Chang Ook Park

Efficacy of allergen-specific immunotherapy for atopic dermatitis: A systematic review and meta-analysis of randomized controlled trials

BACKGROUND Allergen-specific immunotherapy (allergen-SIT) is the only treatment directed at the cause of IgE-mediated allergic diseases. However, there is controversy over the use of SIT for patients with atopic dermatitis. OBJECTIVE We performed a systematic review and meta-analysis to assess the efficacy of SIT for patients with atopic dermatitis. METHODS We performed manual searches of reference lists and computerized searches of the MEDLINE, EMBASE, CINAHL, Web of Science, and Cochrane databases (through December 10, 2012) for randomized controlled trials that compared SIT with placebo for patients with atopic dermatitis. The outcome of interest was a dichotomous variable, in terms of treatment success; a meta-analysis was performed by using a random-effects analysis. Subgroup analyses were carried out to evaluate the effects of long-term treatment (more than 1 year), SIT for severe atopic dermatitis, SIT for children, and subcutaneous and sublingual administration of immunotherapy. RESULTS We analyzed 8 randomized controlled trials that comprised a total of 385 subjects. We found that SIT has a significant positive effect on atopic dermatitis (odds ratio [OR], 5.35; 95% CI, 1.61-17.77; number needed to treat, 3; 95% CI, 2-9). SIT also showed significant efficacy in long-term treatment (OR, 6.42; 95% CI, 1.50-27.52) for patients with severe atopic dermatitis (OR, 3.13; 95% CI, 1.31-7.48), and when administered subcutaneously (OR, 4.27; 95% CI, 1.36-13.39). CONCLUSIONS A meta-analysis provides moderate-level evidence for the efficacy of SIT against atopic dermatitis. However, these findings are based on an analysis of a small number of randomized controlled trials, with considerable heterogeneity among trials.

Association of Stress with Symptoms of Atopic Dermatitis

Psychological stress and atopic dermatitis (AD) symptoms appear to form a vicious cycle. This study compared the degree of stress and impairment of dermatology life quality between patients with AD and healthy controls, and examined for neuropeptides and neurotrophins associated with stress in AD. Questionnaires, comprising five tests evaluating depression, anxiety, interaction anxiousness, private body consciousness, and dermatology life quality, were examined in age- and sex-matched patients with AD (n = 28) and healthy controls (n = 28). Immunohistochemical staining of nerve growth factor, substance P, corticotrophin-releasing factor receptor and neuropeptide Y was performed in the AD-involved and normal skin. Patients with AD showed high scores on all of the questionnaires, including Beck Depression Inventory, state anxiety, trait anxiety, Interaction Anxiousness Scale, Private Body Consciousness subscale, and Dermatology Life Quality Index. All of the parameters, except for Beck Depression Inventory, showed higher values in AD than healthy controls (p < 0.001). Statistically significant correlations were observed between each psychological parameter and Dermatology Life Quality Index. Among the clinical parameters, only pruritus was positively correlated with state anxiety (R = 0.573, p < 0.05) and trait anxiety (R = 0.525, p < 0.05). The Eczema Area and Severity Index score did not show any significant correlations with psychological parameters. Nerve growth factor-reactive cells were observed more abundantly and intensely in both epidermis and dermis of AD involved skin (n = 4) than in healthy controls (n = 3) (p = 0.022 and 0.029, respectively). Also, the number and intensity of neuropeptide Y-positive cells was significantly greater in the entire epidermis of patients with AD than in healthy controls (n = 3) (p = 0.029 and 0.026, respectively). We conclude that anxiety may be associated with the induction of pruritus through neuro-peptide Y and nerve growth factor.

Thymic stromal lymphopoietin–activated invariant natural killer T cells trigger an innate allergic immune response in atopic dermatitis

BACKGROUND Although invariant natural killer T (iNKT) cells have been shown to play a critical role in the pathogenesis of asthma, the role of iNKT cells in atopic dermatitis (AD) has not been well evaluated. OBJECTIVE We investigated whether iNKT cells in patients with AD increased and whether iNKT cells were activated by thymic stromal lymphopoietin (TSLP), which is highly expressed in keratinocytes of AD. METHODS We assessed the population of iNKT cells in PBMCs of patients with AD and healthy controls (HCs) using flow cytometry. Immunohistochemistry was used to evaluate iNKT cells and TSLP expression in AD and HC skin. We also evaluated whether iNKT cells expressed the TSLP receptor, the effects of TSLP on iNKT cells, and iNKT cell-dendritic cell interactions in a TSLP-rich environment. RESULTS There were more iNKT cells among PBMCs of patients with moderate to severe AD than mild AD (P < .05) and HC (P < .001). The number of iNKT cells was significantly larger in severe AD skin lesions than in mild (P < .001) or moderate AD skin lesions (P < .05). TSLP expression increased in lesional skin (P < .001) but not in the sera of patients with AD (P = .729) compared with HC. iNKT cells expressed TSLP receptor protein and mRNA. TSLP directly activated iNKT cells to secrete IL-4 and IL-13, and the concurrent addition of dendritic cells further activated IFN-gamma expression. CONCLUSION Increased iNKT cells activated by TSLP, especially in patients with severe AD, might play an essential role in the innate allergic immune response in AD.

