Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Meta-Analysis
. 2025 Feb 27;2(2):CD000478.
doi: 10.1002/14651858.CD000478.pub5.

Azathioprine and 6-mercaptopurine for maintenance of remission in ulcerative colitis

Johannes Hasskamp  1 , Christian Meinhardt  2 , Petrease H Patton  3 , Antje Timmer  1
Affiliations
Meta-Analysis

Azathioprine and 6-mercaptopurine for maintenance of remission in ulcerative colitis

Johannes Hasskamp et al. Cochrane Database Syst Rev. .

Abstract

Background: Maintenance of remission is essential in inflammatory bowel disease (IBD) in terms of disease course and long-term prognosis. The thiopurines azathioprine and 6-mercaptopurine have longstanding merit in ulcerative colitis, but more therapeutic options have been developed. This review is an update and extension of a review last published in 2016.

Objectives: To assess the effectiveness and safety of azathioprine and 6-mercaptopurine in monotherapy or combined therapy regimens compared to placebo or active controls for the maintenance of remission in ulcerative colitis.

Search methods: We searched Cochrane Central Register of Controlled Trials (until May 2023), ClinicalTrials.gov (until May 2023), Embase (until August 2022), MEDLINE (until May 2023), and WHO ICTRP (until May 2023). We checked reference lists of the included studies and, if needed, contacted the authors to request more data or information.

Selection criteria: Randomized controlled trials (RCTs) of at least 24 weeks' duration comparing azathioprine or 6-mercaptopurine with placebo or any other medication, or comparing different treatment modalities of azathioprine or 6-mercaptopurine, in persons of any age with quiescent ulcerative colitis were eligible. We only considered studies with mixed IBD populations or with a preceding induction period if separate results on participants with ulcerative colitis in remission were available or could be calculated. The primary outcome was failure to maintain clinical or endoscopic remission (relapse). Secondary outcomes included change in disease activity, quality of life, hospitalization, need for surgery, days off work, adverse events, and withdrawal due to adverse events.

Data collection and analysis: Two authors independently extracted data using standard forms, resolved any disagreements by consensus, and assessed study quality using the Cochrane risk of bias tool (RoB 2). We conducted separate analyses by type of control, calculated pooled risk ratios (RRs) or risk differences (RDs) using the fixed-effect model unless heterogeneity was likely, and assessed the certainty of evidence using the GRADE approach.

Main results: We included 10 studies in the review, including 468 adult participants with ulcerative colitis. The risk of bias across these was low for most outcomes, but we considered some outcomes to have some concerns or high risk of bias due to insufficient information on concealment of allocation and outcome measurement. Based on five placebo-controlled studies, azathioprine or 6-mercaptopurine may reduce the risk of failing to maintain remission. In the thiopurine group, 45% (64/143) of participants failed to maintain remission compared to 67% (96/143) of participants receiving placebo (RR 0.66, 95% confidence interval (CI) 0.54 to 0.82; 5 studies, 286 participants; low-certainty evidence). Three studies reported withdrawals due to adverse events. Among participants on azathioprine, 4% (3/80) withdrew due to adverse events compared to 0% (0/82) of placebo participants (RD 0.04, 95% CI -0.02 to 0.09; 3 studies, 162 participants; low-certainty evidence). The evidence is of low certainty when comparing 6-mercaptopurine to 5-aminosalicylate. Based on one three-armed trial, 27% (3/11) of 6-mercaptopurine participants failed to maintain remission compared to 100% (2/2) of 5-aminosalicylate participants (RR 0.35, 95% CI 0.13 to 0.97; 1 study, 13 participants; low-certainty evidence). This trial also involved an induction phase; we only included the results for participants in remission. The single trial comparing 6-mercaptopurine to 5-aminosalicylate did not report separate data on adverse events and withdrawals due to adverse events for the subgroup with successful induction of remission, so we could not analyze these outcomes for this comparison.

Authors' conclusions: Low-certainty evidence suggests that azathioprine or 6-mercaptopurine therapy may be more effective than placebo for the maintenance of remission in ulcerative colitis. More research is needed to evaluate the value of therapeutic drug monitoring and the effects of various treatment modalities on long-term safety.

Trial registration: ClinicalTrials.gov NCT03101800 NCT02910245 NCT02929706 NCT02579733 NCT00542152 NCT03370601 NCT00984568 NCT00537316 NCT03580876 NCT04304950 NCT03151525.

PubMed Disclaimer

Conflict of interest statement

Johannes Hasskamp: none declared.

Petrease H Patton: none declared.

Christian Meinhardt: none declared.

Antje Timmer: none declared.

