Comparison of different skin care regimens in patients with moderate to severe atopic dermatitis receiving systemic treatment: A randomized controlled trial.

BACKGROUND: Moderate to severe AD can be successfully managed by systemic treatments. Current guidelines also recommend emollients or emollients 'plus' and eudermic cleansers for all AD patients to improve the skin barrier and provide anti-irritant and anti-pruritic effects. OBJECTIVES: To investigate the efficacy of skin care (in addition to systemic treatment) with an Emollient 'plus' balm designed to improve the skin barrier and skin microbiome plus a corresponding syndet compared to usual commercial emollients and cleansers. METHODS: In a randomized controlled multicenter study, patients with moderate to severe AD (Severity scoring of atopic dermatitis [SCORAD] score ≥ 40) receiving systemic treatment (cyclosporin A, dupilumab or a Janus kinase inhibitor) were randomized 1:1 to apply twice daily for 10 weeks Emollient 'plus' after pre-cleaning with the syndet (Emollient 'plus' group) or to continue with their usual emollient and cleanser (Control group). Assessments included SCORAD, pruritus on a Visual Analog Scale, Dermatology quality of life questionnaire (DLQI), efficacy and tolerance questionnaires. RESULTS: Included were 57 patients with mean age of 38 years (range 19-70 years). The mean amount of emollient used after 10 weeks was 447.3 g (range 29-1099 g) and 613.2 g (range 97-2565 g) for the Emollient 'plus' versus the Control, respectively (p = 0.0277). After 10 weeks, subjects in the Emollient 'plus' had a significantly greater reduction in current pruritus (p = 0.0277) and a greater reduction in some DLQI items compared to the Control group. CONCLUSIONS: In patients with moderate to severe AD receiving systemic treatment, the Emollient 'plus' regimen significantly improved pruritus and quality of life items compared to the control, while using 23% less product over a 10-week period. These results stress the importance of daily use of emollients, especially emollients 'plus' to improve signs, symptoms and quality of life in patients with AD.

Subgroup Analysis of Crisaborole for Mild-to-Moderate Atopic Dermatitis in Children Aged 2 to < 18 Years.

OBJECTIVES: This post hoc analysis of pooled data from two phase III studies (AD-301: NCT02118766; AD-302: NCT02118792) explored the efficacy and safety of crisaborole ointment, 2%, a nonsteroidal phosphodiesterase 4 inhibitor, for the treatment of mild-to-moderate atopic dermatitis (AD) in pediatric patients (aged 2 to < 18 years) only, stratified by baseline characteristics. METHODS: Pediatric patients with mild or moderate AD per Investigator's Static Global Assessment (ISGA) and percentage of treatable body surface area (%BSA) ≥ 5 at baseline were assessed. Crisaborole or vehicle (2:1 randomization ratio) was applied twice daily for 28 days. Of the 1313 pediatric patients included in this study, 874 received crisaborole and 439 received vehicle. ISGA success was defined as clear (0) or almost clear (1) with ≥ 2-grade improvement from baseline. Efficacy and safety were stratified by age group, sex, baseline ISGA, baseline %BSA per published severity strata, and prior AD therapy. RESULTS: Overall, the proportions of crisaborole-treated and vehicle-treated pediatric patients with ISGA success at week 4 were 32.5 and 21.5%, respectively. ISGA success rates at day 29 (week 4) were generally higher in crisaborole-treated (21.9-38.1%) than vehicle-treated (15.7-26.9%) patients across subgroups. Rates of treatment-related application site pain were 2.4-10.1% for crisaborole-treated patients and 0.6-2.2% for vehicle-treated patients across subgroups. No new safety concerns were noted in any patient subgroup. CONCLUSION: Crisaborole improved global disease severity and was reasonably well tolerated across all pediatric baseline characteristic subgroups. Application site discomfort was greater with crisaborole than with vehicle, but few patients discontinued treatment. GOV REGISTRATION NUMBERS: NCT02118766; NCT02118792 (registration date: April 21, 2014).

