„Rheuma (be-)greifen“ – ein multimodales Lehrkonzept zur Verbesserung der rheumatologischen Lehre für Studierende der Humanmedizin - Schuster, Louis; Valor-Mendez, Larissa; Wacker, Jochen; Dannhardt-Thiem, V.; Schmidt, A.; Knitza, Johannes; Simon, David; Manger, Bernhard; Schett, Georg; Kleyer, Arnd (Zeitschrift für Rheumatologie, 2023)
Background: The German Society for Rheumatology, through its campaign Rheuma2025, aims to improve student teaching in order to ensure patient care for rheumatological patients in the future. Objective: To assess whether a combination of traditional and innovative educational methods provide both an improvement in the quality of teaching and an increase in the attractiveness of rheumatology as a discipline. Material and methods: Establishment of the teaching concept “Rheuma (be-)greifen” consisting of five modules on patient history taking with acting patients, musculoskeletal ultrasound, arthrocentesis, 3D printing of pathological joints and virtual reality applications based on real patient cases in the curricular teaching of medical students. Results: The evaluation of the teaching concept with 93 students of medicine showed a consistently high acceptance of all modules, which were rated as very effective or rather effective. Direct patient-related modules, such as history taking with acting patients, musculoskeletal ultrasound and arthrocentesis, received even higher acceptance than the visualization methods utilizing 3D printing and virtual reality. Conclusion: Innovative teaching methods can help to improve the acceptance of teaching in the field of rheumatology, especially when combined with classical teaching contents.
CRIS-Team Scopus Importer:2023-08-11
Keywords: 3D printing; Medical education; Rheumality©; Rheumatology; Virtual reality

Rheumatic?—A Digital Diagnostic Decision Support Tool for Individuals Suspecting Rheumatic Diseases: A Multicenter Pilot Validation Study - Knevel, Rachel; Knitza, Johannes; Hensvold, Aase; Circiumaru, Alexandra; Bruce, Tor; Evans, Sebastian; Maarseveen, Tjardo; Maurits, Marc; Beaart-van de Voorde, Liesbeth; Simon, David; Kleyer, Arnd; Johannesson, Martina; et al. (Frontiers in Medicine, 2022)
Introduction: Digital diagnostic decision support tools promise to accelerate diagnosis and increase health care efficiency in rheumatology. Rheumatic? is an online tool developed by specialists in rheumatology and general medicine together with patients and patient organizations. It calculates a risk score for several rheumatic diseases. We ran a pilot study retrospectively testing Rheumatic? for its ability to differentiate symptoms from existing or emerging immune-mediated rheumatic diseases from other rheumatic and musculoskeletal complaints and disorders in patients visiting rheumatology clinics. Materials and Methods: The performance of Rheumatic? was tested using in three university rheumatology centers: (A) patients at Risk for RA (Karolinska Institutet, n = 50 individuals with musculoskeletal complaints and anti-citrullinated protein antibody positivity) (B) patients with early joint swelling [dataset B (Erlangen) n = 52]. (C) Patients with early arthritis where the clinician considered it likely to be of auto-immune origin [dataset C (Leiden) n = 73]. In dataset A we tested whether Rheumatic? could predict the development of arthritis. In dataset B and C we tested whether Rheumatic? could predict the development of an immune-mediated rheumatic diseases. We examined the discriminative power of the total score with the Wilcoxon rank test and the area-under-the-receiver-operating-characteristic curve (AUC-ROC). Next, we calculated the test characteristics for these patients passing the first or second expert-based Rheumatic? scoring threshold. Results: The total test scores differentiated between: (A) Individuals developing arthritis or not, median 245 vs. 163, P < 0.0001, AUC-ROC = 75.3; (B) patients with an immune-mediated arthritic disease or not median 191 vs. 107, P < 0.0001, AUC-ROC = 79.0; but less patients with an immune-mediated arthritic disease or not amongst those where the clinician already considered an immune mediated disease most likely (median 262 vs. 212, P < 0.0001, AUC-ROC = 53.6). Threshold-1 (advising to visit primary care doctor) was highly specific in dataset A and B (0.72, 0.87, and 0.23, respectively) and sensitive (0.67, 0.61, and 0.67). Threshold-2 (advising to visit rheumatologic care) was very specific in all three centers but not very sensitive: specificity of 1.0, 0.96, and 0.91, sensitivity 0.05, 0.07, 0.14 in dataset A, B, and C, respectively. Conclusion: Rheumatic? is a web-based patient-centered multilingual diagnostic tool capable of differentiating immune-mediated rheumatic conditions from other musculoskeletal problems. The current scoring system needs to be further optimized.
CRIS-Team Scopus Importer:2022-06-10
Keywords: diagnostics; eHealth; mHealth (mobile health); rheumatology; symptom assessment

RHEUMATIC? - A DIGITAL DIAGNOSTIC DECISION SUPPORT TOOL FOR INDIVIDUALS SUSPECTING RHEUMATIC DISEASES: A MULTICENTER VALIDATION STUDY - Knevel, R.; Knitza, Johannes; Hensvold, A.; Circiumaru, A.; Bruce, T.; Evans, S.; Maarseveen, T.; Maurits, Marc; Beaart-Van De Voorde, L.; Simon, David; Kleyer, Arnd; Johannesson, M.; et al. (Annals of the Rheumatic Diseases, 2021)
CRIS-Team WoS Importer:2021-10-01

Rheumatic paraneoplastic syndromes - A clinical link between malignancy and autoimmunity - Manger, Bernhard; Schett, Georg (Clinical Immunology, 2017)
Paraneoplastic syndromes are rare but can have enormous clinical impact on diagnosis and outcome of neoplastic diseases. The rheumatologist should be familiar with a few typical musculoskeletal manifestations of malignancies to be able to diagnose them early for a timely initiation of anti-tumour therapies. This review describes the characteristic features of various paraneoplastic arthritides and vasculitides, cancer-associated myositis, hypertrophic osteoarthropathy, and tumour-induced osteomalacia. In addition, the current knowledge about underlying pathomechanisms of these syndromes is discussed.
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Rheumatoid arthritis and osteoimmunology: The adverse impact of a deregulated immune system on bone metabolism - Andreev, Darja; Kachler, Katerina; Bozec, Aline; Schett, Georg (Bone, 2022)
The term osteoimmunology describes an interdisciplinary research field that links the investigation of osteology (bone cells) with immunology. The crosstalk between innate and adaptive immune cells and cells involved in bone remodeling, mainly bone-resorbing osteoclasts and bone-forming osteoblasts, becomes particularly obvious in the inflammatory autoimmune disease rheumatoid arthritis (RA). Besides striking inflammation of the joints, RA causes bone loss, leading to joint damage and disabilities as well as generalized osteoporosis. Mechanistically, RA-associated immune cells (macrophages, T cells, B cells etc.) produce high levels of pro-inflammatory cytokines, receptor activator of nuclear factor κB ligand (RANKL) and autoantibodies that promote bone degradation and at the same time counteract new bone formation. Today, antirheumatic therapy effectively ceases joint inflammation and arrests bone erosion. However, the repair of established bone lesions still presents a challenging task and requires improved treatment options. In this review, we outline the knowledge gained over the past years about the immunopathogenesis of RA and the impact of a dysregulated immune system on bone metabolism.
CRIS-Team Scopus Importer:2022-07-01
Keywords: Bone erosion; Osteoblasts; Osteoclasts; Osteoimmunology; Rheumatoid arthritis

Rheumatoid arthritis, as a clinical disease, but not rheumatoid arthritis-associated autoimmunity, is linked to cardiovascular events - Gouze, Helene; Aegerter, Philippe; Said-Nahal, Roula; Zins, Marie; Goldberg, Marcel; Morelle, Guillaume; Schett, Georg; Breban, Maxime; D'Agostino, Maria Antonietta (Arthritis Research & Therapy, 2022)
Background: Rheumatoid arthritis (RA) is characterized by increased cardiovascular (CV) mortality. CV events are particularly high in patients with RA-specific autoimmunity, including rheumatoid factor (RF) and anti-citrullinated protein antibodies (ACPA), raising the question whether RA-specific autoimmunity itself is associated with CV events. Methods: New CV events (myocardial infarction, stroke or death by CV cause) were recorded in 20,625 subjects of the Electricité de France – Gaz de France (GAZEL) cohort. Self-reported RA cases in the GAZEL cohort were validated by phone interview on the basis of a specific questionnaire. In 1618 subjects, in whom plasma was available, RF and ACPA were measured. A piecewise exponential Poisson regression was used to analyze the association of CV events with presence of RA as well as RA-specific autoimmunity (without RA). Results: CV events in GAZEL were associated with age, male sex, smoking, hypertension, hyperlipidemia, and diabetes mellitus (HR from 1.06 to 1.87, p < 0.05). Forty-two confirmed RA cases were identified. Confirmed RA was significantly associated with CV risk increase (HR of 3.03; 95% CI: 1.13–8.11, p = 0.03) independently of conventional CV risk factors. One hundred seventy-eight subjects showed RF or ACPA positivity without presence of RA. CV events were not associated with ACPA positivity (HR: 1.52, 95% CI: 0.47–4.84, p = 0.48) or RF positivity (HR: 1.15, 95% CI: 0.55–2.40, p = 0.70) in the absence of RA. Conclusions: RA, as a clinical chronic inflammatory disease, but not mere positivity for RF or ACPA in the absence of clinical disease is associated with increased CV risk.
CRIS-Team Scopus Importer:2022-03-11
Keywords: Anti-citrullinated protein autoantibody; Autoimmunity; Cardiovascular diseases; Cardiovascular risk; Rheumatoid arthritis

Rheumatoid arthritis is characterized by early changes of the cortical micro-channel (CoMiC) system in the bare area of the joints - Werner, David; Simon, David; Englbrecht, Matthias; Stemmler, Fabian; Simon, Christoph; Berlin, Andreas; Haschka, Judith; Renner, Nina; Buder, Thomas; Engelke, Klaus; Hueber, Axel; Rech, Jürgen; et al. (Arthritis and Rheumatology, 2017)
To characterize the specific structural properties of the erosion-prone bare area of the human joint and to search for early microstructural changes in this region during rheumatoid arthritis Methods: An initial cadaveric study was used for exact localization of the bare area of the metacarpal heads, detection of cortical micro-channels (CoMiCs) in this region by high-resolution peripheral computed tomography (HR-pQCT) and, after anatomical dissection, their validation by micro-computed tomography (?CT). In the second part, number and distribution of CoMiCs were analyzed in 105 healthy individuals and 107 RA patients with similar sex and age distribution.HR-pQCT investigation combined with adaptive thresholding allowed detection of CoMiCs in the bare area of cadaveric joints. Their existence in the bare area was additionally validated by ?CT. In healthy individuals, the number of CoMiCs increased with age. RA patients showed significantly (p<0.001) more CoMiCs (112.9±54.7/joint) than healthy individuals (75.2±41.9/joint) with 20-49 years old RA patients exhibiting similar CoMiC numbers as observed in over 65 year old healthy individuals. Importantly, CoMiCs were found in RA patients already very early in their disease course with enrichment in the erosion-prone radial side of the joint.CoMiCs represent a new form of structural change in the joints of patients with RA. While CoMiCs increase with age, RA patients develop such changes much earlier in life and already at the onset of the disease. CoMiCs therefore represent an interesting new opportunity to assess structural changes in RA. This article is protected by copyright. All rights reserved.
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Rheumatologische paraneoplastische Syndrome - Knitza, Johannes; Schett, Georg; Manger, Bernhard (Aktuelle Rheumatologie, 2020)
Zusammenfassung Rheumatologische paraneoplastische Syndrome sind selten, stellten jedoch eine wichtige Differenzialdiagnose zu klassischen rheumatologischen Krankheitsbildern dar. Durch das Erkennen der eindrücklichen Syndrome mit typischen Labor- und Untersuchungsbefunden ist oftmals eine beschleunigte Diagnose der zugrundeliegenden Malignität und kurative Therapie möglich. In dieser Übersichtsarbeit werden die Charakteristika rheumatologischer paraneoplastischer Syndrome vorgestellt.
CRIS-Team Scopus Importer:2020-12-18
Keywords: Malignom; Myositis; Paraneoplasie; Rheumatologie; Tumorsuche

Risk of developing psoriatic arthritis in psoriasis cohorts with arthralgia: exploring the subclinical psoriatic arthritis stage - Zabotti, Alen; Fagni, Filippo; Gossec, Laure; Giovannini, Ivan; Sticherling, Michael; Tullio, Annarita; Baraliakos, Xenofon; De Marco, Gabriele; De Vita, Salvatore; Errichetti, Enzo; Quartuccio, Luca; Silvagni, Ettore; et al. (RMD Open, 2024)
Objective Subjects with subclinical psoriatic arthritis (PsA), defined as the presence of arthralgia in psoriasis (PsO), are at higher risk of PsA but scant real-world data exist. Our aims were to (1) estimate the probability of PsA development in subclinical PsA, (2) characterise subclinical PsA symptoms and (3) determine the clinical patterns at PsA diagnosis. Methods Patients with PsO, mainly subclinical PsA, were evaluated longitudinally in two European cohorts. The key outcome was new-onset PsA. Musculoskeletal symptoms including inflammatory and non-inflammatory symptoms before PsA diagnosis were collected. Occurrence of PsA was analysed with survival analysis and cumulative incidence functions (CIFs). Results 384 patients with PsO were included with a mean follow-up of 33.0 (±20.9) months. 311 of 384 (80.9%) had subclinical PsA with a PsA incidence rate of 7.7 per 100 patient-years. Subclinical PsA displayed a higher risk of PsA development compared with PsO (HR=11.7 (95% CI 1.57 to 86.7), p=0.016). The probability of new-onset PsA estimated by the CIF was 9.4% (95% CI 4.7% to 10.6%) at month 12 and 22.7% (95% CI 17.2% to 28.6%) at month 36. 58.9% of cases reported inflammatory symptoms in the months immediately prior to PsA diagnosis but prior non-inflammatory symptoms were evident in 83.9% prior to PsA diagnosis. Peripheral joint swelling was the predominant PsA presentation pattern (82.1%). Conclusions The probability of PsA development among subclinical PsA was relatively high, emphasising the importance of emergent musculoskeletal symptoms when aiming for PsA prevention. Joint swelling was the dominant feature in new-onset PsA, likely reflecting clinical confidence in recognising joint swelling.
CRIS-Team Scopus Importer:2024-04-26
Keywords: arthritis; psoriatic; classification; incidence; synovitis; ultrasonography

Risk of infections in rheumatoid arthritis patients treated with tocilizumab - Lang, Veronika R.; Englbrecht, Matthias; Rech, Jürgen; Nüsslein, Hubert; Manger, Karin; Schuch, Florian; Tony, Hans-Peter; Fleck, Martin; Manger, Bernhard; Schett, Georg; Zwerina, Jochen (Rheumatology, 2012)
Objectives: To investigate the occurrence and risk factors for infections in RA patients treated with tocilizumab. Methods: A cohort of all RA patients (n = 112) starting tocilizumab therapy between October 2008 and March 2010 in Northern Bavaria was screened for infections. Mild/moderate and severe infections were recorded. Multivariate logistic regression analysis was used to define risk factors for infection. Results: Overall, 26 patients developed infections [23.2%; 58.0/100 patient-years (py)], 18 of them were mild to moderate (16.1%, 40.1/100 py) and 8 were severe (17.9/100 py). Concomitant use of LEF and prednisone, high disease activity and previous therapy with rituximab were associated with the occurrence of mild/moderate infections. Severe infections were related to longer disease duration, exposure to more than three previous DMARDs and concomitant therapy with proton-pump inhibitors. Conclusion: The rate of infection in RA patients treated with tocilizumab in clinical practice is higher than in the clinical trial populations. Increased attention should especially be given to patients with longer disease duration, previous exposure to multiple DMARDs, i.e. previous exposure to rituximab and those receiving concomitant LEF, prednisone or proton-pump inhibitor treatment. © The Author 2011. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved.
CRIS-Team Scopus Importer:2021-02-03
Keywords: Infections; Rheumatoid arthritis; Tocilizumab

ROS Ameriolates the Clinical Course of Murine Lupus - Hahn, Jonas; Kienhoefer, Deborah; Stoof, Julia; Csepregi, Janka Zsofia; Hultqvist, Malin; Leppkes, Moritz; Herrmann, Martin; Mocsai, Atilla; Schett, Georg; Hoffmann, Markus (2016)
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ROS is the boss - Hahn, Jonas; Kienhofer, Deborah; Stoof, Julia; Csepregi, Janka Zsofia; Reinwald, Christiane; Maueröder, Christian; Urbonaviciute, Vilma; Munoz, Luis Enrique; Hultqvist, Malin; Podolska, Malgorzata; Biermann, Mona; Leppkes, Moritz; et al. (2017)
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Rsk2 controls synovial fibroblast hyperplasia and the course of arthritis - Derer, Anja; Boehm, Christina; Groetsch, Bettina; Gruen, Joachim R.; Gruetzkau, Andreas; Stock, Michael; Böhm, Sybille; Sehnert, Bettina; Gaipl, Udo; Schett, Georg; Hueber, Axel; David, Jean-Pierre (Annals of the Rheumatic Diseases, 2016)
Arthritis is a chronic inflammatory disease characterised by immune cell infiltration and mesenchymal cell expansion in the joints. Although the role of immune cells in arthritis is well characterised, the development of mesenchymal cell hyperplasia needs to be better defined. Here, we analysed the role of the ribosomal S6 kinase Rsk2, which we found to be highly activated in joints of patients with arthritis, in the development of mesenchymal cell hyperplasia.We genetically inactivated Rsk2 in the tumour necrosis factor (TNF)-? transgenic (TNFtg) mice, an animal model for human inflammatory arthritis. Clinical and histological signs of arthritis as well as molecular markers of inflammation and joint destruction were quantified. Fibroblast-like synoviocytes (FLS) were characterised in vitro and the effect of Rsk2 deletion on the pattern of gene expression was determined.Rsk2 deficiency in TNFtg mice results in earlier and exacerbated inflammation as well as increased bone and cartilage destruction. The production of inflammatory cytokines, matrix metalloproteinases and osteoclastogenic molecules was significantly increased in vivo upon Rsk2 inactivation. Bone marrow deficient in Rsk2 could not transfer this phenotype, indicating that Rsk2 expression in mesenchymal cells controls the course of arthritis. Indeed, Rsk2 deficiency was associated with a more activated phenotype and higher proliferative capacity of FLS, thereby increasing cytokines and production of matrix proteinases.Rsk2 emerges as a key regulator of mesenchymal cell numbers in the joint and thereby could be targeted to control the inflammatory and tissue-destructive feature of joints in arthritis.
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R-spondin 1 protects against inflammatory bone damage during murine arthritis by modulating the Wnt pathway - Krönke, Gerhard; Uderhardt, Stefan; Kim, Kyung-Ah; Stock, Michael; Scholtysek, Carina; Zaiss, Mario; Surmann-Schmitt, Cordula; Luther, Julia; Katzenbeisser, Julia; David, Jean-Pierre; Abdollahi-Roodsaz, Shahla; Tran, Karolyn; et al. (Arthritis and Rheumatism, 2010)
Objective. During the course of different musculoskeletal diseases, joints are progressively damaged by inflammatory, infectious, or mechanical stressors, leading to joint destruction and disability. While effective strategies to inhibit joint inflammation, such as targeted cytokine-blocking therapy, have been developed during the last decade, the molecular mechanisms of joint damage are still poorly understood. This study was undertaken to investigate the role of the Wnt pathway modulator R-Spondin 1 (RSpo1) in protecting bone and cartilage in a mouse model of arthritis. Methods. Tumor necrosis factor α (TNFα)-transgenic mice were treated with vehicle or Rspo1. Mice were evaluated for signs of arthritis, and histologic analysis of the hind paws was performed. Moreover, we determined the effect of Rspo1 on Wnt signaling activity and osteoprotegerin (OPG) expression in murine primary osteoblasts. Results. The secreted Wnt pathway modulator RSpo1 was highly effective in preserving the structural integrity of joints in a TNFα-transgenic mouse model of arthritis by protecting bone and cartilage from inflammation-related damage. RSpo1 antagonized the Wnt inhibitor Dkk-1 and modulated Wnt signaling in mouse mesenchymal cells. In osteoblasts, RSpo1 induced differentiation and expression of OPG, thereby inhibiting osteoclastogenesis in vitro. In vivo, RSpo1 promoted osteoblast differentiation and bone formation while blocking osteoclast development, thereby contributing to the integrity of joints during inflammatory arthritis. Conclusion. Our results demonstrate the therapeutic potential of RSpo1 as an anabolic agent for the preservation of joint architecture. © 2010, American College of Rheumatology.
CRIS-Team Scopus Importer:2020-11-20

S100A8 BUT NOT S100A9 LEVEL IS RELATED TO THE EXTENT OF EROSIVE BONE DAMAGE IN PSORIATIC ARTHRITIS PATIENTS - Simon, David; Nas, K.; Faustini, F.; Kleyer, Arnd; Haschka, J.; Englbrecht, Matthias; Hueber, Axel; Kocijan, R.; Sticherling, Michael; Schett, Georg; Rech, Jürgen (2016)
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SARS-CoV-2 vaccination responses in untreated, conventionally treated and anticytokine-treated patients with immune-mediated inflammatory diseases - Simon, David; Tascilar, Koray; Fagni, Filippo; Krönke, Gerhard; Kleyer, Arnd; Meder, Christine; Meder, Christine; Atreya, Raja; Leppkes, Moritz; Kremer, Andreas E.; Pachowsky, Milena; Schuch, Florian; et al. (Annals of the Rheumatic Diseases, 2021)
Objectives: To better understand the factors that influence the humoral immune response to vaccination against SARS-CoV-2 in patients with immune-mediated inflammatory diseases (IMIDs). Methods: Patients and controls from a large COVID-19 study, with (1) no previous history of COVID-19, (2) negative baseline anti-SARS-CoV-2 IgG test and (3) SARS-CoV-2 vaccination at least 10 days before serum collection were measured for anti-SARS-CoV-2 IgG. Demographic, disease-specific and vaccination-specific data were recorded. Results: Vaccination responses from 84 patients with IMID and 182 controls were analysed. While all controls developed anti-SARS-CoV-2 IgG, five patients with IMID failed to develop a response (p=0.003). Moreover, 99.5% of controls but only 90.5% of patients with IMID developed neutralising antibody activity (p=0.0008). Overall responses were delayed and reduced in patients (mean (SD): 6.47 (3.14)) compared with controls (9.36 (1.85); p<0.001). Estimated marginal means (95% CI) adjusted for age, sex and time from first vaccination to sampling were 8.48 (8.12-8.85) for controls and 6.90 (6.45-7.35) for IMIDs. Significantly reduced vaccination responses pertained to untreated, conventionally and anticytokine treated patients with IMID. Conclusions: Immune responses against the SARS-CoV-2 are delayed and reduced in patients with IMID. This effect is based on the disease itself rather than concomitant treatment.
CRIS-Team Scopus Importer:2021-05-21
Keywords: biological therapy; COVID-19; epidemiology; vaccination

Sars-Cov-2 Vaccine-Induced Cellular and Humoral Immunity in Patients after CD19.CAR-T Cell Therapy - Reimann, Hannah; Kremer, Anita; Blumenberg, Viktoria; Schmidt, Katja; Aigner, Michael; Kremer, Andreas; Tenbusch, Matthias; Bruns, Heiko; Harrer, Thomas; Schett, Georg; Müller, Fabian; Mackensen, Andreas; et al. (BLOOD, 2022)
CRIS-Team WoS Importer:2023-03-17

Scurvy : A rare differential diagnosis of rheumatic diseases - Hofheinz, K.; Ganzleben, Ingo; Schliep, S.; Wacker, J.; Schett, Georg; Manger, Bernhard (Zeitschrift für Rheumatologie, 2016)
In December 2014 a patient presented to our clinic with the clinical symptoms of vasculitis. However, treatment with glucocorticoids did not lead to any improvement; therefore, the differential diagnostics were extended to other indications and ultimately led to the diagnosis of scurvy.This article describes the clinical picture of scurvy and its relationship to rheumatic diseases based on a clinical case and additional information from the literature. Differences and similarities with important rheumatological disease symptoms are presented.Scurvy is a rare hypovitaminosis disease which can be manifested in different forms. In addition to vasculitis the symptoms can also resemble arthritis and hemarthrosis is a typical finding. These symptoms can be accompanied by unspecific manifestations, such as muscle pain and due to impaired collagen synthesis characteristic features, such as corkscrew hair can be observed. The causal therapy of scurvy is substitution of ascorbic acid.Scurvy is a rare differential diagnosis in the context of rheumatic diseases. The indications for scurvy can be a lack of response to immunosuppressive and immunomodulatory drugs as well as individual symptoms, such as corkscrew hair.
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SECUKINUMAB EFFICACY IN PSORIATIC ARTHRITIS PATIENTS WITH OR WITHOUT ENTHESITIS AT BASELINE - POOLED ANALYSIS FROM TWO PHASE-III TRIALS OVER 2 YEARS - Wallman, J. K.; Schett, Georg; Mcinnes, I. B.; Quebe-Fehling, E.; Rasouliyan, L.; Pricop, L.; Fasth, A. E.; Gaillez, C. (2018)
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Secukinumab Efficacy on Enthesitis in Patients With Ankylosing Spondylitis: Pooled Analysis of Four Pivotal Phase III Studies - Schett, Georg; Baraliakos, Xenofon; Van Den Bosch, Filip; Deodhar, Atul; Ostergaard, Mikkel; Das Gupta, Ayan; Mpofu, Shephard; Fox, Todd; Winseck, Adam; Porter, Brian; Shete, Abhijit; Gensler, Lianne S. (Journal of Rheumatology, 2021)
Objective: To assess the efficacy of secukinumab on axial and peripheral enthesitis in patients with ankylosing spondylitis (AS) using pooled data from randomized controlled phase III studies.
CRIS-Team WoS Importer:2021-08-13

Secukinumab efficacy on resolution of enthesitis in psoriatic arthritis: pooled analysis of two phase 3 studies - Coates, Laura C.; Wallman, Johan K.; McGonagle, Dennis; Schett, Georg; McInnes, Iain B.; Mease, Philip J.; Rasouliyan, Lawrence; Quebe-Fehling, Erhard; Asquith, Darren L.; Fasth, Andreas E.R.; Pricop, Luminita; Gaillez, Corine (Arthritis Research & Therapy, 2019)
BACKGROUND: Enthesitis is one of the psoriatic arthritis (PsA) domains. Patients with enthesitis are associated with worse outcomes than those without enthesitis. The effect of secukinumab on the resolution of enthesitis in patients with PsA was explored using pooled data from the FUTURE 2 and 3 studies. METHOD: Assessments of enthesitis through week 104 used the Leeds Enthesitis Index. These post hoc analyses included resolution of enthesitis count (EC = 0), median time to first resolution of enthesitis (Kaplan-Meϊer estimate), and shift analysis (as observed) of baseline EC (1, 2, or 3-6) to full resolution (FR), stable (similar or reduction of EC), or worse (EC > baseline). Efficacy outcomes (ACR, PASI, HAQ-DI, SF-36 PCS, and DAS28-CRP) were assessed in patients with or without baseline enthesitis. Results are reported for secukinumab 300 and 150 mg in the overall population and by prior TNFi treatment. RESULTS: A total of 65% (466/712) of patients had baseline enthesitis. In the overall population, FR was achieved as early as week 16 in 65% (300 mg) and 56% (150 mg) versus 44% (placebo) patients, with further improvements to 91% (300 mg) and 88% (150 mg) at week 104. The majority (89%) of patients without enthesitis at baseline maintained this status at week 104. Median days to resolution of EC were shorter with secukinumab 300 and 150 mg versus placebo (57 and 85 vs 167 days, respectively). In patients with EC of 1 or 2, shift analysis from baseline to week 24 showed that more patients achieved FR with secukinumab 300 mg and 150 mg versus placebo, whereas no difference between secukinumab and placebo was shown in the more severe patients with EC of 3-6. Increases in proportions of patients with FR were observed with secukinumab irrespective of the severity of EC from baseline to week 104. Improvements in efficacy outcomes were similar in patients with or without enthesitis treated with secukinumab 300 mg. CONCLUSION: Secukinumab provided early and sustained resolution of enthesitis in patients with PsA over 2 years. Secukinumab 300 mg provided higher resolution than 150 mg in patients with more severe baseline EC and showed similar overall efficacy in patients with or without enthesitis. TRIAL REGISTRATION: FUTURE 2: ClinicalTrials.gov, NCT01752634 (date of study registration: December 19, 2012), and EudraCT, 2012-004439-22 (date of study registration: December 12, 2012) FUTURE 3: ClinicalTrials.gov, NCT01989468 (date of study registration: November 21, 2013), and EudraCT, 2013-004002-25 (date of study registration: December 17, 2013).
CRIS-Team Scopus Importer:2019-12-17
Keywords: Anti-TNF; Biologics; Enthesitis; Interleukin 17A inhibitor; Psoriatic arthritis; Secukinumab

