P178 Association between eleven thiopurine metabolites and mucosal healing in patients with Crohn's disease
S. Reinisch*1, 2, U. Hofmann3, C. Lichtenberger1, S. Winter3, A. Eser1, A. Teml1, 3, C. Dejaco1, G. Novacek1, H. Vogelsang1, E. Schaeffeler3, M. Schwab4, W. Reinisch1, 2
1Medical University of Vienna, Internal Medicine III, Vienna, Austria, 2McMaster University, Gastroenterology, Hamilton, Canada, 3Dr Margarete Fischer-Bosch Institute of Clinical Pharmacology, Clinical Pharmacology, Stuttgart, Germany, 4University Hospital, Clinical Pharmacology, Tübingen, Germany
Thiopurine-related drug response in treatment of patients with Crohn's disease (CD) is still incompletely understood. Thus, therapeutic monitoring of thioguanine nucleotides (TGN) and methylthioinosine derivatives (MMPR) has been suggested to improve thiopurine therapy, however with limited success. The comprehensive assessment of thiopurine metabolite pattern instead of determination of total TGN and MMPR levels has been suggested to be beneficial for prediction of thiopurine response.
Patients with CD on maintenance treatment with azathioprine (AZA) and a stable dose for at least 4 weeks were eligible. We established a novel highly sensitive liquid chromatography-tandem mass spectrometry method for simultaneous quantitation of eleven thiopurine metabolites including mono-, di-, and triphosphates of thioguanosine (TGMP, TGDP, TGTP), methylthioinosine (meTIMP, meTIDP, meTITP), methylthioguanosine (meTGMP, meTGDP, meTGTP), and thioinosine (TIMP, TIDP, TITP). Furthermore, thiopurine S-methyltransferase (TPMT) activity in red blood cell concentrations (RBC) was determined. Blood collection was performed on day of the ileocolonoscopy. Mucosal healing was defined as the absence of any ulcerated lesions.
In total 101 patients (f/m=54/47, median age: 25 years) were included. The median AZA dosage was 2.12 mg/kg/d (range: 0.28-3.13 mg/kg/d) which was stable for median 26 months (range: 1-111 months) before blood collection. Patients without achievement of mucosal healing (non-responder) showed significantly higher concentrations of meTIDP (p= 0.04) and meTITP (p=0.02) in RBC. After stratification of patients in normal and intermediate metabolizers for TPMT the association between non-response and higher RBC concentrations of meTIDP (p= 0.008) and meTITP (p=0.004) held true in patients with normal TPMT activities (n=91). No significant differences between responders and non-responders were found for the isolated thioguanosine phosphate levels (TGMP, TGDP, TGTP).
There was no significant correlation of isolated thioguanosine phosphate levels (e.g. TGDP, TGTP) and mucosal healing. Higher concentrations of methylthioinosine levels in non-responders support the impact of the TPMT metabolizer phenotype regarding thiopurine response.