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Background The transmembrane-TNF transgenic mouse, TgA86, has been shown to develop spontaneously peripheral arthritis with signs of axial involvement. To assess similarity to human spondyloarthritis, we performed detailed characterization of the axial, peripheral, and comorbid pathologies of this model. Methods TgA86 bone pathologies were assessed at different ages using CT imaging of the spine, tail vertebrae, and hind limbs and characterized in detail by histopathological and immunohistochemical analysis. Cardiac function was examined by echocardiography and electrocardiography and bone structural parameters by μCT analysis. The response of TgA86 mice to either early or late anti-TNF treatment was evaluated clinically, histopathologically, and by μCT analysis. Results TgA86 mice developed with 100% penetrance spontaneous axial and peripheral pathology which progressed with time and manifested as reduced body weight and body length, kyphosis, tail bendings, as well as swollen and distorted hind joints. Whole-body CT analysis at advanced ages revealed bone erosions of sacral and caudal vertebrae as well as of sacroiliac joints and hind limbs and, also, new ectopic bone formation and eventually vertebral fusion. The pathology of these mice highly resembled that of SpA patients, as it evolved through an early inflammatory phase, evident as enthesitis and synovitis in the affected joints, characterized by mesenchymal cell accumulation, and neutrophilic infiltration. Subsequently, regression of inflammation was accompanied by ectopic bone formation, leading to ankylosis. In addition, both systemic bone loss and comorbid heart valve pathology were evident. Importantly, early anti-TNF treatment, similar to clinical treatment protocols, significantly reduced the inflammatory phase of both the axial and peripheral pathology of TgA86 mice. Conclusions The TgA86 mice develop a spontaneous peripheral and axial biphasic pathology accompanied by comorbid heart valvular dysfunction and osteoporosis, overall reproducing the progression of pathognomonic features of human spondyloarthritis. Therefore, the TgA86 mouse represents a valuable model for deciphering the role of transmembrane TNF in the pathogenic mechanisms of spondyloarthritis and for assessing the efficacy of human therapeutics targeting different phases of the disease.

Background New medications for Rheumatoid Arthritis (RA) have emerged in the last decades, including Disease Modifying Antirheumatic Drugs (DMARDs) and biologics. However, there is no known cure, since a significant proportion of patients remain or become non-responders to current therapies. The development of new mode-of-action treatment schemes involving combination therapies could prove successful for the treatment of a greater number of RA patients. Methods We investigated the effect of the Tyrosine Kinase inhibitors (TKIs) dasatinib and bosutinib, on the human TNF-dependent Tg197 arthritis mouse model. The inhibitors were administered either as a monotherapy or in combination with a subtherapeutic dose of anti-hTNF biologics and their therapeutic effect was assessed clinically, histopathologically as well as via gene expression analysis and was compared to that of an efficient TNF monotherapy. Results Dasatinib and, to a lesser extent, bosutinib inhibited the production of TNF and proinflammatory chemokines from arthritogenic synovial fibroblasts. Dasatinib, but not bosutinib, also ameliorated significantly and in a dose-dependent manner both the clinical and histopathological signs of Tg197 arthritis. Combination of dasatinib with a subtherapeutic dose of anti-hTNF biologic agents, resulted in a synergistic inhibitory effect abolishing all arthritis symptoms. Gene expression analysis of whole joint tissue of Tg197 mice revealed that the combination of dasatinib with a low subtherapeutic dose of Infliximab most efficiently restores the pathogenic gene expression profile to that of the healthy state compared to either treatment administered as a monotherapy. Conclusion Our findings show that dasatinib exhibits a therapeutic effect in TNF-driven arthritis and can act in synergy with a subtherapeutic anti-hTNF dose to effectively treat the clinical and histopathological signs of the pathology. The combination of dasatinib and anti-hTNF exhibits a distinct mode of action in restoring the arthritogenic gene signature to that of a healthy profile. Potential clinical applications of combination therapies with kinase inhibitors and anti-TNF agents may provide an interesting alternative to high-dose anti-hTNF monotherapy and increase the number of patients responding to treatment.

