Skin Biopsies Of Patients Research Articles

The Spectrum of Cutaneous Granulomatous Inflammation and Detection of Rubella Virus in Skin Biopsies of Patients With Common Variable Immune Deficiency.

There is a known association between common variable immunodeficiency (CVID) and granulomas in multiple organ systems, including the skin, lung, liver, and spleen. Rubella virus has also been detected within cutaneous granulomas in both immunocompetent and immunocompromised hosts. We present a retrospective case series of patients with CVID and granulomatous skin disease and describe the spectrum of clinical and histopathologic features, including the status of rubella virus in the cutaneous granulomas. We retrospectively reviewed the clinical and histopathological characteristics of patients diagnosed with CVID at our institution, with cutaneous findings and skin biopsies available for review between 1990 and 2023, demonstrating granulomatous inflammation. Eight patients met the inclusion criteria. The most common histopathologic pattern was palisaded granulomatous inflammation, seen in five of eight cases. Three cases showed strictly sarcoidal granulomas. Background inflammation was peri-granulomatous (8/8) and the predominant background inflammatory cell type was lymphocytic (6/8). Rubella virus testing was performed for seven of eight cases and found to be positive in one case. Cutaneous granulomatous disease in CVID can present with a spectrum of clinical morphologies, granulomatous patterns, and variable rubella virus persistence. Dermatopathologists should be aware of the spectrum of findings when considering cutaneous CVID-related granulomatous disease in the differential diagnosis.

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.

Features of Vacuoles, E1 enzyme, X-linked, autoinflammatory, and somatic mutation syndrome associated with the c.121A&amp;gt;C, p.(Met41Leu) UBA1 genetic variant: A systematic review

Abstract Introduction/Objective Vacuoles, E1 enzyme, X-linked, autoinflammatory, and somatic mutation (VEXAS) syndrome was first described in 2020. VEXAS is driven by a mutation in the UBA1 gene on hematopoietic progenitor cells that encodes the E1 ubiquitin-activating protein. Loss of this protein leads to various inflammatory clinical presentations ranging from dermatological, pulmonary, rheumatologic and hematologic. Many UBA1 variants have been identified. We did a systematic review focusing on a particular UBA1 variant gene mutation underlying this disease process. Methods/Case Report Databases were searched for articles discussing VEXAS syndrome until April 2024. Only case reports and case series in the English language were included. Data on patient demographics, clinical presentation, laboratory values, bone marrow findings, dermatologic presentation and skin biopsy findings were extracted. Results (if a Case Study enter NA) 332 articles discussing VEXAS syndrome were retrieved, of which 115 were case reports or case series. These were screened for patients carrying a p.Met41Leu UBA1 gene mutation and only the 25 patients with this genetic variant were ultimately included in our study. The average age was 68 years (59-81 years). 24/25 (96%) patients reported dermatologic symptoms ranging from erythema to urticarial eruptions to erythema multiforme. Fever was the second most common presenting complaint (76%) followed by arthritis (68%), chondritis (36%) and thromboembolic disease (28%). Macrocytic anemia was a common laboratory finding (65%). MDS was seen in 52% of the patients. All patients had hematopoietic progenitor cells with vacuoles. Sweet’s syndrome was the most common initial diagnosis (52%) as skin biopsies in most patients showed dermal edema and neutrophilic dermatoses/infiltration. Conclusion The c.121A&amp;gt;C, p.(Met41Leu) UBA1 variant is frequently related to cutaneous manifestations. In patients with clinical features of an inflammatory disorder with dermatological and hematologic abnormalities, testing for the p.Met41Leu UBA1 mutation might lead to an earlier diagnosis and prompt initiation of effective treatment.

Differences in corneal nerve fiber density and fiber length in patients with painful chronic idiopathic axonal polyneuropathy and diabetic polyneuropathy.

