Jonathan Bar

Introduction: Keloids are pathologic scars that result from abnormal wound healing processes following skin trauma, with a higher prevalence in the Black population. The pathogenesis of keloids is not fully understood, hindering effective treatment options for this highly disfiguring and distressing condition. Methods: Biopsies from lesional and non‐lesional skin from keloid patients and healthy skin from age/gender/race‐matched controls were collected and analyzed using RNA‐sequencing, RT‐qPCR, and immunohistochemistry. Spearman analysis was used to evaluate the correlations between biomarker expressions and clinical severity measurements. Results: Both keloidal lesions and non‐lesional skin showed a distinct transcriptomic profile compared to healthy skin. Keloids demonstrated significant upregulation of fibrosis‐related markers (e.g., COL10A1, COL11A1, and BMP1). Lesional and/or non‐lesional samples showed significant upregulation of key immune biomarkers belonging to T‐cells (e.g., CD2, CD3D, and CD3E), T‐cell/NK‐cell activation/migration (e.g., CCL19, CCR7, GZMA, GZMB, and GZMK), Th1 (e.g., OASL, MX1, CCL4), Th2 (e.g., IL4R, OX40/TNFRSF4, and OX40L/TNFSF4), and Th17/22 (e.g., S100A7, S100A8, S100A9, and CCL20). Multiple immune biomarkers expression (e.g., CCL2, CXCL1, and S100A7) in lesional and/or non‐lesional skin significantly and positively correlated with keloid severity parameters (e.g., keloid size, distensibility, and number). Conclusion: Both lesional and non‐lesional keloid skin show distinct upregulation of immune axes, underscoring the role of inflammation in keloid pathogenesis and pointing to potential novel therapeutic targets.

Introduction: Chronic hand eczema (CHE) is a highly prevalent inflammatory skin condition which is often resistant to conventional treatments. Molecular insights of CHE remain limited. Tape stripping combined with high‐throughput RNA sequencing can now provide a better insight into CHE pathogenesis in a minimally invasive fashion. Methods: We collected tape strip samples from lesional and non‐lesional skin of 66 patients with moderate‐to‐severe CHE, comprising 33 with and 33 without comorbid atopic dermatitis (AD), and performed bulk RNA sequencing. Results were compared to tape strips from palmar skin of age/race/sex‐matched healthy controls (HC). Differentially expressed genes (DEGs) (fold change/FCH > 1.5 and false discovery rate/FDR < 0.05) were calculated and correlated with clinical severity scores including hand eczema severity index (HECSI) and modified total lesion symptoms score (mTLSS). Results: Tape strip isolates detected a common phenotype in CHE lesions regardless of AD status, including upregulated type‐1 ( IL12RB2 , IFNGR1 , IFNGR2 , MX1 ) and type‐2‐associated inflammatory mediators ( CCL22 , CCL24 , OX40/ TNFRSF4 , TSLPR/ CRLF2 , GATA3 ), paralleled by downregulated epidermal barrier markers (i.e., FLG or LORICRIN ). Non‐lesional skin demonstrated a similar, albeit milder, dysregulation pattern, with additional reduction in type‐17 pathways. Lesional skin of CHE patients without AD showed greater skewing towards type‐1 immunity ( IL15RA , CXCL9 ), while CHE from AD patients showed a more pronounced type‐2 inflammatory pattern ( IL13 , CCL17 ) and their gene expression biomarkers had greater and more significant correlations with clinical severity markers. Conclusion: Tape stripping can capture detailed immune and skin barrier abnormalities in CHE and identify potential novel subtype‐specific treatment targets. Stronger correlations in patients with AD suggest a more homogenous disease phenotype than in CHE non‐AD patients. Trial Registration: NCT03728504

