Neurokinin 1 receptor antagonists exhibit peripheral effects in prurigo nodularis including reduced ERK1/2 activation.

BACKGROUND: Aprepitant is a neurokinin 1 receptor (NK1R) antagonist used for its antipruritic properties in dermatoses and systemic diseases. The mode of action is still unclear. A peripheral effect is assumed as aprepitant shows efficacy in inflammatory skin diseases including prurigo nodularis (PN). OBJECTIVES: To investigate the peripheral effects of NK1R antagonism in PN and cell culture models. METHODS: Subjects with PN received an aprepitant treatment. Clinical, morphological and immunohistochemical changes were investigated in skin biopsies before and after treatment. Expression of NK1R was analysed by immunohistochemistry and for downstream pathways ((p)ERK1/2) by Western blotting in PN patients and matched healthy volunteers. Effects of NK1R blocking were analysed in cell cultures of primary keratinocytes by Western blotting for (p)ERK1/2 and by qPCR for NK1R, interleukin (IL)-1beta, IL-6, IL-8 and TNFalpha. RESULTS: Aprepitant treatment showed significant reduction in pruritus intensity (P < 0.05) in PN and relevant immunohistochemical changes (down: CD5, CD25, up: CD79a, IL4). NK1R expression was higher in keratinocytes of PN patients compared to healthy controls. After treatment, epidermal NK1R expression increased while expression and activation of ERK1/2 decreased. In vitro, receptor up-regulation and reduced expression and activation of ERK1/2 were confirmed and reduced IL-expression shown when blocking NK1R. CONCLUSION: Our data confirm that NK1R antagonists such as aprepitant exhibit effects in the skin. Epidermal receptor expression, epidermal inflammatory ILs, ERK1/2 MAPK signalling and cutaneous inflammatory infiltrate were targets of NK1R antagonism. This may explain partly the antipruritic effect of NK1R antagonists next to its role in the central nervous system.

Protection of glucotoxicity by a tripeptide derivative of α-melanocyte-stimulating hormone in human epidermal keratinocytes.

BACKGROUND: Chronic skin ulcers are a major complication and a therapeutic challenge in patients with diabetes mellitus. Glucose-induced accumulation of reactive oxygen species (ROS) is considered to be an important pathogenetic factor in diabetes. OBJECTIVES: To characterize the impact of high glucose (HG) on normal human keratinocytes (NHKs) and examine if Lys-d-Pro-Thr (KdPT), a tripeptide derived from α-melanocyte-stimulating-hormone, has protective effects. METHODS: We investigated the key functions of NHKs under HG conditions with or without KdPT in vitro as well as ex vivo employing a skin organ culture model. RESULTS: HG impaired metabolic activity, cell proliferation, viability and migration of NHKs. As shown by atomic force microscopy HG altered the biophysical properties of NHKs, i.e. cell size and elasticity. Glucotoxicity in NHKs was paralleled by the induction of intracellular ROS and endoplasmic reticulum stress. KdPT attenuated HG-induced oxidative stress and antagonized the effects of glucose on cell viability, metabolic activity and migration. Importantly, KdPT also antagonized the suppressive effect of HG on epidermal migration in wounded human skin organ cultures. CONCLUSIONS: Our findings highlight a novel effect of KdPT that could be exploited for the future therapy of diabetic skin ulcers.

Dupilumab treatment improves quality of life in adult patients with moderate-to-severe atopic dermatitis: results from a randomized, placebo-controlled clinical trial.

