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.
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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.

2021 GRAPPA Trainee Symposium: A Summary of Oral and Poster Presentations - Armstrong, April W.; Reddy, Rasika M.; Colaco, Keith; Diaz, Pamela A.; Kaur, Raminderjit; Simon, David; Vecellio, Matteo; Husni, M. Elaine (Journal of Rheumatology, 2022)
The Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA) held a trainee symposium at its 2021 virtual meeting. Dermatology and rheumatology trainees presented their work on psoriasis and psoriatic arthritis (PsA). This report briefly reviews 5 oral presentations: prediction of cardiovascular events in psoriatic disease (PsD), correlation between spine abnormalities and clinical findings, biomechanical stress as a trigger for PsA, differences in DNA methylation among twins with PsD, and critical proteins associated with induction of PsD. In addition, we highlight 22 posters broadly discussing clinical and molecular implications of PsD.
CRIS-Team WoS Importer:2022-12-30

2022 American College of Rheumatology/European Alliance of Associations for Rheumatology classification criteria sets for three types of antineutrophilic cytoplasmic antibody-associated vasculitis - Yazici, Hasan; Tascilar, Koray; Yazici, Yusuf (Current Opinion in Rheumatology, 2023)
Purpose of reviewA critique of the recently published classification criteria for three main types of antineutrophilic cytoplasmic antibody (ANCA)-associated vasculitis.Recent findingsAn ACR and EULAR joint task force recently published classification criteria for three main types of ANCA-associated vasculitis. The criteria were based on patient histories and findings in nearly 7000 patients from 136 sites in 32 countries. As such the study represented hitherto the most intensive attempt to prepare classification criteria vasculitis. We propose, this truly intensive effort was, unfortunately, unsuccessful. There were two main mishaps. The first one was that the proposed criteria were not validated in an independent cohort. This is curious in that the sponsors, ACR and EULAR, require such independent cohorts for validation. The second mishap is that the concept that disease classification criteria need to be 100% sensitive and specific for a diagnosis is unrealistic. Moreover, all-purpose disease classification criteria are not respectful to scientific research and to the probabilistic nature of the art and the science of medicine.SummaryThe new ACR/EULAR ANCA-associated vasculitis guidelines have not been validated in independent cohorts. We propose replacing the term disease criteria with disease guidelines.
CRIS-Team Scopus Importer:2023-01-06
Keywords: ANCA-associated vasculitis; classification; criteria; guidelines; validation

2022 EULAR points to consider for remote care in rheumatic and musculoskeletal diseases - De Thurah, Annette; Bosch, Philipp; Marques, Andrea; Meissner, Yvette; Mukhtyar, Chetan B.; Knitza, Johannes; Najm, Aurelie; Osteras, Nina; Pelle, Tim; Knudsen, Line Raunsbaek; Smucrova, Hana; Berenbaum, Francis; et al. (Annals of the Rheumatic Diseases, 2022)
Background Remote care and telehealth have the potential to expand healthcare access, and the COVID-19 pandemic has called for alternative solutions to conventional face-to-face follow-up and monitoring. However, guidance is needed on the integration of telehealth into clinical care of people with rheumatic and musculoskeletal diseases (RMD). Objective To develop EULAR points to consider (PtC) for the development, prioritisation and implementation of telehealth for people with RMD. Methods A multidisciplinary EULAR task force (TF) of 30 members from 14 European countries was established, and the EULAR standardised operating procedures for development of PtC were followed. A systematic literature review was conducted to support the TF in formulating the PtC. The level of agreement among the TF was established by anonymous online voting. Results Four overarching principles and nine PtC were formulated. The use of telehealth should be tailored to patient's needs and preferences. The healthcare team should have adequate equipment and training and have telecommunication skills. Telehealth can be used in screening for RMD as preassessment in the referral process, for disease monitoring and regulation of medication dosages and in some non-pharmacological interventions. People with RMD should be offered training in using telehealth, and barriers should be resolved whenever possible. The level of agreement to each statement ranged from 8.5 to 9.8/10. Conclusion The PtC have identified areas where telehealth could improve quality of care and increase healthcare access. Knowing about drivers and barriers of telehealth is a prerequisite to successfully establish remote care approaches in rheumatologic clinical practice.
CRIS-Team WoS Importer:2022-05-13

2023 EULAR recommendations on imaging in diagnosis and management of crystal-induced arthropathies in clinical practice - Mandl, Peter; D'Agostino, Maria Antonietta; Navarro-Compán, Victoria; Geßl, Irina; Sakellariou, Garifallia; Abhishek, Abhishek; Becce, Fabio; Dalbeth, Nicola; Ea, Hang Korng; Filippucci, Emilio; Hammer, Hilde Berner; Iagnocco, Annamaria; et al. (Annals of the Rheumatic Diseases, 2024)
Objective: To formulate evidence-based recommendations and overarching principles on the use of imaging in the clinical management of crystal-induced arthropathies (CiAs). Methods: An international task force of 25 rheumatologists, radiologists, methodologists, healthcare professionals and patient research partners from 11 countries was formed according to the EULAR standard operating procedures. Fourteen key questions on the role of imaging in the most common forms of CiA were generated. The CiA assessed included gout, calcium pyrophosphate deposition disease and basic calcium phosphate deposition disease. Imaging modalities included conventional radiography, ultrasound, CT and MRI. Experts applied research evidence obtained from four systematic literature reviews using MEDLINE, EMBASE and CENTRAL. Task force members provided level of agreement (LoA) anonymously by using a Numerical Rating Scale from 0 to 10. Results: Five overarching principles and 10 recommendations were developed encompassing the role of imaging in various aspects of patient management: making a diagnosis of CiA, monitoring inflammation and damage, predicting outcome, response to treatment, guided interventions and patient education. Overall, the LoA for the recommendations was high (8.46-9.92). Conclusions: These are the first recommendations that encompass the major forms of CiA and guide the use of common imaging modalities in this disease group in clinical practice.
CRIS-Team Scopus Importer:2024-02-23
Keywords: Crystal arthropathies; Magnetic Resonance Imaging; Ultrasonography

3Dscript: animating 3D/4D microscopy data using a natural-language-based syntax - Schmid, Benjamin; Tripal, Philipp; Fraaß, Tina; Kersten, Christina; Ruder, Barbara; Grüneboom, Anika; Huisken, Jan; Palmisano, Ralf (Nature Methods, 2019)
CRIS-Team WoS Importer:2019-04-09

3-years Safety and Efficacy Outcomes of Canakinumab Treatment in Cryopyrin-associated Periodic Syndromes (CAPS) - Data from the RELIANCE Registry - Kuemmerle-Deschner, Jasmin B.; Kortus-Goetze, Birgit; Oommen, Prasad T.; Janda, Ales; Rech, Jürgen; Schuetz, Catharina; Kallinich, Tilmann; Weller-Heinemann, Frank; Horneff, Gerd; Foeldvari, Ivan; Meier, Florian; Borte, Michael; et al. (ARTHRITIS & RHEUMATOLOGY, 2022)
CRIS-Team WoS Importer:2023-01-13

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

68/m mit schmerzhaftem und geschwollenem Fuß: Vorbereitung auf die Facharztprüfung: Fall 89 - Hagen, Melanie (Internist, 2021)
CRIS-Team Scopus Importer:2021-09-17

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

A 17-kDa Fragment of Lactoferrin Associates With the Termination of Inflammation and Peptides Within Promote Resolution - Lutaty, Aviv; Soboh, Soaad; Schif-Zuck, Sagie; Zeituni-Timor, Orly; Rostoker, Ran; Podolska, Malgorzata; Herrmann, Martin; Munoz, Luis Enrique; Ariel, Amiram; Schauer, Christine (Frontiers in Immunology, 2018)
During the resolution of inflammation, macrophages engulf apoptotic polymorphonuclear cells (PMN) and can accumulate large numbers of their corpses. Here, we report that resolution phase macrophages acquire the neutrophil-derived glycoprotein lactoferrin (Lf) and fragments thereof in vivo and ex vivo. During the onset and resolving phases of inflammation in murine peritonitis and bovine mastitis, Lf fragments of 15 and 17 kDa occurred in various body fluids, and the murine fragmentation, accumulation, and release were mediated initially by neutrophils and later by efferocytic macrophages. The 17-kDa fragment contained two bioactive tripeptides, FKD and FKE that promoted resolution phase macrophage conversion to a pro-resolving phenotype. This resulted in a reduction in peritoneal macrophage numbers and an increase in the CD11b(low) subset of these cells. Moreover, FKE, but not FKD, peptides enhanced efferocytosis of apoptotic PMN, reduced TNF alpha and interleukin (IL)-6, and increased IL-10 secretion by lipopolysaccharide-stimulated macrophages ex vivo. In addition, FKE promoted neutrophil-mediated resolution at high concentrations (100 mu M) by enhancing the formation of cytokine-scavenging aggregated NETs (tophi) at a low cellular density. Thus, PMN Lf is processed, acquired, and "recycled" by neutrophils and macrophages during inflammation resolution to generate fragments and peptides with paramount pro-resolving activities.
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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

A Barcoded Flow Cytometric Assay to Explore the Antibody Responses Against SARS-CoV-2 Spike and Its Variants - Vesper, Niklas; Ortiz, Yaneth; Bartels-Burgahn, Frauke; Yang, Jianying; De La Rosa, Kathrin; Tenbusch, Matthias; Schulz, Sebastian; Finzel, Stephanie; Jäck, Hans-Martin; Eibel, Hermann; Voll, Reinhard E.; Reth, Michael (Frontiers in Immunology, 2021)
The SARS-CoV-2 pandemic has spread to all parts of the world and can cause life-threatening pneumonia and other severe disease manifestations known as COVID-19. This health crisis has resulted in a significant effort to stop the spread of this new coronavirus. However, while propagating itself in the human population, the virus accumulates mutations and generates new variants with increased fitness and the ability to escape the human immune response. Here we describe a color-based barcoded spike flow cytometric assay (BSFA) that is particularly useful to evaluate and directly compare the humoral immune response directed against either wild type (WT) or mutant spike (S) proteins or the receptor-binding domains (RBD) of SARS-CoV-2. This assay employs the human B lymphoma cell line Ramos, transfected for stable expression of WT or mutant S proteins or a chimeric RBD-CD8 fusion protein. We find that the alpha and beta mutants are more stably expressed than the WT S protein on the Ramos B cell surface and/or bind with higher affinity to the viral entry receptor ACE2. However, we find a reduce expression of the chimeric RBD-CD8 carrying the point mutation N501Y and E484K characteristic for the alpha and beta variant, respectively. The comparison of the humoral immune response of 12 vaccinated probands with 12 COVID-19 patients shows that after the boost, the S-specific IgG class immune response in the vaccinated group is similar to that of the patient group. However, in comparison to WT the specific IgG serum antibodies bind less well to the alpha variant and only poorly to the beta variant S protein. This is in line with the notion that the beta variant is an immune escape variant of SARS-CoV-2. The IgA class immune response was more variable than the IgG response and higher in the COVID-19 patients than in the vaccinated group. In summary, we think that our BSFA represents a useful tool to evaluate the humoral immunity against emerging variants of SARS-CoV-2 and to analyze new vaccination protocols against these variants.
CRIS-Team Scopus Importer:2021-10-22
Keywords: coronavirus; COVID-19; flow cytometry; humoral immunity; RBD; SARS-CoV-2; spike protein; virus variants

