Fibroblast Growth Factor 9/Fibroblast Growth Factor Receptor 3 Signaling Is Upstream of Several Profibrotic Pathways and Induces Fibroblast Activation and Tissue Fibrosis in SSc - Mallano, Tatjana; Distler, Alfiya; Dees, Clara; Huang, Jingang; Distler, Oliver; Schett, Georg; Distler, Jörg; Chakraborty, Debomita (2016)
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Fibroblast growth factor receptor 3 activates a network of profibrotic signaling pathways to promote fibrosis in systemic sclerosis - Chakraborty, Debomita; Zhu, Honglin; Juengel, Astrid; Summa, Lena; Li, Yi-Nan; Matei, Alexandru-Emil; Zhou, Xiang; Huang, Jingang; Thuong Trinh-Minh,; Chen, Chih-Wei; Lafyatis, Robert; Dees, Clara; et al. (Science Translational Medicine, 2020)
Aberrant activation of fibroblasts with progressive deposition of extracellular matrix is a key feature of systemic sclerosis (SSc), a prototypical idiopathic fibrotic disease. Here, we demonstrate that the profibrotic cytokine transforming growth factor. selectively up-regulates fibroblast growth factor receptor 3 (FGFR3) and its ligand FGF9 to promote fibroblast activation and tissue fibrosis, leading to a prominent FGFR3 signature in the SSc skin. Transcriptome profiling, in silico analysis and functional experiments revealed that FGFR3 induces multiple profibrotic pathways including endothelin, interleukin-4, and connective tissue growth factor signaling mediated by transcription factor CREB (cAMP response element-binding protein). Inhibition of FGFR3 signaling by fibroblast-specific knockout of FGFR3 or FGF9 or pharmacological inhibition of FGFR3 blocked fibroblast activation and attenuated experimental skin fibrosis in mice. These findings characterize FGFR3 as an upstream regulator of a network of profibrotic mediators in SSc and as a potential target for the treatment of fibrosis.
CRIS-Team WoS Importer:2020-10-16

FIBROBLAST GROWTH FACTOR RECEPTOR 3 REGULATES THE ACTIVITY OF PROFIBROTIC CYTOKINE AND GROWTH FACTOR PATHWAYS TO DRIVE FIBROBLAST ACTIVATION AND TISSUE FIBROSIS IN SYSTEMIC SCLEROSIS - Chakraborty, Debomita; Zhu, H.; Juengel, A.; Summa, L.; Li, Y. N.; Bergmann, C.; Matei, Alexandru-Emil; Trinh-Minh, T.; Chen, Chih-Wei; Dees, Clara; Ramming, Andreas; Schett, Georg; et al. (ANNALS OF THE RHEUMATIC DISEASES, 2020)
CRIS-Team WoS Importer:2020-08-21

Fibroblast Subpopulations in Systemic Sclerosis: Functional Implications of Individual Subpopulations and Correlations with Clinical Features - Zhu, Honglin; Luo, Hui; Skaug, Brian; Tabib, Tracy; Li, Yi; Tao, Yongguang; Matei, Alexandru-Emil; Lyons, Marka A.; Schett, Georg; Lafyatis, Robert; Assassi, Shervin; Distler, Jörg (Journal of Investigative Dermatology, 2024)
Fibroblasts constitute a heterogeneous population of cells. In this study, we integrated single-cell RNA-sequencing and bulk RNA-sequencing data as well as clinical information to study the role of individual fibroblast populations in systemic sclerosis (SSc). SSc skin demonstrated an increased abundance of COMP+, COL11A1+, MYOC+, CCL19+, SFRP4/SFRP2+, and PRSS23/SFRP2+ fibroblasts signatures and decreased proportions of CXCL12+ and PI16+ fibroblast signatures in the Prospective Registry of Early Systemic Sclerosis and Genetics versus Environment in Scleroderma Outcome Study cohorts. Numerical differences were confirmed by multicolor immunofluorescence for selected fibroblast populations. COMP+, COL11A1+, SFRP4/SFRP2+, PRSS23/SFRP2+, and PI16+ fibroblasts were similarly altered between normal wound healing and patients with SSc. The proportions of profibrotic COMP+, COL11A1+, SFRP4/SFRP2+, and PRSS23/SFRP2+ and proinflammatory CCL19+ fibroblast signatures were positively correlated with clinical and histopathological parameters of skin fibrosis, whereas signatures of CXCL12+ and PI16+ fibroblasts were inversely correlated. Incorporating the proportions of COMP+, COL11A1+, SFRP4/SFRP2+, and PRSS23/SFRP2+ fibroblast signatures into machine learning models improved the classification of patients with SSc into those with progressive versus stable skin fibrosis. In summary, the profound imbalance of fibroblast subpopulations in SSc may drive the progression of skin fibrosis. Specific targeting of disease-relevant fibroblast populations may offer opportunities for the treatment of SSc and other fibrotic diseases.
CRIS-Team Scopus Importer:2024-02-16
Keywords: Dermal fibrosis; Disease outcomes; Fibroblasts; SSc; Subpopulations

FINE STRUCTURE ANALYSIS OF THE INTER-RELATION BETWEEN TOPHUS DEPOSITION AND BONE LESIONS IN GOUT USING A COMBINATION OF DUAL ENERGY AND HIGH-RESOLUTION CT - Bayat, Sara; Simon, David; Pecherstorfer, Caroline; Ellmann, Hanna; Figueiredo, C.; Englbrecht, Matthias; Hueber, A.; Kleyer, Arnd; Rech, Jürgen; Schett, Georg (ANNALS OF THE RHEUMATIC DISEASES, 2020)
CRIS-Team WoS Importer:2020-08-21

Formation of atherosclerotic lesions is independent of eosinophils in male mice - Hofheinz, Katharina; Seibert, Fabian; Ackermann, Jochen; Dietel, Barbara; Tauchi, Miyuki; Oszvar-Kozma, Maria; Kühn, Hartmut; Schett, Georg; Binder, Christoph J.; Krönke, Gerhard (Atherosclerosis, 2020)
Background and aims: Oxidation of low-density lipoprotein (LDL) and oxidized LDL-mediated activation of the innate immune system have been recognized as early key events during the pathogenesis of atherosclerosis. Recent evidence identified eosinophils as a major source of enzymatic lipid oxidation and suggested a potential role of type 2 immunity in atherogenesis. However, the involvement of individual type 2 immune cell subsets involved in this process has been incompletely defined. We therefore sought to determine the role of eosinophils during LDL oxidation and the pathogenesis of this disease. Methods: Using eosinophil-deficient dblGATA1 mice, we studied the role of eosinophils in two established mouse models of atherosclerosis. Results: These experiments revealed that the presence of eosinophils did neither affect biomarkers of LDL oxidation nor atherosclerotic lesion development. Conclusions: The obtained results show that LDL oxidation and development of atherosclerosis are largely independent of eosinophils or eosinophil-mediated LDL oxidation.
CRIS-Team Scopus Importer:2020-09-25
Keywords: Atherosclerosis; Eosinophils; Lipid oxidation

Fra1 Controls Rheumatoid Factor Autoantibody Production by Bone Marrow Plasma Cells and the Development of Autoimmune Bone Loss - Grötsch, Bettina; Lux, Anja; Rombouts, Yoann; Hoffmann, Alana; Andreev, Darja; Nimmerjahn, Falk; Xiang, Wei; Scherer, Hans Ulrich; Schett, Georg; Bozec, Aline (Journal of Bone and Mineral Research, 2019)
Next to proinflammatory cytokines, autoimmunity has been identified as a key trigger for osteoclast activation and bone loss. IgG-rheumatoid factor (IgG-RF) immune complexes, which are present in patients with rheumatoid arthritis, were shown to boost osteoclast differentiation. To date, the regulation of IgG-RF production in the absence of inflammatory triggers is unknown. Herein, we describe Fra1 as a key checkpoint that controls IgG-RF production by plasma cells and regulates autoimmune-mediated bone loss. Fra1 deficiency in B cells (Fra1ΔBcell ) led to increased IgG1-producing bone marrow plasma cells, enhanced IgG-RF production, and increased bone loss associated with elevated osteoclast numbers after immunization. The effect of IgG-RF on osteoclasts in vitro and on osteoclasts associated with bone loss in vivo was dependent on FcγR, especially FcγR3. Furthermore, immunization of WT mice with T-cell-dependent antigens induced a significant and robust decrease in Fra1 expression in bone marrow B cells, which was followed by increased IgG1 production and the induction of osteoclast-mediated bone loss. Overall, these data identify Fra1 as a key mediator of IgG-RF production and autoimmune-mediated bone loss. © 2019 American Society for Bone and Mineral Research.
EVALuna2:69394

FRA-1 TRANSCRIPTION FACTOR EXPRESSION IN MACROPHAGES FOSTER INFLAMMATION DURING RHEUMATOID ARTHRITIS DEVELOPMENT - Hannemann, Nicole; Schnelzer, Anne; Jordan, Jutta; Eberhardt, Martin; Schleicher, Ulrike; Hueber, Axel; Reid, Stephen; Sonnewald, Sophia; Bäuerle, Tobias; Vera, Julio; Bogdan, Christian; Schett, Georg; et al. (2017)
EVALuna2:13497

Fra-2/AP-1 controls adipocyte differentiation and survival by regulating PPAR? and hypoxia - Luther, Julia; Ubieta Hernández, Kenia; Hannemann, Nicole; Jimenez, Maria; Garcia-Cuellar, Maria-Paz; Zech, C.; Schett, Georg; Wagner, E. F.; Bozec, Aline (Cell Death and Differentiation, 2014)
Adipocyte cell number is a crucial factor for controlling of body weight and metabolic function. The regulation of adipocyte numbers in the adult organism is not fully understood but is considered to depend on the homeostasis of cell differentiation and apoptosis. Herein, we show that targeted deletion of the activator protein (AP-1)-related transcription factor Fra-2 in adipocytes in vivo (Fra-2(?adip) mice) induces a high-turnover phenotype with increased differentiation and apoptosis of adipocytes, leading to a decrease in body weight and fat pad mass. Importantly, adipocyte cell numbers were significantly reduced in Fra-2(?adip) mice. At the molecular level, Fra-2 directly binds to the PPAR?2 promoter and represses PPAR?2 expression. Deletion of Fra-2 leads to increased PPAR?2 expression and adipocyte differentiation as well as increased adipocyte apoptosis through upregulation of hypoxia-inducible factors (HIFs). These findings suggest that Fra-2 is an important checkpoint to control adipocyte turnover. Therefore, inhibition of Fra-2 may emerge as a useful strategy to increase adipocyte turnover and to reduce adipocyte numbers and fat mass in the body.
EVALuna2:12913

Fra-2/AP-1 regulates melanoma cell metastasis by downregulating Fam212b - Chen, Guang Liang; Li, Rui; Chen, Xiao Xiang; Wang, Juan; Cao, Shan; Song, Rui; Zhao, Ming Chun; Li, Li Ming; Hannemann, Nicole; Schett, Georg; Qian, Cheng; Bozec, Aline (Cell Death and Differentiation, 2020)
Metastatic melanoma remains a challenging disease. Understanding the molecular mechanisms how melanoma becomes metastatic is therefore of interest. Herein we show that downregulation of the AP-1 transcription factor member Fra-2 in melanoma cells is associated with an aggressive melanoma phenotype in vitro and in vivo. In vitro, Fra-2 knockdown in melanoma cells promoted cell migration and invasion associated with increased Snail-1, Twist-1/2, and matrix metalloproteinase-2 (MMP-2) expression. In vivo, Fra-2 knockdown in a melanoma cell line led to increased metastasis into the lungs and liver. The increased metastatic potential of Fra-2 knockdown melanoma cells was likely due to an accelerated cell cycle transition and increased tissue angiogenesis. Using Fra-2 knockdown cell lines microarray analysis, we identified the protein Fam212b (family with sequence similarity 212 member B) as a downstream target of Fra-2. By additional knockdown of Fam212b in Fra-2 mutant cells, we mitigated the cell migration, invasion, and cell cycle transition phenotype induced by Fra-2 knockdown. Furthermore, Fam212b overexpression enhanced β-catenin pathway. Finally, Fam212b expression is correlated with increased melanoma metastasis and poor clinical outcomes in human patients. In summary, these findings reveal the Fra-2-Fam212b axis as a new pathway of melanoma metastasis, which can be in the future used as potential marker of the metastatic properties of melanoma.
CRIS-Team Scopus Importer:2020-11-20

Fra-2 Expression in Osteoblasts Regulates Systemic Inflammation and Lung Injury through Osteopontin - Luo, Yubin; Grötsch, Bettina; Hannemann, Nicole; Jimenez, Maria; Ipseiz, Natacha; Uluckan, Ozge; Lin, Nengyu; Schett, Georg; Wagner, Erwin F.; Bozec, Aline (Molecular and Cellular Biology, 2018)
Inflammatory responses require mobilization of innate immune cells from the bone marrow. The functionality of this process depends on the state of the bone marrow microenvironment. We therefore hypothesized that molecular changes in osteoblasts, which are essential stromal cells of the bone marrow microenvironment, influence the inflammatory response. Here, we show that osteoblast-specific expression of the AP-1 transcription factor Fra-2 (Fra-2Ob-tet) induced a systemic inflammatory state with infiltration of neutrophils and proinflammatory macrophages into the spleen and liver as well as increased levels of proinflammatory cytokines, such as interleukin-1β (IL-1β), IL-6, and granulocyte-macrophage colony-stimulating factor (GM-CSF). By in vivo inhibition of osteopontin (OPN) in Fra-2Ob-tet mice, we demonstrated that this process was dependent on OPN expression, which mediates alterations of the bone marrow niche. OPN expression was transcriptionally enhanced by Fra-2 and stimulated mesenchymal stem cell (MSC) expansion. Furthermore, in a murine lung injury model, Fra-2Ob-tet mice showed increased inflammatory responses and more severe disease features via an enhanced and sustained inflammatory response to lipopolysaccharide (LPS). Our findings demonstrate for the first time that molecular changes in osteoblasts influence the susceptibility to inflammation by altering evasion of innate immune cells from the bone marrow space.
EVALuna2:34665
Keywords: Fra-2/AP-1; osteopontin; bone niche; systemic inflammation; lung injury; Fra-2; osteoblasts

Fra-2 regulates B cell development by enhancing IRF4 and Foxo1 transcription - Ubieta, Kenia; Garcia, Mireia; Groetsch, Bettina; Uebe, Steffen; Stein, Merle; Ekici, Arif Bülent; Schett, Georg; Mielenz, Dirk; Bozec, Aline; Weber, Georg (Journal of Experimental Medicine, 2017)
The role of AP-1 transcription factors in early B cell development and function is still incompletely characterized. Here we address the role of Fra-2 in B cell differentiation. Deletion of Fra-2 leads to impaired B cell proliferation in the bone marrow. In addition, IL-7-stimulated pro-B cell cultures revealed a reduced differentiation from large pre-B cells to small B cells and immature B cells. Gene profiling and chromatin immunoprecipitation sequencing analyses unraveled a transcriptional reduction of the transcription factors Foxo1, Irf4, Ikaros, and Aiolos in Fra-2-deficient B cells. Moreover, expression of IL7R? and Rag 1/2, downstream targets of Irf4 and Foxo1, were also reduced in the absence of Fra-2. Pro-B cell proliferation and small pre-B cell differentiation were fully rescued by expression of Foxo1 and Irf4 in Fra-2-deficient pro-B cells. Hence, Fra-2 is a key upstream regulator of Foxo1 and Irf4 expression and influences proliferation and differentiation of B cells at multiple stages.
EVALuna2:9366

From 3D Printed Bones to Arthritis Patients - Arthro-Haptic Experience Supporting Disease Awareness - Kleyer, Arnd; Beyer, Laura; Simon, Christoph; Stemmler, Fabian; Rech, Jürgen; Englbrecht, Matthias; Manger, Bernhard; Kroenke, Gerhard; Schett, Georg; Hueber, Axel (2016)
EVALuna2:34456

Frontline Science: Aggregated neutrophil extracellular traps prevent inflammation on the neutrophil-rich ocular surface - Mahajan, Aparna; Grüneboom, Anika; Petru, Lenka; Podolska, Malgorzata; Kling, Lasse; Maueröder, Christian; Dahms, Florian; Christiansen, Silke; Günter, Lochnit; Krenn, Veit; Jünemann, Anselm; Bock, Felix; et al. (Journal of Leukocyte Biology, 2019)
Eye rheum is a physiological discharge, which accumulates at the medial angle of the healthy eye soon after opening in the morning. Microscopic evaluation of eye rheum revealed the presence of viable neutrophils, bacteria, epithelial cells, and particles, aggregated by neutrophil extracellular traps. We observed that in the evening, during eye closure, high C5a recruited neutrophils to the tear film and activated them. In this hypoxic area rich in CO 2 , neutrophils fight microbial aggressors by degranulation. Immediately after eye opening, the microenvironment of the ocular surface changes, the milieu gets normoxic, and loss of CO 2 induces subtle alkalinization of tear film. These conditions favored the formation of neutrophil extracellular traps (NETs) that initially covers the ocular surface and tend to aggregate by eyelid blinking. These aggregated neutrophil extracellular traps (aggNETs) are known as eye rheum and contain several viable neutrophils, epithelial cells, dust particles, and crystals packed together by NETs. Similar to aggNETs induced by monosodium urate crystals, the eye rheum shows a robust proteolytic activity that degraded inflammatory mediators before clinically overt inflammation occur. Finally, the eye rheum passively floats with the tear flow to the medial angle of the eye for disposal. We conclude that the aggNETs-based eye rheum promotes cleaning of the ocular surface and ameliorates the inflammation on the neutrophil-rich ocular surfaces.
CRIS-Team Scopus Importer:2019-05-02
Keywords: degranulation; eye rheum; inflammation; NETs; neutrophils; resolution; serine protease

Full Length Interleukin 33 Aggravates Radiation-Induced Skin Reaction - Kurow, Olga; Frey, Benjamin; Schuster, Louis; Schmitt, Verena; Adam, Susanne; Hahn, Madelaine; Gilchrist, Derek; Mcinnes, Iain B.; Wirtz, Stefan; Gaipl, Udo; Krönke, Gerhard; Schett, Georg; et al. (Frontiers in Immunology, 2017)
The interleukin (IL)-1 family member IL-33 has been described as intracellular alarmin with broad roles in wound healing, skin inflammation but also autoimmunity. Its dichotomy between full length (fl) IL-33 and the mature (m) form of IL-33 and its release by necrosis is still not fully understood. Here, we compare functional consequences of both forms in the skin in vivo, and therefore generated two lines of transgenic mice which selectively overexpress mmIL-33 and flmIL-33 in basal keratinocytes. Transgene mRNA was expressed at high level in skin of both lines but not in organs due to the specific K14 promoter. We could demonstrate that transgenic overexpression of mmIL-33 in murine keratinocytes leads to a spontaneous skin inflammation as opposed to flmIL-33. K14-mmIL-33 mice synthesize and secrete high amounts of mmIL-33 along with massive cutaneous manifestations, like increased epidermis and dermis thickness, infiltration of mast cells in the epidermis and dermis layers and marked hyperkeratosis. Using skin inflammation models such as IL-23 administration, imiquimod treatment, or mechanical irritation did not lead to exacerbated inflammation in the K14-flmIL-33 strain. As radiation induces a strong dermatitis due to apoptosis and necrosis, we determined the effect of fractionated radiation (12 Gy, 4 times). In comparison to wild-type mice, an increase in ear thickness in flmIL-33 transgenic mice was observed 25 days after irradiation. Macroscopic examination showed more severe skin symptoms in irradiated ears compared to controls. In summary, secreted mmIL-33 itself has a potent capacity in skin inflammation whereas fl IL-33 is limited due to its intracellular retention. During tissue damage, fl IL-33 exacerbated radiation-induced skin reaction.
EVALuna2:13432

Fully Human Anti-CD19 CAR T Cells Derived from Systemic Lupus Erythematosus Patients Exhibit Cytotoxicity with Reduced Inflammatory Cytokine Production - Dingfelder, Janin; Aigner, Michael; Taubmann, Jule; Minopoulou, Ioanna; Park, Soo; Kaplan, Charles D.; Cheng, Joseph K.; Van Blarcom, Tom; Schett, Georg; Mackensen, Andreas; Lutzny-Geier, Gloria (Transplantation and Cellular Therapy, 2024)
KYV-101 is an autologous anti-CD19 chimeric antigen receptor (CAR)-T cell therapy under investigation for patients with B-cell driven autoimmune diseases. Hu19-CD828Z is a fully human anti-CD19 CAR designed and demonstrated to have a favorable clinical safety profile. Since anti-CD19 CAR T cells target and kill B cells in both circulation and tissues, the treatment with Hu19-CD828Z CAR T cells offers great potential in depleting autoreactive B cells. Demonstrate that Hu19-CD828Z CAR T cells manufactured from cryopreserved leukaphereses from patients with systemic lupus erythematosus (SLE) exhibit CAR-mediated and CD19-dependent cytokine release, proliferation and cytotoxicity when co-cultured with autologous primary B cells. T cells were enriched from cryopreserved leukaphereses from SLE patients or healthy donors (HD). CAR T cells were generated by transducing these cells with a lentiviral vector encoding Hu19-CD828Z. CAR-mediated and CD19-dependent activity was monitored in vitro in a set of cytotoxicity, cytokine release, and proliferation studies, in response to autologous primary CD19+ B cells, a CD19+ cell line (NALM-6), or a CD19− cell line (U937). Hu19-CD828Z CAR T cells produced from SLE patients or HD induced greater proliferation and dose-dependent cytotoxicity against both autologous primary B cells and the CD19+ NALM-6 cells than nontransduced control T cells or co-cultures with a CD19− cell line. Interestingly, there was lower inflammatory cytokine production from SLE patient-derived CAR T cells compared to HD donor-derived CAR T cells with either CD19+ cells or primary B cells. Hu19-CD828Z CAR T cells generated from SLE patient lymphocytes demonstrate CAR-mediated and CD19-dependent activity against autologous primary B cells with reduced inflammatory cytokine production supporting KYV-101 as a novel potential therapy for the depletion of pathogenic B cells in SLE patients.
CRIS-Team Scopus Importer:2024-04-19
Keywords: Chimeric antigen receptor; Cytokines; Systemic Lupus Erythematosus

