G. Guillet

A role for T cell-derived interleukin 22 in psoriatic skin inflammation.

Interleukin (IL)‐22 is a T cell‐derived cytokine that has been reported recently to induce cutaneous inflammation in an experimental murine model of psoriasis, and to induce in vitro an inflammatory‐like phenotype. In the present study, we assessed the presence of IL‐22 and the IL‐22 receptor 1 (IL‐22R1) in skin lesions, skin‐derived T cells, as well as IL‐22 levels in sera from patients with psoriasis. IL‐22R1 and IL‐10R2 transcripts are expressed at a similar level in psoriatic and healthy skin. In contrast, IL‐22 mRNA expression was up‐regulated in psoriatic skin lesions compared to normal skin, whereas IL‐22 mRNA levels in peripheral blood mononuclear cells from psoriatic patients and normal subjects were similar. Circulating IL‐22 levels were significantly higher in psoriatic patients than in normal subjects. T cells isolated from psoriatic skin produced higher levels of IL‐22 in comparison to peripheral T cells isolated from the same patients. IL‐10 was expressed at similar levels in skin biopsies and peripheral blood mononuclear cells of psoriatic patients and normal subjects. Finally, we show here that supernatants of lesional psoriatic skin‐infiltrating T cells induce an inflammatory response by normal human epidermal keratinocytes, resembling that observed in psoriatic lesions. Taken together, the results reported in this study indicate that IL‐22 is a cytokine produced by skin‐infiltrating lymphocytes that is potentially involved in initiation and/or maintenance of the pathogenesis of psoriasis.

Skin Inflammation Induced by the Synergistic Action of IL-17A, IL-22, Oncostatin M, IL-1α, and TNF-α Recapitulates Some Features of Psoriasis

Keratinocytes play a crucial role in the regulation of skin inflammation, responding to environmental and immune cells stimuli. They produce soluble factors that can act in an autocrine or paracrine manner on immune cells or directly on aggressors. A screening of the activities of 36 cytokines on keratinocyte gene expression identified IL-17A, IL-22, oncostatin M, TNF-α, and IL-1α as potent cytokines in inducing cutaneous inflammation. These five proinflammatory cytokines synergistically increased production of CXCL8 and β-defensin 2 (BD2). In addition, ex vivo studies on human skin explants demonstrated upregulation of BD2, S100A7, and CXCL8 expression in response to the same combination of cytokines. In vivo intradermal injection of these five cytokines in mouse increased CXCL1, CXCL2, CXCL3, S100A9, and BD3 expression, associated with neutrophil infiltration. We confirmed and extended this synergistic effect using quantitative real-time PCR analysis and observed increased expression of nine chemokines and 12 antimicrobial peptides. Production of CXCL, CXCL5, and CXCL8 by keratinocytes stimulated in the presence of this cytokine combination was associated with increased neutrophil chemotactic activity. Similarly, high production of BD2, BD3, and S100A7 was associated with an increased antimicrobial activity. Finally, the transcriptional profile observed in this in vitro model of inflammatory keratinocytes correlated with the one of lesional psoriatic skin. Our results demonstrate the important potentiating activities of IL-17A, IL-22, oncostatin M, TNF-α, and IL-1α on keratinocytes. This is particularly interesting in the context of psoriasis where these cytokines are overexpressed and could synergize to play an important role in upregulation of chemokines and antimicrobial peptides production.

Oncostatin M Secreted by Skin Infiltrating T Lymphocytes Is a Potent Keratinocyte Activator Involved in Skin Inflammation

Cutaneous inflammatory diseases such as psoriasis vulgaris and atopic dermatitis are associated with altered keratinocyte function, as well as with a particular cytokine production profile of skin-infiltrating T lymphocytes. In this study we show that normal human epidermal keratinocytes express a functional type II oncostatin-M (OSM) receptor (OSMR) consisting of the gp130 and OSMRβ components, but not the type I OSMR. The type II OSMR is expressed in skin lesions from both psoriatic patients and those with atopic dermatitis. Its ligand, OSM, induces via the recruitment of the STAT3 and MAP kinase pathways a gene expression profile in primary keratinocytes and in a reconstituted epidermis that is characteristic of proinflammatory and innate immune responses. Moreover, OSM is a potent stimulator of keratinocyte migration in vitro and increases the thickness of a reconstituted epidermis. OSM transcripts are enhanced in both psoriatic and atopic dermatitic skin as compared with healthy skin and mirror the enhanced production of OSM by T cells isolated from diseased lesions. Results from a microarray analysis comparing the gene-modulating effects of OSM with those of 33 different cytokines indicate that OSM is a potent keratinocyte activator similar to TNF-α, IL-1, IL-17, and IL-22 and that it acts in synergy with the latter cytokines in the induction of S100A7 and β-defensin 2 expression, characteristic of psoriatic skin. Taken together, these results demonstrate that OSM and its receptor play an important role in cutaneous inflammatory responses in general and that the specific effects of OSM are associated with distinct inflammatory diseases depending on the cytokine environment.

