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A role for leukotriene antagonists in atopic dermatitis?

Atopic dermatitis is a chronic, relapsing skin condition that affects over 2% of the population. The pathophysiology of this disease is not completely understood, but immunologic abnormalities and the subsequent release of inflammatory mediators play a central role. Treatment with glucocorticoids has long been the standard of care, but their use is limited by their adverse effect profile. Leukotrienes (LTB4, LTC4, LTD4, and LTE4) are metabolites of arachidonic acid produced through the 5-lipoxygenase pathway. They play an important role in inflammatory and atopic conditions. LT modulating agents have been used with success in asthma. Recently, there has been increased interest in the potential utility of LT antagonists in atopic dermatitis. In vitro and in vivo data have demonstrated that LTs may play a key role in atopic dermatitis. The 2 different types of LT-modulating agents are 5-lipoxygenase inhibitors and LT receptor antagonists. Since the 5-lipoxygenase inhibitor acts at an earlier step in the LT synthetic pathway, it has the ability to alter the production of all the LTs, including LTB4, while the receptor antagonists target only the cysteinyl LTs, LTC4, LTD4, and LTE4. This reduction of LTB4 activity may point to a therapeutic advantage in using LT synthesis inhibitors as opposed to LT receptor antagonists for atopic dermatitis. Clinical evidence of the use of LT agents in atopic dermatitis is limited, but initial results have been promising and these agents may one day serve as corticosteroid-sparing treatments for atopic dermatitis.

Anti-Asthmatic Agents↗

Adult-onset atopic dermatitis.

Atopic dermatitis beginning in adult life is not mentioned in the medical literature. In a review of 2604 patients attending a contact dermatitis clinic, 243 patients (9%) were diagnosed with atopic dermatitis which began for the first time at 20 years of age or older with no contact factors present. This compares with 213 patients (8%) who had atopic dermatitis and contact dermatitis. Patients with purely atopic dermatitis had negative patch testing to relevant allergens and the diagnosis was based on a personal or family history of atopy as well as elevated IgE levels and multiple positive skin prick tests. A broad range of age of onset was found, as well as a female preponderance. The commonest sites of dermatitis were generalized involvement, dermatitis of the hands or eczema involving the face.

Adult↗

Use of textiles in atopic dermatitis: care of atopic dermatitis.

Atopic dermatitis (AD) is a chronic relapsing inflammatory skin disease which usually starts during the first years of life. In the management of AD, the correct approach requires a combination of multiple treatments to identify and eliminate trigger factors, and to improve the alteration of the skin barrier. In this article we try to explain the importance of skin care in the management of AD in relation to the use of textiles: they may be useful to improve disrupted skin but they are also a possible cause of triggering or worsening the lesions. Garments are in direct contact with the skin all day long, and for this reason it is important to carefully choose suitable fabrics in atopic subjects who have disrupted skin. Owing to their hygienic properties fabrics produced from natural fibres are preferential. Wool fibres are frequently used in human clothes but are irritant in direct contact with the skin. Wool fibre has frequently been shown to be irritant to the skin of atopic patients, and for this reason wool intolerance was included as a minor criterion in the diagnostic criteria of AD by Hanifin and Rajka in 1980. Cotton is the most commonly used textile for patients with AD; it has wide acceptability as clothing material because of its natural abundance and inherent properties like good folding endurance, better conduction of heat, easy dyeability and excellent moisture absorption. Silk fabrics help to maintain the body temperature by reducing the excessive sweating and moisture loss that can worsen xerosis. However, the type of silk fabric generally used for clothes is not particularly useful in the care and dressing of children with AD since it reduces transpiration and may cause discomfort when in direct contact with the skin. A new type of silk fabric made of transpiring and slightly elastic woven silk is now commercially available (Microair Dermasilk) and may be used for the skin care of children with AD. The presence of increased bacterial colonization has been demonstrated in patients with AD. Such colonization has been included in the group of trigger factors for eczema in AD. Silver products have recently been demonstrated to offer two advantages in the control of bacterial infections. Textiles may be used not only for clothes, but also to prevent dust mite sensitization in atopic patients. A marked clinical improvement of AD was observed in a group of adults and children with positive skin tests (not necessarily towards mites), after an intensive eradication programme for mite allergens. Skin treatment with acaricide and house dust mite control measures can decrease AD symptoms. Different textiles have various potential worsening links with allergies: e.g. clothing has been proposed as an additional source of exposure to mite and cat allergens. On the other hand, special textiles can be used to prevent dust mite sensitization.

