Lesional Skin Biopsies Research Articles

Comparing Improvements in Biopsy Decision Making with Electrical Impedance Spectroscopy Between US and German Dermatologists

Electrical impedance spectroscopy (EIS) is a noninvasive tool that measures the electrophysical properties of pigmented lesions, generating a score to aid in the differentiation of benign and malignant lesions. This research letter compares two studies, conducted in the United States (US) and Germany, evaluating the impact of EIS on biopsy decision-making among dermatologists. Both studies used the same set of clinical and dermoscopic images along with EIS scores for 49 lesions. Findings revealed that American dermatologists had a higher rate of correct biopsy decisions for malignant melanomas (MMs) and severe dysplastic nevi (SDNs) compared to their German counterparts. However, German dermatologists showed greater accuracy in avoiding unnecessary biopsies of benign pigmented skin lesions (PSLs). The addition of both dermoscopy and EIS significantly improved biopsy decision accuracy for MMs and SDNs in both groups, with EIS further mitigating initial reductions in correct biopsy choices for benign lesions. Differences in practice patterns, training, and malpractice concerns may explain the observed variations between US and German dermatologists. These results underscore the utility of EIS as a complementary tool to dermoscopy, enhancing the accuracy of biopsy decisions and improving patient outcomes.

Cutaneous T-cell lymphoma of the mycosis fungoides type: report of case series

Cutaneous T-cell lymphomas represent a heterogeneous group of lymphoproliferative diseases characterized by skin infiltration by mature malignant T cells. More than 40% of cutaneous T-cell lymphomas are represented by mycosis fungoides. As they present non-specific cutaneous manifestations, they are often underdiagnosed. This article reports four cases of mycosis fungoides with different subtypes treated by a multidisciplinary team, highlighting aspects related to clinical heterogeneity and diagnostic, therapeutic and differential diagnostic challenges, followed by a brief review of the literature. The cases described demonstrate the heterogeneity of cutaneous and systemic clinical signs, with presentations that present a significant diagnostic challenge due to other diseases with similar manifestations, especially for non-specialist physicians in basic healthcare units. Mycosis fungoides continues to be a problematic diagnosis, as the cases described had varied presentations and numerous inconclusive biopsies. Low clinical suspicion and technical limitations in the analysis of biopsies of skin lesions were the main factors implicated. It is hoped that this series of cases will bring a better understanding of the diagnostic aspects of this disease.

Topical Mupirocin Treatment Reduces Interferon and Myeloid Signatures in Cutaneous Lupus Erythematous Lesions Through Targeting of Staphyloccal Species.

Cutaneous lupus erythematosus (CLE) is an inflammatory skin manifestation of systemic lupus erythematosus. Type I interferons (IFNs) promote inflammatory responses and are elevated in CLE lesions. We recently reported that CLE lesions are frequently colonized with Staphylococcus aureus. Here, we follow up via a proof-of-concept study to investigate whether type I IFN and inflammatory gene signatures in CLE lesions can be modulated with mupirocin, a topical antibiotic treatment against S aureus-mediated skin infections. Participants with active CLE lesions (n = 12) were recruited and randomized into a week of topical treatment with either 2% mupirocin or petroleum jelly vehicle. Paired samples were collected before and after seven days of treatment to assess microbial lesional skin responses. Microbial samples from nares and lesional skin were used to determine baseline and posttreatment Staphylococcus abundance and microbial community profiles by 16S ribosomal RNA gene sequencing. Inflammatory responses were evaluated by bulk RNA sequencing of lesional skin biopsies. We identified 173 differentially expressed genes in CLE lesions after topical mupirocin treatment. Decreased lesional Staphylococcus burden correlated with decreased IFN pathway signaling and inflammatory gene expression and barrier dysfunction. Interestingly, mupirocin treatment lowered skin monocyte levels, and this mupirocin-associated depletion of monocytes correlated with decreased inflammatory gene expression. Mupirocin treatment decreased lesional Staphylococcus, and this correlated with decreased IFN signaling and inflammatory gene expression. This study suggests a topical antibiotic could be employed to decrease lupus skin inflammation and type I IFN responses by reducing Staphylococcus colonization.

