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.

Characterisation of RSV infections in children without chronic diseases aged 0-36 months during the post-COVID-19 winter season 2022/2023.

Background: Respiratory syncytial virus (RSV) is one of the leading causes of hospitalisation, morbidity, and mortality due to respiratory infection in the first years of life. This longitudinal prospective study outlines the 2022/23 season's viral patterns in Austria after the epidemiological changes determined by public health measures. We aimed to highlight differences within the RSV subtypes and genotypes in 0-36-month-old children without chronic diseases in the outpatient setting. Methods: From November 2022 to March 2023 children younger than 36 months admitted to Vienna's largest paediatric primary healthcare centre with an acute respiratory infection were enrolled in this study. Nasal swabs and multiplex PCR panels detected 20 viruses including RSV subtypes and genotypes. Clinical presentation, features, and treatment of the participants were documented and analysed using the Modified Tal Score (MTS). Patients were scheduled for a telemedical follow-up one week after the initial appointment. Analysis was done using descriptive statistics, including Cramér V and binominal logarithmic regression. Results: Among the 345 samples from 329 children, RSV was the most common virus (31.9%), followed by influenza (17.5%) and rhinovirus infections (20.58%). Of the RSV positive samples, only 13 cases were RSV subtype A (11.8%), whereas 97 were of subtype B (87.3%); ON1 and BA9 were the only detectable RSV genotypes (ON1: BA9 = 1:9.25). RSV was the main predictor of hospitalisation (OR: 7.5, 95% CI: (1.46-38.40), and age had a significant but smaller effect (OR: 0.89, 95% CI: (0.81-0.99). Almost all patients' clinical status improved within the first days. Conclusion: RSV cases showed a rapid onset in late November 2022, and subtype B was predominant throughout the season. RSV infection was associated with higher hospitalisation rates, even after excluding high-risk patients (preterm and severe chronic diseases population).Further testing in the upcoming winter seasons will improve our knowledge of the dominant subtype and its association with disease severity, especially with the development of novel RSV vaccine candidates.

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.

Design and Preclinical Characterization Program toward Asundexian (BAY 2433334), an Oral Factor XIa Inhibitor for the Prevention and Treatment of Thromboembolic Disorders.

Activated coagulation factor XI (FXIa) is a highly attractive antithrombotic target as it contributes to the development and progression of thrombosis but is thought to play only a minor role in hemostasis so that its inhibition may allow for decoupling of antithrombotic efficacy and bleeding time prolongation. Herein, we report our major efforts to identify an orally bioavailable, reversible FXIa inhibitor. Using a protein structure-based de novo design approach, we identified a novel micromolar hit with attractive physicochemical properties. During lead modification, a critical problem was balancing potency and absorption by focusing on the most important interactions of the lead series with FXIa while simultaneously seeking to improve metabolic stability and the cytochrome P450 interaction profile. In clinical trials, the resulting compound from our extensive research program, asundexian (BAY 2433334), proved to possess the desired DMPK properties for once-daily oral dosing, and even more importantly, the initial pharmacological hypothesis was confirmed.

[Blastic plasmacytoid dendritic cell neoplasm (BPDCN) : A rare hematologic neoplasm with frequent cutaneous involvement]. / Blastische plasmazytoide dendritische Zellneoplasie (BPDCN) : Eine seltene hämatologische Neoplasie mit häufiger kutaner Beteiligung.

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare hematological malignancy that derives from precursors of plasmacytoid dendritic cells and is characterized by disseminated, erythematous or bluish-livid plaques or nodi. Because of the disease's rarity the diagnosis and treatment still pose a significant challenge. We present a case of a patient with BPDCN and show clinical and diagnostic characteristics as well as potential treatment regimes.

[Diagnostics of ocular mucous membrane pemphigoid]. / Diagnostik des okulären Schleimhautpemphigoids.

