Omalizumab for the Treatment of Multiple Food Allergies.

BACKGROUND: Food allergies are common and are associated with substantial morbidity; the only approved treatment is oral immunotherapy for peanut allergy. METHODS: In this trial, we assessed whether omalizumab, a monoclonal anti-IgE antibody, would be effective and safe as monotherapy in patients with multiple food allergies. Persons 1 to 55 years of age who were allergic to peanuts and at least two other trial-specified foods (cashew, milk, egg, walnut, wheat, and hazelnut) were screened. Inclusion required a reaction to a food challenge of 100 mg or less of peanut protein and 300 mg or less of the two other foods. Participants were randomly assigned, in a 2:1 ratio, to receive omalizumab or placebo administered subcutaneously (with the dose based on weight and IgE levels) every 2 to 4 weeks for 16 to 20 weeks, after which the challenges were repeated. The primary end point was ingestion of peanut protein in a single dose of 600 mg or more without dose-limiting symptoms. The three key secondary end points were the consumption of cashew, of milk, and of egg in single doses of at least 1000 mg each without dose-limiting symptoms. The first 60 participants (59 of whom were children or adolescents) who completed this first stage were enrolled in a 24-week open-label extension. RESULTS: Of the 462 persons who were screened, 180 underwent randomization. The analysis population consisted of the 177 children and adolescents (1 to 17 years of age). A total of 79 of the 118 participants (67%) receiving omalizumab met the primary end-point criteria, as compared with 4 of the 59 participants (7%) receiving placebo (P<0.001). Results for the key secondary end points were consistent with those of the primary end point (cashew, 41% vs. 3%; milk, 66% vs. 10%; egg, 67% vs. 0%; P<0.001 for all comparisons). Safety end points did not differ between the groups, aside from more injection-site reactions in the omalizumab group. CONCLUSIONS: In persons as young as 1 year of age with multiple food allergies, omalizumab treatment for 16 weeks was superior to placebo in increasing the reaction threshold for peanut and other common food allergens. (Funded by the National Institute of Allergy and Infectious Diseases and others; ClinicalTrials.gov number, NCT03881696.).

Skin biomarkers predict the development of food allergy in early life.

BACKGROUND: Food allergy (FA) often occurs in early childhood with and without atopic dermatitis (AD). FA can be severe and even fatal. For primary prevention, it is important to find early biomarkers to predict the future onset of FA before any clinical manifestations. OBJECTIVE: Our aim was to find early predictors of future onset of FA in the stratum corneum (SC). METHODS: Skin tape strips were collected from the forearm of newborns (n = 129) at age 2 months, before any signs of clinical FA or AD. Children were clinically monitored until they reached age 2 years to confirm the presence or absence of FA and AD. Skin tape strips were subjected to lipidomic analyses by liquid chromatography-tandem mass spectrometry and cytokine determination by Meso Scale Discovery U-Plex assay. RESULTS: Overall, 9 of 129 infants (7.0%) developed FA alone and 9 of 129 infants (7.0%) developed FA concomitantly with AD. In the stratum corneum of children with future FA and concomitant AD and FA, absolute amounts of unsaturated (N24:1)(C18-sphingosine)ceramide and (N26:1)(C18-sphingosine)ceramide and their relative percentages within the molecular group were increased compared with the amounts and percentages in healthy children, with P values ranging from less than .01 to less than .05 according to ANOVA. The children with future AD had normal levels of these molecules. IL-33 level was upregulated in those infants with future FA but not in those with future AD, whereas thymic stromal lymphopoietin was upregulated in those with future AD but not in those with future FA. Logistic regression analysis revealed strong FA predicting power for the combination of dysregulated lipids and cytokines, with an odds ratio reaching 101.4 (95% CI = 5.4-1910.6). CONCLUSION: Noninvasive skin tape strip analysis at age 2 months can identify infants at risk of FA in the future.

CERS1 is a biomarker of Staphylococcus aureus abundance and atopic dermatitis severity.

