Metabolic reprogramming of osteoclasts represents a therapeutic target during the treatment of osteoporosis - Taubmann, Jule; Krishnacoumar, Brenda; Böhm, Christina; Faas, Maria; Müller, Dorothea; Adam, Susanne; Stoll, Cornelia; Böttcher, Martin; Mougiakakos, Dimitrios; Sonnewald, Uwe; Hofmann, Jörg; Schett, Georg; et al. (Scientific Reports, 2020)
Osteoclasts are specialised bone resorbing cells that control both physiological and pathological bone turnover. Functional changes in the differentiation and activity of osteoclasts are accompanied by active metabolic reprogramming. However, the biological significance and the in vivo relevance of these events has remained unclear. Here we show that bone resorption of differentiated osteoclasts heavily relies on increased aerobic glycolysis and glycolysis-derived lactate production. While pharmacological inhibition of glycolysis did not affect osteoclast differentiation or viability, it efficiently blocked bone resorption in vitro and in vivo and consequently ameliorated ovariectomy-induced bone loss. Our experiments thus highlight the therapeutic potential of interfering with osteoclast-intrinsic metabolic pathways as possible strategy for the treatment of diseases characterized by accelerated bone loss.
CRIS-Team Scopus Importer:2020-12-11

Metabolische Arthritiden, seltene Erkrankungen - Manger, Bernhard (Zeitschrift für Rheumatologie, 2019)
CRIS-Team WoS Importer:2019-08-20

METABOLISM AND OSTEOARTHRITIS ARE LINKED BY ADIPOKINES - Huelser, M-L.; Schreiyack, C.; Luo, Y.; Bozec, Aline; Schett, Georg; Neumann, E.; Mueller-Ladner, U. (2017)
EVALuna2:35041

Methods for segmentation of rheumatoid arthritis bone erosions in high-resolution peripheral quantitative computed tomography (HR-pQCT) - Figueiredo, Camille P.; Kleyer, Arnd; Simon, Dominic; Stemmler, Fabian; d'Oliveira, Isabelle; Weißenfels, Anja; Museyko, Oleg; Friedberger, Andreas; Hueber, Axel; Haschka, Judith; Englbrecht, Matthias; Pereira, Rosa M.R.; et al. (Seminars in Arthritis and Rheumatism, 2017)
The comparison between different techniques to quantify the 3-dimensional size of inflammatory bone erosions in rheumatoid arthritis(RA) patients.Anti-cyclic citrullinated peptide antibody(ACPA) positive RA patients received high-resolution peripheral quantitative computed tomography (HR-pQCT) scans of the metacarpophalangeal joints (MCP). Erosions were measured by three different segmentation techniques: (1) manual method with calculation by half-ellipsoid formula, (2) semi-automated modified Evaluation Script for Erosions (mESE), and (3) semi-automated Medical Image Analysis Framework (MIAF) software. Bland & Altman plots were used to describe agreement between methods. Furthermore, shape of erosions was classified as regular or irregular and then compared to the sphericity obtained by MIAF.A total of 76 erosions from 65 RA patients (46 females/19 males), median age 57 years, median disease duration 6.1 years and median disease activity score 28 of 2.8 units were analyzed. While mESE and MIAF showed good agreement in the measurement of erosion size, the manual method with calculation by half-ellipsoid formula underestimated erosions size, particularly with larger erosions. Accurate segmentation is particularly important in larger erosions, which are irregularly shaped. In all three segmentation techniques irregular erosions were larger in size than regular erosions (MIAF: 19.7 vs. 3.4mm(3); mESE: 15.5 vs. 2.3mm(3); manual = 7.2 vs. 1.52mm(3); all p < 0.001). In accordance, sphericity of erosions measured by MIAF significantly decreased with their size (p < 0.001).MIAF and mESE allow segmentation of inflammatory bone erosions in RA patients with excellent inter reader reliability. They allow calculating erosion volume independent of erosion shape and therefore provide an attractive tool to quantify structural damage in individual joints of RA patients.
EVALuna2:13514

Methotrexate Hampers Immunogenicity to BNT162b2 mRNA COVID-19 Vaccine in Immune-Mediated Inflammatory Disease - Haberman, Rebecca; Herati, Ramin; Simon, David; Samanovic, Marie; Tuen, Michael; Blank, Rebecca; Koralov, Sergei; Atreya, Raja; Tascilar, Koray; Allen, Joseph; Castillo, Rochelle; Cornelius, Amber; et al. (ARTHRITIS & RHEUMATOLOGY, 2021)
CRIS-Team WoS Importer:2022-03-11

Methotrexate hampers immunogenicity to BNT162b2 mRNA COVID-19 vaccine in immune-mediated inflammatory disease - Haberman, Rebecca H.; Herati, Ramin Sedaghat; Simon, David; Samanovic, Marie; Blank, Rebecca B.; Tuen, Michael; Koralov, Sergei B.; Atreya, Raja; Tascilar, Koray; Allen, Joseph R.; Castillo, Rochelle; Cornelius, Amber R.; et al. (Annals of the Rheumatic Diseases, 2021)
Objective To investigate the humoral and cellular immune response to messenger RNA (mRNA) COVID-19 vaccines in patients with immune-mediated inflammatory diseases (IMIDs) on immunomodulatory treatment.
CRIS-Team WoS Importer:2021-10-08

Microbiota and metabolites in rheumatic diseases - Tong, Yanli; Marion, Tony; Schett, Georg; Luo, Yubin; Liu, Yi (Autoimmunity Reviews, 2020)
As a gigantic community in the human body, the microbiota exerts pleiotropic roles in human health and disease ranging from digestion and absorption of nutrients from food, defense against infection of pathogens, to regulation of immune system development and immune homeostasis. Recent advances in “omics” studies and bioinformatics analyses have broadened our insights of the microbiota composition of the inner and other surfaces of the body and their interactions with the host. Apart from the direct contact of microbes at the mucosal barrier, metabolites produced or metabolized by the gut microbes can serve as important immune regulators or initiators in a wide variety of diseases, including gastrointestinal diseases, metabolic disorders and systemic rheumatic diseases. This review focuses on the most recent understanding of how the microbiota and metabolites shape rheumatic diseases. Studies that explore the mechanistic interplay between microbes, metabolites and the host could thereby provide clues for novel methods in the diagnosis, therapy, and prevention of rheumatic diseases.
CRIS-Team Scopus Importer:2020-06-02
Keywords: Autoimmunity responses; Metabolites; Microbiota; Rheumatic diseases

Microbiota-Derived Propionate Modulates Megakaryopoiesis and Platelet Function - Dürholz, Kerstin; Schmid, Eva; Frech, Michael; Azizov, Vugar; Otterbein, Nadine; Lucas, Sébastien; Rauh, Manfred; Schett, Georg; Bruns, Heiko; Zaiss, Mario (Frontiers in Immunology, 2022)
Rheumatoid arthritis (RA) is associated with an increased risk for cardiovascular events driven by abnormal platelet clotting effects. Platelets are produced by megakaryocytes, deriving from megakaryocyte erythrocyte progenitors (MEP) in the bone marrow. Increased megakaryocyte expansion across common autoimmune diseases was shown for RA, systemic lupus erythematosus (SLE) and primary Sjögren’s syndrome (pSS). In this context, we evaluated the role of the microbial-derived short chain fatty acid (SCFA) propionate on hematopoietic progenitors in the collagen induced inflammatory arthritis model (CIA) as we recently showed attenuating effects of preventive propionate treatment on CIA severity. In vivo, propionate treatment starting 21 days post immunization (dpi) reduced the frequency of MEPs in the bone marrow of CIA and naïve mice. Megakaryocytes numbers were reduced but increased the expression of the maturation marker CD61. Consistent with this, functional analysis of platelets showed an upregulated reactivity state following propionate-treatment. This was confirmed by elevated histone 3 acetylation and propionylation as well as by RNAseq analysis in Meg-01 cells. Taken together, we identified a novel nutritional axis that skews platelet formation and function.
CRIS-Team Scopus Importer:2022-08-05
Keywords: hematopoietic progenitors; megakaryocytes; microbiota; platelets; rheumatoid arthritis; short-chain fatty acids

Microbiota-derived propionate modulates megakaryopoiesis and platelet function - Schmid, Erik; Dürholz, Kerstin; Frech, Michael; Otterbein, N.; Lucas, Sébastien; Rauh, Manfred; Schett, Georg; Bruns, Heiko; Zaiss, Mario (EUROPEAN JOURNAL OF IMMUNOLOGY, 2022)
CRIS-Team WoS Importer:2023-01-27

Microbiota from Obese Mice Regulate Hematopoietic Stem Cell Differentiation by Altering the Bone Niche - Luo, Yubin; Chen, Guangliang; Hannemann, Nicole; Ipseiz, Natacha; Krönke, Gerhard; Bäuerle, Tobias; Munos, Luis; Wirtz, Stefan; Schett, Georg; Bozec, Aline (Cell Metabolism, 2015)
The effect of metabolic stress on the bone marrow microenvironment is poorly defined. We show that high-fat diet (HFD) decreased long-term Lin(-)Sca-1(+)c-Kit(+) (LSK) stem cells and shifted lymphoid to myeloid cell differentiation. Bone marrow niche function was impaired after HFD as shown by poor reconstitution of hematopoietic stem cells. HFD led to robust activation of PPAR?2, which impaired osteoblastogenesis while enhancing bone marrow adipogenesis. At the same time, expression of genes such as Jag-1, SDF-1, and IL-7 forming the bone marrow niche was highly suppressed after HFD. Moreover, structural changes of microbiota were associated to HFD-induced bone marrow changes. Antibiotic treatment partially rescued HFD-mediated effects on the bone marrow niche, while transplantation of stools from HFD mice could transfer the effect to normal mice. These findings show that metabolic stress affects the bone marrow niche by alterations of gut microbiota and osteoblast-adipocyte homeostasis.
EVALuna2:1968

Microbiota-induced Intestinal Barrier Dysfunction Initiates the Shuttling of Immune Cells from the Gut to the Joints - Tajik, Narges; Frech, Michael; Brandl, Carolin; Canete, Juan; Ciccia, Francesco; Schett, Georg; Zaiss, Mario (ARTHRITIS & RHEUMATOLOGY, 2020)
CRIS-Team WoS Importer:2021-01-15

MICROBIOTA-INDUCED INTESTINAL BARRIER DYSFUNCTION PRECEDES THE ONSET OF ARTHRITIS AND ALLOWS THE SHUTTLING OF IMMUNE CELLS FROM THE GUT THE JOINTS - Zaiss, M.; Taijc, N.; Sarter, K.; Azizov, V.; Bucci, L.; Luo, Y.; Canete, J. D. D.; Ciccia, F.; Schett, Georg (ANNALS OF THE RHEUMATIC DISEASES, 2020)
CRIS-Team WoS Importer:2020-08-21

Microglial expression of CD83 governs cellular activation and restrains neuroinflammation in experimental autoimmune encephalomyelitis - Sinner, Pia; Peckert-Maier, Katrin; Mohammadian, Hashem; Kuhnt, Christine; Draßner, Christina; Panagiotakopoulou, Vasiliki; Rauber, Simon; Linnerbauer, Mathias; Haimon, Zhana; Royzman, Dmytro; Kronenberg-Versteeg, Deborah; Ramming, Andreas; et al. (Nature Communications, 2023)
Microglial activation during neuroinflammation is crucial for coordinating the immune response against neuronal tissue, and the initial response of microglia determines the severity of neuro-inflammatory diseases. The CD83 molecule has been recently shown to modulate the activation status of dendritic cells and macrophages. Although the expression of CD83 is associated with early microglia activation in various disease settings, its functional relevance for microglial biology has been elusive. Here, we describe a thorough assessment of CD83 regulation in microglia and show that CD83 expression in murine microglia is not only associated with cellular activation but also with pro-resolving functions. Using single-cell RNA-sequencing, we reveal that conditional deletion of CD83 results in an over-activated state during neuroinflammation in the experimental autoimmune encephalomyelitis model. Subsequently, CD83-deficient microglia recruit more pathogenic immune cells to the central nervous system, deteriorating resolving mechanisms and exacerbating the disease. Thus, CD83 in murine microglia orchestrates cellular activation and, consequently, also the resolution of neuroinflammation.
CRIS-Team Scopus Importer:2023-08-11

MICRORNA-125B AS A POTENTIAL FIBROTIC AND APOPTOTIC REGULATOR IN SYSTEMIC SCLEROSIS - Kozlova, A.; Pachera, E.; Renoux, F.; Rudnik, M.; Maurer, B.; Juengel, A.; Distler, Jörg; Kania, G.; Distler, O. (2017)
EVALuna2:35035

MICRORNA-125B REGULATES APOPTOSIS IN SYSTEMIC SCLEROSIS - Kozlova, A.; Pachera, E.; Maurer, B.; Juengel, A.; Distler, Jörg; Kania, G.; Distler, O. (2018)
EVALuna2:34993

microRNA-145 mediates xylosyltransferase-I induction in myofibroblasts via suppression of transcription factor KLF4 - Ly, Thanh Diep; Riedel, Lara; Fischer, Bastian; Schmidt, Vanessa; Hendig, Doris; Distler, Jörg; Kuhn, Joachim; Knabbe, Cornelius; Faust, Isabel (Biochemical and Biophysical Research Communications, 2020)
Remodelling of the extracellular matrix by myofibroblasts is crucial for wound repair, but if deregulated, it might contribute to the development of fibrosis. Fibroblast-to-myofibroblast differentiation is promoted by aberrant microRNA-145-5p (miR-145) expression in response to transforming growth factor β1 (TGFβ1). One of several myofibroblast markers is human xylosyltransferase-I (XT-I), which is the initial and rate-limiting enzyme of proteoglycan biosynthesis. Increased serum XT activity was quantified in patients with systemic sclerosis (SSc), but the underlying cellular mechanism of this disease remains unknown. This study aims to determine the underlying molecular basis of XT-I induction by considering the miR-mediated regulation of XT-I. We found that miR-145 is upregulated in TGFβ1-treated dermal fibroblasts and correlates with an increased cellular XYLT1 expression and XT activity. Overexpression of miR-145 in dermal fibroblasts induced XYLT1 expression and XT activity and enhanced TGFβ1-promoted XT activity increase. Since direct XYLT1 3′-UTR targeting by miR-145 could be experimentally excluded, an indirect effect of miR-145 on XT-I regulation was indicated. We identified six transcription factor-binding sites for Krueppel-like factor 4 (KLF4), a zinc-finger transcription regulator and putative miR-145 target, in the XYLT1 promoter in silico. A suppressive role of KLF4 on XYLT1 expression was confirmed by targeted gene silencing in dermal fibroblasts and the quantification of KLF4 expression in SSc fibroblasts. Taken together, this study improves the mechanistic understanding of fibrotic remodelling in SSc by identifying a hitherto unknown miR-145/KLF4 pathway mediating the fibrogenic XT-I induction. This knowledge on XYLT1 may lead to the development of novel approaches in the therapy of fibrosis.
CRIS-Team Scopus Importer:2020-02-07
Keywords: Fibrosis; Krueppel-like factor 4; microRNA-145; Systemic sclerosis; TGFβ; Xylosyltransferase

Microscopic polyangiitis after alemtuzumab treatment in relapsing-remitting MS - Sauer, Eva-Maria; Schliep, Stefan; Manger, Bernhard; Lee, De-Hyung; Linker, Ralf (Neurology, Neuroimmunology and Neuroinflammation, 2018)
EVALuna2:35512

Microstructural Bone Changes Are Associated With Broad-Spectrum Autoimmunity and Predict the Onset of Rheumatoid Arthritis - Simon, David; Kleyer, Arnd; Bui, Cong Duy; Hueber, Axel; Bang, Holger; Ramming, Andreas; Rech, Jürgen; Schett, Georg (Arthritis and Rheumatology, 2022)
Objective To assess if microstructural bone lesions in individuals at risk of developing rheumatoid arthritis (RA) are related to the spectrum of anti-modified protein antibodies (AMPAs) and affect the risk of developing RA. Methods Cortical microchannels as well as cortical and trabecular bone mineral density (BMD) volumes (expressed as mg hydroxyapatite/cm(3)) were analyzed by high-resolution peripheral quantitative computed tomography of the hand joints of individuals at risk of RA. AMPA response was profiled, including reactivities against citrullinated proteins (vimentin, enolase, and fibrinogen) as well as carbamylated and acetylated vimentin. All subjects were followed up for the development of RA. Results Subjects at risk of developing RA (n = 75) who had broad-spectrum AMPAs (6-8 reactivities) had significantly more severe microstructural changes, including a higher mean +/- SD number of cortical microchannels per joint (95 +/- 3) and lower total volumetric BMD (vBMD; 265 +/- 45), trabecular vBMD (176 +/- 42), and cortical vBMD (585 +/- 138), than those with moderate AMPA reactivity (3-5 reactivities) (number of cortical microchannels, 79 +/- 30; total vBMD, 293 +/- 33; trabecular vBMD, 195 +/- 32; and cortical vBMD, 627 +/- 91) and those with narrow AMPA reactivity (1-2 reactivities) (number of cortical microchannels, 47 +/- 20; total vBMD, 311 +/- 34; trabecular vBMD, 211 +/- 30; and cortical vBMD, 674 +/- 56). Progressors to RA had significantly higher numbers of cortical microchannels (103 +/- 30 versus 71 +/- 35) and lower bone volume (258 +/- 37 versus 295 +/- 34) compared to nonprogressors. Furthermore, rate of progression to RA was high in subjects with broad AMPA reactivity (48%) versus those with medium AMPA reactivity (26%) or narrow AMPA reactivity (0%), as well as in those with a high number of cortical microchannels (44%) versus those with a low number of cortical microchannels (10%). Conclusion Microstructural changes in individuals at risk of RA are associated with broad-spectrum autoimmunity and predict the onset of RA. These data support the concept of structural priming of joints by autoimmunity before the onset of the inflammatory phase of the disease.
CRIS-Team WoS Importer:2022-02-11

MICRO-STRUCTURAL CHANGES ASSOCIATED WITH ANTI-CITRULLINATED VIMENTIN AUTOIMMUNITY IN RA-AT-RISK INDIVIDUALS PRECIPITATE THE ONSET OF RHEUMATOID ARTHRITIS - Kleyer, Arnd; Simon, David; Bui, Cong Duy; Hueber, Axel; Bang, Holger; Rech, Jürgen; Krönke, Gerhard; Schett, Georg; Ramming, Andreas (ANNALS OF THE RHEUMATIC DISEASES, 2019)
CRIS-Team WoS Importer:2019-07-16

Misdiagnosis of polymyositis in a young female patient with occult limb-girdle muscular dystrophy - Valor-Mendez, Lara; Türk, Matthias; Schett, Georg; Manger, Bernhard; Knitza, Johannes (Rheumatology Advances in Practice, 2023)
CRIS-Team Scopus Importer:2023-08-11

Mobile Health Usage, Preferences, Barriers, and eHealth Literacy in Rheumatology: Patient Survey Study - Knitza, Johannes; Simon, David; Lambrecht, Antonia; Raab, Christina; Tascilar, Koray; Hagen, Melanie; Kleyer, Arnd; Bayat, Sara; Derungs, Adrian; Amft, Oliver; Schett, Georg; Hueber, Axel (JMIR mHealth and uHealth, 2020)
BACKGROUND: Mobile health (mHealth) defines the support and practice of health care using mobile devices and promises to improve the current treatment situation of patients with chronic diseases. Little is known about mHealth usage and digital preferences of patients with chronic rheumatic diseases. OBJECTIVE: The aim of the study was to explore mHealth usage, preferences, barriers, and eHealth literacy reported by German patients with rheumatic diseases. METHODS: Between December 2018 and January 2019, patients (recruited consecutively) with rheumatoid arthritis, psoriatic arthritis, and axial spondyloarthritis were asked to complete a paper-based survey. The survey included questions on sociodemographics, health characteristics, mHealth usage, eHealth literacy using eHealth Literacy Scale (eHEALS), and communication and information preferences. RESULTS: Of the patients (N=193) who completed the survey, 176 patients (91.2%) regularly used a smartphone, and 89 patients (46.1%) regularly used social media. Patients (132/193, 68.4%) believed that using medical apps could be beneficial for their own health. Out of 193 patients, only 8 (4.1%) were currently using medical apps, and only 22 patients (11.4%) stated that they knew useful rheumatology websites/mobile apps. Nearly all patients (188/193, 97.4%) would agree to share their mobile app data for research purposes. Out of 193 patients, 129 (66.8%) would regularly enter data using an app, and 146 patients (75.6%) would welcome official mobile app recommendations from the national rheumatology society. The preferred duration for data entry was not more than 15 minutes (110/193, 57.0%), and the preferred frequency was weekly (59/193, 30.6%). Medication information was the most desired app feature (150/193, 77.7%). Internet was the most frequently utilized source of information (144/193, 74.6%). The mean eHealth literacy was low (26.3/40) and was positively correlated with younger age, app use, belief in benefit of using medical apps, and current internet use to obtain health information. CONCLUSIONS: Patients with rheumatic diseases are very eager to use mHealth technologies to better understand their chronic diseases. This open-mindedness is counterbalanced by low mHealth usage and competency. Personalized mHealth solutions and clear implementation recommendations are needed to realize the full potential of mHealth in rheumatology.
CRIS-Team Scopus Importer:2020-08-28
Keywords: eHEALS; eHealth; mHealth; mobile applications; rheumatology; telemedicine

Model curriculum of the German society for Rheumatology for advanced training in the discipline internal medicine and rheumatology. English version - Pfeil, Alexander; Krusche, Martin; Vossen, Diana; Berliner, Michael N.; Keysser, Gernot; Krause, Andreas; Lorenz, Hanns-Martin; Manger, Bernhard; Schuch, Florian; Specker, Christof; Wollenhaupt, Juergen; Baraliakos, Xenofon; et al. (Zeitschrift für Rheumatologie, 2021)
CRIS-Team WoS Importer:2021-10-15

Modular lattice constructs for biological joint resurfacing - Gelse, Kolja; Biggemann, Jonas; Stumpf, Martin; Halmheu, Melissa; Grüneboom, Anika; Scholtysek, Carina; Pachowsky, Milena; Kleyer, Arnd; Hueber, Axel; Krönke, Gerhard; Fey, Tobias (Tissue Engineering: Parts A, B, and C, 2019)
Problem: The generation of tissue-engineered cartilage constructs has made great progress over the last decades, however, the fixation of the grafts to the subchondral bone plate is still an unresolved problem. The aim of this study was to investigate a modular lattice concept as an anchoring basis for biological joint resurfacing that is stably fixed to subchondral bone, versatile for any surface shape, and permissive for cellular repopulation. Methods: Ceramic building blocks (hydroxyapatite, β-tricalcium phosphate, biphasic calcium phosphate, alumina and bioactive glass) including anchoring pins were fabricated by transfer injection molding technique. The cellular repopulation of the building blocks and cellular differentiation of human mesenchymal stem cells (hBMSC) was analysed under the influence of platelet-rich plasma, transforming growth factor-β and bone morphogenetic protein-2. A lattice construct of anchoring pins fixed to subchondral bone specimen and interposed hBMSC within collagen-hydrogel were cultured under dynamic conditions in spinner flasks for 4 weeks. The 3D constructs were analyzed by high-resolution micro computertomography (µCT), light-sheet fluorescence microscopy and histology. Pin fixation was analysed by pull-out tests. Results: Building Block-modules of complex shape with anchoring pins can be individually arranged to the subchondral bone by simple press-fit principle. Pull-out tensile stress exceeded 6 MPa. Human BMSCs required stimulation by TGF-β or BMP-2 to undergo chondrogenic differentiation. Dynamic culturinges of 3-dimensional explant constructscultures demonstrated the stability of the modular lattice construct and the interposed cell-loaded hydrogel remained within the lattice elements. hBMSCs within the collagen hydrogel underwent chondrogenic differentiation and formed a matrix that merged with the lattice structure of building blocks. Conclusions: The current work presents a proof-of-principle concept for a lattice structure that provides the stable mechanical bonding and biological milieu for the bone-cartilage interface. The anchoring elements represent an integral part of the lattice structure and provide the basis for future biological joint resurfacing by multilayer constructs. <br

Molecular and epigenetic consequences of pre- and postnatal trauma in a mouse model - Frey, Silke; Steigleder, R.; Distler, Jörg; Kratz, Oliver; Moll, Gunther; Golub, Yulia (2017)
EVALuna2:35017

Monte Carlo Dose Simulation for In-Vivo X-Ray Nanoscopy - Wagner, Fabian; Thies, Mareike; Karolczak, Marek; Pechmann, Sabrina; Huang, Yixing; Gu, Mingxuan; Kling, Lasse; Weidner, Daniela; Aust, Oliver; Schett, Georg; Christiansen, Silke; Maier, Andreas (Informatik aktuell, 2022)
CRIS-Team Scopus Importer:2022-05-06

Moonlighting chromatin: when DNA escapes nuclear control - Singh, Jeeshan; Boettcher, Michael; Dölling, Maximilian; Heuer, Annika; Hohberger, Bettina; Leppkes, Moritz; Naschberger, Elisabeth; Schapher, Mirco; Schauer, Christine; Schoen, Janina; Stürzl, Michael; Vitkov, Ljubomir; et al. (Cell Death and Differentiation, 2023)
Extracellular chromatin, for example in the form of neutrophil extracellular traps (NETs), is an important element that propels the pathological progression of a plethora of diseases. DNA drives the interferon system, serves as autoantigen, and forms the extracellular scaffold for proteins of the innate immune system. An insufficient clearance of extruded chromatin after the release of DNA from the nucleus into the extracellular milieu can perform a secret task of moonlighting in immune-inflammatory and occlusive disorders. Here, we discuss (I) the cellular events involved in the extracellular release of chromatin and NET formation, (II) the devastating consequence of a dysregulated NET formation, and (III) the imbalance between NET formation and clearance. We include the role of NET formation in the occlusion of vessels and ducts, in lung disease, in autoimmune diseases, in chronic oral disorders, in cancer, in the formation of adhesions, and in traumatic spinal cord injury. To develop effective therapies, it is of utmost importance to target pathways that cause decondensation of chromatin during exaggerated NET formation and aggregation. Alternatively, therapies that support the clearance of extracellular chromatin are conceivable. [Figure not available: see fulltext.].
CRIS-Team Scopus Importer:2023-02-17

Moonlighting osteoclasts as undertakers of apoptotic cells - Harre, Ulrike; Keppeler, Hildegard; Ipseiz, Natacha; Derer, Anja; Poller, Kerstin; Aigner, Michael; Schett, Georg; Herrmann, Martin; Lauber, Kirsten (Autoimmunity, 2012)
Created from Fastlane, Scopus look-up
Keywords: Apoptotic cell clearance; Dying cell clearance; Efferocytosis; Osteoclasts; Phagocytosis; Rheumatoid arthritis

Morbus Castleman in der rheumatologischen Praxis - Schmalzing, M.; Sander, O.; Seidl, M.; Marks, R.; Blank, N.; Kötter, I.; Tiemann, M.; Backhaus, M.; Manger, Bernhard; Hübel, K.; Müller-Ladner, U.; Henes, J. (Zeitschrift für Rheumatologie, 2023)
The term Castleman’s disease encompasses a group of rare lymphoproliferative diseases that show histopathological similarities in lymph node biopsy. Diagnostic criteria and a specific ICD-10 code have been available for a few years. Case studies listed at the beginning illustrate that close cooperation between clinicians and pathologists is required to enable a reliable diagnosis. For an optimal histopathological assessment, the pathologist is also dependent on the removal of a complete lymph node. Before distinguishing a potentially fatal multicentric idiopathic Castleman’s disease from the resectable unicentric form, which is important in terms of prognosis and treatment, early diagnosis presupposes that Castleman’s disease is considered in the differential diagnosis. Various immune phenomena and overlaps with autoimmune diseases can increase the probability of misdiagnosis or undetected cases in the clinical routine of rheumatologists. The intention of the present overview is therefore to point out the similarities with autoimmune diseases that are relevant for differential diagnoses and to point out situations that justify a review of the previous diagnosis.
CRIS-Team Scopus Importer:2023-09-08
Keywords: Castleman’s disease; Histopathology; Idiopathic MCD; IL‑6; Lymph node hyperplasia

More on CD19-CAR T Cells in Systemic Lupus Erythematosus - Mougiakakos, Dimitrios; Krönke, Gerhard; Schett, Georg (New England Journal of Medicine, 2021)
CRIS-Team WoS Importer:2021-11-12

Mortality in rheumatoid arthritis: the impact of disease activity, treatment with glucocorticoids, TNF? inhibitors and rituximab - Listing, Joachim; Kekow, Joern; Manger, Bernhard; Burmester, Gerd-Ruediger; Pattloch, Dagmar; Zink, Angela; Strangfeld, Anja (Annals of the Rheumatic Diseases, 2015)
To investigate the impact of disease activity, the course of the disease, its treatment over time, comorbidities and traditional risk factors on survival.Data of the German biologics register RABBIT were used. Cox regression was applied to investigate the impact of time-varying covariates (disease activity as measured by the DAS28, functional capacity, treatment with glucocorticoids, biologic or synthetic disease modifying antirheumatic drugs (DMARDs)) on mortality after adjustment for age, sex, comorbid conditions and smoking.During 31 378 patient-years of follow-up, 463 of 8908 patients died (standardised mortality ratio: 1.49 (95% CI 1.36 to 1.63)). Patients with persistent, highly active disease (mean DAS28 > 5.1) had a significantly higher mortality risk (adjusted HR (HRadj)=2.43; (95% CI 1.64 to 3.61)) than patients with persistently low disease activity (mean DAS28 < 3.2). Poor function and treatment with glucocorticoids > 5 mg/d was significantly associated with an increased mortality, independent of disease activity. Significantly lower mortality was observed in patients treated with tumour necrosis factor ? (TNF?) inhibitors (HRadj=0.64 (95% CI 0.50 to 0.81), rituximab (HRadj=0.57 (95% CI 0.39 to 0.84), or other biologics (HRadj=0.64 (95% CI 0.42 to 0.99), compared to those receiving methotrexate. To account for treatment termination in patients at risk, an HRadj for patients ever exposed to TNF? inhibitors or rituximab was calculated. This resulted in an HRadj of 0.77 (95% CI 0.60 to 0.97).Patients with long-standing high disease activity are at substantially increased risk of mortality. Effective control of disease activity decreases mortality. TNF? inhibitors and rituximab seem to be superior to conventional DMARDs in reducing this risk.
EVALuna2:12956

Mouse models of skin fibrosis - Rigau, Aleix; Luber, Markus; Distler, Jörg (Methods in Molecular Biology, 2021)
Systemic sclerosis (SSc) is a rare systemic autoimmune disease associated with a high mortality. The first histopathological hallmarks are vasculopathy and inflammation, followed by fibrosis of the skin and internal organs. The molecular and cellular mechanisms are incompletely understood. Rodent models provide important insights into the pathogenesis of SSc and are a mainstay for the development of novel targeted therapies. Here we describe the mechanistic insights of inducible and genetic models, and also discuss in detail the limitations and pitfalls of the most frequently used SSc mouse models. We also describe protocols for running the established bleomycin-induced scleroderma skin fibrosis model.
CRIS-Team Scopus Importer:2021-06-11
Keywords: Bleomycin; Chronic graft-versus-host disease; Mouse model; Skin fibrosis; Systemic sclerosis

MULTI-BIOMARKER DISEASE ACTIVITY AND AUTOANTIBODY STATUS LEAD TO COST EFFECTIVE TAPERING ALGORITHMS IN RHEUMATOID ARTHRITIS PATIENTS IN SUSTAINED REMISSION - Hagen, Melanie; Englbrecht, Matthias; Haschka, J.; Reiser, M.; Kleyer, Arnd; Hueber, A.; Manger, Bernhard; Figuereido, C.; Cobra, J. Fogagnolo; Tony, H. -P.; Finzel, S.; Kleinert, S.; et al. (2017)
EVALuna2:34451

