IS THERE AN UNIVERSAL TRANSLATOR? WHICH (ANIMAL) MODELS TELL US MOST? - Distler, Jörg (2018)
EVALuna2:34980

IVIg-mediated amelioration of ITP in mice is dependent on sialic acid and SIGNR1 - Schwab, Inessa; Biburger, Markus; Krönke, Gerhard; Schett, Georg; Nimmerjahn, Falk (European Journal of Immunology, 2012)
Intravenous immunoglobulin G (IVIg) therapy is widely used to treat autoimmune and inflammatory diseases. Recent evidence suggests that in mice, splenic resident cells might be important for the anti-inflammatory activity of IVIg in a model of serum transfer arthritis. Splenectomized human immunothrombocytopenia (ITP) patients, however, still respond to IVIg therapy. To investigate whether the requirement of the spleen is essential for mouse ITP, we used a passive model of induced ITP and demonstrated that IVIg activity was functional in splenectomized animals. Further analysis showed that the IVIg-mediated amelioration of platelet phagocytosis was fully dependent on terminal sialic acid residues in the IVIg preparation and could be blocked with a specific ICAM3 grabbing nonintegrin-related 1 (SIGNR1) specific antibody. These results suggest that, similar to the human system, a spleen-independent but sialic acid- and SIGNR1-dependent pathway is responsible for IVIg-mediated suppression of autoantibody-dependent platelet depletion in mice. © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
Keywords: Fc-receptor · ITP · IVIg · Sialic acid · SIGNR1

I would never take preventive medication! Perspectives and information needs of people who underwent predictive tests for rheumatoid arthritis - Mosor, Erika; Stoffer-Marx, Michaela; Steiner, Guenter; Raza, Karim; Stack, Rebecca J.; Simons, Gwenda; Falahee, Marie; Skingle, Diana; Dobrin, Mircia; Schett, Georg; Englbrecht, Matthias; Smolen, Josef S.; et al. (Arthritis & Rheumatism-Arthritis Care & Research, 2019)
OBJECTIVE: Little is known about the experiences, values and needs of people without arthritis who undergo predictive biomarker testing for the development of rheumatoid arthritis (RA). Our study aimed to explore the perspectives of these individuals and describe their information needs. METHODS: A qualitative, multicenter interview study with a thematic analysis was conducted in Austria, Germany and the UK. Individuals who underwent predictive biomarker testing for RA and had a positive test result, but no diagnosis of any inflammatory joint disease, were interviewed. Participants included patients with arthralgia and asymptomatic individuals. Information and education needs were developed from the qualitative codes and themes using the Arthritis Educational Needs Assessment Tool (ENAT) as a frame of reference. RESULTS: Thematic saturation was reached in 34 individuals (76% female; 24 [71%] with arthralgia and 10 [29%] asymptomatic individuals). Thirty-seven codes were summarized into four themes, namely (i) decision making around whether to undergo initial predictive testing, (ii) willingness to consider further predictive tests and/or (iii) preventive interventions, including medication and (iv) varying reactions after receiving a positive test result. Individuals with arthralgia were more likely to be willing to take preventive action, undergo further testing, and experience psychological distress than asymptomatic individuals. All participants expressed the need for tailored, lay-understandable information. CONCLUSION: Individuals at risk of RA are currently the subjects of research aimed at developing better predictive strategies and preventive approaches. Their perceptions and needs should be addressed to inform the future development of interventions combined with education. This article is protected by copyright. All rights reserved.
EVALuna2:102214

Ixekizumab Improves Signs and Symptoms of Patients with Radiographic and Non-radiographic Axial Spondyloarthritis and Extra-articular Manifestation of Enthesitis Through 16 Weeks - Schett, Georg; Van Den Bosch, Filip; Baraliakos, Xenofon; Sandoval, David; Geneus, Vladimir; Bolce, Rebecca; Liu-Leage, Soyi; Kronbergs, Andris; Mease, Philip (ARTHRITIS & RHEUMATOLOGY, 2020)
CRIS-Team WoS Importer:2021-01-15

JAK1-dependent transphosphorylation of JAK2 limits the antifibrotic effects of selective JAK2 inhibitors on long-term treatment - Zhang, Yun; Liang, Ruifang; Chen, Chih-Wei; Mallano, Tatjana; Dees, Clara; Distler, Alfiya; Reich, Adam; Bergmann, Christina; Ramming, Andreas; Gelse, Kolja; Mielenz, Dirk; Distler, Oliver; et al. (Annals of the Rheumatic Diseases, 2017)
Janus kinase 2 (JAK2) has recently been described as a novel downstream mediator of the pro-fibrotic effects of transforming growth factor-?. Although JAK2 inhibitors are in clinical use for myelodysplastic syndromes, patients often rapidly develop resistance. Tumour cells can escape the therapeutic effects of selective JAK2 inhibitors by mutation-independent transactivation of JAK2 by JAK1. Here, we used selective JAK2 inhibition as a model to test the hypothesis that chronic treatment may provoke resistance by facilitating non-physiological signalling pathways in fibroblasts.The antifibrotic effects of long-term treatment with selective JAK2 inhibitors and reactivation of JAK2 signalling by JAK1-dependent transphosphorylation was analysed in cultured fibroblasts and experimental dermal and pulmonary fibrosis. Combined JAK1/JAK2 inhibition and co-treatment with an HSP90 inhibitor were evaluated as strategies to overcome resistance.The antifibrotic effects of selective JAK2 inhibitors on fibroblasts decreased with prolonged treatment as JAK2 signalling was reactivated by JAK1-dependent transphosphorylation of JAK2. This reactivation could be prevented by HSP90 inhibition, which destabilised JAK2 protein, or with combined JAK1/JAK2 inhibitors. Treatment with combined JAK1/JAK2 inhibitors or with JAK2 inhibitors in combination with HSP90 inhibitors was more effective than monotherapy with JAK2 inhibitors in bleomycin-induced pulmonary fibrosis and in adTBR-induced dermal fibrosis.Fibroblasts can develop resistance to chronic treatment with JAK2 inhibitors by induction of non-physiological JAK1-dependent transactivation of JAK2 and that inhibition of this compensatory signalling pathway, for example, by co-inhibition of JAK1 or HSP90 is important to maintain the antifibrotic effects of JAK2 inhibition with long-term treatment.
EVALuna2:13270

JAK inhibition increases bone mass in steady-state conditions and ameliorates pathological bone loss by stimulating osteoblast function - Adam, Susanne; Simon, Nils; Steffen, Ulrike; Andes, Fabian T.; Scholtysek, Carina; Müller, Dorothea; Weidner, Daniela; Andreev, Darja; Kleyer, Arnd; Culemann, Stephan; Hahn, Madelaine; Schett, Georg; et al. (Science Translational Medicine, 2020)
Janus kinase (JAK)-mediated cytokine signaling has emerged as an important therapeutic target for the treatment of inflammatory diseases such as rheumatoid arthritis (RA). Accordingly, JAK inhibitors compose a new class of drugs, among which tofacitinib and baricitinib have been approved for the treatment of RA. Periarticular bone erosions contribute considerably to the pathogenesis of RA. However, although the immunomodulatory aspect of JAK inhibition (JAKi) is well defined, the current knowledge of how JAKi influences bone homeostasis is limited. Here, we assessed the effects of the JAK inhibitors tofacitinib and baricitinib on bone phenotype (i) in mice during steady-state conditions or in mice with bone loss induced by (ii) estrogen-deficiency (ovariectomy) or (iii) inflammation (arthritis) to evaluate whether effects of JAKi on bone metabolism require noninflammatory/inflammatory challenge. In all three models, JAKi increased bone mass, consistent with reducing the ratio of receptor activator of NF-κB ligand/osteoprotegerin in serum. In vitro, effects of tofacitinib and baricitinib on osteoclast and osteoblast differentiation were analyzed. JAKi significantly increased osteoblast function (P < 0.05) but showed no direct effects on osteoclasts. Additionally, mRNA sequencing and ingenuity pathway analyses were performed in osteoblasts exposed to JAKi and revealed robust up-regulation of markers for osteoblast function, such as osteocalcin and Wnt signaling. The anabolic effect of JAKi was illustrated by the stabilization of β-catenin. In humans with RA, JAKi induced bone-anabolic effects as evidenced by repair of arthritic bone erosions. Results support that JAKi is a potent therapeutic tool for increasing osteoblast function and bone formation.
CRIS-Team Scopus Importer:2020-02-21

JAK Inhibition Re-balances Gene Expression Profile of Circulating Immune Cells in Patients with Psoriatic Arthritis - Raimondo, Maria Gabriella; Anchang, Charles Gwellem; Labinsky, Hannah; Saad, Mina saad aziz; Rauber, Simon; Vogg, Mario; Kampylafka, Eleni; Knitza, Johannes; Soare, Alina; Schett, Georg; Ramming, Andreas (ARTHRITIS & RHEUMATOLOGY, 2022)
CRIS-Team WoS Importer:2023-01-13

JAK-INHIBITORS TOFACITINIB AND BARICITINIB IMPROVE PATHOLOGICAL BONE LOSS IN VIVO - Adam, Susanne; Simon, Nils; Steffen, Ulrike; Harre, Nee; Andes, Fabian; Mueller, Dorothea; Culemann, Stephan; Andreev, Darja; Hahn, Madelaine; Scholtysek, Carina; Schett, Georg; Krönke, Gerhard; et al. (ANNALS OF THE RHEUMATIC DISEASES, 2019)
CRIS-Team WoS Importer:2019-07-12

Jan Mikulicz-Radecki (1850-1905): return of the surgeon - Manger, Bernhard; Schett, Georg (Annals of the Rheumatic Diseases, 2020)
CRIS-Team Scopus Importer:2020-10-16
Keywords: immune system diseases; sarcoidosis; sjogren's syndrome

Joachim Robert Kalden: One of the founders of autoimmunity research and immunotherapy - Burmester, Gerd R.; Manger, Bernhard; Schett, Georg; Schulze-Koops, Hendrik (Annals of the Rheumatic Diseases, 2021)
CRIS-Team Scopus Importer:2021-06-04
Keywords: autoantibodies; autoimmunity; therapeutics

Johann Lucas Schoenlein (1793-1864): impact without publications - Manger, Bernhard; Schett, Georg; Burmester, Gerd R. (Annals of the Rheumatic Diseases, 2020)
CRIS-Team Scopus Importer:2020-11-20
Keywords: arthritis; immune complex diseases; immune system diseases; rheumatoid; systemic vasculitis

Jumonji Domain Containing Protein 3 (JMJD3) As a Novel Epigenetic Mechanism of Fibroblast Activation By Regulation of Fra-2 - Bergmann, Christina; Brandt, Adrian; Dees, Clara; Zhang, Yun; Lin, Neng-Yu; Chen, Chih-Wei; Mallano, Tatjana; Liang, Ruifang; Kam, Pui-See; Distler, Oliver; Schett, Georg; Distler, Jörg (2016)
EVALuna2:35056

Kaempferol prevents aseptic loosening via enhance the Wnt/β-catenin signaling pathway in vitro and in vivo - Qiu, Wenkui; Li, Zhenghui; Su, Zhenyan; Cao, Lichao; Li, Lei; Chen, Xi; Zhang, Wanhong; Li, Yanqing (European Journal of Medical Research, 2023)
Kaempferol has demonstrated notable positive effects on the osteogenic differentiation of mesenchymal stem cells (MSC) and osteoblasts. A substantial body of research has emphasized the role of dislodged titanium particles in aseptic loosening following joint replacement surgery. This study predominantly investigates the suppressive influence of Kaempferol on osteolysis induced by titanium (Ti) alloy particles. In vitro investigations disclosed that Kaempferol effectively enhanced mineralization and alkaline phosphatase (ALP) activity in bone-marrow mesenchymal stem cells exposed to Ti particles. In addition, we conducted a comprehensive analysis of osteogenic differentiation microarray data_sets (GSE37676, GSE79814, and GSE114474) to identify differentially expressed genes. Significantly, Kaempferol upregulated the expression of critical osteogenic markers, including Runt-related transcription factor 2 (Runx2), osteocalcin (OCN), osterix/Sp-7, and β-catenin. In vivo experiments, including H&E staining and Immunohistochemistry, provided compelling evidence that Kaempferol exerted a robust inhibitory effect on periprosthetic osteolysis in mice, with particularly pronounced results at higher doses. Moreover, it elevated the expression levels of osteogenic factors and Wnt/β-catenin signaling components. These findings collectively indicate that Kaempferol mitigates the hindrance to osteogenesis posed by titanium particles by activating the Runx2 and Wnt/β-catenin signaling pathways. This research lays a solid foundation for the prospective utilization of Kaempferol in the management of aseptic loosening following arthroplasty, offering promising therapeutic potential.
CRIS-Team Scopus Importer:2023-11-17

Keratinocyte-derived S100A9 modulates neutrophil infiltration and affects psoriasis-like skin and joint disease - Mellor, Liliana F.; Gago-Lopez, Nuria; Bakiri, Latifa; Schmidt, Felix N.; Busse, Bjorn; Rauber, Simon; Jimenez, Maria; Megias, Diego; Oterino-Soto, Sergio; Sanchez-Prieto, Ricardo; Grivennikov, Sergei; Pu, Xinzhu; et al. (Annals of the Rheumatic Diseases, 2022)
Objectives S100A9, an alarmin that can form calprotectin (CP) heterodimers with S100A8, is mainly produced by keratinocytes and innate immune cells. The contribution of keratinocyte-derived S100A9 to psoriasis (Ps) and psoriatic arthritis (PsA) was evaluated using mouse models, and the potential usefulness of S100A9 as a Ps/PsA biomarker was assessed in patient samples. Methods Conditional S100A9 mice were crossed with DKO* mice, an established psoriasis-like mouse model based on inducible epidermal deletion of c-Jun and JunB to achieve additional epidermal deletion of S100A9 (TKO* mice). Psoriatic skin and joint disease were evaluated in DKO* and TKO* by histology, microCT, RNA and proteomic analyses. Furthermore, S100A9 expression was analysed in skin, serum and synovial fluid samples of patients with Ps and PsA. Results Compared with DKO* littermates, TKO* mice displayed enhanced skin disease severity, PsA incidence and neutrophil infiltration. Altered epidermal expression of selective pro-inflammatory genes and pathways, increased epidermal phosphorylation of STAT3 and higher circulating TNF alpha were observed in TKO* mice. In humans, synovial S100A9 levels were higher than the respective serum levels. Importantly, patients with PsA had significantly higher serum concentrations of S100A9, CP, VEGF, IL-6 and TNF alpha compared with patients with only Ps, but only S100A9 and CP could efficiently discriminate healthy individuals, patients with Ps and patients with PsA. Conclusions Keratinocyte-derived S100A9 plays a regulatory role in psoriatic skin and joint disease. In humans, S100A9/CP is a promising marker that could help in identifying patients with Ps at risk of developing PsA.
CRIS-Team WoS Importer:2022-07-15

Key opinion leaders — a critical perspective - Scher, Jose U.; Schett, Georg (Nature Reviews Rheumatology, 2020)
Enormous progress has been made in the field of rheumatology in the past several decades, historically led by publicly funded academic innovators but in more recent times with much greater involvement of the pharmaceutical industry. This shift in resources has created a complex new model for reinvestment in the medical community in which the vast majority of private funds are redirected towards influencing the prescription behaviour of practitioners through ‘key opinion leaders’, with the main purpose of enhancing and perpetuating profit rather than innovation and critical thinking, and often at the expense of partnerships with scientists (that is, basic and translational researchers) and academic collaborations. This new episteme brings multiple opportunities to rethink approaches to sustaining long-term critical research in the field, ultimately maximizing the return on investment: scientific knowledge for the benefit of patients and society. Central to such strategies should be the rebalancing of academia–industry partnerships towards academic research and the involvement of ‘innovation and knowledge leaders’, rather than mostly key opinion leaders.
CRIS-Team Scopus Importer:2020-12-11

Kidney-transplant patients receiving living- or dead-donor organs have similar psychological outcomes (findings from the PI-KT study) - Müller, Helge H.O.; Lücke, Caroline; Englbrecht, Matthias; Wiesener, Michael; Siller, Teresa; Eckardt, Kai-Uwe; Kornhuber, Johannes; Maler, Juan Manuel (Mental Illness, 2020)
Purpose: Kidney transplantation (KT) is the treatment of choice for end-stage chronic kidney disease (CKD) and is well known to improve the clinical outcome of patients. However, the impact of KT on comorbid psychological symptoms, particularly depression and anxiety, is less clear, and recipients of living-donor (LD) organs may have a different psychological outcome from recipients of dead-donor (DD) organs. Design/methodology/approach: In total, 152 patients were included and analyzed using a cross-sectional design. Of these patients, 25 were pre-KT, 13 were post-KT with a LD transplant and 114 were post-KT with a DD transplant. The patients were tested for a variety of psychometric outcomes using the Hospital Anxiety and Depression Scale, the 12-Item Short Form Health Survey (assessing physical and mental health-related quality of life), the Resilience Scale, the Coping Self-Questionnaire and the Social Support Questionnaire. Findings: The mean age of the patients was 51.25 years and 40 per cent of the patients were female. As expected, the post-KT patients had significantly better scores on the physical component of the Short Form Health Survey than the pre-KT patients, and there were no significant differences between the two post-KT groups. There were no significant differences among the groups in any of the other psychometric outcome parameters tested, including anxiety, depression and the mental component of health-related quality of life. Research limitations/implications: KT and the origin of the donor organ do not appear to have a significant impact on the psychological well-being of transplant patients with CKD. Although the diagnosis and early treatment of psychological symptoms, such as depression and anxiety, remain important for these patients, decisions regarding KT, including the mode of transplantation, should not be fundamentally influenced by concerns about psychological impairments at the population level. Originality/value: CKD is a serious condition involving profound impairment of the physical and psychological well-being of patients. KT is considered the treatment of choice for most of these patients. KT has notable advantages over dialysis with regard to the long-term physical functioning of the renal and cardiovascular system and increases the life expectancy of patients. However, the data on the improvement of psychological impairments after KT are less conclusive.
CRIS-Team Scopus Importer:2020-06-16
Keywords: Coping; Kidney transplantation

Knee biomechanics of single leg hop landings after primary anterior cruciate ligament repair and InternalBraceTM augmentation - Coppers, Birte; Bühl, Linda; Müller, Sebastian; Nüesch, Corina; Mündermann, Annegret; Egloff, Christian (28th Congress of the International Society of Biomechanics - ISB, 2021)

KNEE JOINT PAIN IN AN ELDERLY, HEALTHY POPULATION IS ASSOCIATED WITH INFLAMMATORY ARTICULAR AND ENTHESEAL CHANGES DETECTED BY ULTRASOUND - Simon, David; Kleyer, Arnd; Adinolfi, Antonella; Willeit, Johann; Kiechl, Stefan; Gasperi, Nina; Schett, Georg; Dejaco, Christian; Iagnocco, Annamaria; D'Agostino, Maria-Antonietta (ANNALS OF THE RHEUMATIC DISEASES, 2019)
CRIS-Team WoS Importer:2019-07-12

Lack of inhibitory effects of the anti-fibrotic drug imatinib on endothelial cell functions in vitro and in vivo. - Venalis, Paulius; Maurer, Britta; Akhmetshina, Alfiya; Busch, Nicole; Dees, Clara; Stürzl, Michael; Zwerina, Jochen; Juengel, Astrid; Gay, Steffen; Schett, Georg; Distler, Oliver; Distler, Jörg (Journal of Cellular and Molecular Medicine, 2009)
Systemic sclerosis (SSc) is a systemic autoimmune disease that is characterized by microangiopathy with progressive loss of capillaries and tissue fibrosis. Imatinib exerts potent anti-fibrotic effects and is currently evaluated in clinical trials. The aim of the present study was to exclude that the anti-fibrotic effects of imatinib are complicated by inhibitory effects on endothelial cell functions, which might augment vascular disease in SSc. Endothelial cells and mice were treated with pharmacologically relevant concentrations of imatinib. The expression of markers of vascular activation was assessed with real-time PCR. Proliferation was analysed with the cell counting experiments and the MTT assay. Apoptosis was quantified with caspase 3 assays, annexin V in vitro and with TUNEL staining in vivo. Migration was studied with scratch and transwell assays. Tube forming was investigated with the matrigel assay. Imatinib did not alter the expression of markers of vascular activation. Imatinib did not increase the percentage of annexin V positive cells or the activity of caspase 3. No reduction in proliferation or metabolic activity of endothelial cells was observed. Imatinib did not affect migration of endothelial cells and did not reduce the formation of capillary tubes. Consistent with the in vitro data, no difference in the number of apoptotic endothelial cells was observed in vivo in mice treated with imatinib. Imatinib does not inhibit activation, viability, proliferation, migration or tube forming of endothelial cells in vitro and in vivo. Thus, treatment with imatinib might not augment further endothelial cell damage in SSc.

L-Arginine metabolism inhibits arthritis and inflammatory bone loss - Cao, Shan; Li, Yixuan; Song, Rui; Meng, Xianyi; Fuchs, Maximilian; Liang, Chunguang; Kachler, Katerina; Meng, Xinyu; Wen, Jinming; Schlötzer-Schrehardt, Ursula; Taudte, Verena; Geßner, Arne; et al. (Annals of the Rheumatic Diseases, 2023)
Objectives: To investigate the effect of the L-Arginine metabolism on arthritis and inflammation-mediated bone loss. Methods: L-Arginine was applied to three arthritis models (collagen-induced arthritis, serum-induced arthritis and human TNF transgenic mice). Inflammation was assessed clinically and histologically, while bone changes were quantified by μCT and histomorphometry. In vitro, effects of L-Arginine on osteoclast differentiation were analysed by RNA-seq and mass spectrometry (MS). Seahorse, Single Cell ENergetIc metabolism by profilIng Translation inHibition and transmission electron microscopy were used for detecting metabolic changes in osteoclasts. Moreover, arginine-Associated metabolites were measured in the serum of rheumatoid arthritis (RA) and pre-RA patients. Results: L-Arginine inhibited arthritis and bone loss in all three models and directly blocked TNFα-induced murine and human osteoclastogenesis. RNA-seq and MS analyses indicated that L-Arginine switched glycolysis to oxidative phosphorylation in inflammatory osteoclasts leading to increased ATP production, purine metabolism and elevated inosine and hypoxanthine levels. Adenosine deaminase inhibitors blocking inosine and hypoxanthine production abolished the inhibition of L-Arginine on osteoclastogenesis in vitro and in vivo. Altered arginine levels were also found in RA and pre-RA patients. Conclusion: Our study demonstrated that L-Arginine ameliorates arthritis and bone erosion through metabolic reprogramming and perturbation of purine metabolism in osteoclasts.
CRIS-Team Scopus Importer:2023-11-24
Keywords: Arthritis; Inflammation; Osteoporosis

L-ARGININE REPROGRAMS OSTEOCLAST PURINE METABOLISM AMELIORATING BONE LOSS IN RHEUMATOID ARTHRITIS - Cao, Shan; Song, Rui; Meng, Xianyi; Kachler, Katerina; Fuchs, Maximilian; Meng, X.; Li, Y.; Taudte, Verena; Kunz, Meik; Schlötzer-Schrehardt, Ursula; Schleicher, Ulrike; Chen, X.; et al. (ANNALS OF THE RHEUMATIC DISEASES, 2022)
CRIS-Team WoS Importer:2022-11-04

L-ARGININE SUPPLEMENTATION AMELIORATES BONE EROSION IN RHEUMATOID ARTHRITIS THROUGH INHIBITION OF RANKL/RANK/TRAF6 PATHWAY AND REPROGRAMMING OSTEOCLAST METABOLISM - Cao, Shan; Chen, X.; Schett, Georg; Bozec, Aline (ANNALS OF THE RHEUMATIC DISEASES, 2020)
CRIS-Team WoS Importer:2020-08-21

LDLR dysfunction induces LDL accumulation and promotes pulmonary fibrosis - Shi, Xiangguang; Chen, Yahui; Liu, Qingmei; Mei, Xueqian; Liu, Jing; Tang, Yulong; Luo, Ruoyu; Sun, Dayan; Ma, Yanyun; Wu, Wenyu; Tu, Wenzhen; Zhao, Yinhuan; et al. (Clinical and Translational Medicine, 2022)
Treatments for pulmonary fibrosis (PF) are ineffective because its molecular pathogenesis and therapeutic targets are unclear. Here, we show that the expression of low-density lipoprotein receptor (LDLR) was significantly decreased in alveolar type II (ATII) and fibroblast cells, whereas it was increased in endothelial cells from systemic sclerosis-related PF (SSc-PF) patients and idiopathic PF (IPF) patients compared with healthy controls. However, the plasma levels of low-density lipoprotein (LDL) increased in SSc-PF and IPF patients. The disrupted LDL-LDLR metabolism was also observed in four mouse PF models. Upon bleomycin (BLM) treatment, Ldlr-deficient (Ldlr-/-) mice exhibited remarkably higher LDL levels, abundant apoptosis, increased fibroblast-like endothelial and ATII cells and significantly earlier and more severe fibrotic response compared to wild-type mice. In vitro experiments revealed that apoptosis and TGF-beta 1 production were induced by LDL, while fibroblast-like cell accumulation and ET-1 expression were induced by LDLR knockdown. Treatment of fibroblasts with LDL or culture medium derived from LDL-pretreated endothelial or epithelial cells led to obvious fibrotic responses in vitro. Similar results were observed after LDLR knockdown operation. These results suggest that disturbed LDL-LDLR metabolism contributes in various ways to the malfunction of endothelial and epithelial cells, and fibroblasts during pulmonary fibrogenesis. In addition, pharmacological restoration of LDLR levels by using a combination of atorvastatin and alirocumab inhibited BLM-induced LDL elevation, apoptosis, fibroblast-like cell accumulation and mitigated PF in mice. Therefore, LDL-LDLR may serve as an important mediator in PF, and LDLR enhancing strategies may have beneficial effects on PF.
CRIS-Team WoS Importer:2022-02-11
Keywords: apoptosis; combination treatment; LDL; LDLR; pulmonary fibrosis

Levels of target activation predict antifibrotic responses to tyrosine kinase inhibitors. - Maurer, Britta; Distler, Alfiya; Dees, Clara; Khan, Korsa; Denton, Christopher P.; Abraham, David; Gay, Renate E.; Michel, Beat A.; Gay, Steffen; Distler, Jörg; Distler, Oliver (Annals of the Rheumatic Diseases, 2013)
OBJECTIVES: To assess whether the discrepancy between the strong antifibrotic effects of tyrosine kinase inhibitors (TKIs) in animal models and the inconsistent results in clinical studies might be related to the activation levels of drug targets. METHODS: Skin sections of bleomycin, TSK1, Fra-2 transgenic mice, SSc patients and controls were analysed by histology and immunohistochemistry. Subgroups of mice were treated with the TKIs nilotinib or imatinib. Differences in the activation levels of the TKI targets p-PDGFRβ (platelet derived growth factor β) and p-c-abl were assessed. RESULTS: In bleomycin and TSK1 mice, expression of activated p-PDGFRβ (platelet derived growth factor receptor β) and p-c-abl was ubiquitous with strong upregulation compared with controls. Treatment with TKIs resulted in successful target inhibition and consequently reduced dermal fibrosis. In the Fra-2 model, the activation levels of p-PDGFRβ and p-c-abl were much lower than in the bleomycin and the TSK1 models. Accordingly, nilotinib did not prevent dermal fibrosis and target inhibition was unsuccessful. Notably, in skin biopsies of SSc patients, the mean activation levels of TKI targets were only moderate and in the majority of patients resembled those of the non-responsive Fra-2 model. CONCLUSIONS: Animal models for proof-of-concept studies should be selected based on a similar activation level and expression pattern of drug targets as in human SSc.
EVALuna2:478502

Liver X receptors orchestrate osteoblast/osteoclast crosstalk and counteract pathologic bone loss - Kleyer, Arnd; Scholtysek, Carina; Bottesch, Edith; Hillienhof, Ulrike; Beyer, Christian; Distler, Jörg; Tuckermann, Jan P.; Schett, Georg; Krönke, Gerhard (Journal of Bone and Mineral Research, 2012)
Osteoporosis is characterized by enhanced differentiation of bone-resorbing osteoclasts, resulting in a rapid loss of functional trabecular bone. Bone-forming osteoblasts and osteoblast-derived osteocytes perform a key role in the regulation of osteoclast development by providing both the pro-osteoclastogenic cytokine receptor activator of NF-?B ligand (RANKL) and its natural decoy receptor osteoprotegerin (OPG). By regulating the RANKL/OPG ratio, osteoblasts hence determine the rate of both osteoclast differentiation and bone turnover. Here, we describe a novel role for liver X receptors (LXRs) during the crosstalk of bone-forming osteoblasts and bone-resorbing osteoclasts. By using a system of osteoblast/osteoclast cocultures, we identify LXRs as regulator of RANKL expression and the RANKL/OPG ratio in osteoblasts. Activation of LXRs drastically reduced the RANKL/OPG ratio and interfered with osteoblast-mediated osteoclast differentiation in vitro. During an ovariectomy (OVX)-induced model of postmenopausal osteoporosis, the application of an LXR agonist shifted the RANKL/OPG ratio in vivo, ameliorated the enhanced osteoclast differentiation, and provided complete protection from OVX-induced bone loss. These results reveal an unexpected involvement of LXRs in the regulation of bone turnover and highlight a potential role for LXRs as novel targets in the treatment of osteoporosis and related diseases.
EVALuna2:12795

Loading of nuclear autoantigens prototypically recognized by systemic lupus erythematosus sera into late apoptotic vesicles requires intact microtubules and myosin light chain kinase activity - Zirngibl, Matthias; Fuernrohr, B. G.; Janko, Christina; Munoz, L. E.; Voll, R. E.; Gregory, C. D.; Schett, Georg; Herrmann, Martin; Munoz Becerra, Luis (Clinical and Experimental Immunology, 2015)
Most cases of systemic lupus erythematosus (SLE) are characterized by an impaired clearance of apoptotic cells in various tissues. Non-cleared apoptotic waste is considered an immunogen driving the autoimmune response in patients with SLE. During the execution of apoptosis, membrane blebs are formed and filled with cellular components. Here, we evaluate the cytoskeletal pathway(s) responsible for the loading of SLE prototypic nuclear autoantigens into the apoptotic cell-derived membranous vesicles (ACMV) generated during late phases of apoptosis. HeLa cells expressing a fusion protein of histone H2B with green fluorescent protein (GFP) were irradiated with ultraviolet (UV)-B to induce apoptosis. The appearance and trafficking of chromatin-derived material was monitored by fluorescence microscopy. Specific inhibitors of cytoskeletal pathways were employed to identify the motile elements involved in translocation and trafficking of the nuclear components. We observed that immediately after their appearance the ACMV did not contain histone H2B(GFP) ; in this phase the fluorescence was contained in the nuclear remnants and the cytoplasm. Within consecutive minutes the ACMV were loaded with chromatin-derived material, whereas the loading of simultaneously created ACMV with histone H2B(GFP) was not uniform. Some ACMV were preferentially filled and, consequently, showed a remarkably higher histone H2B(GFP) accumulation. Inhibitors of the cytoskeleton revealed that functional microtubules and myosin light chain kinase are required for nuclear shrinkage and loading of nuclear material into the ACMV, respectively.
EVALuna2:12985