Progressive muscle relaxation therapy for atopic dermatitis: objective assessment of efficacy.

The aims of this study were to validate the efficacy of progressive muscle relaxation (PMR) in patients with atopic dermatitis and to evaluate the serological parameters that may serve as objective measures of the efficacy of PMR. A total of 25 patients with atopic dermatitis were randomly assigned to either a PMR group (n = 15) or a control group (n = 10). Serum levels of nerve growth, neuropeptide Y, and Th2 cytokines (IL-4, IL-5, and IL-13) were measured at baseline and after one month. At baseline, only anxiety was positively correlated with pruritus score (state anxiety: R = 0.496, p = 0.014; trait anxiety: R = 0.423, p = 0.04). Serum levels of neuropeptide Y were inversely related to the State-Trait Anxiety Inventory (STAI) (state anxiety: R = -0.475, p = 0.019; trait anxiety: R = -0.418, p = 0.042) and pruritus scores (R = -0.451, p = 0.035). After one month of PMR therapy, the degree of pruritus and loss of sleep was significantly decreased in the PMR group (p < 0.001), but not among controls. State anxiety scores showed significant improvement after treatment only in the PMR group (p = 0.005). There were no significant changes in the serological parameters in either group. Reductions in Eczema Area and Severity Index (EASI) scores were significant, but similar, in both groups. PMR may be a useful adjunctive modality for the management of atopic dermatitis through the reduction of anxiety. No change was found in biological parameters, but it was observed that neuropeptide Y may be related to high levels of anxiety in atopic dermatitis at baseline.

Corticotropin-releasing hormone downregulates IL-10 production by adaptive forkhead box protein 3–negative regulatory T cells in patients with atopic dermatitis

BACKGROUND Corticotropin-releasing hormone (CRH) is the central regulating hormone of the hypothalamic-pituitary-adrenal axis. CRH also has diverse functional effects in the periphery and is related to the aggravation of several cutaneous diseases; however, the effect of CRH on T cells in patients with atopic dermatitis (AD) has not been well evaluated. OBJECTIVE We investigated whether CRH directly affects peripheral T(H)1, T(H)2, and regulatory T (Treg) cells in patients with AD. METHODS We assessed whether T cells express the CRH receptor protein and mRNA by using flow cytometry, Western blotting, immunofluorescence, immunohistochemistry, and RT-PCR. We evaluated cytokine expression using ELISA after treating the T cells extracted from patients with AD and healthy control subjects (HCs) with CRH. Flow cytometry was then used to evaluate any direct effects of CRH on T(H)1, T(H)2, and Treg cells from patients with AD and HCs. RESULTS T cells from patients with AD expressed significantly lower CRH receptor 1/2 mRNA levels than T cells from HCs. T cells from HCs reacted with different IL-4 and IFN-γ secretions to CRH treatment, whereas T cells from patients with AD did not. IL-10 production was significantly decreased in the supernatants from both the HCs and patients with AD after CRH treatment. CRH upregulated IL-4 production by T(H)2 cells and downregulated IFN-γ production by T(H)1 cells in HCs. CRH also suppressed the production of IL-10 by forkhead box protein 3-negative Treg cells in both groups, but the difference was only significant in patients with AD. CONCLUSIONS CRH-mediated suppression of IL-10 secretion from Treg cells might explain stress-related exacerbations in patients with AD.

Specific Immunotherapy in Atopic Dermatitis

Allergen specific immunotherapy (SIT) using house dust mite (HDM) extracts has been performed mainly with patients of asthma and allergic rhinitis. In the meanwhile, there has been a long debate on the efficacy of SIT in atopic dermatitis (AD) with only a few double-blind placebo-controlled trials. However, several randomized controlled trials of SIT in AD revealed significant improvement of clinical symptoms and also, positive result was shown by a following meta-analysis study of these trials. In order to predict and evaluate the treatment outcome, finding a biomarker that can predict treatment responses and treatment end-points is critical but it is very challenging at the same time due to the complexity of causes and mechanisms of AD. Other considerations including standardization of the easiest and safest treatment protocol and optimizing the treatment preparations should be studied as well. This review summarizes the basics of SIT in AD including the brief mechanisms, treatment methods and schedules, and also highlights the clinical efficacy of SIT in AD along with mild, controllable adverse reactions. Immunologic effects and studies of various biomarkers are also introduced and finally, future considerations with upcoming studies on SIT were discussed.

