Vakzinationstherapie kutaner T‐Zell‐Lymphome

Summary: Primary cutaneous T cell lymphomas (CTCL) are defined as clonal proliferation of skin‐infiltrating T lymphocytes. Despite their heterogeneity, CTCL are generally incurable, which lead to the development of various treatment strategies including vaccination. Here, the attempts to vaccinate against lymphoma will be reviewed with special emphasis on CTCL. Since an universal tumour antigen is not available so far, different targets, including whole tumour cells, idiotypes, cancer/testis antigens, proteins derived from tumour‐associated mutations, and mimotopes, have been investigated for their applicability in CTCL vaccination. The antigenic information can be delivered in different ways. So far, tumour cells fused to dendritic cells, idiotypic proteins/peptides and DNA/RNA preparations have been applied in lymphoma. Since most targets are weak immunogens, adjuvants and other helpers, including dendritic cells, immunogenic peptides and oligonucleotides, cytokines, and viral vectors, are required to enable proper presentation of the antigens and sufficient activation of the immune system. Although first data from CTCL patients prove the suitability of vaccination in CTCL therapy, the number of available antigens, carriers, adjuvants and application schemes creates a multitude of vaccine formulations and identification of the best‐suited approach difficult. Furthermore, the relationship between lymphoma and the host immune system is complex and still not completely understood. In consequence, CTCL vaccination requires a lot of research to be done before its breakthrough.     

Die Mikrozirkulation des kutanen Melanoms

The microcirculation of human skin tumours can be visualized with noninvasive methods from clinical microcirculation research (capillaroscopy and laser Doppler fluxmetry (LDF). The latter can also be used to measure the blood flow in such tumours. This prospective study was designed to evaluate melanoma-associated cutaneous neoangiogenesis. We studied the microcirculation of 114 pigmented skin tumours in 103 patients (63 women, 40 men) averaging 38.8 +/- 21.1 years of age. On the basis of histological findings, we diagnosed melanocytic naevus in 86 cases and malignant melanoma in 28. The malignant melanoma was characterized by a chaotic arrangement of the capillaries, which were dilated and formed corkscrew-shaped or glomerular structures. In the transitional area between healthy and cancerous areas there was hypervascularization. The capillaries of the melanoma appeared to be more permeable towards the low-molecular-weight, water-soluble sodium fluorescein. Laser Doppler flux, a measure of cutaneous circulation in the upper 2 mm of the skin, is higher in the center of the melanoma than in either the middle of melanocytic naevus (p < 0.0005) or in neighbouring healthy skin areas (P < 0.005). In the future, antiangiogenetic therapy strategies could play a significant role in the treatment of malignant melanoma. These methods provide a reliable means of evaluating the specific antiangiogenetic efficacy of treatments for cutaneous melanoma.     

Familiäres Auftreten einer segmentalen Typ‐2‐Manifestation der kutanen Leiomyomatose

Background: There are several malignant or benign skin diseases which can be explained by the phenomenon of mosaicism or segmental manifestation, e. g. segmental neurofibromatosis 1 or cutaneous leiomyomatosis. Loss of heterozygosity is a crucial element for segmental manifestations. Two types of segmental manifestations can be defined in autosomal dominant skin diseases such as cutaneous leiomyomatosis. Type 1 is caused by a novel postzygotic segmental mutation; type 2 reflects an additional postzygotic loss of heterozygosity of the gene locus responsible for cutaneous leiomyomatosis in a initially heterozygous embryo. Loss of heterozygosity is a genetic process when a heterozygous cell becomes homozygous or hemizygous by loosing the corresponding wild‐type allele. This phenomenon can be regarded as a precondition for tumor growth. In type‐2 cases, the segmental manifestation is more distinctive with additional disseminated disease because of a germline mutation with heterozygosity of all somatic cells outside the strongly affected area. Patients and Methods: A 74‐year‐old female patient and her 52‐year‐old son presented with segmental leiomyomas following the lines of Blaschko as well as disseminated skin tumors. The woman has undergone hysterectomy at the age of 29 because of multiple uterine leiomyomas, as had her mother and grandmother. Results: Based on their typical clinical appearance, these cases represent the rare familial occurrence of type‐2 manifestation of leiomyomas which indicates a postzygotic loss of the wild‐type allele. Conclusion: Very unusual is the familial occurrence in mother and son of this type‐2 manifestation of cutaneous leiomyomatosis. Apparently the gene locus is prone to a postzygotic loss of heterozygosity.     

