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

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

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

Patient Experiences and Challenges in the Management of Autoinflammatory Diseases—Data from the International FMF & AID Global Association Survey - Rech, Jürgen; Schett, Georg; Tufan, Abdurrahman; Kuemmerle-Deschner, Jasmin B.; Özen, Seza; Tascilar, Koray; Geck, Leonie; Krickau, Tobias; Cohen, Ellen; Welzel, Tatjana; Kuehn, Marcus; Vetterli, Malena (Journal of Clinical Medicine, 2024)
Background: Autoinflammatory diseases (AIDs) are rare, mostly genetic diseases that affect the innate immune system and are associated with inflammatory symptoms. Both paediatric and adult patients face daily challenges related to their disease, diagnosis and subsequent treatment. For this reason, a survey was developed in collaboration between the FMF & AID Global Association and the Erlangen Center for Periodic Systemic Autoinflammatory Diseases. Methods: The aim of the survey was to collect the personal assessment of affected patients with regard to their current status in terms of diagnostic timeframes, the interpretation of genetic tests, the number of misdiagnoses, and pain and fatigue despite treatment. Results: In total, data from 1043 AID patients (829 adults and 214 children/adolescents) from 52 countries were collected and analyzed. Familial Mediterranean fever (FMF) (521/50%) and Behçet’s disease (311/30%) were the most frequently reported diseases. The average time to diagnosis was 3 years for children/adolescents and 14 years for adults. Prior to the diagnosis of autoinflammatory disease, patients received several misdiagnoses, including psychosomatic disorders. The vast majority of patients reported that genetic testing was available (92%), but only 69% were tested. A total of 217 patients reported that no increase in acute-phase reactants was detected during their disease episodes. The intensity of pain and fatigue was measured in AID patients and found to be high. A total of 88% of respondents received treatment again, while 8% reported no treatment. Conclusions: AID patients, particularly adults, suffer from significant delays in diagnosis, misdiagnosis, and a variety of symptoms, including pain and fatigue. Based on the results presented, raising awareness of these diseases in the wider medical community is crucial to improving patient care and quality of life.
CRIS-Team Scopus Importer:2024-03-22
Keywords: autoinflammatory diseases; Behcet’s disease; diagnosis; familial Mediterranean fever (FMF); fatigue; misdiagnoses; pain; patient survey

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Performance of serum biomarkers reflective of different pathogenic processes in systemic sclerosis-associated interstitial lung disease. - Györfi, Andrea Hermina; Filla, Tim; Dickel, Nicholas; Möller, Florian; Li, Yi Nan; Bergmann, Christina; Matei, Alexandru-Emil; Harrer, Thomas; Kunz, Meik; Schett, Georg; Distler, Jörg H.W. (Rheumatology, 2024)
OBJECTIVE: Interstitial lung disease (ILD) is the leading cause of mortality in SSc. Novel biomarkers are crucial to improve outcomes in SSc-ILD. We aimed to compare the performance of potential serum biomarkers of SSc-ILD that reflect different pathogenic processes: KL-6 and SP-D (epithelial injury), CCL18 (type 2 immune response), YKL-40 (endothelial injury and matrix remodelling) and MMP-7 (ECM remodelling). METHODS: Baseline and follow-up serum samples from 225 SSc patients were analysed by ELISA. Progressive ILD was defined according to the 2022-ATS/ERS/JRS/ALAT guidelines. Linear mixed models and random forest models were used for statistical analyses. RESULTS: Serum levels of KL-6 [MD 35.67 (95% CI 22.44-48.89, P < 0.01)], SP-D [81.13 (28.46-133.79, P < 0.01)], CCL18 [17.07 (6.36-27.77, P < 0.01)], YKL-40 [22.81 (7.19-38.44, P < 0.01)] and MMP-7 [2.84 (0.88-4.80, P < 0.01)] were independently associated with the presence of SSc-ILD. A machine-learning model including all candidates classified patients with or without ILD with an accuracy of 85%. The combination of KL-6 and SP-D was associated with the presence [0.77 (0.53-1.00, P' <0.01)] and previous progression of SSc-ILD [OR 1.28 (1.01-1.61, P' =0.047)]. Higher baseline levels of KL-6 [OR 3.70 (1.52-9.03, P < 0.01)] or SP-D [OR 2.00 (1.06-3.78, P = 0.03)] increased the odds of future SSc-ILD progression, independent of other conventional risk factors, and the combination of KL-6 and SP-D [1.109 (0.665-1.554, P < 0.01)] showed improved performance compared with KL-6 and SP-D alone. CONCLUSION: All candidates performed well as diagnostic biomarkers for SSc-ILD. The combination of KL-6 and SP-D might serve as biomarker for the identification of SSc patients at risk of ILD progression.
EVALuna2:538826

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

Periarticular Bone Loss in Arthritis Is Induced by Autoantibodies Against Citrullinated Vimentin - Engdahl, Cecilia; Bang, Holger; Dietel, Katharina; Lang, Stefanie; Harre, Ulrike; Schett, Georg (Journal of Bone and Mineral Research, 2017)
Periarticular bone loss is a long known but yet insufficiently understood phenomenon in patients with rheumatoid arthritis. This study investigated whether autoimmunity against citrullinated proteins is causally involved in triggering periarticular bone loss. Periarticular bone loss was studied in the standard antigen-induced arthritis (AIA) mouse model with methylated bovine serum albumin (mBSA) as well as a modified model with mutated citrullinated vimentin (MCV) alone or in combination with mBSA. Periarticular bone loss, subchondral osteoclastogenesis, as well as local expression of cytokines, osteoclast genes, and peptidyl-arginine deiminase (PAD) enzymes were assessed after arthritis induction. Immune cell and osteoclast precursor infiltration were detected in the periarticular bone marrow and local lymph nodes. In addition, periarticular bone loss was assessed upon challenge of mice with purified anti-MCV antibody. Despite inducing a milder form of arthritis than mBSA, MCV triggered significant periarticular bone loss associated with an increased infiltration of osteoclast precursors and mature osteoclasts in the periarticular bone marrow. MCV enhanced the expression of the osteoclast inducers RANKL and M-CSF, the cytokines IL-8, IL-1, IL-6, and TNF-?, as well as PAD2 and PAD4 enzymes in the periarticular bone marrow. Furthermore, also anti-MCV antibody challenge induced significant periarticular bone loss and local osteoclastogenesis in the mice. Autoimmunity against citrullinated vimentin triggers periarticular bone loss by osteoclast activation in the bone marrow. These findings may explain why periarticular bone loss is already found very early in the disease course of patients with rheumatoid arthritis. © 2017 American Society for Bone and Mineral Research.
EVALuna2:13415

Persistent inflammation in systemic sclerosis is strongly associated with mortality: a EUSTAR database analysis - Guler, S. A.; Sarbu, A.; Stadler, O.; Allanore, Y.; Bernardino,; Distler, Jörg; Gabrielli, A.; Hoffmann-Vold, A.; Matucci-Cerinic, M.; Mueller-Ladner, U.; Ortiz-Santamaria,; Rednic, S.; et al. (EUROPEAN RESPIRATORY JOURNAL, 2022)
CRIS-Team WoS Importer:2023-03-03

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

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

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

Pharmacological inhibition of porcupine induces regression of experimental skin fibrosis by targeting Wnt signalling - Chen, Chih-Wei; Beyer, Christian; Liu, Jun; Maier, Christiane; Li, Chun; Thuong Trinh-Minh,; Xu, Xiaohan; Cole, Stuart H.; Hsieh, Mindy H.; Ng, Nicholas; Althage, Alana; Meeusen, Shelly; et al. (Annals of the Rheumatic Diseases, 2017)
Wnt signalling has been implicated in activating a fibrogenic programme in fibroblasts in systemic sclerosis (SSc). Porcupine is an O-acyltransferase required for secretion of Wnt proteins in mammals. Here, we aimed to evaluate the antifibrotic effects of pharmacological inhibition of porcupine in preclinical models of SSc.The porcupine inhibitor GNF6231 was evaluated in the mouse models of bleomycin-induced skin fibrosis, in tight-skin-1 mice, in murine sclerodermatous chronic-graft-versus-host disease (cGvHD) and in fibrosis induced by a constitutively active transforming growth factor-?-receptor I.Treatment with pharmacologically relevant and well-tolerated doses of GNF6231 inhibited the activation of Wnt signalling in fibrotic murine skin. GNF6231 ameliorated skin fibrosis in all four models. Treatment with GNF6231 also reduced pulmonary fibrosis associated with murine cGvHD. Most importantly, GNF6231 prevented progression of fibrosis and showed evidence of reversal of established fibrosis.These data suggest that targeting the Wnt pathway through inhibition of porcupine provides a potential therapeutic approach to fibrosis in SSc. This is of particular interest, as a close analogue of GNF6231 has already demonstrated robust pathway inhibition in humans and could be available for clinical trials.
EVALuna2:13348

Phase-orientated disease control by cytokines-lessons from rheumatoid arthritis - Schett, Georg (2017)
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Phenotypes Determined by Cluster Analysis and Their Survival in the Prospective European Scleroderma Trials and Research Cohort of Patients With Systemic Sclerosis - Sobanski, Vincent; Giovannelli, Jonathan; Allanore, Yannick; Riemekasten, Gabriela; Airo, Paolo; Vettori, Serena; Cozzi, Franco; Distler, Oliver; Matucci-Cerinic, Marco; Denton, Christopher; Launay, David; Hachulla, Eric; et al. (Arthritis and Rheumatology, 2019)
Objective Systemic sclerosis (SSc) is a heterogeneous connective tissue disease that is typically subdivided into limited cutaneous SSc (lcSSc) and diffuse cutaneous SSc (dcSSc) depending on the extent of skin involvement. This subclassification may not capture the entire variability of clinical phenotypes. The European Scleroderma Trials and Research (EUSTAR) database includes data on a prospective cohort of SSc patients from 122 European referral centers. This study was undertaken to perform a cluster analysis of EUSTAR data to distinguish and characterize homogeneous phenotypes without any a priori assumptions, and to examine survival among the clusters obtained. Methods A total of 11,318 patients were registered in the EUSTAR database, and 6,927 were included in the study. Twenty-four clinical and serologic variables were used for clustering. Results Clustering analyses provided a first delineation of 2 clusters showing moderate stability. In an exploratory attempt, we further characterized 6 homogeneous groups that differed with regard to their clinical features, autoantibody profile, and mortality. Some groups resembled usual dcSSc or lcSSc prototypes, but others exhibited unique features, such as a majority of lcSSc patients with a high rate of visceral damage and antitopoisomerase antibodies. Prognosis varied among groups and the presence of organ damage markedly impacted survival regardless of cutaneous involvement. Conclusion Our findings suggest that restricting subsets of SSc patients to only those based on cutaneous involvement may not capture the complete heterogeneity of the disease. Organ damage and antibody profile should be taken into consideration when individuating homogeneous groups of patients with a distinct prognosis.
CRIS-Team WoS Importer:2019-08-30

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

Phosphatidylserine is a global immunosuppressive signal in efferocytosis, infectious disease, and cancer - Birge, R. B.; Boeltz, Sebastian; Kumar, S.; Carlson, J.; Wanderley, J.; Calianese, D.; Barcinski, M.; Brekken, R. A.; Huang, X.; Hutchins, J. T.; Freimark, B.; Empig, C.; et al. (Cell Death and Differentiation, 2016)
Apoptosis is an evolutionarily conserved and tightly regulated cell death modality. It serves important roles in physiology by sculpting complex tissues during embryogenesis and by removing effete cells that have reached advanced age or whose genomes have been irreparably damaged. Apoptosis culminates in the rapid and decisive removal of cell corpses by efferocytosis, a term used to distinguish the engulfment of apoptotic cells from other phagocytic processes. Over the past decades, the molecular and cell biological events associated with efferocytosis have been rigorously studied, and many eat-me signals and receptors have been identified. The externalization of phosphatidylserine (PS) is arguably the most emblematic eat-me signal that is in turn bound by a large number of serum proteins and opsonins that facilitate efferocytosis. Under physiological conditions, externalized PS functions as a dominant and evolutionarily conserved immunosuppressive signal that promotes tolerance and prevents local and systemic immune activation. Pathologically, the innate immunosuppressive effect of externalized PS has been hijacked by numerous viruses, microorganisms, and parasites to facilitate infection, and in many cases, establish infection latency. PS is also profoundly dysregulated in the tumor microenvironment and antagonizes the development of tumor immunity. In this review, we discuss the biology of PS with respect to its role as a global immunosuppressive signal and how PS is exploited to drive diverse pathological processes such as infection and cancer. Finally, we outline the rationale that agents targeting PS could have significant value in cancer and infectious disease therapeutics.
EVALuna2:13256

Phospholipid membranes drive abdominal aortic aneurysm development through stimulating coagulation factor activity - Allen-Redpath, Keith; Aldrovandi, Maceler; Lauder, Sarah N.; Gketsopoulou, Anastasia; Tyrrell, Victoria J.; Slatter, David A.; Andrews, Robert; Watkins, W. John; Atkinson, Georgia; Mcneill, Eileen; Gilfedder, Anna; Protty, Majd; et al. (Proceedings of the National Academy of Sciences of the United States of America, 2019)
Abdominal aortic aneurysm (AAA) is an inflammatory vascular disease with high mortality and limited treatment options. How blood lipids regulate AAA development is unknown. Here lipidomics and genetic models demonstrate a central role for procoagulant enzymatically oxidized phospholipids (eoxPL) in regulating AAA. Specifically, through activating coagulation, eoxPL either promoted or inhibited AAA depending on tissue localization. Ang II administration to ApoE − / − mice increased intravascular coagulation during AAA development. Lipidomics revealed large numbers of eoxPL formed within mouse and human AAA lesions. Deletion of eoxPL-generating enzymes (Alox12 or Alox15) or administration of the factor Xa inhibitor rivaroxaban significantly reduced AAA. Alox-deficient mice displayed constitutively dysregulated hemostasis, including a consumptive coagulopathy, characterized by compensatory increase in prothrombotic aminophospholipids (aPL) in circulating cell membranes. Intravenously administered procoagulant PL caused clotting factor activation and depletion, induced a bleeding defect, and significantly reduced AAA development. These data suggest that Alox deletion reduces AAA through diverting coagulation away from the vessel wall due to eoxPL deficiency, instead activating clotting factor consumption and depletion in the circulation. In mouse whole blood, ∼44 eoxPL molecular species formed within minutes of clot initiation. These were significantly elevated with ApoE − / − deletion, and many were absent in Alox − / − mice, identifying specific eoxPL that modulate AAA. Correlation networks demonstrated eoxPL belonged to subfamilies defined by oxylipin composition. Thus, procoagulant PL regulate AAA development through complex interactions with clotting factors. Modulation of the delicate balance between bleeding and thrombosis within either the vessel wall or circulation was revealed that can either drive or prevent disease development.
CRIS-Team Scopus Importer:2019-05-02
Keywords: Aneurysm; Angiotensin; Lipid; Lipoxygenase; Phospholipid

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

PHYSICAL FUNCTION IN RA PATIENTS IN REMISSION UNDERGOING TAPERING AND/OR STOPPING OF DMARDS - Stephan, Marlene; Tascilar, Koray; Hagen, Melanie; Haschka, Judith; Reiser, Michaela; Kleyer, Arnd; Manger, Bernhard; Figuereido, Camille; Cobra, Jayme; Tony, Hans-Peter; Finzel, Stephanie; Kleinert, Stefan; et al. (2019)
EVALuna2:211328

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

Plasma cell-free DNA methylation: a liquid biomarker of hepatic fibrosis - Yigit, Buket; Boyle, Marie; Ozler, Oguz; Erden, Nihan; Tutucu, Faik; Hardy, Timothy; Bergmann, Christina; Distler, Jörg; Adali, Gupse; Dayangac, Murat; Mann, Derek A.; Zeybel, Mujdat; et al. (Gut, 2018)
EVALuna2:213249

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

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

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

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

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

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

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

Polyol pathway-generated fructose is indispensable for growth and survival of non-small cell lung cancer - Schwab, Annemarie; Siddiqui, Mohammad Aarif; Ramesh, Vignesh; Gollavilli, Paradesi Naidu; Turtos, Adriana Martinez; Møller, Sarah Søgaard; Pinna, Luisa; Havelund, Jesper F.; Rømer, Anne Mette A.; Ersan, Pelin Gülizar; Parma, Beatrice; Marschall, Sabine; et al. (Cell Death and Differentiation, 2024)
Despite recent treatment advances, non-small cell lung cancer (NSCLC) remains one of the leading causes of cancer-related deaths worldwide, and therefore it necessitates the exploration of new therapy options. One commonly shared feature of malignant cells is their ability to hijack metabolic pathways to confer survival or proliferation. In this study, we highlight the importance of the polyol pathway (PP) in NSCLC metabolism. This pathway is solely responsible for metabolizing glucose to fructose based on the enzymatic activity of aldose reductase (AKR1B1) and sorbitol dehydrogenase (SORD). Via genetic and pharmacological manipulations, we reveal that PP activity is indispensable for NSCLC growth and survival in vitro and in murine xenograft models. Mechanistically, PP deficiency provokes multifactorial deficits, ranging from energetic breakdown and DNA damage, that ultimately trigger the induction of apoptosis. At the molecular level, this process is driven by pro-apoptotic JNK signaling and concomitant upregulation of the transcription factors c-Jun and ATF3. Moreover, we show that fructose, the PP end-product, as well as other non-glycolytic hexoses confer survival to cancer cells and resistance against chemotherapy via sustained NF-κB activity as well as an oxidative switch in metabolism. Given the detrimental consequence of PP gene targeting on growth and survival, we propose PP pathway interference as a viable therapeutic approach against NSCLC.
CRIS-Team Scopus Importer:2024-11-29

