Dual anti-inflammatory and anti-parasitic action of topical ivermectin 1% in papulopustular rosacea.

BACKGROUND: Recently, therapy of rosacea with inflammatory lesions (papulopustular) has improved substantially with the approval of topical ivermectin 1% cream. It is assumed to have a dual mode of action with anti-inflammatory capacities and anti-parasitic effects against Demodex, which however has not yet been demonstrated in vivo. AIM: To find scientific rationale for the dual anti-inflammatory and anti-parasitic mode of action of topical ivermectin 1% cream in patients with rosacea. METHODS: A monocentric pilot study was performed including 20 caucasion patients with moderate to severe rosacea, as assessed by investigator global assessment (IGA score ≥3) and a Demodex density ≥15/cm2 . Patients were treated with topical ivermectin 1% cream once daily (Soolantra® ) for ≥12 weeks. The density of Demodex mites was assessed with skin surface biopsies. Expression of inflammatory and immune markers was evaluated with RT-PCR and by immunofluorescence staining. RESULTS: The mean density of mites was significantly decreased at week 6 and week 12 (P < 0.001). The gene expression levels of IL-8, LL-37, HBD3, TLR4 and TNF-α were downregulated at both time points. Reductions in gene expression were significant for LL-37, HBD3 and TNF-α at both follow-up time points and at week 12 for TLR4 (all P < 0.05). Reduced LL-37 expression (P < 0.05) and IL-8 expression were confirmed on the protein level by immunofluorescence staining. All patients improved clinically, and 16 of 20 patients reached therapeutic success defined as IGA score ≤1. CONCLUSION: Topical ivermectin 1% cream acts by a dual, anti-inflammatory and anti-parasitic mode of action against rosacea by killing Demodex spp. in vivo, in addition to significantly improving clinical signs and symptoms in the skin.

Fumaderm® in daily practice for psoriasis: dosing, efficacy and quality of life.

BACKGROUND: Patients with psoriasis suffer from chronic skin disease and impaired quality of life. With a prevalence of 1-3% of the population, psoriasis is one of the most common chronic inflammatory autoimmune diseases. Fumaric acid esters (Fumaderm(®)) are approved for the treatment of psoriasis in Germany, but regular Fumaderm therapy with six tablets per day is often limited due to adverse events. OBJECTIVES: This observational study recorded data on quality of life, treatment efficacy and drug dosing in patients suffering from psoriasis treated with Fumaderm under conditions of daily practice in 78 dermatological centres. PATIENTS AND METHODS: In this prospective, multicentre, noninterventional trial we included adult patients with severe plaque psoriasis under outpatient conditions receiving Fumaderm according to the current summary of product characteristics for systemic treatment of psoriasis. At baseline and after 3, 6 and 12 months the dosing regimen under daily conditions, Dermatology Life Quality Index (DLQI) and clinical efficacy with the Psoriasis Area and Severity Index (PASI) were documented. RESULTS: A total of 249 patients were included. The mean DLQI score at study entry was 9·95; the mean PASI was 16·8. The average treatment dose of Fumaderm was 2·8 tablets daily. More than 70% of patients were treated with one to three tablets daily and < 30% were treated with a dose ranging from four to six tablets daily. DLQI and PASI improved in the entire study population by 67·2% and 66·6%, respectively. Specifically, when analysing patients who started Fumaderm within 4 weeks before baseline the mean DLQI score decreased from 11·8 to 2·9 (75% reduction) and the mean PASI score from 19·84 to 7·35 after 12 months (63% improvement). CONCLUSIONS: This is the first field study analysing the use of Fumaderm and the improvement of quality of life in patients with psoriasis under daily outpatient conditions. The improvement of DLQI obtained with Fumaderm was comparable with the improvement observed in patients with psoriasis treated with modern biologics. Importantly, in most patients with good clinical response, the treatment dose was one to three tablets daily.

[Systemic therapy of rosacea]. / Systemische Therapie der Rosazea.

