Spatial proteomics identifies JAKi as treatment for a lethal skin disease.

Toxic epidermal necrolysis (TEN) is a fatal drug-induced skin reaction triggered by common medications and is an emerging public health issue1-3. Patients with TEN undergo severe and sudden epidermal detachment caused by keratinocyte cell death. Although molecular mechanisms that drive keratinocyte cell death have been proposed, the main drivers remain unknown, and there is no effective therapy for TEN4-6. Here, to systematically map molecular changes that are associated with TEN and identify potential druggable targets, we utilized deep visual proteomics, which provides single-cell-based, cell-type-resolution proteomics7,8. We analysed formalin-fixed, paraffin-embedded archived skin tissue biopsies of three types of cutaneous drug reactions with varying severity and quantified more than 5,000 proteins in keratinocytes and skin-infiltrating immune cells. This revealed a marked enrichment of type I and type II interferon signatures in the immune cell and keratinocyte compartment of patients with TEN, as well as phosphorylated STAT1 activation. Targeted inhibition with the pan-JAK inhibitor tofacitinib in vitro reduced keratinocyte-directed cytotoxicity. In vivo oral administration of tofacitinib, baricitinib or the JAK1-specific inhibitors abrocitinib or upadacitinib ameliorated clinical and histological disease severity in two distinct mouse models of TEN. Crucially, treatment with JAK inhibitors (JAKi) was safe and associated with rapid cutaneous re-epithelialization and recovery in seven patients with TEN. This study uncovers the JAK/STAT and interferon signalling pathways as key pathogenic drivers of TEN and demonstrates the potential of targeted JAKi as a curative therapy.

Real-life efficacy of immunotherapy for Sézary syndrome: a multicenter observational cohort study.

Background: Sézary syndrome is an extremely rare and fatal cutaneous T-cell lymphoma (CTCL). Mogamulizumab, an anti-CCR4 monoclonal antibody, has recently been associated with increased progression-free survival in a randomized clinical trial in CTCL. We aimed to evaluate OS and prognostic factors in Sézary syndrome, including treatment with mogamulizumab, in a real-life setting. Methods: Data from patients with Sézary (ISCL/EORTC stage IV) and pre-Sézary (stage IIIB) syndrome diagnosed from 2000 to 2020 were obtained from 24 centers in Europe. Age, disease stage, plasma lactate dehydrogenases levels, blood eosinophilia at diagnosis, large-cell transformation and treatment received were analyzed in a multivariable Cox proportional hazard ratio model. This study has been registered in ClinicalTrials (SURPASSe01 study: NCT05206045). Findings: Three hundred and thirty-nine patients were included (58% men, median age at diagnosis of 70 years, Q1-Q3, 61-79): 33 pre-Sézary (9.7% of 339), 296 Sézary syndrome (87.3%), of whom 10 (2.9%) had large-cell transformation. One hundred and ten patients received mogamulizumab. Median follow-up was 58 months (95% confidence interval [CI], 53-68). OS was 46.5% (95% CI, 40.6%-53.3%) at 5 years. Multivariable analysis showed that age ≥ 80 versus <50 (HR: 4.9, 95% CI, 2.1-11.2, p = 0.001), and large-cell transformation (HR: 2.8, 95% CI, 1.6-5.1, p = 0.001) were independent and significant factors associated with reduced OS. Mogamulizumab treatment was significantly associated with decreased mortality (HR: 0.34, 95% CI, 0.15-0.80, p = 0.013). Interpretation: Treatment with mogamulizumab was significantly and independently associated with decreased mortality in Sézary syndrome. Funding: French Society of Dermatology, Swiss National Science Foundation (IZLIZ3_200253/1) and SKINTEGRITY.CH collaborative research program.

Positron emission tomography-computed tomography vs. brain magnetic resonance imaging for the detection of cerebral metastases of melanoma: a 5-year retrospective study.

