NEJM:Canakinumab可有效治疗全身型幼年特发性关节炎

2013-05-06 shumufeng NEJM

白细胞介素-1是全身性幼年型特发性关节炎(JIA)的中枢致病因子。在两项试验中,研究人员评估了canakinumab治疗的效应和安全性。Canakinumab是一种选择性的完全人源抗-IL-1β单克隆抗体药物。研究由意大利Genoa研究所的Ruperto博士等人完成,他们证实了canakinumab治疗活动性全身性JIA的有效性。论文在线发表于2012年12月21日的国际权威杂志NEJM 。 在

白细胞介素-1是全身性幼年型特发性关节炎(JIA)的中枢致病因子。在两项试验中,研究人员评估了canakinumab治疗的效应和安全性。Canakinumab是一种选择性的完全人源抗-IL-1β单克隆抗体药物。研究由意大利Genoa研究所的Ruperto博士等人完成,他们证实了canakinumab治疗活动性全身性JIA的有效性。论文在线发表于2012年12月21日的国际权威杂志NEJM 。

在试验1中,研究人员随机分配2至19岁的全身性幼年型特发性关节炎(JIA)患者和活动性全身性特征患者(发热;活动性关节;C-反应性蛋白,>30 mg每升;以及糖皮质激素剂量≤1.0 mg每千克体重每天),试验采用双盲设定,单一皮下注射canakinumab或安慰剂(剂量4 mg每千克体重)。试验主要结局为适应性JIA ACR 30应答,定义为JIA的6项核心标准中至少有3项至少改善30%,没有一项标准发作超过30%,以及发热缓解。在试验2中,经过为期32周公开标签的canakinumab治疗后,糖皮质激素下调且有应答的患者继续随机接受canakinumab或安慰剂治疗。试验主要结局为至全身性JIA发作的时间。

结果显示,试验1至15天时,canakinumab治疗组有更多的患者达到适应性JIA ACR 30应答结局(36 of 43 [84%], vs. 4 of 41 [10%] 安慰剂组; P<0.001)。试验2,100名患者(公开标签治疗组共177例患者)在随机经受停药的时期内,继续接受canakinumab药物治疗的患者与继续接受安慰剂治疗的患者相比,前者疾病发作的风险更低(canakinumab治疗组74%的患者无发作vs.安慰剂治疗组这一数据为25%,Kaplan–Meier评估;风险比,0.36; P=0.003)。研究人员发现,平均糖皮质激素剂量从0.34 降低至0.05 mg每千克每天,并且128例患者中有42例(33%)不需要持续给予糖皮质激素。有7例患者出现巨噬细胞活化综合征;与安慰剂组相比,canakinumab治疗组出现更多的感染病例。

研究人员由此得出结论,这2项3期研究显示了canakinumab治疗活动性全身性JIA的有效性。

Two Randomized Trials of Canakinumab in Systemic Juvenile Idiopathic Arthritis

BACKGROUND Interleukin-1 is pivotal in the pathogenesis of systemic juvenile idiopathic arthritis (JIA). We assessed the efficacy and safety of canakinumab, a selective, fully human, anti–interleukin-1β monoclonal antibody, in two trials. METHODS In trial 1, we randomly assigned patients, 2 to 19 years of age, with systemic JIA and active systemic features (fever; ≥2 active joints; C-reactive protein, >30 mg per liter; and glucocorticoid dose, ≤1.0 mg per kilogram of body weight per day), in a double-blind fashion, to a single subcutaneous dose of canakinumab (4 mg per kilogram) or placebo. The primary outcome, termed adapted JIA ACR 30 response, was defined as improvement of 30% or more in at least three of the six core criteria for JIA, worsening of more than 30% in no more than one of the criteria, and resolution of fever. In trial 2, after 32 weeks of open-label treatment with canakinumab, patients who had a response and underwent glucocorticoid tapering were randomly assigned to continued treatment with canakinumab or to placebo. The primary outcome was time to flare of systemic JIA. RESULTS At day 15 in trial 1, more patients in the canakinumab group had an adapted JIA ACR 30 response (36 of 43 [84%], vs. 4 of 41 [10%] in the placebo group; P<0.001). In trial 2, among the 100 patients (of 177 in the open-label phase) who underwent randomization in the withdrawal phase, the risk of flare was lower among patients who continued to receive canakinumab than among those who were switched to placebo (74% of patients in the canakinumab group had no flare, vs. 25% in the placebo group, according to Kaplan–Meier estimates; hazard ratio, 0.36; P=0.003). The average glucocorticoid dose was reduced from 0.34 to 0.05 mg per kilogram per day, and glucocorticoids were discontinued in 42 of 128 patients (33%). The macrophage activation syndrome occurred in 7 patients; infections were more frequent with canakinumab than with placebo. CONCLUSIONS These two phase 3 studies show the efficacy of canakinumab in systemic JIA with active systemic features. (Funded by Novartis Pharma; ClinicalTrials.gov numbers, NCT00889863 andNCT00886769.) 

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