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ZusammenfassungDieser Beitrag beleuchtet die fast 150 Jahre lange Geschichte der Klinik und Poliklinik für Dermatologie, Venerologie und Allergologie des Universitätsklinikums Würzburg und ihrer Vorgängerinstitutionen von der Gründung bis zur Gegenwart. Dargestellt werden die wichtigsten Entwicklungsschritte von den ersten dermatologischen Vorlesungsinhalten im späten 18. Jahrhundert über die erste eigene Abteilung für Hautkrankheiten in Würzburg im Jahre 1872, die mit dem 1921 erfolgten Bezug des Luitpoldkrankenhauses verbundene Erweiterung des Fachgebiets, die Wirren in der Zeit des Nationalsozialismus und die Modernisierungen in der Nachkriegszeit bis hin zum aktuellen Stand als Klinik der universitären Maximalversorgung mit krankheitsorientierter molekularbiologischer und immunologischer Forschung und Lehre.

BACKGROUND: Bullous pemphigoid is a blistering skin disorder with increased mortality. We tested whether a strategy of starting treatment with doxycycline gives acceptable short-term blister control while conferring long-term safety advantages over starting treatment with oral corticosteroids. METHODS: We did a pragmatic, multicentre, parallel-group randomised controlled trial of adults with bullous pemphigoid (three or more blisters at two or more sites and linear basement membrane IgG or C3). Participants were randomly assigned to doxycycline (200 mg per day) or prednisolone (0·5 mg/kg per day) using random permuted blocks of randomly varying size, and stratified by baseline severity (3-9, 10-30, and >30 blisters for mild, moderate, and severe disease, respectively). Localised adjuvant potent topical corticosteroids (

Background. There are myriads of potentially irritant agents causing acute irritant contact dermatitis. In the large majority of cases, dermatitis is mild to moderate, and patients do not need hospitalization. However, some agents or special circumstances may cause severe dermatitis requiring more intensive therapy. Objectives. The aim of this study was to evaluate causative agents of severe acute irritant contact dermatitis requiring hospitalization. Methods. In this single-centre observational cohort study, we included 54 consecutive patients presenting with signs and symptoms of acute irritant contact dermatitis for which hospitalization was necessary. The severity of dermatitis was graded (grade I-IV) according to intensity, and details related to the skin irritation (irritant agent, area of exposure, time interval to onset of symptoms, and duration of hospitalization) were determined. Results. All cases with severe ulcerative dermatitis (grade IV) were caused by wet cement, owing to prolonged skin contact. These cement burns are clearly associated with amateur work, younger age, male preponderance, and leg localization. Conclusions. The study data provide clear-cut evidence that wet cement is a severely irritant substance that regularly causes the most severe form of acute irritant contact dermatitis. The main causative prerequisite for these cement burns is do-it-yourself work with poor protective measures. Language: en

Background Knowledge about the risk for recurrence and secondary cutaneous melanoma (CM) is an important basis for patient counseling and planning of follow-up examinations. Objectives This study aimed to analyze stage- and time-dependent hazard rates (HR) and discusses current surveillance recommendations. Methods Follow-up data of 33,384 patients with incident CM in stages I to III (American Joint Committee on Cancer 2002) were recorded by the German Central Malignant Melanoma Registry in 1976 through 2007. Survival was based on Kaplan-Meier estimates and HRs were calculated. Results Recurrences were recorded in 4999 patients (stage I, 7.1%; stage II, 32.8%; and stage III, 51.0%). Ten-year recurrence-free survival was 78.9% (95% confidence interval 73.1-90.5); in stage I, 89.0%; stage II, 56.9%; and stage III, 36.0%. Whereas HR for recurrent CM showed a constantly low level less than or equal to 1:125 per year for stage IA, clearly higher HRs of greater than or equal to 1:40 were recorded in stage IB for the first 3 years and generally in stages II to III. Of all patients 2.3% developed secondary melanomas, with a consistently low HR of less than 1:220 per year. Limitations As German recommendations discontinued regular follow-up examinations after 10 years, no information can be given beyond this time point. Follow-up data of longer than 5 years were available in 41.4% of patients. Conclusion For patients at stage IA with thin melanoma and low HR for recurrent CM the need for surveillance remains questionable. For patients with higher HR greater than 1:40 per year, intensified surveillance strategies should be taken into account.

Das Muir-Torre-Syndrom (MTS) ist ein seltenes autosomal-dominant vererbtes Tumorsyndrom, gekennzeichnet durch Auftreten von Talgdrusentumoren und/oder multiplen Keratoakanthomen in Kombination mit internen Neoplasien. An der Haut kommen neben Talgdrusenadenomen und Sebazeomen v. a. Talgdrusenkarzinome vor, die in uber 50% mit kolorektalen Karzinomen, seltener mit Karzinomen des ubrigen Gastrointestinal- oder Urogenitaltrakts assoziiert sind. Pathogenetisch liegt ein Defekt des DNA-Mismatch-Repair-Systems zugrunde, wodurch Mikrosatelliteninstabilitat im Tumorgewebe resultiert.

Apoptosis of single keratinocytes (KC) is a characteristic feature of spongiosis formation, the histopathologic hallmark of acute eczematous dermatitis. In acute eczema, activated dermis-infiltrating T cells secrete several proinflammatory cytokines which might be decisive for KC apoptosis or survival. We analyzed the role of tumor necrosis factor alpha (TNF-α) in the determination of KC fate during spongiosis formation in acute eczematous dermatitis. Supernatants of activated human CD4(+) T cells induced apoptosis in primary KC, which could be fully inhibited by individual blockade of interferon-γ (IFN-γ) and CD95 but not by neutralization of TNF-α activity. As compared to CD95-triggering alone, synchronous CD95 and TNF receptor cross-linking in the presence of IFN-γ only marginally enhanced KC apoptosis. Importantly, pre-treatment of KC with TNF-α followed by CD95 stimulation, but not vice versa, significantly amplified KC apoptosis as compared to CD95 stimulation alone. This TNF-α-mediated sensitization to CD95-induced KC cell death could be abrogated by blocking TNF receptor 1 (TNF-R1) but not TNF-R2 mAb. In eczematous dermatitis, the CD95 receptor was expressed throughout the epidermis, whereas immunohistological detection of TNF-R1 was rather restricted to KC around spongiotic vesicle formation. Thus, TNF-α primes KC for CD95-mediated signals which results in an increased susceptibility to apoptosis. TNF-R1 expression and spatial action of TNF-α restricted to spongiotic vesicles promote both CD95-induced KC apoptosis and limitation of spreading KC damage.