MULTI-BIOMARKER DISEASE ACTIVITY (MBDA) IS ASSOCIATED WITH THE PROGRESSION OF STRUCTURAL BONE DAMAGE IN RHEUMATOID ARTHRITIS PATIENTS IN REMISSION - Schett, Georg; Finzel, S.; Hagen, Melanie; Englbrecht, Matthias; Haschka, J.; Figuereido, C.; Cobra, J. Fogagnolo; Rech, Jürgen (2017)
EVALuna2:35029

Multispectral optoacoustic tomography of the human intestine – temporal precision and the influence of postprandial gastrointestinal blood flow - Paulus, Lars-Philip; Wagner, Alexandra; Buehler, Adrian; Raming, Roman; Jüngert, Jörg; Simon, David; Tascilar, Koray; Schnell, Alexander; Günther, Josefine; Rother, Ulrich; Lang, Werner; Hörning, André; et al. (Photoacoustics, 2023)
Multispectral optoacoustic tomography (MSOT) holds great promise as a non-invasive diagnostic tool for inflammatory bowel diseases. Yet, reliability and the impact of physiological processes during fasting and after food intake on optoacoustic signals have not been studied. In the present investigator initiated trial (NCT05160077) the intestines of ten healthy subjects were examined by MSOT at eight timepoints on two days, one fasting and one after food intake. While within-timepoint and within-day reproducibility were good for single wavelength 800 nm and total hemoglobin (ICC 0.722–0.956), between-day reproducibility was inferior (ICC −0.137 to 0.438). However, temporal variability was smaller than variation between individuals (coefficients of variation 8.9%−33.7% vs. 17.0%−48.5%). After food intake and consecutive increased intestinal circulation, indicated by reduced resistance index of simultaneous Doppler ultrasound, optoacoustic signals did not alter significantly. In summary, this study demonstrates high reliability and temporal stability of MSOT for imaging the human intestine during fasting and after food intake.
CRIS-Team Scopus Importer:2023-02-24
Keywords: Gut; Inflammatory bowel disease; Intestinal blood flow; Multispectral optoacoustic imaging; Optoacoustic; Photoacoustic; Postprandial; Reliability; Reproducibility

Murine Metatarsus Bone and Joint Collagen-I Fiber Morphologies and Networks Studied With SHG Multiphoton Imaging - Vielreicher, Martin; Bozec, Aline; Schett, Georg; Friedrich, Oliver (Frontiers in Bioengineering and Biotechnology, 2021)
Chronic inflammatory disease of bones and joints (e.g., rheumatoid arthritis, gout, etc.), but also acute bone injury and healing, or degenerative resorptive processes inducing osteoporosis, are associated with structural remodeling that ultimately have impact on function. For instance, bone stability is predominantly orchestrated by the structural arrangement of extracellular matrix fibrillar networks, i.e., collagen-I, -IV, elastin, and other proteins. These components may undergo distinct network density and orientation alterations that may be causative for decreased toughness, resilience and load bearing capacity or even increased brittleness. Diagnostic approaches are usually confined to coarse imaging modalities of X-ray or computer tomography that only provide limited optical resolution and lack specificity to visualize the fibrillary collagen network. However, studying collagen structure at the microscopic scale is of considerable interest to understand the mechanisms of tissue pathologies. Multiphoton Second Harmonic Generation (SHG) microscopy, is able to visualize the sterical topology of the collagen-I fibrillar network in 3D, in a minimally invasive and label-free manner. Penetration depths exceed those of conventional visible light imaging and can be further optimized through employing decalcification or optical clearing processing ex vivo. The goal of this proof-of-concept study was to use SHG and two-photon excited fluorescence (2-PEF) imaging to mainly characterize the fibrillary collagen organization within ex vivo decalcified normal mouse metatarsus bone and joint. The results show that the technique resolved the fibrillar collagen network of complete bones and joints with almost no artifacts and enabled to study the complex collagen-I networks with various fiber types (straight, crimped) and network arrangements of mature and woven bone with high degree of detail. Our imaging approach enabled to identify cavities within both cortical and trabecular bone architecture as well as interfaces with sharply changing fiber morphology and network structure both within bone, in tendon and ligament and within joint areas. These possibilities are highly advantageous since the technology can easily be applied to animal models, e.g., of rheumatoid arthritis to study structural effects of chronic joint inflammation, and to many others and to compare to the structure of human bone.
CRIS-Team Scopus Importer:2021-07-09
Keywords: bone and joint diseases; bone microstructure; collagen fiber morphology; collagen-I fibrillar networks; multiphoton SHG microscopy; remodeling 3D Morphology

Musculoskeletal Ultrasound Is a Sensitive Imaging Tool for the Assessment of Dynamic Changes of Bone Erosions in Inflammatory Arthritis: A Comparative Analysis with High-Resolution Peripheral Quantitatve Computed Tomography - Finzel, Stephanie; Backhaus, Marina; Kraus, Sebastian; Schett, Georg; Voll, Reinhard (2016)
EVALuna2:35058

Mutual influence of immune system and bones - Kamradt, T.; Amling, M.; Dankbar, B.; Dudeck, A.; Gunzer, M.; Ignatius, Anita; Krönke, Gerhard; Kubatzky, K.; Pap, T.; Prinz, Immo; Schett, Georg; Schinke, T.; et al. (Zeitschrift für Rheumatologie, 2018)
EVALuna2:34148

Myeloperoxidase Modulates Inflammation in Generalized Pustular Psoriasis and Additional Rare Pustular Skin Diseases - Haskamp, Stefan; Bruns, Heiko; Hahn, Madelaine; Hoffmann, Markus; Gregor, Anne; Löhr, Sabine; Hahn, Jonas; Ringer, Mark; Flamann, Cindy; Frey, Benjamin; Lesner, Adam; Thiel, Christian; et al. (American Journal of Human Genetics, 2020)
Generalized pustular psoriasis (GPP) is a severe multi-systemic inflammatory disease characterized by neutrophilic pustulosis and triggered by pro-inflammatory IL-36 cytokines in skin. While 19%–41% of affected individuals harbor bi-allelic mutations in IL36RN, the genetic cause is not known in most cases. To identify and characterize new pathways involved in the pathogenesis of GPP, we performed whole-exome sequencing in 31 individuals with GPP and demonstrated effects of mutations in MPO encoding the neutrophilic enzyme myeloperoxidase (MPO). We discovered eight MPO mutations resulting in MPO -deficiency in neutrophils and monocytes. MPO mutations, primarily those resulting in complete MPO deficiency, cumulatively associated with GPP (p = 1.85E−08; OR = 6.47). The number of mutant MPO alleles significantly differed between 82 affected individuals and >4,900 control subjects (p = 1.04E−09); this effect was stronger when including IL36RN mutations (1.48E−13) and correlated with a younger age of onset (p = 0.0018). The activity of four proteases, previously implicated as activating enzymes of IL-36 precursors, correlated with MPO deficiency. Phorbol-myristate-acetate-induced formation of neutrophil extracellular traps (NETs) was reduced in affected cells (p = 0.015), and phagocytosis assays in MPO-deficient mice and human cells revealed altered neutrophil function and impaired clearance of neutrophils by monocytes (efferocytosis) allowing prolonged neutrophil persistence in inflammatory skin. MPO mutations contribute significantly to GPP's pathogenesis. We implicate MPO as an inflammatory modulator in humans that regulates protease activity and NET formation and modifies efferocytosis. Our findings indicate possible implications for the application of MPO inhibitors in cardiovascular diseases. MPO and affected pathways represent attractive targets for inducing resolution of inflammation in neutrophil-mediated skin diseases.
CRIS-Team Scopus Importer:2020-09-11
Keywords: ACH; acrodermatitis continua suppurativa Hallopeau; activation of IL-36 precursors; acute generalized 4 exanthematous pustulosis; AGEP; efferocytosis; generalized pustular psoriasis; GPP; impaired NETosis; MPO deficiency; myeloperoxidase; oligogenic inheritance

Na+ deposition in the fibrotic skin of systemic sclerosis patients detected by 23Na-magnetic resonance imaging - Kopp, Christoph; Beyer, Christian; Linz, Peter; Dahlmann, Anke; Hammon, Matthias; Jantsch, Jonathan; Neubert, Patrick; Rosenhauer, Daniela; Mueller, Dominik N.; Eckardt, Kai-Uwe; Schett, Georg; Luft, Friedrich C.; et al. (Rheumatology, 2017)
Skin fibrosis is the predominant feature of SSc and arises from excessive extracellular matrix deposition. Glycosaminoglycans are macromolecules of the extracellular matrix, which facilitate Na(+) accumulation in the skin. We used (23)Na-MRI to quantify Na(+) in skin. We hypothesized that skin Na(+) might accumulate in SSc and might be a biomarker for skin fibrosis.In this observational case-control study, skin Na(+) was determined by (23)Na-MRI using a Na(+) volume coil in 12 patients with diffuse cutaneous SSc and in 21 control subjects. We assessed skin fibrosis by the modified Rodnan skin score prior to (23)Na-MRI and on follow-up 12 months later.(23)Na-MRI demonstrated increased Na(+) in the fibrotic skin of SSc patients compared with skin from controls [mean (sd): 27.2 (5.6) vs 21.4 (5.3) mmol/l, P < 0.01]. Na(+) content was higher in fibrotic than in non-fibrotic SSc skin [26.2 (4.8) vs 19.2 (3.4) mmol/l, P < 0.01]. Furthermore, skin Na(+) amount was correlated with changes in follow-up modified Rodnan skin score (R(2) = 0.68).(23)Na-MRI detected increased Na(+) in the fibrotic SSc skin; high Na(+) content was associated with progressive skin disease. Our findings provide the first evidence that (23)Na-MRI might be a promising tool to assess skin Na(+) and thereby predict progression of skin fibrosis in SSc.
EVALuna:33997

Nanoparticles size-dependently initiate self-limiting NETosis-driven inflammation - Munoz, Luis E.; Bilyy, Rostyslav; Biermann, Mona H. C.; Kienhoefer, Deborah; Maueröder, Christian; Hahn, Jonas; Brauner, Jan M.; Weidner, Daniela; Chen, Juan; Scharin-Mehlmann, Marina; Janko, Christina; Friedrich, Ralf P.; et al. (Proceedings of the National Academy of Sciences of the United States of America, 2016)
The critical size for strong interaction of hydrophobic particles with phospholipid bilayers has been predicted to be 10 nm. Because of the wide spreading of nonpolar nanoparticles (NPs) in the environment, we aimed to reveal the ability of living organisms to entrap NPs via formation of neutrophil extracellular traps (NETs). Upon interaction with various cell types and tissues, 10- to 40-nm-sized NPs induce fast (<20 min) damage of plasma membranes and instability of the lysosomal compartment, leading to the immediate formation of NETs. In contrast, particles sized 100-1,000 nm behaved rather inertly. Resulting NET formation (NETosis) was accompanied by an inflammatory reaction intrinsically endowed with its own resolution, demonstrated in lungs and air pouches of mice. Persistence of small NPs in joints caused unremitting arthritis and bone remodeling. Small NPs coinjected with antigen exerted adjuvant-like activity. This report demonstrates a cellular mechanism that explains how small NPs activate the NETosis pathway and drive their entrapping and resolution of the initial inflammatory response.
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NCOA3 AMPLIFIES PROFIBROTIC TRANSCRIPTIONAL PROGRAMS IN SYSTEMIC SCLEROSIS - Dees, Clara; Pötter, Sebastian; Fuchs, Maximilian; Bergmann, Christina; Matei, Alexandru-Emil; Györfi, Andrea-Hermina; Soare, A.; Ramming, Andreas; Ceppi, Paolo; Schett, Georg; Kunz, Meik; Distler, H. W. (ANNALS OF THE RHEUMATIC DISEASES, 2021)
CRIS-Team WoS Importer:2021-09-24

Networks of enzymatically oxidized membrane lipids support calcium-dependent coagulation factor binding to maintain hemostasis - Lauder, Sarah N.; Allen-Redpath, Keith; Slatter, David A.; Aldrovandi, Maceler; O'Connor, Anne; Farewell, Daniel; Percy, Charles L.; Molhoek, Jessica E.; Rannikko, Sirpa; Tyrrell, Victoria J.; Ferla, Salvatore; Milne, Ginger L.; et al. (Science Signaling, 2017)
Blood coagulation functions as part of the innate immune system by preventing bacterial invasion, and it is critical to stopping blood loss (hemostasis). Coagulation involves the external membrane surface of activated platelets and leukocytes. Using lipidomic, genetic, biochemical, and mathematical modeling approaches, we found that enzymatically oxidized phospholipids (eoxPLs) generated by the activity of leukocyte or platelet lipoxygenases (LOXs) were required for normal hemostasis and promoted coagulation factor activities in a Ca2+- and phosphatidylserine (PS)-dependent manner. In wild-type mice, hydroxyeicosatetraenoic acid-phospholipids (HETE-PLs) enhanced coagulation and restored normal hemostasis in clotting-deficient animals genetically lacking p12-LOX or 12/15-LOX activity. Murine platelets generated 22 eoxPL species, all of which were missing in the absence of p12-LOX. Humans with the thrombotic disorder antiphospholipid syndrome (APS) had statistically significantly increased HETE-PLs in platelets and leukocytes, as well as greater HETE-PL immunoreactivity, than healthy controls. HETE-PLs enhanced membrane binding of the serum protein ?2GP1 (?2-glycoprotein 1), an event considered central to the autoimmune reactivity responsible for APS symptoms. Correlation network analysis of 47 platelet eoxPL species in platelets from APS and control subjects identified their enzymatic origin and revealed a complex network of regulation, with the abundance of 31 p12-LOX-derived eoxPL molecules substantially increased in APS. In summary, circulating blood cells generate networks of eoxPL molecules, including HETE-PLs, which change membrane properties to enhance blood coagulation and contribute to the excessive clotting and immunoreactivity of patients with APS.
EVALuna2:13521

Neural Networks for Distinguishing Rheumatoid Arthritis from Psoriatic Arthritis by Using Magnetic Resonance Imaging - Folle, Lukas; Bayat, Sara; Kleyer, Arnd; Fagni, Filippo; Kapsner, Lorenz; Schlereth, Maja; Meinderink, Timo; Breininger, Katharina; Tascilar, Koray; Krönke, Gerhard; Uder, Michael; Sticherling, Michael; et al. (Arthritis Rheumatol., 2022)

Neurodegeneration Enhances the Development of Arthritis - Lang, Stefanie; Harre, Ulrike; Purohit, Pavitra; Dietel, Katharina; Kienhöfer, Deborah; Hahn, Jonas; Baum, Wolfgang; Herrmann, Martin; Schett, Georg; Mielenz, Dirk (Journal of Immunology, 2017)
The prevalence of neurodegenerative disease and arthritis increases with age. Despite both processes being associated with immune activation and inflammation, little is known about the mechanistic interactions between neurodegenerative disease and arthritis. In this article, we show that tau-transgenic (tau-tg) mice that develop neurodegenerative disease characterized by deposition of tau tangles in the brain are highly susceptible to developing arthritis. Already at steady-state conditions, tau-tg mice exhibit peripheral immune activation that is manifested by higher numbers of granulocytes, plasmablasts, and inflammatory Ly6C(hi) CCR2(+) monocytes, as well as increased levels of proinflammatory cytokines, such as TNF-? and IL-17. Upon induction of collagen-induced arthritis (CIA), tau-tg mice displayed an increased incidence and an earlier onset of CIA that was associated with a more pronounced inflammatory cytokine response. Furthermore, induction of CIA led to significantly elevated numbers of Iba-1-expressing cells in the brain, indicative of microglia activation, and the formation of anti-tau Abs in tau-tg mice. These changes were accompanied by the resolution of tau tangles and significantly decreased neurodegenerative pathology. In summary, these data show that neurodegenerative disease enhances the development of arthritis. In addition, arthritis, once induced, triggers innate immune responses in the brain, leading to resolution of neurodegenerative change
EVALuna2:13302

Neutralizing monoclonal antibodies against SARS-CoV-2 for COVID-19 pneumonia in a rituximab treated patient with systemic sclerosis-A case report and literature review - Yalcin Mutlu, Melek; Taubmann, Jule; Wacker, Jochen; Tascilar, Koray; Fagni, Filippo; Gerner, Maximilian; Klett, Daniel; Schett, Georg; Manger, Bernhard; Simon, David (Frontiers in Medicine, 2022)
Patients with immune-mediated diseases (IMID) such as systemic sclerosis (SSc), who are treated with B cell depleting treatments, are at risk for developing severe COVID-19 due to inadequate humoral immune response. During B cell depletion, therapeutic substitution of neutralizing monoclonal antibodies against the SARS-CoV-2 spike protein (mAbs) might be helpful to prevent severe COVID-19. It has been shown, that in non-IMID patients mABs reduce SARS-CoV-2 viral load and lower the risk of COVID-19 associated hospitalization or death. However, there are limited data on the effect of mAbs in IMID patients after exposure, especially in patients treated with B cell depleting agents. Herein, we report a case of a rituximab treated SSc patient who developed COVID-19 and was successfully treated with a combination of mAbs (casirivimab/imdevimab). With this case we show that IMID patients may benefit from post-exposure administration of mAbs. In our case treatment with neutralizing autoantibodies was safe and a possible contributor in protecting the patient from mechanical ventilation and eventually death. We frame this case within the current evidence from the literature and provide a perspective on the future potential role of mAbs for treating IMID patients suffering from COVID-19.
CRIS-Team WoS Importer:2022-08-26

Neutrophil extracellular trap‐driven occlusive diseases - Yaykasli, Kürsat Oguz; Munoz, Luis Enrique; Mahajan, Aparna; Knopf, Jasmin; Schett, Georg; Herrmann, Martin; Schauer, Christine (Cells, 2021)
The enlightenment of the formation of neutrophil extracellular traps (NETs) as a part of the innate immune system shed new insights into the pathologies of various diseases. The initial idea that NETs are a pivotal defense structure was gradually amended due to several deleterious effects in consecutive investigations. NETs formation is now considered a double‐edged sword. The harmful effects are not limited to the induction of inflammation by NETs remnants but also include occlusions caused by aggregated NETs (aggNETs). The latter carries the risk of occluding tubular structures like vessels or ducts and appear to be associated with the pathologies of various diseases. In addition to life‐threatening vascular clogging, other occlusions include painful stone formation in the biliary system, the kidneys, the prostate, and the appendix. AggNETs are also prone to occlude the ductal system of exocrine glands, as seen in ocular glands, salivary glands, and others. Last, but not least, they also clog the pancreatic ducts in a murine model of neutrophilia. In this regard, elucidating the mechanism of NETs‐dependent occlusions is of crucial importance for the development of new therapeutic approaches. Therefore, the purpose of this review is to address the putative mechanisms of NETs‐associated occlusions in the pathogenesis of disease, as well as prospective treatment modalities.
CRIS-Team Scopus Importer:2021-10-08
Keywords: Aggregation; Ducts; Neutrophil extracellular traps; Occlusions; Vessels

Neutrophil Extracellular Traps Drive Dacryolithiasis - Zlatar, Leticija; Timm, Thomas; Lochnit, Günter; Bilyy, Rostyslav; Bäuerle, Tobias; Munoz Becerra, Marco; Schett, Georg; Knopf, Jasmin; Heichel, Jens; Ali, Mohammad Javed; Schapher, Mirco; Paulsen, Friedrich; et al. (Cells, 2023)
Mucopeptide concretions, previously called dacryoliths, are macroscopic stones that commonly obstruct the lacrimal sac. The mechanism behind dacryolithiasis remains unclear; however, the involvement of various immune cells, including neutrophils, has been confirmed. These findings remain limited, and no information on neutrophil extracellular traps (NETs), essentially involved in the pathogenesis of other lithiases, is available yet. Here, we employ microcomputed tomography, magnetic resonance tomography, histochemistry, mass spectrometry, and enzyme activity analyses to investigate the role of neutrophils and NETs in dacryolithiasis. We classify mucopeptide concretions into three types, with respect to the quantity of cellular and acellular material, polysaccharides, and mucosubstances. We propose the role of neutrophils and NETs within the existing model of gradual formation and growth of mucopeptide concretions, with neutrophils contributing to the initial stages of dacryolithiasis, as they localized on the inner (older) parts of the tissue. As NETs localized on the outer (newer) parts of the tissue, we link their role to the late stages of dacryolithiasis, presumably maintaining the proinflammatory environment and preventing efficient clearance. An abundance of IgG on the surface indicates the involvement of the adaptive immune system later as well. These findings bring new perspectives on dacryolithiasis, in which the innate and adaptive immune system are essentially involved.
CRIS-Team Scopus Importer:2023-08-11
Keywords: dacryolithiasis; dacryoliths; lacrimal sac; mucopeptide concretions; neutrophil extracellular traps; neutrophils

Neutrophil extracellular traps drive epithelial‐mesenchymal transition of human colon cancer - Stehr, Antonia; Wang, Guangxia; Demmler, Richard; Stemmler, Marc; Straube, Julia; Tripal, Philipp; Schmid, Benjamin; Geppert, Carol-Immanuel; Hartmann, Arndt; Munoz, Luis Enrique; Schoen, Janina; Völkl, Simon; et al. (Journal of Pathology, 2021)
Neutrophil extracellular traps (NETs) are extracellular structures, composed of nuclear DNA and various proteins released from neutrophils. Evidence is growing that NETs exert manifold functions in infection, immunity, and cancer. Recently, NETs have been detected in colorectal cancer (CRC) tissues but their association with disease progression and putative functional impact on tumourigenesis remained elusive. Using high-resolution stimulated emission depletion (STED) microscopy we showed that citrullinated histone H3 (H3cit) is sufficient to specifically detect citrullinated NETs in colon cancer tissues. Among other evidence this was supported by the close association of H3cit with de-condensed extracellular DNA, the hallmark of NETs. Extracellular DNA was reliably differentiated from nuclear condensed DNA by staining with an anti-DNA-antibody providing a novel and valuable tool to detect NETs in FFPE tissues. Using these markers, the clinical association of NETs has been investigated in a cohort of 85 patients with colon cancer. NETs were frequently detected (n = 37/n = 85, 44%) in colon cancer tissue sections and preferentially localized either only in the tumour centre or both, in the tumour centre and the invasive front. Of note, citrullinated NETs were significantly associated with high histopathologic tumour grades and lymph node metastasis. In vitro, purified NETs induced filopodia formation and cell motility in CRC cell lines. This was associated with increased expression of mesenchymal marker mRNAs (vimentin [VIM], fibronectin [FN1]) and epithelial- mesenchymal transition (EMT) promoting transcription factors (ZEB1 and Slug [SNAI2]) as well as decreased expression of the epithelial markers E-cadherin (CDH1) and EpCAM (EPCAM). These findings indicated that NETs activate an EMT-like process in CRC cells and may contribute to the metastatic progression of CRC.

Neutrophil Extracellular Traps Form a Barrier between Necrotic and Viable Areas in Acute Abdominal Inflammation - Bilyy, Rostyslav; Fedorov, Volodymyr; Vovk, Volodymyr; Leppkes, Moritz; Dumych, Tetiana; Chopyak, Valentyna; Schett, Georg; Herrmann, Martin (Frontiers in Immunology, 2016)
Neutrophils form neutrophil extracellular traps (NETs) of decondensed DNA and histones that trap and immobilize particulate matter and microbial pathogens like bacteria. NET aggregates reportedly surround and isolate large objects like monosodium urate crystals, which cannot be sufficiently cleared from tissues. In the setting of acute necrotizing pancreatitis, massive tissue necrosis occurs, which is organized as pancreatic pseudocysts (1). In contrast to regular cysts, these pseudocysts are not surrounded by epithelial layers. We hypothesize that, instead, the necrotic areas observed in necrotizing pancreatitis are isolated from the surrounding healthy tissues by aggregated NETs. These may form an alternative, putatively transient barrier, separating necrotic areas from viable tissue. To test this hypothesis, we investigated histological samples from the necropsy material of internal organs of two patients with necrotizing pancreatitis and peritonitis accompanied by multiple organ failure. Tissues including the inflammatory zone were stained with hematoxylin and eosin and evaluated for signs of inflammation. Infiltrating neutrophils and NETs were detected by immunohistochemistry for DNA, neutrophil elastase (NE), and citrullinated histone H3. Interestingly, in severely affected areas of pancreatic necrosis or peritonitis, chromatin stained positive for NE and citrullinated histone H3, and may, therefore, be considered NET-derived. These NET structures formed a layer, which separated the necrotic core from the areas of viable tissue remains. A condensed layer of aggregated NETs, thus, spatially shields and isolates the site of necrosis, thereby limiting the spread of necrosis-associated proinflammatory mediators. We propose that necrotic debris may initiate and/or facilitate the formation of the NET-based surrogate barrier.
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Neutrophil Extracellular Traps Initiate Gallstone Formation - Munoz, Luis Enrique; Boeltz, Sebastian; Bilyy, Rostyslav; Schauer, Christine; Mahajan, Aparna; Widulin, Navena; Grüneboom, Anika; Herrmann, Irmgard; Boada, Edgyda; Rauh, Manfred; Krenn, Veit; Biermann, Mona H.C.; et al. (Immunity, 2019)
The presence of gallstones (cholelithiasis) is a highly prevalent and severe disease and one of the leading causes of hospital admissions worldwide. Due to its substantial health impact, we investigated the biological mechanisms that lead to the formation and growth of gallstones. We show that gallstone assembly essentially requires neutrophil extracellular traps (NETs). We found consistent evidence for the presence of NETs in human and murine gallstones and describe an immune-mediated process requiring activation of the innate immune system for the formation and growth of gallstones. Targeting NET formation via inhibition of peptidyl arginine deiminase type 4 or abrogation of reactive oxygen species (ROS) production, as well as damping of neutrophils by metoprolol, effectively inhibit gallstone formation in vivo. Our results show that after the physicochemical process of crystal formation, NETs foster their assembly into larger aggregates and finally gallstones. These insights provide a feasible therapeutic concept to prevent cholelithiasis in patients at risk.
CRIS-Team Scopus Importer:2019-09-17
Keywords: calcium carbonate crystals; cholesterol crystals; gallstone growth; gallstones; lisosomal leakage; lithogenic diet; neutrophil extracellular traps; neutrophils; NOX2; PADi4

Neutrophil Extracellular Traps Promote the Development and Growth of Human Salivary Stones - Schapher, Mirco; Koch, Michael; Weidner, Daniela; Scholz, Michael; Wirtz, Stefan; Mahajan, Aparna; Herrmann, Irmgard; Singh, Jeeshan; Knopf, Jasmin; Leppkes, Moritz; Grüneboom, Anika; Alexiou, Christoph; et al. (Cells, 2020)
Salivary gland stones, or sialoliths, are the most common cause of the obstruction of salivary glands. The mechanism behind the formation of sialoliths has been elusive. Symptomatic sialolithiasis has a prevalence of 0.45% in the general population, is characterized by recurrent painful periprandial swelling of the affected gland, and often results in sialadenitis with the need for surgical intervention. Here, we show by the use of immunohistochemistry, immunofluorescence, computed tomography (CT) scans and reconstructions, special dye techniques, bacterial genotyping, and enzyme activity analyses that neutrophil extracellular traps (NETs) initiate the formation and growth of sialoliths in humans. The deposition of neutrophil granulocyte extracellular DNA around small crystals results in the dense aggregation of the latter, and the subsequent mineralization creates alternating layers of dense mineral, which are predominantly calcium salt deposits and DNA. The further agglomeration and appositional growth of these structures promotes the development of macroscopic sialoliths that finally occlude the efferent ducts of the salivary glands, causing clinical symptoms and salivary gland dysfunction. These findings provide an entirely novel insight into the mechanism of sialolithogenesis, in which an immune system-mediated response essentially participates in the physicochemical process of concrement formation and growth.
CRIS-Team Scopus Importer:2020-10-09
Keywords: lithogenesis; neutrophil extracellular traps; neutrophils; salivary glands; salivary stones; sialadenitis; sialolithiasis; stone development; stone growth

Neutrophilic Dermatoses - Classification and Pathophysiology - Manger, Bernhard (Zeitschrift für Rheumatologie, 2018)
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NEUTROPHILS AND NETS AS ORCHESTRATORS OF INFLAMMATORY DISEASES - Hosari, D.; Hosari, Sami; Mahajan, Aparna; Oreski, Leticija; Schoen, J.; Shan, Xiaomei; Singh, Jeeshan; Wang, H.; Yaykasli, Kürsat Oguz; Knopf, Jasmin; Munoz, Luis Enrique; Schauer, Christine; et al. (CLINICAL AND EXPERIMENTAL RHEUMATOLOGY, 2021)
CRIS-Team WoS Importer:2021-09-17

Neutrophils’ Extracellular Trap Mechanisms: From Physiology to Pathology - Schoen, Janina; Euler, Maximilien; Schauer, Christine; Schett, Georg; Herrmann, Martin; Knopf, Jasmin; Yaykasli, Kürsat Oguz (International Journal of Molecular Sciences, 2022)
Neutrophils are an essential part of the innate immune system and the first line of defense against invading pathogens. They phagocytose, release granular contents, produce reactive oxygen species, and form neutrophil extracellular traps (NETs) to fight pathogens. With the characterization of NETs and their components, neutrophils were identified as players of the innate adaptive crosstalk. This has placed NETs at the center not only of physiological but also pathological processes. Aside from their role in pathogen uptake and clearance, NETs have been demonstrated to contribute to the resolution of inflammation by forming aggregated NETs able to degrade inflammatory mediators. On the other hand, NETs have the potential to foster severe pathological conditions. When homeostasis is disrupted, they occlude vessels and ducts, serve as sources of autoantigens and danger or damage associated molecular patterns, directly damage tissues, and exaggerate complement activity and inflammation. This review focusses on the understanding of NETs from their formation to their functions in both physiological and pathological processes.
CRIS-Team Scopus Importer:2022-11-25
Keywords: aggNETs; autoantigens; DAMP; inflammation resolution; neutrophil extracellular traps; occlusions

Neutrophils prevent rectal bleeding in ulcerative colitis by peptidyl-arginine deiminase-4-dependent immunothrombosis - Leppkes, Moritz; Lindemann, Aylin; Goesswein, Stefanie; Paulus, Susanne; Roth, Dominik; Hartung, Anne; Liebing, Eva; Zundler, Sebastian; Gonzalez-Acera, Miguel; Patankar, Jay; Mascia, Fabrizio; Scheibe, Kristina; et al. (Gut, 2021)
Objective Bleeding ulcers and erosions are hallmarks of active ulcerative colitis (UC). However, the mechanisms controlling bleeding and mucosal haemostasis remain elusive. Design We used high-resolution endoscopy and colon tissue samples of active UC (n = 36) as well as experimental models of physical and chemical mucosal damage in mice deficient for peptidyl-arginine deiminase-4 (PAD4), gnotobiotic mice and controls. We employed endoscopy, histochemistry, live-cell microscopy and flow cytometry to study eroded mucosal surfaces during mucosal haemostasis. Results Erosions and ulcerations in UC were covered by fresh blood, haematin or fibrin visible by endoscopy. Fibrin layers rather than fresh blood or haematin on erosions were inversely correlated with rectal bleeding in UC. Fibrin layers contained ample amounts of neutrophils coaggregated with neutrophil extracellular traps (NETs) with detectable activity of PAD. Transcriptome analyses showed significantly elevated PAD4 expression in active UC. In experimentally inflicted wounds, we found that neutrophils underwent NET formation in a PAD4-dependent manner hours after formation of primary blood clots, and remodelled clots to immunothrombi containing citrullinated histones, even in the absence of microbiota. PAD4-deficient mice experienced an exacerbated course of dextrane sodium sulfate-induced colitis with markedly increased rectal bleeding (96 % vs 10 %) as compared with controls. PAD4-deficient mice failed to remodel blood clots on mucosal wounds eliciting impaired healing. Thus, NET-associated immunothrombi are protective in acute colitis, while insufficient immunothrombosis is associated with rectal bleeding. Conclusion Our findings uncover that neutrophils induce secondary immunothrombosis by PAD4-dependent mechanisms. Insufficient immunothrombosis may favour rectal bleeding in UC.
CRIS-Team WoS Importer:2021-12-17