Ga-68-FAPI-04 PET/CT for molecular assessment of fibroblast activation and risk evaluation in systemic sclerosis-related interstitial lung disease - Schmidkonz, Christian; Distler, Jörg; Treutlein, Christoph; Atzinger, Armin; Prante, Olaf; Ritt, Philipp; Goetz, T.; Bäuerle, Tobias; Cordes, Michael; Köhner, Markus; Kuwert, Torsten; Ramming, Andreas; et al. (European Journal of Nuclear Medicine and Molecular Imaging, 2021)
CRIS-Team WoS Importer:2022-01-07

gagCEST imaging at 3 T MRI in patients with articular cartilage lesions of the knee and intraoperative validation - Söllner, Stefan; Welsch, G. H.; Gelse, Kolja; Goldmann, A.; Kleyer, Arnd; Schett, Georg; Pachowsky, Milena (Osteoarthritis and Cartilage, 2021)
Objective: The aim of this study was to compare glycosaminoglycan chemical exchange saturation transfer (gagCEST) of knee cartilage with intraoperative results for the assessment of early osteoarthritis (OA) and to define gagCEST values for the differentiation between healthy and degenerated cartilage. Design: Twenty-one patients with cartilage lesions or moderate OA were examined using 3 T Magnetic Resonance Imaging (MRI). In this prospective study, regions of interest (ROIs) were examined by a sagittal gagCEST analysis and a morphological high-resolution three-dimensional, fat-saturated proton-density space sequence. Cartilage lesions were identified arthroscopically, graded by the International Cartilage Repair Society (ICRS) score in 42 defined ROIs per patient and consecutively compared with mean gagCEST values using analysis of variance and Spearman's rank correlation test. Receiver operating characteristics (ROC) curves were applied to identify gagCEST threshold values to differentiate between the ICRS grades. Results: A total of 882 ROIs were examined and graduated in ICRS score 0 (67.3%), 1 (25.2%), 2 (6.2%) and the merged ICRS 3 and 4 (1.0%). gagCEST values decreased with increasing grade of cartilage damage with a negative correlation between gagCEST values and ICRS scores. A gagCEST value threshold of 3.55% was identified to differentiate between ICRS score 0 (normal) and all other grades. Conclusions: gagCEST reflects the content of glycosaminoglycan and might provide a diagnostic tool for the detection of early knee-joint cartilage damage and for the non-invasive subtle differentiation between ICRS grades by MRI even at early stages in clinical practice.
CRIS-Team Scopus Importer:2021-06-04
Keywords: Cartilage; Chemical exchange saturation transfer; MRI; Osteoarthritis

Galectin-3 as a novel regulator of osteoblast-osteoclast interaction and bone homeostasis - Simon, Dominic; Derer, Anja; Andes, Fabian T.; Lezuo, Patrick; Bozec, Aline; Schett, Georg; Herrmann, Martin; Harre, Ulrike (Bone, 2017)
Bone tissue undergoes permanent and lifelong remodeling with a concerted action of bone-building osteoblasts and bone-resorbing osteoclasts. A precise cooperation between those two cell types is critical in the complex process of bone renewal. Galectin-3 is a member of the ?-galactoside-binding lectin family playing multiple roles in cell growth, differentiation and aggregation. As it has been described to be expressed in bone, galectin-3 might influence bone homeostasis by regulating the function and/or interplay of osteoblasts and osteoclasts. Here, we investigated the role of galectin-3 in osteoclastogenesis and osteoblast-osteoclast interactions. Bone histomorphometric analysis and ?CT measurements revealed a decreased trabecular bone volume and an increased osteoclast number in 12weeks old male galectin-3 knockout mice compared to wildtype littermates. Galectin-3 deficient bone marrow cells displayed a higher osteoclastogenic capacity in ex vivo differentiation assays, associated with elevated TRAF6 mRNA levels, suggesting an intrinsic inhibition of osteoclastogenesis by galectin-3 interfering with RANKL-mediated signaling. Furthermore, the addition of extracellular galectin-3 to murine or human osteoclastogenesis assays inhibited osteoclast formation and osteoclast numbers were higher in co-culture assays with galectin-3 deficient osteoblasts. In conclusion, our data suggest the secretion of galectin-3 as a novel mechanism for osteoblasts to control osteoclastogenesis and to maintain trabecular bone homeostasis independently of the RANKL/OPG-axis.
EVALuna2:13345

Gender- and site-specific differences of colorectal neoplasia relate to vitamin D - Aigner, E.; Stadlmayr, A.; Huber-Schoenauer, U.; Zwerina, J.; Husar-Memmer, E.; Niederseer, D.; Trauner, M.; Heuberger, A.; Hohla, F.; Schett, Georg; Patsch, W.; Datz, C. (Alimentary Pharmacology & Therapeutics, 2014)
The effect of vitamin D on colorectal adenomas may vary with regard to gender, localisation and histological type of the lesion.To define the role of vitamin D and gender in a Caucasian cohort of subjects undergoing screening colonoscopy after consideration of established risk factors.One thousand five hundred and thirty-two subjects (813 males, 58.8 ± 9.7 years; 719 females, 59.7 ± 10.7 years) were allocated to tertiles of 25-hydroxyvitamin D3 [25(OH)D3 ] serum concentrations. The number, localisation, size and histology of the detected colonic lesions were recorded.Among men, no association was found between vitamin D and the total number, size and histological stage of adenomas at any site. In female subjects, less women with adenomas were found in the highest vitamin D tertile (N = 42/239; 17.2%) as compared to the low vitamin D group (N = 60/240; 25.0%; P = 0.035). In particular, the number of women with adenomas in the proximal colon was significantly lower in the highest tertile (N = 21/239, 8.8%) compared to the low vitamin D group (N = 41/240; 17.1%; P = 0.007). The rates at other sites were not different. The inverse association of vitamin D serum concentrations with the presence of adenomas in the proximal colon was maintained after adjustment for potential confounders. In 80 women on vitamin D supplementation, the rate of adenomas was lower compared to those not on supplementation (3/80; 3.8%; vs. 90/719; 12.5%; P = 0.016).A potential preventive effect of vitamin D on colorectal adenomas was found in the proximal colon in women. This observation is supported by further decrease of lesions in the proximal colon of women on vitamin D supplementation.
EVALuna2:13058

GENDER DIFFERENCES IN PSA OUTCOME PARAMETERS AND THEIR CORRELATION WITH SKIN INVOLVEMENT: A CROSS-SECTIONAL ANALYSIS OF RABBIT-SPA PATIENTS - Regierer, A.; Weiss, A.; Behrens, F.; Feuchtenberger, M.; Schett, Georg; Baraliakos, X.; Zink, A.; Strangfeld, A. (ANNALS OF THE RHEUMATIC DISEASES, 2020)
CRIS-Team WoS Importer:2020-08-21

Gender equity in academic rheumatology, current status and potential for improvement: a cross-sectional study to inform an EULAR task force - Ovseiko, Pavel; Gossec, Laure; Andreoli, Laura; Kiltz, Uta; Van Mens, Leonieke; Hassan, Neelam; Van Der Leeden, Marike; Siddle, Heidi J.; Alunno, Alessia; Mcinnes, Iain B.; Damjanov, Nemanja S.; Apparailly, Florence; et al. (RMD Open, 2022)
Objectives Evidence on the current status of gender equity in academic rheumatology in Europe and potential for its improvement is limited. The EULAR convened a task force to obtain empirical evidence on the potential unmet need for support of female rheumatologists, health professionals and non-clinical scientists in academic rheumatology. Methods This cross-sectional study comprised three web-based surveys conducted in 2020 among: (1) EULAR scientific member society leaders, (2) EULAR and Emerging EULAR Network (EMEUNET) members and (3) EULAR Council members. Statistics were descriptive with significance testing for male/female responses assessed by chi(2) test and t-test. Results Data from EULAR scientific member societies in 13 countries indicated that there were disproportionately fewer women in academic rheumatology than in clinical rheumatology, and they tended to be under-represented in senior academic roles. From 324 responses of EULAR and EMEUNET members (24 countries), we detected no gender differences in leadership aspirations, self-efficacy in career advancement and work-life integration as well as the share of time spent on research, but there were gender differences in working hours and the levels of perceived gender discrimination and sexual harassment. There were gender differences in the ranking of 7 of 26 factors impacting career advancement and of 8 of 24 potential interventions to aid career advancement. Conclusions There are gender differences in career advancement in academic rheumatology. The study informs a EULAR task force developing a framework of potential interventions to accelerate gender-equitable career advancement in academic rheumatology.
CRIS-Team WoS Importer:2022-08-26

Generation and Analysis of Human and Murine Osteoclasts - Steffen, Ulrike; Andes, Fabian T.; Schett, Georg (Current Protocols in Immunology, 2019)
Osteoclasts are the only bone-resorbing cells in the body. Together with bone-forming osteoblasts, they are responsible for bone homeostasis and constant bone remodeling. Aberrant activation of osteoclasts leads to bone loss, as seen in postmenopausal osteoporosis or in autoimmune diseases like rheumatoid arthritis. Although much research has been performed to understand and prevent osteoclast-mediated bone loss, the mechanisms of osteoclast hyperactivation are not completely understood. This unit describes several protocols for ex vivo generation of murine and human osteoclasts, allowing study of the effects of specific cells, cytokines, or chemical substances on osteoclast formation and activity without the need for expensive and time-consuming animal experiments. In addition, we provide protocols for specific staining of osteoclasts and for analysis of resorption activity using calcium phosphate–coated surfaces or bone slices. © 2019 by John Wiley & Sons, Inc.
CRIS-Team Scopus Importer:2019-06-21
Keywords: bone marrow; osteoclast generation; PBMC; resorption; TRAP staining

Genetic Analysis of MPO Variants in Four Psoriasis Subtypes in Patients from Germany - Haskamp, Stefan; Horowitz, Joseph; Oji, Vinzenz; Philipp, Sandra; Sticherling, Michael; Schäkel, Knut; Schuhmann, Sarah; Prinz, Jörg C.; Burkhardt, Harald; Behrens, Frank; Böhm, Beate; Köhm, Michaela; et al. (Journal of Investigative Dermatology, 2021)
CRIS-Team Scopus Importer:2021-03-26

Genome-wide association meta-analysis in Chinese and European individuals identifies ten new loci associated with systemic lupus erythematosus - Morris, David L.; Sheng, Yujun; Zhang, Yan; Wang, Yong-Fei; Zhu, Zhengwei; Tombleson, Philip; Chen, Lingyan; Graham, Deborah S. Cunninghame; Bentham, James; Roberts, Amy L.; Chen, Ruoyan; Zuo, Xianbo; et al. (Nature Genetics, 2016)
Systemic lupus erythematosus (SLE; OMIM 152700) is a genetically complex autoimmune disease. Genome-wide association studies (GWASs) have identified more than 50 loci as robustly associated with the disease in single ancestries, but genome-wide transancestral studies have not been conducted. We combined three GWAS data sets from Chinese (1,659 cases and 3,398 controls) and European (4,036 cases and 6,959 controls) populations. A meta-analysis of these studies showed that over half of the published SLE genetic associations are present in both populations. A replication study in Chinese (3,043 cases and 5,074 controls) and European (2,643 cases and 9,032 controls) subjects found ten previously unreported SLE loci. Our study provides further evidence that the majority of genetic risk polymorphisms for SLE are contained within the same regions across both populations. Furthermore, a comparison of risk allele frequencies and genetic risk scores suggested that the increased prevalence of SLE in non-Europeans (including Asians) has a genetic basis.
EVALuna2:13300

Genome-wide association study of eosinophilic granulomatosis with polyangiitis reveals genomic loci stratified by ANCA status - Lyons, Paul A.; Peters, James E.; Alberici, Federico; Liley, James; Coulson, Richard M.R.; Astle, William; Baldini, Chiara; Bonatti, Francesco; Cid, Maria C.; Elding, Heather; Emmi, Giacomo; Epplen, Jörg; et al. (Nature Communications, 2019)
Eosinophilic granulomatosis with polyangiitis (EGPA) is a rare inflammatory disease of unknown cause. 30% of patients have anti-neutrophil cytoplasmic antibodies (ANCA) specific for myeloperoxidase (MPO). Here, we describe a genome-wide association study in 676 EGPA cases and 6809 controls, that identifies 4 EGPA-associated loci through conventional case-control analysis, and 4 additional associations through a conditional false discovery rate approach. Many variants are also associated with asthma and six are associated with eosinophil count in the general population. Through Mendelian randomisation, we show that a primary tendency to eosinophilia contributes to EGPA susceptibility. Stratification by ANCA reveals that EGPA comprises two genetically and clinically distinct syndromes. MPO+ ANCA EGPA is an eosinophilic autoimmune disease sharing certain clinical features and an HLA-DQ association with MPO+ ANCA-associated vasculitis, while ANCA-negative EGPA may instead have a mucosal/barrier dysfunction origin. Four candidate genes are targets of therapies in development, supporting their exploration in EGPA.
CRIS-Team Scopus Importer:2019-11-22

Glucocorticoid Doses and Acute-Phase Reactants at Giant Cell Arteritis Flare in a Randomized Trial of Tocilizumab - Stone, John H.; Tuckwell, Katie; Dimonaco, Sophie; Klearman, Micki; Aringer, Martin; Blockmans, Daniel; Brouwer, Elisabeth; Cid, Maria C.; Dasgupta, Bhaskar; Rech, Jürgen; Salvarani, Carlo; Schulze-Koops, Hendrik; et al. (Arthritis and Rheumatology, 2019)
OBJECTIVE: To evaluate glucocorticoid doses and serological findings in patients with giant cell arteritis (GCA) flares. METHODS: Patients with GCA were randomly assigned to receive double-blind dosing with subcutaneous tocilizumab (TCZ) 162 mg weekly plus 26-week prednisone (TCZ-QW+Pred-26), every-other-week TCZ plus 26-week prednisone (TCZ-Q2W+Pred-26), placebo plus 26-week prednisone (PBO+Pred-26), or placebo plus 52-week prednisone (PBO+Pred-52). Outcomes were prednisone dose, C-reactive protein (CRP) level, and erythrocyte sedimentation rate (ESR) at the time of flare and remission during 52 weeks. RESULTS: One hundred patients received TCZ-QW+Pred-26, 49 received TCZ-Q2W+Pred-26, 50 received PBO+Pred-26, and 51 received PBO+Pred-52. Among 149 TCZ-treated patients, 36 (24%) experienced flare, 23 (64%) of whom were still receiving prednisone (median dose, 2.0 mg/day). Among 101 PBO+Pred-treated patients, 59 (58%) experienced flare, 45 (76%) of whom were receiving prednisone (median dose, 5.0 mg/day). Many flares occurred while patients were taking more than 10 mg/day prednisone: 9 (25%) in the TCZ groups and 13 (22.0%) in the placebo groups. Thirty-three flares (92%) in TCZ-treated groups and 20 (34%) in PBO+Pred-treated groups occurred with normal CRP. More than half the PBO+Pred-treated patients had elevated CRP without flare. Benefits of the combination of TCZ plus prednisone over prednisone alone for remission induction were apparent by 8 weeks. CONCLUSION: Most GCA flares occurred while patients were still receiving prednisone. Acute-phase reactants were not reliable indicators of flare in patients treated with TCZ plus prednisone or with prednisone alone. The addition of TCZ to prednisone facilitates earlier GCA control. This article is protected by copyright. All rights reserved.
EVALuna2:69393

Glucocorticoid-induced relapse of COVID-19 in a patient with sarcoidosis - Györfi, Andrea-Hermina; Kopp, Markus; May, Matthias; Vetter, Marcel; Uder, Michael; Kremer, Andreas; Schett, Georg; Harrer, Thomas; Distler, Jörg (Annals of the Rheumatic Diseases, 2020)
CRIS-Team Scopus Importer:2020-11-20

Glycosylation of immunoglobulin G determines osteoclast differentiation and bone loss. - Harre, Ulrike; Lang, Stefanie; Pfeifle, René; Rombouts, Yoann; Frühbeißer, Sabine; Amara, Khaled; Bang, Holger; Lux, Anja; Koeleman, Carolien A.; Baum, Wolfgang; Dietel, Katharina; Gröhn, Franziska; et al. (Nature Communications, 2015)
Immunglobulin G (IgG) sialylation represents a key checkpoint that determines the engagement of pro- or anti-inflammatory Fcγ receptors (FcγR) and the direction of the immune response. Whether IgG sialylation influences osteoclast differentiation and subsequently bone architecture has not been determined yet, but may represent an important link between immune activation and bone loss. Here we demonstrate that desialylated, but not sialylated, immune complexes enhance osteoclastogenesis in vitro and in vivo. Furthermore, we find that the Fc sialylation state of random IgG and specific IgG autoantibodies determines bone architecture in patients with rheumatoid arthritis. In accordance with these findings, mice treated with the sialic acid precursor N-acetylmannosamine (ManNAc), which results in increased IgG sialylation, are less susceptible to inflammatory bone loss. Taken together, our findings provide a novel mechanism by which immune responses influence the human skeleton and an innovative treatment approach to inhibit immune-mediated bone los

Gout, hyperuricaemia and crystal-associated disease network (G-CAN) consensus statement regarding labels and definitions of disease states of gout - Bursill, David; Taylor, William J.; Terkeltaub, Robert; Abhishek, Abhishek; So, Alexander K.; Vargas-Santos, Ana Beatriz; Gaffo, Angelo Lino; Rosenthal, Ann; Tausche, Anne Kathrin; Reginato, Anthony; Manger, Bernhard; Sciré, Carlo; et al. (Annals of the Rheumatic Diseases, 2019)
Objective: There is a lack of standardisation in the terminology used to describe gout. The aim of this project was to develop a consensus statement describing the recommended nomenclature for disease states of gout. Methods: A content analysis of gout-related articles from rheumatology and general internal medicine journals published over a 5-year period identified potential disease states and the labels commonly assigned to them. Based on these findings, experts in gout were invited to participate in a Delphi exercise and face-to-face consensus meeting to reach agreement on disease state labels and definitions. Results: The content analysis identified 13 unique disease states and a total of 63 unique labels. The Delphi exercise (n=76 respondents) and face-to-face meeting (n=35 attendees) established consensus agreement for eight disease state labels and definitions. The agreed labels were as follows: 'asymptomatic hyperuricaemia', ' asymptomatic monosodium urate crystal deposition', ' asymptomatic hyperuricaemia with monosodium urate crystal deposition', ' gout', ' tophaceous gout', ' erosive gout', ' first gout flare' and ' recurrent gout flares'. There was consensus agreement that the label ' gout' should be restricted to current or prior clinically evident disease caused by monosodium urate crystal deposition (gout flare, chronic gouty arthritis or subcutaneous tophus). Conclusion: Consensus agreement has been established for the labels and definitions of eight gout disease states, including ' gout' itself. The Gout, Hyperuricaemia and Crystal-Associated Disease Network recommends the use of these labels when describing disease states of gout in research and clinical practice.
CRIS-Team Scopus Importer:2019-09-24
Keywords: gout; hyperuricemia; language; monosodium urate crystals; nomenclature; terminology; urate

Gout mimicking rheumatoid arthritis - Petsch, Christina; Guilhon de Araujo, Elizabeth; Hueber, Axel; Schett, Georg; Manger, Bernhard; Rech, Jürgen (Seminars in Arthritis and Rheumatism, 2017)
EVALuna2:13107

Group 2 Innate Lymphoid Cells Attenuate Inflammatory Arthritis and Protect from Bone Destruction in Mice - Omata, Yasunori; Frech, Michael; Primbs, Tatjana; Lucas, Sebastien; Andreev, Darja; Scholtysek, Carina; Sarter-Zaiss, Kerstin; Kindermann, Markus; Yeremenko, Nataliya; Baeten, Dominique L.; Andreas, Nico; Kamradt, Thomas; et al. (Cell Reports, 2018)
Group 2 innate lymphoid cells (ILC2s) were detected in the peripheral blood and the joints of rheumatoid arthritis (RA) patients, serum-induced arthritis (SIA), and collagen-induced arthritis (CIA) using flow cytometry. Circulating ILC2s were significantly increased in RA patients compared with healthy controls and inversely correlated with disease activity. Induction of arthritis in mice led to a fast increase in ILC2 number. To elucidate the role of ILC2 in arthritis, loss- and gain-of-function mouse models for ILC2 were subjected to arthritis. Reduction of ILC2 numbers in RORαcre/GATA3fl/fl and Tie2cre/RORαfl/fl mice significantly exacerbated arthritis. Increasing ILC2 numbers in mice by IL-25/IL-33 mini-circles or IL-2/IL-2 antibody complex and the adoptive transfer of wild-type (WT) ILC2s significantly attenuated arthritis by affecting the initiation phase. In addition, adoptive transfer of IL-4/13-competent WT but not IL-4/13-/- ILC2s and decreased cytokine secretion by macrophages. These data show that ILC2s have immune-regulatory functions in arthritis.
EVALuna2:34467

Guselkumab, a Selective Interleukin-23 p19 Subunit Inhibitor, Resolves Dactylitis in Patients With Active Psoriatic Arthritis: Pooled Results Through Week 52 From Two Phase 3 Studies - Mcgonagle, Dennis; Mcinnes, Iain B. B.; Deodhar, Atul; Schett, Georg; Shawi, May; Chakravarty, Soumya D. D.; Kollmeier, Alexa P. P.; Xu, Xie L. L.; Sheng, Shihong; Xu, Stephen; Ritchlin, Christopher T. T.; Rahman, Proton; et al. (ACR Open Rheumatology, 2023)
Objective: Previous analyses of pooled DISCOVER-1 and DISCOVER-2 data through Week 24 showed significantly higher rates of dactylitis resolution in patients treated with guselkumab compared with placebo. Here, we investigate associations between dactylitis resolution and other outcomes through 1 year. Methods: Patients were randomized 1:1:1 to receive subcutaneous injections of guselkumab 100 mg at Week 0, Week 4, and then every 4 or 8 weeks, or placebo with crossover to guselkumab at Week 24. Independent assessors determined dactylitis severity score (DSS; 0-3/digit; total = 0-60). Dactylitis resolution (DSS = 0) (prespecified) and at least 20%, at least 50%, and at least 70% DSS improvement from baseline (post hoc) were determined through Week 52 (nonresponder imputation for treatment failure through Week 24 and for missing data through Week 52). ACR50, tender/swollen joints, low disease activity (LDA) as assessed by composite indices, and radiographic progression (DISCOVER-2 only) were assessed in patients with dactylitis versus without dactylitis resolution at Week 24 and Week 52. Results: Patients with dactylitis at baseline (473 of 1118) had more severe joint and skin disease than those without dactylitis (645 of 1118). At Week 52, approximately 75% of guselkumab-randomized patients with dactylitis at baseline had complete resolution; approximately 80% had at least 70% DSS improvement. Through Week 52, new-onset dactylitis (DSS ≥1) was uncommon among patients with a DSS of 0 at baseline. Guselkumab-randomized patients with dactylitis resolution were more likely to achieve ACR50, at least 50% reduction in tender and swollen joints, and LDA at Week 24 and Week 52 than those without resolution. At Week 52, patients with dactylitis resolution had numerically less radiographic progression from baseline (DISCOVER-2). Conclusion: Through 1 year, approximately 75% of guselkumab-randomized patients had complete resolution of dactylitis; patients exhibiting resolution were more likely to achieve other important clinical outcomes. Given the high burden of dactylitis, resolution may be associated with better long-term patient outcomes.
CRIS-Team Scopus Importer:2023-03-31

GUSELKUMAB IMPROVES DACTYLITIS IN PSA PATIENTS WITH INADEQUATE RESPONSE TO TNFI: DATA FROM THE PHASE 3B COSMOS TRIAL - Marzo-Ortega, H.; Theander, E.; Neuhold, M.; Bergmans, P.; Shawi, M.; Perate, M.; Contre, C.; Mcinnes, I.; Schett, Georg (ANNALS OF THE RHEUMATIC DISEASES, 2022)
CRIS-Team WoS Importer:2022-11-04

GUSELKUMAB MAINTAINS RESOLUTION OF DACTYLITIS AND ENTHESITIS IN PATIENTS WITH ACTIVE PSORIATIC ARTHRITIS: RESULTS THROUGH 2 YEARS FROM A PHASE 3 STUDY - Rahman, P.; Mcinnes, I.; Deodhar, A.; Schett, Georg; Mease, P. J.; Shawi, M.; Cua, D.; Sherlock, J.; Kollmeier, A.; Xu, X. L.; Jiang, Y.; Sheng, S.; et al. (ANNALS OF THE RHEUMATIC DISEASES, 2022)
CRIS-Team WoS Importer:2022-11-04

