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PURPOSE We have previously reported on the 3-year results of the phase III German Dermatologic Cooperative Oncology Group trial (DeCOG; ClinicalTrials.gov identifier: NCT02434107 ) comparing distant metastasis-free survival (DMFS), recurrence-free survival (RFS), and overall survival (OS) in patients with positive sentinel lymph-node biopsy who were randomly assigned to complete lymph node dissection (CLND) or observation. Here, we report the final analysis with 72 months of median follow up. PATIENTS AND METHODS The multicenter randomized phase III trial included patients with cutaneous melanoma of the trunk and extremities who were randomly assigned (1:1) to undergo CLND or observation. DMFS was analyzed as the primary end point, and RFS, OS, and recurrences in the regional lymph node basin were secondary end points. The analysis was by intention to treat. Disease and survival information were collected quarterly. RESULTS From January 2006 to December 2014, 5,547 patients were screened to identify 1,256 with metastases in the sentinel lymph node (SLN). Of these, 483 (39%) were included: 241 in the observation arm and 242 in the CLND arm. In the final analysis, median follow up was 72 months (interquartile range, 67-77 months). No significant treatment-related difference was seen in the 5-year DMFS between the observation and CLND arms (67.6% v 64.9%, respectively; hazard ratio [HR], 1.08; P = .87). The 5-year RFS and OS also showed no difference (HR, 1.01 and 0.99, respectively). Grade 3 and 4 adverse effects occurred in 32 patients (13%) in the CLND arm; lymphedema (n = 20) and delayed wound healing (n = 5) were most common and no serious adverse events were reported. CONCLUSION The final results of the German Dermatologic Cooperative Oncology Group trial with a median follow up of 72 months showed higher event rates, but similar HRs compared with those at the 3-year analysis. These results confirm that immediate CLND in SLN-positive patients is not superior to observation in terms of DMFS, RFS, or OS and support not recommending CLND in patients with SLN metastasis.

Two phase III trials of photodynamic therapy (PDT) with BF-200 ALA, a recently approved nanoemulsion formulation of 5-aminolaevulinic acid (ALA) demonstrated high clearance rates in mild-to-moderate actinic keratosis (AK). The comparison to a registered methyl aminolaevulinate (MAL) cream demonstrated significantly superior total patient clearance rates.To evaluate long-term efficacy and safety of PDT for AK 6 and 12 months after the last PDT with BF-200 ALA, MAL or placebo.The follow-up phase (FUP) was performed with patients of two phase III studies. Both studies compared BF-200 ALA with placebo, one of the studies additionally with MAL. Overall recurrence rates and various subgroups (light source, lesion severity, lesion location, complete responders after first PDT) were assessed 6 and 12 months after the last PDT.Recurrence rates were similar for BF-200 ALA and MAL, with a tendency to lower recurrence rates for BF-200 ALA. The proportion of patients who were fully cleared during PDT and remained completely clear for at least 12 months after PDT were 47% for BF-200 ALA (both studies) and 36% for MAL treatment. The subgroup that was illuminated with narrow wavelength LED lamps reached 69% and 53% for BF-200 ALA (both studies, respectively) and 41% for MAL. No safety concerns were reported.The FUP data confirmed the high efficacy and safety of PDT with BF-200 ALA. The slightly lower recurrence rates after BF-200 ALA treatment compared with MAL treatment enhanced the better treatment outcome due to the significantly superior efficacy.

Die heilsame Wirkung des Sonnenlichts war teilweise schon im Altertum bekannt und fand in der zweiten Hälfte des 19. Jahrhunderts wieder zunehmend Beachtung. Den Beginn der modernen Phototherapien markiert die Entwicklung einer Apparatur zur ultravioletten Bestrahlung der Hauttuberkulose durch Finnsen zu Beginn des zwanzigsten Jahrhunderts. Zur Therapie von Hauterkrankungen finden beinahe ausschließlich die spektralen Bereiche unterhalb des sichtbaren Lichtes (ultraviolett) Anwendung. Seit den 1970er Jahren stehen zunehmend leistungsfähige künstliche Strahlenquellen bereit für die Therapie mit UVB, UVA und die Kombination von UVA mit Photosensibilisatoren (Photochemotherapie). Hohe strukturelle und prozedurale Qualitätsstandards sind unabdingbare Voraussetzung für die Durchführung einer gleichermaßen wirkungsvollen wie auch sicheren Phototherapie. Die Leitlinie formuliert den aktuellen Konsens führender Experten auf dem Gebiet der Phototherapie in Bezug auf die Indikationen für die jeweiligen Therapieverfahren, deren Gegenanzeigen und Nebenwirkungen und insbesondere für die Wahl der korrekten Dosis zu Beginn und im Verlauf einer Therapie sowie das Management von Nebenwirkungen.