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 inhibits inflammation and onset of rheumatoid arthritis in individuals at high risk (ARIAA): a randomised, international, multicentre, double-blind, placebo-controlled trial - Rech, Jürgen; Tascilar, Koray; Hagen, Melanie; Kleyer, Arnd; Manger, Bernhard; Schönau, Verena; Hueber, Axel; Kleinert, Stefan; Baraliakos, Xenofon; Braun, Jürgen; Kiltz, Uta; Fleck, Martin; et al. (Lancet, 2024)
Background: Individuals with anti-citrullinated protein antibodies (ACPAs) and subclinical inflammatory changes in joints are at high risk of developing rheumatoid arthritis. Treatment strategies to intercept this pre-stage clinical disease remain to be developed. We aimed to assess whether 6-month treatment with abatacept improves inflammation in preclinical rheumatoid arthritis. Methods: The abatacept reversing subclinical inflammation as measured by MRI in ACPA positive arthralgia (ARIAA) study is a randomised, international, multicentre, double-blind, placebo-controlled trial done in 14 hospitals and community centres across Europe (11 in Germany, two in Spain, and one in the Czech Republic). Adults (aged ≥18 years) with ACPA positivity, joint pain (but no swelling), and signs of osteitis, synovitis, or tenosynovitis in hand MRI were randomly assigned (1:1) to weekly subcutaneous abatacept 125 mg or placebo for 6 months followed by a double-blind, drug-free, observation phase for 12 months. The primary outcome was the proportion of participants with any reduction in inflammatory MRI lesions at 6 months. The primary efficacy analysis was done in the modified intention-to-treat population, which included participants who were randomly assigned and received study medication. Safety analyses were conducted in participants who received the study medication and had at least one post-baseline observation. The study was registered with the EUDRA-CT (2014–000555–93). Findings: Between Nov 6, 2014, and June 15, 2021, 139 participants were screened. Of 100 participants, 50 were randomly assigned to abatacept 125 mg and 50 to placebo. Two participants (one from each group) were excluded due to administration failure or refusing treatment; thus, 98 were included in the modified intention-to-treat population. 70 (71%) of 98 participants were female and 28 (29%) of 98 were male. At 6 months, 28 (57%) of 49 participants in the abatacept group and 15 (31%) of 49 participants in the placebo group showed improvement in MRI subclinical inflammation (absolute difference 26·5%, 95% CI 5·9–45·6; p=0·014). Four (8%) of 49 participants in the abatacept group and 17 (35%) of 49 participants in the placebo group developed rheumatoid arthritis (hazard ratio [HR] 0·14 [0·04–0·47]; p=0·0016). Improvement of MRI inflammation (25 [51%] of 49 participants in the abatacept group, 12 [24%] of 49 in the placebo group; p=0·012) and progression to rheumatoid arthritis (17 [35%] of 49, 28 [57%] of 49; HR 0·14 [0·04–0·47]; p=0·018) remained significantly different between the two groups after 18 months, 12 months after the end of the intervention. There were 12 serious adverse events in 11 participants (four [8%] of 48 in the abatacept group and 7 [14%] of 49 in the placebo group). No deaths occurred during the study. Interpretation: 6-month treatment with abatacept decreases MRI inflammation, clinical symptoms, and risk of rheumatoid arthritis development in participants at high risk. The effects of the intervention persist through a 1-year drug-free observation phase. Funding: Innovative Medicine Initiative.
CRIS-Team Scopus Importer:2024-02-23

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

Abatacept used in combination with non-methotrexate disease-modifying antirheumatic drugs: a descriptive analysis of data from interventional trials and the real-world setting - Alten, Rieke; Burkhardt, Harald; Feist, Eugen; Krüger, Klaus; Rech, Jürgen; Rubbert-Roth, Andrea; Voll, Reinhard E.; Elbez, Yedid; Rauch, Christiane (Arthritis Research & Therapy, 2018)
Methotrexate (MTX) remains the anchor drug in rheumatoid arthritis (RA) treatment, but is poorly tolerated or contraindicated in some patients. There is a wealth of data supporting the use of abatacept in combination with MTX, but data on alternative conventional synthetic disease-modifying antirheumatic drug (csDMARD) combinations with abatacept are scarce.In this post-hoc exploratory analysis, efficacy and safety data were extracted from abatacept RA studies in which combination with csDMARDs other than MTX was permitted: three interventional trials (ATTAIN, ASSURE, and ARRIVE) and one real-world study (ACTION). Patients with moderate-to-severe RA received abatacept in combination with MTX, hydroxychloroquine, sulfasalazine, azathioprine, or leflunomide for 6 months to 2 years according to the study design. Change from baseline in physical function (Health Assessment Questionnaire-Disability Index (HAQ-DI); all studies) and 28-joint Disease Activity Score (C-reactive protein) (DAS28 (CRP); ATTAIN, ARRIVE, and ACTION), American College of Rheumatology response rates (ATTAIN), and safety were assessed for individual and pooled csDMARD combinations for each trial. A meta-analysis was also performed on pooled data for HAQ-DI and DAS28 (CRP) across interventional trials.Across all four studies, 731 patients received abatacept plus one non-MTX csDMARD (hydroxychloroquine n = 152; sulfasalazine n = 123; azathioprine n = 59; and leflunomide n = 397) and 2382 patients received abatacept plus MTX. Mean changes from baseline in HAQ-DI scores for abatacept plus MTX (all csDMARDs pooled) vs abatacept plus a non-MTX csDMARD were -0.54 vs -0.44 (ATTAIN), -0.43 vs -0.43 (ASSURE), and -0.39 vs -0.36 (ARRIVE). Mean changes from baseline in DAS28 (CRP) and ACR response rates were also similar with abatacept plus MTX or non-MTX csDMARDs. Data for individual non-MTX csDMARDs (pooled across studies) and real-world data were consistent with these findings. Rates of treatment-related adverse events and serious adverse events, respectively, for abatacept plus one non-MTX csDMARD vs abatacept plus MTX were 35.7% vs 41.7% and 2.4% vs 2.3% (ATTAIN), 58.0% vs 55.9% and 4.2% vs 1.7% (ASSURE), and 38.1% vs 44.3% and 0.6% vs 2.9% (ARRIVE).Abatacept in combination with non-MTX csDMARDs is clinically effective and well tolerated in patients with moderate-to-severe RA, providing similar benefits to those seen with abatacept plus MTX.ClinicalTrials.gov NCT00048581 . Registered 2 November 2002. ClinicalTrials.gov NCT00048932 . Registered 11 November 2002. ClinicalTrials.gov NCT00124982 . Registered 30 June 2005. ClinicalTrials.gov NCT02109666 . Registered 8 April 2014.
EVALuna2:13528

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

Acceptance of telerheumatology by rheumatologists and general practitioners in Germany: Nationwide cross-sectional survey study - Muehlensiepen, Felix; Knitza, Johannes; Marquardt, Wenke; Engler, Jennifer; Hueber, Axel; Welcker, Martin (Journal of Medical Internet Research, 2021)
Background: The worldwide burden of musculoskeletal diseases is increasing. The number of newly registered rheumatologists has stagnated. Primary care, which takes up a key role in early detection of rheumatic disease, is working at full capacity. COVID-19 and its containment impede rheumatological treatment. Telemedicine in rheumatology (telerheumatology) could support rheumatologists and general practitioners. Objective: The goal of this study was to investigate acceptance and preferences related to the use of telerheumatology care among German rheumatologists and general practitioners. Methods: A nationwide, cross-sectional, self-completed, paper-based survey on telerheumatology care was conducted among outpatient rheumatologists and general practitioners during the pre-COVID-19 period. Results: A total of 73.3% (349/476) of survey participants rated their knowledge of telemedicine as unsatisfactory, poor, or very poor. The majority of survey participants (358/480, 74.6%) answered that they do not currently use telemedicine, although 62.3% (291/467) would like to. Barriers to the implementation of telemedicine include the purchase of technology equipment (182/292, 62.3%), administration (181/292, 62.0%), and poor reimbursement (156/292, 53.4%). A total of 69.6% (117/168) of the surveyed physicians reckoned that telemedicine could be used in rheumatology. Surveyed physicians would prefer to use telemedicine to communicate directly with other physicians (370/455, 81.3%) than to communicate with patients (213/455, 46.8%). Among treatment phases, 64.4% (291/452) of participants would choose to use telemedicine during follow-up. Half of the participants would choose telecounseling as a specific approach to improve rheumatology care (91/170, 53.5%). Conclusions: Before COVID-19 appeared, our results indicated generally low use but high acceptance of the implementation of telerheumatology among physicians. Participants indicated that the lack of a structural framework was a barrier to the effective implementation of telerheumatology. Training courses should be introduced to address the limited knowledge on the part of physicians in the use of telemedicine. More research into telerheumatology is required. This includes large-scale randomized controlled trials, economic analyses, and the exploration of user preferences.
CRIS-Team Scopus Importer:2021-04-16
Keywords: COVID-19; EHealth; Health services research; MHealth; Primary care; Rheumatology; Telemedicine

Acceptance, Usage, and Barriers of Electronic Patient-Reported Outcomes Among German Rheumatologists: Survey Study - Krusche, Martin; Klemm, Philipp; Grahammer, Manuel; Mucke, Johanna; Vossen, Diana; Kleyer, Arnd; Sewerin, Philipp; Knitza, Johannes (JMIR mHealth and uHealth, 2020)
BACKGROUND: The use of patient-reported outcomes (PROs) allows for patient-centered, measurable, and transparent care. Electronic PROs (ePROs) have many benefits and hold great potential to improve current usage of PROs, yet limited evidence exists regarding their acceptance, usage, and barriers among rheumatologists. OBJECTIVE: This study aims to evaluate the current level of acceptance, usage, and barriers among German rheumatologists regarding the use of ePROs. The importance of different ePRO features for rheumatologists was investigated. Additionally, the most frequently used PROs for patients with rheumatoid arthritis (RA) were identified. METHODS: Data were collected via an online survey consisting of 18 questions. The survey was completed by members of the Working Group Young Rheumatology of the German Society for Rheumatology (Arbeitsgemeinschaft Junge Rheumatologie der Deutschen Gesellschaft für Rheumatologie [DGRh]) at the 2019 annual DGRh conference. Only members currently working in clinical adult rheumatology were eligible to complete the survey. RESULTS: A total of 119 rheumatologists completed the survey, of which 107 (89.9%) reported collecting PROs in routine practice and 28 (25.5%) already used ePROs. Additionally, 44% (43/97) were planning to switch to ePROs in the near future. The most commonly cited reason for not switching was the unawareness of suitable software solutions. Respondents were asked to rate the features of ePROs on a scale of 0 to 100 (0=unimportant, 100=important). The most important features were automatic score calculation and display (mean 77.50) and simple data transfer to medical reports (mean 76.90). When asked about PROs in RA, the respondents listed pain, morning stiffness, and patient global assessment as the most frequently used PROs. CONCLUSIONS: The potential of ePROs is widely seen and there is great interest in them. Despite this, only a minority of physicians use ePROs, and the main reason for not implementing them was cited as the unawareness of suitable software solutions. Developers, patients, and rheumatologists should work closely together to help realize the full potential of ePROs and ensure a seamless integration into clinical practice.
CRIS-Team Scopus Importer:2020-08-07
Keywords: eHealth; electronic patient-reported outcome measures; mobile phone; patient perspective; rheumatoid arthritis; rheumatology

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 of prospectively ECG-triggered very low-dose coronary dual-source CT angiography using iterative reconstruction for the detection of coronary artery stenosis: comparison with invasive catheterization - Layritz, Christian; Schmid, Julia; Achenbach, Stephan; Ulzheimer, Stefan; Wüst, Wolfgang; May, Matthias; Ropers, Dieter; Klinghammer, Lutz; Daniel, Werner; Pflederer, Tobias; Lell, Michael (European Heart Journal - Cardiovascular Imaging, 2014)
To evaluate the image quality and diagnostic accuracy of very low-dose computed tomography (CT) angiography (CTA) for the evaluation of coronary artery stenosis.Iterative reconstruction (IR) has shown to substantially reduce image noise and hence permit the use of very low-dose data acquisition protocols in coronary CTA.Fifty symptomatic patients with an intermediate likelihood for coronary artery disease underwent coronary CTA (heart rate: 59 ± 5 bpm, prospectively ECG-triggered axial acquisition, 100 kV, 160 mAs, 2 × 128 × 0.6 mm collimation, 60 mL contrast, 6 mL/s) prior to invasive coronary angiography. CTA images were reconstructed using both standard filtered back projection (FBP) and a raw data-based IR algorithm [Sinogram Affirmed Iterative Reconstruction (SAFIRE), Siemens Healthcare]. Subjective image quality (four-point Likert scale from 0 = non-diagnostic to 3 = excellent image quality), image noise, signal-to-noise ratio (SNR), contrast-to-noise ratio (CNR), as well as the presence of coronary stenosis >50% were independently determined by two observers.The mean dose-length product was 46.8 ± 3.5 mGy cm (estimated effective dose 0.66 ± 0.05 mSv). IR led to significantly improved objective image quality compared with FBP (image noise: 41 ± 12 vs. 49 ± 11 HU, P < 0.0001; CNR: 16 ± 8 vs. 12 ± 4, P < 0.0001; SNR: 13 ± 7 vs. 10 ± 3, P < 0.0001). Four coronary segments were not evaluable on FBP data, whereas all segments showed diagnostic image quality with IR. To detect significant coronary stenosis, sensitivity, specificity, positive predictive value, and negative predictive value were 69% (11/16), 97% (175/180), 69% (11/16), and 97% (175/180) per vessel with FBP data sets, respectively. With IR data sets, the corresponding values were 81% (13/16), 97% (178/184), 68% (13/19), and 98% (178/181). These differences were not statistically significant (P = 0.617).Raw data-based IR significantly improves image quality in very low-dose prospectively ECG-triggered coronary dual-source CTA when compared with standard reconstruction using FBP.
EVALuna2:11955

