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To the Editor:

We read with interest the excellent review by Clarke and Regueiro on the subject of stopping immunomodulators and biologics in inflammatory bowel disease (IBD) patients who are in remission. With the decision regarding the timing of commencement of immunomodulators and biologics now being personalized according to phenotypic predictors of disease severity in an individual patient, it is logical to question whether a similarly algorithmic approach can be taken to ceasing these agents in appropriate patients. For the most part, we agree with their assessment, particularly regarding biologic agents, in which the safety benefits of treatment withdrawal are usually outweighed by the risks of disease recurrence and the development of immunogenicity that predisposes to an inadequate response, or adverse events, upon reintroduction of the biologic therapy.

However, we question whether there may be a subgroup of patients in “deep remission” on thiopurine monotherapy in whom these agents may be safely withdrawn, therefore reducing cumulative drug exposure and the lifetime risk of malignancy or serious infection. Our interest in this issue comes in part from our local environment in Australia, which has the highest rates of skin cancer in the world, four times higher than USA, UK, and Canada.1 In Australia, nonmelanoma skin cancer is the most common cause of cancer, with an incidence of 1878 cases/100,000 population.2 Melanoma, the most lethal form of skin cancer, is the fourth most common cancer in Australia, with an incidence of 46.7 cases/100,000 population and an associated mortality of 5.7 cases/100,000 population.1 Recent data from the French CESAME cohort indicate that IBD patients receiving thiopurines have a standardized incidence ratio (SIR) of 7.06 (95% confidence interval [CI] 4.18–11.16) for nonmelanoma skin cancer compared with the general population, and, importantly, the SIR decreases to 5.19 (95% CI 2.37–9.86) for patients who have stopped thiopurines.3

Lymphoma (in particular non-Hodgkin's lymphoma) and opportunistic serious infections are other potentially life-threatening complications of thiopurine therapy. Large cohort studies and meta-analyses have found an ≈4–5-fold increased risk of lymphoma in patients taking thiopurines.4, 5 This risk decreases to a nonsignificant hazard ratio of 1.02 for patients who discontinue thiopurines.5 Previous studies show an infectious complication rate of 7.4% in all patients on thiopurine monotherapy, with a serious infection rate of 1.8%,6 and an odds ratio for infection of 3.4 (95% CI 1.5–7.5) compared with patients not on thiopurines.7

A major question arising from the Clarke review surrounds the definition of “remission.” Eight of the referenced article used nonstandardized clinical scores with or without biochemical markers for the definition of remission, thereby potentially overestimating the number of patients in true remission at the time of discontinuation of thiopurine therapy. For example, in the Hawthorne et al8 study Baron scores of 1 (abnormal but not hemorrhagic mucosa) were included in the definition of remission, while although Lobel et al9 included a stricter definition of endoscopic remission as “absence of abnormal endoscopic findings,” not all study patients underwent endoscopy. As such, we believe the reason for the high rates of relapse in these studies may be that many of the patients were not in “deep remission.” Furthermore, from these studies markers of subclinical intestinal inflammation associated with relapse after thiopurine withdrawal were a shorter duration of remission, ongoing endoscopic inflammation, an elevated platelet count, C-reactive protein (CRP) and white cell count, a low hemoglobin, and a shorter duration free of corticosteroids.

Crucial to the development of criteria for the safe withdrawal of immunomodulators is the need for standardization of the definition of remission, and “deep remission” in particular. We suggest that a patient should be defined as being in “deep remission” only if they meet all of the following parameters:

  • 1
    Macroscopically normal or healed mucosa on endoscopy consistent with a Mayo or Baron score of 0 for ulcerative colitis (UC), or a Simple Endoscopic Score for Crohn's disease (CD) of 0.
  • 2
    Normalization of all biochemical parameters including hemoglobin, white cell count, platelets, albumin, and an undetectable CRP.

Additionally, we suggest that withdrawal of thiopurine therapy only be considered if a patient has been in “deep remission” for a prolonged period, perhaps at least 1 year, and in the case of UC, all patients should be continued on aminosalicylate therapy.

Withdrawal of therapy leaves the clinician with the conundrum of how best to monitor for relapse. Given that fecal calprotectin has a sensitivity of 93% and specificity of 96% for active disease10 when compared with endoscopy and biopsy, we believe this is an ideal noninvasive test for monitoring early, presymptomatic disease recurrence.

In summary, we believe that the subset of patients who may be suitable for thiopurine withdrawal are those patients who have been in “deep remission” for at least 1 year. We then recommend 6-monthly fecal calprotectin and standard biochemical assessments. If any of these tests return a positive result or the patient develops symptoms, we recommend endoscopic evaluation for disease recurrence and prompt recommencement of thiopurine therapy. Unlike biologic agents, in the absence of the development of mechanical complications it could be safely anticipated that thiopurines will be effective again if they have worked previously in an individual patient. We recognize that in the CD population, if a patient discontinues thiopurine therapy for a prolonged period, disease recurrence at some point in time is probably inevitable. This is perhaps in contrast to the UC population, where if a thiopurine is withdrawn but long-term aminosalicylate therapy continued, a subgroup of patients may be at a reduced relapse risk given the effectiveness of correctly optimized aminosalicylates in UC. In the long term, decreasing a patient's lifetime exposure to thiopurines, and proactively monitoring for disease recurrence, has the potential to minimize life-threatening risks associated with thiopurines. We await with interest the results of further prospective studies to help guide clinical practice in this area.

REFERENCES

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  • 1
    AIHW and AACR. Cancer in Australia: an overview, 2010. Cancer series no. 60, Cat. no. 56. Canberra, Australia; 2010.
  • 2
    AIHW and AACR, Non-melanoma skin cancer: general practice consultations, hospitalisation and mortality. Cancer series no. 43, Cat. no. 39. Canberra, Australia; 2008.
  • 3
    Peyrin-Biroulet L, et al. Increased risk for non-melanoma skin cancers in patients who receive thiopurines for inflammatory bowel disease. Gastroenterology. 2011 [Epub ahead of print].
  • 4
    Kandiel A, et al. Increased risk of lymphoma among inflammatory bowel disease patients treated with azathioprine and 6-mercaptopurine. Gut. 2005; 54: 11211125.
  • 5
    Beaugerie L, et al. Lymphoproliferative disorders in patients receiving thiopurines for inflammatory bowel disease: a prospective observational cohort study. Lancet. 2009; 374: 16171625.
  • 6
    Present DH, et al. 6-Mercaptopurine in the management of inflammatory bowel disease: short- and long-term toxicity. Ann Intern Med. 1989; 111: 641649.
  • 7
    Toruner M, et al. Risk factors for opportunistic infections in patients with inflammatory bowel disease. Gastroenterology. 2008; 134: 929936.
  • 8
    Hawthorne AB, et al. Randomised controlled trial of azathioprine withdrawal in ulcerative colitis. BMJ. 1992; 305: 2022.
  • 9
    Lobel EZ, et al. A search for optimal duration of treatment with 6-mercaptopurine for ulcerative colitis. Am J Gastroenterol. 2004; 99: 462465.
  • 10
    van Rheenen PF, et al. Faecal calprotectin for screening of patients with suspected inflammatory bowel disease: diagnostic meta-analysis. BMJ. 2010; 341: c3369.

Antony B. Friedman MBBS*, Miles P. Sparrow MBBS, FRACP*, * Alfred Hospital and Monash University Melbourne, Victoria, Australia.