On the role of the epidermal differentiation complex in ichthyosis vulgaris, atopic dermatitis and psoriasis

Undisturbed epidermal differentiation is crucial for an intact skin barrier function. The epidermal differentiation complex (EDC) is a cluster of genes on chromosome 1q21 encoding proteins that fulfil important functions in terminal differentiation in the human epidermis, including filaggrin, loricrin, S100 proteins and others. Recently, evidence emerged that variation within EDC genes plays an important role in the pathogenesis of three common skin disorders, ichthyosis vulgaris, atopic dermatitis (AD) and psoriasis. Two loss-of-function mutations in the filaggrin (FLG) gene, R501X and 2282del4, were identified as causative for ichthyosis vulgaris in 15 affected European families, and the mode of inheritance was found to be semidominant. As ichthyosis vulgaris and AD often occur concomitantly in affected individuals, these two mutations were subsequently investigated in AD patients and found to be strongly associated with the disease. Following this first report, seven replication studies have been performed that all confirm an association of these two mutations with AD (or AD subtypes) in several European cohorts. Additionally, two unique loss-of-function mutations in the FLG gene were identified in Japanese ichthyosis vulgaris families and found to be associated with AD in a Japanese cohort. Thus, the FLG mutations are among the most consistently replicated associations for AD. Additionally, linkage analysis has suggested that variation within the EDC might also predispose for psoriasis but the exact susceptibility variation(s) have not yet been elucidated. Taken together, these findings convincingly demonstrate the important role of barrier dysfunction in various common skin disorders.     

Well being,psychopathology and coping strategies in psoriasis compared with atopic dermatitis: a controlled study

Background There is a vast literature describing the association between psoriasis, atopic dermatitis (AD) and psychological distress. Some of these studies were uncontrolled and others used non‐dermatological diseases as control, but only a few used chronic skin diseases as controls. Objective To compare well being, psychopathology and coping strategies of psoriatic, AD and healthy controls in a prospective case‐control study. Methods Thirty‐seven psoriatic patients and 31 AD patients were recruited from the Hadassah Ein Karem Hospital, Jerusalem, Israel, outpatient and inward clinic. The participants in the control group were 31 healthy workers and volunteers with no dermatological diseases from Kaplan Hospital, Rehovot, Israel. We used self‐report questionnaires [Mental Health Inventory (MHI) and Adjustment to Chronic Skin Diseases Questionnaire (ACSD)], a projective technique (Hand Test) and assessment tools (Clinical Global Impression). Results Psoriatic patients experienced reduced well being (P = 0.007) and more anxiety and depression (P = 0.018) than normal controls. Psoriatic patients also displayed more severe psychopathology (P = 0.039) a more passive attitude towards life, and loss of meaning in life (P = 0.001) as measured by the projective technique compared with AD patients and normal controls. Conclusions We propose two explanations, derived from the psychological and the psycho‐neuro‐immunological domains. First, greater mental distress in psoriasis is because of the greater stigma it bears compared with AD. Alternatively, we hypothesize that the psoriatic inflammatory process may possibly have a direct central nervous system effect.     

Comparison of psoriasis and atopic dermatitis guidelines—an argument for aggressive atopic dermatitis management

The development of effective systemic treatments has revolutionized the treatment of inflammatory skin diseases. The availability of safe new treatments and the understanding of psoriasis as a systemic disease with comorbidities and effects on quality of life have driven the current aggressive treatment paradigm of psoriasis. Historically the morbidity of atopic dermatitis (AD) has been dismissed, given the perception of AD as “just” a rash. Differences in the guidelines for psoriasis and AD management may suggest variations in the current conceptualization of disease severity and effects on quality of life. Published guidelines from the American Academy of Dermatology for the management of psoriasis and AD were reviewed. We recorded the similarities and differences in disease assessment and therapy. The threshold to use biologic agents for moderate to severe psoriasis highlights the aggressive nature of modern psoriasis treatment. AD guidelines include an assessment of quality of life but do not designate a disease severity threshold for systemic treatment. AD and psoriasis have a tremendous effect on quality of life. The AD guidelines have a less aggressive approach to disease management than the psoriasis guidelines. We should think critically about rapid advancement to systemic agents in AD management, especially now that more and better agents are being developed.     

