A Melanocortin-4 Receptor Agonist Induces Skin and Hair Pigmentation in Patients with Monogenic Mutations in the Leptin-Melanocortin Pathway.

BACKGROUND AND OBJECTIVES: Gene mutations within the leptin-melanocortin signaling pathway lead to severe early-onset obesity. Recently, a phase 2 trial evaluated new pharmacological treatment options with the MC4R agonist setmelanotide in patients with mutations in the genes encoding proopiomelanocortin (POMC) and leptin receptor (LEPR). During treatment with setmelanotide, changes in skin pigmentation were observed, probably due to off-target effects on the closely related melanocortin 1 receptor (MC1R). Here, we describe in detail the findings of dermatological examinations and measurements of skin pigmentation during this treatment over time and discuss the impact of these changes on patient safety. METHODS: In an investigator-initiated, phase 2, open-label pilot study, 2 patients with loss-of-function POMC gene mutations and 3 patients with loss-of-function variants in LEPR were treated with the MC4R agonist setmelanotide. Dermatological examination, dermoscopy, whole body photographic documentation, and spectrophotometric measurements were performed at screening visit and approximately every 3 months during the course of the study. RESULTS: We report the results of a maximum treatment duration of 46 months. Skin pigmentation increased in all treated patients, as confirmed by spectrophotometry. During continuous treatment, the current results indicate that elevated tanning intensity levels may stabilize over time. Lips and nevi also darkened. In red-haired study participants, hair color changed to brown after initiation of setmelanotide treatment. DISCUSSION: Setmelanotide treatment leads to skin tanning and occasionally hair color darkening in both POMC- and LEPR-deficient patients. No malignant skin changes were observed in the patients of this study. However, the results highlight the importance of regular skin examinations before and during MC4R agonist treatment.

Dysbiosis and Enhanced Beta-Defensin Production in Hair Follicles of Patients with Lichen Planopilaris and Frontal Fibrosing Alopecia.

Despite their distinct clinical manifestation, frontal fibrosing alopecia (FFA) and lichen planopilaris (LPP) display similar histopathologic features. Aberrant innate immune responses to endogenous or exogenous triggers have been discussed as factors that could drive inflammatory cascades and the collapse of the stem cell niche. In this exploratory study, we investigate the bacterial composition of scalp skin and plucked hair follicles (HF) of patients with FFA, LPP and alopecia areata circumscripta (AAc), as well as healthy individuals, in relation to cellular infiltrates and the expression of defense mediators. The most abundant genus in lesional and non-lesional HFs of LPP and FFA patients was Staphylococcus, while Lawsonella dominated in healthy individuals and in AAc patients. We observed statistically significant differences in the ratio of Firmicutes to Actinobacteria between healthy scalp, lesional, and non-lesional sites of FFA and LPP patients. This marked dysbiosis in FFA and LPP in compartments close to the bulge was associated with increased HßD1 and HßD2 expression along the HFs from lesional sites, while IL-17A was increased in lesional HF from AAc patients. The data encourage further studies on how exogenous factors and molecular interactions across the HF epithelium could contribute to disease onset and propagation.

The Potential Relevance of the Microbiome to Hair Physiology and Regeneration: The Emerging Role of Metagenomics.

Human skin and hair follicles are recognized sites of microbial colonization. These microbiota help regulate host immune mechanisms via an interplay between microbes and immune cells, influencing homeostasis and inflammation. Bacteria affect immune responses by controlling the local inflammatory milieu, the breakdown of which can result in chronic inflammatory disorders. Follicular microbiome shifts described in some inflammatory cutaneous diseases suggest a link between their development or perpetuation and dysbiosis. Though the hair follicle infundibulum is an area of intense immunological interactions, bulb and bulge regions represent immune-privileged niches. Immune privilege maintenance seems essential for hair growth and regeneration, as collapse and inflammation characterize inflammatory hair disorders like alopecia areata and primary cicatricial alopecia. Current research largely focuses on immunological aberrations. However, studies suggest that external stimuli and interactions across the follicular epithelium can have profound effects on the local immune system, homeostasis, and cycling. Herein, we review hair follicle bacterial colonization, its possible effects on the underlying tissue, and links to the pathogenesis of alopecia, beyond the pure investigation of specific species abundance. As skin microbiology enters the metagenomics era, multi-dimensional approaches will enable a new level of investigations on the effects of microorganisms and metabolism on host tissue.

