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 Lupus Erythematosus often have increased Radiosensitivity - Schuster, Barbara; Schenker, Hannah; Fietkau, Rainer; Distel, Luitpold (STRAHLENTHERAPIE UND ONKOLOGIE, 2019)
CRIS-Team WoS Importer:2019-06-07

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.
EVALuna2:13525

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)
EVALuna2:35008

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

Periodontal sources of citrullinated antigens and TLR agonists related to RA - Vitkov, Ljubomir; Hannig, Matthias; Minnich, Bernd; Herrmann, Martin (Autoimmunity, 2018)
Anti-citrullinated protein autoantibodies (ACPA) precede the onset of clinical and subclinical rheumatoid arthritis (RA). ACPA are frequently generated in further chronic inflammatory diseases, e.g. chronic obstructive pulmonary disease, lupus, periodontitis (PD), characterized by citrullination and mucosal as well as systemic autoimmunity against citrullinated proteins. PD is of particular interest, as it exhibits two sources of citrullination, namely peptidylarginine deiminase 4 (PAD4) of periodontal neutrophils and neutrophil extracellular traps (NETs) as well as the PAD of Porphyromonas gingivalis (PPAD). Whereas the PAD4-citrullinated host peptides and/or proteins occur physiologically, PPAD-citrullinated ones appear under pathological conditions as neo-antigens. Frequently, the oral pathogens P. gingivalis and A. actinomycetemcomitans directly and indirectly participate in synovitis in RA, providing topical citrullination: P. gingivalis via PPAD and A. actinomycetemcomitans via leukotoxin A-mediated ROS-independent NET formation. In addition, transient bacteraemia due to tooth brushing indicates the possibility that citrullinated peptides and/or proteins from periodontium regularly enter the blood circulation. In this way, the mucosal firewall is evaded and the systemic immune response against citrullinated peptides and/or proteins is facilitated. However, the role of swallowed PD-derived sludge for the induction of oral tolerance remains to be established.We hypothesize (I) PD-driven endotoxemia may increase the host responsiveness to autoantigens via TLR4 activation and (II) this participates in development and propagation of RA (III) circulating PD-derived bacterial DNA is taken up by phagocytes, activates TLR9, and thus increases the responsiveness to autoantigens.
EVALuna2:213273

Periodontitis-Derived Dark-NETs in Severe Covid-19 - Vitkov, Ljubomir; Knopf, Jasmin; Krunić, Jelena; Schoen, Janina; Minnich, Bernd; Hannig, Matthias; Herrmann, Martin; Schauer, Christine (Frontiers in Immunology, 2022)
The frequent severe COVID-19 course in patients with periodontitis suggests a link of the aetiopathogenesis of both diseases. The formation of intravascular neutrophil extracellular traps (NETs) is crucial to the pathogenesis of severe COVID-19. Periodontitis is characterised by an increased level of circulating NETs, a propensity for increased NET formation, delayed NET clearance and low-grade endotoxemia (LGE). The latter has an enormous impact on innate immunity and susceptibility to infection with SARS-CoV-2. LPS binds the SARS-CoV-2 spike protein and this complex, which is more active than unbound LPS, precipitates massive NET formation. Thus, circulating NET formation is the common denominator in both COVID-19 and periodontitis and other diseases with low-grade endotoxemia like diabetes, obesity and cardiovascular diseases (CVD) also increase the risk to develop severe COVID-19. Here we discuss the role of propensity for increased NET formation, DNase I deficiency and low-grade endotoxaemia in periodontitis as aggravating factors for the severe course of COVID-19 and possible strategies for the diminution of increased levels of circulating periodontitis-derived NETs in COVID-19 with periodontitis comorbidity.
CRIS-Team Scopus Importer:2022-05-06
Keywords: dysregulated immunity; inhibition of NET formation; NET hyper-responsiveness; NET-induced damage; neutrophil hyper-responsiveness; trained immunity

Perivascular white matter lesion pattern in a patient with steroid-responsive encephalopathy - Witsch, Jens; Bohner, Georg; Rech, Jürgen; Trendelenburg, George (Journal of Neurology, 2013)
CRIS-Team Scopus Importer:2021-02-03

Persistence on JAK Inhibitors in Daily Practice: Evaluation of the Rhadar-registry - Risser, Linus; Witte, Torsten; Bartz-Bazzanella, Peter; Von Der Decken, Cay; Knitza, Johannes; Fekete, Sandor P.; Zink, Alexander; Gauler, Georg; Wurth, Patrick; Aries, Peer; Karberg, Kirsten; Kuhn, Christoph; et al. (ARTHRITIS & RHEUMATOLOGY, 2021)
CRIS-Team WoS Importer:2022-03-11

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)
EVALuna2:34161

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

Physical phenotype of blood cells is altered in COVID-19 - Kubankova, Marketa; Hohberger, Bettina; Hoffmanns, Jakob; Fürst, Julia; Herrmann, Martin; Guck, Jochen; Kraeter, Martin (Biophysical Journal, 2021)
Clinical syndrome coronavirus disease 2019 (COVID-19) induced by severe acute respiratory syndrome coronavirus 2 is characterized by rapid spreading and high mortality worldwide. Although the pathology is not yet fully understood, hyperinflammatory response and coagulation disorders leading to congestions of microvessels are considered to be key drivers of the still-increasing death toll. Until now, physical changes of blood cells have not been considered to play a role in COVID-19 related vascular occlusion and organ damage. Here, we report an evaluation of multiple physical parameters including the mechanical features of five frequent blood cell types, namely erythrocytes, lymphocytes, monocytes, neutrophils, and eosinophils. More than four million blood cells of 17 COVID-19 patients at different levels of severity, 24 volunteers free from infectious or inflammatory diseases, and 14 recovered COVID-19 patients were analyzed. We found significant changes in lymphocyte stiffness, monocyte size, neutrophil size and deformability, and heterogeneity of erythrocyte deformation and size. Although some of these changes recovered to normal values after hospitalization, others persisted for months after hospital discharge, evidencing the long-term imprint of COVID-19 on the body.
CRIS-Team Scopus Importer:2021-07-30

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

Platform for isolation and characterization of SARS-CoV-2 variants enables rapid characterization of Omicron in Australia - Aggarwal, Anupriya; Stella, Alberto Ospina; Walker, Gregory; Akerman, Anouschka; Esneau, Camille; Milogiannakis, Vanessa; Burnett, Deborah L.; Mcallery, Samantha; Silva, Mariana Ruiz; Lu, Yonghui; Foster, Charles S. P.; Brilot, Fabienne; et al. (Nature Microbiology, 2022)
A platform developed for rapid isolation of SARS-CoV-2 variants also facilitates the characterization of variant immune evasion and viral fitness. The platform enabled rapid detection of the Omicron variant in samples of the first cases in Australia.
CRIS-Team WoS Importer:2022-06-10