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

POS0494 Fear Of Movement Affects Range Of Motion During Repeated Basmi Exercises Assessed By State-Of-The-Art Motion Capture Techniques - Loy, N.; Blazek, V.; Jukic, Elke; Fleischmann, Martha Elisa; Coppers, Birte; Hübner, Julian; Iqbal, M.; Heinrich, Simon; Scheiterer, Eduard; Leyendecker, Sigrid; Greenfield, Julia; Labinski, H.; et al. (Annals of the Rheumatic Diseases, 2024)
Background: Quantification of spinal mobility in chronic axial spondyloarthritis (axSpA) is an important component of disease assessment and is currently assessed using the clinical Bath Ankylosing Spondylitis Metrology Index (BASMI). Functional movement-based outcome measures are dependent on a number of secondary factors and, in particular, the impact of fear of movement on BASMI performance in axSpA patients is currently unknown. Objectives: To investigate the association of range of motion (RoM) for repeated BASMI exercises detected by inertial measurement units (IMU) and optical-measurement system (OMS) motion capture with fear of movement by Tampa Scale of Kinesophobia 17 (TSK) [1)] in axSpA patients. Methods: AxSpa patients (Internal Medicine 3, Universitätsklinikum Erlangen) and healthy controls (HC) were asked to fill out the TSK and BASMI was performed and scored for three repetitions for each task by a trained physician. The BASMI tasks were performed a second time on the same day as the clinical assessment using OMS. Fifty-four retro-reflective markers and 16 IMU devices (myoMOTION by Noraxon, Scottsdale, USA) were placed on defined anatomic sites (Figure 1) and marker motion was detected with 11 infrared cameras (Oqus 7+, Qualisys, Göteborg, Sweden). BASMI values for each task were analysed in distance (cm) or degree of rotation. A correlation matrix was used to assess the relationship between TSK score and BASMI task 5 (lateral neck flexion in degrees) values from the OMS and IMU data, using the Pearson product moment correlation. Exact BASMI values in degrees and clinical BASMI value per group are reported as means ± standard deviation (SD). Results: Fifty participants were included in the study (30 axSpa patients (12/16 male/female, age: 41.9 (SD 12.3), C-reactive protein: 5.2 (13.8) mg/l and visual analog scale (VAS) global: 4.1 (SD 2.7)) and 20 HC (9/11 male/female, age: 28.4 (SD 3.7) and VAS global 0.1 (SD 0.29)). Measurements from two patients were excluded due to failed IMU und OMS data post-processing, resulting in 28 patients for this analysis. Correlation results between the exact BASMI-5 scores (degree of rotation) for each of the three repetitions and the TSK scores are presented in Table 1. AxSpA patients showed a positive, but not significant (p>0.05) correlation between OMS and TSK score, and a positive, significant (p<0.05) correlation between IMU and TSK score data. The correlation remained stable over the three repetitions. For the IMU data, significant correlations with the tendency of higher values over each of the three repetitions for both groups were observed. In contrast, the HC values showed a negative correlation for both the OMS and IMU values with the TSK score. An increase over the three repetitions in the negative correlation can be seen for both measurement systems. Conclusion: Our results suggest positive relationship between fear of movement and cervical movement restriction in axSpa patients. In addition, axSpA patients tended to achieve higher levels of mobility on repetition of exercise than at baseline. This influence of fear of movement on functional outcomes is especially visible in the IMU data for the axSpa patients. In contrast, the relationship between fear of movement and cervical movement tends to be negative for HC, suggesting that in healthy subjects fear of movement assessed over the TSK does not impact the objectively measured cervical mobility. Further analysis will include a wider range of BASMI tasks to identify movements that might be particularly prone to impairments due to fear of movemen

Position statement on genuine physiotherapy research at German university hospitals Positionspapier zur genuinen physiotherapeutischen Forschung an den deutschen Universitätskliniken - Klotz, Susanne G.R.; Bökel, Andrea; Friderichs-Nedohibchenko, Maria; Stickdorn, Isabelle; Vogel, Barbara; Doods, Bernd; Feldmann, Franziska; Ghiazza, Mirko; Giehl, Markus; Hoberg, Annika; Jansen, Lynn; Kohlhofer, Daniel; et al. (GMS German Medical Science, 2024)
In addition to patient care, physiotherapy is increasingly important in research at university hospitals. Genuine physiotherapy research plays a decisive role in this. This position statement describes the opportunities, benefits, framework conditions, challenges, and research priorities of genuine physiotherapy research at German university hospitals.
CRIS-Team Scopus Importer:2024-06-21
Keywords: genuine physiotherapy research; physiotherapy; profession; research; university hospital

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Prevalence of monosodium urate deposits in a population of rheumatoid arthritis patients with hyperuricemia - Petsch, Christina; Araujo, Elizabeth G.; Englbrecht, Matthias; Bayat, Sara; Hueber, Axel; Lell, Michael; Schett, Georg; Manger, Bernhard; Rech, Jürgen; Cavallaro, Alexander Josef (Seminars in Arthritis and Rheumatism, 2015)
To investigate the prevalence of monosodium urate (MSU) crystal deposits, indicative for gout, in a population of rheumatoid arthritis (RA) patients with concomitant hyperuricemia and to analyze the clinical and disease-specific characteristics of RA patients who exhibit MSU crystal deposits.Overall, 100 consecutive patients with the diagnosis of RA and a serum urate level above 6mg/dl underwent dual energy computed tomography (DECT) of both feet and hands to search for MSU crystals in a prospective study between October 2011 and July 2013. Presence and extent of MSU crystal deposits on DECT was assessed by automated volume measurement. Demographic and disease-specific characteristics were recorded and included into two logistic regression models to test for the factors associated with MSU crystal deposits in RA.Hyperuricemic RA patients were mostly male (55%), over 60 years of age (63 ± 11 years), had established disease (8.7 ± 10.5 years) and a mean disease activity score 28 (DAS 28) of 3.2. In total, 20 out of 100 patients displayed MSU crystal deposits in DECT. Interestingly, the majority (70%) of the RA patients positive for MSU crystal deposits were seronegative RA patients. Hence, every third seronegative RA patient had MSU crystal deposits. According to logistic regression model analysis, seronegative status correlated positively with presence of urate deposits (p = 0.019).These data show that a considerable number of RA patients display periarticular MSU crystal deposits. Seronegative patients were shown to be predominantly affected with every third patient being positive for urate deposits.
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Prevention of seronegative rheumatoid arthritis: an entity of its own - Bugatti, Serena; Schett, Georg (The Lancet Rheumatology, 2024)
CRIS-Team Scopus Importer:2024-10-11

Primary anterior cruciate ligament repair-morphological and quantitative assessment by 7-T MRI and clinical outcome after 1.5 years. - Pachowsky, Milena; Söllner, Stefan; Gelse, Kolja; Sambale, Jannik; Nagel, Armin Michael; Schett, Georg; Saake, Marc; Uder, Michael; Roemer, Frank; Heiß, Rafael (European Radiology, 2024)
OBJECTIVES: The purpose of this study was to assess morphological and quantitative changes of the anterior cruciate ligament (ACL) and cartilage after ACL repair. METHODS: 7T MRI of the knee was acquired in 31 patients 1.5 years after ACL repair and in 13 controls. Proton density-weighted images with fat saturation (PD-fs) were acquired to assess ACL width, signal intensity, elongation, and fraying. T2/T2* mapping was performed for assessment of ACL and cartilage. Segmentation of the ACL, femoral, and tibial cartilage was carried out at 12 ROIs. The outcome evaluation consisted of the Lysholm Knee Score and International Knee Documentation Committee (IKDC) subjective score and clinical examination. RESULTS: ACL showed a normal signal intensity in 96.8% and an increased width in 76.5% after repair. Fraying occurred in 22.6% without having an impact on the clinical outcome (Lysholm score: 90.39 ± 9.75, p = 0.76 compared to controls). T2 analysis of the ACL revealed no difference between patients and controls (p = 0.74). Compared to controls, assessment of the femoral and tibial cartilage showed a significant increase of T2* times in all ROIs, except at the posterolateral femur. Patients presented a good outcome in clinical examination with a Lysholm score of 87.19 ± 14.89 and IKDC of 80.23 ± 16.84. CONCLUSION: T2 mapping results suggest that the tissue composition of the ACL after repair is similar to that of a native ACL after surgery, whereas the ACL exhibits an increased width. Fraying of the ACL can occur without having any impact on functional outcomes. T2* analysis revealed early degradation at the cartilage. CLINICAL RELEVANCE STATEMENT: MRI represents a noninvasive diagnostic tool for the morphological and compositional assessment of the anterior cruciate ligament after repair, whereas knowledge about post-surgical alterations is crucial for adequate imaging interpretation. KEY POINTS: • There has been renewed interest in repairing the anterior cruciate ligament with a proximally torn ligament. • T2 times of the anterior cruciate ligament do not differ between anterior cruciate ligament repair patients and controls. • T2 mapping may serve as a surrogate for the evaluation of the anterior cruciate ligament after repair.
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PROFIBROTIC LNCRNA H19X: UNRAVELLING THE EFFECTS ON CHROMATIN REMODELING IN SYSTEMIC SCLEROSIS FIBROBLASTS - Pachera, Elena; Assassi, Shervin; Salazar, Gloria; Frank-Bertoncelj, Mojca; Distler, Jörg; Kania, Gabriela; Distler, Oliver (ANNALS OF THE RHEUMATIC DISEASES, 2019)
CRIS-Team WoS Importer:2019-07-12

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

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

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

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

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

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

Protein kinases G are essential downstream mediators of the antifibrotic effects of sGC stimulators - Matei, Alexandru-Emil; Beyer, Christian; Gyoerfi, Andrea-Hermina; Soare, Alina; Chen, Chih-Wei; Dees, Clara; Bergmann, Christina; Friebe, Andreas; Hofmann, Franz; Distler, Oliver; Schett, Georg; Distler, Jörg; et al. (Annals of the Rheumatic Diseases, 2018)
Stimulators of soluble guanylate cyclase (sGC) are currently investigated in clinical trials for the treatment of fibrosis in systemic sclerosis (SSc). In this study, we aim to investigate the role of protein kinases G (PKG) as downstream mediators of sGC-cyclic guanosine monophosphate (cGMP) in SSc.Mice with combined knockout of PKG1 and 2 were challenged with bleomycin and treated with the sGC stimulator BAY 41-2272. Fibroblasts were treated with BAY 41-2272 and with the PKG inhibitor KT 5823.PKG1 and 2 are upregulated in SSc in a transforming growth factor-?1 (TGF?1)-dependent manner, as an attempt to compensate for the decreased signalling through the sGC-cGMP-PKG pathway. Inhibition or knockout of PKG1 and 2 abrogates the inhibitory effects of sGC stimulation on fibroblast activation in a SMAD-independent, but extracellular signal-regulated kinase (ERK)-dependent manner. In vivo, sGC stimulation fails to prevent bleomycin-induced fibrosis in PKG1 and 2 knockout mice.Our data provide evidence that PKGs are essential mediators of the antifibrotic effects of sGC stimulators through interfering with non-canonical TGF? signalling. TGF?1 promotes its profibrotic effects through inhibition of sGC-cGMP-PKG signalling, sGC stimulation exerts its antifibrotic effects by inhibition of TGF?1-induced ERK phosphorylation.
EVALuna2:13304

Proteomic Approaches to Defining Remission and the Risk of Relapse in Rheumatoid Arthritis - O'Neil, Liam J.; Hu, Pingzhao; Liu, Qian; Islam, Md. Mohaiminul; Spicer, Victor; Rech, Jürgen; Hueber, Axel; Anaparti, Vidyanand; Smolik, Irene; El-Gabalawy, Hani S.; Schett, Georg; Wilkins, John A. (Frontiers in Immunology, 2021)
Objectives: Patients with Rheumatoid Arthritis (RA) are increasingly achieving stable disease remission, yet the mechanisms that govern ongoing clinical disease and subsequent risk of future flare are not well understood. We sought to identify serum proteomic alterations that dictate clinically important features of stable RA, and couple broad-based proteomics with machine learning to predict future flare. Methods: We studied baseline serum samples from a cohort of stable RA patients (RETRO, n = 130) in clinical remission (DAS28<2.6) and quantified 1307 serum proteins using the SOMAscan platform. Unsupervised hierarchical clustering and supervised classification were applied to identify proteomic-driven clusters and model biomarkers that were associated with future disease flare after 12 months of follow-up and RA medication withdrawal. Network analysis was used to define pathways that were enriched in proteomic datasets. Results: We defined 4 proteomic clusters, with one cluster (Cluster 4) displaying a lower mean DAS28 score (p = 0.03), with DAS28 associating with humoral immune responses and complement activation. Clustering did not clearly predict future risk of flare, however an XGboost machine learning algorithm classified patients who relapsed with an AUC (area under the receiver operating characteristic curve) of 0.80 using only baseline serum proteomics. Conclusions: The serum proteome provides a rich dataset to understand stable RA and its clinical heterogeneity. Combining proteomics and machine learning may enable prediction of future RA disease flare in patients with RA who aim to withdrawal therapy.
CRIS-Team Scopus Importer:2021-12-17
Keywords: disease activity; outcomes research; proteomics; rheumatoid arthritis; treatment

Pseudoacrocyanosis: a case for telemedicine in rheumatology - Manger, Bernhard; Manger, Karin (RMD Open, 2022)
Here we describe three patients, two of them medical doctors, who were concerned about striking, sudden-onset bluish discoloration of their hands. After sending electronic images of these changes to befriended rheumatologists, one simple anamnestic question could unveil the surprising cause of their symptoms.
CRIS-Team WoS Importer:2022-09-23

Psoriatic arthritis from a mechanistic perspective - Schett, Georg; Rahman, Proton; Ritchlin, Christopher; Mcinnes, Iain B.; Elewaut, Dirk; Scher, Jose U. (Nature Reviews Rheumatology, 2022)
Psoriatic arthritis (PsA) is part of a group of closely related clinical phenotypes (‘psoriatic disease’) that is defined by shared molecular pathogenesis resulting in excessive, prolonged inflammation in the various tissues affected, such as the skin, the entheses or the joints. Psoriatic disease comprises a set of specific drivers that promote an aberrant immune response and the consequent development of chronic disease that necessitates therapeutic intervention. These drivers include genetic, biomechanical, metabolic and microbial factors that facilitate a robust and continuous mobilization, trafficking and homing of immune cells into the target tissues. The role of genetic variants involved in the immune response, the contribution of mechanical factors triggering an exaggerated inflammatory response (mechanoinflammation), the impact of adipose tissue and altered lipid metabolism and the influence of intestinal dysbiosis in the disease process are discussed. Furthermore, the role of key cytokines, such as IL-23, IL-17 and TNF, in orchestrating the various phases of the inflammatory disease process and as therapeutic targets in PsA is reviewed. Finally, the nature and the mechanisms of inflammatory tissue responses inherent to PsA are summarized.
CRIS-Team Scopus Importer:2022-05-20

PU.1 controls fibroblast polarization and tissue fibrosis - Wohlfahrt, Thomas; Rauber, Simon; Uebe, Steffen; Luber, Markus; Soare, Alina; Ekici, Arif Bülent; Weber, Stefanie; Matei, Alexandru-Emil; Chen, Chih-Wei; Maier, Christiane; Karouzakis, Emmanuel; Kiener, Hans P.; et al. (Nature, 2019)
Fibroblasts are polymorphic cells with pleiotropic roles in organ morphogenesis, tissue homeostasis and immune responses. In fibrotic diseases, fibroblasts synthesize abundant amounts of extracellular matrix, which induces scarring and organ failure. By contrast, a hallmark feature of fibroblasts in arthritis is degradation of the extracellular matrix because of the release of metalloproteinases and degrading enzymes, and subsequent tissue destruction. The mechanisms that drive these functionally opposing pro-fibrotic and pro-inflammatory phenotypes of fibroblasts remain unknown. Here we identify the transcription factor PU.1 as an essential regulator of the pro-fibrotic gene expression program. The interplay between transcriptional and post-transcriptional mechanisms that normally control the expression of PU.1 expression is perturbed in various fibrotic diseases, resulting in the upregulation of PU.1, induction of fibrosis-associated gene sets and a phenotypic switch in extracellular matrix-producing pro-fibrotic fibroblasts. By contrast, pharmacological and genetic inactivation of PU.1 disrupts the fibrotic network and enables reprogramming of fibrotic fibroblasts into resting fibroblasts, leading to regression of fibrosis in several organs.
EVALuna2:35476

PU.1 INHIBITOR DB1976 CONTROLS FIBROBLAST POLARIZATION IN SYSTEMIC SCLEROSISAND LEADS TO REGRESSION OF FIBROSIS IN DIFFERENT MODELS OF ORGAN FIBROSIS - Wohlfahrt, Thomas; Rauber, Simon; Luber, Markus; Soare, Alina; Weber, Stefanie; Matei, Alexandru-Emil; Chen, Chih-Wei; Karouzakis, Emmanuel; Kiener, Hans; Pachera, Elena; Dees, Clara; Kreuter, Alexander; et al. (ANNALS OF THE RHEUMATIC DISEASES, 2019)
CRIS-Team WoS Importer:2019-07-12

Publisher Correction: Revisiting the gut–joint axis: links between gut inflammation and spondyloarthritis (Nature Reviews Rheumatology, (2020), 16, 8, (415-433), 10.1038/s41584-020-0454-9) - Gracey, Eric; Vereecke, Lars; McGovern, Dermot; Fröhling, Mareike; Schett, Georg; Danese, Silvio; De Vos, Martine; Van den Bosch, Filip; Elewaut, Dirk (Nature Reviews Rheumatology, 2020)
An amendment to this paper has been published and can be accessed via a link at the top of the paper.
CRIS-Team Scopus Importer:2020-08-07

