Lesional elastase activity in psoriasis, contact dermatitis, and atopic dermatitis.

Human leukocyte elastase (HLE) is a broad spectrum serine protease derived from neutrophils and macrophages. We developed an assay to determine HLE activity on the skin surface in patients with inflammatory skin diseases. HLE activity was absent in the skin of healthy controls. A massive increase of HLE activity was found in lesional skin of psoriasis (31 times), allergic contact dermatitis (55 times), and atopic dermatitis (35 times), but not in uninvolved skin of diseased patients. Therefore, this assay appears to represent a useful biochemical marker of epidermal inflammation. The presence of proteolytically active HLE in diseased epidermis, which is known to contain specific inhibitors of this enzyme, suggests a pathophysiologic role of this enzymatic activity in psoriasis, contact dermatitis, and atopic dermatitis.     

Periorbital dermatitis: Causes,differential diagnoses and therapy

Periorbital dermatitis is common and frequently difficult to treat. Patients with periorbital dermatitis often suffer severely because their disease is in such a visible location. Because of the variety of clinical appearance, the differential diagnostic considerations are often difficult. We examined the causes of periorbital dermatitis and compared the data of 88 patients from the Department of Dermatology, University Hospital Erlangen to those of the German IVDK (Information Network of the Departments of Dermatology). Between 1999 and 2004, predominant causes of periorbital dermatitis were allergic contact dermatitis (Erlangen 44 %, IVDK 32 %), atopic eczema (Erlangen 25 %, IVDK 14 %), airborne contact dermatitis (Erlangen 10 %, IVDK 2 %) and irritant contact dermatitis (Erlangen 9 %, IVDK 8 %). Less frequent causes for secondary eczematous periocular skin lesions were periorbital rosacea, allergic conjunctivitis or psoriasis vulgaris. Female gender, atopic skin diathesis and age of 40 years and older were identified as risk factors for periocular dermatitis. Common elicitors of periorbital allergic contact dermatitis were leave‐on cosmetic products (face cream, eye shadow) and eye drops with the usual allergens being fragrances, preservatives and drugs. Exact identification of relevant contact allergens and allergen elimination are essential for successful treatment. Calcineurin inhibitors are the first‐line therapy for facial atopic eczema. They may be also effective in periocular eczematous lesions of other origins although they are not approved for such use.     

IL6Rα function in myeloid cells modulates the inflammatory response during irritant contact dermatitis

Irritant contact dermatitis (ICD) is characterized by epidermal hyperplasia, infiltration of leucocytes into lesional skin and inflammatory cytokine release. The cellular infiltrate during ICD comprises primarily cells of the myeloid lineage. Our group has previously shown that the cytokine IL‐6 confers a protective effect to lesional skin during ICD. How IL‐6Rα function in myeloid cells is involved in the inflammatory response during ICD is, however, unknown. In the present study, utilizing a chemical model of ICD, it is shown that mice with a myeloid‐specific knockout of the IL‐6Rα (IL‐6Rα^Δmyeloid) display an exaggerated inflammatory response to benzalkonium chloride (BKC) and Jet propellant‐8 (JP8) fuel, two well‐characterized irritants relative to littermate control. Results from immunohistochemical and flow cytometric analyses revealed that IL‐6Rα^Δmyeloid mouse skin displayed increased epidermal hyperplasia and inflammatory monocyte influx into lesional skin but lower numbers of resident macrophages relative to littermate controls after irritant exposure. Multiplex immunoassay revealed significantly higher levels of pro‐inflammatory cytokines IL‐1α and TNF‐α, but reduced expression of chemokine proteins including CCL2‐5, CCL7, CCL11, CXCL1 and CXCL10 in IL‐6Rα^Δmyeloid mouse skin relative to littermate control following irritant exposure. These results highlight a previously unknown role of IL‐6Rα function in myeloid cells in modulating the inflammatory response and myeloid population dynamics during ICD.     

