中华皮肤科杂志 ›› 2020, Vol. 53 ›› Issue (6): 428-434.doi: 10.35541/cjd.20200068

• 论著 • 上一篇    下一篇

重组人Ⅱ型肿瘤坏死因子受体-抗体融合蛋白治疗中毒性表皮坏死松解症的临床疗效观察

陆晓君1    经晶1    施辛1    戴彩红2    苏玉华1    闫志华3    徐丰4    杨志刚5    凌昕6    缪文进7    陈玲玲8   

  1. 1苏州大学附属第二医院皮肤科  215004；2江苏盛泽医院皮肤科，苏州  215227；3苏州市第七人民医院皮肤科  215151；4苏州市中西医结合医院皮肤科  215101；5联勤保障部队第904医院皮肤科，无锡  214000；6苏州市第九人民医院皮肤科  215200；7张家港市第三人民医院皮肤科  215611；8苏州市立医院本部皮肤科  215002
    陆晓君现在苏州高新区人民医院  215129

  • 收稿日期:2020-02-04 修回日期:2020-04-13 发布日期:2020-06-01
  • 通讯作者: 施辛；陈玲玲 E-mail:shx9@163.com; chenlingling031@126.com
  • 基金资助:
    苏州市第五批姑苏卫生分层培养青年拔尖人才项目（GSWS2019055）

Recombinant human tumor necrosis factor-α receptorⅡ: IgG Fc fusion protein for the treatment of drug-induced toxic epidermal necrolysis: a multicenter clinical observation

Lu Xiaojun1, Jing Jing1, Shi Xin1, Dai Caihong2, Su Yuhua1, Yan Zhihua3, Xu Feng4, Yang Zhigang5, Ling Xin6, Miao Wenjin7, Chen Lingling8   

  1. 1Department of Dermatology, The Second Affiliated Hospital of Soochow University, Suzhou 215004, China; 2Department of Dermatology, Jiangsu Shengze Hospital, Suzhou 215227, China; 3Department of Dermatology, Suzhou Seventh People′s Hospital, Suzhou 215151, China; 4Department of Dermatology, Suzhou Integrated Traditional Chinese and Western Medicine Hospital, Suzhou 215101, China; 5Department of Dermatology, The 904th Hospital of the Joint Logistics Support Force of Chinese People′s Liberation Army, Wuxi 214000, Jiangsu, China; 6Department of Dermatology, Suzhou Ninth People′s Hospital, Suzhou 215200, China; 7Department of Dermatology, Zhangjiagang Third People′s Hospital, Suzhou 215611, China; 8Department of Dermatology, Suzhou Municipal Hospital, Suzhou 215002, China
    Lu Xiaojun is working on the Department of Dermatology, The People′s Hospital of SND, Suzhou 215129, China
  • Received:2020-02-04 Revised:2020-04-13 Published:2020-06-01
  • Contact: Shi Xin; Chen Lingling E-mail:shx9@163.com; chenlingling031@126.com
  • Supported by:
    The Fifth Batch of Suzhou Health Stratification Training Program for Young Top Talents （GSWS2019055）

PDF

8

摘要： 【摘要】 目的 评价重组人Ⅱ型肿瘤坏死因子受体-抗体融合蛋白（rhTNFR：Fc）治疗由药物引起的中毒性表皮坏死松解症（TEN）的疗效及安全性。方法 2009—2018年于苏州大学附属第二医院等8个中心纳入22例TEN患者，男10例、女12例，年龄22 ~ 75岁。采用rhTNFR：Fc 25 mg/次皮下注射治疗，首剂加倍，每3天1次，连续治疗6 ~ 8次。治疗前及治疗后第4、7、10、13、16、19、22、25天评估患者药疹面积和严重程度指数（DASI）评分、DASI改善指数（DASI50、DASI75、DASI90）；微量样本多指标流式蛋白定量技术检测外周血及疱液TNF-α水平。治疗过程中监测患者体温、皮疹变化及肝肾功能，记录不良事件。统计分析采用重复测量方差分析、配对t检验及Pearson相关分析。结果 22例患者中，未合并感染的20例在首次治疗后24 ~ 72 h体温停止升高，48 ~ 120 h恢复正常。22例首次治疗后24 ~ 48 h控制水疱新发，48 ~ 96 h皮肤颜色由鲜红色转为暗紫色，2周后皮损基本恢复正常。治疗2 ~ 4周，19例肝功能异常患者丙氨酸转氨酶及天冬氨酸转氨酶水平恢复正常。治疗4 ~ 13 d，7例肾功能异常者肌酐、尿素氮得到控制。治疗过程中，22例患者DASI评分逐渐下降（F = 532.81，P＜0.01），从治疗前53.64 ± 8.67降至治疗25 d时的2.05 ± 1.21（t = 26.60，P < 0.001）。治疗第10天，22例（100%）改善达DASI50；治疗第19天，22例（100%）改善达DASI75；治疗第25天，20例（90.90%）改善达DASI90。22例患者外周血TNF-α水平随治疗时间的延长逐渐降低，从治疗前（33.95 ± 27.90） ng/L降至第25天时（2.38 ± 0.79） ng/L。治疗前15例患者疱液TNF-α水平为（111.99 ± 99.41） ng/L，疱液/外周血TNF-α比值1.83 ~ 28.21。治疗前，22例患者血清TNF-α水平与DASI评分无明显相关性（P = 0.10），15例患者疱液TNF-α水平与DASI评分呈正相关（r = 0.59，P = 0.02）。治疗过程中未发现各种急性不良反应。22例患者均完成治疗并痊愈出院，出院后随访6个月未见复发及各种并发症。结论 rhTNFR：Fc是治疗由药物引起的TEN有效及安全的药物。

