Abstract Atopic dermatitis (AD) is associated with significant disruption in skin barrier function, mediated by the type 2 inflammatory cytokines interleukin (IL)-4 and IL-13. This study reports the effect of dupilumab treatment in paediatric patients (aged 6–11 years) with moderate-to-severe AD on skin barrier function and clinician- and patient-reported outcomes. PELISTAD (NCT04718870) was an open-label, exploratory study on skin barrier function in children aged 6–11 years with moderate-to-severe AD treated with dupilumab for 16 weeks based on baseline patient weight (300 mg every 4 weeks: ≥ 15 kg to < 30 kg; 200 mg every 2 weeks: ≥ 30 kg to < 60 kg) and matched healthy volunteers. Transepidermal water loss (TEWL) was assessed longitudinally after skin tape stripping from lesional and nonlesional skin of patients with AD treated with dupilumab, and from healthy skin. Eczema Area and Severity Index (EASI) and skin pain numerical rating scale (NRS) were assessed during the same periods. Twenty-three dupilumab-treated patients and 18 healthy volunteers were included in the study. After 16 weeks of dupilumab treatment, median (95% confidence interval) TEWL after five skin tape strips significantly decreased in the lesional skin of patients with AD (33.8, 25.2–42.3) compared with baseline (63.7, 44.1–83.3; P < 0.001). Least squares mean (standard error) TEWL after five skin tape strips in lesional skin (30.7, 3.5) was comparable with that observed in healthy skin (27.8, 4.4) at week 16 (P = 0.62). Similar improvement was observed in nonlesional skin (25.5, 2.1), which did not significantly differ from healthy skin (24.6, 2.6; P = 0.79). Mean (SD) EASI decreased from 34.8 (11.9) at baseline to 11.3 (11.0) at week 16. Improvement was also observed in skin pain NRS, which decreased from mean (SD) 6.8 (2.5) at baseline to 2.3 (1.4) at week 16. Overall safety was consistent with the known dupilumab safety profile. Dupilumab treatment normalizes skin barrier function and improves clinician- and patient-reported outcomes in paediatric patients aged 6–11 years with moderate-to-severe AD. This research was sponsored by Sanofi and Regeneron Pharmaceuticals Inc. ClinicalTrials.gov identifier: NCT04718870.

Background: We analyzed the impact of dupilumab on skin barrier function, clinical outcomes, and patient-reported outcomes (PROs) in patients aged 6–11 years with moderate-to-severe atopic dermatitis (AD).

The effect of the inhibition of type 2 inflammation by dupilumab on stratum corneum (SC) lipids responsible for skin barrier function in children with atopic dermatitis (AD) has not been evaluated. In the PELISTAD open-label study (NCT04718870), pediatric (6-11 years old, n=23) patients with moderate to severe AD were treated with dupilumab for 16 weeks then followed up for three months. Matched healthy children (HC, n=18) were followed for 28 weeks. SC was collected using skin tape stripping (STS) and STS samples were serially evaluated for changes in lipid profile by mass spectrometry. At baseline, lesional SC of AD children, in comparison to HC, had increased level of N(C18S)-Ceramides (mean Fold Change (mFC) 3.314, p=0.00224), decreased levels of esterified omega-hydroxy fatty acid containing ceramides (EO(C18S)S-Ceramides, mFC 0.48, p=0.00424), and increased ratio of N(C18S)-Ceramides-to-EO(C18S)-Ceramides (mFC 6.35, p<0.0001). Treatment with dupilumab significantly improved lipid components (N(C18)S-Ceramides, within 4 weeks, p=0.00125; EO(C18S)-Ceramides, within 8 weeks, p=0.00233; and N(C18S)-Ceramide-to-EO(C18S)-Ceramide ratio, within 2 weeks, p=0.0074). Normalized levels of SC lipids in lesional skin were sustained for up to three months after the end of treatment. Dysregulation of SC barrier lipids in non-lesional skin was less pronounced than that of lesional skin but their normalization followed similar pattern as lesional skin dynamics. Dupilumab normalized the levels of SC lipids in pediatric AD patients within one-two months after the beginning of treatment. These beneficial changes persisted for at least three months after the end of treatment.

