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Atopic dermatitis (AD) is a chronic, heterogenous, inflammatory skin disorder associated with a high skin‐related health burden, typically starting in childhood and often persisting into adulthood. AD is characterized by a wide range of clinical phenotypes, reflecting multiple underlying pathophysiological mechanisms and interactions between genetics, immune system dysregulation and environmental factors. In this review, we describe the diverse cellular and molecular mechanisms involved in AD, including the critical role of T‐cell‐driven inflammation, primarily via T helper (Th) 2‐ and Th17‐derived cytokines, many of which are mediated by the Janus kinase (JAK) signaling pathway. These local inflammatory processes interact with sensory neuronal pathways, contributing to the clinical manifestations of AD, including itch, pain and sleep disturbance. The recent elucidation of the molecular pathways involved in AD has allowed treatment strategies to evolve from broad‐acting systemic immunosuppressive therapies to more targeted agents, including JAK inhibitors and cytokine‐specific biologic agents. Evidence from the clinical development of these targeted therapies has reinforced and expanded our understanding of the pathophysiological mechanisms underlying AD and holds promise for individualized treatment strategies tailored to specific AD subtypes. [ABSTRACT FROM AUTHOR]

Background: The oral Janus kinase 1 (JAK1) inhibitor abrocitinib, which reduces interleukin-4 and interleukin-13 signaling, is being investigated for the treatment of atopic dermatitis. Data from trials comparing JAK1 inhibitors with monoclonal antibodies, such as dupilumab, that block interleukin-4 receptors are limited.Methods: In a phase 3, double-blind trial, we randomly assigned patients with atopic dermatitis that was unresponsive to topical agents or that warranted systemic therapy (in a 2:2:2:1 ratio) to receive 200 mg or 100 mg of abrocitinib orally once daily, 300 mg of dupilumab subcutaneously every other week (after a loading dose of 600 mg), or placebo; all the patients received topical therapy. The primary end points were an Investigator's Global Assessment (IGA) response (defined as a score of 0 [clear] or 1 [almost clear] on the IGA [scores range from 0 to 4], with an improvement of ≥2 points from baseline) and an Eczema Area and Severity Index-75 (EASI-75) response (defined as ≥75% improvement from baseline in the score on the EASI [scores range from 0 to 72]) at week 12. The key secondary end points were itch response (defined as an improvement of ≥4 points in the score on the Peak Pruritus Numerical Rating Scale [scores range from 0 to 10]) at week 2 and IGA and EASI-75 responses at week 16.Results: A total of 838 patients underwent randomization; 226 patients were assigned to the 200-mg abrocitinib group, 238 to the 100-mg abrocitinib group, 243 to the dupilumab group, and 131 to the placebo group. An IGA response at week 12 was observed in 48.4% of patients in the 200-mg abrocitinib group, 36.6% in the 100-mg abrocitinib group, 36.5% in the dupilumab group, and 14.0% in the placebo group (P<0.001 for both abrocitinib doses vs. placebo); an EASI-75 response at week 12 was observed in 70.3%, 58.7%, 58.1%, and 27.1%, respectively (P<0.001 for both abrocitinib doses vs. placebo). The 200-mg dose, but not the 100-mg dose, of abrocitinib was superior to dupilumab with respect to itch response at week 2. Neither abrocitinib dose differed significantly from dupilumab with respect to most other key secondary end-point comparisons at week 16. Nausea occurred in 11.1% of the patients in the 200-mg abrocitinib group and 4.2% of those in the 100-mg abrocitinib group, and acne occurred in 6.6% and 2.9%, respectively.Conclusions: In this trial, abrocitinib at a dose of either 200 mg or 100 mg once daily resulted in significantly greater reductions in signs and symptoms of moderate-to-severe atopic dermatitis than placebo at weeks 12 and 16. The 200-mg dose, but not the 100-mg dose, of abrocitinib was superior to dupilumab with respect to itch response at week 2. Neither abrocitinib dose differed significantly from dupilumab with respect to most other key secondary end-point comparisons at week 16. (Funded by Pfizer; JADE COMPARE ClinicalTrials.gov number, NCT03720470.). [ABSTRACT FROM AUTHOR]

Background: Janus kinase (JAK) inhibition is a new mode of action in atopic dermatitis (AD); clarity about drug class safety considerations in the context of AD is important. Baricitinib, an oral, reversible, selective inhibitor of JAK1/JAK2, is in late‐stage development for adult patients with moderate‐to‐severe AD. Objective: To report pooled safety data for baricitinib in patients with moderate‐to‐severe AD in the clinical development program including long‐term extension (LTE) studies. Methods: This analysis included patient‐level safety data from six double‐blinded, randomized, placebo‐controlled studies (one phase 2 and five phase 3), one double‐blinded, randomized, LTE study and one open‐label LTE study, reported in three data sets: placebo‐controlled, 2‐mg – 4‐mg extended and All‐bari AD. Safety outcomes include treatment‐emergent adverse events, adverse events of special interest and abnormal laboratory changes. Proportions of patients with events and incidence rates were calculated. Results: Data were collected for 2531 patients who were given baricitinib for 2247 patient‐years (median duration 310 days). The frequency of serious infections, opportunistic infections and conjunctival disorders was low and similar between treatment groups in the placebo‐controlled period. The most common serious infections were eczema herpeticum [n = 11, incidence rates (IR) = 0.5], cellulitis (n = 6, IR = 0.3) and pneumonia (n = 3, IR = 0.1). There were four opportunistic infections (IR = 0.2). No malignancies, gastrointestinal perforations, positively adjudicated cardiovascular events or tuberculosis were reported in the placebo‐controlled period in baricitinib‐treated patients. Frequency of herpes simplex was higher in the 4‐mg group (6.1%) vs. the 2‐mg (3.6%) and placebo group (2.7%); IRs in the extended data set (2‐mg IR = 9.6; 4‐mg IR = 14.5) were lower vs. the placebo‐controlled data set (2‐mg IR = 12.4; 4‐mg IR = 21.3). In the All‐bari AD data set, there were two positively adjudicated major adverse cardiovascular events (2‐mg group): two venous thrombosis events (4‐mg group) and one death. Conclusion: This integrated safety analysis in patients with moderate‐to‐severe AD confirms the established safety profile of baricitinib. [ABSTRACT FROM AUTHOR]

Background: Atopic dermatitis (AD) is a heterogeneous inflammatory skin disease with different clinical phenotypes based on factors such as age, race, comorbidities, and clinical signs and symptoms. The effect of these factors on therapeutic responses in AD has only been scarcely studied and not for upadacitinib. Currently, there is no biomarker predicting response to upadacitinib. Objectives: Evaluate the efficacy of the oral Janus kinase inhibitor upadacitinib across patient subgroups (baseline demographics, disease characteristics and prior treatment) in patients with moderate‐to‐severe AD. Methods: Data from phase 3 studies (Measure Up 1, Measure Up 2 and AD Up) were utilized for this post hoc analysis. Adults and adolescents with moderate‐to‐severe AD were randomized to receive once daily oral upadacitinib 15 mg, upadacitinib 30 mg or placebo; patients enrolled in the AD Up study received concomitant topical corticosteroids. Data from the Measure Up 1 and Measure Up 2 studies were integrated. Results: A total of 2584 patients were randomized. A consistently greater proportion of patients achieved at least 75% improvement in the Eczema Area and Severity Index, a 0 or 1 on the validated Investigator Global Assessment for Atopic Dermatitis, and improvement in itch (including an achievement of a reduction of ≥4; and score of 0/1 in Worst Pruritus Numerical Rating Scale) with upadacitinib compared with placebo at Week 16, regardless of age, sex, race, body mass index, AD severity, body surface area involvement, history of atopic comorbidities or asthma, or previous exposure to systemic therapy or cyclosporin. Conclusions: Upadacitinib had consistently high skin clearance rates and itch efficacy across subgroups of patients with moderate‐to‐severe AD through Week 16. These results support upadacitinib as a suitable treatment option in a variety of patients. TRIAL REGISTRATION: ClinicalTrials.gov Identifiers: NCT03569293 (Measure Up 1), NCT03607422 (Measure Up 2) and NCT03568318 (AD Up). [ABSTRACT FROM AUTHOR]