Neutrophils prevent rectal bleeding in Ulcerative Colitis by peptidyl-arginine deiminase-4-dependent immunothrombosis - Leppkes, Moritz; Lindemann, Aylin; Goesswein, S.; Paulus, S.; Roth, Dominik; Hartung, A.; Liebing, Eva; Zundler, Sebastian; Gonzalez Acera, Miguel; Patankar, Jay; Mascia, Fabrizio; Scheibe, Kristina; et al. (JOURNAL OF CROHNS & COLITIS, 2022)
CRIS-Team WoS Importer:2022-05-13

New Insights into Bone Loss in RA - Andreev, Darja; Bozec, Aline (Osteologie, 2021)
The negative impact of rheumatoid arthritis (RA) on bone mineral density is well characterized. Notably, articular bone erosion is a central feature of RA, leading to joint damage and disabilities. In addition, the axial and appendicular skeleton can be affected, which secondly manifests in bone fracture. The main trigger of RA-associated bone loss is excessive bone degradation by osteoclasts and impaired bone formation by osteoblasts. In particular, the inflammatory status, reflected by high level of proinflammatory cytokines, receptor activator of nuclear factor kappa B ligand (RANKL), and autoantibodies induces the formation of bone-resorbing osteoclasts. Today, antirheumatic therapy effectively hampers synovial inflammation and bone erosion. However, current medication is unable to repair established bone lesions. This review outlines the knowledge gained about the pathophysiology of rheumatoid arthritis and the molecular mechanisms that promote osteoclast-mediated bone erosion and inhibit osteoblast-related bone formation, pointing out possible new intervention for inflammatory bone disease.
CRIS-Team WoS Importer:2021-10-01

New insights into the function of bone marrow - Schett, Georg; Bozec, Aline; Bekeredjian-Ding, I.; Chang, H-D.; David, J-P.; Doerner, T.; Graessel, S.; Gunzer, M.; Manz, R.; Mei, H.; Mielenz, Dirk; Mueller-Ladner, U.; et al. (Zeitschrift für Rheumatologie, 2018)
EVALuna2:34147

New insights into the prevalence of depressive symptoms and depression in rheumatoid arthritis - Implications from the prospective multicenter VADERA II study - Englbrecht, Matthias; Alten, Rieke; Aringer, Martin; Baerwald, Christoph G.; Burkharde, Harald; Eby, Nancy; Flacke, Jan-Paul; Fliedner, Gerhard; Henkemeier, Ulf; Hofmann, Michael W.; Kleinert, Stefan; Kneitz, Christian; et al. (PLoS ONE, 2019)
Objectives To investigate the prevalence of depressive symptoms in rheumatoid arthritis (RA) patients using two previously validated questionnaires in a large patient sample, and to evaluate depressive symptoms in the context of clinical characteristics (e.g. remission of disease) and patient-reported impact of disease. Methods In this cross-sectional study, the previously validated Patient Health Questionnaire (PHQ-9) and Beck-Depression Inventory II (BDI-II) were used to assess the extent of depressive symptoms in RA patients. Demographic background, RA disease activity score (DAS28), RA impact of disease (RAID) score, comorbidities, anti-rheumatic therapy and antidepressive treatment, were recorded. Cut-off values for depressive symptomatology were PHQ-9 ≥5 or BDI-II ≥14 for mild depressive symptoms or worse and PHQ-9 ≥ 10 or BDI-II ≥ 20 for moderate depressive symptoms or worse. Prevalence of depressive symptomatology was derived by frequency analysis while factors independently associated with depressive symptomatology were investigated by using multiple logistic regression analyses. Ethics committee approval was obtained, and all patients provided written informed consent before participation. Results In 1004 RA-patients (75.1% female, mean±SD age: 61.0±12.9 years, mean disease duration: 12.2±9.9 years, DAS28 (ESR): 2.5±1.2), the prevalence of depressive symptoms was 55.4% (mild or worse) and 22.8% (moderate or worse). Characteristics independently associated with depressive symptomatology were: age <60 years (OR = 1.78), RAID score >2 (OR = 10.54) and presence of chronic pain (OR = 3.25). Of patients classified as having depressive symptoms, only 11.7% were receiving anti-depressive therapy. Conclusions Mild and moderate depressive symptoms were common in RA patients according to validated tools. In routine clinical practice, screening for depression with corresponding followup procedures is as relevant as incorporating these results with patient-reported outcomes (e.g. symptom state), because the mere assessment of clinical disease activity does not sufficiently reflect the prevalence of depressive symptoms.
CRIS-Team Scopus Importer:2019-06-18

New molecular mechanisms in the pathophysiology of rheumatic diseases - Distler, Jörg (Zeitschrift für Rheumatologie, 2018)
EVALuna2:34954

New possibilities for ocular surface reconstruction : Collagen membranes and biocompatible elastomer nanofibers - Fuchsluger, Thomas; Salehi, S.; Petsch, Christina; Bachmann, B. (Ophthalmologe, 2014)
Amniotic membranes have been used for many years for reconstruction of the ocular surface. Despite having anti-inflammatory and antiangiogenic properties as well as being suitable as a carrier for corneal epithelial cells, amniotic membranes also have some limitations for use at the human cornea: availability is limited, there are major interindividual variations in structure and growth factor content and are not free from the risk of disease transmission. Progress in tissue engineering has been made aiming at the development and improvement of alternative biomaterials.This article presents new approaches for reconstruction of the corneal surface with collagen-based biomaterials and polymers.Electronic databases were searched for articles which evaluated collagenous biomaterials for use at the corneal surface. In addition the authors' own experiences with novel biomaterials are described.In vitro evaluation of the described biomaterials suggested a high biocompatibility with corneal epithelial cells in cell cultures. In vivo experiments with these materials in animal corneas demonstrated a certain variability in degradation and remodeling. Although some materials showed promising experimental results none of these are established in the clinical routine and only few clinical studies have so far been conducted with collagen-based biomaterials.Although the majority of the described biomaterials are currently still in the experimental stage, a transfer into the clinical routine is conceivable and of great therapeutic interest.
EVALuna2:21193

NEW SYSTEMIC SCLEROSIS RISK LOCI IDENTIFIED THROUGH A META-GWAS STRATEGY - Lopez-Isac, E.; Acosta-Herrera, M.; Assassi, S.; Simeon, C. P.; Carreira, P. E.; Castellvi, I.; Ortego-Centeno, N.; Beretta, L.; Lunardi, C.; Gabrielli, A.; Moroncini, G.; Hunzelmann, N.; et al. (2018)
EVALuna2:34987

Next-generation imaging of the skeletal system and its blood supply - Grüneboom, Anika; Kling, Lasse; Christiansen, Silke; Mill, Leonid; Maier, Andreas; Engelke, Klaus; Quick, Harald H.; Schett, Georg; Gunzer, Matthias (Nature Reviews Rheumatology, 2019)
Bone is organized in a hierarchical 3D architecture. Traditionally, analysis of the skeletal system was based on bone mass assessment by radiographic methods or on the examination of bone structure by 2D histological sections. Advanced imaging technologies and big data analysis now enable the unprecedented examination of bone and provide new insights into its 3D macrostructure and microstructure. These technologies comprise ex vivo and in vivo methods including high-resolution computed tomography (CT), synchrotron-based imaging, X-ray microscopy, ultra-high-field magnetic resonance imaging (MRI), light-sheet fluorescence microscopy, confocal and intravital two-photon imaging. In concert, these techniques have been used to detect and quantify a novel vascular system of trans-cortical vessels in bone. Furthermore, structures such as the lacunar network, which harbours and connects osteocytes, become accessible for 3D imaging and quantification using these methods. Next-generation imaging of the skeletal system and its blood supply are anticipated to contribute to an entirely new understanding of bone tissue composition and function, from macroscale to nanoscale, in health and disease. These insights could provide the basis for early detection and precision-type intervention of bone disorders in the future.
CRIS-Team Scopus Importer:2019-08-27

NINTEDANIB DOSE ADJUSTMENTS AND ADVERSE EVENTS IN PATIENTS WITH PROGRESSIVE AUTOIMMUNE DISEASE-RELATED INTERSTITIAL LUNG DISEASES IN THE INBUILD TRIAL - Volkmann, E.; Castellvi, I.; Johnson, S.; Matteson, E.; Distler, Jörg; Seibold, J.; Costabel, U.; James, A.; Coeck, C.; Quaresma, M.; Cottin, V. (ANNALS OF THE RHEUMATIC DISEASES, 2020)
CRIS-Team WoS Importer:2020-08-21

Nintedanib inhibits fibroblast activation and ameliorates fibrosis in preclinical models of systemic sclerosis - Huang, Jingang; Beyer, Christian; Palumbo-Zerr, Katrin; Zhang, Yun; Distler, Alfiya; Gelse, Kolja; Distler, Oliver; Schett, Georg; Wollin, Lutz; Distler, Jörg; Ramming, Andreas (Annals of the Rheumatic Diseases, 2015)
Nintedanib is a tyrosine kinase inhibitor that has recently been shown to slow disease progression in idiopathic pulmonary fibrosis in two replicate phase III clinical trials. The aim of this study was to analyse the antifibrotic effects of nintedanib in preclinical models of systemic sclerosis (SSc) and to provide a scientific background for clinical trials in SSc.The effects of nintedanib on migration, proliferation, myofibroblast differentiation and release of extracellular matrix of dermal fibroblasts were analysed by microtitre tetrazolium and scratch assays, stress fibre staining, qPCR and SirCol assays. The antifibrotic effects of nintedanib were evaluated in bleomycin-induced skin fibrosis, in a murine sclerodermatous chronic graft-versus-host disease model and in tight-skin-1 mice.Nintedanib dose-dependently reduced platelet-derived growth factor-induced and transforming growth factor-?-induced proliferation and migration as well as myofibroblast differentiation and collagen release of dermal fibroblasts from patients with and healthy individuals. Nintedanib also inhibited the endogenous activation of SSc fibroblasts. Nintedanib prevented bleomycin-induced skin fibrosis in a dose-dependent manner and was also effective in the treatment of established fibrosis. Moreover, treatment with nintedanib ameliorated fibrosis in the chronic graft-versus-host disease model and in tight-skin-1 mice in well-tolerated doses.We demonstrate that nintedanib effectively inhibits the endogenous as well as cytokine-induced activation of SSc fibroblasts and exerts potent antifibrotic effects in different complementary mouse models of SSc. These data have direct translational implications for clinical trials with nintedanib in SSc.
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Nintedanib in Patients With Autoimmune Disease-Related Progressive Fibrosing Interstitial Lung Diseases: Subgroup Analysis of the INBUILD Trial - Matteson, Eric L.; Kelly, Clive; Distler, Jörg; Hoffmann-Vold, Anna-Maria; Seibold, James R.; Mittoo, Shikha; Dellaripa, Paul F.; Aringer, Martin; Pope, Janet; Distler, Oliver; James, Alexandra; Schlenker-Herceg, Rozsa; et al. (Arthritis and Rheumatology, 2022)
Objective To analyze the efficacy and safety of nintedanib in patients with fibrosing autoimmune disease-related interstitial lung diseases (ILDs) with a progressive phenotype. Methods The INBUILD trial enrolled patients with a fibrosing ILD other than idiopathic pulmonary fibrosis, with diffuse fibrosing lung disease of >10% extent on high-resolution computed tomography, forced vital capacity percent predicted (FVC%) >= 45%, and diffusing capacity of the lungs for carbon monoxide percent predicted >= 30% to <80%. Patients fulfilled protocol-defined criteria for progression of ILD within the 24 months before screening, despite management deemed appropriate in clinical practice. Subjects were randomized to receive nintedanib or placebo. We assessed the rate of decline in FVC (ml/year) and adverse events (AEs) over 52 weeks in the subgroup with autoimmune disease-related ILDs. Results Among 170 patients with autoimmune disease-related ILDs, the rate of decline in FVC over 52 weeks was -75.9 ml/year with nintedanib versus -178.6 ml/year with placebo (difference 102.7 ml/year [95% confidence interval 23.2, 182.2]; nominal P = 0.012). No heterogeneity was detected in the effect of nintedanib versus placebo across subgroups based on ILD diagnosis (P = 0.91). The most frequent AE was diarrhea, reported in 63.4% and 27.3% of subjects in the nintedanib and placebo groups, respectively. AEs led to permanent discontinuation of trial drug in 17.1% and 10.2% of subjects in the nintedanib and placebo groups, respectively. Conclusion In the INBUILD trial, nintedanib slowed the rate of decline in FVC in patients with progressive fibrosing autoimmune disease-related ILDs, with AEs that were manageable for most patients.
CRIS-Team WoS Importer:2022-05-20

Nintedanib macrophage activation and ameliorates vascular and fibrotic manifestations in the Fra2 mouse model of systemic sclerosis - Huang, Jingang; Maier, Christiane; Zhang, Yun; Soare, Alina; Dees, Clara; Beyer, Christian; Harre, Ulrike; Chen, Chih-Wei; Distler, Oliver; Schett, Georg; Wollin, Lutz; Distler, Jörg (Annals of the Rheumatic Diseases, 2017)
Nintedanib is an inhibitor targeting platelet-derived growth factor receptor, fibroblast growth factor receptor and vascular endothelial growth factor receptor tyrosine kinases that has recently been approved for the treatment of idiopathic pulmonary fibrosis. The aim of this study was to analyse the effects of nintedanib in the fos-related antigen-2 (Fra2) mouse model of systemic sclerosis (SSc).The effects of nintedanib on pulmonary arterial hypertension with proliferation of pulmonary vascular smooth muscle cells (PVSMCs) and luminal occlusion, on microvascular disease with apoptosis of microvascular endothelial cells (MVECs) and on fibroblast activation with myofibroblast differentiation and accumulation of extracellular matrix were analysed. We also studied the effects of nintedanib on the levels of key mediators involved in the pathogenesis of SSc and on macrophage polarisation.Nintedanib inhibited proliferation of PVSMCs and prevented thickening of the vessel walls and luminal occlusion of pulmonary arteries. Treatment with nintedanib also inhibited apoptosis of MVECs and blunted the capillary rarefaction in Fra2-transgenic mice. These effects were associated with a normalisation of the serum levels of vascular endothelial growth factor in Fra2 mice on treatment with nintedanib. Nintedanib also effectively blocked myofibroblast differentiation and reduced pulmonary, dermal and myocardial fibrosis in Fra2-transgenic mice. The antifibrotic effects of nintedanib were associated with impaired M2 polarisation of monocytes and reduced numbers of M2 macrophages.Nintedanib targets core features of SSc in Fra2-transgenic mice and ameliorates histological features of pulmonary arterial hypertension, destructive microangiopathy and pulmonary and dermal fibrosis. These data might have direct implications for the ongoing phase III clinical trial with nintedanib in SSc-associated interstitial lung diseas
EVALuna2:13441

Nintedanib reduces alloimmune-induced chronic airway changes in murine tracheal allografts - Mauer, Julia; Kuckhahn, Annika; Ramsperger-Gleixner, Martina; Ensminger, Stephan M.; Distler, Jörg; Weyand, Michael; Heim, Christian (Transplant Immunology, 2022)
Background: The major obstacle for long-term survival after successful lung transplantation is the development of bronchiolitis obliterans (BO) which is one phenotype of chronic lung allograft dysfunction (CLAD). Nintedanib has beneficial effects treating neoplastic diseases and idiopathic pulmonary fibrosis by blocking tyrosine kinase receptors. These receptors play an important role in alloimmune-mediated proliferative diseases. The aim of this study was to determine the effect of nintedanib on proliferative airway changes after orthotopic trachea transplantation in mice. Methods: C57BL/6 mice (H-2b) donor tracheas were orthotopically transplanted into CBA/J mice (H-2k). After transplantation, recipients were daily treated with nintedanib (60 mg/kg; p.o.). Histological and immunofluorescence analysis were performed after 30 days and intragraft gene expression measurements after 14 days of treatment, respectively. Results: Tracheal allografts from mice treated with nintedanib showed significantly less features of chronic rejection than untreated allografts reflected in a higher epithelium/lamina propria ratio (ELR) [ELR: 0.65 ± 0.13 nintedanib vs. 0.50 ± 0.07 untreated controls; p < 0.05] and a reduced submucosal smooth muscle actin (SMA) content [SMA: 1.26% ± 0.78% nintedanib vs. 2.18% ± 1.01% untreated controls; p < 0.01]. Furthermore, lower T cell, macrophage and dendritic cell infiltration was detected in the nintedanib treated grafts. The protein and intragraft mRNA expression of receptor subtypes was considerably decreased in grafts of nintedanib treated mice. The mRNA expression of relevant immune mediators was affected by nintedanib treatment. Conclusion: Receptor blocking by nintedanib reduced alloimmune-induced inflammation and chronic airway changes in mouse trachea allografts and might be a promising approach to diminish the development of BO in lung transplants.
CRIS-Team Scopus Importer:2022-07-01
Keywords: Bronchiolitis obliterans; Chronic rejection; Nintedanib; Tracheal allografts; Tyrosine kinase inhibitor

NNRTI-based antiretroviral therapy may increase risk of radiation induced side effects in HIV-1-infected patients - Keller, Ulrike; Hecht, Markus; Harrer, Thomas; Harrer, Ellen; Schuster, Barbara; Fietkau, Rainer; Distel, Luitpold (Radiotherapy and Oncology, 2015)
As the incidence of cancer is rising in HIV-1-infected patients, radiotherapy is used more frequently in this patient group. Strong radiation induced side effects have been reported in single patients on antiretroviral therapy. Thus we investigated whether HIV-1 itself or antiretroviral drugs could enhance radiosensitivity in patients.Radiosensitivity after in vitro irradiation of blood lymphocytes was tested in 196 individuals (80 HIV-1-infected patients and 116 healthy controls and cancer patients) using a three color fluorescence in situ hybridization approach to analyze chromosomal aberrations (B/M). Additionally, the NNRTI efavirenz and the NRTIs tenofovir and emtricitabine were tested for radiosensitizing effects in vitro.Lymphocytes from HIV-1-infected patients in the NNRTI + NRTI group were significantly more sensitive to ionizing radiation than in the other groups (patients without treatment or with NRTI + PI or HIV-negative controls). In vitro the triple medication efavirenz, tenofovir and emtricitabine leads to a reduced survival fraction and an increased activation of the DNA repair proteins H2AX, Nbs, Atm and 53BP1 in combination with ionizing radiation.HIV-1 treatment with NNRTI containing therapy regimes possibly sensitizes a subgroup of patients to ionizing radiation. Individual radiosensitivity of HIV-1-infected patients on HAART including NNRTI should be tested before starting radiotherapy.
EVALuna2:13258

No Difference in Treatment Continuation of Different Biologics in Elderly Patients > 70 Years Compared to Younger Patients <= 65 Years - Strangfeld, Anja; Krueger, Klaus; Manger, Bernhard; Kneitz, Christian; Zink, Angela; Schaefer, Martin (ARTHRITIS & RHEUMATOLOGY, 2019)
CRIS-Team WoS Importer:2020-02-07

No evidence of pathogenic involvement of cathelicidins in patient cohorts and mouse models of lupus and arthritis - Kienhofer, D.; Hahn, Jonas; Schubert, I.; Reinwald, Christiane; Ipseiz, N.; Lang, Sabine; Borras, E. Bosch; Amann, Kerstin Ute; Sjowall, C.; Barron, A. E.; Hueber, Axel; Agerberth, B.; et al. (PLoS ONE, 2014)
Apart from their role in the immune defence against pathogens evidence of a role of antimicrobial peptides (AMPs) in autoimmune diseases has accumulated in the past years. The aim of this project was to examine the functional impact of the human cathelicidin LL-37 and the mouse cathelicidin-related AMP (CRAMP) on the pathogenesis of lupus and arthritis. Serum LL-37 and anti-LL-37 levels were measured by ELISA in healthy donors and patients with Systemic Lupus Erythematosus (SLE) and Rheumatoid arthritis (RA). Pristane-induced lupus was induced in female wild type (WT) and cathelicidin-deficient (CRAMP-/-) mice. Serum levels of anti-Sm/RNP, anti-dsDNA, and anti-histone were determined via ELISA, cytokines in sera and peritoneal lavages were measured via Multiplex. Expression of Interferon I stimulated genes (ISG) was determined by real-time PCR. Collagen-induced arthritis (CIA) was induced in male WT and CRAMP-/- mice and arthritis severity was visually scored and analysed histomorphometrically by OsteoMeasure software. Serum levels of anti-LL-37 were higher in SLE-patients compared to healthy donors or patients with RA. However, no correlation to markers of disease activity or organ involvement was observed. No significant differences of autoantibody or cytokine/chemokine levels, or of expression of ISGs were observed between WT and CRAMP-/- mice after pristane-injection. Furthermore, lung and kidney pathology did not differ in the absence of CRAMP. Incidence and severity of CIA and histological parameters (inflammation, cartilage degradation, and bone erosion) were not different in WT and CRAMP-/- mice. Although cathelicidins are upregulated in mouse models of lupus and arthritis, cathelicidin-deficiency did not persistently affect the diseases. Also in patients with SLE, autoantibodies against cathelicidins did not correlate with disease manifestation. Reactivity against cathelicidins in lupus and arthritis could thus be an epiphenomenon caused by extensive overexpression in blood and affected tissues. In addition, other cationic AMPs could functionally compensate for the deficiency of cathelicidins.
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NO INCREASED RISK OF FALLS IN PATIENTS TREATED WITH BIOLOGICS COMPARED TO THOSE UNDER CSDMARDS - Rudi, T.; Schaefer, M.; Manger, Bernhard; Zink, A.; Strangfeld, A. (ANNALS OF THE RHEUMATIC DISEASES, 2020)
CRIS-Team WoS Importer:2020-08-21

Non-Invasive Characterization of Experimental Bone Metastasis in Obesity Using Multiparametric MRI and PET/CT - Gregoric, Gasper; Gaculenko, Anastasia; Nagel, Lisa; Popp, Vanessa; Maschauer, Simone; Prante, Olaf; Saake, Marc; Schett, Georg; Uder, Michael; Ellmann, Stephan; Bozec, Aline; Bäuerle, Tobias (Cancers, 2022)
The growth of primary tumors and metastases is associated with excess body fat. In bone metastasis formation, the bone marrow microenvironment, and particularly adipocytes, play a pivotal role as growth mediators of disseminated tumor cells in the bone marrow. The aim of the present study is to non-invasively characterize the pathophysiologic processes in experimental bone metastasis resulting from accelerated tumor progression within adipocyte-rich bone marrow using multimodal imaging from magnetic resonance imaging (MRI) and positron emission tomography/computed tomography (PET/CT). To achieve this, we have employed small animal models after the administration of MDA-MB 231 breast cancer and B16F10 melanoma cells into the bone of nude rats or C57BL/6 mice, respectively. After tumor cell inoculation, ultra-high field MRI and mu PET/CT were used to assess functional and metabolic parameters in the bone marrow of control animals (normal diet, ND), following a high-fat diet (HFD), and/or treated with the peroxisome proliferator-activated receptor-gamma (PPAR gamma) antagonist bisphenol-A-diglycidylether (BADGE), respectively. In the bone marrow of nude rats, dynamic contrast-enhanced MRI (DCE-MRI) and diffusion-weighted imaging (DWI), as well as [F-18]fluorodeoxyglucose-PET/CT([F-18]FDG-PET/CT), was performed 10, 20, and 30 days after tumor cell inoculation, followed by immunohistochemistry. DCE-MRI parameters associated with blood volume, such as area under the curve (AUC), were significantly increased in bone metastases in the HFD group 30 days after tumor cell inoculation as compared to controls (p < 0.05), while the DWI parameter apparent diffusion coefficient (ADC) was not significantly different between the groups. [F-18]FDG-PET/CT showed an enhanced glucose metabolism due to increased standardized uptake value (SUV) at day 30 after tumor cell inoculation in animals that received HFD (p < 0.05). BADGE treatment resulted in the inversion of quantitative DCE-MRI and [F-18]FDG-PET/CT data, namely a significant decrease in AUC and SUV in HFD-fed animals as compared to ND-fed controls (p < 0.05). Finally, immunohistochemistry and qPCR confirmed the HFD-induced stimulation in vascularization and glucose activity in murine bone metastases. In conclusion, multimodal and multiparametric MRI and [F-18]FDG-PET/CT were able to derive quantitative parameters in bone metastases, revealing an increase in vascularization and glucose metabolism following HFD. Thus, non-invasive imaging may serve as a biomarker for assessing the pathophysiology of bone metastasis in obesity, opening novel options for therapy and treatment monitoring by MRI and [F-18]FDG-PET/CT.
CRIS-Team WoS Importer:2022-06-10

NON-INVASIVE IN VIVO METABOLIC PROFILING OF INFLAMMATION IN JOINTS AND ENTHESES BY OPTOACOUSTIC IMAGING - Tascilar, Koray; Fagni, Filippo; Kleyer, Arnd; Bayat, Sara; Heidemann, Robert; Steiger, F.; Krönke, Gerhard; Bohr, D.; Ramming, Andreas; Hartmann, F.; Klett, Daniel; Federle, Anna; et al. (ANNALS OF THE RHEUMATIC DISEASES, 2022)
CRIS-Team WoS Importer:2022-11-04

Non-invasive metabolic profiling of inflammation in joints and entheses by multispectral optoacoustic tomography - Tascilar, Koray; Fagni, Filippo; Kleyer, Arnd; Bayat, Sara; Heidemann, Robert; Steiger, Florian; Krönke, Gerhard; Bohr, Daniela; Ramming, Andreas; Hartmann, Fabian; Klett, Daniel; Federle, Anna; et al. (Rheumatology, 2022)
Objective To explore the metabolic characteristics of arthritis and enthesitis using multispectral opto-acoustic tomography (MSOT), a technology using near-infrared multispectral laser to stimulate tissues and detect the emitted acoustic energy, enabling non-invasive quantification of tissue components in vivo based on differential absorbance at multiple wavelengths. Methods We performed a cross-sectional study in patients with RA or PsA and healthy controls (HCs). Participants underwent clinical, ultrasonographic and MSOT examination of MCP and wrist joints as well as the entheses of the common extensor tendon at the lateral humeral epicondyles and of the patellar, quadriceps and Achilles tendon. MSOT-measured haemoglobin (Hb), oxygen saturation, collagen and lipid levels were quantified and scaled mean differences between affected and unaffected joints and entheses were calculated as defined by clinical examination or ultrasonography using linear mixed effects models. Results We obtained 1535 MSOT and 982 ultrasonography scans from 87 participants (34 PsA, 17 RA, 36 HCs). Entheseal tenderness was not associated with significant metabolic changes, whereas enthesitis-related sonographic changes were associated with increased total Hb, oxygen saturation and collagen content. In contrast, the presence of arthritis-related clinical and sonographic findings showed increased Hb levels, reduced oxygen saturation and reduced collagen content. Synovial hypertrophy was associated with increased lipid content in the joints. Conclusion MSOT allows determination of distinct metabolic differences between arthritis and enthesitis in a non-invasive setting in humans in vivo.
CRIS-Team WoS Importer:2022-07-22

Notch Signaling Activity Determines Uptake and Biological Effect of Imatinib in Systemic Sclerosis Dermal Fibroblasts - Harrach, Saliha; Barz, Vivien; Pap, Thomas; Pavenstaedt, Hermann; Schlatter, Eberhard; Edemir, Bayram; Distler, Jörg; Ciarimboli, Giuliano; Bertrand, Jessica (Journal of Investigative Dermatology, 2019)
Tyrosine kinase inhibitors have emerged as a therapeutic option for rheumatic diseases such as systemic sclerosis (SSc). Because tyrosine kinases like c-Abl kinase are important for fibroblast activation and fibrosis development in SSc, the c-Abl inhibitor imatinib was proposed for SSc treatment. Transporters for organic cations have become increasingly recognized as an important determinant for uptake and efficacy of tyrosine kinase inhibitors. Therefore, we investigated the role of organic cation transporters in the uptake of imatinib. Moreover, the influence of important SSc pathogenetic factors, like PDGF and Notch pathway activation on these uptake processes, has been studied. We showed that organic cation transporters OCT1e3, novel organic cation transporters OCTN1/2, and the multidrug and toxin extrusion protein MATE1 are expressed in healthy dermal and SSc fibroblasts. Decreased expression levels of MATE1 and decreased imatinib uptake were measured in SSc fibroblasts. In small interfering RNA experiments, MATE1 was identified as key transporter for imatinib uptake and biological effect in dermal fibroblasts. Furthermore, PDGF reduced imatinib uptake by decreasing MATE1 expression in SSc fibroblasts, but not in healthy fibroblasts. Blocking the Notch pathway in SSc fibroblasts increased MATE1 transporter expression and imatinib uptake. In conclusion, MATE1-mediated transport governs therapeutic efficacy of imatinib in SSc.
CRIS-Team WoS Importer:2019-02-21

Novel approaches to target the microenvironment of bone metastasis - Hofbauer, Lorenz C.; Bozec, Aline; Rauner, Martina; Jakob, Franz; Perner, Sven; Pantel, Klaus (NAT REV CLIN ONCOL, 2021)
Bone metastases are a frequent and severe complication of advanced-stage cancers. Breast and prostate cancers, the most common malignancies in women and men, respectively, have a particularly high propensity to metastasize to bone. Conceptually, circulating tumour cells (CTCs) in the bloodstream and disseminated tumour cells (DTCs) in the bone marrow provide a snapshot of the dissemination and colonization process en route to clinically apparent bone metastases. Many cell types that constitute the bone microenvironment, including osteoblasts, osteocytes, osteoclasts, adipocytes, endothelial cells, haematopoietic stem cells and immune cells, engage in a dialogue with tumour cells. Some of these cells modify tumour biology, while others are disrupted and out-competed by tumour cells, thus leading to distinct phases of tumour cell migration, dormancy and latency, and therapy resistance and progression to overt bone metastases. Several current bone-protective therapies act by interrupting these interactions, mainly by targeting tumour cell-osteoclast interactions. In this Review, we describe the functional roles of the bone microenvironment and its components in the initiation and propagation of skeletal metastases, outline the biology and clinical relevance of CTCs and DTCs, and discuss established and future therapeutic approaches that specifically target defined components of the bone microenvironment to prevent or treat skeletal metastases.
CRIS-Team WoS Importer:2021-05-07

Novel Developments in Primary Immunodeficiencies (PID)—a Rheumatological Perspective - Leavis, Helen; Zwerina, Jochen; Manger, Bernhard; Fritsch-Stork, Ruth D.E. (Current Rheumatology Reports, 2019)
Purpose of Review: The purpose of this review is to provide an overview of the most relevant new disorders, disease entities, or disease phenotypes of primary immune deficiency disorders (PID) for the interested rheumatologist, using the new phenotypic classification by the IUIS (International Union of Immunological Societies) as practical guide. Recent Findings: Newly recognized disorders of immune dysregulation with underlying mutations in genes pertaining to the function of regulatory T cells (e.g., CTLA-4, LRBA, or BACH2) are characterized by multiple autoimmune diseases—mostly autoimmune cytopenia—combined with an increased susceptibility to infections due to hypogammaglobulinemia. On the other hand, new mutations (e.g., in NF-kB1, PI3Kδ, PI3KR1, PKCδ) leading to the clinical picture of CVID (common variable immmune deficiency) have been shown to increasingly associate with autoimmune diseases. Summary: The mutual association of autoimmune diseases with PID warrants increased awareness of immunodeficiencies when diagnosing autoimmune diseases with a possible need to initiate appropriate genetic tests.
CRIS-Team Scopus Importer:2019-09-17
Keywords: APDS; CTLA-4 haploinsufficiency; CVID; DADA2; LRBA indusfficiency; NF-kB deficiency

