Lessons from murine models of atopic dermatitis

Atopic dermatitis (AD) is a chronic inflammatory skin disorder affecting between 10-20% of children and 1-3% of adults in the general population. It is associated with high morbidity and has major public health implications. AD is associated with hyper-reactivity of the skin to environmental trigger factors that are harmless in normal individuals. Major contributors to this hyperactivity are the many immune and inflammatory changes taking place in the skin and peripheral blood in AD individuals. AD can be classified into several subgroups, each with different immune and pathological features, suggesting a multifactorial disease and heterogeneity. Historically two types of AD have been identified. They include the “extrinsic or allergic” type of AD, which is characterized by Immunoglobulin E (IgE) mediated sensitization (immediate, type I hypersensitivity) and occurs in 70-80% of individuals. The “non-allergic or intrinsic” type of AD affects 20-30% of individuals and is defined by a more T-cell driven feature (delayed, type IV hypersensitivity), with low IgE levels and absent IgE sensitization. More recently a transition from the intrinsic to the extrinsic type has been reported in young children, and AD individuals can show a combination of above mentioned phenotypes or complete absence of the known features. The clinical diagnosis of AD does not cause major difficulties as there are fairly well defined criteria. Identifying the underlying pathophysiology for the affected individual can be more of a challenge, as there is no gold standard test available for AD and the AD individual might move from one pathophysiological “type” of AD to another. Clinically AD is divided into acute, subacute and chronic forms with correlated histopathological changes. The transition from one clinical form to another is fluent and can be very rapid. AD individuals frequently give a personal and or a family history of asthma and allergic rhinitis, the so called atopic triad. Exacerbation of one of the disorders in this triad can cause concomitant exacerbation of the other two suggesting some underlying common pathways and interdependence (Reitamo et al., 2008). Predisposing factors for AD are multifactorial and involve genetic susceptibility, defects in skin barrier function, immune dysregulation, western life style and exposure to environmental trigger factors. The development of disease is an interplay of gene-gene and gene-environment interactions. The early age of onset and familial predisposition as well as the high concordance rate of AD in monozygotic (77%) and dizygotic (15%) twins suggest a

Atopic Dermatitis (AD) is the most common pruritic inflammatory skin disease which causes economic and social burden. AD is not curable and therapeutic options are limited. Currently, the therapeutic approaches to AD include topical treatment, phototherapy, and systemic treatment. Although traditional therapeutic strategies are efficacious in ameliorating the symptoms of AD in most patients, sometimes it is a tough challenge for physicians as AD is catastrophic and difficult to treat. Several potential treatments for AD are being studied owing to a clearer understanding of its pathogenesis. Additionally, animal models of AD allow comprehensive and thorough investigation of pathogenesis and provide more options of therapeutic interventions. The purpose of non-classical treatment strategies for AD is to decrease skin inflammation, re-direct the imbalanced immune polarization, and induce immune tolerance to allergens. Generally, the intervention for mouse model of AD can be classified into 1) monoclonal antibodies, 2) anti-oxidants, 3) allergen-specific immunotherapy, 4) herbal medicine, 5) treatment with materials extracted from food or micronutrients, 6) microbiota/probiotics, 7) bio-composites films, and 8) others. Since half of the patients with AD lack specific immunoglobulin E against allergens, the pathogenesis of different phenotypes still needs to be clarified. Through novel therapies such as cytokine-targeting therapy, miRNA or suppression of thymic stromal lymphopoietin, patients with AD could have better quality of life with less morbidity.

