Swiss S1 guideline for the treatment of rosacea.

Rosacea (in German sometimes called 'Kupferfinne', in French 'Couperose' and in Italian 'Copparosa') is a chronic and frequently relapsing inflammatory skin disease primarily affecting the central areas of the face. Its geographic prevalence varies from 1% to 22%. The differential diagnosis is wide, and the treatment is sometimes difficult and varies by stage of rosacea. For erythematous lesions and telangiectasia, intense pulsed light (IPL) therapy and lasers are popular treatment option. In addition, a vasoconstrictor agent, brimonidine, has recently been developed. For papulopustular rosacea, topical antibiotics, topical and systemic retinoids, as well as systemic antibiotics are used. A topical acaricidal agent, ivermectin, has undergone clinical development and is now on the market. In the later stages, hyperplasia of the sebaceous glands develops, resulting in phymatous growths such as the frequently observed bulbous nose or rhinophyma. Ablative laser treatments have largely replaced classical abrasive tools. Here, we reviewed the current evidence on the treatment of rosacea, provide a guideline (S1 level) and discuss the differential diagnosis of rosacea.

Epidermal Langerhans cells--a cycling cell population.

The limited number of Langerhans cells (LC) in human epidermis and the resultant technical difficulties have left open the question of LC kinetics. In the present study using flow cytometry (FCM) we have applied 3 methods to estimate LC-DNA distribution: (1) FCM-DNA measurement on highly enriched LC suspensions, (2) FCM-correlated analysis of DNA and OKT-6(+) cells in total epidermal cell suspensions, (3) LC-enriched suspensions (70-90%) were FACS (fluorescence-activated cell sorter) sorted on microscopic slides, and stained with the Feulgen technique, and DNA was measured densitometrically. In the latter method, contaminating keratinocytes were counterlabeled with antikeratin serum to eliminate them from LC-DNA estimation. All 3 in vitro analyses clearly showed that human LC are a cycling cell population in the epidermis. The number of LC in S (1.3-3.3%) and G2/M (1.0-2.5%) phase compares with those found for keratinocytes. Assuming that this percentage of keratinocytes in S and G2/M phases is sufficient to maintain the structural integrity of the epidermis, it was suggested that LC may represent a stable, self-reproducing cell population in normal epidermis.

Migration of Langerhans cells into human epidermis of "reconstructed" skin, normal skin, or healing skin, after grafting onto the nude mouse.

Human skin equivalents composed of keratinocytes cultured on a lattice constituted of human fibroblasts embedded in type I collagen were grafted onto the nude mouse. It is demonstrated, by indirect immunofluorescence and electron microscopy, that, after grafting, mouse Langerhans cells migrate into the human epidermis. Human Langerhans cells are not present in this system. In split-thickness human skin grafts, at long periods (5 and 12 months) after transplantation, a progressive migration of murine Ia(+) cells in the human epidermis and the presence of human Langerhans cells were shown by indirect immunofluorescence. Creation of a wound at the center of the grafted human skin and identification of the Langerhans cell origin shows a repopulation with human Langerhans cells provided the injury was performed early (2 months) after grafting. Injury at a later stage (5 months) resulted in presence of both human and murine Langerhans cells. These observations show 1) that, after grafting of "reconstructed" human skin or of split-thickness human skin onto nude mice, mouse Langerhans cells migrate into the grafted human epidermis; and 2) that the Langerhans cells repopulating a healing grafted epidermis devoid of Langerhans cells derived from the non-injured surrounding epidermis. The present work thus shows that besides bone marrow, lymph nodes, or/and spleen, surrounding cutaneous regions can also serve as sources of Langerhans cells.

Further evidence for the self-reproducing capacity of Langerhans cells in human skin.

