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Background: Risk factors and the temporal relationship between atopic dermatitis (AD) and atopic march remain understudied., Objective: Determine risk factors for atopic march in early-onset AD patients and the temporality between AD and atopic march., Methods: We used the MarketScan Research Database for our retrospective cohort analysis from 2010 to 2018, comparing infants diagnosed with AD before age 1 with controls without early-onset AD. Primary outcomes were hazard ratios (HRs) for the development of asthma, allergic rhinitis, and food allergy., Results: Compared to 55,174 controls, higher proportions of the 27,228 AD patients developed asthma (19.21% vs 8.65%, P < .001), allergic rhinitis (28.27% vs 12.62%, P < .001), food allergy (16.00% vs 2.27%, P < .001), and all atopic triad conditions (10.69% vs 0.71%, P < .001). Among AD patients, higher proportions developed the atopic triad if they were male (HR 1.66, 95% confidence interval [1.45-1.90]), had severe disease (HR 3.16, [2.77-3.60]), or had family atopy history (HR > 3.40, P < .001 for all comparisons). Among AD patients, 20.1% developed allergic rhinitis., Limitations: Our study was based on health care claims data., Conclusion: Early-onset AD is associated with higher rates of developing atopic march conditions compared to controls. Particular attention should be paid toward risk factors and atopic march screening in early-onset AD patients., Competing Interests: Conflicts of interest Dr Drucker has received compensation from the British Journal of Dermatology (reviewer and Section Editor), American Academy of Dermatology (guidelines writer), and National Eczema Association (grant reviewer). Dr Kwatra is an advisory board member/consultant for Abbvie, Amgen, Arcutis Biotherapeutics, Aslan Pharmaceuticals, Cara Therapeutics, Castle Biosciences, Celldex Therapeutics, Galderma, Genzada Pharmaceuticals, Incyte Corporation, Johnson & Johnson, Leo Pharma, Novartis Pharmaceuticals Corporation, Pfizer, Regeneron Pharmaceuticals, Kiniksa Pharmaceuticals, and Sanofi and has served as an investigator for Galderma, Kiniksa Pharmaceuticals, Incyte, Pfizer, and Sanofi outside of the submitted work. Drs Choi, Deng, Parthasarathy, Liao, D'Amiano, Taylor, Bordeaux, Kambala, Cornman, and Canner have no conflicts of interest to declare., (Copyright © 2024 American Academy of Dermatology, Inc. Published by Elsevier Inc. All rights reserved.)

Background: Dupilumab effectively treats atopic dermatitis (AD); however, its role in halting the atopic march remains uncertain., Objective: To investigate dupilumab's effect on atopic march in pediatric AD patients versus conventional immunomodulators., Methods: This retrospective cohort study utilized data from the TriNetX US Collaborative Network (2011-2024). Pediatric AD patients (≤18 years) were categorized into DUPI-cohort (newly prescribed dupilumab) or CONV-cohort (prescribed conventional immunomodulators without dupilumab). After 1:1 propensity-score matching, we analyzed atopic march progression, defined by the incident asthma or allergic rhinitis (AR). Cumulative incidence was plotted using Kaplan-Meier, with risk assessment via Cox regression., Results: The study included 2192 patients in each cohort. The 3-year cumulative incidence of atopic march progression was lower in the DUPI-cohort than the CONV-cohort (20.09% vs 27.22%; P < .001). The DUPI-cohort demonstrated significant risk reduction in atopic march progression (hazard ratio [HR] 0.68, 95% CI 0.55-0.83), individual asthma (HR 0.60, 0.45-0.81), and individual AR (HR 0.69, 0.54-0.88). Younger patients on dupilumab exhibited a greater risk reduction for atopic march progression and individual asthma, contrasting with the opposite age-related pattern for individual AR., Limitations: Observational study., Conclusion: Among pediatric AD patients, dupilumab was associated with reduced risk of atopic march progression compared with conventional therapies., Competing Interests: Conflicts of interest None declared., (Copyright © 2024 American Academy of Dermatology, Inc. Published by Elsevier Inc. All rights reserved.)