Secukinumab for the treatment of psoriasis, psoriatic arthritis, and axial spondyloarthritis: Physical and pharmacological properties underlie the observed clinical efficacy and safety - Kolbinger, Frank; Di Padova, Franco; Deodhar, Atul; Hawkes, Jason E.; Huppertz, Christine; Kuiper, Torsten; McInnes, Iain B.; Ritchlin, Christopher T.; Rosmarin, David; Schett, Georg; Carballido, José M.; Häusermann, Peter; et al. (Pharmacology & Therapeutics, 2021)
Psoriasis, psoriatic arthritis, and axial spondyloarthritis are systemic inflammatory diseases, each commonly manifesting as a spectrum of symptoms, complications, and comorbidities that arise differently in individual patients. Drugs targeting inflammatory cytokines common to the pathogenesis of each of these conditions have been developed, although their specific actions in the different tissues involved are variable. For a drug to be effective, it must be efficiently delivered to and locally bioactive in disease-relevant tissues. Detailed clinical data shed light on the therapeutic effects of individual biologics on specific domains or clinical manifestations of disease and assist in guiding treatment decisions. Pharmacologic, molecular, and functional properties of drugs strongly impact their observed safety and efficacy, and an understanding of these properties provides complementary insight. Secukinumab, a fully human monoclonal IgG1/κ antibody selectively targeting interleukin (IL)-17A, has been in clinical use for >6 years in the treatment of moderate to severe psoriasis, psoriatic arthritis, and both radiographic (also known as ankylosing spondylitis) and nonradiographic axial spondyloarthritis. In this review, we discuss pharmacokinetic and pharmacodynamic data for secukinumab to introduce clinicians to the pharmacological properties of this widely used drug. Understanding how these properties affect the observed clinical efficacy, safety, and tolerability of this drug in the treatment of IL-17A–mediated systemic inflammatory diseases is important for all physicians treating these conditions.
CRIS-Team Scopus Importer:2021-07-30
Keywords: Axial spondyloarthritis; Biologics; IL-17; Psoriasis; Psoriatic arthritis; Secukinumab

SECUKINUMAB IMPROVES CLINICAL AND IMAGING OUTCOMES IN PATIENTS WITH PSORIATIC ARTHRITIS AND AXIAL MANIFESTATIONS WITH INADEQUATE RESPONSE TO NSAIDS: WEEK 52 RESULTS FROM THE MAXIMISE TRIAL - Baraliakos, X.; Gossec, L.; Pournara, E.; Jeka, S.; Blanco, R.; D'Angelo, S.; Schett, Georg; Schulz, B.; Rissler, M.; Nagar, K.; Perella, C.; Coates, L. C. (ANNALS OF THE RHEUMATIC DISEASES, 2020)
CRIS-Team WoS Importer:2020-08-21

Secukinumab leads to shifts from stage-based towards response-based disease clusters-comparative data from very early and established psoriatic arthritis - Kampylafka, Eleni; Tascilar, Koray; Lerchen, Veronika; Linz, Christina; Sokolova, Maria; Zekovic, Ana; Kleyer, Arnd; Simon, David; Rech, Jürgen; Sticherling, Michael; Schett, Georg; Hueber, Axel (Arthritis Research & Therapy, 2020)
Background: Limited information exists about the very early forms of psoriatic arthritis. In particular, differences and responsiveness of patient-reported outcomes (PROs) in very early as compared to established PsA have not been investigated to date. Methods: Cross-sectional and prospective longitudinal evaluation of PROs related to pain (VAS), physical function (HAQ-DI, SF-36 physical), mental function (SF-36 mental), impact of psoriatic skin (DLQI), joint (PsAID), and global disease (VAS) in two small prospective observational studies on secukinumab 300 mg over 6 months in very early disease patients (IVEPSA study, N = 20) and established PsA (PSARTROS study, N = 20). Cluster analysis was performed at baseline and 24-weeks of follow-up. Results: While responses in pain and physical activity-related PROs to secukinumab were more pronounced in established PsA than a very early disease, effects on PROs related to general health perception, as well as those related to emotional and mental well-being, were modified in a similar way in very early disease and established PsA. Cluster analysis based on global disease activity and PROs showed that baseline clusters reflected very early disease and established PsA, while after secukinumab treatment these clusters were abolished and new clusters based on differential responses to physically and mentally oriented PROs formed. Conclusions: Inhibition of IL-17A by secukinumab leads to comprehensive improvement of general health perception and mental well-being in very early and established PsA, while overall responses in pain and physical activity are more pronounced in established disease. Most importantly, treatment restructures the original patients' clusters based on disease stage and leads to the formation of new clusters that reflect their response in physical and mental-orientated PROs. Trial registration: NCT02483234, registered 26 June 2015, retrospectively registered.
CRIS-Team Scopus Importer:2020-10-02
Keywords: Cluster analysis; IL-17A; Psoriatic arthritis; Quality of life; Secukinumab

SECUKINUMAB PROVIDES RAPID AND SUSTAINED PAIN RELIEF IN PSORIATIC ARTHRITIS: 2-YEAR RESULTS FROM THE FUTURE 2 STUDY - Mcinnes, I. B.; Mease, P. J.; Schett, Georg; Kirkham, B.; Strand, V.; Williams, N.; Fox, T.; Pricop, L.; Jugl, S.; Gandhi, K. K. (2017)
EVALuna2:35031

Secukinumab provides rapid and sustained pain relief in psoriatic arthritis over 2 years: results from the FUTURE 2 study - Mcinnes, Iain B.; Mease, Philip J.; Schett, Georg; Kirkham, Bruce; Strand, Vibeke; Williams, Nicole; Fox, Todd; Pricop, Luminita; Jugl, Steffen M.; Gandhi, Kunal K. (Arthritis Research & Therapy, 2018)
BACKGROUND: Pain is one of the most important domains affecting health-related quality of life (HRQoL) in patients with psoriatic arthritis (PsA). Secukinumab has demonstrated rapid and sustained improvements in signs and symptoms, including HRQoL, among patients with active PsA. This analysis evaluates the effect of secukinumab on patient-reported pain in PsA through 104 weeks of treatment. METHODS: Pain was assessed through week 104 using clinically relevant measures, including change from baseline in a pain visual analog scale (VAS) and Short Form-36 (SF-36) bodily domain scores; proportion of patients reporting improvements equal to or better than minimum clinically meaningful differences in the pain VAS and SF-36 bodily pain domain scores; and proportion of patients with no, moderate, or extreme pain/discomfort measured by the EuroQoL 5-Dimension 3-Level Questionnaire (EQ-5D-3 L) pain item scores. Correlations of pain measures were analyzed using Pearson's correlation coefficient. Pre-specified analyses of TNF-naïve patients and patients who stopped TNF-inhibitors (TNFis) due to inadequate responses or safety/tolerability (TNF-IR patients) were performed using "as-observed data." RESULTS: Mean improvements from baseline in pain VAS scores were greater with secukinumab versus placebo by week 3 (- 16.9; P < 0.0001 with secukinumab 300 mg and - 12.6; P < 0.05 with secukinumab 150 mg) and sustained through week 104. SF-36 bodily pain domain scores were significantly greater with 300 mg secukinumab and secukinumab 150 mg versus placebo by week 4 (16.2 and 16.3, respectively; P < 0.0001 for both), and these changes were maintained through week 104. With both secukinumab 300 mg and secukinumab 150 mg, improvements equal to or better than the minimum clinically meaningful differences in pain VAS and SF-36 bodily pain were significant versus placebo at week 3 and week 4, respectively. At week 4, 15%, 9%, and 5% of patients receiving secukinumab 300 mg, secukinumab 150 mg, and placebo, respectively, reported "no pain/discomfort" measured by EQ-5D-3 L; these proportions increased to week 104 with both secukinumab doses. Similarly, improvements in pain measures were significant in both TNF-naïve and TNF-IR patients. CONCLUSION: Secukinumab provided rapid and sustained pain relief in PsA over 2 years of treatment. Improvements in pain were reported regardless of prior exposure to TNFis. TRIAL REGISTRATION: ClinicalTrials.gov, NCT01752634 . Registered on 19 December 2012.
EVALuna2:34468

SECUKINUMAB PROVIDES RAPID AND SUSTAINED RESOLUTION OF ENTHESITIS IN PSORIATIC ARTHRITIS PATIENTS: POOLED ANALYSIS OF TWO PHASE 3 STUDIES, FUTURE 2 AND FUTURE 3 - Coates, Laura C.; Mcgonagle, Dennis; Schett, Georg; Mease, Philip J.; Quebe-Fehling, Erhard; Asquith, Darren L.; Rasouliyan, Lawrence; Mpofu, Shephard; Gaillez, Corine (2018)
EVALuna2:34474

SECUKINUMAB PROVIDES RAPID AND SUSTAINED RESOLUTION OF ENTHESITIS IN PSORIATIC ARTHRITIS PATIENTS: POOLED ANALYSIS OF TWO PHASE 3 STUDIES, FUTURE 2 AND FUTURE 3 - Coates, Laura C.; Mcgonagle, Dennis; Schett, Georg; Mease, Philip J.; Quebe-Fehling, Erhard; Asquith, Darren L.; Rasouliyan, Lawrence; Mpofu, Shepard; Gaillez, Corine (2019)
EVALuna2:213228

SECUKINUMAB PROVIDES SUSTAINED IMPROVEMENT OF ENTHESITIS IN PATIENTS WITH ANKYLOSING SPONDYLITIS: POOLED ANALYSIS OF FOUR PIVOTAL PHASE 3 STUDIES - Schett, Georg; Baraliakos, Xenofon; Van Den Bosch, Filip; Deodhar, Atul; Gensler, Lianne S.; Ostergaard, Mikkel; Agawane, Shital; Das Gupta, Ayan; Mpofu, Shephard; Fox, Todd; Winseck, Adam; Shete, Abhijit; et al. (ANNALS OF THE RHEUMATIC DISEASES, 2019)
CRIS-Team WoS Importer:2019-07-12

Secukinumab Provides Sustained Improvements in Clinical and Imaging Outcomes in Patients with Psoriatic Arthritis and Axial Manifestations: Results from the MAXIMISE Trial - Baraliakos, Xenofon; Gossec, Laure; Pournara, Effie; Jeka, Slawomir; Blanco, Ricardo; D'Angelo, Salvatore; Schett, Georg; Schulz, Barbara; Rissler, Michael; Whyms, Dermot; Perella, Chiara; Coates, Laura (ARTHRITIS & RHEUMATOLOGY, 2020)
CRIS-Team WoS Importer:2021-01-15

Secukinumab Significantly Decreased Joint Synovitis Measured by Power Doppler Ultrasonography in Biologic-naive Patients with Active Psoriatic Arthritis: Primary (12-Week) Results from a Randomized, Placebo-Controlled Phase III Study - D'Agostino, Maria; Schett, Georg; Lopez-Rdz, Alejandra; Senolt, Ladislav; Maldonado-Cocco, Jose; Burgos-Vargas, Ruben; Naredo, Esperanza; Carron, Philippe; Boers, Maarten; Duggan, Anne-Marie; Goyanka, Punit; Gaillez, Corine (ARTHRITIS & RHEUMATOLOGY, 2020)
CRIS-Team WoS Importer:2021-01-15

Secukinumab Treatment Provides Sustained Resolution of Enthesitis at Individual Joints Through 52 Weeks in a Phase 3b, Double-Blind, Randomized, Active-Controlled Study - Kaeley, Gurjit; Schett, Georg; Conaghan, Philip; Mcgonagle, Dennis; Behrens, Frank; Goupille, Philippe; Gaillez, Corine; Parikh, Bhumik; Meng, Xiangyi; Bakewell, Catherine (ARTHRITIS & RHEUMATOLOGY, 2021)
CRIS-Team WoS Importer:2022-03-11

Segmentation and quantification of bone erosions in high-resolution peripheral quantitative computed tomography datasets of the metacarpophalangeal joints of patients with rheumatoid arthritis - Toepfer, Dominique; Finzel, Stephanie; Museyko, Oleg; Schett, Georg; Engelke, Klaus (Rheumatology, 2014)
Objective. To develop a precise three-dimensional (3D) segmentation technique for bone erosions in high-resolution peripheral quantitative CT (HR-pQCT) datasets to measure their volume, surface area and shape parameters. Assessment of bone erosions in patients with RA is important for diagnosis and evaluation of treatment efficacy. HR-pQCT allows quantifying periarticular bone loss in arthritis. Methods. HR-pQCT scans with a spatial resolution of about 120 µm of the second to fourth metacarpophalangeal joints were acquired in patients with RA. Erosions were identified by placing a seed point in each of them. After applying 3D segmentation, the volume, surface area and sphericity of erosions were calculated. Results were compared with an approximation method using manual measurements. Intra- and interoperator precision analysis was performed for both the 3D segmentation and the manual technique. Results. Forty-three erosions were assessed in 18 datasets. Intra- and interoperator precisions (RMSCV/RMSSD) for erosion volume were 5.66%/0.49 mm(3) and 7.76%/0.76 mm(3), respectively. The correlation between manual measurements and their simulation using segmentation volumes was r = 0.87. Precision errors for the manual method were 15.39% and 0.36 mm(3), respectively. Conclusion. We developed a new precise 3D segmentation technique for quantification of bone erosions in HR-pQCT datasets that correlates to the volume, shape and surface area of the erosion. The technique allows fast and effective measurement of the erosion size and could therefore be helpful for rapid and quantitative assessment of erosion size.
EVALuna2:10057

Self-collection of capillary blood and saliva to determine COVID-19 vaccine immunogenicity in patients with immune-mediated inflammatory diseases and health professionals - Schmetzer, Caroline; Vogt, Ekaterina; Stellar, Laura; Godonou, Elie-Tino; Liphardt, Anna-Maria; Muehlensiepen, Felix; Vuillerme, Nicolas; Hueber, Axel; Kleyer, Arnd; Krönke, Gerhard; Schett, Georg; Simon, David; et al. (Frontiers in Public Health, 2022)
Introduction: Being able to independently determine vaccine induced antibody responses by minimal-invasive methods is of great interest to enable a flexible and effective vaccination strategy. This study aimed to evaluate (1) the accuracy, feasibility, usability and acceptability of capillary blood and saliva self-sampling to determine SARS-CoV-2 antibody responses in patients with immune-mediated inflammatory diseases (IMIDs) and health professionals (HP). Methods: IMID patients and HP having received two doses of SARS-CoV-2 vaccines, self-collected capillary blood (Tasso+) and saliva samples. Capillary samples were considered interchangeable with venous blood if three criteria were met: Spearman's correlation coefficient (r) > 0.8, non-significant Wilcoxon signed-rank test (i.e., p > 0.05), and a small bias or 95% of tests within 10% difference through Bland-Altman. Participants completed a survey to investigate self-sampling usability (system usability scale; SUS) and acceptability (net promoter score; NPS). Study personnel monitored correct self-sampling completion and recorded protocol deviations. Results: 60 participants (30 IMID patients and 30 HP) were analyzed. We observed interchangeability for capillary samples with an accuracy of 98.3/100% for Anti-SARS-CoV-2 IgG/IgA antibodies, respectively. Fifty-eight capillary blood samples and all 60 saliva samples were successfully collected within the first attempt. Usability of both self-sampling procedures was rated as excellent, with significantly higher saliva ratings (p < 0.001). Capillary self-sampling was perceived as significantly (p < 0.001) less painful compared to traditional venous blood collection. Participants reported a NPS for capillary and saliva self-sampling of +68% and +63%, respectively. The majority of both groups (73%) preferred capillary self-sampling over professional venous blood collection. Conclusion: Our results indicate that capillary self-sampling is accurate, feasible and preferred over conventional venous blood collection. Implementation could enable easy access, flexible vaccination monitoring, potentially leading to a better protection of vulnerable patient groups. Self-collection of saliva is feasible and safe however more work is needed to determine its application in clinical practice.
CRIS-Team Scopus Importer:2022-11-11
Keywords: capillary blood; COVID-19; remote care; self-collection; self-sampling; telehealth

Semi-Permeable Filters for Interior Region of Interest Dose Reduction in X-Ray Microscopy - Huang, Yixing; Mill, Leonid; Stoll, Robert; Kling, Lasse; Aust, Oliver; Wagner, Fabian; Grüneboom, Anika; Schett, Georg; Christiansen, Silke H.; Maier, Andreas (Bildverarbeitung für die Medizin, 2021)
In osteoporosis research, the number and size of lacunae in cortical bone tissue are important characteristics of osteoporosis development. In order to reconstruct lacunae well in X-ray microscopy while protecting bone marrow from high-dose damage in in-vivo experiments, semi-permeable X-ray filters are proposed for dose reduction. Compared with an opaque filter, image quality with a semi-permeable filter is improved remarkably. For image reconstruction, both iterative reconstruction with reweighted total variation (wTV) and FDK reconstruction from penalized weighted least-square (PWLS) processed projections can reconstruct lacunae when the transmission rate of the filter is as small as 5%. However, PWLS is superior in computation efficiency.<br
Keywords: Osteoporosis research; X-ray filter; X-ray microscopy; dose reduction

SENSITIVE DETECTION OF DYNAMIC CHANGES OF BONE EROSIONS IN INFLAMMATORY ARTHRITIS BY MUSCULOSKELETAL ULTRASOUND: A COMPARATIVE ANALYSIS WITH HIGH-RESOLUTION PERIPHERAL QUANTITATVE COMPUTED TOMOGRAPHY - Finzel, S.; Schett, Georg; Kraus, S.; Voll, R.; Backhaus, M. (2017)
EVALuna2:35046

Sequential interleukin-17/interleukin-23 inhibition in treatment-refractory psoriatic arthritis - Simon, David; Fagni, Filippo; Schett, Georg (Annals of the Rheumatic Diseases, 2022)
CRIS-Team WoS Importer:2022-05-20

Serum Calprotectin Is a Prognostic Marker for Drug-Free Remission in RA - De Moel, Emma; Rech, Jürgen; Mahler, Michael; Roth, Johannes; Schouffoer, Anne; Ronday, Karel; Huizinga, Thomas; Allaart, C. F.; Toes, Rene; Schett, Georg; Van Der Woude, Diane (ARTHRITIS & RHEUMATOLOGY, 2019)
CRIS-Team WoS Importer:2020-02-07

Serum Interleukin-36 α as a Candidate Biomarker to Distinguish Behçet’s Syndrome and Psoriatic Arthritis - Bettiol, Alessandra; Fagni, Filippo; Mattioli, Irene; Bagni, Giacomo; Vitiello, Gianfranco; Grassi, Alessia; Della Bella, Chiara; Benagiano, Marisa; Troilo, Arianna; Holownia, Katarzyna Stella; Simon, David; Argento, Flavia Rita; et al. (International Journal of Molecular Sciences, 2023)
Behçet’s syndrome (BS) is a rare systemic vasculitis characterized by different clinical manifestations. As no specific laboratory tests exist, the diagnosis relies on clinical criteria, and the differential diagnosis with other inflammatory diseases can be challenging. Indeed, in a relatively small proportion of patients, BS symptoms include only mucocutaneous, articular, gastrointestinal, and non-typical ocular manifestations, which are frequently found also in psoriatic arthritis (PsA). We investigate the ability of serum interleukin (IL)-36α—a pro-inflammatory cytokine involved in cutaneous and articular inflammatory diseases—to differentiate BS from PsA. A cross-sectional study was performed on 90 patients with BS, 80 with PsA and 80 healthy controls. Significantly lower IL-36α concentrations were found in patients with BS as compared to PsA, although in both groups IL-36α was significantly increased compared to healthy controls. An empirical cut-off of 420.6 pg/mL displayed a specificity of 0.93, with a sensitivity of 0.70 (AUC 0.82) in discriminating PsA from BS. This cut-off displayed a good diagnostic performance also in BS patients lacking highly specific BS manifestations. Our results indicate that IL-36α might be involved in the pathogenesis of both BS and PsA, and might be a candidate biomarker to support the differential diagnosis of BS.
CRIS-Team Scopus Importer:2023-06-09
Keywords: Behçet disease; biomarkers; cytokines; interleukin 36; vasculitis

Serum Proteomic Signatures Predict Relapse in Rheumatoid Arthritis Patients Undergoing DMARD Withdrawal - O'Neil, Liam; Spicer, Victor; Hitchon, Carol A.; Rech, Jürgen; Hueber, Axel; Wilkins, John; El-Gabalawy, Hani; Schett, Georg (2017)
EVALuna2:33439

Severe Hepatitis E virus infection in a patient with rheumatoid arthritis treated with baricitinib - Valor-Mendez, Larissa; Manger, Bernhard; Schett, Georg; Kleyer, Arnd (Zeitschrift für Rheumatologie, 2021)
A patient with rheumatoid arthritis (RA) was presented, who developed an infection with the hepatitis E virus (HEV) under treatment with the Janus kinase (JAK) 1 and 2 inhibitor baricitinib. In the 3-month routine check-up the patient had clearly elevated transaminase levels with an inconspicuous physical examination. The investigations detected antibodies of IgM and IgG classes against HEV and an elevated C-reactive protein (CRP) level as well as HEV-RNA by real-time PCR, which is indicative of a recent HEV infection. Baricitinib was immediately discontinued. The extensive anamnesis revealed that the patient had eaten beef tartar some days before the consultation, without the occurrence of gastrointestinal symptoms or fever. In the further course the patient completely recovered and the liver function tests and the CRP levels normalized within 3 months. Baricitinib was then restarted. So far only few reports have been published on HEV infections in RA patients who have been treated with JAK inhibitors.
CRIS-Team WoS Importer:2021-06-25

ShaRPy: Shape Reconstruction and Hand Pose Estimation from RGB-D with Uncertainty - Wirth, Vanessa; Liphardt, Anna-Maria; Coppers, Birte; Bräunig, Johanna; Heinrich, Simon; Leyendecker, Sigrid; Kleyer, Arnd; Schett, Georg; Vossiek, Martin; Egger, Bernhard; Stamminger, Marc (Proceedings of the IEEE/CVF International Conference on Computer Vision (ICCV) Workshops, 2023)
Despite their potential, markerless hand tracking technologies are not yet applied in practice to the diagnosis or monitoring of the activity in inflammatory musculoskeletal diseases. One reason is that the focus of most methods lies in the reconstruction of coarse, plausible poses, whereas in the clinical context, accurate, interpretable, and reliable results are required. Therefore, we propose ShaRPy, the first RGB-D Shape Reconstruction and hand Pose tracking system, which provides uncertainty estimates of the computed pose, e.g., when a finger is hidden or its estimate is inconsistent with the observations in the input, to guide clinical decision-making. Besides pose, ShaRPy approximates a personalized hand shape, promoting a more realistic and intuitive understanding of its digital twin. Our method requires only a light-weight setup with a single consumer-level RGB-D camera yet it is able to distinguish similar poses with only small joint angle deviations in a metrically accurate space. This is achieved by combining a data-driven dense correspondence predictor with traditional energy minimization. To bridge the gap between interactive visualization and biomedical simulation we leverage a parametric hand model in which we incorporate biomedical constraints and optimize for both, its pose and hand shape parameters. We evaluate ShaRPy on a keypoint detection benchmark and show qualitative results of hand function assessments for activity monitoring of musculoskeletal diseases.
Keywords: Musculoskeletal diseases; Hand Pose and Shape Estimation; Uncertainty Estimation; Hand Tracking

Short chain fatty acids are potent regulators of systemic bone mass and protect for pathological bone loss by inhibiting osteoclasts - Lucas, S.; Omata, Y.; Böttcher, Martin; Hofmann, Jörg; Krishnacoumar, B.; Krönke, Gerhard; Mougiakakos, Dimitrios; Iljazovic, A.; Sonnewald, Uwe; Strowig, T.; Schett, Georg; Zaiss, Mario (European Journal of Immunology, 2017)

Short-chain fatty acids regulate systemic bone mass and protect from pathological bone loss - Lucas, Sebastien; Omata, Yasunori; Hofmann, Jörg; Böttcher, Martin; Iljazovic, Aida; Sarter, Kerstin; Albrecht, Olivia; Schulz, Oscar; Krishnacoumar, Brenda; Krönke, Gerhard; Herrmann, Martin; Mougiakakos, Dimitrios; et al. (Nature Communications, 2018)
Microbial metabolites are known to modulate immune responses of the host. The main metabolites derived from microbial fermentation of dietary fibers in the intestine, short-chain fatty acids (SCFA), affect local and systemic immune functions. Here we show that SCFA are regulators of osteoclast metabolism and bone mass in vivo. Treatment of mice with SCFA as well as feeding with a high-fiber diet significantly increases bone mass and prevents postmenopausal and inflammation-induced bone loss. The protective effects of SCFA on bone mass are associated with inhibition of osteoclast differentiation and bone resorption in vitro and in vivo, while bone formation is not affected. Mechanistically, propionate (C3) and butyrate (C4) induce metabolic reprogramming of osteoclasts resulting in enhanced glycolysis at the expense of oxidative phosphorylation, thereby downregulating essential osteoclast genes such as TRAF6 and NFATc1. In summary, these data identify SCFA as potent regulators of osteoclast metabolism and bone homeostasis.
EVALuna2:13520

Sialylation of anti-histone immunoglobulin G autoantibodies determines their capabilities to participate in the clearance of late apoptotic cells - Magorivska, I.; Munoz Becerra, Luis; Janko, Christina; Dumych, Tetiana; Rech, J.; Schett, Georg; Nimmerjahn, Falk; Bilyy, R.; Herrmann, Martin (Clinical and Experimental Immunology, 2016)
The Fc portion of immunoglobulin (Ig)G harbours a single glycosylation site. Glycan sialylation is critical for structure and for certain effector functions of IgG. Anti-histone IgG of patients with systemic lupus erythematosus is reportedly responsible for the recruitment of polymorphonuclear cells (PMN) to the clearance of apoptotic cells. Autoantibodies decorating secondary necrotic cells (SNEC) induce proinflammatory responses after activation of blood-borne phagocytes. Analysing the sialylation status of affinity-purified anti-histone IgG in patients with systemic lupus erythematosus (SLE), we demonstrated that the anti-histone IgG was contained preferentially in the non-sialylated fraction. In functional ex-vivo phagocytosis studies, non-sialylated anti-SNEC IgG directed SNEC preferentially into PMN but did not change their cytokine secretion profiles. In contrast, sialylated IgG reduced the phagocytosis by monocytes of SNEC. Moreover, the sialylated anti-SNEC IgG was not simply anti-inflammatory, but switched the cytokine secretion profiles from interleukin (IL)-6/IL-8 to tumour necrosis factor (TNF)-/IL-1. Here we describe how different sialylation statuses of IgG autoantibodies contribute to the complex inflammatory network that regulates chronic inflammation.
Keywords: autoantibodies; IgG; lectin; sialylation; SLE

SIGNAL TRANSDUCER AND ACTIVATOR OF TRANSCRIPTION 3 (STAT3) INTEGRATES SEVERAL PROFIBROTIC PATHWAYS IN SYSTEMIC SCLEROSIS - Chakraborty, D.; Sumova, B.; Mallano, Tatjana; Chen, Chih-Wei; Ramming, A.; Distler, O.; Schett, Georg; Distler, Jörg (2016)
EVALuna2:13487

SIGNATURE OF CIRCULATING MICRORNAS IN OSTEOARTHRITIS - Beyer, Christian; Zampetaki, A.; Lin, N. -Y.; Kleyer, Arnd; Perricone, C.; Iagnocco, A. M.; Distler, A.; Langley, S. L.; Gelse, Kolja; Sesselmann, Stefan; Lorenzini, R.; Niemeier, A.; et al. (2014)
EVALuna2:34462

