title: Risk of lymphoma in patients with inflammatory bowel disease treated with azathioprine and 6-mercaptopurine: a meta-analysis.
abstract: OBJECTIVE
  Thiopurine therapy for inflammatory bowel disease (IBD) has been associated with increased risk for lymphoma. We estimated the relative risk of lymphoma in patients with IBD exposed to thiopurines and compared relative risk values derived from population-based studies with those from referral center-based studies. We investigated whether active use increased risk compared with past use, and whether sex, age, or duration of use affects risk of lymphoma.
  
  
  METHODS
  We searched MEDLINE, EMBASE, and Cochrane databases, as well as conference abstracts and international publications, for the terms "6-MP and lymphoma," "6-mercaptopurine and lymphoma," "thiopurines and lymphoma," "azathioprine and cancer and IBD," "azathioprine and malignancy and IBD," "azathioprine and lymphoma," and "lymphoproliferative and thiopurines." Pooled standardized incidence ratios (SIRs) and 95% confidence intervals (CIs) were estimated. The deviance statistic from Poisson models was used to calculate heterogeneity.
  
  
  RESULTS
  Eighteen studies (among 4383 citations) met our inclusion criteria. Overall, the SIR for lymphoma was 4.92 (95% CI, 3.10-7.78), ranging from 2.80 (95% CI, 1.82-4.32) in 8 population studies to 9.24 (95% CI, 4.69-18.2) in 10 referral studies. Population studies demonstrated an increased risk among current users (SIR = 5.71; 95% CI, 3.72-10.1) but not former users (SIR = 1.42; 95% CI, 0.86-2.34). Level of risk became significant after 1 year of exposure. Men have a greater risk than women (relative risk = 1.98; P < .05); both sexes were at increased risk for lymphoma (SIR for men = 4.50; 95% CI = 3.71-5.40 and SIR for women = 2.29; 95% CI = 1.69-3.05). Patients younger than 30 years had the highest relative risk (SIR = 6.99; 95% CI, 2.99-16.4); younger men had the highest risk. The absolute risk was highest in patients older than 50 years (1:354 cases per patient-year, with a relative risk of 4.78).
  
  
  CONCLUSIONS
  Compared with studies from referral centers, population-based studies of IBD patients show a lower but significantly increased risk of lymphoma among patients taking thiopurines. The increased risk does not appear to persist after discontinuation of therapy. Patients over 50 have the highest absolute risk of lymphoma per year on thiopurines, while men under 35 may also be a high risk group. More study is needed to precisely understand groups highest at risk. The risks of lymphoma and potential benefits of therapy should be considered for all patients with IBD.
authors.affiliation: Medical Oncology Service, National Cancer Institute, National Institutes of Health, Bethesda, Maryland; Division of Gastroenterology, Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: David S
authors.initials: DS
authors.lastname: Kotlyar
authors.affiliation: Division of Gastroenterology, Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania; Center for Clinical Epidemiology and Biostatistics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: James D
authors.initials: JD
authors.lastname: Lewis
authors.affiliation: Gastroenterology, Assistance Publique-Hôpitaux de Paris (AP-HP), Hôpital Saint- Antoine, Université Pierre et Marie Curie Paris-VI, Paris, France.
authors.forename: Laurent
authors.initials: L
authors.lastname: Beaugerie
authors.affiliation: Center for Clinical Epidemiology and Biostatistics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Ann
authors.initials: A
authors.lastname: Tierney
authors.affiliation: Center for Clinical Epidemiology and Biostatistics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Colleen M
authors.initials: CM
authors.lastname: Brensinger
authors.affiliation: Gastroenterology, La Princesa University Hospital, Instituto de Investigación Sanitaria Princesa (IP) and Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Madrid, Spain.
authors.forename: Javier P
authors.initials: JP
authors.lastname: Gisbert
authors.affiliation: Division of Gastroenterology and Hepatology, Department of Medicine, Mayo Clinic, Rochester, Minnesota.
authors.forename: Edward V
authors.initials: EV
authors.lastname: Loftus
authors.affiliation: Inserm U954, Department of Gastroenterology, Nancy University Hospital, Nancy, France.
authors.forename: Laurent
authors.initials: L
authors.lastname: Peyrin-Biroulet
authors.affiliation: Division of Gastroenterology, Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania; Department of Medicine, SUNY Upstate, Binghamton Campus, Binghamton, New York; Medical University, Wroclaw, Poland.
authors.forename: Wojciech C
authors.initials: WC
authors.lastname: Blonski
authors.affiliation: Gastroenterology, Hospital Ramón y Cajal, Madrid, Spain.
authors.forename: Manuel
authors.initials: M
authors.lastname: Van Domselaar
authors.affiliation: Gastroenterology, La Princesa University Hospital, Instituto de Investigación Sanitaria Princesa (IP) and Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Madrid, Spain.
authors.forename: Maria
authors.initials: M
authors.lastname: Chaparro
authors.affiliation: Division of Nephrology, Department of Medicine, Montefiore Medical Center, Bronx, New York.
authors.forename: Sandipani
authors.initials: S
authors.lastname: Sandilya
authors.affiliation: Division of Gastroenterology, Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania; Center for Clinical Epidemiology and Biostatistics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Meenakshi
authors.initials: M
authors.lastname: Bewtra
authors.affiliation: Department of Medicine, University of Munich-Grosshadern, Munich, Germany.
authors.forename: Florian
authors.initials: F
authors.lastname: Beigel
authors.affiliation: GI Unit, Department of Medicine, University of Tor Vergata, Rome, Italy.
authors.forename: Livia
authors.initials: L
authors.lastname: Biancone
authors.affiliation: Division of Gastroenterology, Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania. Electronic address: grl@mail.med.upenn.edu.
authors.forename: Gary R
authors.initials: GR
authors.lastname: Lichtenstein
mesh_terms: D000328:Adult; D000368:Aged; D001379:Azathioprine / Q000009:adverse effects / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents / Q000009:adverse effects / Q000627:therapeutic use*; D015212:Inflammatory Bowel Diseases / Q000150:complications* / Q000188:drug therapy*; D008223:Lymphoma / Q000139:chemically induced / Q000453:epidemiology*; D008297:Male; D015122:Mercaptopurine / Q000009:adverse effects / Q000627:therapeutic use*; D008875:Middle Aged; D012306:Risk; D018570:Risk Assessment; D055815:Young Adult
chemical_list: D007166:Immunosuppressive Agents; D015122:Mercaptopurine; D001379:Azathioprine
keywords: Cancer Risk; Crohn’s Disease; Treatment; Ulcerative Colitis