Optical coherence tomography in contact dermatitis and psoriasis

Optical coherence tomography (OCT) is a new noninvasive imaging technique. In this study, it was used for the investigation of contact dermatitis and psoriasis. In these common inflammatory skin diseases the value of OCT for quantification and monitoring of the changes in comparison with other bioengineering methods was evaluated. Repeated measurements were performed in healthy volunteers after experimental induction of irritant contact dermatitis and in patients with psoriasis. In the OCT images, the thickness of the epidermis and the signal attenuation coefficient in the upper dermis were evaluated. The changes were compared with measurements of transepidermal water loss, hydration, skin colour and surface roughness, and with high-frequency ultrasound measurements. In irritant dermatitis and psoriasis, thickening of the epidermis was detected and could be monitored over time. The light scattering in the upper dermis was lower than in healthy skin. This was interpreted to be due to the inflammation and oedema, leading to a less-dense arrangement of the collagen fibres. The changes in the OCT images did not significantly correlate with the changes shown by the other methods. OCT is an interesting tool for investigation of inflammatory skin diseases. It is a simple method for determination of epidermal thickness and therefore provides, in addition to other methods, information on the severity of the disease and on treatment effects.     

Phenotypes of atopic dermatitis

Atopic dermatitis (AD) is a common disease affecting both children and adults. AD develops from a complex interplay between environmental, genetic, immunologic and biochemical factors. Genetic factors predispose atopic subjects to mount exaggerated Th2 responses and to a poorly efficient epidermal barrier, which may be sufficient to initiate inflammation in the skin and may favor allergic sensitization. Thus AD can present with different clinical pheno‐types. AD is classically distinguished into an intrinsic and extrinsic form, which are clinically identical but the former lacks high level specific IgE and is not associated with respiratory atopy. Although in many cases AD presents with monotonous eczematous lesions on the face, neck and skin folds, it may also present with other features. Very common is nummular eczema, which in many instances may be the dominant expression of AD. In other patients, AD affects limited areas (periorificial eczema, nipple eczema, cheilitis, hand eczema) or its main presentation is with excoriated papules and nodules (atopic prurigo). In conclusion, AD is a multifaceted disease affecting patients with epidermal barrier dysfunction and dry and sensitive skin. The recognition of the less common AD phenotypes is essential for proper patient management.     

IgE-positive epidermal Langerhans cells in allergic contact dermatitis lesions provoked in patients with atopic dermatitis

Summary To see whether or not IgE-bearing epidermal Langerhans cells are specific to skin lesions of atopic dermatitis (AD), we performed immunohistochemical and immunoelectron microscopic examinations of dinitrochlorobenzene (DNCB) contact dermatitis lesions provoked in uninvolved skin of eight patients with AD. In all of the eight examined, IgE-positive epidermal Langerhans cells were observed in the DNCB dermatitis lesions. Typical staining of anti-IgE was absent in the epidermis of normal-appearing skin of five patients with AD. Thus, it is likely that IgE positive epidermal Langerhans cells non-specifically occur in different eczematous diseases provoked in patients with AD.     

Anogenital allergic contact dermatitis, the role of spices and flavour allergy

Background: In patients with vulval or anogenital dermatitis, irritant contact dermatitis is more common than allergic contact dermatitis. The reported frequency and relevance of contact sensitivity in anogenital dermatitis varies greatly. Objective: To determine the frequency and relevance of contact sensitization in a Dutch group of female patients with chronic anogenital complaints. Methods: We reviewed patch test results of 53 women with chronic anogenital complaints, with sole vulval symptoms in 29 women and sole perianal in 5, in whom inflammatory skin diseases like lichen sclerosus, lichen planus, psoriasis, as well as infectious diseases were unlikely or excluded as a cause of their symptoms. All women were tested with the European baseline series plus additional test series according to their personal history. Results: Thirty‐five patients (66%) showed one or more positive test reactions. Seven of these patients (20%) had one or more clinically relevant positive reactions, most often to flavours and spices. Conclusion: A considerable number of patients with anogenital dermatitis have a contact sensitization. Clinically relevant reactions were mainly found to spices and flavours. This is in contrast to the data reported in the literature that shows most contact allergies in vulval patients to ingredients of topical medication.     

