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中华临床医师杂志(电子版)

中华临床医师杂志(电子版) ›› 2019, Vol. 13 ›› Issue (06) : 409 -418. doi: 10.3877/cma.j.issn.1674-0785.2019.06.002

所属专题： 文献；

临床研究

雷珠单抗联合曲安奈德玻璃体注射治疗弥漫性糖尿病黄斑水肿的临床研究
任芝莉1, 张文伟1, 黄伟2, 曾见娣1, 赵晓勇1,†(), 张晓丽1,†()   
  1. 1. 510800　广州，南方医科大学附属花都医院眼科
    2. 157011　黑龙江牡丹江，牡丹江医学院
  • 收稿日期:2018-11-02 出版日期:2019-03-15
  • 通信作者: 赵晓勇, 张晓丽
  • 基金资助:
    广东省自然科学基金(2016A030313419); 广东省科技厅科技项目(2015A030302004；2015A030302003); 广东省医学科学技术研究基金(A2018328); 广东省中医药局科技项目(20161191；20191256); 广州市花都区科技项目(18-HDWS-070)

Clinical efficacy and safety of intra-vitreous injection of Lucentis combined with triamcinolone acetonide in treatment of diffuse diabetic macular edema

Zhili Ren1, Wenwei Zhang1, Wei Huang2, Jiandi Zeng1, Xiaoyong Zhao1,†(), Xiaoli Zhang1,†()   

  1. 1. Department of Ophthalmology, Huadu Hospital, Southern Medical University, Guangdong 510800, China
    2. Mudanjiang Medical College, Mudanjiang 157011, China
  • Received:2018-11-02 Published:2019-03-15
  • Corresponding author: Xiaoyong Zhao, Xiaoli Zhang
  • About author:
    Corresponding authors: Zhao Xiaoyong, Email: ;
    Zhang Xiaoli, Email:
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任芝莉, 张文伟, 黄伟, 曾见娣, 赵晓勇, 张晓丽. 雷珠单抗联合曲安奈德玻璃体注射治疗弥漫性糖尿病黄斑水肿的临床研究[J]. 中华临床医师杂志(电子版), 2019, 13(06): 409-418.

Zhili Ren, Wenwei Zhang, Wei Huang, Jiandi Zeng, Xiaoyong Zhao, Xiaoli Zhang. Clinical efficacy and safety of intra-vitreous injection of Lucentis combined with triamcinolone acetonide in treatment of diffuse diabetic macular edema[J]. Chinese Journal of Clinicians(Electronic Edition), 2019, 13(06): 409-418.

目的

探讨雷珠单抗（Lucentis）联合曲安奈德（TA）玻璃体腔注射治疗弥漫性糖尿病黄斑水肿（DME）所致视力受损患者的临床疗效。

方法

收集2017年1月至2018年10月在南方医科大学附属花都医院眼科确诊为DME患者78例（90眼），采用双盲随机均分为Lucentis组（Lu组）、TA组、Lucentis＋TA组（Lu＋TA组），3组分别以玻璃体腔单次注射Lucentis（0.5 mg/0.05 ml）、TA（2 mg/0.05 ml）和2种联合注射。检测治疗前及治疗后1 d、1周、1个月、3个月最佳矫正视力、黄斑中心视网膜厚度、眼压、眼底黄斑水肿程度和渗漏类型的变化，同时在各时间点取桡静脉血，应用酶联免疫吸附试验方法检测血清血管内皮生长因子（VEGF）、肿瘤坏死因子（TNF）-α和白介素（IL）-1β水平，采用流式细胞分析外周血中性粒细胞的凋亡情况。采用单因素方差分析和t检验比较各组最佳矫正视力、黄斑中心视网膜厚度、眼压、眼底黄斑水肿程度、VEGF、TNF-α和IL-1β水平的组内和组间差异。

结果

各组治疗前平均最佳矫正视力差异无统计学意义（P<0.05），治疗后1 d、1周、1个月、3个月最佳矫正视力明显好转，与治疗前比较差异具有统计学意义（P<0.05），不同时间点Lu+TA组与TA组、Lu组比较，差异均具有统计学意义（P<0.05）。各组治疗前黄斑中心视网膜厚度比较差异无统计学意义（P>0.05），治疗后1 d、1周、1个月、3个月与治疗前相比均显著降低，差异具有统计学意义（P<0.05），不同时间点Lu＋TA组与TA组、Lu组比较，差异均具有统计学意义（P<0.05）。各组治疗前眼压、眼底黄斑水肿程度和渗漏类型比较，差异无统计学意义（P>0.05），治疗后3个月眼压、眼底黄斑水肿程度和渗漏类型与治疗前比较，差异具有统计学意义（P<0.05）。各组治疗前血清VEGF、TNF-α和IL-1β及外周血中性粒细胞凋亡比较，差异无统计学意义（P>0.05），治疗后1 d、1周、1个月、3个月血清VEGF、TNF-α和IL-1β外周血中性粒细胞凋亡与治疗前比较，差异具有统计学意义（P<0.05），不同时间点Lu＋TA组与TA组、Lu组比较，差异均具有统计学意义（P<0.05）。

