Epidermolysis bullosa simplex generalized severe induces a T helper 17 response and is improved by apremilast treatment

International audienceBACKGROUND: Epidermolysis bullosa simplex generalized severe is a genetic disorder caused by mutation in KRT5 or KRT14 genes. Usually considered as a mechanical disease, recent data argue for additional inflammatory mechanisms. OBJECTIVES: The aim of this study was to assess the inflammation in the skin of patients with EBS. METHODS: A first immunohistochemical retrospective study was performed on frozen skin samples from 17 EBS-gen sev patients. A second multicenter prospective study was conducted on 10 patients with severe EBS-gen sev. Blister fluid and epidermis were processed for immunochemistry analysis and quantitative real time PCR. Cytokine expression was analyzed in blister fluid and compared with controls. RESULTS: Histological analysis showed a constant dermal perivascular CD4+ lymphocytes infiltrate in skin biopsies of blister (n=17) as well as in rubbed skin (n=5), an epidermal infiltration of neutrophils and eosinophils in 70% of cases and an increased immunostaining for CXCL9 and CXCL10 in blistering skin. High levels of Th17 cytokines were detected in lesional skin. Three adult patients with EBS-gen sev were treated with apremilast with a dramatic improvement of skin blistering and good tolerance. CONCLUSION: Our study demonstrates the importance of inflammation in EBS-gen sev patients and underlines the key role for Th17 cells in its pathogenesis. In addition, this study provides promising new therapeutic approaches for this disabling disorder. This article is protected by copyright. All rights reserved

PoPe (Projection on Proper elements) for code control: verification, numerical convergence and reduced models. Application to plasma turbulence simulations

The Projection on Proper elements (PoPe) is a novel method of code control dedicated to 1) checking the correct implementation of models, 2) determining the convergence of numerical methods and 3) characterizing the residual errors of any given solution at very low cost. The basic idea is to establish a bijection between a simulation and a set of equations that generate it. Recovering equations is direct and relies on a statistical measure of the weight of the various operators. This method can be used in any dimensions and any regime, including chaotic ones. This method also provides a procedure to design reduced models and quantify the ratio costs to benefits. PoPe is applied to a kinetic and a fluid code of plasma turbulence

Reliability and validity of the vitiligo signs of activity score (VSAS)

Background The associations between disease activity and several clinical signs in vitiligo have been described, but a widely accepted and validated scoring system is lacking. Objectives To validate the Vitiligo Signs of Activity Score (VSAS) for physicians. Methods Three visible clinical signs were scored on 15 body locations: confetti-like depigmentation (c), Koebner phenomenon (k) and hypochromic areas/borders (h). The inter- and intrarater reliability of the global VSAS and VSAS subscores (c-VSAS, k-VSAS and h-VSAS) were tested by four and three raters (physicians), respectively. Construct validity and feasibility were evaluated. Results The VSAS demonstrated good inter-rater reliability, with an intraclass correlation coefficient (ICC) of 0 center dot 87 in the first round and 0 center dot 90 in the second round. The intrarater reliability ICCs were all >= 0 center dot 86. The inter-rater reliabilities of the subscores were excellent for c-VSAS and fair for k-VSAS and h-VSAS (ICC 0 center dot 83, 0 center dot 51 and 0 center dot 53, respectively, in the first round). Evidence for construct validity was provided. The completion time by the raters (median 2 center dot 18 min per patient) improved during the second round (median 1 center dot 33 min per patient). A limitation of the study is the low number of patients, mainly of skin phototypes II-III, from a single tertiary centre. Conclusions The VSAS appears to be a valid and reliable instrument to score visible clinical signs linked to disease activity in a standardized way. What is already known about this topic? Evidence exists for a possible link between several visible clinical signs in vitiligo and disease activity. A widely accepted and validated scoring system to quantify these clinical signs is lacking. What does this study add? The Vitiligo Signs of Activity Score (VSAS) underwent preliminary validation and may assist quantification of visible clinical signs linked to disease activity in a standardized way in clinical practice and trials

Biology of human hair: Know your hair to control it

Hair can be engineered at different levels—its structure and surface—through modification of its constituent molecules, in particular proteins, but also the hair follicle (HF) can be genetically altered, in particular with the advent of siRNA-based applications. General aspects of hair biology are reviewed, as well as the most recent contributions to understanding hair pigmentation and the regulation of hair development. Focus will also be placed on the techniques developed specifically for delivering compounds of varying chemical nature to the HF, indicating methods for genetic/biochemical modulation of HF components for the treatment of hair diseases. Finally, hair fiber structure and chemical characteristics will be discussed as targets for keratin surface functionalization

624 - Vitiligo biomarker CXCL10 correlates with clinical response in the phase 2 randomized, double-blind, vehicle-controlled TRuE-V mechanism of action study