Novel Mechanism Mediated By the IL-23/Th17 Axis Contributing to Auto-Immune Arthritis - Pfeifle, René; Rothe, Tobias; Ipseiz, Natacha; Culemann, Stephan; Harre, Ulrike; Krönke, Gerhard; Schett, Georg (2016)
EVALuna2:35064

Novel mechanism mediated by the IL23/Th17 axis contributing to auto-immune arthritis - Pfeifle, R.; Rothe, T.; Ipseiz, N.; Culemann, S.; Harre, Ulrike; Schett, Georg; Krönke, Gerhard (2017)
EVALuna2:34159

NOVEL TECHNIQUE FOR PRECISE CALCULATION OF BONE EROSION VOLUME IN RA PATIENTS USING HR-PQCT - Figueiredo, C.; Simon, David; Stemmler, F.; Rech, Jürgen; Hueber, Axel; Haschka, J.; Schett, Georg; Kleyer, Arnd (2015)
EVALuna2:34459

NOX2 mediates quiescent handling of dead cell remnants in phagocytes - Hahn, Jonas; Euler, Maximilien; Kilgus, Emelie; Kienhöfer, Deborah; Stoof, Julia; Knopf, Jasmin; Hahn, Madelaine; Harrer, Thomas; Hultqvist, Malin; Olofsson, Peter; Mokhir, Andriy; Holmdahl, Rikard; et al. (Redox Biology, 2019)
The phagocyte NADPH oxidase (the NOX2 complex) generates superoxide, the precursor to reactive oxygen species (ROS). ROS possess both antimicrobial and immunoregulatory function. Inactivating mutations in alleles of the NOX2 complex cause chronic granulomatous disease (CGD), characterized by an enhanced susceptibility to infections and autoimmune diseases such as Systemic lupus erythematosus (SLE). The latter is characterized by insufficient removal of dead cells, resulting in an autoimmune response against components of the cell's nucleus when non-cleared apoptotic cells lose their membrane integrity and present autoantigenic molecules in an inflammatory context. Here we aimed to shed light on the role of the NOX2 complex in handling of secondary necrotic cells (SNECs) and associated consequences for inflammation and autoimmunity during lupus. We show that individuals with SLE and CGD display accumulation of SNECs in blood monocytes and neutrophils. In a CGD phenotypic mouse strain (Ncf1** mice) build-up of SNECs in Ly6CHI blood monocytes was connected with a delayed degradation of the phagosomal cargo and accompanied by production of inflammatory mediators. Treatment with H2O2 or activators of ROS-formation reconstituted phagosomal abundance of SNECs to normal levels. Induction of experimental lupus further induced increased antibody-dependent uptake of SNECs into neutrophils. Lupus-primed Ncf1** neutrophils took up more SNECs than wild type neutrophils, whereas SNEC-accumulation in regulatory Ly6C−/LO monocytes was lower in Ncf1**mice. We deduce that the inflammatory rerouting of immune-stimulatory necrotic material into inflammatory phagocyte subsets contributes to the connection between low ROS production by the NOX2 complex and SLE.
CRIS-Team Scopus Importer:2019-08-06

NR4A1 AGONIST CYTOSPORONE B DOES NOT ATTENUATE CAV IN A MOUSE MODEL DESPITE REPORTED ANTI-PROLIFERATIVE AND ANTI-INFLAMMATORY EFFECTS - Kuckhahn, A.; Ramsperger-Gleixner, Martina; Distler, Jörg; Weyand, Michael; Heim, Christian (TRANSPLANT INTERNATIONAL, 2020)
CRIS-Team WoS Importer:2020-11-06

NR4A1 Regulates Motility of Osteoclast Precursors and Serves as Target for the Modulation of Systemic Bone Turnover - Scholtysek, Carina; Ipseiz, Natacha; Böhm, Christina; Krishnacoumar, Brenda; Stenzel, Martin; Czerwinski, Tina; Palumbo-Zerr, Katrin; Rothe, Tobias; Weidner, Daniela; Klej, Alexandra; Stoll, Cornelia; Distler, Jörg; et al. (Journal of Bone and Mineral Research, 2018)
NR4A1 (Nur77 or NGFI-B), an orphan member of the nuclear receptor superfamily, has been identified as a key regulator of the differentiation and function of myeloid, lymphoid, and mesenchymal cells. The detailed role of NR4A1 in bone biology is incompletely understood. Here, we report a role for NR4A1 as novel factor controlling the migration and recruitment of osteoclast precursors during bone remodeling. Myeloid-specific but not osteoblast-specific deletion of NR4A1 resulted in osteopenia due to an increase in the number of bone-lining osteoclasts. Although NR4A1-deficient osteoclast precursors displayed a regular differentiation into mature osteoclasts, they showed a hyper-motile phenotype that was largely dependent on increased osteopontin expression, suggesting that expression of NR4A1 negatively controlled osteopontin-mediated recruitment of osteoclast precursors to the trabecular bone. Pharmacological activation of NR4A1, in turn, inhibited osteopontin expression and osteopontin-dependent migration of osteoclast precursors resulted in reduced abundance of bone-resorbing osteoclasts in vivo as well as in an ameliorated bone loss after ovariectomy in mice. This study identifies NR4A1 as a crucial player in the regulation of osteoclast biology and bone remodeling and highlights this nuclear receptor as a promising target for therapeutic intervention during the treatment of osteoporosis. © 2018 The Authors. Journal of Bone and Mineral Research Published by Wiley Periodicals Inc.
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N-terminal pro-brain natriuretic peptide is a strong predictor of mortality in systemic sclerosis - Allanore, Yannick; Komocsi, Andras; Vettori, Serena; Hachulla, Eric; Hunzelmann, Nicolas; Distler, Jörg; Avouac, Jerome; Gobeaux, Camille; Launay, David; Czirjak, Laszlo; Kahan, Andre; Meune, Christophe (International Journal of Cardiology, 2016)
Cardiovascular involvement is a major contributor to mortality in systemic sclerosis (SSc). We examined whether N-terminal pro-brain natriuretic peptide (NT-proBNP) is a reliable predictor of mortality in SSc.This multicentre prospective cohort study included 523 patients presenting with SSc, whose mean age was 54±13years, mean disease duration 8±9years, and diffuse cutaneous form in 168. Plasma NT-proBNP was measured at baseline and the patients were followed yearly. Overall mortality was measured at 3years. At baseline, cardiovascular involvement was present in 37 patients, including 17 with pulmonary artery hypertension (PAH) and 20 with a left ventricular ejection fraction (LVEF) <55%. At 3years, 32 (7%) patients had died. The median [25th-75th percentile] NT-proBNP concentration was 203ng/l [129-514] in patients who died within 3years, versus 88ng/l [47-167] in survivors (P<0.001). NT-proBNP was an independent predictor of 3-years mortality in multivariate analysis (P=0.046). The optimal cut-off derived from the ROC curve was 129ng/l; sensitivity and specificity to predict 3y mortality were 78.1 and 66.7%. Using the previously recommended 125-ng/l concentration as threshold value, NT-proBNP reliably and independently predicted 3year mortality, with a sensitivity of 78.1 and a negative predictive value of 97.6%, respectively (P=0.006). The consideration of SSc patients without PAH or LVEF<55% at baseline yielded similar results.NT-proBNP appears as a reliable and independent predictor of mortality in patients with SSc.
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Number of necessary training examples for Neural Networks with different number of trainable parameters - Götz, Theresa Ida; Göb, S.; Sawant, S.; Erick, X. F.; Wittenberg, Thomas; Schmidkonz, Christian; Tomé, A. M.; Lang, E. W.; Ramming, Andreas (Journal of Pathology Informatics, 2022)
In this work, the network complexity should be reduced with a concomitant reduction in the number of necessary training examples. The focus thus was on the dependence of proper evaluation metrics on the number of adjustable parameters of the considered deep neural network. The used data set encompassed Hematoxylin and Eosin (H&E) colored cell images provided by various clinics. We used a deep convolutional neural network to get the relation between a model's complexity, its concomitant set of parameters, and the size of the training sample necessary to achieve a certain classification accuracy. The complexity of the deep neural networks was reduced by pruning a certain amount of filters in the network. As expected, the unpruned neural network showed best performance. The network with the highest number of trainable parameter achieved, within the estimated standard error of the optimized cross-entropy loss, best results up to 30% pruning. Strongly pruned networks are highly viable and the classification accuracy declines quickly with decreasing number of training patterns. However, up to a pruning ratio of 40%, we found a comparable performance of pruned and unpruned deep convolutional neural networks (DCNN) and densely connected convolutional networks (DCCN).
CRIS-Team Scopus Importer:2022-10-28
Keywords: Cell segmentation; Deep neural networks; DNN complexity; Pruning; Training sample size

Obesity as an Influence Parameter of rheumatoid Arthritis and Osteoarthritis (Arthrosis) in the Mouse Model - Sauermilch, Hani Manfred; Huelser, Marie-Lisa; Schreiyaeck, Carina; Luo, Yubin; Bozec, Aline; Schett, Georg; Mueller-Ladner, Ulf; Neumann, Elena (INTERNIST, 2019)
CRIS-Team WoS Importer:2019-05-17

Obesity reduces the real-world effectiveness of cytokine-targeted but not cell-targeted disease-modifying agents in rheumatoid arthritis - Schäfer, Martin; Meißner, Yvette; Kekow, Jörn; Berger, Sylvia; Remstedt, Sven; Manger, Bernhard; Listing, Joachim; Strangfeld, Anja; Zink, Angela (Rheumatology, 2020)
OBJECTIVES: The effectiveness of TNF inhibitors in RA has been shown to be affected by obesity. No such effect has been found for abatacept and rituximab, while for tocilizumab results are ambiguous. Additionally, it remains unresolved whether sex is an effect modifier for obesity. We investigated the impact of obesity on the drug effectiveness of conventional synthetic or biologic DMARDs, taking into account potential sex-specific differences. METHODS: Data from 10 593 RA patients included in the German observational cohort study Rheumatoid Arthritis: oBservation of BIologic Therapy (RABBIT) since 2009 were analysed. Patients had to have a BMI ≥18.5 kg/m2, at least one follow-up and 6 months of observation time. The influence of obesity on drug effectiveness was investigated by regression analysis, adjusting for potential confounders. RESULTS: Obesity had a negative impact on improvement in the DAS with 28 joints using ESR as an inflammation marker of -0.15 (95% CI: -0.26; -0.04) units for women receiving conventional synthetic DMARDs, -0.22 (95% CI: -0.31; -0.12) units for women receiving TNF inhibitors, -0.22 (95% CI: -0.42; -0.03) units for women receiving tocilizumab and -0.41 (95% CI: -0.74; -0.07) units for men receiving tocilizumab. Overall, no negative obesity effects on the effectiveness of rituximab and abatacept were found. CONCLUSION: Obesity has a negative impact on the effectiveness of cytokine-targeted but not cell-targeted therapies in daily practice, affecting more outcomes and therapies in women than in men. Overall, no effects of obesity on treatment effectiveness were found for rituximab and abatacept.
CRIS-Team Scopus Importer:2020-08-07
Keywords: drug dosage; obesity; rheumatoid arthritis; sex

Objective and subjective hand function reflect grade of tenosynovitis in patients with psoriasis and psoriatic arthritis - Coppers, Birte; Bayat, Sara; Elie-Tino, Godonou; Valor-Mendez, Larissa; Simon, David; Corte, Giulia; Tascilar, Koray; Hueber, Axel; Bohr, Daniela; Schönau, Verena; Sticherling, Michael; Schett, Georg; et al. (poster, Deutsche Gesellschaft für Rheumatologie Kongress, 2023)

OBSERVATIONAL STUDY OF OUTCOME IN PATIENTS WITH EARLY DIFFUSE CUTANEOUS SYSTEMIC SCLEROSIS TREATED WITH IMMUNOSUPPRESSIVE THERAPIES (ESOS STUDY) - Herrick, A. L.; Pan, X.; Peytrignet, S.; Hesselstrand, R.; Mouthon, L.; Brown, E.; Czirjak, L.; Distler, Jörg; Distler, O.; Fligelstone, K.; Gregory, W.; Ochiel, R.; et al. (2016)
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O-GLCNACYLATION ON NUP153 REGULATES THE EARLY STAGES OF OSTEOCLASTOGENESIS THROUGH MYC NUCLEAR TRANSLOCATION - Li, You; Chen, C. W.; Trinh, Minh Thuong; Honglin, Z.; Hubel, P.; Pfannstiel, J.; Schett, Georg; Distler, Jörg (ANNALS OF THE RHEUMATIC DISEASES, 2022)
CRIS-Team WoS Importer:2022-11-04

Older age onset of systemic sclerosis - accelerated disease progression in all disease subsets - Moinzadeh, Pia; Kuhr, Kathrin; Siegert, Elise; Mueller-Ladner, Ulf; Riemekasten, Gabriela; Günther, Claudia; Kötter, Ina; Henes, Jörg; Blank, Norbert; Zeidler, Gabriele; Pfeiffer, Christiane; Juche, Aaron; et al. (Rheumatology, 2020)
OBJECTIVES: Systemic sclerosis is a heterogeneous, multisystem disease. It can occur at any age, but most patients develop the disease between the age of 40 to 50 years. There is controversial evidence on whether/how the age at disease onset affects their clinical phenotype. We here investigate the relationship between age at disease onset and symptoms in a large cohort of SSc patients (lcSSc, dcSSc and SSc-overlap syndromes). METHODS: Clinical data of the registry of the German Network for Systemic Scleroderma including 3281 patients were evaluated and subdivided into three age groups at disease onset (<40 years, 40-60 years, >60 years). RESULTS: Among all SSc patients, 24.5% developed their first non-Raynaud phenomenon symptoms at the age <40 years, and 22.5% were older than 60 years of age. In particular, older patients at onset developed the lcSSc subset significantly more often. Furthermore, they had pulmonary hypertension more often, but digital ulcerations less often. Remarkably, the course of the disease was more rapidly progressing in the older cohort (>60 years), except for gastrointestinal and musculoskeletal involvement. No significant difference was found for the use of corticosteroids. However, significantly, fewer patients older than 60 years received immunosuppressive treatment. CONCLUSION: In this large registry, ∼25% of patients developed SSc at an age above 60 years with an increased frequency of lcSSc. In this age group, an onset of internal organ involvement was significantly accelerated across all three subsets. These findings suggest that, in the elderly cohort, more frequent follow-up examinations are required for an earlier detection of organ complications.
CRIS-Team Scopus Importer:2020-11-13
Keywords: age at disease onset; German Network for Systemic Scleroderma; older age; scleroderma; SSc; systemic sclerosis

O-linked N-acetylglucosaminylation of Sp1 inhibits the human immunodeficiency virus type 1 promoter - Jochmann, Ramona; Thurau, Mathias; Jung, Susan; Hofmann, Christian; Naschberger, Elisabeth; Kremmer, Elisabeth; Harrer, Thomas; Miller, Matthew; Schaft, Niels; Stürzl, Michael (Journal of Virology, 2009)
Human immunodeficiency virus type 1 (HIV-1) gene expression and replication are regulated by the promoter/enhancer located in the U3 region of the proviral 5′ long terminal repeat (LTR). The binding of cellular transcription factors to specific regulatory sites in the 5′ LTR is a key event in the replication cycle of HIV-1. Since transcriptional activity is regulated by the posttranslational modification of transcription factors with the monosaccharide O-linked N-acetyl-D-glucosamine (O-GlcNAc), we evaluated whether increased O-GlcNAcylation affects HIV-1 transcription. In the present study we demonstrate that treatment of HIV-1-infected lymphocytes with the O-GlcNAcylation-enhancing agent glucosamine (GlcN) repressed viral transcription in a dose-dependent manner. Overexpression of O-GlcNAc transferase (OGT), the sole known enzyme catalyzing the addition of O-GlcNAc to proteins, specifically inhibited the activity of the HIV-1 LTR promoter in different T-cell lines and in primary CD4+ T lymphocytes. Inhibition of HIV-1 LTR activity in infected T cells was most efficient (>95%) when OGT was recombinantly overexpressed prior to infection. O-GlcNAcylation of the transcription factor Sp1 and the presence of Sp1-binding sites in the LTR were found to be crucial for this inhibitory effect. From this study, we conclude that O-GlcNAcylation of Sp1 inhibits the activity of the HIV-1 LTR promoter. Modulation of Sp1 O-GlcNAcylation may play a role in the regulation of HIV-1 latency and activation and links viral replication to the glucose metabolism of the host cell. Hence, the establishment of a metabolic treatment might supplement the repertoire of antiretroviral therapies against AIDS. Copyright © 2009, American Society for Microbiology. All Rights Reserved.
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Online-Ultraschalllernmodule in der Rheumatologie - Knitza, Johannes; Kleyer, Arnd; Klüppel, M.; Krauser, M.; Wacker, J.; Schett, Georg; Simon, David (Zeitschrift für Rheumatologie, 2020)
CRIS-Team Scopus Importer:2020-03-10

Only a Minor Proportion of Individuals with Anti-Aminoacyl-tRNA Synthetase Autoimmunity Presents with the Clinical Picture of "Antisynthetase-Syndrome" - Knitza, Johannes; Schenker, Hannah; Schett, Georg; Distler, Jörg (2018)
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On the inclusion of motion capture data in optimal control simulations of the human hand - Heinrich, Simon; Coppers, Birte; Liphardt, Anna-Maria; Leyendecker, Sigrid (conference, 18th International Symposium on Computer Methods in Biomechanics and Biomedical Engineering, 2023)

Opportunistic Screening With CT: Comparison of Phantomless BMD Calibration Methods - Bartenschlager, Stefan; Cavallaro, Alexander Josef; Pogarell, Tobias; Chaudry, Oliver; Uder, Michael; Khosla, Sundeep; Schett, Georg; Engelke, Klaus (Journal of Bone and Mineral Research, 2023)
Opportunistic screening is a new promising technique to identify individuals at high risk for osteoporotic fracture using computed tomography (CT) scans originally acquired for an clinical purpose unrelated to osteoporosis. In these CT scans, a calibration phantom traditionally required to convert measured CT values to bone mineral density (BMD) is missing. As an alternative, phantomless calibration has been developed. This study aimed to review the principles of four existing phantomless calibration methods and to compare their performance against the gold standard of simultaneous calibration (ΔBMD). All methods were applied to a dataset of 350 females scanned with a highly standardized CT protocol (DS1) and to a second dataset of 114 patients (38 female) from clinical routine covering a large range of CT acquisition and reconstruction parameters (DS2). Three of the phantomless calibration methods must be precalibrated with a reference dataset containing a calibration phantom. Sixty scans from DS1 and 57 from DS2 were randomly selected for this precalibration. For each phantomless calibration method first the best combination of internal reference materials (IMs) was selected. These were either air and blood or subcutaneous adipose tissue, blood, and cortical bone. In addition, for phantomless calibration a fifth method based on average calibration parameters derived from the reference dataset was applied. For DS1, ΔBMD results (mean (Formula presented.) standard deviation) for the phantomless calibration methods requiring a precalibration ranged from 0.1 (Formula presented.) 2.7 mg/cm3 to 2.4 (Formula presented.) 3.5 mg/cm3 with similar means but significantly higher standard deviations for DS2. Performance of the phantomless calibration method, which does not require a precalibration was worse (ΔBMD DS1: 12.6 (Formula presented.) 13.2 mg/cm3, DS2: 0.5 (Formula presented.) 8.8 mg/cm3). In conclusion, phantomless BMD calibration performs well if precalibrated with a reference dataset. © 2023 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 Scopus Importer:2023-10-20
Keywords: BONE MINERAL DENSITY; PERFORMANCE OF PHANTOMLESS CALIBRATION; OPPORTUNISTIC SCREENING; SIMULTANEOUS CALIBRATION

OPTIMAL DOSE OF TOCILIZUMAB FOR THE TREATMENT OF GIANT CELL ARTERITIS: EFFICACY, SAFETY, AND EXPOSURE-EFFICACY ANALYSIS FROM GIACTA - Stone, J. H.; Tuckwell, K.; Dimonaco, S.; Klearman, M.; Mallalieu, N. L.; Aringer, M.; Blockmans, D.; Brouwer, E.; Cid, M. C.; Dasgupta, B.; Rech, Jürgen; Salvarani, C.; et al. (2017)
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Origin and function of synovial macrophage subsets during inflammatory joint disease - Culemann, Stephan; Grüneboom, Anika; Krönke, Gerhard (Advances in Immunology, 2019)
Mononuclear phagocytes, including monocytes and macrophages, are a central component of the host's innate immune system designated to protect against invading pathogens. However, these cells do not only interact with various parts of the innate and adaptive immune system, but also fulfill indispensable duties during the control of tissue homeostasis and organ function. Moreover, macrophages are crucially involved in tissue remodeling and repair in response to damage. Simultaneously, mononuclear phagocytes might also contribute to the pathogenesis of various inflammatory and autoimmune diseases. In particular, their potential role in inflammatory joint diseases such as rheumatoid arthritis (RA) has drawn increasing attention and substantially shaped our general understanding of the role of monocytes and macrophages during health and disease. This review summarizes our current knowledge about the origin and function of mononuclear phagocytes within the joint and addresses their involvement in joint inflammation.
CRIS-Team Scopus Importer:2019-09-17
Keywords: Inflammation; Macrophages; Monocytes; Rheumatoid arthritis; Synovial macrophages; Synovial tissue; Tissue resident macrophages

Orphan nuclear receptor NR4A1 regulates transforming growth factor-? signaling and fibrosis - Palumbo-Zerr, Katrin; Zerr, Pawel; Distler, Alfiya; Fliehr, Judith; Mancuso, Rossella; Huang, Jingang; Mielenz, Dirk; Tomcik, Michal; Fuernrohr, Barbara G.; Scholtysek, Carina; Dees, Clara; Beyer, Christian; et al. (Nature Medicine, 2015)
Mesenchymal responses are an essential aspect of tissue repair. Failure to terminate this repair process correctly, however, results in fibrosis and organ dysfunction. Therapies that block fibrosis and restore tissue homeostasis are not yet available for clinical use. Here we characterize the nuclear receptor NR4A1 as an endogenous inhibitor of transforming growth factor-? (TGF-?) signaling and as a potential target for anti-fibrotic therapies. NR4A1 recruits a repressor complex comprising SP1, SIN3A, CoREST, LSD1, and HDAC1 to TGF-? target genes, thereby limiting pro-fibrotic TGF-? effects. Even though temporary upregulation of TGF-? in physiologic wound healing induces NR4A1 expression and thereby creates a negative feedback loop, the persistent activation of TGF-? signaling in fibrotic diseases uses AKT- and HDAC-dependent mechanisms to inhibit NR4A1 expression and activation. Small-molecule NR4A1 agonists can overcome this lack of active NR4A1 and inhibit experimentally-induced skin, lung, liver, and kidney fibrosis in mice. Our data demonstrate a regulatory role of NR4A1 in TGF-? signaling and fibrosis, providing the first proof of concept for targeting NR4A1 in fibrotic diseases.
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Orphan Nuclear Receptor Ror alpha Is a Key Regulator of Tgf beta- and WNT-Signaling in Fibrotic Diseases - Kagwiria, Rosebeth; Liang, Ruifang; Matei, Alexandru-Emil; Sihler, Niclas; Chen, Chih-Wei; Burris, Thomas; Distler, Oliver; Schett, Georg; Distler, Jörg (2018)
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Osteitis and synovitis, but not bone erosion, is associated with proteoglycan loss and microstructure damage in the cartilage of patients with rheumatoid arthritis - Herz, Barbara; Albrecht, Andreas; Englbrecht, Matthias; Welsch, Götz; Uder, Michael; Renner, Nina; Schlechtweg, Philipp; Paul, Dominik; Lauer, Lars; Engelke, Klaus; Janka, Rolf Matthias; Rech, Jürgen; et al. (Annals of the Rheumatic Diseases, 2014)
To investigate the relation between anatomic changes of the synovium, the bone, the bone marrow and the cartilage to biochemical properties of the cartilage in patients with rheumatoid arthritis (RA).33 patients with RA received 3-T MRI scans of the metacarpophalangeal joints. Two independent methods, (A) the delayed gadolinium enhanced MRI of the cartilage (dGEMRIC, T2-mapping), which was used to assess the biochemical properties of the cartilage; (B) synovitis, osteitis and bone erosions were quantified according to the RA MRI scoring (RAMRIS) method and cartilage thickness (CT), interbone joint space (IBJS, distance between proximal and distal bone surface) and intercartilage joint space (ICJS, distance between proximal and distal cartilage surface) were measured.Biochemical changes of the cartilage, corresponding to low dGEMRIC and high T2 values, were more likely to be seen in joints with decreased IBJS and ICJS as well as decreased CT. For instance, dGEMRIC was directly correlated to the IBJS (p=0.001) and ICJS (p=0.001), whereas T2 mapping was inversely correlated to IBJS and ICJS (both p=0.017). Moreover, the degree of osteitis, and to some extent synovitis, was correlated to biochemical cartilage changes as measured by dGEMRIC (p=0.003) or the T2 mapping (p=0.013). By contrast, bone erosions did not correlate to the degree of biochemical cartilage changes.These data support the concept that synovitis and osteitis may be two main triggers for cartilage damage. Thus, the actual inflammatory state of a joint, but not so much the degree of bone erosion, appears to influence cartilage properties in RA.
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Osteoarthritis research priorities: a report from a EULAR ad hoc expert committee - Conaghan, Philip G.; Kloppenburg, Margreet; Schett, Georg; Bijlsma, Johannes W. J. (Annals of the Rheumatic Diseases, 2014)
Osteoarthritis (OA) currently affects over 40 million Europeans, with its associated personal suffering and significant economic burden for health systems set to dramatically escalate in a rapidly ageing Europe. Given the very limited effective therapeutic options for OA, the European League Against Rheumatism (EULAR) created an ad hoc committee of OA researchers, clinicians and patients to consider a research agenda focussed on the areas of epidemiology, pathogenesis, imaging and biomarkers, and therapies. The committee deliberated and listed research needs in these areas and also established some cross-area priority themes: predictors of OA progression, especially where this might enable stratified interventions; understanding mechanisms of OA pain; improved understanding of tissue communication in a process where multiple tissue pathologies are common; developing concepts of, and consequently interventions for, early OA where both pain and structural processes may be more effectively targeted than in typical clinical presentations; and the need for new treatment strategies, with examples discussed on pathology-targeted therapies and optimal combinations of therapies. This research agenda should provide useful guidance for all researchers in this field and hopefully lead to improved OA care.
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Osteocyte necrosis triggers osteoclast-mediated bone loss through macrophage-inducible C-type lectin - Andreev, Darja; Liu, Mengdan; Weidner, Daniela; Kachler, Katerina; Faas, Maria; Grüneboom, Anika; Schlötzer-Schrehardt, Ursula; Munoz, Luis Enrique; Steffen, Ulrike; Grötsch, Bettina; Killy, Barbara; Krönke, Gerhard; et al. (Journal of Clinical Investigation, 2020)
Although the control of bone-resorbing osteoclasts through osteocyte-derived RANKL is well defined, little is known about the regulation of osteoclasts by osteocyte death. Indeed, several skeletal diseases, such as bone fracture, osteonecrosis, and inflammation are characterized by excessive osteocyte death. Herein we show that osteoclasts sense damageassociated molecular patterns (DAMPs) released by necrotic osteocytes via macrophage-inducible C-type lectin (Mincle), which induced their differentiation and triggered bone loss. Osteoclasts showed robust Mincle expression upon exposure to necrotic osteocytes in vitro and in vivo. RNA sequencing and metabolic analyses demonstrated that Mincle activation triggers osteoclastogenesis via ITAM-based calcium signaling pathways, skewing osteoclast metabolism toward oxidative phosphorylation. Deletion of Mincle in vivo effectively blocked the activation of osteoclasts after induction of osteocyte death, improved fracture repair, and attenuated inflammation-mediated bone loss. Furthermore, in patients with osteonecrosis, Mincle was highly expressed at skeletal sites of osteocyte death and correlated with strong osteoclastic activity. Taken together, these data point to what we believe is a novel DAMP-mediated process that allows osteoclast activation and bone loss in the context of osteocyte death.
CRIS-Team Scopus Importer:2020-10-16

Osteoimmunology - Schett, Georg (Zeitschrift für Rheumatologie, 2016)
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Osteoimmunology-IMMUNOBONE : Regulation of bone by inflammation - Rauner, M.; Buttgereit, F.; Distler, Jörg; Garbe, A. I.; Herrmann, Martin; Hofbauer, Lorenz; Hoffmann, M.; Jessberger, R.; Kornak, U.; Krönke, Gerhard; Mundlos, S.; Spies, C.; et al. (Zeitschrift für Rheumatologie, 2018)
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Osteoporosis - Lange, Uwe; Schett, Georg (Zeitschrift für Rheumatologie, 2016)
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Osteoprotective action of low-salt diet requires myeloid cell-derived NFAT5 - Schroeder, Agnes; Neubert, Patrick; Titze, Jens; Bozec, Aline; Neuhofer, Wolfgang; Proff, Peter; Kirschneck, Christian; Jantsch, Jonathan (JCI Insight, 2019)
Dietary salt consumption leads to cutaneous Na+ storage and is associated with various disorders, including osteopenia. Here, we explore the impact of Na+ and the osmoprotective transcription factor nuclear factor of activated T cell 5 (NFAT5) on bone density and osteoclastogenesis. Compared with treatment of mice with high-salt diet, low-salt diet (LSD) increased bone density, decreased osteoclast numbers, and elevated Na+ content and Nfat5 levels in the BM. This response to LSD was dependent on NFAT5 expressed in myeloid cells. Simulating in vivo findings, we exposed osteoclast precursors and osteoblasts to elevated Na+ content (high-salt conditions; HS), resulting in increased NFAT5 binding to the promotor region of RANKL decoy receptor osteoprotegerin (OPG). These data not only demonstrate that NFAT5 in myeloid cells determines the Na+ content in BM, but that NFAT5 is able to govern the expression of the osteoprotective gene OPG. This provides insights into mechanisms of Na+-induced cessation of osteoclastogenesis and offers potentially new targets for treating salt-induced osteopenia.
CRIS-Team Scopus Importer:2020-02-21

