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

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

Methotrexate plus ustekinumab versus ustekinumab monotherapy in patients with active psoriatic arthritis (MUST): a randomised, multicentre, placebo-controlled, phase 3b, non-inferiority trial - Koehm, Michaela; Rossmanith, Tanja; Foldenauer, Ann C.; Herrmann, Eva; Brandt-Jürgens, Jan; Burmester, Gerd R.; Kellner, Herbert; Kiltz, Uta; Kofler, David M.; Rech, Jürgen; Mojtahed-Poor, Sorwe; Jonetzko, Christin; et al. (The Lancet Rheumatology, 2023)
Background: The role of methotrexate in combination with biological agents in patients with psoriatic arthritis remains unclear. The MUST phase 3b trial aimed to compare the efficacy of ustekinumab plus placebo with ustekinumab plus methotrexate in patients with active psoriatic arthritis. Methods: In this investigator-initiated, randomised, multicentre, placebo-controlled, phase 3b non-inferiority trial done in 22 centres in Germany, patients with active psoriatic arthritis received open-label ustekinumab and were randomly assigned (1:1) to masked concomitant therapy with placebo or methotrexate (ongoing or new). The primary outcome was non-inferiority of mean Disease Activity Score-28 joints (DAS28) at week 24 for ustekinumab monotherapy (ustekinumab plus placebo) versus ustekinumab combination therapy (ustekinumab plus methotrexate), stratified by previous methotrexate treatment. The key secondary analysis was non-inferiority of DAS28 at week 52. The primary analysis was based on a stratified van Elteren test with an α of 2·5% and a non-inferiority margin of 12·5% by Mann-Whitney estimator. Adverse events and serious adverse events were assessed. This study is registered with ClinicalTrials.gov, NCT03148860. Findings: Between Jan 24, 2017, and April 12, 2021, 186 patients with active psoriatic arthritis were screened, of whom 173 (93%) patients were enrolled and randomly assigned (1:1) to receive concomitant methotrexate therapy (n=88) or placebo (n=85). 84 patients were receiving methotrexate at baseline, and 89 patients had no previous methotrexate treatment. 166 (96%) patients (87 in the ustekinumab plus methotrexate group and 79 in the ustekinumab plus placebo group) were included in the safety and efficacy analyses at week 24 (69 [42%] female; 97 [58%] male; mean age 48·2 years [SE 1·1]). Ustekinumab plus placebo was non-inferior to ustekinumab plus methotrexate in DAS28 at week 24 (2·9 [SD 1·31] vs 3·1 [1·42]); the stratified Mann-Whitney estimator for treatment comparison was 0·5426 (95% CI 0·4545–0·6307). Non-inferiority for ustekinumab plus placebo was also observed in DAS28 at week 52. Serious adverse events occurred in seven (9%) patients in the ustekinumab plus placebo group and eight (9%) patients in the ustekinumab plus methotrexate group. No specific serious adverse events affected more than one patient, and there were no deaths. Interpretation: Interleukin (IL)-12 and IL-23 inhibition with ustekinumab is an effective treatment for psoriatic arthritis independent of methotrexate use; concomitant methotrexate did not increase efficacy of ustekinumab (based on DAS28). On the basis of these data, there is no evidence to support the addition or maintainance of methotrexate when initiating ustekinumab in patients with active psoriatic arthritis. Funding: Janssen Cilag.
CRIS-Team Scopus Importer:2023-01-13

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

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

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

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

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

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

MICRORNA-125B AS A POTENTIAL FIBROTIC AND APOPTOTIC REGULATOR IN SYSTEMIC SCLEROSIS - Kozlova, A.; Pachera, E.; Renoux, F.; Rudnik, M.; Maurer, B.; Juengel, A.; Distler, Jörg; Kania, G.; Distler, O. (2017)
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MICRORNA-125B REGULATES APOPTOSIS IN SYSTEMIC SCLEROSIS - Kozlova, A.; Pachera, E.; Maurer, B.; Juengel, A.; Distler, Jörg; Kania, G.; Distler, O. (2018)
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microRNA-145 mediates xylosyltransferase-I induction in myofibroblasts via suppression of transcription factor KLF4 - Ly, Thanh Diep; Riedel, Lara; Fischer, Bastian; Schmidt, Vanessa; Hendig, Doris; Distler, Jörg; Kuhn, Joachim; Knabbe, Cornelius; Faust, Isabel (Biochemical and Biophysical Research Communications, 2020)
Remodelling of the extracellular matrix by myofibroblasts is crucial for wound repair, but if deregulated, it might contribute to the development of fibrosis. Fibroblast-to-myofibroblast differentiation is promoted by aberrant microRNA-145-5p (miR-145) expression in response to transforming growth factor β1 (TGFβ1). One of several myofibroblast markers is human xylosyltransferase-I (XT-I), which is the initial and rate-limiting enzyme of proteoglycan biosynthesis. Increased serum XT activity was quantified in patients with systemic sclerosis (SSc), but the underlying cellular mechanism of this disease remains unknown. This study aims to determine the underlying molecular basis of XT-I induction by considering the miR-mediated regulation of XT-I. We found that miR-145 is upregulated in TGFβ1-treated dermal fibroblasts and correlates with an increased cellular XYLT1 expression and XT activity. Overexpression of miR-145 in dermal fibroblasts induced XYLT1 expression and XT activity and enhanced TGFβ1-promoted XT activity increase. Since direct XYLT1 3′-UTR targeting by miR-145 could be experimentally excluded, an indirect effect of miR-145 on XT-I regulation was indicated. We identified six transcription factor-binding sites for Krueppel-like factor 4 (KLF4), a zinc-finger transcription regulator and putative miR-145 target, in the XYLT1 promoter in silico. A suppressive role of KLF4 on XYLT1 expression was confirmed by targeted gene silencing in dermal fibroblasts and the quantification of KLF4 expression in SSc fibroblasts. Taken together, this study improves the mechanistic understanding of fibrotic remodelling in SSc by identifying a hitherto unknown miR-145/KLF4 pathway mediating the fibrogenic XT-I induction. This knowledge on XYLT1 may lead to the development of novel approaches in the therapy of fibrosis.
CRIS-Team Scopus Importer:2020-02-07
Keywords: Fibrosis; Krueppel-like factor 4; microRNA-145; Systemic sclerosis; TGFβ; Xylosyltransferase

Microscopic polyangiitis after alemtuzumab treatment in relapsing-remitting MS - Sauer, Eva-Maria; Schliep, Stefan; Manger, Bernhard; Lee, De-Hyung; Linker, Ralf (Neurology, Neuroimmunology and Neuroinflammation, 2018)
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Microstructural Bone Changes Are Associated With Broad-Spectrum Autoimmunity and Predict the Onset of Rheumatoid Arthritis - Simon, David; Kleyer, Arnd; Bui, Cong Duy; Hueber, Axel; Bang, Holger; Ramming, Andreas; Rech, Jürgen; Schett, Georg (Arthritis and Rheumatology, 2022)
Objective To assess if microstructural bone lesions in individuals at risk of developing rheumatoid arthritis (RA) are related to the spectrum of anti-modified protein antibodies (AMPAs) and affect the risk of developing RA. Methods Cortical microchannels as well as cortical and trabecular bone mineral density (BMD) volumes (expressed as mg hydroxyapatite/cm(3)) were analyzed by high-resolution peripheral quantitative computed tomography of the hand joints of individuals at risk of RA. AMPA response was profiled, including reactivities against citrullinated proteins (vimentin, enolase, and fibrinogen) as well as carbamylated and acetylated vimentin. All subjects were followed up for the development of RA. Results Subjects at risk of developing RA (n = 75) who had broad-spectrum AMPAs (6-8 reactivities) had significantly more severe microstructural changes, including a higher mean +/- SD number of cortical microchannels per joint (95 +/- 3) and lower total volumetric BMD (vBMD; 265 +/- 45), trabecular vBMD (176 +/- 42), and cortical vBMD (585 +/- 138), than those with moderate AMPA reactivity (3-5 reactivities) (number of cortical microchannels, 79 +/- 30; total vBMD, 293 +/- 33; trabecular vBMD, 195 +/- 32; and cortical vBMD, 627 +/- 91) and those with narrow AMPA reactivity (1-2 reactivities) (number of cortical microchannels, 47 +/- 20; total vBMD, 311 +/- 34; trabecular vBMD, 211 +/- 30; and cortical vBMD, 674 +/- 56). Progressors to RA had significantly higher numbers of cortical microchannels (103 +/- 30 versus 71 +/- 35) and lower bone volume (258 +/- 37 versus 295 +/- 34) compared to nonprogressors. Furthermore, rate of progression to RA was high in subjects with broad AMPA reactivity (48%) versus those with medium AMPA reactivity (26%) or narrow AMPA reactivity (0%), as well as in those with a high number of cortical microchannels (44%) versus those with a low number of cortical microchannels (10%). Conclusion Microstructural changes in individuals at risk of RA are associated with broad-spectrum autoimmunity and predict the onset of RA. These data support the concept of structural priming of joints by autoimmunity before the onset of the inflammatory phase of the disease.
CRIS-Team WoS Importer:2022-02-11