Background: The atopic march refers to the coexpression and progression of atopic diseases in childhood, often beginning with atopic dermatitis (AD), although children may not progress through each atopic disease., Objective: We hypothesized that future atopic disease expression is modified by AD phenotype and that these differences result from underlying dysregulation of cytokine signaling., Methods: Children (n = 285) were enrolled into the Childhood Origins of Asthma (COAST) birth cohort and followed prospectively. Rates of AD, food allergy, allergic rhinitis, and asthma were assessed longitudinally from birth to 18 years of age. Associations between AD phenotype and food allergy, allergic rhinitis, asthma, allergic sensitization, exhaled nitric oxide, and lung function were determined. Peripheral blood mononuclear cell responses (IL-5, IL-10, IL-13, IFN-γ) to dust mite, phytohemagglutinin, Staphylococcus aureus Cowan I, and tetanus toxoid were compared among AD phenotypes., Results: AD at year 1 was associated with an increased risk of food allergy (P = .004). Both persistent and late-onset AD were associated with an increased risk of asthma (P < .001), rhinitis (P < .001), elevated total IgE (P < .001), percentage of aeroallergens with detectable IgE (P < .001), and elevated exhaled nitric oxide (P = .002). Longitudinal analyses did not reveal consistent differences in peripheral blood mononuclear cell responses among dermatitis phenotypes., Conclusion: AD phenotype is associated with differential expression of other atopic diseases. Our findings suggest that peripheral blood cytokine dysregulation is not a mechanism underlying this process, and immune dysregulation may be mediated at mucosal surfaces or in secondary lymphoid organs., (Copyright © 2024. Published by Elsevier Inc.)

Background: Atopic dermatitis (AD) is thought to precede the onset of other allergic illness (OAI) in a temporal progression (ie, atopic march), yet the timing and progression has been questioned. It is also unclear how parental allergic illness impacts the development of these illnesses in offspring., Objective: (1) Explore risk of incident AD and (2) timing of allergic disease onset in children of mothers with AD compared with mothers without AD from the United Kingdom., Methods: We created a birth cohort of mother-child pairs using IQVIA Medical Research Data database and developed Cox proportional models to examine the above associations (hazard ratio, HR [95% confidence interval, CI])., Results: Among 1,224,243 child-mother pairs, mean child (standard deviation) follow-up time was 10.8 (8.3) years and 50.1% were males (N = 600,905). Children were 59% (HR = 1.59 [1.57, 1.60]) more likely to have AD if their mothers had AD compared with no AD with mean age of first AD diagnosis at 3.3 (4.8) years. Most children with any diagnosis of AD present with AD first (91.0%); however, in those with asthma, only 67.8% developed AD first., Conclusion: Children born to mothers with AD are more prone to develop AD and some develop OAI first, suggesting that not all follow the same sequential pathway., Competing Interests: Conflicts of interest Dr Margolis is or recently has been a consultant for Pfizer, Leo, and Sanofi with respect to studies of atopic dermatitis and served on an advisory board for the National Eczema Association. Dr Chiesa Fuxench has received research grants from Lilly, LEO Pharma, Regeneron, Sanofi, Tioga, and Vanda for work related to atopic dermatitis and from Menlo Therapeutics and Galderma for work related to prurigo nodularis, has served as consultant for the Asthma and Allergy Foundation of America, National Eczema Association, AbbVie, Incyte Corporation, and Pfizer, and received honoraria for CME work in Atopic Dermatitis sponsored by education grants from Regeneron/Sanofi and Pfizer and from Beiersdorf for work related to skin cancer and sun protection. Drs Mitra and Shin and Authors Pozo and Hoffstad have no conflicts of interest to declare., (Copyright © 2023 American Academy of Dermatology, Inc. Published by Elsevier Inc. All rights reserved.)

