Abstract
Background and Aim
Many patients with quiescent Crohn’s disease are maintained on long-term treatment with azathioprine (AZA), but controlled data are limited. We aimed to evaluate the efficacy of AZA therapy for more than 4 years to maintain clinical remission.
Methods
We performed a randomized double-blind placebo-controlled AZA withdrawal trial with a follow-up period of 24 months. Patients had to have continuous AZA therapy ≥4 years without exacerbation of disease during the 12 months before enrollment, and a Crohn’s disease activity index <150 at baseline. Patients were randomized to continue on AZA or switch to placebo. The primary endpoint was time to clinical relapse during follow-up.
Results
After inclusion of 52 patients, the trial was stopped prematurely due to slow recruitment. During the 2-year follow-up, clinical relapse occurred in 4 of 26 (15 %) patients on continued AZA and in 8 of 26 (31 %) patients on placebo. Time to clinical relapse averaged 22.3 months (95 % CI 20.6–24.0) on AZA and 19.2 months (95 % CI 16.4–22.1) on placebo (p = 0.20). According to life-table analysis, the proportion of patients in remission after 12 and 24 months was 96 ± 4 and 86 ± 7 % in patients receiving AZA versus 76 ± 8 and 68 ± 9 % in patients receiving placebo (month 12, p = 0.035; month 24, p = 0.30). A higher AZA dose at enrollment was an independent predictor for relapse (p < 0.05).
Conclusions
AZA withdrawal resulted in a significantly increased relapse risk after 1 year and a nonstatistically significant trend for relapse after 2 years. Our results are in line with previous observations.
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References
Cosnes J, Gower-Rousseau C, Seksik P, Cortot A. Epidemiology and natural history of inflammatory bowel diseases. Gastroenterology. 2011;140:1785–1794.
Petritsch W, Fuchs S, Berghold A, et al. Incidence of inflammatory bowel disease in the province of Styria, Austria, from 1997 to 2007: a population-based study. J Crohn’s Colitis. 2013;7:58–69.
Jostins L, Ripke S, Weersma RK, et al. Host-microbe interactions have shaped the genetic architecture of inflammatory bowel disease. Nature. 2012;491:119–124.
Ardizzone S, Cassinotti A, Manes G, Porro GB. Immunomodulators for all patients with inflammatory bowel disease? Therap Adv Gastroenterol. 2010;3:31–42.
Candy S, Wright J, Gerber M, Adams G, Gerig M, Goodman R. A controlled double blind study of azathioprine in the management of Crohn’s disease. Gut. 1995;37:674–678.
Pearson DC, May GR, Fick GH, Sutherland LR. Azathioprine and 6-mercaptopurine in Crohn Disease. A meta-analysis. Ann Intern Med. 1995;123:132–142.
Prefontaine E, Sutherland LR, Macdonald JK, Cepoiu M. Azathioprine or 6-mercaptopurine for maintenance of remission in Crohn’s disease. Cochrane Database Syst Rev. 2009;(1):CD000067. doi:10.1002/14651858.CD000067.pub2.
Peyrin-Biroulet L, Deltrenre P, Ardizzone S, et al. Azathioprine and 6-mercaptopurine for the prevention of postoperative recurrence in Crohn’s disease: a meta-analysis. Am J Gastroenterol. 2009;104:2089–2096.
Dignass A, Van Assche G, Lindsay JO, et al. The second European evidence-based Consensus on the diagnosis and management of Crohn’s disease: current management. J Crohn’s Colitis. 2010;4:28–62.
Present DH, Korelitz BI, Wisch N, Glass JL, Sachar DB, Pasternack BS. Treatment of Crohn’s disease with 6-mercaptopurine. A long-term, randomized, double-blind study. N Engl J Med. 1980;302:981–987.
Korelitz BI, Adler DJ, Mendelsohn RA, Sacknoff A. Long-term experience with 6-mercaptopurine in the treatment of Crohn’s disease. Am J Gastroenterol. 1993;88:1198–1205.
