Original articles—alimentary tract
Risk of Lymphoma Associated With Combination Anti–Tumor Necrosis Factor and Immunomodulator Therapy for the Treatment of Crohn's Disease: A Meta-Analysis

https://doi.org/10.1016/j.cgh.2009.01.004Get rights and content

Background & Aims

Although anti–tumor necrosis factor (TNF) therapy can effectively treat Crohn's disease (CD), there is concern that it might increase the risk of non-Hodgkin's lymphoma (NHL). A meta-analysis was performed to determine the rate of NHL in adult CD patients who have received anti-TNF therapy and to compare this rate with that of a population-based registry and a population of CD patients treated with immunomodulators.

Methods

MEDLINE, EMBASE, Cochrane Collaboration, and Web of Science were searched. Inclusion criteria included randomized controlled trials, cohort studies, or case series reporting on anti-TNF therapy in adult CD patients. Standardized incidence ratios (SIR) were calculated by comparing the pooled rate of NHL with the expected rate of NHL derived from the Surveillance Epidemiology & End Results (SEER) database and a meta-analysis of CD patients treated with immunomodulators.

Results

Twenty-six studies involving 8905 patients and 21,178 patient-years of follow-up were included. Among anti-TNF treated subjects, 13 cases of NHL were reported (6.1 per 10,000 patient-years). The majority of these patients had previous immunomodulator exposure. Compared with the expected rate of NHL in the SEER database (1.9 per 10,000 patient-years), anti-TNF treated subjects had a significantly elevated risk (SIR, 3.23; 95% confidence interval, 1.5–6.9). When compared with the NHL rate in CD patients treated with immunomodulators alone (4 per 10,000 patient-years), the SIR was 1.7 (95% confidence interval, 0.5–7.1).

Conclusions

The use of anti-TNF agents with immunomodulators is associated with an increased risk of NHL in adult CD patients, but the absolute rate of these events remains low and should be weighed against the substantial benefits associated with treatment.

Section snippets

Data Sources and Searches

A literature search was conducted by using the databases MEDLINE via Ovid (1950–October 2007), EMBASE (1974–2007), and Cochrane Reviews/CENTRAL (1990–2007), and meeting abstracts were searched via Web of Science (1996–2007). The search terms included “Crohn's” and related terms “Infliximab,” “Adalimumab,” “Certolizumab pegol,” and related pharmaceutical names. There were no limits used in our search strategy.

Results of search

Our initial electronic search of MEDLINE identified 644 potentially relevant publications. After eligibility screening by abstract and title, 55 articles were obtained for more detailed review, of which 35 were excluded for reasons shown in Figure 1. A search of Web of Science identified 6 additional abstracts. If meeting abstracts were identified that included more recent and updated information than a previously published article, data from the meeting abstract replaced those of the full

Discussion

Anti-TNF drugs for the treatment of CD appear to be associated with an increased risk of NHL. Although the increased risk is statistically significant when compared with the general population, the absolute risk remains small (6.1 per 10,000 patient-years). When compared with CD patients taking immunomodulators alone, there is a nonstatistically significant increased rate of NHL for those exposed to anti-TNF agents.

The baseline risk of NHL increases with age and is male-predominant.41

Acknowledgments

The authors thank Dr H. Gilbert Welch and Thomas Mead for statistical and search support (Dartmouth Institute for Health Policy and Clinical Practice) and the pharmaceutical companies (Abbott, Centocor, and UCB) and individual authors (L. Biancone, R. Cohen, J. Doumit, S. Hanauer, M. Lemann, V. Pacault, C. Petruzziello, L. Peyrin-Biroulet, L. Rodrigo, B. Sandborn, B. Sands, and O. Schroeder) who supplemented the existing published data to provide further details of their patients.

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    Conflicts of interest The authors disclose the following: Dr Siegel has served as a consultant or on a scientific advisory board for Abbott, Elan, and UCB; has received honoraria for speaking from Abbott, P&G, and UCB; and has received grant support from P&G. Dr Sands has served as a consultant or on a scientific advisory board for Abbott, Biogen/IDEC, Bristol-Myers Squibb, Centocor, Elan, Millenium Pharmaceuticals, Novartis Pharmaceuticals, Otsuka America Pharmaceuticals Inc, and UCB; has received honoraria for speaking from Abbott, Schering-Plough, and UCB; and has received grant support from Abbott, Bristol-Myers Squibb, Centocor, Elan, Millenium Pharmaceutical, Novartis Pharmaceuticals and Otsuka America Pharmaceutical Inc. The remaining authors disclose no conflicts.

    Funding Dr Siegel is supported by a CCFA career development award and by grant number K23DK078678 from the National Institute of Diabetes and Digestive and Kidney Diseases. The content is solely the responsibility of the authors and dose not necessarily represent the official views of the National Institute of Diabetes And Digestive and Kidney Diseases or the National Institute of Health.

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