Guselkumab (TREMFYA (R)) Maintains Resolution of Dactylitis and Enthesitis in Patients with Active Psoriatic Arthritis: Results Through 2 Years from a Phase 3 Study - Rahman, Proton; Mcinnes, Iain; Deodhar, Atul; Schett, Georg; Mease, Philip; Shawi, May; Cua, Daniel; Sherlock, Jonathan; Kollmeier, Alexa; Xu, Xie; Jiang, Yusang; Sheng, Shihong; et al. (ARTHRITIS & RHEUMATOLOGY, 2021)
CRIS-Team WoS Importer:2022-03-11

GUT MICROBIOME, BONE AND JOINT - Schett, Georg (OSTEOPOROSIS INTERNATIONAL, 2021)
CRIS-Team WoS Importer:2022-03-04

HAND FUNCTION IS IMPAIRED IN PATIENTS WITH RHEUMATOID ARTHRITIS, PSORIATIC ARTHRITIS, AND PSORIASIS COMPARED TO HEALTHY CONTROLS - Liphardt, Anna-Maria; Liehr, Sonja; Manger, Eva; Bieniek, Lisa; Kleyer, Arnd; Simon, David; Tascilar, Koray; Sticherling, Michael; Rech, Jürgen; Schett, Georg; Hueber, Axel (ANNALS OF THE RHEUMATIC DISEASES, 2019)
CRIS-Team WoS Importer:2019-07-12

Healthcare utilization and unmet needs of patients with antisynthetase syndrome: An international patient survey - Weiß, Marina; Holzer, M. T.; Muehlensiepen, F.; Ignatyev, Y.; Fiehn, C.; Bauhammer, J.; Schmidt, J.; Schlüter, S.; Dihkan, A.; Scheibner, D.; Schneider, U.; Valor-Mendez, L.; et al. (Rheumatology International, 2023)
Antisynthease syndrome (ASSD) is a rare, complex and understudied autoimmune disease. Internet-based studies can overcome barriers of traditional on-site research and are therefore very appealing for rare diseases. The aim of this study was to investigate patient-reported symptoms, diagnostic delay, symptoms, medical care, health status, working status, disease knowledge and willingness to participate in research of ASSD patients by conducting an international web-based survey. The multilingual questionnaire was created by an international group of rheumatologists and patients and distributed online. 236 participants from 22 countries completed the survey. 184/236 (78.0%) were female, mean age (SD) was 49.6 years (11.3) and most common antisynthetase antibody was Jo-1 (169/236, 71.6%). 79/236 (33.5%) reported to work full-time. Median diagnostic delay was one year. The most common symptom at disease onset was fatigue 159/236 (67.4%), followed by myalgia 130/236 (55.1%). The complete triad of myositis, arthritis and lung involvement verified by a clinician was present in 42/236 (17.8%) at disease onset and in 88/236 (37.3%) during the disease course. 36/236 (15.3%) reported to have been diagnosed with fibromyalgia and 40/236 (16.3%) with depression. The most reported immunosuppressive treatments were oral corticosteroids 179/236 (75.9%), followed by rituximab 85/236 (36.0%). 73/236 (30.9%) had received physiotherapy treatment. 71/236 (30.1%) reported to know useful online information sources related to ASSD. 223/236 (94.5%) were willing to share health data for research purposes once a year. Our results reiterate that internet-based research is invaluable for cooperating with patients to foster knowledge in rare diseases.
CRIS-Team Scopus Importer:2023-08-25
Keywords: Autoantibodies; Diagnosis; Health services research; Myositis; Therapeutics

Heat shock protein 90 (Hsp90) inhibition targets canonical TGF-? signalling to prevent fibrosis - Tomcik, Michal; Zerr, Pawel; Pitkowski, Jana; Palumbo-Zerr, Katrin; Avouac, Jerome; Distler, Oliver; Becvar, Radim; Senolt, Ladislav; Schett, Georg; Distler, Jörg (Annals of the Rheumatic Diseases, 2014)
Targeted therapies for systemic sclerosis (SSc) and other fibrotic diseases are not yet available. We evaluated the efficacy of heat shock protein 90 (Hsp90) inhibition as a novel approach to inhibition of aberrant transforming growth factor (TGF)-? signalling and for the treatment of fibrosis in preclinical models of SSc.Expression of Hsp90 was quantified by quantitative PCR, western blot and immunohistochemistry. The effects of Hsp90 inhibition were analysed in cultured fibroblasts, in bleomycin-induced dermal fibrosis, in tight-skin (Tsk-1) mice and in mice overexpressing a constitutively active TGF-? receptor I (T?RI).Expression of Hsp90? was increased in SSc skin and in murine models of SSc in a TGF-?-dependent manner. Inhibition of Hsp90 by 17-dimethylaminoethylamino-17-demethoxy-geldanamycin (17-DMAG) inhibited canonical TGF-? signalling and completely prevented the stimulatory effects of TGF-? on collagen synthesis and myofibroblast differentiation. Treatment with 17-DMAG decreased the activation of canonical TGF-? signalling in murine models of SSc and exerted potent antifibrotic effects in bleomycin-induced dermal fibrosis, in Tsk-1 mice and in mice overexpressing a constitutively active T?RI. Dermal thickness, number of myofibroblasts and hydroxyproline content were all significantly reduced on treatment with 17-DMAG. No toxic effects were observed with 17-DMAG at antifibrotic doses.Hsp90 is upregulated in SSc and is critical for TGF-? signalling. Pharmacological inhibition of Hsp90 effectively blocks the profibrotic effects of TGF-? in cultured fibroblasts and in different preclinical models of SSc. These results have translational implications, as several Hsp90 inhibitors are in clinical trials for other indications.
EVALuna2:12887

Herpes simplex infection in a patient with rheumatoid arthritis treated with baricitinib: a case report - Valor-Méndez, Larissa; Voskens, Caroline; Rech, Jürgen; Kleyer, Arnd; Schett, Georg (Rheumatology, 2021)
CRIS-Team Scopus Importer:2021-04-19

High Degree of Nonadherence to Disease-modifying Antirheumatic Drugs in Patients with Rheumatoid Arthritis - Rauscher, Veronika; Englbrecht, Matthias; Van Der Heijde, Desiree; Schett, Georg; Hueber, Axel (Journal of Rheumatology, 2015)
To test medication adherence using the Compliance-Questionnaire-Rheumatology (CQR).Invitation letter and CQR were sent to 240 patients with rheumatoid arthritis. Followup CQR was sent 3 months later. Adherence was evaluated using CQR 80% cutoff scores.Seventy-eight patients who were being treated with disease-modifying antirheumatic drugs provided full information on the CQR at both points in time. Eleven patients (14.1%) were classified as adherent based on taking compliance (TC), with only 3 patients (3.8%) adherent in regard to correct dosing (CD) [followup: 13 (16.7%) and 3 (3.8%) for TC and CD, respectively]. Nonadherence was not related to disease activity or side effects.We demonstrated low adherence, suggesting differences between doctors' records and patients' practice of antirheumatic drug therapy.
EVALuna2:13088

HIGH DIMENSIONAL ANALYSIS REVEAL A NETWORK OF CERTAIN TRANSCRIPTION FACTORS THAT LINK VASCULOPATHY AND ORGAN FIBROSIS IN SYSTEMIC SCLEROSIS - Anchang, Charles Gwellem; Lawaree, B. Matalobos; Weber, Stefanie; Rauber, S.; Wohlfahrt, T.; Luber, M.; Kreuter, A.; Schett, Georg; Distler, Jörg; Ramming, A. (ANNALS OF THE RHEUMATIC DISEASES, 2020)
CRIS-Team WoS Importer:2020-08-21

Higher serum levels of short-chain fatty acids are associated with non-progression to arthritis in individuals at increased risk of RA - Martinsson, Klara; Dürholz, Kerstin; Schett, Georg; Zaiss, Mario; Kastbom, Alf (Annals of the Rheumatic Diseases, 2021)
CRIS-Team WoS Importer:2021-12-03

High Fat Diet Alleviates Antigen-Induced Arthritis Severity in Male Mice By Enhancing Both Treg and B10 Cells - Luo, Yubin; Engdahl, Cecilia; Yi Zaho,; Liu, Yi; Schett, Georg; Bozec, Aline (2016)
EVALuna2:35060

High-fat-diet-associated intestinal microbiota exacerbates psoriasis-like inflammation by enhancing systemic γδ T cell IL-17 production - Sonomoto, Koshiro; Song, Rui; Eriksson, Daniel; Hahn, Anne Maria; Meng, Xianyi; Lyu, Pang; Cao, Shan; Liu, Ning; Taudte, Verena; Wirtz, Stefan; Tanaka, Yoshiya; Winkler, Thomas; et al. (Cell Reports, 2023)
Although it is known that psoriasis is strongly associated with obesity, the mechanistic connection between diet and skin lesions is not well established. Herein, we showed that only dietary fat, not carbohydrates or proteins, exacerbates psoriatic disease. Enhanced psoriatic skin inflammation was associated with changes in the intestinal mucus layer and microbiota composition by high-fat diet (HFD). Change of intestinal microbiota by vancomycin treatment effectively blocked activation of psoriatic skin inflammation by HFD, inhibited the systemic interleukin-17 (IL-17) response, and led to increased mucophilic bacterial species such as Akkermansia muciniphila. By using IL-17 reporter mice, we could show that HFD facilitates IL-17-mediated γδ T cell response in the spleen. Notably, oral gavage with live or heat-killed A. muciniphila effectively inhibited HFD-induced enhancement of psoriatic disease. In conclusion, HFD exacerbates psoriatic skin inflammation through changing the mucus barrier and the intestine microbial composition, which leads to an enhanced systemic IL-17 response.
CRIS-Team Scopus Importer:2023-07-28
Keywords: CP: Immunology; CP: Microbiology; high-fat diet; psoriasis; γδT cell

High fat diet increases melanoma cell growth in the bone marrow by inducing osteopontin and interleukin 6 - Chen, Guangliang; Luo, Yubin; Eriksson, Daniel; Meng, Xianyi; Qian, Cheng; Bäuerle, Tobias; Chen, Xiao-Xiang; Schett, Georg; Bozec, Aline (Oncotarget, 2016)
The impact of metabolic stress induced by obesity on the bone marrow melanoma niche is largely unknown. Here we employed diet induced obese mice model, where mice received high-fat (HFD) or normal diet (ND) for 6 weeks before challenge with B16F10 melanoma cells. Tumor size, bone loss and osteoclasts numbers were assessed histologically in the tibial bones. For defining the molecular pathway, osteopontin knock-out mice, interleukin 6 neutralizing antibody or Janus kinase 2 inhibition were carried out in the same model. Mechanistic studies such as adipocyte-melanoma co-cultures for defining adipocyte induced changes of tumor cell proliferation and expression profiles were also performed. As results, HFD enhanced melanoma burden in bone by increasing tumor area and osteoclast numbers. This process was associated with higher numbers of bone marrow adipocytes expressing IL-6 in direct vicinity to tumor cells. Inhibition of IL-6 or of downstream JAK2 blocked HFD-induced tumor progression. Furthermore, the phenotypic changes of melanoma cells triggered macrophage and osteoclast accumulation accompanied by increased osteopontin expression. Osteopontin triggered osteoclastogenesis and also exerted a positive feedback loop to tumor cells, which was abrogated in its absence. Metabolic stress by HFD promotes melanoma growth in the bone marrow by an increase in bone marrow adipocytes and IL-6-JAK2-osteopontin mediated activation of tumor cells and osteoclast differentiation.
EVALuna2:13267

High frequency of autoantibody-secreting cells and long-lived plasma cells within inflamed kidneys of NZB/W F1 lupus mice - Starke, Charlotte; Frey, Silke; Wellmann, Ute; Urbonaviciute, Vilma; Herrmann, Martin; Amann, Kerstin Ute; Schett, Georg; Winkler, Thomas; Voll, Reinhard E. (European Journal of Immunology, 2011)
Autoantibodies to double-stranded (ds) DNA represent a serological hallmark of systemic lupus erythematosus (SLE) and may critically contribute to the pathogenesis of lupus nephritis. Self-reactive antibodies might be partially produced by long-lived plasma cells (PCs), which mainly reside within the bone marrow and spleen. In contrast to short-lived PCs, long-lived PCs are extremely resistant to therapy and may sustain refractory disease courses. Recently, antibody-secreting cells were found within the inflamed kidneys of New Zealand black/white (NZB/W) F1 lupus mice as well as of patients with SLE. To analyze the longevity of the IgG-producing cells present in nephritic kidneys of NZB/W F1 mice we performed in vivo BrdU-labeling. We identified a higher frequency of long-lived than short-lived renal PCs, indicating that survival niches for long-lived PCs also exist within inflamed kidneys. Using ELISPOT assays, we found that on average 31% of renal IgG-producing cells reacted with dsDNA and 24% with nucleolin. Moreover, the frequencies of IgG-secreting cells specific for the autoantigens dsDNA and nucleolin were higher in the kidneys compared with those in the spleen and bone marrow.
Keywords: Autoantibody-secreting cells; Autoimmunity; Long-lived plasma cells; Lupus nephritis

High Impact Sports Leads to Inflammatory Responses at Entheseal Sites Results of the BEAT Study (Badminton Enthesitis Arthrosonography Study) - Simon, David; Kleyer, Arnd; Tascilar, Koray; Bayat, Sara; Knitza, Johannes; Valor-Mendez, Larissa; Schweiger, Marina; Schett, Georg; Hueber, Axel (ARTHRITIS & RHEUMATOLOGY, 2020)
CRIS-Team WoS Importer:2021-01-15

High incidence of disease recurrence after discontinuation of disease-modifying antirheumatic drug treatment in patients with psoriatic arthritis in remission - Araujo, Elizabeth G.; Finzel, Stephanie; Englbrecht, Matthias; Schreiber, Dominik A.; Faustini, Francesca; Hueber, Axel; Nas, Kemal; Rech, Juergen; Schett, Georg (Annals of the Rheumatic Diseases, 2015)
To investigate the possibility of drug-free remission in patients with psoriatic arthritis (PsA) in continuous remission.Prospective observational study in disease-modifying antirheumatic drug (DMARD)-treated PsA patients in continuous disease remission (no musculoskeletal symptoms, no or minimal skin/nail disease) for at least 6 months. Demographic, disease-specific and ultrasound parameters were assessed at baseline. DMARDs (traditional or biologic) were discontinued at the initial visit, and patients were followed for a maximum of 6 months for recurrence of disease.26 patients (methotrexate monotherapy: N=14; tumour necrosis factor inhibitors: N=12) with a mean age of 55.2 years, absence of musculoskeletal symptoms and minimal skin disease (mean Psoriasis Area Severity Index (PASI): 0.21) were enrolled. Incidence of recurrence of disease was high (N=20, 76.9%) and occurred rapidly (74.50±51.72 days) after treatment discontinuation. Male PsA patients were significantly more likely to lose remission. Long disease duration, more severe skin involvement and the presence of synovial hypertrophy by ultrasonographic examination at baseline decreased the likelihood for drug-free remission. Reinitiation of DMARDs promptly restored remission in all PsA patients with recurrence of disease.This study shows that the chance to reach drug-free remission in PsA patients is low. Discontinuation of DMARD therapy cannot be recommended in patients with PsA.
EVALuna2:12954

HIGH PREVALENCE OF INFLAMMATORY AND STRUCTURAL SIGNS OF KNEE OSTEOARTHRITIS IN THE GENERAL POPULATION AGED OVER 60 YEARS - Iagnocco, A.; Perricone, C.; Kleyer, Arnd; Sahinbegovic, E.; Aegerter, P.; Willeit, J.; Kiechl, S.; Schett, Georg; D'Agostino, M. -A. (2013)
EVALuna2:34464

High prevalence of tenosynovial inflammation before onset of rheumatoid arthritis and its link to progression to RA-A combined MRI/CT study - Kleyer, Arnd; Krieter, Manuel; Oliveira, Isabelle; Faustini, Francesca; Simon, Dominic; Kämmerer, Nadine; Cavalcante, Alan; Tabosa, Taiane; Rech, Juergen; Hueber, Axel; Schett, Georg (Seminars in Arthritis and Rheumatism, 2016)
To define the anatomic distribution of the earliest inflammatory and structural changes in individuals with anti-citrullinated protein antibody (ACPA+) positivity but no signs of arthritis.ACPA+ individuals (N = 20) and healthy controls (N = 13) received simultaneous gadolinium-enhanced magnetic resonance imaging (MRI) and high-resolution peripheral quantitative computed tomography (HR-pQCT) of the hands. MRI sequences were scored for synovitis, osteitis, and bone erosions according to the RAMRIS method as well as for presence, localization, and extent of tenosynovitis. Bone erosions were validated by HR-pQCT scanning and related to the inflammatory changes found in the MRI.Tenosynovitis was the most prevalent inflammatory pathology, affecting 80% of ACPA+ individuals but none of the controls. Tenosynovitis at two or more anatomical sites was associated with later development of RA. Synovitis (65%) and osteitis (35%) were present in ACPA+ individuals as well, but at a lower frequency than tenosynovitis. MRI bone erosions were found in 65% of the individuals and additionally confirmed by HR-pQCT. Presence of MRI osteitis was the inflammatory pathology most strongly associated with bone erosions.Tenosynovitis is highly prevalent in ACPA+ individuals without arthritis and associated with later development of RA. Small erosions, often linked to osteitis, are also found in ACPA+ individuals without arthritis.
EVALuna2:13297

HIGH REMISSION RATES IN RA - REAL LIFE DATA FROM BARITICINIB - Bayat, Sara; Tascilar, K.; Kaufmann, V.; Kleyer, Arnd; Simon, David; Knitza, Johannes; Hartmann, F.; Adam, Susanne; Hueber, A.; Schett, Georg (ANNALS OF THE RHEUMATIC DISEASES, 2020)
CRIS-Team WoS Importer:2020-08-21

High-resolution in vivo imaging of bone and joints: a window to microarchitecture - Geusens, Piet; Chapurlat, Roland; Schett, Georg; Ghasem-Zadeh, Ali; Seeman, Ego; De Jong, Joost; Van Den Bergh, Joop (Nature Reviews Rheumatology, 2014)
Imaging is essential to the evaluation of bone and joint diseases, and the digital era has contributed to an exponential increase in the number of publications on noninvasive analytical techniques for the quantification of changes to bone and joints that occur in health and in disease. One such technique is high-resolution peripheral quantitative CT (HR-pQCT), which has introduced a new dimension in the imaging of bone and joints by providing images that are both 3D and at high resolution (82 ?m isotropic voxel size), with a low level of radiation exposure (3-5 ?Sv). HR-pQCT enables the analysis of cortical and trabecular properties separately and to apply micro-finite element analysis for calculating bone biomechanical competence in vivo at the distal sites of the skeleton (distal radius and distal tibia). Moreover, HR-pQCT makes possible the in vivo assessment of the spatial distribution, dimensions and delineation of cortical bone erosions, osteophytes, periarticular cortical and trabecular microarchitecture, and 3D joint-space volume of the finger joints and wrists. HR-pQCT is, therefore, a technique with a high potential for improving our understanding of bone and joint diseases at the microarchitectural level.
EVALuna2:12936

High-resolution quantitative computed tomography demonstrates structural defects in cortical and trabecular bone in IBD patients. - Haschka, Judith; Hirschmann, Simon; Kleyer, Arnd; Englbrecht, Matthias; Faustini, Francesca; Simon, David; Figueiredo, Camille P; Schuster, Louis; Muschitz, Christian; Kocijan, Roland; Resch, Heinrich; Atreya, Raja; et al. (Journal of Crohns & Colitis, 2016)
Background and Aims To investigate the macro- and microstructural changes of bone in patients with inflammatory bowel disease (IBD) and to define the factors associated with bone loss in IBDMethods A total of148 subjects, 59 with Crohn's Disease (CD), 39 with Ulcerative Colitis (UC) and 50 healthy controls were assessed for the geometric, volumetric and microstructural properties of bone using high-resolution peripheral quantitative computed tomography. In addition, demographic and disease-specific characteristics of IBD patients were recorded.Results IBD patients and controls were comparable in age, sex and body mass index. Total (p=0.001), cortical (p<0.001) and trabecular volumetric BMD (p=0.03) were significantly reduced in IBD patients compared to healthy controls. Geometric and microstructure analysis revealed significantly lower cortical area (p=0.001) and cortical thickness (p<0.001) without differences in cortical porosity, pore volume or pore diameter. CD showed a more severe bone phenotype than UC: While cortical bone loss was observed in both diseases, CD additionally showed profound trabecular bone loss with reduced trabecular BMD (p=0.008), bone volume (p=0.008) and trabecular thickness (p=0.009).Multivariate regression models identified the diagnosis of CD, female sex, lower body mass index and the lack of remission as factors independently associated with bone loss in IBD.Conclusion IBD patients develop significant cortical bone loss impairing bone strength. Trabecular bone loss is limited to CD patients, which exhibits a more severe bone phenotype compared to UC patients.
EVALuna2:2046

Hippocampal structure and function are maintained despite severe innate peripheral inflammation - Süß, Patrick; Kalinichenko, Liubov; Baum, Wolfgang; Reichel, Martin; Kornhuber, Johannes; Loskam, Sandra; Ettle, Benjamin; Distler, Jörg; Schett, Georg; Winkler, Jürgen; Müller, Christian P.; Schlachetzki, Johannes (Brain Behavior and Immunity, 2015)
Chronic peripheral inflammation mediated by cytokines such as TNF?, IL-1?, and IL-6 is associated with psychiatric disorders like depression and anxiety. However, it remains elusive which distinct type of peripheral inflammation triggers neuroinflammation and affects hippocampal plasticity resulting in depressive-like behavior. We hypothesized that chronic peripheral inflammation in the human TNF-? transgenic (TNFtg) mouse model of rheumatoid arthritis spreads into the central nervous system and induces depressive state manifested in specific behavioral pattern and impaired adult hippocampal neurogenesis. TNFtg mice showed severe erosive arthritis with increased IL-1? and IL-6 expression in tarsal joints with highly elevated human TNF-? levels in the serum. Intriguingly, IL-1? and IL-6 mRNA levels were not altered in the hippocampus of TNFtg mice. In contrast to the pronounced monocytosis in joints and spleen of TNFtg mice, signs of hippocampal microgliosis or astrocytosis were lacking. Furthermore, locomotion was impaired, but there was no locomotion-independent depressive behavior in TNFtg mice. Proliferation and maturation of hippocampal neural precursor cells as well as survival of newly generated neurons were preserved in the dentate gyrus of TNFtg mice despite reduced motor activity and peripheral inflammatory signature. We conclude that peripheral inflammation in TNFtg mice is mediated by chronic activation of the innate immune system. However, severe peripheral inflammation, though impairing locomotor activity, does not elicit depressive-like behavior. These structural and functional findings indicate the maintenance of hippocampal immunity, cellular plasticity, and behavior despite peripheral innate inflammation.
EVALuna2:12865

How Autoantibodies Regulate Osteoclast Induced Bone Loss in Rheumatoid Arthritis - Steffen, Ulrike; Schett, Georg; Bozec, Aline (Frontiers in Immunology, 2019)
Rheumatoid arthritis (RA) is a chronic inflammatory disease, characterized by autoimmunity that triggers joint inflammation and tissue destruction. Traditional concepts of RA pathogenesis have strongly been focused on inflammation. However, more recent evidence suggests that autoimmunity per se modulates the disease and in particular bone destruction during the course of RA. RA-associated bone loss is caused by increased osteoclast differentiation and activity leading to rapid bone resorption. Autoimmunity in RA is based on autoantibodies such as rheumatoid factor (RF) and autoantibodies against citrullinated proteins (ACPA). These autoantibodies exert effector functions on immune cells and on bone resorbing osteoclasts, thereby facilitating bone loss. This review summarizes potential pathways involved in increased destruction of bone tissue in RA, particularly focusing on the direct and indirect actions of autoantibodies on osteoclast generation and function.
CRIS-Team WoS Importer:2019-07-16