Locally renewing resident synovial macrophages provide a protective barrier for the joint - Culemann, Stephan; Grüneboom, Anika; Nicolás-Ávila, José Ángel; Weidner, Daniela; Lämmle, Katrin Franziska; Rothe, Tobias; Quintana, Juan A.; Kirchner, Philipp; Krljanac, Branislav; Eberhardt, Martin; Ferrazzi, Fulvia; Kretzschmar, Elke; et al. (Nature, 2019)
Macrophages are considered to contribute to chronic inflammatory diseases such as rheumatoid arthritis1. However, both the exact origin and the role of macrophages in inflammatory joint disease remain unclear. Here we use fate-mapping approaches in conjunction with three-dimensional light-sheet fluorescence microscopy and single-cell RNA sequencing to perform a comprehensive spatiotemporal analysis of the composition, origin and differentiation of subsets of macrophages within healthy and inflamed joints, and study the roles of these macrophages during arthritis. We find that dynamic membrane-like structures, consisting of a distinct population of CX3CR1+ tissue-resident macrophages, form an internal immunological barrier at the synovial lining and physically seclude the joint. These barrier-forming macrophages display features that are otherwise typical of epithelial cells, and maintain their numbers through a pool of locally proliferating CX3CR1− mononuclear cells that are embedded into the synovial tissue. Unlike recruited monocyte-derived macrophages, which actively contribute to joint inflammation, these epithelial-like CX3CR1+ lining macrophages restrict the inflammatory reaction by providing a tight-junction-mediated shield for intra-articular structures. Our data reveal an unexpected functional diversification among synovial macrophages and have important implications for the general role of macrophages in health and disease.
CRIS-Team Scopus Importer:2019-08-16

Long COVID: Association of Functional Autoantibodies against G-Protein-Coupled Receptors with an Impaired Retinal Microcirculation - Szewczykowski, Charlotte; Mardin, Christian; Lucio, Marianna; Wallukat, Gerd; Hoffmanns, Jakob; Schröder, Tim; Raith, Franziska; Rogge, Lennart; Heltmann, Felix; Moritz, Michael; Beitlich, Lorenz; Schottenhamml, Julia; et al. (International Journal of Molecular Sciences, 2022)
Long COVID (LC) describes the clinical phenotype of symptoms after infection with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Diagnostic and therapeutic options are limited, as the pathomechanism of LC is elusive. As the number of acute SARS-CoV-2 infections was and is large, LC will be a challenge for the healthcare system. Previous studies revealed an impaired blood flow, the formation of microclots, and autoimmune mechanisms as potential factors in this complex interplay. Since functionally active autoantibodies against G-protein-coupled receptors (GPCR-AAbs) were observed in patients after SARS-CoV-2 infection, this study aimed to correlate the appearance of GPCR-AAbs with capillary microcirculation. The seropositivity of GPCR-AAbs was measured by an established cardiomyocyte bioassay in 42 patients with LC and 6 controls. Retinal microcirculation was measured by OCT–angiography and quantified as macula and peripapillary vessel density (VD) by the Erlangen-Angio Tool. A statistical analysis yielded impaired VD in patients with LC compared to the controls, which was accentuated in female persons. A significant decrease in macula and peripapillary VD for AAbs targeting adrenergic β2-receptor, MAS-receptor angiotensin-II-type-1 receptor, and adrenergic α1-receptor were observed. The present study might suggest that a seropositivity of GPCR-AAbs can be linked to an impaired retinal capillary microcirculation, potentially mirroring the systemic microcirculation with consecutive clinical symptoms.
CRIS-Team Scopus Importer:2022-07-15
Keywords: chronic fatigue syndrome; COVID-19; functionally GPCR autoantibodies; glaucoma; Long-COVID syndrome; OCT–angiography

LONGITUDINAL CHANGE IN THE CENTRAL NERVOUS SYSTEM PAIN RESPONSE AFTER TREATMENT WITH CERTOLIZUMAB OR PLACEBO. A POST-HOC ANALYSIS FROM THE PRECEPRA TRIAL - Rech, Jürgen; Tascilar, K.; Schenker, Hannah; Hagen, Melanie; Sergeeva, Marina; Selvakumar, Mageshwar; Konerth, Laura; Prade, Jutta; Strobelt, Sandra; Schonau, V.; Valor, L.; Hueber, A.; et al. (ANNALS OF THE RHEUMATIC DISEASES, 2020)
CRIS-Team WoS Importer:2020-08-21

LONG NONCODING RNA H19X AS A NEW THERAPEUTIC TARGET FOR FIBROSIS - Pachera, E.; Wunderlin, A.; Assassi, S.; Salazar, G.; Frank-Bertoncelj, M.; Dobrota, R.; Brock, M.; Feghali-Bostwick, C.; Rogler, G. Gerhard; Dijkstra, G.; Van Haaften, T.; Distler, Jörg; et al. (2017)
EVALuna2:35023

Long noncoding RNA H19X is a key mediator of TGF-β-driven fibrosis - Pachera, Elena; Assassi, Shervin; Salazar, Gloria A.; Stellato, Mara; Renoux, Florian; Wunderlin, Adam; Blyszczuk, Przemyslaw; Lafyatis, Robert; Kurreeman, Fina; de Vries-Bouwstra, Jeska; Messemaker, Tobias; Feghali-Bostwick, Carol A.; et al. (Journal of Clinical Investigation, 2020)
TGF-β is a master regulator of fibrosis, driving the differentiation of fibroblasts into apoptosis-resistant myofibroblasts and sustaining the production of extracellular matrix (ECM) components. Here, we identified the nuclear long noncoding RNA (lncRNA) H19X as a master regulator of TGF-β-driven tissue fibrosis. H19X was consistently upregulated in a wide variety of human fibrotic tissues and diseases and was strongly induced by TGF-β, particularly in fibroblasts and fibroblast-related cells. Functional experiments following H19X silencing revealed that H19X was an obligatory factor for TGF-β-induced ECM synthesis as well as differentiation and survival of ECM-producing myofibroblasts. We showed that H19X regulates DDIT4L gene expression, specifically interacting with a region upstream of the DDIT4L gene and changing the chromatin accessibility of a DDIT4L enhancer. These events resulted in transcriptional repression of DDIT4L and, in turn, in increased collagen expression and fibrosis. Our results shed light on key effectors of TGF-β-induced ECM remodeling and fibrosis.
CRIS-Team Scopus Importer:2020-09-11
Keywords: Autoimmune diseases; Autoimmunity; Cell Biology; Epigenetics; Fibrosis

Long Noncoding RNA H19X Is a Key Regulator of Apoptosis and Proliferation of Fibroblasts in Systemic Sclerosis and Other TGF beta-riven Fibrotic Diseases - Pachera, Elena; Wunderlin, Adam; Assassi, Shervin; Salazar, Gloria; Bertoncelj, Mojca Frank; Dobrota, Rucsandra; Brock, Matthias; Feghali-Bostwick, Carol A.; Dijkstra, Gerard; Rogler, Gerhard; Wouter, Tobias Van Haaften; Distler, Jörg; et al. (2017)
EVALuna2:35018

LONG NONCODING RNA H19X IS A MASTER REGULATOR OF EXTRACELLULAR MATRIX PRODUCTION IN SYSTEMIC SCLEROSIS - Pachera, E.; Assassi, S.; Salazar, G.; Frank-Bertoncelj, M.; Distler, Jörg; Kania, G.; Distler, O. (2018)
EVALuna2:35009

LONG-TERM (156-WEEK) IMPROVEMENTS IN DACTYLITIS AND ENTHESITIS WITH APREMILAST INPSORIATIC ARTHRITIS SUBJECTS: ANALYSIS OF A LARGE, POOLED PALACE 1-3 DATABASE - Gladman, Dafna D.; Kavanaugh, Arthur; Gomez-Reino, Juan J.; Wollenhaupt, Jurgen; Cutolo, Maurizio; Schett, Georg; Lespessailles, Eric; Hub, Angela; Edwards, Christopher J.; Birbara, Charles A.; Mease, Philip J. (2018)
EVALuna2:34152

Long-Term (156-Week) Safety Profile of Apremilast, an Oral Phosphodiesterase 4 Inhibitor, in Patients with Psoriatic Arthritis: Pooled Safety Analysis of 3 Phase III, Randomized, Controlled Trials - Mease, Philip J.; Gladman, Dafna D.; Gomez-Reino, Juan J.; Hall, Stephen; Kavanaugh, Arthur; Lespessailles, Eric; Schett, Georg; Shah, Kamal; Teng, Lichen; Wollenhaupt, Juergen (2016)
EVALuna2:35062

Longterm (52-week) Results of a Phase III Randomized, Controlled Trial of Apremilast in Patients with Psoriatic Arthritis - Kavanaugh, Arthur; Mease, Philip J.; Gomez-Reino, Juan J.; Adebajo, Adewale O.; Wollenhaupt, Juergen; Gladman, Dafna D.; Hochfeld, Marla; Teng, Lichen L.; Schett, Georg; Lespessailles, Eric; Hall, Stephen (Journal of Rheumatology, 2015)
To evaluate the efficacy and safety of apremilast, an oral phosphodiesterase 4 inhibitor, over 52 weeks in patients with active psoriatic arthritis (PsA) despite prior treatment.Patients were randomized to placebo (n = 168), apremilast 20 mg BID (n = 168), or apremilast 30 mg BID (n = 168). Patients whose swollen and tender joint counts had not improved by >= 20% at Week 16 were considered nonresponders and were required to be re-randomized (1:1) to apremilast 20 mg BID or 30 mg BID if they were initially randomized to placebo, or continued their initial treatment of apremilast dose. At Week 24, all remaining patients treated with placebo were re-randomized to apremilast 20 mg BID or 30 mg BID.An American College of Rheumatology 20 (ACR20) response at Week 16 was attained by significantly more patients receiving apremilast 20 mg BID (30.4%, p = 0.0166) or 30 mg BID (38.1%, p = 0.0001) than placebo (19.0%). Among patients receiving apremilast continuously for 52 weeks (n = 254), ACR20 response at Week 52 was observed in 63.0% (75/119, 20 mg BID) and 54.6% (71/130, 30 mg BID) of patients. Response was also maintained across secondary outcomes, including measures of PsA signs and symptoms, skin psoriasis severity, and physical function. The nature, incidence, and severity of adverse events were comparable over the 24-week and 52-week periods. The most common adverse events, diarrhea and nausea, generally occurred early and were self-limited.Continuous apremilast treatment resulted in sustained improvements in PsA for up to 52 weeks. Apremilast had an acceptable safety profile and was generally well tolerated.NCT01172938.
EVALuna2:13087

Long-term B-lymphocyte depletion and remission of granulomatosis with polyangiitis after two courses of rituximab treatment - Valor-Méndez, Larissa; Kleyer, Arnd; Rech, Jürgen; Manger, Bernhard; Schett, Georg (Rheumatology, 2021)
CRIS-Team Scopus Importer:2021-06-11

Long-term Combination Therapy with Anti-TNF plus Vedolizumab Induces and Maintains Remission in Therapy-refractory Ulcerative Colitis - Fischer, Sören; Rath, Timo; Geppert, Carol-Immanuel; Manger, Bernhard; Schett, Georg; Neurath, Markus; Atreya, Raja (American Journal of Gastroenterology, 2017)
EVALuna2:6885

Long-term experience with apremilast in patients with psoriatic arthritis: 5-year results from a PALACE 1-3 pooled analysis - Kavanaugh, Arthur; Gladman, Dafna D.; Edwards, Christopher J.; Schett, Georg; Guerette, Benoit; Delev, Nikolay; Teng, Lichen; Paris, Maria; Mease, Philip J. (Arthritis Research & Therapy, 2019)
Background: The efficacy and safety of apremilast were assessed in patients with psoriatic arthritis (PsA) in three phase III clinical trials with similar designs (PALACE 1, 2, and 3). Methods: Following a 24-week, randomized (1:1:1 to apremilast 30 mg twice daily, 20 mg twice daily, or placebo), double-blind phase and a 28-week blinded active treatment phase, patients could receive apremilast in open-label extension studies for an additional 4 years. Eligible adult patients had active PsA for ≥ 6 months and three or more swollen joints and three or more tender joints despite prior treatment with disease-modifying anti-rheumatic drugs. Results: A total of 1493 randomized patients received one or more doses of study medication (placebo: n = 496; apremilast 30 mg twice daily: n = 497; apremilast 20 mg twice daily: n = 500). In patients continuing apremilast treatment, response was sustained without new safety issues. At week 260, 67.2% of remaining patients achieved an ACR20 response, and 44.4% and 27.4% achieved ACR50 and ACR70 responses, respectively. Among patients with baseline enthesitis and dactylitis, 62.4% achieved a Maastricht Ankylosing Spondylitis Enthesitis Score of 0 and 80.9% achieved a dactylitis count of 0, respectively. In patients who had ≥ 3% baseline psoriasis body surface area involvement, 43.6% achieved ≥ 75% reduction from the baseline Psoriasis Area and Severity Index scores. The most commonly reported adverse events (AEs) were diarrhea, nausea, headache, upper respiratory tract infection, and nasopharyngitis, with most diarrhea and nausea AEs occurring within the first 2 weeks of treatment and usually resolving within 4 weeks. Reported rates of depression during the study were low (≤ 1.8%). The majority of patients maintained their weight within 5% of baseline during the study. No new safety concerns or increases in the incidence or severity of AEs were observed over the long term. Conclusions: Apremilast maintained clinical benefit and a favorable safety profile for up to 5 years among patients with PsA. Trial registration: ClinicalTrials.gov NCT01172938, NCT01212757, NCT01212770
CRIS-Team Scopus Importer:2019-05-21
Keywords: Apremilast; Drug safety; Psoriatic arthritis; Treatment efficacy

Long-term follow-up of HIV-1-infected adults who received the F4/AS01(B) HIV-1 vaccine candidate in two randomised controlled trials - Harrer, Thomas; Dinges, Warren; Roman, Francois (Vaccine, 2018)
This Phase I/II open, long-term follow-up study was conducted in antiretroviral therapy (ART)-naive (N = 212) and ART-treated (N = 19) human immunodeficiency virus 1 (HIV-1)-infected adults, who received an HIV-1 investigational vaccine (F4/AS01(B)) or placebo in two previous studies (NCT00814762 and NCT01218113). After a minimum of two years and a maximum of four years of follow-up postvaccination per patient, no significant differences were observed between F4/AS01(B) and placebo groups in terms of viral load, CD4(+) T-cell count and incidence of specific clinical events. Vaccine-induced polyfunctional CD4(+) T-cells persisted up to study end and no relevant vaccine-related safety events were reported in F4/AS01(B) groups. (C) 2018 The Authors. Published by Elsevier Ltd.
EVALuna2:213268

LONG-TERM HUMORAL RESPONSE TO SARS-COV-2 VACCINATION IN PATIENTS WITH IMMUNE-MEDIATED INFLAMMATORY DISEASE - Tascilar, Koray; Simon, David; Kleyer, Arnd; Fagni, Filippo; Krönke, Gerhard; Meder, Christine; Dietrich, Peter; Orlemann, Till; Kliem, Thorsten; Moessner, J.; Liphardt, Anna-Maria; Schönau, Verena; et al. (ANNALS OF THE RHEUMATIC DISEASES, 2022)
CRIS-Team WoS Importer:2022-11-04

Long term outcomes of immunomodulatory drugs in SSc-ILD - data from the German SSc-network - Kreuter, Michael; Bonella, Francesco; Blank, Norbert; Siegert, Elise; Henes, Joerg; Worm, Margitta; Sunderkoetter, Cord; Schmalzing, Marc; Kreuter, Alexander; Günther, Claudia; Susok, Laura; Zeidler, Gabriele; et al. (EUROPEAN RESPIRATORY JOURNAL, 2019)
CRIS-Team WoS Importer:2020-01-31

Long-Term Safety and Tolerability of Apremilast Versus Placebo in Psoriatic Arthritis: A Pooled Safety Analysis of Three Phase III, Randomized, Controlled Trials - Mease, Philip J.; Gladman, Dafna D.; Gomez-Reino, Juan J.; Hall, Stephen; Kavanaugh, Arthur; Lespessailles, Eric; Schett, Georg; Paris, Maria; Delev, Nikolay; Teng, Lichen; Wollenhaupt, Juergen (ACR Open Rheumatology, 2020)
ObjectivePsoriatic arthritis (PsA) requires long-term treatment, yet safety concerns and monitoring requirements make maintenance a challenge. This analysis of pooled Psoriatic Arthritis Long-term Assessment of Clinical Efficacy (PALACE) 1, 2, and 3 data describes 3-year apremilast safety and tolerability in PsA.
CRIS-Team WoS Importer:2021-07-16

LOOSING DAS28-ESR, BUT STAYING IN BOOLEAN REMISSION-IS IT POSSIBLE? DATA FROM THE PROSPECTIVE, RANDOMISED RETRO TRIAL ON RHEUMATOID ARTHRITIS PATIENTS IN STABLE REMISSION - Erhard, J.; Hagen, Melanie; Englbrecht, Matthias; Haschka, J.; Reiser, M.; Kleyer, Arnd; Hueber, Axel; Manger, Bernhard; Figueiredo, C.; Cobra, J. F.; Tony, H. -P.; Finzel, S.; et al. (2018)
EVALuna2:35003

Loss of Phosphatase and Tensin Homolog in APCs Impedes Th17-Mediated Autoimmune Encephalomyelitis - Sahin, Emine; Brunner, Julia S.; Kral, Julia B.; Kuttke, Mario; Hanzl, Leslie; Datler, Hannes; Paar, Hannah; Neuwinger, Nick; Saferding, Victoria; Zinser, Elisabeth; Halfmann, Angela; Soukup, Klara; et al. (Journal of Immunology, 2015)
The PI3K signaling cascade in APCs has been recognized as an essential pathway to initiate, maintain, and resolve immune responses. In this study, we demonstrate that a cell type-specific loss of the PI3K antagonist phosphatase and tensin homolog (PTEN) in myeloid cells renders APCs toward a regulatory phenotype. APCs deficient for PTEN exhibit reduced activation of p38 MAPK and reduced expression of T cell-polarizing cytokines. Furthermore, PTEN deficiency leads to upregulation of markers for alternative activation, such as Arginase 1, with concomitant downregulation of inducible NO synthase in APCs in vitro and in vivo. As a result, T cell polarization was dysfunctional in PTEN(-/-) APCs, in particular affecting the Th17 cell subset. Intriguingly, mice with cell type-specific deletions of PTEN-targeting APCs were protected from experimental autoimmune encephalomyelitis, which was accompanied by a pronounced reduction of IL-17- and IL-22-producing autoreactive T cells and reduced CNS influx of classically activated monocytes/macrophages. These observations support the notion that activation of the PI3K signaling cascade promotes regulatory APC properties and suppresses pathogenic T cell polarization, thereby reducing the clinical symptoms and pathology of experimental autoimmune encephalomyelitis.
EVALuna2:13151

Low amounts of bisecting glycans characterize cerebrospinal fluid-borne IgG - Knopf, Jasmin; Magorivska, Iryna; Maier, Jan-Niklas; Spitzer, Philipp; Bilyy, Rostyslav; Biermann, Mona; Hychka, Kateryna; Bondt, Albert; Wuhrer, Manfred; Toes, Rene E. M.; Schett, Georg; Herrmann, Martin; et al. (Journal of Neuroimmunology, 2018)
Immunoglobulin G (IgG) harbors a conserved N-glycosylation site which is important for its effector functions. Changes in glycosylation of IgG occur in many autoimmune diseases but also in physiological conditions. Therefore, the glycosylation pattern of serum IgG is well characterized. However, limited data is available on the glycosylation pattern of IgG in cerebrospinal fluid (CSF) compared to serum. Here, we report significantly reduced levels of bisected glycans in CSF IgG. Galactosylation and sialylation of IgG4 also differed significantly. Therefore, we propose a common mechanism mediating glycosylation changes of IgG at the transition from serum to CSF in steady state conditions.
EVALuna2:34466

Low-Dose Radiotherapy Ameliorates Advanced Arthritis in hTNF-α tg Mice by Particularly Positively Impacting on Bone Metabolism - Deloch, Lisa; Derer, Anja; Hueber, Axel; Herrmann, Martin; Schett, Georg; Wölfelschneider, Jens; Hahn, Jonas; Rühle, Paul-Friedrich; Stillkrieg, Willy; Fuchs, Jana; Fietkau, Rainer; Frey, Benjamin; et al. (Frontiers in Immunology, 2018)
Inflammation and bone erosion are central in rheumatoid arthritis (RA). Even though effective medications for control and treatment of RA are available, remission is only seen in a subset of patients. Treatment with low-dose radiotherapy (LD-RT) which has been already successfully used for amelioration of symptoms in benign diseases should be a promising approach to reduce pain, inflammation, and particularly bone erosion in patients with RA. Even though anti-inflammatory effects of LD-RT are already described with non-linear dose response relationships, and pain-reducing effects have been clinically observed, the underlying mechanisms are widely unknown. Besides immune cells many other cell types, such as fibroblast-like synoviocytes (FLS), osteoclasts, and osteoblast are present in the affected joint and might be modulated by LD-RT. For this study, these cell types were obtained from human tumor necrosis factor-α transgenic (hTNF-α tg) mice and were consecutively exposed to different doses of ionizing radiation (0.1, 0.5, 1.0, and 2.0 Gy, respectively) in vitro. In order to study the in vivo effects of LD-RT within the arthritic joint, hind paws of arthritic hTNF-α tg mice were locally irradiated with 0.5 Gy, a single dose per fraction that is known for good clinical responses. Starting at a dose of 0.5 Gy, proliferation of FLS was reduced and apoptosis significantly enhanced with no changes in necrosis. Further, expression of RANK-L was slightly reduced following irradiation with particularly 0.5 Gy. Starting from 0.5 Gy, the numbers of differentiated osteoclasts were significantly reduced, and a lower bone resorbing activity of treated osteoclasts was also observed, as monitored via pit formation and Cross Laps presence. LD-RT had further a positive effect on osteoblast-induced mineralization in a discontinuous dose response relationship with 0.5 Gy being most efficient. An increase of the gene expression ratio of OPG/RANK-L at 0.1 and 0.5 Gy and of production of OPG at 0.5 and 1.0 Gy was observed. In vivo, LD-RT resulted in less severe arthritis in arthritic hTNF-α tg mice and in significant reduction of inflammatory and erosive area with reduced osteoclasts and neutrophils. Locally applied LD-RT can, therefore, induce a beneficial micro-environment within arthritic joints by predominantly positively impacting on bone metabolism.
EVALuna2:34663
Keywords: rheumatoid arthritis; inflammation; low-dose radiotherapy; bone metabolism; synovial-like fibroblasts; osteoclasts; osteoblasts

Low-Salt Diet Attenuates B-Cell- and Myeloid-Cell-Driven Experimental Arthritides by Affecting Innate as Well as Adaptive Immune Mechanisms - Sehnert, Bettina; Pohle, Sandy; Heuberger, Cornelia; Rzepka, Rita; Seidl, Maximilian; Nimmerjahn, Falk; Chevalier, Nina; Titze, Jens; Voll, Reinhard E. (Frontiers in Immunology, 2021)
A link between high sodium chloride (salt) intake and the development of autoimmune diseases was previously reported. These earlier studies demonstrated exacerbation of experimental autoimmune encephalomyelitis and colitis by excess salt intake associated with Th17- and macrophage-mediated mechanisms. Little is known about the impact of dietary salt intake on experimental arthritides. Here, we investigated if salt restriction can exert beneficial effects on collagen-induced arthritis (CIA) and K/BxN serum transfer-induced arthritis (STIA). CIA depends on both adaptive and innate immunity, while STIA predominantly mimics the innate immune cell-driven effector phase of arthritis. In both models, low salt (LS) diet significantly decreased arthritis severity compared to regular salt (RS) and high salt (HS) diet. We did not observe an aggravation of arthritis with HS diet compared to RS diet. Remarkably, in STIA, LS diet was as effective as IL-1 receptor blocking treatment. Complement-fixing anti-CII IgG2a antibodies are associated with inflammatory cell infiltration and cartilage destruction. LS diet reduced anti-CII IgG2a levels in CIA and decreased the anti-CII IgG2a/IgG1 ratios pointing toward a more Th2-like response. Significantly less inflammatory joint infiltrates and cartilage breakdown associated with reduced protein concentrations of IL-1 beta (CIA and STIA), IL-17 (CIA), and the monocyte chemoattractant protein-1 (MCP-1) (CIA) were detected in mice receiving LS diet compared to HS diet. However, we did not find a reduced IL-17A expression in CD4+ T cells upon salt restriction in CIA. Analysis of mRNA transcripts and immunoblots revealed a link between LS diet and inhibition of the p38 MAPK (mitogen-activated protein kinase)/NFAT5 (nuclear factor of activated T-cells 5) signaling axis in STIA. Further experiments indicated a decreased leukodiapedesis under LS conditions. In conclusion, dietary salt restriction ameliorates CIA and STIA, indicating a beneficial role of LS diet during both the immunization and effector phase of immune-mediated arthritides by predominantly modulating the humoral immunity and the activation status of myeloid lineage cells. Hence, salt restriction might represent a supportive dietary intervention not only to reduce cardiovascular risk, but also to improve human inflammatory joint diseases like rheumatoid arthritis.
CRIS-Team Scopus Importer:2021-12-31
Keywords: collagen-induced arthritis; cytokines; diet; serum transfer-induced arthritis; sodium chloride

Lymph node and pulmonary tuberculosis during upadacitinib treatment in a psoriatic arthritis patient - Valor-Mendez, Larissa; Manger, Bernhard; Wacker, Jochen; Kleyer, Arnd; Schett, Georg (Rheumatology Advances in Practice, 2022)
CRIS-Team Scopus Importer:2022-07-22

Machine Learning Algorithms for Early Detection of Bone Metastases in an Experimental Rat Model - Ellmann, Stephan; Seyler, Lisa; Gillmann, Clarissa; Popp, Vanessa; Treutlein, Christoph; Bozec, Aline; Uder, Michael; Bäuerle, Tobias (Journal of Visualized Experiments, 2020)
Machine learning (ML) algorithms permit the integration of different features into a model to perform classification or regression tasks with an accuracy exceeding its constituents. This protocol describes the development of an ML algorithm to predict the growth of breast cancer bone macrometastases in a rat model before any abnormalities are observable with standard imaging methods. Such an algorithm can facilitate the detection of early metastatic disease (i.e., micrometastasis) that is regularly missed during staging examinations. The applied metastasis model is site-specific, meaning that the rats develop metastases exclusively in their right hind leg. The model's tumor-take rate is 60%-80%, with macrometastases becoming visible in magnetic resonance imaging (MRI) and positron emission tomography/computed tomography (PET/CT) in a subset of animals 30 days after induction, whereas a second subset of animals exhibit no tumor growth. Starting from image examinations acquired at an earlier time point, this protocol describes the extraction of features that indicate tissue vascularization detected by MRI, glucose metabolism by PET/CT, and the subsequent determination of the most relevant features for the prediction of macrometastatic disease. These features are then fed into a model-averaged neural network (avNNet) to classify the animals into one of two groups: one that will develop metastases and the other that will not develop any tumors. The protocol also describes the calculation of standard diagnostic parameters, such as overall accuracy, sensitivity, specificity, negative/positive predictive values, likelihood ratios, and the development of a receiver operating characteristic. An advantage of the proposed protocol is its flexibility, as it can be easily adapted to train a plethora of different ML algorithms with adjustable combinations of an unlimited number of features. Moreover, it can be used to analyze different problems in oncology, infection, and inflammation.
CRIS-Team Scopus Importer:2020-09-11

Machine learning-based improvement of an online rheumatology referral and triage system - Knitza, Johannes; Janousek, Lena; Kluge, Felix; Von Der Decken, Cay Benedikt; Kleinert, Stefan; Vorbrueggen, Wolfgang; Kleyer, Arnd; Simon, David; Hueber, Axel; Muehlensiepen, Felix; Vuillerme, Nicolas; Schett, Georg; et al. (Frontiers in Medicine, 2022)
Introduction: Rheport is an online rheumatology referral system allowing automatic appointment triaging of new rheumatology patient referrals according to the respective probability of an inflammatory rheumatic disease (IRD). Previous research reported that Rheport was well accepted among IRD patients. Its accuracy was, however, limited, currently being based on an expert-based weighted sum score. This study aimed to evaluate whether machine learning (ML) models could improve this limited accuracy. Materials and methods: Data from a national rheumatology registry (RHADAR) was used to train and test nine different ML models to correctly classify IRD patients. Diagnostic performance was compared of ML models and the current algorithm was compared using the area under the receiver operating curve (AUROC). Feature importance was investigated using shapley additive explanation (SHAP). Results: A complete data set of 2265 patients was used to train and test ML models. 30.5% of patients were diagnosed with an IRD, 69.3% were female. The diagnostic accuracy of the current Rheport algorithm (AUROC of 0.534) could be improved with all ML models, (AUROC ranging between 0.630 and 0.737). Targeting a sensitivity of 90%, the logistic regression model could double current specificity (17% vs. 33%). Finger joint pain, inflammatory marker levels, psoriasis, symptom duration and female sex were the five most important features of the best performing logistic regression model for IRD classification. Conclusion: In summary, ML could improve the accuracy of a currently used rheumatology online referral system. Including further laboratory parameters and enabling individual feature importance adaption could increase accuracy and lead to broader usage.
CRIS-Team Scopus Importer:2022-08-19
Keywords: artificial intelligence; decision support system (DSS); digital health; machine learning; rheumatology; symptom checker; triage

Machine Learning Electronic Health Record Identification of Patients with Rheumatoid Arthritis: Algorithm Pipeline Development and Validation Study - Maarseveen, Tjardo D.; Meinderink, Timo; Reinders, Marcel J. T.; Knitza, Johannes; Huizinga, Tom W. J.; Kleyer, Arnd; Simon, David; Van Den Akker, Erik B.; Knevel, Rachel (JMIR Medical Informatics, 2020)
Background: Financial codes are often used to extract diagnoses from electronic health records. This approach is prone to false positives. Alternatively, queries are constructed, but these are highly center and language specific. A tantalizing alternative is the automatic identification of patients by employing machine learning on format-free text entries.
CRIS-Team WoS Importer:2021-01-15

Machine Learning Identifies an Association Between Pre-existing Radiographic Damage 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; Pricop, Luminita; Zhu, Xuan; James, Davida; Ligozio, Gregory (ARTHRITIS & RHEUMATOLOGY, 2020)
CRIS-Team WoS Importer:2021-01-15

Magnesium Disorders - Manger, Bernhard; Schett, Georg (New England Journal of Medicine, 2024)
CRIS-Team Scopus Importer:2024-08-30

