12/15-Lipoxygenase counteracts inflammation and tissue damage in arthritis - Krönke, Gerhard; Katzenbeisser, Julia; Uderhardt, Stefan; Zaiss, Mario; Scholtysek, Carina; Schabbauer, Gernot; Zarbock, Alexander; Koenders, Marije I.; Axmann, Roland; Zwerina, Jochen; Baenckler, Hans W.; Van Den Berg, Wim; et al. (Journal of Immunology, 2009)
Eicosanoids are essential mediators of the inflammatory response and contribute both to the initiation and the resolution of inflammation. Leukocyte-type 12/15-lipoxygenase (12/15-LO) represents a major enzyme involved in the generation of a subclass of eicosanoids, including the anti-inflammatory lipoxin A4 (LXA4). Nevertheless, the impact of 12/15-LO on chronic inflammatory diseases such as arthritis has remained elusive. By using two experimental models of arthritis, the K/BxN serum-transfer and a TNF transgenic mouse model, we show that deletion of 12/15-LO leads to uncontrolled inflammation and tissue damage. Consistent with these findings, 12/15-LO-deficient mice showed enhanced inflammatory gene expression and decreased levels of LXA4 within their inflamed synovia. In isolated macrophages, the addition of 12/15-LO-derived eicosanoids blocked both phosphorylation of p38MAPK and expression of a subset of proinflammatory genes. Conversely, 12/15-LO-deficient macrophages displayed significantly reduced levels of LXA4, which correlated with increased activation of p38MAPK and an enhanced inflammatory gene expression after stimulation with TNF-α. Taken together, these results support an anti-inflammatory and tissue-protective role of 12/15-LO and its products during chronic inflammatory disorders such as arthritis. Copyright © 2009 by The American Association of Immunologists, Inc.
CRIS-Team Scopus Importer:2020-11-20

12/15-Lipoxygenase during the regulation of inflammation, immunity, and self-tolerance - Uderhardt, Stefan; Krönke, Gerhard (Journal of Molecular Medicine, 2012)
12/15-Lipoxygenase (12/15-LO) catalyzes the oxidation of free and esterified fatty acids thereby generating a whole spectrum of bioactive lipid mediators. This enzyme is involved in the regulation of various homeostatic processes as well as in the pathogenesis of multiple diseases. During the innate and adaptive immune response, 12/15-LO and its products exert both pro- and anti-inflammatory effects. Likewise, this enzyme has been implicated in the pathogenesis of autoimmune disease as well as in the maintenance of self-tolerance. This review will summarize our current knowledge about the role of 12/15-LO and will try to examine the two faces of this enzyme within the context of inflammation and immunity. © 2012 Springer-Verlag.
CRIS-Team Scopus Importer:2020-11-20
Keywords: 12/15-Lipoxygenase; Clearance of apoptotic cells; Immunity; Inflammation; Oxidized phospholipids; Resident macrophages; Resolution of inflammation; Self-tolerance

12/15-Lipoxygenase-mediated enzymatic lipid oxidation regulates DC maturation and function - Rothe, Tobias; Gruber, Florian; Uderhardt, Stefan; Ipseiz, Natacha; Rössner, Susanne; Oskolkova, Olga; Blueml, Stephan; Leitinger, Norbert; Bicker, Wolfgang; Bochkov, Valery N.; Yamamoto, Masayuki; Steinkasserer, Alexander; et al. (Journal of Clinical Investigation, 2015)
DCs are able to undergo rapid maturation, which subsequently allows them to initiate and orchestrate T cell-driven immune responses. DC maturation must be tightly controlled in order to avoid random T cell activation and development of autoimmunity. Here, we determined that 12/15-lipoxygenase-meditated (12/15-LO-mediated) enzymatic lipid oxidation regulates DC activation and fine-tunes consecutive T cell responses. Specifically, 12/15-LO activity determined the DC activation threshold via generation of phospholipid oxidation products that induced an antioxidative response dependent on the transcription factor NRF2. Deletion of the 12/15-LO-encoding gene or pharmacologic inhibition of 12/15-LO in murine or human DCs accelerated maturation and shifted the cytokine profile, thereby favoring the differentiation of Th17 cells. Exposure of 12/15-LO-deficient DCs to 12/15-LO-derived oxidized phospholipids attenuated both DC activation and the development of Th17 cells. Analysis of lymphatic tissues from 12/15-LO-deficient mice confirmed enhanced maturation of DCs as well as an increased differentiation of Th17 cells. Moreover, experimental autoimmune encephalomyelitis in mice lacking 12/15-LO resulted in an exacerbated Th17-driven autoimmune disease. Together, our data reveal that 12/15-LO controls maturation of DCs and implicate enzymatic lipid oxidation in shaping the adaptive immune response.
EVALuna2:13111

12/15-lipoxygenase orchestrates the clearance of apoptotic cells and maintains immunologic tolerance. - Uderhardt, Stefan; Herrmann, Martin; Oskolkova, Olga V.; Aschermann, Susanne; Bicker, Wolfgang; Ipseiz, Natacha; Sarter-Zaiss, Kerstin; Frey, Benjamin; Rothe, Tobias; Voll, Reinhard; Nimmerjahn, Falk; Bochkov, Valery N.; et al. (Immunity, 2012)
Noninflammatory clearance of apoptotic cells (ACs) is crucial to maintain self-tolerance. Here, we have reported a role for the enzyme 12/15-lipoxygenase (12/15-LO) as a central factor governing the sorting of ACs into differentially activated monocyte subpopulations. During inflammation, uptake of ACs was confined to a population of 12/15-LO-expressing, alternatively activated resident macrophages (resMΦ), which blocked uptake of ACs into freshly recruited inflammatory Ly6C(hi) monocytes in a 12/15-LO-dependent manner. ResMΦ exposed 12/15-LO-derived oxidation products of phosphatidylethanolamine (oxPE) on their plasma membranes and thereby generated a sink for distinct soluble receptors for ACs such as milk fat globule-EGF factor 8, which were essential for the uptake of ACs into inflammatory monocytes. Loss of 12/15-LO activity, in turn, resulted in an aberrant phagocytosis of ACs by inflammatory monocytes, subsequent antigen presentation of AC-derived antigens, and a lupus-like autoimmune disease. Our data reveal an unexpected key role for enzymatic lipid oxidation during the maintenance of self-tolerance.

5-YEAR EFFICACY AND SAFETY OF APREMILAST TREATMENT IN SUBJECTS WITH PSORIATIC ARTHRITIS: POOLED ANALYSIS OF THE PALACE STUDIES - Kavanaugh, A.; Gladman, D. D.; Edwards, C. J.; Schett, Georg; Guerette, B.; Delev, N.; Teng, L.; Paris, M.; Mease, P. J. (2018)
EVALuna2:34989

68Ga-FAPI-04 PET-CT for molecular assessment of fibroblast activation and risk evaluation in systemic sclerosis-associated interstitial lung disease: a single-centre, pilot study - Bergmann, Christina; Distler, Jörg; Treutlein, Christoph; Tascilar, Koray; Müller, Astrid; Atzinger, Armin; Matei, Alexandru-Emil; Knitza, Johannes; Györfi, Andrea-Hermina; Lück, Anja; Dees, Clara; Soare, Alina; et al. (The Lancet Rheumatology, 2021)
Background: Interstitial lung disease (ILD) is the most common cause of death in systemic sclerosis. To date, the progression of systemic sclerosis-associated ILD is judged by the accrual of lung damage on CT and pulmonary function tests. However, diagnostic tools to assess disease activity are not available. Here, we tested the hypothesis that quantification of fibroblast activation by PET-CT using a 68Ga-labelled selective inhibitor of prolyl endopeptidase FAP (68Ga-FAPI-04) would correlate with ILD activity and disease progression in patients with systemic sclerosis-associated ILD. Methods: Between Sept 10, 2018, and April 8, 2020, 21 patients with systemic sclerosis-associated ILD confirmed by high-resolution CT (HRCT) within 12 months of inclusion and with onset of systemic sclerosis-associated ILD within 5 years or signs of progressive ILD and 21 controls without ILD were consecutively enrolled. All participants underwent 68Ga-FAPI-04 PET-CT imaging and standard-of-care procedures, including HRCT and pulmonary function tests at baseline. Patients with systemic sclerosis-associated ILD were followed for 6 months with HRCT and pulmonary function tests. We compared baseline 68Ga-FAPI-04 PET-CT uptake with standard diagnostic tools and predictors of ILD progression. The association of 68Ga-FAPI-04 uptake with changes in forced vital capacity was analysed using mixed-effects models. Follow-up 68Ga-FAPI-04 PET-CT scans were obtained in a subset of patients treated with nintedanib (follow-up between 6–10 months) to assess change over time. Findings: 68Ga-FAPI-04 accumulated in fibrotic areas of the lungs in patients with systemic sclerosis-associated ILD compared with controls, with a median standardised uptake value (SUV) mean over the whole lung of 0·80 (IQR 0·60–2·10) in the systemic sclerosis-ILD group and 0·50 (0·40–0·50) in the control group (p<0·0001) and a mean whole lung maximal SUV of 4·40 (range 3·05–5·20) in the systemic sclerosis-ILD group compared with 0·70 (0·65–0·70) in the control group (p<0·0001). Whole-lung FAPI metabolic active volume (wlFAPI-MAV) and whole-lung total lesion FAPI (wlTL-FAPI) were not measurable in control participants, because no 68Ga-FAPI-04 uptake above background level was observed. In the systemic sclerosis-ILD group the median wlFAPI-MAV was 254·00 cm3 (IQR 163·40–442·30), and the median wlTL-FAPI was 183·60 cm3 (98·04–960·70). 68Ga-FAPI-04 uptake was higher in patients with extensive disease, with previous ILD progression, or high EUSTAR activity scores than in those with with limited disease, previously stable ILD, or low EUSTAR activity scores. Increased 68Ga-FAPI-04 uptake at baseline was associated with progression of ILD independently of extent of involvement on HRCT scan and the forced vital capacity at baseline. In consecutive 68Ga-FAPI-04 PET-CTs, changes in 68Ga-FAPI-04 uptake was concordant with the observed response to the fibroblast-targeting antifibrotic drug nintedanib. Interpretation: Our study presents the first in-human evidence that fibroblast activation correlates with fibrotic activity and disease progression in the lungs of patients with systemic sclerosis-associated ILD and that 68Ga-FAPI-04 PET-CT might improve risk assessment of systemic sclerosis-associated ILD. Funding: German Research Foundation, Erlangen Anschubs-und Nachwuchsfinanzierung, Interdisziplinäres Zentrum für Klinische Forschung Erlangen, Bundesministerium für Bildung und Forschung, Deutsche Stiftung Systemische Sklerose, Wilhelm-Sander-Foundation, Else-Kröner-Fresenius-Foundation, European Research Council, Ernst-Jung-Foundation, and Clinician Scientist Program Erlangen.
CRIS-Team Scopus Importer:2021-02-26

68GA-FAPI-04 PET/CT STUDY EXTENSION FOR THE ASSESSMENT OF FIBROBLAST ACTIVATION AND RISK EVALUATION IN SYSTEMIC SCLEROSIS-RELATED INTERSTITIAL LUNG DISEASE - Bergmann, Christina; Distler, Jörg; Treutlein, Christoph; Tascilar, Koray; Müller, Astrid; Atzinger, Armin; Matei, Alexandru-Emil; Knitza, Johannes; Gyorfi, A. H.; Lueck, A.; Dees, Clara; Soare, A.; et al. (ANNALS OF THE RHEUMATIC DISEASES, 2021)
CRIS-Team WoS Importer:2021-10-01

80 Meilensteine der Rheumatologie aus 80 Jahren – I: 1940–1960 - Manger, Bernhard; Schett, Georg (Zeitschrift für Rheumatologie, 2021)
CRIS-Team WoS Importer:2021-07-09

80 Meilensteine der Rheumatologie aus 80 Jahren – II: 1961–1980 - Schett, Georg; Kalden, Joachim; Manger, Bernhard (Zeitschrift für Rheumatologie, 2021)
CRIS-Team WoS Importer:2021-07-09

80 Meilensteine der Rheumatologie aus 80 Jahren – IV: 2000–2020 - Doerner, T.; Schett, Georg (Zeitschrift für Rheumatologie, 2021)
CRIS-Team Scopus Importer:2021-09-10

AB1528-HPR FULL BODY HAPTIC BODYSUIT - AN INSTRUMENT TO MEASURE THE RANGE AND SPEED OF MOTION IN PATIENTS WITH AXIAL SPONDYLOARTHRITIS (axSpA) - PRELIMINARY RESULTS - Weber, N.; Lennartz, Rebecca; Knitza, Johannes; Bayat, Sara; Sadeghi, Misha; Ibrahim, Alzhraa; Karatastan, C.; Sudhakar, A.; Ramzezanzadegan, N.; Kahali, S.; Mirzayev, A.; Schuster, Louis; et al. (Annals of the Rheumatic Diseases, 2022)
Movement of the spine is restricted in axial spondyloarthritis (axSpA) [1]. Spine function is usually assessed by the Bath Ankylosing Spondylitis Metrology Index (BASMI), which is based on a limited set of defined motions that are measured semiquantitatively in the spatial dimension but not in the temporal dimension. Sensor-based measurement of spine function in axSpA patients is in its infancy but may provide a deeper and more detailed understanding of the impact of axSpA on the impairment of spine function [2,3]. In theory, unbiased full body assessment of spine motion may open a new dimension in function analysis in axSpA.<br

Abatacept blocks anti-citrullinated protein antibody and rheumatoid factor mediated cytokine production in human macrophages in IDO-dependent manner - Bozec, Aline; Luo, Yubin; Engdahl, Cecilia; Figueiredo, Camille; Bang, Holger; Schett, Georg (Arthritis Research & Therapy, 2018)
BACKGROUND: The anti-inflammatory effect of abatacept is most pronounced in patients with high-titer autoantibodies (including anticitrullinated protein antibodies [ACPA] and rheumatoid factor [RF]). Considering that autoantibodies trigger inflammatory cytokine production by monocytes and that abatacept binds to monocytes, influencing their functional state, we hypothesized that abatacept may effectively inhibit the production of several different cytokines by ACPA- or RF-challenged monocytes. METHODS: Peripheral blood CD68+ monocytes stimulated with macrophage colony-stimulating factor for 24 h were exposed to random immunoglobulin G alone (negative control), purified ACPA, purified RF, or lipopolysaccharide (positive control) in cell culture plates coated with citrullinated vimentin (to allow ACPA immune complex formation). Stimulations were done in the presence or absence of abatacept or tumor necrosis factor (TNF) antibody (adalimumab) with or without indoleamine 2,3-dioxygenase (IDO) inhibitor 1-methyl-D-tryptophan. Supernatants were analyzed for key proinflammatory cytokines TNF-α, interleukin (IL)-1β, IL-6, IL-8, and chemokine (C-C motif) ligand 2 (CCL2) after 24 h. RESULTS: Exposure to ACPA or RF significantly induced the production of TNF-α (20-fold and 27-fold, respectively), IL-1β (each 4-fold), IL-6 (12-fold and 11-fold, respectively), IL-8 (43-fold and 30-fold, respectively), and CCL2 (each 4-fold) in human monocytes. Abatacept inhibited this autoantibody-mediated upregulation of cytokines, reducing TNF-α by > 75%, IL-1β by > 65%, IL-6 and IL-8 by > 80%, and CCL2 by > 60%. In contrast, a TNF inhibitor did not influence autoantibody-induced proinflammatory cytokine production. IDO inhibition reversed the effect of abatacept and again permitted the induction of cytokine production by ACPA and RF. CONCLUSIONS: These data show that abatacept interferes with autoantibody-mediated cytokine production by monocytes through induction of IDO. This inhibitory effect on the production of several effector cytokines in RA may explain the fast anti-inflammatory effect of abatacept as well as its preferential efficacy in patients with high-titer ACPA and RF.
EVALuna2:34156

ABATACEPT BUT NOT TNF INHIBITORS BLOCK AUTOANTIBODY-MEDIATED CYTOKINE PRODUCTION BY MONOCYTES - Bozec, Aline; Luo, Y.; Engdahl, C.; Figueiredo, C.; Bang, H.; Schett, Georg (2017)
EVALuna2:35034

ABATACEPT DELAYS THE DEVELOPMENT OF RA-CLINICAL RESULTS AFTER 18 MONTHS FROM THE RANDOMIZED, PLACEBO-CONTROLLED ARIAA STUDY IN RA-AT RISK PATIENTS - Rech, Jürgen; Kleyer, Arnd; Ostergaard, M.; Hagen, Melanie; Valor, L.; Tascilar, Koray; Krönke, Gerhard; Schönau, Verena; Kleinert, Stefan; Baraliakos, X.; Braun, J.; Fleck, M.; et al. (ANNALS OF THE RHEUMATIC DISEASES, 2022)
CRIS-Team WoS Importer:2022-11-04

Abatacept Reverses Subclinical Arthritis in Patients with High-risk to Develop Rheumatoid Arthritis -results from the Randomized, Placebo-controlled ARIAA Study in RA-at Risk Patients - Rech, Jürgen; Hueber, Axel; Ostergaard, Mikkel; Tascilar, Koray; Hagen, Melanie; Mendez, Larissa Valor; Kleyer, Arnd; Krönke, Gerhard; Simon, David; Schönau, Verena; Hueber, Axel; Kleinert, Stefan; et al. (ARTHRITIS & RHEUMATOLOGY, 2021)
CRIS-Team WoS Importer:2022-03-11

Abatacept Significantly Reduces Subclinical Inflammation During Treatment (6 Months), This Persists After Discontinuation (12 Months), Resulting in a Delay in the Clinical Development of RA in Patients at Risk of RA (The ARIAA Study) - Rech, Jürgen; Kleyer, Arnd; Ostergaard, Mikkel; Hagen, Melanie; Mendez, Larissa Valor; Tascilar, Koray; Krönke, Gerhard; Schönau, Verena; Simon, David; Kleinert, Stefan; Baraliakos, Xenofon; Braun, Juergen; et al. (ARTHRITIS & RHEUMATOLOGY, 2022)
CRIS-Team WoS Importer:2023-01-13

Aberrant regulation of RANKL/OPG in women at high risk of developing breast cancer - Kiechl, Stefan; Schramek, Daniel; Widschwendter, Martin; Fourkala, Evangelia-Ourania; Zaikin, Alexey; Jones, Allison; Jaeger, Bernadette; Rack, Brigitte; Janni, Wolfgang; Scholz, Christoph; Willeit, Johann; Weger, Siegfried; et al. (Oncotarget, 2016)
Breast cancer is the most common female cancer, affecting approximately one in eight women during their lifetime in North America and Europe. Receptor Activator of NF-kB Ligand (RANKL), its receptor RANK and the natural antagonist osteoprotegerin (OPG) are essential regulators of bone resorption. We have initially shown that RANKL/RANK are essential for hormone-driven mammary epithelial proliferation in pregnancy and RANKL/RANK have been implicated in mammary stem cell biology. Using genetic mouse-models, we and others identified the RANKL/RANK system as a key regulator of sex hormone, BRCA1-mutation, and oncogene-driven breast cancer and we proposed that RANKL/RANK might be involved in the initiation of breast tumors. We now report that in postmenopausal women without known genetic predisposition, high RANKL and progesterone serum levels stratify a subpopulation of women at high risk of developing breast cancer 12-24 months before diagnosis (5.33-fold risk, 95%CI 1.5-25.4; P=0.02). In women with established breast cancer, we demonstrate that RANKL/OPG ratios change dependent on the presence of circulating tumor cells (CTCs). Finally, we show in a prospective human breast cancer cohort that alterations in RANKL/OPG ratios are significantly associated with breast cancer manifestation. These data indicate that the RANKL/RANK/OPG system is deregulated in post-menopausal women at high risk for breast cancer and in women with circulating tumor cells. Thus, serum levels of RANKL/OPG are potentially indicative of predisposition and progression of breast cancer in humans. Advancement of our findings towards clinical application awaits prior validation in independent patient cohorts.
EVALuna2:13387

A blast without power - cell death induced by the tuberculosis-necrotizing toxin fails to elicit adequate immune responses - Maueroeder, C.; Chaurio, R. A.; Dumych, T.; Podolska, M.; Lootsik, M. D.; Culemann, S.; Friedrich, Ralf P.; Bilyy, R.; Alexiou, Christoph; Schett, Georg; Berens, C.; Herrmann, Martin; et al. (Cell Death and Differentiation, 2016)
In this study, we deploy a doxycycline-dependent suicide switch integrated in a tumor challenge model. With this experimental setup, we characterized the immunological consequences of cells dying by four distinct cell death stimuli in vivo. We observed that apoptotic cell death induced by expression of the truncated form of BH3 interacting-domain death agonist (tBid) and a constitutively active form of caspase 3 (revC3), respectively, showed higher immunogenicity than cell death induced by expression of the tuberculosis-necrotizing toxin (TNT). Our data indicate that the early release of ATP induces the silent clearance of dying cells, whereas the simultaneous presence of 'find me' signals and danger-associated molecular patterns (DAMPs) promotes inflammatory reactions and increased immunogenicity. This proposed model is supported by findings showing that the production and release of high concentrations of IL-27 by bone-marrow-derived macrophages (BMDM) is limited to BMDM exposed to those forms of death that simultaneously released ATP and the DAMPs heat-shock protein 90 (HSP90) and high-mobility group box-1 protein (HMGB1). These results demonstrate that the tissue microenvironment generated by dying cells may determine the subsequent immune response.
EVALuna2:13264

A broad look into the future of systemic sclerosis - Riemekasten, Gabriela; Distler, Jörg (Therapeutic Advances in Musculoskeletal Disease, 2022)
Systemic sclerosis (SSc) is a systemic autoimmune disease with the key features of inflammation, vasculopathy and fibrosis. This article focussed on emerging fields based on the authors' current work and expertise. The authors provide a hierarchical structure into the studies of the pathogenesis of SSc starting with the contribution of environmental factors. Regulatory autoantibodies (abs) are discussed, which are parts of the human physiology and are specifically dysregulated in SSc. Abs against the angiotensin II receptor subtype 1 (AT1 R) and the endothelin receptor type A (ETAR) are discussed in more detail. Extracellular vesicles are another novel player to possess disease processes. Fibroblasts are a key effector cell in SSc. Therefore, the current review will provide an overview about their plasticity in the phenotype and function. Promising nuclear receptors as key regulators of transcriptional programmes will be introduced as well as epigenetic modifications, which are pivotal to maintain the profibrotic fibroblast phenotype independent of external stimuli. Fibroblasts from SSc patients exhibit a specific signalling and reactivate developmental pathways and stem cell maintenance such as by employing hedgehog and WNT, which promote fibroblast-to-myofibroblast transition and extracellular matrix generation. Pharmacological interventions, although for other indications, are already in clinical use to address pathologic signalling.
CRIS-Team WoS Importer:2022-09-02

Accelerating AxSpA Diagnosis: Exploring At-home Self-sampling, Symptom Checkers, Medical Student-visits and Asynchronous Reportbased Assessment - Labinsky, Hannah; Von Rohr, Sophie; Raimondo, Maria Gabriella; Vogt, Ekaterina; Horstmann, Britta; Gehring, Isabel; Rojas-Restrepo, Jessica; Proft, Fabian; Muehlensiepen, Felix; Bohr, Daniela; Schett, Georg; Ramming, Andreas; et al. (ARTHRITIS & RHEUMATOLOGY, 2022)
CRIS-Team WoS Importer:2023-01-13

ACCURACY AND PERFORMANCE OF A HANDHELD ULTRASOUND DEVICE TO ASSESS ARTICULAR AND PERIARTICULAR PATHOLOGIES IN PATIENTS WITH INFLAMMATORY ARTHRITIS - Corte, G.; Bayat, Sara; Tascilar, Koray; Valor, L.; Schuster, Louis; Knitza, Johannes; Schett, Georg; Kleyer, Arnd; Simon, David (ANNALS OF THE RHEUMATIC DISEASES, 2021)
CRIS-Team WoS Importer:2021-09-24

Accuracy and tolerability of self-sampling of capillary blood for analysis of inflammation and autoantibodies in rheumatoid arthritis patients-results from a randomized controlled trial - Knitza, Johannes; Tascilar, Koray; Vuillerme, Nicolas; Eimer, Ekaterina; Matusewicz, Paul; Corte, Giulia; Schuster, Louis; Aubourg, Timothee; Bendzuck, Gerlinde; Korinth, Marianne; Elling-Audersch, Corinna; Kleyer, Arnd; et al. (Arthritis Research & Therapy, 2022)
Background: Rheumatoid arthritis (RA) requires early diagnosis and tight surveillance of disease activity. Remote self-collection of blood for the analysis of inflammation markers and autoantibodies could improve the monitoring of RA and facilitate the identification of individuals at-risk for RA.
CRIS-Team WoS Importer:2022-06-10
Keywords: Self-sampling; Capillary blood; Rheumatoid arthritis; Disease activity

Accuracy and usability of a diagnostic decision support system in the diagnosis of three representative rheumatic diseases: a randomized controlled trial among medical students - Knitza, Johannes; Tascilar, Koray; Gruber, Eva; Kaletta, Hannah; Hagen, Melanie; Liphardt, Anna-Maria; Schenker, Hannah; Krusche, Martin; Wacker, Jochen; Kleyer, Arnd; Simon, David; Vuillerme, Nicolas; et al. (Arthritis Research & Therapy, 2021)
Background: An increasing number of diagnostic decision support systems (DDSS) exist to support patients and physicians in establishing the correct diagnosis as early as possible. However, little evidence exists that supports the effectiveness of these DDSS. The objectives were to compare the diagnostic accuracy of medical students, with and without the use of a DDSS, and the diagnostic accuracy of the DDSS system itself, regarding the typical rheumatic diseases and to analyze the user experience. Methods: A total of 102 medical students were openly recruited from a university hospital and randomized (unblinded) to a control group (CG) and an intervention group (IG) that used a DDSS (Ada – Your Health Guide) to create an ordered diagnostic hypotheses list for three rheumatic case vignettes. Diagnostic accuracy, measured as the presence of the correct diagnosis first or at all on the hypothesis list, was the main outcome measure and evaluated for CG, IG, and DDSS. Results: The correct diagnosis was ranked first (or was present at all) in CG, IG, and DDSS in 37% (40%), 47% (55%), and 29% (43%) for the first case; 87% (94%), 84% (100%), and 51% (98%) in the second case; and 35% (59%), 20% (51%), and 4% (51%) in the third case, respectively. No significant benefit of using the DDDS could be observed. In a substantial number of situations, the mean probabilities reported by the DDSS for incorrect diagnoses were actually higher than for correct diagnoses, and students accepted false DDSS diagnostic suggestions. DDSS symptom entry greatly varied and was often incomplete or false. No significant correlation between the number of symptoms extracted and diagnostic accuracy was seen. It took on average 7 min longer to solve a case using the DDSS. In IG, 61% of students compared to 90% in CG stated that they could imagine using the DDSS in their future clinical work life. Conclusions: The diagnostic accuracy of medical students was superior to the DDSS, and its usage did not significantly improve students’ diagnostic accuracy. DDSS usage was time-consuming and may be misleading due to prompting wrong diagnoses and probabilities. Trial registration: DRKS.de, DRKS00024433. Retrospectively registered on February 5, 2021.
CRIS-Team Scopus Importer:2021-09-17
Keywords: Accuracy; Apps; Clinical decision support system; Diagnosis; eHealth

Accuracy, patient-perceived usability, and acceptance of two symptom checkers (Ada and Rheport) in rheumatology: interim results from a randomized controlled crossover trial - Knitza, Johannes; Mohn, Jacob; Bergmann, Christina; Kampylafka, Eleni; Hagen, Melanie; Bohr, Daniela; Morf, Harriet; Guilhon de Araujo, Elizabeth; Englbrecht, Matthias; Simon, David; Kleyer, Arnd; Meinderink, Timo; et al. (Arthritis Research & Therapy, 2021)
Background: Timely diagnosis and treatment are essential in the effective management of inflammatory rheumatic diseases (IRDs). Symptom checkers (SCs) promise to accelerate diagnosis, reduce misdiagnoses, and guide patients more effectively through the health care system. Although SCs are increasingly used, there exists little supporting evidence. Objective: To assess the diagnostic accuracy, patient-perceived usability, and acceptance of two SCs: (1) Ada and (2) Rheport. Methods: Patients newly presenting to a German secondary rheumatology outpatient clinic were randomly assigned in a 1:1 ratio to complete Ada or Rheport and consecutively the respective other SCs in a prospective non-blinded controlled randomized crossover trial. The primary outcome was the accuracy of the SCs regarding the diagnosis of an IRD compared to the physicians’ diagnosis as the gold standard. The secondary outcomes were patient-perceived usability, acceptance, and time to complete the SC. Results: In this interim analysis, the first 164 patients who completed the study were analyzed. 32.9% (54/164) of the study subjects were diagnosed with an IRD. Rheport showed a sensitivity of 53.7% and a specificity of 51.8% for IRDs. Ada’s top 1 (D1) and top 5 disease suggestions (D5) showed a sensitivity of 42.6% and 53.7% and a specificity of 63.6% and 54.5% concerning IRDs, respectively. The correct diagnosis of the IRD patients was within the Ada D1 and D5 suggestions in 16.7% (9/54) and 25.9% (14/54), respectively. The median System Usability Scale (SUS) score of Ada and Rheport was 75.0/100 and 77.5/100, respectively. The median completion time for both Ada and Rheport was 7.0 and 8.5 min, respectively. Sixty-four percent and 67.1% would recommend using Ada and Rheport to friends and other patients, respectively. Conclusions: While SCs are well accepted among patients, their diagnostic accuracy is limited to date. Trial registration: DRKS.de, DRKS00017642. Registered on 23 July 2019
CRIS-Team Scopus Importer:2021-04-30
Keywords: Acceptability; Accuracy; Apps; Diagnosis; eHealth; Rheumatology; Symptom checker; Usability

ACCURATE DETERMINATION OF PERIARTICULAR BONE COMPOSITION IN HEALTHY INDIVIDUALS AND COMPARISON TO ACPA-POSITIVE RHEUMATOID ARTHRITIS PATIENTS - Simon, David; Kleyer, Arnd; Stemmler, F.; Simon, C.; Hueber, Axel; Kampylafka, E.; Englbrecht, Matthias; Figueiredo, C.; Engelke, Klaus; Berlin, Andreas; Haschka, J.; Rech, Jürgen; et al. (2016)
EVALuna2:13492

Acetate, a metabolic product of Heligmosomoides polygyrus, facilitates intestinal epithelial barrier breakdown in a FFAR2-dependent manner - Schälter, Fabian; Frech, Michael; Dürholz, Kerstin; Lucas, Sébastien; Sarter-Zaiss, Kerstin; Lebon, Luc; Esser-Von-Bieren, Julia; Dubey, Lalit Kumar; Vöhringer, David; Schett, Georg; Harris, Nicola L.; Zaiss, Mario (International Journal For Parasitology, 2022)

Acetate, a metabolic product of Heligmosomoides polygyrus, facilitates intestinal epithelial barrier breakdown in a FFAR2-dependent manner - Schälter, Fabian; Frech, Michael; Dürholz, Kerstin; Lucas, Sébastien; Sarter-Zaiss, Kerstin; Lebon, Luc; Esser-von Bieren, Julia; Dubey, Lalit K.; Vöhringer, David; Schett, Georg; Harris, Nicola L.; Zaiss, Mario (International Journal For Parasitology, 2022)
Approximately 2 billion people worldwide and a significant part of the domestic livestock are infected with soil-transmitted helminths, of which many establish chronic infections causing substantial economic and welfare burdens. Beside intensive research on helminth-triggered mucosal and systemic immune responses, the local mechanism that enables infective larvae to cross the intestinal epithelial barrier and invade mucosal tissue remains poorly addressed. Here, we show that Heligmosomoides polygyrus infective L3s secrete acetate and that acetate potentially facilitates paracellular epithelial tissue invasion by changed epithelial tight junction claudin expression. In vitro, impedance-based real-time epithelial cell line barrier measurements together with ex vivo functional permeability assays in intestinal organoid cultures revealed that acetate decreased intercellular barrier function via the G-protein coupled free fatty acid receptor 2 (FFAR2, GPR43). In vivo validation experiments in FFAR2−/− mice showed lower H. polygyrus burdens, whereas oral acetate-treated C57BL/6 wild type mice showed higher burdens. These data suggest that locally secreted acetate – as a metabolic product of the energy metabolism of H. polygyrus L3s – provides a significant advantage to the parasite in crossing the intestinal epithelial barrier and invading mucosal tissues. This is the first and a rate-limiting step for helminths to establish chronic infections in their hosts and if modulated could have profound consequences for their life cycle.
CRIS-Team Scopus Importer:2022-07-08
Keywords: Acetate; Barrier function; Helminths; Intestinal permeability; Microbiota