BACKGROUND: Atopic dermatitis (AD) is an inflammatory skin condition characterized by widely variable cutaneous Staphylococcus aureus abundance that contributes to disease severity and rapidly responds to type 2 immune blockade (ie, dupilumab). The molecular mechanisms regulating S aureus levels between AD subjects remain poorly understood. OBJECTIVE: We investigated host genes that may be predictive of S aureus abundance and correspond with AD severity. METHODS: We studied data derived from the National Institutes of Health/National Institute of Allergy and Infectious Diseases-funded (NCT03389893 [ADRN-09]) randomized, double-blind, placebo-controlled multicenter study of dupilumab in adults (n = 71 subjects) with moderate-to-severe AD. Bulk RNA sequencing of skin biopsy samples (n = 57 lesional, 55 nonlesional) was compared to epidermal S aureus abundance, lipidomic, and AD clinical measures. RESULTS: S aureus abundance and ceramide synthase 1 (CERS1) expression positively correlated at baseline across both nonlesional (r = 0.29, P = .030) and lesional (r = 0.41, P = .0015) skin. Lesional CERS1 expression also positively correlated with AD severity (ie, SCORAD r = 0.44, P = .0006) and skin barrier dysfunction (transepidermal water loss area under the curve r = 0.31, P = .025) at baseline. CERS1 expression (forms C18:0 sphingolipids) was negatively associated with elongation of very long-chain fatty acids (ELOVL6; C16:0→C18:0) expression and corresponded with a shorter chain length sphingolipid composition. Dupilumab rapidly reduced CERS1 expression (day 7) and ablated the relationship with S aureus abundance and ELOVL6 expression by day 21. CONCLUSION: CERS1 is a unique molecular biomarker of S aureus abundance and AD severity that may contribute to dysfunctional skin barrier and shorter-chain sphingolipid composition through fatty acid sequestration as a maladaptive compensatory response to reduced ELOVL6.

CLA+ memory T cells in atopic dermatitis: CLA+ T cells and atopic dermatitis.

Circulating skin-homing cutaneous lymphocyte-associated antigen (CLA)+ T cells constitute a small subset of human memory T cells involved in several aspects of atopic dermatitis: Staphylococcus aureus related mechanisms, the abnormal Th2 immune response, biomarkers, clinical aspects of the patients, pruritus, and the mechanism of action of targeted therapies. Superantigens, IL-13, IL-31, pruritus, CCL17 and early effects on dupilumab-treated patients have in common that they are associated with the CLA+ T cell mechanisms in atopic dermatitis patients. The function of CLA+ T cells corresponds with the role of T cells belonging to the skin-associated lymphoid tissue and could be a reason why they reflect different mechanisms of atopic dermatitis and many other T cell mediated skin diseases. The goal of this review is to gather all this translational information of atopic dermatitis pathology.

Air pollutants contribute to epithelial barrier dysfunction and allergic diseases.

Air pollution is a global problem associated with various health conditions, causing elevated rates of morbidity and mortality. Major sources of air pollutants include industrial emissions, traffic-related pollutants, and household biomass combustion, in addition to indoor pollutants from chemicals and tobacco. Various types of air pollutants originate from both human activities and natural sources. These include particulate matter, pollen, greenhouse gases, and other harmful gases. Air pollution is linked to allergic diseases, including atopic dermatitis, allergic rhinitis, allergic conjunctivitis, food allergy, and bronchial asthma. These pollutants lead to epithelial barrier dysfunction, dysbiosis, and immune dysregulation. In addition, climate change and global warming may contribute to the exacerbation and the development of allergic diseases related to air pollutants. Epigenetic changes associated with air pollutants have also been connected to the onset of allergic diseases. Furthermore, these changes can be passed down through subsequent generations, causing a higher prevalence of allergic diseases in offspring. Modulation of the aryl hydrocarbon receptor could be a valuable strategy for alleviating air pollutant-induced epidermal barrier dysfunction and atopic dermatitis. A more effective approach to preventing allergic diseases triggered by air pollutants is to reduce exposure to them. Implementing public policies aimed at safeguarding individuals from air pollutant exposure may prove to be the most efficient solution. A pressing need exists for global policy initiatives that prioritize efforts to reduce the production of air pollutants.