Osteoprotegerin and Cardiovascular Events in High-Risk Populations: Meta-Analysis of 19 Prospective Studies Involving 27 450 Participants - Tschiderer, Lena; Klingenschmid, Gerhard; Nagrani, Rajini; Willeit, Johann; Laukkanen, Jari A.; Schett, Georg; Kiech, Stefan; Willeit, Peter (Journal of the American Heart Association, 2018)
Background Osteoprotegerin is a cytokine involved in bone metabolism as well as vascular calcification and atherogenesis. Although circulating osteoprotegerin levels are robustly associated with incident cardiovascular disease ( CVD ) in the general population, its relevance as a biomarker among populations at high CVD risk is less clear. Methods and Results Three independent reviewers systematically searched PubMed, EMBASE , and Web of Science to identify prospective studies that had recruited participants on the basis of having conditions related to high CVD risk. A total of 19 studies were eligible for inclusion, reporting on 27 450 patients with diabetes mellitus (2 studies), kidney disease (7 studies), preexisting heart disease (5 studies), or recent acute coronary syndromes (5 studies) at baseline. Over a mean follow-up of 4.2 years, 4066 CVD events were recorded. In a random-effects meta-analysis, the pooled risk ratio for CVD events comparing people in the top versus the bottom tertile of osteoprotegerin concentration was 1.30 (95% confidence interval, 1.12-1.50; P<0.001; I2=68.3%). There was evidence for presence of publication bias ( P value from Egger's test=0.013). Correction for publication bias using the trim-and-fill method reduced the risk ratio to 1.21 (95% confidence interval, 1.03-1.42; P<0.001). The risk ratios did not vary significantly by population type, geographical region, statistical adjustment, sample or assay type, age, sex, or length of follow-up. Conclusions In populations at high CVD risk, elevated circulating osteoprotegerin levels are associated with a higher risk for future CVD events. The magnitude of association appears weaker than in the general population.
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Osteoprotegerin concentration and risk of cardiovascular outcomes in nine general population studies: Literature-based meta-analysis involving 26,442 participants - Tschiderer, Lena; Willeit, Johann; Schett, Georg; Kiechl, Stefan; Willeit, Peter (PLoS ONE, 2017)
Recent experimental and epidemiological studies have suggested that osteoprotegerin, a key regulator in bone metabolism, may be involved in vascular calcification and atherosclerosis. Our aim was to reliably quantify the associations of osteoprotegerin concentration and incidence of first-ever cardiovascular disease outcomes in the general population.Using the electronic databases MEDLINE, EMBASE and Web of Science (January 1975 and April 2017, no language restrictions), nine relevant studies were identified involving a total of 26,442 participants recruited from the general population. Over a mean follow-up of 8.5 years, 2,160 cardiovascular disease, 2,123 coronary heart disease, and 1,102 stroke outcomes were recorded. Study-specific risk ratios were combined with random-effects meta-analysis.When comparing individuals in the top with those in the bottom third of osteoprotegerin concentration, the combined risk ratio was 1.83 (95% confidence interval: 1.46, 2.30; P<0.001; I2 = 76.8%) for cardiovascular disease, 1.72 for coronary heart disease (1.26, 2.37; P = 0.001; I2 = 83.5%), and 1.58 for stroke (1.18, 2.12; P = 0.002; I2 = 65.2%). Associations appeared stronger at younger age (P = 0.018 for cardiovascular disease), in studies that did not employ statistical adjustment (P = 0.023 for cardiovascular disease and 0.018 for coronary heart disease), and potentially in studies that measured osteoprotegerin in plasma rather than in serum (P = 0.005 for cardiovascular disease and 0.018 for coronary heart disease). Magnitudes of associations did not differ according to the proportion of males, geographical region, or osteoprotegerin assay manufacturer. There was no evidence for publication bias for any of the outcomes assessed (all P>0.05).Elevated osteoprotegerin concentration is associated with an increased risk of incident cardiovascular disease in the general population. The mechanisms underlying this observation deserve further investigation.
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OsteoRheumatology: a new discipline? - Favero, Marta; Giusti, Andrea; Geusens, Piet; Goldring, Steven R.; Lems, Willem; Schett, Georg; Bianchi, Gerolamo (RMD Open, 2015)
This review summarises recent evidence about the interaction between bone, the immune system and cartilage in disabling conditions such as osteoarthritis, rheumatoid arthritis and spondyloarthritis. These topics have been recently discussed at the 'OsteoRheumatology' conference held in Genoa in October 2014. The meeting, at its 10th edition, has been conceived to bring together distinguished international experts in the fields of rheumatic and metabolic bone diseases with the aim of discussing emerging knowledge regarding the role of the bone tissue in rheumatic diseases. Moreover, this review focuses on new treatments based on underlying the pathophysiological processes in rheumatic diseases. Although, a number of issues still remain to be clarified, it seems quite clear that in clinical practice, as well as in basic and translational research, there is a need for more knowledge of the interactions between the cartilage, the immune system and the bone. In this context, 'OsteoRheumatology' represents a potential new discipline providing a greater insight into this interplay, in order to face the multifactorial and complex issues underlying common and disabling rheumatic diseases.
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Outcomes of patients with systemic sclerosis treated with rituximab in contemporary practice: A prospective cohort study - Elhai, Muriel; Boubaya, Marouane; Distler, Oliver; Smith, Vanessa; Matucci-Cerinic, Marco; Alegre Sancho, Juan José; Truchetet, Marie Elise; Braun-Moscovici, Yolanda; Iannone, Florenzo; Novikov, Pavel I.; Lescoat, Alain; Siegert, Elise; et al. (Annals of the Rheumatic Diseases, 2019)
Objective: To assess the safety and efficacy of rituximab in systemic sclerosis (SSc) in clinical practice. Methods: We performed a prospective study including patients with SSc from the European Scleroderma Trials and Research (EUSTAR) network treated with rituximab and matched with untreated patients with SSc. The main outcomes measures were adverse events, skin fibrosis improvement, lung fibrosis worsening and steroids use among propensity score-matched patients treated or not with rituximab. Results: 254 patients were treated with rituximab, in 58% for lung and in 32% for skin involvement. After a median follow-up of 2 years, about 70% of the patients had no side effect. Comparison of treated patients with 9575 propensity-score matched patients showed that patients treated with rituximab were more likely to have skin fibrosis improvement (22.7 vs 14.03 events per 100 person-years; OR: 2.79 [1.47-5.32]; p=0.002). Treated patients did not have significantly different rates of decrease in forced vital capacity (FVC)>10% (OR: 1.03 [0.55-1.94]; p=0.93) nor in carbon monoxide diffusing capacity (DLCO) decrease. Patients having received rituximab were more prone to stop or decrease steroids (OR: 2.34 [1.56-3.53], p<0.0001). Patients treated concomitantly with mycophenolate mofetil had a trend for better outcomes as compared with patients receiving rituximab alone (delta FVC: 5.22 [0.83-9.62]; p=0.019 as compared with controls vs 3 [0.66-5.35]; p=0.012). Conclusion: Rituximab use was associated with a good safety profile in this large SSc-cohort. Significant change was observed on skin fibrosis, but not on lung. However, the limitation is the observational design. The potential stabilisation of lung fibrosis by rituximab has to be addressed by a randomised trial.
CRIS-Team Scopus Importer:2019-05-02
Keywords: lung fibrosis; rituximab; skin fibrosis; systemic sclerosis

Overexpression of transmembrane TNF drives development of ectopic lymphoid structures in the bone marrow and B cell lineage alterations in experimental spondyloarthritis - Kaaij, Merlijn H.; Rip, Jasper; Jeucken, Kim C.M.; Kan, Yik Y.; van Rooijen, Charlotte C.N.; Saris, Job; Pots, Desiree; Frey, Silke; Grootjans, Joep; Schett, Georg; van Duivenvoorde, Leonie M.; Nolte, Martijn A.; et al. (Journal of Immunology, 2021)
TNF is important in immune-mediated inflammatory diseases, including spondyloarthritis (SpA). Transgenic (tg) mice overexpressing transmembrane TNF (tmTNF) develop features resembling human SpA. Furthermore, both tmTNF tg mice and SpA patients develop ectopic lymphoid aggregates, but it is unclear whether these contribute to pathology. Therefore, we characterized the lymphoid aggregates in detail and studied potential alterations in the B and T cell lineage in tmTNF tg mice. Lymphoid aggregates developed in bone marrow (BM) of vertebrae and near the ankle joints prior to the first SpA features and displayed characteristics of ectopic lymphoid structures (ELS) including presence of B cells, T cells, germinal centers, and high endothelial venules. Detailed flow cytometric analyses demonstrated more germinal center B cells with increased CD80 and CD86 expression, along with significantly more T follicular helper, T follicular regulatory, and T regulatory cells in tmTNF tg BM compared with non-tg controls. Furthermore, tmTNF tg mice exhibited increased IgA serum levels and significantly more IgA+ plasma cells in the BM, whereas IgA+ plasma cells in the gut were not significantly increased. In tmTNF tg 3 TNF-RI2/2 mice, ELS were absent, consistent with reduced disease symptoms, whereas in tmTNF tg 3 TNF-RII2/2 mice, ELS and clinical symptoms were still present. Collectively, these data show that tmTNF overexpression in mice results in osteitis and ELS formation in BM, which may account for the increased serum IgA levels that are also observed in human SpA. These effects are mainly dependent on TNF-RI signaling and may underlie important aspects of SpA pathology.
CRIS-Team Scopus Importer:2021-11-12

Oxidative Burst-Dependent NETosis Is Implicated in the Resolution of Necrosis-Associated Sterile Inflammation - Biermann, Mona H. C.; Podolska, Malgorzata; Knopf, Jasmin; Reinwald, Christiane; Weidner, Daniela; Maueröder, Christian; Hahn, Jonas; Kienhoefer, Deborah; Barras, Alexandre; Boukherroub, Rabah; Szunerits, Sabine; Bilyy, Rostyslav; et al. (Frontiers in Immunology, 2016)
Necrosis is associated with a profound inflammatory response. The regulation of necrosis-associated inflammation, particularly the mechanisms responsible for resolution of inflammation is incompletely characterized. Nanoparticles are known to induce plasma membrane damage and necrosis followed by sterile inflammation. We observed that injection of metabolically inert nanodiamonds resulted in paw edema in WT and Ncf1** mice. However, while inflammation quickly resolved in WT mice, it persisted over several weeks in Ncf1** mice indicating failure of resolution of inflammation. Mechanistically, NOX2-dependent reactive oxygen species (ROS) production and formation of neutrophil extracellular traps were essential for the resolution of necrosis-induced inflammation: hence, by evaluating the fate of the particles at the site of inflammation, we observed that Ncf1** mice deficient in NADPH-dependent ROS failed to generate granulation tissue therefore being unable to trap the nanodiamonds. These data suggest that NOX2-dependent NETosis is crucial for preventing the chronification of the inflammatory response to tissue necrosis by forming NETosis-dependent barriers between the necrotic and healthy surrounding tissue.
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Palmar fasciitis and polyarthritis syndrome-Systematic literature review of 100 cases - Manger, Bernhard; Schett, Georg (Seminars in Arthritis and Rheumatism, 2014)
To analyse clinical, laboratory, and imaging characteristics of all patients with palmar fasciitis and polyarthritis syndrome (PFPAS) described in the literature.Comparison of the clinical presentation of one patient with acute onset of PFAPS with 99 other published cases identified through a PubMed literature research.Since the original description in 1982 by Medsger et al., there have been numerous case reports and small case series in the literature. In total, 73 articles in English, French and Spanish language were included in the analysis. PFPAS is a rare but characteristic paraneoplastic syndrome in rheumatology. Its distinct clinical feature is a painful swelling of both the hands caused by an inflammation of the palmar fascia, tendon sheaths and small joints of fingers and wrist, and flexion contractures develop rapidly. Since the subcutaneous tissues become indurated and hard, the illustrative term "woody hands" was coined. The most frequent underlying malignancy is ovarian cancer but adenocarcinomas of the breast, gastrointestinal tract and other organs can also cause this syndrome. A helpful diagnostic procedure in order to identify the nature of the underlying malignancy in many cases has been the determination of various serum tumour markers. In cases when a complete removal of the malignancy is possible, PFPAS can also undergo complete remission.Knowledge of the distinct features of this rare paraneoplastic syndrome facilitates early diagnosis and potentially life-saving therapeutic interventions.
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Pancreatic Panniculitis and Polyarthritis - Zundler, Sebastian; Strobel, Deike; Manger, Bernhard; Neurath, Markus; Wildner, Dane (Current Rheumatology Reports, 2017)
Polyarthritis can have numerous reasons and may thus constitute a challenge for differential diagnosis. One rare potential reason for sterile polyarthritis is underlying pancreatic disease with systemic hyperlipasemia, most often accompanied by painful skin lesions caused by a subcutaneous inflammatory process known as panniculitis. Systematic evidence on pancreatic panniculitis and polyarthritis is limited, particularly regarding its feature as facultative paraneoplasia with underlying intra- or even extra-pancreatic malignancy. Therefore, we will summarize the current knowledge about this orphan disease including epidemiological, pathophysiological, diagnostic, and treatment aspects in the present review.Although direct evidence is lacking, it is highly probable that pancreatic polyarthritis and panniculitis are caused by peripheral lipolytic activity of lipase systemically circulating due to benign (e.g., acute or chronic pancreatitis) or malign (e.g., acinar cell carcinoma (ACC) or adenocarcinoma) pancreatic disease. In the latter case, pancreatic polyarthritis and panniculitis are associated with poor outcome. Pancreatic polyarthritis and panniculitis should always be included into diagnostic considerations, and once suspected, a thorough work-up to identify the underlying disease has to be performed.
EVALuna2:13446

Paraneoplastic syndromes in rheumatology - Manger, Bernhard; Schett, Georg (Nature Reviews Rheumatology, 2014)
For patients that present with musculoskeletal symptoms, diagnostic procedures carried out by physicians and rheumatologists are primarily aimed at confirming or excluding the occurrence of primary rheumatic diseases. Another important trigger for musculoskeletal disease, however, is the presence of a tumour. Careful clinical investigation and knowledge of the gestalt of musculoskeletal syndromes related to respective tumour entities is of utmost importance for the diagnosis of paraneoplastic rheumatic diseases such as hypertrophic osteoarthropathy, paraneoplastic polyarthritis, RS3PE syndrome, palmar fasciitis and polyarthritis, cancer-associated myositis and tumour-induced osteomalacia. This places great responsibility on rheumatologists in diagnosing malignancies and referring the patient for effective treatment. The selective influence of tumours on musculoskeletal tissue is surprising and indicates that tumours alter tissues such as the periosteum, synovial membrane, subcutaneous connective tissue, fascia, muscles and bones by specific molecular processes. Some of the underlying mechanisms have been unravelled, providing valuable information on the physiologic and pathophysiologic roles of mediators such as vascular endothelial growth factor and fibroblast growth factor 23.
EVALuna2:12990

Pasteurella multocida toxin- induced osteoclastogenesis requires mTOR activation - Kloos, Bianca; Chakraborty, Sushmita; Lindner, Sonja G.; Noack, Katrin; Harre, Ulrike; Schett, Georg; Kraemer, Oliver H.; Kubatzky, Katharina F. (Cell Communication and Signaling, 2015)
Background: Pasteurella multocida toxin (PMT) is a potent inducer of osteoclast formation. Pigs suffering from an infection with toxigenic Pasteurella multocida strains develop atrophic rhinitis characterised by a loss of turbinate bones and conchae. However, on the molecular level the process of bone loss remains largely uncharacterised. Results: Recently it was found that PMT activates the serine/threonine kinase mammalian target of rapamycin (mTOR) in fibroblasts. Using RAW264.7 macrophages, we investigated the role of the mTOR complex 1 (mTORC1) in PMT-mediated osteoclast formation. PMT induces the differentiation of RAW264.7 macrophages into multinucleated, tartrate resistant acid phosphatase (TRAP) positive osteoclasts that are capable to resorb bone. In the presence of the mTORC1 inhibitor rapamycin, PMT was significantly less able to induce the formation of TRAP-positive osteoclasts. Accordingly, the resulting resorption of bone was strongly reduced. A major target of mTOR is the 70 kDa ribosomal protein S6 kinase 1 (p70 S6K1). Activated p70 S6K1 decreases the expression of programmed cell death protein 4 (PDCD4), a negative transcriptional regulator of osteoclastogenesis, at the protein and gene level. Ultimately this results in the activation of c-Jun, a component of the activator protein 1 (AP-1) complex, which is a major transcription factor for the induction of osteoclast-specific genes. We now demonstrate that c-Jun and its downstream target, the osteoclast-specific bone degrading protease cathepsin K, are upregulated upon PMT treatment in an mTOR-dependent manner. Conclusions: Activation of mTOR signalling plays a central role in the formation of osteoclasts through the bacterial toxin PMT. On the molecular level, PMT-induced activation of mTOR leads to down regulation of PDCD4, a known repressor of AP-1 complex, culminating in the activation of c-Jun, an essential transcription factor for triggering osteoclastogenesis.

Pasteurella multocida Toxin Triggers RANKL-Independent Osteoclastogenesis - Chakraborty, Sushmita; Kloos, Bianca; Harre, Ulrike; Schett, Georg; Kubatzky, Katharina F. (Frontiers in Immunology, 2017)
Bone remodeling is a continuous process to retain the structural integrity and function of the skeleton. A tight coupling is maintained between osteoclast-mediated resorption of old or damaged bones and osteoblast-mediated formation of new bones for bone homeostasis. While osteoblasts differentiate from mesenchymal stem cells, osteoclasts are hematopoietic in origin and derived from myeloid precursor cells. Osteoclast differentiation is driven by two cytokines, cytokine receptor activator of NF-?B ligand (RANKL), and macrophage colony-stimulating factor. Imbalances in the activity of osteoblasts and osteoclasts result in the development of bone disorders. Bacterially caused porcine atrophic rhinitis is characterized by a loss of nasal ventral conche bones and a distortion of the snout. While Bordetella bronchiseptica strains cause mild and reversible symptoms, infection of pigs with toxigenic Pasteurella multocida strains causes a severe and irreversible decay. The responsible virulence factor Pasteurella multocida toxin (PMT) contains a deamidase activity in its catalytical domain that constitutively activates specific heterotrimeric G proteins to induce downstream signaling cascades. While osteoblasts are inhibited by the toxin, osteoclasts are activated, thus skewing bone remodeling toward excessive bone degradation. Still, the mechanism by which PMT interferes with bone homeostasis, and the reason for this unusual target tissue is not yet well understood. Here, we show that PMT has the potential to differentiate bone marrow-derived macrophages into functional osteoclasts. This toxin-mediated differentiation process is independent of RANKL, a cytokine believed to be indispensable for triggering osteoclastogenesis, as addition of osteoprotegerin to PMT-treated macrophages does not show any effect on PMT-induced osteoclast formation. Although RANKL is not a prerequisite, toxin-primed macrophages show enhanced responsiveness to low concentrations of RANKL, suggesting that the PMT-generated microenvironment offers conditions where low concentrations of RANKL lead to an increase in the number of osteoclasts resulting in increased resorption. PMT-mediated release of the osteoclastogenic cytokines such as IL-6 and TNF-?, but not IL-1, supports the differentiation process. Although the production of cytokines and the subsequent activation of signaling cascades are necessary for PMT-mediated differentiation into osteoclasts, they are not sufficient and PMT-induced activation of G protein signaling is essential for efficient osteoclastogenesi
EVALuna2:13413

Pathogenetic insights from the treatment of rheumatoid arthritis - McInnes, Iain B.; Schett, Georg (Lancet, 2017)
Rheumatoid arthritis is a chronic autoimmune disease that causes progressive articular damage, functional loss, and comorbidity. The development of effective biologics and small-molecule kinase inhibitors in the past two decades has substantially improved clinical outcomes. Just as understanding of pathogenesis has led in large part to the development of drugs, so have mode-of-action studies of these specific immune-targeted agents revealed which immune pathways drive articular inflammation and related comorbidities. Cytokine inhibitors have definitively proven a critical role for tumour necrosis factor ? and interleukin 6 in disease pathogenesis and possibly also for granulocyte-macrophage colony-stimulating factor. More recently, clinical trials with Janus kinase (JAK) inhibitors have shown that cytokine receptors that signal through the JAK/STAT signalling pathway are important for disease, informing the pathogenetic function of additional cytokines (such as the interferons). Finally, successful use of costimulatory blockade and B-cell depletion in the clinic has revealed that the adaptive immune response and the downstream events initiated by these cells participate directly in synovial inflammation. Taken together, it becomes apparent that understanding the effects of specific immune interventions can elucidate definitive molecular or cellular nodes that are essential to maintain complex inflammatory networks that subserve diseases like rheumatoid arthritis.
EVALuna2:13424

Patient-individual tapering of DMARDs in rheumatoid arthritis patients in a real-world setting - Birkner, Benjamin; Rech, Jürgen; Edelmann, Edmund; Verheyen, Frank; Schett, Georg; Stargardt, Tom (Rheumatology, 2022)
Objective We aim to provide real-world evidence on the effectiveness of patient-individual tapering of DMARDs for patients with RA in daily clinical practice using medical records and claims data. Methods We utilize data obtained through a controlled prospective cohort study in Germany conducted from July 2018 to March 2021. Participants consist of RA patients in sustained remission (>6 months) who were eligible for tapering at enrolment. Patients treated with individual tapering based on shared decision making (n = 200) are compared with patients without any dose reduction (n = 237). The risk of loss of remission and the risk of flare is assessed with risk-adjusted Kaplan-Meier estimators and Cox regressions. We evaluate differences in costs 1 year before and after baseline based on claims data for the subgroup of patients insured at one major sickness fund in Germany (n = 76). Results The risk of flare (hazard ratio 0.88, 95% CI 0.59, 1.30) or loss of remission (hazard ratio 1.04, 95% CI 0.73, 1.49) was not statistically different between the individual tapering group and the continuation group. Minor increases of disease activity and decreases of quality of life were observed 12 months after baseline, again with no statistically significant difference. Drug costs decreased by 1017euro in the individual tapering group while they increased by 1151euro in the continuation group (P < 0.01). Conclusion Individual tapering of DMARDs does not increase the average risk of experiencing flares or loss of remission. Encouraging rheumatologists and patients to apply tapering in shared decision making may be a feasible approach to allow individualization of treatment in RA.
CRIS-Team WoS Importer:2022-09-16

Patient preferences for the treatment of systemic sclerosis-associated interstitial lung disease: a discrete choice experiment - Bruni, Cosimo; Heidenreich, Sebastian; Duenas, Ashley; Hoffmann-Vold, Anna-Maria; Gabrielli, Armando; Allanore, Yannick; Chatelus, Emmanuel; Distler, Jörg; Hachulla, Eric; Hsu, Vivien M.; Hunzelmann, Nicolas; Khanna, Dinesh; et al. (Rheumatology, 2022)
Objectives Treatments for SSc-associated interstitial lung disease (SSc-ILD) differ in attributes, i.e. mode of administration, adverse events (AEs) and efficacy. As physicians and patients may perceive treatments differently, shared decision-making can be essential for optimal treatment provision. We therefore aimed to quantify patient preferences for different treatment attributes. Methods Seven SSc-ILD attributes were identified from mixed-methods research and clinician input: mode of administration, shortness of breath, skin tightness, cough, tiredness, risk of gastrointestinal AEs (GI-AEs) and risk of serious and non-serious infections. Patients with SSc-ILD completed an online discrete choice experiment (DCE) in which they were asked to repeatedly choose between two alternatives characterized by varying severity levels of the included attributes. The data were analysed using a multinomial logit model; relative attribute importance and maximum acceptable risk measures were calculated. Results Overall, 231 patients with SSc-ILD completed the DCE. Patients preferred twice-daily oral treatments and 6-12 monthly infusions. Patients' choices were mostly influenced by the risk of GI-AEs or infections. Improvement was more important in respiratory symptoms than in skin tightness. Concerning trade-offs, patients accepted different levels of increase in GI-AE risk: +21% if it reduced the infusions' frequency; +15% if changing to an oral treatment; up to +37% if it improved breathlessness; and up to +36% if it reduced the risk of infections. Conclusions This is the first study to quantitatively elicit patients' preferences for treatment attributes in SSc-ILD. Patients showed willingness to make trade-offs, providing a firm basis for shared decision-making in clinical practice.
CRIS-Team WoS Importer:2022-04-08

Patient Preferences in the Medical Product Life Cycle: What do Stakeholders Think? Semi-Structured Qualitative Interviews in Europe and the USA - Janssens, Rosanne; Russo, Selena; van Overbeeke, Eline; Whichello, Chiara; Harding, Sarah; Kübler, Jürgen; Juhaeri, Juhaeri; Bywall, Karin Schölin; Comanescu, Alina; Hueber, Axel; Englbrecht, Matthias; Nikolenko, Nikoletta; et al. (Patient, 2019)
Background: Patient preferences (PP), which are investigated in PP studies using qualitative or quantitative methods, are a growing area of interest to the following stakeholders involved in the medical product lifecycle: academics, health technology assessment bodies, payers, industry, patients, physicians, and regulators. However, the use of PP in decisions along the medical product lifecycle remains limited. As the adoption of PP heavily relies on these stakeholders, knowledge of their perceptions of PP is critical. Objective: This study aimed to characterize stakeholders’ attitudes, needs, and concerns with respect to PP in decision making along the medical product lifecycle. Methods: Semi-structured interviews (n = 143) were conducted with academics (n = 24), health technology assessment/payer representatives (n = 24), industry representatives (n = 24), patients, caregivers and patient representatives (n = 24), physicians (n = 24), and regulators (n = 23) from seven European countries and the USA. Interviews were conducted between April and August 2017. The framework method was used to organize the data and identify themes and key findings in each interviewed stakeholder group. Results: Interviewees reported being unfamiliar (43%), moderately familiar (42%), or very familiar (15%) with preference methods and studies. Interviewees across stakeholder groups generally supported the idea of using PP in the medical product lifecycle but expressed mixed opinions about the feasibility and impact of using PP in decision making. Interviewees from all stakeholder groups stressed the importance of increasing stakeholders’ understanding of the concept of PP and preference methods and ensuring patients’ understanding of the questions asked in PP studies. Key concerns and needs in each interviewed stakeholder group were as follows: (1) academics: investigating the validity, reliability, reproducibility, and generalizability of preference methods; (2) health technology assessment/payer representatives: developing quality criteria for evaluating PP studies and gaining insights into how to weigh them in reimbursement/payer decision making; (3) industry representatives: obtaining guidance on PP studies and recognition on the importance of PP from decision makers; (4) patients, caregivers, and patient representatives: providing an incentive and adequate information towards patients when participating in PP studies; (5) physicians: avoiding bias as a result of commercial agendas in PP studies and clarifying how to deal with subjective and emotional elements when measuring PP; and (6) regulators: avoiding the misuse of PP study results to overrule the traditional efficacy and safety criteria used for marketing authorization and obtaining robust PP study results. Conclusions: Despite the interest all interviewed stakeholder groups reported in PP, the effective use of PP in decision making across the medical product lifecycle is currently hampered by a lack of standardization and consensus on how to both measure and use PP.
CRIS-Team Scopus Importer:2019-07-09

PATIENT PREFERENCES, TRADE-OFFS AND ACCEPTABLE RISKS IN THE TREATMENT OF SYSTEMIC SCLEROSIS-ASSOCIATED INTERSTITIAL LUNG DISEASE: A STEP TOWARDS SHARED DECISION-MAKING - Bruni, C.; Heidenreich, S.; Duenas, A.; Hoffmann-Vold, A. M.; Gabrielli, A.; Allanore, Y.; Chatelus, E.; Distler, Jörg; Hachulla, E.; Hsu, V.; Hunzelmann, N.; Khanna, D.; et al. (ANNALS OF THE RHEUMATIC DISEASES, 2021)
CRIS-Team WoS Importer:2021-09-24

PATIENTS AT RISK FOR RA SHOW THE SAME AMOUNT OF ACUTE SOLUBLE CARTILAGE DEGRADATION MARKERS AFTER PHYSICAL ACTIVITY COMPARED TO PATIENTS WITH ESTABLISHED RA - Bleckwedel-Rolack, Lisa Lena Kathrein; Tascilar, Koray; Nees, Veronika; Hühne, Julia; Hueber, A.; Rech, Jürgen; Schett, Georg; Kleyer, Arnd; Liphardt, Anna-Maria (ANNALS OF THE RHEUMATIC DISEASES, 2021)
CRIS-Team WoS Importer:2021-09-24

PATIENT SELF-SAMPLING IN RHEUMATOID ARTHRITIS: RESULTS FROM A RANDOMIZED CONTROLLED TRIAL - Knitza, Johannes; Tascilar, Koray; Vuillerme, N.; Vogt, E.; Matusewicz, P.; Corte, Giulia; Schuster, Louis; Aubourg, T.; Bendzuck, G.; Korinth, M.; Elling-Audersch, C.; Kleyer, Arnd; et al. (ANNALS OF THE RHEUMATIC DISEASES, 2022)
Background Rheumatoid arthritis (RA) requires early diagnosis and tight surveillance of disease activity. Patient self-sampling of blood for the analysis of autoantibodies and inflammation markers could facilitate the identification of patients at-risk for RA and improve tight disease monitoring [1]. Objectives A randomized, controlled trial to evaluate the feasibility, acceptability and accuracy of an upper arm self-sampling device (UA) and finger prick-test (FP) to measure capillary blood from RA patients for C-reactive protein (CRP) levels and the presence of IgM rheumatoid factor (RF IgM) and anti-cyclic citrullinated protein antibodies (anti-CCP IgG). Methods 50 RA patients were randomly assigned in a 1:1 ratio to self-collection of capillary blood via UA or FP. Venous blood sampling (VBS) was performed as gold standard in both groups to assess the concordance of CRP levels as well as RF IgM and CCP IgG. General acceptability and pain during sampling were measured and compared between UA, FP and VBS. The number of attempts for successful sampling, requests for assistance, volume and duration of sample collection were also assessed. Results 49/50 (98%) patients were able to successfully collect capillary blood. Overall agreement between capillary and venous analyses for CRP (0.992), CCP IgG (0.984) and RF IgM (0.994) were good. In both groups 4/25 (16%) needed a second attempt and 8/25 (32%) in the UA and 7/25 (28%) in the FP group requested assistance. Mean pain scores for capillary self-sampling (1.7/10 ± 1.1 (UA) and 1.9/10 ± 1.9 (FP)) were lower on a numeric rating scale compared to venous blood collection (UA: 2.8/10 ± 1.7; FP: 2.1 ± 2.0). UA patients were more likely to promote the use of capillary blood sampling (net promoter score: +28% vs. -20% for FP) and were more willing to perform blood collection at home (60%) vs. 32% for FP). Conclusion This study shows that self-sampling is accurate, feasible and well accepted among patients. The implementation could allow tight remote monitoring of disease activity as well as identifying patients at-risk for RA and potentially other rheumatic disease
CRIS-Team WoS Importer:2022-11-04

Patient's Perception of Digital Symptom Assessment Technologies in Rheumatology: Results From a Multicentre Study - Knitza, Johannes; Muehlensiepen, Felix; Ignatyev, Yuriy; Fuchs, Franziska; Mohn, Jacob; Simon, David; Kleyer, Arnd; Fagni, Filippo; Böltz, Sebastian; Morf, Harriet; Bergmann, Christina; Labinsky, Hannah; et al. (Frontiers in Public Health, 2022)
Introduction: An increasing number of digital tools, including dedicated diagnostic decision support systems (DDSS) exist to better assess new symptoms and understand when and where to seek medical care. The aim of this study was to evaluate patient's previous online assessment experiences and to compare the acceptability, usability, usefulness and potential impact of artificial intelligence (AI)-based symptom checker (Ada) and an online questionnaire-based self-referral tool (Rheport). Materials and Methods: Patients newly presenting to three German secondary rheumatology outpatient clinics were randomly assigned in a 1:1 ratio to complete consecutively Ada or Rheport in a prospective non-blinded multicentre controlled crossover randomized trial. DDSS completion time was recorded by local study personnel and perceptions on DDSS and previous online assessment were collected through a self-completed study questionnaire, including usability measured with the validated System Usability Scale (SUS). Results: 600 patients (median age 52 years, 418 women) were included. 277/600 (46.2%) of patients used an online search engine prior to the appointment. The median time patients spent assessing symptoms was 180, 7, and 8 min, respectively using online using search engines, Ada and Rheport. 111/275 (40.4%), 266/600 (44.3%) and 395/600 (65.8%) of patients rated the respective symptom assessment as very helpful or helpful, using online search engines, Ada and Rheport, respectively. Usability of both diagnostic decision support systems (DDSS) was “good” with a significantly higher mean SUS score (SD) of Rheport 77.1/100 (16.0) compared to Ada 74.4/100 (16.8), (p < 0.0001). In male patients, usability of Rheport was rated higher than Ada (p = 0.02) and the usability rating of older (52 years ≥) patients of both DDSS was lower than in younger participants (p = 0.005). Both effects were independent of each other. 440/600 (73.3%) and 475/600 (79.2%) of the patients would recommend Ada and Rheport to friends and other patients, respectively. Conclusion: In summary, patients increasingly assess their symptoms independently online, however only a minority used dedicated symptom assessment websites or DDSS. DDSS, such as Ada an Rheport are easy to use, well accepted among patients with musculoskeletal complaints and could replace online search engines for patient symptom assessment, potentially saving time and increasing helpfulness.
CRIS-Team Scopus Importer:2022-03-18
Keywords: artificial intelligence; diagnostic decision support system (DDSS); eHealth; mobile app; rheumatology; symptom assessment [MeSH]; telemedicine

