A comparative analysis of tioguanine versus low‐dose thiopurines combined with allopurinol in inflammatory bowel disease patients

Abstract

| on behalf of the Dutch Initiative on Crohn's Colitis (ICC)This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes. SummaryBackground: Both tioguanine and low-dose thiopurines combined with allopurinol (LDTA) can be considered for the treatment of inflammatory bowel disease (IBD) when conventional thiopurines fail due to adverse events. Aim:To compare the safety of tioguanine and LDTA in IBD patients. Methods:Inflammatory bowel disease patients who failed conventional thiopurines due to adverse events and initiated LDTA in standard care were identified in the prospective ICC Registry. IBD patients who failed conventional thiopurines due to adverse events and initiated tioguanine were enrolled in three university hospitals.Patients on concomitant biologicals were excluded. The primary outcome was discontinuation of therapy due to adverse events. Secondary outcomes included: safety outcomes and surgery-, biological-and corticosteroid-free clinical remission (physician global assessment = 0) after 104 weeks. Both multiple logistic regression and propensity score matching were used to correct for confounders. Results:In total, 182 IBD patients treated with tioguanine (n = 94) or LDTA (n = 88) were included with a median follow-up of 104 weeks (IQR 91-104). Of these, 19% (tioguanine: 20%, LDTA: 18%) of patients discontinued therapy due to adverse events. After adjusting for confounders, there were no differences in terms of discontinuation rate due to adverse events (OR 0.50, 95% CI 0.15-1.68, P = 0.26), adverse events (OR 0.89, 95% CI 0.44-1.81, P = 0.75), infections (OR 1.05, 95% CI 0.40-2.73, P = 0.93), hospitalisations (OR 2.00, 95% CI 0.64-6.23, P = 0.23) or clinical remission (OR 0.74, 95%CI 0.33-1.68, P = 0.48). All results are comparable with the propensity score matched cohort.

Adverse Drug Reactions from Real-World Data in Inflammatory Bowel Disease Patients in the IBDREAM Registry

“…Arthralgia associated with the use of thioguanine was reported with a ‘common’ (≥ 1% to < 10%) cumulative incidence in IBDREAM (1.9%; n = 11). This finding is in line with the cumulative incidence of 5.8% reported in a Dutch retrospective study ( n = 16) [ 27 ], while a Dutch prospective study reported an even higher cumulative incidence of ‘very common’, with 10.6% ( n = 10) [ 21 ]. From the latter 10 cases, seven were possibly related to arthralgia and three cases resulted in discontinuation.…”

“…Similarly, arthralgia, pyrexia and rash associated with the use of mercaptopurine are only reported in the SmPC as part of a hypersensitivity reaction [ 12 ], and not separately. These findings were supported by recent studies [ 21 – 24 ] in which pyrexia, malaise, nausea and diarrhoea associated with the use of azathioprine, and arthralgia, pyrexia and rash associated with the use of mercaptopurine, were reported separately. Symptoms such as arthralgia may also be considered underlying symptoms of IBD.…”

Thiopurines in Inflammatory Bowel Disease. How to Optimize Thiopurines in the Biologic Era?

“…Pharmacogenomics AZA is a prodrug and, after a non-enzymatic change, 88% of it is converted into mercaptopurine (MP), that can be metabolized through different pathways into another active and inactive metabolites, as shown in Figure 1 (27,28). The thiopurine methyltransferase enzyme (TPMT) methylates MP into methylmercaptopurine (MMP), an inactive metabolite associated with some adverse events, mainly hepatotoxicity.…”

“…TP are cheaper compared to biologics; in fact, in some countries, before the biologics, the cost of drugs represented 25% of the IBD care cost and, after them, the cost has increased from 30 to 70% (26). Finally, the overall efficacy of TP has been demonstrated for many years and, in general, patients who respond to these drugs tend to maintain a long remission (4,27). Clinical experience with TP also helps to manage most side effects, and those that are life-threatening are uncommon.…”

Thioguanine Therapy in Inflammatory Bowel Diseases. A Practical Guide

“…When patients experience side-effects related to elevated 6-MMP levels, we discuss two possible strategies: to start with the combination azathioprine/allopurinol therapy or to switch to monotherapy TG. Due to the lower pill burden the latter is often preferred [20]. Also, patients who still experience mild side-effects after a rechallenge with MP can benefit from a switch to TG [21,22].…”