The Clinical Burden of AD and the JAK-STAT Pathway

The National Eczema Association estimates that 31.6 million individuals in the United States have some form of eczema.¹ Patients report that itch, skin redness, and dryness are the most burdensome symptoms of disease, and 15% to 30% of patients with atopic dermatitis (AD) report sleep-related issues.¹ With patients’ high level of disease burden comes an urgent need for novel treatment options.

To better understand the burden of AD and novel treatment pathways, The Dermatologist reached out to Raj Chovatiya, MD, PhD, assistant professor of dermatology and director for the center of eczema and itch at Northwestern University Feinberg School of Medicine in Chicago, IL. He also recently spoke about this topic at the Diversity in Dermatology 2022 Conference.

The Dermatologist: Can you give us a brief overview of your session on the burden of disease and a novel topical pathway?

Dr Chovatiya: In this session, we reviewed the clinical burden of AD, including the prevalence, diagnostic challenges, patient journey, and symptomatic burden, with a focus on unmet needs for targeted, topical therapy to address the signs and symptoms of individuals with mild to moderate AD. We discussed the pathophysiology of AD and the role of the Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathway. Then we highlighted a novel topical JAK inhibitor, ruxolitinib 1.5% cream.²Lastly, we evaluated the efficacy and safety data from the TRuEAD1 and TRuE-AD2 phase 3 studies that led to its recent approval for topical treatment of mild to moderate, inadequately controlled AD in individuals aged 12 years or older.³

The Dermatologist: What is the burden of disease for patients with AD? How has it changed over the years?

Dr Chovatiya: The burden of AD is both immense and quite heterogenous. AD is associated with variable signs, lesion distribution, extent, severity, and symptoms (including itch, skin pain, sleep disturbance, and mental health symptoms); long-term course; and overall quality-of-life burden—all of which contribute to patient burden in AD. Although this burden itself is not new, our increased understanding of how different clinical domains of AD impact patients represents the culmination of decades of research that have dispelled antiquated notions of AD as a largely transient, mild, easily treated, eczematous rash of childhood.⁴

The Dermatologist: What is the novel topical pathway? How will it change the treatment landscape for patients with AD?

Dr Chovatiya: The JAK-STAT pathway is an important upstream signal transduction pathway associated with many of the cytokines (ie, soluble, protein mediators of the immune system) that activate inflammation in the skin.⁵ JAKs are a family of 4 enzymes (JAK1, JAK2, JAK3, and [tyrosine kinase 2] TYK2) that reside intracellularly and are associated in different combinations with different cytokine receptors. JAK-STAT signaling “decodes” the message carried by extracellular cytokines and drives intracellular changes in inflammatory gene expression. Ruxolitinib is a JAK inhibitor that shows increased selectivity for JAK 1/2 in preclinical models and inhibits this proinflammatory signaling cascade. To date, there have been few targeted treatment options for patients with AD, especially for those with mild to moderate disease (which represents most individuals with AD) and in a topical formulation (a treatment route commonly used by patients with AD).

The Dermatologist: What is the key take-home message from your session?

Dr Chovatiya: To sum it up in 3 easy points: (1) AD is associated with an incredible patient burden, and additional targeted, efficacious, safe, and feasible treatment options are needed; (2) Ruxolitinib 1.5% cream represents a novel treatment class (topical JAK inhibitor) that targets an important signaling pathway associated with inflammation in AD; (3) Based on results from the phase 3 TRuE-AD clinical trial program, the majority of patients with AD who used topical ruxolitinib achieved clear or almost clear skin and clinically signifi cant reduction of itch at 8 weeks, with an overall low rate of adverse events.

References
1. Eczema stats. National Eczema Association. Accessed February 17, 2022. https://nationaleczema.org/research/eczema-facts

2. Breaking news: FDA approves Opzelura™ (ruxolitinib) cream. News release. National Eczema Association. September 21, 2021. Updated November 18, 2021. Accessed February 17, 2022. https://nationaleczema.org/opzelura-approval

3. Incyte announces new findings from pooled analyses of the phase 3 TRuE-AD program evaluating ruxolitinib cream in patients with atopic dermatitis. News release. National Eczema Association. April 23, 2021. Updated July 8, 2021. Accessed February 17, 2022. https://nationaleczema.org/incyte-42321

4. Barrett A, Hahn-Pedersen J, Kragh N, Evans E, Gnanasakthy A. Patient-reported outcome measures in atopic dermatitis and chronic hand eczema in adults. Patient. 2019;12(5):445-459. doi:10.1007/s40271-019-00373-y

5. Szalus K, Trzeciak M, Nowicki RJ. JAK-STAT inhibitors in atopic dermatitis from pathogenesis to clinical trials results. Microorganisms. 2020;8(11):1743. doi:10.3390/microorganisms8111743