Update of

References

References to studies included in this review

Hawthorne 1992 {published data only}
    1. Hawthorne AB, Logan RF, Hawkey CJ, Foster PN, Axon AT, Swarbrick ET, et al. Randomised controlled trial of azathioprine withdrawal in ulcerative colitis. BMJ (Clinical Research Ed.) 1992;305(6844):20-2. - PMC - PubMed
Jewell 1974 {published data only}
    1. Jewell DP, Truelove SC. Azathioprine in ulcerative colitis. Gut 1972;13(4):323. - PubMed
    1. Jewell DP, Truelove SC. Azathioprine in ulcerative colitis: an interim report on a controlled therapeutic trial. British Medical Journal 1972;1(5802):709-12. - PMC - PubMed
    1. Jewell DP, Truelove SC. Azathioprine in ulcerative colitis: final report on controlled therapeutic trial. British Medical Journal 1974;4(5945):627-30. - PMC - PubMed
Kiszka‐Kanowitz 2022 {published data only}
    1. Kiszka-Kanowitz M, Theede K, Thomsen SB, Bjerrum JT, Brynskov J, Gottschalck IB, et al. Low-dose azathioprine and allopurinol versus azathioprine monotherapy in patients with ulcerative colitis (AAUC): An investigator-initiated, open, multicenter, parallel-arm, randomised controlled trial. EClinicalMedicine 2022;45:1-9. [DOI: 10.1016/j] - DOI - PMC - PubMed
Löwenberg 2023 {unpublished data only}
    1. Löwenberg M, Volkers A, Gennep S, Mookhoek A, Montazeri N, Clasquin E, et al. Mercaptopurine for the treatment of ulcerative colitis - a randomised placebo-controlled trial. Manuscript Provided by Author. - PMC - PubMed
Mate‐Jimenez 2000 {published data only}
    1. Hermida C, Cantero J, Moreno-Otero R, Mate-Jimenez J. Methotrexate and 6-mercaptopurine in steroid-dependent inflammatory bowel disease patients: A randomized controlled clinical trial. Gut 1999;45(Suppl V):A132.
    1. Mate-Jimenez J, Hermida C, Cantero-Perona J, Moreno-Otero R. 6-mercaptopurine or methotrexate added to prednisone induces and maintains remission in steroid-dependent inflammatory bowel disease. European Journal of Gastroenterology & Hepatology 2000;12(11):1227-33. - PubMed
Paraskeva 2000 {published data only}
    1. Paraskeva KD, Karagiannis JA. Comparative effectiveness and safety of oral azathioprine and low-dose oral cyclosporin in maintenance of the response in patients with acute steroid-resistant ulcerative colitis. Gut 2000;47(Suppl III A241):P932.
Roblin 2017 {published data only}
    1. Roblin X, Boschetti G, Williet N, Nancey S, Marotte H, Berger A, et al. Azathioprine dose reduction in inflammatory bowel disease patients on combination therapy: an open-label, prospective and randomised clinical trial. Alimentary Pharmacology & Therapeutics 2017;46(2):142-9. - PubMed
Sakuraba 2012 {published data only}
    1. Sakuraba A, Sato T, Morohoshi Y, Matsuoka K, Okamoto S, Inoue N, et al. Intermittent granulocyte and monocyte apheresis versus mercaptopurine for maintaining remission of ulcerative colitis: a pilot study. Therapeutic Apheresis and Dialysis 2012;16(3):213-8. - PubMed
Sood 2000 {published data only}
    1. Sood A, Midha V, Sood N, Kaushal V. Role of azathioprine in severe ulcerative colitis: one-year, placebo-controlled, randomized trial. Indian Journal of Gastroenterology 2000;19(1):14-6. - PubMed
Sood 2002 {published data only}
    1. Sood A, Kaushal V, Midha V, Bhatia KL, Sood N, Malhotra V. The beneficial effect of azathioprine on maintenance of remission in severe ulcerative colitis. Journal of Gastroenterology 2002;37(4):270-4. - PubMed

