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PubMed2006

IL-13-stimulated human keratinocytes preferentially attract CD4+CCR4+ T cells: possible role in atopic dermatitis.

Skin inflammation in atopic dermatitis (AD) is characterized by the predominant infiltration of T-helper (Th)2-cells in lesional skin. However, the mechanism of recruitment of these cells in lesional skin of AD is not yet fully elucidated. In this study, we investigated the role of IL-13-stimulated human primary keratinocytes (HPKs) in the recruitment of lymphocytes and further delineated the mechanism of enrichment of these cells. In the migration assays, we observed preferential enrichment of CD4(+)CCR4(+) T cells towards IL-13-stimulated HPKs. Interestingly, CD4(+)CCR4(+) T cells from AD showed a higher chemotactic response than those from healthy individuals. We observed a significant increase in the expression of CCL22 in IL-13-stimulated HPKs as compared to unstimulated cells. Blocking of CCL22 in IL-13-stimulated HPKs by a neutralizing antibody resulted in 70-90% inhibition in migration of CD4(+)CCR4(+) T cells. Moreover, IL-13 upregulated IFN-gamma-induced chemokines, CCL2 and CCL5, in HPKs. Taken together, our data suggest that IL-13-stimulated HPKs participate in a positive feedback loop by preferentially enriching Th2-cells in lesional skin of acute AD patients. However, in chronic phase, IL-13 may act in synergy with IFN-gamma resulting in lymphocytes recruitment of a mixed phenotype at the site of inflammation, thus contributing to the chronification of eczema.

CD4-Positive T-Lymphocytes↗

PubMed1999

Emotional dysfunction, child-family relationships and childhood atopic dermatitis.

A link between atopic dermatitis (AD) and emotional dysfunction is now well established but consideration of this has yet to be widely incorporated into clinical management. A biopsychosocial model of the mind-body interaction is considered in conjunction with the theory of childhood emotional development and the impact of a diseased skin, for its effect on a child growing up with AD. AD inevitably adds to the difficulties of parenting, so that parents and children may become locked into dysfunctional relationships. This adds to the stresses for all concerned, and may contribute to the deterioration of the child's skin condition as part of a psychosomatic vicious cycle. There is a strong indication that the psychological dimensions of AD should be taken into account as part of routine management. Further research will be needed to establish the effectiveness of any psychological intervention.

Affective Symptoms↗

PubMed1999

The prevalence of common skin conditions in Australian school students: 2. Atopic dermatitis.

The prevalence of atopic dermatitis (AD) was recorded following examination by dermatologists and dermatology registrars of a random sample of 2491 school students throughout the State of Victoria, Australia. The overall prevalence, based on clinical examination, was 16.3% (95% confidence interval, CI 14.1-18.5), being higher in girls (17.7%; 95% CI 15.0-20.4) than boys (14.8%; 95% CI 11.8-17.8). Using the U.K. Working Party Diagnostic Criteria for AD reduced the prevalence to 10.8% (95% CI 9.3-12.3) with the prevalence in girls 12.3% (95% CI 10.1-14.4) and in boys 9.2% (95% CI 7.1-11.4). The prevalence was highest in 4-6 year olds (18.7% on clinical examination, 11.5% using the U.K. Working Party Criteria), decreasing with increasing age to 11.6% on clinical examination (8. 6% on U.K. Working Party Criteria) among 16-18 year olds. Most of those with AD were classified as having mild disease (54.1%), with 32.1% classified as having minimal and 13.8% as having moderate to severe disease. Over 80% of those who reported on the questionnaire that they had dermatitis that was then confirmed on examination had been using one or more products to treat it. Nearly 90% of these products were classified as efficacious, with medical practitioners being the major source of advice for their use (77%). Pharmacists (8%), family/friends (6%) and others (9%), including beauticians and naturopaths, made up the remainder of the persons from whom those affected had sought advice about their treatment. These data, the first community-based prevalence data on AD published from Australia, confirm that the condition is common among those of school age. There is a need for AD to be included among those conditions that are discussed in health education lessons in schools.