Skin as the target for allergy prevention and treatment.

The fact that genetic and environmental factors could trigger disruption of the epithelial barrier and subsequently initiate a TH2 inflammatory cascade conversely proposes that protecting the same barrier and promoting adequate interactions with other organs, such as the gut, may be crucial for lowering the risk and preventing atopic diseases, particularly, food allergies. In this review, we provide an overview of structural characteristics that support the epithelial barrier hypothesis in patients with atopic dermatitis, including the most relevant filaggrin gene mutations, the recent discovery of the role of the transient receptor potential vanilloid 1, and the role involvement of the microbiome in healthy and damaged skin. We present experimental and human studies that support the mechanisms of allergen penetration, particularly the dual allergen exposure and the outside-in, inside-out, and outside-inside-outside hypotheses. We discuss classic skin-targeted therapies for food allergy prevention, including moisturizers, steroids, and topical calcineurin inhibitors, along with pioneering trials proposed to change their current use (Prevention of Allergy via Cutaneous Intervention and Stopping Eczema and ALlergy). We provide an overview of the novel therapies that enhance the skin barrier, such as probiotics and prebiotics topical application, read-through drugs, direct and indirect FLG replacement, and interleukin and janus kinases inhibitors. Last, we discuss the newer strategies for preventing and treating food allergies in the form of epicutaneous immunotherapy and the experimental use of single-dose of adeno-associated virus vector gene immunotherapy.

Systemic Therapy for Atopic Dermatitis in Children and Adolescents: A United States Expert Consensus.

Atopic dermatitis (AD) is a chronic, type-2 mediated, inflammatory skin disease characterized by intense pruritus, disruption of skin barrier function, and immune dysregulation. Management strategies for AD are routinely determined based on disease severity. First-line treatment begins with basic skin care and topical anti-inflammatory medication, which is typically sufficient for the management of mild-to-moderate disease. For those patients with moderate-to-severe disease, systemic therapy is often required. This can involve off-label treatment with conventional immunosuppressant medications. However, this approach is limited by a lack of robust clinical trial data and safety concerns that necessitate close monitoring. The emergence of novel targeted biologics and small molecules to treat AD presents an opportunity to optimize AD management and patient outcomes by offering greater efficacy than traditional immunosuppressants and a favorable safety profile. As the treatment landscape shifts, clinicians can benefit from a standardized process of patient assessment and treatment, along with resources to help maintain contemporary knowledge of available therapeutic options. This United States (US)-based, expert-led consensus used a modified Delphi process to develop core recommendations for the use of systemic medications for the management of pediatric patients <18 years of age with moderate-to-severe AD.

Endotypes of atopic dermatitis and food allergy.

Atopic dermatitis (AD) and food allergy (FA) are strongly associated, with one-third of children with AD developing concomitant FA. Epithelial barrier dysfunction is important in both conditions. Genetic factors, such as filaggrin mutations and IL-4 receptor alpha chain polymorphisms, are linked to increased risk. In addition, several environmental exposures lead to reduced filaggrin and contribute to skin barrier dysfunction. Staphylococcus aureus colonization appears to contribute to AD and FA, as well as activating the type 2 immune response. Comprehensive multiomic studies using skin tape stripping have identified distinct atopic endotypes with unique characteristics of the stratum corneum lipids, proteins, S aureus abundance, and type 2 cytokine expression. Our new understanding of AD and FA presents an area of opportunity to move toward improved diagnosis and prevention of atopy.

Epidermal differentiation complex genetic variation in atopic dermatitis and peanut allergy.

