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.

Different cytokine profiles of skin-derived T cell cultures from patients with atopic dermatitis and psoriasis.

OBJECTIVES: To investigate differences in expression of surface markers, cytokine profiles, and presence of CD4(+)CD8(+) T cells in skin-derived T cell cultures from patients with extrinsic atopic dermatitis (AD), intrinsic AD, and psoriasis expanded in the presence of IL-2 and IL-4. MATERIAL: Skin biopsies from patients with extrinsic AD (n = 6), intrinsic AD (n = 9) and psoriasis (n = 9). METHODS: Skin-derived T cell cultures were analyzed for expression of six surface markers, 11 intracellular cytokines, and three T cell subtype signature transcription factors by flow cytometry, and secreted cytokines by multiplex. RESULTS: A different IFN-γ profile emerged between the extrinsic AD and psoriatic T cell cultures; however, there was no difference in IL-17 profile. No differences with regard to cytokine expression were found between extrinsic AD and intrinsic AD cultures; however, cutaneous lymphocyte-associated antigen was expressed by a higher percentage of CD8(+) than CD4(+) T cells in the intrinsic AD cultures. Double-positive CD4(+)CD8(+) T cells were only detected in two out of 15 AD cultures. CONCLUSION: The data suggest that IL-2 and IL-4 affects the cytokine profile during culture. Earlier findings of substantial levels of double-positive CD4(+)CD8(+) T cells in skin derived T cell cultures from AD skin was not reproduced in this study.

In vitro propagation and dynamics of T cells from skin biopsies by methods using interleukins-2 and -4 or anti-CD3/CD28 antibody-coated microbeads.

In order to explore the mechanisms of inflammatory skin disorders, we established two methods of expanding skin-derived lymphocytes, one using high levels of interleukin (IL)-2 and IL-4 (method A) and the other using low levels of cytokines and anti-CD3/CD28 microbeads (method B). Both methods provide advantages for functional studies. With either of these two, we could obtain more than 10(7) cells/ from a 3 mm skin biopsy in 21 days from 23 out of 26 biopsies of various skin diseases. The relevance of these cells was confirmed by shifted T-cell receptor beta chain variable region (TCR-Vbeta) repertoire and antigen-dependent proliferation in antigen-driven skin disorders. The propagation of skin-resident lymphocytes, seen especially in method A, seems to be mediated by a functional defect of regulatory T cells residing in skin sequentially expanding under the conditions of our methods.

The risk of cancer among patients previously hospitalized for atopic dermatitis.

In treatment of severe atopic dermatitis, drugs with carcinogenic potentials are used to manage the disease. We therefore analyzed whether patients having severe atopic eczema had an increased cancer risk. The study population included all individuals hospitalized in Denmark with a primary diagnosis of atopic dermatitis during 1977-1996. Follow-up was conducted in 1996 in the Danish Cancer Register. A total of 6275 persons were included. Among 2030 adult patients, an increased risk of cancer was observed, standard morbidity ratio (SMR)=1.5 (95% CI: 1.2-1.9). Half the excess cases of cancer was keratinocyte carcinomas of the skin diagnosed within the first 9 y of follow-up, SMR=2.4 (95% CI: 1.4-3.9). For men, SMR=2.7 (95%CI: 1.2-5.4). In conclusion, earlier hospitalized adult atopic dermatitis patients had an increased risk of cancer. Half the excess cases of cancer were keratinocyte carcinomas. This may be a result of a detection bias or due to the carcinogenic potentials of some of the therapies of severe atopic dermatitis.

Tacrolimus treatment of atopic eczema/dermatitis syndrome.

PURPOSE OF REVIEW: Atopic dermatitis is today the most common chronic disease of children in Europe, the US and Japan. The 'golden standard' of therapy is topical glucocorticosteroids and emollients. The steroids have been on the market for four decades, are efficacious, but only advised for short-term treatment due to their risks of side effects. RECENT FINDINGS: More than 16,000 persons suffering from atopic dermatitis have been enrolled in clinical studies of tacrolimus. One third of patients with moderate to severe atopic dermatitis experience over 90% improvement in their disease over a 12-week treatment period and up to 70% of patients have over 50% improvement. A 1-year treatment leads to more than 90% improvement in 75% of patients. The most pronounced side effect is a burning sensation occurring in up to 60% of patients. SUMMARY: Atopic dermatitis is a chronic skin disease leading to a demand for long-term treatment control. Such treatment options have not previously been available--except for emollients which are not efficacious for controlling skin inflammation. Tacrolimus and pimecrolimus are new treatment options, free from the potential side effects of topical steroids, which are known for their efficacy in short-term treatment. The new treatment modalities prevent the eczema from relapsing and at the same time they control active eczema. The future will see a shift towards the long-term use of tacrolimus which is able to control the skin inflammation and, hopefully, shorten the course of the eczema.

