Maintenance of remission is a major issue in inflammatory bowel disease. In ulcerative colitis, the evidence for the effectiveness of azathioprine and 6-mercaptopurine for the maintenance of remission is still controversial.
To assess the effectiveness and safety of azathioprine and 6-mercaptopurine for maintaining remission of ulcerative colitis.
The MEDLINE database was used to search literature from 1966 to 2006. A manual search was also performed using references from these articles as well as review articles, proceedings from major gastrointestinal meetings and data available from the Cochrane Collaboration database. Authors of maintenance trials were asked about unpublished studies.
Randomized controlled trials of at least 12 months duration that compared azathioprine or 6-mercaptopurine with placebo or standard maintenance therapy (mesalamine) were included.
Data were extracted by two raters using standard forms. Disagreements were solved by informal consent, including a third rater. Jadad scores were applied to assess study quality. Analyses were performed separately by type of control (placebo, or active comparator). Pooled odds ratios were calculated based on the fixed effects model unless heterogeneity was shown.
Six studies were identified including 286 patients with ulcerative colitis. The study quality was mostly poor. Azathioprine was shown to be superior for the maintenance of remission as compared to placebo based on four trials (failure to maintain remission: OR 0.41; 95% CI 0.24 to 0.70). Two trials that compared 6-mercaptopurine to mesalazine, or azathioprine to sulfasalazine showed significant heterogeneity. Both studies using active comparators were open label. Adverse effects occurred in 11 of 127 patients receiving azathioprine, including acute pancreatitis (3 cases) and significant bone marrow suppression (5 cases).
Azathioprine may be an effective maintenance therapy for patients who have failed or cannot tolerate mesalazine or sulfasalazine and for patients who require repeated courses of steroids. More research is needed to evaluate superiority over standard maintenance therapy, especially in the light of a potential for adverse events from azathioprine.
"AZA is a pro-drug of 6-MP carrying a methyl imidazole group attached to a sulfur carbon of 6-MP and metabolized to 6-MP by cleavage require the action of gluthatione S transferase. For the maintenance of remission in IBD, AZA and 6-MP are the first-line immunomodulators , . Both AZA and 6-MP must be extensively metabolized before the pharmacologically active metabolites, 6-thioguaninenucleotides (6-TGN), are generated. "
[Show abstract][Hide abstract] ABSTRACT: Azathioprine (AZA) is widely used for the treatment of inflammatory bowel disease (IBD) patients. AZA is catabolized by thiopurine S-methyltransferase (TPMT), which exhibits genetic polymorphisms. It has also been reported that 5-aminosalicylic acid (5-ASA) inhibits TPMT activity, and that increased 6-thioguanine nucleotide (6-TGN, a metabolite of AZA) blood concentrations result in an increased number of ADRs. In this study, single nucleotide polymorphisms (SNPs) related to differential gene expression affecting AZA drug metabolism in combination therapy with 5-ASA were examined.
To identify genetic biomarkers for the prediction of 6-TGN blood concentration, ExpressGenotyping analysis was used. ExpressGenotyping analysis is able to detect critical pharmacogenetic SNPs by analyzing drug-induced expression allelic imbalance (EAI) of premature RNA in HapMap lymphocytes. We collected blood samples on 38 patients with inflammatory bowel disease treated with AZA and corroboration of the obtained SNPs was attempted in clinical samples.
A large number of SNPs with AZA/5-ASA-induced EAI within the investigated HapMap lymphocytes was identified by ExpressGenotyping analysis. The respective SNPs were analyzed in IBD patients' blood samples. Among these SNPs, several that have not yet been described to be induced by AZA/5-ASA were found. SNPs within SLC38A9 showed a particular correlation with patients' 6-TGN blood concentrations.
Based on these results, ExpressGenotyping analysis and genotyping of patients appears to be a useful way to identify inter-individual differences in drug responses and ADRs to AZA/5-ASA. This study provides helpful information on genetic biomarkers for optimized AZA/5-ASA treatment of IBD patients.
