Subtypes Of Atopic Dermatitis Research Articles

Disagreement concerning atopic dermatitis subtypes between an English prospective cohort (ALSPAC) and linked electronic health records.

Subtypes of atopic dermatitis (AD) have been derived from the Avon Longitudinal Study of Parents and Children (ALSPAC) based on presence and severity of symptoms reported in questionnaires (Severe-Frequent, Moderate-Frequent, Moderate-Declining, Mild-Intermittent, Unaffected/Rare). Good agreement between ALSPAC and linked electronic health records (EHRs) would increase trust in the clinical validity of these subtypes and allow inferring subtypes from EHRs alone, which would enable their study in large primary care databases. 1. Explore if presence and number of AD records in EHRs agrees with AD symptom and severity reports from ALSPAC; 2. Explore if EHRs agree with ALSPAC-derived AD subtypes; 3. Construct models to classify ALSPAC-derived AD subtype using EHRs. We used data from the ALSPAC prospective cohort study from 11 timepoints until age 14 years (1991-2008), linked to local general practice EHRs. We assessed how far ALSPAC questionnaire responses and derived subtypes agreed with AD as established in EHRs using different AD definitions (e.g., diagnosis and/or prescription) and other AD-related records. We classified AD subtypes using EHRs, fitting multinomial logistic regression models tuning hyperparameters and evaluating performance in the testing set (ROC AUC, accuracy, sensitivity, and specificity). 8,828 individuals out of a total 13,898 had both been assigned an AD subtype and had linked EHRs. The number of AD-related codes in EHRs generally increased with severity of AD subtype, however not all with the Severe-Frequent subtypes had AD in EHRs, and many with the Unaffected/Rare subtype did have AD in EHRs. When predicting ALSPAC AD subtype using EHRs, the best tuned model had ROC AUC of 0.65, sensitivity of 0.29 and specificity of 0.83 (both macro averaged); when different sets of predictors were used, individuals with missing EHR coverage excluded, and subtypes combined, sensitivity was not considerably improved. ALSPAC and EHRs disagreed not just on AD subtypes, but also on whether children had AD or not. Researchers should be aware that individuals considered as having AD in one source may not be considered as having AD in another.

Senescent fibroblasts and innate immune cell activation might play a role in the pathogenesis of elderly atopic dermatitis

BackgroundElderly atopic dermatitis (AD) is a subtype of AD defined by age (≥ 60 years). The molecular characteristics of elderly AD remain to be clarified. ObjectiveWe sought to characterize the molecular features of skin lesions and peripheral blood mononuclear cells (PBMCs) in patients with AD across different age, focusing on elderly AD. MethodsSkin and PBMCs samples were used for RNA sequencing. Analysis of differentially expressed genes and gene set variation analysis were performed. Immunofluorescence staining, quantitative real-time PCR (qRT-PCR), flow cytometry and transwell assay were used for validation. ResultsCompared with healthy controls, the skin transcriptome of AD patients showed common signatures of AD, like barrier dysfunction and enhanced Th1/Th2/Th17 immune pathways. In PBMCs, the expression of Th1/Th2 response genes was more remarkable in adult AD, while expression of Th17-related genes was significantly higher in childhood AD. The gene modules associated with natural killer (NK) cells were downregulated in elderly AD. In skin lesions, elderly AD exhibited enrichment of macrophages, fibroblasts and senescence-associated secretory phenotype (SASP) related genes. The correlation among fibroblasts, SASP and innate immune cells were revealed by the co-localization of fibroblasts, macrophages and NK cells in the lesions across different age groups. Fibroblasts under inflammation or senescence could induce stronger chemotaxis of macrophages and NK cells. ConclusionWe identified the molecular phenotypes of skin lesions and PBMCs in elderly AD individuals. Fibroblasts, innate immune cells, and SASP might play important roles in the pathogenesis of elderly AD.