Patients Receiving Cytokine Inhibitors Have Low Prevalence of SARS-CoV-2 Infection - Simon, David; Tascilar, Koray; Krönke, Gerhard; Kleyer, Arnd; Zaiss, Mario; Heppt, Franz; Meder, Christine; Atreya, Raja; Klenske, Entcho; Dietrich, Peter; Abdullah, Abdullah; Kliem, Thorsten; et al. (ARTHRITIS & RHEUMATOLOGY, 2020)
CRIS-Team WoS Importer:2021-01-15

Patients with COVID-19: in the dark-NETs of neutrophils - Ackermann, Maximilian; Anders, Hans-Joachim; Bilyy, Rostyslav; Bowlin, Gary L.; Daniel, Christoph; De Lorenzo, Rebecca; Egeblad, Mikala; Henneck, Timo; Hidalgo, Andres; Hoffmann, Markus; Hohberger, Bettina; Kanthi, Yogendra; et al. (Cell Death and Differentiation, 2021)
SARS-CoV-2 infection poses a major threat to the lungs and multiple other organs, occasionally causing death. Until effective vaccines are developed to curb the pandemic, it is paramount to define the mechanisms and develop protective therapies to prevent organ dysfunction in patients with COVID-19. Individuals that develop severe manifestations have signs of dysregulated innate and adaptive immune responses. Emerging evidence implicates neutrophils and the disbalance between neutrophil extracellular trap (NET) formation and degradation plays a central role in the pathophysiology of inflammation, coagulopathy, organ damage, and immunothrombosis that characterize severe cases of COVID-19. Here, we discuss the evidence supporting a role for NETs in COVID-19 manifestations and present putative mechanisms, by which NETs promote tissue injury and immunothrombosis. We present therapeutic strategies, which have been successful in the treatment of immunο-inflammatory disorders and which target dysregulated NET formation or degradation, as potential approaches that may benefit patients with severe COVID-19.
CRIS-Team Scopus Importer:2021-06-04

PATIENTS WITH IMMUNE MEDIATED INFLAMMATORY DISEASES ARE OVERREPRESENTED IN LOW-FREQUENCY VIRAL SYMPTOM CLUSTERS - Tascilar, Koray; Simon, David; Krönke, Gerhard; Kleyer, Arnd; Ramming, Andreas; Atreya, Raja; Tenbusch, Matthias; Überla, Klaus; Berking, Carola; Sticherling, Michael; Neurath, Markus; Schett, Georg (ANNALS OF THE RHEUMATIC DISEASES, 2021)
CRIS-Team WoS Importer:2021-09-24

Patients with immune-mediated inflammatory diseases receiving cytokine inhibitors have low prevalence of SARS-CoV-2 seroconversion - Simon, David; Tascilar, Koray; Krönke, Gerhard; Kleyer, Arnd; Zaiss, Mario; Heppt, Franz; Meder, Christine; Atreya, Raja; Klenske, Entcho; Dietrich, Peter; Abdullah, Abdullah; Kliem, Thorsten; et al. (Nature Communications, 2020)
Immune-mediated inflammatory diseases (IMIDs) of the joints, gut and skin are treated with inhibitors of inflammatory cytokines. These cytokines are involved in the pathogenesis of coronavirus disease 2019 (COVID-19). Investigating anti-SARS-CoV-2 antibody responses in IMIDs we observe a reduced incidence of SARS-CoV-2 seroconversion in IMID patients treated with cytokine inhibitors compared to patients receiving no such inhibitors and two healthy control populations, despite similar social exposure. Hence, cytokine inhibitors seem to at least partially protect from SARS-CoV-2 infection.
CRIS-Team Scopus Importer:2020-08-07

Patients with unstable angina pectoris show an increased frequency of the Fc gamma RIIa R131 allele - Raaz-Schrauder, Dorette; Ekici, Arif Bülent; Munoz, Luis Enrique; Klinghammer, Lutz; Voll, Reinhard E.; Leusen, Jeanette H.W.; Van De Winkel, Jan G.J.; Reis, André; Schett, Georg; Garlichs, Christoph; Herrmann, Martin (Autoimmunity, 2012)
Patients with Systemic Lupus Erythematosus (SLE) carry an increased risk for the development of coronary artery disease (CAD). The R131 allele of the Fc gamma receptor IIa (FcγRIIa) is associated with SLE incidence and disease severity but also with CAD. Compared to stable angina pectoris (SAP) the unstable angina (UAP), as a manifestation of destabilizing CAD, is associated with increased risk of persistent instability, myocardial infarction, and death. Identification of clinically relevant determinants for unstable angina promises reduction of UAP-associated mortality in patients with SLE. We conducted a clinical study among 553 consecutive patients with stable angina pectoris (n 330) and unstable angina pectoris (n 223). All patients were genotyped for a frequent functional variant at position 131 of the mature FcγRIIa. UAP, but not SAP was significantly associated with the R/R131 genotype (P < 0.001). In troponin-negative patients with angina carrying the R/R131 genotype the odds ratio for suffering from UAP was 4.02 (95% confidence interval, 2.526.41) compared to those with non-R/R131 genotypes. In a multivariable analysis, the R/R131 genotype independently predicted the risk for development of UAP in a model adjusted for classical atherogenic risk factors. Our data imply that risk stratification of SLE- and other high risk patients with troponin-negative angina could be significantly improved by FcγRIIa genotyping. © Informa UK, Ltd.
CRIS-Team Scopus Importer:2023-07-10
Keywords: Allele R131; Coronary disease; Fc gamma receptor IIa; SLE; Stable; Unstable angina pectoris

Patterns and predictors of skin score change in early diffuse systemic sclerosis from the European Scleroderma Observational Study - Herrick, Ariane L.; Peytrignet, Sebastien; Lunt, Mark; Pan, Xiaoyan; Hesselstrand, Roger; Mouthon, Luc; Silman, Alan J.; Dinsdale, Graham; Brown, Edith; Czirjak, Laszlo; Distler, Jörg; Distler, Oliver; et al. (Annals of the Rheumatic Diseases, 2018)
Our aim was to use the opportunity provided by the European Scleroderma Observational Study to (1) identify and describe those patients with early diffuse cutaneous systemic sclerosis (dcSSc) with progressive skin thickness, and (2) derive prediction models for progression over 12 months, to inform future randomised controlled trials (RCTs).The modified Rodnan skin score (mRSS) was recorded every 3 months in 326 patients. 'Progressors' were defined as those experiencing a 5-unit and 25% increase in mRSS score over 12 months (±3 months). Logistic models were fitted to predict progression and, using receiver operating characteristic (ROC) curves, were compared on the basis of the area under curve (AUC), accuracy and positive predictive value (PPV).66 patients (22.5%) progressed, 227 (77.5%) did not (33 could not have their status assessed due to insufficient data). Progressors had shorter disease duration (median 8.1 vs 12.6 months, P=0.001) and lower mRSS (median 19 vs 21 units, P=0.030) than non-progressors. Skin score was highest, and peaked earliest, in the anti-RNA polymerase III (Pol3+) subgroup (n=50). A first predictive model (including mRSS, duration of skin thickening and their interaction) had an accuracy of 60.9%, AUC of 0.666 and PPV of 33.8%. By adding a variable for Pol3 positivity, the model reached an accuracy of 71%, AUC of 0.711 and PPV of 41%.Two prediction models for progressive skin thickening were derived, for use both in clinical practice and for cohort enrichment in RCTs. These models will inform recruitment into the many clinical trials of dcSSc projected for the coming years.NCT02339441.
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PDGF Receptor Blockade is Associated With Decreased Development of Cardiac Allograft Vasculopathy in a Murine Aortic Transplant Model - Heim, Christian; Gocht, A.; Distler, Jörg; Spriewald, B.; Ramsperger-Gleixner, Martina; Weyand, Michael; Ensminger, S. M. (2018)
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PEPDar: A randomized prospective noninferiority study of ritonavir-boosted darunavir for HIV post-exposure prophylaxis - Faetkenheuer, G.; Jessen, H.; Stoehr, A.; Jung, N.; Jessen, A. B.; Kuemmerle, T.; Berger, M.; Bogner, J. R.; Spinner, C. D.; Stephan, Christoph; Degen, O.; Vogelmann, R.; et al. (HIV Medicine, 2016)
PEPDar compared the tolerability and safety of ritonavir-boosted darunavir (DRV/r)-based post-exposure prophylaxis (PEP) with the tolerability and safety of standard of care (SOC). The primary endpoint was the early discontinuation rate among the per-protocol population.PEPDar was an open-label, randomized, multicentre, prospective, noninferiority safety study. Subjects were stratified by type of event (occupational vs. nonoccupational, i.e. sexual) and were randomized to receive DRV/r plus two nucleoside reverse transcriptase inhibitors (NRTIs) or SOC PEP. Twenty-two private or university HIV clinics in Germany participated. Subjects were >= 18 years old and had documented or potential HIV exposure and indication for HIV PEP. They initiated PEP not later than 72 h after the event and were HIV negative.A total of 324 subjects were screened, the per-protocol population was 305, and 273 subjects completed the study. One hundred and fifty-five subjects received DRV/r-based PEP and 150 subjects received ritonavir-boosted lopinavir (LPV/r)-based PEP for 28-30 days; 298 subjects also received tenofovir/emtricitabine. The early discontinuation rate in the DRV/r arm was 6.5% compared with 10.0% in the SOC arm (P = 0.243). Adverse drug reactions (ADRs) were reported in 68% of DRV/r subjects and 75% of SOC subjects (P = 0.169). Fewer DRV/r subjects (16.1%) had at least one grade 2 or 3 ADR compared with SOC subjects (29.3%) (P = 0.006). All grades of diarrhoea, nausea, and sleep disorders were significantly less frequent with DRV/r, while headache was significantly more frequent. No HIV seroconversion was reported during follow-up.Noninferiority of DRV/r to SOC was demonstrated. DRV/r should be included as a standard component of recommended regimens in PEP guidelines.
EVALuna2:13292

Perceptions of risk and predictive testing held by the first-degree relatives of patients with rheumatoid arthritis in England, Austria and Germany: a qualitative study - Stack, Rebecca J.; Stoffer, Michaela; Englbrecht, Matthias; Mosor, Erika; Falahee, Marie; Simons, Gwenda; Smolen, Josef; Schett, Georg; Buckley, Chris D.; Kumar, Kanta; Hansson, Mats; Hueber, Axel; et al. (BMJ Open, 2016)
The family members of patients with rheumatoid arthritis (RA) are at increased risk of developing RA and are potential candidates for predictive testing. This study explored the perceptions of first-degree relatives of people with RA about being at risk of RA and engaging in predictive testing.34 first-degree relatives (siblings and offspring) of patients with RA from the UK, Germany and Austria participated in semistructured interviews about their perceptions of RA risk and the prospect of predictive testing. Interviews were audio-recorded, transcribed verbatim and analysed using thematic analysis.First-degree relatives were aware of their susceptibility to RA, but were unsure of the extent of their risk. When considering their future risk, some relatives were concerned about the potential impact that RA would have on their lives. Relatives were concerned that knowing their actual risk would increase their anxiety and would affect decisions about their future. Also, relatives were concerned about the levels of uncertainty associated with predictive testing. Those in favour of knowing their future risk felt that they would need additional support to understand the risk information and cope with the emotional impact of this information.Identifying individuals at risk of RA may allow targeted interventions to reduce the risk and consequence of future disease; however, relatives have concerns about predictive testing and risk information. The development of strategies to quantify and communicate risk needs to take these views into account and incorporate approaches to mitigate concerns and minimise the psychological impact of risk information.
EVALuna2:13299

Performance of a handheld ultrasound device to assess articular and periarticular pathologies in patients with inflammatory arthritis - Corte, Giulia; Bayat, Sara; Tascilar, Koray; Valor-Mendez, Larissa; Schuster, Louis; Knitza, Johannes; Fagni, Filippo; Schett, Georg; Kleyer, Arnd; Simon, David (Diagnostics, 2021)
The purpose of this study was to assess the accuracy and performance of a new handheld ultrasound (HHUS) machine in comparison to a conventional cart-based sonographic machine in patients with inflammatory arthritis (IA). IA patients with at least one tender and swollen joint count were enrolled. US was performed on the clinically affected joints using a cart-based sonographic device (Samsung HS40) and a HHUS device (Butterfly iQ). One blinded reader scored all images for the presence of erosions, bony enlargement, synovial hypertrophy, joint effusion, bursitis, tenosynovitis, and enthesitis. Synovitis was graded (B mode and power Doppler (PD)) by the 4-level EULAR-OMERACT scale. To avoid bias by the blinded reader, we included 67 joints of two healthy volunteers in the evaluation. We calculated the overall concordance and the concordance by type of joint and pathological finding. We also measured the time required for the US examination per joint with both devices. Thirty-two patients (20 with RA, 10 with PsA, and one each with gout and SLE-associated arthritis) were included, and 186 joints were examined. The overall raw concordance in B mode was 97% (κappa 0.90, 95% CI (0.89, 0.94)). In B mode, no significant differences were found in relation to type of joint or pathological finding examined. The PD mode of the HHUS device did not detect any PD signal, whereas the cart-based device detected a PD signal in 61 joints (33%). The portable device did not offer any time savings compared to the cart-based device (47.0 versus 46.3 s). The HHUS device was accurate in the assessment of structural damage and inflammation in patients with IA, but only in the B mode. Significant improvements are still needed for HHUS to reliably demonstrate blood flow detection in PD mode.
CRIS-Team Scopus Importer:2021-07-30
Keywords: Handheld ultrasound device; Inflammatory arthritis; Medical ultrasound; Musculoskeletal ultrasound

Periarticular Bone Loss in Arthritis Is Induced By Autoantibodies Against Citrullinated Vimentin - Engdahl, Cecilia; Bang, Holger; Dietel, Katharina; Lang, Stefanie; Harre, Ulrike; Schett, Georg (2016)
EVALuna2:33224

Periarticular Bone Loss in Arthritis Is Induced by Autoantibodies Against Citrullinated Vimentin - Engdahl, Cecilia; Bang, Holger; Dietel, Katharina; Lang, Stefanie; Harre, Ulrike; Schett, Georg (Journal of Bone and Mineral Research, 2017)
Periarticular bone loss is a long known but yet insufficiently understood phenomenon in patients with rheumatoid arthritis. This study investigated whether autoimmunity against citrullinated proteins is causally involved in triggering periarticular bone loss. Periarticular bone loss was studied in the standard antigen-induced arthritis (AIA) mouse model with methylated bovine serum albumin (mBSA) as well as a modified model with mutated citrullinated vimentin (MCV) alone or in combination with mBSA. Periarticular bone loss, subchondral osteoclastogenesis, as well as local expression of cytokines, osteoclast genes, and peptidyl-arginine deiminase (PAD) enzymes were assessed after arthritis induction. Immune cell and osteoclast precursor infiltration were detected in the periarticular bone marrow and local lymph nodes. In addition, periarticular bone loss was assessed upon challenge of mice with purified anti-MCV antibody. Despite inducing a milder form of arthritis than mBSA, MCV triggered significant periarticular bone loss associated with an increased infiltration of osteoclast precursors and mature osteoclasts in the periarticular bone marrow. MCV enhanced the expression of the osteoclast inducers RANKL and M-CSF, the cytokines IL-8, IL-1, IL-6, and TNF-?, as well as PAD2 and PAD4 enzymes in the periarticular bone marrow. Furthermore, also anti-MCV antibody challenge induced significant periarticular bone loss and local osteoclastogenesis in the mice. Autoimmunity against citrullinated vimentin triggers periarticular bone loss by osteoclast activation in the bone marrow. These findings may explain why periarticular bone loss is already found very early in the disease course of patients with rheumatoid arthritis. © 2017 American Society for Bone and Mineral Research.
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Persistent inflammation in systemic sclerosis is strongly associated with mortality: a EUSTAR database analysis - Guler, S. A.; Sarbu, A.; Stadler, O.; Allanore, Y.; Bernardino,; Distler, Jörg; Gabrielli, A.; Hoffmann-Vold, A.; Matucci-Cerinic, M.; Mueller-Ladner, U.; Ortiz-Santamaria,; Rednic, S.; et al. (EUROPEAN RESPIRATORY JOURNAL, 2022)
CRIS-Team WoS Importer:2023-03-03

PERSISTENT INFLAMMATION IN SYSTEMIC SCLEROSIS IS STRONGLY ASSOCIATED WITH SEVERE DISEASE AND MORTALITY: AN ANALYSIS FROM THE EUSTAR DATABASE - Sarbu, A. C.; Guler, S.; Stadler, O.; Allanore, Y.; Bernardino, V.; Distler, Jörg; Gabrielli, A.; Hoffmann-Vold, A. M.; Matucci-Cerinic, M.; Mueller-Ladner, U.; Ortiz-Santamaria, V.; Rednic, S.; et al. (ANNALS OF THE RHEUMATIC DISEASES, 2022)
CRIS-Team WoS Importer:2022-11-04

PGC-1A REGULATES AUTOPHAGY TO PROMOTE FIBROBLAST ACTIVATION AND TISSUE FIBROSIS - Zhang, Y.; Dreissigacker, K.; Distler, D.; Gyoerfi, A. H.; Bergmann, C.; Zhou, X.; Shen, L.; Ludolph, I.; Horch, R.; Ramming, Andreas; Schett, Georg; Distler, Jörg (ANNALS OF THE RHEUMATIC DISEASES, 2020)
CRIS-Team WoS Importer:2020-08-21

PGC-1α regulates autophagy to promote fibroblast activation and tissue fibrosis - Zhang, Yun; Shen, Lichong; Zhu, Honglin; Dreissigacker, Katja; Distler, Diana; Zhou, Xiang; Györfi, Andrea-Hermina; Bergmann, Christina; Meng, Xianyi; Dees, Clara; Trinh-Minh, Thuong; Ludolph, Ingo; et al. (Annals of the Rheumatic Diseases, 2020)
Objectives Coactivators are a heterogeneous family of transcriptional regulators that are essential for modulation of transcriptional outcomes and fine-tune numerous cellular processes. The aim of the present study was to evaluate the role of the coactivator peroxisome proliferator-activated receptor gamma coactivator-1α (PGC-1α) in the pathogenesis of systemic sclerosis (SSc). Methods Expression of PGC-1α was analysed by real-time PCR, western blot and immunofluorescence. Modulation of autophagy was analysed by reporter studies by expression of autophagy-related genes. The effects of PGC-1α knockdown on collagen production and myofibroblast differentiation were analysed in cultured human fibroblasts and in two mouse models with fibroblast-specific knockout of PGC-1α. Results The expression of PGC-1α was induced in dermal fibroblasts of patients with SSc and experimental murine fibrosis. Transforming growth factor beta (TGFβ), hypoxia and epigenetic mechanisms regulate the expression of PGC-1α in fibroblasts. Knockdown of PGC-1α prevented the activation of autophagy by TGFβ and this translated into reduced fibroblast-to-myofibroblast differentiation and collagen release. Knockout of PGC-1α in fibroblasts prevented skin fibrosis induced by bleomycin and by overexpression of a constitutively active TGFβ receptor type I. Moreover, pharmacological inhibition of PGC-1α by SR18292 induced regression of pre-established, bleomycin-induced skin fibrosis. Conclusion PGC-1α is upregulated in SSc and promotes autophagy to foster TGFβ-induced fibroblast activation. Targeting of PGC-1α prevents aberrant autophagy, inhibits fibroblast activation and tissue fibrosis and may over therapeutic potential.
CRIS-Team Scopus Importer:2020-09-11
Keywords: fibroblasts; systemic sclerosis; treatment

Pharmacological inhibition of porcupine induces regression of experimental skin fibrosis by targeting Wnt signalling - Chen, Chih-Wei; Beyer, Christian; Liu, Jun; Maier, Christiane; Li, Chun; Thuong Trinh-Minh,; Xu, Xiaohan; Cole, Stuart H.; Hsieh, Mindy H.; Ng, Nicholas; Althage, Alana; Meeusen, Shelly; et al. (Annals of the Rheumatic Diseases, 2017)
Wnt signalling has been implicated in activating a fibrogenic programme in fibroblasts in systemic sclerosis (SSc). Porcupine is an O-acyltransferase required for secretion of Wnt proteins in mammals. Here, we aimed to evaluate the antifibrotic effects of pharmacological inhibition of porcupine in preclinical models of SSc.The porcupine inhibitor GNF6231 was evaluated in the mouse models of bleomycin-induced skin fibrosis, in tight-skin-1 mice, in murine sclerodermatous chronic-graft-versus-host disease (cGvHD) and in fibrosis induced by a constitutively active transforming growth factor-?-receptor I.Treatment with pharmacologically relevant and well-tolerated doses of GNF6231 inhibited the activation of Wnt signalling in fibrotic murine skin. GNF6231 ameliorated skin fibrosis in all four models. Treatment with GNF6231 also reduced pulmonary fibrosis associated with murine cGvHD. Most importantly, GNF6231 prevented progression of fibrosis and showed evidence of reversal of established fibrosis.These data suggest that targeting the Wnt pathway through inhibition of porcupine provides a potential therapeutic approach to fibrosis in SSc. This is of particular interest, as a close analogue of GNF6231 has already demonstrated robust pathway inhibition in humans and could be available for clinical trials.
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Phase-orientated disease control by cytokines-lessons from rheumatoid arthritis - Schett, Georg (2017)
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Phenotypes Determined by Cluster Analysis and Their Survival in the Prospective European Scleroderma Trials and Research Cohort of Patients With Systemic Sclerosis - Sobanski, Vincent; Giovannelli, Jonathan; Allanore, Yannick; Riemekasten, Gabriela; Airo, Paolo; Vettori, Serena; Cozzi, Franco; Distler, Oliver; Matucci-Cerinic, Marco; Denton, Christopher; Launay, David; Hachulla, Eric; et al. (Arthritis and Rheumatology, 2019)
Objective Systemic sclerosis (SSc) is a heterogeneous connective tissue disease that is typically subdivided into limited cutaneous SSc (lcSSc) and diffuse cutaneous SSc (dcSSc) depending on the extent of skin involvement. This subclassification may not capture the entire variability of clinical phenotypes. The European Scleroderma Trials and Research (EUSTAR) database includes data on a prospective cohort of SSc patients from 122 European referral centers. This study was undertaken to perform a cluster analysis of EUSTAR data to distinguish and characterize homogeneous phenotypes without any a priori assumptions, and to examine survival among the clusters obtained. Methods A total of 11,318 patients were registered in the EUSTAR database, and 6,927 were included in the study. Twenty-four clinical and serologic variables were used for clustering. Results Clustering analyses provided a first delineation of 2 clusters showing moderate stability. In an exploratory attempt, we further characterized 6 homogeneous groups that differed with regard to their clinical features, autoantibody profile, and mortality. Some groups resembled usual dcSSc or lcSSc prototypes, but others exhibited unique features, such as a majority of lcSSc patients with a high rate of visceral damage and antitopoisomerase antibodies. Prognosis varied among groups and the presence of organ damage markedly impacted survival regardless of cutaneous involvement. Conclusion Our findings suggest that restricting subsets of SSc patients to only those based on cutaneous involvement may not capture the complete heterogeneity of the disease. Organ damage and antibody profile should be taken into consideration when individuating homogeneous groups of patients with a distinct prognosis.
CRIS-Team WoS Importer:2019-08-30

Phenotypic Diversity of C. neoformans var. neoformans Clinical Isolates from Localized and Disseminated Infections - Birkenfeld, Zena M.; Dittel, Nikita; Harrer, Thomas; Stephan, Christoph; Kiderlen, Albrecht F.; Rickerts, Volker (Microorganisms, 2022)
Cryptococcus neoformans var. neoformans is the second most prevalent agent of cryptococcosis in central Europe. Infections mostly present with localized skin and disseminated infections. Previous studies did not find these presentations to be determined by the fungal genotype as detected by multilocus sequence typing (MLST). However, phenotypic fungal traits may impact clinical presentation. Here, we studied the growth and virulence factors of C. neoformans var. neoformans isolates from disseminated and localized infections and an environmental isolate. We used coincubation with Acanthamoeba castellanii and the Galleria mellonella infection model to identify phenotypic characteristics potentially associated with clinical presentation. Clinical isolates of C. neoformans var. neoformans present a substantial phenotypic variability. Median survival of Galleria mellonella varied between 6 and 14 days. C. neoformans var. neoformans isolates from disseminated infections showed stronger melanization and larger capsules. They demonstrated superior uptake into an amoeba and increased cytotoxicity for the amoeba. Differences of strains from localized and disseminated infections in coincubation with amoeba are in line with the importance of phagocytes in the pathogenesis of disseminated cryptococcosis. Phenotypic traits and non-vertebrate infection models may help understand the virulence potential of C. neoformans var. neoformans isolates.
CRIS-Team Scopus Importer:2022-02-04
Keywords: Acanthamoeba castellanii; Cryptococcosis; Cryptococcus neoformans; Galleria mellonella; Virulence factors

Phosphatidylserine is a global immunosuppressive signal in efferocytosis, infectious disease, and cancer - Birge, R. B.; Boeltz, Sebastian; Kumar, S.; Carlson, J.; Wanderley, J.; Calianese, D.; Barcinski, M.; Brekken, R. A.; Huang, X.; Hutchins, J. T.; Freimark, B.; Empig, C.; et al. (Cell Death and Differentiation, 2016)
Apoptosis is an evolutionarily conserved and tightly regulated cell death modality. It serves important roles in physiology by sculpting complex tissues during embryogenesis and by removing effete cells that have reached advanced age or whose genomes have been irreparably damaged. Apoptosis culminates in the rapid and decisive removal of cell corpses by efferocytosis, a term used to distinguish the engulfment of apoptotic cells from other phagocytic processes. Over the past decades, the molecular and cell biological events associated with efferocytosis have been rigorously studied, and many eat-me signals and receptors have been identified. The externalization of phosphatidylserine (PS) is arguably the most emblematic eat-me signal that is in turn bound by a large number of serum proteins and opsonins that facilitate efferocytosis. Under physiological conditions, externalized PS functions as a dominant and evolutionarily conserved immunosuppressive signal that promotes tolerance and prevents local and systemic immune activation. Pathologically, the innate immunosuppressive effect of externalized PS has been hijacked by numerous viruses, microorganisms, and parasites to facilitate infection, and in many cases, establish infection latency. PS is also profoundly dysregulated in the tumor microenvironment and antagonizes the development of tumor immunity. In this review, we discuss the biology of PS with respect to its role as a global immunosuppressive signal and how PS is exploited to drive diverse pathological processes such as infection and cancer. Finally, we outline the rationale that agents targeting PS could have significant value in cancer and infectious disease therapeutics.
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Phospholipid membranes drive abdominal aortic aneurysm development through stimulating coagulation factor activity - Allen-Redpath, Keith; Aldrovandi, Maceler; Lauder, Sarah N.; Gketsopoulou, Anastasia; Tyrrell, Victoria J.; Slatter, David A.; Andrews, Robert; Watkins, W. John; Atkinson, Georgia; Mcneill, Eileen; Gilfedder, Anna; Protty, Majd; et al. (Proceedings of the National Academy of Sciences of the United States of America, 2019)
Abdominal aortic aneurysm (AAA) is an inflammatory vascular disease with high mortality and limited treatment options. How blood lipids regulate AAA development is unknown. Here lipidomics and genetic models demonstrate a central role for procoagulant enzymatically oxidized phospholipids (eoxPL) in regulating AAA. Specifically, through activating coagulation, eoxPL either promoted or inhibited AAA depending on tissue localization. Ang II administration to ApoE − / − mice increased intravascular coagulation during AAA development. Lipidomics revealed large numbers of eoxPL formed within mouse and human AAA lesions. Deletion of eoxPL-generating enzymes (Alox12 or Alox15) or administration of the factor Xa inhibitor rivaroxaban significantly reduced AAA. Alox-deficient mice displayed constitutively dysregulated hemostasis, including a consumptive coagulopathy, characterized by compensatory increase in prothrombotic aminophospholipids (aPL) in circulating cell membranes. Intravenously administered procoagulant PL caused clotting factor activation and depletion, induced a bleeding defect, and significantly reduced AAA development. These data suggest that Alox deletion reduces AAA through diverting coagulation away from the vessel wall due to eoxPL deficiency, instead activating clotting factor consumption and depletion in the circulation. In mouse whole blood, ∼44 eoxPL molecular species formed within minutes of clot initiation. These were significantly elevated with ApoE − / − deletion, and many were absent in Alox − / − mice, identifying specific eoxPL that modulate AAA. Correlation networks demonstrated eoxPL belonged to subfamilies defined by oxylipin composition. Thus, procoagulant PL regulate AAA development through complex interactions with clotting factors. Modulation of the delicate balance between bleeding and thrombosis within either the vessel wall or circulation was revealed that can either drive or prevent disease development.
CRIS-Team Scopus Importer:2019-05-02
Keywords: Aneurysm; Angiotensin; Lipid; Lipoxygenase; Phospholipid

PHOTOREALISTIC DEPICTION OF RHEUMATIC PATHOLOGIES BY CINEMATIC RENDERING FACILITATES DISEASE UNDERSTANDING OF PATIENTS WITH RHEUMATIC DISEASES - Pachowsky, Milena; Morf, Harriet; Simon, David; Schönau, Verena; Valor, L.; Knitza, Johannes; Engel, K.; Uder, Michael; Hueber, Axel; Schett, Georg; Kleyer, Arnd (ANNALS OF THE RHEUMATIC DISEASES, 2022)
CRIS-Team WoS Importer:2022-11-04

PHYSICAL FUNCTION IN RA PATIENTS IN REMISSION UNDERGOING TAPERING AND/OR STOPPING OF DMARDS - Stephan, Marlene; Tascilar, Koray; Hagen, Melanie; Haschka, Judith; Reiser, Michaela; Kleyer, Arnd; Manger, Bernhard; Figuereido, Camille; Cobra, Jayme; Tony, Hans-Peter; Finzel, Stephanie; Kleinert, Stefan; et al. (2019)
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Physical Function of RA patients Tapering Treatment—A Post Hoc Analysis of the Randomized Controlled RETRO Trial - Stephan, Marlene; Tascilar, Koray; Yalcin-Mutlu, Melek; Hagen, Melanie; Haschka, Judith; Reiser, Michaela; Hartmann, Fabian; Kleyer, Arnd; Hueber, Axel; Manger, Bernhard; Figueiredo, Camille; Cobra, Jayme Fogagnolo; et al. (Journal of Clinical Medicine, 2023)
Several studies have shown that tapering or stopping disease-modifying anti-rheumatic drugs (DMARDs) in rheumatoid arthritis (RA) patients in sustained remission is feasible. However, tapering/stopping bears the risk of decline in physical function as some patients may relapse and face increased disease activity. Here, we analyzed the impact of tapering or stopping DMARD treatment on the physical function of RA patients. The study was a post hoc analysis of physical functional worsening for 282 patients with RA in sustained remission tapering and stopping DMARD treatment in the prospective randomized RETRO study. HAQ and DAS-28 scores were determined in baseline samples of patients continuing DMARD (arm 1), tapering their dose by 50% (arm 2), or stopping after tapering (arm 3). Patients were followed over 1 year, and HAQ and DAS-28 scores were evaluated every 3 months. The effect of treatment reduction strategy on functional worsening was assessed in a recurrent-event Cox regression model with a study-group (control, taper, and taper/stop) as the predictor. Two-hundred and eighty-two patients were analyzed. In 58 patients, functional worsening was observed. The incidences suggest a higher probability of functional worsening in patients tapering and/or stopping DMARDs, which is likely due to higher relapse rates in these individuals. At the end of the study, however, functional worsening was similar among the groups. Point estimates and survival curves show that the decline in functionality according to HAQ after tapering or discontinuation of DMARDs in RA patients with stable remission is associated with recurrence, but not with an overall functional decline.
CRIS-Team Scopus Importer:2023-06-30
Keywords: DAS28; DMARD; HAQ; PROM’s; Rheumatoid Arthritis