PLD3 and PLD4 are single-stranded acid exonucleases that regulate endosomal nucleic-acid sensing - Gavin, Amanda L.; Huang, Deli; Huber, Christoph; Martensson, Annica; Tardif, Virginie; Skog, Patrick D.; Blane, Tanya R.; Thinnes, Therese C.; Osborn, Kent; Chong, Hayley S.; Kargaran, Farnaz; Kimm, Phoebe; et al. (Nature Immunology, 2018)
The sensing of microbial genetic material by leukocytes often elicits beneficial pro-inflammatory cytokines, but dysregulated responses can cause severe pathogenesis. Genome-wide association studies have linked the gene encoding phospholipase D3 (PLD3) to Alzheimer's disease and have linked PLD4 to rheumatoid arthritis and systemic sclerosis. PLD3 and PLD4 are endolysosomal proteins whose functions are obscure. Here, PLD4-deficient mice were found to have an inflammatory disease, marked by elevated levels of interferon-γ (IFN-γ) and splenomegaly. These phenotypes were traced to altered responsiveness of PLD4-deficient dendritic cells to ligands of the single-stranded DNA sensor TLR9. Macrophages from PLD3-deficient mice also had exaggerated TLR9 responses. Although PLD4 and PLD3 were presumed to be phospholipases, we found that they are 5' exonucleases, probably identical to spleen phosphodiesterase, that break down TLR9 ligands. Mice deficient in both PLD3 and PLD4 developed lethal liver inflammation in early life, which indicates that both enzymes are needed to regulate inflammatory cytokine responses via the degradation of nucleic acids.
EVALuna2:214389

PMA and crystal-induced neutrophil extracellular trap formation involves RIPK1-RIPK3-MLKL signaling - Desai, Jyaysi; Kumar, Santhosh V.; Mulay, Shrikant R.; Konrad, Lukas; Romoli, Simone; Schauer, Christine; Herrmann, Martin; Bilyy, Rostyslav; Mueller, Susanna; Popper, Bastian; Nakazawa, Daigo; Weidenbusch, Marc; et al. (European Journal of Immunology, 2016)
Neutrophil extracellular trap (NET) formation contributes to gout, autoimmune vasculitis, thrombosis, and atherosclerosis. The outside-in signaling pathway triggering NET formation is unknown. Here, we show that the receptor-interacting protein kinase (RIPK)-1-stabilizers necrostatin-1 or necrostatin-1s and the mixed lineage kinase domain-like (MLKL)-inhibitor necrosulfonamide prevent monosodium urate (MSU) crystal- or PMA-induced NET formation in human and mouse neutrophils. These compounds do not affect PMA- or urate crystal-induced production of ROS. Moreover, neutrophils of chronic granulomatous disease patients are shown to lack PMA-induced MLKL phosphorylation. Genetic deficiency of RIPK3 in mice prevents MSU crystal-induced NET formation in vitro and in vivo. Thus, neutrophil death and NET formation may involve the signaling pathway defining necroptosis downstream of ROS production. These data imply that RIPK1, RIPK3, and MLKL could represent molecular targets in gout or other crystallopathies.
EVALuna2:13174

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

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

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

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

Positionspapier der Kommission Digitale Rheumatologie der Deutschen Gesellschaft für Rheumatologie e. V.: Aufgaben, Ziele und Perspektiven für eine moderne Rheumatologie - Knitza, Johannes; Callhoff, J.; Chehab, G.; Hueber, Axel; Kiltz, U.; Kleyer, Arnd; Krusche, M.; Simon, David; Specker, C.; Schneider, M.; Voormann, A.; Welcker, M.; et al. (Zeitschrift für Rheumatologie, 2020)
Digitalization in the healthcare system is a great challenge for rheumatology as for other medical disciplines. The German Society for Rheumatology (DGRh) wants to actively participate in this process and benefit from it. By founding the commission on digital rheumatology, the DGRh has created a committee that deals with the associated tasks, advises the DGRh on questions and positions associated with digital health. For the DGRh, this affects the most diverse areas of digitalization in medicine and rheumatology. This position paper presents the topics and developments currently handled by the commission and the tasks identified.
CRIS-Team Scopus Importer:2020-07-24
Keywords: App; Digitalization; eHealth; Health services research; mHealth

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 early metastatic disease in experimental breast cancer bone metastasis by combining PET/CT and MRI parameters to a Model-Averaged Neural Network - Ellmann, Stephan; Seyler, Lisa; Evers, Jochen; Heinen, Henrik; Bozec, Aline; Prante, Olaf; Kuwert, Torsten; Uder, Michael; Bäuerle, Tobias (Bone, 2019)
Macrometastases in bone are preceded by bone marrow invasion of disseminated tumor cells. This study combined functional imaging parameters from FDG-PET/CT and MRI in a rat model of breast cancer bone metastases to a Model-averaged Neural Network (avNNet) for the detection of early metastatic disease and prediction of future macrometastases. Metastases were induced in 28 rats by injecting MDA-MB-231 breast cancer cells into the right superficial epigastric artery, resulting in the growth of osseous metastases in the right hind leg of the animals. All animals received FDG-PET/CT and MRI at days 0, 10, 20 and 30 after tumor cell injection. In total, 18/28 rats presented with metastases at days 20 or 30 (64.3%). None of the animals featured morphologic bone lesions during imaging at day 10, and the imaging parameters acquired at day 10 did not differ significantly between animals with metastases at or after day 20 and those without (all p > 0.3). The avNNet trained with the imaging parameters acquired at day 10, however, achieved an accuracy of 85.7% (95% CI 67.3-96.0%) in predicting future macrometastatic disease (ROCAUC 0.90; 95% CI 0.76-1.00), and significantly outperformed the predictive capacities of all single parameters (all p <= 0.02). The integration of functional FDG-PET/CT and MRI parameters into an avNNet can thus be used to predict macrometastatic disease with high accuracy, and their combination might serve as a surrogate marker for bone marrow invasion as an early metastatic process that is commonly missed during conventional staging examinations.
CRIS-Team WoS Importer:2019-02-27

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)
EVALuna2:35024

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)
EVALuna2:33139

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.
EVALuna2:13230

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

Preferences for preventive treatments for rheumatoid arthritis: discrete choice survey in the UK, Germany and Romania - Simons, Gwenda; Veldwijk, Jorien; Disantostefano, Rachael L.; Englbrecht, Matthias; Radawski, Christine; Bywall, Karin Scholin; Mendez, Larissa Valor; Hauber, Brett; Raza, Karim; Falahee, Marie (Rheumatology, 2022)
Objective To quantify preferences for preventive therapies for rheumatoid arthritis (RA) across three countries. Methods A web-based survey including a discrete choice experiment was administered to adults recruited via survey panels in the UK, Germany and Romania. Participants were asked to assume they were experiencing arthralgia and had a 60% chance of developing RA in the next 2 years and completed 15 choices between no treatment and two hypothetical preventive treatments. Treatments were defined by six attributes (effectiveness, risks and frequency/route of administration) with varying levels. Participants also completed a choice task with fixed profiles reflecting subjective estimates of candidate preventive treatments. Latent class models (LCMs) were conducted and the relative importance of attributes, benefit-risk trade-offs and predicted treatment uptake was subsequently calculated. Results Completed surveys from 2959 participants were included in the analysis. Most participants preferred treatment over no treatment and valued treatment effectiveness to reduce risk more than other attributes. A five-class LCM best fitted the data. Country, perceived risk of RA, health literacy and numeracy predicted class membership probability. Overall, the maximum acceptable risk for a 40% reduction in the chance of getting RA (60% to 20%) was 21.7%, 19.1% and 2.2% for mild side effects, serious infection and serious side effects, respectively. Predicted uptake of profiles reflecting candidate prevention therapies differed across classes. Conclusion Effective preventive pharmacological treatments for RA were acceptable to most participants. The relative importance of treatment attributes and likely uptake of fixed treatment profiles were predicted by participant characteristics.
CRIS-Team WoS Importer:2022-09-16

Preflight Biomarkers of Bone Remodelling Predict Bone Loss on Long-Duration Spaceflight - Gabel, Leigh; Hulme, Paul; Liphardt, Anna-Maria; Heer, Martina; Zwart, Sara; Sibonga, Jean; Smith, Scott; Boyd, Steven (JOURNAL OF BONE AND MINERAL RESEARCH, 2020)
CRIS-Team WoS Importer:2021-01-08

