Rady Children's Hospital San Diego, San Diego, CA, USA; Department of Pediatrics, University of California San Diego, La Jolla, CA, USA.
Rady Children's Hospital San Diego, San Diego, CA, USA; Department of Pediatrics, University of California San Diego, La Jolla, CA, USA.
Lancet Child Adolesc Health. 2021 Dec;5(12):852-861. doi: 10.1016/S2352-4642(21)00270-4. Epub 2021 Oct 27.
Although intravenous immunoglobulin (IVIG) is effective therapy for Kawasaki disease, 10-20% of patients have recrudescent fever as a sign of persistent inflammation and require additional treatment. We aimed to compare infliximab with a second infusion of IVIG for treatment of resistant Kawasaki disease.
In this multicentre comparative effectiveness trial, patients (aged 4 weeks to 17 years) with IVIG resistant Kawasaki disease and fever at least 36 h after completion of their first IVIG infusion were recruited from 30 hospitals across the USA. Patients were randomly assigned (1:1) to second IVIG (2 g/kg over 8-12 h) or intravenous infliximab (10 mg/kg over 2 h without premedication), by using a randomly permuted block randomisation design with block size of two or four. Patients with fever 24 h to 7 days following completion of first study treatment crossed over to receive the other study treatment. The primary outcome measure was resolution of fever at 24 h after initiation of study treatment with no recurrence of fever attributed to Kawasaki disease within 7 days post-discharge. Secondary outcome measures included duration of fever from enrolment, duration of hospitalisation after randomisation, and changes in markers of inflammation and coronary artery Z score. Efficacy was analysed in participants who received treatment and had available outcome values. Safety was analysed in all randomised patients who did not withdraw consent. This clinical trial is registered with ClinicalTrials.gov, NCT03065244.
Between March 1, 2017, and Aug 31, 2020, 105 patients were randomly assigned to treatment and 103 were included in the intention-to-treat population (54 in the infliximab group, 49 in the second IVIG group). Two patients randomised to infliximab did not receive allocated treatment. The primary outcome was met by 40 (77%) of 52 patients in the infliximab group and 25 (51%) of 49 patients in the second IVIG infusion group (odds ratio 0·31, 95% CI 0·13-0·73, p=0·0076). 31 patients with fever beyond 24 h received crossover treatment: nine (17%) in the infliximab group received second IVIG and 22 (45%) in second IVIG group received infliximab (p=0·0024). Three patients randomly assigned to infliximab and two to second IVIG with fever beyond 24h did not receive crossover treatment. Mean fever days from enrolment was 1·5 (SD 1·4) for the infliximab group and 2·5 (2·5) for the second IVIG group (p=0·014). Mean hospital stay was 3·2 days (2·1) for the infliximab group and 4·5 days (2·5) for the second IVIG group (p<0·001). There was no difference between treatment groups for markers of inflammation or coronary artery outcome. 24 (44%) of 54 patients in the infliximab group and 33 (67%) of 49 in the second IVIG group had at least one adverse event. A drop in haemoglobin concentration of at least 2g/dL was seen in 19 (33%) of 58 patients who received IVIG as either their first or second study treatment (three of whom required transfusion) and in three (7%) of 43 who received only infliximab (none required transfusion; p=0·0028). Haemolytic anaemia was the only serious adverse events deemed definitely or probably related to study treatment, and was reported in nine (15%) of 58 patients who received IVIG as either their first or second study treatment and none who received infliximab only.
Infliximab is a safe, well tolerated, and effective treatment for patients with IVIG resistant Kawasaki disease, and results in shorter duration of fever, reduced need for additional therapy, less severe anaemia, and shorter hospitalisation compared with second IVIG infusion.
Patient Centered Outcomes Research Institute.
虽然静脉注射免疫球蛋白（IVIG）是治疗川崎病的有效疗法，但仍有 10-20%的患者出现复发性发热，表明存在持续炎症，需要额外治疗。我们旨在比较英夫利昔单抗与第二次 IVIG 输注治疗川崎病的抵抗性。
在这项多中心比较疗效试验中，从美国 30 家医院招募了 IVIG 抵抗性川崎病且首次 IVIG 输注后至少 36 小时发热的患者（年龄 4 周至 17 岁）。患者按 1:1 随机分配接受第二次 IVIG（2g/kg 输注 8-12 小时）或静脉注射英夫利昔单抗（10mg/kg 输注 2 小时，无需预先用药），采用随机区组随机设计，区组大小为 2 或 4。首次研究治疗后 24 小时至 7 天发热的患者交叉接受另一种研究治疗。主要结局指标是研究治疗开始后 24 小时内发热缓解，且出院后 7 天内无川崎病相关发热复发。次要结局指标包括从入组到发热的持续时间、随机分组后的住院时间以及炎症标志物和冠状动脉 Z 评分的变化。疗效分析纳入接受治疗且有可用结局值的参与者。安全性分析纳入所有未撤回同意的随机患者。这项临床试验在 ClinicalTrials.gov 注册，编号为 NCT03065244。
2017 年 3 月 1 日至 2020 年 8 月 31 日，105 名患者被随机分配治疗，103 名患者纳入意向治疗人群（英夫利昔单抗组 54 名，第二次 IVIG 组 49 名）。2 名随机分配至英夫利昔单抗组的患者未接受分配的治疗。主要结局在英夫利昔单抗组的 52 名患者中有 40 名（77%）和第二次 IVIG 输注组的 49 名患者中有 25 名（51%）达到（比值比 0.31，95%CI 0.13-0.73，p=0.0076）。31 名发热超过 24 小时的患者接受了交叉治疗：英夫利昔单抗组 9 名（17%）患者接受第二次 IVIG，第二次 IVIG 组 22 名（45%）患者接受英夫利昔单抗（p=0.0024）。3 名随机分配至英夫利昔单抗且发热超过 24 小时的患者和 2 名随机分配至第二次 IVIG 且发热超过 24 小时的患者未接受交叉治疗。从入组到发热的平均发热天数为英夫利昔单抗组 1.5（SD 1.4），第二次 IVIG 组 2.5（2.5）（p=0.014）。英夫利昔单抗组的平均住院时间为 3.2 天（2.1），第二次 IVIG 组为 4.5 天（2.5）（p<0.001）。炎症标志物或冠状动脉结局方面，两组之间无差异。英夫利昔单抗组 54 名患者中有 24 名（44%）和第二次 IVIG 组 49 名患者中有 33 名（67%）至少有 1 项不良事件。58 名接受 IVIG 作为首次或第二次研究治疗的患者中有 19 名（33%）血红蛋白浓度至少下降 2g/dL（其中 3 名需要输血），43 名仅接受英夫利昔单抗的患者中有 3 名（7%）血红蛋白浓度至少下降 2g/dL（均无需输血；p=0.0028）。溶血性贫血是唯一被认为与研究治疗肯定或可能相关的严重不良事件，在 58 名接受 IVIG 作为首次或第二次研究治疗的患者中有 9 名（15%）和在仅接受英夫利昔单抗的患者中无 1 名报告（p=0.0028）。
英夫利昔单抗是治疗 IVIG 抵抗性川崎病的一种安全、耐受良好且有效的治疗方法，与第二次 IVIG 输注相比，它可缩短发热持续时间、减少额外治疗的需要、降低贫血严重程度和缩短住院时间。
患者中心的结果研究协会。
