David S Kotlyar1, James D Lewis2, Laurent Beaugerie3, Ann Tierney4, Colleen M Brensinger4, Javier P Gisbert5, Edward V Loftus6, Laurent Peyrin-Biroulet7, Wojciech C Blonski8, Manuel Van Domselaar9, Maria Chaparro5, Sandipani Sandilya10, Meenakshi Bewtra2, Florian Beigel11, Livia Biancone12, Gary R Lichtenstein13. 1. 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. 2. 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. 3. Gastroenterology, Assistance Publique-Hôpitaux de Paris (AP-HP), Hôpital Saint- Antoine, Université Pierre et Marie Curie Paris-VI, Paris, France. 4. Center for Clinical Epidemiology and Biostatistics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania. 5. 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. 6. Division of Gastroenterology and Hepatology, Department of Medicine, Mayo Clinic, Rochester, Minnesota. 7. Inserm U954, Department of Gastroenterology, Nancy University Hospital, Nancy, France. 8. 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. 9. Gastroenterology, Hospital Ramón y Cajal, Madrid, Spain. 10. Division of Nephrology, Department of Medicine, Montefiore Medical Center, Bronx, New York. 11. Department of Medicine, University of Munich-Grosshadern, Munich, Germany. 12. GI Unit, Department of Medicine, University of Tor Vergata, Rome, Italy. 13. Division of Gastroenterology, Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania. Electronic address: grl@mail.med.upenn.edu.
Abstract
BACKGROUND & AIMS: 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.
BACKGROUND & AIMS: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: Frank I Scott; Ronac Mamtani; Colleen M Brensinger; Kevin Haynes; Zelma C Chiesa-Fuxench; Jie Zhang; Lang Chen; Fenglong Xie; Huifeng Yun; Mark T Osterman; Timothy Beukelman; David J Margolis; Jeffrey R Curtis; James D Lewis Journal: JAMA Dermatol Date: 2016-02 Impact factor: 10.282