Department of Gastroenterology, The First Affiliated Hospital of Zhejiang Chinese Medical University, Zhejiang Provincial Key Laboratory of Gastrointestinal Diseases Pathophysiology, Hangzhou 310006, Zhejiang Province, China.
Department of Clinical Evaluation Center, The First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou 310006, Zhejiang Province, China.
World J Gastroenterol. 2022 Jun 21;28(23):2582-2596. doi: 10.3748/wjg.v28.i23.2582.
Infliximab trough level (ITL) severely affects therapeutic outcomes of Crohn's disease (CD) patients under infliximab (IFX). Recently, frontier research has focused on identifying ITL based on different therapeutic targets. Although previous studies have elaborated clinical value of ITL monitoring on short-term outcomes in CD patients during therapy, studies contraposing the predictive value of ITL on long-term endoscopic outcomes in CD patients are still scarce domestically and overseas.
To explore the predictive value of ITL in combination with inflammatory biomarkers on long-term endoscopic outcomes in CD with clinical remission during IFX maintenance therapy.
CD patients with endoscopic remission under long-term IFX maintenance therapy in the First Affiliated Hospital of Zhejiang Chinese Medicine University from January 2012 to December 2020 were collected. ITL and inflammatory biomarkers were continuously monitored during the therapy. The Step I study was conducted from weeks 14 to 54 of IFX treatment. The Step II study was conducted from weeks 54 to 108 of IFX treatment. Endoscopic outcomes were defined as endoscopic activity (Crohn's disease endoscopic index of severity score > 2 points or Rutgeerts score > i1) and endoscopic remission (Crohn's disease endoscopic index of severity score ≤ 2 points or Rutgeerts ≤ i1). Endoscopic relapse free survival was defined as endoscopic remission at the beginning of the study stage and maintaining endoscopic remission during the study stage.
At week 14, low ITL [odds ratio (OR) = 0.666, 95% confidence interval (CI): 0.514-0.862, < 0.01] and high fecal calprotectin (FCP) level (OR = 1.002, 95%CI: 1.001-1.004, < 0.01) increased the risk of endoscopic activity at week 54. At week 54, low ITL (OR = 0.466, 95%CI: 0.247-0.877, < 0.01) and high C-reactive protein (CRP) level (OR = 1.590, 95%CI: 1.007-2.510, < 0.01) increased the risk of endoscopic activity at week 108. At week 14, ITL ≤ 5.60 μg/mL [area under the curve (AUC) = 0.83, 95%CI: 0.73-0.90, < 0.001] and FCP > 238 μg/g (AUC = 0.82, 95%CI: 0.72-0.89, < 0.001) moderately predicted endoscopic activity at week 54. ITL ≤ 5.60 μg/mL in combination with FCP > 238 μg/g indicated 82.0% possibility of endoscopic activity. At week 54, ITL ≤ 2.10 μg/mL (AUC = 0.85, 95%CI: 0.72-0.93, < 0.001) and CRP > 3.00 mg/L (AUC = 0.73, 95%CI: 0.60-0.84, = 0.012) moderately predicted moderate endoscopic activity at week 108. ITL ≤ 2.10 μg/mL in combination with CRP > 3.00 mg/L indicated 100.0% possibility of endoscopic activity. From weeks 14 to 54 of IFX treatment, patients with ITL > 5.60 μg/mL had higher rate of endoscopic relapse free survival than those with ITL ≤ 5.60 μg/mL (95.83% 46.67%). From weeks 54 to 108 of IFX treatment, patients with ITL > 2.10 μg/mL had higher rate of endoscopic survival free relapsed rate than those with ITL ≤ 2.10 μg/mL (92.68% 30.77%).
Combination of ITL, CRP, and FCP contribute to long-term endoscopic prognosis monitoring. During IFX maintenance treatment, low ITL, high CRP level, and high FCP level were independent risk factors of CD patients with clinical remission in adverse endoscopy outcomes within 1-year follow-up.
英夫利昔单抗（IFX）的药物谷浓度（ITL）严重影响克罗恩病（CD）患者的治疗效果。最近，前沿研究的重点是基于不同的治疗靶点来确定 ITL。虽然之前的研究已经详细阐述了 CD 患者在治疗过程中 ITL 监测对短期结局的临床价值，但国内外仍缺乏关于 ITL 对 CD 患者长期内镜结局预测价值的研究。
探讨在 IFX 维持治疗期间处于临床缓解的 CD 患者中，基于 ITL 联合炎症生物标志物预测长期内镜结局的价值。
收集在浙江中医药大学第一附属医院接受长期 IFX 维持治疗的内镜缓解的 CD 患者。在治疗过程中持续监测 ITL 和炎症生物标志物。第 I 阶段研究从 IFX 治疗的第 14 周到第 54 周进行。第 II 阶段研究从 IFX 治疗的第 54 周到第 108 周进行。内镜结局定义为内镜活动度（克罗恩病内镜严重指数评分>2 分或 Rutgeerts 评分>i1）和内镜缓解（克罗恩病内镜严重指数评分≤2 分或 Rutgeerts≤i1）。内镜无复发缓解定义为研究阶段开始时的内镜缓解，并在研究阶段保持内镜缓解。
在第 14 周时，低 ITL[比值比（OR）=0.666，95%置信区间（CI）：0.514-0.862， < 0.01]和高粪便钙卫蛋白（FCP）水平（OR=1.002，95%CI：1.001-1.004， < 0.01）增加了第 54 周时内镜活动的风险。在第 54 周时，低 ITL（OR=0.466，95%CI：0.247-0.877， < 0.01）和高 C 反应蛋白（CRP）水平（OR=1.590，95%CI：1.007-2.510， < 0.01）增加了第 108 周时内镜活动的风险。在第 14 周时，ITL≤5.60μg/mL[曲线下面积（AUC）=0.83，95%CI：0.73-0.90， < 0.001]和 FCP>238μg/g（AUC=0.82，95%CI：0.72-0.89， < 0.001）中度预测第 54 周时的内镜活动。ITL≤5.60μg/mL 联合 FCP>238μg/g 提示内镜活动的可能性为 82.0%。在第 54 周时，ITL≤2.10μg/mL（AUC=0.85，95%CI：0.72-0.93， < 0.001）和 CRP>3.00mg/L（AUC=0.73，95%CI：0.60-0.84， = 0.012）中度预测第 108 周时的中度内镜活动。ITL≤2.10μg/mL 联合 CRP>3.00mg/L 提示内镜活动的可能性为 100.0%。从 IFX 治疗的第 14 周到第 54 周，ITL>5.60μg/mL 的患者比 ITL≤5.60μg/mL 的患者具有更高的内镜无复发缓解率（95.83% 46.67%）。从 IFX 治疗的第 54 周到第 108 周，ITL>2.10μg/mL 的患者比 ITL≤2.10μg/mL 的患者具有更高的内镜无复发缓解率（92.68% 30.77%）。
ITL、CRP 和 FCP 的联合有助于对 CD 患者的长期内镜预后进行监测。在 IFX 维持治疗期间，低 ITL、高 CRP 水平和高 FCP 水平是 CD 患者在 1 年内随访中出现不良内镜结局的独立危险因素。