Corneal confocal microscopy (CCM) detects small nerve fiber loss and correlates with skin biopsy findings in diabetic neuropathy. In chronic idiopathic axonal polyneuropathy (CIAP) this correlation is unknown. Therefore, we compared CCM and skin biopsy in patients with CIAP to healthy controls, patients with painful diabetic neuropathy (PDN) and diabetics without overt neuropathy (DM). Participants with CIAP and suspected small fiber neuropathy (n = 15), PDN (n = 16), DM (n = 15), and healthy controls (n = 16) underwent skin biopsy and CCM testing. Inter-center intraclass correlation coefficients (ICC) were calculated for CCM parameters. Compared with healthy controls, patients with CIAP and PDN had significantly fewer nerve fibers in the skin (IENFD: 5.7 ± 2.3, 3.0 ± 1.8, 3.9 ± 1.5 fibers/mm, all p < .05). Corneal nerve parameters in CIAP (fiber density 23.8 ± 4.9 no./mm2, branch density 16.0 ± 8.8 no./mm2, fiber length 13.1 ± 2.6 mm/mm2) were not different from healthy controls (24.0 ± 6.8 no./mm2, 22.1 ± 9.7 no./mm2, 13.5 ± 3.5 mm/mm2, all p > .05). In patients with PDN, corneal nerve fiber density (17.8 ± 5.7 no./mm2) and fiber length (10.5 ± 2.7 mm/mm2) were reduced compared with healthy controls (p < .05). CCM results did not correlate with IENFD in CIAP patients. Inter-center ICC was 0.77 for fiber density and 0.87 for fiber length. In contrast to patients with PDN, corneal nerve parameters were not decreased in patients with CIAP and small nerve fiber damage. Therefore, CCM is not a good biomarker for small nerve fiber loss in CIAP patients.

A-222 Flow cytometry of skin biopsies in CTCL patients during Mogamulizumab treatment

A-222 Flow cytometry of skin biopsies in CTCL patients during Mogamulizumab treatment

Microbiome characterization of skin biopsies in Spanish patients with hidradenitis suppurativa shows a decrease in D1 and H1 lineages of Cutibacterium acnes.

Hidradenitis suppurativa (HS) is a chronic inflammatory skin disorder, with dysbiosis and loss of Cutibacterium acnes commonly observed in affected skin. This study analysed the microbiome of lesional, perilesional and healthy skin samples, and found significant differences, including increased Mycoplasma and Bacillus in lesional skin. The reduction of Cutibacterium variants D1 and H1 in HS-affected skin highlights their potential as therapeutic targets, suggesting a strategy of topical replacement therapy.

Overexpression of BAG3 (Bcl2-associated athanogene 3) in serum and skin of patients with systemic sclerosis.

BAG3 (Bcl2-associated athanogene3) is able to induce the transformation of cancer-associated fibroblasts to alpha smooth muscle actin (a-SMA) positive (+) myofibroblasts. In systemic sclerosis (SSc), a-SMA+ myofibroblasts also play an important role in the progression of fibrosis in the skin and involved internal organs. The aim of the study was to investigate whether BAG3 is overexpressed in SSc and may be a biomarker of fibrogenesis. BAG3 serum levels were measured in 106 patients with SSc, 47 with the limited (lc) and 59 the diffuse (dc) SSc, and in age- and sex-matched healthy controls (HC). BAG3 levels were then compared according to their clinical subset, nailfold video-capillaroscopic (NVC) patterns, interstitial lung disease (ILD, and correlated with modified Rodnan skin score (mRSS) and global disease activity. BAG3 expression was also investigated in skin biopsies of 8 dcSSc patients. BAG3 serum levels were significantly higher in dcSSc (143.3 pg/mL, 95%CI 78-208.5) than in HC (0.68 pg/mL, 95%CI 0.13-1.23), and were significantly higher in patients with late NVC pattern and ILD but did not correlate with disease activity and mRSS. Of note, BAG3 was strongly expressed in the skin biopsies of dcSSc patients. BAG3 is overexpressed in dcSSc patients and may contribute to skin and organ fibrosis by prompting the transition of fibroblasts into myofibroblasts and increasing their survival. Thus, BAG3 may play an important role in SSc fibrotic pathogenesis and be a potential biomarker of fibrosis. Further research on its role as a therapeutic target is warranted.