BACKGROUND: Patients with melanoma present a high risk of developing extracutaneous metastases. Positron emission tomography--computed tomography (PET-CT) is one of the preferred examinations for the staging of oncological patients. It is not the method of choice to detect brain metastases, but this technique has shown significant improvement and allows the detection of some of them. However, it is unclear how it performs compared with magnetic resonance imaging (MRI), the current gold standard for diagnosing brain metastases. OBJECTIVES: To compare the accuracy of PET-CT and cerebral MRI to detect brain metastases in patients with melanoma. METHODS: We retrospectively included all patients diagnosed with melanoma stage IIC-IV (American Joint Committee on Cancer 8th Edition, 2017) who presented at the skin tumour board of the University Hospital of Bern between January 2018 and December 2022. All radiological reports extracted from the patient management system were analysed to assess discrepancy between the visibility of brain metastases on PET-CT and brain MRI. RESULTS: In this study including 393 patients, brain MRI demonstrated significantly better performance than PET-CT in detecting brain metastases. In 47 patients, cerebral metastases were detected completely, detected partially, or not detected by PET-CT in 2 (4%), 15 (32%) and 30 (64%), respectively. CONCLUSIONS: Despite the increasing performance of PET-CT, this study highlights the crucial role of brain MRI, which remains the gold standard to detect cerebral metastases. Brain MRI should be performed in patients with high-risk melanoma from stage IIC to exclude brain metastases.

Successful Removal of 17 Tattoos Self-Administered Using Black Eyeliner Ink with Quality-Switched Neodymium-Doped Yttrium Aluminum Garnet 1,064-nm Laser: A Case Report.

Introduction: Tattooing has a rich historical presence in various human civilizations, with the earliest physical evidence dating back to around 3258 BC. While acceptance of tattoos is increasing in the Western world, negative associations remain. Short-pulsed lasers, such as Q-Switched (QS) or picosecond lasers, are the gold standard for tattoo removal. Case Presentation: This case report discusses the successful removal of 17 amateur tattoos, which were self-administered by a 19-year-old female patient using black eyeliner ink and sewing needles. The tattoos, distributed across her body, including the face and hands, were partially or completely removed over 10 sessions using the QS Neodymium-doped Yttrium Aluminum Garnet 1,064-nm laser. Conclusion: The factors that influence the efficacy of tattoo removal are highlighted, including tattoo type, location, and coexisting fibrosis. The psychological and social importance of effective tattoo removal is emphasized, particularly for young people seeking to disassociate from past experiences or affiliations.

Diagnostic management of blastic plasmacytoid dendritic cell neoplasm (BPDCN) in close interaction with therapeutic considerations.

Blastic plasmacytoid dendritic cell neoplasm (BPDCN), a rare malignancy derived from plasmacytoid dendritic cells, can mimic both acute leukemia and aggressive T-cell lymphoma. Therapy of this highly aggressive hematological disease should be initiated as soon as possible, especially in light of novel targeted therapies that have become available. However, differential diagnosis of BPDCN remains challenging. This retrospective study aimed to highlight the challenges to timely diagnoses of BPDCN. We documented the diagnostic and clinical features of 43 BPDCN patients diagnosed at five academic hospitals from 2001-2022. The frequency of BPDCN diagnosis compared to AML was 1:197 cases. The median interval from the first documented clinical manifestation to diagnosis of BPDCN was 3 months. Skin (65%) followed by bone marrow (51%) and blood (45%) involvement represented the most common sites. Immunophenotyping revealed CD4 + , CD45 + , CD56 + , CD123 + , HLA-DR + , and TCL-1 + as the most common surface markers. Overall, 86% (e.g. CD33) and 83% (e.g., CD7) showed co-expression of myeloid and T-cell markers, respectively. In the median, we detected five genomic alterations per case including mutational subtypes typically involved in AML: DNA methylation (70%), signal transduction (46%), splicing factors (38%), chromatin modification (32%), transcription factors (32%), and RAS pathway (30%), respectively. The contribution of patients (30%) proceeding to any form of upfront stem cell transplantation (SCT; autologous or allogeneic) was almost equal resulting in beneficial overall survival rates in those undergoing allogeneic SCT (p = 0.0001). BPDCN is a rare and challenging entity sharing various typical characteristics of other hematological diseases. Comprehensive diagnostics should be initiated timely to ensure appropriate treatment strategies.

