TYK2-Inhibition: Potenzial bei der Behandlung chronisch-entzündlicher Immunerkrankungen - Ghoreschi, Kamran; Augustin, Matthias; Baraliakos, Xenofon; Krönke, Gerhard; Schneider, Matthias; Schreiber, Stefan; Schulze-Koops, Hendrik; Zeißig, Sebastian; Thaçi, Diamant (Journal der Deutschen Dermatologischen Gesellschaft, 2021)
CRIS-Team Scopus Importer:2021-10-29

Type 2 innate lymphoid cell counts are increased in patients with systemic sclerosis and correlate with the extent of fibrosis - Wohlfahrt, Thomas; Usherenko, Svetlana; Englbrecht, Matthias; Dees, Clara; Weber, Stefanie; Beyer, Christian; Gelse, Kolja; Distler, Oliver; Schett, Georg; Distler, Jörg; Ramming, Andreas (Annals of the Rheumatic Diseases, 2016)
Objective Type 2 innate lymphoid cells (ILC2s), a recently identified population of lymphoid cells lacking lineage-specific receptors, promote type 2 immunity and tissue remodelling. However, the contributive role of ILC2s in the pathogenesis of systemic sclerosis (SSc) is unknown. We aimed to evaluate the levels and correlations with fibrotic manifestations in SSc. Methods 69 patients with SSc and 47 healthy controls were included. Blood samples and skin sections were analysed by flow cytometry and immunohistochemically by staining two complementary panels of markers. Results Dermal and circulating ILC2s were significantly elevated in patients with SSc compared with controls. Dermal, but not circulating ILC2s were activated. Stratification of the SSc population in patients with limited cutaneous SSc (lcSSc) and diffuse cutaneous SSc (dcSSc) demonstrated increased levels of ILC2s in both subgroups with significantly higher frequencies in dcSSc compared with lcSSc. Moreover, dermal and circulating ILC2 counts correlated closely with the modified Rodnan skin score and with the presence of pulmonary fibrosis. Conclusions ILC2 counts are elevated in patients with SSc and correlate with the extent of skin fibrosis and the presence of interstitial lung disease providing compelling evidence for profibrotic effect of ILC2s in SSc.
EVALuna2:13149

TYPE 2 INNATE LYMPHOID CELLS ARE RAPIDLY AND PERSISTENTLY RECRUITED IN EXPERIMENTAL FIBROSIS AND THEIR COUNTS CORRELATE WITH THE SEVERITY OF SKIN AND LUNG FIBROSIS IN SYSTEMIC SCLEROSIS - Wohlfahrt, T.; Weber, Stefanie; Englbrecht, Matthias; Dees, Clara; Beyer, Christian; Distler, O.; Schett, Georg; Distler, Jörg; Ramming, A. (2016)
EVALuna2:13485

Type 2 Innate Lymphoid Cells - Cellular Source of Profibrotic Mediators Rapidly and Persistently Recruited in Experimental Fibrosis and Systemic Sclerosis - Weber, Stefanie; Wohlfahrt, Thomas; Rauber, Simon; Luber, Markus; Englbrecht, Matthias; Dees, Clara; Beyer, Christian; Distler, Oliver; Schett, Georg; Distler, Jörg; Ramming, Andreas (2016)
EVALuna2:35067

Type 2 innate lymphoid cells inhibit the differentiation of osteoclasts and protect from ovariectomy-induced bone loss - Omata, Yasunori; Frech, Michael; Lucas, Sébastien; Primbs, Tatjana; Knipfer, Lisa; Wirtz, Stefan; Kadono, Yuho; Saito, Taku; Tanaka, Sakae; Sarter, Kerstin; Schett, Georg; Zaiss, Mario (Bone, 2020)
While the role of T cells in the regulation of bone homeostasis is well defined, little is known about the role of innate lymphoid cells (ILCs) on bone. ILCs are innate immune cells that share cytokine expression patterns with T cells but lack the T cell receptor. In this study we show that type 2 ILCs (ILC2) potently inhibit the generation of bone resorbing osteoclasts in vitro as well as favorably influence bone homeostasis under steady state conditions in vivo using loss and gain of function models. Furthermore, adoptive transfer of ILC2 completely abrogated ovariectomy-induced bone loss by significantly down-regulating osteoclast numbers in vivo. The suppressive effects of ILC2s on osteoclasts in vitro and in vivo as well as the protection from ovariectomy-induced bone loss were linked to their expression of IL-4 and IL-13 as well as STAT6 activation on the myeloid target cell, since deletion of IL-4/IL-13 in ILC2s or STAT6 in osteoclast precursors abrogated the anti-osteoclastogenic effect of ILC2s. Taken together, these findings show that ILC2 have to be considered as potent regulators of bone homeostasis.
CRIS-Team Scopus Importer:2020-04-14
Keywords: Bone loss; Cytokines; ILC2; Osteoclasts; Osteoimmunology; Type 2 innate lymphoid cells type

TYPE 3 INNATE LYMPHOID CELLS ARE KEY DRIVERS OF PSORIATIC ARTHRITIS - Raimondo, M. G.; Rauber, S.; Luber, M.; Rigau, A. Rius; Weber, Stefanie; Anchang, Charles Gwellem; Agarwal, Rahul; Soare, A.; Sticherling, Michael; Rech, Jürgen; Kleyer, Arnd; Distler, Jörg; et al. (ANNALS OF THE RHEUMATIC DISEASES, 2020)
CRIS-Team WoS Importer:2020-08-21

Type 3 Innate Lymphoid Cells in models of psoriasis and psoriatic arthritis - Raimondo, M. G.; Rauber, Simon; Distler, Jörg; Schett, Georg; Ramming, A. (EUROPEAN JOURNAL OF IMMUNOLOGY, 2019)
CRIS-Team WoS Importer:2019-10-08

Tyrosine Kinase Inhibitor Nintedanib Reduces Development of Transplant Vasculopathy in a Murine Aortic Transplantation Model - Gocht, A.; Ensminger, S. M.; Distler, Jörg; Spriewald, B.; Ramsperger-Gleixner, Martina; Weyand, Michael; Heim, Christian (2017)
EVALuna2:35050

Ubiquitous Micro-Modular Homologies among Genomes from Viruses to Bacteria to Human Mitochondrial DNA: Platforms for Recombination during Evolution? - Weber, Stefanie; Ramirez, Christina M.; Dörfler, Walter (Viruses, 2022)
The emerging Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) and its variants have raised tantalizing questions about evolutionary mechanisms that continue to shape biology today. We have compared the nucleotide sequence of SARS-CoV-2 RNA to that of genomes of many different viruses, of endosymbiotic proteobacterial and bacterial DNAs, and of human mitochondrial DNA. The entire 4,641,652 nt DNA sequence of Escherichia coli K12 has been computer-matched to SARS-CoV-2 RNA. Numerous, very similar micro-modular clusters of 3 to 13 nucleotides lengths were detected with sequence identities of 40 to >50% in specific genome segments between SARS-CoV-2 and the investigated genomes. These clusters were part of patch-type homologies. Control sequence comparisons between 1000 randomly computer-composed sequences of 29.9 kb and with the A, C, G, T base composition of SARS-CoV-2 genome versus the reference Wuhan SARS-CoV-2 sequence showed similar patterns of sequence homologies. The universal A, C, G, T genetic coding mode might have succeeded in evolution due in part to its built-in capacity to select for a substantial reservoir of micro-modular domains and employ them as platforms for integrative recombination. Their role in SARS-CoV-2 interspecies transition and the generation of variants appears likely, but their actual involvement will require detailed investigations.
CRIS-Team Scopus Importer:2022-05-13
Keywords: Four letter genetic encoding system; Micro-modular identities in 1000 randomized SARS-CoV-2 genomes; Micro-modular sequence identities; Patch type sequence similarities; SARS-CoV-2 RNA compared to genomes of many viruses; protobacteria; Escherichia coli; Signals for evolution; annealing and integrative recombination; The 4; 641; 652 nt DNA sequence of Escherichia coli K12

Ultra low‐parameter denoising: Trainable bilateral filter layers in computed tomography - Wagner, Fabian; Thies, Mareike; Gu, Mingxuan; Huang, Yixing; Pechmann, Sabrina; Patwari, Mayank; Ploner, Stefan; Aust, Oliver; Uderhardt, Stefan; Schett, Georg; Christiansen, Silke H.; Maier, Andreas (Medical Physics, 2022)
Background Computed tomography (CT) is widely used as an imaging tool to visualize three-dimensional structures with expressive bone-soft tissue contrast. However, CT resolution can be severely degraded through low-dose acquisitions, highlighting the importance of effective denoising algorithms. Purpose Most data-driven denoising techniques are based on deep neural networks and, therefore, contain hundreds of thousands of trainable parameters, making them incomprehensible and prone to prediction failures. Developing understandable and robust denoising algorithms achieving state-of-the-art performance helps to minimize radiation dose while maintaining data integrity. Methods This work presents an open-source CT denoising framework based on the idea of bilateral filtering. We propose a bilateral filter that can be incorporated into any deep learning pipeline and optimized in a purely data-driven way by calculating the gradient flow toward its hyperparameters and its input. Denoising in pure image-to-image pipelines and across different domains such as raw detector data and reconstructed volume, using a differentiable backprojection layer, is demonstrated. In contrast to other models, our bilateral filter layer consists of only four trainable parameters and constrains the applied operation to follow the traditional bilateral filter algorithm by design. Results Although only using three spatial parameters and one intensity range parameter per filter layer, the proposed denoising pipelines can compete with deep state-of-the-art denoising architectures with several hundred thousand parameters. Competitive denoising performance is achieved on x-ray microscope bone data and the 2016 Low Dose CT Grand Challenge data set. We report structural similarity index measures (SSIM) of 0.7094 and 0.9674 and peak signal-to-noise ratio (PSNR) values of 33.17 and 43.07 on the respective data sets. Conclusions Due to the extremely low number of trainable parameters with well-defined effect, prediction reliance and data integrity is guaranteed at any time in the proposed pipelines, in contrast to most other deep learning-based denoising architecture
Keywords: known operator learning; low-dose CT; bilateral filter; denoising

Ultrasound Demonstrates Continued Improvement in Psoriatic Arthritis Synovitis and Enthesitis with Secukinumab: 52-week Results from a Phase III Study - D'Agostino, Maria Antonietta; Schett, Georg; Gaillez, Corine; Guerrero, Carlos; Hanova, Petra; Cazenave, Tomas; Stoenoiu, Maria S.; Backhaus, Marina; Mouterde, Gael; Boers, Maarten; Duggan, Anne-Marie; Goyanka, Punit; et al. (ARTHRITIS & RHEUMATOLOGY, 2021)
CRIS-Team WoS Importer:2022-03-11

Ultrasound-detected inflammation is more common in clinically manifest hand osteoarthritis than in painless bony enlarged finger joints: subanalysis of the population-based Bruneck study - Gasperi, Nina; Schreiber, Nikolaus; Bosch, Philipp; Adinolfi, Antonella; Kleyer, Arnd; Hagen, Melanie; Gasperi, Christiane; Weger, Martin; Kiechl, Stefan; Willeit, Johann; Schett, Georg; Iagnocco, Annamaria; et al. (Therapeutic Advances in Musculoskeletal Disease, 2022)
Purpose: The aim of this article is to examine the extent of structural and inflammatory lesions by ultrasound in elderly subjects with hand osteoarthritis (HOA) fulfilling the ACR classification criteria (Group A), in subjects with painless enlarged finger joints (Group B), and in individuals without clinical abnormalities at hands (Group C).
CRIS-Team WoS Importer:2022-06-03

Ultrasound scans and dual energy CT identify tendons as preferred anatomical location of MSU crystal depositions in gouty joints - Yuan, Yuan; Liu, Chang; Xiang, Xi; Yuan, Tong-Ling; Qiu, Li; Liu, Yi; Luo, Yu-Bin; Zhao, Y.; Herrmann, Martin (Rheumatology International, 2018)
The present study was performed to localize the articular deposition of monosodium urate (MSU) crystal in joints. We compare the detection efficiencies of dual-energy CT (DECT) and ultrasound scans. Analyses by DECT and ultrasound were performed with 184 bilateral joints of the lower limbs of 54 consecutive gout patients. All joints were categorized into (1) knee, (2) ankle, (3) MTP1, and (4) MTP2, and sorted into those with and those without detectable MSU deposition. The comparison of the positive rate between DECT and ultrasound and the agreement was performed using the McNemar test and the Cohen's kappa coefficient, respectively. Next, we listed the MSU crystal deposition as assessed by ultrasound between the DECT-positive and -negative joints according to their interior structure. We included tendons, synovia, cartilage, subcutaneous tissue, etc. Among all joints, the percentages with MSU crystal deposition detected by DECT (99/184, 53.8%) and ultrasound (106/184, 57.6%) were comparable (P = 0.530 > 0.05). For MTP1 (21/34, 61.8%; 12/34, 35.3%; P < 0.05) and MTP2-5 (17/34, 50.0%; 10/34, 29.4%, P < 0.05), ultrasound and DECT were more efficient, respectively. The data concordance in 46 of 50 joints (92.00%; kappa = 0.769, P < 0.05) for knee; and 27 of 34 joints (79.41%; kappa = 0.588, P < 0.05) for MTP2-5 and suggested that tendons were the most frequent anatomical location of MSU crystal deposition. The tendons are the most frequent anatomical location of MSU crystal depositions. The concordance rate of knee joints and MTP2-5 joints shows good agreement between DECT and ultrasound depending on the location.
EVALuna2:213269

Unconventional apoptosis of polymorphonuclear neutrophils (PMN): staurosporine delays exposure of phosphatidylserine and prevents phagocytosis by M?-2 macrophages of PMN - Franz, S.; Munoz, Luis Enrique; Heyder, P.; Herrmann, Martin; Schiller, M.; Munoz Becerra, Luis (Clinical and Experimental Immunology, 2015)
Apoptosis of polymorphonuclear neutrophils (PMN) and subsequent 'silent' removal represents an important check-point for the resolution of inflammation. Failure in PMN clearance resulting in secondary necrosis-driven tissue damage has been implicated in conditions of chronic inflammation and autoimmunity. Apoptotic PMN undergo profound biophysical changes that warrant their efficient recognition and uptake by phagocytes before fading to secondary necrosis. In this study, we demonstrate that staurosporine (STS), a non-selective but potent inhibitor of cyclin-dependent kinase and protein kinase C, exerts a drastic impact on PMN apoptosis. PMN treated with STS underwent an unconventional form of cell death characterized by a delayed exposure of aminophospholipids, including phosphatidylserine (PS) and phosphatidylethanolamine and an increased exposure of neo-glycans. STS caused an impaired cellular fragmentation and accelerated DNA fragmentation. Phagocytosis of STS-treated PMN lacking PS on their surfaces was decreased significantly, which highlights the importance of PS for the clearance of apoptotic PMN. Specific opsonization with immune complexes completely restored phagocytosis of STS-treated PMN, demonstrating the efficiency of back-up clearance pathways in the absence of PS exposure.
EVALuna2:13057

Understanding Ankylosing Spondylitis - - Kleyer, Arnd; Pachowsky, Milena; Schuster, Louis; Valor-Mendez, Larissa; Schett, Georg; Hueber, Axel; Simon, David (ARTHRITIS & RHEUMATOLOGY, 2020)
CRIS-Team WoS Importer:2021-01-15

