Shomron Ben-Horin1,2, Gert Van Assche3, Yehuda Chowers4, Ella Fudim1, Bella Ungar1, Orit Picard1, Miri Yavzori1, Uri Kopylov1, Ren Mao2, Min-Hu Chen2, Yael Peled5, Itai Gueta6, Rami Eliakim1, Ronen Loebstein1, Noa Markovits7. 1. Department of Gastroenterology, Sheba Medical Center Tel Hashomer & Sackler School of Medicine, Tel-Aviv University, Israel. 2. Department of Gastroenterology, First Affiliated Hospital, Sun YatSen University, Guangzhou, China. 3. Division of Gastroenterology and Hepatology, University Hospitals Leuven, Belgium. 4. Rambam Health Care Campus & Bruce Rappaport School of Medicine, Technion Institute of Technology, Haifa, Israel. 5. The Olga and Lev Leviev Heart Center, Sheba Medical Center Tel Hashomer & Sackler School of Medicine, Tel-Aviv University, Israel. 6. Institute of Clinical Pharmacology, Sheba Medical Center Tel Hashomer, Tel-Aviv University, Israel. 7. The Institute of Clinical Pharmacology, Sheba Medical Center Tel Hashomer & Sackler School of Medicine, Tel-Aviv University, Israel.
Abstract
BACKGROUND AND AIMS: Discontinuation of thiopurine analogues is common prior to live vaccines, during infection or when de-escalating therapy. Data regarding clearance of active metabolites and immune re-constitution is scant. We aimed to determine drug elimination and immune re-constitution following thiopurine cessation. METHODS: The elimination kinetics of 6-thioguanine nucleotides (6-TGN) were determined in nine inflammatory bowel disease [IBD] patients discontinuing thiopurines. Immune reconstitution was evaluated by toxic shock syndrome toxin 1 [TSST1] or anti-CD3 [OKT3]-induced CD4+ T-cell proliferation, following an initial exposure to TSST1 and 6-mercaptopurine [6MP], separately or combined. RESULTS: All patients discontinuing thiopurines displayed first-order elimination kinetics of 6-TGN, with a median elimination half-life of 6.8 days [interquartile range 5.9-8.4]. Resting CD4+ T-cells exposed to 6MP preserved their response to subsequent polyclonal or Vβ2+-preferential stimulation. By contrast, exposure of TSST1-activated CD4+ T-cells to 6MP inhibited their subsequent Vβ2+clonal response to further stimulation [p = 0.008], whereas overall response to further non-Vβ2-selective stimulation with OKT3 was unaltered [p = 0.9]. CONCLUSIONS: Upon 6MP/azathioprine discontinuation, a 6-TGN elimination half-life of less than 10 days is expected in most patients. Immune reconstitution, however, may take longer for T-cell clones exposed to stimulation during thiopurine treatment. These findings may be useful when considering thiopurine cessation.
BACKGROUND AND AIMS: Discontinuation of thiopurine analogues is common prior to live vaccines, during infection or when de-escalating therapy. Data regarding clearance of active metabolites and immune re-constitution is scant. We aimed to determine drug elimination and immune re-constitution following thiopurine cessation. METHODS: The elimination kinetics of 6-thioguanine nucleotides (6-TGN) were determined in nine inflammatory bowel disease [IBD] patients discontinuing thiopurines. Immune reconstitution was evaluated by toxic shock syndrome toxin 1 [TSST1] or anti-CD3 [OKT3]-induced CD4+ T-cell proliferation, following an initial exposure to TSST1 and 6-mercaptopurine [6MP], separately or combined. RESULTS: All patients discontinuing thiopurines displayed first-order elimination kinetics of 6-TGN, with a median elimination half-life of 6.8 days [interquartile range 5.9-8.4]. Resting CD4+ T-cells exposed to 6MP preserved their response to subsequent polyclonal or Vβ2+-preferential stimulation. By contrast, exposure of TSST1-activated CD4+ T-cells to 6MP inhibited their subsequent Vβ2+clonal response to further stimulation [p = 0.008], whereas overall response to further non-Vβ2-selective stimulation with OKT3 was unaltered [p = 0.9]. CONCLUSIONS: Upon 6MP/azathioprine discontinuation, a 6-TGN elimination half-life of less than 10 days is expected in most patients. Immune reconstitution, however, may take longer for T-cell clones exposed to stimulation during thiopurine treatment. These findings may be useful when considering thiopurine cessation.
Authors: Aysha H Al-Ani; Ralley E Prentice; Clarissa A Rentsch; Doug Johnson; Zaid Ardalan; Neel Heerasing; Mayur Garg; Sian Campbell; Joe Sasadeusz; Finlay A Macrae; Siew C Ng; David T Rubin; Britt Christensen Journal: Aliment Pharmacol Ther Date: 2020-05-26 Impact factor: 9.524