The limited number of Langerhans cells (LC) in the epidermis is one of the main reasons for the technical difficulties in resolving the question of LC kinetics. In the present paper, we describe a method to evaluate the LC replication potential in epidermis. The procedure is based on the specific incorporation of bromodeoxyuridine (BrdU), a thymidine analogue, into the DNA during the S-phase of the cell cycle. Mice, bearing human skin grafts, were injected s.c. every 6 h for up to 17 days with BrdU. At different times, the incorporated BrdU as well as the human epidermal LC were revealed on skin sections using anti-BrdU and OKT-6 monoclonal antibodies, respectively. After 6 h, 4.9% of the LC were labeled with BrdU. Then, the number of OKT-6(+) BrdU(+) cells increased in a linear manner and achieved 34% at 120 h, 67% at 240 h, and 94% at 400 h during the course of continuous labeling procedures. Based on this result we calculated a total cell cycle time of 392 h (16.3 days) and 12 h for the S-phase for human epidermal LC. Applying this technique, we were able to show also that 48 h after local treatment with 12-O-tetradecanoylphorbol-13-acetate or after stripping, the number of BrdU-labeled LC was considerably increased. Furthermore, after i.p. injection of colchicine in the nude mouse, human epidermal LC undergoing mitosis were evidenced by electron microscopy in the graft. From these results we conclude that the LC are actively cycling--therewith a self-reproducing cell population in human epidermis.

Comparison of eicosanoid generation by highly purified human Langerhans cells and keratinocytes.

The present study was conducted to investigate the eicosanoid metabolism of highly enriched human Langerhans cells and keratinocytes. Arachidonic acid (100 microM) was added to the cells which were then stimulated with 1 microM calcium ionophore A 23187 for 10 and 30 min. The supernatants were examined for cyclooxygenase and lipoxygenase products using different chromatographic systems and radioimmunoassays. Compounds were identified by comparison with authentic standards. The major cyclooxygenase product of both cell types was prostaglandin D2, with minor amounts of prostaglandin E2. The main products of the lipoxygenase pathway were 5-hydroxyeicosatetraenoic acid (5-HETE), 12-HETE, 15-HETE, and their corresponding hydroperoxy derivatives, with small amounts of leukotrienes B4 and C4. The major differences in the metabolism of the two cell types were related to faster kinetics of generation of the mediators and a more complete conversion of arachidonic acid by the LC. Because eicosanoids have been implicated to be potent mediators of inflammation and immunomodulators, the present data underline the potential contributory role of epidermal cells to eicosanoid-associated pathologic processes.

Migration of Langerhans cells into the epidermis of human skin grafted into nude mice.

In a previous study, it was demonstrated that human Langerhans cells (LC) are preserved in human skin grafted onto a nude mouse. Moreover, although it was observed that mouse LC of the host invade skin grafts from allogeneic mouse or rat, they do not penetrate in human skin grafts. In most of the human skin equivalent systems produced in vitro, LC appear to be lost. The present study was designed to investigate whether the mouse LC will repopulate a human skin equivalent. For this purpose, two different systems of skin equivalent have been grafted into the nude mouse. They were composed of human keratinocytes deposited on dead human dermis, or on lattice composed of human fibroblasts embedded in type I collagen. At different times after grafting, the presence of LC in the transplants was assayed either by indirect immunofluorescence or by electron microscopy. Indirect immunofluorescence was performed on frozen sections or on epidermal sheets with anti-Ia, anti-HLA-DR, or OKT6 antibodies. It was observed that, at 2 months after grafting, Ia(+) HLA-DR(-) OKT6(-) cells are present in grafted human epidermis. Moreover, LC with typical Birbeck granules are also detected by electron microscopy. It could be concluded, from this study, that mouse LC can repopulate human epidermis devoid of human LC.

In vitro effect of UV radiation on immune function and membrane markers of human Langerhans cells.

Human Langerhans cells (LC) are located in the epidermal tissue which is naturally accessible to UV irradiation. They may be the first immunocompetent cells exposed to its effect. In the present study, the epidermal tissue was dissociated with trypsin, and epidermal cell (EC) suspensions, which contain keratinocytes, melanocytes, and LC were irradiated with UVB (10 or 20 mJ/cm2). After irradiation LC retained their surface determinants: T-6 and HLA-Dr. In addition, their number did not decrease during 3 days of culture following UVB exposure as compared with nonirradiated EC cultured in parallel. On the contrary, UV irradiation of EC resulted in decreased lymphocyte-stimulating ability in a mixed skin cell-lymphocyte culture reaction (MSLR). EC used directly after irradiation in MSLR induced about half the lymphocyte response compared to nonirradiated EC. After 24-h culture, the irradiated EC did not produce any lymphocyte response, whereas the 48-h cultures showed a slight lymphocyte stimulation. At 72 h the cultures from irradiated and nonirradiated EC showed similar responses in MSLR. The doses of UV radiation which decreased MSLR responses did not affect EC viability and did not significantly reduce their DNA content. It is suggested that under the experimental conditions used in this study the defect induced by UV irradiation was essentially functional and was the result of the transient inhibition of the antigen processing function of LC rather than of an alteration in membrane antigen expression (T-6 and HLA-Dr).