The diagnosis of ocular mucous membrane pemphigoid (MMP) remains a challenge as the timing and choice of diagnostic methods have a decisive influence on its quality. A systematic approach is required that includes a comprehensive medical history, critical evaluation of the clinical findings and targeted laboratory testing. The diagnosis is complicated by the fact that some patients present purely clinically the symptoms of MMP without fulfilling the required immunohistochemical and laboratory criteria. Basically, the diagnosis of ocular MMP is based on three pillars: 1) medical history and clinical findings, 2) positive immunohistological (direct immunofluorescence) tissue sample and 3) specific serological autoantibodies. As the diagnosis of ocular MMP often implies prolonged systemic immunomodulatory treatment in predominantly older patients, the accurate diagnosis and approach are of critical relevance. The aim of this article is to present the recently updated diagnostic procedure.

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.

Prioritizing Small Sets of Molecules for Synthesis through in-silico Tools: A Comparison of Common Ranking Methods.

Prioritizing molecules for synthesis is a key role of computational methods within medicinal chemistry. Multiple tools exist for ranking molecules, from the cheap and popular molecular docking methods to more computationally expensive molecular-dynamics (MD)-based methods. It is often questioned whether the accuracy of the more rigorous methods justifies the higher computational cost and associated calculation time. Here, we compared the performance on ranking the binding of small molecules for seven scoring functions from five docking programs, one end-point method (MM/GBSA), and two MD-based free energy methods (PMX, FEP+). We investigated 16 pharmaceutically relevant targets with a total of 423 known binders. The performance of docking methods for ligand ranking was strongly system dependent. We observed that MD-based methods predominantly outperformed docking algorithms and MM/GBSA calculations. Based on our results, we recommend the application of MD-based free energy methods for prioritization of molecules for synthesis in lead optimization, whenever feasible.

Collaborative Assessment of Molecular Geometries and Energies from the Open Force Field.

Force fields form the basis for classical molecular simulations, and their accuracy is crucial for the quality of, for instance, protein-ligand binding simulations in drug discovery. The huge diversity of small-molecule chemistry makes it a challenge to build and parameterize a suitable force field. The Open Force Field Initiative is a combined industry and academic consortium developing a state-of-the-art small-molecule force field. In this report, industry members of the consortium worked together to objectively evaluate the performance of the force fields (referred to here as OpenFF) produced by the initiative on a combined public and proprietary dataset of 19,653 relevant molecules selected from their internal research and compound collections. This evaluation was important because it was completely blind; at most partners, none of the molecules or data were used in force field development or testing prior to this work. We compare the Open Force Field "Sage" version 2.0.0 and "Parsley" version 1.3.0 with GAFF-2.11-AM1BCC, OPLS4, and SMIRNOFF99Frosst. We analyzed force-field-optimized geometries and conformer energies compared to reference quantum mechanical data. We show that OPLS4 performs best, and the latest Open Force Field release shows a clear improvement compared to its predecessors. The performance of established force fields such as GAFF-2.11 was generally worse. While OpenFF researchers were involved in building the benchmarking infrastructure used in this work, benchmarking was done entirely in-house within industrial organizations and the resulting assessment is reported here. This work assesses the force field performance using separate benchmarking steps, external datasets, and involving external research groups. This effort may also be unique in terms of the number of different industrial partners involved, with 10 different companies participating in the benchmark efforts.

Early identification of axial psoriatic arthritis among patients with psoriasis: a prospective multicentre study.

OBJECTIVES: To evaluate a dermatologist-centred screening tool followed by a structured rheumatological examination including MRI of sacroiliac joints and spine for the recognition of psoriatic arthritis with axial involvement (axPsA). METHODS: This was a prospective multicentre study. Adult patients with a confirmed diagnosis of psoriasis who had chronic back pain (≥3 months), onset <45 years and had not been treated with any biologic or targeted synthetic disease-modifying antirheumatic drug in the 12 weeks before screening were referred to a specialised rheumatology clinic. A rheumatological investigation including clinical, laboratory and genetic assessments as well as imaging with conventional radiography and MRI of sacroiliac joints and spine was performed. The primary outcome of the study was the proportion of patients diagnosed with axPsA among all referred patients with PsO. RESULTS: Rheumatologists examined 100 patients of those who qualified for referral. 14 patients (including 3 with both axial and peripheral involvement) were diagnosed with axPsA and 5 were diagnosed with peripheral PsA solely. All patients diagnosed with axPsA had active inflammatory and/or structural (post)inflammatory changes in the sacroiliac joints and/or spine on imaging. In five patients, MRI changes indicative of axial involvement were found only in the spine. All but one patient with PsA (13/14 with axPsA and 5/5 with pPsA) fulfilled the Classification Criteria for Psoriatic Arthritis criteria for PsA. The Assessment of SpondyloArthritis International Society criteria for axSpA were fulfilled in 9 (64.3%) patients diagnosed with axPsA. CONCLUSIONS: Applying a dermatologist-centred screening tool may be useful for the early detection of axPsA in at-risk patients with psoriasis .