Gianotti-Crosti syndrome: a study of 26 cases

We have studied 26 patients presenting with a symmetrical papular or papulovesicular acrolocated eruption of more than 10 days duration. Mean age at onset was 2 years (range 10 months to 5.75 years). Lymphadenopathy was noted in eight cases, and hepatomegaly in one case. In 12 cases, histopathology and direct immunofluorescence were non‐contributory, Cytolytic hepatitis occurred in one case and was associated with HBs antigenemia. A history of recent immunization was given in two cases. There was serological evidence of recent EpsteinBarr virus infection in seven out of 13 cases tested. Coxsackie B viruses were isolated from three patients, and cytomegalovirus was probably associated with the syndrome in one case. We conclude that the Gianotti‐Crosti syndrome is not rare in France, and that non‐hepatitis B virus (HBV)‐associated cases are more frequent than the classical HBV ‐associated papular acrodermatitis of childhood.

Hidradenitis suppurativa: the role of deficient cutaneous innate immunity.

OBJECTIVE To evaluate the expression of innate immunity markers at the site of nodules caused by hidradenitis suppurativa (HS). DESIGN Prospective analysis of 12 patients with HS. SETTING Unité de Cancéro-Dermatologie, Nantes Hospital, Nantes; Service de Dermatologie, Poitiers Hospital, Poitiers; and Service de Dermatologie, Clinique de Courlancy, Reims, France PATIENTS Twelve patients (Hurley stage I or II) in whom the disease had progressed for at least 6 months and who had a minimum of 2 closed nodules in typical sites. MAIN OUTCOME MEASURES Two biopsies were performed at baseline: one in a closed inflammatory nodule and one in healthy adjoining skin. Patients were treated for 3 months with zinc gluconate at a dosage of 90 mg/d. A new biopsy was then performed in the same nodule. Innate immunity markers (toll-like receptors 2, 3, 4, 7, and 9; intercellular adhesion molecule 1; interleukin [IL] 6 and 10; tumor necrosis factor; α melanocyte stimulating hormone; transforming growth factor β; β-defensin 2 and 4; and insulinlike growth factor 1) were studied by immunohistochemical analysis. RESULTS We observed significantly decreased expression (P < .001) of all the innate immunity markers studied except IL-10 in nonlesional and lesional HS skin. The downregulation of innate markers was significantly stronger in lesional HS skin compared with normal skin except for tumor necrosis factor. Three months of zinc treatment induced a significant increase in the expression of all the markers involved in innate immunity. CONCLUSION Our study demonstrates for the first time, to our knowledge, that a deficiency of the main innate immunity markers in typical HS sites may explain the development of chronic inflammatory nodules in this disease.

Evaluation of a new moisturizer (Exomega milk®) in children with atopic dermatitis

Background: Although the benefits of emollient therapy are widely accepted in atopic dermatitis, there is a relative lack of clinical evidence supporting their efficacy in these conditions. The aim of this study was to evaluate the efficacy, the tolerance and the effects on childrens quality of life of a new moisturizer milk (Exomega milk®) in childhood atopic dermatitis. Methods: This controlled, randomized, multi‐centric study had two parallel groups, involving children aged 6 months to 12 years, with mild and moderate atopic dermatitis (Scorad<35). The treated group applied the moisturizer milk twice a day for 2 months, in association with a cleansing bar. The non‐treated group had only the cleansing bar. The use of strong and moderate topical corticoids was allowed and quantified. The following parameters were evaluated: Scorad, tolerance and the childrens quality of life index. Results: A total of 76 children (mean age 4 years) were included: 37 in the treated group, 39 in the non‐treated group. After 2 months, the decrease of the Scorad index in the treated group was not statistically significant (p = 0.051) but detailed evaluation showed a significant improvement of xerosis (p = 0.01) and pruritus (p = 0.01) in the treated group compared with the non‐treated group. Clinical improvement in the treated group after 2 months of treatment was correlated to a significant improvement of the childrens quality of life index (p = 0.0011). Tolerance was good to excellent in 97% of cases. Conclusion: The milk emollient studied was found to provide an interesting auxiliary treatment in childhood atopic dermatitis since it gave positive results, in particular on xerosis and pruritus, as well as an improvement of the quality of life of the children.

