雷珠单抗联合激光治疗视网膜静脉阻塞合并黄斑水肿的效果及安全性.pdf

2023,43(6)http:/J Clin Pathol Res 临床与病理杂志雷珠单抗联合激光治疗视网膜静脉阻塞合并黄斑水肿的效果及安全性丁连娥，胡风云，陈芬芬，曹晓莉，郑纯（中国人民解放军联勤保障部队第九一医院眼科，合肥 230031）摘 要 目的：分析和评价雷珠单抗联合激光治疗视网膜静脉阻塞合并黄斑水肿(retinal vein occlusion complicated with macular edema，RVO-ME)的疗效及安全性。方法：选取2019年1月至2022年1月由中国人民解放军联勤保障部队第901医院眼科诊治的80例(80眼)RVO-ME患者，将其分为研究组与对照组，每组40例(40眼)。对照组患者给予视网膜激光光凝术治疗，研究组患者给予视网膜激光光凝术联合玻璃体注射雷珠单抗治疗。2组患者术后均随访6个月。对2组患者的症状指标和治疗前、治疗6个月末的最佳矫正视力(best corrected visual acuity，BCVA)、黄斑中心厚度(central macular thickness，CMT)、黄斑区视网膜平均厚度(cube average thickness，CAT)进行对比。对于注射雷珠单抗后研究组患者的药物不良反应进行观察，对2组患者的术后并发症进行随访。结果：研究组患者的眼底出血吸收时间、渗出吸收时间、黄斑水肿改善时间等症状指标均低于对照组(均P0.05)。治疗6个月末，2组患者的BCVA均较治疗前增高，CMT、CAT均较治疗前降低(均P0.05)；研究组患者的BCVA高于对照组，CMT、CAT均低于对照组(均P0.05)。结论：与单纯应用视网膜光凝术治疗比较，对于RVO-ME患者采用视网膜光凝术联合玻璃体注射雷珠单抗进行治疗，对于促进症状缓解、改善术后近期视功能具有积极的意义，且不会提升术后并发症的发生率，安全性较好。关键词 雷珠单抗；视网膜激光光凝术；视网膜静脉阻塞；黄斑水肿；疗效评价；安全性评价Efficacy and safety of ranibizumab combined with laser treatment for retinal vein occlusion complicated with macular edemaDING Lian e,HU Fengyun,CHEN Fenfen,CAO Xiaoli,ZHENG Chun(Department of Ophthalmology,No.901 Hospital of Joint Service Support Force of People s Liberation Army,Hefei 230031,China)DOI：10.11817/j.issn.2095-6959.2023.222575收稿日期(Date of reception)：2022-12-02第一作者(First author)：丁连娥，Email:,ORCID:0009-0003-3548-6776通信作者(Corresponding author)：丁连娥，Email:,ORCID:0009-0003-3548-67761175临床与病理杂志,2023,43(6)http:/ABSTRACT Objective:To analyze and evaluate the efficacy and safety of ranibizumab combined with laser treatment for retinal vein occlusion complicated with macular edema(RVO-ME).Methods:A total of 80 patients(80 eyes)with RVO-ME from Department of Ophthalmology of No.901 Hospital of the Joint Logistics Support Force of the Chinese Peoples Liberation Army from January 2019 to January 2022 were selected.The patients were divided into a study group and a control group by random number table method,each group with 40 patients(40 eyes).The patients in the control group were treated with retinal laser photocoagulation,and the patients in the study group were treated with retinal laser photocoagulation combined with vitreous injection of ranibizumab.The patients in both groups were followed up for 6 months.The symptom indexes and the best corrected visual acuity(BCVA),the central macular thickness(CMT),the