Department of Pediatric Gastroenterology, Emma Children's Hospital, Amsterdam, UMC, Vrije Universiteit Amsterdam, 1105 AZ, Amsterdam, The Netherlands.
Department of Clinical Pharmacology and Pharmacy, Amsterdam, UMC, Vrije Universiteit Amsterdam, 1105 AZ, Amsterdam, The Netherlands.
Dig Dis Sci. 2022 Jan;67(1):241-251. doi: 10.1007/s10620-021-06836-3. Epub 2021 Feb 3.
In the recent era of growing availability of biological agents, the role of thiopurines needs to be reassessed with the focus on toxicity.
We assessed the incidence and predictive factors of thiopurine-induced adverse events (AE) resulting in therapy cessation in pediatric inflammatory bowel disease (IBD), related to thiopurine metabolites and biochemical abnormalities, and determined overall drug survival.
We performed a retrospective, single-center study of children diagnosed with IBD between 2000 and 2019 and treated with thiopurine therapy. The incidence of AE and overall drug survival of thiopurines were evaluated using the Kaplan-Meier method. Correlations between thiopurine metabolites and biochemical tests were computed using Spearman's correlation coefficient.
Of 391 patients with IBD, 233 patients (162 Crohn's disease, 62 ulcerative colitis, and 9 IBD-unclassified) were prescribed thiopurines (230 azathioprine and 3 mercaptopurine), of whom 50 patients (22%) discontinued treatment, at least temporary, due to thiopurine-induced AE (median follow-up 20.7 months). Twenty-six patients (52%) were rechallenged and 18 of them (70%) tolerated this. Sixteen patients (6%) switched to a second thiopurine agent after azathioprine intolerance and 10 of them (63%) tolerated this. No predictive factors for development of AE could be identified. Concentrations of 6-thioguanine nucleotides (6-TGN) were significantly correlated with white blood cell and neutrophil count, 6-methylmercaptopurine (6-MMP) concentrations with alanine aminotransferase and gamma-glutamyltranspeptidase.
Approximately 20% of pediatric patients with IBD discontinued thiopurine treatment due to AE. A rechallenge or switch to mercaptopurine is an effective strategy after development of AE. Concentrations of 6-TGN and 6-MMP are associated with biochemical abnormalities.
在当前生物制剂日益普及的时代，需要重新评估硫嘌呤的作用，重点关注其毒性。
我们评估了硫嘌呤诱导的不良事件（AE）导致儿科炎症性肠病（IBD）治疗停止的发生率和预测因素，这些 AE 与硫嘌呤代谢物和生化异常有关，并确定了总体药物存活率。
我们对 2000 年至 2019 年间被诊断为 IBD 并接受硫嘌呤治疗的儿童进行了回顾性单中心研究。使用 Kaplan-Meier 方法评估 AE 的发生率和硫嘌呤的总体药物存活率。使用 Spearman 相关系数计算硫嘌呤代谢物和生化检测之间的相关性。
在 391 名 IBD 患者中，有 233 名患者（162 名克罗恩病、62 名溃疡性结肠炎和 9 名 IBD 未分类）接受了硫嘌呤（230 名硫唑嘌呤和 3 名巯基嘌呤）治疗，其中 50 名患者（22%）因硫嘌呤诱导的 AE 而至少暂时停止治疗（中位随访 20.7 个月）。26 名患者（52%）被重新挑战，其中 18 名（70%）耐受。在不耐受硫唑嘌呤后，16 名患者（6%）改用第二种硫嘌呤药物，其中 10 名（63%）耐受。未能确定 AE 发生的预测因素。6-硫鸟嘌呤核苷酸（6-TGN）浓度与白细胞和中性粒细胞计数显著相关，6-甲基巯基嘌呤（6-MMP）浓度与丙氨酸氨基转移酶和γ-谷氨酰转肽酶相关。
大约 20%的儿科 IBD 患者因 AE 而停止硫嘌呤治疗。AE 发生后，重新挑战或改用巯基嘌呤是一种有效的策略。6-TGN 和 6-MMP 浓度与生化异常有关。
