Switching Gears in Atopic Dermatitis: How Upadacitinib Helps Patients Reach Optimal Targets After Dupilumab Inadequacy

In the ever-evolving landscape of atopic dermatitis (AD) management, dermatologists are increasingly guided by the imperative to aim higher. The AHEAD consensus has redefined success, not just as partial symptom control, but as achievement of minimal disease activity (MDA) through optimal skin clearance and itch relief.¹ New data from the Level Up study reinforces this mindset by showing that switching from dupilumab (DUPI) to upadacitinib (UPA) enables more patients to achieve these optimal targets—quickly and effectively.²

Level Up: A Real-World-Inspired Study Design

Level Up is a global head-to-head, phase 3b/4 study evaluating adult and adolescent patients with moderate to severe AD with inadequate response to systemic therapy. In Period 1, upadacitinib demonstrated superior efficacy versus dupilumab across multiple end points, including EASI 75, EASI 90, itch reduction, and MDA at week 16—results now published in the British Journal of Dermatology.³

Importantly, the study design also reflects real-world clinical practice: patients who did not achieve EASI 75 on DUPI after 16 weeks were directly switched to UPA 15 mg once daily without a washout period, mirroring how dermatologists manage patients in routine care. Patients were eligible for escalation to 30 mg after one month if certain criteria were met.²

All outcomes assessed one month post-switch reflect the effect of UPA 15 mg monotherapy, as use of new topical treatments during this phase led to patients being classified as non-responders.² 

What happened after the switch? A rapid and meaningful improvement:

One Month Post-Switch:

• 67% achieved EASI 75 (moderate target for skin)
• 58% achieved WP-NRS ≥4 (moderate target for itch)
• 32% achieved EASI 90 (optimal target for skin)
• 28% achieved WP-NRS 0/1 (optimal target for itch)
  

Four Months Post-Switch:

• 80% achieved EASI 75(moderate target for skin)
• 60% achieved WP-NRS ≥4 (moderate target for itch)
• 59% achieved EASI 90(optimal target for skin)
• 37% achieved WP-NRS 0/1 (optimal target for itch)
• 27% achieved both EASI 90 & WP-NRS 0/1 (meeting criteria for MDA)

From Moderate to Optimal Targets: Aligning with AHEAD

The AHEAD recommendations emphasize not settling for "good enough." Instead, they define moderate and optimal treatment targets —then modify therapy if those targets are not met within 3 to 6 months. Examples include:

• EASI 90 or IGA 0/1 for optimal skin clearance
• Worst Itch NRS 0/1 for optimal itch relief

Level Up data reinforces this paradigm, demonstrating that a timely switch to UPA can enable patients with a partial response to DUPI to achieve optimal outcomes and cross into MDA territory.

Reinforced by Real-World Evidence

The TARGET-DERM AD registry confirms the value of hitting optimal targets.⁴ In a cohort of nearly 2000 patients, those who achieved both clear/almost-clear skin (IGA 0/1) and complete itch relief (WI-NRS 0/1) were significantly more likely to report ideal quality-of-life scores (DLQI 0/1), restful sleep (Sleep-NRS 0/1), and reduced pain (Pain-NRS 0/1). Odds ratios of reporting these optimal outcomes were as high as 41.7 for POEM and 16.1 for sleep outcomes​.

Level Up Switch findings are further supported by a recent real-world multicenter study published in the Journal of the American Academy of Dermatology, which showed that nearly 77% of adult patients with AD who discontinued DUPI due to lack of efficacy or adverse events achieved treatment success (EASI 75 or IGA 0/1) after 16 weeks on UPA. Importantly, EASI 100/IGA 0 was achieved in over half of patients, and the safety profile remained favorable with no discontinuations and low rates of adverse events.⁵ 

Safety Reassurance Amid Efficacy Gains

The Level Up study also confirmed a reassuring safety profile post-switch. Only 6.7% of patients experienced acne vulgaris. No serious infections were reported, and no new safety signals emerged—providing further reassurance for clinicians considering a treatment switch. These findings align with 6-year long-term safety data, which show no new safety signals and consistent tolerability over time.

Practice Implications

In line with AHEAD, the convergence of data from Level Up and TARGET-DERM paints a clear picture:

• Don’t settle for partial improvement.
• Switch early if targets are not met.
• Aim for optimal clearance and itch relief to truly improve lives.

With the availability of highly effective and fast-acting agents like UPA, achieving optimal outcomes in AD is not just aspirational—it’s actionable.

Christopher G. Bunick, MD, PhD, is editor in chief of Dermatology Times and associate professor of dermatology and translational biomedicine at Yale School of Medicine. Level Up data were presented at the Fall Clinical 2024 dermatology conference. Dr Bunick was a principal investigator in the LEVEL UP trial.

References

1. Silverberg JI, Gooderham M, Katoh N, et al. Combining treat‐to‐target principles and shared decision‐making: international expert consensus‐based recommendations with a novel concept for minimal disease activity criteria in atopic dermatitis. J Eur Acad Dermatol Venereol. 2024 Nov;38(11):2139-2148. doi: 10.1111/jdv.20229
2. Bunick C, Magnolo N, Moore A, et al. Switching from dupilumab to upadacitinib in adults and adolescents with moderate-to-severe atopic dermatitis and inadequate response to dupilumab: efficacy and safety results from the phase 3b/4 LEVEL UP study.
   J of Skin. 2024;8(6):s451. doi:10.25251/skin.8.supp.451
3. Silverberg JI, Bunick CG, Hong HC, et al. Efficacy and safety of upadacitinib versus dupilumab in adults and adolescents with moderate-to-severe atopic dermatitis: week 16 results of an open-label randomized efficacy assessor-blinded head-to-head phase IIIb/IV study (Level Up). Br J Dermatol. 2024 Dec 23;192(1):36-45. doi: 10.1093/bjd/ljae404.
4. Silverberg JI, Calimlim BM, Grada A, et al. Real-world evidence on the benefits of optimal itch relief and skin clearance in atopic dermatitis management: a study from the TARGET-DERM AD registry. J Dermatolog Treat. 2024 Dec;35(1):2428729. doi:
5. Georgakopoulos JR, Sheka D, Rankin B, et al. Real-world effectiveness and safety of upadacitinib for the treatment of atopic dermatitis in adult patients switched from dupilumab: a multicenter retrospective study. J Am Acad Dermatol. 2023 Dec;89(6):1308-1311. doi: 10.1016/j.jaad.2023.08.059.