Allergens↗

Cellular and immunologic mechanisms in atopic dermatitis.

Atopic dermatitis is a chronic inflammatory skin disease that is frequently associated with respiratory allergies. Atopic dermatitis develops as a result of a complex interrelationship of environmental, immunologic, genetic, and pharmacologic factors. Efforts to understand the relative contributions of these factors have led to research seeking to identify the relevant effector cells and mediators involved in the pathogenesis of atopic dermatitis. These factors include the pattern of local cytokine release, the differentiation of helper T cells, multiple roles of IgE, skin-directed cell responses, infectious agents, and superantigens. This article reviews these cellular and immunologic mechanisms underlying atopic dermatitis and discusses how an understanding of their role in the inflammatory process may lead to improved treatments for atopic dermatitis.

Dermatitis, Atopic↗

[Atopic dermatitis].

Atopic dermatitis is an important manifestation of the atopic diathesis with increasing incidence. The average lifetime prevalence in Switzerland is about 13%. The skin disease is characterised by severe itching, eczematous skin lesions with often distinctive distribution, dryness of the skin and a personal of family history of atopic diseases. The following article summarises some clinical, epidemiological, therapeutical and pathogenetical aspects of atopic dermatitis. Studies from the allergy unit of Zurich contributed to a better understanding of the disease. Thus, Storck was contributing various studies about neurovegetative and circulatory dysregulations in patients with atopic dermatitis. Furthermore, he already realised in 1955 a relation between exacerbations of eczema and the sensitisation to inhalatory allergens. Schnyder demonstrated that asthma, rhinitis and atopic dermatitis have the same genetic background and Wüthrich contributed important data about the natural history of the disease and the occurrence and relevance of total and specific IgE antibodies.

Adolescent↗

The presence of surface CD30 on T cells in atopic dermatitis.

Atopic dermatitis (AD) has cellular immunohistochemical features similar to those of allergic contact dermatitis (ACD) and there is plenty of evidence for T-cell activation in this disease. The involvement of CD30+ T cells in acute stages of atopic dermatitis might establish CD30 as a helpful marker in differentiating those two diseases. Tissue sections from the skin of 12 patients with active atopic dermatitis and 13 with allergic contact (nickel-induced) dermatitis were immunohistochemically analyzed for cell-surface antigens, including CD30, CD3, CD4, and CD45RO. The severity of the disease was graded by the SCORAD clinical scoring system. The analysis of CD30+, CD45RO+, CD3+, and CD4+ cells in the dermis and epidermis showed a much wider range of values and statistically higher median (p<0.01) in the inflammatory infiltrate of acute atopic dermatitis compared with that of allergic contact dermatitis. Our results showed an association of CD30 expression with atopic dermatitis, but not allergic contact dermatitis. CD30 expression in AD might be helpful in histologic differentiation of these disorders and further characterization of atopy patch testing. The results suggested a specific regulatory function of CD30+ T cells in acute AD. Abundant CD45R0+ cells were detected in both AD and ACD lesions.

Adult↗

Peripheral blood mononuclear cell responses to Dermatophagoides farinae in canine atopic dermatitis.

Atopic dermatitis is a chronic inflammatory and pruritic skin disease commonly seen in dogs and humans that is characterised by the presence of allergen-specific IgE. Data from skin tests and serological analysis suggest that the house dust mite Dermatophagoides farinae is the most important allergen in dogs with atopic dermatitis. The aim of this study was to determine if D. farinae specific peripheral blood mononuclear cell (PBMC) responses could be detected in dogs with atopic dermatitis. PBMCs were isolated by the density centrifugation from dogs with atopic dermatitis that were skin test positive for D. farinae, dogs with atopic dermatitis that were skin test negative for D. farinae, and healthy dogs. Cells were cultured with increasing concentrations of the D. farinae extract, no antigen, vaccine antigens or concanavalin A (ConA). There was significantly greater responsiveness of PBMCs from the D. farinae positive dogs than from either the D. farinae negative or healthy dogs (ANOVA, P<0.05). In contrast, no significant differences were observed in the control responses between the three groups. This is the first study to demonstrate that D. farinae specific circulating memory cells are involved in the pathogenesis of canine house dust mite hypersensitivity.

Animals↗

Expression of interleukin-4 in the epidermis of transgenic mice results in a pruritic inflammatory skin disease: an experimental animal model to study atopic dermatitis.