Background: Atopic march has long been recognized as the progression from atopic dermatitis (AD) to food allergy and asthma during infancy and childhood. However, effective blocking is hampered by the lack of specific biomarkers., Objectives: We aimed to investigate the pathologic progression of atopic march trajectories from skin to gut., Methods: We built an atopic march mouse model by mechanical skin injury and percutaneous sensitization to peanut allergen. Anaphylaxis from the skin to the small intestine was then investigated by ELISA, RNA sequencing, quantitative real-time PCR, histopathologic analysis, and flow cytometry. The findings from the mice results were also verified by the serum samples of allergic pediatric patients., Results: After modeling, inflammation in the skin and small intestine manifested as a mixed type of T H 2 and T H 17. Further analysis identified elevated succinate in the circulation and expanded tuft cells with upregulated IL-25 in the small intestine, resulting in increased intestinal type 2 innate lymphoid cells and an enhanced type 2 inflammatory response. In addition, free mitochondrial DNA (mtDNA) released after tissue damage was also involved in inflammation march from injured skin to small intestine through the STING pathway. Analysis of clinical samples verified that serum concentrations of succinate and mtDNA were higher in AD allergic children than non-AD allergic children., Conclusions: Succinate and mtDNA play key roles in skin-to-gut cross talk during the atopic march from AD to food allergy, and can be considered as biomarkers for risk assessment or targets for atopic march prevention strategies., (Copyright © 2023. Published by Elsevier Inc.)

Background: Atopic march refers to the sequential development of allergic diseases from infancy through adolescence, typically beginning with atopic dermatitis (AD), followed by food allergy and then airway diseases, later evolving to broader or worsened spectrum of allergic diatheses. No intervention has shown to alter its course., Objective: We sought to determine the rate of acquisition of new or worsened allergic events for dupilumab versus placebo in patients with AD., Methods: Allergy-associated events from 12 clinical trials were grouped into 17 allergy categories, and IgE changes from baseline were defined. A new/worsened event was considered one step of atopic march. Treatment effect was assessed by incidence rate ratios (IRRs), dupilumab versus placebo, by meta-analysis., Results: The duration of pooled AD studies was 4 to 52 weeks (1359 patient-years; n = 2296 dupilumab, n = 1229 placebo, median age 35 years). The median age at AD onset was 2 years. Baseline allergic disease burden was comparable between groups. Dupilumab reduced the risk of new/worsening allergies by 34% (IRR 0.66; 95% confidence interval [CI], 0.52-0.84) and new allergies by 37% (IRR 0.63; 95% CI, 0.48-0.83) versus placebo. Including IgE category shift, the IRR for combined new/worsening allergies was reduced by 54% (IRR 0.46; 95% CI, 0.36-0.57). These treatment benefits did not reverse on treatment discontinuation in off-treatment follow-up., Conclusions: The acquisition/worsening of allergic conditions suggestive of atopic march was observed in a pooled adult/adolescent AD study population with inadequately controlled AD. Treatment with dupilumab reduced new/worsened allergy events versus placebo; inclusion of IgE category change increased the apparent benefit., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

The atopic march was described more than 20 years ago on the basis of initial observations, and it is now seen in prospective studies. The concept has evolved and is now considered to be the progression of atopic dermatitis to other atopic conditions, including asthma, allergic rhinitis, food allergy, and eosinophilic esophagitis in a nonlinear fashion. The progression can include some or all of the aforementioned atopic conditions. The pathogenesis is part of the classic type 2 inflammatory process involving IL-4, IL-5, and IL-13 preceded by induction of the alarmins (thymic stromal lymphopoietin, IL-33, and IL-25), leading to production of IgE in a genetically predisposed individual. The development of new biologics that interact with T2 pathway represent possible ways to prevent or modify the atopic march., (Copyright © 2023 American Academy of Allergy, Asthma Immunology. Published by Elsevier Inc. All rights reserved.)

