抗英夫利昔单抗可加速清除，而增加剂量可逆转免疫原性并重新获得儿科克罗恩病的临床应答。
Antibodies-to-infliximab accelerate clearance while dose intensification reverses immunogenicity and recaptures clinical response in paediatric Crohn's disease.
机构信息
Gastroenterology, Hepatology, and Nutrition, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
Clinical Pharmacology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
出版信息
Aliment Pharmacol Ther. 2022 Mar;55(5):593-603. doi: 10.1111/apt.16733. Epub 2021 Dec 22.
BACKGROUND
Antibodies to infliximab (ATI) are associated with secondary loss of response and increased risk for drug reactions. Limited studies have associated ATI with increased infliximab clearance.
AIMS
We assessed the impact of ATI on infliximab clearance and loss of response in an inception paediatric Crohn's disease cohort with 1-year follow-up.
METHODS
This multi-centre prospective cohort study collected peak and trough serum infliximab/ATI concentrations from 660 infusions (78 patients) during the first year of therapy. Clinicians were blinded to these research labs. The primary outcome was the difference in infliximab clearance between ATI-positive (ATI) and ATI-negative (no-ATI) patients. Secondary outcomes included pre-treatment predictors of ATI (including HLA-DQA1 genotyping). Clinical remission, loss of response and infliximab clearance were compared between pre-ATI, during ATI and following ATI resolution with MANOVA. Time to ATI was calculated by Cox proportional Hazards model.
RESULTS
ATI were detected in 68% (53/78) patients with a median concentration of 76 ng/mL (range 23-1828). Maximum ATI concentration was <200 ng/mL in 73.6% (39/53). Median clearance in ATI patients was higher (with higher clearance if loss of response), compared to no-ATI patients (P < 0.001). Neutrophil CD64 ratio >6 and starting dose <7.5 mg/kg independently predicted ATI in multivariable regression, while HLA-DQA1*05 presence did not. Dose adjustment resolved ATI in 37.5% (12/32) patients with concomitant infliximab concentration and clearance recovery. A maximum ATI level of ≤99 ng/mL predicted ATI resolution (area under the receiver operating curve 0.80 [95% CI 0.64-0.96]).
CONCLUSIONS
In this real-world cohort, ATI as low as 23 ng/mL impacted drug clearance. Our data suggest that dose optimisation for low-level ATI can improve infliximab clearance and prevent loss of response.
背景
抗英夫利昔单抗（ATI）与继发治疗应答丧失和药物反应风险增加相关。有限的研究表明 ATI 与英夫利昔单抗清除率增加相关。
目的
我们评估了抗英夫利昔单抗（ATI）对 1 年随访的起始小儿克罗恩病队列中英夫利昔单抗清除率和应答丧失的影响。
方法
本多中心前瞻性队列研究在治疗的第一年中，从 660 次输注（78 例患者）中收集英夫利昔单抗/ATI 的峰值和谷值血清浓度。临床医生对这些研究实验室是盲目的。主要结局是 ATI 阳性（ATI）和 ATI 阴性（无-ATI）患者之间英夫利昔单抗清除率的差异。次要结局包括治疗前 ATI 的预测因素（包括 HLA-DQA1 基因分型）。通过 MANOVA 比较治疗前、ATI 期间和 ATI 解决后临床缓解、应答丧失和英夫利昔单抗清除率。使用 Cox 比例风险模型计算 ATI 时间。
结果
68%（53/78）的患者检测到 ATI，中位数浓度为 76ng/mL（范围 23-1828）。73.6%（39/53）的最大 ATI 浓度<200ng/mL。与无-ATI 患者相比，ATI 患者的清除率更高（如果应答丧失则清除率更高）（P<0.001）。多变量回归中，中性粒细胞 CD64 比值>6 和起始剂量<7.5mg/kg 独立预测 ATI，而 HLA-DQA1*05 不存在。在 32 例患者中，有 37.5%（12/32）通过剂量调整解决了 ATI，同时伴有英夫利昔单抗浓度和清除率的恢复。最大 ATI 水平≤99ng/mL 预测 ATI 解决（接受者操作特征曲线下面积 0.80 [95%CI 0.64-0.96]）。
结论
在这个真实世界的队列中，低至 23ng/mL 的 ATI 也会影响药物清除率。我们的数据表明，低水平 ATI 的剂量优化可以提高英夫利昔单抗清除率并预防应答丧失。
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