Atopic dermatitis, a common, chronic, inflammatory skin disease that occurs with increasing prevalence, is characterized by hyperactivated cytokines of helper T cell subset 2 and is frequently associated with staphylococcal infection. An experimental animal model of atopic dermatitis induced by transgenically introduced cytokine is not available. We generated a transgenic mouse line expressing epidermal interleukin-4, a critical cytokine of helper T cell subset 2. Here we show that transgenic mice spontaneously developed a pruritic inflammatory skin disease reproducing all key features of human atopic dermatitis, including xerosis, conjunctivitis, inflammatory skin lesions, Staphylococcus aureus infection, histopathology of chronic dermatitis with T cell, mast cell, macrophage-like mononuclear cell, and eosinophil infiltration, and elevation of total serum IgE and IgG1. The onset and early progression of skin disease coincided with increased total serum IgE and IgG1. The mouse disease occurred at a 43% annual incidence rate and primarily affected the poorly haired skin: ear (100%), neck (65%), eye (53%), face (29%), tail (12%), leg (12%), and torso (6%). As a group the affected transgenic mice manifested with a skin disorder that fulfilled the clinical diagnostic criteria established for atopic dermatitis in human patients. Pending further characterization to authenticate it as a model of atopic dermatitis, this experimental animal model of pruritic inflammatory skin disease may facilitate investigations for the roles of interleukin-4 in cutaneous inflammation and skin infection in human patients.

Animals↗

Overactivation of IL-4-induced activator protein-1 in atopic dermatitis.

Atopic dermatitis is regarded as mediated by Th2-type immunity. In fact, it frequently coincides with the elevation of immunoglobulin (Ig)-E in patients' sera. Due to the pivotal role of interleukin (IL)-4 in regulation of IgE, we hypothesized if atopic dermatitis represents a hyper-reactive condition in response to IL-4 when it coincides the higher serum level of IgE. To address this possibility, peripheral blood mononuclear cells (PBMC) isolated from patients with atopic dermatitis with the high serum IgE level, from those with psoriasis or from healthy volunteers were stimulated with recombinant IL-4 and analyzed for activation of transcription factors including activator protein (AP)-1 or signal transducers and activators of transcription (STAT)-6 by employing electrophoretic mobility shift assays. Although no significant difference between atopy patients and other groups was observed in the STAT-6 binding activity in IL-4-stimulated PBMC, it over-activated the binding of AP-1 in PBMC of the patients with atopic dermatitis. The AP-1 binding was interfered by the use of an antibody directed against JunB. This is the indication that IL-4-overactivated AP-1 is composed of JunB. Furthermore, semi-quantitative RT-PCR analyses revealed marked down-modulation of a Th1 cytokine, interferon (IFN)-gamma, in IL-4-stimulated PBMC derived from atopy patients, but not that from healthy individuals. Together, our present study indicates that AP-1 is over-activated by IL-4 in PBMC of the atopic patients with the higher IgE level, thereby implying that IL-4-induced over-activation of AP-1 might be one of pathogenic factors in atopic dermatitis.

Dermatitis, Atopic↗

Advances in the understanding and treatment of atopic dermatitis.

Atopic dermatitis is the most common chronic skin disease of young children and is frequently associated with asthma and allergies. Th2-type cytokine secreting T cells expressing the cutaneous lymphocyte-associated antigen play a central role in the induction of local IgE responses and recruitment of eosinophils in this disease. Chronic inflammation in atopic dermatitis likely involves a number of interdependent factors, including repeated or persistent exposure to allergens, which can lead to Th2-cell expansion. In addition, exotoxins secreted by Staphylococcus aureus acting as both superantigens and allergens can contribute to persistent inflammation or exacerbations of atopic dermatitis. Treatment of atopic dermatitis with topical agents such as tacrolimus ointment and phosphodiesterase-4 inhibitors offers new approaches directed at correction of the immune dysfunction associated with this disease.

Adjuvants, Immunologic↗

T-helper 1, T-helper 2 and immunosuppressive cytokines in canine atopic dermatitis.

