Introduction 15% of patients with inflammatory bowel disease (IBD) prescribed azathioprine (AZA)/mercaptopurine (MP) demonstrate a skewed drug metabolism with low thioguanine nucleotides (TGN) and unexpectedly high methylmercaptopurine (MeMP) levels. This predicts a lack of treatment efficacy and excess adverse events; however studies on the effect of thiopurine hypermethylation (TH) in adult IBD patients are lacking. Importantly, where identified TH can be circumvented with the use of low dose AZA/MP and allopurinol. The aim of this study is to characterise the impact of TH in IBD patients and determine if thiopurine metabolite profiles at week 4 of treatment can predict its occurrence to allow early combination treatment.
Methods 273 patients with IBD, who were anti-TNF-α therapy naïve and matched for red blood cell thiopurine-S-methyltransferase activity, were retrospectively identified. Of these 181 patients demonstrated average MeMP:TGN ratios <11 (at least 2 profiles between weeks 12 – 52) and were used as a control group that was compared to 92 patients with average MeMP:TGN ratios ≥11. Clinical outcomes were recorded for the first 12 months of therapy. A failure of AZA/MP as monotherapy was determined by 3 gastroenterologists with expertise in IBD. Thiopurine metabolite profiles were measured in 139 patients at week 4 of therapy and were compared to average metabolite profiles between 12 – 52 weeks of treatment.
Results The average MeMP:TGN ratios in those with and without TH were 21.0 and 2.52 respectively (p = <0.0001). The normalised dose of thiopurine was higher in patients with TH (1.91 vs. 2.09 mg/ kg; p = < 0.0001). Patients with TH were more likely to fail AZA/MP monotherapy as first line treatment during the first 12 months of therapy, in comparison with patients with normal methylation profiles (p = 0.0088, Gehan-Breslow-Wilcoxon Test). The difference in the number of treatment failures at 12 months was 15.7%. There was no difference in the occurrence of gastrointestinal intolerance, myelotoxicity or pancreatitis between groups, however there was an excess of hepatotoxicity with TH (p = 0.0006; OR = 8.058; 95% CI: 2.188 – 29.670; Fisher’s exact). TH was demonstrated in 83.7% of cases by 12 weeks of therapy. A MeMP : TGN level > 6.17 at week 4 accurately predicted TH (ratio ≥11) after 12 weeks of therapy (AUC = 0.839; p = < 0.0001; sensitivity = 75.4%; specificity = 88.4%).
Conclusion TH is associated with an excess of thiopurine treatment failures as monotherapy immunosuppression during the first 12 months of treatment. We also confirm its association with hepatotoxicity. A MeMP:TGN >6.17 may be useful in early identification of patients likely to benefit from combination treatment.
Disclosure of Interest None Declared.
Statistics from Altmetric.com
If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.