Background: Dupilumab, a human monoclonal antibody against interleukin-4 receptor alpha, inhibits signaling of interleukin-4 and interleukin-13, type 2 cytokines that may be important drivers of atopic or allergic diseases such as atopic dermatitis.Methods: In two randomized, placebo-controlled, phase 3 trials of identical design (SOLO 1 and SOLO 2), we enrolled adults with moderate-to-severe atopic dermatitis whose disease was inadequately controlled by topical treatment. Patients were randomly assigned in a 1:1:1 ratio to receive, for 16 weeks, subcutaneous dupilumab (300 mg) or placebo weekly or the same dose of dupilumab every other week alternating with placebo. The primary outcome was the proportion of patients who had both a score of 0 or 1 (clear or almost clear) on the Investigator's Global Assessment and a reduction of 2 points or more in that score from baseline at week 16.Results: We enrolled 671 patients in SOLO 1 and 708 in SOLO 2. In SOLO 1, the primary outcome occurred in 85 patients (38%) who received dupilumab every other week and in 83 (37%) who received dupilumab weekly, as compared with 23 (10%) who received placebo (P<0.001 for both comparisons with placebo). The results were similar in SOLO 2, with the primary outcome occurring in 84 patients (36%) who received dupilumab every other week and in 87 (36%) who received dupilumab weekly, as compared with 20 (8%) who received placebo (P<0.001 for both comparisons). In addition, in the two trials, an improvement from baseline to week 16 of at least 75% on the Eczema Area and Severity Index was reported in significantly more patients who received each regimen of dupilumab than in patients who received placebo (P<0.001 for all comparisons). Dupilumab was also associated with improvement in other clinical end points, including reduction in pruritus and symptoms of anxiety or depression and improvement in quality of life. Injection-site reactions and conjunctivitis were more frequent in the dupilumab groups than in the placebo groups.Conclusions: In two phase 3 trials of identical design involving patients with atopic dermatitis, dupilumab improved the signs and symptoms of atopic dermatitis, including pruritus, symptoms of anxiety and depression, and quality of life, as compared with placebo. Trials of longer duration are needed to assess the long-term effectiveness and safety of dupilumab. (Funded by Sanofi and Regeneron Pharmaceuticals; SOLO 1 ClinicalTrials.gov number, NCT02277743 ; SOLO 2 ClinicalTrials.gov number, NCT02277769 .). [ABSTRACT FROM AUTHOR]

Atopic conditions (atopic dermatitis, rhinitis, and asthma) belong to the most common noncommunicable diseases and are driven by chronic inflammatory reactions. They have a strong impact on the quality of life and represent a substantial and growing socio-economic burden. Interestingly, there is an increasing interest in the development of new therapeutic options with a number of biologics and small molecules targeting potential key mechanisms in atopic conditions. However, besides the safety issue, most of the new active substances are still evaluated according to the traditional efficacy paradigm focusing on the success in treating exacerbations and flares. Instead, the future approaches in drug development and assessment should rather concentrate on the long-term control of these diseases and consider their potential as disease-modifying strategies in the era of precision medicine. To reach this goal, a number of unsolved issues have to be addressed and consensually accepted by the stakeholders in this field. Thus, a successful and rapid development of new treatments requests a paradigm shift and a new way of thinking in the mind of physicians, pharmaceutical industry, regulators, and HTAs. This seems mandatory in order to optimize drug development and to facilitate the accessibility of new therapies to the growing population of patients suffering from atopic conditions on a global level. [ABSTRACT FROM AUTHOR]

Moderate-to-severe forms of atopic dermatitis ( AD) have a substantial impact on the quality of life of patients and their relatives, carrying a significant socioeconomic burden. They often require a systemic therapy, and ciclosporine A (CsA) is the only medicinal product approved for this indication in a limited number of European countries. However, due to the safety profile of CsA and its approval conditions, this treatment can only be prescribed for a limited period of time. Thus, moderate-to-severe forms of AD represent a significant unmet medical need and are subject to off-label prescriptions. Besides giving some insights into the approval procedures for medicinal products in the European Union, this short review is aimed to provide some relevant background information for off-label prescription in AD. It also provides a clinical algorithm for the off-label prescription of systemic immunosuppressants in AD, discusses the apparent dilemma between approval and guidelines, and finally suggests practical rules to be considered in the context of off-label prescription. [ABSTRACT FROM AUTHOR]

Systemic therapy for atopic dermatitis ( AD) is indicated in patients with severe disease refractory to adequate topical treatment. Currently available drugs aim to decrease inflammation by suppressing and/or modulating immune responses and thus may indirectly improve skin barrier function, resulting in a decrease in clinical signs and symptoms in particular pruritus. Before considering systemic treatment, patient adherence to topical treatment including skin care has to be ensured. The selection of the drug depends on the disease severity, localization, complications, concomitant diseases, and age of the patient, but also on their availability and costs as well as the doctor's experience. Bearing in mind the potential risk of resistance, systemic therapy with antibiotics should be exclusively considered in clinically manifest infections such as in children. Here, we review recently published clinical trials and case reports on systemic therapy of pediatric and adult patients with AD to draw conclusions for clinical practice. Although AD is a common disease, controlled clinical studies investigating the efficacy of systemic drugs are scarce, except for cyclosporine, which has been approved for the therapy of severe AD. [ABSTRACT FROM AUTHOR]

The concept of disease modification has been introduced to define the therapeutic strategies aimed to break, stop, or reverse the natural course of a chronic invalidating disease. This strategy is tightly related to the biomarker-based stratification of affected patients using genetic and other biological markers. With regard to the progress in understanding the genetic background of atopic dermatitis ( AD), its natural history and its pivotal role in the emergence of allergic asthma, the time is mature to foster the research field of biomarkers in AD and to consider the elaboration of disease-modifying strategies in the management of AD with the goal to stop or even reverse the atopic march. [ABSTRACT FROM AUTHOR]

