Immunophenotyping and viral studies in pityriasis lichenoides et varioliformis acuta lesions.

BACKGROUND: The underlying pathogenesis of pityriasis lichenoides et varioliformis acuta (PLEVA) remains unclear, although immunologic injury and viral etiology have been suggested. OBJECTIVE: To evaluate and expand the immunophenotype of PLEVA and to search for possible viral pathogens. METHODS: Formalin-fixed, paraffin-embedded specimens of 20 patients with PLEVA and 9 patients with common inflammatory dermatoses (ID) were studied for immunophenotyping and for human herpesvirus (HHV) 1 and 2, cytomegalovirus (CMV), HHV-8, parvovirus B19, and Epstein-Barr virus (EBV) immunohistochemistry. The presence of HHV-6, HHV-7, and enteroviruses was assayed molecularly. RESULTS: The numbers of CD8+ T cells and T-cell intracellular antigen-1 (TIA-1)+ cells were statistically significantly higher in PLEVA compared to the ID group. Immunohistochemistry for human HHV-1 and HHV-2, CMV and HHV-8, parvovirus B19, and in situ hybridization for EBV were all negative. There was molecular evidence for HHV-7 in only one PLEVA case (5%). Molecular studies for HHV-6 and enterovirus involvement were negative in all the PLEVA specimens. CONCLUSIONS: The predominant T-cell infiltrate in PLEVA is dominated by CD8+ cells, and by increased numbers of TIA1+ cells, which may indicate a cytotoxic T-cell damage to the epidermis. Viral presence was not detected.

To ASLO or Not to ASLO: Utility of the ASLO Test in Dermatology.

BACKGROUND: Group A Streptococcus (GAS) causes a wide spectrum of acute infections and immune-related diseases, most of which include a dermatological presentation. However, dermatological findings have a wide range of other possible etiologies. The diagnosis of GAS-related disease requires an indication of preceding GAS infection by direct culture or by measuring antistreptolysin O (ASLO) titer. OBJECTIVES: To explore the correlation between ASLO positivity and dermatological diseases. METHODS: We analyzed clinical data from all cases of patients over 18 years of age who underwent ASLO testing between the years 2016 and 2020 in the Department of Dermatology at Rambam Health Care Campus. RESULTS: Of 152 adult patients with ASLO tests, 100 had diagnoses that were potentially related to streptococcal infection. Vasculitis and psoriasis were the most suspected diagnoses. Positive ASLO test was found in 44 (29%) patients. The diagnoses showing the highest ratio of positive ASLO were psoriasis (60%), erythema nodosum (46%), skin infections (43%), Sweet syndrome (33%), and vasculitis (15%). Psoriasis types included plaque psoriasis (8 patients), guttate psoriasis (3 patients), and palmoplantar pustulosis and erythroderma (2 patients each). CONCLUSIONS: Although the applicability of ASLO for the spectrum of dermatological diseases remains unclear, our results enhance the practical relevance of the test. We showed a higher prevalence of positive ASLO tests in psoriasis and erythema nodosum cases and a lower prevalence in vasculitis. Notably, ASLO was positive in all psoriasis subtypes, suggesting high utility of the test for psoriasis.

[COMPREHENSIVE GUIDELINES AND INDICATIONS FOR DIGITAL MONITORING OF PATIENTS AT HIGH-RISK FOR MELANOMA: A POSITION PAPER BY THE ISRAELI ASSOCIATION FOR DERMATOLOGY].

