Recent developments in the management of patients with atopic dermatitis

Management of most patients with AD should be directed toward basic therapy--lubricants, moderate potency topical steroids, and antihistamines. Only the severe or unresponsive patient should be considered for management with some of the techniques that have been discussed previously. In part, this is because the addition of extra therapy will substantially decrease long-term compliance, increase the cost of medical care, and produce a dissatisfied patient. There are, however, definite situations in which dietary manipulation, topical and systemic antiseptics, dietary supplementation, and ultraviolet light may be useful. The uses of environmental control, biofeedback, and coal tar were not discussed but may also be useful in certain situations. Finally, all physicians should realize that Herpes simplex infection in patients with AD can be a serious and sometimes life-threatening problem. Rapid, accurate diagnosis is the key to effective management with the newer anti-viral agents.     

趋化因子及其受体与特应性皮炎

趋化因子及其受体在许多疾病的病理生理过程中起着重要作用,是当前医学科研领域的一个热点。近年来趋化因子及其受体在特应性皮炎（AD）中的研究显示CC型趋化因子、CX3C型趋化因子、CXC型趋化因子及其受体与AD的发病机制、临床表现、SCORAD评分、病情活动、治疗反应、治疗监测等关系密切,这对探讨AD发病机制和探索新的治疗方案具有重要意义。     

Food hypersensitivity reactions and peripheral blood eosinophilia in patients suffering from atopic dermatitis

The aim of our study is to evaluate the count of eosinophils in peripheral blood in atopic dermatitis (AD) patients over 14 years of age and to compare it with the occurrence of food hypersensitivity (FH) reactions. Complete allergological and dermatological examination was performed in 212 patients included in the study (90 men, 122 women, average age 26.7 years, average SCORAD 32.9). According to our results, in AD patients the difference in count of eosinophils in patients with and without FH reactions is not statistically significant. When evaluating the occurrence of FH reactions to single foods, the count of eosinophils is significantly higher only in patients suffering from reactions to carrot.     

Protease and protease-activated receptor-2 signaling in the pathogenesis of atopic dermatitis

Proteases in the skin are essential to epidermal permeability barrier homeostasis. In addition to their direct proteolytic effects, certain proteases signal to cells by activating protease-activated receptors (PARs), the G-protein-coupled receptors. The expression of functional PAR-2 on human skin and its role in inflammation, pruritus, and skin barrier homeostasis have been demonstrated. Atopic dermatitis (AD) is a multifactorial inflammatory skin disease characterized by genetic barrier defects and allergic inflammation, which is sustained by gene-environmental interactions. Recent studies have revealed aberrant expression and activation of serine proteases and PAR-2 in the lesional skin of AD patients. The imbalance between proteases and protease inhibitors associated with genetic defects in the protease/protease inhibitor encoding genes, increase in skin surface pH, and exposure to proteolytically active allergens contribute to this aberrant protease/ PAR-2 signaling in AD. The increased protease activity in AD leads to abnormal desquamation, degradation of lipid-processing enzymes and antimicrobial peptides, and activation of primary cytokines, thereby leading to permeability barrier dysfunction, inflammation, and defects in the antimicrobial barrier. Moreover, up-regulated proteases stimulate PAR-2 in lesional skin of AD and lead to the production of cytokines and chemokines involved in inflammation and immune responses, itching sensation, and sustained epidermal barrier perturbation with easier allergen penetration. In addition, PAR-2 is an important sensor for exogenous danger molecules, such as exogenous proteases from various allergens, and plays an important role in AD pathogenesis. Together, these findings suggest that protease activity or PAR-2 may be a future target for therapeutic intervention for the treatment of AD.     

