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De-escalation of Therapy in Inflammatory Bowel Disease

  • Catarina Frias Gomes
  • Jean-Frédéric Colombel
  • Joana Torres
Inflammatory Bowel Disease (S Hanauer, Section Editor)
Part of the following topical collections:
  1. Topical Collection on Inflammatory Bowel Disease

Abstract

Purpose of Review

Currently, inflammatory bowel disease treatment is based on immunomodulators (IM) and/or biologic as this strategy may prevent the development of irreversible damage. Nevertheless, long-term treatment may be associated with non-negligible side effects and with high costs, and therefore the question on whether therapy can be de-escalated is often posed in clinical practice.

Recent Findings

Recent studies have shown a predictable rate of relapse after stop biologic or IM therapy withdrawal. Overall, around 40–50% of patients will eventually relapse over the following year after drug withdrawal, and the rates will increase over time. Stratification of patients and therapeutic drug monitoring could be promising alternatives to guide therapeutic management.

Summary

We reviewed the current evidence on de-escalation strategy and summarised the recent results on discontinuation and dose reduction. Nowadays, de-escalation strategy is still a case-by-case decision in highly selected patients.

Keywords

Immunomodulators Anti-TNF  Withdrawal Relapse Dose reduction Therapeutic drug monitoring 

Notes

Author Contributions

All authors contributed to the manuscript concept and design. CG reviewed the literature and drafted the manuscript. All authors critically revised the manuscript. All authors have approved the manuscript.

Compliance With Ethical Standards

Conflict of Interest

Joana Torres reports consulting fees from Takeda and AbbVie.

Jean-Frederic Colombel reports grants from Janssen and Janssen and Takeda; is working as a consultant and/or speaker for AbbVie, Amgen, Boehringer-Ingelheim, Ferring Pharmaceuticals, Genentech, Janssen and Janseen, Medimmune, Merck & Co., Nextbiotix, Novartis Pharmaceuticals Corporation, Otsuka Pharmaceutical Development and Commercialization, Inc., Pfizer, Protagonist, Second Genome, Gilead, Seres Therapeutics, Shire, Takeda, and Theradiag; and holds stock options with Intestinal Biotech Development and Genfit.

Catarina Frias Gomes declares no conflict of interest.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

References

Papers of particular interest, published recently, have been highlighted as: • Of importance