BACKGROUND: Deleterious variation in the epidermal differentiation complex (EDC) on chromosome 1 is a well-known genetic determinant of atopic dermatitis (AD) and has been associated with risk of peanut allergy (PA) in population-based studies. OBJECTIVE: Our aim was to determine the effect of genetic variation in the EDC on AD trajectory and risk of PA in early life. METHODS: Genome sequencing was used to measure genetic variation in the EDC in the Learning Early about Peanut Allergy (LEAP) study participants. Association tests were done to identify gene- and variant-level predicted deleterious variation associated with AD severity by using the Scoring Atopic Dermatitis (SCORAD) tool (n = 559) at baseline and each follow-up visit, as well as PA and food allergy in peanut avoiders (n = 275). Predicted deleterious variants included missense variants that were frameshift insertions, frameshift deletions, stop-gain mutations, or stop-loss mutations. Associations between variant load, SCORAD score, and PA were tested by using linear and generalized linear regression models. RESULTS: The genes FLG, FLG2, HRNR, and TCHH1 harbored the most predicted deleterious variation (30, 6, 3, and 1 variant, respectively). FLG variants were associated with SCORAD score at all time points; 4 variants (R1798X, R501X, S126X, and S761fs) drove the association with SCORAD score at each time point, and higher variant load was associated with greater AD severity over time. There was an association between these variants and PA, which remained significant independent of baseline AD severity (odds ratio = 2.63 [95% CI = 1.11-6.01] [P = .02]). CONCLUSIONS: Variation in FLG predicted to be deleterious is associated with AD severity at baseline and longitudinally and has an association with PA independent of baseline severity.

Longitudinal dynamics of the gut microbiome and metabolome in peanut allergy development.

BACKGROUND: Rising rates of peanut allergy (PA) motivate investigations of its development to inform prevention and therapy. Microbiota and the metabolites they produce shape food allergy risk. OBJECTIVE: We sought to gain insight into gut microbiome and metabolome dynamics in the development of PA. METHODS: We performed a longitudinal, integrative study of the gut microbiome and metabolome of infants with allergy risk factors but no PA from a multicenter cohort followed through mid-childhood. We performed 16S rRNA sequencing, short chain fatty acid measurements, and global metabolome profiling of fecal samples at infancy and at mid-childhood. RESULTS: In this longitudinal, multicenter sample (n = 122), 28.7% of infants developed PA by mid-childhood (mean age 9 years). Lower infant gut microbiome diversity was associated with PA development (P = .014). Temporal changes in the relative abundance of specific microbiota and gut metabolite levels significantly differed in children who developed PA. PA-bound children had different abundance trajectories of Clostridium sensu stricto 1 sp (false discovery rate (FDR) = 0.015) and Bifidobacterium sp (FDR = 0.033), with butyrate (FDR = 0.045) and isovalerate (FDR = 0.036) decreasing over time. Metabolites associated with PA development clustered within the histidine metabolism pathway. Positive correlations between microbiota, butyrate, and isovalerate and negative correlations with histamine marked the PA-free network. CONCLUSION: The temporal dynamics of the gut microbiome and metabolome in early childhood are distinct for children who develop PA. These findings inform our thinking on the mechanisms underlying and strategies for potentially preventing PA.

Stratum corneum lipid and cytokine biomarkers at age 2 months predict the future onset of atopic dermatitis.