How Well Does Ultrasound-assessed Synovitis in Reduced Joint Sets Predict the Response to Secukinumab in Patients with Active Psoriatic Arthritis and Inadequate Response to Conventional DMARDs? - Exploratory Results from a Phase 3b Study - D'Agostino, Maria-Antonietta; Conaghan, Philip G.; Gaillez, Corine; Naredo, Esperanza; Mandl, Peter; Carron, Philippe; Senolt, Ladislav; Eduardo Rosa, Javier; Lopez Rdz, Alejandra; Goyanka, Punit; Sahoo, Braja Gopal; Bao, Weibin; et al. (ARTHRITIS & RHEUMATOLOGY, 2022)
CRIS-Team WoS Importer:2023-01-13

HR-pQCT in vivo imaging of periarticular bone changes in chronic inflammatory diseases: Data from acquisition to impact on treatment indications - Figueiredo, Camille P.; Perez, Mariana O.; Sales, Lucas Peixoto; Schett, Georg; Pereira, Rosa M. R. (Modern Rheumatology, 2020)
Imaging is essential for the assessment of bone and inflammatory joint diseases. There are several imaging techniques available that differ regarding resolution, radiation exposure, time expending, precision, cost, availability or ability to predict disease progression. High-resolution peripheral quantitative computed tomography (HR-pQCT) that was introduced in 2004 allows the in vivo evaluation of peripheral bone microarchitecture and demonstrated high precision in assessing bone changes in inflammatory musculoskeletal diseases. This review summarizes the use of HR-pQCT for the evaluation of the hand skeleton in inflammatory joint diseases. We conducted a review of the literature regarding the protocols that involve hand joints assessment and evaluation of bone changes as erosions and osteophytes in chronic inflammatory diseases. Apart from measuring bone density and structure of the radius and the tibia, HR-pQCT has contributed to assessment of bone erosions and osteophytes, considered the hallmark of diseases as rheumatoid arthritis and psoriatic arthritis, respectively. In this way, there are some conventions recently established by rheumatic study groups that we just summarized here in order to standardize HR-pQCT measurements.
CRIS-Team Scopus Importer:2020-09-18
Keywords: Arthritis; bone erosion; bone spur; computed tomography

Humoral and Cellular Immune Responses to SARS–CoV-2 Infection and Vaccination in Autoimmune Disease Patients With B Cell Depletion - Simon, David; Tascilar, Koray; Schmidt, Katja; Manger, Bernhard; Weckwerth, Leonie; Sokolova, Maria; Bucci, Laura; Fagni, Filippo; Manger, Karin; Schuch, Florian; Ronneberger, Monika; Hueber, Axel; et al. (Arthritis and Rheumatology, 2021)
Objective: B cell depletion is an established therapeutic principle in a wide range of autoimmune diseases. However, B cells are also critical for inducing protective immunity after infection and vaccination. We undertook this study to assess humoral and cellular immune responses after infection with or vaccination against SARS–CoV-2 in patients with B cell depletion and controls who are B cell–competent. Methods: Antibody responses (tested using enzyme-linked immunosorbent assay) and T cell responses (tested using interferon-γ enzyme-linked immunospot assay) against the SARS–CoV-2 spike S1 and nucleocapsid proteins were assessed in a limited number of previously infected (n = 6) and vaccinated (n = 8) autoimmune disease patients with B cell depletion, as well as previously infected (n = 30) and vaccinated (n = 30) healthy controls. Results: As expected, B cell and T cell responses to the nucleocapsid protein were observed only after infection, while respective responses to SARS–CoV-2 spike S1 were found after both infection and vaccination. A SARS–CoV-2 antibody response was observed in all vaccinated controls (30 of 30 [100%]) but in none of the vaccinated patients with B cell depletion (0 of 8). In contrast, after SARS–CoV-2 infection, both the patients with B cell depletion (spike S1, 5 of 6 [83%]; nucleocapsid, 3 of 6 [50%]) and healthy controls (spike S1, 28 of 30 [93%]; nucleocapsid, 28 of 30 [93%]) developed antibodies. T cell responses against the spike S1 and nucleocapsid proteins were found in both infected and vaccinated patients with B cell depletion and in the controls. Conclusion: These data show that B cell depletion completely blocks humoral but not T cell SARS–CoV-2 vaccination response. Furthermore, limited humoral immune responses are found after SARS–CoV-2 infection in patients with B cell depletion.
CRIS-Team Scopus Importer:2021-12-03

Hypoxia-inducible factor-1α is a critical transcription factor for IL-10-producing B cells in autoimmune disease - Meng, Xianyi; Groetsch, Bettina; Luo, Yubin; Knaup, Karl; Wiesener, Michael Sean; Chen, Xiao-Xiang; Jantsch, Jonathan; Fillatreau, Simon; Schett, Georg; Bozec, Aline (Nature Communications, 2018)
Hypoxia-inducible factors (HIFs) are key elements for controlling immune cell metabolism and functions. While HIFs are known to be involved in T cells and macrophages activation, their functions in B lymphocytes are poorly defined. Here, we show that hypoxia-inducible factor-1? (HIF-1?) contributes to IL-10 production by B cells. HIF-1? regulates IL-10 expression, and HIF-1?-dependent glycolysis facilitates CD1dhiCD5+ B cells expansion. Mice with B cell-specific deletion of Hif1a have reduced number of IL-10-producing B cells, which result in exacerbated collagen-induced arthritis and experimental autoimmune encephalomyelitis. Wild-type CD1dhiCD5+ B cells, but not Hif1a-deficient CD1dhiCD5+ B cells, protect recipient mice from autoimmune disease, while the protective function of Hif1a-deficient CD1dhiCD5+ B cells is restored when their defective IL-10 expression is genetically corrected. Taken together, this study demonstrates the key function of the hypoxia-associated transcription factor HIF-1? in driving IL-10 expression in CD1dhiCD5+ B cells, and in controlling their protective activity in autoimmune disease.
EVALuna2:13529

Hypoxia Promotes Neutrophil Survival After Acute Myocardial Infarction - Dölling, Maximilian; Eckstein, Markus; Singh, Jeeshan; Schoen, Janina; Shan, Xiaomei; Bozec, Aline; Knopf, Jasmin; Schett, Georg; Munoz Becerra, Luis; Herrmann, Martin; Schauer, Christine (Frontiers in Immunology, 2022)
Phagocytosis, degranulation, and neutrophil extracellular traps (NETs) formation build the armory of neutrophils for the first line of defense against invading pathogens. All these processes are modulated by the microenvironment including tonicity, pH and oxygen levels. Here we investigated the neutrophil infiltration in cardiac tissue autopsy samples of patients with acute myocardial infarction (AMI) and compared these with tissues from patients with sepsis, endocarditis, dermal inflammation, abscesses and diseases with prominent neutrophil infiltration. We observed many neutrophils infiltrating the heart muscle after myocardial infarction. Most of these had viable morphology and only few showed signs of nuclear de-condensation, a hallmark of early NET formation. The abundance of NETs was the lowest in acute myocardial infarction when compared to other examined diseases. Since cardiac oxygen supply is abruptly abrogated in acute myocardial infarction, we hypothesized that the resulting tissue hypoxia increased the longevity of the neutrophils. Indeed, the viable cells showed increased nuclear hypoxia inducible factor-1α (HIF-1α) content, and only neutrophils with low HIF-1α started the process of NET formation (chromatin de-condensation and nuclear swelling). Prolonged neutrophil survival, increased oxidative burst and reduced NETs formation were reproduced under low oxygen tensions and by HIF-1α stabilization in vitro. We conclude that nuclear HIF-1α is associated with prolonged neutrophil survival and enhanced oxidative stress in hypoxic areas of AMI.
CRIS-Team Scopus Importer:2022-03-04
Keywords: acute myocardial infarction; DNA decondensation; hypoxia inducible factor 1; NET formation; neutrophil extracellular traps; neutrophils

Identification, localization and differentiation of erosions and physiological bone channels by ultrasound in rheumatoid arthritis patients - Finzel, Stephanie; Aegerter, Philippe; Schett, Georg; D'Agostino, Maria-Antonietta (Rheumatology, 2020)
Objectives. Ultrasound (US) can detect cortical bone lesions in RA. However, not all cortical bone lesions are erosions. Herein, we aimed to define whether US can differentiate between physiological bone channels and pathological erosions in RA and to provide topographic description of their differential localization.
CRIS-Team WoS Importer:2021-01-29

Identification of a Distinct Monocyte-Driven Signature in Systemic Sclerosis Using Biophysical Phenotyping of Circulating Immune Cells - Matei, Alexandru-Emil; Kubankova, Marketa; Xu, Liyan; Györfi, Andrea-Hermina; Boxberger, Evgenia; Soteriou, Despina; Papava, Maria; Prater, Julia; Hong, Xuezhi; Bergmann, Christina; Kraeter, Martin; Schett, Georg; et al. (Arthritis and Rheumatology, 2023)
Objective Pathologically activated circulating immune cells, including monocytes, play major roles in systemic sclerosis (SSc). Their functional characterization can provide crucial information with direct clinical relevance. However, tools for the evaluation of pathologic immune cell activation and, in general, of clinical outcomes in SSc are scarce. Biophysical phenotyping (including characterization of cell mechanics and morphology) provides access to a novel, mostly unexplored layer of information regarding pathophysiologic immune cell activation. We hypothesized that the biophysical phenotyping of circulating immune cells, reflecting their pathologic activation, can be used as a clinical tool for the evaluation and risk stratification of patients with SSc.Methods We performed biophysical phenotyping of circulating immune cells by real-time fluorescence and deformability cytometry (RT-FDC) in 63 SSc patients, 59 rheumatoid arthritis (RA) patients, 28 antineutrophil cytoplasmic antibody-associated vasculitis (AAV) patients, and 22 age- and sex-matched healthy donors.Results We identified a specific signature of biophysical properties of circulating immune cells in SSc patients that was mainly driven by monocytes. Since it is absent in RA and AAV, this signature reflects an SSc-specific monocyte activation rather than general inflammation. The biophysical properties of monocytes indicate current disease activity, the extent of skin or lung fibrosis, and the severity of manifestations of microvascular damage, as well as the risk of disease progression in SSc patients.Conclusion Changes in the biophysical properties of circulating immune cells reflect their pathologic activation in SSc patients and are associated with clinical outcomes. As a high-throughput approach that requires minimal preparations, RT-FDC-based biophysical phenotyping of monocytes can serve as a tool for the evaluation and risk stratification of patients with SSc.
CRIS-Team WoS Importer:2023-04-14

Identification of circulating microRNA patterns in patients in psoriasis and psoriatic arthritis - Haschka, Judith; Simon, David; Bayat, Sara; Messner, Zora; Kampylafka, Eleni; Fagni, Filippo; Skalicky, Susanna; Hackl, Matthias; Resch, Heinrich; Zwerina, Jochen; Kleyer, Arnd; Cavallaro, Alexander Josef; et al. (Rheumatology, 2023)
Objective miRNAs are small non-coding RNAs that control gene expression. Specific intra- and extracellular miRNA signatures have been identified in various diseases. Whether certain miRNA signatures are associated with psoriasis (PsO) and PsA is currently unknown. We aimed to search for circulating miRNA signatures associated with PsO and PsA patients. Methods Expression of miRNAs was analysed by reverse transcription quantitative real-time PCR (RT-qPCR) in the serum of PsA, PsO patients and healthy controls. Demographic and disease-specific characteristics and imaging data from hand MRI were recorded. In the discovery phase, 192 miRNA assays were analysed in 48 samples (PsA, PsO, controls: each N = 16). For validation, 17 selected miRNAs were measured in the total population. Results A total of 141 patients and controls were analysed (51 PsA, 40 PsO, 50 controls). In the discovery phase 51 miRNAs in PsO and 64 miRNAs in PsA were down- or upregulated compared with controls, with 33 miRNAs being changed in both (adj. P < 0.05). The 17 top candidates from discovery were assessed in the validation phase, 9 of them discriminated PsA and PsO from controls [area under the curve (AUC) >= 0.70, all P < 0.05]. Four miRNAs (miR-19b-3p, miR-21-5p, miR-92a-3p and let-7b-5p) were significantly differently regulated between PsO and PsA. A combination of these miRNAs increased the AUC to 0.92 in multivariate regression model to discriminate PsO and PsA. Conclusion miRNA signatures in PsA and PsO patients differ from controls. Nine miRNAs were differentially regulated in PsA and PsO patients, five of them previously reported to be involved in bone and cartilage metabolism, indicating an intimate association of psoriatic inflammation and bone/cartilage changes.
CRIS-Team WoS Importer:2023-03-17

Identification of Circulating MicroRNA Signatures in Patients with Psoriasis and Psoriatic Arthritis to Develop Novel Strategies for Early Diagnosis of a Bone and Joint Involvement - Haschka, Judith; Simon, David; Bayat, Sara; Kleyer, Arnd; Kampylafka, Eleni; Muschitz, Christian; Skalicky, Susanna; Hackl, Matthias; Resch, Heinrich; Schett, Georg; Kocijan, Roland; Rech, Jürgen; et al. (ARTHRITIS & RHEUMATOLOGY, 2019)
CRIS-Team WoS Importer:2020-02-07

IDENTIFICATION OF CIRCULATING MICRORNA SIGNATURES IN PATIENTS WITH PSORIASIS WITH SUBCLINICAL JOINT DISEASE AND PATIENTS WITH PSORIATIC ARTHRITIS - Haschka, J.; Simon, David; Bayat, Sara; Messner, Z.; Kampylafka, E.; Fagni, Filippo; Skalicky, S.; Hackl, M.; Resch, H.; Zwerina, J.; Kleyer, Arnd; Sticherling, Michael; et al. (ANNALS OF THE RHEUMATIC DISEASES, 2022)
CRIS-Team WoS Importer:2022-11-04

IDENTIFYING ADULT HYPOPHOSPHATASIA IN THE RHEUMATOLOGY UNIT - Feurstein, J.; Behanova, M.; Haschka, J.; Roetzer, K.; Uyanik, G.; Witsch-Baumgartner, M.; Schett, Georg; Zwerina, J.; Kocijan, R. (ANNALS OF THE RHEUMATIC DISEASES, 2021)
CRIS-Team WoS Importer:2021-09-24

Identifying adult hypophosphatasia in the rheumatology unit - Feurstein, Julia; Behanova, Martina; Haschka, Judith; Roetzer, Katharina; Uyanik, Gökhan; Hadzimuratovic, Benjamin; Witsch-Baumgartner, Martina; Schett, Georg; Zwerina, Jochen; Kocijan, Roland (Orphanet Journal of Rare Diseases, 2022)
Background: The most frequent manifestation in adult hypophosphatasia (HPP) is musculoskeletal pain. The unspecific nature of its clinical presentation may prevent correct diagnosis. The aim of the study was to assess the prevalence of ALPL mutations in adult patients treated in rheumatological outpatient facilities with evident musculoskeletal symptoms typical for HPP. Methods: Over a period of 10 years 9,522 patients were screened in the rheumatology outpatient clinic of the Hanusch hospital Vienna. Serum ALP levels ≤ 40 U/L were found in 524 patients. After screening for secondary causes, 73 patients were invited for clinical evaluation. Genetic testing was performed in 23 patients with suspected HPP. Logistic regression models with Firth penalisation were used to estimate the unadjusted and BMI-adjusted association of each clinical factor with HPP. Results: Mutations in the ALPL gene were observed in 57% of genetically screened patients. Arthralgia, fractures, and pain were the leading symptoms in individuals with ALPL mutation. Chondrocalcinosis (OR 29.12; 95% CI 2.02–1593.52) and dental disease (OR 8.33; 95% CI 0.93–143.40) were associated with ALPL mutation, independent of BMI. Onset of symptoms in patients with ALPL mutation was at 35.1 (14.3) years, with a mean duration from symptoms to diagnosis of 14.4 (8.1) years. Bone mineral density (BMD) and trabecular bone score (TBS) as well as bone turnover markers were not indicative for HPP or ALPL mutation. Conclusion: HPP can mimic rheumatologic diseases. Thus, HPP should be considered as a possible diagnosis in adult patients presenting with musculoskeletal pain of unknown origin in rheumatology outpatient clinics. In patients with persistently low ALP serum levels and unclear musculoskeletal pain, HPP as the underlying cause has to be considered.
CRIS-Team Scopus Importer:2022-12-23
Keywords: Alkaline phosphatase; ALPL gene; Arthralgia; Hypophosphatasia; Musculoskeletal pain

IgA2 Antibodies against SARS-CoV-2 Correlate with NET Formation and Fatal Outcome in Severely Diseased COVID-19 Patients - Staats, Leonie A. N.; Pfeiffer, Hella; Knopf, Jasmin; Lindemann, Aylin; Fürst, Julia; Kremer, Andreas; Hackstein, Holger; Neurath, Markus; Munoz, Luis Enrique; Achenbach, Susanne; Leppkes, Moritz; Herrmann, Martin; et al. (Cells, 2020)
Infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) leads to an adaptive immune response in the host and the formation of anti-SARS-CoV-2 specific antibodies. While IgG responses against SARS-CoV-2 have been characterized quite well, less is known about IgA. IgA2 activates immune cells and induces inflammation and neutrophil extracellular trap (NET) formation which may contribute to organ injury and fatal outcome in SARS-CoV-2-infected patients. SARS-CoV-2 spike protein specific antibody levels were measured in plasma samples of 15 noninfected controls and 82 SARS-CoV-2-infected patients with no or mild symptoms, moderate symptoms (hospitalization) or severe disease (intensive care unit, ICU). Antibody levels were compared to levels of C-reactive protein (CRP) and circulating extracellular DNA (ecDNA) as markers for general inflammation and NET formation, respectively. While levels of SARS-CoV-2-specific IgG were similar in all patient groups, IgA2 antibodies were restricted to severe disease and showed the strongest discrimination between nonfatal and fatal outcome in patients with severe SARS-CoV-2 infection. While anti-SARS-CoV-2 IgG and IgA2 levels correlated with CRP levels in severely diseased patients, only anti-SARS-CoV-2 IgA2 correlated with ecDNA. These data suggest that the formation of anti-SARS-CoV-2 IgA2 during SARS-CoV-2 infection is a marker for more severe disease related to NET formation and poor outcome.
CRIS-Team WoS Importer:2021-01-15

IgA2 immune complexes selectively promote inflammation by human CD103+ dendritic cells - Mes, Lynn; Steffen, Ulrike; Chen, Hung-Jen; Veth, Jennifer; Hoepel, Willianne; Griffith, Guillermo Romeo; Schett, Georg; Den Dunnen, Jeroen (Frontiers in Immunology, 2023)
While immunoglobulin A (IgA) is well known for its neutralizing and anti-inflammatory function, it is becoming increasingly clear that IgA can also induce human inflammatory responses by various different immune cells. Yet, little is known about the relative role of induction of inflammation by the two IgA subclasses i.e. IgA1, most prominent subclass in circulation, and IgA2, most prominent subclass in the lower intestine. Here, we set out to study the inflammatory function of IgA subclasses on different human myeloid immune cell subsets, including monocytes, and in vitro differentiated macrophages and intestinal CD103+ dendritic cells (DCs). While individual stimulation with IgA immune complexes only induced limited inflammatory responses by human immune cells, both IgA subclasses strongly amplified pro-inflammatory cytokine production upon co-stimulation with Toll-like receptor (TLR) ligands such as Pam3CSK4, PGN, and LPS. Strikingly, while IgA1 induced slightly higher or similar levels of pro-inflammatory cytokines by monocytes and macrophages, respectively, IgA2 induced substantially more inflammation than IgA1 by CD103+ DCs. In addition to pro-inflammatory cytokine proteins, IgA2 also induced higher mRNA expression levels, indicating that amplification of pro-inflammatory cytokine production is at least partially regulated at the level of gene transcription. Interestingly, cytokine amplification by IgA1 was almost completely dependent on Fc alpha receptor I (FcαRI), whilst blocking this receptor only partially reduced cytokine induction by IgA2. In addition, IgA2-induced amplification of pro-inflammatory cytokines was less dependent on signaling through the kinases Syk, PI3K, and TBK1/IKKϵ. Combined, these findings indicate that IgA2 immune complexes, which are most abundantly expressed in the lower intestine, particularly promote inflammation by human CD103+ intestinal DCs. This may serve an important physiological function upon infection, by enabling inflammatory responses by this otherwise tolerogenic DC subset. Since various inflammatory disorders are characterized by disturbances in IgA subclass balance, this may also play a role in the induction or exacerbation of chronic intestinal inflammation.
CRIS-Team Scopus Importer:2023-04-21
Keywords: CD103; FcαRI; IgA subclasses; inflammation; intestine

IGA ACPA ARE ASSOCIATED WITH PROGRESSION TO RHEUMATOID ARTHRITIS IN INDIVIDUALS AT-RISK AND DECLINE IN LEVELS AROUND THE DISEASE ONSET - Sokolova, Maria; Hartmann, F.; Sieghart, D.; Steiner, G.; Kleyer, Arnd; Schett, Georg; Steffen, Ulrike (ANNALS OF THE RHEUMATIC DISEASES, 2022)
CRIS-Team WoS Importer:2022-11-04

IgA anti-citrullinated protein antibodies are associated with flares during DMARD tapering in rheumatoid arthritis. - Sokolova, Maria; Hagen, Melanie; Bang, Holger; Schett, Georg; Rech, Jürgen; Steffen, Ulrike (Rheumatology, 2022)
OBJECTIVES: A substantial proportion of RA patients flare upon withdrawal of DMARDs, and thus the definition of prognostic markers is crucial. ACPA positivity has been identified as a risk factor for flare. However, only the role of IgG ACPA is established in this context, while the role of IgA ACPA is poorly defined. We thus aimed to investigate the role of IgA ACPA in flaring of RA. METHODS: Serum levels of IgA1 and IgA2 ACPA at baseline and after 12 months were measured in 108 patients from the randomized controlled RETRO study. RA patients in stable remission for at least 6 months at study recruitment were assigned to either one of the DMARD tapering arms or to continuation of DMARDs. RESULTS: In patients remaining in remission but not in the ones who flared, IgA2 ACPA levels and proportion of IgA2 in ACPA (IgA2% ACPA) significantly declined (median of 17.5%; P < 0.0001). This seemed to be independent of the treatment choice, as there was no difference in IgA2 ACPA dynamics between the study arms. IgA2% ACPA was associated with disease activity (DAS28) at flare (r = 0.36; P = 0.046). IgA and IgG ACPA showed a tendency towards independent contribution to the risk of flare with the highest risk if a patient had both antibody classes. CONCLUSION: In this study, IgA ACPA was identified as a risk factor for flare in combination with IgG ACPA. IgA2 ACPA levels were associated with flare severity and declined in patients in stable remission.
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IgA Complexes Induce Neutrophil Extracellular Trap Formation More Potently Than IgG Complexes - Gimpel, Anna-Katharina; Maccataio, Antonio; Unterweger, Harald; Sokolova, Maria; Schett, Georg; Steffen, Ulrike (Frontiers in Immunology, 2022)
Neutrophil extracellular trap (NET) formation is a powerful instrument to fight pathogens, but may induce collateral damage in the affected tissues. Besides pathogen-derived factors, immune complexes are potent inducers of NET formation. Neutrophils express IgA and IgG specific Fc receptors (FcRs) and therefore respond to complexed IgA and IgG. Especially in the context of autoimmune diseases, IgA and IgG immune complexes have been shown to trigger NET formation, a process that putatively contributes to disease severity. However, it is of question if both antibody classes stimulate neutrophils to the same extent. In this study, we compared the capability of IgA and IgG complexes formed by heat aggregation to induce NET formation. While stimulation of neutrophils with IgA complexes robustly induced NET formation, complexed IgG only marginally increased the amount of NETs compared to the unstimulated control. Mixing IgA with IgG before heat aggregation did not increase the effect of complexed IgA on neutrophils. By contrast, the presence of IgG complexes seemed to disturb neutrophil stimulation by IgA complexes. The capacity of complexed IgG to induce NET formation could not be increased by the addition of autologous serum or the removal of terminal sialic acid in the Fc glycan. Together, our data show that IgA is a much more potent inducer of NET formation than IgG. IgA may thus be the main driving force in (auto)immune complex-mediated NET formation.
CRIS-Team Scopus Importer:2022-02-11
Keywords: IgA; IgG; immune complex; NET; neutrophil