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

Acetylated histones contribute to the immunostimulatory potential of neutrophil extracellular traps in systemic lupus erythematosus - Pieterse, Elmar; Hofstra, Julia; Berden, J.; Herrmann, Martin; Dieker, Jurgen; Van Der Vlag, Johan (Clinical and Experimental Immunology, 2015)
In addition to disturbed apoptosis and insufficient clearance of apoptotic cells, there is recent evidence for a role of neutrophils in the aetiopathogenesis of systemic lupus erythematosus (SLE). In response to various stimuli, neutrophils can rapidly release DNA fibres decorated with citrullinated histones and anti-microbial peptides. These structures are referred to as neutrophil extracellular traps (NETs). In addition to apoptotic cell-derived microparticles, these NETs may comprise a further source of autoantigens, able to drive the autoimmune response in SLE. Our group recently identified specific histone modifications occurring during apoptosis that play an important role in the autoimmune response in SLE. In the current study, we evaluated the presence and immunostimulatory potential of these previously identified histone modifications in NETs. Compared to NETs from healthy donors, the histones present in NETs formed by SLE-derived neutrophils contain increased amounts of acetylated and methylated residues, which we previously observed to be associated with apoptosis and SLE. Treatment of neutrophils with histone deacetylase (HDAC) inhibitor Trichostatin A (TSA), prior to induction of NETosis, induced NETs containing hyperacetylated histones, endowed with an increased capacity to activate macrophages. This implies that specific histone modifications, in particular acetylation, might enhance the immunostimulatory potential of NETs in SLE.
EVALuna2:13096

A closed ecological system in a space experiment - Strauch, Sebastian; Schuster, Martin; Lebert, Michael; Richter, Peter; Schmittnägel, Martina; Häder, Donat-Peter (Life in Space for Life on Earth, 2008)
The Russian FOTON-M3 mission, a satellite for midlength experiments in space and recovery afterwards,included a closed artificial ecosystem (OMEGAHAB for Oreochromis Mossambicus-Euglena Gracilis-Aquatic HABitat) with the photosynthetic flagellate Euglena gracilis as oxygen producer and larvae of Oreochromis mossambicus, a Tilapia species, as consumer. During the 12-day orbital flight the algae were observed 10 minutes per day by means of a miniaturized microscope to analyse their swimming behavior. The fishes were also filmed to monitor their development and movement. An identical experiment was carried out as ground control. A data downlink provided the measured temperature values of he space experiment every day to readjust the temperature of the ground reference in order to eliminate the influence of the different temperature on the velocity of the development of the fishes. The system worked very well and confirmed the design in principle. OMEGAHAB was the most successful German experiment of that kind as yet.

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

Active NET formation in Libman-Sacks endocarditis without antiphospholipid antibodies: A dramatic onset of systemic lupus erythematosus - Appelgren, Daniel; Dahle, Charlotte; Knopf, Jasmin; Bilyy, Rostyslav; Vovk, Volodymyr; Sundgren, Pia C.; Bengtsson, Anders A.; Wettero, Jonas; Munoz, Luis Enrique; Herrmann, Martin; Hoog, Anders; Sjowall, Christopher (Autoimmunity, 2018)
Although neutrophil extracellular traps (NETs) have been highlighted in several systemic inflammatory diseases, their clinical correlates and potential pathological role remain obscure. Herein, we describe a dramatic onset of systemic lupus erythematosus (SLE) with clear-cut pathogenic implications for neutrophils and NET formation in a young woman with cardiac (Libman-Sacks endocarditis) and central nervous system (psychosis and seizures) involvement. Despite extensive search, circulating antiphospholipid autoantibodies, a hallmark of Libman-Sacks endocarditis, could not be detected. Instead, we observed active NET formation in the tissue of the mitral valve, as well as in the circulation. Levels of NET remnants were significantly higher in serially obtained sera from the patient compared with sex-matched blood donors (p=.0011), and showed a non-significant but substantial correlation with blood neutrophil counts (r=0.65, p=.16). The specific neutrophil elastase activity measured in serum seemed to be modulated by the provided immunosuppressive treatment. In addition, we found anti-Ro60/SSA antibodies in the cerebrospinal fluid of the patient but not NET remnants or increased elastase activity. This case illustrates that different disease mechanisms mediated via autoantibodies can occur simultaneously in SLE. NET formation with release of cytotoxic NET remnants is a candidate player in the pathogenesis of this non-canonical form of Libman-Sacks endocarditis occurring in the absence of traditional antiphospholipid autoantibodies. The case description includes longitudinal results with clinical follow-up data and a discussion of the potential roles of NETs in SLE.
EVALuna2:213274

Actual Treatment Options for Giant Cell Arteritis - Moosig, Frank; Schmalzing, Marc; Aries, Peer Malte; Henes, Joerg; Lamprecht, Peter; Rech, Jürgen; Witte, Torsten (Deutsche Medizinische Wochenschrift, 2019)
To prevent serious complications such as permanent loss of vision and structural vascular damage, treatment must be initiated quickly in patients with giant-cell arteritis (GCA). So far, usually long-term corticosteroids in cumulative high dosages have been the standard therapy option. However, steroids are often insufficient to achieve adequate disease control and are associated with serious adverse events. Therefore, steroid-sparing therapy options are the focus of interest.
CRIS-Team WoS Importer:2019-05-21

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 defined metabolic state in pre B cells governs B-cell development and is counterbalanced by Swiprosin-2/EFhd1 - Stein, Merle; Dütting, Sebastian; Mougiakakos, Dimitrios; Boesl, Michael R.; Fritsch, Kristin; Reimer, Dorothea; Urbanczyk, Sophia; Steinmetz, Tobit; Schuh, Wolfgang; Bozec, Aline; Winkler, Thomas; Jäck, Hans-Martin; et al. (Cell Death and Differentiation, 2017)
B-cell development in the bone marrow comprises proliferative and resting phases in different niches. We asked whether B-cell metabolism relates to these changes. Compared to pro B and small pre B cells, large pre B cells revealed the highest glucose uptake and ROS but not mitochondrial mass, whereas small pre B cells exhibited the lowest mitochondrial membrane potential. Small pre B cells from Rag1;33.C9 μ heavy chain knock-in mice revealed decreased glycolysis (ECAR) and mitochondrial spare capacity compared to pro B cells from Rag1 mice. We were interested in the step regulating this metabolic switch from pro to pre B cells and uncovered that Swiprosin-2/EFhd1, a Ca-binding protein of the inner mitochondrial membrane involved in Ca-induced mitoflashes, is expressed in pro B cells, but downregulated by surface pre B-cell receptor expression. Knockdown and knockout of EFhd1 in 38B9 pro B cells decreased the oxidative phosphorylation/glycolysis (OCR/ECAR) ratio by increasing glycolysis, glycolytic capacity and reserve. Prolonged expression of EFhd1 in EFhd1 transgenic mice beyond the pro B cell stage increased expression of the mitochondrial co-activator PGC-1α in primary pre B cells, but reduced mitochondrial ATP production at the pro to pre B cell transition in IL-7 cultures. Transgenic EFhd1 expression caused a B-cell intrinsic developmental disadvantage for pro and pre B cells. Hence, coordinated expression of EFhd1 in pro B cells and by the pre BCR regulates metabolic changes and pro/pre B-cell development.Cell Death and Differentiation advance online publication, 19 May 2017; doi:10.1038/cdd.2017.52.

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

Adhesion/growth-regulatory galectins in the human eye: localization profiles and tissue reactivities as a standard to detect disease-associated alterations - Schlötzer-Schrehardt, Ursula; Andre, Sabine; Janko, Christina; Kaltner, Herbert; Kopitz, Juergen; Gabius, Hans-Joachim; Herrmann, Martin (Graefes Archive For Clinical and Experimental Ophthalmology, 2012)
To characterize the localization profiles of seven adhesion/growth-regulatory galectins in the normal human eye using immunodetection of endogenous galectins and binding of labeled galectins to sections, useful as a basis to detect disease-associated alterations.Non-cross-reactive anti-galectin antibodies and biotinylated galectins were tested on acetone-fixed cryosections of normal human donor eyes. Controls included omission of first-step reagent, testing of an antibody against a galectin specific for rat (galectin-5), and blocking of galectin binding with lactose.Galectin presence was not restricted to one or few members of this family. Signal occurrence can even include all tested or most proteins (conjunctival or corneal epithelium), whereas choroid positivity is fully accounted for by galectin-9. Regional specificity and characteristic profiles for each protein, immuno- and galectin histochemically, were determined. Differences in tissue reactivity among the galectins were detected.That the galectins have characteristic localization/reactivity profiles supports the concept of a network with potential for non-overlapping functions. The reported data thus prompt to proceed to the respective analysis of specimens from ocular diseases.
EVALuna2:12715

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 alcohol drinking and emotional tone are mediated by neutral sphingomyelinase during development in males - Kalinichenko, Liubov; Mühle, Christiane; Jia, Tianye; Anderheiden, Felix; Datz, Maria; Eberle, Anna-Lisa; Eulenburg, Volker; Granzow, Jonas; Hofer, Martin Jürgen; Hohenschild, Julia; Huber, Sabine; Kämpf, Stefanie; et al. (Cerebral Cortex, 2022)
Alcohol use, abuse, and addiction, and resulting health hazards are highly sex-dependent with unknown mechanisms. Previously, strong links between the SMPD3 gene and its coded protein neutral sphingomyelinase 2 (NSM) and alcohol abuse, emotional behavior, and bone defects were discovered and multiple mechanisms were identified for females. Here we report strong sex-dimorphisms for central, but not for peripheral mechanisms of NSM action in mouse models. Reduced NSM activity resulted in enhanced alcohol consumption in males, but delayed conditioned rewarding effects. It enhanced the acute dopamine response to alcohol, but decreased monoaminergic systems adaptations to chronic alcohol. Reduced NSM activity increased depression- and anxiety-like behavior, but was not involved in alcohol use for the self-management of the emotional state. Constitutively reduced NSM activity impaired structural development in the brain and enhanced lipidomic sensitivity to chronic alcohol. While the central effects were mostly opposite to NSM function in females, similar roles in bone-mediated osteocalcin release and its effects on alcohol drinking and emotional behavior were observed. These findings support the view that the NSM and multiple downstream mechanism may be a source of the sex-differences in alcohol use and emotional behavior.
CRIS-Team WoS Importer:2022-04-15
Keywords: neutral sphingomyelinase; osteocalcin; depression; alcohol; anxiety

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 Imaging of Lung Homing Human Lymphocytes in an Experimental In Vivo Model of Allergic Inflammation Based on Light-sheet Microscopy - Schulz-Kuhnt, Anja; Zundler, Sebastian; Grüneboom, Anika; Neufert, Clemens; Wirtz, Stefan; Neurath, Markus; Atreya, Imke (Journal of Visualized Experiments, 2019)
Overwhelming tissue accumulation of highly activated immune cells represents a hallmark of various chronic inflammatory diseases and emerged as an attractive therapeutic target in the clinical management of affected patients. In order to further optimize strategies aiming at therapeutic regulation of pathologically imbalanced tissue infiltration of pro-inflammatory immune cells, it will be of particular importance to achieve improved insights into disease- and organ-specific homing properties of peripheral lymphocytes. The here described experimental protocol allows to monitor lung accumulation of fluorescently labeled and adoptively transferred human lymphocytes in the context of papain-induced pulmonary inflammation. In contrast to standard in vitro assays frequently used for the analysis of immune cell migration and chemotaxis, the now introduced in vivo setting takes into account lung-specific aspects of tissue organization and the influence of the complex inflammatory scenario taking place in the living murine organism. Moreover, three-dimensional cross-sectional light-sheet fluorescence microscopic imaging does not only provide quantitative data on infiltrating immune cells, but also depicts the pattern of immune cell localization within the inflamed lung. Overall, we are able to introduce an innovative technique of high value for immunological research in the field of chronic inflammatory lung diseases, which can be easily applied by following the provided step-by-step protocol.
CRIS-Team Scopus Importer:2019-05-24

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

ADVANCES IN THE DETECTION OF PATHOGENIC AUTOANTIBODIES IN SLE - Munoz, Luis Enrique (ANNALS OF THE RHEUMATIC DISEASES, 2019)
CRIS-Team WoS Importer:2019-07-12