P77 Bimekizumab in psoriatic disease: Exploring the fast onset, high level and durable clinical and molecular responses: design and rationale behind the exploratory, multicentre, open-label Phase 3b BE UNIQUE study

Abstract Bimekizumab (BKZ) has shown rapid normalization of the psoriatic skin transcriptome and tissue-resident memory T-cell (Trm) signatures by Week (Wk)8, which may promote clinical response durability. Questions remain on the very early/longer-term effects of BKZ on key inflammatory pathways/mechanisms behind observed rapid, high, durable clinical responses in patients with psoriasis and psoriatic arthritis (PsA). We describe a study designed to investigate molecular/cellular changes associated with BKZ responses; we hypothesize that fast, durable, complete normalization of inflammatory biomarkers correlates with rapid, high, long-term clinical responses. BE UNIQUE is an ongoing multicentre Phase 3b study enrolling adults with moderate-to-severe psoriasis [psoriasis area and severity index (PASI) ≥12, body surface area (BSA) ≥10%, IGA ≥3]: 40 without concomitant PsA (Cohort A), 40 with concomitant active PsA (Cohort B). Active PsA is defined as disease meeting Classification Criteria for Psoriatic Arthritis, ≥1 tender joint count and ≥1 swollen joint count (SJC). In Part 1, patients will receive BKZ 320 mg every 4 weeks (Q4W) to Wk16, then Q8W to Wk48. In Part 2 (Wks48–96), patients with PASI = 0 [and low PsA activity for Cohort B (SJC≤1 and no increase in concomitant medications for PsA symptom treatment vs. baseline)] will be randomized 1:1 to BKZ Q8W or Q12W; patients with PASI >0 and/or without low PsA activity will continue on BKZ Q8W. Lesional skin biopsies will be taken at baseline/Wk1/48/96 and non-lesional skin biopsies at baseline/Wk48, with optional synovial tissue biopsy at baseline/Wk48 for Cohort B. Randomized patients with a PASI >3 during Part 2 will enter an escape period and receive BKZ Q8W to study end; a lesional skin biopsy will be taken on escape period entry, rather than Wk96. Biopsies will undergo transcriptomics. Blood samples will be collected. Baseline skin biopsies/blood samples will be taken from a matching Control Cohort (10 healthy individuals). Primary objective: assess gene expression score changes using reverse transcription-polymerase chain reaction of skin biopsies, using preselected genes based on BKZ mechanism of action/psoriatic disease pathways, including CCL20/CXCL1/CXCL8/IL12B/IL17A/IL17C/IL17F/IL23A/IL36A/IL36G/KRT16/S100A7, alongside markers of tissue-specific T-cell populations, for example, Trms. Secondary objective: evaluate BKZ safety/tolerability. Exploratory objectives include investigating BKZ effect on skin and blood bulk/single cell/spatial transcriptomics, BKZ systemic effects on gene/protein expression and BKZ clinical response. BE UNIQUE will enable the exploration of mechanisms underlying rapid, high, durable clinical responses observed with BKZ treatment and whether clinical response durability is associated with molecular/cellular changes in skin, blood and joints in psoriatic disease.

Identification and validation of interferon-stimulated gene 15 as a biomarker for dermatomyositis by integrated bioinformatics analysis and machine learning.

Dermatomyositis (DM) is an autoimmune disease that primarily affects the skin and muscles. It can lead to increased mortality, particularly when patients develop associated malignancies or experience fatal complications such as pulmonary fibrosis. Identifying reliable biomarkers is essential for the early diagnosis and treatment of DM. This study aims to identify and validate pivotal diagnostic biomarker for DM through integrated bioinformatics analysis and clinical sample validation. Gene expression datasets GSE46239 and GSE142807 from the Gene Expression Omnibus (GEO) database were merged for analysis. Differentially expressed genes (DEGs) were identified and subjected to enrichment analysis. Advanced machine learning methods were utilized to further pinpoint hub genes. Weighted gene co-expression network analysis (WGCNA) was also conducted to discover key gene modules. Subsequently, we derived intersection gene from these methods. The diagnostic performance of the candidate biomarker was evaluated using analysis with dataset GSE128314 and confirmed by immunohistochemistry (IHC) in skin lesion biopsy specimens. The CIBERSORT algorithm was used to analyze immune cell infiltration patterns in DM, then the association between the hub gene and immune cells was investigated. Gene set enrichment analysis (GSEA) was performed to understand the biomarker's biological functions. Finally, the drug-gene interactions were predicted using the DrugRep server. Interferon-stimulated gene 15 (ISG15) was identified by intersecting DEGs, advanced machine learning-selected genes and key module genes from WGCNA. ROC analysis showed ISG15 had a high Area under the curve (AUC) of 0.950. IHC findings confirmed uniformly positive expression of ISG15, particularly in perivascular regions and lymphocytes, contrasting with universally negative expression in controls. Further analysis revealed that ISG15 is involved in abnormalities in various immune cells and inflammation-related pathways. We also predicted three drugs targeting ISG15, supported by molecular docking studies. Our study identifies ISG15 as a highly specific diagnostic biomarker for DM, ISG15 may be closely related to the pathogenesis of DM, demonstrating promising potential for clinical application.