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

Microvesicles from cerebrospinal fluid of patients with Alzheimer’s disease display reduced concentrations of tau and APP protein - Spitzer, Philipp; Mulzer, Linda-Marie; Oberstein, Timo; Munoz, Luis Enrique; Lewczuk, Piotr; Kornhuber, Johannes; Herrmann, Martin; Maler, Juan Manuel (Scientific Reports, 2019)
Microvesicles are small membranous particles generated during cellular activation or stress. The analysis of the content and the surface of microvesicles allow conclusions about the cells they are originating from and the underlying pathology. Therefore, CSF microvesicles have been suggested to be promising targets to monitor the (etio)pathology of neurodegenerative diseases. Microvesicles in the CSF of 15 patients with Alzheimer’s disease and 15 controls were analyzed by flow cytometry regarding the levels of CD3, CD4, CD45, CD64, BACE1, Aβ, APP and tau. The results were replicated in a second cohort comprising 14 patients with Alzheimer’s disease and 9 controls. The levels of tau and APP were reduced in microvesicles of Alzheimer’s disease patients. A significant change was neither observed in the number of microvesicles nor in the expression of the other antigens. Tau and APP in microvesicles separated patients with Alzheimer’s disease from controls with an AUC of 0.84 and 0.89 respectively. We conclude that tau and APP in CSF microvesicles are promising biomarkers which could directly provide information about the Alzheimer pathology on a cellular level.
CRIS-Team Scopus Importer:2019-05-21

Midgut Volvulus Adds a Murine, Neutrophil-Driven Model of Septic Condition to the Experimental Toolbox - Elrod, Julia; Kiwit, Antonia; Lenz, Moritz; Rohde, Holger; Börnigen, Daniela; Alawi, Malik; Mohr, Christoph; Pagerols Raluy, Laia; Trochimiuk, Magdalena; Knopf, Jasmin; Reinshagen, Konrad; Herrmann, Martin; et al. (Cells, 2023)
Background: Severe infections that culminate in sepsis are associated with high morbidity and mortality. Despite continuous efforts in basis science and clinical research, evidence based-therapy is mostly limited to basic causal and supportive measures. Adjuvant therapies often remain without clear evidence. The objective of this study was to evaluate the septic volvulus ischemia-reperfusion model in comparison to two already established models and the role of neutrophil extacellular traps (NETs) in this model. Methods: The technique of the murine model of midgut volvulus was optimized and was compared to two established models of murine sepsis, namely cecal ligation and puncture (CLP) and intra-peritoneal (i.p.) injection of lipopolysaccharide (LPS). Results: Midgut volvulus for 15 min caused a comparable mortality (38%) as CLP (55%) and peritoneal LPS injection (25%) at 48 h. While oxidative stress was comparable, levels of circulating free DNA (cfDNA), and splenic/hepatic and pulmonary translocation of bacteria were decreased and increased, respectively at 48 h. DNases were increased compared to the established models. Proteomic analysis revealed an upregulation of systemic Epo, IL-1b, Prdx5, Parp1, Ccl2 and IL-6 at 48 h in comparison to the healthy controls. Discussion and Conclusion: Midgut volvulus is a stable and physiological model for sepsis. Depending on the duration and subsequent tissue damage, it represents a combination of ischemia-reperfusion injury and hyperinflammation.
CRIS-Team Scopus Importer:2023-02-17
Keywords: CLP; extracellular DNA; LPS; sepsis; sepsis model; volvulus

miR-148a controls metabolic programming and survival of mature CD19-negative plasma cells in mice - Pracht, Katharina; Meinzinger, Julia; Schulz, Sebastian; Daum, Patrick; Corte-Real, Joana; Hauke, Manuela; Roth, Eduard; Kindermann, Dorothea; Mielenz, Dirk; Schuh, Wolfgang; Wittmann, Jürgen; Jäck, Hans-Martin (European Journal of Immunology, 2021)
Long-lived antibody-secreting plasma cells are essential to establish humoral memory against pathogens. While a regulatory transcription factor network has been established in plasma cell differentiation, the regulatory role of miRNAs remains enigmatic. We have recently identified miR-148a as the most abundant miRNA in primary mouse and human plasma cells. To determine whether this plasma cell signature miRNA controls the in vivo development of B cells into long-lived plasma cells, we established mice with genomic, conditional, and inducible deletions of miR-148a. The analysis of miR-148a-deficient mice revealed reduced serum Ig, decreased numbers of newly formed plasmablasts and reduced CD19-negative, CD93-positive long-lived plasma cells. Transcriptome and metabolic analysis revealed an impaired glucose uptake, a reduced oxidative phosphorylation-based energy metabolism, and an altered abundance of homing receptors CXCR3 (increase) and CXCR4 (reduction) in miR-148a-deficient plasma cells. These findings support the role of miR-148a as a positive regulator of the maintenance of long-lived plasma cells.
CRIS-Team Scopus Importer:2021-02-05
Keywords: CXC receptors; Glut-1; miR-148a; Oxidative phosphorylation; Plasma cells

miR-148a is upregulated by Twist1 and T-bet and promotes Th1-cell survival by regulating the proapoptotic gene Bim - Haftmann, Claudia; Stittrich, Anna-Barbara; Zimmermann, Jakob; Fang, Zhuo; Hradilkova, Kristyna; Bardua, Markus; Westendorf, Kerstin; Heinz, Gitta A.; Riedel, Rene; Siede, Julia; Lehmann, Katrin; Weinberger, Esther E.; et al. (European Journal of Immunology, 2015)
Repeatedly activated T helper 1 (Th1) cells present during chronic inflammation can efficiently adapt to the inflammatory milieu, for example, by expressing the transcription factor Twist1, which limits the immunopathology caused by Th1 cells. Here, we show that in repeatedly activated murine Th1 cells, Twist1 and T-bet induce expression of microRNA-148a (miR-148a). miR-148a regulates expression of the proapoptotic gene Bim, resulting in a decreased Bim/Bcl2 ratio. Inhibition of miR-148a by antagomirs in repeatedly activated Th1 cells increases the expression of Bim, leading to enhanced apoptosis. Knockdown of Bim expression by siRNA in miR-148a antagomir-treated cells restores viability of the Th1 cells, demonstrating that miR-148a controls survival by regulating Bim expression. Thus, Twist1 and T-bet not only control the differentiation and function of Th1 cells, but also their persistence in chronic inflammation.
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miR-148a promotes plasma cell differentiation and targets the germinal center transcription factors Mitf and Bach2 - Porstner, Martina; Winkelmann, Rebecca; Daum, Patrick; Schmid, Julia; Pracht, Katharina; Corte-Real, Joana; Schreiber, Sandra; Haftmann, Claudia; Brandl, Andreas; Mashreghi, Mir-Farzin; Gelse, Kolja; Hauke, Manuela; et al. (European Journal of Immunology, 2015)
B cells undergo affinity maturation and class switch recombination of their immunoglobulin receptors during a germinal center (GC) reaction, before they differentiate into long-lived antibody-secreting plasma cells (PCs). Transcription factors such as Bach2 and Mitf are essential during this process, as they delay premature differentiation of GC B cells by repressing Blimp-1 and IRF4, two transcription factors required for terminal PC differentiation. Therefore, Bach2 and Mitf expression must be attenuated in activated B cells to allow terminal PC differentiation, but the precise mechanism remains enigmatic. Here, we provide evidence that miR-148a, a small noncoding microRNA, fosters PC differentiation and survival. Next-generation sequencing revealed that miR-148a is the most abundant microRNA in primary human and murine PCs, and its expression is upregulated in activated murine B cells and coincides with Blimp-1 synthesis. miR-148a targets Bach2, Mitf and proapoptotic factors such as PTEN and Bim. When prematurely expressed, miR-148a promotes the differentiation and survival of plasmablasts and reduces frequencies of IgG1(+) cells in primary B-cell cultures. In summary, we propose that miR-148a is a new player in the regulatory network controlling terminal PC differentiation and could, therefore, be a therapeutic target for interfering with PC differentiation and survival.
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miRNA meets plasma cells "How tiny RNAs control antibody responses" - Meinzinger, Julia; Jäck, Hans-Martin; Pracht, Katharina (Clinical Immunology, 2018)
We review the importance of small non-coding microRNAs for the generation of germinal center B cells and their differentiation in antibody-secreting plasma cells. In the last part, we briefly elucidate the role of microRNAs in some plasma cell disorders.
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Misdiagnosis of polymyositis in a young female patient with occult limb-girdle muscular dystrophy - Valor-Mendez, Lara; Türk, Matthias; Schett, Georg; Manger, Bernhard; Knitza, Johannes (Rheumatology Advances in Practice, 2023)
CRIS-Team Scopus Importer:2023-08-11

