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Infliximab Treatment Induces Levels of the Active Azathioprine Metabolite TGTP in Crohn's Disease

Infliximab Treatment Induces Levels of the Active Azathioprine Metabolite TGTP in Crohn's Disease To the Editor: Recent studies by Colombel et al1 revealed that combination therapy with azathioprine plus infliximab is more effective than monotherapy in the treatment of patients with active Crohn's disease (CD). The underlying mechanism could be the result of synergistic apoptosis inducing the effects of these substances. While azathioprine induces T-cell apoptosis through mitochondrial pathways,2 infliximab blocks the mTNF/TNFR2 pathway to achieve T-cell death.3 Furthermore, drug interactions between azathioprine and infliximab may exist. Using a validated assay system,4,5 we determined levels of the active metabolite of azathioprine, 6-thioguanosine triphosphate (6-TGTP), as well as levels of 6-thioguanosine diphosphate (6-TGDP), total 6-thioguanine nucletotides (6-TGN) and methylated products (6-methylmercaptopurine ribonucleotides, 6-MMPR; 6-methylthioguanine nucleotides, 6-MTGN)2 in infliximab-treated patients with CD. Analysis of 81 patients revealed that infliximab treatment results in significantly higher 6-TGTP levels (mean: 113 vs. 87 pmol/8 x 108 red blood cells; P < 0.05) compared to azathioprine monotherapy. In contrast, 5-aminosalicylates and corticosteroids had no significant effect. There was also a trend toward higher 6-TGN levels in azathioprine plus infliximab-treated patients compared to patients given azathioprine monotherapy, although this finding did not reach statistical significance. No significant changes in the levels of the inactive precursor metabolite 6-TGDP were noted between azathioprine and azathioprine plus infliximab-treated groups (Fig. 1). This is the first report indicating that isolated 6-TGTP levels are altered by infliximab therapy corroborating previous data by Roblin et al.6 who reported a significant increase of total 6-TGN levels within 1-3 weeks after the first infusion. Figure 1. View largeDownload slide Levels of azathioprine metabolites in infliximab-treated and non-inflixi-mab-treated patients with CD (n = 81). S, sum of TGTP and TGDP. R, ratio of TGTP/TGDP+TGTP. Figure 1. View largeDownload slide Levels of azathioprine metabolites in infliximab-treated and non-inflixi-mab-treated patients with CD (n = 81). S, sum of TGTP and TGDP. R, ratio of TGTP/TGDP+TGTP. Thus, several mechanisms including synergy in apoptosis induction and direct effects of infliximab on 6-TGTP levels may contribute to the efficacy of azathioprine plus infliximab therapy in CD. The observation that 6-TGTP levels are induced in infliximab-treated patients further underlines the value of combination therapy7,8 for optimized immunosuppression in selected patients with CD. References 1. Colombel JF, Sandborn WJ, Reinisch W, et al.  . Infliximab, azathioprine, or combination therapy for Crohn's disease. N Engl J Med . 2010; 362: 1383– 1395. Google Scholar CrossRef Search ADS PubMed  2. Tiede I, Fritz G, Strand S, et al.  . CD28-dependent Rac1 activation is the molecular target of azathioprine in primary human CD4+ T lymphocytes. J Clin Invest.  2003; 111: 1133– 1145. Google Scholar CrossRef Search ADS PubMed  3. Atreya R, Zimmer M, Bartsch B, et al.  . Antibodies against tumor necrosis factor (TNF) induce T-cell apoptosis in patients with inflammatory bowel diseases via TNF receptor 2 and intestinal CD14 macrophages. Gastroenterology . 2011; 141: 2026– 2038. Google Scholar CrossRef Search ADS PubMed  4. Karner S, Shi S, Fischer C, et al.  . Determination of 6-thioguanosine diphosphate and triphosphate and nucleoside diphosphate kinase activity in erythrocytes: novel targets for thiopurine therapy? Ther Drug Monit.  2010; 32: 119– 128. Google Scholar PubMed  5. Neurath MF, Kiesslich R, Teichgräber U, et al.  . 6-Thioguanosine diphospate and triphosphate levels in red blood cells and response to azathioprine therapy in Crohn's disease. Clin Gastroenterol Hepatol . 2005; 3: 1007– 1014. Google Scholar CrossRef Search ADS PubMed  6. Hanauer SB, Roblin X, Serre-Debeauvais F, Phelip JM, Bessard G, Bonaz B. Drug interaction between infliximab and azathioprine in patients with Crohn's disease. Aliment Pharmacol Ther . 2003; 18: 917– 925. Google Scholar CrossRef Search ADS PubMed  7. Hanauer SB. Crohn's disease: step up or top down therapy. Best Pract Res Clin Gastroenterol . 2003; 17: 131– 137. Google Scholar CrossRef Search ADS PubMed  8. D'Haens G. Top-down therapy for Crohn's disease: rationale and evidence. Acta Clin Belg . 2009; 64: 540– 546. Google Scholar CrossRef Search ADS PubMed  Copyright © 2013 Crohn's & Colitis Foundation of America, Inc. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Inflammatory Bowel Diseases Oxford University Press

Infliximab Treatment Induces Levels of the Active Azathioprine Metabolite TGTP in Crohn's Disease