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 gene regulation system with four distinct expression levels - Jäck, Hans-Martin; Gmeiner, Peter; Berens, Christian; et al. (Journal of Gene Medicine, 2006)
Background: The amount of a particular protein, and not just its presence or absence, frequently determines the outcome of a developmental process or disease progression. These dosage effects can be studied by conditionally expressing such proteins at different levels. With typical gene regulation systems like the Tet-On system, intermediate expression levels can be obtained by varying the effector concentration. However, this strategy is limited to situations in which these concentrations can be precisely controlled and, thus, not suited for animal models or gene therapy approaches. Here, we present a Tet transregulator setup that allows establishment of four levels of promoter activity largely independent of effector concentration. Methods: A newly introduced transsilencer is combined with a reverse transactivator. As the regulators respond differentially to tetracycline derivatives, four expression levels are obtained by adding different effectors. To facilitate integration of the components, we generated versatile all-in-one vectors. Apart from a cassette expressing the transregulators and a selection marker, these vectors encode a bidirectional, regulated promoter driving expression of GFP and the gene of interest. The features of this stepwise regulation system were analyzed by transient and stable transfections of human cell lines. Results: We demonstrate in a variety of experimental settings that coexpression of these transregulators leads to robust stepwise regulation. Depending on the respective effectors, four expression levels are achieved with different responsive promoters, cell lines and target genes. Conclusions: This system shows that a promoter can be adjusted to different activities and provides an excellent strategy to investigate protein dosage effects. Copyright © 2006 John Wiley & Sons, Ltd.
UnivIS-Import:2015-04-14:Pub.2006.nat.dchph.lphch.agener
Keywords: Conditional gene expression; Stepwise regulation; Tet system; Tetracyclines

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

Age-related Differences in Immune Reactions to SARS-CoV-2 Spike and Nucleocapsid Antigens - Morhart, Patrick; Kehl, Sven; Schuh, Wolfgang; Hermes, Katharina; Meltendorf, Stefan; Neubert, Antje; Schneider, Michael; Brunner-Weinzierl, Monika; Schneider, Holm; Lingel, Holger (In Vivo, 2023)
Background/Aim: The manifestation and severity of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections show a clear correlation to the age of a patient. The younger a person, the less likely the infection results in significant illness. To explore the immunological characteristics behind this phenomenon, we studied the course of SARS-CoV-2 infections in 11 households, including 8 children and 6 infants/neonates of women who got infected with SARS-CoV-2 during pregnancy. Materials and Methods: We investigated the immune responses of peripheral blood mononuclear cells (PBMCs), umbilical cord blood mononuclear cells (UCBCs), and T cells against spike and nucleocapsid antigens of SARS-COV-2 by flow cytometry and cytokine secretion assays. Results: Upon peptide stimulation, UCBC from neonates showed a strongly reduced IFN-γ production, as well as lower levels of IL-5, IL-13, and TNF-α alongside with decreased frequencies of surface CD137/PD-1 co-expressing CD4+ and CD+8 T cells compared with adult PBMCs. The PBMC response of older children instead was characterized by elevated frequencies of IFN-γ+ CD4+ T cells, but significantly lower levels of multiple cytokines (IL-5, IL-6, IL-9, IL-10, IL-17A, and TNF-α) and a marked shift of the CD4+/CD8+ T-cell ratio towards CD8+ T cells in comparison to adults. Conclusion: The increased severity of SARS-CoV-2 infections in adults could result from the strong cytokine production and lower potential to immunomodulate the excessive inflammation, while the limited IFN-γ production of responding T cells in infants/neonates and the additional higher frequencies of CD8+ T cells in older children may provide advantages during the course of a SARS-CoV-2 infection.
CRIS-Team Scopus Importer:2023-01-13
Keywords: children; COVID-19; immune response; inflammation; neonates; pediatric immunology; SARS-CoV-2; spike protein

Age Related Increase of Intermuscular Adipose Tissue of the Thigh can be Prevented by Exercise in Sarcopenic Men - Engelke, Klaus; Chaudry, Oliver; Ghasemikaram, Mansour; Nagel, Armin Michael; Jakob, Franz; Kemmler, Wolfgang (JOURNAL OF BONE AND MINERAL RESEARCH, 2022)
CRIS-Team WoS Importer:2022-05-27

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.
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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

Agonistic autoantibodies against ß2-adrenergic receptor influence retinal microcirculation in glaucoma suspects and patients - Hohberger, Bettina; Hosari, Sami; Wallukat, Gerd; Kunze, Rudolf; Krebs, Johann Ferdinand; Müller, Magdalena; Hennig, Till; Lämmer, Robert; Horn, Folkert; Garcia Munoz, Luis Enrique; Herrmann, Martin; Mardin, Christian (PLoS ONE, 2021)
PURPOSE: Agonistic β2-adrenergic receptor autoantibodies (β2-agAAb) have been observed in sera of patients with ocular hypertension and open-angle glaucoma (OAG). They target the β2-receptors on trabecular meshwork, ciliary body and pericytes (Junemann et al. 2018; Hohberger et al. 2019). In addition to their influence on the intraocular pressure, an association to retinal microcirculation is discussed. This study aimed to investigate foveal avascular zone (FAZ) characteristics by en face OCT angiography (OCT-A) in glaucoma suspects and its relationship to β2-agAAb status in patients with OAG. MATERIAL AND METHODS: Thirty-four patients (28 OAG, 6 glaucoma suspects) underwent standardized, clinical examination including sensory testing as white-on-white perimetry (Octopus G1, mean defect, MD) and structural measures as retinal nerve fibre layer (RNFL) thickness, neuroretinal rim width (BMO-MRW), retinal ganglion cell layer (RGCL) thickness, and inner nuclear layer (INL) thickness with high-resolution OCT. FAZ characteristics were measured by OCT-A scans of superficial vascular plexus (SVP), intermediate capillary plexus (ICP), and deep capillary plexus (DCP). FAZ-R was calculated (area FAZ (SVP)/area FAZ (ICP)). Using cardiomyocyte bioassays we analysed serum samples for the presence of β2-agAAb. RESULTS: (I) Total mean FAZ area [mm2]: 0.34±0.16 (SVP), 0.24±0.12 (ICP), and 0.49±0.24 (DCP); mean FAZ-R 1.58±0.94. No correlation was seen for FAZ-R with MD, RNFL, BMO-MRW, RGCL thickness and INL thickness (p>0.05). (II) ß2-agAAb have been observed in 91% patients and showed no correlation with MD, RNFL, BMO-MRW, RGCL thickness and INL thickness (p>0.05). (III) FAZ-R correlated significantly with the β2-agAAb-induced increase of the beat rate of cardiomyocyte (p = 0.028). CONCLUSION: FAZ characteristics did not correlate with any glaucoma associated functional and morphometric follow-up parameter in the present cohort. However, level of β2-agAAb showed a significantly correlation with FAZ-ratio. We conclude that β2-agAAb might be a novel biomarker in glaucoma pathogenesis showing association to FAZ-ratio with OCT-A.
CRIS-Team Scopus Importer:2021-05-21

Agonistic Autoantibodies to the β2-Adrenergic Receptor Involved in the Pathogenesis of Open-Angle Glaucoma - Juenemann, Anselm; Hohberger, Bettina; Rech, Jürgen; Sheriff, Ahmed; Fu, Qin; Schlötzer-Schrehardt, Ursula; Voll, Reinhard Edmund; Bartel, Sabine; Kalbacher, Hubert; Hoebeke, Johan; Rejdak, Robert; Horn, Folkert; et al. (Frontiers in Immunology, 2018)
Glaucoma is a frequent ocular disease that may lead to blindness. Primary open-angle glaucoma (POAG) and ocular hypertension (OHT) are common diseases with increased intraocular pressure (IOP), which are mainly responsible for these disorders. Their pathogenesis is widely unknown. We screened the sera of patients with POAG and OHT for the prevalence of autoantibodies (AAb) against G protein-coupled receptors (GPCRs) in comparison to controls. Employing frequency modulation of spontaneously contracting neonatal rat cardiomyocytes in vitro, agonistic GPCR AAb were to be detected in roughly 75% of the patients with POAG and OHT, however, not in controls. Using inhibitory peptides the AAb' target was identified as β2 adrenergic receptor (β2AR). The AAb interact with the second extracellular loop of β2AR. The peptides 181-187 and 186-192 were identified as binding sites of the AAb within the extracellular loop II. The binding of the AAb to β2ARs was verified by surface-plasmon-resonance analysis. The isotype of the AAb was (immunoglobulin) IgG3. In an additional pilot principal-of-proof study, including four patients with POAG, the removal of the AAb against the β2AR and other immunoglobulins G by immunoadsorption resulted in a transient reduction of IOP. These findings might indicate a possible role of agonistic AAb directed against β2ARs in the dynamics of aqueous humor and might support a contribution of adaptive autoimmunity in the etiopathogenesis of POAG and OHT.
EVALuna2:33846

Agonistic beta 2-adrenergic receptor autoantibodies characterize the aqueous humor of patients with primary and secondary open-angle glaucoma - Hohberger, Bettina; Woern, Max; Lämmer, Robert; Herrmann, Martin; Mardin, Christian; Kruse, Friedrich; Kunze, Rudolf; Wallukat, Gerd (INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE, 2020)
CRIS-Team WoS Importer:2020-09-11

Agonistic beta 2-Adrenergic Receptor Autoantibodies Characterize the Aqueous Humor of Patients With Primary and Secondary Open-Angle Glaucoma - Hohberger, Bettina; Worn, Max; Lämmer, Robert; Mahajan, Aparna; Mardin, Christian; Schlötzer-Schrehardt, Ursula; Kunze, Rudolph; Herrmann, Martin; Wallukat, Gerd (Frontiers in Immunology, 2021)
Purpose
CRIS-Team WoS Importer:2021-05-28

A human periodontal ligament fibroblast cell line as a new model to study periodontal stress - Weider, Matthias; Schröder, Agnes; Docheva, Denitsa; Rodrian, Gabriele; Enderle, Isabel; Seidel, Corinna Lesley; Andreev, Darja; Wegner, Michael; Bozec, Aline; Deschner, James; Kirschneck, Christian; Proff, Peter; et al. (International Journal of Molecular Sciences, 2020)
The periodontal ligament (PDL) is exposed to different kinds of mechanical stresses such as bite force or orthodontic tooth movement. A simple and efficient model to study molecular responses to mechanical stress is the application of compressive force onto primary human periodontal ligament fibroblasts via glass disks. Yet, this model suffers from the need for primary cells from human donors which have a limited proliferative capacity. Here we show that an immortalized cell line, PDL-hTERT, derived from primary human periodontal ligament fibroblasts exhibits characteristic responses to glass disk-mediated compressive force resembling those of primary cells. These responses include induction and secretion of pro-inflammatory markers, changes in expression of extracellular matrix-reorganizing genes and induction of genes related to angiogenesis, osteoblastogenesis and osteoclastogenesis. The fact that PDL-hTERT cells can easily be transfected broadens their usefulness, as molecular gain- and loss-of-function studies become feasible.
CRIS-Team Scopus Importer:2020-11-13
Keywords: Bone remodeling; Cell culture techniques; Mechanical loading; Orthodontic tooth movement

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

Akzeptanz der Videosprechstunde unter Patienten/innen mit entzündlich rheumatischen Erkrankungen ist geschlechts- und ortsabhängig – Ergebnisse einer Online-Umfrage unter Patienten/innen und Ärzten/innen - Vossen, Diana; Knitza, Johannes; Klemm, Philipp; Haase, Isabell; Mucke, Johanna; Kernder, Anna; Meyer, Marco; Kleyer, Arnd; Sewerin, Philipp; Bendzuck, Gerlinde; Eis, Sabine; Krusche, Martin; et al. (Zeitschrift für Rheumatologie, 2021)
Introduction: In order to successfully integrate telemedicine into the daily routine of rheumatology, both the patient’s and the physician’s perspective are important. For this purpose, a detailed study by means of a web-based survey was conducted by the Working Group Young Rheumatology (AGJR) of the German Society for Rheumatology (DGRh) and the German Rheumatism League National Association. By means of subgroup analysis of the data regarding video consultation, the aim was now to find out which requirements and wishes patients and physicians have for video consultations. Methods: The prospective survey was distributed via social media, QR code and email. Descriptive statistics and regression analysis related to video consultation were performed and correlations were shown. Results: The data indicated positive attitudes toward video consultation on the part of both patients (n = 299) and rheumatologists (n = 129). A correlation between age and positive opinion of the video consultation was found among the patients (r = 0.161, p = 0.006), especially among female patients a positive approval of the video consultation was found with increasing age (r = 0.244, p < 0.001 to male patients: r = −0.190, p = 0.145). Regarding the travelling time to the treating rheumatologist, male patients found the video consultation more attractive with increasing travelling time (r = 0.229, p = 0.078). With respect to the wishes of patients and physicians, video consultation should be used primarily for follow-up or emergency appointments. Video consultation for initial appointments, on the other hand, was very rarely mentioned. Conclusion: During the COVID 19 pandemic, video consultation was increasingly popular among rheumatology patients as well as among rheumatologists.
CRIS-Team Scopus Importer:2021-09-10
Keywords: COVID-19 pandemic; Online survey; Patient care; Rheumatic inflammatory systemic diseases; Video consultation

