Correlation between Thiopurine S-Methyltransferase Genotype and Adverse Events in Inflammatory Bowel Disease Patients.

Davide Giuseppe Ribaldone,Francesco Luzza,Marco Astegiano,Gian Paolo Caviglia,Ludovico Abenavoli,Danila Riganò,Danilo Agnesod,Giovanni Di Perri,Roberto Canaparo,Amedeo De Nicolò,Rinaldo Pellicano,Alessandro Adriani,Marco Simiele,Giorgio Maria Saracco,Antonio D’Avolio

doi:10.3390/medicina55080441

Abstract

Background and Objectives: In patients with inflammatory bowel diseases (IBD), the use of azathioprine results in adverse events at a rate of 5% to 20%. The aim of the study was to assess a possible correlation between genetic variability of the enzyme thiopurine S-methyltransferase (TPMT) and the development of toxicity to azathioprine. Materials and Methods: A retrospective, single center, blind, case-control study was conducted on 200 IBD patients, of whom 60 cases suspended azathioprine due to toxicity (leukopenia, pancreatitis, hepatitis, and nausea or vomiting), and 140 controls continued treatment with the drug without adverse events. Results: In the entire cohort, only 8 cases of heterozygous mutations of TPMT were observed, corresponding to 4% mutated haplotype rate, much lower than that reported in literature (close to 10%). No homozygous mutation was found. Regarding the TPMT allelic variants, we did not find any statistically significant difference between patients who tolerated azathioprine and those who suffered from adverse events. (OR = 0.77, 95% CI = 0.08–7.72; p = 0.82). Conclusions: According to our study, in IBD patients, the search for TPMT gene mutations before starting treatment with azathioprine is not helpful in predicting the occurrence of adverse events. Importantly, patients with allelic variants should not be denied the therapeutic option of azathioprine, as they may tolerate this drug.

Highlights

The inflammatory bowel diseases (IBD) include Crohn’s disease (CD) and ulcerative colitis (UC), both characterized by chronic and uncontrolled inflammation of the intestinal mucosa.Thiopurines, mainly represented by 6-mercaptopurine and the prodrug azathioprine, are used in cases of steroid-dependent IBD or to reduce the risk of recurrence after surgery in CD [1,2], as they have cytotoxic and immunosuppressive properties [3]
Azathioprine is converted to 6-mercaptopurine by glutathione-S-transferase and undergoes several metabolic transformations that lead to the production of two different active nucleosides: The conversion of 6-mercaptopurine by the enzyme hypoxanthine guanine phosphoribosyltransferase leads to the formation of 6-thioguanine (6-TG), and the thiopurine methyltransferase (TPMT) pathway leads to the methylation of 6-mercaptopurine, forming 6-methylmercaptopurine riboside (6-MMPr) [3]
Among the 2427 patients affected by IBD who were followed regularly at our outpatient clinic, 702 were on active treatment or had been previously treated with azathioprine

Summary

Introduction

The inflammatory bowel diseases (IBD) include Crohn’s disease (CD) and ulcerative colitis (UC), both characterized by chronic and uncontrolled inflammation of the intestinal mucosa.Thiopurines, mainly represented by 6-mercaptopurine and the prodrug azathioprine, are used in cases of steroid-dependent IBD or to reduce the risk of recurrence after surgery in CD [1,2], as they have cytotoxic and immunosuppressive properties [3]. Azathioprine is converted to 6-mercaptopurine by glutathione-S-transferase and undergoes several metabolic transformations that lead to the production of two different active nucleosides: The conversion of 6-mercaptopurine by the enzyme hypoxanthine guanine phosphoribosyltransferase leads to the formation of 6-thioguanine (6-TG), and the thiopurine methyltransferase (TPMT) pathway leads to the methylation of 6-mercaptopurine, forming 6-methylmercaptopurine riboside (6-MMPr) [3]. These metabolites have some differences in their effect on target cells: The current opinion is that 6-TG may be responsible for the immunosuppressive effect, while 6-MMPr may be a secondary metabolic product (dependent on TPMT activity) with a less effective action, but a stronger toxic effect on the liver [5]. Patients with allelic variants should not be denied the therapeutic option of azathioprine, as they may tolerate this drug

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