TYK2 inhibition with deucravacitinib ameliorates erosive oral lichen planus.

Erosive oral lichen planus (OLP) is a challenging disease. This T cell driven disorder frequently shows a treatment unresponsive course and strongly limits patients' quality of life. The disease lacks FDA or EMA approved drugs for its treatment and the efficacy of the commonly administered treatments (i.e. topical and systemic steroids, steroid sparing agents) is often only partial. Although the etiopathogenesis of the disease still needs to be fully elucidated, recent advances helped to identify interferon-É£ (IFN-É£) as a pivotal cytokine in OLP pathogenesis, thus making the interference with its signalling a therapeutic target. Janus kinase (JAK) inhibitors therefore gained relevance for their inhibitory effect on IFN-É£ signalling. While some drugs such as abrocitinib, upadacitinib, tofacitinib directly interfere with IFN-É£ signalling through blockade of JAK1 and/or JAK2, deucravacitinib, a selective TYK-2 inhibitor indirectly interferes on IFN-É£ activation through interference with interleukin (IL)-12, a potent promotor for Th1/IFN-É£ responses. This mechanism of action makes deucravacitinib a candidate drug for the treatment of OLP. Here we provide initial evidence that deucravacitinib 6 mg daily has a beneficial effect in three patients with oral OLP.

Federated Learning for Decentralized Artificial Intelligence in Melanoma Diagnostics.

Importance: The development of artificial intelligence (AI)-based melanoma classifiers typically calls for large, centralized datasets, requiring hospitals to give away their patient data, which raises serious privacy concerns. To address this concern, decentralized federated learning has been proposed, where classifier development is distributed across hospitals. Objective: To investigate whether a more privacy-preserving federated learning approach can achieve comparable diagnostic performance to a classical centralized (ie, single-model) and ensemble learning approach for AI-based melanoma diagnostics. Design, Setting, and Participants: This multicentric, single-arm diagnostic study developed a federated model for melanoma-nevus classification using histopathological whole-slide images prospectively acquired at 6 German university hospitals between April 2021 and February 2023 and benchmarked it using both a holdout and an external test dataset. Data analysis was performed from February to April 2023. Exposures: All whole-slide images were retrospectively analyzed by an AI-based classifier without influencing routine clinical care. Main Outcomes and Measures: The area under the receiver operating characteristic curve (AUROC) served as the primary end point for evaluating the diagnostic performance. Secondary end points included balanced accuracy, sensitivity, and specificity. Results: The study included 1025 whole-slide images of clinically melanoma-suspicious skin lesions from 923 patients, consisting of 388 histopathologically confirmed invasive melanomas and 637 nevi. The median (range) age at diagnosis was 58 (18-95) years for the training set, 57 (18-93) years for the holdout test dataset, and 61 (18-95) years for the external test dataset; the median (range) Breslow thickness was 0.70 (0.10-34.00) mm, 0.70 (0.20-14.40) mm, and 0.80 (0.30-20.00) mm, respectively. The federated approach (0.8579; 95% CI, 0.7693-0.9299) performed significantly worse than the classical centralized approach (0.9024; 95% CI, 0.8379-0.9565) in terms of AUROC on a holdout test dataset (pairwise Wilcoxon signed-rank, P < .001) but performed significantly better (0.9126; 95% CI, 0.8810-0.9412) than the classical centralized approach (0.9045; 95% CI, 0.8701-0.9331) on an external test dataset (pairwise Wilcoxon signed-rank, P < .001). Notably, the federated approach performed significantly worse than the ensemble approach on both the holdout (0.8867; 95% CI, 0.8103-0.9481) and external test dataset (0.9227; 95% CI, 0.8941-0.9479). Conclusions and Relevance: The findings of this diagnostic study suggest that federated learning is a viable approach for the binary classification of invasive melanomas and nevi on a clinically representative distributed dataset. Federated learning can improve privacy protection in AI-based melanoma diagnostics while simultaneously promoting collaboration across institutions and countries. Moreover, it may have the potential to be extended to other image classification tasks in digital cancer histopathology and beyond.

Dermatologist-like explainable AI enhances trust and confidence in diagnosing melanoma.

