Background and aims

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.

Methods

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.

Results

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.

Conclusions

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.

中文翻译：

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亚临床持续性炎症是克罗恩病进展的危险因素：一项为期 2 年的前瞻性真实世界研究的结果

背景和目标

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。

方法

基于注册的、前瞻性、观察性、多中心 DIRECT（研究接受抗 TNF-α 治疗或维多珠单抗治疗的成人炎症性肠病患者粪便钙卫蛋白与血清药物水平和抗药物抗体发展的相关性）研究在三级医疗机构中跟踪了英夫利昔单抗治疗的 CD 患者 2 年。持续性炎症定义基于连续 2 次或至少 3 次就诊的 FC（>150 μg/g、>250 μg/g 或 >350 μg/g）或血清 CRP（>3 μg/mL）浓度。根据反映疾病进展的综合结果对患者进行分类，其中包括手术；住院；新的瘘管、脓肿或狭窄；和治疗升级。

结果

在 322 名 DIRECT 研究患者中，180 名无症状、接受维持治疗的英夫利昔单抗被纳入分析。出现复合终点的患者（n = 96）表现出较高的 FC 中位数水平（205 [四分位距，98-515] μg/g；P  = .045），但 CRP 没有（2.50 [四分位距，0.80-6.00] μg /毫升; P = .895)。生物标志物定义的持续性亚临床炎症患病率从 24% 到 81% 不等。考虑到连续 2 次就诊中 FC >250 μg/g，患病率为 50%，达到终点的几率增加了 3 倍（优势比，2.996 [95% 置信区间，1.557–5.776]）和结果时间持续性炎症受试者的发生率显着降低（中位时间：11 个月）。临床相关和治疗相关成分均与持续性炎症显着相关。基于 CRP >3 μg/mL、FC >150 μg/g、FC >350 μg/g、双重生物标志物（FC >250 μg/g 和/或 CRP >3 μg/mL）或更多访视的定义没有改善预测能力。

结论

在无症状英夫利昔单抗治疗的 CD 患者中，持续性炎症（通过 2 次连续就诊的 FC > 250 μg/g 简单而容易地定义）与复合结果的发生风险显着增加和发生复合结果的时间更短相关。