Department of Gastroenterology, Copenhagen University Hospital Herlev, Herlev Ringvej 75, 2730, Herlev, Denmark.
Pediatric Oncology Research Laboratory, Rigshospitalet, University Hospital of Copenhagen, Copenhagen, Denmark.
Dig Dis Sci. 2018 Jun;63(6):1583-1591. doi: 10.1007/s10620-018-5020-9. Epub 2018 Mar 21.
Interactions between thiopurines and infliximab presumably contribute to superior effect of infliximab-thiopurine combination therapy in patients with inflammatory bowel disease (IBD). We examined whether principal cytotoxic thiopurine metabolites influence adalimumab (ADL) and anti-ADL antibodies (Abs).
Ninety-eight IBD patients previously treated with infliximab (96%) in whom trough ADL and anti-ADL Abs had been assessed as part of their clinical care were included. Thiopurine metabolites [6-thioguanine nucleotides (6-TGN) and methylated mercaptopurine metabolites (6-MeMP)] were determined at similar time points.
ADL-thiopurine combination therapy was not associated with reduced anti-ADL Ab positivity compared to ADL monotherapy: 8/31 (26%) versus 19/67 (28%), p = 1.00. Concentrations of thiopurine metabolites were similar in anti-ADL Ab-positive and negative patients (6-TGN median 109 pmol/8 × 10 RBC vs. 112, p = 0.80; 6-MeMP 448 RBC vs. 720, p = 0.94). ADL trough levels did not differ between anti-ADL Ab-negative patients on ADL-thiopurine combination therapy and those on monotherapy (9.5 μg/mL vs. 7.6, p = 0.31). ADL levels were also comparable between patients on ADL mono- and combination therapy after stratification for 6-TGN/6-MeMP quartiles. There were no correlations between levels of 6-TGN and ADL (r = - 0.17, p = 0.45; r = - 0.38, p = 0.08), or 6-MeMP and ADL (r = - 0.23, p = 0.31; r = - 0.35, p = 0.11). Anti-ADL Ab positivity was associated with ADL treatment failure (OR 6 [2-20], p < 0.01). Higher trough ADL (9.6 μg/mL vs. 7.3, p < 0.05), but not concomitant thiopurine treatment, metabolite levels, or dosage, was associated with clinical remission.
Effectiveness of ADL therapy associated with circulating ADL levels and anti-ADL Ab formation. In this study, there appeared no direct interactions between thiopurine metabolites and ADL or anti-ADL Abs.
推测巯嘌呤与英夫利昔单抗的相互作用有助于英夫利昔单抗-巯嘌呤联合治疗在炎症性肠病（IBD）患者中的疗效。我们研究了主要细胞毒性巯嘌呤代谢物是否会影响阿达木单抗（ADL）和抗 ADL 抗体（Abs）。
本研究纳入了 98 例先前接受过英夫利昔单抗（96%）治疗的 IBD 患者，这些患者在临床治疗中评估了 ADL 的谷浓度和抗 ADL Abs。在相似的时间点测定了巯嘌呤代谢物[6-硫鸟嘌呤核苷酸（6-TGN）和甲基化硫嘌呤代谢物（6-MeMP）]。
ADL-巯嘌呤联合治疗与 ADL 单药治疗相比，抗 ADL Ab 阳性率无降低：31 例中有 8 例（26%）与 67 例中有 19 例（28%）相比，p=1.00。抗 ADL Ab 阳性和阴性患者的巯嘌呤代谢物浓度相似（6-TGN 中位数 109 pmol/8×10 RBC 与 112，p=0.80；6-MeMP 448 RBC 与 720，p=0.94）。ADL 谷浓度在 ADL-巯嘌呤联合治疗和单药治疗的抗 ADL Ab 阴性患者之间无差异（9.5μg/mL 与 7.6，p=0.31）。在按 6-TGN/6-MeMP 四分位距分层后，ADL 单药和联合治疗的患者之间的 ADL 水平也相当。6-TGN 水平与 ADL 之间无相关性（r=-0.17，p=0.45；r=-0.38，p=0.08），6-MeMP 与 ADL 之间也无相关性（r=-0.23，p=0.31；r=-0.35，p=0.11）。抗 ADL Ab 阳性与 ADL 治疗失败相关（OR 6 [2-20]，p<0.01）。较高的 ADL 谷浓度（9.6μg/mL 与 7.3，p<0.05），而不是同时使用巯嘌呤治疗、代谢物水平或剂量，与临床缓解相关。
ADL 治疗的有效性与循环 ADL 水平和抗 ADL Ab 的形成有关。在这项研究中，巯嘌呤代谢物与 ADL 或抗 ADL Abs 之间似乎没有直接相互作用。
