Department of Gastroenterology, Copenhagen University Hospital, Herlev, Denmark.
Paediatric Oncology Research Laboratory, Rigshospitalet, University Hospital of Copenhagen, Denmark.
J Crohns Colitis. 2018 Feb 28;12(3):298-305. doi: 10.1093/ecco-jcc/jjx149.
Interactions between principal cytotoxic thiopurine metabolites, that is 6-thioguanine nucleotides [6-TGN], and infliximab [IFX] and anti-IFX antibodies [Abs] may contribute to higher effectiveness of IFX-thiopurine combination therapy than monotherapies in inflammatory bowel disease.
To examine if thiopurine metabolites influenced trough IFX and anti-IFX Abs, 89 patients previously assessed for anti-IFX Abs were included. To assess if IFX influenced thiopurine metabolites, eight patients who had responded to 12 weeks of intensified IFX at a constant thiopurine dosing were included.
In the first cohort, IFX-thiopurine combination therapy reduced anti-IFX Ab detection [8/40; 20%] as compared with IFX monotherapy [22/49; 45%], odds ratio [OR] 0.31 [0.12-0.80], p < 0.05. 6-TGN was significantly lower in anti-IFX Ab-positive patients (50 pmol/8 × 108 red blood cells [RBC] vs 105, p < 0.01). All anti-IFX Ab-positive patients had 6-TGN < 117 pmol/8 × 108 RBC (sensitivity 100% [63-100], specificity 47% [29-65], area under the curveROC = 0.82, p < 0.01). Trough IFX was similar between anti-IFX Ab-negative patients in IFX monotherapy and IFX-thiopurine combination therapy [5.1 μg/mL vs 4.9, p = 0.76]. 6-TGN and IFX did not correlate [rP = 0.04, p = 0.83; rS = 0.02, p = 0.89, respectively]. In the second cohort, trough IFX increased during IFX intensification [ΔIFX median 6.5 μg/mL, p = 0.02], but 6-TGN was stable [6-TGN at Weeks 0, 4, 8, 12: 90 pmol/8 × 108 RBC, 93, 101, 90; p > 0.05]. Methylated mercaptopurine metabolite associations were consistently negative.
Superior effect of IFX-thiopurine combination therapy over monotherapies partly relates to decrease in anti-IFX Abs, which associates with 6-TGN levels and has a lower therapeutic threshold than during thiopurine monotherapy. Additional benefit likely ascribes to synergy between different anti-inflammatory modes of action rather than direct drug interactions.
主要细胞毒性硫代嘌呤代谢物（即 6-硫鸟嘌呤核苷酸[6-TGN]）与英夫利昔单抗[IFX]和抗 IFX 抗体[Abs]之间的相互作用可能导致 IFX-硫嘌呤联合治疗比炎症性肠病的单药治疗更有效。
为了研究硫嘌呤代谢物是否影响 IFX 的谷浓度和抗 IFX Abs，纳入了 89 名先前评估过抗 IFX Abs 的患者。为了评估 IFX 是否影响硫嘌呤代谢物，纳入了 8 名在持续硫嘌呤给药剂量下接受 12 周强化 IFX 治疗后有应答的患者。
在第一个队列中，与 IFX 单药治疗相比（IFX 单药治疗[22/49；45%]，IFX-硫嘌呤联合治疗降低了抗 IFX Ab 的检测率[8/40；20%]，比值比[OR]为 0.31 [0.12-0.80]，p < 0.05。抗 IFX Ab 阳性患者的 6-TGN 明显降低（50 pmol/8×108 RBC 与 105，p < 0.01）。所有抗 IFX Ab 阳性患者的 6-TGN < 117 pmol/8×108 RBC（敏感性 100% [63-100]，特异性 47% [29-65]，ROC 曲线下面积 AUC = 0.82，p < 0.01）。在 IFX 单药治疗和 IFX-硫嘌呤联合治疗的抗 IFX Ab 阴性患者中，IFX 的谷浓度相似[5.1 μg/mL 与 4.9，p = 0.76]。6-TGN 和 IFX 之间没有相关性[rP = 0.04，p = 0.83；rS = 0.02，p = 0.89]。在第二个队列中，IFX 强化期间 IFX 的谷浓度增加[IFX 中位数增加 6.5 μg/mL，p = 0.02]，但 6-TGN 保持稳定[第 0、4、8、12 周时的 6-TGN：90 pmol/8×108 RBC、93、101、90；p > 0.05]。甲基化巯基嘌呤代谢物的相关性始终为负。
IFX-硫嘌呤联合治疗优于单药治疗的部分原因是抗 IFX Abs 减少，这与 6-TGN 水平相关，且其治疗阈值低于硫嘌呤单药治疗。额外的益处可能归因于不同抗炎作用模式之间的协同作用，而不是直接的药物相互作用。
