Abstract and Introduction
Abstract
Background: Adverse drug reactions are a significant reason for therapeutic failure during thiopurine treatment of inflammatory bowel disease. Some smaller series in this patient population have shown that a switch to mercaptopurine may be successful in many cases of azathioprine intolerance.
Aim: To assess the long-term outcome of mercaptopurine treatment in a large patient population with azathioprine intolerance.
Methods: We identified 135 patients (74 women; median age 40 years) with Crohn's disease (n = 88) or ulcerative colitis (n = 47) and reviewed their medical records.
Results: A total of 70 patients (52%) tolerated mercaptopurine and were followed up for 736 (362-1080) days; 65 patients discontinued mercaptopurine due to adverse events after 25 (8-92) days. Mercaptopurine was tolerated in 71% (12/17) with hepatotoxicity and in 68% (13/19) with arthralgia/myalgia during azathioprine treatment. Previous abdominal surgery was more common in mercaptopurine intolerant patients [39/65 (60%) vs. 27/70 (39%); P = 0.02] and thiopurine methyltransferase activity was higher in mercaptopurine tolerant patients than in mercaptopurine intolerant patients [13.2 (11.4-15.3) vs. 11.8 (9.6-14.2) U/mL red blood cells; P = 0.04; n = 81].
Conclusions: A trial of mercaptopurine should be considered in azathioprine intolerance, as half of the patients tolerate a switch to mercaptopurine. Patients with hepatotoxicity or arthralgia/myalgia during azathioprine treatment might benefit more often than those with other types of adverse events.
Introduction
The thiopurine drugs, azathioprine (AZA) and mercaptopurine (MP), are well established in the treatment of inflammatory bowel disease (IBD) and have proven to be effective in both inducing and maintaining remission of Crohn's disease (CD) and ulcerative colitis (UC). Individual variations in drug metabolism are of importance for differences in tolerance to thiopurines, which undergo extensive metabolic transformation resulting in several active and inactive metabolites.
Genetic polymorphisms in the gene for thiopurine methyltransferase (TPMT *2 to *25), one of the major thiopurine metabolizing enzymes, are associated with a decreased TPMT activity. Studies have shown that patients with a very low enzyme activity are at risk for severe, and sometimes fatal, myelotoxicity and patients who are TPMT heterozygous for one allele with low activity have an intermediate risk for myelotoxicity. Whether other types of adverse event (AE) in IBD patients can be attributed to the TPMT polymorphism is less clear.
The clinical practice in Sweden has by tradition been to initiate treatment with AZA, whereas MP has mainly been used in AZA-intolerant patients. AEs to AZA or MP occur in 9-34% of patients and often necessitate dose reduction or discontinuation of the administered drug. Different approaches to the management of patients with thiopurine intolerance have been proposed, including the use of de-sensitization techniques and switch to another thiopurine drug. It has been postulated that some early idiosyncratic reactions, such as digestive intolerance, pancreatitis, cholestasis and flu-like symptoms during AZA therapy, might be due to the nitro-imidazole moiety found in AZA, which is released to produce MP. Previous observations in smaller groups of patients, where 45-73% of patients intolerant to AZA were able to tolerate MP support the assumption.
The primary aim of this study was to evaluate the long-term clinical outcome of AZA-intolerant IBD patients who had been shifted to MP. A secondary aim was to grade success rate of MP challenge related to the type of AE on AZA.