LC-OCT for early diagnosis and characterization of dermatologic adverse events to oncologic drugs and correlation to histopathology.

Targeted and immune therapies have recently been associated with the occurrence of multiple cutaneous toxicities, often challenging to differentiate by clinical examination alone without histology. Line-field confocal optical coherence tomography (LC-OCT) is a non-invasive and innovative imaging technique that has been shown to be almost as effective as histology in diagnosing several skin conditions. Our study aimed to assess the effectiveness of LC-OCT in predicting the clinical evolution of early maculopapular eruptions related to antineoplastic targeted therapy and immunotherapy. In the period between May 2023 and December 2023, consecutive patients with clinical cutaneous maculopapular reactions caused by oncologic targeted therapy or immunotherapy were enrolled at the dermatologic outpatient clinic of the Fondazione Policlinico A. Gemelli IRCCS, Rome. Patients underwent clinical dermatological examination, video-dermoscopy, LC-OCT, and incisional skin biopsy of a target cutaneous lesion. To investigate the evolutionary pattern of maculopapular lesions (psoriasic eruption, lichenoid eruption, eczematous eruption, bullous eruption), LC-OCT and histopathological images have been compared based on specific characteristics (hyperkeratosis, acanthosis, spongiosis; papillomatosis; lichenoid inflammatory infiltrate; presence of intraepidermal/subepidermal cleavage plan with formation of a bulla). Eighteen patients were included in this study (11 males, 7 females, median age 64.5). LC-OCT demonstrated an overall concordance with histology of 77.8%, with a Cohen's Kappa of 0.69 (P < 0.0001). Sensitivity exceeded 70%, and specificity was ≥88.2%. The Area Under the Curve (AUC) ranged from 0.9 to 1 for psoriasis and lichenoid eruption and from 0.7 to 0.9 for eczematous and bullous eruption. LC-OCT appears to be a promising tool for the early differential diagnosis of adverse skin reactions related to targeted therapy and immunotherapy, offering the potential to avoid skin biopsies in fragile cancer patients.

Th17 and T Regulatory Cytokines in Serum, Lesional Skin, and Stimulated Peripheral Blood Mononuclear Cell Culture Supernatants from Type 1 Leprosy Reaction Patients.

There are conflicting reports regarding the roles of T helper-17 (Th17) and T regulatory (Treg) cells in type 1 leprosy reactions (T1Rs). Also, literature on the correlation of immunological parameters with a validated scoring system and the effect of treatment on cytokines is lacking. Adult patients with untreated T1R and nonreactional spectrum-matched controls were included in the study for comparison of levels of Th17 and Treg pathway cytokines in serum, skin lesions (reactional), and peripheral blood mononuclear cells (PBMCs) culture supernatants. Venous blood samples were collected at baseline and after resolution of reaction (post treatment with nonsteroidal anti-inflammatory drugs [NSAIDs] or steroids) for serum cytokine estimation and PBMC stimulation assays, and lesional (reactional) skin biopsy for cytokine messenger RNA (mRNA) estimation. Thirty-two cases of T1R were recruited (23 patients completed follow-up). Serum levels of cytokines were not significantly different between cases and controls or between pre- and post-treatment samples. Tissue mRNA and Mycobacterium leprae (M. leprae) antigen-stimulated PBMC culture supernatant levels of Interleukin (IL)-17A, IL-17F, IL-6, and IL-23 were significantly higher in T1R than in controls. Levels of IL-10 and Transforming Growth Factor-beta (TGF-β) were comparable among the two groups. The levels of all cytokines were significantly reduced after treatment. There was no significant difference in magnitude of the fall between those treated with steroids versus NSAIDs. This study suggests heightened Th17 response in T1R, with a prominent inability of the regulatory cytokines IL-10 and TGF-β to control the associated inflammation. The dynamics of change after resolution of T1R were comparable between NSAID and oral steroid treatment groups.

