563 - Dupilumab improves skin lipid composition in atopic dermatitis irrespective of patient filaggrin (FLG) mutation status
Authors: Berdyshev Evgeny , Goleva Elena , Bronoff Anna-Sofia , Richers Brittany N , Garcia Shannon , Ramírez-Gama Marco , Taylor Patricia , Bissonnette Robert , Zahn Joseph , Agueusop Inoncent , Bafna Shantanu , Boguniewicz Mark , Zhang Annie 
Published: February 2024

Abstract

Introduction/Background
Type 2 inflammatory cytokines interleukin 4 (IL-4) and IL-13 play an important role in skin barrier disruption in atopic dermatitis (AD). Filaggrin and ceramides play a crucial role in skin barrier integrity. Loss of function mutations in the FLG gene are associated with the impaired skin barrier function and more severe AD.1,2 FLG mutations only affect a minority of AD patients; however, increased IL-4 and IL-13 cytokines are a common cause of reduced filaggrin expression in patients with AD, independent of FLG genotype.

Objectives
To explore whether dupilumab treatment improves skin barrier function in patients with or without FLG mutations.

Methods
In the BArrier function and LIpidomics STudy in Atopic Dermatitis (BALISTAD; NCT04447417), a 16-week study in patients with AD aged 12 to 65 years, adult patients with AD received dupilumab 300 mg every 2 weeks; adolescent patients with AD received dupilumab 200 mg every 2 weeks if their baseline weight was &lt;60 kg and 300 mg if ≥60 kg. FLG mutations were evaluated in DNA from blood samples of consenting patients with AD and healthy volunteers. Transepidermal water loss (TEWL) was assessed longitudinally after 5 skin tape strippings (STS) from AD lesions (n = 26) and from the skin of healthy participants (n =26) (age: 12 to 63 years) over a 16-week course of dupilumab treatment. Quantitative N(C18)S-ceramide analysis of STS samples collected on Days 1, 15, 29, 57, and 85, and at Week 16 from AD lesions and from the skin of healthy participants was performed using liquid chromatography tandem mass spectrometry.

Results
At baseline, mean TEWL after 5 STS (TEWL5) was significantly higher in AD lesional skin than healthy skin (p&lt;0.0001). The mean TEWL5 in AD lesions in subjects with FLG mutations (n = 6/19) was significantly higher at baseline than in AD subjects without mutations (P &lt; 0.0001). Dupilumab treatment significantly reduced TEWL5 in AD lesional skin as early as Week 2 with a progressive decrease through Week 16 (P &lt; 0.0001). Reduction in mean TEWL5 was similar from Week 2 to Week 16 in AD patients with and without FLG mutations. At Week 16, TEWL5 was comparable to healthy skin in the lesional skin of AD patients with and without FLG mutations (P &gt; 0.05). AD skin lesions had increased levels of N(C18)S-ceramides at baseline (P &lt; 0.0001); but no differences were noted in subjects with or without FLG mutations (P &gt; 0.05). Dupilumab treatment significantly reduced levels of N(C18)S-ceramides in AD lesional skin as early as Week 2 with a progressive decrease through Week 16 (P &lt; 0.0001). Dupilumab treatment decreased levels of N(C18)S-ceramides in STS samples similarly in subjects with and without FLG mutations from Week 2 to Week 16.

Conclusions
Dupilumab treatment normalizes TEWL5 and decreases levels of N(C18)S-ceramides in AD lesional skin of subjects with and without FLG mutations.