Clinical features and biomarker differences of severe intrinsic and extrinsic atopic dermatitis

Objectives Atopic dermatitis (AD) can be classified into intrinsic AD(IAD) and extrinsic AD(EAD). However, the differences in clinical features and pathogenesis between these two subtypes of AD are currently unclear. This study aimed to analyse the differences in clinical features and peripheral blood biomarkers between Chinese patients with severe IAD and EAD in order to elucidate the physiopathogenesis of AD. Materials and methods A total of 316 hospitalised patients definitively diagnosed with severe AD were included in this study. There were 72 cases of severe IAD and 244 cases of severe EAD. The clinical features of the patients were recorded in details. Serum total IgE, IgA, IgG, IgM, complementC3/C4, peripheral blood cell counts, lactate dehydrogenase (LDH), C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), IL-2R, IL-6, IL-8, and TNF-α in AD patients and 60 age-matched healthy controls were analysed. IAD and EAD had similar severity/Scoring Atopic Dermatitis (SCORAD) scores. Results Compared with healthy controls, IAD patients had significantly higher total IgE, eosinophils, monocytes, LDH, CRP, IL-2R, IL-6, IL-8 and TNF-α, and lower IgM and C4. EAD patients had significantly higher total IgE, IgA, eosinophils, white blood cell (WBC) counts, neutrophils, monocytes, basophils, LDH, CRP, IL-2R, IL-6, IL-8, TNF-α and lower IgM than healthy controls. IAD patients had a higher percentage of rural/urban living and female/male, a shorter course of disease and lower total IgE, eosinophils, WBC counts, neutrophils, monocytes, basophils, LDH, IgG and C4 than EAD patients. SCORAD scores, eosinophils, LDH expression levels increased with total IgE uniquely in patients with EAD. Conclusions IAD and EAD exhibit specific clinical features and molecular changes. IAD has a more complex physiopathogenesis, and deserves further investigation.

How Do Classical Subtypes Correspond to Endotypes in Atopic Dermatitis?

Since atopic dermatitis (AD) is a heterogeneous condition, the subtyping of AD is a crucial issue. The classical subtypes of AD are represented by extrinsic and intrinsic subtypes, European-American and Asian subtypes, and adult and pediatric subtypes. While the subtyping of AD was historically conducted based on the phenotype, recent findings on the mechanisms of AD have revealed the importance of the endotype, which can characterize individual patients more accurately. Considering the current development of AD therapies, AD endotyping is a prerequisite for a personalized therapeutic choice. Endotypes of AD can be stratified from different viewpoints, including cytokine expression patterns, allergen properties, epidermal barrier conditions, ceramide variation, the involvement of innate immunity, and serum biomarkers. Among them, the cytokine-based endotype seems to be the most useful one and is categorized into type 2 cytokine (IL-4, IL-13 and IL-31)-high, type 1 cytokine (IFN-γ)-high, and/or type 3 cytokine (IL-22 and IL-17)-high, or mixed subtypes. Recently proposed biomarker endotyping aims at individualized treatment options, although the daily clinical use of endotypes is a future issue. To better understand the endotypes for clinicians, attempts to adjust each of the classical subtypes to endotypes are required. This review will discuss the correspondence of the classical subtypes to the various endotypes that have recently been proposed.

Development and Validation of Diagnostic Criteria for Elderly Atopic Dermatitis

Objective: Elderly atopic dermatitis (AD) is a newly identified subtype of AD. Whether specific diagnostic criteria are needed for elderly AD has been debated. This study aimed to propose diagnostic criteria for elderly AD and evaluate the sensitivity. Methods: A hospital-based study was conducted. We screened the clinical features of 1,312 patients with AD of different ages in 1 cohort and proposed a set of diagnostic criteria for elderly AD. The criteria were then validated in another cohort of 223 patients clinically diagnosed with elderly AD by dermatologists specialized in AD to examine the diagnostic sensitivity compared with other criteria by chi-square test. Results: Based on the patients’ clinical features, a set of diagnostic criteria for elderly AD were proposed. The new diagnostic criteria showed significantly higher sensitivity than the classical diagnostic criteria (P < 0.001), especially for mild and moderate AD (P < 0.001). Of all 223 patients with elderly AD, 93.3% fulfilled our criteria, while only 43.5%, 65.5%, and 52.0% fulfilled the Hanifin and Rajka criteria, the Japanese Dermatology Academy criteria, and the United Kingdom Working Party criteria, respectively. Conclusion: The newly proposed criteria for elderly AD yielded high diagnostic sensitivity, particularly for mild and moderate AD.

Immunological Aspects of Skin Aging in Atopic Dermatitis.