INTRODUCTION: Early detection may lead to reduced morbidity and mortality from melanoma. This study aims to establish guidelines for selecting patients suitable for digital monitoring of skin lesions. METHODS: A literature review was conducted, followed by consensus among experts appointed by the Israeli Dermatology Association. RESULTS: Two effective methods for early melanoma diagnosis were identified: Total-body photography (TBP) and digital dermoscopy. TBP involves capturing clinical images of the entire skin area for long-term monitoring (6-12 months). Digital dermoscopy focuses on close-up images of distinct lesions for short-term monitoring (3-4 months). Various risk factors for melanoma were identified, including genetic and familial factors, as well as demographic and phenotypic characteristics. Based on these risk factors and feasibility of clinical follow-up, a comprehensive list of indications for TBP was developed, categorized into three groups based on the expected level of benefit. Digital dermoscopy surveillance is recommended for patients with flat or slightly raised skin lesions showing dermoscopic features that do not definitively indicate melanoma. DISCUSSION: TBP significantly improves early melanoma detection, enhancing sensitivity and specificity while reducing unnecessary biopsies. However, due to its high cost and limited coverage by the Israeli public health care system, prioritizing patients who would benefit most from TBP is crucial. The compiled list of indications aligns with international recommendations and provides further details within the article.

Paediatric Mycosis Fungoides: Clinical Variants, Treatment Modalities and Response to Therapy.

Mycosis fungoides is a rare cutaneous lymphoma in the paediatric population. The aim of this study was to examine the epidemiological, clinical, and histological characteristics, as well as the treatment modalities and response to therapy of paediatric patients with mycosis fungoides. This retrospective cohort study reviewed the records of 37 paediatric patients treated at Rambam Medical Center, Israel, between 2013 and 2021. Extracted data included epidemiology, clinical presentation, histological reports, infiltrate clonality status, treatment modalities and response to therapy. The mean follow-up period was 60 months. All patients were diagnosed with stage IA or IB disease. Folliculotropic mycosis fungoides was the most prevalent variant (49%). Most patients were treated with phototherapy (90%), with a response rate of 85%, and a complete response rate of 55% after the first course. There were no significant differences in response to phototherapy between the folliculotropic or other variants (p = 0.072). Similarly, delayed diagnosis, atopic diathesis, clonality, phototherapy type or number of treatments, were not associated with response to therapy, while protracted phototherapy was associated with prolonged remission. In conclusion, mycosis fungoides in the paediatric population is an indolent disease with a favourable prognosis and potentially prolonged response to phototherapy.

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.

Exacerbation of Hailey-Hailey Disease Following SARS-CoV-2 Vaccination.

is missing (Short communication).

Histopathological Findings in Nail Clippings With Periodic Acid-Schiff-Positive Fungi.

BACKGROUND: Periodic acid-Schiff (PAS) staining of nail clippings is an adjunct diagnostic tool for onychomycosis. OBJECTIVE: To detect histopathological findings as clues to the presence of PAS-positive (+) fungal elements in nail clippings. METHODS: Four hundred sixteen consecutive nail clippings suspected of onychomycosis were stained with hematoxylin and eosin, and with PAS stains. All cases were studied histopathologically. The clinical files of the cases with neutrophils were reviewed. RESULTS: PAS+ staining for fungi were demonstrated in 159 (38%) of the nail clippings. Neutrophils, parakeratosis, plasma globules, and bacteria were observed in 43 (27%), 108 (67%), 80 (50%), and 80 (50%) of the PAS+ cases, respectively, and in 17 (6%), 109 (41%), 84 (32%) and 140 (54%) of the PAS- cases, respectively (P < 0.01). Neutrophils showed by far the highest specificity (93%), although with low sensitivity (27%) for the presence of PAS+ fungi. Among the 43 PAS+ and 17 PAS- specimens with neutrophils, only 1 (2.3%) and 3 (17%) had overt psoriasis, respectively. CONCLUSION: Neutrophils in nail clippings may serve as a clue for onychomycosis. PAS staining with neutrophils is not necessarily associated with psoriasis.

Follicular eruption with folliculotropic lymphocytic infiltrates associated with anti-tumor necrosis factor alpha therapy: Report and study of 3 cases.