Signature of circulating microRNAs in osteoarthritis - Beyer, Christian; Zampetaki, Anna; Lin, Neng-Yu; Kleyer, Arnd; Perricone, Carlo; Iagnocco, Annamaria; Distler, Alfiya; Langley, Sarah R.; Gelse, Kolja; Sesselmann, Stefan; Lorenzini, Rolando; Niemeier, Andreas; et al. (Annals of the Rheumatic Diseases, 2015)
Osteoarthritis is the most common form of arthritis and a major socioeconomic burden. Our study is the first to explore the association between serum microRNA levels and the development of severe osteoarthritis of the knee and hip joint in the general population.We followed 816 Caucasian individuals from 1995 to 2010 and assessed joint arthroplasty as a definitive outcome of severe osteoarthritis of the knee and hip. After a microarray screen, we validated 12 microRNAs by real-time PCR in the entire cohort at baseline.In Cox regression analysis, three microRNAs were associated with severe knee and hip osteoarthritis. let-7e was a negative predictor for total joint arthroplasty with an adjusted HR of 0.75 (95% CI 0.58 to 0.96; p=0.021) when normalised to U6, and 0.76 (95% CI 0.6 to 0.97; p=0.026) after normalisation to the Ct average. miRNA-454 was inversely correlated with severe knee or hip osteoarthritis with an adjusted HR of 0.77 (95% CI 0.61 to 0.97; p=0.028) when normalised to U6. This correlation was lost when data were normalised to Ct average (p=0.118). Finally, miRNA-885-5p showed a trend towards a positive relationship with arthroplasty when normalised to U6 (HR 1.24; 95% CI 0.95 to 1.62; p=0.107) or to Ct average (HR 1.30; 95% CI 0.99 to 1.70; p=0.056).Our study is the first to identify differentially expressed circulating microRNAs in osteoarthritis patients necessitating arthroplasty in a large, population-based cohort. Among these microRNAs, let-7e emerged as potential predictor for severe knee or hip osteoarthritis.
EVALuna2:10852

SIMILAR EFFICACY AND DRUG SURVIVAL RATES OF BARICITINIB MONOTHERAPY AND BARICITINIB/METHOTREXATE COMBINATION THERAPY IN REAL-LIFE TREATMENT OF RHEUMATOID ARTHRITIS - RESULTS FROM A PROSPECTIVE COHORT OF BARICITINIB-TREATED PATIENTS - Bayat, Sara; Tascilar, Koray; Bohr, D.; Simon, David; Kronke, G.; Hartmann, F.; Knitza, Johannes; Schett, Georg; Kleyer, Arnd (ANNALS OF THE RHEUMATIC DISEASES, 2022)
CRIS-Team WoS Importer:2022-11-04

Similar Impact of Psoriatic Arthritis and Rheumatoid Arthritis on Objective and Subjective Parameters of Hand Function - Liphardt, Anna-Maria; Manger, Eva; Liehr, Sonja; Bieniek, Lisa Maria; Kleyer, Arnd; Simon, David; Tascilar, Koray; Sticherling, Michael; Rech, Jürgen; Schett, Georg; Hueber, Axel (ACR Open Rheumatology, 2020)
ObjectiveThe objective of this study was to compare the impact of psoriatic disease (psoriatic arthritis [PsA] and psoriasis) and rheumatoid arthritis (RA) on objective and subjective parameters of hand function.
CRIS-Team WoS Importer:2021-07-16

Similar Impact of Psoriatic Arthritis and Rheumatoid Arthritis on Objective and Subjective Parameters of Hand Function - Liphardt, Anna-Maria; Manger, Eva; Liehr, Sonja; Bieniek, Lisa; Kleyer, Arnd; Simon, David; Tascilar, Koray; Sticherling, Michael; Rech, Jürgen; Schett, Georg; Hueber, Axel (ARTHRITIS & RHEUMATOLOGY, 2020)
CRIS-Team WoS Importer:2021-01-15

Simultaneous quantification of bone erosions and enthesiophytes in the joints of patients with psoriasis or psoriatic arthritis - effects of age and disease duration - Simon, David; Kleyer, Arnd; Faustini, Francesca; Englbrecht, Matthias; Haschka, Judith; Berlin, Andreas; Kraus, Sebastian; Hueber, Axel; Kocijan, Roland; Sticherling, Michael; Rech, Jürgen; Schett, Georg (Arthritis Research & Therapy, 2018)
BACKGROUND: Comprehensive simultaneous quantification of bone erosion and enthesiophytes in the joints of patients with psoriatic arthritis (PsA) has not been performed. Herein, we aimed to compare the extent of bone erosion and enthesiophytes in patients with PsA, psoriasis (PSO) and healthy controls, assess the influence of age and disease duration on the development of erosions and enthesiophytes and define their impact on physical function. METHODS: Patients with PsA or with PSO and controls were analysed by high-resolution peripheral quantitative computed tomography (HR-pQCT). The extent of bone erosions and enthesiophytes was assessed and plotted according to different categories of age, duration of PSO and duration of PsA, respectively. In addition, demographic and disease-specific data, including physical function (health assessment questionnaire) were collected. RESULTS: A total of 203 patients were analysed; 101 had PsA, 55 had PSO and 47 were healthy individuals. Patients with PsA had significantly more and larger erosions (p = 0.002/p = 0.003) and enthesiophytes (p < 0.001) compared to patients with PSO and healthy controls. Patients with PSO and healthy controls did not differ in erosions, while enthesiophytes were more frequent in patients with PSO than in healthy controls. Bone erosions, but not enthesiophytes, showed strong age-dependency in all three groups. In contrast, enthesiophytes were mostly influenced by the duration of PSO and PsA and, in contrast to bone erosions, were associated with poorer physical function. CONCLUSIONS: Bone erosions are age-dependent, enhanced in PsA and increase with disease duration. Enthesiophytes are less age-dependent, are enhanced in both PSO and PsA and strongly influenced by disease duration. Enthesiophytes impact physical function in PsA suggesting the need for early therapeutic interventions to prevent damage.
EVALuna2:34666

Sirt1 regulates canonical TGF-? signalling to control fibroblast activation and tissue fibrosis - Zerr, Pawel; Palumbo-Zerr, Katrin; Huang, Jingang; Tomcik, Michal; Sumova, Barbora; Distler, Oliver; Schett, Georg; Distler, Jörg (Annals of the Rheumatic Diseases, 2016)
Sirt1 is a member of the sirtuin family of proteins. Sirt1 is a class III histone deacetylase with important regulatory roles in transcription, cellular differentiation, proliferation and metabolism. As aberrant epigenetic modifications have been linked to the pathogenesis of systemic sclerosis (SSc), we aimed to investigate the role of Sirt1 in fibroblast activation.Sirt1 expression was analysed by real-time PCR, western blot and immunohistochemistry. Sirt1 signalling was modulated with the Sirt1 agonist resveratrol and by fibroblast-specific knockout. The role of Sirt1 was evaluated in bleomycin-induced skin fibrosis and in mice overexpressing a constitutively active transforming growth fac-tor-? (TGF-?) receptor I (TBRIact).The expression of Sirt1 was decreased in patients with SSc and in experimental fibrosis in a TGF-?-dependent manner. Activation of Sirt1 potentiated the profibrotic effects of TGF-? with increased Smad reporter activity, elevated transcription of TGF-? target genes and enhanced release of collagen. In contrast, knockdown of Sirt1 inhibited TGF-?/SMAD signalling and reduced release of collagen in fibroblasts. Consistently, mice with fibroblast-specific knockdown of Sirt1 were less susceptible to bleomycin- or TBRIact-induced fibrosis.We identified Sirt1 as a crucial regulator of TGF-?/Smad signalling in SSc. Although Sirt1 is downregulated, this decrease is not sufficient to counterbalance the excessive activation of TGF-? signalling in SSc. However, augmentation of this endogenous regulatory mechanism, for example, by knockdown of Sirt1, can effectively inhibit TGF-? signalling and exerts potent antifibrotic effects. Sirt1 may thus be a key regulator of fibroblast activation in SSc.
EVALuna2:12980

SIZE MATTERS - EXTENT OF MONOSODIUM URATE DEPOSITS BUT NOT SERUM URATE LEVEL PREDICTS COMPLETE RESOLUTION OF MONOSODIUM URATE CRYSTAL DEPOSITS IN PATIENTS WITH GOUT - Bayat, Sara; Ellmann, Hanna; Guilhon de Araujo, Elizabeth; Manger, Bernhard; Hagen, Melanie; Kleyer, Arnd; Lell, Michael; Schenker, Hannah; Simon, David; Tascilar, Koray; Baraf, Herbert S. B.; Schett, Georg; et al. (ANNALS OF THE RHEUMATIC DISEASES, 2019)
CRIS-Team WoS Importer:2019-07-12

Soluble CD83 Triggers Resolution of Arthritis and Sustained Inflammation Control in IDO Dependent Manner - Royzman, Dmytro; Andrev, Darja; Stich, Lena; Rauh, Manfred; Bäuerle, Tobias; Ellmann, Stephan; Boon, Louis; Kindermann, Markus; Peckert, Katrin; Bozec, Aline; Schett, Georg; Steinkasserer, Alexander; et al. (Frontiers in Immunology, 2019)
Interference with autoimmune-mediated cytokine production is a key yet poorly developed approach to treat autoimmune and inflammatory diseases such as rheumatoid arthritis. Herein, we show that soluble CD83 (sCD83) enhances the resolution of autoimmune antigen-induced arthritis (AIA) by strongly reducing the expression levels of cytokines such as IL-17A, IFN gamma, IL-6, and TNF alpha within the joints. Noteworthy, also the expression of RANKL, osteoclast differentiation, and joint destruction was significantly inhibited by sCD83. In addition, osteoclasts which were cultured in the presence of synovial T cells, derived from sCD83 treated AIA mice, showed a strongly reduced number of multinuclear large osteoclasts compared to mock controls. Enhanced resolution of arthritis by sCD83 was mechanistically based on IDO, since inhibition of IDO by 1-methyltryptophan completely abrogated sCD83 effects on AIA. Blocking experiments, using anti-TGF-beta antibodies further revealed that also TGF-beta is mechanistically involved in the sCD83 induced reduction of bone destruction and cartilage damage as well as enhanced resolution of inflammation. Resolution of arthritis was associated with increased numbers of regulatory T cells, which are induced in a sCD83-IDO-TGF-beta dependent manner. Taken together, sCD83 represents an interesting approach for downregulating cytokine production, inducing regulatory T cells and inducing resolution of autoimmune arthritis.
CRIS-Team WoS Importer:2019-04-12

SPATIOTEMPORAL DYNAMICS OF BONE LOSS BEFORE AND AFTER THE ONSET OF RHEUMATOID ARTHRITIS - Tascilar, Koray; Simon, David; Liphardt, Anna-Maria; Meinderink, Timo; Bayat, Sara; Rech, Jürgen; Hueber, A.; Krönke, Gerhard; Schett, Georg; Kleyer, Arnd (ANNALS OF THE RHEUMATIC DISEASES, 2021)
CRIS-Team WoS Importer:2021-10-01

Spondyloarthritis: may the force be with you? - Mcgonagle, Dennis; Thomas, Rebecca C.; Schett, Georg (Annals of the Rheumatic Diseases, 2014)
EVALuna2:12926

Standards of care for people with rheumatoid arthritis in Europe : Translation and comments of the eumusc.net recommendations supported by EULAR performed by a national task force of the professional organisations DGRh and VRA supported by "Deutsche Rheu - Braun, J.; Krause, A.; Aringer, M.; Burmester, G.; Bessler, F.; Engel, J. -M.; Faubel, U.; Fischer-Betz, R.; Genth, E.; Gromnica-Ihle, E.; Hellmich, B.; Koetter, I.; et al. (Zeitschrift für Rheumatologie, 2016)
In a joint initiative by the boards of the German Society for Rheumatology (DGRh) and the Association of Rheumatology Clinics (VRA) the European "standards of care" for rheumatoid arthritis, recently suggested by the European Musculoskeletal Conditions Surveillance and Information Network (eumusc.net) and supported by the European League Against Rheumatism (EULAR), were translated and annotated. The recommendations include aspects of the management of the disease, actual medical care, and access to information - this includes all types of support people with RA need, and, last but not least communication of the necessary knowledge. Furthermore, health care structures such as the availability of medical staff with relevant expertise are also important.
EVALuna2:13278

STAT3 As an Important Integrator of Profibrotic Pathways in Systemic Sclerosis - Sumova, Barbora; Mallano, Tatjana; Chen, Chih-Wei; Distler, Alfiya; Bergmann, Christina; Distler, Oliver; Schett, Georg; Senolt, Ladislav; Distler, Jörg; Chakraborty, Debomita; Ramming, Andreas (2017)
EVALuna2:33429

Stepwise asynchronous telehealth assessment of patients with suspected axial spondyloarthritis: results from a pilot study - Labinsky, Hannah; von Rohr, Sophie; Raimondo, Maria Gabriella; Bohr, Daniela; Morf, Harriet; Horstmann, Britta; Seese, Felix; Proft, Fabian; Muehlensiepen, Felix; Boy, Katharina; Kuhn, Sebastian; Schmalzing, Marc; et al. (Rheumatology International, 2023)
Patients with axial spondyloarthritis (axSpA) suffer from one of the longest diagnostic delays among all rheumatic diseases. Telemedicine (TM) may reduce this diagnostic delay by providing easy access to care. Diagnostic rheumatology telehealth studies are scarce and largely limited to traditional synchronous approaches such as resource-intensive video and telephone consultations. The aim of this study was to investigate a stepwise asynchronous telemedicine-based diagnostic approach in patients with suspected axSpA. Patients with suspected axSpA completed a fully automated digital symptom assessment using two symptom checkers (SC) (bechterew-check and Ada). Secondly, a hybrid stepwise asynchronous TM approach was investigated. Three physicians and two medical students were given sequential access to SC symptom reports, laboratory and imaging results. After each step, participants had to state if axSpA was present or not (yes/no) and had to rate their perceived decision confidence. Results were compared to the final diagnosis of the treating rheumatologist. 17 (47.2%) of 36 included patients were diagnosed with axSpA. Diagnostic accuracy of bechterew-check, Ada, TM students and TM physicians was 47.2%, 58.3%, 76.4% and 88.9% respectively. Access to imaging results significantly increased sensitivity of TM-physicians (p < 0.05). Mean diagnostic confidence of false axSpA classification was not significantly lower compared to correct axSpA classification for both students and physicians. This study underpins the potential of asynchronous physician-based telemedicine for patients with suspected axSpA. Similarly, the results highlight the need for sufficient information, especially imaging results to ensure a correct diagnosis. Further studies are needed to investigate other rheumatic diseases and telediagnostic approaches.
CRIS-Team Scopus Importer:2023-07-07
Keywords: Diagnosis; Health service research; Spondyloarthritis; Symptom checker; Telehealth; Telemedicine

Stimulation of the soluble guanylate cyclase (sGC) inhibits fibrosis by blocking non-canonical TGF? signalling - Beyer, Christian; Zenzmaier, Christoph; Palumbo-Zerr, Katrin; Mancuso, Rossella; Distler, Alfiya; Dees, Clara; Zerr, Pawel; Huang, Jingang; Maier, Christiane; Pachowsky, Milena; Friebe, Andreas; Sandner, Peter; et al. (Annals of the Rheumatic Diseases, 2015)
We have previously described the antifibrotic role of the soluble guanylate cyclase (sGC). The mode of action, however, remained elusive. In the present study, we describe a novel link between sGC signalling and transforming growth factor ? (TGF?) signalling that mediates the antifibrotic effects of the sGC.Human fibroblasts and murine sGC knockout fibroblasts were treated with the sGC stimulator BAY 41-2272 or the stable cyclic guanosine monophosphate (cGMP) analogue 8-Bromo-cGMP and stimulated with TGF?. sGC knockout fibroblasts were isolated from sGCI(fl/fl) mice, and recombination was induced by Cre-adenovirus. In vivo, we studied the antifibrotic effects of BAY 41-2272 in mice overexpressing a constitutively active TGF-?1 receptor.sGC stimulation inhibited TGF?-dependent fibroblast activation and collagen release. sGC knockout fibroblasts confirmed that the sGC is essential for the antifibrotic effects of BAY 41-2272. Furthermore, 8-Bromo-cGMP reduced TGF?-dependent collagen release. While nuclear p-SMAD2 and 3 levels, SMAD reporter activity and transcription of classical TGF? target genes remained unchanged, sGC stimulation blocked the phosphorylation of ERK. In vivo, sGC stimulation inhibited TGF?-driven dermal fibrosis but did not change p-SMAD2 and 3 levels and TGF? target gene expression, confirming that non-canonical TGF? pathways mediate the antifibrotic sGC activity.We elucidated the antifibrotic mode of action of the sGC that increases cGMP levels, blocks non-canonical TGF? signalling and inhibits experimental fibrosis. Since sGC stimulators have shown excellent efficacy and tolerability in phase 3 clinical trials for pulmonary arterial hypertension, they may be further developed for the simultaneous treatment of fibrosis and vascular disease in systemic sclerosis.
EVALuna2:12978

STRUCTURAL DAMAGE PROGRESSION IN PATIENTS TREATED WITH METHOTREXATE, BARICITINIB MONOTHERAPY OR BARICITINIB plus METHOTREXATE BASED ON THEIR LEVEL OF CLINICAL RESPONSE IN THE PHASE 3 RA-BEGIN STUDY - Van Der Heijde, D.; Durez, P.; Schett, Georg; Naredo, E.; Ostergaard, M.; Meszaros, G.; Bello, N.; De La Torre, I.; Lopez-Romero, P.; Schlichting, D.; Nantz, E.; Fleischmann, R. (2017)
EVALuna2:35028

Structural damage progression in patients with early rheumatoid arthritis treated with methotrexate, baricitinib, or baricitinib plus methotrexate based on clinical response in the phase 3 RA-BEGIN study - Van Der Heijde, Desiree; Durez, Patrick; Schett, Georg; Naredo, Esperanza; Ostergaard, Mikkel; Meszaros, Gabriella; De Leonardis, Francesco; De La Torre, Inmaculada; Lopez-Romero, Pedro; Schlichting, Douglas; Nantz, Eric; Fleischmann, Roy (Clinical Rheumatology, 2018)
The objective of this study was to evaluate structural damage progression based on clinical response in rheumatoid arthritis patients with no or limited prior disease-modifying anti-rheumatic drug treatment receiving the Janus kinase (JAK)1/JAK2 inhibitor baricitinib 4 mg, methotrexate (MTX), or the combination. Data from the phase 3 RA-BEGIN study were analysed post hoc. Proportions of patients with structural damage progression (change from baseline greater than the smallest detectable change in modified total Sharp score) at week 52 were evaluated based on sustained Disease Activity Score for 28-joint count with serum high-sensitivity C-reactive protein (DAS28-hsCRP) ≤ 3.2 or Simplified Disease Activity Index (SDAI) score ≤ 11; no formal statistical comparisons between treatments were performed to test these proportions. Baseline factors associated with risk of structural damage progression, including Clinical Disease Activity Index (CDAI) score, were identified using multivariate analysis. Patients achieving versus not achieving sustained DAS28-hsCRP ≤ 3.2 or SDAI score ≤ 11 were less likely to experience structural damage progression at week 52. In patients achieving these responses, structural damage progression was less likely with baricitinib monotherapy or plus MTX than with MTX monotherapy. In patients not achieving these sustained clinical thresholds, structural damage progression was less likely with baricitinib plus MTX than with either monotherapy. Independent of treatment, baseline factors significantly associated with increased risk of structural damage progression included higher hsCRP and CDAI score, smoking, female sex, and lower body mass index. In conclusion, patients achieving versus not achieving sustained DAS28-hsCRP ≤ 3.2 or SDAI score ≤ 11 were less likely to show structural damage progression, irrespective of treatment.
EVALuna2:34479

STRUCTURAL ENTHESEAL LESIONS IN PSORIASIS PATIENTS ARE ASSOCIATED WITH AN INCREASED RISK OF PROGRESSION TO PSORIATIC ARTHRITIS - A PROSPECTIVE COHORT STUDY - Simon, David; Tascilar, K.; Kleyer, Arnd; Bayat, Sara; Kampylafka, E.; Hueber, Axel; Rech, Jürgen; Schuster, Louis; Engel, K.; Sticherling, Michael; Schett, Georg (ANNALS OF THE RHEUMATIC DISEASES, 2020)
CRIS-Team WoS Importer:2020-08-21

Student-led clinics and ePROs to accelerate diagnosis and treatment of patients with axial spondyloarthritis: results from a prospective pilot study - von Rohr, Sophie; Knitza, Johannes; Grahammer, Manuel; Schmalzing, Marc; Kuhn, Sebastian; Schett, Georg; Ramming, Andreas; Labinsky, Hannah (Rheumatology International, 2023)
We aimed to investigate (1) student-led clinics and (2) electronic patient-reported outcomes (ePROs) to accelerate diagnosis and treatment of patients with axial spondyloarthritis (axSpA). Patients with suspected axSpA completed an initial student-led clinic visit (T-1) prior to their planned actual rheumatologist visit (T0). Acceleration of patient appointment and NSAID therapy start, availability of diagnostic findings, and treatment response at T0 were evaluated. Beginning at T-1, patients completed electronic BASDAI questionnaires every 2 weeks. Concordance of paper-based and electronic BASDAI was evaluated. Patient acceptance of ePRO reporting and student-led clinics was measured using the net promoter score (NPS). 17/36 (47.2%) included patients were diagnosed with axSpA. Student-led clinics (T-1) significantly accelerated patient appointments by more than 2 months (T0, T-1, p < 0.0001) and axSpA guideline-conform NSAID treatment (p < 0.0001). At T0, diagnostic workup was completed for all patients and 7/17 (41.2%) axSpA patients presented with a clinically important improvement or were in remission. 34/36 (94.4%) patients completed at least 80% of the ePROs between T-1 and T0. Electronic and paper-administered BASDAI correlated well (r = 0.8 p < 0.0001). Student-led clinics and ePROs were well accepted by patients with NPS scores of + 62.0% (mean ± SD 9.2/10.0 ± 0.9) and + 30.5% (mean ± SD 8.0/10.0 ± 1.7), respectively. In conclusion, student-led clinics and ePRO monitoring were well accepted, accelerated diagnostic workup and treatment in patients with axSpA.
CRIS-Team Scopus Importer:2023-08-11
Keywords: Axial spondyloarthritis; axSpA; Diagnostic delay; Electronic patient-reported outcome; ePRO; Student

Stunning of neutrophils accounts for the anti-inflammatory effects of clodronate liposomes - Culemann, Stephan; Knab, Katharina; Euler, Maximilien; Wegner, Anja; Garibagaoglu, Hilal; Ackermann, Jochen; Fischer, Kim; Kienhoefer, Deborah; Crainiciuc, Georgiana; Hahn, Jonas; Grüneboom, Anika; Nimmerjahn, Falk; et al. (Journal of Experimental Medicine, 2023)
The authors show that the anti-inflammatory effects of clodronate liposomes do not result from the depletion of mononuclear phagocytes but from a functional stunning of polymorphonuclear neutrophils. These findings necessitate a critical revision of the current literature on the role of monocytes and macrophages in inflammation.
CRIS-Team WoS Importer:2023-04-28

Subclinical joint inflammation in patients with psoriasis without concomitant psoriatic arthritis: a cross-sectional and longitudinal analysis - Faustini, Francesca; Simon, Dominic; Oliveira, Isabelle; Kleyer, Arnd; Haschka, Judith; Englbrecht, Matthias; Cavalcante, Alan Rodrigues; Kraus, Sebastian; Tabosa, Taiane Ponte; Figueiredo, Camille; Hueber, Axel; Kocijan, Roland; et al. (Annals of the Rheumatic Diseases, 2016)
To search for subclinical inflammatory joint disease in patients with psoriasis without psoriatic arthritis (PsA), and to determine whether such changes are associated with the later development of PsA.Eighty-five subjects without arthritis (55 with psoriasis and 30 healthy controls) received high field MRI of the hand. MRI scans were scored for synovitis, osteitis, tenosynovitis and periarticular inflammation according to the PsAMRIS method. Patients with psoriasis additionally received complete clinical investigation, high-resolution peripheral quantitative CT for detecting erosions and enthesiophytes and were followed up for at least 1 year for the development of PsA.47% of patients with psoriasis showed at least one inflammatory lesion on MRI. Synovitis was the most prevalent inflammatory lesion (38%), while osteitis (11%), tenosynovitis (4%) and periarticular inflammation (4%) were less frequent. The mean (±SD) PsAMRIS synovitis score was 3.0±2.5 units. Enthesiophytes and bone erosions were not different between patients with psoriasis with or without inflammatory MRI changes. The risk for developing PsA was as high as 60% if patients had subclinical synovitis and symptoms related to arthralgia, but only 13% if patients had normal MRIs and did not report arthralgia.Prevalence of subclinical inflammatory lesions is high in patients with cutaneous psoriasis. Arthralgia in conjunction with MRI synovitis constitutes a high-risk constellation for the development of PsA.
EVALuna2:13265

SUBCLINICAL MRI INFLAMMATION DOES NOT PREDICT RELAPSE RISK IN RHEUMATOID ARTHRITIS PATIENTS TAPERING DMARDS - Doliveira, I.; Mensing, W.; Figueiredo, C.; Englbrecht, Matthias; Haschka, J.; Hueber, Axel; Kleyer, Arnd; Schett, Georg; Rech, Jürgen; Cavallaro, Alexander Josef (2016)
EVALuna2:13480

SUBJECTIVE ASSESSMENT OF PHYSICAL FUNCTION DOES NOT SUFFICIENTLY EXPLAIN VARIANCE OF MEASURED HAND FUNCTION AND GRIP STRENGTH IN ARTHRITIS PATIENTS AND NON-ARTHRITIS CONTROLS - Liphardt, Anna-Maria; Tascilar, Koray; Coppers, Birte; Manger, Eva; Liehr, Sonja; Bieniek, Lisa Maria; Bayat, Sara; Simon, David; Sticherling, Michael; Rech, Jürgen; Hueber, A.; Schett, Georg; et al. (ANNALS OF THE RHEUMATIC DISEASES, 2022)
CRIS-Team WoS Importer:2022-11-04

Successful Generation of CD19 Chimeric Antigen Receptor T Cells from Patients with Advanced Systemic Lupus Erythematosus - Kretschmann, S.; Völkl, Simon; Reimann, Hannah; Krönke, Gerhard; Schett, Georg; Achenbach, Susanne; Lutzny-Geier, Gloria; Müller, Fabian; Mougiakakos, Dimitrios; Dingfelder, Janin; Flamann, Cindy; Hanssens, L.; et al. (Transplantation and Cellular Therapy, 2022)
Although it has been shown that the production of functional chimeric antigen receptor T cells is feasible in patients with B-cell malignancies, it is currently unclear whether sufficient amounts of functional autologous CAR T cells can be generated from patients with autoimmune diseases. Intrinsic T-cell abnormalities and T-cell–targeted immune suppression in patients with autoimmunity may hamper the retrieval of sufficient T cells and their transduction and expansion into CAR T cells. Patients with active systemic lupus erythematosus (SLE) underwent leukapheresis after tapering glucocorticoids and stopping T-cell–suppressive drugs. This material was used as source for manufacturing anti-CD19 CAR T-cell products (CAR) in clinical scale. Cells were transduced with a lentiviral anti-CD19 CAR vector and expanded under good manufacturing practice (GMP) conditions using a closed, semi-automatic system. Functionality of these CAR T cells derived from autoimmune patient cells was tested in vitro. Six SLE patients were analyzed. Leukapheresis could be successfully performed in all patients yielding sufficient T-cell numbers for clinical scale CAR T-cell production. In addition, CAR T cells showed high expansion rates and viability, leading to CAR T cells in sufficient doses and quality for clinical use. CAR T cells from all patients showed specific cytotoxicity against CD19+ cell lines in vitro. GMP grade generation of CD19 CAR T-cell products suitable for clinical use is feasible in patients with autoimmune disease.
CRIS-Team Scopus Importer:2022-12-23
Keywords: Chimeric antigen receptor; Systemic lupus erythematosus; T cells

Successful remission induction with a combination therapy of rituximab, cyclophosphamide, and steroids in a patient with refractory optic neuritis in Wegener's granulomatosis - Huchzermeyer, Cord; Mardin, Christian Y.; Holbach, Leonard; Zwerina, Jochen; Schett, Georg; Rech, Juergen (Clinical Rheumatology, 2013)
A 56-year old patient with a history of limited Wegener's granulomatosis presented with signs and symptoms of optic neuritis. Radiologic signs of orbital inflammation were absent. Testing of visual acuity and visual field allowed close monitoring of disease activity. Thus, rapid improvement of visual function was achieved with high-dose steroids. Despite maintenance therapy with cyclophosphamide recurrence occurred repeatedly as soon as tapering of steroids was begun. After remission induction with rituximab, the patient retained good visual function under maintenance therapy with azathioprine and low-dose corticosteroids. Optic neuritis in Wegener's granulomatosis without signs of orbital involvement is rare and most likely caused by occlusive vasculitis of the vasa nervorum. In this patient with optic neuritis refractory to conventional therapy, rituximab in combination with cyclophosphamide and corticosteroids was well tolerated and successfully used for remission induction, followed by maintenance therapy with azathioprine and low dose corticosteroids.
EVALuna2:12699

Successful treatment of adult-onset Still's disease refractory to TNF and IL-1 blockade by IL-6 receptor blockade - Rech, Jürgen; Ronneberger, Monika; Englbrecht, Matthias; Finzel, Stephanie; Katzenbeisser, Julia; Manger, Karin; Manger, Bernhard; Schett, Georg (Annals of the Rheumatic Diseases, 2011)
CRIS-Team Scopus Importer:2021-02-03