Crisaborole is an ointment approved for the treatment of mild-to-moderate eczema. In two phase III clinical trials, eczema improved after 28 days of crisaborole use in patients aged ≥ 2 years. Patients with eczema rashes used crisaborole or plain ointment twice a day for 28 days. The clinical trials excluded patients with serious infections. Eczema treatment within 2 weeks of the trials was not allowed. We looked at whether traits of children aged 2­17 years affected how well crisaborole improved eczema. We studied boys and girls by age and how bad their eczema was at the start of the study. We combined data from both clinical trials to calculate the percentages of children with clear or almost clear skin at day 29. We also studied the frequency of side effects at day 29. After 4 weeks, 33% of children receiving crisaborole compared with 22% of children receiving plain ointment had clear or almost clear skin, a meaningful difference in favor of crisaborole. This was also true across groups. Most patients did not have side effects related to crisaborole. The most common side effect related to crisaborole was application site pain. This side effect occurred in up to one in ten children receiving crisaborole. Up to 1 in 50 patients receiving plain ointment had application site pain. Few children stopped crisaborole treatment, and there were no new safety concerns. In conclusion, compared with plain ointment, crisaborole improved eczema in more children, and side effects were minor.

Translating the Investigator's Static Global Assessment to the Eczema Area and Severity Index in Studies of Crisaborole for Atopic Dermatitis.

INTRODUCTION: Atopic dermatitis (AD) severity was measured in two phase 3 US studies of crisaborole ointment, 2%, in patients aged ≥ 2 years using the Investigator's Static Global Assessment (ISGA), an FDA-recommended scale. Eczema Area and Severity Index (EASI) is a validated scale used globally to assess AD severity in clinical trials. The objective of this study is to aid interpretability of ISGA by translating ISGA scores to EASI scores. METHODS: ISGA was mapped to EASI using published EASI severity strata by Chopra et al. and Leshem et al. and pooled data from phase 3 trials CrisADe CORE 1 and CORE 2, which evaluated crisaborole in patients aged ≥ 2 years with mild-to-moderate AD (crisaborole, n = 1016; vehicle, n = 506). Least squares mean (LSM) percentage change from baseline (%CFB) in EASI and proportion of patients with 50%, 75%, and 90% improvement (EASI-50, EASI-75, and EASI-90, respectively) on day 29 were computed for mapped EASI. The relationship between changes in ISGA and changes in EASI was assessed using data from three abrocitinib trials. RESULTS: ISGA was mapped to EASI using 70,000 random simulations. LSM (standard error) for %CFB in mapped EASI at day 29 (crisaborole versus vehicle) was -26.3% (17) versus 45.2% (35) (P = 0.0671) using Chopra strata and -43.1% (4.6) versus -5.2% (8.4) (P < 0.0001) using Leshem strata. EASI-50, EASI-75, and EASI-90 rates were 72.1% versus 57.6%, 63.0% versus 47.8%, and 55.0% versus 40.1%, respectively, using Chopra strata (P < 0.0001 for each difference). These rates were 68.8% versus 54.0%, 54.8% versus 40.5%, and 38.9% versus 27.2%, respectively (P < 0.0001 for each difference) using Leshem strata. Mean two-point improvement in ISGA was comparable to EASI-90. CONCLUSION: Mapped EASI results were consistent with ISGA results in crisaborole phase 3 trials. Simulation methodologies yielded consistent results and may aid in interpretability of ISGA across clinical studies. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02118766, NCT02118792.

Serlopitant reduced pruritus in patients with prurigo nodularis in a phase 2, randomized, placebo-controlled trial.

BACKGROUND: Anecdotal evidence suggests that neurokinin 1 receptor antagonism reduces pruritus intensity in chronic pruritic conditions such as prurigo nodularis (PN). OBJECTIVE: This study assessed safety and efficacy of the neurokinin 1 receptor antagonist serlopitant for treatment of pruritus in PN. METHODS: In this randomized, double-blind, placebo-controlled study, 128 patients with chronic, treatment-refractory PN for more than 6 weeks received serlopitant, 5 mg, or placebo orally once daily for 8 weeks. The primary end point was change in average itch visual analog scale score at weeks 4 and 8. RESULTS: Average itch visual analog scale scores significantly improved with serlopitant versus with placebo at weeks 4 and 8: the least squares mean difference (serlopitant minus placebo) was -1.0 at week 4 (P = .02) and -1.7 at week 8 (P < .001). The least squares mean difference between serlopitant and placebo reached statistical significance at week 2 (-0.9 [P = .011]). The most frequently reported treatment-emergent adverse events in the serlopitant group were nasopharyngitis, diarrhea, and fatigue. LIMITATIONS: The 8-week duration may be insufficient to assess clinically relevant resolution of PN lesions. CONCLUSIONS: Serlopitant reduced pruritus in patients with treatment-refractory PN and was well tolerated.

Aprepitant in Anti-histamine-refractory Chronic Nodular Prurigo: A Multicentre, Randomized, Double-blind, Placebo-controlled, Cross-over, Phase-II trial (APREPRU).