BACKGROUND: We have encountered three cases of follicular eruptions with folliculotropic infiltrates of non-atypical lymphocytes associated with anti-tumor necrosis factor alpha (TNF-α) therapy. METHODS: Three patients aged 15 to 56 years treated with anti-TNF-α therapy (one with adalimumab, and two with infliximab) developed follicular eruptions characterized histopathologically by folliculotropic lymphocytic infiltrates. These were studied clinically, histopathologically, immunophenotypically, and molecularly. RESULTS: All three cases were characterized histopathologically by folliculotropic cell infiltrates of non-atypical T (CD3+) lymphocytes with variable follicular exocytosis. Marked reduction in CD7 staining and marked predominance of CD4+ cells over CD8+ cells were observed in 1 and 2 cases, respectively. T-cell receptor (TCR) gene rearrangement studies were monoclonal in 1 case. Discontinuation of anti-TNF-α therapy in all three cases, with corticosteroid creams in 1 case, led to complete resolution. Rechallenge with adalimumab in 1 case resulted in exacerbation. Replacement of therapy with non-anti-TNF-α biologic agents in 2 cases was not associated with recurrence. CONCLUSION: Follicular eruptions with folliculotropic lymphocytic infiltrates associated with anti-TNF-α therapy may show some immunophenotypical variations and/or monoclonal TCR gene rearrangements but lack sufficient cytomorphological features of folliculotropic MF. They may resolve with discontinuation of anti-TNF-α therapy.

Neonatal Autoimmune Subepidermal IgG/IgA Blistering Disease With Severe Laryngeal and Esophageal Involvement: A Report of a Case and Review of the Literature.

Neonatal autoimmune subepidermal blistering disease is rare. Mucosal involvement is more common in neonatal linear immunoglobulin A (IgA) bullous dermatosis. We describe a neonate with subepidermal cutaneous blistering disease with severe laryngeal and esophageal involvement leading to acute respiratory distress. Histopathology demonstrated a subepidermal blister with neutrophils and eosinophils at the dermal base. Collagen IV was detected at the dermal floor, and direct immunofluorescence showed linear IgG, IgA, and C3 deposits at the basement membrane zone. The patient demonstrated markedly increased serum levels of anti-BP180 NC16A and anti-BP230 IgG antibodies (Abs) but failed to show anti-LAD-1 IgA Abs. His healthy mother showed serum anti-LAD-1 IgA Abs but did not show anti-BP180 and anti-BP230 Abs. The neonate responded promptly to systemic corticosteroid therapy. A review of the literature detected 11 cases of neonatal subepidermal blistering disease with linear IgA deposits. Nine of these cases demonstrated coexisting linear IgG deposits, often with C3. Respiratory compromise was present in most of the cases. Neutrophils and eosinophils were commonly present in the inflammatory cell infiltrates. Besides our case, 2 cases of neonatal IgG/IgA subepidermal blistering disease with esophageal involvement were previously described. IgA Abs were present in the sera of both cases. Anti-LAD-1 IgA Abs were detected in the mother's serum of our case alone, but IgA Abs do not cross the placenta. Our case was consistent with neonatal IgG/IgA pemphigoid. Neonatal IgG/IgA subepidermal blistering disease may be associated with severe laryngeal and esophageal involvement leading to respiratory compromise. Expedited diagnosis and prompt treatment are warranted.

Primary Cutaneous Clonal CD8+ T-Cell Lymphoproliferative Disorder Associated With Immunodeficiency due to RAG1 Mutation.