Alcohol consumption in rheumatoid arthritis: A path through the immune system - Azizov, Vugar; Zaiss, Mario (Nutrients, 2021)
Benefits and harms of different components of human diet have been known for hundreds of years. Alcohol is one the highest consumed, abused, and addictive substances worldwide. Con-sequences of alcohol abuse are increased risks for diseases of the cardiovascular system, liver, and nervous system, as well as reduced immune system function. Paradoxically, alcohol has also been a consistent protective factor against the development of autoimmune diseases such as type 1 diabetes, multiple sclerosis, systemic lupus erythematosus, and rheumatoid arthritis (RA). Here, we focused on summarizing current findings on the effects of alcohol, as well as of its’ metabolites, acetaldehyde and acetate, on the immune system and RA. Heavy or moderate alcohol consumption can affect intestinal barrier integrity, as well as the microbiome, possibly contributing to RA. Additionally, systemic increase in acetate negatively affects humoral immune response, diminishing TFH cell as well as professional antigen-presenting cell (APC) function. Hence, alcohol consumption has pro-found effects on the efficacy of vaccinations, but also elicits protection against autoimmune diseases. The mechanism of alcohol’s negative effects on the immune system is multivariate. Future studies addressing alcohol and its’ metabolite acetate’s effect on individual components of the immune system remains crucial for our understanding and development of novel therapeutic pathways.
CRIS-Team Scopus Importer:2021-05-14
Keywords: Acetaldehyde; Acetate; Alcohol; RA; Rheumatoid arthritis

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

A life span perspective on competencies for a healthy, physically active lifestyle: Findings of a data pooling initiative with over 7000 individuals - Carl, Johannes; Blaschke, Simon; Sudeck, Gorden; Schmid, Julia; Eckert, Katharina; Geidl, Wolfgang; Jaunig, Johannes; Köppel, Maximilian; Wiskemann, Joachim; Liphardt, Anna-Maria; Pfeifer, Klaus (European journal of sport science, 2024)
Individuals are recommended to lead active lifestyles throughout the life course. The model of physical activity-related health competence (PAHCO) adopts a competence approach by integrating physical, cognitive, and motivational determinants for health-enhancing PA (movement competence, control competence, self-regulation competence). Drawing on a comprehensive dataset pooling, the goal of the present study was to model the idiosyncratic courses of 10 PAHCO indicators over the life span. We identified studies that empirically operationalized PAHCO, combining data of 7134 individuals (age range: 15–97 years; 61% female) from 18 different populations (prevention and rehabilitation sectors). We applied a stepwise multilevel analysis approach with disjunct sub-samples (n = 48) to examine linear and quadratic associations between age and PAHCO. Indicators of movement competence (i.e., manageability of endurance, strength, and balance demands; task-specific self-efficacy) congruently showed negative associations with age (0.054 ≤ (Formula presented.) ≤ 0.211). However, parameters of control competence remained stable across the life span (−0.066 ≤ β ≤ 0.028). The three indicators of self-regulation competence revealed an inconsistent relationship with age, though uncovering positive associations for self-control (β = 0.106) and emotional attitude toward PA (β = 0.088). The associations of some indicators varied significantly across sub-samples. The results suggest differential analyses for associations between PAHCO and age. While the physically determined PAHCO indicators (movement competence) probably decline across the life span, the ability to ensure regularity of PA (self-regulation competence) or align PAs with an individual's health (control competence) appear to remain constant or improve with increasing age. The findings reinforce a de-stigmatizing approach for PA promotion practices with considerable space for aligning activities with health also in the elderly.
CRIS-Team Scopus Importer:2024-05-03
Keywords: age; competence; exercise; health; physical activity

ALIGNed on adherence: subanalysis of adherence in immune-mediated inflammatory diseases in the DACH region of the global ALIGN study - Kolios, A. G. A.; Hueber, Axel; Michetti, P.; Mrowietz, U.; Mustak-Blagusz, M.; Sator, P. -G.; Reinshagen, M.; Wilsmann-Theis, D.; Gomis-Kleindienst, S.; Luckey, U.; Roessler, A.; Schiefke, I. (Journal of the European Academy of Dermatology and Venereology, 2019)
Background: Non-adherence to medication is a challenging problem in daily clinical practice. Objective: To assess reasons for non-adherence in patients with chronic immune-mediated inflammatory diseases (IMIDs) in a direct comparison including evaluation of treatment necessity and concerns. Methods: ALIGN was a non-interventional, multicountry, multicentre, self-administered, cross-sectional, epidemiologic survey study. Here, we investigate the German, Austrian and Swiss (DACH) cohort. Six hundred thirty-one patients with different IMIDs (rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, plaque psoriasis, Crohn's disease and ulcerative colitis) under systemic therapies were evaluated concerning adherence, beliefs of necessity and concerns towards treatment in patients with IMIDs. Results: The DACH cohort had significantly different levels of adherence depending on the IMID (P < 0.05) and the type of therapy (P < 0.05). Based on the significant influence of concerns on treatment adherence (P < 0.05) and the high belief of treatment necessity, patients could be classified in four attitudinal segments, which were unequally distributed throughout various IMIDs. High concerns had a significant influence on non-adherence, whereas necessity did not. Older age, female sex, TNFi mono-, conventional combination and TNFi combination therapy are positively associated with adherence. Conclusions: In the DACH region, patients are less concerned about medication and believe in the necessity of treatment. Therefore, we suggest adapting the communication in the various patient groups.
CRIS-Team Scopus Importer:2019-06-18

Allogeneic Hematopoietic Cell Transplantation in Patients <= 60 Years with Intermediate-Risk Acute Myeloid Leukemia in First Remission - Results of the Randomized Etal-1 Trial- - Bornhaeuser, Martin; Schliemann, Christoph; Schetelig, Johannes; Rollig, Christoph; Kramer, Michael; Glass, Bertram; Platzbecker, Uwe; Burchert, Andreas; Haenel, Mathias; Mueller, Lutz Peter; Klein, Stefan; Bug, Gesine; et al. (BLOOD, 2021)
CRIS-Team WoS Importer:2022-09-09

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

Alpha-1 antitrypsin in autoimmune diseases: Roles and therapeutic prospects - Sun, Rui; Xu, Zhiqiang; Zhu, Chenxi; Chen, Tao; Munoz, Luis Enrique; Dai, Lunzhi; Zhao, Yi (International Immunopharmacology, 2022)
Alpha-1 antitrypsin (A1AT) is a protease inhibitor in the serum. Its primary function is to inhibit the activity of a series of proteases, including proteinase 3, neutrophil elastase, metalloproteases, and cysteine-aspartate proteases. In addition, A1AT also has anti-inflammatory, anti-apoptotic, anti-oxidative stress, anti-viral, and antibacterial activities and plays essential roles in the regulation of tissue repair and lymphocyte differentiation and activation. The overactivation of the immune system characterizes the pathogenesis of autoimmune diseases. A1AT treatment shows beneficial effects on patients and animal models with autoimmune diseases such as rheumatoid arthritis and systemic lupus erythematosus. This review summarizes the functions and therapeutic prospects of A1AT in autoimmune diseases.
CRIS-Team WoS Importer:2022-07-29

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 cardiac gene expression of noradrenaline enzymes, transporter and β-adrenoceptors in rat model of rheumatoid arthritis - Dronjak, Sladjana; Stefanovic, Bojana; Jovanovic, Predrag; Spasojevic, Natasa; Jankovic, Milica; Jeremic, Ivica; Hoffmann, Markus (Autonomic Neuroscience-Basic & Clinical, 2017)
Baseline sympathetic activity was found to be elevated in rheumatoid arthritis (RA) patients and it is related to increased cardiovascular risk in these patients. Although many studies have highlighted the association between RA and increased cardiac sympathetic activity, the underlying mechanistic links remain unclear. The aim of the present study was to understand how diseases-triggered changes in gene expression may result in maladaptive physiological changes. Our results suggest that the equilibrium between noradrenaline synthesis, release and reuptake was disrupted in the ventricles of arthritic rats. In the acute phase of the arthritic process, decreased gene expression of MAO-A might lead to accumulation of noradrenaline in myocardial interstitial space, whereas increased gene expression of NET protected cardiomyocytes from the deleterious effects of enhanced noradrenaline. During the chronic phase, reduced expression of ?1-adrenoceptor and decreased efficiency of noradrenaline reuptake contribute to progressive damage of the myocardium and limits heart efficiency.
EVALuna2:13461

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

Altered molecular pathways and prognostic markers in active systemic juvenile idiopathic arthritis: Integrated bioinformatic analysis - Ren, Yi; Labinsky, Hannah; Palmowski, Andriko; Bäcker, Henrik; Müller, Michael; Kienzle, Arne (Bosnian Journal of Basic Medical Sciences, 2022)
Systemic juvenile idiopathic arthritis (SJIA) is a severe childhood-onset inflammatory disease characterized by arthritis accompanied by systemic auto-inflammation and extra-articular symptoms. While recent advances have unraveled a range of risk factors, the pathomechanisms involved in SJIA and potential prognostic markers for treatment success remain partly unknown. In this study, we included 70 active SJIA and 55 healthy control patients from the National Center for Biotechnology Information to analyze for differentially expressed genes (DEGs) using R. Functional enrichment analysis, protein-protein interaction (PPI), and gene module construction were performed for DEGs and hub gene set. We additionally examined immune system cell composition with CIBERSORT and predicted prognostic markers and potential treatment drugs for SJIA. In total, 94 upregulated and 24 downregulated DEGs were identified. Two specific modules of interest and eight hub genes (ARG1, DEFA4, HP, MMP8, MMP9, MPO, OLFM4, and PGLYRP1) were screened out. Functional enrichment analysis suggested that complex neutrophil-related functions play a decisive role in the disease pathogenesis. CIBERSORT indicated neutrophils, M0 macrophages, CD8+ T cells, and naïve B cells to be relevant drivers of disease progression. In addition, we identified TPM2 and GZMB as potential prognostic markers for treatment response to canakinumab. Moreover, sulindac sulfide, (-)-catechin, and phenanthridinone were identified as promising treatment agents. This study provides a new insight into molecular and cellular pathogenesis of active SJIA and highlights potential targets for further research.
CRIS-Team Scopus Importer:2022-04-29
Keywords: hub genes; neutrophil; prognostic marker; Systemic juvenile idiopathic arthritis

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 net formation induces resolution of inflammation - Euler, Maximilien; Hahn, Jonas; Herrmann, Martin; Mokhir, Andriy; Hoffmann, Markus (FREE RADICAL BIOLOGY AND MEDICINE, 2019)
CRIS-Team WoS Importer:2019-06-28

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

Amyloidogenic amyloid-?-peptide variants induce microbial agglutination and exert antimicrobial activity - Spitzer, Philipp; Condic, Mateja; Herrmann, Martin; Oberstein, Timo; Scharin-Mehlmann, Marina; Gilbert, Daniel; Friedrich, Oliver; Groemer, Teja; Kornhuber, Johannes; Lang, Roland; Maler, Juan Manuel (Scientific Reports, 2016)
Amyloid-? (A?) peptides are the main components of the plaques found in the brains of patients with Alzheimer's disease. However, A? peptides are also detectable in secretory compartments and peripheral blood contains a complex mixture of more than 40 different modified and/or N- and C-terminally truncated A? peptides. Recently, anti-infective properties of A? peptides have been reported. Here, we investigated the interaction of A? peptides of different lengths with various bacterial strains and the yeast Candida albicans. The amyloidogenic peptides A?1-42, A?2-42, and A?3p-42 but not the non-amyloidogenic peptides A?1-40 and A?2-40 bound to microbial surfaces. As observed by immunocytochemistry, scanning electron microscopy and Gram staining, treatment of several bacterial strains and Candida albicans with A? peptide variants ending at position 42 (A?x-42) caused the formation of large agglutinates. These aggregates were not detected after incubation with A?x-40. Furthermore, A?x-42 exerted an antimicrobial activity on all tested pathogens, killing up to 80% of microorganisms within 6 h. A?1-40 only had a moderate antimicrobial activity against C. albicans. Agglutination of A?1-42 was accelerated in the presence of microorganisms. These data demonstrate that the amyloidogenic A?x-42 variants have antimicrobial activity and may therefore act as antimicrobial peptides in the immune system.
EVALuna2:7714

