Does the severity of atopic dermatitis change with allergic sensitization? Is it real or a myth?

Objective: Atopic dermatitis (AD) is a chronic inflammatory skin disease that can occur at any age. This study aimed to evaluate the impact of food allergy on disease severity as well as clinical/laboratory findings in children with AD. Methods: Clinical and laboratory data of AD patients evaluated for food allergy between January 2021 and December 2022 were examined retrospectively. Results: Of the 52 patients evaluated, 32 (61.5%) were males, with a median age of 6 months (2–118 months). Among them, 26 (50%) had food allergies (FA) and five (9.6%) had inhalant allergen sensitivity. No significant difference in AD severity was observed between patients with and without FA. However, the FA group showed higher serum lactate dehydrogenase (LDH) levels (343.3 ± 81.5 U/L vs 297.7 ± 77.4 U/L; P = 0.011) and lower red cell distribution width (RDW). Inhalant allergen sensitivity was associated with higher AD severity. Conclusion: While guidelines recommend investigating food allergies in moderate to severe AD, this study found no significant difference in the relationship between AD severity and the presence of FA. However, inhalant allergen sensitivity was linked to increased AD severity. Therefore, a comprehensive patient history should include an evaluation of food allergies in children with AD, regardless of disease severity. Elimination and provocation tests related to suspected food items should be performed, and allergenic foods should be removed from the diet if they are found to contribute to the allergy (AU)

Clinical Characteristics of Atopic Dermatitis in Korean School-Aged Children and Adolescents According to Onset Age and Severity.

BACKGROUND: Atopic dermatitis (AD) is a heterogeneous disease with different age of onset, disease course, clinical symptoms, severity, and risk of comorbidity. The characteristics of children with AD also vary by age or country. However, little is known about the clinical characteristics of AD in Korean school-aged children and adolescents. Furthermore, there are few studies on phenotypic differences according to onset age. This study aimed to explore the clinical characteristics and phenotypes according to onset age and severity of AD in children and adolescents in Korea. METHODS: AD patients aged 6-18 years who presented to 18 hospitals nationwide were surveyed. The patients were examined for disease severity by pediatric allergy specialists, and data on history of other allergic diseases, familial allergy history, onset age, trigger factors, lesion sites, treatment history and quality of life were collected. The results of the patient's allergy test were also analyzed. The patients were classified into infancy-onset (< 2 years of age), preschool-onset (2-5 years of age), and childhood-onset (≥ 6 years of age) groups. Study population was analyzed for clinical features according to onset-age groups and severity groups. RESULTS: A total of 258 patients with a mean age of 10.62 ± 3.18 years were included in the study. Infancy-onset group accounted for about 60% of all patients and presented significantly more other allergic diseases, such as allergic rhinitis and asthma (P = 0.002 and P = 0.001, respectively). Food allergy symptoms and diagnoses were highly relevant to both earlier onset and more severe group. Inhalant allergen sensitization was significantly associated with both infancy-onset group and severe group (P = 0.012 and P = 0.024, respectively). A family history of food allergies was significantly associated with infancy-onset group (P = 0.036). Severe group was significantly associated with a family history of AD, especially a paternal history of AD (P = 0.048 and P = 0.004, respectively). Facial (periorbital, ear, and cheek) lesions, periauricular fissures, hand/foot eczema, and xerosis were associated with infancy-onset group. The earlier the onset of AD, the poorer the quality of life (P = 0.038). Systemic immunosuppressants were used in only 9.6% of the patients in the severe group. CONCLUSION: This study analyzed the clinical features of AD in Korean children and adolescents through a multicenter nationwide study and demonstrated the phenotypic differences according to onset age and severity. Considering the findings that the early-onset group is more severe and accompanied by more systemic allergic diseases, early management should be emphasized in young children and infants.

US health care utilization and costs in adult patients with atopic dermatitis by disease severity.