Adolescent↗

PubMed2000

Epidemiology of atopic dermatitis.

Although research into atopic dermatitis (AD) has been dominated by the study of cells and chemical mechanisms over the last 40 years, the last 7 years has witnessed a respectable growth within the field of AD epidemiology. Significant advances include valid disease definitions that can be used in epidemiological studies, global prevalence studies, and studies which quantify the morbidity and economic cost of the disease. These have all helped to argue the case for more research into AD. Epidemiological studies demonstrating that AD is commoner in wealthier families, linkage with small family size, increased prevalence in migrant groups, and the increasing prevalence of the disease all argue strongly towards an important role for the environment in determining disease expression. Future research gaps include evaluation of gene-environment interactions, better studies of the natural history of AD, and better clinical trials that answer questions that are important to physicians and their patients.

Age Factors↗

PubMed2001

Azathioprine for atopic dermatitis.

For adults with atopic dermatitis (AD) refractory to topical treatment, the choices of second-line therapy are limited. Furthermore, there are concerns about the long-term safety of treatments such as cyclosporin. Limited open studies suggest that azathioprine may be effective, although controlled trial data is lacking. Nevertheless, many UK dermatologists use azathioprine to treat patients with severe AD, despite the potential risk of serious toxicity. Azathioprine myelotoxicity and drug efficacy are now known to be related to the activity of a key enzyme in azathioprine metabolism, thiopurinemethyltransferase (TPMT). Recently, the facility for TPMT measurement has become more widely available, providing the possibility to optimize the therapeutic effect of azathioprine, yet minimise the risk of toxicity. We review the evidence concerning the use of azathioprine for AD, and have identified 128 cases in eight open studies, including our own prospective trial. Improvement in the majority was noted in seven studies, although objective measures of disease activity were used in only one trial. Measurements of TPMT activity were performed in the two most recent studies only. These data underscore the requirement for a prospective randomised controlled trial, and highlight the need to further investigate the role of TPMT measurement in azathioprine usage.

Azathioprine↗

PubMed1999

The descriptive epidemiology of atopic dermatitis in the community.

Atopic dermatitis (AD) is a common condition in the community, particularly amongst children. Although comparison of prevalence data between surveys is made difficult by differences in methodology, the available data suggest that there has been a substantial rise in the prevalence of AD, and that social, geographical and racial variation in disease frequency exists. There is a lack of quality data relating to the prognosis of AD. Recently a reliable set of diagnostic criteria has been developed and a number of severity scoring systems have been proposed for use in epidemiological studies.

Dermatitis, Atopic↗

PubMed2005

Topical streptococcal preparation, OK-432, for atopic dermatitis.

Effective treatment of atopic dermatitis (AD) may in some cases prove quite difficult. OK-432, prepared from the penicillin-treated Su strain of type III Group A Streptococcus pyogenes, has been shown to be effective for treating not only cancer but verruca vulgaris as well, suggesting this agent to create the Th1 pathway through IL-12 induction. Four AD patients consented to trial use of the OK-432 ointment. OK-432 was found to bring about complete cure in the present four cases. Based on results from its use, OK-432 may be concluded to be highly effective for treating AD.

Administration, Topical↗

PubMed1991

High frequency of IL-4-producing CD4+ allergen-specific T lymphocytes in atopic dermatitis lesional skin.