Senescence-related genes are associated with the immunopathology signature of American tegumentary leishmaniasis lesions and may predict progression to mucosal leishmaniasis.

The American tegumentary leishmaniasis (ATL) is caused by protozoans of the genus Leishmania and varies from mild localized cutaneous leishmaniasis (LCL) form to more severe manifestations such as the diffuse cutaneous leishmaniasis (DCL) form and the mucosal leishmaniasis (ML) form. Previously, we demonstrated the accumulation of senescent cells in skin lesions of patients with LCL. Moreover, lesional transcriptomic analyses revealed a robust co-induction of senescence and pro-inflammatory gene signatures, highlighting the critical role of senescent T cells in orchestrating pathology. In this work we hypothesized that senescent cells might operate differently among the ATL spectrum, potentially influencing immunopathological mechanisms and clinical outcome. We analysed previously published RNA-Seq datasets of skin biopsies of healthy subjects and lesional skin from DCL patients, LCL patients, and LCL patients that, after treatment, progressed to mucosal leishmaniasis (MLP). Our findings demonstrate a robust presence of a CD8 T-cell signature associated with both LCL and MLP lesions. Moreover, both inflammatory and cytotoxic signatures were significantly upregulated, showing a strong increase in MLP and LCL groups, but not DCL. The senescence signature was elevated between LCL and MLP groups, representing the only distinguishable signature of immunopathology between them. Interestingly, our analyses further revealed the senescence signature's capacity to predict progression from LCL to mucosal forms, which was not observed with other signatures. Both the senescence-signature score and specific senescence-associated genes demonstrated an increased capacity to predict mucosal progression, with correct predictions exceeding 97% of cases. Collectively, our findings contribute to a comprehensive understanding of immunosenescence in ATL and suggest that senescence may represent the latest and most important signature of the immunopathogenisis. This highlights its potential value in predicting disease severity.

Impact of skin biopsy practices: A comprehensive nationwide study on skin cancer and melanoma biopsies.

Due to a multitude of factors, skin cancer incidence is increasing and challenges medical professionals in biopsy decision-making. While skin cancer may have a profound impact on the patient and be costly for society, there is little knowledge about the number and cost of benign skin lesions biopsied as collateral damage. This study evaluates the number and costs of skin biopsies in Denmark over 15 years, focusing on benign and malignant skin lesions and melanomas across medical settings. It aims to determine the benign to malignant ratio (BMR) and number needed to biopsy (NNB) and estimate the direct cost of benign skin lesion biopsies in the Cancer Pathway from the perspective of a public healthcare system. The study included 4,481,207 biopsy specimens from January 2007 to June 2022 from the Danish Pathology Data Bank, of which 151,988 from the Cancer Pathway were included in the primary analysis of BMR. The national reimbursement rates for biopsies were used, alongside histopathological examination costs extracted from several pathology departments, for a Monte-Carlo simulation of a simple cost and sensitivity analysis. The number of biopsies increased by 39.1% from 2007 to 2021. Overall BMR for malignancy was 4.1:1, and NNB for melanoma was 31.8, but biopsies performed on clinical suspicion of malignancy or melanoma had a BMR and NNB of 1.5:1 and 2.8, respectively. The cost of benign skin biopsies performed on suspicion of cancer or melanoma in 2021 was €6.6M, predominantly in hospitals. A healthcare system that employs filtering functions before biopsy of skin lesions can achieve some of the lowest BMR reported in the world, but with most benign skin lesion excisions due to suspicion of malignancy performed in the expensive hospital setting. Including clinical reason for biopsy in diagnostic accuracy studies using NNB is crucial.

Distinct Variations in Gene Expression and Cell Composition across Lichen Planus Subtypes.

