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Atopic dermatitis (AD) is a complex and heterogeneous skin disease for which achieving complete clinical clearance for most patients has proven challenging through single cytokine inhibition. Current studies integrate biomarkers and evaluate their role in AD, aiming to advance our understanding of the diverse molecular profiles implicated. Although traditionally characterized as a T H 2-driven disease, extensive research has recently revealed the involvement of T H 1, T H 17, and T H 22 immune pathways as well as the interplay of pivotal immune molecules, such as OX40, OX40 ligand (OX40L), thymic stromal lymphopoietin, and IL-33. This review explores the mechanistic effects of treatments for AD, focusing on mAbs and Janus kinase inhibitors. It describes how these treatments modulate immune pathways and examines their impact on key inflammatory and barrier biomarkers. [ABSTRACT FROM AUTHOR]

Atopic dermatitis (AD) is a heterogeneous, chronic, relapsing, inflammatory skin disease associated with considerable physical, psychological, and economic burden. The pathology of AD includes complex interactions involving abnormalities in immune and skin barrier genes, skin barrier disruption, immune dysregulation, microbiome disturbance, and other environmental factors. Many of the cytokines involved in AD pathology, including IL-4, IL-13, IL-22, IL-31, thymic stromal lymphopoietin, and IFN-γ, signal through the Janus kinase (JAK)–signal transducer and activation of transcription (STAT) pathway. The JAK family includes JAK1, JAK2, JAK3, and tyrosine kinase 2; the STAT family includes STAT1, STAT2, STAT3, STAT4, STAT5A/B, and STAT6. Activation of the JAK-STAT pathway has been implicated in the pathology of several immune-mediated inflammatory diseases, including AD. However, the exact mechanisms of JAK-STAT involvement in AD have not been fully characterized. This review aims to discuss current knowledge about the role of the JAK-STAT signaling pathway and, specifically, the role of JAK1 in the pathology and symptomology of AD. [ABSTRACT FROM AUTHOR]

Pruritus is the most common and burdensome symptom of atopic dermatitis (AD). Pruritus-targeted treatments in AD are lacking, particularly for patients with milder skin disease. We sought to evaluate the impact of the selective κ-opioid receptor agonist difelikefalin (DFK) on pruritus intensity and pruritus- and immune-related biomarkers in subjects with moderate to severe AD-related pruritus. A phase 2 clinical trial investigated the efficacy and safety of oral DFK 0.25, 0.5, and 1.0 mg in subjects with moderate to severe AD-related pruritus. A biomarker substudy evaluated the effects of DFK on the expression of pruritus, T H 2-associated genes, and skin barrier–related genes. In the clinical trial (N = 401), all DFK doses reduced itch versus placebo; however, the results were not statistically significant at week 12. In a subgroup of subjects in the trial with mild to moderate skin inflammation and moderate to severe itch (itch-dominant AD phenotype), DFK reduced itch at week 12 versus placebo. In the biomarker substudy, DFK downregulated the expression of key pruritus-related genes (eg, IL-31 and TRPV1) and the AD phenotype (eg, CCL17). Gene set variation analysis confirmed that DFK, but not placebo, downregulated pruritus-related genes and T H 2 pathways. DFK improved skin barrier integrity markers and upregulated the expression of claudins and lipid metabolism–associated genes (eg, SEC14L6, ELOVL3, CYP1A2, and AKR1D1). DFK treatment reduced itch in subjects with moderate to severe AD-related pruritus, particularly those with an "itch-dominant" AD phenotype, and had an impact on the expression of pruritus, T H 2-associated genes, and skin barrier–related genes. DFK is a promising therapy for AD-related pruritus; further clinical studies are warranted. [ABSTRACT FROM AUTHOR]

Therapies specifically targeting nonhistaminergic pruritus are largely lacking. Difelikefalin (DFK) has been found to reduce itch in various chronic pruritic conditions, including atopic dermatitis (AD). We sought to investigate the ability of DFK to impact scratching behavior, inflammatory mediators, and neuronal signaling in a murine model of AD. The ears of C57BL/6 mice were topically treated with MC903 for 12 consecutive days to induce AD-like inflammation and itch. Before MC903 treatment, mice were treated with either DFK (0.5 mg/kg, intraperitoneal injection twice daily) or vehicle (saline). Skin ear thickness, histological analysis, flow cytometry, RNA-sequencing, and differential gene expression analyses of mouse ear skin were used to examine the effect of DFK on skin inflammation. Scratching behavior was quantified to measure itch behavior in mice that were topically treated with MC903 for 6 consecutive days; then, mice received a single injection of either DFK (1.0 mg/kg, intraperitoneal injection) or saline. Calcium imaging and single-cell RNA-sequencing were used in mouse dorsal root ganglia neurons to determine the size of the neurons activated with DFK treatment. Statistical significance was determined by Mann-Whitney test, unless otherwise noted. DFK rapidly suppressed itch without altering AD-like skin inflammation in MC903 (calcipotriol)-treated mice. In vitro Ca2+ influx trace of dorsal root ganglia suggested that a major target for DFK is the larger-diameter mechanoreceptors (eg, Aꞵ-fibers), rather than small-diameter pruriceptive C-fibers. These studies support a potential neuromodulatory role of DFK for reducing itch associated with AD in mice. [ABSTRACT FROM AUTHOR]

Atopic dermatitis (AD) is a common disease that is associated with atopic and nonatopic comorbidities. There has been a growing interest in this area of AD, because presence or risk of comorbidities can in many ways impact the management of patients with AD. Thus, some treatments for AD may improve its comorbidities as well, whereas others may increase their risk. In this review article, we discuss various comorbidities of AD mostly on the basis of the results of recent multiple systematic reviews and meta-analyses to update readers about this rapidly developing area of dermatology. We emphasize the important information provided by studies presenting both relative risk and absolute risk, and show that AD is associated with, among others, atopic comorbidities such as asthma, rhinitis, and food allergy, nonatopic comorbidities such as ocular, psychiatric, infectious, endocrine, autoimmune, and cardiovascular diseases, and certain cancers. Clinicians need to be aware of these and be cognizant about positive and negative effects of existing and new treatments for AD. [ABSTRACT FROM AUTHOR]

Upadacitinib is a selective reversible Janus kinase (JAK) inhibitor with established efficacy in moderate-to-severe atopic dermatitis (AD). We evaluated the safety of upadacitinib in patients with moderate-to-severe AD. Integrated safety data from the 16-week placebo-controlled periods of 1 phase 2b and 3 ongoing phase 3 studies (16 weeks) and longer-term safety data from patients receiving upadacitinib during the blinded extension periods of the three phase 3 studies were analyzed (all upadacitinib exposure). Treatment-emergent adverse events (TEAEs) were presented as exposure-adjusted rates per 100 patient-years (PY). Safety results were similar between the 16-week and all upadacitinib exposure groups. The latter group included 2485 patients (333 adolescents), receiving upadacitinib 15 mg (n = 1239) or 30 mg (n = 1246) for a mean duration of approximately 1 year. Upadacitinib was well tolerated by both adults and adolescents. TEAEs and discontinuation due to AEs were reported more frequently in patients receiving 30 mg upadacitinib (respectively, 311.9 and 5.7 events per 100 PY) versus 15 mg (respectively, 274.6 and 4.4 events per 100 PY). Serious adverse event rates (15/30 mg, 7.1/7.7 events per 100 PY) were similar in both groups. Acne was the most frequently reported adverse event (15/30 mg, 13.3/20.2 events per 100 PY). Serious infection rates were similar across treatment groups. Adjudicated major adverse cardiovascular event and venous thromboembolic event rates were ≤0.1 events per 100 PY. Rates of malignant neoplasms were within the expected range for the general population. Upadacitinib was well tolerated, and no new important safety risks were observed among adults and adolescents with moderate-to-severe AD treated for approximately 1 year compared to the known safety profile of upadacitinib. [ABSTRACT FROM AUTHOR]

Janus kinase (JAK) inhibitors have shown encouraging results in the treatment of alopecia areata (AA), an autoimmune form of hair loss, in small, uncontrolled studies and case reports. We conducted a biopsy substudy during the randomized, double-blind, placebo-controlled first 24 weeks of a phase 2a clinical trial that evaluated the efficacy and safety of ritlecitinib, an inhibitor of JAK3 and the tyrosine kinase expressed in hepatocellular carcinoma (TEC) kinase family, and brepocitinib, an inhibitor of tyrosine kinase 2 (TYK2)/JAK1 in the treatment of AA. Change in biomarkers in lesional scalp biopsy samples between baseline and weeks 12 and 24 was an exploratory end point, and 46 patients participated from the ritlecitinib (n = 18), brepocitinib (n = 16), and placebo (n = 12) groups. Correlations of biomarkers with hair regrowth, measured using the Severity of Alopecia Tool (SALT) score, were also evaluated. Clinical Trial Registration: NCT02974868. At week 24, both ritlecitinib and brepocitinib demonstrated improvement exceeding 100% in the lesional scalp transcriptome toward a nonlesional profile. At week 12, the improvements in scalp tissue were greater with brepocitinib than ritlecitinib; however, at week 24, the improvements were greater with ritlecitinib. For both ritlecitinib and brepocitinib, improvement in the SALT scores was positively associated with expression of T H 1 markers and negatively associated with expression of hair keratins. Larger, long-term clinical trials are warranted. [ABSTRACT FROM AUTHOR]

