Upadacitinib Shows Earlier Skin Barrier Restoration Than Dupilumab in Atopic Dermatitis
Key Takeaways
- In an optional biopsy cohort from the head-to-head Level Up study, upadacitinib was associated with broad changes in lesional skin gene expression by Week 4, including inflammatory and skin-barrier pathways.
- Among patients achieving EASI75, histologic assessments showed reduced epidermal thickness and increased filaggrin staining with upadacitinib as early as Week 4; corresponding changes with dupilumab were not statistically significant in this cohort.
- The biomarker findings come from a small, optional biopsy cohort and require confirmation in larger studies.
A biomarker analysis from the head-to-head Level Up study found that upadacitinib produced early molecular and histologic changes consistent with restoration of the skin barrier in adults with moderate-to-severe atopic dermatitis (AD), with broader changes than dupilumab in the study’s optional biopsy cohort.
Presented by Christopher G. Bunick, MD, PhD, Associate Professor of Dermatology at Yale School of Medicine, at the 2026 European Academy of Dermatology and Venereology (EADV) Congress in Vienna, Austria, the analysis examined lesional and nonlesional skin biopsies collected from Level Up participants.1 The open-label, assessor-blinded biomarker cohort included baseline lesional biopsies from 33 patients: 14 randomized to upadacitinib 15 mg once daily and 19 to dupilumab per label. Investigators assessed bulk transcriptomics as well as epidermal proliferation, epidermal thickness, and filaggrin immunostaining.
Upadacitinib Altered Inflammatory and Skin Barrier Markers by Week 4
By Week 4, upadacitinib was associated with downregulation of pathways linked to type 2, type 1, and type 17/22 inflammation and with normalization of keratinization and tissue-remodeling responses. Expression of skin barrier-associated genes, including FLG, FLG2, LCE family genes, and LOR, also increased as early as Week 4. The investigators reported more modest gene-expression changes with dupilumab in the biopsy cohort.
Histologic analyses among EASI75 responders provided a structural correlate. Upadacitinib-treated patients demonstrated significant reductions in epidermal thickness at Weeks 4 and 16 and increased filaggrin staining at both time points, whereas the corresponding changes in the dupilumab group were not statistically significant.
“In the head-to-head Level Up study, histology provided structural evidence of skin barrier restoration with upadacitinib,” Dr. Bunick told Practical Dermatology. “Among patients achieving EASI 75, biopsies showed reduced epidermal thickening and increased filaggrin staining as early as Week 4. These changes accompanied increased expression of skin barrier genes and were more pronounced than those observed with dupilumab in this biopsy cohort.”
1. Bunick CG, Eyerich K, Cotter D, et al. Upadacitinib targets multiple disease-relevant inflammatory pathways and restores skin barrier in atopic dermatitis lesions: extending beyond type 2 responses. Poster presented at: European Academy of Dermatology and Venereology (EADV) Congress; September 30-October 3, 2026; Vienna, Austria.