Non‐infectious granulomatous dermatoses

Granulomatous dermatoses comprise a wide range of etiologically and clinically distinct skin diseases that share a common histology characterized by the accumulation of histiocytes include macrophages. While the pathogenesis of these disorders is not fully understood, the underlying mechanism is thought to involve a reaction pattern caused by an immunogenic stimulus. Antigen‐presenting cells and the effect of various cytokines play a key role. Our understanding of granulomatous reaction patterns has been advanced by insights drawn from observations of such reactions in patients on immunomodulatory therapy and in individuals with genetic immunodeficiency. Traditionally, a distinction is made between infectious and non‐infectious granulomatous dermatoses. The present CME article addresses granulomatous skin diseases for which there is no evidence of a causative infectious agent. Common representatives include granuloma annulare, necrobiosis lipoidica and cutaneous sarcoidosis. Granulomatous dermatoses may be part of the clinical spectrum of various systemic disorders or may be associated therewith. Some neoplastic disorders may mimic granulomatous dermatoses histologically. Given the pathogenetic diversity involved, the clinical presentation, too, is quite varied. Overall, however, each disorder is characterized by typical clinical features. The diagnosis always requires thorough clinicopathologic correlation. Treatment is preferably based on the underlying pathogenesis and frequently involves anti‐inflammatory agents. In most cases, however, there is insufficient study data. The dermal nature of these disorders frequently poses a therapeutic challenge, especially with respect to topical treatment.     

Die Extrakorporale Photopherese bei Progressiver Systemischer Sklerodermie: Unterscheidung von Respondern und Non‐Respondern

Background: The benefit of extracorporeal photopheresis (ExP) in progressive systemic sclerosis (PSS) is controversial. There is limited experience with the long‐term use of ExP in PSS. The purpose of the present study was to distinguish between responders and non‐responders by using ExP in PSS and to evaluate activation markers for PSS. Patients and methods: 20 subjects with PSS were treated for 12 months with ExP (interval: 1x/month) as an immunomodulating monotherapy (11/20) or combination therapy (9/20). The course of PSS was assessed by both specially designed clinical score and serological parameters (CRP, ANA, beta‐galactosidase, P‐III‐P, CD4/CD8‐ratio, TNF‐alpha, Il‐2‐R, Il‐6). Results: After 12 cycles of ExP, 30 % of the subjects showed a partial remission and 25 %, stable disease (55 % responders) while 45 % had a progression (non‐responders). Although there was no correlation between the clinical course and the serological parameters, an increase of beta‐galactosidase during therapy marked a progression of PSS in non‐responders. Responders with a short PSS‐course before ExP, moderate ANA titres, normal TNF‐alpha levels and lack of Scl‐70 had a good prognosis. Conclusions: About the half of the subjects with PSS profited by the long‐term use of ExP. Thereby the mild immunomodulating effect of ExP seems to be insufficient to control markedly progressive courses of PSS.     

Histologie der kutanen Vaskulitiden

Identification of vasculitis by skin biopsy represents the diagnostic gold standard. Skin biopsies should be taken from fresh lesions or from margin of an ulceration and should contain all layers of the skin including subcutis. Classification of vasculitis is based on histological criteria considering the size of the predominantly affected vessel, the distribution of vasculitis in the dermis and subcutis, and the predominant inflammatory cell-type. In cutaneous vasculitis, small and medium-sized vessels of the arterial and/or venous system are predominant affected. Vasculitis of the larger-sized blood vessels is based on inflammatory cells within the wall of the vessel; in small vessel vasculitis, additional features include fibrin within the vessel wall and/or an intraluminal thrombus and/or perivascular and interstitial infiltrates of neutrophils, nuclear dust and extravasated erythrocytes are required for the diagnosis of vasculitis. Leukocytoclastic vasculitis is the most common form of cutaneous vasculitis. An correct diagnosis requires careful correlation of medical history, the clinical, serological, imaging and direct immunofluorescence data, and histologic findings.     