Case report: Area of focus of management of severe pityriasis rubra pilaris by dose optimization of adalimumab biosimilar in combination with acitretin and montelukast.

Pityriasis rubra pilaris (PRP) is a rare inflammatory skin disorder characterized by hyperkeratotic follicular papules, orange-red scaling plaques with islands of sparing and palmoplantar keratoderma. While spontaneous resolution occurs in some cases, treatment can be challenging for others. The use of biologics in PRP management has gained attention in recent studies, although their high costs and potential side effects present limitations. We present a case of a 71-year-old patient with treatment-resistant PRP who showed significant improvement through optimized adalimumab treatment. Considering the emerging role of phospholipase A2 in PRP pathogenesis, montelukast was added, further enhancing the therapeutic response. By maintaining montelukast and prolonging the adalimumab interval to 3 and 4 weeks, effective dose optimization was achieved without PRP relapse. This case report highlights the potential for adalimumab dose optimization by shortening the initial treatment interval for increased effectiveness and lengthening the interval during the maintenance phase to conserve medication doses. Montelukast appears to assist in sustaining clinical outcomes during interval prolongation, necessitating further investigation through additional studies.

Dimethyl Fumarate Used as an Effective Treatment for Granuloma Annulare Disseminatum: An Immunohistochemical Case Study.

This investigation demonstrates the use of dimethyl fumarate (DMF) for the treatment of disseminated granuloma annulare (GAD), a rare and chronic inflammatory skin disease. In this case, progressive GAD was treated with DMF, resulting in significant improvement of skin lesions within 5 weeks and complete healing within 7 months. Clinical response was associated with a reduction in inflammatory cells, including both T cell subsets (CD4+ > CD8+), CD183+/CXCR3+ cells, Langerhans cells (CD1a+), myeloid DCs, M1- and M2-like macrophages and the activation marker HLA-DR in immunohistochemical analysis. These findings support the use of DMF as a promising treatment option for this rare skin condition.

Image Perceptual Similarity Metrics for the Assessment of Basal Cell Carcinoma.

Efficient management of basal cell carcinomas (BCC) requires reliable assessments of both tumors and post-treatment scars. We aimed to estimate image similarity metrics that account for BCC's perceptual color and texture deviation from perilesional skin. In total, 176 clinical photographs of BCC were assessed by six physicians using a visual deviation scale. Internal consistency and inter-rater agreement were estimated using Cronbach's α, weighted Gwet's AC2, and quadratic Cohen's kappa. The mean visual scores were used to validate a range of similarity metrics employing different color spaces, distances, and image embeddings from a pre-trained VGG16 neural network. The calculated similarities were transformed into discrete values using ordinal logistic regression models. The Bray-Curtis distance in the YIQ color model and rectified embeddings from the 'fc6' layer minimized the mean squared error and demonstrated strong performance in representing perceptual similarities. Box plot analysis and the Wilcoxon rank-sum test were used to visualize and compare the levels of agreement, conducted on a random validation round between the two groups: 'Human-System' and 'Human-Human.' The proposed metrics were comparable in terms of internal consistency and agreement with human raters. The findings suggest that the proposed metrics offer a robust and cost-effective approach to monitoring BCC treatment outcomes in clinical settings.

Skin hyperpigmentation index in melasma: A complementary method to classic scoring systems.

BACKGROUND: Due to relapsing nature of melasma with significant impact on quality of life, an objective measurement score is warranted, especially to follow-up the patients with melasma and their therapy response in a quantitative and precise manner. AIMS: To prove concordance of skin hyperpigmentation index (SHI) with well-established scores in melasma and demonstrate its superiority regarding inter-rater reliability. Development of SHI mapping for its integration in common scores. METHODS: Calculation of SHI and common melasma scores by five dermatologists. Inter-rater reliability was assessed by intraclass correlation coefficient (ICC) and concordance by Kendall correlation coefficient. RESULTS: Strong concordance of SHI with melasma area and severity index (MASI)-Darkness (0.48; 95% CI: 0.32, 0.63), melasma severity index (MSI)-Pigmentation (0.45; 95% CI: 0.26, 0.61), and melasma severity scale (MSS) (0.6; 95% CI: 0.42, 0.74). Using step function for mapping SHI into pigmentation scores showed an improvement of inter-rater reliability with a difference in (ICC of 0.22 for MASI-Darkness and 0.19 for MSI-Pigmentation), leading to an excellent agreement. CONCLUSION: Skin hyperpigmentation index could be an important additional cost-and time-conserving assessment method, to follow-up the patients with melasma undergoing brightening therapies in clinical studies, as well as in routine clinical practice. It is in strong concordance with well-established scores but superior regarding inter-rater reliability.