Magnetic resonance imaging techniques for the quantitative analysis of skeletal muscle: State of the art. - Engelke, Klaus; Chaudry, Oliver; Gast, Lena; Eldib, Mootaz AB; Wang, Ling; Laredo, Jean Denis; Schett, Georg; Nagel, Armin Michael (Journal of Orthopaedic Translation, 2023)
BACKGROUND: Magnetic resonance imaging (MRI) is the dominant 3D imaging modality to quantify muscle properties in skeletal muscle disorders, in inherited and acquired muscle diseases, and in sarcopenia, in cachexia and frailty. METHODS: This review covers T1 weighted and Dixon sequences, introduces T2 mapping, diffusion tensor imaging (DTI) and non-proton MRI. Technical concepts, strengths, limitations and translational aspects of these techniques are discussed in detail. Examples of clinical applications are outlined. For comparison 31P-and 13C-MR Spectroscopy are also addressed. RESULTS: MRI technology provides a rich toolset to assess muscle deterioration. In addition to classical measures such as muscle atrophy using T1 weighted imaging and fat infiltration using Dixon sequences, parameters characterizing inflammation from T2 maps, tissue sodium using non-proton MRI techniques or concentration or fiber architecture using diffusion tensor imaging may be useful for an even earlier diagnosis of the impairment of muscle quality. CONCLUSION: Quantitative MRI provides new options for muscle research and clinical applications. Current limitations that also impair its more widespread use in clinical trials are lack of standardization, ambiguity of image segmentation and analysis approaches, a multitude of outcome parameters without a clear strategy which ones to use and the lack of normal data.
EVALuna2:540329

Mapping and predicting mortality from systemic sclerosis - Elhai, Muriel; Meune, Christophe; Boubaya, Marouane; Avouac, Jerome; Hachulla, Eric; Balbir-Gurman, Alexandra; Riemekasten, Gabriela; Airo, Paolo; Joven, Beatriz; Vettori, Serena; Cozzi, Franco; Ullman, Susanne; et al. (Annals of the Rheumatic Diseases, 2017)
To determine the causes of death and risk factors in systemic sclerosis (SSc).Between 2000 and 2011, we examined the death certificates of all French patients with SSc to determine causes of death. Then we examined causes of death and developed a score associated with all-cause mortality from the international European Scleroderma Trials and Research (EUSTAR) database. Candidate prognostic factors were tested by Cox proportional hazards regression model by single variable analysis, followed by a multiple variable model stratified by centres. The bootstrapping technique was used for internal validation.We identified 2719 French certificates of deaths related to SSc, mainly from cardiac (31%) and respiratory (18%) causes, and an increase in SSc-specific mortality over time. Over a median follow-up of 2.3 years, 1072 (9.6%) of 11 193 patients from the EUSTAR sample died, from cardiac disease in 27% and respiratory causes in 17%. By multiple variable analysis, a risk score was developed, which accurately predicted the 3-year mortality, with an area under the curve of 0.82. The 3-year survival of patients in the upper quartile was 53%, in contrast with 98% in the first quartile.Combining two complementary and detailed databases enabled the collection of an unprecedented 3700 deaths, revealing the major contribution of the cardiopulmonary system to SSc mortality. We also developed a robust score to risk-stratify these patients and estimate their 3-year survival. With the emergence of new therapies, these important observations should help caregivers plan and refine the monitoring and management to prolong these patients' survival.
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Markerless RGB-D Hand Pose Estimation for Activity Monitoring of Musculoskeletal Diseases - Wirth, Vanessa; Liphardt, Anna-Maria; Coppers, Birte; Bräunig, Johanna; Heinrich, Simon; Leyendecker, Sigrid; Kleyer, Arnd; Schett, Georg; Vossiek, Martin; Egger, Bernhard; Stamminger, Marc (IEEE-EMBS International Conference on Biomedical and Health Informatics (BHI’23), 2023)

Massive nodulous lesions on hands and feet in a RA patient and improvement under baricitinib treatment - Valor-Méndez, Larissa; Hagen, Melanie; Kleyer, Arnd; Manger, Bernhard; Schett, Georg (RMD Open, 2020)
CRIS-Team Scopus Importer:2020-12-04
Keywords: Arthritis; Methotrexate; Rheumatoid; Therapeutics

Mast cells in early rheumatoid arthritis associate with disease severity and support B cell autoantibody production - Rivellese, Felice; Mauro, Daniele; Nerviani, Alessandra; Pagani, Sara; Fossati-Jimack, Liliane; Messemaker, Tobias; Kurreeman, Fina A.S.; Toes, René E.M.; Rauber, Simon; Schett, Georg; Jones, Gareth W.; Jones, Simon A.; et al. (Annals of the Rheumatic Diseases, 2018)
OBJECTIVES: Mast cells (MCs) are involved in the pathogenesis of rheumatoid arthritis (RA). However, their contribution remains controversial. To establish their role in RA, we analysed their presence in the synovium of treatment-naïve patients with early RA and their association and functional relationship with histological features of synovitis. METHODS: Synovial tissue was obtained by ultrasound-guided biopsy from treatment-naïve patients with early RA (n=99). Immune cells (CD3/CD20/CD138/CD68) and their relationship with CD117+MCs in synovial tissue were analysed by immunohistochemistry (IHC) and immunofluorescence (IF). The functional involvement of MCs in ectopic lymphoid structures (ELS) was investigated in vitro, by coculturing MCs with naïve B cells and anticitrullinated protein antibodies (ACPA)-producing B cell clones, and in vivo in interleukin-27 receptor alpha (IL27ra)-deficient and control mice during antigen-induced arthritis (AIA). RESULTS: High synovial MC counts are associated with local and systemic inflammation, autoantibody positivity and high disease activity. IHC/IF showed that MCs reside at the outer border of lymphoid aggregates. Furthermore, human MCs promote the activation and differentiation of naïve B cells and induce the production of ACPA, mainly via contact-dependent interactions. In AIA, synovial MC numbers increase in IL27ra deficient mice, in association with ELS and worse disease activity. CONCLUSIONS: Synovial MCs identify early RA patients with a severe clinical form of synovitis characterised by the presence of ELS.
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Measuring treatment effect on psoriatic arthritis-related domains: insights from the SPIRIT-H2H study at weeks 24 and 52 - Behrens, Frank; Leage, Soyi Liu; Sapin, Christophe; El Baou, Celine; De La Torre, Inmaculada; Meszaros, Gabriella; Schett, Georg; Combe, Bernard; Van Den Bosch, Filip; Gossec, Laure (Clinical Rheumatology, 2021)
Introduction Improvements in both musculoskeletal and non-musculoskeletal manifestations are important treatment goals in psoriatic arthritis (PsA).
CRIS-Team WoS Importer:2021-09-24

MECHANICAL LOADING-INDUCED BHLHE40 PROMOTES INFLAMMATORY ARTHRITIS - Gracey, E.; Cambre, I.; Gilis, E.; Stappers, F.; Planckaert, G.; Bozec, Aline; Elewaut, D. (ANNALS OF THE RHEUMATIC DISEASES, 2022)
CRIS-Team WoS Importer:2022-11-04

MECHANICAL STRAIN DETERMINES THE SITE-SPECIFIC DIRECTION OF INFLAMMATION AND TISSUE DAMAGE IN ARTHRITIS - Cambre, I.; Gaublomme, D.; Burssens, A.; Jacques, P.; Elewaut, D.; Lories, R.; Schett, Georg; Kollias, G.; De Muynck, A.; Meuris, L.; Callewaert, N.; Lambrecht, S.; et al. (2018)
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Mechanical strain determines the site-specific localization of inflammation and tissue damage in arthritis. - Cambre, Isabelle; Gaublomme, Djoere; Burssens, Arne; Jacques, Peggy; Schryvers, Nadia; De Muynck, Amelie; Meuris, Leander; Lambrecht, Stijn; Carter, Shea; De Bleser, Pieter; Saeys, Yvan; Van Hoorebeke, Luc; et al. (Nature Communications, 2018)
Many pro-inflammatory pathways leading to arthritis have global effects on the immune system rather than only acting locally in joints. The reason behind the regional and patchy distribution of arthritis represents a longstanding paradox. Here we show that biomechanical loading acts as a decisive factor in the transition from systemic autoimmunity to joint inflammation. Distribution of inflammation and erosive disease is confined to mechano-sensitive regions with a unique microanatomy. Curiously, this pathway relies on stromal cells but not adaptive immunity. Mechano-stimulation of mesenchymal cells induces CXCL1 and CCL2 for the recruitment of classical monocytes, which can differentiate into bone-resorbing osteoclasts. Genetic ablation of CCL2 or pharmacologic targeting of its receptor CCR2 abates mechanically-induced exacerbation of arthritis, indicating that stress-induced chemokine release by mesenchymal cells and chemo-attraction of monocytes determines preferential homing of arthritis to certain hot spots. Thus, mechanical strain controls the site-specific localisation of inflammation and tissue damage in arthritis.
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Mechanisms leading from systemic autoimmunity to joint-specific disease in rheumatoid arthritis - Catrina, Anca I.; Svensson, Camilla I.; Malmstrom, Vivianne; Schett, Georg; Klareskog, Lars (Nature Reviews Rheumatology, 2016)
A key unanswered question in the pathophysiology of rheumatoid arthritis (RA) is how systemic autoimmunity progresses to joint-specific inflammation. In patients with seropositive RA (that is, characterized by the presence of autoantibodies) evidence is accumulating that immunity against post-translationally modified (such as citrullinated) autoantigens might be triggered in mucosal organs, such as the lung, long before the first signs of inflammation are seen in the joints. However, the mechanism by which systemic autoimmunity specifically homes to the joint and bone compartment, thereby triggering inflammation, remains elusive. This Review summarizes potential pathways involved in this joint-homing mechanism, focusing particularly on osteoclasts as the primary targets of anti-citrullinated protein antibodies (ACPAs) in the bone and joint compartment. Osteoclasts are dependent on citrullinating enzymes for their normal differentiation and are unique in displaying citrullinated antigens on their cell surface in a non-inflamed state. The binding of ACPAs to osteoclasts releases the chemokine IL-8, leading to bone erosion and pain. This process initiates a chain of events that could lead to attraction and activation of neutrophils, resulting in a complex series of proinflammatory processes in the synovium, eventually leading to RA.
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Ménage-à-Trois: The Ratio of Bicarbonate to CO2 and the pH Regulate the Capacity of Neutrophils to Form NETs - Maueröder, Christian; Mahajan, Aparna; Paulus, Susanne; Goesswein, Stefanie; Hahn, Jonas; Kienhoefer, Deborah; Biermann, Mona H.; Tripal, Philipp; Friedrich, Ralf P.; Munoz Becerra, Luis; Neurath, Markus; Becker, Christoph; et al. (Frontiers in Immunology, 2016)
In this study, we identified and characterized the potential of a high ratio of bicarbonate to CO2 and a moderately alkaline pH to render neutrophils prone to undergo neutrophil extracellular trap (NET) formation. Both experimental settings increased the rate of spontaneous NET release and potentiated the NET-inducing capacity of phorbol esters (phorbol-2-myristate-13-acetate), ionomycin, monosodium urate, and LPS. In contrast, an acidic environment impaired NET formation both spontaneous and induced. Our findings indicate that intracellular alkalinization of neutrophils in response to an alkaline environment leads to an increase of intracellular calcium and neutrophil activation. We further found that the anion channel blocker DIDS strongly reduced NET formation induced by bicarbonate. This finding suggests that the effects observed are due to a molecular program that renders neutrophils susceptible to NET formation. Inflammatory foci may be characterized by an acidic environment. Our data indicate that NET formation is favored by the higher pH at the border regions of inflamed areas. Moreover, our findings highlight the necessity for strict pH control during assays of NET formation.
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Messung des krankheitsbezogenen Wissens von Patient*innen mit axialer Spondyloarthritis – Entwicklung und Anwendung des G-ASKQ7-Fragebogens - Schuster, Louis; Henes, Jörg; Diener, Matthias; Mühlensiepen, Felix; Andreica, Ioana; Hueber, Axel; Schett, Georg; Knitza, Johannes (Zeitschrift für Rheumatologie, 2024)
Hintergrund/Ziel: Patientenedukation ist integraler Bestandteil der Behandlung von Patient*innen mit axialer Spondyloarthritis (axSpA). Allerdings sind die verfügbaren validen Messinstrumente zur Erhebung des krankheitsbezogenen Wissens veraltet und im Falle der axSpA nur in englischer Sprache verfügbar. Die Ziele dieser Studie waren daher (1) die Entwicklung eines geeigneten deutschsprachigen Instruments zur Messung krankheitsspezifischen Wissens bei axSpA-Patient*innen und (2) die Pilotierung dieses Instruments. Methoden: Verfügbare Messinstrumente speziell für die axSpA wurden von einem Expertengremium geprüft, und ein Entwurf des aktuellen G‑ASKQ7 wurde abgestimmt. Nach Evaluation der Augenscheinvalidität und entsprechenden Anpassungen wurden erwachsene konsekutive axSpA-Patient*innen der rheumatologischen Hochschulambulanz des Universitätsklinikums Erlangen gebeten, den Fragebogen auszufüllen. Es wurden Korrelationen zwischen dem erreichten Summenscore und weiteren erhobenen Parametern (Alter, Geschlecht und Krankheitsdauer) untersucht. Ergebnisse: Der entwickelte G‑ASKQ7-Fragebogen umfasst 7 Fragen, wurde als leicht verständlich bewertet und innerhalb von durchschnittlich 6,3 ±2,0 min ausgefüllt; 65 axSpA-Patient*innen (36 Frauen; mittleres Alter: 45,3 ± 12,4 Jahre; mittlere Erkrankungsdauer: 8,6 ±7,3 Jahre) beantworteten den finalen Fragebogen. Der G‑AKSQ7-Mittelwert lag bei 17,8/25 und war bei Frauen (19,0/25) signifikant höher als bei Männern (16,3/25) (p = < 0,05). Am häufigsten wurde Frage 7 (79,3 %) mit Hinblick auf das Selbstmanagement der Erkrankung korrekt beantwortet. Frage 4 mit Blick auf die Messung der Krankheitsaktivität wurde am schlechtesten beantwortet (55,8 %). Es konnte keine signifikante Korrelation zwischen der Krankheitsdauer (p = 0,57; r = 0,07; Pearson-Korrelationstest) oder dem Alter (p = 0,67; r = −0,05; Pearson-Korrelationstest) und dem krankheitsbezogenen Wissen festgestellt werden. Diskussion: Der G‑ASKQ7 bietet erstmals ein deutschsprachiges Instrument zur Ermittlung des krankheitsspezifischen Wissens von axSpA-Patient*innen. Durch eine routinemäßige Erhebung mittels G‑ASKQ7 kann der individuelle Wissensbedarf von Patient*innen niedrigschwellig ermittelt werden, und Edukationsinhalte können gezielt auf Patient*innen abgestimmt werden. Eine kontinuierliche Aktualisierung und weitere Evaluationsstudien sind erforderlich.
CRIS-Team Scopus Importer:2024-11-22
Keywords: Axial spondyloarthritis; Health competence; Health services research; Patient education; Self-management

Metabolic and molecular imaging in inflammatory arthritis - Noversa de Sousa, Rita; Tascilar, Koray; Corte, Giulia; Atzinger, Armin; Minopoulou, Ioanna; Ohrndorf, Sarah; Waldner, Maximilian; Schmidkonz, Christian; Kuwert, Torsten; Knieling, Ferdinand; Kleyer, Arnd; Ramming, Andreas; et al. (RMD Open, 2024)
It is known that metabolic shifts and tissue remodelling precede the development of visible inflammation and structural organ damage in inflammatory rheumatic diseases such as the inflammatory arthritides. As such, visualising and measuring metabolic tissue activity could be useful to identify biomarkers of disease activity already in a very early phase. Recent advances in imaging have led to the development of so-called ‘metabolic imaging’ tools that can detect these changes in metabolism in an increasingly accurate manner and non-invasively. Nuclear imaging techniques such as 18F-D-glucose and fibroblast activation protein inhibitor-labelled positron emission tomography are increasingly used and have yielded impressing results in the visualisation (including whole-body staging) of inflammatory changes in both early and established arthritis. Furthermore, optical imaging-based bedside techniques such as multispectral optoacoustic tomography and fluorescence optical imaging are advancing our understanding of arthritis by identifying intra-articular metabolic changes that correlate with the onset of inflammation with high precision and without the need of ionising radiation. Metabolic imaging holds great potential for improving the management of patients with inflammatory arthritis by contributing to early disease interception and improving diagnostic accuracy, thereby paving the way for a more personalised approach to therapy strategies including preventive strategies. In this narrative review, we discuss state-of-the-art metabolic imaging methods used in the assessment of arthritis and inflammation, and we advocate for more extensive research endeavours to elucidate their full field of application in rheumatology.
CRIS-Team Scopus Importer:2024-02-23

Metabolic profiling of single cells by exploiting NADH and FAD fluorescence via flow cytometry - Abir, Ariful Haque; Weckwerth, Leonie; Wilhelm, Artur; Thomas, Jana; Reichardt, Clara; Munoz, Luis Enrique; Völkl, Simon; Appelt, Uwe; Mroz, Markus; Niesner, Raluca; Hauser, Anja; Fischer, Rebecca Sophie; et al. (Molecular Metabolism, 2024)
Objective: The metabolism of different cells within the same microenvironment can differ and dictate physiological or pathological adaptions. Current single-cell analysis methods of metabolism are not label-free. Methods: The study introduces a label-free, live-cell analysis method assessing endogenous fluorescence of NAD(P)H and FAD in surface-stained cells by flow cytometry. Results: OxPhos inhibition, mitochondrial uncoupling, glucose exposure, genetic inactivation of glucose uptake and mitochondrial respiration alter the optical redox ratios of FAD and NAD(P)H as measured by flow cytometry. Those alterations correlate strongly with measurements obtained by extracellular flux analysis. Consequently, metabolically distinct live B-cell populations can be resolved, showing that human memory B-cells from peripheral blood exhibit a higher glycolytic flexibility than naïve B cells. Moreover, the comparison of blood-derived B- and T-lymphocytes from healthy donors and rheumatoid arthritis patients unleashes rheumatoid arthritis-associated metabolic traits in human naïve and memory B-lymphocytes. Conclusions: Taken together, these data show that the optical redox ratio can depict metabolic differences in distinct cell populations by flow cytometry.
CRIS-Team Scopus Importer:2024-07-19
Keywords: FAD; Flow cytometry; Fluorescence; Metabolism; NADH; Real-time

Metabolic regulation of plasma cell generation in germinal centers through EFhd2 - Weckwerth, Leonie; Gottwald, A.; Mielenz, Dirk (EUROPEAN JOURNAL OF IMMUNOLOGY, 2022)
CRIS-Team WoS Importer:2023-01-27

Metabolic reprogramming of osteoclasts represents a therapeutic target during the treatment of osteoporosis - Taubmann, Jule; Krishnacoumar, Brenda; Böhm, Christina; Faas, Maria; Müller, Dorothea; Adam, Susanne; Stoll, Cornelia; Böttcher, Martin; Mougiakakos, Dimitrios; Sonnewald, Uwe; Hofmann, Jörg; Schett, Georg; et al. (Scientific Reports, 2020)
Osteoclasts are specialised bone resorbing cells that control both physiological and pathological bone turnover. Functional changes in the differentiation and activity of osteoclasts are accompanied by active metabolic reprogramming. However, the biological significance and the in vivo relevance of these events has remained unclear. Here we show that bone resorption of differentiated osteoclasts heavily relies on increased aerobic glycolysis and glycolysis-derived lactate production. While pharmacological inhibition of glycolysis did not affect osteoclast differentiation or viability, it efficiently blocked bone resorption in vitro and in vivo and consequently ameliorated ovariectomy-induced bone loss. Our experiments thus highlight the therapeutic potential of interfering with osteoclast-intrinsic metabolic pathways as possible strategy for the treatment of diseases characterized by accelerated bone loss.
CRIS-Team Scopus Importer:2020-12-11

Metabolic rewiring controlled by HIF-1α tunes IgA-producing B-cell differentiation and intestinal inflammation - Meng, Xianyi; Asadi Asadabad, Sahar; Cao, Shan; Song, Rui; Lin, Zhen; Safhi, Mohammed; Qin, Yi; Tcheumi Tactoum, Estelle Manuella; Taudte, Verena; Ekici, Arif Bülent; Mielenz, Dirk; Wirtz, Stefan; et al. (Cellular & Molecular Immunology, 2024)
Germinal centers where B cells undergo clonal expansion and antibody affinity maturation are hypoxic microenvironments. However, the function of hypoxia-inducible factor (HIF)-1α in immunoglobulin production remains incompletely characterized. Here, we demonstrated that B cells lacking HIF-1α exhibited significantly lower glycolytic metabolism and impaired IgA production. Loss of HIF-1α in B cells affects IgA-producing B-cell differentiation and exacerbates dextran sodium sulfate (DSS)-induced colitis. Conversely, promoting HIF-1α stabilization via a PHD inhibitor roxadustat enhances IgA class switching and alleviates intestinal inflammation. Mechanistically, HIF-1α facilitates IgA class switching through acetyl-coenzyme A (acetyl-CoA) accumulation, which is essential for histone H3K27 acetylation at the Sα region. Consequently, supplementation with acetyl-CoA improved defective IgA production in Hif1a-deficient B cells and limited experimental colitis. Collectively, these findings highlight the critical importance of HIF-1α in IgA class switching and the potential for targeting the HIF-1α-dependent metabolic‒epigenetic axis to treat inflammatory bowel diseases and other inflammatory disorders.
CRIS-Team Scopus Importer:2024-11-22
Keywords: B cells; HIF-1α; Hypoxia; IgA; Intestinal inflammation

Metabolic rewiring promotes anti-inflammatory effects of glucocorticoids - Auger, Jean-Philippe; Zimmermann, Max; Faas, Maria; Stifel, Ulrich; Chambers, David; Krishnacoumar, Brenda; Taudte, R. Verena; Grund, Charlotte; Erdmann, Gitta; Scholtysek, Carina; Uderhardt, Stefan; Ben Brahim, Oumaima; et al. (Nature, 2024)
Glucocorticoids represent the mainstay of therapy for a broad spectrum of immune-mediated inflammatory diseases. However, the molecular mechanisms underlying their anti-inflammatory mode of action have remained incompletely understood1. Here we show that the anti-inflammatory properties of glucocorticoids involve reprogramming of the mitochondrial metabolism of macrophages, resulting in increased and sustained production of the anti-inflammatory metabolite itaconate and consequent inhibition of the inflammatory response. The glucocorticoid receptor interacts with parts of the pyruvate dehydrogenase complex whereby glucocorticoids provoke an increase in activity and enable an accelerated and paradoxical flux of the tricarboxylic acid (TCA) cycle in otherwise pro-inflammatory macrophages. This glucocorticoid-mediated rewiring of mitochondrial metabolism potentiates TCA-cycle-dependent production of itaconate throughout the inflammatory response, thereby interfering with the production of pro-inflammatory cytokines. By contrast, artificial blocking of the TCA cycle or genetic deficiency in aconitate decarboxylase 1, the rate-limiting enzyme of itaconate synthesis, interferes with the anti-inflammatory effects of glucocorticoids and, accordingly, abrogates their beneficial effects during a diverse range of preclinical models of immune-mediated inflammatory diseases. Our findings provide important insights into the anti-inflammatory properties of glucocorticoids and have substantial implications for the design of new classes of anti-inflammatory drugs.
CRIS-Team Scopus Importer:2024-04-19

Metabolische Arthritiden, seltene Erkrankungen - Manger, Bernhard (Zeitschrift für Rheumatologie, 2019)
CRIS-Team WoS Importer:2019-08-20

METABOLISM AND OSTEOARTHRITIS ARE LINKED BY ADIPOKINES - Huelser, M-L.; Schreiyack, C.; Luo, Y.; Bozec, Aline; Schett, Georg; Neumann, E.; Mueller-Ladner, U. (2017)
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Methods for segmentation of rheumatoid arthritis bone erosions in high-resolution peripheral quantitative computed tomography (HR-pQCT) - Figueiredo, Camille P.; Kleyer, Arnd; Simon, Dominic; Stemmler, Fabian; d'Oliveira, Isabelle; Weißenfels, Anja; Museyko, Oleg; Friedberger, Andreas; Hueber, Axel; Haschka, Judith; Englbrecht, Matthias; Pereira, Rosa M.R.; et al. (Seminars in Arthritis and Rheumatism, 2017)
The comparison between different techniques to quantify the 3-dimensional size of inflammatory bone erosions in rheumatoid arthritis(RA) patients.Anti-cyclic citrullinated peptide antibody(ACPA) positive RA patients received high-resolution peripheral quantitative computed tomography (HR-pQCT) scans of the metacarpophalangeal joints (MCP). Erosions were measured by three different segmentation techniques: (1) manual method with calculation by half-ellipsoid formula, (2) semi-automated modified Evaluation Script for Erosions (mESE), and (3) semi-automated Medical Image Analysis Framework (MIAF) software. Bland & Altman plots were used to describe agreement between methods. Furthermore, shape of erosions was classified as regular or irregular and then compared to the sphericity obtained by MIAF.A total of 76 erosions from 65 RA patients (46 females/19 males), median age 57 years, median disease duration 6.1 years and median disease activity score 28 of 2.8 units were analyzed. While mESE and MIAF showed good agreement in the measurement of erosion size, the manual method with calculation by half-ellipsoid formula underestimated erosions size, particularly with larger erosions. Accurate segmentation is particularly important in larger erosions, which are irregularly shaped. In all three segmentation techniques irregular erosions were larger in size than regular erosions (MIAF: 19.7 vs. 3.4mm(3); mESE: 15.5 vs. 2.3mm(3); manual = 7.2 vs. 1.52mm(3); all p < 0.001). In accordance, sphericity of erosions measured by MIAF significantly decreased with their size (p < 0.001).MIAF and mESE allow segmentation of inflammatory bone erosions in RA patients with excellent inter reader reliability. They allow calculating erosion volume independent of erosion shape and therefore provide an attractive tool to quantify structural damage in individual joints of RA patients.
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Methotrexate Hampers Immunogenicity to BNT162b2 mRNA COVID-19 Vaccine in Immune-Mediated Inflammatory Disease - Haberman, Rebecca; Herati, Ramin; Simon, David; Samanovic, Marie; Tuen, Michael; Blank, Rebecca; Koralov, Sergei; Atreya, Raja; Tascilar, Koray; Allen, Joseph; Castillo, Rochelle; Cornelius, Amber; et al. (ARTHRITIS & RHEUMATOLOGY, 2021)
CRIS-Team WoS Importer:2022-03-11

Methotrexate hampers immunogenicity to BNT162b2 mRNA COVID-19 vaccine in immune-mediated inflammatory disease - Haberman, Rebecca H.; Herati, Ramin Sedaghat; Simon, David; Samanovic, Marie; Blank, Rebecca B.; Tuen, Michael; Koralov, Sergei B.; Atreya, Raja; Tascilar, Koray; Allen, Joseph R.; Castillo, Rochelle; Cornelius, Amber R.; et al. (Annals of the Rheumatic Diseases, 2021)
Objective To investigate the humoral and cellular immune response to messenger RNA (mRNA) COVID-19 vaccines in patients with immune-mediated inflammatory diseases (IMIDs) on immunomodulatory treatment.
CRIS-Team WoS Importer:2021-10-08

Microbiota and metabolites in rheumatic diseases - Tong, Yanli; Marion, Tony; Schett, Georg; Luo, Yubin; Liu, Yi (Autoimmunity Reviews, 2020)
As a gigantic community in the human body, the microbiota exerts pleiotropic roles in human health and disease ranging from digestion and absorption of nutrients from food, defense against infection of pathogens, to regulation of immune system development and immune homeostasis. Recent advances in “omics” studies and bioinformatics analyses have broadened our insights of the microbiota composition of the inner and other surfaces of the body and their interactions with the host. Apart from the direct contact of microbes at the mucosal barrier, metabolites produced or metabolized by the gut microbes can serve as important immune regulators or initiators in a wide variety of diseases, including gastrointestinal diseases, metabolic disorders and systemic rheumatic diseases. This review focuses on the most recent understanding of how the microbiota and metabolites shape rheumatic diseases. Studies that explore the mechanistic interplay between microbes, metabolites and the host could thereby provide clues for novel methods in the diagnosis, therapy, and prevention of rheumatic diseases.
CRIS-Team Scopus Importer:2020-06-02
Keywords: Autoimmunity responses; Metabolites; Microbiota; Rheumatic diseases

Microbiota-Derived Propionate Modulates Megakaryopoiesis and Platelet Function - Dürholz, Kerstin; Schmid, Eva; Frech, Michael; Azizov, Vugar; Otterbein, Nadine; Lucas, Sébastien; Rauh, Manfred; Schett, Georg; Bruns, Heiko; Zaiss, Mario (Frontiers in Immunology, 2022)
Rheumatoid arthritis (RA) is associated with an increased risk for cardiovascular events driven by abnormal platelet clotting effects. Platelets are produced by megakaryocytes, deriving from megakaryocyte erythrocyte progenitors (MEP) in the bone marrow. Increased megakaryocyte expansion across common autoimmune diseases was shown for RA, systemic lupus erythematosus (SLE) and primary Sjögren’s syndrome (pSS). In this context, we evaluated the role of the microbial-derived short chain fatty acid (SCFA) propionate on hematopoietic progenitors in the collagen induced inflammatory arthritis model (CIA) as we recently showed attenuating effects of preventive propionate treatment on CIA severity. In vivo, propionate treatment starting 21 days post immunization (dpi) reduced the frequency of MEPs in the bone marrow of CIA and naïve mice. Megakaryocytes numbers were reduced but increased the expression of the maturation marker CD61. Consistent with this, functional analysis of platelets showed an upregulated reactivity state following propionate-treatment. This was confirmed by elevated histone 3 acetylation and propionylation as well as by RNAseq analysis in Meg-01 cells. Taken together, we identified a novel nutritional axis that skews platelet formation and function.
CRIS-Team Scopus Importer:2022-08-05
Keywords: hematopoietic progenitors; megakaryocytes; microbiota; platelets; rheumatoid arthritis; short-chain fatty acids

Microbiota-derived propionate modulates megakaryopoiesis and platelet function - Schmid, Erik; Dürholz, Kerstin; Frech, Michael; Otterbein, N.; Lucas, Sébastien; Rauh, Manfred; Schett, Georg; Bruns, Heiko; Zaiss, Mario (EUROPEAN JOURNAL OF IMMUNOLOGY, 2022)
CRIS-Team WoS Importer:2023-01-27

Microbiota from Obese Mice Regulate Hematopoietic Stem Cell Differentiation by Altering the Bone Niche - Luo, Yubin; Chen, Guangliang; Hannemann, Nicole; Ipseiz, Natacha; Krönke, Gerhard; Bäuerle, Tobias; Munos, Luis; Wirtz, Stefan; Schett, Georg; Bozec, Aline (Cell Metabolism, 2015)
The effect of metabolic stress on the bone marrow microenvironment is poorly defined. We show that high-fat diet (HFD) decreased long-term Lin(-)Sca-1(+)c-Kit(+) (LSK) stem cells and shifted lymphoid to myeloid cell differentiation. Bone marrow niche function was impaired after HFD as shown by poor reconstitution of hematopoietic stem cells. HFD led to robust activation of PPAR?2, which impaired osteoblastogenesis while enhancing bone marrow adipogenesis. At the same time, expression of genes such as Jag-1, SDF-1, and IL-7 forming the bone marrow niche was highly suppressed after HFD. Moreover, structural changes of microbiota were associated to HFD-induced bone marrow changes. Antibiotic treatment partially rescued HFD-mediated effects on the bone marrow niche, while transplantation of stools from HFD mice could transfer the effect to normal mice. These findings show that metabolic stress affects the bone marrow niche by alterations of gut microbiota and osteoblast-adipocyte homeostasis.
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Microbiota-induced Intestinal Barrier Dysfunction Initiates the Shuttling of Immune Cells from the Gut to the Joints - Tajik, Narges; Frech, Michael; Brandl, Carolin; Canete, Juan; Ciccia, Francesco; Schett, Georg; Zaiss, Mario (ARTHRITIS & RHEUMATOLOGY, 2020)
CRIS-Team WoS Importer:2021-01-15