To cite this article: Seitz CS, Brocker E-B, Trautmann A. Diagnosis of drug hypersensitivity in children and adolescents: Discrepancy between physician-based assessment and results of testing. Pediatric Allergy Immunology 2011; 22: 405–410. Abstract Background: Diagnosis of drug hypersensitivity is often based on history alone. But such a vague diagnosis may cause limitations of therapeutic options in the future. To confirm or rule out drug hypersensitivity, skin testing, in vitro studies, and challenge tests are necessary. However, the diagnostic value of this complex and time-consuming allergologic work-up, especially in children, remains controversial. Objective: Aim of this retrospective analysis was to compare the results of diagnostic testing in children and adolescents with drug hypersensitivity diagnosed on clinical grounds, i.e., temporal relationship and observation of symptoms alone. Methods: We studied 43 children and adolescents (23 females, 20 males, mean age 13) with a history of immediate or delayed hypersensitivity symptoms in temporal relation to drug treatment using standardized skin testing followed by oral challenges. Patients with suspected penicillin hypersensitivity were further evaluated with in vitro tests. Results: Drug hypersensitivity was excluded in 40 patients by tolerated oral challenge tests with the incriminated drug. In two patients, positive challenge tests confirmed non-steroidal anti-inflammatory drug hypersensitivity. One patient with amoxicillin-associated exanthema developed positive late skin test reactions to aminopenicillins. Conclusion: In childhood and adolescence, allergologic testing in cases of suspected drug hypersensitivity is of importance both to establish a correct diagnosis and to prevent unjustified withholding of a drug or class of drugs.

Basal cell carcinoma (BCC) is the most common neoplasm in the Caucasian population. Only a fraction of BCC exhibits pigmentation. Lack of melanocyte colonization has been suggested to be due to p53-inactivating mutations in the BCC cells interfering with the p53-proopiomelanocortin pathway and the production of alpha melanocyte-stimulating hormone in the tumor. To evaluate this, we determined tumor pigmentation as well as expression of melan-A and of p53 in 49 BCC tissues by means of immunohistochemistry. As expected, we observed a positive relation between tumor pigmentation and melan-A positive intra-tumoral melanocytes. Melanocyte colonization and, to a lesser extent, p53 overexpression showed intraindividual heterogeneity in larger tumors. p53 overexpression, which is indicative of p53 mutations, was not correlated to melanocyte colonization of BCC. Sequencing of exon 5–8 of the p53 gene in selected BCC cases revealed that colonization by melanocytes and BCC pigmentation is neither ablated by p53 mutations nor generally present in BCCs with wild-type p53.

Chelation therapy with (RS)-2,3-Bis(sulfonyl)propane-1-sulfonic acid (DMPS) after an occupational lead exposure led to the development of a severe bullous drug eruption. Skin tests and histology/immunohistology of the test reactions indicated a T-cell-mediated immune response against DMPS. Metal-binding thiol groups as in DMPS are chemically highly reactive and therefore effectively mediate the development of immunogenic hapten (DMPS)-protein complexes. Therefore, the pharmacological effects and sensitization potential of dithiols are tightly connected. Cross-reactivity of DMPS to other chelators like D-penicillamine is possible; the indications for chelation therapy should be weighed carefully.

Summary. Phaeohyphomycotic cysts developed on the right knee of a 72-year-old woman undergoing immunosuppressive treatment for ulcerative colitis 6 years after accidental inoculation of soil in a bicycle accident. The lesions were red, firm, slightly raised, 0.5–1 cm in size and completely asymptomatic. The diagnosis was made by histo-pathological examination of three excised cysts and by repeated isolation of Exophiala jeanselmei in pure culture. The excised cyst walls contained large numbers of dematiaceous fungal elements in the form of hyphae, yeast-like cells and some cells dividing internally by a transverse septum. The patient was treated with 200 mg of itraconazole daily, but the treatment had to be stopped because of severe side-effects after 6 weeks. Histologically the cysts were cleared of dematiaceous elements, but E. jeanselmei could still be isolated from one of two skin biopsies 1 month after the end of therapy. Zusammenfassung. Bei einer 72-jahrigen Frau, die wegen einer Colitis ulcerosa mit Kortiko-steroiden behandelt wurde, entwickelten sich 6 Jahre nach einem Fahrradunfall und einer leichten Verletzung im Bereich des rechten Knies phaeo hyphomykotische Zysten. Die Hautveranderungen waren rot, fest in der Beschaffenheit, leicht erha-ben, ungefahr 0.5–1 cm gros und vollkommen asymptomatisch. Die Diagnose konnte erst nach histopathologischer Untersuchung und wiederhol-ter Isolierung von Exophiala jeanselmei in Reinkultur gestellt werden. Im Bereich der Zystenwande fanden sich grose Mengen an pigmentierten Pilz-elementen in Form von Hyphen, hefeartigen Zellen und einigen Zellen, welche sich mit einem transversen Septum teilten. Nach Diagnosesstel-lung wurde eine Therapie mit Itraconazol 200 mg pro Tag oral begonnen. Aufgrund von Nebenwir-kungen muste die Behandlung nach 6 Wochen abgesetzt werden. Bei der histologischen Untersuchung fanden sich keine Pilzelemente mehr, aber E. jeanselmei konnte aus einem von zwei Hautbiop-saten einen Monat nach Therapieende isoliert werden.