Canakinumab leads to rapid reduction of neutrophilic inflammation and long-lasting response in Schnitzler syndrome.

Interleukin-1 (IL-1)-blocking therapies are effective in reducing disease severity and inflammation in Schnitzler syndrome. Here, we present a patient with Schnitzler syndrome treated successfully using canakinumab for over 10 years. Complete clinical response was associated with a decrease in dermal neutrophil number and expression of the pro-inflammatory cytokines IL-1ß, IL-8, and IL-17 as assessed by immunohistochemical studies.

A desmosomal cadherin controls multipotent hair follicle stem cell quiescence and orchestrates regeneration through adhesion signaling.

Stem cells (SCs) are critical to maintain tissue homeostasis. However, it is currently not known whether signaling through cell junctions protects quiescent epithelial SC reservoirs from depletion during disease-inflicted damage. Using the autoimmune model disease pemphigus vulgaris (PV), this study reveals an unprecedented role for a desmosomal cadherin in governing SC quiescence and regeneration through adhesion signaling in the multipotent mouse hair follicle compartment known as the bulge. Autoantibody-mediated, mechanical uncoupling of desmoglein (Dsg) 3 transadhesion activates quiescent bulge SC which lose their multipotency and stemness, become actively cycling, and finally delaminate from their epithelial niche. This then initiates a self-organized regenerative program which restores Dsg3 function and bulge morphology including SC quiescence and multipotency. These profound changes are triggered by the sole loss of functional Dsg3, resemble major signaling events in Dsg3-/- mice, and are driven by SC-relevant EGFR activation and Wnt modulation requiring longitudinal repression of Hedgehog signaling.

The Feasibility of Immunocryosurgery in the Treatment of Non-Superficial, Facial Basal Cell Carcinoma That Relapsed after Standard Surgical Excision: An Experience Report from Two Centers.

In this retrospective, chart review study, we evaluated the feasibility of immunocryosurgery in facial, non-superficial basal cell carcinomas (BCC) that had relapsed after standard surgery. Inclusion criteria were (a) 'biopsy confirmed relapse of facial BCC', (b) known 'calendar year of surgical excision(s)', and (c) 'relapse within 10 years after the last surgical excision'. Tumors treated from 1 January 2011 to 31 December 2020 with a standard 5-week immunocryosurgery cycle (daily imiquimod application for 5 weeks and a cryosurgery session at day 14) were included. Descriptive statistics, Kaplan-Meier method, and Cox proportional hazards model were calculated with significance at p < 0.05. From the n = 27 BCC evaluated, n = 20 (74.1 ± 8.4%) cleared after one immunocryosurgery cycle. Two of the remaining cases cleared completely after a repeat cycle, one patient favored surgery, and four BCC did not clear despite additional immunocryosurgery cycles (feasibility 81.5 ± 7.5%). Of the 22 tumors with clinical outcome 'complete clearance with immunocryosurgery', three BCC relapsed at 9, 28, and 50 months. Overall, the 5-year treatment efficacy rate was 60.2 ± 13.4% (mean follow-up 94.6 ± 15.1 months). In total, 20/27 BCC relapses after surgery (74.1%) were tumor-free at the end of personalized follow-up times (66.7 ± 12.4% tumor free patients at 5-year follow-up). Number of tumor relapses before immunocryosurgery was the single predictor of tumor progression after immunocryosurgery (p = 0.012). Conclusively, immunocryosurgery could be further evaluated as an alternative, definitive treatment of selected facial BCC relapsing after surgery.

Long-Term Dose Optimization of Adalimumab via Dose Spacing in Patients with Psoriasis.