MICROBIOTA-INDUCED INTESTINAL BARRIER DYSFUNCTION PRECEDES THE ONSET OF ARTHRITIS AND ALLOWS THE SHUTTLING OF IMMUNE CELLS FROM THE GUT THE JOINTS - Zaiss, M.; Taijc, N.; Sarter, K.; Azizov, V.; Bucci, L.; Luo, Y.; Canete, J. D. D.; Ciccia, F.; Schett, Georg (ANNALS OF THE RHEUMATIC DISEASES, 2020)
CRIS-Team WoS Importer:2020-08-21

Microglial expression of CD83 governs cellular activation and restrains neuroinflammation in experimental autoimmune encephalomyelitis - Sinner, Pia; Peckert-Maier, Katrin; Mohammadian, Hashem; Kuhnt, Christine; Draßner, Christina; Panagiotakopoulou, Vasiliki; Rauber, Simon; Linnerbauer, Mathias; Haimon, Zhana; Royzman, Dmytro; Kronenberg-Versteeg, Deborah; Ramming, Andreas; et al. (Nature Communications, 2023)
Microglial activation during neuroinflammation is crucial for coordinating the immune response against neuronal tissue, and the initial response of microglia determines the severity of neuro-inflammatory diseases. The CD83 molecule has been recently shown to modulate the activation status of dendritic cells and macrophages. Although the expression of CD83 is associated with early microglia activation in various disease settings, its functional relevance for microglial biology has been elusive. Here, we describe a thorough assessment of CD83 regulation in microglia and show that CD83 expression in murine microglia is not only associated with cellular activation but also with pro-resolving functions. Using single-cell RNA-sequencing, we reveal that conditional deletion of CD83 results in an over-activated state during neuroinflammation in the experimental autoimmune encephalomyelitis model. Subsequently, CD83-deficient microglia recruit more pathogenic immune cells to the central nervous system, deteriorating resolving mechanisms and exacerbating the disease. Thus, CD83 in murine microglia orchestrates cellular activation and, consequently, also the resolution of neuroinflammation.
CRIS-Team Scopus Importer:2023-08-11

MICRORNA-125B AS A POTENTIAL FIBROTIC AND APOPTOTIC REGULATOR IN SYSTEMIC SCLEROSIS - Kozlova, A.; Pachera, E.; Renoux, F.; Rudnik, M.; Maurer, B.; Juengel, A.; Distler, Jörg; Kania, G.; Distler, O. (2017)
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MICRORNA-125B REGULATES APOPTOSIS IN SYSTEMIC SCLEROSIS - Kozlova, A.; Pachera, E.; Maurer, B.; Juengel, A.; Distler, Jörg; Kania, G.; Distler, O. (2018)
EVALuna2:34993

microRNA-145 mediates xylosyltransferase-I induction in myofibroblasts via suppression of transcription factor KLF4 - Ly, Thanh Diep; Riedel, Lara; Fischer, Bastian; Schmidt, Vanessa; Hendig, Doris; Distler, Jörg; Kuhn, Joachim; Knabbe, Cornelius; Faust, Isabel (Biochemical and Biophysical Research Communications, 2020)
Remodelling of the extracellular matrix by myofibroblasts is crucial for wound repair, but if deregulated, it might contribute to the development of fibrosis. Fibroblast-to-myofibroblast differentiation is promoted by aberrant microRNA-145-5p (miR-145) expression in response to transforming growth factor β1 (TGFβ1). One of several myofibroblast markers is human xylosyltransferase-I (XT-I), which is the initial and rate-limiting enzyme of proteoglycan biosynthesis. Increased serum XT activity was quantified in patients with systemic sclerosis (SSc), but the underlying cellular mechanism of this disease remains unknown. This study aims to determine the underlying molecular basis of XT-I induction by considering the miR-mediated regulation of XT-I. We found that miR-145 is upregulated in TGFβ1-treated dermal fibroblasts and correlates with an increased cellular XYLT1 expression and XT activity. Overexpression of miR-145 in dermal fibroblasts induced XYLT1 expression and XT activity and enhanced TGFβ1-promoted XT activity increase. Since direct XYLT1 3′-UTR targeting by miR-145 could be experimentally excluded, an indirect effect of miR-145 on XT-I regulation was indicated. We identified six transcription factor-binding sites for Krueppel-like factor 4 (KLF4), a zinc-finger transcription regulator and putative miR-145 target, in the XYLT1 promoter in silico. A suppressive role of KLF4 on XYLT1 expression was confirmed by targeted gene silencing in dermal fibroblasts and the quantification of KLF4 expression in SSc fibroblasts. Taken together, this study improves the mechanistic understanding of fibrotic remodelling in SSc by identifying a hitherto unknown miR-145/KLF4 pathway mediating the fibrogenic XT-I induction. This knowledge on XYLT1 may lead to the development of novel approaches in the therapy of fibrosis.
CRIS-Team Scopus Importer:2020-02-07
Keywords: Fibrosis; Krueppel-like factor 4; microRNA-145; Systemic sclerosis; TGFβ; Xylosyltransferase

Microscopic polyangiitis after alemtuzumab treatment in relapsing-remitting MS - Sauer, Eva-Maria; Schliep, Stefan; Manger, Bernhard; Lee, De-Hyung; Linker, Ralf (Neurology, Neuroimmunology and Neuroinflammation, 2018)
EVALuna2:35512

Microstructural Bone Changes Are Associated With Broad-Spectrum Autoimmunity and Predict the Onset of Rheumatoid Arthritis - Simon, David; Kleyer, Arnd; Bui, Cong Duy; Hueber, Axel; Bang, Holger; Ramming, Andreas; Rech, Jürgen; Schett, Georg (Arthritis and Rheumatology, 2022)
Objective To assess if microstructural bone lesions in individuals at risk of developing rheumatoid arthritis (RA) are related to the spectrum of anti-modified protein antibodies (AMPAs) and affect the risk of developing RA. Methods Cortical microchannels as well as cortical and trabecular bone mineral density (BMD) volumes (expressed as mg hydroxyapatite/cm(3)) were analyzed by high-resolution peripheral quantitative computed tomography of the hand joints of individuals at risk of RA. AMPA response was profiled, including reactivities against citrullinated proteins (vimentin, enolase, and fibrinogen) as well as carbamylated and acetylated vimentin. All subjects were followed up for the development of RA. Results Subjects at risk of developing RA (n = 75) who had broad-spectrum AMPAs (6-8 reactivities) had significantly more severe microstructural changes, including a higher mean +/- SD number of cortical microchannels per joint (95 +/- 3) and lower total volumetric BMD (vBMD; 265 +/- 45), trabecular vBMD (176 +/- 42), and cortical vBMD (585 +/- 138), than those with moderate AMPA reactivity (3-5 reactivities) (number of cortical microchannels, 79 +/- 30; total vBMD, 293 +/- 33; trabecular vBMD, 195 +/- 32; and cortical vBMD, 627 +/- 91) and those with narrow AMPA reactivity (1-2 reactivities) (number of cortical microchannels, 47 +/- 20; total vBMD, 311 +/- 34; trabecular vBMD, 211 +/- 30; and cortical vBMD, 674 +/- 56). Progressors to RA had significantly higher numbers of cortical microchannels (103 +/- 30 versus 71 +/- 35) and lower bone volume (258 +/- 37 versus 295 +/- 34) compared to nonprogressors. Furthermore, rate of progression to RA was high in subjects with broad AMPA reactivity (48%) versus those with medium AMPA reactivity (26%) or narrow AMPA reactivity (0%), as well as in those with a high number of cortical microchannels (44%) versus those with a low number of cortical microchannels (10%). Conclusion Microstructural changes in individuals at risk of RA are associated with broad-spectrum autoimmunity and predict the onset of RA. These data support the concept of structural priming of joints by autoimmunity before the onset of the inflammatory phase of the disease.
CRIS-Team WoS Importer:2022-02-11

MICRO-STRUCTURAL CHANGES ASSOCIATED WITH ANTI-CITRULLINATED VIMENTIN AUTOIMMUNITY IN RA-AT-RISK INDIVIDUALS PRECIPITATE THE ONSET OF RHEUMATOID ARTHRITIS - Kleyer, Arnd; Simon, David; Bui, Cong Duy; Hueber, Axel; Bang, Holger; Rech, Jürgen; Krönke, Gerhard; Schett, Georg; Ramming, Andreas (ANNALS OF THE RHEUMATIC DISEASES, 2019)
CRIS-Team WoS Importer:2019-07-16

Minimally invasive ultrasound-guided biopsy of the common extensor tendon enthesis: a cadaveric study to standardise the technique - Rizzo, Chiara; Coronel, Luis; De Lorenzis, Enrico; Rubortone, Pietro; Möller, Ingrid; Miguel Perez, Maribel; Tur, Carlo; Raimondo, Maria Gabriella; Belmonte, Beatrice; Cancila, Valeria; Ramming, Andreas; Schett, Georg; et al. (RMD Open, 2025)
OBJECTIVE: To develop and validate a minimally invasive ultrasound (US)-guided biopsy technique to collect entheseal tissue from the common extensor tendon (CET) enthesis at the lateral humeral epicondyle. METHODS: Seven sonographers performed a US examination of the CET on six human cadaveric upper limbs to locate the enthesis using an anatomical landmark-based approach. An adapted mini-arthroscopic system was introduced under US guidance to the target site for sample collection. At the end of the procedure, a dye was injected through the guide needle, followed by dissection, to confirm the sampling location. Histology and immunohistochemistry analyses were performed to assess the quality and representativeness of the samples. The reliability of the procedure among operators was evaluated by analysing the rate of successful sampling. RESULTS: 24 samples were collected. The target site to be biopsied was identified as the insertion of the extensor carpi radialis brevis component of the CET. On dissection, the stain used to verify sampling accuracy was confirmed within the defined target area, with no damage to adjacent structures. Histology and immunohistochemistry indicated that most of the samples exhibited characteristics consistent with entheseal tissue (21 out of 24). All participants identified the CET and successfully completed the procedure, demonstrating reliable sample quality across operators. CONCLUSION: We developed a landmark-based approach to perform a minimally invasive full controlled US-guided biopsy of the CET enthesis that showed to be feasible and reproducible. We believe that this standardised, minimally invasive technique will widespread a reliable collection of entheseal tissue for future clinical and translational studies.
CRIS-Team Scopus Importer:2025-05-16
Keywords: Arthritis; Psoriatic; Tendinopathy; Ultrasonography

Misdiagnosis of polymyositis in a young female patient with occult limb-girdle muscular dystrophy - Valor-Mendez, Lara; Türk, Matthias; Schett, Georg; Manger, Bernhard; Knitza, Johannes (Rheumatology Advances in Practice, 2023)
CRIS-Team Scopus Importer:2023-08-11

Mobile Health Usage, Preferences, Barriers, and eHealth Literacy in Rheumatology: Patient Survey Study - Knitza, Johannes; Simon, David; Lambrecht, Antonia; Raab, Christina; Tascilar, Koray; Hagen, Melanie; Kleyer, Arnd; Bayat, Sara; Derungs, Adrian; Amft, Oliver; Schett, Georg; Hueber, Axel (JMIR mHealth and uHealth, 2020)
BACKGROUND: Mobile health (mHealth) defines the support and practice of health care using mobile devices and promises to improve the current treatment situation of patients with chronic diseases. Little is known about mHealth usage and digital preferences of patients with chronic rheumatic diseases. OBJECTIVE: The aim of the study was to explore mHealth usage, preferences, barriers, and eHealth literacy reported by German patients with rheumatic diseases. METHODS: Between December 2018 and January 2019, patients (recruited consecutively) with rheumatoid arthritis, psoriatic arthritis, and axial spondyloarthritis were asked to complete a paper-based survey. The survey included questions on sociodemographics, health characteristics, mHealth usage, eHealth literacy using eHealth Literacy Scale (eHEALS), and communication and information preferences. RESULTS: Of the patients (N=193) who completed the survey, 176 patients (91.2%) regularly used a smartphone, and 89 patients (46.1%) regularly used social media. Patients (132/193, 68.4%) believed that using medical apps could be beneficial for their own health. Out of 193 patients, only 8 (4.1%) were currently using medical apps, and only 22 patients (11.4%) stated that they knew useful rheumatology websites/mobile apps. Nearly all patients (188/193, 97.4%) would agree to share their mobile app data for research purposes. Out of 193 patients, 129 (66.8%) would regularly enter data using an app, and 146 patients (75.6%) would welcome official mobile app recommendations from the national rheumatology society. The preferred duration for data entry was not more than 15 minutes (110/193, 57.0%), and the preferred frequency was weekly (59/193, 30.6%). Medication information was the most desired app feature (150/193, 77.7%). Internet was the most frequently utilized source of information (144/193, 74.6%). The mean eHealth literacy was low (26.3/40) and was positively correlated with younger age, app use, belief in benefit of using medical apps, and current internet use to obtain health information. CONCLUSIONS: Patients with rheumatic diseases are very eager to use mHealth technologies to better understand their chronic diseases. This open-mindedness is counterbalanced by low mHealth usage and competency. Personalized mHealth solutions and clear implementation recommendations are needed to realize the full potential of mHealth in rheumatology.
CRIS-Team Scopus Importer:2020-08-28
Keywords: eHEALS; eHealth; mHealth; mobile applications; rheumatology; telemedicine

Model curriculum of the German society for Rheumatology for advanced training in the discipline internal medicine and rheumatology. English version - Pfeil, Alexander; Krusche, Martin; Vossen, Diana; Berliner, Michael N.; Keysser, Gernot; Krause, Andreas; Lorenz, Hanns-Martin; Manger, Bernhard; Schuch, Florian; Specker, Christof; Wollenhaupt, Juergen; Baraliakos, Xenofon; et al. (Zeitschrift für Rheumatologie, 2021)
CRIS-Team WoS Importer:2021-10-15

Modular lattice constructs for biological joint resurfacing - Gelse, Kolja; Biggemann, Jonas; Stumpf, Martin; Halmheu, Melissa; Grüneboom, Anika; Scholtysek, Carina; Pachowsky, Milena; Kleyer, Arnd; Hueber, Axel; Krönke, Gerhard; Fey, Tobias (Tissue Engineering: Parts A, B, and C, 2019)
Problem: The generation of tissue-engineered cartilage constructs has made great progress over the last decades, however, the fixation of the grafts to the subchondral bone plate is still an unresolved problem. The aim of this study was to investigate a modular lattice concept as an anchoring basis for biological joint resurfacing that is stably fixed to subchondral bone, versatile for any surface shape, and permissive for cellular repopulation. Methods: Ceramic building blocks (hydroxyapatite, β-tricalcium phosphate, biphasic calcium phosphate, alumina and bioactive glass) including anchoring pins were fabricated by transfer injection molding technique. The cellular repopulation of the building blocks and cellular differentiation of human mesenchymal stem cells (hBMSC) was analysed under the influence of platelet-rich plasma, transforming growth factor-β and bone morphogenetic protein-2. A lattice construct of anchoring pins fixed to subchondral bone specimen and interposed hBMSC within collagen-hydrogel were cultured under dynamic conditions in spinner flasks for 4 weeks. The 3D constructs were analyzed by high-resolution micro computertomography (µCT), light-sheet fluorescence microscopy and histology. Pin fixation was analysed by pull-out tests. Results: Building Block-modules of complex shape with anchoring pins can be individually arranged to the subchondral bone by simple press-fit principle. Pull-out tensile stress exceeded 6 MPa. Human BMSCs required stimulation by TGF-β or BMP-2 to undergo chondrogenic differentiation. Dynamic culturinges of 3-dimensional explant constructscultures demonstrated the stability of the modular lattice construct and the interposed cell-loaded hydrogel remained within the lattice elements. hBMSCs within the collagen hydrogel underwent chondrogenic differentiation and formed a matrix that merged with the lattice structure of building blocks. Conclusions: The current work presents a proof-of-principle concept for a lattice structure that provides the stable mechanical bonding and biological milieu for the bone-cartilage interface. The anchoring elements represent an integral part of the lattice structure and provide the basis for future biological joint resurfacing by multilayer constructs. <br

Modulation of Interleukin-23 Signaling With Guselkumab in Biologic-Naive Patients Versus Tumor Necrosis Factor Inhibitor–Inadequate Responders With Active Psoriatic Arthritis - Siebert, Stefan; Coates, Laura C.; Schett, Georg; Raychaudhuri, Siba P.; Chen, Warner; Gao, Sheng; Seridi, Loqmane; Chakravarty, Soumya D.; Shawi, May; Lavie, Frederic; Sharaf, Mohamed; Zimmermann, Miriam; et al. (Arthritis and Rheumatology, 2024)
Objective: We assessed and compared immunologic differences and associations with clinical response to guselkumab, a fully human interleukin (IL)–23p19 subunit inhibitor, in participants with active psoriatic arthritis (PsA) who were biologic-naive or had inadequate response to tumor necrosis factor inhibitors (TNFi-IR). Methods: Serum biomarker levels at baseline and after treatment with guselkumab 100 mg every 8 weeks were compared between biologic-naive (n = 251) and TNFi-IR (n = 93) subgroups identified in the pooled DISCOVER-1/DISCOVER-2/COSMOS data set. Baseline biomarker levels determined by achievement of week 24 clinical responses (≥75%/90% improvement in Psoriasis Area and Severity Index [PASI 75/90], Investigator's Global Assessment [IGA] of psoriasis score 0/1 and ≥2-point improvement], ≥20% improvement in American College of Rheumatology criteria [ACR20]) were compared between prior treatment subgroups. Results: Baseline IL-22, TNFα, and beta defensin-2 (BD-2) levels were significantly lower in biologic-naive than in TNFi-IR participants. With guselkumab, week 24 IL-17A, IL-17F, IL-22, serum amyloid A, C-reactive protein, IL-6, and BD-2 levels were significantly reduced from baseline in biologic-naive and TNFi-IR participants (≥1.4-fold difference, nominal P < 0.05). Clinical responders to guselkumab exhibited significantly higher baseline levels of several biomarkers than nonresponders (IL-17A, IL-17F, BD-2 in biologic-naive PASI 90 responders; IL-17A, BD-2 in TNFi-IR IGA 0/1 responders; IL-22, BD-2 in TNFi-IR PASI 90 responders [nominal P < 0.05]) and trended higher in TNFi-IR ACR20 responders. Conclusion: Guselkumab modulates IL-23 signaling and provides consistent pharmacodynamic effects in both biologic-naive and TNFi-IR PsA patients. Significantly elevated baseline IL-22, TNFα, and BD-2 levels and associations between baseline IL-22, IL-17A, and BD-2 levels and skin responses to guselkumab suggest greater dysregulation of IL-23/Th17 signaling in patients with TNFi-IR.
CRIS-Team Scopus Importer:2024-05-24

Molecular and epigenetic consequences of pre- and postnatal trauma in a mouse model - Frey, Silke; Steigleder, R.; Distler, Jörg; Kratz, Oliver; Moll, Gunther; Golub, Yulia (2017)
EVALuna2:35017

Monte Carlo Dose Simulation for In-Vivo X-Ray Nanoscopy - Wagner, Fabian; Thies, Mareike; Karolczak, Marek; Pechmann, Sabrina; Huang, Yixing; Gu, Mingxuan; Kling, Lasse; Weidner, Daniela; Aust, Oliver; Schett, Georg; Christiansen, Silke; Maier, Andreas (Informatik aktuell, 2022)
CRIS-Team Scopus Importer:2022-05-06

Moonlighting chromatin: when DNA escapes nuclear control - Singh, Jeeshan; Boettcher, Michael; Dölling, Maximilian; Heuer, Annika; Hohberger, Bettina; Leppkes, Moritz; Naschberger, Elisabeth; Schapher, Mirco; Schauer, Christine; Schoen, Janina; Stürzl, Michael; Vitkov, Ljubomir; et al. (Cell Death and Differentiation, 2023)
Extracellular chromatin, for example in the form of neutrophil extracellular traps (NETs), is an important element that propels the pathological progression of a plethora of diseases. DNA drives the interferon system, serves as autoantigen, and forms the extracellular scaffold for proteins of the innate immune system. An insufficient clearance of extruded chromatin after the release of DNA from the nucleus into the extracellular milieu can perform a secret task of moonlighting in immune-inflammatory and occlusive disorders. Here, we discuss (I) the cellular events involved in the extracellular release of chromatin and NET formation, (II) the devastating consequence of a dysregulated NET formation, and (III) the imbalance between NET formation and clearance. We include the role of NET formation in the occlusion of vessels and ducts, in lung disease, in autoimmune diseases, in chronic oral disorders, in cancer, in the formation of adhesions, and in traumatic spinal cord injury. To develop effective therapies, it is of utmost importance to target pathways that cause decondensation of chromatin during exaggerated NET formation and aggregation. Alternatively, therapies that support the clearance of extracellular chromatin are conceivable. [Figure not available: see fulltext.].
CRIS-Team Scopus Importer:2023-02-17

Moonlighting osteoclasts as undertakers of apoptotic cells - Harre, Ulrike; Keppeler, Hildegard; Ipseiz, Natacha; Derer, Anja; Poller, Kerstin; Aigner, Michael; Schett, Georg; Herrmann, Martin; Lauber, Kirsten (Autoimmunity, 2012)
Created from Fastlane, Scopus look-up
Keywords: Apoptotic cell clearance; Dying cell clearance; Efferocytosis; Osteoclasts; Phagocytosis; Rheumatoid arthritis

Morbus Castleman in der rheumatologischen Praxis - Schmalzing, M.; Sander, O.; Seidl, M.; Marks, R.; Blank, N.; Kötter, I.; Tiemann, M.; Backhaus, M.; Manger, Bernhard; Hübel, K.; Müller-Ladner, U.; Henes, J. (Zeitschrift für Rheumatologie, 2023)
The term Castleman’s disease encompasses a group of rare lymphoproliferative diseases that show histopathological similarities in lymph node biopsy. Diagnostic criteria and a specific ICD-10 code have been available for a few years. Case studies listed at the beginning illustrate that close cooperation between clinicians and pathologists is required to enable a reliable diagnosis. For an optimal histopathological assessment, the pathologist is also dependent on the removal of a complete lymph node. Before distinguishing a potentially fatal multicentric idiopathic Castleman’s disease from the resectable unicentric form, which is important in terms of prognosis and treatment, early diagnosis presupposes that Castleman’s disease is considered in the differential diagnosis. Various immune phenomena and overlaps with autoimmune diseases can increase the probability of misdiagnosis or undetected cases in the clinical routine of rheumatologists. The intention of the present overview is therefore to point out the similarities with autoimmune diseases that are relevant for differential diagnoses and to point out situations that justify a review of the previous diagnosis.
CRIS-Team Scopus Importer:2023-09-08
Keywords: Castleman’s disease; Histopathology; Idiopathic MCD; IL‑6; Lymph node hyperplasia

More on CD19-CAR T Cells in Systemic Lupus Erythematosus - Mougiakakos, Dimitrios; Krönke, Gerhard; Schett, Georg (New England Journal of Medicine, 2021)
CRIS-Team WoS Importer:2021-11-12

Mortality in rheumatoid arthritis: the impact of disease activity, treatment with glucocorticoids, TNF? inhibitors and rituximab - Listing, Joachim; Kekow, Joern; Manger, Bernhard; Burmester, Gerd-Ruediger; Pattloch, Dagmar; Zink, Angela; Strangfeld, Anja (Annals of the Rheumatic Diseases, 2015)
To investigate the impact of disease activity, the course of the disease, its treatment over time, comorbidities and traditional risk factors on survival.Data of the German biologics register RABBIT were used. Cox regression was applied to investigate the impact of time-varying covariates (disease activity as measured by the DAS28, functional capacity, treatment with glucocorticoids, biologic or synthetic disease modifying antirheumatic drugs (DMARDs)) on mortality after adjustment for age, sex, comorbid conditions and smoking.During 31 378 patient-years of follow-up, 463 of 8908 patients died (standardised mortality ratio: 1.49 (95% CI 1.36 to 1.63)). Patients with persistent, highly active disease (mean DAS28 > 5.1) had a significantly higher mortality risk (adjusted HR (HRadj)=2.43; (95% CI 1.64 to 3.61)) than patients with persistently low disease activity (mean DAS28 < 3.2). Poor function and treatment with glucocorticoids > 5 mg/d was significantly associated with an increased mortality, independent of disease activity. Significantly lower mortality was observed in patients treated with tumour necrosis factor ? (TNF?) inhibitors (HRadj=0.64 (95% CI 0.50 to 0.81), rituximab (HRadj=0.57 (95% CI 0.39 to 0.84), or other biologics (HRadj=0.64 (95% CI 0.42 to 0.99), compared to those receiving methotrexate. To account for treatment termination in patients at risk, an HRadj for patients ever exposed to TNF? inhibitors or rituximab was calculated. This resulted in an HRadj of 0.77 (95% CI 0.60 to 0.97).Patients with long-standing high disease activity are at substantially increased risk of mortality. Effective control of disease activity decreases mortality. TNF? inhibitors and rituximab seem to be superior to conventional DMARDs in reducing this risk.
EVALuna2:12956

Mouse models of skin fibrosis - Rigau, Aleix; Luber, Markus; Distler, Jörg (Methods in Molecular Biology, 2021)
Systemic sclerosis (SSc) is a rare systemic autoimmune disease associated with a high mortality. The first histopathological hallmarks are vasculopathy and inflammation, followed by fibrosis of the skin and internal organs. The molecular and cellular mechanisms are incompletely understood. Rodent models provide important insights into the pathogenesis of SSc and are a mainstay for the development of novel targeted therapies. Here we describe the mechanistic insights of inducible and genetic models, and also discuss in detail the limitations and pitfalls of the most frequently used SSc mouse models. We also describe protocols for running the established bleomycin-induced scleroderma skin fibrosis model.
CRIS-Team Scopus Importer:2021-06-11
Keywords: Bleomycin; Chronic graft-versus-host disease; Mouse model; Skin fibrosis; Systemic sclerosis

MULTI-BIOMARKER DISEASE ACTIVITY AND AUTOANTIBODY STATUS LEAD TO COST EFFECTIVE TAPERING ALGORITHMS IN RHEUMATOID ARTHRITIS PATIENTS IN SUSTAINED REMISSION - Hagen, Melanie; Englbrecht, Matthias; Haschka, J.; Reiser, M.; Kleyer, Arnd; Hueber, A.; Manger, Bernhard; Figuereido, C.; Cobra, J. Fogagnolo; Tony, H. -P.; Finzel, S.; Kleinert, S.; et al. (2017)
EVALuna2:34451

MULTI-BIOMARKER DISEASE ACTIVITY (MBDA) IS ASSOCIATED WITH THE PROGRESSION OF STRUCTURAL BONE DAMAGE IN RHEUMATOID ARTHRITIS PATIENTS IN REMISSION - Schett, Georg; Finzel, S.; Hagen, Melanie; Englbrecht, Matthias; Haschka, J.; Figuereido, C.; Cobra, J. Fogagnolo; Rech, Jürgen (2017)
EVALuna2:35029

Multispectral optoacoustic tomography of the human intestine – temporal precision and the influence of postprandial gastrointestinal blood flow - Paulus, Lars-Philip; Wagner, Alexandra; Buehler, Adrian; Raming, Roman; Jüngert, Jörg; Simon, David; Tascilar, Koray; Schnell, Alexander; Günther, Josefine; Rother, Ulrich; Lang, Werner; Hörning, André; et al. (Photoacoustics, 2023)
Multispectral optoacoustic tomography (MSOT) holds great promise as a non-invasive diagnostic tool for inflammatory bowel diseases. Yet, reliability and the impact of physiological processes during fasting and after food intake on optoacoustic signals have not been studied. In the present investigator initiated trial (NCT05160077) the intestines of ten healthy subjects were examined by MSOT at eight timepoints on two days, one fasting and one after food intake. While within-timepoint and within-day reproducibility were good for single wavelength 800 nm and total hemoglobin (ICC 0.722–0.956), between-day reproducibility was inferior (ICC −0.137 to 0.438). However, temporal variability was smaller than variation between individuals (coefficients of variation 8.9%−33.7% vs. 17.0%−48.5%). After food intake and consecutive increased intestinal circulation, indicated by reduced resistance index of simultaneous Doppler ultrasound, optoacoustic signals did not alter significantly. In summary, this study demonstrates high reliability and temporal stability of MSOT for imaging the human intestine during fasting and after food intake.
CRIS-Team Scopus Importer:2023-02-24
Keywords: Gut; Inflammatory bowel disease; Intestinal blood flow; Multispectral optoacoustic imaging; Optoacoustic; Photoacoustic; Postprandial; Reliability; Reproducibility

Murine Metatarsus Bone and Joint Collagen-I Fiber Morphologies and Networks Studied With SHG Multiphoton Imaging - Vielreicher, Martin; Bozec, Aline; Schett, Georg; Friedrich, Oliver (Frontiers in Bioengineering and Biotechnology, 2021)
Chronic inflammatory disease of bones and joints (e.g., rheumatoid arthritis, gout, etc.), but also acute bone injury and healing, or degenerative resorptive processes inducing osteoporosis, are associated with structural remodeling that ultimately have impact on function. For instance, bone stability is predominantly orchestrated by the structural arrangement of extracellular matrix fibrillar networks, i.e., collagen-I, -IV, elastin, and other proteins. These components may undergo distinct network density and orientation alterations that may be causative for decreased toughness, resilience and load bearing capacity or even increased brittleness. Diagnostic approaches are usually confined to coarse imaging modalities of X-ray or computer tomography that only provide limited optical resolution and lack specificity to visualize the fibrillary collagen network. However, studying collagen structure at the microscopic scale is of considerable interest to understand the mechanisms of tissue pathologies. Multiphoton Second Harmonic Generation (SHG) microscopy, is able to visualize the sterical topology of the collagen-I fibrillar network in 3D, in a minimally invasive and label-free manner. Penetration depths exceed those of conventional visible light imaging and can be further optimized through employing decalcification or optical clearing processing ex vivo. The goal of this proof-of-concept study was to use SHG and two-photon excited fluorescence (2-PEF) imaging to mainly characterize the fibrillary collagen organization within ex vivo decalcified normal mouse metatarsus bone and joint. The results show that the technique resolved the fibrillar collagen network of complete bones and joints with almost no artifacts and enabled to study the complex collagen-I networks with various fiber types (straight, crimped) and network arrangements of mature and woven bone with high degree of detail. Our imaging approach enabled to identify cavities within both cortical and trabecular bone architecture as well as interfaces with sharply changing fiber morphology and network structure both within bone, in tendon and ligament and within joint areas. These possibilities are highly advantageous since the technology can easily be applied to animal models, e.g., of rheumatoid arthritis to study structural effects of chronic joint inflammation, and to many others and to compare to the structure of human bone.
CRIS-Team Scopus Importer:2021-07-09
Keywords: bone and joint diseases; bone microstructure; collagen fiber morphology; collagen-I fibrillar networks; multiphoton SHG microscopy; remodeling 3D Morphology