cube average thickness(CAT)between the 2 groups were compared.The drug-related adverse reactions of patients in the study group after injection of ranibizumab were observed,and the postoperative complications in the 2 groups were followed up and observed.Results:The absorption time of fundus hemorrhage,the absorption time of exudation and the improvement time of macular edema in the study group were lower than those in the control group(all P0.05).At the end of 6 months after treatment,BCVA in the 2 groups was higher than those before treatment,while CMT,CAT were lower than those before treatment(all P0.05).BCVA in the study group was higher than that in the control group,CMT,CAT in the study group were lower than those in the control group(all P0.05).Conclusion:Compared with the application of retinal photocoagulation alone,the application of retinal photocoagulation combined with vitreous injection of ranibizumab for RVO-ME patients has positive significance in promoting symptom relief,improving the recent visual function after surgery,will not increase the incidence of postoperative complications and has high safety.KEY WORDS ranibizumab;retinal laser photocoagulation;retinal vein occlusion;macular edema;efficacy evaluation;safety evaluation视网膜静脉阻塞(retinal vein occlusion，RVO)是眼科常见的视网膜疾病，在全球30岁以上人群中的患病率约为 1%1，确切发病机制至今尚未阐明。RVO以单眼病变居多，一般表现为视网膜静脉迂曲扩张、出血、水肿、渗出等，分为视网膜分支静脉阻塞(branch retinal vein occlusion，BRVO)和视网膜中央静脉阻塞(central retinal vein occlusion，CRVO)两类，其中，BRVO的发病率明显高于CRVO2。黄斑水肿(macular edema，ME)是RVO的最常见并发症，其发病机制复杂且容易复发，其主要病因是RVO造成黄斑部位视网膜毛细血管压力升高、通透性增加，导致血管内血液成分渗出至血管外引起水肿3。目前临床针对RVO-ME的治疗方法主要包括视网膜激光光凝术、玻璃体内注射抗(vascular endothelial growth factor，VEGF)药物等，近年来出现了大量将激光治疗与抗VEGF药物联合应用的研究报道，但是相关研究样本异质性较大且结果多有分歧，学术界迄今不仅对于抗VEGF药物治疗方案尚未形成统一的观点，1176雷珠单抗联合激光治疗视网膜静脉阻塞合并黄斑水肿的效果及安全性 丁连娥，等而且对于上述联合治疗方案的效果和安全性也未达成共识4，基于此，本研究采用随机对照的前瞻性研究方法针对抗 VEGF 药物雷珠单抗联合激光治疗RVO-ME的疗效及安全性进行了分析和评价。1 对象与方法 1.1 对象选取2019年1月至2022年1月由中国人民解放军联勤保障部队第901医院眼科诊治的80例(80眼)RVO-ME患者，采用随机数字表法将患者分为研究组与对照组，每组40例(40眼)，患者均签署知情同意书自愿参与研究，研究方案经中国人民解放军联勤保障部队第901医院医学伦理学委员会审批通过(审批号：202219587)。纳入标准：RVO-ME的诊断标准参照欧洲视网膜专家协会(European Society of Retina Specialists，EURETINA)于2019年制订的视网膜静脉阻塞诊疗指南5，均为单眼患病，病变类型均为缺血型，经眼底检查可见黄斑区弥漫性渗漏，黄斑中心凹厚度250 m，患眼视力低于0.5。排除标准：合并冠心病、控制不良的高血压、心脑卒中、重要器官功能不全、凝血功能异常的患者；合并除RVO外其他眼部疾病的患者；非RVO原因所致ME的患者；既往有眼部手术史的患者；对本研究应用治疗方法有应用禁忌的患者。