Reflectance confocal microscopy as a non-invasive imaging tool in vulvar high-grade squamous intraepithelial lesions and lichen sclerosus:A descriptive morphological study in patients and healthy volunteers

Incorrect and delayed diagnosis of vulvar high-grade squamous intraepithelial neoplasia (vHSIL) and lichen sclerosus (LS) increases malignant progression risks and negatively impacts prognosis and quality of life. There is a need to improve diagnosis and monitoring. Reflectance confocal microscopy is a non-invasive imaging tool that visualizes skin structures at cellular resolution. The objectives were to explore feasibility and patient acceptability of vulvar RCM imaging and to identify RCM characteristics that are discriminative for vulvar HSIL and LS. This was a prospective, cross-sectional, observational clinical trial in patients with vHSIL and LS compared to healthy volunteers. RCM images and vulvar tissue samples were obtained. Five (5) patients with vHSIL, 10 patients with LS and 10 healthy volunteers were enrolled. In total, 100 image series of vulvar skin were obtained, including lesional and nonlesional sites. The RCM technique was considered acceptable for application by patients and healthy controls. Healthy vulvar skin was characterized by a homogenous, normal honeycomb patterned epidermis and a clear epidermal-dermal junctions. Vulvar HSIL and LS displayed an atypical honeycomb pattern of the epidermis and lymphocytic influx with presence of melanophages. Distinct features specifically observed in LS included the presence of hyalinised vessels and sclerotic areas in the dermis. RCM is a non-invasive imaging technique that is feasible and clinically acceptable to apply on vulvar skin, both in patients with premalignant lesions and healthy controls. Recognition and validation of disease-specific characteristics could make reflectance confocal microscopy a clinical tool to non-invasively aid identification of vulvar premalignancies.</p

Dermatoscopy and Optical Coherence Tomography in Vulvar High-Grade Squamous Intraepithelial Lesions and Lichen Sclerosus:A Prospective Observational Trial

Objective This study aimed to examine potential discriminatory characteristics of dermatoscopy and dynamic optical coherence tomography (D-OCT) on vulvar high-grade squamous intraepithelial lesions (vHSIL) and lichen sclerosus (LS) compared with healthy vulvar skin. Methods A prospective observational clinical trial was performed in 10 healthy volunteers, 5 vHSIL and 10 LS patients. Noninvasive imaging measurements using dermatoscopy and D-OCT were obtained at several time points, including lesional and nonlesional vulvar skin. Morphologic features of vHSIL and LS were compared with healthy controls. Epidermal thickness and blood flow were determined using D-OCT. Patients reported tolerability of each study procedure, including reference vulvar biopsies. The main outcome measures were feasibility and tolerability of imaging modalities, dermatoscopy and OCT characteristics, OCT epidermal thickness and D-OCT dermal blood flow. Results The application of dermatoscopy and D-OCT is feasible and tolerable. In vHSIL, dermatoscopic warty structures were present. In LS, sclerotic areas and arborizing vessels were observed. Structural OCT in the vulvar area aligned with histology for hyperkeratosis and dermal-epidermal junction visualization. Currently, the OCT algorithm is unable to calculate the epidermal thickness of the uneven vulvar area. Dynamic optical coherence tomography showed statistically significant increased blood flow in LS patients (mean ± SD, 0.053 ± 0.029) to healthy controls (0.040 ± 0.012; p =.0024). Conclusions The application of dermatoscopy and D-OCT is feasible and tolerable in vHSIL and LS patients. Using dermatoscopy and D-OCT, the authors describe potential characteristics to aid differentiation of diseased from healthy vulvar skin, which could complement clinical assessments.</p

Oral prednisolone suppresses skin inflammation in a healthy volunteer imiquimod challenge model