IgA subclasses have different effector functions associated with distinct glycosylation profiles - Steffen, Ulrike; Koeleman, Carolien A.; Sokolova, Maria V.; Bang, Holger; Kleyer, Arnd; Rech, Jürgen; Unterweger, Harald; Schicht, Martin; Garreis, Fabian; Hahn, Jonas; Andes, Fabian T.; Hahn, Madelaine; et al. (Nature Communications, 2020)
Monomeric serum immunoglobulin A (IgA) can contribute to the development of various autoimmune diseases, but the regulation of serum IgA effector functions is not well defined. Here, we show that the two IgA subclasses (IgA1 and IgA2) differ in their effect on immune cells due to distinct binding and signaling properties. Whereas IgA2 acts pro-inflammatory on neutrophils and macrophages, IgA1 does not have pronounced effects. Moreover, IgA1 and IgA2 have different glycosylation profiles, with IgA1 possessing more sialic acid than IgA2. Removal of sialic acid increases the pro-inflammatory capacity of IgA1, making it comparable to IgA2. Of note, disease-specific autoantibodies in patients with rheumatoid arthritis display a shift toward the pro-inflammatory IgA2 subclass, which is associated with higher disease activity. Taken together, these data demonstrate that IgA effector functions depend on subclass and glycosylation, and that disturbances in subclass balance are associated with autoimmune disease.
CRIS-Team Scopus Importer:2020-01-21

IgG4 immune response in Churg-Strauss syndrome - Vaglio, Augusto; Strehl, Johanna D.; Manger, Bernhard; Maritati, Federica; Alberici, Federico; Beyer, Christian; Rech, Jürgen; Rech, Juergen; Sinico, Renato A.; Bonatti, Francesco; Battistelli, Luisita; Distler, Jörg; et al. (Annals of the Rheumatic Diseases, 2012)
Objective: T-helper type 2 responses are crucial in Churg-Strauss syndrome (CSS) and may enhance the production of IgG4 antibodies. The authors assessed the IgG4 immune response in CSS patients. Methods: The authors included 46 consecutive patients with CSS (24 with active and 22 with quiescent disease), 26 with granulomatosis with polyangiitis (GPA, Wegener's), 25 with atopic asthma and 20 healthy controls and determined serum IgG, IgM, IgA, IgE and IgG subclass levels. Tissue infiltration by IgG4 plasma cells was assessed in nine patients with CSS, 10 with GPA, 22 with chronic sinusitis (11 with and 11 without eosinophilia). Results: IgG4 levels were markedly higher in active CSS patients than in controls (p<0.001 vs all control groups). Serum IgG4 correlated with the number of disease manifestations (r=0.52, p=0.01) and the Birmingham vasculitis activity score (r=0.64, p=0.001). Longitudinal analysis in 12 CSS cases showed that both the IgG4 level and IgG4/IgG ratio dropped during disease remission (p=3×10 -5 and p=6×10 -4, respectively). Tissue analysis did not show an increased IgG4 plasma cell infiltration in CSS biopsies compared with control groups. Conclusions: Serum IgG4 levels are markedly elevated in active CSS and correlate with the number of organ manifestations and disease activity.
CRIS-Team Scopus Importer:2021-02-03

IgG4-related fasciitis - Morf, Harriet; Roemer, Frank; Agaimy, Abbas; Schett, Georg; Manger, Bernhard (Rheumatology, 2022)
CRIS-Team WoS Importer:2022-02-18

IL-17-22-23 PATHWAYS IN PSORIATIC ARTHRITIS AND PSORIASIS - Nas, K.; Cevik, R.; Yildiz, I.; Rech, Jürgen; Schett, Georg (2017)
EVALuna2:35044

IL-17/23 IN THE TRANSITION FROM AUTOIMMUNITY TO INFLAMMATION - Pfeifle, R.; Rothe, Tobias; Scherer, H. U.; Wuhrer, M.; Rombouts, Y.; Koeleman, C. A.; Toes, R.; Holmdahl, R.; Herrmann, Martin; Blueml, S.; Nimmerjahn, Falk; Schett, Georg; et al. (2016)
EVALuna2:13361

IL-33-induced metabolic reprogramming controls the differentiation of alternatively activated macrophages and the resolution of inflammation - Faas, Maria; Ipseiz, Natacha; Ackermann, Jochen; Culemann, Stephan; Grüneboom, Anika; Schröder, Fenja; Rothe, Tobias; Scholtysek, Carina; Eberhardt, Martin; Böttcher, Martin; Kirchner, Philipp; Stoll, Cornelia; et al. (Immunity, 2021)
Alternatively activated macrophages (AAMs) contribute to the resolution of inflammation and tissue repair. However, molecular pathways that govern their differentiation have remained incompletely understood. Here, we show that uncoupling protein-2-mediated mitochondrial reprogramming and the transcription factor GATA3 specifically controlled the differentiation of pro-resolving AAMs in response to the alarmin IL-33. In macrophages, IL-33 sequentially triggered early expression of pro-inflammatory genes and subsequent differentiation into AAMs. Global analysis of underlying signaling events revealed that IL-33 induced a rapid metabolic rewiring of macrophages that involved uncoupling of the respiratory chain and increased production of the metabolite itaconate, which subsequently triggered a GATA3-mediated AAM polarization. Conditional deletion of GATA3 in mononuclear phagocytes accordingly abrogated IL-33-induced differentiation of AAMs and tissue repair upon muscle injury. Our data thus identify an IL-4-independent and GATA3-dependent pathway in mononuclear phagocytes that results from mitochondrial rewiring and controls macrophage plasticity and the resolution of inflammation.
CRIS-Team Scopus Importer:2021-11-19
Keywords: alternatively activated macrophage; GATA3; interleukin-33; itaconate; mitochondrial rewiring; resolution of inlammation; UCP2; uncoupling

IL-36R signalling activates intestinal epithelial cells and fibroblasts and promotes mucosal healing in vivo - Scheibe, Kristina; Backert, Ingo; Wirtz, Stefan; Hueber, Axel; Schett, Georg; Vieth, Michael; Probst, Hans Christian; Bopp, Tobias; Neurath, Markus; Neufert, Clemens (Gut, 2016)
Interleukin (IL)-36R signalling plays a proinflammatory role in different organs including the skin, but the expression of IL-36R ligands and their molecular function in intestinal inflammation are largely unknown.We studied the characteristics of IL-36R ligand expression in IBDs and experimental colitis. The functional role of IL-36R signalling in the intestine was addressed in experimental colitis and wound healing models in vivo by using mice with defective IL-36R signalling (IL-36R-/-) or Myd88, neutralising anti-IL-36R antibodies, recombinant IL-36R ligands and RNA-seq genome expression analysis.Expression of IL-36? and IL-36? was significantly elevated in active human IBD and experimental colitis. While IL-36? was predominantly detected in nuclei of the intestinal epithelium, IL-36? was mainly found in the cytoplasm of CD14(+) inflammatory macrophages. Functional studies showed that defective IL-36R signalling causes high susceptibility to acute dextran sodium sulfate colitis and impairs wound healing. Mechanistically, IL-36R ligands released upon mucosal damage activated IL-36R(+) colonic fibroblasts via Myd88 thereby inducing expression of chemokines, granulocyte-macrophage colony-stimulating factor (GM-CSF) and IL-6. Moreover, they induced proliferation of intestinal epithelial cells (IECs) and expression of the antimicrobial protein lipocalin 2. Finally, treatment of experimental intestinal wounds with IL-36R ligands significantly accelerated mucosal healing in vivo.IL-36R signalling is activated upon intestinal damage, stimulates IECs and fibroblasts and drives mucosal healing. Modulation of the IL-36R pathway emerges as a potential therapeutic strategy for induction of mucosal healing in IBD.
EVALuna2:2028

IL9 MODULATION OF OSTEOCLASTS DIFFERENTIATION AND IMPACTS ON BONE METABOLISM - Saad, M.; Rauber, S.; Schett, Georg; Ramming, Andreas (ANNALS OF THE RHEUMATIC DISEASES, 2020)
CRIS-Team WoS Importer:2020-08-21

IL-9-Producing Innate Lymphoid Cells - Keyplayers That Orchestrate Resolution of Chronic Inflammation in Arthritis - Rauber, Simon; Luber, Markus; Weber, Stefanie; Maul, Lisa; Soare, Alina; Wohlfahrt, Thomas; Bozec, Aline; Herrmann, Martin; Zaiss, Mario; Fearon, Ursula; Veale, Douglas J.; Canete, Juan; et al. (2017)
EVALuna2:33440

Imaging in inflammatory arthritis: progress towards precision medicine - Minopoulou, Ioanna; Kleyer, Arnd; Yalcin-Mutlu, Melek; Fagni, Filippo; Kemenes, Stephan; Schmidkonz, Christian; Atzinger, Armin; Pachowsky, Milena; Engel, Klaus; Folle, Lukas; Roemer, Frank; Waldner, Maximilian; et al. (Nature Reviews Rheumatology, 2023)
Imaging techniques such as ultrasonography and MRI have gained ground in the diagnosis and management of inflammatory arthritis, as these imaging modalities allow a sensitive assessment of musculoskeletal inflammation and damage. However, these techniques cannot discriminate between disease subsets and are currently unable to deliver an accurate prediction of disease progression and therapeutic response in individual patients. This major shortcoming of today’s technology hinders a targeted and personalized patient management approach. Technological advances in the areas of high-resolution imaging (for example, high-resolution peripheral quantitative computed tomography and ultra-high field MRI), functional and molecular-based imaging (such as chemical exchange saturation transfer MRI, positron emission tomography, fluorescence optical imaging, optoacoustic imaging and contrast-enhanced ultrasonography) and artificial intelligence-based data analysis could help to tackle these challenges. These new imaging approaches offer detailed anatomical delineation and an in vivo and non-invasive evaluation of the immunometabolic status of inflammatory reactions, thereby facilitating an in-depth characterization of inflammation. By means of these developments, the aim of earlier diagnosis, enhanced monitoring and, ultimately, a personalized treatment strategy looms closer.
CRIS-Team Scopus Importer:2023-09-29

Imaging in rheumatoid arthritis, psoriatic arthritis, axial spondyloarthritis, and osteoarthritis: An international viewpoint on the current knowledge and future research priorities - Baraliakos, Xenofon; Conaghan, Philip G.; D'Agostino, Maria-Antonietta; Maksymowych, Walter; Naredo, Esperanza; Ostergaard, Mikkel; Schett, Georg; Emery, Paul (European Journal of Rheumatology, 2019)
Imaging is increasingly used in the routine management of rheumatic diseases as well as in the clinical trials of these disorders. This viewpoint, authored by a group of international imaging experts following two meetings dedicated to imaging in rheumatology, reports a consensus about the current knowledge and addresses where further research should be focused based on the views of the international imaging experts and discussion of the evidence with attending imaging practitioners. The goal was to maximize the potential of imaging to improve the clinical management of four rheumatic diseases. These rheumatic diseases include rheumatoid arthritis, psoriatic arthritis, axial spondyloarthritis, and osteoarthritis.
CRIS-Team WoS Importer:2019-04-23

Immobilization by 21 days of bed rest results in type II collagen degradation in healthy individuals - Liphardt, Anna-Maria; Elie-Tino, Godonou; Dreiner, Maren; Mündermann, Annegret; Tascilar, Koray; Djalal, Nadja; Heer, Martina; Schett, Georg; Zaucke, Frank; Niehoff, Anja (Osteoarthritis and Cartilage, 2023)
Objective: To investigate the effects of 21 days of bed rest immobilization (with and without exercise and nutrition interventions) on type II collagen biomarker concentrations in healthy individuals. Design: Twelve healthy male participants (age 34.2 ± 8.3 years; body mass index 22.4 ± 1.7 kg/m²) were exposed to 6 days ambulatory baseline data collection (BDC), 21 days head-down-tilt bed rest (HDT, CON) + interventions (HDT + resistive vibration exercise (2 times/week, 25 minutes): RVE; HDT + RVE + whey protein (0.6 g/kg body weight/day) and bicarbonate supplementation (90 mmol KHCO3/day: NeX), and 6 days of re-ambulation (R) in a cross-over designed study. The starting HDT condition was randomized (CON-RVE-NEX, RVE-NEX-CON, NEX-CON-RVE). Blood and urine samples were collected before, during, and after HDT. Serum concentrations (s) of CPII, C2C, C1,2C, and urinary concentrations (u) of CTX-II and Coll2–1NO2 were measured. Results: Twenty-one days of HDT resulted in increased sCPII (p < 0.001), sC2C (p < 0.001), and sC1,2C (p = 0.001) (highest increases: sCPII (+24.2% - HDT5), sC2C (+24.4% - HDT7), sC1,2C (+13.5% - HDT2). sC2C remained elevated at R+1 (p = 0.002) and R+6 (p < 0.001) compared to baseline. NeX led to lower sCPII (p < 0.001) and sC1,2C (p = 0.003) compared to CON. uCTX-II (second void and 24-hour urine) increased during HDT (p < 0.001, highest increase on HDT21: second void +82.8% (p < 0.001); 24-hour urine + 77.8% (p < 0.001). NeX resulted in lower uCTX-II concentrations in 24-hour urine (p = 0.012) compared to CON. Conclusions: Twenty-one days of bed rest immobilization results in type II collagen degradation that does not recover within 6 days of resuming ambulation. The combination of resistive vibration exercise and protein/bicarbonate supplementation minimally counteracted this effect.
CRIS-Team Scopus Importer:2023-12-15
Keywords: Bed rest; Cartilage biomarkers; Collagen metabolism; Immobilization; MNX-study; Type II collagen

Immune mechanisms of depression in rheumatoid arthritis - Brock, James; Basu, Neil; Schlachetzki, Johannes C.M.; Schett, Georg; McInnes, Iain B.; Cavanagh, Jonathan (Nature Reviews Rheumatology, 2023)
Depression is a common and disabling comorbidity in rheumatoid arthritis that not only decreases the likelihood of remission and treatment adherence but also increases the risk of disability and mortality in patients with rheumatoid arthritis. Compelling data that link immune mechanisms to major depressive disorder indicate possible common mechanisms that drive the pathology of the two conditions. Preclinical evidence suggests that pro-inflammatory cytokines, which are prevalent in rheumatoid arthritis, have various effects on monoaminergic neurotransmission, neurotrophic factors and measures of synaptic plasticity. Neuroimaging studies provide insight into the consequences of inflammation on the brain (for example, on neural connectivity), and clinical trial data highlight the beneficial effects of immune modulation on comorbid depression. Major depressive disorder occurs more frequently in patients with rheumatoid arthritis than in the general population, and major depressive disorder also increases the risk of a future diagnosis of rheumatoid arthritis, further highlighting the link between rheumatoid arthritis and major depressive disorder. This Review focuses on interactions between peripheral and central immunobiological mechanisms in the context of both rheumatoid arthritis and major depressive disorder. Understanding these mechanisms will provide a basis for future therapeutic development, not least in depression.
CRIS-Team Scopus Importer:2023-12-08

Immunoglobulin G-dependent inhibition of inflammatory bone remodeling requires pattern recognition receptor Dectin-1 - Seeling, Michaela; Pöhnl, Matthias; Kara, Sibel; Horstmann, Nathalie; Riemer, Carolina Daniela; Wöhner, Miriam; Liang, Chunguang; Brückner, Christin; Eiring, Patrick; Werner, Anja; Biburger, Markus; Altmann, Leon; et al. (Immunity, 2023)
Immunoglobulin G (IgG) antibodies are major drivers of inflammation during infectious and autoimmune diseases. In pooled serum IgG (IVIg), however, antibodies have a potent immunomodulatory and anti-inflammatory activity, but how this is mediated is unclear. We studied IgG-dependent initiation of resolution of inflammation in cytokine- and autoantibody-driven models of rheumatoid arthritis and found IVIg sialylation inhibited joint inflammation, whereas inhibition of osteoclastogenesis was sialic acid independent. Instead, IVIg-dependent inhibition of osteoclastogenesis was abrogated in mice lacking receptors Dectin-1 or FcγRIIb. Atomistic molecular dynamics simulations and super-resolution microscopy revealed that Dectin-1 promoted FcγRIIb membrane conformations that allowed productive IgG binding and enhanced interactions with mouse and human IgG subclasses. IVIg reprogrammed monocytes via FcγRIIb-dependent signaling that required Dectin-1. Our data identify a pathogen-independent function of Dectin-1 as a co-inhibitory checkpoint for IgG-dependent inhibition of mouse and human osteoclastogenesis. These findings may have implications for therapeutic targeting of autoantibody and cytokine-driven inflammation.
CRIS-Team Scopus Importer:2023-05-12
Keywords: bone; Dectin-1; Fc-receptor; glycosylation; IgG; inflammation; osteoclast; rheumatoid arthritis

IMMUNOLOGICAL DIFFERENCES BETWEEN PSA PATIENTS WHO ARE TUMOR NECROSIS FACTOR INHIBITOR-NAIVE AND WHO HAVE INADEQUATE RESPONSE TO TUMOR NECROSIS FACTOR INHIBITORS - Siebert, S.; Coates, L.; Schett, Georg; Raychaudhuri, S. P.; Chen, W.; Gao, S.; Chakravarty, S. D.; Shawi, M.; Lavie, F.; Theander, E.; Neuhold, M.; Kollmeier, A.; et al. (ANNALS OF THE RHEUMATIC DISEASES, 2022)
CRIS-Team WoS Importer:2022-11-04

Impact of Cytokine Inhibitor Therapy on the Prevalence, Seroconversion Rate, and Longevity of the Humoral Immune Response Against SARS-CoV-2 in an Unvaccinated Cohort - Simon, David; Tascilar, Koray; Kleyer, Arnd; Fagni, Filippo; Krönke, Gerhard; Meder, Christine; Dietrich, Peter; Orlemann, Till; Kliem, Thorsten; Moessner, Johanna; Liphardt, Anna-Maria; Schoenau, Verena; et al. (Arthritis and Rheumatology, 2022)
Objective To investigate the impact of biologic disease-modifying antirheumatic drug (bDMARD) treatment on the prevalence, seroconversion rate, and longevity of the humoral immune response against SARS-CoV-2 in patients with immune-mediated inflammatory diseases (IMIDs). Methods Anti-SARS-CoV-2 IgG antibodies were measured in a prospective cohort of health care professional controls and non-health care controls and IMID patients receiving no treatment or receiving treatment with conventional or biologic DMARDs during the first and second COVID-19 waves. Regression models adjusting for age, sex, sampling time, and exposure risk behavior were used to calculate relative risks (RRs) of seropositivity. Seroconversion rates were assessed in participants with polymerase chain reaction (PCR)-positive SARS-CoV-2 infection. Antibody response longevity was evaluated by reassessing participants who tested positive during the first wave. Results In this study, 4,508 participants (2,869 IMID patients and 1,639 controls) were analyzed. The unadjusted RR (0.44 [95% confidence interval (95% CI) 0.31-0.62]) and adjusted RR (0.50 [95% CI 0.34-0.73]) for SARS-CoV-2 IgG antibodies were significantly lower in IMID patients treated with bDMARDs compared to non-health care controls (P < 0.001), primarily driven by treatment with tumor necrosis factor inhibitors, interleukin-17 (IL-17) inhibitors, and IL-23 inhibitors. Adjusted RRs for untreated IMID patients (1.12 [95% CI 0.75-1.67]) and IMID patients receiving conventional synthetic DMARDs (0.70 [95% CI 0.45-1.08]) were not significantly different from non-health care controls. Lack of seroconversion in PCR-positive participants was more common among bDMARD-treated patients (38.7%) than in non-health care controls (16%). Overall, 44% of positive participants lost SARS-CoV-2 antibodies by follow-up, with higher rates in IMID patients treated with bDMARDs (RR 2.86 [95% CI 1.43-5.74]). Conclusion IMID patients treated with bDMARDs have a lower prevalence of SARS-CoV-2 antibodies, seroconvert less frequently after SARS-CoV-2 infection, and may exhibit a reduced longevity of their humoral immune response.
CRIS-Team WoS Importer:2022-04-08

IMPACT OF IMMOBILIZATION ON SERUM LEVELS OF CARTILAGE OLIGOMERIC MATRIX PROTEIN AND IMPLICATIONS FOR CLINICAL PRACTICE IN MUSCULOSKELETAL DISORDERS - Liphardt, A. -M.; Bruggemann, G. -P.; Zaucke, Frank; Eckstein, F.; Bloch, W.; Mundermann, A.; Mester, J.; Schett, Georg; Rech, Jürgen; Niehoff, Anja (2016)
EVALuna2:13473

IMPACT OF PRIMARY HAND OSTEOARTHRITIS ON MICROSTRUCTURE AND BIOMECHANICS IN FINGER JOINTS - Simon, David; Tascilar, Koray; Unbehend, Sara; Bayat, Sara; Meinderink, Timo; Berlin, Andreas; Rech, Jürgen; Hueber, Axel; Schett, Georg; Kleyer, Arnd (ANNALS OF THE RHEUMATIC DISEASES, 2019)
CRIS-Team WoS Importer:2019-07-16

IMPACT OF SECUKINUMAB TREATMENT ON PSORIATIC ARTHRITIS PATIENTS WITH OR WITHOUT ENTHESITIS AT BASELINE: POOLED DATA FROM FUTURE 2 AND FUTURE 3 PHASE 3 STUDIES - Mcinnes, Iain B.; Wallman, Johan K.; Schett, Georg; Quebe-Fehling, Erhard; Rasouliyan, Lawrence; Pricop, Luminita; Fasth, Andreas E.; Gaillez, Corine (2019)
EVALuna2:213229

Impact of secukinumab treatment on psoriatic arthritis patients with or without enthesitis at baseline: pooled data from two phase 3 studies (FUTURE 2 and FUTURE 3) - Wallman, J. K.; Schett, Georg; Mcinnes, I. B.; Quebe-Fehling, E.; Rasouliyan, L.; Pricop, L.; Gaillez, C.; Fasth, A. E. (2018)
EVALuna2:35014

