STAT4 expression and activation is increased during mitosis in vitro and in vivo in skin- and mucosa-derived cell types: implications in neoplastic and inflammatory skin diseases.

BACKGROUND: The signal transducer and activator of transcription-4 (STAT4/Stat4) is a transcription factor known to convey signals from interleukin-12, interleukin-23, and interferon-alpha/beta to the nucleus, resulting in activation of dendritic cells, T-helper cell differentiation and production of interferon-gamma. OBJECTIVE: To demonstrate a novel role for STAT4 in cell mitosis. RESULTS: Phosphoserine STAT4 (pSerSTAT4) is increased in cells undergoing mitosis and is distributed throughout the cytoplasm during this stage of the cell cycle, whilst phosphotyrosine STAT4 (pTyrSTAT4) is confined to the chromosomal compartment. This distinct pattern of pSerSTAT4 during mitosis is seen in vitro in human keratinocytes and in other cell types. This is also present in vivo in cells undergoing mitosis in normal skin, psoriasis and squamous cell carcinoma. Inhibition of STAT4 phosphorylation by lisofylline and depletion of STAT4 by RNA interference results in a delay in progression of mitosis and leads to a reduction in cells completing cytokinesis. CONCLUSION: Our data demonstrate that STAT4 plays a role in enabling the normal and timely division of cells undergoing mitosis.

Prostaglandin E2 and nitric oxide mediate the acute inflammatory (erythemal) response to topical 5-aminolaevulinic acid photodynamic therapy in human skin.

BACKGROUND: Topical 5-aminolaevulinic acid photodynamic therapy (5-ALA-PDT) causes a clinical inflammatory response in human skin. While histamine mediates the immediate reaction, the mediators of the prolonged erythema are unknown. OBJECTIVES: To look for involvement of the proinflammatory mediators prostaglandin (PG)E2 and nitric oxide (NO) in topical PDT-induced erythema in human skin. METHODS: A series of studies was performed in healthy volunteers (n = 35). Following definition of the erythemal time course and dose response to 5-ALA-PDT, duplicate 5-ALA dose series were iontophoresed into the skin of each ventral forearm and exposed to 100 J cm(-2) broadband red light. Within subject, arms were randomized to control, or treatment with the cyclooxygenase and NO synthase inhibitors indometacin and Nω -nitro-l-arginine methyl ester (l-NAME), respectively, and the impact on 5-ALA-PDT-induced erythema was quantified. Additionally, release of PGE2 and NO was directly assessed by sampling dermal microdialysate at intervals following 5-ALA-PDT administration. RESULTS: A 5-ALA dose-related delayed erythema occurred by 3 h (r = 0·97, P < 0·01), with erythema persisting to 48 h post-PDT. Topical indometacin applied immediately post-PDT reduced the slope of erythemal response at 3 h and 24 h (P < 0·05). Intradermal injection of l-NAME into 5-ALA-PDT-treated sites reduced the slope of response at 24 h post-PDT (P < 0·001), while significantly inhibiting erythema from 3 h to 48 h post-PDT (P < 0·01). Analysis of dermal microdialysate showed release of NO and PGE2 following treatment. CONCLUSIONS: Topical 5-ALA-PDT upregulates PGE2 and NO in human skin, where they play a significant role in the clinical inflammatory response. The potential relevance of these mediators to PDT in human cutaneous pathology warrants study.

In vitro diagnostic assays are effective during the acute phase of delayed-type drug hypersensitivity reactions.

BACKGROUND: Previous reports have suggested that drug-specific lymphocyte proliferation assays (LPA) can be used retrospectively to confirm the culprit drug following delayed-type drug hypersensitivity reactions (DHR). However, only limited evidence supports their use in aiding acute clinical management. The aim of this study was to compare the LPA against combination cytokine assays for potential use in the acute setting. METHODS: A total of 43 patients with DHR (19 during the acute reaction, 20 after recovery, four during acute and after recovery) and 14 control subjects without DHR were investigated using ex vivo analysis of drug-specific proliferation, and interferon (IFN)-γ and interleukin (IL)-4 production. RESULTS: Healthy controls showed negative drug-specific proliferation and cytokine release in contrast to individuals with a known sensitivity (P < 0·0001). The assays demonstrated a test specificity of 95% (LPA), 83% (IFN-γ) and 92% (IL-4). The sensitivity of combined measurement of drug-specific IFN-γ and IL-4 cytokines during acute DHR was better than LPA (82% vs. 50%), but all assays were less sensitive during the recovery phase. The correlation between LPA and IFN-γ assays was strong (r = 0·7, P < 0·0001), whereas the IL-4 assay did not correlate as well with either of these assays. In contrast to LPA, drug enzyme-linked immunosorbent spot assays showed positive responses in patients concurrently taking immunosuppressive medication. CONCLUSIONS: In vitro assays of drug-specific IFN-γ and IL-4 production offer potential for use as rapid diagnostic tests. Cytokine detection offers distinct advantages over the LPA, including a shorter assay time, a greater sensitivity and effectiveness in testing immunosuppressed patients.