Musculoskeletal Ultrasound Is a Sensitive Imaging Tool for the Assessment of Dynamic Changes of Bone Erosions in Inflammatory Arthritis: A Comparative Analysis with High-Resolution Peripheral Quantitatve Computed Tomography - Finzel, Stephanie; Backhaus, Marina; Kraus, Sebastian; Schett, Georg; Voll, Reinhard (2016)
EVALuna2:35058

Mutual Amplification of GLI2/Hedgehog and Transcription Factor JUN/AP-1 Signaling in Fibroblasts in Systemic Sclerosis: Potential Implications for Combined Therapies - Bergmann, Christina; Chenguiti Fakhouri, Sara; Trinh-Minh, Thuong; Filla, Tim; Rius Rigau, Aleix Rius; Ekici, Arif Bülent; Merlevede, Benita; Hallenberger, Ludwig; Zhu, Honglin; Dees, Clara; Matei, Alexandru Emil; Auth, Janina; et al. (Arthritis and Rheumatology, 2024)
Objective: Deregulation of the cJUN/AP-1 and hedgehog/GLI2 signaling pathways has been implicated in fibroblast activation in systemic sclerosis (SSc). However, the consequences of their concomitant up-regulation are unknown. Here, we tested the hypothesis that mutual amplification of both pathways might drive persistent fibroblast activation. Methods: Cultured fibroblasts and skin sections of patients with diffuse SSc and healthy volunteers were analyzed. cJUN/AP-1 signaling and hedgehog/GLI2 signaling were inhibited using knockdown and pharmacologic approaches. Hedgehog signaling was activated in mice by fibroblast-specific overexpression of constitutively active Smoothened. Results: cJUN and GLI2 are concomitantly up-regulated and colocalize in fibroblasts of patients with SSc compared to healthy controls. Activation of hedgehog/GLI2 signaling induces the expression of cJUN in vitro and in vivo, whereas inactivation of GLI2 inhibits cJUN expression. Likewise, inactivation of cJUN impairs the expression of GLI2. This mutual regulation occurs at the level of transcription with binding of cJUN and GLI2 to specific binding motifs. Interference with this mutual amplification of cJUN signaling and GLI2 signaling inhibits fibroblast activation and collagen release: Inhibition of cJUN/AP-1 signaling ameliorates hedgehog-induced fibroblast activation and skin fibrosis in SmoACT mice with a reduction of skin thickness of 103% (P = 0.0043) in the treatment group compared to the fibrotic control group. Moreover, combined pharmacologic inhibition of cJUN/AP-1 and hedgehog/GLI2 exerts additive antifibrotic effects in a model of TGFβ-driven experimental fibrosis (TBRACT mice). Conclusion: The transcription factors cJUN and GLI2 reinforce each other's activity to promote fibroblast activation in SSc. Interruption of this crosstalk by combined inhibition of both pathways exerts additive antifibrotic effects at well-tolerated doses.
CRIS-Team Scopus Importer:2024-12-06

Mutual influence of immune system and bones - Kamradt, T.; Amling, M.; Dankbar, B.; Dudeck, A.; Gunzer, M.; Ignatius, Anita; Krönke, Gerhard; Kubatzky, K.; Pap, T.; Prinz, Immo; Schett, Georg; Schinke, T.; et al. (Zeitschrift für Rheumatologie, 2018)
EVALuna2:34148

Myeloperoxidase Modulates Inflammation in Generalized Pustular Psoriasis and Additional Rare Pustular Skin Diseases - Haskamp, Stefan; Bruns, Heiko; Hahn, Madelaine; Hoffmann, Markus; Gregor, Anne; Löhr, Sabine; Hahn, Jonas; Ringer, Mark; Flamann, Cindy; Frey, Benjamin; Lesner, Adam; Thiel, Christian; et al. (American Journal of Human Genetics, 2020)
Generalized pustular psoriasis (GPP) is a severe multi-systemic inflammatory disease characterized by neutrophilic pustulosis and triggered by pro-inflammatory IL-36 cytokines in skin. While 19%–41% of affected individuals harbor bi-allelic mutations in IL36RN, the genetic cause is not known in most cases. To identify and characterize new pathways involved in the pathogenesis of GPP, we performed whole-exome sequencing in 31 individuals with GPP and demonstrated effects of mutations in MPO encoding the neutrophilic enzyme myeloperoxidase (MPO). We discovered eight MPO mutations resulting in MPO -deficiency in neutrophils and monocytes. MPO mutations, primarily those resulting in complete MPO deficiency, cumulatively associated with GPP (p = 1.85E−08; OR = 6.47). The number of mutant MPO alleles significantly differed between 82 affected individuals and >4,900 control subjects (p = 1.04E−09); this effect was stronger when including IL36RN mutations (1.48E−13) and correlated with a younger age of onset (p = 0.0018). The activity of four proteases, previously implicated as activating enzymes of IL-36 precursors, correlated with MPO deficiency. Phorbol-myristate-acetate-induced formation of neutrophil extracellular traps (NETs) was reduced in affected cells (p = 0.015), and phagocytosis assays in MPO-deficient mice and human cells revealed altered neutrophil function and impaired clearance of neutrophils by monocytes (efferocytosis) allowing prolonged neutrophil persistence in inflammatory skin. MPO mutations contribute significantly to GPP's pathogenesis. We implicate MPO as an inflammatory modulator in humans that regulates protease activity and NET formation and modifies efferocytosis. Our findings indicate possible implications for the application of MPO inhibitors in cardiovascular diseases. MPO and affected pathways represent attractive targets for inducing resolution of inflammation in neutrophil-mediated skin diseases.
CRIS-Team Scopus Importer:2020-09-11
Keywords: ACH; acrodermatitis continua suppurativa Hallopeau; activation of IL-36 precursors; acute generalized 4 exanthematous pustulosis; AGEP; efferocytosis; generalized pustular psoriasis; GPP; impaired NETosis; MPO deficiency; myeloperoxidase; oligogenic inheritance

Na+ deposition in the fibrotic skin of systemic sclerosis patients detected by 23Na-magnetic resonance imaging - Kopp, Christoph; Beyer, Christian; Linz, Peter; Dahlmann, Anke; Hammon, Matthias; Jantsch, Jonathan; Neubert, Patrick; Rosenhauer, Daniela; Mueller, Dominik N.; Eckardt, Kai-Uwe; Schett, Georg; Luft, Friedrich C.; et al. (Rheumatology, 2017)
Skin fibrosis is the predominant feature of SSc and arises from excessive extracellular matrix deposition. Glycosaminoglycans are macromolecules of the extracellular matrix, which facilitate Na(+) accumulation in the skin. We used (23)Na-MRI to quantify Na(+) in skin. We hypothesized that skin Na(+) might accumulate in SSc and might be a biomarker for skin fibrosis.In this observational case-control study, skin Na(+) was determined by (23)Na-MRI using a Na(+) volume coil in 12 patients with diffuse cutaneous SSc and in 21 control subjects. We assessed skin fibrosis by the modified Rodnan skin score prior to (23)Na-MRI and on follow-up 12 months later.(23)Na-MRI demonstrated increased Na(+) in the fibrotic skin of SSc patients compared with skin from controls [mean (sd): 27.2 (5.6) vs 21.4 (5.3) mmol/l, P < 0.01]. Na(+) content was higher in fibrotic than in non-fibrotic SSc skin [26.2 (4.8) vs 19.2 (3.4) mmol/l, P < 0.01]. Furthermore, skin Na(+) amount was correlated with changes in follow-up modified Rodnan skin score (R(2) = 0.68).(23)Na-MRI detected increased Na(+) in the fibrotic SSc skin; high Na(+) content was associated with progressive skin disease. Our findings provide the first evidence that (23)Na-MRI might be a promising tool to assess skin Na(+) and thereby predict progression of skin fibrosis in SSc.
EVALuna:33997

Nanoparticles size-dependently initiate self-limiting NETosis-driven inflammation - Munoz, Luis E.; Bilyy, Rostyslav; Biermann, Mona H. C.; Kienhoefer, Deborah; Maueröder, Christian; Hahn, Jonas; Brauner, Jan M.; Weidner, Daniela; Chen, Juan; Scharin-Mehlmann, Marina; Janko, Christina; Friedrich, Ralf P.; et al. (Proceedings of the National Academy of Sciences of the United States of America, 2016)
The critical size for strong interaction of hydrophobic particles with phospholipid bilayers has been predicted to be 10 nm. Because of the wide spreading of nonpolar nanoparticles (NPs) in the environment, we aimed to reveal the ability of living organisms to entrap NPs via formation of neutrophil extracellular traps (NETs). Upon interaction with various cell types and tissues, 10- to 40-nm-sized NPs induce fast (<20 min) damage of plasma membranes and instability of the lysosomal compartment, leading to the immediate formation of NETs. In contrast, particles sized 100-1,000 nm behaved rather inertly. Resulting NET formation (NETosis) was accompanied by an inflammatory reaction intrinsically endowed with its own resolution, demonstrated in lungs and air pouches of mice. Persistence of small NPs in joints caused unremitting arthritis and bone remodeling. Small NPs coinjected with antigen exerted adjuvant-like activity. This report demonstrates a cellular mechanism that explains how small NPs activate the NETosis pathway and drive their entrapping and resolution of the initial inflammatory response.
EVALuna2:13106

NCOA3 AMPLIFIES PROFIBROTIC TRANSCRIPTIONAL PROGRAMS IN SYSTEMIC SCLEROSIS - Dees, Clara; Pötter, Sebastian; Fuchs, Maximilian; Bergmann, Christina; Matei, Alexandru-Emil; Györfi, Andrea-Hermina; Soare, A.; Ramming, Andreas; Ceppi, Paolo; Schett, Georg; Kunz, Meik; Distler, H. W. (ANNALS OF THE RHEUMATIC DISEASES, 2021)
CRIS-Team WoS Importer:2021-09-24

Networks of enzymatically oxidized membrane lipids support calcium-dependent coagulation factor binding to maintain hemostasis - Lauder, Sarah N.; Allen-Redpath, Keith; Slatter, David A.; Aldrovandi, Maceler; O'Connor, Anne; Farewell, Daniel; Percy, Charles L.; Molhoek, Jessica E.; Rannikko, Sirpa; Tyrrell, Victoria J.; Ferla, Salvatore; Milne, Ginger L.; et al. (Science Signaling, 2017)
Blood coagulation functions as part of the innate immune system by preventing bacterial invasion, and it is critical to stopping blood loss (hemostasis). Coagulation involves the external membrane surface of activated platelets and leukocytes. Using lipidomic, genetic, biochemical, and mathematical modeling approaches, we found that enzymatically oxidized phospholipids (eoxPLs) generated by the activity of leukocyte or platelet lipoxygenases (LOXs) were required for normal hemostasis and promoted coagulation factor activities in a Ca2+- and phosphatidylserine (PS)-dependent manner. In wild-type mice, hydroxyeicosatetraenoic acid-phospholipids (HETE-PLs) enhanced coagulation and restored normal hemostasis in clotting-deficient animals genetically lacking p12-LOX or 12/15-LOX activity. Murine platelets generated 22 eoxPL species, all of which were missing in the absence of p12-LOX. Humans with the thrombotic disorder antiphospholipid syndrome (APS) had statistically significantly increased HETE-PLs in platelets and leukocytes, as well as greater HETE-PL immunoreactivity, than healthy controls. HETE-PLs enhanced membrane binding of the serum protein ?2GP1 (?2-glycoprotein 1), an event considered central to the autoimmune reactivity responsible for APS symptoms. Correlation network analysis of 47 platelet eoxPL species in platelets from APS and control subjects identified their enzymatic origin and revealed a complex network of regulation, with the abundance of 31 p12-LOX-derived eoxPL molecules substantially increased in APS. In summary, circulating blood cells generate networks of eoxPL molecules, including HETE-PLs, which change membrane properties to enhance blood coagulation and contribute to the excessive clotting and immunoreactivity of patients with APS.
EVALuna2:13521

Neural Networks for Distinguishing Rheumatoid Arthritis from Psoriatic Arthritis by Using Magnetic Resonance Imaging - Folle, Lukas; Bayat, Sara; Kleyer, Arnd; Fagni, Filippo; Kapsner, Lorenz; Schlereth, Maja; Meinderink, Timo; Breininger, Katharina; Tascilar, Koray; Krönke, Gerhard; Uder, Michael; Sticherling, Michael; et al. (Arthritis Rheumatol., 2022)

Neurodegeneration Enhances the Development of Arthritis - Lang, Stefanie; Harre, Ulrike; Purohit, Pavitra; Dietel, Katharina; Kienhöfer, Deborah; Hahn, Jonas; Baum, Wolfgang; Herrmann, Martin; Schett, Georg; Mielenz, Dirk (Journal of Immunology, 2017)
The prevalence of neurodegenerative disease and arthritis increases with age. Despite both processes being associated with immune activation and inflammation, little is known about the mechanistic interactions between neurodegenerative disease and arthritis. In this article, we show that tau-transgenic (tau-tg) mice that develop neurodegenerative disease characterized by deposition of tau tangles in the brain are highly susceptible to developing arthritis. Already at steady-state conditions, tau-tg mice exhibit peripheral immune activation that is manifested by higher numbers of granulocytes, plasmablasts, and inflammatory Ly6C(hi) CCR2(+) monocytes, as well as increased levels of proinflammatory cytokines, such as TNF-? and IL-17. Upon induction of collagen-induced arthritis (CIA), tau-tg mice displayed an increased incidence and an earlier onset of CIA that was associated with a more pronounced inflammatory cytokine response. Furthermore, induction of CIA led to significantly elevated numbers of Iba-1-expressing cells in the brain, indicative of microglia activation, and the formation of anti-tau Abs in tau-tg mice. These changes were accompanied by the resolution of tau tangles and significantly decreased neurodegenerative pathology. In summary, these data show that neurodegenerative disease enhances the development of arthritis. In addition, arthritis, once induced, triggers innate immune responses in the brain, leading to resolution of neurodegenerative change
EVALuna2:13302

Neutralizing monoclonal antibodies against SARS-CoV-2 for COVID-19 pneumonia in a rituximab treated patient with systemic sclerosis-A case report and literature review - Yalcin Mutlu, Melek; Taubmann, Jule; Wacker, Jochen; Tascilar, Koray; Fagni, Filippo; Gerner, Maximilian; Klett, Daniel; Schett, Georg; Manger, Bernhard; Simon, David (Frontiers in Medicine, 2022)
Patients with immune-mediated diseases (IMID) such as systemic sclerosis (SSc), who are treated with B cell depleting treatments, are at risk for developing severe COVID-19 due to inadequate humoral immune response. During B cell depletion, therapeutic substitution of neutralizing monoclonal antibodies against the SARS-CoV-2 spike protein (mAbs) might be helpful to prevent severe COVID-19. It has been shown, that in non-IMID patients mABs reduce SARS-CoV-2 viral load and lower the risk of COVID-19 associated hospitalization or death. However, there are limited data on the effect of mAbs in IMID patients after exposure, especially in patients treated with B cell depleting agents. Herein, we report a case of a rituximab treated SSc patient who developed COVID-19 and was successfully treated with a combination of mAbs (casirivimab/imdevimab). With this case we show that IMID patients may benefit from post-exposure administration of mAbs. In our case treatment with neutralizing autoantibodies was safe and a possible contributor in protecting the patient from mechanical ventilation and eventually death. We frame this case within the current evidence from the literature and provide a perspective on the future potential role of mAbs for treating IMID patients suffering from COVID-19.
CRIS-Team WoS Importer:2022-08-26

Neutrophil Depletion Changes the N-Glycosylation Pattern of IgG in Experimental Murine Sepsis - Yaykasli, Kürsat Oguz; van Schie, Karin A.; Toes, René E.M.; Wuhrer, Manfred; Koeleman, Carolien A.M.; Bila, Galyna; Negrych, Nazar; Schett, Georg; Knopf, Jasmin; Herrmann, Martin; Bilyy, Rostyslav (International Journal of Molecular Sciences, 2024)
Sepsis is a life-threatening condition with a rising disease burden worldwide. It is a multifactorial disease and is defined as a dysregulated host response to infection. Neutrophils have been shown to be involved in the pathogenesis of sepsis by exacerbating inflammation. However, the exact effector mechanism of action still remains a mystery. Changes in the glycosylation pattern of the immunoglobulin G (IgG) Fc region are described for several diseases including meningococcal sepsis. In this study, we investigated the possible contribution of neutrophils and neutrophil implication, potentially related to degranulation or neutrophil extracellular trap (NET) formation in changing the IgG Fc N-glycosylation pattern in a murine sepsis model. We have measured the serum level of cytokines/chemokines and immunoglobulins, the serum activity of neutrophil elastase (NE), and analyzed the IgG Fc glycosylation pattern by Liquid Chromatography-Electrospray Ionization-Mass Spectrometry (LC-ESI-MS) and Lectin enzyme-linked immunosorbent assay (ELISA). We observed an increased activity of NE- and neutrophil-associated cytokines such as keratinocyte chemoattractant (KC) with the development of sepsis. Regarding the IgG Fc N-glycosylation, we observed an increase in fucosylation and α1,3-galactosylation and a decrease for sialyation. Interestingly, these changes were not uniform for all IgG subclasses. After depletion of neutrophils, we saw a change in the exposure of fucose and α2,6-linked sialic acid during the time course of our experimental sepsis model. In conclusion, neutrophils can influence changes in the IgG glycosylation pattern in experimental sepsis.
CRIS-Team Scopus Importer:2024-07-12
Keywords: IgG Fc glycosylation; neutrophil extracellular traps (NETs); neutrophils; sepsis

Neutrophil extracellular trap‐driven occlusive diseases - Yaykasli, Kürsat Oguz; Munoz, Luis Enrique; Mahajan, Aparna; Knopf, Jasmin; Schett, Georg; Herrmann, Martin; Schauer, Christine (Cells, 2021)
The enlightenment of the formation of neutrophil extracellular traps (NETs) as a part of the innate immune system shed new insights into the pathologies of various diseases. The initial idea that NETs are a pivotal defense structure was gradually amended due to several deleterious effects in consecutive investigations. NETs formation is now considered a double‐edged sword. The harmful effects are not limited to the induction of inflammation by NETs remnants but also include occlusions caused by aggregated NETs (aggNETs). The latter carries the risk of occluding tubular structures like vessels or ducts and appear to be associated with the pathologies of various diseases. In addition to life‐threatening vascular clogging, other occlusions include painful stone formation in the biliary system, the kidneys, the prostate, and the appendix. AggNETs are also prone to occlude the ductal system of exocrine glands, as seen in ocular glands, salivary glands, and others. Last, but not least, they also clog the pancreatic ducts in a murine model of neutrophilia. In this regard, elucidating the mechanism of NETs‐dependent occlusions is of crucial importance for the development of new therapeutic approaches. Therefore, the purpose of this review is to address the putative mechanisms of NETs‐associated occlusions in the pathogenesis of disease, as well as prospective treatment modalities.
CRIS-Team Scopus Importer:2021-10-08
Keywords: Aggregation; Ducts; Neutrophil extracellular traps; Occlusions; Vessels

Neutrophil extracellular traps and DNases orchestrate formation of peritoneal adhesions. - Elrod, Julia; Heuer, Annika; Knopf, Jasmin; Schoen, Janina; Schönfeld, Lavinia; Trochimiuk, Magdalena; Stiel, Carolin; Appl, Birgit; Raluy, Laia Pagerols; Saygi, Ceren; Zlatar, Leticija; Hosari, Sami; et al. (iScience, 2023)
Peritoneal adhesions are poorly understood but highly prevalent conditions that can cause intestinal obstruction and pelvic pain requiring surgery. While there is consensus that stress-induced inflammation triggers peritoneal adhesions, the molecular processes of their formation still remain elusive. We performed murine models and analyzed human samples to monitor the formation of adhesions and the treatment with DNases. Various molecular analyses were used to evaluate the adhesions. The experimental peritoneal adhesions of the murine models and biopsy material from humans are largely based on neutrophil extracellular traps (NETs). Treatment with DNASE1 (Dornase alfa) and the human DNASE1L3 analog (NTR-10), significantly reduced peritoneal adhesions in experimental models. We conclude that NETs serve as essential scaffold for the formation of adhesions; DNases interfere with this process. Herein, we show that therapeutic application of DNases can be employed to prevent the formation of murine peritoneal adhesions. If this can be translated into the human situation requires clinical studies.
EVALuna2:551953

Neutrophil extracellular traps characterize caseating granulomas - Zlatar, Leticija; Knopf, Jasmin; Singh, Jeeshan; Wang, Han; Muñoz-Becerra, Marco; Herrmann, Irmgard; Chukwuanukwu, Rebecca; Eckstein, Markus; Eichhorn, Philip; Rieker, Ralf; Naschberger, Elisabeth; Burkovski, Andreas; et al. (Cell Death & Disease, 2024)
Tuberculosis (TB) remains one of the top 10 causes of death worldwide and still poses a serious challenge to public health. Recent attention to neutrophils has uncovered unexplored areas demanding further investigation. Therefore, the aim of this study was to determine neutrophil activation and circulatory neutrophil extracellular trap (NET) formation in various types of TB. Sera from TB patients (n = 91) and healthy controls (NHD; n = 38) were analyzed for NE-DNA and MPO–DNA complexes, cell-free DNA (cfDNA), and protease activity (elastase). We show that these NET parameters were increased in TB sera. Importantly, NET formation and NE activity were elevated in TB patients with extensive tissue damage when compared to those with minor damage and in patients with relapse, compared to new cases. We discuss the importance of balancing NET formation to prevent tissue damage or even relapse and argue to analyze circulating NET parameters to monitor the risk of disease relapse. To investigate the tissues for NETs and to find the source of the circulating NET degradation products, we collected sections of granulomas in lung and lymph node biopsies. Samples from other diseases with granulomas, including sarcoidosis (SARC) and apical periodontitis (AP), served as controls. Whereas NET formation characterizes the caseating granulomas, both caseating and non-caseating granulomas harbor DNA with unusual conformation. As TB is associated with hypercoagulation and thromboembolism, we further imaged the pulmonary vessels of TB patients and detected vascular occlusions with neutrophil aggregates. This highlights the dual role of neutrophils in the pathology of TB.
CRIS-Team Scopus Importer:2024-08-09

Neutrophil Extracellular Traps Drive Dacryolithiasis - Zlatar, Leticija; Timm, Thomas; Lochnit, Günter; Bilyy, Rostyslav; Bäuerle, Tobias; Munoz Becerra, Marco; Schett, Georg; Knopf, Jasmin; Heichel, Jens; Ali, Mohammad Javed; Schapher, Mirco; Paulsen, Friedrich; et al. (Cells, 2023)
Mucopeptide concretions, previously called dacryoliths, are macroscopic stones that commonly obstruct the lacrimal sac. The mechanism behind dacryolithiasis remains unclear; however, the involvement of various immune cells, including neutrophils, has been confirmed. These findings remain limited, and no information on neutrophil extracellular traps (NETs), essentially involved in the pathogenesis of other lithiases, is available yet. Here, we employ microcomputed tomography, magnetic resonance tomography, histochemistry, mass spectrometry, and enzyme activity analyses to investigate the role of neutrophils and NETs in dacryolithiasis. We classify mucopeptide concretions into three types, with respect to the quantity of cellular and acellular material, polysaccharides, and mucosubstances. We propose the role of neutrophils and NETs within the existing model of gradual formation and growth of mucopeptide concretions, with neutrophils contributing to the initial stages of dacryolithiasis, as they localized on the inner (older) parts of the tissue. As NETs localized on the outer (newer) parts of the tissue, we link their role to the late stages of dacryolithiasis, presumably maintaining the proinflammatory environment and preventing efficient clearance. An abundance of IgG on the surface indicates the involvement of the adaptive immune system later as well. These findings bring new perspectives on dacryolithiasis, in which the innate and adaptive immune system are essentially involved.
CRIS-Team Scopus Importer:2023-08-11
Keywords: dacryolithiasis; dacryoliths; lacrimal sac; mucopeptide concretions; neutrophil extracellular traps; neutrophils

Neutrophil extracellular traps drive epithelial‐mesenchymal transition of human colon cancer - Stehr, Antonia; Wang, Guangxia; Demmler, Richard; Stemmler, Marc; Straube, Julia; Tripal, Philipp; Schmid, Benjamin; Geppert, Carol-Immanuel; Hartmann, Arndt; Munoz, Luis Enrique; Schoen, Janina; Völkl, Simon; et al. (Journal of Pathology, 2021)
Neutrophil extracellular traps (NETs) are extracellular structures, composed of nuclear DNA and various proteins released from neutrophils. Evidence is growing that NETs exert manifold functions in infection, immunity, and cancer. Recently, NETs have been detected in colorectal cancer (CRC) tissues but their association with disease progression and putative functional impact on tumourigenesis remained elusive. Using high-resolution stimulated emission depletion (STED) microscopy we showed that citrullinated histone H3 (H3cit) is sufficient to specifically detect citrullinated NETs in colon cancer tissues. Among other evidence this was supported by the close association of H3cit with de-condensed extracellular DNA, the hallmark of NETs. Extracellular DNA was reliably differentiated from nuclear condensed DNA by staining with an anti-DNA-antibody providing a novel and valuable tool to detect NETs in FFPE tissues. Using these markers, the clinical association of NETs has been investigated in a cohort of 85 patients with colon cancer. NETs were frequently detected (n = 37/n = 85, 44%) in colon cancer tissue sections and preferentially localized either only in the tumour centre or both, in the tumour centre and the invasive front. Of note, citrullinated NETs were significantly associated with high histopathologic tumour grades and lymph node metastasis. In vitro, purified NETs induced filopodia formation and cell motility in CRC cell lines. This was associated with increased expression of mesenchymal marker mRNAs (vimentin [VIM], fibronectin [FN1]) and epithelial- mesenchymal transition (EMT) promoting transcription factors (ZEB1 and Slug [SNAI2]) as well as decreased expression of the epithelial markers E-cadherin (CDH1) and EpCAM (EPCAM). These findings indicated that NETs activate an EMT-like process in CRC cells and may contribute to the metastatic progression of CRC.
Keywords: epithelial–mesenchymal transition (EMT); colorectal neoplasms; stimulated emission depletion (STED) microscopy; neutrophils; migration; extracellular traps

Neutrophil Extracellular Traps Form a Barrier between Necrotic and Viable Areas in Acute Abdominal Inflammation - Bilyy, Rostyslav; Fedorov, Volodymyr; Vovk, Volodymyr; Leppkes, Moritz; Dumych, Tetiana; Chopyak, Valentyna; Schett, Georg; Herrmann, Martin (Frontiers in Immunology, 2016)
Neutrophils form neutrophil extracellular traps (NETs) of decondensed DNA and histones that trap and immobilize particulate matter and microbial pathogens like bacteria. NET aggregates reportedly surround and isolate large objects like monosodium urate crystals, which cannot be sufficiently cleared from tissues. In the setting of acute necrotizing pancreatitis, massive tissue necrosis occurs, which is organized as pancreatic pseudocysts (1). In contrast to regular cysts, these pseudocysts are not surrounded by epithelial layers. We hypothesize that, instead, the necrotic areas observed in necrotizing pancreatitis are isolated from the surrounding healthy tissues by aggregated NETs. These may form an alternative, putatively transient barrier, separating necrotic areas from viable tissue. To test this hypothesis, we investigated histological samples from the necropsy material of internal organs of two patients with necrotizing pancreatitis and peritonitis accompanied by multiple organ failure. Tissues including the inflammatory zone were stained with hematoxylin and eosin and evaluated for signs of inflammation. Infiltrating neutrophils and NETs were detected by immunohistochemistry for DNA, neutrophil elastase (NE), and citrullinated histone H3. Interestingly, in severely affected areas of pancreatic necrosis or peritonitis, chromatin stained positive for NE and citrullinated histone H3, and may, therefore, be considered NET-derived. These NET structures formed a layer, which separated the necrotic core from the areas of viable tissue remains. A condensed layer of aggregated NETs, thus, spatially shields and isolates the site of necrosis, thereby limiting the spread of necrosis-associated proinflammatory mediators. We propose that necrotic debris may initiate and/or facilitate the formation of the NET-based surrogate barrier.
EVALuna2:2179

Neutrophil Extracellular Traps Initiate Gallstone Formation - Munoz, Luis Enrique; Boeltz, Sebastian; Bilyy, Rostyslav; Schauer, Christine; Mahajan, Aparna; Widulin, Navena; Grüneboom, Anika; Herrmann, Irmgard; Boada, Edgyda; Rauh, Manfred; Krenn, Veit; Biermann, Mona H.C.; et al. (Immunity, 2019)
The presence of gallstones (cholelithiasis) is a highly prevalent and severe disease and one of the leading causes of hospital admissions worldwide. Due to its substantial health impact, we investigated the biological mechanisms that lead to the formation and growth of gallstones. We show that gallstone assembly essentially requires neutrophil extracellular traps (NETs). We found consistent evidence for the presence of NETs in human and murine gallstones and describe an immune-mediated process requiring activation of the innate immune system for the formation and growth of gallstones. Targeting NET formation via inhibition of peptidyl arginine deiminase type 4 or abrogation of reactive oxygen species (ROS) production, as well as damping of neutrophils by metoprolol, effectively inhibit gallstone formation in vivo. Our results show that after the physicochemical process of crystal formation, NETs foster their assembly into larger aggregates and finally gallstones. These insights provide a feasible therapeutic concept to prevent cholelithiasis in patients at risk.
CRIS-Team Scopus Importer:2019-09-17
Keywords: calcium carbonate crystals; cholesterol crystals; gallstone growth; gallstones; lisosomal leakage; lithogenic diet; neutrophil extracellular traps; neutrophils; NOX2; PADi4

Neutrophil Extracellular Traps Promote the Development and Growth of Human Salivary Stones - Schapher, Mirco; Koch, Michael; Weidner, Daniela; Scholz, Michael; Wirtz, Stefan; Mahajan, Aparna; Herrmann, Irmgard; Singh, Jeeshan; Knopf, Jasmin; Leppkes, Moritz; Grüneboom, Anika; Alexiou, Christoph; et al. (Cells, 2020)
Salivary gland stones, or sialoliths, are the most common cause of the obstruction of salivary glands. The mechanism behind the formation of sialoliths has been elusive. Symptomatic sialolithiasis has a prevalence of 0.45% in the general population, is characterized by recurrent painful periprandial swelling of the affected gland, and often results in sialadenitis with the need for surgical intervention. Here, we show by the use of immunohistochemistry, immunofluorescence, computed tomography (CT) scans and reconstructions, special dye techniques, bacterial genotyping, and enzyme activity analyses that neutrophil extracellular traps (NETs) initiate the formation and growth of sialoliths in humans. The deposition of neutrophil granulocyte extracellular DNA around small crystals results in the dense aggregation of the latter, and the subsequent mineralization creates alternating layers of dense mineral, which are predominantly calcium salt deposits and DNA. The further agglomeration and appositional growth of these structures promotes the development of macroscopic sialoliths that finally occlude the efferent ducts of the salivary glands, causing clinical symptoms and salivary gland dysfunction. These findings provide an entirely novel insight into the mechanism of sialolithogenesis, in which an immune system-mediated response essentially participates in the physicochemical process of concrement formation and growth.
CRIS-Team Scopus Importer:2020-10-09
Keywords: lithogenesis; neutrophil extracellular traps; neutrophils; salivary glands; salivary stones; sialadenitis; sialolithiasis; stone development; stone growth

