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Original Investigation
November 7, 2017

Association Between Use of Thiopurines or Tumor Necrosis Factor Antagonists Alone or in Combination and Risk of Lymphoma in Patients With Inflammatory Bowel Disease

Author Affiliations
  • 1Department of Epidemiology, Agence Nationale de Sécurité du Médicament et des produits de santé (ANSM), Saint-Denis, France
  • 2Sorbonne Universités, UPMC Univ Paris 06, INSERM, Institut Pierre Louis d’Epidémiologie et de Santé Publique, UMR_S 1136, F-75012, Paris, France
  • 3Department of Gastroenterology, Hôpital Saint Antoine, Assistance Publique-Hôpitaux de Paris, Paris, France
  • 4Department of Public Health, Hôpital Saint Antoine, AP-HP, F-75012, Paris, France
  • 5Department of Gastroenterology, Hôpitaux Universitaires Paris Sud, Assistance Publique-Hôpitaux de Paris, Université Paris-Sud, Le Kremlin Bicêtre, France
JAMA. 2017;318(17):1679-1686. doi:10.1001/jama.2017.16071
Key Points

Question  Is exposure to thiopurines and anti–tumor necrosis factor (TNF) agents, used alone or in combination, associated with an increased risk of lymphoma in patients with inflammatory bowel disease (IBD)?

Findings  In this cohort study of 189 289 patients with IBD, the risk of incident lymphoma was significantly higher in patients exposed to thiopurine monotherapy, anti-TNF monotherapy, or combination therapy compared with those who were unexposed. The risk was higher in patients exposed to combination therapy compared with thiopurine or anti-TNF monotherapy.

Meaning  The use of thiopurine monotherapy or anti-TNF monotherapy in patients with IBD was associated with a small but statistically significant increased risk of lymphoma, and this risk was higher with combination therapy than with each of these treatments used alone.

Abstract

Importance  An increased risk of lymphoma has been reported among patients receiving thiopurines for inflammatory bowel disease (IBD). The risk of lymphoma associated with anti–tumor necrosis factor (TNF) agents either alone or in combination with thiopurines is uncertain.

Objective  To assess the risk of lymphoma associated with thiopurines and anti-TNF agents, used alone or in combination, for the management of IBD.

Design, Setting, and Participants  Nationwide cohort study based on French National Health Insurance databases. Patients aged 18 years or older identified with IBD were included from January 1, 2009, through December 31, 2013, and followed up until December 31, 2015.

Exposures  At each time of the follow-up, patients were categorized as being exposed to thiopurine monotherapy, anti-TNF monotherapy, or combination therapy, or being unexposed.

Main Outcomes and Measures  The primary outcome was incident lymphoma.

Results  Among the 189 289 patients included (54% women; median age, 43 years [interquartile range, 32-56 years]) and followed up for a median of 6.7 years, 123 069 were never exposed during follow-up, 50 405 were exposed to thiopurine monotherapy, 30 294 to anti-TNF monotherapy, and 14 229 to combination therapy. Overall, 336 lymphoma cases occurred: 220 in unexposed patients (incidence rate [IR] per 1000 person-years, 0.26; 95% CI, 0.23-0.29), 70 in patients exposed to thiopurine monotherapy (IR, 0.54; 95% CI, 0.41-0.67), 32 in patients exposed to anti-TNF monotherapy (IR, 0.41; 95% CI, 0.27-0.55), and 14 in patients exposed to combination therapy (IR, 0.95; 95% CI, 0.45-1.45). In a multivariable Cox model, compared with unexposed patients, the risk of lymphoma was higher among those exposed to thiopurine monotherapy (adjusted hazard ratio [aHR], 2.60; 95% CI, 1.96-3.44; P < .001), anti-TNF monotherapy (aHR, 2.41; 95% CI, 1.60-3.64; P < .001), or combination therapy (aHR, 6.11; 95% CI, 3.46-10.8; P < .001). The risk was higher in patients exposed to combination therapy vs those exposed to thiopurine monotherapy (aHR, 2.35; 95% CI, 1.31-4.22; P < .001) or anti-TNF monotherapy (aHR, 2.53; 95% CI, 1.35-4.77; P < .001).

Conclusions and Relevance  Among adults with IBD, the use of thiopurine monotherapy or anti-TNF monotherapy was associated with a small but statistically significant increased risk of lymphoma compared with exposure to neither medication, and this risk was higher with combination therapy than with each of these treatments used alone. These findings may inform decisions regarding the benefits and risks of treatment.

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