Successful treatment of refractory palmoplantar psoriasis in a psoriatic arthritis patient with the JAK inhibitor tofacitinib - Valor-Mendez, Larissa; Sticherling, Michael; Kleyer, Arnd; Schett, Georg (Clinical and Experimental Rheumatology, 2021)
CRIS-Team WoS Importer:2021-03-26

"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, Erika; Stoffer, Michaela; Steiner, Guenter; Raza, Karim; Stack, Rebecca J.; Simons, Gwenda; Falahee, Marie; Schett, Georg; Englbrecht, Matthias; Smolen, Josef S.; Hueber, Axel; Stamm, Tanja (2017)
EVALuna2:33438

Suppression of neutrophils by sodium exacerbates oxidative stress and arthritis - Zlatar, Leticija; Mahajan, Aparna; Munoz Becerra, Marco; Weidner, Daniela; Bila, Galyna; Bilyy, Rostyslav; Titze, Jens; Hoffmann, Markus H.; Schett, Georg; Herrmann, Martin; Steffen, Ulrike; Muñoz, Luis E.; et al. (Frontiers in Immunology, 2023)
Introduction: Typical Western diet, rich in salt, contributes to autoimmune disease development. However, conflicting reports exist about the effect of salt on neutrophil effector functions, also in the context of arthritis. Methods: We investigated the effect of sodium chloride (NaCl) on neutrophil viability and functions in vitro, and in vivo employing the murine K/BxN-serum transfer arthritis (STA) model. Results and discussion: The effects of NaCl and external reactive oxygen species (H2O2) were further examined on osteoclasts in vitro. Hypertonic sodium-rich media caused primary/secondary cell necrosis, altered the nuclear morphology, inhibited phagocytosis, degranulation, myeloperoxidase (MPO) peroxidation activity and neutrophil extracellular trap (NET) formation, while increasing total ROS production, mitochondrial ROS production, and neutrophil elastase (NE) activity. High salt diet (HSD) aggravated arthritis by increasing inflammation, bone erosion, and osteoclast differentiation, accompanied by increased NE expression and activity. Osteoclast differentiation was decreased with 25 mM NaCl or 100 nM H2O2 addition to isotonic media. In contrast to NaCl, external H2O2 had pro-resorptive effects in vitro. We postulate that in arthritis under HSD, increased bone erosion can be attributed to an enhanced oxidative milieu maintained by infiltrating neutrophils, rather than a direct effect of NaCl.
CRIS-Team Scopus Importer:2023-09-01
Keywords: K/BxN serum transfer arthritis; neutrophil extracellular traps (NETs); neutrophils; osteoclasts; reactive oxygen species; sodium chloride

Sustained clinical remission under infliximab/rituximab combination therapy in a patient with granulomatosis with polyangiitis - Valor-Méndez, Larissa; Kleyer, Arnd; Rech, Jürgen; Manger, Bernhard; Schett, Georg (Autoimmunity Highlights, 2021)
Background: Granulomatosis with polyangiitis (GPA) is a systemic autoimmune disease characterized by small and medium vessel vasculitis. The use of biological therapies such as rituximab and infliximab has improved the treatment of ocular manifestations in GPA. Case report: We report a case of a 45-year-old Caucasian male suffering with rhinitis, sinubronchitis and exophthalmos. These clinical findings, subsequent biopsy and MRI were consistent with positive anti-neutrophil cytoplasm antibody (ANCA)/proteinase-3 and he was diagnosed with GPA with orbital involvement. He was refractory to cyclophosphamide at stable doses of methotrexate and a therapy with rituximab was started. Eventually and because of family planning methotrexate was replaced by azathioprine. Symptoms worsened and MRI revealed an increase in the granulomatous lesion in the orbit. Therefore, we decided to add infliximab to the combination of azathioprine and rituximab, our patient achieved then a long-term response. During the 10 years of the combined treatment, no adverse effects or systemic involvement occurred. Conclusions: This case suggests that the individual use of a combination of rituximab and infliximab may be a promising strategy for the treatment in the long term of refractory orbital GPA.
CRIS-Team Scopus Importer:2021-03-19
Keywords: Combined therapy; Granulomatosis with polyangiitis (GPA); Infliximab; Rituximab

Syntenin-1-mediated arthritogenicity is advanced by reprogramming RA metabolic macrophages and Th1 cells - Meyer, Anja; Sienes, Ryan E.; Nijim, Wes; Zanotti, Brian; Umar, Sadiq; Volin, Michael V.; Van Raemdonck, Katrien; Lewis, Myles; Pitzalis, Costantino; Arami, Shiva; Al-Awqati, Mina; Chang, Huan J.; et al. (Annals of the Rheumatic Diseases, 2023)
ObjectivesSyntenin-1, a novel endogenous ligand, was discovered to be enriched in rheumatoid arthritis (RA) specimens compared with osteoarthritis synovial fluid and normal synovial tissue (ST). However, the cellular origin, immunoregulation and molecular mechanism of syntenin-1 are undescribed in RA. MethodsRA patient myeloid and lymphoid cells, as well as preclinical models, were used to investigate the impact of syntenin-1/syndecan-1 on the inflammatory and metabolic landscape. ResultsSyntenin-1 and syndecan-1 (SDC-1) co-localise on RA ST macrophages (M phi s) and endothelial cells. Intriguingly, blood syntenin-1 and ST SDC-1 transcriptome are linked to cyclic citrullinated peptide, erythrocyte sedimentation rate, ST thickness and bone erosion. Metabolic CD14(+)CD86(+)GLUT1(+)M phi s reprogrammed by syntenin-1 exhibit a wide range of proinflammatory interferon transcription factors, monokines and glycolytic factors, along with reduced oxidative intermediates that are downregulated by blockade of SDC-1, glucose uptake and/or mTOR signalling. Inversely, IL-5R and PDZ1 inhibition are ineffective on RA M phi s-reprogrammed by syntenin-1. In syntenin-1-induced arthritis, F4/80(+)iNOS(+)RAPTOR(+)M phi s represent glycolytic RA M phi s, by amplifying the inflammatory and glycolytic networks. Those networks are abrogated in SDC-1(-/-) animals, while joint prorepair monokines are unaffected and the oxidative metabolites are moderately replenished. In RA cells and/or preclinical model, syntenin-1-induced arthritogenicity is dependent on mTOR-activated M phi remodelling and its ability to cross-regulate Th1 cells via IL-12 and IL-18 induction. Moreover, RA and joint myeloid cells exposed to Syntenin-1 are primed to transform into osteoclasts via SDC-1 ligation and RANK, CTSK and NFATc1 transcriptional upregulation. ConclusionThe syntenin-1/SDC-1 pathway plays a critical role in the inflammatory and metabolic landscape of RA through glycolytic M phi and Th1 cell cross-regulation (graphical abstract).
CRIS-Team WoS Importer:2023-01-20

Systemic and local bone loss in Psoriasis and Psoriatic Arthritis - Kocijan, Roland; Englbrecht, Matthias; Kleyer, Arnd; Haschka, Judith; Simon, David; Finzel, Stephanie; Kraus, Sebastian; Muschitz, Christian; Resch, Heinrich; Engelke, Klaus; Rech, Jürgen; Schett, Georg (2014)
EVALuna2:13062

Systemic PPAR gamma Antagonism Reduces Metastatic Tumor Progression in Adipocyte-Rich Bone in Excess Weight Male Rodents - Gaculenko, Anastasia; Gregoric, Gasper; Popp, Vanessa; Seyler, Lisa; Ringer, Mark; Kachler, Katerina; Wu, Zhengquan; Kisel, Wadim; Hofbauer, Christine; Hofbauer, Lorenz C.; Uder, Michael; Schett, Georg; et al. (Journal of Bone and Mineral Research, 2021)
Primary tumors are widely associated with an excess in body fat. The role of adipose tissue on tumor cell homing to bone is yet poorly defined. In this study, we aimed to assess whether bone colonization by tumor cells is favored by an adipocyte-rich bone marrow. We delineated the accompanying alterations of the bone microenvironment and established a treatment approach that interferes with high fat diet (HFD)-induced bone metastasis formation. We were able to show that adipocytes affect skeletal tumor growth in a metastatic model of breast cancer in male rats and melanoma in male mice as well as in human breast cancer bone biopsies. Indeed, HFD-induced bone marrow adiposity was accompanied by accelerated tumor progression and increased osteolytic lesions. In human bone metastases, bone marrow adiposity correlated with tumor cell proliferation. By antagonization of the adipocyte differentiation and storage pathway linked to the peroxisome proliferator-activated receptor gamma (PPAR gamma) with bisphenol-A-diglycidylether (BADGE), we were able to decelerate tumor progression and subsequent osteolytic damage in the bones of two distinct metastatic animal models exposed to HFD. Overall these data show that adipose tissue is a critical factor in bone metastases and cancer-induced bone loss. 2021 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).
CRIS-Team WoS Importer:2021-09-03

Systemic versus local adipokine expression differs in a combined obesity and osteoarthritis mouse model - Hülser, Marie Lisa; Luo, Yubin; Frommer, Klaus; Hasseli, Rebecca; Köhler, Kernt; Diller, Magnus; Van Nie, Lina; Rummel, Christoph; Roderfeld, Martin; Roeb, Elke; Schett, Georg; Bozec, Aline; et al. (Scientific Reports, 2021)
Osteoarthritis (OA) is a degenerative joint disease characterized by cartilage loss and reduced joint function. OA risk factors are age and obesity. Many adipokines are altered by obesity but also OA although systemic adipokine regulation in OA is not always clear. Therefore, metabolic effects of diet-induced obesity on OA development as well as the influence of obesity and OA progression on systemic vs. local adipokine expression in joints were compared. C57Bl/6-mice fed with HFD (high fat diet) or normal diet prior to destabilization of the medial meniscus (DMM) were sacrificed 4/6/8 weeks after surgery. Sera were evaluated for adiponectin, leptin, visfatin, cytokines. Liver grading and staging for non-alcoholic steatohepatitis (NASH) was performed and crown-like structures (CLS) in adipose tissue measured. OA progression was scored histologically. Adipokine-expressing cells and types were evaluated by immunohistochemistry. Time-dependent changes in DMM-progression were reflected by increased systemic adiponectin levels in DMM especially combined with HFD. While HFD increased serum leptin, DMM reduced systemic leptin significantly. OA scores correlated with bodyweight, leptin and hepatic scoring. Locally, increased numbers of adiponectin- and leptin-producing fibroblasts were observed in damaged menisci but visfatin was not changed. Local adipokine expression was independent from systemic levels, suggesting different mechanisms of action.
CRIS-Team Scopus Importer:2021-08-27

T2 Mapping as a New Method for Quantitative Assessment of Cartilage Damage in RA - Renner, Nina; Kleyer, Arnd; Krönke, Gerhard; Simon, David; Söllner, Stefan; Rech, Jürgen; Uder, Michael; Janka, Rolf Matthias; Schett, Georg; Welsch, Goetz; Pachowsky, Milena (Journal of Rheumatology, 2019)
OBJECTIVE: Rheumatoid arthritis (RA) is associated with damage of the articular cartilage and the periarticular bone. While imaging of bone damage has substantially improved in the last years, direct imaging of the articular cartilage of the hand joints in patients with RA is still challenging. METHODS: 3 Tesla Magnetic Resonance Imaging (MRI) was done in 30 RA patients and T2 relaxation times visualizing alteration in the collagen network and hydration of articular cartilage were mapped in six cartilage regions of the metacarpophalangeal joints 2 and 3. Values were related to autoantibody (anti-citrullinated peptide antibodies (ACPA), rheumatoid factor (RF)) status, disease duration, disease activity as well as sex and age of the RA patients. RESULTS: T2 relaxation times could be reliably measured in the six regions of the metacarpophalangeal joints. Significantly higher relaxation times indicating more advanced cartilage alterations were observed in ACPA-positive (p=0.001-0.010) and RF-positive patients (p=0.013-0.025) as well as those with longer disease duration (>3 years; p=0.028-0.043). Current disease activity, sex and age did not influence T2 relaxation times. CONCLUSION: These data show that cartilage damage can be localized and quantified in the hand joints of RA patients by T2 mapping. Furthermore, ACPA and RF positivity as well as disease duration appear to be the crucial factors influencing cartilage damage.
EVALuna2:210913

Tapering biologic and conventional DMARD therapy in rheumatoid arthritis: current evidence and future directions - Schett, Georg; Emery, Paul; Tanaka, Yoshiya; Burmester, Gerd; Pisetsky, David S.; Naredo, Esperanza; Fautrel, Bruno; Van Vollenhoven, Ronald (Annals of the Rheumatic Diseases, 2016)
Improvements in the control of inflammation in rheumatoid arthritis (RA) by conventional synthetic and biologic disease-modifying antirheumatic drugs (DMARDs) have led to a substantial change in the clinical outcomes of patients during the last 30 years. Current treatment can lead to sustained remission in some patients raising questions about the optimal management strategies in this subgroup of patients. Today, tapering of DMARDs and even their discontinuation appears as an interesting concept for achieving a more tailored and dynamic treatment approach of RA, especially in patients, who achieved full disease control by DMARD treatment. In this review article, current developments of DMARD tapering are discussed. The article provides an overview of existing studies on this topic and addresses new strategies to reach drug-free remission. Furthermore, concepts for defining patients eligible for DMARD tapering are described and potential future strategies in using biomarkers in predicting the risk for disease relapse after initiation of DMARD tapering are addressed. These findings are finally considered in light of the vision to achieve cure as an ultimate goal in patients with RA achieving full control of inflammation.
EVALuna2:13285

Targeting GM-CSF in rheumatological conditions: risk of PAP – Authors' reply - Genovese, Mark C.; Buckley, Christopher D.; Saurigny, Didier; Schett, Georg; Davy, Katherine; Gupta, Anubha; Smith, Julia E.; Patel, Jatin; Tak, Paul P. (The Lancet Rheumatology, 2021)
CRIS-Team Scopus Importer:2021-07-02

Targeting GM-CSF in rheumatological conditions: risk of PAP Reply - Genovese, Mark C.; Buckley, Christopher D.; Saurigny, Didier; Schett, Georg; Davy, Katherine; Gupta, Anubha; Smith, Julia E.; Patel, Jatin; Tak, Paul P. (The Lancet Rheumatology, 2021)
CRIS-Team WoS Importer:2021-07-16

Targeting intestinal tight junctions to inhibit onset of arthritis - Tajik, N.; Schulz, O.; Frech, Michael; Lucas, Sébastien; Sarter-Zaiss, Kerstin; Schett, Georg; Zaiss, Mario (EUROPEAN JOURNAL OF IMMUNOLOGY, 2019)
CRIS-Team WoS Importer:2019-10-08

Targeting of canonical WNT signaling ameliorates experimental sclerodermatous chronic graft-versus-host disease - Zhang, Yun; Shen, Lichong; Dreißigacker, Katja; Zhu, Honglin; Trinh, Minh Thuong; Meng, Xianyi; TRAN MANH, CUONG; Dees, Clara; Matei, Alexandru-Emil; Chen, Chih-Wei; Ditschkowski, Markus; Krauss, Stefan; et al. (Blood, 2021)
Chronic graft-versus-host disease (cGVHD) is a major life-threatening complication of allogeneic hematopoietic stem cell transplantation. The molecular mechanisms underlying cGVHD remain poorly understood, and targeted therapies for clinical use are not well established. Here, we examined the role of the canonical WNT pathway in sclerodermatous cGVHD (sclGVHD). WNT signaling was activated in human sclGVHD with increased nuclear accumulation of the transcription factor β-catenin and a WNT-biased gene expression signature in lesional skin. Treatment with the highly selective tankryase inhibitor G007-LK, the CK1α agonist pyrvinium, or the LRP6 inhibitor salinomycin abrogated the activation of WNT signaling and protected against experimental cGVHD, without a significant impact on graft-versus-leukemia effect (GVL). Treatment with G007-LK, pyrvinium, or salinomycin almost completely prevented the development of clinical and histological features in the B10.D2 (H-2d) → BALB/c (H-2d) and LP/J (H-2b) → C57BL/6 (H-2b) models of sclGVHD. Inhibition of canonical WNT signaling reduced the release of extracellular matrix from fibroblasts and reduced leukocyte influx, suggesting that WNT signaling stimulates fibrotic tissue remodeling by direct effects on fibroblasts and by indirect inflammation-dependent effects in sclGVHD. Our findings may have direct translational potential, because pyrvinium is in clinical use, and tankyrase inhibitors are in clinical trials for other indications.
CRIS-Team Scopus Importer:2021-05-28

Targeting of fibroblast activation protein in rheumatoid arthritis patients: imaging and ex vivo photodynamic therapy - Dorst, Daphne N.; Rijpkema, Mark; Buitinga, Mijke; Walgreen, Birgitte; Helsen, Monique M. A.; Brennan, Evan; Klein, Christian; Laverman, Peter; Ramming, Andreas; Schmidkonz, Christian; Kuwert, Torsten; Schett, Georg; et al. (Rheumatology, 2021)
Objective Activated synovial fibroblasts are key effector cells in RA. Selectively depleting these based upon their expression of fibroblast activation protein (FAP) is an attractive therapeutic approach. Here we introduce FAP imaging of inflamed joints using Ga-68-FAPI-04 in a RA patient, and aim to assess feasibility of anti-FAP targeted photodynamic therapy (FAP-tPDT) ex vivo using 28H1-IRDye700DX on RA synovial explants. Methods Remnant synovial tissue from RA patients was processed into 6 mm biopsies and, from several patients, into primary fibroblast cell cultures. Both were treated using FAP-tPDT. Cell viability was measured in fibroblast cultures and biopsies were evaluated for histological markers of cell damage. Selectivity of the effect of FAP-tPDT was assessed using flow cytometry on primary fibroblasts and co-cultured macrophages. Additionally, one RA patient intravenously received Ga-68-FAPI-04 and was scanned using PET/CT imaging. Results In the RA patient, FAPI-04 PET imaging showed high accumulation of the tracer in arthritic joints with very low background signal. In vitro, FAP-tPDT induced cell death in primary RA synovial fibroblasts in a light dose-dependent manner. An upregulation of cell damage markers was observed in the synovial biopsies after FAP-tPDT. No significant effects of FAP-tPDT were noted on macrophages after FAP-tPDT of neighbouring fibroblasts. Conclusion In this study the feasibility of selective FAP-tPDT in synovium of rheumatoid arthritis patients ex vivo is demonstrated. Furthermore, this study provides the first indication that FAP-targeted PET/CT can be used to image arthritic joints, an important step towards application of FAP-tPDT as a targeted locoregional therapy for RA.
CRIS-Team WoS Importer:2022-02-25

Targeting zonulin and intestinal epithelial barrier function to prevent onset of arthritis - Tajik, Narges; Frech, Michael; Schulz, Oscar; Schälter, Fabian; Lucas, Sébastien; Azizov, Vugar; Dürholz, Kerstin; Steffen, Franziska; Omata, Yasunori; Rings, Andreas; Bertog, Marko; Rizzo, Aroldo; et al. (Nature Communications, 2020)
Gut microbial dysbiosis is associated with the development of autoimmune disease, but the mechanisms by which microbial dysbiosis affects the transition from asymptomatic autoimmunity to inflammatory disease are incompletely characterized. Here, we identify intestinal barrier integrity as an important checkpoint in translating autoimmunity to inflammation. Zonulin family peptide (zonulin), a potent regulator for intestinal tight junctions, is highly expressed in autoimmune mice and humans and can be used to predict transition from autoimmunity to inflammatory arthritis. Increased serum zonulin levels are accompanied by a leaky intestinal barrier, dysbiosis and inflammation. Restoration of the intestinal barrier in the pre-phase of arthritis using butyrate or a cannabinoid type 1 receptor agonist inhibits the development of arthritis. Moreover, treatment with the zonulin antagonist larazotide acetate, which specifically increases intestinal barrier integrity, effectively reduces arthritis onset. These data identify a preventive approach for the onset of autoimmune disease by specifically targeting impaired intestinal barrier function.
CRIS-Team Scopus Importer:2020-05-05

TARGET OUTCOMES IN PSA: SIMULTANEOUS ACHIEVEMENT OF ACR50-PASI100 AND BEYOND: INSIGHTS FROM SPIRIT-H2H AT WEEK 24 - Smolen, J. S.; Behrens, F.; Leage, S. Liu; Sapin, C.; De La Torre, I.; Meszaros, G.; Schett, Georg; Gossec, L.; Ostor, A.; Combe, B.; Van Den Bosch, F. (ANNALS OF THE RHEUMATIC DISEASES, 2020)
CRIS-Team WoS Importer:2020-08-21

Target Outcomes in Psoriatic Arthritis: Simultaneous Achievement of ACR50-Psoriasis Area and Severity Index 100 and Beyond: Insights from Open-Label, Assessor-Blinded Study at Week 24 - Smolen, Josef; Behrens, Frank; Liu-Leage, Soyi; Sapin, Christophe; De La Torre, Inmaculada; Meszaros, Gabriella; Schett, Georg; Gossec, Laure; Ostor, Andrew; Combe, Bernard; Van Den Bosch, Filip (ARTHRITIS & RHEUMATOLOGY, 2020)
CRIS-Team WoS Importer:2021-01-15

T Cell Costimulation Molecules CD80/86 Inhibit Osteoclast Differentiation by Inducing the IDO/Tryptophan Pathway - Bozec, Aline; Zaiss, Mario; Kagwiria, Rosebeth; Voll, Reinhard; Rauh, Manfred; Chen, Zhu; Müller-Schmucker, Sandra; Kroczek, Richard A.; Heinzerling, Lucie; Moser, Muriel; Mellor, Andrew L.; David, Jean-Pierre; et al. (Science Translational Medicine, 2014)
Bone resorption is seminal for the physiological remodeling of bone during life. However, this process needs to be strictly controlled; excessive bone resorption results in pathologic bone loss, osteoporosis, and fracture. We describe a control mechanism of bone resorption by the adaptive immune system. CD80/86, a pair of molecules expressed by antigen-presenting cells and involved in T cell costimulation, act as negative regulator for the generation of bone-resorbing osteoclasts. CD80/86-deficient mice were osteopenic because of increased osteoclast differentiation. CD80/86-deficient osteoclasts escaped physiological inhibition by CTLA-4 or regulatory T cells. Mechanistically, engagement of CD80/86 by CTLA-4 induced activation of the enzyme indoleamine 2,3-dioxygenase (IDO) in osteoclast precursors, which degraded tryptophan and promoted apoptosis. Concordantly, IDO-deficient mice also showed an osteopenic bone phenotype with higher numbers of osteoclast precursors and osteoclasts. Also, IDO-deficient mononuclear cells escaped the anti-osteoclastogenic effect of CTLA-4. This molecular mechanism was also present in humans because targeting CD80/86 by abatacept, a CTLA-4-immunoglobulin fusion protein, reduced, whereas blockade of CTLA-4 by ipilimumab antibody enhanced, the frequency of peripheral osteoclast precursors and osteoclastogenesis. In summary, these data show an important role of the adaptive immune system, in particular T cell CD80/86 costimulation molecules, in the physiological regulation of bone resorption and preservation of bone mass, as well as affect the understanding of the function of current and future drugs fostering or blocking the effects of CTLA-4 in humans.
EVALuna2:12912

T cells as key players for bone destruction in gouty arthritis? - Harre, Ulrike; Derer, Anja; Schorn, Christine; Schett, Georg; Herrmann, Martin (Arthritis Research & Therapy, 2011)
The deposition of monosodium urate (MSU) crystals in synovial fluid and tissue leads to gouty arthritis frequently associated with synovial inflammation and bone erosions. The cellular mechanism that links MSU crystals to an increased number of osteoclasts has not yet been fully understood. In a recent issue of Arthritis Research & Therapy Lee and colleagues proposed that bone destruction in chronic gouty arthritis is at least in part dependent on expression by T cells of receptor activator of NF-κB ligand (RANKL). The authors showed that pro-resorptive cytokines such as IL-1β, IL-6, and TNFα are expressed within tophi and stromal infiltrates. In vitro stimulation with MSU crystals revealed monocytes as a source for these cytokines, whereas T cells produce RANKL, the major trigger of osteoclastogenesis. © 2011 BioMed Central Ltd.
Created from Fastlane, Scopus look-up

TELERA-Asynchronous TELEmedicine for Patients With Rheumatoid Arthritis: Study Protocol for a Prospective, Multi-Center, Randomized Controlled Trial - Mucke, Johanna; Knitza, Johannes; Muehlensiepen, Felix; Grahammer, Manuel; Stenzel, Ramona; Simon, David; Kleyer, Arnd; Krönke, Gerhard; Sharp, Charlotte; Bendzuck, Gerlinde; Korinth, Marianne; Elling-Audersch, Corinna; et al. (Frontiers in Medicine, 2021)
Innovative strategies are needed to adequately assess and monitor disease activity of patients with rheumatoid arthritis (RA) in times of scarce appointments. The aim of the TELERA study is to evaluate the feasibility and performance of asynchronous telemedicine visits based on patient-generated data and patient's drug history. RA patients use a medical app, ABATON, that captures the results of a self-performed quick CRP-test, joint-count, and electronic patient-reported outcomes in between visits. This is a prospective, multi-center, randomized controlled trial performed in four German university centers. The estimated sample size is 120 patients. The main outcome is the agreement of rheumatologists' treatment decisions based on asynchronous telemedicine patient-generated data with traditional in-person rheumatology clinic-based decisions and with patient suggestions. The TELERA trial will provide evidence regarding the implementation of remote care in rheumatology.
CRIS-Team WoS Importer:2022-01-14

TEMPORAL MIGRATION OF IMMUNE CELLS FROM PSORIATIC SKIN TO JOINTS INITIATING SYNOVIAL INFLAMMATION IN PSORIATIC ARTHRITIS - Raimondo, Maria Gabriella; Rauber, Simon; Xu, Cong; Mohammadian, Hashem; Vogg, Mario; Anchang, Charles Gwellem; Rigau, Aleix; Luber, M.; Labinsky, Hannah; Soare, A.; Distler, Jörg; Fearon, U.; et al. (ANNALS OF THE RHEUMATIC DISEASES, 2022)
CRIS-Team WoS Importer:2022-11-04

Tendon and ligament mechanical loading in the pathogenesis of inflammatory arthritis - Gracey, Eric; Burssens, Arne; Cambre, Isabelle; Schett, Georg; Lories, Rik; Mcinnes, Iain B.; Asahara, Hiroshi; Elewaut, Dirk (Nature Reviews Rheumatology, 2020)
Mechanical loading is an important factor in musculoskeletal health and disease. Tendons and ligaments require physiological levels of mechanical loading to develop and maintain their tissue architecture, a process that is achieved at the cellular level through mechanotransduction-mediated fine tuning of the extracellular matrix by tendon and ligament stromal cells. Pathological levels of force represent a biological (mechanical) stress that elicits an immune system-mediated tissue repair pathway in tendons and ligaments. The biomechanics and mechanobiology of tendons and ligaments form the basis for understanding how such tissues sense and respond to mechanical force, and the anatomical extent of several mechanical stress-related disorders in tendons and ligaments overlaps with that of chronic inflammatory arthritis in joints. The role of mechanical stress in ‘overuse’ injuries, such as tendinopathy, has long been known, but mechanical stress is now also emerging as a possible trigger for some forms of chronic inflammatory arthritis, including spondyloarthritis and rheumatoid arthritis. Thus, seemingly diverse diseases of the musculoskeletal system might have similar mechanisms of immunopathogenesis owing to conserved responses to mechanical stress.
CRIS-Team Scopus Importer:2020-03-06

TGF beta-Dependent Upregulation of XIAP Fosters Fibroblast Activation and Tissue Fibrosis By Promoting Canonical Wnt Signaling - Bergmann, Christina; Hallenberger, Ludwig; Brandt, Adrian; Merlevede, Benita; Dees, Clara; Chen, Chih-Wei; Beyer, Christian; Distler, Oliver; Schett, Georg; Distler, Jörg (2017)
EVALuna2:33427

TGF-beta-Induced Epigenetic Silencing of SOCS3 Facilitates STAT3 Signaling to Promote Fibroblast Activation and Tissue Fibrosis in Systemic Sclerosis - Dees, Clara; Zhang, Yun; Pötter, Sebastian; Bergmann, Christina; Distler, Oliver; Schett, Georg; Distler, Jörg; Ramming, Andreas (2017)
EVALuna2:33431