Contrasting pathogenesis of atopic dermatitis and psoriasis--part I: clinical and pathologic concepts

Atopic dermatitis and psoriasis are 2 of the most common inflammatory skin diseases. They are similar in that they are complex inherited diseases involving genes that encode immune components and structural proteins that regulate differentiation of epidermal cells. Each disease is characterized by proliferation of epidermal keratinocytes and abnormal cornification or terminal differentiation in the epidermis; skin lesions contain immune infiltrates of T cells, dendritic cells, and other types of leukocytes. We review similarities between the diseases and differences in epidermal barrier defects and immune cells. We also propose mechanisms of pathogenesis based on differences in the balance of immune cell subsets that could cause the phenotypes that distinguish these diseases. The first part of this 2-part review focuses on the clinical and pathologic features of the diseases; the second part discusses differences in immune cell subsets between atopic dermatitis and psoriasis and recent?therapeutic strategies.     

Epidermal barrier in atopic dermatitis

Atopic dermatitis (AD) is a complex disease that affects up to 20% of children and impacts the quality of patients and families in a significant manner. New insights into the pathophysiology of AD point to an important role of structural abnormalities in the epidermis combined with immune dysregulation. Filaggrin (FLG) is synthesized as a large precursor, profilaggrin, and is expressed in the upper layers of the epidermis. FLG plays a critical role in the epidermal barrier, and FLG mutations cause abnormal epidermal function. FLG mutations are strongly associated with early-onset, and persistent severe AD. In addition, FLG deficiency in the epidermis is related to allergic sensitization and asthma. The basic skin care including repair and protection of the skin barrier with proper hydration and topical anti-inflammatory therapy is important to control the severity of skin disease in patients with AD.     

The severity of atopic dermatitis and analysis of the food hypersensitivity reactions

Aim of this study is to evaluate the dependence between the occurrence of food hypersensitivity reactions and the severity of atopic dermatitis. The detailed personal history about the food hypersensitivity reactions was recorded and the severity of atopic dermatitis was evaluated with SCORAD index. The statistical evaluation of the dependence between the occurrence of food hypersensitivity reactions and the severity of atopic dermatitis was performed. Two hundred and eighty-five patients were examined – 90 men and 195 women, average age 26.2 (s.d. = 9.5). The significant dependence between the severity of atopic dermatitis and the occurrence of food hypersensitivity reactions was confirmed; 96% of patients with severe form of atopic dermatitis suffer from food reactions. In evaluating the single foods, the significant dependence was found between the severity of atopic dermatitis and the reactions to nuts, apples, and fishes.     

Skin-prick test and RAST responses to cereals in children with atopic dermatitis. Characterization of IgE-binding components in wheat and oats by an immunoblotting method

Background Hypersensitiviiy to cereals may occur via inhalation or ingestion. Although cereals are essential in the daily nutrition, only little information is available of the allergens causing symptoms in patients with atopic dermatitis (AD). Objective The purpose of the present study was to analyse the IgE immune-response to various cereals and specific cereal fractions of wheat and oats in children with severe AD and correlate the results with challenge studies. Methods Skin-Prick tests (SPT) with a NaCL suspension of wheat. oats, rice, corn. millet and buckwheat and the ethenol soluble sliadin fraction of wheat were performed to 34 wheat/oats challange positive or negative children with AD Simultaneously serum total IgE and specific IgE antibody radioallergosorbent test (RAST), levels to wheat, oats and gluten were determined, In addition serum samples of these 34 AD patients and five age matched controls were analysed with IgE immunoblotting using neutral and acidic protien extracts of wheat and oats. Results From the 34 AD children 33 were SPT positive with wheat and 18 with oats. Positive RAST to wheat and oats could be detected in 32 and 30 samples respectively. From the oral Wheat challange positive children 12/14 appeared positive with gliadin SPT and revealed positive RAST to gluten, but each of the wheat challenge negative were negtive in SPT with gliadin. In immunoblotting using neutral and acidic fractions of cereals the IgE binding with sera of challenge positive children showed the most intensive staining, but no correlation was found between differrent staining patterns and the clinical wheat sensitivity. The 26,38 and 69 KDa bands in wheat and the 46 and 66 KDa in oats could be classified as major IgE binding proteins of these cereals (>50% of the sera were positive). SPT with rice, corn, miller or buckwheat and oats was positive in 16/34 patients. Conclusion Intensive IgE staining to natural acidic soluble proteins in wheat and oats was seen with major IgE binding to 26.38 and 69 KDa protiens in wheat and 46 and 66 KDa in oats, but no specific IgE staining patterns correlating with clinical cereal sensitivity were found. The strong association between the positive SPT with the ethnol soluble gliadin suggest that also gliadin is an important allergen in wheat-allergic children with AD. The allergens in rice, corn, millet and buckwheat should be better studied before they can be recommended as alternatives for cereal allergic children.     