Alterations of epidermal lectin binding sites in acute contact dermatitis

We investigated alterations of epidermal lectin binding sites, as well as of pemphigus and bullous pemphigoid antigens, in 28 human patch test reactions, both allergic (nickel, formaldehyde, N,N'-1,3-dimethylbutyl-N'-phenylenediamine) and irritant (sodium lauryl sulfate). The epidermal reactivity to a panel of lectins and human antisera to pemphigus vulgaris and bullous pemphigoid antigens was compared with samples obtained from normal skin and from skin under tape occlusion. We observed selective perturbations of lectin and antibody binding in acute contact dermatitis, whether allergic or irritant. The main findings were a loss of terminal sialic acids and longer bi- and triantennary mannosyl residues as well as a loss of pemphigus vulgaris antigen. The only difference between allergic and irritant patch test reactions was in topography of loss of WGA binding sites: in the former, it was most pronounced in the lower and middle epidermis, whereas in the latter it was seen in the uppermost subcorneal layers. Our findings support a common pathway of cell membrane alterations of keratinocytes in acute contact dermatitis.     

The association of smoking with contact dermatitis and hand eczema – a review

Given the high prevalence of allergic contact dermatitis (ACD), irritant contact dermatitis (ICD), hand eczema (HE), and smoking, and the impact that smoking has on skin disease, the authors reviewed the existing literature to assess the association between smoking and contact dermatitis or hand eczema. Using the PubMed and SCOPUS databases, a literature search identified articles related to allergic contact dermatitis, irritant contact dermatitis, and hand eczema and a possible association with smoking. The search period included articles prior to and including April 2016. Seven of eight articles described a positive relationship between smoking and allergic or irritant contact dermatitis, while nine of nineteen articles found a positive association between smoking and hand eczema. Published studies document that smoking may be an important risk factor for both allergic and irritant contact dermatitis as well as hand eczema.     

Evaluation of efficacy of a skin lipid mixture in patients with irritant contact dermatitis, allergic contact dermatitis or atopic dermatitis: a multicenter study

Disturbances of skin barrier function occur in several skin diseases, e.g., atopic dermatitis (AD), irritant/allergic contact dermatitis (ICD, ACD). Skin barrier damage triggers the production of cytokines that stimulate lipogenesis which may also cause inflammatory processes. The aim of this study was to evaluate the efficacy of a topical skin lipid mixture in the treatment of ICD, ACD and AD. 580 consecutive patients suffering from ICD, ACD or AD were treated with a skin lipid mixture containing ceramide-3 and patented nanoparticles. Patients received the lipid mixture alone or in combination with topical corticosteroids until clearance or for 8 weeks. Both treatment groups statistically improved all parameters considered at week 4 and 8 as compared to baseline. Between the 2 treatment groups, there was a statistically significant difference in favour of combined therapy for (ICD, ACD, AD, respectively): erythema, pruritus and overall disease severity; erythema and pruritus; erythema, pruritus, fissuring and overall disease severity. No statistically significant difference was found for (ICD, ACD, AD, respectively): dryness, scaling and fissuring; scaling, fissuring and overall disease severity; dryness and scaling. Between the 2 ACD treatment groups, there was a statistically significant difference in favour of the skin lipid mixture for dryness. In conclusion, the study shows that balanced lipid mixtures are effective in improving barrier properties and the clinical condition of the skin in contact dermatitis.     

Occupational contact dermatitis in nurses with hand eczema

Occupationally related dermatitis is a common problem in nurses, who are exposed to a wide variety of allergenic and irritant substances. In a group of 44 nurses with hand dermatitis (40 female, 4 male), 18 were thought to have a predominantly allergic contact dermatitis, 15 an irritant dermatitis, 7 other form of eczema, 3 atopic dermatitis and one pompholyx. 10 of the 15 irritant cases were diagnosed as occupational. Of the 18 patients with allergic contact dermatitis, the allergens were thought to be occupationally relevant in 8 cases. In 6 of these 8 the dermatitis was due to natural rubber latex (3) or other rubber chemicals (3). 2 had additional evidence of immediate-type hypersensitivity to natural rubber latex (one was patch test allergic to latex, the other to thiuram mix). Natural rubber latex allergy, both delayed and immediate, is a significant problem, and nurses at risk should be tested for both types of hypersensitivity, as well as being patch tested to standard, rubber and medicaments series.     

