Effect of Upadacitinib on Biomarkers of Systemic Inflammation in Patients with Moderate-to-Severe Atopic Dermatitis

Abstract

Moderate-to-severe atopic dermatitis (AD) is an inflammatory skin disease associated with systemic inflammation, indicated by elevated markers in skin lesions and blood. High-sensitivity C-reactive protein (Hs-CRP) is a biomarker sensitive to low-grade inflammation and is used to assess systemic inflammation and comorbidity risk. This study evaluated markers of systemic inflammation, including Hs-CRP, absolute eosinophil counts (AEC), and the Olink cardiovascular (CV) panel, in patients with moderate-to-severe AD treated with upadacitinib (UPA). Biomarker data were analyzed from the Heads Up (HU) study, in which dupilumab (DUPI) was included as an active comparator, as well as from the monotherapy Phase 3 trials Measure Up (MU) 1 and  2. Select serum biomarkers, Hs-CRP and AEC, were assessed at baseline and weeks 2, 4, 8, 12, and 16. A certified immunochemiluminometric assay was used to measure Hs-CRP; AEC was determined from blood samples. In HU, 672 patients were enrolled, with an optional biomarker cohort consisting of 116 patients in the UPA 30mg (UPA30) group and 118 patients in the DUPI group who provided serum samples for Olink analysis. Between‑group, visit‑wise comparisons of Hs‑CRP and AEC used analysis of covariance (ANCOVA) with baseline as a covariate. Within‑group Hs‑CRP change from baseline used paired t‑tests; Olink percent changes were analyzed via paired NPX (log2) analyses with FDR‑adjusted q‑values. In the integrated MU studies and HU, Hs-CRP was significantly reduced with UPA treatment from baseline to week 16 (p<0.001). In the integrated MU studies, UPA 15mg (UPA15) and UPA30 groups showed statistically significant mean reductions versus placebo by week 2 and through week 16 (p<0.05). At week 16, mean Hs-CRP levels were 1.44 mg/L, 1.97 mg/L, and 2.86 mg/L for UPA15, UPA30, and placebo, respectively. In HU, greater reduction in Hs-CRP was observed with UPA30 versus DUPI at week 16 (1.58 mg/L vs 2.25 mg/L; p<0.05). For AEC, in the integrated MU studies, UPA15 and UPA30 groups showed statistically significant mean reductions versus placebo by week 2 and through week 16 (p<0.05). At week 16, mean AEC values were 0.28 × 10⁹ cells/L, 0.23 × 10⁹ cells/L, and 0.39 × 10⁹ cells/L for UPA15, UPA30, and placebo, respectively. In HU, UPA-treated patients showed greater reduction in AEC than DUPI-treated patients at week 16 (0.20 × 10⁹ cells/L vs 0.42 × 10⁹ cells/L; p<0.001). Proteins associated with inflammation and CV risk, including interleukin-2 receptor alpha, lymphotactin, and tumor necrosis factor receptor superfamily member 1A, measured by the Olink CV II/III panel, were significantly decreased from baseline (p<0.001) in UPA30–treated patients in HU. Treatment with UPA in patients with moderate-to-severe AD was associated with rapid and sustained reductions in markers of systemic inflammation, including Hs-CRP, AEC, and protein mediators from the Olink CV panel.