Beyond classic “allergic”/atopic comorbidities, atopic dermatitis (AD) emerges as systemic disease with increased cardiovascular risk. To better define serum inflammatory and cardiovascular risk proteins, we used an OLINK high-throughput proteomic assay to analyze moderate-to-severe AD (n = 59) compared to psoriasis (n = 22) and healthy controls (n = 18). Compared to controls, 10 proteins were increased in serum of both diseases, including Th1 (IFN-γ, CXCL9, TNF-β) and Th17 (CCL20) markers. 48 proteins each were uniquely upregulated in AD and psoriasis. Consistent with skin expression, AD serum showed up-regulation of Th2 (IL-13, CCL17, eotaxin-1/CCL11, CCL13, CCL4, IL-10), Th1 (CXCL10, CXCL11) and Th1/Th17/Th22 (IL-12/IL-23p40) responses. Surprisingly, some markers of atherosclerosis (fractalkine/CX3CL1, CCL8, M-CSF, HGF), T-cell development/activation (CD40L, IL-7, CCL25, IL-2RB, IL-15RA, CD6) and angiogenesis (VEGF-A) were significantly increased only in AD. Multiple inflammatory pathways showed stronger enrichment in AD than psoriasis. Several atherosclerosis mediators in serum (e.g. E-selectin, PI3/elafin, CCL7, IL-16) correlated with SCORAD, but not BMI. Also, AD inflammatory mediators (e.g. MMP12, IL-12/IL-23p40, CXCL9, CCL22, PI3/Elafin) correlated between blood and lesional as well as non-lesional skin. Overall, the AD blood signature was largely different compared to psoriasis, with dysregulation of inflammatory and cardiovascular risk markers, strongly supporting its systemic nature beyond atopic/allergic association.

Background Atopic dermatitis (AD) is the most common inflammatory disease. Evolving disease models link changes in epidermal growth and differentiation to Th2/Th22 cytokine activation. However, these models have not been tested by in-vivo suppression of T-cell cytokines. CsA is an immune-suppressant highly effective for severe disease, but its mechanism in AD skin lesions has not been studied. Objective To establish the ability of a systemic immune-suppressant to modulate immune and epidermal alterations that form the pathogenic disease phenotype, and to correlate changes with clinical improvement. Methods CsA effects on AD skin pathology were evaluated using geneexpression and immunohistochemistry studies in baseline, week 2 and 12 lesional and non-lesional biopsies from 19 patients treated with 5 mg/kg/d CsA for 12 weeks. Results After 2 and 12 weeks of treatment, we observed significant reductions of 51% and 72%, respectively, in Scoring of AD/SCORAD. Clinical improvements were associated with significant gene expression changes in lesional but also non-lesional skin, particularly reductions of Th2-, Th22-, and some Th17-related molecules (i.e IL-13, IL-22, CCL17, S100As, elafin/PI3), and modulation of epidermal hyperplasia and differentiation measures. Conclusions This is the first study that establishes a relationship between cytokine activation and molecular epidermal alterations as well as correlations between disease biomarkers in the skin and clinical improvement. The reversal of the molecular phenotype with CsA and the associated biomarkers can serve as a reference for the successful modulation of tissue inflammation with specific immune-antagonists in future studies, contributing to the understanding of the specific cytokines involved in epidermal pathology.

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Fezakinumab was well-tolerated, with sustained clinical improvements after last drug dosing.

Background Atopic dermatitis (AD) is the most common inflammatory skin disease, but treatment options for moderate-to-severe disease are limited. Ustekinumab is an IL-12/IL-23p40 antagonist that suppresses Th1, Th17 and Th22 activation, commonly used for psoriasis patients. Objective We sought to assess efficacy and safety of ustekinumab in moderate-to-severe AD patients. Methods In this phase II, double-blind, placebo-controlled study, 33 patients with moderate-to-severe AD were randomly assigned to either ustekinumab (n=16) or placebo (n=17), with subsequent crossover at 16wks, and last dose at 32wks. Background therapy with mild topical steroids was allowed to promote retention. Study endpoints included clinical (SCORAD50) and biopsy-based measures of tissue structure and inflammation, using protein and gene expression studies. Results The ustekinumab group achieved higher SCORAD50 responses at 12wks, 16wks (the primary endpoint), and 20wks compared to placebo, but the difference between groups was not significant. The AD molecular profile/transcriptome showed early robust gene modulation, with sustained further improvements until 32wks in the initial ustekinumab-group. Distinct and more robust modulation of Th1, Th17 and Th22 but also Th2-related AD genes was seen after 4wks of ustekinumab treatment (i.e. MMP12, IL-22, IL-13, IFN-γ, elafin/PI3, CXCL1, CCL17; p<0.05). Epidermal responses (K16, terminal differentiation) showed faster (4wks) and long-term regulation (32wks) from baseline in the ustekinumab-group. No severe adverse events were observed. Conclusions Ustekinumab had clear clinical and molecular effects, but clinical outcomes might have been obscured by a profound “placebo” effect, most likely due to background topical glucocorticosteroids and possibly insufficient dosing for AD.

This is the first report showing a profound effect of IL-22 blockade on multiple inflammatory pathways in AD. These data, supported by robust effects in patients with high IL-22 baseline expression, suggest a central role for IL-22 in AD, indicating the need for a precision medicine approach for improving therapeutic outcomes in patients with AD.

Petrolatum robustly modulates antimicrobials and epidermal differentiation barrier measures. These data shed light on the beneficial molecular responses of petrolatum in barrier-defective states, such as AD and postoperative wound care.

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