Strong induction of AIM2 expression in human epidermis in acute and chronic inflammatory skin conditions

Absent in melanoma 2 (AIM2) is a double‐stranded DNA receptor, and its activation initiates an interleukin‐1 beta processing inflammasome. AIM2 is implicated in host defense against several pathogens, but could hypothetically also contribute to autoinflammatory or autoimmune diseases, such as is the case for NLRP3. Using thoroughly characterised antibodies, we analysed AIM2 expression in human tissues and primary cells. A strong epidermal upregulation of AIM2 protein expression was observed in several acute and chronic inflammatory skin disorders, such as psoriasis, atopic dermatitis, venous ulcera, contact dermatitis, and experimental wounds. We also found AIM2 induction by interferon‐gamma in submerged and three‐dimensional in vitro models of human epidermis. Our data highlight the dynamics of epidermal AIM2 expression, showing Langerhans cell and melanocyte‐restricted expression in normal epidermis but a pronounced induction in subpopulations of epidermal keratinocytes under inflammatory conditions.     

Distinct molecular signatures of mild extrinsic and intrinsic atopic dermatitis

Atopic dermatitis (AD) is a common inflammatory skin disease with underlying defects in epidermal function and immune responses. In this study, we used microarray analysis to investigate differences in gene expression in lesional skin from patients with mild extrinsic or intrinsic AD compared to skin from healthy controls and from lesional psoriasis skin. The primary aim was to identify differentially expressed genes involved in skin barrier formation and inflammation, and to compare our results with those reported for patients with moderate and severe AD. In contrast to severe AD, expression of the majority of genes associated with skin barrier formation was unchanged or upregulated in patients with mild AD compared to normal healthy skin. Among these, no significant differences in the expression of filaggrin (FLG) and loricrin at both mRNA and protein level were found in lesional skin from patients with mild AD, despite the presence of heterozygous FLG mutations in the majority of patients with mild extrinsic AD. Several inflammation‐associated genes such as S100A9, MMP12, CXCL10 and CCL18 were highly expressed in lesional skin from patients with mild psoriasis and were also increased in patients with mild extrinsic and intrinsic AD similar to previous reports for severe AD. Interestingly, expression of genes involved in inflammatory responses in intrinsic AD resembled that of psoriasis more than that of extrinsic AD. Overall, differences in expression of inflammation‐associated genes found among patients with mild intrinsic and extrinsic AD correlated with previous findings for patients with severe intrinsic and extrinsic AD.     

Interleukin-4 and the interleukin-4 receptor in allergic contact dermatitis

Cutaneous immune responses involving T helper (TH) type 1 (TH1) and type 2 (TH2) T cells, characterised by secretion of interferon-γ (Ifn-γ) and interleukin-4 (IL-4), respectively, have both been reported in allergic contact dermatitis (ACD). We used immunohistochemistry to localize expression of IL-4 in ACD lesions and unaffected skin. Atopic dermatitis (AD) and psoriasis biopsies provided positive and negative IL-4 immunoreactivity controls. To investigate the rôle of IL-4 in ACD, we investigated expression of IL-4 receptors in ACD, AD and psoriatic skin. IL-4 immunoreactivity was found in cells in the dermal infiltrate in 3 out of 7 ACD lesions, but not in unaffected skin from these patients. IL-4 immunoreactivity was found in the dermal infiltrate of all lesional and unaffected AD biopsies, but in none of the psoriatic biopsies. IL-4 receptor α chain immunoreactivity, associated with dermal mast cells, was found in all patients. Local expression of IL-4 in ACD indicates either TH2 or TH0 immunoregulation in some allergic contact dermatitis lesions. Our findings do not support exclusive TH1 or TH2 cutaneous immune responses in ACD. Expression of IL-4 receptors by cutaneous mast cells provides a route through which local effects of IL-4 might be mediated.     