The cutaneous immune response is important for the regulation of skin aging well as for the development of immune-mediated skin diseases. Aging of the human skin undergoes immunosenescence with immunological alterations and can be affected by environmental stressors and internal factors, thus leading to various epidermal barrier abnormalities. The dysfunctional epidermal barrier, immune dysregulation, and skin dysbiosis in the advanced age, together with the genetic factors, facilitate the late onset of atopic dermatitis (AD) in the elderly, whose cases have recently been on the rise. Controversial to the healthy aged skin, where overproduction of many cytokines is found, the levels of Th2/Th22 related cytokines inversely correlated with age in the skin of older AD patients. As opposed to an endogenously aged skin, the expression of the terminal differentiation markers significantly increases with age in AD. Despite the atenuated barrier disturbances in older AD patients, the aged skin carries an impairment associated with the aging process, which reflects the persistence of AD. The chronicity of AD in older patients might not directly affect skin aging but does not allow spontaneous remission. Thus, adult- and elderly subtypes of AD are considered as a lifelong disease.

Distinct clinical features and serum cytokine pattern of elderly atopic dermatitis in China.

Elderly atopic dermatitis (AD) is a newly defined subtype of AD stratified by age-related clinical pictures. To analyse the clinical features and molecular profile of elderly AD patients in China, comparing with infantile, childhood and adolescent/adult AD. A total of 1312 patients diagnosed by Hanifin and Rajka diagnostic criteria of AD from Huashan Hospital, Shanghai, China, were divided into four groups by age (2-18, 19-40, 41-60 and >60years), and clinical features were evaluated by questionnaire and physical examination. Serum total IgE, eosinophil counts and various cytokines were further analysed in some of the patients and healthy controls. Elderly AD showed significantly higher male/female ratio and rural/urban ratio than other age groups, and more than half of elderly AD first appeared after 60years old. Skin lesions of elderly AD were more often seen in the trunk and extensor sites of the extremities. Level of serum IgE and eosinophil counts were significantly lower in elderly AD than those in other age groups. Serum levels of IL-4, TARC, IL-17A, IL-6, IL-22, IL-33 and TSLP were significantly higher in elderly AD patients than those of healthy controls, indicating a mixed Th2/Th17/Th22 inflammation. Elderly AD demonstrated unique clinical characteristics compared with other age groups and showed mixed Th2/Th17/Th22 skewing, indicating a unique pathogenesis for elderly AD.

Simple Markers for Systemic Inflammation in Pediatric Atopic Dermatitis Patients.

Background:Atopic dermatitis is a dermatological disease characterized by chronic inflammation. In recent years, systemic inflammation is also mentioned along with local inflammation for its pathogenesis. Neutrophil-lymphocyte ratio (NLR), platelet-lymphocyte ratio (PLR), and mean platelet volume (MPV) are nonspecific indicators of systemic inflammation, and they were shown to be associated with the disease and its prognosis in allergic or nonallergic diseases.Aims and Objectives:The aim of this study was to evaluate the values of NLR, PLR, and MPV in atopic dermatitis patients and also to investigate the associations of them with the atopic dermatitis disease severity and duration.Materials and Methods:Two hundred and fifty-two atopic dermatitis patients and 75 control group individuals were included in the study. Mean/median values of NLR, PLR, and MPV were compared among patients and controls, severity groups classified according to SCORing Atopic Dermatitis (SCORAD) and intrinsic and extrinsic groups. Correlation of disease duration and SCORAD with NLR, PLR, and MPV values were examined. Disease duration and its association with NLR were evaluated by correlation and linear regression analysis.Results:Mean NLR and median PLR values of atopic dermatitis patients were higher than those of controls (0.97 ± 0.69 and 80.86 [59.86–108.23], respectively). NLR and PLR values were found to be positively correlated with disease duration and NLR was positively associated with disease duration after adjustment. NLR value was also higher in the extrinsic group than the intrinsic group.Conclusion:Presence of systemic inflammation in the pathogenesis of atopic dermatitis was considered to be associated with increased NLR and PLR values. These parameters were also associated with disease duration and might vary between subtypes of atopic dermatitis. NLR and PLR were cheaper and easily accessible alternatives to the systemic inflammation biomarkers that were expensive and not accessible for all laboratories, particularly in economically disadvantaged countries.

Epidermal barrier in hereditary ichthyoses, atopic dermatitis, and psoriasis.