References to studies excluded from this review

Ardizzone 1997 {published data only}
    1. Ardizzone S, Molteni P, Imbesi V, Bollani S, Bianchi Porro G. Azathioprine in steroid-resistant and steroid-dependent ulcerative colitis. Journal of Clinical Gastroenterology 1997;25(1):330-3. - PubMed
Ardizzone 2006 {published data only}
    1. Ardizzone S, Maconi G, Russo A, Imbesi V, Colombo E, Bianchi Porro G. Randomised controlled trial of azathioprine and 5-aminosalicylic acid for treatment of steroid dependent ulcerative colitis. Gut 2006;55(1):47-53. - PMC - PubMed
Cassinotti 2009 {published data only}
    1. Cassinotti A, Actis GC, Duca P, Massari A, Colombo E, Gai E, et al. Maintenance treatment with azathioprine in ulcerative colitis: outcome and predictive factors after drug withdrawal. American Journal of Gastroenterology 2009;104(11):2760-7. - PubMed
Chang 2020 {published data only}
    1. Chang JY, Park SJ, Jung ES, Jung S, Moon CM, Chun J, et al. Genotype-based treatment with thiopurine reduces incidence of myelosuppression in patients with inflammatory bowel diseases. Clinical Gastroenterology and Hepatology 2020;18(9):2010-8. - PubMed
Chao 2018 {published data only}
    1. Chao K. Pre-genotype NUDT 15 R139C on reducing thiopurine-induced leucopenia in inflammatory bowel disease. https://www.clinicaltrials.gov 2016.
Chebli 2010 {published data only}
    1. Chebli LA, Felga GG, Chaves LD, Pimentel FF, Guerra DM, Gaburri PD, et al. Early onset steroid-dependent ulcerative colitis is a predictor of azathioprine response: a longitudinal 12-month follow-up study. Medical Science Monitor 2010;16(2):PI1-6. - PubMed
Coenen 2015 {published data only}
    1. Broekman M, Coenen MJ, Van Marrewijk CJ, Wanten GJ, Wong DR, Verbeek AL, et al. More dose-dependent side effects with mercaptopurine over azathioprine in IBD treatment due to relatively higher dosing. Inflammatory Bowel Diseases 2017;23(10):1873-81. [DOI: 10.1097/MIB.0000000000001163] - DOI - PMC - PubMed
    1. Broekman M, Coenen MJ, Wanten GJ, Van Marrewijk CJ, Kievit W, Klungel OH, et al. Patients' beliefs about medicine are associated with early thiopurine discontinuation in patients withinflammatory bowel diseases. European Journal of Gastroenterology & Hepatology 2018;30(2):167-173. [DOI: 10.1097/MEG.0000000000001025] - DOI - PMC - PubMed
    1. Broekman M, Wong DR, Wanten GJ, Roelofs HM, Van Marrewijk CJ, Klungel OH, et al. The glutathione transferase Mu null genotype leads to lower6-MMPR levels in patients treated with azathioprine but not with mercaptopurine. Pharmacogenomics Journal 2018;18(1):160-6. [DOI: 10.1038/tpj.2016.87] - DOI - PubMed
    1. Coenen MJ, Jong DJ, Marrewijk CJ, Derijks LJ, Vermeulen SH, Wong DR, et al. Identification of patients with variants in TPMT and dose reduction reduces hematologic events during thiopurine treatment of inflammatory bowel disease. Gastroenterology 2015;149(4):907-17. [DOI: 10.1053/j.gastro.2015.06.002] - DOI - PubMed
    1. Sluiter RL, Van Marrewijk CJ, De Jong DJ, Scheffer H, Guchelaar HJ, Derijks LJ, et al. Genotype-guided thiopurine dosing does not lead to additional costs in patients with inflammatory bowel disease. Journal of Crohn's & Colitis 2019;13(7):838-45. [DOI: 10.1093/ecco-jcc/jjz009] - DOI - PMC - PubMed
Cuffari 2004 {published data only}
    1. Cuffari C, Dassopoulos T, Turnbough L, Thompson RE, Bayless TM. Thiopurine methyltransferase activity influences clinical response to azathioprine in inflammatory bowel disease. Clinical Gastroenterology and Hepatology 2004;2(5):410-7. - PubMed
Domenech 2002 {published data only}
    1. Domènech E, Garcia-Planella E, Bernal I, Rosinach M, Cabré E, Fluvià L, et al. Azathioprine without oral ciclosporin in the long-term maintenance of remission induced by intravenous ciclosporin in severe, steroid-refractory ulcerative colitis. Alimentary Pharmacology & Therapeutics 2002;16(12):2061-5. - PubMed
Fernandez‐Banares 1996 {published data only}
    1. Fernández-Bañares F, Bertrán X, Esteve-Comas M, Cabré E, Menacho M, Humbert P, et al. Azathioprine is useful in maintaining long-term remission induced by intravenous cyclosporine in steroid-refractory severe ulcerative colitis. American Journal of Gastroenterology 1996;91(12):2498-9. - PubMed
Friedman 2015 {published data only}
    1. Friedman AB, Brookes JD, Ward MG, Headon B, Nihill LN, Reynolds J, et al. Adverse events to thiopurines can be overcome and the majority of patients respond to therapy - clinical outcomes from the EATME study. Journal of Gastroenterology and Hepatology 2015;30(Suppl. 3):125-6.
Friedman 2018 {published data only}
    1. Friedman AB, Brown SJ, Bampton P, Barclay ML, Chung A, Macrae FA, et al. Randomised clinical trial: efficacy, safety and dosage of adjunctive allopurinol in azathioprine/mercaptopurine nonresponders (AAA Study). Alimentary Pharmacology & Therapeutics 2018;47:1092-102. - PubMed
Hibi 2003 {published data only}
    1. Hibi T, Naganuma M, Kitahora T, Kinjyo F, Shimoyama T. Low-dose azathioprine is effective and safe for maintenance of remission in patients with ulcerative colitis. Journal of Gastroenterology 2003;38(8):740-6. - PubMed
Holtmann 2006 {published data only}
    1. Holtmann MH, Krummenauer F, Claas C, Kremeyer K, Lorenz D, Rainer O, et al. Long-term effectiveness of azathioprine in IBD beyond 4 years: a European multicenter study in 1176 patients. Digestive Diseases and Sciences 2006;51(9):1516-24. - PubMed