PLoS ONE 04/2014; 9(4):e95080. DOI:10.1371/journal.pone.0095080 · 3.23 Impact Factor
"Thiopurines, including azathioprine (AZA) and its analogue, mercaptopurine (MP), are commonly used to treat IBD. AZA/MP is effective as steroid-sparing agents  and has been demonstrated to induce and maintain remission in patients with IBD . However, thiopurines have been implicated in the development of malignancy due to its immunosuppressive and potential mutagenic effects, especially lymphoma  and skin cancers . "
[Show abstract][Hide abstract] ABSTRACT: Inflammatory bowel disease (IBD) is commonly treated with thiopurines such as azathioprine and mercaptopurine for the maintenance of remission. Studies examining chemopreventive of these medications on colorectal neoplasm in IBD patients have yielded conflicting results. We performed a meta-analysis to assess the role of thiopurines for this indication.
We performed a systematic search of PubMed, Web of Science, EMBASE and Cochrane to identify studies reporting colorectal neoplasm from IBD patients treated with thiopurines and conducted a meta-analysis of pooled relative risk (RR) using the random effects model.
Nine case-control and ten cohort studies fulfilled the inclusion criteria. The use of thiopurines was associated with a statistically significant decreased incidence of colorectal neoplasm (summary RR=0.71, 95% CI=0.54-0.94, p=0.017), even after adjustment for duration and extent of the disease, but there was high heterogeneity among studies (I (2)=68.0%, p<0.001). The RR of advanced neoplasm (high-grade dysplasia and cancer) was 0.72 (95%CI=0.50-1.03, p=0.070) and that of cancer was 0.70 (95% CI=0.46-1.09, p=0.111) for thiopurine-treated patients. Heterogeneity of the studies was affected by the sample size (</≥100 cases) and whether the patients had longstanding colitis (≥7 years).
The current meta-analysis revealed that thiopurines had a chemopreventive effect of colorectal neoplasms and a tendency of reducing advanced colorectal neoplasms in IBD. Due to the heterogeneity of included studies, these results should be interpreted with caution.
PLoS ONE 11/2013; 8(11):e81487. DOI:10.1371/journal.pone.0081487 · 3.23 Impact Factor
"For patients with steroid-dependent or steroid-refractory ulcerative colitis (UC), immunomodulatory agents, such as azathioprine (AZA), 6-mercaptopurine (6-MP), cyclosporine , or methotrexate, have been used for the induction and maintenance of clinical remission of the disease          . While thiopurines (AZA/6-MP) are the most commonly used agents to maintain clinical remission in patients with UC  , the use of AZA/6-MP for inducing remission of active UC is still controversial      . "
[Show abstract][Hide abstract] ABSTRACT: Background: The role of azathioprine (AZA) and 6-mercaptopurine (6-MP) in the induction of remission in patients with ulcerative colitis (UC) remains unclear. Aims: To compare the efficacy and safety of low-dose thiopurine (AZA/6-MP) and cytapheresis (CAP) for the induction of remission in patients with steroid-dependent UC. Patients and Methods: We reviewed the clinical course of 65 patients with steroid-dependent UC with moderate activity, who were treated with either low-dose AZA/6-MP (T-group, n = 38) or with CAP (C-group, n = 27). The efficacy and safety for the first 10 weeks after the start of the therapies were compared between the two groups. The cumulative probability curves of treatment failure were estimated by the Kaplan-Meier method. Clinical remission was defined as an ulcerative colitis activity index value of less than 150 without any other treatments. Results: Neither clinical characteristics, concomitant therapies, nor laboratory data (except for serum albumin levels) were different between the two groups. The remission rate at 10 weeks was not different between the two groups (55.3% in the T-group and 70.4% in the C-group, p = 0.22 in the intention-to-treat analysis). The frequencies of adverse events did not differ be-tween the two groups (p = 0.12). The cumulative pro-bability of treatment failure at 10 weeks was 44.7% for the T-group and 29.6% for the C-group (p = 0.23). Conclusions: Low-dose thiopurine therapy is an alter-native candidate for the induction of remission in pa-tients with steroid-dependent, moderate UC.
Open Journal of Gastroenterology 01/2012; 02(01). DOI:10.4236/ojgas.2012.21002
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