Plasma cell-free DNA methylation: a liquid biomarker of hepatic fibrosis - Yigit, Buket; Boyle, Marie; Ozler, Oguz; Erden, Nihan; Tutucu, Faik; Hardy, Timothy; Bergmann, Christina; Distler, Jörg; Adali, Gupse; Dayangac, Murat; Mann, Derek A.; Zeybel, Mujdat; et al. (Gut, 2018)
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Plasma Hsp90 levels in patients with systemic sclerosis and relation to lung and skin involvement: a cross-sectional and longitudinal study - Štorkánová, Hana; Oreská, Sabína; Špiritović, Maja; Heřmánková, Barbora; Bubová, Kristýna; Komarc, Martin; Pavelka, Karel; Vencovský, Jiří; Distler, Jörg; Šenolt, Ladislav; Bečvář, Radim; Tomčík, Michal (Scientific Reports, 2021)
Our previous study demonstrated increased expression of Heat shock protein (Hsp) 90 in the skin of patients with systemic sclerosis (SSc). We aimed to evaluate plasma Hsp90 in SSc and characterize its association with SSc-related features. Ninety-two SSc patients and 92 age-/sex-matched healthy controls were recruited for the cross-sectional analysis. The longitudinal analysis comprised 30 patients with SSc associated interstitial lung disease (ILD) routinely treated with cyclophosphamide. Hsp90 was increased in SSc compared to healthy controls. Hsp90 correlated positively with C-reactive protein and negatively with pulmonary function tests: forced vital capacity and diffusing capacity for carbon monoxide (DLCO). In patients with diffuse cutaneous (dc) SSc, Hsp90 positively correlated with the modified Rodnan skin score. In SSc-ILD patients treated with cyclophosphamide, no differences in Hsp90 were found between baseline and after 1, 6, or 12 months of therapy. However, baseline Hsp90 predicts the 12-month change in DLCO. This study shows that Hsp90 plasma levels are increased in SSc patients compared to age-/sex-matched healthy controls. Elevated Hsp90 in SSc is associated with increased inflammatory activity, worse lung functions, and in dcSSc, with the extent of skin involvement. Baseline plasma Hsp90 predicts the 12-month change in DLCO in SSc-ILD patients treated with cyclophosphamide.
CRIS-Team Scopus Importer:2021-01-15

PLASMA LEVELS OF HSP90 ARE INCREASED IN INTERSTITIAL LUNG DISEASE AND SKIN FIBROSIS IN PATIENTS WITH SYSTEMIC SCLEROSIS - Storkanova, H.; Oreska, S.; Spiritovic, M.; Hermankova, B.; Pavelka, K.; Vencovsky, J.; Distler, Jörg; Senolt, L.; Becvar, R.; Tomcik, M. (2018)
EVALuna2:35000

PLASMA LEVELS OF HSP90 ARE INCREASED IN PATIENTS WITH SYSTEMIC SCLEROSIS WITH MORE SEVERE ORGAN INVOLVEMENT - Storkanova, H.; Oreska, S.; Spiritovic, M.; Pavelka, Karel; Vencovsky, J.; Distler, Jörg; Senolt, L.; Becvar, R.; Tomcik, M. (2018)
EVALuna2:35011

Platelet Phagocytosis via P-selectin Glycoprotein Ligand 1 and Accumulation of Microparticles in Systemic Sclerosis - Manfredi, Angelo A.; Ramirez, Giuseppe A.; Godino, Cosmo; Capobianco, Annalisa; Monno, Antonella; Franchini, Stefano; Tombetti, Enrico; Corradetti, Sara; Distler, Jörg; Bianchi, Marco E.; Rovere-Querini, Patrizia; Maugeri, Norma (Arthritis and Rheumatology, 2021)
Objective It is unclear why activated platelets and platelet-derived microparticles (MPs) accumulate in the blood of patients with systemic sclerosis (SSc). This study was undertaken to investigate whether defective phagocytosis might contribute to MP accumulation in the blood of patients with SSc. Methods Blood samples were obtained from a total of 81 subjects, including 25 patients with SSc and 26 patients with stable coronary artery disease (CAD). Thirty sex- and age-matched healthy volunteers served as controls. Studies were also conducted in NSG mice, in which the tail vein of the mice was injected with MPs, and samples of the lung parenchyma were obtained for analysis of the pulmonary microvasculature. Tissue samples from human subjects and from mice were assessed by flow cytometry and immunochemical analyses for determination of platelet-neutrophil interactions, phagocytosis, levels and distribution of P-selectin, P-selectin glycoprotein ligand 1 (PSGL-1), and HMGB1 on platelets and MPs, and concentration of byproducts of neutrophil extracellular trap (NET) generation/catabolism. Results Activated P-selectin+ platelets and platelet-derived HMGB1+ MPs accumulated in the blood of SSc patients but not in the blood of healthy controls. Patients with CAD, a vasculopathy independent of systemic inflammation, had fewer P-selectin+ platelets and a negligible number of MPs. The expression of the receptor for P-selectin, PSGL-1, in neutrophils from SSc patients was significantly decreased, raising the possibility that phagocytes in SSc do not recognize activated platelets, leading to a failure of phagocytosis and continued neutrophil release of MPs. As evidence of this process, activated platelets were not detected in the neutrophils from SSc patients, whereas they were consistently present in the neutrophils from patients with CAD. HMGB1+ MPs elicited generation of NETs, which were only detected in the plasma of SSc patients. In mice, P-selectin-PSGL-1 interaction resulted in platelet phagocytosis in vitro and influenced the ability of MPs to elicit NETs, endothelial activation, and migration of leukocytes through the pulmonary microvasculature. Conclusion The clearance of activated platelets via PSGL-1 limits the undesirable effects of MP-elicited neutrophil activation. This balance is disrupted in patients with SSc. Its reconstitution might curb vascular inflammation and prevent fibrosis.
CRIS-Team WoS Importer:2021-12-31

Poly(ADP-ribose) polymerase-1 regulates fibroblast activation in systemic sclerosis - Zhang, Yun; Pötter, Sebastian; Chen, Chih-Wei; Liang, Ruifang; Gelse, Kolja; Ludolph, Ingo; Horch, Raymund E.; Distler, Oliver; Schett, Georg; Distler, Jörg; Dees, Clara (Annals of the Rheumatic Diseases, 2018)
OBJECTIVES: The enzyme poly(ADP-ribose) polymerase-1 (PARP-1) transfers negatively charged ADP-ribose units to target proteins. This modification can have pronounced regulatory effects on target proteins. Recent studies showed that PARP-1 can poly(ADP-ribosyl)ate (PARylate) Smad proteins. However, the role of PARP-1 in the pathogenesis of systemic sclerosis (SSc) has not been investigated. METHODS: The expression of PARP-1 was determined by quantitative PCR and immunohistochemistry. DNA methylation was analysed by methylated DNA immunoprecipitation assays. Transforming growth factor-β (TGFβ) signalling was assessed using reporter assays, chromatin immunoprecipitation assays and target gene analysis. The effect of PARP-1 inactivation was investigated in bleomycin-induced and topoisomerase-induced fibrosis as well as in tight-skin-1 (Tsk-1) mice. RESULTS: The expression of PARP-1 was decreased in patients with SSc, particularly in fibroblasts. The promoter of PARP-1 was hypermethylated in SSc fibroblasts and in TGFβ-stimulated normal fibroblasts. Inhibition of DNA methyltransferases (DNMTs) reduced the promoter methylation and reactivated the expression of PARP-1. Inactivation of PARP-1 promoted accumulation of phosphorylated Smad3, enhanced Smad-dependent transcription and upregulated the expression of TGFβ/Smad target genes. Inhibition of PARP-1 enhanced the effect of TGFβ on collagen release and myofibroblast differentiation in vitro and exacerbated experimental fibrosis in vivo. PARP-1 deficiency induced a more severe fibrotic response to bleomycin with increased dermal thickening, hydroxyproline content and myofibroblast counts. Inhibition of PARylation also exacerbated fibrosis in Tsk-1 mice and in mice with topoisomerase-induced fibrosis. CONCLUSION: PARP-1 negatively regulates canonical TGFβ signalling in experimental skin fibrosis. The downregulation of PARP-1 in SSc fibroblasts may thus directly contribute to hyperactive TGFβ signalling and to persistent fibroblast activation in SSc.
EVALuna2:34150

POLYAUTOIMMUNITY AND MAJOR ORGAN INVOLVEMENT PREVALENCE IN SJOGREN'S SYNDROME: THYROID, LIVER, LUNG AND KIDNEY AS TARGETS. A SINGLE CENTER CROSS SECTIONAL STUDY - Valor, Larissa; Schenker, Hannah; Hagen, Melanie; Knitza, Johannes; Rech, Jürgen; Schett, Georg (ANNALS OF THE RHEUMATIC DISEASES, 2019)
CRIS-Team WoS Importer:2019-07-12

Polymorphisms in the Hsp70 gene locus are genetically associated with systemic lupus erythematosus - Fuernrohr, Barbara G.; Wach, Sven; Kelly, Jennifer A.; Haslbeck, Martin; Weber, Christian K.; Stach, Christian M.; Hueber, Axel J.; Graef, Daniela; Spriewald, Bernd M.; Manger, Karin; Herrmann, Martin; Kaufman, Kenneth M.; et al. (Annals of the Rheumatic Diseases, 2010)
Background: Heat shock proteins (Hsps) play a role in the delivery and presentation of antigenic peptides and are thought to be involved in the pathogenesis of multifactorial diseases. Objective: To investigate genes encoding cytosolic Hsp70 proteins for associations of allelic variants with systemic lupus erythematosus (SLE). Methods: Case-control studies of two independent Caucasian SLE cohorts were performed. In a haplotype-tagging single-nucleotide polymorphism approach, common variants of HspA1L, HspA1A and HspA1B were genotyped and principal component analyses were performed for the cohort from the Oklahoma Medical Research Foundation (OMRF). Relative quantification of mRNA was carried out for each Hsp70 gene in healthy controls. Conditional regression analysis was performed to determine if allelic variants in Hsp70 act independently of HLA-DR3. Results: On analysis of common genetic variants of HspA1L, HspA1A and HspA1B, a haplotype significantly associated with SLE in the Erlangen-SLE cohort was identified, which was confirmed in the OMRF cohort. Depending on the cohorts, OR ranging from 1.43 to 1.88 and 2.64 to 3.16 was observed for individuals heterozygous and homozygous for the associated haplotype, respectively. Patients carrying the risk haplotype or the risk allele more often displayed autoantibodies to Ro and La in both cohorts. In healthy controls bearing this haplotype, the amount of HspA1A mRNA was significantly increased, whereas total Hsp70 protein concentration was not altered. Conclusions: Allelic variants of the Hsp70 genes are significantly associated with SLE in Caucasians, independently of HLA-DR3, and correlate with the presence of autoantibodies to Ro and La. Hence, the Hsp70 gene locus appears to be involved in SLE pathogenesis.

Pomalidomide in Patients with Interstitial Lung Disease due to Systemic Sclerosis: A Phase II, Multicenter, Randomized, Double-blind, Placebo-controlled, Parallel-group Study - Hsu, Vivien M.; Denton, Christopher P.; Domsic, Robyn T.; Furst, Daniel E.; Rischmueller, Maureen; Stanislav, Marina; Steen, Virginia D.; Distler, Jörg; Korish, Shimon; Cooper, Alyse; Choi, Suktae; Schafer, Peter H.; et al. (Journal of Rheumatology, 2017)
To evaluate the safety and efficacy of pomalidomide (POM) on forced vital capacity (FVC), modified Rodnan skin score (mRSS), and gastrointestinal (GI) symptomatology over 52 weeks of treatment in patients with interstitial lung disease due to systemic sclerosis (SSc).Twenty-three adult patients diagnosed with SSc were randomized 1:1 POM:placebo (PBO).Mean change at Week 52 from baseline in predicted FVC% -5.2 and -2.8; mRSS -2.7 and -3.7; and UCLA Scleroderma Clinical Trial Consortium Gastrointestinal Tract (SCTC GIT 2.0) score 0.1 and 0.0, with POM and PBO, respectively. Statistical significance was not achieved for any of these 3 primary endpoints at 52 weeks.Because of recruitment challenges, subject enrollment was discontinued early. In an interim analysis, the study did not meet its Week 52 primary endpoints. Therefore, a decision was made to terminate all study phases. POM was generally well tolerated, with an adverse event profile consistent with the known safety and tolerability profile of POM in other diseases. Study results were neither positive nor negative because too few subjects were enrolled to make meaningful conclusions. Clinical Trials number: NCT01559129.
EVALuna2:13459

Possible adaptations of vascularised human skin equivalents to include rare cell populations and study fibroblast heterogeneity. Response to: ‘In search for the ideal anatomical composition of vascularised human skin equivalents for systemic sclerosis translational research: should we recruit the telocytes?’ by Manetti and Matucci-Cerinic - Matei, Alexandru-Emil; Distler, Jörg (Annals of the Rheumatic Diseases, 2019)
CRIS-Team Scopus Importer:2019-10-29
Keywords: disease activity; systemic sclerosis; treatment

Post-COVID-19 Syndrome: Retinal Microcirculation as a Potential Marker for Chronic Fatigue - Schlick, Sarah; Lucio, Marianna; Wallukat, Gerd; Bartsch, Alexander; Skornia, Adam; Hoffmanns, Jakob; Szewczykowski, Charlotte; Schröder, Thora; Raith, Franziska; Rogge, Lennart; Heltmann, Felix; Moritz, Michael; et al. (International Journal of Molecular Sciences, 2022)
Post-COVID-19 syndrome (PCS) is characterized by persisting sequelae after infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). PCS can affect patients with all COVID-19 disease severities. As previous studies have revealed impaired blood flow as a provoking factor triggering PCS, it was the aim of the present study to investigate the potential association between self-reported chronic fatigue and retinal microcirculation in patients with PCS, potentially indicating an objective biomarker. A prospective study was performed, including 201 subjects: 173 patients with PCS and 28 controls. Retinal microcirculation was visualized by OCT angiography (OCT-A) and quantified using the Erlangen-Angio-Tool as macula and peripapillary vessel density (VD). Chronic fatigue (CF) was assessed according to the variables of Bell’s score, age and gender. VDs in the superficial vascular plexus (SVP), intermediate capillary plexus (ICP) and deep capillary plexus (DCP) were analyzed, considering the repetitions (12 times). Seropositivity for autoantibodies targeting G protein-coupled receptors (GPCR-AAbs) was determined by an established cardiomyocyte bioassay. Taking account of the repetitions, a mixed model was performed to detect possible differences in the least square means between the different groups included in the analysis. An age effect in relation to VD was observed between patients and controls (p < 0.0001). Gender analysis showed that women with PCS showed lower VD levels in the SVP compared to male patients (p = 0.0015). The PCS patients showed significantly lower VDs in the ICP as compared to the controls (p = 0.0001 (CI: 0.32; 1)). Moreover, considering PCS patients, the mixed model revealed a significant difference between those with chronic fatigue (CF) and those without CF with respect to VDs in the SVP (p = 0.0033 (CI: −4.5; −0.92)). The model included variables of age, gender and Bell’s score, representing a subjective marker for CF. Consequently, retinal microcirculation might serve as an objective biomarker in subjectively reported chronic fatigue in patients with PCS.
CRIS-Team Scopus Importer:2022-12-09
Keywords: chronic fatigue; chronic fatigue syndrome; COVID-19; functional GPCR autoantibodies; long COVID syndrome; OCT angiography; post-COVID-19 syndrome; retinal microcirculation

Potent anti-inflammatory activity of the lectin-like domain of TNF in joints - Pinto, Ana Carolina Matias Dinelly; Nunes, Rodolfo De Melo; Nogueira, Igor Albuquerque; Fischer, Bernhard; Lucas, Rudolf; Girao-Carmona, Virginia Claudia Carneiro; De Oliveira, Vivian Louise Soares; Amaral, Flavio Almeida; Schett, Georg; Rocha, Francisco Airton Castro (Frontiers in Immunology, 2022)
In view of the crucial role of tumor necrosis factor (TNF) in joint destruction, TNF inhibitors, including neutralizing anti-TNF antibodies and soluble TNF receptor constructs, are commonly used therapeutics for the treatment of arthropathies like rheumatoid arthritis (RA). However, not all patients achieve remission; moreover, there is a risk of increased susceptibility to infection with these agents. Spatially distinct from its receptor binding sites, TNF harbors a lectin-like domain, which exerts unique functions that can be mimicked by the 17 residue solnatide peptide. This domain binds to specific oligosaccharides such as N′N′-diacetylchitobiose and directly target the α subunit of the epithelial sodium channel. Solnatide was shown to have anti-inflammatory actions in acute lung injury and glomerulonephritis models. In this study, we evaluated whether the lectin-like domain of TNF can mitigate the development of immune-mediated arthritis in mice. In an antigen-induced arthritis model, solnatide reduced cell influx and release of pro-inflammatory mediators into the joints, associated with reduction in edema and tissue damage, as compared to controls indicating that TNF has anti-inflammatory effects in an acute model of joint inflammation via its lectin-like domain.
CRIS-Team Scopus Importer:2022-11-25
Keywords: arthritis; cytokines; inflammation; neutrophils; tumor necrosis factor

POTENTIAL CELLULAR AND MOLECULAR TARGETS - Distler, Jörg (ANNALS OF THE RHEUMATIC DISEASES, 2019)
CRIS-Team WoS Importer:2019-07-16

Potential of nintedanib in treatment of progressive fibrosing interstitial lung diseases - Wollin, Lutz; Distler, Jörg; Redente, Elizabeth F.; Riches, David W.H.; Stowasser, Susanne; Schlenker-Herceg, Rozsa; Maher, Toby M.; Kolb, Martin (European Respiratory Journal, 2019)
A proportion of patients with fibrosing interstitial lung diseases (ILDs) develop a progressive phenotype characterised by decline in lung function, worsening quality of life and early mortality. Other than idiopathic pulmonary fibrosis (IPF), there are no approved drugs for fibrosing ILDs and a poor evidence base to support current treatments. Fibrosing ILDs with a progressive phenotype show commonalities in clinical behaviour and in the pathogenic mechanisms that drive disease worsening. Nintedanib is an intracellular inhibitor of tyrosine kinases that has been approved for treatment of IPF and has recently been shown to reduce the rate of lung function decline in patients with ILD associated with systemic sclerosis (SSc-ILD). In vitro data demonstrate that nintedanib inhibits several steps in the initiation and progression of lung fibrosis, including the release of pro-inflammatory and pro-fibrotic mediators, migration and differentiation of fibrocytes and fibroblasts, and deposition of extracellular matrix. Nintedanib also inhibits the proliferation of vascular cells. Studies in animal models with features of fibrosing ILDs such as IPF, SSc-ILD, rheumatoid arthritis-ILD, hypersensitivity pneumonitis and silicosis demonstrate that nintedanib has anti-fibrotic activity irrespective of the trigger for the lung pathology. This suggests that nintedanib inhibits fundamental processes in the pathogenesis of fibrosis. A trial of nintedanib in patients with progressive fibrosing ILDs other than IPF (INBUILD) will report results in 2019.
CRIS-Team Scopus Importer:2019-09-27

PPARβ/δ: A master regulator of mesenchymal stem cell functions - Djouad, Farida; Ipseiz, Natacha; Luz-Crawford, Patricia; Scholtysek, Carina; Krönke, Gerhard; Jorgensen, Christian (Biochimie, 2016)
Peroxisome proliferator-activated receptors (PPARs) have emerged as key regulators of physiological and immunological processes. Recently, one of their members PPAR?/? has been identified as major player in the maintenance of bone homeostasis, by promoting Wnt signalling activity in osteoblast and mesenchymal stem cells (MSC). PPAR?/? not only controls the fate of MSC but also regulates their immunosuppressive properties by directly modulating their NF-?B activity. In this review, we discuss how the regulation of PPAR?/? provides an innovative strategy for an optimisation of MSC-based therapy.
EVALuna2:13380

PPARβ/δ-dependent MSC metabolism determines their immunoregulatory properties - Contreras-Lopez, R. A.; Elizondo-Vega, R.; Torres, M. J.; Vega-Letter, A. M.; Luque-Campos, N.; Paredes-Martinez, M. J.; Pradenas, C.; Tejedor, G.; Oyarce, K.; Salgado, M.; Jorgensen, C.; Khoury, M.; et al. (Scientific Reports, 2020)
Mesenchymal stem cell (MSC)-based therapy is being increasingly considered a powerful opportunity for several disorders based on MSC immunoregulatory properties. Nonetheless, MSC are versatile and plastic cells that require an efficient control of their features and functions for their optimal use in clinic. Recently, we have shown that PPARβ/δ is pivotal for MSC immunoregulatory and therapeutic functions. However, the role of PPARβ/δ on MSC metabolic activity and the relevance of PPARβ/δ metabolic control on MSC immunosuppressive properties have never been addressed. Here, we demonstrate that PPARβ/δ deficiency forces MSC metabolic adaptation increasing their glycolytic activity required for their immunoregulatory functions on Th1 and Th17 cells. Additionally, we show that the inhibition of the mitochondrial production of ATP in MSC expressing PPARβ/δ, promotes their metabolic switch towards aerobic glycolysis to stably enhance their immunosuppressive capacities significantly. Altogether, these data demonstrate that PPARβ/δ governs the immunoregulatory potential of MSC by dictating their metabolic reprogramming and pave the way for enhancing MSC immunoregulatory properties and counteracting their versatility.
CRIS-Team Scopus Importer:2020-07-24

PPARβ/δ directs the therapeutic potential of mesenchymal stem cells in arthritis - Luz-Crawford, P.; Ipseiz, N.; Espinosa-Carrasco, G.; Caicedo, A.; Tejedor, G.; Toupet, K.; Loriau, J.; Scholtysek, C.; Stoll, C.; Khoury, M.; Noel, D.; Jorgensen, C.; et al. (Annals of the Rheumatic Diseases, 2016)
To define how peroxisome proliferator-activated receptor (PPAR) ?/? expression level in mesenchymal stem cells (MSCs) could predict and direct both their immunosuppressive and therapeutic properties. PPAR?/? interacts with factors such as nuclear factor-kappa B (NF-?B) and regulates the expression of molecules including vascular cell adhesion molecule (VCAM)-1 and intercellular adhesion molecule (ICAM)-1. Since these molecules are critical for MSC function, we investigated the role of PPAR?/? on MSC immunosuppressive properties.We either treated human MSCs (hMSCs) with the irreversible PPAR?/? antagonist (GSK3787) or derived MSCs from mice deficient for PPAR?/? (PPAR?/?(-/-) MSCs). We used the collagen-induced arthritis (CIA) as model of immune-mediated disorder and the MSC-immune cell coculture assays.Modulation of PPAR?/? expression in hMSCs either using GSK3787 or hMSCs from different origin reveals that MSC immunosuppressive potential is inversely correlated with Ppard expression. This was consistent with the higher capacity of PPAR?/?(-/-) MSCs to inhibit both the proliferation of T lymphocytes, in vitro, and arthritic development and progression in CIA compared with PPAR?/?(+/+) MSCs. When primed with proinflammatory cytokines to exhibit an immunoregulatory phenotype, PPAR?/?(-/-) MSCs expressed a higher level of mediators of MSC immunosuppression including VCAM-1, ICAM-1 and nitric oxide (NO) than PPAR?/?(+/+) MSCs. The enhanced NO2 production by PPAR?/?(-/-) MSCs was due to the increased retention of NF-?B p65 subunit on the ?B elements of the inducible nitric oxide synthase promoter resulting from PPAR?/? silencing.Our study is the first to show that the inhibition or knockdown of PPAR?/? in MSCs primes their immunoregulatory functions. Thus, the regulation of PPAR?/? expression provides a new strategy to generate therapeutic MSCs with a stable regulatory phenotype.
EVALuna2:13232

PPARβ/δ governs Wnt signaling and bone turnover - Scholtysek, Carina; Katzenbeisser, Julia; Fu, He; Uderhardt, Stefan; Ipseiz, Natacha; Stoll, Cornelia; Zaiss, Mario; Stock, Michael; Donhauser, Laura-Robina; Boehm, Christina; Kleyer, Arnd; Heß, Andreas; et al. (Nature Medicine, 2013)
Peroxisome proliferator-activated receptors (PPARs) act as metabolic sensors and central regulators of fat and glucose homeostasis. Furthermore, PPAR? has been implicated as major catabolic regulator of bone mass in mice and humans. However, a potential involvement of other PPAR subtypes in the regulation of bone homeostasis has remained elusive. Here we report a previously unrecognized role of PPAR?/? as a key regulator of bone turnover and the crosstalk between osteoblasts and osteoclasts. In contrast to activation of PPAR?, activation of PPAR?/? amplified Wnt-dependent and ?-catenin-dependent signaling and gene expression in osteoblasts, resulting in increased expression of osteoprotegerin (OPG) and attenuation of osteoblast-mediated osteoclastogenesis. Accordingly, PPAR?/?-deficient mice had lower Wnt signaling activity, lower serum concentrations of OPG, higher numbers of osteoclasts and osteopenia. Pharmacological activation of PPAR?/? in a mouse model of postmenopausal osteoporosis led to normalization of the altered ratio of tumor necrosis factor superfamily, member 11 (RANKL, also called TNFSF11) to OPG, a rebalancing of bone turnover and the restoration of normal bone density. Our findings identify PPAR?/? as a promising target for an alternative approach in the treatment of osteoporosis and related diseases.
EVALuna2:8501

PPARδ-mediated mitochondrial rewiring of osteoblasts determines bone mass - Müller, Dorothea; Stoll, Cornelia; Palumbo-Zerr, Katrin; Böhm, Christina; Krishnacoumar, Brenda; Ipseiz, Natacha; Taubmann, Jule; Zimmermann, Max; Böttcher, Martin; Mougiakakos, Dimitrios; Tuckermann, Jan; Djouad, Farida; et al. (Scientific Reports, 2020)
Bone turnover, which is determined by osteoclast-mediated bone resorption and osteoblast-mediated bone formation, represents a highly energy consuming process. The metabolic requirements of osteoblast differentiation and mineralization, both essential for regular bone formation, however, remain incompletely understood. Here we identify the nuclear receptor peroxisome proliferator-activated receptor (PPAR) δ as key regulator of osteoblast metabolism. Induction of PPARδ was essential for the metabolic adaption and increased rate in mitochondrial respiration necessary for the differentiation and mineralization of osteoblasts. Osteoblast-specific deletion of PPARδ in mice, in turn, resulted in an altered energy homeostasis of osteoblasts, impaired mineralization and reduced bone mass. These data show that PPARδ acts as key regulator of osteoblast metabolism and highlight the relevance of cellular metabolic rewiring during osteoblast-mediated bone formation and bone-turnover.
CRIS-Team Scopus Importer:2020-06-02

Pre-assessment of patients with suspected axial spondyloarthritis combining student-led clinics and telemedicine: a qualitative study - Boy, Katharina; von Rohr-Wahlen-Jürgaß, Sophie; May, Susann; Kuhn, Sebastian; Schett, Georg; Labinsky, Hannah; Knitza, Johannes; Muehlensiepen, Felix (Rheumatology International, 2024)
Objective: Patients referred to rheumatologists are currently facing months of inefficient waiting time due to the increasing demand and rising workforce shortage. We piloted a pre-assessment of patients with suspected axial spondyloarthritis (axSpA) combining student-led clinics and telemedicine (symptom assessment, symptom monitoring and at-home capillary self-sampling) to improve access to rheumatology care. The aim of this study was to explore (1) current challenges accessing axSpA care and (2) patients’ first-hand experiences. Methods: Embedded within a clinical trial, this study was based on qualitative interviews with patients with suspected axSpA (n = 20). Data was analysed via qualitative content analysis. Results: Student-led clinics were perceived as high-quality care, comparable to conventional rheumatologist-led visits. Patients expressed that their interactions with the students instilled a sense of trust. History-taking and examinations were perceived as comprehensive and meticulous. Telehealth tools were seen as empowering, offering immediate and continuous access to symptom assessment at home. Patients reported a lack of specificity of the electronic questionnaires, impeding accurate responses. Patients requested a comments area to supplement questionnaire responses. Some patients reported receiving help to complete the blood collection. Conclusion: Patients’ access to rheumatology care is becoming increasingly burdensome. Pre-assessment including student-led clinics and telemedicine was highly accepted by patients. Patient interviews provided valuable in-depth feedback to improve the piloted patient pathway.
CRIS-Team Scopus Importer:2024-02-09
Keywords: Diagnosis; Diagnostic delay; eHealth; Rheumatology; Self-sampling; Symptom checkers; Telemedicine

Precision of handheld multispectral optoacoustic tomography for muscle imaging - Wagner, Anna; Danko, Vera; Federle, Anna; Klett, Daniel; Simon, David; Heiß, Rafael; Jüngert, Jörg M.; Uder, Michael; Schett, Georg; Neurath, Markus; Wölfle, Joachim; Waldner, Maximilian; et al. (Photoacoustics, 2021)
Photo-or optoacoustic imaging (OAI) allows quantitative imaging of target tissues. Using multi-wavelength illumination with subsequent ultrasound detection, it may visualize a variety of different chromophores at centimeter depth. Despite its non-invasive, label-free advantages, the precision of repeated measurements for clinical applications is still elusive. We present a multilayer analysis of n = 1920 imaging datasets obtained from a prospective clinical trial (NCT03979157) in n = 10 healthy adult volunteers. All datasets were analyzed for 13 single wavelengths (SWL) between 660 nm–1210 nm and five MSOT-parameters (deoxygenated/oxygenated/total hemoglobin, collagen and lipid) by a semi-automated batch mode software. Intraclass correlation coefficients (ICC) were good to excellent for intrarater (SWL: 0.82–0.92; MSOT-parameter: 0.72−0.92) and interrater reproducibility (SWL: 0.79−0.87; MSOT-parameter: 0.78−0.86), with the exception for MSOT-parameter lipid (interrater ICC: 0.56). Results were stable over time, but exercise-related effects as well as inter-and intramuscular variability were observed. The findings of this study provide a framework for further clinical OAI implementation.
CRIS-Team Scopus Importer:2020-12-25
Keywords: MSOT; Multispectral optoacoustic tomography; Muscle imaging; Optoacoustics; Photoacoustics

Predictability of a modified Mini- Nutritional- Assessment version on six-month and one-year mortality in hospitalized geriatric patients: a comparative analysis - Becker, Lea; Volkert, Dorothee; Sieber, Cornel; Gaßmann, Karl-Günter; Ritt, Martin (Scientific Reports, 2019)
Recently we introduced a modified Mini Nutritional Assessment (MNA) Short Form (MNA-SF) and Long Form (MNA-SF) with operationalization of the ‘mobility’ and ‘neuropsychological problems’ items of the MNA using scores on Barthel Index mobility item and Mini Mental State Examination and Geriatric Depression Scale scores. We have now evaluated the abilities of this modified MNA-SF and MNA-LF to predict mortality in comparison with the standard MNA-SF and MNA-LF and the Nutritional Risk Screening 2002 (NRS 2002) and the Malnutrition Universal Screening Tool (MUST). A prospective analysis was performed in 240 hospitalised geriatric patients aged ≥ 65 years. Malnutrition and/or malnutrition risk were assessed using the modified MNA-SF and MNA-LF, the standard MNA-SF and MNA-LF, and the NRS 2002 and MUST. The modified MNA-SF and MNA-LF and the standard MNA-SF and MNA-LF assessments (all p < 0.05), but not NRS 2002 or MUST (all p ≥ 0.05), predicted six-month and/or one-year mortality. Prediction of six-month and/or one-year mortality by the modified MNA-SF was comparable with predictions by the standard MNA-SF and MNA-LF (all p ≥ 0.05). The modified MNA-LF showed better prediction of six-month and one-year mortality than the standard MNA-SF and MNA-LF (all p < 0.05). The modified MNA-LF (all adjusted p < 0.05), but none of the other instruments (all adjusted p ≥ 0.05), predicted six-month and one-year mortality independently of age, sex, frailty, comorbidity and ADL disability burden. The modified MNA-SF and MNA-LF emerged as potentially valuable tools for predicting mortality in patients hospitalised on geriatric wards.
CRIS-Team Scopus Importer:2019-07-02

