Expression pattern of somatostatin receptor subtypes 1-5 in human skin: an immunohistochemical study of healthy subjects and patients with psoriasis or atopic dermatitis

In psoriasis and atopic dermatitis, the inflammatory events have neurogenic components and the neuropeptides modify the functions of immuno-active cells in the skin. Somatostatin is a neuropeptide with several neuroendocrine and immunomodulating properties and mediates its actions by five distinct subtypes of G-protein-coupled receptors (SSTR1-5). This study describes the distribution of SSTR1-5, analysed with immunohistochemistry, in psoriasis, atopic dermatitis and controls. Normal human skin and lesional skin from patients with psoriasis or atopic dermatitis showed many similarities, but also some differences, as regards SSTR expression. SSTR1-3 were strongly expressed in the epidermis of healthy skin, and in the skin of patients with psoriasis or atopic dermatitis. It is noteworthy that SSTR4 and 5 were strongly expressed in the epidermis of psoriasis patients, but weakly expressed in the epidermis of those with atopic dermatitis and normal skin. The intensity of the staining also varied considerably between the different layers of the epidermis, especially in psoriasis patients. In all cases, the dendritic cells, found mostly in the papillary and upper reticular dermis, showed a strong expression of SSTR1-4, but a weak expression of SSTR5. SSTR1-5 were strongly expressed in the sweat glands in all skin biopsies. Hair follicles and sebaceous glands expressed all five subtypes. Striated muscle fibres showed an intense positive expression of SSTR1-4, but a weak or negative expression of SSTR5. The wide distribution and expression pattern of all five SSTRs in human skin suggest that somatostatin is involved in the interactions between the nervous system and the skin.     

心理应激对特应性皮炎不利影响的内在机制研究概况

研究表明［１］,心理应激状态包括焦虑、抑郁、恐惧、愤怒、激动等情绪会加重特应性皮炎（atopic dermatitis,AD）患者瘙痒的症状。日本Kodama等［2］将经历过阪神大地震的1 457名AD患者按照其受灾的严重程度分为A（严重的房屋财产损毁）、B（轻度的受损）、C（对照组）三组进行研究,结果显示,A组和B组分别有38%和34%的患者出现皮肤症状恶化,而对照组只有7%患者出现相同的进展;相应的63%和48%的A组和B组患者伴随应激性心理状态,而只有19%的C组患者伴随此情绪。Christina等［3］的研究显示,对AD患者进行认知行为压力管理训练可使处于心理应激状态的患者皮质醇觉醒应答下降,并观测到皮炎减轻。此外,经过该训练的患者在急性应激状态下表现得更加平静,唾液皮质醇水平更低。因此,对应激心理状态的控制或许为AD患者提供一条常规治疗以外的新途径……     

Urinary biomarker of oxidative stress in patients with psoriasis vulgaris and atopic dermatitis

Background  The involvement of oxidative stress in the pathogenesis of various skin disorders has been suggested for decades. However, few clinical studies have assessed oxidative stress in skin diseases. The easiest and least invasive method to assess oxidative stress in patients may be the measurement of oxidation products in urine.
Objective  This study aims to assess oxidative stress in psoriasis and atopic dermatitis patients.
Methods  Urine samples were collected from 29 psoriasis patients (25 males and 4 females), 21 atopic dermatitis patients (14 males and 7 females) and 20 healthy controls (16 males and 4 females). The severity and extent of psoriasis and atopic dermatitis was assessed by their area and severity index. We measured nitrate as a metabolite of nitric oxide, malondialdehyde as a major lipid oxidation product, and 8-hydroxydeoxyguanosine (8-OHdG) as a DNA oxidation marker.
Results  Urinary nitrate and 8-OHdG levels, but not malondialdehyde, were significantly higher in psoriasis patients than those in healthy controls. On the contrary, only urinary nitrate level was significantly higher in atopic dermatitis patients than those in healthy controls. The severity and extent of both psoriasis and atopic dermatitis significantly correlated with urinary nitrate level and malondialdehyde level, but it did not correlate with urinary 8-OHdG level.
Conclusions  Measurement of these three urinary oxidative products is non-invasive. Above all, measurement of urinary nitrate may be most useful in the clinical assessment of oxidative stress in both psoriasis and atopic dermatitis patients. There is a possibility that urinary 8-OHdG level may indicate the different pathogenesis between psoriasis and atopic dermatitis.     