Unilateral plantar erythema nodosum in sarcoidosis - Hueber, Axel; Schett, Georg; Manger, Bernhard (Arthritis and Rheumatology, 2017)
A 32-year old male Caucasian patient presented with mild exertional dyspnea, pain and swelling of both ankles, and general malaise. On examination symmetrical arthritis of both ankles and a vivid nodular erythema with slight pain on pressure was detected on the sole of the right foot (A). A therapy with ibuprofen had not led to any improvement of symptoms. This article is protected by copyright. All rights reserved.
EVALuna2:13347

Unmet Information Needs of Patients with Rheumatic Diseases: Results of a Cross-Sectional Online Survey Study in Germany - Becker, Christian; Diener, Matthias; Hueber, Axel J.; Henes, Joerg; Krusche, Martin; Ignatyev, Yuriy; May, Susann; Erstling, Ulrike; Elling-Audersch, Corinna; Knitza, Johannes; Muehlensiepen, Felix (International Journal of Environmental Research and Public Health, 2022)
To effectively self-manage a chronic disease, patients require specific education. In clinical routines, rheumatologists and other healthcare professionals often cannot devote the necessary time to adequately educate their patients. Digital technologies such as mobile applications represent promising tools to overcome this problem. This study aims to identify unmet information needs of patients with rheumatic diseases to inform the conception of a mobile education application. An online national survey was developed together with rheumatic patients and rheumatologists and distributed between June and September 2021 via social media (Instagram, Facebook, Twitter), QR code and email. Self-reported rheumatic patients, rheumatologists, specialized rheumatology nurses (SRN) and self-reported relatives of rheumatic patients were eligible to participate in the survey. Three major topics were addressed: (1) How well do patients feel informed about disease-relevant topics; (2) how important do patients rate different disease-relevant topics; and (3) patient willingness to adopt digital education services. Responses of 254 patients and 53 SRN were analyzed. Most patients were female (91%; n = 231), the median age was 48 years and the most common disease was rheumatoid arthritis (23%; n = 59). Only 24% of patients perceived their disease education level as very good or good compared to an SRN estimate of 42%. The three information topics rated as most important (very/important) were: individual disease (98%), medication (94%) and coping techniques (91%). In total, 89% of patients asserted that they would very likely, likely or rather likely use digital education tools in the future to learn about their condition, and 82% of SRN would very likely, likely or rather likely recommend digital information services to their patients. These findings depict currently unmet patient information needs and a high willingness of patients and SRN to use digital education services. A mobile education application is currently adapted based on these results and will be evaluated in a multicenter study.
CRIS-Team WoS Importer:2022-07-08

Unraveling the mysteries of plasma cells - Schuh, Wolfgang; Mielenz, Dirk; Jäck, Hans-Martin (Advances in Immunology, 2020)
Antibody-secreting plasma cells are the central pillars of humoral immunity. They are generated in a fundamental cellular restructuring process from naive B cells upon contact with antigen. This outstanding process is guided and controlled by a complex transcriptional network accompanied by a fascinating morphological metamorphosis, governed by the combined action of Blimp-1, Xbp-1 and IRF-4. The survival of plasma cells requires the intimate interaction with a specific microenvironment, consisting of stromal cells and cells of hematopoietic origin. Cell-cell contacts, cytokines and availability of metabolites such as glucose and amino acids modulate the survival abilities of plasma cells in their niches. Moreover, plasma cells have been shown to regulate immune responses by releasing cytokines. Furthermore, plasma cells are central players in autoimmune diseases and malignant transformation of plasma cells can result in the generation of multiple myeloma. Hence, the development of sophisticated strategies to deplete autoreactive plasma cells and myeloma cells represents a challenge for current and future research.
CRIS-Team Scopus Importer:2020-03-10
Keywords: Blimp-1; IRF-4; Longevity; Multiple myeloma; Plasma cell; Survival niche; Xbp-1

Unsupervised Super Resolution in X-ray Microscopy using a Cycle-consistent Generative Model - Raghunath, Adarsh; Wagner, Fabian; Thies, Mareike; Gu, Mingxuan; Pechmann, Sabrina; Aust, Oliver; Weidner, Daniela; Neag, Georgiana; Schett, Georg; Christiansen, Silke H.; Uderhardt, Stefan; Maier, Andreas (Bildverarbeitung für die Medizin 2023, 2023)
X-ray microscopy (XRM) is a tomographic imaging modality that has gained interest in the context of understanding bone-related diseases on the micro scale due to its high spatial resolution and strong bone to soft tissue contrast. Although in-vivo imaging of bone structures on the micro scale is desired from a medical perspective, high radiation dose so-far prohibits imaging living animals. Research has been focused on generating high-quality reconstructions while maintaining a low X-ray dosage. However, low dose acquisitions result in noisy images with a lower resolution. This study focuses on using an unsupervised deep-learning approach to accurately reconstruct high-resolution (HR) XRM images from their noisy low-resolution (LR) counterparts. We consider an unsupervised approach in a general case where paired data (low-/high resolution pairs) are unavailable. We propose the use of a cycle-consistent generative adversarial network (GAN) for this super resolution task which is to learn the mapping from noisy LR to HR images. Quantitative and qualitative assessments show that our method produces accurate high-resolution XRM reconstructions from their noisy low-resolution counterparts, increasing the peak signal-to-noise ratio (PSNR)/structural similarity index (SSIM) from 18.15/0.52 (baseline) to 31.94/0.73 (proposed method). We believe that our proposed XRM super resolution pipeline provides a valuable tool toward high-resolution in-vivo XRM imaging.<br

Update of EULAR recommendations for the treatment of systemic sclerosis - Kowal-Bielecka, Otylia; Fransen, Jaap; Avouac, Jerome; Becker, Mike; Kulak, Agnieszka; Allanore, Yannick; Distler, Oliver; Clements, Philip; Cutolo, Maurizio; Czirjak, Laszlo; Damjanov, Nemanja; Del Galdo, Francesco; et al. (Annals of the Rheumatic Diseases, 2017)
The aim was to update the 2009 European League against Rheumatism (EULAR) recommendations for the treatment of systemic sclerosis (SSc), with attention to new therapeutic questions. Update of the previous treatment recommendations was performed according to EULAR standard operating procedures. The task force consisted of 32 SSc clinical experts from Europe and the USA, 2 patients nominated by the pan-European patient association for SSc (Federation of European Scleroderma Associations (FESCA)), a clinical epidemiologist and 2 research fellows. All centres from the EULAR Scleroderma Trials and Research group were invited to submit and select clinical questions concerning SSc treatment using a Delphi approach. Accordingly, 46 clinical questions addressing 26 different interventions were selected for systematic literature review. The new recommendations were based on the available evidence and developed in a consensus meeting with clinical experts and patients. The procedure resulted in 16 recommendations being developed (instead of 14 in 2009) that address treatment of several SSc-related organ complications: Raynaud's phenomenon (RP), digital ulcers (DUs), pulmonary arterial hypertension (PAH), skin and lung disease, scleroderma renal crisis and gastrointestinal involvement. Compared with the 2009 recommendations, the 2016 recommendations include phosphodiesterase type 5 (PDE-5) inhibitors for the treatment of SSc-related RP and DUs, riociguat, new aspects for endothelin receptor antagonists, prostacyclin analogues and PDE-5 inhibitors for SSc-related PAH. New recommendations regarding the use of fluoxetine for SSc-related RP and haematopoietic stem cell transplantation for selected patients with rapidly progressive SSc were also added. In addition, several comments regarding other treatments addressed in clinical questions and suggestions for the SSc research agenda were formulated. These updated data-derived and consensus-derived recommendations will help rheumatologists to manage patients with SSc in an evidence-based way. These recommendations also give directions for future clinical research in SSc.
EVALuna2:13433

Update on imaging in gout: contrasting and comparing the role of dual-energy computed tomography to traditional diagnostic and monitoring techniques - Bayat, Sara; Baraf, H. S. B.; Rech, Jürgen (Clinical and Experimental Rheumatology, 2018)
In this systematic literature review, we update imaging modalities in gout, with a focus on newer technologies, particularly Dual-energy computed tomography (DECT). Conventional radiography (CR), ultrasonography (US), magnetic resonance imaging (MRI), computed tomography (CT) and dual-energy CT (DECT) have been used to evaluate different stages and clinical manifestations of gout and hyperuricaemia. We compare and contrast these modalities across the spectrum of this disease and of clinical scenarios and objectives (1).
EVALuna2:35013

Update on the "Choosing Wisely" initiative in infectious diseases in Germany. - Draenert, Rika; Jung, Norma; Addo, Marylyn; Berner, Reinhard; Bickel, Markus; Bogner, Johannes R.; Cornely, Oliver A.; De With, Katja; Faetkenheuer, Gerd; Hagel, Stefan; Hanses, Frank; Harrer, Thomas; et al. (Infection, 2020)
PURPOSE: The Choosing Wisely® initiative is an international campaign addressing over- and underuse of diagnostic and therapeutic measures in infectious diseases among others. Since 2016, the German Society for Infectious Diseases (DGI) has constantly designed new items in this regard. Here we report the most recent recommendations. METHODS: The recommendations of the DGI are part of the "Klug entscheiden" initiative of the German Society of Internal Medicine (DGIM). Topics for the new items were suggested by members of the DGI, checked for scientific evidence and consented within the DGI and the DGIM before publication. RESULTS: The new recommendations are: (1) individuals with immune-suppression, advanced liver cirrhosis or renal insufficiency should receive a dual pneumococcal vaccination. (2) In case of positive blood cultures with Candida spp. thorough diagnostics and treatment should be initiated. (3) In case of suspected meningitis, adult patients should receive dexamethasone and antibiotics immediately after venipuncture for blood cultures and before potential imaging. (4) In case of suspected meningitis a CT scan before lumbar puncture should not be ordered-except for symptoms indicating high CSF pressure or focal brain pathology or in cases of severe immune-suppression. (5) In patients with suspected severe infections, a minimum of two pairs of blood cultures should be drawn using separate venipunctures prior to antibiotic therapy-regardless of body temperature. There is no need of a minimum time interval in between the blood draws. CONCLUSION: Applying these new Choosing Wisely® recommendations will increase patient safety and the value of health care.
EVALuna2:216771
Keywords: Blood cultures; Choosing Wisely; Infectious diseases; Meningitis; Vaccination

Updates on NET formation in health and disease - Leppkes, Moritz; Schick, Maximilian; Hohberger, Bettina; Mahajan, Aparna; Knopf, Jasmin; Schett, Georg; Munoz, Luis Enrique; Herrmann, Martin (Seminars in Arthritis and Rheumatism, 2019)
Following a recent presentation at ATT Mallorca in May 2019, this paper gives insight into the current research of neutrophil extracellular traps (NETs) and their role in conditions of health and disease. Though NETs reportedly support disease progression and play a role in the development of autoimmune diseases, we argue that NETs are mandatory for the mammalian immune system. They are especially important to patrol and surveil outer and inner body surfaces and are capable to perform major anti-microbial activities. Neutrophils are the first cells to be recruited to wounds, where they form NETs and aggregated NETs (aggNETs). The latter close the wounds and are ever-present in skinfolds, where the integrity of the skin is impaired. On infected ocular surfaces NETs form an antimicrobial barrier, which prevents bacterial dissemination into the brain. In the oral cavity, NETs display anti-bacterial properties. Although NETs on internal body surfaces like ducts and vessels offer superficial surveillance, exaggerated aggNET formation may directly block vessels and ducts and thus cause thrombi and ductal occlusion, respectively. In the case of biliopancreatic ducts, clogging by aggNETs may even cause acute pancreatitis. Insufficient clearance of apoptotic remnants and NETs can lead to autoimmune diseases or unwanted, chronic inflammation. To prevent this, macrophages cloak dead cells, while apoptotic cells are cleared. We conclude that neutrophils, NETs and aggNETs can be considered double edged swords that orchestrate the innate immune response but carry the risk to precipitate autoimmunity and epithelial damage.
CRIS-Team Scopus Importer:2019-12-03
Keywords: aggNETs; Apoptosis; Clearance; Ductal occlusion; Innate inflammation; NETs; Thrombi

Upper zone of growth plate and cartilage matrix associated protein protects cartilage during inflammatory arthritis - Seuffert, Fritz; Weidner, Daniela; Baum, Wolfgang; Schett, Georg; Stock, Michael (Arthritis Research & Therapy, 2018)
BACKGROUND: ADAMTS aggrecanases play a major role in cartilage degeneration during degenerative and inflammatory arthritis. The cartilage-specific secreted protein Upper zone of growth plate and cartilage matrix associated protein (Ucma) has been shown to block ADAMTS-triggered aggrecanolysis in experimental osteoarthritis. Here we aimed to investigate whether and how Ucma may affect cartilage destruction and osteophyte formation in the context of inflammatory arthritis. METHODS: Ucma-ADAMTS5 protein interactions were studied using slot blot and solid phase binding assays. Chondrocyte cultures were stimulated with ADAMTS5 or IL-1β in the presence or absence of Ucma and aggrecanolysis was assessed by neoepitope formation. Arthritis was induced by transfer of K/BxN serum into wild-type (WT), Ucma-deficient and WT mice treated with recombinant Ucma. Cartilage proteoglycan loss and cartilage damage was assessed by safranin-O stain, aggrecanase-induced neoepitope formation and histomorphometry, respectively. Osteophytes were assessed by histomorphometry, micro-computed tomography, RNA in-situ hybridisation for collagen10a1 and osteocalcin, and staining for TRAP activity. Gene expression analyses were performed using real-time RT-PCR. RESULTS: Ucma physically interacted with ADAMTS5 and blocked its aggrecanase activity in chondrocyte cultures. Ucma was highly expressed in the articular cartilage and in osteophytes during arthritis. Ucma had no effect on inflammation and bone erosion. In contrast, Ucma-deficient mice developed significantly more severe cartilage proteoglycan loss and cartilage destruction. Conversely, treatment with Ucma inhibited cartilage degeneration in arthritis. Ucma effectively inhibited ADAMTS5-triggered or IL-1β-triggered aggrecanolysis in vitro and in vivo. Furthermore, osteophyte formation was reduced in Ucma-deficient mice. CONCLUSIONS: These results indicate that Ucma inhibits aggrecanolysis by physical interaction with ADAMTS5 and protects from cartilage degeneration in inflammatory arthritis. Ucma therefore represents an interesting novel and specific target for preventing cartilage degradation in the context of inflammatory arthritis.
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Upregulation of CCR4 in activated CD8(+) T cells indicates enhanced lung homing in patients with severe acute SARS-CoV-2 infection - Spoerl, Silvia; Kremer, Anita; Aigner, Michael; Eisenhauer, Nina; Koch, Pauline; Meretuk, Lina; Loeffler, Patrick; Tenbusch, Matthias; Maier, Clara; Überla, Klaus; Heinzerling, Lucie; Frey, Benjamin; et al. (European Journal of Immunology, 2021)
COVID-19 is a life-threatening disease leading to bilateral pneumonia and respiratory failure. The underlying reasons why a smaller percentage of patients present with severe pulmonary symptoms whereas the majority is only mildly affected are to date not well understood.
CRIS-Team WoS Importer:2021-05-07

Uricosuric agent benzbromarone vs. allopurinol: comparable effect - Manger, Bernhard (Deutsche Medizinische Wochenschrift, 2015)
EVALuna2:13109