Pre-flight exercise and bone metabolism predict unloading-induced bone loss due to spaceflight - Gabel, Leigh; Liphardt, Anna-Maria; Hulme, Paul A.; Heer, Martina; Zwart, Sara R.; Sibonga, Jean D.; Smith, Scott M.; Boyd, Steven (British Journal of Sports Medicine, 2021)
Objectives: Bone loss remains a primary health concern for astronauts, despite in-flight exercise. We examined changes in bone microarchitecture, density and strength before and after long-duration spaceflight in relation to biochemical markers of bone turnover and exercise. Methods: Seventeen astronauts had their distal tibiae and radii imaged before and after space missions to the International Space Station using high-resolution peripheral quantitative CT. We estimated bone strength using finite element analysis and acquired blood and urine biochemical markers of bone turnover before, during and after spaceflight. Pre-flight exercise history and in-flight exercise logs were obtained. Mixed effects models examined changes in bone and biochemical variables and their relationship with mission duration and exercise. Results: At the distal tibia, median cumulative losses after spaceflight were -2.9% to -4.3% for bone strength and total volumetric bone mineral density (vBMD) and -0.8% to -2.6% for trabecular vBMD, bone volume fraction, thickness and cortical vBMD. Mission duration (range 3.5-7 months) significantly predicted bone loss and crewmembers with higher concentrations of biomarkers of bone turnover before spaceflight experienced greater losses in tibia bone strength and density. Lower body resistance training volume (repetitions per week) increased 3-6 times in-flight compared with pre-spaceflight. Increases in training volume predicted preservation of tibia bone strength and trabecular vBMD and thickness. Conclusions: Findings highlight the fundamental relationship between mission duration and bone loss. Pre-flight markers of bone turnover and exercise history may identify crewmembers at greatest risk of bone loss due to unloading and may focus preventative measures.
CRIS-Team Scopus Importer:2021-03-05
Keywords: biochemistry; biomechanics; bone; exercise; osteoporosis

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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Prenatal Alcohol Exposure Is Associated With Adverse Cognitive Effects and Distinct Whole-Genome DNA Methylation Patterns in Primary School Children - Frey, Silke; Eichler, Anna; Stonawski, Valeska; Kriebel, Jennifer; Wahl, Simone; Gallati, Sabina; Goecke, Tamme W.; Fasching, Peter A.; Beckmann, Matthias W.; Kratz, Oliver; Moll, Gunther; Heinrich, Hartmut; et al. (Frontiers in Behavioral Neuroscience, 2018)
Prenatal alcohol exposure (PAE) is known to elicit a broad range of systemic effects, including neurophysiological alterations that result in adverse behavioral and cognitive outcomes. However, molecular pathways underlying these long-term intrauterine effects remain to be investigated. Here, we tested a hypothesis that PAE may lead to epigenetic alterations to the DNA resulting in attentional and cognitive alterations of the children. We report the results of the study that included 156 primary school children of the Franconian Cognition and Emotion Studies (FRANCES) cohort which were tested for an objective marker of PAE, ethyl glucuronide (EtG) in meconium at birth. Thirty-two newborns were found to be exposed to alcohol with EtG values above 30 ng/g (EtG+). Previously we described PAE being associated with lower IQ and smaller amplitude of the event-related potential component P3 in go trials (Go-P3), which indicates a reduced capacity of attentional resources. Whole-genome methylation analysis of the buccal cell DNA revealed 193 differentially methylated genes in children with positive meconium EtG, that were clustered into groups involved in epigenetic modifications, neurodegeneration, neurodevelopment, axon guidance and neuronal excitability. Furthermore, we detected mediation effects of the methylation changes in DPP10 and SLC16A9 genes on the EtG related cognitive and attention-related deficits. Our results suggest that system-wide epigenetic changes are involved in long-term effects of PAE. In particular, we show an epigenetic mediation of PAE effects on cognition and attention-related processes.
EVALuna2:36368

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)
EVALuna2:33811

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

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

Profound neutralization evasion and augmented host cell entry are hallmarks of the fast-spreading SARS-CoV-2 lineage XBB.1.5 - Hoffmann, Markus; Arora, Prerna; Nehlmeier, Inga; Kempf, Amy; Cossmann, Anne; Schulz, Sebastian; Morillas Ramos, Gema; Manthey, Luis A.; Jäck, Hans-Martin; Behrens, Georg M.N.; Pöhlmann, Stefan (Cellular & Molecular Immunology, 2023)
CRIS-Team Scopus Importer:2023-03-17

Prognostic Value of Homotypic Cell Internalization by Nonprofessional Phagocytic Cancer Cells - Schwegler, Manuela; Wirsing, Anna Maria; Schenker, Hannah; Ott, Laura; Ries, Johannes; Buettner-Herold, Maike; Fietkau, Rainer; Putz, Florian; Distel, Luitpold (BioMed Research International, 2015)
Background. In this study, we investigated the prognostic role of homotypic tumor cell cannibalism in different cancer types. Methods. The phenomenon of one cell being internalized into another, which we refer to as "cell-in-cell event," was assessed in 416 cases from five head and neck cancer cohorts, as well as one anal and one rectal cancer cohort. The samples were processed into tissue microarrays and immunohistochemically stained for E-cadherin and cleaved caspase-3 to visualize cell membranes and apoptotic cell death. Results. Cell-in-cell events were found in all of the cohorts. The frequency ranged from 0.7 to 17.3 cell-in-cell events per mm(2). Hardly any apoptotic cells were found within the cell-in-cell structures, although apoptotic cell rates were about 1.6 to two times as high as cell-in-cell rates of the same tissue sample. High numbers of cell-in-cell events showed adverse effects on patients' survival in the head and neck and in the rectal cancer cohorts. In multivariate analysis, high frequency was an adverse prognostic factor for overall survival in patients with head and neck cancer (p = 0.008). Conclusion. Cell-in-cell events were found to predict patient outcomes in various types of cancer better than apoptosis and proliferation and might therefore be used to guide treatment strategies.
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Programmable Hierarchical Construction of Mixed/Multilayered Polysaccharide Nanocapsules through Simultaneous/Sequential Nanoprecipitation Steps - Yan, Xibo; Ramos, Ricardo Almeida Neves Sampayo; Alcouffe, Pierre; Munoz, Luis Enrique; Bilyy, Rostyslav O.; Ganachaud, François; Bernard, Julien (Biomacromolecules, 2019)
We report here on a one-pot construction of oil-filled hierarchical capsular assemblies using the nanoprecipitation technique. Relying on multicomponent phase diagrams, we show that simultaneous and/or sequential nanoprecipitations involving polymer combinations can be precisely programmed to design a new class of mixed/multilayered multicomponent nanocapsules, with a precise control of the dimensions, shell thickness/composition, and spatial distribution of the building blocks. The simplicity and tunability of this approach are exemplified here with a library of neutral and ionic polysaccharides giving access to a range of functional multilayered nanocarriers of interest for biomedical applications.
CRIS-Team Scopus Importer:2019-10-15