BACKGROUND: Dupilumab, a human anti-interleukin-4 receptor alpha monoclonal antibody, significantly improved clinical signs and symptoms in adults with moderate-to-severe atopic dermatitis in a randomized, double-blind, placebo-controlled, phase IIa trial. OBJECTIVES: We evaluate health-related quality of life (HRQoL) and correlation of HRQoL with secondary clinical and patient-reported outcomes in a subset of patients from this trial of dupilumab. METHODS: Patients were randomized to 300 mg weekly subcutaneous dupilumab or placebo for 12 weeks (trial registration: NCT01548404). The Quality of Life Index of Atopic Dermatitis (QoLIAD) score (exploratory outcome) and its correlation with efficacy outcomes [Eczema Area and Severity Index (EASI); primary end point; SCORing Atopic Dermatitis (SCORAD), SCORAD visual analogue scale (VAS) scores for sleep and pruritus, pruritus numerical rating scale (NRS) and 5-dimensional pruritus] were assessed in 64 adults with moderate-to-severe atopic dermatitis. RESULTS: Mean QoLIAD scores at baseline ± standard error (SE) were 13·3 ± 1·34 and 11·3 ± 1·09 for the placebo and dupilumab groups, respectively. Dupilumab significantly improved QoLIAD score after 12 weeks of treatment vs. placebo (mean % change from baseline in QoLIAD score ± SE: -64·0 ± 6·91 vs. -11·1 ± 9·31). Least squares mean % difference from baseline vs. placebo in QoLIAD score ±SE was -52·0 ± 11·43, P < 0·001). QoLIAD scores significantly correlated with changes in efficacy outcomes, including EASI (r = 0·44), 5-dimensional pruritus (r = 0·49), pruritus NRS (r = 0·41), total SCORAD (r = 0·56) and SCORAD VAS scores for sleep (r = 0·47) and pruritus (r = 0·54); all P < 0·05. CONCLUSIONS: Dupilumab improved QoLIAD scores in adults with atopic dermatitis and was significantly associated with improvements in study outcomes.

Pathogenesis and clinical presentation of rosacea as a key for a symptom-oriented therapy.

Rosacea is a common chronic inflammatory skin disorder that typically occurs in adults and affects the face. Synonyms of rosacea include "acne rosacea", "couperose" and "facial erythrosis", in German also "Kupferfinne" and "Rotfinne". The disorder is characterised by a chronic and flaring course and is caused by a genetically predisposed, multifactorial process. A higher incidence is seen in people with fair skin and a positive family history. The characteristic rosacea symptoms manifest primarily, but not exclusively centrofacially, with forehead, nose, chin and cheeks significantly affected. Based on the various main symptoms a classification of the individual clinical pictures can be performed. However, a classification often does not reflect the clinical reality, since the various symptoms commonly coexist. The present review provides an introduction on pathogenesis and clinical manifestations of rosacea and prefers a symptom-oriented therapy approach.

Rosazea-Management: Update über allgemeine Maßnahmen und topische Therapieoptionen.

Obwohl bislang für die Rosazea keine kurative Therapie besteht, können verschiedene Optionen zur Behandlung der Symptome und zur Vorbeugung von Exazerbationen empfohlen werden. Neben Selbsthilfemaßnahme wie der Vermeidung von Triggerfaktoren und einer geeigneten Hautpflege sollte das Rosazea-Management bei Patienten mit erythematöser und leichter bis schwerer papulopustulöser Rosazea die Anwendung topischer Präparate als First-Line-Therapie umfassen. Da Überlappungen der charakteristischen Rosazea-Symptome im klinischen Alltag die Regel sind, sollte die medikamentöse Therapie auf die individuellen Symptome zugeschnitten werden; auch eine Kombinationstherapie kann erforderlich sein. Zu den für die Behandlung der Hauptsymptome der Rosazea zugelassenen Wirkstoffen gehören Brimonidin gegen das Erythem sowie Ivermectin, Metronidazol oder Azelainsäure gegen entzündliche Läsionen. Ihre Wirksamkeit wurde in zahlreichen validen, gut kontrollierten Studien belegt. Darüber hinaus existieren verschiedene nicht zugelassene topische Behandlungsmöglichkeiten, deren Wirksamkeit und Sicherheit noch in größeren, kontrollierten Studien zu untersuchen ist.

State of the art: systemic rosacea management.

Based on numerous trials, oral tetracyclines and most commonly their second-generation derivative doxycycline have become the main pillar in systemic rosacea treatment. However, the only preparation that has been approved so far in this setting is 40 mg doxycycline in an anti-inflammatory dosage and with a modified release formulation. With the introduction of this once-daily, non-antibiotic dosing of doxycycline, oral therapy is more commonly prescribed as first-line treatment in moderate to severe papulopustular rosacea. In addition, topical and oral strategies are often used in combination due to the more substantial improvements compared to monotherapy. Although several other non-approved oral agents like macrolides, isotretinoin, and carvedilol have been evaluated for systemic treatment and showed promising results, yet the experience with these drugs in rosacea is limited, and thus they should be reserved for special situations.

Aktueller Stand der systemischen Rosazea-Therapie.