Atopic dermatitis (AD) is a common, chronic inflammatory skin disease often associated with a significant long-term disease burden. AD can profoundly impact a patient’s physical and mental health. Current AD management recommendations do not capture patient perspectives on their treatment needs, expectations and drivers of decision-making. Qualitative patient research is needed to support the creation of patient-centric recommendations for AD assessment and management. To study a large, international, ethnically diverse population of patients with AD that will enable the creation of patient-centric recommendations for AD management. Adult patients (≥18 years old) receiving treatment for AD were recruited from patient market research databases, clinician referrals, and local advertising. All patients were screened via a questionnaire to ensure a balanced and diverse range of ages, gender, educational levels, geographic locations, and AD severities, and to confirm that they were currently receiving treatment for AD. Patients participated in a 45-minute, 1 : 1 telephone interview conducted in their native language by the research team. These interviews explored the impact of AD on patients’ lives, patients’ most troublesome symptoms, how patients make treatment decisions and patients’ treatment expectations. Patients were also questioned on their current knowledge of AD scoring systems and what they thought was most important to include in AD scoring systems. A large ethnically diverse global patient population (N = 88; 15 countries) was included in the study. AD was reported to have a substantial, broad impact on patients’ lives, with patients being affected by AD at all times of the day and night. Itch, skin redness, dry/flaky skin and sleep disturbance were the most frequently reported signs and symptoms, with over 75% of patients experiencing them every 1–3 days. The itch was cited by 37% of patients as being the primary reason for changing AD treatments. In addition, the research revealed that mental health issues such as anxiety and depression are common in patients suffering from AD, and these features have the greatest negative impact on patients’ daily lives. Patients reported that AD impairs their quality of life, with many perceiving that clinicians underestimate this burden; this was reported more often for non-specialists compared with dermatologists. Patients also felt they were often not given enough time to express themselves in medical appointments and reported an inability to optimally communicate with their clinicians. Patients had little awareness of AD severity scoring systems, with almost no survey respondents reporting their use during previous healthcare encounters. When questioned about their preferences for different AD scoring systems, patients favoured using a combination of patient-reported outcomes to reflect disease burden and clinician-reported outcomes to ensure consistency across different physicians and patient populations. These preferences indicate that an optimal scoring system would consider a diverse range of symptoms, and the variable nature of AD, and be accessible regardless of education level. No single AD scoring system was preferred by all patients. Patients indicated that they would like AD scoring systems to be incorporated into clinical practice, to help them communicate their AD burden to clinicians, and to provide a clear framework for monitoring treatment response. This global patient study generated insights into the burden of AD on patients’ lives, their expectations of treatment, and their views on AD scoring methods. Results provided an evidence base for the development of patient-centric recommendations for AD management.

Atopic dermatitis (AD) is a chronic inflammatory disease affecting children and adolescence. The traditional therapeutic options for AD, including emollients topically and immune modulatory agents systemically focusing on reducing skin inflammation and restoring the function of the epidermal barrier, are proven ineffective in many cases. Several studies have linked vitamin D supplementation with either a decreased risk to develop AD or a clinical improvement of the symptoms of AD patients. In this report, we present a girl with severe AD who under adequate supplementation with cholecalciferol was treated with calcitriol and subsequently with paricalcitol. She had significant improvement—almost healing of her skin lesions within 2 months, a result sustained for more than 3 years now. Because of hypercalciuria as a side effect from calcitriol therapy, treatment was continued with paricalcitol, a vitamin D analogue used in secondary hyperparathyroidism in chronic kidney disease. Calcitriol therapy may be considered as a safe and efficacious treatment option for patients with severe AD, particularly for those with refractory AD, under monitoring for possible side effects. Treatment with paricalcitol resolves hypercalciuria, is safe, and should be further investigated as an alternative treatment of atopic dermatitis and possibly other diseases of autoimmune origin.

Atopic dermatitis (AD) is a chronic, relapsing and pruritic inflammatory skin disorder. The prevalence of AD has been increasing significantly in recent decades, especially in developed nations. The pathogenesis of AD is still not completely understood. AD may be the results of interactions of abnormalities of immune system, genetics, environment and epidermal barrier defects. There is a wide spectrum of clinical manifestations in AD. Accordingly, there have been a number of methods and laboratory markers to assess the severity of AD. In spite of the facts that various severity assessing criteria and laboratory markers were reported or, more or less, applied, owing to the complexity of disease, race differences and environmental uncertainties, there is disagreement about the definitions and clinical application of these criteria or markers. Nevertheless, easy and quick assessing severity methods for AD are required to guide both the daily clinical and research studies. Here, we describe some recent advances in the assessment of the severity of AD.