结论

Lucentis联合TA治疗对控制糖尿病黄斑水肿以及提高DME患者最佳矫正视力、改善黄斑厚度及降低黄斑水肿程度优于Lucentis和TA单一治疗，且Lucentis与TA玻璃体腔注射有协同治疗作用，同时可以降低DME患者术后VEGF和炎性因子的水平。

关键词: 雷珠单抗, 曲安奈德, 玻璃体注射, 弥漫性糖尿病黄斑水肿
Objective

To evaluate the clinical efficacy and safety of Lucentis (Lu) combined with triamcinolone acetonide (TA) in the treatment of visual impairment caused by diffuse diabetic macular edema (DME).

Methods

From January 2017 to October 2018, 78 patients (90 eyes) with DME treated at the Department of Ophthalmology of Huadu Hospital Affiliated to Southern Medical University were randomly divided into an Lu group, TA group, and Lu+ TA group, in which Lucentis (0.5 mg/0.05 mL), TA (2 mg/0.05 ml), and Lucentis (0.5 mg/0.05 ml) plus TA (2 mg/0.05 ml) were injected into the vitreous cavity, respectively. Before treatment and 1 day, 1 week, 1 month, and 3 months after treatment, the best corrected visual acuity, central retinal thickness, intraocular pressure, degree of ocular fundus macular edema, and leakage type were measured, and radial vein blood was collected at each time point. Serum levels of vascular endothelial growth factor (VEGF), tumor necrosis factor-α (TNF-α), and interleukin-1β (IL-1β) were measured by enzyme-linked immunosorbent assay (ELISA), and the apoptosis of neutrophils in peripheral blood was analyzed by flow cytometry. Single-factor ANOVA and t-test were used to compare the best corrected visual acuity, retinal thickness of macular center, intraocular pressure, degree of macular edema, and the levels of VEGF, TNF-α, and IL-1β in and between groups.

Results

There was no significant difference in the mean best corrected visual acuity among the three groups before treatment (P>0.05). The best corrected visual acuity improved significantly at 1 day, 1 week, 1 month, and 3 months after treatment, and there was a significant difference between the Lu+ TA group and Lu group at different time points (P<0.05). There was no significant difference in macular central retinal thickness among the three groups before treatment (P>0.05). The retinal thickness at 1 day, 1 week, 1 month, and 3 months after treatment was significantly lower than that before treatment (P<0.05). There was no significant difference in retinal thickness between among the three groups before treatment (P<0.05), but there was a significant difference between the Lu+ TA group and Lu group at different time points (P<0.05). There was no significant difference in intraocular pressure (IOP), degree of fundus macular edema, or leakage type among the three groups before treatment (P>0.05), but IOP, fundus macular edema degree, and leakage type at 3 months after treatment were significantly different from those before treatment (P<0.05). There was no significant difference in serum VEGF, TNF-α, IL-1β, or neutrophil apoptosis among the three groups before treatment, but serum VEGF, TNF-α, and IL-1β as well as the apoptosis of peripheral blood neutrophils at 1 day, 1 week, 1 month, and 3 months after treatment were significantly higher than those before treatment (P<0.05), and there was a significant difference between the Lu + TA group and Lu group at different time points (P<0.05).

Conclusions

Lu combined with TA can control diabetic macular edema, improve the best corrected visual acuity and macular thickness, and decrease the degree of macular edema in DME patients. Lu combined with TA is superior to Lu and TA alone in the treatment of diabetic macular edema, because intra-vitreous Lu and TA vitreous injection have a synergetic effect. In addition, the combination therapy can reduce the levels of VEGF and inflammatory factors in patients with DME.

