Should infliximab be used as an adjuvant to IVIG in the treatment of children with Kawasaki disease who are at high risk for resistance to conventional therapy?
Should infliximab be used as an adjuvant to IVIG in the treatment of children with Kawasaki disease who are at high risk for resistance to conventional therapy?
复制标题
英夫利昔单抗是否应该作为 IVIG 的佐剂来治疗对常规治疗具有高耐药风险的川崎病儿童？
DOI：
10.1007/s00246-013-0731-3
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发表时间：
2013
影响因子：
1.6
通讯作者：
Gold-vonSimson,Gabrielle
中科院分区：
文献类型：
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作者：
Davies,Shelby;Gold-vonSimson,Gabrielle
致编辑：Sivakumar和Pavithran bbb最近发表的题为“顽固性川崎病的广泛冠状动脉瘤伴血栓形成”的文章，简明地描述了川崎病（KD）治疗的局限性。对于难治性患者，目前尚无公认的治疗方案，英夫利昔单抗作为一线辅助治疗的疗效也尚未得到研究。尽管一项回顾性研究显示，英夫利昔单抗可改善多种临床结果，但使用英夫利昔单抗作为二线治疗并没有得到强有力的研究的令人信服的支持[10]。正如本病例所示，KD的治疗既不普遍也不直观。如果在更早的时间点使用英夫利昔单抗，在这一人群中的疗效可能会得到增强，特别是对治疗耐药风险较高的儿童。对静脉注射免疫球蛋白（IVIG）一线治疗有耐药性的儿童发生冠状动脉瘤的风险更高。因此，为了避免这种毁灭性的后果，英夫利昔单抗是否应该作为IVIG的辅助药物用于治疗高危KD患儿？这些高危患者（男性，年轻，发烧复发）可能通过风险分层算法识别，并可能从更积极的早期治疗中获益。已有研究表明，肿瘤坏死因子(TNF) - α抑制剂可减轻小鼠模型中的炎症和动脉内膜炎，特别是抑制中性粒细胞粘附内皮细胞，这在血管炎[2]的早期阶段可见。这个概念验证实验进一步阐明了tnf - α抑制剂在治疗全血管炎中的作用。基于动脉内膜炎的机制和其他患者使用英夫利昔单抗治疗的成功，我们认为高风险KD患者可能受益于英夫利昔单抗联合常规IVIG治疗的早期治疗[1,3]。为了与这一假设保持一致，加州大学圣地亚哥分校的研究人员最近完成了一项针对急性KD患儿的英夫利昔单抗加标准治疗与安慰剂加标准治疗的III期安慰剂对照、多中心随机临床试验，以确定在初始治疗中加入英夫利昔单抗是否可以降低治疗耐药儿童的百分比。本研究的结果可能会进一步指导我们对KD的初步治疗。
To the Editor, The recently published article, entitled ‘‘Extensive Coronary Aneurysms with Thrombosis in Resistant Kawasaki Disease’’by Sivakumar and Pavithran [4], concisely delineates the limitations in the treatment of Kawasaki disease (KD). There is no one accepted treatment algorithm for treatment-refractory patients, and the efficacy of infliximab as a first-line therapy adjunct has not yet been studied. Although a retrospective study showed improvement in various clinical outcomes, use of infliximab as second-line therapy is not convincingly supported by highly powered studies [5]. As this case illustrates, the treatment of KD is neither universal nor intuitive. The efficacy of infliximab in this population would perhaps be enhanced if administered at an earlier time point, especially in children who are at high risk for resistance to therapy. Children who are resistant to first-line treatment with intravenous immunoglobulin (IVIG) carry a higher risk for development of coronary artery aneurysms [3]. Therefore, to avoid such devastating outcomes, should infliximab be used as an adjunct to IVIG in the treatment of children with KD who are at high risk? These high-risk patients (male, young age, recurrence of fever) could possibly be identified with a risk stratification algorithm and may benefit from more aggressive early therapy. It has been shown that tumor-necrosis factor (TNF)–alpha inhibitors decrease inflammation and endoarteritis in murine models, specifically the inhibition of neutrophil adhesion to endothelial cells, which is seen in the early phase of vasculitis [2]. This proof-of-concept experiment further elucidates the role of TNF-alpha inhibitors in the treatment of panvasculitis. Based on the mechanism of endoarteritis and the success of other patients treated with infliximab, we believe that high-risk KD patients may benefit from early treatment with infliximab in conjunction with conventional IVIG therapy [1, 3]. In keeping with this hypothesis, researchers at The University of California at San Diego recently completed a phase III placebo-controlled, multicenter, randomized clinical trial of infliximab plus standard therapy versus placebo plus standard therapy in children with acute KD to determine if the addition of infliximab to primary therapy can decrease the percentage of children who are resistant to therapy. Results of this study will perhaps further guide our primary management of KD.