The efficacy of ritlecitinib, an oral JAK3/TEC family kinase inhibitor, on active and stable lesions was evaluated in patients with active non-segmental vitiligo in a phase 2b trial (NCT03715829). Patients were randomized to placebo or daily ritlecitinib 50 mg (with or without 4-week 100-mg or 200-mg loading dose), 30 mg, or 10 mg for 24 weeks. Active lesions showed greater baseline expression of inflammatory/immune markers IFNG and CCL5, levels of CD103, and T-cell infiltrates than stable lesions. Patients with more active than stable vitiligo lesions showed higher baseline serum levels of CXCL9 and PD-L1, while patients with more stable than active lesions showed higher baseline serum levels of HO-1. At Week 24, ritlecitinib 50 mg significantly stabilized mean percent change from baseline in depigmentation extent in both active lesions and stable lesions vs. placebo-response, with stable lesions showing greater repigmentation. After 24 weeks of treatment, ritlecitinib 50 mg increased expression of melanocyte markers in stable lesions, while Th1/Th2-related and co-stimulatory molecules decreased significantly in both stable and active lesions. Serum from patients with more active than stable lesions showed decreased levels of ICOS and NK cell activation markers. These data, confirmed at transcription/protein levels, indicate that stable lesion repigmentation occurs early with ritlecitinib, while active lesions require stabilization of inflammation first. ClinicalTrials.gov: NCT03715829.

Introduction: Tape‐strips, a minimally invasive method validated for the evaluation of several skin diseases, may help identify asthma‐specific biomarkers in the skin of children with allergic asthma.Methods: Skin tape‐strips were obtained and analyzed with RNA‐Seq from children with moderate allergic asthma (MAA) (n = 11, mean age 7.00; SD = 1.67), severe allergic asthma (SAA) (n = 9, mean age 9.11; SD = 2.37), and healthy controls (HCs) (n = 12, mean age 7.36; SD = 2.03). Differentially expressed genes (DEGs) were identified by fold change ≥2 with a false discovery rate p < .01). MAA and SAA shared downregulation of G‐protein‐coupled receptor (OR4A16, TAS1R3), upregulation of TGF‐β/ErbB signaling‐related (ACVR1B, EGFR, ID1/2), and upregulation of mitochondrial‐related (HIGD2A, VDAC3, NDUFB9) genes. Skin transcriptomic biomarkers correlated with the annualized exacerbation rate and with lung function parameters. A two‐gene classifier (TSSC4‐FAM212B) was able to differentiate asthma from HCs with 100% accuracy.Conclusion: Tape‐strips detected epithelial barrier and asthma‐associated signatures in normal‐appearing skin from children with allergic asthma and may serve as an alternative to invasive approaches for evaluating asthma endotypes.

Alopecia areata is an autoimmune hair loss disease that is non-scarring and is characterized by chronic inflammation at the hair follicle level. Clinically, patients’ presentation varies from patchy, circumscribed scalp involvement to total body and scalp hair loss. Current management is guided by the degree of scalp and body involvement, with topical and intralesional steroid injections as primarily first-line for mild cases and broad immunosuppressants as the mainstay for more severe cases. Until recently, the limited number of blinded, randomized, placebo-controlled clinical trials for this disease had made establishing an evidence-based treatment paradigm challenging. However, growing insights into the pathogenesis of alopecia areata through blood and tissue analysis of human lesions have identified several promising targets for therapy. T-helper (Th) 1/interferon skewing has traditionally been described as the driver of disease; however, recent investigations suggest activation of additional immune mediators, including the Th2 pathway, interleukin (IL)-9, IL-23, and IL-32, as contributors to alopecia areata pathogenesis. The landscape of alopecia areata treatment has the potential to be transformed, as several novel targeted drugs are currently undergoing clinical trials. Given the recent US FDA approval of baricitinib and ritlecitinib, Janus kinase (JAK) inhibitors are a promising drug class for treating severe alopecia areata cases. This article will review the efficacy, safety, and tolerability of current treatments for alopecia areata, and will provide an overview of the emerging therapies that are leading the revolution in the management of this challenging disease.