While numerous genetic loci associated with atopic dermatitis (AD) have been discovered, to date, work leveraging the combined burden of AD risk variants across the genome to predict disease risk has been limited. This study aims to determine whether polygenic risk scores (PRSs) relying on genetic determinants for AD provide useful predictions for disease occurrence and severity. It also explicitly tests the value of including genome-wide association studies of related allergic phenotypes and known FLG loss-of-function (LOF) variants. AD PRSs were constructed for 1619 European American individuals from the Atopic Dermatitis Research Network using an AD training dataset and an atopic training dataset including AD, childhood onset asthma, and general allergy. Additionally, whole genome sequencing data were used to explore genetic scoring specific to FLG LOF mutations. Genetic scores derived from the AD-only genome-wide association studies were predictive of AD cases (PRS AD : odds ratio [OR], 1.70; 95% CI, 1.49-1.93). Accuracy was first improved when PRSs were built off the larger atopy genome-wide association studies (PRS AD+ : OR, 2.16; 95% CI, 1.89-2.47) and further improved when including FLG LOF mutations (PRS AD++ : OR, 3.23; 95% CI, 2.57-4.07). Importantly, while all 3 PRSs correlated with AD severity, the best prediction was from PRS AD++ , which distinguished individuals with severe AD from control subjects with OR of 3.86 (95% CI, 2.77-5.36). This study demonstrates how PRSs for AD that include genetic determinants across atopic phenotypes and FLG LOF variants may be a promising tool for identifying individuals at high risk for developing disease and specifically severe disease. [ABSTRACT FROM AUTHOR]

In previous human skin single-cell data, inflammatory cells constituted only a small fraction of the overall cell population, such that functional subsets were difficult to ascertain. Our aims were to overcome the aforesaid limitation by applying single-cell transcriptomics to emigrating cells from skin and elucidate ex vivo gene expression profiles of pathogenic versus regulatory immune cell subsets in the skin of individuals with psoriasis. We harvested emigrating cells from human psoriasis skin after incubation in culture medium without enzyme digestion or cell sorting and analyzed cells with single-cell RNA sequencing and flow cytometry simultaneously. Unsupervised clustering of harvested cells from psoriasis skin and control skin identified natural killer cells, T-cell subsets, dendritic cell subsets, melanocytes, and keratinocytes in different layers. Comparison between psoriasis cells and control cells within each cluster revealed that (1) cutaneous type 17 T cells display highly differing transcriptome profiles depending on IL-17A versus IL-17F expression and IFN-γ versus IL-10 expression; (2) semimature dendritic cells are regulatory dendritic cells with high IL-10 expression, but a subset of semimature dendritic cells expresses IL-23A and IL-36G in psoriasis; and (3) CCL27-CCR10 interaction is potentially impaired in psoriasis because of decreased CCL27 expression in basal keratinocytes. We propose that single-cell transcriptomics applied to emigrating cells from human skin provides an innovative study platform to compare gene expression profiles of heterogenous immune cells in various inflammatory skin diseases. [ABSTRACT FROM AUTHOR]

Although atopic dermatitis (AD) often presents in infancy and persists into adulthood, comparative characterization of AD skin among different pediatric age groups is lacking. We sought to define skin biopsy profiles of lesional and nonlesional AD across different age groups (0-5-year-old infants with disease duration <6 months, 6-11-year-old children, 12-17-year-old adolescents, ≥18-year-old adults) versus age-appropriate controls. We performed gene expression analyses by RNA-sequencing and real-time PCR (RT-PCR) and protein expression analysis using immunohistochemistry. T H 2/T H 22 skewing, including IL-13, CCL17/thymus and activation-regulated chemokine, IL-22, and S100As, characterized the common AD signature, with a global pathway-level enrichment across all ages. Nevertheless, specific cytokines varied widely. For example, IL-33, IL-1RL1/IL-33R, and IL-9, often associated with early atopic sensitization, showed greatest upregulations in infants. T H 17 inflammation presented a 2-peak curve, with highest increases in infants (including IL-17A and IL-17F), followed by adults. T H 1 polarization was uniquely detected in adults, even when compared with adolescents, with significant upregulation in adults of IFN-γ and CXCL9/CXCL10/CXCL11. Although all AD age groups had barrier abnormalities, only adults had significant decreases in filaggrin expression. Despite the short duration of the disease, infant AD presented robust downregulations of multiple barrier-related genes in both lesional and nonlesional skin. Clinical severity scores significantly correlated with T H 2/T H 22-related markers in all pediatric age groups. The shared signature of AD across ages is T H 2/T H 22-skewed, yet differential expression of specific T H 2/T H 22-related genes, other T H pathways, and barrier-related genes portray heterogenetic, age-specific molecular fingerprints. [ABSTRACT FROM AUTHOR]

[Display omitted] Rademikibart (CBP-201) is a next-generation IL-4 receptor alpha–targeting antibody. We sought to evaluate rademikibart in adults with moderate to severe atopic dermatitis. A total of 226 patients were randomized, double-blind, to subcutaneous rademikibart (300 mg every 2 weeks [Q2W], 150 mg Q2W, 300 mg every 4 weeks [Q4W]; plus 600-mg loading dose) or placebo. Randomization began in July 2020. The trial was completed in October 2021. The WW001 phase 2 trial achieved its primary end point: significant percent reduction from baseline in least-squares mean Eczema Area Severity Index (EASI) to week 16 with rademikibart 300 mg Q2W (−63.0%; P =.0007), 150 mg Q2W (−57.6%; P =.0067), 300 mg Q4W (−63.5%; P =.0004) versus placebo (−39.7%). EASI scores decreased significantly with 300 mg Q2W and Q4W at the earliest assessment (week 2), with no evidence of plateauing by week 16. Significant improvements were also observed in secondary end points, including pruritus. Across the primary and secondary end points, efficacy tended to be comparable with 300 mg Q2W and Q4W dosing. Rademikibart and placebo had similar, low incidence of treatment-emergent adverse events (TEAEs) (48% vs 54%), serious TEAEs (1.8% vs 3.6%), TEAEs leading to treatment discontinuation (1.2% vs 1.8%), conjunctivitis of unspecified cause (2.9% vs 0%), herpes (0.6% vs 1.8%), and injection-site reactions (1.8% vs 1.8%). Although no discontinuations were attributed to coronavirus disease 2019, pandemic-related restrictions likely had an impact on trial conduct. Rademikibart was efficacious and well tolerated at Q2W and Q4W intervals. Q4W dosing is a more convenient frequency than approved for current therapies. [ABSTRACT FROM AUTHOR]

Molecular studies in atopic dermatitis (AD) are largely restricted to patients with moderate-to-severe disease. Our aim was to evaluate skin and blood abnormalities in mild, moderate, and severe AD. Skin and blood samples were obtained from 61 patients with AD (20 with mild or limited disease, 17 with moderate disease, and 24 with severe disease) and 20 healthy subjects. Immune and barrier markers were measured in lesional, nonlesional, and healthy skin by quantitative real-time PCR and immunohistochemistry, and in blood by using the OLINK proteomic assay. Cellular markers of epidermal hyperplasia and T-cell/dendritic cell infiltration were increased in AD tissues of all patients in all severity groups versus in those of controls, whereas downstream T H 2 cell–, T H 22 cell–, T H 1 cell–, and T H 17 cell–related mediators demonstrated incremental elevations with increasing disease severity, in both lesional and nonlesional skin. Whereas the levels of the T H 2 (IL13, CCL17, and CCL26) and T H 22 (IL-22) cytokines were significantly elevated in both AD lesional and nonlesional skin of all patients regardless of the severity of their disease, patients with mild or limited AD showed increases in their levels of T H 1 cell (IFNG, CXCL9, and CXCL10) and T H 17 cell (IL-17A, CCL20, and CXCL1) markers in lesional but not nonlesional skin. Regulatory T-cell–related mediators (IL-10 and FOXP3) were comparably upregulated in all groups, without displaying the severity-based gradient in other immune axes. Unsupervised clustering aligned samples along a severity spectrum, where nonlesional mild or limited AD skin clustered with the samples from healthy controls. Furthermore, whereas the blood profiles of patients with moderate and severe AD showed gradual increases in the levels of T H 1 cell–, T H 2 cell–, and T H 17 cell–related and atherosclerosis and/or cardiovascular risk (CCL7, FGF21, and IGFBP1) proteins, the blood profiles of patients with mild or limited AD lacked significant differences from those of the controls. Mild and limited AD show high levels of T H 2/T H 22 cell activation that is primarily localized to skin lesions and lacks the systemic inflammation of moderate and severe disease. [Display omitted] [ABSTRACT FROM AUTHOR]

