To the Editor:

We thank Drs. Friedman and Sparrow for their insightful and thoughtful comments. Their observations and practical proposals for stopping immunomodulators and biologics in inflammatory bowel disease (IBD) patients in remission are important. The crux of their letter centers around two important and central concepts in managing patients with IBD: 1) the risk of long-term thiopurine treatment, and 2) the definition of remission.

Drs. Friedman and Sparrow eloquently summarize the data on risk of nonmelanoma skin cancers, opportunistic infections, and lymphomas secondary to thiopurines. While the risks of these complications are rare, they are increased in patients treated with thiopurines. Weighing the risk versus benefit of treatment is a daily contemplation for any clinician managing Crohn's disease (CD) and ulcerative colitis (UC) patients. Identifying patients who may stop thiopurines (or any therapy for that matter) and continue to sustain long-term remission and health is the “holy grail” of IBD care. To that end, Friedman and Sparrow explore the definition of remission as a potential factor by which patients may withdraw thiopurines.

The concept of remission in IBD has evolved from subjective activity scores to more recent objective parameters of mucosal healing and diminution of inflammation. As noted, several of the studies referenced on thiopurine withdrawal were completed prior to the concept of “very deep remission.” We agree that the subjective endpoints used may have contributed to high rates of relapse after thiopurine discontinuation. However, the trends in relapse were similar in all studies regardless of the definition of remission. The study by Cassinoti et al1 using colectomy or clinical relapse as endpoints showed that one-third of the patients relapsed within 12 months, half within 2 years, and two-thirds within 5 years. The 1-year relapse rate in Hawthorne et al's2 study using clinical and endoscopic endpoints was 36%. Furthermore, Fraser et al's3 study, which defined remission as no need for oral steroids for at least 3 months and a Harvey–Bradshaw index of <4 and relapse as active disease requiring steroids or the need for a surgical procedure, showed a 1-year relapse rate of 37% with no difference between patients with CD and UC.

We wholeheartedly agree that patients in very deep remission could represent a specific population in whom thiopurines could be withdrawn. The definition of very deep remission in our review was defined as clinical remission (CDAI <150) and endoscopic remission.4 The parameters suggested by Friedman and Sparrow to define a deep remission are more clinically practical and would be of interest for future study.

In sum, we agree that it may be possible to identify a subset of IBD patients in very deep remission who may successfully stop thiopurines. It is our opinion that this may represent approximately one-quarter to one-third of patients and the questions that remain a challenge to clinicians making these decisions are:

  • 1)
    What is the definition of very deep remission and how should this be applied to clinical practice?
  • 2)
    What is the optimal duration of remission prior to stopping thiopurines?
  • 3)
    What are the immunogenetic, biochemical, and clinical predictors of relapse?
  • 4)
    For IBD patients who stop thiopurines and then relapse, will the treatment be as effective again and could silent disease progression off of thiopurines lead to complications no longer amenable to medical therapy?


  1. Top of page
  • 1
    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: 27602777.
  • 2
    Hawthorne AB, Logan RF, Hawkey CJ, et al. Randomised controlled trial of azathioprine withdrawal in ulcerative colitis. BMJ. 1992; 305: 2022.
  • 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: 485489.
  • 4
    Clarke K, Regueiro M. Stopping immunomodulators and biologics in inflammatory bowel disease patients in remission. Inflamm Bowel Dis. 2011 [Epub ahead of print].

Kofi Clarke MD*, Miguel Regueiro MD*, * Division of Gastroenterology Hepatology, and Nutrition University of Pittsburgh School of Medicine Pittsburgh, Pennsylvania.