Missing in action-The meaning of cell death in tissue damage and inflammation - Munoz Becerra, Luis; Leppkes, Moritz; Fuchs, Tobias A.; Hoffmann, Markus; Herrmann, Martin (Immunological Reviews, 2017)
Billions of cells die every day in higher organisms as part of the normal process of tissue homeostasis. During special conditions like in development, acute infections, mechanical injuries, and immunity, cell death is a common denominator and it exerts profound effects in the outcome of these scenarios. To prevent the accumulation of aged, superfluous, infected, damaged and dead cells, professional phagocytes act in a rapid and efficient manner to clear the battle field and avoid spread of the destruction. Neutrophils are the most abundant effector immune cells that extravasate into tissues and can turn injured tissues into gory battle fields. In peace times, neutrophils tend to patrol tissues without provoking inflammatory reactions. We discuss in this review actual and forgotten knowledge about the meaning of cell death during homeostatic processes and drive the attention to the importance of the action of neutrophils during patrolling and for the maintenance or recovery of the homeostatic state once the organism gets attacked or injured, respectively. In this fashion, we disclose several disease conditions that arise as collateral damage of physiological responses to death.
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Mitochondrial metabolism influences plasma cell differentiation - Urbanczyk, Sophia; Baris, O.; Reimer, Dorothea; Steinmetz, Tobit; Mougiakakos, Dimitrios; Wiesner, R.; Mielenz, Dirk (EUROPEAN JOURNAL OF IMMUNOLOGY, 2019)
CRIS-Team WoS Importer:2019-10-08

Mitochondrial respiration in B lymphocytes is essential for humoral immunity by controlling the flux of the TCA cycle - Urbanczyk, Sophia; Baris, Olivier R.; Hofmann, Jörg; Taudte, Verena; Guegen, Naïg; Golombek, Florian; Castiglione, Kathrin; Meng, Xianyi; Bozec, Aline; Thomas, Jana; Weckwerth, Leonie; Mougiakakos, Dimitrios; et al. (Cell Reports, 2022)
To elucidate the function of oxidative phosphorylation (OxPhos) during B cell differentiation, we employ CD23Cre-driven expression of the dominant-negative K320E mutant of the mitochondrial helicase Twinkle (DNT). DNT-expression depletes mitochondrial DNA during B cell maturation, reduces the abundance of respiratory chain protein subunits encoded by mitochondrial DNA, and, consequently, respiratory chain super-complexes in activated B cells. Whereas B cell development in DNT mice is normal, B cell proliferation, germinal centers, class switch to IgG, plasma cell maturation, and T cell-dependent as well as T cell-independent humoral immunity are diminished. DNT expression dampens OxPhos but increases glycolysis in lipopolysaccharide and B cell receptor-activated cells. Lipopolysaccharide-activated DNT-B cells exhibit altered metabolites of glycolysis, the pentose phosphate pathway, and the tricarboxylic acid cycle and a lower amount of phosphatidic acid. Consequently, mTORC1 activity and BLIMP1 induction are curtailed, whereas HIF1α is stabilized. Hence, mitochondrial DNA controls the metabolism of activated B cells via OxPhos to foster humoral immunity.
CRIS-Team Scopus Importer:2022-06-17
Keywords: B lymphocyte; class switch recombination; CP: Immunology; germinal center; HIF1; hypoxia inducible factor 1; mammalian target of Rapamycin; mitochondrial DNA; mitochondrial respiration; mTOR; oxidative phosphorylation; phosphatidic acid; plasma cell; TCA cycle

Mitochondria Permeability Transition versus Necroptosis in Oxalate-Induced AKI - Mulay, Shrikant Ramesh; Honarpisheh, Mohsen M.; Foresto-Neto, Orestes; Shi, Chongxu; Desai, Jyaysi; Zhao, Zhi Bo; Marschner, Julian A.; Popper, Bastian; Buhl, Ewa Miriam; Boor, Peter; Linkermann, Andreas; Liapis, Helen; et al. (Journal of the American Society of Nephrology, 2019)
BACKGROUND: Serum oxalate levels suddenly increase with certain dietary exposures or ethylene glycol poisoning and are a well known cause of AKI. Established contributors to oxalate crystal-induced renal necroinflammation include the NACHT, LRR and PYD domains-containing protein-3 (NLRP3) inflammasome and mixed lineage kinase domain-like (MLKL) protein-dependent tubule necroptosis. These studies examined the role of a novel form of necrosis triggered by altered mitochondrial function. METHODS: To better understand the molecular pathophysiology of oxalate-induced AIK, we conducted in vitro studies in mouse and human kidney cells and in vivo studies in mice, including wild-type mice and knockout mice deficient in peptidylprolyl isomerase F (Ppif) or deficient in both Ppif and Mlkl. RESULTS: Crystals of calcium oxalate, monosodium urate, or calcium pyrophosphate dihydrate, as well as silica microparticles, triggered cell necrosis involving PPIF-dependent mitochondrial permeability transition. This process involves crystal phagocytosis, lysosomal cathepsin leakage, and increased release of reactive oxygen species. Mice with acute oxalosis displayed calcium oxalate crystals inside distal tubular epithelial cells associated with mitochondrial changes characteristic of mitochondrial permeability transition. Mice lacking Ppif or Mlkl or given an inhibitor of mitochondrial permeability transition displayed attenuated oxalate-induced AKI. Dual genetic deletion of Ppif and Mlkl or pharmaceutical inhibition of necroptosis was partially redundant, implying interlinked roles of these two pathways of regulated necrosis in acute oxalosis. Similarly, inhibition of mitochondrial permeability transition suppressed crystal-induced cell death in primary human tubular epithelial cells. PPIF and phosphorylated MLKL localized to injured tubules in diagnostic human kidney biopsies of oxalosis-related AKI. CONCLUSIONS: Mitochondrial permeability transition-related regulated necrosis and necroptosis both contribute to oxalate-induced AKI, identifying PPIF as a potential molecular target for renoprotective intervention.
CRIS-Team Scopus Importer:2019-10-08
Keywords: acute renal failure; cell biology and structure; cyclosporine; kidney tubule; mitochondria

Mobile Apps in Rheumatology: Review and Analysis Using the Mobile App Rating Scale (MARS) - Knitza, Johannes; Tascilar, Koray; Messner, Eva-Maria; Meyer, Marco; Vossen, Diana; Pulla, Almut; Bosch, Philipp; Kittler, Julia; Kleyer, Arnd; Sewerin, Philipp; Mucke, Johanna; Haase, Isabell; et al. (ARTHRITIS & RHEUMATOLOGY, 2019)
CRIS-Team WoS Importer:2020-02-07

