Skip to main content
SpringerLink
Log in

Poor Drug Sustainability in Inflammatory Bowel Disease Patients in Clinical Remission on Thiopurine Monotherapy

  • Original Article
  • Published:
Digestive Diseases and Sciences Aims and scope Submit manuscript

Abstract

Background

Immunomodulator monotherapy is an important component in the treatment of inflammatory bowel disease (IBD). However, there is conflicting literature about thiopurines maintaining long-term remission in patients with active IBD.

Aim

To determine the durable clinical remission rate in adults with Crohn’s disease (CD) or ulcerative colitis (UC) on thiopurine monotherapy over 5 years.

Methods

We performed a retrospective analysis of adult patients identified at McGill University Health Centre from 2009 to 2012. We included IBD patients who initiated thiopurine monotherapy and were in remission for at least 3 months (Harvey–Bradshaw Index (HBI) < 5 points for CD and partial Mayo Score (pMS) < 2 points in UC). The primary endpoint was sustained clinical remission on thiopurines during a 5-year follow-up. This included patients who had not relapsed or discontinued the drug due to side effects. The secondary endpoint was clinical relapse over the follow-up period, which was defined as HBI > 5 in CD and pMS > 2 in UC.

Results

There were 148 patients included in the study (100 CD; 48 UC). At 5 years, 23% (34/148) patients remained in clinical remission on thiopurine monotherapy (25 CD and 9 UC patients). Thirty-three percent (33/100) of CD and 46% (22/48) of UC patients relapsed while on thiopurines. There was no difference in relapse rates between CD and UC patients. Eighty-four percent (42/50) of patients with CD with side effects and all UC (17/17) patients who experienced side effects discontinued the drug.

Conclusion

This analysis demonstrates that there is poor sustainability of clinical remission in IBD patients on thiopurine monotherapy given that a high proportion of patients discontinue thiopurines due to either relapse or side effects.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

Abbreviations

IBD:

Inflammatory bowel disease

UC:

Ulcerative colitis

CD:

Crohn’s disease

HBI:

Harvey–Bradshaw Index

pMS:

Partial Mayo Score

AZA:

Azathioprine

6-MP:

Mercaptopurine

References

  1. Fumery M, Singh S, Dulai PS, et al. Natural history of adult ulcerative colitis in population-based cohorts: a systematic review. Clin Gastroenterol Hepatol. 2018;16:343–356.e3.

    Article  Google Scholar 

  2. Burisch J, Kiudelis G, Kupcinskas L, et al. Natural disease course of Crohn’s disease during the first 5 years after diagnosis in a European population-based inception cohort: an Epi-IBD study. Gut. 2019;68:423–433. https://doi.org/10.1136/gutjnl-2017-315568.

    Article  PubMed  Google Scholar 

  3. Sahasranaman S, Howard D, Roy S. Clinical pharmacology and pharmacogenetics of thiopurines. Eur J Clin Pharmacol. 2008;64:753–767.

    Article  CAS  Google Scholar 

  4. Candy S, Wright J, Gerber M, et al. A controlled double blind study of azathioprine in the management of Crohn’s disease. Gut. 1995;37:674–678.

    Article  CAS  Google Scholar 

  5. Markowitz J, Grancher K, Kohn N, et al. A multicenter trial of 6-mercaptopurine and prednisone in children with newly diagnosed Crohn’s disease. Gastroenterology. 2000;119:895–902.

    Article  CAS  Google Scholar 

  6. O’Donoghue DP, Dawson AM, Powell-Tuck J, et al. Double-blind withdrawal trial of azathioprine as maintenance treatment for crohn’s disease. Lancet. 1978;312:955–957.

    Article  Google Scholar 

  7. Pearson DC, May GR, Fick G, et al. Azathioprine for maintaining remission of Crohn’s disease. Cochrane Database Syst Rev. 2000;CD000067. https://doi.org/10.1002/14651858.CD000067.

  8. Pearson DC, May GR, Fick GH, et al. Azathioprine and 6-mercaptopurine in Crohn disease. A meta-analysis. Ann Intern Med. 1995;123:132–142.

    Article  CAS  Google Scholar 

  9. Present DH, Korelitz BI, Wisch N, et al. Treatment of Crohn’s disease with 6-mercaptopurine. A long-term, randomized, double-blind study. N Engl J Med. 1980;302:981–987. https://doi.org/10.1056/NEJM198005013021801.

    Article  CAS  Google Scholar 

  10. Timmer A, McDonald JWD, Tsoulis DJ, et al. Azathioprine and 6-mercaptopurine for maintenance of remission in ulcerative colitis. Cochrane Database Syst Rev. 2012;CD000478. https://doi.org/10.1002/14651858.CD000478.pub3.

