Incidence rate of alopecia areata in Israel: A 15-year analysis of population-based data and the emergence of young male adults as the most at-risk group.

Incidence rate and temporal trends in alopecia areata (AA) vary worldwide. As a common disorder with a major impact on life quality, there is a continuous need for comprehensive epidemiological characterization and global updates of the disease burden. We sought to perform an epidemiologic characterization of AA patients and to explore temporal trends across different subgroups using long-term health data. A retrospective population-based study was conducted in a large healthcare organization in Israel. Data were analyzed for all patients with AA between 2005 and 2019. A total of 30 805 patients for 29 504 798 person-years were identified during the study period, representing an overall incidence rate of 104.4 cases per 100 000 person-years. Young adults and patients of middle socioeconomic status had the highest incidence rate compared to the whole cohort. Incidence rates in females were lower than in males (incidence rate ratio 0.72, 95% confidence interval 0.71-0.74). In a temporal trends analysis, the yearly incidence rate for the whole cohort was stable throughout the study period. Males between the ages of 18 and 30 had a significant increase in incidence during the study years, where the incidence rate increased from 119.54 to 162.36 per 100 000 person-years. Despite the limitation of lack of analysis by subgroups of disease severity and other personal data, our study clearly indicates that young male adults of middle socioeconomic status emerge as the most at risk associated with AA over a decade and a half. In an effort to delineate risk factors for this gender gap, different stressors are speculated as triggers.

Clinical and molecular features in a cohort of Middle Eastern patients with epidermolysis bullosa.

BACKGROUND: Epidermolysis bullosa (EB) features skin and mucosal fragility due to pathogenic variants in genes encoding components of the cutaneous basement membrane. Based on the level of separation within the dermal-epidermal junction, EB is sub-classified into four major types including EB simplex (EBS), junctional EB (JEB), dystrophic EB (DEB), and Kindler EB (KEB) with 16 EB-associated genes reported to date. METHODS: We ascertained a cohort of 151 EB patients of various Middle Eastern ethnic backgrounds. RESULTS: The cohort was comprised of EBS (64%, 97/151), DEB (21%, 31/151), JEB (12%, 18/151), and KEB (3%, 5/151). KRT14 and KRT5 variants were most common among EBS patients with 43% (42/97) and 46% (45/97) of EBS patients carrying mutations in either of these two genes, respectively. Truncal involvement was more common in KRT14-associated EBS as compared to EBS due to KRT5 mutations (p < .05). Mutations in COL17A1 and laminin 332-encoding genes were identified in 55% (10/18) and 45% (8/18) of JEB patients. Scarring alopecia, caries, and EB nevi were most common among JEB patients carrying COL17A1 mutations as compared to laminin 332-associated JEB (p < .05). Abnormal nails were evident in most DEB and JEB patients while poikiloderma was exclusively observed in KEB (p < .001). CONCLUSIONS: EB patients of Middle Eastern origin were found to feature specific phenotype-genotype correlations of relevance to the diagnosis and genetic counseling of patients in this region.

Intralesional human papillomavirus vaccine for the treatment of recalcitrant cutaneous warts.

Human papillomavirus (HPV) is ubiquitously distributed in the population worldwide and its most frequent clinical presentation is cutaneous warts. Despite various treatment options currently available, many patients experience persistent and refractory disease. We sought to evaluate the clinical effectiveness and safety profile of intralesional HPV 9-valent vaccine for the treatment of recalcitrant warts. A retrospective study was performed for all cases of cutaneous warts treated with intralesional 9-valent HPV vaccine between January 2017 and March 2021. Epidemiologic, clinical, and treatment data, including safety and effectiveness scores, were reviewed. Our cohort was composed of 20 patients: 13 adults and seven children. Twelve patients (60%) displayed a complete response whereas 8 patients (40%) showed a partial response. Older age was associated with a better response to treatment, while a history of laser therapy was associated with a worse prognosis. Adverse events were local, transient, and negligible. No systemic adverse effects were reported. Intralesional 9-valent HPV vaccine may be considered for the treatment of recalcitrant cutaneous warts. Controlled studies are required to confirm these results.