In the past 2 years, there continue to be advances in our understanding of the genetic and epigenetic underpinnings of atopy pertaining to disease risk and disease severity. The joint role of genetics and the environment has been emphasized in multiple studies. Combining genetics with family history, biomarkers, and comorbidities is further refining our ability to predict the development of individual atopic diseases as well as the advancement of the atopic march. Polygenic risk scores will be an important next step for the field moving toward clinical translation of the genetic findings thus far. A systems biology approach, as illustrated by studies of the microbiome and epigenome, will be necessary to fully understand disease development and to develop increasingly targeted therapeutics., (Copyright © 2022 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Background: The atopic march has been studied mostly in White populations, biasing our current paradigms., Objective: We sought to define the atopic march in Black and White children and explore mechanisms for racial differences., Methods: Utilizing the Mechanisms of Progression of Atopic Dermatitis to Asthma in Children (MPAACH) cohort (n = 601), we assessed longitudinal sensitization, food allergy (FA), allergic rhinitis, risk of asthma development (through the Pediatric Asthma Risk Score), Scoring for Atopic Dermatitis (SCORAD), transepidermal water loss, skin filaggrin (FLG) expression, exposures, and genetic heritability to define AD progression endotypes in Black and White children., Results: White MPAACH children were more likely to be sensitized to aero and food allergens (P = .0001) and over 3 times more likely to develop FA and/or allergic rhinitis (AR) without asthma risk (P < .0001). In contrast, Black children were over 6 times more likely to proceed to high asthma risk without FA, sensitization, or AR (P < .0001). White children had higher lesional and nonlesional transepidermal water loss (both P < .001) as well as decreased nonlesional keratinocyte FLG expression (P = .02). Black children had increased genetic heritability for asthma risk and higher rates of exposures to secondhand smoke and traffic-related air pollution., Conclusions: Black and White children with AD have distinct allergic trajectories defined by different longitudinal endotypes. Black children exhibit higher asthma risk despite a more intact skin barrier and less sensitization, FA, and AR. White children have less asthma risk, despite a more dysfunctional skin barrier, and more FA, AR, and sensitization. The observed racial differences are likely due in part to increased genetic heritability for asthma risk and harmful environmental exposures in Black children. Collectively, our findings provide a new paradigm for an atopic march that is inclusive of Black children., (Copyright © 2021 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Background: 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., Objectives: 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., Methods: 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., Results: 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)., Conclusions: 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., (Copyright © 2021. Published by Elsevier Inc.)

Atopic diathesis encompassing atopic dermatitis (AD), allergic rhinoconjunctivitis, food allergy, eosinophilic esophagitis, and asthma is a widely prevalent condition with a broad heterogeneity in clinical course, age of onset, and lifespan persistence. A primary event in AD is the commonly inherited epidermal barrier dysfunction. Together with the host-microbiome interactions, barrier defect and allergen exposure modulate both innate and adaptive immunity, thus triggering and maintaining the inflammatory response. Microbiome diversity, together with the host's contact with nonpathogenic microbes in childhood, is a prerequisite for functional maturation of the immune system, which is in part mediated by microbiome-induced epigenetic changes. Yet, whether microbiome alterations are the result or the reason for barrier impairment and inflammatory response of the host is unclear. Exposure to locally prevalent microbial species could contribute to further modification of the disease course. The objective of this review is to reveal the link between changes in the skin microbiota, barrier dysfunction, and inflammation in AD. Addressing unmet needs includes determining the genetic background of AD susceptibility; the epigenetic modifications induced by the microbiota and other environmental factors; the role of globally diverse provoking factors; and the implementation of personalized, phenotype-specific therapies such as a epidermal barrier restoration in infancy and microbiota modulation via systemic or topical interventions, all of which open gaps for future research., (Copyright © 2021 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Objectives: To compare the impact of different formulas on the occurrence of other atopic manifestations and the time of immune tolerance acquisition., Study Design: In a 