Publisher Correction to: Collagen Turnover Biomarkers Associate with Active Psoriatic Arthritis and Decrease with Guselkumab Treatment in a Phase 3 Clinical Trial (DISCOVER-2) (Rheumatology and Therapy, (2022), 10.1007/s40744-022-00444-x) - Schett, Georg; Loza, Matthew J.; Palanichamy, Arumugam; Fitzgerald, Oliver; Ritchlin, Christopher; Bay-Jensen, Anne-Christine; Nielsen, Signe Holm; Gao, Sheng; Hsia, Elizabeth C.; Kollmeier, Alexa P.; Xu, Xie L.; Baribaud, Frederic; et al. (Rheumatology and Therapy, 2022)
The original version of the article is updated. • In the Results section of the Abstract, the text ‘rat- adjusted’ should have read ‘rate adjusted’. • In the Key Summary Points box under the heading ‘What did the study ask?’, the text ‘collage’ should have read ‘collagen’. • In the details below Table 1, the text ‘he mean’ should have read ‘the mean’. • In the Methods section under the heading ‘Statistical Methods’ the text ‘C 50 improvement in ACR criteria’ should have read ‘C 50% improvement in ACR criteria’. • In the Results section under the heading ‘Collagen Biomarkers and Baseline Clinical Features in PsA Patients’ the text ‘PSA’ should have read ‘PsA’. • In Table 2, under the PASI column, the value ‘0.13’ should be in italics ‘0.13’. • In Table 2, the ‘Enthesitis’ column heading should read ‘Enthesitis Score’ with a footnote of: Leeds Enthesitis Index 0–6; the ‘Dactylitis Score’ column heading should have a footnote of: Dactylitis Severity Score 0–60.
CRIS-Team Scopus Importer:2022-07-15

Purinergic signalling in systemic sclerosis - Hoeppner, Jakob; Bruni, Cosimo; Distler, Oliver; Robson, Simon C.; Burmester, Gerd R.; Siegert, Elise; Distler, Jörg (Rheumatology, 2021)
SSc is a chronic autoimmune rheumatic disease that involves numerous organs and presents major management challenges. The histopathologic hallmarks of SSc include vasculopathy, fibrosis and autoimmune phenomena involving both innate and adaptive immune systems. Purinergic signalling is a pathway that may be implicated in the pathophysiology of several of these disease manifestations. Extracellular purines are potent signalling mediators, which have been shown to be dysregulated in SSc. As examples, purines can exacerbate vasculopathy and provoke platelet dysfunction; as well as contributing to immune dysregulation. Elements of purinergic signalling further promote organ and tissue fibrosis in several disease models. Here, we provide an overview of extracellular purine metabolism in purinergic signalling and link disorders of these to the molecular pathology of SSc. We also discuss targeting the purinergic signalling and explore the translational applications for new therapeutic options in SSc.
CRIS-Team WoS Importer:2022-05-13

Quality of a Supporting Mobile App for Rheumatic Patients: Patient-Based Assessment Using the User Version of the Mobile Application Scale (uMARS) - Lambrecht, Antonia; Vuillerme, Nicolas; Raab, Christina; Simon, David; Messner, Eva-Maria; Hagen, Melanie; Bayat, Sara; Kleyer, Arnd; Aubourg, Timothee; Schett, Georg; Hueber, Axel; Knitza, Johannes (Frontiers in Medicine, 2021)
Introduction: Mobile applications promise to improve current health care. However, current mobile app quality ratings are mostly physician-based. The aim of this study was (1) to assess the quality of the self-management app Rheuma Auszeit using the validated uMARS (User Version of the Mobile App Rating Scale) app quality assessment tool and (2) to evaluate the association between uMARS scores and patients' characteristics.
CRIS-Team WoS Importer:2021-08-20

Quantification and impact of secondary osteoarthritis in patients with anti-citrullinated protein antibodies positive rheumatoid arthritis - Figueiredo, Camille P.; Simon, David; Englbrecht, Matthias; Haschka, Judith; Kleyer, Arnd; Bayat, Sara; Hueber, Axel; Pereira, Rosa M. R.; Rech, Juergen; Schett, Georg (Arthritis and Rheumatology, 2016)
To search for evidence of secondary osteoarthritis in patients with rheumatoid arthritis (RA) in a cross-sectional and longitudinal setting and to relate osteophyte formation to functional outcome.Anti-citrullinated protein antibody positive (ACPA+) RA patients underwent high-resolution peripheral quantitative computed tomography (HR-pQCT) of the hand. Cross-sectional and longitudinal measurements were performed. Number and size of osteophytes as well as bone erosions were documented. Relation of osteophytes to bone erosions and to demographic and disease specific data was evaluated by multiple logistic regression models.202 ACPA+ RA patients were enrolled in the cross-sectional and 77 subjects in the longitudinal analysis (interval: 1.5 years). The mean number and size of osteophytes was 1.3±2.3 and 9.4±23.9 mm³ respectively. Osteophyte number was significantly (p<0.001) correlated to erosion number and osteophyte size to erosion size (p<0.001). Moreover, presence and size of osteophytes were related to age (p<0.001), disease duration (p<0.001) and to function as measured by the health assessment questionnaire (HAQ). Multivariate regression analyses showed an independent association between osteophytes and erosions. In the longitudinal analysis the mean number (p=0.033) and size (p<0.001) of osteophytes significantly increased in RA patients during their disease course. Conclusion Age, disease duration and bone erosions are associated with osteophytes indicating development of secondary osteoarthritis in patients with RA. This article is protected by copyright. All rights reserved.
EVALuna2:13275

QUANTIFICATION AND IMPACT OF SECONDARY OSTEOARTHRITIS USING HR-PQCT IN ANTI-CITRULLINATED PROTEIN ANTIBODY RHEUMATOID ARTHRITIS PATIENTS - Figueiredo, C.; Simon, David; Englbrecht, Matthias; Haschka, J.; Kleyer, Arnd; Bayat, Sara; Hueber, Axel; Pereira, R. M.; Rech, Jürgen; Schett, Georg (2017)
EVALuna2:13465

Quantification of 68Ga-FAPI-04 in systemic sclerosis-associated interstitial lung disease – Authors' reply - Distler, Jörg; Bergmann, Christina; Kuwert, Torsten; Schmidkonz, Christian (The Lancet Rheumatology, 2021)
CRIS-Team Scopus Importer:2021-07-16

Quantification of Ga-68-FAPI-04 in systemic sclerosis-associated interstitial lung disease Reply - Distler, Jörg; Bergmann, Christina; Kuwert, Torsten; Schmidkonz, Christian (The Lancet Rheumatology, 2021)
CRIS-Team WoS Importer:2021-07-16

Quantification of hand muscle volume and composition in patients with rheumatoid arthritis, psoriatic arthritis and psoriasis - Friedberger, Andreas; Figueiredo, Camille; Grimm, Alexandra; Oliveira, Isabelle; Bäuerle, Tobias; Rech, Jürgen; Kleyer, Arnd; Simon, David; Uder, Michael; Schett, Georg; Engelke, Klaus (BMC Musculoskeletal Disorders, 2020)
Background Psoriasis (Pso), psoriatic arthritis (PsA) and rheumatoid arthritis (RA) are inflammatory diseases. PsA and RA are characterized by bone and muscle loss. In RA, bone loss has been extensively characterized, but muscle loss has, to the best of our knowledge, not been quantified to date. Methods A random forest based segmentation method was used to analyze hand muscle volume in T1 weighted MRI images of 330 patients suffering from Pso, PsA or RA. In addition, fat volume was quantified using MRI Dixon sequences in a small subset (n = 32). Results Males had a higher relative muscle volume than females (14% for Pso, 11% for PsA, n.s. for RA). Between 40 and 80 years male Pso patients lost 13%, male PsA patients 16%, male RA patients 23% and female PsA patients 30% of their relative muscle volume. After adjustment for age, relative muscle volume in males RA patients was 16% and in female RA patients 9% lower than in Pso patients. In male RA patients relative muscle volume was 13% lower in than in male PsA patients. There was no difference in females. A significant negative correlation (R-2 = 0.18) between relative intramuscular fat content relative hand muscle volume was observed. Conclusion These preliminary data showed that relative hand muscle volume significantly decreased with age in male and female patients with Pso, PsA and RA patients. Independent of age, relative hand muscle volume was significantly smaller in patients with RA compared to the patients with Pso and the difference was twice as large in males compared to females. Also in male but not in female RA patients relative hand muscle volume was significantly smaller than in PsA patients.
CRIS-Team WoS Importer:2020-04-14

Quantification of pre-existing radiographic damage and its relationship with joint activity and long-term clinical outcomes with secukinumab therapy in patients with psoriatic arthritis - Mease, Philip; Van Der Heijde, Desiree; Kirkham, Bruce; Schett, Georg; Orbai, Ana-Maria; Ritchlin, Christopher; Merola, Joseph F.; Pricop, Luminita; James, David A.; Zhu, Xuan; Ligozio, Gregory (Arthritis Research & Therapy, 2022)
Background: Psoriatic arthritis (PsA) patient data from two phase 3 secukinumab trials (FUTURE 1, 5) were analysed to quantify the prevalence and extent of pre-existing radiographic damage (RD) at baseline; investigate the association of RD with swollen/tender joint counts (SJC/TJC) at baseline; and investigate the extent to which RD at baseline correlated with response to secukinumab. Methods: Pooled data (N = 1554) provided baseline radiographic bone erosion and joint space narrowing (JSN) scores at pre-specified locations per the van der Heijde-modified total Sharp score (vdH-mTSS) for PsA and swollen and tender joint scores in the same joints at multiple visits. Overall patient RD and individual joints RD bone erosion and JSN scores were assessed. The association between joint activity (tenderness, swelling) and vdH-mTSS was assessed at the overall patient-level and individual joint tender, swollen scores (yes/no) and RD joint JSN and bone erosion scores at the individual joint-level. Treatment response was assessed using SJC/TJC at weeks 16 and 52 and the proportion of patients achieving minimal disease activity (MDA) over all assessments within 1 year from FUTURE 5 alone. Results: A substantial prevalence of pre-existing RD with higher prevalence of erosion than JSN was observed (86% and 60% of patients had positive erosion and JSN scores, respectively); higher RD prevalence was associated with longer time since PsA diagnosis. Joint activity was weakly associated with RD at baseline at the patient-level (Pearson's coefficients: range 0.12-0.18), but strongly associated at the individual joint-level, with a higher probability of tender/swollen joints to associate with higher JSN/erosion scores: all 42 analysed joints showed statistical significance at the 0.05 level (unadjusted) for the relationship between joint tenderness (yes/no) and its JSN score, all but one for tenderness and bone erosion scores, and all but 2 for swollen and JSN scores and for swollen and bone erosion score. Secukinumab (150/300 mg), reduced TJC and SJC across all values of baseline erosion and JSN scores at weeks 16 and 52. Patients with higher levels of RD were less likely to achieve zero tender/zero swollen joint status and had lower chance of achieving MDA. Conclusions: PsA patients showed substantial prevalence of RD at baseline that correlated with time since diagnosis, but patient's individual joint activity was strongly associated with pre-existing RD at those joints. Patients with the highest RD at baseline had a reduced likelihood of achieving zero joint count status.
CRIS-Team WoS Importer:2023-02-03

Quantitative and Qualitative Changes of Bone in Psoriasis and Psoriatic Arthritis Patients - Kocijan, Roland; Englbrecht, Matthias; Haschka, Judith; Simon, David; Kleyer, Arnd; Finzel, Stephanie; Kraus, Sebastian; Resch, Heinrich; Muschitz, Christian; Engelke, Klaus; Sticherling, Michael; Rech, Jürgen; et al. (Journal of Bone and Mineral Research, 2015)
Psoriatic arthritis (PsA) is a chronic inflammatory disease characterized by periarticular bone loss and new bone formation. Current data regarding systemic bone loss and bone mineral density (BMD) in PsA are conflicting. The aim of this study was to evaluate bone microstructure and volumetric BMD (vBMD) in patients with PsA and psoriasis. We performed HR-pQCT scans at the ultradistal and periarticular radius in 50 PsA patients, 30 psoriasis patients, and 70 healthy, age- and sex-related controls assessing trabecular bone volume (BV/TV), trabecular number (Tb.N), inhomogeneity of the trabecular network, cortical thickness (Ct.Th), and cortical porosity (Ct.Po), as well as vBMD. Trabecular BMD (Tb.BMD, p = 0.021, 12.0%), BV/TV (p = 0.020, -11.9%), and Tb.N (p = 0.035, 7.1%) were significantly decreased at the ultradistal radius and the periarticular radius in PsA patients compared to controls. In contrast, bone architecture of the ultradistal radius and periarticular radius was similar in patients with psoriasis and healthy controls. Duration of skin disease was associated with low BV/TV and Tb.N in patients with PsA. These data suggest that trabecular BMD and bone microstructure are decreased in PsA patients. The observation that duration of skin disease determines bone loss in PsA supports the concept of subclinical musculoskeletal disease in psoriasis patients. © 2015 American Society for Bone and Mineral Research.
EVALuna2:10104

QUANTITATIVE ASSESSMENT AND ANALYSIS OF HAND MUSCLE VOLUME - Friedberger, Andreas; Figueiredo, C.; Museyko, Oleg; Grimm, Alexandra; D'Oliveira, I.; Bäuerle, Tobias; Rech, Jürgen; Chaudry, Oliver; Uder, Michael; Schett, Georg; Engelke, Klaus (2017)
EVALuna2:14726

Racial differences in SSc disease presentation: a European scleroderma trials and research group (EUSTAR) study - Jaeger, V. K.; Siegert, E.; Hachulla, E.; Airo, P.; Valentini, G.; Matucci-Cerinic, M.; Scorza, R.; Distler, O.; Cozzi, F.; Carreira, P.; Allanore, Y.; Mueller-Ladner, U.; et al. (2018)
EVALuna2:34975

Racial differences in systemic sclerosis disease presentation: a European Scleroderma Trials and Research group study - Jaeger, Veronika K.; Tikly, Mohammed; Xu, Dong; Siegert, Elise; Hachulla, Eric; Airo, Paolo; Valentini, Gabriele; Cerinic, Marco Matucci; Distler, Oliver; Cozzi, Franco; Carreira, Patricia; Allanore, Yannick; et al. (Rheumatology, 2020)
Objectives. Racial factors play a significant role in SSc. We evaluated differences in SSc presentations between white patients (WP), Asian patients (AP) and black patients (BP) and analysed the effects of geographical locations.
CRIS-Team WoS Importer:2020-07-24

RANKL-Induced Btn2a2 – A T Cell Immunomodulatory Molecule – During Osteoclast Differentiation Fine-Tunes Bone Resorption - Frech, Michael; Schuster, Gregor; Andes, Fabian T.; Schett, Georg; Zaiss, Mario; Sarter, Kerstin (Frontiers in Endocrinology, 2021)
Butyrophilins, which are members of the extended B7 family of immunoregulators structurally related to the B7 family, have diverse functions on immune cells as co-stimulatory and co-inhibitory molecules. Despite recent advances in the understanding on butyrophilins’ role on adaptive immune cells during infectious or autoimmune diseases, nothing is known about their role in bone homeostasis. Here, we analyzed the role of one specific butyrophilin, namely Btn2a2, as we have recently shown that Btn2a2 is expressed on the monocyte/macrophage lineage that also gives rise to bone degrading osteoclasts. We found that expression of Btn2a2 on monocytes and pre-osteoclasts is upregulated by the receptor activator of nuclear factor κ-B ligand (RANKL), an essential protein required for osteoclast formation. Interestingly, in Btn2a2-deficient osteoclasts, typical osteoclast marker genes (Nfatc1, cathepsin K, TRAP, and RANK) were downregulated following RANKL stimulation. In vitro osteoclast assays resulted in decreased TRAP positive osteoclast numbers in Btn2a2-deficient cells. However, Btn2a2-deficient osteoclasts revealed abnormal fusion processes shown by their increased size. In vivo steady state µCT and histological analysis of bone architecture in complete Btn2a2-deficient mice showed differences in bone parameters further highlighting the fine-tuning effect of BTN2a2. Moreover, in rheumatoid arthritis patients and experimental arthritis, we detected significantly decreased serum levels of the secreted soluble Btn2a2 protein. Taken together, we identified the involvement of the immunomodulatory molecule Btn2a2 in osteoclast differentiation with potential future implications in basic and translational osteoimmunology.
CRIS-Team Scopus Importer:2021-08-27
Keywords: bone homeostasis; bone resorption; osteoclast (OC); RANKL (receptor activator for nuclear factor k B ligand); T cell

Rapid single-cell physical phenotyping of mechanically dissociated tissue biopsies - Soteriou, Despina; Kubankova, Marketa; Schweitzer, Christine; Lopez Posadas, Rocío; Pradhan, Rashmita; Thoma, Oana-Maria; Györfi, Andrea-Hermina; Matei, Alexandru-Emil; Waldner, Maximilian; Distler, Jörg; Scheuermann, Stefan; Langejuergen, Jens; et al. (Nature Biomedical Engineering, 2023)
A method for the sequential assessment of the physical phenotypes of suspended cells singularized from tissue biopsies by mechanical dissociation allows for rapid diagnoses.
CRIS-Team WoS Importer:2023-05-05

Rare Loss-of-Function Mutation in SERPINA3 in Generalized Pustular Psoriasis - Frey, Silke; Sticht, Heinrich; Wilsmann-Theis, Dagmar; Gerschütz, Anne; Wolf, Katharina; Löhr, Sabine; Haskamp, Stefan; Frey, Benjamin; Hahn, Madelaine; Ekici, Arif Bülent; Uebe, Steffen; Thiel, Christian; et al. (Journal of Investigative Dermatology, 2020)
CRIS-Team Scopus Importer:2020-03-06

Rare meets rarer: anti-synthetase syndrome in a patient with facio-scapulo-humeral muscular dystrophy - Valor-Mendez, Larissa; Manger, Bernhard; Winterholler, Martin; Schett, Georg; Tuerk, Mattias; Knitza, Johannes (Rheumatology, 2022)
CRIS-Team WoS Importer:2022-07-08