Use of biosimilars in the treatment of rheumatoid arthritis An overview - Morf, Harriet; Witte, Thorben (Zeitschrift für Rheumatologie, 2021)
Biologics have been an integral part of the treatment of rheumatoid arthritis for approximately 20 years. As patents for pharmaceuticals generally expire after 10 years, in recent years biosimilars have come onto the market. Many studies have shown that they are an equivalent alternative to the reference drug with comparable safety and efficacy. In some cases, they even showed lower rates of adverse drug reactions compared to the reference drugs. Furthermore, considerable costs can be saved by biosimilars, which amount to an annual three-digit million sum in Germany alone. Large regional differences in the prescription frequency of biosimilars in Germany can be identified, which are also reflected in the savings potential. A switch to a biosimilar is possible and desirable with the involvement of the patient. In this sense, the initial prescription of a biosimilar instead of the reference drug is also to be advocated.
CRIS-Team WoS Importer:2021-12-03

Use of medical apps and online platforms among German rheumatologists Results of the 2016 and 2018 DGRh conference surveys and research conducted by rheumadocs - Knitza, Johannes; Vossen, D.; Geffken, I.; Krusche, M.; Meyer, M.; Sewerin, Philipp; Kleyer, Arnd; Hueber, Axel (Zeitschrift für Rheumatologie, 2019)
Background Apps and online platforms play an ever increasing role in the daily work routine of physicians. The aim of this study was to investigate which medical apps and online platforms are used by German rheumatologists for certain tasks and to identify usage trends. Methods Data were collected via a SurveyMonkey survey conducted by members of rheumadocs (Young German Rheumatology Association) at the 2016 and 2018 German Society for Rheumatology (DGRh) conferences. Results In 2016 and 2018 the survey was completed by 75 and 84 assistant and specialist rheumatologists, respectively. In 2016, 37% of rheumatologists were using medical apps in routine care which changed to 49% in 2018. In 2016, 47% compared to 68% in 2018, planned to integrate medical apps into routine care. In total, 20 different medical apps were recommended for colleagues to use; however only 2 of these apps were specific for rheumatology. In contrast to 52 app recommendations for colleagues, only 8 app recommendations for patients were recorded. Most recommendations to physicians received the app "Arznei aktuell" (21%). "Embryotox" was the app, most recommended to patients (38%). In 2016 the online database PubMed was most popular and 97% of participants were familiar with it. Use of other online platforms showed great age dependency in 2016: Amboss (a digital learning platform) was used by 31% of the age group 21-30 years and was not used at all by the age group 51-60 years. Discussion Use of medical apps and planned integration of medical apps into routine care is increasing among German rheumatologists. On the other hand, recommendable rheumatological apps for rheumatologists and especially for patients are currently largely unknown to rheumatologists.
EVALuna2:213131

Use of methotrexate in adult-onset Still's disease - Manger, Bernhard; Rech, Jürgen; Schett, Georg (Clinical and Experimental Rheumatology, 2010)
Adult-onset Still's disease, a febrile, multisystem rheumatic disease, has variable outcomes. Some patients experience remission after a single or multiple inflammatory episodes, while others progress to a chronic course with substantial joint destruction. Although no controlled clinical trials with immunosuppressive agents in this disease have been reported, a number of small uncontrolled studies and case reports describe the use of methotrexate therapy. Methotrexate has shown efficacy for the control of systemic and articular symptoms and its favourable safety profile appears similar to that seen in other rheumatic diseases, when for this indication. The combination of methotrexate and corticosteroids has, over the years, become the first step in the standard of care in adult-onset Still's disease. If the response to this treatment is incomplete, additional therapies, such as biologic agents may be appropriate. © Copyright CLINICAL AND EXPERIMENTAL RHEUMATOLOGY 2010.
CRIS-Team Scopus Importer:2021-02-03
Keywords: Adult-onset Still's disease; Methotrexate; Prognosis; Therapy

Using surface-bound IgG-catcher constructs to identify antigen-specific plasma cells - Kilo, Johanna; Roth, Edith; Jäck, Hans-Martin; Schulz, Sonja (EUROPEAN JOURNAL OF IMMUNOLOGY, 2022)
CRIS-Team WoS Importer:2023-01-27

Ustekinumab Is Superior to TNF Inhibitor Treatment in Resolving Enthesitis in Psa Patients with Active Enthesitis-Results from the Enthesial Clearance in Psoriatic Arthritis Study - Guilhon de Araujo, Elizabeth; Englbrecht, Matthias; Höpken, Sabrina; Finzel, Stephanie; Hueber, Axel; Rech, Jürgen; Schett, Georg (2017)
EVALuna2:33426

Vaccine Hesitancy Among Patients with Idiopathic Inflammatory Myopathies and Rheumatic Diseases in 2021-2022: A Comparative Analysis of COVID-19 Vaccination in Autoimmune Diseases Surveys - Naveen, R.; Joshi, Mrudula; Sen, Parikshit; Agarwal, Vishwesh; Shinjo, Samuel; Kardes, Sinan; Lilleker, James B.; Chinoy, Hector; Makol, Ashima; Distler, Oliver; Kim, Minchul; Nikiphorou, Elena; et al. (ARTHRITIS & RHEUMATOLOGY, 2022)
CRIS-Team WoS Importer:2023-01-13

Vaccine hesitancy decreases in rheumatic diseases, long-term concerns remain in myositis: a comparative analysis of the COVAD surveys - Sen, Parikshit; Naveen, R.; Houshmand, Nazanin; Kia, Siamak Moghadam; Joshi, Mrudula; Saha, Sreoshy; Jagtap, Kshitij; Agarwal, Vishwesh; Nune, Arvind; Nikiphorou, Elena; Tan, Ai Lyn; Shinjo, Samuel Katsuyuki; et al. (Rheumatology, 2023)
Objective COVID-19 vaccines have a favorable safety profile in patients with autoimmune rheumatic diseases (AIRDs) such as idiopathic inflammatory myopathies (IIMs); however, hesitancy continues to persist among these patients. Therefore, we studied the prevalence, predictors and reasons for hesitancy in patients with IIMs, other AIRDs, non-rheumatic autoimmune diseases (nrAIDs) and healthy controls (HCs), using data from the two international COVID-19 Vaccination in Autoimmune Diseases (COVAD) e-surveys. Methods The first and second COVAD patient self-reported e-surveys were circulated from March to December 2021, and February to June 2022 (ongoing). We collected data on demographics, comorbidities, COVID-19 infection and vaccination history, reasons for hesitancy, and patient reported outcomes. Predictors of hesitancy were analysed using regression models in different groups. Results We analysed data from 18 882 (COVAD-1) and 7666 (COVAD-2) respondents. Reassuringly, hesitancy decreased from 2021 (16.5%) to 2022 (5.1%) (OR: 0.26; 95% CI: 0.24, 0.30, P < 0.001). However, concerns/fear over long-term safety had increased (OR: 3.6; 95% CI: 2.9, 4.6, P < 0.01). We noted with concern greater skepticism over vaccine science among patients with IIMs than AIRDs (OR: 1.8; 95% CI: 1.08, 3.2, P = 0.023) and HCs (OR: 4; 95% CI: 1.9, 8.1, P < 0.001), as well as more long-term safety concerns/fear (IIMs vs AIRDs - OR: 1.9; 95% CI: 1.2, 2.9, P = 0.001; IIMs vs HCs - OR: 5.4 95% CI: 3, 9.6, P < 0.001). Caucasians [OR 4.2 (1.7-10.3)] were likely to be more hesitant, while those with better PROMIS physical health score were less hesitant [OR 0.9 (0.8-0.97)]. Conclusion Vaccine hesitancy has decreased from 2021 to 2022, long-term safety concerns remain among patients with IIMs, particularly in Caucasians and those with poor physical function.
CRIS-Team WoS Importer:2023-04-07

Vaccine hesitancy in patients with autoimmune diseases: Data from the coronavirus disease-2019 vaccination in autoimmune diseases study - Sen, Parikshit; Lilleker, James B.; Agarwal, Vishwesh; Kardes, Sinan; Milchert, Marcin; Gheita, Tamer; Salim, Babur; Velikova, Tsvetelina; Gracia-Ramos, Abraham Edgar; Parodis, Ioannis; O'Callaghan, Albert Selva; Nikiphorou, Elena; et al. (Indian Journal of Rheumatology, 2022)
CRIS-Team WoS Importer:2022-07-08

Validation of standardized questionnaires evaluating symptoms of depression in rheumatoid arthritis patients - approaches to screening for a frequent and yet underrated challenge - Englbrecht, Matthias; Alten, Rieke; Aringer, Martin; Baerwald, Christoph G.; Burkhardt, Harald; Eby, Nancy; Fliedner, Gerhard; Gauger, Bettina; Henkemeier, Ulf; Hofmann, Michael W.; Kleinert, Stefan; Kneitz, Christian; et al. (Arthritis & Rheumatism-Arthritis Care & Research, 2016)
To validate standard self-reporting questionnaires for depression screening in patients with rheumatoid arthritis (RA) and compare these measures to each other and to the Montgomery-Åsberg Depression Rating Scale (MADRS), a standardized structured interview.In 9 clinical centers across Germany, depressive symptomatology was assessed in 262 adult RA patients at baseline (T0) and at 12 ± 2 weeks follow-up (T1) using the WHO Five Well-Being Index (WHO-5), the Patient Health Questionnaire-9 (PHQ-9), and the Beck Depression Inventory (BDI-II). Construct validity of these depression questionnaires (using convergent and discriminant validity) was evaluated using Spearman correlations at both time points. The test-retest reliability of the questionnaires was evaluated in RA patients who had not undergone psychotherapeutic intervention or received antidepressants between T0 and T1. The sensitivity and the specificity of the questionnaires were calculated using the results of the MADRS, a structured interview, as gold standard.According to the Spearman correlation coefficients all questionnaires met convergent validity criteria (? > |0.50|) with the BDI-II performing best while correlations with age and disease activity for all questionnaires met the criteria for discriminant validity (? < |0.50|). The only questionnaire to meet the predefined retest reliability criterion (? >= 0.70) was the BDI-II (rs = 0.77) which also achieved the best results for both sensitivity and specificity >80% when using the MADRS as the gold standard.The BDI-II best met the predefined criteria and the PHQ-9 met most validity criteria with lower sensitivity and specificity. This article is protected by copyright. All rights reserved.
EVALuna:32493

Validation of the Mobile Application Rating Scale (MARS) - Terhorst, Yannik; Philippi, Paula; Sander, Lasse B.; Schultchen, Dana; Paganini, Sarah; Bardus, Marco; Santo, Karla; Knitza, Johannes; Machado, Gustavo C.; Schoeppe, Stephanie; Bauereiß, Natalie; Portenhauser, Alexandra; et al. (PLoS ONE, 2020)
BACKGROUND: Mobile health apps (MHA) have the potential to improve health care. The commercial MHA market is rapidly growing, but the content and quality of available MHA are unknown. Instruments for the assessment of the quality and content of MHA are highly needed. The Mobile Application Rating Scale (MARS) is one of the most widely used tools to evaluate the quality of MHA. Only few validation studies investigated its metric quality. No study has evaluated the construct validity and concurrent validity. OBJECTIVE: This study evaluates the construct validity, concurrent validity, reliability, and objectivity, of the MARS. METHODS: Data was pooled from 15 international app quality reviews to evaluate the metric properties of the MARS. The MARS measures app quality across four dimensions: engagement, functionality, aesthetics and information quality. Construct validity was evaluated by assessing related competing confirmatory models by confirmatory factor analysis (CFA). Non-centrality (RMSEA), incremental (CFI, TLI) and residual (SRMR) fit indices were used to evaluate the goodness of fit. As a measure of concurrent validity, the correlations to another quality assessment tool (ENLIGHT) were investigated. Reliability was determined using Omega. Objectivity was assessed by intra-class correlation. RESULTS: In total, MARS ratings from 1,299 MHA covering 15 different health domains were included. Confirmatory factor analysis confirmed a bifactor model with a general factor and a factor for each dimension (RMSEA = 0.074, TLI = 0.922, CFI = 0.940, SRMR = 0.059). Reliability was good to excellent (Omega 0.79 to 0.93). Objectivity was high (ICC = 0.82). MARS correlated with ENLIGHT (ps<.05). CONCLUSION: The metric evaluation of the MARS demonstrated its suitability for the quality assessment. As such, the MARS could be used to make the quality of MHA transparent to health care stakeholders and patients. Future studies could extend the present findings by investigating the re-test reliability and predictive validity of the MARS.
CRIS-Team Scopus Importer:2020-11-13

VALUE AND LIMITATIONS IN HR-PQCT IMAGING IN CHRONIC ARTHRITIS. CURRENT STATUS AND FUTURE DIRECTIONS - Engelke, Klaus; Figueiredo, C.; Kleyer, Arnd; Simon, David; Schett, Georg (OSTEOPOROSIS INTERNATIONAL, 2019)
CRIS-Team WoS Importer:2019-08-02

Variable effects of different serotonin receptor subtype antagonists on the development of transplant vasculopathy in murine aortic allografts - Heim, Christian; Gocht, Annika; Distler, Jörg; Spriewald, Bernd; Ramsperger-Gleixner, Martina; Weyand, Michael; Ensminger, Stephan M. (2016)
EVALuna2:35070

Vascular endothelial growth factor aggravates fibrosis and vasculopathy in experimental models of systemic sclerosis - Maurer, Britta; Distler, Alfiya; Suliman, Yossra A.; Gay, Renate E.; Michel, Beat A.; Gay, Steffen; Distler, Jörg; Distler, Oliver (Annals of the Rheumatic Diseases, 2014)
High levels of vascular endothelial growth factor (VEGF), a key angiogenic factor, are present in patients with systemic sclerosis (SSc), but its role in the pathogenesis of fibrosis and its contribution to the disturbed angiogenesis of SSc remains hypothetical.Mono (+/-) and double (+/+) VEGF transgenic (tg) mice and their wildtype (wt) controls were analysed. The bleomycin model was applied to VEGF tg mice to evaluate effects of VEGF under proinflammatory conditions. Additionally, tight skin (TSK) 1/VEGF+/+ mice were generated to mimic later non-inflammatory stages of SSc.VEGF+/+, but not VEGF+/- tg mice, spontaneously developed significant skin fibrosis, indicating profibrotic effect of VEGF in a gene-dosing manner. In the proinflammatory bleomycin model, the profibrotic effect became more pronounced with induction of skin fibrosis in VEGF+/- tg mice and even more enhanced fibrosis in VEGF+/+ tg mice. Analysis in TSK1/VEGF+/+ mice showed similar profibrotic effects of VEGF also under non-inflammatory in vivo conditions. In vitro analysis revealed that VEGF is able to directly induce collagen synthesis in dermal fibroblasts. Additionally, there was an inverse gene-dosing effect on the efficacy of angiogenesis in that a higher number of microvessels was observed in VEGF+/- tg mice than in VEGF+/+ tg mice.These data provide the first evidence for VEGF as a novel molecular link between fibrosis and vasculopathy in the pathogenesis of SSc. They suggest that high levels of VEGF potently induce fibrosis in inflammatory and non-inflammatory stages, and also contribute to the relatively insufficient angiogenesis characteristic for SSc.
EVALuna2:12948