Neutrophilic Dermatoses - Classification and Pathophysiology - Manger, Bernhard (Zeitschrift für Rheumatologie, 2018)
EVALuna2:213266

NEUTROPHILS AND NETS AS ORCHESTRATORS OF INFLAMMATORY DISEASES - Hosari, D.; Hosari, Sami; Mahajan, Aparna; Oreski, Leticija; Schoen, J.; Shan, Xiaomei; Singh, Jeeshan; Wang, H.; Yaykasli, Kürsat Oguz; Knopf, Jasmin; Munoz, Luis Enrique; Schauer, Christine; et al. (CLINICAL AND EXPERIMENTAL RHEUMATOLOGY, 2021)
CRIS-Team WoS Importer:2021-09-17

Neutrophils’ Extracellular Trap Mechanisms: From Physiology to Pathology - Schoen, Janina; Euler, Maximilien; Schauer, Christine; Schett, Georg; Herrmann, Martin; Knopf, Jasmin; Yaykasli, Kürsat Oguz (International Journal of Molecular Sciences, 2022)
Neutrophils are an essential part of the innate immune system and the first line of defense against invading pathogens. They phagocytose, release granular contents, produce reactive oxygen species, and form neutrophil extracellular traps (NETs) to fight pathogens. With the characterization of NETs and their components, neutrophils were identified as players of the innate adaptive crosstalk. This has placed NETs at the center not only of physiological but also pathological processes. Aside from their role in pathogen uptake and clearance, NETs have been demonstrated to contribute to the resolution of inflammation by forming aggregated NETs able to degrade inflammatory mediators. On the other hand, NETs have the potential to foster severe pathological conditions. When homeostasis is disrupted, they occlude vessels and ducts, serve as sources of autoantigens and danger or damage associated molecular patterns, directly damage tissues, and exaggerate complement activity and inflammation. This review focusses on the understanding of NETs from their formation to their functions in both physiological and pathological processes.
CRIS-Team Scopus Importer:2022-11-25
Keywords: aggNETs; autoantigens; DAMP; inflammation resolution; neutrophil extracellular traps; occlusions

Neutrophils prevent rectal bleeding in ulcerative colitis by peptidyl-arginine deiminase-4-dependent immunothrombosis - Leppkes, Moritz; Lindemann, Aylin; Goesswein, Stefanie; Paulus, Susanne; Roth, Dominik; Hartung, Anne; Liebing, Eva; Zundler, Sebastian; Gonzalez-Acera, Miguel; Patankar, Jay; Mascia, Fabrizio; Scheibe, Kristina; et al. (Gut, 2021)
Objective Bleeding ulcers and erosions are hallmarks of active ulcerative colitis (UC). However, the mechanisms controlling bleeding and mucosal haemostasis remain elusive. Design We used high-resolution endoscopy and colon tissue samples of active UC (n = 36) as well as experimental models of physical and chemical mucosal damage in mice deficient for peptidyl-arginine deiminase-4 (PAD4), gnotobiotic mice and controls. We employed endoscopy, histochemistry, live-cell microscopy and flow cytometry to study eroded mucosal surfaces during mucosal haemostasis. Results Erosions and ulcerations in UC were covered by fresh blood, haematin or fibrin visible by endoscopy. Fibrin layers rather than fresh blood or haematin on erosions were inversely correlated with rectal bleeding in UC. Fibrin layers contained ample amounts of neutrophils coaggregated with neutrophil extracellular traps (NETs) with detectable activity of PAD. Transcriptome analyses showed significantly elevated PAD4 expression in active UC. In experimentally inflicted wounds, we found that neutrophils underwent NET formation in a PAD4-dependent manner hours after formation of primary blood clots, and remodelled clots to immunothrombi containing citrullinated histones, even in the absence of microbiota. PAD4-deficient mice experienced an exacerbated course of dextrane sodium sulfate-induced colitis with markedly increased rectal bleeding (96 % vs 10 %) as compared with controls. PAD4-deficient mice failed to remodel blood clots on mucosal wounds eliciting impaired healing. Thus, NET-associated immunothrombi are protective in acute colitis, while insufficient immunothrombosis is associated with rectal bleeding. Conclusion Our findings uncover that neutrophils induce secondary immunothrombosis by PAD4-dependent mechanisms. Insufficient immunothrombosis may favour rectal bleeding in UC.
CRIS-Team WoS Importer:2021-12-17

Neutrophils prevent rectal bleeding in Ulcerative Colitis by peptidyl-arginine deiminase-4-dependent immunothrombosis - Leppkes, Moritz; Lindemann, Aylin; Goesswein, S.; Paulus, S.; Roth, Dominik; Hartung, A.; Liebing, Eva; Zundler, Sebastian; Gonzalez Acera, Miguel; Patankar, Jay; Mascia, Fabrizio; Scheibe, Kristina; et al. (JOURNAL OF CROHNS & COLITIS, 2022)
CRIS-Team WoS Importer:2022-05-13

Neutrophils seeking new neighbors: radiotherapy affects the cellular framework and the spatial organization in a murine breast cancer model - Reichardt, Clara; Munoz Becerra, Marco; Rius Rigau, Aleix Rius; Rückert, Michael; Fietkau, Rainer; Schett, Georg; Gaipl, Udo; Frey, Benjamin; Munoz Becerra, Luis (Cancer Immunology, Immunotherapy, 2024)
Neutrophils are known to contribute in many aspects of tumor progression and metastasis. The presence of neutrophils or neutrophil-derived mediators in the tumor microenvironment has been associated with poor prognosis in several types of solid tumors. However, the effects of classical cancer treatments such as radiation therapy on neutrophils are poorly understood. Furthermore, the cellular composition and distribution of immune cells in the tumor is of increasing interest in cancer research and new imaging technologies allow to perform more complex spatial analyses within tumor tissues. Therefore, we aim to offer novel insight into intra-tumoral formation of cellular neighborhoods and communities in murine breast cancer. To address this question, we performed image mass cytometry on tumors of the TS/A breast cancer tumor model, performed spatial neighborhood analyses of the tumor microenvironment and quantified neutrophil-extracellular trap degradation products in serum of the mice. We show that irradiation with 2 × 8 Gy significantly alters the cellular composition and spatial organization in the tumor, especially regarding neutrophils and other cells of the myeloid lineage. Locally applied radiotherapy further affects neutrophils in a systemic manner by decreasing the serum neutrophil extracellular trap concentrations which correlates positively with survival. In addition, the intercellular cohesion is maintained due to radiotherapy as shown by E-Cadherin expression. Radiotherapy, therefore, might affect the epithelial–mesenchymal plasticity in tumors and thus prevent metastasis. Our findings underscore the growing importance of the spatial organization of the tumor microenvironment, particularly with respect to radiotherapy, and provide insight into potential mechanisms by which radiotherapy affects epithelial–mesenchymal plasticity and tumor metastasis.
CRIS-Team Scopus Importer:2024-03-15
Keywords: Cancer; Cellular neighborhood; Image mass cytometry; Neutrophil; Radiotherapy

Neutrophil-To-lymphocyte ratio as a biomarker for clinical response after autologous haematopoietic stem cell transplantation in systemic sclerosis - Keret, Shiri; Kaly, Lisa; Schett, Georg; Bergmann, Christina; Feldman, Erik; Zuckerman, Tsila; Yehudai-Ofir, Dana; Shouval, Aniela; Awisat, Abid; Rosner, Itzhak; Rozenbaum, Michael; Boulman, Nina; et al. (Rheumatology, 2025)
Objective: SSc is a complex disease that affects various target organs, making it difficult to assess response and determine remission or relapse. A baseline neutrophil-To-lymphocyte ratio (NLR) >2.95 is associated with severe progressive skin and lung disease and decreased 5-year survival in SSc. However, it is unknown whether NLR changes in response to treatment. To retrospectively evaluate NLR changes as a biomarker for treatment response in SSc. Methods: Progressive diffuse SSc patients who were treated with autologous haematopoietic stem cell transplantation (AHSCT group), with combination therapy of rituximab and MMF (combination group) or chimeric antigen receptor-T-cell (CAR-T) therapy group, were recruited along with healthy controls (HC group). NLR, modified Rodnan Skin Score (mRSS) and forced vital capacity (FVC)% predicted were repeatedly assessed over 2 years. Results: Fifteen patients were recruited in the AHSCT group, 15 in the combination group and 6 patients in the CAR-T group. Baseline mean NLR was high (>2.95) in AHSCT, combination groups and CAR-T compared with HC. All treatment arms showed a statistically significant decrease in mRSS values and an increase in FVC% at each time point up to 12 months. In a linear mixed model, NLR significantly decreased up to 24 months only in the AHSCT group. NLR correlated with mRSS and FVC exclusively in the AHSCT group. NLR increased above 3 in two patients who experienced a relapse after AHSCT. Conclusion: NLR is a simple biomarker that correlated with outcome measures in SSc following AHSCT but not with conventional therapy or CAR-T therapy. It is suggested that a decrease in NLR following AHSCT may indicate remission, whereas an increase may be associated with exacerbation. Further research is needed to validate these novel findings.
CRIS-Team Scopus Importer:2025-05-16
Keywords: autologous haematopoietic stem cell transplantation; biomarker; MMF; neutrophils-To-lymphocytes ratio; rituximab; SSc

New Insights into Bone Loss in RA - Andreev, Darja; Bozec, Aline (Osteologie, 2021)
The negative impact of rheumatoid arthritis (RA) on bone mineral density is well characterized. Notably, articular bone erosion is a central feature of RA, leading to joint damage and disabilities. In addition, the axial and appendicular skeleton can be affected, which secondly manifests in bone fracture. The main trigger of RA-associated bone loss is excessive bone degradation by osteoclasts and impaired bone formation by osteoblasts. In particular, the inflammatory status, reflected by high level of proinflammatory cytokines, receptor activator of nuclear factor kappa B ligand (RANKL), and autoantibodies induces the formation of bone-resorbing osteoclasts. Today, antirheumatic therapy effectively hampers synovial inflammation and bone erosion. However, current medication is unable to repair established bone lesions. This review outlines the knowledge gained about the pathophysiology of rheumatoid arthritis and the molecular mechanisms that promote osteoclast-mediated bone erosion and inhibit osteoblast-related bone formation, pointing out possible new intervention for inflammatory bone disease.
CRIS-Team WoS Importer:2021-10-01

New insights into the function of bone marrow - Schett, Georg; Bozec, Aline; Bekeredjian-Ding, I.; Chang, H-D.; David, J-P.; Doerner, T.; Graessel, S.; Gunzer, M.; Manz, R.; Mei, H.; Mielenz, Dirk; Mueller-Ladner, U.; et al. (Zeitschrift für Rheumatologie, 2018)
EVALuna2:34147

New insights into the prevalence of depressive symptoms and depression in rheumatoid arthritis - Implications from the prospective multicenter VADERA II study - Englbrecht, Matthias; Alten, Rieke; Aringer, Martin; Baerwald, Christoph G.; Burkharde, Harald; Eby, Nancy; Flacke, Jan-Paul; Fliedner, Gerhard; Henkemeier, Ulf; Hofmann, Michael W.; Kleinert, Stefan; Kneitz, Christian; et al. (PLoS ONE, 2019)
Objectives To investigate the prevalence of depressive symptoms in rheumatoid arthritis (RA) patients using two previously validated questionnaires in a large patient sample, and to evaluate depressive symptoms in the context of clinical characteristics (e.g. remission of disease) and patient-reported impact of disease. Methods In this cross-sectional study, the previously validated Patient Health Questionnaire (PHQ-9) and Beck-Depression Inventory II (BDI-II) were used to assess the extent of depressive symptoms in RA patients. Demographic background, RA disease activity score (DAS28), RA impact of disease (RAID) score, comorbidities, anti-rheumatic therapy and antidepressive treatment, were recorded. Cut-off values for depressive symptomatology were PHQ-9 ≥5 or BDI-II ≥14 for mild depressive symptoms or worse and PHQ-9 ≥ 10 or BDI-II ≥ 20 for moderate depressive symptoms or worse. Prevalence of depressive symptomatology was derived by frequency analysis while factors independently associated with depressive symptomatology were investigated by using multiple logistic regression analyses. Ethics committee approval was obtained, and all patients provided written informed consent before participation. Results In 1004 RA-patients (75.1% female, mean±SD age: 61.0±12.9 years, mean disease duration: 12.2±9.9 years, DAS28 (ESR): 2.5±1.2), the prevalence of depressive symptoms was 55.4% (mild or worse) and 22.8% (moderate or worse). Characteristics independently associated with depressive symptomatology were: age <60 years (OR = 1.78), RAID score >2 (OR = 10.54) and presence of chronic pain (OR = 3.25). Of patients classified as having depressive symptoms, only 11.7% were receiving anti-depressive therapy. Conclusions Mild and moderate depressive symptoms were common in RA patients according to validated tools. In routine clinical practice, screening for depression with corresponding followup procedures is as relevant as incorporating these results with patient-reported outcomes (e.g. symptom state), because the mere assessment of clinical disease activity does not sufficiently reflect the prevalence of depressive symptoms.
CRIS-Team Scopus Importer:2019-06-18

New molecular mechanisms in the pathophysiology of rheumatic diseases - Distler, Jörg (Zeitschrift für Rheumatologie, 2018)
EVALuna2:34954

New possibilities for ocular surface reconstruction : Collagen membranes and biocompatible elastomer nanofibers - Fuchsluger, Thomas; Salehi, S.; Petsch, Christina; Bachmann, B. (Ophthalmologe, 2014)
Amniotic membranes have been used for many years for reconstruction of the ocular surface. Despite having anti-inflammatory and antiangiogenic properties as well as being suitable as a carrier for corneal epithelial cells, amniotic membranes also have some limitations for use at the human cornea: availability is limited, there are major interindividual variations in structure and growth factor content and are not free from the risk of disease transmission. Progress in tissue engineering has been made aiming at the development and improvement of alternative biomaterials.This article presents new approaches for reconstruction of the corneal surface with collagen-based biomaterials and polymers.Electronic databases were searched for articles which evaluated collagenous biomaterials for use at the corneal surface. In addition the authors' own experiences with novel biomaterials are described.In vitro evaluation of the described biomaterials suggested a high biocompatibility with corneal epithelial cells in cell cultures. In vivo experiments with these materials in animal corneas demonstrated a certain variability in degradation and remodeling. Although some materials showed promising experimental results none of these are established in the clinical routine and only few clinical studies have so far been conducted with collagen-based biomaterials.Although the majority of the described biomaterials are currently still in the experimental stage, a transfer into the clinical routine is conceivable and of great therapeutic interest.
EVALuna2:21193

NEW SYSTEMIC SCLEROSIS RISK LOCI IDENTIFIED THROUGH A META-GWAS STRATEGY - Lopez-Isac, E.; Acosta-Herrera, M.; Assassi, S.; Simeon, C. P.; Carreira, P. E.; Castellvi, I.; Ortego-Centeno, N.; Beretta, L.; Lunardi, C.; Gabrielli, A.; Moroncini, G.; Hunzelmann, N.; et al. (2018)
EVALuna2:34987

Next-generation imaging of the skeletal system and its blood supply - Grüneboom, Anika; Kling, Lasse; Christiansen, Silke; Mill, Leonid; Maier, Andreas; Engelke, Klaus; Quick, Harald H.; Schett, Georg; Gunzer, Matthias (Nature Reviews Rheumatology, 2019)
Bone is organized in a hierarchical 3D architecture. Traditionally, analysis of the skeletal system was based on bone mass assessment by radiographic methods or on the examination of bone structure by 2D histological sections. Advanced imaging technologies and big data analysis now enable the unprecedented examination of bone and provide new insights into its 3D macrostructure and microstructure. These technologies comprise ex vivo and in vivo methods including high-resolution computed tomography (CT), synchrotron-based imaging, X-ray microscopy, ultra-high-field magnetic resonance imaging (MRI), light-sheet fluorescence microscopy, confocal and intravital two-photon imaging. In concert, these techniques have been used to detect and quantify a novel vascular system of trans-cortical vessels in bone. Furthermore, structures such as the lacunar network, which harbours and connects osteocytes, become accessible for 3D imaging and quantification using these methods. Next-generation imaging of the skeletal system and its blood supply are anticipated to contribute to an entirely new understanding of bone tissue composition and function, from macroscale to nanoscale, in health and disease. These insights could provide the basis for early detection and precision-type intervention of bone disorders in the future.
CRIS-Team Scopus Importer:2019-08-27

NINTEDANIB DOSE ADJUSTMENTS AND ADVERSE EVENTS IN PATIENTS WITH PROGRESSIVE AUTOIMMUNE DISEASE-RELATED INTERSTITIAL LUNG DISEASES IN THE INBUILD TRIAL - Volkmann, E.; Castellvi, I.; Johnson, S.; Matteson, E.; Distler, Jörg; Seibold, J.; Costabel, U.; James, A.; Coeck, C.; Quaresma, M.; Cottin, V. (ANNALS OF THE RHEUMATIC DISEASES, 2020)
CRIS-Team WoS Importer:2020-08-21

Nintedanib inhibits fibroblast activation and ameliorates fibrosis in preclinical models of systemic sclerosis - Huang, Jingang; Beyer, Christian; Palumbo-Zerr, Katrin; Zhang, Yun; Distler, Alfiya; Gelse, Kolja; Distler, Oliver; Schett, Georg; Wollin, Lutz; Distler, Jörg; Ramming, Andreas (Annals of the Rheumatic Diseases, 2015)
Nintedanib is a tyrosine kinase inhibitor that has recently been shown to slow disease progression in idiopathic pulmonary fibrosis in two replicate phase III clinical trials. The aim of this study was to analyse the antifibrotic effects of nintedanib in preclinical models of systemic sclerosis (SSc) and to provide a scientific background for clinical trials in SSc.The effects of nintedanib on migration, proliferation, myofibroblast differentiation and release of extracellular matrix of dermal fibroblasts were analysed by microtitre tetrazolium and scratch assays, stress fibre staining, qPCR and SirCol assays. The antifibrotic effects of nintedanib were evaluated in bleomycin-induced skin fibrosis, in a murine sclerodermatous chronic graft-versus-host disease model and in tight-skin-1 mice.Nintedanib dose-dependently reduced platelet-derived growth factor-induced and transforming growth factor-?-induced proliferation and migration as well as myofibroblast differentiation and collagen release of dermal fibroblasts from patients with and healthy individuals. Nintedanib also inhibited the endogenous activation of SSc fibroblasts. Nintedanib prevented bleomycin-induced skin fibrosis in a dose-dependent manner and was also effective in the treatment of established fibrosis. Moreover, treatment with nintedanib ameliorated fibrosis in the chronic graft-versus-host disease model and in tight-skin-1 mice in well-tolerated doses.We demonstrate that nintedanib effectively inhibits the endogenous as well as cytokine-induced activation of SSc fibroblasts and exerts potent antifibrotic effects in different complementary mouse models of SSc. These data have direct translational implications for clinical trials with nintedanib in SSc.
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Nintedanib in Patients With Autoimmune Disease-Related Progressive Fibrosing Interstitial Lung Diseases: Subgroup Analysis of the INBUILD Trial - Matteson, Eric L.; Kelly, Clive; Distler, Jörg; Hoffmann-Vold, Anna-Maria; Seibold, James R.; Mittoo, Shikha; Dellaripa, Paul F.; Aringer, Martin; Pope, Janet; Distler, Oliver; James, Alexandra; Schlenker-Herceg, Rozsa; et al. (Arthritis and Rheumatology, 2022)
Objective To analyze the efficacy and safety of nintedanib in patients with fibrosing autoimmune disease-related interstitial lung diseases (ILDs) with a progressive phenotype. Methods The INBUILD trial enrolled patients with a fibrosing ILD other than idiopathic pulmonary fibrosis, with diffuse fibrosing lung disease of >10% extent on high-resolution computed tomography, forced vital capacity percent predicted (FVC%) >= 45%, and diffusing capacity of the lungs for carbon monoxide percent predicted >= 30% to <80%. Patients fulfilled protocol-defined criteria for progression of ILD within the 24 months before screening, despite management deemed appropriate in clinical practice. Subjects were randomized to receive nintedanib or placebo. We assessed the rate of decline in FVC (ml/year) and adverse events (AEs) over 52 weeks in the subgroup with autoimmune disease-related ILDs. Results Among 170 patients with autoimmune disease-related ILDs, the rate of decline in FVC over 52 weeks was -75.9 ml/year with nintedanib versus -178.6 ml/year with placebo (difference 102.7 ml/year [95% confidence interval 23.2, 182.2]; nominal P = 0.012). No heterogeneity was detected in the effect of nintedanib versus placebo across subgroups based on ILD diagnosis (P = 0.91). The most frequent AE was diarrhea, reported in 63.4% and 27.3% of subjects in the nintedanib and placebo groups, respectively. AEs led to permanent discontinuation of trial drug in 17.1% and 10.2% of subjects in the nintedanib and placebo groups, respectively. Conclusion In the INBUILD trial, nintedanib slowed the rate of decline in FVC in patients with progressive fibrosing autoimmune disease-related ILDs, with AEs that were manageable for most patients.
CRIS-Team WoS Importer:2022-05-20

Nintedanib macrophage activation and ameliorates vascular and fibrotic manifestations in the Fra2 mouse model of systemic sclerosis - Huang, Jingang; Maier, Christiane; Zhang, Yun; Soare, Alina; Dees, Clara; Beyer, Christian; Harre, Ulrike; Chen, Chih-Wei; Distler, Oliver; Schett, Georg; Wollin, Lutz; Distler, Jörg (Annals of the Rheumatic Diseases, 2017)
Nintedanib is an inhibitor targeting platelet-derived growth factor receptor, fibroblast growth factor receptor and vascular endothelial growth factor receptor tyrosine kinases that has recently been approved for the treatment of idiopathic pulmonary fibrosis. The aim of this study was to analyse the effects of nintedanib in the fos-related antigen-2 (Fra2) mouse model of systemic sclerosis (SSc).The effects of nintedanib on pulmonary arterial hypertension with proliferation of pulmonary vascular smooth muscle cells (PVSMCs) and luminal occlusion, on microvascular disease with apoptosis of microvascular endothelial cells (MVECs) and on fibroblast activation with myofibroblast differentiation and accumulation of extracellular matrix were analysed. We also studied the effects of nintedanib on the levels of key mediators involved in the pathogenesis of SSc and on macrophage polarisation.Nintedanib inhibited proliferation of PVSMCs and prevented thickening of the vessel walls and luminal occlusion of pulmonary arteries. Treatment with nintedanib also inhibited apoptosis of MVECs and blunted the capillary rarefaction in Fra2-transgenic mice. These effects were associated with a normalisation of the serum levels of vascular endothelial growth factor in Fra2 mice on treatment with nintedanib. Nintedanib also effectively blocked myofibroblast differentiation and reduced pulmonary, dermal and myocardial fibrosis in Fra2-transgenic mice. The antifibrotic effects of nintedanib were associated with impaired M2 polarisation of monocytes and reduced numbers of M2 macrophages.Nintedanib targets core features of SSc in Fra2-transgenic mice and ameliorates histological features of pulmonary arterial hypertension, destructive microangiopathy and pulmonary and dermal fibrosis. These data might have direct implications for the ongoing phase III clinical trial with nintedanib in SSc-associated interstitial lung diseas
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Nintedanib reduces alloimmune-induced chronic airway changes in murine tracheal allografts - Mauer, Julia; Kuckhahn, Annika; Ramsperger-Gleixner, Martina; Ensminger, Stephan M.; Distler, Jörg; Weyand, Michael; Heim, Christian (Transplant Immunology, 2022)
Background: The major obstacle for long-term survival after successful lung transplantation is the development of bronchiolitis obliterans (BO) which is one phenotype of chronic lung allograft dysfunction (CLAD). Nintedanib has beneficial effects treating neoplastic diseases and idiopathic pulmonary fibrosis by blocking tyrosine kinase receptors. These receptors play an important role in alloimmune-mediated proliferative diseases. The aim of this study was to determine the effect of nintedanib on proliferative airway changes after orthotopic trachea transplantation in mice. Methods: C57BL/6 mice (H-2b) donor tracheas were orthotopically transplanted into CBA/J mice (H-2k). After transplantation, recipients were daily treated with nintedanib (60 mg/kg; p.o.). Histological and immunofluorescence analysis were performed after 30 days and intragraft gene expression measurements after 14 days of treatment, respectively. Results: Tracheal allografts from mice treated with nintedanib showed significantly less features of chronic rejection than untreated allografts reflected in a higher epithelium/lamina propria ratio (ELR) [ELR: 0.65 ± 0.13 nintedanib vs. 0.50 ± 0.07 untreated controls; p < 0.05] and a reduced submucosal smooth muscle actin (SMA) content [SMA: 1.26% ± 0.78% nintedanib vs. 2.18% ± 1.01% untreated controls; p < 0.01]. Furthermore, lower T cell, macrophage and dendritic cell infiltration was detected in the nintedanib treated grafts. The protein and intragraft mRNA expression of receptor subtypes was considerably decreased in grafts of nintedanib treated mice. The mRNA expression of relevant immune mediators was affected by nintedanib treatment. Conclusion: Receptor blocking by nintedanib reduced alloimmune-induced inflammation and chronic airway changes in mouse trachea allografts and might be a promising approach to diminish the development of BO in lung transplants.
CRIS-Team Scopus Importer:2022-07-01
Keywords: Bronchiolitis obliterans; Chronic rejection; Nintedanib; Tracheal allografts; Tyrosine kinase inhibitor

Nipocalimab, an anti-FcRn monoclonal antibody, in participants with moderate to severe active rheumatoid arthritis and inadequate response or intolerance to anti-TNF therapy: results from the phase 2a IRIS-RA study - Taylor, Peter C.; Schett, Georg; Huizinga, Tom Wj; Wang, Qingmin; Ibrahim, Fowzia; Zhou, Bei; Liva, Sophia G.; Shaik, Jafar Sadik B.; Xiong, Yuan; Leu, Jocelyn H.; Panchakshari, Rohit A.; Loza, Matthew J.; et al. (RMD Open, 2024)
OBJECTIVES: To investigate the efficacy, safety, pharmacokinetics and pharmacodynamics of nipocalimab in participants with moderate to severe active rheumatoid arthritis (RA) and inadequate response or intolerance to ≥1 antitumour necrosis factor agent. METHODS: In this phase 2a study, participants with RA seropositive for anticitrullinated protein antibodies (ACPA) or rheumatoid factors were randomised 3:2 to nipocalimab (15 mg/kg intravenously every 2 weeks) or placebo from Weeks 0 to 10. Efficacy endpoints (primary endpoint: change from baseline in Disease Activity Score 28 using C reactive protein (DAS28-CRP) at Week 12) and patient-reported outcomes (PROs) were assessed through Week 12. Safety, pharmacokinetics and pharmacodynamics were assessed through Week 18. RESULTS: 53 participants were enrolled (nipocalimab/placebo, n=33/20). Although the primary endpoint did not reach statistical significance for nipocalimab versus placebo, a numerically higher change from baseline in DAS28-CRP at Week 12 was observed (least squares mean (95% CI): -1.03 (-1.66 to -0.40) vs -0.58 (-1.24 to 0.07)), with numerically higher improvements in all secondary efficacy outcomes and PROs. Serious adverse events were reported in three participants (burn infection, infusion-related reaction and deep vein thrombosis). Nipocalimab significantly and reversibly reduced serum immunoglobulin G, ACPA and circulating immune complex levels but not serum inflammatory markers, including CRP. ACPA reduction was associated with DAS28-CRP remission and 50% response rate in American College of Rheumatology (ACR) criteria; participants with a higher baseline ACPA had greater clinical improvement. CONCLUSIONS: Despite not achieving statistical significance in the primary endpoint, nipocalimab showed consistent, numerical efficacy benefits in participants with moderate to severe active RA, with greater benefit observed for participants with a higher baseline ACPA. TRIAL REGISTRATION NUMBER: NCT04991753.
CRIS-Team Scopus Importer:2024-07-12
Keywords: Anti-Citrullinated Protein Antibodies; Arthritis; Rheumatoid; Patient Reported Outcome Measures; Rheumatoid Factor

NNRTI-based antiretroviral therapy may increase risk of radiation induced side effects in HIV-1-infected patients - Keller, Ulrike; Hecht, Markus; Harrer, Thomas; Harrer, Ellen; Schuster, Barbara; Fietkau, Rainer; Distel, Luitpold (Radiotherapy and Oncology, 2015)
As the incidence of cancer is rising in HIV-1-infected patients, radiotherapy is used more frequently in this patient group. Strong radiation induced side effects have been reported in single patients on antiretroviral therapy. Thus we investigated whether HIV-1 itself or antiretroviral drugs could enhance radiosensitivity in patients.Radiosensitivity after in vitro irradiation of blood lymphocytes was tested in 196 individuals (80 HIV-1-infected patients and 116 healthy controls and cancer patients) using a three color fluorescence in situ hybridization approach to analyze chromosomal aberrations (B/M). Additionally, the NNRTI efavirenz and the NRTIs tenofovir and emtricitabine were tested for radiosensitizing effects in vitro.Lymphocytes from HIV-1-infected patients in the NNRTI + NRTI group were significantly more sensitive to ionizing radiation than in the other groups (patients without treatment or with NRTI + PI or HIV-negative controls). In vitro the triple medication efavirenz, tenofovir and emtricitabine leads to a reduced survival fraction and an increased activation of the DNA repair proteins H2AX, Nbs, Atm and 53BP1 in combination with ionizing radiation.HIV-1 treatment with NNRTI containing therapy regimes possibly sensitizes a subgroup of patients to ionizing radiation. Individual radiosensitivity of HIV-1-infected patients on HAART including NNRTI should be tested before starting radiotherapy.
EVALuna2:13258