1.2 治疗方法对照组患者给予视网膜激光光凝术治疗，具体方法为向患眼滴入复方托吡卡胺滴眼液(J20180051，参天制药中国有限公司)散瞳，而后采用盐酸丙美卡因滴眼液(国药准字HJ20160133，比利时Alcon公司)表面麻醉后安装视网膜镜，采用美国IRIDEX 532 nm眼科激光治疗仪于ME中心凹500 m外行点射状或格栅状光凝治疗，设置治疗仪功率为100150 mW，激光光斑直径为100 m，曝光时间为0.1 s。研究组患者在对照组疗法的基础上联合给予玻璃体腔内注射雷珠单抗治疗，具体方法为注射前3 d给予左氧氟沙星滴眼液(J20150106，参天制药中国有限公司)滴眼，每日4次，注射前散瞳及表面麻醉方法同对照组，置入开睑器后，以于颞下角膜缘后4 mm处为穿刺点，采用专用注射器向玻璃体腔内缓慢注入0.05 mL 雷珠单抗(S20170003 Novartis Pharma Stein AG，10 mg/mL，0.2 mL/支)，拔针后以无菌棉签按压1 min，采用妥布霉素地塞米松眼膏(HJ20181126，西班牙 ALCON CUSI s.a.公司)涂抹结膜囊后包扎。术后1周行眼科检查确认无异常后再给予视网膜激光光凝术治疗，手术方法同对照组。2组患者术后均随访6个月。如随访期内因治疗需要再次行雷珠单抗注射或激光光凝术则被视为退出病例。1.3 观察指标1.3.1 基线资料通过调取医院信息系统门诊及住院病案信息对2组患者的年龄、性别、患眼部位、阻塞部位、病程等基线资料进行比较。1.3.2 症状指标对2组患者的眼底出血吸收时间、渗出吸收时间、ME改善时间等症状指标进行观察和对比。1.3.3 视功能指标于治疗前及治疗6个月末对患者的最佳矫正视力(best corrected visual acuity，BCVA)、黄斑中心厚度(central macular thickness，CMT)、黄斑区视网膜平均厚度(cube average thickness，CAT)进行检测和分析，其中，BCVA采用标准视力表进行检测，CMT、CAT采用光学相干断层扫描检查进行检测。1.3.4 药物不良反应及术后并发症于注射雷珠单抗后对研究组患者的药物相关不良反应进行观察，于术后对2组患者的术后并发症进行随访和观察。1.4 统计学处理采用SPSS 23.0统计学软件进行数据处理，正态分布的连续计量资料以均数标准差(xs)表示，2组之间比较采用独立样本t检验，同组治疗前、后的比较采用配对t检验，计数资料以例(%)表示，样本率的比较采用2检验，当行列表有20%以上单元格理论频数小于5时采用Fisher确切概率法，假设检验均为双侧检测，取=0.05为检验水平，以P0.05，表1)。1177临床与病理杂志,2023,43(6)http:/2.2 2组患者症状指标比较2 组患者在行视网膜激光光凝术治疗后均达到了 ME 症状减轻、眼底出血吸收的治疗效果(图 14)。研究组患者的眼底出血吸收时间、渗出吸收时间、黄斑水肿改善时间等症状指标均短于对照组，2 组之间的差异均有统计学意义(均 P0.05)，治疗6个月末，2组患者的BCVA较治疗前增高，CMT、CAT均较治疗前降低，差异均有统计学意义(均 P0.05)；研究组患者的 BCVA 高于对照组，CMT、CAT均低于对照组，2组之间的差异均有统计学意义(均P0.05，表4)。表1 2组患者基线资料比较(n=40)Table 1 Comparisons of the baseline data between the 2 groups(n=40)组别研究组对照组t/2P年龄/岁59.0612.3558.9611.740.0370.942性别/例(%)男25(62.50)29(72.50)0.9120.34女15(37.50)11(27.50)患眼部位/例(%)左眼18(45.00)20(50.00)0.2010.654右眼22(55.00)20(50.00)阻塞部位/例(%)BRVO29(72.50)32(80.00)0.6210.431CRVO11(27.50)8(20.00)病程/d12.345.0412.185.810.1320.869计量资料以均数标准差(xs)表示。BRVO：视网膜分支静脉阻塞；CRVO：视网膜中央静脉阻塞。图1 左眼视网膜颞上静脉阻塞治疗前视网膜大量出血Figure 1 Plenty of retinal hemorrhage before the treatment of retinal superior temporal vein occlusion in the left eye图2 左眼视网膜颞上静脉阻塞治疗后3个月出血明显吸收Figure 2 Hemorrhage in the left eye was obviously absorbed 3 months after the treatment of retinal superior temporal vein occlusion1178雷珠单抗联合激光治疗视网膜静脉阻塞合并黄斑水肿的效果及安全性 丁连娥，等图3 视网膜颞上静脉阻塞治疗前黄斑部隆起，囊样空间呈低反射，血液区呈高反射Figure 3 Retinal superior temporal vein occlusion before the treatment of the