Known in part since antiquity, the salutary effects of sunlight again garnered increasing attention in the second half of the 19(th) century. The development of a device for ultraviolet irradiation of cutaneous tuberculosis by Finnsen at the onset of the twentieth century truly marked the beginning of modern phototherapy. In dermatology, treatment methods almost exclusively use wavelengths below the visible light range (ultraviolet light). Since the early 1970s, increasingly powerful artificial light sources have become available for UVB and UVA therapy as well as the combination of UVA and photosensitizers (photochemotherapy). High structural and procedural quality standards are an essential prerequisite for the implementation of effective as well as safe phototherapy. The following guidelines outline the current consensus of leading experts in the field of phototherapy with respect to indications, contraindications, and side effects of various treatment options available. Particular focus is also on adequate UV doses at the beginning and over the further course of treatment as well as on management of side effects.

Hintergrund: Photodynamische Therapie in Verbindung mit Methylamino-Lavulinsaure (MAL-PDT) und mit Ingenolmebutat-Gel (IMB) sind zugelassene therapeutische Optionen bei multiplen aktinischen Keratosen (AK). Ziel: Das Ziel dieser randomisierten klinischen Studie mit intraindividuellem Halbseitenvergleich war es, die Behandlungsergebnisse von MAL-PDT und IMB zu vergleichen. Methoden: Zwei symmetrische kontralaterale Areale mit einer vergleichbaren Zahl AK-Lasionen wurden ausgewahlt und per Randomisierung der Behandlung entweder mit einem 3-tagigen IMB-Zyklus oder einer einzelnen MAL-PDT-Sitzung zugeteilt. Am nachsten Tag wurde ein Score zur Beurteilung der lokalen Hautreaktionen (LHR) erhoben. Die Patienten beurteilten die Schmerzen und die Heilungsdauer der behandelten Areale. Ergebnisse: Nach 90 Tagen wurden der Anteil der Lasionen in Vollremission, die Anzahl der Patienten mit Vollremission aller Lasionen, das kosmetische Ergebnis und die Praferenz des Patienten beurteilt. Schlussfolgerung: Unseren Ergebnissen zufolge zeigten IMB und MAL-PDT vergleichbare Wirksamkeit, allerdings war das kosmetische Ergebnis nach MAL-PDT besser. Die Schmerzen waren unter PDT starker, aber unter IMB waren die LHR ausgepragter und die Heilung dauerte langer. Die Patienten bevorzugten die MAL-PDT.

Photosensitivity is an important and distinguishing sign in various subtypes of cutaneous lupus erythematosus (CLE); however, it remains poorly defined. The purpose of this study was to evaluate whether standardized photoprovocation is a reproducible method to assess photosensitivity in subjects with CLE. A total of 47 subjects with CLE (subacute cutaneous lupus erythematosus (SCLE), n=14; discoid lupus erythematosus (DLE), n=20; lupus erythematosus tumidus (LET), n=13) and 13 healthy volunteers underwent photoprovocation at seven European sites. Of these, 22 (47%) subjects (57% SCLE, 35% DLE, and 54% LET) and none of the healthy volunteers developed photoprovoked lesions according to clinical analysis. Of these 22 subjects, 19 (86%) developed lesions that were histopathologically confirmed as specific for lupus erythematosus (LE). In CLE subjects who developed UV-induced lesions, 86% had Fitzpatrick's phototypes I or II, and the mean minimal erythema dose (MED) was significantly lower compared with subjects without UV-induced lesions (P=0.004). No significant differences in photoprovocation results were observed between study sites. Safety parameters showed no clinically meaningful differences between CLE subjects and healthy volunteers after photoprovocation. In conclusion, a standardized, safe, and reproducible protocol for photoprovocation using UVA and UVB radiation induced skin lesions in approximately half of all CLE subjects and showed comparable results across multiple sites. This method may therefore be used for future diagnostic testing and clinical trials.

9501Background: The multicenter DeCOG-SLT trial assessed in a randomized phase 3 trial whether complete lymph node dissection (CLND) resulted in increased survival compared with observation in pati...

Rosacea is one of the most common dermatoses of adults. A good understanding of the illness and its particularities is necessary for the differential diagnoses of the many clinical subtypes and in order to enable a stage- and phase-specific treatment approach. Topical treatments that are widely accepted are metronidazole and azelaic acid; agents under investigation that may have promising therapeutic effectiveness are permethrin and calcineurin inhibitors. Systemically, antibiotics, such as tetracyclines and macrolides, and in severe cases isotretinoin, can be used. Surgically, rhinophymas and teleangiectasias can be treated using lasers, dermabrasion or currettage. This review will give an overview regarding rosacea, a challenging condition with multiple therapeutic options.

