中华皮肤科杂志 ›› 2021, Vol. 54 ›› Issue (7): 590-596.doi: 10.35541/cjd.20201071

• 论著 • 上一篇    下一篇

英夫利西单抗治疗重度斑块状银屑病的疗效和安全性及其对PD-1、PD-L1表达的影响

虞英媛1，2    李影2    余增洋1    郑建锋2    张希琳2    丁杨峰2    史玉玲1，2   

  1. 1南京医科大学上海市第十人民医院临床医学院，上海  200072；2上海市皮肤病医院  200443 
  • 收稿日期:2020-11-05 修回日期:2021-04-20 发布日期:2021-07-02
  • 通讯作者: 史玉玲 E-mail:shiyuling1973@tongji.edu.cn
  • 基金资助:
    国家自然科学基金（81673050、81872522、82073429）；上海市教委“科研创新计划”自然科学重大项目（2019-01-07-00-07-E00046）；上海市科委“科技创新行动计划”项目（18140901800）；上海市卫计委优秀学科带头人计划项目（2018BR30）；上海申康中心临床研究培育项目（SHDC12018X06、SHDC2020CR1014B）

Efficacy and safety of infliximab in the treatment of severe plaque psoriasis and its effect on the expression of programmed cell death-1 and programmed cell death ligand-1

Yu Yingyuan1,2, Li Ying2, Yu Zengyang1, Zheng Jianfeng2, Zhang Xilin2, Ding Yangfeng2, Shi Yuling1,2   

  1. 1Clinical Medical College of Shanghai Tenth People′s Hospital of Nanjing Medical University, Shanghai 200072, China; 2Shanghai Skin Disease Hospital, Shanghai 200443, China
  • Received:2020-11-05 Revised:2021-04-20 Published:2021-07-02
  • Contact: Shi Yuling E-mail:shiyuling1973@tongji.edu.cn
  • Supported by:
    National Natural Science Foundation of China （81673050, 81872522, 82073429）; Innovation Program of Shanghai Municipal Education Commission （2019-01-07-00-07-E00046）; Program of Science and Technology Commission of Shanghai Municipality （18140901800）; Excellent Subject Leader Program of Shanghai Municipal Commission of Health and Family Planning （2018BR30）; Clinical Research Program of Shanghai Hospital Development Center （SHDC12018X06, SHDC2020CR1014B）

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摘要： 【摘要】 目的 探讨英夫利西单抗治疗重度斑块状银屑病的疗效和安全性及其对银屑病皮损组织中程序性死亡蛋白1（PD-1）及程序性死亡蛋白配体1（PD-L1）表达的影响。方法 2019年2 - 4月收集就诊于上海市皮肤病医院的17例重度斑块状银屑病患者，在第0、2、6、14、22、30、38、46周给予5 mg/kg 英夫利西单抗静脉滴注治疗。第2、6、10、14、22、30、38、46、52周评价疗效，疗效指标为银屑病皮损面积和严重程度（PASI）评分，记录不良反应。采用实时PCR检测志愿者对照（8例）和银屑病患者治疗前（14例）及治疗10周后（5例）皮肤组织PD-1和PD-L1表达水平，采用免疫荧光法检测5例志愿者及银屑病患者皮肤组织PD-1和PD-L1的表达水平。采用独立样本t检验比较斑块状银屑病患者与对照皮肤样本PD-1、PD-L1的表达，采用配对t检验比较英夫利西单抗治疗前后患者皮损PD-1、PD-L1的表达。结果 英夫利西单抗治疗第2、6、10、14、22、30、38、46、52周，斑块状银屑病达到 PASI75的患者比例分别为1/17、6/16、9/16、10/16、15/15、14/15、13/14、11/13和10/11。12例患者出现抗核抗体转为阳性，为最常见的不良反应，1例出现输液反应，为最严重的不良反应。银屑病患者治疗前皮损处PD-1、PD-L1的表达（1.111 ± 0.391，0.902 ± 0.169）显著高于对照组（0.620 ± 0.225，t = 3.116，P = 0.007；0.474 ± 0.360，t = 3.208，P = 0.006）；治疗后银屑病好转皮损处PD-1、PD-L1的表达（0.570 ± 0.230，0.150 ± 0.050）较治疗前（1.238 ± 0.414，0.966 ± 0.184）显著降低（t = 3.107，P = 0.036；t = 8.423，P = 0.001）。结论 英夫利西单抗治疗斑块状银屑病疗效良好，安全性较高，但治疗过程中的监测非常必要；经英夫利西单抗治疗后，皮损中异常上调的PD-1、PD-L1表达水平降低，提示PD-1、PD-L1可能参与银屑病炎症调节。