Animal models for inflammatory arthritides such as rheumatoid arthritis (RA) and psoriatic arthritis are widely accepted and frequently used to identify pathological mechanisms and validate novel therapeutic strategies. Unfortunately, many publications reporting on these animal studies lack detailed description and appropriate assessment of the distinct histopathological features of arthritis: joint inflammation, cartilage damage and bone erosion. Therefore, the European consortium BeTheCure, consisting of 38 academic and industrial partners from 15 countries, set as goal to standardise the histological evaluation of joint sections from animal models of inflammatory arthritis. The consensual approach of a task force including 16 academic and industrial scientists as well as laboratory technicians has resulted in the development of the Standardised Microscopic Arthritis Scoring of Histological sections (‘SMASH’) recommendations for a standardised processing and microscopic scoring of the characteristic histopathological features of arthritis, exemplified by four different rodent models for arthritis: murine collagen-induced arthritis, collagen–antibody-induced arthritis, human tumour necrosis factor transgenic Tg197 mice and rat pristane-induced arthritis, applicable to any other inflammatory arthritis model. Through standardisation, the SMASH recommendations are designed to improve and maximise the information derived from in vivo arthritis experiments and to promote reproducibility and transparent reporting on such studies. In this manuscript, we will discuss and provide recommendations for analysis of histological joint sections: identification of the regions of interest, sample preparation, staining procedures and quantitative scoring methods. In conclusion, awareness of the different features of the arthritis pathology in animal models of inflammatory arthritis is of utmost importance for reliable research outcome, and the standardised histological processing and scoring methods in these SMASH recommendations will help increase uniformity and reproducibility in preclinical research on inflammatory arthritis.

BackgroundSpondyloarthritis (SpA) describes a group of diseases characterised by a paradoxical simultaneous bone destruction and formation manifested as axial and peripheral pathologies. TNF is a key pathogenic factor with the strongest evidence of its leading role arising from the therapeutic effect of its inhibition in SpA patients. The TgA86 is a mouse model that overexpresses TNF and exhibits signs of spontaneous SpA. Our objective was to characterise the TgA86 pathology, identify its similarity to human disease and ultimately explore its potential to be used as the basis of a preclinical platform for the evaluation of SpA therapeutics and diagnostics.Materials and methodsTgA86 transgenic mice express deregulated mouse transmembrane TNF and develop with 100% incidence chronic inflammatory arthritis and axial pathology clinically manifested by a characteristic tail bending. We used clinical observations, histopathological analysis, x-ray and mu CT radiographic read-outs to establish a standardised pipeline for the evaluation of the TgA86 pathology.ResultsHistopathological, x-ray and mu CT analysis of the vertebral column revealed the presence of pathological findings closely resembling those observed in human SpA patients. More specifically, disease characteristics included soft tissue swelling, bone erosion, increased bone formation and replacement of the vertebra bar-bell shape with a rectangular shape. Moreover, TgA86 mice exhibited a concomitant development of aortic valve disease, an extraarticular co-morbidity observed in a significant percentage of SpA patients. This data support the similarity of the TgA86 pathology to that of the human disease. We further used a standardised set of the above-mentioned read-outs to validate the response of this model to human therapeutics. TgA86 animals treated with the commercially available human therapeutic Etanercept, exhibited significant amelioration of both peripheral and axial pathologies in a reproducible and dose-dependent manner thus establishing the translational value of this model in the evaluation of human therapeutics.ConclusionBiomedcode has standardised and validated a novel TgA86-based highly reproducible and sensitive efficacy preclinical platform for the evaluation of therapeutics targeting SpA. This platform can be further used to validate and evaluate the therapeutic effect of the blockade of additional pathological pathways associated with SpA including IL-17, Wnt signalling and others.