Kim 2018 {published data only}
    1. Kim ES. Azathioprine based on endoscopy after clinical remission in moderate to severe ulcerative colitis (ACE). ClinicalTrials.gov.
Kirk 1982 {published data only}
    1. Kirk AP, Lennard-Jones JE. Controlled trial of azathioprine in chronic ulcerative colitis. British Medical Journal 1982;284(6325):1291-2. - PMC - PubMed
Kiszka‐Kanowitz 2016 {published data only}
    1. Kiszka-Kanowitz M, Theede K, Nielsen AM. Randomized clinical trial: a pilot study comparing efficacy of low-dose azathioprine and allopurinol to azathioprine on clinical outcomes in inflammatory bowel disease. Scandinavian Journal of Gastroenterology 2016;51(12):1-6. [DOI: 10.1080/00365521.2016.1216589] - DOI - PubMed
Laharie 2018 {published data only}2006‐005299‐42
    1. Laharie D, Bourreille A, Branche J, Allez M, Bouhnik Y, Filippi J, et al. Long-term outcome of patients with steroid- refractory acute severe UC treated with ciclosporin or infliximab. Gut 2018;67(2):237-43. - PubMed
Lille 2017 {published data only}
    1. Evaluation of the clinical and immunological impact of two therapeutic strategies in chronic inflammatory diseases (STAMP). ClinicalTrials.gov.
Liu 2017 {published data only}0970‐938X
    1. Liu G, Li DC, Li PP, Li RR, Chen SY. Nanoparticle methotrexate delivery system for the treatment of paediatric patients with inflammatory bowel disease. Biomedical Research (Tokyo, Japan) 2017;28(8):3328-35.
Logan 2015 {published data only}99666810
    1. Logan R. A randomised, open study of aminosalicylate withdrawal in patients with ulcerative colitis in established remission on combination treatment of azathioprine (or 6- mercaptopurine) and an aminosalicylate. WHO ICTRP.
Mantzaris 2004 {published data only}
    1. Mantzaris GJ, Sfakianakis M, Archavlis E, Petraki K, Christidou A, Karagiannidis A, et al. A prospective randomized observer-blind 2-year trial of azathioprine monotherapy versus azathioprine and olsalazine for the maintenance of remission of steroid-dependent ulcerative colitis. American Journal of Gastroenterology 2004;99(6):1122-8. - PubMed
Merck 2013 {published data only}
    1. Conventional step-up versus infliximab monotherapy in patients with ulcerative colitis (P05553) (MUNIX). ClinicalTrials.gov.
Merck 2015 {published data only}
    1. Efficacy & safety of infliximab monotherapy vs combination therapy vs AZA monotherapy in ulcerative colitis (part 1) maintenance vs intermittent therapy for maintaining remission (part 2)(study P04807). ClinicalTrials.gov.
Nakase 2011 {published data only}000006141
    1. Nakase H, Matsuura M. Comparative study of Infliximab monotherapy vs combined therapy with azathiopurine for inducing and maintaining clinical remission in steroid-dependent or -resistant ulcerative colitis. https://www.umin.ac.jp 2011.
Panaccione 2014 {published data only}
    1. Panaccione R, Ghosh S, Middleton S, Márquez JR, Scott BB, Flint L, et al. Combination therapy with infliximab and azathioprine is superior to monotherapy with either agent in ulcerative colitis. Gastroenterology 2014;146(2):392-400. - PubMed
Paoluzi 2002 {published data only}
    1. Paoluzi OA, Pica R, Marcheggiano A, Crispino P, Iacopini F, Iannoni C, et al. Azathioprine or methotrexate in the treatment of patients with steroid-dependent or steroid-resistant ulcerative colitis: results of an open-label study on efficacy and tolerability in inducing and maintaining remission. Alimentary Pharmacology & Therapeutics 2002;16(10):1751-9. [PMID: ] - PubMed
Roblin 2020 {published data only}
    1. Roblin X, Williet N, Boschetti G, Phelip JM, Del Tedesco E, Berger AE, et al. Addition of azathioprine to the switch of anti-TNF inpatients with IBD in clinical relapse with undetectableanti-TNF trough levels and antidrug antibodies: aprospective randomised trial. Gut 2020;69(7):1206-12. - PubMed
Rosenberg 1975 {published data only}
    1. Rosenberg JL, Wall AJ, Levin B, Binder HJ, Kirsner JB. A controlled trial of azathioprine in the management of chronic ulcerative colitis. Gastroenterology 1975;69(1):96-9. - PubMed
Sayani 2005 {published data only}
    1. Sayani FA, Prosser C, Bailey RJ, Jacobs P, Fedorak RN. Thiopurine methyltransferase enzyme activity determination before treatment of inflammatory bowel disease with azathioprine: Effect on cost and adverse events. Canadian Journal of Gastroenterology and Hepatology 2005;19(3):147-51. - PubMed
Sood 2003 {published data only}
    1. Sood A, Midha V, Sood N, Avasthi G. Azathioprine versus sulfasalazine in maintenance of remission in severe ulcerative colitis. Indian Journal of Gastroenterology 2003;22(3):79-81. - PubMed
Spencer 2019 {published data only}
    1. Spencer E, Norris E, Williams C, Dubinsky MC. The impact of thiopurine metabolite monitoring on the durability of thiopurine monotherapy in pediatric IBD. Inflammatory Bowel Diseases 2019;25(1):142-9. - PubMed
Suzuki 2018 {published data only}000030988
    1. Suzuki Y. Open-label, randomized, two-parallel-arm, single center study to designed to evaluate azathioprine versus adalimumab after induction of tacrolimus in refractory ulcerative colitis therapy. https://www.umin.ac.jp 2018.
Swanson 2020 {unpublished data only}
    1. Swanson G. Chronotherapy in inflammatory bowel disease. ClinicalTrials.gov.

