2018 ACR聚焦：上海医生芝加哥发声，向世界展示中国狼疮治疗新里程
2018年10月19日~24日，美国风湿病学会（American College of Rheumatology，ACR）年会在芝加哥召开。这是国际公认的风湿病学领域最大规模的年度学术盛会之一。系统性红斑狼疮/狼疮肾炎作为最常见的风湿病之一，是历届ACR会议的学术焦点。美国当地时间10月21日，一项由中国医生开展的狼疮肾炎多中心研究应邀做了口头发言，上海交通大学医学院附属仁济医院风湿科的扶琼医生代表课题组介绍了来氟米特与硫唑嘌呤比较用于狼疮肾炎维持治疗的疗效与安全性，展示了用智能疾病管理系统（Smart System of Disease Management , SSDM）开展随访及病人教育的临床研究新模式，受到国际风湿科医生广泛关注。
来氟米特（爱若华®）是治疗风湿病的一线免疫抑制剂，国内已批准适应症为
成人活动性类风湿关节炎（1999年）和狼疮肾炎（2009年）。爱若华®是近40年来国内外（除日本以外）被批准治疗狼疮肾炎的唯一药物。近日，由上海交通大学医学院附属仁济医院风湿科鲍春德教授领衔的来氟米特（爱若华®）维持治疗狼疮肾炎的前瞻性、随机对照的国内多中心临床试验中期总结论文被接收为2018年ACR年会口头发言。这是继2004年ASN（美国肾脏病学会）年会和2010年温哥华国际狼疮大会之后，来氟米特（爱若华®）治疗狼疮肾炎的临床研究第三次走上国际学术大会的讲台，也是中国学者引领狼疮肾炎治疗的新里程碑。
该试验由上海交通大学医学院附属仁济医院风湿科鲍春德教授领衔，国内共有7个风湿病中心参与，参与单位分别为：上海交通大学医学院附属仁济医院、安徽医科大学第一附属医院、中山大学孙逸仙纪念医院、蚌埠医学院第一附属医院、西安交通大学第一附属医院、温州医科大学附属第一医院和南京鼓楼医院。
文摘译文如下
来氟米特与硫唑嘌呤对照维持治疗狼疮肾炎：一项前瞻、多中心、随机、开放临床试验
以往的研究证实，霉酚酸酯（MMF）和硫唑嘌呤（AZA）在维持治疗狼疮肾炎（LN）上的疗效是相当的。来氟米特（LEF）是一种免疫抑制剂，已被广泛应用于治疗类风湿关节炎。2009年，中国食品药品监督管理局批准LEF治疗LN。然而，目前还未有LEF维持治疗LN患者的随机对照试验的报道。这项研究的目的是比较LEF和AZA维持治疗LN的有效性及安全性。
在2010年至2015年期间，7个中国风湿病中心共纳入了270例活检证实的活动性LN（III/IV/Ⅴ型）成年患者。所有患者接受6个月（每月一次）的静脉用环磷酰胺（0.5 g/m2体表面积）联合皮质激素（起始1 mg/kg/d，以后按照试验方案逐渐减量）治疗。达到临床缓解（完全缓解-CR或部分缓解-PR）的患者被随机分配，分别接受强的松（10 mg/d）联合口服LEF（20 mg/d）或口服AZA（起始剂量50 mg/d，一月后增加至100 mg/d）维持治疗24个月。
主要疗效终点为治疗24月时的肾脏复发比例。次要终点包括：各临床指标、肾外复发和不良反应。通过非参数统计检验比较随访期间的各临床和实验室指标。采用Kaplan Meier法来分析至终点事件的时间。这项研究已在ClinicalTrials.gov上注册（NCT 01172002）。
共有215例达到CR或PR的患者被随机分配至LEF组（108例）和AZA组（107例）。两组患者的基线时临床、生物学和病理指标没有显著性差异。LEF治疗组和AZA治疗组各有12例（11.1%）和15例（14.0%）患者出现肾脏复发（p=0.520）。至肾脏复发的时间两组也没有显著性差异（LEF组9.83月 vs. AZA组10.93月，p=0.241）。对于诱导期达到CR的患者，与AZA组相比，LEF组的肾脏复发风险更低（6.7% vs. 14.3%，p=0.116）。随着治疗时间的延长，两组患者的CR比例不断增加（LEF：在治疗24月后从60.2%增加至87.7%，而AZA：从71.9%增加至88.7%）。在2年随访期间，两组患者的24h尿蛋白水平、血清肌酐值、血清白蛋白水平、血清C3和血清C4水平改善相当。两组均未观察到任何血清肌酐值持续翻倍或终末期肾衰竭。AZA组2例患者和LEF组有1例患者出现肾外复发。
在2年治疗期间，两组的不良事件发生率是相当的，分别为LEF组43.5%（47/108）和AZA组42.1%（45/107）。两组患者的白细胞减少（28.7%和28.97%）、肝酶异常升高（21.3%和20.56%）和贫血（12.0%和12.2%）的发生率没有显著性差异。
在维持治疗LN的有效性和安全性方面，LEF不劣于AZA。维持治疗2年内，LEF组患者具有更低的复发率及更高的CR率趋势。LEF可以作为维持治疗LN的新选择。
在这项研究中，维持缓解3年以上的患者，将进入开放性研究阶段，患者将同时纳入SSDM平台，从而进行更有效的长期随访。
文摘原文如下
Leflunomide Versus Azathioprine for Maintenance Therapy of Lupus Nephritis: A Prospective, Multicenter, Randomized, Open-Label Clinical Trial
Fu Qiong1, Bao Chunde1, Lu Liangjing1, Xu Jianhua2, Dai Lie3, Li Zhijun4, He Lan5, Zhu Xiaochun6, Sun Lingyun7
Background/Purpose:
Previous studies have compared mycophenolate mofetil (MMF) and azathioprine (AZA) as maintenance therapy of lupus nephritis (LN). Leflunomide (LEF) is an immunosuppressive agent widely used in the treatment of rheumatoid arthritis. In 2009, China Food and Drug Administration approved leflunomide for the treatment of LN. However, a randomized controlled trial of LEF for the maintenance treatment in patients with LN has not been reported. The aim of the investigator-initiated study was to compare the efficacy and safety of LEF versus AZA as maintenance therapy for LN.