Lupus erythematosus (LE) represents an autoimmune disease with great clinical variability in which photosensitivity is a common feature for all forms and subsets. The nature and characteristics of clinical photosensitivity in LE have been elucidated through standardized phototesting procedures. The development of skin lesions after UV-injury is typically delayed starting from a few days up to three weeks after the irradiation, and may persist for months. Therefore, patients may not be aware of the detrimental effects of sunlight for their disease. The most photosensitive subset of LE is LE tumidus, followed by subacute cutaneous LE. Phototesting has also been crucial for studying the pathophysiology of LE-photosensitivity. Abnormalities of generation and clearance of UV-triggered apoptotic cells in LE are an important source of autoantigens. Recent data demonstrate the linkage of innate with adoptive immune pathways in UV-induced autoimmune response. Plasmocytoid dendritic cells (PDC) and their secreted IFN-alpha play a central role in the LE-pathogenesis. The recruitment of relevant leukocyte subsets is dependant on certain chemokines, which have been characterized in recent studies. An amplification cycle has been postulated, in which UV induces apoptosis and necrosis resulting in the production and release of chemokines. Subsequently, effector memory T cells as well as PDCs are recruited and activated perpetuating an amplification process that leads to UV-induced cutaneous LE lesion.

Thorsten Neubert, Percy LehmannZentrum für Dermatologie, Allergologie und Umweltmedizin, Helios Klinikum Wuppertal, Klinikum der Universität Witten-Herdecke, Wuppertal, GermanyAbstract: Bowen’s disease (squamous cell carcinoma in situ) has a 3%–5% risk to develop into invasive squamous cell carcinoma. Non-melanoma skin cancer is the most common cancer among Caucasians and its incidence has increased during the last decades dramatically. Multiple treatment options for Bowen’s disease have been described and are established with advantages and disadvantages. Bowen’s disease occurs more often in elderly patients (with a higher risk of comorbidities) and is frequently located on body sites with poor wound healing. Therefore there is need for non-invasive/non-destructive but effective treatment options. We would like to give an overview of established therapies and more detailed information about the newer treatment options for Bowen’s disease with topical diclofenac, topical imiquimod and photodynamic therapy.Keywords: Bowen’s disease, photodynamic therapy, imiquimod, diclofenac

Objective. Systemic sclerosis (SSc) is a rare, heterogeneous disease, which affects different organs and therefore requires interdisciplinary diagnostic and therapeutic management. To improve the detection and follow-up of patients presenting with different disease manifestations, an interdisciplinary registry was founded with contributions from different subspecialties involved in the care of patients with SSc. Methods. A questionnaire was developed to collect a core set of clinical data to determine the current disease status. Patients were grouped into five descriptive disease subsets, i.e. lcSSc, dcSSc, SSc sine scleroderma, overlap-syndrome and UCTD with scleroderma features. Results. Of the 1483 patients, 45.5% of patients had lcSSc and 32.7% dcSSc. Overlap syndrome was diagnosed in 10.9% of patients, while 8.8% had an undifferentiated form. SSc sine scleroderma was present in 1.5% of patients. Organ involvement was markedly different between subsets; pulmonary fibrosis for instance was significantly more frequent in dcSSc (56.1%) than in overlap syndrome (30.6%) or lcSSc (20.8%). Pulmonary hypertension was more common in dcSSc (18.5%) compared with lcSSc (14.9%), overlap syndrome (8.2%) and undifferentiated disease (4.1%). Musculoskeletal involvement was typical for overlap syndromes (67.6%). A family history of rheumatic disease was reported in 17.2% of patients and was associated with early disease onset (P < 0.005). Conclusion. In this nationwide register, a descriptive classification of patients with disease manifestations characteristic of SSc in five groups allows to include a broader spectrum of patients with features of SSc.