Several skin disorders are associated with impaired skin barrier function. Primary dysfunction is caused by monogenic defects in key components of the epidermis (for example ichthyoses). Secondary barrier impairment occurs in inflammatory dermatoses marked by disturbed epidermal homeostasis (eczema, psoriasis, etc.). In these disorders, inflammation impedes the synthesis or maintenance of skin barrier components. Recent evidence suggests a combination of primary and secondary barrier dysfunction in atopic dermatitis and, to a lesser extent, also in psoriasis. In the future, subtypes of atopic dermatitis may likely be defined, in which one or the other is prevalent.

Pathogenesis of atopic dermatitis.

Atopic dermatitis (AD) is the most common allergic inflammatory skin disease. Interactions of genetic, environmental and immunological factors result in the initiation and progress of AD. Although the clinical picture, characterized by acute flare-ups of eczematous, pruritic lesions on dry skin at typical predilection such as the flexural folds, is quite homogenous, the trigger factors of the disease are diverse and the pathophysiologic network involved is complex. Therefore, first attempts have been made to classify subtypes of AD based on the most relevant causal factors in the individual patient. To optimize such a stratification of patients, detailed knowledge about cofactors impacting on manifestation of AD as well as impairment of the course of the disease is indispensable. AD shares general features of barrier dysfunction and skin inflammation with other inflammatory diseases of the skin such as psoriasis or allergic contact dermatitis, but a plethora of disease-specific genetic, immunologic and environmental factors have been identified in AD as well. It is the purpose of this review to illustrate key concepts of the pathogenesis of AD. Important findings of recent years will be summarized and cofactors of the pathogenesis will be controversially discussed. We will summarize knowledge on pathogenic factors on the immunologic level contributing to skin barrier dysfunction in AD and the role of the microbiome as first line of defence. Furthermore, we will elucidate the role of innate lymphoid cells in AD and outline the pattern of T helper cell subtypes present in the skin during different stages of AD.

Antinuclear antibodies in atopic dermatitis: a cross-sectional study on 346 children.

Atopic dermatitis (AD) is a chronic inflammatory skin disease that can be classified into an extrinsic or intrinsic type. A high percentage of patients, especially adults with the extrinsic type of AD, have been reported to show antibodies to antinuclear proteins (ANA). We aimed to study the prevalence of ANA in children with AD and to evaluate clinical differences between patients with ANA-positive and ANA-negative AD. A total 346 serum samples from children with active AD (mean age 5.8years) and 117 hospital controls without known skin, inflammatory, or immune-mediated disease (mean age 7.9years) were tested for IgG ANA with indirect immunofluorescence on HEp-2 cells, total serum IgE levels, and IgE type antibodies to food allergen panels. In total, 47 patients with AD (13.6%) and 15 subjects in the control group (12.8%) were ANA positive at screening dilution 1:10 (P>0.05). In patients with AD, ANA was found already at the age of 2years, significantly more often in females (P<0.005) and at slightly higher titers (up to 1:160). No differences were found in ANA positivity regarding the severity of AD or sensitization to food allergens. No significant differences were observed between AD and the control group, or between different subtypes of AD in ANA prevalence. In both groups, ANA frequency increased with age, but in patients with AD, ANA had a tendency to appear earlier. Therefore, active AD during the early years of life could dispose selected patients towards earlier development of systemic autoreactivity and stress the need for regular follow-up of patients with ANA-positive AD.

Loss-of-Function Variations Within the Filaggrin Gene Predispose for Atopic Dermatitis With Allergic Sensitizations

Weidinger S, Illig T, Baurecht H, et al. J Allergy Clin Immunol. 2006;118:214–219 PURPOSE OF THE STUDY. Evaluation for genetic basis for impaired epidermal skin barrier in atopic dermatitis (AD). STUDY POPULATION. White German families with AD (N = 476). METHODS. Evaluation of the association of the loss-of-function mutations Arg501Xaa and 2282del4 within the filaggrin (FLG) gene by using the transmission-disequilibrium test. RESULTS. This study revealed prominent associations between the 2 loss-of-function FLG mutations and AD, as previously observed in a traditional Mendelian linkage analysis and case-control cohort analysis approach. In addition, an association of the FLG mutations was made in particular with the extrinsic subtype of AD, which is characterized by high total serum immunoglobulin E levels and concomitant allergic sensitization. Furthermore, FLG mutations were significantly associated with palmar hyperlinearity in patients with AD, which represents a shared feature of AD and ichthyosis vulgaris. CONCLUSIONS. These data implicate FLG as the first strong genetic factor identified in a common complex disease. REVIEWER COMMENTS. These findings confirm the importance of FLG as a genetic factor in AD as found by other investigators. This is the strongest genetic evidence to date to identify a cause of the breakdown of the epidermal barrier in AD. Filaggrin may be the “mortar” that is essential within the “bricks” of keratinocytes to maintain the integrity of the epithelial barrier. These findings further support the crucial role of the skin barrier in preventing allergic sensitization.