METHODS:
270 adult patients with biopsy-confirmed active LN (class III/IV/Ⅴ) were enrolled in 7 Chinese rheumatology centers from 2010 to 2015. All patients received induction therapy with six monthly intravenous cyclophosphamide (0.5 g per square meter of body-surface area) plus steroids (starting from 1 mg/kg/d and tapering according to protocol). The patients who achieved remission (complete or partial remission, CR or PR) were randomized to receive prednisone (10 mg/d) in combination with either oral LEF (20 mg/d) or oral AZA (initial dose 50 mg/d, and after one month increased to 100 mg/d) as maintenance therapy for 24 months.
The primary efficacy end point was the rate of renal flare in 24 months. Secondary outcomes included clinical parameters, extrarenal flare and adverse effects. The clinical and laboratory parameters were compared during follow-up by using nonparametric statistical tests. Time to event analysis was performed by the Kaplan-Meier method. This study has been registered on ClinicalTrials.gov (NCT 01172002).
RESULTS:
A total of 215 patients who had achieved CR or PR were randomly allocated to LEF group (n=108) and AZA group (n=107). The baseline clinical, biological and pathological characteristics of patients in two groups did not differ. Renal flares were observed in 12 (11.1%) LEF-treated and 15 (14.0%) AZA-treated patients (p=0.520). Time to renal flare did not statistically differ (LEF 9.83 months vs. AZA 10.93 months, p=0.241). For LN patients who achieved CR in induction phase, lower risk of renal flare was observed in LEF group than in AZA group (6.7% vs. 14.3 %, p=0.116). The CR rate in both groups continued to increase with time（LEF: from 60.2% to 87.7% after 24 months, and AZA: 71.9% to 88.7%). Over a 2-year period, 24h proteinuria, serum creatinine, serum albumin, serum C3 and serum C4 improved similarly in both groups. Sustained doubling of serum creatinine or end-stage renal failure was not observed in both groups. Extrarenal flare occurred in 2 patients from AZA group and 1 patient from LEF group.
The incidence of adverse events during the 2-year treatment was similar in the two groups: LEF (43.5%, 47/108) and AZA (42.1%, 45/107), respectively. There was no significant difference in the incidence of leukopenia (28.7% and 28.97%), abnormal elevation of liver enzyme (21.3% and 20.56%), and anaemia (12.0% and 12.2%) between groups.
CONCLUSIONS:
LEF is non-inferior to AZA for maintenance therapy of LN in terms of efficacy and safety profile. With maintenance therapy for 2 years, a trend of lower rate of relapse and higher CR rate was observed in the LEF group. LEF may become a new candidate medicine for maintenance therapy of LN.
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