A decision support system for the detection of cutaneous fungal infections using artificial intelligence

Cutaneous fungal infections are one of the most common skin conditions, hence, the burden of determining fungal elements upon microscopic examination with periodic acid-Schiff (PAS) and Gomori methenamine silver (GMS) stains, is very time consuming. Despite some morphological variability posing challenges to training artificial intelligence (AI)-based solutions, these structures are favored potential targets, enabling the recruitment of promising AI-based technologies. Herein, we present a novel AI solution for identifying skin fungal infections, potentially providing a decision support system for pathologists. Skin biopsies of patients diagnosed with a cutaneous fungal infection at the Sheba Medical Center, Israel between 2014 and 2023, were used. Samples were stained with PAS and GMS and digitized by the Philips IntelliSite scanner. DeePathology® STUDIO fungal elements were annotated and deemed as ground truth data after an overall revision by two specialist pathologists. Subsequently, they were used to create an AI-based solution, which has been further validated in other regions of interests. The study participants were divided into two cohorts. In the first cohort, the overall sensitivity of the algorithm was 0.8, specificity 0.97, F1 score 0.78; in the second, the overall sensitivity of the algorithm was 0.93, specificity 0.99, F1 score 0.95. The results obtained are encouraging as proof of concept for an AI-based fungi detection algorithm. DeePathology® STUDIO can be employed as a decision support system for pathologists when diagnosing a cutaneous fungal infection using PAS and GMS stains, thereby, saving time and money.

Metagenomics reveals unique gut mycobiome biomarkers in psoriasis.

In present, the diagnosis of psoriasis is mainly based on the patient's typical clinical manifestations, dermoscopy and skin biopsy, and unlike other immune diseases, psoriasis lacks specific indicators in the blood. Therefore, we are required to search novel biomarkers for the diagnosis of psoriasis. In this study, we analyzed the composition and the differences of intestinal fungal communities composition between psoriasis patients and healthy individuals in order to find the intestinal fungal communities associated with the diagnosis of psoriasis. We built a machine learning model and identified potential microbial markers for the diagnosis of psoriasis. The results of AUROC (area under ROC) showed that Aspergillus puulaauensis (AUROC=0.779), Kazachstania africana (AUROC=0.750) and Torulaspora delbrueckii (AUROC=0.745) had high predictive ability (AUROC>0.7) for predicting psoriasis, While Fusarium keratoplasticum (AUROC=0.670) was relatively lower (AUROC<0.7). The strategy based on the prediction of intestinal fungal communities provides a new idea for the diagnosis of psoriasis and is expected to become an auxiliary diagnostic method for psoriasis.

Differential Pharmacodynamic Effects on Psoriatic Biomarkers by Guselkumab Versus Secukinumab Correlate with Long-Term Efficacy: An ECLIPSE Substudy

IL-23 is a cytokine produced by myeloid cells that drives the T helper 17 pathway and plays an essential role in the pathophysiology of plaque psoriasis. IL-23 activation initiates a cascade of cytokines subsequently inducing the expression of many psoriasis-related proteins. This study aimed to better understand the underlying mechanisms driving the differences between IL-23 and IL-17A blockade in patients with psoriasis and their implications for durability of clinical responses. Serum and/or skin biopsies were isolated from patients treated with guselkumab or secukinumab for evaluation of potential biomarkers of pharmacodynamic response to treatment. Guselkumab treatment led to significantly greater reductions of IL-17F and IL-22 serum levels than treatment with secukinumab at weeks 24 and 48, demonstrating sustained regulation of the IL-23/T helper 17 pathway. Analyses of proteomic and transcriptomic profiles of patient sera and skin biopsies demonstrated differential regulation of proteins involved in chemokine, TNF, and relevant immune signaling pathways to a greater degree with guselkumab than with secukinumab treatment. These data provide insights into the differences between the mechanisms and impact of IL-23 and IL-17A blockade in psoriasis, with implications for efficacy observations and treatment paradigms. Trial Registration: The original study was registered at ClinicalTrials.gov (NCT03090100).

Which factors influence Demodex mite density in standardized superficial skin biopsy in patients with rosacea? A prospective cross-sectional analysis.