  1. 1.
    Torres J, Mehandru S, Colombel JF, Peyrin-Biroulet L. Crohn’s disease. Lancet. 2016;16:31711.Google Scholar
  2. 2.
    Ungaro R, Mehandru S, Allen PB, Peyrin-Biroulet L, Colombel JF. Ulcerative colitis. Lancet. 2017;389(10080):1756–70.CrossRefPubMedGoogle Scholar
  3. 3.
    Gomollón F, Dignass A, Annese V, Tilg H, Van Assche G, Lindsay JO, et al. 3rd European evidence-based consensus on the diagnosis and management of Crohn’s disease 2016: part 1: diagnosis and medical management. J Crohn’s Colitis. 2017;11(1):3–25.CrossRefGoogle Scholar
  4. 4.
    Torres J, Cravo M, Colombel J. Anti-TNF withdrawal in inflammatory bowel disease. GE Port J Gastrenterologia. 2016;23(3):153–61.CrossRefGoogle Scholar
  5. 5.
    van der Valk M, Mangen M, Leenders M, Dijkstra G, van Bodegraven AA, Fidder HH, et al. Healthcare costs of inflammatory bowel disease have shifted from hospitalisation and surgery towards anti-TNFα therapy: results from the COIN study. Gut. 2014;63(1):72–9.CrossRefPubMedGoogle Scholar
  6. 6.
    Siegel, Corey A. et al. International differences in gastroenterologists' perspective on stopping therapy for patients with Crohn's disease. Gastroenterology. 2017;152(5)S371.Google Scholar
  7. 7.
    Siegel C, Thompson K, Walls D, Gollins J, Buisson A, Olympie A, et al. DOP032 Crohn’s disease patients’ perspectives towards de-escalating immunosuppressive therapy: a comparative French and American survey. J Crohns Colitis. 2018;12(Suppl 1):S053.Google Scholar
  8. 8.
    Papamichael K, Vermeire S. Withdrawal of anti-tumour alfa necrosis factor therapy in inflammatory bowel disease. World J Gastroenterol. 2015;21(16):4773–8.CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Louis E, Belaiche J, Reenaers C. Are we giving biologics too much time? When should we stop treatment? World J Gastroenterol. 2008;14(36):5528–31.CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Guidance on the use of infliximab and adalimumab for the treatment of Crohn's disease. NICE technology appraisal guidance 187 (2010).Google Scholar
  11. 11.
    Blackmore L, Harris A. A prospective study of infliximab withdrawal after 12 months of treatment in patients with Crohn’s disease: how will NICE guidance affect patient care? Clin Med (Northfield Il). 2012;12(3):235–8.CrossRefGoogle Scholar
  12. 12.
    Magro F, Gionchetti P, Eliakim R, Ardizzone S, Armuzzi A, Barreiro-de Acosta M, et al. Third European evidence-based consensus on diagnosis and management of ulcerative colitis. Part 1: definitions, diagnosis, extra-intestinal manifestations, pregnancy, cancer surveillance, surgery, and ileo-anal pouch disorders. J Crohn’s Colitis. 2017;11(6):649–70.CrossRefGoogle Scholar
  13. 13.
    Doherty G, Katsanos KH, Burisch J, Allez M, Papamichael K, Stallmach A, et al. European Crohn’s and Colitis Organisation topical review on treatment withdrawal (exit strategies) in inflammatory bowel disease. J Crohn’s Colitis. 2018;12:17–31.CrossRefGoogle Scholar
  14. 14.
    Wenzl HH, Primas C, Novacek G, Teml A, Öfferlbauer-Ernst A, Högenauer C, et al. Withdrawal of long-term maintenance treatment with azathioprine tends to increase relapse risk in patients with Crohn’s disease. Dig Dis Sci. 2015;60(5):1414–23.CrossRefPubMedGoogle Scholar
  15. 15.
    Vilien M, Dahlerup JF, Munck LK, Nørregaard P, Grønbæk K, Fallingborg J. Randomized controlled azathioprine withdrawal after more than two years treatment in Crohn’s disease: increased relapse rate the following year. Aliment Pharmacol Ther. 2004;19(11):1147–52.CrossRefPubMedGoogle Scholar
  16. 16.
    Lémann M, Mary JY, Colombel JF, Duclos B, Soule JC, Lerebours E, et al. A randomized, double-blind, controlled withdrawal trial in Crohn’s disease patients in long-term remission on azathioprine. Gastroenterology. 2005;128(7):1812–8.CrossRefPubMedGoogle Scholar