Identification of anti-microbial peptides and traces of microbial DNA in infrainfundibular compartments of human scalp terminal hair follicles.

BACKGROUND: The upper follicular compartment, a well-known reservoir of cutaneous microbiota, constitutes a space for intensive cross-barrier dialogue. The lower follicle comprises the bulb and bulge, structures with relative immune-privileged status, crucial for physiological cycling, and widely considered to be microbial-free. OBJECTIVES: Following our initial immunohistochemical screening for regulatory cytokines and defensin expression in anagen hair follicles, we aimed to confirm our results with a follow-up ELISA investigation. We postulated that exposure to microbial components may trigger expression, and thus opted to investigate microbial presence in this area. MATERIALS & METHODS: We performed immunohistochemical staining for selected cytokines and antimicrobial peptides, and Gram and Giemsa staining on tissue sections from healthy individuals. Based on ELISA analyses, we confirmed a marked presence of IL-17A- and HBD2 in infrainfundibular compartments from plucked anagen hair follicles of 12 individuals (six females, six males; frontal and occipital scalp sites). 16S rRNA sequencing on microbial DNA extracted from lower follicles, as well as fluorescence in situ hybridization (FISH) were applied to explore bacterial presence in the infrainfundibular compartments. RESULTS: 16S rRNA sequencing yielded reproducible data of bacterial presence in infrainfundibular compartments of plucked scalp follicles; Lawsonella clevelandensis, Staphylococcaceae and Propionibacteriaceae were the most abundant bacteria. Also, FISH revealed biofilm structures formed by Cutibacterium acnes (formerly Propionibacterium acnes) and Staphylococcus sp. below the infundibulum. CONCLUSION: As the skin microbiome largely influences the local immune system, the presence of bacteria in proximity to follicular immune-privileged areas may be of relevance to hair cycling in health and disease.

Vernarbende Alopezien.

Primär vernarbende Alopezien (PVA) werden nach der Klassifikation der North American Hair Research Society nach ihrem prominenten entzündlichen Infiltrat in vier Gruppen eingeteilt: PVA mit lymphozytärem, neutrophilem, gemischtzelligem oder unspezifischem Entzündungsmuster. Der Haarausfall kann subklinisch beginnen und langsam fortschreiten, so dass der genaue Erkrankungsbeginn oft schwer nachzuvollziehen ist. Die Diagnose wird häufig verzögert gestellt. Während die meisten vernarbenden Alopezien bei vollständiger Ausprägung anhand des klinischen Bildes klar zugeordnet werden können, ist die Diagnosestellung in der Frühphase oder im Endstadium häufig schwierig. Bei Erstvorstellung sollte eine ausführliche Anamnese und dermatologische Ganzkörperuntersuchung, inklusive Trichoskopie durchgeführt werden. In klinisch unklaren Fällen sollte eine Biopsie erfolgen. Aufgrund der Seltenheit der PVA gibt es bisher nur eine niedrige Evidenz über die Wirksamkeiten der Vielzahl der verschiedenen angewandten Therapien. Ziele der Therapie einer PVA sind, den Haarausfall zu stoppen oder zumindest zu verzögern, die klinischen Entzündungszeichen zu reduzieren, weitere Vernarbung zu verhindern sowie die subjektiven Symptome zu lindern. Ein Nachwachsen in bereits vernarbten Arealen sollte nicht erwartet werden. Eine antientzündliche Therapie mit topischen Kortikosteroiden der Klasse III-IV und/oder mit intrakutanen intraläsionalen Triamcinolonacetonid-Injektionen kommt bei den meisten PVA in Betracht. Die Wahl der systemischen Therapie hängt von der Art des prädominierenden entzündlichen Infiltrates ab und umfasst antimikrobielle/antibiotische oder immunmodulatorische/immunsuppressive Ansätze. Psychologische Unterstützung und Camouflage-Techniken sollten den Patienten angeboten werden.