Rare rheumatic diseases - Manger, Bernhard; Swoboda, Bernd (Zeitschrift für Rheumatologie, 2016)
EVALuna2:10906

Rationale, current state and opportunities in combining biologic disease modifying antirheumatic drugs in rheumatoid and psoriatic arthritis - Mutlu, Melek Yalcin; Tascilar, Koray; Schett, Georg (Joint Bone Spine, 2023)
The advent of biologic disease modifying antirheumatic drugs (bDMARDs) has considerably improved patient outcomes in inflammatory arthritis. However, not all patients reach the state of remission, as disease can be resistant even to single cytokine inhibition by bDMARDs. Simultaneous or sequential inhibition of multiple cytokines may be considered in situations where disease control is not adequate under singular inhibition of cytokines. Although there have been some disappointing experiences in the past with combination of bDMARDs, the ongoing improvement of our understanding about inflammatory pathways and the overall better safety understanding of bDMARDs seem to make new biologic treatment combinations possible. This review covers the rationale and current evidence for bDMARDs combination in inflammatory arthritis.
CRIS-Team Scopus Importer:2023-06-09
Keywords: Biologicals; Combination therapy; Cytokine blockade; Psoriatic arthritis; Rheumatoid arthritis

Rationale for the evaluation of nintedanib as a treatment for systemic sclerosis–associated interstitial lung disease - Wollin, Lutz; Distler, Jörg; Denton, Christopher P.; Gahlemann, Martina (Journal of Scleroderma and Related Disorders, 2019)
Interstitial lung disease is a common manifestation of systemic sclerosis. Systemic sclerosis–associated interstitial lung disease is characterized by progressive pulmonary fibrosis and a reduction in pulmonary function. Effective treatments for systemic sclerosis–associated interstitial lung disease are lacking. In addition to clinical similarities, systemic sclerosis–associated interstitial lung disease shows similarities to idiopathic pulmonary fibrosis in the pathophysiology of the underlying fibrotic processes. Idiopathic pulmonary fibrosis and systemic sclerosis–associated interstitial lung disease culminate in a self-sustaining pathway of pulmonary fibrosis in which fibroblasts are activated, myofibroblasts accumulate, and the excessive extracellular matrix is deposited. Nintedanib is a tyrosine kinase inhibitor that has been approved for the treatment of idiopathic pulmonary fibrosis. In patients with idiopathic pulmonary fibrosis, nintedanib slows disease progression by decreasing the rate of lung function decline. In this review, we summarize the antifibrotic, anti-inflammatory, and attenuated vascular remodeling effects of nintedanib demonstrated in in vitro studies and in animal models of aspects of systemic sclerosis. Nintedanib interferes at multiple critical steps in the pathobiology of systemic sclerosis–associated interstitial lung disease, providing a convincing rationale for its investigation as a potential therapy. Finally, we summarize the design of the randomized placebo-controlled SENSCIS ® trial that is evaluating the efficacy and safety of nintedanib in patients with systemic sclerosis–associated interstitial lung disease.
CRIS-Team Scopus Importer:2019-05-03
Keywords: Fibroblasts; fibrosis; scleroderma; systemic sclerosis–associated interstitial lung disease; tyrosine kinase inhibitor

Rationnel, état des lieux et perspectives des combinaisons de traitements de fond biologiques dans la prise en charge de la polyarthrite rhumatoïde et du rhumatisme psoriasique - Mutlu, Melek Yalcin; Tascilar, Koray; Schett, Georg (Revue du Rhumatisme (Edition Francaise), 2023)
The advent of biologic disease modifying anti-rheumatic drugs (bDMARDs) has considerably improved patient outcomes in inflammatory arthritis. However, not all patients reach the state of remission as disease can be resistant even to single cytokine inhibition by bDMARDs. Simultaneous or sequential inhibition of multiple cytokines may be considered in situations, where disease control is not adequate under singular inhibition of cytokines. Although there have been some disappointing experiences in the past with combination of bDMARDs, the ongoing improvement of our understanding about inflammatory pathways and the overall better safety understanding of bDMARDs seem to make new biologic treatment combinations possible. This review covers the rationale and current evidence for bDMARDs combination in inflammatory arthritis.
CRIS-Team Scopus Importer:2023-09-22
Keywords: Agents biologiques; Biologicals; Combination therapy; Cytokine blockade; Inhibition des cytokines; Polyarthrite rhumatoïde; Psoriatic arthritis; Rheumatoid arthritis; Rhumatisme psoriasique; Traitements combinés

Reactive arthritis and cutaneous vasculitis after SARS-CoV-2 infection - Schenker, Hannah; Hagen, Melanie; Simon, David; Schett, Georg; Manger, Bernhard (Rheumatology, 2021)
CRIS-Team Scopus Importer:2021-02-05

Reactive oxygen species deficiency induces autoimmunity with type 1 interferon signature - Kelkka, Tiina; Kienhoefer, Deborah; Hoffmann, Markus; Linja, Marjo; Wing, Kajsa; Sareila, Outi; Hultqvist, Malin; Laajala, Essi; Chen, Zhi; Vasconcelos, Julia; Neves, Esmeralda; Guedes, Margarida; et al. (Antioxidants & Redox Signaling, 2014)
Abstract Aims: Chronic granulomatous disease (CGD) is a primary immunodeficiency caused by mutations in the phagocyte reactive oxygen species (ROS)-producing NOX2 enzyme complex and characterized by recurrent infections associated with hyperinflammatory and autoimmune manifestations. A translational, comparative analysis of CGD patients and the corresponding ROS-deficient Ncf1(m1J) mutated mouse model was performed to reveal the molecular pathways operating in NOX2 complex deficient inflammation.A prominent type I interferon (IFN) response signature that was accompanied by elevated autoantibody levels was identified in both mice and humans lacking functional NOX2 complex. To further underline the systemic lupus erythematosus (SLE)-related autoimmune process, we show that naïve Ncf1(m1J) mutated mice, similar to SLE patients, suffer from inflammatory kidney disease with IgG and C3 deposits in the glomeruli. Expression analysis of germ-free Ncf1(m1J) mutated mice reproduced the type I IFN signature, enabling us to conclude that the upregulated signaling pathway is of endogenous origin.Our findings link the previously unexplained connection between ROS deficiency and increased susceptibility to autoimmunity by the discovery that activation of IFN signaling is a major pathway downstream of a deficient NOX2 complex in both mice and humans.We conclude that the lack of phagocyte-derived oxidative burst is associated with spontaneous autoimmunity and linked with type I IFN signature in both mice and humans. Antioxid. Redox Signal. 21, 2231-2245.
EVALuna2:13008

REAL-WORLD EFFECTIVENESS AND PERCEIVED USEFULNESS OF SYMPTOM CHECKERS IN RHEUMATOLOGY: INTERIM REPORT FROM THE PROSPECTIVE MULTICENTER BETTER STUDY - Knitza, Johannes; Mohn, J.; Bergmann, C.; Kampylafka, E.; Hagen, Melanie; Bohr, D.; Araujo, E.; Englbrecht, M.; Simon, David; Kleyer, Arnd; Meinderink, Timo; Vorbruggen, W.; et al. (ANNALS OF THE RHEUMATIC DISEASES, 2020)
CRIS-Team WoS Importer:2020-08-21

Real-World-Evidence of Digital Health Applications (DiGAs) in Rheumatology: Insights from the DiGAReal Registry - Albrecht, Alexander; Taubmann, Jule; Minopoulou, Ioanna; Hatscher, Lukas; Kleinert, Stefan; Mühlensiepen, Felix; Welcker, Martin; Leipe, Jan; Schulz, Nils; Klemm, Philipp; Hueber, Axel; Schett, Georg; et al. (Rheumatology and Therapy, 2025)
Introduction: Prescribable digital health applications (DiGAs) present scalable solutions to improve patient self-management in rheumatology, however real-world evidence is scarce. Therefore, we aimed to assess the effectiveness, usage, and usability of DiGAs prescribed by rheumatologists, as well as patient satisfaction. Methods: The DiGAReal registry includes adult patients with rheumatic conditions who received a DiGA prescription. Data at baseline (T0) and the 3-month follow-up (T1) were collected through electronic questionnaires. Study outcomes included DiGA-specific outcome assessments as well as generic outcome assessments, including the Patient Global Impression of Change (PGIC), Patient Activation Measure (PAM®), and the German Telehealth Usability and Utility Short Questionnaire (TUUSQ). Changes between T0 and T1 were analyzed using descriptive statistics and paired tests. Results: A total of 191 patients were included between June 2022 and April 2023. Of these, 127 completed the 3-month follow-up, and 114 reported using the prescribed DiGA, with 66% reporting weekly use and 15% completing the full DiGA program. The most commonly prescribed DiGAs targeted pain management (53%). Symptom improvement was reported by 51% of patients using a DiGA, with significant reductions in exhaustion levels (p = 0.03). Significant DiGA-specific improvements were observed for DiGAs addressing back pain (p = 0.05) and insomnia (p = 0.006). However, no overall significant changes were detected in patient activation, health literacy, pain, overall health, or disease activity. Back pain and weight management DiGAs were the most effective, frequently used, and best-rated DiGAs, with symptom improvements reported by 50% to 82% of patients. Conclusion: The findings suggest that DiGAs can improve symptom management in rheumatic patients, especially for conditions like back pain and weight control. Further real-world evidence is needed and may support value-based digital health efforts and reimbursement frameworks.
CRIS-Team Scopus Importer:2025-02-17
Keywords: Digital health applications; Digital therapeutics; Patient self-management; Real-world evidence; Rheumatology

Real-world usage of digital health applications (DiGA) in rheumatology: results from a German patient survey. - Labinsky, Hannah; Gupta, Latika; Raimondo, Maria Gabriella; Schett, Georg; Knitza, Johannes (Rheumatology International, 2023)
Mobile health applications and digital therapeutics (DTx) aim to improve current patient care. Real-world data on DTx are, however, scarce. The aim of this study was to evaluate the adherence, acceptance, and efficacy of DTx in a clinical routine rheumatology setting. We conducted a prospective observational cohort study assessing the use, adherence, acceptance, and efficacy of the DTx DiGA (Digitale Gesundheitsanwendungen) by survey over 12 weeks. Patients included had to have a rheumatic disease and had been prescribed a DiGA. Acceptance was assessed using the Net promoter score (NPS). 48 patients were prescribed DiGA. Of these, 39/48 (81%) completed the follow-up survey. 21/39 (54%) patients downloaded the DTx and 20/39 (51%) used the DTx at least once. 9/39 (23%) of patients stopped quickly afterward and 5/39 (13%) reported having completed the whole DTx program. Lack of time and commitment were reported as the main reasons for non-use. Overall acceptance of DiGA was high (Net promoter score (NPS) mean (SD) 7.8/10 (2.3)). While the majority of patients (60%) reported no improvement, one subgroup of patients (7/20, 35%) who regularly used an exercise-based DTx for back pain reported symptom improvement. Acceptance of DTx in patients with rheumatic diseases is high, however onboarding to DTx use and adherence to DTx is still challenging in patients with rheumatic diseases. In a subgroup of patients with back pain, however, the use of an exercise-based DTx led to symptom improvement.
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Receptor Tyrosine Kinase Inhibitor Nintedanib as Treatment Option in Bronchiolitis Obliterans after Airway Transplantation - Heim, Christian; Mauer, J.; Kuckhahn, A.; Distler, Jörg; Spriewald, B.; Ramsperger-Gleixner, Martina; Weyand, Michael; Ensminger, S. M. (JOURNAL OF HEART AND LUNG TRANSPLANTATION, 2019)
CRIS-Team WoS Importer:2019-04-04

Recombinant Adenosine Deaminase Ameliorates Inflammation, Vascular Disease, and Fibrosis in Preclinical Models of Systemic Sclerosis - Zhang, Yun; Zhu, Honglin; Layritz, Florian; Luo, Hui; Wohlfahrt, Thomas; Chen, Chih-Wei; Soare, Alina; Bergmann, Christina; Ramming, Andreas; Groeber, Florian; Reuter, Christian; Fornasini, Gianfranco; et al. (Arthritis and Rheumatology, 2020)
Objective: Systemic sclerosis (SSc) is characterized by fibrosis, vascular disease, and inflammation. Adenosine signaling plays a central role in fibroblast activation. We undertook this study to evaluate the therapeutic effects of adenosine depletion with PEGylated adenosine deaminase (PEG-ADA) in preclinical models of SSc. Methods: The effects of PEG-ADA on inflammation, vascular remodeling, and tissue fibrosis were analyzed in Fra-2 mice and in a B10.D2→BALB/c (H-2d) model of sclerodermatous chronic graft-versus-host disease (GVHD). The effects of PEG-ADA were confirmed in vitro in a human full-thickness skin model. Results: PEG-ADA effectively inhibited myofibroblast differentiation and reduced pulmonary fibrosis by 34.3% (with decreased collagen expression) (P = 0.0079; n = 6), dermal fibrosis by 51.8% (P = 0.0006; n = 6), and intestinal fibrosis by 17.7% (P = 0.0228; n = 6) in Fra-2 mice. Antifibrotic effects of PEG-ADA were also demonstrated in sclerodermatous chronic GVHD (reduced by 38.4%) (P = 0.0063; n = 8), and in a human full-thickness skin model. PEG-ADA treatment decreased inflammation and corrected the M2/Th2/group 2 innate lymphoid cell 2 bias. Moreover, PEG-ADA inhibited proliferation of pulmonary vascular smooth muscle cells (reduced by 40.5%) (P < 0.0001; n = 6), and prevented thickening of the vessel walls (reduced by 39.6%) (P = 0.0028; n = 6) and occlusions of pulmonary arteries (reduced by 63.9%) (P = 0.0147; n = 6). Treatment with PEG-ADA inhibited apoptosis of microvascular endothelial cells (reduced by 65.4%) (P = 0.0001; n = 6) and blunted the capillary rarefication (reduced by 32.5%) (P = 0.0199; n = 6). RNA sequencing demonstrated that treatment with PEG-ADA normalized multiple pathways related to fibrosis, vasculopathy, and inflammation in Fra-2 mice. Conclusion: Treatment with PEG-ADA ameliorates the 3 cardinal features of SSc in pharmacologically relevant and well-tolerated doses. These findings may have direct translational implications, as PEG-ADA has already been approved by the Food and Drug Administration for the treatment of patients with ADA-deficient severe combined immunodeficiency disease.
CRIS-Team Scopus Importer:2020-07-10

Reconstruction of the miR-506-Quaking axis in Idiopathic Pulmonary Fibrosis using integrative multi-source bioinformatics - Stojanović, Stevan D.; Fuchs, Maximilian; Liang, Chunguang; Schmidt, Kevin; Xiao, Ke; Just, Annette; Pfanne, Angelika; Pich, Andreas; Warnecke, Gregor; Braubach, Peter; Petzold, Christina; Jonigk, Danny; et al. (Scientific Reports, 2021)
The family of RNA-binding proteins (RBP) functions as a crucial regulator of multiple biological processes and diseases. However, RBP function in the clinical setting of idiopathic pulmonary fibrosis (IPF) is still unknown. We developed a practical in silico screening approach for the characterization of RBPs using multi-sources data information and comparative molecular network bioinformatics followed by wet-lab validation studies. Data mining of bulk RNA-Sequencing data of tissues of patients with IPF identified Quaking (QKI) as a significant downregulated RBP. Cell-type specific expression was confirmed by single-cell RNA-Sequencing analysis of IPF patient data. We systematically analyzed the molecular interaction network around QKI and its functional interplay with microRNAs (miRs) in human lung fibroblasts and discovered a novel regulatory miR-506-QKI axis contributing to the pathogenesis of IPF. The in silico results were validated by in-house experiments applying model systems of miR and lung biology. This study supports an understanding of the intrinsic molecular mechanisms of IPF regulated by the miR-506-QKI axis. Initially applied to human lung disease, the herein presented integrative in silico data mining approach can be adapted to other disease entities, underlining its practical relevance in RBP research.
CRIS-Team Scopus Importer:2021-06-25

Redox modulation of HMGB1-related signaling - Janko, Christina; Filipovic, Milos; Munoz Becerra, Luis; Schorn, Christine; Schett, Georg; Ivanovic-Burmazovic, Ivana; Herrmann, Martin (Antioxidants & Redox Signaling, 2014)
Significance: In the cells' nuclei, high-mobility group box protein 1 (HMGB1) is a nonhistone chromatin-binding protein involved in the regulation of transcription. Extracellularly, HMGB1 acts as a danger molecule with properties of a proinflammatory cytokine. It can be actively secreted from myeloid cells or passively leak from any type of injured, necrotic cell. Increased serum levels of active HMGB1 are often found in pathogenic inflammatory conditions and correlate with worse prognoses in cancer, sepsis, and autoimmunity. By damaging cells, superoxide and peroxynitrite promote leakage of HMGB1. Recent Advances: The activity of HMGB1 strongly depends on its redox state: Inflammatory-active HMGB1 requires an intramolecular disulfide bond (Cys23 and Cys45) and a reduced Cys106. Oxidation of the latter blocks its stimulatory activity and promotes immune tolerance. Critical Issues: Reactive oxygen and nitrogen species create an oxidative environment and can be detoxified by superoxide dismutase (SOD), catalase, and peroxidases. Modifications of the oxidative environment influence HMGB1 activity. Future Directions: In this review, we hypothesize that manipulations of an oxidative environment by SOD mimics or by hydrogen sulfide are prone to decrease tissue damage. Both the concomitant decreased HMGB1 release and its redox chemical modifications ameliorate inflammation and tissue damage. Antioxid. Redox Signal. 20, 1075-1085. © Mary Ann Liebert, Inc.