Basierend auf den Daten zahlreicher Studien sind orale Tetracycline - und hier insbesondere Doxycyclin als Tetracyclin der zweiten Generation - die Grundpfeiler der systemischen Rosazea-Therapie. Bisher ist dafür jedoch nur Doxycyclin 40 mg in antientzündlicher Dosierung mit veränderter Wirkstofffreisetzung zugelassen. Seit Einführung der Therapie mit Doxycyclin einmal täglich in nicht antibiotischer Dosierung wird die orale Therapie häufiger als Erstbehandlung bei mittelschwerer bis schwerer papulopustulöser Rosazea verschrieben. Oft wird diese Behandlung aufgrund der besseren Wirksamkeit im Vergleich zur Monotherapie auch mit einer topischen Behandlung kombiniert. Obwohl in der Systemtherapie weitere, nicht zugelassene Wirkstoffe wie Makrolide, Isotretinoin und Carvedilol mit viel versprechenden Ergebnissen untersucht wurden, ist die vorliegende Erfahrung bisher begrenzt, so dass diese Substanzen speziellen Situationen vorbehalten bleiben sollten.

Pathogenese und Klinik der Rosazea als Schlüssel für eine symptomorientierte Therapie.

Rosazea ist eine häufige chronisch-entzündliche Hauterkrankung, die typischerweise bei Erwachsenen vorkommt und das Gesicht betrifft. Synonyme der Rosazea sind Acne rosacea, Kupferfinne, Rotfinne, Couperose und Rosacea. Die Erkrankung ist durch einen chronischen und schubartigen Verlauf gekennzeichnet und wird durch ein genetisch prädisponiertes, multifaktorielles Geschehen bedingt. Ein vermehrtes Auftreten wird bei hellem Hauttyp und positiver Familienanamnese verzeichnet. Die charakteristischen Rosazea-Symptome manifestieren sich vorwiegend, aber nicht ausschließlich zentrofazial, wobei Stirn, Nase, Kinn und die Wangen maßgeblich betroffen sind. Dabei werden unterschiedliche Hauptsymptome voneinander unterschieden, anhand derer eine Klassifikation der verschiedenen klinischen Bilder vorgenommen werden kann. Eine Klassifizierung wird oftmals jedoch nicht der klinischen Realität gerecht, da die verschiedenen Symptome häufig gemeinsam auftreten. Diese Übersichtarbeit führt in die Pathogenese und Klinik der Rosazea ein und plädiert für einen symptomorientierten Therapieansatz.

Rosacea Management: Update on general measures and topical treatment options.

Although there is presently no cure for rosacea, there are several recommended treatment options available to control many of the symptoms and to prevent them from getting worse. In addition to self-help measures like avoidance of trigger factors and proper skin care, rosacea management should include topical medications as one of the first-line choices for patients with erythematous and mild to severe papulopustular rosacea. Since mixed forms of characteristic rosacea symptoms are more common, medical treatment must be symptom-tailored for each individual case and will often involve a combination therapy. Approved topical agents for the major symptoms of rosacea encompass brimonidine for erythema and ivermectin, metronidazole or azelaic acid for inflammatory lesions, all of which have shown their efficacy in numerous valid, well-controlled trials. In addition, there are several other, not approved topical treatments which are possible options that require further validation in larger well-controlled studies.

Regulation of melanocortin 1 receptor in allergic rhinitis in vitro and in vivo.

BACKGROUND: α-melanocyte-stimulating hormone (α-MSH) was shown to inhibit allergic airway inflammation and exert suppressive effects on human basophils. OBJECTIVE: This study aims to extend our current knowledge on the melanocortin 1 receptor (MC1R) expression in nasal tissue of patients with allergic rhinitis (AR) and functional effects of α-MSH in human basophils especially from patients with allergic rhinitis. METHODS: MC1R expression before and after nasal allergen provocation was studied in nasal mucosal tissue of AR patients and in a mouse model of allergic airway inflammation using immunofluorescence. In vitro regulation of the MC1R and CD203c surface expression on whole-blood basophils of patients with AR and controls was assessed with flow cytometry. Functional effects of α-MSH on isolated basophils were analysed regarding apoptosis with flow cytometry and chemotaxis using a Boyden chamber assay. RESULTS: We detected an accumulation of MC1R-positive basophils in nasal mucosa tissue of patients with AR 24 h after nasal allergen provocation. Such accumulation was not present in mucosa sections from healthy controls. In mice with allergic airway inflammation, we found a clear accumulation of MC1R-positive basophils in the nasal tissue compared to control mice. MC1R expression was inducible in AR patients and controls by stimulation with anti-IgE. α-MSH inhibited anti-IgE and grass pollen induced upregulation of CD203c, but had no effect on chemotaxis or apoptosis of basophils in vitro. CONCLUSIONS AND CLINICAL RELEVANCE: MC1R-positive basophils accumulate in the nasal mucosa of patients with AR after nasal allergen provocation. Since α-MSH suppresses proinflammatory effector functions in human basophils via the MC1R, it constitutes an interesting novel target for modulating the allergic inflammatory response.