Dose spacing (DS) can be useful for optimizing treatment with biologics in psoriasis patients. However, interval prolongation might increase the production of anti-drug antibodies (ADA) and, therefore, reduce the drug's effectiveness. The long-term effects of DS with adalimumab in psoriatic patients have not been reported. The goal of our study was to evaluate the long-term follow-up of psoriatic patients after adalimumab DS regarding the clinical course and determination of circulating adalimumab, TNFα levels, and anti-adalimumab antibodies. We retrospectively included seven patients treated with adalimumab for moderate-to-severe psoriasis and benefiting from DS from 2010 to 2021. The dose interval of adalimumab was extended to three weeks for all patients and then to four weeks for three of the seven patients. Adalimumab trough levels, TNFα levels, and ADA against adalimumab were measured. For six of the seven patients, absolute PASI values remained below 3 throughout the follow-up period (median = 8.0 years; range: 1.7−11.5) after DS. All the patients were satisfied with the effectiveness of their treatment regime. Within the follow-up period, an average of 63 doses of adalimumab per patient were spared. The median adalimumab trough levels were 4.7 µg/mL (range: 1.9−12.5). TNFα levels remained under 10 pg/mL (undetectable) in all except one patient. ADA against adalimumab remained negative (<10 µg/mL) during the follow-up in all patients. Our data indicate that therapeutic drug monitoring, including the measurement of trough concentrations and ADA, together with the clinical response and patient's preference, can be helpful for clinical decision making and treatment optimization in psoriasis.

Treatment with IL5-/IL-5 receptor antagonists in drug reaction with eosinophilia and systemic symptoms (DRESS).

Purpose: Drug reaction with eosinophilia and systemic symptoms (DRESS) is a severe delayed drug hypersensitivity reaction with exanthema, eosinophilia, and organ manifestations. After culprit drug withdrawal, systemic corticosteroids (CS) are the most widely used treatment, often requiring high doses for months. Blocking the IL-5/IL­5 receptor axis with mepolizumab, reslizumab, and benralizumab is a promising targeted treatment with a good safety profile and no immunosuppressive effect. The aim of this study is to summarize current experience with the anti-IL5/IL-5-receptor therapy in DRESS. Methods: A retrospective analysis of all patients diagnosed with DRESS and treated with mepolizumab, reslizumab, or benralizumab in DRESS was performed. In addition, a PubMed-Medline search for publications on DRESS with anti-IL-5/IL­5 receptor treatment was performed. Results: Of the 14 cases identified, 6 patients were treated with mepolizumab, 6 with benralizumab, 1 patient with reslizumab, and 1 patient was switched from benralizumab to mepolizumab. The main indication for an IL­5 blockade was a therapy-refractory course (7/14 [50.0%]), recurrent relapses (3/14 [21.4%]), and severe organ dysfunction (2/14 [14.3%]). In 13/14 (93%) cases, a rapid clinical improvement with suppression of eosinophilia and reduction of CS could be achieved. In all but two cases under mepolizumab (dose 100-600 mg) or reslizumab (dose according to body weight), two or more doses were necessary until resolution of DRESS. In 4/7 cases under benralizumab, a single 30 mg dose was sufficient. Conclusion: Blockade of the IL-5/IL­5 receptor axis appears to be a promising treatment in DRESS with fast clinical improvement, which may allow more rapid reduction of CS, and a good safety profile. In addition, a summary of recommendations on when to use blockade of the IL-5/IL­5 receptor axis in DRESS treatment is provided.

Defining the Molecular Landscape of Cancer-Associated Stroma in Cutaneous Squamous Cell Carcinoma.