Reduced Decline in Forced Vital Capacity in Patients with Progressive Fibrosing Autoimmune Disease-Related Interstitial Lung Diseases (ILDs) Treated with Nintedanib - Matteson, Eric; Distler, Oliver; Distler, Jörg; Kuwana, Masataka; Pope, Janet; Seibold, James; James, Alexandra; Schlenker-Herceg, Rozsa; Rohr, Klaus; Flaherty, Kevin (ARTHRITIS & RHEUMATOLOGY, 2020)
CRIS-Team WoS Importer:2021-01-15

Reduced Fluorescence versus Forward Scatter Time-of-Flight and Increased Peak versus Integral Fluorescence Ratios Indicate Receptor Clustering in Flow Cytometry - Fuernrohr, Barbara G.; Stein, Merle; Rhodes, Benjamin; Chana, Prabhjoat S.; Schett, Georg; Vyse, Timothy J.; Herrmann, Martin; Mielenz, Dirk (Journal of Immunology, 2015)
Clustering of surface receptors is often required to initiate signal transduction, receptor internalization, and cellular activation. To study the kinetics of clustering, we developed an economic high-throughput method using flow cytometry. The quantification of receptor clustering by flow cytometry is based on the following two observations: first, the fluorescence signal length (FL time-of-flight [ToF]) decreases relative to the forward scatter signal length (FSc-ToF), and second, the peak FL (FL-peak) increases relative to the integral FL (FL-integral) upon clustering of FL-labeled surface receptors. Receptor macroclustering can therefore be quantified using the ratios FL-ToF/FSc-ToF (method ToF) or FL-peak/FL-integral (method Peak). We have used these methods to analyze clustering of two immune receptors known to undergo different conformational and oligomeric states: the BCR and the complement receptor 3 (CR3), on murine splenocytes, purified B cells, and human neutrophils. Engagement of both the BCR and CR3, on immortalized as well as primary murine B cells and human neutrophil, respectively, resulted in decreased FL-ToF/FSc-ToF and increased FL-peak/FL-integral ratios. Manipulation of the actin-myosin cytoskeleton altered BCR clustering which could be measured using the established parameters. To confirm clustering of CR3 on neutrophils, we applied imaging flow cytometry. Because receptor engagement is as a biological process dependent on cell viability, energy metabolism, and temperature, receptor clustering can only be quantified by gating on viable cells under physiological conditions. In summary, with this novel method, receptor clustering on nonadherent cells can easily be monitored by high-throughput conventional flow cytometry.
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REDUCED JOINT SYNOVITIS ASSESSMENT VERSUS THE GLOBAL EULAR OMERACT SYNOVITIS SCORE (GLOESS) TO PREDICT THE RESPONSE TO SECUKINUMAB IN PATIENTS WITH ACTIVE PSORIATIC ARTHRITIS AND INADEQUATE RESPONSE TO CONVENTIONAL DISEASE-MODIFYING ANTI-RHEUMATIC DRUGS: EXPLORATORY RESULTS FROM THE ULTIMATE TRIAL - D'Agostino, M. A.; Boers, M.; Schett, Georg; Conaghan, P. G.; Naredo, E.; Mandl, P.; Carron, P.; Backhaus, M.; Lopez-Rodriguez, A.; Hanova, P.; Goyanka, P.; Sahoo, B. G.; et al. (ANNALS OF THE RHEUMATIC DISEASES, 2022)
CRIS-Team WoS Importer:2022-11-04

Reduced Muscle Strength Is Associated With Insulin Resistance in Type 2 Diabetes Patients With Osteoarthritis - Zaharia, Oana Patricia; Pesta, Dominik Hans; Bobrov, Pavel; Kupriyanova, Yuliya; Herder, Christian; Karusheva, Yanislava; Bódis, Kálmán; Bönhof, Gidon Josia; Knitza, Johannes; Simon, David; Kleyer, Arnd; Hwang, Jong Hee; et al. (Journal of Clinical Endocrinology and Metabolism, 2021)
CONTEXT: Type 2 diabetes is associated with a greater risk for musculoskeletal disorders, yet its impact on joint function remains unclear. OBJECTIVE: We hypothesized that patients with type 2 diabetes and osteoarthritis would exhibit musculoskeletal impairment, which would associate with insulin resistance and distinct microRNA profiles. METHODS: Participants of the German Diabetes Study with type 2 diabetes (T2D, n = 39) or normal glucose tolerance (CON, n = 27), both with (+OA) or without osteoarthritis (-OA) underwent intravenous glucose tolerance and hyperinsulinemic-euglycemic clamp tests. Musculoskeletal function was assessed by isometric knee extension strength (KES), grip strength, range of motion (ROM), and balance skills, while neural function was measured by nerve conductance velocity (NCV). Arthritis-related symptoms were quantified using the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) questionnaire, serum arthritis-related microRNA using quantitative polymerase chain reaction. RESULTS: Insulin sensitivity was lower in T2D+OA vs T2D-OA (4.4 ± 2.0 vs 5.7 ± 3.0 mg* kg-1*min-1) and in CON+OA vs CON-OA (8.1 ± 2.0 vs 12.0 ± 2.6 mg*kg-1,*min-1, both P < .05). In T2D+OA, KES and ROM were 60% and 22% lower than in CON+OA, respectively (both P < .05). Insulin sensitivity correlated positively with KES (r = 0.41, P < .05) among T2D, and negatively with symptom severity in CON and T2D (r = -0.60 and r = -0.46, respectively, P < .05). CON+OA and T2D+OA had inferior balance skills than CON-OA, whereas NCV was comparable in T2D+OA and T2D-OA. Expression of arthritis-related microRNAs was upregulated in T2D compared to CON, but downregulated in CON+OA compared to CON-OA (P < .05), and did not differ between T2D+OA and T2D-OA. CONCLUSION: Musculoskeletal impairment and osteoarthritis-related symptoms are associated with insulin resistance. Type 2 diabetes can mask changes in arthritis-related microRNA profiles.
CRIS-Team Scopus Importer:2021-04-16
Keywords: insulin secretion; insulin sensitivity; muscle strength; osteoarthritis; type 2 diabetes

Re-exposure with a TNF inhibitor bio-similar was well tolerated and led to sustained control of psoriatic arthritis after allergic reaction to the TNF inhibitor bio-originator - Valor-Mendez, Larissa; Dorn, Carla; Manger, Bernhard; Schett, Georg; Kleyer, Arnd (Rheumatology Advances in Practice, 2022)
CRIS-Team WoS Importer:2022-11-04

Refinement and Usability Analysis of an eHealth App for Ankylosing Spondylitis as a Complementary Treatment to Physical Therapy: Development and Usability Study - Nitschke, Marlies; Nwosu, Obioma Bertrand; Grube, Lara; Knitza, Johannes; Seifer, Ann-Kristin; Eskofier, Björn; Schett, Georg; Morf, Harriet (JMIR Formative Research, 2023)
Background: Mobile eHealth apps have been used as a complementary treatment to increase the quality of life of patients and provide new opportunities for the management of rheumatic diseases. Telemedicine, particularly in the areas of prevention, diagnostics, and therapy, has become an essential cornerstone in the care of patients with rheumatic diseases. Objective: This study aims to improve the design and technology of YogiTherapy and evaluate its usability and quality. Methods: We newly implemented the mobile eHealth app YogiTherapy with a modern design, the option to change language, and easy navigation to improve the app’s usability and quality for patients. After refinement, we evaluated the app by conducting a study with 16 patients with AS (4 female and 12 male; mean age 48.1, SD 16.8 y). We assessed the usability of YogiTherapy with a task performance test (TPT) with a think-aloud protocol and the quality with the German version of the Mobile App Rating Scale (MARS). Results: In the TPT, the participants had to solve 6 tasks that should be performed on the app. The overall task completion rate in the TPT was high (84/96, 88% completed tasks). Filtering for videos and navigating to perform an assessment test caused the largest issues during the TPT, while registering in the app and watching a yoga video were highly intuitive. Additionally, 12 (75%) of the 16 participants completed the German version of MARS. The quality of YogiTherapy was rated with an average MARS score of 3.79 (SD 0.51) from a maximum score of 5. Furthermore, results from the MARS questionnaire demonstrated a positive evaluation regarding functionality and aesthetics. Conclusions: The refined and tested YogiTherapy app showed promising results among most participants. In the future, the app could serve its function as a complementary treatment for patients with AS. For this purpose, surveys with a larger number of patients should still be conducted. As a substantial advancement, we made the app free and openly available on the iOS App and Google Play store
Keywords: ankylosing spondylitis; axial spondylarthritis; DHA; digital health application; eHealth; self-assessment; Usability; Yoga; YogiTherapy

Reframing immune-mediated inflammatory diseases - Boutrid, Nada; Rahmoune, Hakim; Schett, Georg; McInnes, Iain; Neurath, Markus (New England Journal of Medicine, 2021)
We were surprised to find that celiac disease was not among the panel of disorders discussed by Schett et al. (Aug. 12 issue)1 in their review article on cytokines and immune-mediated inflammatory conditions. It is well established that cytokine release is at the core of the structural damage and subsequent clinical manifestations in celiac disease, and we note in particular the evolving role of interleukins (mainly interleukin-15).2 In fact, interleukin-15 has a crucial role in innate and adaptive immune responses and is overexpressed in various autoimmune conditions, including celiac disease.3 This interleukin-15 action is orchestrated by tumor necrosis factor α and implicates the innate lymphoid cells; these two components are involved in the celiac-immunomediated enteropathy and several extraintestinal manifestations of celiac disease.4 It is not surprising that numerous trials — including trials in animal models and clinical trials, notably the PRV-015 in Gluten-free Diet Non-responsive Celiac Disease (PROACTIVE) trial5 — are exploring the option of blocking interleukin-15 to decrease or resolve lesions caused by celiac disease.5
CRIS-Team Scopus Importer:2021-12-10

Reframing Immune-Mediated Inflammatory Diseases through Signature Cytokine Hubs - Schett, Georg; Mcinnes, Iain B.; Neurath, Markus (New England Journal of Medicine, 2021)
Immune-mediated inflammatory diseases (IMIDs) are a heterogeneous group of diseases characterized by chronic inflammation and organ damage. IMIDs were traditionally classified on the basis of the predominant organ involvement. Improving the pathogenic characterization of IMIDs, however, should allow for a refined mechanistic understanding of these diseases and should make it possible to develop a molecular-based classification. The transition from organ-based to molecular-based classification was initiated by insights into associated genetic mutations and polymorphisms of key immune pathways and the development of monoclonal antibodies that target signature cytokine hubs in IMIDs. As compared with an organ-based classification, molecular classification better addresses pathophysiological commonalities across IMIDs that affect different organs but also accounts for substantial mechanistic differences among IMIDs that affect the same organ (Fig. 1).
CRIS-Team Scopus Importer:2021-08-27

REGULATION OF ARTHRITIS BY TYPE 2 INNATE LYMPHOID CELLS - Omata, Yasunori; Lucas, Sebastien; Garcia, Mireia; Wirtz, Stefan; Bozec, Aline; Schett, Georg; Zaiss, Mario (2017)
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REGULATION OF AUTOANTIBODY ACTIVITY BY T CELL SUBSETS - Krönke, Gerhard (ANNALS OF THE RHEUMATIC DISEASES, 2019)
CRIS-Team WoS Importer:2019-07-12

Regulation of autoantibody activity by the IL-23-TH17 axis determines the onset of autoimmune disease. - Pfeifle, René; Rothe, Tobias; Ipseiz, Natacha; Scherer, Hans U.; Culemann, Stephan; Harre, Ulrike; Ackermann, Jochen; Seefried, Martina; Kleyer, Arnd; Uderhardt, Stefan; Haugg, Benjamin; Huebert, Axel J.; et al. (Nature Immunology, 2017)
The checkpoints and mechanisms that contribute to autoantibody-driven disease are as yet incompletely understood. Here we identified the axis of interleukin 23 (IL-23) and the TH17 subset of helper T cells as a decisive factor that controlled the intrinsic inflammatory activity of autoantibodies and triggered the clinical onset of autoimmune arthritis. By instructing B cells in an IL-22- and IL-21-dependent manner, TH17 cells regulated the expression of β-galactoside α2,6-sialyltransferase 1 in newly differentiating antibody-producing cells and determined the glycosylation profile and activity of immunoglobulin G (IgG) produced by the plasma cells that subsequently emerged. Asymptomatic humans with rheumatoid arthritis (RA)-specific autoantibodies showed identical changes in the activity and glycosylation of autoreactive IgG antibodies before shifting to the inflammatory phase of RA; thus, our results identify an IL-23-TH17 cell-dependent pathway that controls autoantibody activity and unmasks a preexisting breach in immunotoleranc

Regulation of bone and joint inflammation by type 2 innate lymphoid cells - Omata, Yasunori; Zaiss, Mario; Frech, Michael; Schett, Georg; Tanaka, Sakae (Elsevier, 2023)
The innate and adaptive immune systems regulate inflammation in arthritis. The innate immune system works as one of the “first responders” against the invasion of pathogens, followed by adaptive immunity activation. The cross-talk between innate and adaptive immune cells has protective roles against pathogens and induces immunological responses. Recently, a new type of innate immune cells, innate lymphoid cells (ILCs), was discovered; it was found that they play a profound role in immunological responses. ILCs function closely with T helper cells, depending on their respective subsets. In this chapter, we mainly focus on one subset, type 2 ILCs (ILC2s), and review their role in inflammatory arthritis and bone homeostasis.
CRIS-Team Scopus Importer:2023-04-28
Keywords: Adaptive immunity; Arthritis; Bone; Innate immunity; Innate lymphoid cells (ILC); Osteoclast; T cell

Regulation of Fibroblast Apoptosis and Proliferation by MicroRNA-125b in Systemic Sclerosis - Kozlova, Anastasiia; Pachera, Elena; Maurer, Britta; Juengel, Astrid; Distler, Jörg; Kania, Gabriela; Distler, Oliver (Arthritis and Rheumatology, 2019)
Objective To analyze the expression, regulation, and role of microRNA-125b (miR-125b) in systemic sclerosis (SSc). Methods MiR-125b expression was assessed by quantitative polymerase chain reaction (qPCR) of RNA from dermal fibroblasts and whole skin biopsy specimens from healthy controls and SSc patients. To identify downstream effectors, RNA from healthy control fibroblasts was sequenced after miR-125b knockdown and further validated using qPCR and Western blotting. Fibrosis, apoptosis, and proliferation were assessed by Caspase-Glo 3/7 assay, Western blotting, immunofluorescence staining for cleaved caspase 3, and annexin V real-time assay in dermal fibroblasts. Results Expression of miR-125b was significantly down-regulated in SSc skin biopsy specimens by 53% (median fold change 0.47 [interquartile range 0.35-0.69]; P < 0.001) and in SSc dermal fibroblasts by 47% (median fold change 0.53 [interquartile range 0.36-0.58]; P < 0.001) compared to healthy control skin biopsy specimens and fibroblasts, respectively (n = 10 samples per group). Treatment with the histone deacetylase inhibitors trichostatin A and tubastatin A significantly decreased the expression of miR-125b in dermal fibroblasts. MiR-125b knockdown significantly reduced cell proliferation and alpha-smooth muscle actin (alpha-SMA) expression at the messenger RNA (mRNA) and protein levels. RNA-Seq identified BAK1, BMF, and BBC3 as potential targets of miR-125b. Quantitative PCR confirmed that knockdown of miR-125b up-regulated these genes (P < 0.01; n = 12). Bcl-2 homologous antagonist killer 1 showed the strongest induction confirmed at the protein level (P < 0.01; n = 10). Consequently, miR-125b knockdown increased apoptosis compared to scrambled control. Accordingly, miR-125b overexpression decreased apoptosis. Conclusion Our findings indicate that miR-125b is down-regulated in SSc skin and primary dermal fibroblasts. MiR-125b down-regulation increases apoptosis and decreases proliferation and alpha-SMA expression in dermal fibroblasts, indicating that its compensatory, antifibrotic mechanism may be a potential novel therapeutic option.
CRIS-Team WoS Importer:2019-11-12

Regulation of plasma cell homeostasis and antibody secretion through modulation of autophagy and endoplasmic reticulum stress by Trk-fused-gene (TFG) - Thomas, Jana; Steinmetz, Tobit; Mielenz, Dirk (EUROPEAN JOURNAL OF IMMUNOLOGY, 2022)
CRIS-Team WoS Importer:2023-01-27

Regulatory eosinophils induce the resolution of experimental arthritis and appear in remission state of human rheumatoid arthritis - Andreev, Darja; Liu, Mengdan; Kachler, Katerina; Llerins Perez, Mireia; Kirchner, Philipp; Kölle, Julia; Gießl, Andreas; Rauber, Simon; Song, Rui; Aust, Oliver; Grüneboom, Anika; Kleyer, Arnd; et al. (Annals of the Rheumatic Diseases, 2020)
Objectives: Eosinophils possess pro-inflammatory functions in asthma. However, our recent studies have suggested that innate lymphoid cells type 2 (ILC2s) and eosinophils have proresolving properties in rheumatoid arthritis (RA). Nothing is known yet about the mechanisms determining the double-edged role of eosinophils. Therefore, we investigated whether asthma, a paradigm eosinophilic disease, can elicit resolution of chronic arthritis. Methods: Ovalbumin-triggered eosinophilic asthma was combined with K/BxN serum-induced arthritis, where lung and synovial eosinophil subsets were compared by single-cell RNA sequencing (scRNA-seq). To investigate the involvement of the ILC2-interleukin-5 (IL-5) axis, hydrodynamic injection (HDI) of IL-25 and IL-33 plasmids, IL-5 reporter mice and anti-IL-5 antibody treatment were used. In patients with RA, the presence of distinct eosinophil subsets was examined in peripheral blood and synovial tissue. Disease activity of patients with RA with concomitant asthma was monitored before and after mepolizumab (anti-IL-5 antibody) therapy. Results: The induction of eosinophilic asthma caused resolution of murine arthritis and joint tissue protection. ScRNA-seq revealed a specific subset of regulatory eosinophils (rEos) in the joints, distinct from inflammatory eosinophils in the lungs. Mechanistically, synovial rEos expanded on systemic upregulation of IL-5 released by lung ILC2s. Eosinophil depletion abolished the beneficial effect of asthma on arthritis. rEos were consistently present in the synovium of patients with RA in remission, but not in active stage. Remarkably, in patients with RA with concomitant asthma, mepolizumab treatment induced relapse of arthritis. Conclusion: These findings point to a hitherto undiscovered proresolving signature in an eosinophil subset that stimulates arthritis resolution.
CRIS-Team Scopus Importer:2020-11-20
Keywords: arthritis; autoimmune diseases; cytokines; immune system diseases; inflammation; rheumatoid

Regulatory T cells protect from local and systemic bone destruction in arthritis. - Zaiss, Mario; Frey, Benjamin; Heß, Andreas; Zwerina, Jochen; Luther, Julia; Nimmerjahn, Falk; Engelke, Klaus; Kollias, George; Huenig, Thomas; Schett, Georg; David, Jean-Pierre (Journal of Immunology, 2010)
We previously demonstrated the suppressive effects of regulatory T cells (Treg cells) on osteoclast differentiation in vitro. In this article, we show that blood markers of bone resorption inversely correlate with the amount of circulating Treg cells in healthy controls and rheumatoid arthritis patients, further suggesting that Treg cells may control bone destruction in vivo. Indeed, bone marrow from Foxp3-transgenic (Foxp3tg) mice fully protected human TNF transgenic (hTNFtg) mice from TNF-alpha-induced bone destruction, whereas Foxp3-deficient bone marrow enhanced local and systemic bone loss. The same protective effect was also obtained by treating hTNFtg mice with the CD28 superagonist mAb (CD28 SA), which increased Treg cell numbers. In both models, bone protection by Treg cells was associated with reduced osteoclast numbers, resulting in less bone-resorbing activity. Reduced osteoclast numbers were not caused by an intrinsic defect in osteoclast differentiation because osteoclast precursors from hTNFtg/Foxp3tg chimeras responded normally to M-CSF and receptor activator of NF-kappaB ligand. Although a decrease in the clinical signs of arthritis was observed in Foxp3tg bone marrow-transferred and CD28 SA-treated hTNFtg mice, the bone-protective effect of Treg cells was independent of the suppression of inflammation, as demonstrated by the increased systemic bone density observed in wild-type mice treated with CD28 SA. This work demonstrated that increasing Treg cell numbers improved clinical signs of arthritis and suppressed local and systemic bone destruction. Thus, enhancing the activity of Treg cells would be beneficial for the treatment of inflammation-induced bone loss observed in rheumatoid arthritis.