The only medication which is authorized for therapy of rosacea is doxycycline. It is usually administered at a dose of 40-100 mg daily for 3-6 months. In case of a lack of efficacy or in case of contraindications (e.g. pregnancy, children below 8 years), azithromycin or metronidazole are alternative systemic therapies. Those forms of rosacea which involve hyperplasia of sebaceous glands respond well to retinoids such as isotretinoin. Dapsone has been successfully used for the treatment of granulomatous rosacea and rosacea fulminans. Erythema can be reduced by use of beta blockers. If patients do not respond to various therapies or if they are immunocompromised, the differential diagnosis of demodicosis should be considered; here the treatment is oral ivermectin. Some forms of rosacea (rosacea fulminans and granulomatous rosacea) may be treated initially with oral corticosteroids. Ophthalmic rosacea is treated topically as well as with tetracyclines or macrolides.

The M-DC8-positive leukocytes are a subpopulation of the CD14+ CD16+ monocytes.

Recently, a population of M-DC8-positive leukocytes has been described as a new subpopulation of human dendritic cells (DC). In view of the expression of the CD16 antigen on these cells, as well as the finding that DC can arise from blood monocytes, we hypothesized that the expression of M-DC8 is mainly associated with the CD14+ CD16+ phenotype of blood monocytes. Immunofluorescence analysis of whole blood showed that the percentage of M-DC8+ cells is about three times lower than the percentage of CD14+ CD16+ monocytes among all leukocytes (0.32% versus 1.10%). Further, in addition to the expression of CD16, these M-DC8+ cells were also positive for CD14 at low density. Multicolor flow cytometric analysis of whole blood revealed that more than one third of the CD14+ CD16+ monocyte population expressed the M-DC8 antigen (42.3%), and almost all M-DC8+ cells were CD14-CD16-double-positive (87.5%). Finally, the M-DC8 antigen was also expressed on alveolar macrophages from healthy individuals, i.e., cells that are phenotypically and functionally related to the CD14+ CD16+ monocytes. Taken together, the data presented here clearly demonstrate that the M-DC8+ leukocytes are a subpopulation of the CD14+ CD16+ monocytes and may represent DC

Differential chemokine receptor expression and function in human monocyte subpopulations.

The subset of human blood monocytes expressing low levels of CD14 and high levels of CD16 (CD14+CD16+) exhibits features resembling mature tissue macrophages and can be expanded in inflammatory conditions. We analyzed expression of CC chemokine receptors (CCR) in CD14+CD16+ versus CD14++ monocytes, which may be crucial for specific trafficking. Multicolor flow cytometric analysis of whole peripheral blood revealed that, as opposed to CD14++ monocytes, the CD14+CD16+ subset lacked surface expression of monocyte chemotactic protein-1 (MCP-1) receptor CCR2, however, it showed significantly higher surface expression of the macrophage inflammatory protein 1alpha (MIP-1alpha)/RANTES receptor CCR5. This was paralleled by differences in mRNA expression in the subsets, as shown by reverse transcriptase-polymerase chain reaction using sorted cells. In comparison to CD14++ monocytes, CD14+CD16+ cells expressed lower CCR2 but higher CCR5 transcript levels, whereas CCR1 levels were equivalent. Flow cytometric analysis of isolated human monocytes recovered after transendothelial chemotaxis assays revealed that the percentage of CD14+CD16+ cells was dramatically reduced in the fraction migrating toward MCP-1 compared with the fraction that did not migrate or the input, showing that polarized CCR2 expression was accompanied by a differential chemotactic responsiveness. Moreover, CD11b surface expression was preferentially up-regulated by MCP-1 in CD14++ cells but by MIP-1alpha in CD14+CD16+ monocytes, confirming the functional relevance of distinct CCR expression. The characteristics of CD14+CD16+ cells may reflect preactivation by cytokines and determine their predilective localization during specific inflammatory conditions or susceptibility to infection.