Lymphoproliferative disorders in patients receiving thiopurines for inflammatory bowel disease: a prospective observational cohort study

• Published in: The Lancet (British edition) Vol. 374; no. 9701; pp. 1617 - 1625
• Main Authors: Beaugerie, Laurent, Prof, Brousse, Nicole, Prof, Bouvier, Anne Marie, MD, Colombel, Jean Frédéric, Prof, Lémann, Marc, Prof, Cosnes, Jacques, Prof, Hébuterne, Xavier, Prof, Cortot, Antoine, Prof, Bouhnik, Yoram, Prof, Gendre, Jean Pierre, Prof, Simon, Tabassome, Prof, Maynadié, Marc, Prof, Hermine, Olivier, Prof, Faivre, Jean, Prof, Carrat, Fabrice, Prof
• Format: Journal Article
• Language: English
• Published: Kidlington Elsevier Ltd 07.11.2009; Elsevier; Elsevier Limited
• Subjects: Adult; Age Distribution; Aged; Biological and medical sciences; Bowel disease; Cancer; Colitis, Ulcerative; Colitis, Ulcerative - drug therapy; Colitis, Ulcerative - epidemiology; Crohn Disease; Crohn Disease - drug therapy; Crohn Disease - epidemiology; Drug Therapy, Combination; Female; France; France - epidemiology; Gastroenterology; Gastroenterology. Liver. Pancreas. Abdomen; General aspects; Hematologic and hematopoietic diseases; Human health and pathology; Humans; Hépatology and Gastroenterology; Immunosuppressive Agents; Immunosuppressive Agents - adverse effects; Incidence; Inflammatory bowel disease; Internal Medicine; Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis; Life Sciences; Lymphoma; Lymphoproliferative Disorders; Lymphoproliferative Disorders - chemically induced; Lymphoproliferative Disorders - epidemiology; Male; Medical sciences; Middle Aged; Multivariate Analysis; Observational studies; Other diseases. Semiology; Proportional Hazards Models; Prospective Studies; Purines; Purines - adverse effects; Risk Factors; Sex Distribution; Stomach. Duodenum. Small intestine. Colon. Rectum. Anus; Time Factors; Tumor Necrosis Factor-alpha; Tumor Necrosis Factor-alpha - antagonists & inhibitors; France; France, Paris; Human; Observational study; Thiopurine derivatives; Patient; Hemopathy; Inflammatory disease; Medicine; Prospective; Crohn disease; Cohort study; Lymphoproliferative syndrome; Digestive diseases; Intestinal disease; Public health; Ulcerative colitis
• ISSN: 0140-6736; 1474-547X
• DOI: 10.1016/S0140-6736(09)61302-7

Summary Background Reports of an increased risk of lymphoproliferative disorders in patients receiving thiopurines for inflammatory bowel disease are controversial. We assessed this risk in a prospective observational cohort study. Methods 19 486 patients with inflammatory bowel disease, of whom 11 759 (60·3%) had Crohn's disease and 7727 (39·7%) had ulcerative colitis or unclassified inflammatory bowel disease, were enrolled in a nationwide French cohort by 680 gastroenterologists, who reported details of immunosuppressive therapy during the observation period, cases of cancer, and deaths. The risk of lymphoproliferative disorder was assessed according to thiopurine exposure. Median follow-up was 35 months (IQR 29–40). Findings At baseline, 5867 (30·1%) of patients were receiving, 2809 (14·4%) had discontinued, and 10 810 (55·5%) had never received thiopurines. 23 new cases of lymphoproliferative disorder were diagnosed, consisting of one case of Hodgkin's lymphoma and 22 cases of non-Hodgkin lymphoproliferative disorder. The incidence rates of lymphoproliferative disorder were 0·90 per 1000 (95% CI 0·50–1·49) patient-years in those receiving, 0·20/1000 (0·02–0·72) patient-years in those who had discontinued, and 0·26/1000 (0·10–0·57) patient-years in those who had never received thiopurines (p=0·0054). The multivariate-adjusted hazard ratio of lymphoproliferative disorder between patients receiving thiopurines and those who had never received the drugs was 5·28 (2·01–13·9, p=0·0007). Most cases associated with thiopurine exposure matched the pathological range of post-transplant disease. Interpretation Patients receiving thiopurines for inflammatory bowel disease have an increased risk of developing lymphoproliferative disorders. Funding Programme Hospitalier de Recherche Clinique National ( AOM05157 ), Association François Aupetit, Délégation Inter-régionale de la Recherche clinique Ile de France-Assistance Publique Hôpitaux de Paris (AP-HP), Ligue contre le Cancer, and Fonds de Recherche de la Société Nationale Française de Gastro-entérologie.