Data From a One-Stop-Shop Comprehensive Cancer Screening Center.

PURPOSE: Cancer is the second leading cause of death globally. However, by implementing evidence-based prevention strategies, 30%-50% of cancers can be detected early with improved outcomes. At the integrated cancer prevention center (ICPC), we aimed to increase early detection by screening for multiple cancers during one visit. METHODS: Self-referred asymptomatic individuals, age 20-80 years, were included prospectively. Clinical, laboratory, and epidemiological data were obtained by multiple specialists, and further testing was obtained based on symptoms, family history, individual risk factors, and abnormalities identified during the visit. Follow-up recommendations and diagnoses were given as appropriate. RESULTS: Between January 1, 2006, and December 31, 2019, 8,618 men and 8,486 women, average age 47.11 ± 11.71 years, were screened. Of 259 cancers detected through the ICPC, 49 (19.8%) were stage 0, 113 (45.6%) stage I, 30 (12.1%) stage II, 25 (10.1%) stage III, and 31(12.5%) stage IV. Seventeen cancers were missed, six of which were within the scope of the ICPC. Compared with the Israeli registry, at the ICPC, less cancers were diagnosed at a metastatic stage for breast (none v 3.7%), lung (6.7% v 11.4%), colon (20.0% v 46.2%), prostate (5.6% v 10.5%), and cervical/uterine (none v 8.5%) cancers. When compared with the average stage of detection in the United States, detection was earlier for breast, lung, prostate, and female reproductive cancers. Patient satisfaction rate was 8.35 ± 1.85 (scale 1-10). CONCLUSION: We present a proof of concept study for a one-stop-shop approach to cancer screening in a multidisciplinary outpatient clinic. We successfully detected cancers at an early stage, which has the potential to reduce morbidity and mortality as well as offer substantial cost savings.[Media: see text].

Monitoring oral propranolol for infantile hemangiomata.

Treating infantile hemangiomas with oral propranolol may be initiated in accordance with various protocols some require hospitalization. However, different adverse events have been reported during treatment, thus it is of special importance to find a protocol which is both safe and feasible. We performed a retrospective cohort study of all cases of infantile hemangiomas treated with oral propranolol at our institute between January 2010 and February 2020. Pretreatment evaluation consisted of pediatric cardiologist evaluation including electrocardiography and echocardiography. The propranolol starting dosage was 0.5 mg/kg bid; 2 weeks later the dosage was escalated to 1 mg/kg bid. During the initiation and escalation visits, heart rate and blood pressure were measured before and every hour for a total of 3 h, and blood glucose level was measured within the first hour of treatment. A total of 131 children were treated during the study period. Scalp, facial and genital region infantile hemangiomas were more prevalent in regard to their relative body surface area. No symptomatic bradycardia, hypotension, hypoglycemia, or any other adverse events were documented; few patients had asymptomatic bradycardia and hypotension, which were more common in infants below 6-months of age. Only one patient had asymptomatic hypoglycemia, not requiring any intervention. Initiation and escalation of propranolol treatment for infantile hemangiomas proved to be safe, and without symptomatic adverse effects. However, considering the young age of the patients and the possible asymptomatic adverse reactions, we recommend the following simple protocol as presented, for pretreatment evaluation and short monitoring during treatment initiation and dose escalation.

The relationship between atopy and allergic contact dermatitis in Israeli patients.