Relapse rates in patients with rheumatoid arthritis in stable remission tapering or stopping antirheumatic therapy: interim results from the prospective randomised controlled RETRO study - Haschka, Judith; Englbrecht, Matthias; Hueber, Axel; Manger, Bernhard; Kleyer, Arnd; Reiser, Michaela; Finzel, Stephanie; Tony, Hans-Peter; Kleinert, Stefan; Feuchtenberger, Martin; Fleck, Martin; Manger, Karin; et al. (Annals of the Rheumatic Diseases, 2016)
To prospectively analyse the risk for disease relapses in patients with rheumatoid arthritis (RA) in sustained remission, either continuing, tapering or stopping disease-modifying antirheumatic drugs (DMARDs) in a prospective randomised controlled trial.Reduction of Therapy in patients with Rheumatoid arthritis in Ongoing remission is a multicentre, randomised controlled, parallel-group phase 3 trial evaluating the effects of tapering and stopping all conventional and/or biological DMARDs in patients with RA in stable remission. Patients (disease activity score 28 (DAS28)<2.6 for least 6 months) were randomised into three arms, either continuing DMARDs (arm 1), tapering DMARDs by 50% (arm 2) or stopping DMARDs after 6 months tapering (arm 3). The primary endpoint was sustained remission during 12 months.In this interim analysis, the first 101 patients who completed the study were analysed. At baseline, all patients fulfilled DAS28 remission and 70% also American College of Rheumatology- European League Against Rheumatism Boolean remission. 82.2% of the patients received methotrexate, 40.6% biological DMARDs and 9.9% other DMARDs. Overall, 67 patients (66.3%) remained in remission for 12 months, whereas 34 patients (33.7%) relapsed. The incidence of relapses was related to study arms (p=0.007; arm 1: 15.8%; arm 2: 38.9%; arm 3: 51.9%). Multivariate logistic regression identified anticitrullinated protein antibodies (ACPA) positivity (p=0.038) and treatment reduction (in comparison to continuation) as predictors for relapse (arm 2: p=0.012; arm 3: p=0.003).This randomised controlled study testing three different treatment strategies in patients with RA in sustained remission demonstrated that more than half of the patients maintain in remission after tapering or stopping conventional and biological DMARD treatment. Relapses occurred particularly in the first 6 months after treatment reduction and were associated with the presence of ACPA.2009-015740-42.
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RELATIONSHIP BETWEEN ANTI-MDA5 ANTIBODIES AND CANCER: RETROSPECTIVE ANALYSIS OF AN INTERNATIONAL AND MULTIDISCIPLINARY COHORT - De Stefano, Ludovico; Castaneda, Santos; De Langhe, Ellen; Distler, Jörg; Knitza, Johannes; Cavazzana, Ilaria; Meyer, Alain; Rojas-Serrano, Jorge; Arrigoni, Eugenio; Furini, Federica; Govoni, Marcello; Parrocchini, Paola; et al. (ANNALS OF THE RHEUMATIC DISEASES, 2019)
CRIS-Team WoS Importer:2019-07-16

Relations of vitamin D status, gender and type 2 diabetes in middle-aged Caucasians - Stadlmayr, Andreas; Aigner, Elmar; Huber-Schoenauer, Ursula; Niederseer, David; Zwerina, Jochen; Husar-Memmer, Emma; Hohla, Florian; Schett, Georg; Patsch, Wolfgang; Datz, Christian (Acta Diabetologica, 2015)
Vitamin D (Vit D) deficiency may be linked to the development of obesity-associated complications such as insulin resistance and type 2 diabetes. We therefore evaluated the relationship of Vit D serum concentrations with metabolic parameters and type 2 diabetes in middle-aged Caucasian men and women. One thousand six hundred and thirty-one Caucasians (832 males, 58.8 ± 9.7 years; 799 females, 59.7 ± 10.7 years) were evaluated in a cross-sectional study. Vit D status was assessed by measuring the serum concentration of 25-hydroxyvitamin D3 [25(OH)D3]. Type 2 diabetes prevalence was ascertained by medical history, fasting plasma glucose concentrations, oral glucose tolerance testing and/or glycosylated hemoglobin. Men displayed higher crude or seasonally adjusted 25(OH)D3 serum concentrations than women (24.64 ± 10.98 vs. 22.88 ± 11.6 ng/ml; P < 0.001). Strong associations between body mass index (BMI) and 25(OH)D3 were observed in both genders (P < 0.001). Seasonally adjusted levels of 25(OH)D3 revealed stronger associations with type 2 diabetes in women than men (P < 0.001). However, adjustment for BMI and other confounding variables revealed an independent inverse association of 25(OH)D3 with diabetes only in women (P < 0.001), whereas the association was abrogated in men. Using a 15 ng/ml 25(OH)D3 cutoff for binary comparison, adjusted odds ratios for having newly diagnosed or known type 2 diabetes more than doubled (2.95 [95 % CI 1.37-4.89] and 3.26 [1.59-6.68], respectively), in women below the cutoff. We conclude that in women, but not in men, low 25(OH)D3 serum levels are independently associated with type 2 diabetes. These findings suggest sex-specific effects of Vit D in the pathogenesis of type 2 diabetes.
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RELMα-expressing macrophages protect against fatal lung damage and reduce parasite burden during helminth infection - Krljanac, Branislav; Schubart, Christoph; Naumann, Ronald; Wirtz, Stefan; Culemann, Stephan; Krönke, Gerhard; Vöhringer, David (Science immunology, 2019)
Alternatively activated macrophages (AAMs) can contribute to wound healing, regulation of glucose and fat metabolism, resolution of inflammation, and protective immunity against helminths. Their differentiation, tissue distribution, and effector functions are incompletely understood. Murine AAMs express high levels of resistin-like molecule (RELM) α, an effector protein with potent immunomodulatory functions. To visualize RELMα+ macrophages (MΦs) in vivo and evaluate their role in defense against helminths, we generated RELMα reporter/deleter mice. Infection with the helminth Nippostrongylus brasiliensis induced expansion of RELMα+ lung interstitial but not alveolar MΦs in a STAT6-dependent manner. RELMα+ MΦs were required for prevention of fatal lung damage during primary infection. Furthermore, protective immunity was lost upon specific deletion of RELMα+ MΦs during secondary infection. Thus, RELMα reporter/deleter mice reveal compartmentalization of AAMs in different tissues and demonstrate their critical role in resolution of severe lung inflammation and protection against migrating helminths.
CRIS-Team Scopus Importer:2019-06-18

Remission in psoriatic arthritis-where are we now? - Coates, Laura C.; Conaghan, Philip G.; D'Agostino, Maria Antonietta; De Wit, Maarten; Fitzgerald, Oliver; Kvien, Tore K.; Lories, Rik; Mease, Philip; Nash, Peter; Schett, Georg; Soriano, Enrique R.; Emery, Paul (Rheumatology, 2017)
Advances in treatments and treatment strategies for PsA have led to many patients responding well to management of their disease, and targeting remission as a treatment goal is now a possibility. Treat to target is a strategy aimed at maximizing benefit, irrespective of the type of medication used, by monitoring disease activity and using it to guide therapy. The measurement of response to treatment has been the subject of wide discussions among experts for some time, and many instruments exist. Comparisons of the different measures and their different strengths and weaknesses is ongoing. The impact of modern imaging techniques on monitoring disease progression is also evolving, and advanced techniques using both MRI and US have the potential to improve management of PsA through identification of risk factors for poor prognosis as well as accurate assessment of inflammation and damage, including subclinical disease. Increased understanding of the pathways that drive the pathogenesis of PsA will be key to identifying specific biomarkers for the disease and developing effective treatment strategies. Targets for response, considerations for use of a treat to target strategy in PsA, different imaging techniques and serological aspects of remission are all discussed in this review, and areas for further research are identified.
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Remote self-collection of capillary blood using upper arm devices for autoantibody analysis in patients with immune-mediated inflammatory rheumatic diseases - Zarbl, Joshua; Eimer, Ekaterina; Gigg, Camilla; Bendzuck, Gerlinde; Korinth, Marianne; Elling-Audersch, Corinna; Kleyer, Arnd; Simon, David; Böltz, Sebastian; Krusche, Martin; Mucke, Johanna; Muehlensiepen, Felix; et al. (RMD Open, 2022)
Objectives To evaluate the feasibility, accuracy, usability and acceptability of two upper arm self-sampling devices for measurement of autoantibodies and C reactive protein (CRP) levels in patients with immune-mediated rheumatic diseases (IMRDs). Methods 70 consecutive patients with IMRD with previously documented autoantibodies were assigned to supervised and unsupervised self-collection of capillary blood with the Tasso+ or TAP II device. Interchangeability of 17 biomarkers with standard venesection was assessed by: concordance, correlation, paired sample hypothesis testing and Bland-Altman plots. Patients completed an evaluation questionnaire, including the System Usability Scale (SUS) and Net Promoter Score (NPS). Results While 80.0% and 77.0% were able to safely and successfully collect capillary blood using the Tasso+ and TAP II within the first attempt, 69 of 70 (98.6%) patients were successful in collecting capillary blood within two attempts. Concordance between venous and capillary samples was high; 94.7% and 99.5% for positive and negative samples, respectively. For connective tissue disease screen, anti-Ro52 and anti-proteinase 3 autoantibody levels, no significant differences were observed. Self-sampling was less painful than standard venesection for the majority of patients (Tasso+: 71%; TAP II: 63%). Both devices were well accepted (NPS; both: +28%), usability was perceived as excellent (SUS; Tasso+: 88.6 of 100; TAP II: 86.0 of 100) and 48.6 %/62.9% of patients would prefer to use the Tasso+/TAP II, respectively, instead of a traditional venous blood collection. Conclusions Remote self-collection of capillary blood using upper arm-based devices for autoantibody and CRP analysis in patients with autoimmune rheumatic diseases is feasible, accurate and well accepted among patients.
CRIS-Team WoS Importer:2022-09-23

Removing the bone brake - Schett, Georg; Bozec, Aline (Cell Metabolism, 2014)
Osteoporosis results from an imbalance between bone resorption and bone formation. While bone resorption inhibitors are widely used to treat osteoporosis, stimulating bone formation is more challenging. Recently, McClung et al. (2014) found that neutralization of sclerostin, a potent inhibitor of bone formation, effectively increased bone mass in postmenopausal women.
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Renal leishmaniasis as unusual cause of nephrotic syndrome in an HIV patient - Amann, Kerstin Ute; Bogdan, Christian; Harrer, Thomas; Rech, Jürgen (Journal of the American Society of Nephrology, 2012)
Renal involvement is a rare complication in HIV-1-infected patients leading to various pathologies and clinical symptoms. In addition to the classic HIV-1-associated nephropathy with collapsing-type focal segmental glomerulosclerosis and characteristic tubulocystic changes, which is more common in Afro-American than in Caucasian HIV-1 patients, immune complex GNs such as membranous GN and membranoproliferative GN are particularly common renal manifestations. Besides HIV-1 itself, a number of opportunistic infections may cause renal disease in HIV-1-infected patients. In this study, we report an unusual case of HIV-1 infection with a severe renal manifestation of systemic leishmaniasis that developed years after repeated visits to Mediterranean countries. The case presents several remarkable clinical, pathologic, and therapeutic aspects that may be important for daily clinical practice. Copyright © 2012 by the American Society of Nephrology.
CRIS-Team Scopus Importer:2021-02-03

Repair of bone erosions in rheumatoid arthritis treated with tumour necrosis factor inhibitors is based on bone apposition at the base of the erosion - Finzel, Stephanie; Rech, Jürgen; Schmidt, Sarah; Engelke, Klaus; Englbrecht, Matthias; Stach, Christian; Schett, Georg (Annals of the Rheumatic Diseases, 2011)
Objectives: To investigate whether bone erosions in patients with rheumatoid arthritis (RA) show evidence of repair. Methods: 127 erosions were identified in metacarpophalangeal joints 2-4 of the right hands of 30 RA patients treated with tumour necrosis factor inhibitors (TNFi) and 21 sex, age and disease activity-matched patients treated with methotrexate. All erosions were assessed for their exact maximal width and depth by high-resolution μCT imaging at baseline and after 1 year. Results: All erosions detected at baseline could be visualised at follow-up after 1 year. At baseline, the mean width of bone erosions in the TNFi group was 2.0 mm;their mean depth was 2.3 mm, which was not significantly different from the methotrexate-treated group (width 2.4 mm;depth 2.4 mm). Mean depth of erosions significantly decreased after 1 year of treatment with TNFi (-0.1 mm; p=0.016), whereas their width remained unchanged. In contrast, mean depth and width of erosive lesions increased in the methotrexate-treated group. The reduction in the depth of lesions was confined to erosions showing evidence of sclerosis at the base of the lesion. Moreover, deeper lesions in the TNFi group were particularly prone to repair (-0.4 mm;p=0.02) compared with more shallow lesions. Conclusions: Bone erosions in RA patients treated with TNFi show evidence of limited repair in contrast to bone erosions in patients treated with methotrexate. Repair is associated with a decrease in the depth of lesions and sclerosis at the bases of the lesions. Repair thus emerges from the endosteal rather than periosteal bone compartment and probably involves the bone marrow.
CRIS-Team Scopus Importer:2021-02-03

Reply. - Simon, David; Fagni, Filippo; Tascilar, Koray; Schett, Georg (Arthritis and Rheumatology, 2022)
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Reply - Soare, Alina; Distler, Jörg (Arthritis and Rheumatology, 2020)
CRIS-Team WoS Importer:2020-12-04

Reply to Hou: Central nervous system effects of TNF-α blockade - Heß, Andreas; Rech, Jürgen; Brune, Kay; Schett, Georg (Proceedings of the National Academy of Sciences of the United States of America, 2011)
CRIS-Team Scopus Importer:2021-02-03