Imiquimod (IMQ) is a topical agent that induces local inflammation via the Toll-like receptor 7 pathway. Recently, an IMQ-driven skin inflammation model was developed in healthy volunteers for proof-of-pharmacology trials. The aim of this study was to profile the cellular, biochemical, and clinical effects of the marketed anti-inflammatory compound prednisolone in an IMQ model. This randomized, double-blind, placebo-controlled study was conducted in 24 healthy volunteers. Oral prednisolone (0.25 mg/kg/dose) or placebo (1:1) was administered twice daily for 6 consecutive days. Two days after treatment initiation with prednisolone or placebo, 5 mg imiquimod (IMQ) once daily for two following days was applied under occlusion on the tape-stripped skin of the back for 48 h in healthy volunteers. Non-invasive (imaging and biophysical) and invasive (skin punch biopsies and blister induction) assessments were performed, as well as IMQ ex vivo stimulation of whole blood. Prednisolone reduced blood perfusion and skin erythema following 48 h of IMQ application (95% CI [−26.4%, −4.3%], p = 0.0111 and 95% CI [−7.96, −2.13], p = 0.0016). Oral prednisolone suppressed the IMQ-elevated total cell count (95% CI [−79.7%, −16.3%], p = 0.0165), NK and dendritic cells (95% CI [−68.7%, −5.2%], p = 0.0333, 95% CI [−76.9%, −13.9%], p = 0.0184), and classical monocytes (95% CI [−76.7%, −26.6%], p = 0.0043) in blister fluid. Notably, TNF, IL-6, IL-8, and Mx-A responses in blister exudate were also reduced by prednisolone compared to placebo. Oral prednisolone suppresses IMQ-induced skin inflammation, which underlines the value of this cutaneous challenge model in clinical pharmacology studies of novel anti-inflammatory compounds. In these studies, prednisolone can be used as a benchmark.</p

Pharmacodynamic Effects of Topical Omiganan in Patients With Mild to Moderate Atopic Dermatitis in a Randomized, Placebo-Controlled, Ph

Omiganan is an indolicidin analog with antimicrobial properties that could be beneficial for patients with atopic dermatitis. In this randomized, double-blind, placebo-controlled, phase II trial we explored the efficacy, pharmacodynamics, and safety of topical omiganan once daily in 36 patients with mild to moderate atomic dermatitis. Patients were randomized to apply topical omiganan 1%, omiganan 2.5%, or vehicle gel to one target lesion once daily for 28 consecutive days. Small but significant improvements in local objective SCORing Atopic Dematitis index and morning itch were observed in the omiganan 2.5% group compared with the vehicle gel group (−18.5%; 95% confidence interval, −32.9 to −1.0; P = 0.04; and −8.2; 95% confidence interval, −16.3 to −0.2; P = 0.05, respectively). A shift from lesional to nonlesional skin microbiota was observed in both omiganan treatment groups, in contrast to the vehicle group. Thus, treatment with topical omiganan improved dysbiosis in patients with mild to moderate atopic dermatitis, and small but statistically significant improvements in clinical scores were detected. Our findings warrant further exploration in future clinical trials

Omiganan Enhances Imiquimod-Induced Inflammatory Responses in Skin of Healthy Volunteers

Omiganan (OMN; a synthetic cationic peptide) and imiquimod (IMQ; a TLR7 agonist) have synergistic effects on interferon responses in vitro. The objective of this study was to translate this to a human model for proof-of-concept, and to explore the potential of OMN add-on treatment for viral skin diseases. Sixteen healthy volunteers received topical IMQ, OMN, or a combination of both for up to 4 days on tape-stripped skin. Skin inflammation was quantified by laser speckle contrast imaging and 2D photography, and molecular and cellular responses were analyzed in biopsies. IMQ treatment induced an inflammatory response of the skin. Co-treatment with OMN enhanced this inflammatory response to IMQ, with increases in perfusion (+17.1%; 95% confidence interval (CI) 5.6%–30%; P < 0.01) and erythema (+1.5; 95% CI 0.25%–2.83; P = 0.02). Interferon regulatory factor-driven and NFκB-driven responses following TLR7 stimulation were enhanced by OMN (increases in IL-6, IL-10, MXA, and IFNɣ), and more immune cell infiltration was observed (in particular CD4+, CD8+, and CD14+ cells). These findings are in line with the earlier mechanistic in vitro data, and support evaluation of imiquimod/OMN combination therapy in human papillomavirus-induced skin diseases