Rosacea is a chronic cutaneous disease that manifests with facial erythema, telangiectasia, papules and pustules on the central face. Although the pathogenesis is not well established, rosacea appears to have a close relationship with Demodex mites. The aim of the study was to elucidate the factors influencing Demodex mite density by standardized superficial skin biopsy (SSSB) in patients with rosacea. This prospective, cross-sectional study included 200 patients with rosacea. Clinical characteristics of the patients were recorded and SSSB was used to measure Demodex density (Dd). If Dd was < 5 D/cm2 in the first SSSB, SSSB was repeated 4 more times to avoid false negative results. Of 200 patients, 152 (76%) were females and 48 (24%) males with a mean age of 43.47 ± 11.87 years. Ninety-nine patients (49.5%) had erythematotelangiectatic (ETR) and 101 patients (50.5%) had papulopustular (PPR) subtype of rosacea. Among 200 patients, the ratio of cumulative positive results of the consecutive SSSBs were as follows: 1st SSSB = 125 (62.5%), 2nd SSSB = 155 (77.5%), 3rd SSSB = 170 (85%), 4th SSSB = 173 (86.5%) and 5th SSSB = 174 (87%). The ratio of detecting Demodex infestation in the first SSSB was significantly lower in patients with PPR (55/101, 54.5%) than in patients with ETR (70/99, 70.7%). Median total Demodex mite density and D. folliculorum density were significantly higher in the ETR group than in the PPR group. There was a statistically significant relationship between density of Demodex tails in dermoscopy and positive/negative results of Demodex infestation in SSSB. As a conclusion, Demodex mite density by SSSB was influenced by various factors such as subtypes of rosacea, types of Demodex species, and dermoscopic findings.

ATP2C1 knockdown induces abnormal expressions of cytoskeletal and tight junction proteins mimicking Hailey-Hailey disease.

Background Hailey-Hailey disease (HHD) is a rare, autosomal dominant, hereditary skin disorder characterised by epidermal acantholysis. The HHD-associated gene ATPase calcium-transporting type 2C member 1 (ATP2C1) encodes the protein secretory pathway Ca2+ ATPase1 (SPCA1), playing a critical role in HHD pathogenesis. Aims We aimed to investigate the effect of ATP2C1 knockdown on keratinocytes that mimicked acantholysis in HHD. Methods Immunohistochemistry (IHC) was employed to evaluate the levels of cytoskeletal and tight junction proteins such as SPCA1, P-cofilin, F-actin, claudins, occludin, and zonula occludens 1 in the skin biopsies of patients with HHD. Subsequently, the expression of these proteins in cultured ATP2C1 knockdown keratinocytes was analysed using Western blotting and immunofluorescence. Furthermore, we assessed the proliferation, apoptosis, and intracellular Ca2+ concentrations in the ATP2C1-knocked keratinocytes. Results The results showed decreased levels of these proteins (SPCA1, P-cofilin, F-actin, claudins, occluding, and zonula occludens 1) in HHD skin lesions. Moreover, their levels decreased in human keratinocytes transfected with ATP2C1 short hairpin RNA, accompanied by morphological acantholysis. Furthermore, the proliferation and apoptosis of the keratinocytes, as well as intracellular calcium concentrations in these cells, were not affected. Limitations The limitations of this study are the absence of animal experiments and the failure to explore the relationship between skeletal and tight junction proteins. Conclusion The present study indicated that ATP2C1 inhibition led to abnormal levels of the cytoskeletal and tight junction proteins in the keratinocytes. Therefore, keratinocytes can mimic HHD-like acantholysis and serve as an in vitro model, helping develop treatment strategies against HHD.

VEXAS syndrome: Focus on dermatological manifestations and their histopathological correlate

