Switching from dupilumab to upadacitinib improves skin clearance, itch in atopic dermatitis

Results from period 2 of the phase 3b/4 LEVEL UP study suggest that switching from dupilumab to upadacitinib may improve skin clearance and itch outcomes in adolescents and adults with moderate-to-severe atopic dermatitis (AD) who do not achieve adequate response after 16 weeks of dupilumab therapy.¹

Upadacitinib switch evaluated in phase 3b/4 LEVEL UP trial

Atopic dermatitis is a chronic inflammatory skin disease characterized by pruritus and eczematous lesions. Although dupilumab and upadacitinib are both approved for moderate-to-severe disease, a substantial proportion of patients treated with dupilumab do not reach moderate or optimal treatment targets within 16 weeks.

LEVEL UP (NCT05601882) was a global, randomized, open-label, efficacy assessor–blinded, head-to-head trial comparing upadacitinib with dupilumab in patients aged 12 to younger than 65 years.² In period 1, patients received upadacitinib 15 mg once daily with possible escalation to 30 mg, or dupilumab per label, for 16 weeks. Patients who did not achieve at least 75% improvement in Eczema Area and Severity Index (EASI 75) at week 16 entered period 2.

In period 2, patients previously treated with dupilumab were switched directly to upadacitinib 15 mg without a washout period, with potential dose escalation to 30 mg at week 20 based on clinical response.

Skin clearance outcomes after switching from dupilumab

A total of 208 patients switched from dupilumab to upadacitinib. At entry into period 2 (week 16), mean EASI score was 13.5 (SD, 7.9), mean body surface area involvement was 22.6% (SD, 15.6), and mean weekly average Worst Pruritus Numerical Rating Scale (WP-NRS) score was 4.1 (SD, 2.3).

By week 32, 79.6% of patients achieved EASI 75. More stringent outcomes were also observed: 58.7% achieved EASI 90, and 19.9% achieved complete clearance (EASI 100).

Simultaneous achievement of near-complete skin clearance and minimal itch—defined as EASI 90 and WP-NRS 0/1—was reached by 26.8% of patients at week 32. Improvements were observed as early as week 20, 4 weeks after switching.

The authors reported, “Many of these patients experienced clinically meaningful improvements in skin clearance and itch relief within 1 month (4 weeks) after switching.”

Itch reduction and dose escalation findings

Among patients with baseline WP-NRS ≥ 4 who had not achieved at least a 4-point reduction at week 16, 60.2% experienced a ≥ 4-point improvement by week 32. Additionally, 37.0% achieved WP-NRS 0 or 1 among those with baseline WP-NRS greater than 1.

Nearly half of patients (47.6%) required dose escalation to upadacitinib 30 mg between weeks 20 and 32. Among those who achieved simultaneous EASI 90 and WP-NRS 0/1 at week 32, most remained on the 15 mg dose.

The study was designed without a washout period to reflect routine practice and, as the authors noted, “to better align with the real-world experience of patients.”

Safety profile consistent with prior upadacitinib data

Safety outcomes during period 2 were consistent with the known safety profile of upadacitinib. Treatment-emergent adverse events were reported in 48.1% of patients who switched.

The most frequently reported adverse events were nasopharyngitis (8.7%), acne (6.7%), upper respiratory tract infection (5.8%), and atopic dermatitis (5.8%). No serious infections were reported in the switch group. One nonserious opportunistic infection (eczema herpeticum) occurred. There were no reported malignancies, adjudicated major adverse cardiovascular events, venous thromboembolic events, gastrointestinal perforations, or deaths.

The authors wrote, “The overall safety profile of UPA reported here was consistent with the previous studies and the established long-term safety profile documented for up to 6 years of exposure [12], with no new safety signals identified.”

Clinical implications for treatment targets in moderate-to-severe AD

The authors concluded, “The results from the LEVEL UP switch study, combined with existing evidence, indicate that UPA is a promising option for patients experiencing issues with DUPI, such as inadequate response or tolerability problems.” They added that “UPA offers clinicians an effective means to help patients achieve optimal outcomes and overcome therapeutic inertia, in alignment with AHEAD treat-to-target recommendations.”

Limitations included the open-label design and the absence of a comparator group in period 2. The population was limited to patients younger than 65 years because dose escalation to 30 mg was required based on protocol-defined response criteria.

For clinicians managing moderate-to-severe AD, these data support consideration of switching to upadacitinib when patients do not meet treatment targets after 16 weeks of dupilumab therapy.

References

1. Bunick CG, Magnolo N, Moore A, et al. Switching from Dupilumab to Upadacitinib in Adults and Adolescents with Moderate-to-Severe Atopic Dermatitis After Inadequate Response to Dupilumab: Efficacy and Safety Results from Period 2 of Phase 3b/4 Study (LEVEL UP). American Journal of Clinical Dermatology. Published online January 14, 2026. doi:https://doi.org/10.1007/s40257-025-01003-0
2. Guttman-Yassky E, Teixeira HD, Simpson EL, et al. Once-daily upadacitinib versus placebo in adolescents and adults with moderate-to-severe atopic dermatitis (Measure Up 1 and Measure Up 2): results from two replicate double-blind, randomised controlled phase 3 trials. Lancet (London, England). 2021;397(10290):2151-2168. doi:https://doi.org/10.1016/S0140-6736(21)00588-2