Background: Topical glucocorticosteroids are the gold standard in treatment of atopic dermatitis (AD). Recently, topical calcineurin inhibitors have been developed for treatment of this condition. This study compared efficacy and safety of 0.1% methylprednisolone aceponate (MPA) ointment with 0.03% tacrolimus ointment for 3 weeks, in children and adolescents with severe to very severe flare of AD. Methods: The primary end point was treatment success, defined as a score of ‘clear’ or ‘almost clear’ in the static Investigator's Global Assessment (IGA) score. Secondary end points were the percentage change in the Eczema Area and Severity Index (EASI) and patients’ assessment of itch and sleep, Children's Dermatology Life Quality Index, patient's assessment of global response, affected Body Surface Area and medication costs. Results: 265 patients were randomized to either MPA ( n = 129) or tacrolimus ( n = 136) treatment, 257 patients completed the study. Methylprednisolone aceponate 0.1% ointment once daily provided rapid and relevant clinical benefit. Tacrolimus 0.03% ointment twice daily was equally effective with regard to success rate. Methylprednisolone aceponate was superior to tacrolimus for EASI, itch and sleep. Both treatments were well tolerated. Drug-related adverse events were only observed in the tacrolimus group. Medication costs were significantly lower for MPA. Conclusions: While both treatment groups showed similar efficacy results regarding treatment success (IGA), significant advantages were observed for EASI, itch and sleep with MPA 0.1%. These advantages and the significantly lower treatment costs highlight the benefits of MPA treatment, underlining its first-line role in treatment of children and adolescents with severe AD. [ABSTRACT FROM AUTHOR]

Linked article: R. Cheng et al. J Eur Acad Dermatol Venereol 2020; 34: 542–548. https://doi.org/10.1111/jdv.15979. [ABSTRACT FROM AUTHOR]

Background: Pimecrolimus cream 1% (Elidel, Novartis Pharmaceuticals AG) effectively improves/relieves pruritus associated with atopic dermatitis (AD), but few data are available regarding the timing of relief. The purpose of this study was to investigate the timing of pruritus relief produced with pimecrolimus in adults with mild/moderate AD and moderate/severe pruritus. Methods: Patients were randomized to 7 days of treatment with pimecrolimus ( n = 100) or vehicle ( n = 98). Pruritus severity was assessed daily on a 4-point scale (0 = absent, 3 = severe), reflecting the previous 24 h experience. Patients who completed this core study were eligible to enter a voluntary 5-week, open-label extension study. Results: A significant effect was noted within 48 h of treatment, with pruritus improving in 56% of pimecrolimus-treated patients and 34% of vehicle-treated patients ( P = 0.003). Pruritus relief was maintained during the remainder of the core and extension phases, and was accompanied by an improvement in the Investigator's Global Assessment score. Conclusion: Pimecrolimus cream 1% significantly reduced pruritus within 48 h. [ABSTRACT FROM AUTHOR]

Atopic eczema (AE) belongs to the group of atopic diseases that have become increasingly prevalent over the last decades. The pathophysiology of AE has long remained enigmatic, but much scientific effort has been invested in elucidating the genetic background and the immunological mechanisms underlying AE, leading to a better understanding of this complex disease and to new therapeutic strategies. This review provides an update on the scientific progress that has been achieved in clarifying the pathophysiological mechanisms of AE. Copyright © 2005 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Atopic dermatitis(AD) is a biphasic inflammatory skin disease characterized by an initial phase predominated by Th2 cytokines which switches into a second and more chronic Th1 dominated eczematous phase. Two different, the high affinity receptor for IgE(FcεRI) bearing dendritic cell subtypes have been identified in the skin of AD patients: FcεRIhigh Langerhans cells(LC) and FcεRIhigh inflammatory dendritic epidermal cells(IDEC). These two dendritic cell subtypes are supposed to contribute distinctly to the biphasic nature and the outcome of T-cell responses in AD. In the light of recent developments a picture emerges that different IgE-receptor bearing DC subtypes in the blood and the skin of AD patients play a pivotal role in the complex pathophysiological network of AD. [ABSTRACT FROM AUTHOR]

Focuses on atopic dermatitis (AD). Discovery of the disease; Basic clinical aspects; Incidence; Definition and diagnostic criteria of AD; Epidemiologic studies on AD; Immunohistology of AD lesions.

This issue contains summaries of the best articles relevant to pediatric allergy and immunology, elected by members of the Section on Allergy and Immunology of the American Academy of Pediatrics. This information is from articles that appeared in the medical literature between December 1, 1996 and November 30, 1997. Among the articles are studies related to atopic dermatitis, food allergy, immunotherapy, pathophysiology, urticaria and angioedema and many more. Titles include: 'A Short-Term Trial of Tacrolimus Ointment for Atopic Dermatitis,' Allergenicity of Gourmet Nut Oils Processed by Different Methods, ' Treatment of Anaphylactic Sensitivity to Peanuts by Immunotherapy with Injections of Aqueous Peanut Extract,' 'Life-Threatening Fish Allerge Successfully Treated with Immunotherapy,' and many more.

The author reflects on the need for a harmonized nomenclature for the condition atopic dermatitis, atopic eczema, or eczema to determine the different levels of the most common skin disease. He cites the study by Kantor et al. which established the widespread acceptance of the term atopic dermatitis which is ripe for international agreement. The author believes that the term can impact the data mining of the scientific community in terms of search strategies in databases.

Summary: Background: Tralokinumab is a fully human monoclonal antibody that specifically neutralizes interleukin‐13, a key driver of atopic dermatitis (AD). Objectives: To evaluate the efficacy and safety of tralokinumab in combination with topical corticosteroids (TCS) in patients with moderate‐to‐severe AD who were candidates for systemic therapy. Methods: This was a double‐blind, placebo plus TCS controlled phase III trial. Patients were randomized 2 : 1 to subcutaneous tralokinumab 300 mg or placebo every 2 weeks (Q2W) with TCS as needed over 16 weeks. Patients who achieved an Investigator's Global Assessment (IGA) score of 0/1 and/or 75% improvement in Eczema Area and Severity Index (EASI 75) at week 16 with tralokinumab were rerandomized 1 : 1 to tralokinumab Q2W or every 4 weeks (Q4W), with TCS as needed, for another 16 weeks. Results: At week 16, more patients treated with tralokinumab than with placebo achieved IGA 0/1: 38·9% vs. 26·2% [difference (95% confidence interval): 12·4% (2·9–21·9); P = 0·015] and EASI 75: 56·0% vs. 35·7% [20·2% (9·8–30·6); P < 0·001]. Of the patients who were tralokinumab responders at week 16, 89·6% and 92·5% of those treated with tralokinumab Q2W and 77·6% and 90·8% treated with tralokinumab Q4W maintained an IGA 0/1 and EASI 75 response at week 32, respectively. Among patients who did not achieve IGA 0/1 and EASI 75 with tralokinumab Q2W at 16 weeks, 30·5% and 55·8% achieved these endpoints, respectively, at week 32. The overall incidence of adverse events was similar across treatment groups. Conclusions: Tralokinumab 300 mg in combination with TCS as needed was effective and well tolerated in patients with moderate‐to‐severe AD. What is already known about this topic?Atopic dermatitis (AD) is a chronic interleukin (IL)‐13‐mediated disease.In clinical practice, biologics are commonly initiated as add‐on therapy to topical corticosteroids (TCS).Tralokinumab is a fully human monoclonal antibody that binds specifically to the IL‐13 cytokine with high affinity, thereby preventing receptor interaction and subsequent downstream signalling.Tralokinumab combined with TCS showed early and sustained efficacy and safety in a 12‐week, phase IIb trial in moderate‐to‐severe AD. What does this study add?This is the first phase III trial evaluating a targeted anti‐IL‐13 biologic in combination with TCS.These data demonstrate that tralokinumab plus TCS can achieve significant improvements in AD signs and symptoms and quality of life, as well as exert a steroid‐sparing effect.Response with tralokinumab in combination with TCS was maintained over 32 weeks.Tralokinumab may be considered a targeted biological treatment option for patients with moderate‐to‐severe AD. Linked Comment: Morra and Drucker. Br J Dermatol 2021; 184:386–387. Plain language summary available online [ABSTRACT FROM AUTHOR]

The article discusses the changes in the pathogenesis and biomarkers in atopic dermatitis (AD) since the 1994 publication of the Diagnostic Criteria for Atopic Dermatitis (AD). Topics discussed include the serum immunoglobulin E (IgE) as the earliest molecules tested as a biomarker in AD and increased risk of AD development associated with a genetically mediated keratinocyte deficiency of filaggrin.