Van Assche G, Dignass A, Reinisch W, et al. The second European evidence-based Consensus on the diagnosis and management of Crohn’s disease: special situations. J Crohn’s Colitis. 2010;4:63–101.
O’Donoghue DP, Dawson AM, Powel-Tuck K, Brown RL, Lennard-Jones JE. Double-blind withdrawal trial of azathioprine as maintenance treatment for Crohn’s disease. Lancet. 1978;2:955–957.
Bouhnik Y, Lémann M, Mary JY, et al. Long-term follow up of patients with Crohn’s disease treated with azathioprine or 6-mercaptopurine. Lancet. 1996;347:215–219.
Kim PS, Zlatanic J, Korelitz BI, Gleim GW. Optimum duration of treatment with 6-mercaptopurine for Crohn’s disease. Am J Gastroenterol. 1999;94:3254–3257.
Vilien M, Dahlerup JF, Munck LK, Nørregaard P, Grønbaek 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 Therap. 2004;19:1147–1152.
Sokol H, Seksik P, Nion-Larmurier I, Vienne A, Beaugerie L, Cosnes J. Current smoking, not duration of remission, delays Crohn’s disease relapse following azathioprine withdrawal. Inflamm Bowel Dis. 2010;16:362–363.
Lémann M, Mary J-Y, Colombel J-F, 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.
Treton X, Bouhnik Y, Mary JY, et al. Azathioprine withdrawal in patients with Crohn’s disease maintained on prolonged remission: a high risk of relapse. Clin Gastroenterol Hepatol. 2009;7:80–85.
Fraser AG, Orchard TR, Jewell DP. The efficacy of azathioprine for the treatment of inflammatory bowel disease: a 30 years review. Gut. 2002;50:485–489.
Mantzaris GJ, Roussos A, Christidou A, et al. The long-term efficacy of azathioprine does not wane after four years of continuous treatment in patients with steroid-dependent luminal Crohn’s disease. J Crohn’s Colitis. 2007;1:28–34.
French H. Mark Dalzell A, Srinivasan R, El-Matary W. Relapse rate following azathioprine withdrawal in maintaining remission for Crohn’s disease: a meta-analysis. Dig Dis Sci. 2011;56:1929–1936.
Beaugerie L, Brousse N, Bouvier AM, et al. Lymphoproliferative disorders in patients receiving thiopurines for inflammatory bowel disease: a prospective observational cohort study. Lancet. 2009;374:1617–1625.
Sokol H, Beaugerie L, Maynadié M, et al. Excess primary intestinal lymphoproliferative disorders in patients with inflammatory bowel disease. Inflamm Bowel Dis. 2012;18:2063–2071.
Peyrin-Biroulet L, Khosrotehrani K, Carrat F, et al. Increased risk for nonmelanoma skin cancers in patients who receive thiopurines for inflammatory bowel disease. Gastroenterology. 2011;141:1621–1628.
Long MD, Martin CF, Pipkin CA, Herfarth HH, Sandler RS, Kappelman MD. Risk of melanoma and nonmelanoma skin cancer among patients with inflammatory bowel disease. Gastroenterology. 2012;143:390–399.
Connell WR, Kamm MA, Ritchie JK, Lennard-Jones JE. Bone marrow toxicity caused by azathioprine in inflammatory bowel disease: 27 years of experience. Gut. 1993;34:1081–1085.
Toruner M, Loftus EV Jr, Harmsen WS, et al. Risk factors for opportunistic infections in patients with inflammatory bowel disease. Gastroenterology. 2008;134:929–936.
Present DH, Meltzer SJ, Krumholz MP, Wolke A, Korelitz BI. 6-mercaptopurine in the management of inflammatory bowel disease: short- and long-term toxicity. Ann Intern Med. 1989;111:641–649.
Higgins PD. Who wants to take a thiopurine holiday? Am J Gastroenterol. 2011;106:556–558.