Our current understanding of atopic dermatitis (AD) and psoriasis pathophysiology is largely derived from skin biopsy studies that cause scarring and may be impractical in large-scale clinical trials. Although tape strips show promise as a minimally invasive technique in these common diseases, a comprehensive molecular profiling characterizing and differentiating the 2 diseases in tape strips is unavailable. Our aim was to construct a global transcriptome of tape strips from lesional and nonlesional skin of adults with moderate-to-severe AD and psoriasis. A total of 20 tape strips were obtained from lesional and nonlesional skin of patients with AD and psoriasis and skin from controls (n = 20 each); the strips were subjected to RNA sequencing (RNA-seq), with quantitative RT-PCR validation of immune and barrier biomarkers. We detected RNA-seq profiles in 96 of 100 of samples (96%), with 4123 and 5390 genes differentially expressed in AD and psoriasis lesions versus in controls, respectively (fold change ≥ 2; false discovery rate [FDR] < 0.05). Nonlesional tape-stripped skin from patients with AD was more similar to lesional skin than to nonlesional skin of patients with psoriasis, which showed larger differentiation from lesions. AD and psoriasis tissues shared increases in levels of dendritic cell and T-cell markers (CD3, ITGAX/CD11c, and CD83), but AD tissues showed preferential T H 2 skewing (IL-13, CCL17/TARC, and CCL18), whereas psoriasis was characterized by higher levels of expression of T H 17-related (IL-17A/F and IL-36A/IL-36G), T H 1-related (IFN-γ and CXCL9/CXCL10), and innate immunity–related (nitric oxide synthase 2/inducible nitric oxide synthase and IL-17C) products (FDR < 0.05). Terminal differentiation (FLG2 and LCE5A), tight junction (CLDN8), and lipid biosynthesis and metabolism (FA2H and ALOXE3) products were significantly downregulated in both AD and psoriasis (FDR < 0.05). Nitric oxide synthase 2/inducible nitric oxide synthase expression (determined by quantitative PCR) differentiated AD and psoriasis with 100% accuracy. RNA-seq tape strip profiling detected distinct immune and barrier signatures in lesional and nonlesional AD and psoriasis skin, suggesting their utility as a minimally invasive alternative to biopsies for detecting disease biomarkers. [ABSTRACT FROM AUTHOR]

Atopic dermatitis (AD) is a prevalent inflammatory skin disease with a complex pathogenesis involving immune cell and epidermal abnormalities. Despite whole tissue biopsy studies that have advanced the mechanistic understanding of AD, single cell–based molecular alterations are largely unknown. Our aims were to construct a detailed, high-resolution atlas of cell populations and assess variability in cell composition and cell-specific gene expression in the skin of patients with AD versus in controls. We performed single-cell RNA sequencing on skin biopsy specimens from 5 patients with AD (4 lesional samples and 5 nonlesional samples) and 7 healthy control subjects, using 10× Genomics. We created transcriptomic profiles for 39,042 AD (lesional and nonlesional) and healthy skin cells. Fibroblasts demonstrated a novel COL6A5 + COL18A1 + subpopulation that was unique to lesional AD and expressed CCL2 and CCL19 cytokines. A corresponding LAMP3 + dendritic cell (DC) population that expressed the CCL19 receptor CCR7 was also unique to AD lesions, illustrating a potential role for fibroblast signaling to immune cells. The lesional AD samples were characterized by expansion of inflammatory DCs (CD1A + FCER1A +) and tissue-resident memory T cells (CD69 + CD103 +). The frequencies of type 2 (IL13 +)/type 22 (IL22 +) T cells were higher than those of type 1 (IFNG +) in lesional AD, whereas this ratio was slightly diminished in nonlesional AD and further diminished in controls. AD lesions were characterized by expanded type 2/type 22 T cells and inflammatory DCs, and by a unique inflammatory fibroblast that may interact with immune cells to regulate lymphoid cell organization and type 2 inflammation. [ABSTRACT FROM AUTHOR]

Atopic dermatitis is a chronic inflammatory skin disease characterized by pruritic skin lesions. We sought to evaluate the safety and efficacy of multiple doses of the selective Janus kinase 1 inhibitor upadacitinib in patients with moderate to severe atopic dermatitis. In the 16-week, double-blind, placebo-controlled, parallel-group, dose-ranging portion of this 88-week trial in 8 countries (ClinicalTrials.gov , NCT02925117 ; ongoing, not recruiting), adults with moderate to severe disease and inadequate control by topical treatment were randomized 1:1:1:1, using an interactive response system and stratified geographically, to once-daily upadacitinib oral monotherapy 7.5, 15, or 30 mg or placebo. The primary end point was percentage improvement in Eczema Area and Severity Index from baseline at week 16. Efficacy was analyzed by intention-to-treat in all randomized patients. Safety was analyzed in all randomized patients who received study medication, based on actual treatment. Patients (N = 167) enrolled from November 21, 2016, to April 20, 2017. All were randomized and analyzed for efficacy (each upadacitinib group, n = 42; placebo, n = 41); 166 were analyzed for safety (each upadacitinib group, n = 42; placebo, n = 40). The mean (SE) primary efficacy end point was 39% (6.2%), 62% (6.1%), and 74% (6.1%) for the upadacitinib 7.5-, 15-, and 30-mg groups, respectively, versus 23% (6.4%) for placebo (P =.03, <.001, and <.001). Serious adverse events occurred in 4.8% (2 of 42), 2.4% (1 of 42), and 0% (0 of 42) of upadacitinib groups (vs 2.5% [1 of 40] for placebo). A dose-response relationship was observed for upadacitinib efficacy; the 30-mg once-daily dose showed the greatest clinical benefit. Dose-limiting toxicity was not observed. [ABSTRACT FROM AUTHOR]

The circulating immune phenotype was defined in adults and young children with early atopic dermatitis (AD), but chronologic changes in the blood of infants and children with AD through adolescence have not been explored. We sought to compare immune activation and cytokine polarization in the blood of 0- to 5-year-old (n = 39), 6- to 11-year-old (n = 26), 12- to 17-year-old (n = 21) and 18-year-old or older (n = 43) patients with AD versus age-matched control subjects. Flow cytometry was used to measure IFN-γ, IL-9, IL-13, IL-17, and IL-22 cytokine levels in CD4+/CD8+ T cells, with inducible costimulator molecule and HLA-DR defining midterm and long-term T-cell activation, respectively, within skin-homing/cutaneous lymphocyte antigen (CLA)+ versus systemic/CLA− T cells. Unsupervised clustering differentiated patients based on their blood biomarker frequencies. Although CLA+ T H 1 frequencies were significantly lower in infants with AD versus all older patients (P <.01), frequencies of CLA+ T H 2 T cells were similarly expanded across all AD age groups compared with control subjects (P <.05). After infancy, CLA− T H 2 frequencies were increased in patients with AD in all age groups, suggesting systemic immune activation with disease chronicity. IL-22 frequencies serially increased from normal levels in infants to highly significant levels in adolescents and adults compared with levels in respective control subjects (P <.01). Unsupervised clustering aligned the AD profiles along an age-related spectrum from infancy to adulthood (eg, inducible costimulator molecule and IL-22). The adult AD phenotype is achieved only in adulthood. Unique cytokine signatures characterizing individual pediatric endotypes might require age-specific therapies. Future longitudinal studies, comparing the profile of patients with cleared versus persistent pediatric AD, might define age-specific changes that predict AD clearance. [ABSTRACT FROM AUTHOR]

Crisaborole ointment 2% is a nonsteroidal phosphodiesterase 4 inhibitor for the treatment of mild-to-moderate atopic dermatitis (AD). The mechanism of action of crisaborole and its effects on lesional measures of disease severity are not yet well defined. This phase 2a, single-center, vehicle-controlled, intrapatient study was designed to further characterize the mechanism of action of crisaborole through evaluation of clinical efficacy and changes in skin biomarkers in adults (n = 40) with mild-to-moderate AD. Two target lesions were randomized in an intrapatient (1:1) manner to double-blind crisaborole/vehicle applied twice daily for 14 days. Patients then applied crisaborole (open-label) to all affected areas for 28 days. Punch biopsy specimens were collected for biomarker analysis at baseline, day 8 (optional), and day 15. Crisaborole treatment resulted in early improvement in lesional signs/symptoms versus vehicle, with improvement in pruritus (pruritus numeric rating scale) observed as early as 24 hours after the first application. Crisaborole-treated lesions showed significant percentage improvement from baseline in lesional transcriptomic profile compared with vehicle at day 8 (91.15% vs 36.02%, P < 10−15) that was sustained until day 15 (92.90% vs 49.59%, P < 10−15). Crisaborole significantly modulated key AD biomarkers versus vehicle, including T H 2 and T H 17/T H 22 pathways and epidermal hyperplasia/proliferation. Molecular profiles and epidermal pathology normalized toward nonlesional skin and correlated with clinical changes in lesion severity and barrier function. Crisaborole reversed biomarker profiles of skin inflammation and barrier function, with associated improvements in clinical efficacy measures, highlighting the therapeutic utility of targeting phosphodiesterase 4 in patients with AD. [ABSTRACT FROM AUTHOR]

