TY - JOUR
T1 - Pharmacokinetics and immune reconstitution following discontinuation of thiopurine analogues
T2 - Implications for drug withdrawal strategies
AU - Ben-Horin, Shomron
AU - Van Assche, Gert
AU - Chowers, Yehuda
AU - Fudim, Ella
AU - Ungar, Bella
AU - Picard, Orit
AU - Yavzori, Miri
AU - Kopylov, Uri
AU - Mao, Ren
AU - Chen, Min Hu
AU - Peled, Yael
AU - Gueta, Itai
AU - Eliakim, Rami
AU - Loebstein, Ronen
AU - Markovits, Noa
N1 - Publisher Copyright:
Copyright © 2018 European Crohn's and Colitis Organisation (ECCO). Published by Oxford University Press. All rights reserved.
PY - 2018/11/28
Y1 - 2018/11/28
N2 - 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 toTSST1 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.
AB - 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 toTSST1 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.
KW - Immune reconstitution
KW - Inflammatory bowel disease
KW - Thiopurine analogues
UR - http://www.scopus.com/inward/record.url?scp=85057554096&partnerID=8YFLogxK
U2 - 10.1093/ecco-jcc/jjy122
DO - 10.1093/ecco-jcc/jjy122
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AN - SCOPUS:85057554096
SN - 1873-9946
VL - 12
SP - 1410
EP - 1417
JO - Journal of Crohn's and Colitis
JF - Journal of Crohn's and Colitis
IS - 12
ER -