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

Analysis of Surface Levels of IL-1 Receptors and Macrophage Scavenger Receptor I in Peripheral Immune Cells of Patients With Alzheimer Disease - Spitzer, Philipp; Weinbeer, Johannes; Herrmann, Martin; Oberstein, Timo; Condic, Mateja; Lewczuk, Piotr; Kornhuber, Johannes; Maler, Juan Manuel (Journal of Geriatric Psychiatry and Neurology, 2019)
Increased concentrations of interleukin 1 (IL-1) in the cerebrospinal fluid and serum of patients with Alzheimer disease (AD) reduced phagocytic capacity point to an inflammatory activation of mononuclear phagocytes in AD. Interleukin 1 receptors (IL-1R) and the macrophage scavenger receptor I (MSRI) are important players in IL-1 signaling and phagocytosis. In 20 patients with AD and 17 controls, IL-1RI, IL-1RII, and MSRI were assessed on peripheral blood mononuclear cells by flow cytometry. IL-1β, soluble IL-1 receptors, and IL-1R antagonist (IL-1Ra) were measured by enzyme-linked immunosorbent assay. The fraction of IL-1RI+ monocytes was increased by 10% and the expression of MSRI was reduced by 12% in AD. A 3.6% increased fraction of IL-1RI+ lymphocytes was accompanied by a 6.1% reduced expression of IL-1RII. The IL-1RI on monocytes and lymphocytes discriminated patients with AD with an accuracy of 0.79 and 0.75, respectively. The IL-1Ra was elevated in AD. Changes in the expression of IL-1 receptors and MSRI on peripheral blood cells fit to the concept of a proinflammatory state of the peripheral immune system. However, the observed differences are not strong enough to suggest their application as biomarkers for AD.
CRIS-Team Scopus Importer:2019-05-03
Keywords: Alzheimer disease; biomarker; dementia; IL-1RI; MSRI; neurodegeneration; neuroinflammation

ANALYTICAL APPROACH FOR DETERMINING THE SUITABILITY OF NINE CADIDATE BLOOD MARKERS FOR INVESTIGATING THE RESPONSE OF ARTICULAR CARTILAGE TO AMBULATORY LOAD - Herger, S.; Vach, W.; Liphardt, Anna-Maria; Egloff, C.; Nueesch, C.; Muendermann, A. (OSTEOARTHRITIS AND CARTILAGE, 2020)
CRIS-Team WoS Importer:2020-05-29

Analyzing web searches for axial spondyloarthritis in Germany: a novel approach to exploring interests and unmet needs - Berr, Kristina; Tizek, Linda; Schielein, Maximilian C.; Welcker, Martin; Knitza, Johannes; Kleinert, Stefan; Zink, Alexander (Rheumatology International, 2023)
Axial spondyloarthritis (axSpA) is an underdiagnosed condition with a high disease burden. Due to delayed diagnosis and limited access to specialist care, conventional health data might not sufficiently capture the perspective of affected individuals. The aim of this study was to assess public interest, unmet needs, and disease burden of axSpA in Germany through the analysis of thematic, geographic, and temporal patterns in national web search data. Google Ads Keyword Planner was used to identify axSpA-related keywords and their monthly search volume in Germany between January 2017 and December 2020. Identified keywords were qualitatively categorized into six categories. Overall, 265 axSpA-related keywords with a search volume of 3,881,490 queries were identified. Nearly 81% of the total search volume was assigned to the category terms and definition, while 19% referred to either outcomes, symptoms, diagnosis, management, or causes. In the category outcomes, prognostic outcomes like “life expectancy” generated more searches than physical manifestations like “pain”. Less populated cities showed significantly more searches per 100,000 inhabitants than larger cities. Searches were seasonally stable with a Germany-wide peak in July 2017. This study provides an overview of public interest in axSpA based on web search data in Germany. The identified search patterns could be used to guide public health campaigns and optimize axSpA management in Germany.
CRIS-Team Scopus Importer:2023-01-27
Keywords: Axial spondyloarthritis; Burden of disease; Infodemiology; Unmet needs; Web search data

"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

A new printable alginate / hyaluronic acid / gelatin hydrogel suitable for biofabrication of in vitro and in vivo metastatic melanoma models - Schmid, Rafael; Schmidt, Sonja; Detsch, Rainer; Horder, Hannes; Blunk, Torsten; Schrüfer, Stefan; Schubert, Dirk W.; Fischer, Lena; Thievessen, Ingo; Heltmann-Meyer, Stefanie; Steiner, Dominik; Schneidereit, Dominik; et al. (Advanced Functional Materials, 2021)
Two-dimensional (2D) cancer models have been the standard for drug development over the past few years, but they frequently do not resemble in vivo properties adequately. 3D models are superior in many aspects and are, therefore, more similar to human pathophysiology. Over the past years, the emerging field of biofabrication has made significant advances, resulting in even more sophisticated 3D models. With this study, a hydrogel is created for biofabrication that is suitable for mimicking the tumor microenvironment in vitro and is further tested as a new vascularized melanoma model in vivo. The alginate/hyaluronic acid/gelatin bioink shows good shape-fidelity, high cell survival rates, and enables successful cultivation of melanoma cells and adipose-derived stem cells as well as cell differentiation in vitro. In vivo, in the arteriovenous loop model, it proves to be a unique method to study melanoma progression, tumor vascularization, and ultimately and reliably metastases in an isolated and controlled environment. These results show that this 3D model is very application-oriented for molecular research and therapy developmen

A New Printable Alginate/Hyaluronic Acid/Gelatin Hydrogel Suitable for Biofabrication of In Vitro and In Vivo Metastatic Melanoma Models - Schmid, Rafael; Schmidt, Sonja; Detsch, Rainer; Horder, Hannes; Blunk, Torsten; Schrüfer, Stefan; Schubert, Dirk W.; Fischer, Lena; Thievessen, Ingo; Heltmann-Meyer, Stefanie; Steiner, Dominik; Schneidereit, Dominik; et al. (Advanced Functional Materials, 2021)
Two-dimensional (2D) cancer models have been the standard for drug development over the past few years, but they frequently do not resemble in vivo properties adequately. 3D models are superior in many aspects and are, therefore, more similar to human pathophysiology. Over the past years, the emerging field of biofabrication has made significant advances, resulting in even more sophisticated 3D models. With this study, a hydrogel is created for biofabrication that is suitable for mimicking the tumor microenvironment in vitro and is further tested as a new vascularized melanoma model in vivo. The alginate/hyaluronic acid/gelatin bioink shows good shape-fidelity, high cell survival rates, and enables successful cultivation of melanoma cells and adipose-derived stem cells as well as cell differentiation in vitro. In vivo, in the arteriovenous loop model, it proves to be a unique method to study melanoma progression, tumor vascularization, and ultimately and reliably metastases in an isolated and controlled environment. These results show that this 3D model is very application-oriented for molecular research and therapy development.
CRIS-Team Scopus Importer:2021-10-22
Keywords: bioinks; metastasis; stem cells; tissue engineering; tumors

A new printable alginate / hyaluronic acid / gelatin hydrogel suitable for biofabrication of in vitro and in vivo metastatic melanoma models - Schmid, Rafael; Schmidt, Sonja; Detsch, Rainer; Horder, Hannes; Blunk, Torsten; Schrüfer, Stefan; Schubert, Dirk W.; Fischer, Lena; Thievessen, Ingo; Heltmann-Meyer, Stefanie; Steiner, Dominik; Schneidereit, Dominik; et al. (Advanced Functional Materials, 2022)

A new staining protocol for detection of murine antibody-secreting plasma cell subsets by flow cytometry - Pracht, Katharina; Meinzinger, Julia; Daum, Patrick; Schulz, Sebastian; Reimer, Dorothea; Hauke, Manuela; Roth, Edith; Mielenz, Dirk; Berek, Claudia; Corte-Real, Joana; Jäck, Hans-Martin; Schuh, Wolfgang (European Journal of Immunology, 2017)
We provide a robust four-color fluorescence-based flow cytometry protocol that distinguishes viable dividing plasmablasts from nondividing plasma cells and, based on CD19 surface abundance, identifies two mature plasma cell populations in the spleen and the bone marrow of mice.
EVALuna2:13650

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

Animal Models of Rheumatoid Arthritis (I): Pristane-Induced Arthritis in the Rat - Tuncel, Jonatan; Haag, Sabrina; Hoffmann, Markus; Yau, Anthony C. Y.; Hultqvist, Malin; Olofsson, Peter; Backlund, Johan; Nandakumar, Kutty Selva; Weidner, Daniela; Fischer, Anita; Leichsenring, Anna; Lange, Franziska; et al. (PLoS ONE, 2016)
To facilitate the development of therapies for rheumatoid arthritis (RA), the Innovative Medicines Initiative BTCure has combined the experience from several laboratories worldwide to establish a series of protocols for different animal models of arthritis that reflect the pathogenesis of RA. Here, we describe chronic pristane-induced arthritis (PIA) model in DA rats, and provide detailed instructions to set up and evaluate the model and for reporting data.We optimized dose of pristane and immunization procedures and determined the effect of age, gender, and housing conditions. We further assessed cage-effects, reproducibility, and frequency of chronic arthritis, disease markers, and efficacy of standard and novel therapies.Out of 271 rats, 99.6% developed arthritis after pristane-administration. Mean values for day of onset, day of maximum arthritis severity and maximum clinical scores were 11.8±2.0 days, 20.3±5.1 days and 34.2±11 points on a 60-point scale, respectively. The mean frequency of chronic arthritis was 86% but approached 100% in long-term experiments over 110 days. Pristane was arthritogenic even at 5 microliters dose but needed to be administrated intradermally to induce robust disease with minimal variation. The development of arthritis was age-dependent but independent of gender and whether the rats were housed in conventional or barrier facilities. PIA correlated well with weight loss and acute phase reactants, and was ameliorated by etanercept, dexamethasone, cyclosporine A and fingolimod treatment.PIA has high incidence and excellent reproducibility. The chronic relapsing-remitting disease and limited systemic manifestations make it more suitable than adjuvant arthritis for long-term studies of joint-inflammation and screening and validation of new therapeutics.
EVALuna2:13308

An integrative approach unveils FOSL1 as an oncogene vulnerability in KRAS-driven lung and pancreatic cancer - Vallejo, Adrian; Perurena, Naiara; Guruceaga, Elisabet; Mazur, Pawel K.; Martinez-Canarias, Susana; Zandueta, Carolina; Valencia, Karmele; Arricibita, Andrea; Gwinn, Dana; Sayles, Leanne C.; Chuang, Chen-Hua; Guembe, Laura; et al. (Nature Communications, 2017)
KRAS mutated tumours represent a large fraction of human cancers, but the vast majority remains refractory to current clinical therapies. Thus, a deeper understanding of the molecular mechanisms triggered by KRAS oncogene may yield alternative therapeutic strategies. Here we report the identification of a common transcriptional signature across mutant KRAS cancers of distinct tissue origin that includes the transcription factor FOSL1. High FOSL1 expression identifies mutant KRAS lung and pancreatic cancer patients with the worst survival outcome. Furthermore, FOSL1 genetic inhibition is detrimental to both KRAS-driven tumour types. Mechanistically, FOSL1 links the KRAS oncogene to components of the mitotic machinery, a pathway previously postulated to function orthogonally to oncogenic KRAS. FOSL1 targets include AURKA, whose inhibition impairs viability of mutant KRAS cells. Lastly, combination of AURKA and MEK inhibitors induces a deleterious effect on mutant KRAS cells. Our findings unveil KRAS downstream effectors that provide opportunities to treat KRAS-driven cancers.
EVALuna2:13408