Vitiligo is an autoimmune depigmenting disorder with no effective and safe treatments. Its pathogenesis is not fully elucidated. This substudy of a randomized, double-blind, placebo-controlled phase 2b trial (NCT03715829) evaluated effects of ritlecitinib, an oral JAK3/TEC family kinase inhibitor, on skin and blood biomarkers in participants with nonsegmental vitiligo (NSV). Sixty-five adults with NSV participated in the substudy and received daily treatment for 24 weeks with placebo (n = 14) or ritlecitinib with or without a 4-week loading dose: 200 (loading dose)/50 mg (n = 13), 100/50 mg (n = 12), 50 mg (n = 11), 30 mg (n = 8), or 10 mg (n = 6). Skin (lesional and nonlesional) biopsy samples were obtained at baseline and at 4 and 24 weeks. Changes from baseline to weeks 4 and 24 in skin and blood molecular and cellular biomarkers were evaluated by RNA sequencing, quantitative real-time PCR, proteomic analysis, and flow cytometry. Ritlecitinib-treated groups showed downregulation of immune biomarkers and upregulation of melanocyte-related markers at weeks 4 and 24 compared to baseline and/or placebo. Significant reductions were seen in CD3+/CD8+ T-cell infiltrates, with significant increases in melanocyte markers (tyrosinase; Melan-A) in NSV lesions in the 50 mg ritlecitinib groups (both P <.05). There was significant, dose-dependent downregulation in T-cell activation, NK, cytotoxic, and regulatory markers in lesional skin (IL-2, IL2-RA, IL-15, CCR7, CD5, CRTAM, NCR1, XCL1, KIR3DL1, FASLG, KLRD; P <.05). T H 1 and T H 2 markers were also downregulated in lesional skin and blood in a dose-dependent manner (P <.05). Changes in immune biomarkers correlated with clinical response. Ritlecitinib significantly downregulated proinflammatory biomarkers and increased melanocyte products in skin and blood of participants with NSV, suggesting its potential in treatment. Ritlecitinib-mediated changes positively correlated with clinical response. [ABSTRACT FROM AUTHOR]

Moderate-to-severe atopic dermatitis (AD) has been associated with significant disease burden and systemic abnormalities and often requires systemic treatments. Currently, safe and effective oral systemic treatments for moderate-to-severe AD are not yet available. ASN002 is an oral inhibitor of the Janus kinase/spleen tyrosine kinase signaling pathways, targeting several cytokine axes (T H 2/T H 22/T H 17/T H 1) and epidermal differentiation. We sought to evaluate the effect of ASN002 on the cellular and molecular biomarker profile of patients with moderate-to-severe AD and to correlate changes in biomarkers to improvements in clinical severity measures and pruritus. Thirty-six patients with moderate-to-severe AD were randomized to groups with dose escalation of ASN002 (20, 40, and 80 mg) and a placebo group. Skin biopsy specimens were performed at baseline, day 15, and day 29. Gene expression studies were conducted by using microarray and quantitative RT-PCR, and cellular infiltrates and protein expression were studied by using immunohistochemistry. ASN002 reversed the lesional skin transcriptome toward a nonlesional phenotype. It also rapidly and significantly suppressed key inflammatory pathways implicated in AD pathogenesis, including T H 2 (IL4 receptor [IL4R] , IL13 , CCL13 /monocyte chemoattractant protein 4, CCL17 /thymus and activation-regulated chemokine, CCL18 /pulmonary and activation-regulated chemokine, CCL22 /macrophage-derived chemokine, and CCL26 /eotaxin-3), T H 17/T H 22 (lipocalins, PI3 /elafin, CCL20 , S100A7 / S100A8 / S100A9 , and IL36G / IL36RN), and T H 1 (IFNG , CXCL9 / CXCL11 , and MX1) axes and barrier-related measures (filaggrin [FLG] and CLDN23). Significant improvements in AD gene signatures were observed predominantly in the 40- and 80-mg groups. Smaller and largely nonsignificant molecular changes were seen in the 20-mg and placebo groups. The Janus kinase/spleen tyrosine kinase inhibitor ASN002 significantly suppressed key AD inflammatory pathways, corresponding to clinical response. ASN002 might be an effective novel therapeutic agent for moderate-to-severe AD. [ABSTRACT FROM AUTHOR]

Psoriasis is a chronic inflammatory skin disease characterized by IL-17-mediated immune responses. p38 is known to be highly activated in the psoriatic epidermis; however, whether p38 is involved in the development of psoriasis is unclear. We sought to demonstrate that activation of p38 mitogen-activated protein kinase is sufficient to induce psoriatic inflammation in mice and that cutaneous p38 activities are the topical therapeutic targets for psoriasis. A p38 activator, anisomycin, was applied daily to murine skin. Transcriptomic analyses were performed to evaluate the similarities of the skin responses to those in human psoriasis and the existing animal model. BIRB796, a small-molecule inhibitor targeting p38 activities, was applied to the murine psoriatic models topically or to human psoriatic skin specimens ex vivo. Topical treatment with anisomycin induced key signatures in psoriasis, such as epidermal thickening, neutrophil infiltration, and gene expression of Il1a , Il1b , Il6 , Il24 , Cxcl1 , Il23a , and Il17a , in treated murine skin. These responses were fully abrogated by topical treatment with BIRB796, and were reduced in IL-17A–deficient mice. Transcriptomic analyses demonstrated the similarities of anisomycin-induced dermatitis to human psoriasis and imiquimod-induced murine psoriatic dermatitis. Furthermore, BIRB796 targeting of p38 activities reduced expression of psoriasis-related genes in both human keratinocytes stimulated with recombinant IL-17A in vitro and psoriatic skin specimens ex vivo. Therefore our findings suggest that cutaneous p38 activation can be a key event in patients with psoriasis and a potential topical therapeutic target of a small molecule. [ABSTRACT FROM AUTHOR]

Skin is replete with immunocompetent cells that modulate signaling pathways to maintain a salubrious immunogenic/tolerogenic balance. This fertile immune environment plays a significant role in the development of allergic responses and sensitivities, but the mechanisms underlying these pathways have been underappreciated and underused with respect to developing therapeutics. Among the complex repertoire of cells that promote tolerogenic pathways in the periphery, 2 key classes include dendritic cells and regulatory T (Treg) cells. Immature dendritic cells are the first line of defense, patrolling the periphery, sampling antigens, and secreting cytokines that suppress immune cells and promote the survival of Treg cells. Skin-homing Treg cells also play a critical role in mitigating the reactivity of immune cells, secreting high levels of cytokines that promote tolerance. Therapeutic approaches that capitalize on our knowledge of the rich cellular and molecular environment are emerging and show great promise. We will discuss the advantages and challenges of 5 such strategies and how these therapies might mitigate the atopic march by facilitating tolerance. We conclude that skin is a multifaceted structure that provides a fertile ground for therapeutic discovery. Accordingly, ongoing work in this domain will no doubt continue to deliver exciting progress for improved health outcomes. [ABSTRACT FROM AUTHOR]

Atopic dermatitis (AD) shows differential clinical presentation in older compared with younger patients. Nevertheless, changes in the AD molecular profile with age are unknown. We sought to characterize age-related changes in the AD profile. We evaluated age-specific changes in lesional and nonlesional tissues and blood from patients with moderate-to-severe AD (n = 246) and age-matched control subjects (n = 71) using immunohistochemistry, quantitative real-time PCR, and Singulex in a cross-sectional study. Patients were analyzed by age group (18-40, 41-60, and ≥61 years). Although disease severity/SCORAD scores were similar across AD age groups (mean, approximately 60 years; P =.873), dendritic cell infiltrates (CD1b+ and FcεRI+, P <.05) decreased with age. T H 2 measures (IL5 , IL13 , CCL13 , CCL18 , and CCL26) significantly decreased with age in patients with AD, despite increasing with age in control subjects. Consistent with T H 2 axis decreases, serum IgE levels and eosinophil counts negatively correlated with age in patients with AD (r = −0.24 and r = −0.23, respectively; P <.05). T H 22-secreted IL 22 expression levels also decreased with age uniquely in patients with AD (P <.05). Expression of T H 1-related (IFNG , IL12/23p40 , STAT1 , and CXCL9 ; P <.05 for CXCL9) and T H 17-related (IL 17A and IL 20 ; P <.05 for IL 20) markers increased with age in both patients with AD and control subjects. Expression of terminal differentiation measures significantly increased in older patients with AD (loricrin [LOR] and filaggrin [FLG] , P <.05), whereas expression of S100As (S100A8 , P <.01) and hyperplasia markers (epidermal thickness, keratin 16, and Ki67; P <.05 for keratin 16) decreased. Serum trends in AD mimicked skin findings, with T H 2 downregulation (CCL26; r = −0.32, P <.1) and T H 1 upregulation (IFN-γ; r = 0.48, P <.01) with age. The adult AD profile varies with age. Although T H 1/T H 17 skewing increases in both patients with AD and control subjects, patients with AD show unique decreases in T H 2/T H 22 polarization and normalization of epithelial abnormalities. Thus age-specific treatment approaches might be beneficial for AD. [ABSTRACT FROM AUTHOR]