36-month prospective cohort study, the occurrence of other atopic manifestations (eczema, urticaria, asthma, and rhinoconjunctivitis) and the time of immune tolerance acquisition were comparatively evaluated in immunoglobulin E-mediated children with cow's milk allergy (CMA) treated with extensively hydrolyzed casein formula containing the probiotic L. rhamnosus GG (EHCF + LGG), rice hydrolyzed formula, soy formula, extensively hydrolyzed whey formula (EHWF), or amino acid-based formula., Results: In total, 365 subjects were enrolled into the study, 73 per formula cohort. The incidence of atopic manifestations was 0.22 (Bonferroni-corrected 95% CI 0.09-0.34) in the EHCF + LGG cohort; 0.52 (0.37-0.67) in the rice hydrolyzed formula cohort; 0.58 (0.43-0.72) in the soy formula cohort; 0.51 (0.36-0.66) in the EHWF cohort; and 0.77 (0.64-0.89) in the amino acid-based formula cohort. The incidence of atopic manifestations in the rice hydrolyzed formula, soy formula, EHWF, and amino acid-based formula cohorts vs the EHCF + LGG cohort was always greater than the prespecified absolute difference of 0.25 at an alpha-level of 0.0125, with corresponding risk ratios of 2.37 (1.46-3.86, P < .001) for rice hydrolyzed formula vs EHCF + LGG; 2.62 (1.63-4.22, P < .001) for soy formula vs EHCF + LGG; 2.31 (1.42-3.77, P < .001) for EHWF vs EHCF + LGG; and 3.50 (2.23-5.49, P < .001) for amino acid-based formula vs EHCF + LGG. The 36-month immune tolerance acquisition rate was greater in the EHCF + LGG cohort., Conclusions: The use of EHCF + LGG for CMA treatment is associated with lower incidence of atopic manifestations and greater rate of immune tolerance acquisition., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: The allergic march refers to the natural history of allergic conditions during infancy and childhood. However, population-level disease incidence patterns do not necessarily reflect the development of allergic disease in individuals. A better understanding of the factors that predispose to different allergic trajectories is needed., Objective: Our aim was to determine the demographic and genetic features that are associated with the major allergic march trajectories., Methods: Presence or absence of common allergic conditions (atopic dermatitis [AD], IgE-mediated food allergy [IgE-FA], asthma, and allergic rhinitis [AR]) was ascertained in a pediatric primary care birth cohort of 158,510 subjects. Hierarchic clustering and decision tree modeling were used to associate demographic features with allergic outcomes. Genome-wide association study was used to test for risk loci associated with specific allergic trajectories., Results: We found an association between self-identified black race and progression from AD to asthma. Conversely, Asian or Pacific Islander race was associated with progression from AD to IgE-mediated food allergy, and white race was associated with progression from AD to AR. Genome-wide association study of trajectory groups identified risk loci associated with progression from AD to asthma (rs60242841) and from AD to AR (rs9565267, rs151041509, and rs78171803). Consistent with our epidemiologic associations, rs60242841 was more common in individuals of African ancestry than in individuals of European ancestry, whereas rs9565267 and rs151041509 were more common in individuals of European ancestry than in individuals of African ancestry., Conclusion: We have identified novel associations between race and progression along distinct allergic trajectories. Ancestral genetic differences may contribute to these associations. These results uncover important health disparities, refine the concept of the allergic march, and represent a step toward developing individualized medical approaches for these conditions., (Copyright © 2020 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Food allergy (FA), a growing public health burden in the United States, and familial aggregation studies support strong roles for both genes and environment in FA risk. Deepening our understanding of the molecular and cellular mechanisms driving FAs is paramount to improving its prevention, diagnosis, and clinical management. In this review, we document lessons learned from the genetics of FA that have aided our understanding of these mechanisms. Although current genetic association studies suffer from low power, heterogeneity in definition of FA, and difficulty in our ability to truly disentangle FA from food sensitization (FS) and general atopy genetics, they reveal a set of genetic loci, genes, and variants that continue to implicate the importance of barrier and immune function genes across the atopic march, and FA in particular. The largest reported effects on FA are from MALT1 (odds ratio, 10.99), FLG (average odds ratio, ∼2.9), and HLA (average odds ratio, ∼2.03). The biggest challenge in the field of FA genetics is to elucidate the specific mechanism of action on FA risk and pathogenesis for these loci, and integrative approaches including genetics/genomics with transcriptomics, proteomics, and metabolomics will be critical next steps to translating these genetic insights into practice., (Copyright © 2020 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