AbstractBackgroundVEXAS ‘Vacuoles, E1 Enzyme, X‐linked, Autoinflammatory, Somatic syndrome’ is a rare autoinflammatory syndrome, first described in October 2020 by Beck et al. It is caused by somatic mutations in the UBA1 gene, coding for the E1 enzyme, responsible for ubiquitination. It manifests in adulthood, mainly in men, with constitutional symptoms, haematological abnormalities and often skin lesions with neutrophilic dermatoses most frequently reported. Since skin lesions are a frequent and early manifestation, recognising these may prove very useful for diagnosis.ObjectivesTo focus on the dermatological manifestations of VEXAS and their histopathological correlate.MethodsWe retrospectively collected data and revised skin biopsies of VEXAS patients diagnosed in our tertiary care centre, and compared those with the literature.ResultsWe identified nine men between 62 and 84 years old. The most frequently encountered UBA1 mutation was p.Met41Thr. Skin manifestations occurred in all patients; mostly as erythematous to purpuric papules/plaques, often with annular pattern. Histopathological, early VEXAS lesions showed a gradient in infiltrate with neutrophils being concentrated in the superficial interstitium and lymphocytes situated deeper around the blood vessels. Later in the disease course, the pattern became more variable and less specific with more nuclear debris, histiocytes, neutrophils and ulceration. Haematological and constitutional manifestations were present in all patients, followed by musculoskeletal (88.8%), eye (77.7%) and cardiovascular manifestations (66.6%). Polychondritis was present in 6/9 (66.6%) patients, as were respiratory symptoms, though only 33.3% had proven lung disease. The mortality rate was 22% 10 months after diagnosis.ConclusionsThis is the first cohort which describes in detail VEXAS skin manifestations with revision of all available skin biopsies, which led to the conclusion that early histopathological abnormalities in VEXAS syndrome may be easy to recognise, while the histopathological image becomes less specific over time and mimics other diseases as VEXAS progresses.

A deep learning approach for Direct Immunofluorescence pattern recognition of Autoimmune Bullous Diseases.

Artificial intelligence (AI) is reshaping healthcare, using machine and deep learning to enhance disease management. Dermatology has seen improved diagnostics, particularly in skin cancer detection, through the integration of AI. However, the potential of AI in automating immunofluorescence imaging for autoimmune bullous skin diseases remains untapped. While direct immunofluorescence (DIF) supports diagnosis, its manual interpretation can hinder efficiency. The use of deep learning to automatically classify DIF patterns, including the Intercellular Pattern (ICP) and the Linear Pattern (LP), holds promise for improving the diagnosis of autoimmune bullous skin diseases. The objectives of this study are to develop AI algorithms for automated classification of autoimmune bullous skin disease DIF patterns, such as ICP and LP. This aims to enhance diagnostic accuracy, streamline disease management, and improve patient outcomes through deep learning-driven immunofluorescence interpretation. We collected immunofluorescence images from skin biopsies of patients suspected of AIBD between January 2022 and January 2024. Skin tissue was obtained via 5-mm punch biopsy, prepared for direct immunofluorescence. Experienced dermatologists classified the images into three classes: ICP, LP, and negative. To evaluate our deep learning approach, we divided the images into training (436) and test sets (93). We employed transfer learning with pre-trained deep neural networks and conducted 5-fold cross-validation to assess model performance. Our dataset's class imbalance was addressed using weighted loss and data augmentation strategies. The models were trained for 50 epochs using Pytorch, achieving an image size of 224x224 for both CNNs and the Swin Transformer. Our study compared six CNNs and the Swin transformer for AIBDs image classification, with the Swin transformer achieving the highest average validation accuracy of 98.5%. On a separate test set, the best model attained an accuracy of 94.6%, demonstrating 95.3% sensitivity and 97.5% specificity across AIBDs classes. Visualization with Grad-CAM highlighted the model's reliance on characteristic patterns for accurate classification. The study highlighted CNN's accuracy in identifying DIF features. This approach aids automated analysis and reporting, offering reproducibility, speed, data handling, and cost-efficiency. Integrating deep learning in skin immunofluorescence promises precise diagnostics and streamlined reporting in this branch of dermatology.

Evaluation of the histopathological spectrum of skin biopsies in patients with chronic kidney disease: A single-center experience.

Patients with chronic kidney disease (CKD), particularly those with end-stage renal disease (ESRD), frequently experience skin problems. Here, we present and discuss the histopathology results of skin biopsies performed on renal patients at our facility. We retrospectively reviewed all histopathological reports and slides of skin biopsies taken from CKD patients for the last 5 years at the Pathology Department of King Saud University Medical City, King Saud University in Riyadh. This is a retrospective cross-sectional study. Patients were 19 (43.2%) males and 25 (56.8%) females, with a mean age of 53.4 19.8 years. Diabetic nephropathy, hypertensive nephropathy, and lupus nephritis were the three most common kidney pathologies (59.1%, 11.4%, and 11.4%, respectively). Seventeen patients (38.5%) were receiving hemodialysis. Acquired perforating collagenosis (APC), which was observed in 16 (36.4%) of our patients, was the most prevalent skin pathology, followed by bullous drug reactions in nine (20.5%), leukocytoclastic vasculitis (LCV) in eight (18.2%), calciphylaxis in six (13.6%), and prurigo nodularis in five (11.4%) patients. Erythematous plaques and papules were the most prevalent skin conditions at the time of presentation in 12 patients (27.3%), followed by pruritus in six (13.6%) and ulcerations in six (13.6%) patients. Collected data were analyzed using the Statistical Package for Social Sciences (SPSS) version 26.0. A spectrum of skin conditions may be seen in CKD patients. The quality of life of CKD patients will be significantly improved by identifying and managing these conditions. Pathologists' familiarity with this spectrum is important, as a correct histopathologic diagnosis will lead to a better outcome.