A comparative analysis of articular bone in large cohort of patients with chronic inflammatory diseases of the joints, the gut and the skin - Simon, David; Kleyer, Arnd; Englbrecht, Matthias; Stemmler, Fabian; Simon, Christoph; Berlin, Andreas; Kocijan, Roland; Haschka, Judith; Hirschmann, Simon; Atreya, Raja; Neurath, Markus; Sticherling, Michael; et al. (Bone, 2018)
Chronic inflammatory diseases are associated with bone loss. While the occurrence of systemic bone loss is well described in chronic inflammatory diseases, the impact of these conditions on articular bone has not been systematically investigated. Recent refinements in high-resolution CT assessment of the joints now allow the accurate measure of articular bone composition. In this study 476 subjects comprising healthy individuals and patients with anticitrullinated protein antibody (ACPA)-positive rheumatoid arthritis (RA), ACPA-negative RA, Crohn's disease (CD), ulcerative colitis (UC), psoriasis (PsO) and psoriatic arthritis (PsA) were subjected to high-resolution quantitative computed tomography (HR-pQCT) of the hand. Metacarpal heads were assessed for total, trabecular and cortical volumetric bone mineral density (vBMD). Only ACPA+RA, but not the remaining inflammatory diseases (ACPA-RA, CD, UC, PsO, PsA) showed significant (p < 0.001) loss of articular bone affecting both the trabecular and the cortical compartments. Age and body mass index were also associated with articular bone changes, the former with lower, the latter with higher articular bone mass. In multivariate models, presence of ACPA+RA was an independent factor for articular bone loss. Among chronic inflammatory diseases ACPA+RA is the most potent precipitator for articular bone loss pointing out the role of autoimmunity in the development of articular bone disease in the context of chronic inflammatory disease.
EVALuna2:34480

A comparative analysis of magnetic resonance imaging and high-resolution peripheral quantitative computed tomography of the hand for the detection of erosion repair in rheumatoid arthritis - Regensburger, Adrian; Rech, Juergen; Englbrecht, Matthias; Finzel, Stephanie; Kraus, Sebastian; Hecht, Karolin; Kleyer, Arnd; Haschka, Judith; Hueber, Axel; Schett, Georg; Faustini, Francesca; Cavallaro, Alexander Josef (Rheumatology, 2015)
To investigate whether MRI allows the detection of osteosclerosis as a sign of repair of bone erosions compared with high-resolution peripheral quantitative computed tomography (HR-pQCT) as a reference and whether the presence of osteosclerosis on HR-pQCT is linked to synovitis and osteitis on MRI.A total of 103 RA patients underwent HR-pQCT and MRI of the dominant hand. The presence and size of erosions and the presence and extent (grades 0-2) of osteosclerosis were assessed by both imaging modalities, focusing on MCP 2 and 3 and wrist joints. By MRI, the presence and grading of osteitis and synovitis were assessed according to the Rheumatoid Arthritis MRI Score (RAMRIS).Parallel evaluation was feasible by both modalities on 126 bone erosions. Signs of osteosclerosis were found on 87 erosions by HR-pQCT and on 22 by MRI. False-positive results (MRI(+)CT(-)) accounted for 3%, while false-negative results (MRI(-)CT(+)) accounted for 76%. MRI sensitivity for the detection of osteosclerosis was 24% and specificity was 97%. The semi-quantitative scoring of osteosclerosis was reliable between MRI and HR-pQCT [intraclass correlation coefficient 0.917 (95% CI 0.884, 0.941), P < 0.001]. The presence of osteosclerosis on HR-pQCT showed a trend towards an inverse relationship to the occurrence and extent of osteitis on MRI [?(2)(1) = 3.285; ? coefficient = -0.124; P = 0.070] but not to synovitis [?(2)(1) = 0.039; ? coefficient = -0.14; P = 0.844].MRI can only rarely detect osteosclerosis associated with bone erosions in RA. Indeed, the sensitivity compared with HR-pQCT is limited, while the specificity is high. The presence of osteitis makes osteosclerosis more unlikely, whereas the presence of synovitis is not related to osteosclerosis.
EVALuna2:13125

A COMPARISON OF TWO METHODS TO SEGMENT BONE EROSIONS IN THE METACARPOPHALANGEAL JOINTS OF RHEUMATOID ARTHRITIS PATIENTS - Figueiredo, C.; Simon, David; Stemmler, F.; Weißenfels, Anja; Weishäupl, Dirk; Museyko, Oleg; Friedberger, Andreas; Rech, Jürgen; Hueber, Axel; Haschka, J.; Schett, Georg; Engelke, Klaus; et al. (2016)
EVALuna2:13471

ACPA and bone loss in rheumatoid arthritis topical collection on rheumatoid arthritis - Kocijan, Roland; Harre, Ulrike; Schett, Georg (Current Rheumatology Reports, 2013)
Rheumatoid arthritis (RA) is an autoimmune inflammatory disease characterized by bone loss. Degree of inflammation and autoantibody positivity have both been identified as important initiators of skeletal damage in RA. Whereas it is well appreciated that inflammation initiates bone loss via the action of cytokines, the effect of autoantibodies in initiating bone destruction has long been underestimated. It has, nonetheless, been known for years that antibodies against citrullinated proteins (ACPA) and rheumatoid factor are associated with a more destructive disease course. It was recently shown that ACPA bind osteoclast precursor cells and directly promote their differentiation into bone-resorbing osteoclasts. Other results have shown that in ACPA-positive individuals bone loss starts even before the onset of clinical disease; this is indicative of the independent effect of these antibodies in initiating skeletal damage. The observation that the mere presence of ACPA is associated with pathological changes suggests that these antibodies have functional properties and initiate the onset of disease long before patients consult the rheumatologist because of symptomatic joint disease. These findings also indicate that "RA" is a syndrome rather than a single disease, suggesting that autoantibody-positive patients are both genetically and clinically distinct phenotypes. © 2013 Springer Science+Business Media New York.
Created from Fastlane, Scopus look-up
Keywords: ACPA; Anti-citrullinated protein antibodies; Autoantibodies; Bone loss; Rheumatoid arthritis

A cross-disease meta-GWAS identifies four new susceptibility loci shared between systemic sclerosis and Crohn’s disease - González-Serna, David; Ochoa, Eguzkine; López-Isac, Elena; Julià, Antonio; Degenhardt, Frauke; Ortego-Centeno, Norberto; Radstake, Timothy R.D.J.; Franke, Andre; Marsal, Sara; Mayes, Maureen D.; Martín, Javier; Márquez, Ana; et al. (Scientific Reports, 2020)
Genome-wide association studies (GWASs) have identified a number of genetic risk loci associated with systemic sclerosis (SSc) and Crohn’s disease (CD), some of which confer susceptibility to both diseases. In order to identify new risk loci shared between these two immune-mediated disorders, we performed a cross-disease meta-analysis including GWAS data from 5,734 SSc patients, 4,588 CD patients and 14,568 controls of European origin. We identified 4 new loci shared between SSc and CD, IL12RB2, IRF1/SLC22A5, STAT3 and an intergenic locus at 6p21.31. Pleiotropic variants within these loci showed opposite allelic effects in the two analysed diseases and all of them showed a significant effect on gene expression. In addition, an enrichment in the IL-12 family and type I interferon signaling pathways was observed among the set of SSc-CD common genetic risk loci. In conclusion, through the first cross-disease meta-analysis of SSc and CD, we identified genetic variants with pleiotropic effects on two clinically distinct immune-mediated disorders. The fact that all these pleiotropic SNPs have opposite allelic effects in SSc and CD reveals the complexity of the molecular mechanisms by which polymorphisms affect diseases.
CRIS-Team Scopus Importer:2020-02-14

A crucial role for Jagunal homolog 1 in humoral immunity and antibody glycosylation in mice and humans - Hagelkruys, Astrid; Wirnsberger, Gerald; Stadlmann, Johannes; Wöhner, Miriam; Horrer, Marion; Vilagos, Bojan; Jonsson, Gustav; Kogler, Melanie; Tortola, Luigi; Novatchkova, Maria; Bönelt, Peter; Hoffmann, David; et al. (Journal of Experimental Medicine, 2020)
Jagunal homolog 1 (JAGN1) has been identified as a critical regulator of neutrophil biology in mutant mice and rare-disease patients carrying JAGN1 mutations. Here, we report that Jagn1 deficiency results in alterations in the endoplasmic reticulum (ER) of antibody-producing cells as well as decreased antibody production and secretion. Consequently, mice lacking Jagn1 in B cells exhibit reduced serum immunoglobulin (Ig) levels at steady state and fail to mount an efficient humoral immune response upon immunization with specific antigens or when challenged with viral infections. We also demonstrate that Jagn1 deficiency in B cells results in aberrant IgG N-glycosylation leading to enhanced Fc receptor binding. Jagn1 deficiency in particular affects fucosylation of IgG subtypes in mice as well as rare-disease patients with loss-of-function mutations in JAGN1. Moreover, we show that ER stress affects antibody glycosylation. Our data uncover a novel and key role for JAGN1 and ER stress in antibody glycosylation and humoral immunity in mice and humans.
CRIS-Team Scopus Importer:2020-10-16

Activating Transcription Factor 3-a New Linkage Between Vasculopathy and Organ Fibrosis in Systemic Sclerosis - Wohlfahrt, Thomas; Soare, Alina; Mallano, Tatjana; Gourlaouen, Morgane; Moss, Stephen; Maurer, Britta; Distler, Oliver; Hai, Tsonwin; Schett, Georg; Distler, Jörg; Ramming, Andreas (2016)
EVALuna2:35069

Activating transcription factor 3 regulates canonical TGF? signalling in systemic sclerosis - Mallano, Tatjana; Palumbo-Zerr, Katrin; Zerr, Pawel; Zeller, Barbara; Beyer, Christian; Dees, Clara; Huang, Jingang; Hai, Tsonwin; Distler, Oliver; Schett, Georg; Distler, Jörg; Ramming, Andreas (Annals of the Rheumatic Diseases, 2016)
Activating transcription factor 3 (ATF3), a member of the ATF/cAMP-responsive element binding (CREB) family of transcription factors, regulates cellular response to stress including oxidative stress. The aim of this study was to analyse the role of ATF3 in fibroblast activation in systemic sclerosis (SSc).ATF3 was analysed by reverse transcription quantitative PCR, western blot and immunohistochemistry. ATF3 knockout fibroblasts and mice were used to study the functional role of ATF3. Knockdown experiments, reporter assays and coimmunoprecipitation were performed to study the effects of ATF3 on Smad and activation protein 1 (AP-1) signalling. The role of c-Jun was analysed by costaining, specific inactivation and coimmunoprecipitation.Transforming growth factor-? (TGF?) upregulates the expression of ATF3 in SSc fibroblasts. ATF3-deficient fibroblasts were less sensitive to TGF?, whereas ectopic expression of ATF3 enhanced the profibrotic effects of TGF?. Mechanistically, ATF3 interacts with Smad3 directly on stimulation with TGF? and regulates Smad activity in a c-Jun-dependent manner. Knockout of ATF3 protected mice from bleomycin-induced fibrosis and fibrosis induced by overexpression of a constitutively active TGF? receptor I. Reporter assays and analyses of the expression of Smad target genes demonstrated that binding of ATF3 regulates the transcriptional activity of Smad3.We demonstrate for the first time a key role for ATF3 in fibrosis. Knockout of the ATF3 gene reduced the stimulatory effect of TGF? on fibroblasts by interfering with canonical Smad signalling and protected the mice from experimental fibrosis in two different models. ATF3 might thus be a candidate for molecular targeted therapies for SSc.
EVALuna2:13127

Activation of canonical Wnt signalling is required for TGF-β-mediated fibrosis - Akhmetshina, Alfiya; Palumbo, Katrin; Dees, Clara; Bergmann, Christina; Venalis, Paulius; Zerr, Pawel; Horn, Angelika; Kireva, Trayana; Beyer, Christian; Zwerina, Jochen; Schneider, Holm; Sadowski, Anika; et al. (Nature Communications, 2012)
The transforming growth factor-β (TGF-β) signalling pathway is a key mediator of fibroblast activation that drives the aberrant synthesis of extracellular matrix in fibrotic diseases. Here we demonstrate a novel link between transforming growth factor-β and the canonical Wnt pathway. TGF-β stimulates canonical Wnt signalling in a p38-dependent manner by decreasing the expression of the Wnt antagonist Dickkopf-1. Tissue samples from human fibrotic diseases show enhanced expression of Wnt proteins and decreased expression of Dickkopf-1. Activation of the canonical Wnt pathway stimulates fibroblasts in vitro and induces fibrosis in vivo. Transgenic overexpression of Dickkopf-1 ameliorates skin fibrosis induced by constitutively active TGF-β receptor type I signalling and also prevents fibrosis in other TGF-β-dependent animal models. These findings demonstrate that canonical Wnt signalling is necessary for TGF-β-mediated fibrosis and highlight a key role for the interaction of both pathways in the pathogenesis of fibrotic diseases. © 2012 Macmillan Publishers Limited. All rights reserved.
CRIS-Team Scopus Importer:2020-07-01

Activation of liver X receptors inhibits experimental fibrosis by interfering with interleukin-6 release from macrophages - Beyer, Christian; Huang, Jingang; Beer, Juergen; Zhang, Yun; Palumbo-Zerr, Katrin; Zerr, Pawel; Distler, Alfiya; Dees, Clara; Maier, Christiane; Munoz, Louis; Krönke, Gerhard; Uderhardt, Stefan; et al. (Annals of the Rheumatic Diseases, 2015)
To investigate the role of liver X receptors (LXRs) in experimental skin fibrosis and evaluate their potential as novel antifibrotic targets.We studied the role of LXRs in bleomycin-induced skin fibrosis, in the model of sclerodermatous graft-versus-host disease (sclGvHD) and in tight skin-1 (Tsk-1) mice, reflecting different subtypes of fibrotic disease. We examined both LXR isoforms using LXR?-, LXR?- and LXR-?/?-double-knockout mice. Finally, we investigated the effects of LXRs on fibroblasts and macrophages to establish the antifibrotic mode of action of LXRs.LXR activation by the agonist T0901317 had antifibrotic effects in bleomycin-induced skin fibrosis, in the sclGvHD model and in Tsk-1 mice. The antifibrotic activity of LXRs was particularly prominent in the inflammation-driven bleomycin and sclGvHD models. LXR?-, LXR?- and LXR?/?-double-knockout mice showed a similar response to bleomycin as wildtype animals. Low levels of the LXR target gene ABCA-1 in the skin of bleomycin-challenged and control mice suggested a low baseline activation of the antifibrotic LXR signalling, which, however, could be specifically activated by T0901317. Fibroblasts were not the direct target cells of LXRs agonists, but LXR activation inhibited fibrosis by interfering with infiltration of macrophages and their release of the pro-fibrotic interleukin-6.We identified LXRs as novel targets for antifibrotic therapies, a yet unknown aspect of these nuclear receptors. Our data suggest that LXR activation might be particularly effective in patients with inflammatory disease subtypes. Activation of LXRs interfered with the release of interleukin-6 from macrophages and, thus, inhibited fibroblast activation and collagen release.
EVALuna2:12871

Activation of STAT3 integrates common profibrotic pathways to promote fibroblast activation and tissue fibrosis - Chakraborty, Debomita; Sumova, Barbora; Mallano, Tatjana; Chen, Chih-Wei; Distler, Alfiya; Bergmann, Christina; Ludolph, Ingo; Horch, Raymund E.; Gelse, Kolja; Ramming, Andreas; Distler, Oliver; Schett, Georg; et al. (Nature Communications, 2017)
Signal transducer and activator of transcription 3 (STAT3) is phosphorylated by various kinases, several of which have been implicated in aberrant fibroblast activation in fibrotic diseases including systemic sclerosis (SSc). Here we show that profibrotic signals converge on STAT3 and that STAT3 may be an important molecular checkpoint for tissue fibrosis. STAT3 signaling is hyperactivated in SSc in a TGF?-dependent manner. Expression profiling and functional studies in vitro and in vivo demonstrate that STAT3 activation is mediated by the combined action of JAK, SRC, c-ABL, and JNK kinases. STAT3-deficient fibroblasts are less sensitive to the pro-fibrotic effects of TGF?. Fibroblast-specific knockout of STAT3, or its pharmacological inhibition, ameliorate skin fibrosis in experimental mouse models. STAT3 thus integrates several profibrotic signals and might be a core mediator of fibrosis. Considering that several STAT3 inhibitors are currently tested in clinical trials, STAT3 might be a candidate for molecular targeted therapies of SS
EVALuna2:13455

Activation of the alpha7 nicotinic acetylcholine receptor ameliorates skin fibrosis and reduces TGF-beta1-induced collagen synthesis in human dermal fibroblasts by modulating JunB - Stegemann, A.; Dreissigacker, K.; Summa, L.; Flis, D.; Distler, Jörg; Ziolkowski, W.; Steinbrink, K.; Boehm, M. (EXPERIMENTAL DERMATOLOGY, 2023)
CRIS-Team WoS Importer:2023-06-02

ACUTE PHASE REACTANT LEVELS AND PREDNISONE DOSES AT DISEASE FLARE IN PATIENTS WITH GIANT CELL ARTERITIS: PROSPECTIVE DATA FROM THE GIACTA TRIAL - Stone, J. H.; Tuckwell, K.; Dimonaco, S.; Klearman, M.; Aringer, M.; Blockmans, D.; Brouwer, E.; Cid, M. C.; Dasgupta, B.; Rech, Jürgen; Salvarani, C.; Schulze-Koops, H.; et al. (2018)
EVALuna2:35001

ACUTE PHASE REACTANT LEVELS AND PREDNISONE DOSES AT DISEASE FLARE IN PATIENTS WITH GIANT CELL ARTERITIS: PROSPECTIVE DATA FROM THE GIACTA TRIAL - Stone, John H.; Tuckwell, Katie; Dimonaco, Sophie; Klearman, Micki; Aringer, Martin; Blockmans, Daniel; Brouwer, Elisabeth; Cid, Maria C.; Dasgupta, Bhaskar; Rech, Jürgen; Salvarani, Carlo; Schulze-Koops, Hendrik; et al. (2019)
EVALuna2:213231

Acyltransferase skinny hedgehog regulates TGFβ-dependent fibroblast activation in SSc - Liang, Ruifang; Kagwiria, Rosebeth; Zehender, Ariella; Dees, Clara; Bergmann, Christina; Krasowska, Dorota; Michalska-Jakubus, Małgorzata; Kreuter, Alexander; Kraner, Max; Schett, Georg; Distler, Jörg; Ramming, Andreas (Annals of the Rheumatic Diseases, 2019)
Objectives: Systemic sclerosis (SSc) is characterised by aberrant hedgehog signalling in fibrotic tissues. The hedgehog acyltransferase (HHAT) skinny hedgehog catalyses the attachment of palmitate onto sonic hedgehog (SHH). Palmitoylation of SHH is required for multimerisation of SHH proteins, which is thought to promote long-range, endocrine hedgehog signalling. The aim of this study was to evaluate the role of HHAT in the pathogenesis of SSc. Methods: Expression of HHAT was analysed by real-time polymerase chain reaction(RT-PCR), immunofluorescence and histomorphometry. The effects of HHAT knockdown were analysed by reporter assays, target gene studies and quantification of collagen release and myofibroblast differentiation in cultured human fibroblasts and in two mouse models. Results: The expression of HHAT was upregulated in dermal fibroblasts of patients with SSc in a transforming growth factor-β (TGFβ)/SMAD-dependent manner. Knockdown of HHAT reduced TGFβ-induced hedgehog signalling as well as myofibroblast differentiation and collagen release in human dermal fibroblasts. Knockdown of HHAT in the skin of mice ameliorated bleomycin-induced and topoisomerase-induced skin fibrosis. Conclusion: HHAT is regulated in SSc in a TGFβ-dependent manner and in turn stimulates TGFβ-induced long-range hedgehog signalling to promote fibroblast activation and tissue fibrosis. Targeting of HHAT might be a novel approach to more selectively interfere with the profibrotic effects of long-range hedgehog signalling.
CRIS-Team Scopus Importer:2019-06-21
Keywords: dermal fibrosis; hedgehog signaling; skinny hedgehog; systemic sclerosis; TGFβ

A Cytokine-like Protein DKK3 Is Atheroprotective - Yu, Baoqi; Kiechl, Stefan; Qi, Dan; Wang, Xiaocong; Song, Yanting; Weger, Siegfried; Mayr, Agnes; Le Bras, Alexandra; Karamariti, Eirini; Zhang, Zhongyi; del Barco Barrantes, Ivan; Niehrs, Christof; et al. (Circulation, 2017)
Background -Dickkopf-related protein (DKK) 3 is a secreted protein that is involved in the regulation of cardiac remodeling and vascular smooth muscle cell differentiation, but little is known about its role in atherosclerosis. Methods -We tested the hypothesis that DKK3 is atheroprotective using both epidemiological and experimental approaches. Blood DKK3 levels were measured in the Bruneck Study in 2000 (n=684) and then in 2005 (n=574). DKK3-deficient mice were crossed to ApoE(-/-) mice to evaluate atherosclerosis development and vessel injury-induced neointimal formation. Endothelial cell migration and the underlying mechanisms were studied using in vitro cell culture models. Results -In the prospective population-based Bruneck Study, the level of plasma DKK3 was inversely related to carotid artery intima-media thickness and five-year progression of carotid atherosclerosis, independently from standard risk factors for atherosclerosis. Experimentally, we analyzed the area of atherosclerotic lesions, femoral artery injury-induced re-endothelialization and neointima formation in both DKK3(-/-)/ApoE(-/-) and DKK3(+/+)/ApoE(-/-) mice. It was demonstrated that DKK3 deficiency accelerated atherosclerosis and delayed re-endothelialization with consequently exacerbated neointima formation. To explore the underlying mechanisms, we performed transwell and scratch migration assays using cultured human endothelial cells, which exhibited a significant induction in cell migration in response to DKK3 stimulation. This DKK3-induced migration was associated with activation of ROR2 and DVL1, activated Rac1 GTPases and upregulated JNK and c-jun phosphorylation in endothelial cells. Knockdown of ROR2 receptor using specific siRNA or transfection of a dominant negative form of Rac1 in endothelial cells markedly inhibited cell migration and downstream JNK and c-jun phosphorylation. Conclusions -This study provides the evidence for a role of DKK3 in the protection against atherosclerosis involving endothelial migration and repair, with great therapeutic potential implications against atherosclerosis.
EVALuna:34144

ADAPTOR PROTEINS ACTIVATE FIBROBLASTS IN SYSTEMIC SCLEROSIS - Ariza, Y.; Weber, Stefanie; Neise, N.; Kreuter, A.; Schett, Georg; Distler, Jörg; Ramming, Andreas (ANNALS OF THE RHEUMATIC DISEASES, 2020)
CRIS-Team WoS Importer:2020-08-21

Additive effect of anti-citrullinated protein antibodies and rheumatoid factor on bone erosions in patients with RA - Hecht, Carolin; Englbrecht, Matthias; Rech, Juergen; Schmidt, Sarah; Araujo, Elizabeth; Engelke, Klaus; Finzel, Stephanie; Schett, Georg (Annals of the Rheumatic Diseases, 2015)
To determine whether there is an additive effect of anticitrullinated protein antibodies (ACPA) and rheumatoid factor (RF) on the number and size of bone erosions in patients with rheumatoid arthritis (RA) METHODS: 242 patients with RA received high-resolution peripheral quantitative CT (HR-pQCT) scans of the metacarpophalangeal joints. Demographic and disease-specific parameters including ACPA and RF levels were recorded from all patients. Erosion numbers and their size were assessed in 238 patients at 714 individual joints (MCP 2, 3 and 4) and 5712 sites (each 4 quadrants in metacarpal heads and phalangeal bases). The volume of erosions was calculated by a semiellipsoid formula.Of the 238 patients, 112 patients showed RF and ACPAs (ACPAs+RF+), 28 only RF (RF+), 29 only ACPAs (ACPA+) and 69 were antibody negative (NEG). Erosion number and size were highest in RF+ACPAs+ patient group with significant differences compared with NEG patients with respect to erosion number (p=0.001) and to ACPA-negative patients with respect to erosion size (p<0.001). Results maintained significance in a linear mixed model showing ACPAs+RF+ status and disease duration being associated with higher number (p=0.017 and p=0.005, respectively), and larger size (p=0.014 and p=0.013, respectively) of bone erosions. Furthermore, erosion size was influenced by the presence and titre of RF only in ACPA-positive patients with RA but not in ACPA-negative patients.ACPAs and RF show an additive effect on erosion number and erosion size. Concomitant presence of ACPAs and RF is associated with higher erosive disease burden in patients with RA. Furthermore, RF influences erosion size only in ACPA-positive but not in ACPA-negative patients.
EVALuna2:10081

A Detailed Analysis of the Association between Urate Deposition and Erosions and Osteophytes in Gout - Pecherstorfer, Caroline; Simon, David; Unbehend, Sara; Ellmann, Hanna; Englbrecht, Matthias; Hartmann, Fabian; Figueiredo, Camille; Hueber, Axel; Haschka, Judith; Kocijan, Roland; Kleyer, Arnd; Schett, Georg; et al. (ACR Open Rheumatology, 2020)
ObjectiveTo characterize in detail the structural bone changes associated with the deposition of monosodium urate crystals in the first metatarsophalangeal (MTP1) joint in patients with tophaceous gout.
CRIS-Team WoS Importer:2021-07-16

Adipocytokine as a Link between Metabolism and Osteoarthritis - Huelser, Marie-Lisa; Schreiyaeck, Carina; Luo, Yubin; Bozec, Aline; Schett, Georg; Mueller-Ladner, Ulf; Neumann, Elena (2017)
EVALuna2:35051

Adipocytokines and Obesity in the Context of Rheumatoid and Osteoarthritis Mouse Models - Sauermilch, Hani Manfred; Huelser, Marie-Lisa; Schreiyaeck, Carina; Luo, Yubin; Bozec, Aline; Schett, Georg; Mueller-Ladner, Ulf; Neumann, Elena (ARTHRITIS & RHEUMATOLOGY, 2019)
CRIS-Team WoS Importer:2020-02-07

Adipocytokines in an Osteoarthritis Mouse Model - Huelser, Marie-Lisa; Schreiyaeck, Carina; Luo, Yubin; Bozec, Aline; Schett, Georg; Neumann, Elena; Mueller-Ladner, Ulf (2017)
EVALuna2:33433

ADIPOCYTOKINES LINKING OBESITY AND OSTEOARTHRITIS - Huelser, M-L; Schreiyaeck, C.; Luo, Y.; Bozec, Aline; Schett, Georg; Neumann, E.; Mueller-Ladner, U. (2018)
EVALuna2:34154

Adipokine in the Arthritis Mouse Model - Huelser, Marie-Lisa; Schreiyaeck, Carina; Luo, Yubin; Bozec, Aline; Schett, Georg; Neumann, Elena; Mueller-Ladner, Ulf (2018)
EVALuna2:34473

ADIPOKINES AS LINK BETWEEN ARTHRITIS AND METABOLISM - Huelser, Marie-Lisa; Schreiyaeck, Carina; Luo, Yubin; Bozec, Aline; Schett, Georg; Mueller-Ladner, Ulf; Neumann, Elena (2017)
EVALuna2:13495

Adipokines in bone disease - Neumann, Elena; Junker, Susann; Schett, Georg; Frommer, Klaus; Mueller-Ladner, Ulf (Nature Reviews Rheumatology, 2016)
Adipose tissue secretes highly bioactive factors, the adipokines. Systemic levels of adipokines are often altered in the presence of inflammation. In turn, adipokines affect different tissues and cells systemically as well as locally, contributing to immunomodulatory and bone remodelling mechanisms. The role of adipokines has been evaluated in chronic inflammatory diseases, such as rheumatoid arthritis, as well as in primarily degenerative joint diseases, such as osteoarthritis, particularly with regard to their levels of expression and their effects on joint tissues including synovial membrane, cartilage and bone. Distinct adipokines have been found to modulate matrix remodelling as well as inflammatory responses. In this Review, we summarize current knowledge relating to adipokines in rheumatic diseases, with a particular focus on the effects of adipokines on bone remodelling.
EVALuna2:13276

Adopted orphans as regulators of inflammation, immunity and skeletal homeostasis - Ipseiz, Natacha; Scholtysek, Carina; Culemann, Stephan; Krönke, Gerhard (Swiss Medical Weekly, 2014)
Adopted orphan nuclear receptors, such as peroxisome proliferator-activated receptors (PPARs) and liver X receptors (LXRs), have emerged as key regulators of inflammation and immunity and likewise control skeletal homeostasis. These properties render them attractive targets for the therapy of various inflammatory and autoimmune diseases affecting the musculoskeletal system. This review summarises the current knowledge on the role of these families of receptors during innate and adaptive immunity as well as during the control of bone turnover and discuss the potential use of targeting these molecules during the treatment of chronic diseases such as osteoarthritis, rheumatoid arthritis and osteoporosis.
EVALuna2:13065

A dual role for UCMA in osteoarthritis-Inhibition of aggrecanases and promotion of bone turnover - Stock, Michael; Menges, Stefanie; Eitzinger, Nicole; Gesslein, Maria; Botschner, Renate; Wormser, Laura; Distler, Alfiya; Schlötzer-Schrehardt, Ursula; Dietel, Katharina; Distler, Jörg; Beyer, Christian; Gelse, Kolja; et al. (Arthritis and Rheumatology, 2017)
Cartilage damage and subchondral bone changes are closely connected in osteoarthritis. How these processes are interlinked is however incompletely understood to date. Here, we investigate the mechanistic role of the cartilage-derived protein UCMA in osteoarthritis-related cartilage and bone changes.UCMA expression was assessed in healthy and osteoarthritic human and mouse cartilage. DMM-induced osteoarthritis was performed in WT and Ucma-deficient mice analysing cartilage and bone changes. UCMA-collagen interactions, effect of UCMA on aggrecanase activity and the impact of recombinant UCMA on osteoclast differentiation were studied in vitro.UCMA was found overexpressed in human and mouse osteoarthritic cartilage. DMM-triggered cartilage changes were aggravated in Ucma-deficient mice compared to WT littermates, showing increased structural damage, proteoglycan loss and chondrocyte cell death indicating chondroprotective effects of UCMA. Moreover, UCMA inhibited ADAMTS-dependent aggrecanase activity and directly interacted with cartilage-specific collagen types. In contrast, osteoarthritis-related bone changes were significantly reduced in Ucma-deficient mice, showing less pronounced osteophyte formation and subchondral bone sclerosis. Mechanistically, UCMA directly promoted osteoclast differentiation in vitro.UCMA links cartilage with bone changes in osteoarthritis, supporting cartilage integrity as an endogenous inhibitor of aggrecanases on the one hand, and promoting osteoclastogenesis and subchondral bone turnover on the other hand. Hence, UCMA represents an important link between cartilage and bone in osteoarthritis. This article is protected by copyright. All rights reserved.
EVALuna2:10230

Adult-onset Still's disease and chronic recurrent multifocal osteomyelitis: A hitherto undescribed manifestation of autoinflammation - Rech, Jürgen; Manger, Bernhard; Lang, B.; Schett, Georg; Wilhelm, Martin; Birkmann, J. (Rheumatology International, 2012)
Still's disease and chronic recurrent multifocal osteomyelitis (CRMO) are febrile rheumatic diseases of unknown etiology, which predominantly affect children but can also have their initial manifestation in adults. Both can present as intermittent, relapsing episodes and are considered potential candidates within the expanding spectrum of autoinflammatory disorders, although no genetic abnormalities have been described for either of them. Here, we describe a man with an initial manifestation of abacterial multifocal osteitis at the age of 41. During a relapsing- remitting course of his illness, he increasingly developed symptoms of adult-onset Still's disease (AOSD), and the diagnosis was established according to the Yamaguchi criteria. When treated with anakinra, not only the acute symptoms disappeared promptly, but also the osteitis went into complete remission. This is to our knowledge the first description of a simultaneous occurrence of these two manifestations of autoinflammation in adulthood. © Springer-Verlag 2011.
CRIS-Team Scopus Importer:2021-02-03
Keywords: Adult-onset Still's syndrome; Anakinra; Chronic recurrent multifocal osteomyelitis

Adult onset Still's disease associated with malignancy-Cause or coincidence? - Hofheinz, Katharina; Schett, Georg; Manger, Bernhard (Seminars in Arthritis and Rheumatism, 2016)
To analyze all patients with adult onset Still's disease (AOSD) and malignancy described in the literature and to discuss their relation to each other.Demographic, clinical, and laboratory characteristics of one index patient with AOSD seen in our institution who subsequently developed a malignant disease were compared with all other cases of AOSD and malignancy identified by a PubMed literature research. Furthermore, characteristics of AOSD patients with malignancy were compared to those without malignancy.We found 46 articles in English, French, Japanese, Korean, and Spanish language reporting 47 cases in addition to our own case. In 36 patients, the diagnosis of AOSD could be confirmed by retrospectively applying classification criteria according to Yamaguchi, Fautrel, and Crispin. The median time between diagnosis of AOSD and subsequent detection of a malignant disease was 9 months, 50% had a hematological disorder and 50% a solid tumor. In 33%, the symptoms of AOSD resolved after successful therapy of the neoplastic disease. Red flags for paraneoplastic AOSD were onset of symptoms at higher age, atypical features of rash, highly elevated lactate dehydrogenase, atypical cells in the differential blood count, and high concentrations of the soluble interleukin-2 receptor.A disease resembling AOSD can precede the clinical appearance of a hematologic malignancy or a solid tumor. Thorough diagnostic work-up of AOSD to rule out malignancy and awareness to conspicuous signs for malignancy-associated AOSD are therefore essential in the clinical work-up of such patients.
EVALuna2:13178

