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JAK inhibitors: A risk assessment

Presented By
Prof. Brett King, Yale School of Medicine, USA
AAD 2022
Janus kinase (JAK) inhibitors have entered the arena in dermatology and show efficacy in numerous indications. Recently, the drug class got a black box warning from the American FDA. A decision that was criticised by experts during the 2022 AAD Annual Meeting.

“JAK inhibitors are changing the landscape of what we do in dermatology,” explained Prof. Brett King (Yale School of Medicine, CT, USA) [1]. Besides corticosteroids, no drug class is used in so many indications. Recently, the FDA issued a black box warning for JAK inhibitors. These warnings appear printed on the package insert of the drug surrounded by a black border (hence the name). By doing so, the FDA wants to alert consumers about the serious or life-threatening side effects the drug might have. As Prof. King pointed out, commonly reported adverse events with JAK inhibitors are upper respiratory tract infections, headache, nasopharyngitis, nausea, and acne. The black box warning refers to serious infection, mortality malignancies, major adverse cardiovascular events (MACE), and thrombosis.

Prof. King explained that the genesis of this warning is based on the experience with the pan-JAK inhibitor tofacitinib in patients with rheumatoid arthritis. In a recently published, open-label, safety endpoint trial (NCT02092467), patients were included with active rheumatoid arthritis despite methotrexate treatment who were 50 years of age or older, and had at least 1 additional cardiovascular risk factor [2]. The average BMI in the study population was 30±6 (kg/m2). Participants were randomly assigned in a 1:1:1 ratio to receive tofacitinib at a dose of 5 mg or 10 mg twice daily or a tumour necrosis factor inhibitor. The coprimary endpoints were adjudicated MACE and cancers, excluding non-melanoma skin cancer.

In this trial, after a median follow-up of 4 years, risks of MACE and cancers were higher with tofacitinib with a hazard ratio of 1.33 (95% CI 0.91–1.94) for MACE and 1.48 (95% CI 1.04–2.09) for cancers. Also, 57% of the participants were additionally treated with prednisone. “My point is not to diminish these results, but we have to ask: does this sound like our atopic dermatitis patient population?” Prof. King commented. In general, patients that are treated for atopic dermatitis have a much lower risk profile than rheumatologic patients included in the trial described above. “You cannot extrapolate these data to other populations. All participants were treated with methotrexate and 57% with prednisone. The point is that the risk seen in this trial is a very worst-case scenario,” Prof. King concluded.

Moreover, the FDA warning included all JAK inhibitors, regardless of whether they inhibit all cytokines, like the pan-JAK inhibitor tofacitinib, or JAK1-selective agents such as abrocitinib and upadacitinib. Even topical JAK inhibitors like the 1.5% ruxolitinib cream will get the boxed warning.

To optimise the safety of JAK inhibitor therapy, Prof. King recommended caution in the following patients: older patients (>65 years), obese patients, current or past smokers, those with a history of diabetes, coronary artery disease, thromboembolism, or inherited coagulation disorder, and those with a history of malignancy other than treated non-melanoma skin cancer.

    1. King B. S032, AAD 2022 Annual Meeting, 25–29 March, Boston, MA, USA.

    2. Ytterberg SR, et al. N Engl J Med 2022;386:316–326.


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