Abstract
Azathioprine and 6-mercaptopurine, often referred to as thiopurine compounds, are commonly used in the management of inflammatory bowel disease. However, patients receiving these drugs are prone to developing adverse drug reactions or therapeutic resistance. Achieving predefined levels of two major thiopurine metabolites, 6-thioguanine nucleotides and 6-methylmercaptopurine, is a long-standing clinical practice in ensuring therapeutic efficacy; however, their correlation with treatment response is sometimes unclear. Various genetic markers have also been used to aid the identification of patients who are thiopurine-sensitive or refractory. The recent discovery of novel Asian-specific DNA variants, namely those in the NUDT15 gene, and their link to thiopurine toxicity, have led clinicians and scientists to revisit the utility of Caucasian biomarkers for Asian individuals with inflammatory bowel disease. In this review, we explore the limitations associated with the current methods used for therapeutic monitoring of thiopurine metabolites and how the recent discovery of ethnicity-specific genetic markers can complement thiopurine metabolites measurement in formulating a strategy for more accurate prediction of thiopurine response. We also discuss the challenges in thiopurine therapy, alongside the current strategies used in patients with reduced thiopurine response. The review is concluded with suggestions for future work aiming at using a more comprehensive approach to optimize the efficacy of thiopurine compounds in inflammatory bowel disease.
Highlights
Inflammatory bowel disease (IBD) is an idiopathic, chronic inflammatory disorder caused by dysregulation of the gut immune response (Matricon et al, 2010)
High enzyme activity correlated with leukopenia and higher 6-thioguanine nucleotides (6-TGNs) levels Enzyme activity inversely correlated with methyl-thioinosine monophsophate (meTIMP) concentrations; no association with 6-TGN levels Azathioprine resistance
Low inosine triphosphate pyrophosphatase (ITPA) enzyme activity can increase the 6-TGN levels and the risk of hematological toxicities in acute lymphoblastic leukemia patients (Stocco et al, 2009; Hareedy et al, 2015); a meta-analysis of six studies has concluded that ITPA 94C > A was not significantly associated with any of the reported adverse drug reactions (Van Dieren et al, 2007), and more recent studies have shown that low ITPA enzyme activity was not always correlated with side effects from thiopurine therapy (Shipkova et al, 2011; Chiengthong et al, 2016)
Summary
Reviewed by: Ignacio Catalan-Serra, Norwegian University of Science and Technology, Norway Niels Vande Casteele, University of California, San Diego, United States. Azathioprine and 6-mercaptopurine, often referred to as thiopurine compounds, are commonly used in the management of inflammatory bowel disease. Patients receiving these drugs are prone to developing adverse drug reactions or therapeutic resistance. We explore the limitations associated with the current methods used for therapeutic monitoring of thiopurine metabolites and how the recent discovery of ethnicity-specific genetic markers can complement thiopurine metabolites measurement in formulating a strategy for more accurate prediction of thiopurine response. The review is concluded with suggestions for future work aiming at using a more comprehensive approach to optimize the efficacy of thiopurine compounds in inflammatory bowel disease
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