Advanced machine learning for predicting individual risk of flares in rheumatoid arthritis patients tapering biologic drugs - Vodencarevic, Asmir; Tascilar, Koray; Reiser, Michaela; Hueber, Axel; Haschka, Judith; Bayat, Sara; Meinderink, Timo; Knitza, Johannes; Mendez, Larissa; Hagen, Melanie; Krönke, Gerhard; Rech, Jürgen; et al. (Arthritis Research & Therapy, 2021)
Background: Biological disease-modifying anti-rheumatic drugs (bDMARDs) can be tapered in some rheumatoid arthritis (RA) patients in sustained remission. The purpose of this study was to assess the feasibility of building a model to estimate the individual flare probability in RA patients tapering bDMARDs using machine learning methods. Methods: Longitudinal clinical data of RA patients on bDMARDs from a randomized controlled trial of treatment withdrawal (RETRO) were used to build a predictive model to estimate the probability of a flare. Four basic machine learning models were trained, and their predictions were additionally combined to train an ensemble learning method, a stacking meta-classifier model to predict the individual flare probability within 14 weeks after each visit. Prediction performance was estimated using nested cross-validation as the area under the receiver operating curve (AUROC). Predictor importance was estimated using the permutation importance approach. Results: Data of 135 visits from 41 patients were included. A model selection approach based on nested cross-validation was implemented to find the most suitable modeling formalism for the flare prediction task as well as the optimal model hyper-parameters. Moreover, an approach based on stacking different classifiers was successfully applied to create a powerful and flexible prediction model with the final measured AUROC of 0.81 (95%CI 0.73–0.89). The percent dose change of bDMARDs, clinical disease activity (DAS-28 ESR), disease duration, and inflammatory markers were the most important predictors of a flare. Conclusion: Machine learning methods were deemed feasible to predict flares after tapering bDMARDs in RA patients in sustained remission.
CRIS-Team Scopus Importer:2021-03-19
Keywords: Flare prediction; Machine learning; Rheumatoid arthritis

Advanced neural networks for classification of MRI in psoriatic arthritis, seronegative, and seropositive rheumatoid arthritis - 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. (Rheumatology, 2022)
Objectives: To evaluate whether neural networks can distinguish between seropositive rheumatoid arthritis (RA), seronegative RA and psoriatic arthritis (PsA) based on inflammatory patterns from hand MRI and to test how psoriasis patients with subclinical inflammation fit into such patterns. Methods: ResNet neural networks were utilized to compare (i) seropositive RA vs. PsA, (ii) seronegative RA vs. PsA and (iii) seropositive vs. seronegative RA with respect to hand MRI data. Results from T1 coronal, T2 coronal, T1 coronal and axial fat suppressed contrast-enhanced (CE) and T2 fat suppressed axial sequences were used. The performance of such trained networks was analyzed by the area-under-the-receiver-operating-characteristic curve (AUROC) with and without presentation of demographic and clinical parameters. Additionally, the trained networks were applied to psoriasis patients without clinical arthritis. Results: MRI scans from 649 patients (135 seronegative RA, 190 seropositive RA, 177 PsA, 147 psoriasis) were fed into ResNet neural networks. AUROC was 75% for seropositive RA vs. PsA, 74% for seronegative RA vs. PsA and 67% for seropositive vs. seronegative RA. All MRI sequences were relevant for classification, however, when deleting contrast agent-based sequences the loss of performance was only marginal. The addition of demographic and clinical data to the networks did not provide significant improvements for classification. Psoriasis patients were mostly assigned to PsA by the neural networks, suggesting that a PsA-like MRI pattern may be present early in the course of psoriatic disease. Conclusion: Neural networks can be successfully trained to distinguish MRI inflammation related to seropositive RA, seronegative RA, and PsA.
Keywords: Rheumatoid arthritis; Psoriatic arthritis; neural networks; deep learning

Advancing oral immunology for improving oral health - Deschner, James; Schröder, Agnes; Weber, Manuel; Galler, Kerstin Martina; Proff, Peter; Kirschneck, Christian; Bozec, Aline; Jantsch, Jonathan (Journal of Orofacial Orthopedics / Fortschritte der Kieferorthopädie, 2023)
Although substantial progress has been made in dentistry in terms of diagnosis and therapy, current treatment methods in periodontology, orthodontics, endodontics, and oral and maxillofacial surgery, nevertheless, suffer from numerous limitations, some of which are associated with a dramatic reduction in the quality of life. Many general mechanisms of inflammation and immunity also apply to the oral cavity and oral diseases. Nonetheless, there are special features here that are attributable, on the one hand, to developmental biology and, on the other hand, to the specific anatomical situation, which is characterized by a close spatial relationship of soft and hard tissues, exposure to oral microbiota, and to a rapid changing external environment. Currently, a comprehensive and overarching understanding is lacking about how the immune system functions in oral tissues (oral immunology) and how oral immune responses contribute to oral health and disease. Since advances in translational immunology have created a game-changing shift in therapy in rheumatology, allergic diseases, inflammatory bowel disease, and oncology in recent years, it is reasonable to assume that a better understanding of oral immunology might lead to practice-changing diagnostic procedures and therapies in dentistry and thereby also profoundly improve oral health in general.
CRIS-Team Scopus Importer:2023-06-30
Keywords: Host microbial interactions; Immune responses; Immune system; Oral diseases; Oral microbiota

A fast and robust method to clone and functionally validate T-cell receptors - Birkholz, Katrin; Hofmann, Christian; Hoyer, Stefanie; Schulz, Bastian; Harrer, Thomas; Kämpgen, Eckhart; Schuler, Gerold; Dörrie, Jan; Schaft, Niels (Journal of Immunological Methods, 2009)
Sequencing, cloning and functional testing of T-cell-receptor (TCR) α- and β-chains from T-cell clones is often required in immunotherapy and in immunological research. However, the determination of the TCR chains by a simple PCR is not possible, since, in contrast to the 3′ constant domain and untranslated region (UTR), no conserved sequences are present in the 5′ region. Furthermore, subsequent functional testing of cloned TCRs requires laborious cell-culture experiments, often involving primary human material and time-consuming viral transduction strategies. Here we present a universal PCR-based protocol, adapted from the capswitch technology, that allows for amplification of the TCR α- and β-chain mRNAs without knowledge of the TCR variable domain subtype by attaching a designed sequence to the mRNA's 5′ end. Two different MelanA/HLA-A2-specific and one HIVgag/HLA-A2-specific TCR were cloned that way, and were functionally tested by a newly developed easy, fast, and low-cost method: we electroporated Jurkat T cells simultaneously with TCR-encoding RNA and an NFAT-reporter construct, and measured the activation status of the cells upon specific stimulation. The results of this assay correlated with the cytokine release, functional avidity, proliferative activity, and the ability to recognize MelanA/HLA-A2-presenting tumor cells of bulk T cells electroporated with RNA encoding the same TCR. Together these two protocols represent a rapid and low-cost tool for the identification and functional testing of TCRs of T-cell clones, which can then be applied in immunotherapy or immunological research. © 2009 Elsevier B.V. All rights reserved.
CRIS-Team Scopus Importer:2021-10-01
Keywords: Cellular immunology; Immunotherapy; Signal transduction; T cells; TCR

Affinity purified anti-citrullinated protein/peptide antibodies target antigens expressed in the rheumatoid joint - Ossipova, Elena; Cerqueira, Catia Fernandes; Reed, Evan; Kharlamova, Nastya; Israelsson, Lena; Holmdahl, Rikard; Nandakumar, Kutty Selva; Engstrom, Marianne; Harre, Ulrike; Schett, Georg; Catrina, Anca I.; Malmstrom, Vivianne; et al. (Arthritis Research & Therapy, 2014)
A major subset of patients with rheumatoid arthritis (RA) is characterized by the presence of circulating autoantibodies directed to citrullinated proteins/peptides (ACPAs). These autoantibodies, which are commonly detected by using an enzyme-linked immunosorbent assay (ELISA) based on synthetic cyclic citrullinated peptides (CCPs), predict clinical onset and a destructive disease course. In the present study, we have used plasma and synovial fluids from patients with RA, for the affinity purification and characterization of anti-CCP2 reactive antibodies, with an aim to generate molecular tools that can be used in vitro and in vivo for future investigations into the pathobiology of the ACPA response. Specifically, this study aims to demonstrate that the surrogate marker CCP2 can capture ACPAs that bind to autoantigens expressed in vivo in the major inflammatory lesions of RA (that is, in the rheumatoid joint).Plasma (n = 16) and synovial fluid (n = 26) samples were collected from RA patients with anti-CCP2 IgG levels of above 300 AU/mL. Total IgG was isolated on Protein G columns and subsequently applied to CCP2 affinity columns. Purified anti-CCP2 IgG was analyzed for reactivity and specificity by using the CCPlus® ELISA, in-house peptide ELISAs, Western blot, and immunohisto-/immunocytochemistry.Approximately 2% of the total IgG pool in both plasma and synovial fluid was CCP2-reactive. Purified anti-CCP2 reactive antibodies from different patients showed differences in binding to CCP2 and differences in binding to citrullinated peptides from ?-enolase, vimentin, fibrinogen, and collagen type II, illustrating different ACPA fine-specificity profiles. Furthermore, the purified ACPA bound not only in vitro citrullinated proteins but, more importantly, in vivo-generated epitopes on synovial fluid cells and synovial tissues from patients with RA.We have isolated ACPAs from plasma and synovial fluid and demonstrated that the CCP2 peptides, frequently used in diagnostic ELISAs, de facto act as surrogate antigens for at least four different, well-characterized, largely non-cross-reactive, ACPA fine specificities. Moreover, we have determined the concentration and proportion of CCP2-reactive IgG molecules in rheumatoid plasma and synovial fluid, and we have shown that the purified ACPAs can be used to detect both in vitro- and in vivo-generated citrullinated epitopes by various techniques. We anticipate that these antibodies will provide us with new opportunities to investigate the potential pathogenic effects of human ACPAs.
EVALuna2:12981

A FRAMEWORK OF POTENTIAL INTERVENTIONS TO ACCELERATE GENDER-EQUITABLE CAREER ADVANCEMENT IN ACADEMIC RHEUMATOLOGY - Ovseiko, P. V.; Gossec, L.; Andreoli, L.; Kiltz, U.; Van Mens, L.; Hassan, N.; Van Der Leeden, M.; Siddle, H. J.; Alunno, A.; Mcinnes, I.; Damjanov, N.; Apparailly, F.; et al. (ANNALS OF THE RHEUMATIC DISEASES, 2021)
CRIS-Team WoS Importer:2021-10-01

Age- and Sex-Dependent Changes of Intra-articular Cortical and Trabecular Bone Structure and the Effects of Rheumatoid Arthritis - Simon, David; Kleyer, Arnd; Stemmler, Fabian; Simon, Christoph; Berlin, Andreas; Hueber, Axel; Haschka, Judith; Renner, Nina; Figueiredo, Camille; Neuhuber, Winfried; Buder, Thomas; Englbrecht, Matthias; et al. (Journal of Bone and Mineral Research, 2016)
The objective of this cross-sectional study was to define normal sex- and age-dependent values of intra-articular bone mass and microstructures in the metacarpal heads of healthy individuals by high-resolution peripheral quantitative computed tomography (HR-pQCT) and test the effect of rheumatoid arthritis (RA) on these parameters. Human cadaveric metacarpal heads were used to exactly define intra-articular bone. Healthy individuals of different sex and age categories and RA patients with similar age and sex distribution received HR-pQCT scans of the second metacarpal head and the radius. Total, cortical, and trabecular bone densities as well as microstructural parameters were compared between 1) the different ages and sexes in healthy individuals; 2) between metacarpal heads and the radius; and 3) between healthy individuals and RA patients. The cadaveric study allowed exact definition of the intra-articular (intracapsular) bone margins. These data were applied in measuring intra-articular and radial bone parameters in 214 women and men (108 healthy individuals, 106 RA patients). Correlations between intra-articular and radial bone parameters were good (r = 0.51 to 0.62, p < 0.001). In contrast to radial bone, intra-articular bone remained stable until age 60 years (between 297 and 312 mg HA/cm(3) ) but decreased significantly (p < 0.001) in women thereafter (237.5 ± 44.3) with loss of both cortical and trabecular bone. Similarly, RA patients showed significant (p < 0.001) loss of intra-articular total (263.0 ± 44.8), trabecular (171.2 ± 35.6), and cortical bone (610.2 ± 62.0) compared with sex- and age-adjusted controls. Standard sex- and age-dependent values for physiological intra-articular bone were defined. Postmenopausal state and RA led to significant decrease of intra-articular bone. © 2016 American Society for Bone and Mineral Research.
EVALuna:33251

Age-associated B cells contribute to the pathogenesis of rheumatoid arthritis by inducing activation of fibroblast-like synoviocytes via TNF-alpha-mediated ERK1/2 and JAK-STAT1 pathways - Qin, Yi; Cai, Ming-Long; Jin, Hui-Zhi; Huang, Wei; Zhu, Chen; Bozec, Aline; Huang, Jingang; Chen, Zhu (Annals of the Rheumatic Diseases, 2022)
Objectives Age-associated B cells (ABCs) are a recently identified B cell subset, whose expansion has been increasingly linked to the pathogenesis of autoimmune disorders. This study aimed to investigate whether ABCs are involved in the pathogenesis and underlying mechanisms of rheumatoid arthritis (RA). Methods ABCs were assessed in collagen-induced arthritis (CIA) mice and patients with RA using flow cytometry. Transcriptomic features of RA ABCs were explored using RNA-seq. Primary fibroblast-like synoviocytes (FLS) derived from the synovial tissue of patients with RA were cocultured with ABCs or ABCs-conditioned medium (ABCsCM). IL-6, MMP-1, MMP-3 and MMP-13 levels in the coculture supernatant were detected by ELISA. Signalling pathways related to ABCs-induced FLS activation were examined using western blotting. Results Increased ABCs levels in the blood, spleen and inflammatory joints of CIA mice were observed. Notably, ABCs were elevated in the blood, synovial fluid and synovial tissue of patients with RA and positively correlated with disease activity. RNA-seq revealed upregulated chemotaxis-related genes in RA ABCs compared with those in naive and memory B cells. Coculture of FLS with RA ABCs or ABCsCM led to an active phenotype of FLS, with increased production of IL-6, MMP-1, MMP-3 and MMP-13. Mechanistically, ABCsCM-derived TNF-alpha promoted the upregulation of interferon-stimulated genes in FLS, with elevated phosphorylation of ERK1/2 and STAT1. Furthermore, blockage of ERK1/2 and Janus Kinase (JAK)-STAT1 pathways inhibited the activation of FLS induced by ABCsCM. Conclusions Our results suggest that ABCs contribute to the pathogenesis of RA by inducing the activation of FLS via TNF-alpha-mediated ERK1/2 and JAK-STAT1 pathways.
CRIS-Team WoS Importer:2022-07-08

A genome-wide association study follow-up suggests a possible role for PPARG in systemic sclerosis susceptibility - Lopez-Isac, Elena; Bossini-Castillo, Lara; Simeon, Carmen P.; Victoria Egurbide, Maria; Jose Alegre-Sancho, Juan; Luis Callejas, Jose; Andres Roman-Ivorra, Jose; Freire, Mayka; Beretta, Lorenzo; Santaniello, Alessandro; Airo, Paolo; Lunardi, Claudio; et al. (Arthritis Research & Therapy, 2014)
A recent genome-wide association study (GWAS) comprising a French cohort of systemic sclerosis (SSc) reported several non-HLA single-nucleotide polymorphisms (SNPs) showing a nominal association in the discovery phase. We aimed to identify previously overlooked susceptibility variants by using a follow-up strategy.Sixty-six non-HLA SNPs showing a P value <10-4 in the discovery phase of the French SSc GWAS were analyzed in the first step of this study, performing a meta-analysis that combined data from the two published SSc GWASs. A total of 2,921 SSc patients and 6,963 healthy controls were included in this first phase. Two SNPs, PPARG rs310746 and CHRNA9 rs6832151, were selected for genotyping in the replication cohort (1,068 SSc patients and 6,762 healthy controls) based on the results of the first step. Genotyping was performed by using TaqMan SNP genotyping assays.We observed nominal associations for both PPARG rs310746 (PMH = 1.90 × 10-6, OR, 1.28) and CHRNA9 rs6832151 (PMH = 4.30 × 10-6, OR, 1.17) genetic variants with SSc in the first step of our study. In the replication phase, we observed a trend of association for PPARG rs310746 (P value = 0.066; OR, 1.17). The combined overall Mantel-Haenszel meta-analysis of all the cohorts included in the present study revealed that PPARG rs310746 remained associated with SSc with a nominal non-genome-wide significant P value (PMH = 5.00 × 10-7; OR, 1.25). No evidence of association was observed for CHRNA9 rs6832151 either in the replication phase or in the overall pooled analysis.Our results suggest a role of PPARG gene in the development of SSc.
EVALuna2:12970

Aggregated NETs Sequester and Detoxify Extracellular Histones - Knopf, Jasmin; Leppkes, Moritz; Schett, Georg; Herrmann, Martin; Munoz, Luis Enrique (Frontiers in Immunology, 2019)
In response to various infectious and sterile stimuli neutrophils release chromatin decorated with bactericidal proteins, referred to as NETs. Their scaffolds are formed from chromatin fibers which display an apparent diameter of 15-17 nm and mainly consist from DNA (2 nm) and DNA-associated histones (11 nm). The NET-forming strands are thus not naked DNA but higher ordered chromatin structures. The histones may be released from the NET, especially if their tail arginines have been citrullinated. Several studies indicate that extracellular histones are toxic for mammalian epithelia and endothelia and contribute to the microvascular dysfunction observed e.g., in patients suffering from autoimmune diseases or sepsis. NETs formed at sites of very high neutrophil densities tend to clump and form fairly stable enzymatically active aggregates, referred to as aggNETs. The latter are endowed with a bunch of enzymes that cleave, bind, and/or modify autologous as well as foreign macromolecules. The tight binding of the serine proteases to the matrix precludes the spread of these toxic enzymes into the tissue but still allows the access of soluble inflammatory mediators to the enzymatic active internal surfaces of the NETs where they are degraded. Here, we describe that externally added histones are removed from culture supernatants of aggNETs. We will address the fate of the histones and discuss the feature on the background of neutrophil-driven diseases and the resolution of inflammation.
CRIS-Team WoS Importer:2019-09-24

Aggregated neutrophil extracellular traps limit inflammation by degrading cytokines and chemokines - Schauer, Christine; Janko, Christina; Munoz Becerra, Luis; Zhao, Yi; Kienhöfer, Deborah; Frey, Benjamin; Lell, Michael; Manger, Bernhard; Rech, Juergen; Naschberger, Elisabeth; Holmdahl, Rikard; Krenn, Veit; et al. (Nature Medicine, 2014)
Gout is characterized by an acute inflammatory reaction and the accumulation of neutrophils in response to monosodium urate (MSU) crystals. Inflammation resolves spontaneously within a few days, although MSU crystals can still be detected in the synovial fluid and affected tissues. Here we report that neutrophils recruited to sites of inflammation undergo oxidative burst and form neutrophil extracellular traps (NETs). Under high neutrophil densities, these NETs aggregate and degrade cytokines and chemokines via serine proteases. Tophi, the pathognomonic structures of chronic gout, share characteristics with aggregated NETs, and MSU crystals can induce NETosis and aggregation of NETs. In individuals with impaired NETosis, MSU crystals induce uncontrolled production of inflammatory mediators from neutrophils and persistent inflammation. Furthermore, in models of neutrophilic inflammation, NETosis-deficient mice develop exacerbated and chronic disease that can be reduced by adoptive transfer of aggregated NETs. These findings suggest that aggregated NETs promote the resolution of neutrophilic inflammation by degrading cytokines and chemokines and disrupting neutrophil recruitment and activation.
Created from Fastlane, Scopus look-up

Aggregated neutrophil extracellular traps occlude Meibomian glands during ocular surface inflammation - Mahajan, Aparna; Hasíková, Lenka; Hampel, Ulrike; Grüneboom, Anika; Shan, Xiaomei; Herrmann, Irmgard; Garreis, Fabian; Bock, Felix; Knopf, Jasmin; Singh, Jeeshan; Mahajan, Siddharth; Leppkes, Moritz; et al. (Ocular Surface, 2021)
Purpose: Obstructive Meibomian gland dysfunction (MGD) is one of the leading causes of evaporative dry eye disease. Meibomian glands at the eyelid secrete lipids that prevent evaporation of the aqueous tear film. The pathogenesis of obstructive MGD is incompletely understood to date. Herein, we aim to investigate the pathogenesis of obstructive MGD using murine and human samples with various forms of ocular surface inflammation. Method: The presence of Neutrophil extracellular Traps (NETs) was detected with immunofluorescence analysis of ocular surface discharge and biopsy samples from patients with blepharitis. Tear fluid from patients with MGD and blepharitis were evaluated for the presence of inflammatory mediators using bead based immunoassay. Murine model of allergic eye disease (AED) was performed to investigate the role of NETs in MG occlusion. Results: we show that the ocular discharge from patients with blepharitis contains aggregated neutrophil extracellular traps (aggNETs). Furthermore, the ducts of human Meibomian glands affected by blepharitis were largely congested by aggNETs. Tear fluid from patients with MGD showed elevated neutrophil chemoattractants (C5a, IL6, IL8 and IL18). C5a and IL8 correlated with the degree of deficiency of tear fluid. In the murine model of allergic eye disease (AED), aggNETs accumulated in the MG leading to occlusion of their ducts and the retrograde pent-up of the fluid followed by acinar atrophy. Constraining aggNET formation by genetic or pharmacological inhibition of peptidyl arginine deiminase type 4 (PADI4) effectively reduced MG damage. Conclusion: We conclude that aggNETs occlude MG causing MGD after ocular surface inflammation.
CRIS-Team Scopus Importer:2021-01-15
Keywords: Blepharitis; Meibomian gland dysfunction (MGD); Neutrophil extracellular traps (NETs); Occlusion

Aggregated neutrophil extracellular traps resolve inflammation by proteolysis of cytokines and chemokines and protection from antiproteases - Hahn, Jonas; Schauer, Christine; Czegley, Christine; Kling, Lasse; Petru, Lenka; Schmid, Benjamin; Weidner, Daniela; Reinwald, Christiane; Biermann, Mona H.C.; Blunder, Stefan; Ernst, Jurgen; Lesner, Adam; et al. (The FASEB Journal, 2018)
Papillon-Lefèvre syndrome (PLS) is characterized by nonfunctional neutrophil serine proteases (NSPs) and fulminant periodontal inflammation of unknown cause. Here we investigated neutrophil extracellular trap (NET)-associated aggregation and cytokine/chemokine-release/degradation by normal and NSP-deficient human and mouse granulocytes. Stimulated with solid or soluble NET inducers, normal neutrophils formed aggregates and both released and degraded cytokines/chemokines. With increasing cell density, proteolytic degradation outweighed release. Maximum output of cytokines/chemokines occurred mostly at densities between 2 × 107 and 4 × 107 neutrophils/cm3. Assessment of neutrophil density in vivo showed that these concentrations are surpassed during inflammation. Association with aggregated NETs conferred protection of neutrophil elastase against α1-antitrypsin. In contrast, eosinophils did not influence cytokine/chemokine concentrations. The proteolytic degradation of inflammatory mediators seen in NETs was abrogated in Papillon-Lefèvre syndrome (PLS) neutrophils. In summary, neutrophil-driven proteolysis of inflammatory mediators works as a built-in safeguard for inflammation. The absence of this negative feedback mechanism might be responsible for the nonresolving periodontitis seen in PLS.-Hahn, J., Schauer, C., Czegley, C., Kling, L., Petru, L., Schmid, B., Weidner, D., Reinwald, C., Biermann, M. H. C., Blunder, S., Ernst, J., Lesner, A., Bäuerle, T., Palmisano, R., Christiansen, S., Herrmann, M., Bozec, A., Gruber, R., Schett, G., Hoffmann, M. H. Aggregated neutrophil extracellular traps resolve inflammation by proteolysis of cytokines and chemokines and protection from antiproteases.
EVALuna2:34668

AKAP6 orchestrates the nuclear envelope microtubule-organizing center by linking golgi and nucleus via AKAP9 - Vergarajauregui, Silvia; Becker, Robert; Steffen, Ulrike; Sharkova, Maria; Esser, Tilman; Petzold, Jana; Billing, Florian; Kapiloff, Michael S.; Schett, Georg; Thievessen, Ingo; Engel, Felix (eLife, 2020)
The switch from centrosomal microtubule-organizing centers (MTOCs) to noncentrosomal MTOCs during differentiation is poorly understood. Here, we identify AKAP6 as key component of the nuclear envelope MTOC. In rat cardiomyocytes, AKAP6 anchors centrosomal proteins to the nuclear envelope through its spectrin repeats, acting as an adaptor between nesprin-1 alpha and Pcnt or AKAP9. In addition, AKAP6 and AKAP9 form a protein platform tethering the Golgi to the nucleus. Both Golgi and nuclear envelope exhibit MTOC activity utilizing either AKAP9, or Pcnt-AKAP9, respectively. AKAP6 is also required for formation and activity of the nuclear envelope MTOC in human osteoclasts. Moreover, ectopic expression of AKAP6 in epithelial cells is sufficient to recruit endogenous centrosomal proteins. Finally, AKAP6 is required for cardiomyocyte hypertrophy and osteoclast bone resorption activity. Collectively, we decipher the MTOC at the nuclear envelope as a bi-layered structure generating two pools of microtubules with AKAP6 as a key organizer.
CRIS-Team WoS Importer:2021-01-01

Alcohol-sourced acetate impairs T cell function by promoting cortactin acetylation - Azizov, Vugar; Hübner, Michel; Frech, Michael; Hofmann, Jörg; Kubankova, Marketa; Lapuente, Dennis; Tenbusch, Matthias; Guck, Jochen; Schett, Georg; Zaiss, Mario (iScience, 2023)
Alcohol is among the most widely consumed dietary substances. Excessive alcohol consumption damages the liver, heart, and brain. Alcohol also has strong immunoregulatory properties. Here, we report how alcohol impairs T cell function via acetylation of cortactin, a protein that binds filamentous actin and facilitates branching. Upon alcohol consumption, acetate, the metabolite of alcohol, accumulates in lymphoid organs. T cells exposed to acetate, exhibit increased acetylation of cortactin. Acetylation of cortactin inhibits filamentous actin binding and hence reduces T cell migration, immune synapse formation and activation. While mutated, acetylation-resistant cortactin rescues the acetate-induced inhibition of T cell migration, primary mouse cortactin knockout T cells exhibited impaired migration. Acetate-induced cytoskeletal changes effectively inhibited activation, proliferation, and immune synapse formation in T cells in vitro and in vivo in an influenza infection model in mice. Together these findings reveal cortactin as a possible target for mitigation of T cell driven autoimmune diseases.
CRIS-Team Scopus Importer:2023-07-21
Keywords: Immunology; Molecular biology

Allopurinol is positively associated with cardiovascular health - Manger, Bernhard (Deutsche Medizinische Wochenschrift, 2016)
EVALuna2:13298

A LONGITUDINAL DUAL ENERGY COMPUTED TOMOGRAPHY STUDY ON THE EFFECT OF URATE LOWERING THERAPIES ON THE REDUCTION OF TOPHUS BURDEN IN PATIENTS WITH CHRONIC GOUT - Ellmann, Hanna; Bayat, Sara; D'Oliveira, I.; Englbrecht, Matthias; Araujo, E.; Mendonca, S.; Lell, Michael; Manger, Bernhard; Schett, Georg; Rech, Jürgen; Cavallaro, Alexander Josef (2016)
EVALuna2:13439

Alteration of Gut Microbiota in Individuals at High-Risk for Rheumatoid Arthritis Associated With Disturbed Metabolome and the Initiation of Arthritis Through the Triggering of Mucosal Immunity Imbalance - Luo, Yubin; Tong, Yanli; Wu, Liang; Niu, Haitao; Li, Yanhong; Su, Lin Chong; Wu, Yuxi; Bozec, Aline; Zaiss, Mario; Qing, Pingying; Zhao, Hua; Tan, Chunyu; et al. (Arthritis and Rheumatology, 2023)
Objective: In this study, we aimed to decipher the gut microbiome (GM) and serum metabolic characteristic of individuals at high risk for rheumatoid arthritis (RA) and to investigate the causative effect of GM on the mucosal immune system and its involvement in the pathogenesis of arthritis. Methods: Fecal samples were collected from 38 healthy individuals and 53 high-risk RA individuals with anti–citrullinated protein antibody (ACPA) positivity (Pre-RA), 12 of 53 Pre-RA individuals developed RA within 5 years of follow-up. The differences in intestinal microbial composition between the healthy controls and Pre-RA individuals or among Pre-RA subgroups were identified by 16S ribosomal RNA sequencing. The serum metabolite profile and its correlation with GM were also explored. Moreover, antibiotic-pretreated mice that received GM from the healthy control or Pre-RA groups were then evaluated for intestinal permeability, inflammatory cytokines, and immune cell populations. Collagen-induced arthritis (CIA) was also applied to test the effect of fecal microbiota transplantation (FMT) from Pre-RA individuals on arthritis severity in mice. Results: Stool microbial diversity was lower in Pre-RA individuals than in healthy controls. The bacterial community structure and function significantly differed between healthy controls and Pre-RA individuals. Although there were differences to some extent in the bacterial abundance among the Pre-RA subgroups, no robust functional differences were observed. The metabolites in the serum of the Pre-RA group were dramatically different from those in the healthy controls group, with KEGG pathway enrichment of amino acid and lipid metabolism. Moreover, intestinal bacteria from the Pre-RA group increased intestinal permeability in FMT mice and zonula occludens-1 expression in the small intestine and Caco-2 cells. Moreover, Th17 cells in the mesenteric lymph nodes and Peyer's patches were also increased in mice receiving Pre-RA feces compared to healthy controls. The changes in intestinal permeability and Th17-cell activation prior to arthritis induction enhanced CIA severity in PreRA-FMT mice compared with HC-FMT mice. Conclusion: Gut microbial dysbiosis and metabolome alterations already occur in individuals at high risk for RA. FMT from preclinical individuals triggers intestinal barrier dysfunction and changes mucosal immunity, further contributing to the development of arthritis.
CRIS-Team Scopus Importer:2023-09-29

Altered glycan accessibility on native immunoglobulin G complexes in early rheumatoid arthritis and its changes during therapy - Stuemer, J.; Biermann, Mona; Knopf, Jasmin; Magorivska, I.; Kastbom, A.; Svaerd, A.; Janko, Christina; Bilyy, R.; Schett, Georg; Sjoewall, C.; Herrmann, Martin; Munoz, Luis Enrique; et al. (Clinical and Experimental Immunology, 2017)
The goal of this study was to investigate the glycosylation profile of native immunoglobulin (Ig)G present in serum immune complexes in patients with rheumatoid arthritis (RA). To accomplish this, lectin binding assays, detecting the accessibility of glycans present on IgG-containing immune complexes by biotinylated lectins, were employed. Lectins capturing fucosyl residues (AAL), fucosylated tri-mannose N-glycan core sites (LCA), terminal sialic acid residues (SNA) and O-glycosidically linked galactose/N-acetylgalactosamine (GalNac-L) were used. Patients with recent-onset RA at baseline and after 3-year follow-up were investigated. We found that native IgG was complexed significantly more often with IgM, C1q, C3c and C-reactive protein (CRP) in RA patients, suggesting alterations of the native structure of IgG. The total accessibility of fucose residues on captured immune complexes to the respective lectin was significantly higher in patients with RA. Moreover, fucose accessibility on IgG-containing immune complexes correlated positively with the levels of antibodies to cyclic citrullinated peptides (anti-CCP). We also observed a significantly higher accessibility to sialic acid residues and galactose/GalNAc glyco-epitopes in native complexed IgG of patients with RA at baseline. While sialic acid accessibility increased during treatment, the accessibility of galactose/GalNAc decreased. Hence, successful treatment of RA was associated with an increase in the SNA/GalNAc-L ratio. Interestingly, the SNA/GalNAc-L ratio in particular rises after glucocorticoid treatment. In summary, this study shows the exposure of glycans in native complexed IgG of patients with early RA, revealing particular glycosylation patterns and its changes following pharmaceutical treatment.
EVALuna2:13418

Altered glycosylation of complexed native IgG molecules is associated with disease activity of systemic lupus erythematosus - Sjowall, Christopher; Zapf, J.; Von Loehneysen, S.; Magorivska, I.; Biermann, M.; Janko, Christina; Winkler, Sophie; Bilyy, R.; Schett, Georg; Herrmann, Martin; Munoz Becerra, Luis (Lupus, 2015)
In addition to the redundancy of the receptors for the Fc portion of immunoglobulins, glycans result in potential ligands for a plethora of lectin receptors found in immune effector cells. Here we analysed the exposure of glycans containing fucosyl residues and the fucosylated tri-mannose N-type core by complexed native IgG in longitudinal serum samples of well-characterized patients with systemic lupus erythematosus. Consecutive serum samples of a cohort of 15 patients with systemic lupus erythematosus during periods of increased disease activity and remission were analysed. All patients fulfilled the 1982 American College of Rheumatology classification criteria. Sera of 15 sex- and age-matched normal healthy blood donors served as controls. The levels and type of glycosylation of complexed random IgG was measured with lectin enzyme-immunosorbent assays. After specifically gathering IgG complexes from sera, biotinylated lectins Aleuria aurantia lectin and Lens culinaris agglutinin were employed to detect IgG-associated fucosyl residues and the fucosylated tri-mannose N-glycan core, respectively. In sandwich-ELISAs, IgG-associated IgM, IgA, C1q, C3c and C-reactive protein (CRP) were detected as candidates for IgG immune complex constituents. We studied associations of the glycan of complexed IgG and disease activity according to the physician's global assessment of disease activity and the systemic lupus erythematosus disease activity index 2000 documented at the moment of blood taking. Our results showed significantly higher levels of Aleuria aurantia lectin and Lens culinaris agglutinin binding sites exposed on IgG complexes of patients with systemic lupus erythematosus than on those of normal healthy blood donors. Disease activity in systemic lupus erythematosus correlated with higher exposure of Aleuria aurantia lectin-reactive fucosyl residues by immobilized IgG complexes. Top levels of Aleuria aurantia lectin-reactivity were found in samples taken during the highest activity of systemic lupus erythematosus. Our results show that native circulating IgG complexes from active systemic lupus erythematosus patients expose fucosyl residues and their glycan core is accessible to soluble lectins. Two putative mechanisms may contribute to the increased exposure of these glycans: (1) the canonical N-glycosylation site of the IgG-CH2 domain; (2) an IgG binding non-IgG molecule, like complement or C-reactive protein. In both cases the complexed IgG may be alternatively targeted to lectin receptors of effector cells, e.g. dendritic cells.
EVALuna2:13017