Improvement of psoriasis and cutaneous side-effects during tyrosine kinase inhibitor therapy for renal metastatic adenocarcinoma. A role for epidermal growth factor receptor (EGFR) inhibitors in psoriasis?

also suggested that response to this agent lasts at most for 3 months after the last infusion. Thus, after this time the maintenance of PASI improvement could reasonably be attributed to the effect of efalizumab alone. The potential problem of this approach is that reintroduction of infliximab in both patients might reveal a lack of response due to antibody formation targeting the drug. Intermittent treatment accounts for high incidence of antibody formation and higher concentration of antibodies correlated with shortened duration of response owing to lower concentrations of the agent. Also, the flare-up described in 15% of patients after an average 9-week period of efalizumab discontinuation was observed in both cases and was not prevented by previous infliximab therapy. Overall, our report suggests the feasibility of sequential biological therapy with a ‘hit and run’ approach for the treatment of psoriasis. Optimal efficacy was obtained with infliximab, a powerful rapid-acting TNF-a antagonist and maintained with a safe, well-tolerated continuous therapy with efalizumab. Such a sequential therapy may represent a good alternative to conventional rotational principles.

Inhibition of keratinocyte differentiation by the synergistic effect of IL-17A, IL-22, IL-1α, TNFα and oncostatin M.

Keratinocyte differentiation program leading to an organized epidermis plays a key role in maintaining the first line of defense of the skin. Epidermal integrity is regulated by a tight communication between keratinocytes and leucocytes, particularly under cytokine control. Imbalance of the cytokine network leads to inflammatory diseases such as psoriasis. Our attempt to model skin inflammation showed that the combination of IL-17A, IL-22, IL-1α, OSM and TNFα (Mix M5) synergistically increases chemokine and antimicrobial-peptide expression, recapitulating some features of psoriasis. Other characteristics of psoriasis are acanthosis and down-regulation of keratinocyte differentiation markers. Our aim was to characterize the specific roles of these cytokines on keratinocyte differentiation, and to compare with psoriatic lesion features. All cytokines decrease keratinocyte differentiation markers, but IL-22 and OSM were the most powerful, and the M5 strongly synergized the effects. In addition, IL-22 and OSM induced epidermal hyperplasia in vitro and M5 induced epidermal thickening and decreased differentiation marker expression in a mouse model, as observed in human psoriatic skin lesions. This study highlights the precise role of cytokines in the skin inflammatory response. IL-22 and OSM more specifically drive epidermal hyperplasia and differentiation loss while IL-1α, IL-17A and TNFα were more involved in the activation of innate immunity.

Temozolomide and cisplatin combination in naive patients with metastatic cutaneous melanoma: results of a phase II multicenter trial.

Temozolomide (TMZ) is a second-generation alkylating agent that has recently shown some efficacy in stage IV melanoma. The purpose of this study was to test the efficacy and safety of combination therapy with TMZ and cisplatin (CDDP) in patients with metastatic melanoma. Chemo-naive patients with metastatic cutaneous melanoma were included in a phase II study of combined therapy with TMZ (200 mg/m2/day), days 1–5, and CDDP (75 mg/m2/day) on day 1. The treatment was given every 28 days, for up to six cycles. The primary endpoint was the overall response rate and the secondary endpoints were progression-free survival, probability of survival, and tolerance. Thirty patients were enrolled into this study. Median age was 59 years. A total of 126 cycles were administered. Grade 3 and 4 hematological toxicity was observed in 14 patients (46.6%) and clinical toxicity in seven patients (23.3%). No complete response was observed among the 30 included patients. Five patients (16.7%) achieved a partial response. An additional six patients (20%) showed disease stabilization and 17 patients (56.6%) revealed progressive disease. Median survival and median response duration were 8 and 7.2 months, respectively. One- and 2-year survivals were 36.7 and 13.3%. One- and 2-year progression-free survivals were 13.3 and 3.3%. Our results suggest that concurrent adjunction of CDDP to TMZ regimen increases toxicity according to this schedule and does not improve the outcome of stage IV melanoma. The objective response rate is close to response rates observed with single-agent chemotherapy.

Allergic contact dermatitis from natural rubber latex in atopic dermatitis and the risk of later Type I allergy

The aims of the study were to assess whether contact dermatitis in children could be due to a delayed hypersensitivity reaction to natural rubber latex (NRL) and to define risk factors for later occurrence of Type I hypersensitivity to this allergen. Among 1800 children investigated for contact dermatitis, 55 were referred on suspicion of rubber allergy and had patch tests to NRL, as well as prick tests and blood tests for specific immunoglobulin E (IgE). A 2‐year follow‐up was then carried out. Delayed hypersensitivity to NRL was confirmed in 32 children. Patch testing with NRL proved to be positive, and clinical improvement confirmed the diagnosis and relevance of patch tests. 30 of these 32 patients had associated atopic dermatitis (AD). Prick tests and blood tests for specific IgE to latex were negative at the time of diagnosis. A 2‐year follow‐up showed that 10 of 27 patients presenting initially with a positive patch test without associated Type I sensitization later developed immediate hypersensitivity. Children with AD are at high risk for allergy to NRL protein. Exclusion of this allergen should be strongly advised in atopics because of the dual risk of dermatitis and later evolution into severe Type I hypersensitivity.