Alopecia areata im Tiermodell – Neue Einblicke in Pathogenese und Therapie einer T‐Zell‐vermittelten Autoimmunerkrankung

Alopecia areata is a common disease, but for ethical reasons it seems difficult to perform large‐scale studies to elucidate the pathogenesis and to develop new therapeutic approaches in man. It is therefore helpful to develop appropriate animal models. The Dundee experimental bald rat (DEBR) and the C3H/HeJ mouse are well‐established animal models for alopecia areata and can be used for the study of genetic aspects, pathogenesis and therapy of the disease. In C3H/HeJ mice alopecia areata can be experimentally induced by grafting lesional skin from an affected mouse to a histocompatible recipient which offers the possibility to study the influence of various factors on the development of the disease. Studies on the C3H/HeJ mouse and the DEBR have corroborated the concept that alopecia areata is a T‐cell mediated autoimmune disease and various steps and aspects of the pathogenesis have been elucidated. Based on this knowledge new therapeutic options may be developed such as inhibition of lymphocyte‐homing by an anti‐CD44v10 antibody, or inhibition of costimulation by monoclonal antibodies. Therapeutic studies in the C3H/HeJ mouse and the DEBR suggest that alopecia areata can be treated by topical tacrolimus but treatment in humans may only be successful after development of an improved vehicle that facilitates penetration of tacrolimus down to the hair bulb. Current investigations in mice are designed to elucidate the mechanisms how contact sensitizers act in the treatment of alopecia areata, and this will hopefully lead to the development of more specific approaches based on the beneficial effect of contact sensitizers.     

Non‐invasive imaging of mid‐dermal elastolysis

Mid‐dermal elastolysis (MDE) is a rare disease that is characterized histopathologically by selective loss of elastic tissue in the mid dermis. We aimed to assess MDE using noninvasive skin imaging techniques in vivo. We examined both the lesional and adjacent healthy skin of a woman with the reticular variant of MDE, using confocal scanning laser microscopy, optical coherence tomography (OCT) and high‐frequency ultrasound (HFUS). The median diameter of blood vessels at the top of dermal papillae was significantly increased in erythematous lesional skin compared with healthy skin. The mid‐dermal signal intensity detected by OCT was higher in healthy skin than in lesional skin. With HFUS, mid‐dermal density values were significantly higher in healthy skin than in lesional skin. Our preliminary findings indicate that noninvasive skin imaging methods such as OCT and HFUS might be suitable techniques for the evaluation and monitoring of elastolytic skin disorders such as MDE.     

Erfahrungen mit der kutanen Leishmaniasis

Background

The German S1 guidelines from 2009 contain a variety of recommendations for the treatment of cutaneous leishmaniasis.

Patients and methods

We report the results of our diagnostic procedures and treatment of 32 international patients in autumn 2010 in northern Afghanistan.

Results

Giemsa stain confirmed the clinical diagnosis within 24 hours. Eleven simple lesions and one larger ulcer responded well to cryotherapy and intralesional sodium stibogluconate. More complex lesions in 19 patients responded well to oral miltefosine. One patient refused outpatient therapy.

Conclusions

Cryotherapy and intralesional antimony compounds showed good results in early lesions of cutaneous leishmaniasis in northern Afghanistan. Outpatient treatment of complex lesions with miltefosine was successful in all cases.     

Aktuelles zur kutanen Neurobiologie von Pruritus

The pathogenesis of chronic and acute pruritus is not yet completely understood. Interactions of neurons with resident and nonresident skin cells seem to play an important role in the regulation of pruritus. Neuronal cells which express specific receptors and are capable of releasing neuromediators play an active role in this interaction. Furthermore, released neuromediators can activate immune cells including mast cells and eosinophils, which are increased in the inflammatory infiltrate of many pruritic skin diseases. Mast cells and eosinophils express receptors for neuromediators themselves. In addition, they can release neurotrophins including nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF) and cytokines including interleukin (IL)-31 which correlate with disease activity in patients with inflammatory skin diseases including atopic dermatitis and induce neuronal outgrowth. In part, a correlation of these mediators has also been described with pruritus. Although the interplay between transient and resident cells in the skin with peripheral nerves, mast cells, and eosinophils plays an important role in the mutual activation, the neurobiological mechanisms that lead to pruritus are not completely clear yet.