Amelioration of Fibrotic Remodeling of Human 3-Dimensional Full-Thickness Skin by Transglutamase 2 Inhibition - Zhou, Xiang; Trinh-Minh, Thuong; Matei, Alexandru Emil; Györfi, Andrea Hermina; Hong, Xuezhi; Bergmann, Christina; Schett, Georg; Atkinson, John; Bowcutt, Rowann; Patel, Jessal; Johnson, Timothy S.; Distler, Jörg H.W. (Arthritis and Rheumatology, 2023)
Objective: Fibrotic tissues are characterized by excessive crosslinking between extracellular matrix (ECM) proteins, rendering them more resistant to degradation. Although increased crosslinking of ECM is thought to play an important role for progression of tissue fibrosis, enhanced ECM crosslinking has not yet been targeted therapeutically in systemic sclerosis (SSc). Here, we investigated the role of transglutaminase 2 (TG2), a central crosslinking enzyme, in the activation of SSc fibroblasts. Methods: We assessed TG2 expression and activity using TG2 staining, Western blotting, and TG2 activity assays. We inhibited TG2 in fibroblasts cultured under standard 2-dimensional conditions and in a 3-dimensional full-thickness equivalent skin model using monoclonal inhibitory anti-TG2 antibodies. Results: TG2 expression was increased in the skin of patients with SSc compared with healthy controls, with levels particularly high in patients with SSc-associated interstitial lung disease. TG2 expression and TG2 activity were also increased in SSc dermal fibroblasts. Moreover, the levels of circulating TG2 in the plasma samples from SSc patients were increased versus samples from healthy controls. Anti-TG2 antibodies did not show consistent antifibrotic effects across different fibroblast cell lines under 2-dimensional culture conditions; however, anti-TG2 antibodies effectively reduced transforming growth factor β–induced dermal thickening, myofibroblast differentiation, and collagen accumulation in the 3-dimensional full-thickness model of human skin. Conclusion: We provide the first evidence, to our knowledge, that inhibition of TG2 might be a potential antifibrotic approach in SSc. Our findings have translational potential as anti-TG2 antibodies are currently evaluated in a phase II clinical trial in chronic allograft injury and would thus be available for clinical studies in SSc (ClinicalTrials.gov identifier: NCT04335578). (Figure presented.).
CRIS-Team Scopus Importer:2023-07-21

A MINIMAL-INVASIVE METHOD TO RETRIEVE AND IDENTIFY ENTHESEAL TISSUE FROM PSORIATIC ARTHRITIS PATIENTS - Raimondo, Maria Gabriella; Pachowsky, Milena; Xu, Cong; Rauber, Simon; Tascilar, Koray; Labinsky, Hannah; Soare, A.; Bräuer, Lars; Rech, Jürgen; Simon, David; Kleyer, Arnd; Schett, Georg; et al. (ANNALS OF THE RHEUMATIC DISEASES, 2022)
CRIS-Team WoS Importer:2022-11-04

A model of chronic enthesitis and new bone formation characterized by multimodal imaging - Czegley, Christine; Gillmann, Clarissa; Schauer, Christine; Seyler, Lisa; Reinwald, Christiane; Hahn, Madelaine; Uder, Michael; Jochmann, Katja; Naschberger, Elisabeth; Stock, Michael; Schett, Georg; Bäuerle, Tobias; et al. (Disease Models & Mechanisms, 2018)
Enthesitis is a key feature of several different rheumatic diseases. Its pathophysiology is only partially known due to the lack of access to human tissue and the shortage of solid animal models for enthesitis. Here we aimed to develop a model, which mimics the effector phase of enthesitis and reliably leads to inflammation and new bone formation.Enthesitis was induced by local injection of monosodium urate crystals (MSU) into the metatarsal entheses of wild type (WT) or oxidative burst-deficient Ncf1** mice. Quantitative variables of inflammation (edema, swelling) and vascularization (tissue perfusion) were assessed by MRI, bone forming-activity by [18F]-fluoride-PET and destruction of cortical bone and new bone formation by CT. Non-invasive imaging was validated by histochemical and histomorphometric analysis.While injection of MSU crystals into WT mice triggered transient mild enthesitis with no new bone formation, Ncf1** mice developed chronic enthesitis accompanied by massive enthesiophytes. In MRI, inflammation and blood flow in the entheses were chronically increased while PET/CT showed osteoproliferation with enthesiophyte formation. Histochemical analyses showed chronic inflammation, increased vascularization, osteoclast differentiation and bone deposition in the affected entheseal sites.Herein we describe a fast and reliable effector model of chronic enthesitis, which is characterized by a combination of inflammation, vascularization and new bone formation. This model will help to disentangle the molecular pathways involved in the effector phase of enthesitis.
EVALuna2:34481

AMPLIFICATION OF THE PRO-FIBROTIC JAK2-STAT3 SIGNALING AXIS BY TGFB-INDUCED EPIGENETIC SILENCING OF SOCS3 - Dees, Clara; Poetter, S.; Zhang, Yun; Bergmann, C.; Zhou, X.; Luber, M.; Karouzakis, E.; Ramming, Andreas; Distler, O.; Schett, Georg; Distler, Jörg (ANNALS OF THE RHEUMATIC DISEASES, 2020)
CRIS-Team WoS Importer:2020-08-21

A Multiplex Kindred with Hennekam Syndrome due to Homozygosity for a CCBE1 Mutation that does not Prevent Protein Expression - Jackson, Carolyn C.; Best, Lucy; Lorenzo, Lazaro; Casanova, Jean-Laurent; Wacker, Jochen; Bertz, Simone; Agaimy, Abbas; Harrer, Thomas (Journal of Clinical Immunology, 2016)
Collagen and calcium-binding EGF domain-containing protein 1 (CCBE1) bi-allelic mutations have been associated with syndromes of widespread congenital lymphatic dysplasia, including Hennekam Syndrome (HS). HS is characterized by lymphedema, lymphangiectasia, and intellectual disability. CCBE1 encodes a putative extracellular matrix protein but the HS-causing mutations have not been studied biochemically. We report two HS siblings, born to consanguineous parents of Turkish ancestry, whose clinical phenotype also includes protein losing enteropathy, painful relapsing chylous ascites, and hypogammaglobulinemia. We identified by whole exome and Sanger sequencing the homozygous CCBE1 C174Y mutation in both siblings. This mutation had been previously reported in another HS kindred from the Netherlands. In over-expression studies, we found increased intracellular expression of all forms (monomers, dimers, trimers) of the CCBE1 C174Y mutant protein, by Western blot, despite mutant mRNA levels similar to wild-type (WT). In addition, we detected increased secretion of the mutant CCBE1 protein by ELISA. We further found the mutant and WT proteins to be evenly distributed in the cytoplasm, by immunofluorescence and confocal microscopy. Finally, we found a strong decrease of lymphatic vessels, with a corresponding diminished expression of CCBE1, by immunohistochemistry of the patients' intestinal biopsies. In contrast, mucosal blood vessels and muscularis mucosae showed normal CCBE1 staining. Our findings show that the mutant CCBE1 C174Y protein is not loss-of-function by loss-of-expression.
EVALuna2:6762

An advanced optical clearing protocol allows label-free detection of tissue necrosis via multiphoton microscopy in injured whole muscle - Schneidereit, Dominik; Broellochs, Anita; Ritter, Paul; Kreiß, Lucas; Mokhtari, Zeinab; Beilhack, Andreas; Krönke, Gerhard; Ackermann, Jochen; Faas, Maria; Grüneboom, Anika; Schürmann, Sebastian; Friedrich, Oliver (Theranostics, 2021)
Rationale: Structural remodeling or damage as a result of disease or injury is often not evenly distributed throughout a tissue but strongly depends on localization and extent of damaging stimuli. Skeletal muscle as a mechanically active organ can express signs of local or even systemic myopathic damage, necrosis, or repair. Conventionally, muscle biopsies (patients) or whole muscles (animal models) are mechanically sliced and stained to assess structural alterations histologically. Three-dimensional tissue information can be obtained by applying deep imaging modalities, e.g. multiphoton or light-sheet microscopy. Chemical clearing approaches reduce scattering, e.g. through matching refractive tissue indices, to overcome optical penetration depth limits in thick tissues.
CRIS-Team WoS Importer:2021-01-22

An AI-Powered Clinical Decision Support System to Predict Flares in Rheumatoid Arthritis: A Pilot Study - Labinsky, Hannah; Ukalovic, Dubravka; Hartmann, Fabian; Runft, Vanessa; Wichmann, Andre; Jakubcik, Jan; Gambel, Kira; Otani, Katharina; Morf, Harriet; Taubmann, Jule; Fagni, Filippo; Kleyer, Arnd; et al. (Diagnostics, 2023)
Treat-to-target (T2T) is a main therapeutic strategy in rheumatology; however, patients and rheumatologists currently have little support in making the best treatment decision. Clinical decision support systems (CDSSs) could offer this support. The aim of this study was to investigate the accuracy, effectiveness, usability, and acceptance of such a CDSS-Rheuma Care Manager (RCM)-including an artificial intelligence (AI)-powered flare risk prediction tool to support the management of rheumatoid arthritis (RA). Longitudinal clinical routine data of RA patients were used to develop and test the RCM. Based on ten real-world patient vignettes, five physicians were asked to assess patients' flare risk, provide a treatment decision, and assess their decision confidence without and with access to the RCM for predicting flare risk. RCM usability and acceptance were assessed using the system usability scale (SUS) and net promoter score (NPS). The flare prediction tool reached a sensitivity of 72%, a specificity of 76%, and an AUROC of 0.80. Perceived flare risk and treatment decisions varied largely between physicians. Having access to the flare risk prediction feature numerically increased decision confidence (3.5/5 to 3.7/5), reduced deviations between physicians and the prediction tool (20% to 12% for half dosage flare prediction), and resulted in more treatment reductions (42% to 50% vs. 20%). RCM usability (SUS) was rated as good (82/100) and was well accepted (mean NPS score 7/10). CDSS usage could support physicians by decreasing assessment deviations and increasing treatment decision confidence.
CRIS-Team WoS Importer:2023-01-27

Analyses of association of psoriatic arthritis and psoriasis vulgaris with functional NCF1 variants - Löhr, Sabine; Ekici, Arif Bülent; Uebe, Steffen; Büttner, Christian; Köhm, Michaela; Behrens, Frank; Böhm, Beate; Sticherling, Michael; Schett, Georg; Simon, David; Mössner, Rotraut; Nimeh, Ali; et al. (Rheumatology, 2019)
CRIS-Team Scopus Importer:2019-07-02

Analysis of ATP8B4 F436L missense variant in a large Systemic sclerosis cohort - Lopez-Isac, Elena; Bossini-Castillo, Lara; Palma, Ana B.; Assassi, Shervin; Mayes, Maureen D.; Simeon, Carmen P.; Ortego-Centeno, Norberto; Vicente, Esther; Tolosa, Carlos; Rubio-Rivas, Manuel; Roman-Ivorra, Jose A.; Beretta, Lorenzo; et al. (Arthritis and Rheumatology, 2017)
EVALuna:33747

Analysis of Hand Joint Space Morphology in Women and Men with Hereditary Hemochromatosis - Heilmeier, Ursula; Burghardt, Andrew J.; Tse, Justin J.; Kapoor, Puneet; Stok, Kathryn S.; Manske, Sarah; Voll, Reinhard E.; Schett, Georg; Finzel, Stephanie (Calcified Tissue International, 2023)
Hereditary hemochromatosis (HH) causes unbalanced iron deposition in many organs including the joints leading to severe cartilage loss and bone damage in the metacarpophalangeal joints (MCPJ). High-resolution peripheral quantitative computed tomography (HR-pQCT) and its joint space width (JSW) quantification algorithm quantifies in vivo 3D joint morphology. We therefore aimed to (i) determine feasibility and performance of the JSW algorithm in HH, (ii) quantify joint space morphology, and (iii) investigate the relationship between morphological and clinical parameters in HH. Here, we performed an exploratory study on 24 HH patients and sex- and age-matched controls using HR-pQCT imaging of MCPJ. Mineralized bone structure was automatically segmented from the grayscale image data and periosteal surface bone masks and joint space masks were generated. Mean, minimal, and maximal joint space width (JSW; JSW.MIN; JSW.MAX), JSW heterogeneity (JSW.SD), JSW asymmetry (JSW.AS), and joint space volume (JSV) were computed. Demographics and, for HH patients, disease-specific parameters were recorded. Segmentation of JS was very good with 79.7% of MCPJs successfully segmented at first attempt and 20.3% requiring semi-manual correction. HH men showed larger JSV at all MCPs (+ 25.4% < JSV < + 41.8%, p < 0.05), larger JSW.MAX at MCP 3-4 (+ 14%, 0.006 < p < 0.062), and wider JSW (+ 13%, p = 0.043) at MCP 4 relative to HH women. Compared to controls, both HH men and HH women showed larger JSW.AS and smaller JSW.MIN at all MCP levels, reaching significance for HH men at MCP 2 and 3 (JSW.AS: + 323% < JSW.AS < + 359%, 0.020 < p < 0.043; JSW.MIN: − 216% < JSW.MIN < − 225%, p < 0.043), and for women at MCP 3 (JSW.AS: + 180%, p = 0.025; JSW.MIN: − 41.8%, p = 0.022). Time since HH diagnosis was correlated positively with MCP 4 JSW.AS and JSW.SD (0.463 < ρ < 0.499, p < 0.040), and the number of phlebotomies since diagnosis was correlated with JSW.SD at all MCPs (0.432 < ρ < 0.535, p < 0.050). HR-pQCT-based JSW quantification in MCPJ of HH patients is feasible, performs well even in narrow JS, and allows to define the microstructural joint burden of HH.
CRIS-Team Scopus Importer:2023-02-17
Keywords: Hemochromatosis arthropathy; Hereditary hemochromatosis; High-resolution peripheral computed tomography; Joint space

Analysis of periarticular bone changes in patients with cutaneous psoriasis without associated psoriatic arthritis - Simon, Dominic; Faustini, F.; Englbrecht, Matthias; Kleyer, Arnd; Kocijan, R.; Haschka, Judith; Finzel, Stephanie; Kraus, Sebastian; Hueber, Axel; Sticherling, Michael; Schett, Georg; Rech, J. (Annals of the Rheumatic Diseases, 2016)
To search for structural bone changes in the joints of psoriasis patients without psoriatic arthritis (PsA).55 psoriasis patients without any current or past symptoms of arthritis or enthesitis and 47 healthy controls were examined by high-resolution peripheral quantitative CT scans of the metacarpophalangeal joints. Number, size and exact localisation of erosions and enthesiophytes were recorded by analysing axial scans of the metacarpal heads and phalangeal bases and were confirmed in additional coronal and/or sagittal sections. In addition, we collected demographic and clinical data including subtype, duration and severity of psoriasis.Psoriasis patients showed a larger and significantly increased number of enthesiophytes (total number 306; mean±SD/patient 5.62±3.30) compared with healthy controls (total number 138; mean±SD/patient 3.04±1.81, p<0.001). Enthesiophytes were typically found at the dorsal and palmar sides of the metacarpal heads where functional entheses related to extensor and flexor tendons are localised. Bone erosions were rare and not significantly different between psoriasis patients and healthy controls. If present, erosions were almost exclusively found at the radial side of the second metacarpal head in both psoriasis patients and healthy controls.Psoriasis patients without PsA show substantial signs of enthesiophyte formation compared with healthy controls. These changes represent new bone formation at mechanically exposed sites of the joint and substantiate the concept of the existence of a 'Deep Koebner Phenomenon' at enthesial sites in psoriasis patients.
EVALuna2:13130

"AND SUDDENLY YOU ARE A PERSON AT RISK OF DEVELOPING RHEUMATOID ARTHRITIS!" DIFFERENT PERSPECTIVES OF INDIVIDUALS ON PREDICTIVE TESTING - RESULTS OF AN INTERNATIONAL QUALITATIVE INTERVIEW STUDY - Mosor, E.; Stoffer, M.; Steiner, G.; Raza, K.; Stack, R. J.; Simons, Gwenda; Falahee, Marie; Schett, Georg; Hueber, Axel; Engelbrecht, M.; Smolen, J.; Stamm, T. (2017)
EVALuna2:35047

A new method for quantitative assessment of hand muscle volume and fat in magnetic resonance images - Friedberger, Andreas; Figueiredo, Camille; Bäuerle, Tobias; Schett, Georg; Engelke, Klaus (BMC Rheumatology, 2020)
Background: Rheumatoid arthritis (RA) is characterized by systemic inflammation and bone and muscle loss. Recent research showed that obesity facilitates inflammation, but it is unknown if obesity also increases the risk or severity of RA. Further research requires an accurate quantification of muscle volume and fat content. Methods: The aim was to develop a reproducible (semi) automated method for hand muscle segmentation and quantification of hand muscle fat content and to reduce the time consuming efforts of manual segmentation. T1 weighted scans were used for muscle segmentation based on a random forest classifier. Optimal segmentation parameters were determined by cross validation with 30 manually segmented hand datasets (gold standard). An operator reviewed the automatically created segmentation and applied corrections if necessary. For fat quantification, the segmentation masks were automatically transferred to MRI Dixon sequences by rigid registration. In total 76 datasets from RA patients were analyzed. Accuracy was validated against the manual gold standard segmentations. Results: Average analysis time per dataset was 10 min, more than 10 times faster compared to manual outlining. All 76 datasets could be analyzed and were accurate as judged by a clinical expert. 69 datasets needed minor manual segmentation corrections. Segmentation accuracy compared to the gold standard (Dice ratio 0.98 ± 0.04, average surface distance 0.04 ± 0.10 mm) and reanalysis precision were excellent. Intra- and inter-operator precision errors were below 0.3% (muscle) and 0.7% (fat). Average Hausdorff distances were higher (1.09 mm), but high values originated from a shift of the analysis VOI by one voxel in scan direction. Conclusions: We presented a novel semi-automated method for quantitative assessment of hand muscles with excellent accuracy and operator precision, which highly reduced a traditional manual segmentation effort. This method may greatly facilitate further MRI image based muscle research of the hands.
CRIS-Team Scopus Importer:2021-04-19
Keywords: Fat quantification; Hand muscle; Random forest segmentation; Rheumatoid arthritis

A NEW METHOD FOR THE QUANTITATIVE ANALYSIS OF HAND MUSCLE VOLUME FOR PATIENTS WITH RHEUMATOID ARTHRITIS - Friedberger, Andreas; Museyko, Oleg; Figueiredo, C.; Bäuerle, Tobias; Chaudry, Oliver; Grimm, Alexandra; Schett, Georg; Engelke, Klaus (2016)
EVALuna2:13491

A new platform for autoimmune diseases. Inducing tolerance with liposomes encapsulating autoantigens - Almenara-Fuentes, Lidia; Rodriguez-Fernandez, Silvia; Rosell-Mases, Estela; Kachler, Katerina; You, Axel; Salvado, Miriam; Andreev, Darja; Steffen, Ulrike; Bang, Holger; Bozec, Aline; Schett, Georg; Le Panse, Rozen; et al. (Nanomedicine : nanotechnology, biology, and medicine, 2023)
Autoimmune diseases (AIDs) are caused by the loss of self-tolerance and destruction of tissues by the host's immune system. Several antigen-specific immunotherapies, focused on arresting the autoimmune attack, have been tested in clinical trials with discouraging results. Therefore, there is a need for innovative strategies to restore self-tolerance safely and definitively in AIDs. We previously demonstrated the therapeutic efficacy of phosphatidylserine (PS)-liposomes encapsulating autoantigens in experimental type 1 diabetes and multiple sclerosis. Here, we show that PS-liposomes can be adapted to other autoimmune diseases by simply replacing the encapsulated autoantigen. After administration, they are distributed to target organs, captured by phagocytes and interact with several immune cells, thus exerting a tolerogenic and immunoregulatory effect. Specific PS-liposomes demonstrate great preventive and therapeutic efficacy in rheumatoid arthritis and myasthenia gravis. Thus, this work highlights the therapeutic potential of a platform for several autoimmunity settings, which is specific, safe, and with long-term effects.
CRIS-Team Scopus Importer:2022-12-23
Keywords: Autoimmune diseases; Immunotherapy; Myasthenia gravis; Nanomedicine; Preclinical mouse models; Rheumatoid arthritis

Angiotensin AT2 Receptor Stimulation Alleviates Collagen-Induced Arthritis by Upregulation of Regulatory T Cell Numbers - Sehnert, Bettina; Valero-Esquitino, Veronica; Schett, Georg; Unger, Thomas; Steckelings, Ulrike Muscha; Voll, Reinhard Edmund (Frontiers in Immunology, 2022)
The angiotensin AT2 receptor (AT2R) is a main receptor of the protective arm of the renin-angiotensin system and exerts for instance anti-inflammatory effects. The impact of AT2R stimulation on autoimmune diseases such as rheumatoid arthritis (RA) is not yet known. We investigated the therapeutic potential of AT2R-stimulation with the selective non-peptide AT2R agonist Compound 21 (C21) in collagen-induced arthritis (CIA), an animal model for inflammatory arthritis. Arthritis was induced by immunization of DBA/1J mice with collagen type II (CII). Prophylactic and therapeutic C21 treatment alleviates arthritis severity and incidence in CIA. Joint histology revealed significantly less infiltrates of IL-1 beta and IL-17A expressing cells and a well-preserved articular cartilage in C21- treated mice. In CIA, the number of CD4+CD25+FoxP3+ regulatory T (Treg) cells significantly increased upon C21 treatment compared to vehicle. T cell differentiation experiments demonstrated increased expression of FoxP3 mRNA, whereas IL-17A, STAT3 and IFN-gamma mRNA expression were reduced upon C21 treatment. In accordance with the mRNA data, C21 upregulated the percentage of CD4+FoxP3+ cells in Treg polarizing cultures compared to medium-treated controls, whereas the percentage of CD4+IL-17A+ and CD4+IFN-gamma+ T cells was suppressed. To conclude, C21 exerts beneficial effects on T cell-mediated experimental arthritis. We found that C21-induced AT2R-stimulation promotes the expansion of CD4+ regulatory T cells and suppresses IL-17A production. Thus, AT2R-stimulation may represent an attractive treatment strategy for arthritis.
CRIS-Team Scopus Importer:2022-08-05
Keywords: angiotensin AT2 receptor agonist; collagen-induced arthritis (CIA); cytokines; regulatory T cells; renin–angiotensin system

Ankylosing spondylitis is characterized by an increased turnover of several different metalloproteinase-derived collagen species: a cross-sectional study - Bay-Jensen, Anne C.; Leeming, Diana J.; Kleyer, Arnd; Veidal, Sanne S.; Schett, Georg; Karsdal, Morten A. (Rheumatology International, 2012)
Ankylosing spondylitis (AS) is characterized by gradual cementation of the vertebrae, a process that is described by excessive extracellular matrix remodeling. Specific matrix metalloproteinase (MMP)-derived collagen fragments are released to the circulation, and measurement of those might act as biomarkers of ankylosis. The aim of the study was to investigate the diagnostic value of five novel assays measuring different collagen species. Five newly developed ELISAs measuring MMP-degraded collagen fragments in serum of 40 AS patients and 40 age-matched controls were measured: collagen type I (C1M), type II (C2M), type III (C3M), type IV (C4M) and type VI (C6M) as well as the bone formation marker osteocalcin. The levels of the five collagen neoepitopes were significantly higher in AS patients, except for osteocalcin. Cartilage degradation (C2M) was only significantly correlated with the basement membrane (C4M) in the AS patients. In contrast, C3M was significantly correlated with all of the other collagen markers. The highest diagnostic value was achieved when combining the C2M, C3M and C6M markers, AUC 87% (P < 0.0001). Moreover, a combination of the markers correlated with the clinical mSASS score (P = 0.004, R = 0.44). Novel and unique biomarkers of tissue remodeling may provide diagnostic value and aid in understanding of the AS pathology. Each of the biomarkers tells a unique story, and by combining them in a panel there, we found a strong correlation with mSASSS. We speculate that such panel will be a valuable tool for monitoring patients as effect of treatment, for the prediction of responders and for diagnostic purposes.
EVALuna2:12789

An open-label study to evaluate biomarkers and safety in systemic sclerosis patients treated with paquinimod - Hesselstrand, Roger; Distler, Jörg; Riemekasten, Gabriela; Wuttge, Dirk M.; Torngren, Marie; Nyhlen, Helen C.; Andersson, Fredrik; Eriksson, Helena; Sparre, Birgitta; Tuvesson, Helen; Distler, Oliver (Arthritis Research & Therapy, 2021)
Objectives: To evaluate the changes in disease-related biomarkers and safety of paquinimod, an oral immunomodulatory compound, in patients with systemic sclerosis (SSc). Methods: In this open-label, single-arm, multicenter study, SSc patients with a rapidly progressive disease received paquinimod for 8 weeks. Blood and skin biopsies were collected at baseline, during treatment, and at follow-up for the analyses of type I interferon (IFN) activity, chemokine (C-C motif) ligand 2 (CCL2), and the number of myofibroblasts. The safety of paquinimod was evaluated throughout the study. Results: Nine SSc patients were enrolled and completed the study treatment with paquinimod at 3 mg/day for 8 weeks. After the treatment, a reduction of type I IFN activity in the plasma from one patient with elevated baseline IFN activity was recorded. A trend towards reduced IFN activity in the skin after treatment was also observed in patients. The serum level of CCL2 was reduced in 7 of 9 patients after paquinimod treatment. There was a median reduction of 10% of the number of myofibroblasts in skin biopsies at week 8 compared to baseline. No change in modified Rodnan skin score and quality of life was detected in the study. Reported adverse events (AEs) were mild to moderate and expected with the most common being arthralgia (n = 3) and headache (n = 3), and C-reactive protein (CRP) increase. Conclusions: Analysis of biomarkers before and after treatment suggest reduced type I IFN activity and reduced number of myofibroblasts in lesional skin. Paquinimod was overall well tolerated with mild to moderate and expected AEs. Trial registration: ClinicalTrials.gov, NCT01487551. Registered on 7 September 2011.
CRIS-Team Scopus Importer:2021-08-13
Keywords: Clinical trial; Paquinimod; Skin fibrosis; Systemic sclerosis

ANTAGONISM OF PLATELET-DERIVED SEROTONIN (5-HT) MODULATES MACROPHAGE-MEDIATED TRANSPLANT VASCULOPATHY AFTER AORTIC TRANSPLANTATION BUT NOT LARGE AIRWAY REMODELING IN MURINE TRACHEAL ALLOGRAFTS - Bujnoch, Daniel; Gocht, A.; Distler, Jörg; Spriewald, B.; Ramsperger-Gleixner, Martina; Weyand, Michael; Ensminger, S.; Heim, Christian (2018)
EVALuna2:34953

Antibodies against citrullinated proteins of IgA isotype are associated with progression to rheumatoid arthritis in individuals at-risk. - Sokolova, Maria; Hartmann, Fabian; Sieghart, Daniela; Bang, Holger; Steiner, Guenter; Kleyer, Arnd; Schett, Georg; Steffen, Ulrike (RMD Open, 2023)
OBJECTIVE: Events triggering disease outbreak in individuals at-risk for rheumatoid arthritis (RA at-risk) remain unclear, and the role of the various anticitrullinated protein antibody (ACPA) isotypes in this process is still to be established. We aimed to investigate the prevalence of IgA ACPA in RA at-risk individuals, their role in the transition from the RA at-risk status to RA and their dynamics during this transition. METHODS: Cross-sectional measurement of serum IgA1 and IgA2 ACPA levels was conducted in healthy controls, RA at-risk individuals and patients with RA and compared with the frequency of RA development in at risk individuals during a follow-up of 14 months. In addition, longitudinal measurements of serum IgA1 and IgA2 ACPA levels prior to, at and after the onset of RA were performed. RESULTS: Approximately two-thirds of RA at-risk individuals were positive for serum IgA1 and IgA2 ACPA in levels comparable to IgG ACPA positive patients with RA. IgA1, but not IgA2 ACPA positivity was associated with the transition from the RA at-risk state to RA within the following 14 months. Interestingly, during this transition process, IgA1 ACPA levels declined at RA onset and also thereafter during the early phase of RA. This decline was confirmed in a second, independent cohort. CONCLUSION: Both IgA1 and IgA2 ACPA are present in RA at-risk individuals, but only IgA1 ACPA are associated with the progression to RA. The observed decline in serum IgA1 ACPA levels before the onset of RA might indicate starting barrier leakiness prior to disease outbreak.
EVALuna2:520716

Anti-CD19 CAR T cells for refractory myasthenia gravis - Haghikia, Aiden; Hegelmaier, Tobias; Wolleschak, Denise; Böttcher, Martin; Desel, Christiane; Borie, Dominic; Motte, Jeremias; Schett, Georg; Schroers, Roland; Gold, Ralf; Mougiakakos, Dimitrios (Lancet Neurology, 2023)
CRIS-Team Scopus Importer:2023-11-24

Anti-CD19 CAR T cell therapy for refractory systemic lupus erythematosus - Mackensen, Andreas; Müller, Fabian; Mougiakakos, Dimitrios; Böltz, Sebastian; Wilhelm, Artur; Aigner, Michael; Völkl, Simon; Simon, David; Kleyer, Arnd; Munoz, Luis Enrique; Kretschmann, Sascha; Kharboutli, Soraya; et al. (Nature Medicine, 2022)
Systemic lupus erythematosus (SLE) is a life-threatening autoimmune disease characterized by adaptive immune system activation, formation of double-stranded DNA autoantibodies and organ inflammation. Five patients with SLE (four women and one man) with a median (range) age of 22 (6) years, median (range) disease duration of 4 (8) years and active disease (median (range) SLE disease activity index Systemic Lupus Erythematosus Disease Activity Index: 16 (8)) refractory to several immunosuppressive drug treatments were enrolled in a compassionate-use chimeric antigen receptor (CAR) T cell program. Autologous T cells from patients with SLE were transduced with a lentiviral anti-CD19 CAR vector, expanded and reinfused at a dose of 1 × 106 CAR T cells per kg body weight into the patients after lymphodepletion with fludarabine and cyclophosphamide. CAR T cells expanded in vivo, led to deep depletion of B cells, improvement of clinical symptoms and normalization of laboratory parameters including seroconversion of anti-double-stranded DNA antibodies. Remission of SLE according to DORIS criteria was achieved in all five patients after 3 months and the median (range) Systemic Lupus Erythematosus Disease Activity Index score after 3 months was 0 (2). Drug-free remission was maintained during longer follow-up (median (range) of 8 (12) months after CAR T cell administration) and even after the reappearance of B cells, which was observed after a mean (±s.d.) of 110 ± 32 d after CAR T cell treatment. Reappearing B cells were naïve and showed non-class-switched B cell receptors. CAR T cell treatment was well tolerated with only mild cytokine-release syndrome. These data suggest that CD19 CAR T cell transfer is feasible, tolerable and highly effective in SLE.
CRIS-Team Scopus Importer:2022-09-30

Anti-citrullinated protein antibody positivity correlates with cartilage damage and proteoglycan levels in patients with rheumatoid arthritis in the hand joints - Renner, Nina; Krönke, Gerhard; Rech, Jürgen; Uder, Michael; Janka, Rolf Matthias; Lauer, Lars; Paul, Dominik; Herz, Barbara; Schlechtweg, Philipp; Hennig, Friedrich; Schett, Georg; Welsch, Götz (Arthritis and Rheumatology, 2014)
Objective: To investigate the factors associated with cartilage proteoglycan content in patients with rheumatoid arthritis (RA) Methods: 32 RA patients received high-field 3 Tesla Gadolinium-Enhanced MRI of Cartilage (dGEMRIC) for determining cartilage proteoglycan content. Measurements were performed in three individual cartilage regions (medial, central, lateral) of the metacarpophalangeal joints 2 and 3. dGEMRIC values were then related to disease duration, disease activity, anti-citrullinated protein antibody (ACPA) status, rheumatoid factor status and C-reactive protein level. Results: dGEMRIC values were not significantly different between the MCP2 and MCP3 joint. Inter-class correlations were high (>0.92) for all three (medial, central and lateral) cartilage compartments. dGEMRIC values were significantly lower in RA patients with longer disease duration (>=3 years) and those with ACPA positivity than those with a short disease duration (<3 years)(p=0.034) or negative ACPA (p=0.0002), respectively. In contrast, no association between cartilage proteoglycan content and disease activity, C-reactive protein level and rheumatoid factor status was found. Conclusion: Decreased cartilage proteoglycan content in RA patients is associated with disease duration and ACPA positivity but not with the actual disease activity, CRP level or rheumatoid factor status. These data suggest that the cumulative burden of inflammation as well as ACPA are the determinants for cartilage damage in RA.
EVALuna2:12983

Anti-citrullinated Vimentin Antibodies Are Associated to Early Deterioration of Cortical Bone and Volumetric Bone Mineral Density in Finger Joints in RA-at-risk Patients - Schett, Georg; Simon, David; Hueber, Axel; Bang, Holger; Rech, Jürgen; Krönke, Gerhard; Kleyer, Arnd (ARTHRITIS & RHEUMATOLOGY, 2019)
CRIS-Team WoS Importer:2020-02-11