Peripheral blood skin-homing/cutaneous lymphocyte antigen (CLA)+ T cells emerge as biomarkers of cutaneous immune activation in patients with inflammatory skin diseases (atopic dermatitis [AD] and alopecia areata [AA]). However, blood phenotyping across these subsets is not yet available in patients with vitiligo. We sought to measure cytokine production by circulating skin-homing (CLA+) versus systemic (CLA−) "polar" CD4+/CD8+ ratio and activated T-cell subsets in patients with vitiligo compared with patients with AA, AD, or psoriasis and control subjects. Flow cytometry was used to measure levels of the cytokines IFN-γ, IL-13, IL-9, IL-17, and IL-22 in CD4+/CD8+ T cells in the blood of 19 patients with moderate-to-severe nonsegmental/generalized vitiligo, moderate-to-severe AA (n = 32), psoriasis (n = 24), or AD (n = 43) and control subjects (n = 30). Unsupervised clustering differentiated subjects into groups based on cellular frequencies. Patients with Vitiligo showed the highest CLA+/CLA− T H 1/type 1 cytotoxic T-cell polarization, with parallel T H 2/T H 9/T H 17/T H 22 level increases to levels often greater than those seen in patients with AA, AD, or psoriasis (P <.05). Total regulatory T-cell counts were lower in patients with vitiligo than in control subjects and patients with AD or psoriasis (P <.001). Vitiligo severity correlated with levels of multiple cytokines (P <.1), whereas duration was linked with IFN-γ and IL-17 levels (P <.04). Patients and control subjects grouped into separate clusters based on blood biomarkers. Vitiligo is characterized by a multicytokine polarization among circulating skin-homing and systemic subsets, which differentiates it from other inflammatory/autoimmune skin diseases. Future targeted therapies should delineate the relative contribution of each cytokine axis to disease perpetuation. [ABSTRACT FROM AUTHOR]

Atopic dermatitis (AD) affects up to 20% of children worldwide and is an increasing public health problem, particularly in developed countries. Although AD in infants and young children can resolve, there is a well-recognized increased risk of sequential progression from AD to other atopic diseases, including food allergy (FA), allergic rhinitis, allergic asthma, and allergic rhinoconjunctivitis, a process referred to as the atopic march. The mechanisms underlying the development of AD and subsequent progression to other atopic comorbidities, particularly FA, are incompletely understood and the subject of intense investigation. Other major research objectives are the development of effective strategies to prevent AD and FA, as well as therapeutic interventions to inhibit the atopic march. In 2017, the Division of Allergy, Immunology, and Transplantation of the National Institute of Allergy and Infectious Diseases sponsored a workshop to discuss current understanding and important advances in these research areas and to identify gaps in knowledge and future research directions. International and national experts in the field were joined by representatives from several National Institutes of Health institutes. Summaries of workshop presentations, key conclusions, and recommendations are presented herein. [ABSTRACT FROM AUTHOR]

Background Ichthyoses are a group of rare skin disorders lacking effective treatments. Although genetic mutations are progressively delineated, comprehensive molecular phenotyping of ichthyotic skin could suggest much-needed pathogenesis-based therapy. Objective We sought to profile the molecular fingerprint of the most common orphan ichthyoses. Methods Gene, protein, and serum studies were performed on skin and blood samples from 29 patients (congenital ichthyosiform erythroderma, n = 9; lamellar ichthyosis, n = 8; epidermolytic ichthyosis, n = 8; and Netherton syndrome, n = 4), as well as age-matched healthy control subjects (n = 14), patients with psoriasis (n = 30), and patients with atopic dermatitis (AD; n = 16). Results Using criteria of a fold change of greater than 2 and a false discovery rate of less than 0.05, 132 differentially expressed genes were shared commonly among all ichthyoses, including many IL-17 and TNF-α–coregulated genes, which are considered hallmarks of psoriasis (defensin beta 4A, kynureninase, and vanin 3). Although striking upregulation of TH17 pathway genes (IL17F and IL36B/G) resembling that seen in patients with psoriasis was common to all patients with ichthyoses in a severity-related manner, patients with Netherton syndrome showed the greatest T-cell activation (inducible costimulator [ ICOS ]) and a broader immune phenotype with T H 1/IFN-γ, OASL, and T H 2/IL-4 receptor/IL-5 skewing, although less than seen in patients with AD (all P <.05). Ichthyoses lacked the epidermal differentiation and tight junction alterations of patients with AD (loricrin, filaggrin, and claudin 1) but showed characteristic alterations in lipid metabolism genes (ELOVL fatty acid elongase 3 and galanin), with parallel reductions in extracellular lipids and corneocyte compaction in all ichthyoses except epidermolytic ichthyosis, suggesting phenotypic variations. Transepidermal water loss, a functional barrier measure, significantly correlated with IL-17–regulated gene expression (IL17F and IL36A/IL36B/IL36G). Conclusion Similar to patients with AD and psoriasis, in whom cytokine dysregulation and barrier impairment orchestrate disease phenotypes, psoriasis-like immune dysregulation and lipid alterations characterize the ichthyoses. These data support the testing of IL-17/IL-36–targeted therapeutics for patients with ichthyosis similar to those used in patients with psoriasis. [ABSTRACT FROM AUTHOR]

Atopic dermatitis (AD) is a prevalent disease worldwide and is associated with systemic comorbidities representing a significant burden on patients, their families, and society. Therapeutic options for AD remain limited, in part because of a lack of well-characterized animal models. There has been increasing interest in developing experimental approaches to study the pathogenesis of human AD in vivo , in vitro , and in silico to better define pathophysiologic mechanisms and identify novel therapeutic targets and biomarkers that predict therapeutic response. This review critically appraises a range of models, including genetic mutations relevant to AD, experimental challenge of human skin in vivo , tissue culture models, integration of "omics" data sets, and development of predictive computational models. Although no one individual model recapitulates the complex AD pathophysiology, our review highlights insights gained into key elements of cutaneous biology, molecular pathways, and therapeutic target identification through each approach. Recent developments in computational analysis, including application of machine learning and a systems approach to data integration and predictive modeling, highlight the applicability of these methods to AD subclassification (endotyping), therapy development, and precision medicine. Such predictive modeling will highlight knowledge gaps, further inform refinement of biological models, and support new experimental and systems approaches to AD. [ABSTRACT FROM AUTHOR]

Background Dupilumab is an IL-4 receptor α mAb inhibiting signaling of IL-4 and IL-13, key drivers of type 2–driven inflammation, as demonstrated by its efficacy in patients with atopic/allergic diseases. Objective This placebo-controlled, double-blind trial (NCT01979016) evaluated the efficacy, safety, and effects of dupilumab on molecular/cellular lesional and nonlesional skin phenotypes and systemic type 2 biomarkers of patients with moderate-to-severe atopic dermatitis (AD). Methods Skin biopsy specimens and blood were evaluated from 54 patients randomized 1:1 to weekly subcutaneous doses of 200 mg of dupilumab or placebo for 16 weeks. Results Dupilumab (vs placebo) significantly improved clinical signs and symptoms of AD, was well tolerated, and progressively shifted the lesional transcriptome toward a nonlesional phenotype (weeks 4–16). Mean improvements in a meta-analysis–derived AD transcriptome (genes differentially expressed between lesional and nonlesional skin) were 68.8% and 110.8% with dupilumab and −10.5% and 55.0% with placebo (weeks 4 and 16, respectively; P <.001). Dupilumab significantly reduced expression of genes involved in type 2 inflammation (IL13 , IL31 , CCL17 , CCL18 , and CCL26), epidermal hyperplasia (keratin 16 [K16] and MKi67), T cells, dendritic cells (ICOS , CD11c , and CTLA4), and T H 17/T H 22 activity (IL17A , IL-22 , and S100As) and concurrently increased expression of epidermal differentiation, barrier, and lipid metabolism genes (filaggrin [FLG] , loricrin [LOR] , claudins, and ELOVL3). Dupilumab reduced lesional epidermal thickness versus placebo (week 4, P =.001; week 16, P =.0002). Improvements in clinical and histologic measures correlated significantly with modulation of gene expression. Dupilumab also significantly suppressed type 2 serum biomarkers, including CCL17, CCL18, periostin, and total and allergen-specific IgEs. Conclusion Dupilumab-mediated inhibition of IL-4/IL-13 signaling through IL-4 receptor α blockade significantly and progressively improved disease activity, suppressed cellular/molecular cutaneous markers of inflammation and systemic measures of type 2 inflammation, and reversed AD-associated epidermal abnormalities. [ABSTRACT FROM AUTHOR]

Background IL-13 has an important role in atopic dermatitis (AD) pathogenesis. Tralokinumab is a fully human mAb that potently and specifically neutralizes IL-13. Objective We sought to evaluate the efficacy and safety of tralokinumab in adults with moderate-to-severe AD. Methods In this phase 2b study (NCT02347176), 204 adults were randomized 1:1:1:1 to receive 45, 150, or 300 mg of subcutaneous tralokinumab, or placebo, every 2 weeks for 12 weeks with concomitant topical glucocorticoids. Coprimary end points were change from baseline in Eczema Area Severity Index score and percentage of participants with an Investigator's Global Assessment response (0/1 score and reduction of ≥2 grades from baseline) at week 12. Results At week 12, 300 mg of tralokinumab significantly improved change from baseline in Eczema Area Severity Index score versus placebo (adjusted mean difference, −4.94; 95% CI, −8.76 to −1.13; P =.01), and a greater percentage of participants achieved an Investigator's Global Assessment response (26.7% vs 11.8%). Greater responses were found in participants with greater concentrations of biomarkers of increased IL-13 activity. Participants treated with 300 mg of tralokinumab demonstrated improvements in SCORAD, Dermatology Life Quality Index, and pruritus numeric rating scale (7-day mean) scores versus placebo. Upper respiratory tract infection was the most frequent treatment-emergent adverse event reported as related to study drug in the placebo (3.9%) and pooled tralokinumab (3.9%) groups. Conclusions Tralokinumab treatment was associated with early and sustained improvements in AD symptoms and an acceptable safety and tolerability profile, thereby providing evidence for targeting IL-13 in patients with AD. [ABSTRACT FROM AUTHOR]

