Featured Student: Joey Cascone

Joey Cascone is a 4th-year medical student in the MD-only program at the University of Missouri-Kansas City rural satellite campus. His research and clinical interests are focused on narrowing the gap in health care disparities for underserved populations, both rural and urban. Joey is particularly interested in the cutaneous manifestations of autoimmune disease and malignancy. He enjoys cooking and baking, playing piano, and playing golf in his spare time.

Introduction

Atopic dermatitis (AD) is one of the most prevalent chronic skin diseases worldwide. It is characterized by recurrent, relapsing skin rashes and potentially intense pruritus. The pathogenesis is multifaceted but ultimately marked by impaired epidermal barrier function and aberrant immune responses. Medicines that target both of these aspects offer the best chance at sustainable treatment. Dupilumab is a monoclonal antibody that targets the IL-4 receptor alpha. It modulates both the type 2 immune response and improves skin barrier function in AD. Abrocitinib is a JAK inhibitor capable of modulating the cytokine signals implicated in type 2 immunity. While JAK inhibitors have previously demonstrated a quicker onset of action compared to dupilumab in AD, their role in restoring impaired skin barrier function has not previously been identified. The purpose of this study, published by Dr. Jui-Wen Chang and colleagues in JAAD, was to determine whether JAK inhibitors differ from dupilumab in restoring skin barrier function in AD patients.

Study Design and Methods
This small prospective cohort study evaluated 33 adult patients with moderate-to-severe AD along with 17 age and gender matched healthy controls from March 2023 to March 2024. AD patients were assigned to either the dupilumab group (N = 16) or the abrocitinib group (N = 17). Itch intensity using the Peak Pruritus Numeric Rating Scale (PP-NRS) and lesion severity using the Eczema Area and Severity Index (EASI) were measured at baseline, week 4, and week 12. Skin samples from lesional and non-lesional skin were collected for proteomic analysis at these time points. All patients used emollients twice daily for the duration of the study, except within 3 hours before skin sample collection.

Results

Both dupilumab and abrocitinib significantly improved skin lesions, with EASI scores significantly decreasing by week 4 in both groups. There was no statistically significant difference in EASI score between the two groups. Both treatments significantly reduced pruritus by week 4 and demonstrated meaningful reduction in itch overall. However, the abrocitinib group demonstrated a greater reduction in itch compared to the dupilumab group at week 12, though within-group analysis showed no significant reduction in itch for both groups at that time point.

Abrocitinib was associated with a greater decrease in lesional transepidermal water loss (TEWL) at week 4 and decreased non-lesional TEWL overall compared to dupilumab. Within-group analysis showed statistically significant improvements in lesional and non-lesional hydration by week 4 in abrocitinib only. Neither drug showed statistically significant improvements in skin hydration at week 12. No significant differences were observed between the two groups in skin hydration.

Proteomic analysis revealed widespread differences in protein expression between AD and healthy skin in both lesional and non-lesional areas. After 12 weeks of treatment, skin protein

profiles for both lesional and non-lesional skin in the abrocitinib group showed greater improvement toward healthy control profiles compared to those in the dupilumab group. In lesional skin, abrocitinib increased expression of proteins involved in keratinocyte differentiation and integrity, including filaggrin-2, PSMB6, KRT10, and KRT5, while dupilumab only increased expression of PSMB6. Expression of inflammatory proteins such as IL-18 and STAT1, and KRT16, a protein associated with keratinocyte barrier dysfunction, were significantly decreased only in the abrocitinib group. For non-lesional skin, KRT16, IL-18, and involucrin were significantly decreased only in the abrocitinib group.

Limitations

This study is clearly limited by the relatively small number of cases and controls. For this reason, further research is required to determine the mechanistic roles of each aforementioned biomarker and their significance in AD and skin barrier function. Additionally, while emollient use was standardized, other uncontrollable factors could influence skin barrier measures at each time point. Further research with larger cohorts and longer observation is necessary to better determine any differences in benefit between abrocitinib and dupilumab.

Significance

While both dupilumab and abrocitinib demonstrated improved skin barrier function, abrocitinib had a stronger effect in this measure overall through expanded modulation of skin barrier proteins and inflammatory markers. Abrocitinib may also demonstrate a modest clinical improvement in terms of itch reduction after 12 weeks of treatment compared to dupilumab. Regardless, both medicines are effective for the treatment of atopic dermatitis as there was improvement in EASI score with no statistically significant difference between the two groups at any measured time point. These findings contribute to a better understanding of how these two therapies affect the pathophysiology of AD.