Summary Background Complete lymph node dissection is recommended in patients with positive sentinel lymph node biopsy results. To date, the effect of complete lymph node dissection on prognosis is controversial. In the DeCOG-SLT trial, we assessed whether complete lymph node dissection resulted in increased survival compared with observation. Methods In this multicentre, randomised, phase 3 trial, we enrolled patients with cutaneous melanoma of the torso, arms, or legs from 41 German skin cancer centres. Patients with positive sentinel lymph node biopsy results were eligible. Patients were randomly assigned (1:1) to undergo complete lymph node dissection or observation with permuted blocks of variable size and stratified by primary tumour thickness, ulceration of primary tumour, and intended adjuvant interferon therapy. Treatment assignment was not masked. The primary endpoint was distant metastasis-free survival and analysed by intention to treat. All patients in the intention-to-treat population of the complete lymph node dissection group were included in the safety analysis. This trial is registered with ClinicalTrials.gov, number NCT02434107. Follow-up is ongoing, but the trial no longer recruiting patients. Findings Between Jan 1, 2006, and Dec 1, 2014, 5547 patients were screened with sentinel lymph node biopsy and 1269 (23%) patients were positive for micrometastasis. Of these, 483 (39%) agreed to randomisation into the clinical trial; due to difficulties enrolling and a low event rate the trial closed early on Dec 1, 2014. 241 patients were randomly assigned to the observation group and 242 to the complete lymph node dissection group. Ten patients did not meet the inclusion criteria, so 233 patients were analysed in the observation group and 240 patients were analysed in the complete lymph node dissection group, as the intention-to-treat population. 311 (66%) patients (158 in the observation group and 153 in the dissection group) had sentinel lymph node metastases of 1 mm or less. Median follow-up was 35 months (IQR 20–54). Distant metastasis-free survival at 3 years was 77·0% (90% CI 71·9–82·1; 55 events) in the observation group and 74·9% (69·5–80·3; 54 events) in the complete lymph node dissection group. In the complete lymph node dissection group, grade 3 and 4 events occurred in 15 patients (6%) and 19 patients (8%) patients, respectively. Adverse events included lymph oedema (grade 3 in seven patients, grade 4 in 13 patients), lymph fistula (grade 3 in one patient, grade 4 in two patients), seroma (grade 3 in three patients, no grade 4), infection (grade 3 in three patients, no grade 4), and delayed wound healing (grade 3 in one patient, grade 4 in four patients); no serious adverse events were reported. Interpretation Although we did not achieve the required number of events, leading to the trial being underpowered, our results showed no difference in survival in patients treated with complete lymph node dissection compared with observation only. Consequently, complete lymph node dissection should not be recommended in patients with melanoma with lymph node micrometastases of at least a diameter of 1 mm or smaller. Funding German Cancer Aid.

Topical photodynamic therapy (PDT) is a widely approved therapy for actinic keratoses, squamous cell carcinoma in-situ, superficial and certain thin basal cell carcinomas. Recurrence rates are typically equivalent to existing therapies, although inferior to surgery for nodular basal cell carcinoma. PDT can be used both as a lesional or as a field therapy and has the potential to delay/reduce the development of new lesions. PDT has also been studied for its place in the treatment of, as well as its potential to prevent, superficial skin cancers in immune-suppressed patients, although sustained clearance rates are lower than for immunocompetent individuals. Many additional indications have been evaluated, including photo-rejuvenation and inflammatory and infective dermatoses. This S2 guideline considers all current and emerging indications for the use of topical photodynamic therapy in Dermatology, prepared by the PDT subgroup of the European Dermatology Forum guidelines committee. It presents consensual expert recommendations reflecting current published evidence. An unabridged version of this guideline is available online at: http://www.euroderm.org/edf/index.php/edf-guidelines.

A 34-year-old female patient with a three year history of generalized granuloma annulare was treated systemically with dapsone (DADPS). Six weeks after the onset of treatment, the patient developed an extensive tonsillitis of the baseofthe tongue with fever and malaise. Routine laboratory work showed a leukocytopenia with agranulocytosis. Further investigation revealed a marked decrease of the enzyme activity of N-acetyltransferase 2, which plays an important role in dapsone metabolism. Treatment included the cessation of dapsone, antibiotic coverage, and G-CSF leading to the rapid improvement of symptoms and normalization of leukocyte counts. Dapsone-induced angina agranulocytotica is a rare event and is interpreted as an idiosyncratic reaction. Depending on genetic polymorphisms of various enzymes, dapsone can be metabolized to immunologically or toxicologically relevant intermediates. Because of the risk of severe hematologic reactions, dapsone should only be employed for solid indications and with appropriate monitoring.

Background: In a recent study, we demonstrated that lupus erythematosus (LE) tumidus (LET) is a distinct subset of cutaneous LE (CLE), which is clinically characterized by erythematous, urticaria-like, nonscarring plaques in sun-exposed areas. Objective: Our purpose was to analyze skin biopsy specimens from 80 patients with this disease and to determine whether it could be differentiated from other variants of CLE on histopathologic grounds. Methods: Skin biopsy specimens from 53 primary and 38 UVA- and/or UVB-induced lesions of 80 patients with LET were examined and compared with skin biopsy specimens from patients with discoid LE (DLE) and subacute CLE (SCLE). Results: Specimens from LET lesions showed a characteristic and diagnostic pattern of perivascular and periadnexal cellular infiltrates in the papillary and reticular dermis composed almost entirely of lymphocytes. In some cases, few scattered neutrophils were present. Furthermore, interstitial mucin deposition was observed in all specimens, as confirmed by colloidal iron staining. In contrast to discoid LE and subacute CLE lesions, epidermal atrophy or alteration at the dermoepidermal junction was not detected. Conclusion: Skin lesions of patients with LET present with specific histopathologic features, and the differences compared with subacute CLE and discoid LE further support the concept to consider LET as a separate entity of CLE. (J Am Acad Dermatol 2003;48:901-8.)