BACKGROUND: Although previous studies have reported the economic burden of atopic dermatitis (AD) in adults, updates are needed using more current data and measure of disease severity. OBJECTIVE: To describe the health care resource utilization (HCRU) and associated costs in US adults diagnosed with AD overall and by disease severity. METHODS: This real-world retrospective study identified adults aged at least 18 years who received a clinical diagnosis of AD in a dermatology electronic medical record (EMR) database between 2016 and 2018 (first record = index date), which was linked to an administrative claims database. Patients were required to have an AD diagnostic code and at least 6 months of continuous enrollment in medical and pharmacy benefits before and after the index date. Baseline severity was assessed using the Physician Global Assessment score closest to the index date. Inpatient and outpatient services, visits to specialists and its seasonality, treatment use, and associated annual direct health care costs were reported using descriptive statistics. RESULTS: Annual all-cause direct health care costs were $10,474 per patient per year and primarily driven by outpatient visits and pharmacy use. Compared with patients with clear to mild disease, more AD patients with severe disease had at least 1 dermatology (73.0% vs 58.5%) and allergy/immunology office visit (16.0% vs 5.5%) and AD-related medications (90.0% vs 64.3%). All-cause total annual costs in patients with severe disease ($23,242) were significantly higher than in patients with clear to mild disease ($8,936; P = 0.0002). Little seasonal variation in dermatology office visits was observed. CONCLUSIONS: Significant economic burden primarily driven by outpatient and pharmacy utilization was observed in AD patients, which increased with disease severity. DISCLOSURES: This work was sponsored by Eli Lilly and Company. Gorritz and Wade are employees of IQVIA, which was contracted by Eli Lilly and Company to conduct this study and develop the manuscript. Wang was employed by IQVIA at the time of this study. Malatestinic and Goldblum are employees and stockholders of Eli Lilly and Company. Boytsov was an employee of Eli Lilly at the time of this research.

The Role of Diet Modification in Atopic Dermatitis: Navigating the Complexity.

Diet has long been understood to have an intricate association with atopic dermatitis, although much remains unelucidated. Skin barrier dysfunction with dysbiosis and consequent impairment of immune tolerance likely underly the pathogenesis of coincident atopic dermatitis and food allergy. There is a wide range of possible skin reactions to food, complicating the diagnosis and understanding of food allergies. Many patients, parents, and providers incorrectly suspect diet as causative of atopic dermatitis symptoms and many have tried elimination diets. This frequently leads to inaccurate labeling of food allergies, contributing to a dangerous spiral of inappropriate testing, referrals, and dietary changes, while neglecting established atopic dermatitis treatment essentials. Alternatively, certain dietary supplements or the introduction of certain foods may be beneficial for atopic dermatitis management or prevention. Greater consensus on the role of diet among providers of patients with atopic dermatitis is strongly encouraged to improve the management of atopic dermatitis.

A real-world study of the longitudinal course of itch severity and frequency in adults with atopic dermatitis.

Itch is a complex symptom that is both common and burdensome in atopic dermatitis (AD). Yet, little is known about the longitudinal course of itch in AD. A prospective, dermatology practice-based study was performed of adults with AD (n = 463). Patients were assessed at baseline and approximately 6, 12, 18 and 24 months. Itch was assessed using Numeric Rating Scale (NRS) average and worst-itch scores, and frequency of itch in the past week. Repeated-measures regression models were constructed to examine itch over time. Overall, 31.5% and 22.5% had moderate (4-6) or severe (7-10) NRS average-itch scores; 27.4% and 36.4% had moderate (4-6) or severe (7-10) NRS worst-itch scores; 12.7% and 62.0% had itch from eczema 3-4 and ≥ 5 days in the past week; 27.4% and 45.1% reported sometimes and often/almost always having itch, respectively. Among patients with baseline moderate (4-6) or severe (7-10) NRS average-itch scores, 21.2% and 16.3% continued to have moderate or severe scores at ≥ 1 follow-up visits. In repeated-measures regression models, persistent NRS average-itch scores were associated with baseline NRS average-itch [adjusted ß (95% CI): 0.75 (0.68, 0.82)] and food allergy [- 0.45 (- 0.84, - 0.07)]. Persistent NRS worst-itch was associated with baseline worst-itch NRS [0.73 (0.66, 0.80)] and Medicaid insurance [1.06 (0.17, 1.94)]. AD patients had a heterogeneous longitudinal course with fluctuating and complex overlapping patterns of average- and worst-itch intensity, and frequency.

Angiogenesis in Chronic Inflammatory Skin Disorders.