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Copyright
Copyright © 2013 Crohn's & Colitis Foundation of America, Inc.
ISSN
1078-0998
eISSN
1536-4844
DOI
10.1002/ibd.22998
pmid
22532373
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Abstract

To the Editor: Recent studies by Colombel et al1 revealed that combination therapy with azathioprine plus infliximab is more effective than monotherapy in the treatment of patients with active Crohn's disease (CD). The underlying mechanism could be the result of synergistic apoptosis inducing the effects of these substances. While azathioprine induces T-cell apoptosis through mitochondrial pathways,2 infliximab blocks the mTNF/TNFR2 pathway to achieve T-cell death.3 Furthermore, drug interactions between azathioprine and infliximab may exist. Using a validated assay system,4,5 we determined levels of the active metabolite of azathioprine, 6-thioguanosine triphosphate (6-TGTP), as well as levels of 6-thioguanosine diphosphate (6-TGDP), total 6-thioguanine nucletotides (6-TGN) and methylated products (6-methylmercaptopurine ribonucleotides, 6-MMPR; 6-methylthioguanine nucleotides, 6-MTGN)2 in infliximab-treated patients with CD. Analysis of 81 patients revealed that infliximab treatment results in significantly higher 6-TGTP levels (mean: 113 vs. 87 pmol/8 x 108 red blood cells; P < 0.05) compared to azathioprine monotherapy. In contrast, 5-aminosalicylates and corticosteroids had no significant effect. There was also a trend toward higher 6-TGN levels in azathioprine plus infliximab-treated patients compared to patients given azathioprine monotherapy, although this finding did not reach statistical significance. No significant changes in the levels of the inactive precursor metabolite 6-TGDP were noted between azathioprine and azathioprine plus infliximab-treated groups (Fig. 1). This is the first report indicating that isolated 6-TGTP levels are altered by infliximab therapy corroborating previous data by Roblin et al.6 who reported a significant increase of total 6-TGN levels within 1-3 weeks after the first infusion. Figure 1. View largeDownload slide Levels of azathioprine metabolites in infliximab-treated and non-inflixi-mab-treated patients with CD (n = 81). S, sum of TGTP and TGDP. R, ratio of TGTP/TGDP+TGTP. Figure 1. View largeDownload slide Levels of azathioprine metabolites in infliximab-treated and non-inflixi-mab-treated patients with CD (n = 81). S, sum of TGTP and TGDP. R, ratio of TGTP/TGDP+TGTP. Thus, several mechanisms including synergy in apoptosis induction and direct effects of infliximab on 6-TGTP levels may contribute to the efficacy of azathioprine plus infliximab therapy in CD. The observation that 6-TGTP levels are induced in infliximab-treated patients further underlines the value of combination therapy7,8 for optimized immunosuppression in selected patients with CD. References 1. Colombel JF, Sandborn WJ, Reinisch W, et al.  . Infliximab, azathioprine, or combination therapy for Crohn's disease. N Engl J Med . 2010; 362: 1383– 1395. Google Scholar CrossRef Search ADS PubMed  2. Tiede I, Fritz G, Strand S, et al.  . CD28-dependent Rac1 activation is the molecular target of azathioprine in primary human CD4+ T lymphocytes. J Clin Invest.  2003; 111: 1133– 1145. Google Scholar CrossRef Search ADS PubMed  3. Atreya R, Zimmer M, Bartsch B, et al.  . Antibodies against tumor necrosis factor (TNF) induce T-cell apoptosis in patients with inflammatory bowel diseases via TNF receptor 2 and intestinal CD14 macrophages. Gastroenterology . 2011; 141: 2026– 2038. Google Scholar CrossRef Search ADS PubMed  4. Karner S, Shi S, Fischer C, et al.  . Determination of 6-thioguanosine diphosphate and triphosphate and nucleoside diphosphate kinase activity in erythrocytes: novel targets for thiopurine therapy? Ther Drug Monit.  2010; 32: 119– 128. Google Scholar PubMed  5. Neurath MF, Kiesslich R, Teichgräber U, et al.  . 6-Thioguanosine diphospate and triphosphate levels in red blood cells and response to azathioprine therapy in Crohn's disease. Clin Gastroenterol Hepatol . 2005; 3: 1007– 1014. Google Scholar CrossRef Search ADS PubMed  6. Hanauer SB, Roblin X, Serre-Debeauvais F, Phelip JM, Bessard G, Bonaz B. Drug interaction between infliximab and azathioprine in patients with Crohn's disease. Aliment Pharmacol Ther . 2003; 18: 917– 925. Google Scholar CrossRef Search ADS PubMed  7. Hanauer SB. Crohn's disease: step up or top down therapy. Best Pract Res Clin Gastroenterol . 2003; 17: 131– 137. Google Scholar CrossRef Search ADS PubMed  8. D'Haens G. Top-down therapy for Crohn's disease: rationale and evidence. Acta Clin Belg . 2009; 64: 540– 546. Google Scholar CrossRef Search ADS PubMed  Copyright © 2013 Crohn's & Colitis Foundation of America, Inc.

Journal

Inflammatory Bowel Diseases – Oxford University Press

Published: Apr 1, 2013

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