自体外周血干细胞移植治疗难治性学龄前儿童风湿病

Treatment of refractory rheumatism among preschool children with autologous peripheral blood hematopoietic stem cell transplantation

目的探讨自体外周血干细胞移植(auto-PBHSCT)治疗难治性学龄前儿童风湿病的可行性、安全性和有效性。方法幼年皮肌炎(JDM)、幼年系统性红斑狼疮(JSLE)、幼年类风湿关节炎(JRA)各1例,均为男性患儿,年龄分别为3、6、6岁,病程分别为14、3.6、22个月,常规治疗中病情进展,库欣征明显,患病后患儿身高均无增长。JDM 患儿肌力Ⅱ级,吞咽肌和呼吸肌受损,明显 Gottron's征和向阳性皮疹;JSLE 患儿表现为蝶形红斑、蛋白尿、贫血,脑 MRI 显示脱髓鞘病变,系统性红斑狼疮疾病活动性指数(SLEDAI)≥12分;JRA 患儿双膝、踝、腕、肘严重多关节炎。以环磷酰胺(CTX)+粒细胞集落刺激因子(G-CSF)进行外周造血干细胞动员,经 CliniMACS 细胞分选仪分选 CD34^+细胞。预处理方案:JSLE 和 JRA 为卡氮芥(BCNU)+足叶乙甙(VP16)+阿糖胞苷(Ara-C)+马法兰(MEL)及抗胸腺球蛋白(ATG);JDM 为 CTX+Mel 及 ATG。回输 CD34^+细胞数分别为9.45×10~6/kg、5.46×10~6/kg 和9.60×10~6/kg。观察移植治疗前后风湿病状态和免疫学指标的变化。结果 3例患儿移植后分别于+9 d、+13 d、+11 d 粒细胞≥0.5×10~9/L,+14 d、+18 d 和+13 d 血小板≥20×10~9/L。CD4处于低水平,CD4/CD8倒置。JDM 移植后1个月皮疹消失,肌力Ⅴ级,移植后2个月血清肌酶、肌电图恢复正常。JSLE 移植后3个月皮疹消退,无蛋白尿,脑 MRI 病变吸收,移植后8个月自身抗体转阴性,SLEDAI 为2～3分。JRA 移植后3周关节炎好转,移植后3个月无关节肿胀及活动受限。均停用激素和免疫抑制药物,库欣征消退,18个月身高增长10～15 cm,均已上小学或学前班,随访25～27个月无复发。结论 auto-PBHSCT 治疗难治性学龄前儿童风湿病近期疗效显著,安全性及远期疗效有待进一步观察。

Objective To investigate the feasibility and safety of autologous peripheral blood hematopoietic stem cell transplantation （auto-PBHSCT） and its therapeutic effect on refractory rheumatism among preschool children. Methods Three boys with juvenile rheumatoid arthritis （JRA）, juvenile systemic lupus erythematosus （JSLE） and juvenile dermatomyositis （JDM） respectively, 3 to 6 years old with the mean age of 5 years with 3.5 to 22 months course of disease with 14 months on average, received auto-PBHSCT. Their conditions were so severe that conventional therapy failed to control the diseases. The changes of both clinical manifestations and immunologic indexes were observed before and after transplantation with long term following up at specialty clinic of rheumatism. Result The time when neutrophil count 〉10. 5 × 10^9/L in the 3 children was days ＋9, ＋ 13 and ＋ 11 respectively, that of platelet count ≥20 × 10^9/L was days ＋ 14, ＋ 18 and ＋ 13 respectively. The cellular immune function remained abnormal with CD4 cells at a low level and CIM/CD8 being inverted. As to the JDM child, the skin rash had disappeared and his muscle tone was improved to grade 5 within one month after the transplantation. The EMG and serum creatase level returned to normal and muscle MRI findings were improved greatly within 2 months after the transplantation. As to the JSLE child, skin rash and proteinuria had disappeared, MRI of brain showed that the pathological changes had been absorbed and EEG returned to normal 3 months after the transplantation, all the autoantibodies turned to negative within 8 months after transplantation. As to the JRA child, the arthritis had been improved remarkably within 3 weeks after auto-PBHSCT. There was no swelling of joints nor movement limitation 3 months post transplantation. The steroids and immunosuppressive drugs were diseontinued post transplantation. Cushing syndrome disappeared. Their body heights inereased by 10 to 15 em in the past 18 months, and they all returned to school. There was no relapse during follow-up periods of 25-27 months. Conclusion The therapy with auto-PBHSCT for refractory rheumatism among preschool children was remarkably effective in a short-term, yet the safety and long-term effect still need to be further studied.