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

Prolonged Ex vivo expansion and differentiation of naïve murine CD43(-) B splenocytes - Zambrano, Kenny; Jerome, Valerie; Freitag, Ruth; Buchholz, Rainer; Jäck, Hans-Martin; Hübner, Holger; Schuh, Wolfgang; Buchholz, Rainer (Biotechnology Progress, 2016)
Ex vivo expansion of naive primary B cells is still a challenge, yet would open new possibilities for in vitro studies of the immune response or the production of monoclonal antibodies. In our hands, unstimulated murine B cells did not expand in significant numbers, while culture viability decreased rapidly within a few days. Activation mimicking in vivo stimulation through either T cell-independent or T-cell dependent signaling, led to several division cycles, albeit accompanied by irreversible differentiation. By co-culturing B cells under moderate hypothermia (30°C) on live feeder fibroblasts expressing recombinant CD40 ligand (CD154) and by repeatedly transferring cultured B cells to new feeder cell cultures, we could extend the growth of primary mouse B cells compared to cultures maintained at 37°C. B cells under these conditions showed an activated phenotype as shown by the presence of AID and IRF4, two factors required for IgH class switch recombination in antigen-activated B cells. In contrast to cells cultured at 37°C, B cells under hyperthermia did surprisingly not differentiate into Blimp-1 expressing plasmablasts. Thus, the repeated batch process under hyperthermic conditions represents a first step towards the development of a continuous cultivation system for the expansion of primary B cells. © 2016 American Institute of Chemical Engineers Biotechnol. Prog., 32:978-989, 2016.
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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.
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Propionic Acid Shapes the Multiple Sclerosis Disease Course by an Immunomodulatory Mechanism - Duscha, Alexander; Gisevius, Barbara; Hirschberg, Sarah; Yissachar, Nissan; Stangl, Gabriele I.; Eilers, Eva; Bader, Verian; Haase, Stefanie; Kaisler, Johannes; David, Christina; Schneider, Ruth; Troisi, Riccardo; et al. (Cell, 2020)
Short-chain fatty acids are processed from indigestible dietary fibers by gut bacteria and have immunomodulatory properties. Here, we investigate propionic acid (PA) in multiple sclerosis (MS), an autoimmune and neurodegenerative disease. Serum and feces of subjects with MS exhibited significantly reduced PA amounts compared with controls, particularly after the first relapse. In a proof-of-concept study, we supplemented PA to therapy-naive MS patients and as an add-on to MS immunotherapy. After 2 weeks of PA intake, we observed a significant and sustained increase of functionally competent regulatory T (Treg) cells, whereas Th1 and Th17 cells decreased significantly. Post-hoc analyses revealed a reduced annual relapse rate, disability stabilization, and reduced brain atrophy after 3 years of PA intake. Functional microbiome analysis revealed increased expression of Treg-cell-inducing genes in the intestine after PA intake. Furthermore, PA normalized Treg cell mitochondrial function and morphology in MS. Our findings suggest that PA can serve as a potent immunomodulatory supplement to MS drugs.
CRIS-Team Scopus Importer:2020-03-27
Keywords: autoimmune diseases; immune modulation; microbiome; multiple sclerosis; neuroregeneration; propionic acid; regulatory T cells

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

Prospect of Plasmacytoid Dendritic Cells in Enhancing Anti-Tumor Immunity of Oncolytic Herpes Viruses - Schuster, Philipp; Lindner, Georg; Thomann, Sabrina; Haferkamp, Sebastian; Schmidt, Barbara (Cancers, 2019)
The major type I interferon-producing plasmacytoid dendritic cells (pDC) surround and infiltrate certain tumors like malignant melanoma, head and neck cancer, and ovarian and breast cancer. The presence of pDC in these tumors is associated with an unfavorable prognosis for the patients as long as these cells are unstimulated. Upon activation by synthetic Toll-like receptor agonists or viruses, however, pDC develop cytotoxic activities. Viruses have the additional advantage to augment cytotoxic activities of pDC via lytic replication in malignant lesions. These effects turn cold tumors into hotspots, recruiting further immune cells to the site of inflammation. Activated pDC contribute to cross-presentation of tumor-associated antigens by classical dendritic cells, which induce cytotoxic T-cells in particular in the presence of checkpoint inhibitors. The modification of oncolytic herpes viruses via genetic engineering favorably affects this process through the enhanced production of pro-inflammatory cytokines, curbing of tumor blood supply, and removal of extracellular barriers for efficient viral spread. Importantly, viral vectors may contribute to stimulation of memory-type adaptive immune responses through presentation of tumor-related neo- and/or self-antigens. Eventually, both replication-competent and replication-deficient herpes simplex virus 1 (HSV-1) may serve as vaccine vectors, which contribute to tumor regression by the stimulation of pDC and other dendritic cells in adjuvant and neo-adjuvant situations.
CRIS-Team WoS Importer:2019-07-09

Proteasomal degradation induced by DPP9-mediated processing competes with mitochondrial protein import - Finger, Yannik; Habich, Markus; Gerlich, Sarah; Urbanczyk, Sophia; van de Logt, Erik; Koch, Julian; Schu, Laura; Lapacz, Kim Jasmin; Ali, Muna; Petrungaro, Carmelina; Salscheider, Silja Lucia; Pichlo, Christian; et al. (EMBO Journal, 2020)
Plasticity of the proteome is critical to adapt to varying conditions. Control of mitochondrial protein import contributes to this plasticity. Here, we identified a pathway that regulates mitochondrial protein import by regulated N-terminal processing. We demonstrate that dipeptidyl peptidases 8/9 (DPP8/9) mediate the N-terminal processing of adenylate kinase 2 (AK2) en route to mitochondria. We show that AK2 is a substrate of the mitochondrial disulfide relay, thus lacking an N-terminal mitochondrial targeting sequence and undergoing comparatively slow import. DPP9-mediated processing of AK2 induces its rapid proteasomal degradation and prevents cytosolic accumulation of enzymatically active AK2. Besides AK2, we identify more than 100 mitochondrial proteins with putative DPP8/9 recognition sites and demonstrate that DPP8/9 influence the cellular levels of a number of these proteins. Collectively, we provide in this study a conceptual framework on how regulated cytosolic processing controls levels of mitochondrial proteins as well as their dual localization to mitochondria and other compartments.
CRIS-Team Scopus Importer:2020-08-28
Keywords: adenylate kinase 2; dipeptidyl peptidase 9; MIA40; mitochondrial protein import; quality control

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

Protektive Makrophagen: Neue Einblicke zur Rolle von Synovialmakrophagen bei entzündlichen Gelenkerkrankungen - Knab, Katharina; Chambers, David; Krönke, Gerhard (Zeitschrift für Rheumatologie, 2021)
Macrophages are among the phylogenetically oldest cells of the immune system and are found in all tissues and organs. In addition to playing an important role in immune response against pathogenic microorganisms, these cells were previously described to play a vital role in chronic inflammatory diseases such as rheumatoid arthritis. Using novel techniques such as single-cell sequencing and advanced microscopy techniques it has now been shown that macrophages are far more versatile. Thus, these cells contribute considerably to tissue homeostasis and tissue regeneration. As each tissue has to fulfill special requirements, macrophages vary in their phenotype and function between organs. New data have now identified a specialised population of epithelioid macrophages that exert a protective and anti-inflammatory function in synovial tissue and prevent the initial onset as well as episodes of joint inflammation in rheumatoid arthritis.
CRIS-Team Scopus Importer:2021-11-05
Keywords: Macrophage heterogeneity; Macrophage ontogeny; Resident macrophages; Synovial macrophages; Synovial microenvironment

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

Prothrombotic State, Platelet Activation and Netosis in Systemic Lupus Erythematosus - Monzon Manzano, Elena; Fernandez-Bello, Ihosvany; Justo Sanz, Raul; Valor, Larissa; Javier Lopez-Longo, Francisco; Robles, Angel; Alvarez Roman, Teresa; Canales, Miguel A.; Jimenez-Yuste, Victor; Butta, Nora (BLOOD, 2019)
CRIS-Team WoS Importer:2021-10-18