The development of T-cell lymphomas, granulomatous reactions, and autoimmunity has been observed in immunodeficiency due to milder forms of recombination activating gene (RAG) deficiency. A few cases of cutaneous clonal papulonodular CD8 lymphocytic infiltrates and cutaneous CD8 granulomatous T-cell lymphoma have been described in association with common variable immunodeficiency, and with X-linked agammaglobulinemia. We describe a 15-year-old girl with several autoimmune disorders and recurrent infections that presented with several nodules on her cheek. Histopathological studies demonstrate histological, immunohistochemical, and molecular findings compatible with a primary cutaneous clonal CD8 T-cell lymphoproliferative disorder. Vacuolar interface changes were also seen in the involved skin, reminiscent of cutaneous lupus erythematosus. Molecular genetic analysis revealed a germline novel homozygous missense mutation in RAG1 (T1003>C). The parents were heterozygous carriers. The facial cutaneous lesions recurred despite local radiation therapy. Because of recurrent life-threatening systemic infections, allogeneic bone marrow transplantation was performed. The pathogenesis of this primary cutaneous clonal CD8 T-cell lymphoproliferative disorder may have been related to a chronic stimulation of autoreactive T cells in the involved skin paired with reduced RAG1 activity.

Follicular Eruption With Folliculotropic Lymphocytic Infiltrates Associated With Iatrogenic Immunosuppression: Report and Study of 3 Cases, and Review of the Literature.

BACKGROUND: Several cases of folliculotropic mycosis fungoides, associated with immunosuppressive therapy, including calcineurin inhibitors, have been reported in solid organ transplant patients. We have encountered 3 patients on immunosuppressive therapy who developed follicular eruptions with folliculocentric infiltrates of nonatypical lymphocytes. OBJECTIVE: To characterize these follicular eruptions and review the literature. METHODS: Three patients, aged 7-15 years, who were treated with systemic immunosuppressive therapy developed follicular eruptions characterized histopathologically by folliculocentric lymphocytic infiltrates. These were studied clinically, histopathologically, immunophenotypically, and molecularly for T-cell receptor (TCR) gene rearrangement. RESULTS: All 3 cases were characterized histopathologically by folliculocentric infiltrates of nonatypical CD3 T lymphocytes with variable follicular exocytosis. Two cases also showed follicular mucinosis. Marked reduction in CD7 staining, and marked predominance of CD4 cells over CD8 cells was observed in all 3 cases. The TCR gene rearrangement studies were monoclonal in 2 cases. Oral calcineurin inhibitors (2 cyclosporine A and 1 tacrolimus) were part of the therapeutic regimen in all 3 patients. Their cessation along with local corticosteroid creams in 2 patients, and phototherapy with oral acitretin in one patient, was associated with complete clinical remission. CONCLUSIONS: Patients undergoing systemic immunosuppressive therapy that includes calcineurin inhibitors might develop follicular eruption with some immunophenotypical variations and a monoclonal TCR gene rearrangement but lack sufficient cytomorphological features of folliculotropic mycosis fungoides. Altering the immunosuppressive agent including calcineurin inhibitors may result in regression of the eruptions.

[DERMATOLOGIC CONDITIONS IN MONOZYGOTIC TWINS].

INTRODUCTION: Genetic twin studies may shed light on the genetic basis as well as environmental and epigenetic factors in disease pathogenesis. Herein, we present four pairs of monozygotic twins sharing similar phenotypes in three dermatologic conditions, and a literature review regarding twin studies in these diseases.

[AT THE BOTTOM OF THE ULCER - THE IMPORTANCE OF A BIOPSY IN DIAGNOSING HARD TO TREAT ULCERS].

INTRODUCTION: We report a case of a patient who presented with bilateral chronic painful necrotic leg ulcers. A skin biopsy revealed histopathological findings compatible with calciphylaxis, a rare phenomenon accompanied by high morbidity and mortality. Treatment options are limited and are based mainly on case reports and small series, so further research is needed in this area. This case highlights the importance of a skin biopsy in the diagnosis of chronic ulcers.

Demodex Folliculitis of the Scalp: Clinicopathological Study of an Uncommon Entity.