BACKGROUND: Atopic dermatitis (AD) commonly occurs in children and can progress into severe phenotypes or atopic march, causing significant impairment in quality of life. It is important to find early biomarkers of future onset of AD before any clinical manifestations. OBJECTIVE: We sought to find early predictors of future onset of AD in skin stratum corneum (SC). METHODS: Skin tape strips were collected from the forearm of newborns (n = 111) with and without family history of atopic diseases at the age of 2 months before any signs of clinical AD. Children were clinically monitored until they reached age 2 years to ensure the presence or absence of AD. Skin tape strips were subjected to lipidomic analyses by the liquid chromatography electrospray ionization tandem mass spectrometry and cytokine determination by Meso Scale Discovery U-Plex assay. RESULTS: Overall, 22 of 74 (29.7%) and 5 of 37 (13.5%) infants developed AD in the risk group and the control group, respectively. In the SC of future AD children, protein-bound ceramides were decreased (P < .001), whereas unsaturated sphingomyelin species (P < .0001) and "short-chain" nonhydroxy fatty acid sphingosine and alpha-hydroxy fatty acid sphingosine ceramides were elevated (P < .01 and .05, respectively) as compared with healthy children. Thymic stromal lymphopoietin and IL-13 levels were increased in the SC of future AD subjects (by 74.5% and 78.3%, P = .0022 and P < .0001, respectively). Multivariable logistic regression analysis revealed strong AD predicting power of the combination of family history, type 2 cytokines, and dysregulated lipids, with an odds ratio reaching 54.0 (95% CI, 9.2-317.5). CONCLUSIONS: Noninvasive skin tape strip analysis at age 2 months can identify asymptomatic children at risk of future AD development with a high probability.

The IL-4Rα Q576R polymorphism is associated with increased severity of atopic dermatitis and exaggerates allergic skin inflammation in mice.

BACKGROUND: Atopic dermatitis (AD) is characterized by TH2-dominated skin inflammation and systemic response to cutaneously encountered antigens. The TH2 cytokines IL-4 and IL-13 play a critical role in the pathogenesis of AD. The Q576->R576 polymorphism in the IL-4 receptor alpha (IL-4Rα) chain common to IL-4 and IL-13 receptors alters IL-4 signaling and is associated with asthma severity. OBJECTIVE: We sought to investigate whether the IL-4Rα R576 polymorphism is associated with AD severity and exaggerates allergic skin inflammation in mice. METHODS: Nighttime itching interfering with sleep, Rajka-Langeland, and Eczema Area and Severity Index scores were used to assess AD severity. Allergic skin inflammation following epicutaneous sensitization of mice 1 or 2 IL-4Rα R576 alleles (QR and RR) and IL-4Rα Q576 (QQ) controls was assessed by flow cytometric analysis of cells and quantitative RT-PCR analysis of cytokines in skin. RESULTS: The frequency of nighttime itching in 190 asthmatic inner-city children with AD, as well as Rajka-Langeland and Eczema Area and Severity Index scores in 1116 White patients with AD enrolled in the Atopic Dermatitis Research Network, was higher in subjects with the IL-4Rα R576 polymorphism compared with those without, with statistical significance for the Rajka-Langeland score. Following epicutaneous sensitization of mice with ovalbumin or house dust mite, skin infiltration by CD4+ cells and eosinophils, cutaneous expression of Il4 and Il13, transepidermal water loss, antigen-specific IgE antibody levels, and IL-13 secretion by antigen-stimulated splenocytes were significantly higher in RR and QR mice compared with QQ controls. Bone marrow radiation chimeras demonstrated that both hematopoietic cells and stromal cells contribute to the mutants' exaggerated allergic skin inflammation. CONCLUSIONS: The IL-4Rα R576 polymorphism predisposes to more severe AD and increases allergic skin inflammation in mice.

Rapid reduction in Staphylococcus aureus in atopic dermatitis subjects following dupilumab treatment.

BACKGROUND: Atopic dermatitis (AD) is an inflammatory disorder characterized by dominant type 2 inflammation leading to chronic pruritic skin lesions, allergic comorbidities, and Staphylococcus aureus skin colonization and infections. S aureus is thought to play a role in AD severity. OBJECTIVES: This study characterized the changes in the host-microbial interface in subjects with AD following type 2 blockade with dupilumab. METHODS: Participants (n = 71) with moderate-severe AD were enrolled in a randomized (dupilumab vs placebo; 2:1), double-blind study at Atopic Dermatitis Research Network centers. Bioassays were performed at multiple time points: S aureus and virulence factor quantification, 16s ribosomal RNA microbiome, serum biomarkers, skin transcriptomic analyses, and peripheral blood T-cell phenotyping. RESULTS: At baseline, 100% of participants were S aureus colonized on the skin surface. Dupilumab treatment resulted in significant reductions in S aureus after only 3 days (compared to placebo), which was 11 days before clinical improvement. Participants with the greatest S aureus reductions had the best clinical outcomes, and these reductions correlated with reductions in serum CCL17 and disease severity. Reductions (10-fold) in S aureus cytotoxins (day 7), perturbations in TH17-cell subsets (day 14), and increased expression of genes relevant for IL-17, neutrophil, and complement pathways (day 7) were also observed. CONCLUSIONS: Blockade of IL-4 and IL-13 signaling, very rapidly (day 3) reduces S aureus abundance in subjects with AD, and this reduction correlates with reductions in the type 2 biomarker, CCL17, and measures of AD severity (excluding itch). Immunoprofiling and/or transcriptomics suggest a role for TH17 cells, neutrophils, and complement activation as potential mechanisms to explain these findings.