Vascularised human skin equivalents as a novel in vitro model of skin fibrosis and platform for testing of antifibrotic drugs - Matei, Alexandru-Emil; Chen, Chih-Wei; Kiesewetter, Lisa; Györfi, Andrea-Hermina; Li, Yi Nan; Trinh-Minh, Thuong; Xu, Xiaohan; Tran Manh, Cuong; Van Kuppevelt, Toin; Hansmann, Jan; Jüngel, Astrid; Schett, Georg; et al. (Annals of the Rheumatic Diseases, 2019)
Objectives: Fibrosis is a complex pathophysiological process involving interplay between multiple cell types. Experimental modelling of fibrosis is essential for the understanding of its pathogenesis and for testing of putative antifibrotic drugs. However, most current models employ either phylogenetically distant species or rely on human cells cultured in an artificial environment. Here we evaluated the potential of vascularised in vitro human skin equivalents as a novel model of skin fibrosis and a platform for the evaluation of antifibrotic drugs. Methods: Skin equivalents were assembled on a three-dimensional extracellular matrix by sequential seeding of endothelial cells, fibroblasts and keratinocytes. Fibrotic transformation on exposure to transforming growth factor-β (TGFβ) and response to treatment with nintedanib as an established antifibrotic agent were evaluated by quantitative polymerase chain reaction (qPCR), capillary Western immunoassay, immunostaining and histology. Results: Skin equivalents perfused at a physiological pressure formed a mature, polarised epidermis, a stratified dermis and a functional vessel system. Exposure of these models to TGFβ recapitulated key features of SSc skin with activation of TGFβ pathways, fibroblast to myofibroblast transition, increased release of collagen and excessive deposition of extracellular matrix. Treatment with the antifibrotic agent nintedanib ameliorated this fibrotic transformation. Conclusion: Our data provide evidence that vascularised skin equivalents can replicate key features of fibrotic skin and may serve as a platform for evaluation of antifibrotic drugs in a pathophysiologically relevant human setting.
CRIS-Team Scopus Importer:2019-10-01
Keywords: fibroblasts; systemic sclerosis; treatment

VASCULARIZED THREE-DIMENSIONAL MODELS OF HUMAN SKIN FIBROSIS - Matei, Alexandru-Emil; Chen, Chih-Wei; Kiesewetter, L.; Györfi, Andrea-Hermina; Li, Y. N.; Trinh-Minh, T.; Van Kuppevelt, T.; Hansmann, J.; Juengel, A.; Schett, Georg; Groeber-Becker, F.; Distler, Jörg (ANNALS OF THE RHEUMATIC DISEASES, 2020)
CRIS-Team WoS Importer:2020-08-21

Vascular occlusion by neutrophil extracellular traps in COVID-19 - Leppkes, Moritz; Knopf, Jasmin; Naschberger, Elisabeth; Lindemann, Aylin; Singh, Jeeshan; Herrmann, Irmgard; Stürzl, Michael; Staats, Léonie; Mahajan, Aparna; Kremer, Anita; Amann, Kerstin Ute; Evert, Katja; et al. (EBioMedicine, 2020)
Background: Coronavirus induced disease 2019 (COVID-19) can be complicated by severe organ damage leading to dysfunction of the lungs and other organs. The processes that trigger organ damage in COVID-19 are incompletely understood. Methods: Samples were donated from hospitalized patients. Sera, plasma, and autopsy-derived tissue sections were examined employing flow cytometry, enzyme-linked immunosorbent assays, and immunohistochemistry. Patient findings: Here, we show that severe COVID-19 is characterized by a highly pronounced formation of neutrophil extracellular traps (NETs) inside the micro-vessels. Intravascular aggregation of NETs leads to rapid occlusion of the affected vessels, disturbed microcirculation, and organ damage. In severe COVID-19, neutrophil granulocytes are strongly activated and adopt a so-called low-density phenotype, prone to spontaneously form NETs. In accordance, markers indicating NET turnover are consistently increased in COVID-19 and linked to disease severity. Histopathology of the lungs and other organs from COVID-19 patients showed congestions of numerous micro-vessels by aggregated NETs associated with endothelial damage. Interpretation: These data suggest that organ dysfunction in severe COVID-19 is associated with excessive NET formation and vascular damage. Funding: Deutsche Forschungsgemeinschaft (DFG), EU, Volkswagen-Stiftung
CRIS-Team Scopus Importer:2020-08-14
Keywords: Aggregated neutrophil extracellular traps; Coagulopathy; Endothelialitis; Immunothrombosis; SARS-CoV-2

Vasoactive Therapy in Systemic Sclerosis: Real-life Therapeutic Practice in More Than 3000 Patients - Moinzadeh, Pia; Riemekasten, Gabriela; Siegert, Elise; Fierlbeck, Gerhard; Henes, Joerg; Blank, Norbert; Melchers, Inga; Mueller-Ladner, Ulf; Frerix, Marc; Kreuter, Alexander; Tigges, Christian; Lahner, Nina; et al. (Journal of Rheumatology, 2016)
Vasculopathy is a key factor in the pathophysiology of systemic sclerosis (SSc) and the main cause for Raynaud phenomenon (RP), digital ulcers (DU), and/or pulmonary arterial hypertension (PAH). It is so far unknown how patients with SSc are treated with vasoactive agents in daily practice. To determine to which extent patients with SSc were treated with different vasoactive agents, we used data from the German Network for Systemic Scleroderma registry.The data of 3248 patients with SSc were analyzed.Patients were treated with vasoactive drugs in 61.1% of cases (1984/3248). Of these, 47.6% received calcium channel inhibitors, followed by 34.2% treated with angiotensin-converting enzyme (ACE) inhibitors, 21.1% treated with intravenous (IV) prostanoids, 10.1% with pentoxifylline, 8.8% with angiotensin 1 receptor antagonists (AT1RA), 8.7% with endothelin 1 receptor antagonists (ET1RA), 4.1% with phosphodiesterase type 5 (PDE5) inhibitors, and 5.3% with others. Patients with RP received vasoactive therapy in 63.3% of cases, with DU in 70.1%, and with PAH in 78.2% of cases. Logistic regression analysis revealed that patients with PAH were significantly more often treated with PDE5 inhibitors and ET1RA, and those with DU with ET1RA and IV prostanoids. In addition, 41.8% of patients were treated with ACE inhibitors and/or AT1RA. Patients registered after 2009 received significantly more often ET1RA, AT1RA, and IV prostanoids compared with patients registered prior to 2005.These data clearly indicate that many patients with SSc do not yet receive sufficient vasoactive therapy. Further, in recent years, a marked change of treatment regimens can be observed.
EVALuna2:13183

Vedolizumab-associated enthesitis: correlation or causality? - Vitali, Francesco; Simon, David; Neurath, Markus; Schett, Georg; Zundler, Sebastian (Rheumatology, 2021)
CRIS-Team WoS Importer:2022-02-04

Versorgungsrealität der stationären vasoaktiven Therapie mit Prostazyklinderivaten bei Patienten mit akralen Durchblutungsstörungen bei systemischer Sklerose in Deutschland - Juche, A.; Siegert, E.; Mueller-Ladner, U.; Riemekasten, G.; Günther, C.; Kötter, I.; Henes, J.; Blank, N.; Voll, R. E.; Ehrchen, J.; Schmalzing, M.; Susok, L.; et al. (Zeitschrift für Rheumatologie, 2020)
Background: Raynaud’s phenomenon and the frequently ensuing digital ulcerations represent an early and very distressing symptom in patients with systemic sclerosis (scleroderma, SSc) causing significant limitations in the ability to work and quality of life. The use of vasoactive drugs (especially intravenous prostacyclin derivatives) is recommended to reduce the risk of hypoxic tissue damage up to the loss of fingers. Methods: In order to obtain information about the current state of treatment of patients with prostacyclin derivatives in routine clinical life in Germany, a survey was conducted among the centers affiliated to the German Network for Systemic Scleroderma (DNSS). In addition, a separate patient survey was conducted by the schleroderma self-help group (Sklerodermie Selbsthilfe e. V.), which only covered the symptoms Raynaud’s syndrome, digital ulcers and the use of intravenous prostacyclin derivatives. Results: Of the 433 patients surveyed 56% stated that they had already been treated with prostacyclin derivatives (iloprost/alprostadil) because of their illness and symptoms. A total of 61% received the treatment for severe Raynaud’s phenomenon and 39% for digital ulcerations. Most respondents not only experienced an improvement in Raynaudʼs phenomenon and digital ulcers but also a significant improvement of limitations in everyday life. They also needed significantly less outside help and absenteeism from work was much lower. Conclusion: Patients consistently reported a positive effect of treatment with prostacyclin derivatives on Raynaudʼs phenomenon, acral ulcerations, pain and daily restrictions and felt well and safely cared for during inpatient treatment. These positive effects in the patientsʼ perceptions provide crucial information supporting and confirming the current European and international treatment recommendations.
CRIS-Team Scopus Importer:2020-02-25
Keywords: Digital ulceration; Iloprost; Raynaud’s phenomenon; Scleroderma; Systemic sclerosis

Vesicular Messages from Dental Biofilms for Neutrophils - Vitkov, Ljubomir; Krunić, Jelena; Dudek, Johanna; Bobbili, Madhusudhan Reddy; Grillari, Johannes; Hausegger, Bernhard; Mladenović, Irena; Stojanović, Nikola; Krautgartner, Wolf Dietrich; Oberthaler, Hannah; Schauer, Christine; Herrmann, Martin; et al. (International Journal of Molecular Sciences, 2024)
The encounter between dental biofilm and neutrophils in periodontitis remains elusive, although it apparently plays a crucial role in the periodontal pathology and constitutes a key topic of periodontology. Dental biofilm and neutrophils were isolated from orally healthy persons and patients with periodontitis. We investigated biofilm and its particle-shedding phenomenon with electron microscopy and nanoparticle tracking analysis (NTA); biofilm shedding–neutrophil interactions were examined ex vivo with epi-fluorescence microscopy. For this purpose, we used acellular dental biofilm shedding, purified lipopolysaccharide (LPS), and phorbol 12-myristate 13-acetate (PMA) as activators, and the interleukin 8 receptor beta (CXCR2) inhibitor and the anti-interleukin 8 receptor alpha (CXCR1) antibody as modulators. The shedding of acellular dental biofilms overwhelmingly consists of bacterial extracellular vesicles (BEVs). The latter induced the moderate formation of neutrophil extracellular traps (NETs) in orally healthy subjects and a strong formation in patients with periodontitis. A CXCR2 inhibitor and an anti-CXCR1 antibody had a minor effect on NET formation. Neutrophils from patients with periodontitis exhibited NET hyper-responsiveness. BEVs were stronger inducers of NET formation than purified LPS and PMA. A plateau of neutrophil responsiveness is reached above the age of 40 years, indicating the abrupt switch of maladaptive trained immunity (TI) into the activated modus. Our results suggest that dental biofilms consist of and disseminate immense amounts of outer membrane vesicles (OMVs), which initiate NET formation via a non-canonical cytosolic LPS/caspase-4/11/Gasdermin D pathway. This modus of NET formation is independent of neutrophil elastase (NE), myeloperoxidase (MPO), peptidylarginine deiminase 4 (PAD4), and toll-like receptors (TLR). In periodontitis, the hyper-responsiveness of neutrophils to BEVs and the increased NET formation appear to be a consequence of TI.
CRIS-Team Scopus Importer:2024-04-12
Keywords: bacterial extracellular vesicles; caspase 4; dental biofilm; outer membrane vesicles; periodontitis; trained immunity

VEXAS syndrome mimicking lupus-like disease - Valor-Mendez, Larissa; Sticherling, Michael; Zeschick, Martin; Atreya, Raja; Schmidt, Daniela; Waldfahrer, Frank; Saake, Marc; Hüffmeier, Ulrike; Schett, Georg; Rech, Jürgen (Rheumatology, 2023)
CRIS-Team WoS Importer:2023-03-17

Virological Traits of the SARS-CoV-2 BA.2.87.1 Lineage - Zhang, Lu; Dopfer-Jablonka, Alexandra; Nehlmeier, Inga; Kempf, Amy; Graichen, Luise; Calderón Hampel, Noemí; Cossmann, Anne; Stankov, Metodi V.; Morillas Ramos, Gema; Schulz, Sebastian; Jäck, Hans-Martin; Behrens, Georg M.N.; et al. (Vaccines, 2024)
Transmissibility and immune evasion of the recently emerged, highly mutated SARS-CoV-2 BA.2.87.1 are unknown. Here, we report that BA.2.87.1 efficiently enters human cells but is more sensitive to antibody-mediated neutralization than the currently dominating JN.1 variant. Acquisition of adaptive mutations might thus be needed for efficient spread in the population.
CRIS-Team Scopus Importer:2024-05-31
Keywords: ACE2 binding; antibody evasion; BA.2.87.1; host cell entry; SARS-CoV-2; spike protein

"Virtual Rheumatology" A new Teaching Concept for the Rheumatology of Future? - Kleyer, Arnd; Simon, David; Hartmann, F.; Schuster, Louis; Hueber, Axel (Zeitschrift für Rheumatologie, 2019)
CRIS-Team WoS Importer:2019-03-26

Virtual teaching for medical students during SARS-CoV-2 pandemic. - Pfeil, Alexander; Franz, Marcus; Hoffmann, Tobias; Klemm, Philipp; Oelzner, Peter; Müller-Ladner, Ulf; Hueber, Axel; Lange, Uwe; Wolf, Gunter; Schett, Georg; Simon, David; Kleyer, Arnd (Clinical and Experimental Rheumatology, 2021)
EVALuna2:474299

Virtual teaching for medical students during SARS-CoV-2 pandemic - Pfeil, A.; Franz, M.; Hoffmann, T.; Klemm, P.; Oelzner, P.; Muller-Ladner, U.; Lange, U.; Wolf, G.; Schett, Georg; Simon, David; Kleyer, Arnd; Hueber, Axel (Clinical and Experimental Rheumatology, 2021)
CRIS-Team WoS Importer:2022-02-11

Visualization of melanoma tumor with lectin-conjugated rare-earth doped fluoride nanocrystals - Dumych, Tetiana; Lutsyk, Maxym; Banski, Mateusz; Yashchenko, Antonina; Sojka, Bartlomiej; Horbay, Rostyslav; Lutsyk, Alexander; Stoika, Rostyslav; Misiewicz, Jan; Podhorodecki, Artur; Bilyy, Rostyslav (Croatian Medical Journal, 2014)
To develop specific fluorescent markers for melanoma tumor visualization, which would provide high selectivity and reversible binding pattern, by the use of carbohydrate-recognizing proteins, lectins, combined with the physical ability for imaging deep in the living tissues by utilizing red and near infrared fluorescent properties of specific rare-earth doped nanocrystals (NC).B10F16 melanoma cells were inoculated to C57BL/6 mice for inducing experimental melanoma tumor. Tumors were removed and analyzed by lectin-histochemistry using LABA, PFA, PNA, HPA, SNA, GNA, and NPL lectins and stained with hematoxylin and eosin. NPL lectin was conjugated to fluorescent NaGdF4:Eu(3+)-COOH nanoparticles (5 nm) via zero length cross-linking reaction, and the conjugates were purified from unbound substances and then used for further visualization of histological samples. Fluorescent microscopy was used to visualize NPL-NaGdF4:Eu(3+) with the fluorescent emission at 600-720 nm range.NPL lectin selectively recognized regions of undifferentiated melanoblasts surrounding neoangiogenic foci inside melanoma tumor, PNA lectin recognized differentiated melanoblasts, and LCA and WGA were bound to tumor stroma regions. NPL-NaGdF4:Eu(3+) conjugated NC were efficiently detecting newly formed regions of melanoma tumor, confirmed by fluorescent microscopy in visible and near infrared mode. These conjugates possessed high photostability and were compatible with convenient xylene-based mounting systems and preserved intensive fluorescent signal at samples storage for at least 6 months.NPL lectin-NaGdF4:Eu(3+) conjugated NC permitted distinct identification of contours of the melanoma tissue on histological sections using red excitation at 590-610 nm and near infrared emission of 700-720 nm. These data are of potential practical significance for development of glycans-conjugated nanoparticles to be used for in vivo visualization of melanoma tumor.
EVALuna2:13247