Cicatricial alopecia.

In the classification of the North American Hair Research Society, primary cicatricial alopecias (PCA) are divided into four groups according to their prominent inflammatory infiltrate: PCAs with lymphocytic, neutrophilic, mixed or nonspecific cell inflammation pattern. The hair loss can begin subclinically and progress slowly so that the exact onset of the disease is often difficult to determine. The diagnosis is often delayed. While most forms of cicatricial alopecia can be clearly diagnosed based on clinical presentation in the acute disease stage, diagnosis can be challenging in the subacute, early or late disease stages. At first presentation, a detailed patient history and dermatological examination of the body, including trichoscopy, should be performed. In clinically unclear cases, a biopsy should be performed. Due to the scarcity of primary cicatricial alopecia, there is little evidence on the efficacy of the various therapies. The aims of treatment are to stop or at least delay hair loss and progression of the scarring process, reduce clinical inflammation signs as well as to alleviate subjective symptoms. Hair re-growth in already scarred areas should not be expected. Anti-inflammatory treatment with topical corticosteroids class III to IV and / or with intracutaneous intralesional triamcinolone acetonide injections can be considered in most of the primary cicatricial alopecias. The choice of systemic therapy depends on the type of predominant inflammatory infiltrate and includes antimicrobial, antibiotic or immunomodulating/immunosuppressive agents. Psychological support and camouflage techniques should be offered to the patients.

Prevention and treatment of diaper dermatitis.

Diaper dermatitis (DD) is one of the most common skin conditions that infants suffer from and their caregivers manage in the first months post-birth. As such, questions of effective prevention and treatment of the condition often arise. Nonmedical skincare practices that support healthy skin barrier function can prevent DD manifestation or alleviate the condition in many cases. The usage of barrier emollients and improved diaper technology contributes to keeping moisture and irritants away from an infant's delicate skin. This paper addresses facts behind commonly asked questions from caregivers regarding DD and discusses effective measures to prevent and treat the condition.

Influence of sunflower seed oil or baby lotion on the skin barrier function of newborns: A pilot study.

BACKGROUND: Skin care influences skin barrier function during the first postnatal weeks. Although the use of natural oils in preterms has been investigated, there are currently no data comparing the effect of sunflower oil to an emollient on barrier development in healthy term newborns. METHODS: In a prospective, randomized clinical study, 50 healthy full-term newborns aged ≤72 h were randomly assigned to two groups: group baby lotion (L, n=22) and sunflower seed oil (SSO, n=24). The skin barrier function was evaluated in three anatomical areas (front, abdomen, and thigh) by noninvasive assessment of transepidermal water loss (TEWL), stratum corneum hydration (SCH), sebum, and skin pH at inclusion and after five weeks. RESULTS: In both groups, skin pH decreased and SCH increased statistically significantly in all measured areas at W5 compared to baseline. TEWL decreased statistically significantly on the forearm in both groups, on the upper leg in group L, and on the abdomen in group SSO. CONCLUSIONS: Both skin care regimes did not harm skin barrier function adaptation in healthy term neonates during the first five weeks of life.

The effectiveness of using a bath oil to reduce signs of dry skin: A randomized controlled pragmatic study.