Lichen planus (LP) is a highly prevalent inflammatory skin disease. While various clinical subtypes have been defined, detailed comparisons of these variants are lacking. This study aimed to elucidate differences in gene expression and cellular composition across LP subtypes. Lesional skin biopsies from 28 LP patients (classical, oral, genital, and lichen planopilaris) and seven non-diseased skin controls (NDC) were analyzed. Gene expression profiling of 730 inflammation-related genes was conducted using NanoString. Immune cell compositions were assessed by multiplex immunohistochemistry. Gene expression profiles revealed unique inflammatory signatures for each LP subtype. Lichen planopilaris exhibited the most divergence, with downregulated gene expression and upregulation of complement pathway genes (C5-7), along with elevated M2 macrophages. Oral and genital LP demonstrated similar profiles with strong upregulation of TNF-related and Toll-like receptor-associated genes. Oral LP showed the highest upregulation of cytotoxicity-associated genes, as well as high numbers of CD8+ IL-17A+ (Tc17) cells (8.02%). Interferon gene signatures were strongly upregulated in oral and classical LP. The study highlights distinct differences in inflammatory gene expression and cell composition across LP subtypes, emphasizing the need for tailored therapeutic approaches.

Association between Vitamin D Receptor Polymorphisms, Tight Junction Proteins and Clinical Features of Adult Patients with Atopic Dermatitis.

Few studies have explored the intricate connections between vitamin D receptor (VDR) gene polymorphisms, VDR, tight junction (TJ) protein expression and clinical features of atopic dermatitis (AD). From 43 adult AD patients, VDR polymorphisms were genotyped from peripheral blood samples using polymerase chain reaction-restriction fragment length polymorphism. VDR, occludin, claudin-1 and ZO-1 protein expression from skin lesion biopsies were assessed by immunohistochemistry. The A1012G heterozygous VDR polymorphism exhibited a lower odds ratio (OR) for juvenile AD onset (OR: 0.046, 95% CI 0.004-0.51, p=0.012). In contrast, the presence of ≥2 homozygous VDR polymorphisms were significantly associated with positive skin prick test (SPT) (10/20, 50%) vs. negative SPT (1/23, 4.3%; p=0.0003). The most highly expressed TJ proteins in lesions of AD patients were claudin-1 and zonulin-1 (ZO-1), while VDR and occludin were less prevalent. A significant correlation was observed between ZO-1 expression and a body mass index ≥30 kg/m2 (OR: 12.1, 95% CI 1.06-137.9, p=0.045). Claudin-1 expression was associated with a positive SPT (OR: 8.23, 95% CI 1.04-65.5, p=0.046) and serum 25(OH)D levels were negatively correlated with ZO-1 expression (rho= -0.43, p=0.0058). This study provides novel insights into the relationship between VDR gene polymorphisms, VDR, TJ protein expression, and clinical features in adult AD patients, highlighting a significant role of vitamin D in the pathophysiology of this disease.

Lymphocytic Variant of Triple-Negative Breast Cancer Carcinoma Erysipeloides: A Rare Case of Carcinoma Erysipeloides Following TNBC Mastectomy

Background: Carcinoma erysipeloides (CE) is a rare but significant cutaneous manifestation of metastatic breast cancer, often misdiagnosed due to its rarity and nonspecific presentation. This is particularly true in patients with triple-negative breast cancer (TNBC), where the disease may progress undetected by conventional imaging modalities. This manuscript aims to elucidate the challenges and implications of diagnosing CE in breast cancer survivors, emphasizing the insufficiency of PET scans in detecting such cutaneous metastases and the potential for mismanagement due to diagnostic oversight. Case Presentation: We present a detailed case study of a 43-year-old female with a history of metastatic TNBC, who developed suspicious skin lesions post-treatment. Despite initial negative PET scan results, further investigations revealed CE through histopathological examination of skin biopsies. The case highlights the critical need for biopsy in the presence of new skin lesions in breast cancer survivors, irrespective of imaging results. It also underscores the possibility of lymphatic spread of CE, which could lead to life-threatening complications if not properly managed. Conclusion: The diagnosis of carcinoma erysipeloides must be considered in patients with breast cancer presenting with unusual skin lesions. Increased vigilance and dermatological assessment should be integral to the post-cancer follow-up regimen. The findings advocate for revising current treatment protocols and guidelines to better manage and potentially prevent the complications associated with this diagnosis. Enhanced surveillance for dermatological changes and a more aggressive approach to the biopsy of new skin lesions in cancer patients are recommended to improve outcomes and prevent the misdiagnosis of CE.