Contrasting pathogenesis of atopic dermatitis and psoriasis--part II: immune cell subsets and therapeutic concepts

Atopic dermatitis (AD) and psoriasis are among the most common inflammatory skin diseases. In the first part of this 2-part review, we discussed the similarities and differences between AD and psoriasis with respect to clinical features and pathology. The diseases are characterized by infiltration of skin lesions by large numbers of inflammatory cells; the second part of this review focuses on immune cell subsets that distinguish each disease and the therapeutic strategies that might be used or developed based on this information. We discuss the interactions among different populations of immune cells that ultimately create the complex inflammatory phenotype of AD and compare these with psoriasis. Therapeutic strategies have been developed for psoriasis based on the cytokine network that promotes inflammation in this disease. Antibodies against IL-12 and IL-23p40 antibody and antagonists of TNF are used to treat patients with psoriasis, and studies are underway to test specific antagonists of IL-23, IL-17, IL-17 receptor, IL-20, and IL-22. We discuss how these therapeutic approaches might be applied to AD.     

Comparison of the allergenicity and antigenicity of Polistes venom and other vespid venoms

The crossantigenicity of Polistes venom with other vespid venoms was examined with rabbit and human antisera. Venom preparations from various Polistes species were obtained by electrical stimulation of individual insects and venom sac dissection. Rabbit antibodies were raised to the venom (P. apachus) and venom sac extract (P. exclamans). Human antisera were obtained from patients allergic to Polistes and other vespid venoms. The venom appeared to be more potent than the venom sac preparations in reactions with rabbit IgG and human IgE antibodies. Among the Polistes species, P. exclamans, P. instablis, and P. apachus venoms showed several lines of precipitation with rabbit antisera, and P. annularis and P. fuscatus venoms only one line, suggesting quantitative or qualitative antigenic differences. In RAST analysis, most sera reacted equally to all Polistes species but occasional exceptions were noted, again suggesting differences in venom allergens. P. exclamans-coupled discs gave the most consistent results. In gel diffusion experiments, there was no crossreactivity between Polistes and yellow jacket venoms and only limited crossreactivity between Polistes and hornet venoms. Patients sensitive to Polistes venom showed varying degrees of reactivity to yellow jacket and hornet venoms in RAST analysis. Patients sensitive to other vespid venoms also showed varying degrees os sensitivity to Polistes venom. Polistes venom appears to contain a genus-unique antigen (allergen). In addition, there appear to be some crossreacting antigens in Polistes and other vespid venoms but to a much lesser degree than found previously in the analysis of the relationship of yellow jacket and hornet venoms.     

Association of HLA-DRB1 genetic variants with the persistence of atopic dermatitis

Atopic dermatitis (AD) is a waxing and waning illness of childhood that is likely caused by interactions between an altered skin barrier and immune dysregulation. The goal of our study was to evaluate the association of DRB1 genetic variants and the persistence of AD using whole exome sequencing and high resolution typing. DRB1 was interrogated based on previous reports that utilized high throughput techniques. We evaluated an ongoing nation-wide long-term cohort of children with AD in which patients are asked every 6 months about their medication use and their AD symptoms. In total, 87 African-American and 50 European-American children were evaluated. Genetic association analysis was performed using a software tool focusing on amino acid variable positions shared by HLA-DRB1 alleles covering the antigen presenting domain. Amino acid variations at position 9 (pocket 9), position 26, and position 78 (pocket 4) were marginally associated with the prevalence of AD. However, the odds ratio was 0.30 (0.14, 0.68; p = 0.003) for residue 78, 0.27 (0.10, 0.69; p = 0.006) for residue 26 and not significant for residue 9 with respect to the persistence of AD. In conclusion, amino acid variations at peptide-binding pockets of HLA-DRB1 were associated with the persistence of AD in African-American children.     