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

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

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

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

Molecular and Translational Classifications of DAMPs in Immunogenic Cell Death - Garg, Abhishek D.; Galluzzi, Lorenzo; Apetoh, Lionel; Baert, Thais; Birge, Raymond B.; Bravo-San Pedro, Jose Manuel; Breckpot, Karine; Brough, David; Chaurio, Ricardo; Cirone, Mara; Coosemans, An; Coulie, Pierre G.; et al. (Frontiers in Immunology, 2015)
The immunogenicity of malignant cells has recently been acknowledged as a critical determinant of efficacy in cancer therapy. Thus, besides developing direct immunostimulatory regimens, including dendritic cell-based vaccines, checkpoint-blocking therapies, and adoptive T-cell transfer, researchers have started to focus on the overall immunobiology of neoplastic cells. It is now clear that cancer cells can succumb to some anticancer therapies by undergoing a peculiar form of cell death that is characterized by an increased immunogenic potential, owing to the emission of the so-called "damage-associated molecular patterns" (DAMPs). The emission of DAMPs and other immunostimulatory factors by cells succumbing to immunogenic cell death (ICD) favors the establishment of a productive interface with the immune system. This results in the elicitation of tumor-targeting immune responses associated with the elimination of residual, treatment-resistant cancer cells, as well as with the establishment of immunological memory. Although ICD has been characterized with increased precision since its discovery, several questions remain to be addressed. Here, we summarize and tabulate the main molecular, immunological, preclinical, and clinical aspects of ICD, in an attempt to capture the essence of this phenomenon, and identify future challenges for this rapidly expanding field of investigation.
EVALuna2:13239

Mononuclear phagocytes orchestrate prolyl hydroxylase inhibition-mediated renoprotection in chronic tubulointerstitial nephritis - Schley, Gunnar; Klanke, Bernd; Kalucka, Joanna; Schatz, Valentin; Daniel, Christoph; Mayer, Marleen; Goppelt-Strübe, Margarete; Herrmann, Martin; Thorsteinsdottir, Margret; Palsson, Runolfur; Beneke, Angelika; Katschinski, Dörthe M.; et al. (Kidney International, 2019)
Prolyl hydroxylase domain enzyme inhibitors (PHDIs) stabilize hypoxia-inducible factors (HIFs), and are protective in models of acute ischemic and inflammatory kidney disease. Whether PHDIs also confer protection in chronic inflammatory kidney disease models remains unknown. Here we investigated long-term effects of PHDI treatment in adenine-induced nephropathy as a model for chronic tubulointerstitial nephritis. After three weeks, renal dysfunction and tubulointerstitial damage, including proximal and distal tubular injury, tubular dilation and renal crystal deposition were significantly attenuated in PHDI-treated (the isoquinoline derivative ICA and Roxadustat) compared to vehicle-treated mice with adenine-induced nephropathy. Crystal-induced renal fibrosis was only partially diminished by treatment with ICA. Renoprotective effects of ICA treatment could not be attributed to changes in adenine metabolism or urinary excretion of the metabolite 2,8-dihydroxyadenine. ICA treatment reduced inflammatory infiltrates of F4/80+ mononuclear phagocytes in the kidneys and supported a regulatory, anti-inflammatory immune response. Furthermore, interstitial deposition of complement C1q was decreased in ICA-treated mice fed an adenine-enriched diet. Tubular cell-specific HIF-1α and myeloid cell-specific HIF-1α and HIF-2α expression were not required for the renoprotective effects of ICA. In contrast, depletion of mononuclear phagocytes with clodronate largely abolished the nephroprotective effects of PHD inhibition. Thus, our findings indicate novel and potent systemic anti-inflammatory properties of PHDIs that confer preservation of kidney function and structure in chronic tubulointerstitial inflammation and might counteract kidney disease progression.
CRIS-Team Scopus Importer:2019-06-04
Keywords: adenine; chronic inflammation; chronic kidney disease; hypoxia-inducible factor; mononuclear phagocyte; PHD inhibitor

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

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

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

MOR103, a human monoclonal antibody to granulocyte-macrophage colony-stimulating factor, in the treatment of patients with moderate rheumatoid arthritis: results of a phase Ib/IIa randomised, double-blind, placebo-controlled, dose-escalation trial - Behrens, Frank; Tak, Paul P.; Ostergaard, Mikkel; Stoilov, Rumen; Wiland, Piotr; Huizinga, Thomas W.; Berenfus, Vadym Y.; Vladeva, Stoyanka; Rech, Jürgen; Rubbert-Roth, Andrea; Korkosz, Mariusz; Rekalov, Dmitriy; et al. (Annals of the Rheumatic Diseases, 2015)
To determine the safety, tolerability and signs of efficacy of MOR103, a human monoclonal antibody to granulocyte-macrophage colony-stimulating factor (GM-CSF), in patients with rheumatoid arthritis (RA).Patients with active, moderate RA were enrolled in a randomised, multicentre, double-blind, placebo-controlled, dose-escalation trial of intravenous MOR103 (0.3, 1.0 or 1.5 mg/kg) once a week for 4 weeks, with follow-up to 16 weeks. The primary outcome was safety.Of the 96 randomised and treated subjects, 85 completed the trial (n=27, 24, 22 and 23 for pooled placebo and MOR103 0.3, 1.0 and 1.5 mg/kg, respectively). Treatment emergent adverse events (AEs) in the MOR103 groups were mild or moderate in intensity and generally reported at frequencies similar to those in the placebo group. The most common AE was nasopharyngitis. In two cases, AEs were classified as serious because of hospitalisation: paronychia in a placebo subject and pleurisy in a MOR103 0.3 mg/kg subject. Both patients recovered fully. In exploratory efficacy analyses, subjects in the MOR103 1.0 and 1.5 mg/kg groups showed significant improvements in Disease Activity Score-28 scores and joint counts and significantly higher European League Against Rheumatism response rates than subjects receiving placebo. MOR103 1.0 mg/kg was associated with the largest reductions in disease activity parameters.MOR103 was well tolerated and showed preliminary evidence of efficacy in patients with active RA. The data support further investigation of this monoclonal antibody to GM-CSF in RA patients and potentially in those with other immune-mediated inflammatory diseases.NCT0102325
EVALuna2:13236

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

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

Morphological, functional, and molecular assessment of breast cancer bone metastases by experimental ultrasound techniques compared with magnetic resonance imaging and histological analysis - Heinen, Henrik; Seyler, Lisa; Popp, Vanessa; Hellwig, Konstantin; Bozec, Aline; Uder, Michael; Ellmann, Stephan; Bäuerle, Tobias (Bone, 2021)
Background: The imaging of bone metastases, which is regularly performed by cross-sectional modalities, is clinically vital when characterizing and staging osseous lesions. In this paper, we aimed to establish a novel methodology using experimental ultrasound (US) techniques to assess the morphological, functional, and molecular features of breast cancer bone metastases in an animal model, compared with magnetic resonance imaging (MRI) and histological analysis. Materials and methods: Nude rats were implanted intra-arterially with MDA-MB-231 breast cancer cells to induce osteolytic metastasis in their right hind legs. Once tumors had developed, an experimental US technique using automatic 3D scanning and MRI were performed. For assessment of perfusion, functional imaging techniques included contrast-enhanced US (CEUS) and dynamic contrast-enhanced MRI (DCE-MRI). For molecular ultrasound, anti-VEGFR2 conjugated microbubbles were applied and correlated with immunostaining for VEGFR2 expression. Results: 3D US enabled the automatic assessment of osteolytic lesions, including the largest tumor diameters along the x-, y- and z-axes as well as the segmented tumor volumes, without significant differences between US and MRI (p > 0.18). The CEUS and DCE-MRI of osseous lesions showed corresponding results for the parameters peak enhancement, wash-in area under the curve (both, r > 0.5) and wash-in perfusion index (r > 0.3) when differentiating between tumor, necrotic tissue and healthy muscle tissue (all, p < 0.01). Finally, molecular US allowed the non-invasive assessment of increased VEGFR2 expression in skeletal lesions compared with surrounding muscle tissue (p = 0.03), while a control antibody could not discriminate between these tissues (p = 0.44)—a factor which was confirmed by histological analysis. Conclusion: To the best of our knowledge, this is the first report on an imaging protocol for breast cancer bone metastasis using an experimental US scanner. Therefore, we present a novel methodology to characterize these osseous lesions on the morphological, functional, and molecular level in correlation with MRI and histological analysis.
CRIS-Team Scopus Importer:2021-01-01
Keywords: Animal model; Bone metastases; Imaging; Magnetic resonance imaging; Microbubbles; Ultrasound

