22 Up to one third of rapid thiopurine-S-methyltransferase metabolizers manifest clinical and/or laboratory Azathioprine side effects: A single centre experience

Background According to ECCO-ESPGHAN consensus guidelines, Azathioprine (AZA) can be used for maintenance of remission in paediatric inflammatory bowel disease (IBD). AZA side effects are well documented. Haematological toxicity affects 2–14% of patients and idiosyncratic pancreatitis up to 7% of them, requiring modification of AZA dosage or its cessation. Thiopurine-S-methyltransferase (TPMT) activity should be tested prior to AZA commencement. Slow metabolizers should not be started on AZA and intermediate ones should get a dose reduction. This study evaluates the incidence of AZA side effects in TPMT rapid metabolizers. Methods Retrospective evaluation of prospectively collected data in children tested for TPMT and who received AZA between 3/13 and 10/22. Focusing on the incidence of side effects in rapid metabolizers. Results Ninety children had TPMT tested. Only 1 intermediate a 1 slow metabolizer were identified. All rapid metabolizers were diagnosed with IBD, 62 (70,5%) with Crohn's (CD), 16 (18,2%) with ulcerative colitis (UC), 7 with very early onset IBD (VEO-IBD) and 1 with IBD undifferentiated. Forty-seven were male (53,4%) and 41 female. The median age at diagnosis was 13.5±3,9 years. Of the 88 rapid metabolizers, 82 (93%) received AZA. The remaining 6 had different treatment strategies. Clinical and/or laboratory side effects were documented in 27 cases (32,9%). Haematological toxicity was most frequent affecting 19 participants (23.1%). In 13 cases (68,4%) leukopenia resolved spontaneously, in 4 cases (21%) dose reduction was required, and in 3 cases (15,8%) AZA had to be stopped. Pancreatitis was identified in 6 patients (7,3%). Half of the cases were discovered by laboratory findings and the remainder had a clinical correlate. In 2 cases, laboratory pancreatitis normalized on follow-up examination, in the remaining ones AZA had to be withdrawn. Haematological toxicity manifested on average within 10,9 months since treatment start (0.5–43 months), pancreatitis within 0,54 months with one case manifesting after 79 months of treatment. In this single case, autoimmune pancreatitis is debated. Boys had AZA side effects slightly more frequently (15/27, 55%). CD patients had AZA side effects the most (16/27, 59%). Conclusion Being a rapid TPMT metabolizer should reduce the risk of AZA side effects. However, these data demonstrate a 32,9% occurrence of them, emphasising the importance of clinical and laboratory follow-up in patients on AZA.