Unit of Pharmacology and Therapeutics, Department of Biomedicine, Faculty of Medicine, University of Porto, Porto, Portugal; Department of Gastroenterology, São João Hospital University Centre, Porto, Portugal; Center for Health Technology and Services Research, Porto, Portugal; Unidade de Farmacologia Clínica, São João Hospital University Centre, Porto, Portugal; Portuguese Inflammatory Bowel Disease Group, Porto, Portugal.
Unit of Pharmacology and Therapeutics, Department of Biomedicine, Faculty of Medicine, University of Porto, Porto, Portugal.
Clin Gastroenterol Hepatol. 2022 Sep;20(9):2059-2073.e7. doi: 10.1016/j.cgh.2021.12.004. Epub 2021 Dec 9.
Subclinical intestinal inflammation is common in Crohn's disease (CD). We aimed to explore its impact in the disease progression of infliximab-treated patients and the usefulness of fecal calprotectin (FC) and C-reactive protein (CRP) as surrogate minimally invasive biomarkers.
The registry-based, prospective, observational, multicenter DIRECT (study to investigate the correlation of fecal calprotectin with serum Drug levels and development of an antI-dRug antibodiEs among adult patients with inflammatory bowel disease reCeiving anti-TNF-alfa treatment or vedoluzimab treatment) study followed infliximab-treated CD patients for 2 years in a tertiary care setting. Persistent inflammation definition was based on FC (>150 μg/g, >250 μg/g, or >350 μg/g) or serum CRP (>3 μg/mL) concentrations over 2 consecutive or at least 3 visits. Patients were categorized according to a composite outcome reflecting disease progression that incorporated surgery; hospitalizations; new fistulae, abscess, or stricture; and treatment escalation.
Of 322 DIRECT study patients, 180 asymptomatic, infliximab treated on maintenance regimen were included in the analysis. Patients developing the composite endpoint (n = 96) presented higher median levels of FC (205 [interquartile range, 98-515] μg/g; P = .045) but not of CRP (2.50 [interquartile range, 0.80-6.00] μg/mL; P = .895). Biomarker-defined persistent subclinical inflammation prevalence ranged from 24% to 81%. Considering FC >250 μg/g in 2 consecutive visits, prevalence was 50%, odds of achieving the endpoint were increased 3-fold (odds ratio, 2.996 [95% confidence interval, 1.557-5.776]), and time-to-outcome occurrence was significantly lower among subjects with persistent inflammation (median time: 11 months). Both clinical-related and treatment-related components were significantly associated with persistent inflammation. Definitions based on CRP >3 μg/mL, FC >150 μg/g, FC >350 μg/g, double biomarkers (FC >250 μg/g and/or CRP >3 μg/mL), or more visits did not improve predictive ability.
Persistent inflammation, defined simply and readily by FC >250 μg/g over 2 consecutive visits, was associated with a significantly higher risk and shorter time to occurrence of a composite outcome reflecting disease progression in asymptomatic infliximab-treated CD patients.
亚临床肠道炎症在克罗恩病（CD）中很常见。我们旨在探讨其对英夫利昔单抗治疗患者疾病进展的影响，以及粪便钙卫蛋白（FC）和 C 反应蛋白（CRP）作为替代微创生物标志物的有用性。
本基于登记的、前瞻性、观察性、多中心 DIRECT（研究粪便钙卫蛋白与血清药物水平的相关性以及接受抗 TNF-α 治疗或 vedolizumab 治疗的炎症性肠病成年患者中抗药物抗体的发展）研究在三级保健环境中对英夫利昔单抗治疗的 CD 患者进行了 2 年的随访。持续性炎症的定义基于 FC（>150μg/g、>250μg/g 或>350μg/g）或血清 CRP（>3μg/mL）浓度连续 2 次或至少 3 次就诊时升高。患者根据反映疾病进展的复合结局进行分类，包括手术；住院；新瘘管、脓肿或狭窄；以及治疗升级。
在 322 名 DIRECT 研究患者中，纳入了 180 名无症状、接受英夫利昔单抗维持治疗的患者进行分析。发生复合终点（n=96）的患者 FC 中位数水平更高（205[四分位距，98-515]μg/g；P=0.045），但 CRP 中位数水平（2.50[四分位距，0.80-6.00]μg/mL；P=0.895）无差异。生物标志物定义的持续性亚临床炎症的患病率为 24%至 81%。考虑到 2 次连续就诊时 FC>250μg/g，患病率为 50%，达到终点的几率增加了 3 倍（比值比，2.996[95%置信区间，1.557-5.776]），且持续性炎症患者的结局发生时间明显更短（中位时间：11 个月）。临床相关和治疗相关因素均与持续性炎症显著相关。基于 CRP>3μg/mL、FC>150μg/g、FC>350μg/g、双标志物（FC>250μg/g 和/或 CRP>3μg/mL）或更多就诊的定义并未提高预测能力。
简单且容易地通过 FC>250μg/g 连续 2 次就诊定义的持续性炎症与无症状英夫利昔单抗治疗 CD 患者疾病进展复合结局的更高风险和更短时间发生显著相关。
