Gastroenterology 2014;146:865–870
CORRESPONDENCE Readers may submit letters to the editor concerning articles that appeared in Gastroenterology within one month of publication. Detailed guidelines regarding the content are included in the Instructions to Authors.
Get the Best Out of Thiopurine Therapy Dear Sir: With great interest we read the provocative study by Panés et al concluding that administration of azathioprine (AZA) early in the disease course of Crohn’s disease was no more effective than placebo to achieve sustained steroidfree remission.1 The rationale of the trial design was in part based on a pediatric study in which mercaptopurine (MP) was administered.2 Young age at diagnosis is a known risk factor for a more severe course of Crohn’s disease. In population-based cohorts, about 40% of adult patients do not need corticosteroid therapy. Thiopurines are therefore more likely to be beneficial in children than in adults. An extrapolation of findings in consecutive series of pediatric patients with Crohn’s disease in a referral setting cannot be compared with a selected series of adult Spanish patients collected over many years in many hospitals from various nature. One of the significantly contributing factors to the remarkable outcome of the study is the much higher occurrence of adverse events (including inefficacy) in the AZA-treated group, leading to timely and unwanted discontinuation of thiopurine therapy. In the pediatric study by Markowitz et al,2 early MP therapy did lead to a significant reduction in the number of relapses and corticosteroids requirements. Although AZA and MP are members of the thiopurine family and both are considered effective and (relatively) safe, they are not comparable when it comes to tolerability and toxicity. Several studies have demonstrated that a rechallenge with MP should be considered in AZA intolerance (including hepatotoxicity), because approximately half of the patients tolerate this switch.3,4 Thiopurine metabolite testing (6-thioguaninenucleotides and 6-methylmercaptopurine) is another well-known strategy for optimizing thiopurine usage in inflammatory bowel disease. Metabolite levels may explain therapeutic failure, because noncompliance, under- or overdosing or ultramethylation (eg, aberrant thiopurine metabolism) are often observed.5 Clinical strategies based on these metabolite patterns, for example allopurinol co-administration alongside low-dose thiopurine in case of preferential 6-methylmercaptopurine formation,6 have been applied successfully in daily practice.5 An alternative and easy-to-use approach to beneficially influence thiopurine metabolism may be a split-dose administration. Dividing the total daily thiopurine dose leads to a reduction in 6-methylmercaptopurine levels and resolution of the associated side effects (elevated transaminases, leukopenia, and flu-like symptoms), without negatively affecting clinical disease activity.7 We speculate, in our opinion with a solid scientific basis, that a larger number of Crohn’s disease patients would have tolerated and benefitted from thiopurine therapy throughout the
study of Panés, when MP was considered the thiopurine of choice (instead of AZA), when a (mandatory) rechallenge with MP was incorporated in the trial design and when therapeutic drug monitoring was applied to guide optimization of therapy. It may well be that the outcomes of the study would substantially change with these thiopurine optimizing strategies, because the group of Crohn’s disease patients with unsuccessful treatment in the AZA-arm would be more restricted to genuine therapeutic failures. In (our) daily clinical inflammatory bowel disease practice, all these clinical strategies are used to enhance efficacy and to avoid or bypass adverse effects of thiopurine therapy. Therefore, it is challenging and difficult to extrapolate the results of the presented study to Crohn’s disease populations in general. Changing the general practice to introduce thiopurines following a corticosteroid inductionscheme seems to be premature, based on these study results. NANNE K. H. DE BOER ADRIAAN A. VAN BODEGRAVEN Department of Gastroenterology and Hepatology VU University Medical Center Amsterdam, The Netherlands
References 1. 2. 3. 4. 5. 6. 7.
Panés J, et al. Gastroenterology 2013;145:766–774. Markowitz J, et al. Gastroenterology 2000;119:895–902. Lees CW, et al. Aliment Pharmacol Ther 2008;27: 220–227. Hindorf U, et al. Aliment Pharmacol Ther 2009;29: 654–661. Haines ML, et al. Inflamm Bowel Dis 2011;17:1301–1307. Hoentjen F, et al. Inflamm Bowel Dis 2013;19:363–369. Shih DQ, et al. Aliment Pharmacol Ther 2012;36: 449–458.
Conflicts of interest The authors disclose no conflicts
http://dx.doi.org/10.1053/j.gastro.2013.08.062
Early Use of Azathioprine in Crohn’s Disease Dear Sir: We read with interest the papers by Cosnes et al1 (RAPID), and Panés et al2 (AZTEC) in the October issue of Gastroenterology, investigating the benefits of early azathioprine in adults with newly diagnosed Crohn’s disease. We
CORRESPONDENCE Readers may submit letters to the editor concerning articles that appeared in Gastroenterology within one month of publication. Detailed guidelines regarding the content are included in the Instructions to Authors.
