PTH-093 Increasing azathioprine dose with metabolite monitoring in AIH

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Abstract

Introduction

Initial treatment of AIH, involves prednisolone plus azathioprine (AZA) 1 mg/kg/day. Blood levels of active AZA 6-thioguanine (6-TGN) and 6-methyl-mercaptupurine (6-MMP) metabolites are determined by activity of thiopurine methyl transferase (TPMT). High metabolite levels are associated with efficacy (6-TGN) and toxicity (6-TGN and 6-MMP) (Dhaliwal Hepatology, 2012. 56:1401–8).

Aim

To see if AZA metabolite monitoring could optimise AZA dose and improve histological remission rates.

Methods

In 26 patients with AIH (1999 International Group Criteria, presenting 2013–2016), we aimed to increase AZA dose from 1 to 2 mg/kg after 3 months, with metabolite monitoring, to achieve 6-TGN levels between 250–500 pmol/8 × 108 RBCs and 6-MMP levels<5000 pmol/8×108 RBCs. 13 patients underwent repeat liver biopsy after two years treatment.

Results

5 patients did not achieve a dose of 2 mg/kg/day AZA (raised 6-TGN (n=3), nausea (n=1), metabolites in target range on lower dose (n=1)). In 15 of the other 21 patients, AZA was initially increased to 2 mg/kg/day but had been reduced by the end of follow-up, with corresponding rises and then falls in 6-TGN and 6-MMP land in mean cell volume (MCV) (table 1). Reasons for dose reduction included: metabolite levels above target range (6-MMP: n=4, 6-TGN: n=4, both: n=1), nausea (n=3), malignancy (n=1) and leucopenia (n=1). In 4 patients who developed nausea on AZA, 6-TGN levels were (601, 4 34 528 and 434). No patients developed hepatotoxicity.

Results

Serum ALT normalised in 23 and 25 patients within 6 and 12 months respectively. However, only 7 out of 13 patients who had follow up biopsy achieved histological remission (similar to our previous experience (Dhaliwal, Am J Gastroenterol, 2015; 110 993–99)). 6-TGN levels did not differ between those who did and did not attain remission (median 345 v 275; p=0.295).

Conclusions

Increasing AZA dose from 1 to 2 mg/kg/day after 3 months, with metabolite monitoring was (a) limited by high metabolite levels and side effects and (b) did not Result in higher rates of remission, compared to standard therapy.

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