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.     

特应性皮炎患者血中结合珠蛋白含量的检测及临床意义

目的：检测特应性皮炎（AD）患者血中结合珠蛋白（Hp）含量，并分析与病情严重程度之间的相关性。方法：采用醋酸纤维素薄膜电泳后比色的方法检测124例特应性皮炎患者（其中轻度40例、中度44例、重度40例）和134例正常对照者血中Hp水平。结果：与正常对照组相比，患者组血中Hp含量明显增高（P〈0．001），其中病情中度和重度患者组均显著增高（P〈0．05），轻度组增高无统计学意义。Hp含量与AD病情严重程度呈正相关（P〈0．001）。结论：Hp可能通过一种负反馈机制来抑制皮损局部的过度炎症反应，而参与了AD患者体内的免疫调节和抗炎作用。     

The role of selected neuropeptides in pathogenesis of atopic dermatitis

Background Atopic dermatitis (AD) is an inflammatory skin disease of a chronic course. The role of neuropeptides in pathogenesis of this disorder is probably not crucial; however, there is evidence that these substances influence the development and course of AD. Objective The aim of this study was to evaluate the plasma level of substance P, neuropeptide Y (NPY) and calcitonin gene related peptide (CGRP) in AD patients during exacerbation and remission of the disease. Material and methods Forty‐nine patients with AD, aged 17 to 56 years, participated in the study. Among this group, there were 25 males (51%) and 24 females (49%). The disease lasted from 1 to 55 years. The severity of the disease was assessed with SCORAD index. The severity of pruritus was evaluated with Visual Analog Scale and a specially designed questionnaire. Neuropeptides plasma level was detected with radioimmunoassay. Results Substance P plasma level in AD patients during exacerbation and remission was significantly higher than in the control group. There was a negative correlation between substance P plasma level and total IgE level. CGRP plasma level during exacerbation of AD was significantly lower than in healthy controls and increased in the remission. Significantly higher CGRP concentration was observed in patients suffering from severe pruritus; however, both in patients with more and less severe pruritus, CGRP plasma level was lower than in controls. Higher CGRP plasma level was also observed in patients with more severe disease. NPY plasma level in patients with AD was significantly increased both during exacerbation and remission. During remission of AD, NPY concentration was higher than during exacerbation.     

迟发型特应性皮炎的研究进展

特应性皮炎（AD）是一种炎症性皮肤病,与皮肤屏障功能受损密切相关。遗传因素、生活方式、环境因素的暴露都可导致该病的发生。尽管AD常见于婴幼儿,仍有成年后首次出现AD症状,被称为迟发型AD（AOAD）。与儿童期始发的AD相比,AOAD在分型、免疫学机制及与其他疾病的关联方面都存在着显著的差异。皮损分布与婴幼儿期初发的AD相似,但以亚急性和慢性皮炎为主要表现,呈现干燥的、肥厚的皮炎损害,少见渗出。Th1/Th2失衡及抗原提呈细胞的功能亢进是AD发生的免疫学基础。FLG基因突变会影响AD的发生,IL-13升高使FLG存在获得性的表达缺陷仅发生于成年人,提示了AOAD不同于婴幼儿期初发并迁延至成年期的AD。感染、皮肤及肠道菌群改变、吸烟等均可成为诱发AOAD的重要因素,因此在诊断AOAD时询问相关疾病史和吸烟史有助于AOAD的诊断。     