  17. 17.
    O’Donoghue D, Dawson AM, Powell-Tuck J, Bown R, Lennard-Jones J. Double-blind withdrawal trial of azathioprine as maintenance treatment for Crohn’s disease. Lancet. 1978;2:955–7.CrossRefPubMedGoogle Scholar
  18. 18.
    Boyapati RK, Torres J, Palmela C, Parker, CE, Silverberg OM, Upadhyaya SD et al. Withdrawal of immunosuppressant or biologic therapy for patients with quiescent Crohn's disease. Cochrane Database Syst Rev. 2018;12(5):CD012540.Google Scholar
  19. 19.
    Treton X, Bouhnik Y, Mary JY, Colombel JF, Duclos B, Soule JC, et al. Azathioprine withdrawal in patients with Crohn’s disease maintained on prolonged remission: a high risk of relapse. Clin Gastroenterol Hepatol. 2009;7(1):80–5.CrossRefPubMedGoogle Scholar
  20. 20.
    Farmer RG, Michener WM. Long-term follow-up of patients with Crohn’s disease. Dig Dis Sci. 1979;24(10):752–7.CrossRefPubMedGoogle Scholar
  21. 21.
    Kim PS, Zlatanic J, Korelitz BI, Gleim GW. Optimum duration of treatment with 6-mercaptopurine for Crohn’s disease. Am J Gastroenterol. 1999;94(11):3254–7.CrossRefPubMedGoogle Scholar
  22. 22.
    Treton X, Bouhnik Y, Mary JY, Colombel JF, Duclos B, Soule JC, et al. Azathioprine withdrawal in patients with Crohn’s disease maintained on prolonged remission: a high risk of relapse. Clin Gastroenterol Hepatol. 2009;7(1):80–5.CrossRefPubMedGoogle Scholar
  23. 23.
    • Torres J, Boyapati R, Kennedy N, Louis E, Colombel J, Satsangi J. Systematic review of effects of withdrawal of Immunomodulators or biologic agents from patients with inflammatory bowel disease. Gastroenterology. 2015;149(7):1716–30. This article provides the relapse rates after imunomodulator, combination therapy and biologic withdrawal. Factors associated with relapse and response to re-treatment were also highlighted. CrossRefPubMedGoogle Scholar
  24. 24.
    Hawthorne AB, Logan RF, Hawkey CJ, Foster PN, Axon AT, Swarbrick ET, et al. Randomised controlled trial of azathioprine withdrawal in ulcerative colitis. BMJ. 1992;305(6844):20–2.CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Van Assche G, Magdelaine-Beuzelin C, D’Haens G, Baert F, Noman M, Vermeire S, et al. Withdrawal of immunosuppression in Crohn’s disease treated with scheduled infliximab maintenance: a randomized trial. Gastroenterology. 2008;134(7):1861–8.CrossRefPubMedGoogle Scholar
  26. 26.
    Filippi J, Laharie D, Michiels C, Flamand M, Bouguen G, Nancey S, et al. Efficacy of sustained combination therapy for at least 6 months with thiopurines and infliximab in patients with ulcerative colitis in clinical remission: a retrospective multicenter French experience. J Crohn’s Colitis. 2015;9(3):252–8.CrossRefGoogle Scholar
  27. 27.
    Louis E, Mary JY, Verniermassouille G, Grimaud JC, Bouhnik Y, Laharie D, et al. Maintenance of remission among patients with Crohn’s disease on antimetabolite therapy after infliximab therapy is stopped. Gastroenterology. 2012;142(1):63–70.CrossRefPubMedGoogle Scholar
  28. 28.
    Molnár T, Lakatos PL, Farkas K, Nagy F, Szepes Z, Miheller P, et al. Predictors of relapse in patients with ulcerative colitis in remission after 1 year of biological therapy. Aliment Pharmacol Ther. 2013;37(2):225–33.CrossRefPubMedGoogle Scholar
  29. 29.
    Papamichael K, Vande Casteele N, Gils A, Tops S, Hauenstein S, Singh S, et al. Long-term outcome of patients with Crohn’s disease who discontinued infliximab therapy upon clinical remission. Clin Gastroenterol Hepatol. 2015;13(6):1103–10.CrossRefPubMedGoogle Scholar
  30. 30.
    • Casanova MJ, Chaparro M, García-Sánchez V, Nantes O, Leo E, Rojas-Feria M, et al. Evolution after anti-TNF discontinuation in patients with inflammatory bowel disease: a multicenter long-term follow-up study. Am J Gastroenterol. 2017;112(1):120–31. Casanova et al. found that the incidence rate relapse was 19 and 17% per patient-year in Crohn’s disease and ulcerative colitis, after anti-TNF withdrawal. CrossRefPubMedGoogle Scholar
