ArticlesLymphoproliferative disorders in patients receiving thiopurines for inflammatory bowel disease: a prospective observational cohort study
Introduction
Crohn's disease and ulcerative colitis (collectively referred to as inflammatory bowel disease) are chronic inflammatory gastrointestinal disorders of unknown origin. The thiopurine azathioprine and its metabolite, 6-mercaptopurine, are used for their immunosuppressive properties to maintain remission in these disorders.1, 2 They are recommended in various forms of chronic clinically active inflammatory bowel disease, including steroid-dependent forms.3 Organ transplant recipients receiving these drugs as part of their immunosuppressive therapy are at an increased risk of developing lymphoproliferative disorders,4 with a frequent pathogenic association with Epstein-Barr virus.5 No excess risk of lymphoproliferative disorder has been shown in large population-based studies of patients with inflammatory bowel disease,6, 7 but conflicting data have been reported for patients given thiopurines.8, 9, 10 In view of the increasing use of these drugs as maintenance treatment of inflammatory bowel disease, and the availability of alternative maintenance treatments,11, 12, 13 settlement of this issue by means of prospective studies is important. We therefore initiated a nationwide prospective observational cohort, called CESAME (Cancers Et Surrisque Associé aux Maladies inflammatoires intestinales En France), which was designed mainly to assess the possible excess risk of lymphoproliferative disorder in patients with inflammatory bowel disease receiving thiopurines.
Section snippets
Study design
In this prospective cohort study, the incidence rates of lymphoproliferative disorder were compared in patients treated and not treated with thiopurines during a 3-year follow-up. We also compared reported cases of lymphoproliferative disorder in the cohort with the number of cases expected in the general population with the same age and sex distributions.
Patients with inflammatory bowel disease were recruited to the study from May, 2004, to June, 2005. Follow-up ended on Dec 31, 2007. From
Statistical analysis
We estimated that a minimum of 50 000 person-years of follow-up would be needed for the study to have statistical power of 80% to detect an lymphoproliferative disorder hazard ratio (HR) of at least 3·5 in patients given thiopurines relative to patients not given these drugs, assuming an absolute incidence rate of 20 cases per 100 000 person-years in untreated patients and that 40% of patients with inflammatory bowel disease would be exposed to thiopurines.
Patients were excluded from all
Results
20 775 patients were enrolled in the study. Of these, 19 486 patients (94%) were included in all analyses because they were enrolled by investigators who continued to participate in the study. Follow-up was complete (ie, included a final visit) for 16 459 of these patients (85%), part complete (interim visits but no final visit) for 588 (3%), and non-existent for 2439 (13%). At study entry, 5867 (30%) patients were receiving thiopurines, 2809 (14%) had discontinued thiopurines, and 10 810 (56%)
Discussion
We have shown that risk of lymphoproliferative disorder was five times higher in patients exposed to thiopurines than in those never exposed to these drugs. Old age, male sex, and longer duration of inflammatory bowel disease were also associated with increased risk of incident lymphoproliferative disorder.
Our hypothesis of a constant risk of lymphoproliferative disorder during thiopurine therapy is supported by three considerations. First, in the post-transplant setting the risk of lymphoma is
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