Oral alitretinoin (9-cis-retinoic acid) therapy for chronic hand dermatitis in patients refractory to standard therapy: results of a randomized, double-blind, placebo-controlled, multicenter trial.

OBJECTIVE: To assess the efficacy and safety of oral alitretinoin (9-cis-retinoic acid), 10 mg/d, 20 mg/d, and 40 mg/d, compared with placebo control, in the treatment of chronic hand dermatitis. DESIGN: Multicenter, randomized, double-blind, placebo-control, prospective trial. SETTING: A total of 43 outpatient clinics in 10 European countries. PATIENTS: Of 348 patients screened, 319 with moderate or severe refractory chronic hand dermatitis were randomized, in the ratio of 1:1:1:1, to 4 treatment groups and received allocated intervention. Of 75 patients who withdrew, 24 withdrew owing to adverse events. INTERVENTIONS: Placebo or 10 mg, 20 mg, or 40 mg of oral alitretinoin (9-cis-retinoic acid) taken once daily for 12 weeks. Safety was assessed for all patients during a follow-up period of 4 weeks, and responders were observed for a follow-up period of 3 months. MAIN OUTCOME MEASURE: Physician's global assessment of overall chronic hand dermatitis severity. RESULTS: Alitretinoin led to a significant and dose-dependent improvement in disease status, with responses in up to 53% of patients, and up to a 70% mean reduction in disease signs and symptoms. Treatment was generally well tolerated, with dose-dependent effects comprising headache, flushing, mucocutaneous events, hyperlipidemia, and decreased hemoglobin and decreased free thyroxin levels. Three months after discontinuation of treatment, the rate of relapse was 26%, independent of dose. CONCLUSION: Alitretinoin given at well-tolerated doses induced substantial clearing of chronic hand dermatitis in patients refractory to conventional therapy.

[Phytodermatitis caused by burning bush of Moses]. / Fytofotodermatit forårsaget af Moses' braendende busk.

The most well-known cause of phytophotodermatitis in Denmark is accidental contact with plants belonging to the Apiaceae (Umbelliferae), such as hodgweed (Heracleum spondylium). However, many other plants with furocoumarins (psoralens) may induce the same kind of reaction. We describe a case of phytophotodermatitis caused by Dictamnus alba, gas plant or burning bush also known from the Bible as the "burning bush of Moses".

[Melanotan-induced lentigines and nevi]. / Melanotan inducerer lentigines og naevi.

A 25-year-old man had self-injected more than 150 doses of melanotan to increase his skin pigmentation, which had increased significantly. At the same time, his nevi had become darker and new nevi and lentigines developed; they also occurred on his genitals causing his referral. Two nevi were excised, but showed no signs of malignant transformation.

[Topical immune modulation and risk of cancer]. / Cancerrisiko ved topikale immunmodulatorer.

This article reviews if local immunosuppression of atopic dermatitis is associated with an increased risk of cancer - as implicated by a warning issued by the FDA and EMEA health authorities because systemic immunosuppression of transplanted patients leads to a significant increase of non-melanoma skin cancer and lymphoma. So far, no studies support that the use of topical immunosuppression increases the risk of local or systemic cancer.

T-cell receptor excision circles (TREC) in CD4+ and CD8+ T-cell subpopulations in atopic dermatitis and psoriasis show major differences in the emission of recent thymic emigrants.

We used T-cell receptor excision circles (TREC) to evaluate thymic function in adult patients with atopic dermatitis and psoriasis. We observed that men, but not women, with atopic dermatitis had a significantly faster decline in TREC content with increasing age compared with healthy men. In contrast, both men and women with psoriasis had significantly reduced TREC levels, which were, on average, only 30% of that of healthy persons. In atopic dermatitis the levels of TREC declined with increasing levels of IgE, disease intensity and extent of eczema. Furthermore, patients with atopic dermatitis showed signs of altered thymus function, as they had a significantly greater variation in TREC content measured over time than healthy controls, especially within the CD8+ T-cell subpopulation. Because both atopic dermatitis and psoriasis patients have an increased number of T-cells, this indicates that atopic dermatitis patients can have compensatory emissions of thymic emigrants, whereas psoriatic patients do not, thus supporting different thymic function in these two diseases.