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Original Investigation |

Association Between Tumor Necrosis Factor-α Antagonists and Risk of Cancer in Patients With Inflammatory Bowel Disease

Nynne Nyboe Andersen, MD1; Björn Pasternak, MD, PhD1; Saima Basit, MSc1; Mikael Andersson, MSc1; Henrik Svanström, MSc1; Sarah Caspersen, MD2; Pia Munkholm, MD, DMSc2; Anders Hviid, MSc, DMSc1; Tine Jess, MD, DMSc1
[+] Author Affiliations
1Department of Epidemiology Research, Statens Serum Institut, Copenhagen, Denmark
2Gastroenterology Unit, Herlev University Hospital, Copenhagen, Denmark
JAMA. 2014;311(23):2406-2413. doi:10.1001/jama.2014.5613.
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Importance  A Cochrane review and network meta-analysis concluded that there is need for more research on adverse effects, including cancer, after treatment with tumor necrosis factor α (TNF-α) antagonists and that national registries and large databases would provide relevant sources of data to evaluate these effects.

Objective  To investigate whether patients with inflammatory bowel disease (IBD) exposed to TNF-α antagonists were at increased risk of developing cancer.

Design, Setting, and Participants  Nationwide register-based cohort study in Denmark, 1999-2012. Participants were 56 146 patients 15 years or older with IBD identified in the National Patient Registry, of whom 4553 (8.1%) were exposed to TNF-α antagonists. Cancer cases were identified in the Danish Cancer Registry.

Main Outcomes and Measures  Rate ratios (RRs) for incident cancer (overall and site-specific) comparing TNF-α antagonist users and nonusers, estimated using Poisson regression adjusted for age, calendar year, disease duration, propensity scores, and use of other IBD medications.

Results  During 489 433 person-years of follow-up (median, 9.3 years [interquartile range, 4.2-14.0]), 81 of 4553 patients exposed to TNF-α antagonists (1.8%) (median follow-up, 3.7 years [interquartile range, 1.8-6.0]) and 3465 of 51 593 unexposed patients (6.7%) developed cancer, yielding a fully adjusted RR of 1.07 (95% CI, 0.85-1.36). There was no significantly increased risk of cancer in analyses according to time since first TNF-α antagonist exposure (less than 1 year: RR, 1.10 [95% CI, 0.67-1.81]; 1 to less than 2 years: RR, 1.22 [95% CI, 0.77-1.93]; 2 to less than 5 years: RR, 0.82 [95% CI, 0.54-1.24]; 5 or more years: RR, 1.33 [95% CI, 0.88-2.03]) and in analyses according to the number of TNF-α antagonist doses received (1 to 3 doses: RR, 1.02 [95% CI, 0.71-1.47]; 4 to 7 doses: RR, 0.89 [95% CI, 0.55-1.42]; 8 or more doses: RR, 1.29 [95% CI, 0.90-1.85]). No site-specific cancers were in significant excess in fully adjusted models.

Conclusions and Relevance  In this Danish nationwide study, exposure to TNF-α antagonists among patients with IBD was not associated with an increased risk of cancer over a median follow-up of 3.7 years among those exposed. An increased risk associated with longer-term accumulated doses and follow-up cannot be excluded.

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Figure 1.
Formation of Study Cohort

IBD indicates inflammatory bowel disease; TNF, tumor necrosis factor.

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Figure 2.
Risk of Cancer According to Age at First Exposure to a TNF-α Antagonist, Accumulated Doses of TNF-α Antagonists, and Time Since First Dose of a TNF-α Antagonist, Comparing Exposed and Unexposed Patients With Inflammatory Bowel Disease

For each age category, patients exposed to tumor necrosis factor α (TNF-α) antagonists were compared with unexposed patients (469 874 person-years and 3465 cases). RR indicates rate ratio; error bars indicate 95% CIs. Analyses were adjusted for age, calendar year, disease duration, baseline propensity scores, and use of 5-aminosalicylates/sulphasalazine, local and systemic corticosteroids, methotrexate/cyclosporine/cyclophosphamide, and azathioprine.

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