Demodex is a saprophytic mite in humans commonly present in the pilosebaceous units, which has been implicated as a pathogen in several skin conditions. The clinical presentation and histopathology of Demodex folliculitis of the scalp have been described in only a few case reports. This study was performed to further elucidate the clinicopathological features of this entity. We have studied 333 consecutively submitted scalp biopsies performed for hair loss and alopecia. All specimens were completely step-sectioned. Biopsies with Demodex mites were further studied histopathologically, and the patients' clinical files were reviewed. There were 17 biopsies (5.1%) with Demodex in at least 1 pilosebaceous unit. Based on the clinical presentation, histopathology, and response to therapy, Demodex was considered to be nonpathogenic in 13 cases. The remaining 4 cases were characterized by hair loss, scalp erythema, scales, and pustules. There were 2 or more pilosebaceous units with Demodex along mononuclear and/or neutrophilic infiltrates around and in the involved follicles and occasionally granulomas. All 4 cases responded completely to metronidazole therapy. In conclusion, Demodex is infrequently found in scalp biopsies for hair loss and alopecia, and, in most cases, it does not seem to be pathogenic. Occasionally, however, it is associated with folliculitis characterized by hair loss, erythema, scales, and pustules clinically; neutrophilic and/or mononuclear-cell folliculitis with occasional granulomas histopathologically; and a prompt response to anti-Demodex therapy.

The Incidence of Acantholysis in Pityriasis Rubra Pilaris-Histopathological Study Using Multiple-Step Sections and Clinicopathologic Correlations.

BACKGROUND: The classical histopathological findings in the epidermis of pityriasis rubra pilaris (PRP) do not include acantholysis; however, acantholysis was described in several case reports and a few series of PRP with variable frequencies. We sought to establish the incidence of acantholysis in biopsies from consecutively referred PRP cases using multiple-step sections and clinicopathologic correlations. METHODS: Twenty-three biopsies from 12 consecutively referred patients with classical (type 1) PRP were studied histopathologically. Each specimen was completely step sectioned. The clinical files of the patients were also reviewed. RESULTS: Small foci of acantholysis were observed in some of the step sections of 5 of 23 (22%) biopsies obtained from 4 patients. Three biopsies showed suprabasal acantholysis, 1 of which also demonstrated mild dyskeratosis and 2 showed midepidermal acantholytic foci as well. The remaining 2 biopsies demonstrated midepidermal and subcorneal acantholysis, respectively. Small erosions were described in the physical examination of 2 of the 4 (50%) patients with acantholysis and in 1 of the 8 (12.5%) patients without acantholysis. LIMITATIONS: The number of cases. CONCLUSIONS: Small foci of acantholysis may be found in the minority of PRP biopsies, and it may be related to small erosions clinically in some patients.

Human amnion membrane as a substrate for the detection of autoantibodies in pemphigus vulgaris and bullous pemphigoid.

BACKGROUND: Human amnion membrane (HAM) was suggested to be a superior antigenic substrate for immunoblotting in detecting autoantibodies of autoimmune bullous skin diseases. OBJECTIVES: To determine the properties of HAM as an antigenic substrate for the detection of autoantibodies in pemphigus vulgaris and bullous pemphigoid. METHODS: Immunomapping and tandem liquid chromatography mass spectrometry were used to delineate the antigenic structure of HAM. Immunoblotting and indirect immunofluorescence were used to study the diagnostic utility of HAM in 25 pemphigus patients, 41 pemphigoid patients, and 36 controls, and the results were compared to those of indirect immunofluorescence on monkey esophagus, immunoblotting using normal human skin, and enzyme-linked immunosorbent assay. RESULTS: Immunomapping demonstrated the presence of all the antigens known to be targeted in autoimmune bullous skin diseases, in both normal human skin and HAM, except for the absence of BP230, and low threshold levels of Dsg1, Dsg3 and Dsc3 in HAM. HAM indirect immunofluorescence demonstrated anti-basement membrane zone antibodies in 48.7% of the pemphigoid patients, and anti-intercellular space antibodies in 72.0% of the pemphigus patients. HAM immunoblotting did not demonstrate anti-BP230 antibodies, but detected anti-BP180 antibodies in 53.7% of the pemphigoid patients. It did not demonstrate anti-Dsg1 and/ or anti-Dsg3 antibodies in any of the pemphigus patients. These results were inferior to those of ELISA and monkey esophagus indirect immunofluorescence. CONCLUSIONS: Compared to other studied methods, HAM does not offer advantages in detecting autoantibodies in bullous pemphigoid and pemphigus vulgaris.