References to studies awaiting assessment

Asati 2016 {published data only}
    1. Asati P, Tripathi M, Jain A, Shukla S, Dixit V, Budhiraja S. Comparative response of combination therapy vs. mono therapy in steroid dependent ulcerative colitis patients. In: Inflammatory Bowel Diseases. Vol. 22. 2016:S39.
B‐COM 2020 {published data only}2020‐003420‐16
    1. SPRINT: An open-label, multicenter study to evalate step-up vs top-down treatment algorithms in moderate to severe ulcerative colitis. clinicaltrialsregister.eu.
Bodini 2014 {published data only}
    1. Bodini G, Savarino V, Dulbecco P, Baldissarro I, Savarino E. IBD recurrence after stopping anti-TNF-alpha therapy: a prospective randomized controlled study comparing mesalamine and azathioprine - ad interim results. United European Gastroenterology Journal 2014;2(1S):A214-A215.
Leong 2018 {published data only}12618000812291
    1. Leong R. Vedolizumab blood levels with or without immunomodulators in patients with ulcerative colitis. https://www.anzctr.org.au 2018.
Sahu 2020 {published data only}2020/06/025914
    1. Sahu P. Treatment of patients with ulcerative colitis. http://www.ctri.nic.in 2020.

References to ongoing studies

Ahuja 2017 {published data only}2017/01/007629
    1. Ahuja V. Efficacy and tolerability of Azathioprine and Methotrexate for maintenance of remission in Ulcerative colitis - A Randomized Control Study. http://www.ctri.nic.in 2017.
Ahuja 2020 {published data only}2020/05/025281
    1. Ahuja V. A study to compare the effectiveness and safety of high standard dose with low start up dose strategy of azathioprine in patients with ulcerative colitis. https://www.ctri.nic.in 2020.
Danese 2017 {published data only}
    1. Danese S, Fiorino G. Two therapeutic strategies for the maintenance of remission in patients with ulcerative colitis (SCILLA). https://www.clinicaltrials.gov 2017.
Halfvarsson 2020 {published data only}2019‐002942‐19‐DK
    1. Halfvarsson J. NORDTREAT The Nordic IBD treatment strategy trial - a randomized controlled trial of access to a protein profile. https://www.clinicaltrialsregister.eu 2021.
Irving 2024 {published data only}95420128
    1. Irving P, Rahman A. Subcutaneous CT-P13 monotherapy versus combination with immunomodulation when switching from intravenous infliximab in inflammatory bowel disease - A multicentre, randomised withdrawal trial. WHO ICTRP 2022.
Karling 2016 {published data only}2016‐004112‐35
    1. Karling P. Low-dose azathioprine and allopurinol- versus azathioprine monotherapy in patients with Inflammatory Bowel Disease: An investigator-initiated, open, multicentre, parallel-arm, randomized controlled trial. https://www.clinicaltrialregister.eu 2016. - PMC - PubMed
Vasudevan 2020 {published data only}ACTRN12613001347752
    1. Vasudevan A, Con D, Friedman A, Parsons N, De Cruz P, Kashkooli S, et al. De novo combination allopurinol-thiopurine versus standard thiopurine in inflammatory bowel disease patients escalating to immunomodulators: A randomized controlled trial (DECIDER study). Journal of Gastroenterology and Hepatology 2020;35(Suppl. 1):108-57. [DOI: 10.1111/jgh.15271] - DOI
Zheng 2017 {published data only}
    1. Zheng K, Shen H, Jia J, Lu Y, Zhu L, Zhang L, et al. Traditional Chinese medicine combination therapy for patients with steroid- dependent ulcerative colitis: study protocol for a randomized controlled trial. Trials 2017;18(8):1-6. - PMC - PubMed

