Claudia Günther

The integration of immunohistochemical biomarkers like PRAME (Preferentially Expressed Antigen in Melanoma) into the histomorphological assessment of melanocytic lesions is gaining prominence. While PRAME’s diagnostic value is widely recognized, its independent weight compared directly to classical morphology remains underexplored in large, challenging cohorts. This retrospective study quantifies the diagnostic utility of PRAME alongside traditional histomorphology in a high-risk cohort of 954 primary melanocytic lesions (335 nevi, 215 melanomas in situ, 404 invasive melanomas) where PRAME was clinically requested to resolve diagnostic ambiguity. Using Firth’s penalized likelihood regression, a baseline diagnostic model utilizing 13 histomorphological features was established and subsequently integrated with PRAME expression. The pure morphology baseline model demonstrated a high cross-validated area under the curve (AUC) of 0.969. As a standalone marker, PRAME achieved an AUC of 0.895, with a diffuse expression score of 4+ yielding peak specificity (94.3%) and moderate sensitivity (77.9%). Integrating PRAME into the morphological model significantly enhanced diagnostic accuracy (AUC: 0.980; p < 0.001), establishing PRAME as a dominant independent predictor of malignancy alongside core features like junctional atypia and upward melanocytes (Odds Ratio 19.08 for Score 4+). Analysis of discordant cases revealed that completely PRAME-negative melanomas were morphologically indistinguishable from typical PRAME-positive melanomas. Conversely, diffusely PRAME-positive (4+) nevi exhibited significantly higher rates of upward migrating melanocytes, constituting a critical diagnostic pitfall. In conclusion, while classic histomorphology remains the indispensable gold standard in dermatopathology, PRAME functions as a highly objective, reproducible tie-breaker. The synergistic integration of PRAME with morphological assessment effectively resolves diagnostic ambiguity and maximizes diagnostic confidence in challenging melanocytic lesions.

Zusammenfassung: Die deutschsprachige, konsens‐ und evidenzbasierte S3‐Leitlinie zum Lichen sclerosus (LS) wurde unter Federführung der Deutschen Dermatologischen Gesellschaft e.V . (DDG) und der Deutschen Gesellschaft für Gynäkologie und Geburtshilfe e.V . (DGGG) auf Basis der europäischen „EuroGuiDerm Guideline on lichen sclerosus“ entwickelt. Besonderes Augenmerk galt dabei der Anpassung an die medizinischen Versorgungssituation im deutschsprachigen Raum. Das interdisziplinäre Leitliniengremium umfasste 24 Experten aus 16 Fachgesellschaften und schloss auch Patientenvertreter aktiv in den Entwicklungsprozess ein. Die Leitlinie enthält unter anderem umfassende Empfehlungen zur Diagnostik, zum Patientenmanagement, zur Nachsorge und Patientenschulung sowie zur Therapie des genitalen und extragenitalen LS bei Frauen, Männern, Mädchen und Jungen. Unabhängig von Alter und Geschlecht gelten ultrapotente oder potente topische Glukokortikoide in Kombination mit pflegenden Externa weiterhin als Standardtherapie des genitalen LS. Bei unzureichendem Ansprechen auf diese Therapie ist bei männlichen Patienten mit LS bedingter Phimose eine Zirkumzision mit vollständiger Entfernung der Vorhaut indiziert. Für den extragenitalen LS wird ergänzend zur topischen Therapie eine Phototherapie mit UV‐Licht empfohlen. Topische Calcineurininhibitioren können als Zweitlinientherapie zum Einsatz kommen.

Summary: The German‐language, consensus‐ and evidence‐based S3 guideline on lichen sclerosus (LS) was developed based on the European “EuroGuiDerm Guideline on lichen sclerosus” under the leadership of the German Dermatological Society (DDG) and the German Society for Gynecology and Obstetrics (DGGG). Particular emphasis was placed on adapting the recommendations to the healthcare conditions in German‐speaking countries. The interdisciplinary guideline development group consisted of 24 experts from 16 medical societies and actively included patient representatives in the development process. The guideline provides comprehensive recommendations on diagnosis, patient management, follow‐up care, and patient education, as well as the treatment of both genital and extragenital LS in women, men, girls, and boys. Regardless of age or sex, ultrapotent or potent topical glucocorticosteroids in combination with emollients remain the standard therapy for genital LS. In male patients with LS‐associated phimosis who do not respond sufficiently to standard therapy, circumcision with complete removal of the foreskin is indicated. For extragenital LS, phototherapy with UV light is recommended as an adjunct to topical treatment. Topical calcineurin inhibitors are second‐line therapy.

Background: The aim was to assess the long‐term effect of belimumab on the cutaneous manifestations of patients with systemic lupus erythematosus (SLE). Methods: The retrospective analysis included 29 patients with SLE. Cutaneous disease activity was assessed using the Cutaneous Lupus Erythematosus Disease Area and Severity Index (CLASI) and the Revised CLASI (RCLASI) activity scores before treatment with belimumab and at 3, 6, 12, and up to 60 months of treatment. Eleven patients were treated for the whole observation period; however, only 8 patients were evaluable at 48 months, and only 6 at 60 months due to loss of follow‐up. Results: Compared to the baseline score, a significant reduction of the CLASI and RCLASI activity score was seen during the treatment (mean CLASI baseline 8.76 ± 5.12, after 3 months 5.59 ± 3.87, p < 0.001, after 60 months 4.67 ± 3.86, p = 0.017; mean RCLASI baseline 10.93 ± 6.57, after 3 months 7.62 ± 6.03, after 60 months 5.33 ± 4.31, p = 0.012). The percentage of patients achieving a CLASI 100 response increased continuously over time, reaching a maximum of 30% after 60 months. Response was most remarkable among patients with acute or discoid cutaneous lupus. The treatment was well tolerated by the patients, with the most common adverse events being respiratory infections, headaches, and arthralgia, among others. Conclusion: This retrospective analysis demonstrated that belimumab has long‐term benefits for cutaneous manifestations of patients with lupus erythematosus. However, prospective studies in larger patient populations are needed to confirm the findings.