Pilomatricomas are benign skin tumors originating from hair follicle matrix cells. In 2% to 3.5% of cases they occur in multiplicity and then may be associated with genetic diseases, such as myotonic dystrophy Curschmann-Steinert, familial adenomatous polyposis (Gardner syndrome), and Rubinstein-Taybi syndrome. A 15-year-old boy treated with temozolomide and oxcarbazepine for gliomatosis cerebri with symptomatic epilepsy developed four firm cutaneous nodules on his face and right upper arm in the course of 1 year. All four tumors were excised under local anesthesia. Histological examination confirmed the clinical diagnosis of pilomatricomas. This is the first published case of a patient suffering from gliomatosis cerebri and developing multiple pilomatricomas. Whether this observation represents a new association or is a mere coincidence cannot be clarified at present.

Merkel cell carcinoma (MCC) is a highly aggressive neuroendocrine carcinoma of the skin. The incidence of this rare tumor is increasing rapidly; the American Cancer Society estimates for 2008 almost 1500 new cases in the U.S. Thus, the incidence of MCC will exceed the incidence of cutaneous T-cell lymphoma. Moreover, the mortality rate of MCC with 33% is considerably higher than that of cutaneous melanoma. These clinical observations are especially disturbing as we are only recently beginning to understand the pathogenesis of MCC. For the same reason, the therapeutic approach is often unclear; reliable data are only available for the therapy of locoregional disease.

This study analysed the changes of excision margins in correlation with tumour thickness as recorded over the last three decades in Germany. The study also evaluated surgical management in different geographical regions and treatment options for metastasized melanoma. A total of 42 625 patients with invasive primary cutaneous melanoma, recorded by the German Central Malignant Melanoma Registry between 1976 and 2005 were included. Multiple linear regression analysis was used to investigate time trends of excision margins adjusted for tumour thickness. Excision margins of 5.0 cm were widely used in the late 1970s but since then have been replaced by smaller margins that are dependent on tumour thickness. In the case of primary melanoma, one-step surgery dominated until 1985 and was mostly replaced by two-step excisions since the early 1990s. In eastern Germany, one-step management remained common until the late 1990s. During the last three decades loco-regional metastases were predominantly treated by surgery (up to 80%), whereas systemic therapy decreased. The primary treatment of distant metastases has consistently been systemic chemotherapy. This descriptive retrospective study revealed a significant decrease in excision margins to a maximum of 2.00 cm. A significant trend towards two-step excisions in primary cutaneous melanoma was observed throughout Germany. Management of metastasized melanoma showed a tendency towards surgical procedures in limited disease and an ongoing trend to systemic treatment in advanced disease.

Behcet's disease is a chronic relapsing systemic vasculitis of unknown etiology, affecting predominantly oral and genital mucocutaneous tissues and also the eyes. The disease is spread worldwide with a higher prevalence rate in countries along the ancient Silk Route, but it is rare (1-10/100,000) in Central and Northern Europe. Genetic, environmental, immunologic, inflammatory and rheologic factors are involved in the pathogenesis and the course of the disease. Any vascularized organ may be affected. Eye involvement is frequent, and may eventually result in loss of vision. Further important complications are cerebral manifestations, thrombotic syndromes, and arterial aneurysms with a high risk of rupture. Diagnosis and therapy of Behcet's disease are best managed by an interdisciplinary team. Skin lesions may be controlled by systemic treatment with colchicine, alternatively with dapsone, and in severe cases with thalidomide. Active systemic disease should be treated more aggressively using immunosuppressants. Despite advances in treatment relapses are still frequent, and systemic disease remains associated with an adverse prognosis.

Transient aquagenic palmar hyperwrinkling (TAPH) is a rarely reported cutaneous condition clinically characterized by swelling and hyperwrinkling of the palms, and associated with burning sensations after briefly immersing the hands in water. Upon the withdrawal of water, the symptoms rapidly disappear. We report on a 10-year-old boy with type I diabetes, who developed the typical symptoms of TAPH concomitantly with the onset of palmar hyperhidrosis. Determination of the sodium chloride concentration of the sweat revealed elevated levels. Subsequent screening for the most common mutations of the gene responsible for cystic fibrosis (CF) was negative. Review of the literature shows that TAPH may develop in conditions of increased water absorption due to an increased sweat quantity, such as hyperhidrosis, or an increased sweat electrolyte concentration, such as CF. In the majority of reported cases TAPH has been associated with CF; therefore, it is a cutaneous sign, which should be recognized by dermatologists, and patients should be referred for evaluation of the sodium chloride concentration of the sweat.

Received 3 December 2006; returned 26 February 2007; revised 20 March 2007; accepted 18 April 2007Objectives: Aminopenicillin-induced exanthema poses a problem in the management of infectious dis-eases. Due to theoretically possible immunological cross-reactivity, all b-lactam drugs, i.e. penicillins,penicillin derivatives and cephalosporins, are usually avoided. The available alternative antibiotics(macrolides, quinolones and glycopeptides) may be less effective, have more side effects, and theiruse increases medical costs. Moreover, their use contributes to the increasing bacterial resistance toantibiotics. The aim of the study is to demonstrate that patients with aminopenicillin-inducedexanthema may receive specific b-lactams for future antibiotic therapy.Methods: Skin testing followed by oral challenges to identify b-lactams that are tolerated by patientsdespite confirmed delayed-type non-immunoglobulin E (IgE)-mediated allergic hypersensitivity to ami-nopenicillins.Results: Sixty-nine out of 71 patients (97.2%) with non-IgE-mediated allergic hypersensitivity to amino-penicillins tolerate cephalosporins without an aminobenzyl side chain such as cefpodoxime or cefix-ime and 51 patients (71.8%) also tolerate phenoxymethyl penicillin.Conclusions: The majority of patients with non-IgE-mediated allergic hypersensitivity to aminopenicil-lins do not cross-react to certain cephalosporins or phenoxymethyl penicillin. Skin and drug challengetests can be helpful to determine individual cross-reactivity.Keywords: drug challenge, drug provocation, non-IgE-mediated allergic hypersensitivity, skin tests

To scrutinize published data from small mono-centric studies and case reports which implicated high response rates and promising survival times for a combination therapy consisting of epifocal dinitrochlorobenzene (DNCB) and dacarbazine (DTIC) for metastasized melanoma. This therapy merges the effects of an allergic contact dermatitis elicited at the site of a cutaneous metastasis, and systemic chemotherapy. We performed a retrospective survey with nine German centers and evaluated 72 patients treated from 1993 to 2005. The objective response rate in stage III melanoma (n = 39) was 62%. In contrast, only 9% objective responses were observed in 33 stage IV patients. Interestingly, more than half of patients with objective remissions remained progression-free for more than 1 year irrespective of the stage of disease. Epifocal DNCB combined with DTIC is effective in patients with regionally metastasized melanoma not amenable to surgery or isolated limb perfusion, whereas in stage IV disease in spite of few durable remissions the addition of DNCB does not improve the therapeutic efficacy of DTIC.