Elevated cutaneous expression of stem cell factor in chronic spontaneous urticaria: a prospective cohort study.

Tissue expression of endothelial cell markers of microcirculatory changes in chronic spontaneous urticaria (CSU) is poorly understood. To explore the expression of specific endothelial cell markers [stem cell factor (SCF), vascular endothelial growth factor (VEGF) and membrane attack complex (MAC)] in lesional and nonlesional CSU skin through immunohistochemistry (IHC) and in serum. Lesional and nonlesional skin biopsies from patients with CSU (n = 23) and healthy controls (n = 9) were studied by IHC for expression of SCF, VEGF and MAC. In this population, we also investigated blood levels of VEGF and SCF. Patients were also assessed for clinical characteristics, disease activity and markers of autoimmune CSU. The study was registered at ClinicalTrials.gov (NCT03443362). Epidermal SCF reactivity was significantly higher in CSU lesional skin than in healthy skin (P = 0.026). In the dermis, SCF immunoreactivity was seen particularly in endothelial, perivascular and epithelial cells. In CSU lesional skin, the mean perivascular SCF staining was significantly more intense than in healthy controls (P < 0.001). Furthermore, CSU nonlesional skin also showed significantly higher SCF staining in dermal perivascular cells than in healthy controls (P < 0.001). Patients with CSU had the highest SCF immunoreactivity scores in the epidermis and/or on dermal endothelial cells. These patients did not have significantly higher SCF serum levels. To our knowledge, this is the first study to show elevated cutaneous expression of SCF in CSU. These findings underline the potential therapeutic possibilities of anti-Kit antibodies in CSU treatment.

Digital Ulceration in a Patient with Interstitial Lung Disease: An Unusual Case of Microscopic Polyangiitis

OBJECTIVES Microscopic polyangiitis (MPA) is part of the associated vasculitis family of the neutrophil cytoplasmic antibody (ANCA). MPA can be distinguished by its positivity for antibodies against myeloperoxidase (MPO-ANCA). The condition can involve any organ of the body, particularly the lungs, kidneys, and skin. This case highlights an atypical case of MPA in which a patient had interstitial lung disease (ILD) and later developed a vasculitic skin lesion without renal involvement. A 65-year-old female already diagnosed with ILD was evaluated for digital ulcers associated with bilateral pins and needle sensation in both upper and lower limbs. Examination revealed lesions on the index and middle finger of the left hand. The MPO-ANCA antibody test was positive, and a diagnosis of MPA was made based on a skin lesion biopsy. There was subsequent initiation of combination therapy consisting of azathioprine, hydroxychloroquine, prednisolone, and nifedipine. The patient was instructed for close follow-up. This case report highlights the importance of considering an underlying vasculitis in patients with ILD and emphasizes the significance of a thorough diagnostic evaluation and multidisciplinary management. This case also highlights that patients with interstitial lung diseases should be evaluated for secondary causes, and early treatment of the exact causes can prevent the late sequelae of the disease, such as skin manifestations in this patient.

Estimation of the tissue and serum levels of IL-35 in Mycosis fungoides: a case-control study

Mycosis fungoides (MF) is the most common primary cutaneous T-cell lymphoma (CTCL) with its etiology not yet fully understood. Interleukin (IL)-35 is an inhibitory cytokine that belongs to the IL-12 family. Elevated IL-35 in the plasma and the tumor microenvironment increases tumorigenesis and indicates poor prognosis in different types of malignancies. The objective of this study is to estimate the expression levels of IL-35 in tissue and serum of MF patients versus healthy controls. This case-control study included 35 patients with patch, plaque, and tumor MF as well as 30 healthy controls. Patients were fully assessed, and serum samples and lesional skin biopsies were taken prior to starting treatment. The IL-35 levels were measured in both serum and tissue biopsies by ELISA technique. Both tissue and serum IL-35 levels were significantly higher in MF patients than in controls (P < 0.001) and tissue IL-35 was significantly higher than serum IL-35 in MF patients (P < 0.001). Tissue IL-35 was significantly higher in female patients and patients with recurrent MF compared to male patients and those without recurrent disease (P < 0.001). Since both tissue and serum IL-35 levels are increased in MF, IL-35 is suggested to have a possible role in MF pathogenesis. IL-35 can be a useful diagnostic marker for MF. Tissue IL-35 can also be an indicator of disease recurrence.

