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P154. Tolerability and safety of conventional thiopurines concomitantly with allopurinol in IBD-patients with a skewed thiopurine metabolism

M.L. Seinen, D.P. van Asseldonk, N.K.H. de Boer, C.J.J. Mulder, G. Bouma, A.A. van Bodegraven

VU University Medical Center, Amsterdam, The Netherlands

Background and Aim: Conventional therapeutic thiopurine derivatives, azathioprine (AZA) and 6-mercaptopurine (6-MP), are pivotal in inflammatory bowel disease (IBD) treatment, having a positive balance between efficacy and safety. Costs are relatively low. Unfortunately, up to 60% of IBD-patients discontinue thiopurine therapy, often due to gastrointestinal complaints and hepatoxicity, allegedly related to high 6-MMP levels. Addition of allopurinol to conventional thiopurines reduces 6-MMP levels and thus appears to reduce adverse reactions. The aim of this study is to assess adverse reactions of combination treatment of low-dose thiopurines along with allopurinol, in IBD patients with a prior adverse reaction to monotherapy with full-dose conventional thiopurine.

Material and Methods: IBD-patients with a skewed thiopurine metabolism profile, arbitrarily defined as 6-MMP:6-TGN > 7.5 were eligible. Treatment with full-dose conventional thiopurine was discontinued, mainly due to hepatotoxicity. Hepatotoxicity was defined as ≥ grade 1 of the WHO-toxicity criteria. Subsequently, patients were treated with 100 mg allopurinol and low-dose (= 25–33% of the full-dose) AZA or 6-MP. All patients were stringently monitored at baseline, week 1, 2, 4, 6, 8, 12 (and every 12 weeks further on). Levels of 6-TGN and 6-MMP (during monotherapy) were compared with levels at 4 and 12 weeks (during combination therapy).

Results: Of the 19 included patients (15 female; 16 CD and 3 UC), eleven patients were enrolled because of hepatoxicity and 8 patients due to other adverse events during thiopurine monotherapy. The median age at initiating allopurinol was 41 years (IQR 30–55 years) and the median duration of IBD was 2 years (IQR 1–10 years). At 4 weeks, levels of 6-TGN were increased (from 333 to 649 pmol/8×108 RBC; p < 0.001) whereas 6-MMP-levels were decreased (from 12970 to 1217 pmol/8×108 RBC; p < 0.001). These levels remained stable in the concurrent 8 weeks of combination therapy (p = 0.2 [6-TGN]; p = 0.1 [6-MMP]). Five patients discontinued therapy, all due to adverse events (4 weeks (IQR 1.5–7.0 weeks) median duration of combination treatment). Three of these patients also initiated combination treatment due adverse events. Leukocytopenia occurred in one case after 4 week, who inadvertently continued full-dose AZA. Hepatoxicity did not reoccur in 10 out of 11 patients (91%).

Conclusion: The majority of IBD patients that fail to tolerate full dose conventional thiopurine treatment due to a skewed metabolism, can be safely and effectively treated with a low dose AZA/6MP in conjunction with allopurinol.