Brinkman D M C, de Kleer I M, ten Cate R, van Rossum M A J, Bekkering W P, Fasth A, van Tol M J D, Kuis W, Wulffraat N M, Vossen J M
Department of Paediatrics, Leiden University Medical Centre, Leiden, The Netherlands.
Arthritis Rheum. 2007 Jul;56(7):2410-21. doi: 10.1002/art.22656.
To assess the safety and efficacy of intensive immunosuppression followed by T cell-depleted autologous hematopoietic stem cell transplantation (ASCT) for induction of disease remission in children with refractory progressive juvenile idiopathic arthritis (JIA).
Twenty-two patients with progressive refractory JIA were followed up over a median period of 80 months after pretreatment with intensive immunosuppression followed by ASCT in a multicenter, prospective, phase II clinical trial. Hematopoietic stem cells were harvested from the patients' bone marrow, depleted of T cells, and kept frozen until used for ASCT. Pretreatment of patients consisted of a combination of antithymocyte globulin, cyclophosphamide, and low-dose total body irradiation. Patients were followed up for ASCT-related complications, recovery of hematologic and immune system parameters, and disease outcomes.
Reconstitution of hematologic values to normal range was rapid. Recovery of immune system parameters, especially normalization of CD4+, CD45RA+ naive T cells, was delayed, occurring at >/=6 months after ASCT. The prolonged period of immune deficiency resulted in a large number of viral infections and may have contributed to the development of macrophage activation syndrome (MAS), leading to death, in 2 patients. After ASCT, 8 of the 20 evaluable patients reached complete clinical remission of their JIA, 7 were partial responders, and 5 experienced a relapse of their disease (occurring 7 years after ASCT in 1 patient). Later during followup, 2 of the patients whose disease relapsed died from infections that developed after restarting immunosuppressive medication.
Intensive immunosuppression followed by ASCT resulted in sustained complete remission or marked improvement in 15 of 22 patients with progressive refractory JIA. The procedure, however, is associated with significant morbidity and risk of mortality due to prolonged and severe depression of T cell immunity. After fatal complications due to MAS were observed in some patients, the protocol was amended in 1999, to ensure less profound depletion of T cells, better control of systemic disease before transplantation, antiviral prophylaxis after transplantation, and slow tapering of corticosteroids. Following these protocol modifications, no additional ASCT-related deaths were observed among the 11 patients who received the modified treatment.
评估强化免疫抑制联合去除T细胞的自体造血干细胞移植（ASCT）诱导难治性进展性幼年特发性关节炎（JIA）患儿疾病缓解的安全性和有效性。
在一项多中心、前瞻性II期临床试验中，对22例进展性难治性JIA患者进行强化免疫抑制预处理后行ASCT，中位随访时间80个月。从患者骨髓中采集造血干细胞，去除T细胞，冷冻保存直至用于ASCT。患者预处理包括抗胸腺细胞球蛋白、环磷酰胺和低剂量全身照射联合应用。对患者进行随访，观察ASCT相关并发症、血液学和免疫系统参数恢复情况以及疾病转归。
血液学指标迅速恢复至正常范围。免疫系统参数的恢复，尤其是CD4+、CD45RA+初始T细胞的正常化延迟，在ASCT后≥6个月出现。免疫缺陷期延长导致大量病毒感染，可能促成了2例患者发生巨噬细胞活化综合征（MAS）并导致死亡。ASCT后，20例可评估患者中有8例JIA达到完全临床缓解，7例部分缓解，5例疾病复发（1例患者在ASCT后7年复发）。在后续随访中，2例疾病复发患者因重新开始免疫抑制治疗后发生感染而死亡。
强化免疫抑制联合ASCT使22例进展性难治性JIA患者中的15例获得持续完全缓解或显著改善。然而，该治疗方法因T细胞免疫长期严重受抑而伴有显著的发病率和死亡风险。在部分患者观察到MAS导致的致命并发症后，1999年对方案进行了修订，以确保T细胞去除程度减轻、移植前更好地控制全身疾病、移植后进行抗病毒预防以及缓慢减量糖皮质激素。采用这些方案修改后，接受改良治疗的11例患者中未观察到额外的ASCT相关死亡。