In this article, the author focuses on the multiple immunological pathways underlying atopic dermatitis (AD). He states that AD represents a genetic complex disease where gene-gene interactions and gene-environment interactions form a highly complex mosaic. He mentions that AD has a deep impact on the gene expression of filaggrin (FLG) and proteins of epidermal barrier. He discusses the lack of appropriate secretion of antimicrobial peptides (AMP) in inflamed skin of AD.

The article focuses on the subject matter of the journal's publication. According to the author, the format of the journal took up the diversity of allergic diseases into account by introducing a specific theme into some of its issues. These special themes would include one or two review papers as well as three to five original papers already accepted for publication. This year, two themes were proposed, for food allergy and for atopic dermatitis.

Discusses various aspects of atopic dermatitis (AD). Identification of the yeast Malassezia sympodialis as factor triggering AD; Level of circulating antibodies to staphylococcal enterotoxin B; Effective topical treatment regimen; Benefit of probiotics; Predominance of a Th2 cytokine profile.

The evidence‐ and consensus‐based guideline on atopic eczema was developed in accordance with the EuroGuiDerm Guideline and Consensus Statement Development Manual. Four consensus conferences were held between December 2020 and July 2021. Twenty‐nine experts (including clinicians and patient representatives) from 12 European countries participated. This second part of the guideline includes recommendations and detailed information on basic therapy with emollients and moisturizers, topical anti‐inflammatory treatment, antimicrobial and antipruritic treatment and UV phototherapy. Furthermore, this part of the guideline covers techniques for avoiding provocation factors, as well as dietary interventions, immunotherapy, complementary medicine and educational interventions for patients with atopic eczema and deals with occupational and psychodermatological aspects of the disease. It also contains guidance on treatment for paediatric and adolescent patients and pregnant or breastfeeding women, as well as considerations for patients who want to have a child. A chapter on the patient perspective is also provided. The first part of the guideline, published separately, contains recommendations and guidance on systemic treatment with conventional immunosuppressive drugs, biologics and janus kinase (JAK) inhibitors, as well as information on the scope and purpose of the guideline, and a section on guideline methodology. [ABSTRACT FROM AUTHOR]

Atopic dermatitis (AD) is a chronic inflammatory skin disease that develops on a complex genetic background, the so-called atopic diathesis. Genetic epidemiological studies based on linkage analysis with full genome scan strategies, as well as association and case-controlled studies, have unravelled several chromosomal loci with putative candidate genes. These loci were revealed to be distinct from those newly identified for allergic asthma. Some of these genes localized on chromosomes 3, 17 and 20 are shared with psoriasis, another chronic inflammatory skin disease. These observations suggest, at least, the role of putative genes involved in the down-regulation of inflammation in the skin. Single nucleotide polymorphisms have been identified in several genes for which the functional significance remains to be determined. In most (70–80%), but not all patients, AD is characterized by the presence of elevated total serum IgE levels. However, a subgroup of atopic patients (20–30%) exhibit normal IgE levels. Mechanisms contributing to the extrinsic/IgE-mediated and the intrinsic/non-IgE-mediated forms have been the focus of intensive research in recent years. These forms have been particularly studied in the context of AD, which has lead to new nomenclature recently approved by the World Allergy Organization. Moreover, we now have increasing evidence for the putative role of an autoimmune phenomenon in the complex pathophysiology of atopic dermatitis. Mainly adult patients exhibit specific IgE directed against self-proteins of epidermal origin. A new picture emerges in which the natural history of AD seems to be divided into three phases. First, an initial intrinsic phase, eczema, occurs in early infancy. This is then followed in 60–80% of cases by a sensitization to food and/or environmental allergens with the development of the extrinsic phase, true AD. In this form, it is speculated that antigen-presenting cells expressing the high-affinity receptor for IgE (FcεRI) play a major role in the control of inflammation. Consequently, these AD patients will have benefit from prevention measures. Finally, most probably due to molecular mimicry, an IgE sensitization to self-proteins is observed in 60–80% of AD patients. Whether these specific IgE antibodies have a pathophysiological role or are only to be considered as an epiphenomenon remains to be clarified. In summary, due to rapid advancements in the research field of atopic diseases, it now becomes possible for the first time to delineate a new disease classification of allergic and nonallergic subtypes of atopic diseases, thereby bringing hope to the clinician for a more specific treatment approach for each subgroup of these patients. [ABSTRACT FROM AUTHOR]

The evidence‐ and consensus‐based guideline on atopic eczema was developed in accordance with the EuroGuiDerm Guideline and Consensus Statement Development Manual. Four consensus conferences were held between December 2020 and July 2021. Twenty‐nine experts (including clinicians and patient representatives) from 12 European countries participated. This first part of the guideline includes general information on its scope and purpose, the health questions covered, target users and a methods section. It also provides guidance on which patients should be treated with systemic therapies, as well as recommendations and detailed information on each systemic drug. The systemic treatment options discussed in the guideline comprise conventional immunosuppressive drugs (azathioprine, ciclosporin, glucocorticosteroids, methotrexate and mycophenolate mofetil), biologics (dupilumab, lebrikizumab, nemolizumab, omalizumab and tralokinumab) and janus kinase inhibitors (abrocitinib, baricitinib and upadacitinib). Part two of the guideline will address avoidance of provocation factors, dietary interventions, immunotherapy, complementary medicine, educational interventions, occupational and psychodermatological aspects, patient perspective and considerations for paediatric, adolescent, pregnant and breastfeeding patients. [ABSTRACT FROM AUTHOR]

Background and objectives: The economic burden of atopic dermatitis (AD) is of particular interest. The present study aims to analyse the association of disease‐related characteristics, annual costs and treatment benefits in AD. Methods: Between August 2017 and June 2019, a cross‐sectional observational study in patients with AD was conducted in Germany. Cost‐of‐illness data were assessed from the societal perspective. Disease characteristics included severity, time since diagnosis and therapy, as well as atopic comorbidity and the implementation of prevention measures. Subgroup analyses of the total costs were conducted for these characteristics. A linear regression model was applied to analyse the impact of disease characteristics on the costs. Furthermore, associations of biologic treatment with outcome parameters were analysed. Results: A total of 1291 patients from 111 centres were included in the analyses. The total costs amounted on average to € 3660 ± € 6428 per patient and year. Higher costs were shown in various patient groups, for example, in patients using biologics (€ 20 983 vs. € 2470). In a regression analysis, gender, education and the number of implemented prevention measures were identified as significant predictors of costs. Patients treated with biologics showed consistently better outcome parameters and were more often satisfied with their treatment. Conclusions: Gender, education and implemented prevention measures are significant cost determinants in AD. The results confirm that treatment with biologics is the main cost driver in AD. However, incremental patient‐relevant benefits of high‐priced therapy are reflected by the significantly better clinical outcomes in the group treated with biologics. [ABSTRACT FROM AUTHOR]