Pathogenic implication of epidermal scratch injury in psoriasis and atopic dermatitis

Mechanical scratching, a common external stress affecting the skin, is induced by various causes, such as pruritus. Scratch injury to epidermal keratinocytes upregulates the production and release of chemokine (C-C motif) ligand 20 (CCL20) in vitro, which selectively chemoattracts interleukin (IL)-17A-producing immune cells that express chemokine (C-C motif) receptor 6 (CCR6). In IL-17A-dominant psoriasis, scratch-induced CCL20 upregulation and subsequent accumulation of IL-17A-producing immune cells and CCR6⁺ mature dendritic cells may trigger the development of psoriatic lesions, a process known as the Koebner phenomenon. In IL-4/IL-13-dominant atopic dermatitis, pruritus and subsequent scratching are the primary symptoms. Scratch-induced CCL20 production from keratinocytes may explain why IL-17A levels are also elevated in atopic dermatitis. In contrast, mechanical scratching is likely to negatively regulate IL-13 signaling by upregulating the expression of IL-13 receptor α2, which serves as a decoy receptor for IL-13 in keratinocytes. In this review, we summarize current reports on topics related to the pathogenic role of epidermal scratch injury in psoriasis and atopic dermatitis.     

Serum mast cell tryptase is not a useful marker for disease severity in psoriasis or atopic dermatitis

Background  Severity in psoriasis and atopic dermatitis (AD) is commonly assessed with the Psoriasis Area and Severity Index (PASI) and the SCORing Atopic Dermatitis (SCORAD), respectively. Until today no serum marker is available to reflect the clinical scoring in both diseases. As mast cells play an important role in the pathogenesis of early psoriasis and AD, tryptase, a major compound of mast cell granules that is released upon activation, could in principle serve as such a marker.
Objectives  To assess the correlation between serum tryptase and severity of psoriasis and AD as well as the correlation between total IgE levels and severity of AD.
Methods  Serum samples from patients hospitalized for psoriasis and AD were collected at time of admission and time of discharge from hospital. PASI and SCORAD assessments were performed at the same time points. Outpatients presenting with naevi and other benign noninflammatory skin lesions served as control group. Serum tryptase values and total IgE levels of patients with AD were measured using a fluoroenzyme immunoassay technique.
Results  No correlation of serum tryptase level with either the severity of psoriasis or the severity of AD was seen. Total IgE levels in patients with AD at time of admission and discharge from hospital remained the same.
Conclusions  Serum total tryptase did not prove to be a useful tool in assessing severity of psoriasis or AD. Total IgE levels did not correlate with severity of AD.     

Phenotyping of epidermal dendritic cells allows the differentiation between extrinsic and intrinsic forms of atopic dermatitis

Atopic dermatitis (AD) is a clinically characteristic, chronic inflammatory skin disease of unknown origin. IgE-mediated uptake and antigen focusing of environmental allergens by dendritic cells (DCs) is assumed to be a central immunopathogenetic event. A so-called intrinsic type of AD (IAD) has been delineated from the more common extrinsic AD (EAD) by normal serum IgE levels, negative RAST tests and negative immediate-type skin reactions towards environmental allergens. The recently characterized human autoantigen Hom S 1 has been proposed to play a part in the pathogenesis of IAD. OBJECTIVES: To compare clinical and laboratory data between patients with IAD and EAD, and to investigate potential differences in the inflammatory micromilieu of the epidermal compartment in IAD and EAD lesions. METHODS: Epidermal DC phenotyping, a recently validated technique based on the three-colour flow cytometric analysis of Langerhans cells and the so-called inflammatory dendritic epidermal cells from epidermal single-cell suspensions, was performed on samples from 69 patients with AD (seven with IAD and 62 with EAD) and 94 controls. RESULTS: Patients with EAD tended to have an earlier onset of disease but similar disease duration and family history of atopic diseases. Quantitative analysis of CD36 expression on DCs as a marker of inflammation, as well as the percentage of inflammatory dendritic epidermal cells in the CD1a+ epidermal DC pool, indicated a comparable disease activity in IAD and EAD. EAD was characterized by a significantly higher FcepsilonRI expression on the CD1a+ epidermal DCs than IAD. Using the FcepsilonRI/FcgammaRII expression ratio as a disease marker for AD, values for IAD fell below the diagnostic cut-off level of 1.5 for this ratio. CONCLUSIONS: While IAD is clinically similar to EAD, the inflammatory microenvironment in this condition seems different from classical EAD and can be distinguished by phenotyping of epidermal DCs.     