Rarity of hypertension in adult patients with atopic dermatitis

BACKGROUND: Patients with atopic dermatitis show a tendency for vasoconstriction of the small vessels in the skin. As peripheral vasoconstriction contributes to the cause of hypertension, it is natural to suppose that blood pressures might be on the high side in adult patients with atopic dermatitis. In the literature, however, there was little information on the subject. OBJECTIVES: To study the incidence of hypertension in adult patients with atopic dermatitis. PATIENTS/METHODS: Blood pressure was measured in 521 adult patients with active atopic dermatitis (235 males; 286 females) aged 30-59 years, and 87 adults with "healed" atopic dermatitis (26 males; 61 females) aged 34-52 years. The blood pressures were classified as definite hypertension, borderline hypertension or normal blood pressure. RESULTS: In those patients aged 30-39 years with active atopic dermatitis, the incidence of definite hypertension in the male patients and the female patients was 1.1% and 1.6%, respectively. The incidence remained almost at a plateau for the 30-39-year-old age group through to the 50-59-year-old age group, in both the male and female patients. There was no difference in the incidence of definite hypertension between patients with severe dermatitis and patients with mild dermatitis. Adult patients with "healed" atopic dermatitis also showed a low incidence of definite hypertension. CONCLUSIONS: These findings indicate that hypertension is rare in adult patients with atopic dermatitis. It is most probable that the rarity of hypertension is a primary feature of the disease.     

Anxiety accelerates T-helper 2-tilted immune responses in patients with atopic dermatitis

BACKGROUND: Stress, which mediates anxiety, worsens skin symptoms in patients with atopic dermatitis (AD). The contribution of anxiety to immune dysfunction, which plays a critical role in the pathogenesis of AD, requires clarification. OBJECTIVES: To examine the relationship between anxiety and atopy-relevant immune function in AD. METHODS: Eighty-five patients with AD and 58 normal individuals without a history of allergic disorders were enrolled in this study. To assess anxiety, the state-trait anxiety inventory was completed for both groups. In the AD group, measurements were made of SCORAD scores, serum IgE levels, itching (visual analogue scale), blood eosinophil count and T-helper (Th) 1/Th2 ratio in the peripheral blood. RESULTS: Anxiety was significantly higher among the subjects with AD than the normal subjects, and trait anxiety (TA) was higher than state anxiety (SA) in the AD group. Serum total IgE levels were correlated positively with TA and the TA/SA ratio and inversely with SA, and the Th1/Th2 ratio was correlated inversely with TA and the TA/SA ratio. CONCLUSIONS: The patients with AD had higher anxiety levels than normal individuals, and those with a stronger perception of TA than SA showed enhanced serum IgE synthesis and Th2 shifting.     

Temperament and character dimensions in patients with atopic dermatitis

The aim of this study was to assess the personality traits of young male patients with atopic dermatitis (AD), and to examine the correlations between temperament and character dimensions with clinical and other psychological factors. Fifty young adult male AD patients and 83 healthy controls were examined using the temperament and character inventory, the Beck depression inventory and the state-trait anxiety inventory. The AD patients scored higher on harm avoidance and lower on reward dependence, self-directedness and cooperativeness than the healthy controls. The illness duration and anxiety correlated negatively with the self-directedness score, and depression correlated negatively with reward dependence and the persistence scores in AD patients. These results suggest that AD patients have distinctive temperament and character dimensions compared to healthy controls. Moreover, illness duration and anxiety might be associated with some personality problems, and some temperament dimensions (e.g. reward dependence, persistence) may be linked to depressive symptoms in AD patients.     

Effectiveness of dupilumab in pediatric patients with a nummular phenotype of atopic dermatitis

The nummular phenotype of atopic dermatitis is clinically characterized by pruritic, coin-shaped plaques that are frequently recalcitrant to treatment. In this study, a retrospective chart review was conducted to evaluate the effectiveness and safety of dupilumab in children with nummular lesions of dermatitis. Twelve out of 14 patients demonstrated significant clinical improvement at a median time of 2.5 months (interquartile range, 1–4) after dupilumab initiation. A single case of paradoxical psoriasiform eruption was the only side effect reported in our cohort.     