In atopic dermatitis (AD) hypersensitivity reactions to allergens are commonly observed and are assumed to make a major contribution in the pathomechanism of the disease. It may be expected that allergen-reactive Th cells play a central role in these reactions. In the present study the occurrence and function of allergen-specific T lymphocytes in dermal inflammatory lesions were studied. To this aim panels of randomly cloned CD4+ T cells from lesional skin biopsies of two housedust mite Dermatophagoides pteronyssinus (Dp)-allergic AD patients were screened for reactivity with Dp allergens. The results were compared with similar tests for Dp reactivity of T-lymphocyte clones (TLC) from the peripheral blood of these patients. In the panels of TLC generated from lesional skin (S-TLC), a considerable number of TLC appeared to be Dp-specific, 47% (n = 17) and 10% (n = 29), respectively. In the panels from the peripheral blood, the percentages of Dp-specific TLC were only 0% (n = 22) and 3% (n = 34), suggesting accumulation or expansion of these T cells in lesional skin. The function of these TLC was studied by assaying the secretion of IL-4 and IFN-gamma, which have been shown to be produced in aberrant ratios by Dp-specific TLC from the peripheral blood of AD patients (Wierenga et al: J Immunol 144:4651, 1990). All Dp-specific S-TLC produced IL-4 in combination with no or low levels of IFN-gamma, whereas many of the non-Dp-specific S-TLC and blood-derived TLC (B-TLC) were observed to produce high levels of IFN-gamma without significant amounts of IL-4. A functional consequence of these cytokine profiles was demonstrated by the finding that TLC producing substantial amounts of IL-4 enhanced expression of the low-affinity Fc receptor for IgE (CD23) on antigen-presenting cells to a greater extent than did IFN-gamma-producing TLC.

Adult↗

PubMed1996

Serum levels of eosinophil cationic protein reflect the state of in vitro degranulation of blood hypodense eosinophils in atopic dermatitis.

In patients with atopic dermatitis (AD), serum levels of eosinophil cationic protein (ECP) have been shown to be a good reflector of disease severity. To elucidate what serum levels of ECP actually reflect, ECP levels in serum and plasma and cytological aspects of blood eosinophils were examined in AD patients (n = 27) and compared to healthy subjects (n = 12). Significantly elevated levels of serum ECP were noted in AD patients, while plasma ECP were uniformly recorded at nadir levels in both AD patients and normal subjects. In addition to blood eosinophilia, AD patients had significantly increased numbers of hypodense eosinophils (HEo) with morphological characteristics consistent with an activated state. Serum ECP levels strongly correlated with HEo numbers rather than with total eosinophil counts. These results indicate that elevated levels of serum ECP may be a consequence of in vitro degranulation of "activated" HEo, not of ECP supplementation from lesional skin. In addition, the dynamic correlations of eosinophil-associated parameters (total eosinophil counts, HEo numbers, and serum ECP levels) with AD severity suggest that inflammatory events in lesional skin may be involved in causing not only eosinophilopoiesis in bone marrow, but also development of HEo in the periphery, whose degree in turn may be mirrored in the levels of serum ECP in vitro.

Adult↗

PubMed1979

Plasma complement and histamine changes in atopic dermatitis.

Fifteen patients with atopic dermatitis were investigated to evaluate the total of complement and histamine. In five patients total serum complement haemolytic activity (CH50) was significantly decreased as was the haemolytic activity of complement components C2 (C2H50) and C3 (C3H50). By counter immunoelectrophoresis split products of C3 were detected. There was no evidence for alternative pathway activation or the presence of an activator of the alternative pathway. In three patients plasma histamine concentrations were elevated. The intensity of the complement and histamine changes observed seemed to be correlated to the severity of the disease.

Adolescent↗

PubMed1988

UVB phototherapy of atopic dermatitis.

UVB phototherapy of atopic dermatitis was investigated in two paired-comparison studies. In study I, 17 patients were treated for 8 weeks with ultraviolet B radiation (UVB) on one half of the body and with visible light (placebo) on the other. A severity score based on eight clinical variables was determined before, during and after treatment. The total score, pruritus score and overall evaluation score were significantly better on the UVB treated sides than on the placebo treated sides (P less than 0.001). In 13 patients the UVB treated side healed or improved considerably, while the placebo treated side improved considerably in one patient only. In study II, 25 patients were treated for 8 weeks with 0.8 of the minimal erythema dose (MED) of UVB on one half of the body and with 0.4 MED UVB on the other. No statistically significant differences between these dosage regimens were found.

Adolescent↗

PubMed2005

Deficiency in immunoglobulin G2 antibodies against staphylococcal enterotoxin C1 defines a subgroup of patients with atopic dermatitis.

