Treatment for inflammatory bowel disease increases the risk of infection-related cancers

October 18, 2009

Patients with Crohn's disease or ulcerative colitis (collectively referred to as inflammatory bowel disease [IBD]) regularly receive treatment with thiopurine drugs to maintain remission. But an Article published Online First (www.thelancet.com) and in an upcoming edition of The Lancet shows that this treatment increases the risk of malignant lymphoproliferative disorders (LD)--cancers associated with viral infection, particularly those linked to Epstein-Barr virus (EBV) infection. The Article is written by Professor Laurent Beaugerie, Hôpital Saint-Antoine, Paris, France, and colleagues.

The thiopurine azathioprine and its metabolite, 6-mercaptopurine, are used for their immunosuppressive properties to maintain remission in IBD. Organ transplant recipients receiving these drugs as part of their immunosuppressive therapy are at an increased risk of developing LD, especially via infection by EBV. To date, no excess risk of LD has been shown in patients with IBD, but data involving patients given thiopurines have been conflicting. In view of the increasing numbers of IBD patients using thiopurines, the authors decided the possible increased risk for these patients must be investigated.

This observational cohort study analysed 19 486 patients with inflammatory bowel disease, of whom 60% had Crohn's disease and 40% had ulcerative colitis or unclassified inflammatory bowel disease. All were enrolled in a nationwide French cohort by 680 gastroenterologists, who reported details of immunosuppressive therapy during the observation period, cases of cancer (LD), and deaths. The risk of LD was assessed according to thiopurine exposure. Median follow-up was 35 months.

At baseline, 30% of patients were receiving, 14% had discontinued, and 56% had never received thiopurines. 23 new cases of LD were diagnosed, consisting of one case of Hodgkin's lymphoma and 22 cases of non-Hodgkin lymphoma. The incidence rates of LD were 0•90 per 1000 patient-years in those receiving, 0•20/1000 patient-years in those who had discontinued, and 0•26/1000 patient-years in those who had never received thiopurines (p=0•0054). Statistical analysis showed that patients receiving thiopurines had a more-than-five-fold increased risk of LD compared with those who had never received the drugs. Most cases associated with thiopurine exposure were similar to those seen in post-transplant disease. Old age, male sex, and longer duration of inflammatory bowel disease were also associated with increased risk of LD.

The authors conclude: "Extrapolating our results, the absolute cumulative risk of lymphoproliferative disorder in young patients receiving a 10-year course of thiopurines remains low (< 1%) and does not undermine the positive risk-benefit ratio of these drugs. For elderly patients and unlimited treatment periods, the question should be addressed in dedicated studies."

In an accompanying Comment, Dr Geert D'Haens, Imelda GI Clinical Research Centre, Bonheiden, Belgium and University Hospital Gasthuisberg, Leuven, Belgium and Dr Paul Rutgeerts University Hospital Gasthuisberg, Leuven, Belgium, say: "Although we recognise the slightly increased risk of lymphoma, these agents will probably remain one of the cornerstones of treatment. Nonetheless, physicians should be cautious when prolonged combined and deep immunosuppression is needed to achieve disease control."
-end-
Professor Laurent Beaugerie, Hôpital Saint-Antoine, Paris, France. T) +33 1 49 28 31 69 / +33 6 63 19 55 94 E) laurent.beaugerie@sat.aphp.fr

Dr Geert D'Haens, Imelda GI Clinical Research Centre, Bonheiden, Belgium. T) +32 15505161 / +32 474987756 E) geert.dhaens@imelda.be

For full Article and Comment, see: http://press.thelancet.com/bowel.pdf

Lancet

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