Background Although atopic dermatitis (AD) often starts in early childhood, detailed tissue profiling of early-onset AD in children is lacking, hindering therapeutic development for this patient population with a particularly high unmet need for better treatments. Objective We sought to globally profile the skin of infants with AD compared with that of adults with AD and healthy control subjects. Methods We performed microarray, RT-PCR, and fluorescence microscopy studies in infants and young children (<5 years old) with early-onset AD (<6 months disease duration) compared with age-matched control subjects and adults with longstanding AD. Results Transcriptomic analyses revealed profound differences between pediatric patients with early-onset versus adult patients with longstanding AD in not only lesional but also nonlesional tissues. Although both patient populations harbored T H 2-centered inflammation, pediatric AD also showed significant T H 17/T H 22 skewing but lacked the T H 1 upregulation that characterizes adult AD. Pediatric AD exhibited relatively normal expression of epidermal differentiation and cornification products, which is downregulated in adults with AD. Defects in the lipid barrier (eg, ELOVL fatty acid elongase 3 [ELOVL3] and diacylglycerol o-acyltransferase 2 [DGAT2]) and tight junction regulation (eg, claudins 8 and 23) were evident in both groups. However, some lipid-associated mediators (eg, fatty acyl-CoA reductase 2 and fatty acid 2-hydroxylase) showed preferential downregulation in pediatric AD, and lipid barrier genes (FA2H and DGAT2) showed inverse correlations with transepidermal water loss, a functional measure of the epidermal barrier. Conclusions Skin samples from children and adult patients with AD share lipid metabolism and tight junction alterations, but epidermal differentiation complex defects are only present in adult AD, potentially resulting from chronic immune aberration that is not yet present in early-onset disease. [ABSTRACT FROM AUTHOR]

Background: Atopic dermatitis (AD) and allergic contact dermatitis (ACD) are both forms of eczema and are common inflammatoryskindiseaseswith a central role of T-cell-derived IL-22 in their pathogenesis. Although prostaglandin (PG) E2 is known to promote inflammation, little is known about its role in processes related to AD and ACD development, including IL-22 upregulation. Objectives: We sought to investigate whether PGE2 has a role in IL-22 induction and development of ACD, which has increased prevalence in patients with AD. Methods: T-cell cultures and in vivo sensitization of mice with haptens were used to assess the role of PGE2 in IL-22 production. The involvement of PGE2 receptors and their downstream signals was also examined. The effects of PGE2 were evaluated by using the oxazolone-induced ACD mouse model. The relationship of PGE2 and IL-22 signaling pathways in skin inflammation were also investigated by using genomic profiling in human lesional AD skin. Results: PGE2 induces IL-22 from T cells through its receptors, E prostanoid receptor (EP) 2 and EP4, and involves cyclic AMP signaling. Selective deletion of EP4 in T cells prevents hapteninduced IL-22 production in vivo, and limits atopic-like skin inflammation in the oxazolone-induced ACD model. Moreover, both PGE2 and IL-22 pathway genes were coordinately upregulated in human AD lesional skin but were at less than significant detection levels after corticosteroid or UVB treatments. Conclusions: Our results define a crucial role for PGE2 in promoting ACD by facilitating IL-22 production from T cells. [ABSTRACT FROM AUTHOR]

It is unknown whether skin biomarkers collected in infancy can predict the onset of atopic dermatitis (AD) and be used in future prevention trials to identify children at risk. This study sought to examine whether skin biomarkers can predict AD during the first 2 years of life. This study enrolled 300 term and 150 preterm children at birth and followed for AD until the age of 2 years. Skin tape strips were collected at 0 to 3 days and 2 months of age and analyzed for selected immune and barrier biomarkers. Hazard ratio (HR) with 95% confidence interval (CI) using Cox regression was calculated for the risk of AD. The 2-year prevalence of AD was 34.6% (99 of 286) and 21.2% (25 of 118) among term and preterm children, respectively. Skin biomarkers collected at birth did not predict AD. Elevated thymus- and activation-regulated chemokine/C-C motif chemokine ligand 17 -levels collected at 2 months of age increased the overall risk of AD (HR: 2.11; 95% CI: 1.36-3.26; P =.0008) and moderate-to-severe AD (HR: 4.97; 95% CI: 2.09-11.80; P =.0003). IL-8 and IL-18 predicted moderate-to-severe AD. Low filaggrin degradation product levels increased the risk of AD (HR: 2.04; 95% CI: 1.32-3.15; P =.001). Elevated biomarker levels at 2 months predicted AD at other skin sites and many months after collection. This study showed that noninvasively collected skin biomarkers of barrier and immune pathways can precede the onset of AD. [ABSTRACT FROM AUTHOR]

Skin barrier abnormalities have been suggested to play an essential role in initiation of early atopic dermatitis (AD). Antigen penetration through a compromised barrier likely leads to increased innate immune responses, antigen-presenting cell stimulation, and priming of overt cutaneous disease. In a T H 2-promoting environment, T-cell/B-cell interactions occurring in regional lymph nodes lead to excessive IgE switch. Concurrent redistribution of memory T cells into the circulation not only leads to exacerbation of AD through T-cell skin infiltration but also spreads beyond the skin to initiate the atopic march, which includes food allergy, asthma, and allergic rhinitis. Possible primary interventions to prevent AD are focusing on improving skin barrier integrity, including supplementing barrier function with moisturizers. As for secondary prophylaxis in children with established AD, this can be stratified into prevention of disease exacerbations by using proactive approaches (with either topical corticosteroids or topical calcineurin inhibitors) in mild AD cases or the prevention of other atopic disorders that will probably mandate systemic immunosuppression in severe AD cases. [ABSTRACT FROM AUTHOR]

Background Atopic dermatitis (AD) is caused by a complex interplay between immune and barrier abnormalities. Murine models of AD are essential for preclinical assessments of new treatments. Although many models have been used to simulate AD, their transcriptomic profiles are not fully understood, and a comparison of these models with the human AD transcriptomic fingerprint is lacking. Objective We sought to evaluate the transcriptomic profiles of 6 common murine models and determine how they relate to human AD skin. Methods Transcriptomic profiling was performed by using microarrays and quantitative RT-PCR on biopsy specimens from NC/Nga, flaky tail, Flg -mutated, ovalbumin-challenged, oxazolone-challenged, and IL-23–injected mice. Gene expression data of patients with AD, psoriasis, and contact dermatitis were obtained from previous patient cohorts. Criteria of a fold change of 2 or greater and a false discovery rate of 0.05 or less were used for gene arrays. Results IL-23–injected, NC/Nga, and oxazolone-challenged mice show the largest homology with our human meta-analysis–derived AD transcriptome (37%, 18%, 17%, respectively). Similar to human AD, robust T H 1, T H 2, and also T H 17 activation are seen in IL-23–injected and NC/Nga mice, with similar but weaker inflammation in ovalbumin-challenged mice. Oxazolone-challenged mice show a T H 1-centered reaction, and flaky tail mice demonstrate a strong T H 17 polarization. Flg -mutated mice display filaggrin downregulation without significant inflammation. Conclusion No single murine model fully captures all aspects of the AD profile; instead, each model reflects different immune or barrier disease aspects. Overall, among the 6 murine models, IL-23–injected mice best simulate human AD; still, the translational focus of the investigation should determine which model is most applicable. [ABSTRACT FROM AUTHOR]

Background The ichthyoses are rare genetic disorders associated with generalized scaling, erythema, and epidermal barrier impairment. Pathogenesis-based therapy is largely lacking because the underlying molecular basis is poorly understood. Objective We sought to characterize molecularly cutaneous inflammation and its correlation with clinical and barrier characteristics. Methods We analyzed biopsy specimens from 21 genotyped patients with ichthyosis (congenital ichthyosiform erythroderma, n = 6; lamellar ichthyosis, n = 7; epidermolytic ichthyosis, n = 5; and Netherton syndrome, n = 3) using immunohistochemistry and RT-PCR and compared them with specimens from healthy control subjects, patients with atopic dermatitis (AD), and patients with psoriasis. Clinical measures included the Ichthyosis Area Severity Index (IASI), which integrates erythema (IASI-E) and scaling (IASI-S); transepidermal water loss; and pruritus. Results Ichthyosis samples showed increased epidermal hyperplasia (increased thickness and keratin 16 expression) and T-cell and dendritic cell infiltrates. Increases of general inflammatory (IL-2), innate (IL-1β), and some T H 1/interferon (IFN-γ) markers in patients with ichthyosis were comparable with those in patients with psoriasis or AD. TNF-α levels in patients with ichthyosis were increased only in those with Netherton syndrome but were much lower than in patients with psoriasis and those with AD. Expression of T H 2 cytokines (IL-13 and IL-31) was similar to that seen in control subjects. The striking induction of IL-17–related genes or markers synergistically induced by IL-17 and TNF-α (IL-17A/C, IL-19, CXCL1, PI3, CCL20, and IL36G; P < .05) in patients with ichthyosis was similar to that seen in patients with psoriasis. IASI and IASI-E scores strongly correlated with IL-17A ( r = 0.74, P < .001) and IL-17/TNF–synergistic/additive gene expression. These markers also significantly correlated with transepidermal water loss, suggesting a link between the barrier defect and inflammation in patients with ichthyosis. Conclusion Our data associate a shared T H 17/IL-23 immune fingerprint with the major orphan forms of ichthyosis and raise the possibility of IL-17–targeting strategies. [ABSTRACT FROM AUTHOR]