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 epidemiology, comorbid disease profiles and risk factors: Results from a claims database analysis - Rech, Jürgen; Sticherling, Michael; Stoessel, Daniel; Biermann, Mona H.C.; Häberle, Benjamin M.; Reinhardt, Maximilian (Rheumatology Advances in Practice, 2020)
Objective. Psoriasis is a systemic inflammatory disease often accompanied by comorbidities, including metabolic syndrome, cardiovascular diseases and depression. Up to 41% of psoriasis patients develop psoriatic arthritis (PsA), making it one of the most relevant manifestations. A large health claims data set was analysed to determine the rate of PsA development in psoriasis patients. Furthermore, comorbid disease profiles of psoriasis patients with or without PsA were compared, and potential risk factors for the development of PsA were identified. Methods. This was a non-interventional, retrospective analysis of anonymized insurance health claims data using a subset of the Institute of Applied Health Research Berlin (InGef) database. The primary outcome was the prevalence and incidence of diagnosed PsA among psoriasis patients in Germany. Risk factors for the development of PsA in psoriasis patients were determined by conditional logistic regression analysis. Results. The cumulative percentage of patients with existing psoriasis developing concomitant PsA over 4 years was 3.44%, with a mean time to diagnosis of PsA of 1.5 years. Psoriasis patients diagnosed with acute rheumatism (odds ratio: 2.93, 95% CI=1.76, 4.86; P<0.001) or pain in unspecific joints (odds ratio: 1.74, 95% CI=1.01, 2.99; P=0.047) showed an increased risk for development of PsA later on. Interestingly, fewer than half of the patients with concomitant PsA consulted a rheumatologist. Conclusions. Unspecific arthritic symptoms are likely to precede PsA diagnoses and can develop soon after onset of psoriasis, with accumulating risk over time. There is a high unmet need for early rheumatological assessment of psoriasis patients.
CRIS-Team Scopus Importer:2020-12-04
Keywords: Comorbid disease; Epidemiology; Incidence; Insurance health claims data; PsA; Psoriasis; Risk factors

Psoriatic Arthritis - Epidemiology, Incidence Rate in Psoriasis Patients, Comorbidity Profiles and Risk Factor Analysis - Rech, Jürgen; Sticherling, Michael; Biermann, Mona; Haeberle, Benjamin; Reinhardt, Maximilian (ARTHRITIS & RHEUMATOLOGY, 2019)
CRIS-Team WoS Importer:2020-02-07

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.
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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 control for bone quality parameters affected by subject motion in high-resolution peripheral quantitative computed tomography - Pauchard, Yves; Liphardt, Anna-Maria; Macdonald, Heather M.; Hanley, David A.; Boyd, Steven K. (Bone, 2012)
Subject motion during high-resolution peripheral quantitative computed tomography (HR-pQCT) causes image artifacts that affect morphological analysis of bone quality. The aim of our study was to determine effectiveness of techniques for quality control in the presence of motion in vivo including automated and manual approaches. First, repeatability of manual grading was determined within and between laboratories. Given proper training using a standardized scale and training images (provided by the manufacturer), we found that manual grading is suitable for repeatable image quality grading within and across sites (ICC>0.7). Both a new automated technique providing motion measures based on projection moments, and traditional manual grading (1=best, 5=worst) were subsequently used to assess subject data for motion in N=137 image pairs (scan/re-scan) from the Canadian Multicentre Osteoporosis Study (CaMos) Calgary cohort. High quality image pairs were selected and measurement precision was estimated by calculating the coefficient of variation (CV). Consistent with previous data, density parameters (e.g. total bone mineral density) are more robust than structural (e.g. trabecular number) or finite element parameters (e.g. failure load). To obtain acceptable measurement precision, images should not exceed a manual grading of 3 (on a scale from 1 to 5) or an automatic (?(T)) grading of 1.2. Automatic and manual grading provide comparable quality control, but the advantage of the automated technique is its ability to provide a motion value at scan time (providing a basis for real time decision regarding re-scan requirements), and the assessment is objective. Notably, automatic motion measurement can be performed retrospectively based on original scan data, and is therefore well suited for multi-center studies as well as any research where objective quality control is paramount.
EVALuna2:13508

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

Quality of citation data using the natural language processing tool ChatGPT in rheumatology: Creation of false references - Hueber, Axel J.; Kleyer, Arnd (RMD Open, 2023)
CRIS-Team Scopus Importer:2023-07-07
Keywords: Arthritis; Qualitative research; Therapeutics

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 human swiprosin-1/EFhd2 expression on protein and RNA level - Fürnrohr, Barbara G.; Mielenz, Dirk (Calcium-Binding Proteins of the EF-Hand Superfamily, 2019)
Many Ca 2+ -binding proteins are differentially regulated under pro-inflammatory conditions in different organs. Specific quantification of RNA and protein expression of those proteins demands validated protocols. Peripheral blood mononuclear cells (PBMC) can mirror an inflammatory status originating from several organs and can therefore be an important diagnostic tool. Swiprosin-1/EFhd2 (EFhd2) is a 30 kDa Ca 2+ and F-actin binding, cytoskeletal protein with two central EF hands and a C-terminal coiled-coil domain. Unbiased gene expression analyses and proteomics revealed that EFhd2 is regulated under pro-inflammatory conditions in several cell types and tissues. Here we describe validated protocols to quantify the expression of the human orthologue of Swiprosin-1/EFhd2 on RNA and protein level in PBMC. Both methods reveal that EFhd2 is stronger expressed in monocytes than in B cells of healthy donors. Thus, initial experiments relying on qPCR are likely to provide results with functional relevance. The higher expression of EFhd2 in monocytes could be related to monocyte migration under inflammatory conditions.
CRIS-Team Scopus Importer:2019-07-26
Keywords: Alcohol; Anxiety; B cell; Flow cytometry; Inflammation; Neurodegeneration; Neuroninflammation; Peripheral blood mononuclear cell; qPCR; Swiprosin-1/EFhd2

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

Quantitative T2 Mapping Shows Increased Degeneration in Adjacent Intervertebral Discs Following Kyphoplasty - Pachowsky, Milena; Kleyer, Arnd; Wagner, Lisa; Langenbach, Andreas; Simon, David; Janka, Rolf Matthias; May, Matthias; Welsch, Goetz H. (Cartilage, 2018)
Objective A minimally invasive treatment of osteoporotic and nonosteoporotic thoracic and lumbar spine fractures is cement augmentation (kyphoplasty). Little is known about the impact on adjacent intervertebral discs. A quantitative magnetic resonance imaging (MRI) approach in addition to morphological MRI is desirable to evaluate changes in the intervertebral disc. Our study aims to evaluate the feasibility of T2 mapping for the detection of subtle changes in the intervertebral discs in spines after kyphoplasty. Design Intervertebral discs were assessed by quantitative MRI (3.0 T) using T2 relaxation time mapping. Region of interest (ROI; 6 per disc) analyses were performed. The ROIs at the anterior and posterior edges were interpreted as annulus fibrosus (AF). The 2 very inner zones were regarded as nucleus pulposus (NP) and the regions in between as intermediate transition zone. We compared T2 relaxation time values of intervertebral discs adjacent to the vertebrae after kyphoplasty with those nonadjacent to vertebrae after kyphoplasty, especially in the NP. Results The analysis of the ROIs showed that the intervertebral discs of the adjacent vertebral segments are associated with reduced T2 values compared to those that are nonadjacent to the affected vertebrae. Conclusion This study is to our knowledge the first investigation of intervertebral discs after kyphoplasty by quantitative MRI. Quantitative T2 mapping shows increased degeneration in adjacent intervertebral discs following kyphoplasty. Besides its contribution to a broader knowledge of postoperative changes after kyphoplasty, our findings may help to improve differentiation between healthy and degenerated intervertebral discs using these techniques.
EVALuna2:212498