Angiogenesis, the growth of new blood vessels from preexisting vessels, is associated with inflammation in various pathological conditions. Well-known angiogenetic factors include vascular endothelial growth factor (VEGF), angiopoietins, platelet-derived growth factor, transforming growth factor-ß, and basic fibroblast growth factor. Yes-associated protein 1 (YAP) and transcriptional co-activator with PDZ-binding motif (TAZ) have recently been added to an important angiogenic factor. Accumulating evidence indicates associations between angiogenesis and chronic inflammatory skin diseases. Angiogenesis is deeply involved in the pathogenesis of psoriasis. VEGF, angiopoietins, tumor necrosis factor-a, interleukin-8, and interleukin-17 are unregulated in psoriasis and induce angiogenesis. Angiogenesis may be involved in the pathogenesis of atopic dermatitis, and in particular, mast cells are a major source of VEGF expression. Angiogenesis is an essential process in rosacea, which is induced by LL-37 from a signal cascade by microorganisms, VEGF, and MMP-3 from mast cells. In addition, angiogenesis by increased VEGF has been reported in chronic urticaria and hidradenitis suppurativa. The finding that VEGF is expressed in inflammatory skin lesions indicates that inhibition of angiogenesis is a useful strategy for treatment of chronic, inflammatory skin disorders.

Dysregulation of the epithelial barrier by environmental and other exogenous factors.

The "epithelial barrier hypothesis" proposes that the exposure to various epithelial barrier-damaging agents linked to industrialization and urbanization underlies the increase in allergic diseases. The epithelial barrier constitutes the first line of physical, chemical, and immunological defense against environmental factors. Recent reports have shown that industrial products disrupt the epithelial barriers. Innate and adaptive immune responses play an important role in epithelial barrier damage. In addition, recent studies suggest that epithelial barrier dysfunction plays an essential role in the pathogenesis of the atopic march by allergen sensitization through the transcutaneous route. It is evident that external factors interact with the immune system, triggering a cascade of complex reactions that damage the epithelial barrier. Epigenetic and microbiome changes modulate the integrity of the epithelial barrier. Robust and simple measurements of the skin barrier dysfunction at the point-of-care are of significant value as a biomarker, as recently reported using electrical impedance spectroscopy to directly measure barrier defects. Understanding epithelial barrier dysfunction and its mechanism is key to developing novel strategies for the prevention and treatment of allergic diseases. The aim of this review is to summarize recent studies on the pathophysiological mechanisms triggered by environmental factors that contribute to the dysregulation of epithelial barrier function.

Interferon-γ downregulates tight junction function, which is rescued by interleukin-17A.

Although atopic dermatitis (AD) has been reported to be a typical type 2 immune response disease, it is also an inflammatory skin disease that involves cytokines, such as Th1, Th17 and Th22. However, little is known about the mechanism by which the candidate cytokines, alone or in combination, are involved in AD pathology. Differences in cytokine balance, which contribute to the complexity of AD pathology, may influence the stratum corneum barrier function through tight junction (TJ) functional stability and contribute to disease severity. To confirm the regulatory mechanism of TJ protein expression in AD, we investigated the Th1 and Th17 pathways, which are the initiation factors of chronic AD pathology. We examined the effects of these cytokines on TJ protein expression in normal human epidermal keratinocytes in vitro, and also examined their function in a human skin equivalent model. We observed a time- and dose-dependent inhibitory effect of IFN-γ on claudin-1 expression via the IFN-γ receptor/JAK/STAT signalling pathway. IFN-γ impaired TJ function in a human skin equivalent model. Moreover, we investigated co-stimulation with IL-17A, which is highly expressed in AD skin lesions and found that IL-17A restores IFN-γ-induced TJ dysfunction. This restoration of TJ function was mediated by atypical protein kinase C zeta activation without recovery of TJ protein expression. These results are informative for personalized AD treatment via systemic therapies using anti-cytokine antibodies and/or JAK inhibitors.

Atopic dermatitis trajectories to age 8 years in the GUSTO cohort.

BACKGROUND: The heterogeneity of childhood atopic dermatitis (AD) underscores the need to understand latent phenotypes that may inform risk stratification and disease prognostication. OBJECTIVE: To identify AD trajectories across the first 8 years of life and investigate risk factors associated with each trajectory and their relationships with other comorbidities. METHODS: Data were collected prospectively from 1152 mother-offspring dyads in the Growing Up in Singapore Towards healthy Outcomes (GUSTO) cohort from ages 3 months to 8 years. AD was defined based on parent-reported doctor's diagnosis. An unsupervised machine learning technique was used to determine AD trajectories. RESULTS: Three AD trajectories were identified as follows: early-onset transient (6.3%), late-onset persistent (6.3%) and early-onset persistent (2.1%), alongside a no AD/reference group (85.2%). Early-onset transient AD was positively associated with male gender, family history of atopy, house dust mite sensitization and some measures of wheezing. Early-onset persistent AD was associated with antenatal/intrapartum antibiotic use, food sensitization and some measures of wheezing. Late-onset persistent AD was associated with a family history of atopy, some measures of house dust mite sensitization and some measures of allergic rhinitis and wheezing. CONCLUSION AND CLINICAL RELEVANCE: Three AD trajectories were identified in this birth cohort, with different risk factors and prognostic implications. Further work is needed to understand the molecular and immunological origins of these phenotypes.