Background Atopic dermatitis ( AD) starts most often during the first years of life and goes into remission in a high proportion of cases during childhood. However, in severe cases, AD persists until adulthood or starts and relapses later in life. So far, studies investigating the natural course of AD during adolescence and adulthood are rare. The aim of our study was to classify different courses of AD and to correlate these with specific risk factors for severe variants of AD. Methods A detailed clinical examination and retrospective evaluation of the history of the disease were performed in a collective of 725 adolescent and adult patients with AD. Laboratory data including total and specific Ig E were evaluated. Results Six hundred and seven patients of 725 patients could be classified into course types. Of these 607 patients 85.7% could be classified into five main different course types of all 31 course types recorded. The highest differences in the number of sensitizations, total immunoglobulin E serum levels and predilection of the skin lesions were observed between patients with an early type of onset of AD and a chronic persisting course until adulthood and patients with a late type of onset of AD, that is, after the 20th year of life. Conclusion Our data show that the natural course of AD can be divided into subgroups that display different clinical features. The data support the assumption of a broad heterogeneity of AD in adolescence and adulthood and emphasize the future need for careful stratification of patients with AD. [ABSTRACT FROM AUTHOR]

There are remarkable differences in the diagnostic and therapeutic management of atopic dermatitis practiced by dermatologists and pediatricians in different countries. Therefore, the European Academy of Allergy and Clinical Immunology and the American Academy of Allergy, Asthma and Immunology nominated expert teams who were given the task of finding a consensus to serve as a guideline for clinical practice in Europe as well as in North America. The consensus report is part of the PRACTALL initiative, which is endorsed by both academies. [ABSTRACT FROM AUTHOR]

For a long time, therapeutic strategies of atopic dermatitis (AD) have been dominated by the application of local or systemic steroids or other immunosuppressive agents, which have been limited by their potential for unwanted local or systemic side effects. Recently, the use of a new generation of topical nonsteroidal, immunomodulatory drugs has revolutionized the therapeutic options of this often recalcitrant allergic-inflammatory skin disease. Research work has focused on the identification of the exact mode of action and the immune specificities of the so-called‘topical immunomodulators’ (TIMs) such astacrolimusand pimecrolimusin AD. In addition to the previous findings about the mode of action of TIMs on T cells, other target cells of TIMs such as keratinocytes, mast cells, eosinophils and dendritic cells have been identified recently as potential therapeutic targets. In this overview, we provide a research update about the anti-inflammatory and anti-allergic properties of TIMs on effector cells of AD that may be involved in the complex pathophysiology of AD. [ABSTRACT FROM AUTHOR]

Focuses on advances in research on the genetic contribution in atopic eczema/dermatitis syndrome (AEDS). Overview of the syndrome; Epidemiological background; Genetic background; Studies in patients with allergic asthma; Maternal/paternal inheritance; Immunoglobulin E responsiveness; Genetic linkage to psoriasis susceptibility loci.

Atopic dermatitis (AD) is a chronic and relapsing, inflammatory skin disease characterized by impaired skin barrier function and immune system dysregulation that results in dryness, skin microbiome dysbiosis and intense pruritus. It is highly heterogeneous, and its management is demanding. Patients with AD are at greater risk of comorbidities such as attention‐deficit hyperactivity disorder as well as other atopic diseases. Early‐onset AD cases typically improve or resolve in late childhood; however, it is proposed that the prevalence of persistent or adult‐onset AD is higher than previously thought. Basic therapy consists of emollient application and trigger avoidance, and when insufficient, topical corticosteroids (TCS) are the first‐line treatment. However, corticophobia/steroid aversion and TCS side‐effects, particularly on sensitive skin areas, lead to low compliance and insufficient disease control. Several long‐ and short‐term randomized controlled and daily practice studies have demonstrated that topical calcineurin inhibitors, such as pimecrolimus, have similar anti‐inflammatory effects to low‐to‐medium strength TCS, reduce pruritus and improve the quality of life of patients. In addition, pimecrolimus does not cause skin atrophy, is steroid‐sparing and has a good safety profile, with no evidence for an increased risk of malignancies or skin infections. In general, pimecrolimus cream is well‐accepted and well‐tolerated, encouraging patient adherence and leading to its use by many physicians as a preferred therapy for children and sensitive skin areas. [ABSTRACT FROM AUTHOR]

Background: Progress in the management of atopic dermatitis (AD) and the recent introduction of the first biologic have raised interest in the costs of treating AD. Objectives: Since there is a lack of recent data, the objective of this study was to determine the annual costs of adults with AD from the societal perspective. Methods: A nationwide cross‐sectional study was conducted in 111 dermatological offices under routine conditions. Cost parameters were collected with a standardised questionnaire on disease‐related costs. This questionnaire allows the determination of costs for systemic and topical treatment, outpatient and inpatient visits, rehabilitation stays and travel costs. Direct costs were determined for the statutory health insurance (SHI) and for the patients (out‐of‐pocket costs). Societal costs also included the indirect costs due to incapacity to work. Costs were calculated for all severity grades and further stratified by mild and moderate‐to‐severe AD. Results: From August 2017 to June 2019, N = 1291 adult patients from all over Germany were included. The total annual costs in the group with all severity grades (n = 706) amounted to € 3616 ± € 6452 (median € 874) per patient. For patients with mild AD (n = 367), the annual costs were € 1466 ± € 3029 (median € 551) per patient, while they were € 5229 ± € 7538 (median € 1791) for patients with moderate‐to‐severe AD (n = 682). The total economic burden for treating adult patients with AD in Germany is estimated at more than € 2.2 billion. Conclusions: In total, the data from this study show that compared to for example psoriasis, AD has a moderate level of costs‐of‐illness in Germany. The approval of new therapies is expected to lead to markedly more resource utilisation in the next years. [ABSTRACT FROM AUTHOR]

Dr. Chernyshov, Dr. Stalder, Dr. Svensson, Dr. Kunz reports no conflict of interest. At least 3 weeks are recommended between the two COVID-19 vaccine doses, which increases the risk of AD flares and loss of AD control if the systemic AD medication is paused or reduced in dose for longer periods. European Task Force on Atopic Dermatitis: position on vaccination of adult patients with atopic dermatitis against COVID-19 (SARS-CoV-2) being treated with systemic medication and biologics. [Extracted from the article]

Editor Atopic dermatitis (AD), a common inflammatory skin condition characterized by chronic or relapsing episodes of eczema, itch and sleep disturbance,1 is associated with psychiatric, infectious and allergic comorbidities. Dr. Hijnen has been investigator, speaker or consultant for Abbvie, Eli Lilly, Incyte, LeoPharma, MedImmune/Astrazeneca, Pfizer, Sanofi and ThermoFisher. Dr. Ring has been an advisor or speaker for AbbVie, Allergika, Sanofi-Genzyme, Pfizer, Bencard, LEO Pharma and Mylan. [Extracted from the article]

