Abstract
PurposeThiopurine drugs are well established treatments in the management of inflammatory bowel disease (IBD), but their use is limited by significant adverse drug reactions (ADRs). Thiopurine S-methyltransferase (TPMT) is an important enzyme involved in thiopurine metabolism. Several clinical guidelines recommend determining TPMT genotype or phenotype before initiating thiopurine therapy. Although several studies have investigated the association between TPMT polymorphisms and thiopurine-induced ADRs, the results are inconsistent. The purpose of this study is to evaluate whether there is an association between TPMT polymorphisms and thiopurine-induced ADRs using meta-analysis.MethodsWe explored PubMed, Web of Science and Embase for articles on TPMT polymorphisms and thiopurine-induced ADRs. Studies that compared TPMT polymorphisms with-ADRs and without-ADRs in IBD patients were included. Relevant outcome data from all the included articles were extracted and the pooled odds ratio (OR) with corresponding 95% confidence intervals were calculated using Revman 5.3 software.ResultsFourteen published studies, with a total of 2,206 IBD patients, which investigated associations between TPMT polymorphisms and thiopurine-induced ADRs were included this meta-analysis. Our meta-analysis demonstrated that TPMT polymorphisms were significantly associated with thiopurine-induced overall ADRs and bone marrow toxicity; pooled ORs were 3.36 (95%CI: 1.82–6.19) and 6.67 (95%CI: 3.88–11.47), respectively. TPMT polymorphisms were not associated with the development of other ADRs including hepatotoxicity, pancreatitis, gastric intolerance, flu-like symptoms and skin reactions; the corresponding pooled ORs were 1.27 (95%CI: 0.60–2.71), 0.97 (95%CI: 0.38–2.48), 1.82 (95%CI: 0.93–3.53), 1.28 (95%CI: 0.47–3.46) and 2.32 (95%CI: 0.86–6.25), respectively.ConclusionsOur meta-analysis demonstrated an association of TPMT polymorphisms with overall thiopurine-induced ADRs and bone marrow toxicity, but not with hepatotoxicity, pancreatitis, flu-like symptoms, gastric intolerance and skin reactions. These findings suggest that pretesting the TPMT genotype could be helpful in clinical practice before initiating thiopurine therapy. However, white blood cell count analysis should be the mainstay for follow-up.
Highlights
Inflammatory bowel disease (IBD), with its two major clinical subtypes, Crohn’s disease (CD) and ulcerative colitis (UC), is a polygenic disease that manifests due to environmental trigger factors on the background of a complex genetic predisposition [1, 2]
Our meta-analysis demonstrated that Thiopurine S-methyltransferase (TPMT) polymorphisms were significantly associated with thiopurine-induced overall adverse drug reactions (ADRs) and bone marrow toxicity; pooled odds ratio (OR) were 3.36 (95%confidence interval (CI): 1.82–6.19) and 6.67 (95%CI: 3.88–11.47), respectively
TPMT Polymorphisms and Thiopurine-Induced ADRs in IBD Patients polymorphisms were not associated with the development of other ADRs including hepatotoxicity, pancreatitis, gastric intolerance, flu-like symptoms and skin reactions; the corresponding pooled ORs were 1.27 (95%CI: 0.60–2.71), 0.97 (95%CI: 0.38–2.48), 1.82, 1.28 (95%CI: 0.47–3.46) and 2.32 (95%CI: 0.86–6.25), respectively
Summary
Inflammatory bowel disease (IBD), with its two major clinical subtypes, Crohn’s disease (CD) and ulcerative colitis (UC), is a polygenic disease that manifests due to environmental trigger factors on the background of a complex genetic predisposition [1, 2]. Bone marrow toxicity (BMT), hepatotoxicity, pancreatitis, gastric intolerance, skin reactions and flu-like symptoms are among the most common reasons to discontinue thiopurine therapy [6]. Very low or deficient enzyme activity resulting from polymorphisms in the TPMT encoding genes may be associated with thiopurine-induced adverse drug reactions [11]. In a study of 219 IBD patients, TPMT polymorphisms were significantly associated with pancreatitis, but were not associated with bone marrow toxicity [17]. These results were contradicted by another study of 93 IBD patients [18]
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