The atopic march recognizes the increased occurrence of asthma, allergic rhinitis, or both after atopic dermatitis (AD) onset. Mechanisms for developing atopic comorbidities after AD onset are poorly understood but can involve the impaired cutaneous barrier, which facilitates cutaneous sensitization. The association can also be driven or amplified in susceptible subjects by a systemic T H 2-dominant immune response to cutaneous inflammation. However, these associations might merely involve shared genetic loci and environmental triggers, including microbiome dysregulation, with the temporal sequence reflecting tissue-specific peak time of occurrence of each disease, suggesting more of a clustering of disorders than a march. Prospective longitudinal cohort studies provide an opportunity to explore the relationships between postdermatitis development of atopic disorders and potential predictive phenotypic, genotypic, and environmental factors. Recent investigations implicate disease severity and persistence, age of onset, parental atopic history, filaggrin (FLG) mutations, polysensitization, and the nonrural environment among risk factors for development of multiple atopic comorbidities in young children with AD. Early intervention studies to repair the epidermal barrier or alter exposure to the microbiome or allergens might elucidate the relative roles of barrier defects, genetic locus alterations, and environmental exposures in the risk and sequence of occurrence of T H 2 activation disorders., (Copyright © 2018 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Background: The atopic march describes the progression from atopic dermatitis during infancy to asthma and allergic rhinitis in later childhood. In a Canadian birth cohort we investigated whether concomitant allergic sensitization enhances subsequent development of these allergic diseases at age 3 years., Methods: Children completed skin prick testing at age 1 year. Children were considered sensitized if they produced a wheal 2 mm or larger than that elicited by the negative control to any of 10 inhalant or food allergens. Children were also assessed for atopic dermatitis by using the diagnostic criteria of the UK Working Party. At age 3 years, children were assessed for asthma, allergic rhinitis, food allergy, and atopic dermatitis. Data from 2311 children were available., Results: Atopic dermatitis without allergic sensitization was not associated with an increased risk of asthma at age 3 years after adjusting for common confounders (relative risk [RR], 0.46; 95% CI, 0.11-1.93). Conversely, atopic dermatitis with allergic sensitization increased the risk of asthma more than 7-fold (RR, 7.04; 95% CI, 4.13-11.99). Atopic dermatitis and allergic sensitization had significant interactions on both the additive (relative excess risk due to interaction, 5.06; 95% CI, 1.33-11.04) and multiplicative (ratio of RRs, 5.80; 95% CI, 1.20-27.83) scales in association with asthma risk. There was also a positive additive interaction between atopic dermatitis and allergic sensitization in their effects on food allergy risk (relative excess risk due to interaction, 15.11; 95% CI, 4.19-35.36)., Conclusions: Atopic dermatitis without concomitant allergic sensitization was not associated with an increased risk of asthma. In combination, atopic dermatitis and allergic sensitization had strong interactive effects on both asthma and food allergy risk at age 3 years., (Copyright © 2017 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Background: Atopic dermatitis is associated with other allergic conditions, but variations in this "atopic march" are poorly understood., Objective: To determine the impact of the age of atopic dermatitis onset on the risk for asthma and seasonal allergies., Methods: A cohort study was performed using the Pediatric Eczema Elective Registry, which is an observational cohort of subjects with pediatric onset atopic dermatitis., Results: In total, 3966 children were included, and 73% reported atopic dermatitis onset before age 2 years. At baseline, subjects with atopic dermatitis onset at ages 3 to 7 or 8 to 17 years had significantly lower rates of seasonal allergies and asthma than those with onset before age 2. During follow-up, the adjusted relative risks for incident seasonal allergies were 0.82 (95% confidence interval, 0.72-0.91) and 0.64 (95% CI confidence interval, 0.47-0.83) in the 3- to 7- and 8- to 17-years-old at onset groups compared with the age 2 years or younger at onset group. The adjusted risk for incident asthma was not significantly different between the older onset groups and the earliest onset group., Limitations: Misclassification bias may arise from using self-reported onset age data., Conclusions: The timing of atopic dermatitis onset may explain part of the variation in the atopic march. These findings may improve future risk stratification of patients for treatment., (Copyright © 2017 American Academy of Dermatology, Inc. Published by Elsevier Inc. All rights reserved.)