Lewis JD, Schwartz JS, Lichtenstein GR. Azathioprine for maintenance of remission in Crohn’s disease: benefits outweigh the risk of lymphoma. Gastroenterology. 2000;118:1018–1024.
Camus M, Seksik P, Bourrier A, et al. Long-term outcome of patients with Crohn’s disease who respond to azathioprine. Clin Gastroenterol Hepatol. 2013;11:389–394.
Holtmann M, Krummenaeur F, Claas C, et al. Long-term effectiveness of azathioprine in IBD beyond 4 years: a European multicenter study in 1176 patients. Dig Dis Sci. 2006;51:1516–1524.
Best WR, Becktel JM, Singelton JW. Rederived values of the eight coefficients of the Crohn’s Disease Activity Index (CDAI). Gastroenterology. 1979;77:843–846.
Irvine EJ. Usual therapy improves perianal Crohn’s disease as measured by a new disease activity index. McMaster IBD Study Group. J Clin Gastroenterol. 1995;20:27–32.
Guyatt G, Mitchell A, Irvine EJ, et al. A new measure of health status for clinical trials in inflammatory bowel disease. Gastroenterology. 1989;96:804–810.
Rutgeerts P, Feagan BG, Lichtenstein GR, et al. Comparison of scheduled and episodic treatment strategies of infliximab in Crohn’s disease. Gastroenterology. 2004;126:402–413.
Peto R, Pike MC, Armitage P, et al. Design and analysis of randomized clinical trials requiring prolonged observation of each patient. I. Introduction and design. Br J Cancer. 1976;34:585–612.
Nyman M, Hansson I, Eriksson S. Long-term immunosuppressive treatment in Crohn’s disease. Scand J Gastroenterol. 1985;20:1197–1203.
Summers RW, Switz DM, Sessions JT, et al. National Cooperative Crohn’s Disease Study: results of drug treatment. Gastroenterology. 1979;77:847–869.
Dubinsky MC, Lamothe S, Yang HY, et al. Pharmacogenomics and metabolite measurement for 6-mercaptopurine therapy in inflammatory bowel disease. Gastroenterology. 2000;118:705–713.
Chouchana L, Narjoz C, Beaune P, Loriot MA, Roblin X. Review article: the benefits of pharmacogenetics for improving thiopurine therapy in inflammatory bowel disease. Aliment Pharmacol Ther. 2012;35:15–36.
Dassopoulos T, Dubinsky MC, Bentsen JL, et al. Randomised clinical trial: individualised vs. weight-based dosing of azathioprine in Crohn’s disease. Aliment Pharmacol Ther. 2014;39:163–175.
Reinisch W, Angelberger S, Petritsch W, et al. International AZT-2 Study Group. Azathioprine versus mesalazine for prevention of postoperative clinical recurrence in patients with Crohn’s disease with endoscopic recurrence: efficacy and safety results of a randomized, double-blind, double-dummy, multicentre trial. Gut. 2010;59:752–759.
Smith MA, Irving PM, Marinaki AM, Sanderson JD. Review article: malignancy on thiopurine treatment with special reference to inflammatory bowel disease. Aliment Pharmacol Ther. 2010;32:119–130.
Acknowledgments
We are thankful to GlaxoSmithKline, Vienna, Austria, for providing the study medication, case report forms, and patient diaries. Representatives of GlaxoSmithKline did not have any role in study design, protocol development, data analysis, data interpretation, writing of the manuscript, or in the decision to submit the manuscript. We thank Marieluise Harrer and Georgiana Prinz for their help in patient recruitment and data acquisition. There was no funding or other financial support for this work.
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Wenzl, H.H., Primas, C., Novacek, G. et al. Withdrawal of Long-Term Maintenance Treatment with Azathioprine Tends to Increase Relapse Risk in Patients with Crohn’s Disease. Dig Dis Sci 60, 1414–1423 (2015). https://doi.org/10.1007/s10620-014-3419-5
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DOI: https://doi.org/10.1007/s10620-014-3419-5