Processing and statistical analysis of laser Doppler data applied to the assessment of systemic anti-inflammatory drugs.

Continuous laser Doppler measurements of methyl nicotinate-induced skin inflammation have been used to evaluate the activities of three oral non-steroidal anti-inflammatory drugs, indomethacin 50 mg (Indocid), tiaprofenic acid 100 mg (Surgam) and sodium acetylsalicylate 1 g (Catalgine). They were compared in a single-blind, randomized, intra-individual comparison (N = 16) versus placebo (lactose). One hour after each drug was ingested, four concentrations of methyl nicotinate were applied to the subject's forearms. Simultaneous skin blood flow (SBF) measurements were then carried out on the four tested zones, by use of four calibrated laser Doppler flowmeters. Computerized processing of recorded SBF levels provided data related to flow amplitude, kinetics and magnitude (area under the curve) of the reactions. A detailed statistical analysis was performed to establish the selectivity of this type of test and the following points were demonstrated: adjustment of SBF data to baseline did not improve precision, data had to be log-transformed before analysis, and magnitude data gave the best product discrimination. Under the conditions of this study, i.e. one hour after oral administration and for the indicated doses, the tested products could be classified, in terms of anti-inflammatory activity, as follows: Lactose less than Indomethacin 50 mg = Tiaprofenic acid 100 mg less than Sodium acetylsalicylate 1 g.

Topical metronidazole maintains remissions of rosacea.

BACKGROUND: Rosacea is a chronic skin disease that requires long-term therapy. Oral antibiotics and topical metronidazole successfully treat rosacea. Because long-term use of systemic antibiotics carries risks for systemic complications and adverse reactions, topical treatments are preferred. OBJECTIVE: To determine if the use of topical metronidazole gel (Metrogel) could prevent relapse of moderate to severe rosacea. DESIGN: A combination of oral tetracycline and topical metronidazole gel was used to treat 113 subjects with rosacea (open portion of the study). Successfully treated subjects (n = 88) entered a randomized, double-blind, placebo-controlled study applying either 0.75% topical metronidazole gel (active agent) or topical metronidazole vehicle gel (placebo) twice daily (blinded portion of the study). SETTING: Subjects were enrolled at 6 separate sites in large cities at sites associated with major medical centers. SUBJECTS: One hundred thirteen subjects with at least 6 inflammatory papules and pustules, moderate to severe facial erythema and telangiectasia entered the open phase of the study. Eighty-eight subjects responded to treatment with systemic tetracycline and topical metronidazole gel as measured by at least a 70% reduction in the number of inflammatory lesions. These subjects were randomized to receive 1 of 2 treatments: either 0.75% metronidazole gel or placebo gel. INTERVENTIONS: Subjects were evaluated monthly for up to 6 months to determine relapse rates. MAIN OUTCOME MEASURES: Inflammatory papules and pustules were counted at each visit. Relapse was determined by the appearance of a clinically significant increase in the number of papules and pustules. Prominence of telangiectases and dryness (roughness and scaling) were also observed. RESULTS: In the open phase, treatment with tetracycline and metronidazole gel eliminated all papules and pustules in 67 subjects (59%). The faces of 104 subjects (92%) displayed fewer papules and pustules after treatment, and 82 subjects (73%) exhibited less erythema. In the randomized double-blind phase, the use of topical metronidazole significantly prolonged the disease-free interval and minimized recurrence compared with subjects treated with the vehicle. Eighteen (42%) of 43 subjects applying the vehicle experienced relapse, compared with 9 (23%) of 39 subjects applying metronidazole gel (P<.05). The metronidazole group had fewer papules and/or pustules after 6 months of treatment (P<.01). Relapse of erythema also occurred less often in subjects treated with metronidazole (74% vs 55%). CONCLUSION: In a majority of subjects studied, continued treatment with metronidazole gel alone maintains remission of moderate to severe rosacea induced by treatment with oral tetracycline and topical metronidazole gel.

Human Langerhans cells in epidermal cell culture, in vitro skin explants and skin grafts onto "nude" mice.