Lupus erythematosus (LE) is a rare disorder in childhood. Most patients reported in the literature present with systemic manifestations, and, to date, fewer than 20 children with chronic cutaneous LE have been documented. In this article, we describe 3 patients with childhood LE tumidus, an uncommon but distinct subtype of chronic cutaneous LE. The lesions are characterized by erythematous, urticaria-like, nonscarring plaques in sun-exposed areas and, unlike in other variants of chronic cutaneous LE, there is no epidermal involvement. The clinical, photobiological, and histologic features as well as the differential diagnoses of childhood LE tumidus are discussed and compared with the adult form of this disease.

Methotrexate is beneficial in rheumatoid arthritis and has been used in small studies of patients with systemic lupus erythematosus. We describe a patient with severe subacute cutaneous lupus erythematosus refractory to therapy with antimalarials and corticosteroids. Treatment with methotrexate resulted in complete clearing of the skin lesions without any side effects. (J Am Acad Dermatol 2002;46:600-3.)

The role of aminolevulinic acid hydrochloride (ALA) in photodynamic therapy (PDT) of in situ neoplasias and tumours of epithelial tumours is steadily increasing and it has been shown to be the drug with most clinical use in PDT. In dermatology, topical PDT with ALA is already postulated to be the treatment of choice for actinic keratoses and superficial basal cell carcinomas. In gastroenterology, pulmonology, uro- and nephrology, neurology and gynaecology ALA has an important role as a photosensitiser not only in the diagnosis of neoplastic tissue but as therapy; first experiences have been made with PDT in these organs. Besides the therapeutic efficacy of this technique, the fluorescence of ALA-induced porphyrins can be effectively used to detect and delineate epithelial and endothelial neoplasms. In dermatology, other indications for ALA-treatment are non-tumoural applications, especially psoriasis, viral-induced diseases, or acne vulgaris. ALA is an effective compound in the diagnosis or therapy of various epithelial and endothelial neoplastic lesions.

Scarring alopecia is a rare complication of scalp psoriasis which in most cases occurs in areas of long-standing lesions. A HIV-positive 35 year-old Moroccan patient (CDC C3) developed scalp psoriasis with scarring alopecia within five weeks. Topical antipsoriatic therapy resulted in alleviation of psoriatic lesions and stopped the progression of the alopecia. This case report suggests potential pathogenic links between scalp psoriasis, scarring alopecia, and HIV-infection. In addition, early and efficient antipsoriatic treatment is recommended to prevent the disfiguring complication of scarring alopecia.

Der Lupus erythematodes (LE) ist eine Erkrankung, die ein breites Spektrum von kutanen und systemischen Manifestationen aufweist und seit vielen Jahrzehnten die medizinische Wissenschaft beschaftigt. Die grose Vielfalt der klinischen Befunde erlaubt es nicht, ein einheitliches Krankheitsbild zu definieren, so dass eine Klassifikation verschiedener Subtypen, die sich bezuglich klinischer, photobiologischer, histologischer und serologischer Merkmale unterscheiden, eingefuhrt wurde. Neben den gut definierten klassischen Formen wie systemischer LE (SLE), subakut kutaner LE (SCLE) und diskoider LE (DLE) gibt es seltene Manifestationen, die immer wieder diagnostische Schwierigkeiten bereiten. Der bullose LE (BLE) und die Urtikariavaskulitis werden als charakteristische, aber nicht spezifische Manifestationsformen des systemischen LE aufgefuhrt. Der LE tumidus (LET), der LE hypertrophicus/verrucosus (LEHV), der Chilblain LE und der LE profundus (LEP) werden als seltene Subtypen des chronisch kutanen LE betrachtet. Das anulare Erythem und die papulose Muzinose werden als weitere seltene kutane Manifestationsformen des LE beschrieben. In dieser klinischen Ubersicht werden die charakteristischen Merkmale dieser seltenen Sonderformen des LE herausgestellt, um zum weiteren Verstandnis und zur genaueren Differenzierung der verschiedenen Subtypen beizutragen.