TGF beta Promotes Fibrosis By MYST1-Dependent Epigenetic Regulation of Autophagy - Zehender, Ariella; Lin, Neng-Yu; Stefanica, Adrian; Chen, Chih-Wei; Soare, Alina; Wohlfahrt, Thomas; Rauber, Simon; Bergmann, Christina; Distler, Oliver; Schett, Georg; Distler, Jörg; Ramming, Andreas (2017)
EVALuna2:33446

TGF-β-induced epigenetic deregulation of SOCS3 facilitates STAT3 signaling to promote fibrosis - Dees, Clara; Pötter, Sebastian; Zhang, Yun; Bergmann, Christina; Zhou, Xiang; Luber, Markus; Wohlfahrt, Thomas; Karouzakis, Emmanuel; Ramming, Andreas; Gelse, Kolja; Yoshimura, Akihiko; Jaenisch, Rudolf; et al. (Journal of Clinical Investigation, 2020)
Fibroblasts are key effector cells in tissue remodeling. They remain persistently activated in fibrotic diseases, resulting in progressive deposition of extracellular matrix. Although fibroblast activation may be initiated by external factors, prolonged activation can induce an “autonomous,” self-maintaining profibrotic phenotype in fibroblasts. Accumulating evidence suggests that epigenetic alterations play a central role in establishing this persistently activated pathologic phenotype of fibroblasts. We demonstrated that in fibrotic skin of patients with systemic sclerosis (SSc), a prototypical idiopathic fibrotic disease, TGF-β induced the expression of DNA methyltransferase 3A (DNMT3A) and DNMT1 in fibroblasts in a SMAD-dependent manner to silence the expression of suppressor of cytokine signaling 3 (SOCS3) by promoter hypermethylation. Downregulation of SOCS3 facilitated activation of STAT3 to promote fibroblast-to-myofibroblast transition, collagen release, and fibrosis in vitro and in vivo. Reestablishment of the epigenetic control of STAT3 signaling by genetic or pharmacological inactivation of DNMT3A reversed the activated phenotype of SSc fibroblasts in tissue culture, inhibited TGF-β-dependent fibroblast activation, and ameliorated experimental fibrosis in murine models. These findings identify a pathway of epigenetic imprinting of fibroblasts in fibrotic disease with translational implications for the development of targeted therapies in fibrotic diseases.
CRIS-Team Scopus Importer:2020-05-12

TGFβ promotes fibrosis by MYST1-dependent epigenetic regulation of autophagy - Zehender, Ariella; Li, Yi-Nan; Lin, Neng Yu; Stefanica, Adrian; Nüchel, Julian; Chen, Chih-Wei; Hsu, Hsiao Han; Zhu, Honglin; Ding, Xiao; Huang, Jingang; Shen, Lichong; Györfi, Andrea-Hermina; et al. (Nature Communications, 2021)
Activation of fibroblasts is essential for physiological tissue repair. Uncontrolled activation of fibroblasts, however, may lead to tissue fibrosis with organ dysfunction. Although several pathways capable of promoting fibroblast activation and tissue repair have been identified, their interplay in the context of chronic fibrotic diseases remains incompletely understood. Here, we provide evidence that transforming growth factor-β (TGFβ) activates autophagy by an epigenetic mechanism to amplify its profibrotic effects. TGFβ induces autophagy in fibrotic diseases by SMAD3-dependent downregulation of the H4K16 histone acetyltransferase MYST1, which regulates the expression of core components of the autophagy machinery such as ATG7 and BECLIN1. Activation of autophagy in fibroblasts promotes collagen release and is both, sufficient and required, to induce tissue fibrosis. Forced expression of MYST1 abrogates the stimulatory effects of TGFβ on autophagy and re-establishes the epigenetic control of autophagy in fibrotic conditions. Interference with the aberrant activation of autophagy inhibits TGFβ-induced fibroblast activation and ameliorates experimental dermal and pulmonary fibrosis. These findings link uncontrolled TGFβ signaling to aberrant autophagy and deregulated epigenetics in fibrotic diseases and may contribute to the development of therapeutic interventions in fibrotic diseases.
CRIS-Team Scopus Importer:2021-08-06

Th2 and eosinophil responses ameliorate arthritis and inflammatory bone loss - Andreev, Darja; Chen, Zhu; Oeser, Katharina; Krljanac, B.; Hueber, Axel; Kleyer, Arnd; Weigmann, Benno; Vöhringer, David; Schett, Georg; Bozec, Aline (2017)
EVALuna2:33419

Th2 and eosinophil responses suppress inflammatory arthritis - Chen, Zhu; Andreev, Darja; Oeser, Katharina; Krljanac, Branislav; Hueber, Axel; Kleyer, Arnd; Vöhringer, David; Schett, Georg; Bozec, Aline (Nature Communications, 2016)
Th2-eosinophil immune responses are well known for mediating host defence against helminths. Herein we describe a function of Th2-eosinophil responses in counteracting the development of arthritis. In two independent models of arthritis, Nippostrongylus brasiliensis infection leads to Th2 and eosinophil accumulation in the joints associated with robust inhibition of arthritis and protection from bone loss. Mechanistically, this protective effect is dependent on IL-4/IL-13-induced STAT6 pathway. Furthermore, we show that eosinophils play a central role in the modulation of arthritis probably through the increase of anti-inflammatory macrophages into arthritic joints. The presence of these pathways in human disease is confirmed by detection of GATA3-positive cells and eosinophils in the joints of rheumatoid arthritis patients. Taken together, these results demonstrate that eosinophils and helminth-induced activation of the Th2 pathway axis effectively mitigate the course of inflammatory arthritis.
EVALuna2:13286

The 12/15-lipoxygenase pathway counteracts fibroblast activation and experimental fibrosis - Krönke, Gerhard; Reich, Nicole; Scholtysek, Carina; Akhmetshina, Alfiya; Uderhardt, Stefan; Zerr, Pawel; Palumbo, Katrin; Lang, Veronika; Dees, Clara; Distler, Oliver; Schett, Georg; Distler, Jörg (Annals of the Rheumatic Diseases, 2012)
Background: Idiopathic and inflammation-dependent fibrotic diseases such systemic sclerosis (SSc) impose a major burden on modern societies. Understanding endogenous mechanisms, which counteract fibrosis, may yield new therapeutic approaches. Lipoxins are highly potent lipid mediators, which have recently been found to be decreased in SSc. Objectives: To determine the potential role of 12/15-lipoxygenase (12/15-LO), the key enzyme for the synthesis of lipoxins, in fibrosis. Methods: Two mouse models for experimental dermal fibrosis (bleomycin-induced dermal fibrosis and tight-skin 1 mouse model) together with bone marrow transfers were used in wildtype and 12/15-LO -/- mice to elucidate the role of this enzyme during dermal fibrosis. Primary dermal fibroblasts of wildtype and 12/15-LO -/- mice, and 12/15-LO-derived eicosanoids, were used to identify underlying molecular mechanisms Results: In both models, 12/15-LO -/- mice exhibited a significant exacerbation of the fibrotic tissue response. Bone marrow transfer experiments disclosed a predominant role of mesenchymal cell-derived 12/15-LO in these antifibrotic effects. Indeed, 12/15-LO -/- fibroblasts showed an enhanced activation of the mitogen-activated protein-kinase pathway and an increased col 1a2 mRNA expression in response to stimulation with transforming growth factor β (TGFβ), whereas 12/15-LO-derived eicosanoids blocked these TGFβ-induced effects. Conclusions: These data indicate that 12/15-LO and its metabolites have a prominent antifibrotic role during dermal fibrosis. This opens new opportunities for therapeutic approaches in the treatment of fibrotic diseases.
CRIS-Team Scopus Importer:2020-11-20

The 12/15-lipoxygenase pathway promotes osteoclast development and differentiation - Krönke, Gerhard; Uderhardt, Stefan; Katzenbeisser, Julia; Schett, Georg (Autoimmunity, 2009)
Although 12/15-lipoxygenase (12/15-LO) has been implicated as negative regulator of systemic bone mass in mice and humans, the underlying mechanisms remain elusive. Here, we show that 12/15-LO is a positive regulator of osteoclast (OC) development. Enzymatic inhibition as well as genetic ablation of 12/15-LO significantly impaired osteoclastogenesis. Conversely, addition of the 12/15-LO-derived eicosanoids 12- and 15-HETE augmented differentiation of precursors into fully matured OCs. Together these data point towards a crucial role of 12/15-LO in the regulation of OC development. Therefore, 12/15-LO and its human homologue 15-LO may display novel targets for the treatment of diseases such as osteoporosis and rheumatoid arthritis. © 2009 Informa UK Ltd All rights reserved.
CRIS-Team Scopus Importer:2020-11-20
Keywords: 12/15-LO; HETE; OC

THE 4-D+ NANOSCOPE: THE RESOLUTION FOR BIOLOGICAL SAMPLES - Kling, L.; Mill, L.; Grüneboom, Anika; Sarau, G.; Herrmann, Martin; Schett, Georg; Maier, Andreas; Christiansen, S. H. (ANNALS OF THE RHEUMATIC DISEASES, 2019)
CRIS-Team WoS Importer:2019-07-16

The ageing joint-standard age- and sex-related values of bone erosions and osteophytes in the hand joints of healthy individuals - Berlin, Andreas; Simon, David; Tascilar, K.; Figueiredo, C.; Bayat, Sara; Finzel, Stephanie; Klaus, E.; Rech, Jürgen; Hueber, Axel; Kleyer, Arnd; Schett, Georg (Osteoarthritis and Cartilage, 2019)
Objective: To analyze the age-related changes of the physiological hand joint architecture. Method: To address this concept, healthy individuals (each 10 women and 10 men in six different age decades spanning from 21 to 80 years) were recruited through a field campaign, investigated for the absence of rheumatic diseases and other comorbidities and received high-resolution quantitative computed tomography (HR-pQCT) examination of the hand joints. Number and extent of erosions and osteophytes were quantified across the ages and different sexes. Results: Bone erosions [median (Q1–Q3), 1 (0–2)] and osteophytes [2 (1–4)] were found in healthy women and men with no significant sex differences. Structural changes however accumulated with age: the overall incidence rate ratio (IRR) for the number of erosions and osteophytes per age were 1.04 (95% CI: erosions 1.03–1.06; osteophytes: 1.03–1.05). This means a 4% increase in the number of erosions and osteophytes per year. Using third decade as reference, healthy individuals in the age decades from 50 years had higher IRR for erosion numbers (sixth, seventh, eigth decade: 4.87 (2.20–11.75), 6.81 (3.08–16.46) and 6.92 (3.11–16.79)) compared to younger subjects (fourth, fifth decade: 1.80 (0.69–4.87), 1.53 (0.59–4.10)). The IRRs of osteophytes also indicate a gradual increase after the fifth decade, with IRRs of 2.32 (1.32–4.17), 4.17 (2.38–7.49) and 6.86 (3.97–12.20) for the sixth, seventh and eigth decades, respectively. Conclusions: Structural changes in the hand joints of healthy individuals are age dependent. While being rare under 50 years of age, erosions and osteophytes accumulate above the age of 50, suggesting that the threshold between “normal” and “pathological” is shifted with the increase of age.
CRIS-Team Scopus Importer:2019-06-07
Keywords: Bone erosions; Computed tomography; Hand joints; Healthy individuals; Osteophytes

THE ANTI-RO52 PREVALENCE IN THE SJOGREN'S SYNDROME PICTURE: A SINGLE CENTER CROSS SECTIONAL STUDY - Valor, Larissa; Schenker, Hannah; Hagen, Melanie; Knitza, Johannes; Rech, Jürgen; Schett, Georg (ANNALS OF THE RHEUMATIC DISEASES, 2019)
CRIS-Team WoS Importer:2019-07-16

THE AP1 TRANSCRIPTION FACTOR CJUN AMPLIFIES HEDGEHOG-INDUCED FIBROBLAST ACTIVATION AND TISSUE FIBROSIS - Bergmann, C.; Merlevede, B.; Beyer, Christian; Hallenberger, L.; Brandt, Adrian; Dees, Clara; Pötter, Sebastian; Bozec, Aline; Schett, Georg; Distler, Jörg (2018)
EVALuna2:34992

The AP-1 Transcription Factor c-Jun Promotes Arthritis by Regulating Cyclooxygenase-2 and Arginase-1 Expression in Macrophages - Hannemann, Nicole; Jordan, Jutta; Paul, Sushmita; Reid, Stephen; Baenkler, Hanns-Wolf; Sonnewald, Sophia; Bäuerle, Tobias; Vera, Julio; Schett, Georg; Bozec, Aline (Journal of Immunology, 2017)
Activation of proinflammatory macrophages is associated with the inflammatory state of rheumatoid arthritis. Their polarization and activation are controlled by transcription factors such as NF-?B and the AP-1 transcription factor member c-Fos. Surprisingly, little is known about the role of the AP-1 transcription factor c-Jun in macrophage activation. In this study, we show that mRNA and protein levels of c-Jun are increased in macrophages following pro- or anti-inflammatory stimulations. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment cluster analyses of microarray data using wild-type and c-Jun-deleted macrophages highlight the central function of c-Jun in macrophages, in particular for immune responses, IL production, and hypoxia pathways. Mice deficient for c-Jun in macrophages show an amelioration of inflammation and bone destruction in the serum-induced arthritis model. In vivo and in vitro gene profiling, together with chromatin immunoprecipitation analysis of macrophages, revealed direct activation of the proinflammatory factor cyclooxygenase-2 and indirect inhibition of the anti-inflammatory factor arginase-1 by c-Jun. Thus, c-Jun regulates the activation state of macrophages and promotes arthritis via differentially regulating cyclooxygenase-2 and arginase-1 levels.
EVALuna2:13412

The AP-1 transcription factor Fra1 inhibits follicular B cell differentiation into plasma cells - Groetsch, Bettina; Brachs, Sebastian; Lang, Christiane; Luther, Julia; Derer, Anja; Schlötzer-Schrehardt, Ursula; Bozec, Aline; Fillatreau, Simon; Berberich, Ingolf; Hobeika, Elias; Reth, Michael; Wagner, Erwin F.; et al. (Journal of Experimental Medicine, 2014)
The cornerstone of humoral immunity is the differentiation of B cells into antibody-secreting plasma cells. This process is tightly controlled by a regulatory gene network centered on the transcriptional repressor B lymphocyte-induced maturation protein 1 (Blimp1). Proliferation of activated B cells is required to foster Blimp1 expression but needs to be terminated to avoid overshooting immune reactions. Activator protein 1 (AP-1) transcription factors become quickly up-regulated upon B cell activation. We demonstrate that Fra1, a Fos member of AP-1, enhances activation-induced cell death upon induction in activated B cells. Moreover, mice with B cell-specific deletion of Fra1 show enhanced plasma cell differentiation and exacerbated antibody responses. In contrast, transgenic overexpression of Fra1 blocks plasma cell differentiation and immunoglobulin production, which cannot be rescued by Bcl2. On the molecular level, Fra1 represses Blimp1 expression and interferes with binding of the activating AP-1 member c-Fos to the Blimp1 promoter. Conversely, overexpression of c-Fos in Fra1 transgenic B cells releases Blimp1 repression. As Fra1 lacks transcriptional transactivation domains, we propose that Fra1 inhibits Blimp1 expression and negatively controls plasma cell differentiation through binding to the Blimp1 promoter. In summary, we demonstrate that Fra1 negatively controls plasma cell differentiation by repressing Blimp1 expression.
EVALuna2:13013

The B cell response to citrullinated antigens in the development of rheumatoid arthritis - Scherer, Hans Ulrich; Huizinga, Tom W. J.; Krönke, Gerhard; Schett, Georg; Toes, Rene E. M. (Nature Reviews Rheumatology, 2018)
The immune response to citrullinated antigens is found almost exclusively in patients with rheumatoid arthritis (RA). It is a dynamic response that expands before the onset of disease and generates antibodies (anti-citrullinated protein antibodies (ACPAs)) that are extensively glycosylated in the variable domain. This feature of ACPAs is remarkable and warrants detailed investigation, as it can offer insights into the earliest immunologic mechanisms that lead up to the development of RA. The acquisition of variable domain glycans, in fact, could enable ACPA-expressing B cells to breach tolerance. Although the underlying mechanisms are still elusive, data to support this concept are emerging, owing to the reliable identification and isolation of citrullinated antigen-directed B cells from patients with RA. This technological proficiency also allows for the generation of an increasing number of well-defined monoclonal ACPAs, and provides the opportunity to test and define the mechanisms by which the citrullinated antigen-directed B cell response contributes to the onset and persistence of inflammation. Together with a revised perception of the HLA-risk effect and novel insights into how T cells can govern antibody effector functions, these developments shape an increasingly clear picture of the B cell response to citrullinated antigens in the development of RA.
EVALuna2:34155

The bone marrow side of axial spondyloarthritis - Mauro, Daniele; Gandolfo, Saviana; Tirri, Enrico; Schett, Georg; Maksymowych, Walter P.; Ciccia, Francesco (Nature Reviews Rheumatology, 2023)
Spondyloarthritis (SpA) is characterized by the infiltration of innate and adaptive immune cells into entheses and bone marrow. Molecular, cellular and imaging evidence demonstrates the presence of bone marrow inflammation, a hallmark of SpA. In the spine and the peripheral joints, bone marrow is critically involved in the pathogenesis of SpA. Evidence suggests that bone marrow inflammation is associated with enthesitis and that there are roles for mechano-inflammation and intestinal inflammation in bone marrow involvement in SpA. Specific cell types (including mesenchymal stem cells, innate lymphoid cells and γδ T cells) and mediators (Toll-like receptors and cytokines such as TNF, IL-17A, IL-22, IL-23, GM-CSF and TGFβ) are involved in these processes. Using this evidence to demonstrate a bone marrow rather than an entheseal origin for SpA could change our understanding of the disease pathogenesis and the relevant therapeutic approach.
CRIS-Team Scopus Importer:2023-07-21

The complement system drives local inflammatory tissue priming by metabolic reprogramming of synovial fibroblasts - Friščić, Jasna; Böttcher, Martin; Reinwald, Christiane; Bruns, Heiko; Wirth, Benjamin; Popp, Sebastian; Walker, Kellie Irene; Ackermann, Jochen A.; Chen, Xi; Turner, Jason; Zhu, Honglin; Seyler, Lisa; et al. (Immunity, 2021)
Arthritis typically involves recurrence and progressive worsening at specific predilection sites, but the checkpoints between remission and persistence remain unknown. Here, we defined the molecular and cellular mechanisms of this inflammation-mediated tissue priming. Re-exposure to inflammatory stimuli caused aggravated arthritis in rodent models. Tissue priming developed locally and independently of adaptive immunity. Repeatedly stimulated primed synovial fibroblasts (SFs) exhibited enhanced metabolic activity inducing functional changes with intensified migration, invasiveness and osteoclastogenesis. Meanwhile, human SF from patients with established arthritis displayed a similar primed phenotype. Transcriptomic and epigenomic analyses as well as genetic and pharmacological targeting demonstrated that inflammatory tissue priming relies on intracellular complement C3- and C3a receptor-activation and downstream mammalian target of rapamycin- and hypoxia-inducible factor 1α-mediated metabolic SF invigoration that prevents activation-induced senescence, enhances NLRP3 inflammasome activity, and in consequence sensitizes tissue for inflammation. Our study suggests possibilities for therapeutic intervention abrogating tissue priming without immunosuppression.
CRIS-Team Scopus Importer:2021-04-19
Keywords: arthritis; cell metabolism; cellular senescence; complement system; inflammasome; inflammation; mechanistic target of rapamycin; synovial fibroblasts; tissue priming; trained immunity

The effects of Kv1.3 and IKCa1 channel inhibition on cytokine production and calcium influx of T lymphocytes in rheumatoid arthritis and ankylosing spondylitis - Toldi, Gergely; Munoz, Luis Enrique; Herrmann, Martin; Schett, Georg; Balog, Attila; Munoz Becerra, Luis (Immunologic Research, 2016)
Kv1.3 and IKCa1 lymphocyte potassium channels have been implicated as important targets of selective immunomodulation. We compared the alterations in cytokine production upon selective inhibition of Kv1.3 or IKCa1 channels (by MGTX and TRAM, respectively) in healthy donors (HD), RA and AS patients. We also determined calcium influx kinetics and its sensitivity to Kv1.3 and IKCa1 channel inhibition following PHA activation in CD4, Th1, Th2 and CD8 cells as well as monocytes. The application of TRAM resulted in a lower production of TNF-a and IL1-RA in all three study groups. Inhibition by TRAM had contrary effects on the production of IL-1b and IL-5: While their production was increased by PBMCs of RA patients, this effect was not observed in HD and AS PBMCs. While treatment with MGTX resulted in a similar decrease in calcium influx in the CD4 and Th2 subsets across all study groups, TRAM treatment had opposite effects on RA and HD samples: It decreased calcium influx in the Th2 and CD8 subsets in RA, while only Th1 cells were affected in HDs. The effects of IKCa1 channel inhibition are controversial in samples of RA and AS patients, since it shifts the inflammatory balance into the pro-inflammatory direction.
EVALuna2:13123
Keywords: AS; Calcium influx; Cytokine; IKCa1; Kv1.3; RA

The gut-bone axis: how bacterial metabolites bridge the distance - Zaiss, Mario; Jones, Rheinallt M.; Schett, Georg; Pacifici, Roberto (Journal of Clinical Investigation, 2019)
The gut microbiome is a key regulator of bone health that affects postnatal skeletal development and skeletal involution. Alterations in microbiota composition and host responses to the microbiota contribute to pathological bone loss, while changes in microbiota composition that prevent, or reverse, bone loss may be achieved by nutritional supplements with prebiotics and probiotics. One mechanism whereby microbes influence organs of the body is through the production of metabolites that diffuse from the gut into the systemic circulation. Recently, short-chain fatty acids (SCFAs), which are generated by fermentation of complex carbohydrates, have emerged as key regulatory metabolites produced by the gut microbiota. This Review will focus on the effects of SCFAs on the musculoskeletal system and discuss the mechanisms whereby SCFAs regulate bone cells.
CRIS-Team Scopus Importer:2019-08-06

The gut-joint axis in rheumatoid arthritis - Zaiss, Mario; Joyce Wu, Hsin-Jung; Mauro, Daniele; Schett, Georg; Ciccia, Francesco (Nature Reviews Rheumatology, 2021)
Intestinal dysbiosis is thought to be involved in the early stages of rheumatoid arthritis (RA). In this Review, the authors discuss the gut-joint axis in RA and the potentially pathogenic role of gut-derived immune cells in the joints.
CRIS-Team WoS Importer:2021-04-09

The Histone Demethylase Jumonji Domain-Containing Protein 3 (JMJD3) As Central Mediator of Fibroblast Activation - Bergmann, Christina; Brandt, Adrian; Dees, Clara; Zhang, Yun; Chen, Chih-Wei; Mallano, Tatjana; Wohlfahrt, Thomas; Liang, Ruifang; Kagwiria, Rosebeth; Bozec, Aline; Rieker, Ralf; Abraham, David; et al. (2017)
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The histone demethylase Jumonji domain-containing protein 3 (JMJD3) regulates fibroblast activation in systemic sclerosis - Bergmann, Christina; Brandt, Adrian; Merlevede, Benita; Hallenberger, Ludwig; Dees, Clara; Wohlfahrt, Thomas; Pötter, Sebastian; Zhang, Yun; Chen, Chih-Wei; Mallano, Tatjana; Liang, Ruifang; Kagwiria, Rosebeth; et al. (Annals of the Rheumatic Diseases, 2017)
Systemic sclerosis (SSc) fibroblasts remain activated even in the absence of exogenous stimuli. Epigenetic alterations are thought to play a role for this endogenous activation. Trimethylation of histone H3 on lysine 27 (H3K27me3) is regulated by Jumonji domain-containing protein 3 (JMJD3) and ubiquitously transcribed tetratricopeptide repeat on chromosome X (UTX) in a therapeutically targetable manner. The aim of this study was to explore H3K27me3 demethylases as potential targets for the treatment of fibrosis.JMJD3 was inactivated by small interfering RNA-mediated knockdown and by pharmacological inhibition with GSKJ4. The effects of targeted inactivation of JMJD3 were analysed in cultured fibroblasts and in the murine models of bleomycin-induced and topoisomerase-I (topoI)-induced fibrosis. H3K27me3 at the FRA2 promoter was analysed by ChIP.The expression of JMJD3, but not of UTX, was increased in fibroblasts in SSc skin and in experimental fibrosis in a transforming growth factor beta (TGF?)-dependent manner. Inactivation of JMJD3 reversed the activated fibroblast phenotype in SSc fibroblasts and prevented the activation of healthy dermal fibroblasts by TGF?. Pharmacological inhibition of JMJD3 ameliorated bleomycin-induced and topoI-induced fibrosis in well-tolerated doses. JMJD3 regulated fibroblast activation in a FRA2-dependent manner: Inactivation of JMJD3 reduced the expression of FRA2 by inducing accumulation of H3K27me3 at the FRA2 promoter. Moreover, the antifibrotic effects of JMJD3 inhibition were reduced on knockdown of FRA2.We present first evidence for a deregulation of JMJD3 in SSc. JMJD3 modulates fibroblast activation by regulating the levels of H3K27me3 at the promoter of FRA2. Targeted inhibition of JMJD3 limits the aberrant activation of SSc fibroblasts and exerts antifibrotic effects in two murine models.
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THE HOMEOPROTEIN ENGRAILED-1 REGULATES CANONICAL TGF-beta SIGNALING VIA FIBROBLAST DIFFERENTIATION AND TISSUE FIBROSIS - Mallano, Tatjana; Palumbo-Zerr, K.; Beyer, Christian; Dees, Clara; Huang, J.; Wohlfahrt, T.; Distler, O.; Schett, Georg; Distler, Jörg (2016)
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The human sialic acid-binding immunoglobulin-like lectin Siglec-9 and its murine homolog Siglec-E control osteoclast activity and bone resorption - Andes, F. T.; Adam, Susanne; Hahn, Madelaine; Aust, O.; Frey, Silke; Grüneboom, Anika; Nitschke, Lars; Schett, Georg; Steffen, Ulrike (Bone, 2020)
Regulation of osteoclast differentiation and function is a central element in bone homeostasis. While the role of soluble factors, such as cytokines, hormones and growth factors, in controlling osteoclast differentiation has been intensively characterized, the function of surface receptors is less well understood. Sialic acid-binding immunoglobulin-like lectin (Siglec)-9 and its murine homolog Siglec-E are sialic acid-recognizing inhibitory receptors from the CD33-related Siglec-family and mainly expressed on myeloid cells. We found Siglec-9 and Siglec-E to be expressed at all stages of human and murine osteoclastogenesis, respectively. Siglec-E knockout mice displayed lower bone mass despite unchanged osteoclast numbers and an increased bone formation rate. Ex vivo osteoclast assays using Siglec-E knockout cells or a blocking antibody against human Siglec-9 confirmed the suppressive effect of Siglec-9/Siglec-E on osteoclast function. Although osteoclast numbers were unchanged or even slightly decreased, the blockade/absence of Siglec-9/Siglec-E resulted in an augmented resorption activity of mature osteoclasts. This increased resorption activity was associated with enlarged actin rings. Together, our results suggest Siglec-9/Siglec-E to inhibit osteoclast activation independently from osteoclast differentiation and thereby propose a new mechanism for the control of local bone resorption.
CRIS-Team Scopus Importer:2020-10-16
Keywords: Bone; Osteoclasts; Resorption; Siglec-9; Siglec-E

THE IMPACT OF IL-17A THERAPY ON IGG SIALYLATION IN HUMANS - Pfeifle, René; Kittler, Julia; Wuhrer, M.; Schett, Georg; Krönke, Gerhard (ANNALS OF THE RHEUMATIC DISEASES, 2021)
CRIS-Team WoS Importer:2021-09-24