Management of Melasma: Laser and Other Therapies-Review Study.

Melasma is a commonly occurring pigmented skin condition that can significantly affect one's appearance, described as symmetric hyperpigmentation that presents as irregular brown to gray-brown macules on various facial areas, such as the cheeks, forehead, nasal bridge, and upper lip, along with the mandible and upper arms. Due to its complex pathogenesis and recurrent nature, melasma management is challenging and the outcomes following treatment are not always deemed satisfactory. Solely treating hyperpigmentation may prove ineffective unless paired with regenerative techniques and photoprotection, since one of the main reasons for recurrence is sun exposure. Hence, the treatment protocol starts with addressing risk factors, implementing stringent UV protection, and then treatment using different strategies, like applying topical treatments, employing chemical peels, laser and light therapies, microneedling, and systemic therapy. This review aims to provide a summary of the effectiveness and safety of the frequently employed laser and light therapies for treating melasma, focusing on laser therapy as a treatment for melasma.

miR-184 represses ß-catenin and behaves as a skin tumor suppressor.

miR-184-knockout mice display perturbed epidermal stem cell differentiation. However, the potential role of miR-184 in skin pathology is unclear. Here, we report that miR-184 controls epidermal stem cell dynamics and that miR-184 ablation enhances skin carcinogenesis in mice. In agreement, repression of miR-184 in human squamous cell carcinoma (SCC) enhances neoplastic hallmarks of human SCC cells in vitro and tumor development in vivo. Characterization of miR-184-regulatory network, suggests that miR-184 inhibits pro-oncogenic pathways, cell proliferation, and epithelial to mesenchymal transformation. Of note, depletion of miR-184 enhances the levels of ß-catenin under homeostasis and following experimental skin carcinogenesis. Finally, the repression of ß-catenin by miR-184, inhibits the neoplastic phenotype of SCC cells. Taken together, miR-184 behaves as an epidermal tumor suppressor, and may provide a potentially useful target for skin SCC therapy.

Clinical-Epidemiological Characteristics of Hidradenitis Suppurativa: A Retrospective Cohort Study from a Tertiary Care Centre in Northern Israel.

BACKGROUND: Hidradenitis suppurativa (HS) is characterised by inflamed lesions that typically appear in apocrine-rich flexural areas. Although studies have reported clinical and epidemiological data from western countries, data from the Middle East are scarce. The aim of this study is to characterise the differences in the clinical characteristics of patients with HS of Arab and Jewish ancestry and review the clinical characteristics, the course of the disease, the comorbidities, and the response to treatment. METHODS: This is a retrospective study. We collected clinical and demographic data from patient files between 2015-2018 at the Rambam Healthcare Campus dermatology clinic-a tertiary hospital located in the north of Israel. Our results were compared to those of a previously published Israeli control group registered in Clalit Health Services. RESULTS: Of the 164 patients with HS, 96 (58.5%) were men and 68 (41.5%) were women. The average age at diagnosis was 27.5 years and the average latency between the onset and diagnosis of the disease was 4 years. We found a higher adjusted prevalence of HS in Arab patients (56%) than in their Jewish counterparts (44%). Gender, smoking, and obesity, as well as axilla and buttock lesions, were risk factors for severe HS, with no differences between ethnicities. No differences were documented in comorbidities and in response to adalimumab, with a high overall response rate of 83%. CONCLUSIONS: Our findings revealed differences between Arab and Jewish patients with HS in terms of incidence and gender predominance, while no differences were documented in comorbidities and response to adalimumab.