名患者恢復(fù)了一定的視力。盡管如此，抗VEGF對(duì)兒童有無(wú)毒副作用、生長(zhǎng)發(fā)育是否有影響尚待進(jìn)一步的研究，且兒童的用藥劑量還需根據(jù)患兒的年齡與病情做更為深入的探討。

2.3.2 PDT聯(lián)合抗VEGF或激素治療 DENALI研究[13]中321名AMD患者隨機(jī)分為雷尼珠單抗組、雷尼珠單抗聯(lián)合標(biāo)準(zhǔn)PDT治療組以及雷尼珠單抗伍用減量PDT治療組，結(jié)果顯示抗VEGF伍用標(biāo)準(zhǔn)PDT相對(duì)于其他兩種方法在視力改善、減輕中央網(wǎng)膜厚度等方面均有優(yōu)勢(shì)。在PDT伍用貝伐珠單抗治療PCV的研究中，88.2%的入組患者避免了3年后視力降低[14]。PDT伍用曲安奈德治療繼發(fā)于CNV的AMD，可以減少PDT治療的次數(shù)[50]。

2.3.3 激光聯(lián)合激素 糖皮質(zhì)激素作為減輕炎癥反應(yīng)的藥物應(yīng)用于臨床各科中效果肯定。Tunc等[51]報(bào)導(dǎo)了Tenon囊內(nèi)注射曲安奈德聯(lián)合黃斑局部光凝能有效改善糖尿病性黃斑水腫患者治療早期的視力。Gillies[52]在比較了激光前6周行ITVA和安慰劑治療，隨訪6個(gè)月后，發(fā)現(xiàn)視力比較兩組無(wú)異，激光前6周ITVA組的視網(wǎng)膜黃斑中心厚度較對(duì)照組低，但是該組需要降眼壓治療。Callanan等[8]以最佳矯正視力、OCT和FFA評(píng)價(jià)激素與激素聯(lián)合激光治療黃斑囊樣水腫療效，結(jié)果顯示，在隨訪12個(gè)月時(shí)，最佳矯正視力提高10個(gè)字母的患者比例兩者差異無(wú)統(tǒng)計(jì)學(xué)意義，但滲漏面積減少和最佳矯正視力平均提高的字母數(shù)聯(lián)合治療組均好于激素單獨(dú)治療組。Pichi等[53]比較Ozurdex聯(lián)合激光治療分支RVO Cbranch RVO，（BRVO），相比單獨(dú)黃斑區(qū)格柵樣光凝，聯(lián)合治療的最佳矯正視力更佳，且延長(zhǎng)了眼內(nèi)注藥的時(shí)間間隔。

3 小 結(jié)

隨著人均壽命的增長(zhǎng)與生活質(zhì)量的提高，老齡化所帶來的疾病正日益突出，其中新生血管性眼病成為影響日常生活質(zhì)量的重要因素。目前各種療法對(duì)于新生血管性眼病的治療各有利弊。眼底激光能減少視網(wǎng)膜耗氧、封閉滲漏、應(yīng)對(duì)新生血管，并且經(jīng)濟(jì)實(shí)惠。PDT作為一種特殊的激光治療，曾作為新生血管性眼病的一線治療方案，但光敏劑因副作用大、治療費(fèi)用高而難以推廣?？筕EGF藥物雖屬針對(duì)病因的治療，但新生血管常常退而復(fù)現(xiàn)，須重復(fù)注射，給患者和整個(gè)社會(huì)帶來經(jīng)濟(jì)負(fù)擔(dān)。必要時(shí)可多種方法聯(lián)合治療，如手術(shù)解決并發(fā)癥與反復(fù)發(fā)作的難題和激素抗炎治療等，未來必將誕生更為經(jīng)濟(jì)有效的治療方法。

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（編輯: 李菁竹）

Progress in the treatment of ocular neovascular diseases

CHEN Ze-Li, ZHU Li-Na, YU Zi-Kui, LIU Lin*

(Department of Ophthalmology, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai 200127, China)

With population ageing and improvement of life quality, ocular neovascular disease, mainly manifesting as age-related macular degeneration and diabetic retinopathy, gradually becomes a major factor affecting the quality of life in the patients. Neovascularization is its main pathological manifestation. What’s more, the disease is characterized by its complicated causes, various mechanisms, and poor prognosis. In recent years, there are a variety of drugs and treatment methods emerged and improved, such as laser therapy, anti-VEGF drugs, and surgical treatment, which have provided more and better therapies to treat such diseases. This article reviewed the advances in the treatment of the ocular neovascular diseases.

ocular diseases,neovascular; anti-VEGF; laser; photodynamic therapy

(124119a9500),(PW2013D-1),(SHDC12013905).

R77; R349.51

A

10.11915/j.issn.1671?5403.2015.01.009

2014?12?16

上海市科學(xué)技術(shù)委員會(huì)科研計(jì)劃項(xiàng)目（124119a9500）；上海市浦東新區(qū)衛(wèi)生局衛(wèi)生（計(jì)生）科技項(xiàng)目（PW2013D-1）；上海申康醫(yī)院發(fā)展中心郊區(qū)三級(jí)醫(yī)院臨床能力建設(shè)項(xiàng)目（SHDC12013905）

柳 林, E-mail: 18918358758@163.com