Abstract: Introduction/Background: Ruxolitinib cream is a topical formulation of the selective Janus kinase (JAK) 1/JAK2 inhibitor ruxolitinib and is the first and only repigmentation treatment approved by the US Food and Drug Administration and European Commission for nonsegmental vitiligo in patients ≥12 years old. Objectives: To evaluate treatment-associated changes in biomarkers among patients with vitiligo, correlate changes in key biomarkers with efficacy, and assess the safety and tolerability of ruxolitinib cream. Methods: The phase 2, randomized, double-blind, vehicle-controlled TRuE-V mechanism of action study (NCT04896385) was conducted in adult patients (≥18 years) with vitiligo ≤50% of total body surface area. Patients were randomized 2:1 to twice-daily 1.5% ruxolitinib cream or vehicle cream for 24 weeks, after which all patients could apply 1.5% ruxolitinib cream through Week 52. Changes from baseline in local and systemic immune biomarkers, including C-X-C motif chemokine ligand 10 (CXCL10), were evaluated at Weeks 4, 12, and 24. The relative expression of >3000 serum protein analytes was assessed using the Olink Explore platform, and a validated Meso Scale Discovery (MSD) assay was used to confirm absolute levels of serum CXCL10. Relative CXCL10 expression was determined by quantitative polymerase chain reaction (qPCR) from isolated biopsy samples. Punch biopsies (2.5 mm) were taken from lesional and nonlesional skin at baseline and lesional skin (even if the lesion had cleared) at Weeks 12, 24, and 40. Treatment efficacy was determined by the percentage change from baseline in facial and total Vitiligo Area Scoring Index (F-VASI and T-VASI, respectively). Safety was evaluated by the frequency and severity of adverse events. Results: The study enrolled 60 patients (ruxolitinib cream, n=41; vehicle, n=19). Patients’ mean (SD) age was 44.7 (12.8) years, 56.7% were male, and 53.3% had lighter skin (Fitzpatrick skin types I–III). At baseline, patients had a median (range) disease duration of 12.0 (0.1–52.9) years and mean (SD) F-VASI and T-VASI scores of 1.1 (0.6) and 12.1 (9.4), respectively. Olink Explore identified few differentially expressed proteins in patient sera (adjusted P<0.05 and log2 fold change >1.25), including CXCL10, SH2D1A, and granzyme B. As early as Week 12, serum CXCL10 levels (in MSD assay) were significantly reduced in ruxolitinib cream–treated patients compared with baseline. Skin CXCL10 levels were similar in lesional and nonlesional skin at baseline but were significantly lowered in lesional skin at Week 12 with ruxolitinib cream. In ruxolitinib cream–treated patients, significant mean [SD] percentage reductions from baseline were seen in F-VASI scores at Week 12 (–32.9 [33.6]) and in T-VASI scores at Week 24 (–21.2 [18.5]). Further, T-VASI scores significantly correlated with a change in serum CXCL10 levels between baseline and Week 24. Most systemic proteins did not correlate or only weakly correlated with F-VASI and T-VASI scores. Through Week 24, 46.3% of 41 patients who applied ruxolitinib cream reported treatment-emergent adverse events (none serious), the most common being COVID-19 (9.8%), application site acne (4.9%), and application site rash (4.9%). Conclusions: Taken together, these data are consistent with the role of the interferon-gamma:CXCL10 axis as a central mediator of vitiligo pathogenesis. Serum CXCL10 levels decreased significantly in patients who applied ruxolitinib cream, which correlated with improvement in T-VASI scores. Additionally, skin CXCL10 levels were significantly reduced after 12 weeks of ruxolitinib cream treatment

Association of combined PD- L1 expression and tumour- infiltrating lymphocyte features with survival and treatment outcomes in patients with metastatic melanoma

BackgroundRecent advances obtained with immune checkpoint inhibitors (ICIs) targeting the programmed cell death- 1 (PD- 1) protein have significantly improved the outcome of patients with metastatic melanoma. The PD- L1 expression in tumour cells as detected by immunohistochemistry is a predictive biomarker in some solid tumours, but appears insufficient as prognostic or predictive factor of response to ICIs in metastatic melanomas.ObjectivesWe investigated whether the presence and the features of pretreatment CD8+tumour- infiltrating T lymphocytes (TILs) could be a complementary prognostic or predictive biomarker in patients with metastatic melanoma.MethodsIn this retrospective study, we evaluated the association of PD- L1 expression - ¥5% of tumour cells combined with TIL features (CD8, CD28, Ki67) with the overall survival (OS) among 51 patients treated with ICIs and 54 patients treated with other treatment options (non- ICIs).ResultsPD- L1 positivity was observed in 33% and 39% of primary melanomas and matched metastases, respectively, with, however, poor concordance between the primary and the matched metastatic site (κ = 0.283). No significant association was noted between PD- L1 expression and CD8+TIL profile analysed as single markers and OS or response to immunotherapy. Instead, their combined analysis in primary melanoma samples showed that the PD- L1- /CD8+status was significantly associated with prolonged OS in the whole population (P = 0.04) and in the subgroup treated with non- ICIs (P = 0.009). Conversely, the PD- L1+/CD8+ status was a good prognostic factor in patients treated with ICIs (P = 0.022), whereas was significantly associated with poor prognosis in patients treated with non- ICIs (P = 0.014). While the expression of CD28 was not related to outcome, the Ki67 expression was significantly associated with poor OS in the subgroup CD8+TIL+/PD- L1- (P = 0.02).ConclusionsThe pretreatment combination of PD- L1 expression with the level of CD8+TILs could better assess OS and predict therapeutic response of patients with metastatic melanoma treated by either immunotherapy or other treatment regimens.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/155478/1/jdv16016_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/155478/2/jdv16016.pd