Diagnosis and treatment of atopic dermatitis in children and adults: European Academy of Allergology and Clinical Immunology/American Academy of Allergy, Asthma and Immunology/PRACTALL Consensus Report

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.

Loss-of-function variations within the filaggrin gene predispose for atopic dermatitis with allergic sensitizations

Atopic dermatitis (AD) is a chronic inflammatory skin disease with a strong genetic background. One of the characteristic features of AD and causative factor for the disease is an impaired epidermal skin barrier based on a primary defect of epidermal differentiation. Recently, 2 loss-of-function mutations (R501X and 2282derl4) in the filaggrin gene (FLG) that cause ichthyosis vulgaris, one of the most common inherited skin disorders of keratinization, have been reported to be strong predisposing factors for AD. We evaluated the association of the loss-of-function mutations R501X and 2282del4 within the FLG gene in a large collection of 476 well-characterized white German families with AD by using the transmission-disequilibrium test. Our family-based approach revealed prominent associations between the 2 loss-of-function FLG mutations and AD, as previously observed in a traditional Mendelian linkage analysis and case-control cohort analysis approach. In addition, we observed associations of the FLG mutations in particular with the extrinsic subtype of AD, which is characterized by high total serum IgE levels and concomitant allergic sensitizations. Furthermore, FLG mutations are significantly associated with palmar hyperlinearity in patients with AD, which represents a shared feature of AD and ichthyosis vulgaris. Together these data implicate that FLG is the first really strong genetic factor identified in a common complex disease. These findings underline the crucial role of the skin barrier in preventing allergic sensitization.

Aktuelles zur atopischen Dermatitis (Neurodermitis)

Atopic dermatitis (AD) or atopic (AE) is a multifactorial skin disease caused by a variety of factors such as genetic conditions, alterated skin structure, immunologic deviations and environmental factors, among others. According to the new WAO nomenclature, the term eczema should be used as the umbrella term to cover all different subtypes of atopic dermatitis, i.e. the IgE-associated (atopic eczema) and the non-IgE-associated type (non-atopic eczema). Besides some comments on the new nomenclature and the so-called march, we provide an overview of the diagnostic importance of atopy patch tests, especially in the formerly called intrinsic type of AE and the role of Staphylococcus aureus-enterotoxins with superantigenic activity, and of fungi (Coprinus comatus and Malassezia furfur sive sympodialis) as illness-specific allergens in AD/AE. The use of antiinfectious and antifungal drugs (topic or systemic) may be of notable benefit in some AD/AE patients. Especially in children with AD/AE, is easily aggravated by contact with irritating factors (e.g. aggressive detergents, synthetic and woolen clothes). Also, skin colonization with Staphylococcus aureus is known as a major trigger of the disease. Silver-coated textiles and a silk fabric coated with AEGIS AEM 5772/5, an antimicrobial substance, efficiently reduce Staphylococcus aureus colonization in patients with AD/AE. Some new studies even have shown a superior improvement by treatment with silver-coated textiles or specially manufactured silk clothes compared to cotton textiles or mild topical corticosteroids. Finally, the development of a new class of steroid-free, topic immunomodulatory drugs (tacrolimus and pimecrolimus) has substantially improved the treatment of AD/AE. Nevertheless, patient education is still very important in the management of the disease since it often follows an unpredictable course.

Epidemiology, clinical features, and immunology of the "intrinsic" (non-IgE-mediated) type of atopic dermatitis (constitutional dermatitis).

Departmentof Pharmacology, University of Bern, Bern, SwitzerlandKey words: atopic dermatitis; clinical features;constitutional dermatitis; epidemiology; extrinsictype; immunopathology; intrinsic type.Prof. Dr B. Wu¨thrichAllergy Unit, Department of DermatologyUniversity Hospital8091 ZurichSwitzerlandAccepted for publication 22 March 2001