Artificial intelligence (AI) systems have been shown to help dermatologists diagnose melanoma more accurately, however they lack transparency, hindering user acceptance. Explainable AI (XAI) methods can help to increase transparency, yet often lack precise, domain-specific explanations. Moreover, the impact of XAI methods on dermatologists' decisions has not yet been evaluated. Building upon previous research, we introduce an XAI system that provides precise and domain-specific explanations alongside its differential diagnoses of melanomas and nevi. Through a three-phase study, we assess its impact on dermatologists' diagnostic accuracy, diagnostic confidence, and trust in the XAI-support. Our results show strong alignment between XAI and dermatologist explanations. We also show that dermatologists' confidence in their diagnoses, and their trust in the support system significantly increase with XAI compared to conventional AI. This study highlights dermatologists' willingness to adopt such XAI systems, promoting future use in the clinic.

Non-biologic immunosuppressive drugs for inflammatory and autoimmune skin diseases.

Non-biologic immunosuppressive drugs, such as azathioprine, dapsone or methotrexate are fundamental treatment options for a wide range of autoimmune and chronic inflammatory skin diseases. Some of these drugs were initially used for malignancies (e.g., azathioprine or methotrexate) or infectious diseases (e.g., hydroxychloroquine or dapsone) but are nowadays mostly used for their immunosuppressive/immunomodulating action. Although dermatologists have years of clinical experience with these drugs, some of the mechanisms of action are not fully understood and are the subject of research. Although these drugs are commonly used, lack of experience or knowledge regarding their safety profiles and management leads to skepticism among physicians. Here, we summarize the mechanism of action and detailed management of adverse effects of the most commonly used immunosuppressive drugs for skin diseases. Furthermore, we discuss the management of these drugs during pregnancy and breastfeeding, as well as their interaction and handling during vaccination.

Selectivity, efficacy and safety of JAKinibs: new evidence for a still evolving story.

Fundamental insight gained over the last decades led to the discovery of cytokines as pivotal drivers of inflammatory diseases such as rheumatoid arthritis, psoriasis/psoriasis arthritis, inflammatory bowel diseases, atopic dermatitis and spondylarthritis. A deeper understanding of the pro-inflammatory and anti-inflammatory effects of various cytokines has prompted new cytokine-targeting therapies, which revolutionised the treatment options in the last years for patients with inflammatory disorders. Disease-associated immune responses typically involve a complex interplay of multiple cytokines. Therefore, blockade of one single cytokine does not necessarily lead to a persistent remission in all patients with inflammatory disorders and fostered new therapeutic strategies targeting intracellular pathways shared by multiple cytokines. By inhibiting JAK-STAT signalling pathways common to families of cytokines, JAK-inhibitors (JAKinibs) have created a new paradigm for the treatment of inflammatory diseases. Multiple agents have been approved for various disorders and more are being investigated for several new indications. Second-generation selective JAKinibs have been devised with the aim to achieve an increased selectivity and a possible reduced risk of side effects. In the current review, we will summarise the current body of evidence of pan versus selective JAKinibs and the most recent insights on new side effects and indications, including COVID-19.

Acidosis-mediated increase in IFN-γ-induced PD-L1 expression on cancer cells as an immune escape mechanism in solid tumors.

Immune checkpoint inhibitors have revolutionized cancer therapy, yet the efficacy of these treatments is often limited by the heterogeneous and hypoxic tumor microenvironment (TME) of solid tumors. In the TME, programmed death-ligand 1 (PD-L1) expression on cancer cells is mainly regulated by Interferon-gamma (IFN-γ), which induces T cell exhaustion and enables tumor immune evasion. In this study, we demonstrate that acidosis, a common characteristic of solid tumors, significantly increases IFN-γ-induced PD-L1 expression on aggressive cancer cells, thus promoting immune escape. Using preclinical models, we found that acidosis enhances the genomic expression and phosphorylation of signal transducer and activator of transcription 1 (STAT1), and the translation of STAT1 mRNA by eukaryotic initiation factor 4F (elF4F), resulting in an increased PD-L1 expression. We observed this effect in murine and human anti-PD-L1-responsive tumor cell lines, but not in anti-PD-L1-nonresponsive tumor cell lines. In vivo studies fully validated our in vitro findings and revealed that neutralizing the acidic extracellular tumor pH by sodium bicarbonate treatment suppresses IFN-γ-induced PD-L1 expression and promotes immune cell infiltration in responsive tumors and thus reduces tumor growth. However, this effect was not observed in anti-PD-L1-nonresponsive tumors. In vivo experiments in tumor-bearing IFN-γ-/- mice validated the dependency on immune cell-derived IFN-γ for acidosis-mediated cancer cell PD-L1 induction and tumor immune escape. Thus, acidosis and IFN-γ-induced elevation of PD-L1 expression on cancer cells represent a previously unknown immune escape mechanism that may serve as a novel biomarker for anti-PD-L1/PD-1 treatment response. These findings have important implications for the development of new strategies to enhance the efficacy of immunotherapy in cancer patients.

