Skip to main content

Advertisement

SpringerLink
Log in

Therapeutic Efficacy and Adverse Events of Tacrolimus in Patients with Crohn’s Disease: Systematic Review and Meta-Analysis

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

Abstract

Background

Only a few randomized controlled trials (RCTs) and some uncontrolled trials have reported the efficacy and adverse events (AEs) of tacrolimus (Tac) in patients with refractory Crohn’s disease (CD). The aim of this study was to undertake a systematic review and meta-analysis of the therapeutic efficacy and AEs of Tac in patients with CD.

Methods

We investigated studies reporting the therapeutic efficacy of Tac in patients with CD from 1950 until December 2017. Study subjects were categorized into three groups: systemic administration of Tac for patients with luminal CD (Group 1); systemic administration of Tac for patients with perianal CD (Group 2); and topical administration of Tac for patients with localized CD (Group 3). The primary endpoint of this study was the remission rate. Secondary endpoints were partial response rate, factors related to remission, and the incidence of AEs.

Results

The remission rate of Group 1, 2, and 3 was 37.1, 32.0, and 22.7%, respectively. The partial response rate of those was 42.3, 42.9, and 44.3%, respectively. In addition, the incidence of AEs of those was 50.9, 65.5, and 40.0%, respectively. No life-threatening AEs were observed in any study.

Conclusion

This systematic review and meta-analysis demonstrated that Tac therapy was effective for subpopulation of CD patients and that the incidence of AEs was tolerable. Therefore, Tac therapy should be considered an option for patients with CD. However, there have been few well-designed RCTs on this subject and further studies are required.

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

Similar content being viewed by others

References

  1. Waters OR, Lawrance IC. Understanding the use of immunosuppressive agents in the clinical management of IBD. Curr Drug Targets. 2011;12:1364–1371.

    Article  CAS  PubMed  Google Scholar 

  2. Liu J, Farmer JD Jr, Lane WS, Friedman J, Weissman I, Schreiber SL. Calcineurin is a common target of cyclophilin-cyclosporin A and FKBP-FK506 complexes. Cell. 1991;66:807–815.

    Article  CAS  PubMed  Google Scholar 

  3. Stepkowski SM. Molecular targets for existing and novel immunosuppressive drugs. Expert Rev Mol Med. 2000;2:1–23.

    Article  CAS  PubMed  Google Scholar 

  4. Yoshino T, Nakase H, Honzawa Y, et al. Immunosuppressive effects of tacrolimus on macrophages ameliorate experimental colitis. Inflamm Bowel Dis. 2010;16:2022–2033.

    Article  PubMed  Google Scholar 

  5. Fellermann K, Ludwig D, Stahl M, David-Walek T, Stange EF. Steroid-unresponsive acute attacks of inflammatory bowel disease: immunomodulation by tacrolimus (FK506). Am J Gastroenterol. 1998;93:1860–1866.

    Article  CAS  PubMed  Google Scholar 

  6. Ogata H, Matsui T, Nakamura M, et al. A randomised dose finding study of oral tacrolimus (FK506) therapy in refractory ulcerative colitis. Gut. 2006;55:1255–1262.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Yamamoto S, Nakase H, Mikami S, et al. Long-term effect of tacrolimus therapy in patients with refractory ulcerative colitis. Aliment Pharmacol Ther. 2008;28:589–597.

    Article  CAS  PubMed  Google Scholar 

  8. Ogata H, Kato J, Hirai F, et al. Double-blind, placebo-controlled trial of oral tacrolimus (FK506) in the management of hospitalized patients with steroid-refractory ulcerative colitis. Inflamm Bowel Dis. 2012;18:803–808.

    Article  PubMed  Google Scholar 

  9. Schmidt KJ, Herrlinger KR, Emmrich J, et al. Short-term efficacy of tacrolimus in steroid-refractory ulcerative colitis—experience in 130 patients. Aliment Pharmacol Ther. 2013;37:129–136.

    Article  CAS  PubMed  Google Scholar 

  10. Miyoshi J, Matsuoka K, Inoue N, et al. Mucosal healing with oral tacrolimus is associated with favorable medium- and long-term prognosis in steroid-refractory/dependent ulcerative colitis patients. J Crohns Colitis. 2013;7:e609–e614.

    Article  PubMed  Google Scholar 

  11. Ierardi E, Principi M, Francavilla R, et al. Oral tacrolimus long-term therapy in patients with Crohn’s disease and steroid resistance. Aliment Pharmacol Ther. 2001;15:371–377.

    Article  CAS  PubMed  Google Scholar 

  12. Baumgart DC, Wiedenmann B, Dignass AU. Rescue therapy with tacrolimus is effective in patients with severe and refractory inflammatory bowel disease. Aliment Pharmacol Ther. 2003;17:1273–1281.