Impaired Mitochondrial Transcription Factor A Expression Promotes Mitochondrial Damage to Drive Fibroblast Activation and Fibrosis in Systemic Sclerosis - Zhou, Xiang; Trinh, Minh Thuong; TRAN MANH, CUONG; Gießl, Andreas; Bergmann, Christina; Györfi, Andrea-Hermina; Schett, Georg; Distler, Jörg (Arthritis and Rheumatology, 2022)
Objective Mitochondrial transcription factor A (TFAM) controls the transcription of core proteins required for mitochondrial homeostasis. This study was undertaken to investigate changes in TFAM expression in systemic sclerosis (SSc), to analyze mitochondrial function, and to evaluate the consequences for fibroblast activation. Methods TFAM expression was analyzed by immunofluorescence and Western blotting. The effects of TFAM knockout were investigated in cultured fibroblasts and in murine models of bleomycin-induced skin fibrosis, bleomycin-induced lung fibrosis, and skin fibrosis induced by overexpression of constitutively active transforming growth factor beta type I receptor (TGF beta R Iota). Results TFAM expression was down-regulated in fibroblasts in SSc skin and in cultured SSc fibroblasts. The down-regulation of TFAM was associated with decreased mitochondrial number and accumulation of damaged mitochondria with release of mitochondrial DNA (mtDNA), accumulation of deletions in mtDNA, metabolic alterations with impaired oxidative phosphorylation, and release of the mitokine GDF15. Normal fibroblasts subjected to long-term, but not acute, exposure to TGF beta mimicked SSc fibroblasts, with down-regulation of TFAM and accumulation of mitochondrial damage. Down-regulation of TFAM promoted fibroblast activation with up-regulation of fibrosis-relevant Gene Ontology terms in RNA-Seq, partially in a reactive oxygen species-dependent manner. Mice with fibroblast-specific knockout of Tfam were prone to fibrotic tissue remodeling, with fibrotic responses even to NaCl instillation and enhanced sensitivity to bleomycin injection and overexpression of constitutively active TGF beta RI. TFAM knockout fostered Smad3 signaling to promote fibroblast activation. Conclusion Alterations in the key mitochondrial transcription factor TFAM in response to prolonged activation of TGF beta and associated mitochondrial damage induce transcriptional programs that promote fibroblast-to-myofibroblast transition and drive tissue fibrosis.
CRIS-Team WoS Importer:2022-04-15

Impaired periodontium and temporomandibular joints in TNF-α transgenic mice - Dobsak, Toni; Heimel, Patrick; Tangl, Stefan; Schwarze, Uwe Y.; Schett, Georg; Gruber, Reinhard (Journal of Clinical Periodontology, 2017)
TNF-? is a pathological factor causing the characteristic symptoms of periodontal disease and rheumatoid arthritis. In this study we describe the phenotypes of human tumor necrosis factor (TNF)-? transgenic mice (hTNFtg) with respect to their periodontium and the temporomandibular joint (TMJ).Periodontal structures, TMJ, and skull shape of hTNFtg mice and wild-type (WT) littermates were assessed by micro computed tomography, automated segmentation, geometric morphometrics and histologic ground sections.We show that hTNFtg mice have an eroded lamina dura and reduced periodontal ligament space compared to (WT) littermates. Transgenic mice further exhibit severe destruction of the TMJ. Geometric morphometrics revealed that hTNFtg mice have a more laterally positioned TMJ with a concomitantly enlarged zygomatic process. Mandibular and maxillary teeth occluded properly.Our findings suggest that chronic inflammation in hTNFtg mice causes destructive changes of the periodontium and the TMJ. This article is protected by copyright. All rights reserved.
EVALuna2:13443

Implementing an automated monitoring process in a digital, longitudinal observational cohort study - Lindner, Lisa; Weiss, Anja; Reich, Andreas; Kindler, Siegfried; Behrens, Frank; Braun, Juergen; Listing, Joachim; Schett, Georg; Sieper, Joachim; Strangfeld, Anja; Regierer, Anne C. (Arthritis Research & Therapy, 2021)
Background Clinical data collection requires correct and complete data sets in order to perform correct statistical analysis and draw valid conclusions. While in randomized clinical trials much effort concentrates on data monitoring, this is rarely the case in observational studies- due to high numbers of cases and often-restricted resources. We have developed a valid and cost-effective monitoring tool, which can substantially contribute to an increased data quality in observational research. Methods An automated digital monitoring system for cohort studies developed by the German Rheumatism Research Centre (DRFZ) was tested within the disease register RABBIT-SpA, a longitudinal observational study including patients with axial spondyloarthritis and psoriatic arthritis. Physicians and patients complete electronic case report forms (eCRF) twice a year for up to 10 years. Automatic plausibility checks were implemented to verify all data after entry into the eCRF. To identify conflicts that cannot be found by this approach, all possible conflicts were compiled into a catalog. This "conflict catalog" was used to create queries, which are displayed as part of the eCRF. The proportion of queried eCRFs and responses were analyzed by descriptive methods. For the analysis of responses, the type of conflict was assigned to either a single conflict only (affecting individual items) or a conflict that required the entire eCRF to be queried. Results Data from 1883 patients was analyzed. A total of n = 3145 eCRFs submitted between baseline (T0) and T3 (12 months) had conflicts (40-64%). Fifty-six to 100% of the queries regarding eCRFs that were completely missing were answered. A mean of 1.4 to 2.4 single conflicts occurred per eCRF, of which 59-69% were answered. The most common missing values were CRP, ESR, Schober's test, data on systemic glucocorticoid therapy, and presence of enthesitis. Conclusion Providing high data quality in large observational cohort studies is a major challenge, which requires careful monitoring. An automated monitoring process was successfully implemented and well accepted by the study centers. Two thirds of the queries were answered with new data. While conventional manual monitoring is resource-intensive and may itself create new sources of errors, automated processes are a convenient way to augment data quality.
CRIS-Team WoS Importer:2021-07-23

IMPROVING THE STUDY OF BONE DISEASES BY CORRELATIVE ELECTRON-, ION- AND X-RAY MICROSCOPY INCLUDING THEIR ANALYTICAL TECHNIQUES - Christiansen, S. H.; Kling, L.; Sarau, G.; Keding, R.; Pillatsch, L.; Michler, Johann; Milovanovic, P.; Busse, B.; Herrmann, M.; Schett, Georg (2018)
EVALuna2:34982

INACTIVATION OF ALDEHYDE DEHYDROGENASE 3A2 INHIBITS FIBROBLAST ACTIVATION AND TISSUE FIBROSIS - Xu, Xiaohan; Li, Y. N.; Chen, Chih-Wei; Trinh-Minh, T.; Schett, Georg; Distler, Jörg (ANNALS OF THE RHEUMATIC DISEASES, 2021)
CRIS-Team WoS Importer:2021-10-01

Inactivation of autophagy ameliorates glucocorticoid-induced and ovariectomy-induced bone loss - Lin, Neng-Yu; Chen, Chih-Wei; Kagwiria, Rosebeth; Liang, Ruifang; Beyer, Christian; Distler, Alfiya; Luther, Julia; Engelke, Klaus; Schett, Georg; Distler, Jörg (Annals of the Rheumatic Diseases, 2016)
Autophagy has recently been shown to regulate osteoclast activity and osteoclast differentiation. Here, we aim to investigate the impact of autophagy inhibition as a potential therapeutic approach for the treatment of osteoporosis in preclinical models.Systemic bone loss was induced in mice by glucocorticoids and by ovariectomy (OVX). Autophagy was targeted by conditional inactivation of autophagy-related gene 7 (Atg7) and by treatment with chloroquine (CQ). Bone density was evaluated by microCT. The role of autophagy on osteoclastogenesis was analysed by osteoclastogenesis and bone resorption assays. The quantification of receptor activator of nuclear factor ? B ligand and osteoprotegerin proteins in cocultures was performed using ELISA whereas that of osteoclast and osteoblast differentiation markers was by qPCR.Selective deletion of Atg7 in monocytes from Atg7(fl/fl)_x_LysM-Cre mice mitigated glucocorticoid-induced and OVX-induced osteoclast differentiation and bone loss compared with Atg7(fl/fl) littermates. Pharmacological inhibition of autophagy by treatment with CQ suppressed glucocorticoid-induced osteoclastogenesis and protected mice from bone loss. Similarly, inactivation of autophagy shielded mice from OVX-induced bone loss. Inhibition of autophagy led to decreased osteoclast differentiation with lower expression of osteoclast markers such as NFATc1, tartrate-resistant acid phosphatase, OSCAR and cathepsin K and attenuated bone resorption in vitro. In contrast, osteoblast differentiation was not affected by inhibition of autophagy.Pharmacological or genetic inactivation of autophagy ameliorated glucocorticoid-induced and OVX-induced bone loss by inhibiting osteoclastogenesis. These findings may have direct translational implications for the treatment of osteoporosis, since inhibitors of autophagy such as CQ are already in clinical use.
EVALuna2:10103

Inactivation of evenness interrupted (EVI) reduces experimental fibrosis by combined inhibition of canonical and non-canonical Wnt signalling - Distler, Alfiya; Ziemer, Clara; Beyer, Christian; Lin, Neng-Yu; Chen, Chih-Wei; Palumbo-Zerr, Katrin; Dees, Clara; Weidemann, Alexander; Distler, Oliver; Schett, Georg; Distler, Jörg (Annals of the Rheumatic Diseases, 2014)
Canonical as well as non-canonical Wnt signalling pathways have emerged as core pathways of fibrosis. Their profibrotic effects are mediated via distinct intracellular cascades independently of each other. Thus, inhibition of both pathways may have additive antifibrotic effects. Here, we knocked down evenness interrupted (EVI) to simultaneously target for the first time canonical and non-canonical Wnt signalling in experimental fibrosis.The antifibrotic effects of siRNA-mediated knockdown of EVI were evaluated in the mouse models of bleomycin-induced skin fibrosis and in fibrosis induced by adenoviral overexpression of a constitutively active TGF-? receptor I (AdTBRI).Knockdown of EVI decreased the release of canonical and non-canonical Wnt ligands by fibroblasts and reduced the activation of canonical and non-canonical Wnt cascades in experimental fibrosis with decreased accumulation of ?-catenin and phosphorylated JNK and cJun. Inactivation of EVI exerted potent antifibrotic effects and reduced dermal thickening, myofibroblast differentiation and accumulation of collagen in the mouse models of bleomycin-induced and AdTBR-induced fibrosis.Inhibition of Wnt secretion by knockdown of EVI inhibits canonical and non-canonical Wnt signalling and effectively reduces experimental fibrosis in different preclinical models. Inhibition of Wnt secretion may thus be an interesting approach for the treatment of fibrosis.
EVALuna2:3691

Inactivation of tankyrases reduces experimental fibrosis by inhibiting canonical Wnt signalling - Akhmetshina, Alfiya; Deloch, Lisa; Huang, Jingang; Dees, Clara; Lin, Neng-Yu; Palumbo-Zerr, Katrin; Beyer, Christian; Weidemann, Alexander; Distler, Oliver; Schett, Georg; Distler, Jörg (Annals of the Rheumatic Diseases, 2013)

Increased bone density and resistance to ovariectomy-induced bone loss in FoxP3-transgenic mice based on impaired osteoclast differentiation. - Zaiss, Mario; Sarter, Kerstin; Heß, Andreas; Engelke, Klaus; Boehm, Christina; Nimmerjahn, Falk; Voll, Reinhard; Schett, Georg; David, Jean-Pierre (Arthritis and Rheumatism, 2010)
OBJECTIVE Immune activation triggers bone loss. Activated T cells are the cellular link between immune activation and bone destruction. The aim of this study was to determine whether immune regulatory mechanisms, such as naturally occurring Treg cells, also extend their protective effects to bone homeostasis in vivo. METHODS Bone parameters in FoxP3-transgenic (Tg) mice were compared with those in their wild-type (WT) littermate controls. Ovariectomy was performed in FoxP3-Tg mice as a model of postmenopausal osteoporosis, and the bone parameters were analyzed. The bones of RAG-1(-/-) mice were analyzed following the adoptive transfer of isolated CD4+CD25+ T cells. CD4+CD25+ T cells and CD4+ T cells isolated from FoxP3-Tg mice and WT mice were cocultured with monocytes to determine their ability to suppress osteoclastogenesis in vitro. RESULTS FoxP3-Tg mice developed higher bone mass and were protected from ovariectomy-induced bone loss. The increase in bone mass was found to be the result of impaired osteoclast differentiation and bone resorption in vivo. Bone formation was not affected. Adoptive transfer of CD4+CD25+ T cells into T cell-deficient RAG-1(-/-) mice also increased the bone mass, indicating that Treg cells directly affect bone homeostasis without the need to engage other T cell lineages. CONCLUSION These data demonstrate that Treg cells can control bone resorption in vivo and can preserve bone mass during physiologic and pathologic bone remodeling.

Increased Cartilage Damage in Metacarpophalangeal Joints of ACPA Positive Rheumatoid Arthritis (RA) Patients Using T2 Mapping in 3 Tesla Magnetresonance Imaging (MRI) - Renner, Nina; Kleyer, Arnd; Simon, David; Krönke, Gerhard; Rech, Jürgen; Schett, Georg; Welsch, Goetz; Pachowsky, Milena (2017)
EVALuna2:33441

INCREASE OF CORTICAL MICRO-CHANNELS (COMICS) AS A NEW FEATURE OF STRUCTURAL DAMAGE IN PAIENTS WITH RHEUMATOID ARTHRITIS - Werner, David; Simon, David; Englbrecht, Matthias; Stemmler, F.; Berlin, Andreas; Haschka, J.; Renner, Nina; Buder, Thomas; Rech, Jürgen; Engelke, Klaus; Hueber, Axel; Schett, Georg; et al. (2017)
EVALuna2:34454

Independent development of inflammation and new bone formation in ankylosing spondylitis - Schett, Georg (Arthritis & Rheumatism-Arthritis Care & Research, 2012)
EVALuna2:13248

Individually Tailored Predictions of Flare Probability for Rheumatoid Arthritis Patients on Biologic DMARDs Based on Machine Learning Stacking Meta-Classifier - Vodencarevic, Asmir; Simon, David; Hartmann, Fabian; Reiser, Michaela; Hueber, Axel; Tascilar, Koray; Kleyer, Arnd; Zimmermann-Rittereiser, Marcus; Schett, Georg (ARTHRITIS & RHEUMATOLOGY, 2019)
CRIS-Team WoS Importer:2020-02-07

Induction of apoptosis in circulating angiogenic cells by microparticles. - Distler, Jörg; Akhmetshina, Alfiya; Dees, Clara; Juengel, Astrid; Stürzl, Michael; Gay, Steffen; Pisetsky, David S.; Schett, Georg; Distler, Oliver (Arthritis & Rheumatism-Arthritis Care & Research, 2011)
Systemic sclerosis (SSc) is an autoimmune disease marked by aberrant activation and apoptosis of endothelial cells (ECs) and decreased numbers of circulating angiogenic cells (CACs). The aim of this study was to analyze whether microparticles might link pathologic activation and apoptosis of ECs with reduced numbers of CACs. Apoptosis was quantified by staining for annexin V and measurement of caspase 3 activity. The uptake of microparticles by CACs was determined by fluorescence-activated cell sorting and by fluorescence microscopy. Tritiated arachidonic acid and phosphatidylinositol 3,5-bisphosphate were used to demonstrate the transfer of arachidonic acid and highlight the role of the acid sphingomyelinase in microparticle-induced apoptosis of endothelial progenitor cells. Microparticles derived from activated or apoptotic ECs, the expression of which is strongly increased in the blood of patients with SSc, induce apoptosis in CACs in a dose-dependent manner. Microparticles, which are rich in arachidonic acid, are phagocytosed by CACs. Inhibition of phagocytosis prevents the induction of apoptosis in CACs by microparticles. Microparticles can transport arachidonic acid from ECs to CACs, and purified arachidonic acid mimics the proapoptotic effects of microparticles. Arachidonic acid activates the acid sphingomyelinase, and inhibition of acid sphingomyelinase prevents microparticle-induced apoptosis of CACs. Thus, phagocytosis of microparticles might stimulate the activity of acid sphingomyelinase and activate the apoptotic machinery. The induction of apoptosis in CACs by microparticles derived from ECs provides a novel link between aberrant activation or apoptosis of ECs, decreased numbers of CACs, and impaired formation of new vessels in SSc. OBJECTIVE METHODS RESULTS CONCLUSION

Induction of osteoclastogenesis and bone loss by human autoantibodies against citrullinated vimentin. - Harre, Ulrike; Georgess, Dan; Bang, Holger; Bozec, Aline; Axmann, Roland; Ossipova, Elena; Jakobsson, Per-Johan; Baum, Wolfgang; Nimmerjahn, Falk; Szarka, Eszter; Sarmay, Gabriella; Krumbholz, Grit; et al. (Journal of Clinical Investigation, 2012)
Autoimmunity is complicated by bone loss. In human rheumatoid arthritis (RA), the most severe inflammatory joint disease, autoantibodies against citrullinated proteins are among the strongest risk factors for bone destruction. We therefore hypothesized that these autoantibodies directly influence bone metabolism. Here, we found a strong and specific association between autoantibodies against citrullinated proteins and serum markers for osteoclast-mediated bone resorption in RA patients. Moreover, human osteoclasts expressed enzymes eliciting protein citrullination, and specific N-terminal citrullination of vimentin was induced during osteoclast differentiation. Affinity-purified human autoantibodies against mutated citrullinated vimentin (MCV) not only bound to osteoclast surfaces, but also led to robust induction of osteoclastogenesis and bone-resorptive activity. Adoptive transfer of purified human MCV autoantibodies into mice induced osteopenia and increased osteoclastogenesis. This effect was based on the inducible release of TNF-α from osteoclast precursors and the subsequent increase of osteoclast precursor cell numbers with enhanced expression of activation and growth factor receptors. Our data thus suggest that autoantibody formation in response to citrullinated vimentin directly induces bone loss, providing a link between the adaptive immune system and bon

INDUCTION OF SUSTAINED REMISSION IN EARLY INFLAMMATORY ARTHRITIS WITH THE COMBINATION OF INFLIXIMAB PLUS METHOTREXATE, METHOTREXATE ALONE OR PLACEBO: THE DINORA TRIAL - Stamm, T. A.; Machold, K.; Aletaha, D.; Alasti, F.; Lipsky, P.; Pisetsky, D.; Landewe, R.; Van Der Heijde, D.; Sepriano, A.; Aringer, M.; Boumpas, D.; Burmester, G.; et al. (2017)
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Induction of sustained remission in early inflammatory arthritis with the combination of infliximab plus methotrexate: the DINORA trial - Stamm, Tanja Alexandra; Machold, Klaus Peter; Aletaha, Daniel; Alasti, Farideh; Lipsky, Peter; Pisetsky, David; Landewe, Robert; Van Der Heijde, Desiree; Sepriano, Alexandre; Aringer, Martin; Boumpas, Dimitri; Burmester, Gerd; et al. (Arthritis Research & Therapy, 2018)
BACKGROUND: In the present study, we explored the effects of immediate induction therapy with the anti-tumour necrosis factor (TNF)α antibody infliximab (IFX) plus methotrexate (MTX) compared with MTX alone and with placebo (PL) in patients with very early inflammatory arthritis. METHODS: In an investigator-initiated, double-blind, randomised, placebo-controlled, multi-centre trial (ISRCTN21272423, http://www.isrctn.com/ISRCTN21272423 ), patients with synovitis of 12 weeks duration in at least two joints underwent 1 year of treatment with IFX in combination with MTX, MTX monotherapy, or PL randomised in a 2:2:1 ratio. The primary endpoint was clinical remission after 1 year (sustained for at least two consecutive visits 8 weeks apart) with remission defined as no swollen joints, 0-2 tender joints, and an acute-phase reactant within the normal range. RESULTS: Ninety patients participated in the present study. At week 54 (primary endpoint), 32% of the patients in the IFX + MTX group achieved sustained remission compared with 14% on MTX alone and 0% on PL. This difference (p < 0.05 over all three groups) was statistically significant for IFX + MTX vs PL (p < 0.05), but not for IFX + MTX vs MTX (p = 0.10), nor for MTX vs PL (p = 0.31). Remission was maintained during the second year on no therapy in 75% of the IFX + MTX patients compared with 20% of the MTX-only patients. CONCLUSIONS: These results indicate that patients with early arthritis can benefit from induction therapy with anti-TNF plus MTX compared with MTX alone, suggesting that intensive treatment can alter the disease evolution. TRIAL REGISTRATION: The trial was registered at http://www.isrctn.com/ISRCTN21272423 on 4 October 2007 (date applied)/12 December 2007 (date assigned). The first patient was included on 24 October 2007.
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INDUCTION OF TH2 CELLS AND EOSINOPHIL BY INFECTION WITH NIPPOSTRONGYLUS BRASILIENSIS PROTECTS AGAINST RHEUMATOID ARTHRITIS - Chen, Zhu; Oeser, Katharina; Baum, Wolfgang; Vöhringer, David; Schett, Georg; Bozec, Aline (2014)
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Inefficient clearance of dying cells in patients with SLE: Anti-dsDNA autoantibodies, MFG-E8, HMGB-1 and other players - Kruse, Kristin; Janko, Christina; Urbonaviciute, Vilma; Mierke, Claudia T.; Winkler, Thomas; Voll, Reinhard E.; Schett, Georg; Munoz, Luis E.; Herrmann, Martin (Apoptosis, 2010)
Systemic lupus erythematosus (SLE) is a complex disease resulting from inflammatory responses of the immune system against several autoantigens. Inflammation is conditioned by the continuous presence of autoantibodies and leaked autoantigens, e.g. from not properly cleared dying and dead cells. Various soluble molecules and biophysical properties of the surface of apoptotic cells play significant roles in the appropriate recognition and further processing of dying and dead cells. We exemplarily discuss how Milk fat globule epidermal growth factor 8 (MFG-E8), biophysical membrane alterations, High mobility group box 1 (HMGB1), C-reactive protein (CRP), and anti-nuclear autoantibodies may contribute to the etiopathogenesis of the disease. Up to date knowledge about these key elements may provide new insights that lead to the development of new treatment strategies of the disease. © 2010 Springer Science+Business Media, LLC.
Keywords: ANA; Biophysical features; Clearance; CRP; HMGB-1; MFG-E8; Phosphatidylserine; Plasma membrane

Inflammatory activation of the FcγR and IFNγR pathways co-influences the differentiation and activity of osteoclasts - Grötsch, Bettina; Schachtschabel, Elisabeth; Tripal, Philipp; Schmid, Benjamin; Smith, Ana-Suncana; Schett, Georg; Bozec, Aline (Frontiers in Immunology, 2022)
Osteoclasts are polykaryons formed by cell–cell fusion of highly motile progenitors of the myeloid lineage. Osteoclast activity can preserve skeletal strength and bone homeostasis. However, osteoclasts are responsible for bone destruction in rheumatoid arthritis (RA). Fc receptors activated by IgG immune complexes (IC) can boost osteoclast differentiation and bone loss in the course of RA. In contrast, interferon (IFN) γ secreted by immune cells blocks osteoclast activation. Despite their hypothetical importance in the regulation of osteoclast differentiation in RA, the interconnection between the two pathways has not been described so far. Here, we show by total internal reflection fluorescence (TIRF) microscopy that FcγR3 and IFNγ receptor (IFNγR) locate at close vicinity to each other on the human osteoclast surface. Moreover, the average distance increases during the differentiation process. Interestingly, FcγR and IFNγR activation shapes the position of both receptors to each other. Surprisingly, the inhibitory action of IFNγ on in-vitro human osteoclast differentiation depends on the osteoclast differentiation stage. Indeed, IFNγR activation in early osteoclast precursors completely inhibits the formation of polynucleated osteoclasts, while in premature osteoclasts, it further enhanced their fusion. In addition, gene expression analyses showed that IFNγR activation on early precursor cells but not on premature osteoclasts could induce FcγR expression, suggesting a co-regulation of both receptors on human osteoclast precursors. Phosphokinase array data of precursor cells demonstrate that the observed divergence of IFNγR signaling is dependent on the mitogen−activated protein kinase (MAPK) downstream signaling pathway. Overall, our data indicate that FcγR and IFNγR signaling pathways co-influence the differentiation and activity of osteoclasts dependent on the differentiation state, which might reflect the different stages in RA.
CRIS-Team Scopus Importer:2022-10-07
Keywords: FcγR3; IFNγR; IFNγR signaling; ITAM signaling; Osteoclast; rheumatoid arthritis (RA)