Get the Best Out of Thiopurine Therapy Dear Sir: With great interest we read the provocative study by Panés et al concluding that administration of azathioprine (AZA) early in the disease course of Crohn’s disease was no more effective than placebo to achieve sustained steroidfree remission.1 The rationale of the trial design was in part based on a pediatric study in which mercaptopurine (MP) was administered.2 Young age at diagnosis is a known risk factor for a more severe course of Crohn’s disease. In population-based cohorts, about 40% of adult patients do not need corticosteroid therapy. Thiopurines are therefore more likely to be beneficial in children than in adults. An extrapolation of findings in consecutive series of pediatric patients with Crohn’s disease in a referral setting cannot be compared with a selected series of adult Spanish patients collected over many years in many hospitals from various nature. One of the significantly contributing factors to the remarkable outcome of the study is the much higher occurrence of adverse events (including inefficacy) in the AZA-treated group, leading to timely and unwanted discontinuation of thiopurine therapy. In the pediatric study by Markowitz et al,2 early MP therapy did lead to a significant reduction in the number of relapses and corticosteroids requirements. Although AZA and MP are members of the thiopurine family and both are considered effective and (relatively) safe, they are not comparable when it comes to tolerability and toxicity. Several studies have demonstrated that a rechallenge with MP should be considered in AZA intolerance (including hepatotoxicity), because approximately half of the patients tolerate this switch.3,4 Thiopurine metabolite testing (6-thioguaninenucleotides and 6-methylmercaptopurine) is another well-known strategy for optimizing thiopurine usage in inflammatory bowel disease. Metabolite levels may explain therapeutic failure, because noncompliance, under- or overdosing or ultramethylation (eg, aberrant thiopurine metabolism) are often observed.5 Clinical strategies based on these metabolite patterns, for example allopurinol co-administration alongside low-dose thiopurine in case of preferential 6-methylmercaptopurine formation,6 have been applied successfully in daily practice.5 An alternative and easy-to-use approach to beneficially influence thiopurine metabolism may be a split-dose administration. Dividing the total daily thiopurine dose leads to a reduction in 6-methylmercaptopurine levels and resolution of the associated side effects (elevated transaminases, leukopenia, and flu-like symptoms), without negatively affecting clinical disease activity.7 We speculate, in our opinion with a solid scientific basis, that a larger number of Crohn’s disease patients would have tolerated and benefitted from thiopurine therapy throughout the
study of Panés, when MP was considered the thiopurine of choice (instead of AZA), when a (mandatory) rechallenge with MP was incorporated in the trial design and when therapeutic drug monitoring was applied to guide optimization of therapy. It may well be that the outcomes of the study would substantially change with these thiopurine optimizing strategies, because the group of Crohn’s disease patients with unsuccessful treatment in the AZA-arm would be more restricted to genuine therapeutic failures. In (our) daily clinical inflammatory bowel disease practice, all these clinical strategies are used to enhance efficacy and to avoid or bypass adverse effects of thiopurine therapy. Therefore, it is challenging and difficult to extrapolate the results of the presented study to Crohn’s disease populations in general. Changing the general practice to introduce thiopurines following a corticosteroid inductionscheme seems to be premature, based on these study results. NANNE K. H. DE BOER ADRIAAN A. VAN BODEGRAVEN Department of Gastroenterology and Hepatology VU University Medical Center Amsterdam, The Netherlands
References 1. 2. 3. 4. 5. 6. 7.
Panés J, et al. Gastroenterology 2013;145:766–774. Markowitz J, et al. Gastroenterology 2000;119:895–902. Lees CW, et al. Aliment Pharmacol Ther 2008;27: 220–227. Hindorf U, et al. Aliment Pharmacol Ther 2009;29: 654–661. Haines ML, et al. Inflamm Bowel Dis 2011;17:1301–1307. Hoentjen F, et al. Inflamm Bowel Dis 2013;19:363–369. Shih DQ, et al. Aliment Pharmacol Ther 2012;36: 449–458.
Conflicts of interest The authors disclose no conflicts
http://dx.doi.org/10.1053/j.gastro.2013.08.062
Early Use of Azathioprine in Crohn’s Disease Dear Sir: We read with interest the papers by Cosnes et al1 (RAPID), and Panés et al2 (AZTEC) in the October issue of Gastroenterology, investigating the benefits of early azathioprine in adults with newly diagnosed Crohn’s disease. We
