Systematic Review With Meta-analysis

Comparative Risk of Lymphoma With Anti-tumour Necrosis Factor Agents and/or Thiopurines in Patients With Inflammatory Bowel Disease

Antoine Chupin; Vittorio Perduca; Antoine Meyer; Christophe Bellanger; Franck Carbonnel; Catherine Dong


Aliment Pharmacol Ther. 2020;52(8):1289-1297. 

In This Article

Abstract and Introduction


Background: The risk of lymphoma in patients with inflammatory bowel disease (IBD) treated with anti-TNF agents remains unclear.

Aim: To assess the comparative risk of lymphoma with anti-TNF agents and/or thiopurines in IBD

Methods: We searched PubMed, EMBASE and Cochrane Library to identify studies that evaluated lymphoproliferative disorders associated with anti-TNF agents with or without thiopurines. The risk of lymphoma was assessed through four comparator groups: combination therapy (anti-TNF plus thiopurine), anti-TNF monotherapy, thiopurine monotherapy and control group. Pooled incidence rate ratios (IRR) were estimated through Poisson-normal models.

Results: Four observational studies comprising 261 689 patients were included. As compared with patients unexposed to anti-TNF and thiopurines, those exposed to anti-TNF monotherapy, thiopurine monotherapy or combination therapy had pooled IRR (per 1000 patient-years) of lymphoma of 1.52 (95% CI: 1.06–2.19; P = 0.023), 2.23 (95% CI: 1.79–2.79; P < 0.001) and 3.71 (95% CI: 2.30–6.00; P ≤ 0.01), respectively. The risk of lymphoma associated with combination therapy was higher than with thiopurines or anti-TNF alone with pooled IRR of 1.70 (95% CI: 1.03–2.81; P = 0.039) and 2.49 (95% CI: 1.39–4.47; P = 0.002), respectively. The risk did not differ between anti-TNF monotherapy and thiopurine monotherapy with pooled IRR of 0.72 (95% CI: 0.48–1.07; P = 0.107). All observational studies were of high quality according to the Newcastle-Ottawa scale.

Conclusions: There is an increased risk of lymphoma in IBD patients treated with anti-TNF agents, either alone or when combined with thiopurines.


Inflammatory bowel diseases (IBD) are chronic inflammatory disorders of the gastrointestinal tract that affect approximately 10 million patients around the world.[1] The efficacy of thiopurines and tumour necrosis factor antagonists (anti-TNF) is well established for the treatment of IBD. Thiopurines are immunomodulators that are effective in maintaining remission. Anti-TNF agents have shown efficacy to induce and maintain remission in patients with Crohn's disease (CD) and ulcerative colitis (UC).[2] Combination therapy with infliximab plus azathioprine is more effective than either infliximab and azathioprine alone to induce remission.[3]

These medications have potential serious adverse effects such as infections and malignancy.[4–7] Lymphoma has been shown to be associated with thiopurines.[8] The risk of lymphoma in patients treated with anti-TNF agents is unclear. In post-marketing surveillance,[9,10] in a nationwide Danish study[11] and in a meta-analysis published in 2008,[12] neither cancer nor site-specific cancers (including lymphoma) were associated with exposure to anti-TNF agents in patients with IBD. In 2009, a meta-analysis of all clinical trials with a combination of anti-TNF agents and thiopurines suggested an increased risk of non-Hodgkin's lymphoma in adult CD patients.[13] Recently, a French nationwide cohort study of nearly 190 000 IBD patients reported a three-fold increase in the risk of lymphoma in patients treated with anti-TNF monotherapy, and a six-fold increase in the risk of lymphoma in patients treated with combination therapy.[14] A meta-analysis published in 2018 found a significant association between exposure to anti-TNF agents and risk of lymphoma.[15] A recent review of observational studies could neither confirm nor exclude any association between lymphoma and exposure to anti-TNF in IBD patients.[16] Meta-analyses of rare adverse events require specific methods. We performed a systematic review and meta-analysis to investigate the association of anti-TNF and thiopurines, alone or combined, with the risk of lymphoma in patients with IBD. For this purpose, we used generalised linear mixed models, which are well suited for meta-analysis of rare events.