Burt Richard K, Traynor Ann, Statkute Laisvyde, Barr Walter G, Rosa Robert, Schroeder James, Verda Larissa, Krosnjar Nela, Quigley Kathleen, Yaung Kimberly, Villa Bs Marcello, Takahashi Miyuki, Jovanovic Borko, Oyama Yu
Division of Immunotherapy, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, Ill 60611, USA.
JAMA. 2006 Feb 1;295(5):527-35. doi: 10.1001/jama.295.5.527.
Manifestations of systemic lupus erythematosus (SLE) may in most patients be ameliorated with medications that suppress the immune system. Nevertheless, there remains a subset of SLE patients for whom current strategies are insufficient to control disease.
To assess the safety of intense immunosuppression and autologous hematopoietic stem cell support in patients with severe and treatment-refractory SLE.
DESIGN, SETTING, AND PARTICIPANTS: A single-arm trial of 50 patients with SLE refractory to standard immunosuppressive therapies and either organ- or life-threatening visceral involvement. Patients were enrolled from April 1997 through January 2005 in an autologous nonmyeloablative hematopoietic stem cell transplantation (HSCT) study at a single US medical center.
Peripheral blood stem cells were mobilized with cyclophosphamide (2.0 g/m2) and granulocyte colony-stimulating factor (5 microg/kg per day), enriched ex vivo by CD34+ immunoselection, cryopreserved, and reinfused after treatment with cyclophosphamide (200 mg/kg) and equine antithymocyte globulin (90 mg/kg).
The primary end point was survival, both overall and disease-free. Secondary end points included SLE Disease Activity Index (SLEDAI), serology (antinuclear antibody [ANA] and anti-double-stranded (ds) DNA), complement C3 and C4, and changes in renal and pulmonary organ function assessed before treatment and at 6 months, 12 months, and then yearly for 5 years.
Fifty patients were enrolled and underwent stem cell mobilization. Two patients died after mobilization, one from disseminated mucormycosis and another from active lupus after postponing the transplantation for 4 months. Forty-eight patients underwent nonmyeloablative HSCT. Treatment-related mortality was 2% (1/50). By intention to treat, treatment-related mortality was 4% (2/50). With a mean follow-up of 29 months (range, 6 months to 7.5 years) for patients undergoing HSCT, overall 5-year survival was 84%, and probability of disease-free survival at 5 years following HSCT was 50%. Secondary analysis demonstrated stabilization of renal function and significant improvement in SLEDAI score, ANA, anti-ds DNA, complement, and carbon monoxide diffusion lung capacity adjusted for hemoglobin.
In treatment-refractory SLE, autologous nonmyeloablative HSCT results in amelioration of disease activity, improvement in serologic markers, and either stabilization or reversal of organ dysfunction. These data are nonrandomized and thus preliminary, providing the foundation and justification for a definitive randomized trial. Clinical Trial Registration ClinicalTrials.gov Identifier: NCT00271934.
大多数系统性红斑狼疮（SLE）患者的症状可通过抑制免疫系统的药物得到改善。然而，仍有一部分SLE患者，当前的治疗策略不足以控制病情。
评估强化免疫抑制和自体造血干细胞支持对重症及治疗抵抗性SLE患者的安全性。
设计、地点和参与者：一项单臂试验，纳入50例对标准免疫抑制治疗无效且有器官或危及生命的内脏受累的SLE患者。患者于1997年4月至2005年1月在美国一家医疗中心参加自体非清髓性造血干细胞移植（HSCT）研究。
用环磷酰胺（2.0 g/m²）和粒细胞集落刺激因子（每日5 μg/kg）动员外周血干细胞，通过CD34⁺免疫选择在体外富集，冷冻保存，并在接受环磷酰胺（200 mg/kg）和马抗胸腺细胞球蛋白（90 mg/kg）治疗后回输。
主要终点是总体生存率和无病生存率。次要终点包括SLE疾病活动指数（SLEDAI）、血清学（抗核抗体[ANA]和抗双链（ds）DNA）、补体C3和C4，以及治疗前、6个月、12个月，然后在5年内每年评估的肾和肺器官功能变化。
50例患者入组并接受了干细胞动员。2例患者在动员后死亡，1例死于播散性毛霉菌病，另1例在移植推迟4个月后死于活动性狼疮。48例患者接受了非清髓性HSCT。治疗相关死亡率为2%（1/50）。按意向性分析，治疗相关死亡率为4%（2/50）。接受HSCT的患者平均随访29个月（范围6个月至7.5年），总体5年生存率为84%，HSCT后5年无病生存概率为50%。二次分析显示肾功能稳定，SLEDAI评分、ANA、抗ds DNA、补体以及经血红蛋白校正的一氧化碳弥散肺容量有显著改善。
在治疗抵抗性SLE中，自体非清髓性HSCT可改善疾病活动度，改善血清学指标，并使器官功能障碍稳定或逆转。这些数据是非随机的且因此是初步的，为确定性随机试验提供了基础和依据。临床试验注册ClinicalTrials.gov标识符：NCT00271934。