Inflammatory Arthritis and Bone Metabolism Regulated by Type 2 Innate and Adaptive Immunity - Omata, Yasunori; Frech, Michael; Saito, Taku; Schett, Georg; Zaiss, Mario; Tanaka, Sakae (International Journal of Molecular Sciences, 2022)
While type 2 immunity has traditionally been associated with the control of parasitic infections and allergic reactions, increasing evidence suggests that type 2 immunity exerts regulatory functions on inflammatory diseases such as arthritis, and also on bone homeostasis. This review summarizes the current evidence of the regulatory role of type 2 immunity in arthritis and bone. Key type 2 cytokines, like interleukin (IL)-4 and IL-13, but also others such as IL-5, IL-9, IL-25, and IL-33, exert regulatory properties on arthritis, dampening inflammation and inducing resolution of joint swelling. Furthermore, these cytokines share anti-osteoclastogenic properties and thereby reduce bone resorption and protect bone. Cellular effectors of this action are both T cells (i.e., Th2 and Th9 cells), but also non-T cells, like type 2 innate lymphoid cells (ILC2). Key regulatory actions mediated by type 2 cytokines and immune cells on both inflammation as well as bone homeostasis are discussed.
CRIS-Team Scopus Importer:2022-01-28
Keywords: Osteoclast; Rheumatoid arthritis; Type 2 immunity; Type 2 innate lymphoid cells

Inflammatory arthritis and systemic bone loss are attenuated by gastrointestinal helminth parasites - Sarter, Kerstin; Kulagin, Manuel; Schett, Georg; Harris, Nicola L.; Zaiss, Mario M. (Autoimmunity, 2017)
Infections with different helminth species have been observed to ameliorate a variety of chronic inflammatory diseases. Herein, we show that the natural murine helminth species, Heligmosomoides polygyrus bakeri (Hp) is capable of attenuating disease severity in two different inflammatory arthritis models. Furthermore, we show that excretory-secretory (ES) products from Hp directly suppress osteoclast differentiation in vitro. Taken together, these results demonstrate that helminth infections can dampen autoimmune diseases and highlight a previously unrecognized and important role for ES products, by directly impacting on bone destruction.
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Inflammatory bone spur formation in psoriatic arthritis is different from bone spur formation in hand osteoarthritis - Finzel, Stephanie; Sahinbegovic, Enijad; Kocijan, Roland; Engelke, Klaus; Englbrecht, Matthias; Schett, Georg (Arthritis and Rheumatology, 2014)
To investigate the different patterns of bone spur formation in psoriatic arthritis (PsA) and hand osteoarthritis (OA), using high-resolution peripheral quantitative computed tomography (QCT).The study group comprised 70 subjects (25 patients with PsA, 25 patients with hand OA, and 20 healthy controls). The 2 patient groups were similar with regard to age and sex distribution and clinical involvement of the metacarpophalangeal (MCP) joints. All patients underwent high-resolution peripheral QCT scanning of the second, third, and fourth MCP joints of the dominantly affected hand. Demographic and disease-specific data were recorded, and the number, size, and distribution of bone spurs were assessed and compared between patients with PsA and patients with hand OA.The overall number and size of bone spurs were similar in patients with PsA and patients with hand OA. However, localization of lesions within individual joints was substantially different between patients with PsA and those with hand OA. In PsA, bone spurs dominated the radial sides of the joints (for the metacarpal head of the second joint, P < 0.001 versus hand OA; for the base of the second phalangeal joint, P < 0.001 versus hand OA), whereas the palmar and dorsal quadrants were the predilection sites in hand OA. Detailed anatomic analysis showed that bone spurs in the entheseal regions were prominent in patients with PsA but rare in patients with hand OA, and that bone spurs in patients with hand OA typically emerged at the cartilage-bone interphase and the joint margins.Our findings show that the overall number and size of bone spurs are similar in patients with PsA and patients with hand OA. Nonetheless, the anatomic sites of bone proliferation are different between these 2 groups of patients.
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Inflammatory monocytes and Fcγ receptor IV on osteoclasts are critical for bone destruction during inflammatory arthritis in mice. - Seeling, Michaela; Hillenhoff, Ulrike; David, Jean Pierre; Schett, Georg; Tuckermann, Jan; Lux, Anja; Nimmerjahn, Falk (Proceedings of the National Academy of Sciences of the United States of America, 2013)
Destruction of bone tissue by osteoclasts represents a severe pathological phenotype during inflammatory arthritis and results in joint pain and bone malformations. Previous studies have established the essential role of cytokines including TNFα and receptor-ligand interactions, such as the receptor activator of nuclear factor-kappa B-receptor activator of nuclear factor-kappa B ligand interaction for osteoclast formation during joint inflammation. Moreover, autoantibodies contribute to joint inflammation in inflammatory arthritis by triggering cellular fragment crystallizable (Fc)γ receptors (FcγR), resulting in the release of proinflammatory cytokines and chemokines essential for recruitment and activation of innate immune effector cells. In contrast, little is known about the expression pattern and function of different FcγRs during osteoclast differentiation. This would allow osteoclasts to directly interact with autoantibody immune complexes, rather than being influenced indirectly via proinflammatory cytokines released upon immune complex binding to other FcγR-expressing innate immune cells. To address this question, we studied FcγR expression and function on osteoclasts during the steady state and during acute joint inflammation in a model of inflammatory arthritis. Our results suggest that osteoclastogenesis is directly influenced by IgG autoantibody binding to select activating FcγRs on immature osteoclasts, resulting in enhanced osteoclast generation and, ultimately, bone destruction.

Inflammatory osteolysis: a conspiracy against bone - Mbalaviele, Gabriel; Novack, Deborah V.; Schett, Georg; Teitelbaum, Steven L. (Journal of Clinical Investigation, 2017)
There are many causes of inflammatory osteolysis, but regardless of etiology and cellular contexts, the osteoclast is the bone-degrading cell. Thus, the impact of inflammatory cytokines on osteoclast formation and function was among the most important discoveries advancing the treatment of focal osteolysis, leading to development of therapeutic agents that either directly block the bone-resorptive cell or do so indirectly via cytokine arrest. Despite these advances, a substantial number of patients with inflammatory arthritis remain resistant to current therapies, and even effective anti-inflammatory drugs frequently do not repair damaged bone. Thus, insights into events such as those impacted by inflammasomes, which signal through cytokine-dependent and -independent mechanisms, are needed to optimize treatment of inflammatory osteolysis.
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Influence of Antisynthetase Antibodies Specificities on Antisynthetase Syndrome Clinical Spectrum Time Course - Cavagna, Lorenzo; Trallero-Araguas, Ernesto; Meloni, Federica; Cavazzana, Ilaria; Rojas-Serrano, Jorge; Feist, Eugen; Zanframundo, Giovanni; Morandi, Valentina; Meyer, Alain; Pereira Da Silva, Jose Antonio; Matos Costa, Carlo Jorge; Molberg, Oyvind; et al. (Journal of Clinical Medicine, 2019)
Antisynthetase syndrome (ASSD) is a rare clinical condition that is characterized by the occurrence of a classic clinical triad, encompassing myositis, arthritis, and interstitial lung disease (ILD), along with specific autoantibodies that are addressed to different aminoacyl tRNA synthetases (ARS). Until now, it has been unknown whether the presence of a different ARS might affect the clinical presentation, evolution, and outcome of ASSD. In this study, we retrospectively recorded the time of onset, characteristics, clustering of triad findings, and survival of 828 ASSD patients (593 anti-Jo1, 95 anti-PL7, 84 anti-PL12, 38 anti-EJ, and 18 anti-OJ), referring to AENEAS (American and European NEtwork of Antisynthetase Syndrome) collaborative group's cohort. Comparisons were performed first between all ARS cases and then, in the case of significance, while using anti-Jo1 positive patients as the reference group. The characteristics of triad findings were similar and the onset mainly began with a single triad finding in all groups despite some differences in overall prevalence. The "ex-novo" occurrence of triad findings was only reduced in the anti-PL12-positive cohort, however, it occurred in a clinically relevant percentage of patients (30%). Moreover, survival was not influenced by the underlying anti-aminoacyl tRNA synthetase antibodies' positivity, which confirmed that antisynthetase syndrome is a heterogeneous condition and that antibody specificity only partially influences the clinical presentation and evolution of this condition.
CRIS-Team WoS Importer:2020-01-03

Influence of antiTNF-alpha antibody treatment on fracture healing under chronic inflammation - Timmen, Melanie; Hidding, Heriburg; Wieskoetter, Britta; Baum, Wolfgang; Pap, Thomas; Raschke, Michael J.; Schett, Georg; Zwerina, Jochen; Stange, Richard (BMC Musculoskeletal Disorders, 2014)
The overexpression of tumor necrosis factor (TNF)-? leads to systemic as well as local loss of bone and cartilage and is also an important regulator during fracture healing. In this study, we investigate how TNF-? inhibition using a targeted monoclonal antibody affects fracture healing in a TNF-? driven animal model of human rheumatoid arthritis (RA) and elucidate the question whether enduring the anti TNF-? therapy after trauma is beneficial or not.A standardized femur fracture was applied to wild type and human TNF-? transgenic mice (hTNFtg mice), which develop an RA-like chronic polyarthritis. hTNFtg animals were treated with anti-TNF antibody (Infliximab) during the fracture repair. Untreated animals served as controls. Fracture healing was evaluated after 14 and 28 days of treatment by clinical assessment, biomechanical testing and histomorphometry.High levels of TNF-? influence fracture healing negatively, lead to reduced cartilage and more soft tissue in the callus as well as decreased biomechanical bone stability. Blocking TNF-? in hTNFtg mice lead to similar biomechanical and histomorphometrical properties as in wild type.High levels of TNF-? during chronic inflammation have a negative impact on fracture healing. Our data suggest that TNF-? inhibition by an anti-TNF antibody does not interfere with fracture healing.
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Inhibited Arginase-1 Expression by Fra-1 in Myeloid Cells Enhance Rheumatoid Arthritis Inflammation - Hannemann, Nicole; Schnelzer, A.; Jordan, J.; Eberhardt, Martin; Schleicher, Ulrike; Uebe, Steffen; Ekici, Arif Bülent; Reid, Stephen; Sonnewald, Sophia; Bäuerle, Tobias; Bogdan, Christian; Vera, Julio; et al. (2017)
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Inhibition of activator protein 1 signaling abrogates transforming growth factor β-mediated activation of fibroblasts and prevents experimental fibrosis - Avouac, Jerome; Palumbo, Katrin; Tomcik, Michal; Zerr, Pawel; Dees, Clara; Horn, Angelika; Maurer, Britta; Akhmetshina, Alfiya; Beyer, Christian; Sadowski, Anika; Schneider, Holm; Shiozawa, Shunichi; et al. (Arthritis and Rheumatism, 2012)
Objective To investigate whether c-Jun and c-Fos contribute to the pathologic activation of fibroblasts in systemic sclerosis (SSc) and to evaluate the antifibrotic potential of selective activator protein 1 (AP-1) inhibition. Methods Expression of c-Jun and c-Fos was determined by real-time polymerase chain reaction (PCR) and immunohistochemical analysis. Fibroblasts were stimulated with transforming growth factor β (TGFβ) and incubated with T-5224, a small-molecule inhibitor of AP-1, or were transfected with small interfering RNA (siRNA) duplexes against c-Jun and c-Fos. Collagen synthesis was quantified by real-time PCR and hydroxyproline assay. Differentiation of resting fibroblasts into myofibroblasts was assessed by staining for α-smooth muscle actin and stress fibers. The antifibrotic potential of T-5224 was evaluated in mouse models of dermal fibrosis induced by bleomycin or by adenoviral overexpression of a constitutively active TGFβ receptor type I. Results Up-regulation of c-Jun and c-Fos was detected in mouse models of SSc and in the skin and dermal fibroblasts of patients with SSc. Stimulation of healthy fibroblasts with TGFβ induced the expression of c-Jun and c-Fos. Treatment with T-5224 or nucleofection with siRNA directed against c-Jun and c-Fos abrogated the profibrotic effects of TGFβ. T-5224 decreased the release of collagen selectively in SSc fibroblasts. T-5224 was well tolerated and prevented dermal fibrosis induced by bleomycin or by adenoviral activation of TGFβ signaling. Conclusion AP-1 is up-regulated in a TGFβ-dependent manner in SSc. The selective AP-1 inhibitor T-5224 reduced collagen synthesis selectively in SSc fibroblasts and efficiently prevented the development of experimental dermal fibrosis. Thus, AP-1 might be a promising new molecular target for the treatment of SSc. Copyright © 2012 by the American College of Rheumatology.
CRIS-Team Scopus Importer:2020-07-01

INHIBITION OF ARGINASE-1 EXPRESSION BY THE TRANSCRIPTION FACTOR FRA-1 IN MACROPHAGES EXACERBATES RHEUMATOID ARTHRITIS INFLAMMATION - Hannemann, Nicole; Cao, Shan; Schnelzer, A.; Jordan, J.; Eberhardt, Martin; Schleicher, Ulrike; Uebe, Steffen; Ekici, Arif Bülent; Rech, Jürgen; Bäuerle, Tobias; Bogdan, Christian; Vera, Julio; et al. (ANNALS OF THE RHEUMATIC DISEASES, 2019)
CRIS-Team WoS Importer:2019-05-17

Inhibition of bone remodeling in young mice by bisphosphonate displaces the plasma cell niche into the spleen - Teufel, Stefan; Groetsch, Bettina; Luther, Julia; Derer, Anja; Schinke, Thorsten; Amling, Michael; Schett, Georg; Mielenz, Dirk; David, Jean-Pierre (Journal of Immunology, 2014)
The bone marrow provides niches for early B cell differentiation and long-lived plasma cells. Therefore, it has been hypothesized that perturbing bone homeostasis might impact B cell function and Ab production. This hypothesis is highly relevant for patients receiving long-term treatment with antiresorptive drugs. We therefore analyzed the humoral immune response of mice chronically treated with ibandronate, a commonly used bisphosphonate. We confirmed the increased bone mass caused by inhibition of osteoclast activity and also the strongly reduced bone formation because of decreased osteoblast numbers in response to ibandronate. Thus, bisphosphonate drastically inhibited bone remodeling. When ibandronate was injected into mice after a primary immunization to mimic common antiosteoporotic treatments, the generation of the various B cell populations, the response to booster immunization, and the generation of plasma cells were surprisingly normal. Mice also responded normally to immunization when ibandronate was applied to naive mice. However, there, ibandronate shunted the homing of bone marrow plasma cells. Interestingly, ibandronate reduced the numbers of megakaryocytes, a known component of the bone marrow plasma cell niche. In line with normal Ab responses, increased plasma cell populations associated with increased megakaryocyte numbers were then observed in the spleens of the ibandronate-treated mice. Thus, although inhibition of bone remodeling disturbed the bone marrow plasma cell niche, a compensatory niche may have been created by relocating the megakaryocytes into the spleen, thereby allowing normal B cell responses. Therefore, megakaryocytes may act as a key regulator of plasma cell niche plasticity.
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Inhibition of Hedgehog Acyltransferase Alleviates the Profibrotic Effects of Transforming Growth Factor beta in Systemic Sclerosis - Liang, Ruifang; Kagwiria, Rosebeth; Dees, Clara; Zhang, Yun; Distler, Oliver; Schett, Georg; Distler, Jörg (2017)
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INHIBITION OF NOTCH1 PROMOTES HEDGEHOG SIGNALING IN A HES1-DEPENDENT MANNER AND EXACERBATES EXPERIMENTAL OSTEOARTHRITIS - Lin, N. Y.; Distler, A.; Beyer, Christian; Philipi-Schobinger, A.; Stock, Michael; Niemeier, A.; Dell'Accio, F.; Schett, Georg; Distler, Jörg (2016)
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Inhibition of Notch1 promotes hedgehog signalling in a HES1-dependent manner in chondrocytes and exacerbates experimental osteoarthritis - Lin, Neng-Yu; Distler, Alfiya; Beyer, Christian; Philipi-Schöbinger, Ariella; Breda, Silvia; Dees, Clara; Stock, Michael; Tomcik, Michal; Niemeier, Andreas; Dell'Accio, Francesco; Gelse, Kolja; Mattson, Mark P; et al. (Annals of the Rheumatic Diseases, 2016)
Notch ligands and receptors have recently been shown to be differentially expressed in osteoarthritis (OA). We aim to further elucidate the functional role of Notch signalling in OA using Notch1 antisense transgenic (Notch1 AS) mice.Notch and hedgehog signalling were analysed by real-time PCR and immunohistochemistry. Notch-1 AS mice were employed as a model of impaired Notch signalling in vivo. Experimental OA was induced by destabilisation of the medial meniscus (DMM). The extent of cartilage destruction and osteophyte formation was analysed by safranin-O staining with subsequent assessment of the Osteoarthritis Research Society International (OARSI) and Mankin scores and µCT scanning. Collagen X staining was used as a marker of chondrocyte hypertrophy. The role of hairy/enhancer of split 1 (Hes-1) was investigated with knockdown and overexpression experiments.Notch signalling was activated in human and murine OA with increased expression of Jagged1, Notch-1, accumulation of the Notch intracellular domain 1 and increased transcription of Hes-1. Notch1 AS mice showed exacerbated OA with increases in OARSI scores, osteophyte formation, increased subchondral bone plate density, collagen X and osteocalcin expression and elevated levels of Epas1 and ADAM-TS5 mRNA. Inhibition of the Notch pathway induced activation of hedgehog signalling with induction of Gli-1 and Gli-2 and increased transcription of hedgehog target genes. The regulatory effects of Notch signalling on Gli-expression were mimicked by Hes-1.Inhibition of Notch signalling activates hedgehog signalling, enhances chondrocyte hypertrophy and exacerbates experimental OA including osteophyte formation. These data suggest that the activation of the Notch pathway may limit aberrant hedgehog signalling in OA.
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Inhibition of Nuclear Receptor Coactivator 3 Attenuates Fibrosis in Murine Models of Systemic Sclerosis - Pötter, Sebastian; Dees, Clara; Bergmann, Christina; Distler, Oliver; Schett, Georg; Distler, Jörg; Ramming, Andreas (2018)
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Inhibition of Osteoarthritis by Adipose-Derived Stromal Cells Overexpressing Fra-1 in Mice - Schwabe, Kay; Garcia, Mireia; Ubieta, Kenia; Hannemann, Nicole; Herbort, Bettina; Luther, Julia; Noel, Daniele; Jorgensen, Christian; Casteilla, Louis; David, Jean-Pierre; Stock, Michael; Herrmann, Martin; et al. (Arthritis and Rheumatology, 2016)
To determine whether overexpression of the activator protein 1 (AP-1) transcription factor Fra-1 in adipose-derived stromal cells (ADSCs) is an effective treatment of collagenase-induced osteoarthritis (OA).OA was induced by injection of collagenase into the knee joints of male C57BL/6 mice. ADSCs were isolated from the inguinal fat pads of 8-week-old wild-type or Fra-1-transgenic mice and injected into the knee joints of mice with collagenase-induced OA 7 days after OA induction. Histologic analyses of cartilage destruction and chondrocyte cell death were performed. Adipogenic differentiation capacity was evaluated, gene expression was analyzed, and cytokine profiling was performed in stromal vascular fractions (SVFs) and ADSCs.OA-related cartilage destruction and chondrocyte cell death were significantly reduced in mouse knee joints treated with ADSCs from Fra-1-transgenic mice compared to mouse knee joints treated with ADSCs from wild-type mice. This effect did not result from the higher number of adipogenic progenitors observed in SVFs from Fra-1-transgenic compared to wild-type mouse fat pads, since injection of wild-type mouse ADSCs enriched for adipogenic progenitors did not show any additional chondroprotective effects compared to nonsorted ADSCs. However, Fra-1-transgenic mouse ADSCs showed decreased adipogenic differentiation capacity. Moreover, Fra-1 significantly inhibited proinflammatory interleukin-6 and pentraxin 3 expression, while increasing the expression of extracellular matrix proteins, such as periostin and spondin 1. These findings suggest that Fra-1 overexpression leads to an increased chondroprotective effect of ADSCs in OA.ADSCs overexpressing Fra-1 effectively protect against OA. Our data indicate that genetic modifications of ADSCs, such as Fra-1 overexpression, may improve their potential to protect articular cartilage against OA-mediated damage.
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Inhibition of phosphodiesterase 4 (PDE4) reduces dermal fibrosis by interfering with the release of interleukin-6 from M2 macrophages - Maier, Christiane; Bergmann, Christina; Weinkam, Rita; Kittan, Nicolai; Schett, Georg; Distler, Jörg; Beyer, Christian; Ramming, Andreas (Annals of the Rheumatic Diseases, 2017)
To investigate the disease-modifying effects of phosphodiesterase 4 (PDE4) inhibition in preclinical models of systemic sclerosis (SSc).We studied the effects of PDE4 inhibition in a prevention and a treatment model of bleomycin-induced skin fibrosis, in the topoisomerase mouse model as well as in a model of sclerodermatous chronic graft-versus-host disease. To better understand the mode of action of PDE4 blockade in preclinical models of SSc, we investigated fibrosis-relevant mediators in fibroblasts and macrophages from healthy individuals and patients suffering from diffuse-cutaneous SSc on blockade of PDE4.Specific inhibition of PDE4 by rolipram and apremilast had potent antifibrotic effects in bleomycin-induced skin fibrosis models, in the topoisomerase I mouse model and in murine sclerodermatous chronic graft-versus-host disease. Fibroblasts were not the direct targets of the antifibrotic effects of PDE4 blockade. Reduced leucocyte infiltration in lesional skin on PDE4 blockade suggested an immune-mediated mechanism. Further analysis revealed that PDE4 inhibition decreased the differentiation of M2 macrophages and the release of several profibrotic cytokines, resulting in reduced fibroblast activation and collagen release. Within these profibrotic mediators, interleukin-6 appeared to play a central role.PDE4 inhibition reduces inflammatory cell activity and the release of profibrotic cytokines from M2 macrophages, leading to decreased fibroblast activation and collagen release. Importantly, apremilast is already approved for the treatment of psoriasis and psoriatic arthritis. Therefore, PDE4 inhibitors might be further developed as potential antifibrotic therapies for patients with SSc. Our findings suggest that particularly patients with inflammation-driven fibrosis might benefit from PDE4 blockade.
EVALuna2:13394