Atopic dermatitis in older patients: particular points

We review the particular characteristics of atopic dermatitis (AD) in adult life, and compare findings with those of AD in childhood. AD affects 1–3% of adults world‐wide, and can present as adult‐onset AD, or as infantile/childhood AD that persists, or recurs after many years. Eczema in adults usually exists for years, compromising quality of life, sex life and occupational choices. The flexural areas, shoulders, head‐and‐neck, and hands are typically affected. In elderly adults, eczematous erythroderma is common. The intrinsic (non‐IgE‐allergic) eczema subtype affects 5–15% of cases. Classical food allergy has a low importance, although non‐IgE‐mediated and pseudoallergic reactions can cause eczema. Sensitivity to aeroallergens, especially dust mite, is demonstrated in the majority of adult AD patients, including elderly adults, by immunoglobulin E‐mediated tests and/or atopy patch tests. Occupational allergic and irritant contact dermatitis is increased. In adults, as in children, Staphylococcus aureus colonization is very high, whereas adult skin is more heavily colonized with Malassezia yeasts. Immediate and delayed sensitization to Malassezia sympodialis is specific for intrinsic and extrinsic AD, occurring especially in head‐and‐neck eczema. Concerning therapy, older patients are prone to certain adverse drug effects. In conclusion, differences exist between childhood and adult disease. As we should be seeing more adults with AD in the future, there is a need for more clinical and immunological studies in older patients.     

Antigen-presenting cells and keratinocytes express interleukin-12 in allergic contact dermatitis

Interleukin‐12 (IL‐12) has previously been suggested as playing a major rôle in the activation of cytotoxic lymphocytes. Recent reports indicate that cytotoxic CD8+ cells are critically involved in the elicitation phase of contact hypersensitivity reactions. In this study, the in situ expression of IL‐12 was investigated in normal human skin and in allergic contact dermatitis by immunohistochemistry. Skin biopsy specimens were obtained from allergic patch test reactions after 3 days, and from normal skin in 8 subjects. In contrast to normal skin, a strong enhancement of IL‐12 immunoreactivity was observed in the mononuclear cell infiltrate of allergic contact dermatitis. IL‐12 immunoreactivity was mainly located in the cytoplasm of dermal dendritic cells and macrophages as well as of some Langerhans cells. IL‐12‐positive cells were often found in close apposition to lymphocytes. Furthermore, positive immunostaining was also detected in keratinocytes at sites of marked exocytosis and spongiosis in the epidermis. In conclusion, the enhanced in situ expression of IL‐12 may contribute to the activation of cytotoxic lymphocytes and thereby represent an important factor in the pathogenesis of contact hypersensitivity reactions in humans.     

Lack of effect of ustekinumab in treatment of allergic contact dermatitis

Background. Allergic contact dermatitis is a chronic inflammatory T cell mediated disease that can be recalcitrant to existing treatments. Ustekinumab is a monocloncal antibody blocking IL‐12 and IL‐23, shown to be effective and safe for patients with psoriasis. Despite both IL‐12 and IL‐23 involvement in contact allergy, the effect of Ustekinumab on allergic contact dermatitis has not been reported. Objectives. To evaluate the clinical effect of Ustekinumab in patients with allergic contact dermatitis. Methods. A retrospective, case cohort study of patients with allergic contact dermatitis treated with Ustekinumab in our department. Results. Five patients had been treated with Ustekinumab for allergic contact dermatitis, with limited effect. Conclusion. Our observation suggests that, although theoretically plausible, Ustekinumab does not seem to be a valuable therapeutic approach for chronic allergic contact dermatitis.     

sICAM-1, sE-selectin and sVCAM-1 are constitutively present in human skin lymph and increased in allergic contact dermatitis

The expression of intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1) and E-selectin is important for the regulation of the leucocyte traffic into and in inflammatory dermatoses. ICAM-1, VCAM-1 and E-selectin were initially identified as cell-surface proteins, but recent evidence suggests that they also exist in a soluble form. The collection of human afferent lymph exclusively deriving from a selected skin area allows insight into local pathomechanisms as well as signal transmission in skin disorders. In the present study we measured the concentrations of the soluble adhesion molecules (sAM) sICAM-1, sVCAM-1 and sE-selectin in human skin lymph derived from normal untreated skin, irritant contact dermatitis (CD) and the induction and elicitation phases of allergic CD. The strong elicitation reactions of allergic CD produced an increase in sAM output to about three times the baseline values but in the weaker irritant CD we observed no increase at all. In the induction phase of allergic CD the concentrations during the first 9 days of the experiment remained unchanged, as in the lymph derived from normal untreated skin, but were slightly increased thereafter. To our knowledge, no in vivo data exist on the local involvement of sAM in irritant and allergic CD in humans. Our results provide evidence of increased concentrations of sAM mainly in strong allergic CD. Received: 12 June 1996