Clinical polymorphism of zoonotic cutaneous leishmaniasis: combination of the clinical and the parasitological diagnosis.

Zoonotic cutaneous leishmaniasis (ZCL) is a neglected tropical disease caused by Leishmania (L.) major. This zoonosis is characterized by a broad-spectrum clinical polymorphism and may be underestimated and poorly treated since it is a simulator of various dermatoses. The aim of our study was to analyze the clinical polymorphism of patients with ZCL. A total of 142 patients with confirmed CL based on the microscopic examination of skin lesion biopsies were included in this study. Molecular typing of Leishmania species revealed that all patients were infected with L. major.In total, 14 clinical formswere observed. Six were typical and eight were atypical. The typical ZCL forms are grouped as follows: papular (26.76%), ulcero-crusted (26.05%), ulcerated (13.38%), impetiginous (9.86%), nodular (9.15%), and papulo-nodular (5.63%) lesions. In atypical ZCL forms, we described erythematous (2.81%), erysipeloid (1.4%), sporotrichoid, (1.4%), keratotic (0.7%) lupoid (0.7%), lichenoid (0.7%), psoriasiform (0.7%), and zosteriform (0.7%) lesions. Here, the lichenoid and the keratotic forms caused by L. major were reported for the first time in Tunisia. These findings will help physicians to be aware of the unusual lesions of ZCL that could be confused with other dermatological diseases. For this reason, it will be necessary to improve the diagnosis of CL especially in endemic areas. Such large clinical polymorphism caused by L. major may be the result of a complex association between the vector microbiota, the parasite, and the host immune state, and further studies should be carried out in order to reveal the mechanisms involved in clinical polymorphism of ZCL.

Eosinophilic Cellulitis (Well’s Syndrome) and Eosinophilic Granulomatosis with Polyangiitis (Churgg-strauss Syndrome); Different Clinical Entities, or a Single Spectrum of Disease? A Case Study, Discussion and Literature Review

This case study represents an unusual presentation female in her seventies who presented with a chronic eosinophilic rash without systemic involvement on a background of psoriatic arthritis (pSA) and Sjogren’s Syndrome (sSS). Biopsy of the lesions identified flame figures. The differentials for such lesions are wide, however this case discusses three of the most likely differentials including Eiosinophilic Cellulitis (Well’s Syndrome), Eosionophilic Granlomatosis with Polyangiitis (Churgg Strauss Syndrome) and Granulomatous Dermatitis (GD). A common aberrant eiosinophilic response is dicussed and a review of the literature identifies the possibility that these diagnoses represent a single spectrum of disease, rather than separate clinical entities. Whilst the provoking incident was not able to be established in this case, the possibility of covid-19 vaccination contributing to the development of lesions is discussed. This case highlights the importance of conducting skin biopsies of unusual lesions that do not follow an expected clinical course and that skin biopsies might need to be performed opportunistically by emergency departments especially in rural areas where dermatology services are lacking. A lack of knowledge of various complex systemic diseases that present with unusual skin lesions often results in missed diagnosis and delayed patient care. Education of primary care physicians and healthcare professionals working in emergency departments is required to ensure timely biopsy and appropriate serology with screening for underlying systemic diseases including malignancy is required to prevent missed diagnosis and delayed care.

O22 Unravelling the pathophysiology of KLICK syndrome to identify therapeutically targetable pathways