Summary: Background: Baricitinib, an oral selective Janus kinase 1 and 2 inhibitor, effectively reduced atopic dermatitis (AD) severity in a phase II study with concomitant topical corticosteroids. Objectives: To evaluate the efficacy and safety of baricitinib in patients with moderate‐to‐severe AD who had an inadequate response to topical therapies. Methods: In two independent, multicentre, double‐blind, phase III monotherapy trials, BREEZE‐AD1 and BREEZE‐AD2, adults with moderate‐to‐severe AD were randomized 2 : 1 : 1 : 1 to once‐daily placebo, baricitinib 1 mg, 2 mg, or 4 mg for 16 weeks. Results: At week 16, more patients achieved the primary end point of Validated Investigator's Global Assessment of AD (0, 1) on baricitinib 4 mg and 2 mg compared with placebo in BREEZE‐AD1 [N = 624; baricitinib 4 mg 16·8% (P < 0·001), 2 mg 11·4% (P < 0·05), 1 mg 11·8% (P < 0·05), placebo 4·8%], and BREEZE‐AD2 [N = 615; baricitinib 4 mg 13·8% (P = 0·001), 2 mg 10·6% (P < 0·05), 1 mg 8·8% (P = 0·085), placebo 4·5%]. Improvement in itch was achieved as early as week 1 for 4 mg and week 2 for 2 mg. Improvements in night‐time awakenings, skin pain and quality‐of‐life measures were observed by week 1 for both 4 mg and 2 mg (P ≤ 0·05, all comparisons). The most common adverse events in patients treated with baricitinib were nasopharyngitis and headache. No cardiovascular events, venous thromboembolism, gastrointestinal perforation, significant haematological changes, or death were observed with any baricitinib dosage. Conclusions: Baricitinib improved clinical signs and symptoms in patients with moderate‐to‐severe AD within 16 weeks of treatment and induced rapid reduction of itch. The safety profile remained consistent with prior findings from baricitinib clinical development in AD, with no new safety concerns. What is already known about this topic? Atopic dermatitis (AD) is a chronic heterogeneous inflammatory skin disease with few approved therapies for patients with moderate‐to‐severe disease. What does this study add? These two phase III trials show that baricitinib, an oral inhibitor of Janus kinase 1 and 2, significantly improved clinical signs and symptoms of AD compared with placebo within the first 16 weeks of treatment.Baricitinib may represent a first‐in‐class oral treatment option for adult patients with moderate‐to‐severe AD. Linked Comment: Drucker. Br J Dermatol 2020; 183:199–200. Plain language summary available online [ABSTRACT FROM AUTHOR]

Atopic dermatitis (AD) is a common inflammatory skin disease that affects both children and adults, including a large number of adults of reproductive age. Several guidelines for the treatment of AD exist, yet specific recommendations for the treatment of pregnant or lactating women and for adults planning to have a child are often lacking. This position paper from the European Task force on Atopic Dermatitis (ETFAD) is based on up‐to‐date scientific literature on treating pregnant and lactating women as wells as adults with AD planning to have a child. It is based on the expert opinions of members of the ETFAD and on existing safety data on the proposed treatments, many of which are derived from patients with other inflammatory diseases or from transplantation medicine. For treating future parents, as well as pregnant and lactating women with AD, the use of topical treatments including moisturizers, topical corticosteroids, tacrolimus, antiseptics such as chlorhexidine, octenidine, potassium permanganate and sodium hypochlorite (bleach) is deemed to be safe. Ultraviolet (UV) therapy may also be used. Systemic treatment should be prescribed only after careful consideration. According to the opinion of the ETFAD, treatment should be restricted to systemic corticosteroids and cyclosporine A, and, in selected cases, azathioprine. [ABSTRACT FROM AUTHOR]

Background: Conjunctivitis is common in patients with atopic dermatitis (AD) in general and a commonly reported adverse event in AD clinical trials with dupilumab. Objective: To survey opinions and experience about conjunctivitis occurring in AD, including those during dupilumab treatment in a group of AD experts from the International Eczema Council (IEC). Methods: Electronic survey and in‐person discussion of management strategies. Results: Forty‐six (53.5%) IEC members from 19 countries responded to the survey. Consensus was reached for several statements regarding diagnostic workup, referral and treatment. IEC members suggest that patients with AD should (i) routinely be asked about ocular complaints or symptoms, (ii) obtain information about the potential for conjunctivitis before starting dupilumab therapy and (iii) if indicated, be treated with dupilumab despite previous or current conjunctivitis. In cases of new‐onset conjunctivitis, there was consensus that dupilumab treatment should be continued when possible, with appropriate referral to an ophthalmologist. Limitations: The study relies on expert opinion from dermatologists. Responses from few dermatologists without dupilumab access were not excluded from the survey. Conclusion: The IEC recommends that dermatologists address conjunctivitis in patients with AD, especially during treatment with dupilumab. [ABSTRACT FROM AUTHOR]

Background: The skin of atopic dermatitis (AD) patients presents a significant dysbalance of the microbiome with a high colonization by Staphylococcus aureus (S. aureus), which positively correlates with the severity of the disease. Objective: Understanding the role of epidermal dendritic cells (DC) as link between the innate and the adaptive immune systems in AD. Methods: Comparative phenotypic and functional analysis of TLR2 on Langerhans cells (LC) and inflammatory dendritic epidermal cells (IDEC) in organotypic models as well as freshly isolated cells from healthy and AD skin. Results: In situ analysis of freshly isolated LC and IDEC from AD skin revealed decreased TLR2 expression compared to LC from healthy skin. In contrast to IDEC, LC from AD skin failed to display any evidence for in situ activation. Exposure to TLR2 ligand Pam3Cys resulted in maturation and increased migratory activity of LC from normal skin. LC and IDEC from AD were unresponsive to TLR2 ligand in that they failed to mature and displayed a high spontaneous migratory activity. Keratinocytes from both healthy and AD skin expressed similar levels of TLR2. The production of IL‐6 and IL‐10 was impaired by Pam3Cys in supernatants from AD skin. IL‐18 was significantly higher in supernatants from AD skin and not influenced by TLR2 ligation, when compared to healthy skin. Conclusion: Our results suggest that TLR2‐mediated sensing of S. aureus‐derived signals is strongly impaired in LC from AD skin. This phenomenon may partly contribute to the immune deviation in AD and the lack of S. aureus clearance. Langerhans cells (LC) and inflammatory dendritic epidermal cells (IDEC) in atopic dermatits skin express less TLR2 compared to LC from healthy skin. Exposure to TLR2 ligand resulted in maturation and increased migratory activity of LC from normal skin. LC and IDEC in atopic dermatits skin do not respond to TLR2 activation but displayed a high spontaneous migratory activity. [ABSTRACT FROM AUTHOR]

Background The ideal nomenclature of atopic dermatitis (AD) / atopic eczema (AE) has long been contested. However, it is becoming increasingly clear that the disparate nomenclature of this disease may have important deleterious ramifications for clinical care and research. Materials and Methods An electronic questionnaire regarding the preferred nomenclature for AD was sent to councilors of the International Eczema Council (IEC) (n=77), an international group of clinicians and researchers with expertise in AD/AE. The survey consisted of 2 questions for consensus regarding the preference for an atopic prefix, and preference for the term AD or AE, and an exploratory question about the acceptability of the terms AD, AE or eczema. Consensus was defined a priori as at least 90% agreement for each question with a response rate of at least 90%. Results Seventy-one of 77 (92.2%) IEC councilors and associates responded to the survey, with all respondents completing the entire survey. Consensus was reached for question 1, with 69 of 71 respondents (97.2%) preferring the atopic prefix. However, consensus was not reached for question 2, with 40 respondents (58.0%) preferring the term AD and 30 (43,5%) preferring AE. Sixty-three respondents (88.7%) and 55 (77.5%) felt that the terms AD and AE were acceptable, whereas only 11 (15.5%) felt that eczema was acceptable. Conclusions The IEC noted that the term eczema is imprecise, and its use is confusing. The consensus of the IEC was to recommend use of the prefix 'atopic' (i.e., AD or AE) in all publications, presentations and discussions about the disorder. [ABSTRACT FROM AUTHOR]