The impact of rheumatoid factor and ACPA on bone erosion in rheumatoid arthritis - Hecht, Carolin; Schett, Georg; Finzel, Stephanie (Annals of the Rheumatic Diseases, 2015)
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The Influence of Hand Osteoarthritis on Bone Microstructure and Biomechanical Properties of Radial Bone - Simon, David; Unbehend, Sara; Bayat, Sara; Rech, Jürgen; Hueber, Axel; Schett, Georg; Kleyer, Arnd (2018)
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The Interaction of Physical Function and Emotional Well-being in Rheumatoid Arthritis-What is the Impact on Disease Activity and Coping? - Englbrecht, Matthias; Araujo, Madeleine Kruckow Elizabeth; Rech, Jürgen; Schett, Georg; et al. (Seminars in Arthritis and Rheumatism, 2013)
Objective: To evaluate the impact of the interaction of physical function and emotional well-being on disease-related parameters and coping with rheumatoid arthritis. Methods: A cross-sectional survey among 177 RA patients included demographic and disease-related variables as well as the following patient-reported outcome measures: Health Assessment Questionnaire-Disability Index (HAQ-DI) (physical function), Mental Component Summary Scale of the SF-36 (MCSS) for emotional well-being, Rheumatoid Arthritis Disease Activity Index (RADAI), and Coping with Rheumatoid Arthritis Questionnaire (C-RAQ). Based on HAQ-DI and MCSS, six categories representing various levels of physical and emotional impairment were formed. Multivariate analysis of variance and a subsequent discriminant analysis were used to evaluate whether demographic and disease-related variables and coping strategies differed between these categories. Results: Patients with moderate to high impairment of physical function and emotional well-being reported significantly higher disease activity and a more frequent use of distancing and active problem solving coping strategies than patients with low-level impairment (. p<0.001-0.043). Furthermore, these patients reported experiencing significantly higher levels of helplessness (. p<0.001-0.032). Results from the discriminant analysis highlighted a combination of disease activity and helplessness to differentiate best between patients with either low or high impairment of physical function and emotional well-being (. p<0.001). Conclusion: Aside from perceived disease activity, helplessness, and distancing as well as active problem solving allowed for a good discrimination between the different levels of impairment of physical function and emotional well-being. Encouraging and educating patients on how to cognitively reframe their current situation might play a key role in reducing the level of helplessness resulting from impairments of physical function and emotional well-being. © 2013 Elsevier Inc.
CRIS-Team Scopus Importer:2021-02-03
Keywords: Coping; Disease activity; Emotional well-being; Health-related quality of life; Patient-reported outcomes; Physical function; Rheumatoid arthritis

The need for comparative data in spondyloarthritis - Choy, Ernest; Baraliakos, Xenofon; Behrens, Frank; D'Angelo, Salvatore; De Vlam, Kurt; Kirkham, Bruce W.; Ostergaard, Mikkel; Schett, Georg; Rissler, Michael; Chaouche-Teyara, Kamel; Perella, Chiara (Arthritis Research & Therapy, 2019)
Spondyloarthritis comprises a group of inflammatory diseases, characterised by inflammation within axial joints and/or peripheral arthritis, enthesitis and dactylitis. An increasing number of biologic treatments, including biosimilars, are available for the treatment of spondyloarthritis. Although there are a growing number of randomised controlled trials assessing treatments in spondyloarthritis, there is a paucity of data from head-to-head studies. Comparative data are required so that clinicians and payers have the level of evidence required to inform clinical decision-making and health economic assessments. In the absence of head-to-head studies, statistical methods such as network meta-analyses and matching-adjusted indirect comparisons (MAICs) are used for assessing comparative effectiveness. Network meta-analysis can be used to compare treatments for trials using a common comparator (e.g. placebo); however, for those without a common comparator or where considerable heterogeneity exists between the study populations, a MAIC that controls for differences in study design and baseline patient characteristics may be used. MAICs, unlike network meta-analyses, are of value for longer-term comparisons beyond the placebo-controlled phase of clinical trials, which is important for chronic diseases requiring long-term treatment, like spondyloarthritis. At present, there are a number of limitations that restrict the effectiveness of MAIC, such as the poor availability of individual patient-level data from trials, which results in patient-level data from one trial being compared with published whole-population data from another. Despite these limitations, drug reimbursement agencies are increasingly accepting MAIC as a means of comparative effectiveness and greater methodological guidance is needed. This report highlights a number of challenges that are specific to conducting comparative studies like MAIC in spondyloarthritis, including disease heterogeneity, the paucity of biomarkers and the duration of studies required for radiographic endpoints in this slow-progressing disease.
CRIS-Team Scopus Importer:2019-05-07
Keywords: Biological therapy; Clinical trials; Psoriatic arthritis; Radiography; Spondyloarthropathy

The nuclear receptor constitutive androstane receptor/NR1I3 enhances the profibrotic effects of transforming growth factor β and contributes to the development of experimental dermal fibrosis - Avouac, Jerome; Palumbo-Zerr, Katrin; Ruzehaji, Nadira; Tomcik, Michal; Zerr, Pawel; Dees, Clara; Distler, Alfiya; Beyer, Christian; Schneider, Holm; Distler, Oliver; Schett, Georg; Allanore, Yannick; et al. (Arthritis and Rheumatology, 2014)
Objective Nuclear receptors regulate cell growth, differentiation, and homeostasis. Selective nuclear receptors promote fibroblast activation, which leads to tissue fibrosis, the hallmark of systemic sclerosis (SSc). This study was undertaken to investigate the effects of constitutive androstane receptor (CAR)/NR1I3, an orphan nuclear receptor, on fibroblast activation and experimental dermal fibrosis. Methods CAR expression was quantified by quantitative polymerase chain reaction, Western blotting, immunohistochemistry, and immunofluorescence. CAR expression was modulated by small molecules, small interfering RNA, forced overexpression, and site-directed mutagenesis. The effects of CAR activation were analyzed in cultured fibroblasts, in bleomycin-induced dermal fibrosis, and in mice overexpressing a constitutively active transforming growth factor β (TGFβ) receptor type I (TβRI-CA). Results Up-regulation of CAR was detected in the skin and in dermal fibroblasts in SSc patients. Stimulation of healthy fibroblasts with TGFβ induced the expression of CAR messenger RNA and protein in a Smad-dependent manner. Pharmacologic activation or overexpression of CAR in healthy fibroblasts significantly increased the stimulatory effects of TGFβ on collagen synthesis and myofibroblast differentiation, and amplified the stimulatory effects of TGFβ on COL1A2 transcription activity. Treatment with CAR agonist increased the activation of canonical TGFβ signaling in murine models of SSc and exacerbated bleomycin-induced and TβRI-CA-induced fibrosis with increased dermal thickening, myofibroblast counts, and collagen accumulation. Conclusion Our findings indicate that CAR is up-regulated in SSc and regulates TGFβ signaling. Activation of CAR increases the profibrotic effects of TGFβ in cultured fibroblasts and in different preclinical models of SSc. Thus, inactivation of CAR might be a novel approach to target aberrant TGFβ signaling in SSc and in other fibrotic diseases.
CRIS-Team Scopus Importer:2020-07-01

The Nuclear Receptor Nr4a1 Acts as a Microglia Rheostat and Serves as a Therapeutic Target in Autoimmune-Driven Central Nervous System Inflammation - Rothe, Tobias; Ipseiz, Natacha; Faas, Maria; Lang, Stefanie; Perez-Branguli, Francesc; Metzger, Daniel; Ichinose, Hiroshi; Winner, Beate; Schett, Georg; Krönke, Gerhard (Journal of Immunology, 2017)
Microglia cells fulfill key homeostatic functions and essentially contribute to host defense within the CNS. Altered activation of microglia, in turn, has been implicated in neuroinflammatory and neurodegenerative diseases. In this study, we identify the nuclear receptor (NR) Nr4a1 as key rheostat controlling the activation threshold and polarization of microglia. In steady-state microglia, ubiquitous neuronal-derived stress signals such as ATP induced expression of this NR, which contributed to the maintenance of a resting and noninflammatory microglia phenotype. Global and microglia-specific deletion of Nr4a1 triggered the spontaneous and overwhelming activation of microglia and resulted in increased cytokine and NO production as well as in an accelerated and exacerbated form of experimental autoimmune encephalomyelitis. Ligand-induced activation of Nr4a1 accordingly ameliorated the course of this disease. Our current data thus identify Nr4a1 as regulator of microglia activation and potentially new target for the treatment of inflammatory CNS diseases such as multiple sclerosis.
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The nuclear receptor Nr4a1 mediates anti-inflammatory effects of apoptotic cells - Ipseiz, Natacha; Uderhardt, Stefan; Scholtysek, Carina; Steffen, Martin; Schabbauer, Gernot; Bozec, Aline; Schett, Georg; Krönke, Gerhard (Journal of Immunology, 2014)
Uptake of apoptotic cells (ACs) by macrophages ensures the nonimmunogenic clearance of dying cells, as well as the maintenance of self-tolerance to AC-derived autoantigens. Upon ingestion, ACs exert an inhibitory influence on the inflammatory signaling within the phagocyte. However, the molecular signals that mediate these immune-modulatory properties of ACs are incompletely understood. In this article, we show that the phagocytosis of apoptotic thymocytes was enhanced in tissue-resident macrophages where this process resulted in the inhibition of NF-?B signaling and repression of inflammatory cytokines, such as IL-12. In parallel, ACs induced a robust expression of a panel of immediate early genes, which included the Nr4a subfamily of nuclear receptors. Notably, deletion of Nr4a1 interfered with the anti-inflammatory effects of ACs in macrophages and restored both NF-?B signaling and IL-12 expression. Accordingly, Nr4a1 mediated the anti-inflammatory properties of ACs in vivo and was required for maintenance of self-tolerance in the murine model of pristane-induced lupus. Thus, our data point toward a key role for Nr4a1 as regulator of the immune response to ACs and of the maintenance of tolerance to "dying self."
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The Nuclear Receptor ROR-Alpha As a Key Checkpoint of Tissue Repair - Kagwiria, Rosebeth; Liang, Ruifang; Chen, Chih-Wei; Burris, Thomas; Schett, Georg; Distler, Jörg (2017)
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The Pathogenicity of Anti-β2GP1-IgG Autoantibodies Depends on Fc Glycosylation. - Fickentscher, Christoph; Magorivska, Iryna; Janko, Christina; Biermann, Mona; Bilyy, Rostyslav; Nalli, Cecilia; Tincani, Angela; Medeghini, Veronica; Meini, Antonella; Nimmerjahn, Falk; Schett, Georg; Munoz, Luis E.; et al. (Journal of immunology research, 2015)
To analyze the glycosylation of anti-β2GP1, we investigated purified IgG from healthy children, patients with APS, and asymptomatic adult carriers of antiphospholipid antibodies. We observed that in the sera of healthy children and of patients with APS, IgG3 and IgG2 were predominant, respectively. The potentially protective anti-β2GP1-IgM was lower in the sera of healthy children. Although anti-β2GP1-associated C1q did not differ between children and patients with antiphospholipid syndrome, the associated C3c was significantly higher in the sera of healthy children. This indicates a more efficient clearance of anti-β2GP1 immune complexes in the healthy children. This clearance is not accompanied by inflammation or coagulatory events. It is likely that the most important pathogenic factor of the anti-β2GP1-IgG is related to the different glycosylation observed in healthy and diseased individuals. We detected a significantly higher sialylation of anti-β2GP1-IgG isolated from the sera of healthy children and asymptomatic adults when compared with that of patients with clinically apparent antiphospholipid syndrome. Low sialylated IgG reportedly ameliorates inflammation and inflammation promotes hyposialylation. Thus, both reactions create a vicious circle that precipitates the pathology of the antiphospholipid syndrome including thrombus-formation. We conclude that the increased sialylation of anti-β2GP1-IgG of sera of healthy individuals limits their pathogenicity.

THE PHYSIOLOGICAL FINGER JOINT ARCHITECTURE - AGE-RELATED INCREASE OF EROSIONS AND OSTEOPHYTES IN THE JOINTS OF HEALTHY INDIVIDUALS - Simon, David; Berlin, Andreas; Tascilar, Koray; Bayat, Sara; Engelke, Klaus; Rech, Jürgen; Figuereido, Camille; Hueber, Axel; Schett, Georg; Kleyer, Arnd (ANNALS OF THE RHEUMATIC DISEASES, 2019)
CRIS-Team WoS Importer:2019-07-12

The potential of omics technologies for the treatment of immune‐mediated inflammatory diseases - Anchang, Charles Gwellem; Xu, Cong; Raimondo, Maria Gabriella; Atreya, Raja; Maier, Andreas; Schett, Georg; Zaburdaev, Vasily; Rauber, Simon; Ramming, Andreas (International Journal of Molecular Sciences, 2021)
Immune‐mediated inflammatory diseases (IMIDs), such as inflammatory bowel diseases and inflammatory arthritis (e.g., rheumatoid arthritis, psoriatic arthritis), are marked by increasing worldwide incidence rates. Apart from irreversible damage of the affected tissue, the systemic nature of these diseases heightens the incidence of cardiovascular insults and colitis‐associated neo-plasia. Only 40–60% of patients respond to currently used standard‐of‐care immunotherapies. In addition to this limited long‐term effectiveness, all current therapies have to be given on a lifelong basis as they are unable to specifically reprogram the inflammatory process and thus achieve a true cure of the disease. On the other hand, the development of various OMICs technologies is consid-ered as “the great hope” for improving the treatment of IMIDs. This review sheds light on the pro-gressive development and the numerous approaches from basic science that gradually lead to the transfer from “bench to bedside” and the implementation into general patient care procedures.
CRIS-Team Scopus Importer:2021-07-30
Keywords: Advanced imaging technologies; Immune‐mediated inflammatory diseases (IMIDs); Single‐cell RNA sequencing; Spatial sequencing

The Progression of Cell Death Affects the Rejection of Allogeneic Tumors in Immune-Competent Mice - Implications for Cancer Therapy - Chaurio Gonzalez, Ricardo Alfredo; Munoz, Luis E.; Maueröder, Christian; Janko, Christina; Harrer, Thomas; Fuernrohr, Barbara G.; Niederweis, Michael; Bilyy, Rostyslav; Schett, Georg; Herrmann, Martin; Berens, Christian (Frontiers in Immunology, 2014)
Large amounts of dead and dying cells are produced during cancer therapy and allograft rejection. Depending on the death pathway and stimuli involved, dying cells exhibit diverse features, resulting in defined physiological consequences for the host. It is not fully understood how dying and dead cells modulate the immune response of the host. To address this problem, different death stimuli were studied in B16F10 melanoma cells by regulated inducible transgene expression of the pro-apoptotic active forms of caspase-3 (revCasp-3), Bid (tBid), and the Mycobacterium tuberculosis-necrosis inducing toxin (CpnTCTD). The immune outcome elicited for each death stimulus was assessed by evaluating the allograft rejection of melanoma tumors implanted subcutaneously in BALB/c mice immunized with dying cells. Expression of all proteins efficiently killed cells in vitro (>90%) and displayed distinctive morphological and physiological features as assessed by multiparametric flow cytometry analysis. BALB/c mice immunized with allogeneic dying melanoma cells expressing revCasp-3 or CpnTCTD showed strong rejection of the allogeneic challenge. In contrast, mice immunized with cells dying either after expression of tBid or irradiation with UVB did not, suggesting an immunologically silent cell death. Surprisingly, immunogenic cell death induced by expression of revCasp-3 or CpnTCTD correlated with elevated intracellular reactive oxygen species (ROS) levels at the time point of immunization. Conversely, early mitochondrial dysfunction induced by tBid expression or UVB irradiation accounted for the absence of intracellular ROS accumulation at the time point of immunization. Although ROS inhibition in vitro was not sufficient to abrogate the immunogenicity in our allo-immunization model, we suggest that the point of ROS generation and its intracellular accumulation may be an important factor for its role as damage associated molecular pattern in the development of allogeneic responses.
EVALuna2:13056

Therapeutic benefit of apremilast on enthesitis and dactylitis in patients with psoriatic arthritis: a pooled analysis of the PALACE 1-3 studies - Gladman, Dafna D.; Kavanaugh, Arthur; Gómez-Reino, Juan J.; Wollenhaupt, Jürgen; Cutolo, Maurizio; Schett, Georg; Lespessailles, Eric; Guerette, Benoit; Delev, Nikolay; Teng, Lichen; Edwards, Christopher J.; Birbara, Charles A.; et al. (RMD Open, 2018)
Objective: The Psoriatic Arthritis Long-term Assessment of Clinical Efficacy (PALACE) clinical trial programme findings demonstrated that apremilast, an oral phosphodiesterase 4 inhibitor, is effective for treating psoriatic arthritis (PsA). Enthesitis and dactylitis are difficult-to-treat features of PsA leading to disability and affecting quality of life. PALACE 1, 2 and 3 data were pooled to assess the efficacy of apremilast on enthesitis and dactylitis outcomes in patients with these conditions at baseline. Methods: Patients with enthesitis (n=945) or dactylitis (n=633) at baseline were analysed after receiving double-blind treatment with placebo, apremilast 30 mg two times per day or apremilast 20 mg two times per day up to 52 weeks and continuing up to 5 years. Data were analysed through 156 weeks. Enthesitis was evaluated by Maastricht Ankylosing Spondylitis Enthesitis Score (MASES) and dactylitis via dactylitis count. Results: At week 24, patients receiving apremilast 30 mg two times per day demonstrated a significantly greater mean change in enthesitis (-1.3 vs -0.9; p<0.05) and dactylitis (-1.8 vs -1.3; p<0.01) vs placebo. Patients in the 30 mg dose group showed significantly greater mean (-23.6% vs -7.0%; p<0.05) and median (-50.0% vs -21.1%; p<0.05) per cent changes in MASES; mean and median per cent changes in dactylitis count were numerically, but not significantly, different for either apremilast dose in patients with dactylitis. In the patient population remaining on apremilast, observed mean and median improvements in both conditions were sustained through 156 weeks. Conclusion: Apremilast is effective for the treatment of active PsA, including improvements in enthesitis and dactylitis up to 3 years. Trial registration numbers: NCT01172938, NCT01212757 and NCT01212770.
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The revised Bristol Rheumatoid Arthritis Fatigue measures and the Rheumatoid Arthritis Impact of Disease scale: validation in six countries - Hewlett, Sarah; Kirwan, John; Bode, Christina; Cramp, Fiona; Carmona, Loreto; Dures, Emma; Englbrecht, Matthias; Fransen, Jaap; Greenwood, Rosemary; Hagel, Sofia; Van De Laar, Maart; Molto, Anna; et al. (Rheumatology, 2017)
To evaluate the Bristol Rheumatoid Arthritis Fatigue Multidimensional Questionnaire (BRAF-MDQ), the revised Bristol Rheumatoid Arthritis Numerical Rating Scales (BRAF-NRS V2) and the Rheumatoid Arthritis Impact of Disease (RAID) scale in six countries.We surveyed RA patients in France, Germany, The Netherlands, Spain, Sweden and the UK, including the HAQ, 36-item Short Form Health Survey (SF-36) and potential revisions of the BRAF-NRS coping and Spanish RAID coping items. Factor structure and internal consistency were examined by factor analysis and Cronbach's ? and construct validity by Spearman's correlation.A total of 1276 patients participated (76% female, 25% with a disease duration <5 years, median HAQ 1.0). The original BRAF-MDQ four-factor structure and RAID single-factor structure were confirmed in every country with ?66% of variation in items explained by each factor and all item factor loadings of 0.71-0.98. Internal consistency for the BRAF-MDQ total and subscales was a Cronbach's ? of 0.75-0.96 and for RAID, 0.93-0.96. Fatigue construct validity was shown for the BRAF-MDQ and BRAF-NRS severity and effect scales, correlated internally with SF-36 vitality and with RAID fatigue (r = 0.63-0.93). Broader construct validity for the BRAFs and RAID was shown by correlation with each other, HAQ and SF-36 domains (r = 0.46-0.82), with similar patterns in individual countries. The revised BRAF-NRS V2 Coping item had stronger validity than the original in all analyses. The revised Spanish RAID coping item performed as well as the original.Across six European countries, the BRAF-MDQ identifies the same four aspects of fatigue, and along with the RAID, shows strong factor structure and internal consistency and moderate-good construct validity. The revised BRAF-NRS V2 shows improved construct validity and replaces the original.
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The role of ACPAs in at-risk individuals: Early targeting of the bone and joints - Schett, Georg (Best Practice & Research in Clinical Rheumatology, 2017)
Autoimmunity precedes inflammation in patients with rheumatoid arthritis (RA), opening the possibility to search for early changes in the tissue preceding the onset of systemic inflammation. Autoantibodies are important and early drivers of bone damage in RA. This article summarizes current evidence for the role of RA-related autoantibodies in mediating bone loss. Rheumatoid factor (RF) and antibodies recognizing modified (citrullinated) proteins have been used as diagnostic markers for RA over many years. Their role as pathogenic players, however, has long been unrecognized. Recently, several pieces of evidence suggested that bone-resorbing osteoclasts are highly responsive to RA-related autoantibodies, providing a novel association between autoimmunity and bone. These developments have allowed the unraveling of the underlying mechanisms, which are responsible for the well-known clinical observation that anti-citrullinated protein antibodies and RF are associated with a more severe disease course. Furthermore, these mechanisms also explain the onset of inflammation in the joints of RA patients.
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The Role of Dietary Fiber in Rheumatoid Arthritis Patients: A Feasibility Study - Häger, Julian; Bang, Holger; Hagen, Melanie; Frech, Michael; Träger, Pascal; Sokolova, Maria V.; Steffen, Ulrike; Tascilar, Koray; Sarter, Kerstin; Schett, Georg; Rech, Jürgen; Zaiss, Mario (Nutrients, 2019)
Short-chain fatty acids are microbial metabolites that have been shown to be key regulators of the gut-joint axis in animal models. In humans, microbial dysbiosis was observed in rheumatoid arthritis (RA) patients as well as in those at-risk to develop RA, and is thought to be an environmental trigger for the development of clinical disease. At the same time, diet has a proven impact on maintaining intestinal microbial homeostasis. Given this association, we performed a feasibility study in RA patients using high-fiber dietary supplementation with the objective to restore microbial homeostasis and promote the secretion of beneficial immunomodulatory microbial metabolites. RA patients (n = 36) under routine care received daily high-fiber bars or cereals for 28 days. Clinical assessments and laboratory analysis of immune parameters in blood and stool samples from RA patients were done before and after the high-fiber dietary supplementation. We observed an increase in circulating regulatory T cell numbers, favorable Th1/Th17 ratios, as well as decreased markers of bone erosion in RA patients after 28 days of dietary intervention. Furthermore, patient-related outcomes of RA improved. Based on these results, we conclude that controlled clinical studies of high-fiber dietary interventions could be a viable approach to supplement or complement current pharmacological treatment strategies.
CRIS-Team Scopus Importer:2019-10-18
Keywords: gut–joint axis; high-fiber diet (HFD); microbiota; rheumatoid arthritis (RA); short chain fatty acids (SCFA)

The role of IL-23 in joint disease - Schett, Georg (Rheumatology, 2021)
CRIS-Team WoS Importer:2022-02-11

The role of joint-draining lymph node stromal cells in inflammatory arthritis - Schälter, Fabian; Azizov, Vugar; Frech, Michael; Dürholz, Kerstin; Sokolova, Maria; Hendel, Anna; Focke, Kristin; Sarter-Zaiss, Kerstin; Van Baarsen, L. G. M.; Krautwald, S.; Schett, Georg; Zaiss, Mario (EUROPEAN JOURNAL OF IMMUNOLOGY, 2022)
CRIS-Team WoS Importer:2023-01-27

THE ROLE OF THE IL-23/TH17 AXIS AS MODULATOR OF B CELL-MEDIATED (AUTO)IMMUNE RESPONSES - Pfeifle, René; Kittler, Julia; Rothe, Tobias; Schett, Georg; Krönke, Gerhard (2019)
EVALuna2:213239

The soluble CD83 protein prevents bone destruction by inhibiting the formation of osteoclasts and inducing resolution of inflammation in arthritis - Royzman, Dmytro; Andreev, Darja; Stich, Lena; Peckert, Katrin; Wild, Andreas; Zinser, Elisabeth; Mühl-Zürbes, Petra; Jones, Evan; Adam, Susanne; Frey, Silke; Fuchs, Maximilian; Kunz, Meik; et al. (Frontiers in Immunology, 2022)
Here we show that soluble CD83 induces the resolution of inflammation in an antigen-induced arthritis (AIA) model. Joint swelling and the arthritis-related expression levels of IL-1 beta, IL-6, RANKL, MMP9, and OC-Stamp were strongly reduced, while Foxp3 was induced. In addition, we observed a significant inhibition of TRAP(+) osteoclast formation, correlating with the reduced arthritic disease score. In contrast, cell-specific deletion of CD83 in human and murine precursor cells resulted in an enhanced formation of mature osteoclasts. RNA sequencing analyses, comparing sCD83- with mock treated cells, revealed a strong downregulation of osteoclastogenic factors, such as Oc-Stamp, Mmp9 and Nfatc1, Ctsk, and Trap. Concomitantly, transcripts typical for pro-resolving macrophages, e.g., Mrc1/2, Marco, Klf4, and Mertk, were upregulated. Interestingly, members of the metallothionein (MT) family, which have been associated with a reduced arthritic disease severity, were also highly induced by sCD83 in samples derived from RA patients. Finally, we elucidated the sCD83-induced signaling cascade downstream to its binding to the Toll-like receptor 4/(TLR4/MD2) receptor complex using CRISPR/Cas9-induced knockdowns of TLR4/MyD88/TRIF and MTs, revealing that sCD83 acts via the TRIF-signaling cascade. In conclusion, sCD83 represents a promising therapeutic approach to induce the resolution of inflammation and to prevent bone erosion in autoimmune arthritis.
CRIS-Team WoS Importer:2022-09-09

The structural basis of MRI bone erosions: An assessment by microCT - Albrecht, Andreas; Finzel, Stephanie; Englbrecht, Matthias; Rech, Jürgen; Hueber, Axel; Schlechtweg, Philipp; Uder, Michael; Schett, Georg (Annals of the Rheumatic Diseases, 2013)
Objective To determine whether erosions appearing in MRI in patients with rheumatoid arthritis (RA) represent true erosions. Methods 50 RA patients received 1.5 T MRI and microCT (μCT) of the dominant hand. Erosion counts were assessed in coronal T1 weighted MRI sections and in coronal as well as axial μCT sections of the metacarpophalangeal (MCP) joints II-IV. Extent of erosions was assessed by RA MRI Score (RAMRIS) erosion score (MRI) and by three-dimensional assessment of erosion volume (μCT). Results 111 of the 600 evaluated joint regions showed erosions in the MRI and 137 in the μCT. In only 28 regions false negative lesions (μCT positive, MRI negative) were found, all of which were very small lesions with a volume of less than 10 mm3. Only two results were false-positive (μCT negative, MRI positive). RAMRIS erosion scores were strongly correlated to erosion volumes in the μCT (Pearson's r=0.514, p<0.001). Mean RAMRIS erosion scores were below 1 with erosion volumes up to 1.5 mm3, below 2 with erosion volumes up to 20 mm3 and over 2 with volumes of more than 20 mm3. Discussion MRI erosions are generally based on true cortical breaks as shown by μCT. MRI is sensitive to detect bone erosions and only very small lesions escape detection. Moreover, RAMRIS erosion scores are closely linked to the absolute size of bone erosions in the μCT.
CRIS-Team Scopus Importer:2021-02-03

The transcriptional regulator DREAM modulates glial cell proliferation dependent on the regional inflammatory microenvironment - Süß, Patrick; Masanetz, Rebecca Katharina; Baum, Wolfgang; Schett, Georg; Schlachetzki, Johannes; Winkler, Jürgen (JOURNAL OF NEUROCHEMISTRY, 2022)
CRIS-Team WoS Importer:2022-09-09

The Transcription Factor FRA-1/AP-1 Controls Lipocalin-2 Expression and Inflammation in Sepsis Model - Cao, Shan; Schnelzer, Anne; Hannemann, Nicole; Schett, Georg; Soulat, Didier; Bozec, Aline (Frontiers in Immunology, 2021)
Sepsis is a life-threatening condition characterized by excessive inflammation in its early phase. This is followed by an aberrant resolution phase associated to a prolonged period of immune suppression that can ultimately lead to multiple organ dysfunctions. This immunosuppression can be mediated by the functional reprogramming of gene transcription in monocytes/macrophages in response to prolonged lipopolysaccharide (LPS) exposure. Surprisingly, there is no report on the role of AP-1 transcription factors in this reprogramming process. Herein, we used the endotoxin tolerance model on murine bone marrow-derived macrophages in which tolerant cells stimulated twice with LPS were compared to naïve cells stimulated once. Out of all AP-1 transcription factors tested, Fosl1 gene stood out because of its unique regulation in tolerized cells. Moreover, we could correlate FRA-1 expression to the expression of an essential anti-inflammatory molecule involved in sepsis response, Lipocalin 2 aka NGAL. Identical results were obtained in human PBMC following the endotoxin tolerance model. When using FRA-1 deficient macrophages, we could confirm that FRA-1 regulates NGAL expression during the tolerant state. Interestingly, ChIP-seq and ChIP-qPCR revealed the binding of FRA-1 on Lcn2 promoter after LPS stimulation in these cells. Finally, we used an in vivo septic model of consecutive injection of LPS, in which the second stimulation is performed before the resolution of inflammation, in wild type and FRA-1 deficient mice. NGAL secretion was elevated in lung, spleen and serum of wild type tolerant mice, whereas it was significantly lower in tolerant FRA-1 deficient mice. Moreover, an increased inflammatory state likely dependent of the low level of NGAL was observed in these FRA-1 deficient mice. This was characterized by an increase of neutrophil infiltration in lung and an increase of apoptotic follicular cells in spleen. This suggests that FRA-1 expression supports resolution of inflammation in this model. Collectively, our data indicate that FRA-1 is involved in myeloid cell tolerance responses by mediating the functional reprogramming of Lcn2 transcription in response to prolonged LPS exposure. In conclusion, FRA-1 may have a protective role in the tolerance response of sepsis through the regulation of NGAL, leading to resolution of inflammation.
CRIS-Team Scopus Importer:2021-11-19
Keywords: AP-1/Fra-1; endotoxin tolerance; lipocalin-2; macrophage; sepsis; transcription factor