  11. Panes J, Lopez-Sanroman A, Bermejo F, et al. Early azathioprine therapy is no more effective than placebo for newly diagnosed Crohn’s disease. Gastroenterology. 2013;145:766-74.e1.

    Article  Google Scholar 

  12. Cosnes J, Bourrier A, Laharie D, et al. Early administration of azathioprine vs conventional management of Crohn’s disease: a randomized controlled trial. Gastroenterology. 2013;145:758–765.e2. https://doi.org/10.1053/j.gastro.2013.04.048.

    Article  CAS  PubMed  Google Scholar 

  13. Chaparro M, Ordas I, Cabre E, et al. Safety of thiopurine therapy in inflammatory bowel disease: long-term follow-up study of 3931 patients. Inflamm Bowel Dis. 2013;19:1404–1410.

    Article  Google Scholar 

  14. Fraser AG, Orchard TR, Jewell DP. The efficacy of azathioprine for the treatment of inflammatory bowel disease: a 30 year review. Gut. 2002;50:485–489.

    Article  CAS  Google Scholar 

  15. Anstey A, Lennard L, Mayou SC, et al. Pancytopenia related to azathioprine—an enzyme deficiency caused by a common genetic polymorphism: a review. J R Soc Med. 1992;85:752–756.

    CAS  PubMed  PubMed Central  Google Scholar 

  16. Connell WR, Kamm MA, Ritchie JK, et al. Bone marrow toxicity caused by azathioprine in inflammatory bowel disease: 27 years of experience. Gut. 1993;34:1081–1085.

    Article  CAS  Google Scholar 

  17. Gisbert JP, Gonzalez-Lama Y, Mate J. Thiopurine-induced liver injury in patients with inflammatory bowel disease: a systematic review. Am J Gastroenterol. 2007;102:1518–1527.

    Article  CAS  Google Scholar 

  18. D’Haens G, Baert F, van Assche G, et al. Early combined immunosuppression or conventional management in patients with newly diagnosed Crohn’s disease: an open randomised trial. Lancet. 2008;371:660–667.

    Article  Google Scholar 

  19. Lemann M, Mary JY, Colombel JF, et al. A randomized, double-blind, controlled withdrawal trial in Crohn’s disease patients in long-term remission on azathioprine. Gastroenterology. 2005;128:1812–1818.

    Article  CAS  Google Scholar 

  20. Mate-Jimenez J, Hermida C, Cantero-Perona J, et al. 6-mercaptopurine or methotrexate added to prednisone induces and maintains remission in steroid-dependent inflammatory bowel disease. Eur J Gastroenterol Hepatol. 2000;12:1227–1233.

    Article  CAS  Google Scholar 

  21. Rosenberg JL, Levin B, Wall AJ, et al. A controlled trial of azathioprine in Crohn’s disease. Am J Dig Dis. 1975;20:721–726. https://doi.org/10.1159/000443127.

    Article  CAS  PubMed  Google Scholar 

  22. Summers RW, Switz DM, Sessions JT Jr, et al. National cooperative Crohn’s disease study: results of drug treatment. Gastroenterology. 1979;77:847–869.

    Article  CAS  Google Scholar 

  23. Willoughby JM, Beckett J, Kumar PJ, et al. Controlled trial of azathioprine in Crohn’s disease. Lancet. 1971;2:944–947.

    Article  CAS  Google Scholar 

  24. Jewell DP, Truelove SC. Azathioprine in ulcerative colitis: final report on controlled therapeutic trial. Br Med J. 1974;4:627–630.

    Article  CAS  Google Scholar 

  25. van Gennep S, de Boer NK, D’Haens GR, et al. Thiopurine treatment in ulcerative colitis: a critical review of the evidence for current clinical practice. Inflamm Bowel Dis. 2017;24:67–77.

    Article  Google Scholar 

  26. Gearry RB, Barclay ML, Burt MJ, et al. Thiopurine drug adverse effects in a population of New Zealand patients with inflammatory bowel disease. Pharmacoepidemiol Drug Saf. 2004;13:563–567.

    Article  CAS  Google Scholar 

  27. Chande N, Patton PH, Tsoulis DJ, et al. Azathioprine or 6-mercaptopurine for maintenance of remission in Crohn’s disease. Cochrane Database Syst Rev. 2015;CD000067. https://doi.org/10.1002/14651858.CD000067.pub3.

  28. Colombel JF, Sandborn WJ, Reinisch W, et al. Infliximab, azathioprine, or combination therapy for Crohn’s disease. N Engl J Med. 2010;362:1383–1395. https://doi.org/10.1056/NEJMoa0904492.

