Thiopurines are important drugs for the treatment of inflammatory conditions related to the colon and the small intestine. Therapy failure, however, is common: up to 57% discontinues thiopurine therapy, due to either side effects or lack of desired effect. Some of these side effects are potentially fatal and include liver damage, decrease in blood cell counts and inflammation of the pancreas.
Allopurinol might reduce these side effects of thiopurines, by channelling conversion of thiopurines towards the effective compounds, rather than the toxic ones. Studies have demonstrated that - with the addition of allopurinol - toxic thiopurine compounds were indeed lowered with 94%, while levels of beneficial compounds were increased. Hence, in clinical practice, some physicians start the use of allopurinol accompanied with a reduced thiopurine dose (by 50-75%) in patients with a proven thiopurine conversion towards toxic compounds.
Despite these data on this beneficial interaction between thiopurines and allopurinol, evidence on clinical endpoints is limited. Some of the studies observed a decreasing trend of liver damage but had not enough patients to study this association more carefully. Moreover, other side effects, such as lowered blood cell counts and pancreas damage, have not been thoroughly studied. Finally, the majority of these studies had a relatively short time window of follow-up.
The objectives of this study are therefore, firstly, to evaluate the rates of liver damage, and, secondary, to assess decrease in blood cell counts and pancreas damage in adult and children thiopurine users with or without allopurinol.
Thiopurines are important in the treatment of IBD, but therapy failure is a common clinical phenomenon. Up to 57% discontinues thiopurine therapy, due to either adverse events or limited clinical response. Some of these adverse events are potentially fatal and include hepatotoxicity, myelotoxicity and pancreatitis. (15)(15)
Allopurinol might enhance the risk-benefit ratio of thiopurines. Mechanistically, allopurinol promotes metabolism of thiopurines towards beneficial 6-thioguanine metabolites (6-TGN) rather than the assumed hepatotoxic 6-methylmercaptopurine metabolites (6-MMP). Pharmacokinetic studies have shown that the addition of allopurinol indeed effectively lowers 6-MMP concentrations by 94%, at the cost of increases in 6-TGN concentrations. Based on this mechanism, various IBD guidelines advocate the use of allopurinol, in adjunction with a reduced thiopurine dose (by 50-75%) in patients with skewed thiopurine metabolism.
Evidence on clinical endpoints (rather than pharmacokinetic evidence) on the addition of allopurinol is scarce. Some of the pharmacokinetic studies observed a decreasing trend in hepatotoxicity, but were not powered to study this association more carefully. Moreover, the impact on other toxicity parameters (e.g. pancreatitis) has not been thoroughly studied. Finally, the majority of these studies had a relatively short follow-up time window.
The objectives of this study are therefore to primarily evaluate the rates of hepatotoxicity, and secondary to assess rates of myelotoxicity and pancreas toxicity in adult and paediatrics thiopurine users with or without allopurinol.
Rate ratios for hepatotoxicity, myelotoxicity and pancreas toxicity will be calculated among allopurinol-thiopurine co-users versus thiopurine-monotherapy users. For this purpose, time-dependent cox proportional hazards models will be used, adjusted for potential confounders using propensity scores. All analyses will be stratified based on the defined azathioprine dose reduction category, age, gender and where relevant potential effect modifiers. Statistical interaction will be tested using Wald tests.
Our primary outcome will be hepatotoxicity. As secondary outcomes we will investigate myelotoxicity and pancreas toxicity.
- Chief Investigator -
- Corresponding Applicant -
Anthonius de Boer - Collaborator - Utrecht University
Erik van Maarseveen - Collaborator - University Medical Centre Utrecht
Jeroen Houwen - Collaborator - Utrecht University
Toine Egberts - Collaborator - Utrecht University