The transcription factor GLI2 as a downstream mediator of transforming growth factor-?-induced fibroblast activation in SSc - Liang, Ruifang; Sumova, Barbora; Cordazzo, Cinzia; Mallano, Tatjana; Zhang, Yun; Wohlfahrt, Thomas; Dees, Clara; Krasowska, Dorota; Michalska-Jakubus, Malgorzata; Distler, Oliver; Schett, Georg; Senolt, Ladislav; et al. (Annals of the Rheumatic Diseases, 2016)
Hedgehog signalling plays a critical role during the pathogenesis of fibrosis in systemic sclerosis (SSc). Besides canonical hedgehog signalling with smoothened (SMO)-dependent activation of GLI transcription factors, GLI can be activated independently of classical hedgehog ligands and receptors (so-called non-canonical pathways). Here, we aimed to evaluate the role of non-canonical hedgehog signalling in SSc and to test the efficacy of direct GLI inhibitors that target simultaneously canonical and non-canonical hedgehog pathways.The GLI inhibitor GANT-61 was used to inhibit canonical as well as non-canonical hedgehog signalling, while the SMO inhibitor vismodegib was used to selectively target canonical hedgehog signalling. Furthermore, GLI2 was selectively depleted in fibroblasts using the Cre-LoxP system. The effects of pharmacological or genetic of GLI2 on transforming growth factor-? (TGF-?) signalling were analysed in cultured fibroblasts, in bleomycin-induced pulmonary fibrosis and in mice with overexpression of a constitutively active TGF-? receptor I.TGF-? upregulated GLI2 in a Smad3-dependent manner and induced nuclear accumulation and DNA binding of GLI2. Fibroblast-specific knockout of GLI2 protected mice from TBR(act)-induced fibrosis. Combined targeting of canonical and non-canonical hedgehog signalling with direct GLI inhibitors exerted more potent antifibrotic effects than selective targeting of canonical hedgehog signalling with SMO inhibitors in experimental dermal and pulmonary fibrosis.Our data demonstrate that hedgehog pathways and TGF-? signalling both converge to GLI2 and that GLI2 integrates those signalling to promote tissue fibrosis. These findings may have translational implications as non-selective inhibitors of GLI2 are in clinical use and selective molecules are currently in development.
EVALuna2:13344

The tyrosine phosphatase SHP2 controls TGFβ-induced STAT3 signaling to regulate fibroblast activation and fibrosis - Zehender, Ariella; Huang, Jingang; Gyoerfi, Andrea-Hermina; Matei, Alexandru-Emil; Thuong Trinh-Minh,; Xu, Xiaohan; Li, Yi-Nan; Chen, Chih-Wei; Lin, Jianping; Dees, Clara; Beyer, Christian; Gelse, Kolja; et al. (Nature Communications, 2018)
Uncontrolled activation of TGFβ signaling is a common denominator of fibrotic tissue remodeling. Here we characterize the tyrosine phosphatase SHP2 as a molecular checkpoint for TGFβ-induced JAK2/STAT3 signaling and as a potential target for the treatment of fibrosis. TGFβ stimulates the phosphatase activity of SHP2, although this effect is in part counterbalanced by inhibitory effects on SHP2 expression. Stimulation with TGFβ promotes recruitment of SHP2 to JAK2 in fibroblasts with subsequent dephosphorylation of JAK2 at Y570 and activation of STAT3. The effects of SHP2 on STAT3 activation translate into major regulatory effects of SHP2 on fibroblast activation and tissue fibrosis. Genetic or pharmacologic inactivation of SHP2 promotes accumulation of JAK2 phosphorylated at Y570, reduces JAK2/STAT3 signaling, inhibits TGFβ-induced fibroblast activation and ameliorates dermal and pulmonary fibrosis. Given the availability of potent SHP2 inhibitors, SHP2 might thus be a potential target for the treatment of fibrosis.
EVALuna2:34477

The ups and downs of bone in health and rheumatic disease - Harre, Ulrike; Schett, Georg (Nature Reviews Rheumatology, 2013)
Created from Fastlane, Scopus look-up

The Urge for Mobile Apps in Rheumatology - a German Patient Perspective - Knitza, Johannes; Raab, Christina; Lambrecht, Antonia; Simon, David; Hagen, Melanie; Bayat, Sara; Schett, Georg; Kleyer, Arnd; Hueber, Axel (ARTHRITIS & RHEUMATOLOGY, 2019)
CRIS-Team WoS Importer:2020-02-07

The value of (18)F-FDG-PET/CT in identifying the cause of fever of unknown origin (FUO) and inflammation of unknown origin (IUO): data from a prospective study - Schoenau, Verena; Vogel, Kristin; Englbrecht, Matthias; Wacker, Jochen; Schmidt, Daniela; Manger, Bernhard; Kuwert, Torsten; Schett, Georg (Annals of the Rheumatic Diseases, 2017)
Fever of unknown origin (FUO) and inflammation of unknown origin (IUO) are diagnostically challenging conditions. Diagnosis of underlying disease may be improved by (18)F-fluorodesoxyglucose positron emission tomography ((18)F-FDG-PET).Prospective study to test diagnostic utility of (18)F-FDG-PET/CT in a large cohort of patients with FUO or IUO and to define parameters that increase the likelihood of diagnostic (18)F-FDG-PET/CT. Patients with FUO or IUO received (18)F-FDG-PET/CT scanning in addition to standard diagnostic work-up. (18)F-FDG-PET/CT results were classified as helpful or non-helpful in establishing final diagnosis. Binary logistic regression was used to identify clinical parameters associated with a diagnostic (18)F-FDG-PET/CT.240 patients were enrolled, 72 with FUO, 142 with IUO and 26 had FUO or IUO previously (exFUO/IUO). Diagnosis was established in 190 patients (79.2%). The leading diagnoses were adult-onset Still's disease (15.3%) in the FUO group, large vessel vasculitis (21.1%) and polymyalgia rheumatica (18.3%) in the IUO group and IgG4-related disease (15.4%) in the exFUO/IUO group. In 136 patients (56.7% of all patients and 71.6% of patients with a diagnosis), (18)F-FDG-PET/CT was positive and helpful in finding the diagnosis. Predictive markers for a diagnostic (18)F-FDG-PET/CT were age over 50 years (p=0.019), C-reactive protein (CRP) level over 30 mg/L (p=0.002) and absence of fever (p=0.001).(18)F-FDG-PET/CT scanning is helpful in ascertaining the correct diagnosis in more than 50% of the cases presenting with FUO and IUO. Absence of intermittent fever, higher age and elevated CRP level increase the likelihood for a diagnostic (18)F-FDG-PET/CT.
EVALuna2:13447

The Wnt antagonists DKK1 and SFRP1 are downregulated by promoter hypermethylation in systemic sclerosis - Dees, Clara; Schlottmann, Inga; Funke, Robin; Distler, Alfiya; Palumbo-Zerr, Katrin; Zerr, Pawel; Lin, Neng-Yu; Beyer, Christian; Distler, Oliver; Schett, Georg; Distler, Jörg (Annals of the Rheumatic Diseases, 2014)
Activated Wnt signalling with decreased expression of endogenous inhibitors has recently been characterised as a central pathomechanism in systemic sclerosis (SSc). Aberrant epigenetic modifications also contribute to the persistent activation of SSc fibroblasts. We investigated whether increased Wnt signalling and epigenetic changes in SSc are causally linked via promoter hypermethylation-induced silencing of Wnt antagonists.The methylation status of endogenous Wnt antagonists in leucocytes and fibroblasts was evaluated by methylation-specific PCR. 5-aza-2'-deoxycytidine was used to inhibit DNA methyltransferases (Dnmts) in cultured fibroblasts and in the mouse model of bleomycin-induced skin fibrosis. Activation of Wnt signalling was assessed by analysing Axin2 mRNA levels and by staining for ?-catenin.The promoters of DKK1 and SFRP1 were hypermethylated in fibroblasts and peripheral blood mononuclear cells of patients with SSc. Promoter hypermethylation resulted in impaired transcription and decreased expression of DKK1 and SFRP1 in SSc. Treatment of SSc fibroblasts or bleomycin-challenged mice with 5-aza prevented promoter methylation-induced silencing and increased the expression of both genes to normal levels. Reactivation of DKK1 and SFRP1 transcription by 5-aza inhibited canonical Wnt signalling in vitro and in vivo and effectively ameliorated experimental fibrosis.We demonstrate that hypermethylation of the promoters of DKK1 and SFRP1 contributes to aberrant Wnt signalling in SSc and that Dnmt inhibition effectively reduces Wnt signalling. These data provide a novel link between epigenetic alterations and increased Wnt signalling in SSc and also have translational implications because Dnmt inhibitors are already approved for clinical use.
EVALuna2:12884

Tixagevimab/cilgavimab for the prevention of COVID-19 in vaccine-refractory patients with autoimmune diseases: a prospective cohort study. - Minopoulou, Ioanna; Tascilar, Koray; Corte, Giulia; Mutlu, Melek Yalcin; Schmidt, Katja; Bohr, Daniela; Hartmann, Fabian; Manger, Karin; Manger, Bernhard; Korn, Klaus; Kleyer, Arnd; Simon, David; et al. (Rheumatology, 2024)
OBJECTIVES: To investigate the effects of passive immunization with the anti-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) monoclonal antibodies tixagevimab/cilgavimab on humoral responses and on coronavirus disease 2019 (COVID-19) outcomes in vaccine-refractory patients with immune-mediated inflammatory diseases (IMIDs) at high risk of severe COVID-19. METHODS: A prospective cohort study was performed on a cohort of high-risk vaccine-refractory IMID patients treated with a single dose of tixagevimab/cilgavimab (150 mg/150 mg). COVID-19 outcomes as well as serum and salivary anti-SARS-CoV-2 IgG were assessed at baseline and for at least 6 months. Results were compared with an untreated high-risk vaccine-refractory IMID population. Standardized incidence ratios (SIRs) of COVID-19 compared with the general population were calculated for both groups. RESULTS: A total of 38 high-risk IMID patients received tixagevimab/cilgavimab and were compared with 114 untreated high-risk IMID controls. Serum anti-spike IgG increased to 6.6 OD (s.d. 0.8) at day 1 and remained positive up to month 6 [6.3 OD (s.d. 1.4)]. Salivary anti-spike IgG peaked at month 2 [1.6 OD (s.d. 1.1)] and decreased from month 3 [0.8 OD (s.d. 0.3)]. No severe or extended infection was observed in the tixagevimab/cilgavimab group. Compared with the general population, the SIR of COVID-19 in treated patients was 0.76 (95% CI 0.24, 1.58) despite the increased risk profile. The SIR of the control group was 1.51 (95% CI 1.07, 2.02), corresponding to a significantly increased incidence. CONCLUSIONS: Passive immunization with tixagevimab/cilgavimab is safe and effective in inducing anti-SARS-CoV-2 immunity and potentially in preventing COVID-19 in high-risk vaccine-refractory IMID patients. These data provide a proof of concept for the use of monoclonal antibodies as a preventative strategy against SARS-CoV-2 in vulnerable populations.
EVALuna2:540332

TOCILIZUMAB ACHIEVES BETTER REPAIR OF FOCAL BONE EROSIONS THAN TUMOUR NECROSIS FACTOR INHIBITION IN RA PATIENTS - DATA FROM THE PROSPECTIVE REBONE STUDY ON EROSION REPAIR - Schett, Georg; Finze, S.; Kraus, Sebastian; Regensburger, Adrian; Kocijan, R.; Rech, Jürgen (2018)
EVALuna2:34991

To NET or not to NET: current opinions and state of the science regarding the formation of neutrophil extracellular traps - Boeltz, Sebastian; Amini, Poorya; Anders, Hans-Joachim; Andrade, Felipe; Bilyy, Rostyslav; Chatfield, Simon; Cichon, Iwona; Clancy, Danielle M.; Desai, Jyaysi; Dumych, Tetiana; Dwivedi, Nishant; Gordon, Rachael Ann; et al. (Cell Death and Differentiation, 2019)
Since the discovery and definition of neutrophil extracellular traps (NETs) 14 years ago, numerous characteristics and physiological functions of NETs have been uncovered. Nowadays, the field continues to expand and novel mechanisms that orchestrate formation of NETs, their previously unknown properties, and novel implications in disease continue to emerge. The abundance of available data has also led to some confusion in the NET research community due to contradictory results and divergent scientific concepts, such as pro- and anti-inflammatory roles in pathologic conditions, demarcation from other forms of cell death, or the origin of the DNA that forms the NET scaffold. Here, we present prevailing concepts and state of the science in NET-related research and elaborate on open questions and areas of dispute.
CRIS-Team WoS Importer:2019-02-22

TOPHUS RESOLUTION WITH PEGLOTICASE A PROSPECTIVE DUAL ENERGY COMPUTED TOMOGRAPHY STUDY - Schett, Georg; Araujo, E.; Bayat, Sara; Petsch, Christina; Englbrecht, Matthias; Faustini, F.; Kleyer, Arnd; Hueber, A.; Cavallaro, A.; Lell, Michael; Dalbeth, N.; Manger, Bernhard; et al. (2015)
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Tophus resolution with pegloticase: a prospective dual-energy CT study - Araujo, Elizabeth G.; Bayat, Sara; Petsch, Christina; Englbrecht, Matthias; Faustini, Francesca; Kleyer, Arnd; Hueber, Axel; Lell, Michael; Dalbeth, Nicola; Manger, Bernhard; Schett, Georg; Rech, Juergen; et al. (RMD Open, 2015)
To investigate the effect of intensive lowering of serum uric acid (SUA) levels by pegloticase on the resolution of tophi in patients with refractory gout.Descriptive study in patients with refractory gout receiving pegloticase treatment. SUA levels were measured before and after each infusion. Dual-energy CT (DECT) scans were taken from all patients before the first infusion and after the last infusion. Computerised tophus volumes were calculated for the baseline and follow-up assessments and compared with each other.10 patients with refractory gout and baseline mean SUA level of 8.1 mg/dL were enrolled. Patients were treated for a mean of 13.3 weeks. Pegloticase effectively reduced tophi in all patients showing a decrease in volume by 71.4%. Responders, showing reduction of SUA level below 6 mg/dL during at least 80% of the treatment time, were virtually cleared from tophi (-94.8%). Dependent on their anatomical localisation, resolution of tophi showed different dynamics, with articular tophi showing fast, and tendon tophi slow, resolution.Tophi are highly sensitive to pegloticase treatment, particularly when located at articular sites. Debulking of disease and a tophus-free state can be reached within a few months of pegloticase treatment. DECT allows for comprehensively assessing tophus burden and monitoring treatment responses.
EVALuna2:13180

Toward Earlier Diagnosis Using Combined eHealth Tools in Rheumatology: The Joint Pain Assessment Scoring Tool (JPAST) Project - Knitza, Johannes; Knevel, Rachel; Raza, Karim; Bruce, Tor; Eimer, Ekaterina; Gehring, Isabel; Mathsson-Alm, Linda; Poorafshar, Maryam; Hueber, Axel; Schett, Georg; Johannesson, Martina; Catrina, Anca; et al. (JMIR mHealth and uHealth, 2020)
Outcomes of patients with inflammatory rheumatic diseases have significantly improved over the last three decades, mainly due to therapeutic innovations, more timely treatment, and a recognition of the need to monitor response to treatment and to titrate treatments accordingly. Diagnostic delay remains a major challenge for all stakeholders. The combination of electronic health (eHealth) and serologic and genetic markers holds great promise to improve the current management of patients with inflammatory rheumatic diseases by speeding up access to appropriate care. The Joint Pain Assessment Scoring Tool (JPAST) project, funded by the European Union (EU) European Institute of Innovation and Technology (EIT) Health program, is a unique European project aiming to enable and accelerate personalized precision medicine for early treatment in rheumatology, ultimately also enabling prevention. The aim of the project is to facilitate these goals while at the same time, reducing cost for society and patients.
CRIS-Team Scopus Importer:2020-05-29
Keywords: apps; eHealth; mHealth; rheumatology; symptom-checkers

Towards a Computable Data Corpus of Temporal Correlations between Drug Administration and Lab Value Changes - Newe, Axel; Wimmer, Stefan; Neubert, Antje; Becker, Linda; Prokosch, Hans-Ulrich; Beckmann, Matthias; Fietkau, Rainer; Forster, Christian; Neurath, Markus; Schett, Georg; Ganslandt, Thomas (PLoS ONE, 2015)
Background The analysis of electronic health records for an automated detection of adverse drug reactions is an approach to solve the problems that arise from traditional methods like spontaneous reporting or manual chart review. Algorithms addressing this task should be modeled on the criteria for a standardized case causality assessment defined by the World Health Organization. One of these criteria is the temporal relationship between drug intake and the occurrence of a reaction or a laboratory test abnormality. Appropriate data that would allow for developing or validating related algorithms is not publicly available, though. Methods In order to provide such data, retrospective routine data of drug administrations and temporally corresponding laboratory observations from a university clinic were extracted, transformed and evaluated by experts in terms of a reasonable time relationship between drug administration and lab value alteration. Result The result is a data corpus of 400 episodes of normalized laboratory parameter values in temporal context with drug administrations. Each episode has been manually classified whether it contains data that might indicate a temporal correlation between the drug administration and the change of the lab value course, whether such a change is not observable or whether a decision between those two options is not possible due to the data. In addition, each episode has been assigned a concordance value which indicates how difficult it is to assess. This is the first open data corpus of a computable ground truth of temporal correlations between drug administration and lab value alterations. Discussion The main purpose of this data corpus is the provision of data for further research and the provision of a ground truth which allows for comparing the outcome of other assessments of this data with the outcome of assessments made by human experts. It can serve as a contribution towards systematic, computerized ADR detection in retrospective data. With this lab value curve data as a basis, algorithms for detecting temporal relationships can be developed, and with the classification made by human experts, these algorithms can immediately be validated. Due to the normalization of the lab value data, it allows for a generic approach rather than for specific or solitary drug/lab value combination

TOWARDS DEVELOPMENT OF AN ULTRASOUND ENTHESITIS SCORE IN PSORIATIC ARTHRITIS: 24-WEEK RESULTS FROM THE PHASE III RANDOMISED ULTIMATE STUDY - D'Agostino, M. A.; Conaghan, P. G.; Gaillez, C.; Boers, M.; Naredo, E.; Carron, P.; Hanova, P.; Cazenave, T.; Bakewell, C.; Duggan, A. M.; Goyanka, P.; Schett, Georg (ANNALS OF THE RHEUMATIC DISEASES, 2021)
CRIS-Team WoS Importer:2021-10-01

Towards In-Vivo X-Ray Nanoscopy: Acquisition Parameters vs. Image Quality - Mill, Leonid; Kling, Lasse; Grüneboom, Anika; Schett, Georg; Christiansen, Silke; Maier, Andreas (Informatik aktuell, 2019)
X-ray microscopy is a powerful imaging technique that permits the investigation of specimen on nanoscale with resolution of up to 700 nm in 3-D. In the context of bio-medical research this is a promising technology that allows to study the microstructure of biological tissues. However, X-ray microscopy (XRM) systems are not designed for in-vivo applications and are mainly used in the field of material sciences in which dose is irrelevant. High resolution scans may take up to 10 hours. Our long-term goal is to utilize this modality to study the effects of disease dynamics and treatment in-vivo on mice bones. Therefore, a first step towards this ambitious goal is to evaluate the current state-of-the-art to determine the required system parameters. In this work, we investigate the impact of different XRM settings on the image quality. By changing various acquisition parameters such as exposure time, voltage, current and number of projections, we simulate the outcome of XRM scans, while reducing the X-ray energy. We base our simulations on a high resolution ex-vivo scan of a mouse tibia. The resulting reconstructions are evaluated qualitatively as well as quantitatively by calculating the contrast-to-noise ratio (CNR). We demonstrate that we can reach comparable image quality while reducing the total X-ray energy which forms a foundation towards the upcoming experiments.
CRIS-Team Scopus Importer:2019-05-14

Towards in-vivo X-ray nanoscopy: The effect of motion on image quality - Mill, Leonid; Bier, Bastian; Syben-Leisner, Christopher; Kling, Lasse; Grüneboom, Anika; Christiansen, Silke; Schett, Georg; Maier, Andreas (Informatik aktuell, 2018)
Novel X-Ray Microscopy (XRM) systems allow to study the internal structure of a specimen on nanoscale. A possible use of this non-destructive technology is motivated in the medical research area. In-Vivo investigation of medication over a period of time and its effects on perfusion and bony structure might lead to a better understanding of drug mechanisms and diseases like Osteoporosis and could lead to new approaches to their treatment. The first step towards in-vivo XRM imaging is to investigate the suitability of recent XRM systems for this task and subsequently to determine the system parameters. In this context, the impact of mice motion on the image quality is studied in this work. This paper aims to simulate the effects of breathing motion and muscle relaxation of the mice on the reconstructed images, which already effects the projection images. We therefore assume a mouse’s respiration motion pattern, which happens four time during a single projection acquisitions, and the muscle relaxation movement due to anesthesia and simulate its impacts on image quality. Additionally, we show that a frame rate of at least 16 fps is needed to capture in-vivo movements in order to apply state-of-the-art motion correction methods.<br

Towards preventive treatment of rheumatoid arthritis - Rech, Jürgen; Schett, Georg (Lancet, 2022)
CRIS-Team Scopus Importer:2022-08-05

Transcription factor Fra-1 targets arginase-1 to enhance macrophage-mediated inflammation in arthritis - Hannemann, Nicole; Cao, Shan; Eriksson, Daniel; Schnelzer, Anne; Jordan, Jutta; Eberhardt, Martin; Schleicher, Ulrike; Rech, Jürgen; Uebe, Steffen; Ekici, Arif Bülent; Canete, Juan D.; Chen, Xiaoxiang; et al. (Journal of Clinical Investigation, 2019)
The polarization of macrophages is regulated by transcription factors, such as NF-κB and activator protein 1 (AP-1). In this manuscript, we delineated the role of the transcription factor Fos-related antigen 1 (Fra-1) during macrophage activation and development of arthritis. Network level interaction analysis of microarray data derived from Fra-1- or Fra-2-deficient macrophages revealed a central role of Fra-1, but not of Fra-2, in orchestrating the expression of genes related to wound response, Toll-like receptor activation, and interleukin signaling. ChIP sequencing and standard ChIP analyses of macrophages identified arginase 1 (Arg1) as a target of Fra-1. Luciferase reporter assays revealed that Fra-1 downregulated Arg1 expression by direct binding to the promoter region. Using macrophage-specific Fra-1- or Fra-2-deficient mice, we observed enhanced expression and activity of Arg1 and a reduction of arthritis in the absence of Fra-1, but not of Fra-2. This phenotype was reversed by treatment with the arginase inhibitor Nω-hydroxy-nor-arginine, while -arginine supplementation increased arginase activity and alleviated arthritis, supporting the notion that reduced arthritis in macrophage-specific Fra-1-deficient mice resulted from enhanced Arg1 expression and activity. Moreover, patients with active rheumatoid arthritis (RA) showed increased Fra-1 expression in the peripheral blood and elevated Fra-1 protein in synovial macrophages compared with RA patients in remission. In addition, the Fra-1/ARG1 ratio in synovial macrophages was related to RA disease activity. In conclusion, these data suggest that Fra-1 orchestrates the inflammatory state of macrophages by inhibition of Arg1 expression and thereby impedes the resolution of inflammation.
CRIS-Team Scopus Importer:2019-07-16

Transcriptomic characterization of classical monocytes highlights the involvement of immuno-inflammation in bone erosion in Rheumatoid Arthritis - Sales, Lucas Peixoto; Hounkpe, Bidossessi Wilfried; Perez, Mariana Ortega; Caparbo, Valéria Falco; Domiciano, Diogo Souza; Borba, Eduardo Ferreira; Schett, Georg; Figueiredo, Camille Pinto; Pereira, Rosa Maria Rodrigues (Frontiers in Immunology, 2023)
Introduction: Evidence-based data suggest that under inflammatory conditions, classical monocytes are the main source of osteoclasts and might be involved in bone erosion pathophysiology. Here, we analyze the transcriptomic profile of classical monocytes in erosive and non-erosive rheumatoid arthritis patients in order to better understand their contribution to bone erosion. Methods: Thirty-nine premenopausal RA patients were consecutively enrolled and divided into two groups based on the presence of bone erosions on hand joints. Classical monocytes were isolated from peripheral blood through negative selection, and RNA-seq was performed using a poly-A enrichment kit and Illumina® platform. Classical monocytes transcriptome from healthy age-matched women were also included to identify differentially expressed genes (DEGs). Therefore, gene sets analysis was performed to identify the enriched biological pathways. Results: RNA-seq analysis resulted in the identification of 1,140 DEGs of which 89 were up-regulated and 1,051 down-regulated in RA patients with bone erosion compared to those without bone erosions. Among up-regulated genes, there was a highlighted expression of IL18RAP and KLF14 related to the production of pro-inflammatory cytokines, innate and adaptive immune response. Genes related to collagen metabolism (LARP6) and bone formation process (PAPPA) were down-regulated in RA patients with erosions. Enriched pathways in patients with erosions were associated with greater activation of immune activation, and inflammation. Interestingly, pathways associated with osteoblast differentiation and regulation of Wnt signaling were less activated in RA patients with erosions. Conclusion: These findings suggest that alterations in expression of monocyte genes related to the inflammatory process and impairment of bone formation might have an important role in the pathophysiology of bone erosions in RA patients.
CRIS-Team Scopus Importer:2023-11-03
Keywords: bone erosions; bone formation; classical monocytes; inflammation; rheumatoid arthritis

Transferrin receptor 2 controls bone mass and pathological bone formation via BMP and Wnt signalling - Rauner, Martina; Baschant, Ulrike; Roetto, Antonella; Pellegrino, Rosa Maria; Rother, Sandra; Salbach-Hirsch, Juliane; Weidner, Heike; Hintze, Vera; Campbell, Graeme; Petzold, Andreas; Lemaitre, Regis; Henry, Ian; et al. (Nature Metabolism, 2019)
Transferrin receptor 2 (Tfr2) is mainly expressed in the liver and controls iron homeostasis. Here, we identify Tfr2 as a regulator of bone homeostasis that inhibits bone formation. Mice lacking Tfr2 display increased bone mass and mineralization independent of iron homeostasis and hepatic Tfr2. Bone marrow transplantation experiments and studies of cell-specific Tfr2-knockout mice demonstrate that Tfr2 impairs BMP-p38MAPK signalling and decreases expression of the Wnt inhibitor sclerostin, specifically in osteoblasts. Reactivation of MAPK or overexpression of sclerostin rescues skeletal abnormalities in Tfr2-knockout mice. We further show that the extracellular domain of Tfr2 binds bone morphogenic proteins (BMPs) and inhibits BMP-2-induced heterotopic ossification by acting as a decoy receptor. These data indicate that Tfr2 limits bone formation by modulating BMP signalling, possibly through direct interaction with BMP either as a receptor or as a co-receptor in complex with other BMP receptors. Finally, the Tfr2 extracellular domain may be effective in the treatment of conditions associated with pathological bone formation.
CRIS-Team Scopus Importer:2019-10-29

Transmembrane TNF drives osteoproliferative joint inflammation reminiscent of human spondyloarthritis - Kaaij, Merlijn H.; van Tok, Melissa N.; Blijdorp, Iris C.; Ambarus, Carmen A.; Stock, Michael; Pots, Désiree; Knaup, Véronique L.; Armaka, Marietta; Christodoulou-Vafeiadou, Eleni; van Melsen, Tessa K.; Masdar, Huriatul; Eskes, Harry J.P.P.; et al. (Journal of Experimental Medicine, 2020)
TNF plays a key role in immune-mediated inflammatory diseases including rheumatoid arthritis (RA) and spondyloarthritis (SpA). It remains incompletely understood how TNF can lead to different disease phenotypes such as destructive peripheral polysynovitis in RA versus axial and peripheral osteoproliferative inflammation in SpA. We observed a marked increase of transmembrane (tm) versus soluble (s) TNF in SpA versus RA together with a decrease in the enzymatic activity of ADAM17. In contrast with the destructive polysynovitis observed in classical TNF overexpression models, mice overexpressing tmTNF developed axial and peripheral joint disease with synovitis, enthesitis, and osteitis. Histological and radiological assessment evidenced marked endochondral new bone formation leading to joint ankylosis over time. SpA-like inflammation, but not osteoproliferation, was dependent on TNF-receptor I and mediated by stromal tmTNF overexpression. Collectively, these data indicate that TNF can drive distinct inflammatory pathologies. We propose that tmTNF is responsible for the key pathological features of SpA.
CRIS-Team Scopus Importer:2020-07-24