Atopic dermatitis is a common inflammatory skin disease of humans and dogs. Human atopic dermatitis is associated with T-helper (Th) 2 type responses, although Th1 cytokines are present in chronic lesions. This study used semi-quantitative reverse transcriptase polymerase chain reactions to determine the expression of gene transcripts for immunosuppressive cytokines (transforming growth factor beta [TGFbeta] and interleukin [IL]-10), Th2 type cytokines (IL-4 and IL-6) and Th1 type cytokines (interferon gamma [IFNgamma], tumour necrosis factor alpha [TNFalpha], IL-2 and IL-12) in lesional atopic, non-lesional atopic and healthy canine skin. Canine atopic dermatitis was associated with over-expression of IL-4 mRNA and reduced transcription of TGFbeta compared to healthy skin (ANOVA, p<0.05). Higher levels of IFNgamma, TNFalpha and IL-2 mRNA were seen in lesional compared to non-lesional and healthy skin (p<0.05). There were no significant differences in IL-10, IL-6 or IL-12 transcription. This is the first report to demonstrate that canine atopic dermatitis is associated with over-production of IL-4 and under expression of TGFbeta.

Animals↗

Factors influencing the localization of atopic dermatitis.

Atopic dermatitis is clinically characterized by the involvement of preferential sites. Some of these localizations, such as the face in the first year of life and later on the flexural aspect of the limbs, are constant and thus characteristic of atopic dermatitis. They are probably determined by factors that are identical for all subjects, whereas the less constant localizations are probably influenced by individual factors. The author discusses from a clinical point of view the factors that can influence localization and the lack of involvement of certain sites in atopic dermatitis. An unusual localization of atopic dermatitis, such as around congenital nevi, is also discussed.

Age Factors↗

[Topical immunomodulators, such as tacrolimus and pimecrolimus, in the treatment of atopic dermatitis].

Atopic dermatitis is a chronic inflammatory skin disease with a relapsing course. Topical corticosteroids are the usual treatment of atopic dermatitis. Long-term use of topical corticosteroids may lead to local side effects, such as skin atrophy, and systemic side effects, such as induction of hypothalamus-pituitary-adrenal axis suppression. Tacrolimus and pimecrolimus are new topical immunosuppressive drugs known as topical immunomodulators (TIMs). Clinical efficacy of these drugs has been demonstrated in various long- and short-term placebo-controlled studies. The efficacy oftacrolimus is comparable to a class 2 dermatocorticosteroid and the efficacy of pimecrolimus is comparable to a class 1 dermatocorticosteroid. A major advantage of the use of TIMs is that they do not result in skin atrophy. Tacrolimus may cause local irritation, which mostly disappears after 2 weeks. Little is known about the long-term safety of TIMs. It is expected that TIMs will have an important role in the treatment of mild to moderate atopic dermatitis. Combined treatment with dermatocorticosteroids and TIMs needs further investigation. For patients with severe atopic dermatitis, the addition of TIMs to oral immunosuppressive drugs, such as cyclosporin, may allow for dose reductions of oral medication.

Administration, Topical↗

[Atopic dermatitis].

Atopic dermatitis is an extremely common condition whose prevalence is on the increasing for the past three decades particularly in North Europe, where it affects 15% of children, since birth to seventh year. A simultaneous increase of atopic respiratory disorders such as asthma and allergic rhinitis has been reported. Clinical diagnostic criteria of atopic dermatitis are well known and the recent studies concern particularly the interactions between genetic and environmental provocative factors, such as house dust mites, maternal smoking and food allergens. In susceptible families, the maternal and infants avoidance of these triggers may allow to decrease the incidence or the severity of atopic dermatitis. The conventional treatment remains symptomatic with topical steroids. However, the better understanding of pathogenesis of atopic dermatitis holds the hope of immunomodulating treatment, particularly in refractory cases.

Adult↗

In vitro genetically aberrant T-cell clones with continuous growth are associated with atopic dermatitis.

Atopic dermatitis is a disease with a genetic predisposition affecting the immune system, with T lymphocytes participating in the immune dysregulation. Most in vitro T lymphocyte studies of atopic dermatitis have focused on antigen-specific T-cell clones. However, antigen-non-specific regulatory T lymphocytes may also take part in the pathway leading to antigen-specific clonal T-lymphocyte proliferation. T lymphocytes from skin biopsy specimens from three patients with severe atopic dermatitis were cultured in the presence of IL-2 and IL-4, but without antigen added. Initially, proliferation was oligo- or polyclonal, but in all cases overgrowth by T cells with clonal chromosomal aberrations was subsequently observed. These abnormal T-cell clones demonstrated continuous growth and complete or partial phenotypic loss of the T-cell antigen receptor complex. In summary, these findings suggest that a subset of aberrant skin-homing T lymphocytes is associated with atopic dermatitis.