An international survey of current management practices for polymyalgia rheumatica by general practitioners and rheumatologists - Donskov, Agnete Overgaard; Mackie, Sarah Louise; Hauge, Ellen Margrethe; Toro-Gutierrez, Carlos Enrique; Hansen, Ib Tonder; Hemmig, Andrea Katharina; Van Der Maas, Aatke; Gheita, Tamer; Nielsen, Berit Dalsgaard; Douglas, Karen M. J.; Conway, Richard; Rezus, Elena; et al. (Rheumatology, 2023)
Objectives To explore current management practices for PMR by general practitioners (GPs) and rheumatologists including implications for clinical trial recruitment. Methods An English language questionnaire was constructed by a working group of rheumatologists and GPs from six countries. The questionnaire focused on: 1: Respondent characteristics; 2: Referral practices; 3: Treatment with glucocorticoids; 4: Diagnostics; 5: Comorbidities; and 6: Barriers to research. The questionnaire was distributed to rheumatologists and GPs worldwide via members of the International PMR/Giant Cell Arteritis Study Group. Results In total, 394 GPs and 937 rheumatologists responded to the survey. GPs referred a median of 25% of their suspected PMR patients for diagnosis and 50% of these were returned to their GP for management. In general, 39% of rheumatologists evaluated patients with suspected PMR >2 weeks after referral, and a median of 50% of patients had started prednisolone before rheumatologist evaluation. Direct comparison of initial treatment showed that the percentage prescribing >25 mg prednisolone daily for patients was 30% for GPs and 12% for rheumatologists. Diagnostic imaging was rarely used. More than half (56%) of rheumatologists experienced difficulties recruiting people with PMR to clinical trials. Conclusion This large international survey indicates that a large proportion of people with PMR are not referred for diagnosis, and that the proportion of treatment-naive patients declined with increasing time from referral to assessment. Strategies are needed to change referral and management of people with PMR, to improve clinical practice and facilitate recruitment to clinical trials.
CRIS-Team WoS Importer:2023-03-24

An in vivo gene delivery approach for the isolation of reasonable numbers of type 2 innate lymphoid cells - Frech, Michael; Knipfer, Lisa; Wirtz, Stefan; Zaiss, Mario (MethodsX, 2020)
Group 2 innate lymphoid cells (ILC2s) are a recently recognized subset of innate lymphocytes with crucial role in mucosal immunity and tissue homeostasis. Over the past decade, substantial advances in our understanding of ILC2 biology have established them as an essential element in innate and adaptive immunity. However, their relatively low abundance and laborious purification from mucosal tissues make their study difficult. Moreover, due to a lack of an ILC2-specific Cre mouse-line, adoptive transfer of ILC2s into ILC-deficient hosts is inevitable. Herein we describe an in-depth protocol for the induction, isolation, and expansion of murine ILC2s. By combining an in vivo gene delivery approach to boost ILC2 numbers and a cell culture strategy to expand isolated cells, large quantities of highly pure ILC2s can be obtained. The isolated cells maintain their phenotype and can be used for subsequent cell transfer or in vitro studies. In comparison to previous protocols, this approach is cost-effective and efficient with potential yield of more than 20 million ILC2s isolated per mouse. • Group 2 innate lymphoid cells (ILC2s) are extensively studied in mouse models and humans in recent years. • Low abundance of ILC2s and current lack of specific ILC2 knockout mice makes in vivo research challenging. • This method allows high and pure ILC2 numbers for in vitro or adoptive in vivo transfer experiments.
CRIS-Team Scopus Importer:2020-09-25
Keywords: Cell culture; Cytokines; Fluorescent activated cell sorting; Group 2 innate lymphoid cells; Isolation and expansion of murine ILC2s

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

Annexin A5 regulates surface αvβ5 integrin for retinal clearance phagocytosis - Yu, Chen; Munoz Becerra, Luis; Mallavarapu, Mallika; Herrmann, Martin; Finnemann, Silvia C. (Journal of cell science, 2019)
Diurnal clearance phagocytosis by the retinal pigment epithelium (RPE) is a conserved efferocytosis process whose binding step is mediated by αvβ5 integrin receptors. Two related annexins, A5 (ANXA5) and A6 (ANXA6), share an αvβ5 integrin-binding motif. Here, we report that ANXA5, but not ANXA6, regulates the binding capacity for spent photoreceptor outer segment fragments or apoptotic cells by fibroblasts and RPE. Similar to αvβ5-deficient RPE, ANXA5-/- RPE in vivo lacks the diurnal burst of phagocytosis that follows photoreceptor shedding in wild-type retina. Increasing ANXA5 in cells lacking αvβ5 or increasing αvβ5 in cells lacking ANXA5 does not affect particle binding. Association of cytosolic ANXA5 and αvβ5 integrin in RPE in culture and in vivo further supports their functional interdependence. Silencing ANXA5 is sufficient to reduce levels of αvβ5 receptors at the apical phagocytic surface of RPE cells. The effect of ANXA5 on surface αvβ5 and on particle binding requires the C-terminal ANXA5 annexin repeat but not its unique N-terminus. These results identify a novel role for ANXA5 specifically in the recognition and binding step of clearance phagocytosis, which is essential to retinal physiology.This article has an associated First Person interview with the first author of the paper.
CRIS-Team Scopus Importer:2019-10-25
Keywords: Annexin A5; Clearance phagocytosis; Efferocytosis; Integrin; Retina; RPE

Annual meeting of the German Society for Rheumatology going virtual—successfully defying the pandemic Deutscher Rheumatologiekongress virtuell – erfolgreich tagen trotz Pandemie - Richter, Jutta G.; Chehab, Gamal; Knitza, Johannes; Krotova, Anna; Schneider, Matthias; Voormann, Anna Julia; Schulze-Koops, Hendrik; Specker, Christof (Zeitschrift für Rheumatologie, 2021)
Background: In 2020 the COVID-19 pandemic led to the annual meeting of the German Society for Rheumatology (DGRh) being conducted as the virtual German Rheumatology Congress. Aim: How is the virtual German Rheumatology Congress accepted and what are the possibilities of optimization for the future? Material and method: The registered participants were asked to take part in an online congress evaluation. Results: Of 2566 congress attendees, 721 participated in the evaluation. The majority (80.2%) were (very) satisfied with the event overall. Compared to the traditional format collegial exchange was perceived as worse using the virtual approach. The technology platform was predominantly described as easy to use and easily accessible. The selected topics of the congress met the expectations of 89% of the participants. The presented contents were estimated to be relevant for their professional activities by 85.2% of the participants. The majority of participants (85.3%) would welcome the congress contents to be permanently available on demand. Discussion: Overall, the participants appreciated the virtual format of the German Rheumatology Congress. Optimization aspects could be shown and these could be considered in the implementation of further (digital) congresses. The results of this work provide suggestions for improvement on how the DGRh can meet and exceed the needs of participants in organizing a virtual or hybrid conference in the future.
CRIS-Team Scopus Importer:2021-05-14
Keywords: Acceptance; COVID-19 pandemic; Digital Continuing Medical Education; Digital rheumatology; Virtual meeting

A noninvasive diagnostic approach to retrospective donor HLA typing in kidney transplant patients using urine - Bach, Christian; Knaup, Karl; Herrmann, Markus; Krumbiegel, Mandy; Pfister, Frederick; Büttner-Herold, Maike; Steffen, Martin; Zecher, Daniel; Lopau, Kai; Schneider, Karen; Dieterle, Anne; Amann, Kerstin Ute; et al. (Transplant International, 2021)
Antibody-mediated rejection (AMR) is a major obstacle to long-term kidney transplantation. AMR is mostly caused by donor specific HLA antibodies, which can arise before or any time after transplantation. Incomplete donor HLA typing and unavailability of donor DNA regularly preclude the assessment of donor-specificity of circulating anti-HLA antibodies. In our centre, this problem arises in approximately 20% of all post-transplant HLA-antibody assessments. We demonstrate that this diagnostic challenge can be resolved by establishing donor renal tubular cell cultures from recipient´s urine as a source of high-quality donor DNA. DNA was then verified for genetic origin and purity by fluorescence in situ hybridization and short tandem repeat analysis. Two representative cases highlight the diagnostic value of this approach which is corroborated by analysis of ten additional patients. The latter were randomly sampled from routine clinical care patients with available donor DNA as controls. In all 12 cases, we were able to perform full HLA typing of the respective donors confirmed by cross-comparison to results from the stored 10 donor DNAs. We propose that this noninvasive diagnostic approach for HLA typing in kidney transplant patients is valuable to determine donor specificity of HLA antibodies, which is important in clinical assessment of suspected AMR.
CRIS-Team Scopus Importer:2021-06-25
Keywords: antibody-mediated rejection; HLA typing; HLA-antibody post-transplantation; rejection

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

An outer membrane channel protein of Mycobacterium tuberculosis with exotoxin activity - Danilchanka, Olga; Sun, Jim; Pavlenok, Mikhail; Maueröder, Christian; Speer, Alexander; Siroy, Axel; Marrero, Joeli; Trujillo, Carolina; Mayhew, David L.; Doornbos, Kathryn S.; Munoz, Luis E.; Herrmann, Martin; et al. (Proceedings of the National Academy of Sciences of the United States of America, 2014)
The ability to control the timing and mode of host cell death plays a pivotal role in microbial infections. Many bacteria use toxins to kill host cells and evade immune responses. Such toxins are unknown in Mycobacterium tuberculosis. Virulent M. tuberculosis strains induce necrotic cell death in macrophages by an obscure molecular mechanism. Here we show that the M. tuberculosis protein Rv3903c (channel protein with necrosis-inducing toxin, CpnT) consists of an N-terminal channel domain that is used for uptake of nutrients across the outer membrane and a secreted toxic C-terminal domain. Infection experiments revealed that CpnT is required for survival and cytotoxicity of M. tuberculosis in macrophages. Furthermore, we demonstrate that the C-terminal domain of CpnT causes necrotic cell death in eukaryotic cells. Thus, CpnT has a dual function in uptake of nutrients and induction of host cell death by M. tuberculosis.
EVALuna2:12914

A Novel Mechanism for Generating the Interferon Signature in Lupus: Opsonization of Dead Cells by Complement and IgM - Zhuang, Haoyang; Han, Shuhong; Li, Yi; Kienhöfer, Deborah; Lee, Pui; Shumyak, Stepan; Meyerholz, Richard; Rosadzinski, Krzysztof; Rosner, Danielle; Chan, Annie; Xu, Yuan; Segal, Mark; et al. (Arthritis and Rheumatology, 2016)
In vitro studies suggest that the type I interferon (IFN) signature seen in most lupus patients results from Fc? receptor-mediated uptake of nucleic acid-containing immune complexes by plasmacytoid dendritic cells and engagement of endosomal Toll-like receptors. The aim of this study was to reexamine the pathogenesis of the IFN signature in vivo.Lupus was induced in mice by injecting pristane. Some mice were treated with normal immunoglobulin or with cobra venom factor to deplete complement. The IFN signature was evaluated by polymerase chain reaction. The IFN signature also was determined in C4-deficient patients and control subjects.Wild-type C57BL/6 mice with pristane-induced lupus developed a strong IFN signature, which was absent in immunoglobulin-deficient (?MT), C3(-/-) , and CD18(-/-) mice. Intravenous infusion of normal IgM, but not IgG, restored the IFN signature in ?MT mice, and the IFN signature in wild-type mice was inhibited by depleting complement, suggesting that opsonization by IgM and complement is involved in IFN production. Consistent with that possibility, the levels of "natural" IgM antibodies reactive with dead cells were increased in pristane-treated wild-type mice compared with untreated controls, and in vivo phagocytosis of dead cells was impaired in C3-deficient mice. To examine the clinical relevance of these findings, we identified 10 C4-deficient patients with lupus-like disease and compared them with 152 C4-intact patients and 21 healthy controls. In comparison with C4-intact patients, C4-deficient patients had a different clinical/serologic phenotype and lacked the IFN signature.These studies define previously unrecognized roles of natural IgM, complement, and complement receptors in generating the IFN signature in lupus.
EVALuna2:13289

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-DNA-IgM Favors the Detection of NET-Associated Extracellular DNA - Wang, Han; Stehr, Antonia; Singh, Jeeshan; Zlatar, Leticija; Hartmann, Arndt; Evert, Katja; Naschberger, Elisabeth; Von Stillfried, Saskia; Boor, Peter; Munoz, Luis Enrique; Knopf, Jasmin; Stürzl, Michael; et al. (International Journal of Molecular Sciences, 2023)
During inflammatory responses, neutrophils enter the sites of attack where they execute various defense mechanisms. They (I) phagocytose microorganisms, (II) degranulate to release cytokines, (III) recruit various immune cells by cell-type specific chemokines, (IV) secrete anti-microbials including lactoferrin, lysozyme, defensins and reactive oxygen species, and (V) release DNA as neutrophil extracellular traps (NETs). The latter originates from mitochondria as well as from decondensed nuclei. This is easily detected in cultured cells by staining of DNA with specific dyes. However, in tissues sections the very high fluorescence signals emitted from the condensed nuclear DNA hamper the detection of the widespread, extranuclear DNA of the NETs. In contrast, when we employ anti-DNA-IgM antibodies, they are unable to penetrate deep into the tightly packed DNA of the nucleus, and we observe a robust signal for the extended DNA patches of the NETs. To validate anti-DNA-IgM, we additionally stained the sections for the NET-markers histone H2B, myeloperoxidase, citrullinated histone H3, and neutrophil elastase. Altogether, we have described a fast one-step procedure for the detection of NETs in tissue sections, which provides new perspectives to characterize neutrophil-associated immune reactions in disease.
CRIS-Team Scopus Importer:2023-03-10
Keywords: anti-DNA-IgM; extracellular DNA; NETs