Phenotype standardization for immune-mediated drug-induced skin injury.

Advances in genetic research and molecular biology techniques have made it possible to begin to characterize the underlying genetic factors that predispose patients to serious forms of drug-induced skin injury (DISI). To facilitate research in this area, we have set out standardized phenotypic definitions for (i) Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN), (ii) acute generalized exanthematous pustulosis (AGEP), and (iii) hypersensitivity syndrome (HSS; also known as drug reaction with eosinophilia and systemic symptoms (DRESS) and drug-induced hypersensitivity syndrome (DIHS)). A DISI Expert Working Group comprising participants with varied expertise reviewed and debated current terminology and diagnostic criteria for DISI and agreed on the minimum phenotypic criteria for selected forms of DISI (SJS/TEN, AGEP, and HSS). In addition, an algorithm has been developed to aid appropriate clinical categorization of patients with DISI. These standardized criteria will be important in facilitating adequate and accurate patient recruitment in order to advance research in pharmacogenomic, immunological, mechanistic, and epidemiological studies.

Repeated low-dose skin exposure is an effective sensitizing stimulus, a factor to be taken into account in predicting sensitization risk.

BACKGROUND: Contact sensitization by ingredients in personal products is an important clinical problem. It is not clear how sensitization is induced by the generally low concentrations at which they occur but it might be the result of repeated exposure. OBJECTIVES: To compare the strength of contact sensitization induced by a single exposure to 2,4-dinitrochlorobenzene (DNCB) (60 microg cm(-2)) or three repeated exposures to a subsensitizing dose (10 microg cm(-2)). METHODS: Two groups (n = 10) of healthy adult volunteers were randomized to receive either a single patch of DNCB 60 microg cm(-2) or three once-weekly applications to the same site of 10 microg cm(-2) DCNB. Four weeks after the last application, sensitization was quantified by measurement of responses (skinfold thickness) to a graded series of four challenge doses. RESULTS: All the volunteers were sensitized and the strength of the responses was virtually identical between the groups. CONCLUSIONS: The same degree of sensitization was induced by three exposures to DNCB 10 microg cm(-2) as by one exposure to 60 microg cm(-2) of DNCB. Thus repeated exposure to low doses of contact sensitizers may increase the sensitizing potency. This must be taken into account in future risk assessments.

Inflammatory disease processes and interactions with nutrition.

Inflammation is a stereotypical physiological response to infections and tissue injury; it initiates pathogen killing as well as tissue repair processes and helps to restore homeostasis at infected or damaged sites. Acute inflammatory reactions are usually self-limiting and resolve rapidly, due to the involvement of negative feedback mechanisms. Thus, regulated inflammatory responses are essential to remain healthy and maintain homeostasis. However, inflammatory responses that fail to regulate themselves can become chronic and contribute to the perpetuation and progression of disease. Characteristics typical of chronic inflammatory responses underlying the pathophysiology of several disorders include loss of barrier function, responsiveness to a normally benign stimulus, infiltration of inflammatory cells into compartments where they are not normally found in such high numbers, and overproduction of oxidants, cytokines, chemokines, eicosanoids and matrix metalloproteinases. The levels of these mediators amplify the inflammatory response, are destructive and contribute to the clinical symptoms. Various dietary components including long chain omega-3 fatty acids, antioxidant vitamins, plant flavonoids, prebiotics and probiotics have the potential to modulate predisposition to chronic inflammatory conditions and may have a role in their therapy. These components act through a variety of mechanisms including decreasing inflammatory mediator production through effects on cell signaling and gene expression (omega-3 fatty acids, vitamin E, plant flavonoids), reducing the production of damaging oxidants (vitamin E and other antioxidants), and promoting gut barrier function and anti-inflammatory responses (prebiotics and probiotics). However, in general really strong evidence of benefit to human health through anti-inflammatory actions is lacking for most of these dietary components. Thus, further studies addressing efficacy in humans linked to studies providing greater understanding of the mechanisms of action involved are required.

BSACI guidelines for the management of drug allergy.

