Association between Thiopurine S-methyltransferase Polymorphisms and Thiopurine-Induced Adverse Drug Reactions in Patients with Inflammatory Bowel Disease: A Meta-Analysis

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.

Thiopurine S-methyltransferase polymorphisms in acute lymphoblastic leukemia, inflammatory bowel disease and autoimmune disorders: influence on treatment response

“…Moreover, a subgroup analysis of this study, which compared only carriers of TPMT variants between the two arms, revealed that the pharmacogenetic approach was able to significantly decrease the risk of hematologic ADRs by 10-fold in carriers of at least one genetic variant (frequency: 2.6% vs 22.9%; relative risk: 0.11; 95% CI: 0.01–0.85) 22. The results of the secondary aim of this study excluded any significant association between TPMT genotypes and anemia, hepatotoxicity, pancreatitis, skin rash, GI and general malaise, which is consistent with the results of the aforementioned meta-analysis and other results in the literature 2,22,65. It also suggested that factors other than TPMT genotype play an important role in the development of thiopurine-induced ADRs 24…”

“…Indeed, many studies2,14,22,65 have found that certain ADRs were not associated with a reduced TPMT activity such as pancreatitis and hepatotoxicity. This holds true in the context of ALL, IBD and the different types of autoimmune disorders.…”

“…Indeed, it was mentioned earlier that a fraction of TPMT wild-type patients can still have intermediate TPMT-activity and that other factors play a role in the development of this ADR 16,33,36. Moreover, other side effects such as hepatotoxicity, pancreatitis, nausea and vomiting cannot be predicted by TPMT testing 1,14,65. The adoption of pretreatment TPMT screening seems to vary according to discipline, as reported by one survey, with 94% of dermatologists, 60% of gastroenterologists and only 47% rheumatologists requesting it 76.…”

“…However, from an evidence-based perspective, and besides the universally accepted association with hematotoxicity, the recommendations for preemptive genetic testing still have some margin to evolve. Plus, even in well-established scenarios, like in the case of myelosuppression in TPMT-deficient patients, strong evidence is still lacking to support that the pharmacogenetic approach would result in a significantly better outcome 14,65…”

Clinical Pharmacokinetic and Pharmacodynamic Considerations in the Treatment of Ulcerative Colitis

“…6-TG thioguanine, 6-TGN 6-thioguanine nucleotide, 6-MMP 6-methylmercaptopurine, 6-MP 6-mercaptopurine, 6-TIMP 6-thioinosine monophosphate, 6-TUA 6-thiouric acid, GST glutathione S-transferase, HPRT hypoxanthine-guanine phosphoribosyltransferase, IMPDH inosine 5-monophosphate dehydrogenase, TPMT thiopurine S-methyltransferase, XO xanthine oxidase resulting in side effects [72]. A meta-analysis by Liu et al showed an association between TPMT polymorphisms, thiopurine-induced overall side effects and bone marrow toxicity [73].…”