Stocco Gabriele, Martelossi Stefano, Arrigo Serena, Barabino Arrigo, Aloi Marina, Martinelli Massimo, Miele Erasmo, Knafelz Daniela, Romano Claudio, Naviglio Samuele, Favretto Diego, Cuzzoni Eva, Franca Raffaella, Decorti Giuliana, Ventura Alessandro
*Department of Life Sciences, University of Trieste, Trieste, Italy; †Department of Pediatrics, Institute for Maternal and Child Health Burlo Garofolo, Trieste, Italy; ‡Gastroenterology and Endoscopy Unit, Gaslini Institute for Children, Genoa, Italy; §Pediatric Gastroenterology and Liver Unit, Sapienza University of Rome, Rome, Italy; ‖Department of Translational Medical Science, Section of Pediatrics, University of Naples Federico II, Naples, Italy; ¶Hepatology, Gastroenterology and Nutrition Unit, Bambino Gesù Children's Hospital, Rome, Italy; **Department of Pediatric, University of Messina, Messina, Italy; ††PhD School in Science of Reproduction and Development, University of Trieste, Trieste, Italy; and ‡‡Department of Medical, Surgical and Health Sciences, University of Trieste, Trieste, Italy.
Inflamm Bowel Dis. 2017 Apr;23(4):628-634. doi: 10.1097/MIB.0000000000001051.
Early-onset inflammatory bowel disease (IBD) is generally aggressive, with a high probability of complications and need of surgery. Despite the introduction of highly effective biological drugs, treatment with azathioprine continues to be important even for early-onset IBD; however, in these patients azathioprine response seems to be reduced. This study evaluated azathioprine doses, metabolite concentrations, and their associations with patients' age in children with IBD treated at 6 tertiary pediatric referral centers.
Azathioprine doses, metabolites, and clinical effects were assessed after at least 3 months of therapy in 17 early-onset (age < 6 yr, cases) and 51 nonearly-onset (aged > 12 and <18 yrs, controls) patients with IBD. Azathioprine dose was titrated on therapeutic efficacy (response and adverse effects). Azathioprine metabolites and thiopurine methyltransferase activity were determined by high-performance liquid chromatography with ultra violet-vis detection (HPLC-UV) methods.
Frequency of patients in remission was similar among early-onset and control groups, respectively (82% and 84%, P value = 0.72). Early-onset patients required higher doses of azathioprine (median 2.7 versus 2.0 mg·kg·d, P value = 1.1 × 10). Different doses resulted in comparable azathioprine active thioguanine nucleotide metabolite concentrations (median 263 versus 366 pmol/8 × 10 erythrocytes, P value = 0.41) and methylmercaptopurine nucleotide concentrations (median 1455 versus 1532 pmol/8 × 10 erythrocytes, P value = 0.60). Lower ratios between thioguanine nucleotide metabolites and azathioprine doses were found in early-onset patients (median 98 versus 184 pmol/8 × 10 erythrocytes·mg·kg·d, P value = 0.017). Interestingly, early-onset patients presented also higher thiopurine methyltransferase activity (median 476 versus 350 nmol methylmercaptopurine/mg hemoglobin/h, P-value = 0.046).
This study demonstrated that patients with early-onset IBD present increased inactivating azathioprine metabolism, likely because of elevated activity of the enzyme thiopurine methyltransferase.
早发性炎症性肠病（IBD）通常具有侵袭性，并发症发生率高且需要手术治疗。尽管引入了高效生物药物，但对于早发性IBD患者，硫唑嘌呤治疗仍然很重要；然而，在这些患者中，硫唑嘌呤的反应似乎有所降低。本研究评估了在6家三级儿科转诊中心接受治疗的IBD患儿的硫唑嘌呤剂量、代谢物浓度及其与患者年龄的关系。
对17例早发性（年龄<6岁，病例组）和51例非早发性（年龄>12岁且<18岁，对照组）IBD患者进行至少3个月的治疗后，评估硫唑嘌呤剂量、代谢物和临床效果。根据治疗效果（反应和不良反应）调整硫唑嘌呤剂量。采用高效液相色谱-紫外检测（HPLC-UV）法测定硫唑嘌呤代谢物和硫嘌呤甲基转移酶活性。
早发性组和对照组患者的缓解频率相似（分别为82%和84%，P值=0.72）。早发性患者需要更高剂量的硫唑嘌呤（中位数为2.7 对比 2.0 mg·kg·d，P值=1.1×10）。不同剂量导致硫唑嘌呤活性硫鸟嘌呤核苷酸代谢物浓度相当（中位数为263对比366 pmol/8×10红细胞，P值=0.41）以及甲基巯基嘌呤核苷酸浓度相当（中位数为1455对比1532 pmol/8×10红细胞，P值=0.60）。早发性患者的硫鸟嘌呤核苷酸代谢物与硫唑嘌呤剂量的比率较低（中位数为98对比184 pmol/8×10红细胞·mg·kg·d，P值=0.017）。有趣的是，早发性患者的硫嘌呤甲基转移酶活性也较高（中位数为476对比350 nmol甲基巯基嘌呤/mg血红蛋白/h，P值=0.046）。
本研究表明，早发性IBD患者的硫唑嘌呤代谢失活增加，可能是由于硫嘌呤甲基转移酶的活性升高。