The anti-IL-4 receptor alpha antibody dupilumab: facing a new era in treating atopic dermatitis.

INTRODUCTION: Atopic dermatitis is the most common chronic inflammatory skin disease with high prevalence rates in adults and even higher among children. For the numerous patients suffering from moderate to severe disease, standard systemic treatment regimens such as cyclosporine A, methotrexate or azathioprine are not suited for long-term treatment due to their unfavorable safety profile. A promising alternative would be the newly developed IL-4 receptor alpha antibody dupilumab which has been investigated in several clinical trials during the last years. AREAS COVERED: Recently, four phase I and II studies have been published providing a favorable efficacy and safety profile. Clinical scores such as EASI were reduced by 74% after 12 weeks of treatment with early onset of first improvement after already one week. Safety data showed no evidence of drug-related serious adverse events and no organ toxicity. EXPERT OPINION: First clinical data of treating AD with dupilumab provided strong evidence for a highly significant efficacy and safety. In the case, future phase III studies will confirm these findings, dupilumab has the potential to become a new first line standard treatment for patients with severe AD.

Comparison of three methods for measuring psoriasis severity in clinical studies (Part 2 of 2): use of quality of life to assess construct validity of the Lattice System Physician's Global Assessment, Psoriasis Area and Severity Index and Static Physician's Global Assessment.

BACKGROUND: Systems for determining psoriasis severity in clinical trials have not been sufficiently validated against patients' perceived quality of life. OBJECTIVE: To validate three systems of physician-determined psoriasis severity (the Lattice System Physician's Global Assessment [LS-PGA], Psoriasis Area and Severity Index [PASI] and static Physician's Global Assessment [sPGA]). METHODS: Data were from a 24-week randomized, double-blind, placebo-controlled, multicenter trial of therapy with oral calcineurin inhibitors in 445 patients. Construct validity was measured by correlations of the three severity scores with patients' self-reported quality of life (QoL) from the Dermatology Life Quality Index (DLQI) and a DLQI item about psoriasis symptoms. RESULTS: All severity systems were moderately and positively correlated with QoL, indicating construct validity. QoL was most consistently related to physicians' assessments of body surface area involved with psoriasis (iBSA) followed by, in the order of consistency, plaque elevation, erythema and scale. CONCLUSIONS: The LS-PGA weights iBSA and aspects of plaque morphology in concert with their relative effects on QoL. The LS-PGA, sPGA and PASI are validated by their relationship to QoL in a clinical trial.

Comparison of three methods for measuring psoriasis severity in clinical studies (Part 1 of 2): change during therapy in Psoriasis Area and Severity Index, Static Physician's Global Assessment and Lattice System Physician's Global Assessment.

BACKGROUND: Accurate and reliable assessment of changes in psoriasis severity is critical in clinical trials of therapies. OBJECTIVE: To compare Psoriasis Area and Severity Index (PASI), static Physician's Global Assessment (sPGA), and the Lattice System Physician's Global Assessment (LS-PGA) in a trial of systemic treatments for plaque psoriasis vulgaris and to assess whether they measure change in psoriasis induced by therapy. METHODS: Patients were randomized to voclosporin or cyclosporine for 24 weeks (the '24-week-treatment' group, n = 366), or placebo for 12 weeks followed by voclosporin for 12 weeks (the 'initial-placebo' group, n = 89). RESULTS: All scoring systems changed in concert and were sensitive enough to detect reductions in severity during placebo therapy as well as with active therapy (P < 0.01 for each measurement). At study onset, there were poorer correlations of sPGA with PASI (r = 0.45) and LS-PGA (r = 0.39) than between PASI and LS-PGA (r = 0.68). After therapy, all correlations were stronger, but sPGA continued to be less well correlated (with PASI, r = 0.85; with LS-PGA, r = 0.79) than LS-PGA with PASI (r = 0.90). Two- or three-step improvements in LS-PGA showed very good to excellent accuracy in corresponding to PASI-50 and PASI-75, respectively, and were more accurate than comparable changes in sPGA. CONCLUSION: PASI, sPGA and LS-PGA are responsive to the varying degrees of improvement in psoriasis induced by either placebo or active therapy. While the three systems capture similar information, each has different reasons for use in a clinical trial.