Additional references

Annese 2015
    1. Annese V, Beaugerie L, Egan L, Biancone L, Bolling C, Brandts C, et al. European evidence-based consensus: inflammatory bowel disease and malignancies. Journal of Crohn's & Colitis 2015;9(11):945-65. - PubMed
Ansari 2010
    1. Ansari A, Patel N, Sanderson J, O'Donohue J, Duley JA, Florin TH. Low-dose azathioprine or mercaptopurine in combination withallopurinol can bypass many adverse drug reactions in patientswith inflammatory bowel disease. Alimentary Pharmacology & Therapeutics 2010;31(6):640-7. [DOI: 10.1111/j.1365-2036.2009.04221.x] - DOI - PubMed
Axelrad 2016
    1. Axelrad JE, Roy A, Lawlor G, Korelitz B, Lichtiger S. Thiopurines and inflammatory bowel disease: Current evidence and a historical perspective. World Journal of Gastroenteroly 2016;22(46):10103-17. [DOI: 10.3748/wjg.v22.i46.10103] - DOI - PMC - PubMed
Barnhill 2020
    1. Barnhill MS, Steinberg JM, Jennings JJ, Lewis JH. Hepatotoxicty of agents used in the management of inflammatory bowel disease: a 2020 update. Current Gastroenteroly Reports 2020;22(9):47. - PubMed
Bowen 1966
    1. Bowen GE, Irons GV Jr, Rhodes JB, Kirsner JB. Early experiences with azathioprine in ulcerative colitis; a note of caution. Journal of the American Medical Association 1966;195(6):460-4. - PubMed
Bradford 2011
    1. Bradford K, Shih DQ. Optimizing 6-mercaptopurine and azathioprine therapy in the management of inflammatory bowel disease. World Journal of Gastroenteroly 2011;17(37):4166-73. [DOI: 10.3748/wjg.v17.i37.4166] - DOI - PMC - PubMed
Burr 2021
    1. Burr NE, Gracie DJ, Black CJ, Ford AC. Efficacy of biological therapies and small molecules in moderate to severe ulcerative colitis: systematic review and network meta-analysis. Gut 2021;71(10):1976-87. [DOI: 10.1136/gutjnl-2021-326390] - DOI - PubMed
Chaparro 2013
    1. Chaparro M, Ordas I, Cabre E, Garcia-Sanchez V, Bastida G, Penalva M, et al. Safety of thiopurine therapy in inflammatory bowel disease: long-term follow-up study of 3931 patients. Inflammatory Bowel Diseases 2013;19(7):1404-10. - PubMed
Christophorou 2015
    1. Christophorou D, Funakoshi N, Duny Y, Valats JC, Pineton De Chambrun G, et al. Systematic review with meta-analysis: infliximab and immunosuppressant therapy vs. infliximab alone for active ulcerative colitis. Alimentary Pharmacology & Therapeutics 2015;41(7):603-12. [DOI: 10.1111/apt.13102] - DOI - PubMed
Chupin 2020
    1. Chupin A, Perduca V, Meyer A, Bellanger C, Carbonnel F, Dong C. Systematic review with meta-analysis: comparative risk of lymphoma with anti-tumour necrosis factor agents and/or thiopurines in patients with inflammatory bowel disease. Alimentary Pharmacology & Therpeutics 2020;52(8):1289-97. - PubMed
Covidence 2021 [Computer program]
    1. Covidence systematic review software. Melbourne, Australia: Veritas Health Innovation, 2021. [AVAILABLE AT: covidence.org]
de Boer 2018
    1. De Boer NK, Peyrin-Biroulet L, Jharap B, Sanderson JD, Meijer B, Atreya I, et al. Thiopurines in inflammatory bowel disease: new findings and perspectives. Journal of Crohn's & Colitis 2018;12(5):610-20. - PubMed
Du 2020
    1. Du L, Ha C. Epidemiology and pathogenesis of ulcerative colitis. Gastroenteroly Clinics of North America 2020;49(4):643-54. [DOI: 10.1016/j.gtc.2020.07.005] - DOI - PubMed
EMA 2009
    1. European Medicines Agency. EU/3/09/694 - orphan designation for treatment of acute lymphoblastic leukaemiaShare. https://www.ema.europa.eu/en/medicines/human/orphan-designations/eu-3-09... 2009.
FDA 2018
    1. Food and Drug Administration. TABLOID- thioguanine tablet Aspen Global Inc. https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/012429s028lbl.pdf 2018.
FDA 2022
    1. Food and Drug Administration. Ulcerative Colitis: Developing Drugs for Treatment Guidance for Industry. Draft Guidance. https://www.fda.gov/regulatory-information/search-fda-guidance-documents... 2022.
Feuerstein 2019
    1. Feuerstein JD, Moss AC, Farraye FA. Ulcerative colitis. Mayo Clinic Proceedings 2019;94(7):1357-73. [DOI: 10.1016/j.mayocp.2019.01.018] - DOI - PubMed
Feuerstein 2020
    1. Feuerstein JD, Isaacs KL, Schneider Y, Siddique SM, Falck-Ytter, Singh S, et al. AG Clinical Practice Guidelines on the Management of Moderate to Severe Ulcerative Colitis. Gastroenterology 2020;158:1450-1461. - PMC - PubMed
Gisbert 2009
    1. Gisbert JP, Linares PM, McNicholl AG, Maté J, Gomollón F. Meta-analysis: the efficacy of azathioprine and mercaptopurine in ulcerative colitis. Alimentary Pharmacology & Therapeutics 2009;30(2):126-37. [DOI: 10.1111/j.1365-2036.2009.04023.x] - DOI - PubMed
Guan 2019
    1. Guan Q. A comprehensive review and update on the pathogenesis of inflammatory bowel disease. Journal of Immunology Research 2019;2019:1-16. [DOI: 10.1155/2019/7247238] - DOI - PMC - PubMed
Guyatt 2008
    1. Guyatt GH, Oxman AD, Vist GE, Kunz R, Falck-Ytter Y, Alonso-Coello P, et al. GRADE: an emerging consensus on rating quality of evidence and strength of recommendations. British Medical Journal 2008;336(7650):924-6. - PMC - PubMed
Hashash 2021