Anti-granulocyte-macrophage colony-stimulating factor antibody otilimab in patients with hand osteoarthritis: a phase 2a randomised trial - Schett, Georg; Bainbridge, Chris; Berkowitz, Mario; Davy, Katherine; Fernandes, Sofia; Griep, Eduard; Harrison, Stephen; Gupta, Anubha; Lloyd-Hughes, James; Roberts, Alexandra; Layton, Mark; Nowak, Nonna Anna; et al. (The Lancet Rheumatology, 2020)
Background: Granulocyte-macrophage colony-stimulating factor (GM-CSF) is a key mediator of signs and symptoms in preclinical models of osteoarthritis. We explored the efficacy, safety, and pharmacokinetics of an anti-GM-CSF antibody, otilimab, in patients with hand osteoarthritis. Methods: This double-blind, randomised, placebo-controlled phase 2a study was done in 16 centres in the Netherlands, Germany, Poland, the UK, and the USA. Patients aged 18 years or older with inflammatory hand osteoarthritis, who had received at least one course of unsuccessful non-steroidal anti-inflammatory drugs, with two or more swollen and tender interphalangeal joints (on the same hand), signs of inflammation or synovitis identified with MRI in the affected hand, and a self-reported 24 h average hand pain intensity over the past 7 days of 5 or more on a 0–10 numerical rating scale were eligible for inclusion. Patients were randomly assigned (1:1) via interactive response technology (blocked randomisation; block size of four) to receive either subcutaneous otilimab 180 mg or placebo, administered weekly from week 0 to week 4, then every other week until week 10. Patients, investigators, and trial staff were masked to treatment; at least one administrator at each site was unmasked to prepare and administer treatment. The primary endpoint was change from baseline in 24 h average hand pain numeric rating scale averaged over 7 days before the visit at week 6. Secondary endpoints were: change from baseline in 24 h average and worst hand pain intensity at each visit; proportion of patients showing 30% and 50% reductions in 24 h average and worst hand pain intensity at each visit; change from baseline in Australian and Canadian Hand Osteoarthritis Index (AUSCAN) 3·1 numeric rating scale questionnaire components at each visit; change in number of swollen and tender hand joints at each visit; change from baseline in Patient and Physician Global Assessment of disease activity; serum concentration of otilimab; and safety parameters. Efficacy endpoints were assessed in the intention-to-treat population. The safety population included all patients who received at least one dose of study treatment. The study is registered with ClinicalTrials.gov, NCT02683785. Findings: Between March 17, 2016, and Nov 29, 2017, 44 patients were randomly assigned (22 in the placebo group and 22 in the otilimab group). At week 6, difference in change from baseline in 24 h average hand pain numeric rating scale between the otilimab and placebo groups was −0·36 (95% CI −1·31 to 0·58; p=0·44); at week 12, the difference was −0·89 (–2·06 to 0·28; p=0·13). Patients receiving otilimab showed greater improvement in AUSCAN components versus placebo at each visit. The change from baseline in the 24 h worst hand pain numeric rating scale in the otilimab group at week 6 showed a difference over placebo of −0·33 (95% CI −1·28 to 0·63; p=0·49); at week 12, this difference was −1·01 (95% CI −2·22 to 0·20; p=0·098). The proportion of patients achieving 30% or higher or 50% or higher reduction from baseline in the 24 h average and worst hand pain numeric rating scale scores was consistently greater (although non-significant) with otilimab versus placebo. Similarly, patients receiving otilimab showed greater improvement in AUSCAN pain, functional impairment, and stiffness scores versus placebo at each visit. No differences were observed between otilimab and placebo in the change from baseline in the number of swollen and tender joints across the study. The Patient Global Assessment was consistently lower than placebo at all visits; the Physician Global Assessment showed reductions across the study period, but the changes were similar in both treatment groups. Median otilimab serum concentrations increased during weekly dosing from 1730 ng/mL at week 1 to a maximum of 3670 ng/mL at week 4, but declined after transitioning to dosing every other week (weeks 6–10). In total, 84 adverse events were reported by 24 patients: 54 adverse events in 13 (59%) patients in the otilimab group and 30 adverse events in 11 (50%) patients in the placebo group. The most common adverse events were cough (reported in 4 [9%] patients; 2 in each group), and nasopharyngitis (in 3 [7%] patients; 1 in the placebo group and 2 in the otilimab group). Three serious adverse events occurred in this study (all in the otilimab group) and were deemed not related to the study medication. There were no deaths during the study. Interpretation: There was no significant difference between otilimab and placebo in the primary endpoint, although we noted a non-significant trend towards a reduction in pain and functional impairment with otilimab, which supports a potential role for GM-CSF in hand osteoarthritis-associated pain. There were no unexpected safety findings in this study, with no treatment-related serious adverse events reported. Funding: GlaxoSmithKline.
CRIS-Team Scopus Importer:2020-10-09

Anti-inflammatory and immune-regulatory cytokines in rheumatoid arthritis - Chen, Zhu; Bozec, Aline; Schett, Georg; Ramming, Andreas (Nature Reviews Rheumatology, 2018)
Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by a failure of spontaneous resolution of inflammation. Although the pro-inflammatory cytokines and mediators that trigger RA have been the focus of intense investigations, the regulatory and anti-inflammatory cytokines responsible for the suppression and resolution of disease in a context-dependent manner have been less well characterized. However, knowledge of the pathways that control the suppression and resolution of inflammation in RA is clinically relevant and conceptually important for understanding the pathophysiology of the disease and for the development of treatments that enable long-term remission. Cytokine-mediated processes such as the activation of T helper 2 cells by IL-4 and IL-13, the resolution of inflammation by IL-9, IL-5-induced eosinophil expansion, IL-33-mediated macrophage polarization, the production of IL-10 by regulatory B cells and IL-27-mediated suppression of lymphoid follicle formation are all involved in governing the regulation and resolution of inflammation in RA. By better understanding these immune-regulatory signalling pathways, new therapeutic strategies for RA can be envisioned that aim to balance and resolve, rather than suppress, inflammation.
EVALuna2:34662

Anti-inflammatory, but not osteoprotective, effect of the TRAF6/CD40 inhibitor 6877002 in rodent models of local and systemic osteolysis - Marino, Silvia; Hannemann, Nicole; Bishop, Ryan T.; Zeng, Feier; Carrasco, Giovana; Meurisse, Sandrine; Li, Boya; Sophocleous, Antonia; Sparatore, Anna; Bäuerle, Tobias; Vukicevic, Slobodan; Auberval, Marielle; et al. (Biochemical Pharmacology, 2022)
NFκB plays a key role in inflammation and skeletal disorders. Previously, we reported that pharmacological inhibition of NFκB at the level of TRAF6 suppressed RANKL, CD40L and IL1β-induced osteoclastogenesis and attenuated cancer-induced bone disease. TNFα is also known to regulate TRAF6/NFκB signalling, however the anti-inflammatory and osteoprotective effects associated with inhibition of the TNFα/TRAF6/NFκB axis have not been investigated. Here, we show that in vitro and ex vivo exposure to the verified small-molecule inhibitor of TRAF6, 6877002 prevented TNFα-induced NFκB activation, osteoclastogenesis and calvarial osteolysis, but it had no effects on TNFα-induced apoptosis or growth inhibition in osteoblasts. Additionally, 6877002 disrupted T-cells support for osteoclast formation and synoviocyte motility, without affecting the viability of osteoblasts in the presence of T-cells derived factors. Using the collagen-induced arthritis model, we show that oral and intraperitoneal administration of 6877002 in mice reduced joint inflammation and arthritis score. Unexpectedly, no difference in trabecular and cortical bone parameters were detected between vehicle and 6877002 treated mice, indicating lack of osteoprotection by 6877002 in the arthritis model described. Using two independent rodent models of osteolysis, we confirmed that 6877002 had no effect on trabecular and cortical bone loss in both osteoporotic rats or RANKL- treated mice. In contrast, the classic anti-osteolytic alendronate offered complete osteoprotection in RANKL- treated mice. In conclusion, TRAF6 inhibitors may be of value in the management of the inflammatory component of bone disorders, but may not offer protection against local or systemic bone loss, unless combined with anti-resorptive therapy such as bisphosphonates.
CRIS-Team Scopus Importer:2021-12-24
Keywords: Inflammation; NFκB; Osteoclast; Ovariectomy; T-cell; TNFα

Anti-Interleukin-1 Therapy Does Not Affect the Response to SARS-CoV-2 Vaccination and Infection in Patients with Systemic Autoinflammatory Diseases. - Geck, Leonie; Tascilar, Koray; Simon, David; Kleyer, Arnd; Schett, Georg; Rech, Jürgen (Journal of Clinical Medicine, 2023)
Patients with systemic autoinflammatory diseases (sAIDs) are a section of the population at high risk of severe COVID-19 outcomes, but evidence on the efficacy of SARS-CoV-2 vaccination in this group of patients is scarce. To investigate the efficacy of SARS-CoV-2 vaccination in patients with sAIDs receiving interleukin-1 (IL-1) inhibition is important. Vaccination and infection responses from 100 sAID patients and 100 healthy controls (HCs) were analyzed. In total, 98% of patients were treated with IL-1 inhibitors at the time of vaccination (n = 98). After the second SARS-CoV-2 vaccination, sAID patients showed similar anti-SARS-CoV-2 antibody responses (mean (standard deviation (SD)): 6.7 (2.7)) compared to HCs (5.7 (2.4)) as well as similar neutralizing antibodies (85.1 ± 22.9% vs. 82.5 ± 19.7%). Anti-SARS-CoV-2 antibody responses and neutralizing antibodies were similar in sAID patients after SARS-CoV-2 infection and double vaccination. Furthermore, while antibodies increased after the first and second vaccination in sAID patients, they did not further increase after the third and fourth vaccination. No difference was found in antibody responses between anakinra and anti-IL-1 antibody treatment and the additional use of colchicine or other drugs did not impair vaccination responses. Primary and booster SARS-CoV-2 vaccinations led to protective antibody responses in sAID patients, which were at the same level of vaccination responses in HCs and in sAID patients after SARS-CoV-2 infection. Immunomodulatory treatments used in sAID do not seem to affect antibody responses to the SARS-CoV-2 vaccine.
EVALuna2:551948

Antimodified protein antibody response pattern influences the risk for disease relapse in patients with rheumatoid arthritis tapering disease modifying antirheumatic drugs - Figueiredo, Camille P.; Bang, Holger; Cobra, Jayme Fogagnolo; Englbrecht, Matthias; Hueber, Axel; Haschka, Judith; Manger, Bernhard; Kleyer, Arnd; Reiser, Michaela; Finzel, Stephanie; Tony, Hans-Peter; Kleinert, Stefan; et al. (Annals of the Rheumatic Diseases, 2017)
To perform a detailed analysis of the autoantibody response against post-translationally modified proteins in patients with rheumatoid arthritis (RA) in sustained remission and to explore whether its composition influences the risk for disease relapse when tapering disease modifying antirheumatic drug (DMARD) therapy.Immune responses against 10 citrullinated, homocitrullinated/carbamylated and acetylated peptides, as well as unmodified vimentin (control) and cyclic citrullinated peptide 2 (CCP2) were tested in baseline serum samples from 94 patients of the RETRO study. Patients were classified according to the number of autoantibody reactivities (0-1/10, 2-5/10 and >5/10) or specificity groups (citrullination, carbamylation and acetylation; 0-3) and tested for their risk to develop relapses after DMARD tapering. Demographic and disease-specific parameters were included in multivariate logistic regression analysis for defining the role of autoantibodies in predicting relapse.Patients varied in their antimodified protein antibody response with the extremes from recognition of no (0/10) to all antigens (10/10). Antibodies against citrullinated vimentin (51%), acetylated ornithine (46%) and acetylated lysine (37%) were the most frequently observed subspecificities. Relapse risk significantly (p=0.011) increased from 18% (0-1/10 reactivities) to 34% (2-5/10) and 55% (>5/10). With respect to specificity groups (0-3), relapse risk significantly (p=0.021) increased from 18% (no reactivity) to 28%, 36% and finally to 52% with one, two or three antibody specificity groups, respectively.The data suggest that the pattern of antimodified protein antibody response determines the risk of disease relapse in patients with RA tapering DMARD therapy.2009-015740-42; Results.
EVALuna2:13295

ANTI-MODIFIED PROTEIN ANTIBODY RESPONSE PATTERN INFLUENCES THE RISK FOR DISEASE RELAPSE IN RHEUMATOID ARTHRITIS PATIENTS TAPERING DISEASE MODIFYING ANTI-RHEUMATIC DRUGS - Figueiredo, C.; Bang, H.; Cobra, J. F.; Englbrecht, Matthias; Hueber, A. J.; Haschka, J.; Manger, Bernhard; Kleyer, A.; Reiser, M.; Finzel, S.; Tony, H-P.; Kleinert, S.; et al. (2016)
EVALuna2:13494

ANTI-S100A4 MONOCLONAL ANTIBODY TREATMENT AMELIORATES SKIN FIBROSIS IN INFLAMMATORY AND NON-INFLAMMATORY PRE-CLINICAL MODELS OF SYSTEMIC SCLEROSIS - Tomcik, M.; Trinh, Minh Thuong; Trinh-Minh, T.; TRAN MANH, CUONG; Storkanova, H.; Storkanova, L.; Senolt, L.; Klingelhofer, J.; Hussain, R. I.; Hallen, J.; Distler, Jörg (ANNALS OF THE RHEUMATIC DISEASES, 2021)
CRIS-Team WoS Importer:2021-10-01

Anti-TNF-refractory colitis after checkpoint inhibitor therapy: Possible role of CMV-mediated immunopathogenesis - Lankes, Katharina; Hundorfean, Gheorghe; Harrer, Thomas; Pommer, Ansgar J.; Agaimy, Abbas; Angelovska, Irena; Tajmir-Riahi, Azadeh; Göhl, Jonas; Schuler, Gerold; Neurath, Markus; Hohenberger, Werner; Heinzerling, Lucie (OncoImmunology, 2016)
Immune-related adverse events (irAEs) induced by checkpoint inhibitors are well known. Since fatal outcomes have been reported early detection and adequate management are crucial. In particular, colitis is frequently observed and can result in intestinal perforation. This is the first report of an autoimmune colitis that was treated according to algorithms but became resistant due to a CMV reactivation. The 32-y-old male patient with metastatic melanoma treated within an anti-PD-1/ipilimumab combination study developed severe immune-mediated colitis (CTCAE grade 3) with up to 18 watery stools per day starting 2 weeks after treatment initiation. After improving upon therapy with immunosuppressive treatment (high dose steroids and infliximab) combined with parenteral nutrition diarrhea again exacerbated. Additionally, the patient had asymptomatic grade 3 CTCAE amylase and lipase elevation. Colitis was monitored by weekly endoscopies and colon biopsies were analyzed histologically with CMV staining, multi-epitope ligand cartography (MELC) and qRT-PCR for inflammatory genes. In the course, CMV reactivation was detected in the colon and treated with antiviral medication in parallel to a reduction of corticosteroids. Subsequently, symptoms improved. The patient showed a complete response for 2 y now including regression of bone metastases. CMV reactivation under checkpoint inhibitor therapy in combination with immunosuppressive treatment for autoimmune side effects has to be considered in these patients and if present treated. Potentially, CMV reactivation is underdiagnosed. Treatment algorithms should include CMV diagnostics.
EVALuna2:2063

Aortic dissection and fever: cause or consequence - Manger, Bernhard; Schett, Georg (Zeitschrift für Rheumatologie, 2017)
EVALuna2:13346

A Phase IIa Study of Anti-GM-CSF Antibody GSK3196165 in Subjects with Inflammatory Hand Osteoarthritis - Schett, Georg; Bainbridge, Chris; Berkowitz, Mario; Davy, Katherine; Fernandes, Sofia; Griep, Eduard; Harrison, Stephen; Layton, Mark; Nowak, Nonna Anna; Patel, Jatin; Rech, Jürgen; Watts, Sarah; et al. (2018)
EVALuna2:34968

A Phase IIb, Randomized, Double-blind Study in Patients with Rheumatoid Arthritis Evaluating the Safety and Efficacy of Evobrutinib Compared with Placebo in Patients with an Inadequate Response to Methotrexate - Peterfy, Charles; Buch, Maya; Choy, Ernest; Schett, Georg; Parsons-Rich, Dana; Patel, Anand; Zima, Yulia; Le Bolay, Claire; Genovese, Mark (ARTHRITIS & RHEUMATOLOGY, 2020)
CRIS-Team WoS Importer:2021-01-15

A Pleomorphic Puzzle: Heterogeneous Pulmonary Vascular Occlusions in Patients with COVID-19 - Singh, Jeeshan; Herrmann, Irmgard; Mahajan, Aparna; Schauer, Christine; Shan, Xiaomei; Hartmann, Arndt; Rieker, Ralf; Evert, Katja; Falkeis, Christina; Naschberger, Elisabeth; von Stillfried, Saskia; Boor, Peter; et al. (International Journal of Molecular Sciences, 2022)
Vascular occlusions in patients with coronavirus diseases 2019 (COVID-19) have been frequently reported in severe outcomes mainly due to a dysregulation of neutrophils mediating neutrophil extracellular trap (NET) formation. Lung specimens from patients with COVID-19 have previously shown a dynamic morphology, categorized into three types of pleomorphic occurrence based on histological findings in this study. These vascular occlusions in lung specimens were also detected using native endogenous fluorescence or NEF in a label-free method. The three types of vascular occlusions exhibit morphology of DNA rich neutrophil elastase (NE) poor (type I), NE rich DNA poor (type II), and DNA and NE rich (type III) cohort of eleven patients with six males and five females. Age and gender have been presented in this study as influencing variables linking the occurrence of several occlusions with pleomorphic contents within a patient specimen and amongst them. This study reports the categorization of pleomorphic occlusions in patients with COVID-19 and the detection of these occlusions in a label-free method utilizing NEF.
CRIS-Team Scopus Importer:2022-12-23
Keywords: age; COVID-19; gender; immunothrombosis; native endogenous fluorescence; occlusions; pleomorphism; SARS-CoV-2

Application of clinical and molecular profiling data to improve patient outcomes in psoriatic arthritis - Fitzgerald, Oliver; Behrens, Frank; Barton, Anne; Bertheusen, Heidi; Boutouyrie-Dumont, Bruno; Coates, Laura; Davies, Owen; De Wit, Maarten; Fagni, Filippo; Goodyear, Carl S.; Gurke, Robert; Hahnefeld, Lisa; et al. (Therapeutic Advances in Musculoskeletal Disease, 2023)
Achieving a good outcome for a person with Psoriatic Arthritis (PsA) is made difficult by late diagnosis, heterogenous clinical disease expression and in many cases, failure to adequately suppress inflammatory disease features. Single-centre studies have certainly contributed to our understanding of disease pathogenesis, but to adequately address the major areas of unmet need, multi-partner, collaborative research programmes are now required. HIPPOCRATES is a 5-year, Innovative Medicines Initiative (IMI) programme which includes 17 European academic centres experienced in PsA research, 5 pharmaceutical industry partners, 3 small-/medium-sized industry partners and 2 patient-representative organizations. In this review, the ambitious programme of work to be undertaken by HIPPOCRATES is outlined and common approaches and challenges are identified. It is expected that, when completed, the results will ultimately allow for changes in the approaches to diagnosing, managing and treating PsA allowing for better short-term and long-term outcomes.
EVALuna2:540326

APREMILAST, AN ORAL PHOSPHODIESTERASE-4 INHIBITOR, IS ASSOCIATED WITH LONG-TERM (104-WEEK) IMPROVEMENTS IN ENTHESITIS AND DACTYLITIS IN PATIENTS WITH PSORIATIC ARTHRITIS: POOLED RESULTS FROM THREE PHASE III RANDOMIZED CONTROLLED TRIALS - Gladman, Dafna D.; Kavanaugh, Arthur; Adebajo, Adewale O.; Gomez-Reino, Juan J.; Wollenhaupt, Juergen; Cutolo, Maurizio; Schett, Georg; Lespessailles, Eric; Mcilraith, Melissa; Hu, Chiachi; Edwards, Christopher J.; Birbara, Charles A.; et al. (2016)
EVALuna2:13313

Apremilast, an Oral Phosphodiesterase 4 Inhibitor, is Associated with Long-term (104-Week) Improvements in Enthesitis and Dactylitis in Patients with Psoriatic Arthritis: Pooled Results from Three Phase III, Randomized, Controlled Trials - Gladman, Dafna; Kavanaugh, Arthur; Adebajo, Adewale; Gomez-Reino, Juan; Wollenhaupt, Juergen; Cutolo, Maurizio; Schett, Georg; Lespessailles, Eric; Mcilraith, Melissa; Hu, Chiachi; Edwards, Christopher; Birbara, Charles; et al. (2016)
EVALuna2:13365

Apremilast inhibits inflammatory osteoclastogenesis - Degboe, Yannick; Sunzini, Flavia; Sood, Shatakshi; Bozec, Aline; Sokolova, Maria; Zekovic, Ana; Mcinnes, Iain B.; Schett, Georg; Goodyear, Carl S. (Rheumatology, 2022)
Objectives. Psoriatic arthritis (PsA) is associated with bone erosion and inflammation-induced bone loss, which are mediated by osteoclasts (OC) and modulated by inflammatory cytokines. Apremilast (APR) (a selective phosphodiesterase 4 inhibitor) is efficacious in PsA and acts by inhibiting cytokine production. However, there are no direct data informing whether and how APR affects osteoclast formation in humans.
CRIS-Team WoS Importer:2022-02-18

Apremilast in psoriatic arthritis - Schett, Georg (Clinical and Experimental Rheumatology, 2015)
Apremilast is a small molecule inhibitor of phosphodiesterase (PDE) 4 approved for the treatment of psoriatic arthritis (PsA). The efficacy and safety of apremilast in PsA have been demonstrated in four phase III trials. The compound has been approved for the treatment of moderate to severe PsA in the United States and in Europe. Apremilast also shows efficacy in psoriatic skin disease. Its mode of action is based on an increase of immune-regulatory cAMP in immune cells, which is mediated through the inhibition of the cAMP-degrading enzyme PDE4. Higher levels of cAMP inhibit cytokines involved in the pathogenesis of psoriasis, such as TNF-alpha or IL-23, resulting in clinical improvement.
EVALuna2:13176

Apremilast Treatment and Long-Term (156-Week) Improvements in Enthesitis and Dactylitis in Patients with Psoriatic Arthritis: Pooled Analysis of a Large Database of 3 Phase III, Randomized, Controlled Trials - Gladman, Dafna D.; Kavanaugh, Arthur; Gomez-Reino, Juan J.; Wollenhaupt, Juergen; Cutolo, Maurizio; Schett, Georg; Lespessailles, Eric; Mcilraith, Melissa; Hu, Chiachi; Edwards, Christopher J.; Birbara, Charles A.; Mease, Philip J. (2016)
EVALuna2:35059

APREMILAST TREATMENT AND LONG-TERM (UP TO 156 WEEKS) IMPROVEMENTS IN DACTYLITIS AND ENTHESITIS IN PATIENTS WITH PSORIATIC ARTHRITIS: ANALYSIS OF A LARGE DATABASE OF THE PHASE III CLINICAL DEVELOPMENT PROGRAM - Gladman, D. D.; Kavanaugh, A.; Gomez-Reino, J. J.; Wollenhaupt, J.; Cutolo, M.; Schett, Georg; Lespessailles, E.; Mcilraith, M.; Hu, C.; Edwards, C. J.; Birbara, C. A.; Mease, P. J. (2017)
EVALuna2:35039

A role for 12/15-lipoxygenase-derived proresolving mediators in postoperative ileus: protectin DX-regulated neutrophil extravasation - Stein, Kathy; Stoffels, Melissa; Lysson, Mariola; Schneiker, Bianca; Dewald, Oliver; Krönke, Gerhard; Kalff, Joerg C.; Wehner, Sven (Journal of Leukocyte Biology, 2016)
Resolution of inflammation is an active counter-regulatory mechanism involving polyunsaturated fatty acid-derived proresolving lipid mediators. Postoperative intestinal motility disturbances, clinically known as postoperative ileus, occur frequently after abdominal surgery and are mediated by a complex inflammation of the intestinal muscularis externa. Herein, we tested the hypothesis that proresolving lipid mediators are involved in the resolution of postoperative ileus. In a standardized experimental model of postoperative ileus, we detected strong expression of 12/15-lipoxygenase within the postoperative muscularis externa of C57BL/6 mice, predominately located within CX3CR1(+)/Ly6C(+) infiltrating monocytes rather than Ly6G(+) neutrophils. Mass spectrometry analyses demonstrated that a 12/15-lipoxygenase increase was accompanied by production of docosahexaenoic acid-derived lipid mediators, particularly protectin DX and resolvin D2, and their common precursor 17-hydroxy docosahexaenoic acid. Perioperative administration of protectin DX, but not resolvin D2 diminished blood-derived leukocyte infiltration into the surgically manipulated muscularis externa and improved the gastrointestinal motility. Flow cytometry analyses showed impaired Ly6G(+)/Ly6C(+) neutrophil extravasation after protectin DX treatment, whereas Ly6G(-)/Ly6C(+) monocyte numbers were not affected. 12/15-lipoxygenase-deficient mice, lacking endogenous protectin DX synthesis, demonstrated increased postoperative leukocyte levels. Preoperative intravenous administration of a docosahexaenoic acid-rich lipid emulsion reduced postoperative leukocyte infiltration in wild-type mice but failed in 12/15-lipoxygenase-deficient mice mice. Protectin DX application reduced leukocyte influx and rescued 12/15-lipoxygenase-deficient mice mice from postoperative ileus. In conclusion, our results show that 12/15-lipoxygenase mediates postoperative ileus resolution via production of proresolving docosahexaenoic acid-derived protectin DX. Perioperative, parenteral protectin DX or docosahexaenoic acid supplementation, as well as modulation of the 12/15-lipoxygenase pathway, may be instrumental in prevention of postoperative ileus.
EVALuna2:13152

Arthritis and bone loss: a hen and egg story - Kleyer, Arnd; Schett, Georg (Current Opinion in Rheumatology, 2014)
In this review, we will discuss the relation between bone loss and inflammation in rheumatoid arthritis.We highlight recent discoveries on the pathomechanisms of bone loss in rheumatoid arthritis and challenge traditional concepts by suggesting that bone loss may precede inflammation.During the clinical course of rheumatoid arthritis, inflammation is the key trigger for progressive local and systemic bone damage. Inflammatory cytokines induce the expression of molecules supporting the differentiation of osteoclasts, which are the primary bone-resorbing cells. However, bone loss can be observed in patients with recent-onset rheumatoid arthritis, suggesting that the start of the destructive phase of disease may be much earlier than previously expected. Recent data suggest that bone loss already starts during the autoimmune phase of the disease long before inflammation starts. Antibodies against citrullinated proteins thereby seem to be an important trigger for bone loss in the preclinical disease phase of rheumatoid arthritis. Although traditional concepts preferred a 'hen-egg' concept with inflammation coming first, later triggering bone loss, new data suggest an alternative 'egg-hen' concept, where bone loss arises before the clinical disease onset and may be important for priming of the joint for susceptibility to chronic inflammation.
EVALuna2:12918

A SET OF INFLAMMATORY MARKERS ALLOWING TO DETECT SYSTEMIC INFLAMMATION IN PSORIATIC SKIN, ENTHESEAL AND JOINT DISEASE IN THE ABSENCE OF CRP AND THEIR LINK TO CLINICAL DISEASE MANIFESTATION - Sokolova, Maria; Nas, Kemal; Luo, Yubin; Simon, David; Zhao, Yi; Rech, Jürgen; Zaiss, Mario; Schett, Georg (ANNALS OF THE RHEUMATIC DISEASES, 2019)
CRIS-Team WoS Importer:2019-07-16

A set of serum markers detecting systemic inflammation in psoriatic skin, entheseal, and joint disease in the absence of C-reactive protein and its link to clinical disease manifestations - Sokolova, Maria V.; Simon, David; Nas, Kemal; Zaiss, Mario; Luo, Yubin; Zhao, Yi; Rech, Jürgen; Schett, Georg (Arthritis Research & Therapy, 2020)
BACKGROUND: C-reactive protein (CRP) is often normal in patients with psoriatic disease. Herein, we aimed to define markers of systemic inflammation in patients with monomorphic and polymorphic psoriatic skin, entheseal, and joint disease. METHODS: Three-step approach: (i) selection of serum markers elevated in psoriatic arthritis compared healthy controls from a panel of 10 different markers reflecting the pathophysiology of psoriatic disease; (ii) testing of these selected markers as well as C-reactive protein (CRP) in a larger cohort of 210 individuals- 105 healthy controls and 105 patients with psoriatic disease with either monomorphic skin (S), entheseal (E) or joint (A) involvement or polymorphic disease with various combinations of skin, entheseal and joint disease (SE, SA, EA, SEA); (iii) testing whether tumor necrosis factor (TNF) and interleukin (IL)-17 inhibitor therapy normalizes these markers. RESULTS: CRP was not elevated or was rarely elevated in the subgroups (S 0%, E 0%, A 20%, SE 7%, SA 33%, EA 27%, SEA 33%) despite active psoriatic disease. In sharp contrast, beta-defensin 2 and lipocalin-2 levels were elevated in the majority of patients with monomorphic skin (93% and 73%) and entheseal (both 53%), but not joint disease (27% and 20%). Conversely, elevations of calprotectin and IL-8 were found in the majority of patients with monomorphic joint disease (both 73%). IL-22 was elevated in all three monomorphic disease manifestations (S 60%, E 46%; A 60%). Furthermore, the vast majority of patients with polymorphic psoriatic disease (SE, SA, EA, SEA) showed widespread marker elevation. IL-17- and TNF inhibitor treatment significantly lowered all 5 markers of inflammation in PsA patients. CONCLUSIONS: Systemic inflammation is detectable in the majority of patients with psoriatic disease, even if CRP is normal. The respective marker pattern depends on the manifestation of psoriatic disease with respect to skin, entheseal, and joint involvement.
CRIS-Team Scopus Importer:2020-02-21
Keywords: Enthesitis; Inflammation; Psoriasis; Psoriatic arthritis; Serum markers

Aspirin for prevention of preeclampsia in lupus pregnancy - Schramm, Amelie; Clowse, Megan E B (Autoimmune Diseases, 2014)
Preeclampsia, the onset of hypertension and proteinuria during pregnancy, is a common medical disorder with high maternal and fetal mortality and morbidity. The underlying pathology remains poorly understood and includes inflammation, endothelial dysfunction, and an unbalanced thromboxane A2/prostacyclin ratio. For women with systemic lupus erythematosus (SLE), particularly those with preexisting renal disease or with active lupus, the risk of developing preeclampsia is up to 14% higher than it is among healthy individuals. The mechanism is still unknown and the data for preventing preeclampsia in lupus pregnancies are rare. Modulating the impaired thromboxane A2/prostacyclin ratio by administration of low-dose aspirin appears to be the current best option for the prevention of preeclampsia. After providing an overview of the pathogenesis of preeclampsia, preeclampsia in lupus pregnancies, and previous trials for prevention of preeclampsia with aspirin treatment, we recommend low-dose aspirin administration for all lupus patients starting prior to 16 weeks of gestation. Patients with SLE and antiphospholipid syndrome should receive treatment with heparin and low-dose aspirin during pregnancy.
EVALuna2:13462

ASSESSMENT OF KNEE JOINT SYNOVITIS AT ULTRA-HIGH FIELD (7T) MRI: A MULTI-DIMENSIONAL APPROACH USING CONTRAST-ENHANCED AND NON-ENHANCED SEQUENCES - Roemer, Frank; Treutlein, Christoph; Guermazi, A.; Nagel, Armin Michael; Schett, Georg; Uder, Michael; Bäuerle, Tobias (OSTEOARTHRITIS AND CARTILAGE, 2020)
CRIS-Team WoS Importer:2020-05-29

Assessment of myocardial fibrosis in patients with systemic sclerosis using [Ga-68]Ga-FAPI-04-PET-CT - Treutlein, Christoph; Distler, Jörg; Tascilar, Koray; Chenguiti Fakhouri, Sara; Györfi, Andrea-Hermina; Atzinger, Armin; Matei, Alexandru-Emil; Dees, Clara; Büttner-Herold, Maike; Kuwert, Torsten; Prante, Olaf; Bäuerle, Tobias; et al. (European Journal of Nuclear Medicine and Molecular Imaging, 2022)
Purpose Myocardial fibrosis (MF) is a factor of poor prognosis in systemic sclerosis (SSc). Direct in-vivo visualization of fibroblast activation as early readout of MF has not been feasible to date. Here, we characterize (68)Gallium-labeled-Fibroblast-Activation-Inhibitor-04 ([Ga-68]Ga-FAPI-04)-PET-CT as a diagnostic tool in SSc-related MF.Methods In this proof-of-concept trial, six SSc patients with and eight without MF of the EUSTAR cohort Erlangen underwent [Ga-68]Ga-FAPI-04-PET-CT and cardiac MRI (cMRI) and clinical and serologic investigations just before baseline and during follow-up between January 2020 and December 2020. Myocardial biopsy was performed as clinically indicated.Results [Ga-68]Ga-FAPI-04 tracer uptake was increased in SSc-related MF with higher uptake in SSc patients with arrhythmias, elevated serum-NT-pro-BNP, and increased late gadolinium enhancement (LGE) in cMRI. Histologically, myocardial biopsies from cMRI- and [Ga-68]Ga-FAPI-04-positive regions confirmed the accumulation of FAP(+) fibroblasts surrounded by collagen deposits. We observed similar but not equal spatial distributions of [Ga-68]Ga-FAPI-04 uptake and quantitative cMRI-based techniques. Using sequential [Ga-68]Ga-FAPI-04-PET-CTs, we observed dynamic changes of [Ga-68]Ga-FAPI-04 uptake associated with changes in the activity of SSc-related MF, while cMRI parameters remained stable after regression of molecular activity and rather indicated tissue damage.Conclusions We present first in-human evidence that [Ga-68]Ga-FAPI-04 uptake visualizes fibroblast activation in SSc-related MF and may be a diagnostic option to monitor cardiac fibroblast activity in situ.
CRIS-Team WoS Importer:2023-02-10