儿童特应性皮炎血清特异性IgE和斑贴试验结果的临床分析

目的:回顾性分析广州地区特应性皮炎(AD)患儿常见变应原,为AD预防和诊治提供依据.方法:ELISA检测138例AD患儿血清特异性IgE(sIgE),并分析其吸入组、食入组变应原;其中43例患儿同时接受了用于检测日常接触类变应原的皮肤斑贴试验,分析其结果分布特征.结果:吸入性特异性总IgE抗体检测结果阳性率为57.97...     

The Role of Cow Milk Allergy in Increasing the Severity of Atopic Dermatitis

Previous studies have shown that up to 33% of children with atopic dermatitis have experienced food hypersensitivity and among different kinds of food allergens Cow Milk (CM) has almost always been one of the most common food allergens in children. The aim of this study is to evaluate the cow milk allergy (CMA) as an increasing factor of severity of atopic dermatitis. One hundred and nineteen children (between 1.5 months and 12 years of age) with atopic dermatitis in the sense of Hanifin and Rajka's criteria entered this study and the severity of atopic dermatitis was identified via the SCORAD index. In order to make the diagnosis of cow milk allergy, a careful history, and a familial history of allergy was taken and the results of skin prick test (SPT) with CM and 4 other food allergen extracts, Radioallergosorbent test (RAST) with CM allergens and a food challenge test with cow milk (fresh or dried) were used. Also a total serum IgE determination and an eosinophil count (with a stool exam) were accomplished. The clinical manifestations of atopic dermatitis in patients was started from their first day of life up to 10 years of age. The family history in 83% of the patients was positive. Positive skin prick test and RAST with CM allergens were positive in 37.9% and 29.3% of cases respectively and the response to challenge test with cow milk was positive in 35 out of 40 patients and in total 44.5% had CMA according to a positive history of cow milk allergy and a positive outcome of the IgE tests (SPT and/or RAST) or a positive challenge test with CM allergens. The results showed that the most common food allergens in patients with atopic dermatitis are certainly cow milk allergens (44.5%) whereas other food allergens are tomato (29.41%), egg (28.57%), nuts (9.24%) and wheat (3.36%) according to the skin prick test. The mean total serum IgE was 307.11 ± 6.56 IU/ml (range = 6–5000) in children with CMA and 81.04 ± 5.97 IU/ml (range = 1–5000) in children without CMA while the mean eosinophil count was 569.52 ± 3.02 count/ml (range = 67–8500) and 314.22 ± 2.94 count/ml (range = 5–5000) respectively. The mean severity of atopic dermatitis according to the SCORAD index was 60.76 in children with CMA and 44.29 in children without CMA. The severity of atopic dermatitis in patients with CMA was significantly higher than patients without CMA (p < 0.0001). Also the mean total serum IgE and mean eosionophil counts in children with CMA were significantly higher than in children without CMA (P < 0.01 and p < 0.0001, respectively). It shows the important role of CM allergen proteins in the induction and in increasing the severity of AD in children.     