  31. 31.
    Kennedy NA, Warner B, Johnston EL, Flanders L, Hendy P, Ding NS, et al. Relapse after withdrawal from anti-TNF therapy for inflammatory bowel disease: an observational study, plus systematic review and meta-analysis. Aliment Pharmacol Ther. 2016;43(8):910–23.CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Fiorino G, Cortes PN, Ellul P, Felice C, Karatzas P, Silva M, et al. Discontinuation of infliximab in patients with ulcerative colitis is associated with increased risk of relapse: a multinational retrospective cohort study. Clin Gastroenterol Hepatol. 2016;14(10):1426–32.CrossRefPubMedGoogle Scholar
  33. 33.
    Louis E, Mary J, Vernier-massouille G, Grimaud J, Bouhnik Y, Laharie D, et al. Maintenance of remission among patients with Crohn’s disease on antimetabolite therapy after infliximab therapy is stopped. Gastroenterol Hepatol (N Y). 2012;142:63–70.Google Scholar
  34. 34.
    Brooks AJ, Sebastian S, Cross SS, Robinson K, Warren L, Wright A, et al. Outcome of elective withdrawal of anti-tumour necrosis factor-α therapy in patients with Crohn’s disease in established remission. J Crohn’s Colitis. 2017;11(12):1456–1462.Google Scholar
  35. 35.
    Dai C, Liu WX, Jiang M, Sun MJ. Mucosal healing did not predict sustained clinical remission in patients with IBD after discontinuation of one-year infliximab therapy. PLoS One. 2014;9(10):1–6.Google Scholar
  36. 36.
    Kennedy NA, Warner BJE, et al. DOP035. Anti-TNF withdrawal in IBD: relapse and recapture rates and predictive factors from 160 patients in a pan-UK study. J Crohns Colitis. 9(Suppl 1):S41–2.Google Scholar
  37. 37.
    • Reenaers C, Mary J, Nachury M, Bouhnik Y, Laharie D, Allez M, et al. Outcomes 7 years after infliximab withdrawal for patients with Crohn’s disease in sustained remission. Clin Gastroenterol Hepatol. 2017;S1542–3565(17):31225–9. Reenaers et al. reported the long-term outcomes from the STORI trial. Google Scholar
  38. 38.
    Iimuro M, Nakamura S, Sato T, Ogawa T, Kawai M, Nogami K. Long term outcome of top-down therapy in Crohn’s disease: a single-center experience. Inflamm Bow Dis. 2011;17:S49–50.CrossRefGoogle Scholar
  39. 39.
    Rismo R, Olsen T, Cui G, Paulssen E, Christiansen I, Johnsen I, et al. Normalization of mucosal cytokine gene expression levels predicts long-term remission after discontinuation of anti-TNF therapy in Crohn’s disease. Scand J Gastroenterol. 2013;48:311–9.CrossRefPubMedGoogle Scholar
  40. 40.
    Bortlik M, Duricova D, Machkova N, Hruba V, Lukas M, Mitrova K. Discontinuation of anti-tumor necrosis factor therapy in inflammatory bowel disease patients: a prospective observation. Scand J Gastroenterol. 2015:1–7.Google Scholar
  41. 41.
    Echarri A, Ollero V, Rodriguez JA, Gallego JC, Castro J. P403 predictors of relapse after discontinuing anti-TNF therapy in Crohn’s disease patients on deep remission. J Crohns Colitis. 2013;7:S171.CrossRefGoogle Scholar
  42. 42.
    Oussalah A, Chevaux JB, Fay R, Sandborn WJ, Bigard MA, Peyrin-Biroulet L. Predictors of infliximab failure after azathioprine withdrawal in Crohn’s disease treated with combination therapy. Am J Gastroenterol. 2010;105(5):1142–9.CrossRefPubMedGoogle Scholar
  43. 43.
    Domènech E, Hinojosa J, Nos P, Garcia-Planella E, Cabré E, Bernal I, et al. Clinical evolution of luminal and perianal Crohn’s disease after inducing remission with infliximab: how long should patients be treated? Aliment Pharmacol Ther. 2005;22(11–12):1107–13.CrossRefPubMedGoogle Scholar
  44. 44.
    De Suray N, Salleron J, Vernier-Massouille G, et al. Close monitoring of CRP and fecal calprotectin is able to predict clinical relapse in patients with Crohn’s disease in remission after infliximab withdrawal. A sub-analysis of the STORI study. Gastroenterology. 2012;1:S149.CrossRefGoogle Scholar