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

Radioresistance shapes the immunogenic Properties of Triple-negative Breast Cancer Cells - Gehre, S.; Rückert, Michael; Sengedorj, Azzaya; Grottker, F.; Reichardt, Clara; Meyer, F.; Borgmann, K.; Fietkau, Rainer; Gaipl, Udo (STRAHLENTHERAPIE UND ONKOLOGIE, 2022)
CRIS-Team WoS Importer:2022-06-03

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 frameshift mutation in SERPINA3 contributes to generalized pustular psoriasis - Hüffmeier, Ulrike; Sticht, Heinrich; Wenzel, J.; Wilsmann-Theis, D.; Wolff, K.; Löhr, Sabine; Frey, Benjamin; Hahn, M.; Ekici, Arif Bülent; Uebe, S.; Thiel, Christian; Wiesmann da Silva Reis, André; et al. (EUROPEAN JOURNAL OF HUMAN GENETICS, 2019)
CRIS-Team WoS Importer:2019-10-25

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 homeostasis - the balance for preventing autoimmunity - Kienhoefer, D.; Boeltz, Sebastian; Hoffmann, Markus (Lupus, 2016)
Being mainly known for their role in the antimicrobial defense and collateral damage they cause in tissues as agents of oxidative stress, reactive oxygen species were considered "the bad guys" for decades. However, in the last years it was shown that the absence of reactive oxygen species can lead to the development of immune-mediated inflammatory diseases. Animal models of lupus, arthritis and psoriasis revealed reactive oxygen species-deficiency as a potent driver of pathogenesis. On the contrary, in chronic stages oxidative stress can still contribute to progression of inflammation. It seems that a neatly adjusted redox balance is necessary to sustain an immune state that both prevents the development of overt autoimmunity and attenuates chronic stages of disease.
EVALuna2:13283

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

Reactogenicity correlates only weakly with humoral immunogenicity after COVID-19 vaccination with BNT162b2 mRNA (Comirnaty®) - Held, Jürgen; Esse, Jan; Tascilar, Koray; Steininger, Philipp; Schober, Kilian; Irrgang, Pascal; Alsalameh, Rayya; Tenbusch, Matthias; Seggewies, Christof; Bogdan, Christian (Vaccines, 2021)
mRNA vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), such as BNT162b2 (Comirnaty®), have proven to be highly immunogenic and efficient but also show marked reactogenicity, leading to adverse effects (AEs). Here, we analyzed whether the severity of AEs predicts the antibody response against the SARS-CoV-2 spike protein. Healthcare workers without prior SARS-CoV-2 infection, who received a prime-boost vaccination with BNT162b2, completed a standardized electronic questionnaire on the duration and severity of AEs. Serum specimens were collected two to four weeks after the boost vaccination and tested with the COVID-19 ELISA IgG (Vircell-IgG), the LIAISON® SARS-CoV-2 S1/S2 IgG CLIA (DiaSorin-IgG) and the iFlash-2019-nCoV NAb surrogate neutralization assay (Yhlo-NAb). A penalized linear regression model fitted by machine learning was used to correlate AEs with antibody levels. Eighty subjects were enrolled in the study. Systemic, but not local, AEs occurred more frequently after the boost vaccination. Elevated SARS-CoV-2 IgG antibody levels were measured in 92.5% of subjects with Vircell-IgG and in all subjects with DiaSorin-IgG and Yhlo-NAb. Gender, age and BMI showed no association with the antibody levels or with the AEs. The linear regression model identified headache, malaise and nausea as AEs with the greatest variable importance for higher antibody levels (Vircell-IgG and DiaSorin-IgG). However, the model performance for predicting antibody levels from AEs was very low for Vircell-IgG (squared correlation coefficient r2 = 0.04) and DiaSorin-IgG (r2 = 0.06). AEs did not predict the surrogate neutralization (Yhlo-NAb) results. In conclusion, AEs correlate only weakly with the SARS-CoV-2 spike protein antibody levels after COVID-19 vaccination with BNT162b2 mRNA.
CRIS-Team Scopus Importer:2021-10-22
Keywords: Adverse effects; Adverse reactions; Antibody; BioNTech; Machine learning; MRNA vaccine; Pfizer; SARS-CoV-2; Side effects

Real-time cell analysis of human cancer cell lines after chemotherapy with functionalized magnetic nanoparticles - Dürr, Stephan; Lyer, Stefan; Mann, Johannes; Janko, Christina; Tietze, Rainer; Schreiber, Eveline; Herrmann, Martin; Alexiou, Christoph (Anticancer Research, 2012)
Background: Magnetic drug targeting is a new and innovative approach in cancer treatment. In order to avoid the adverse effects of chemotherapy, the therapeutic agent is linked to superparamagnetic nanoparticles which are injected into a tumour-supporting artery and is focused by an external magnetic field to the tumour region in order to provoke maximum local impact. Analysis of nanoparticles and chemotherapeutic substances in human cancer cell culture is necessary to provide respective information for in vivo applications. Materials and Methods: The effect of pure mitoxantrone and mitoxantrone bound to nanoparticles was tested on human cancer cell lines using real-time cell analysis (RTCA) and lactate dehydrogenase (LDH) assays. RTCA was performed by impedance measuring. The impedance is expressed as the cell index (CI), which is a parameter of cell viability. Results: RTCA showed that mitoxantrone when bound to nanoparticles was more toxic than the drug alone. The CI clearly decreased faster after adding the chemotherapeutic bound to nanoparticles than when adding the pure drug alone. However, in the first experiments, the particles themselves showed no toxicity at therapeutically relevant concentrations. These results were confirmed by LDH assays. Conclusion: The toxic effects of chemotherapeutic agents (e.g. mitoxantrone) on human cancer cell lines (e.g. MCF-7) can be enhanced if these drugs are bound to magnetic nanoparticles. These preliminary data show a dependency on the different application modes of RTCA. The results presented here are a first step for a better understanding of the effectiveness of magnetic drug targeting as a new and innovative cancer treatment.
CRIS-Team Scopus Importer:2022-06-27
Keywords: Cell culture; Magnetic drug targeting MCF-7 breast cancer cells; Magnetic nanoparticles; Real-time cell analysis

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 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-Mediated NETosis on Neutrophils - Chen, Tao; Li, Yanhong; Sun, Rui; Hu, Huifang; Liu, Yi; Herrmann, Martin; Zhao, Yi; Munoz, Luis Enrique (Frontiers in Immunology, 2021)
Neutrophil extracellular traps (NETs), a web-like structures containing chromatin, have a significant role in assisting the capture and killing of microorganisms by neutrophils during infection. The specific engagement of cell-surface receptors by extracellular signaling molecules activates diverse intracellular signaling cascades and regulates neutrophil effector functions, including phagocytosis, reactive oxygen species release, degranulation, and NET formation. However, overproduction of NETs is closely related to the occurrence of inflammation, autoimmune disorders, non-canonical thrombosis and tumor metastasis. Therefore, it is necessary to understand neutrophil activation signals and the subsequent formation of NETs, as well as the related immune regulation. In this review, we provide an overview of the immunoreceptor-mediated regulation of NETosis. The pathways involved in the release of NETs during infection or stimulation by noninfectious substances are discussed in detail. The mechanisms by which neutrophils undergo NETosis help to refine our views on the roles of NETs in immune protection and autoimmune diseases, providing a theoretical basis for research on the immune regulation of NETs.
CRIS-Team Scopus Importer:2021-12-03
Keywords: chemokine receptor; complement receptors; Fc receptors; neutrophil extracellular traps; pattern recognition receptors

