Dubinsky Marla C, Yang Huiying, Hassard Philip V, Seidman Ernest G, Kam Lori Y, Abreu Maria T, Targan Stephan R, Vasiliauskas Eric A
Division of Gastroenterology and Genetics, Department of Medicine and Pediatrics, Cedars-Sinai Medical Center, UCLA, Los Angeles, California 90048, USA.
Gastroenterology. 2002 Apr;122(4):904-15. doi: 10.1053/gast.2002.32420.
BACKGROUND & AIMS: Approximately 40% of inflammatory bowel disease (IBD) patients fail to benefit from 6-mercaptopurine (6-MP)/azathioprine (AZA). Recent reports suggest 6-thioguanine nucleotide (6-TGN) levels (>235) independently correlate with remission. An inverse correlation between 6-TGN and thiopurine methyltransferase (TPMT) has been described. The objectives of this study were to determine whether dose escalation optimizes both 6-TGN levels and efficacy in patients failing therapy because of subtherapeutic 6-TGN levels and its effect on TPMT.
Therapeutic efficacy and adverse events were recorded at baseline and upon reevaluation after dose escalation in 51 IBD patients. 6-MP metabolite levels and TPMT activity were recorded blinded to clinical information.
Fourteen of 51 failing 6-MP/AZA at baseline achieved remission upon dose escalation, which coincided with significant rises in 6-TGN levels. Despite increased 6-MP/AZA doses, 37 continued to fail therapy at follow-up. Dose escalation resulted in minor changes in 6-TGN, yet a significant increase in 6-methylmercaptopurine ribonucleotides (6-MMPR) (P < or = 0.01) and 6-MMPR:6-TGN ratio (P < 0.001). 6-MMPR rises were associated with dose-dependent hepatotoxicity in 12 patients (24%). TPMT was not influenced by dose escalation.
Serial metabolite monitoring identifies a novel phenotype of IBD patients resistant to 6-MP/AZA therapy biochemically characterized by suboptimal 6-TGN and preferential 6-MMPR production upon dose escalation.
约40%的炎症性肠病（IBD）患者无法从6-巯基嘌呤（6-MP）/硫唑嘌呤（AZA）治疗中获益。近期报告表明，6-硫鸟嘌呤核苷酸（6-TGN）水平（>235）与缓解独立相关。已描述6-TGN与硫嘌呤甲基转移酶（TPMT）之间呈负相关。本研究的目的是确定剂量递增是否能优化因6-TGN水平未达治疗量而治疗失败患者的6-TGN水平及疗效，以及其对TPMT的影响。
记录51例IBD患者在基线时及剂量递增后重新评估时的治疗疗效和不良事件。在对临床信息不知情的情况下记录6-MP代谢物水平和TPMT活性。
51例基线时6-MP/AZA治疗失败的患者中，14例在剂量递增后实现缓解，这与6-TGN水平显著升高同时出现。尽管6-MP/AZA剂量增加，但37例在随访时仍治疗失败。剂量递增导致6-TGN仅有微小变化，但6-甲基巯基嘌呤核糖核苷酸（6-MMPR）显著增加（P≤0.01），且6-MMPR:6-TGN比值增加（P<0.001）。12例患者（24%）中6-MMPR升高与剂量依赖性肝毒性相关。TPMT不受剂量递增影响。
连续代谢物监测确定了一种对6-MP/AZA治疗耐药的IBD患者新表型，其生化特征为6-TGN未达最佳水平，且在剂量递增时优先产生6-MMPR。