Staphylococcus aureus causes aberrant epidermal lipid composition and skin barrier dysfunction.

BACKGROUND: Staphylococcus (S) aureus colonization is known to cause skin barrier disruption in atopic dermatitis (AD) patients. However, it has not been studied how S. aureus induces aberrant epidermal lipid composition and skin barrier dysfunction. METHODS: Skin tape strips (STS) and swabs were obtained from 24 children with AD (6.0 ± 4.4 years) and 16 healthy children (7.0 ± 4.5 years). Lipidomic analysis of STS samples was performed by mass spectrometry. Skin levels of methicillin-sensitive and methicillin-resistant S. aureus (MSSA and MRSA) were evaluated. The effects of MSSA and MRSA were evaluated in primary human keratinocytes (HEKs) and organotypic skin cultures. RESULTS: AD and organotypic skin colonized with MRSA significantly increased the proportion of lipid species with nonhydroxy fatty acid sphingosine ceramide with palmitic acid ([N-16:0 NS-CER], sphingomyelins [16:0-18:0 SM]), and lysophosphatidylcholines [16:0-18:0 LPC], but significantly reduced the proportion of corresponding very long-chain fatty acids (VLCFAs) species (C22-28) compared to the skin without S. aureus colonization. Significantly increased transepidermal water loss (TEWL) was found in MRSA-colonized AD skin. S. aureus indirectly through interleukin (IL)-1ß, tumor necrosis factor (TNF)-α, IL-6, and IL-33 inhibited expression of fatty acid elongase enzymes (ELOVL3 and ELOVL4) in HEKs. ELOVL inhibition was more pronounced by MRSA and resulted in TEWL increase in organotypic skin. CONCLUSION: Aberrant skin lipid profiles and barrier dysfunction are associated with S. aureus colonization in AD patients. These effects are attributed to the inhibition of ELOVLs by S. aureus-induced IL-1ß, TNF-α, IL-6, and IL-33 seen in keratinocyte models and are more prominent in MRSA than MSSA.

Allergen recognition by specific effector Th2 cells enables IL-2-dependent activation of regulatory T-cell responses in humans.

Type 2 allergen-specific T cells are essential for the induction and maintenance of allergies to foods, and Tregs specific for these allergens are assumed to be involved in their resolution. However, it has not been convincingly demonstrated whether allergen-specific Treg responses are responsible for the generation of oral tolerance in humans. We observed that sustained food allergen exposure in the form of oral immunotherapy resulted in increased frequency of Tregs only in individuals with lasting clinical tolerance. We sought to identify regulatory components of the CD4+ T-cell response to food allergens by studying their functional activation over time in vitro and in vivo. Two subsets of Tregs expressing CD137 or CD25/OX40 were identified with a delayed kinetics of activation compared with clonally enriched pathogenic effector Th2 cells. Treg activation was dependent on IL-2 derived from effector T cells. In vivo exposure to peanut in the form of an oral food challenge of allergic subjects induced a delayed and persistent activation of Tregs after initiation of the allergen-specific Th2 response. The novel finding of our work is that a sustained wave of Treg activation is induced by the release of IL-2 from Th2 effector cells, with the implication that therapeutic administration of IL-2 could improve current OIT approaches.