Background: Bullous pemphigoid (BP) is a common autoimmune blistering dermatosis often difficult to distinguish from other inflammatory conditions. Timely diagnosis is crucial for appropriate management. Line‐field confocal optical coherence tomography (LC‐OCT), a noninvasive imaging technique that uses an 800nm laser to generate high‐resolution vertical and horizontal cross‐sectional images of the skin, is evaluated as a diagnostic tool for BP.Materials and Methods: A prospective, single‐center study was conducted on 26 patients with suspected BP. LC‐OCT imaging, histopathology, and direct immunofluorescence (DIF) were performed. LC‐OCT images were assessed for the presence of key diagnostic features, including subepidermal cleavage and eczema criteria.Results: Based on histopathology, DIF, indirect immunofluorescence (IIF), and ELISA, the final diagnoses were 15 BP cases and 11 non‐BP cases. LC‐OCT correctly identified 12 of 15 BP cases and all 11 non‐BP cases, demonstrating a sensitivity of 0.8 and a specificity of 1.0. The presence of subepidermal cleavage was a key diagnostic criterion for BP (p = 0.000). The absence of alternating hypo‐ and hyper‐reflective layers (p = 0.000), thickened and disrupted stratum corneum (p = 0.014), spongiosis (p = 0.036), and thickened epidermis (p = 0.043), which occurred significantly less frequently in BP cases, further supported the diagnosis.Conclusion: LC‐OCT demonstrates high sensitivity and specificity in diagnosing BP, offering a rapid, point‐of‐care diagnostic approach. LC‐OCT can be used to evaluate unclear inflammatory skin conditions and guide further investigations. However, LC‐OCT has limitations in diagnosing non‐bullous stages of BP; thus, histology and DIF remain the gold standard for definitive diagnosis.

Psoriatic disease initially affects the skin, but later extends to the joints. Herein, we describe a two-step process that orchestrates spreading of inflammation from the skin to the joints. Induction of psoriatic skin disease in photoconvertible mice, followed by sequencing and computational characterization of skin-derived cells in the joints, identified a unique population of CD2 ⁺ MHC-II ⁺ CCR2 ⁺ myeloid precursors that built up a skin-derived myeloid cell compartment in the joints. Single-cell cross-species reference mapping and mitochondrial variant tracing showed an orthologue human cell population. Interactome analyses in the joints showed that in a second step, resident regulatory CD200 ⁺ fibroblasts critically regulate the priming of the CD2 ⁺ MHC-II ⁺ CCR2 ⁺ myeloid precursors, which subsequently regulate the IL-17 expression in T cells. Hence, spreading of inflammation requires a distinct migratory myeloid precursor population and a permissive local tissue environment, similar to tumour metastasis. Graphical

Background: Pemphigus vulgaris (PV) is a CD4+ T-cell-dependent autoantibody-mediated blistering disease associated with human leucocyte antigen (HLA) class II molecules. IgG autoantibodies against the primary autoantigen desmoglein 3 (Dsg3), a desmosomal adhesion protein on epidermal keratinocytes, cause loss of epidermal cell adhesion. Objectives: To assess the clinical applicability of an innovative nanoparticle platform for the induction of immune tolerance exploiting the natural tolerance potential of liver sinusoidal endothelial cells. An open-label first-in-human study was conducted with TPM203, a mixture of four nanoparticle-coupled immunodominant Dsg3 T-cell peptides. Methods: The efficacy and mechanism of action of TPM203 were first tested in a humanized HLA-DRB1*0402-transgenic PV mouse model. In the clinical phase I trial, TPM203 was administered intravenously in patients with PV with no-to-moderate disease activity in single ascending and multiple doses (three doses of TPM203 two weeks apart). Primary endpoints included safety and tolerability. As a secondary endpoint, pharmacokinetics were assessed. Exploratory endpoints comprised changes in Dsg3-specific and bulk T- and B-cell frequencies, anti-Dsg3 IgG levels and autoantibody-induced keratinocyte dissociation. The trial was registered with EudraCT (2019-001727-12). Results: In the PV mouse model, two administrations of TPM203 significantly reduced anti-Dsg3 IgG. On the cellular level, TPM203 led to a significant decrease in CD4+ T cells in the spleen, accompanied by increased frequencies of regulatory T (Treg) cells. In the clinical trial, the 17 patients with PV enrolled across single- and multiple-dose groups did not experience any serious or severe adverse events, or treatment-related PV worsening. Pharmacokinetics confirmed rapid TPM203 clearance from the circulation. Significant TPM203-induced modulations in bulk lymphocyte subsets included an increase in Treg cells, and reductions in T helper 17.1 and CD27+ memory B cells, when dose groups were combined for analysis. Dsg3-specific T cells were found to be significantly reduced at week 8 following single administration of TPM203. Anti-Dsg3 IgG levels trended downward in the three lower single ascending dose groups, while IgG-induced keratinocyte-dissociating capacity was significantly reduced after multiple doses. Conclusions: Administered for the first time in humans, TPM203 was shown to be a safe and well-tolerated nanoparticle-based therapeutic approach with the potential to promote tolerance induction in PV, justifying further clinical development in this and other autoimmune diseases. An author video to accompany this article is available online.