Reply to "Neutrophils are not required for resolution of acute gouty arthritis in mice" - Reinwald, Christiane; Schauer, Christine; Csepregi, Janka Zsofia; Kienhoefer, Deborah; Weidner, Daniela; Malissen, Marie; Mocsai, Attila; Schett, Georg; Herrmann, Martin; Hoffmann, Markus (Nature Medicine, 2016)
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Reply to: Osteoporosis: An Independent Determinant of Bone Erosions in Rheumatoid Arthritis? - Simon, David; Simon, Christoph; Kleyer, Arnd; Schett, Georg (Journal of Bone and Mineral Research, 2017)
We thank Rossini and colleagues for their letter (1) commenting on our article (2) "Age- and Sex-Dependent Changes of intra-articular Cortical and Trabecular Bone Structure and the Effects of Rheumatoid Arthritis". In fact, we could not more agree with the view of the authors and congratulate them for this concise summary of the key mechanism involved in bone loss of rheumatoid arthritis. In addition, we think that this letter raises two important points related to inflammatory bone loss: First, Rossini and colleagues point out that bone loss in rheumatoid arthritis arises from a combination of (i) factors specific to rheumatoid arthritis, in particular inflammation and autoimmunity and (ii) more common factors related to age, sex and menopausal status. Hence, age, postmenopausal state and inflammation/autoimmunity join efforts to trigger bone disease in patients with rheumatoid arthritis. Our data support this concept by showing age-, sex- and disease- associated changes of intra-articular bone mass and microstructures, which is likely the most sensitive indicator of bone loss in the context of arthritis. This article is protected by copyright. All rights reserved.
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Rescue therapy of antisynthetase syndrome with CD19-targeted CAR-T cells after failure of several B-cell depleting antibodies - Taubmann, Jule; Knitza, Johannes; Müller, Fabian; Völkl, Simon; Aigner, Michael; Kleyer, Arnd; Gary, Regina; Kretschmann, Sascha; Böltz, Sebastian; Atzinger, Armin; Kuwert, Torsten; Roemer, Frank; et al. (Rheumatology, 2024)
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Research consortium Neuroimmunology and pain in the research network musculoskeletal diseases - Schaible, H-G.; Chang, H. -D.; Graessel, S.; Haibel, H.; Heß, Andreas; Kamradt, T.; Radbruch, A.; Schett, Georg; Stein, C.; Straub, R. H. (Zeitschrift für Rheumatologie, 2018)
BACKGROUND: The research consortium Neuroimmunology and Pain (Neuroimpa) explores the importance of the relationships between the immune system and the nervous system in musculoskeletal diseases for the generation of pain and for the course of fracture healing and arthritis. MATERIAL AND METHODS: The spectrum of methods includes analyses at the single cell level, in vivo models of arthritis and fracture healing, imaging studies on brain function in animals and humans and analysis of data from patients. RESULTS: Proinflammatory cytokines significantly contribute to the generation of joint pain through neuronal cytokine receptors. Immune cells release opioid peptides which activate opioid receptors at peripheral nociceptors and thereby evoke hypoalgesia. The formation of new bone after fractures is significantly supported by the nervous system. The sympathetic nervous system promotes the development of immune-mediated arthritis. The studies show a significant analgesic potential of the neutralization of proinflammatory cytokines and of opioids which selectively inhibit peripheral neurons. Furthermore, they show that the modulation of neuronal mechanisms can beneficially influence the course of musculoskeletal diseases. DISCUSSION: Interventions in the interactions between the immune system and the nervous system hold a great therapeutic potential for the treatment of musculoskeletal diseases and pain.
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Reset of inflammatory priming of joint tissue and reduction of the severity of arthritis flares by bromodomain inhibition - Friščić, Jasna; Reinwald, Christiane; Böttcher, Martin; Houtman, Miranda; Euler, Maximilien; Chen, Xi; Walker, Kellie I.; Kirchner, Philipp; Zhu, Honglin; Wirth, Benjamin; Weidner, Daniela; Krüger, René; et al. (Arthritis and Rheumatology, 2023)
Objective: We have recently shown that priming of synovial fibroblasts (SFs) drives arthritis flares. Pathogenic priming of SFs is essentially mediated by epigenetic reprogramming. Bromodomain and extra-terminal motif (BET) proteins translate epigenetic changes into transcription. Here we used a BET inhibitor to target inflammatory tissue priming and reduce flare severity in experimental arthritis. Methods: BALB/c mice were treated intraperitoneally or locally into the paw with I-BET151, which blocks interaction of BET proteins with acetylated histones. Effect of I-BET151 on acute arthritis and/or inflammatory tissue priming was assessed in a model of repeated injections of monosodium urate crystals or zymosan into the paw. I-BET151 was given either from before arthritis induction, at peak inflammation, or after healing of the first arthritis bout. Transcriptomic (RNA-Seq), epigenomic (ATAC-Seq) and functional analysis (invasion, cytokine production, migration, senescence, metabolic flux) was performed on murine and human SFs treated with I-BET151 in vitro or in vivo. Results: Systemic I-BET151 administration did not affect acute inflammation but abolished inflammatory tissue priming and diminished flare severity in both preventive and therapeutic treatment settings. I-BET151 was also effective when applied locally in the joint. BET inhibition also inhibited osteoclast differentiation, while macrophage activation in the joint was not affected. Flare reduction after BET inhibition was mediated, at least in part, by rolling back the primed transcriptional, metabolic and pathogenic phenotype of SFs. Conclusion: Inflammatory tissue priming is dependent on transcriptional regulation by BET proteins, which makes them promising therapeutic targets for preventing arthritis flares in previously affected joints.
CRIS-Team Scopus Importer:2023-01-27

Resolution of chronic inflammatory disease: universal and tissue-specific concepts - Schett, Georg; Neurath, Markus (Nature Communications, 2018)
Inflammation and its resolution is under-studied in medicine despite being essential for understanding the development of chronic inflammatory disease. In this review article, we discuss the resolution of inflammation in both a biological and translational context. We introduce the concept of impaired resolution leading to diseases like rheumatoid arthritis, Crohn's disease, and asthma, as well as the cellular and molecular components that contribute to resolution of joint, gut, and lung inflammation, respectively. Finally, we discuss potential intervention strategies for fostering the resolution process, and their implications for the therapy of inflammatory diseases.
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Resolution of enthesitis by guselkumab and relationships to disease burden: 1-year results of two phase 3 psoriatic arthritis studies. - Mcgonagle, Dennis; Mcinnes, Iain B.; Deodhar, Atul; Schett, Georg; Shawi, May; Kafka, Shelly; Karyekar, Chetan S.; Kollmeier, Alexa P.; Hsia, Elizabeth C.; Xu, Xie L.; Sheng, Shihong; Agarwal, Prasheen; et al. (Rheumatology, 2021)
OBJECTIVE: To further characterize the effect of guselkumab, a selective IL-23p19-subunit inhibitor approved for PsA, on enthesitis and assess relationships between enthesitis resolution and patient status/outcomes. METHODS: Adults with active PsA despite standard therapies in the phase 3 DISCOVER-1 and DISCOVER-2 studies were randomized 1:1:1 to guselkumab 100 mg every 4 weeks (Q4W); guselkumab 100 mg at week 0, week 4, Q8W; or placebo through week 20 followed by guselkumab 100 mg Q4W. Independent assessors evaluated enthesitis using the Leeds Enthesitis Index (LEI; total score 0-6). Enthesitis findings through week 24 were pre-specified to be pooled across studies; post hoc and week 52 analyses also employed pooled data. RESULTS: Among 1118 randomized, treated patients in DISCOVER-1 and 2 who had ≥1 LEI site evaluated, 65% had enthesitis at baseline. These patients exhibited numerically more swollen and tender joints, systemic inflammation and impaired physical function than patients without enthesitis. Guselkumab Q4W and Q8W were superior to placebo in resolving pre-existing enthesitis at week 24 (45 and 50% vs 29%; both adjusted P = 0.0301). Enthesitis resolution rates continued to rise; 58% of guselkumab-randomized patients achieved resolution at week 52, including patients with mild (LEI = 1; 70-75%), moderate (LEI = 2; 69-73%) or severe (LEI = 3-6; 42-44%) enthesitis at baseline. Among guselkumab-randomized patients with resolved enthesitis at week 24, 42% achieved minimal disease activity at week 52, vs 17% of patients with unresolved enthesitis. CONCLUSION: Guselkumab resulted in higher proportions of PsA patients with resolved enthesitis by week 24, with maintenance of resolution rates through 1 year. As enthesitis confers greater disease burden, sustained resolution could portend better patient outcomes. CLINICAL TRIAL REGISTRATION: DISCOVER 1 (NCT03162796) and DISCOVER 2 (NCT03158285).
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Resolution of inflammation by interleukin-9-producing type 2 innate lymphoid cells - Rauber, Simon; Luber, Markus; Weber, Stefanie; Maul, Lisa; Soare, Alina; Wohlfahrt, Thomas; Lin, Neng-Yu; Dietel, Katharina; Bozec, Aline; Herrmann, Martin; Kaplan, Mark H.; Weigmann, Benno; et al. (Nature Medicine, 2017)
Inflammatory diseases such as arthritis are chronic conditions that fail to resolve spontaneously. While the cytokine and cellular pathways triggering arthritis are well defined, those responsible for the resolution of inflammation are incompletely characterized. Here we identified interleukin (IL)-9-producing type 2 innate lymphoid cells (ILC2s) as the mediators of a molecular and cellular pathway that orchestrates the resolution of chronic inflammation. In mice, the absence of IL-9 impaired ILC2 proliferation and activation of regulatory T (Treg) cells, and resulted in chronic arthritis with excessive cartilage destruction and bone loss. In contrast, treatment with IL-9 promoted ILC2-dependent Treg activation and effectively induced resolution of inflammation and protection of bone. Patients with rheumatoid arthritis in remission exhibited high numbers of IL-9(+) ILC2s in joints and the circulation. Hence, fostering IL-9-mediated ILC2 activation may offer a novel therapeutic approach inducing resolution of inflammation rather than suppression of inflammatory responses.
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Resolution of inflammation in arthritis - Schett, Georg (Seminars in Immunopathology, 2019)
Rheumatoid arthritis is among the most frequent and severe chronic inflammatory diseases. The disease is characterized by ongoing synovial inflammation, which leads to the destruction of cartilage and bone. In RA, the mechanisms of resolution of inflammation, which are normally intact in the joints, are either suppressed or overruled. Little efforts have been undertaken to understand the mechanisms of resolution of arthritis until recently, when several molecular mechanisms have been identified that determine the chronicity and resolution of inflammation in the joints, respectively. This review describes the key concepts of resolution of arthritis mentioning the key mechanisms involved, such as regulatory macrophages, pro-resolving lipid, fatty acid and cytokine mediators, aggregated neutrophil extracellular trap formation, antibody glycosylation changes, and stromal cell alterations that are involved in determining the decision between chronicity and resolution of arthritis. Each of these mechanisms represents a potential therapeutic approach that allows skewing the balance of the inflammatory processes towards resolution.
CRIS-Team Scopus Importer:2019-11-26

Resolution of synovitis and arrest of catabolic and anabolic bone changes in patients with psoriatic arthritis by IL-17A blockade with secukinumab: results from the prospective PSARTROS study - Kampylafka, Eleni; D'Oliveira, Isabelle; Linz, Christina; Lerchen, Veronika; Stemmler, Fabian; Simon, David; Englbrecht, Matthias; Sticherling, Michael; Rech, Juergen; Kleyer, Arnd; Schett, Georg; Hueber, Axel (Arthritis Research & Therapy, 2018)
BACKGROUND: Although the effects of interleukin-17A (IL-17A) inhibition on the signs and symptoms of psoriatic arthritis (PsA) are well defined, little is known about its impact of local inflammatory and structural changes in the joints. The PSARTROS study was designed to elucidate the effects of IL-17A inhibition on inflammation and bone changes in joints affected by PsA. METHODS: This was a prospective open-label study in 20 patients with active PsA receiving 24 weeks of treatment with the IL-17A inhibitor secukinumab. Magnetic resonance imaging (MRI), power Doppler ultrasound (PDUS), and high-resolution peripheral quantitative computer tomography (HR-pQCT) of the hands were performed at baseline and after 24 weeks to assess synovitis, periarticular inflammation, bone erosion, enthesiophyte formation, and bone structure. Demographic and clinical measures of joint disease (DAPSA and DAS28-ESR), skin disease (PASI and BSA), and composite measures (minimal disease activity, or MDA) were also recorded. RESULTS: Treatment with secukinumab led to significant improvement of signs and symptoms of PsA; 46% reached MDA and 52% DAPSA low disease activity. MRI synovitis (P = 0.034) and signal in PDUS (P = 0.030) significantly decreased after 24 weeks of treatment. Bone erosions in MRI and HR-pQCT and enthesiophytes in the HR-pQCT did not show any progression, and structural integrity and functional bone strength remained stable. CONCLUSIONS: IL-17 inhibition by secukinumab over 24 weeks led to a significant decrease of synovial inflammation and no progression of catabolic and anabolic bone changes in the joints of patients with PsA. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02483234 , June 26, 2015; retrospectively registered.
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RESOLUTION OF VASCULAR INFLAMMATION IN PATIENTS WITH GIANT CELL ARTERITIS RECEIVING GLUCOCORTICOIDS, METHOTREXATE OR TOCILIZUMAB TREATMENT-DATA FROM THE ITALIAN/GERMAN RIGA STUDY - Schonau, Verena; Roth, Jessica; Tascilar, Koray; Rech, Jürgen; Schmidt, Daniela; Kuwert, Torsten; Crescentini, Filippo; Boiardi, Luigi; Casali, Massim Iliano; Versari, Annibale; Schett, Georg; Salvarani, Carlo; et al. (ANNALS OF THE RHEUMATIC DISEASES, 2019)
CRIS-Team WoS Importer:2019-07-12

Resolution of vascular inflammation in patients with new-onset giant cell arteritis: data from the RIGA study - Schönau, Verena; Roth, Jessica; Tascilar, Koray; Corte, Giulia; Manger, Bernhard; Rech, Jürgen; Schmidt, Daniela; Cavallaro, Alexander Josef; Uder, Michael; Crescentini, Filippo; Boiardi, Luigi; Casali, Massimiliano; et al. (Rheumatology, 2021)
OBJECTIVES: Efficacy evaluation of GCA treatment is primarily based on non-specific symptoms and laboratory markers. We aimed to assess the change in vascular inflammation in patients with large vessel (LV)-GCA under different treatments using [18F]FDG PET/CT. METHODS: Observational study on patients with new-onset, active LV-GCA starting treatment with either prednisolone monotherapy (PRED) or combination with MTX or tocilizumab (TOC). All patients underwent baseline and follow-up PET/CT. The aorta and its major branches were assessed using PET vascular activity score (PETVAS) by independent readers. Cumulative glucocorticoid doses and cessation of glucocorticoid treatment were documented in all patients. RESULTS: We included 88 LV-GCA patients, 27 were treated with PRED, 42 with MTX and 19 with TOC. PETVAS decreased from 18.9-8.0 units at follow-up in the overall population (P <0.001). PETVAS changes were numerically higher in patients receiving MTX (-12.3 units) or TOC (-11.7 units) compared with PRED (-8.7). Mean cumulative prednisolone dosages were 5637, 4418 and 2984 mg in patients treated with PRED, MTX and TOC (P =0.002). Risk ratios for glucocorticoid discontinuation at the time of follow-up PET/CT were 6.77 (95% CI: 1.01, 45.29; P =0.049) and 16.25 (95% CI: 2.60, 101.73; P =0.003) for MTX and TOC users compared with PRED users. CONCLUSION: Treatment of LV-GCA inhibits vascular inflammation in the aorta and its major branches. While similar control of vascular inflammation was achieved with PRED, MTX and TOC treatments, TOC showed a strong glucocorticoid sparing effect, supporting the concept of initial combination therapy.
CRIS-Team Scopus Importer:2021-09-24
Keywords: 18F-fluorodeoxyglucose positron emission tomography/computed tomography; giant cell arteritis; glucocorticoids; large vessel vasculitis; methotrexate; tocilizumab; treatment

Respiratory syncytial virus (RSV) disease in hospitalised adults in Europe: comparison of retrospective patient chart reviews of adults=65 (=65y) and - Launay, Odile; Thalhammer, Florian; Harrer, Thomas; Cheret, Arnaud; De La Rosa, Guy; Sander, Ian; Stolper, Robert; Zakar, Jessica; Weber, Karin (2018)
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Response of human rheumatoid arthritis osteoblasts and osteoclasts to adiponectin - Krumbholz, Grit; Junker, Susann; Meier, Florian M P; Rickert, Markus; Steinmeyer, Jürgen; Rehart, Stefan; Lange, Uwe; Frommer, Klaus W; Schett, Georg; Müller-Ladner, Ulf; Neumann, Elena (Clinical and Experimental Rheumatology, 2017)
Adiponectin is an effector molecule in the pathophysiology of rheumatoid arthritis, e.g. by inducing cytokines and matrix degrading enzymes in synovial fibroblasts. There is growing evidence that adiponectin affects osteoblasts and osteoclasts although the contribution to the aberrant bone metabolism in rheumatoid arthritis is unclear. Therefore, the adiponectin effects on rheumatoid arthritis-derived osteoblasts and osteoclasts were evaluated.Adiponectin and its receptors were examined in bone tissue. Primary human osteoblasts and osteoclasts were stimulated with adiponectin and analysed using realtime polymerase chain-reaction and immunoassays. Effects on matrix-production by osteoblasts and differentiation and resorptive activity of osteoclasts were examined.Immunohistochemistry of rheumatoid arthritis bone tissue showed adiponectin expression in key cells of bone remodelling. Adiponectin altered gene expression and cytokine release in osteoblasts and increased IL-8 secretion by osteoclasts. Adiponectin inhibited osterix and induced osteoprotegerin mRNA in osteoblasts. In osteoclasts, MMP-9 and tartrate resistant acid phosphatase expression was increased. Accordingly, mineralisation capacity of osteoblasts decreased whereas resorptive activity of osteoclasts increased.The results confirm the proinflammatory potential of adiponectin and support the idea that adiponectin influences rheumatoid arthritis bone remodelling through alterations in osteoblast and osteoclast.
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Response to: 'Correspondence on 'Glucocorticoid-induced relapse of COVID-19 in a patient with sarcoidosis'' by Jeny et al. - Györfi, Andrea-Hermina; Schett, Georg; Distler, Jörg (Annals of the Rheumatic Diseases, 2022)
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Response to: 'Idiopathic inflammatory myopathies and antisynthetase syndrome: Contribution of antisynthetase antibodies to improve current classification criteria' by Greco et al - Knitza, Johannes; Cavagna, Lorenzo; Schett, Georg; Distler, Jörg (Annals of the Rheumatic Diseases, 2019)
CRIS-Team Scopus Importer:2019-05-02
Keywords: autoantibodies; dermatomyositis; polymyositis