These guidelines have been prepared by the Standards of Care Committee (SOCC) of the British Society for Allergy and Clinical Immunology (BSACI) and are intended for allergists and others with a special interest in allergy. As routine or validated tests are not available for the majority of drugs, considerable experience is required for the investigation of allergic drug reactions and to undertake specific drug challenge. A missed or incorrect diagnosis of drug allergy can have serious consequences. Therefore, investigation and management of drug allergy is best carried out in specialist centres with large patient numbers and adequate competence and resources to manage complex cases. The recommendations are evidence-based but where evidence was lacking consensus was reached by the panel of specialists on the committee. The document encompasses epidemiology, risk factors, clinical patterns of drug allergy, diagnosis and treatment procedures. In order to achieve a correct diagnosis we have placed particular emphasis on obtaining an accurate clinical history and on the physical examination, as these are critical to the choice of skin tests and subsequent drug provocation. After the diagnosis of drug allergy has been established, communication of results and patient education are vital components of overall patient management.

Control of salicylate intolerance with fish oils.

We report three patients with disabling salicylate-induced intolerance who experienced abrogation of symptoms following dietary supplementation with omega-3 polyunsaturated fatty acids (PUFAs). All three patients experienced severe urticaria, asthma requiring systemic steroid therapy and anaphylactic reactions. After dietary supplementation with 10 g daily of fish oils rich in omega-3 PUFAs for 6-8 weeks all three experienced complete or virtually complete resolution of symptoms allowing discontinuation of systemic corticosteroid therapy. Symptoms relapsed after dose reduction. Fish oil appears a safe and effective treatment for this difficult and often serious condition.

'Lambing ears': a blistering disorder affecting farmers at lambing time.

BACKGROUND: At lambing time some farmers experience blistering and crusting of the pinnae. This occupational disease, termed 'lambing ears', does not feature in the medical literature. OBJECTIVES: To define the condition and explore its pathogenesis. METHODS: We obtained five biopsies from affected individuals and sent questionnaires to 69 farmers in the U.K. Farming communities abroad were also contacted. RESULTS: The eruption lasts for the duration of the lambing practice. The histological features are dominated by a pandermal perivascular and diffuse, predominantly T-cell lymphocytic infiltrate. Only the pinnae are affected and its incidence is related to the degree of involvement a farmer has with the animals around parturition. The condition also occurs, but less frequently, in farmers who are calving. CONCLUSIONS: This occupational disease occurs with close contact to lambing ewes or calving cows. The histology and distribution are comparable with the juvenile spring eruption variant of polymorphic light eruption, but its demographics are unique.

A double-blind, placebo-controlled trial of montelukast in adult atopic eczema.

BACKGROUND: Montelukast is an antagonist of cys-leukotriene receptors used mainly in the treatment of asthma- and seasonal-allergic rhinitis. Initial reports concerning the use of montelukast in atopic dermatitis (AD) have been encouraging, although not consistent. OBJECTIVES: We have undertaken a randomized, double-blind, parallel-group, placebo-controlled trial to investigate further the efficacy of montelukast in the treatment of atopic eczema. METHODS: Following a screening visit, subjects received placebo treatment for 2 weeks in a single-blind phase, followed after visit 2 by an 8-week, double-blind period of treatment with montelukast 10 mg daily or placebo. Subjects were patients aged 16-60 years under our care for treatment of AD of moderate severity, defined by a six-area, six-sign atopic dermatitis (SASSAD) score in the range 12-50. Response to treatment was assessed by investigators and by subjects using a seven-point scale, with response defined as marked improvement or better. In addition, the SASSAD score was used to monitor the severity of clinical signs. The proportion of skin involved was estimated and visual analogue scales were used to record the severity of pruritus and sleep disturbance. Topical corticosteroid usage was recorded using a five-point scale. Adverse events were recorded. RESULTS: Sixty subjects were recruited and 54 completed the study. The treatment groups were well matched for disease severity at baseline (SASSAD scores were 25 and 29 in the montelukast and placebo groups, respectively). There were no significant differences between the treatment groups in any of the parameters used to assess treatment response. The improvement in mean SASSAD score from baseline (visit 2) to the end of treatment was marginally superior in the placebo group, 1.41 points on montelukast vs. 1.76 on placebo, a difference of 0.35 (95% confidence interval -6.1 to 6.8). Adverse events were generally of a mild nature except for a brief septicaemic illness in one subject receiving montelukast. CONCLUSIONS: The data do not support previous reports of efficacy of montelukast in treatment of AD.

The relationships between exposure dose and response in induction and elicitation of contact hypersensitivity in humans.

