Division of Gastroenterology, Hepatology, and Nutrition, Department of Paediatrics and IBD Centre, SickKids Hospital, University of Toronto, Toronto, ON, Canada.
Division of Gastroenterology, Hepatology and Nutrition, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
Aliment Pharmacol Ther. 2021 Jun;53(12):1300-1308. doi: 10.1111/apt.16388. Epub 2021 Apr 28.
The phase 3 (UNIFI) trial of ustekinumab (anti-interleukin 12/23) demonstrated efficacy even after prior biologic failure in adult ulcerative colitis (UC), but paediatric data are lacking.
To prospectively monitor efficacy and serum concentrations of ustekinumab given to children with UC refractory to other biologics.
Children with anti-TNF refractory UC initiating ustekinumab intravenously at sites of the Canadian Children IBD Network prior to 12/2019 are included. The primary endpoint was steroid-free clinical remission with subcutaneous ustekinumab at 52 weeks (Paediatric Ulcerative Colitis Activity Index <10, no steroids ≥4 weeks). Ustekinumab levels were measured after week 20. Endoscopic improvement was defined as Mayo endoscopic subscore ≤1, or faecal calprotectin (FCP) <250 μg/g if not re-colonoscoped.
At six sites between 01/2018 and 11/2019, 25 children (median [IQR] age 14.8 years [12.3-16.2], 72% female) with UC duration 2.3 years (1.1-4.2) received intravenous ustekinumab (median dose/kg of 6.4 [5.5-7.5] mg). All patients had failed prior infliximab therapy, and 12 (48%) also vedolizumab. Five patients discontinued ustekinumab after IV induction (four undergoing colectomy). On intent to treat basis, 44% achieved the primary endpoint of steroid-free remission at week 52, including nine (69%) of 13 who previously treated with anti-TNF only vs two (17%) of 12 who previously failed also by vedolizumab (P = 0.008). Seven of 11 remitters met the criteria for endoscopic improvement. The median (IQR) trough levels (μg/mL) were greater with q4 vs q8 weekly dosing (8.7 [4.6-9.9] vs 3.8 [12.7-4.8]) P = 0.02, but greater exposure was not associated with a superior rate of clinical remission. No adverse events were associated with therapy.
Ustekinumab demonstrated efficacy in this paediatric cohort with otherwise treatment-refractory UC. Treatment failure was not due to inadequate drug exposure.
乌司奴单抗（抗白细胞介素 12/23）的 3 期（UNIFI）试验显示，在成人溃疡性结肠炎（UC）中即使在先前的生物制剂治疗失败后仍具有疗效，但缺乏儿科数据。
前瞻性监测对先前对其他生物制剂治疗反应不佳的 UC 患儿给予乌司奴单抗的疗效和血清浓度。
纳入 2019 年 12 月前在加拿大儿童炎症性肠病网络的各个地点开始静脉内乌司奴单抗治疗且对抗 TNF 反应不佳的 UC 儿童。主要终点是在 52 周时无皮质类固醇的临床缓解（小儿溃疡性结肠炎活动指数<10，无皮质类固醇≥4 周）。在第 20 周后测量乌司奴单抗水平。内镜改善定义为 Mayo 内镜亚评分≤1，或如果未重新进行结肠镜检查，则粪便钙卫蛋白（FCP）<250μg/g。
2018 年 1 月至 2019 年 11 月，在六个地点，25 名 UC 患儿（中位[IQR]年龄 14.8[12.3-16.2]岁，72%为女性）接受了静脉内乌司奴单抗治疗（中位剂量/kg 为 6.4[5.5-7.5]mg）。所有患儿均对先前的英夫利昔单抗治疗无效，且 12 名（48%）患儿还对维得利珠单抗治疗无效。5 名患儿在静脉诱导后停用乌司奴单抗（4 例行结肠切除术）。根据意向治疗原则，44%的患儿在第 52 周时达到无皮质类固醇缓解的主要终点，其中 13 名患儿中的 9 名（69%）之前仅接受过抗 TNF 治疗，而 12 名患儿中的 2 名（17%）之前对维得利珠单抗也治疗失败（P=0.008）。11 名缓解者中有 7 名符合内镜改善标准。每 4 周给药 1 次（8.7[4.6-9.9]μg/ml）与每 8 周给药 1 次（3.8[12.7-4.8]μg/ml）相比，谷浓度（μg/ml）更高（P=0.02），但更高的暴露与临床缓解率更高无关。没有与治疗相关的不良事件。
乌司奴单抗在该儿科队列中对其他治疗反应不佳的 UC 患儿具有疗效。治疗失败不是由于药物暴露不足所致。
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