DAMP molecules S100A9 and S100A8 activated by IL‐17A and house‐dust mites are increased in atopic dermatitis

S100A9 and S100A8 are called damage‐associated molecular pattern (DAMP) molecules because of their pro‐inflammatory properties. Few studies have evaluated S100A9 and S100A8 function as DAMP molecules in atopic dermatitis (AD). We investigated how house‐dust mites affect S100A9 and S100A8 expression in Th2 cytokine‐ and Th17 cytokine‐treated keratinocytes, and how secretion of these molecules affects keratinocyte‐derived cytokines. Finally, we evaluated expression of these DAMP molecules in AD patients. S100A9 expression and S100A8 expression were strongly induced in IL‐17A‐ and Dermatophagoides (D.) farinae‐treated keratinocytes, respectively. Furthermore, co‐treatment with D. farinae and IL‐17A strongly increased expression of S100A9 and S100A8 compared with D. farinae‐Th2 cytokine co‐treatment. The IL‐33 mRNA level increased in a dose‐dependent manner in S100A9‐treated keratinocytes, but TSLP expression did not change. S100A8/A9 levels were also higher in the lesional skin and serum of AD patients, and correlated with disease severity. Taken together, S100A9 and S100A8 may be involved in inducing DAMP‐mediated inflammation in AD triggered by IL‐17A and house‐dust mites.

Increased expression of CC chemokine ligand 18 in extrinsic atopic dermatitis patients.

Background:  Although most patients with atopic dermatitis (AD) show high total and allergen‐specific serum immunoglobulin E (IgE) levels, a small subgroup of AD patients have normal total IgE levels and negative serum allergen‐specific IgE. This subgroup has been termed ‘intrinsic’ AD (IAD) as a counterpart to ‘extrinsic’ AD (EAD). However, the difference of chemokines between IAD and EAD has not yet been evaluated.

The Influence of Pregnancy and Menstruation on the Deterioration of Atopic Dermatitis Symptoms

BACKGROUND Female patients with atopic dermatitis (AD) often experience cutaneous deterioration associated with their pregnancy or menstrual cycle. OBJECTIVE We wanted to determine the prevalence of symptom aggravation as related to pregnancy and the menstrual cycle in female patients with AD. METHODS One hundred female patients with AD were included in the study and interviews were performed. The total IgE level and the Eczema Area and Severity Index score of the patients were retrospectively reviewed. RESULTS Ninety seven patients replied the questionnaire, and among them, 23 patients had completed at least 1 pregnancy. Among the 23 women who experienced pregnancy, 14 (61%) had noticed deterioration of their clinical symptoms during pregnancy. Of the 97 females, 31 (32%) patients had noticed deterioration of their AD as related to their menstrual cycle. For the patients who were sub-grouped as the intrinsic type of AD, the prevalence of symptom aggravation as related to pregnancy was significantly higher as compared to that of the extrinsic type of AD patients (p=0.048). CONCLUSION Of the 97 patients, 45 (46%) females answered that they have experienced deterioration of AD during pregnancy or in relation to their menstrual cycle, and this suggests the relation of a hormonal influence on the clinical manifestations of AD.

Corticotropin‐releasing factor decreases IL‐18 in the monocyte‐derived dendritic cell

Abstract:  Recent evidence suggests that crosstalk between mast cells, nerves and keratinocytes might be involved in the exacerbation of inflammatory conditions by stress, but the mechanism by which this occurs remains unclear. Corticotropin‐releasing factor (CRF), which activates the hypothalamo‐pituitary‐adrenal (HPA) axis under stress, also has pro‐inflammatory peripheral effects. However, there have been no reports about CRF receptor expression and the functional role of CRF in the dendritic cell (DC), which is considered to be the link between allergen uptake and the clinical manifestations of allergic diseases, such as atopic dermatitis. The purpose of this study was to investigate the expression of CRF receptors and the functional role of CRF in the monocyte‐derived DC (MoDC) of atopic dermatitis patients and non‐atopic healthy controls. In this study, mRNAs for CRF‐R1α and 1β, as well as the CRF‐R1 protein, were detected in MoDCs. CRF‐R2α (but not R2β or R2γ) mRNA and the CRF‐R2 protein were present in MoDCs. Exposure of DCs to CRF resulted in a decrease of IL‐18 in both atopic dermatitis patients and non‐atopic healthy controls. However, CRF did not alter the expression of IL‐6, CCL17, CCL18, and CCL22. Therefore, our results demonstrate that CRF could modulate immune responses by acting directly upon DCs.