No difference in clinical parameters and drug retention in PsA patients receiving b/tsDMARD monotherapy versus combination with methotrexate: data from the RABBIT-SpA registry - Regierer, Anne Constanze; Kiefer, David; Schett, Georg; Krause, Andreas; Weiß, Anja; Sewerin, Philipp; Strangfeld, Anja (RMD Open, 2024)
Background The potential benefit of methotrexate (MTX) in combination with biologic (b) and targeted synthetic (ts) disease modifying anti-rheumatic drugs (DMARDs) in psoriatic arthritis (PsA) is still a matter of debate. Objectives To compare clinical and patient reported characteristics as well as drug retention rates in PsA patients receiving b/tsDMARD monotherapy or in combination with MTX. Methods RABBIT-SpA is a prospective longitudinal cohort study including axSpA and PsA patients. In this analysis, PsA patients were stratified into two groups: starting b/ tsDMARD as monotherapy or in combination with MTX. Treatment retention was compared by drug survival analysis. Results 69% of the patients (n=900) started b/tsDMARD as monotherapy while 31% were treated in combination with MTX (n=405). At baseline, clinical domains like skin, nail and joint affection, dactylitis, enthesitis and axial involvement were similar between the groups. Only the patients’ satisfaction concerning tolerability of the previous treatment was significantly better in the combination group at treatment start. Drug retention rates did not differ between the groups (p=0.4). At 6/12 months, 66%/48% of patients in monotherapy and 67%/48% in the combination group were still on their original treatment. Conclusions We did not identify any clinical parameters with notable influence on the choice of b/tsDMARD mono or MTX-combination therapy in PsA. Drug retention rates are similar between mono and combination therapy. It seems that the decision to continue MTX at initiation of b/ tsDMARDs is mostly based on the subjective tolerability of MTX treatment.
CRIS-Team Scopus Importer:2024-08-02
Keywords: Biological Therapy; Epidemiology; Methotrexate; Psoriatic Arthritis

No Difference in Treatment Continuation of Different Biologics in Elderly Patients > 70 Years Compared to Younger Patients <= 65 Years - Strangfeld, Anja; Krueger, Klaus; Manger, Bernhard; Kneitz, Christian; Zink, Angela; Schaefer, Martin (ARTHRITIS & RHEUMATOLOGY, 2019)
CRIS-Team WoS Importer:2020-02-07

No evidence of pathogenic involvement of cathelicidins in patient cohorts and mouse models of lupus and arthritis - Kienhofer, D.; Hahn, Jonas; Schubert, I.; Reinwald, Christiane; Ipseiz, N.; Lang, Sabine; Borras, E. Bosch; Amann, Kerstin Ute; Sjowall, C.; Barron, A. E.; Hueber, Axel; Agerberth, B.; et al. (PLoS ONE, 2014)
Apart from their role in the immune defence against pathogens evidence of a role of antimicrobial peptides (AMPs) in autoimmune diseases has accumulated in the past years. The aim of this project was to examine the functional impact of the human cathelicidin LL-37 and the mouse cathelicidin-related AMP (CRAMP) on the pathogenesis of lupus and arthritis. Serum LL-37 and anti-LL-37 levels were measured by ELISA in healthy donors and patients with Systemic Lupus Erythematosus (SLE) and Rheumatoid arthritis (RA). Pristane-induced lupus was induced in female wild type (WT) and cathelicidin-deficient (CRAMP-/-) mice. Serum levels of anti-Sm/RNP, anti-dsDNA, and anti-histone were determined via ELISA, cytokines in sera and peritoneal lavages were measured via Multiplex. Expression of Interferon I stimulated genes (ISG) was determined by real-time PCR. Collagen-induced arthritis (CIA) was induced in male WT and CRAMP-/- mice and arthritis severity was visually scored and analysed histomorphometrically by OsteoMeasure software. Serum levels of anti-LL-37 were higher in SLE-patients compared to healthy donors or patients with RA. However, no correlation to markers of disease activity or organ involvement was observed. No significant differences of autoantibody or cytokine/chemokine levels, or of expression of ISGs were observed between WT and CRAMP-/- mice after pristane-injection. Furthermore, lung and kidney pathology did not differ in the absence of CRAMP. Incidence and severity of CIA and histological parameters (inflammation, cartilage degradation, and bone erosion) were not different in WT and CRAMP-/- mice. Although cathelicidins are upregulated in mouse models of lupus and arthritis, cathelicidin-deficiency did not persistently affect the diseases. Also in patients with SLE, autoantibodies against cathelicidins did not correlate with disease manifestation. Reactivity against cathelicidins in lupus and arthritis could thus be an epiphenomenon caused by extensive overexpression in blood and affected tissues. In addition, other cationic AMPs could functionally compensate for the deficiency of cathelicidins.
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NO INCREASED RISK OF FALLS IN PATIENTS TREATED WITH BIOLOGICS COMPARED TO THOSE UNDER CSDMARDS - Rudi, T.; Schaefer, M.; Manger, Bernhard; Zink, A.; Strangfeld, A. (ANNALS OF THE RHEUMATIC DISEASES, 2020)
CRIS-Team WoS Importer:2020-08-21

Noncanonical WNT5A controls the activation of latent TGF-β to drive fibroblast activation and tissue fibrosis - Trinh-Minh, Thuong; Chen, Chih-Wei; Tran-Manh, Cuong; Li, Yi Nan; Zhu, Honglin; Zhou, Xiang; Chakraborty, Debomita; Zhang, Yun; Rauber, Simon; Dees, Clara; Lin, Neng-Yu; Kah, Delf-Thorge Eric; et al. (Journal of Clinical Investigation, 2024)
Transforming growth factor β (TGF-β) signaling is a core pathway of fibrosis, but the molecular regulation of the activation of latent TGF-β remains incompletely understood. Here, we demonstrate a crucial role of WNT5A/JNK/ROCK signaling that rapidly coordinates the activation of latent TGF-β in fibrotic diseases. WNT5A was identified as a predominant noncanonical WNT ligand in fibrotic diseases such as systemic sclerosis, sclerodermatous chronic graft-versus-host disease, and idiopathic pulmonary fibrosis, stimulating fibroblast-to-myofibroblast transition and tissue fibrosis by activation of latent TGF-β. The activation of latent TGF-β requires rapid JNK- and ROCK-dependent cytoskeletal rearrangements and integrin αV (ITGAV). Conditional ablation of WNT5A or its downstream targets prevented activation of latent TGF-β, rebalanced TGF-β signaling, and ameliorated experimental fibrosis. We thus uncovered what we believe to be a novel mechanism for the aberrant activation of latent TGF-β in fibrotic diseases and provided evidence for targeting WNT5A/JNK/ROCK signaling in fibrotic diseases as a new therapeutic approach.
CRIS-Team Scopus Importer:2024-05-24
Keywords: Dermatology; Fibrosis; Pulmonology

Non-Invasive Characterization of Experimental Bone Metastasis in Obesity Using Multiparametric MRI and PET/CT - Gregoric, Gasper; Gaculenko, Anastasia; Nagel, Lisa; Popp, Vanessa; Maschauer, Simone; Prante, Olaf; Saake, Marc; Schett, Georg; Uder, Michael; Ellmann, Stephan; Bozec, Aline; Bäuerle, Tobias (Cancers, 2022)
The growth of primary tumors and metastases is associated with excess body fat. In bone metastasis formation, the bone marrow microenvironment, and particularly adipocytes, play a pivotal role as growth mediators of disseminated tumor cells in the bone marrow. The aim of the present study is to non-invasively characterize the pathophysiologic processes in experimental bone metastasis resulting from accelerated tumor progression within adipocyte-rich bone marrow using multimodal imaging from magnetic resonance imaging (MRI) and positron emission tomography/computed tomography (PET/CT). To achieve this, we have employed small animal models after the administration of MDA-MB 231 breast cancer and B16F10 melanoma cells into the bone of nude rats or C57BL/6 mice, respectively. After tumor cell inoculation, ultra-high field MRI and mu PET/CT were used to assess functional and metabolic parameters in the bone marrow of control animals (normal diet, ND), following a high-fat diet (HFD), and/or treated with the peroxisome proliferator-activated receptor-gamma (PPAR gamma) antagonist bisphenol-A-diglycidylether (BADGE), respectively. In the bone marrow of nude rats, dynamic contrast-enhanced MRI (DCE-MRI) and diffusion-weighted imaging (DWI), as well as [F-18]fluorodeoxyglucose-PET/CT([F-18]FDG-PET/CT), was performed 10, 20, and 30 days after tumor cell inoculation, followed by immunohistochemistry. DCE-MRI parameters associated with blood volume, such as area under the curve (AUC), were significantly increased in bone metastases in the HFD group 30 days after tumor cell inoculation as compared to controls (p < 0.05), while the DWI parameter apparent diffusion coefficient (ADC) was not significantly different between the groups. [F-18]FDG-PET/CT showed an enhanced glucose metabolism due to increased standardized uptake value (SUV) at day 30 after tumor cell inoculation in animals that received HFD (p < 0.05). BADGE treatment resulted in the inversion of quantitative DCE-MRI and [F-18]FDG-PET/CT data, namely a significant decrease in AUC and SUV in HFD-fed animals as compared to ND-fed controls (p < 0.05). Finally, immunohistochemistry and qPCR confirmed the HFD-induced stimulation in vascularization and glucose activity in murine bone metastases. In conclusion, multimodal and multiparametric MRI and [F-18]FDG-PET/CT were able to derive quantitative parameters in bone metastases, revealing an increase in vascularization and glucose metabolism following HFD. Thus, non-invasive imaging may serve as a biomarker for assessing the pathophysiology of bone metastasis in obesity, opening novel options for therapy and treatment monitoring by MRI and [F-18]FDG-PET/CT.
CRIS-Team WoS Importer:2022-06-10

NON-INVASIVE IN VIVO METABOLIC PROFILING OF INFLAMMATION IN JOINTS AND ENTHESES BY OPTOACOUSTIC IMAGING - Tascilar, Koray; Fagni, Filippo; Kleyer, Arnd; Bayat, Sara; Heidemann, Robert; Steiger, F.; Krönke, Gerhard; Bohr, D.; Ramming, Andreas; Hartmann, F.; Klett, Daniel; Federle, Anna; et al. (ANNALS OF THE RHEUMATIC DISEASES, 2022)
CRIS-Team WoS Importer:2022-11-04

Non-invasive metabolic profiling of inflammation in joints and entheses by multispectral optoacoustic tomography - Tascilar, Koray; Fagni, Filippo; Kleyer, Arnd; Bayat, Sara; Heidemann, Robert; Steiger, Florian; Krönke, Gerhard; Bohr, Daniela; Ramming, Andreas; Hartmann, Fabian; Klett, Daniel; Federle, Anna; et al. (Rheumatology, 2022)
Objective To explore the metabolic characteristics of arthritis and enthesitis using multispectral opto-acoustic tomography (MSOT), a technology using near-infrared multispectral laser to stimulate tissues and detect the emitted acoustic energy, enabling non-invasive quantification of tissue components in vivo based on differential absorbance at multiple wavelengths. Methods We performed a cross-sectional study in patients with RA or PsA and healthy controls (HCs). Participants underwent clinical, ultrasonographic and MSOT examination of MCP and wrist joints as well as the entheses of the common extensor tendon at the lateral humeral epicondyles and of the patellar, quadriceps and Achilles tendon. MSOT-measured haemoglobin (Hb), oxygen saturation, collagen and lipid levels were quantified and scaled mean differences between affected and unaffected joints and entheses were calculated as defined by clinical examination or ultrasonography using linear mixed effects models. Results We obtained 1535 MSOT and 982 ultrasonography scans from 87 participants (34 PsA, 17 RA, 36 HCs). Entheseal tenderness was not associated with significant metabolic changes, whereas enthesitis-related sonographic changes were associated with increased total Hb, oxygen saturation and collagen content. In contrast, the presence of arthritis-related clinical and sonographic findings showed increased Hb levels, reduced oxygen saturation and reduced collagen content. Synovial hypertrophy was associated with increased lipid content in the joints. Conclusion MSOT allows determination of distinct metabolic differences between arthritis and enthesitis in a non-invasive setting in humans in vivo.
CRIS-Team WoS Importer:2022-07-22

Notch Signaling Activity Determines Uptake and Biological Effect of Imatinib in Systemic Sclerosis Dermal Fibroblasts - Harrach, Saliha; Barz, Vivien; Pap, Thomas; Pavenstaedt, Hermann; Schlatter, Eberhard; Edemir, Bayram; Distler, Jörg; Ciarimboli, Giuliano; Bertrand, Jessica (Journal of Investigative Dermatology, 2019)
Tyrosine kinase inhibitors have emerged as a therapeutic option for rheumatic diseases such as systemic sclerosis (SSc). Because tyrosine kinases like c-Abl kinase are important for fibroblast activation and fibrosis development in SSc, the c-Abl inhibitor imatinib was proposed for SSc treatment. Transporters for organic cations have become increasingly recognized as an important determinant for uptake and efficacy of tyrosine kinase inhibitors. Therefore, we investigated the role of organic cation transporters in the uptake of imatinib. Moreover, the influence of important SSc pathogenetic factors, like PDGF and Notch pathway activation on these uptake processes, has been studied. We showed that organic cation transporters OCT1e3, novel organic cation transporters OCTN1/2, and the multidrug and toxin extrusion protein MATE1 are expressed in healthy dermal and SSc fibroblasts. Decreased expression levels of MATE1 and decreased imatinib uptake were measured in SSc fibroblasts. In small interfering RNA experiments, MATE1 was identified as key transporter for imatinib uptake and biological effect in dermal fibroblasts. Furthermore, PDGF reduced imatinib uptake by decreasing MATE1 expression in SSc fibroblasts, but not in healthy fibroblasts. Blocking the Notch pathway in SSc fibroblasts increased MATE1 transporter expression and imatinib uptake. In conclusion, MATE1-mediated transport governs therapeutic efficacy of imatinib in SSc.
CRIS-Team WoS Importer:2019-02-21

Novel approaches to target the microenvironment of bone metastasis - Hofbauer, Lorenz C.; Bozec, Aline; Rauner, Martina; Jakob, Franz; Perner, Sven; Pantel, Klaus (NAT REV CLIN ONCOL, 2021)
Bone metastases are a frequent and severe complication of advanced-stage cancers. Breast and prostate cancers, the most common malignancies in women and men, respectively, have a particularly high propensity to metastasize to bone. Conceptually, circulating tumour cells (CTCs) in the bloodstream and disseminated tumour cells (DTCs) in the bone marrow provide a snapshot of the dissemination and colonization process en route to clinically apparent bone metastases. Many cell types that constitute the bone microenvironment, including osteoblasts, osteocytes, osteoclasts, adipocytes, endothelial cells, haematopoietic stem cells and immune cells, engage in a dialogue with tumour cells. Some of these cells modify tumour biology, while others are disrupted and out-competed by tumour cells, thus leading to distinct phases of tumour cell migration, dormancy and latency, and therapy resistance and progression to overt bone metastases. Several current bone-protective therapies act by interrupting these interactions, mainly by targeting tumour cell-osteoclast interactions. In this Review, we describe the functional roles of the bone microenvironment and its components in the initiation and propagation of skeletal metastases, outline the biology and clinical relevance of CTCs and DTCs, and discuss established and future therapeutic approaches that specifically target defined components of the bone microenvironment to prevent or treat skeletal metastases.
CRIS-Team WoS Importer:2021-05-07

Novel Developments in Primary Immunodeficiencies (PID)—a Rheumatological Perspective - Leavis, Helen; Zwerina, Jochen; Manger, Bernhard; Fritsch-Stork, Ruth D.E. (Current Rheumatology Reports, 2019)
Purpose of Review: The purpose of this review is to provide an overview of the most relevant new disorders, disease entities, or disease phenotypes of primary immune deficiency disorders (PID) for the interested rheumatologist, using the new phenotypic classification by the IUIS (International Union of Immunological Societies) as practical guide. Recent Findings: Newly recognized disorders of immune dysregulation with underlying mutations in genes pertaining to the function of regulatory T cells (e.g., CTLA-4, LRBA, or BACH2) are characterized by multiple autoimmune diseases—mostly autoimmune cytopenia—combined with an increased susceptibility to infections due to hypogammaglobulinemia. On the other hand, new mutations (e.g., in NF-kB1, PI3Kδ, PI3KR1, PKCδ) leading to the clinical picture of CVID (common variable immmune deficiency) have been shown to increasingly associate with autoimmune diseases. Summary: The mutual association of autoimmune diseases with PID warrants increased awareness of immunodeficiencies when diagnosing autoimmune diseases with a possible need to initiate appropriate genetic tests.
CRIS-Team Scopus Importer:2019-09-17
Keywords: APDS; CTLA-4 haploinsufficiency; CVID; DADA2; LRBA indusfficiency; NF-kB deficiency

Novel Mechanism Mediated By the IL-23/Th17 Axis Contributing to Auto-Immune Arthritis - Pfeifle, René; Rothe, Tobias; Ipseiz, Natacha; Culemann, Stephan; Harre, Ulrike; Krönke, Gerhard; Schett, Georg (2016)
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Novel mechanism mediated by the IL23/Th17 axis contributing to auto-immune arthritis - Pfeifle, R.; Rothe, T.; Ipseiz, N.; Culemann, S.; Harre, Ulrike; Schett, Georg; Krönke, Gerhard (2017)
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NOVEL TECHNIQUE FOR PRECISE CALCULATION OF BONE EROSION VOLUME IN RA PATIENTS USING HR-PQCT - Figueiredo, C.; Simon, David; Stemmler, F.; Rech, Jürgen; Hueber, Axel; Haschka, J.; Schett, Georg; Kleyer, Arnd (2015)
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NOX2 mediates quiescent handling of dead cell remnants in phagocytes - Hahn, Jonas; Euler, Maximilien; Kilgus, Emelie; Kienhöfer, Deborah; Stoof, Julia; Knopf, Jasmin; Hahn, Madelaine; Harrer, Thomas; Hultqvist, Malin; Olofsson, Peter; Mokhir, Andriy; Holmdahl, Rikard; et al. (Redox Biology, 2019)
The phagocyte NADPH oxidase (the NOX2 complex) generates superoxide, the precursor to reactive oxygen species (ROS). ROS possess both antimicrobial and immunoregulatory function. Inactivating mutations in alleles of the NOX2 complex cause chronic granulomatous disease (CGD), characterized by an enhanced susceptibility to infections and autoimmune diseases such as Systemic lupus erythematosus (SLE). The latter is characterized by insufficient removal of dead cells, resulting in an autoimmune response against components of the cell's nucleus when non-cleared apoptotic cells lose their membrane integrity and present autoantigenic molecules in an inflammatory context. Here we aimed to shed light on the role of the NOX2 complex in handling of secondary necrotic cells (SNECs) and associated consequences for inflammation and autoimmunity during lupus. We show that individuals with SLE and CGD display accumulation of SNECs in blood monocytes and neutrophils. In a CGD phenotypic mouse strain (Ncf1** mice) build-up of SNECs in Ly6CHI blood monocytes was connected with a delayed degradation of the phagosomal cargo and accompanied by production of inflammatory mediators. Treatment with H2O2 or activators of ROS-formation reconstituted phagosomal abundance of SNECs to normal levels. Induction of experimental lupus further induced increased antibody-dependent uptake of SNECs into neutrophils. Lupus-primed Ncf1** neutrophils took up more SNECs than wild type neutrophils, whereas SNEC-accumulation in regulatory Ly6C−/LO monocytes was lower in Ncf1**mice. We deduce that the inflammatory rerouting of immune-stimulatory necrotic material into inflammatory phagocyte subsets contributes to the connection between low ROS production by the NOX2 complex and SLE.
CRIS-Team Scopus Importer:2019-08-06

NR4A1 AGONIST CYTOSPORONE B DOES NOT ATTENUATE CAV IN A MOUSE MODEL DESPITE REPORTED ANTI-PROLIFERATIVE AND ANTI-INFLAMMATORY EFFECTS - Kuckhahn, A.; Ramsperger-Gleixner, Martina; Distler, Jörg; Weyand, Michael; Heim, Christian (TRANSPLANT INTERNATIONAL, 2020)
CRIS-Team WoS Importer:2020-11-06

NR4A1 Regulates Motility of Osteoclast Precursors and Serves as Target for the Modulation of Systemic Bone Turnover - Scholtysek, Carina; Ipseiz, Natacha; Böhm, Christina; Krishnacoumar, Brenda; Stenzel, Martin; Czerwinski, Tina; Palumbo-Zerr, Katrin; Rothe, Tobias; Weidner, Daniela; Klej, Alexandra; Stoll, Cornelia; Distler, Jörg; et al. (Journal of Bone and Mineral Research, 2018)
NR4A1 (Nur77 or NGFI-B), an orphan member of the nuclear receptor superfamily, has been identified as a key regulator of the differentiation and function of myeloid, lymphoid, and mesenchymal cells. The detailed role of NR4A1 in bone biology is incompletely understood. Here, we report a role for NR4A1 as novel factor controlling the migration and recruitment of osteoclast precursors during bone remodeling. Myeloid-specific but not osteoblast-specific deletion of NR4A1 resulted in osteopenia due to an increase in the number of bone-lining osteoclasts. Although NR4A1-deficient osteoclast precursors displayed a regular differentiation into mature osteoclasts, they showed a hyper-motile phenotype that was largely dependent on increased osteopontin expression, suggesting that expression of NR4A1 negatively controlled osteopontin-mediated recruitment of osteoclast precursors to the trabecular bone. Pharmacological activation of NR4A1, in turn, inhibited osteopontin expression and osteopontin-dependent migration of osteoclast precursors resulted in reduced abundance of bone-resorbing osteoclasts in vivo as well as in an ameliorated bone loss after ovariectomy in mice. This study identifies NR4A1 as a crucial player in the regulation of osteoclast biology and bone remodeling and highlights this nuclear receptor as a promising target for therapeutic intervention during the treatment of osteoporosis. © 2018 The Authors. Journal of Bone and Mineral Research Published by Wiley Periodicals Inc.
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N-terminal pro-brain natriuretic peptide is a strong predictor of mortality in systemic sclerosis - Allanore, Yannick; Komocsi, Andras; Vettori, Serena; Hachulla, Eric; Hunzelmann, Nicolas; Distler, Jörg; Avouac, Jerome; Gobeaux, Camille; Launay, David; Czirjak, Laszlo; Kahan, Andre; Meune, Christophe (International Journal of Cardiology, 2016)
Cardiovascular involvement is a major contributor to mortality in systemic sclerosis (SSc). We examined whether N-terminal pro-brain natriuretic peptide (NT-proBNP) is a reliable predictor of mortality in SSc.This multicentre prospective cohort study included 523 patients presenting with SSc, whose mean age was 54±13years, mean disease duration 8±9years, and diffuse cutaneous form in 168. Plasma NT-proBNP was measured at baseline and the patients were followed yearly. Overall mortality was measured at 3years. At baseline, cardiovascular involvement was present in 37 patients, including 17 with pulmonary artery hypertension (PAH) and 20 with a left ventricular ejection fraction (LVEF) <55%. At 3years, 32 (7%) patients had died. The median [25th-75th percentile] NT-proBNP concentration was 203ng/l [129-514] in patients who died within 3years, versus 88ng/l [47-167] in survivors (P<0.001). NT-proBNP was an independent predictor of 3-years mortality in multivariate analysis (P=0.046). The optimal cut-off derived from the ROC curve was 129ng/l; sensitivity and specificity to predict 3y mortality were 78.1 and 66.7%. Using the previously recommended 125-ng/l concentration as threshold value, NT-proBNP reliably and independently predicted 3year mortality, with a sensitivity of 78.1 and a negative predictive value of 97.6%, respectively (P=0.006). The consideration of SSc patients without PAH or LVEF<55% at baseline yielded similar results.NT-proBNP appears as a reliable and independent predictor of mortality in patients with SSc.
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Number of necessary training examples for Neural Networks with different number of trainable parameters - Götz, Theresa Ida; Göb, S.; Sawant, S.; Erick, X. F.; Wittenberg, Thomas; Schmidkonz, Christian; Tomé, A. M.; Lang, E. W.; Ramming, Andreas (Journal of Pathology Informatics, 2022)
In this work, the network complexity should be reduced with a concomitant reduction in the number of necessary training examples. The focus thus was on the dependence of proper evaluation metrics on the number of adjustable parameters of the considered deep neural network. The used data set encompassed Hematoxylin and Eosin (H&E) colored cell images provided by various clinics. We used a deep convolutional neural network to get the relation between a model's complexity, its concomitant set of parameters, and the size of the training sample necessary to achieve a certain classification accuracy. The complexity of the deep neural networks was reduced by pruning a certain amount of filters in the network. As expected, the unpruned neural network showed best performance. The network with the highest number of trainable parameter achieved, within the estimated standard error of the optimized cross-entropy loss, best results up to 30% pruning. Strongly pruned networks are highly viable and the classification accuracy declines quickly with decreasing number of training patterns. However, up to a pruning ratio of 40%, we found a comparable performance of pruned and unpruned deep convolutional neural networks (DCNN) and densely connected convolutional networks (DCCN).
CRIS-Team Scopus Importer:2022-10-28
Keywords: Cell segmentation; Deep neural networks; DNN complexity; Pruning; Training sample size

Obesity as an Influence Parameter of rheumatoid Arthritis and Osteoarthritis (Arthrosis) in the Mouse Model - Sauermilch, Hani Manfred; Huelser, Marie-Lisa; Schreiyaeck, Carina; Luo, Yubin; Bozec, Aline; Schett, Georg; Mueller-Ladner, Ulf; Neumann, Elena (INTERNIST, 2019)
CRIS-Team WoS Importer:2019-05-17

Obesity reduces the real-world effectiveness of cytokine-targeted but not cell-targeted disease-modifying agents in rheumatoid arthritis - Schäfer, Martin; Meißner, Yvette; Kekow, Jörn; Berger, Sylvia; Remstedt, Sven; Manger, Bernhard; Listing, Joachim; Strangfeld, Anja; Zink, Angela (Rheumatology, 2020)
OBJECTIVES: The effectiveness of TNF inhibitors in RA has been shown to be affected by obesity. No such effect has been found for abatacept and rituximab, while for tocilizumab results are ambiguous. Additionally, it remains unresolved whether sex is an effect modifier for obesity. We investigated the impact of obesity on the drug effectiveness of conventional synthetic or biologic DMARDs, taking into account potential sex-specific differences. METHODS: Data from 10 593 RA patients included in the German observational cohort study Rheumatoid Arthritis: oBservation of BIologic Therapy (RABBIT) since 2009 were analysed. Patients had to have a BMI ≥18.5 kg/m2, at least one follow-up and 6 months of observation time. The influence of obesity on drug effectiveness was investigated by regression analysis, adjusting for potential confounders. RESULTS: Obesity had a negative impact on improvement in the DAS with 28 joints using ESR as an inflammation marker of -0.15 (95% CI: -0.26; -0.04) units for women receiving conventional synthetic DMARDs, -0.22 (95% CI: -0.31; -0.12) units for women receiving TNF inhibitors, -0.22 (95% CI: -0.42; -0.03) units for women receiving tocilizumab and -0.41 (95% CI: -0.74; -0.07) units for men receiving tocilizumab. Overall, no negative obesity effects on the effectiveness of rituximab and abatacept were found. CONCLUSION: Obesity has a negative impact on the effectiveness of cytokine-targeted but not cell-targeted therapies in daily practice, affecting more outcomes and therapies in women than in men. Overall, no effects of obesity on treatment effectiveness were found for rituximab and abatacept.
CRIS-Team Scopus Importer:2020-08-07
Keywords: drug dosage; obesity; rheumatoid arthritis; sex

Objective and subjective hand function reflect grade of tenosynovitis in patients with psoriasis and psoriatic arthritis - Coppers, Birte; Bayat, Sara; Elie-Tino, Godonou; Valor-Mendez, Larissa; Simon, David; Corte, Giulia; Tascilar, Koray; Hueber, Axel; Bohr, Daniela; Schönau, Verena; Sticherling, Michael; Schett, Georg; et al. (poster, Deutsche Gesellschaft für Rheumatologie Kongress, 2023)

OBSERVATIONAL STUDY OF OUTCOME IN PATIENTS WITH EARLY DIFFUSE CUTANEOUS SYSTEMIC SCLEROSIS TREATED WITH IMMUNOSUPPRESSIVE THERAPIES (ESOS STUDY) - Herrick, A. L.; Pan, X.; Peytrignet, S.; Hesselstrand, R.; Mouthon, L.; Brown, E.; Czirjak, L.; Distler, Jörg; Distler, O.; Fligelstone, K.; Gregory, W.; Ochiel, R.; et al. (2016)
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O-GLCNACYLATION ON NUP153 REGULATES THE EARLY STAGES OF OSTEOCLASTOGENESIS THROUGH MYC NUCLEAR TRANSLOCATION - Li, You; Chen, Chih-Wei; Trinh, Minh Thuong; Honglin, Z.; Hubel, P.; Pfannstiel, J.; Schett, Georg; Distler, Jörg (ANNALS OF THE RHEUMATIC DISEASES, 2022)
CRIS-Team WoS Importer:2022-11-04

Older age onset of systemic sclerosis - accelerated disease progression in all disease subsets - Moinzadeh, Pia; Kuhr, Kathrin; Siegert, Elise; Mueller-Ladner, Ulf; Riemekasten, Gabriela; Günther, Claudia; Kötter, Ina; Henes, Jörg; Blank, Norbert; Zeidler, Gabriele; Pfeiffer, Christiane; Juche, Aaron; et al. (Rheumatology, 2020)
OBJECTIVES: Systemic sclerosis is a heterogeneous, multisystem disease. It can occur at any age, but most patients develop the disease between the age of 40 to 50 years. There is controversial evidence on whether/how the age at disease onset affects their clinical phenotype. We here investigate the relationship between age at disease onset and symptoms in a large cohort of SSc patients (lcSSc, dcSSc and SSc-overlap syndromes). METHODS: Clinical data of the registry of the German Network for Systemic Scleroderma including 3281 patients were evaluated and subdivided into three age groups at disease onset (<40 years, 40-60 years, >60 years). RESULTS: Among all SSc patients, 24.5% developed their first non-Raynaud phenomenon symptoms at the age <40 years, and 22.5% were older than 60 years of age. In particular, older patients at onset developed the lcSSc subset significantly more often. Furthermore, they had pulmonary hypertension more often, but digital ulcerations less often. Remarkably, the course of the disease was more rapidly progressing in the older cohort (>60 years), except for gastrointestinal and musculoskeletal involvement. No significant difference was found for the use of corticosteroids. However, significantly, fewer patients older than 60 years received immunosuppressive treatment. CONCLUSION: In this large registry, ∼25% of patients developed SSc at an age above 60 years with an increased frequency of lcSSc. In this age group, an onset of internal organ involvement was significantly accelerated across all three subsets. These findings suggest that, in the elderly cohort, more frequent follow-up examinations are required for an earlier detection of organ complications.
CRIS-Team Scopus Importer:2020-11-13
Keywords: age at disease onset; German Network for Systemic Scleroderma; older age; scleroderma; SSc; systemic sclerosis