Visualizing transfer of microbial biomolecules by outer membrane vesicles in microbe-host-communication in vivo - Bittel, Miriam; Reichert, Patrick; Sarfati, Ilann; Dressel, Anja; Leikam, Stefanie; Uderhardt, Stefan; Stolzer, Iris; Phu, Tuan Anh; Ng, Martin; Vu, Ngan K.; Tenzer, Stefan; Distler, Ute; et al. (Journal of Extracellular Vesicles, 2021)
The intestinal microbiota influences mammalian host physiology in health and disease locally in the gut but also in organs devoid of direct contact with bacteria such as the liver and brain. Extracellular vesicles (EVs) or outer membrane vesicles (OMVs) released by microbes are increasingly recognized for their potential role as biological shuttle systems for inter-kingdom communication. However, physiologically relevant evidence for the transfer of functional biomolecules from the intestinal microbiota to individual host cells by OMVs in vivo is scarce. By introducing Escherichia coli engineered to express Cre-recombinase (E. coliCre) into mice with a Rosa26.tdTomato-reporter background, we leveraged the Cre-LoxP system to report the transfer of bacterial OMVs to recipient cells in vivo. Colonizing the intestine of these mice with E. coliCre, resulted in Cre-recombinase induced fluorescent reporter gene-expression in cells along the intestinal epithelium, including intestinal stem cells as well as mucosal immune cells such as macrophages. Furthermore, even far beyond the gut, bacterial-derived Cre induced extended marker gene expression in a wide range of host tissues, including the heart, liver, kidney, spleen, and brain. Together, our findings provide a method and proof of principle that OMVs can serve as a biological shuttle system for the horizontal transfer of functional biomolecules between bacteria and mammalian host cells.
CRIS-Team Scopus Importer:2021-10-29
Keywords: Cre-Loxp; extracellular vesicles; inflammation; intestinal stem cells; microbiome; outer membrane vesicles

Vitamin D-dependent induction of cathelicidin in human macrophages results in cytotoxicity against high-grade B cell lymphoma - Bruns, Heiko; Büttner, Maike; Fabri, Mario; Mougiakakos, Dimitrios; Bittenbring, Joerg T.; Hoffmann, Markus; Beier, Fabian; Pasemann, Shirin; Jitschin, Regina; Hofmann, Andreas D.; Neumann, Frank; Daniel, Christoph; et al. (Science Translational Medicine, 2015)
Infiltration by macrophages represents a characteristic morphological hallmark in high-grade lymphatic malignancies such as Burkitt's lymphoma (BL). Although macrophages can, in principle, target neoplastic cells and mediate antibody-dependent cellular cytotoxicity (ADCC), tumor-associated macrophages (TAMs) regularly fail to exert direct cytotoxic functions. The underlying mechanisms responsible for this observation remain unclear. We demonstrate that inflammatory M1 macrophages kill proliferating high-grade B cell lymphoma cells by releasing the antimicrobial peptide cathelicidin in a vitamin D-dependent fashion. We show that cathelicidin directly induces cell death by targeting mitochondria of BL cells. In contrast, anti-inflammatory M2 macrophages and M2-like TAMs in BL exhibit an altered vitamin D metabolism, resulting in a reduced production of cathelicidin and consequently in inability to lyse BL cells. However, treatment of M2 macrophages with the bioactive form of vitamin D, 1,25D3, or a vitamin D receptor agonist effectively induces cathelicidin production and triggers tumoricidal activity against BL cells. Furthermore, rituximab-mediated cytotoxicity of vitamin D-treated M2 macrophages is cathelicidin-dependent. Finally, vitamin D treatment of 25-hydroxyvitamin D (25D)-deficient volunteers in vivo or primary TAMs in vitro improves rituximab-mediated ADCC against B cell lymphoma cells. These data indicate that activation of the vitamin D signaling pathway activates antitumor activity of TAMs and improves the efficacy of ADC
EVALuna2:13103

Vitamin D receptor regulates TGF-? signalling in systemic sclerosis - Zerr, Pawel; Vollath, Stefan; Palumbo-Zerr, Katrin; Tomcik, Michal; Huang, Jingang; Distler, Alfiya; Beyer, Christian; Dees, Clara; Gela, Kolja; Distler, Oliver; Schett, Georg; Distler, Jörg (Annals of the Rheumatic Diseases, 2015)
Vitamin D receptor (VDR) is a member of the nuclear receptor superfamily. Its ligand, 1,25-(OH)2D, is a metabolically active hormone derived from vitamin D3. The levels of vitamin D3 are decreased in patients with systemic sclerosis (SSc). Here, we aimed to analyse the role of VDR signalling in fibrosis.VDR expression was analysed in SSc skin, experimental fibrosis and human fibroblasts. VDR signalling was modulated by siRNA and with the selective agonist paricalcitol. The effects of VDR on Smad signalling were analysed by reporter assays, target gene analyses and coimmunoprecipitation. The effects of paricalcitol were evaluated in the models of bleomycin-induced fibrosis and fibrosis induced by overexpression of a constitutively active transforming growth factor-? (TGF-?) receptor I (TBRI(CA)).VDR expression was decreased in fibroblasts of SSc patients and murine models of SSc in a TGF-?-dependent manner. Knockdown of VDR enhanced the sensitivity of fibroblasts towards TGF-?. In contrast, activation of VDR by paricalcitol reduced the stimulatory effects of TGF-? on fibroblasts and inhibited collagen release and myofibroblast differentiation. Paricalcitol stimulated the formation of complexes between VDR and phosphorylated Smad3 in fibroblasts to inhibit Smad-dependent transcription. Preventive and therapeutic treatment with paricalcitol exerted potent antifibrotic effects and ameliorated bleomycin- as well as TBRI(CA)-induced fibrosis.We characterise VDR as a negative regulator of TGF-?/Smad signalling. Impaired VDR signalling with reduced expression of VDR and decreased levels of its ligand may thus contribute to hyperactive TGF-? signalling and aberrant fibroblast activation in SSc.
EVALuna2:12977

Vitamin k-dependent proteins in skeletal development and disease - Stock, Michael; Schett, Georg (International Journal of Molecular Sciences, 2021)
Vitamin K and Vitamin K-dependent proteins (VKDPs) are best known for their pivotal role in blood coagulation. Of the 14 VKPDs identified in humans to date, 6 play also important roles in skeletal biology and disease. Thus, osteocalcin, also termed bone Gla-protein, is the most abundant non-collagenous protein in bone. Matrix Gla protein and Ucma/GRP on the other hand are highly abundant in cartilage. Furthermore, periostin, protein S, and growth arrest specific 6 protein (GAS 6) are expressed in skeletal tissues. The roles for these VKDPs are diverse but include the control of calcification and turnover of bone and cartilage. Vitamin K plays an important role in osteoporosis and serum osteocalcin levels are recognized as a promising marker for osteoporosis. On the other hand, matrix Gla protein and Ucma/GRP are associated with osteoarthritis. This review focuses on the roles of these three VKDPs, osteocalcin, matrix Gla protein and Ucma/GRP, in skeletal development and disease but will also summarize the roles the other skeletal VKDPs (periostin, protein S and GAS6) in skeletal biology.
CRIS-Team Scopus Importer:2021-09-10
Keywords: GRP; Matrix Gla protein; Osteocalcin; Ucma; Vitamin K; Vitamin K-dependent proteins

Von der konventionellen Bildgebung zum Cutting Edge Imaging in der Rheumatologie - Simon, David; Kemenes, Stephan; Minopoulou, Ioanna; Kleyer, Arnd (Zeitschrift für Rheumatologie, 2023)
Imaging instruments, such as conventional X‑ray, ultrasound and magnetic resonance imaging (MRI) are now fully established and highly valued in the care of rheumatology patients. However, the information provided by these imaging modalities in their current form is of limited utility for the prognostic prediction of individual patient outcomes. This article illuminates an important part of the development of imaging and shows that the vision of personalized medicine is becoming increasingly more tangible due to the further development of high-resolution imaging techniques, molecular imaging and artificial intelligence.
CRIS-Team Scopus Importer:2023-09-01
Keywords: Artificial intelligence; Magnetic resonance imaging; Molecular imaging; Personalized medicine; Sonography

What Are the Peripheral Blood Determinants for Increased Osteoclast Formation in the Various Inflammatory Diseases Associated With Bone Loss? - De Vries, Teun J.; El Bakkali, Ismail; Kamradt, Thomas; Schett, Georg; Jansen, Ineke D. C.; D'Amelio, Patrizia (Frontiers in Immunology, 2019)
Local priming of osteoclast precursors (OCp) has long been considered the main and obvious pathway that takes place in the human body, where local bone lining cells and RANKL-expressing osteocytes may facilitate the differentiation of OCp. However, priming of OCp away from bone, such as in inflammatory tissues, as revealed in peripheral blood, may represent a second pathway, particularly relevant in individuals who suffer from systemic bone loss such as prevalent in inflammatory diseases. In this review, we used a systematic approach to review the literature on osteoclast formation in peripheral blood in patients with inflammatory diseases associated with bone loss. Only studies that compared inflammatory (bone) disease with healthy controls in the same study were included. Using this core collection, it becomes clear that experimental osteoclastogenesis using peripheral blood from patients with bone loss diseases in prevalent diseases such as rheumatoid arthritis, osteoporosis, periodontitis, and cancer-related osteopenia unequivocally point toward an intrinsically increased osteoclast formation and activation. In particular, such increased osteoclastogenesis already takes place without the addition of the classical osteoclastogenesis cytokines M-CSF and RANKL in vitro. We show that T-cells and monocytes as OCp are the minimal demands for such unstimulated osteoclast formation. In search for common and disease-specific denominators of the diseases with inflammation-driven bone loss, we demonstrate that altered T-cell activity and a different composition-such as the CD14+CD16+ vs. CD14+CD16- monocytes-and priming of OCp with increased M-CSF, RANKL, and TNF-alpha levels in peripheral blood play a role in increased osteoclast formation and activity. Future research will likely uncover the barcodes of the OCp in the various inflammatory diseases associated with bone loss.
CRIS-Team WoS Importer:2019-04-02

What Characterizes Osteoarthritis: Ultrasound-Detected Inflammation but Not Osteophytes Is More Common in Hand Osteoarthritis Than in Painless Bony Enlargements - Gasperi, Nina; Adinolfi, Antonella; Kleyer, Arnd; Hagen, Melanie; Gasperi, Christiane; Weger, Martin; Kiechl, Stefan; Willeit, Johann; Schett, Georg; Iagnocco, Annamaria; Gasperi, Arno; Mayr, Agnes; et al. (2018)
EVALuna2:34958

What constitutes the fat signal detected by MRI in the spine of patients with ankylosing spondylitis? A prospective study based on biopsies obtained during planned spinal osteotomy to correct hyperkyphosis or spinal stenosis - Baraliakos, Xenofon; Boehm, Heinrich; Bahrami, Reza; Samir, Ahmed; Schett, Georg; Luber, Markus; Ramming, Andreas; Braun, Juergen (Annals of the Rheumatic Diseases, 2019)
Objective: Study the MRI signal of fatty lesions (FL) by immunohistological analysis of vertebral body biopsies of patients with ankylosing spondylitis (AS) compared with degenerative disc disease (DDD). Methods: Biopsies obtained during planned surgery from vertebral edges where MRI signals of FL was detected were stained with H&E. Immunofluorescence (IF) staining was performed to quantify osteoblasts and osteoclasts. Bone marrow (BM) composition, grade of cellularity and quantification of cells were analysed on six randomly chosen high-power fields (HPF; 0.125 mm2) at 200-fold magnification per patient by two experienced researchers in a blinded manner. Results: Biopsies of 21 patients with AS and 18 with DDD were analysed. Adipocytes were found in the BM of 19 patients with AS (90.5%) versus 5 with DDD (27.8%) (p<0.001), while inflammatory infiltrates were found in in the BM of 8 patients with AS (38.1%) versus 14 with DDD (77.8%) (p=0.035) and fibrosis in 6 patients with AS (28.6%) versus 4 with DDD (22.2%) (p=n.s.). The most frequently detected cells were adipocytes in AS (43.3%) versus DDD (16.1%, p=0.002) and inflammatory mononuclear cells in DDD (55%) versus AS (11.0%, p=0.001). Using IF staining, there was more osteoblastic than osteoclastic activity (6.9 vs 0.17 cells/HPF) in FL as compared with inflammatory BM (1.3 vs 7.4 cells/HPF), respectively. Conclusion: MRI FL correspond to presence of adipocytes, resulting to change of cellular homeostasis towards diminution of osteoclasts in the BM of patients with AS. The cross-talk between the different cell types and osteitis, fat and new bone formation needs further study.
CRIS-Team Scopus Importer:2019-06-04
Keywords: axial spondyloarthritis; biopsy; fatty lesions; magnetic resonance imaging

WHICH CELLS CORRESPOND TO THE TYPICAL SIGNALS FOR FATTY AND INFLAMMATORY LESIONS SEEN IN MAGNETIC RESONANCE IMAGING IN ANKYLOSING SPONDYLITIS? A PROSPECTIVE STUDY USING BIOPSY MATERIAL OBTAINED DURING SPINAL SURGERY - Baraliakos, X.; Boehm, H.; Samir, A.; Schett, Georg; Braun, J. (2016)
EVALuna2:13493

WHICH CELLS CORRESPOND TO TYPICAL SIGNALS FOR FATTY AND INFLAMMATORY LESIONS SEEN ON MRI IN AS? - Baraliakos, X.; Boehm, H.; Samir, A.; Schett, Georg; Braun, J. (2016)
EVALuna2:13470

Why and How to Include Data in Biomechanical Optimal Control Simulations - Heinrich, Simon; Coppers, Birte; Liphardt, Anna-Maria; Leyendecker, Sigrid (conference, Interdisciplinary Handsymposium 2023, 2023)

