Thiopurine monitoring in children with inflammatory bowel disease: a systematic review

Abstract

Aims The aim was to systematically review the evidence on the clinical usefulness of thiopurine metabolite and white blood count (WBC) monitoring in the assessment of clinical outcomes in children with inflammatory bowel disease (IBD). Methods Medline, Embase, Cochrane Central Register of controlled trials and http://www.clinicaltrials.gov were screened in adherence to the PRISMA statement by two independent reviewers for identification of eligible studies. Eligible studies were randomized controlled trials (RCTs), cohort studies and large case series of children with inflammatory bowel disease (IBD) (<18 years) who underwent monitoring of thiopurine metabolites and/or WBC. Results Fifteen papers were identified (n = 1026). None of the eligible studies were RCTs. High 6‐thioguanine nucleotide (6TGN) concentrations were not consistently associated with leucopenia. Leucopenia was not associated with achievement of clinical remission. A positive but not consistent correlation between 6TGN and clinical remission was reported. Haematological toxicity could not be reliably assessed with 6TGN measurements only. A number of studies supported the use of high 6‐methylmercaptopurine ribonucleotides (6MMPR) as an indicator of hepatotoxicity. Low thiopurine metabolite concentration may be indicative of non‐compliance. Conclusion Thiopurine metabolite testing does not safely predict clinical outcome, but may facilitate toxicity surveillance and treatment optimization in poor responders. Current evidence favours the combination of thiopurine metabolite/WBC monitoring and clinic follow‐up for prompt identification of haematologic/hepatic toxicity safe dose adjustment, and treatment modification in cases of suboptimal clinical outcome or non‐compliance. Well designed RCTs for the identification of robust surrogate markers of thiopurine efficacy and toxicity are required.

NUDT15 polymorphisms are better than thiopurine S‐methyltransferase as predictor of risk for thiopurine‐induced leukopenia in Chinese patients with Crohn's disease

“…Moreover, some researches even showed that it was 6‐MMPR, but not 6‐TGN that was correlated with leukopenia, which was manifested by the observation that patients with 6‐MMPR concentrations >11 450 pmol/8 × 10 8 RBC during steady state at week 5 had an increased risk of developing leukopenia. The controversy was clearly demonstrated in a recent review by Konidari . Thus, the exact relationship between the concentration of thiopurine metabolites 6TGN and 6‐MMPR and leukopenia was still extremely obscure, and further investigation to explore the confounding factors is warranted.…”

Overview of systematic reviews of therapeutic ranges: methodologies and recommendations for practice

“…Other literature searches included Google Scholar and DirectScience [17], clinical trials registers [11] and the UK national health system database [9]. Two systematic reviews included a grey literature search via the Cochrane Register of Controlled Trials (CENTRAL) [8, 11].…”

Revisiting the Role of Thiopurines in Inflammatory Bowel Disease Through Pharmacogenomics and Use of Novel Methods for Therapeutic Drug Monitoring

“…However, because of substantial inter- and intra-population differences, defining a threshold 6-TGN level that universally predicts positive clinical outcomes is difficult ( Wright et al, 2004 ; Teml et al, 2007 ). The observed differences arise from a lack of a standard method for 6-TGN testing, variable study designs, or the intricacies of thiopurine pharmacology that we have yet to understand fully ( Konidari et al, 2014 ).…”

“…Many studies have documented age- and ethnicity-related differences in the 6-TGN concentrations needed to produce a clinical benefit. A meta-analysis of fifteen studies involving pediatric IBD patients concluded that even though there was positive correlation between clinical outcomes and 6-TGN levels, a definitive therapeutic cut-off could not be ascertained ( Konidari et al, 2014 ). A retrospective cohort study has reported that lower 6-TGN levels of 180–355 pmol/8 × 10 8 RBC were adequate for Chinese adults to maintain remission ( Mao et al, 2017 ).…”