ASSESSMENT OF SYSTEMIC SCLEROSIS RELATED MYOCARDIAL FIBROSIS BY 68GA-FAPI-04 PET/CT - Treutlein, Christoph; Schmidkonz, Christian; Tascilar, Koray; Chenguiti Fakhouri, Sara; Dees, Clara; Györfi, Andrea-Hermina; Matei, Alexandru-Emil; Bäuerle, Tobias; Kuwert, Torsten; Uder, Michael; Schett, Georg; Distler, Jörg; et al. (ANNALS OF THE RHEUMATIC DISEASES, 2022)
CRIS-Team WoS Importer:2022-11-04

Association analyses of functional NCF1 variants in psoriatic arthritis and psoriasis vulgaris - Hüffmeier, Ulrike; Löhr, Sabine; Ekici, Arif Bülent; Uebe, S.; Koehm, M.; Behrens, F.; Boehm, B.; Sticherling, Michael; Schett, Georg; Moessner, R.; Nimeh, A.; Assmann, G.; et al. (EUROPEAN JOURNAL OF HUMAN GENETICS, 2019)
CRIS-Team WoS Importer:2019-10-25

Association between bone catabolism and anti-citrullinated protein antibodies in rheumatoid arthritis - Harre, U.; Schett, Georg (Zeitschrift für Rheumatologie, 2016)
Anti-citrullinated protein antibodies (ACPA) are highly specific for rheumatoid arthritis and according to the ACR-EULAR 2010 guidelines represent an important serological marker for the diagnosis of the disease. Patients with rheumatoid arthritis who are positive for ACPA display more severe bone erosion and have an overall poorer prognosis in progression of the disease compared to ACPA negative patients. For a long time it was unknown how ACPA exactly affect bone homeostasis. In this article, recent findings about the mechanisms by which ACPA contribute to bone loss are discussed.
EVALuna2:13306

Association Between Vascular Cell Adhesion Molecule 1 and Atrial Fibrillation - Willeit, Karin; Pechlaner, Raimund; Willeit, Peter; Skroblin, Philipp; Paulweber, Bernhard; Schernthaner, Christiana; Toell, Thomas; Egger, Georg; Weger, Siegfried; Oberhollenzer, Martin; Kedenko, Ludmilla; Iglseder, Bernhard; et al. (JAMA Cardiology, 2017)
Accumulating evidence links inflammation and atrial fibrillation (AF).To assess whether markers of systemic and atrial inflammation are associated with incident AF in the general population.The Bruneck Study is a prospective, population-based cohort study with a 20-year follow-up (n = 909). The population included a random sample of the general community aged 40 to 79 years. Levels of 13 inflammation markers were measured at baseline in 1990. Findings were replicated in a case-control sample nested within the prospective Salzburg Atherosclerosis Prevention Program in Subjects at High Individual Risk (SAPHIR) study (n = 1770). Data analysis was performed from February to May 2016.Levels of 13 inflammation markers.Incident AF over a 20-year follow-up period in the Bruneck Study.Of the 909 participants included in the Bruneck Study, mean [SD] age was 58.8 (11.4) years and 448 (49.3%) were women. Among the 880 participants free of prevalent AF (n = 29) at baseline, 117 developed AF during the 20-year follow-up period (incidence rate, 8.2; 95% CI, 6.8-9.6 per 1000 person-years). The levels of soluble vascular cell adhesion molecule 1 (VCAM-1) and osteoprotegerin were significantly associated with incident AF (hazard ratio [HR], 1.49; 95% CI, 1.26-1.78; and 1.46; 95% CI, 1.25-1.69, respectively; P < .001 with Bonferroni correction for both), but osteoprotegerin lost significance after age and sex adjustment (HR, 1.05; 95% CI, 0.87-1.27; P > .99 with Bonferroni correction). Matrix metalloproteinase 9, metalloproteinase inhibitor 1, monocyte chemoattractant protein-1, P-selectin, fibrinogen, receptor activator of nuclear factor-?B ligand, high-sensitivity C-reactive protein, adiponectin, leptin, soluble intercellular adhesion molecule 1, and E-selectin all fell short of significance (after Bonferroni correction in unadjusted and age- and sex-adjusted analyses). The HR for a 1-SD higher soluble VCAM-1 level was 1.34 (95% CI, 1.11-1.62; Bonferroni-corrected P = .03) in a multivariable model. The association was of a dose-response type, at least as strong as that obtained for N-terminal pro-B-type natriuretic peptide (multivariable HR for a 1-SD higher N-terminal pro-B-type natriuretic peptide level, 1.15; 95% CI, 1.04-1.26), internally consistent in various subgroups, and successfully replicated in the SAPHIR Study (age- and sex-adjusted, and multivariable odds ratios for a 1-SD higher soluble VCAM-1 level, 1.91; 95% CI, 1.24-2.96, P = .003; and 2.59; 95% CI, 1.45-4.60; P = .001).Levels of soluble VCAM-1, but not other inflammation markers, are significantly associated with new-onset AF in the general community. Future studies should address whether soluble VCAM-1 is capable of improving AF risk classification beyond the information provided by standard risk scores.
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ASSOCIATION OF ANTI-CITRULLINATED PROTEIN ANTIBODIES OF IgA SUBCLASSES WITH SUSTAINED REMISSION AND FLARE IN RHEUMATOID ARTHRITIS - Sokolova, Maria; Rech, Jürgen; Hagen, Melanie; Schett, Georg; Steffen, Ulrike (ANNALS OF THE RHEUMATIC DISEASES, 2021)
CRIS-Team WoS Importer:2021-09-24

Association of brain functional magnetic resonance activity with response to tumor necrosis factor inhibition in rheumatoid arthritis - Rech, Jürgen; Heß, Andreas; Finzel, Stephanie; Kreitz, Silke; Sergeeva, Marina; Englbrecht, Matthias; Dörfler, Arnd; Saake, Marc; Schett, Georg (Arthritis and Rheumatism, 2013)
Objective To test whether brain activity predicts the response to tumor necrosis factor inhibitors (TNFi) in patients with rheumatoid arthritis (RA). Since clinical and laboratory parameters have proven unsuccessful in predicting response, we followed a radically different concept, hypothesizing that response to TNFi depends on central nervous system activity rather than the clinical signs of disease. Methods Sequential testing by functional magnetic resonance imaging (MRI) of the brain, anatomic MRI of the hand, and clinical assessment of arthritis were carried out in 10 patients with active RA before and 3, 7, and 28 days after the start of TNFi treatment. Results Baseline demographic and disease-specific parameters were identical in TNFi responders and nonresponders. The mean ± SEM decrease in the Disease Activity Score in 28 joints after 28 days was -1.8 ± 0.3 in TNFi responders (n = 5) and -0.2 ± 0.1 in nonresponders (n = 5). Responders showed significantly higher baseline activation in thalamic, limbic, and associative areas of the brain than nonresponders. Moreover, brain activity decreased within 3 days after TNFi exposure in the responders, preceding clinical responses (day 7) and responses observed on the anatomic hand MRI (day 28). Conclusion These data suggest that response to TNFi depends on brain activity in RA patients, reflecting the subjective perception of disease. Copyright © 2013 by the American College of Rheumatology.
CRIS-Team Scopus Importer:2021-02-03

ASSOCIATION OF OSTEOPROTEGERIN WITH CARDIOVASCULAR RISK IN GENERAL AND HIGH-RISK POPULATIONS: META-ANALYSIS OF 28 PROSPECTIVE STUDIES INVOLVING 53,892 PARTICIPANTS - Klingenschmid, G.; Tschiderer, L.; Nagrani, R.; Willeit, J.; Laukkanen, J.; Schett, Georg; Kiechl, S.; Willeit, P. (ATHEROSCLEROSIS, 2019)
CRIS-Team WoS Importer:2019-09-10

Association of Structural Entheseal Lesions With an Increased Risk of Progression From Psoriasis to Psoriatic Arthritis - Simon, David; Tascilar, Koray; Kleyer, Arnd; Bayat, Sara; Kampylafka, Eleni; Sokolova, Maria; Zekovic, Ana; Hueber, Axel; Rech, Jürgen; Schuster, Louis; Engel, Klaus; Sticherling, Michael; et al. (Arthritis and Rheumatology, 2021)
Objective. To test whether the presence of structural entheseal lesions in psoriasis patients influences the risk of progression to psoriatic arthritis (PsA).
CRIS-Team WoS Importer:2022-01-07

A surrogate cell-based SARS-CoV-2 spike blocking assay - Schuh, Wolfgang; Baus, Lena; Steinmetz, Tobit; Schulz, Sebastian; Weckwerth, Leonie; Roth, Edith; Hauke, Manuela; Krause, Stefan; Morhart, Patrick; Rauh, Manfred; Hoffmann, Markus; Vesper, Niklas; et al. (European Journal of Immunology, 2021)
To monitor infection by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and successful vaccination against coronavirus disease 2019 (COVID-19), the kinetics of neutralizing or blocking anti-SARS-CoV-2 antibody titers need to be assessed. Here, we report the development of a quick and inexpensive surrogate SARS-CoV-2 blocking assay (SUBA) using immobilized recombinant human angiotensin-converting enzyme 2 (hACE2) and human cells expressing the native form of surface SARS-CoV-2 spike protein. Spike protein-expressing cells bound to hACE2 in the absence or presence of blocking antibodies were quantified by measuring the optical density of cell-associated crystal violet in a spectrophotometer. The advantages are that SUBA is a fast and inexpensive assay, which does not require biosafety level 2- or 3-approved laboratories. Most importantly, SUBA detects blocking antibodies against the native trimeric cell-bound SARS-CoV-2 spike protein and can be rapidly adjusted to quickly pre-screen already approved therapeutic antibodies or sera from vaccinated individuals for their ACE2 blocking activities against any emerging SARS-CoV-2 variants.
CRIS-Team Scopus Importer:2021-10-08
Keywords: COVID-19; hACE2; SARS-CoV-2; Spike protein; Surrogate blocking assay

A Symptom Checker App Is Better at Classifying Inflammatory Disease Than Physicians Who Are Presented Identical Information - Gräf, Markus; Knitza, Johannes; Leipe, Jan; Krusche, Martin; Welcker, Martin; Kuhn, Sebastian; Mucke, Johanna; Hueber, Axel; Hornig, Johannes; Klemm, Philipp; Kleinert, Stefan; Aries, Peer; et al. (ARTHRITIS & RHEUMATOLOGY, 2022)
CRIS-Team WoS Importer:2023-01-13

A synthetic PPAR-? agonist triterpenoid ameliorates experimental fibrosis: PPAR-?-independent suppression of fibrotic responses - Wei, Jun; Zhu, Hongyan; Komura, Kazuhiro; Lord, Gabriel; Tomcik, Michal; Wang, Wenxia; Doniparthi, Sruthi; Tamaki, Zenshiro; Hinchcliff, Monique; Distler, Jörg; Varga, John (Annals of the Rheumatic Diseases, 2014)
Persistent fibroblast activation initiated by transforming growth factor ? (TGF-?) is a fundamental event in the pathogenesis of systemic sclerosis, and its pharmacological inhibition represents a potential therapeutic strategy. The nuclear receptor, peroxisome proliferator-activated receptor ? (PPAR-?), exerts potent fibrotic activity. The synthetic oleanane triterpenoid, 2-cyano-3,12-dioxo-olean-1,9-dien-28-oic acid (CDDO), is a PPAR-? agonist with potential effects on TGF-? signalling and dermal fibrosis.To examine the modulation of fibrogenesis by CDDO in explanted fibroblasts, skin organ cultures and murine models of scleroderma.The effects of CDDO on experimental fibrosis induced by bleomycin injection or by overexpression of constitutively active type I TGF-? receptor (TgfbR1ca) were evaluated. Modulation of fibrotic gene expression was examined in human skin organ cultures. To delineate the mechanisms underlying the antifibrotic effects of CDDO, explanted skin fibroblasts cultured in two-dimensional monolayers or in three-dimensional full-thickness human skin equivalents were studied.CDDO significantly ameliorated dermal fibrosis in two complementary mouse models of scleroderma, as well as in human skin organ cultures and in three-dimensional human skin equivalents. In two-dimensional monolayer cultures of explanted normal fibroblasts, CDDO abrogated fibrogenic responses induced by TGF-?. These CDDO effects occurred via disruption of Smad-dependent transcription and were associated with inhibition of Akt activation. In scleroderma fibroblasts, CDDO attenuated the elevated synthesis of collagen. Remarkably, the in vitro antifibrotic effects of CDDO were independent of PPAR-?.The PPAR-? agonist triterpenoid CDDO attenuates fibrogenesis by antagonistically targeting canonical TGF-?/Smad and Akt signalling in a PPAR-?-independent manner. These findings identify this synthetic triterpenoid as a potential new therapy for the control of fibrosis.
EVALuna2:12974

At-home blood self-sampling in rheumatology: a qualitative study with patients and health care professionals. - Muehlensiepen, Felix; May, Susann; Zarbl, Joshua; Vogt, Ekaterina; Boy, Katharina; Heinze, Martin; Böltz, Sebastian; Labinsky, Hannah; Bendzuck, Gerlinde; Korinth, Marianne; Elling-Audersch, Corinna; Vuillerme, Nicolas; et al. (BMC Health Services Research, 2022)
BACKGROUND: The goal of the study was to investigate patients' with systemic rheumatic diseases and healthcare professionals' experiences and preferences regarding self-sampling of capillary blood in rheumatology care. METHODS: Patients performed a supervised and consecutive unsupervised capillary blood self-collection using an upper arm based device. Subsequently, patients (n = 15) and their attending health care professionals (n = 5) participated in an explorative, qualitative study using problem-centered, telephone interviews. Interview data were analyzed using structured qualitative content analysis. RESULTS: Interviewed patients reported easy application and high usability. Patients and health care professionals alike reported time and cost savings, increased independence and flexibility, improved monitoring and reduction of risk of infection during Covid-19 as benefits. Reported drawbacks include limited blood volume, limited usability in case of functional restrictions, and environmental concerns. Older, immobile patients with long journeys to traditional blood collection sites and young patients with little time to spare for traditional blood collection appointments could be user groups, likely to benefit from self-sampling services. CONCLUSIONS: At-home blood self-sampling could effectively complement current rheumatology telehealth care. Appropriateness and value of this service needs to be carefully discussed with patients on an individual basis. TRIAL REGISTRATION: WHO International Clinical Trials Registry: DRKS00024925. Registered on 15/04/2021.
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Augmented neutralization of SARS-CoV-2 Omicron variant by boost vaccination and monoclonal antibodies - Schulz, Sebastian; Hoffmann, Markus; Roth, Edith; Pracht, Katharina; Burnett, Deborah L.; Mazigi, Ohan; Schuh, Wolfgang; Manger, Bernhard; Mielenz, Dirk; Goodnow, Christopher C.; Christ, Daniel; Poehlmann, Stefan; et al. (European Journal of Immunology, 2022)
Effective vaccines and monoclonal antibodies have been developed against coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). However, the appearance of virus variants with higher transmissibility and pathogenicity is a major concern because of their potential to escape vaccines and clinically approved SARS-CoV-2- antibodies. Here, we use flow cytometry-based binding and pseudotyped SARS-CoV-2 neutralization assays to determine the efficacy of boost immunization and therapeutic antibodies to neutralize the dominant Omicron variant. We provide compelling evidence that the third vaccination with BNT162b2 increases the amount of neutralizing serum antibodies against Delta and Omicron variants, albeit to a lower degree when compared to the parental Wuhan strain. Therefore, a third vaccination is warranted to increase titers of protective serum antibodies, especially in the case of the Omicron variant. We also found that most clinically approved and otherwise potent therapeutic antibodies against the Delta variant failed to recognize and neutralize the Omicron variant. In contrast, some antibodies under preclinical development potentially neutralized the Omicron variant. Our studies also support using a flow cytometry-based antibody binding assay to rapidly monitor therapeutic candidates and serum titers against emerging SARS-CoV-2 variants.
CRIS-Team WoS Importer:2022-04-08

Author Correction: Anti-CD19 CAR T cell therapy for refractory systemic lupus erythematosus. - Mackensen, Andreas; Müller, Fabian; Mougiakakos, Dimitrios; Böltz, Sebastian; Wilhelm, Artur; Aigner, Michael; Völkl, Simon; Simon, David; Kleyer, Arnd; Munoz, Luis Enrique; Kretschmann, Sascha; Kharboutli, Soraya; et al. (Nature Medicine, 2023)
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Author Correction: DeepNAPSI multi-reader nail psoriasis prediction using deep learning. - Folle, Lukas; Fenzl, Pauline; Fagni, Filippo; Thies, Mareike; Christlein, Vincent; Meder, Christine; Simon, David; Minopoulou, Ioanna; Sticherling, Michael; Schett, Georg; Maier, Andreas; Kleyer, Arnd (Scientific Reports, 2023)
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Author Correction: Transferrin receptor 2 controls bone mass and pathological bone formation via BMP and Wnt signaling (Nature Metabolism, (2019), 1, 1, (111-124), 10.1038/s42255-018-0005-8) - Rauner, Martina; Baschant, Ulrike; Roetto, Antonella; Pellegrino, Rosa Maria; Rother, Sandra; Salbach-Hirsch, Juliane; Weidner, Heike; Hintze, Vera; Campbell, Graeme; Petzold, Andreas; Lemaitre, Regis; Henry, Ian; et al. (Nature Metabolism, 2019)
In the version of this article initially published, affiliation 14 was incorrect, and Deutsche Forschungsgemeinschaft grants SFB1036 and SFB1118 were missing from the Acknowledgements. The errors have been corrected in the HTML and PDF versions of the article.
CRIS-Team Scopus Importer:2019-10-29

Autoantibodies against galectins are associated with antiphospholipid syndrome in patients with systemic lupus erythematosus - Sarter, Kerstin; Janko, Christina; Andre, Sabine; Munoz, Luis Enrique; Schorn, Christine; Winkler, Sophie; Rech, Jürgen; Kaltner, Herbert; Lorenz, Hanns-Martin; Schiller, Martin; Andreoli, Laura; Manfredi, Angelo A.; et al. (Glycobiology, 2013)
The presence of autoantibodies against immunoregulatory effectors can be relevant for onset and/or the progression of autoimmune disease. Emerging insights into an immunological activity profile including a role as opsonins give reason to systematically monitor sera of patients for immunoglobulin G (IgG) autoantibodies, preferably for several galectins at the same time. Here, we report on a study of chronic inflammatory rheumatic diseases, i.e. systemic lupus erythematosus (SLE; pilot cohort p, n = 40; confirmation cohort c, n = 109), rheumatoid arthritis (RA; p, n = 32; c, n = 25) and primary antiphospholipid syndrome (APS; c, n = 64). Enzyme-linked immunosorbent assay-based series using galectin-1, -2, -3, -4, -7, -8 and -9 and natural processing products, i.e. the truncated version of galectin-3 and the N-terminal domains of galectin-4, -8 and -9, were performed. Normal healthy donors (p, n = 20; c, n = 21) and patients with paraproteins (c, n = 19) served as controls. Highly significant optical density-value readings for IgG autoantibodies were consistently detected for the proto-type galectin-7 (SLE) and the tandem repeat-type galectin-8 and -9 (SLE and RA). Their presence was independent from the autoantibody status against double-stranded DNA (for patients with SLE) or a rheumatoid factor (for patients with RA), respectively. Importantly, anti-galectin-2 autoantibodies highly significantly correlated with the appearance of a secondary APS in patients with SLE so that this parameter may serve as an additional biomarker for APS. Equally of note, the presence of IgG autoantibodies against galectins capable to act as an opsonin may contribute to a sustained immune dysregulation in patients with chronic inflammatory rheumatic diseases. © The Author 2012. Published by Oxford University Press. All rights reserved.
CRIS-Team Scopus Importer:2021-02-03
Keywords: antiphospholipid syndrome; autoantibodies; galectins; systemic lupus erythematosus

Autoantibodies in Rheumatoid Arthritis: Historical Background and Novel Findings - Sokolova, Maria; Schett, Georg; Steffen, Ulrike (Clinical Reviews in Allergy & Immunology, 2021)
Autoantibodies represent a hallmark of rheumatoid arthritis (RA), with the rheumatoid factor (RF) and antibodies against citrullinated proteins (ACPA) being the most acknowledged ones. RA patients who are positive for RF and/or ACPA (“seropositive”) in general display a different etiology and disease course compared to so-called “seronegative” patients. Still, the seronegative patient population is very heterogeneous and not well characterized. Due to the identification of new autoantibodies and advancements in the diagnosis of rheumatic diseases in the last years, the group of seronegative patients is constantly shrinking. Aside from antibodies towards various post-translational modifications, recent studies describe autoantibodies targeting some native proteins, further broadening the spectrum of recognized antigens. Next to the detection of new autoantibody groups, much research has been done to answer the question if and how autoantibodies contribute to the pathogenesis of RA. Since autoantibodies can be detected years prior to RA onset, it is a matter of debate whether their presence alone is sufficient to trigger the disease. Nevertheless, there is gathering evidence of direct autoantibody effector functions, such as stimulation of osteoclastogenesis and synovial fibroblast migration in in vitro experiments. In addition, autoantibody positive patients display a worse clinical course and stronger radiographic progression. In this review, we discuss current findings regarding different autoantibody types, the underlying disease-driving mechanisms, the role of Fab and Fc glycosylation and clinical implications.
CRIS-Team Scopus Importer:2021-09-17
Keywords: ACPA; Autoimmunity; Immunoglobulin; Rheumatoid arthritis

Autoantibodies Recognizing Secondary NEcrotic Cells Promote Neutrophilic Phagocytosis and Identify Patients With Systemic Lupus Erythematosus - Biermann, Mona; Boeltz, Sebastian; Pieterse, Elmar; Knopf, Jasmin; Rech, Jürgen; Bilyy, Rostyslav; Van Der Vlag, Johan; Tincani, Angela; Distler, Jörg; Krönke, Gerhard; Schett, Georg; Herrmann, Martin; et al. (Frontiers in Immunology, 2018)
Deficient clearance of apoptotic cells reportedly contributes to the etiopathogenesis of the autoimmune disease systemic lupus erythematosus (SLE). Based on this knowledge, we developed a highly specific and sensitive test for the detection of SLE autoantibodies (AAb) utilizing secondary NEcrotic cell (SNEC)-derived material as a substrate. The goal of the present study was to validate the use of SNEC as an appropriate antigen for the diagnosis of SLE in large cohort of patients. We confirmed the presence of apoptotically modified autoantigens on SNEC (dsDNA, high mobility group box 1 protein, apoptosis-associated chromatin modifications, e.g., histones H3-K27-me3; H2A/H4 AcK8,12,16; and H2B-AcK12). Anti-SNEC AAb were measured in the serum of 155 patients with SLE, 89 normal healthy donors (NHD), and 169 patients with other autoimmune connective tissue diseases employing SNEC-based indirect enzyme-linked immunosorbent assay (SNEC ELISA). We compared the test performance of SNEC ELISA with the routine diagnostic tests dsDNA Farr radioimmunoassay (RIA) and nucleosome-based ELISA (anti-dsDNA-NcX-ELISA). SNEC ELISA distinguished patients with SLE with a specificity of 98.9% and a sensitivity of 70.6% from NHD clearly surpassing RIA and anti-dsDNA-NcX-ELISA. In contrast to the other tests, SNEC ELISA significantly discriminated patients with SLE from patients with rheumatoid arthritis, primary anti-phospholipid syndrome, spondyloarthropathy, psoriatic arthritis, and systemic sclerosis. A positive test result in SNEC ELISA significantly correlated with serological variables and reflected the uptake of opsonized SNEC by neutrophils. This stresses the relevance of SNECs in the pathogenesis of SLE. We conclude that SNEC ELISA allows for the sensitive detection of pathologically relevant AAb, enabling its diagnostic usage. A positive SNEC test reflects the opsonization of cell remnants by AAb, the neutrophil recruitment to tissues, and the enhancement of local and systemic inflammatory responses.
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Autoantibody-mediated bone loss - Harre, Ulrike; Kittan, Nicolai A.; Schett, Georg (Current Osteoporosis Reports, 2014)
In rheumatoid arthritis (RA), the presence of autoantibodies such as the rheumatoid factor and antibodies against citrullinated proteins is highly correlated with the severity of disease and bone loss. For many years, the involvement of autoantibodies in bone resorption has merely been attributed to enhanced tissue infiltration and the production of inflammatory cytokines that promote osteoclastogenesis. However, recent research provides evidence for a direct activation of osteoclasts and their precursors by autoantibodies, which is independent of inflammation. The depletion of B-cells with rituximab that substantially reduces autoantibody levels seems to be as effective as the well-established treatment with tumor necrosis factor-antagonists in RA patients that do not respond to methotrexate, highlighting the significance of autoantibodies for RA and bone los
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Autoimmune Colitis and Subsequent CMV-induced Hepatitis After Treatment With Ipilimumab - Uslu, Ugur; Agaimy, Abbas; Hundorfean, Gheorghe; Harrer, Thomas; Schuler, Gerold; Heinzerling, Lucie (Journal of Immunotherapy, 2015)
Ipilimumab, a humanized CTLA-4 antibody, improves overall survival in patients with metastatic melanoma. However, immune-related adverse effects occur in about 65% of ipilimumab-treated patients and have to be adequately managed. A 55-year-old patient developed grade 3 autoimmune colitis 7 weeks after initiation of ipilimumab treatment and subsequently hepatitis with grade 3 elevation of transaminases and ?-glutamyl transferase. Colitis manifested with up to 18 watery and bloody stools per day and severe attacks of abdominal pain. After exclusion of infectious causes, immunosuppression with corticosteroids was initiated. Because of recurrent abdominal pain, spontaneous perforation of the colon had to be excluded. Elevated liver function tests (grade 3 CTCAE) occurred and differential diagnosis included immune-mediated, toxic, and viral hepatitis. It is interesting to note that, not an immune-mediated but a cytomegalovirus-induced hepatitis was diagnosed by serum blood tests and liver biopsy and was subsequently successfully treated. Careful elaboration of the patient under immunotherapy was essential as further immunosuppression mandatory for autoimmune hepatitis would have worsened the viral hepatitis. In conclusion, cytomegalovirus reactivation should be included in the differential in patients under immunotherapy with checkpoint inhibitors and has to be considered as a cause for morbidity.
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Autoimmunity as a trigger for structural bone damage in rheumatoid arthritis - Schett, Georg (Modern Rheumatology, 2017)
Bone loss is a central feature of rheumatoid arthritis (RA). It is considered to represent a sign of irreversible structural damage triggered by chronic inflammation. Recent evidence, however, suggests that autoantibodies are an important and earlier driver for bone damage in RA. This article summarizes current evidence for the role of RA-related autoantibodies in mediating bone loss. Rheumatoid factor and antibodies recognizing modified (citrullinated) proteins are the central features of autoimmunity in RA patients. Despite being used as diagnostic markers for many years, ascertaining the differentiation of RA from other forms of inflammatory arthritides, the role of these antibodies as pathogenic players has long been unrecognized. Recently, several pieces of evidence suggested that bone-resorbing osteoclasts are highly responsive to RA-related autoantibodies, providing a novel link between autoimmunity and bone. These developments have allowed unraveling the underlying mechanisms, which are responsible for the well-known clinical observation that RA-related autoantibodies are associated with a more severe disease course. At present, rheumatoid factor and antibodies recognizing citrullinated proteins are considered as potent osteoclast inducers and triggers for bone loss in arthritis.
EVALuna2:13388

Autoinflammation and autoimmunity across rheumatic and musculoskeletal diseases - Szekanecz, Zoltan; Mcinnes, Iain B.; Schett, Georg; Szamosi, Szilvia; Benko, Szilvia; Szucs, Gabriella (Nature Reviews Rheumatology, 2021)
Most rheumatic and musculoskeletal diseases (RMDs) can be placed along a spectrum of disorders, with autoinflammatory diseases (including monogenic systemic autoinflammatory diseases) and autoimmune diseases (such as systemic lupus erythematosus and antiphospholipid syndrome) representing the two ends of this spectrum. However, although most autoinflammatory diseases are characterized by the activation of innate immunity and inflammasomes and classical autoimmunity typically involves adaptive immune responses, there is some overlap in the features of autoimmunity and autoinflammation in RMDs. Indeed, some ‘mixed-pattern’ diseases such as spondyloarthritis and some forms of rheumatoid arthritis can also be delineated. A better understanding of the pathogenic pathways of autoinflammation and autoimmunity in RMDs, as well as the preferential cytokine patterns observed in these diseases, could help us to design targeted treatment strategies.
CRIS-Team Scopus Importer:2021-08-13

Autoinflammation leading to autoimmunity in adult-onset Still’s disease: more than simple coincidence? - Valor-Mendez, Larissa; Manger, Bernhard; Cavallaro, Alexander Josef; Achenbach, Stephan; Schett, Georg; Rech, Jürgen (European Journal of Medical Research, 2021)
Background: Adult-onset Still’s disease (AOSD) should be considered in the differential diagnosis of patients with endocarditis, with or without a cardiac decompensation. Case presentation: We report the case of a 68-year-old Caucasian male diagnosed with AOSD after an initial acute manifestation of endocarditis with severe aortic acute manifestation of endocarditis with severe aortic insufficiency. The histological findings revealed Libman–Sacks endocarditis. He was treated with the IL-1 receptor inhibitor anakinra. Two years later the patient developed a symptomatic dilated cardiomyopathy with reduced ejection fraction (23.5%) and functional anti-beta-1-adrenergic receptor antibodies, which was initially treated with plasmapheresis; anakinra was maintained. While his AOSD symptoms responded well, our patient presented with recurrent arthritis in multiple joints, dual-energy CT showed urate deposition compatible with a gouty arthropathy. Over 7 years, he presented with recurrent episodes of arthritis and the adjustment of dosages of colchicine and febuxostat was needed. In 2018, our patient died due to a deterioration of his underlying cardiac disease. Conclusions: Only two cases with initial endocarditis prior to AOSD diagnosis have been published, and we are not aware of any other cases reporting -β1AR-Ab development with DCM and gout in the setting of AOSD treated with anakinra.
CRIS-Team Scopus Importer:2021-10-01
Keywords: Adult-onset Still’s disease; Anakinra; ANTI-beta-1-adrenergic receptor antibodies; Dilated cardiomyopathy; Gout; IL-1 receptor inhibitor; Libman–Sacks endocarditis

Autologous hematopoietic stem cell transplantation for systemic sclerosis: Position statement of the stem cell therapy working party of the German Society of Rheumatology Autologe hämatopoetische Stammzelltransplantation bei systemischer Sklerose: Positionspapier des Arbeitskreises Stammzelltherapie der Deutschen Gesellschaft für Rheumatologie - Alexander, T.; Henes, J.; Distler, Jörg; Schmalzing, M.; Blank, N.; Kötter, I.; Hiepe, F. (Zeitschrift für Rheumatologie, 2020)
There have been three randomized controlled trials on autologous hematopoietic stem cell transplantation (AHSCT) in systemic sclerosis (SSc) that demonstrated significant superiority with respect to survival, improvement of cutaneous fibrosis, lung function and quality of life compared to standard treatment; however, these advantages must be carefully weighed against the transplantation-related risks. For this reason, an expert group from the stem cell therapy working party of the German Society for Rheumatology (DGRh) has now developed recommendations for the use of AHSCT in SSc. Based on the high-quality evidence, AHSCT is considered as the standard option for the treatment of selected SSc patients. Potential candidates for AHSCT are those with early, rapidly progressive, diffuse cutaneous SSc with visceral manifestations who have not yet developed severe damage to internal organs. A close cooperation between rheumatologists and transplantation centers is crucial for optimizing patient selection and treatment outcomes.
CRIS-Team Scopus Importer:2020-05-02
Keywords: Autologous stem cell transplantation; Cell therapy; DGRh; Guidelines; Systemic sclerosis

Autologous hematopoietic stem cell transplantation improves long-term survival-data from a national registry - Blank, Norbert; Schmalzing, Marc; Moinzadeh, Pia; Oberste, Max; Siegert, Elise; Mueller-Ladner, Ulf; Riemekasten, Gabriela; Guenther, Claudia; Koetter, Ina; Zeidler, Gabriele; Pfeiffer, Christiane; Juche, Aaron; et al. (Arthritis Research & Therapy, 2022)
Background Current recommendations on the management of systemic sclerosis (SSc) suggest that autologous hematopoietic stem cell therapy (HSCT) can be a rescue therapy for patients with rapidly progressive SSc. Objectives To assess the safety and efficacy of HSCT for patients with SSc and to compare these with non-HSCT patients in a control cohort with adjusted risk factors. Methods A retrospective analysis of data from the multicentric German network for systemic scleroderma (DNSS) with 5000 patients with SSc. Control groups consisted of all patients with diffuse cutaneous (dc)-SSc (group A) and an adjusted high-risk cohort of male patients with Scl70-positive dc-SSc (group B). Results Eighty SSc patients received an HSCT 4.1 +/- 4.8 years after SSc diagnosis. Among them, 86.3% had dc-SSc, 43.5% were males, and 71.3% were positive for Scl70 antibodies. The control group A (n=1513) showed a significant underrepresentation of these risk factors for mortality. When the survival of the control group B (n=240) was compared with the HSCT group, a lower mortality of the latter was observed instead. Within 5 years after HSCT, we observed an improvement of the mRSS from 17.6 +/- 11.5 to 11.0 +/- 8.5 (p=0.001) and a stabilization of the DLCO. We did not see differences in transplant-related mortality between patients who received HSCT within 3 years after SSc diagnosis or later. Conclusion Our analysis of real-life data show that the distribution of risk factors for mortality is critical when HSCT cohorts are compared with non-HSCT control groups.
CRIS-Team WoS Importer:2022-12-02