BACKGROUND AND AIM: Atopic dermatitis (AD) is a common chronic inflammatory skin disease often accompanied by cutaneous Staphylococcus aureus colonization and, in this regard, especially complicated by the presence of superantigen-producing strains. Because IgG antibodies comprise an important defence mechanism of the adaptive immune system against bacteria, it was investigated whether AD patients have an abnormal pattern or distribution of superantigen-specific IgG subclass antibodies in association with disease severity and activity. METHODS: Staphylococcal enterotoxin B (SEB) and staphylococcal enterotoxin C1 (SEC1) specific IgG antibody subclasses were assessed in n=89 adult AD patients with mild to severe disease activity as determined by the SCORAD score and in n=28 healthy age-matched controls. Results were correlated with the current status of bacterial skin colonization and severity score. RESULTS: Thirty-eight per cent of the AD patients showed a selective deficiency in IgG2 antibodies against SEC1 compared with only 14% in the control group. The absence of these antibodies was found in both currently colonized and non-colonized AD patients and was associated with a severe phenotype (SCORAD more than 40 points in two-thirds of the deficient patients). However, these patients had normal production levels of IgG2 antibodies against pneumococcal capsular polysaccharide (PCP) and SEB, but higher IgG1 and IgG4 titres against SEC1. Except for elevated total IgG1, total IgG subclass levels were normal in this AD subgroup. Yet, peripheral blood mononuclear cells (PBMCs) derived from these patients clearly produced IL-4 and IL-5 upon SEC1 re-stimulation whereas PBMCs from those providing SEC1-specific IgG2 antibodies failed in the production of these cytokines. CONCLUSION: A subgroup of AD patients suffers from a selective deficiency to produce anti-SEC1 IgG2 antibodies. This patient group is characterized by a severe AD phenotype.

Adolescent↗

PubMed2006

Respiratory symptoms, bronchial hyper-responsiveness, and eosinophilic airway inflammation in patients with moderate-to-severe atopic dermatitis.

BACKGROUND: Patients with atopic dermatitis (AD) often have symptoms suggestive of asthma or rhinitis. The prevalence and signs of respiratory disease in AD patients have been studied to a limited extent. OBJECTIVES: To assess the prevalence and clustering of respiratory symptoms, bronchial hyper-responsiveness (BHR), and eosinophilic airway inflammation in patients with moderate-to-severe AD. METHODS: Eighty-six consecutive patients with moderate-to-severe AD and 49 randomly selected control subjects without AD were studied by questionnaire, flow volume spirometry, histamine challenge to detect BHR, induced sputum test to detect eosinophilic airway inflammation, and skin prick tests (SPTs) and total serum immunoglobulin (Ig)E measurements to detect atopy. RESULTS: The patients with AD showed increased risk of physician-diagnosed asthma (36% vs. 2%, odds ratio (OR) 10.1, confidence interval (CI) 1.3-79.7, P=0.03), physician-diagnosed allergic rhinitis (AR) (45% vs. 6%, OR 4.5, CI 1.2-16.7, P=0.02), BHR (51% vs. 10%, OR 5.5, CI 1.5-20.1, P=0.01), and sputum eosinophilia (81% vs. 11%, OR 76.1, CI 9.3-623.5, P<0.0001) compared with the control subjects. In AD patients, elevated s-IgE and positive SPTs were associated with the occurrence of physician-diagnosed asthma and AR, BHR, and the presence of sputum eosinophilia. CONCLUSIONS: BHR and eosinophilic airway inflammation are more common in patients with AD than in control subjects. The highest prevalences were seen in patients with AD who were SPT positive and had high IgE levels. Longitudinal studies are needed to assess the outcome of patients with signs of airway disease, in order to identify those who need early initiation of asthma treatment.

Adult↗

PubMed2006

Overexpression of the suppressor of cytokine signalling 3 (SOCS3) in severe atopic dermatitis.