Leukoderma in patients with atopic dermatitis

Atopic dermatitis (AD) is occasionally associated with vitiligo, however, the incidence and conditions of vitiligo or leukoderma, and the characteristics of concurrent AD, remain unclear. We conducted a prospective observational study to investigate the leukoderma‐related clinical manifestations and bioparameters of AD. Because vitiligo in AD lesions is occasionally associated with inflammation, we used leukoderma in this study. Enrolled were all AD patients who had been followed up in our AD outpatient clinic and visited within the previous 4 months. During this period, we carefully inspected whether the patients had leukoderma. Eight of 52 patients had leukoderma (15.4%) and were designated as the leukoderma group, and the remaining 44 patients comprised the non‐leukoderma group. While the ages were statistically not different between the two groups, female preponderance was significantly observed in the leukoderma group. The leukoderma patients tended to have higher values of SCORAD, CCL17/thymus and activation regulated chemokine and lactate dehydrogenase than the non‐leukoderma patients. The leukoderma group was also characterized by a lower frequency of allergic rhinitis and a higher frequency of prurigo lesions. Thus, despite the possession of high AD severity, the leukoderma patients may possibly retain a relatively T‐helper 1‐skewing state in relation to the development of leukoderma and less association with rhinitis.     

213例儿童特应性皮炎临床及病理特点分析

本研究对213例AD儿童患者临床及组织病理学特点进行分析,患儿平均发病年龄为0.88±1.73岁,约85.9%的患者表现为慢性皮炎;约78.9%的患者有个人或家族遗传过敏史。组织病理学示角化过度、微水疱形成、棘层肥厚、海绵水肿、浅层血管周围炎症及嗜酸性粒细胞浸润。     

Coping as mediator of the relationship between stress and itch in patients with atopic dermatitis: a regression and mediation analysis

Even though it has been shown that stress and itch are associated in patients with atopic dermatitis (AD), it remains unclear whether this relationship occurs due to certain coping strategies being activated under stress. Therefore, this study investigates the role of coping as possible mediating factor between stress and itch in 31 patients with AD. Coping and itch were assessed by self‐reported measures, while stress was measured both by a validated questionnaire and by a physiological stress marker, the postawakening cortisol. Using a regression and a mediation analysis, this study showed a relationship between perceived stress and itch (corrected R² = 0.21), which was fully mediated by negative itch‐related cognitions. 62.3% of the variance of itch intensity could be explained by negative itch‐related cognitions. This finding helps to explain the positive effects of cognitive restructuring in the treatment of chronic itch.     

Low risk of melanoma in patients with atopic dermatitis

Background There is a possible association between atopy and cancer based on the concept of atopic diseases as a hyper‐reactive state of the immune system. Melanoma is an immunogenic tumour, and since patients with atopic dermatitis (AD) are subjected to local and systemic immunosuppressives, it would be expected to find an influence of AD on the melanoma risk. There is a positive correlation between the number of naevi and melanoma risk, and children and adults with AD have fewer naevi than controls although many patients receive ultraviolet treatment. Objective This study aims to investigate the melanoma risk in a retrospective cohort of AD patients compared with the population. Study design 6280 AD patients born 1935–1979 visited five Dermatology clinics during 1986–2004. Mean follow‐up time was 36.7 years (SD 6.9) corresponding to 230 742 person‐years at risk. The cohort file was linked to the National Cancer register. Results Six AD patients with melanoma were identified, and the Poisson regression analysis adjusted for age group, sex and year resulted in an incidence rate ratio of 0.49 (95% confidence interval: 0.27–1.35, P = 0.08) for the AD group compared with the total population in the region. Conclusion A low risk to develop melanoma was found in AD patients. However, the results must be interpreted with caution since the small number of expected cases of melanoma makes the risk estimate sensitive to chance effects. We hypothesize that formation of naevi and progression to melanoma is counteracted by the inflammatory process in the skin of AD patients.     