Verstandnis des Prinzips der Fluoreszenzdetektion Entwicklung der Fluoreszenzdetektion von Tumoren der Haut Prinzip der FDAP Moglichkeiten und Grenzen der FDAP Sicherer und selektiver Einsatz der FDAP Die wichtigste Methode zur Diagnosesicherung von Hauttumoren und ihren Vorstufen ist die histopathologische Untersuchung. Praoperativ stehen bislang die Dermatoskopie und die Sonographie als nicht invasive Methoden zur Verfugung. Wir mochten die Fluoreszenzdiagnostik mit δ-Aminolavulinsaure-induzierten Porphyrinen (FDAP), ein neues diagnostisches, fur die Dermatologie interessantes Verfahren vorstellen. Sie ermoglicht, neoplastisches oder entzundlich verandertes Gewebe von der umliegenden gesunden Haut durch Detektion der typischen, ziegelroten Porphyrinfluoreszenz abzugrenzen.

Autoimmunity plays a key role in the immunopathogenesis of psoriasis; however, little is known about the recruitment of pathogenic cells to skin lesions. We report here that the CC chemokine, macrophage inflammatory protein-3α, recently renamed CCL20, and its receptor CCR6 are markedly up-regulated in psoriasis. CCL20-expressing keratinocytes colocalize with skin-infiltrating T cells in lesional psoriatic skin. PBMCs derived from psoriatic patients show significantly increased CCR6 mRNA levels. Moreover, skin-homing CLA+ memory T cells express high levels of surface CCR6. Furthermore, the expression of CCR6 mRNA is 100- to 1000-fold higher on sorted CLA+ memory T cells than other chemokine receptors, including CXCR1, CXCR2, CXCR3, CCR2, CCR3, and CCR5. In vitro, CCL20 attracted skin-homing CLA+ T cells of both normal and psoriatic donors; however, psoriatic lymphocytes responded to lower concentrations of chemokine and showed higher chemotactic responses. Using ELISA as well as real-time quantitative PCR, we show that cultured primary keratinocytes, dermal fibroblasts, and dermal microvascular endothelial and dendritic cells are major sources of CCL20, and that the expression of this chemokine can be induced by proinflammatory mediators such as TNF-α/IL-1β, CD40 ligand, IFN-γ, or IL-17. Taken together, these findings strongly suggest that CCL20/CCR6 may play a role in the recruitment of T cells to lesional psoriatic skin.

In the treatment of psoriasis with topical vitamin D3 analogues, lesional and perilesional irritation is the main side-effect. The aim of this study was to investigate whether local side-effects generated by tacalcitol, a vitamin D3 analogue, show concentration dependence. 3 different concentrations of tacalcitol (0.4; 4; 40 microg/g ointment) and the vehicle were applied on normal skin of the back of 25 healthy volunteers under occlusive conditions for 5 days. Assessment of erythema, infiltration and scaling as well as measurement of transepidermal water loss (TEWL) was performed on days 1 to 5. On day 5, additional skin barrier tests (DMSO test, alkali resistance test) were performed. Erythema and slight infiltration, but no scaling, were observed in a number of subjects without significant differences. TEWL also did not show significant differences for the test formulations, though there was a tendency towards lower values in the untreated areas. In the skin barrier tests, a tendency towards higher alkali resistance in the test areas treated with 40 microg tacalcitol/g ointment was detected. Thus, under occlusive conditions, the irritant potential of tacalcitol is very low. There is no convincing evidence of concentration dependence in irritation generated by tacalcitol when applied under occlusive conditions.

Das anulare Erythem wird in der asiatischen Literatur als eine kutane Manifestationsform des Sjogren-Syndroms beschrieben und als eine eigenstandige klinische Sonderform dargestellt. Da pathophysiologische Gemeinsamkeiten mit dem subakut kutanen Lupus erythematodes bestehen, die insbesondere auf dem Nachweis von Anti-Ro/SS-A oder Anti-La/SS-B Antikorpern beruhen, sind beide Krankheitsbilder jedoch schwer voneinander zu differenzieren. Der histopathologische Nachweis von dermalen Muzinablagerungen erschwert zusatzlich die Abgrenzung vom Lupus erythematodes tumidus. Wir stellen einen chinesischen Patienten mit grosflachigem anularem Erythem, Xerophthalmie und Anti-Ro/SS-A Antikorpern vor. Anhand klinischer, histopathologischer und immungenetischer Befunde werden im Rahmen einer Literaturubersicht die Gemeinsamkeiten und Unterschiede zwischen anularem Erythem bei Sjogren-Syndrom und kutanem Lupus erythematodes herausgestellt.