Inhibition of sumoylation prevents experimental fibrosis - Khodzhigorova, Aisa; Distler, Alfiya; Lang, Veronika; Dees, Clara; Schneider, Holm; Beyer, Christian; Gelse, Kolja; Distler, Oliver; Schett, Georg; Distler, Jörg (Annals of the Rheumatic Diseases, 2012)
Objectives: Fibrosis is a predominant cause of death in systemic sclerosis (SSc). First epigenetic modifications have recently been shown to contribute to activation of SSc fibroblasts. Here, we investigated inhibition of sumoylation as a novel antifibrotic approach. Methods: Sumoylation was inhibited by siRNA-mediated knockdown of the Small Ubiquitin-like MOdifiers (SUMO) E2-conjugating enzyme Ubc9, which is essential for sumoylation. The effects of knockdown of Ubc9 were analysed in bleomycin-induced dermal fibrosis, and in the model of fibrosis induced by overexpression of a constitutively active TGF-beta receptor type I (TBR). SUMO-1 and phosphorylated Smad3 were detected by immunohistochemistry. Results: Increased staining for SUMO-1 was detected in patients with SSc and in experimental fibrosis. Inhibition of sumoylation exerted potent antifibrotic effects and prevented dermal thickening, myofibroblast differentiation and accumulation of collagen induced by bleomycin, or by overexpression of constitutively active TBR. Moreover, knockdown of Ubc9 reduced the accumulation of phosphorylated Smad3 in experimental fibrosis indicating that inhibition of sumoylation may normalise canonical TGF-β signalling in vivo. Conclusions: We demonstrate that inhibition of sumoylation reduces canonical TGF-β signalling and prevents experimental fibrosis in different preclinical models. These data provide first evidence that targeting of aberrant sumoylation may be a novel therapeutic approach for fibrotic diseases.
CRIS-Team Scopus Importer:2020-07-01

INNATE LYMPHOID CELLS ARE PREDICTORS OF DISEASE PROGRESSION IN SYSTEMIC SCLEROSIS: A 3-YEARS FOLLOW-UP STUDY - Soare, A.; Weber, Stefanie; Schett, Georg; Distler, Jörg; Ramming, Andreas (ANNALS OF THE RHEUMATIC DISEASES, 2020)
CRIS-Team WoS Importer:2020-08-21

INNATE LYMPHOID CELLS CORRELATE WITH DISEASE ACTIVITY AND BONE REMODELLING IN PSORIATIC ARTHRITIS - Soare, A.; Weber, Stefanie; Maul, L.; Rauber, Simon; Gheorghiu, A. M.; Houssni, I.; Kleyer, Arnd; Luber, M.; Rech, Jürgen; Schett, Georg; Distler, Jörg; Ramming, A. (2018)
EVALuna2:34985

INNATE LYMPHOID CELLS INDUCE A FIBROTIC PHENOTYPE OF FIBROBLASTS - Weber, Stefanie; Anchang, Charles Gwellem; Rauber, S.; Luber, M.; Raimondo, M. G.; Ariza, Y.; Rigau, A. Rius; Kreuter, A.; Schett, Georg; Distler, Jörg; Ramming, A. (ANNALS OF THE RHEUMATIC DISEASES, 2020)
CRIS-Team WoS Importer:2020-08-21

Innate Lymphoid Cells - New Players in Psoriatic Arthritis - Soare, Alina; Weber, Stefanie; Maul, Lisa; Gheorghiu, Ana Maria; Housni, Ismail; Kleyer, Arnd; Luber, Markus; Rauber, Simon; Simon, David; Rech, Jürgen; Schett, Georg; Distler, Jörg; et al. (2017)
EVALuna2:33444

Innovative cellular therapies for autoimmune diseases: expert-based position statement and clinical practice recommendations from the EBMT practice harmonization and guidelines committee. - Greco, Raffaella; Alexander, Tobias; Del Papa, Nicoletta; Müller, Fabian; Saccardi, Riccardo; Sanchez-Guijo, Fermin; Schett, Georg; Sharrack, Basil; Snowden, John A.; Tarte, Karin; Onida, Francesco; Sánchez-Ortega, Isabel; et al. (EClinicalMedicine, 2024)
Autoimmune diseases (ADs) are characterized by loss of immune tolerance, high chronicity, with substantial morbidity and mortality, despite conventional immunosuppression (IS) or targeted disease modifying therapies (DMTs), which usually require repeated administration. Recently, novel cellular therapies (CT), including mesenchymal stromal cells (MSC), Chimeric Antigen Receptors T cells (CART) and regulatory T cells (Tregs), have been successfully adopted in ADs. An international expert panel of the European Society for Blood and Marrow Transplantation and the International Society for the Cell and Gene Therapy, reviewed all available evidence, based on the current literature and expert practices, on use of MSC, CART and Tregs, in AD patients with rheumatological, neurological, and gastroenterological indications. Expert-based consensus and recommendations for best practice and quality of patient care were developed to support clinicians, scientists, and their multidisciplinary teams, as well as patients and care providers and will be regularly updated.
EVALuna2:554515

Intensity and longevity of SARS-CoV-2 vaccination response in patients with immune-mediated inflammatory disease: a prospective cohort study. - Simon, David; Tascilar, Koray; Fagni, Filippo; Kleyer, Arnd; Krönke, Gerhard; Meder, Christine; Dietrich, Peter; Orlemann, Till; Mößner, Johanna; Taubmann, Jule; Mutlu, Melek Yalcin; Knitza, Johannes; et al. (The Lancet Rheumatology, 2022)
Background: Concerns have been raised about the reduced immunogenicity of vaccines against SARS-CoV-2 in patients with immune-mediated inflammatory diseases and the higher risk of breakthrough infections. The objective of our study was to investigate the intensity and longevity of SARS-CoV-2 vaccination responses in patients with immune-mediated inflammatory diseases, and to assess the effects of diagnosis, treatment, and adapted vaccination schedules. Methods: SARS-CoV-2 IgG antibody response after SARS-CoV-2 vaccination was measured over time in a large prospective cohort of healthy controls and participants with immune-mediated inflammatory diseases (attending or admitted to affiliated centres) between Dec 15, 2020, and Dec 1, 2021. Cohort participants with immune-mediated inflammatory diseases and control participants with no diagnosis of immune-mediated inflammatory diseases, were eligible for this analysis. Demographic data and disease-specific data were collected using a questionnaire. Humoral response was compared across treatment and disease groups, and with respect to the receipt of additional vaccinations. SARS-CoV-2 antibody response was measured by ELISA using optical density ratio units and modelled over time with age and sex adjustment using mixed-effects models. Using these models, marginal mean antibody titres and marginal risks of a poor response (optical density ratio <1·1) were calculated for each week starting from week 8 after the first vaccination to week 40. Findings: Among 5076 individuals registered, 2535 participants with immune-mediated inflammatory diseases (mean age 55·0 [15·2] years; 1494 [58·9%] women and 1041 [41·1%] men) and 1198 healthy controls (mean age 40·7 [13·5] years; 554 [46·2%] women and 644 [53·8%] men) were included in this analysis. Mean antibody titres were higher in healthy controls compared with people with immune-mediated inflammatory diseases at all timepoints, with a peak antibody response in healthy controls (mean optical density ratio 12·48; 95% CI 11·50-13·53) of more than twice that in participants with immune-mediated inflammatory diseases (5·50; 5·23-5·77; mean difference 6·98; 5·92-8·04). A poor response to vaccination was observed in participants with immune-mediated inflammatory diseases who were taking B-cell inhibitors (peak mean difference from healthy controls 11·68; 10·07-13·29) and T-cell inhibitors (peakmean difference from healthy controls 10·43; 8·33-12·53). Mean differences in antibody responses between different immune-mediated inflammatory diseases were small. Participants with immune-mediated inflammatory diseases who were given a third vaccine dose had higher mean antibody titres than did healthy controls vaccinated with two vaccine doses at 40 weeks after the initial vaccination (mean difference 1·34; 0·01-2·69). Interpretation: People with immune-mediated inflammatory diseases show a lower and less durable SARS-CoV-2 vaccination response and are at risk of losing humoral immune protection. Adjusted vaccination schedules with earlier booster doses or more frequent re-doses, or both, could better protect people with immune-mediated inflammatory diseases. Funding: Deutsche Forschungsgemeinschaft, Bundesministerium für Bildung und Forschung, European Research Council, Innovative Medicine Initiative, Friedrich-Alexander-Universität Erlangen-Nürnberg, Else Kröner-Memorial Foundation.
EVALuna2:506737

Interleukin 17 Blockade in Psoriasis Patients with Subclinical Joint Inflammation- Prospective Open Study to Influence the Course of the Disease by means of Secukinumab - Kampylafka, E.; Oliveira, I.; Linz, C.; Lerchen, V.; Englbrecht, Matthias; Simon, David; Rech, Jürgen; Kleyer, Arnd; Schett, Georg; Sticherling, Michael; Hueber, Axel (JOURNAL DER DEUTSCHEN DERMATOLOGISCHEN GESELLSCHAFT, 2019)
CRIS-Team WoS Importer:2019-05-17

Interleukin-17 Blockade Leads to Shifts from Stage-based Towards Response-based Disease Clusters- Comparative Data from Very Early and Established Psoriatic Arthritis - Kampylafka, Eleni; Tascilar, Koray; Lerchen, Veronika; Linz, Christina; Sokolova, Maria; Zekovic, Ana; Kleyer, Arnd; Simon, David; Rech, Jürgen; Sticherling, Michael; Schett, Georg; Hueber, Axel (ARTHRITIS & RHEUMATOLOGY, 2020)
CRIS-Team WoS Importer:2021-01-15

Interleukin-1 function and role in rheumatic disease - Schett, Georg; Dayer, Jean-Michel; Manger, Bernhard (Nature Reviews Rheumatology, 2016)
Interleukin (IL)-1, first described 35 years ago as a secreted product of monocytes and neutrophils, refers to IL-1? and IL-1?, two key cytokines in the activation of innate immunity. These cytokines were among the first proteins identified as orchestrators of leukocyte communication, creating the class of secreted products now known as interleukins. The IL-1 family comprises a total of 11 members, including the two activating cytokines IL-1? and IL-1? as well as an inhibitory mediator, the IL-1 receptor antagonist. IL-1 is processed and activated by a caspase-1 dependent mechanism in conjunction with inflammasome assembly, as well as by caspase-1 independent processes that involve neutrophil proteases. Once activated, IL-1? and IL-1? act as potent proinflammatory cytokines at the local level, triggering vasodilatation and attracting monocytes and neutrophils to sites of tissue damage and stress. Importantly, these cytokines are crucial for the induction of matrix enzymes and serve as potent mediators of tissue damage by altering cartilage and bone homeostasis. Systemically, IL-1 cytokines foster the hypothalamic fever response and promote hyperalgesia. Uncontrolled IL-1 activation is a central component of some inflammatory diseases, including rare hereditary syndromes with mutations in inflammasome-associated genes or more frequent diseases such as gout, characterized by neutrophil infiltration and IL-1 activation. Apart from these connections to inflammatory diseases, an important role for IL-1 in inflammatory atherogenesis is also predicted. To date, four potent inhibitors of IL-1 are available for clinical use or in late-stage clinical development, which not only constitute efficacious therapies, but also helped improve our understanding of the role of IL-1 in human disease.
EVALuna2:13192

Interleukin-36 receptor mediates the crosstalk between plasma cells and synovial fibroblasts - Schmitt, Verena; Hahn, Madelaine; Kästele, Verena; Wagner, Olga; Wiendl, Maximilian; Derer, Anja; Taddeo, Adriano; Hahne, Stefanie; Radbruch, Andreas; Jäck, Hans-Martin; Schuh, Wolfgang; Mielenz, Dirk; et al. (European Journal of Immunology, 2017)
The IL-1 family member IL-36? has proinflammatory and pathogenic properties in psoriasis. IL-36? binds to the IL-36 receptor leading to nuclear factor kappa B/mitogen activated protein kinase mediated cytokine release. The IL-36R antagonist prevents recruitment of IL-1 receptor accessory protein and therefore IL-36-dependent cell activation. In inflamed human tissue, we previously could show that resident B cells and plasma cells (PC) express IL-36?. Further, fibroblast-like synoviocytes (FLS) produced proinflammatory cytokines upon IL-36?-stimulation. We hypothesize an IL-36-specific crosstalk between B cells/PCs and FLS permitting a proinflammatory B cell niche. Here, we firstly demonstrated that B cell lines and B cells from healthy donors express IL-36? and stimulation increased IL-36? in B cells and primary plasmablasts/PCs. Moreover, FLS respond specifically to IL-36? by proliferation and production of matrix metalloproteinases via p38/HSP27 signaling. Importantly, IL-36R-deficiency abrogated IL-36?-induced production of inflammatory mediators in FLS and changed the intrinsic FLS-phenotype. Using an in vitro co-culture system, we could show that IL-36R-deficient FLS had a limited capacity to support PC survival compared to wild-type FLS. Hence, we demonstrated an IL-36R-dependent crosstalk between B cells/PCs and FLS. Our data support the concept of initiation and maintenance of a proinflammatory niche by B cells in the joints. This article is protected by copyright. All rights reserved.
EVALuna2:13406

Interleukin-3 is a predictive marker for severity and outcome during SARS-CoV-2 infections - Bénard, Alan; Jacobsen, Anne; Brunner, Maximilian; Krautz, Christian; Klösch, Bettina; Swierzy, Izabela; Naschberger, Elisabeth; Podolska, Malgorzata; Kouhestani, Dina; David, Paul; Birkholz, Torsten; Castellanos, Ixchel; et al. (Nature Communications, 2021)
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a worldwide health threat. In a prospective multicentric study, we identify IL-3 as an independent prognostic marker for the outcome during SARS-CoV-2 infections. Specifically, low plasma IL-3 levels is associated with increased severity, viral load, and mortality during SARS-CoV-2 infections. Patients with severe COVID-19 exhibit also reduced circulating plasmacytoid dendritic cells (pDCs) and low plasma IFNα and IFNλ levels when compared to non-severe COVID-19 patients. In a mouse model of pulmonary HSV-1 infection, treatment with recombinant IL-3 reduces viral load and mortality. Mechanistically, IL-3 increases innate antiviral immunity by promoting the recruitment of circulating pDCs into the airways by stimulating CXCL12 secretion from pulmonary CD123+ epithelial cells, both, in mice and in COVID-19 negative patients exhibiting pulmonary diseases. This study identifies IL-3 as a predictive disease marker for SARS-CoV-2 infections and as a potential therapeutic target for pulmunory viral infections.
CRIS-Team Scopus Importer:2021-03-05

Interleukin-6 receptor blockade induces limited repair of bone erosions in rheumatoid arthritis: A micro CT study - Finzel, Stephanie; Rech, Jürgen; Schmidt, Sarah; Engelke, Klaus; Englbrecht, Matthias; Schett, Georg (Annals of the Rheumatic Diseases, 2013)
Introduction: Interleukin-6 receptor (IL-6R) blockade improves the signs and symptoms of rheumatoid arthritis (RA) and retards bone damage. Whether IL-6R blockade allows repair of existing bone erosions is so far unclear. Methods: This study examined bone erosions in the metacarpophalangeal joints of 20 patients receiving treatment with the IL-6R blocker tocilizumab using micro CT (μCT). The maximal width and depth of individual bone erosions was measured at baseline and after 1 year of treatment. Results: 133 bone erosions were identified at baseline with a mean (±SD) size of 2.23±1.26 mm and depth of 2.16±1.50 mm. Distribution analysis showed predominant involvement of the second compared with the third and fourth metacarpophalangeal joints, the metacarpal heads compared with the phalangeal bases and the radial quadrants compared with all other surfaces. Repair of bone erosions during tocilizumab treatment was confined to those lesions showing sclerosis at baseline and/or at follow-up and those with a width larger than 1.6 mm. The mean decrease in width of sclerosed erosions was thus 0.14±0.05 mm (p=0.0086) and 0.20±0.08 mm (p=0.019) for sclerosing lesions after 1 year of treatment. Conclusions: Blockade of IL-6R by tocilizumab can induce limited repair in a subset of erosions, particularly in large lesions with sclerosis. Repair of erosions during tocilizumab treatment reflects the favourable impact of IL-6R blockade on local bone remodelling in patients with RA.
CRIS-Team Scopus Importer:2021-02-03

Interspecies Single-Cell RNA-Seq Analysis Reveals the Novel Trajectory of Osteoclast Differentiation and Therapeutic Targets - Omata, Yasunori; Okada, Hiroyuki; Uebe, Steffen; Izawa, Naohiro; Ekici, Arif Bülent; Sarter-Zaiss, Kerstin; Saito, Taku; Schett, Georg; Tanaka, Sakae; Zaiss, Mario (JBMR Plus, 2022)
Bone turnover is finely tuned by cells in the bone milieu, including osteoblasts, osteoclasts, and osteocytes. Osteoclasts are multinucleated giant cells with a bone-resorbing function that play a critical role in regulating skeletal homeostasis. Osteoclast differentiation is characterized by dramatic changes in morphology and gene expression following receptor activator of nuclear factor-kappa-Beta ligand (RANKL) stimulation. We performed single-cell RNA-sequencing analyses of human and murine osteoclast-lineage cells (OLCs) and found that OLCs in the mitotic phase do not differentiate into mature osteoclasts. We also identified a guanosine triphosphatase (GTPase) family member, RAB38, as a highly expressed molecule in both human and murine osteoclast clusters; RAB38 gene expression is associated with dynamic changes in histone modification and transcriptional regulation. Silencing Rab38 expression by using short hairpin RNA (shRNA) inhibited osteoclast differentiation and maturation. In summary, we established an integrated fate map of human and murine osteoclastogenesis; this will help identify therapeutic targets in bone diseases. (c) 2022 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.
CRIS-Team WoS Importer:2022-05-27

INTESTINAL HIF1 alpha EXPRESSION PROTECTS AGAINST EPITHELIAL CELL DEATH IN ARTHRITIS - Lyu, Pang; Wen, Jinming; Stolzer, Iris; Gießl, Andreas; Song, Rui; Meng, Xiangjun; Cao, Shan; Günther, Claudia; Schett, Georg; Bozec, Aline (ANNALS OF THE RHEUMATIC DISEASES, 2022)
CRIS-Team WoS Importer:2022-11-04

INTRAARTICULAR MICRO CHANNELS OF MCP JOINTS INCREASE DURING DEVELOPMENT OF RHEUMATOID ARTHRITIS - Werner, David; Simon, David; Rech, Jürgen; Haschka, J.; Buder, Thomas; Neuhuber, Winfried; Schett, Georg; Hueber, Axel; Kleyer, Arnd (2015)
EVALuna2:34457

Intratumor Heterogeneity Correlates With Reduced Immune Activity and Worse Survival in Melanoma Patients - Lin, Zhen; Meng, Xianyi; Wen, Jinming; Corral, José María; Andreev, Darja; Kachler, Katerina; Schett, Georg; Chen, Xiaoxiang; Bozec, Aline (Frontiers in Oncology, 2020)
Background: Human malignant melanoma is a highly aggressive, heterogeneous and drug-resistant cancer. Due to a high number of clones, harboring various mutations that affect key pathways, there is an exceptional level of phenotypic variation and intratumor heterogeneity (ITH) in melanoma. This poses a significant challenge to personalized cancer medicine. Hitherto, it remains unclear to what extent the heterogeneity of melanoma affects the immune microenvironment. Herein, we explore the interaction between the tumor heterogeneity and the host immune response in a melanoma cohort utilizing The Cancer Genome Atlas (TCGA). Methods: Clonal Heterogeneity Analysis Tool (CHAT) was used to estimate intratumor heterogeneity, and immune cell composition was estimated using CIBERSORT. The Overall Survival (OS) among groups was analyzed using Kaplan–Meier curves with the log-rank test and multivariate cox regression. RNA-seq data were evaluated to identify differentially expressed immunomodulatory genes. The reverse phase protein array (RPPA) data platform was used to validate immune responses at protein level. Results: Tumors with high heterogeneity were associated with decreased overall survival (p = 0.027). High CHAT tumors were correlated with less infiltration by anti-tumor CD8 T cells (p = 0.0049), T follicular cells (p = 0.00091), and M1 macrophages (p = 0.0028), whereas tumor-promoting M2 macrophages were increased (p = 0.02). High CHAT tumors correlated with a reduced expression of immunomodulatory genes, particularly Programmed Cell Death 1 (PD1) and its ligand PD-L1. In addition, high CHAT tumors exhibited lower immune Cytotoxic T lymphocytes (CTLs)-mediated toxicity pathway score (p = 2.9E−07) and cytotoxic pathway score (p = 2.9E−08). High CHAT tumors were also associated with a lower protein level of immune-regulatory kinases, such as lymphocyte-specific protein tyrosine kinase (LCK) (p = 3.4e−5) and spleen tyrosine kinase (SYK) (p = 0.0011). Conclusions: Highly heterogeneous melanoma tumors are associated with reduced immune cell infiltration and immune response activation as well as decreased survival. Our results reveal that intratumor heterogeneity is an indicative factor for patient survival due to its impact on anti-tumor immune response.
CRIS-Team Scopus Importer:2020-12-25
Keywords: immunomodulator; intratumor heterogeneity; melanoma; The Cancer Genome Atlas; tumor infiltrating lymphocytes

IN VIVO DETECTION OF CORTICAL MICRO CHANNELS IN METACARPOPHALANGEAL JOINTS WITH XTREME-CT - A NEW INSTRUMENT TO VISUALIZE COMMUNICATION BETWEEN THE BONE MARROW AND THE JOINT SPACE - Haschka, J.; Simon, David; Rech, Jürgen; Hueber, Axel; Schett, Georg; Kleyer, Arnd (2014)
EVALuna2:12861

In Vivo Models of Rheumatoid Arthritis - Grötsch, Bettina; Bozec, Aline; Schett, Georg (Methods in Molecular Biology, 2019)
Rheumatoid arthritis (RA) models in mice induced by immunization enable the analyses of molecular mechanism involved in disease development, progression, and resolution of inflammation. Here, we describe three different models mimicking clinic symptoms of human rheumatoid arthritis, which could be transferable to any genetically modified mouse. We will present the protocol for collagen-induced arthritis (CIA), K/BxN serum-induced arthritis (SIA), and the antigen-induced arthritis (AIA) models. To do so, we will detail their way of induction but also how to analyze RA clinical score and pathology characterization. Finally, we will briefly discuss the main characteristics and disadvantages of all three models.
EVALuna2:69396

In-vivo results for rheumatoid arthritis diagnosis with a 360 degrees pulse-echo imaging system - Koch, Andreas; Finzel, Stephanie; Kobler, Andreas; Schett, Georg; Lerch, Reinhard; Ermert, Helmut (IEEE SERVICE CENTER, 445 HOES LANE, PO BOX 1331, PISCATAWAY, NJ 08855-1331 USA, 2012)
Progress in medical ultrasound in recent years makes sonography a valuable method for early rheumatoid arthritis (RA) diagnosis today. However, detecting in ammatory processes in periarticular bones requires expert knowledge and training. 360 degrees compound imaging has already proven to increase ultrasound B-mode image quality significantly, e.g. in breast cancer imaging. Therefore an existing Ultrasound Computed Tomography (USCT) system has been modified for RA diagnosis, with respect to finger joint imaging. Well known concepts in USCT to reconstruct the speed of sound (SOS) distribution can not be applied, as the bone inhibits transmission measurements of fingers. Therefore, an image based local contrast quanti. cation method is proposed to estimate a mean SOS for the soft tissue surrounding the finger joint. Based on this estimation, ultrasound B-mode images can be corrected for refraction and TOF to yield high image quality in 360 degrees compound imaging. This method has been validated by measurements on tissue mimicking phantoms. Healthy volunteers and RA patients have been examined with the USCT system. In-vivo results show a great potential for 360 degrees compound imaging to visualize synovitis as well as bone erosion in RA of finger joints.
Keywords: rheumatoid arthritis; ultrasound computed tomography; full angle spatial compounding; speed of sound estimation; refraction correction; nger joints; in-vivo results

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)
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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

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

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.
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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

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-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)
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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.
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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)
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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 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 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

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

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-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 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

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.
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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 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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Metabolic and molecular imaging in inflammatory arthritis - de Sousa, Rita Noversa; 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 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 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

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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