Calcitonin gene-related peptide modulates interleukin-13 in circulating cutaneous lymphocyte-associated antigen-positive T cells in patients with atopic dermatitis

Background  Neuropeptides (NPs) may play an important role in the pathogenesis of atopic dermatitis (AD) by regulating immune responses and contributing to the cross-talk between the immune and nervous systems.
Objectives  To assess the ability of NPs to influence interleukin (IL)-13 and interferon (IFN)-γ production and the expression of the activation marker HLA-DR in skin memory T cells [cutaneous lymphocyte-associated antigen (CLA)+ T cells] from patients with AD with severe, chronic lesions and intense pruritus, and from nonatopic controls.
Methods  Cells were cultured in the presence and absence of different NPs, calcitonin gene-related peptide (CGRP), somatostatin (SOM) and substance P (SP). IL-13 and IFN-γ production and HLA-DR expression were measured in both CLA+ and CLA− T-cell subsets by flow cytometry.
Results  CGRP increased IL-13 production in peripheral blood mononuclear cells from patients with AD ( P  <   0·05), with no changes detected in the presence of SOM or SP. These patients with AD had a lower expression of CGRP receptor compared with controls ( P  <   0·05). Memory T cells incubated with CGRP also showed an increase in IL-13 ( P  <   0·05) and HLA-DR ( P  <   0·05) in CLA+ T cells from patients with AD compared with controls, but not in CLA− T cells. Patients with a higher production of IL-13 were those with higher total IgE and percentage of skin area involved. Furthermore, the IL-13/IFN-γ ratio was increased in patients with AD after cells were cultured with CGRP ( P  <   0·05).
Conclusions  Our results suggest an immunomodulatory role of CGRP towards a Th2 pattern in CLA+ T cells, which may contribute to exacerbating clinical symptoms in patients with AD.     

Dermatological future of european patients with atopic dermatitis

Background  The dermatological becoming of children presenting with atopic dermatitis (AD) is not well known.
Objective  We performed a study on the presence of AD and other dermatological diseases in subjects with a previous history of AD.
Methods  An opinion poll was conducted in eight countries through a telephone interview: Belgium, France, Germany, Greece, Italy, Portugal, Spain and Switzerland.
Results  Among 4369 interviewees, 12.25% declared a history of AD in infancy and 12.4% declared to suffer from a dermatological disease (27% of patients had a history of AD and 10.3% did not have it). Current declared cases of atopic eczema or contact eczema were more frequent in patients with previous history of AD (39.3% vs. 21.5%), whereas these patients appeared less affected by rosacea (2.9% vs. 7.9%). Some differences were observed between different countries.
Conclusion  The main interests of this study are the large number of subjects, originating from eight different countries, and its focus on the dermatological future of patients with AD, which is not limited to AD itself.     

Biologics in atopic dermatitis

Atopic dermatitis (AD) accounts for a significant share of chronic inflammatory skin disorders. There is a niche for the development of biologics to treat recalcitrant autoinflammatory stage AD seen mostly in adults. The heterogeneity of patient response to various existing biotherapies points to involvement of various immune responses and suggests that therapies must preferably target early development of allergen‐specific B‐ and T‐cell clones. In addition to immune targets, tissue factors that help restore the normal epidermal environment constitute interesting therapeutic tools. Several approaches are needed to find the appropriate targets in a field where so many have been investigated without definitive proof of concept for human systemic therapy. The keys to success are probably (1) to influence the inflammatory skin pattern towards less pruritogenic effects, requiring us to better understand pruritogenic inflammation and (2) to limit the amplification loop of disease by attacking abnormal regulatory mechanisms which perpetuate skin autoinflammation.