BackgroundSpondyloarthritis (SpA) describes a group of diseases characterised by a paradoxical simultaneous bone destruction and formation manifested as axial and peripheral pathologies. TNF is a key pathogenic factor with the strongest evidence of its leading role arising from the therapeutic effect of its inhibition in SpA patients. The TgA86 is a mouse model that overexpresses TNF and exhibits signs of spontaneous SpA. Our objective was to characterise the TgA86 pathology, identify its similarity to human disease and ultimately explore its potential to be used as the basis of a preclinical platform for the evaluation of SpA therapeutics and diagnostics.Materials and methodsTgA86 transgenic mice express deregulated mouse transmembrane TNF and develop with 100% incidence chronic inflammatory arthritis and axial pathology clinically manifested by a characteristic tail bending. We used clinical observations, histopathological analysis, x-ray and μCT radiographic read-outs to establish a standardised pipeline for the evaluation of the TgA86 pathology.ResultsHistopathological, x-ray and μCT analysis of the vertebral column revealed the presence of pathological findings closely resembling those observed in human SpA patients. More specifically, disease characteristics included soft tissue swelling, bone erosion, increased bone formation and replacement of the vertebra bar-bell shape with a rectangular shape. Moreover, TgA86 mice exhibited a concomitant development of aortic valve disease, an extraarticular co-morbidity observed in a significant percentage of SpA patients. This data support the similarity of the TgA86 pathology to that of the human disease. We further used a standardised set of the above-mentioned read-outs to validate the response of this model to human therapeutics. TgA86 animals treated with the commercially available human therapeutic Etanercept, exhibited significant amelioration of both peripheral and axial pathologies in a reproducible and dose-dependent manner thus establishing the translational value of this model in the evaluation of human therapeutics.ConclusionBiomedcode has standardised and validated a novel TgA86-based highly reproducible and sensitive efficacy preclinical platform for the evaluation of therapeutics targeting SpA. This platform can be further used to validate and evaluate the therapeutic effect of the blockade of additional pathological pathways associated with SpA including IL-17, Wnt signalling and others.

Objective: Interleukin-23 (IL-23) is a crucial cytokine implicated in chronic inflammation and autoimmunity, associated with various diseases like psoriasis, psoriatic arthritis, and systemic lupus erythematosus (SLE). This study aimed to create and characterize a transgenic mouse model (TghIL23A) overexpressing human IL23A, providing a valuable tool for investigating the pathogenic role of hIL23A and evaluating the efficacy of anti-human-IL23A therapeutics. Methods: TghIL23A mice were generated via microinjection of CBAxC57BL/6 zygotes with a fragment of the human IL23A gene, flanked by its 5'-regulatory sequences and the 3'UTR of human beta-globin. The TghIL23A pathology was assessed through hematological and biochemical analyses, cytokine and anti-nuclear antibody detection, histopathological examination of skin and renal tissues. The response to the anti-hIL23A therapeutic agent guselkumab, was evaluated in groups of 8 mixed-sex mice receiving subcutaneous treatment twice weekly for 10 weeks, using clinical, biomarker and histopathological readouts. Results: TghIL23A mice exhibited interactions between hIL23A and mouse IL23/IL12p40, and developed a chronic multiorgan autoimmune disease marked by proteinuria, anti-dsDNA antibodies, severe inflammatory lesions in the skin and milder phenotypes in the kidneys and lungs. The TghIL23A pathological features exhibited significant similarities to those observed in human SLE patients. Conclusions: We have generated and characterized a novel genetic mouse model of SLE, providing proof-of-concept for the etiopathogenic role of hIL-23A. This new model has a normal lifespan and integrates several characteristics of the human disease's complexity and chronicity making it an attractive preclinical tool for studying IL23-dependent pathogenic mechanisms and assessing the efficacy of anti-hIL23A or modeled disease-related therapeutics.Competing Interest StatementThe authors have declared no competing interest.

