Skin cancers under Janus kinase inhibitors: A World Health Organization drug safety database analysis

Abstract

Janus kinase (JAK) inhibitors are targeted therapies with a potential imunomodulatory and anti-inflammatory effect, indicated in various dysimmune pathologies. Skin cancers have been reported to occur in patients treated with JAK inhibitors. However, drug safety in clinical trials did not confirm that risk, but these studies are performed on controlled population and in a limited time of follow up. The aim of this study is to evaluate in real life condition if a disproportionality signal exists between JAK inhibitors treatment and skin cancers. We performed cases/non cases analysis in VigiBase® (the World Health Organization international database of suspected adverse drug reaction) using information component to search for a disproportionality signal of skin cancers from JAK inhibitor. We extracted all reports of skin cancers from the French Pharmacovigilance database occurring since 1978 up to 31st December 2019 for the three existing JAK inhibitors on market: ruxolitinib, tofacitinib and baricitinib. Only melanoma, squamous cell carcinoma and Merkel cell carcinoma were analyzed, according to the pathophysiology of these cancers and their link with immunosuppression. A disproportionality signal was found positive for squamous cell carcinoma with ruxolitinib (IC025=3.92) and tofacitinib (IC025=0.82), for melanoma with ruxolitinib (IC025=0.81) and tofacitinib (IC025=0.74), and Merkel cell carcinoma with ruxolitinib (IC025=4) and tofactinib (IC025=1.01) and only for Merkel cell carcinoma with baricitinib (IC025=0.53). Moreover, Merkel cell carcinoma, a very rare skin cancer more prevalent in immunodepressed patients was particularly represented in our sample and was associated with a significant disproportionality signal with all the studied JAK inhibitors. Our study shows that JAK inhibitors could be associated with an extra risk to develop skin cancers. Could an anti-viral or immunovigilance disruption mechanism brought by JAK inhibitors explain an over-risk with Merkel cell carcinoma, which were notably represented in our sample? Considering pharmacovigilance method limitations, further pharmacoepidemiological studies are required to assess a causal link between JAK inhibitors treatment and skin cancers development.