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

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

MRI of Potassium and Sodium Enables Comprehensive Analysis of Ion Perturbations in Skeletal Muscle Tissue After Eccentric Exercise. - Gast, Lena; Baier, Laura Marie; Meixner, Christian; Chaudry, Oliver; Engelke, Klaus; Uder, Michael; Nagel, Armin Michael; Heiß, Rafael (Investigative Radiology, 2023)
OBJECTIVES: The aims were to investigate if potassium ( 39 K) magnetic resonance imaging (MRI) can be used to analyze changes in the apparent tissue potassium concentration (aTPC) in calf muscle tissue after eccentric exercise and in delayed-onset muscle soreness, and to compare these to corresponding changes in the apparent tissue sodium concentration (aTSC) measured with sodium ( 23 Na) MRI. MATERIALS AND METHODS: Fourteen healthy subjects (7 female, 7 male; 25.0 ± 2.8 years) underwent 39 K and 23 Na MRI at a 7 T MR system, as well as 1 H MRI at a 3 T MR system. Magnetic resonance imaging data and blood samples were collected at baseline (t0), directly after performing eccentric exercise (t1) and 48 hours after exercise (t2). Self-reported muscle soreness was evaluated using a 10-cm visual analog scale for pain (0, no pain; 10, worst pain) at t0, t1, and t2. Quantification of aTPC/aTSC was performed after correcting the measured 39 K/ 23 Na signal intensities for partial volume and relaxation effects using 5 external reference phantoms. Edema volume and 1 H T 2 relaxation times were determined based on the 1 H MRI data. Participants were divided according to their increase in creatine kinase (CK) level into high (CK t2 ≥ 10·CK t0 ) and low CK (CK t2 < 10·CK t0 ) subjects. RESULTS: Blood serum CK and edema volume were significantly increased 48 hours after exercise compared with baseline ( P < 0.001). Six participants showed a high increase in blood serum CK level at t2 relative to baseline, whereas 8 participants had only a low to moderate increase in blood serum CK. All participants reported increased muscle soreness both at rest and when climbing stairs at t1 (0.4 ± 0.7; 1.4 ± 1.2) and t2 (1.6 ± 1.4; 4.8 ± 1.9) compared with baseline (0 ± 0; 0 ± 0). Moreover, aTSC was increased at t1 in exercised muscles of all participants (increase by 57% ± 24% in high CK, 73% ± 33% in low CK subjects). Forty-eight hours after training, subjects with high increase in blood serum CK still showed highly increased aTSC (increase by 79% ± 57% compared with t0). In contrast, aTPC at t2 was elevated in exercised muscles of low CK subjects (increase by 19% ± 11% compared with t0), in which aTSC had returned to baseline or below. Overall, aTSC and aTPC showed inverse evolution, with changes in aTSC being approximately twice as high as in aTPC. CONCLUSIONS: Our results showed that 39 K MRI is able to detect changes in muscular potassium concentrations caused by eccentric exercise. In combination with 23 Na MRI, this enables a more holistic analysis of tissue ion concentration changes.
EVALuna2:520477

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

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

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

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

Musculoskeletal research in human space flight – unmet needs for the success of crewed deep space exploration - Liphardt, Anna-Maria; Fernandez-Gonzalo, Rodrigo; Albracht, Kirsten; Rittweger, Jörn; Vico, Laurence (npj microgravity, 2023)
Based on the European Space Agency (ESA) Science in Space Environment (SciSpacE) community White Paper “Human Physiology – Musculoskeletal system”, this perspective highlights unmet needs and suggests new avenues for future studies in musculoskeletal research to enable crewed exploration missions. The musculoskeletal system is essential for sustaining physical function and energy metabolism, and the maintenance of health during exploration missions, and consequently mission success, will be tightly linked to musculoskeletal function. Data collection from current space missions from pre-, during-, and post-flight periods would provide important information to understand and ultimately offset musculoskeletal alterations during long-term spaceflight. In addition, understanding the kinetics of the different components of the musculoskeletal system in parallel with a detailed description of the molecular mechanisms driving these alterations appears to be the best approach to address potential musculoskeletal problems that future exploratory-mission crew will face. These research efforts should be accompanied by technical advances in molecular and phenotypic monitoring tools to provide in-flight real-time feedback.
CRIS-Team Scopus Importer:2023-02-10

Musculoskeletal Ultrasound Is a Sensitive Imaging Tool for the Assessment of Dynamic Changes of Bone Erosions in Inflammatory Arthritis: A Comparative Analysis with High-Resolution Peripheral Quantitatve Computed Tomography - Finzel, Stephanie; Backhaus, Marina; Kraus, Sebastian; Schett, Georg; Voll, Reinhard (2016)
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Mutual influence of immune system and bones - Kamradt, T.; Amling, M.; Dankbar, B.; Dudeck, A.; Gunzer, M.; Ignatius, Anita; Krönke, Gerhard; Kubatzky, K.; Pap, T.; Prinz, Immo; Schett, Georg; Schinke, T.; et al. (Zeitschrift für Rheumatologie, 2018)
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Myeloperoxidase Modulates Inflammation in Generalized Pustular Psoriasis and Additional Rare Pustular Skin Diseases - Haskamp, Stefan; Bruns, Heiko; Hahn, Madelaine; Hoffmann, Markus; Gregor, Anne; Löhr, Sabine; Hahn, Jonas; Ringer, Mark; Flamann, Cindy; Frey, Benjamin; Lesner, Adam; Thiel, Christian; et al. (American Journal of Human Genetics, 2020)
Generalized pustular psoriasis (GPP) is a severe multi-systemic inflammatory disease characterized by neutrophilic pustulosis and triggered by pro-inflammatory IL-36 cytokines in skin. While 19%–41% of affected individuals harbor bi-allelic mutations in IL36RN, the genetic cause is not known in most cases. To identify and characterize new pathways involved in the pathogenesis of GPP, we performed whole-exome sequencing in 31 individuals with GPP and demonstrated effects of mutations in MPO encoding the neutrophilic enzyme myeloperoxidase (MPO). We discovered eight MPO mutations resulting in MPO -deficiency in neutrophils and monocytes. MPO mutations, primarily those resulting in complete MPO deficiency, cumulatively associated with GPP (p = 1.85E−08; OR = 6.47). The number of mutant MPO alleles significantly differed between 82 affected individuals and >4,900 control subjects (p = 1.04E−09); this effect was stronger when including IL36RN mutations (1.48E−13) and correlated with a younger age of onset (p = 0.0018). The activity of four proteases, previously implicated as activating enzymes of IL-36 precursors, correlated with MPO deficiency. Phorbol-myristate-acetate-induced formation of neutrophil extracellular traps (NETs) was reduced in affected cells (p = 0.015), and phagocytosis assays in MPO-deficient mice and human cells revealed altered neutrophil function and impaired clearance of neutrophils by monocytes (efferocytosis) allowing prolonged neutrophil persistence in inflammatory skin. MPO mutations contribute significantly to GPP's pathogenesis. We implicate MPO as an inflammatory modulator in humans that regulates protease activity and NET formation and modifies efferocytosis. Our findings indicate possible implications for the application of MPO inhibitors in cardiovascular diseases. MPO and affected pathways represent attractive targets for inducing resolution of inflammation in neutrophil-mediated skin diseases.
CRIS-Team Scopus Importer:2020-09-11
Keywords: ACH; acrodermatitis continua suppurativa Hallopeau; activation of IL-36 precursors; acute generalized 4 exanthematous pustulosis; AGEP; efferocytosis; generalized pustular psoriasis; GPP; impaired NETosis; MPO deficiency; myeloperoxidase; oligogenic inheritance