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 <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<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 < 0.0001). Dupilumab treatment significantly reduced TEWL5 in AD lesional skin as early as Week 2 with a progressive decrease through Week 16 (P < 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 > 0.05). AD skin lesions had increased levels of N(C18)S-ceramides at baseline (P < 0.0001); but no differences were noted in subjects with or without FLG mutations (P > 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 < 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.

Abstract The objective of this analysis is to report the effect of dupilumab treatment on skin barrier function and patient-reported outcomes (PROs) in adults and adolescents with moderate-to-severe atopic dermatitis (AD). BALISTAD (NCT04447417) was an open-label trial in which transepidermal water loss (TEWL) was assessed repeatedly before and after skin tape stripping (STS) samples were taken from lesional and nonlesional skin of 26 patients with AD treated with dupilumab, and from normal skin of 26 matched healthy volunteers aged 12–65 years over a period of 16 weeks. PROs assessed included Patient-Oriented Eczema Measure (POEM), Peak Pruritus Numerical Rating Scale (PP-NRS) and Dermatological Life Quality Index [DLQI; for patients > 17 years old; Children’s DLQI (CDLQI) for patients aged > 12 to < 17 years]. At baseline, the median TEWL after five STS was statistically significantly higher in the lesional and nonlesional skin of patients with AD compared with healthy skin (P < 0.001 and P < 0.01, respectively) and statistically significantly decreased following dupilumab initiation as early as week 2 (P < 0.001 and P < 0.05, respectively). After 16 weeks of dupilumab treatment, there was no statistically significant difference in adjusted mean TEWL in AD lesional and nonlesional skin compared with matched healthy skin (P = 0.225 and P = 0.163, respectively). Significant improvement from baseline [mean (SD) change from baseline] was seen as early as week 2 in mean POEM [−8.4 (5.1)], DLQI [−5.3 (4.7)], CDLQI [−6.2 (4.7)] and PP-NRS [−2.2 (1.8); P < 0.001 and P < 0.05)] for CDLQI. Improvement was sustained through to week 16 [mean (SD) change from baseline; P < 0.001] for POEM [−13.6 (8.5)], DLQI [−8.6 (7.4)] and PP-NRS [−4.2 (2.6)] and with a P-value of < 0.01 for CDLQI [−9.2 (5.0)]. Dupilumab treatment normalizes epidermal barrier function in lesional and nonlesional skin in patients with moderate-to-severe AD, as measured with TEWL, and improves PROs. Funding sources: research sponsored by Sanofi and Regeneron Pharmaceuticals Inc.

BACKGROUND: Atopic dermatitis (AD) skin lesions are associated with oozing, bleeding, and erythema. This suggests that AD is associated with vascular changes. Dupilumab is an antibody to the alpha subunit of IL-4 receptor that demonstrates strong efficacy in the treatment of AD. IL-4 is known to reduce the permeability barrier function of vascular endothelium.OBJECTIVE: To examine the effects of dupilumab on vascular barrier function in AD skin.METHODS: Using proteomic analysis, we evaluated the plasma protein composition in skin tapes of lesional and nonlesional skin of adults and adolescents with moderate to severe AD over the course of a 16-week treatment with dupilumab and compared those with matched healthy subjects.RESULTS: At baseline, 115 plasma proteins were detected in AD skin and globally increased (1.5-fold or greater) compared with healthy skin. Functionally, these proteins included immunoglobulins, proteins involved in the coagulation process, enzymes, protease inhibitors, transport proteins, acute-phase proteins, complement proteins, and other pleiotropic proteins. Noteworthy, fibrinogens, fibronectin, and heme-binding proteins haptoglobin and hemopexin were among the top proteins originating from plasma and were increased in AD lesional versus healthy skin at baseline (P < .0001). Dupilumab treatment resulted in significantly reduced levels of plasma proteins in AD skin (P < .0001), with most dropping to levels seen in healthy skin or no longer detectable at week 16.CONCLUSIONS: Inhibition of IL-4/IL-13 action by dupilumab significantly reduces the efflux of plasma proteins into AD skin. Several of these proteins, such as fibrinogens and fibronectin, are known to enhance Staphylococcus aureus colonization and are associated with AD skin severity. (c) 2023 American Academy of Allergy, Asthma & Immunology (J Allergy Clin Immunol Pract 2023;11:1421-8)

