Risk of lymphoma in patients with inflammatory bowel disease treated with azathioprine and 6-mercaptopurine: A meta-analysis

David S. Kotlyar, James D. Lewis, Laurent Beaugerie, Ann Tierney, Colleen M. Brensinger, Javier P. Gisbert, Edward Vincent Loftus, Jr, Laurent Peyrin-Biroulet, Wojciech C. Blonski, Manuel Van Domselaar, Maria Chaparro, Sandipani Sandilya, Meenakshi Bewtra, Florian Beigel, Livia Biancone, Gary R. Lichtenstein

Research output: Contribution to journalArticle

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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.

Original languageEnglish (US)
Pages (from-to)847-858
Number of pages12
JournalClinical Gastroenterology and Hepatology
Volume13
Issue number5
DOIs
StatePublished - May 1 2015

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6-Mercaptopurine
Azathioprine
Inflammatory Bowel Diseases
Meta-Analysis
Lymphoma
Confidence Intervals
Incidence
Referral and Consultation
Population

Keywords

  • Cancer risk
  • Crohn's disease
  • Treatment
  • Ulcerative colitis

ASJC Scopus subject areas

  • Gastroenterology
  • Hepatology
  • Medicine(all)

Cite this

Kotlyar, D. S., Lewis, J. D., Beaugerie, L., Tierney, A., Brensinger, C. M., Gisbert, J. P., ... Lichtenstein, G. R. (2015). Risk of lymphoma in patients with inflammatory bowel disease treated with azathioprine and 6-mercaptopurine: A meta-analysis. Clinical Gastroenterology and Hepatology, 13(5), 847-858. https://doi.org/10.1016/j.cgh.2014.05.015

Risk of lymphoma in patients with inflammatory bowel disease treated with azathioprine and 6-mercaptopurine : A meta-analysis. / Kotlyar, David S.; Lewis, James D.; Beaugerie, Laurent; Tierney, Ann; Brensinger, Colleen M.; Gisbert, Javier P.; Loftus, Jr, Edward Vincent; Peyrin-Biroulet, Laurent; Blonski, Wojciech C.; Van Domselaar, Manuel; Chaparro, Maria; Sandilya, Sandipani; Bewtra, Meenakshi; Beigel, Florian; Biancone, Livia; Lichtenstein, Gary R.

In: Clinical Gastroenterology and Hepatology, Vol. 13, No. 5, 01.05.2015, p. 847-858.

Research output: Contribution to journalArticle

Kotlyar, DS, Lewis, JD, Beaugerie, L, Tierney, A, Brensinger, CM, Gisbert, JP, Loftus, Jr, EV, Peyrin-Biroulet, L, Blonski, WC, Van Domselaar, M, Chaparro, M, Sandilya, S, Bewtra, M, Beigel, F, Biancone, L & Lichtenstein, GR 2015, 'Risk of lymphoma in patients with inflammatory bowel disease treated with azathioprine and 6-mercaptopurine: A meta-analysis', Clinical Gastroenterology and Hepatology, vol. 13, no. 5, pp. 847-858. https://doi.org/10.1016/j.cgh.2014.05.015
Kotlyar, David S. ; Lewis, James D. ; Beaugerie, Laurent ; Tierney, Ann ; Brensinger, Colleen M. ; Gisbert, Javier P. ; Loftus, Jr, Edward Vincent ; Peyrin-Biroulet, Laurent ; Blonski, Wojciech C. ; Van Domselaar, Manuel ; Chaparro, Maria ; Sandilya, Sandipani ; Bewtra, Meenakshi ; Beigel, Florian ; Biancone, Livia ; Lichtenstein, Gary R. / Risk of lymphoma in patients with inflammatory bowel disease treated with azathioprine and 6-mercaptopurine : A meta-analysis. In: Clinical Gastroenterology and Hepatology. 2015 ; Vol. 13, No. 5. pp. 847-858.
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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.",
keywords = "Cancer risk, Crohn's disease, Treatment, Ulcerative colitis",
author = "Kotlyar, {David S.} and Lewis, {James D.} and Laurent Beaugerie and Ann Tierney and Brensinger, {Colleen M.} and Gisbert, {Javier P.} and {Loftus, Jr}, {Edward Vincent} and Laurent Peyrin-Biroulet and Blonski, {Wojciech C.} and {Van Domselaar}, Manuel and Maria Chaparro and Sandipani Sandilya and Meenakshi Bewtra and Florian Beigel and Livia Biancone and Lichtenstein, {Gary R.}",
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TY - JOUR

T1 - Risk of lymphoma in patients with inflammatory bowel disease treated with azathioprine and 6-mercaptopurine

T2 - A meta-analysis

AU - Kotlyar, David S.

AU - Lewis, James D.

AU - Beaugerie, Laurent

AU - Tierney, Ann

AU - Brensinger, Colleen M.

AU - Gisbert, Javier P.

AU - Loftus, Jr, Edward Vincent

AU - Peyrin-Biroulet, Laurent

AU - Blonski, Wojciech C.

AU - Van Domselaar, Manuel

AU - Chaparro, Maria

AU - Sandilya, Sandipani

AU - Bewtra, Meenakshi

AU - Beigel, Florian

AU - Biancone, Livia

AU - Lichtenstein, Gary R.

PY - 2015/5/1

Y1 - 2015/5/1

N2 - 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.

AB - 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.

KW - Cancer risk

KW - Crohn's disease

KW - Treatment

KW - Ulcerative colitis

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