Antimalarials represent the first line in treatment of cutaneous lupus erythematosus (LE). However, some patients show no improvement on monotherapy with chloroquine or hydroxychloroquine. A 30-year-old female patient had treatment-resistant cutaneous LE exhibiting features of both LE tumidus and subacute cutaneous LE. Previously, the patient had been unsuccessfully treated with chloroquine, hydroxychloroquine, dapsone, and azathioprine, each in combination with variable doses of prednisolone. However, the LE lesions increased during these therapeutic regimens. A combination of chloroquine and mepacrine therapy led to improvement and then total clearing after 4 months of treatment.

Das periorbitale Odem ist ein Symptom, das initial oder im Verlauf von Erkrankungen verschiedenster Genese auftreten kann. Eine mogliche Assoziation stellt der Lupus erythematodes profundus dar. Diese Krankheit ist durch subkutane knotige und plattenartige Infiltrate gekennzeichnet, welche zu Ulzerationen und narbigen Einziehungen fuhren konnen. Anhand eines Fallberichts wird aufgezeigt, das ein periorbitales Odem als Initialsymptom den typischen Hautveranderungen eines Lupus erythematodes profundus vorausgehen kann. Die Kenntnis der moglichen Differentialdiagnosen bei periorbitalem Odem sowie der unterschiedlichen Varianten eines Lupus erythematodes ist fur die Diagnosestellung von entscheidender Bedeutung.

The clinical efficacy and tolerability of the topical receptor-selective retinoid tazarotene in the treatment of congenital ichthyoses was investigated. Twelve consecutive patients with different forms of congenital ichthyosis were enrolled in an open, non-randomized, intraindividually controlled, half-side pilot study. Diagnoses were X-linked recessive ichthyosis, non-erythrodermic autosomal recessive lamellar ichthyosis, autosomal dominant ichthyosis vulgaris and ichthyosis bullosa of Siemens (IBS). Tazarotene 0.05% gel was applied unilaterally daily on a defined body area measuring 10% of the body surface area. The contralateral side was treated with an ointment containing 10% urea. After 14 days, application frequency was reduced to three times a week, and stopped after another 2 weeks. The follow-up period was 3 months. Reduction in scaling and roughness was used to assess the clinical response in the tazarotene-treated area compared with the control area. Clinical and laboratory assessments were performed every 14 days during the trial. Unilateral improvement in favour of the tazarotene-treated side was observed in nine of 12 patients (75%). Four patients (33%) achieved an excellent response and four (33%) achieved a good response. No therapeutic effect was seen in patients with IBS. The remission persisted during the reduction phase and after discontinuation for up to 2 months. Local irritation in three patients was the only side-effect detectable. Short-term topical application of tazarotene 0.05% gel is a very effective and well-tolerated treatment modality in different forms of congenital ichthyoses and may be an alternative to systemic retinoid therapy.

Photodynamic therapy with topically applied δ-aminolaevulinic acid is used to treat skin tumours by employing endogenously formed porphyrins as photosensitizers. This study examines the time course of porphyrin metabolite formation after topical application of δ-aminolaevulinic acid. Porphyrin biosynthesis in human skin tumours (basal cell carcinoma, squamous cell carcinoma), in psoriatic lesions, and in normal skin was investigated. Skin areas were treated with δ-aminolaevulinic acid, and levels of total porphyrins, porphyrin metabolites and proteins were measured in samples excised after 1, 2, 4, 6, 9, 12 and 24 h. There was an increase in porphyrin biosynthesis in all tissues with maximum porphyrin levels in tumours between 2 and 6 h and in psoriatic lesions 6 h after treatment. The pattern of porphyrins showed no significant difference between normal and neoplastic skin, protoporphyrin being the predominant metabolite. The results suggest that optimum irradiation time for superficial epithelial skin tumours may be as soon as 2 h after application of δ-aminolaevulinic acid, whereas for treatment of psoriatic lesions an application time of 6 h is more suitable. © 1999 Cancer Research Campaign

Topically applied delta-aminolevulinic acid is used efficiently for the treatment of solar keratoses by photodynamic therapy. Recent animal studies suggest that porphyrin sensitization of epithelial tissue is improved by using esters rather than free delta-aminolevulinic acid. The present study examines porphyrin metabolite formation after topical application of delta-aminolevulinic acid or delta-amino-levulinic acid methylester in human solar keratoses versus adjacent normal skin. Level of total porphyrins, porphyrin metabolites and protein were measured in skin samples excised after 1 and 6 h. Higher levels of porphyrins were observed in solar keratoses than in normal skin with both substances. Maximum porphyrin levels were present in solar keratoses treated with delta-aminolevulinic acid for 6 h. However, the ratio of porphyrins in solar keratoses versus adjacent normal skin was higher with delta-aminolevulinic acid methylester. The pattern of porphyrins showed no significant difference between normal and afflicted skin, protoporphyrin being predominant. The results suggest that application of free delta-aminolevulinic acid may be more effective in sensitizing solar keratoses. However, treatment with delta-aminolevulinic acid methylester leads to a preferential enrichment of porphyrins within lesional skin.