Why does the gout attack stop? A roadmap for the immune pathogenesis of gout - Schett, Georg; Schauer, Christine; Hoffmann, Markus; Herrmann, Martin (RMD Open, 2015)
Gout is one of the most severe and frequent rheumatic diseases. Clinical manifestations of gout arise from uric acid crystal deposition in the musculoskeletal tissue. At high concentrations of uric acid in the body (hyperuricaemia), needle-shaped monosodium urate (MSU) crystals are formed. The structures are ingested by neutrophils and monocytes and thereby trigger robust activation of the inflammasome, an intracellular protein complex mounting an inflammatory response. Inflammasome activation builds interleukin-1, which acts as a proinflammatory mediator and induces vasodilation, recruitment of additional leucocytes and the expression of proinflammatory cytokines and chemokines. This process is associated with the clinical manifestation of an acute gout attack. Such attacks, however, stop rather rapidly and the process of resolution of inflammation in gout is now better defined. Neutrophils having ingested MSU crystals undergo a specific form of cell death called NETosis, which is characterised by the formation of neutrophil extracellular traps (NETs). During this process, DNA is extruded, allowing the dense packaging of MSU crystals as well as the degradation of proinflammatory cytokines, thereby allowing the stopping of the inflammatory process. Reactive oxygen species are essential for forming NETs and for allowing the resolution of inflammation in gout. This process of NETosis is critical for understanding tophaceous gout, since tophi are composed of NETs and densely packed MSU crystals.
EVALuna2:13175

Why has the incidence of heart failure decreased by half in Türkiye? - Tascilar, Koray (The Lancet Regional Health - Europe, 2023)
CRIS-Team Scopus Importer:2023-10-27

Why remission is not enough: underlying disease mechanisms in RA that prevent cure - Schett, Georg; Tanaka, Yoshiya; Isaacs, John D. (Nature Reviews Rheumatology, 2020)
Cure is the aspirational aim for the treatment of all diseases, including chronic inflammatory conditions such as rheumatoid arthritis (RA); however, it has only been during the twenty-first century that remission, let alone cure, has been a regularly achievable target in RA. Little research has been carried out on how to cure RA, and the term ‘cure’ still requires definition for this disease. Even now, achieving a cure seems to be a rare occurrence among individuals with RA. Therefore, this Review is aimed at addressing the obstacles to the achievement of cure in RA. The differences between remission and cure in RA are first defined, followed by a discussion of the underlying factors (referred to as drivers) that prevent the achievement of cure in RA by triggering sustained immune activation and effector cytokine production. Such drivers include adaptive immune system activation, mesenchymal tissue priming and so-called ‘remote’ (non-immune and non-articular) factors. Strategies to target these drivers are also presented, with an emphasis on the development of strategies that could complement currently used cytokine inhibition and thereby improve the likelihood of curing RA.
CRIS-Team Scopus Importer:2020-12-25

WNT16 antagonises excessive canonical WNT activation and protects cartilage in osteoarthritis - Nalesso, Giovanna; Thomas, Bethan Lynne; Sherwood, Joanna Claire; Yu, Jing; Addimanda, Olga; Eldridge, Suzanne Elizabeth; Thorup, Anne-Sophie; Dale, Leslie; Schett, Georg; Zwerina, Jochen; Eltawil, Noha; Pitzalis, Costantino; et al. (Annals of the Rheumatic Diseases, 2017)
Both excessive and insufficient activation of WNT signalling results in cartilage breakdown and osteoarthritis. WNT16 is upregulated in the articular cartilage following injury and in osteoarthritis. Here, we investigate the function of WNT16 in osteoarthritis and the downstream molecular mechanisms.Osteoarthritis was induced by destabilisation of the medial meniscus in wild-type and WNT16-deficient mice. Molecular mechanisms and downstream effects were studied in vitro and in vivo in primary cartilage progenitor cells and primary chondrocytes. The pathway downstream of WNT16 was studied in primary chondrocytes and using the axis duplication assay in Xenopus.WNT16-deficient mice developed more severe osteoarthritis with reduced expression of lubricin and increased chondrocyte apoptosis. WNT16 supported the phenotype of cartilage superficial-zone progenitor cells and lubricin expression. Increased osteoarthritis in WNT16-deficient mice was associated with excessive activation of canonical WNT signalling. In vitro, high doses of WNT16 weakly activated canonical WNT signalling, but, in co-stimulation experiments, WNT16 reduced the capacity of WNT3a to activate the canonical WNT pathway. In vivo, WNT16 rescued the WNT8-induced primary axis duplication in Xenopus embryos.In osteoarthritis, WNT16 maintains a balanced canonical WNT signalling and prevents detrimental excessive activation, thereby supporting the homeostasis of progenitor cells.
EVALuna2:13281

WNT5A PROMOTES FIBROBLAST ACTIVATION AND TISSUE FIBROSIS BY ROR2/RYK DEPENDENT ACTIVATION OF PCP-SIGNALING - Chen, Chih-Wei; Lin, N. -Y.; Zhang, Yun; Huang, J.; Palumbo-Zerr, K.; Schambony, Alexandra; Beyer, Christian; Schett, Georg; Distler, Jörg (2016)
EVALuna2:13488

WNT5A Promotes Tissue Fibrosis By Wnt/PCP-Dependent Activation of Latent TGF-beta - Chen, Chih-Wei; Thuong Trinh-Minh,; Lin, Neng-Yu; Zhang, Yun; Groeber, Florian; Beyer, Christian; Schett, Georg; Distler, Jörg (2017)
EVALuna2:33430

Working with "H2S": Facts and apparent artifacts - Wedmann, Rudolf; Bertlein, Sarah; Macinkovic, Igor; Böltz, Sebastian; Miljkovic, Jan; Munoz Becerra, Luis; Herrmann, Martin; Filipovic, Milos (Nitric Oxide-Biology and Chemistry, 2014)
Hydrogen sulfide (H2S) is an important signaling molecule with physiological endpoints similar to those of nitric oxide (NO). Growing interest in its physiological roles and pharmacological potential has led to large sets of contradictory data. The principle cause of these discrepancies can be the common neglect of some of the basic H2S chemistry. This study investigates how the experimental outcome when working with H2S depends on its source and dose and the methodology employed. We show that commercially available NaHS should be avoided and that traces of metal ions should be removed because these can reduce intramolecular disulfides and change protein structure. Furthermore, high H2S concentrations may lead to a complete inhibition of cell respiration, mitochondrial membrane potential depolarization and superoxide generation, which should be considered when discussing the biological effects observed upon treatment with high concentrations of H2S. In addition, we provide chemical evidence that H2S can directly react with superoxide. H2S is also capable of reducing cytochrome c(3+) with the concomitant formation of superoxide. H2S does not directly react with nitrite but with NO electrodes that detect H2S. In addition, H2S interferes with the Griess reaction and should therefore be removed from the solution by Cd(2+) or Zn(2+) precipitation prior to nitrite quantification. 2-Phenyl-4,4,5,5-tetramethylimidazoline-1-oxyl 3-oxide (PTIO) is reduced by H2S, and its use should be avoided in combination with H2S. All these constraints must be taken into account when working with H2S to ensure valid data.
EVALuna2:12902

Xanthine dehydrogenase as a prognostic biomarker related to tumor immunology in hepatocellular carcinoma - Lin, Zhen; Xie, Yi-Zhao; Zhao, Ming-Chun; Hou, Pin-Pin; Tang, Juan; Chen, Guang-Liang (Cancer Cell International, 2021)
Background: Xanthine dehydrogenase (XDH) is a critical enzyme involved in the oxidative metabolism of purines, pterin and aldehydes and a central component of the innate immune system. However, the prognostic value of XDH in predicting tumor-infiltrating lymphocyte abundance, the immune response, and survival in different cancers, including hepatocellular carcinoma (HCC), is still unclear. Methods: XDH expression was analyzed in multiple databases, including Oncomine, the Tumor Immune Estimation Resource (TIMER), the Kaplan–Meier plotter database, the Gene Expression Profiling Interactive Analysis (GEPIA) database, and The Cancer Genome Atlas (TCGA). XDH-associated transcriptional profiles were detected with an mRNA array, and the levels of infiltrating immune cells were validated by immunohistochemistry (IHC) of HCC tissues. A predictive signature containing multiple XDH-associated immune genes was established using the Cox regression model. Results: Decreased XDH mRNA expression was detected in human cancers originating from the liver, bladder, breast, colon, bile duct, kidney, and hematolymphoid system. The prognostic potential of XDH mRNA expression was also significant in certain other cancers, including HCC, breast cancer, kidney or bladder carcinoma, gastric cancer, mesothelioma, lung cancer, and ovarian cancer. In HCC, a low XDH mRNA level predicted poorer overall survival, disease-specific survival, disease-free survival, and progression-free survival. The prognostic value of XDH was independent of the clinical features of HCC patients. Indeed, XDH expression in HCC activated several immune-related pathways, including the T cell receptor, PI3K-AKT, and MAPK signaling pathways, which induced a cytotoxic immune response. Importantly, the microenvironment of XDHhigh HCC tumors contained abundant infiltrating CD8 + T cells but not exhausted T cells. A risk prediction signature based on multiple XDH-associated immune genes was revealed as an independent predictor in the TCGA liver cancer cohort. Conclusion: These findings suggest that XDH is a valuable prognostic biomarker in HCC and other cancers and indicate that it may function in tumor immunology. Loss of XDH expression may be an immune evasion mechanism for HCC.
CRIS-Team Scopus Importer:2021-09-17
Keywords: Biomarker; Exhaustion marker; Hepatocellular carcinoma; Immunity; XDH

XIAP AS NOVEL INTEGRATOR OF TGF BETA SIGNALLING AND CANONICAL WNT SIGNALLING IN TISSUE FIBROSIS - Bergmann, C.; Hallenberger, L.; Merlevede, B.; Brandt, Adrian; Dees, Clara; Chen, Chih-Wei; Stock, Michael; Beyer, Christian; Distler, O.; Schett, Georg; Distler, Jörg (2018)
EVALuna2:34997

X-linked inhibitor of apoptosis protein (XIAP) inhibition in systemic sclerosis (SSc) - Bergmann, Christina; Hallenberger, Ludwig; Chenguiti Fakhouri, Sara; Chenguiti Fakhouri, Sara; Merlevede, Benita; Brandt, Adrian; Dees, Clara; Zhu, Honglin; Zehender, Ariella; Zhou, Xiang; Schwab, Annemarie; Chen, Chih-Wei; et al. (Annals of the Rheumatic Diseases, 2021)
X-linked inhibitor of apoptosis protein (XIAP) is a multifunctional protein with important functions in apoptosis, cellular differentiation and cytoskeletal organisation and is emerging as potential target for the treatment of various cancers. The aim of the current study was to investigate the role of XIAP in the pathogenesis of systemic sclerosis (SSc). The expression of XIAP in human skin samples of patients with SSc and chronic graft versus host disease (cGvHD) and healthy individuals was analysed by quantitative PCR, immunofluorescence (IF) and western blot. XIAP was inactivated by siRNA-mediated knockdown and pharmacological inhibition. The effects of XIAP inactivation were analysed in cultured fibroblasts and in the fibrosis models bleomycin-induced and topoisomerase-I-(topoI)-induced fibrosis and in Wnt10b-transgenic mice. The expression of XIAP, but not of other inhibitor of apoptosis protein family members, was increased in fibroblasts in SSc and sclerodermatous cGvHD. Transforming growth factor beta (TGF-β) induced the expression of XIAP in a SMAD3-dependent manner. Inactivation of XIAP reduced WNT-induced fibroblast activation and collagen release. Inhibition of XIAP also ameliorated fibrosis induced by bleomycin, topoI and overexpression of Wnt10b in well-tolerated doses. The profibrotic effects of XIAP were mediated via WNT/β-catenin signalling. Inactivation of XIAP reduces binding of β-catenin to TCF to in a TLE-dependent manner to block WNT/β-catenin-dependent transcription. Our data characterise XIAP as a novel link between two core pathways of fibrosis. XIAP is overexpressed in SSc and cGvHD in a TGF-β/SMAD3-dependent manner and in turn amplifies the profibrotic effects of WNT/β-catenin signalling on fibroblasts via transducin-like enhancer of split 3. Targeted inactivation of XIAP inhibits the aberrant activation of fibroblasts in murine models of SSc.
CRIS-Team Scopus Importer:2021-05-07
Keywords: fibroblasts; pulmonary fibrosis; scleroderma; systemic

[YIA] AMPLIFICATION OF ROS/NET FORMATION INDUCES RESOLUTION OF INFLAMMATION - Euler, Maximilien; Hahn, Jonas; Herrmann, Martin; Mokhir, Andriy; Hoffmann, Markus (FREE RADICAL BIOLOGY AND MEDICINE, 2022)
CRIS-Team WoS Importer:2022-09-16

Young-GRAPPA at the Annual GRAPPA Meeting: Presentation of a New Group Within GRAPPA and Its Vision - van Mens, Leonieke J.J.; Ayan, Gizem; Coates, Laura C.; Coras, Roxana; Silva, Dimitri L.F.; Herrera, Sebastián; Ishchenko, Alla; Jethwa, Hannah; Johnsson, Hanna; Simon, David; Vivekanantham, Arani; Proft, Fabian (Journal of Rheumatology, 2022)
At the 2021 Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA) annual meeting, a separate group was created (Young-GRAPPA) to address the challenges of young researchers and physicians beginning their careers. This paper presents the initial organizational framework and different components and aims of this group. We were able to enroll over 50 young researchers as a result of this meeting.
CRIS-Team Scopus Importer:2022-09-02
Keywords: GRAPPA; psoriasis; psoriatic arthritis

Young-GRAPPA (Y-GRAPPA) at the 2022 GRAPPA Annual Meeting: One Year in Y-GRAPPA. Where Do We Stand, Where Do We Go? - Ayan, Gizem; Coras, Roxana; Grynszpan, Rachel; Herrera, Sebastián; Jethwa, Hannah; Johnsson, Hanna J.; Silva, Dimitri L.F.; van Mens, Leonieke; Mulder, Michelle L.M.; Simon, David; Vivekanantham, Arani; Proft, Fabian (Journal of Rheumatology, 2023)
Young-GRAPPA (Y-GRAPPA) was introduced at the 2021 Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA) annual meeting. Here we present the 1-year progress of Y-GRAPPA and future plans of this enthusiastic group of young clinicians and early career researchers interested in psoriasis and psoriatic arthritis.
CRIS-Team Scopus Importer:2023-11-24
Keywords: arthritis; GRAPPA; psoriasis; psoriatic; psoriatic arthritis; spondyloarthritis

Zoledronate causes a systemic shift of macrophage polarization towards M1 in vivo - Weber, Manuel; Homm, Andi; Müller, Stefan; Frey, Silke; Amann, Kerstin Ute; Ries, Jutta; Geppert, Carol-Immanuel; Preidl, Raimund; Möst, Tobias; Kämmerer, Peer W.; Kesting, Marco Rainer; Wehrhan, Falk (International Journal of Molecular Sciences, 2021)
Background: Immunomodulatory properties of bisphosphonates (BP) are suggested to contribute to the development of medication‐associated osteonecrosis of the jaw (MRONJ). Further-more, bisphosphonate‐derived immune modulation might contribute to the anti‐metastatic effect observed in breast cancer patients. Macrophages are potential candidates for the mediation of immunomodulatory effects of bisphosphonates. The study aimed to investigate the influence of bisphosphonates alone and in combination with surgical trauma on systemic macrophage polarization (M1 vs. M2) using an in vivo rat model. Methods: A total of 120 animals were divided into four groups. Groups 2 and 4 were treated with 8 × 40 μg/kg body weight of the BP Zoledronate i.p. (week 0–7). Groups 3 and 4 were exposed to surgical trauma (week 8, tooth extraction + tibia fracture), whereas in Group 1 neither medication nor surgical trauma was applied. After 8, 10, 12 and 16 weeks, skin, lung and spleen were immunohistochemically examined for macrophage polarization via expression analysis of CD68, CD163 and iNOS using a tissue microarray (TMA). Results: A significant shift of macrophage polarization towards M1 was observed in skin, spleen and lung tissue of animals, with and without surgical trauma, treated with BP when compared to those without BP application. Surgical trauma did not cause a significant increase towards M1 polarization. Conclusions: BP application leads to a systemic pro‐inflammatory situation in vivo, independent of surgical trauma, as evidenced by the shift in macrophage polarization towards M1 in various somatic tissues. This provides a possible explanation for the clinically observed anti‐tumor effect of bisphosphonates and might also contribute to pathogenesis of MRONJ.
CRIS-Team Scopus Importer:2021-02-05
Keywords: Antiresorptives; Bisphosphonate; Immune modulation; M1; M2; Macrophage polarization; Zoledronate