A comparative study of childhood psoriasis and atopic dermatitis and greater understanding of the overlapping condition, psoriasis-dermatitis

Background and Objectives: Psoriasis (Pso) in children may be confused clinically with atopic dermatitis (AD) and, indeed, the two conditions may co‐exist. The aim of this study was to determine historical and clinical features that are different in paediatric Pso and AD and to describe children who have features of both: psoriasis‐dermatitis overlap (PD). Methods: Children with features of psoriasis or eczema, or both, who were referred to paediatric outpatients and/or private rooms were evaluated. Data were collected from 170 consecutive children aged less than 12 years between July 2011 and November 2011. Participants were classified by described criteria as having Pso (n = 64), AD (n = 62) or PD (n = 44). Results: Only 9.4% of children with Pso were correctly diagnosed by the referring doctor. Children with Pso relative to AD were more likely to have had a history of scaly scalp and nappy rash in infancy, a family history of psoriasis, current scalp and periauricular rashes, defined, patchy plaque morphology and papulosquamous rashes not typical of adult psoriasis on extensor elbows and knees. Children with PD had features of both but presented most often as typical paediatric psoriasis combined with flexural eczema. Children with Pso and PD responded well to specific treatment strategies for psoriasis, including potent topical corticosteroids (TCS), calcipotriol and phototherapy. Both Pso and PD tended to require more potent TCS than AD to achieve disease suppression. Conclusion: We found that Pso and PD in children both differ clinically from AD and have identified historical and clinical features that characterise childhood Pso.     

Comparative study of the impact of chronic urticaria, psoriasis and atopic dermatitis on the quality of life

BACKGROUND: A better management of chronic skin disorders (CSDs) requires a knowledge of their impact from the patient's point of view. OBJECTIVES: To determine which aspects of the patient's life are mainly impaired in the different CSDs, and provide comparative references to estimate better the real impact of the different CSDs. PATIENTS AND METHODS: A prospective cross-sectional and matched study of 1356 adult outpatients to compare the health-related quality of life (HRQL) profile in chronic urticaria (466 CU), psoriasis (464 PSO) and atopic dermatitis (426 AD), using the VQ-Dermato, a multidimensional instrument in French validated for CSDs. RESULTS: After adjustment for confounders, HRQL dimensions were differently affected in the three CSDs. The 'physical discomfort' dimension was more degraded in AD and CU than in PSO (P < 0.001), and 'leisure activities' more in PSO than in CU (P < 0.001). 'Self-perception' and 'treatment-induced restrictions' dimensions were much less affected in CU than in PSO and AD (P < 0.001). In PSO, the 'daily living activities' dimension was much less impaired than in CU and AD (P < 0.001). No aspect of HRQL was really spared in AD. CONCLUSIONS: The comparison shows that CU, PSO and AD are characterized by completely different qualitative profiles of impact on HRQL, which are influenced by their clinical characteristics and usual treatment options. It underlines the severe impairment of CU which is often underestimated.     