Oral prednisolone suppresses skin inflammation in a healthy volunteer imiquimod challenge model

Imiquimod (IMQ) is a topical agent that induces local inflammation via the Toll-like receptor 7 pathway. Recently, an IMQ-driven skin inflammation model was developed in healthy volunteers for proof-of-pharmacology trials. The aim of this study was to profile the cellular, biochemical, and clinical effects of the marketed anti-inflammatory compound prednisolone in an IMQ model. This randomized, double-blind, placebo-controlled study was conducted in 24 healthy volunteers. Oral prednisolone (0.25 mg/kg/dose) or placebo (1:1) was administered twice daily for 6 consecutive days. Two days after treatment initiation with prednisolone or placebo, 5 mg imiquimod (IMQ) once daily for two following days was applied under occlusion on the tape-stripped skin of the back for 48 h in healthy volunteers. Non-invasive (imaging and biophysical) and invasive (skin punch biopsies and blister induction) assessments were performed, as well as IMQ ex vivo stimulation of whole blood. Prednisolone reduced blood perfusion and skin erythema following 48 h of IMQ application (95% CI [−26.4%, −4.3%], p = 0.0111 and 95% CI [−7.96, −2.13], p = 0.0016). Oral prednisolone suppressed the IMQ-elevated total cell count (95% CI [−79.7%, −16.3%], p = 0.0165), NK and dendritic cells (95% CI [−68.7%, −5.2%], p = 0.0333, 95% CI [−76.9%, −13.9%], p = 0.0184), and classical monocytes (95% CI [−76.7%, −26.6%], p = 0.0043) in blister fluid. Notably, TNF, IL-6, IL-8, and Mx-A responses in blister exudate were also reduced by prednisolone compared to placebo. Oral prednisolone suppresses IMQ-induced skin inflammation, which underlines the value of this cutaneous challenge model in clinical pharmacology studies of novel anti-inflammatory compounds. In these studies, prednisolone can be used as a benchmark

Lesional skin of seborrheic dermatitis patients is characterized by skin barrier dysfunction and correlating alterations in the stratum corneum ceramide composition

Seborrheic dermatitis (SD) is a chronic inflammatory skin disease characterized by erythematous papulosquamous lesions in sebum rich areas such as the face and scalp. Its pathogenesis appears multifactorial with a disbalanced immune system, Malassezia driven microbial involvement and skin barrier perturbations. Microbial involvement has been well described in SD, but skin barrier involvement remains to be properly elucidated. To determine whether barrier impairment is a critical factor of inflammation in SD alongside microbial dysbiosis, a cross-sectional study was performed in 37 patients with mild-to-moderate facial SD. Their lesional and non-lesional skin was comprehensively and non-invasively assessed with standardized 2D-photography, optical coherence tomography (OCT), microbial profiling including Malassezia species identification, functional skin barrier assessments and ceramide profiling. The presence of inflammation was established through significant increases in erythema, epidermal thickness, vascularization and superficial roughness in lesional skin compared to non-lesional skin. Lesional skin showed a perturbed skin barrier with an underlying skewed ceramide subclass composition, impaired chain elongation and increased chain unsaturation. Changes in ceramide composition correlated with barrier impairment indicating interdependency of the functional barrier and ceramide composition. Lesional skin showed significantly increased Staphylococcus and decreased Cutibacterium abundances but similar Malassezia abundances and mycobial composition compared to non-lesional skin. Principal component analysis highlighted barrier properties as main discriminating features. To conclude, SD is associated with skin barrier dysfunction and changes in the ceramide composition. No significant differences in the abundance of Malassezia were observed. Restoring the cutaneous barrier might be a valid therapeutic approach in the treatment of facial SD