Physical influences on the skin barrier and pathogenesis of allergy.

PURPOSE OF REVIEW: As the incidence of allergic conditions has increased in recent decades, the effects of climate change have been implicated. There is also increased knowledge on the effects of other physical influences, such as scratching and Staphylococcus aureus . The skin barrier is the first line of defense to the external environment, so understanding the ways that these factors influence skin barrier dysfunction is important. RECENT FINDINGS: Although the impact on environmental exposures has been well studied in asthma and other allergic disorders, there is now more literature on the effects of temperature, air pollution, and detergents on the skin barrier. Factors that cause skin barrier dysfunction include extreme temperatures, air pollution (including greenhouse gases and particulate matter), wildfire smoke, pollen, scratching, S. aureus, and detergents. SUMMARY: Understanding the ways that external insults affect the skin barrier is important to further understand the mechanisms in order to inform the medical community on treatment and prevention measures for atopic conditions.

The impact of temperature on the skin barrier and atopic dermatitis.

Climate change is a global threat to public health and causes or worsens various diseases including atopic dermatitis (AD), allergic, infectious, cardiovascular diseases, physical injuries, and mental disorders. The incidence of allergy, such as AD, has increased over the past several decades, and environmental factors such as climate change have been implicated as a potential mechanism. A substantial amount of literature has been published on the impact of climate factors, including cold and hot temperatures, on the skin barrier and AD. Studies in several countries have found a greater incidence of AD in children born in the colder seasons of fall and winter. The effect of cold and warm temperatures on itch, skin flares, increased outpatient visits, skin barrier dysfunction, development of AD, and asthma exacerbations have been reported. Understanding mechanisms by which changes in temperature influence allergies is critical to the development of measures for the prevention and treatment of allergic disorders, such as AD and asthma. Low and high temperatures induce the production of proinflammatory cytokines and lipid mediators such as interleukin-1ß, thymic stromal lymphopoietin, and prostaglandin E2, and cause itch and flares by activation of TRPVs such as TRPV1, TRPV3, and TRPV4. TRPV antagonists may attenuate temperature-mediated itch, skin barrier dysfunction, and exacerbation of AD.

Safety, pharmacokinetics, and efficacy of ruxolitinib cream in children and adolescents with atopic dermatitis.

BACKGROUND: Therapies for children with atopic dermatitis (AD) have safety and tolerability concerns that may limit long-term use. Ruxolitinib cream, a Janus kinase (JAK) inhibitor, is effective and well tolerated in adolescents and adults with AD. OBJECTIVE: To analyze the safety and tolerability of ruxolitinib cream in pediatric patients. Pharmacokinetics and efficacy were also evaluated in this phase 1 study (NCT03257644). METHODS: Patients aged 2 to 17 years with AD (affected body surface area 8%-20%; Investigator's Global Assessment score ≥2) were enrolled stepwise in 6 age-descending, strength-increasing cohorts to apply 0.5%, 0.75%, or 1.5% ruxolitinib cream twice daily for 28 days. Safety, pharmacokinetics, and efficacy were analyzed at baseline, week 2 (day 10), and week 4 (day 29). RESULTS: Among 71 patients, 44 (62.0%) had a baseline Investigator's Global Assessment score of 3; median (range) body surface area affected at baseline was 12.2% (1.7%-20.4%). Ruxolitinib cream was well tolerated, with 4 patients (5.6%) experiencing treatment-related adverse events (all grades 1/2). No clinically meaningful changes in mean chemistry or hematology values were observed, and no consistent pattern of change in bone biomarkers was detected. Mean plasma ruxolitinib levels within each cohort (range, 23.1-97.9 nM) were well below the half-maximal inhibitory concentration for thrombopoietin phosphorylation of STAT3 (281 nM). All cohorts experienced improvements in exploratory efficacy end points. CONCLUSION: Ruxolitinib cream was well tolerated in pediatric patients with AD, with no effect on blood counts or bone biomarkers. Mean plasma concentration was low. Efficacy was consistent with data from previous studies in adolescents and adults. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03257644.