The aim of this multicentre, randomized, double-blind, placebo-controlled, cross-over, phase-II study was to determine the antipruritic effect of aprepitant vs. placebo in 58 patients with anti-histamine-refractory chronic pruritus in chronic nodular prurigo. Patients were randomized to receive either first oral aprepitant 80 mg/day or placebo for 4 weeks. Following a 2-week wash-out phase, the patients were crossed-over to receive the other treatment for 4 weeks. Primary efficacy criterion was the intra-individual difference between mean itch intensity (visual analogue scale) at baseline compared with the end of treatment period. Prurigo lesions, pruritus course, quality of life, patient benefits, and safety were secondary parameters. No significant differences were found between aprepitant treatment and placebo for any of the parameters investigated. Under the experimental conditions of the study, aprepitant, 80 mg daily for 4 weeks, did not have an antipruritic effect in patients with chronic prurigo. (DRKS00005594; EudraCT Number: 2013-001601-85).

Melatonin and Its Metabolites Ameliorate UVR-Induced Mitochondrial Oxidative Stress in Human MNT-1 Melanoma Cells.

Melatonin (Mel) is the major biologically active molecule secreted by the pineal gland. Mel and its metabolites, 6-hydroxymelatonin (6(OH)Mel) and 5-methoxytryptamine (5-MT), possess a variety of functions, including the scavenging of free radicals and the induction of protective or reparative mechanisms in the cell. Their amphiphilic character allows them to cross cellular membranes and reach subcellular organelles, including the mitochondria. Herein, the action of Mel, 6(OH)Mel, and 5-MT in human MNT-1 melanoma cells against ultraviolet B (UVB) radiation was investigated. The dose of 50 mJ/cm² caused a significant reduction of cell viability up to 48%, while investigated compounds counteracted this deleterious effect. UVB exposure increased catalase activity and led to a simultaneous Ca++ influx (16%), while tested compounds prevented these disturbances. Additional analysis focused on mitochondrial respiration performed in isolated mitochondria from the liver of BALB/cJ mice where Mel, 6(OH)Mel, and 5-MT significantly enhanced the oxidative phosphorylation at the dose of 10-6 M with lower effects seen at 10-9 or 10-4 M. In conclusion, Mel, 6(OH)Mel and 5-MT protect MNT-1 cells, which express melatonin receptors (MT1 and MT2) against UVB-induced oxidative stress and mitochondrial dysfunction, including the uncoupling of oxidative phosphorylation.

The tripeptide KdPT ameliorates ongoing psoriasis-like skin inflammation in murine and human skin.

Psoriasis is a chronic inflammatory disease appearing as scaly erythematous cutaneous lesions, which are characterized by parakeratosis and acanthosis as well as the infiltration of immune cells, such as T helper-1 and T helper-17 cells. Here, we demonstrated that KdPT, a tripeptide structurally related to the C-terminal amino acids of alpha-melanocyte-stimulating hormone, which was previously shown to exhibit anti-inflammatory effects in intestinal inflammation, ameliorated ongoing disease in the mouse model of imiquimod-induced psoriasis-like skin inflammation and in the small xenotransplant mouse model of psoriasis. We could show that systemic KdPT treatment significantly reduced hyperkeratosis and acanthosis in murine as well as human skin. Moreover, KdPT upregulated Foxp3 in CD4+ T cells from mice and from peripheral blood of individuals with psoriasis and decreased the expression of type 1 inflammatory cytokines, indicating that the beneficial effect of KdPT was, at least in part, mediated by the induction of functional regulatory T cells that suppressed the activation of pathogenic CD4+ IFN-γ+ and CD4+ IL-17+ T cells. Thus, these data might suggest KdPT as a potential novel therapeutic alternative for the treatment of psoriasis.

Targeting of NADPH oxidase in vitro and in vivo suppresses fibroblast activation and experimental skin fibrosis.

