脐带间充质干细胞治疗熊去氧胆酸应答不佳的原发性胆汁性胆管炎的临床观察

Clinical observation of umbilical cord mesenchymal stem cell therapy on patients with primary biliary cholangitis with poor response to ursodeoxycholic acid

目的探讨脐带间充质干细胞(UC-MSCs)输注治疗熊去氧胆酸(UDCA)应答不佳的原发性胆汁性胆管炎(PBC)患者的安全性和有效性,分析影响UC-MSCs疗效应答的相关因素。方法选取解放军总医院第五医学中心2010年8月至2017年10月接受UC-MSCs输注治疗UDCA应答不佳的PBC患者29例。患者均以4周为间隔给予3次外周静脉输注细胞1.0×10^(6)个/kg。通过实验室指标、生命体征及不良事件发生情况评估UC-MSCs治疗的安全性。通过患者临床症状、肝功指标和Child-Pugh评分评估治疗的有效性。以“巴黎Ⅰ标准”作为疗效标准,评价患者UC-MSCs治疗后的疗效应答情况,比较有效患者及无效患者基线临床症状和肝脏功能差异,分析影响UC-MSCs疗效的相关因素。采用独立样本t检验分析年龄;采用Mann-Whitney U检验比较两组UDCA治疗时间、激素治疗时间、实验室数据等,采用Wilcoxon秩和检验比较组间数据;采用χ^(2)检验比较性别、临床症状和Child-Pugh分级等指标。多因素Cox回归分析对影响UC-MSCs疗效的相关因素。结果1例患者在治疗后因合并严重感染出现高热,所有患者未出现UC-MSCs相关严重不良事件。UC-MSCs输注后与基线相比,患者的血清碱性磷酸酶(ALP)[281.00(182.50,428.50)比201.00(149.50,402.00)]、γ-谷氨酰转移酶(GGT)[156.00(73.00,390.00)比84.00(43.50,312.50)]、总胆固醇(TC)[5.10(3.14,7.69)比3.94(3.00,6.01)]均下降(P<0.05)。其中,9例(31﹪)患者治疗后疗效明显,达到“巴黎Ⅰ标准”,与无效组患者基线相比,有效组患者天冬氨酸转氨酶(AST)[93.50(77.75,100.75)比53.00(46.00,78.00)]、ALP[342.00(237.25,516.00)比185.00(152.50,295.50)]、总胆红素(TBIL)[58.50(33.45,69.33)比13.10(11.25,20.25)]均下降(P<0.05)。多因素Cox回归分析显示,血清TBIL是影响UC-MSCs疗效的重要独立因素[HR为0.817(95﹪CI:0.715~0.935),P<0.05]。结论UC-MSCs输注对UDCA治疗应答不佳的PBC患者是安全可行的且耐受性良好,部分患者肝功能得到一定的改善。血清TBIL是影响UC-MSCs治疗疗效的独立重要因素,提示在疾病进展早期TBIL较低的阶段进行UC-MSCs治疗可能有效改善和减缓患者疾病进程。

Objective The objective of this study was to evaluate the safety and efficacy of umbilical cord mesenchymal stem cell(UC-MSCs)infusion for patients with ursodeoxycholic acid(UDCA)-resistant primary biliary cirrhosis(PBC),and analyzed related factors influencing the therapeutic effect of UC-MSCs.Methods Twenty-nine patients with UDCA-resistant PBC were enrolled in this trial of UC-MSCs from August 2010 to October 2017 in the Fifth Medical Center of Chinese PLA General Hospital.UC-MSCs were intravenously infused 3 times at a density of 1.0×10^(6) cells per kg of body weightat intervals of 4 weeks.The safety of UC-MSCs treatmentwas measured using vital signs,laboratory tests and occurrence of adverse events.The clinical symptoms,liver function indexes,and Child-Pugh scores were used to evaluate the efficacy of UC-MSCs treatment.The"Paris I criteria"was used as the curative effect standard to evaluate the curative effect response of patients after UC-MSCs treatment,to compare the differences in baseline clinical symptoms and liver function between the effective and ineffective patients,and to analyze the related factors affecting the curative effect of UC-MSCs.Student t test was used to analyze age,Mann-Whitney U test was used to compare the time of UDCA treatment,hormone treatment time and laboratory data between the two groups,Wilcoxon rank sum test was used to compare the data between groups,and χ^(2) test was used to compare the gender,clinical symptoms,Child-Pugh grading and other indicators.Multivariate Cox regression analysis on the related factors affecting the efficacy of UC-MSCs.Results One patient developed high fever due to severe infection after treatment,and no serious adverse events related to UC-MSCs occurred in all patients.Serum alkaline phosphatase(ALP)[281.00(182.50,428.50)vs 201.00(149.50,402.00)],γ-glutamyltransferase(GGT)[156.00(73.00,390.00)vs 84.00(43.50,312.50)],and total cholesterol(TC)[5.10(3.14,7.69)vs 3.94(3.00,6.01)]decreased after UC-MSCs infusion compared with baseline(P all<0.05).Among them,9 patients(31﹪)had obvious curative effect after treatment and reached the"Paris I standard".Compared with the baseline of 20 patients in the ineffective group,aspartate aminotransferase(AST)[53.00(46.00,78.00)vs 93.50(77.75,100.75)],ALP[185.00(152.50,295.50)vs 342.00(237.25,516.00)],and total bilirubin(TBIL)[13.10(11.25,20.25)vs 58.50(33.45,69.33)]were all lower than those in the ineffective group(P all<0.05).Multivariate Cox regression analysis showed that serum TBIL was an important independent factor affecting the efficacy of UC-MSCs[HR:0.817(95﹪CI:0.715~0.935),P<0.05].Conclusions UC-MSCs infusion was safe,feasible and well-tolerated in PBC patients who resistant to UDCA,and some patients have improved liver function.Serum TBIL was an independent important factor affecting the therapeutic efficacy of UC-MSCs,suggesting that UC-MSCs treatment in the early stage of disease progression with low TBIL may effectively improve and slow down the disease process of patients.