Response to: 'Is the PET/CT first choice for differential diagnosis of FUO/IUO?' by Armagan et al - Schönau, Verena; Schett, Georg (Annals of the Rheumatic Diseases, 2018)
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Response to peripheral immune stimulation within the brain: magnetic resonance imaging perspective of treatment success - Sergeeva, Marina; Rech, Juergen; Schett, Georg; Heß, Andreas (Arthritis Research & Therapy, 2015)
Chronic peripheral inflammation in diseases such as rheumatoid arthritis leads to alterations in central pain processing and consequently to mood disorders resulting from sensitization within the central nervous system and enhanced vulnerability of the medial pain pathway. Proinflammatory cytokines such as tumor necrosis factor (TNF) alpha play an important role herein, and therapies targeting their signaling (i.e., anti-TNF therapies) have been proven to achieve good results. However, the phenomenon of rapid improvement in the patients' subjective feeling after the start of TNF? neutralization remained confusing, because it was observed long before any detectable signs of inflammation decline. Functional magnetic resonance imaging (fMRI), enabling visualization of brain activity upon peripheral immune stimulation with anti-TNF, has helped to clarify this discrepancy. Moreover, fMRI appeared to work as a reliable tool for predicting prospective success of anti-TNF therapy, which is valuable considering the side effects of the drugs and the high therapy costs. This review, which is mainly guided by neuroimaging studies of the brain, summarizes the state-of-the-art knowledge about communication between the immune system and the brain and its impact on subjective well-being, addresses in more detail the outcome of the abovementioned anti-TNF fMRI studies (rapid response to TNF? blockade within the brain pain matrix and differences in brain activation patterns between prospective therapy responders and nonresponders), and discusses possible mechanisms for the latter phenomena and the predictive power of fMRI.
EVALuna2:13172

Response to secukinumab on synovitis using Power Doppler ultrasound in psoriatic arthritis: 12-week results from a phase III study, ULTIMATE - D'Agostino, Maria Antonietta; Schett, Georg; Lopez-Rdz, Alejandra; Senolt, Ladislav; Fazekas, Katalin; Burgos-Vargas, Ruben; Maldonado-Cocco, Jose; Naredo, Esperanza; Carron, Philippe; Duggan, Anne-Marie; Goyanka, Punit; Boers, Maarten; et al. (Rheumatology, 2021)
Objectives. To investigate the dynamics of response of synovitis to IL-17A inhibition with secukinumab in patients with active PsA using Power Doppler ultrasound.
CRIS-Team WoS Importer:2022-05-13

Response to the correspondence on “CD19-CAR T-cell therapy induces deep tissue depletion of B cells” - Tur, Carlo; Eckstein, Markus; Schett, Georg; Raimondo, Maria Gabriella (Annals of the Rheumatic Diseases, 2025)
CRIS-Team Scopus Importer:2025-05-23

Response to the editor of JBMR regarding the letter related to "Opportunistic screening with CT: comparison of phantomless BMD calibration methods". - Bartenschlager, Stefan; Cavallaro, Alexander Josef; Pogarell, Tobias; Chaudry, Oliver; Uder, Michael; Khosla, Sundeep; Schett, Georg; Engelke, Klaus (Journal of Bone and Mineral Research, 2024)
EVALuna2:570800

Response to: 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 - Schönau, Verena; Schett, Georg (Annals of the Rheumatic Diseases, 2017)
EVALuna2:13516

RESPONSIVENESS OF A COMBINED POWER DOPPLER AND GREYSCALE ULTRASOUND SCORE FOR ASSESSING SYNOVITIS AT JOINT LEVEL IN PSORIATIC ARTHRITIS PATIENTS WITH INADEQUATE RESPONSE TO CSDMARDS: DATA FROM THE ULTIMATE TRIAL - D'Agostino, M. A.; Boers, M.; Gaillez, C.; Gamez, C.; Ventura, L.; Padovano, J. Rosa I.; Mandl, P.; Kleyer, Arnd; Bakewell, C.; Bao, W.; Goyanka, P.; Conaghan, P. G.; et al. (ANNALS OF THE RHEUMATIC DISEASES, 2022)
Background Power Doppler ultrasound (PDUS) is a sensitive non-invasive imaging tool that allows the visualisation of articular and periarticular inflammation in patients with psoriatic arthritis (PsA).1 ULTIMATE (NCT02662985) was the first large randomised clinical trial that showed the responsiveness of the Global OMERACT-EULAR ultrasound synovitis score (GLOESS) in PsA and confirmed the rapid and continued benefits of secukinumab through 52 weeks.2,3 Objectives To report the distribution of ultrasound-detected synovitis at joint level, by degree of severity at baseline and over time, and the contribution of each core component of GLOESS, synovial hypertrophy (SH) by greyscale (GS; B-mode) and power Doppler (PD) signal, to responsiveness.3 Methods This was a 52-week study with a 12-week double-blind, placebo-controlled treatment period followed by a 12-week open-label period and a 6-month open-label extension secukinumab treatment period.3 The number of joints with synovitis measured by GLOESS2 was assessed up to Week 52. The assessments included distribution of synovitis based on composite PDUS score across 24 pairs of joints (with worse score of the pair of the joints used) by grade of severity (0-3) and change from baseline to Week 52 in each core component of GLOESS.3-5 Data are presented as observed. Results A total of 166 patients (mean age, 46.7 years; males, 45.2%) were enrolled, of which 90% (75/83) of secukinumab and 83% (69/83) of placebo-secukinumab participants completed 52 weeks. The mean (SD) number of PDUS detected synovitis at baseline was 9.2 (4.9) and 10.2 (5.2) in the secukinumab and placebo group, respectively. The most frequent locations with synovitis at baseline were: wrist, metatarsophalangeal (MTP), knees and metacarpophalangeal (MCP) joints (Table 1). An early and continued improvement in GLOESS was observed in both secukinumab and placebo-secukinumab groups after switching to active therapy, as previously reported at Week 12 and through Week 52.2,3 Among the two core components of GLOESS, SH was mainly responsible for the change in GLOESS from baseline to Week 52, in contrast with PD signal in this dataset. The distribution of synovitis by grade of severity showed that MTP joints, wrist, knee, MCP1/2 and tibiotalar joints mostly contributed to the composite PDUS at Week 12 (Figure 1). Similar patterns were observed through 52 week
CRIS-Team WoS Importer:2022-11-04

RESPONSIVENESS OF ULTRASOUND SYNOVITIS AND CLINICAL OUTCOMES IN PSORIATIC ARTHRITIS TREATED WITH SECUKINUMAB: DATA FROM THE ULTIMATE TRIAL - Boers, M.; Conaghan, P. G.; Schett, Georg; Mandl, P.; Naredo, E.; Van Den Bosch, F.; Burgos-Vargas, R.; Duggan, A. M.; Goyanka, P.; Gaillez, C.; D'Agostino, M. A. (ANNALS OF THE RHEUMATIC DISEASES, 2021)
CRIS-Team WoS Importer:2021-10-01

Retraction Note: Combined effect of genetic background and gender in a mouse model of bleomycin-induced skin fibrosis (Arthritis Research & Therapy, (2015), 17, 1, (145), 10.1186/s13075-015-0659-5) - Ruzehaji, Nadira; Avouac, Jerome; Elhai, Muriel; Frechet, Maxime; Frantz, Camelia; Ruiz, Barbara; Distler, Jörg; Allanore, Yannick (Arthritis Research & Therapy, 2023)
The Editors-in-Chief has retracted this article because after the publication of the article concerns were raised about image overlap. Further investigation by the Publisher found the following concerns to be valid. Partial image overlap between Fig. 1A (upper-left panel, NaCl- BALB/c male mouse) and Fig. 2A (upper-left panel, NaCl—BALB/c female mouse) Partial overlap between Fig. 1A (upper-right panel, NaCl- DBA/2 male mouse) and Fig. 2A (upper-right panel, NaCl-DBA/2 female mouse). Partial image overlap between Fig. 2A (upper-right panel, NaCl-DBA/2) with Fig. 6A (left panel, NaCl) Partial image overlap in Fig. 2A (lower-middle panel, Bleomycin- C57BL/6) with Fig. 5A (upper-right panel, NaCl + Control mAb) of [1]. Partial image overlap in Fig. 3D (lower-middle panel, Bleomycin C57BL6/2) with Fig. 6B (lower-right panel, KLH BLM) of [2]. The authors provided the raw data for validation. However, further checks by the Publisher identified some differences between the raw data and the figures, as well as overlap in raw images. The authors were unable to provide ethical approval for experiments involving Balb/c mice strain. The Editors-in-Chief therefore no longer has confidence in the presented data. Nadine Ruzehaji, Muriel Elhai, Jerome Avouac, Camelia Frantz and Yannick Allanore agree to this retraction. Maxime Frechet and Joerg H. Distler have not responded to any correspondence from the editor/publisher about this retraction. The editor was not able to obtain a current email address for Barbara Ruiz.
CRIS-Team Scopus Importer:2023-11-24

RETRO - STUDY OF REDUCTION OF THERAPY IN PATIENTS WITH RHEUMATOID ARTHRITIS IN ONGOING REMISSION - Haschka, J.; Englbrecht, Matthias; Hueber, Axel; Manger, Bernhard; Kleyer, Arnd; Reiser, M.; Finzel, Stephanie; Tony, H. -P.; Kleinert, S.; Feuchtenberger, M.; Fleck, M.; Manger, Karin; et al. (2015)
EVALuna2:34460

Review and Analysis of German Mobile Apps for Inflammatory Bowel Disease Management Using the Mobile Application Rating Scale: Systematic Search in App Stores and Content Analysis - Gerner, Maximilian; Vuillerme, Nicolas; Aubourg, Timothée; Messner, Eva Maria; Terhorst, Yannik; Hörmann, Verena; Ganzleben, Ingo; Schenker, Hannah; Schett, Georg; Atreya, Raja; Neurath, Markus; Knitza, Johannes; et al. (JMIR mHealth and uHealth, 2022)
Background: Patients suffering from inflammatory bowel disease (IBD) frequently need long-term medical treatment. Mobile apps promise to complement and improve IBD management, but so far there has been no scientific analysis of their quality. Objective: This study evaluated the quality of German mobile apps targeting IBD patients and physicians treating IBD patients using the Mobile Application Rating Scale (MARS). Methods: The German Apple App Store and Google Play Store were systematically searched to identify German IBD mobile apps for patient and physician use. MARS was used by 6 physicians (3 using Android smartphones and 3 using iPhones) to independently assess app quality. Apps were randomly assigned so that the 4 apps with the most downloads were rated by all raters and the remaining apps were rated by 1 Android and 1 iOS user. Results: In total, we identified 1764 apps in the Apple App Store and Google Play Store. After removing apps that were not related to IBD (n=1386) or not available in German (n=317), 61 apps remained. After removing duplicates (n=3) and apps for congresses (n=7), journals (n=4), and clinical studies (n=6), as well as excluding apps that were available in only 1 of the 2 app stores (n=20) and apps that could only be used with an additional device (n=7), we included a total of 14 apps. The app “CED Dokumentation und Tipps” had the highest overall median MARS score at 4.11/5. On the whole, the median MARS scores of the 14 apps ranged between 2.38/5 and 4.11/5. As there was no significant difference between iPhone and Android raters, we used the Wilcoxon comparison test to calculate P values. Conclusions: The MARS ratings showed that the quality of German IBD apps varied. We also discovered a discrepancy between app store ratings and MARS ratings, highlighting the difficulty of assessing perceived app quality. Despite promising results from international studies, there is little evidence for the clinical benefits of German IBD apps. Clinical studies and patient inclusion in the app development process are needed to effectively implement mobile apps in routine care.
CRIS-Team Scopus Importer:2022-05-20
Keywords: app store; chronic disease; Crohn disease; IBD; IBS; inflammatory bowel disease; mHealth; mobile apps; quality; rating; rating scale; telemedicine; ulcerative colitis; usability

Review: Frontiers of Antifibrotic Therapy in Systemic Sclerosis - Distler, Jörg; Feghali-Bostwick, Carol; Soare, Alina; Asano, Yoshihide; Distler, Oliver; Abraham, David J. (Arthritis and Rheumatology, 2017)
EVALuna2:13105

Revised European Scleroderma Trials and Research Group Activity Index is the best predictor of short-term severity accrual - Fasano, Serena; Riccardi, Antonella; Messiniti, Valentina; Caramaschi, Paola; Rosato, Edoardo; Maurer, Britta; Smith, Vanessa; Siegert, Elise; De Langhe, Ellen; Riccieri, Valeria; Airó, Paolo; Mihai, Carina; et al. (Annals of the Rheumatic Diseases, 2019)
Background: The European Scleroderma Trials and Research Group (EUSTAR) recently developed a preliminarily revised activity index (AI) that performed better than the European Scleroderma Study Group Activity Index (EScSG-AI) in systemic sclerosis (SSc). Objective: To assess the predictive value for short-term disease severity accrual of the EUSTAR-AI, as compared with those of the EScSG-AI and of known adverse prognostic factors. Methods: Patients with SSc from the EUSTAR database with a disease duration from the onset of the first non-Raynaud sign/symptom ≤5 years and a baseline visit between 2003 and 2014 were first extracted. To capture the disease activity variations over time, EUSTAR-AI and EScSG-AI adjusted means were calculated. The primary outcome was disease progression defined as a Î "≥1 in the Medsger's severity score and in distinct items at the 2-year follow-up visit. Logistic regression analysis was carried out to identify predictive factors. Results: 549 patients were enrolled. At multivariate analysis, the EUSTAR-AI adjusted mean was the only predictor of any severity accrual and of that of lung and heart, skin and peripheral vascular disease over 2 years. Conclusion: The adjusted mean EUSTAR-AI has the best predictive value for disease progression and development of severe organ involvement over time in SSc.
CRIS-Team Scopus Importer:2019-09-03
Keywords: autoimmune diseases; outcomes research; systemic sclerosis

Revisiting the gut–joint axis: links between gut inflammation and spondyloarthritis - Gracey, Eric; Vereecke, Lars; McGovern, Dermot; Fröhling, Mareike; Schett, Georg; Danese, Silvio; De Vos, Martine; Van den Bosch, Filip; Elewaut, Dirk (Nature Reviews Rheumatology, 2020)
Gut inflammation is strongly associated with spondyloarthritis (SpA), as exemplified by the high prevalence of inflammatory bowel disease (IBD) and the even higher occurrence of subclinical gut inflammation in patients with SpA. The gut–joint axis of inflammation in SpA is further reinforced by similarities in immunopathogenesis at both anatomical sites and by the clinical success of therapies blocking TNF and IL-23 in IBD and in some forms of SpA. Many genetic risk factors are shared between SpA and IBD, and changes in the composition of gut microbiota are seen in both diseases. Current dogma is that inflammation in SpA initiates in the gut and leads to joint inflammation; however, although conceptually attractive, some research does not support this causal relationship. For example, therapies targeting IL-17A are efficacious in the joint but not the gut, and interfering with gut trafficking by targeting molecules such as α4β7 in IBD can lead to onset or flares of SpA. Several important knowledge gaps remain that must be addressed in future studies. Determining the true nature of the gut–joint axis has real-world implications for the treatment of patients with co-incident IBD and SpA and for the repurposing of therapeutics from one disease to the other.
CRIS-Team Scopus Importer:2020-07-24

„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 manifestations of scurvy - Ferrari, Claudia; Possemato, Niccolo; Pipitone, Nicolo; Manger, Bernhard; Salvarani, Carlo (Current Rheumatology Reports, 2015)
This paper reviews the rheumatological manifestations of scurvy, based on articles published in English from 1965 until October 2014, with a particular focus on rheumatological manifestations. Scurvy is a rare, uncommon disease in developed countries. Due to its clinical heterogeneity, the disease can easily mimic rheumatologic conditions leading to a delay in diagnosis and treatment.
EVALuna2:12959

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.
EVALuna2:13435

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.
EVALuna2:13409

Rheumatologic Manifestations of Hemoglobinopathies - Manger, Bernhard (Zeitschrift für Rheumatologie, 2019)
CRIS-Team WoS Importer:2019-08-20

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

Rheumatologische Weiterbildungsstellen in Deutschland - Pfeil, Alexander; Krusche, Martin; Proft, Fabian; Vossen, Diana; Braun, Jurgen; Baraliakos, Xenofon; Berliner, Michael N.; Keysser, Gernot; Krause, Andreas; Lorenz, Hanns-Martin; Manger, Bernhard; Schuch, Florian; et al. (Zeitschrift für Rheumatologie, 2022)
Background In the next few years many general practitioners and specialists will retire. As in other disciplines the question arises in rheumatology whether sufficient training positions are available to maintain or expand the supply of care according to demand. Therefore, the German Society of Rheumatology (DGRh) has assigned its committee for education and training to review the currently available training opportunities in Germany. The aim of this work is the quantitative survey of the training capacity to become a specialist in internal medicine and rheumatology. Methods Within the framework of this study, a survey was conducted via the homepages of the 17 state medical associations to determine the postgraduate medical officers, their place of work and the duration of their postgraduate training capabilities. Based on the data, a nationwide survey of training positions was conducted. Results Specialized rheumatology training is established at 229 training centers in Germany, whereby data from 187 training sites were available for analysis. The training locations are distributed as followed: 52.4% clinical sector and 47.6% outpatient sector. In total, 478.4 training positions are available in Germany (clinical sector: 391.4 and outpatient sector: 87) and 17.2% of the positions (clinical sector: 11.4% and outpatient sector: 43.1%) are not occupied. Conclusion Based on this study, it can be shown that most of the continuing education positions are available in the clinical sector. In contrast, half of the training positions in the outpatient area are not filled. In order to improve the training situation, it is essential to integrate outpatient colleagues into the training program. This presupposes that further training is supported or financed by the healthcare system. In this context, optimal rheumatological care must be permanently guaranteed throughout Germany in order to provide sufficient care for the approximately 2 million patients with inflammatory rheumatic diseases.
CRIS-Team WoS Importer:2022-11-04

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

RITUXIMAB IN SYSTEMIC SCLEROSIS : SAFETY AND EFFICACY DATA FROM THE EUSTAR NETWORK - Elhai, M.; Distler, O.; Smith, V.; Matucci-Cerinic, M.; Alegre-Sancho, J. J.; Truchetet, M. -E.; Braun-Moscovici, Y.; Iannone, F.; Chotchaeva, F.; Lescoat, A.; Siegert, E.; Castellvi, I.; et al. (2018)
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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)
EVALuna2:35053

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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