Jill Roberts Center for IBD, Division of Gastroenterology and Hepatology, Weill Cornell Medicine, New York, New York, USA.
Kaiser Permanente San Diego, San Diego, California, USA.
Inflamm Bowel Dis. 2021 Aug 19;27(9):1443-1451. doi: 10.1093/ibd/izaa313.
Infliximab and adalimumab concentrations are associated with important outcomes in inflammatory bowel disease (IBD). Antibodies to infliximab (ATI) and adalimumab (ATA) are associated with reduced drug concentrations and worse outcomes. Because the efficacy of dose escalation to overcome antibodies is unclear, we assessed the impact of this strategy to overcome immunogenicity in IBD.
Infliximab and adalimumab dosing, drug, and antibody concentrations were extracted from a database of patients with IBD having specimens collected for therapeutic drug monitoring. The primary outcome compared proportions with either infliximab ≥5 μg/mL or adalimumab ≥7.5 μg/mL and undetectable antibodies between dose-escalated and non-escalated patients. Area under the receiver operating characteristic curve analyses determined antibody concentrations below which dose escalation was associated with the primary outcome.
The study included 63,176 patients treated with infliximab and 46,429 patients treated with adalimumab. We detected ATI and ATA in 23.6% (n = 14,900) of patients treated with infliximab and 19.6% (n = 9101) of patients treated with adalimumab. In patients with ATI, infliximab dose escalation (n = 453) yielded higher proportions achieving the primary outcome (47.5% vs 30.9%; P < 0.001), greater drug concentration increases (5.9 μg/mL vs 0.2 μg/mL; P < 0.001), and ATI reductions (4.3 U/mL vs 1.9 U/mL; P = 0.002) compared to no escalation (n = 204). An ATI threshold of 8.55 U/mL was associated with achieving the primary outcome with dose escalation (area under the curve = 0.66). For patients with ATI ≤8.55 U/mL (n = 274), higher proportions (59.1% vs 29.6%; P < 0.001) achieved the primary outcome compared with those with ATI >8.55 U/mL (n = 179). No patients treated with adalimumab achieved the primary outcome (0/390), regardless of dose escalation (n = 87).
Dose escalation increased drug concentrations and eliminated antibodies with infliximab but not adalimumab. Initial ATI ≤8.55 U/mL was associated with increased efficacy of dose escalation using this assay.
英夫利昔单抗和阿达木单抗的浓度与炎症性肠病（IBD）的重要结局相关。抗英夫利昔单抗（ATI）和抗阿达木单抗（ATA）与药物浓度降低和预后不良相关。由于增加剂量以克服抗体的疗效尚不清楚，我们评估了该策略在 IBD 中克服免疫原性的效果。
从 IBD 患者的数据库中提取英夫利昔单抗和阿达木单抗的剂量、药物和抗体浓度，这些患者的标本用于治疗药物监测。主要结局比较了剂量递增组和非递增组中英夫利昔单抗≥5μg/mL 或阿达木单抗≥7.5μg/mL 且抗体不可检测的比例。受试者工作特征曲线下面积分析确定了抗体浓度低于该值时，剂量递增与主要结局相关。
该研究纳入了 63176 例接受英夫利昔单抗治疗和 46429 例接受阿达木单抗治疗的患者。我们在 23.6%（n=14900）接受英夫利昔单抗治疗的患者和 19.6%（n=9101）接受阿达木单抗治疗的患者中检测到了 ATI 和 ATA。在有 ATI 的患者中，英夫利昔单抗剂量递增（n=453）产生了更高的主要结局（47.5% vs. 30.9%；P<0.001）、更高的药物浓度增加（5.9μg/mL vs. 0.2μg/mL；P<0.001）和 ATI 降低（4.3U/mL vs. 1.9U/mL；P=0.002），与未递增组（n=204）相比。ATI 阈值为 8.55U/mL 与剂量递增达到主要结局相关（曲线下面积=0.66）。对于 ATI≤8.55U/mL（n=274）的患者，与 ATI>8.55U/mL（n=179）的患者相比，更高比例（59.1% vs. 29.6%；P<0.001）达到了主要结局。没有接受阿达木单抗治疗的患者达到了主要结局（0/390），无论剂量递增与否（n=87）。
英夫利昔单抗剂量递增增加了药物浓度并消除了抗体，但阿达木单抗没有。初始 ATI≤8.55U/mL 与使用该检测方法增加剂量递增的疗效相关。
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