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Metabolite monitoring to guide thiopurine therapy in systemic autoimmune diseases

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Abstract

6-Thioguanine nucleotide (6-TGN) is the active metabolite of thiopurine drugs azathioprine and 6-mercaptopurine. 6-Methylmercaptopurine (6-MMP) is an inactive and potentially hepatotoxic metabolite. A subgroup of patients (shunters) preferentially produce 6-MMP instead of 6-TGN, therefore displaying thiopurine resistance and risk for hepatotoxicity. Outside inflammatory bowel disease literature, few data exist regarding individualized thiopurine therapy based on metabolite monitoring. This study sought to describe metabolite monitoring in patients receiving weight-based thiopurine for systemic autoimmune diseases. Patients were enrolled using a laboratory database, and data were retrospectively collected. The correlation between the highest thiopurine dose (mg/kg) and the 6-TGN concentration (pmol/8 × 108 erythrocytes) was estimated with Pearson’s correlation coefficient. Seventy-one patients with various systemic autoimmune conditions were enrolled. The correlation between the thiopurine dose and the 6-TGN level was weak for the overall patient sample (r = 0.201, p = 0.092) and for the subgroup of non-shunters (r = 0.278, p = 0.053). Subjects with 6-MMP levels >5700 pmol/8 × 108 erythrocytes had more hepatic cytolysis compared to subjects with 6-MMP <5700, OR = 4.36 (CI 95% 1.18–16.13, p = 0.027). Twenty-two patients (31%) were identified as shunters. Six shunters developed hepatotoxicity, five of which had 6-MMP concentration >5700. Eleven non-shunters had hepatotoxicity, one of which had 6-MMP >5700. Thiopurine metabolite monitoring shows wide variability in 6-TGN levels among patients treated with weight-based thiopurine for systemic autoimmune diseases. Thirty-one percent of the patients in our series fulfilled the shunter definition. Thiopurine metabolite monitoring and dose adjustment to improve maintenance of remission and avoid hepatotoxicity should be studied prospectively.

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Acknowledgement

We are grateful to Maxime Rhéaume, MD, for the critical review of this manuscript.

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Authors and Affiliations

  1. Department of Medicine, Hôpital du Sacré-Cœur de Montréal, 5400 Gouin Ouest, Montréal, Québec, H4J 1C5, Canada

    Aurélie Chapdelaine, Anne-Marie Mansour & Yves Troyanov

  2. Faculty of Medicine, Université de Montréal, 5400 Gouin Ouest, Montréal, Québec, H4J 1C5, Canada

    Anne-Marie Mansour

  3. Department of Pharmacy, Hôpital du Sacré-Cœur de Montréal, 5400 Gouin Ouest, Montréal, Québec, H4J 1C5, Canada

    David R. Williamson & Maxime Doré

  4. Faculty of Pharmacy, Université de Montréal, 5400 Gouin Ouest, Montréal, Québec, H4J 1C5, Canada

    David R. Williamson

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  1. Aurélie Chapdelaine
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Correspondence to Aurélie Chapdelaine.

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Institutional research ethics committee approved the study protocol, which did not imply clinical experiments on human subjects. In the context of a retrospective design, patient’s formal consent was not applicable.

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Chapdelaine, A., Mansour, AM., Troyanov, Y. et al. Metabolite monitoring to guide thiopurine therapy in systemic autoimmune diseases. Clin Rheumatol 36, 1341–1348 (2017). https://doi.org/10.1007/s10067-017-3554-4

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