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


RESULTS
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.


CONCLUSIONS
Patients receiving thiopurines for inflammatory bowel disease have an increased risk of developing lymphoproliferative disorders.


BACKGROUND
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.
Beaugerie
Laurent
L
Department of Gastroenterology, Assistance Publique-Hôpitaux de Paris (AP-HP), Hôpital Saint-Antoine, Université Pierre et Marie Curie Paris-VI, Paris, France. laurent.beaugerie@sat.aphp.fr
Brousse
Nicole
N
Bouvier
Anne Marie
AM
Colombel
Jean Frédéric
JF
Lémann
Marc
M
Cosnes
Jacques
J
Hébuterne
Xavier
X
Cortot
Antoine
A
Bouhnik
Yoram
Y
Gendre
Jean Pierre
JP
Simon
Tabassome
T
Maynadié
Marc
M
Hermine
Olivier
O
Faivre
Jean
J
Carrat
Fabrice
F
D000328:Adult; D017677:Age Distribution; D000368:Aged; D003093:Colitis, Ulcerative / Q000188:drug therapy* / Q000453:epidemiology; D003424:Crohn Disease / Q000188:drug therapy* / Q000453:epidemiology; D004359:Drug Therapy, Combination; D005260:Female; D005602:France / Q000453:epidemiology; D006801:Humans; D007166:Immunosuppressive Agents / Q000009:adverse effects*; D015994:Incidence; D008232:Lymphoproliferative Disorders / Q000139:chemically induced / Q000453:epidemiology; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D016016:Proportional Hazards Models; D011446:Prospective Studies; D011687:Purines / Q000009:adverse effects*; D012307:Risk Factors; D017678:Sex Distribution; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors
D007166:Immunosuppressive Agents; D011687:Purines; D014409:Tumor Necrosis Factor-alpha