[Mucosal lichen planus-a diagnostic and therapeutic challenge]. / Lichen planus mucosae ­ eine diagnostische und therapeutische Herausforderung.

Mucosal lichen planus (MLP) is a chronic inflammatory disease of the mucosa. This condition can affect the mouth, esophagus, pharynx, genitalia, anus, and conjunctiva. This disease shows a tendency to chronicity with phases of relapses for a duration of 3-10 years. It presents with varying morphologies including lacy or fern-like, slightly raised striae, erosions, erythema, and atrophy. The pathophysiology is not yet fully understood and is dominated by the classic band-like lymphocytic infiltrate along the dermoepidermal junction. MLP is very challenging to treat, since the clinical course entails frequent relapses and shows resistance to therapy. The most commonly used local treatments are topical corticosteroids or calcineurin inhibitors. In addition to systemic glucocorticosteroids and traditional systemic drugs such as oral retinoids or methotrexate, emerging anti-inflammatory therapies such as Janus kinase inhibitors and biologics may be promising and are currently being evaluated in clinical trials.

[Granulomatous dermatoses]. / Granulomatöse Dermatosen.

The group of granulomatous dermatoses refers to a multitude of clinically different diseases, which are characterized by a histopathologically similar pattern of inflammation. The cause of granulomatous inflammatory reactions can be infections and also noninfectious stimuli, such as cell disintegration or foreign bodies. The aim of this immunological defence reaction is encapsulation in order to prevent further spread and delimitation from healthy tissue. This is histologically expressed as a granuloma in the sense of a circumscribed aggregation of histiocytes and multinucleated giant cells mostly in dermal connective tissue. The following can be histologically differentiated: sarcoid granuloma characterized by a sparse lymphocytic inflammatory infiltrate and tuberculous granuloma with central necrosis and denser lymphocytic inflammatory infiltrate. Neutrophilic granulocytes together with macrophages occur in suppurative granulomas and palisaded granulomas are characterized by peripherally arrayed macrophages.

Dsg1 and Dsg3 Composition of Desmosomes Across Human Epidermis and Alterations in Pemphigus Vulgaris Patient Skin.

Desmosomes are important epidermal adhesion units and signalling hubs, which play an important role in pemphigus pathogenesis. Different expression patterns of the pemphigus autoantigens desmoglein (Dsg)1 and Dsg3 across different epidermal layers have been demonstrated. However, little is known about changes in desmosome composition in different epidermal layers or in patient skin. The aim of this study was thus to characterize desmosome composition in healthy and pemphigus skin using super-resolution microscopy. An increasing Dsg1/Dsg3 ratio from lower basal (BL) to uppermost granular layer (GL) was observed. Within BL desmosomes, Dsg1 and Dsg3 were more homogeneously distributed whereas superficial desmosomes mostly comprised one of the two molecules or domains containing either one but not both. Extradesmosomal, desmoplakin (Dp)-independent, co-localization of Dsg3 with plakoglobin (Pg) was found mostly in BL and extradesmosomal Dsg1 co-localization with Pg in all layers. In contrast, in the spinous layer (SL) most Dsg1 and Dsg3 staining was confined to desmosomes, as revealed by the co-localization with Dp. In pemphigus patient skin, Dsg1 and Dsg3 immunostaining was altered especially along blister edges. The number of desmosomes in patient skin was reduced significantly in basal and spinous layer keratinocytes with only few split desmosomes found. In addition, Dsg1-Pg co-localization at the apical BL and Dsg3-Pg co-localization in SL were significantly reduced in patients, suggesting that that extradesmosomal Dsg molecules were affected. These results support the hypothesis that pemphigus is a desmosome assembly disease and may help to explain histopathologic differences between pemphigus phenotypes.