Connecticut Children's Medical Center, Hartford, Connecticut, USA.
Cincinnati Children's Hospital Medical Center and the University of Cincinnati College of Medicine, Cincinnati, Ohio, USA.
Inflamm Bowel Dis. 2022 Feb 1;28(2):151-160. doi: 10.1093/ibd/izab061.
Develop a clinical and biological predictive model for colectomy risk in children newly diagnosed with ulcerative colitis (UC).
This was a multicenter inception cohort study of children (ages 4-17 years) newly diagnosed with UC treated with standardized initial regimens of mesalamine or corticosteroids (CS) depending upon initial disease severity. Therapy escalation to immunomodulators or infliximab was based on predetermined criteria. Patients were phenotyped by clinical activity per the Pediatric Ulcerative Colitis Activity Index (PUCAI), disease extent, endoscopic/histologic severity, and laboratory markers. In addition, RNA sequencing defined pretreatment rectal gene expression and high density DNA genotyping by the Affymetrix UK Biobank Axiom Array. Coprimary outcomes were colectomy over 3 years and time to colectomy. Generalized linear models, Cox proportional hazards multivariate regression modeling, and Kaplan-Meier plots were used.
Four hundred twenty-eight patients (mean age 13 years) started initial theapy with mesalamine (n = 136), oral CS (n = 144), or intravenous CS (n = 148). Twenty-five (6%) underwent colectomy at ≤1 year, 33 (9%) at ≤2 years, and 35 (13%) at ≤3 years. Further, 32/35 patients who had colectomy failed infliximab. An initial PUCAI ≥ 65 was highly associated with colectomy (P = 0.0001). A logistic regression model predicting colectomy using the PUCAI, hemoglobin, and erythrocyte sedimentation rate had a receiver operating characteristic area under the curve of 0.78 (95% confidence interval [0.73, 0.84]). Addition of a pretreatment rectal gene expression panel reflecting activation of the innate immune system and response to external stimuli and bacteria to the clinical model improved the receiver operating characteristic area under the curve to 0.87 (95% confidence interval [0.82, 0.91]).
A small group of children newly diagnosed with severe UC still require colectomy despite current therapies. Our gene signature observations suggest additional targets for management of those patients not responding to current medical therapies.
为新诊断患有溃疡性结肠炎（UC）的儿童制定结肠切除术风险的临床和生物学预测模型。
这是一项多中心的发病队列研究，纳入了新诊断为 UC 的儿童（4-17 岁），他们接受了基于疾病严重程度的标准化初始美沙拉嗪或皮质类固醇（CS）治疗方案。根据预定标准，将免疫调节剂或英夫利昔单抗升级为治疗方案。根据儿科溃疡性结肠炎活动指数（PUCAI）、疾病范围、内镜/组织学严重程度和实验室标志物对患者进行表型分析。此外，通过 Affymetrix UK Biobank Axiom 阵列进行 RNA 测序定义预处理直肠基因表达和高密度 DNA 基因分型。主要转归为 3 年内结肠切除术和结肠切除术时间。使用广义线性模型、Cox 比例风险多变量回归建模和 Kaplan-Meier 图。
428 名患者（平均年龄 13 岁）接受初始治疗，其中 136 名患者接受美沙拉嗪治疗，144 名患者接受口服 CS 治疗，148 名患者接受静脉 CS 治疗。25 名（6%）患者在≤1 年内、33 名（9%）患者在≤2 年内和 35 名（13%）患者在≤3 年内进行了结肠切除术。此外，32/35 名接受结肠切除术的患者对英夫利昔单抗治疗失败。初始 PUCAI≥65 与结肠切除术高度相关（P=0.0001）。使用 PUCAI、血红蛋白和红细胞沉降率预测结肠切除术的逻辑回归模型的受试者工作特征曲线下面积为 0.78（95%置信区间 [0.73, 0.84]）。将反映固有免疫系统激活和对外界刺激和细菌反应的预处理直肠基因表达谱添加到临床模型中，可将受试者工作特征曲线下面积提高至 0.87（95%置信区间 [0.82, 0.91]）。
尽管有目前的治疗方法，但一小部分新诊断为严重 UC 的儿童仍需要结肠切除术。我们的基因特征观察结果表明，对于那些对当前医学治疗无反应的患者，可能需要额外的治疗靶点。
