Accepted Manuscript Optimize thiopurine therapy in autoimmune hepatitis Berrie Meijer, Gerd Bouma, Nanne KH. de Boer

PII: DOI: Reference:

S1542-3565(16)00125-7 10.1016/j.cgh.2016.02.006 YJCGH 54634

To appear in: Clinical Gastroenterology and Hepatology Accepted Date: 4 February 2016 Please cite this article as: Meijer B, Bouma G, de Boer NK, Optimize thiopurine therapy in autoimmune hepatitis, Clinical Gastroenterology and Hepatology (2016), doi: 10.1016/j.cgh.2016.02.006. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

ACCEPTED MANUSCRIPT

LETTER TO THE EDITOR Optimize thiopurine therapy in autoimmune hepatitis

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Berrie Meijer1, Gerd Bouma1, Nanne KH de Boer1 University Medical Center, Department of Gastroenterology and Hepatology;

Amsterdam, the Netherlands

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Conflicts of interest

Corresponding Author Berrie Meijer, M.D.

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VU University Medical Center

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The authors have nothing to declare

Department of Gastroenterology and Hepatology

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Room PK 2X 136

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De Boelelaan 1118

1081HZ Amsterdam

E: [email protected] T: +31 20 444 4481 F: +31 20 444 0554

ACCEPTED MANUSCRIPT Dear Sirs, With interest we read the study by Hübener et al. concluding that patients with autoimmune hepatitis (AIH) and prior azathioprine (AZA) intolerance benefit from a

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switch to mercaptopurine (MP) in 75% of the cases, whereas the remaining 25% was intolerant to MP with the same adverse event that led to discontinuation of AZA.1

The role of thiopurines has been extensively researched in patients with inflammatory

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bowel disease (IBD).2 Several strategies to optimize therapy in individual patients have

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been developed, which may be pertinent for AIH treatment as well.3-6

Rechallenge of thiopurine therapy (i.e. re-introduction of MP after AZA) is one of the frequently used approaches, but there are several other methods to optimize thiopurine therapy before switching to another class of immunosuppressive drugs.

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A first approach in optimizing thiopurine therapy is therapeutic drug monitoring (TDM) Hereto, two essential metabolites are measured; 6-methylmercaptopurine (6-MMP), which plays an essential role in the development of adverse effects (especially

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hepatotoxicity), and 6-thioguanine nucleotides (6-TGN), which are the active endmetabolites leading to apoptosis of activated T-lymphocytes. Based on the levels of 6-

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TGN and 6-MMP, thiopurine dosing can be adjusted in individual patients, and this may result in higher efficacy and less adverse events.3 In IBD, efficacy of AZA or MP is associated with 6-TGN concentrations above 235 pmol/8 x 108 in red blood cells (RBC).3 Optimal dose of thiopurines in AIH have been less thoroughly investigated. According to one study, 6-TGN concentrations above 220 pmol/8 x 108 RBC are associated with clinical benefit of therapy.4

ACCEPTED MANUSCRIPT Another approach includes the addition of allopurinol (100mg daily) as a co-drug to low-dose thiopurine therapy (i.e. 25-33% of original thiopurine dose) in patients with a skewed metabolism (defined as 6-MMP/6-TGN ratio above 20). Allopurinol alters the thiopurine metabolism by inhibiting xanthine oxidase (XO) and thiopurine

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methyltransferase (TPMT) function, resulting in a decrease in 6-MMP concentrations and higher levels of 6-TGN.5

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Patients who are intolerant may benefit from split-dose administration of the drug. While this results in a reduction of 6-MMP levels and associated adverse events,

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treatment efficacy is not adversely influenced in IBD patients.6

Finally, patients with intolerance to MP and AZA despite these optimization strategies may benefit from 6-thioguanine (6-TG). This drug leads to direct formation of 6-TGN without producing the harmful side-product 6-MMP. Prospective studies, mainly in IBD

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patients show encouraging results regarding tolerability, safety and efficacy when administered in low doses (±20mg per day).7,8 Preliminary observations have found

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similar results.

In conclusion, for those patients intolerant to AZA several effective optimization

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strategies exist that can be exploited before switching to a different class of immunosuppressive drugs.

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References 1. Hübener S. et al. Clin Gastroenterol and Hepatol 2015;xx:xx-xx.

3. Haines ML. et al. Inflamm Bowel Dis 2011;17:1301-7

5. de Boer YS. Aliment Pharmacol Ther 2013;37:640-6

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4. Dhaliwal HK. et al. Hepatology 2012;56:1401-8

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2. Hindorf U. et al. Aliment Pharmacol Ther 2009;29:654-61

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6. Shih DQ. et al. Aliment Pharmacol Ther 2012;36:449-58

7. de Boer NK. et al. Eur J Gastroenterol Hepatol 2005;17:457-61

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8. van Asseldonk DP. et al. Digest and Liver Dis 2011;43:110-5

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