Blood T Helper Memory Cells: A Tool for Studying Skin Inflammation in HS?

Hidradenitis suppurativa (HS) is an inflammatory skin disease characterized by painful lesions on intertriginous body areas such as the axillary, inguinal, and perianal sites. Given the limited treatment options for HS, expanding our knowledge of its pathogenetic mechanisms is a prerequisite for novel therapeutic developments. T cells are assumed to play a crucial role in HS pathogenesis. However, it is currently unknown whether blood T cells show specific molecular alterations in HS. To address this, we studied the molecular profile of CD4+ memory T (Thmem) cells purified from the blood of patients with HS and matched healthy participants. About 2.0% and 1.9% of protein-coding transcripts were found to be up- and down-regulated in blood HS Thmem cells, respectively. These differentially expressed transcripts (DETs) are known to be involved in nucleoside triphosphate/nucleotide metabolic processes, mitochondrion organization, and oxidative phosphorylation. The detected down-regulation of transcripts involved in oxidative phosphorylation suggest a metabolic shift of HS Thmem cells towards glycolysis. The inclusion of transcriptome data from skin from HS patients and healthy participants in the analyses revealed that in HS skin lesions, the expression pattern of transcripts identified as DETs in blood HS Thmem cells was very similar to the expression pattern of the totality of protein-coding transcripts. Furthermore, there was no significant association between the extent of the expressional changes in the DETs of blood HS Thmem cells and the extent of the expressional changes in these transcripts in HS skin lesions compared to healthy donor skin. Additionally, a gene ontology enrichment analysis did not demonstrate any association of the DETs of blood HS Thmem cells with skin disorders. Instead, there were associations with different neurological diseases, non-alcoholic fatty liver disease, and thermogenesis. The levels of most DETs linked to neurological diseases showed a positive correlation to each other, suggesting common regulatory mechanisms. In summary, the transcriptomic changes in blood Thmem cells observed in patients with manifest cutaneous HS lesions do not appear to be characteristic of the molecular changes in the skin. Instead, they could be useful for studying comorbidities and identifying corresponding blood biomarkers in these patients.

Management of Infections in Psoriatic Patients Treated with Systemic Therapies: A Lesson from the Immunopathogenesis of Psoriasis.

Modern treatments continue to be developed based on identifying targets within the innate and adaptive immune pathways associated with psoriasis. Whilst there is a sound biologic rationale for increased risk of infection following treatment with immunomodulators, the clinical evidence is confounded by these agents being used in patients affected with several comorbidities. In an era characterized by an ever greater and growing risk of infections, it is necessary to always be updated on this risk. In this mini-review, we will discuss recent updates in psoriasis immunopathogenesis as a rationale for systemic therapy, outline the risk of infections linked to the disease itself and systemic therapy as well, and provide an overview of the prevention and management of infections.

Rapid and sustained improvements in Generalized Pustular Psoriasis Physician Global Assessment scores with spesolimab for treatment of generalized pustular psoriasis flares in the randomized, placebo-controlled Effisayil 1 study.