Myositis-specific and myositis-associated autoantibodies predict trajectories of damage over time in idiopathic inflammatory myopathies - Espinosa-Ortega, F.; Holmqvist, M.; Lodin, K.; Dastmalchi, M.; Danieli, M. G.; Venkovsky, J.; Knitza, Johannes; Oliveira, S.; Diederichsen, L. P.; Wedderburn, L.; Andersson, H.; Del Mercado, M. Vazquez; et al. (SCANDINAVIAN JOURNAL OF RHEUMATOLOGY, 2021)
CRIS-Team WoS Importer:2021-09-03

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

Nanomaterial Exposure Induced Neutrophil Extracellular Traps: A New Target in Inflammation and Innate Immunity - Yang, Hang; Marion, Tony N.; Liu, Yi; Zhang, Lingshu; Cao, Xue; Hu, Huifang; Zhao, Yi; Herrmann, Martin (Journal of Immunology Research, 2019)
Nanotechnology has become a novel subject with impact in many research and technology areas. Nanoparticles (NPs), as a key component in nanotechnology, are widely used in many areas such as optical, magnetic, electrical, and mechanical engineering. The biomedical and pharmaceutical industries have embraced NPs as a viable drug delivery modality. As such, the potential for NP-induced cytotoxicity has emerged as a major concern for NP drug delivery systems. Thus, it is important to understand how NPs affect the innate immune system. As the most abundant myeloid cell type in innate immune responses, neutrophils are critical for concerns about potentially toxic side effects of NPs. When activated by innate immune stimuli, neutrophils may initiate NETosis to release neutrophil extracellular traps (NETs). Herein, we have reviewed the relationship between NPs and the induction of NETosis and release of NETs.
CRIS-Team WoS Importer:2019-03-22

Nanoparticles size-dependently initiate self-limiting NETosis-driven inflammation - Munoz, Luis E.; Bilyy, Rostyslav; Biermann, Mona H. C.; Kienhoefer, Deborah; Maueröder, Christian; Hahn, Jonas; Brauner, Jan M.; Weidner, Daniela; Chen, Juan; Scharin-Mehlmann, Marina; Janko, Christina; Friedrich, Ralf P.; et al. (Proceedings of the National Academy of Sciences of the United States of America, 2016)
The critical size for strong interaction of hydrophobic particles with phospholipid bilayers has been predicted to be 10 nm. Because of the wide spreading of nonpolar nanoparticles (NPs) in the environment, we aimed to reveal the ability of living organisms to entrap NPs via formation of neutrophil extracellular traps (NETs). Upon interaction with various cell types and tissues, 10- to 40-nm-sized NPs induce fast (<20 min) damage of plasma membranes and instability of the lysosomal compartment, leading to the immediate formation of NETs. In contrast, particles sized 100-1,000 nm behaved rather inertly. Resulting NET formation (NETosis) was accompanied by an inflammatory reaction intrinsically endowed with its own resolution, demonstrated in lungs and air pouches of mice. Persistence of small NPs in joints caused unremitting arthritis and bone remodeling. Small NPs coinjected with antigen exerted adjuvant-like activity. This report demonstrates a cellular mechanism that explains how small NPs activate the NETosis pathway and drive their entrapping and resolution of the initial inflammatory response.
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NaV1.7 and pain: contribution of peripheral nerves - Hoffmann, Tal; Sharon, Ohad; Wittmann, Jürgen; Carr, Richard W.; Vyshnevska, Alina; De Col, Roberto; Nassar, Mohammed A.; Reeh, Peter; Weidner, Christian (Pain, 2018)
The sodium channel NaV1.7 contributes to action potential (AP) generation and propagation. Loss-of-function mutations in patients lead to congenital indifference to pain, though it remains unclear where on the way from sensory terminals to central nervous system the signalling is disrupted. We confirm that conditional deletion of NaV1.7 in advillin-expressing sensory neurons leads to impaired heat and mechanical nociception in behavioural tests. With single-fiber recordings from isolated skin, we found (1) a significantly lower prevalence of heat responsiveness to normally mechanosensitive C-fibers, although (2) the rare heat responses seemed quite vigorous, and (3) heat-induced calcitonin gene-related peptide release was normal. In biophysical respects, although electrical excitability, rheobase, and chronaxy were normal, (4) axonal conduction velocity was 20% slower than in congenic wild-type mice (5) and when challenged with double pulses (<100 milliseconds interval), the second AP showed more pronounced latency increase (6). On prolonged electrical stimulation at 2 Hz, (7) activity-dependent slowing of nerve fiber conduction was markedly less, and (8) was less likely to result in conduction failure of the mutant single fibers. Finally, recording of compound APs from the whole saphenous nerve confirmed slower conduction and less activity-dependent slowing as well as the functional absence of a large subpopulation of C-fibers (9) in conditional NaV1.7 knockouts. In conclusion, the clear deficits in somatic primary afferent functions shown in our study may be complemented by previously reported synaptic dysfunction and opioidergic inhibition, together accounting for the complete insensitivity to pain in the human mutants lacking NaV1.7.
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NCOA3 AMPLIFIES PROFIBROTIC TRANSCRIPTIONAL PROGRAMS IN SYSTEMIC SCLEROSIS - Dees, Clara; Pötter, Sebastian; Fuchs, Maximilian; Bergmann, Christina; Matei, Alexandru-Emil; Györfi, Andrea-Hermina; Soare, A.; Ramming, Andreas; Ceppi, Paolo; Schett, Georg; Kunz, Meik; Distler, H. W. (ANNALS OF THE RHEUMATIC DISEASES, 2021)
CRIS-Team WoS Importer:2021-09-24

Neither Add-on nor Withdrawal of Methotrexate Impacts Efficacy of IL12/23 Inhibition in Active PsA: Data from a Multicenter Investigator-initiated Randomized Placebo-controlled Clinical Trial on Arthritis, Dactylitis, Enthesitis, Psoriasis, QoL and Function - Koehm, Michaela; Rossmanith, Tanja; Foldenauer, Ann Christina; Herrmann, Eva; Kellner, Herbert; Kiltz, Uta; Rech, Juergen; Burmester, Gerd-Rüdiger; Kofler, David; Brandt-Juergens, Jan; Jonetzko, Christin; Burkhardt, Harald; et al. (ARTHRITIS & RHEUMATOLOGY, 2021)
Methotrexate (MTX) is often used as first-line DMARD-therapy in active psoriatic arthritis (PsA). Randomized clinical trials usually require treatment failure or intolerance of csDMARD/MTX before initiation of a biological treatment. The value of MTX in combination with bDMARDs is still unclear. We designed an investigator-initiated, randomized, placebo-controlled trial (IIT) in active PsA to examine if outcomes of treatment with ustekinumab (UST) in combination with MTX (either newly initiated or ongoing) were different from UST only (+Placebo; PBO). The aim of the trial was to evaluate non-inferiority of efficacy on arthritis (DAS28 at W24) and compare efficacy on PsA domains for UST+MTX vs UST+PBO.<br
CRIS-Team WoS Importer:2022-03-11
Keywords: Biologicals; Late-Breaking 2021; Psoriatic arthritis; spondyloarthritis

NET Formation in Systemic Lupus Erythematosus: Changes during the COVID-19 Pandemic - Knopf, Jasmin; Sjoewall, Johanna; Frodlund, Martina; Hinkula, Jorma; Herrmann, Martin; Sjoewall, Christopher (Cells, 2022)
The severity of the coronavirus disease in 2019 (COVID-19) is strongly linked to a dysregulated immune response. This fuels the fear of severe disease in patients with autoimmune disorders continuously using immunosuppressive/immunomodulating medications. One complication of COVID-19 is thromboembolism caused by intravascular aggregates of neutrophil extracellular traps (NETs) occluding the affected vessels. Like COVID-19, systemic lupus erythematosus (SLE) is characterized by, amongst others, an increased risk of thromboembolism. An imbalance between NET formation and clearance is suggested to play a prominent role in exacerbating autoimmunity and disease severity. Serologic evidence of exposure to SARS-CoV-2 has a minor impact on the SLE course in a Swedish cohort reportedly. Herein, we assessed NET formation in patients from this cohort by neutrophil elastase (NE) activity and the presence of cell-free DNA, MPO-DNA, and NE-DNA complexes and correlated the findings to the clinical parameters. The presence of NE-DNA complexes and NE activity differed significantly in pre-pandemic versus pandemic serum samples. The latter correlated significantly with the hemoglobin concentration, blood cell counts, and complement protein 3 and 4 levels in the pre-pandemic but only with the leukocyte count and neutrophil levels in the pandemic serum samples. Taken together, our data suggest a change, especially in the NE activity independent of exposure to SARS-CoV-2.
CRIS-Team WoS Importer:2022-09-23