Background: Our knowledge of etiopathogenesis of atopic dermatitis (AD) is largely derived from skin biopsies, which are associated with pain, scarring and infection. In contrast, tape‐stripping is a minimally invasive, nonscarring technique to collect skin samples.Methods: To construct a global AD skin transcriptomic profile comparing tape‐strips to whole‐skin biopsies, we performed RNA‐seq on tape‐strips and biopsies taken from the lesional skin of 20 moderate‐to‐severe AD patients and the skin of 20 controls. Differentially expressed genes (DEGs) were defined by fold‐change (FCH) ≥2.0 and false discovery rate <0.05.Results: We detected 4104 (2513 Up; 1591 Down) and 1273 (546 Up; 727 Down) DEGs in AD versus controls, in tape‐strips and biopsies, respectively. Although both techniques captured dysregulation of key immune genes, tape‐strips showed higher FCHs for innate immunity (IL‐1B, IL‐8), dendritic cell (ITGAX/CD11C, FCER1A), Th2 (IL‐13, CCL17, TNFRSF4/OX40), and Th17 (CCL20, CXCL1) products, while biopsies showed higher upregulation of Th22 associated genes (IL‐22, S100As) and dermal cytokines (IFN‐γ, CCL26). Itch‐related genes (IL‐31, TRPV3) were preferentially captured by tape‐strips. Epidermal barrier abnormalities were detected in both techniques, with terminal differentiation defects (FLG2, PSORS1C2) better represented by tape‐strips and epidermal hyperplasia changes (KRT16, MKI67) better detected by biopsies.Conclusions: Tape‐strips and biopsies capture overlapping but distinct features of the AD molecular signature, suggesting their respective utility for monitoring specific AD‐related immune, itch, and barrier abnormalities in clinical trials and longitudinal studies.

Background Griseofulvin and Terbinafine are considered effective first‐line therapies for tinea capitis (TC). Hematologic dyscrasias and hepatic injury are possible adverse effects with both drugs. There is a debate in the literature regarding the necessity of laboratory monitoring during Griseofulvin and Terbinafine treatment. Objectives We aimed at assessing the prevalence and severity of hematologic and hepatic laboratory test abnormalities in a pediatric cohort of African immigrants in Tel‐Aviv with TC who were treated with Terbinafine or Griseofulvin. Methods We conducted a retrospective study of all TC cases diagnosed and treated at the pediatric dermatology clinic, Tel‐Aviv Medical center, between June 2013 and March 2019. Epidemiologic, clinical and laboratory data were collected. Results Our cohort included 321 patients of whom 225 (70%) were treated with Griseofulvin and 96 (30%) with Terbinafine. We identified a total of 64 (20%) patients with hematologic or hepatic laboratory test abnormalities that in most cases (96.3%) were considered as mild. No difference in laboratory abnormalities prevalence was identified between the Griseofulvin and Terbinafine groups (21.3% and 16.6% respectively). Only one patient treated with Griseofulvin revealed significantly increased levels of hepatic aminotransferases that required discontinuation of treatment. Conclusions Mild elevation in hepatic transaminases is relatively common among pediatric patients treated with systemic antifungal treatment for TC. However, significant laboratory abnormalities are extremely rare and may be diagnosed and addressed early through periodic laboratory tests monitoring.

Summary: Outbreaks of tinea capitis (TC) can be a source of medical and economic burden for healthcare systems; Griseofulvin and terbinafine are considered to be effective first‐line treatments for TC. In order to compare the efficacy of griseofulvin and terbinafine for the treatment of TC in a paediatric population of African immigrants in the Tel Aviv area, we conducted a retrospective cohort study of all cases of TC diagnosed and treated between March 2016 and February 2018 at a dedicated TC paediatric dermatology clinic at the Tel Aviv Medical Center (which serves as a referral centre for the paediatric refugee population in the Tel Aviv metropolitan area). Epidemiologic, clinical and laboratory data were collected, and 304 patients were included. Trichophyton violaceum (TV), Trichophyton soudanense (TS) and Microsporum audouinii (MA) were the prominent causative organisms. Treatment with griseofulvin suspension for 12 weeks was compared with (a) griseofulvin suspension for 8 weeks and with (b) terbinafine tablets for 4 weeks. There was no statistically significant difference between the groups regarding age, sex, country of birth, ethnicity and the causative organism. Twelve weeks of griseofulvin treatment had a statistically significant better cure rate than 4 weeks of terbinafine. Treatment was significantly more effective when TC was due to infections with MA and TS as compared with TV. No statistically significant difference was observed between 12‐ and 8‐week treatment with griseofulvin.