Treatment of a patient with severe systemic sclerosis (SSc) using CD19-targeted CAR T cells. - Bergmann, Christina; Müller, Fabian; Distler, Jörg; Györfi, Andrea Hermina; Völkl, Simon; Aigner, Michael; Kretschmann, Sascha; Reimann, Hannah; Harrer, Thomas; Bayerl, Nadine; Böltz, Sebastian; Wirsching, Andreas; et al. (Annals of the Rheumatic Diseases, 2023)
EVALuna2:537682

Treatment of psoriatic arthritis in a phase 3 randomised, placebo-controlled trial with apremilast, an oral phosphodiesterase 4 inhibitor - Kavanaugh, Arthur; Mease, Philip J.; Gomez-Reino, Juan J.; Adebajo, Adewale O.; Wollenhaupt, Juergen; Gladman, Dafna D.; Lespessailles, Eric; Hall, Stephen; Hochfeld, Marla; Hu, Chiachi; Hough, Douglas; Stevens, Randall M.; et al. (Annals of the Rheumatic Diseases, 2014)
Apremilast, an oral phosphodiesterase 4 inhibitor, regulates inflammatory mediators. Psoriatic Arthritis Long-term Assessment of Clinical Efficacy 1 (PALACE 1) compared apremilast with placebo in patients with active psoriatic arthritis despite prior traditional disease-modifying antirheumatic drug (DMARD) and/or biologic therapy.In the 24-week, placebo-controlled phase of PALACE 1, patients (N=504) were randomised (1:1:1) to placebo, apremilast 20 mg twice a day (BID) or apremilast 30 mg BID. At week 16, patients without >=20% reduction in swollen and tender joint counts were required to be re-randomised equally to either apremilast dose if initially randomised to placebo or remained on their initial apremilast dose. Patients on background concurrent DMARDs continued stable doses (methotrexate, leflunomide and/or sulfasalazine). Primary outcome was the proportion of patients achieving 20% improvement in modified American College of Rheumatology response criteria (ACR20) at week 16.At week 16, significantly more apremilast 20 mg BID (31%) and 30 mg BID (40%) patients achieved ACR20 versus placebo (19%) (p<0.001). Significant improvements in key secondary measures (physical function, psoriasis) were evident with both apremilast doses versus placebo. Across outcome measures, the 30-mg group generally had higher and more consistent response rates, although statistical comparison was not conducted. The most common adverse events were gastrointestinal and generally occurred early, were self-limiting and infrequently led to discontinuation. No imbalance in major adverse cardiac events, serious or opportunistic infections, malignancies or laboratory abnormalities was observed.Apremilast was effective in the treatment of psoriatic arthritis, improving signs and symptoms and physical function. Apremilast demonstrated an acceptable safety profile and was generally well tolerated.NCT01172938.
EVALuna2:12921

Treatment of refractory hypocomplementaemic urticarial vasculitis syndrome progressing to systemic lupus erythematosus with belimumab. - Valor-Méndez, Larissa; Schett, Georg; Manger, Bernhard (Clinical and Experimental Rheumatology, 2022)
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Treatment patterns of individualized real-life tapering approaches based on shared decision-making in rheumatoid arthritis - Birkner, Benjamin; Rech, Jürgen; Edelmann, Edmund; Verheyen, Frank; Schett, Georg; Stargardt, Tom (Zeitschrift für Rheumatologie, 2023)
Objective: To provide real-world evidence on patient-individual tapering patterns of disease-modifying antirheumatic drugs (DMARDs) in rheumatoid arthritis (RA) patients in daily clinical practice. Methods: Data obtained through a controlled prospective cohort study in Germany conducted from July 2018 to March 2021 were analyzed. Participants consist of RA patients in sustained remission who were eligible for DMARD tapering at enrolment. Data from RA patients who experienced tapering of DMARDs at least once during the observational period (n = 200) were used. Descriptive analyses of medical outcomes at baseline and at time of first tapering, time to first tapering, tapering patterns by substance group, and tapering intensity were documented. Results: We did not observe meaningful differences in either disease activity or quality of life measures between substance groups at enrolment, time of first tapering, and at 6 or 12 months after tapering. Median time until first tapering varied between substance groups (csDMARDs: 108 days; bDMARDs: 189 days; combination: 119 days). Most patients received one iteration of tapering only (147/200 patients, 73.5%). Dose reduction was applied for patients treated with csDMARDs (79/86 patients, 91.8%), spacing of interval was the most frequent strategy for patients treated with bDMARDs only (43/48 patients, 89.5%). Necessity for increased DMARD dosage was observed in only 10% of patients (20/200). Tapering intensity by substance was overall heterogenous, indicating high individualization. Conclusion: We identify highly heterogeneous tapering patterns between substance groups and within substances. Identification and recognition of patient-individual approaches of tapering will help to further improve the management of RA for both patients and rheumatologists.
CRIS-Team Scopus Importer:2023-07-07
Keywords: Cohort study; Disease-modifying antirheumatic drugs (DMARD’s); Dose tapering; Real world conditions; Rheumatoid arthritis

Treatment tapering and stopping in patients with rheumatoid arthritis in stable remission (RETRO): a multicentre, randomised, controlled, open-label, phase 3 trial - Tascilar, Koray; Hagen, Melanie; Kleyer, Arnd; Simon, David; Reiser, Michaela; Hueber, Axel; Manger, Bernhard; Englbrecht, Matthias; Finzel, Stephanie; Tony, Hans Peter; Schuch, Florian; Kleinert, Stefan; et al. (The Lancet Rheumatology, 2021)
Background: Owing to increasing remission rates, the management of patients with rheumatoid arthritis in sustained remission is of growing interest. The Rheumatoid Arthritis in Ongoing Remission (RETRO) study investigated tapering and withdrawal of disease-modifying antirheumatic drugs (DMARDs) in patients with rheumatoid arthritis in stable remission to test whether remission could be retained without the need to take DMARD therapy despite an absence of symptoms. Methods: RETRO was an investigator-initiated, multicentre, prospective, randomised, controlled, open-label, parallel-group phase 3 trial in patients aged at least 18 years with rheumatoid arthritis for at least 12 months before randomisation who were in sustained Disease Activity Score using 28 joints with erythrocyte sedimentation rate (ESR) remission (score <2·6 units). Eligible patients were recruited consecutively from 14 German hospitals or rheumatology practices and randomly assigned (1:1:1) without stratification and regardless of baseline treatment, using a sequence that was computer-generated by the study statistician, to continue 100% dose DMARD (continue group), taper to 50% dose DMARD (taper group), or 50% dose DMARD for 6 months before stopping DMARDs (stop group). Neither patients nor investigators were masked to the treatment assignment. Patients were assessed every 3 months and screened for disease activity and relapse. The primary endpoint was the proportion of patients in sustained DAS28-ESR remission without relapse at 12 months, analysed using a log-rank test of trend and Cox regression. Analysis by a trained statistician of the primary outcome and safety was done in a modified intention-to-treat population that included participants with non-missing baseline data. This study is completed and closed to new participants and is registered with ClinicalTrials.gov (NCT02779114). Findings: Between May 26, 2010, and May 29, 2018, 303 patients were enrolled and allocated to continue (n=100), taper (n=102), or stop DMARDs (n=101). 282 (93%) of 303 patients were analysed (93 [93%] of 100 for continue, 93 [91%] of 102 for taper, and 96 [95%] of 101 for stop). Remission was maintained at 12 months by 81·2% (95% CI 73·3–90·0) in the continue group, 58·6% (49·2–70·0) in the taper group, and 43·3% (34·6–55·5) in the stop group (p=0·0005 with log-rank test for trend). Hazard ratios for relapse were 3·02 (1·69–5·40; p=0.0003) for the taper group and 4·34 (2·48–7·60; p<0.0001)) for the stop group, in comparison with the continue group. The majority of patients who relapsed regained remission after reintroduction of 100% dose DMARDs. Serious adverse events occurred in ten of 93 (11%) patients in the continue group, seven of 93 (8%) patients in taper group, and 13 of 96 (14%) patients in the stop group. None were considered to be related to the intervention. The most frequent type of serious adverse event was injuries or procedural complications (n=9). Interpretation: Reducing antirheumatic drugs in patients with rheumatoid arthritis in stable remission is feasible, with maintenance of remission occurring in about half of the patients. Because relapse rates were significantly higher in patients who tapered or stopped antirheumatic drugs than in patients who continued with a 100% dose, such approaches will require tight monitoring of disease activity. However, remission was regained after reintroduction of antirheumatic treatments in most of those who relapsed in this study. These results might help to prevent overtreatment in a substantial number of patients with rheumatoid arthritis. Funding: None.
CRIS-Team Scopus Importer:2021-11-05

TREATMENT TAPERING AND WITHDRAWAL IN RHEUMATOID ARTHRITIS WITH STABLE REMISSION - FINAL ANALYSIS OF THE RETRO STUDY - Hagen, Melanie; Tascilar, Koray; Reiser, Maximilian; Valor, L.; Haschka, J.; Kleyer, Arnd; Hueber, A.; Manger, Bernhard; Cobra, J.; Figuereido, C.; Finzel, S.; Tony, H. P.; et al. (ANNALS OF THE RHEUMATIC DISEASES, 2021)
CRIS-Team WoS Importer:2021-10-01

Treatment with DNases rescues hidden neutrophil elastase from aggregated NETs - Podolska, Malgorzata; Mahajan, Aparna; Hahn, Jonas; Knopf, Jasmin; Maueröder, Christian; Petru, Lenka; Ullmann, Marc; Schett, Georg; Leppkes, Moritz; Herrmann, Martin; Munoz, Luis Enrique; Schauer, Christine (Journal of Leukocyte Biology, 2019)
The release of neutrophil extracellular traps (NETs) is one of the weapons neutrophils have in their armory. NETs consist of extracellular chromatin fibers decorated with a plethora of cytoplasmic and granular proteins, such as the antimicrobial serine protease neutrophil elastase (NE). Because the first description of NETs as beneficial to the host, reports on their double-faced role in health and disease have considerably increased recently. On one hand, NETs reportedly trap and kill bacteria and also participate in the resolution of the acute inflammation associated with infection and with tissue damage. On the other hand, numerous negative aspects of NETs contribute to the etiopathogenesis of autoimmune disorders. Employing soluble and solid fluorescent substrates, we demonstrate the interaction of NE with aggregated NETs (aggNETs), the limitation of its enzymatic activity and the containment of the enzyme from surrounding tissues. These events prevent the spread of inflammation and tissue damage. The detection of DNase 1-dependent elevation of NE activity attests the continuous presence of patrolling neutrophils forming NETs and aggNETs even under conditions physiologic conditions.
CRIS-Team Scopus Importer:2019-09-17
Keywords: aggregated NETs; DNase 1; NETs; neutrophil elastase; neutrophils

Trial of Tocilizumab in Giant-Cell Arteritis - Stone, J. H.; Tuckwell, K.; Dimonaco, S.; Klearman, M.; Aringer, M.; Blockmans, D.; Brouwer, E.; Cid, M. C.; Dasgupta, B.; Rech, J.; Salvarani, C.; Schett, Georg; et al. (New England Journal of Medicine, 2017)
Giant-cell arteritis commonly relapses when glucocorticoids are tapered, and the prolonged use of glucocorticoids is associated with side effects. The effect of the interleukin-6 receptor alpha inhibitor tocilizumab on the rates of relapse during glucocorticoid tapering was studied in patients with giant-cell arteritis.In this 1-year trial, we randomly assigned 251 patients, in a 2:1:1:1 ratio, to receive subcutaneous tocilizumab (at a dose of 162 mg) weekly or every other week, combined with a 26-week prednisone taper, or placebo combined with a prednisone taper over a period of either 26 weeks or 52 weeks. The primary outcome was the rate of sustained glucocorticoid-free remission at week 52 in each tocilizumab group as compared with the rate in the placebo group that underwent the 26-week prednisone taper. The key secondary outcome was the rate of remission in each tocilizumab group as compared with the placebo group that underwent the 52-week prednisone taper. Dosing of prednisone and safety were also assessed.Sustained remission at week 52 occurred in 56% of the patients treated with tocilizumab weekly and in 53% of those treated with tocilizumab every other week, as compared with 14% of those in the placebo group that underwent the 26-week prednisone taper and 18% of those in the placebo group that underwent the 52-week prednisone taper (P<0.001 for the comparisons of either active treatment with placebo). The cumulative median prednisone dose over the 52-week period was 1862 mg in each tocilizumab group, as compared with 3296 mg in the placebo group that underwent the 26-week taper (P<0.001 for both comparisons) and 3818 mg in the placebo group that underwent the 52-week taper (P<0.001 for both comparisons). Serious adverse events occurred in 15% of the patients in the group that received tocilizumab weekly, 14% of those in the group that received tocilizumab every other week, 22% of those in the placebo group that underwent the 26-week taper, and 25% of those in the placebo group that underwent the 52-week taper. Anterior ischemic optic neuropathy developed in one patient in the group that received tocilizumab every other week.Tocilizumab, received weekly or every other week, combined with a 26-week prednisone taper was superior to either 26-week or 52-week prednisone tapering plus placebo with regard to sustained glucocorticoid-free remission in patients with giant-cell arteritis. Longer follow-up is necessary to determine the durability of remission and safety of tocilizumab. (Funded by F. Hoffmann-La Roche; ClinicalTrials.gov number, NCT01791153 .).
EVALuna2:13434

Tribbles homologue 3 stimulates canonical TGF-? signalling to regulate fibroblast activation and tissue fibrosis - Tomcik, Michal; Palumbo-Zerr, Katrin; Zerr, Pawel; Sumova, Barbora; Avouac, Jerome; Dees, Clara; Distler, Alfiya; Becvar, Radim; Distler, Oliver; Schett, Georg; Senolt, Ladislav; Distler, Jörg (Annals of the Rheumatic Diseases, 2016)
Tribbles homologue 3 (TRB3) is a pseudokinase that modifies the activation of various intracellular signalling pathways to control fundamental processes extending from mitosis and cell activation to apoptosis and modulation of gene expression. Here, we aimed to analyse the role of TRB3 in fibroblast activation in systemic sclerosis (SSc).The expression of TRB3 was quantified by quantitative PCR, western blot and immunohistochemistry. The role of TRB3 was analysed in cultured fibroblasts and in experimental fibrosis using small interfering RNA (siRNA)-mediated knockdown and overexpression of TRB3.TRB3 expression was increased in fibroblasts of patients with SSc and in murine models of SSc in a transforming growth factor-? (TGF-?)/Smad-dependent manner. Overexpression of TRB3 stimulated canonical TGF-? signalling and induced an activated phenotype in resting fibroblasts. In contrast, knockdown of TRB3 reduced the profibrotic effects of TGF-? and decreased the collagen synthesis. Moreover, siRNA-mediated knockdown of TRB3 exerted potent antifibrotic effects and ameliorated bleomycin as well as constitutively active TGF-? receptor I-induced fibrosis with reduced dermal thickening, decreased hydroxyproline content and impaired myofibroblast differentiation.The present study characterises TRB3 as a novel profibrotic mediator in SSc. TGF-? induces TRB3, which in turn activates canonical TGF-?/Smad signalling and stimulates the release of collagen, thereby inducing a positive feedback loop that may contribute to aberrant TGF-? signalling in SSc.
EVALuna2:13129

Tumor immunotherapy: lessons from autoimmunity - Maueröder, Christian; Munoz Becerra, Luis; Chaurio Gonzalez, Ricardo Alfredo; Herrmann, Martin; Schett, Georg; Berens, Christian (Frontiers in Immunology, 2014)
EVALuna2:12986

Tumor necrosis factor α and RANKL blockade cannot halt bony spur formation in experimental inflammatory arthritis - Schett, Georg; Stolina, Marina; Dwyer, Denise; Zack, Debra; Uderhardt, Stefan; Krönke, Gerhard; Kostenuik, Paul; Feige, Ulrich (Arthritis and Rheumatism, 2009)
Objective. To investigate the kinetics of bony spur formation and the relationship of bony spur formation to synovial inflammation and bone erosion in 2 rat arthritis models, and to address whether bony spur formation depends on the expression of tumor necrosis factor α (TNFα) or RANKL. Methods. Analysis of the kinetics of synovial inflammation, bone erosion, osteoclast formation, and growth of bony spurs was performed in rat collagen-induced arthritis (CIA) and adjuvant-induced arthritis (AIA). In addition, inhibition experiments were performed to assess whether inhibition of TNFα and RANKL by pegylated soluble TNF receptor type I (pegTNFRI) and osteoprotegerin (OPG), respectively, affected bony spur formation. Results. Bony spurs emerged from the periosteal surface close to joints, and initial proliferation of mesenchymal cells was noted as early as 3 days and 5 days after onset of CIA and AIA, respectively. Initiation of bony spur formation occurred shortly after the onset of inflammation and bone erosion. Neither pegTNFRI nor OPG could significantly halt the osteophytic responses in CIA and AIA. Conclusion. These results suggest that bony spur formation is triggered by inflammation and initial structural damage in these rat models of inflammatory arthritis. Moreover, emergence of bony spurs depends on periosteal proliferation and is not affected by inhibition of either TNFα or RANKL. Bony spur formation can thus be considered a process that occurs independent of TNFα and RANKL and is triggered by destructive arthritis. © 2009, American College of Rheumatology.
CRIS-Team Scopus Importer:2020-11-20

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

TYPE 2 INNATE LYMPHOID CELLS ARE RAPIDLY AND PERSISTENTLY RECRUITED IN EXPERIMENTAL FIBROSIS AND THEIR COUNTS CORRELATE WITH THE SEVERITY OF SKIN AND LUNG FIBROSIS IN SYSTEMIC SCLEROSIS - Wohlfahrt, T.; Weber, Stefanie; Englbrecht, Matthias; Dees, Clara; Beyer, Christian; Distler, O.; Schett, Georg; Distler, Jörg; Ramming, A. (2016)
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Type 2 Innate Lymphoid Cells - Cellular Source of Profibrotic Mediators Rapidly and Persistently Recruited in Experimental Fibrosis and Systemic Sclerosis - Weber, Stefanie; Wohlfahrt, Thomas; Rauber, Simon; Luber, Markus; Englbrecht, Matthias; Dees, Clara; Beyer, Christian; Distler, Oliver; Schett, Georg; Distler, Jörg; Ramming, Andreas (2016)
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Type 2 innate lymphoid cells inhibit the differentiation of osteoclasts and protect from ovariectomy-induced bone loss - Omata, Yasunori; Frech, Michael; Lucas, Sébastien; Primbs, Tatjana; Knipfer, Lisa; Wirtz, Stefan; Kadono, Yuho; Saito, Taku; Tanaka, Sakae; Sarter, Kerstin; Schett, Georg; Zaiss, Mario (Bone, 2020)
While the role of T cells in the regulation of bone homeostasis is well defined, little is known about the role of innate lymphoid cells (ILCs) on bone. ILCs are innate immune cells that share cytokine expression patterns with T cells but lack the T cell receptor. In this study we show that type 2 ILCs (ILC2) potently inhibit the generation of bone resorbing osteoclasts in vitro as well as favorably influence bone homeostasis under steady state conditions in vivo using loss and gain of function models. Furthermore, adoptive transfer of ILC2 completely abrogated ovariectomy-induced bone loss by significantly down-regulating osteoclast numbers in vivo. The suppressive effects of ILC2s on osteoclasts in vitro and in vivo as well as the protection from ovariectomy-induced bone loss were linked to their expression of IL-4 and IL-13 as well as STAT6 activation on the myeloid target cell, since deletion of IL-4/IL-13 in ILC2s or STAT6 in osteoclast precursors abrogated the anti-osteoclastogenic effect of ILC2s. Taken together, these findings show that ILC2 have to be considered as potent regulators of bone homeostasis.
CRIS-Team Scopus Importer:2020-04-14
Keywords: Bone loss; Cytokines; ILC2; Osteoclasts; Osteoimmunology; Type 2 innate lymphoid cells type

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

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

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

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

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

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

Unilateral plantar erythema nodosum in sarcoidosis - Hueber, Axel; Schett, Georg; Manger, Bernhard (Arthritis and Rheumatology, 2017)
A 32-year old male Caucasian patient presented with mild exertional dyspnea, pain and swelling of both ankles, and general malaise. On examination symmetrical arthritis of both ankles and a vivid nodular erythema with slight pain on pressure was detected on the sole of the right foot (A). A therapy with ibuprofen had not led to any improvement of symptoms. This article is protected by copyright. All rights reserved.
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Unsupervised Super Resolution in X-ray Microscopy using a Cycle-consistent Generative Model - Raghunath, Adarsh; Wagner, Fabian; Thies, Mareike; Gu, Mingxuan; Pechmann, Sabrina; Aust, Oliver; Weidner, Daniela; Neag, Georgiana; Schett, Georg; Christiansen, Silke H.; Uderhardt, Stefan; Maier, Andreas (Bildverarbeitung für die Medizin 2023, 2023)
X-ray microscopy (XRM) is a tomographic imaging modality that has gained interest in the context of understanding bone-related diseases on the micro scale due to its high spatial resolution and strong bone to soft tissue contrast. Although in-vivo imaging of bone structures on the micro scale is desired from a medical perspective, high radiation dose so-far prohibits imaging living animals. Research has been focused on generating high-quality reconstructions while maintaining a low X-ray dosage. However, low dose acquisitions result in noisy images with a lower resolution. This study focuses on using an unsupervised deep-learning approach to accurately reconstruct high-resolution (HR) XRM images from their noisy low-resolution (LR) counterparts. We consider an unsupervised approach in a general case where paired data (low-/high resolution pairs) are unavailable. We propose the use of a cycle-consistent generative adversarial network (GAN) for this super resolution task which is to learn the mapping from noisy LR to HR images. Quantitative and qualitative assessments show that our method produces accurate high-resolution XRM reconstructions from their noisy low-resolution counterparts, increasing the peak signal-to-noise ratio (PSNR)/structural similarity index (SSIM) from 18.15/0.52 (baseline) to 31.94/0.73 (proposed method). We believe that our proposed XRM super resolution pipeline provides a valuable tool toward high-resolution in-vivo XRM imaging.<br

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

Upper zone of growth plate and cartilage matrix associated protein protects cartilage during inflammatory arthritis - Seuffert, Fritz; Weidner, Daniela; Baum, Wolfgang; Schett, Georg; Stock, Michael (Arthritis Research & Therapy, 2018)
BACKGROUND: ADAMTS aggrecanases play a major role in cartilage degeneration during degenerative and inflammatory arthritis. The cartilage-specific secreted protein Upper zone of growth plate and cartilage matrix associated protein (Ucma) has been shown to block ADAMTS-triggered aggrecanolysis in experimental osteoarthritis. Here we aimed to investigate whether and how Ucma may affect cartilage destruction and osteophyte formation in the context of inflammatory arthritis. METHODS: Ucma-ADAMTS5 protein interactions were studied using slot blot and solid phase binding assays. Chondrocyte cultures were stimulated with ADAMTS5 or IL-1β in the presence or absence of Ucma and aggrecanolysis was assessed by neoepitope formation. Arthritis was induced by transfer of K/BxN serum into wild-type (WT), Ucma-deficient and WT mice treated with recombinant Ucma. Cartilage proteoglycan loss and cartilage damage was assessed by safranin-O stain, aggrecanase-induced neoepitope formation and histomorphometry, respectively. Osteophytes were assessed by histomorphometry, micro-computed tomography, RNA in-situ hybridisation for collagen10a1 and osteocalcin, and staining for TRAP activity. Gene expression analyses were performed using real-time RT-PCR. RESULTS: Ucma physically interacted with ADAMTS5 and blocked its aggrecanase activity in chondrocyte cultures. Ucma was highly expressed in the articular cartilage and in osteophytes during arthritis. Ucma had no effect on inflammation and bone erosion. In contrast, Ucma-deficient mice developed significantly more severe cartilage proteoglycan loss and cartilage destruction. Conversely, treatment with Ucma inhibited cartilage degeneration in arthritis. Ucma effectively inhibited ADAMTS5-triggered or IL-1β-triggered aggrecanolysis in vitro and in vivo. Furthermore, osteophyte formation was reduced in Ucma-deficient mice. CONCLUSIONS: These results indicate that Ucma inhibits aggrecanolysis by physical interaction with ADAMTS5 and protects from cartilage degeneration in inflammatory arthritis. Ucma therefore represents an interesting novel and specific target for preventing cartilage degradation in the context of inflammatory arthritis.
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Use of methotrexate in adult-onset Still's disease - Manger, Bernhard; Rech, Jürgen; Schett, Georg (Clinical and Experimental Rheumatology, 2010)
Adult-onset Still's disease, a febrile, multisystem rheumatic disease, has variable outcomes. Some patients experience remission after a single or multiple inflammatory episodes, while others progress to a chronic course with substantial joint destruction. Although no controlled clinical trials with immunosuppressive agents in this disease have been reported, a number of small uncontrolled studies and case reports describe the use of methotrexate therapy. Methotrexate has shown efficacy for the control of systemic and articular symptoms and its favourable safety profile appears similar to that seen in other rheumatic diseases, when for this indication. The combination of methotrexate and corticosteroids has, over the years, become the first step in the standard of care in adult-onset Still's disease. If the response to this treatment is incomplete, additional therapies, such as biologic agents may be appropriate. © Copyright CLINICAL AND EXPERIMENTAL RHEUMATOLOGY 2010.
CRIS-Team Scopus Importer:2021-02-03
Keywords: Adult-onset Still's disease; Methotrexate; Prognosis; Therapy

Ustekinumab Is Superior to TNF Inhibitor Treatment in Resolving Enthesitis in Psa Patients with Active Enthesitis-Results from the Enthesial Clearance in Psoriatic Arthritis Study - Guilhon de Araujo, Elizabeth; Englbrecht, Matthias; Höpken, Sabrina; Finzel, Stephanie; Hueber, Axel; Rech, Jürgen; Schett, Georg (2017)
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Validation of standardized questionnaires evaluating symptoms of depression in rheumatoid arthritis patients - approaches to screening for a frequent and yet underrated challenge - Englbrecht, Matthias; Alten, Rieke; Aringer, Martin; Baerwald, Christoph G.; Burkhardt, Harald; Eby, Nancy; Fliedner, Gerhard; Gauger, Bettina; Henkemeier, Ulf; Hofmann, Michael W.; Kleinert, Stefan; Kneitz, Christian; et al. (Arthritis & Rheumatism-Arthritis Care & Research, 2016)
To validate standard self-reporting questionnaires for depression screening in patients with rheumatoid arthritis (RA) and compare these measures to each other and to the Montgomery-Åsberg Depression Rating Scale (MADRS), a standardized structured interview.In 9 clinical centers across Germany, depressive symptomatology was assessed in 262 adult RA patients at baseline (T0) and at 12 ± 2 weeks follow-up (T1) using the WHO Five Well-Being Index (WHO-5), the Patient Health Questionnaire-9 (PHQ-9), and the Beck Depression Inventory (BDI-II). Construct validity of these depression questionnaires (using convergent and discriminant validity) was evaluated using Spearman correlations at both time points. The test-retest reliability of the questionnaires was evaluated in RA patients who had not undergone psychotherapeutic intervention or received antidepressants between T0 and T1. The sensitivity and the specificity of the questionnaires were calculated using the results of the MADRS, a structured interview, as gold standard.According to the Spearman correlation coefficients all questionnaires met convergent validity criteria (? > |0.50|) with the BDI-II performing best while correlations with age and disease activity for all questionnaires met the criteria for discriminant validity (? < |0.50|). The only questionnaire to meet the predefined retest reliability criterion (? >= 0.70) was the BDI-II (rs = 0.77) which also achieved the best results for both sensitivity and specificity >80% when using the MADRS as the gold standard.The BDI-II best met the predefined criteria and the PHQ-9 met most validity criteria with lower sensitivity and specificity. This article is protected by copyright. All rights reserved.
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VALUE AND LIMITATIONS IN HR-PQCT IMAGING IN CHRONIC ARTHRITIS. CURRENT STATUS AND FUTURE DIRECTIONS - Engelke, Klaus; Figueiredo, C.; Kleyer, Arnd; Simon, David; Schett, Georg (OSTEOPOROSIS INTERNATIONAL, 2019)
CRIS-Team WoS Importer:2019-08-02

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

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

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

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

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

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