Eczema herpeticum in atopic dermatitis

Atopic dermatitis (AD) is one of the most common chronic inflammatory skin diseases leading to pruritic skin lesions. A subset of AD patients exhibits a disseminated severe HSV infection called eczema herpeticum (EH) that can cause life-threatening complications. This review gives an overview of the clinical picture, and characteristics of the patients as well as the diagnosis and therapy of EH. A special focus lies on the pathophysiological hallmarks identified so far that predispose for EH. This aspect covers genetic aberrations, immunological changes, and environmental influences displaying a complex multifactorial situation, which is not completely understood. Type 2 skewing of virus-specific T cells in ADEH⁺ patients has been implicated in immune profile abnormalities, along with impaired functions of dendritic cells and natural killer cells. Furthermore, aberrations in interferon pathway-related genes such as IFNG and IFNGR1 have been identified to increase the risk of EH. IL-4, IL-25, and thymic stromal lymphopoietin (TSLP) are overexpressed in EH, whereas antimicrobial peptides like human β-defensins and LL-37 are reduced. Concerning the epidermal barrier, single nucleotide polymorphisms (SNPs) in skin barrier proteins such as filaggrin were identified in ADEH⁺ patients. A dysbalance of the skin microbiome also contributes to EH due to an increase of Staphylococcus aureus, which provides a supporting role to the viral infection via secreted toxins such as α-toxin. The risk of EH is reduced in AD patients treated with dupilumab. Further research is needed to identify and specifically target risk factors for EH in AD patients.     

Eosinophils in patients suffering from atopic dermatitis and the relation to the occurrence of food allergy and other atopic diseases

The aim of our study is to evaluate the count of eosinophils in peripheral blood in atopic dermatitis (AD) patients older than 14 years of age and to compare it with the occurrence of some other atopic diseases and parameters. One hundred and seventy-two patients were included in the study. According to our results, in AD patients with asthma bronchiale, rhinitis, food allergy, positive family history about atopy, with permanent skin lesions, with total IgE above 200 IU/ml, with the onset of AD under 5 years of age and in patients suffering from moderate or severe form of AD, the count of eosinophils is higher than the normal level of eosinophils. The normal count of eosinophils is recorded in patients suffering from mild form of AD and in patients suffering from food sensitization.     

Antigliadin IgE--indicator of wheat allergy in atopic dermatitis

BACKGROUND: Cereal grains are recognized as the cause of adverse reactions in some patients exposed to grain or flour by either inhalation or ingestion. Cereal-related diseases, such as celiac disease and baker's asthma, have been well studied and the causative cereal proteins have been characterized. Although cereals form an essential part of daily nutrition, the allergenic proteins causing symptoms on ingestion in atopic dermatitis (AD) have remained obscure. In this study, we have investigated the allergenic fraction of wheat in AD. METHODS: Skin prick tests (SPT) with a NaCl wheat suspension and the ethanol-soluble wheat gliadin were performed on 18 wheat-challenge-positive or -negative children with AD, six adult AD patients with suspected cereal allergy, and one adult with wheat-dependent exercise-induced urticaria/anaphylaxis. Serum total IgE and specific IgE-antibody levels to wheat and gluten were measured with the radioallergosorbent test (RAST) simultaneously. In addition serum samples of all 25 patients were analyzed by IgE immunoblotting with the ethanol-soluble wheat-protein extract. RESULTS: Thirteen of the AD children were wheat-challenge-positive, 11/12 of them appeared to be positive with gliadin SPT, and all had an elevated gluten RAST value. Those challenge-negative were negative with both gliadin SPT and gluten RAST. Positive wheat SPT and RAST alone were not associated with positive challenges. Four of the adult patients responded to a cereal-free diet, although only two of them appeared to be positive with gliadin SPT and gluten RAST. A broad and intensive staining of gliadin peptides in IgE-immunoblotting studies was seen in challenge-positive children with positive gliadin SPT and/ or gluten RAST. Besides staining of peptides in the main gliadin area of 30-46 kDa, a characteristic finding was the staining of small, <14-kDa proteins with sera of challenge- and gliadin-SPT-positive patients. CONCLUSIONS: We found that wheat-allergic AD patients have IgE antibodies against gliadin that can be detected by both SPT and the sensitive immunoblotting method. This suggests that gliadin peptides are important allergens, and ingestion of wheat causes symptoms of AD. A broad and intensive IgE staining was seen of gliadin peptides against both the previously characterized peptides in the main gliadin area and small, previously uncharacterized peptides of less than 14 kDa. The gliadin SPT and gluten RAST are good screening methods. Further characterization of the IgE-stained gliadin proteins is needed.