The NLRP3 Inflammasome Gene Is Overexpressed in Hidradenitis Suppurativa Lesions: A Preliminary Study on the Role of Pyroptosis in Disease Pathogenesis.

Hidradenitis suppurativa (HS) is a debilitating inflammatory skin disorder, and its pathogenesis remains incompletely understood. This study aimed to investigate the role of the P2X7 receptor (P2X7R) and NLRP3 inflammasome in HS pathogenesis. RNA sequencing and real-time PCR were performed to assess the gene expression levels of P2X7R and NLRP3 in the skin biopsies of HS patients and healthy controls (HC). The results of our study revealed a significantly increased expression of the NLRP3 gene in both the lesional and perilesional skin of HS patients compared to healthy controls. Moreover, the mRNA levels of NLRP3 were significantly higher in lesional skin compared to non-lesional skin in HS patients, indicating the spread of inflammation to adjacent tissues. In contrast, no significant differences in P2X7R gene expression were observed between the three groups. These findings suggest the involvement of NLRP3 inflammasomes in HS pathogenesis, while P2X7R may not play a significant role in the disease. This research sheds light on the complex inflammatory pathways in HS, highlighting the potential of NLRP3 as a therapeutic target. Understanding the molecular mechanisms underlying HS is crucial for the development of targeted treatment modalities for this debilitating condition.

Characterization of Vascular Niche in Systemic Sclerosis by Spatial Proteomics.

Systemic sclerosis (SSc) is a connective tissue disease that can serve as a model to study vascular changes in response to inflammation, autoimmunity, and fibrotic remodeling. Although microvascular changes are the earliest histopathologic manifestation of SSc, the vascular pathophysiology remains poorly understood. We applied spatial proteomic approaches to deconvolute the heterogeneity of vascular cells at the single-cell level in situ and characterize cellular alterations of the vascular niches of patients with SSc. Skin biopsies of patients with SSc and control individuals were analyzed by imaging mass cytometry, yielding a total of 90 755 cells including 2987 endothelial cells and 4096 immune cells. We identified 7 different subpopulations of blood vascular endothelial cells (VECs), 2 subpopulations of lymphatic endothelial cells, and 3 subpopulations of pericytes. A novel population of CD34+;αSMA+ (α-smooth muscle actin);CD31+ VECs was more common in SSc, whereas endothelial precursor cells were decreased. Co-detection by indexing and tyramide signal amplification confirmed these findings. The microenvironment of CD34+;αSMA+;CD31+ VECs was enriched for immune cells and myofibroblasts, and CD34+;αSMA+;CD31+ VECs expressed markers of endothelial-to-mesenchymal transition. The density of CD34+;αSMA+;CD31+ VECs was associated with clinical progression of fibrosis in SSc. Using spatial proteomics, we unraveled the heterogeneity of vascular cells in control individuals and patients with SSc. We identified CD34+;αSMA+;CD31+ VECs as a novel endothelial cell population that is increased in patients with SSc, expresses markers for endothelial-to-mesenchymal transition, and is located in close proximity to immune cells and myofibroblasts. CD34+;αSMA+;CD31+ VEC counts were associated with clinical outcomes of progressive fibrotic remodeling, thus providing a novel cellular correlate for the crosstalk of vasculopathy and fibrosis.

Clinical and morphological characteristics of patients with urticarian rasches

Clinical and morphological characteristics of patients with urticarian rasches

Identification of immunological patterns characterizing immune-related psoriasis reactions in oncological patients in therapy with anti-PD-1 checkpoint inhibitors.

