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

Disclosures

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

In This Article

Abstract and Introduction

Abstract

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.

Introduction

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.

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