BACKGROUND: Dry skin (xerosis cutis) is increasingly recognized as a relevant health problem in daily life and in health and nursing care. The use of bath additives such as oils is common to reduce dry skin, but empirical evidence supporting this practice is limited. OBJECTIVES: The aim of this study was to investigate the effectiveness of using a bath oil additive in improving skin barrier function and ameliorating dry skin in comparison to non-oil containing skin cleansers for bathing or showering. DESIGN: Single centre randomized observer blind pragmatic parallel group trial. SETTINGS: Outpatient/community care. PARTICIPANTS: Volunteers showing clinically mild to moderate dry skin recruited from the city of Berlin. METHODS: Healthy children and adults were randomly assigned to use either a commercially available bath oil or to continue using their regular non-oil containing skin cleansers every other day over a study period of 28days. Skin barrier parameters and the severity of dry skin were assessed at baseline and at two follow-up visits at the study centre. Transepidermal water loss was the primary outcome. RESULTS: All sixty participants randomized completed the trial. Median age was 32.5 (IQR 8.3 to 69) years. At the end of study the mean transepidermal water loss in the intervention group was statistically significant lower compared to the control group (mean difference -1.9 (95% CI -3.1 to -0.8) g/m2/h). Stratum corneum hydration was statistically significantly higher in the intervention group at the end of the study. Skin surface pH and roughness were comparable in both groups and remained unchanged, while both groups showed a trend to improvement in dry skin symptoms CONCLUSIONS: This pragmatic trial provides empirical evidence that the regular use of the investigated bath oil is effective in improving the skin barrier function in children and adults with mild dry skin when used in routine skin care and supports its use as a basic element for the management of a broad spectrum of dry skin conditions. TRIAL REGISTRATION: ClinicalTrials.gov Identifier NCT02557698.

Influence of sunflower seed oil on the skin barrier function of preterm infants: a randomized controlled trial.

BACKGROUND: Inadequate skin care may increase morbidity in preterm infants. Skin care practices that support skin maturation have barely been investigated. OBJECTIVES: To investigate the effect of sunflower seed oil (SSO) on skin barrier development in low-birth-weight premature infants. METHODS: 22 preterm infants (<48 h after birth, 1,500-2,500 g) were randomized into group C (control) and group SSO, receiving daily SSO application during the first 10 postnatal days, followed by no intervention. Transepidermal water loss (TEWL), stratum corneum hydration (SCH), skin pH and sebum were measured <48 h after birth and on postnatal days 5, 11 and 21 on the forehead, abdomen, thigh and buttock. RESULTS: Skin pH decreased, while sebum remained stable in both groups. In group C, TEWL remained stable; in group SSO, TEWL increased significantly on the abdomen, leg and buttock until day 11, followed by a decrease after SSO application had been stopped. Abdomen SCH remained stable in group C, but continuously decreased in group SSO until day 21. CONCLUSION: SSO application may retard postnatal skin barrier maturation in preterm infants.

Skin barrier function in infancy: a systematic review.

The skin of neonates and infants exhibits distinct anatomical and functional properties that might be clinically reflected by its characteristic susceptibility to skin barrier disruption. In this systematic review, we aimed to characterize skin barrier maturation as reflected by transepidermal water loss (TEWL) and skin surface pH during the first 2 years of life. We systematically searched MEDLINE and EMBASE via OVID from 1975 to 2013 to identify primary studies reporting TEWL and/or skin surface pH values in healthy full-term infants aged 0-24 months without any cutaneous diseases. After full text assessment, 36 studies reporting n = 8,483 TEWL measurements for 26 anatomical areas and n = 6,437 skin surface pH measurements for 14 anatomical areas were included. The mean age of the subjects ranged from 1.4 h to 1.2 years. The lowest pH of 4.63 was identified on the forehead at the age of 25.6 weeks, whereas the highest of 7.31 was on the volar forearm at 0.0 weeks. The lowest TEWL value of 3.1 g/m(2)/h was reported for the back at 0.6 weeks and the highest of 43.1 g/m(2)/h for the upper leg at 58.7 weeks. The skin surface pH reveals a steep decline during the first postnatal week, succeeded by a further gradual site-specific acidification process during the first month. A competent permeability barrier in most anatomical areas is indicated by TEWL, which does not exhibit a time-dependent development during the first 2 years of life.