Introduction: Whether individuals with atopic diseases have a different risk of contact allergy compared to those who are non-atopic is controversial and data are conflicting. Aim: To explore the association between atopy and allergic contact dermatitis (ACD). Material and methods: This retrospective cross-sectional study included 301 patients referred to a tertiary clinic to evaluate ACD. Demographic details including personal and familial mucosal or cutaneous atopic status were recorded. Patch tests were tailored to their clinical presentations and relevant exposures. Results: At least 1 positive patch test reaction was observed in 177 patients (59% of the study cohort), of which 52% had a history of atopic diseases, compared with 44% of patients with a negative patch test result (p = 0.2). Additionally, 147 patients had an atopic background, of which 92 (62%) had ≥ 1 positive patch test result, compared with 55% of non-atopic patients (p = 0.2). Nickel sulphate was the most common contact allergen (13.4% of the patch test reactions). Conclusions: We identified a positive tendency for atopic diseases among individuals with ACD and vice versa. Our study supports the aggregate data from previous studies despite the non-significant differences between the study and control groups. However, further research performed in larger populations of patients is necessary to evaluate the real association between atopy and ACD on a solid basis. Our results indicate the necessity of systematic patch testing in patient setups with atopic background and chronic dermatitis.

Superimposed type 2 segmental atopic dermatitis: case series and review of the literature.

Generalized acquired dermatoses can seldom manifest more prominently or exclusively along the lines of Blaschko. Six individuals with segmental atopic dermatitis (AD) have been reported to date. We present three additional cases of segmental cutaneous manifestations superimposed on generalized AD, and review the relevant literature.

Clinical efficacy of fecal microbial transplantation treatment in adults with moderate-to-severe atopic dermatitis.

BACKGROUND: Atopic dermatitis (AD) is a remitting relapsing chronic eczematous pruritic disease. Several studies suggest that gut microbiota may influence AD by immune system regulation. METHODS: We performed the first in-human efficacy and safety assessment of fecal microbiota transplantation (FMT) for AD adult patients. All patients received 2 placebo transplantations followed by 4 FMTs each 2 weeks apart. AD severity and fecal microbiome profile were evaluated by the Scoring Atopic Dermatitis Score (SCORAD), the weekly frequency of topical corticosteroids usage, and gut microbiota metagenomic analysis, at the study beginning, before every FMT, and 1-8 months after the last FMT. RESULTS: Nine patients completed the study protocol. There was no significant change in the SCORAD score following the two placebo transplants. The average SCORAD score significantly decreased from baseline at Weeks 4-12 (before and 2 weeks after 4 times of FMT) (59.2 ± 34.9%, Wilcoxon p = .011), 50% and 75% decrease was achieved by 7 (77%) and 4 (44%) patients, respectively. At Week 18 (8 weeks after the last FMT) the average SCORAD score decreased from baseline at Week 4 (85.5 ± 8.4%, Wilcoxon p = .018), 50% and 75% decrease was achieved by 7 (77%) and 6 (66.7%) patients respectively. Weekly topical corticosteroids usage was diminished during the study and follow-up period as well. Two patients had a quick relapse and were switched to a different treatment. Two patients developed exacerbations alleviated after an additional fifth FMT. Metagenomic analysis of the fecal microbiota of patients and donors showed bacterial strains transmission from donors to patients. No adverse events were recorded during the study and follow-up period. CONCLUSIONS: FMT may be a safe and effective therapeutic intervention for AD patients, associated with transfer of specific microbial species from the donors to the patients. Further studies are required to reconfirm these results.

A review of combined treatments for melasma involving energy-based devices and proposed pathogenesis-oriented combinations.

BACKGROUND: Melasma is an acquired disorder of hyperpigmentation, affecting a million individuals worldwide. Energy-based devices (EBDs) employed to treat melasma include various types of lasers, intense pulsed light (IPL), and radiofrequency (RF). Recent studies have attempted to address recalcitrant and recurring melasma by combining energy-based devices with topical or oral medications. OBJECTIVE: This article reviews EBDs-based augmented treatment for melasma and suggests practical pathogenesis-oriented treatment regimens. Treatment algorithms are proposed to address various components of melasma. METHODS: A systematic PubMed search was conducted acquiring information from various studies on combination treatments of melasma involving EBDs. RESULTS: The 286 retrieved articles were filtered by title to contain at least one type of energy-based modality such as laser, IPL, or RF along with at least one other treatment method. Based on their subject matter, combinations were further categorized into the subheadings: laser plus medication, laser plus laser, and IPL- and RF-containing treatment methods. CONCLUSION: There are many energy-based combination treatments that have been explored for mitigation of melasma including laser therapy with medication, multi-laser therapies, IPL, RF, and microneedling devices. Melasma is an exceedingly difficult condition to treat, however, choosing the appropriate tailor-made treatment combination can improve the final outcome.