NETs Are Double-Edged Swords with the Potential to Aggravate or Resolve Periodontal Inflammation - Vitkov, Ljubomir; Minnich, Bernd; Knopf, Jasmin; Hannig, Matthias; Herrmann, Martin; Schauer, Christine (Cells, 2020)
Periodontitis is a general term for diseases characterised by inflammatory destruction of tooth-supporting tissues, gradual destruction of the marginal periodontal ligament and resorption of alveolar bone. Early-onset periodontitis is due to disturbed neutrophil extracellular trap (NET) formation and clearance. Indeed, mutations that inactivate the cysteine proteases cathepsin C result in the massive periodontal damage seen in patients with deficient NET formation. In contrast, exaggerated NET formation due to polymorphonuclear neutrophil (PMN) hyper-responsiveness drives the pathology of late-onset periodontitis by damaging and ulcerating the gingival epithelium and retarding epithelial healing. Despite the gingival regeneration, periodontitis progression ends with almost complete loss of the periodontal ligament and subsequent tooth loss. Thus, NETs help to maintain periodontal health, and their dysregulation, either insufficiency or surplus, causes heavy periodontal pathology and edentulism.
CRIS-Team WoS Importer:2021-01-15

Network- and systems-based re-engineering of dendritic cells with non-coding RNAs for cancer immunotherapy - Lai, Xin; Dreyer, Florian; Cantone, Martina; Eberhardt, Martin; Gerer, Kerstin F.; Jaitly, Tanushree; Uebe, Steffen; Lischer, Christopher; Ekici, Arif Bülent; Wittmann, Jürgen; Jäck, Hans-Martin; Schaft, Niels; et al. (Theranostics, 2021)
Dendritic cells (DCs) are professional antigen-presenting cells that induce and regulate adaptive immunity by presenting antigens to T cells. Due to their coordinative role in adaptive immune responses, DCs have been used as cell-based therapeutic vaccination against cancer. The capacity of DCs to induce a therapeutic immune response can be enhanced by re-wiring of cellular signalling pathways with microRNAs (miRNAs). Methods: Since the activation and maturation of DCs is controlled by an interconnected signalling network, we deploy an approach that combines RNA sequencing data and systems biology methods to delineate miRNA-based strategies that enhance DC-elicited immune responses. Results: Through RNA sequencing of IKKβ-matured DCs that are currently being tested in a clinical trial on therapeutic anti-cancer vaccination, we identified 44 differentially expressed miRNAs. According to a network analysis, most of these miRNAs regulate targets that are linked to immune pathways, such as cytokine and interleukin signalling. We employed a network topology-oriented scoring model to rank the miRNAs, analysed their impact on immunogenic potency of DCs, and identified dozens of promising miRNA candidates, with miR-15a and miR-16 as the top ones. The results of our analysis are presented in a database that constitutes a tool to identify DC-relevant miRNA-gene interactions with therapeutic potential (www.synmirapy.net/dc-optimization). Conclusions: Our approach enables the systematic analysis and identification of functional miRNA-gene interactions that can be experimentally tested for improving DC immunogenic potenc
CRIS-Team WoS Importer:2020-12-11
Keywords: dendritic cell; therapeutic vaccination in cancer; systems biology; network biology; microRNAs: bioinformatics

NETworking for Health and in Disease: Neutrophil Extracellular Traps in Pediatric Surgical Care - Dölling, Maximilian; Herrmann, Martin; Boettcher, Michael (Children, 2024)
This comprehensive review examines the role of Neutrophil Extracellular Traps (NETs) in pediatric surgery. Focusing on NET formation, functions, and implications, this study highlights their dual impact in infection control and contribution to tissue damage after surgery. It covers the role of NET formation in a range of pediatric conditions including immunothrombosis, formation of peritoneal adhesions, appendicitis, burns, gallstones, tumors, and necrotizing enterocolitis (NEC). The results underscore the significance of NETs in fighting infections and their association with complications like sepsis and delayed wound healing. The breakdown products of NETs as a diagnostic tool of the clinical course of acute appendicitis will also be discussed. Understanding NET formation in the pathophysiology can potentially help to find new therapeutic approaches such as the application of DNase and elastase inhibitors to change the clinical course of various diseases in pediatric surgery such as improvement of wound healing, adhesion formation, NEC, and many more.
CRIS-Team Scopus Importer:2024-04-05
Keywords: appendicitis; burns; diabetes mellitus; extracellular traps; gallstones; necrotizing enterocolitis; thromboinflammation; tissue adhesions; tumor microenvironment; wound healing

Networks of enzymatically oxidized membrane lipids support calcium-dependent coagulation factor binding to maintain hemostasis - Lauder, Sarah N.; Allen-Redpath, Keith; Slatter, David A.; Aldrovandi, Maceler; O'Connor, Anne; Farewell, Daniel; Percy, Charles L.; Molhoek, Jessica E.; Rannikko, Sirpa; Tyrrell, Victoria J.; Ferla, Salvatore; Milne, Ginger L.; et al. (Science Signaling, 2017)
Blood coagulation functions as part of the innate immune system by preventing bacterial invasion, and it is critical to stopping blood loss (hemostasis). Coagulation involves the external membrane surface of activated platelets and leukocytes. Using lipidomic, genetic, biochemical, and mathematical modeling approaches, we found that enzymatically oxidized phospholipids (eoxPLs) generated by the activity of leukocyte or platelet lipoxygenases (LOXs) were required for normal hemostasis and promoted coagulation factor activities in a Ca2+- and phosphatidylserine (PS)-dependent manner. In wild-type mice, hydroxyeicosatetraenoic acid-phospholipids (HETE-PLs) enhanced coagulation and restored normal hemostasis in clotting-deficient animals genetically lacking p12-LOX or 12/15-LOX activity. Murine platelets generated 22 eoxPL species, all of which were missing in the absence of p12-LOX. Humans with the thrombotic disorder antiphospholipid syndrome (APS) had statistically significantly increased HETE-PLs in platelets and leukocytes, as well as greater HETE-PL immunoreactivity, than healthy controls. HETE-PLs enhanced membrane binding of the serum protein ?2GP1 (?2-glycoprotein 1), an event considered central to the autoimmune reactivity responsible for APS symptoms. Correlation network analysis of 47 platelet eoxPL species in platelets from APS and control subjects identified their enzymatic origin and revealed a complex network of regulation, with the abundance of 31 p12-LOX-derived eoxPL molecules substantially increased in APS. In summary, circulating blood cells generate networks of eoxPL molecules, including HETE-PLs, which change membrane properties to enhance blood coagulation and contribute to the excessive clotting and immunoreactivity of patients with APS.
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Neural Networks for Distinguishing Rheumatoid Arthritis from Psoriatic Arthritis by Using Magnetic Resonance Imaging - Folle, Lukas; Bayat, Sara; Kleyer, Arnd; Fagni, Filippo; Kapsner, Lorenz; Schlereth, Maja; Meinderink, Timo; Breininger, Katharina; Tascilar, Koray; Krönke, Gerhard; Uder, Michael; Sticherling, Michael; et al. (Arthritis Rheumatol., 2022)