Although there is increasing evidence that oxidative stress is involved in collagen synthesis and myofibroblast activation, the NADPH oxidase (Nox) system is incompletely investigated in the context of human dermal fibroblasts (HDFs) and skin fibrosis. Using the pan-Nox inhibitor diphenyleneiodonium (DPI) as an initial tool, we show that gene expression of collagen type I, α-smooth muscle actin (α-SMA) and fibronectin 1 is suppressed in HDFs. Detailed expression analysis of all Nox isoforms and adaptors revealed expression of RNA and protein expression of Nox4, p22phox and Poldip2 but neither Nox1 nor Nox2. Nox4 could be immunolocalized to the endoplasmic reticulum. Importantly, TGF-ß1 had a dose- and time-dependent upregulating effect on NADH activity and Nox4 gene expression in HDFs. Genetic silencing of Nox4 as demonstrated by siRNA in HDFs as well as in murine fibroblasts established from Nox4 knockout mice confirmed that TGF-ß1 -mediated collagen type I gene, α-SMA and fibronectin 1 gene expressions were Nox4-dependent. This TGF-ß1 effect was mediated by Smad3 as shown by in silico promoter analysis, pharmacological inhibition and gene silencing of Smad3. The relevance of these findings is highlighted in the bleomycin-induced scleroderma mouse model. DPI treatment attenuated skin fibrosis and myofibroblast activation. Moreover, Nox4 knockdown by siRNA reduced skin collagen synthesis, α-SMA and fibronectin 1 expression in vivo. Finally, analyses of HDFs from patients with systemic sclerosis confirmed the expression of Nox4 and its adaptors, whereas Nox1 and Nox2 were not detectable. Our findings indicate that Nox4 targeting is a promising future treatment for fibrotic skin diseases.

Dihydroavenanthramide D inhibits mast cell degranulation and exhibits anti-inflammatory effects through the activation of neurokinin-1 receptor.

Chronic pruritus is difficult to treat. Current treatment options are frequently ineffective and new therapeutic approaches are urgently needed. Avenanthramides are active substances in oats that exhibit anti-inflammatory effects. Their potential to interrupt pruritus mechanisms was investigated in this study. It was found that the synthetic analog dihydroavenanthramide D (DHAvD) can interact with the neurokinin-1 receptor (NK1R) and inhibit mast cell degranulation. DHAvD also affects inflammatory processes and reduces secretion of the cytokine interleukin-6. Our findings indicate that DHAvD may act as a NK1R inhibitor and could be a promising candidate for topical treatments of chronic pruritus.

Increasing Comorbidities Suggest that Atopic Dermatitis Is a Systemic Disorder.

Atopic dermatitis comorbidities extend well beyond the march to allergic conditions (food allergy, asthma, allergic rhinitis, allergic conjunctivitis, and eosinophilic esophagitis), suggesting both cutaneous and systemic immune activation. In reviewing atopic dermatitis comorbidities, Councilors of the International Eczema Council found a strong pattern of immune activation in peripheral blood and the propensity to both skin and systemic infections. Associations with cardiovascular, neuropsychiatric, and malignant diseases were increasingly reported, but confirmation of their link with atopic dermatitis requires longitudinal studies. Given the possibility of atopic dermatitis-related systemic immune activation, future investigations of new interventions should concurrently examine the impact on these comorbidities.

Melanocortin-1 receptor activation is neuroprotective in mouse models of neuroinflammatory disease.

In inflammation-associated progressive neuroinflammatory disorders, such as multiple sclerosis (MS), inflammatory infiltrates containing T helper 1 (TH1) and TH17 cells cause demyelination and neuronal degeneration. Regulatory T cells (Treg) control the activation and infiltration of autoreactive T cells into the central nervous system (CNS). In MS and experimental autoimmune encephalomyelitis (EAE) in mice, Treg function is impaired. We show that a recently approved drug, Nle4-d-Phe7-α-melanocyte-stimulating hormone (NDP-MSH), induced functional Treg, resulting in amelioration of EAE progression in mice. NDP-MSH also prevented immune cell infiltration into the CNS by restoring the integrity of the blood-brain barrier. NDP-MSH exerted long-lasting neuroprotective effects in mice with EAE and prevented excitotoxic death and reestablished action potential firing in mouse and human neurons in vitro. Neuroprotection by NDP-MSH was mediated via signaling through the melanocortin-1 and orphan nuclear 4 receptors in mouse and human neurons. NDP-MSH may be of benefit in treating neuroinflammatory diseases such as relapsing-remitting MS and related disorders.

α-MSH modulates cell adhesion and inflammatory responses of synovial fibroblasts from osteoarthritis patients.