Immunotherapy with biologics targeting programmed cell death protein-1 (PD-1) is highly effective in the treatment of various malignancies. Nevertheless, it is frequently responsible for unexpected cutaneous manifestations, including psoriasis-like dermatitis. The pathogenesis of anti-PD-1-induced psoriasis has yet to be clarified, even though it is plausible that some innate and adaptive immunity processes are in common with canonical psoriasis. The genetic predisposition to psoriasis of patients could also be a contributing factor. Here, we investigated the immunological and genetic profiles of two patients with metastatic melanoma and one patient affected by lung cancer, who developed severe psoriasis after receiving anti-PD-1 nivolumab therapy. The immune patterns of the three patients were compared with those detectable in classical, chronic plaque-type psoriasis or paradoxical psoriasis induced by anti-TNF-α therapy, mostly sustained by adaptive and innate immunity processes, respectively. Therefore, immunohistochemistry and mRNA analyses of innate and adaptive immunity molecules were conducted on skin biopsy of patients. Genetic analysis of polymorphisms predisposing to psoriasis was carried out by NGS technology. We found that anti-PD-1-induced psoriasis showed immunological features similar to chronic psoriasis, characterized by the presence of cellular players of adaptive immunity, with abundant CD3+, CD8+ T cells and CD11c+ dendritic cells infiltrating skin lesions, and producing IL-23, IL-6, TNF-α, IFN-γ and IL-17. On the contrary, a lower number of innate immunity cells (BDCA2+ plasmacytoid dendritic cells, CD15+ neutrophils, CD117+ mast cells) and reduced IFN-α/β, lymphotoxin (LT)-α/β, were observed in anti-PD-1-induced psoriasis lesions, as compared with anti-TNF-α-induced paradoxical psoriasis. Importantly, the disintegrin and metalloprotease domain containing thrombospondin type 1 motif-like 5 (ADAMTSL5) psoriasis autoantigen was significantly upregulated in psoriasis lesions of anti-PD-1-treated patients, at levels comparable with chronic plaque-type psoriasis. Finally, NGS analysis revealed that all patients carried several allelic variants in psoriasis susceptibility genes, such as HLA-C, ERAP1 and other genes of the major psoriasis susceptibility PSORS1 locus. Our study showed that adaptive immunity predominates over innate immunity in anti-PD-1-induced psoriasis lesions, consistently with the local ADAMTSL5 overexpression. The presence of numerous SNPs in psoriasis susceptibility genes of the three patients also suggested their strong predisposition to the disease.

Eradication of skin microbiota restores cytokine production and release in polymorphic light eruption.

Polymorphic light eruption (PLE) has been mechanistically linked to cytokine abnormalities. Emerging preclinical evidence posits the skin microbiome as a critical modulator of ultraviolet (UV)-induced cytokine expression, thereby influencing subsequent immune responses. This intricate relationship remains underexplored in the context of PLE. Hence, we investigated the differential responses between disinfected and non-disinfected skin following both single and repetitive exposures to solar-simulated UV radiation in patients with PLE. An experimental, half-body pilot study was conducted involving six PLE patients and 15 healthy controls. Participants' skin was exposed to single and multiple doses of solar-simulated UV radiation, both in disinfected and in non-disinfected skin areas. The co-primary outcomes were PLE score and cytokine expression in blister fluid analysed through OLINK proteomic profiling. Secondary outcomes were erythema, pigmentation, induction of apoptotic cells in vacuum-generated suction blisters, and density of infiltrate in skin biopsies of PLE patients. Among the 71 cytokines analysed, baseline expression levels of 20 specific cytokines-integral to processes such as apoptosis, inflammation, immune cell recruitment, cellular growth, and differentiation-were significantly impaired in PLE patients compared with healthy controls. Notably, skin disinfection reversed the observed cytokine imbalances following a single UV exposure at the minimal erythema dose (MED) level and exhibited even more pronounced effects after multiple UV exposures. However, no significant differences were evident in PLE score, erythema, pigmentation, or rates of apoptotic cell induction upon UV radiation. These findings provide evidence for UV-driven cytokine regulation by the skin microbiota and imply microbiome involvement in the PLE immune response.