Upadacitinib Shows Broader Inflammatory Effects and Earlier Skin Barrier Restoration Than Dupilumab in Atopic Dermatitis

New skin biopsy analyses from the head-to-head Level Up study suggest that upadacitinib (Rinvoq) may exert broader and earlier molecular effects than dupilumab (Dupixent) in moderate-to-severe atopic dermatitis (AD), including modulation of inflammatory pathways beyond type 2 inflammation and early restoration of skin barrier integrity.

The findings were presented by Christopher G. Bunick, MD, PhD, associate professor of dermatology at Yale School of Medicine and editor in chief of Dermatology Times, at the 2026 European Academy of Dermatology and Venereology (EADV) Congress in Vienna, Austria. The analysis was designed to further investigate how dupilumab and upadacitinib affect inflammatory pathways within the skin of patients with moderate-to-severe AD.

“Skin biopsies from the head-to-head Level Up study showed broader effects on inflammatory signals with upadacitinib than with dupilumab, including signals beyond Type 2 inflammation. Histology in EASI75 responders also showed reduced epidermal thickening and increased filaggrin staining, supporting early structural skin barrier restoration. Together, these findings offer a potential biological explanation for the clinical efficacy differences between the treatments,” — Christopher G. Bunick, MD, PhD, associate professor of dermatology at Yale School of Medicine and editor in chief of Dermatology Times

Looking Beyond Type 2 Inflammation

Although type 2 inflammation is a defining component of AD, its pathophysiology is heterogeneous. Particularly in chronic disease, type 1 and type 17/22 inflammatory responses may also contribute. Dupilumab reduces type 2 inflammation through antagonism of interleukin (IL)-4 receptor alpha, whereas upadacitinib is a selective Janus kinase (JAK) 1 inhibitor capable of modulating multiple inflammatory pathways through JAK-STAT signaling.

To investigate these differences at the tissue level, investigators analyzed optional skin biopsies from adults enrolled in Level Up. The open-label, assessor-blinded biomarker cohort compared upadacitinib 15 mg once daily with dupilumab administered according to its label. At baseline, lesional biopsies were available from 33 patients, including 14 receiving upadacitinib and 19 receiving dupilumab. Nonlesional biopsies were collected from 28 patients, and tissue from 33 healthy controls was also evaluated.

Investigators used bulk transcriptomics to evaluate differentially expressed genes and performed pathway and upstream analyses. Histological assessments examined epidermal proliferation using Ki67, filaggrin immunostaining as a marker of barrier integrity, and epidermal thickness.

Broad Gene Expression Changes Observed by Week 4

Upadacitinib produced substantial changes in lesional skin gene expression as early as week 4, which persisted through week 16. Investigators also observed convergence between lesional and nonlesional gene expression profiles. By comparison, dupilumab produced more modest gene expression changes in lesional skin in this biomarker cohort.

At baseline, lesional skin demonstrated molecular characteristics associated with AD, including dysregulated skin barrier pathways and increased type 2, type 1, type 17/22, and innate immune responses. By week 4, upadacitinib treatment was associated with downregulation of pathways related to type 2, type 1, and type 17/22 inflammation, as well as normalization of keratinization and tissue-remodeling responses.

More specifically, upadacitinib decreased markers of type 2 inflammation and inflammatory mediators extending beyond the type 2 pathway, including IL-22, PI3, S100A12, and the interferon-related chemokines CXCL10 and CXCL11. Changes in several of these markers were apparent by week 4.

Early Changes in Skin Barrier Markers

The molecular analysis also demonstrated changes in genes associated with skin barrier function. Upadacitinib increased expression of IL-34 and IL-37, described in the analysis as negative regulators of inflammation, while increasing expression of barrier-associated genes including FLG, FLG2, LCE family genes, and LOR. These changes were observed as early as week 4.

Histological findings provided additional evidence of structural changes in the skin. Among patients who achieved at least a 75% improvement in Eczema Area and Severity Index (EASI75), upadacitinib was associated with reductions in epidermal hyperproliferation and increased expression of barrier integrity proteins, including filaggrin, by week 4. The representative biopsy images presented at EADV showed reductions in epidermal thickness and changes in filaggrin staining among upadacitinib responders; comparable statistically significant changes were not observed with dupilumab in this cohort.

Potential Mechanistic Explanation for Clinical Differences

The investigators concluded that the tissue findings were consistent with effects previously observed in peripheral blood analyses. Overall, upadacitinib decreased AD-associated proteins earlier and to a greater degree than dupilumab and broadly attenuated inflammatory pathways extending beyond type 2 inflammation.

Dupilumab demonstrated some convergence toward molecular normalization between lesional and nonlesional skin, although changes in pathway activity, gene expression, and histological features were more modest in this cohort. The investigators noted that JAK1 inhibition may produce more rapid and comprehensive tissue-level effects than IL-4Rα antagonism, but emphasized that confirmatory studies are needed.

These findings provide a potential mechanistic framework for understanding differences previously observed between the therapies in Level Up, suggesting that broader modulation of AD-associated inflammatory pathways alongside early changes in epidermal barrier integrity may contribute to the clinical response observed with upadacitinib.

Study Funding and Disclosures

The study was funded by AbbVie, which participated in trial design, research, data collection and analysis, interpretation, and review of the presentation. Several study authors are AbbVie employees and may hold company stock or stock options. Bunick has served as an investigator and/or consultant for AbbVie and numerous other pharmaceutical and biotechnology companies.

References

1. Fyhrquist N, et al. J Allergy Clin Immunol. 2025;156:24-40.e4.
2. Guttman-Yassky E, et al. J Allergy Clin Immunol. 2019;143:155-172.
3. Mohamed MEF, et al. Clin Transl Sci. 2024;17:e13688.
4. Eyerich K, et al. J Am Acad Dermatol. 2025;93:AB226.
5. 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. Presented at: European Academy of Dermatology and Venereology (EADV) Congress; September 30-October 3, 2026; Vienna, Austria.