Abstract Introduction and aims Keratosis linearis with ichthyosis congenita and sclerosing keratoderma (KLICK) syndrome is an ultrarare genodermatosis associated with a homozygous pathogenic variant, c.-95delC in POMP, which encodes for proteasome maturation protein. Clinical manifestations include linear hyperkeratotic papules in the flexures, palmoplantar keratoderma and pseudoainhum. The pathophysiology of KLICK syndrome is poorly understood, resulting in nonspecific, limited treatment options. The aim of this work is to characterize KLICK syndrome at the cellular and molecular level, with the utilization of transcriptomic techniques for potential drug repurposing. Methods A lesional skin biopsy was obtained, following informed consent, from a 32-year-old female patient with KLICK syndrome. Histology and immunostaining were used to characterize the disrupted skin architecture. RNA sequencing was used to identify key dysregulated pathways and the L1000FWD reverse transcriptomics tool enabled the generation of a shortlist of potential therapeutics for KLICK syndrome. CRISPR editing techniques and induced pluripotent stem cell (iPSC) reprogramming Methods were used to generate cellular based models carrying the pathogenic POMP variant in order to support evaluation of the shortlisted therapeutic options. Results KLICK syndrome skin histology featured hyperkeratosis, hypergranulosis and delayed cellular flattening. Consistent with pathological features, pathway analysis of transcriptomic data revealed keratinocyte differentiation and epidermis development as key upregulated pathways in KLICK syndrome. Interestingly, the Panther pathway analysis tool suggested dysregulation in epidermal growth factor receptor (EGFR) signalling, and reverse transcriptomics identified erlotinib, an EGFR inhibitor, as a potential therapeutic treatment for KLICK syndrome. HaCaT keratinocytes were successfully edited using CRISPR-Cas9 to carry the KLICK patient POMP variant and a KLICK patient iPSC line was generated to support in vitro KLICK syndrome modelling. Conclusions KLICK syndrome is a hyperproliferative inflammatory skin disorder associated with a pathogenic variant in POMP. Reverse transcriptomics is a useful tool for shortlisting drugs with biologically relevant mechanisms of action with potential for treatment of rare genetic diseases such as KLICK syndrome.

Inhibition of RNase 7 by RNase inhibitor promotes inflammation and Staphylococcus aureus growth: Implications for atopic dermatitis.

The antimicrobial ribonuclease RNase 7 is abundantly expressed in the epidermis of lesional skin of atopic dermatitis (AD). Host RNase inhibitor (RI) binds to RNase 7 and blocks its ribonuclease activity. This study aimed to evaluate the impact of RNase 7-RI interactions on AD. Cultured human primary keratinocytes, with siRNA-mediated downregulation of RNase 7 and RI, were stimulated with the synthetic RNA polyinosinic-polycytidylic acid (poly I:C). Induction of proinflammatory mediators was analyzed by real-time PCR and ELISA. RI expression in AD non-lesional and lesional skin biopsies and healthy controls was analyzed by real-time PCR and immunostaining. RI protein release invivo on the AD skin surface was determined by western blot. Antimicrobial and ribonuclease assays were used to investigate the functional role of RI. RNase 7 inhibited the RNA-induced expression of proinflammatory mediators in keratinocytes. Accordingly, downregulation of RNase 7 in keratinocytes enhanced RNA-mediated induction of proinflammatory mediators, whereas downregulation of RI had the opposite effect. RI was released by damaged keratinocytes and epidermis. Invivo expression and release of RI on the skin surface were enhanced in lesional AD skin. Rinsing solution from the surface of lesional AD skin blocked the ribonuclease activity of RNase 7. The anti-Staphylococcus aureus activity of RNase 7 was abrogated by RI. Our data suggest a novel role of RI as a trigger factor of inflammation in AD by blocking the ribonuclease and antimicrobial activity of RNase 7, thereby enhancing RNA-mediated inflammation and S. aureus growth.

Dermoscopic structures and patterns used in melanoma detection.

Melanoma is the leading cause of skin cancer-related deaths. Yet, early detection remains the most cost-effective means of preventing death from melanoma. Early detection can be achieved by a physician and/or the patient (also known as a self-skin exam). Skin exams performed by physicians are further enhanced using dermoscopy. Dermoscopy is a non-invasive technique that allows for the visualization of subsurface structures that are otherwise not visible to the naked eye. Evidence demonstrates that dermoscopy improves the diagnostic accuracy for skin cancer, including melanoma; it decreases the number of unnecessary skin biopsies of benign lesions and improves the benign-to-malignant biopsy ratio. Yet, these improvements are contingent on acquiring dermoscopy training. Dermoscopy is used by clinicians who evaluate skin lesions and perform skin cancer screenings. In general, under dermoscopy nevi tend to appear as organized lesions, with one or two structures and colors, and no melanoma-specific structures. In contrast, melanomas tend to manifest a disorganized pattern, with more than two colors and, usually, at least one melanoma-specific structure. This review is intended to familiarize the reader with the dermoscopic structures and patterns used in melanoma detection.