The Implications of Pruritogens in the Pathogenesis of Atopic Dermatitis.

Atopic dermatitis (AD) is a prototypic inflammatory disease that presents with intense itching. The pathophysiology of AD is multifactorial, involving environmental factors, genetic susceptibility, skin barrier function, and immune responses. A recent understanding of pruritus transmission provides more information about the role of pruritogens in the pathogenesis of AD. There is evidence that pruritogens are not only responsible for eliciting pruritus, but also interact with immune cells and act as inflammatory mediators, which exacerbate the severity of AD. In this review, we discuss the interaction between pruritogens and inflammatory molecules and summarize the targeted therapies for AD.

Efficacy of a probiotic supplement in patients with atopic dermatitis: a randomized, double-blind, placebo-controlled clinical trial.

BACKGROUND: Atopic dermatitis (AD) is a multifactorial long-standing inflammatory skin disease with a high incidence worldwide in both adults and children. According to the recognized correlation between skin and intestine-the so-called "gut-skin axis"-gut unbalances can affect skin by inducing systemic inflammation and triggering dermatological diseases such as AD. OBJECTIVES: To evaluate the efficacy of a food supplement containing selected strains of probiotics in ameliorating AD symptoms and skin conditions in adult volunteers. MATERIALS & METHODS: Eighty adult subjects showing mild-to-severe AD, skin dryness, desquamation, erythema and itching were enrolled in a randomized controlled trial to receive, for 56 days, a placebo or a mixture of lactobacilli (L. plantarum PBS067, L. reuteri PBS072 and L. rhamnosus LRH020). The latter was chosen according to the patients' production of post-biotic metabolites and B-group vitamins, anti-inflammatory and anti-oxidant capacity and anti-microbial activity. Clinical and instrumental dermatological evaluation was performed at T0d, T28d and T56d, and then at T84d (after a one-month wash-out). Inflammatory cytokine levels from skin tape stripping, sampled close to AD lesions at T0d and T56d, were also measured. RESULTS: Subjects receiving the probiotic mixture showed an improvement in skin smoothness, skin moisturization, self-perception, and a decrease in SCORAD index as well as in the levels of inflammatory markers associated with AD at T28d, with a positive trend up to T56d which was maintained at T84d. CONCLUSION: Administration of selected probiotic strains resulted in a fast and sustained improvement in AD-related symptoms and skin conditions.

Targeted Use of Placebo Effects Decreases Experimental Itch in Atopic Dermatitis Patients: A Randomized Controlled Trial.

Evidence from pain research shows that the effectiveness of active pharmacological treatments can be enhanced by placebo effects. The "open drug administration" is superior to "hidden drug administration.​" In a randomized controlled trial, we aimed to show that the targeted use of placebo effects increases the efficacy of an antihistamine (dimetindene) infusion in participants with atopic dermatitis. We openly infused dimetindene (drug) in full sight with information (intervention group 1: OPEN-DRUG+INST), openly infused drug with an additional classical conditioning learning experience (intervention group 2: OPEN-DRUG+INST+COND) or infused drug without any information or sight (i.e., hidden administration (control group 1: HIDDEN-DRUG)). Control group 2 received a placebo infusion (saline) declared as dimetindene and also experienced the conditioning experience (PLAC+INST+COND). Itch was experimentally induced with histamine via a skin prick test. Outcome was assessed at the subjective (primary end point: experimental itch intensity, numeric rating scale), and objective level (secondary end point: wheal size, mm2 ). Experimental-induced itch intensity decreased in all groups but at different rates (P < 0.001). The groups with the open administration, whether it was dimetindene or placebo, had significantly stronger reductions in itch compared to the HIDDEN-DRUG group (OPEN-DRUG+INST+COND: P < 0.001; OPEN-DRUG+INST: P = 0.009; and PLAC+INST+COND: P < 0.001). Additional drug conditioning mediated via expectation led to a stronger reduction of itching (P = 0.001). Results on wheal size were similar (P = 0.048), however, no significant difference between the HIDDEN-DRUG group and the PLAC+INST+COND group (P = 0.967) was found. We conclude that specifically generated targeted placebo effects can significantly increase the action of a drug (dimetindene) and should be used in clinical practice.