Background Aryl hydrocarbon receptor (AhR), an important regulator of immune responses, is activated by UVB irradiation in the skin. Langerhans cells ( LC) in the epidermis of patients with atopic dermatitis ( AD) carry the high-affinity receptor for IgE, Fcε RI, and are crucially involved in the pathogenesis of AD by inducing inflammatory responses and regulating tolerogenic processes. Objectives We investigated AhR and AhR repressor (Ah RR) expression and functional consequences of AhR activation in human ex vivo skin cells and in in vitro-generated LC. Methods Epidermal cells from healthy skin were analyzed for their expression of AhR and Ah RR. LC generated from CD34+ hematopoietic stem cells ( CD34 LC) were treated with the UV photoproduct and AhR ligand 6-formylindolo[3,2-b]carbazole ( FICZ). Cell surface receptors, transcription factors, and the tolerogenic tryptophan-degrading enzyme indoleamine 2,3-dioxygenase ( IDO) were analyzed using flow cytometry and quantitative PCR. Results Epidermal LC and CD34 LC express AhR and Ah RR. AhR was also found in keratinocytes, which lack Ah RR. AhR activation of LC by FICZ caused downregulation of Fcε RI in CD34 LC without affecting their maturation. AhR-mediated regulation of Fcε RI did not involve any known transcription factors related to this receptor. Furthermore, we could show upregulation of IDO mediated by AhR engagement. Conclusions Our study shows that AhR activation by FICZ reduces Fcε RI and upregulates IDO expression in LC. This AhR-mediated anti-inflammatory feedback mechanism may dampen the allergen-induced inflammation in AD. [ABSTRACT FROM AUTHOR]

Atopic dermatitis ( AD) is a clinically defined, highly pruritic, chronic inflammatory skin disease of children and adults. The diagnosis is made using evaluated clinical criteria. Disease activity is best measured with a composite score assessing both objective signs and subjective symptoms, such as SCORAD. The management of AD must consider the clinical and pathogenic variabilities of the disease and also target flare prevention. Basic therapy includes hydrating topical treatment, as well as avoidance of specific and unspecific provocation factors. Anti-inflammatory treatment of visible skin lesions is based on topical glucocorticosteroids and the topical calcineurin inhibitors tacrolimus and pimecrolimus. Topical calcineurin inhibitors are preferred in sensitive locations. Tacrolimus and mid-potent steroids are proven for proactive therapy, which is long-term intermittent anti-inflammatory therapy of the frequently relapsing skin areas. Systemic anti-inflammatory or immunosuppressive treatment is indicated for severe refractory cases. Biologicals targeting key mechanisms of the atopic immune response are promising emerging treatment options. Microbial colonization and superinfection may induce disease exacerbation and can justify additional antimicrobial treatment. Systemic antihistamines (H1R-blockers) may diminish pruritus, but do not have sufficient effect on lesions. Adjuvant therapy includes UV irradiation, preferably UVA1 or narrow-band UVB 311 nm. Dietary recommendations should be patient specific and elimination diets should only be advised in case of proven food allergy. Allergen-specific immunotherapy to aeroallergens may be useful in selected cases. Psychosomatic counselling is recommended to address stress-induced exacerbations. 'Eczema school' educational programmes have been proven to be helpful for children and adults. [ABSTRACT FROM AUTHOR]

Background Atopic dermatitis ( AD) is a heterogenous and highly complex disease characterized by an increased microbial colonization. For unknown reasons, a subgroup of patients with AD develops Eczema herpeticum ( EH), a severe viral complication due to spreading of herpes simplex virus ( HSV). Indoleamine 2,3-dioxygenase ( IDO1) is a tryptophan (Trp)-catabolizing enzyme which is assumed to be instrumental in the antibacterial and antiviral defence mechanisms. Methods Comparative investigation of the IDO1 expression and activity in freshly isolated monocytes, plasmacytoid DC ( pDC) and in vitro-generated Langerhans cells ( LC) obtained from AD patients with HSV infections and EH and nonatopic controls. Results We demonstrate an increase in Trp degradation in the serum of patients during acute EH episodes. Circulating pDC from patients with history of EH display an increased IDO1 expression. An increased Trp degradation is detected in the supernatants of circulating monocytes from AD patients with acute EH. Mature LC from AD patients with history of EH and with acute EH display an increased IDO1 expression and activity, respectively. In LC from patients with history of EH, viral signals induce an exaggerated IDO1 expression and activity. Conclusion IDO1 expression and activity in LC seem to be involved in the pathophysiology of EH in AD and could represent a predictive biomarker for patients with risk to develop EH and other viral complications. [ABSTRACT FROM AUTHOR]

Background A unique type of CD11cpos dendritic cells ( DC) is abundant in inflamed tissue, for example, in chronic inflammatory skin diseases. Due to their remarkable production of tumor necrosis factor ( TNF)-α and inducible NO synthase ( iNOS), these cells have been referred to as TNF and iNOS-producing DC (Tip- DC). While Tip- DC have been mainly characterized in murine models of infection, functional data about their human counterpart are lacking. Objectives We sought to generate human Tip- DC in vitro und thus provide a new model for the investigation of their phenotype and function. Methods We generated human Tip- DC from monocytic precursor cells of healthy individuals, atopic and psoriatic patients using human serum. Resting and stimulated cells were analyzed by flow cytometry, real-time PCR, and by ELISA. INOS activity was measured by fluorometric detection of NO. Results Tip-DC closely resembled their in vivo counterparts by expressing CD11c, CD86, and CD40 while lacking CD1a, CD1c, or CD207/Langerin. Bacterial stimulation of Tip- DC from healthy donors, atopic dermatitis, or psoriasis patients resulted in a similar increase in iNOS activity and TNF-α production. In kinetic experiments, TNF-α, a putative activator of Tip- DC, could not induce NOS2. Upon bacterial stimulation, TNFA, IL6, IL12B, and IL23A mRNA appeared in a first wave, while IL12A and NOS2 mRNA were up-regulated later on but not blocked by anti- TNF-α agents, implying a biphasic pro-inflammatory response. Conclusions We developed a new model for the study of human Tip- DC and provide the first evidence of their pro-inflammatory capacity. [ABSTRACT FROM AUTHOR]