Transient receptor potential vanilloid 1 plays a major role in low temperature-mediated skin barrier dysfunction.

BACKGROUND: Children born in the fall and winter are at increased risk for developing atopic dermatitis and food allergy. Because these seasons are associated with low temperatures, we hypothesized that exposure to low temperatures may compromise keratinocyte differentiation and contribute to skin barrier dysfunction. OBJECTIVE: We examined whether low temperature causes skin barrier dysfunction. METHODS: Primary human epidermal keratinocytes (HEK) were differentiated in 1.3 mmol CaCl2 media and cultured at different temperatures. The cells were transfected with transient receptor potential cation channel subfamily V member 1 (TRPV1) or STAT3 small interfering RNA (siRNA) to examine the effects of these gene targets in HEK exposed to low temperature. Gene expression of TRPV1, epidermal barrier proteins, and keratinocyte-derived cytokines were evaluated. Organotypic skin equivalents were generated using HEK transfected with control or TRPV1 siRNA and grown at 25°C or 37°C. Transepidermal water loss (TEWL) and levels of epidermal barrier proteins were evaluated. RESULTS: Filaggrin (FLG) and loricrin (LOR) expression, but not keratin (KRT)-1 and KRT-10 expression, was downregulated in HEK incubated at 25°C, while TRPV1 silencing increased intracellular Ca2+ influx (keratinocyte differentiation signal) and enhanced the expression of epidermal differentiation proteins. IL-1ß and thymic stromal lymphopoietin induced by low temperature inhibited FLG expression in keratinocytes through the TRPV1/STAT3 pathway. Moreover, low temperature-mediated inhibition of FLG and LOR was recovered, and TEWL was decreased in organotypic skin transfected with TRPV1 siRNA. CONCLUSION: TRPV1 is critical in low temperature-mediated skin barrier dysfunction. Low temperature exposure induced thymic stromal lymphopoietin, an alarmin implicated in epicutaneous allergen sensitization.

Allergen-specific T cells and clinical features of food allergy: Lessons from CoFAR immunotherapy cohorts.

BACKGROUND: Allergen-specific IL-4+ and IL-13+ CD4+ cells (type 2 cells) are essential for helping B cells to class-switch to IgE and establishing an allergic milieu in the gastrointestinal tract. The role of T cells in established food allergy is less clear. OBJECTIVE: We examined the food allergen-specific T-cell response in participants of 2 food allergen immunotherapy trials to assess the relationship of the T-cell response to clinical phenotypes, including response to immunotherapy. METHODS: Blood was obtained from 84 participants with peanut allergy and 142 participants with egg allergy who underwent double-blind placebo-controlled food challenges. Peanut- and egg-responsive T cells were identified by CD154 upregulation after stimulation with the respective extract. Intracellular cytokines and chemokine receptors were also detected. The response to peanut epicutaneous immunotherapy (Peanut Epicutaneous Phase II Immunotherapy Clinical Trial [CoFAR6]; 49 participants receiving epicutaneous immunotherapy) and egg oral immunotherapy or a baked egg diet (Baked Egg or Egg Oral Immunotherapy for Children With Egg Allergy [CoFAR7]; 92 participants) was monitored over time. RESULTS: Peanut-specific type 2 and CCR6+ T cells were negatively correlated with each other and differently associated with immune parameters, including specific IgE level and basophil activation test result. At baseline, type 2 cells, but not CCR6+ cells, were predictive of clinical parameters, including a successfully consumed dose of peanut and baked egg tolerance. Exposure to peanut or egg immunotherapy was associated with a decrease in type 2 cell frequency. At baseline, high egg-specific type 2 cell frequency was the immune feature most predictive of oral immunotherapy failure. CONCLUSION: Food-specific type 2 T cells at baseline are informative of threshold of reactivity and response to immunotherapy.