Background The transmembrane-TNF transgenic mouse, TgA86, has been shown to develop spontaneously peripheral arthritis with signs of axial involvement. To assess similarity to human spondyloarthritis we performed detailed characterization of the axial, peripheral and comorbid pathologies of this model. Methods TgA86 bone pathologies were assessed at different ages using CT imaging of the spine, tail vertebrae and hind limbs and characterized in detail by histopathological and immunohistochemical analysis. Cardiac function was examined by echocardiography and electrocardiography and bone structural parameters by µCT analysis. The response of TgA86 mice to either early or late anti-TNF treatment was evaluated clinically, histopathologically and by µCT analysis. Results TgA86 mice developed with 100% penetrance spontaneous axial and peripheral pathology which progressed with time and manifested as reduced body weight and body length, kyphosis, tail bendings as well as swollen and distorted hind joints. Whole body CT analysis at advanced ages revealed bone erosions of sacral and caudal vertebrae as well as of sacroiliac joints and hind limps, and also, new ectopic bone formation and eventually vertebral fusion. The pathology of these mice highly resembled that of SpA patients, as it evolved through an early inflammatory phase, evident as enthesitis and synovitis in the affected joints, characterized by mesenchymal cell accumulation and neutrophilic infiltration. Subsequently, regression of inflammation was accompanied by ectopic bone formation, leading to ankylosis. In addition, both systemic bone loss and comorbid heart valve pathology were evident. Importantly, early anti-TNF treatment, similar to clinical treatment protocols, significantly reduced the inflammatory phase of both the axial and peripheral pathology of TgA86 mice. Conclusions The TgA86 mice develop a spontaneous peripheral and axial biphasic pathology accompanied by comorbid heart valvular dysfunction and osteoporosis, overall reproducing the progression of pathognomonic features of human spondyloarthritis. Therefore, the TgA86 mouse represents a valuable model for deciphering the role of transmembrane TNF in the pathogenic mechanisms of spondyloarthritis and for assessing the efficacy of human therapeutics targeting different phases of the disease.

Background: The transmembrane-TNF transgenic mouse, TgA86, has been shown to develop spontaneously peripheral arthritis with signs of axial involvement. To assess similarity to human spondyloarthritis we performed detailed characterization of the axial, peripheral and comorbid pathologies of this model. Methods: TgA86 bone pathologies were assessed at different ages using CT imaging of the spine, tail vertebrae and hind limbs and characterized in detail by histopathological and immunohistochemical analysis. Cardiac function was examined by echocardiography and electrocardiography and bone structural parameters by μCT analysis. The response of TgA86 mice to either early or late anti-TNF treatment was evaluated clinically, histopathologically and by μCT analysis. Results: TgA86 mice developed with 100% penetrance spontaneous axial and peripheral pathology which progressed with time and manifested as reduced body weight and body length, kyphosis, tail bendings as well as swollen and distorted hind joints. Whole body CT analysis at advanced ages revealed bone erosions of sacral and caudal vertebrae as well as of sacroiliac joints and hind limps, and also, new ectopic bone formation and eventually vertebral fusion. The pathology of these mice highly resembled that of SpA patients, as it evolved through an early inflammatory phase, evident as enthesitis and synovitis in the affected joints, characterized by mesenchymal cell accumulation and neutrophilic infiltration. Subsequently, regression of inflammation was accompanied by ectopic bone formation, leading to ankylosis. In addition, both systemic bone loss and comorbid heart valve pathology were evident. Importantly, early anti-TNF treatment, similar to clinical treatment protocols, significantly reduced the inflammatory phase of both the axial and peripheral pathology of TgA86 mice. Conclusions: The TgA86 mice develop a spontaneous peripheral and axial biphasic pathology accompanied by comorbid heart valvular dysfunction and osteoporosis, overall faithfully reproducing the progression of pathognomonic features of human spondyloarthritis. Therefore, the TgA86 mouse represents a valuable model for deciphering the pathogenic mechanisms of spondyloarthritis and for assessing the efficacy of human therapeutics targeting different phases of the disease. Competing Interest Statement Prof. George Kollias participates in the BoD of Biomedcode; Dr. Florian Meier has received grants from Pfizer. All other authors declare no competing interests.

Coronavirus disease 2019 (COVID-19)-associated pulmonary aspergillosis (CAPA) has emerged as an important complication among patients with acute respiratory failure due to SARS-CoV-2 infection. Almost 2.5 years since the start of the COVID-19 pandemic, it continues to raise concerns as an extra factor that contributes to increased mortality, which is mostly because its diagnosis and management remain challenging. The present study utilises the cases of forty-three patients hospitalised between August 2020 and February 2022 whose information was gathered from ten ICUs and special care units based in northern Greece. The main aim was to describe the gained experience in diagnosing CAPA, according to the implementation of the main existing diagnostic consensus criteria and definitions, and present the different classification of the clinical cases due to the alternative algorithms.