关键词: 表皮坏死松解症, 中毒性； 肿瘤坏死因子α； 治疗结果； 生物制剂； 肿瘤坏死因子α拮抗剂

Abstract: 【Abstract】 Objective To evaluate the efficacy and safety of recombinant human tumor necrosis factor-α receptorⅡ: IgG Fc fusion protein （rhTNFR:Fc） in the treatment of drug-induced toxic epidermal necrolysis （TEN）. Methods From 2009 to 2018, 22 patients with TEN were enrolled from 8 centers such as the Second Affiliated Hospital of Soochow University, including 10 males and 12 females, whose age ranged from 22 to 75 years. These patients were subcutaneously injected with rhTNFR:Fc at a dose of 25 mg once every 3 days for 6 - 8 consecutive sessions, and the initial dose was doubled. The drug eruption area and severity index （DASI） score and DASI improvement indices （DASI50, DASI75 and DASI90） were assessed before treatment and on days 4, 7, 10, 13, 16, 19, 22 and 25 after treatment; cytometric bead array （CBA） technology was used to detect the level of tumor necrosis factor （TNF）-α in peripheral blood and blister fluid samples. During the treatment, body temperature, rash changes, liver and kidney function of patients were monitored, and adverse reactions were recorded. Statistical analysis was carried out by using repeated measures analysis of variance, paired t test and Pearson correlation analysis. Results Of the 22 patients, the temperature stopped rising in 20 patients without infections 24 - 72 hours after the first treatment, and returned to normal after 48 - 120 hours. Among the 22 patients, new blisters stopped appearing 24 - 48 hours after the first treatment, the skin color changed from bright red to dark purple after 48 - 96 hours, and most skin lesions subsided after 2 weeks. After 2 - 4 weeks of treatment, levels of alanine aminotransferase and aspartate aminotransferase returned to normal in 19 patients with abnormal liver function. After 4 - 13 days of treatment, levels of creatinine and urea nitrogen stopped rising in 7 patients with abnormal renal function. During the treatment, the DASI score of the 22 patients gradually decreased （F = 532.81, P < 0.01）, from 53.64 ± 8.67 before treatment to 2.05 ± 1.21 on day 25 after treatment （t = 26.60, P < 0.001）. On day 10 after treatment, 22 patients （100%） achieved DASI50; on day 19, 22 （100%） achieved DASI75; on day 25, 20 （90.90%） achieved DASI90. The level of TNF-α in peripheral blood of the 22 patients gradually decreased along with the extension of treatment duration, from 33.95 ± 27.90 ng/L before treatment to 2.38 ± 0.79 ng/L on day 25. Before treatment, the level of TNF-α in blister fluid of 15 patients was 111.99 ± 99.41 ng/L, and the ratio of blister-fluid TNF-α level to peripheral blood TNF-α level was 1.83 - 28.21. Before treatment, no correlation was observed between the serum level of TNF-α and DASI score in the 22 patients （P = 0.10）, while the blister-fluid TNF-α level was positively correlated with DASI score in the 15 patients （r = 0.59, P = 0.02）. No acute adverse reactions were observed during the treatment. All the 22 patients completed the treatment and were discharged with complete recovery. During 6 months of follow-up after discharge, no recurrence or any complication was observed. Conclusion rhTNFR:Fc is effective and safe for the treatment of drug-induced TEN.

Key words: Epidermal necrolysis, toxic, Tumor necrosis factor-alpha, Treatment outcome, Biological agents, Tumor necrosis factor-alpha antagonists

引用本文

陆晓君 经晶 施辛 戴彩红 苏玉华 闫志华 徐丰 杨志刚 凌昕 缪文进 陈玲玲. 重组人Ⅱ型肿瘤坏死因子受体-抗体融合蛋白治疗中毒性表皮坏死松解症的临床疗效观察[J]. 中华皮肤科杂志, 2020,53(6):428-434. doi:10.35541/cjd.20200068

Lu Xiaojun, Jing Jing, Shi Xin, Dai Caihong, Su Yuhua, Yan Zhihua, Xu Feng, Yang Zhigang, Ling Xin, Miao Wenjin, Chen Lingling. Recombinant human tumor necrosis factor-α receptorⅡ: IgG Fc fusion protein for the treatment of drug-induced toxic epidermal necrolysis: a multicenter clinical observation[J]. Chinese Journal of Dermatology, 2020, 53(6): 428-434.doi:10.35541/cjd.20200068