    1. Hashash JG, Carla GA, Hussein HR, Ala IS. Biologic monotherapy versus combination therapy with immunomodulators in the induction and maintenance of remission of Crohn's disease and ulcerative colitis. Annals of Gastroenterology 2021;34(5):612-24. [DOI: 10.20524/aog.2021.0645] - DOI - PMC - PubMed
Higgins 2003
    1. Higgins JP, Thompson SG, Altman DG. Measuring inconsistency in meta-analysis. British Medical Journal 2003;327(7414):557-60. - PMC - PubMed
Hoentjen 2013
    1. Hoentjen F, Seinen ML, Hanauer SB, Boer NK, Rubin DT, Bouma G, et al. Safety and effectiveness of long-term allopurinol-thiopurine maintenance treatment in inflammatory bowel disease. Inflammatory Bowel Diseases 2013;19(2):363-9. [DOI: 10.1002/ibd.23021] - DOI - PubMed
Jena 2023
    1. Jena A, Neelam PB, Telaprolu H, Mangipudi UK, Dutta U, Sebastian S, et al. Effectiveness and safety of thioguanine as a maintenance therapy of inflammatory bowel disease: Systematic review, meta-analysis and meta-regression. Clinics and Research in Hepatology and Gastroenterology 2023;47(7):102155. [DOI: 10.1016/j.clinre.2023.102155] - DOI - PubMed
Jewell 1974
    1. Jewell DP, Truelove SC. Azathioprine in ulcerative colitis: final report on controlled therapeutic trial. British Medical Journal 1974;4(5945):627-30. - PMC - PubMed
Kaplan 2017
    1. Kaplan GG, Ng SC. Understanding and preventing the global increase of inlammatory bowel disease. Gastroenterology 2017;152(2):313-21. [DOI: 10.1053/j.gastro.2016.10.020] - DOI - PubMed
Kapur 2019
    1. Kapur S, Hanuaer SB. The evolving role of thiopurines in inflammatory bowel disease. Current Treatment Options in Gastroenteroly 2019;17(3):420-33. - PubMed
Khan 2011
    1. Khan KJ, Dubinsky MC, Ford AC, Ullman TA, Talley NJ, Moayyedi P. Efficacy of immunosuppressive therapy for inflammatory bowel disease:a systematic review and meta-analysis. American Journal of Gastroenteroly 2011;106(4):630-42. [DOI: 10.1038/ajg.2011.64] - DOI - PubMed
Kucharzik 2023
    1. Kucharzik T, Dignass A, Atreya R, Bokemeyer B, Esters P, Herrlinger K, et al. Updated S3 Guideline Ulcerative Colitis (Version 6.1) [Aktualisierte S3-Leitlinie Colitis ulcerosa (Version 6.1)]. Deutsche Gesellschaft für Gastroenterologie, Verdauungs- und Stoffwechselkrankheiten 2023. [AVAILABLE FROM: https://www.dgvs.de/wissen/leitlinien/leitlinien-dgvs/colitis-ulcerosa]
Le Berre 2021
    1. Le Berre C, Peyrin-Biroulet L, Sandborn WJ, Colombel JF, Rubin D, Chowers Y, et al. Selecting end points for disease-modification trials in inflammatory bowel disease: the SPIRIT consensus from the IOIBD. Gastroenterology 2021;160(e21):1452-60. [DOI: 10.1053/j.gastro.2020.10.065] - DOI - PubMed
Ma 2018
    1. Ma C, Panaccione R, Fedorak RN, Parker CE, Nguyen TM, Khanna R, et al. Heterogeneity in definitions of endpoints for clinical trials of ulcerative colitis: a systematic review for development of a core outcome set. Clinical Gastroenteroly and Hepatology 2018;16(5):637-47. [DOI: 10.1016/j.cgh.2017.08.025] - DOI - PubMed
Mantzaris 2017
    1. Mantzaris GJ. Thiopurines and methotrexate use in IBD patients in a biologic era. Current Treatment Options in Gastroenteroly 2017;15(1):84-104. [DOI: 10.1007/s11938-017-0128-0] - DOI - PubMed
Ng 2017
    1. Ng SC, Shi HY, Hamidi N, Underwood FE, Tang W, Benchimol EI, et al. Worldwide incidence and prevalence of inflammatory bowel disease in the 21st century: a systematic review of population-based studies. Lancet 2017;390(10114):2769-78. [DOI: 10.1016/s0140-6736(17)32448-0] - DOI - PubMed
Nguyen 2020
    1. Nguyen AL, Sparrow MP. Evolving role of thiopurines in inflammatory bowel disease in the era of biologics and new small molecules. Digestive Diseases and Sciences 2020;66(10):3250-62. [DOI: 10.1007/s10620-020-06662-z] - DOI - PubMed
Panaccione 2014
    1. Panaccione R, Ghosh S, Middleton S, Marquez JR, Scott BB, Flint L, et al. Combination therapy with infliximab and azathioprine is superior to monotherapy with either agent in ulcerative colitis. Gastroenterology 2014;146(2):392-400 e3. - PubMed
Peyrin‐Biroulet 2011
    1. Peyrin-Biroulet L, Khosrotehrani K, Carrat F, Bouvier AM, Chevaux JB, Simon T, et al. Increased risk for nonmelanoma skin cancers in patients who receive thiopurines for inflammatory bowel disease. Gastroenterology 2011;141(5):1621-28 e1-5. - PubMed
Raine 2022
    1. Raine T, Bonovas S, Burisch J, Kucharzik T, Adamina M, Annese V, et al. ECCO guidelines on therapeutics in ulcerative colitis: medical treatment. Journal of Crohn's & Colitis 2022;16(1):2-17. - PubMed
Relling 2019
    1. Relling MV, Schwab M, Whirl-Carillo M, Suarez-Kurtz G, Pui CH, Stein CM, et al. Clinical pharmacogenetics implementation consortium guideline for thiopurine dosing based on TPMT and NUDT15 genotypes: 2018 update. Clinical Pharmacology and Therapeutics 2019;105(5):1095-105. [DOI: 10.1002/cpt.1304] - DOI - PMC - PubMed
RevMan 2023 [Computer program]
    1. Review Manager (RevMan). Version 6.0.0. The Cochrane Collaboration, 2023. Available at https://revman.cochrane.org.
Roblin 2020