INTRODUCTION: The synovium is a target for neuropeptides. Melanocortins have attained particular attention as they elicit antiinflammatory effects. Although synovial fluid from patients with rheumatic diseases contains α-melanocyte-stimulating hormone (α-MSH) it is unknown whether synovial fibroblasts generate α-MSH and respond to melanocortins. METHODS: Synovial tissue was obtained from osteoarthritis (OA) patients. Cells were isolated and prepared either as primary mixed synoviocytes or propagated as synovial fibroblasts (OASFs). Melanocortin receptor (MC) and proopiomelanocortin (POMC) expression were investigated by endpoint RT-PCR, immunofluorescence and Western immunoblotting. Functional coupling of MC1 was assessed by cAMP and Ca(2+) assays. Cell adhesion was monitored by the xCELLigence system. Secretion of α-MSH, tumour necrosis factor (TNF), interleukin (IL)-6 and IL-8 was determined by ELISA. RESULTS: OASFs in vitro expressed MC1. MC1 transcripts were present in synovial tissue and appropriate immunoreactivity was detected in synovial fibroblasts in situ. OASFs contained truncated POMC transcripts but neither full-length POMC mRNA, POMC protein nor α-MSH were detectable. In accordance with this only truncated POMC transcripts were present in synovial tissue. α-MSH increased cAMP dose-dependently but did not alter calcium in OASFs. α-MSH also enhanced adhesion of OASFs to fibronectin and reduced TNF, IL-6 and IL-8 secretion in primary mixed synoviocyte cultures. In OASFs, α-MSH modulated basal and TNF/IL-1ß-mediated secretion of IL-6 and IL-8. CONCLUSION: Synovial fibroblasts express MC1in vitro and in situ. α-MSH elicits biological effects in these cells suggesting an endogenous immunomodulatory role of melanocortins within the synovium. Our results encourage in vivo studies with melanocortins in OA models.

From morphology to biochemical state - intravital multiphoton fluorescence lifetime imaging of inflamed human skin.

The application of multiphoton microscopy in the field of biomedical research and advanced diagnostics promises unique insights into the pathophysiology of inflammatory skin diseases. In the present study, we combined multiphoton-based intravital tomography (MPT) and fluorescence lifetime imaging (MPT-FLIM) within the scope of a clinical trial of atopic dermatitis with the aim of providing personalised data on the aetiopathology of inflammation in a non-invasive manner at patients' bedsides. These 'optical biopsies' generated via MPT were morphologically analysed and aligned with classical skin histology. Because of its subcellular resolution, MPT provided evidence of a redistribution of mitochondria in keratinocytes, indicating an altered cellular metabolism. Two independent morphometric algorithms reliably showed an even distribution in healthy skin and a perinuclear accumulation in inflamed skin. Moreover, using MPT-FLIM, detection of the onset and progression of inflammatory processes could be achieved. In conclusion, the change in the distribution of mitochondria upon inflammation and the verification of an altered cellular metabolism facilitate a better understanding of inflammatory skin diseases and may permit early diagnosis and therapy.

Anti-pruritic Effect of Sertaconazole 2% Cream in Atopic Dermatitis Subjects: A Prospective, Randomized, Double-blind, Vehicle-controlled, Multi-centre Clinical Trial of Efficacy, Safety and Local Tolerability.

This study was a prospective, parallel-group, randomized, double-blind, vehicle-controlled, multi-centre clinical trial to compare the efficacy of topical sertaconazole 2% cream with vehicle in reducing chronic pruritus in subjects with atopic dermatitis, and to assess its safety and local tolerability. A total of 70 subjects applied either of the 2 treatments twice daily for a period of 4 weeks on affected, itchy skin areas. Treatment efficacy was evaluated primarily considering the item itch intensity on a 5-point verbal rating scale. Insomnia, state of atopic dermatitis (Scoring Atopic Dermatitis; SCORAD), quality of life and therapy benefit were also assessed. No significant difference between active treatment and vehicle was found at any of the time-points for any of the investigated parameters. Under the experimental conditions of the study, sertaconazole 2% cream did not exert anti-pruritic effects that were better than vehicle in subjects with atopic dermatitis who had chronic pruritus. Trial registration ClinicalTrials.gov #NCT01792713.

The skin in psoriasis: assessment and challenges.

The coexistence of psoriasis arthritis (PsA) and psoriasis vulgaris in about 20% of patients with psoriasis leads to a need for rheumatologic-dermatologic team work. We summarise the role of dermatologists in assessment of the skin in psoriasis. Chronic plaque psoriasis must be differentiated from other subtypes such as generalised pustular psoriasis (GPP) or palmoplantar pustulosis (PPP). Therapeutic management is based on the evaluation of the disease severity. Quantitative scoring of skin severity includes calculation of the Psoriasis Area and Severity Index (PASI), body surface area (BSA) as well as the Dermatology Life Quality Index (DLQI). These scoring systems do not replace the traditional dermatologic medical history and physical examination of the patient. The skin should be examined for additional skin diseases; moreover, patients should be monitored for comorbidity, most importantly PsA and cardiovascular comorbidity.