Short-term clinical observation of ustekinumab dose escalation in patients with Crohn's disease
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摘要: 目的 评估乌司奴单克隆抗体(UST)优化治疗克罗恩病(CD)的短期临床疗效及安全性，并分析UST优化治疗的影响因素。方法 回顾性收集2021年12月—2022年7月于南京大学医学院附属鼓楼医院消化科首次接受UST治疗的CD患者的临床资料，观察疾病活动度、炎症反应指标及CD相关再住院情况，记录治疗期间所有可能与药物相关的不良反应以评估药物安全性。将所有予UST重新静脉诱导、缩短给药间期或增加药物剂量的患者分为优化组，其余为未优化组，比较两组间临床资料的差异，探究影响UST优化治疗的相关因素。结果 共纳入87例CD患者，活动期患者25例(28.7%)，基线CD活动指数评分(CDAI)为105.38(76.63，154.81)分，51.7%的患者至少经历过一种生物制剂治疗失败。29例患者因监测血药浓度偏低、内镜下活动性溃疡、临床症状控制不佳、炎症反应指标高进行UST优化治疗，纳入优化组，其余58例纳入未优化组。中位随访28周，活动期患者的临床应答及缓解率分别为76.0%、68.0%，优化组和未优化组的药物持续使用率分别为96.6%、98.3%。治疗(23±2)周后，两组患者的血沉比较差异有统计学意义(Z=-2.571，P=0.010)。优化组的CD相关住院率为13.8%，未优化组为1.7%，两组差异有统计学意义(χ2=5.199，P=0.040)。多因素logistic回归分析显示，狭窄型病变(B2比B1：OR=5.919，95%CI：1.036~33.832，P=0.046)、治疗第(23±2)周血沉(OR=1.124，95%CI：1.020~1.238，P=0.018)是UST优化治疗的独立影响因素。治疗期间有16例(18.4%)患者出现不良反应，所有患者均继续使用UST。结论 UST对于传统治疗或抗肿瘤坏死因子-α单克隆抗体治疗失败的CD患者仍有良好的诱导缓解作用，优化治疗可帮助部分患者再次获得临床应答，且狭窄型病变、治疗第(23±2)周血沉是影响UST优化治疗的独立因素。Abstract: Objective To evaluate the short-term efficacy and safety of ustekinumab(UST) dose escalation in patients with Crohn's disease(CD), and analyze the influence factors of UST dose escalation.Methods Patients who were diagnosed as CD and treated with UST in Nanjing Drum Tower Hospital, from December 2021 to July 2022 were enrolled. Disease activity, inflammatory response indicators and CD-related hospitalization were observed. All possible drug-related adverse events were recorded to evaluate drug safety. Patients who underwent UST reinduction and/or interval shortening to < 8 weeks and/or increase the dose were divided into optimized group and others were in unoptimized group according to whether required dose intensification or not. The differences in clinical data between two groups were compared to explore related factors that affect UST dose escalation.Results A total of 87 patients with CD were included, of which 25 patients(29.1%) were active CD. Baseline CD active index(CDAI) was 105.38(76.63, 154.81)scores, 51.7% had experienced at least one failure of biologic therapy. Twenty-nine received UST dose escalation due to low blood drug concentration, endoscopic active ulcers, poor clinical symptom, high inflammatory response index. After a median follow-up of 28 weeks, 76.0% active CD patients achieved clinical response, 68.0% achieved clinical remission. The UST retention rate of optimized group and unoptimized group were 96.6% and 98.3%. At (23±2) weeks, CRP was 3.6(2.3, 5.9) mg/L, ESR 7.5(3.8, 21.3) mm/1 h. The difference of ESR after UST therapy between two groups was statistically significant(Z=-2.571, P=0.010). The rates of CD-related hospitalization in both groups were 13.8% and 1.7%, and the difference was statistically significant(χ2=5.199, P=0.040). The multivariate logistic regression analysis showed that montreal B2(B2 vs B1: OR=5.919, 95%CI: 1.036-33.832, P=0.046) and ESR at (23±2) weeks(OR=1.124, 95%CI: 1.020-1.238, P=0.018) were independent influence factors of UST dose escalation. Adverse events were reported in 16(18.4%) of 87 patients, but all patients continued their medication.Conclusion UST was effective and well tolerated for CD, especially who failed the therapy of conventional or anti-tumor necrosis factor-α monoclonal antibody. UST dose escalation can help some patients reachieve clinical response. Moreover, montreal B2 and ESR at (23±2) weeks were independent influence factors of UST dose escalation.
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Key words:
- Crohn's disease /
- ustekinumab /
- dose escalation /
- short-term efficacy /
- safety
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表 1 UST优化组与未优化组患者的临床资料比较
例(%)，M(Q1，Q3) 临床资料 优化组(n=29) 未优化组(n=58) χ2/Z P 性别 男 16(55.2) 39(67.2) 1.211 0.271 女 13(45.8) 19(32.8) 首次诱导年龄/岁 33.0(28.0，44.0) 30.5(22.0，37.8) -1.487 0.137 BMI 20.5(17.9，22.8) 20.0(17.6，21.6) -0.743 0.458 病程/月 36.0(14.0，90.5) 39.0(12.0，66.0) -0.829 0.407 蒙特利尔分型 A1型 3(10.3) 7(12.1) A2型 20(69.0) 43(74.1) 0.790 0.759 A3型 6(20.7) 8(13.8) 发病部位 回肠末端(L1) 11(37.9) 22(37.9) 结肠(L2) 2(6.8) 4(6.9) 1.023 0.875 回结肠(L3) 16(55.1) 32(55.2) 累及上消化道(L4) 3(10.2) 10(17.2) 疾病行为 非狭窄非穿透(B1) 6(20.7) 27(46.6) 狭窄(B2) 20(69.0) 26(44.8) 5.744 0.054 穿透(B3) 3(10.3) 5(8.6) 肠道切除史 10(34.5) 8(13.8) 5.043 0.025 合并肛周病变 15(51.7) 35(60.3) 0.588 0.443 合并肠外表现 4(13.8) 13(22.4) 0.914 0.339 CDAI/分a) 98.8(80.1，148.8) 112.4(73.6，157.1) -0.424 0.672 既往用药史 氨基水杨酸制剂 20(69.0) 43(74.1) 0.259 0.611 糖皮质激素 10(34.5) 24(41.4) 0.386 0.534 免疫抑制剂 15(51.7) 23(39.7) 1.145 0.285 生物制剂 18(62.1) 27(46.6) 1.864 0.172 注：a)CDAI评分缺失1例，因肠道造瘘无法计算大便次数。 
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表 2 UST优化治疗的多因素logistic回归分析
因素 OR 95%CI P 病变行为 B2比B1 5.919 1.036~33.832 0.046 B3比B1 2.385 0.086~66.392 0.608 B2比B3 2.482 0.127~48.548 0.549 既往肠道切除史 1.378 0.119~15.934 0.798 生物制剂使用史 1.012 0.199~5.142 0.988 第(23±2)周血沉 1.124 1.020~1.238 0.018
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