Immunoregulatory conditions in atopic dermatitis (AD) involve both Th1 and Th2, although primarily Th2. The suppressor of cytokine signalling 3 (SOCS3) may mediate Th2 regulatory response through negative regulation of Th1 pathways. We examined SOCS3 expression in skin lesions of patients with severe AD and compared it with that in patients with the Th1 disorder, psoriasis. We assessed SOCS3 expression in skin lesions from seven patients with severe AD and five patients with typical psoriasis, and in skin from three normal subjects, using immunohistochemical staining, in situ hybridization and reverse transcription PCR. Strong SOCS3 expression was found in skin lesions in all patients with AD, but only weak expression in patients with psoriasis and in normal subjects. Overexpression of SOCS3 is prominent in the skin of patients with severe AD and consequently may prove useful for evaluating the severity of AD as a Th2-dominant condition.

Adult↗

PubMed2006

Patch testing of experimentally sensitized beagle dogs: development of a model for skin lesions of atopic dermatitis.

In humans with atopic dermatitis (AD), the epicutaneous application of allergens (atopy patch tests or APT) to which the patients are sensitized often results in the development of inflammation resembling that of spontaneous skin lesions. Dogs are affected with a natural homologue of human AD, but information on the induction of positive patch testing reactions is limited. The objectives of this pilot study were to determine the nature and cellular dynamics of inflammation occurring after APT in dogs hypersensitive to house dust mite and flea allergens. Laboratory Beagles were sensitized experimentally to Dermatophagoides farinae house dust mites (two dogs), Ctenocephalides felis flea saliva (one dog) or both (two dogs). Two other dogs served as nonsensitized controls. Both allergens and saline were applied epicutaneously. Macroscopic evaluations and skin biopsies were performed at 4, 24, 48 and 96 h after starting allergenic challenge. Biopsies were evaluated histologically and immunohistochemically with a panel of monoclonal antibodies specific for canine leucocyte antigens. Positive macroscopic reactions consisted of erythema, oedema and induration, and they occurred between 24 and 96 h after allergen application. Macroscopic and microscopic APT reactions developed only whenever serum IgE was present against tested allergens. Microscopically, positive APT was associated with epidermal hyperplasia, Langerhans' cell hyperplasia, and eosinophil and lymphocyte epidermotropism. Dermal inflammation was mixed and arranged in a superficial perivascular to interstitial pattern. Numerous IgE+-CD1+ dendritic cells and gamma-delta T-lymphocytes were observed. Macroscopically and microscopically, APT reactions in these experimentally sensitized animals resembled those seen in lesional biopsy specimens of dogs and humans with spontaneous AD. Therefore, APT in hypersensitive dogs provides a relevant experimental model to investigate the pathogenesis and treatment of both canine and human AD skin lesions.

Animals↗

PubMed2006

Burden of Atopic dermatitis in Canada.

BACKGROUND: Atopic dermatitis (AD) is relatively common worldwide; costs associated with the disease have been reported recently for various countries, but no estimates of costs in Canada are currently available. The objective of this study was to estimate the costs associated with AD in Canada, assessed from resource use determined for a Canadian setting. METHODS: Seventy-six patients in Ontario with AD were surveyed to determine information about severity of disease, healthcare practitioner visits, over-the-counter medication use, household expenses and absenteeism relating to their condition. Based on this information, costs were determined based on the Ontario billing schedule, estimated prescription use, reported out-of-pocket expenses and stated family income. Data about sleep disturbance and concern over topical corticosteroid use were also obtained. RESULTS: Patients reported an average of 3.6 publicly funded doctor visits per year for AD; 58% of these visits were to general practitioners and 28% to dermatologists. The annual per patient expenditure was estimated to be 282, 454 Canadian dollars and 1242 Canadian dollars for patients with mild, moderate and severe AD, respectively. The total cost of AD in Canada was estimated to be 1.4 billion Canadian dollars annually. More than half of the patients experienced sleep disturbances owing to their condition, and 71% reported having concerns about topical corticosteroid use. CONCLUSIONS: Although the cost per patient of AD in Canada is relatively low, owing to the prevalence of the disease, the total cost to society is large. Most of the cost is borne by patients and their employers, primarily owing to indirect costs associated with absenteeism.