Cutaneous squamous cell carcinoma (cSCC) is the second most common skin cancer worldwide. Cancer-associated stroma (CAS) is central to tumor development and strongly influences therapy response. Perineural infiltration (PNI) represents a major risk factor for cSCC and likely influences CAS reprogramming. However, stromal reprogramming in cSCC remains poorly characterized, and it is unknown whether and how PNI influences CAS. To address these questions, we analyzed CAS and matched normal stroma from 20 cSCC cases (11 without PNI and 9 with PNI) by laser-capture microdissection using RNA sequencing. Our analysis reveals extensive stromal reprogramming strongly driven by changes in immune cells, as validated using immunohistochemistry. Furthermore, CAS of cSCC displays markers of immune exhaustion, and multiplex spatial analysis suggests that PD-L1 expression on NK T cells contributes to T-cell exhaustion and immunosuppression. Finally, PNI is characterized by increased IL-17A. In PNI-negative cases, IL-17A derives predominantly from CD3+ cells. However, with PNI, we observe an increased contribution of fibroblasts to high IL-17A, which coincides with a significant increase in FAP+ cells. Our analysis elucidates the molecular landscape of CAS in cSCC and identifies the presence of immunosuppressive mechanisms, supporting further research into immunotherapy and anti‒IL-17A in cSCC, especially for cases with PNI.

Post-Irradiation Morphea of the Breast in a Patient with Subacute Cutaneous Lupus Erythematosus: Case Report and a Literature Review.

The appearance of morphea after radiotherapy, especially in the context of breast cancer, is a rare but known phenomenon. The incidence of post-irradiation morphea (PIM) of the breast is approximately one in every 500 patients, a higher rate than morphea of any other etiology, which is three per 100,000 per year. PIM usually appears less than 1 year after irradiation (range 1 month to 32 years). The histological pattern of PIM is different from the one in post-irradiation fibrosis, which is a common side effect of radiotherapy and usually appears during the first 3 months after irradiation. Several theories have been proposed to explain the pathogenesis of PIM, probably caused by a disturbance of the cytokine pattern. The development of PIM in patients with autoimmune diseases has been described in the literature. To our knowledge, we report the first case of PIM in a patient with subacute cutaneous lupus erythematosus. We should therefore pay attention when looking at patients with PIM to search for an underlying autoimmune disease.

The Fate of Epidermal Tight Junctions in the stratum corneum: Their Involvement in the Regulation of Desquamation and Phenotypic Expression of Certain Skin Conditions.

We evaluated the presence of tight junction (TJ) remnants in the stratum corneum (SC) of in vitro reconstructed human epidermis and human skin explants subjected or not to an aggressive topical treatment with beta-lipohydroxy salicylic acid (LSA) for 24 h. LSA-treated samples showed an increased presence of TJ remnants in the two lowermost layers of the SC, as quantified with standard electron microscopy. The topical aggression-induced overexpression of TJ-like cell-cell envelope fusions may influence SC functions: (1) directly, through an enhanced cohesion, and (2) indirectly, by impeding accessibility of peripheral corneodesmosomes to extracellular hydrolytic enzymes and, thus, slowing down desquamation. Observations of ichthyotic epidermis in peeling skin disease (PSD; corneodesmosin deficiency; two cases) and ichthyosis hypotrichosis sclerosing cholangitis syndrome (IHSC/NISCH; absence of claudin-1; two cases) also demonstrated increased persistence of TJ-like intercellular fusions in pathological SC and contributed to the interpretation of the diseases' pathological mechanisms.

Efficacy Assessment of the High-Frequency High-Intensity Focused Ultrasound as a New Treatment for Actinic Keratosis.

BACKGROUND: Actinic keratosis (AK) is the most common precancerous cutaneous lesion, with risk of progression to cutaneous squamous cell carcinoma. In the current study, we evaluated the efficacy of 20-MHz high-intensity focused ultrasound (HIFU), as a new treatment modality for AK. MATERIALS AND METHODS: Patients with AK lesions (grades I-III) treated with HIFU were included in the study. The clinical assessment was performed 3 months after therapy. RESULTS: Twenty-one patients (14 men, 7 women) with 108 AK lesions (grades I-III) were included in the current study. Ages ranged from 62 to 85 years (mean 72.6 years). Clinically complete resolution of the actinic damage in the treated area was detected in 72.2% of lesions. Furthermore, 28 lesions (26%) showed a reduction of the AK grade, or partial response, after the therapy. Most of the patients experienced annoying but short pain during the procedure. However, late adverse effects of the therapy, such as hypopigmentation, hyperpigmentation and erythema were reported only in a small portion of the lesions. CONCLUSIONS: 20-MHz HIFU could be an effective and safe alternative treatment for AK.