Oxytocin modulates proliferation and stress responses of human skin cells: implications for atopic dermatitis

The neuropeptide hormone oxytocin (OXT) mediates a wide spectrum of tissue‐specific actions, ranging from cell growth, cell differentiation, sodium excretion to stress responses, reproduction and complex social behaviour. Recently, OXT expression was detected in keratinocytes, but expression of its receptor and function are still unexplored in human skin. Here, we showed that both OXT and its receptor are expressed in primary human dermal fibroblasts and keratinocytes. OXT‐induced dose‐dependent calcium fluxes in both cell types demonstrating that the OXT receptor (OXTR) is functionally expressed. We also showed that OXT decreases proliferation of dermal fibroblasts and keratinocytes in a dose‐dependent manner. In order to further investigate OXT‐mediated functions in skin cells, we performed OXTR knockdown experiments. OXTR knockdown in dermal fibroblasts and keratinocytes led to elevated levels of reactive oxygen species and reduced levels of glutathione (GSH). Moreover, OXTR‐depleted keratinocytes exhibited an increased release of the pro‐inflammatory cytokines IL6, CCL5 and CXCL10. Our data indicate that the OXT system modulates key processes which are dysregulated in atopic dermatitis (AD) such as proliferation, inflammation and oxidative stress responses. Furthermore, we detected a downregulation of the OXT system in peri‐lesional and lesional atopic skin. Taken together, these data suggest that the OXT system is a novel neuroendocrine mediator in human skin homoeostasis and clinically relevant to stressed skin conditions like AD.     

The eczema area and severity index (EASI): assessment of reliability in atopic dermatitis. EASI Evaluator Group

OBJECTIVE: To test the reliability of the eczema area and severity index (EASI) scoring system by assessing inter- and intra-observer consistency. DESIGN: Training of evaluators, application, and assessment over 2 consecutive days. SETTING: An academic center. PATIENTS: Twenty adults and children with atopic dermatitis (AD); cohort 1 (10 patients > or = 8 years) and cohort 2 (10 patients < 8 years). INTERVENTIONS: None. MAIN OUTCOME MEASURE: The EASI was used by 15 dermatologist evaluators to assess atopic dermatitis in cohort 1 and cohort 2 on 2 consecutive days. Inter- and intraobserver reliability were analyzed. RESULTS: Overall intra-evaluator reliability of the EASI was in the fair-to-good range. Inter-evaluator reliability analyses indicated that the evaluators assessed the patients consistently across both study days. CONCLUSIONS: This study demonstrated that the EASI can be learned quickly and utilized reliably in the assessment of severity and extent of AD. There was consistency among the evaluators between consecutive days of evaluation. These results support the use of the EASI in clinical trials of therapeutic agents for AD.     

Expression of TWEAK in normal human skin, dermatitis and epidermal neoplasms: association with proliferation and differentiation of keratinocytes

Background: Tumor necrosis factor‐like weak inducer of apoptosis (TWEAK) has been implicated in the pathogenesis of various inflammatory pathologies and cancer. We aimed to investigate its expression in normal human skin, inflammatory skin diseases and epidermal neoplasms. Methods: Immunohistochemistry for TWEAK was performed in samples of healthy skin, plaque psoriasis, lichen planus, prurigo nodularis, discoid lupus erythematosus, lichen sclerosus, seborrheic keratosis, common warts, actinic keratosis, Bowen's disease, keratoacanthoma and basal and squamous cell carcinoma. Double immunofluorescence was used to investigate co‐localization of TWEAK with cytokeratin‐10 and proliferating cell nuclear antigen (PCNA). Results: TWEAK was robustly expressed in the epidermis of healthy skin and decreased in inflammatory conditions, both in the context of epidermal hyperplasia and atrophy. Decreased TWEAK immunoreactivity was regularly observed in common warts, actinic keratosis and Bowen's disease, particularly in areas of marked proliferation as evidenced by PCNA‐positive nuclei. In squamous cell carcinoma, expression of TWEAK ranged from strong to completely absent, and it mostly corresponded with the expression of cytokeratin‐10. TWEAK was absent in keratoacanthoma and basal cell carcinoma. Conclusions: TWEAK is a constitutively expressed epidermal protein whose downregulation might be an early indicator of disturbed differentiation or pathologic proliferation of keratinocytes that accompany inflammatory and neoplastic skin diseases. Peternel S, Manestar‐Bla?i? T, Brajac I, Prpi?‐Massari L, Ka?telan M. Expression of TWEAK in normal human skin, dermatitis and epidermal neoplasms: association with proliferation and differentiation of keratinocytes.     