Predictors of the CD24/CD11b Biomarker among Healthy Subjects.

The CD24 gene has raised considerable interest in tumor biology as a new prognostic factor and a biomarker for the early detection of cancer. There are currently no studies that assess predictors of CD24 in blood tests among healthy individuals. Our aims were (1) to evaluate predictors of the CD24/CD11b biomarker among healthy subjects and (2) to assess CD24/CD11b levels of participants with and without benign tumors. Our cohort included 1640 healthy subjects, aged 20-85, recruited at the Health Promotion and Integrated Cancer Prevention Center (ICPC) in the Tel Aviv Medical Center. Eligible subjects completed a detailed questionnaire on medical history and other epidemiologic information. CD24/CD11b expression in peripheral blood leukocytes (PBLs) obtained from blood samples of participants was analyzed by flow cytometry. Our results showed that the average levels of CD24/CD11b in healthy patients (22.8 ± 9.3) was statistically significant lower compared to subjects with benign cancers (26.1 ± 10.5, p < 0.001). Our multivariable analysis demonstrated that elevated levels of CRP (coefficient ß: 1.98, p = 0.011) were significantly associated with high levels of CD24/CD11b expression among healthy participants. Other risk factors of cancer were not associated with elevated CD24 levels among healthy subjects. In conclusion, our findings may assist in further development and optimization of the CD24/CD11b biomarker to serve as a cancer screening test for early detection of cancer among the healthy population.

Feasibly of CD24/CD11b as a Screening Test for Hematological Malignancies.

An estimated 1.24 million blood cancer cases occur annually worldwide, accounting for approximately 6% of all cancer cases. Currently, there are no standardized hematology cancer screening tests that are recommended for the general population. CD24 is a mucin-like cell surface molecule and P-selectin ligand, which plays a significant role in the maturation of B-lymphocytes and was found to be overexpressed in a number of hematological malignancies. Our primary aim was to assess the sensitivity and specificity of the CD24/CD11b-based blood test for the detection of hematological malignancies. Our cohort included 488 subjects with positive hematological cancer diagnosis (n = 122) and healthy subjects (n = 366). CD24/CD11b expression in peripheral blood leukocytes (PBLs) obtained from blood samples of participants was analyzed by flow cytometry. Our results demonstrated that the average levels of CD24/CD11b in healthy patients (21.7 ± 9.0) were statistically significantly lower compared to levels of CD24/CD11b in cancer patients (29.5 ± 18.7, p < 0.001). The highest levels of CD24/CD11b were found in multiple myeloma (39.1 ± 23.6), followed by chronic myeloid leukemia (33.0 ± 13.7) and non-Hodgkin lymphoma (32.3 ± 13.3). The test had an overall sensitivity for hematologic cancers of 78.5% (95% CI, 70.7-86.3%) and specificity of 80.2% (95% CI, 76.1-84.3%). In conclusion, our findings indicate the feasibility of a CD24/CD11b-based blood test as a screening test of hematological malignancies.

The pathogenesis of melasma and implications for treatment.

