Till Assmann

CCL27–CCR10 interactions regulate T cell–mediated skin inflammation

The skin-associated chemokine CCL27 (also called CTACK, ALP and ESkine) and its receptor CCR10 (GPR-2) mediate chemotactic responses of skin-homing T cells in vitro. Here we report that most skin-infiltrating lymphocytes in patients suffering from psoriasis, atopic or allergic-contact dermatitis express CCR10. Epidermal basal keratinocytes produced CCL27 protein that bound to extracellular matrix, mediated adhesion and was displayed on the surface of dermal endothelial cells. Tumor necrosis factor-α and interleukin-1β induced CCL27 production whereas the glucocorticosteroid clobetasol propionate suppressed it. Circulating skin-homing CLA+ T cells, dermal microvascular endothelial cells and fibroblasts expressed CCR10 on their cell surface. In vivo, intracutaneous CCL27 injection attracted lymphocytes and, conversely, neutralization of CCL27–CCR10 interactions impaired lymphocyte recruitment to the skin leading to the suppression of allergen-induced skin inflammation. Together, these findings indicate that CCL27–CCR10 interactions have a pivotal role in T cell–mediated skin inflammation.

Topical tacrolimus for pyoderma gangrenosum

1discuss the requirements for successful management of pyoderma gangrenosum, including appropriate local and systemic treatment. Whereas high-dose systemic glucocorticosteroids represent the mainstay of therapeutic strategies, non-steroidal immunosuppressive agents such as the macrolide lactones cyclosporin A (CsA) and tacrolimus (FK506) have been increasingly used as adjunctive or alternative therapy. 2,3

Applications of tacrolimus for the treatment of skin disorders.

During the last decades, systemic and topical glucocorticosteroids assumed a dominant role in immunosuppressive therapy in dermatology. However, their administration is limited because of numerous adverse effects. Consequently, there is a large need for alternative non-steroidal anti-inflammatory therapeutics with a superior risk/benefit ratio. In recent years, a new class of anti-inflammatories, the macrolide lactones, has attracted special interest. During the last decade, a member of this class, tacrolimus, proved to be a powerful suppressor of the immune system. Introduced into clinical practice to prevent allograft rejection, it is now routinely used in organ transplantation. Recently, several placebo-controlled multicenter studies showed the therapeutic efficiency of systemic and topical tacrolimus in common inflammatory skin diseases such as psoriasis and atopic eczema.Short-term tacrolimus ointment therapy disclosed significant efficacy vs. placebo and a safety profile with only few local side effects in patients with atopic eczema. Further clinical trials including greater extent of exposure (experienced by children), and comparison between tacrolimus ointment and glucocorticosteroids are being conducted and the results will show whether this drug opens a new era in the treatment of inflammatory skin disorders. The aim of this review is to summarize the current knowledge regarding the pharmacokinetic properties, adverse effects and therapeutic indications of tacrolimus in dermatology.

Topical tacrolimus for the treatment of inflammatory skin diseases

Chronic inflammatory skin disorders, such as atopic eczema, can cause considerable impairment of life quality. Their treatment is mainly driven by systemic or topical glucocorticosteroids which have the risk of many side effects. Recently, immunosuppressive macrolides which act via the inhibition of cytokine expression in T-lymphocytes have been shown to exert good therapeutic potency in inflammatory skin disorders. Cyclosporin, widely used in transplantation medicine, is also effective in psoriasis and atopic eczema but is not suitable for topical treatment. Tacrolimus (FK506) has been found to be 10 - 100 times more potent than cyclosporin and to penetrate skin much better due to a lower molecular weight. Initial clinical investigations have shown efficacy of topical tacrolimus in patients with atopic eczema. Large multi-centre studies have proven that long-term therapy with 0.03 and 0.1% tacrolimus ointment reveals effectiveness and safety both in adults and in children with severe atopic eczema. A burning sensation at the site of application is the most frequently observed local side effect. Relevant systemic adverse events were not detected. In Japan and the US, the drug is already licensed for the treatment of atopic eczema. The European admission for the pharmaceutical market is expected in the year 2002. Tacrolimus represents a milestone in topical therapy of inflammatory skin disorders which has so far been dominated by corticosteroid formulations and gives hope for the development of further topical immunosuppressive agents of its class in the future.