Ein 70-jahriger Patient stellte sich mit einer seit 6 Monaten bestehenden, ausgedehnten, grosenprogredienten perianalen Erosion vor. Daruber hinaus fanden sich einige kleinere Erosionen mit umgebender weislich retikularer Zeichnung am Penis. Die klinische Diagnose eines erosiven Lichen ruber wurde histologisch bestatigt. Nach Versagen mehrerer topischer Therapien und Absetzen des β-Blockers konnte der Befund durch 3 Zyklen einer Dexamethason-Pulstherapie (100 mg Dexamethason i.v. an 3 aufeinanderfolgenden Tagen in 4-wochigen Abstanden) zur langfristigen Abheilung gebracht werden.

Background No data are available on the incidence and immunoreactivity of autoimmune subepidermal blistering skin diseases in East Africa. Methods All patients with frank blisters/erosions on the skin and/or mucous membranes that attended the Department of Dermatology at Mbarara University, Uganda, from May 2000 to June 2002, were investigated. The diagnosis was based on the clinical presentation and on the presence of circulating autoantibodies detected by indirect immunofluorescence microscopy on 1 m NaCl-split human skin and by Western blotting of recombinant and cell-derived forms of BP180, BP230, and type VII collagen. Results Twenty-two patients with autoimmune subepidermal blistering skin disorders were identified, including nine with bullous pemphigoid (41%), four with linear immunoglobulin A (IgA) disease (18%), three with mucous membrane pemphigoid (14%), two with linear IgG/IgA bullous dermatosis (9%), and one each with cicatricial pemphigoid and epidermolysis bullosa acquisita (5%). In addition, two patients with immunoreactivity to both the epidermal and dermal side of salt-split skin by indirect immunofluorescence microscopy, who were unreactive to type VII collagen, were provisionally diagnosed as “mixed pemphigoid” (9%). In patients with subepidermal blistering diseases, IgG reactivity correlated significantly with old age, whereas younger patients preferentially developed IgA autoantibodies (P = 0.024). Conclusions The age of patients with autoimmune subepidermal blistering diseases appears to influence the immunoglobulin class of autoantibodies. The high frequency of IgA autoantibodies in Ugandan patients may be explained by the age distribution of the Ugandan population.

Treatment of autoimmune blistering diseases consists of systemic glucocorticosteroids usually in combination with additional immunosuppressants such as azathioprine and mycophenolate mofetil or immunomodulators such as dapsone, antibiotics, intravenous immunoglobulins, and immunoadsorption. In some patients, these treatment regimens are not sufficient to control disease activity and/or lead to intolerable adverse events. Rituximab, originally developed for the treatment of non-Hodgkin's lymphoma, is an anti-CD20 humanized monoclonal antibody leading to transitory B-cell depletion. For this indication, rituximab is widely employed, and severe side-effects rarely observed. Subsequently, the B-cell-depleting effect of rituximab has been exploited successfully in various autoimmune disorders, including autoimmune blistering diseases. Here, we review the effect of rituximab in such diseases. To date, application of rituximab has been reported in 26 treatment-resistant patients with the vulgaris, foliaceus, and paraneoplastic variants of pemphigus as well as in bullous pemphigoid and epidermolysis bullosa acquisita. All but a single patient showed clinical improvement with reduction of lesion formation. In about a third, a clinical remission requiring further immunsuppressive medication was achieved, and in about a quarter, complete remission was induced. In addition, the mode of action and adverse events of rituximab as well as adjuvant immunosuppressive treatments, and the effect on levels of circulating autoantibodies in these patients are discussed.

Ein 40-jahriger Mann mit einer seit 3 Jahren bekannten Thrombozytopenie stellte sich wegen retikularer und gesprenkelter Hyper- und Hypopigmentierungen besonders im Bereich des Thorax und der oberen Extremitaten vor. Die Mehrzahl der Finger- und Fusnagel fehlte oder war dystroph. Hinzu kamen ein weitgehender Verlust der Zahne sowie multiple Leukoplakien an Zunge und Mundschleimhaut. Weiterhin zeigte sich eine Atresie der Tranenkanale. Aufgrund der typischen Befundkonstellation stellten wir die Diagnose einer X-chromosomal vererbten Dyskeratosis congenita (Zinsser-Engman-Cole-Syndrom, OMIM #305000), die durch Sequenzierung des Gendefekts [Punktmutation im Exon 11 des Dyskerin 1 (DKC1)-Gens] bestatigt werden konnte.

We report on a 24-year-old, male Ugandan patient with a 2-week history of itchy papules, vesicles, erosions, and crusts distributed on the entire body, accompanied by minor erosions on the palate, tongue, and lower lip. Conjunctivae and genital mucosa were not involved. Circulating IgG and IgA autoantibodies were found against recombinant full-length BP180, BP180 4575, and the C-terminus of BP230. In addition, IgG reactivity was observed against the 16th noncollagenous region of the BP180 ectodomain, the cell-derived soluble ectodomain of BP180 (linear IgA disease antigen 1), and the alpha3 and gamma2 chains of laminin 5. No reactivity was detected with type VII collagen, alpha6beta4 integrin, and the p200 protein. Oral prednisolone and dapsone led to clearance of lesions that mostly healed with scarring and milia formation. Here, we describe a scarring mucocutaneous variant of an autoimmune blistering skin disorder that extends the current clinical and immunopathologic spectrum of this group of diseases.