Atopic dermatitis (AD) is a complex skin disease frequently associated with other diseases of the atopic diathesis. Recent evidence supports the concept that AD can also recognize other comorbidities, such as chronic inflammatory bowel or cardiovascular diseases. These comorbidities might result from chronic cutaneous inflammation or from a common, yet-to-be-defined immunologic background leading to immune deviations. The activation of immune cells and their migration to the skin play an essential role in the pathogenesis of AD. In patients with AD, an underlying immune deviation might result in higher susceptibility of the skin to environmental factors. There is a high unmet medical need to define immunologic endotypes of AD because it has significant implications on upcoming stratification of the phenotype of AD and the resulting targeted therapies in the development of precision medicine. This review article emphasizes studies on environmental factors affecting AD development and novel biological agents used in the treatment of AD. Best evidence of the clinical efficacy of novel immunologic approaches using biological agents in patients with AD is available for the anti–IL-4 receptor α-chain antibody dupilumab, but a number of studies are currently ongoing with other specific antagonists to immune system players. These targeted molecules can be expressed on or drive the cellular players infiltrating the skin (eg, T lymphocytes, dendritic cells, or eosinophils). Such approaches can have immunomodulatory and thereby beneficial clinical effects on the overall skin condition, as well as on the underlying immune deviation that might play a role in comorbidities. An effect of these immunologic treatments on pruritus and the disturbed microbiome in patients with AD has other potential consequences for treatment. [ABSTRACT FROM AUTHOR]

Background Topical glucocorticosteroids are considered an efficient treatment option for atopic dermatitis (AD), but a global assessment of glucocorticosteroid responses on key disease circuits upon weeks to months of treatment is currently lacking. Objective We sought to assess short (4 weeks) and long-term (16 weeks) application of topical glucocorticosteroids on AD skin and define response biomarkers. Methods The effects of triamcinolone acetonide cream 0.025% were assessed based on gene expression and immunohistochemistry studies at baseline, 4 weeks, and 16 weeks in biopsy specimens from 15 patients with moderate-to-severe AD. Results At 16 weeks, only 3 patients were clinical responders (by using SCORAD50 criteria), but 6 patients qualified as responders based on histologic criteria. Baseline characteristics indicated more severe disease in nonresponders. While 3 of 15 patients experienced only transient benefit after 4 weeks, others showed progressive improvements toward 16 weeks. Topical glucocorticosteroid use in patients with AD resulted in improvements of the AD genomic signature of 25.6% at 4 weeks and 71.8% at 16 weeks, respectively, and even 123.9% in the histologic responder group. Cytokines (IL-12p40, IL-13, IL-22, CCL17, CCL18, peptidase inhibitor 3 [PI3]/elafin, and S100As) showed consistent decreases from baseline toward 16 weeks with corresponding improvements in epidermal disease hallmarks (keratin 16 and loricrin) in lesional skin from responders ( P < .05). Nonresponders largely showed lesser/nonsignificant reductions in key inflammatory and barrier markers (keratin 16, IL-13, IL-22, CCL17, CCL18, PI3/elafin, S100As, and loricrin). The combination of IL-21 and IFN-γ baseline expression closely predicted individual clinical glucocorticosteroid responses at 16 weeks of treatment. Conclusion Our study indicates that even low-potency glucocorticosteroids can broadly affect immune and barrier responses in patients with moderate-to-severe AD, associating higher baseline severity with increased steroid resistance in patients with AD. [ABSTRACT FROM AUTHOR]

Background Atopic dermatitis (AD) shows very high prevalence in Asia, with a large unmet need for effective therapeutics. Direct comparisons between European American (EA) and Asian patients with AD are unavailable, but earlier blood studies detected increased IL-17 + –producing cell counts in Asian patients with AD. Objective We sought to characterize the Asian AD skin phenotype and compare it with the EA AD skin phenotype. Methods We performed genomic profiling (real-time PCR) and immunohistochemistry on lesional and nonlesional biopsy specimens from 52 patients with AD (25 EAs and 27 Asians), 10 patients with psoriasis (all EAs), and 27 healthy subjects (12 EAs and 15 Asians). Results Although disease severity/SCORAD scores were similar between the AD groups (58.0 vs 56.7, P = .77), greater acanthosis, higher Ki67 counts, and frequent parakeratosis were characteristics of lesional epidermis from Asian patients with AD ( P < .05). Most (24/27) Asian patients had high IgE levels. A principal component analysis using real-time PCR data clustered the Asian AD phenotype between the EA AD and psoriasis phenotypes. T H 2 skewing characterized both Asian and EA patients with AD but not patients with psoriasis. Significantly higher T H 17 and T H 22 ( IL17A, IL19 , and S100A12 in lesional and IL-22 in nonlesional skin; P < .05) and lower T H 1/interferon ( CXCL9, CXCL10, MX1 , and IFNG in nonlesional skin; P < .05) gene induction typified AD skin in Asian patients. Conclusion The Asian AD phenotype presents (even in the presence of increased IgE levels) a blended phenotype between that of EA patients with AD and those with psoriasis, including increased hyperplasia, parakeratosis, higher T H 17 activation, and a strong T H 2 component. The relative pathogenic contributions of the T H 17 and T H 2 axes in creating the Asian AD phenotype need to be tested in future clinical trials with appropriate targeted therapeutics. [ABSTRACT FROM AUTHOR]

Background Alopecia areata (AA) is a common T cell–mediated disorder with limited therapeutics. A molecular profile of cytokine pathways in AA tissues is lacking. Although studies have focused on T H 1/IFN-γ responses, several observations support a shared genetic background between AA and atopy. Objective We sought to define the AA scalp transcriptome and associated biomarkers with comparisons with atopic dermatitis (AD) and psoriasis. Methods We performed microarray and RT-PCR profiling of 27 lesional and 17 nonlesional scalp samples from patients with AA for comparison with normal scalp samples (n = 6). AA gene expression was also compared with samples from patients with lesional or nonlesional AD and those with psoriasis. A fold change of greater than 1.5 and a false discovery rate of less than 0.05 were used for differentially expressed genes (DEGs). Results We established the AA transcriptomes (lesional vs nonlesional: 734 DEGs [297 upregulated and 437 downregulated]; lesional vs normal: 4230 DEGs [1980 upregulated and 2250 downregulated]), including many upregulated immune and downregulated hair keratin genes. Equally impressive as upregulation in T H 1/interferon markers ( IFNG and CXCL10/CXCL9 ) were those noted in T H 2 ( IL13 , CCL18, CCL26 , thymic stromal lymphopoietin, and periostin), T H 9/IL-9, IL-23 (p40 and p19), and IL-16 mediators (all P < .05). There were no increases in T H 17/T H 22 markers. Hair keratin (KRT) expressions (ie, KRT86 and KRT85 ) were significantly suppressed in lesional skin. Greater scalp involvement (>25%) was associated with greater immune and keratin dysregulation and larger abnormalities in nonlesional scalp samples (ie, CXCL10 and KRT85 ). Conclusions Our data associate the AA signature with T H 2, T H 1, IL-23, and IL-9/T H 9 cytokine activation, suggesting consideration of anti-T H 2, anti-T H 1, and anti–IL-23 targeting strategies. Similar to psoriasis and AD, clinical trials with selective antagonists are required to dissect key pathogenic pathways. [ABSTRACT FROM AUTHOR]

Background Genomic profiling of lesional and nonlesional skin of patients with atopic dermatitis (AD) using microarrays has led to increased understanding of AD and identification of novel therapeutic targets. However, the limitations of microarrays might decrease detection of AD genes. These limitations might be lessened with next-generation RNA sequencing (RNA-seq). Objective We sought to define the lesional AD transcriptome using RNA-seq and compare it using microarrays performed on the same cohort. Methods RNA-seq and microarrays were performed to identify differentially expressed genes (criteria: fold change, ≥2.0; false discovery rate ≤0.05) in lesional versus nonlesional skin from 18 patients with moderate-to-severe AD, with real-time PCR (RT-PCR) and immunohistochemistry used for validation. Results Both platforms showed robust disease transcriptomes and correlated well with RT-PCR. The common AD transcriptome identified by using both techniques contained 217 genes, including inflammatory ( S100A8/A9/A12, CXCL1 , and 2′-5′-oligoadenylate synthetase-like [ OASL ]) and barrier ( MKi67 , keratin 16 [ K16 ], and claudin 8 [ CLDN8 ]) AD-related genes. Although fold change estimates determined by using RNA-seq showed somewhat better agreement with RT-PCR (intraclass correlation coefficient, 0.57 and 0.70 for microarrays and RNA-seq vs RT-PCR, respectively), bias was not eliminated. Among genes uniquely identified by using RNA-seq were triggering receptor expressed on myeloid cells 1 (TREM-1) signaling (eg, CCL2 , CCL3 , and single immunoglobulin domain IL1R1 related [ SIGIRR ]) and IL-36 isoform genes. TREM-1 is a surface receptor implicated in innate and adaptive immunity that amplifies infection-related inflammation. Conclusions This is the first report of a lesional AD phenotype using RNA-seq and the first direct comparison between platforms in this disease. Both platforms robustly characterize the AD transcriptome. Through RNA-seq, we unraveled novel disease pathology, including increased expression of the novel TREM-1 pathway and the IL-36 cytokine in patients with AD. [ABSTRACT FROM AUTHOR]

