Alimentary Pharmacology and Therapeutics

Letter to the Editor Letter: thiopurine withdrawal during sustained clinical remission in inflammatory bowel disease J. M. Benítez*, V. García-Sánchez* & J. P. Gisbert† *Department of Gastroenterology, Hospital Universitario Reina Sofía, IMIBIC, Cordoba University, Cordoba, Spain. † Department of Gastroenterology, Hospital Universitario de La Princesa, IIS-IP and CIBEREHD, Madrid, Spain. E-mail: [email protected] doi:10.1111/apt.13066

SIRS, Nowadays, one of the concerns of physicians dedicated to inflammatory bowel disease (IBD) is to know whether the benefit of immunosuppressive maintenance treatment in patients with sustained remission exceeds the long-term risks from such therapy. In this respect, many questions arise. Should we really stop treatment? How long should we continue the therapy before its withdrawal? How long should the patient have remained in remission before discontinuation of treatment? Which factors are associated with an increased risk of relapse? This topic of great interest has been reported by Kennedy et al.1 Thiopurines have proven to be effective in maintaining remission in patients with Crohn’s disease (CD) and ulcerative colitis (UC).2–5 The safety profile of thiopurines is well-known and the cumulative incidence of adverse events is approximately 25%, with an annual risk of 7% per patient per year of treatment.6 Because of the potential risk of adverse effects, especially in the elderly, discontinuation of treatment has been recommended by some experts if the disease has remained in remission for a prolonged period. However, there is no convincing evidence for this. When interpreting the results of Kennedy’s study, a few key questions must be kept in mind. The first one is what is the most appropriate definition of remission? The authors considered ‘sustained remission’ as clinical remission with no use of corticosteroids within the

preceding 6 months up to drug withdrawal. Apart from clinical remission, a biological and endoscopic remission should be considered to select patients who have better control of intestinal inflammation and who are therefore the best candidates for treatment discontinuation. Unfortunately, this endoscopic evaluation was not performed prior to thiopurine withdrawal in the present study. To date, this is one of the largest studies to evaluate prognosis of patients after thiopurine withdrawal. This strategy appears to be associated with a high cumulative relapse rate: 21–41% and 61–85% at 1 and 5 years, respectively, for CD7, 8; and 35–77% and 65–75% at 1 and 5 years, respectively, for UC.3, 9, 10 Kennedy et al. reported lower relapse rates, around 23% for CD and 12% for UC at 12 months, and 39% and 26%, respectively, at 5 years. This could be attributed to a strict sustained remission including continuous thiopurine use for more than 3 years. Regarding predictors of relapse, only CRP and white cell count were identified as independent predictors at 1 and 2 years of thiopurine withdrawal. CRP has been identified as a predictor in previously published studies7 and it indicates that we should aim to achieve not only clinical remission but also biological remission at withdrawal. However, it is difficult to give a potential predictive value to white cell count in UC as both relapsers and nonrelapsers showed leucocyte counts within normal range. On the other hand, faecal calprotectin has demonstrated a predictive value for relapse in IBD,11 but it was evaluated in only a few patients by Kennedy et al. Clinical conditions related to treatment have been associated with higher risk of relapse in other studies such as extent of disease, time in remission and duration of treatment9; however, no clinical predictors were identified in the present study. This circumstance, along with the retrospective nature of the study, limits its ability to disclose relevant predictors. Despite the limitations, the authors must be commended for having performed such a study, assessing this important and clinically relevant topic. Currently, there are no definitive predictive factors capable of

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Letter to the Editor selecting patients who might be candidates for discontinuing these drugs. Ideally, a combination of clinical, biological and endoscopic predictors would allow selection of subgroups of patients. However, therapeutic strategies should be individualised according to the specific characteristics of each patient.

ACKNOWLEDGEMENT Declaration of personal and funding interests: None. REFERENCES 1. Kennedy NA, Kalla R, Warner B, 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: 1313–23. 2. Chande N, Tsoulis DJ, MacDonald JK. Azathioprine or 6mercaptopurine for induction of remission in Crohn’s disease. Cochrane Database Syst Rev 2013; 30: 4. 3. Fraser AG, Orchard TR, Jewell DP. The efficacy of azathioprine for the treatment of inflammatory bowel disease: a 30 year review. Gut 2002; 50: 485–9. 4. Gisbert JP, Linares PM, McNicholl AG, et al. Meta-analysis: the efficacy of azathioprine and mercaptopurine in ulcerative colitis. Aliment Pharmacol Ther 2009; 30: 126–37.

Aliment Pharmacol Ther 2015; 41: 494-495 ª 2015 John Wiley & Sons Ltd

5. Khan KJ, Dubinsky MC, Ford AC, et al. Efficacy of immunosuppressive therapy for inflammatory bowel disease: a systematic review and meta-analysis. Am J Gastroenterol 2011; 106: 630–42. 6. Chaparro M, Ordás 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: 1404–10. 7. Lemann 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: 1812–8. 8. Vilien M, Dahlerup JF, Munck LK, et al. 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: 1147–52. 9. Cassinotti A, Actis GC, Duca P, et al. Maintenance treatment with azathioprine in ulcerative colitis: outcome and predictive factors after drug withdrawal. Am J Gastroenterol 2009; 104: 2760–7. 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; 9: CD000478. 11. Louis E, Mary J-Y, Vernier-Massouille G, et al. Maintenance of remission among patients with Crohn’s disease on antimetabolite therapy after infliximab therapy is stopped. Gastroenterology 2012; 142: 63–70 e5; quiz e31.


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Letter: Thiopurine withdrawal during sustained clinical remission in inflammatory bowel disease.

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