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.
EVALuna2:13122

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

Regions at Risk in the Knee Joint of Young Professional Soccer Players: Longitudinal Evaluation of Early Cartilage Degeneration by Quantitative T2 Mapping in 3 T MRI - Schenker, Hannah; Simon, David; Waldenmeier, Leonie; Evers, Christoph; Janka, Rolf Matthias; Welsch, Goetz H.; Pachowsky, Milena (Cartilage, 2020)
Purpose. The study aims to detect regions at risk for (pre-)osteoarthritis in the tibiofemoral joint of young professional soccer players by evaluating cartilage composition by T2 mapping in a 3 T magnetic resonance imaging setting. Methods. In this longitudinal study, 20 professional adolescent soccer players were included. Tibiofemoral cartilage was assessed by quantitative T2 mapping and T2 values were evaluated by regions of interest analysis. Statistical evaluation, using Wilcoxon signed-rank tests, was performed to compare global T2 values and subregional T2 values between a baseline and a follow-up investigation 4.3 years later. Based on the average of playing time (15 years) we divided the cohort in 2 groups and differences were evaluated. Results. When comparing baseline and follow-up, our findings showed statistically significant increases of the global medial tibial and femoral T2 values. The most noticeable results of the subregional T2 analysis were statistically significant increases in the medial posterior zones (deep femoral 36.1 vs. 39.5, P = 0.001; superficial femoral 57.0 vs. 62.4, P = 0.034; deep tibial 28.3 vs. 34.1, P = 0.009; superficial tibial 43.2 vs. 55.3, P = 0.002). Conclusion. The elevation of T2 values in the medial, especially medial posterior, compartment of the knee joint indicates that these regions are at risk for early cartilage degeneration already at the time of adolescence. The findings can help individualize and optimize training concepts and to be aware of the chronic stress on these vulnerable areas. Prevention programs should be established in young players to avoid further cartilage damage.
CRIS-Team Scopus Importer:2020-06-02
Keywords: adolescent; cartilage; MRI; sports; T2 mapping

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 Energy Metabolism during Early B Lymphocyte Development - Urbanczyk, Sophia; Stein, Merle; Schuh, Wolfgang; Jäck, Hans-Martin; Mougiakakos, Dimitrios; Mielenz, Dirk (International Journal of Molecular Sciences, 2018)
The most important feature of humoral immunity is the adaptation of the diversity of newly generated B cell receptors, that is, the antigen receptor repertoire, to the body's own and foreign structures. This includes the transient propagation of B progenitor cells and B cells, which possess receptors that are positively selected via anabolic signalling pathways under highly competitive conditions. The metabolic regulation of early B-cell development thus has important consequences for the expansion of normal or malignant pre-B cell clones. In addition, cellular senescence programs based on the expression of B cell identity factors, such as Pax5, act to prevent excessive proliferation and cellular deviation. Here, we review the basic mechanisms underlying the regulation of glycolysis and oxidative phosphorylation during early B cell development in bone marrow. We focus on the regulation of glycolysis and mitochondrial oxidative phosphorylation at the transition from non-transformed pro- to pre-B cells and discuss some ongoing issues. We introduce Swiprosin-2/EFhd1 as a potential regulator of glycolysis in pro-B cells that has also been linked to Ca2+-mediated mitoflashes. Mitoflashes are bioenergetic mitochondrial events that control mitochondrial metabolism and signalling in both healthy and disease states. We discuss how Ca2+ fluctuations in pro- and pre-B cells may translate into mitoflashes in early B cells and speculate about the consequences of these changes.
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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 osteosarcoma cell lung metastasis by the c-Fos/AP-1 target FGFR1. - Weekes, Daniel; Kashima, T. G.; Zandueta, C.; Perurena, Naiara; Thomas, D. P.; Sunters, A.; Vuillier, C.; Bozec, Aline; El-Emir, E.; Miletich, Isabelle; Patino-Garcia, A.; Lecanda, F.; et al. (Oncogene, 2016)
Osteosarcoma is the most common primary malignancy of the skeleton and is prevalent in children and adolescents. Survival rates are poor and have remained stagnant owing to chemoresistance and the high propensity to form lung metastases. In this study, we used in vivo transgenic models of c-fos oncogene-induced osteosarcoma and chondrosarcoma in addition to c-Fos-inducible systems in vitro to investigate downstream signalling pathways that regulate osteosarcoma growth and metastasis. Fgfr1 (fibroblast growth factor receptor 1) was identified as a novel c-Fos/activator protein-1(AP-1)-regulated gene. Induction of c-Fos in vitro in osteoblasts and chondroblasts caused an increase in Fgfr1 RNA and FGFR1 protein expression levels that resulted in increased and sustained activation of mitogen-activated protein kinases (MAPKs), morphological transformation and increased anchorage-independent growth in response to FGF2 ligand treatment. High levels of FGFR1 protein and activated pFRS2α signalling were observed in murine and human osteosarcomas. Pharmacological inhibition of FGFR1 signalling blocked MAPK activation and colony growth of osteosarcoma cells in vitro. Orthotopic injection in vivo of FGFR1-silenced osteosarcoma cells caused a marked twofold to fivefold decrease in spontaneous lung metastases. Similarly, inhibition of FGFR signalling in vivo with the small-molecule inhibitor AZD4547 markedly reduced the number and size of metastatic nodules. Thus deregulated FGFR signalling has an important role in osteoblast transformation and osteosarcoma formation and regulates the development of lung metastases. Our findings support the development of anti-FGFR inhibitors as potential antimetastatic therapy.
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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

Relationship between different serum cartilage biomarkers in the acute response to running and jumping in healthy male individuals - Maren, Dreiner; Tobias, Munk; Frank, Zaucke; Liphardt, Anna-Maria; Anja, Niehoff (Scientific Reports, 2022)
The effect of physical activity on serum cartilage biomarkers is largely unknown. The purpose of the study was to systematically analyze the acute effect of two frequently used exercise interventions (running and jumping) on the correlation of seven serum biomarkers that reflect cartilage extracellular matrix metabolism. Fifteen healthy male volunteers (26 ± 4 years, 181 ± 4 cm, 77 ± 6 kg) participated in the repeated measurement study. In session 1, the participants accomplished 15 × 15 series of reactive jumps within 30 min. In session 2, they ran on a treadmill (2.2 m/s) for 30 min. Before and after both exercise protocols, four blood samples were drawn separated by 30 min intervals. Serum concentrations of seven biomarkers were determined: COMP, MMP-3, MMP-9, YKL-40, resistin, Coll2-1 and Coll2-1 NO2. All biomarkers demonstrated an acute response to mechanical loading. Both the COMP and MMP-3 responses were significantly (p = 0.040 and p = 0.007) different between running and jumping (COMP: jumping + 31%, running + 37%; MMP-3: jumping + 14%, running + 78%). Resistin increased only significantly (p < 0.001) after running, and Coll2-1 NO2 increased significantly (p = 0.001) only after jumping. Significant correlations between the biomarkers were detected. The relationships between individual serum biomarker concentrations may reflect the complex interactions between degrading enzymes and their substrates in ECM homeostasis.
CRIS-Team Scopus Importer:2022-04-29