Background Atopic dermatitis (AD) is the most common inflammatory disease. The prevalence of allergic contact dermatitis to allergens (eg, fragrance) is higher in patients with AD, despite a trend toward weaker clinical allergic contact dermatitis reactions. The role of the AD skin phenotype in modulating allergic sensitization to common sensitizers has not been evaluated. Objective We sought to investigate whether patients with AD have altered tissue immune responses on allergen challenge. Methods Gene expression and immunohistochemistry studies were performed on biopsy specimens from 10 patients with AD and 14 patients without AD patch tested with common contact allergens (nickel, fragrance, and rubber). Results Although 1085 differentially expressed genes (DEGs) were commonly modulated in patch-tested skin from patients with AD and patients without AD versus control skin, 1185 DEGs were uniquely altered in skin from patients without AD, and only 246 DEGs were altered in skin from patients with AD. Although many inflammatory products (ie, matrix metalloproteinase 12/matrix metalloproteinase 1/S100A9) were upregulated in both groups, higher-magnitude changes and upregulation of interferon responses were evident only in the non-AD group. Stratification by allergen showed decreased expression of immune, T H 1-subset, and T H 2-subset genes in nickel-related AD responses, with increased T H 17/IL-23 skewing. Rubber/fragrance showed similar trends of lesser magnitude. Negative regulators showed higher expression in patients with AD. Conclusions Through contact sensitization, our study offers new insights into AD. Allergic immune reactions were globally attenuated and differentially polarized in patients with AD, with significant decreases in levels of T H 1 products, some increases in levels of T H 17 products, and inconsistent upregulation in levels of T H 2 products. The overall hyporesponsiveness in skin from patients with background AD might be explained by baseline immune abnormalities, such as increased T H 2, T H 17, and negative regulator levels compared with those seen in non-AD skin. [ABSTRACT FROM AUTHOR]

Psoriasis and atopic dermatitis (AD) are common inflammatory skin diseases characterized by immune-mediated inflammation and abnormal keratinocyte differentiation. Although T-cell infiltration characterizes both diseases, T-cell polarization differs. Psoriasis is currently the best model for translational medicine because many targeted therapeutics have been developed and testing of targeted therapeutics has cemented psoriasis as IL-23/T H 17 polarized. In patients with AD, although therapeutic development is approximately a decade behind that in patients with psoriasis, there is now active development and testing of targeted therapeutics against various immune axes (T H 2, T H 22, and IL-23/T H 17). These clinical trials and subsequent molecular analyses using human samples will be able to clarify the relative roles of polar cytokines in patients with AD. [ABSTRACT FROM AUTHOR]

Background The molecular signature of atopic dermatitis (AD) lesions is associated with T H 2 and T H 22 activation and epidermal alterations. However, the epidermal and dermal AD transcriptomes and their respective contributions to abnormalities in respective immune and barrier phenotypes are unknown. Objective We sought to establish the genomic profile of the epidermal and dermal compartments of lesional and nonlesional AD skin compared with normal skin. Methods Laser capture microdissection was performed to separate the epidermis and dermis of lesional and nonlesional skin from patients with AD and normal skin from healthy volunteers, followed by gene expression (microarrays and real-time PCR) and immunostaining studies. Results Our study identified novel immune and barrier genes, including the IL-34 cytokine and claudins 4 and 8, and showed increased detection of key AD genes usually undetectable on arrays (ie, IL22 , thymic stromal lymphopoietin [TSLP] , CCL22 , and CCL26 ). Overall, the combined epidermal and dermal transcriptomes enlarged the AD transcriptome, adding 674 upregulated and 405 downregulated differentially expressed genes between lesional and nonlesional skin to the AD transcriptome. We were also able to localize individual transcripts as primarily epidermal (defensin, beta 4A [DEFB4A] ) or dermal ( IL22 , cytotoxic T-lymphocyte antigen 4 [CTLA4] , and CCR7 ) and link their expressions to possible cellular sources. Conclusions This is the first report that establishes robust epidermal and dermal genomic signatures of lesional and nonlesional AD skin and normal skin compared with whole tissues. These data establish the utility of laser capture microdissection to separate different compartments and cellular subsets in patients with AD, allowing localization of key barrier or immune molecules and enabling detection of gene products usually not detected on arrays. [ABSTRACT FROM AUTHOR]

Background Severe atopic dermatitis (AD) has a high unmet need for effective and safe therapeutics. In early-phase trials, dupilumab, a fully human mAb targeting IL-4 receptor α, markedly improved disease activity, but the effect of IL-4/IL-13 blockade on AD at the molecular level has not been characterized. Objectives We sought to evaluate dupilumab modulation of the AD molecular signature. Methods We performed transcriptomic analyses of pretreatment and posttreatment skin biopsy specimens from patients with moderate-to-severe AD treated weekly with 150 or 300 mg of dupilumab or placebo. Results Exacerbation of the AD transcriptome was observed in placebo-treated patients. Dupilumab improved the AD signature in a dose-dependent manner. Expression of genes upregulated in AD lesions decreased in patients treated with dupilumab by 26% (95% CI, 21% to 32%) and 65% (95% CI, 60% to 71%) for treatment with 150 and 300 mg, respectively. Genes downregulated in AD lesions increased by 21% (95% CI, 16% to 27%) and 32% (95% CI, 26% to 37%) with dupilumab (150 and 300 mg, respectively). The molecular changes paralleled improvements in clinical scores. A dupilumab treatment signature of 821 probes (>2-fold change, P < .05) significantly modulated in the 300-mg dupilumab group at week 4 compared with baseline was identified in this sample set. Significant ( P < .05) decreases in mRNA expression of genes related to hyperplasia ( K16 and MKI67 ), T cells, and dendritic cells ( CD1b and CD1c ) and potent inhibition of T H 2-associated chemokines ( CCL17 , CCL18 , CCL22 , and CCL26 ) were noted without significant modulation of T H 1-associated genes (IFNG) . Conclusions This is the first report showing rapid improvement of the AD molecular signature with targeted anti–IL-4 receptor α therapy. These data suggest that IL-4 and IL-13 drive a complex, T H 2-centered inflammatory axis in patients with AD. [ABSTRACT FROM AUTHOR]

Atopic dermatitis (AD) is the most common chronic inflammatory skin disease. It often precedes the development of food allergy and asthma. Recent insights into AD reveal abnormalities in terminal differentiation of the epidermal epithelium leading to a defective stratum corneum, which allows enhanced allergen penetration and systemic IgE sensitization. Atopic skin is also predisposed to colonization or infection by pathogenic microbes, most notably Staphylococcus aureus and herpes simplex virus. Causes of this abnormal skin barrier are complex and driven by a combination of genetic, environmental, and immunologic factors. These factors likely account for the heterogeneity of AD onset and the severity and natural history of this skin disease. Recent studies suggest prevention of AD can be achieved through early interventions to protect the skin barrier. Onset of lesional AD requires effective control of local and systemic immune activation for optimal management. Early intervention might improve long-term outcomes for AD and reduce the systemic allergen sensitization that leads to associated allergic diseases in the gastrointestinal and respiratory tract. [ABSTRACT FROM AUTHOR]

Background Allergic contact dermatitis (ACD) is the most common occupational disease. Although murine contact hypersensitivity provides a framework for understanding ACD, it carries important differences from its human counterpart. Unlike the contact hypersensitivity model, which is induced by potent sensitizers (ie, dinitrofluorobenzene), human ACD is induced by weak-to-moderate sensitizers (ie, nickel), which cannot induce reactions in mice. Distinct hapten-specific immune-polarizing responses to potent inducers were suggested in mice, with unclear relevance to human ACD. Objective We explored the possibility of distinct T-cell polarization responses in skin to common clinically relevant ACD allergens. Methods Gene-expression and cellular studies were performed on common allergens (ie, nickel, fragrance, and rubber) compared with petrolatum-occluded skin, using RT-PCR, gene arrays, and immunohistochemistry. Results Despite similar clinical reactions in all allergen groups, distinct immune polarizations characterized different allergens. Although the common ACD transcriptome consisted of 149 differentially expressed genes across all allergens versus petrolatum, a much larger gene set was uniquely altered by individual allergens. Nickel demonstrated the highest immune activation, with potent inductions of innate immunity, TH1/TH17 and a TH22 component. Fragrance, and to a lesser extent rubber, demonstrated a strong TH2 bias, some TH22 polarization, and smaller TH1/TH17 contributions. Conclusions Our study offers new insights into the pathogenesis of ACD, expanding the understanding of T-cell activation and associated cytokines in allergen-reactive tissues. It is the first study that defines the common transcriptome of clinically relevant sensitizers in human skin and identifies unique pathways preferentially activated by different allergens, suggesting that ACD cannot be considered a single entity. [ABSTRACT FROM AUTHOR]