Background: B cells undergo maturation and class-switching in response to antigen exposure and T-cell help. Early B-cell differentiation has not been defined in patients with early-onset atopic dermatitis (AD)., Objective: We sought to define the frequency of B-cell subsets associated with progressive B-cell maturation and IgE class-switching., Methods: We studied 27 children and 34 adults with moderate-to-severe AD (mean SCORAD score, 55 and 65, respectively) and age-matched control subjects (15 children and 27 adults). IgD/CD27 and CD24/CD38 core gating systems and an 11-color flow cytometric panel were used to determine the frequencies of circulating B-cell subsets. Serum total and allergen-specific IgE (sIgE) levels were measured by using ImmunoCAP., Results: Compared with adults, children showed T-cell predominance in the skin. Circulating CD19 + CD20 + B-cell counts were lower in patients with pediatric AD than in control subjects (24% vs 33%, P = .04), whereas CD3 + T-cell counts were higher (62% vs 52%, P = .05). A decreased B-cell/T-cell lymphocyte ratio with age was observed only in pediatric control subjects (r = -0.48, P = .07). In pediatric patients with AD, a positive correlation was observed between B-cell/T-cell ratio and nonswitched memory B-cell counts (r = 0.42, P = .03). Higher frequencies of positive sIgE levels were seen in pediatric patients with AD (P < .0001). Diverse sIgE levels correlated with SCORAD scores and age of pediatric patients with AD (P < .01). Positive correlations were observed between activated B-cell and memory T-cell counts (P < .02). In patients with AD, IgE sensitization to most allergens clustered with age, T H 1, T H 2, total IgE levels, and B-cell memory subsets., Conclusions: Peripheral B and T cells are altered in pediatric patients with early AD, but T cells predominate in skin lesions., (Copyright © 2016 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

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., (Copyright © 2017 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Background: Children with cow's milk allergy (CMA) have an increased risk of other allergic manifestations (AMs)., Objective: We performed a parallel-arm randomized controlled trial to test whether administration of an extensively hydrolyzed casein formula (EHCF) containing the probiotic Lactobacillus rhamnosus GG (LGG) can reduce the occurrence of other AMs in children with CMA., Methods: Children with IgE-mediated CMA were randomly allocated to the EHCF or EHCF+LGG groups and followed for 36 months. The main outcome was occurrence of at least 1 AM (eczema, urticaria, asthma, and rhinoconjunctivitis). The secondary outcome was tolerance acquisition, which was defined as the negativization of a double-blind food challenge results at 12, 24, and 36 months. AMs were diagnosed according to standardized criteria. Tolerance acquisition was evaluated every 12 months., Results: A total of 220 children (147 boys [67%]) with a median age of 5.0 months (interquartile range, 3.0-8.0 months) were randomized; 110 children were placed in the EHCF group, and 110 children were placed in the EHCF+LGG group. In the complete case analysis the absolute risk difference for the occurrence of at least 1 AM over 36 months was -0.23 (95% CI, -0.36 to -0.10; P < .001), and the absolute risk difference for the acquisition of cow's milk tolerance was 0.20 (95% CI, 0.05-0.35; P < .01) at 12 months, 0.24 (95% CI, 0.08-0.41; P < .01) at 24 months, and 0.27 (95% CI, 0.11-0.43; P < .001) at 36 months. In the sensitivity analysis the effect size of the main outcome was virtually unchanged when the occurrence of AMs was assigned to all 27 missing children., Conclusions: EHCF+LGG reduces the incidence of other AMs and hastens the development of oral tolerance in children with IgE-mediated CMA., (Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.)

Atopic dermatitis (AD), food allergy, allergic rhinitis, and asthma are common atopic disorders of complex etiology. The frequently observed atopic march from early AD to asthma, allergic rhinitis, or both later in life and the extensive comorbidity of atopic disorders suggest common causal mechanisms in addition to distinct ones. Indeed, both disease-specific and shared genomic regions exist for atopic disorders. Their prevalence also varies among races; for example, AD and asthma have a higher prevalence in African Americans when compared with European Americans. Whether this disparity stems from true genetic or race-specific environmental risk factors or both is unknown. Thus far, the majority of the genetic studies on atopic diseases have used populations of European ancestry, limiting their generalizability. Large-cohort initiatives and new analytic methods, such as admixture mapping, are currently being used to address this knowledge gap. Here we discuss the unique and shared genetic risk factors for atopic disorders in the context of ancestry variations and the promise of high-throughput "-omics"-based systems biology approach in providing greater insight to deconstruct their genetic and nongenetic etiologies. Future research will also focus on deep phenotyping and genotyping of diverse racial ancestry, gene-environment, and gene-gene interactions., Competing Interests: Statement M.E.R. is a consultant for Genentech, Novartis, Receptos, and NKT Therapeutics and has an equity interest in NKT Therapeutics, Immune Pharmaceuticals, and Celsus Therapeutics, as well as royalty interest from Teva Pharmaceuticals and Cincinnati Children’s Medical Center–owned patents concerning eosinophilic esophagitis. The rest of the authors declare that they have no competing interests., (Copyright © 2016 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)