Atopic Dermatitis (AD) is a common inflammatory itching skin disease1. This skin disorder affects a large number of children and adults2. Epidemiological studies show that up to 25% of children and up to 3% of adult are affected worldwide3. Several studies in addition suggest an increasing prevalence of AD. The clinical picture of AD is dominated by chronic eczematous skin lesions in typical localizations4. In infants and small children, the rash is often present on the skin around the knees and elbows and the cheeks5. In teenagers and adults, the rash is often present in the creases of the wrists, elbows, knees or ankles, and on the face or neck. Symptoms commonly could vary from person to person. The most common symptoms are dry, itchy skin and rashes on the face, inside the elbows and behind the knees, and on the hands and feet6. Itching is the most relevant and common symptom of atopic dermatitis. Scratching and rubbing in response to itching irritates the skin, increases inflammation, and actually increases itchiness. Itching is a particular problem during sleep when conscious control of scratching is lost. The appearance of the skin that is affected by atopic dermatitis depends on the amount of scratching and the presence of secondary skin infections. The skin may be red and scaly, be thick and leathery, contain small raised bumps, or leak fluid and become crusty and infected. These features can also be found in people who do not have atopic dermatitis or who have other types of skin disorders. Atopic dermatitis may also affect the skin around the eyes, the eyelids, and the eyebrows and lashes. Scratching and rubbing the eye area can cause the skin to redden and swell. Some people with atopic dermatitis develop an extra fold of skin under their eyes. Patchy loss of eyebrows and eyelashes may also result from scratching or rubbing. In addition clinically unaffected skin in AD is not normal. It is frequently dry and has a greater irritant skin response than normal healthy skin7. Microscopic studies reveal a sparse perivascular T-cell infiltrate in unaffected AD skin that is not seen in normal healthy skin8. There is a marked infiltration of CD41 activated memory T cells in acute AD9. Antigenpresenting cells (eg, Langerhans cells inflammatory dendritic epidermal cells and macrophages) in lesional and, to a lesser extent, in nonlesional skin bear IgE molecules10.

Atopic dermatitis (AD) is a common and complex skin disorder, and the 5q22.1 region had been reported to be associated with AD. To confirm the susceptibility gene for AD in the 5q22.1 region by haplotype and targeted capture sequencing. The haplotypes were reconstructed with the genotyping data of four SNPs and six deletions from 3624 Chinese Hans AD patients and 5076 controls. The targeted capture sequencing spanning 5q22.1 region was performed in the selected samples. The gene level enrichment analysis was done using loss of function variants. A total of 62 haplotypes were found, and the H15 haplotype had the strongest association with AD (P = 3.92 × 10−10, OR 0.17, 95% CI 0.09–0.32). However, no co-segregation mutation sites were found in the sequencing analysis within the 16 selected samples, while the enrichment analysis indicated that TMEM232 was significantly associated with AD (P = 7.33 × 10–5, OR 0.33, 95% CI 0.19–0.58). This study confirms previous findings that the TMEM232 gene is associated with AD by haplotype analysis and targeted capture sequencing.

Atopic dermatitis (AD) is one of the most common skin diseases of dogs. Defects in the skin barrier and overproduction of inflammatory cytokines may be the pathogenesis of canine AD. Therefore, the present study was aimed to quantify the gene expression of certain skin barrier proteins and inflammatory cytokines in dogs with AD. Eleven dogs with AD and three healthy dogs were included in the present study. The skin barrier proteins, namely Filaggrin (FLG) and Involucrin (IVL), gene expression was quantified by Real-time PCR in the lesional skin tissues of the atopic dogs and normal skin of the healthy dogs. In addition to the skin proteins, the gene expressions of the interleukin (IL)-13, IL-31, and tumour necrosis factor (TNF)-α were also quantified in the peripheral blood mononuclear cells (PBMCs) of these dogs. Compared to the healthy dogs, significantly higher (P ≤ 0.01) FLG gene expression and significantly (P ≤ 0.05) lower expression of the IVL gene were quantified in the skin of atopic dogs. Further, the dogs with AD revealed significantly higher expression of TNF-α (P ≤ 0.01), IL-31 (P ≤ 0.05), and IL-13 (P ≤ 0.05) as compared to the healthy dogs. The findings of our present study evidently suggest significantly increased and decreased expressions of FLG and IVL genes, respectively, which may be responsible for disruption of the skin barrier in dogs with AD. While, the over-expressions of TNF-α, IL-31, and IL-13 genes might be attributed to the clinical pathology and manifestations of AD in dogs. However, further studies are warranted to substantiate our hypothesis about pathogenesis and clinical manifestation of AD in dogs by including a large number of animals.