Adolescent↗

PubMed2005

Antigen specific cytokine response in pediatric patients with atopic dermatitis.

The physiopathology of atopic dermatitis (AD) has still to be elucidated. T effector cells with cutaneous homing receptors or T-cell derived cytokines have been assumed to be implicated in the pathogenetic mechanisms in AD and to be responsible for the different immunologic responses of patients. In fact, the large majority of AD patients display high IgE levels while others do not develop an abnormal IgE response. Although, there are not significant clinical features characterizing the two different groups, patients with normal IgE belong to a younger age range, raising the possibility that the hypothesized dichotomy of AD might be due to age. In the present study we included 172 outpatient children attending the Pediatric Department of our institution. Serum IgE levels and percentages of peripheral T lymphocytes expressing the cutaneous homing antigen (CLA) were evaluated and results were analyzed in relation to the activity of the disease (SCORAD index) or age. In the overall patients, the IgE levels increased significantly with age (0-1 yr: 19.50 IU/ml; 1-3 yr: 62.0 IU/ml; 3-8 yr: 96.0 IU/ml; >8 yr: 148.5 IU/ml; p<0.001) and with the severity of the disease (SCORAD low: 46.80 IU/ml; medium: 42.90 IU/ml; high: 148.5 IU/ml; p=0.01). Percentages of CLA+ peripheral T lymphocytes also increased with age (0-1 yr: 3.3; 1-3 yr: 4.85; 3-8 yr: 10.6; >8 yr: 12.5; p<0.001), although they were not significantly different in patients with different SCORAD (p=0.89). We further investigated the cellular immune response to a specific antigen in 25 subjects, matched for age, SCORAD, and CLA+ T-cell percentages. Among them, 13 patients had casein serum specific IgE and 12 had no evidence of casein sensitization. Peripheral blood mononuclear cells were kept in short-term culture with endotoxin-free casein fractions and IFN-gamma, TNF-alpha, IL-5, IL-10 cytokine-producing cells were detected by ELISpot. Statistical analysis showed significant higher numbers of TNF-alpha- or IL-10-producing cultures (stimulation index >3) in the 'allergic' patients than in the milk tolerant subjects (p=0.01 and 0.05). The analysis of individual responses confirmed this finding but also provide evidence of a significant increase in IFN-gamma-producing cells (p=0.05) induced by casein stimulation in the group of 'non-allergic' children. Our data showed that immunologic parameters as IgE levels or CLA+ T cells in AD pediatric patients are influenced by the age, confirming that age could represent a bias in the analysis of immune response in those patients. Although, we demonstrated in children with AD the existence of different cytokine patterns of the lymphocyte response that could account for the different immunologic features between the two hypothesized forms of AD, which are not dependent on age.

Adolescent↗

PubMed1997

Bronchial hyper-responsiveness in atopic dermatitis.

Most patients with atopic dermatitis (AD) have symptoms of asthma at some point in their lives, but some do not have any clinical evidence of asthma. Thirty-two patients with AD who had never suffered from bronchial asthma were investigated by the methacholine inhalation test for the presence of bronchial hyper-responsiveness (BHR). Serum immunoglobulin E (IgE) levels, mite specific IgE antibody, peripheral eosinophil counts, serum levels of eosinophil cationic proteins (ECP), and serum levels of major basic proteins (MBP) were determined and a skin test to acetylcholine and adrenaline was performed. The percentage of cases who showed BHR (minimum dose; Dmin < 50 units) was 31.3% in AD patients and 19.0% in 21 healthy controls. In those cases, Dmin of methacholine in AD was significantly lower than that in the controls (P < 0.01). Serum MBP levels were significantly higher in AD with BHR than in those without it (P < 0.05). These results indicate that some AD patients without asthma have BHR, and it may be related to serum MBP levels.

Adolescent↗