Background Epidermal Langerhans cells ( LC) expressing the high-affinity receptor for IgE (Fcε RI) play a key role in atopic dermatitis ( AD). AD skin is highly colonized with Staphylococcus aureus (S.a.), which are sensed by Toll-like receptor 2 ( TLR2). We hypothesized that TLR2 may impact on the expression of Fcε RI on LC. Objectives To study a putative impact of TLR2 signaling on Fcε RI, we analyzed Fcε RI and known transcription factors of the receptor after ligand binding to TLR2. Methods We generated LC from CD34+ progenitors in vitro ( CD34 LC) expressing Fcε RI and TLR2 as well as its partners TLR1 and TLR6. The expression of Fcε RI and known transcription factors of the receptor was analyzed on the protein and RNA level by flow cytometry, Western blotting, and real-time PCR. Results For CD34LC from 123 donors, we observed a high heterogeneity in FcεRI surface expression correlating with mRNA level of its α-chain. Stimulation of TLR1/2 or TLR2/6 dramatically down-regulated FcεRI on protein and mRNA level of both α- and γ-chain. Further analysis of putative transcription factors for FCER1A revealed the lack of GATA1 in CD34LC, weak expression of ELF1 and YY1, and high expression of PU.1. While ELF1 and YY1 appeared to be little affected by TLR2 engagement, PU.1 was significantly down-regulated. Conclusions Taken together, our findings show that in human, LC ligation of TLR2 by S.a.-derived products down-regulates Fcε RI and its transcription factor PU.1, thus suggesting that Fcε RI is controlled by PU.1 in these cells. [ABSTRACT FROM AUTHOR]

Background: Factors favoring the emergence of eczema herpeticum (EH) in patients with atopic dermatitis (AD) remain elusive. The aim of this work was to identify changes in clinical and laboratory parameters in acute EH patients, before and after 6 weeks of treatment, as well as differences between AD patients with and without a history of EH. Methods: A total of 235 adult subjects were included and subdivided into six groups: (i) AD patients with acute EH, (ii) AD patients with history of EH, (iii) AD without EH but with recurrent herpes simplex virus (HSV) infections, (iv) AD without EH or recurrent HSV infections and healthy non-AD controls (v) with and (vi) without recurrent HSV infections. Clinical examination of AD, assessment of atopic status and severity were performed. Total IgE, allergenspecific IgE and differential blood count were analyzed. Clinical diagnosis of acute EH was confirmed by PCR. Results: More male patients with AD were affected by EH than female patients. Acute episodes of EH are characterized by lower levels of lymphocytes and higher levels of monocytes. AD patients with history of EH display higher total IgE serum levels (ADEH+HSV+ vs ADEH)HSV+, P < 0.001) and higher sensitization profiles and stronger severity of AD (EASI and SCORAD; ADEH+HSV+ vs ADEH)HSV+, P < 0.001). Concomitant asthma and rhinitis were identified as correlates of EH. Conclusion: From these data, we conclude that AD patients with EH display a distinct clinical and biological phenotype. [ABSTRACT FROM AUTHOR]

Background: Most functions of tetraspanins are not related to cell-surface receptor ligand binding, but are mediated by direct interactions with their partner proteins. Functions of trimeric FcϵRI, expressed by antigen-presenting cells (APCs), range from amplification of allergic inflammatory reactions to their active suppression. Cell-type-specific protein-protein interactions might play a role in the regulation of these bidirectional tasks. Therefore, we intended to study the interactions of trimeric FceRI with tetraspanins. Methods: The expression levels of tetraspanins CD9, CD37, CD53, CD63, CD81, CD82, and CD151 on skin dendritic cells of atopic dermatitis (AD) patients or healthy individuals were detected by flow cytometry. Tetraspanin expression on FcϵRIpos and FcϵRIneg monocyte subpopulations was evaluated. Flow cytometry, confocal microscopy, immunoprecipitation, and immunoblotting experiments were performed to observe the relationship between tetraspanins CD9 and CD81 and FcϵRI. Furthermore, plate stimulation experiments were performed, and cytokines in the supernatants were detected. Results: We found that human FϵRIpos APCs expressed high amounts of tetraspanins and that the tetraspanins CD9 and CD81 were associated with FcϵRI. Concomitant activation of FcϵRI and CD9 on human monocytes increased FceRImediated cytokine release. Conclusion: Taken together, we show for the first time that CD9 and CD81 act as molecular partners of trimeric FϵRI on human APC, which might be of importance in allergic diseases such as AD. [ABSTRACT FROM AUTHOR]

Background: There is evidence that excessive protease activity in the skin is an important factor in the development of atopic dermatitis. SRD44 is a topically formulated novel protease inhibitor that selectively inhibits Staphylococcal-derived aureolysin and matrix metalloproteinases (MMPs). Methods: This was a double-blind, vehicle-controlled randomized trial conducted in thirteen hospital dermatology outpatient clinics in Germany (9), Bulgaria (3) and Finland (1). Ninety-three out of 103 screened adult subjects with confirmed atopic dermatitis affecting ≤20% of body surface area, with an IGA score of 2 or 3 at randomization were randomized following a washout period to either SRD441 ointment or matching vehicle twice daily for 28 days. The primary efficacy endpoint was the clearance of Atopic dermatitis (AD score of 0 or 1 IGA) at Day 21. Secondary endpoints included measures of SCORing Atopic Dermatitis, pruritus self-assessment, rescue medication use and occurrence of new exacerbations. A range of safety and tolerance endpoints were included. Results: There were no significant treatment differences in IGA success rates at Day 21 (SRD441 ointment, 11.1%; vehicle ointment, 12.5%; P = 1.000). Evaluation of secondary efficacy variables revealed no clinical or important statistical differences between treatment groups. Eighteen subjects (19.4%) discontinued the study drug because of an AE (seven subjects [15.6%] in the SRD441 group and 11 subjects [22.9%] in the vehicle group). Twenty-seven subjects (60.0%) in the SRD441 group and 34 subjects (70.8%) in the vehicle group reported an adverse event (AE). Conclusions: SRD441 ointment did not demonstrate efficacy in the treatment of atopic dermatitis raising questions on the effectiveness of MMPs as a target for the treatment of atopic dermatitis. NCT00882245. [ABSTRACT FROM AUTHOR]

To cite this article: Mahachie John JM, Baurecht H, Rodríguez E, Naumann A, Wagenpfeil S, Klopp N, Mempel M, Novak N, Bieber T, Wichmann H-E, Ring J, Illig T, Cattaert T, Van Steen K, Weidinger S. Analysis of the high affinity IgE receptor genes reveals epistatic effects of FCER1A variants eczema risk. Allergy 2010; 65: 875–882. Background: High levels of total and allergen-specific IgE levels are a key feature in allergic diseases. The high-affinity receptor for IgE, which is composed of one alpha (FCER1A), one beta (FCER1B), and two gamma (FCER1G) subunits, represents the central receptor of IgE-induced reactions. In a genome-wide association scan, we recently identified associations between functional FCER1A variants and total serum IgE levels. Previous studies had reported linkage and association of FCER1B variants with IgE and atopic traits. The FCER1G gene has not yet been investigated with regard to atopy. Filaggrin ( FLG) is the strongest known risk gene for eczema, in particular the allergic subtype of eczema. Methods: We investigated the association of FCER1A, FCER1B, and FCER1G variants with IgE in a large population-based cohort ( n = 4261) and tested for epistatic effects using the model-based multifactor dimensionality reduction (MB-MDR) method. In addition, we investigated a potential interaction between FLG and FCER1A variants in a large collection of eczema cases ( n = 1018) and population controls. Results: Three strongly correlated FCER1A polymorphisms were significantly associated with total and specific IgE levels as well as allergic sensitization. No associations were seen for FCER1B and FCER1G. After adjustment for FLG effects, a significant epistatic effect of the FC ER1A variants rs10489854 and rs2511211 on eczema risk was detected. Conclusions: These results suggest that FCER1A variants by themselves and in combination influence IgE levels and act synergistically to influence eczema risk. [ABSTRACT FROM AUTHOR]