Department of Gastroenterology, Copenhagen University Hospital Herlev, Herlev, Denmark.
Institute for Inflammation Research, Rigshospitalet, Copenhagen, Denmark.
Scand J Gastroenterol. 2020 Aug;55(8):884-890. doi: 10.1080/00365521.2020.1786852. Epub 2020 Jul 6.
Primary non-response to infliximab (IFX) inherits a poor prognosis in inflammatory bowel disease (IBD). We explored underlying mechanisms and therapeutic thresholds in an effort to provide basis for optimizing therapy.
A prospectively followed cohort of 166 IBD patients having received standard IFX induction therapy (5 mg/kg at weeks 2, 6, and 14) had trough IFX and anti-IFX antibodies (Abs) retrospectively assessed at weeks 2 ( = 148) and 6 ( = 108). Circulating TNFα was measured in matched primary non-responders ( = 29) and responders ( = 21) at baseline and weeks 6 and 14. Clinical outcome at week 14 was supported by disease activity scores in half of patients.
In all, 18 patients (11%) had primary non-response. Infliximab was consistently lower throughout the induction phase in non-responders as compared to responders (Week 2: IFX median 18.9 μg/mL vs. 23.3, < .05. Week 6: 8.4 vs. 17.0, < .05). Optimal IFX thresholds associated with response was 22.9 μg/mL at week 2 (sensitivity 51%, specificity 80%, AUC 0.67, < .05) and 11.8 at week 6 (72%, 77%, 0.71, < .05). Anti-IFX Abs occurred in 28% of primary non-responders and associated with low IFX and treatment failure (OR 13.7 [2.8-67.5], < .01). Markers of disease activity (disease activity scores, albumin, CRP) also associated with low IFX. Circulating TNFα was higher throughout induction in non-responders with ulcerative colitis but not Crohn's disease.
IBD patients with primary IFX failure generally have lower IFX trough than responders during early induction phase. Pharmacokinetic failure seems common in ulcerative colits, whereas pharmacodynamic failure appears common in Crohn's disease.
英夫利昔单抗（IFX）初次无应答在炎症性肠病（IBD）中预后不良。我们探索了潜在的机制和治疗阈值，以期为优化治疗提供依据。
前瞻性随访了 166 例接受 IFX 标准诱导治疗（第 2、6 和 14 周时 5mg/kg）的 IBD 患者，回顾性评估了第 2 周（=148 例）和第 6 周（=108 例）时的 IFX 谷浓度和抗 IFX 抗体（Abs）。在基线和第 6 周和第 14 周时，对匹配的原发性无应答者（=29 例）和应答者（=21 例）测量循环 TNFα。半数患者的疾病活动评分支持第 14 周的临床结果。
共有 18 例（11%）患者出现原发性无应答。与应答者相比，无应答者在整个诱导期的 IFX 始终较低（第 2 周：IFX 中位数 18.9μg/mL 比 23.3μg/mL，<.05；第 6 周：8.4μg/mL 比 17.0μg/mL，<.05）。与应答相关的最佳 IFX 阈值为第 2 周 22.9μg/mL（敏感性 51%，特异性 80%，AUC 0.67，<.05）和第 6 周 11.8μg/mL（72%，77%，0.71，<.05）。原发性无应答者中有 28%出现抗 IFX Abs，与低 IFX 和治疗失败相关（OR 13.7[2.8-67.5]，<.01）。疾病活动标志物（疾病活动评分、白蛋白、CRP）也与低 IFX 相关。在诱导期内，无应答者的循环 TNFα在整个诱导期内均升高，溃疡性结肠炎患者升高，但克罗恩病患者无升高。
IFX 初次治疗失败的 IBD 患者在早期诱导期内 IFX 谷浓度通常低于应答者。药代动力学失败在溃疡性结肠炎中较为常见，而药效学失败在克罗恩病中较为常见。