    Article  CAS  PubMed  Google Scholar 

  13. Baumgart DC, Pintoffl JP, Sturm A, Wiedenmann B, Dignass AU. Tacrolimus is safe and effective in patients with severe steroid-refractory or steroid-dependent inflammatory bowel disease—a long-term follow-up. Am J Gastroenterol. 2006;101:1048–1056.

    Article  CAS  PubMed  Google Scholar 

  14. Ng SC, Arebi N, Kamm MA. Medium-term results of oral tacrolimus treatment in refractory inflammatory bowel disease. Inflamm Bowel Dis. 2007;13:129–134.

    Article  PubMed  Google Scholar 

  15. Benson A, Barrett T, Sparberg M, Buchman AL. Efficacy and safety of tacrolimus in refractory ulcerative colitis and Crohn’s disease: a single-center experience. Inflamm Bowel Dis. 2008;14:7–12.

    Article  PubMed  Google Scholar 

  16. Tamaki H, Nakase H, Matsuura M, et al. The effect of tacrolimus (FK-506) on Japanese patients with refractory Crohn’s disease. J Gastroenterol. 2008;43:774–779.

    Article  CAS  PubMed  Google Scholar 

  17. Gerich ME, Pardi DS, Bruining DH, Kammer PP, Becker BD, Tremaine WT. Tacrolimus salvage in anti-tumor necrosis factor antibody treatment-refractory Crohn’s disease. Inflamm Bowel Dis. 2013;19:1107–1111.

    Article  PubMed  Google Scholar 

  18. Thin LW, Murray K, Lawrance IC. Oral tacrolimus for the treatment of refractory inflammatory bowel disease in the biologic era. Inflamm Bowel Dis. 2013;19:1490–1498.

    Article  PubMed  Google Scholar 

  19. Truffinet O, Martinez-Vinson C, Guerriero E, Hugot JP, Viala J. Tacrolimus exerts only a transient effectiveness in refractory pediatric Crohn disease: a case series. J Pediatr Gastroenterol Nutr. 2017;64:721–725.

    Article  CAS  PubMed  Google Scholar 

  20. Lowry PW, Weaver AL, Tremaine WJ, Sandborn WJ. Combination therapy with oral tacrolimus (FK506) and azathioprine or 6-mercaptopurine for treatment-refractory Crohn’s disease perianal fistulae. Inflamm Bowel Dis. 1999;5:239–245.

    Article  CAS  PubMed  Google Scholar 

  21. Sandborn WJ, Present DH, Isaacs KL, et al. Tacrolimus for the treatment of fistulas in patients with Crohn’s disease: a randomized, placebo-controlled trial. Gastroenterology. 2003;125:380–388.

    Article  CAS  PubMed  Google Scholar 

  22. González-Lama Y, Abreu L, Vera MI, et al. Long-term oral tacrolimus therapy in refractory to infliximab fistulizing Crohn’s disease: a pilot study. Inflamm Bowel Dis. 2005;11:8–15.

    Article  PubMed  Google Scholar 

  23. Casson DH, Eltumi M, Tomlin S, Walker-Smith JA, Murch SH. Topical tacrolimus may be effective in the treatment of oral and perineal Crohn’s disease. Gut. 2000;47:436–440.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Hart AL, Plamondon S, Kamm MA. Topical tacrolimus in the treatment of perianal Crohn’s disease: exploratory randomized controlled trial. Inflamm Bowel Dis. 2007;13:245–253.

    Article  PubMed  Google Scholar 

  25. Rice SA, Woo PN, El-Omar E, Keenan RA, Ormerod AD. Topical tacrolimus 0.1% ointment for treatment of cutaneous Crohn’s disease. BMC Res Notes. 2013;6:19.

  26. McSharry K, Dalzell AM, Leiper K, El-Matary W. Systematic review: the role of tacrolimus in the management of Crohn’s disease. Aliment Pharmacol Ther. 2011;34:1282–1294.

    Article  CAS  PubMed  Google Scholar 

  27. Higgins JP, Altman DG, Gotzsche PC, et al. The Cochrane Collaboration’s tool for assessing risk of bias in randomised trials. BMJ. 2011;343:d5928.

    Article  PubMed  PubMed Central  Google Scholar 

  28. Wells GA, Shea B, O’Connell D, et al. The Newcastle–Ottawa scale (NOS) for assessing the quality of nonrandomised studies in meta-analyses, 2009. http://www.ohri.ca/programs/clinical_epidemiology/oxford.asp. Accessed 1 Nov 2018.

  29. Shamseer L, Moher D, Clarke M, et al. Preferred reporting items for systematic review and meta-analysis protocols (PRISMA-P) 2015: elaboration and explanation. BMJ. 2015;350:g7647.