Use of proliferation rate, p53 staining and perforating elastic fibers in distinguishing keratoacanthoma from hypertrophic lichen planus: a pilot study

Background: Distinguishing keratoacanthoma (KA) and hypertrophic lichen planus (LP) histopathologically can be difficult, and the challenge is compounded by the tendency of KA to arise in association with hypertrophic LP. Methods: In this pilot study, we compared 18 cases each of KA and hypertrophic LP for proliferation index (MIB‐1), p53 staining and the presence of perforating elastic fibers (elastic Verhoeff‐van Gieson) to determine the utility of these staining modalities in distinguishing KA from hypertrophic LP. Results: Proliferation index in KA compared to hypertrophic LP is 88.2 (mean positive MIB‐1 cells/×100 field), SD = 56.6 and 47.3, SD = 68.4, respectively. p53 staining in KA compared to hypertrophic LP is 251 (mean positive cells/×100 field), SD = 117 and 158, SD = 119, respectively. Fifteen of eighteen (83%) keratoacanthomata demonstrate perforating elastic fibers compared to 1/18 (6%) for hypertrophic LP. Conclusion: Proliferation index is not significantly different between KA and hypertrophic LP (p = 0.059). Expression of p53 is increased in KA over hypertrophic LP (p = 0.024). The presence of perforating elastic fibers in KA is significantly different from hypertrophic LP (p < 0.0001) and suggests that elastic Verhoeff‐van Gieson staining may be of practical benefit in distinguishing KA from hypertrophic LP in difficult cases. Bowen AR, Burt L, Boucher K, Tristani‐Firouzi P, Florell SR. Use of proliferation rate, p53 staining and perforating elastic fibers in the distinction of keratoacanthoma and hypertrophic lichen planus: a pilot study.     

Ciclosporin vs. clobetasol in the topical management of atrophic and erosive oral lichen planus: a double-blind, randomized controlled trial

BACKGROUND: Oral lichen planus (OLP) is a chronic inflammatory disease that can be painful, especially in the atrophic and erosive forms. Several drugs have been used with varying results, but most treatments are empirical, and do not have adequate control groups or correct study designs. OBJECTIVES: To compare the effectiveness of clobetasol and ciclosporin in the topical management of OLP and to evaluate which is more cost-effective and which gives the longest remission from signs and symptoms. METHODS: A randomized, comparative, double-blind study was designed. Forty consecutive patients were divided into two groups to receive clobetasol propionate or ciclosporin for 2 months. Both drugs were placed in 4% hydroxyethyl cellulose bioadhesive gel. Antimycotic prophylaxis was also given. After the end of therapy, patients underwent a 2-month follow-up. RESULTS: Eighteen of 19 clobetasol-treated patients (95%) improved after 2 months of therapy, while 13 of 20 ciclosporin-treated patients (65%) had a clinical response (P = 0.04). Symptomatology improved in 18 clobetasol-treated patients (95%) and in 17 ciclosporin-treated patients (85%) (not statistically significantly different). Two months after the end of therapy, 33% of clobetasol-treated patients and 77% of ciclosporin-treated patients were stable (P = 0.04). Clobetasol produced significantly more side-effects than ciclosporin (P = 0.04). The daily cost of ciclosporin treatment was 1.82 compared with 0.35 for clobetasol therapy. CONCLUSIONS: Clobetasol is more effective than ciclosporin in inducing clinical improvement, but the two drugs have comparable effects on symptoms. Conversely, clobetasol gives less stable results than ciclosporin when therapy ends and has shown a higher incidence of side-effects. The daily cost of ciclosporin is more than five times higher than clobetasol.     

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.