macular part bulged,the cystoid space shows low reflection and the blood area shows high reflection图4 视网膜颞上静脉阻塞治疗后黄斑水肿明显减轻Figure 4 Macular edema is significantly reduced after the treatment of retinal superior temporal vein occlusion表2 2组患者症状指标比较(n=40，xs)Table 2 Comparisons of the symptom indicators between the 2 groups(n=40,xs)组别研究组对照组tP眼底出血吸收时间/周2.280.263.250.3813.3240.001渗出吸收时间/周10.190.4213.062.267.8960.001黄斑水肿改善时间/周4.350.395.870.4416.350.001表3 2组患者视功能指标比较(n=40，xs)Table 3 Comparisons of the visual function indicators between the 2 groups(n=40,xs)组别研究组对照组tPBCVA治疗前0.300.070.310.060.6860.32治疗6个月末0.490.05*0.400.04*8.890.001CMT/m治疗前522.3186.19521.0889.120.0630.939治疗6个月末294.5333.75*402.2857.04*10.2820.001CAT/m治疗前397.4478.65396.7676.030.0390.963治疗6个月末309.8845.19*352.7153.79*3.8560.001与治疗前比较，*P0.05。BCVA：最佳矫正视力；CMT：黄斑中心厚度；CAT：黄斑区视网膜平均厚度。1179临床与病理杂志,2023,43(6)http:/3 讨 论 本研究结果显示：对于RVO-ME行视网膜激光光凝术能够有效改善患者的近期视功能指标，具有较为确切的近期疗效。通过临床观察，学者6发现在接受眼底激光治疗后，RVO患者的视网膜静脉迂曲扩张及视网膜出血、水肿等症状会出现明显的消退，这反映了激光治疗对于控制RVO病情发展具有积极的意义，其对于BRVO和CRVO特别是缺血型RVO的疗效均已被相关研究7证实，对于新发病的RVO 患者，早期应用激光治疗，可促进视网膜出血、渗出的吸收，降低RVO-ME的发生率，改善视力预后，效果会优于晚期应用。对于 RVO-ME 患者，视网膜光凝术治疗可有效缓解ME，并可在术后612个月保持病情基本稳定8。但也有学者9-10认为：虽然视网膜光凝术对于RVO的疗效确切，但患者的长期视力预后未能得到改善，ME的复发率也未得到有效降低，且易导致未累及黄斑区的缺血型RVO患者的对比敏感度下降，特别是高频区改变更加明显。因此，虽然视网膜光凝术目前已成为治疗RVO-ME的常规方法之一，但单独应用时难以达到理想的疗效，在这一疗法基础上探索应用联合治疗方案以达到提高疗效的目的，仍然是一项重要的临床课题。虽然RVO-ME的病理机制至今未完全阐明，但相关研究11已证实VEGF的过表达在其中可能具有十分重要的作用，这使得抗VEGF药物与皮质类固醇激素类药物共同成为了目前针对RVO-ME治疗的常规药物。雷珠单抗是临床上用于玻璃体内注射的最常用抗VEGF药物，近年来，多项研究12-14证实了对于RVO-ME患者采用视网膜光凝术联合玻璃体注射雷珠单抗的方案能够有效缓解症状、改善视功能且不良反应较轻微，未观察到术后并发症的增加，应用安全性高，但这些研究在雷珠单抗及激光应用方法、研究对象疾病类型等方面存在诸多差异，难以形成一致性结论。为进一步分析此方案的疗效和安全性，研究者利用循证医学荟萃分析方法进行了荟萃研究，但研究结果仍然分歧较大，有研究15肯定了激光联合玻璃体腔注射雷珠单抗的疗效，但也有学者16-17认为该方法的远期收益与单独注射药物无明显差异，联合视网膜激光光凝治疗仅对减少抗VEGF药物注射次数有意义。同时，有研究18则报道联合治疗方案既不能提升患者的视力收益，也不能减少抗VEGF药物注射次数。本研究结果肯定了视网膜光凝术联合玻璃体注射雷珠单抗治疗方案在近期随访中的疗效和安全性，提示了玻璃体注射雷珠单抗等抗VEGF药物可达到提升视网膜光凝术近期疗效的目的，其主要原因是雷珠单抗能够特异性地阻止VEGF与其受体结合，发挥抑制血管内皮细胞生长、新血管形成和降低微血管通透性的作用，从而调节黄斑区微血管血流密度、促进黄斑区渗液的吸收和水肿的消退19-20，其作用机制除抑制VEGF表达，还可能与调控微小RNA表达及下调房水炎症因子、胰岛素样生长因子、转化生长因子、水通道蛋白等表达有关21。限于研究时间，本研究的术后随访时间较短，无法对患者的远期视力收益和复发等远期预后情况进行随访观察，这是本文的不足之处。综上所述，与单纯应用视网膜光凝术治疗比较，对于RVO-ME患者采用视网膜光凝术联合玻璃体注射雷珠单抗进行治疗，对于促进症状缓解、改善术后近期视功能具有积极的意义，且不会提升术后并发症发生率，安全性较好。利益冲突声明：作者声称无任何利益冲突。参考文献1Song 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