Photosensitivity is a main criterion for the diagnosis of systemic lupus erythematosus (LE), and ultraviolet (UV) irradiation plays a key role in the pathogenesis of cutaneous LE. Patients with a tentative diagnosis of LE are routinely tested for skin lesion development after experimental UV irradiation, providing an ideal opportunity to evaluate early, preclinical events involved in the pathogenesis of LE. Several reports have shown expression of the cytokine-inducible nitric oxide synthase (iNOS) in autoimmune diseases. Therefore, we investigated the role of iNOS expression at mRNA and protein level in the pathogenesis of LE lesions. Skin biopsies from patients with different subtypes of LE were examined, and iNOS expression was found in six of 18 biopsies from cutaneous LE patients and two of three biopsies from systemic LE patients. In biopsies taken 4-20 d after UV irradiation, epidermal iNOS expression was seen in all patients (n = 10) after UVB and in four of 10 patients provoked by UVA. In healthy controls (n = 8) epidermal iNOS expression was detected 24 h after UV irradiation, persisting for another day before subsiding on day 3. In LE patients (n = 8) the exact reverse situation was seen: an iNOS-specific signal was undetectable in keratinocytes for 2 d after UV irradiation, but became positive on day 3 and persisted for up to 25 d in the evolving skin lesions. Our findings demonstrate a time-restricted, UV-induced iNOS expression in human skin; moreover, the results indicate that both the kinetics of iNOS induction as well as the time span of local iNOS expression may be critical to the development of cutaneous LE lesions.

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.

The aim of this investigation was to establish a new model for phototoxicity which is more advanced than the widely used cultures of yeasts, bacteria or cells of various origin, and at the same time to avoid animal testing. We studied the extraembryonal vasculature of the incubated hen's egg. This model was originally introduced by toxicologists as an alternative to the rabbit's eye irritation test (Draize test). In the photo hen's egg test, substances are applied to the embryo's yolk-sac blood vessel system at a non-toxic concentration and are irradiated with 5 J/cm2 ultraviolet A (UVA) (320-400 nm). Promethazine, haematoporphyrin, ciprofloxacin and 8-methoxypsoralen were tested in this system. Death of the embryo, membrane discoloration and haemorrhage are parameters for phototoxic damage, which were recorded during an observation period of 24 h. These well-known phototoxic substances induced pronounced damage of the yolk-sac membrane and blood vessels which was not found in the controls (test substance alone, UVA alone or untreated) using a 2 x 2 factorial test design. The photo hen's egg test serves as a valid screening model for substances supposed to be photosensitizers owing to a phototoxic mechanism.

The Muir-Torre syndrome (MTS) is a rare autosomal-dominant condition characterized by the occurrence of sebaceous skin lesions and internal tumours in a patient. It has been demonstrated that at least a subgroup of MTS exhibits clinical and molecular genetic features of hereditary nonpolyposis colorectal cancer, including microsatellite instability in skin and visceral tumours, because of mutations in DNA mismatch repair genes. We have identified germline mutations in the hMSH2 gene in two unrelated MTS patients ascertained because of their skin tumours. Our results, together with published MTS cases, support the hypothesis that MTS with its characteristic skin lesions is confined to mutations in the hMSH2 gene.

The purpose of this study was to examine the effectiveness and side-effects of the vitamin D analogue calcipotriol, applied topically to psoriatic skin lesions in intertriginous areas, in an open and uncontrolled trial. Twelve patients with psoriasis vulgaris who presented with psoriatic lesions in the axilla, and inguinal and anal folds, were treated with calcipotriol ointment (50 micrograms/g) twice daily for 6 weeks. Examination and photographic documentation were performed before treatment, at 3 weeks of treatment, and at 6 weeks of treatment. The mean improvement in the extent and severity of the psoriatic plaques was determined with a semiquantitative grading system closely related to the psoriasis area and severity index (M-PASI). Two of 12 patients showed insufficient response to therapy. Five of 12 patients showed a quick response within 3 weeks or less, and five of 12 patients showed a slow response which could be seen only after 6 weeks of treatment. Minimal burning was reported in one patient, slight lesional and/or perilesional irritation in five patients, and, in the remaining, no side-effects occurred. Topical calcipotriol is an effective and safe treatment for intertriginous psoriasis.