In order to find a model system which best preserves human Langerhans cells (LC) outside of the human body, three possibilities were examined: epidermal cell culture, skin explants, and skin grafts onto "nude" mice. Using OKT-6 and anti-HLA-DR monoclonal antibodies, we quantified LC in epidermal sheets or epidermal cell cultures. All observations were carried out over a period of 4 weeks. We found that under epidermal cell culture conditions, LC rapidly disappeared, to the extent that after 10 days only rare HLA-DR-positive cells could be observed. In contrast, in the presence of intact dermis (explants and grafts), 60%-80% of the original number of LC, morphologically unchanged, dendritic and OKT-6 and HLA-DR-positive, were seen. These findings suggest that human LC are either a long-lived cell population or else can proliferate locally. The systems studied may be a useful tool for future investigation of LC function.

Topical retinoids. Their uses in dermatology.

The retinoids provide an important new way of treating dermatologic disorders. They have also proved to have a role in the prevention of new lesion formation. New retinoids, of which adapalene is one, have recently been synthesized in order to obtain similar or better efficacy while reducing skin irritation potential. These new molecules are currently under clinical investigation. Preliminary results are encouraging. In the near future, an expanded range of topical retinoids should be available.

Effect of desonide ointment, 0.05%, on the hypothalamic-pituitary-adrenal axis of children with atopic dermatitis.

Desonide ointment has demonstrated a good safety and efficacy profile during the many years it has been used in treating dermatoses. However, there have been no controlled clinical trials to evaluate its systemic safety when used in treating children. Suppression of the hypothalamic-pituitary-adrenal (HPA) axis can occur after repeated application of topical corticosteroids. In general, the degree of suppression of the HPA axis function is related to the daily dosage of steroid given, the duration of its administration, the extent of body surface covered, and the potency of the corticosteroid. This study sought to determine the comparative effects of 0.05 percent desonide and 2.5 percent hydrocortisone ointments on the HPA axis of children with atopic dermatitis. There was no suppression of early morning cortisol in either treatment group. The ACTH-stimulated mean cortisol values after four weeks of treatment were not significantly different from the baseline values for either treatment group. We conclude that neither 0.05 percent desonide ointment nor 2.5 percent hydrocortisone ointment compromised the HPA axis of children with atopic dermatitis treated topically for four weeks.

[Clinical trials in dermatology. The phase I trials]. / Les essais cliniques en dermatologie. Les essais de phase I.

Application of the new topical product on the diseased skin should be preceded by its safety evaluation on the healthy skin in human volunteers. We propose here guidelines for the evaluation of the irritation, sensitization, phototoxicity and photoallergy potentials for topical products. The methods for evaluation of percutaneous absorption are also discussed. The studies presented here are not the object of any regulations. Therefore, we propose here an approach for the safety evaluation of topical products in human volunteers.

[Clinical trials in dermatology. Evaluation of the tolerability and efficacy of a topical anti-inflammatory treatment in atopic dermatitis]. / Les essais cliniques en dermatologie. Evaluation de la tolérance et de l'efficacité d'un traitement anti-inflammatoire topique dans le traitement de la dermatite atopique.

Study designs for assessment of topical anti-inflammatory drugs in atopic dermatitis are discussed. Atopic dermatitis is a chronic disease with symmetrically distributed lesions. In order to avoid individual and spontaneous variation and to obtain an early impression of the efficacy of a new topical drug, bilaterally paired lesions can be used. Further drug development requires controlled double-blind parallel group design. General recommendations regarding inclusion criteria, and the measurement of efficacy and safety parameters are presented. Methods available for data evaluation and the particularities of different clinical designs are discussed.

[Clinical trials in dermatology. Evaluation of the tolerability and efficacy of a topical antipsoriatic treatment]. / Les essais cliniques en dermatologie. Evaluation de la tolérance et de l'efficacité d'un traitement topique antipsoriasique.

There has been considerable variations between different authors in the evaluation of antipsoriatic therapies. Improvement homogeneity must be achieved in this field. The main specific methods have been investigated: inclusion criteria, assessment of disease progress and safety parameters in phase II and III clinical trials, evaluating antipsoriatic treatment.

[Clinical trials in dermatology. Evaluation of the tolerability and efficacy of a topical antifungal agent in the treatment of superficial mycoses]. / Les essais cliniques en dermatologie. Evaluation de la tolérance et de l'efficacité d'un antifongique topique dans le traitement des mycoses superficielles.