  45. 45.
    Molander P, Färkkilä M, Salminen K, Kemppainen H, Blomster T, Koskela R, et al. Outcome after discontinuation of TNFα-blocking therapy in patients with inflammatory bowel disease in deep remission. J Crohns Colitis. 2014;20(6):1.Google Scholar
  46. 46.
    Molnar T, Farkas K, Miheller P, et al. Is the efficacy of successful infliximab induction therapy maintained for one year lasting without retreatment in different behavior types of Crohn’s disease? J Crohns Colitis. 2008;2:322–6.CrossRefPubMedGoogle Scholar
  47. 47.
    Molander P, Färkkilä M, Ristimäki A, Salminen K, Kemppainen H, Blomster T, et al. Does fecal calprotectin predict short-term relapse after stopping TNFα-blocking agents in inflammatory bowel disease patients in deep remission? J Crohns Colitis. 2015;9(1):33–40.PubMedGoogle Scholar
  48. 48.
    Drobne D, Bossuyt P, Breynaert C, Cattaert T, Vande Casteele N, Compernolle G, et al. Withdrawal of immunomodulators after co-treatment does not reduce trough level of infliximab in patients with Crohn’s disease. Clin Gastroenterol Hepatol. 2015;13(3):514–21.CrossRefPubMedGoogle Scholar
  49. 49.
    Ben-Horin S, Chowers Y, Ungar B, Kopylov U, Loebstein R, Weiss B, et al. Undetectable anti-TNF drug levels in patients with long-term remission predict successful drug withdrawal. Aliment Pharmacol Ther. 2015;42(3):356–64.CrossRefPubMedGoogle Scholar
  50. 50.
    Papamichael K, Vande Casteele N, Gils A, Tops S, Hauenstein S, Singh S, et al. Long-term outcome of patients with Crohn’s disease who discontinued infliximab therapy upon clinical remission. Clin Gastroenterol Hepatol. 2015;13(6):1103–10.CrossRefPubMedGoogle Scholar
  51. 51.
    Kennedy NA, Kalla R, Warner B, Gambles CJ, Musy R, Reynolds S, et al. Thiopurine withdrawal during sustained clinical remission in inflammatory bowel disease: relapse and recapture rates, with predictive factors in 237 patients. Aliment Pharmacol Ther. 2014;40(11–12):1313–23.CrossRefPubMedPubMedCentralGoogle Scholar
  52. 52.
    Williet N, Roblin X. Trend towards dose reduction of azathioprine as monotherapy in inflammatory bowel disease patients: what about for combination therapy? Ther Adv Gastroenterol. 2017;10(1):5–10.CrossRefGoogle Scholar
  53. 53.
    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. Aliment Pharmacol Ther. 2017;46(2):142–9.CrossRefPubMedGoogle Scholar
  54. 54.
    Sorrentino D, Paviotti A, Terrosu G, Avellini C, Geraci M, Zarifi D. Low-dose maintenance therapy with infliximab prevents postsurgical recurrence of Crohn’s disease. Clin Gastroenterol Hepatol. 2010;8(7):591–9.CrossRefPubMedGoogle Scholar
  55. 55.
    Vande Casteele N, Compernolle G, Ballet V, Van Assche G, Gils A, Vermeire S, et al. OP11 Individualised infliximab treatment using therapeutic drug monitoring: a prospective controlled Trough level Adapted infliXImab Treatment (TAXIT) trial. J Crohn’s Colitis. 2012;6:S6.CrossRefGoogle Scholar
  56. 56.
    Van Steenbergen S, Bian S, Vermeire S, Van Assche G, Gils A, Ferrante M. Dose de-escalation to adalimumab 40 mg every 3 weeks in patients with Crohn’s disease—a nested case-control study. Aliment Pharmacol Ther. 2017;45(7):923–32.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  • Catarina Frias Gomes
    • 1
  • Jean-Frédéric Colombel
    • 2
    • 3
  • Joana Torres
    • 1
  1. 1.Surgical Department, Gastroenterology DivisionHospital Beatriz ÂngeloLouresPortugal
  2. 2.Medicine Department, Gastroenterology DivisionIcahn School of Medicine at Mount SinaiNew YorkUSA
  3. 3.The Henry D. Janowitz Division of GastroenterologyIcahn School of Medicine at Mount SinaiNew YorkUSA

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