Department of Gastroenterology, St Vincent's Hospital Melbourne, Melbourne, Victoria, Australia.
Department of Medicine, The University of Melbourne, Melbourne, Victoria, Australia.
Intern Med J. 2024 Nov;54(11):1856-1866. doi: 10.1111/imj.16504. Epub 2024 Sep 5.
Thiopurine co-therapy with anti-tumour necrosis factor-alpha (anti-TNFα) agents is associated with higher anti-TNFα drug levels and reduced immunogenicity in inflammatory bowel disease (IBD).
We aimed to evaluate the association between 6-thioguanine nucleotide (6-TGN) and anti-TNFα levels and the optimal 6-TGN threshold level associated with higher anti-TNFα levels in combination therapy.
We performed a retrospective cross-sectional multicentre study of patients with IBD on combination anti-TNFα and thiopurine maintenance therapy between January 2015 and August 2021. Primary outcomes were infliximab and adalimumab levels. Secondary outcomes were antibodies to infliximab (ATI) or adalimumab (ATA). Univariable and multivariable linear regression were performed to identify variables associated with anti-TNFα levels. Receiver operator characteristic curves were used to define the optimal 6-TGN cut-off levels associated with therapeutic anti-TNFα levels.
The study included 743 paired 6-TGN and anti-TNFα levels (640 infliximab and 103 adalimumab). 6-TGN levels were associated with infliximab levels, but not adalimumab levels, on univariable and multivariable regression. The optimal 6-TGN cut-off associated with therapeutic infliximab levels (≥5 mcg/mL) was 261 pmol/8 × 10 red blood cell (RBC) (area under the curve (AUC) = 0.57) for standard infliximab dosing and 227.5 pmol/8 × 10 RBC (AUC = 0.58) for escalated dosing. For therapeutic adalimumab levels (≥7.5 mcg/mL), the 6-TGN cut-off was 218.5 pmol/8 × 10 RBC (AUC = 0.59) for standard adalimumab dosing and 237.5 pmol/8 × 10 RBC (AUC = 0.63) for escalated dosing.
6-TGN levels were weakly associated with infliximab but not adalimumab levels in combination therapy. 6-TGN levels in the lower end of the therapeutic range (230-260 pmol/8 × 10 RBC) may be adequate to maintain higher infliximab levels, particularly with escalated infliximab dosing.
硫嘌呤与抗肿瘤坏死因子-α（抗 TNFα）药物联合治疗与更高的抗 TNFα 药物水平和降低炎症性肠病（IBD）的免疫原性相关。
我们旨在评估 6-硫鸟嘌呤核苷酸（6-TGN）与抗 TNFα 水平之间的关系，并确定与联合治疗中更高的抗 TNFα 水平相关的最佳 6-TGN 阈值水平。
我们对 2015 年 1 月至 2021 年 8 月期间接受抗 TNFα 和硫嘌呤维持治疗的 IBD 患者进行了回顾性横断面多中心研究。主要结局是英夫利昔单抗和阿达木单抗的水平。次要结局是英夫利昔单抗抗体（ATI）或阿达木单抗抗体（ATA）。我们进行了单变量和多变量线性回归，以确定与抗 TNFα 水平相关的变量。使用受试者工作特征曲线确定与治疗性抗 TNFα 水平相关的最佳 6-TGN 截断值。
该研究纳入了 743 对 6-TGN 和抗 TNFα 水平（640 例英夫利昔单抗和 103 例阿达木单抗）。单变量和多变量回归均显示，6-TGN 水平与英夫利昔单抗水平相关，但与阿达木单抗水平无关。与治疗性英夫利昔单抗水平（≥5 mcg/mL）相关的最佳 6-TGN 截断值为 261 pmol/8×10 红细胞（RBC）（曲线下面积（AUC）=0.57）用于标准英夫利昔单抗剂量和 227.5 pmol/8×10 RBC（AUC=0.58）用于递增剂量。对于治疗性阿达木单抗水平（≥7.5 mcg/mL），6-TGN 截断值为 218.5 pmol/8×10 RBC（AUC=0.59）用于标准阿达木单抗剂量和 237.5 pmol/8×10 RBC（AUC=0.63）用于递增剂量。
在联合治疗中，6-TGN 水平与英夫利昔单抗水平弱相关，但与阿达木单抗水平不相关。治疗范围内较低端（230-260 pmol/8×10 RBC）的 6-TGN 水平可能足以维持较高的英夫利昔单抗水平，特别是在递增英夫利昔单抗剂量时。