There is no single method for evaluating topical antifungal drugs. The localisation and the type of fungal, determine the treatment duration (from few days to several months). The main methodological characteristics of clinical trials in tinea pedis treatment (athlete's foot type) are reported. Aspects related to other clinical forms such as tinea versicolor and onychomycosis are also described. In any case, the main criteria of activity remains the mycological examination based on KOH microbiology and culture performed at the end of the treatment and again afterwards.

[Clinical trials in dermatology. Statistical support]. / Les essais cliniques en dermatologie. Support statistique.

To determine the efficacy or safety of new topical treatments, more or less standardized studies must be performed. This article presents several examples of statistical analyses of the data currently seen in the dermatology area, and some guidelines for study sample size determination. More importantly, it indicates, for as soon as phase I studies, the need for preliminary informations such as development strategy, historical data, literature references or pilot studies, to determine or adapt appropriate designs and sample sizes. This need can be filled by close collaboration among clinicians, statisticians and sponsor.

[Clinical trials in dermatology. Evaluation of the tolerability and efficacy of a topical anti-acne]. / Les essais cliniques en dermatologie. Evaluation de la tolérance et de l'efficacité d'un antiacnéique topique.

Acne is a frequent dermatologic disease of the teenagers. Methodology of antiacne preparations clinical trials has evolved recently, leading to better comprehension of acne treatment on acne lesions. The main rules for good clinical evaluation of acne treatments are: an objective counting of each individual lesions on a defined area (face, back), a global acne assessment, a therapy duration from 1 to 3 months or more, a skin safety evaluation for erythema, desquamation, dryness, itching, burning and oiliness with a 0 to 3 scoring system.

[Comparative study of the efficacy and tolerability of 0.1 and 0.03 p.100 adapalene gel and 0.025 p.100 tretinoin gel in the treatment of acne]. / Etude comparative de l'efficacité et de la tolérance de gels d'adapalène à 0.1 et 0.03 p. 100 et d'un gel de trétinoïne à 0.025 p. 100 dans le traitement de l'acné.

INTRODUCTION: Adapalene is a new chemical entity with retinoid activity. PATIENTS AND METHODS: 0.1 p. 100 adapalene gel (Différine gel), 0.03 p. 100 adapalene gel and a commercially available 0.025 p. 100 tretinoin gel (Aberel gel) were compared in 89 male and female patients with acne. RESULTS: Inflammatory, non inflammatory, total lesion counts, and the global facial acne grade regularly decreased as a function of time in the three treatment groups. No statistically or clinicaly significant differences were observed for these parameters between 0.1 p. 100 adapalene gel and 0.025 p. 100 tretinoin gel following a 12-week treatment. Conversely, both of these gels were significantly more effective than 0.03 p. 100 adapalene gel with regards to inflammatory and total lesion counts, and the global facial acne grade. The differences of efficacy seen between both adapalene gels demonstrate a dose-dependent activity of the drug in the topical treatment of acne. The three products induced retinoid-like skin irritation with significant differences in intensity in favour of adapalene for erythema, dryness, scaling and burning after application and in favour of tretinoin for persistent burning. No treatment-related medical events were reported and adapalene plasma levels were lower than 0.15 ng/ml (limit of detection of the analytical method). CONCLUSIONS: The topical treatment of acne with adapalene gels was found to be safe and effective, with a dose-related response. The efficacy of 0.1 p. 100 adapalene gel and of 0.025 p. 100 tretinoin gel are not different but skin tolerance of 0.1 p. 100 adapalene gel is superior.

[Occupational dermatoses reported in the Lódz district in the years 1972-1976]. / Choroby zawodowe skóry zgloszone z terenu lódzkiego województwa miejskiego w latach 1972--1976.

108 cases were evaluated. It was stated that they were mostly caused by an exposure to allergic effects of industrial allergens: metal compounds, epoxides, paragroup compounds, turpentine, formalin and rubber components. Location and clinical picture of dermatoses constitute mainly dermatitis and contact eczema on the skin of hands. The cases referred mainly to the men employed in building, chemical, textile and metal industries. Opening a center performing allergic tests with industrial allergents, which at the same time could determine their occurrence in work environment, provides the basic condition for a proper diagnosis and prophylaxis of occupational dermatoses.