    Article  PubMed  Google Scholar 

  30. Gomollón F, Dignass A, Annese V, et al. 3rd European evidence-based consensus on the diagnosis and management of Crohn’s disease 2016: part 1: diagnosis and medical management. J Crohns Colitis. 2017;11:3–25.

    Article  PubMed  Google Scholar 

  31. Hida N, Nakamura S, Hahm KB, et al. A questionnaire-based survey on the diagnosis and management of inflammatory bowel disease in East Asian countries in 2012. Digestion. 2014;89:88–103.

    Article  PubMed  Google Scholar 

  32. Ooi CJ, Makharia GK, Hilmi I, et al. Asia-Pacific consensus statements on Crohn’s disease. Part 2: management. J Gastroenterol Hepatol. 2016;31:56–68.

  33. Matsuoka K, Kobayashi T, Ueno F, et al. Evidence-based clinical practice guidelines for inflammatory bowel disease. J Gastroenterol. 2018;53:305–353.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Hesselink DA, Bouamar R, Elens L, van Schaik RH, van Gelder T. The role of pharmacogenetics in the disposition of and response to tacrolimus in solid organ transplantation. Clin Pharmacokinet.. 2014;53:123–139.

    Article  CAS  PubMed  Google Scholar 

  35. Sandborn WJ, Feagan BG, Rutgeerts P, et al. Vedolizumab as induction and maintenance therapy for Crohn’s disease. N Engl J Med. 2013;369:711–721.

    Article  CAS  PubMed  Google Scholar 

  36. Sands BE, Feagan BG, Rutgeerts P, et al. Effects of vedolizumab induction therapy for patients with Crohn’s disease in whom tumor necrosis factor antagonist treatment failed. Gastroenterology. 2014;147:e3.

    Article  CAS  Google Scholar 

  37. Sandborn WJ, Feagan BG, Fedorak RN, et al. A randomized trial of ustekinumab, a human interleukin-12/23 monoclonal antibody, in patients with moderate-to-severe Crohn’s disease. Gastroenterology. 2008;135:1130–1141.

    Article  CAS  PubMed  Google Scholar 

  38. Wils P, Bouhnik Y, Michetti P, et al. Subcutaneous ustekinumab provides clinical benefit for two-thirds of patients with Crohn’s disease refractory to anti-tumor necrosis factor agents. Clin Gastroenterol Hepatol. 2016;14:e1–e2.

    Article  CAS  Google Scholar 

  39. Minami N, Yoshino T, Matsuura M, et al. Tacrolimus or infliximab for severe ulcerative colitis: short-term and long-term data from a retrospective observational study. BMJ Open Gastroenterol. 2015;2:e000021.

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgments

This work was supported in part by Health and Labour Sciences Research Grants for research on intractable diseases from the Ministry of Health, Labour and Welfare of Japan (Investigation and Research for Intractable Inflammatory Bowel Disease) and the Japan Society for the Promotion of Science (JSPS) KAKENHI Grant Number JP17J02428 (to T.I.) and JP18H02799 (to H.N.). The funders of the study had no role in the study design, data collection, data analysis, data interpretation, or writing of the report.

Author information

Authors and Affiliations

  1. Department of Gastroenterology and Hepatology, Sapporo Medical University School of Medicine, Minami 1-jo Nishi 16-chome, Chuo-ku, Sapporo, Hokkaido, 060-8543, Japan

    Tomoya Iida & Hiroshi Nakase

  2. Center for Translational Research, The Institute of Medical Science Hospital, The University of Tokyo, Tokyo, 108-8639, Japan

    Masanori Nojima

Authors
  1. Tomoya Iida
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Masanori Nojima
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Hiroshi Nakase
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

All authors helped to perform the research. Iida T and Nakase H designed the study. Iida T and Nakase H collected the data, and Nojima M analyzed it. Iida T and Nakase H wrote the manuscript. Nakase H directed the research. All authors have approved the final draft of the manuscript.

Corresponding author

Correspondence to Hiroshi Nakase.

Ethics declarations

Conflict of interest

Nakase H has conflict of interest to Tanabe Pharmaceutical Co. Ltd., Mochida Pharmaceutical Co. Ltd., Janssen Pharmaceutical K.K., Hoya Group Pentax Medical, Boehringer Ingelheim GmbH, and Daiichi Sankyo Company, Limited (to HN). All of them had no role in the study design, data collection, data analysis, data interpretation, or writing of the 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 52 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Iida, T., Nojima, M. & Nakase, H. Therapeutic Efficacy and Adverse Events of Tacrolimus in Patients with Crohn’s Disease: Systematic Review and Meta-Analysis. Dig Dis Sci 64, 2945–2954 (2019). https://doi.org/10.1007/s10620-019-05619-1

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10620-019-05619-1

Keywords

Search

Navigation