New immunosuppressive drugs in dermatology (mycophenolate mofetil, tacrolimus): unapproved uses, dosages, or indications

In the past two decades, many new small molecules with immunosuppressive properties have been discovered. These xenobiotic drugs have been particularly developed for clinical use in organ transplantation to prevent allograft rejection. During clinical investigation in transplantation, some of these substances have also been observed to provide therapeutic efficacy in inflammatory skin disorders. Subsequently, a large number of clinical trials have been performed in the field of immunomodulatory therapy in dermatologic disorders to evaluate the safety and efficacy of these new drugs. This chapter focuses on the mechanisms of action and the clinical experience in dermatology with mycophenolate mofetil (MMF) and tacrolimus.

A local lymph node assay to analyse immunosuppressive effects of topically applied drugs

Topical glucocorticosteroids represent the mainstay of antiinflammatory therapy in the treatment of inflammatory skin diseases. Their clinical use, however, is limited by local and systemic side-effects. Thus, in dermatopharmacology there is a large demand for alternative non-steroidal antiinflammatories. Other than transplantation models, most of the frequently used in vivo test systems for assessment of drug-induced immunosuppression measure changes in inflammatory skin responses by means of skin erythema and edema after challenge of sensitized animals. The aim of this study was to develop an alternative mouse model to detect and analyse immunosuppressive effects of topically applied drugs. On the basis of a modified local lymph node assay, we analysed effects of topical hydrocortisone, dexamethasone, mometasone furoate and FK506 (tacrolimus) during the induction phase of contact hypersensitivity. On 4 consecutive days, NMRI mice were treated on the dorsal surfaces of both ears with increasing concentrations of test compound. During the last 3 days, the mice received in addition the contact sensitizer, oxazolone (1%). On day 5, draining auricular lymph nodes were removed in order to assess lymph node cell counts and perform flow cytometric analysis of lymph node cell subpopulations (CD4+/CD25+, Ia+/CD69+, Ia+/B220+). All test compounds proved to exert significant immunosuppressive effects after topical application, but showed differences in their immunomodulatory potential. In conclusion, the local lymph node assay serves as an appropriate model to characterize immunosuppressive effects of topically applied drugs by measuring immunologically relevant end-points.

Topical tacrolimus for oral cicatricial pemphigoid

association with other pathogens. Necrotizing fasciitis due to S. marcescens exclusively has been only reported in four cases including ours, summarized in Table 1. Risk factors and underlying conditions were found in two patients including diabetes mellitus and cancer treated with chemotherapy. The two other cases had no underlying condition. Of note one of these latter patients had taken diclofenac prior to the onset of necrotizing fasciitis and the deleterious role of nonsteroidal anti-inflammatory drugs in cellulitis is well known. The bacteria were found in bullae and ⁄ or tissue in all patients and in blood cultures in three of these four patients. Two patients died from necrotizing fasciitis despite aggressive surgery and antibiotics. The route of infection remains questionable. Pathogenesis of necrotizing fasciitis due to this agent is unclear. However, injection of purified proteinases from S. marcescens into rat dermis can induce increased vascular permeability, necrosis of epidermal tissue, dermal inflammation and oedema, and infiltration of neutrophils into the subcutaneous fat and muscle. Treatment of necrotizing fasciitis due to S. marcescens does not differ from that due to other pathogens and includes surgical debridement and antibiotics. Most strains are susceptible to third generation cephalosporins, fluoroquinolones, imipenem ⁄ cilastin, and amikacin but definitive therapy should be based on the results of sensitivity testing because of a high rate of multiple drug resistance.

Ein Update zur Freiluftsaison 2014

Hautkrebs hat einen wichtigen Stellenwert in der täglichen dermatologischen Sprechstunde. Eng verknüpft mit diesem Thema ist die Lichtschutzberatung, wobei die Therapie und Prävention der po-lymorphen Lichtdermatose, des Lupus erythematodes und anderer photosensitiver Dermatosen ebenso detaillierte Kenntnisse über Lichtschutzpräparate verlangen.