β2-microglobulin triggers NLRP3 inflammasome activation in tumor-associated macrophages to promote multiple myeloma progression - Hofbauer, Daniel; Mougiakakos, Dimitrios; Broggini, Luca; Zaiss, Mario; Büttner-Herold, Maike; Bach, Christian; Spriewald, Bernd; Neumann, Frank; Bisht, Savita; Nolting, Jens; Zeiser, Robert; Hamarsheh, Shaima'a; et al. (Immunity, 2021)
As substantial constituents of the multiple myeloma (MM) microenvironment, pro-inflammatory macrophages have emerged as key promoters of disease progression, bone destruction, and immune impairment. We identify beta-2-microglobulin (β2m) as a driver in initiating inflammation in myeloma-associated macrophages (MAMs). Lysosomal accumulation of phagocytosed β2m promotes β2m amyloid aggregation in MAMs, resulting in lysosomal rupture and ultimately production of active interleukin-1β (IL-1β) and IL-18. This process depends on activation of the NLRP3 inflammasome after β2m accumulation, as macrophages from NLRP3-deficient mice lack efficient β2m-induced IL-1β production. Moreover, depletion or silencing of β2m in MM cells abrogates inflammasome activation in a murine MM model. Finally, we demonstrate that disruption of NLRP3 or IL-18 diminishes tumor growth and osteolytic bone destruction normally promoted by β2m-induced inflammasome signaling. Our results provide mechanistic evidence for β2m's role as an NLRP3 inflammasome activator during MM pathogenesis. Moreover, inhibition of NLRP3 represents a potential therapeutic approach in MM.
CRIS-Team Scopus Importer:2021-08-13
Keywords: inflammation; macrophages; multiple myeloma; NLRP3; phagocytosis; tumor-associated macrophages

Androgen Deprivation Therapy for Prostate Cancer and the Risk of Rheumatoid Arthritis: A Population-Based Cohort Study - Klil-Drori, Adi J.; Santella, Christina; Tascilar, Koray; Yin, Hui; Aprikian, Armen; Azoulay, Laurent (Drug Safety, 2019)
Introduction: Two recent observational studies have investigated the association between androgen deprivation therapy (ADT) and rheumatoid arthritis (RA), but generated discrepant findings and had important methodological limitations. Thus, the objective of this study was to determine whether the use of ADT is associated with an increased risk of RA in men with prostate cancer. Patients and Methods: We conducted a population-based cohort study using the United Kingdom Clinical Practice Research Datalink. The cohort included all men, at least 40 years of age, newly diagnosed with prostate cancer between 1 January 1988 and 31 March 2014, with follow-up until 30 September 2014. Exposure to ADT was treated as a time-varying variable and lagged by 1 year to account for diagnostic delays and latency. Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) of RA, comparing use of ADT with non-use. Secondary analyses were conducted to assess whether the association varied according to ADT type and cumulative duration of use. Finally, we conducted several sensitivity analyses to assess the robustness of our findings. Results: The cohort included 32,302 men followed for a median of 3.3 years. During follow-up, 63 patients were newly diagnosed with RA, generating an incidence rate of 46.5/100,000 person-years. Compared with non-use, the use of ADT was not associated with an increased risk of RA (HR 0.84, 95% CI 0.49–1.45). In secondary analyses, the association did not vary according to ADT type or with cumulative duration of use (p trend = 0.53). The results remained consistent in sensitivity analyses. Conclusion: In this population-based study, the use of ADT was not associated with an increased risk of RA in men with prostate cancer.
CRIS-Team Scopus Importer:2019-07-09

B-lymphocyte hyperactivation and autoantibody production in the pathophysiology of cutaneous systemic sclerosis Hiperactivación del linfocito B y producción de los autoanticuerpos anticentrómero, antitopoisomerasa-I, anti-ARNPol-III en la fisiopatología de la esclerosis sistémica cutánea - Hernández-Flórez, Diana; Martínez-Barrio, Julia; López-Longo, Francisco Javier; Valor, Lara (Revista Colombiana de Reumatología, 2020)
CRIS-Team Scopus Importer:2020-04-07

Complement component C4 structural variation and quantitative traits contribute to sex-biased vulnerability in systemic sclerosis. - Kerick, Martin; Acosta-Herrera, Marialbert; Pilar Simeon-Aznar, Carmen; Luis Callejas, Jose; Assassi, Shervin; Proudman, Susanna M.; Nikpour, Mandana; Hunzelmann, Nicolas; Moroncini, Gianluca; De Vries-Bouwstra, Jeska K.; Orozco, Gisela; Barton, Anne; et al. (npj Genomic Medicine, 2022)
Copy number (CN) polymorphisms of complement C4 play distinct roles in many conditions, including immune-mediated diseases. We investigated the association of C4 CN with systemic sclerosis (SSc) risk. Imputed total C4, C4A, C4B, and HERV-K CN were analyzed in 26,633 individuals and validated in an independent cohort. Our results showed that higher C4 CN confers protection to SSc, and deviations from CN parity of C4A and C4B augmented risk. The protection contributed per copy of C4A and C4B differed by sex. Stronger protection was afforded by C4A in men and by C4B in women. C4 CN correlated well with its gene expression and serum protein levels, and less C4 was detected for both in SSc patients. Conditioned analysis suggests that C4 genetics strongly contributes to the SSc association within the major histocompatibility complex locus and highlights classical alleles and amino acid variants of HLA-DRB1 and HLA-DPB1 as C4-independent signals.
EVALuna2:520827

Comprehensive analysis of the major histocompatibility complex in systemic sclerosis identifies differential HLA associations by clinical and serological subtypes. - Acosta-Herrera, Marialbert; Kerick, Martin; Lopez-Isac, Elena; Assassi, Shervin; Beretta, Lorenzo; Simeon-Aznar, Carmen Pilar; Ortego-Centeno, Norberto; Proudman, Susanna M.; Hunzelmann, Nicolas; Moroncini, Gianluca; De Vries-Bouwstra, Jeska K.; Orozco, Gisela; et al. (Annals of the Rheumatic Diseases, 2021)
OBJECTIVE: The greatest genetic effect reported for systemic sclerosis (SSc) lies in the major histocompatibility complex (MHC) locus. Leveraging the largest SSc genome-wide association study, we aimed to fine-map this region to identify novel human leucocyte antigen (HLA) genetic variants associated with SSc susceptibility and its main clinical and serological subtypes. METHODS: 9095 patients with SSc and 17 584 controls genome-wide genotyped were used to impute and test single-nucleotide polymorphisms (SNPs) across the MHC, classical HLA alleles and their composite amino acid residues. Additionally, patients were stratified according to their clinical and serological status, namely, limited cutaneous systemic sclerosis (lcSSc), diffuse cutaneous systemic sclerosis (dcSSc), anticentromere (ACA), antitopoisomerase (ATA) and anti-RNApolIII autoantibodies (ARA). RESULTS: Sequential conditional analyses showed nine SNPs, nine classical alleles and seven amino acids that modelled the observed associations with SSc. This confirmed previously reported associations with HLA-DRB1*11:04 and HLA-DPB1*13:01, and revealed a novel association of HLA-B*08:01. Stratified analyses showed specific associations of HLA-DQA1*02:01 with lcSSc, and an exclusive association of HLA-DQA1*05:01 with dcSSc. Similarly, private associations were detected in HLA-DRB1*08:01 and confirmed the previously reported association of HLA-DRB1*07:01 with ACA-positive patients, as opposed to the HLA-DPA1*02:01 and HLA-DQB1*03:01 alleles associated with ATA presentation. CONCLUSIONS: This study confirms the contribution of HLA class II and reveals a novel association of HLA class I with SSc, suggesting novel pathways of disease pathogenesis. Furthermore, we describe specific HLA associations with SSc clinical and serological subtypes that could serve as biomarkers of disease severity and progression.
EVALuna2:475534

Correction to: Predictors of abatacept retention over 2 years in patients with rheumatoid arthritis: results from the real-world ACTION study (Clinical Rheumatology, (2019), 38, 5, (1413-1424), 10.1007/s10067-019-04449-w) - Alten, Rieke; Mariette, Xavier; Lorenz, Hanns Martin; Nüsslein, Hubert; Galeazzi, Mauro; Navarro, Federico; Chartier, Melanie; Heitzmann, Julia; Poncet, Coralie; Rauch, Christiane; Le Bars, Manuela (Clinical Rheumatology, 2019)
The article listed above was initially published with incorrect copyright information. Upon publication of this Correction, the copyright of this article changed to “The Author(s)”. The original article has been corrected. Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
CRIS-Team Scopus Importer:2019-05-28

Distinct fibroblast subsets drive inflammation and damage in arthritis - Croft, Adam P.; Campos, Joana; Jansen, Kathrin; Turner, Jason D.; Marshall, Jennifer; Attar, Moustafa; Savary, Loriane; Wehmeyer, Corinna; Naylor, Amy J.; Kemble, Samuel; Begum, Jenefa; Dürholz, Kerstin; et al. (Nature, 2019)
The identification of lymphocyte subsets with non-overlapping effector functions has been pivotal to the development of targeted therapies in immune-mediated inflammatory diseases (IMIDs)1,2. However, it remains unclear whether fibroblast subclasses with non-overlapping functions also exist and are responsible for the wide variety of tissue-driven processes observed in IMIDs, such as inflammation and damage3–5. Here we identify and describe the biology of distinct subsets of fibroblasts responsible for mediating either inflammation or tissue damage in arthritis. We show that deletion of fibroblast activation protein-α (FAPα)+ fibroblasts suppressed both inflammation and bone erosions in mouse models of resolving and persistent arthritis. Single-cell transcriptional analysis identified two distinct fibroblast subsets within the FAPα+ population: FAPα+THY1+ immune effector fibroblasts located in the synovial sub-lining, and FAPα+THY1− destructive fibroblasts restricted to the synovial lining layer. When adoptively transferred into the joint, FAPα+THY1− fibroblasts selectively mediate bone and cartilage damage with little effect on inflammation, whereas transfer of FAPα+ THY1+ fibroblasts resulted in a more severe and persistent inflammatory arthritis, with minimal effect on bone and cartilage. Our findings describing anatomically discrete, functionally distinct fibroblast subsets with non-overlapping functions have important implications for cell-based therapies aimed at modulating inflammation and tissue damage.
CRIS-Team Scopus Importer:2019-06-18

Efficacy and safety of guselkumab and adalimumab for pustulotic arthro-osteitis and their impact on peripheral blood immunophenotypes - Ueno, Masanobu; Miyagawa, Ippei; Miyazaki, Yusuke; Hanami, Kentaro; Fukuyo, Shunsuke; Kubo, Satoshi; Nakayamada, Shingo; Tanaka, Yoshiya (Arthritis Research & Therapy, 2022)
Objectives: We compared the treatment effectiveness between guselkumab and adalimumab in patients with pustulotic arthro-osteitis (PAO). In addition, we performed peripheral blood immunophenotyping to elucidate the immunological background and analyzed the impact of therapeutic drugs to verify the validity of immunological phenotypes as therapeutic targets. Methods: Patients were treated with guselkumab 100 mg (guselkumab group; n = 12) and adalimumab 40 mg (adalimumab group; n = 13). Arthritis disease activity, skin lesion activity, and patient-reported outcomes (PROs) were evaluated and compared between the two groups. The retention rate and adverse events were evaluated. Comprehensive phenotyping of peripheral immune cells was performed in both groups, and phenotypes were compared before and after treatment. Results: At 6 months, both groups showed significant improvement in arthritis disease activity and PROs. In the guselkumab group, skin symptoms significantly improved. The 6-month continuation rates were 91.7% (11/12) and 69.2% (9/13) in the guselkumab and adalimumab groups, respectively. Adverse events occurred in 2/12 and 5/13 patients in the guselkumab (16.7%) and adalimumab (38.5%) groups, respectively. Peripheral blood immunophenotyping showed that the proportion of activated T helper (Th) 1 cells was significantly lower in patients with PAO than in healthy controls and that the proportion of activated Th17 cells was significantly higher in patients with PAO, which significantly decreased after treatment with guselkumab. Conclusion: Although guselkumab and adalimumab have comparable efficacy for PAO, their impact on immunophenotypes varies.
CRIS-Team Scopus Importer:2022-11-04
Keywords: Adalimumab; Guselkumab; Palmoplantar pustulosis; Pustulotic arthro-osteitis

GENETIC EVIDENCE OF EOSINOPHIL NUMBER UNDERPINNING PR3-AAV AND PLAUSIBLE HOST GENETIC PREDISPOSITION TO MICROBIAL DRIVERS OF DISEASE - Wong, Limy; Mescia, Federica; Alberici, Federico; Ball, Miriam J.; Baslund, Bo; Brenchley, Paul; Bruchfeld, Annette; Cid, Maria C.; Tervaert, Jan Willem Cohen; Coulson, Richard M. R.; Farahi, Neda; Feighery, Conleth; et al. (RHEUMATOLOGY, 2019)
CRIS-Team WoS Importer:2019-08-16

Guidelines for the assessment of bone density and microarchitecture in vivo using high-resolution peripheral quantitative computed tomography - Whittier, D. E.; Boyd, S. K.; Burghardt, A. J.; Paccou, J.; Ghasem-Zadeh, A.; Chapurlat, R.; Engelke, Klaus; Bouxsein, M. L. (Osteoporosis international, 2020)
Introduction: The application of high-resolution peripheral quantitative computed tomography (HR-pQCT) to assess bone microarchitecture has grown rapidly since its introduction in 2005. As the use of HR-pQCT for clinical research continues to grow, there is an urgent need to form a consensus on imaging and analysis methodologies so that studies can be appropriately compared. In addition, with the recent introduction of the second-generation HrpQCT, which differs from the first-generation HR-pQCT in scan region, resolution, and morphological measurement techniques, there is a need for guidelines on appropriate reporting of results and considerations as the field adopts newer systems. Methods: A joint working group between the International Osteoporosis Foundation, American Society of Bone and Mineral Research, and European Calcified Tissue Society convened in person and by teleconference over several years to produce the guidelines and recommendations presented in this document. Results: An overview and discussion is provided for (1) standardized protocol for imaging distal radius and tibia sites using HR-pQCT, with the importance of quality control and operator training discussed; (2) standardized terminology and recommendations on reporting results; (3) factors influencing accuracy and precision error, with considerations for longitudinal and multi-center study designs; and finally (4) comparison between scanner generations and other high-resolution CT systems. Conclusion: This article addresses the need for standardization of HR-pQCT imaging techniques and terminology, provides guidance on interpretation and reporting of results, and discusses unresolved issues in the field.
CRIS-Team Scopus Importer:2020-06-05
Keywords: Bone microarchitecture; Guidelines; High-resolution peripheral quantitative computed tomography; Imaging protocol