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.
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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

Anti-TNFs in axial spondyloarthritis - Kocijan, Roland; Muschitz, Christian; Rech, Juergen (Wiener Medizinische Wochenschrift, 2015)
Since there is no evidence regarding the efficacy of conventional synthetic disease modifying anti-rheumatic drugs in the improvement of axial spondyloarthritis (SpA), anti-tumor necrosis factors (anti-TNFs) are recommended if nonsteroidal anti-inflammatory drugs fail, or in case of high disease activity. Anti-TNFs show encouraging data regarding pain reduction, improved mobility and quality of life in both ankylosing spondylitis and non-radiographic axial spondyloarthritis. However, withdrawal of anti-TNF therapy leads to relapse of disease activity in SpA. Moreover, osteoproliferation does not seem to be influenced by anti-TNFs.
EVALuna2:13160

Aortic dissection and fever: cause or consequence - Manger, Bernhard; Schett, Georg (Zeitschrift für Rheumatologie, 2017)
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A pair of non‐competing neutralizing human monoclonal antibodies protecting from disease in a SARS‐CoV‐2 infection model - Peter, Antonia Sophia; Roth, Edith; Schulz, Sebastian; Fraedrich, Kirsten; Steinmetz, Tobit; Damm, Dominik; Hauke, Manuela; Richel, Elie; Müller-Schmucker, Sandra; Habenicht, Katharina Marie; Eberlein, Valentina; Issmail, Leila; et al. (European Journal of Immunology, 2021)
TRIANNI mice carry an entire set of human immunoglobulin V region gene segments and are a powerful tool to rapidly isolate human monoclonal antibodies. After immunizing these mice with DNA encoding the spike protein of SARS-CoV-2 and boosting with spike protein, we identified 29 hybridoma antibodies that reacted with the SARS-CoV-2 spike protein. Nine antibodies neutralize SARS-CoV-2 infection at IC50 values in the subnanomolar range. ELISA-binding studies and DNA sequence analyses revealed one cluster of three clonally related neutralizing antibodies that target the receptor-binding domain and compete with the cellular receptor hACE2. A second cluster of six clonally related neutralizing antibodies bind to the N-terminal domain of the spike protein without competing with the binding of hACE2 or cluster 1 antibodies. SARS-CoV-2 mutants selected for resistance to an antibody from one cluster are still neutralized by an antibody from the other cluster. Antibodies from both clusters markedly reduced viral spread in mice transgenic for human ACE2 and protected the animals from SARS-CoV-2-induced weight loss. The two clusters of potent non-competing SARS-CoV-2 neutralizing antibodies provide potential candidates for therapy and prophylaxis of COVID-19. The study further supports transgenic animals with a human immunoglobulin gene repertoire as a powerful platform in pandemic preparedness initiatives.

A patient with ankylosing spondylitis Ein patient mit spondylitis ankylosans - Waltering, Isabel; Rech, Jürgen; Rose, Olaf; Derendorf, Hartmut (Deutsche Apotheker Zeitung, 2016)
CRIS-Team Scopus Importer:2021-02-03

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)
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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 phase II study of alemtuzumab, fludarabine, cyclophosphamide, and doxorubicin (Campath-FCD) in peripheral T-cell lymphomas - Weidmann, Eckhart; Hess, Georg; Chow, Kai U.; Krause, Stefan W.; Subklewe, Marion; Kruse, Judith; Weisel, Katja C.; Soekler, Martin; Kim, Soo-Zin; Napieralski, Simone; Rech, Jürgen; Dreyling, Martin; et al. (Leukemia & Lymphoma, 2010)
The clinical course of peripheral T-cell lymphoma (PTCL) is usually aggressive and the prognosis unfavorable. Therefore, there is a need for improvement of treatment options. Patients with newly diagnosed (n27) or refractory/relapsed (n11) PTCL received a combination of alemtuzumab, fludarabine, cyclophosphamide, and doxorubicin. The overall response rate (ORR) was 61, with a complete response rate of 39. In newly diagnosed patients the ORR was 63, the median overall survival 25.9 months, and progression-free survival 11.8 months. In relapsed/refractory patients the median OS was 6.1 months. The most frequent grade 3/4 toxicities were leukopenia (95 of patients) and thrombocytopenia (58). Cytomegalovirus (CMV) reactivation occurred in 12 patients, but only two had CMV disease. Treatment-related deaths occurred in six newly diagnosed patients and one with relapsed/refractory disease. In conclusion, Campath-FCD is active in PTCL but is associated with significant toxicity and is, therefore, not recommended for use or further study. Further studies are warranted to investigate other approaches to combining alemtuzumab with chemotherapy for the treatment of PTCL. © 2010 Informa Healthcare USA, Inc.
CRIS-Team Scopus Importer:2021-02-03
Keywords: Alemtuzumab; Fludarabine; Peripheral T-cell lymphoma (PTCL)

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

APOBEC3 enzymes restrict marginal zone B cells - Beck-Engeser, Gabriele B.; Winkelmann, Rebecca; Wheeler, Matthew L.; Shansab, Maryam; Yu, Philipp; Wuensche, Sarah; Walchhuetter, Anja; Metzner, Mirjam; Vettermann, Christian; Eilat, Dan; Defranco, Anthony; Jäck, Hans-Martin; et al. (European Journal of Immunology, 2015)
In general, a long-lasting immune response to viruses is achieved when they are infectious and replication competent. In the mouse, the neutralizing antibody response to Friend murine leukemia virus is contributed by an allelic form of the enzyme Apobec3 (abbreviated A3). This is counterintuitive because A3 directly controls viremia before the onset of adaptive antiviral immune responses. It suggests that A3 also affects the antibody response directly. Here, we studied the relative size of cell populations of the adaptive immune system as a function of A3 activity. We created a transgenic mouse that expresses all seven human A3 enzymes and compared it to WT and mouse A3-deficient mice. A3 enzymes decreased the number of marginal zone B cells, but not the number of follicular B or T cells. When mouse A3 was knocked out, the retroelement hitchhiker-1 and sialyl transferases encoded by genes close to it were overexpressed three and two orders of magnitude, respectively. We suggest that A3 shifts the balance, from the fast antibody response mediated by marginal zone B cells with little affinity maturation, to a more sustained germinal center B-cell response, which drives affinity maturation and, thereby, a better neutralizing response.
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Apoptotic cell clearance and its role in the origin and resolution of chronic inflammation - Munoz, Luis Enrique; Berens, Christian; Lauber, Kirsten; Gaipl, Udo; Herrmann, Martin (Frontiers in Immunology, 2015)
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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

Application of Risk Scores in the Daily Management of Primary Biliary Cholangitis: Response to Corpechot and Chazouillères - Efe, Cumali; Taşçilar, Koray; Montano-Loza, Aldo J.; Yoshida, Eric M.; Wahlin, Staffan (American Journal of Gastroenterology, 2019)
CRIS-Team Scopus Importer:2019-10-15

Apps und ihre Anwendungsgebiete in der Rheumatologie - Krusche, M.; Ruffer, N.; Grahammer, M.; Knitza, Johannes (Zeitschrift für Rheumatologie, 2020)
The increasing use of smartphones is accompanied by a significant increase in the use of mobile applications (apps). Chronically ill patients could permanently profit from this development.This development is fuelled by the Digital Healthcare Act (DVG), whereby patients have a legal claim to certain apps, so-called digital health applications (DiGAs), which are reimbursed by the statutory health insurance companies. Especially in the field of rheumatology, there are various opportunities to implement apps in the management of chronic diseases and their comorbidities. Furthermore, rheumatic patients and rheumatologists are becoming interested in apps and are willing to use them in the daily routine. This article tries to shed light on the chances and risks of apps and gives a first insight into the digital landscape of rheumatology apps in Germany.
CRIS-Team Scopus Importer:2020-06-09
Keywords: Digital health; eHealth; mHealth; Mobile applications; Rheumatology

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)
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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)
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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)
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Are agonistic beta 2-adrenergic receptor autoantibodies present in normal tension glaucoma and secondary open-angle glaucoma? - Hohberger, Bettina; Mardin, Christian Y.; Hosari, Sami; Lämmer, Robert; Kunze, Rudolf; Juenemann, Anselm; Schlötzer-Schrehardt, Ursula; Wallukat, Gerd; Herrmann, Martin (INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE, 2019)
CRIS-Team WoS Importer:2019-10-29

A real-world rheumatology registry and research consortium: The German RheumaDatenRhePort (RHADAR) registry - Kleinert, Stefan; Bartz-Bazzanella, Peter; von der Decken, Cay; Knitza, Johannes; Witte, Torsten; Fekete, Sándor P.; Konitzny, Matthias; Zink, Alexander; Gauler, Georg; Wurth, Patrick; Aries, Peer; Karberg, Kirsten; et al. (Journal of Medical Internet Research, 2021)
Real-world data are crucial to continuously improve the management of patients with rheumatic and musculoskeletal diseases (RMDs). The German RheumaDatenRhePort (RHADAR) registry encompasses a network of rheumatologists and researchers in Germany providing pseudonymized real-world patient data and allowing timely and continuous improvement in the care of RMD patients. The RHADAR modules allow automated anamnesis and adaptive coordination of appointments regarding individual urgency levels. Further modules focus on the collection and integration of electronic patient-reported outcomes in between consultations. The digital RHADAR modules ultimately allow a patient-centered adaptive approach to integrated medical care starting as early as possible in the disease course. Such a closed-loop system consisting of various modules along the whole patient pathway enables comprehensive and timely patient management in an unprecedented manner.
CRIS-Team Scopus Importer:2021-06-04
Keywords: Patient-reported outcomes; Real-world data; Registry; Rheumatology; Symptom checker

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.
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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.
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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.
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Assessing metabolic demands in B cells - Mielenz, Dirk; Urbanczyk, Sophia; Stein, Merle; Reimer, Dorothea; Winkler, Thomas; Jäck, Hans-Martin (2017)
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Assessing muscle-specific potassium concentrations in human lower leg using potassium magnetic resonance imaging - Gast, Lena; Baier, Laura-Marie; Chaudry, Oliver; Meixner, Christian; Müller, Max; Engelke, Klaus; Uder, Michael; Heiß, Rafael; Nagel, Armin Michael (NMR in Biomedicine, 2022)
Noninvasively assessing tissue potassium concentrations (TPCs) using potassium magnetic resonance imaging (39K MRI) could give valuable information on physiological processes connected to various pathologies. However, because of inherently low 39K MR image resolution and strong signal blurring, a reliable measurement of the TPC is challenging. The aim of this work was to investigate the feasibility of a muscle-specific TPC determination with a focus on the influence of a varying residual quadrupolar interaction in human lower leg muscles. The quantification accuracy of a muscle-specific TPC determination was first assessed using simulated 39K MRI data. In vivo 39K and corresponding sodium (23Na) MRI data of healthy lower leg muscles (n = 14, seven females) were acquired on a 7-T MR system using a double-resonant 23Na/39K birdcage Tx/Rx RF coil. Additional 1H MR images were acquired on a 3-T MR system and used for tissue segmentation. Quantification of TPC was performed after a region-based partial volume correction (PVC) using five external reference phantoms. Simulations not only underlined the importance of PVC for correctly assessing muscle-specific TPC values, but also revealed the strong impact of a varying residual quadrupolar interaction between different muscle regions on the measured TPC. Using 39K T2* decay curves, we found significantly higher residual quadrupolar interaction in tibialis anterior muscle (TA; ωq = 194 ± 28 Hz) compared with gastrocnemius muscle (medial/lateral head, GM/GL; ωq = 151 ± 25 Hz) and soleus muscle (SOL; ωq = 102 ± 32 Hz). If considered in the PVC, TPC in individual muscles was similar (TPC = 98 ± 11/96 ± 14/99 ± 8/100 ± 12 mM in GM/GL/SOL/TA). Comparison with tissue sodium concentrations suggested that residual quadrupolar interactions might also influence the 23Na MRI signal of lower leg muscles. A TPC determination of individual lower leg muscles is feasible and can therefore be applied in future studies. Considering a varying residual quadrupolar interaction for PVC of 39K MRI data is essential to reliably assess potassium concentrations in individual muscles.
CRIS-Team Scopus Importer:2022-09-16
Keywords: 7 T; muscle MRI; potassium (; sodium (; tissue potassium concentration; tissue sodium concentration; ultrahigh field strengths

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.
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