Upadacitinib treatment of atopic dermatitis patients leads to reductions in epidermal hyperplasia and cellular infiltrates

Upadacitinib (upa), an oral, once-daily, selective Janus Kinase 1 (JAK1) inhibitor, was investigated for the treatment of atopic dermatitis (AD) in a phase 2 study in 167 adults with moderate-to-severe AD randomized to upa 7.5mg, 15mg, and 30mg (n=42 per group) or placebo (n=41). Mean % improvements from baseline to 16 wk in Eczema Area and Severity Index (EASI: 39.4%/61.7%/74.4% vs 23%, P<0.05/<0.001/<0.001) and pruritus NRS (39.6%/48.0%/68.9% vs 9.7%, P<0.01/<0.001/<0.001) were significantly greater for 7.5/15/30mg upa vs placebo. Lesional and non-lesional biopsies were collected from 50 patients (n=15/14/12/9 for placebo/7.5/15/30mg upa) at wk 0, 4, and 16 of treatment to examine cellular changes in skin tissues following upa treatment using immunohistochemistry analysis. We observed significant, dose-dependent reductions in measures of epidermal hyperplasia (epidermal thickness, K16 immunoreactivity, Ki67+ cells) at wk 16 in 15mg and 30mg upa dose groups (P<0.05). Similarly, significant attenuations in the number of dendritic cells (both CD11c+ and FcεR1+) and CD3+ T-cells in the skin were observed at wk 16 in the 30mg and 15mg upa dose groups (P<0.001) but not in the 7.5mg and placebo groups. Change in SCORing AD (SCORAD) at wk 16 was correlated with changes in epidermal thickness (R=0.642; P<0.01), CD11c+ cells (R=0.435; P<0.1), and CD3+ cells (R=0.492; P≤0.1). Change in EASI at wk 16 was correlated with change in CD11c+ cells (R=0.628; P≤0.01). In addition, we observed restored expression of filaggrin (which shows a discontinuous expression at baseline) at wk 16 of treatment with upa, particularly with the higher doses. In summary, 15mg and 30mg upa but not placebo treatment induced significant changes in epidermal hyperplasia and cellular infiltrates, which were also associated with clinical improvements.