Staphylococcus aureus colonizes patients with atopic dermatitis (AD) and exacerbates disease by promoting inflammation. The present study investigated the safety and mechanisms of action of Staphylococcus hominis A9 ( Sh A9), a bacterium isolated from healthy human skin, as a topical therapy for AD. Sh A9 killed S. aureus on the skin of mice and inhibited expression of a toxin from S. aureus ( psm α) that promotes inflammation. A first-in-human, phase 1, double-blinded, randomized 1-week trial of topical Sh A9 or vehicle on the forearm skin of 54 adults with S. aureus -positive AD (NCT03151148) met its primary endpoint of safety, and participants receiving Sh A9 had fewer adverse events associated with AD. Eczema severity was not significantly different when evaluated in all participants treated with Sh A9 but a significant decrease in S. aureus and increased Sh A9 DNA were seen and met secondary endpoints. Some S. aureus strains on participants were not directly killed by Sh A9, but expression of mRNA for psm α was inhibited in all strains. Improvement in local eczema severity was suggested by post-hoc analysis of participants with S. aureus directly killed by Sh A9. These observations demonstrate the safety and potential benefits of bacteriotherapy for AD.

Atopic dermatitis (AD+) with peanut allergy (PA+) is associated with increased transepidermal water loss (TEWL), low urocanic acid (UCA, a filaggrin breakdown product), and reduced ratio of EOS-ceramides to NS-ceramides. Here we explored whether PA without AD (AD-PA+) also had skin barrier abnormalities. Skin tape strips (STS) were collected from non-lesional skin of AD+PA+ (n=30), AD-PA+ (n=14), AD+PA- (n=21), and 33 non-atopics (NA). The content of cis- and trans-UCA as well as skin sphingolipids were evaluated by liquid chromatography tandem mass spectrometry. The total content of UCA in stratum corneum of AD-PA+ subjects was significantly reduced in comparison to NA (Median: 27 vs 42 mg/mg protein; p=0.001), was as low as in non-lesional skin of AD+PA- (30 mg/mg protein; p=<0.0001 vs NA) and insignificantly above UCA level in AD+PA+ subjects (21; p=0.2). The ratio between cis- and trans-UCA was the same in NA, AD-PA+, and AD+PA- groups (1,2;1.3;1.3, respectively), with AD+PA+ group having the lowest cis/trans-UCA ratio (0.3; p=0.0029 vs NA). The TEWL in AD-PA+ subjects was not different from that in healthy skin. Interestingly, in contrast to the dynamics of UCA content within studied groups, AD-PA+ subjects had increased EOS/NS-ceramide ratio vs NA (1.9 vs 1.0; p=0.0092) while AD+PA- and AD+PA+ groups had decreased proportion of EOS-ceramides (0.7 and 0.4, respectively; p=0.0275 and <0.0001). Our data demonstrate that irrespective of AD, PA is associated with decreased skin UCA content with concomitant increase in EOS/NS-ceramide ratio that separates it from AD+PA- and AD+PA+ groups.

Patients with atopic dermatitis and food allergy have an immature epithelial barrier and type 2 immune activation in their skin.

Atopic dermatitis (AD) is highly associated with food allergy (FA); in that situation, sensitization is thought to occur from allergen exposure due to skin barrier dysfunction. Little is known about patients with FA who do not have AD. This study examined the differences between patients with FA who had a history of AD and those who did not have a history of AD. The NJH Research Database was queried for patients ages 0-18 years who had a diagnosis of FA from 3/2008-1/2016 (n=5822). 4913 of those patients had a history of AD. Diagnoses of milk, egg, and peanut allergies were defined either as a history of an immediate reaction to a food and positive skin test or an Immunocap equal to or greater than the 95% positive predictive value for that food. Charts were then reviewed for no AD history (n=93) as well as clinical and laboratory characteristics. In the no-AD group, diagnosis of egg (P=0.02) and peanut (P<0.001) allergies were significantly more associated with antibiotic use. Significantly more FA children in the no-AD group (P<0.001) had a history of GER medication use. Patients with FA and AD differ from those with FA and no history of AD. The non-AD group was associated with antibiotic use and GER medication use. These data suggest that the gut barrier could be where the non-AD group becomes sensitized to food.