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 monitoring in rheumatology: seeing the right patient at the right time - Chan, Antoni; Knitza, Johannes (Nature Reviews Rheumatology, 2023)
CRIS-Team Scopus Importer:2023-08-18

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

Renal lesion, shoulder and pelvic pain - Görtz, Rüdiger Stephan; Wacker, Jochen (MMW Fortschritte der Medizin, 2014)
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Renal uptake of the antiapoptotic protein survivin is mediated by megalin at the apical membrane of the proximal tubule - Jobst-Schwan, Tilman; Knaup, Karl; Nielsen, Rikke; Hackenbeck, Thomas; Büttner-Herold, Maike; Lechler, Philipp; Kroening, Sven; Goppelt-Strübe, Margarete; Schlötzer-Schrehardt, Ursula; Fuernrohr, Barbara G.; Voll, Reinhard E.; Amann, Kerstin Ute; et al. (American Journal of Physiology-Renal Physiology, 2013)
The inhibitor of apoptosis protein survivin is a bifunctional molecule that regulates cellular division and survival. We have previously shown that survivin protein can be found at high concentrations in the adult kidney, particularly in the proximal tubules. Here, survivin is localized primarily at the apical membrane, a pattern that may indicate absorption of the protein. Several proteins in primary urine are internalized by megalin, an endocytosis receptor, which is in principle found in the same localization as survivin. Immunolabeling for survivin in different species confirmed survivin signal localizing to the apical membrane of the proximal tubule. Immunoelectron microscopy also showed apical localization of survivin in human kidneys. Furthermore, in polarized human primary tubular cells endogenous as well as external recombinant survivin is stored in the apical region of the cells. Costaining of survivin and megalin by immunohistochemistry and immunoelectron microscopy confirmed colocalization. Finally, by surface plasmon resonance we were able to demonstrate that survivin binds megalin and cubilin and that megalin knockout mice lose survivin through the urine. Survivin accumulates at the apical membrane of the renal tubule by reuptake, which is achieved by the endocytic receptor megalin, collaborating with cubilin. For this to occur, survivin will have to circulate in the blood and be filtered into the primary urine. It is not known at this stage what the functional role of tubular survivin is. However, a small number of experimental and clinical reports implicate that renal survivin is important for functional integrity of the kidney. © 2013 by the American Physiological Society.
Created from Fastlane, Scopus look-up
Keywords: Acute kidney injury; Apoptosis; Glomerular filtration; Lysosomes; Proteinuria

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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Reply to the comment on "Accuracy and usability of a diagnostic decision support system in the diagnosis of three representative rheumatic diseases: a randomized controlled trial among medical students" COMMENT - Knitza, Johannes; Hueber, Axel (Arthritis Research & Therapy, 2022)
CRIS-Team WoS Importer:2022-06-03

Reproducibility of aortic annulus measurements by computed tomography - Schuhbaeck, Annika; Achenbach, Stephan; Pflederer, Tobias; Schmid, Julia; Nef, Holger; Rixe, Johannes; Hecker, Franziska; Schneider, Christian; Lell, Michael; Uder, Michael; Arnold, Martin; Marwan, Mohamed (European Radiology, 2014)
To evaluate a systematic approach for measurement of aortic annulus dimensions by cardiac computed tomography.CT data sets of 64 patients were evaluated. An oblique cross-section aligned with the aortic root was created by systematically identifying the caudal insertion points of the three aortic cusps and sequentially aligning them in a double oblique plane. Aortic annulus dimensions, distances of coronary ostia and a suitable fluoroscopic projection angle were independently determined by two observers.Interobserver intraclass correlation coefficients (ICC) for aortic annulus diameters were excellent (ICC 0.89-0.93). Agreement for prosthesis size selection was excellent (? = 0.86 for mean, ? = 0.84 for area-derived and ? = 0.91 for circumference-derived diameter). Mean distances of the left/right coronary ostium were 13.4 ± 2.4/14.4 ± 2.8 mm for observer 1 and 13.2 ± 2.7/13.5 ± 3.2 mm for observer 2 (p = 0.30 and p = 0.0001, respectively; ICC 0.76/0.77 for left/right coronary artery). A difference of less than 10° for fluoroscopic projection angle was achieved in 84.3% of patients.A systematic approach to generate a double oblique imaging plane exactly aligned with the aortic annulus demonstrates high interobserver and intraobserver agreements for derived measurements which are not influenced by aortic root calcification.o Systematic approach to generate a double oblique imaging plane for TAVI evaluation. o This method is straightforward and software independent. o An approach with high reproducibility, not influenced by aortic root calcification.
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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

Resistant starch intake alleviates collagen-induced arthritis in mice by modulating gut microbiota and promoting concomitant propionate production - Bai, Yunqiang; Li, Yanhong; Marion, Tony; Tong, Yanli; Zaiss, Mario; Tang, Zhigang; Zhang, Qiuping; Liu, Yi; Luo, Yubin (Journal of Autoimmunity, 2020)
Gut dysbiosis precedes clinic symptoms in rheumatoid arthritis (RA) and has been implicated in the initiation and persistence of RA. The early treatment of RA is critical to better clinical outcome especially for joint destruction. Although dietary interventions have been reported to be beneficial for RA patients, it is unclear to whether diet-induced gut microbiome changes can be a preventive strategy to RA development. Here, we investigated the effect of a high fiber diet (HFD) rich with resistant starch (RS) on collagen-induced arthritis (CIA) and gut microbial composition in mice. RS-HFD significantly reduced arthritis severity and bone erosion in CIA mice. The therapeutic effects of RS-HFD were correlated with splenic regulatory T cell (Treg) expansion and serum interleukin-10 (IL-10) increase. The increased abundance of Lactobacillus and Lachnoclostridium genera concomitant with CIA were eliminated in CIA mice fed the RS-HFD diet. Notably, RS-HFD also led to a predominance of Bacteroidetes, and increased abundances of Lachnospiraceae_NK4A136_group and Bacteroidales_S24-7_group genera in CIA mice. Accompanied with the gut microbiome changes, serum levels of the short-chain fatty acid (SCFA) acetate, propionate and isobutyrate detected by GC-TOFMS were also increased in CIA mice fed RS-HFD. While, addition of β-acids from hops extract to the drinking water of mice fed RS-HFD significantly decreased serum propionate and completely eliminated RS-HFD-induced disease improvement, Treg cell increase and IL-10 production in CIA mice. Moreover, exogenous propionate added to drinking water replicated the protective role of RS-HFD in CIA including reduced bone damage. The direct effect of propionate on T cells in vitro was further explored as at least one mechanistic explanation for the dietary effects of microbial metabolites on immune regulation in experimental RA. Taken together, RS-HFD significantly reduced CIA and bone damage and altered gut microbial composition with concomitant increase in circulating propionate, indicating that RS-rich diet might be a promising therapy especially in the early stage of RA.
CRIS-Team Scopus Importer:2020-11-27
Keywords: Collagen-induced arthritis (CIA); IL-10; Resistant starch; Short-chain fatty acids (SCFAs); Treg cells

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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Respiratory syncytial virus (RSV) disease in hospitalised adults in Europe with COPD: Impact of GOLD score on RSV disease burden - Harrer, Thomas; Thalhammer, Florian; Launay, Odile; 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 contamination of isolated mouse Kupffer cells with liver sinusoidal endothelial cells - Iannacone, Matteo; Blériot, Camille; Andreata, Francesco; Ficht, Xenia; Laura, Chiara; Garcia-Manteiga, Jose M.; Uderhardt, Stefan; Ginhoux, Florent (Immunity, 2022)
CRIS-Team Scopus Importer:2022-07-22

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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