Summary A 70-year-old patient presented erosions on the oral mucosa and skin, predominantly in perianal and inguinal areas. Histopathologically, subepidermal blistering was observed. By direct immunofluorescence microscopy, linear deposits of IgG and C3 were seen at the dermal-epidermal junction. By indirect immunofluorescence microscopy, binding of IgG autoantibodies to the dermal side of NaCl-split skin was detected. These autoantibodies were shown to target both the non-processed and processed α3- as well as the β3-subunit of laminin 5 by immunoblot analysis using extracellular matrix of cultured human keratinocytes. Based on these results, the diagnosis of an anti-laminin 5 mucous membrane pemphigoid was established. Oral treatment with dapsone, combined with intravenous dexamethasone pulse therapy, led to rapid improvement. Zusammenfassung Ein 70-jahriger Patient litt an einer ausgepragten ulzerosen Stomatitis sowie Erosionen der Haut, vorwiegend perianal und inguinal. Die Histologie zeigte eine subepitheliale Spaltbildung, die direkte Immunfluoreszenz lineare Ablagerungen von IgG und C3 an der dermo-epidermalen Junktionszone. In der indirekten Immunfluoreszenz auf NaCl-separierter humaner Spalthaut fanden sich IgG-Autoantikorper, die am Boden der artifiziellen Blase banden. Im Immunoblot mit extrazellularer Matrix kultivierter humaner Keratinozyten erkannten diese die prozessierte und nicht prozessierte α3-Kette sowie die β3-Untereinheit von Laminin 5. In Zusammenschau dieser Befunde diagnostizierten wir ein Schleimhautpemphigoid vom anti-Laminin 5-Typ. Unter oraler Gabe von Dapson und intravenoser Pulstherapie mit Dexamethason konnte eine rasche Besserung erzielt werden.

Zusammenfassung Die von der grundlagenwissenschaftlichen und translationalen Forschung erarbeiteten Erkenntnisse uber die Ursachen und Mechanismen der Melanomentstehung und -progression werden sich in den nachsten Jahren auf die Therapie auswirken. Die zunehmende Aufklarung der molekularen Pathogenese maligner Erkrankungen und die differenzierte Analyse der verschiedenen Signal- und Regulationswege innerhalb und auserhalb der malignen Zelle fuhrte zu neuen, relativ spezifischen Ansatzpunkten, um in den malignen Prozess einzugreifen. Diese Interventionen zielen auf einzelne Molekule ab, welche mit der malignen Grunderkrankung assoziiert sind oder sie sogar induzieren, weshalb diese Interventionen auch als „targeted therapy” bezeichnet werden. Diese Arbeit gibt eine kurze Ubersicht uber therapeutische Moglichkeiten, welche auf einer Modulation der Ras/MAPK- und des PI3K/AKT-Signaltransduktionsweges abzielen. Summary Recent results from basic and translational research on the causes and mechanisms of melanoma genesis and progression will impact on future therapeutic approaches. The increasing understanding of the molecular pathology of malignant disease and the detailed analysis of the signal transduction pathways involved allows specific intervention with these oncogenic events. These interventions address the molecules associated with or responsible for the malignant transformation and have therefore been termed “targeted therapy”. The present review focuses on the therapeutic options involving modulation of the Ras/MAPK- and PI3K/AKT-signal transduction pathways.

Background Recently, it has been shown that UVB phototherapy may be more effective than UVA in the treatment of vitiligo. Currently, however, no studies have compared the efficacy of UVB311 nm and broad-band UVB therapy. Calcipotriol has recently been reported to be effective adjunctive treatment for vitiligo, enhancing the efficacy of 8-methoxypsoralen plus UVA (PUVA) therapy. Methods Ten patients were enrolled in the study; nine completed the 12 months of therapy. The upper part of the body was treated twice weekly with UVB311 nm and the lower part with broad-band UVB. Calcipotriol was applied onto the vitiligo lesions of the right side of the body and placebo on the left side. Repigmentation was documented by photography, planimetry, and Vitiligo Disease Activity (VIDA) score. The quality of life was measured by the Dermatology Life Quality Index (DLQI). Results After 7–16 weeks, six of the nine patients showed initial repigmentation on the side treated with UVB311 nm. After 6 months of treatment, none of the patients showed repigmentation on the areas treated with broad-band UVB, which prompted us to apply UVB311 nm all over the body. At the end of 12 months, two patients showed > 75% repigmentation, two showed 51–75%, two showed 26–50%, and three showed 0–25%. In all patients with progressive vitiligo (seven of the nine patients), disease activity was stopped. Remarkably, vitiligo lesions treated with calcipotriol initially showed delayed repigmentation compared with control areas; however, there was no therapeutic difference between calcipotriol and placebo, both in combination with UVB311 nm, by the end of the study. The DLQI score improved significantly by an average of 28%. Conclusion UVB311 nm therapy was effective in the treatment of vitiligo, whereas broad-band UVB had no effect. Combination with calcipotriol ointment was not superior to UVB311 nm monotherapy. The quality of life significantly improved with narrow-band UVB311 nm phototherapy.

Bullous pemphigoid (BP) is an autoimmune blistering skin disease associated with circulating autoantibodies to the hemidesmosomal antigens BP180 and BP230. We report two cases of therapy-refractory BP adjuvantly treated by tryptophan immunoadsorption. In both patients, this treatment was associated with rapid clinical improvement and reduction in the required corticosteroid dosage. In addition, levels of circulating anti-BP180 autoantibodies decreased markedly. Antibodies that were eluted from the tryptophan matrix bound to BP180 and induced dermal-epidermal separation in cryosections of human skin. Our observations suggest that immunoadsorption may be a helpful adjuvant treatment in severe BP.

Matrix metalloproteinases (MMPs) are essential for tumor progression, invasion and metastases formation. Expression of these proteinases is not only restricted to the tumor cells themselves, but also is found in normal stromal cells. Moreover, immunohistochemistry suggests stromal cells as the major source. To scrutinize this hypothesis we established a slowly growing, syngeneic tumor model using the B16-melanoma cell line B78D14. In vitro analysis demonstrated that B78D14 cells secreted MMP-2, MT1-MMP, and to a lesser degree MMP-9; in addition they expressed both MT1-MMP and EMMPRIN on their surface. In subcutaneous (s.c.) tumors of these cells MMP-2 expression was predominantly present at the tumor-stroma border indicating stromal cells as primary source for this protease in vivo. Indeed, double staining experiments and in situ zymography confirmed that tumor adjacent stromal cells at the invasive front expressed MMP-2 and only at this site activated MMP-2 was detectable. Notably, in an experimental pulmonary metastases model neither tumor nor stromal cells expressed MMP-2, suggesting that the capacity of stromal cells is largely dependent on the surrounding microenvironment.

