Background/Purpose: There is a concern that tumor necrosis factor inhibitors (TNFi) may interplay with tumor biology and increase the risk of cancer, in particular cancer types already associated with states of immune perturbation, such as skin cancers. We therefore investigated the risk of first squamous cell (SCC) and basal cell (BCC) cancers in TNFi-treated rheumatoid arthritis (RA) compared to biologics-naïve RA, and also in biologics-naïve RA compared to the general population, taking several potential confounders into account.

Methods: Through register-linkages, we assembled a cohort of biologics-naïve patients with RA (n=54,450), one cohort of patients with RA starting TNFi-treatment as first biologic 1998-2011 (n=10,974), and a general population comparator cohort (matched 5:1 to the biologics-naïve RA-patients). Individuals with a history of organ transplantation and/or invasive malignancy were excluded. The primary outcome was defined as first in situ or invasive SCC (1998-2011), and first BCC (2004-2011) during follow-up. Hazard ratios (HR) were estimated adjusting for several potential confounders including invasive malignancy during follow-up, use of immuno-suppressive medications and history of non-melanoma skin cancer. We performed a series of sensitivity analyses using different definitions of the study population, risk window, and outcome.

Results: Comparing biologics-naïve RA to the general population, the HR of first in situ or invasive SCC in RA was 2.01 (95% CI 1.80-2.33). Based on 168 vs. 803 first invasive or in situ SCC, the adjusted HR was 1.20 (95% CI 0.96-1.51) comparing TNFi-treated to biologics-naïve RA. The HR of SCC was driven mainly by in situ lesions. Similarly, comparing biologics-naïve RA to the general population, the HR of first BCC was 1.22 (95% CI 1.23-1.34). Based on 169 vs. 1,439 first BCC, the adjusted HR was 1.01 (95% CI 0.85-1.21) comparing TNFi-treated to biologics-naïve RA.

Conclusion: RA (in the absence of TNFi-treatment) was associated with a doubled risk of SCC. TNFi-treatment was associated with a further 20% increase in the risk of in situ, but not invasive SCC. For BCC, RA (in the absence of TNFi treatment) was a much weaker risk factor, and TNFi treatment did not increased the risk of BCC. Whilst we cannot exclude surveillance bias as an explanation for our findings regarding SCC, the risks observed call for vigilance of skin lesions in RA, irrespective of treatment.