Division of Immunotherapy, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA.
Lancet. 2011 Aug 6;378(9790):498-506. doi: 10.1016/S0140-6736(11)60982-3. Epub 2011 Jul 21.
Non-randomised studies of haemopoietic stem-cell transplantation (HSCT) in systemic sclerosis have shown improvements in lung function and skin flexibility but high treatment-related mortality. We aimed to assess safety and efficacy of autologous non-myeloablative HSCT in a phase 2 trial compared with the standard of care, cyclophosphamide.
In our open-label, randomised, controlled phase 2 trial, we consecutively enrolled patients at Northwestern Memorial Hospital (Chicago, IL, USA) who were aged younger than 60 years with diffuse systemic sclerosis, modified Rodnan skin scores (mRSS) of more than 14, and internal organ involvement or restricted skin involvement (mRSS <14) but coexistent pulmonary involvement. We randomly allocated patients 1:1 by use of a computer-generated sequence with a mixed block design (blocks of ten and four) to receive HSCT, 200 mg/kg intravenous cyclophosphamide, and 6·5 mg/kg intravenous rabbit antithymocyte globulin or to receive 1·0 g/m(2) intravenous cyclophosphamide once per month for 6 months. The primary outcome for all enrolled patients was improvement at 12 months' follow-up, defined as a decrease in mRSS (>25% for those with initial mRSS >14) or an increase in forced vital capacity by more than 10%. Patients in the control group with disease progression (>25% increase in mRSS or decrease of >10% in forced vital capacity) despite treatment with cyclophosphamide could switch to HSCT 12 months after enrolment. This study is registered with ClinicalTrials.gov, number NCT00278525.
Between Jan 18, 2006, and Nov 10, 2009 we enrolled 19 patients. All ten patients randomly allocated to receive HSCT improved at or before 12 months' follow-up, compared with none of nine allocated to cyclophosphamide (odds ratio 110, 95% CI 14·04-∞; p=0·00001). Eight of nine controls had disease progression (without interval improvement) compared with no patients treated by HSCT (p=0·0001), and seven patients switched to HSCT. Compared with baseline, data for 11 patients with follow-up to 2 years after HSCT suggested that improvements in mRSS (p<0·0001) and forced vital capacity (p<0·03) persisted.
Non-myeloablative autologous HSCT improves skin and pulmonary function in patients with systemic sclerosis for up to 2 years and is preferable to the current standard of care, but longer follow-up is needed.
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对造血干细胞移植（HSCT）治疗系统性硬化症的非随机研究表明，它可以改善肺功能和皮肤弹性，但治疗相关死亡率较高。我们旨在评估自体非清髓性 HSCT 与环磷酰胺标准治疗相比的安全性和有效性，该研究为一项 2 期临床试验。
在我们的开放标签、随机对照 2 期临床试验中，我们连续纳入了西北纪念医院（美国芝加哥）年龄小于 60 岁的弥漫性系统性硬化症患者，改良 Rodnan 皮肤评分（mRSS）大于 14，有内脏器官受累或限制皮肤受累（mRSS <14）但合并肺部受累。我们采用基于计算机生成的序列和混合区组设计（区组大小为 10 和 4），将患者以 1:1 的比例随机分配接受 HSCT（静脉注射 200mg/kg 环磷酰胺和 6.5mg/kg 兔抗胸腺细胞球蛋白）或接受 1.0g/m2 静脉注射环磷酰胺，每月一次，共 6 个月。所有入组患者的主要终点是 12 个月随访时的改善，定义为 mRSS 降低（初始 mRSS >14 的患者降低>25%）或用力肺活量增加超过 10%。尽管接受环磷酰胺治疗，但疾病仍进展（mRSS 增加>25%或用力肺活量降低>10%）的对照组患者可在入组后 12 个月转为 HSCT。该研究在 ClinicalTrials.gov 注册，编号为 NCT00278525。
2006 年 1 月 18 日至 2009 年 11 月 10 日，我们共纳入了 19 名患者。随机分配接受 HSCT 的 10 名患者均在 12 个月随访时或之前改善，而接受环磷酰胺治疗的 9 名患者无一例改善（比值比 110，95%CI 14.04-∞；p=0.00001）。9 名对照组中有 8 名（无间隔改善）疾病进展，而接受 HSCT 治疗的患者无一例（p=0.0001），且 7 名患者转为 HSCT。与基线相比，接受 HSCT 治疗的 11 名患者在 2 年随访时的数据表明，mRSS（p<0.0001）和用力肺活量（p<0.03）持续改善。
非清髓性自体 HSCT 可改善系统性硬化症患者的皮肤和肺功能，持续时间长达 2 年，优于目前的标准治疗，但需要更长时间的随访。
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