Prediction of disease relapses by multibiomarker disease activity and autoantibody status in patients with rheumatoid arthritis on tapering DMARD treatment - Rech, Juergen; Hueber, Axel; Finzel, Stephanie; Englbrecht, Matthias; Haschka, Judith; Manger, Bernhard; Kleyer, Arnd; Reiser, Michaela; Cobra, Jayme Fogagnolo; Figueiredo, Camille; Tony, Hans-Peter; Kleinert, Stefan; et al. (Annals of the Rheumatic Diseases, 2016)
To analyse the role of multibiomarker disease activity (MBDA) score in predicting disease relapses in patients with rheumatoid arthritis (RA) in sustained remission who tapered disease modifying antirheumatic drug (DMARD) therapy in RETRO, a prospective randomised controlled trial.MBDA scores (scale 1-100) were determined based on 12 inflammation markers in baseline serum samples from 94 patients of the RETRO study. MBDA scores were compared between patients relapsing or remaining in remission when tapering DMARDs. Demographic and disease-specific parameters were included in multivariate logistic regression analysis for defining predictors of relapse.Moderate-to-high MBDA scores were found in 33% of patients with RA overall. Twice as many patients who relapsed (58%) had moderate/high MBDA compared with patients who remained in remission (21%). Baseline MBDA scores were significantly higher in patients with RA who were relapsing than those remaining in stable remission (N=94; p=0.0001) and those tapering/stopping (N=59; p=0.0001). Multivariate regression analysis identified MBDA scores as independent predictor for relapses in addition to anticitrullinated protein antibody (ACPA) status. Relapse rates were low (13%) in patients who were MBDA-/ACPA-, moderate in patients who were MBDA+/ACPA- (33.3%) and MBDA-ACPA+ (31.8%) and high in patients who were MBDA+/ACPA+ (76.4%).MBDA improved the prediction of relapses in patients with RA in stable remission undergoing DMARD tapering. If combined with ACPA testing, MBDA allowed prediction of relapse in more than 80% of the patients.EudraCT 2009-015740-42.
EVALuna2:13128

Prediction of Disease Relapses by Multi-biomarker Disease Activity Score and Autoantibody Status in RA Patients Tapering DMARD Treatment in Stable Remission - Hagen, Melanie; Tascilar, Koray; Reiser, Michaela; Haschka, Judith; Kleyer, Arnd; Valor, Larissa; Manger, Bernhard; Schett, Georg; Rech, Jürgen (ARTHRITIS & RHEUMATOLOGY, 2019)
CRIS-Team WoS Importer:2020-02-07

Prediction of Disease Relapses By Multi-Biomarker Disease Test Activity in Rheumatoid Arthritis Patients Tapering DMARD Treatment - Rech, Jürgen; Hueber, Axel; Englbrecht, Matthias; Finzel, Stephanie; Haschka, Judith; Manger, Bernhard; Kleyer, Arnd; Reiser, Michaela; Tony, Hans-Peter; Kleinert, Stefan; Feuchtenberger, Martin; Fleck, Martin; et al. (2015)
EVALuna2:13331

PREDICTION OF FLARES FOR RHEUMATOID ARTHRITIS PATIENTS ON BIOLOGIC DMARDS USING MACHINE LEARNING AND SUBSETS OF VARIABLES AVAILABLE TO PHYSICIANS, PATIENTS AND PAYERS - Vodencarevic, A.; Tascilar, K.; Hartmann, F.; Reiser, M.; Bayat, Sara; Knitza, Johannes; Valor, L.; Hagen, Melanie; Hueber, Axel; Kleyer, Arnd; Zimmermann-Rittereiser, M.; Schett, Georg; et al. (ANNALS OF THE RHEUMATIC DISEASES, 2020)
CRIS-Team WoS Importer:2020-08-21

PREDICTION OF PROGRESSIVE SKIN THICKENING IN EARLY DIFFUSE SYSTEMIC SCLEROSIS USING THREE-MONTHLY SKIN SCORES FROM THE EUROPEAN SCLERODERMA OBSERVATIONAL STUDY (ESOS) - Herrick, A.; Peytrignet, S.; Pan, X.; Hesselstrand, R.; Mouthon, L.; Brown, E.; Czirjak, L.; Distler, Jörg; Distler, O.; Fligelstone, K.; Gregory, W.; Ochiel, R.; et al. (2017)
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Prediction of Response to Certolizumab-Pegol in Rheumatoid Arthritis By Functional MRI of the Brain - an Interim Analysis of an Ongoing Investigator Initiated Phase III Trial - Schenker, Hannah; Heß, Andreas; Konerth, Laura; Sergeeva, Marina; Prade, Jutta; Kleyer, Arnd; Reiser, Michaela; Hueber, Axel; Englbrecht, Matthias; Feist, Eugen; Voll, Reinhard; Bannert, Bettina; et al. (2017)
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Prediction of response to Certolizumab-Pegol in rheumatoid arthritis (PreCePRA) by functional MRI of the brain – Study protocol for a randomized double-blind controlled study - Schenker, Hannah; Tascilar, Koray; Konerth, Laura; Sergeeva, Marina; Prade, Jutta; Strobelt, Sandra; Kleyer, Arnd; Simon, David; Mendez, L.; Hagen, Melanie; Schönau, V.; Hueber, A.; et al. (Contemporary Clinical Trials Communications, 2021)
Background: Tumor necrosis factor inhibitors (TNFi) signify a major advance in the treatment of rheumatoid arthritis (RA). However, treatment success initially remains uncertain as approximately half of the patients do not respond adequately to TNFi. Thus, an unmet need exists to better predict therapeutic outcome of biologicals. Objectives: We investigated whether brain activity associated with arthritis measured by functional magnetic resonance imaging (fMRI) of the brain can serve as a predictor of response to TNFi in RA patients. Methods: PreCePRA is a multi-center, randomized, double-blind, placebo-controlled fMRI trial on patients with RA [1] [2]. Active RA patients failing csDMARDs therapy with a DAS28 > 3.2 and at least three tender and/or swollen joints underwent a brain BOLD (blood-oxygen-level dependent) fMRI scan upon joint compression at screening. Patients were then randomized into a 12-week double-blinded treatment phase with 200 mg Certolizumab Pegol (CZP) every two weeks (arm 1: fMRI BOLD signal activated volume > 2000 voxel, i.e. 2 cm3; arm 2: fMRI BOLD signal activated volume <2000 voxel) or placebo (arm 3). DAS28 low disease activity at 12 weeks was assigned as primary endpoint. A 12-week follow-up phase in which patients were switched from the placebo to the treatment arm followed the blinded phase. fMRI was carried out at screening as well as after 12 and 24 weeks of receiving CZP or placebo. Conclusion: We hypothesize that high-level central nervous representation of pain in patients with rheumatoid arthritis predicts response to the TNFi CZP which we further investigate in the PreCePRA trial.
CRIS-Team Scopus Importer:2021-06-04
Keywords: functional MRI; Neuroimaging; Rheumatoid arthritis; TNF inhibition

PREDICTION OF RESPONSE TO CERTOLIZUMAB PEGOL TREATMENT BY FUNCTIONAL MRI OF THE BRAIN: AN INTERNATIONAL, MULTI-CENTER, RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED TRIAL (PRECEPRA) - Rech, Jürgen; Tascilar, K.; Schenker, Hannah; Sergeeva, Marina; Selvakumar, Mageshwar; Konerth, Laura; Prade, Jutta; Strobelt, Sandra; Hagen, Melanie; Schonau, V.; Valor, L.; Hueber, A.; et al. (ANNALS OF THE RHEUMATIC DISEASES, 2020)
CRIS-Team WoS Importer:2020-08-21

Prediction of worsening of skin fibrosis in patients with diffuse cutaneous systemic sclerosis using the EUSTAR database - Maurer, Britta; Graf, Nicole; Michel, Beat A; Müller-Ladner, Ulf; Czirják, László; Denton, Christopher P; Tyndall, Alan; Metzig, Carola; Lanius, Vivian; Khanna, Dinesh; Distler, Oliver; EUSTAR co-authors,; et al. (Annals of the Rheumatic Diseases, 2015)
To identify predictive parameters for the progression of skin fibrosis within 1 year in patients with diffuse cutaneous SSc (dcSSc).An observational study using the EUSTAR database was performed. Inclusion criteria were dcSSc, American College of Rheumatology (ACR) criteria fulfilled, modified Rodnan skin score (MRSS) >=7 at baseline visit, valid data for MRSS at 2nd visit, and available follow-up of 12±2 months. Worsening of skin fibrosis was defined as increase in MRSS >5 points and >=25% from baseline to 2nd visit. In the univariate analysis, patients with progressive fibrosis were compared with non-progressors, and predictive markers with p<0.2 were included in the logistic regression analysis. The prediction models were then validated in a second cohort.A total of 637 dcSSc patients were eligible. Univariate analyses identified joint synovitis, short disease duration (<=15 months), short disease duration in females/patients without creatine kinase (CK) elevation, low baseline MRSS (<=22/51), and absence of oesophageal symptoms as potential predictors for progressive skin fibrosis. In the multivariate analysis, by employing combinations of the predictors, 17 models with varying prediction success were generated, allowing cohort enrichment from 9.7% progressive patients in the whole cohort to 44.4% in the optimised enrichment cohort. Using a second validation cohort of 188 dcSSc patients, short disease duration, low baseline MRSS and joint synovitis were confirmed as independent predictors of progressive skin fibrosis within 1 year resulting in a 4.5-fold increased prediction success rate.Our study provides novel, evidence-based criteria for the enrichment of dcSSc cohorts with patients who experience worsening of skin fibrosis which allows improved clinical trial design.
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Predictors for the Development of Systemic Sclerosis Associated Interstitial Lung Disease (SSc-ILD) - Data from the German SSc-Network - Kreuter, M.; Bonella, F.; Blank, N.; Siegert, E.; Henes, J.; Worm, M.; Sunderkoetter, C.; Schmalzing, M.; Kreuter, A.; Guenther, C.; Susok, L.; Zeidler, G.; et al. (AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE, 2019)
CRIS-Team WoS Importer:2019-05-21

Predictors of disease worsening defined by progression of organ damage in diffuse systemic sclerosis: a European Scleroderma Trials and Research (EUSTAR) analysis - Becker, Mike; Graf, Nicole; Sauter, Rafael; Allanore, Yannick; Curram, John; Denton, Christopher P.; Khanna, Dinesh; Matucci-Cerinic, Marco; Pena, Janethe De Oliveira; Pope, Janet E.; Distler, Oliver; Matucci-Cerinic, Marco; et al. (Annals of the Rheumatic Diseases, 2019)
Objectives Mortality and worsening of organ function are desirable endpoints for clinical trials in systemic sclerosis (SSc). The aim of this study was to identify factors that allow enrichment of patients with these endpoints, in a population of patients from the European Scleroderma Trials and Research group database.
CRIS-Team WoS Importer:2019-10-04

Predictors of progression in systemic sclerosis patients with interstitial lung disease - Distler, Oliver; Assassi, Shervin; Cottin, Vincent; Cutolo, Maurizio; Danoff, Sonye K.; Denton, Christopher P.; Distler, Jörg; Hoffmann-Vold, Anna-Maria; Johnson, Sindhu R.; Ladner, Ulf Mueller; Smith, Vanessa; Volkmann, Elizabeth R.; et al. (European Respiratory Journal, 2020)
Systemic sclerosis (SSc) is a systemic autoimmune disease affecting multiple organ systems, including the lungs. Interstitial lung disease (ILD) is the leading cause of death in SSc. There are no valid biomarkers to predict the occurrence of SSc-ILD, although auto-antibodies against anti-topoisomerase I and several inflammatory markers are candidate biomarkers that need further evaluation. Chest auscultation, presence of shortness of breath and pulmonary function testing are important diagnostic tools, but lack sensitivity to detect early ILD. Baseline screening with high-resolution computed tomography (HRCT) is therefore necessary to confirm an SSc-ILD diagnosis. Once diagnosed with SSc-ILD, patients' clinical courses are variable and difficult to predict, although certain patient characteristics and biomarkers are associated with disease progression. It is important to monitor patients with SSc-ILD for signs of disease progression, although there is no consensus about which diagnostic tools to use or how often monitoring should occur. In this article, we review methods used to define and predict disease progression in SSc-ILD. There is no valid definition of SSc-ILD disease progression, but we suggest that either a decline in forced vital capacity (FVC) from baseline of >= 10%, or a decline in FVC of 5-9% in association with a decline in diffusing capacity of the lung for carbon monoxide of >= 15% represents progression. An increase in the radiographic extent of ILD on HRCT imaging would also signify progression. A time period of 1- 2 years is generally used for this definition, but a decline over a longer time period may also reflect clinically relevant disease progression.
CRIS-Team WoS Importer:2020-07-31

PRE-EXPOSURE PROPHYLAXIS FOR SARS-COV-2 INFECTION WITH SUBCUTANEOUS CASIRIVIMAB/IMDEVIMAB IN PATIENTS WITH IMMUNE MEDIATED INFLAMMATORY DISEASES. - Fagni, Filippo; Schmidt, Katja; Bohr, Daniela; Valor, L.; Hartmann, F.; Tascilar, Koray; Manger, K.; Manger, Bernhard; Kleyer, Arnd; Simon, David; Schett, Georg; Harrer, Thomas (ANNALS OF THE RHEUMATIC DISEASES, 2022)
CRIS-Team WoS Importer:2022-11-04

Premature Osteoarthritis as Presenting Sign of Type II Collagenopathy: A Case Report and Literature Review - Husar-Memmer, Emma; Ekici, Arif Bülent; Al Kaissi, Ali; Sticht, Heinrich; Manger, Bernhard; Schett, Georg; Zwerina, Jochen (Seminars in Arthritis and Rheumatism, 2013)
Osteoarthritis (OA) is a frequent, chronic, and often disabling disease. Early-onset OA should prompt rheumatologists to search for underlying causes. We describe the clinical presentation and diagnosis of a patient with severe premature OA.We report a patient with severe polyarticular OA starting in young adulthood due to a heterozygous mutation in the COL2A1 gene. We discuss the clinical features, diagnosis, and known mutations of previously reported cases identified through a PubMed literature review.A 43-year-old Caucasian woman of normal stature presented with a 24-year history of symmetrical polyarticular OA involving both large and small joints. At the time of presentation, the patient already underwent 6 joint replacement surgeries. Family history was unremarkable. Clinical, serologic, radiographic, and histologic studies did not reveal any specific cause for this unusual clinical presentation. Genetic analysis revealed a heterozygous COL2A1 mutation (R519C) consistent with the clinical phenotype. Reviewing the literature, we discuss the clinical spectrum of type II collagenopathies emphasizing premature OA as the sole clinical manifestation.Unusual clinical presentations of OA should prompt investigations to search for an underlying cause. Type II collagenopathy should be considered in young adults with severe symmetrical OA even in the absence of other clinical features. A correct diagnosis allows classification and genetic counseling of the patient.
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Presence of HLA-B27 is associated with changes of serum levels of mediators of the Wnt and hedgehog pathway - Aschermann, Sarah; Englbrecht, Matthias; Bergua, Antonio; Spriewald, Bernd M.; Said-Nahal, Rhula; Breban, Maxime; Schett, Georg; Rech, Juergen (Joint Bone Spine, 2016)
HLA-B27 is present in 5% of the Caucasian population and is strongly associated with the development of spondyloarthritis (SpA), a disease characterized by inflammation and substantial bone changes. We hypothesized that the presence of HLA-B27 in itself is associated with alterations of key regulatory of bone homeostasis.Sera of 241 individuals were assessed for the serum levels of Wnt pathway regulators, sclerostin and dickkopf (Dkk)-1 as well as Indian hedgehog (IHH) and collagen type I cleavage products (CTX1). Of the 151 HLA-B27+ subjects, 31 had SpA, 30 had anterior uveitis, 30 were healthy individuals and 60 healthy siblings of patients with SpA.Sclerostin levels were significantly (P<0.001) lower in HLA-B27+ subjects (314±21pg/mL) compared to HLA-B27 negative controls (mean±SEM: 492±30pg/mL), no matter if subjects were either healthy, or affected by SpA or uveitis. Similar results were found for Dkk-1. No differences between the groups with respect to the bone resorption marker CTX1 were found. In contrast, IHH levels were significantly (P<0.001) higher in the carriers of HLA-B27 than in the negative controls.Changes in key regulators of the Wnt pathway as well as IHH, a molecule regulating endochondral ossification, are found in HLA-B27 carriers, independent if they were healthy or affected by uveitis or SpA.
EVALuna2:13168

PREVALENCE AND CHARACTERISTICS OF SPONDYLOARTHRITIS ACCORDING TO ASAS CRITERIA IN PATIENTS WITH INFLAMMATORY BOWEL DISEASE - RESULTS FROM THE SPICE COHORT - Haschka, J.; Hirschmann, S.; Kleyer, Arnd; Englbrecht, Matthias; Zimmermann, Julia; Faustini, F.; Simon, David; Figueiredo, C. P.; Muschitz, C.; Kocijan, R.; Resch, H.; Atreya, Raja; et al. (2017)
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Prevalence and clinical associations of ultrasound-confirmed enthesitis in systemic lupus erythematosus - Fagni, Filippo; Bettiol, Alessandra; Silvestri, Elena; Fedi, Roberto; Palermo, Adalgisa; Urban, Maria Letizia; Mazzotta, Ruggero; Malandrino, Danilo; Bello, Federica; Mattioli, Irene; Simon, David; Di Scala, Gerardo; et al. (Rheumatology, 2023)
Objectives To assess the prevalence of US-confirmed enthesitis in a cohort of patients with SLE and to analyse the clinical associations to enthesitis during the course of SLE. Methods In a retrospective analysis of the SLE cohort of the Lupus Unit of the Careggi University Hospital, US examinations of SLE patients presenting with tender and/or swollen joints were retrieved to assess the presence of enthesitis. Patients with US-proven enthesitis were compared with SLE controls with tender and/or swollen joints who showed no US evidence of enthesitis. Clinical and laboratory features were compared at disease onset and during follow-up. Results A total of 400 patients fulfilling EULAR/ACR classification criteria for SLE were assessed. Of these, 106 underwent articular US examination. Evidence of enthesitis was found in 31/106 (29.2%) patients. Seventy-one patients without US-enthesitis were included as controls; four were excluded due to lack of follow-up data. Laboratory and clinical features were comparable between cases and controls at disease onset. Throughout a median follow-up of 10.0 (interquartile range [IQR] 8.3-23.3) years for cases and 12.4 (IQR 7.2-13.3) years for controls, patients with enthesitis were less likely to develop renal involvement (22.6% vs 46.5%, P = 0.028) and failed B cell depletion more frequently (75.0% vs 0%). Conclusion In SLE patients with clinically active joints, US-proven enthesitis is a fairly common finding. Enthesitis in SLE could be the hallmark of a distinct disease phenotype with less renal involvement, more arthritis and low response to anti-CD 20 therapy, potentially requiring a tailored treatment.
CRIS-Team WoS Importer:2023-04-21

Prevalence of monosodium urate deposits in a population of rheumatoid arthritis patients with hyperuricemia - Petsch, Christina; Araujo, Elizabeth G.; Englbrecht, Matthias; Bayat, Sara; Hueber, Axel; Lell, Michael; Schett, Georg; Manger, Bernhard; Rech, Jürgen; Cavallaro, Alexander Josef (Seminars in Arthritis and Rheumatism, 2015)
To investigate the prevalence of monosodium urate (MSU) crystal deposits, indicative for gout, in a population of rheumatoid arthritis (RA) patients with concomitant hyperuricemia and to analyze the clinical and disease-specific characteristics of RA patients who exhibit MSU crystal deposits.Overall, 100 consecutive patients with the diagnosis of RA and a serum urate level above 6mg/dl underwent dual energy computed tomography (DECT) of both feet and hands to search for MSU crystals in a prospective study between October 2011 and July 2013. Presence and extent of MSU crystal deposits on DECT was assessed by automated volume measurement. Demographic and disease-specific characteristics were recorded and included into two logistic regression models to test for the factors associated with MSU crystal deposits in RA.Hyperuricemic RA patients were mostly male (55%), over 60 years of age (63 ± 11 years), had established disease (8.7 ± 10.5 years) and a mean disease activity score 28 (DAS 28) of 3.2. In total, 20 out of 100 patients displayed MSU crystal deposits in DECT. Interestingly, the majority (70%) of the RA patients positive for MSU crystal deposits were seronegative RA patients. Hence, every third seronegative RA patient had MSU crystal deposits. According to logistic regression model analysis, seronegative status correlated positively with presence of urate deposits (p = 0.019).These data show that a considerable number of RA patients display periarticular MSU crystal deposits. Seronegative patients were shown to be predominantly affected with every third patient being positive for urate deposits.
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PROFIBROTIC LNCRNA H19X: UNRAVELLING THE EFFECTS ON CHROMATIN REMODELING IN SYSTEMIC SCLEROSIS FIBROBLASTS - Pachera, Elena; Assassi, Shervin; Salazar, Gloria; Frank-Bertoncelj, Mojca; Distler, Jörg; Kania, Gabriela; Distler, Oliver (ANNALS OF THE RHEUMATIC DISEASES, 2019)
CRIS-Team WoS Importer:2019-07-12

Progressive fibrosing interstitial lung disease associated with systemic autoimmune diseases - Fischer, Aryeh; Distler, Jörg (Clinical Rheumatology, 2019)
Interstitial lung disease (ILD) is a common manifestation of systemic autoimmune diseases and a leading cause of death in these patients. A proportion of patients with autoimmune ILDs develop a progressive fibrosing form of ILD, characterized by increasing fibrosis on high-resolution computed tomography, worsening of lung function, and early mortality. Autoimmune disease–related ILDs have a variable clinical course and not all patients will require treatment, but all patients should be monitored for signs of progression. Apart from systemic sclerosis–associated ILD, the limited evidence to support the efficacy of immunosuppression as a treatment for ILDs is based mainly on small retrospective series and expert opinion. Non-clinical data suggest that there are commonalities in the mechanisms that drive progressive fibrosis in ILDs with an immunological trigger as in other forms of progressive fibrosing ILD. This suggests that nintedanib and pirfenidone, drugs known to slow disease progression in patients with idiopathic pulmonary fibrosis, may also slow the progression of ILD associated with systemic autoimmune diseases. In the SENSCIS® trial, nintedanib reduced the rate of ILD progression in patients with systemic sclerosis–associated ILD. The results of other large clinical trials will provide further insights into the role of anti-fibrotic therapies in the treatment of autoimmune disease–related ILDs.
CRIS-Team Scopus Importer:2019-08-30
Keywords: Connective tissue diseases; Mortality; Pulmonary fibrosis; Rheumatic diseases; Systemic sclerosis

Progressive skin fibrosis is associated with a decline in lung function and worse survival in patients with diffuse cutaneous systemic sclerosis in the European Scleroderma Trials and Research (EUSTAR) cohort - Wu, Wanlong; Jordan, Suzana; Graf, Nicole; Pena, Janethe De Oliveira; Curram, John; Allanore, Yannick; Matucci-Cerinic, Marco; Pope, Janet E.; Denton, Christopher P.; Khanna, Dinesh; Distler, Oliver; Matucci-Cerinic, Marco; et al. (Annals of the Rheumatic Diseases, 2019)
Objectives To determine whether progressive skin fibrosis is associated with visceral organ progression and mortality during follow-up in patients with diffuse cutaneous systemic sclerosis (dcSSc).
CRIS-Team WoS Importer:2019-06-25

Promotion of colorectal cancer cell death by ezetimibe via mTOR signaling-dependent mitochondrial dysfunction - Zheng, Yuanyuan; Yang, Wenjuan; Jia, Yewei; Ji, Jie; Wu, Liwei; Feng, Jiao; Li, Yan; Cheng, Ziqi; Zhang, Jie; Li, Jingjing; Dai, Weiqi; Xu, Xuanfu; et al. (Frontiers in Pharmacology, 2023)
Introduction: Colorectal cancer (CRC) is the fourth most common cancer worldwide, with high morbidity and mortality rates. In recent years, high-fat diet has been shown to increase CRC morbidity, highlighting the possibility of the application of hypolipidemic drugs for CRC treatment. In this study, we preliminarily evaluated the effects and mechnisms of ezetimibe against CRC through the blockage of lipid absorption in small intesine. Methods: In this study, CRC cell proliferation, invasion, apoptosis, and autophagy were evaluated using cellular and molecular assays. Fluorescent microscopy, and a flow cytometric assay were used to assess mitochondrial activity in vitro. A subcutaneous xenograft mouse model was used to evaluate the effects of ezetimibe in vivo. Results: We found that ezetimibe inhibited CRC cell proliferation, and migration, and facilitated autophage-associated apoptosis in HCT116 and Caco2 cells. Ezetimibe-induced mitochondrial dysfunction in CRC cells was found to be correlated with mTOR signaling activity. Discussion: Ezetimibe exhibits effects against CRC through the promotion of cancer cell death via mTOR signaling-dependent mitochondrial dysfunction, highlighting its potential value in CRC therapy.
CRIS-Team Scopus Importer:2023-03-03
Keywords: cell death; colorectal cancer; ezetimibe; mitochondrial dysfunction; MTOR signaling

Propionate induced bacterial-derived histamine promotes resolution of synovial inflammation - Dürholz, Kerstin; Lucas, Sébastien; Schmid, Eva; Schaelter, F.; Frech, Michael; Azizov, Vugar; Hofmann, Jörg; Iljazovic, A.; Strowig, T.; Taudte, Verena; Fromm, Martin; Xiang, Wei; et al. (EUROPEAN JOURNAL OF IMMUNOLOGY, 2022)
CRIS-Team WoS Importer:2023-01-27

Propionic acid beneficially modifies osteoporosis biomarkers in patients with multiple sclerosis. - Duscha, Alexander; Hegelmaier, Tobias; Dürholz, Kerstin; Desel, Christiane; Gold, Ralf; Zaiss, Mario; Haghikia, Aiden (Therapeutic Advances in Neurological Disorders, 2022)
BACKGROUND: The impact of the gut and its microbiota are increasingly appreciated in health and disease. Short-chain fatty acids (SCFAs) are among the main metabolites synthesized from bacterial fermentation. Recently, we showed the anti-inflammatory and potentially neuroprotective effect of propionic acid (PA) in multiple sclerosis (MS). Osteoporosis is one of the most common co-morbidities for MS patients with limited therapeutic options available. Osteoporosis is closely linked to an imbalance of cells of the immune system and an immune-mediated impact on bone structure via the gut has been shown. Interestingly, intake of SCFA leads to bone mass increase and concomitant reduction of inflammation-induced bone loss in mice. OBJECTIVE: To determine the impact of PA supplementation on markers of bone metabolism in MS patients. METHODS: We investigated the influence of 14 days supplementation with PA on bone metabolism in 20 MS patients. To this end, β-CrossLaps and osteocalcin, established markers of bone metabolism, were measured in serum before and after PA intake and correlated with phenotypic and functional immunodata. RESULTS: Supplementation with PA induced a significant increase in serum levels of osteocalcin, a surrogate marker for bone formation. Levels of β-CrossLaps, a marker for bone resorption, were significantly decreased after therapy. Regulatory T-cell (Treg) numbers and suppressive capacity positively correlated with serum levels of osteocalcin while Th17 cell numbers showed an inverse correlation. Our findings are in line with animal studies showing that SCFA induced increased bone formation and reduced bone resorption. CONCLUSION: In addition to its immune regulatory, disease-modifying effect on MS disease course, supplementation with PA beneficially influences serum levels of β-CrossLaps and osteocalcin and may thus also protect against osteoporosis, a common co-morbidity in MS.
EVALuna2:513178

Prospective Studies on the Risk of Rheumatoid Arthritis: The European Risk RA Registry - Studenic, Paul; Hensvold, Aase; Kleyer, Arnd; Van Der Helm-Van Mil, Annette; Pratt, Arthur G.; Sieghart, Daniela; Krönke, Gerhard; Williams, Ruth; De Souza, Savia; Karlfeldt, Susanne; Johannesson, Martina; Krogh, Niels Steen; et al. (Frontiers in Medicine, 2022)
Background: The accumulation of risk for the development of rheumatoid arthritis (RA) is regarded as a continuum that may start with interacting environmental and genetic factors, proceed with the initiation of autoimmunity, and result in the formation of autoantibodies such as anti-citrullinated peptide antibodies (ACPA). In parallel, at-risk individuals may be asymptomatic or experience joint pain (arthralgia) that is itself non-specific or clinically suspicious for evolving RA, even in the absence of overt arthritis. Optimal strategies for the management of people at-risk of RA, both for symptom control and to delay or prevent progression to classifiable disease, remain poorly understood. Methods: To help address this, groups of stakeholders from academia, clinical rheumatology, industry and patient research partners have collaborated to advance understanding, define and study different phases of the at-risk state. In this current report we describe different European initiatives in the field and the successful effort to build a European Registry of at-risk people to facilitate observational and interventional research. Results: We outline similarities and differences between cohorts of at-risk individuals at institutions spanning several countries, and how to best combine them within the new database. Over the past 2 years, besides building the technical infrastructure, we have agreed on a core set of variables that all partners should strive to collect for harmonization purposes. Conclusion: We emphasize to address this process from different angles and touch on the biologic, epidemiologic, analytic, and regulatory aspects of collaborative studies within a meta-database of people at-risk of RA.
CRIS-Team Scopus Importer:2022-03-18
Keywords: database; multi-center study; observational; prevention; rheumatoid arthritis

Protein kinases G are essential downstream mediators of the antifibrotic effects of sGC stimulators - Matei, Alexandru-Emil; Beyer, Christian; Gyoerfi, Andrea-Hermina; Soare, Alina; Chen, Chih-Wei; Dees, Clara; Bergmann, Christina; Friebe, Andreas; Hofmann, Franz; Distler, Oliver; Schett, Georg; Distler, Jörg; et al. (Annals of the Rheumatic Diseases, 2018)
Stimulators of soluble guanylate cyclase (sGC) are currently investigated in clinical trials for the treatment of fibrosis in systemic sclerosis (SSc). In this study, we aim to investigate the role of protein kinases G (PKG) as downstream mediators of sGC-cyclic guanosine monophosphate (cGMP) in SSc.Mice with combined knockout of PKG1 and 2 were challenged with bleomycin and treated with the sGC stimulator BAY 41-2272. Fibroblasts were treated with BAY 41-2272 and with the PKG inhibitor KT 5823.PKG1 and 2 are upregulated in SSc in a transforming growth factor-?1 (TGF?1)-dependent manner, as an attempt to compensate for the decreased signalling through the sGC-cGMP-PKG pathway. Inhibition or knockout of PKG1 and 2 abrogates the inhibitory effects of sGC stimulation on fibroblast activation in a SMAD-independent, but extracellular signal-regulated kinase (ERK)-dependent manner. In vivo, sGC stimulation fails to prevent bleomycin-induced fibrosis in PKG1 and 2 knockout mice.Our data provide evidence that PKGs are essential mediators of the antifibrotic effects of sGC stimulators through interfering with non-canonical TGF? signalling. TGF?1 promotes its profibrotic effects through inhibition of sGC-cGMP-PKG signalling, sGC stimulation exerts its antifibrotic effects by inhibition of TGF?1-induced ERK phosphorylation.
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