O-linked N-acetylglucosaminylation of Sp1 inhibits the human immunodeficiency virus type 1 promoter - Jochmann, Ramona; Thurau, Mathias; Jung, Susan; Hofmann, Christian; Naschberger, Elisabeth; Kremmer, Elisabeth; Harrer, Thomas; Miller, Matthew; Schaft, Niels; Stürzl, Michael (Journal of Virology, 2009)
Human immunodeficiency virus type 1 (HIV-1) gene expression and replication are regulated by the promoter/enhancer located in the U3 region of the proviral 5′ long terminal repeat (LTR). The binding of cellular transcription factors to specific regulatory sites in the 5′ LTR is a key event in the replication cycle of HIV-1. Since transcriptional activity is regulated by the posttranslational modification of transcription factors with the monosaccharide O-linked N-acetyl-D-glucosamine (O-GlcNAc), we evaluated whether increased O-GlcNAcylation affects HIV-1 transcription. In the present study we demonstrate that treatment of HIV-1-infected lymphocytes with the O-GlcNAcylation-enhancing agent glucosamine (GlcN) repressed viral transcription in a dose-dependent manner. Overexpression of O-GlcNAc transferase (OGT), the sole known enzyme catalyzing the addition of O-GlcNAc to proteins, specifically inhibited the activity of the HIV-1 LTR promoter in different T-cell lines and in primary CD4+ T lymphocytes. Inhibition of HIV-1 LTR activity in infected T cells was most efficient (>95%) when OGT was recombinantly overexpressed prior to infection. O-GlcNAcylation of the transcription factor Sp1 and the presence of Sp1-binding sites in the LTR were found to be crucial for this inhibitory effect. From this study, we conclude that O-GlcNAcylation of Sp1 inhibits the activity of the HIV-1 LTR promoter. Modulation of Sp1 O-GlcNAcylation may play a role in the regulation of HIV-1 latency and activation and links viral replication to the glucose metabolism of the host cell. Hence, the establishment of a metabolic treatment might supplement the repertoire of antiretroviral therapies against AIDS. Copyright © 2009, American Society for Microbiology. All Rights Reserved.
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Online-Ultraschalllernmodule in der Rheumatologie - Knitza, Johannes; Kleyer, Arnd; Klüppel, M.; Krauser, M.; Wacker, J.; Schett, Georg; Simon, David (Zeitschrift für Rheumatologie, 2020)
CRIS-Team Scopus Importer:2020-03-10

Only a Minor Proportion of Individuals with Anti-Aminoacyl-tRNA Synthetase Autoimmunity Presents with the Clinical Picture of "Antisynthetase-Syndrome" - Knitza, Johannes; Schenker, Hannah; Schett, Georg; Distler, Jörg (2018)
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On the inclusion of motion capture data in optimal control simulations of the human hand - Heinrich, Simon; Coppers, Birte; Liphardt, Anna-Maria; Leyendecker, Sigrid (conference, 18th International Symposium on Computer Methods in Biomechanics and Biomedical Engineering, 2023)

Opportunistic Screening With CT: Comparison of Phantomless BMD Calibration Methods - Bartenschlager, Stefan; Cavallaro, Alexander Josef; Pogarell, Tobias; Chaudry, Oliver; Uder, Michael; Khosla, Sundeep; Schett, Georg; Engelke, Klaus (Journal of Bone and Mineral Research, 2023)
Opportunistic screening is a new promising technique to identify individuals at high risk for osteoporotic fracture using computed tomography (CT) scans originally acquired for an clinical purpose unrelated to osteoporosis. In these CT scans, a calibration phantom traditionally required to convert measured CT values to bone mineral density (BMD) is missing. As an alternative, phantomless calibration has been developed. This study aimed to review the principles of four existing phantomless calibration methods and to compare their performance against the gold standard of simultaneous calibration (ΔBMD). All methods were applied to a dataset of 350 females scanned with a highly standardized CT protocol (DS1) and to a second dataset of 114 patients (38 female) from clinical routine covering a large range of CT acquisition and reconstruction parameters (DS2). Three of the phantomless calibration methods must be precalibrated with a reference dataset containing a calibration phantom. Sixty scans from DS1 and 57 from DS2 were randomly selected for this precalibration. For each phantomless calibration method first the best combination of internal reference materials (IMs) was selected. These were either air and blood or subcutaneous adipose tissue, blood, and cortical bone. In addition, for phantomless calibration a fifth method based on average calibration parameters derived from the reference dataset was applied. For DS1, ΔBMD results (mean (Formula presented.) standard deviation) for the phantomless calibration methods requiring a precalibration ranged from 0.1 (Formula presented.) 2.7 mg/cm3 to 2.4 (Formula presented.) 3.5 mg/cm3 with similar means but significantly higher standard deviations for DS2. Performance of the phantomless calibration method, which does not require a precalibration was worse (ΔBMD DS1: 12.6 (Formula presented.) 13.2 mg/cm3, DS2: 0.5 (Formula presented.) 8.8 mg/cm3). In conclusion, phantomless BMD calibration performs well if precalibrated with a reference dataset. © 2023 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).
CRIS-Team Scopus Importer:2023-10-20
Keywords: BONE MINERAL DENSITY; PERFORMANCE OF PHANTOMLESS CALIBRATION; OPPORTUNISTIC SCREENING; SIMULTANEOUS CALIBRATION

OPTIMAL DOSE OF TOCILIZUMAB FOR THE TREATMENT OF GIANT CELL ARTERITIS: EFFICACY, SAFETY, AND EXPOSURE-EFFICACY ANALYSIS FROM GIACTA - Stone, J. H.; Tuckwell, K.; Dimonaco, S.; Klearman, M.; Mallalieu, N. L.; Aringer, M.; Blockmans, D.; Brouwer, E.; Cid, M. C.; Dasgupta, B.; Rech, Jürgen; Salvarani, C.; et al. (2017)
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Origin and function of synovial macrophage subsets during inflammatory joint disease - Culemann, Stephan; Grüneboom, Anika; Krönke, Gerhard (Advances in Immunology, 2019)
Mononuclear phagocytes, including monocytes and macrophages, are a central component of the host's innate immune system designated to protect against invading pathogens. However, these cells do not only interact with various parts of the innate and adaptive immune system, but also fulfill indispensable duties during the control of tissue homeostasis and organ function. Moreover, macrophages are crucially involved in tissue remodeling and repair in response to damage. Simultaneously, mononuclear phagocytes might also contribute to the pathogenesis of various inflammatory and autoimmune diseases. In particular, their potential role in inflammatory joint diseases such as rheumatoid arthritis (RA) has drawn increasing attention and substantially shaped our general understanding of the role of monocytes and macrophages during health and disease. This review summarizes our current knowledge about the origin and function of mononuclear phagocytes within the joint and addresses their involvement in joint inflammation.
CRIS-Team Scopus Importer:2019-09-17
Keywords: Inflammation; Macrophages; Monocytes; Rheumatoid arthritis; Synovial macrophages; Synovial tissue; Tissue resident macrophages

Orphan nuclear receptor NR4A1 regulates transforming growth factor-? signaling and fibrosis - Palumbo-Zerr, Katrin; Zerr, Pawel; Distler, Alfiya; Fliehr, Judith; Mancuso, Rossella; Huang, Jingang; Mielenz, Dirk; Tomcik, Michal; Fuernrohr, Barbara G.; Scholtysek, Carina; Dees, Clara; Beyer, Christian; et al. (Nature Medicine, 2015)
Mesenchymal responses are an essential aspect of tissue repair. Failure to terminate this repair process correctly, however, results in fibrosis and organ dysfunction. Therapies that block fibrosis and restore tissue homeostasis are not yet available for clinical use. Here we characterize the nuclear receptor NR4A1 as an endogenous inhibitor of transforming growth factor-? (TGF-?) signaling and as a potential target for anti-fibrotic therapies. NR4A1 recruits a repressor complex comprising SP1, SIN3A, CoREST, LSD1, and HDAC1 to TGF-? target genes, thereby limiting pro-fibrotic TGF-? effects. Even though temporary upregulation of TGF-? in physiologic wound healing induces NR4A1 expression and thereby creates a negative feedback loop, the persistent activation of TGF-? signaling in fibrotic diseases uses AKT- and HDAC-dependent mechanisms to inhibit NR4A1 expression and activation. Small-molecule NR4A1 agonists can overcome this lack of active NR4A1 and inhibit experimentally-induced skin, lung, liver, and kidney fibrosis in mice. Our data demonstrate a regulatory role of NR4A1 in TGF-? signaling and fibrosis, providing the first proof of concept for targeting NR4A1 in fibrotic diseases.
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Orphan Nuclear Receptor Ror alpha Is a Key Regulator of Tgf beta- and WNT-Signaling in Fibrotic Diseases - Kagwiria, Rosebeth; Liang, Ruifang; Matei, Alexandru-Emil; Sihler, Niclas; Chen, Chih-Wei; Burris, Thomas; Distler, Oliver; Schett, Georg; Distler, Jörg (2018)
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Osteitis and synovitis, but not bone erosion, is associated with proteoglycan loss and microstructure damage in the cartilage of patients with rheumatoid arthritis - Herz, Barbara; Albrecht, Andreas; Englbrecht, Matthias; Welsch, Götz; Uder, Michael; Renner, Nina; Schlechtweg, Philipp; Paul, Dominik; Lauer, Lars; Engelke, Klaus; Janka, Rolf Matthias; Rech, Jürgen; et al. (Annals of the Rheumatic Diseases, 2014)
To investigate the relation between anatomic changes of the synovium, the bone, the bone marrow and the cartilage to biochemical properties of the cartilage in patients with rheumatoid arthritis (RA).33 patients with RA received 3-T MRI scans of the metacarpophalangeal joints. Two independent methods, (A) the delayed gadolinium enhanced MRI of the cartilage (dGEMRIC, T2-mapping), which was used to assess the biochemical properties of the cartilage; (B) synovitis, osteitis and bone erosions were quantified according to the RA MRI scoring (RAMRIS) method and cartilage thickness (CT), interbone joint space (IBJS, distance between proximal and distal bone surface) and intercartilage joint space (ICJS, distance between proximal and distal cartilage surface) were measured.Biochemical changes of the cartilage, corresponding to low dGEMRIC and high T2 values, were more likely to be seen in joints with decreased IBJS and ICJS as well as decreased CT. For instance, dGEMRIC was directly correlated to the IBJS (p=0.001) and ICJS (p=0.001), whereas T2 mapping was inversely correlated to IBJS and ICJS (both p=0.017). Moreover, the degree of osteitis, and to some extent synovitis, was correlated to biochemical cartilage changes as measured by dGEMRIC (p=0.003) or the T2 mapping (p=0.013). By contrast, bone erosions did not correlate to the degree of biochemical cartilage changes.These data support the concept that synovitis and osteitis may be two main triggers for cartilage damage. Thus, the actual inflammatory state of a joint, but not so much the degree of bone erosion, appears to influence cartilage properties in RA.
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Osteoarthritis research priorities: a report from a EULAR ad hoc expert committee - Conaghan, Philip G.; Kloppenburg, Margreet; Schett, Georg; Bijlsma, Johannes W. J. (Annals of the Rheumatic Diseases, 2014)
Osteoarthritis (OA) currently affects over 40 million Europeans, with its associated personal suffering and significant economic burden for health systems set to dramatically escalate in a rapidly ageing Europe. Given the very limited effective therapeutic options for OA, the European League Against Rheumatism (EULAR) created an ad hoc committee of OA researchers, clinicians and patients to consider a research agenda focussed on the areas of epidemiology, pathogenesis, imaging and biomarkers, and therapies. The committee deliberated and listed research needs in these areas and also established some cross-area priority themes: predictors of OA progression, especially where this might enable stratified interventions; understanding mechanisms of OA pain; improved understanding of tissue communication in a process where multiple tissue pathologies are common; developing concepts of, and consequently interventions for, early OA where both pain and structural processes may be more effectively targeted than in typical clinical presentations; and the need for new treatment strategies, with examples discussed on pathology-targeted therapies and optimal combinations of therapies. This research agenda should provide useful guidance for all researchers in this field and hopefully lead to improved OA care.
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Osteocyte necrosis triggers osteoclast-mediated bone loss through macrophage-inducible C-type lectin - Andreev, Darja; Liu, Mengdan; Weidner, Daniela; Kachler, Katerina; Faas, Maria; Grüneboom, Anika; Schlötzer-Schrehardt, Ursula; Munoz, Luis Enrique; Steffen, Ulrike; Grötsch, Bettina; Killy, Barbara; Krönke, Gerhard; et al. (Journal of Clinical Investigation, 2020)
Although the control of bone-resorbing osteoclasts through osteocyte-derived RANKL is well defined, little is known about the regulation of osteoclasts by osteocyte death. Indeed, several skeletal diseases, such as bone fracture, osteonecrosis, and inflammation are characterized by excessive osteocyte death. Herein we show that osteoclasts sense damageassociated molecular patterns (DAMPs) released by necrotic osteocytes via macrophage-inducible C-type lectin (Mincle), which induced their differentiation and triggered bone loss. Osteoclasts showed robust Mincle expression upon exposure to necrotic osteocytes in vitro and in vivo. RNA sequencing and metabolic analyses demonstrated that Mincle activation triggers osteoclastogenesis via ITAM-based calcium signaling pathways, skewing osteoclast metabolism toward oxidative phosphorylation. Deletion of Mincle in vivo effectively blocked the activation of osteoclasts after induction of osteocyte death, improved fracture repair, and attenuated inflammation-mediated bone loss. Furthermore, in patients with osteonecrosis, Mincle was highly expressed at skeletal sites of osteocyte death and correlated with strong osteoclastic activity. Taken together, these data point to what we believe is a novel DAMP-mediated process that allows osteoclast activation and bone loss in the context of osteocyte death.
CRIS-Team Scopus Importer:2020-10-16

Osteocytes support bone metastasis of melanoma cells by CXCL5 - Jia, Yewei; Zhang, Fulin; Meng, Xianyi; Andreev, Darja; Lyu, Pang; Zhang, Wenshuo; Lai, Chaobo; Schett, Georg; Bozec, Aline (Cancer Letters, 2024)
Bone metastasis is a common complication of certain cancers such as melanoma. The spreading of cancer cells into the bone is supported by changes in the bone marrow environment. The specific role of osteocytes in this process is yet to be defined. By RNA-seq and chemokines screening we show that osteocytes release the chemokine CXCL5 when they are exposed to melanoma cells. Osteocytes-mediated CXCL5 secretion enhanced the migratory and invasive behaviour of melanoma cells. When the expression of the CXCL5 receptor, CXCR2, was down-regulated in melanoma cells in vitro, we observed a significant decrease in melanoma cell migration in response to osteocytes. Furthermore, melanoma cells with down-regulated CXCR2 expression showed less bone metastasis and less bone loss in the bone metastasis model in vivo. Furthermore, when simultaneously down-regulating CXCL5 in osteocytes and CXCR2 in melanoma cells, melanoma progression was abrogated in vivo. In summary, these data suggest a significant role of osteocytes in bone metastasis of melanoma, which is mediated through the CXCL5-CXCR2 pathway.
CRIS-Team Scopus Importer:2024-04-26

Osteoimmunology - Schett, Georg (Zeitschrift für Rheumatologie, 2016)
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Osteoimmunology-IMMUNOBONE : Regulation of bone by inflammation - Rauner, M.; Buttgereit, F.; Distler, Jörg; Garbe, A. I.; Herrmann, Martin; Hofbauer, Lorenz; Hoffmann, M.; Jessberger, R.; Kornak, U.; Krönke, Gerhard; Mundlos, S.; Spies, C.; et al. (Zeitschrift für Rheumatologie, 2018)
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Osteoporosis - Lange, Uwe; Schett, Georg (Zeitschrift für Rheumatologie, 2016)
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Osteoprotective action of low-salt diet requires myeloid cell-derived NFAT5 - Schroeder, Agnes; Neubert, Patrick; Titze, Jens; Bozec, Aline; Neuhofer, Wolfgang; Proff, Peter; Kirschneck, Christian; Jantsch, Jonathan (JCI Insight, 2019)
Dietary salt consumption leads to cutaneous Na+ storage and is associated with various disorders, including osteopenia. Here, we explore the impact of Na+ and the osmoprotective transcription factor nuclear factor of activated T cell 5 (NFAT5) on bone density and osteoclastogenesis. Compared with treatment of mice with high-salt diet, low-salt diet (LSD) increased bone density, decreased osteoclast numbers, and elevated Na+ content and Nfat5 levels in the BM. This response to LSD was dependent on NFAT5 expressed in myeloid cells. Simulating in vivo findings, we exposed osteoclast precursors and osteoblasts to elevated Na+ content (high-salt conditions; HS), resulting in increased NFAT5 binding to the promotor region of RANKL decoy receptor osteoprotegerin (OPG). These data not only demonstrate that NFAT5 in myeloid cells determines the Na+ content in BM, but that NFAT5 is able to govern the expression of the osteoprotective gene OPG. This provides insights into mechanisms of Na+-induced cessation of osteoclastogenesis and offers potentially new targets for treating salt-induced osteopenia.
CRIS-Team Scopus Importer:2020-02-21

Osteoprotegerin and Cardiovascular Events in High-Risk Populations: Meta-Analysis of 19 Prospective Studies Involving 27 450 Participants - Tschiderer, Lena; Klingenschmid, Gerhard; Nagrani, Rajini; Willeit, Johann; Laukkanen, Jari A.; Schett, Georg; Kiech, Stefan; Willeit, Peter (Journal of the American Heart Association, 2018)
Background Osteoprotegerin is a cytokine involved in bone metabolism as well as vascular calcification and atherogenesis. Although circulating osteoprotegerin levels are robustly associated with incident cardiovascular disease ( CVD ) in the general population, its relevance as a biomarker among populations at high CVD risk is less clear. Methods and Results Three independent reviewers systematically searched PubMed, EMBASE , and Web of Science to identify prospective studies that had recruited participants on the basis of having conditions related to high CVD risk. A total of 19 studies were eligible for inclusion, reporting on 27 450 patients with diabetes mellitus (2 studies), kidney disease (7 studies), preexisting heart disease (5 studies), or recent acute coronary syndromes (5 studies) at baseline. Over a mean follow-up of 4.2 years, 4066 CVD events were recorded. In a random-effects meta-analysis, the pooled risk ratio for CVD events comparing people in the top versus the bottom tertile of osteoprotegerin concentration was 1.30 (95% confidence interval, 1.12-1.50; P<0.001; I2=68.3%). There was evidence for presence of publication bias ( P value from Egger's test=0.013). Correction for publication bias using the trim-and-fill method reduced the risk ratio to 1.21 (95% confidence interval, 1.03-1.42; P<0.001). The risk ratios did not vary significantly by population type, geographical region, statistical adjustment, sample or assay type, age, sex, or length of follow-up. Conclusions In populations at high CVD risk, elevated circulating osteoprotegerin levels are associated with a higher risk for future CVD events. The magnitude of association appears weaker than in the general population.
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Osteoprotegerin concentration and risk of cardiovascular outcomes in nine general population studies: Literature-based meta-analysis involving 26,442 participants - Tschiderer, Lena; Willeit, Johann; Schett, Georg; Kiechl, Stefan; Willeit, Peter (PLoS ONE, 2017)
Recent experimental and epidemiological studies have suggested that osteoprotegerin, a key regulator in bone metabolism, may be involved in vascular calcification and atherosclerosis. Our aim was to reliably quantify the associations of osteoprotegerin concentration and incidence of first-ever cardiovascular disease outcomes in the general population.Using the electronic databases MEDLINE, EMBASE and Web of Science (January 1975 and April 2017, no language restrictions), nine relevant studies were identified involving a total of 26,442 participants recruited from the general population. Over a mean follow-up of 8.5 years, 2,160 cardiovascular disease, 2,123 coronary heart disease, and 1,102 stroke outcomes were recorded. Study-specific risk ratios were combined with random-effects meta-analysis.When comparing individuals in the top with those in the bottom third of osteoprotegerin concentration, the combined risk ratio was 1.83 (95% confidence interval: 1.46, 2.30; P<0.001; I2 = 76.8%) for cardiovascular disease, 1.72 for coronary heart disease (1.26, 2.37; P = 0.001; I2 = 83.5%), and 1.58 for stroke (1.18, 2.12; P = 0.002; I2 = 65.2%). Associations appeared stronger at younger age (P = 0.018 for cardiovascular disease), in studies that did not employ statistical adjustment (P = 0.023 for cardiovascular disease and 0.018 for coronary heart disease), and potentially in studies that measured osteoprotegerin in plasma rather than in serum (P = 0.005 for cardiovascular disease and 0.018 for coronary heart disease). Magnitudes of associations did not differ according to the proportion of males, geographical region, or osteoprotegerin assay manufacturer. There was no evidence for publication bias for any of the outcomes assessed (all P>0.05).Elevated osteoprotegerin concentration is associated with an increased risk of incident cardiovascular disease in the general population. The mechanisms underlying this observation deserve further investigation.
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OsteoRheumatology: a new discipline? - Favero, Marta; Giusti, Andrea; Geusens, Piet; Goldring, Steven R.; Lems, Willem; Schett, Georg; Bianchi, Gerolamo (RMD Open, 2015)
This review summarises recent evidence about the interaction between bone, the immune system and cartilage in disabling conditions such as osteoarthritis, rheumatoid arthritis and spondyloarthritis. These topics have been recently discussed at the 'OsteoRheumatology' conference held in Genoa in October 2014. The meeting, at its 10th edition, has been conceived to bring together distinguished international experts in the fields of rheumatic and metabolic bone diseases with the aim of discussing emerging knowledge regarding the role of the bone tissue in rheumatic diseases. Moreover, this review focuses on new treatments based on underlying the pathophysiological processes in rheumatic diseases. Although, a number of issues still remain to be clarified, it seems quite clear that in clinical practice, as well as in basic and translational research, there is a need for more knowledge of the interactions between the cartilage, the immune system and the bone. In this context, 'OsteoRheumatology' represents a potential new discipline providing a greater insight into this interplay, in order to face the multifactorial and complex issues underlying common and disabling rheumatic diseases.
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Outcomes of patients with systemic sclerosis treated with rituximab in contemporary practice: A prospective cohort study - Elhai, Muriel; Boubaya, Marouane; Distler, Oliver; Smith, Vanessa; Matucci-Cerinic, Marco; Alegre Sancho, Juan José; Truchetet, Marie Elise; Braun-Moscovici, Yolanda; Iannone, Florenzo; Novikov, Pavel I.; Lescoat, Alain; Siegert, Elise; et al. (Annals of the Rheumatic Diseases, 2019)
Objective: To assess the safety and efficacy of rituximab in systemic sclerosis (SSc) in clinical practice. Methods: We performed a prospective study including patients with SSc from the European Scleroderma Trials and Research (EUSTAR) network treated with rituximab and matched with untreated patients with SSc. The main outcomes measures were adverse events, skin fibrosis improvement, lung fibrosis worsening and steroids use among propensity score-matched patients treated or not with rituximab. Results: 254 patients were treated with rituximab, in 58% for lung and in 32% for skin involvement. After a median follow-up of 2 years, about 70% of the patients had no side effect. Comparison of treated patients with 9575 propensity-score matched patients showed that patients treated with rituximab were more likely to have skin fibrosis improvement (22.7 vs 14.03 events per 100 person-years; OR: 2.79 [1.47-5.32]; p=0.002). Treated patients did not have significantly different rates of decrease in forced vital capacity (FVC)>10% (OR: 1.03 [0.55-1.94]; p=0.93) nor in carbon monoxide diffusing capacity (DLCO) decrease. Patients having received rituximab were more prone to stop or decrease steroids (OR: 2.34 [1.56-3.53], p<0.0001). Patients treated concomitantly with mycophenolate mofetil had a trend for better outcomes as compared with patients receiving rituximab alone (delta FVC: 5.22 [0.83-9.62]; p=0.019 as compared with controls vs 3 [0.66-5.35]; p=0.012). Conclusion: Rituximab use was associated with a good safety profile in this large SSc-cohort. Significant change was observed on skin fibrosis, but not on lung. However, the limitation is the observational design. The potential stabilisation of lung fibrosis by rituximab has to be addressed by a randomised trial.
CRIS-Team Scopus Importer:2019-05-02
Keywords: lung fibrosis; rituximab; skin fibrosis; systemic sclerosis

Overexpression of transmembrane TNF drives development of ectopic lymphoid structures in the bone marrow and B cell lineage alterations in experimental spondyloarthritis - Kaaij, Merlijn H.; Rip, Jasper; Jeucken, Kim C.M.; Kan, Yik Y.; van Rooijen, Charlotte C.N.; Saris, Job; Pots, Desiree; Frey, Silke; Grootjans, Joep; Schett, Georg; van Duivenvoorde, Leonie M.; Nolte, Martijn A.; et al. (Journal of Immunology, 2021)
TNF is important in immune-mediated inflammatory diseases, including spondyloarthritis (SpA). Transgenic (tg) mice overexpressing transmembrane TNF (tmTNF) develop features resembling human SpA. Furthermore, both tmTNF tg mice and SpA patients develop ectopic lymphoid aggregates, but it is unclear whether these contribute to pathology. Therefore, we characterized the lymphoid aggregates in detail and studied potential alterations in the B and T cell lineage in tmTNF tg mice. Lymphoid aggregates developed in bone marrow (BM) of vertebrae and near the ankle joints prior to the first SpA features and displayed characteristics of ectopic lymphoid structures (ELS) including presence of B cells, T cells, germinal centers, and high endothelial venules. Detailed flow cytometric analyses demonstrated more germinal center B cells with increased CD80 and CD86 expression, along with significantly more T follicular helper, T follicular regulatory, and T regulatory cells in tmTNF tg BM compared with non-tg controls. Furthermore, tmTNF tg mice exhibited increased IgA serum levels and significantly more IgA+ plasma cells in the BM, whereas IgA+ plasma cells in the gut were not significantly increased. In tmTNF tg 3 TNF-RI2/2 mice, ELS were absent, consistent with reduced disease symptoms, whereas in tmTNF tg 3 TNF-RII2/2 mice, ELS and clinical symptoms were still present. Collectively, these data show that tmTNF overexpression in mice results in osteitis and ELS formation in BM, which may account for the increased serum IgA levels that are also observed in human SpA. These effects are mainly dependent on TNF-RI signaling and may underlie important aspects of SpA pathology.
CRIS-Team Scopus Importer:2021-11-12

Oxidative Burst-Dependent NETosis Is Implicated in the Resolution of Necrosis-Associated Sterile Inflammation - Biermann, Mona H. C.; Podolska, Malgorzata; Knopf, Jasmin; Reinwald, Christiane; Weidner, Daniela; Maueröder, Christian; Hahn, Jonas; Kienhoefer, Deborah; Barras, Alexandre; Boukherroub, Rabah; Szunerits, Sabine; Bilyy, Rostyslav; et al. (Frontiers in Immunology, 2016)
Necrosis is associated with a profound inflammatory response. The regulation of necrosis-associated inflammation, particularly the mechanisms responsible for resolution of inflammation is incompletely characterized. Nanoparticles are known to induce plasma membrane damage and necrosis followed by sterile inflammation. We observed that injection of metabolically inert nanodiamonds resulted in paw edema in WT and Ncf1** mice. However, while inflammation quickly resolved in WT mice, it persisted over several weeks in Ncf1** mice indicating failure of resolution of inflammation. Mechanistically, NOX2-dependent reactive oxygen species (ROS) production and formation of neutrophil extracellular traps were essential for the resolution of necrosis-induced inflammation: hence, by evaluating the fate of the particles at the site of inflammation, we observed that Ncf1** mice deficient in NADPH-dependent ROS failed to generate granulation tissue therefore being unable to trap the nanodiamonds. These data suggest that NOX2-dependent NETosis is crucial for preventing the chronification of the inflammatory response to tissue necrosis by forming NETosis-dependent barriers between the necrotic and healthy surrounding tissue.
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Palmar fasciitis and polyarthritis syndrome-Systematic literature review of 100 cases - Manger, Bernhard; Schett, Georg (Seminars in Arthritis and Rheumatism, 2014)
To analyse clinical, laboratory, and imaging characteristics of all patients with palmar fasciitis and polyarthritis syndrome (PFPAS) described in the literature.Comparison of the clinical presentation of one patient with acute onset of PFAPS with 99 other published cases identified through a PubMed literature research.Since the original description in 1982 by Medsger et al., there have been numerous case reports and small case series in the literature. In total, 73 articles in English, French and Spanish language were included in the analysis. PFPAS is a rare but characteristic paraneoplastic syndrome in rheumatology. Its distinct clinical feature is a painful swelling of both the hands caused by an inflammation of the palmar fascia, tendon sheaths and small joints of fingers and wrist, and flexion contractures develop rapidly. Since the subcutaneous tissues become indurated and hard, the illustrative term "woody hands" was coined. The most frequent underlying malignancy is ovarian cancer but adenocarcinomas of the breast, gastrointestinal tract and other organs can also cause this syndrome. A helpful diagnostic procedure in order to identify the nature of the underlying malignancy in many cases has been the determination of various serum tumour markers. In cases when a complete removal of the malignancy is possible, PFPAS can also undergo complete remission.Knowledge of the distinct features of this rare paraneoplastic syndrome facilitates early diagnosis and potentially life-saving therapeutic interventions.
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Pancreatic Panniculitis and Polyarthritis - Zundler, Sebastian; Strobel, Deike; Manger, Bernhard; Neurath, Markus; Wildner, Dane (Current Rheumatology Reports, 2017)
Polyarthritis can have numerous reasons and may thus constitute a challenge for differential diagnosis. One rare potential reason for sterile polyarthritis is underlying pancreatic disease with systemic hyperlipasemia, most often accompanied by painful skin lesions caused by a subcutaneous inflammatory process known as panniculitis. Systematic evidence on pancreatic panniculitis and polyarthritis is limited, particularly regarding its feature as facultative paraneoplasia with underlying intra- or even extra-pancreatic malignancy. Therefore, we will summarize the current knowledge about this orphan disease including epidemiological, pathophysiological, diagnostic, and treatment aspects in the present review.Although direct evidence is lacking, it is highly probable that pancreatic polyarthritis and panniculitis are caused by peripheral lipolytic activity of lipase systemically circulating due to benign (e.g., acute or chronic pancreatitis) or malign (e.g., acinar cell carcinoma (ACC) or adenocarcinoma) pancreatic disease. In the latter case, pancreatic polyarthritis and panniculitis are associated with poor outcome. Pancreatic polyarthritis and panniculitis should always be included into diagnostic considerations, and once suspected, a thorough work-up to identify the underlying disease has to be performed.
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Paraneoplastic syndromes in rheumatology - Manger, Bernhard; Schett, Georg (Nature Reviews Rheumatology, 2014)
For patients that present with musculoskeletal symptoms, diagnostic procedures carried out by physicians and rheumatologists are primarily aimed at confirming or excluding the occurrence of primary rheumatic diseases. Another important trigger for musculoskeletal disease, however, is the presence of a tumour. Careful clinical investigation and knowledge of the gestalt of musculoskeletal syndromes related to respective tumour entities is of utmost importance for the diagnosis of paraneoplastic rheumatic diseases such as hypertrophic osteoarthropathy, paraneoplastic polyarthritis, RS3PE syndrome, palmar fasciitis and polyarthritis, cancer-associated myositis and tumour-induced osteomalacia. This places great responsibility on rheumatologists in diagnosing malignancies and referring the patient for effective treatment. The selective influence of tumours on musculoskeletal tissue is surprising and indicates that tumours alter tissues such as the periosteum, synovial membrane, subcutaneous connective tissue, fascia, muscles and bones by specific molecular processes. Some of the underlying mechanisms have been unravelled, providing valuable information on the physiologic and pathophysiologic roles of mediators such as vascular endothelial growth factor and fibroblast growth factor 23.
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