The mainstay of treatment of pemphigus vulgaris is systemic corticosteroids. Intravenous immunoglobulins have been reported as an adjuvant corticosteroid-sparing regimen in recalcitrant pemphigus vulgaris. The purpose of the study was to monitor disease activity, serum levels of autoantibodies and doses of oral corticosteroids in 4 patients with recalcitrant pemphigus vulgaris adjuvantly treated with intravenous immunoglobulins (2 g kg(-1) monthly). After initiation of intravenous immunoglobulins, all patients showed clinical improvement and a decrease in autoantibody serum levels, as detected by both indirect immunofluorescence microscopy and ELISA. Corticosteroids and immunosuppressants could be reduced and even discontinued in one patient. In 3 patients, intravenous immunoglobulins were discontinued after 12 cycles. Subsequently, new blisters developed and autoantibody levels rose again. After re-initiation of intravenous immunoglobulins, in 2 patients, the condition quickly improved again, along with a decrease in autoantibody serum levels. It is concluded that the administration of intravenous immunoglobulins was associated with a decrease in circulating autoantibodies and clinical improvement in our patients.

Anti-p200 pemphigoid is an autoimmune subepidermal blistering disease characterized by autoantibodies to a 200-kDa protein (p200) of the dermal–epidermal junction (DEJ). p200 has been demonstrated to be distinct from all major DEJ autoantigens and is thought to be important for cell-matrix adhesion. This study provides the first biochemical characterization of p200. Differential extraction experiments demonstrated that efficient recovery of p200 from the dermis was strongly dependent on the presence of reducing agents, suggesting that it forms highly insoluble oligomers and/or is extensively cross-linked to other extracellular matrix components by disulfide bonding. p200 was resistant to digestion with bacterial collagenase, whereas this treatment did degrade major collagenous proteins of the dermis, including type I, VI, and VII collagen. This finding firmly established the noncollagenous nature of p200. N-Glycosidase F reduced the molecular size of the p200 autoantigen from 200 to 190 kDa without decreasing its immunoreactivity. In contrast, digestion of p200 with neuraminidase, O-glycosidase, chondroitinase ABC, and heparitinase I had no effect on its electrophoretic mobility. These data suggest that the p200 molecule contains N-glycans but lacks O-linked oligosaccharides and chondroitin/heparan sulfate side chains. Two-dimensional gel electrophoresis demonstrated that p200 is an acidic protein with an isoelectric point of 5.4 to 5.6. Six different p200-specific sera recognized an identical protein spot of two-dimensionally separated dermal extracts, confirming that patients with this novel autoimmune disease indeed form a single pathobiochemical entity.

The skin and the mucosa of the respiratory and gastrointestinal tracts are continuously exposed to microorganisms, but only a limited number of these enter the body and cause disease. To resist microbial infection, the host has developed a multitude of defense mechanisms involving the innate and adaptive immune systems. Dendritic cells (DCs) provide the link between these arms of the immune system. The initiation of an immune response is critically dependent on the activation of DCs, which can discriminate between different classes of microorganisms and elicit tailored antimicrobial immune responses. They have an extraordinary capacity to stimulate naive T cells and initiate primary immune responses. In turn, some pathogens interfere with DC function to block or delay their elimination by the host. Progress in understanding the role of DCs in the host response to microbes is reviewed.

Morbus Kohlmeier-Degos is a rare systemic disease characterized by pathognomonic cutaneous lesions with typical histology. We report the case of a 22-year-old woman with a benign course of this disease and discuss therapeutical options. The patient presented with whitish papules on neck, trunk and extremities that slowly developed within seven months. Examination of the skin revealed about 20 papules of 2-5 mm size. The lesions were partly skin-colored, partly with an erythematous rim and showed a central porcelain-like atrophy. Histology showed an interface-dermatitis and a wedge-shaped mucin deposition with sclerosis of the upper reticular dermis. Organ manifestation was absent. The patient was started on a daily therapy of 300 mg acetyl salicylic acid. Over the course of 24 months single new lesions appeared at a reduced frequency. Apart from the malignant form of Morbus Kohlmeier-Degos there exists a benign course which may be successfully controlled with anti-platelet therapy. We speculate that the lack of vessel occlusion in the histology could be a hallmark of a benign form of this rare disease.

Local therapies have been highly effective in the treatment of melanoma. The objective of this study was to evaluate the use of a novel intralesional chemotherapy - cisplatin/adrenaline injectable gel - for the treatment of refractory or recurrent cutaneous and soft tissue melanoma metastases. The gel is injected directly into the lesion and delivers high concentrations of cisplatin at the injection site, where it is retained for extended periods, with little systemic exposure. A total of 28 patients with refractory or recurrent melanoma were enrolled in this open-label, multicentre study. Of these, 25 patients with 244 lesions were evaluable for efficacy. Lesions were injected with 0.5 ml (2 mg cisplatin + 0.05 mg adrenaline) of gel/cm(3) of tumour. Patients received up to six weekly treatments within an 8 week period. The objective response rate (complete responses [CRs] plus partial responses [PRs]) for all the tumours treated (1-72 per patient) was 53% (130 out of 244; 114 CRs, 16 PRs). The response rate for the target tumours (i.e. each patient's single, most symptomatic, largest or most threatening tumour) was 44%. The median response duration for all tumours was 347 days (range 30-783 days) and median number of treatments per tumour was five (range one to twelve). Systemic toxicity was negligible; local adverse reactions such as erythema, necrosis or pain occurred frequently, but were easily managed in most cases. In conclusion, cisplatin/adrenaline injectable gel was well tolerated, easy to administer, and effective in treating metastatic melanoma confined to the skin or soft tissues.