Atopic dermatitis (AD) is a chronic, inflammatory disease characterized by sensitive and dry skin, eczematous lesions and intense pruritus. Patients with moderate-to-severe AD often require systemic treatments if their symptoms are insufficiently controlled with topical treatments or phototherapy. While numerous systemic therapies are currently available for moderate-to-severe AD, more data evaluating patient satisfaction with various characteristics of these treatments are needed to help guide physicians and their patients with joint treatment decision-making. This study aims to investigate patient satisfaction with AD treatments according to the degree and speed of itch improvement and the degree of skin clearance. A cross-sectional, web-based survey was used to evaluate patient preferences for characteristics associated with systemic AD therapies. Respondents were required to have a physician-confirmed diagnosis of AD (currently moderate or severe), to be aged ≥18 years, to be a US resident, and to read and understand English. Assessments included worst itch experienced in the past 24 h (using a scale from 0 to 10, with 0 defined as no itch and 10 defined as the worst imaginable itch), time to noticeable itch reduction following initiation of their current treatment (1–6 days, 7–13 days or ≥14 days) and the amount of body surface area still affected by AD (≤2%, 3–10% or >10%; patient-assessed). Patient satisfaction with itch improvement, speed of itch improvement and skin clearance with their current treatment was also assessed and classified into three categories: satisfied, dissatisfied or neither. P values were determined by Chi-square tests (or Fisher’s exact test where appropriate). Of the 213 individuals recruited by physicians to participate in the survey, 200 respondents fulfilled the eligibility criteria, consented to participate and completed surveys. A total of 186 respondents indicated that they were currently receiving treatment for their AD; treatments included over-the-counter creams, ointments or medicines (26.9%, n = 50), prescription creams (72.0%, n = 134), oral corticosteroids (16.7%, n = 31) or dupilumab (11.3%, n = 21). Treatment satisfaction differed based on the patient's itch level within the past 24 h (P < 0.001): 85.2% (n = 23) of the 27 patients reporting the lowest levels of itch (0–1) indicated they were satisfied with their current treatment, whereas only 7.1% (n = 1) of the 14 patients reporting the worst levels of itch (8–10) were satisfied with their current treatment. Among the 73 respondents who experienced the fastest itch reduction (within 1–6 days), 65.8% (n = 48) were satisfied with their treatment. For the 36 respondents experiencing itch reduction ≥14 days post treatment, 13.9% (n = 5) were satisfied with their treatment (P < 0.001). Of the 75 respondents with the highest degree of skin clearance (≤2% of body surface area still affected), 65.3% (n = 49) were satisfied with their treatment. Among the 21 respondents with the lowest degree of skin clearance (>10% of body surface area still affected), 14.3% (n = 3) were satisfied with their treatment (P < 0.001). Safety was not evaluated, which may limit the findings in this analysis. In patients with moderate-to-severe AD, the majority of respondents experiencing the lowest levels of itch, the fastest onset of itch improvement and the highest degree of skin clearance also reported satisfaction with their current treatment. These findings underscore the stringent thresholds for both the degree and speed of symptom improvement required to achieve patient satisfaction. This highlights patients’ desire for treatments offering both rapid and extensive itch reduction and skin clearance and may help broaden physicians’ understanding of patient preferences and inform treatment decisions.

Atopic dermatitis (AD) is a skin disease characterized by inflammation, pruritus, and chronic or relapsing eczematous lesions. AD negatively affects quality of life for both patients with AD and their caregivers. We conducted a review of the literature on the beneficial effects of sacran on allergic skin diseases using published biochemical, experimental, and clinical reports. Sacran is a marine alga-derived glycosaminoglycan-like sulfated polysaccharide; it is extracted from the Japanese indigenous cyanobacterium Aphanothece sacrum, which is mass-aquacultured in rivers with a high ionic concentration and possesses plenty of a jelly-like extracellular matrix with high water content (97.5–98.3%). Sacran is a heteropolysaccharide composed of various sugar residues (galactose, glucose, mannose, xylose, rhamnose, fucose, galacturonic acid, and glucuronic acid) and contains traces of alanine, galactosamine, uronic acids (these uronic acids have yet to be determined chemically), and muramic acid; 11% of the monosaccharides contain a sulfate group, and 22% of them contain a carboxyl group. Our previous studies have shown that topical sacran markedly reduced transepidermal water loss (TEWL) in dry skin human subjects and displayed similar anti-allergic effects than hydrocortisone and tacrolimus in animal experiments. Moreover, our recent clinical studies showed that topical sacran significantly decreased the severity of AD skin lesions, itch, and sleep disorder in AD patients within 4 weeks of topical treatment. Taken together, findings from these studies suggest that topical sacran may serve as an alternative adjuvant and therapeutic anti-allergic agent.