Like all physiological systems, the human immune system exhibits dose-response relationships in its reactions. The strength of sensitization is related to the potency of the immunogen and the dose that reaches the immune system. In skin, as sensitizing dose per unit area (mug cm(-2)) is increased on a log scale, there is a sigmoid dose-response curve for subsequent reactivity. Similarly, the response to elicitation shows a classical sigmoid response to increasing challenge dose, with the dose per unit area again being the determinant. There is a clear inverse correlation between the strength of sensitization and the subsequent dose of antigen to which an individual will respond. This is reflected in the different challenge systems used to diagnose the existence of allergic contact sensitization to a given allergen. The occluded patch test aims to use the highest concentration possible to detect the weakest degrees of allergy, whereas the repeated open application test uses much lower concentrations similar to those encountered in real life, applied repeatedly but without occlusion, to assess clinical relevance. Many authors have attempted to use the lowest concentrations to which rare, highly sensitized individuals can react to define the concentrations which might be free of risk in terms of inducing allergic sensitization. However, it is clear that the dose-response relationships for induction of sensitivity by repeated low-dose exposures must be carefully defined in future studies. This article reviews the dose-response relationships of human contact sensitization.

Killed Mycobacterium vaccae suspension in children with moderate-to-severe atopic dermatitis: a randomized, double-blind, placebo-controlled trial.

BACKGROUND: The hygiene hypothesis is often proposed to explain the high prevalence of atopy in the western world. Dysregulation of the immune system may result from inadequate exposure to micro-organisms such as mycobacteria. A small trial suggested that a killed extract of Mycobacterium vaccae ameliorates atopic dermatitis (AD). OBJECTIVES: To confirm in a large clinical trial whether killed M. vaccae ameliorates AD in 5-16-year-old children. METHODS: This was a randomized, placebo-controlled, double-blind, multi-centre study of the effect of intradermal injection of killed M. vaccae (0.1 or 1 mg) on patients, aged 5-16, with moderate-to-severe AD. Patients were followed up for 24 weeks. The primary end point was the change in severity of AD at 12 weeks, assessed using the six area, six-sign, atopic dermatitis (SASSAD) score. Secondary end points included changes in disease extent, patient's global assessment and children's dermatology life quality index. RESULTS: There were 166 patients randomized. The mean SASSAD score fell to a similar degree at week 12 in all treatment arms: from 33 to 24, (26%) in the high-dose group, from 30 to 23 (25%) in the low-dose group and from 36 to 27 (24%) in the placebo group (P>0.05). Secondary end points followed the same trend. Adverse events were generally those expected to occur in this population. Injection site reactions occurred in 32 patients at week 4. CONCLUSIONS: M. vaccae was no more effective than the placebo in ameliorating the severity of AD.

Multiple Spitz naevi: a report of both variants with clinical and histopathological correlation.

Spitz naevi are usually solitary lesions. Multiple Spitz naevi are extremely rare and reported as widespread (disseminated) or grouped (agminated). We report two cases of multiple Spitz naevi and review their aetiology and treatment.

Type 2 diabetes, psoriasis and thiazolidinediones.

Thiazolidinediones, synthetic ligands for the peroxisome proliferator-activated receptor-gamma (PPAR-gamma) receptor, are insulin-sensitizing drugs licensed for use in selected patients with type 2 diabetes mellitus. The potential therapeutic applications of the thiazolidinediones extend to other clinical specialties such as dermatology. Rosiglitazone and pioglitazone are being evaluated for the treatment of psoriasis. Type 2 diabetes and psoriasis may coexist prompting speculation that dual benefits might accrue for patients with both conditions. A recent open pilot study suggests that oral pioglitazone may be beneficial for moderate chronic plaque psoriasis. However, changes in antidiabetic medication must be made in the knowledge of the cautions and contraindications to oral agents as well as the impact on metabolic control. Further studies are required before the use of thiazolidinediones for psoriasis can be advocated.

What's new in the management of cutaneous T-cell lymphoma?

The aetiology and clinical management of primary cutaneous T-cell lymphoma (CTCL) and specifically of mycosis fungoides and Sezary syndrome are poorly defined. Interesting new insights into CTCL disease biology as well as a number of emerging of novel therapeutic interventions make this an increasingly interesting area for dermatologists and oncologists involved in the treatment of CTCL. This review article covers much of this new information including new drugs, such as denileukin diftitox (Ontak) a targeted cytotoxic biological agent, Bexarotene an RXR selective retinoid, anti-CD4 monoclonal antibodies (mAb), new cytotoxics agents and vaccines.