Summary Background: Scleromyxoedema is a rare disease of unknown aetiology that is characterized by deposition of mucin and sclerotic induration of the skin; it is associated with paraproteinaemia. Patients suffer from progressive disability due to immobilization and cosmetic disfigurement. Treatment of scleromyxoedema is a therapeutic challenge. The antimalarial hydroxychloroquine has a rapid and reliable effect in reticular erythematous mucinosis. Patients and methods: Four consecutive patients (two women, two men; median age: 50 years) with scleromyxoedema, three of them with IgG λ paraprotein, were treated with hydroxychloroquine. Treatment was initiated with 600 mg p. o. for 10 days, followed by 400 mg for at least 4 weeks, and 200 mg thereafter. Results: Complete remission of skin manifestations was achieved in one patient, whereas three patients achieved a partial remission of 61+, 5 and 25 months' duration. Notably, three patients felt increased mobility and reduced firmness of skin during the first week of treatment, which was reflected in a rapid reduction in dermal thickness. In one patient, dysphagia was reverted as evidenced by normalization of oesophageal clearance. Paraproteinaemia was not influenced at all. Side effects included one case of electroretinogram abnormalities after 19 months of therapy and one case of leucopenia after 3 months. Conclusion: Hydroxychloroquine is an effective form of therapy for scleromyxoedema, leading to rapid and prolonged alleviation of symptoms. Zusammenfassung Hintergrund: Das Skleromyxodem ist eine seltene Erkrankung unbekannter Atiologie, die durch eine Muzineinlagerung und Sklerosierung der Haut charakterisiert ist; haufig ist eine Paraproteinamie assoziiert. Die Patienten leiden unter zunehmender Versteifung und kosmetischer Beeintrachtigung. Das Skleromyxodem stellt eine therapeutische Herausforderung dar. Das Antimalaria-Mittel Hydroxychloroquin hat einen schnellen und zuverlassigen Effekt bei der retikularen erythematosen Muzinose. Patienten und Methodik: Vier konsekutive Patienten (zwei Frauen, zwei Manner, medianes Alter 50 Jahre) mit Skleromyxodem, das in drei Fallen mit einer IgG-λ-Paraproteinamie assoziiert war, wurden mit Hydroxychloroquin behandelt. Die Initialdosis war 600 mg per os fur 10 Tage, in den folgenden vier Wochen 400 mg und danach 200 mg taglich. Ergebnisse: Ein Patient kam in komplette Remission, die anderen drei Patienten zeigten eine partielle Remission von 61+, 5 und 25 Monaten Dauer. Bemerkenswerterweise trat bei drei Patienten eine subjektiv bessere Mobilitat und verminderte Verhartung der Haut schon in der ersten Behandlungswoche auf, die durch eine schnelle Reduktion der Dermisdicke objektiviert wurde. Bei einem Patienten besserte sich eine Dysphagie parallel zu einer Normalisierung der oesophagealen Clearance. Die Paraproteinamie wurde nicht beeinflusst. Als Nebenwirkungen traten bei einer Patientin nach 19 Monaten Therapie Elektroretinogramm-Veranderungen auf, bei einer Patientin wurde eine Leukopenie nach drei Monaten beobachtet. Schlusfolgerung: Hydroxychloroquin stellt eine effektive Behandlungsmoglichkeit des Skleromyxodems dar, die zu schneller und dauerhafter Symptomlinderung fuhrt.

Zusammenfassung Neue Erkenntnisse uber T-Lymphozyten, Keratinozyten und deren Interaktion fuhren zu einem besseren funktionellen Verstandnis der ekzematosen Entzundung und konnen sowohl das klinische wie auch das histologische Bild des Ekzems plausibel erklaren. Neben aktivierten Endothelzellen und Adhasionsmolekulen steuert ein komplexes Zusammenspiel verschiedener Chemokine die Rekrutierung der T-Lymphozyten aus den Blutgefasen und die Migration in die Dermis und Epidermis. Die T-Lymphozyten schadigen die Epidermis durch proinflammatorische Zytokine und konnen uber „Killermolekule” den apoptotischen Zelltod einzelner Keratinozyten verursachen. Es kommt zur Degradierung von Adhasionsmolekulen auf Keratinozyten und damit zur Auflosung des epidermalen Zellverbandes (Spongiose). Die Keratinozyten aktivieren daraufhin Reparaturmechanismen, die beim chronischen Ekzem Akanthose und Parakeratose zur Folge haben. Summary New experimental results on the role of T cells and keratinocytes have led to a better understanding of eczematous inflammation and can help explain both the clinical and histological pictures of eczema. Besides activated endothelial cells and adhesion molecules, a complex interaction of numerous chemokines controls the recruitment of T cells from the blood vessels and their migration into the dermis and epidermis. Activated T cells damage the epidermis by pro-inflammatory cytokines and can induce apoptosis of individual keratinocytes through “killer molecules”. Cleavage of adhesion molecules on keratinocytes leads to spongiotic changes. Keratinocytes then activate repair mechanisms, which cause acanthosis and parakeratosis in chronic eczema.

Most patients with epidermolysis bullosa acquisita develop an autoimmune response to the non-collagenous (NC) 1 domain of type VII collagen. We report a 4-year-old girl of white European descent presenting with widespread blistering disease involving the face, hands, genital area and oral mucosa. Histopathology revealed subepidermal blisters, and linear deposits of IgG and C3 were seen along the dermal-epidermal junction on direct immunofluorescence (IF) microscopy of a perilesional skin biopsy. On indirect IF microscopy, circulating autoantibodies exclusively stained the dermal side of 1 mol L-1 NaCl-split skin. The patient's IgG autoantibodies labelled a 290-kDa protein on Western blotting of dermal extracts, and reacted with the NC1, NC2 and triple helical domains of type VII collagen on immunoblotting of recombinant and cell-derived fragments obtained by pepsin and collagenase digestion of the full-length protein. Oral methylprednisolone and dapsone led to clearance of lesions, which healed with mild scarring and milia formation. Treatment was discontinued after 1 year and the patient has now been in remission for more than 3 years.