BACKGROUND: Effisayil 1 was a randomized, placebo-controlled study of spesolimab, which is an anti-IL-36 receptor antibody, in patients presenting with a generalized pustular psoriasis flare. OBJECTIVE: To assess the effects of spesolimab over the 12-week study. METHODS: The primary endpoint of the study was Generalized Pustular Psoriasis Physician Global Assessment (GPPGA) pustulation subscore of 0 at week 1. Patients (N = 53) were randomized (2:1) to receive a single intravenous dose of 900 mg spesolimab or placebo on day 1. Patients could receive open-label spesolimab for persistent flare symptoms on day 8. RESULTS: Most patients receiving spesolimab achieved a GPPGA pustulation subscore of 0 (60.0%) and GPPGA total score of 0 or 1 (60.0%) by week 12. In patients randomized to placebo who received open-label spesolimab on day 8, the proportion with GPPGA pustulation subscore of 0 increased from 5.6% at day 8 to 83.3% at week 2. No factors predictive of spesolimab response were identified in patient demographics or clinical characteristics. LIMITATIONS: The effect of initial randomization was not determined conventionally beyond week 1 due to patients receiving open-label spesolimab. CONCLUSION: Rapid control of generalized pustular psoriasis flare symptoms with spesolimab was sustained over 12 weeks, further supporting its potential use as a therapeutic option for patients.

Interleukin-21 in autoimmune and inflammatory skin diseases.

Studies on the role of interleukins (ILs) in autoimmune and inflammatory diseases allow for the better understanding of pathologic mechanisms of disease and reshaping of treatment modalities. The development of monoclonal antibodies targeting specific ILs or IL signaling pathways (i.e., anti-IL-17/IL-23 in psoriasis or anti-IL-4/IL-13 in atopic dermatitis) is the shining example of therapeutic interventions in research. IL-21, belonging to the group of ɣc-cytokines (IL-2, IL-4, IL-7, IL-9, and IL-15), is gaining attention for its pleiotropic role in several types of immune cells as activator of various inflammatory pathways. In both health and disease, IL-21 sustains T- and B-cell activity. Together with IL-6, IL-21 helps to generate Th17 cells, promotes CXCR5 expression in T cells, and their maturation into follicular T helper cells. In B cells, IL-21 sustains their proliferation and maturation into plasma cells and promotes class switching and antigen-specific antibody production. Due to these characteristics, IL-21 is a main factor in numerous immunologic disorders, such as rheumatoid arthritis and MS. Studies in preclinical skin disease models and on human skin strongly suggest that IL-21 is crucially involved in inflammatory and autoimmune cutaneous disorders. Here, we summarize the current knowledge of IL-21 in well-known skin diseases.

Interleukin-19 Levels Are Increased in Palmoplantar Pustulosis and Reduced following Apremilast Treatment.

Palmoplantar pustulosis (PPP) is a chronic inflammatory skin disease characterised by neutrophilic granulocyte (neutrophil)-filled pustules on the palms and soles. The pathogenesis of PPP is poorly understood. This study conducted an identification of the immune mediators associated with PPP and an exploration of apremilast treatment effects on them. We screened for immune mediators elevated in blood taken from 68 patients with PPP versus control participants and included the most promising parameters in the protocol of phase the 2, multicentre study of apremilast (PDE4 inhibitor) in 21 patients with moderate-to-severe PPP (APLANTUS; EudraCT 2016-005122-11) for respective analysis of blood and skin samples of study patients. We investigated stimulated neutrophils and three-dimensional reconstituted epidermis cultures. Interleukin (IL)-19 was found to be the most upregulated immune mediator in the blood of PPP patients. IL-19 serum levels were independent of patients' age, gender, and BMI but were associated with strongly upregulated cutaneous IL-19 expression and correlated with the number of palmoplantar pustules. In patients participating in the APLANTUS study, apremilast reduced pustules more effectively than erythema and scaling. Moreover, this treatment significantly reduced IL-19 blood and skin levels. The reduction in IL-19 blood levels at week 4 correlated with the reduction in pustule counts at week 20 (end of treatment). IL-19 was expressed by neutrophils activated in vitro and induced CXCL6, a neutrophil-attracting chemokine, in epidermis models. This work demonstrates elevated IL-19 levels in the blood and skin of PPP patients and suggests a relevant role of this cytokine in the appearance of pustules in this disorder. It also suggests the suitability of IL-19 blood levels as a predictive biomarker for the treatment response of PPP patients, which should be validated in further studies.