    Article  CAS  PubMed  Google Scholar 

  29. Hazlewood GS, Rezaie A, Borman M, et al. Comparative effectiveness of immunosuppressants and biologics for inducing and maintaining remission in Crohn’s disease: a network meta-analysis. Gastroenterology. 2015;148:344–54.e5.

    Article  CAS  Google Scholar 

  30. Shah ED, Siegel CA, Chong K, et al. Evaluating study withdrawal among biologics and immunomodulators in treating ulcerative colitis: a meta-analysis of controlled clinical trials. Inflamm Bowel Dis. 2016;22:933–939.

    Article  Google Scholar 

  31. Suarez Ferrer C, Gonzalez-Lama Y, Gonzalez-Partida I, et al. Usefulness of thiopurine monotherapy for Crohn’s disease in the era of biologics: a long-term single-center experience. Dig Dis Sci. 2019;64:875–879. https://doi.org/10.1007/s10620-018-5381-0.

    Article  CAS  PubMed  Google Scholar 

  32. Moran GW, Dubeau M-F, Kaplan GG, et al. Clinical predictors of thiopurine-related adverse events in Crohn’s disease. World J Gastroenterol. 2015;21:7795–7804.

    Article  CAS  Google Scholar 

  33. Qiu Y, Mao R, Zhang SH, et al. Safety profile of thiopurines in Crohn disease: analysis of 893 patient-years follow-up in a southern China Cohort. Medicine (Baltimore). 2015;94:e1513.

    Article  CAS  Google Scholar 

Download references

Funding

None.

Author information

Authors and Affiliations

  1. Department of Internal Medicine, McGill University Health Center, Rm D05.5840, 1001 Décarie Boulevard, Montreal, QC, H4A 3J1, Canada

    Bhairavi Balram & Joshua Lubov

  2. Division of Gastroenterology, Montreal General Hospital, McGill University Health Center, 1650 Cedar Avenue, C7-200, Montreal, QC, H3G 1A4, Canada

    Waqqas Afif, Alain Bitton, Gary Wild, Peter L. Lakatos & Talat Bessissow

  3. Centre Hospitalier Universitaire Sainte-Justine, Unité de Pharmacologie Clinique, Montreal, QC, H3T 1C5, Canada

    Yves Theoret

  4. First Department of Medicine, Semmelweis University, Budapest, Hungary

    Peter L. Lakatos

Authors
  1. Bhairavi Balram
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Joshua Lubov
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Yves Theoret
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Waqqas Afif
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Alain Bitton
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Gary Wild
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Peter L. Lakatos
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Talat Bessissow
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Bhairavi Balram.

Ethics declarations

Conflict of interest

T. Bessissow has received honoraria and acted as a consultant for Janssen, AbbVie, Takeda, and Pfizer and acted as speaker for Janssen, AbbVie, Takeda, Ferring, Actavis, PendoPharm, and Shire. T. Bessissow has served as a speaker, a consultant, and an advisory board member for Janssen, AbbVie, Takeda, Pfizer, Ferring, PendoPharm, Shire and has received research funding from AbbVie and Janssen. PL Lakatos has been a speaker and/or advisory board member: AbbVie, EGIS, Falk Pharma, GmbH, Ferring, Genetech, Jansen, Kyowa, Hakko Kirin Pharma, Mitsubishi Tanabe Pharma Corporation, MSD, Otsuka Pharma, Pharmacosmos, Pfizer, Roche, Shire, and Takeda and has received unrestricted grants: AbbVie, MSD, and Pfizer. Waqqas Afif has served as a speaker and/or advisory board for AbbVie, Janssen, Takeda, Merck, Pfizer, Ferring, Shire, and received research grants from AbbVie, Theradiag, and Prometheus. Alain Bitton has received honorarium for participation in advisory boards from Allergan. Alain Bitton is a Consultant, Advisory Board: AbbVie, Janssen, Shire, Warner Chilcott, Takeda, and Speaker: AbbVie, Janssen, Shire, Warner Chilcott, Aptalis. GW has been a speaker and/or advisory board member for AbbVie, Janssen, Pfizer, Shire, and Takeda. B. Balram, Y. Theoret, and J. Lubov have no conflicts of interest to report.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Electronic Supplementary Material

Below is the link to the electronic supplementary material.

Supplementary material 1 (DOCX 13 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Balram, B., Lubov, J., Theoret, Y. et al. Poor Drug Sustainability in Inflammatory Bowel Disease Patients in Clinical Remission on Thiopurine Monotherapy. Dig Dis Sci 66, 1650–1657 (2021). https://doi.org/10.1007/s10620-020-06427-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10620-020-06427-8

Keywords

Search

Navigation