Das Melanom der Haut ist ein invasiv wachsender und fruhzeitig metastasierender Tumor. Fur die Ablosung einzelner Melanomzellen vom Primartumor, Migration dieser Zellen durch Basalmembranen, Extravasation aus Blut- und Lymphgefasen bis hin zur Bildung von Fernmetastasen ist ein komplexes Zusammenwirken von Tumorzellen, extrazellularer Matrix (ECM) und den tumorumgebenden Bindegewebszellen notwendig. Diese Prozesse erfordern die koordinierte Expression und/oder deren Aktivierung von proteolytischen Enzymen. Neben Aspartyl- und Cysteinproteinasen sind daran insbesondere Serinproteinasen mit den Komponenten des Plasminogenaktivierungssystems (uPA, uPAR, tPA, PAI-1 und PAI-2) sowie die Matrix-Metalloproteinasen (MMP) mit ihren spezifischen Inhibitoren (TIMP) beteiligt. Die Interaktion von Melanomzellen mit Zellen oder Komponenten der ECM erfolgt uber spezifische Adhasionsrezeptoren, wie z. B. Integrine oder CD44, die z. T. auch funktionell aktive Proteinasen binden konnen. In dieser Ubersichtsarbeit werden diese funktionellen Aspekte und ihre Bedeutung fur die Melanomprogression dargestellt.

Die Fanconi-Anamie ist ein seltenes, autosomal-rezessiv vererbtes Fehlbildungssyndrom mit variabler klinischer Expression. Bisher konnten 8 verschiedene genetische Komplementationsgruppen charakterisiert werden; fur 4 von ihnen wurde das Gen bereits kloniert. Klinisches Leitsymptom ist eine in den ersten Lebensjahren auftretende Panmyelopathie. Diese und das erhohte Risiko der Entwicklung von akuten myeloischen Leukamien, Lebertumoren und mukokutanen Stachelzellkarzinomen fuhren dazu, dass die meisten Betroffenen das Erwachsenenalter nicht erreichen. Zudem konnen Fehlbildungen an verschiedenen Organsystemen und am Skelett auftreten. Charakteristische Hautveranderungen sind flachige Hyperpigmentierungen, kleinfleckige Hypopigmentierungen und Cafe-au-lait-Flecken, die schon vor Manifestation der Panzytopenie auftreten und zu einer fruhzeitigen Diagnosestellung beitragen konnen. Anhand des von uns vorgestellten Falles eines 11-jahrigen Jungen mit Fanconi-Anamie sollen die klinischen Symptome der Erkrankung unter besonderer Berucksichtigung der kutanen Manifestationen beschrieben und ein Uberblick uber Klinik, Verlauf und Therapie der Erkrankung gegeben werden. Ferner werden neuere Erkenntnisse der molekularen Grundlagen des Gendefekts angesprochen.

Selection and activation of T cells is tightly regulated by both antigen-specific receptors and co-receptors to ensure that responses to self antigens are largely avoided. By T cell receptor clonotypic mapping and staining with tetrameric HLA-peptide complexes, we demonstrate the presence of melanocyte differentiation antigen MART-1 specific T cells in the areas of destruction of both neoplastic and normal melanocytic cells in a case of a primary melanoma and its associated hypopigmentation. These self reactive T cells expressed CD94/NKG2 major histocompatibility complex class I specific C-type lectin-like receptors. This family of receptors includes both activating and inhibitory isoforms. Thus, we performed a detailed analysis that revealed the exclusive presence of inhibitory NKG2-A/B receptors in the vitiligo-like leukoderma, whereas both the inhibitory receptors and the activating NKG2-C/E isoforms were present within the tumor. Our data suggest the differential expression of killer inhibitory receptors as a possible mechanism to regulate T cell responses to self antigens.

Eosinophilic ulcers of the oral mucosa represent a rare, self-limiting disease of unknown origin. Single lesions occur typically in the oral cavity or on the lower lip. Characteristically, they have a short history and resolve spontaneously. Diagnosis is verified by the histologic feature of a deep polymorphic inflammatory infiltrate with numerous eosinophils. The clinical aspect shows a usually nontender ulcer with a white or yellowish base and elevated indurated borders or a tumor with central ulceration. Lymphadenopathy is not found. Differential diagnoses include malignant tumors and the primary stage of syphilis. We present three cases recently diagnosed in our department to show the characteristics and the different appearances of the disease. A 74-year-old woman presented with an ulcer at the base of the tongue, a 59-year-old man had one on the lower lip, and in a 48-year-old man the lesion was atypically located at the edge of the mouth. Here we demonstrate the importance of knowledge of the disease, its course, and the characteristic histology to avoid troublesome diagnostic and therapeutic procedures.

Bullous pemphigoid (BP), pemphigoid (herpes) gestationis (PG), cicatricial pemphigoid (CP), and lichen planus pemphigoides (LPP) are autoimmune subepidermal bullous diseases that are characterized by circulating autoantibodies to the transmembrane hemidesmosomal protein BP180/type XVII collagen. Previous studies demonstrated that the majority of patients with BP, PG, and LPP show antibodies to an immunodominant, membrane-proximal non-collagenous domain (NC16A) on the extracellular portion of BP180. By the use of non-overlapping peptides of the NC16A domain, we previously demonstrated that autoantibodies from BP and PG patients mainly react with epitopes clustered within the N-terminus of this immunodominant site of BP180; antibodies from patients with LPP also recognized the C-terminal portion of NC16A. However, some of these results had been obtained indirectly by preadsorption studies. The aim of the present study was to analyze the fine specificity of IgG autoantibodies to NC16A in sera from patients with CP and to compare their reactivity with antibodies from BP, PG, and LPP patients using a series of new overlapping fragments covering the entire NC16A domain. We confirm that BP and PG sera mainly react with N-terminal epitopes of NC16A, whereas sera from patients with LPP also bind to C-terminal portions, of this domain. Interestingly, out of ten patients with CP, the sera of seven reacted with NC16A; within NC16A, these sera bound to both C-terminal fragments and an N-terminal epitope right next to the cell membrane. Our data demonstrate a heterogeneous binding pattern of autoantibodies to BP180 NC16A in patients with CP.