Patel Rupal M, Shulman Stanford T
Department of Pharmacy, Ann and Robert H. Lurie Children's Hospital of Chicago, Chicago, IL, USA.
Department of Pediatrics, Northwestern University Feinberg School of Medicine, Ann and Robert H. Lurie Children's Hospital of Chicago, Chicago, IL, USA.
J Clin Pharm Ther. 2015 Dec;40(6):620-5. doi: 10.1111/jcpt.12334. Epub 2015 Nov 7.
Kawasaki disease (KD) is an acute self-limiting systemic vasculitis with specific predilection for the coronary arteries that affects previously healthy young infants and children. It is the leading cause of childhood-acquired heart disease in the developed world. Although the stimulus for the cascade of inflammation in KD is unknown, prompt treatment within 10 days of symptom onset has been shown to improve clinical outcomes and reduce the risk of coronary artery complications. Standard initial therapy is intravenous immunoglobulin (IVIG) and aspirin. Non-responders to initial therapy remain a challenge. This present review summarizes the treatment options for initial and refractory KD, including the role of steroids and other immunosuppressive therapies.
Literature search using PubMed database to identify pharmacologic studies in KD using the terms Kawasaki disease, intravenous immunoglobulin, refractory, corticosteroids, infliximab, cyclosporine, methotrexate, high risk from January 1988-May 2015 was performed. Bibliographies of selected references were also evaluated for relevant articles. Results were limited to those published in English. All articles identified from the PubMed searches were evaluated.
Initial IVIG therapy results in rapid resolution of clinical symptoms in 80-90% of patients and has been shown to reduce the risk of coronary disease. Although concomitant aspirin remains the standard of care for the initial management of KD, the evidence to support its efficacy in improving coronary artery outcomes are lacking. Initial therapy with corticosteroids in addition to intravenous immunoglobulin and aspirin improves outcomes in patients in Japan. However, identifying patients at high risk who may benefit from additional corticosteroids in heterogeneous populations has been challenging. Therapeutic options for non-responders to initial therapy are also challenging given the paucity of data. Patients who fail to respond to the first dose of IVIG will most often receive a second dose. Patients who fail to respond to two doses of IVIG present a unique challenge as the appropriate treatment remains uncertain. Although their effectiveness remains unproven, treatment with infliximab, cyclosporine or methotrexate may be considered in those patients who fail multiple doses of IVIG and steroids.
The role of steroids in high-risk non-Japanese patients is unclear, with the biggest challenge being early identification of patients at high risk of developing adverse coronary artery outcomes. Limited data evaluating other immunosuppressive agents are available and should be reserved for patients failing two doses of IVIG. Although recent advances in research have broadened our understanding of the epidemiology, genetic susceptibility and pathogenesis of KD, the aetiology of KD remains unclear. Ongoing research will help determine more precise pathogenesis and may assist in developing a diagnostic test as well as identifying new targets for more precise treatment interventions.
川崎病（KD）是一种急性自限性全身性血管炎，特别易累及冠状动脉，影响此前健康的婴幼儿和儿童。它是发达国家儿童后天性心脏病的主要病因。尽管KD炎症级联反应的刺激因素尚不清楚，但症状出现后10天内及时治疗已被证明可改善临床结局并降低冠状动脉并发症的风险。标准初始治疗是静脉注射免疫球蛋白（IVIG）和阿司匹林。初始治疗无反应者仍是一个挑战。本综述总结了初始及难治性KD的治疗选择，包括类固醇和其他免疫抑制疗法的作用。
使用PubMed数据库进行文献检索，以识别1988年1月至2015年5月期间使用川崎病、静脉注射免疫球蛋白、难治性、皮质类固醇、英夫利昔单抗、环孢素、甲氨蝶呤、高风险等术语的KD药理学研究。还对所选参考文献的书目进行了评估以查找相关文章。结果仅限于以英文发表的文章。对从PubMed检索中识别出的所有文章进行了评估。
初始IVIG治疗可使80 - 90%的患者临床症状迅速缓解，并已证明可降低冠心病风险。尽管联合使用阿司匹林仍是KD初始治疗的标准护理措施，但缺乏支持其改善冠状动脉结局疗效的证据。在日本，除静脉注射免疫球蛋白和阿司匹林外，初始使用皮质类固醇治疗可改善患者结局。然而，在异质性人群中识别可能从额外皮质类固醇治疗中获益的高危患者一直具有挑战性。鉴于数据匮乏，初始治疗无反应者的治疗选择也具有挑战性。对第一剂IVIG无反应的患者通常会接受第二剂。对两剂IVIG均无反应的患者面临独特挑战，因为合适的治疗方法仍不确定。尽管英夫利昔单抗、环孢素或甲氨蝶呤治疗的有效性尚未得到证实，但对于多剂IVIG和类固醇治疗均失败的患者可考虑使用。
类固醇在非日本高危患者中的作用尚不清楚，最大的挑战是早期识别有发生不良冠状动脉结局高风险的患者。评估其他免疫抑制剂的有限数据可用，应仅用于两剂IVIG治疗失败的患者。尽管最近的研究进展拓宽了我们对KD流行病学、遗传易感性和发病机制的理解，但KD的病因仍不清楚。正在进行的研究将有助于确定更精确的发病机制，并可能有助于开发诊断测试以及识别更精确治疗干预的新靶点。