IL-31 Inhibition as a Therapeutic Approach for the Management of Chronic Pruritic Dermatoses.

Chronic pruritus is a debilitating symptom with limited treatment options. Identifying molecular targets underlying chronic pruritic dermatoses is essential for the development of novel, targeted therapies. IL-31 is an important mediator of itch by integrating dermatologic, neural, and immune systems. IL-31 helps induce and maintain chronic pruritus via both indirect stimulation of inflammatory cells and through direct neural sensitization. IL-31 is overexpressed in various chronic pruritic skin conditions, and exogenous IL-31 induces itch and scratching behavior. Studies have demonstrated that IL-31R and IL-31 antagonism significantly reduces itch in patients with atopic dermatitis and prurigo nodularis, two extremely pruritic skin conditions. Emerging evidence, including recent phase II clinical trials of IL-31R antagonists, demonstrates that IL-31 plays an important role in itch signaling. Additional studies are ongoing to evaluate IL-31R and IL-31 antagonism as treatments of chronic pruritus.

Advances in the pathophysiology of atopic dermatitis revealed by novel therapeutics and clinical trials.

Atopic dermatitis (AD) is an inflammatory skin disease arising from a complex interplay of genetic, immune, and environmental factors. The development and successful marketing of the anti-IL-4/IL-13 monoclonal antibody, dupilumab, and the topical nonsteroidal phosphodiesterase 4 (PDE4) inhibitor, crisaborole, as well as the Janus kinase (JAK) inhibitor, delgocitinib, have brought hope for developing new therapeutic agents. The efficacy of these treatments contributes to our understanding of the pathophysiology of AD. Dupilumab modulates the Th2-related immune response, demonstrating that IL-4 and IL-13 contribute to epidermal hyperplasia, skin homeostasis, and innate immune responses on the skin surface in AD. The effectiveness of crisaborole reveals that PDE4 contributes to Th2 and Th17/Th22 inflammation and lesional skin barrier dysfunction, while delgocitinib shows that JAK-associated signaling is essential for the inflammatory reaction in AD. This review provides a brief overview of recent research on therapeutic monoclonal antibodies and small biologic molecules for AD and what these treatments reveal about AD pathophysiology.

Association between nasal and nasopharyngeal bacterial colonization in early life and eczema phenotypes.

BACKGROUND: An association has been reported between early life Staphylococcus aureus nasal carriage and higher risk of childhood eczema, but it is unclear whether this relationship is causal and associations with other bacterial species are unclear. OBJECTIVE: To examine the associations of early life nasal and nasopharyngeal bacterial carriage with eczema phenotypes, and the direction of any associations identified. METHODS: Among 996 subjects of a population-based prospective cohort study, nasal swabs for Staphylococcus  aureus, and nasopharyngeal swabs for Streptococcus pneumoniae, Moraxella catarrhalis and Haemophilus influenzae were collected and cultured from age 6 weeks to 6 years. Never, early, mid-, late transient and persistent eczema phenotypes were identified from parental-reported physician-diagnosed eczema from age 6 months until 10 years. Multinomial regression models and cross-lagged models were applied. RESULTS: Staphylococcus aureus nasal carriage at 6 months was associated with an increased risk of early transient and persistent eczema (OR (95% CI): 2.69 (1.34, 5.39) and 4.17 (1.12, 15.51)). The associations between Staphylococcus aureus nasal carriage and eczema were mostly cross-sectional, and not longitudinal. No associations of Staphylococcus pneumoniae, Moraxella catarrhalis and Haemophilus influenza nasopharyngeal bacterial carriage with eczema and eczema phenotypes were observed (OR range (95% CI): 0.71 (0.35, 1.44) to 1.77 (0.84, 3.73)). CONCLUSIONS: Early life Staphylococcus aureus nasal carriage, but not Staphylococcus pneumoniae, Moraxella catarrhalis and Haemophilus influenza nasopharyngeal carriage, was associated with early transient and persistent eczema. Staphylococcus aureus nasal carriage and eczema were mostly cross-sectionally associated, and not longitudinally, making a causal relationship in either direction unlikely.