Key words: Lucentis, Triamcinolone acetonide, Intra-vitreous injection, Diffuse diabetic macular edema
表1 3组糖尿病性黄斑水肿患者患眼基线情况比较
组别 只数 年龄（岁，±s） 性别（男/女） 糖尿病病程（年，±s） 眼压（mmHg，±s） 术前视力（LogMAR，±s）
Lu组 30 53.55±5.67 12/13 12.38±2.21 15.27±1.25 1.83±0.76
TA组 30 54.11±5.12 12/14 12.29±2.23 15.31±1.17 1.86±0.73
Lu＋TA组 30 53.67±5.27 13/14 12.41±2.20 15.29±1.21 1.85±0.75
F值 ? 2.557 2.556 2.693 2.554 2.703
P值 ? 0.984 0.985 0.937 0.989 0.912
表2 3组糖尿病性黄斑水肿患者患眼治疗前及治疗后最佳矫正视力比较（±s）
组别 只数 治疗前 治疗后1 d 治疗后1周 治疗后1个月 治疗后3个月
Lu组 30 54.51±3.52 58.22±4.21a 63.54±3.83a 68.27±3.63a 73.74±3.54a
TA组 30 54.37±3.43 58.27±4.33b 63.60±3.75b 68.31±3.57b 73.88±3.51b
Lu＋TA组 30 54.49±3.48 63.32±6.89c 71.88±4.51c 79.85±4.63c 85.67±4.83c
F值 ? 0.021 16.342 18.551 21.202 25.473
P值 ? 0.992 0.043 0.035 0.021 0.015
表3 3组糖尿病性黄斑水肿患者患眼治疗前及治疗后黄斑中心视网膜厚度比较（μm，±s）
组别 只数 治疗前 治疗后1 d 治疗后1周 治疗后1个月 治疗后3个月
Lu组 30 623.15±22.28 550.39±26.57a 428.47±25.53a 322.86±25.52a 214.36±25.31a
TA组 30 624.31±22.25 552.36±26.12b 427.98±25.49b 323.41±25.48b 213.37±25.24b
Lu＋TA组 30 623.20±22.24 511.31±23.58c 351.97±23.63c 257.43±23.67c 153.68±23.23c
F值 ? 0.062 17.781 18.593 21.231 28.815
P值 ? 0.983 0.041 0.034 0.020 0.014
表4 3组糖尿病性黄斑水肿患者患眼治疗前及治疗后眼压比较（mmHg，±s）
组别 只数 治疗前 治疗后1 d 治疗后1周 治疗后1个月 治疗后3个月
Lu组 30 15.27±2.25 16.32±2.21a 17.55±2.12a 18.56±2.14a 19.57±2.13a
TA组 30 15.31±2.17 16.34±2.18b 17.53±2.22b 18.55±2.16b 19.54±2.12b
Lu＋TA组 30 15.29±2.21 17.59±2.23c 18.66±2.24c 19.71±2.13c 20.59±2.16c
F值 ? 0.053 16.632 18.693 21.914 26.252
P值 ? 1.012 0.044 0.033 0.027 0.016
图1 糖尿病性黄斑水肿患者眼底彩色照相　图a为轻度糖尿病性黄斑水肿，图b为中度糖尿病性黄斑水肿，图c为重度糖尿病性黄斑水肿
图2 糖尿病性黄斑水肿患者眼底荧光血管造影　图a为局限性渗漏，图b为弥漫性渗漏，图c为囊样水肿性渗漏
图3 3组糖尿病性黄斑水肿患者患眼治疗前和治疗后渗漏类型变化比较（%）
表5 3组糖尿病性黄斑水肿患者患眼治疗前和治疗后血清VEGF、TNF-α和IL-1β水平比较（±s）
组别 只数 VEGF（pg/ml）
治疗前 治疗后1d 治疗后1周 治疗后1个月 治疗后3个月
Lu组 30 275.34±5.51 240.39±3.69a 204.57±3.26a 168.36±2.87a 138.95±2.31a
TA组 30 274.33±5.33 241.26±3.52b 204.56±3.12b 169.37±2.96b 139.55±2.78b
Lu＋TA组 30 276.24±5.29 211.45±3.96c 170.15±2.47c 135.36±3.21c 115.33±3.76c
F值 ? 0.043 18.390 20.143 24.751 28.892
P值 ? 1.012 0.039 0.030 0.028 0.010
组别 只数 TNF-α（pg/dl）
治疗前 治疗后1d 治疗后1周 治疗后1个月 治疗后3个月
Lu组 30 35.77±4.59 32.56±1.33d 29.79±2.31d 26.98±3.86d 23.22±1.28d
TA组 30 36.83±3.36 32.54±1.21e 29.74±2.16e 27.45±3.15e 23.14±1.39e
Lu＋TA组 30 36.96±3.31 30.12±1.59f 25.52±2.33f 21.81±3.21f 19.33±2.16f
F值 ? 0.063 18.660 21.224 25.692 29.393
P值 ? 0.952 0.038 0.029 0.027 0.009
组别 只数 IL-1β（ng/ml）
治疗前 治疗后1d 治疗后1周 治疗后1个月 治疗后3个月
Lu组 30 117.63±2.70 101.23±2.29g 80.19±3.35g 70.31±3.34g 64.25±2.77g
TA组 30 117.55±2.63 101.56±2.31h 80.22±3.37h 70.38±3.65h 64.87±2.89
Lu＋TA组 30 117.96±2.52 92.30±3.96i 75.69±2.57i 63.21±3.54i 55.14±2.03i
F值 ? 0.032 19.923 21.234 25.552 29.363
P值 ? 1.231 0.0310 0.029 0.028 0.012
图4 流式细胞分析检测雷珠单抗组患眼外周血中性粒细胞凋亡
图5 流式细胞分析检测曲安奈德组患眼外周血中性粒细胞凋亡
图6 流式细胞分析检测雷珠单抗＋曲安奈德组患眼外周血中性粒细胞凋亡
图7 3组患眼治疗前及治疗后3个月Q2＋Q3凋亡率比较
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