Complications of Anti-TNF Therapies

Tina Ding; Chris Deighton


Future Rheumatol. 2007;2(6):587-597. 

In This Article

Do Anti-TNF Drugs Increase the Risk of Malignancies?

TNF-α plays an important role in surveillance of malignancy[88] and hence there is a theoretical risk of increased tumor formation with anti-TNF-α agents. As with infections, data on the overall occurrence of cancer following treatment with anti-TNF-α blockers are contradictory. In summary, analyses of some randomized clinical trials raise the possibility of an increase in the occurrence of cancer. By contrast, observational studies have typically not detected an increased overall cancer risk, although excess risks of certain tumors are reported.

Already referred to above, the Bongartz et al. meta-analysis also raised concerns about a threefold increased rate of malignancy with infliximab and adalimumab (OR: 3.3; 95% CI: 1.2-9.1).[49] Moreover, the risks appear to be dose dependent, with those on high-dose therapy (defined as ≥6 mg/kg infliximab every 8 weeks or ≥40 mg adalimumab every other week) having the greatest risk (OR: 4.3; 95% CI: 1.6-11.8), with no important increased risk below these doses. Concerns on the methodology were discussed above.[50] All nine clinical trials included in this meta-analysis excluded patients with pre-existing malignancies. In addition, there was an unexpectedly low malignancy rate in the control arms when compared with the general population for this age group, which might artificially raise the comparative rates for the anti-TNF intervention arms. Four out of the nine trials included had a higher drop-out rate in their control arms, leading to less follow-up and less opportunity to develop tumors. This could lead to bias towards detection of malignancy in the anti-TNF arms during the later periods of follow-up.[50]

Other studies have given reassurance that biases in this meta-analysis might inflate cancer risk. Setoguchi et al. describe a retrospective cohort study on two US Medicare databases and controls, which included 1152 RA patients treated with biologic therapies and 7306 treated with methotrexate.[89] There was no increased risk of overall cancers, with a pooled adjusted hazard ratio for biologic users of 0.99 (95% CI: 0.71-1.36). Analysis of a Swedish registry by Geborek et al.[90] revealed no increase in the overall cancer risk (standardized incidence ratios [SIRs]: 1.1; 95% CI: 0.6-1.8) in patients receiving anti-TNF therapy compared with those that are not. Another Swedish group using a different registry have shown similar results (adjusted relative risk of 0.93 [0.76-1.13]).[91] Results from Spanish registries[55] actually showed the rate of cancer events to be significantly higher (relative risk [RR]: 2.9) in RA patients not on anti-TNF (n = 789) compared with RA patients treated with TNF blockers (n = 4459).

In support of above studies, the most recent data from a large US observational study concluded that biologics use in RA was not associated with increased overall risk of any malignancy.[92] However, when examined separately, the risks for both nonmelanotic skin cancer and melanoma were increased with biologic therapy (OR: 1.5; 95% CI: 1.2-1.8; OR: 2.3; 95% CI 0.9-5.4, respectively). Similarly, data from a large cohort study by Chakravarty et al.[93] showed an increased risk for developing nonmelanoma skin cancer (NMSC) in RA patients treated with anti-TNF agents (hazard ratio: 1.19, p = 0.042). In the meta-analysis of Bongartz et al., many malignancies in the anti-TNF arms of the trials were NMSC (nine out of 35).[49] The Swedish Biologic Register signals a possible increased occurrence of NMSC in RA cohort treated with anti-TNF (RR: 1.55; 95% CI: 0.76-3.15, n = 10).[91]

In screening patients prior to undergoing anti-TNF therapies, caution needs to be exercised where there is a history of previous malignancy. Watson et al. compared a group of 154 patients with RA and previous cancer with a group of 9844 patients with RA but no previous malignancy. Six patients (4%) who had previous malignancy developed a new cancer, compared with 158 patients (1.6%) without previous malignancy (IRR: 2.5 [95% CI: 1.2-5.8]).[94] These data are yet to be fully published, but ongoing caution in these patients is required.


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