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

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

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。

Objective To evaluate the efficacy and safety of recombinant human tumor necrosis factor-αreceptorⅡ: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 n 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-αin 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-αin blister fluid of 15 patients was 111.99±99.41 ng/L,and the ratio of blister-fluid TNF-αlevel to peripheral blood TNF-αlevel was 1.83-28.21.Before treatment,no correlation was observed between the serum level of TNF-αand DASI score in the 22 patients(P=0.10),while the blister-fluid TNF-αlevel 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.