Skin sign outcomes with upadacitinib vs dupilumab in moderate-to-severe atopic dermatitis: a post hoc analysis of the level up study

Introduction: Atopic dermatitis (AD) is a chronic, relapsing inflammatory disease characterized by eczematous lesions and intense itch. The Eczema Area and Severity Index (EASI) assesses the severity of 4 clinical signs — erythema, edema, excoriation, and lichenification — however, treatment response based on the total EASI score can obscure how individual signs respond. In the phase 3b/4 Level Up study (NCT05601882), upadacitinib (UPA) was superior to dupilumab (DUPI) in achieving both high skin clearance (EASI 90) and little-to-no itch in adolescents and adults with moderate-to-severe AD. Given their distinct mechanisms of action with UPA, a JAK1 inhibitor, and DUPI, an IL-4/IL-13 inhibitor, it remains unclear whether UPA’s superiority extends across the individual signs, particularly harder-to-treat signs such as lichenification and excoriation. This post hoc analysis of Level Up assessed improvement in each of the 4 lesion signs with UPA versus DUPI. Methods: Patients in Level Up were randomized to UPA 15 mg (with potential dose escalation starting at week 4 for inadequate clinical response) or DUPI per label for 16 weeks. For each lesion sign, the proportions of patients achieving ≥75%/≥90%/100% EASI improvement from baseline (EASI 75/90/100) were reported over 16 weeks, with non-responder imputation for missing data. Nominal P values for between-group differences were based on Cochran-Mantel-Haenszel tests stratified by baseline vIGA-AD category and age group. Results: A total of 458 patients were randomized to UPA and 462 to DUPI. Across all 4 lesion signs, greater proportions of patients receiving UPA than DUPI achieved sign-specific EASI 75/90/100, with treatment differences evident as early as week 2. At week 2, EASI 75/90/100 response rates for erythema were 23.6% vs 6.3%, 6.8% vs 1.5%, and 2.6% vs 0.7% for UPA vs DUPI, respectively. Similar trends were observed for edema (EASI 75 [26.0% vs 12.4%], EASI 90 [11.9% vs 5.2%], EASI 100 [7.5% vs 3.9%]), excoriation (EASI 75 [37.4% vs 17.6%], EASI 90 [21.0% vs 8.9%], EASI 100 [12.3% vs 6.3%]), and lichenification (EASI 75 [22.5% vs 9.6%], EASI 90 [9.4% vs 2.8%], EASI 100 [6.1% vs 2.2%]). Treatment differences were maintained through week 16. At week 16, sign-specific EASI 75/90/100 response rates for UPA vs DUPI were as follows: erythema – 54.1% vs 34.5%, 36.0% vs 19.5%, 17.9% vs 7.4%; edema – 60.4% vs 40.0%, 43.6% vs 27.4%, 26.0% vs 18.7%; excoriation – 62.6% vs 44.0%, 48.4% vs 33.1%, 35.0% vs 23.7%; and lichenification – 56.9% vs 38.6%, 40.7% vs 23.5%, 24.9% vs 13.7%. All comparisons across all time points evaluated were nominally significant (P < .05). Conclusion: Treatment of moderate-to-severe AD with UPA resulted in a greater proportion of patients achieving EASI 75/90/100 in the 4 AD lesion signs of erythema, edema/papulation, excoriation, and lichenification compared with DUPI. Improvements were observed as early as week 2 and sustained through week 16. Sign-level differences may help clinicians individualize therapy and counsel patients on expected improvement trajectories, particularly for chronic, harder-to-treat signs such as lichenification and excoriation.