Elevating Standards in Atopic Dermatitis Through JAK Inhibitors and Optimal Treatment Targets

“Patients are telling us in the patient-reported outcomes that it's not just about clear skin, it's also about controlling the high burden of symptoms, and that most important one is itch. This new standard of care in atopic dermatitis, hitting EASI 90 and itch 0/1, is moving the bar higher,” said Christopher Bunick, MD, PhD, in an interview with Dermatology Times at the 2024 Fall Clinical Dermatology Conference in Las Vegas, Nevada.

Bunick, associate professor of dermatology and translational biomedicine at the Yale University School of Medicine in New Haven, Connecticut, and Dermatology Times’ 2024 Winter Editor in Chief, presented sessions on “Systemic Therapies for Inflammatory Skin Diseases: How to Choose Between Monoclonal Antibodies, JAK Inhibitors, and Other Therapies” and “Is EASI 75 Good Enough or Can We Do Better? Elevating Efficacy Long-Term Safety With JAK Inhibitors in Moderate-to-Severe Atopic Dermatitis.”

Alongside April Armstrong, MD, MPH; Emma Guttman-Yassky, MD, PhD; and Lisa Swanson, MD, Bunick discussed mechanisms of action and drug safety of JAK inhibitors and biologics for inflammatory skin diseases. In his second session, Bunick presented with Brad Glick, DO, MPH, and Alexandra Golant, MD, to review the connection between the Aiming High in Eczema and Atopic Dermatitis recommendations, or the AHEAD recommendations, all the way through the new standard of care for atopic dermatitis.

Bunick’s Session Highlights

Session 1: Systemic Therapies for Inflammatory Skin Diseases

1) Systemic Corticosteroids in Atopic Dermatitis: Bunick emphasized that corticosteroids, while still frequently used (in about 20% of patients with atopic dermatitis), contradict current American Academy of Dermatology (AAD) guidelines, especially for long-term management. Despite known safety and efficacy concerns, 25% of these patients continue using corticosteroids beyond 3 months. Bunick’s recommendations were clear: clinicians should pivot away from corticosteroids, except for short duration as a transition to advanced systemic therapies, which offer better long-term safety and efficacy. His message encouraged clinicians to align treatment protocols with AAD guidelines to minimize the risks associated with prolonged corticosteroid exposure.

2) Long-Term Safety of JAK Inhibitors: Addressing the concerns surrounding the long-term safety of JAK inhibitors, Bunick highlighted recent findings demonstrating promising safety profiles for upadacitinib and abrocitinib. Upadacitinib’s 5-year data and abrocitinib’s 4-year data both show minimal serious adverse events, such as malignancy, major adverse cardiovascular events (MACE), and venous thromboembolism (VTE). Importantly, the incidence rates of these adverse events are either consistent with or lower than those in the general atopic dermatitis population. However, a slight increase in shingles rates (approximately 3 to 5 cases per 100 patient-years) was noted, a manageable issue with prophylactic shingles vaccination. Bunick’s review of upadacitinib and abrocitinib highlighted the long-term safety of JAK inhibitors and reinforced their suitability as alternatives to corticosteroids.

3) Managing Alopecia Areata: Shifting focus to alopecia areata, Bunick discussed the differing effects of baricitinib and ritlecitinib. He explored a unique aspect of baricitinib use, particularly its association with weight gain in some patients, with a reported incidence of 15 to 21 events per 100 patient-years. Bunick presented findings from the BRAVE studies suggesting that JAK2 inhibition can interfere with the leptin signaling pathway, effectively mimicking a fasted state and potentially leading to weight gain. In contrast, ritlecitinib, which selectively binds irreversibly to JAK3, avoids JAK2 interactions and does not impact the leptin pathway, reducing the likelihood of such adverse effects. According to Bunick, this distinction is critical for clinicians when choosing between JAK inhibitors for alopecia areata, particularly for patients at risk of metabolic changes.

4) Comparing Atopic Dermatitis Biologics: Bunick concluded his first session by examining various biologics for atopic dermatitis, noting differences in the IL-4 and IL-13 targeting profiles of dupilumab, rademikibart, tralokinumab, and lebrikizumab. Each biologic exhibits distinct target engagement characteristics, which may translate to variations in efficacy and safety. As the therapeutic landscape for atopic dermatitis broadens, understanding these nuances helps dermatologists tailor treatment plans more precisely to patient needs, potentially optimizing outcomes while managing risk.

Session 2: Is EASI 75 Good Enough or Can We Do Better?

1) Optimal Treatment Targets: EASI 90 and NRS 0/1: The AHEAD recommendations advocate for a dual-treatment target approach—achieving both EASI 90 (skin clearance) and NRS 0 or 1 (itch clearance). Bunick highlighted data indicating that achieving skin clearance alone without itch control results in significant quality-of-life (QoL) deficits. Patients with a remaining itch score as low as 2 or 3 still report substantial impacts on daily functioning and overall QoL. Bunick explained that this dual-target approach reflects a new standard that aims not only to control physical symptoms, but also to address the broader impact of atopic dermatitis on patients’ lives.

2) LEVEL UP: Bunick discussed insights from the LEVEL UP trial, a head-to-head comparison of upadacitinib and dupilumab. The trial included a period 2 switch phase, wherein patients unresponsive to dupilumab at week 16 were transitioned to upadacitinib without a washout period. By week 32, 70% of these patients achieved EASI 75. Additionally, 27% reached the more ambitious goal of EASI 90 and NRS 0 or 1, demonstrating the efficacy of upadacitinib in cases where dupilumab had not achieved optimal results.

3) Therapeutic Inertia and Clinical Practice: The LEVEL UP findings underscore the need to overcome therapeutic inertia—the reluctance to adjust or switch treatments when a patient is not achieving target outcomes. Bunick emphasized that clinicians must be vigilant in assessing response milestones, specifically at week 16 for patients on biologics like dupilumab. If patients fail to reach EASI 75 by this checkpoint, it may be beneficial to consider alternative systemic therapies that have demonstrated robust efficacy.

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