关键词: 银屑病, 肿瘤坏死因子α, 生物制剂, 程序性细胞死亡受体1, 抗原, CD274, 治疗结果, 共抑制分子, 英夫利西单抗

Abstract: 【Abstract】 Objective To investigate the efficacy and safety of infliximab in the treatment of severe plaque psoriasis and its effect on the expression of programmed cell death-1 （PD-1） and programmed cell death ligand-1 （PD-L1） in psoriatic lesions. Methods A total of 17 patients with severe plaque psoriasis were enrolled from Shanghai Skin Disease Hospital from February 2019 to April 2019, and were treated with intravenous drips of infliximab at a dose of 5 mg/kg at weeks 0, 2, 6, 14, 22, 30, 38 and 46. Efficacy was evaluated by using the psoriasis area and severity index （PASI） score at weeks 2, 6, 10, 14, 22, 30, 38, 46 and 52, and adverse events were recorded during the trial. Real-time PCR was performed to determine the expression of PD-1 and PD-L1 in skin tissues of 8 volunteer controls, as well as in skin lesions of 14 patients with plaque psoriasis before treatment and 5 patients with plaque psoriasis after 10-week treatment, and immunofluorescence assay to measure the expression of PD-1 and PD-L1 in skin tissues of 5 volunteers and 5 patients with psoriasis. The independent sample t-test was used to compare the expression of PD-1 and PD-L1 in skin tissues between the patients with plaque psoriasis and controls, and paired t-test to compare the expression of PD-1 and PD-L1 in the skin lesions of patients before and after infliximab treatment. Results After 2, 6, 10, 14, 22, 30, 38, 46 and 52 weeks of infliximab treatment, the proportion of patients with plaque psoriasis achieving PASI75 was 1/17, 6/16, 9/16, 10/16, 15/15, 14/15, 13/14, 11/13 and 10/11, respectively. Antinuclear antibody staining turned positive in 12 patients, which was the most common adverse reaction, and 1 patient experienced an infusion reaction, which was the most severe adverse reaction. Before the treatment, the expression of PD-1 and PD-L1 （1.111 ± 0.391, 0.902 ± 0.169, respectively） was significantly higher in the skin lesions of patients with psoriasis than in the skin tissues of controls （0.620 ± 0.225, t = 3.116, P = 0.007; 0.474 ± 0.360, t = 3.208, P = 0.006, respectively）; after infliximab treatment, the expression of PD-1 and PD-L1 （0.570 ± 0.230, 0.150 ± 0.050, respectively） in the improved skin lesions was significantly lower than that in the corresponding lesions before the treatment （1.238 ± 0.414, t = 3.107, P = 0.036; 0.966 ± 0.184, t = 8.423, P = 0.001, respectively）. Conclusions Infliximab is effective and safe for the treatment of plaque psoriasis, but monitoring is necessary during treatment. The expression of PD-1 and PD-L1 is aberrantly upregulated in plaque psoriasis lesions, and decreased after infliximab treatment, suggesting that PD-1/PD-L1 may be involved in inflammation regulation in psoriasis.

Key words: Psoriasis, Tumor necrosis factor-alpha, Biological agents, Programmed cell death 1 receptor, Antigens, CD274, Treatment outcome, Co-inhibitory receptors, Infliximab