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Risks and benefits of azathioprine therapy
  1. D P B McGovern1,
  2. D P Jewell2
  1. 1The Wellcome Trust Centre for Human Genetics, Headington, Oxford, UK
  2. 2Gastroenterology Unit, University of Oxford, Oxford, UK
  1. Correspondence to:
    Dr D P B McGovern
    The Wellcome Trust Centre for Human Genetics, Roosevelt Drive, Headington, Oxford OX3 7BN, UK; dermotwell.ox.ac.uk

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The risk of lymphoma may be increased by about fourfold in patients with inflammatory bowel disease treated with thiopurines. The increased risk could be a result of the medications, the severity of the underlying disease, or a combination of the two

The benefits of the thiopurines, azathioprine (AZA), and 6-mercaptopurine (6-MP) in maintaining remission and corticosteroid sparing in inflammatory bowel disease (IBD) are beyond doubt. However, adverse events as well as benefits should always be considered when the effectiveness of any treatment is being evaluated. The “short term” side effects of thiopurines have been well documented and there have been a number of studies examining the role of thiopurine methyltransferase activity in predicting the risk of these side effects. In this issue of Gut, Kandiel and colleagues1 address the difficult issue of the long term risk of lymphoma associated with thiopurine therapy (see page 1121). Using the technique of meta-analysis of cohort studies, the authors concluded that there was about a fourfold increase in lymphoma in IBD patients treated with thiopurines. The headline from this study will cause alarm among patients and clinicians alike but, as in all studies, closer examination of the limitations (as acknowledged by the authors) of the study is necessary before firm conclusions can be drawn. Meta-analyses have their own particular methodological problems and are only as good as the constituent studies. The authors demonstrated heterogeneity between the studies suggesting that the studies were “different” with respect to study population or methodology. The consistent risk of lymphoma, even after sensitivity analyses (to ensure that rogue studies had not radically influenced the risk), is somewhat reassuring but the negative correlation between size of cohort and risk of lymphoma is of concern.

Association does not prove causation and it is possible that the demonstrated risk is with IBD itself and not with thiopurines. The authors cite evidence that there is no association between IBD and lymphoma but other data suggest that there may be a significant but small association.2,3 The authors address this by demonstrating an increased lymphoma risk in patients treated with thiopurines when compared with IBD patients who had not received thiopurines. Thiopurine use however may simply be a marker for more severe disease which may itself increase the risk of lymphoma. This effect of disease severity may be small and already underpowered studies may have missed such a relationship. The studies included in this analysis were mainly from tertiary referral centres and the largest population based study found no thiopurine-lymphoma association, further raising the possibility of a disease severity bias. Smoking has a deleterious effect on Crohn’s disease4 and smokers are, in theory at least, more likely to require secondline therapies for Crohn’s disease and are also at increased risk of Hodgkin’s lymphoma,5 thereby adding more complexity to the demonstrated association.

Should thiopurines be used more judiciously or even stopped? Quite the contrary! We believe that the case of thiopurines and lymphoma remains unproven but even if the relationship is proved to be causative, the data suggest that thiopurines are of benefit in IBD. The suggested fourfold risk is likely to be an exaggeration, and risk-benefit model analyses have suggested that a 10-fold risk is necessary for the overall effect of thiopurines in IBD to be detrimental.6 The alternatives are not without significant risk. These include uncontrolled inflammation, repeated courses of corticosteroids, alternative immunosuppressants (methotrexate and infliximab administration have also been associated with an increased risk of lymphoma), and surgery. So what should clinicians tell their patients? The risk of lymphoma in IBD patients receiving thiopurines is small, if there at all, but the benefits far outweigh the risks.

Study data suggest that thiopurines are effective for up to five years7 and indeed anecdotal evidence suggests that they may be effective for much longer than that. Vigilance and further large scale studies will be required in the future to ensure that long term thiopurine therapy is not associated with a significant risk of neoplasia. For the present, clinicians should be reassured that, on the whole, these drugs are safe in the long term and are of significant benefit to patients with IBD, and their appropriate use should be actively encouraged.

The risk of lymphoma may be increased by about fourfold in patients with inflammatory bowel disease treated with thiopurines. The increased risk could be a result of the medications, the severity of the underlying disease, or a combination of the two

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  • Conflict of interest: None declared.

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