Atopic dermatitis (AD) is characterized by intense itch and symptoms that adversely impact quality of life (QoL). Upadacitinib is a selective Janus kinase-1 inhibitor approved for moderate-to-severe AD. We assessed the effect of once daily oral upadacitinib (15 or 30 mg), with or without concurrent topical corticosteroid treatment, on patient-reported outcomes for adults and adolescents with moderate-to-severe atopic dermatitis during the double-blind, placebo-controlled phase 3 clinical trials, Measure Up 1 (NCT03569293), Measure Up 2 (NCT03607422) and AD Up (NCT03568318). Assessments included itch (Worst Pruritus Numerical Rating Scale), skin pain and symptom severity (AD Symptom Scale), symptom frequency (Patient Oriented Eczema Measure) and sleep, daily activities and emotional state (AD Impact Scale). Post hoc analysis of 2240 adults and 344 adolescents randomized patients was performed. By Week 2, more patients receiving upadacitinib achieved a clinically relevant response in itch, skin pain, symptom severity, symptom frequency, sleep, daily activities and emotional state vs. placebo across studies among adults (upadacitinib 15 mg: 30.8–87.3%; upadacitinib 30 mg: 38.0–89.9%; placebo: 2.1–43.1%; nominal P < 0.001 for all comparisons) and adolescents (upadacitinib 15 mg: 19.4–82.9%; upadacitinib 30 mg: 35.3–97.6%; placebo: 0–41.0%; nominal P < 0.05 for 37/42 comparisons). These trends continued through week 16 where response rates for all outcomes improved with upadacitinib vs. placebo in adults (upadacitinib 15 mg: 42.9–80.4%; upadacitinib 30 mg: 60.9–84.6%; placebo: 10.1–38.1%; nominal P < 0.001 for all comparisons) and adolescents (upadacitinib 15 mg: 33.3–78.0%; upadacitinib 30 mg: 50.0–85.7%; placebo: 2.8–43.6%; nominal P < 0.05 for 41/42 comparisons). These findings highlight the rapid, sustained efficacy of once daily oral upadacitinib in improving symptom burden and QoL in adults and adolescents with moderate-to-severe AD.

Atopic dermatitis (AD) is a chronic allergic disease associated with toxin (superantigen)-producing Staphylococcus aureus skin infections, impaired delayed hypersensitivity responses, and the expansion of IL-4-secreting Th2 cells, as well as diminished IFN-gamma synthesis. IL-12 is known to induce IFN-gamma synthesis and to augment Th1 responses. In this study, therefore, we examined the potential role of IL-12 in the immunopathogenesis of AD. We show that, after stimulation with staphylococcal toxic shock syndrome toxin-1 (TSST-1) or IL-12, PBMC from patients with AD are deficient in their ability to produce IFN-gamma. PBMC from AD patients, however, produced normal quantities of IL-12 and expressed normal levels of IL-12R. Induction of IFN-gamma by TSST-1 was decreased by neutralizing anti-IL-12 Ab in normal donors, but not in AD patients. The latter observation is consistent with a defective response to IL-12 in AD PBMC. Because AD is associated with increased production of IL-4 and IL-10, we examined the effect of IL-4 on IL-12- or TSST-1-induced IFN-gamma production in normal donors. IL-4 inhibited IL-12-induced IFN-gamma production. Furthermore, Ab neutralization of IL-4 caused increased production of IFN-gamma in AD PBMC. However, neutralization of IL-10 activity caused an even greater augmentation of IFN-gamma production. Our data suggest that despite normal levels of IL-12 production and IL-12R expression, PBMC from AD patients are unable to generate normal IL-12-induced IFN-gamma responses. This defective response may be due to the excess production of IL-4 and IL-10 in this common allergic condition.