    1. Roblin X, Williet N, Boschetti G, Phelip J, Del Tedesco E, Berger A, et al. Addition of azathioprine to the switch of anti-TNF in patients with IBD in clinical relapse with undetectable anti-TNF trough levels and antidrug antibodies: a prospective randomised trial. Gut 2020;69(7):1206-12. - PubMed
Rubin 2019
    1. Rubin DT, Ananthakrishnan AN, Siegel CA, Sauer BG, Long MD. ACG clinical guideline: ulcerative colitis in adults. American Journal of Gastroenteroly 2019;114(3):384-413. - PubMed
Schroeder 1987
    1. Schroeder KW, Tremaine WJ, Ilstrup DM. Coated oral 5-aminsalicylic acid therapy for mildly to moderately active ulcerative colitis. New England Journal of Medicine 1987;317(26):1625-9. [DOI: 10.1056/NEJM198712243172603] - DOI - PubMed
Schünemann 2011
    1. Schünemann HJ, Oxman AD, Vist GE, Higgins JP, Deeks JJ, Glasziou P, et al. Chapter 12: Interpreting results and drawing conclusions. In: Higgins JP, Green S, editors(s). Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 (updated March 2011). The Cochrane Collaboration, 2011. Available from www.cochrane-handbook.org.
Singh 2020
    1. Singh S, Facciorusso A, Dulai PS, Jairath V, Sandborn WJ. Comparative risk of serious infections with biologic and/or immunosuppressive therapy in patients with inflammatory bowel diseases: a systematic review and meta-analysis. Clinical Gastroenterology and Hepatology 2020;18(1):69-81 e3. - PMC - PubMed
Sousa 2021
    1. Sousa P, Ministro P, Armuzzi A, Dignass A, Hoivik ML, Barreiro-de Acosta M, et al. Thiopurines: Use them or lose them? International survey on current and future use of thiopurines in inflammatory bowel disease. Digestive and Liver Disease 2021;53(12):1571-9. - PubMed
Sparrow 2005
    1. Sparrow MP, Hande SA, Friedman S, Lim WC, Reddy SI, Cao D, et al. Allopurinol safely and effectively optimizes tioguanine metabolites in inflammatory bowel disease patients not responding to azathioprine and mercaptopurine. Alimentary Pharmacology & Therapeutics 2005;22(5):441-6. [DOI: 10.1111/j.1365-2036.2005.02583.x] - DOI - PubMed
Sparrow 2007
    1. Sparrow MP, Hande SA, Friedman S, Cao D, Hanauer SB. Effect of allopurinol on clinical outcomes in inflammatory bowel disease nonresponders to azathioprine or 6-mercaptopurine. Clinical Gastroenterology and Hepatology 2007;5(2):209-14. [DOI: 10.1016/j.cgh.2006.11.020] - DOI - PubMed
Sterne 2019
    1. Sterne JA, Savovi? J, Page MJ, Elbers RG, Blencowe NS, Boutron I, et al. RoB 2: a revised tool for assessing risk of bias in randomised trials. British Medical Journal 2019;366:I4898. - PubMed
Teich 2016
    1. Teich N, Mohl W, Bokemeyer B, Bundgens B, Buning J, Miehlke S, et al. Azathioprine-induced acute pancreatitis in patients with inflammatory bowel diseases--A prospective study on incidence and severity. Journal of Crohn's & Colitis 2016;10(1):61-8. - PMC - PubMed
Tiede 2003
    1. Tiede I, Fritz G, Strand S, Poppe D, Dvorsky R, Strand D, et al. CD28-dependent Rac1 activation is the molecular target of azathioprine in primary human CD4+ T lymphocytes. Journal of Clinical Investigation 2003;111(8):1133-45. [DOI: 10.1172/jci200316432] - DOI - PMC - PubMed
Turner 2021
    1. Turner D, Ricciuto A, Lewis A, D'Amico F, Dhaliwal J, Griffiths AM, et al. STRIDE-II: an update on the selecting therapeutic targets in inflammatory bowel disease (STRIDE) initiative of the international organization for the study of IBD (IOIBD): determining therapeutic goals for treat-to-target strategies in IBD. Gastroenterology 2021;160(5):1570-83. - PubMed
Ungaro 2017
    1. Ungaro R, Mehandru S, Allen PB, Peyrin-Biroulet L, Colombel J-F. Ulcerative colitis. Lancet 2017;389(10080):1756-70. - PMC - PubMed
van Gennep 2019
    1. Gennep S, Konte K, Meijer B, Heymans MW, D'Haens GR, Lowenberg M, et al. Systematic review with meta-analysis: risk factors for thiopurine-induced leukopenia in IBD. Alimentary Pharmacology & Therapeutics 2019;50(5):484-506. - PubMed
Wei 2016
    1. Wei SC. Differences in the public medical insurance systems for inflammatory bowel disease treatment in Asian countries. Intestinal Research 2016;14(3):218-23. [DOI: 10.5217/ir.2016.14.3.218] - DOI - PMC - PubMed

References to other published versions of this review

Timmer 2007
    1. Timmer A, McDonald JW, MacDonald JK. Azathioprine and 6-mercaptopurine for maintenance of remission in ulcerative colitis. Cochrane Database of Systematic Reviews 2007, Issue 1. Art. No: CD000478. [DOI: 10.1002/14651858.CD000478.pub2] - DOI - PubMed
Timmer 2012
    1. Timmer A, McDonald JW, Tsoulis DJ, Macdonald JK. Azathioprine and 6-mercaptopurine for maintenance of remission in ulcerative colitis. Cochrane Database of Systematic Reviews 2012, Issue 9. Art. No: CD000478. [DOI: 10.1002/14651858.CD000478.pub3] [PMID: ] - DOI - PubMed
Timmer 2016
    1. Timmer A, Patton PH, Chande N, McDonald JW, MacDonald JK. Azathioprine and 6-mercaptopurine for maintenance of remission in ulcerative colitis. Cochrane Database of Systematic Reviews 2016, Issue 5. Art. No: CD000478. [DOI: 10.1002/14651858.CD000478.pub4] - DOI - PMC - PubMed

MeSH terms

Associated data

LinkOut - more resources