Daily photoprotection to prevent photoaging

Background: Extrinsic skin aging or photoaging was previously thought to be almost exclusively due to solar ultraviolet (UV) radiation. However, recent literature has described other contributing factors and clarification is thus required as to what extent and what type of daily photoprotection is needed to mitigate extrinsic skin aging. Methods: We reviewed the existing scientific evidence on daily photoprotection, and specific requirements at the product level, to prevent extrinsic skin aging. We critically reviewed the existing evidence on potential ecological and toxicological risks which might be associated with daily photoprotection. Results: Evidence shows that broad protection against the entire solar range of UVB, UVA, UVA1, visible light, and short infrared (IRA) is required to prevent extrinsic aging. Other exposome factors, such as air pollution and smoking, also contribute to skin aging. Daily broad-spectrum sunscreen photoprotection should thus contain antioxidant ingredients for additional benefits against UV, IRA, and pollution-induced oxidative stress as well as anti-aging active ingredients to provide clinical benefits against skin aging signs, such as wrinkles and dark spots. Broad-spectrum sunscreen containing pigments, such as iron oxide, may be required for melasma prevention. There is no conclusive clinical evidence that daily sunscreen use is unsafe or that it compromises vitamin D synthesis. Conclusion: Daily use of broad-spectrum sunscreen containing antioxidant and anti-aging active ingredients can effectively reduce extrinsic aging.</p

RNA-seq analysis of ageing human retinal pigment epithelium: Unexpected up-regulation of visual cycle gene transcription

Ageing presents adverse effects on the retina and is the primary risk factor for age‐related macular degeneration (AMD). We report the first RNA‐seq analysis of age‐related transcriptional changes in the human retinal pigment epithelium (RPE), the primary site of AMD pathogenesis. Whole transcriptome sequencing of RPE from human donors ranging in age from 31 to 93 reveals that ageing is associated with increasing transcription of main RPE‐associated visual cycle genes (including LRAT, RPE65, RDH5, RDH10, RDH11; pathway enrichment BH‐adjusted P = 4.6 × 10(−6)). This positive correlation is replicated in an independent set of 28 donors and a microarray dataset of 50 donors previously published. LRAT expression is positively regulated by retinoid by‐products of the visual cycle (A2E and all‐trans‐retinal) involving modulation by retinoic acid receptor alpha transcription factor. The results substantiate a novel age‐related positive feedback mechanism between accumulation of retinoid by‐products in the RPE and the up‐regulation of visual cycle genes

The role of Probiotics in allergic diseases

Allergic disorders are very common in the pediatric age group. While the exact etiology is unclear, evidence is mounting to incriminate environmental factors and an aberrant gut microbiota with a shift of the Th1/Th2 balance towards a Th2 response. Probiotics have been shown to modulate the immune system back to a Th1 response. Several in vitro studies suggest a role for probiotics in treating allergic disorders. Human trials demonstrate a limited benefit for the use of probiotics in atopic dermatitis in a preventive as well as a therapeutic capacity. Data supporting their use in allergic rhinitis are less robust. Currently, there is no role for probiotic therapy in the treatment of bronchial asthma. Future studies will be critical in determining the exact role of probiotics in allergic disorders

Inhibition of T-cell activity in alopecia areata: recent developments and new directions

Alopecia areata (AA) is an autoimmune disease that has a complex underlying immunopathogenesis characterized by nonscarring hair loss ranging from small bald patches to complete loss of scalp, face, and/or body hair. Although the etiopathogenesis of AA has not yet been fully characterized, immune privilege collapse at the hair follicle (HF) followed by T-cell receptor recognition of exposed HF autoantigens by autoreactive cytotoxic CD8+ T cells is now understood to play a central role. Few treatment options are available, with the Janus kinase (JAK) 1/2 inhibitor baricitinib (2022) and the selective JAK3/tyrosine kinase expressed in hepatocellular carcinoma (TEC) inhibitor ritlecitinib (2023) being the only US Food and Drug Administration–approved systemic medications thus far for severe AA. Several other treatments are used off-label with limited efficacy and/or suboptimal safety and tolerability. With an increased understanding of the T-cell–mediated autoimmune and inflammatory pathogenesis of AA, additional therapeutic pathways beyond JAK inhibition are currently under investigation for the development of AA therapies. This narrative review presents a detailed overview about the role of T cells and T-cell–signaling pathways in the pathogenesis of AA, with a focus on those pathways targeted by drugs in clinical development for the treatment of AA. A detailed summary of new drugs targeting these pathways with expert commentary on future directions for AA drug development and the importance of targeting multiple T-cell–signaling pathways is also provided in this review