Automated Bone Density Measurements using Deep Learning - Folle, Lukas; Meinderink, Timo; Simon, David; Liphardt, Anna-Maria; Thies, Mareike; Krönke, Gerhard; Schett, Georg; Kleyer, Arnd; Maier, Andreas (23, 2022)
Introduction Hand bone loss is characteristic of rheumatoid or psoriatic arthritis, which clinically manifests with pain, swelling, and stiffness of the affected joints. Typically, hand joints are affected already in the early stages of arthritis1. High-resolution peripheral quantitative computed tomography (HR-pQCT) allows to visualize structural changes in the bone in 3D and enables measurements derived from the scans of the patient’s hand such as the volume of a bone. For this, a segmentation of the scans is necessary, which is reader-dependent and time-consuming, especially in challenging cases2. This work aims to replace this manual expert segmentation with a neural network (figure 1). Materials and methods The segmentation network was trained using 541 HR-pQCT patient scans (RA, PsA, and OA patients with motion grades up to 3) as input and the corresponding expert segmentation of the second metacarpal bone as reference. To optimize the parameters of the network, the current prediction was compared with the expert segmentation using the Dice coefficient. Pre-processing steps included resizing, flipping of left hands, and intensity normalization. The architecture of the segmentation network is based on the 2D U-Net, which was pre-trained on ImageNet. The predictions were resized to the original resolution and converted to the scanner-specific data format as post-processing steps. The scanner then calculated the average bone-mineral density (D100) based on the scan and the corresponding network-generated segmentation. The scans were split into training, validation, and testing with ratios of 70%, 20%, and 10% respectively. Results and discussion The bone segmentation using the neural network on the test set reached a Dice coefficient of 97.2%. A quantitative comparison of the network prediction (blue) and the expert annotation (red) is presented in figure 2. The deviation of the expert annotation from the bone contour is likely due to the shift of the scan when exceeding the specified maximum number of slices of the scanner. Since the neural network operates on a slice level, such deviations are implicitly accounted for. The results of the vBMD analysis are summarized in figure 3. Significant Pearson correlation with 0.999 (p<.001) was achieved for the D100 on the test set. Still, a slight offset is present in the predictions, which might lead to underestimating the D100. However, this could be eliminated in a calibration step beforehand. Conclusion Neural networks can be used to generate accurate segmentations of the MCP2 head even with erosions present and can be integrated into the clinical workflow with a performance on par with expert annotators and save time through the automation of the annotation process. <
Keywords: deep learning; bone imaging; segmentation

Automated three-dimensional registration of high-resolution peripheral quantitative computed tomography data to quantify size and shape changes of arthritic bone erosions - Toepfer, Dominique; Gerner, Bastian; Finzel, Stephanie; Kraus, Sebastian; Museyko, Oleg; Schett, Georg; Engelke, Klaus (Rheumatology, 2015)
To monitor size and shape changes of bone erosions and changes in BMD in the vicinity of the erosion and in the periarticular trabecular compartment of patients with RA using high-resolution peripheral quantitative CT (HR-pQCT) imaging and to compare an automated three-dimensional (3D) image processing technique with manual measurements of erosion width and depth.The shape of 40 bone erosions and composition of bone around the erosions were analysed in the MCP joints of 22 RA patients both manually and by semi-automated 3D image processing at two different time points. Periosteal segmentation was performed using volume growing and morphological operations. Image registration was applied for transfer of baseline segmentations to follow-up datasets.Eight erosions decreased in size, 6 increased and 28 remained stable. Increasing erosions were more spherical and smaller at baseline compared with decreasing or stable erosions. BMD in the vicinity of shrinking erosions increased, while it decreased next to expanding erosions. There was moderate agreement in the determination of erosion volume between semi-automated and manual measurements, but agreement was poor when assessing changes in volume over time.Longitudinal changes in erosion size and shape and of BMD in the vicinity of an erosion can be measured. BMD changes are associated with progression and regression of erosions. However, the semi-automated and manual approaches did not classify longitudinal changes of erosion volume in the same way. Further research is necessary to define the nature of these differences.
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Autophagy regulates TNFα-mediated joint destruction in experimental arthritis - Lin, Neng-Yu; Beyer, Christian; Gießl, Andreas; Kireva, Trayana; Scholtysek, Carina; Uderhardt, Stefan; Munoz, Luis Enrique; Dees, Clara; Distler, Alfiya; Wirtz, Stefan; Krönke, Gerhard; Spencer, Brian; et al. (Annals of the Rheumatic Diseases, 2013)
Objectives: Autophagy is a homeostatic process to recycle dispensable and damaged cell organelles. Dysregulation of autophagic pathways has recently been implicated in the pathogenesis of various diseases. Here, we investigated the role of autophagy during joint destruction in arthritis. Methods: Autophagy in osteoclasts was analysed in vitro and ex vivo by transmission electron microscopy, Western blotting and immunohistochemistry for Beclin1 and Atg7. Small molecule inhibitors, LysMCre-mediated knockout of Atg7 and lentiviral overexpression of Beclin1 were used to modulate autophagy in vitro and in vivo. Osteoclast differentiation markers were quantified by realtime PCR. The extent of bone and cartilage destruction was analysed in human tumour necrosis factor α transgenic (hTNFα tg) mice after adoptive transfer with myeloid specific Atg7-deficient bone marrow. Results: Autophagy was activated in osteoclasts of human rheumatoid arthritis (RA) showing increased expression of Beclin1 and Atg7. TNFα potently induced the expression of autophagy-related genes and activated autophagy in vitro and in vivo. Activation of autophagy by overexpression of Beclin1-induced osteoclastogenesis and enhanced the resorptive capacity of cultured osteoclasts, whereas pharmacologic or genetic inactivation of autophagy prevented osteoclast differentiation. Arthritic hTNFα tg mice transplanted with Atg7fl/fl×LysMCre+ bone marrow cells (BMC) showed reduced numbers of osteoclasts and were protected from TNFα-induced bone erosion, proteoglycan loss and chondrocyte death. Conclusions: These findings demonstrate that autophagy is activated in RA in a TNFα-dependent manner and regulates osteoclast differentiation and bone resorption. We thus provide evidence for a central role of autophagy in joint destruction in RA.
CRIS-Team Scopus Importer:2020-11-20

Autopsy versus clinical findings in patients with systemic sclerosis in a case series from patients of the EUSTAR database - Sandmeier, B.; Jaeger, V. K.; Nagy, G.; Carreira, P. E.; Tzankov, A.; Widuchowska, M.; Antic, M.; Distler, O.; Reichert, H.; Distler, Jörg; Walker, U. A.; Huegle, T. (Clinical and Experimental Rheumatology, 2015)
Subclinical organ pathology occurs regularly in systemic sclerosis (SSc) and affects correct prognosis as well as treatment choices. We aimed to evaluate autopsy data for organ involvement with subsequent correlation to clinical data in order to assess discrepancies in pathological and clinical findings in SSc.A standardised autopsy questionnaire from diseased patients registered in the European Scleroderma Trials and Research group (EUSTAR) cohort was analysed on cause of death and various manifestations in different organ systems. Clinical data obtained from the EUSTAR database of the corresponding patients including cause of death and disease manifestations of lung, heart, kidney, gastrointestinal, skin or musculoskeletal organ involvement were retrospectively analysed and compared to autopsy data.11 patients (6 women, 5 male) aged between 23 and 84 were included. Cause of death defined by pathologist and clinician were identical in 9/11 cases. In 8 individuals, cause of death was related to heart and lung pathologies. Heart and lung involvement (both 10/11) were the most frequently detected organ involvement at autopsy. Here, myocardial fibrosis occurred in 66% and lung fibrosis in 50% of the patients. Clinically, diastolic function abnormalities (6/11), conduction block (4/11), reduced DCLO (6/11) and dyspnea (8/11) were the most prevalent cardiopulmonary findings. For heart and renal involvement we found higher prevalence in autopsy than by clinical diagnosis. Especially myocardial fibrosis and renal arteriosclerosis were only obtained by autopsy in several individuals.Clinical diagnostic procedures are limited in detection of end-organ damage, especially for cardiac involvement. All the more post mortem examinations are needed for quality verification of clinical diagnosis and might help as to better understand the disease processes as well as to improve patient care.
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A virtual reality based app to educate health care professionals and medical students about inflammatory arthritis: Feasibility study - Klemm, Philipp; Kleyer, Arnd; Tascilar, Koray; Schuster, Louis; Meinderink, Timo; Steiger, Florian; Lange, Uwe; Möller-Ladner, Ulf; Knitza, Johannes; Sewerin, Philipp; Mucke, Johanna; Pfeil, Alexander; et al. (JMIR Serious Games, 2021)
Background: Inflammatory arthritides (IA) such as rheumatoid arthritis or psoriatic arthritis are disorders that can be difficult to comprehend for health professionals and students in terms of the heterogeneity of clinical symptoms and pathologies. New didactic approaches using innovative technologies such as virtual reality (VR) apps could be helpful to demonstrate disease manifestations as well as joint pathologies in a more comprehensive manner. However, the potential of using a VR education concept in IA has not yet been evaluated. Objective: We evaluated the feasibility of a VR app to educate health care professionals and medical students about IA. Methods: We developed a VR app using data from IA patients as well as 2D and 3D-visualized pathological joints from X-ray and computed tomography generated images. This VR app (Rheumality) allows the user to interact with representative arthritic joint and bone pathologies of patients with IA. In a consensus meeting, an online questionnaire was designed to collect basic demographic data (age, sex); profession of the participants; and their feedback on the general impression, knowledge gain, and potential areas of application of the VR app. The VR app was subsequently tested and evaluated by health care professionals (physicians, researchers, and other professionals) and medical students at predefined events (two annual rheumatology conferences and academic teaching seminars at two sites in Germany). To explore associations between categorical variables, the ? 2 or Fisher test was used as appropriate. Two-sided P values =.05 were regarded as significant. Results: A total of 125 individuals participated in this study. Among them, 56% of the participants identified as female, 43% identified as male, and 1% identified as nonbinary; 59% of the participants were 18-30 years of age, 18% were 31-40 years old, 10% were 41-50 years old, 8% were 51-60 years old, and 5% were 61-70 years old. The participants (N=125) rated the VR app as excellent, with a mean rating of 9.0 (SD 1.2) out of 10, and many participants would recommend use of the app, with a mean recommendation score of 3.2 (SD 1.1) out of 4. A large majority (120/125, 96.0%) stated that the presentation of pathological bone formation improves understanding of the disease. We did not find any association between participant characteristics and evaluation of the VR experience or recommendation scores. Conclusions: The data show that IA-Targeting innovative teaching approaches based on VR technology are feasible.
CRIS-Team Scopus Importer:2021-06-04
Keywords: Feasibility; Inflammatory arthritis; Psoriatic arthritis; Rheumatoid arthritis; Virtual reality

A Yoga Exercise App Designed for Patients With Axial Spondylarthritis: Development and User Experience Study - Truong, Minh Tam; Nwosu, Obioma Bertrand; Gaytan Torres, Maria Elena; Segura Vargas, Maria Paula; Seifer, Ann-Kristin; Nitschke, Marlies; Ibrahim, Alzhraa; Knitza, Johannes; Krusche, Martin; Eskofier, Björn; Schett, Georg; Morf, Harriet (JMIR Formative Research, 2022)
Background: Besides anti-inflammatory medication, physical exercise represents a cornerstone of modern treatment for patients with axial spondyloarthritis (AS). Digital health apps (DHAs) such as the yoga app YogiTherapy could remotely empower patients to autonomously and correctly perform exercises. Objective: This study aimed to design and develop a smartphone-based app, YogiTherapy, for patients with AS. To gain additional insights into the usability of the graphical user interface (GUI) for further development of the app, this study focused exclusively on evaluating users’ interaction with the GUI. Methods: The development of the app and the user experience study took place between October 2020 and March 2021. The DHA was designed by engineering students, rheumatologists, and patients with AS. After the initial development process, a pilot version of the app was evaluated by 5 patients and 5 rheumatologists. The participants had to interact with the app’s GUI and complete 5 navigation tasks within the app. Subsequently, the completion rate and experience questionnaire (attractiveness, perspicuity, efficiency, dependability, stimulation, and novelty) were completed by the patients. Results: The results of the posttest questionnaires showed that most patients were already familiar with digital apps (4/5, 80%). The task completion rates of the usability test were 100% (5/5) for the tasks T1 and T2, which included selecting and starting a yoga lesson and navigating to an information page. Rheumatologists indicated that they were even more experienced with digital devices (2/5, 40% experts; 3/5, 60% intermediates). In this case, they scored task completion rates of 100% (5/5) for all 5 usability tasks T1 to T5. The mean results from the User Experience Questionnaire range from −3 (most negative) to +3 (most positive). According to rheumatologists’ evaluations, attractiveness (mean 2.267, SD 0.401) and stimulation (mean 2.250, SD 0.354) achieved the best mean results compared with dependability (mean 2.000, SD 0.395). Patients rated attractiveness at a mean of 2.167 (SD 0.565) and stimulation at a mean of 1.950 (SD 0.873). The lowest mean score was reported for perspicuity (mean 1.250, SD 1.425). Conclusions: The newly developed and tested DHA YogiTherapy demonstrated moderate usability among rheumatologists and patients with rheumatic diseases. The app can be used by patients with AS as a complementary treatment. The initial evaluation of the GUI identified significant usability problems that need to be addressed before the start of a clinical evaluation. Prospective trials are also needed in the second step to prove the clinical benefits of the ap

Baricitinib Improves Bone Biomechanical Properties in Rheumatoid Arthritis (RA) - Results of a Prospective Interventional Study - Kemenes, Stephan; Hartmann, Fabian; Tascilar, Koray; Simon, David; Bayat, Sara; Krönke, Gerhard; Mendez, Larissa Valor; Schuster, Louis; Liphardt, Anna-Maria; Schett, Georg; Kleyer, Arnd (ARTHRITIS & RHEUMATOLOGY, 2022)
CRIS-Team WoS Importer:2023-01-13

Baricitinib Improves Bone Properties and Biomechanics in Patients With Rheumatoid Arthritis: Results of the Prospective Interventional BARE BONE Trial - Simon, David; Minopoulou, Ioanna; Kemenes, Stephan; Bayat, Sara; Tascilar, Koray; Mutlu, Melek Yalcin; Valor-Méndez, Larissa; Krönke, Gerhard; Hueber, Axel J.; Schett, Georg; Kleyer, Arnd (Arthritis and Rheumatology, 2023)
Objective: Rheumatoid arthritis (RA) is characterized by erosive joint damage, deterioration of bone mass, and biomechanics. Preclinical evidence suggests a beneficial effect of Janus kinase inhibition (JAKi) on bone properties, but clinical data are scarce to date. In this study, we evaluated the effect of JAKi through baricitinib (BARI) on 1) volumetric bone mineral density (vBMD), bone microstructure, biomechanics, and erosion repair and 2) synovial inflammation in RA patients. Methods: Prospective, single-arm, interventional, open-label, single-center phase 4 study in RA patients with pathological bone status and clinical indication of JAKi (BARE BONE trial). Participants received BARI (4 mg/day) over 52 weeks. To assess bone properties and synovial inflammation, high-resolution computed tomography scans and magnetic resonance imaging were performed at baseline (BL), week 24, and week 52. Clinical response and safety were monitored. Results: Thirty RA patients were included. BARI significantly improved disease activity (Disease Activity Score in 28 joints using the erythrocyte sedimentation rate: 4.82 ± 0.90 to 2.71 ± 0.83) and synovial inflammation (RAMRIS synovitis score: 5.3 [4.2] to 2.7 [3.5]). We observed a significant improvement in trabecular vBMD with a mean change of 6.11 mgHA/mm3 (95% confidence interval [95% CI] 0.01–12.26). Biomechanical properties also improved with mean change from baseline in estimated stiffness of 2.28 kN/mm (95% CI 0.30–4.25) and estimated failure load of 98.8 N (95% CI 15.9–181.7). The number and size of erosions in the metacarpal joints remained stable. No new safety signals with BARI treatment were observed. Conclusion: Bones of RA patients improve with BARI therapy, as shown by an increase in trabecular bone mass and an improvement of biomechanical properties.
CRIS-Team Scopus Importer:2023-09-29

BARICITINIB LEADS TO RAPID AND PERSISTENT RESOLUTION OF SYNOVITIS AS MEASURED BY HAND MRI IN PATIENTS WITH ACTIVE RHEUMATOID ARTHRITIS (RA) FAILING CS/BDMARD THERAPY - Kemenes, S.; Bayat, Sara; Simon, David; Krönke, Gerhard; Bohr, D.; Valor, L.; Hartmann, F.; Schuster, Louis; Tascilar, Koray; Schett, Georg; Kleyer, Arnd (ANNALS OF THE RHEUMATIC DISEASES, 2022)
CRIS-Team WoS Importer:2022-11-04

BASELINE CLINICAL DISEASE ACTIVITY IS NOT CRITICAL FOR PREDICTING REMISSION OF ADULTS ONSET STILL'S DISEASE - Groetsch, J.; Tascilar, Koray; Schett, Georg; Foell, D.; Rech, Jürgen (ANNALS OF THE RHEUMATIC DISEASES, 2022)
CRIS-Team WoS Importer:2022-11-04

Baseline Structural Damage Predicts Response to Abatacept in Patients with Psoriatic Arthritis: A Post Hoc Analysis from a Phase III Study - Schett, Georg; Lehman, T.; Ahmad, H. A.; Johnsen, A.; Banerjee, S.; Mease, Philip J. (2017)
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B cells are critical for autoimmune pathology in Scurfy mice. - Aschermann, Susanne; Lehmann, Christian; Mihai, Sidonia; Schett, Georg; Dudziak, Diana; Nimmerjahn, Falk (Proceedings of the National Academy of Sciences of the United States of America, 2013)
Impaired regulatory T-cell function results in a severe chronic autoimmune disease affecting multiple organs in Scurfy mice and humans with the immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome. Previous studies have shown that T helper cells but not cytotoxic T cells are critical for the disease pathology. Whether this T-cell subset is responsible directly for tissue inflammation or rather indirectly via the interaction with B cells or myeloid cells is largely unknown. To study this and to identify potential therapeutic targets for this lethal disease we investigated the contribution of B cells to this complex autoimmune phenotype. We show that B cells and the production of autoantibodies plays a major role for skin, liver, lung, and kidney inflammation and therapeutic depletion of B cells resulted in reduced tissue pathology and in prolonged survival. In contrast, the absence of B cells did not impact systemic T-cell activation and hyperreactivity, indicating that autoantibody production by B cells may be a major factor for the autoimmune pathology in mice deficient for regulatory T cells.

BDCA2 Targeting of Human Plasmacytoid Dendritic Cells via CBS004 Reverts Dependent IFN Activation and Tissue Fibrosis in vitro and in vivo - Ross, Rebecca; Corinaldesi, Clarissa; Migneco, Gemma; El-Sherbiny, Yasser; Holmes, Steve; Distler, Jörg; Mckimmie, Clive; Del Galdo, Francesco (ARTHRITIS & RHEUMATOLOGY, 2019)
CRIS-Team WoS Importer:2020-02-07

Befragung zu den Arbeits-, Weiterbildungs- und Forschungsbedingungen von Assistenzärztinnen und -ärzten in der internistisch-rheumatologischen Weiterbildung – BEWUSST - Proft, Fabian; Vossen, Diana; Baraliakos, Xenofon; Berliner, Michael N.; Fleck, Martin; Keyßer, Gernot; Krause, Andreas; Lorenz, Hanns Martin; Manger, Bernhard; Schuch, Florian; Specker, Christof; Wollenhaupt, Jürgen; et al. (Zeitschrift für Rheumatologie, 2023)
Background: Data on the training and continuing education situation of residents in the field of internal medicine and rheumatology are not available for Germany. For this reason, the Commission for Education and Training of the German Society of Rheumatology (DGRh) initiated the BEWUSST survey on the working, training and research conditions of residents in rheumatology. Methods: A total of 102 questions on the topics of working conditions in everyday professional life, continuing medical education and training, compatibility of career and family, compatibility of work and research, perspectives as a rheumatologist and practical activities were included in an online questionnaire. Results: A total of 102 participants took part in the survey. Of the respondents 48.1% were satisfied with their professional situation, 40.2% of the participants were supervised by a specialist mentor and 54.9% were working as scientists during their work as a physician. A compatibility of family and career was possible for 34.7%. After completion of the residency 52.9% of the respondents aspired to a combined clinical and outpatient activity. Conclusion: Half of the trainee rheumatologists are satisfied with their professional activities, although mentoring of the assistants in training should be further improved. With respect to the desired combined clinical and outpatient activity, the existing options should be expanded or new professional fields of activity should be established, so that the specialty remains attractive for the upcoming generations.
CRIS-Team Scopus Importer:2023-08-25
Keywords: Compatibility of career and family; Compatibility of work and research; Fields of activity; Perspectives; Speciality of internal medicine and rheumatology

Bilateral Orbital IgG4-Related Disease with Systemic and Corneal Involvement Showing an Excellent Response to Steroid and Rituximab Therapy: Report of a Case with 11 Years Follow-Up - Berta, Agnes I.; Agaimy, Abbas; Braun, Joachim M.; Manger, Bernhard; Kruse, Friedrich Eduard; Holbach, Leonard (Orbit, 2015)
IgG4-related disease is a newly recognized fibro-inflammatory condition. The purpose of this report is to present a patient with 11 years of follow-up, who revealed characteristic features of IgG4-related disease with systemic, orbital and corneal involvement and showed a favorable response to steroids and rituximab treatment.
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Bilateral vision loss in a patient with weight loss and neurologic symptoms - La Mancusa, Antonia; Rech, J.; Harrer, Thomas; Knorr, H.; Bergua, A. (Klinische Monatsblätter für Augenheilkunde, 2011)
EVALuna2:12701

Bimekizumab in patients with active psoriatic arthritis: results from a 48-week, randomised, double-blind, placebo-controlled, dose-ranging phase 2b trial - Ritchlin, Christopher T.; Kavanaugh, Arthur; Merola, Joseph F.; Schett, Georg; Scher, Jose U.; Warren, Richard B.; Gottlieb, Alice B.; Assudani, Deepak; Bedford-Rice, Kathy; Coarse, Jason; Ink, Barbara; McInnes, Iain B. (Lancet, 2020)
Background: Dual neutralisation of interleukin 17A (IL17A) and interleukin 17F (IL17F) is a potential novel therapeutic approach in psoriatic arthritis. We assessed bimekizumab, a monoclonal antibody that selectively neutralises IL17A and IL17F, in patients with active psoriatic arthritis. Methods: BE ACTIVE was a randomised, double-blind, placebo-controlled, dose-ranging phase 2b study done at 41 sites in the Czech Republic, Germany, Hungary, Poland, Russia, and the USA. Eligible patients aged 18 years or older with active adult-onset psoriatic arthritis and symptoms for at least 6 months were randomly assigned (1:1:1:1:1) to placebo, 16 mg bimekizumab, 160 mg bimekizumab, 160 mg bimekizumab with a one-off 320 mg loading dose, or 320 mg bimekizumab, which were administered as subcutaneous injections every 4 weeks for 12 weeks. After 12 weeks, patients assigned to the placebo and 16 mg bimekizumab groups were randomly reassigned (1:1) to either 160 mg or 320 mg bimekizumab, and all other patients remained on their originally assigned initial dose up to 48 weeks. Both participants and researchers were blinded to treatment allocation in the first 12 weeks, and blinded to the dose of bimekizumab thereafter. The primary endpoint was the proportion of patients with at least 50% improvement in the American College of Rheumatology response criteria at week 12, which was assessed in all patients who received at least one dose of study treatment and had a valid measurement of the primary efficacy endpoint at baseline. The trial, including all follow-up, has been completed. This trial is registered with ClinicalTrials.gov, NCT02969525. Findings: Between Oct 27, 2016, and July 16, 2018, 308 patients were screened, and 206 were randomly assigned: 42 to the placebo group, and 41 each to the four bimekizumab groups. At 12 weeks, compared with the placebo group, significantly more patients in the 16 mg bimekizumab (odds ratio [OR] 4·2 [95% CI 1·1–15·2]; p=0·032), 160 mg bimekizumab (8·1 [2·3–28·7]; p=0·0012), and 160 mg (loading dose) bimekizumab (9·7 [2·7–34·3]; p=0·0004) groups achieved an ACR50 response. At 12 weeks, 24 (57%) of 42 patients in the placebo group and 68 (41%) of the 164 patients in the bimekizumab groups reported treatment-emergent adverse events. Most of these adverse events were mild or moderate. Serious treatment-emergent adverse events occurred in nine patients, eight of whom were receiving bimekizumab. No deaths or cases of inflammatory bowel disease were reported. Interpretation: Bimekizumab doses of 16 mg and 160 mg (with or without a 320 mg loading dose) were associated with significant improvements in ACR50 compared with placebo, with an acceptable safety profile. Our results support phase 3 investigation of bimekizumab as a treatment for psoriatic arthritis. Funding: UCB Pharma.
CRIS-Team Scopus Importer:2020-02-14

Bimekizumab in Patients with Psoriatic Arthritis: 3-Year Results for Overall and Tumor Necrosis Factor Inhibitor (TNFi)-Naive Populations from a Phase 2b Open-Label Extension Study - Mease, Philip; Deodhar, Atul; Merola, Joseph; Mcinnes, Iain; Assudani, Deepak; Bajracharya, Rajan; Coarse, Jason; Ink, Barbara; Schett, Georg (ARTHRITIS & RHEUMATOLOGY, 2021)
CRIS-Team WoS Importer:2022-03-11

Binding Immunoglobulin Protein (BIP) Inhibits TNF-α-Induced Osteoclast Differentiation and Systemic Bone Loss in an Erosive Arthritis Model. - Hall, Christopher; McGowan, Neil; Babb, Rebecca; Devlia, Vikesh; Lucas, Sébastien; Meghji, Sajeda; Henderson, Brian; Bozec, Aline; David, Jean-Pierre; Panayi, Gabriel S.; Grigoriadis, Agamemnon E.; Corrigall, Valerie M.; et al. (ACR Open Rheumatology, 2019)
Objective: The association between inflammation and dysregulated bone remodeling is apparent in rheumatoid arthritis and is recapitulated in the human tumor necrosis factor transgenic (hTNFtg) mouse model. We investigated whether extracellular binding immunoglobulin protein (BiP) would protect the hTNFtg mouse from both inflammatory arthritis as well as extensive systemic bone loss and whether BiP had direct antiosteoclast properties in vitro. Methods: hTNFtg mice received a single intraperitoneal administration of BiP at onset of arthritis. Clinical disease parameters were measured weekly. Bone analysis was performed by microcomputed tomography and histomorphometry. Mouse bone marrow macrophage and human peripheral blood monocyte precursors were used to study the direct effect of BiP on osteoclast differentiation and function in vitro. Monocyte and osteoclast signaling was analyzed by Western blotting, flow cytometry, and imaging flow cytometry. Results: BiP-treated mice showed reduced inflammation and cartilage destruction, and histomorphometric analysis revealed a decrease in osteoclast number with protection from systemic bone loss. Abrogation of osteoclast function was also observed in an ex vivo murine calvarial model. BiP inhibited differentiation of osteoclast precursors and prevented bone resorption by mature osteoclasts in vitro. BiP also induced downregulation of CD115/c-Fms and Receptor Activator of NF-κB (RANK) messenger RNA and protein, causing reduced phosphorylation of the p38 mitogen-activated protein kinases, extracellular signal-regulated kinases 1/2 and p38, with suppression of essential osteoclast transcription factors, c-Fos and NFATc1. BiP directly inhibited TNF-α- or Receptor Activator of NF-κB Ligand (RANKL)-induced NF-κB nuclear translocation in THP-1 monocytic cells and preosteoclasts by the canonical and noncanonical pathways. Conclusion: BiP combines an anti-inflammatory function with antiosteoclast activity, which establishes it as a potential novel therapeutic for inflammatory disorders associated with bone loss.
EVALuna2:423610

Biomechanical properties of bone are impaired in patients with ACPA-positive rheumatoid arthritis and associated with the occurrence of fractures - Stemmler, Fabian; Simon, David; Liphardt, Anna-Maria; Englbrecht, Matthias; Rech, Jürgen; Hueber, Axel; Engelke, Klaus; Schett, Georg; Kleyer, Arnd (Annals of the Rheumatic Diseases, 2018)
OBJECTIVES: Bone loss is a well-established consequence of rheumatoid arthritis (RA). To date, bone disease in RA is exclusively characterised by bone density measurements, while the functional properties of bone in RA are undefined. This study aimed to define the impact of RA on the functional properties of bone, such as failure load and stiffness. METHODS: Micro-finite element analysis (µFEA) was carried out to measure failure load and stiffness of bone based on high-resolution peripheral quantitative CT data from the distal radius of anti-citrullinated protein antibody (ACPA)-positive RA (RA+), ACPA-negative RA (RA-) and healthy controls (HC). In addition, total, trabecular and cortical bone densities as well as microstructural parameters of bone were recorded. Correlations and multivariate models were used to determine the role of demographic, disease-specific and structural data of bone strength as well as its relation to prevalent fractures. RESULTS: 276 individuals were analysed. Failure load and stiffness (both P<0.001) of bone were decreased in RA+, but not RA-, compared with HC. Lower bone strength affected both female and male patients with RA+, was related to longer disease duration and significantly (stiffness P=0.020; failure load P=0.012) associated with the occurrence of osteoporotic fractures. Impaired bone strength was correlated with altered bone density and microstructural parameters, which were all decreased in RA+. Multivariate models showed that ACPA status (P=0.007) and sex (P<0.001) were independently associated with reduced biomechanical properties of bone in RA. CONCLUSION: In summary, µFEA showed that bone strength is significantly decreased in RA+ and associated with fractures.
EVALuna2:34448

BIOMECHANICAL PROPERTIES OF RADIAL BONE ARE DIFFERENT BETWEEN AUTO-ANTIBODY POSITIVE AND NEGATIVE RHEUMATOID ARTHRITIS - Stemmler, F.; Simon, David; Liphardt, Anna-Maria; Englbrecht, Matthias; Rech, Jürgen; Hueber, Axel; Engelke, Klaus; Schett, Georg; Kleyer, Arnd (2018)
EVALuna2:34998

Biomechanical stress in the context of competitive sports training triggers enthesitis - Simon, David; Kleyer, Arnd; Bayat, Sara; Knitza, Johannes; Valor-Mendez, Larissa; Schweiger, Marina; Schett, Georg; Tascilar, Koray; Hueber, Axel (Arthritis Research & Therapy, 2021)
Objective To evaluate the influence of mechanical stress on the development of immediate enthesitis. Methods The BEAT study is an interventional study that assessed entheses in competitive badminton players before and immediately after a 60-min intensive training session. Power Doppler (PD) signal and Gray scale (GS) changes were assessed in the insertion sites of both Achilles tendon, patellar tendons, and lateral humeral epicondyles and quantified using a validated scoring system. Results Thirty-two badminton players were included. One hundred ninety-two entheseal sites were examined twice. The respective empirical total scores for PD examination were 0.1 (0.3) before and 0.5 (0.9) after training. Mean total GS scores were 2.9 (2.5) and 3.1 (2.5) before and after training, respectively. The mean total PD score difference of 0.4 between pre- and post-training was significant (p = 0.0014), whereas no significant difference for the mean total GS score was observed. Overall, seven participants (22%) showed an increased empirical total PD score. A mixed effects model showed a significant increase of PD scores after training, with a mean increase per site of 0.06 (95% CI 0.01 to 0.12, p = 0.017). Conclusions Mechanical stress leads to rapid inflammatory responses in the entheseal structures of humans. These data support the concept of mechanoinflammation in diseases associated with enthesitis.
CRIS-Team WoS Importer:2021-07-09

BIOMECHANICAL STRESS IN THE CONTEXT OF COMPETITIVE SPORTS TRAINING TRIGGERS ENTHESITIS - Simon, David; Kleyer, Arnd; Bayat, Sara; Knitza, Johannes; Valor, L.; Schweiger, M.; Schett, Georg; Tascilar, Koray; Hueber, Axel (ANNALS OF THE RHEUMATIC DISEASES, 2021)
CRIS-Team WoS Importer:2021-09-24

BIOPHYSICAL PROPERTIES OF MONOCYTES INDICATE DISEASE ACTIVITY, SEVERITY OF FIBROTIC OR MICROVASCULAR MANIFESTATIONS AND THE RISK FOR PROGRESSION IN SYSTEMIC SCLEROSIS - Matei, Alexandru-Emil; Marketa, K.; Xu, L.; Györfi, Andrea-Hermina; Boxberger, E.; Soteriou, D.; Papava, Maria; Prater, Julia; Hong, Xuezhi; Kraeter, M.; Schett, Georg; Guck, J.; et al. (ANNALS OF THE RHEUMATIC DISEASES, 2022)
CRIS-Team WoS Importer:2022-11-04

Blockade of Dickkopf (DKK)-1 induces fusion of sacroiliac joints - Uderhardt, Stefan; Diarra, Danielle; Katzenbeisser, J.; David, Jean-Pierre; Zwerina, J.; Richards, W.; Krönke, Gerhard; Schett, Georg (Annals of the Rheumatic Diseases, 2010)
Objective: To study whether Dickkopf (DKK)-1, an inhibitor of wingless (Wnt) signalling, is involved in the fusion of sacroiliac joints. Methods: Mice transgenic for tumour necrosis factor (TNFtg mice), which develop bilateral sacroiliitis, were treated with vehicle, anti-TNF antibody or anti-DKK1 antibody. Sacroiliac joints were analysed for histological signs of inflammation, bone erosion, osteoclast formation and ankylosis. Moreover, expression of collagen type X, β-catenin and DKK-1 was assessed by immunohistochemistry. Results: There were no signs of spontaneous ankylosis of the sacroiliac joints in TNFtg mice. TNF blockade effectively reduced inflammation, bone erosion and osteoclast numbers in the sacroiliac joints, but did not lead to ankylosis. Blockade of DKK1 had no effect on inflammatory signs of sacroiliitis, but significantly reduced bone erosions and osteoclast counts. Moreover, DKK1 blockade promoted expression of collagen type X, the formation of hypertrophic chondrocytes and ankylosis of sacroiliac joints. Conclusion: DKK1 influences inflammatory remodelling of sacroiliac joints by prevention of joint ankylosis. This may indicate an important role of the Wnt signalling pathway in the structural bone changes of axial joint disease. Although this model does not reflect the entire spectrum of ankylosing spondylitis in humans, it helps to explain the pathophysiological processes of sacroiliac joint ankylosis, which is a hallmark of the spondyloarthritides.
CRIS-Team Scopus Importer:2020-11-20

Blockade of IL-36 Receptor Signaling Does Not Prevent from TNF-Induced Arthritis - Derer, Anja; Groetsch, Bettina; Harre, Ulrike; Böhm, Christina; Towne, Jennifer; Schett, Georg; Frey, Silke; Hueber, Axel (PLoS ONE, 2014)
Interleukin (IL)-36? is a newly described member of the IL-1 cytokine family with a known inflammatory and pathogenic function in psoriasis. Recently, we could demonstrate that the receptor (IL-36R), its ligand IL-36? and its antagonist IL-36Ra are expressed in synovial tissue of arthritis patients. Furthermore, IL-36? induces MAP-kinase and NF?B signaling in human synovial fibroblasts with subsequent expression and secretion of pro-inflammatory cytokines.To understand the pathomechanism of IL-36 dependent inflammation, we investigated the biological impact of IL-36? signaling in the hTNFtg mouse. Also the impact on osteoclastogenesis by IL-36? was tested in murine and human osteoclast assays.Diseased mice showed an increased expression of IL-36R and IL-36? in inflamed knee joints compared to wildtype controls. However, preventively treating mice with an IL-36R blocking antibody led to no changes in clinical onset and pattern of disease. Furthermore, blockade of IL-36 signaling did not change histological signs of TNF-induced arthritis. Additionally, no alteration on bone homeostasis was observed in ex vivo murine and human osteoclast differentiation assays.Thus we conclude that IL-36? does not affect the development of inflammatory arthriti
EVALuna2:12991

Blockade of the hedgehog pathway inhibits osteophyte formation in arthritis. - Ruiz-Heiland, Gisela; Horn, Angelika; Zerr, Pawel; Hofstetter, Willy; Baum, Wolfgang; Stock, Michael; Distler, Jörg; Nimmerjahn, Falk; Schett, Georg; Zwerina, Jochen (Annals of the Rheumatic Diseases, 2012)
BACKGROUND Osteophyte formation is a common phenomenon in arthritis. Bone formation by endochondral ossification is considered a key pathophysiological process in the formation of osteophytes. OBJECTIVE To examine the hypothesis that inhibition of smoothened (Smo), a key component of the hedgehog pathway inhibits osteophyte formation as the hedgehog pathway mediates endochondral ossification. METHODS Arthritis was induced in 8-week-old C57/BL6 mice by serum transfer (K/BxN model). Mice were then treated by daily administration of either vehicle or LDE223, a specific small molecule inhibitor for Smo, over 2 weeks starting at the onset of disease. Clinical course of arthritis, histological and molecular changes of bone in the affected joints as well as systemic bone changes were assessed. RESULTS Serum transfer-induced arthritis led to severe osteophyte formation within 2 weeks of onset. Blockade of Smo inhibited hedgehog signalling in vivo and also significantly inhibited osteophyte formation, whereas the clinical and histopathological signs of arthritis were not affected. Also, systemic bone mass did not change. Smo inhibitor particularly blocked the formation of hypertrophic chondrocytes and collagen type X expression. CONCLUSIONS The data indicate that blockade of hedgehog signalling by targeting Smo specifically inhibits osteophyte formation in arthritis without affecting inflammation and without eliciting bone destruction at the local and systemic level. Blockade of Smo may thus be considered as a strategy to specifically influence the periosteal bone response in arthritis associated with bone apposition.

