Lookup NU author(s): Dr Sally Coulthard,
Dr Chris Redfern
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
Background: Use ofazathioprine (AZA) for inflammatory bowel disease is limited by side effects or poor efficacy. Combining low-dose azathioprine with allopurinol (LDAA) by-passes side effects, improves efficacy and may be appropriate as first-line therapy. We test the hypothesis that standard-dose azathioprine (AZA) and LDAA treatments work by similar mechanisms, using incorporation of the metabolite deoxythioguanosine into patient DNA, white-blood cell counts and transcriptome analysis as biological markers of drug effect. Methods: DNA was extracted from peripheral whole-blood from IBD patients treated with AZA or LDAA, and analysed for DNA-incorporated deoxythioguanosine. Measurement of red-blood cell (RBC) thiopurine metabolites was part of usual clinical practice, and pre- and on-treatment (12 weeks) blood samples were used for transcriptome analysis. Results: There were no differences in reduction of white-cell counts between the two treatment groups but patients on LDAA had lower DNA-incorporated deoxythioguanosine than those on AZA; for both groups, incorporated deoxythioguanosine was lower in patients on thiopurines for 24 weeks or more (maintenance of remission) compared to patients treated for less than 24 weeks (achievement of remission). Patients on LDAA had higher levels of RBC thioguanine nucleotides than those on AZA, but there was no correlation between these, or their methylated metabolites, and incorporated deoxythioguanosine. Transcriptome analysis suggested down-regulation of immune responses consistent with effective immunosuppression in patients receiving LDAA, with evidence for different mechanisms of action between the two therapies. Conclusions: LDAA is biologically effective despite lower deoxythioguanosine incorporation into DNA, and has different mechanisms of action compared to standard-dose azathioprine.
Author(s): Coulthard SA, Berry P, McGarrity S, McLaughlin S, Ansari A, Redfern CPF
Publication type: Article
Publication status: Published
Journal: Inflammatory Bowel Diseases
Pages: e-pub ahead of print
Online publication date: 27/04/2017
Acceptance date: 20/03/2017
ISSN (print): 1078-0998
ISSN (electronic): 1536-4844
Publisher: Wolters Kluwer Health, Inc.
PubMed id: 28452864
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