Atopic dermatitis (AD) is chronic recurrent inflammatory skin disease with a high prevalence and significant negative effect on patients' quality of life. AD pathogenesis is based on the complex interactions between genetic factors, immune mechanisms, state of the skin barrier and environmental effects. The climate itself is the complex of many components, such as: temperature, humidity, precipitation, wind and season. All of them play fundamental role in the natural ecosystem and human health establishment. The climate is changing rapidly, and these changes are progressing faster than ever in the last thousand years. This review shows how climate and environmental changes can affect the course of AD. The data on utilization efficiency of emollient plus for moderating of climatic conditions adverse effects on epidermal structures at patients with AD is presented.

Atopic dermatitis (AD) is a chronic inflammatory condition that affects 15% of children and 7.3% of adults in the USA. While topical corticosteroids (TCs) and topical calcineurin inhibitors (TCIs) are considered the mainstay of topical treatments for AD management, long-term use is cautioned due to possible adverse effects (AEs). We present and review the efficacy and safety of new FDA-approved topical agents, topical agents currently in clinical trials, and TCs and TCIs that are currently available for AD management. We also present and compare the safety and efficacy of new and old FDA-approved topical agents, along with other topical treatments that are currently in clinical trials for AD management. An extensive review of the literature was performed using the PubMed, Cochrane, Scopus and ClinicalKey databases with year parameters set between 2014 and 2022. Search keywords included ‘atopic dermatitis’, ‘topical treatments’, ‘comparison’, ‘effectiveness’, ‘new topical treatments for AD’, ‘JAK inhibitors’, ‘PDE-4 inhibitors’, ‘delgocitinib’, ‘crisaborole’ and ‘tapinarof’. We identified four topical drug classes that are efficacious in treating AD: corticosteroids, calcineurin inhibitors, phosphodiesterase-4 (PDE-4) inhibitors and aryl hydrocarbon receptor agonists. Criteria for treatment success were an IGA score of 0 or 1 and improvement ≥2 grades from baseline. Treatment varied among studies from 2 to 24 weeks. Topical corticosteroids were the most effective after adjusting for vehicle (0.05% clobetasol propionate emulsion foam, 38%; 0.1% clocortolone pivalate, 31.6% IGA reduction), followed by tapinarof 1% cream with 29% of patients achieving treatment success, TCIs (0.03% tacrolimus ointment, 24.8%; 1% pimecrolimus cream, 32.1% vehicle-adjusted achieving IGA of ≤2) and PDE-4 inhibitors (2% crisaborole ointment, 10.4%). Tapinarof was the most efficacious in treating AD. There is a lack of head-to-head trials for topical treatments for AD. Due to the tremendous burden of AD on patients’ physical and mental health, there is a need for additional therapies.

Atopic dermatitis (AD) is a refractory and recurrent inflammatory skin disease. Various factors including heredity, environmental agent, innate and acquired immunity, and skin barrier function participate in the pathogenesis of AD. T -helper (Th) 2-dominant immunological milieu has been suggested in the acute phase of AD. Antigen 85B (Ag85B) is a 30-kDa secretory protein well conserved in Mycobacterium species. Ag85B has strong Th1-type cytokine inducing activity, and is expected to ameliorate Th2 condition in allergic disease. To perform Ag85B function in vivo, effective and less invasive vaccination method is required. Recently, we have established a novel functional virus vector; recombinant human parainfluenza type 2 virus vector (rhPIV2): highly expressive, replication-deficient, and very low-pathogenic vector. In this study, we investigated the efficacy of rhPIV2 engineered to express Ag85B (rhPIV2/Ag85B) in a mouse AD model induced by repeated oxazolone (OX) challenge. Ear swelling, dermal cell infiltrations and serum IgE level were significantly suppressed in the rhPIV2/Ag85B treated mouse group accompanied with elevated IFN-γ and IL-10 mRNA expressions, and suppressed IL-4, TNF-α and MIP-2 mRNA expressions. The treated mice showed no clinical symptom of croup or systemic adverse reactions. The respiratory tract epithelium captured rhPIV2 effectively without remarkable cytotoxic effects. These results suggested that rhPIV2/Ag85B might be a potent therapeutic tool to control allergic disorders.