BACKGROUND: Melasma is a complex and poorly understood disorder, with high rates of treatment failure and recurrences. OBJECTIVES: We aimed to review the current knowledge of the pathogenesis of melasma and apply this knowledge to clinical implications on relevant therapeutic interventions. METHODS: A systematic PubMed search was performed using the search term "((melasma[Text Word]) OR facial melanosis[Text Word]) AND (pathogenesis OR causality[MeSH Terms])" for articles published between 1990 and 2020. Included articles were then evaluated by two authors and assessed for relevant pathomechanistic pathways, after which they were divided into groups with minimal overlap. We then reviewed current treatment modalities for melasma and divided them according to the involved pathomechanistic pathway. RESULTS: A total of 309 search results were retrieved among which 76 relevant articles were identified and reviewed. Five main pathomechanisms observed in melasma were identified: (1) melanocyte inappropriate activation; (2) aggregation of melanin and melanosomes in dermis and epidermis; (3a) increased mast cell count and (3b) solar elastosis; (4) altered basement membrane; and (5) increased vascularization. Treatment modalities were then divided based on these five pathways and detailed in 6 relevant tables. CONCLUSION: The pathophysiology of melasma is multifactorial, resulting in treatment resistance and high recurrence rates. This wide variety of pathomechanisms should ideally be addressed separately in the treatment regimen in order to maximize results.

Treatment options for DOCK8 deficiency-related severe dermatitis.

BACKGROUND: Cutaneous manifestations of dedicator of cytokinesis 8 gene (DOCK8) deficiency, a combined type of T and B cell immunodeficiency, previously designated as autosomal recessive hyper IgE syndrome, includes dermatitis and skin infections. There are limited treatment options for dermatitis related to the syndrome. OBJECTIVE: To describe a cohort of patients with DOCK8 deficiency with a focus on the treatment of their cutaneous manifestations. METHODS: A retrospective study on all children with the genetic diagnosis of DOCK8 deficiency treated at the Sheba Medical Center between 1/1/2003 and 1/1/2021 was preformed. Collected data included: demographic features, family history, laboratory, genetic testing, skin manifestations, treatment, and disease course. Description of two cases of severe recalcitrant dermatitis treated with dupilumab is detailed. RESULTS: Nine children with a genetic diagnosis of DOCK8 deficiency were included, of whom six were girls (66%) with a median age of 8.5 (±2.2 SD) years. The median age at diagnosis was 2.8 (±2.6 SD) years. Six patients were born to consanguineous parents. Five out of six patients who received hematopoietic stem cell transplantation (HSCT) had a complete response, and one was recently transplanted. Of note, two patients, while awaiting HSCT, were treated with dupilumab for their severe dermatitis resulting in a marked improvement of the cutaneous manifestations and pruritus. CONCLUSIONS: Hematopoietic stem cell transplantation is the gold standard and most effective therapy for patients with DOCK8 deficiency. Dupilumab, a biological therapy indicated for atopic dermatitis and other Th2 derived dermatoses, is an excellent option for dermatitis in patients with DOCK8 deficiency and can be used as a bridge before HSCT. Larger studies are needed to confirm this observation.

Molecular epidemiology of non-syndromic autosomal recessive congenital ichthyosis in a Middle-Eastern population.

Autosomal recessive congenital ichthyosis (ARCI) is a rare and heterogeneous skin cornification disorder presenting with generalized scaling and varying degrees of erythema. Clinical manifestations range from lamellar ichthyosis (LI), congenital ichthyosiform erythroderma (CIE) through the most severe form of ARCI, Harlequin ichthyosis (HI). We used homozygosity mapping, whole-exome and direct sequencing to delineate the relative distribution of pathogenic variants as well as identify genotype-phenotype correlations in a cohort of 62 Middle Eastern families with ARCI of various ethnic backgrounds. Pathogenic variants were identified in most ARCI-associated genes including TGM1 (21%), CYP4F22 (18%), ALOX12B (14%), ABCA12 (10%), ALOXE3 (6%), NIPAL4 (5%), PNPLA1 (3%), LIPN (2%) and SDR9C7 (2%). In 19% of cases, no mutation was identified. Our cohort revealed a higher prevalence of CYP4F22 and ABCA12 pathogenic variants and a lower prevalence of TGM1 and NIPAL4 variants, as compared to data obtained in other regions of the world. Most variants (89%) in ALOX12B were associated with CIE and were the most common cause of ARCI among patients of Muslim origin (26%). Palmoplantar keratoderma associated with fissures was exclusively a result of pathogenic variants in TGM1. To our knowledge, this is the largest cohort study of ARCI in the Middle-Eastern population reported to date. Our data demonstrate the importance of population-tailored mutation screening strategies and shed light upon specific genotype-phenotype correlations.