Interactions between Muscle and Bone-Where Physics Meets Biology - Herrmann, Marietta; Engelke, Klaus; Ebert, Regina; Müller-Deubert, Sigrid; Rudert, Maximilian; Ziouti, Fani; Jundt, Franziska; Felsenberg, Dieter; Jakob, Franz (Biomolecules, 2020)
Muscle and bone interact via physical forces and secreted osteokines and myokines. Physical forces are generated through gravity, locomotion, exercise, and external devices. Cells sense mechanical strain via adhesion molecules and translate it into biochemical responses, modulating the basic mechanisms of cellular biology such as lineage commitment, tissue formation, and maturation. This may result in the initiation of bone formation, muscle hypertrophy, and the enhanced production of extracellular matrix constituents, adhesion molecules, and cytoskeletal elements. Bone and muscle mass, resistance to strain, and the stiffness of matrix, cells, and tissues are enhanced, influencing fracture resistance and muscle power. This propagates a dynamic and continuous reciprocity of physicochemical interaction. Secreted growth and differentiation factors are important effectors of mutual interaction. The acute effects of exercise induce the secretion of exosomes with cargo molecules that are capable of mediating the endocrine effects between muscle, bone, and the organism. Long-term changes induce adaptations of the respective tissue secretome that maintain adequate homeostatic conditions. Lessons from unloading, microgravity, and disuse teach us that gratuitous tissue is removed or reorganized while immobility and inflammation trigger muscle and bone marrow fatty infiltration and propagate degenerative diseases such as sarcopenia and osteoporosis. Ongoing research will certainly find new therapeutic targets for prevention and treatment.
CRIS-Team Scopus Importer:2020-03-27
Keywords: bone; mechanosensing; mechanotransduction; muscle; myokines; osteokines adaptation

Lack of periosteal apposition in the head and neck of femur after menopause in Chinese women with high risk for hip fractures — A cross-sectional study with QCT - Su, Yongbin; Wang, Ling; Liu, Xiaoyan; Yang, Minghui; Yi, Chen; Liu, Yandong; Huang, Pengju; Guo, Zhe; Yu, Aihong; Cheng, Xiaoguang; Wu, Xinbao; Blake, Glen M.; et al. (Bone, 2020)
In elderly subjects and in particular in those with osteoporosis the evidence on age related volume changes of the hip is still very limited. Even less is known about bone changes of the femoral head. The aim of this study is to explore associations of bone size of the femoral head and neck with age in postmenopausal women with very high risk of hip fracture and to investigate associations of femoral head and neck bone mineral density. MIAF (medical image analysis framework)-Femur was used for the analysis of CT datasets from 319 females with acute hip fractures age 50 to 98. Integral BMD and volume of the head and neck were assessed. The femoral head was divided into four quadrants to address differential vBMD and volume responses of its superior, inferior, posterior and anterior parts. Areal BMD (aBMD) of femoral neck was also obtained. In this population of postmenopausal women we did not observe age-related changes in bone volume of the femoral head or neck between ages 50 and 98 years. Integral vBMD in the head in the 90–98 year group was 48.0 mg/cm3 lower than that in 50–59 year group, which accounts for nearly 30% decrease in vBMD with 40 years increase. Age-related vBMD changes in the head quadrants were similar to that in total. With age, the trend line correlation coefficients for vBMD in quadrants were relatively small, but significant (p < 0.001) for all. The femoral head integral vBMD correlates well with neck vBMD and FN aBMD. FN aBMD explained 45% of head integral vBMD variance (p < 0.0001). Elderly women had relative preservation of femoral head and neck bone volume from 50 yrs. over four decades but markedly lower integral vBMD of proximal femur. The findings of our study call in question about the concept of bone expansion with aging even in elderly age.
CRIS-Team Scopus Importer:2020-08-14
Keywords: Age; Femoral head; Femoral neck; Hip fracture; Quantitative computed tomography

Muscle density discriminates hip fracture better than computed tomography X-ray absorptiometry hip areal bone mineral density - Wang, Ling; Yin, Lu; Zhao, Yue; Su, Yongbin; Sun, Wei; Liu, Yandong; Yang, Minghui; Yu, Aihong; Blake, Glen Mervyn; Cheng, Xiaoguang; Wu, Xinbao; Veldhuis, Annegreet; et al. (Journal of Cachexia, Sarcopenia and Muscle, 2020)
Background: Muscle weakness is a key factor in the increase risk of falls and might also play a significant role in the increase of risk of hip fracture. Computed tomography-measured muscle size and muscle density are well-established imaging biomarkers used in studies of physical function, frailty or cancer, but limited to hip fracture. In particular, it is warranted to have a better understanding of the performance of muscle size and density in the discrimination of acute hip fractures. We also aim to determine age-related differences of muscle size and density in healthy controls and hip fracture patients. Methods: Four hundred thirty-eight low-energy acute hip fracture cases and 316 healthy controls from the China Action on Spine and Hip Status study were included in the study. Muscle cross-sectional area and density were measured for the gluteus maximus and gluteus medius and minimus. Areal bone mineral density (aBMD) of the femoral neck and total hip was measured. Using propensity score matching, we generated three samples with cases and controls matched for age, body mass index, and gender: femoral neck fracture (FNF), intertrochanteric fracture (ITF), and any hip fracture vs. controls, respectively. Results: Handgrip strength, gluteus muscle area and density, and bone parameters of the matched hip fracture groups were lower than those of the correspondence control groups, respectively (P < 0.05). The univariate analysis showed that associations of aBMD with FNF and with ITF were significantly weaker than associations between fracture and muscle parameters. Gluteus medius and minimus muscle density showed the highest areas under the curve (AUC) with FNF (0.88, 95% confidence interval, 0.85–0.92) and trochanteric fracture (0.95, 95% confidence interval, 0.92–0.97). The model including all muscle and bone parameters provided the highest AUC (FNF: AUC 0.912; ITF: AUC 0.958), and AUC results of another selected model without muscle density showed that association with fracture significantly dropped (FNF: AUC 0.755; ITF: AUC 0.858). Separate results for the two age groups younger and older than 70 years showed no age-related significant differences in discriminate models. Conclusions: Muscle density performs better than aBMD from hip computed tomography X-ray absorptiometry and muscle size in discrimination of hip fracture. Combination of aBMD and muscle density provided the best discrimination. The integration of muscle assessments may trigger a paradigm shift in hip fracture prediction. Gluteus muscle density should also be evaluated as treatment outcome.
CRIS-Team Scopus Importer:2020-09-25
Keywords: Acute hip fracture; Bone mineral density; Muscle density; Muscle size

Opportunistic Screening Using Low-Dose CT and the Prevalence of Osteoporosis in China: A Nationwide, Multicenter Study - Cheng, Xiaoguang; Zhao, Kaiping; Zha, Xiaojuan; Du, Xia; Li, Yongli; Chen, Shuang; Wu, Yan; Li, Shaolin; Lu, Yong; Zhang, Yuqin; Xiao, Xigang; Li, Yuehua; et al. (Journal of Bone and Mineral Research, 2020)
Opportunistic screening for osteoporosis can be performed using low-dose computed tomography (LDCT) imaging obtained for other clinical indications. In this study we explored the CT-derived bone mineral density (BMD) and prevalence of osteoporosis from thoracic LDCT in a large population cohort of Chinese men and women. A total of 69,095 adults (40,733 men and 28,362 women) received a thoracic LDCT scan for the purpose of lung cancer screening between 2018 and 2019, and data were obtained for analysis from the China Biobank Project, a prospective nationwide multicenter population study. Lumbar spine (L-1-L-2) trabecular volumetric bone mineral density (vBMD) was derived from these scans using quantitative computed tomography (QCT) software and the American College of Radiology QCT diagnostic criteria for osteoporosis were applied. Geographic regional differences in the prevalence of osteoporosis were assessed and the age-standardized, population prevalence of osteoporosis in Chinese men and women was estimated from the 2010 China census. The prevalence of osteoporosis by QCT for the Chinese population aged >50 years was 29.0% for women and 13.5% for men, equating to 49.0 million and 22.8 million, respectively. In women, this rate is comparable to estimates from dual-energy X-ray absorptiometry (DXA), but in men, the prevalence is double. Prevalence varied geographically across China, with higher rates in the southwest and lower rates in the northeast. Trabecular vBMD decreased with age in both men and women. Women had higher peak trabecular vBMD (185.4 mg/cm(3)) than men (176.6 mg/cm(3)) at age 30 to 34 years, but older women had lower trabecular vBMD (62.4 mg/cm(3)) than men (92.1 mg/cm(3)) at age 80 years. We show that LDCT-based opportunistic screening could identify large numbers of patients with low lumbar vBMD, and that future cohort studies are now required to evaluate the clinical utility of such screening in terms of fracture prevention and supporting national health economic analyses. (c) 2020 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).
CRIS-Team WoS Importer:2020-11-20

Predictors of abatacept retention over 2 years in patients with rheumatoid arthritis: results from the real-world ACTION study - Alten, Rieke; Mariette, Xavier; Lorenz, Hanns Martin; Nüsslein, Hubert; Galeazzi, Mauro; Navarro, Federico; Chartier, Melanie; Heitzmann, Julia; Poncet, Coralie; Rauch, Christiane; Le Bars, Manuela (Clinical Rheumatology, 2019)
Objectives: Evaluate abatacept retention over 2 years in the AbataCepT In rOutiNe clinical practice (ACTION) study. Method: ACTION was an international, observational study of patients with moderate-to-severe rheumatoid arthritis (RA) who initiated intravenous abatacept. Crude abatacept retention rates over 2 years were estimated using Kaplan–Meier analyses in biologic-naive and -failure patients. Clinically relevant risk factors and significant prognostic factors for retention were evaluated using a Cox proportional hazards multivariable model. Results: Overall, 2350/2364 enrolled patients were evaluable; 673 (28.6%) were biologic naive and 1677 (71.4%) had prior biologic failure (1 biologic, 728/1677 [43.4%]; ≥ 2 biologics, 949/1677 [56.6%]). Abatacept retention rate (95% confidence interval [CI]) at 2 years was 47.9% (45.7, 50.0): 54.5% (50.4, 58.3) for biologic-naive vs 45.2% (42.7, 47.7) for biologic-failure patients (log-rank P < 0.001). For patients with 1 and ≥ 2 prior biologic failures, respectively, retention rates (95% CI) were 50.2% (46.3, 53.9) vs 41.3% (38.0, 44.6; log-rank P < 0.001). Main reasons for discontinuation (biologic-naive vs biologic-failure, respectively) were lack of efficacy (61.4 vs 67.7%) and safety (21.3 vs 21.2%). Rheumatoid factor (RF) and anti-cyclic citrullinated peptide (anti-CCP) double positivity versus negativity were predictive of higher retention in both biologic-naive (hazard ratio [HR] [95% CI] 0.71 [0.53, 0.96]; P = 0.019) and biologic-failure patients (HR [95% CI] 0.76 [0.62, 0.94]; P = 0.035). Conclusions: Abatacept initiation as earlier vs later line of therapy in RA may achieve higher 2-year retention rates. RF and anti-CCP seropositivity could predict increased abatacept retention, irrespective of treatment line. Trial registration: NCT02109666.
CRIS-Team Scopus Importer:2019-05-28
Keywords: Biologic; Efficacy; Predictor; Remission; Rheumatoid arthritis

Reliability and change in erosion measurements by high-resolution peripheral quantitative computed tomography in a longitudinal dataset of rheumatoid arthritis patients - Finzel, Stephanie; Manske, Sarah L.; Barnabe, Cheryl C.M.; Burghardt, Andrew J.; Marotte, Hubert; Scharmga, Andrea; Hauge, Ellen Margrethe; Chapurlat, Roland; Engelke, Klaus; Li, Xiaojuan; van Teeffelen, Bente C.J.; Conaghan, Philip G.; et al. (Journal of Rheumatology, 2021)
Objective. The aim of this multireader exercise was to assess the reliability and change over time of erosion measurements in patients with rheumatoid arthritis (RA) using high-resolution peripheral quantitative computed tomography (HR-pQCT). Methods. HR-pQCT scans of 23 patients with RA were assessed at baseline and 12 months. Four experienced readers examined the dorsal, palmar, radial, and ulnar surfaces of the metacarpal head (MH) and phalangeal base (PB) of the second and third digits, blinded to time order. In total, 368 surfaces (23 patients' 16 surfaces) were evaluated per timepoint to characterize cortical breaks as pathological (erosion) or physiological, and to quantify erosion width and depth. Reliability was evaluated by intraclass correlation coefficients (ICC), percentage agreement, and Light k; change over time was defined by means ± SD of erosion numbers and dimensions. Results. ICC for the mean measurements of width and depth of the pathological breaks ranged between 0.819-0.883, and 0.771-0.907, respectively. Most physiological cortical breaks were found at the palmar PB, whereas most pathological cortical breaks were located at the radial MH. There was a significant increase in both the numbers and the dimensions of erosions between baseline and follow-up (P = 0.0001 for erosion numbers, width, and depth in axial plane; P = 0.001 for depth in perpendicular plane). Conclusion. This exercise confirmed good reliability of HR-pQCT erosion measurements and their ability to detect change over time.
CRIS-Team Scopus Importer:2021-04-02
Keywords: Computed tomography; Metacarpophalangeal joint; Outcomes; Rheumatoid arthritis

'SMASH' recommendations for standardised microscopic arthritis scoring of histological sections from inflammatory arthritis animal models - Hayer, Silvia; Vervoordeldonk, Margriet J.; Denis, Maria C.; Armaka, Marietta; Hoffmann, Markus; Bäcklund, Johan; Nandakumar, Kutty Selva; Niederreiter, Birgit; Geka, Christina; Fischer, Anita; Woodworth, Nina; Blüml, Stephan; et al. (Annals of the Rheumatic Diseases, 2021)
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.
CRIS-Team Scopus Importer:2021-03-05
Keywords: arthritis; arthritis; arthritis; experimental; psoriatic; rheumatoid; synovitis

Using alendronic acid coupled fluorescently labelled SM liposomes as a vehicle for bone targeting - Medina, Oula Penate; Medina, Tuula Penate; Humbert, Jana; Qi, Bao; Baum, Wolfgang; Will, Olga; Damm, Timo; Glueer, Claus (Current Pharmaceutical Design, 2020)
Background: We recently developed a liposomal nanoparticle system that can be used for drug delivery and simultaneously be monitored by optical or photoacoustic imaging devices. Here we tested the efficacy of alendronate as a homing molecule in SM-liposomes for bone targeting. Methods: Alendronate was immobilized covalently on the liposomal surface and the fluorescent dye indocyanine green was used as a payload in the liposomes. The indocyanine green delivery was analyzed by 3D optical tomography, optical fluorescence scanner, photoacoustic imaging, and by ex-vivo biodistribution studies. Results: The results show that the alendronate, coupled to the liposomal surface, increases sphingomyelin containing liposome targeting up to several-folds. Conclusion: The alendronate targeted liposomes open possibilities for an application in active bone targeting.
CRIS-Team Scopus Importer:2021-04-19
Keywords: Alendronic acid; ICG; Liposomes; Multimodal imaging; Sphingomyelin