Retreatment in patients with psoriasis achieving response with etanercept after relapse due to treatment interruption: results from the CRYSTEL study.

BACKGROUND: In clinical practice, patients with psoriasis may require intermittent therapy as part of their long-term treatment programme. Those achieving Physician's Global Assessment (PGA) of ≤ 1 (almost clear/clear) are more likely to be selected as candidates for intermittent therapy than those with a higher PGA (≥ 2; mild or worse), who may relapse sooner or have a delayed response. The objective of this analysis was to determine if patients achieving PGA ≤ 1 using intermittent etanercept (ETN) therapy could regain response (defined as PGA ≤ 2) after relapse. METHODS: In the CRYSTEL study (clinicaltrials.gov NCT00195507), patients with moderate-to-severe psoriasis were treated with ETN 50 mg twice weekly (BIW) for ≤ 12 weeks (or for an extra 12 weeks with ETN 25 mg BIW until PGA ≤ 2 was achieved). Patients who reached PGA ≤ 1 during this time were selected for this post hoc analysis (Cycle 1). Treatment was paused, and patients who relapsed (PGA > 2) were retreated with ETN 25 mg BIW until recovery (PGA ≤ 2, Cycle 2). Treatment cycles were continued for up to 54 weeks. The proportion of PGA responders and the time to attain response were calculated, and patient satisfaction was evaluated using the Patient Satisfaction Survey. RESULTS: During Cycle 1, 131 patients achieved PGA ≤ 1 within a median of 9 weeks and subsequently relapsed after treatment cessation. In Cycle 2, 119 (91%) patients attained PGA ≤ 2 within a median time of 7 weeks. The majority of patients were either 'very satisfied', 'satisfied' or 'somewhat satisfied' during both Cycle 1 (100% in total) and Cycle 2 (97% in total). CONCLUSION: Patients achieving the stringent criteria of PGA ≤ 1 with ETN therapy before ceasing treatment, and subsequently relapsing, were able to quickly regain response during retreatment. The majority of patients considered their therapy to be satisfactory.

Cutaneous manifestations of rheumatic diseases. Clinical presentation and underlying pathophysiology.

Being the largest organ of the human body, skin is frequently affected in many rheumatic diseases. Thus, it can serve as an important indicator for the correct diagnosis of a rheumatic disease and also as a marker of disease activity in distinct rheumatic disorders. In this review we will highlight the clinical features of these cutaneous manifestations of the major rheumatic diseases. We will also provide an update on the complex pathobiology of these diseases based on the most recent developments in clinical and translational research.

Beneficial effects of the melanocortin analogue Nle4-D-Phe7-α-MSH in acne vulgaris.

BACKGROUND: α-Melanocyte-stimulating hormone (α-MSH) is a melanocortin peptide that increases skin pigmentation during ultraviolet light-mediated tanning. As α-MSH has been shown to possess anti-inflammatory effects, we assessed the clinical potential of a superpotent α-MSH analogue, afamelanotide (Nle(4)-D-Phe(7)-α-MSH), in patients with acne vulgaris, the most common inflammatory skin disorder. METHODS: Afamelanotide (16 mg) was given in a phase II open-label pilot study subcutaneously as a sustained-release resorbable implant formulation to 3 patients with mild-to-moderate facial acne vulgaris. Evaluation included lesion count, adverse effects and patient-reported outcome. Monitoring of laboratory parameters included differential blood counts, electrolytes, urine analysis, and liver and kidney function tests. Skin melanin density was measured by reflectance spectrophotometry. RESULTS: The total number as well as the number of inflammatory acne lesions declined in all patients 56 days after the first injection of afamelanotide. Life quality as measured by Dermatology Life Quality Index likewise improved in all 3 patients 56 days after the first injection of afamelanotide. There were no adverse effects except mild and short-term fatigue in one patient. All patients experienced increased pigmentation especially on the face. Clinically relevant changes in laboratory parameters were not detected. CONCLUSIONS: Afamelanotide appears to have anti-inflammatory effects in patients with mild-to-moderate acne vulgaris. Future trials are needed to confirm the anti-inflammatory action of this melanocortin analogue in patients with acne vulgaris.