Laboratory monitoring during antifungal treatment of paediatric tinea capitis.

Griseofulvin and terbinafine are considered effective first-line therapies for tinea capitis (TC). Haematological 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. We aimed at assessing the prevalence and severity of haematological and hepatic laboratory test abnormalities in a paediatric cohort of African immigrants in Tel-Aviv with TC who were treated with Terbinafine or Griseofulvin. We conducted a retrospective study of all TC cases diagnosed and treated at the paediatric dermatology clinic, Tel-Aviv Medical centre, between June 2013 and March 2019. Epidemiologic, clinical and laboratory data were collected. 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 haematological 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. Mild elevation in hepatic transaminases is relatively common among paediatric 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.

Enhanced Percutaneous Delivery of Beta-Blockers Using Thermal Resurfacing Drug Delivery System for Topical Treatment of Infantile Hemangiomas.

BACKGROUND: Infantile hemangiomas (IHs) are the most common vascular tumors in children. In the past few years, topical beta-blockers (bBs) have been reported to be an effective treatment of superficial IHs. OBJECTIVE: We sought to evaluate the clinical effectiveness and safety profile of enhanced percutaneous delivery of bBs for the treatment of IH. METHODS: A retrospective study of all cases of IHs treated with enhanced percutaneous delivery of bBs between 2018 and 2019 was performed. Epidemiologic, clinical, and treatment data, including effectiveness score and safety, were reviewed. RESULTS: The study included 11 patients with a total of 11 IHs. Of the total number of IHs, 7 (63.7%) showed a good response to treatment and 4 (36.3%) had a partial response; thus all patients (100%) had good or partial response to treatment. No systemic or local adverse effects were reported. LIMITATIONS: This is an uncontrolled retrospective study. CONCLUSION: Enhanced percutaneous delivery of bBs is a safe and efficient topical therapy for IH.

A new approach in the treatment of pediatric hypertrophic burn scars: Tixel-associated topical triamcinolone acetonide and 5-fluorouracil delivery.

BACKGROUND: Pediatric hypertrophic burn scars are challenging to treat due to their widespread nature and pain associated with the treatment. Intralesional triamcinolone acetonide (TAC) injection with or without 5-fluorouracil (5FU) is considered first-line treatment for severe hypertrophic scars. The pain associated with the procedure, the uneven topography, and epidermal atrophy, all limit the application of this treatment modality. AIMS: We sought to evaluate the clinical effectiveness and safety profile of a novel thermomechanical system (Tixel, Novoxel) for transdermal delivery of a topical solution containing TAC and 5-FU in the treatment of hypertrophic scars. PATIENTS/METHODS: A retrospective study of pediatric hypertrophic burn scars treated between 2015 and 2017 was performed. Epidemiologic, treatment data, effectiveness score, and safety were reviewed. RESULTS: Four children (one male and three females, ages 3-10 years old) with hypertrophic burn scars treated with the Tixel device were evaluated. Mean scar VSS was reduced from 8.4 ± 0.8-5.2 ± 0.5 (P-value - .001) after eight treatments. The mean improvement of toughness, thickness, color, and general aesthetic impression was 3.1 ± 0.43 â†’ 2.2 ± 0.31, 3.4 ± 0.5 â†’ 1.9 ± 0.63, 2.7 ± 0.21 â†’ 2.4 ± 0.25, and 3.23 ± 0.44 â†’ 1.6 ± 0.64, respectively. Mean treatment pain VAS score was 1.74 ± 0.9. Patient's parents rated their satisfaction level as "moderate-high." No topical or systemic complications were observed. CONCLUSION: Thermomechanical decomposition of the stratum corneum, in combination with topical application of TAC and 5-FU, is a safe, relatively painless, and efficient modality for the treatment of pediatric hypertrophic burn scars.