Adult↗

Expression of Fc receptors for IgG during acute and chronic cutaneous inflammation in atopic dermatitis.

Atopic dermatitis is an allergic skin disease characterized by elevated total and antigen-specific serum IgE and IgG4 levels. In acute and chronic cutaneous inflammation, large cellular infiltrates including T cells, dendritic cells and macrophages are found, especially in the dermis. These cells play an important part in the regulation of local inflammatory reactions. Receptors binding IgG (FcgammaR) are involved in dendritic cell and macrophage function. In this study, we examined the in vivo distribution and cellular expression of the three classes of leucocyte FcgammaR in human skin during acute and chronic cutaneous inflammation in atopic dermatitis. Atopy patch test skin was used as a model for acute inflammation in atopic dermatitis, while chronic lesional skin was used to investigate FcgammaR expression in chronically inflamed skin. In atopy patch test sites no increase in the number of CD1a+ dendritic cells and a slight increase in macrophages compared with non-lesional skin was observed. Our results showed increased expression of FcgammaRI (CD64) and FcgammaRIII (CD16) in acutely inflamed skin as well as in chronically inflamed lesional skin, compared with healthy and non-lesional atopic dermatitis skin. FcgammaRI was expressed by RFD1+, RFD7+ and CD68+, but not by CD1a+ dermal dendritic cells. RFD1+ dendritic cells and CD68+ macrophages were the main FcgammaRIII-expressing cells during the acute inflammatory reaction. The significant increase in expression of FcgammaRIII (CD16) and FcgammaRI (CD64) probably results from upregulation of the receptors on resident cells. Insight into the presence of FcgammaR+ cells in human skin during inflammation is important both for our understanding of skin immune reactions and the development of new therapeutic concepts.

Acute Disease↗

Deficiency of epidermal protein-bound omega-hydroxyceramides in atopic dermatitis.

Atopic dermatitis is a common skin disease of unknown etiology with an impaired permeability barrier function. To learn more about the molecular pathology in lesional skin, we analyzed levels of free extractable as well as protein-bound barrier lipids in the epidermis of atopic dermatitis subjects. The amount of protein-bound omega-hydroxyceramides in healthy epidermis comprised 46-53 wt% of total protein-bound lipids, whereas this percentage was decreased to 23-28 wt% in nonlesional areas and even down to 10-25 wt% in affected atopic skin areas of the subjects. Furthermore, the partial amount of free extractable very long chain fatty acids with more than 24 carbon atoms was reduced in affected regions down to 25 wt% and in nonlesional regions of the atopic dermatitis subjects down to 40 wt% compared to healthy controls. This "hydrocarbon chain length deficiency" regarding the barrier lipids in atopic skin was supported by metabolic labeling studies with [14C]-serine in cultured epidermis. The biosynthesis of free glucosylceramides and free ceramides was remarkably decreased in affected skin areas of the atopic subjects compared to healthy control subjects. Especially affected were the de novo syntheses of ceramide 4 (i.e., ceramide EOH, consisting of a very long chain N-acyl omega-hydroxy fatty acid esterified with linoleic acid and 6-hydroxysphingosine as sphingoid base) and ceramide 3 (ceramide NP, consisting of a nonhydroxy N-acyl fatty acid and phytosphingosine). In conclusion, this study revealed that the lesional epidermis in atopic dermatitis has considerable deficiencies within main barrier lipid components, which may contribute to the severely damaged permeability barrier.

Adolescent↗

Skin levels of vasoactive intestinal polypeptide in atopic dermatitis.

Atopic dermatitis (AD) can be exacerbated by various factors, including emotional stress, scratching and sweating. The aim of the present study was to evaluate the hypothesis that the inflammatory reaction in AD is also neurogenic. For this purpose, the levels of vasoactive intestinal polypeptide were measured radioimmunologically in whole-tissue homogenates of lesional skin of 13 patients with atopic dermatitis. Radioimmunoassay was performed using an antiserum, AH78, recognizing the carboxy-terminal fragment vasoactive intestinal polypeptide (22-28). Vasoactive intestinal polypeptide immunoreactivity was detected in relatively low amounts in control skin (0.428 +/- 0.08 pmol/g tissue), whereas a marked increase in the peptide was observed in lesional skin of patients with atopic dermatitis (5.62 +/- 1.25 pmol/g tissue). These results seem to suggest that vasoactive intestinal polypeptide could have a pathogenetic relevance in skin lesions of atopic dermatitis.

Adolescent↗