Blockade of TNF-α rapidly inhibits pain responses in the central nervous system - Heß, Andreas; Axmann, Roland; Rech, Jürgen; Finzel, Stephanie; Heindl-Erdmann, Cornelia; Kreitz, Silke; Sergeeva, Marina; Saake, Marc; Garcia, Meritxell; Kollias, George; Straub, Rainer H.; Sporns, Olaf; et al. (Proceedings of the National Academy of Sciences of the United States of America, 2011)
There has been a consistent gap in understanding how TNF-α neutralization affects the disease state of arthritis patients so rapidly, considering that joint inflammation in rheumatoid arthritis is a chronic condition with structural changes. We thus hypothesized that neutralization of TNF-α acts through the CNS before directly affecting joint inflammation. Through use of functional MRI (fMRI), we demonstrate that within 24 h after neutralization of TNF-α, nociceptive CNS activity in the thalamus and somatosensoric cortex, but also the activation of the limbic system, is blocked. Brain areas showing blood-oxygen level-dependent signals, a validated method to assess neuronal activity elicited by pain, were significantly reduced as early as 24 h after an infusion of a monoclonal antibody to TNF-α. In contrast, clinical and laboratory markers of inflammation, such as joint swelling and acute phase reactants, were not affected by anti-TNF-α at these early time points. Moreover, arthritic mice overexpressing human TNF-α showed an altered pain behavior and amore intensive, widespread, and prolonged brain activity upon nociceptive stimuli compared with wild-type mice. Similar to humans, these changes, as well as the rewiring of CNS activity resulting in tight clustering in the thalamus, were rapidly reversed after neutralization of TNF-α. These results suggest that neutralization of TNF-α affects nociceptive brain activity in the context of arthritis, long before it achieves antiinflammatory effects in the joints.
CRIS-Team Scopus Importer:2021-02-03
Keywords: Antiinflammatory therapy; Cytokines

Blockade of Tyrosine Kinases as Preventive Strategy Against Cardiac Allograft Vasculopathy in a Murine Aortic Transplant Model - Gocht, Annika; Distler, Jörg; Spriewald, Bernd; Ramsperger-Gleixner, Martina; Ensminger, Stephan M.; Weyand, Michael; Heim, Christian (2018)
EVALuna2:34976

Blocking IL-1, IL-33 and IL-36 Signaling with the Anti-IL1RAP Antibody mCAN10 Ameliorates Inflammation and Fibrosis in Preclinical Models of Systemic Sclerosis - Gronberg, Caitriona; Rattik, Sara; Kunz, Meik; Thoung Trinh-Minh,; TRAN MANH, CUONG; Zhou, Xiang; Skoog, Petter; Liberg, David; Distler, Jörg (ARTHRITIS & RHEUMATOLOGY, 2022)
CRIS-Team WoS Importer:2023-01-13

Blood-Based Biomarkers of Inflammation and Tissue Remodeling Can Discriminate Between Rheumatoid Arthritis, Psoriasis, and Psoriatic Arthritis and Are Associated with Hand Function - Port Linares, Helena; Coppers, Birte; Bayat, Sara; Elie-Tino, Godonou; Fagni, Filippo; Corte, Giulia; Bay-Jensen, Anne-Christine; Tascilar, Koray; Hueber, Axel; Schönau, Verena; Sticherling, Michael; Heinrich, Simon; et al. (poster, American College of Rheumatology Convergence, 2023)

Blood-borne phagocytes internalize urate microaggregates and prevent intravascular NETosis by urate crystals - Pieterse, Elmar; Jeremic, Ivica; Czegley, Christine; Weidner, Daniela; Biermann, Mona; Veissi, Susan; Maueröder, Christian; Schauer, Christine; Bilyy, Rostyslav; Dumych, Tetiana; Hoffmann, Markus; Munoz, Luis Enrique; et al. (Scientific Reports, 2016)
Hyperuricemia is strongly linked to cardiovascular complications including atherosclerosis and thrombosis. In individuals with hyperuricemia, needle-shaped monosodium urate crystals (nsMSU) frequently form within joints or urine, giving rise to gouty arthritis or renal calculi, respectively. These nsMSU are potent instigators of neutrophil extracellular trap (NET) formation. Little is known on the mechanism(s) that prevent nsMSU formation within hyperuricemic blood, which would potentially cause detrimental consequences for the host. Here, we report that complement proteins and fetuins facilitate the continuous clearance by blood-borne phagocytes and resident macrophages of small urate microaggregates (UMA; <1 ?m in size) that initially form in hyperuricemic blood. If this clearance fails, UMA exhibit bipolar growth to form typical full-sized nsMSU with a size up to 100 ?m. In contrast to UMA, nsMSU stimulated neutrophils to release NETs. Under conditions of flow, nsMSU and NETs formed densely packed DNase I-resistant tophus-like structures with a high obstructive potential, highlighting the importance of an adequate and rapid removal of UMA from the circulation. Under pathological conditions, intravascularly formed nsMSU may hold the key to the incompletely understood association between NET-driven cardiovascular disease and hyperuricemia.
EVALuna2:13377

Body mass index distribution in rheumatoid arthritis: a collaborative analysis from three large German rheumatoid arthritis databases - Albrecht, Katinka; Richter, Adrian; Callhoff, Johanna; Huscher, Doerte; Schett, Georg; Strangfeld, Anja; Zink, Angela (Arthritis Research & Therapy, 2016)
METARTHROS (Metabolic impact on joint and bone disease) is a nationwide German network to investigate the overlap between inflammatory and metabolic diseases. The objective of this study was to compare the body mass index (BMI) distribution in patients with early and established rheumatoid arthritis (RA) with data from the general population, and to evaluate the association of BMI with patient characteristics and clinical markers.The BMI distribution was examined with data collected at inclusion of patients in the early arthritis cohort CAPEA, the biologics register RABBIT, and the National database of the German Collaborative Arthritis Centers. A data source with a representative sample of the German population (German Ageing Survey) was used as a comparator. BMI categories of <18.5 kg/m(2) (underweight), 18.5 to <25 kg/m(2) (normal weight), 25 to <30 kg/m(2) (overweight), and >=30 kg/m(2) (obese) were used. Patients were stratified by age and sex, and compared to controls from the German Ageing Survey. Associations between BMI and markers of disease activity were analysed with non-parametric tests and linear models.Data from 1207 (CAPEA), 12,230 (RABBIT), and 3424 (National database) RA patients and 6202 population controls were evaluated. The mean age was 56, 56, 62, and 62 years, respectively, the mean disease duration was 13 weeks, 9.9 years, and 13.5 years, respectively, and the mean disease activity score (DAS28) was 5.1, 5.2, and 3.1, respectively. In all RA cohorts, obesity was more frequent (23.8 %, 23.4 %, 21.4 %, respectively) than in controls (18.2 %). This applied to all age groups <70 years, was independent of disease duration, and was more pronounced in females. In all cohorts, the age at RA onset was associated with BMI, being higher in overweight/obese patients compared to normal-weight patients. Current smoking was negatively associated with BMI. Linear analyses revealed increased erythrocyte sedimentation rate (ESR) values in underweight and obese females, and an increasing disparity between tender joint counts (TJCs) and swollen joint counts (SJCs) in higher BMI categories.Compared to the general population, a higher prevalence of obesity was observed in all RA cohorts. The dominance of obesity in females and the different behaviour of disease activity markers in relation to the BMI in females indicate that additional parameters need to be considered when analysing the impact of obesity on inflammation in RA.
EVALuna2:13296

Bone anabolic changes progress in psoriatic arthritis patients despite treatment with methotrexate or tumour necrosis factor inhibitors - Finzel, Stephanie; Kraus, Sebastian; Schmidt, Sarah; Hueber, Axel; Rech, Jürgen; Engelke, Klaus; Englbrecht, Matthias; Schett, Georg (Annals of the Rheumatic Diseases, 2013)
Objectives: To investigate whether methotrexate or tumour necrosis factor inhibitors (TNFi) affect osteophyte formation in patients with psoriatic arthritis (PsA). Methods: 41 patients with PsA were examined for the presence of osteophytes and erosions at the metacarpophalangeal joints by high-resolution micro-CT imaging. The size of each individual lesion was quantified at baseline and 1-year follow-up in PsA patients treated with TNFi (N=28) or methotrexate (N=13). Groups were comparable for age, sex, disease duration and activity and baseline burden of osteophytes. Results: In total, 415 osteophytes (TNFi N=284, methotrexate N=131) were detected. Osteophyte size increased significantly from baseline to follow-up in the TNFi group (mean±SEM change +0.23±0.02 mm; p<0.0001) and the methotrexate group (+0.27±0.03 mm, p<0.0001). In both treatment groups, the majority of osteophytes showed progression (TNFi 54.3%, methotrexate 61.1%), whereas regression of lesions was rare (less than 10%). In contrast to osteophytes, clinical disease activity decreased in both groups of PsA patients and erosions showed an arrest of progression in both groups. Conclusions: Osteophytes progress in PsA patients treated with either methotrexate or TNFi. These data provide the first evidence that pathological bone formation in the appendicular skeleton of patients with PsA is not affected by current antirheumatic treatment strategies.
CRIS-Team Scopus Importer:2021-02-03

Bone- and cartilage-protective effects of a monoclonal antibody against colony-stimulating factor 1 receptor in experimental arthritis - Toh, Myew-Ling; Bonnefoy, Jean-Yves; Accart, Nathalie; Cochin, Sandrine; Pohle, Sandy; Haegel, Helene; De Meyer, Micael; Zemmour, Christophe; Preville, Xavier; Guillen, Christine; Thioudellet, Christine; Ancian, Philippe; et al. (Arthritis and Rheumatology, 2014)
Colony-stimulating factor 1 receptor (CSF-1R) essentially modulates monocyte proliferation, migration, and activation, which are considered important for the pathogenesis of rheumatoid arthritis (RA). We undertook this study to determine CSF-1R expression in human RA as well as the efficacy of a specific anti-CSF-1R monoclonal antibody (AFS98) in 2 different animal models of RA.CSF-1R expression was examined in blood, synovium, and bone samples from RA patients, osteoarthritis (OA) patients, and healthy subjects. The efficacy of AFS98 was examined by clinical assessment, histology, and bone histomorphometry in collagen-induced arthritis (CIA) and serum-transfer arthritis.CSF-1R expression was increased in the synovium of RA patients compared to OA patients and healthy controls in fibroblast-like synoviocytes, follicular dendritic cells, macrophages, and osteoclasts. Circulating RA monocytes and neutrophils but not lymphocytes were CSF-1R+. In mice, blockade of CSF-1R abrogated cartilage damage, bone erosion, and systemic bone loss, and this was associated with the depletion of osteoclasts in both models. While blockade of CSF-1R did not affect inflammation in passive serum-transfer arthritis, it significantly reduced inflammation in CIA, and this was associated with the absence of synovial macrophages and reduced splenic CD11b+Gr-1- monocytes.CSF-1R was broadly expressed in human RA. Blockade of CSF-1R protected against bone and cartilage destruction in both mouse models and also showed significant antiinflammatory effects in the CIA model. These data provide evidence for CSF-1R as a therapeutic target in RA.
EVALuna2:12982

Bone Formation in Psoriatic Arthritis: A Report from the GRAPPA 2013 Annual Meeting - Schett, Georg (Journal of Rheumatology, 2014)
The simultaneous presence of bone erosions and bony spurs (osteophytes, enthesophytes) in the joints of patients with psoriatic arthritis (PsA) suggests that the disease leads to enhanced bone resorption as well as increased bone formation, the latter of which has not been observed in patients with rheumatoid arthritis. At the 2013 Annual Meeting of the Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA), members heard an update on the current research into the cytokine signature in PsA and its effects on new bone formation.
EVALuna2:12916

Bone Loss Before Clinical Onset of Rheumatoid Arthritis o Subjects with Anti-Citrullinated Protein Antibodies - Finzel, Stephanie; Lang, Veronika; Kleyer, Arnd; Rech, Jürgen; Manger, Bernhard; Guilhon de Araujo, Elizabeth; Hueber, Axel; Harre, Ulrike; Schett, Georg (2012)
EVALuna2:34465

Bone loss before the clinical onset of rheumatoid arthritis in subjects with anticitrullinated protein antibodies - Kleyer, Arnd; Finzel, Stephanie; Rech, Jürgen; Manger, Bernhard; Krieter, Manuel; Faustini, Francesca; Araujo, Elisabeth; Hueber, Axel; Harre, Ulrike; Engelke, Klaus; Schett, Georg (Annals of the Rheumatic Diseases, 2014)
Anticitrullinated protein antibodies (ACPA) are a major risk factor for bone loss in rheumatoid arthritis (RA). We have recently shown that ACPA directly induce bone loss by stimulating osteoclast differentiation. As ACPA precede the clinical onset of RA by years, we hypothesised that ACPA positive healthy individuals may already show skeletal changes.We performed a comparative micro-CT analysis of the bone microstructure in the metacarpophalangeal joints of ACPA positive and ACPA negative healthy individuals without clinical signs of arthritis.ACPA positive (n=15) and negative (n=15) healthy individuals were not different in age (48.2±4.1 vs 51.4±3.8 years, p=0.57) or gender (eight women and two men in both groups). Bone mineral density was significantly reduced in ACPA positive individuals (mean±SEM 280±11 mg/cm(3)) compared with controls (327±6). Bone loss was based on cortical bone changes, with significant (p=0.044) reduction in cortical thickness in the ACPA positive group (mean±SEM 0.22±0.03 mm) compared with controls (0.32±0.03 mm). Areas of cortical porosity were significantly (p=0.0005) more widespread in ACPA positive (mean±SEM 7.4±1.4%) than in ACPA negative individuals (1.0±0.3%).Structural bone damage starts before the clinical onset of arthritis in subjects with ACPA. These findings revise the concept that bone damage is an exclusive consequence of synovitis in patients with R
EVALuna2:10080

Bone Mass, Bone Microstructure and Biomechanics in Patients with Hand Osteoarthritis - Simon, David; Tascilar, Koray; Unbehend, Sara; Bayat, Sara; Berlin, Andreas; Liphardt, Anna-Maria; Meinderink, Timo; Rech, Jürgen; Hueber, Axel; Schett, Georg; Kleyer, Arnd (Journal of Bone and Mineral Research, 2020)
The impact of primary hand osteoarthritis (HOA) on bone mass, microstructure, and biomechanics in the affected skeletal regions is largely unknown. HOA patients and healthy controls (HCs) underwent high-resolution peripheral quantitative computed tomography (HR-pQCT). We measured total, trabecular, and cortical volumetric bone mineral densities (vBMDs), microstructural attributes, and performed micro–finite element analysis for bone strength. Failure load and scaled multivariate outcome matrices from distal radius and second metacarpal (MCP2) head measurements were analyzed using multiple linear regression adjusting for age, sex, and functional status and reported as adjusted Z-score differences for total and direct effects. A total of 105 subjects were included (76 HC: 46 women, 30 men; 29 HOA: 23 women, six men). After adjustment, HOA was associated with significant changes in the multivariate outcome matrix from the MCP2 head (p <.001) (explained by an increase in cortical vBMD (Δz = 1.07, p =.02) and reduction in the trabecular vBMD (Δz = −0.07, p =.09). Distal radius analysis did not show an overall effect of HOA; however, there was a gender-study group interaction (p =.044) explained by reduced trabecular vBMD in males (Δz = −1.23, p =.02). HOA was associated with lower failure load (−514 N; 95%CI, −1018 to −9; p = 0.05) apparent in males after adjustment for functional status. HOA is associated with reduced trabecular and increased cortical vBMD in the MCP2 head and a reduction in radial trabecular vBMD and bone strength in males. Further investigations of gender-specific changes of bone architecture in HOA are warranted. © 2020 The Authors. Journal of Bone and Mineral Research published by American Society for Bone and Mineral Research.
CRIS-Team Scopus Importer:2020-06-09
Keywords: ANALYSIS/QUANTITATION OF BONE; BIOMECHANICS; BONE QCT/MICROCT; DISEASES AND DISORDERS OF/RELATED TO BONE; ORTHOPAEDICS; OSTEOARTHRITIS

Bone microstructure and volumetric bone mineral density in patients with hyperuricemia with and without psoriasis - Simon, David; Haschka, J.; Muschitz, C.; Kocijan, A.; Baierl, A.; Kleyer, Arnd; Schett, Georg; Kapiotis, S.; Resch, H.; Sticherling, Michael; Rech, Jürgen; Kocijan, R. (Osteoporosis international, 2020)
Summary: We analyzed volumetric bone mineral density (vBMD) and bone microstructure using HR-pQCT in subjects with normouricemia (NU) and subjects with hyperuricemia (HU) with and without psoriasis (PSO). HU was associated with higher cortical vBMD and thickness. Differences in average and trabecular vBMD were found between patients with PSO + HU and NU. Introduction: Hyperuricemia (HU) and gout are co-conditions of psoriasis and psoriatic arthritis. Current data suggest a positive association between HU and areal bone mineral density (BMD) and a negative influence of psoriasis on local bone, even in the absence of arthritis. However, the influence of the combination of HU and psoriasis on bone is still unclear. The aim of this study was to assess the impact of HU with and without psoriasis on bone microstructure and volumetric BMD (vBMD). Methods: Healthy individuals with uric acid levels within the normal range (NU), with hyperuricemia (HU), patients with hyperuricemia and psoriasis (PSO + HU), and patients with uric acid within the normal range and psoriasis (PSO + NU) were included in our study. Psoriasis patients had no current or past symptoms of arthritis. Average, trabecular, and cortical vBMD (mgHA/cm3); trabecular number (Tb.N, 1/mm) and thickness (Tb.Th, mm); inhomogeneity of the network (1/N.SD, mm); and cortical thickness (Ct.Th., mm) were carried out at the ultradistal radius using high-resolution peripheral quantitative computed tomography. In addition, bone turnover markers such as DKK-1, sclerostin, and P1NP were analyzed. Results: In total, 130 individuals were included (44 NU participants (34% female), 50 HU (24%), 16 PSO + HU (6%), 20 PSO + NU (60%)). Subjects were aged: NU 54.5 (42.8, 62.1), HU 57.5 (18.6, 65.1), PSO + HU 52.0 (42.3, 57.8), and PSO + NU 42.5 (34.8, 56.8), respectively. After adjusting for age, sex, BMI, and diabetes, patients in the HU group revealed significantly higher values of cortical vBMD (p < 0.001) as well as cortical thickness (p = 0.04) compared to the NU group. PSO + NU showed no differences to NU, but PSO + HU demonstrated both lower average (p = 0.03) and trabecular vBMD (p = 0.02). P1NP was associated with average, cortical, and trabecular vBMD as well as cortical thickness while sclerostin levels were related to trabecular vBMD. Conclusion: Hyperuricemia in otherwise healthy subjects was associated with a better cortical vBMD and higher cortical thickness. However, patients with both psoriasis and hyperuricemia revealed a lower vBMD.
CRIS-Team Scopus Importer:2020-01-21
Keywords: Bone Mineral Density; HR-pQCT; Hyperuricemia; Psoriasis

Bone Microstructure Assessed By Hrpqct in Subjects with Hyperuricemia without Arthritis - Kocijan, Roland; Nia, Arastoo; Muschitz, Christian; Simon, David; Geiger, Corinna; Haschka, Judith; Kleyer, Arnd; Bayat, Sara; Rech, Jürgen; Kocijan, Annemarie; Dzirlo, Larissa; Graninger, Monika; et al. (2015)
EVALuna2:13325

Bone Microstructure in Patients with Cutaneous Psoriasis and No History of Psoriatic Arthritis Shows Bone Anabolic Changes at a Greater Extent Than in Healthy Controls - Simon, David; Faustini, Francesca; Englbrecht, Matthias; Kleyer, Arnd; Kocijan, Roland; Haschka, Judith; Finzel, Stephanie; Kraus, Sebastian; Hueber, Axel; Sticherling, Michael; Schett, Georg; Rech, Jürgen (2014)
EVALuna2:13229

Bone Morphogenetic Protein Antagonist Gremlin-1 Increases Myofibroblast Transition in Dermal Fibroblasts: Implications for Systemic Sclerosis - Duffy, Laura; Henderson, John; Brown, Max; Pryzborski, Stefan; Fullard, Nicola; Summa, Lena; Distler, Jörg; Stratton, Richard; O'Reilly, Steven (Frontiers in Cell and Developmental Biology, 2021)
Objective: Systemic Sclerosis is an autoimmune connective tissue disease which results in fibrosis of the skin and lungs. The disease is characterized by activation of myofibroblasts but what governs this is unknown. Gremlin-1 is a BMP antagonist that is developmentally regulated and we sought to investigate its role in Systemic Sclerosis. Methods: Dermal fibroblasts were transfected with Grem1pcDNA3.1 expression vectors or empty vectors. Various markers of myofibroblasts were measured at the mRNA and protein levels. Scratch wound assays were also performed. Media Transfer experiments were performed to evaluate cytokine like effects. Various inhibitors of TGF-β signaling and MAPK signaling were used post-transfection. siRNA to Gremlin-1 in SSc dermal fibroblasts were performed to evaluate the role of Gremlin-1. Different cytokines were incubated with fibroblasts and Gremlin-1 measured. Bleomycin was used as model of fibrosis and immunohistochemistry performed. Results: Overexpression of Gremlin-1 was achieved in primary dermal fibroblasts and lead to activation of quiescent cells to myofibroblasts indicated by collagen and α-Smooth muscle actin. Overexpression also led to functional effects. This was associated with increased TGF-β1 levels and SBE luciferase activity but not increased Thrombospondin-1 expression. Inhibition of Gremlin-1 overexpression cells with antibodies to TGF-β1 but not isotype controls led to reduced collagen and various TGF-β pathway chemical inhibitors also led to reduced collagen levels. In SSc cells siRNA mediated reduction of Gremlin-1 reduced collagen expression and CTGF gene and protein levels in these cells. IL-13 did not lead to elevated Gremlin-1 expression nor did IL-11. Gremlin-1 was elevated in an animal model of fibrosis compared to NaCl-treated mice. Conclusion: Gremlin-1 is a key regulator of myofibroblast transition leading to enhanced ECM deposition. Strategies that block Gremlin-1 maybe a possible therapeutic target in fibrotic diseases such as SSc.
CRIS-Team Scopus Importer:2021-07-02
Keywords: BMP; collagen; ECM; fibrosis; gremlin-1

Brain fMRI Predicts Responses to Certolizumab Pegol in RA. an International, Multi-center, Randomized, Double-blind, Placebocontrolled Trial (PreCePRA) - Rech, Jürgen; Schenker, Hannah; Tascilar, Koray; Hagen, Melanie; Kleyer, Arnd; Simon, David; Mendez, Larissa Valor; Schoenau, Verena; Prade, Jutta; Sergeeva, Marina; Sulvakumar, Mageshvar; Strobelt, Sandra; et al. (ARTHRITIS & RHEUMATOLOGY, 2020)
CRIS-Team WoS Importer:2021-01-15

Brief Report: IRF4 Newly Identified as a Common Susceptibility Locus for Systemic Sclerosis and Rheumatoid Arthritis in a Cross-Disease Meta-Analysis of Genome-Wide Association Studies - Lopez-Isac, Elena; Martin, Jose-Ezequiel; Assassi, Shervin; Simeon, Carmen P.; Carreira, Patricia; Ortego-Centeno, Norberto; Freire, Mayka; Beltran, Emma; Narvaez, Javier; Alegre-Sancho, Juan J.; Fernandez-Gutierrez, Benjamin; Balsa, Alejandro; et al. (Arthritis and Rheumatology, 2016)
Systemic sclerosis (SSc) and rheumatoid arthritis (RA) are autoimmune diseases that have similar clinical and immunologic characteristics. To date, several shared SSc-RA genetic loci have been identified independently. The aim of the current study was to systematically search for new common SSc-RA loci through an interdisease meta-genome-wide association (meta-GWAS) strategy.The study was designed as a meta-analysis combining GWAS data sets of patients with SSc and patients with RA, using a strategy that allowed identification of loci with both same-direction and opposite-direction allelic effects. The top single-nucleotide polymorphisms were followed up in independent SSc and RA case-control cohorts. This allowed an increase in the sample size to a total of 8,830 patients with SSc, 16,870 patients with RA, and 43,393 healthy controls.This cross-disease meta-analysis of the GWAS data sets identified several loci with nominal association signals (P < 5 × 10(-6) ) that also showed evidence of association in the disease-specific GWAS scans. These loci included several genomic regions not previously reported as shared loci, as well as several risk factors that were previously found to be associated with both diseases. Follow-up analyses of the putatively new SSc-RA loci identified IRF4 as a shared risk factor for these 2 diseases (Pcombined = 3.29 × 10(-12) ). Analysis of the biologic relevance of the known SSc-RA shared loci identified the type I interferon and interleukin-12 signaling pathways as the main common etiologic factors.This study identified a novel shared locus, IRF4, for the risk of SSc and RA, and highlighted the usefulness of a cross-disease GWAS meta-analysis strategy in the identification of common risk loci.
EVALuna2:13279

Brief Report: Tumor Necrosis Factor and Interleukin-6 Differentially Regulate Dkk-1 in the Inflamed Arthritic Joint - Yeremenko, Nataliya; Zwerina, Karin; Rigter, Gemma; Pots, Desiree; Fonseca, Joao E.; Zwerina, Jochen; Schett, Georg; Baeten, Dominique (Arthritis and Rheumatology, 2015)
Tumor necrosis factor (TNF) drives bone destruction, but it also inhibits new bone formation by inducing Dkk-1, an inhibitor of the Wnt pathway. Accordingly, blocking of Dkk-1 reverses the phenotype in experimental arthritis from a pattern of bone destruction to a pattern of bone formation. To delineate the potential role of Dkk-1 in the structural phenotype of human arthritis, we analyzed the expression of Dkk-1 and its regulation by proinflammatory cytokines in the inflamed peripheral joints of patients with spondyloarthritis (SpA) and rheumatoid arthritis (RA).Expression of Dkk-1 and proinflammatory cytokines was determined by enzyme-linked immunosorbent assay and microarray analysis in synovial fluid (SF) and synovial tissue, respectively. Regulation of Dkk-1 production by proinflammatory cytokines was assessed in fibroblast-like synoviocyte (FLS) cultures.TNF and interleukin-1? (IL-1?) levels, were higher in RA SF than in SpA SF (P < 0.001 for both), whereas levels of IL-6 were not. Levels of Dkk-1 were similar in SpA SF and RA SF and were not correlated with TNF and IL-1? levels. However, Dkk-1 levels showed an inverse correlation with IL-6 levels in both SpA SF (r = -0.31, P = 0.04) and RA SF (r = -0.39, P = 0.01); this result was reproduced at the messenger RNA level in synovial tissue. In vitro experiments with FLS confirmed that Dkk-1 production was strongly induced by TNF but clearly suppressed by IL-6. Moreover, IL-6 was able to suppress the TNF-induced up-regulation of Dkk-1 production by FLS.The inverse correlation of Dkk-1 levels with IL-6 levels observed in vivo in the inflamed joints was mirrored by the differential regulation of Dkk-1 production by TNF and IL-6 in vitro. The relative balance between these and other factors in the arthritic joints may determine functional Wnt signaling and tissue remodeling.
EVALuna2:13134

Btn2a2 Regulates ILC2-T Cell Cross Talk in Type 2 Immune Responses - Frech, Michael; Omata, Yasunori; Schmalzl, Angelika; Wirtz, Stefan; Taher, Leila; Schett, Georg; Zaiss, Mario; Sarter, Kerstin (Frontiers in Immunology, 2022)
Innate lymphoid cells (ILC) not only are responsible for shaping the innate immune response but also actively modulate T cell responses. However, the molecular processes regulating ILC-T cell interaction are not yet completely understood. The protein butyrophilin 2a2 (Btn2a2), a co-stimulatory molecule first identified on antigen-presenting cells, has a pivotal role in the maintenance of T cell homeostasis, but the main effector cell and the respective ligands remain elusive. We analyzed the role of Btn2a2 in the ILC-T cell cross talk. We found that the expression of Btn2a2 is upregulated in ILC2 following stimulation with IL-33/IL-25/TSLP. In vitro and in vivo experiments indicated that lack of Btn2a2 expression on ILC2 resulted in elevated T cell responses. We observed an enhanced proliferation of T cells as well as increased secretion of the type 2 cytokines IL-4/IL-5/IL-13 following cocultures with Btn2a2-deficient ILC2. In vivo transfer experiments confirmed the regulatory role of Btn2a2 on ILC2 as Btn2a2-deficient ILC2 induced stronger T cell responses and prevented chronic helminth infections. Taken together, we identified Btn2a2 as a significant player in the regulation of ILC2-T cell interactions.
CRIS-Team WoS Importer:2022-02-18