The impact of thiopurine-S-methyltransferase genotype on the adverse drug reactions to azathioprine in patients with inflammatory bowel diseases

Abstract

Background and aims: The thiopurine drugs, azathioprine (AZA) and 6-mercaptopurine, are established in the treatment of infl ammatory bowel diseases (IBD). Polymorphisms in thiopurine S-methyltransferase (TPMT) gene have been associated with adverse drug reactions (ADRs) to AZA. Methods: The aim of this study was to evaluate TPMT polymorphisms and AZA-related toxicity in a Slovak cohort of 220 IBD patients treated with AZA. In every patient, the dose and duration of AZA therapy, concomitant 5-aminosalicylate (5-ASA) medication, frequency, type, time to onset, dose of ADR and concomitant 5-ASA at the onset of ADR were recorded. Each patient was also genotyped for the presence of variant TPMT alleles (*2,*3A,*3B,*3C). Frequency, type and circumstances of ADRs were compared according to TPMT status. Results: Of the 220 patients, 205 (93.2 %) were wild-type (TPMT*1/*1), one (0.5%) carried a TPMT*1/*3C allele, 13 (5.9 %) carried TPMT *1/*3A allele and one was homozygous for TMPT *3A allele. No TPMT *2 mutation was found. The incidence of adverse drug reactions was 62/205 (30.2 %) in the wild-type group as compared to 13/15 (86.7 %) in the TPMT mutation group, p=2.10-5. Leukopenia (WBC< 3.0*10^9/L) occurred in 21/205 (10.2 %) patients with wild type TPMT versus 11/15 (73.3 %) patients with TPMT mutations, p=0.000001. There was no signifi cant difference between TMPT groups in gastrointestinal or other ADRs. No impact of 5-ASA on the incidence and severity of AZA adverse drug reactions was observed. Conclusion: The incidence of leukopenia in TPMT mutant patients was signifi cantly higher and more severe as compared to TPMT wild type patients. We observed no impact of concomitant 5-ASA therapy on AZA induced toxicity (Tab. 4, Fig. 2, Ref. 37).

Enrichment of Genetic Variants in the Glucocorticoid Receptor Signalling Pathway in Autoimmune Hepatitis with Failure of Standard Treatment

“…Azathioprine intolerance was not related to the presence of TPMT mutations, and hence, it was probably ascribable to high drug exposure. Similar observations have been done in systemic lupus erythematosus and inflammatory bowel diseases .…”

Systematic review with meta‐analysis: risk factors for thiopurine‐induced leukopenia in IBD

“…In contrast, a randomised controlled trial comparing AZA monotherapy with AZA therapy combined with olsalazine showed significant lower mean WBC counts in the combination treatment group (4.65 ± 0.4 vs 4.05 ± 0.3) . Eight studies found no significant effect of concomitant 5‐ASA use on the development of TIL . In contrast, a threefold higher risk for leukopenia was found for concomitant 5‐ASA use after correction for baseline WBC count in multivariable regression analysis and a significant higher leukopenia rate in the concomitant 5‐ASA group compared to patients without concomitant 5‐ASA use were found in two Chinese cohort studies .…”

“…The association of TPMT genotype polymorphisms and TIL was assessed in 31 studies, the association of TPMT enzymatic activity and TIL in 12 (Table S1). …”

“…Detailed information of 19 studies evaluating the effect of concomitant treatment agents on the development of TIL can be found in Table S4 …”

“…However, despite this altered metabolism with increased 6‐TGN levels, no significant change in WBC count was observed . One might conclude that co‐treatment with 5‐ASA has no clinical significant effect on the development of leukopenia . Allopurinol is co‐administered in addition to low dose thiopurine treatment in IBD patients with a skewed metabolism (high 6‐MMP levels and low 6‐TGN levels), aiming for inhibition of XDH (and potentially TPMT), which in turn leads to a preferential 6‐TGN metabolisation and reduced 6‐MMP levels (Figure ) .…”