Neurodegeneration Enhances the Development of Arthritis - Lang, Stefanie; Harre, Ulrike; Purohit, Pavitra; Dietel, Katharina; Kienhöfer, Deborah; Hahn, Jonas; Baum, Wolfgang; Herrmann, Martin; Schett, Georg; Mielenz, Dirk (Journal of Immunology, 2017)
The prevalence of neurodegenerative disease and arthritis increases with age. Despite both processes being associated with immune activation and inflammation, little is known about the mechanistic interactions between neurodegenerative disease and arthritis. In this article, we show that tau-transgenic (tau-tg) mice that develop neurodegenerative disease characterized by deposition of tau tangles in the brain are highly susceptible to developing arthritis. Already at steady-state conditions, tau-tg mice exhibit peripheral immune activation that is manifested by higher numbers of granulocytes, plasmablasts, and inflammatory Ly6C(hi) CCR2(+) monocytes, as well as increased levels of proinflammatory cytokines, such as TNF-? and IL-17. Upon induction of collagen-induced arthritis (CIA), tau-tg mice displayed an increased incidence and an earlier onset of CIA that was associated with a more pronounced inflammatory cytokine response. Furthermore, induction of CIA led to significantly elevated numbers of Iba-1-expressing cells in the brain, indicative of microglia activation, and the formation of anti-tau Abs in tau-tg mice. These changes were accompanied by the resolution of tau tangles and significantly decreased neurodegenerative pathology. In summary, these data show that neurodegenerative disease enhances the development of arthritis. In addition, arthritis, once induced, triggers innate immune responses in the brain, leading to resolution of neurodegenerative change
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Neutralisation sensitivity of SARS-CoV-2 lineages EG.5.1 and XBB.2.3 - Zhang, Lu; Kempf, Amy; Nehlmeier, Inga; Cossmann, Anne; Dopfer-Jablonka, Alexandra; Stankov, Metodi V.; Schulz, Sebastian; Jäck, Hans-Martin; Behrens, Georg M.N.; Pöhlmann, Stefan; Hoffmann, Markus (Lancet Infectious Diseases, 2023)
CRIS-Team Scopus Importer:2023-10-13

Neutralisation sensitivity of the SARS-CoV-2 XBB.1 lineage - Arora, Prerna; Cossmann, Anne; Schulz, Sebastian; Ramos, Gema Morillas; Stankov, Metodi V.; Jäck, Hans-Martin; Behrens, Georg M.N.; Pöhlmann, Stefan; Hoffmann, Markus (Lancet Infectious Diseases, 2023)
CRIS-Team Scopus Importer:2023-02-10

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

Neutral sphingomyelinase mediates the co-morbidity trias of alcohol abuse, major depression and bone defects - Kalinichenko, Liubov; Mühle, Christiane; Jia, Tianye; Anderheiden, Felix; Datz, Maria; Eberle, Anna-Lisa; Eulenburg, Volker; Granzow, Jonas; Hofer, Martin Jürgen; Hohenschild, Julia; Huber, Sabine; Kämpf, Stefanie; et al. (Molecular Psychiatry, 2021)
Mental disorders are highly comorbid and occur together with physical diseases, which are often considered to arise from separate pathogenic pathways. We observed in alcohol-dependent patients increased serum activity of neutral sphingomyelinase. A genetic association analysis in 456,693 volunteers found associations of haplotypes of SMPD3 coding for NSM-2 (NSM) with alcohol consumption, but also with affective state, and bone mineralisation. Functional analysis in mice showed that NSM controls alcohol consumption, affective behaviour, and their interaction by regulating hippocampal volume, cortical connectivity, and monoaminergic responses. Furthermore, NSM controlled bone–brain communication by enhancing osteocalcin signalling, which can independently supress alcohol consumption and reduce depressive behaviour. Altogether, we identified a single gene source for multiple pathways originating in the brain and bone, which interlink disorders of a mental–physical co-morbidity trias of alcohol abuse—depression/anxiety—bone disorder. Targeting NSM and osteocalcin signalling may, thus, provide a new systems approach in the treatment of a mental–physical co-morbidity trias.
CRIS-Team Scopus Importer:2021-10-08

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

Neutrophil Extracellular Trap-Borne Elastase Prevents Inflammatory Relapse in Intercritical Gout - Liu, Lei; Shan, Lizhen; Wang, Han; Schauer, Christine; Schoen, Janina; Zhu, Lingjiang; Lu, Ci; Wang, Zitao; Xue, Yu; Wu, Huaxiang; Herrmann, Martin (Arthritis and Rheumatology, 2023)
Objective. Gout flares that occur during urate-lowering therapy (ULT) are typically related to the shrinkage of tophi due to aggregated neutrophil extracellular traps (NETs) that have captured monosodium urate crystals in the tissues. The present study was undertaken to analyze the blocking effect of alpha(1)-antitrypsin on neutrophil elastase, and it was found that alpha(1)-antitrypsin induced rapid inflammation in the presence of unstable tophi.
CRIS-Team WoS Importer:2023-05-19

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

Neutrophil extracellular traps and DNases orchestrate formation of peritoneal adhesions. - Elrod, Julia; Heuer, Annika; Knopf, Jasmin; Schoen, Janina; Schönfeld, Lavinia; Trochimiuk, Magdalena; Stiel, Carolin; Appl, Birgit; Raluy, Laia Pagerols; Saygi, Ceren; Zlatar, Leticija; Hosari, Sami; et al. (iScience, 2023)
Peritoneal adhesions are poorly understood but highly prevalent conditions that can cause intestinal obstruction and pelvic pain requiring surgery. While there is consensus that stress-induced inflammation triggers peritoneal adhesions, the molecular processes of their formation still remain elusive. We performed murine models and analyzed human samples to monitor the formation of adhesions and the treatment with DNases. Various molecular analyses were used to evaluate the adhesions. The experimental peritoneal adhesions of the murine models and biopsy material from humans are largely based on neutrophil extracellular traps (NETs). Treatment with DNASE1 (Dornase alfa) and the human DNASE1L3 analog (NTR-10), significantly reduced peritoneal adhesions in experimental models. We conclude that NETs serve as essential scaffold for the formation of adhesions; DNases interfere with this process. Herein, we show that therapeutic application of DNases can be employed to prevent the formation of murine peritoneal adhesions. If this can be translated into the human situation requires clinical studies.
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Neutrophil Extracellular Traps Drive Dacryolithiasis - Zlatar, Leticija; Timm, Thomas; Lochnit, Günter; Bilyy, Rostyslav; Bäuerle, Tobias; Munoz Becerra, Marco; Schett, Georg; Knopf, Jasmin; Heichel, Jens; Ali, Mohammad Javed; Schapher, Mirco; Paulsen, Friedrich; et al. (Cells, 2023)
Mucopeptide concretions, previously called dacryoliths, are macroscopic stones that commonly obstruct the lacrimal sac. The mechanism behind dacryolithiasis remains unclear; however, the involvement of various immune cells, including neutrophils, has been confirmed. These findings remain limited, and no information on neutrophil extracellular traps (NETs), essentially involved in the pathogenesis of other lithiases, is available yet. Here, we employ microcomputed tomography, magnetic resonance tomography, histochemistry, mass spectrometry, and enzyme activity analyses to investigate the role of neutrophils and NETs in dacryolithiasis. We classify mucopeptide concretions into three types, with respect to the quantity of cellular and acellular material, polysaccharides, and mucosubstances. We propose the role of neutrophils and NETs within the existing model of gradual formation and growth of mucopeptide concretions, with neutrophils contributing to the initial stages of dacryolithiasis, as they localized on the inner (older) parts of the tissue. As NETs localized on the outer (newer) parts of the tissue, we link their role to the late stages of dacryolithiasis, presumably maintaining the proinflammatory environment and preventing efficient clearance. An abundance of IgG on the surface indicates the involvement of the adaptive immune system later as well. These findings bring new perspectives on dacryolithiasis, in which the innate and adaptive immune system are essentially involved.
CRIS-Team Scopus Importer:2023-08-11
Keywords: dacryolithiasis; dacryoliths; lacrimal sac; mucopeptide concretions; neutrophil extracellular traps; neutrophils

Neutrophil Extracellular Traps Drive Endothelial-to-Mesenchymal Transition - Pieterse, Elmar; Rother, Nils; Garsen, Marjolein; Hofstra, Julia M.; Satchell, Simon C.; Hoffmann, Markus; Loeven, Markus A.; Knaapen, Hanneke K.; Van Der Heijden, Olivier W. H.; Berden, Jo H. M.; Hilbrands, Luuk B.; Van Der Vlag, Johan (Arteriosclerosis, Thrombosis, and Vascular Biology, 2017)
An excessive release and impaired degradation of neutrophil extracellular traps (NETs) leads to the continuous exposure of NETs to the endothelium in a variety of hematologic and autoimmune disorders, including lupus nephritis. This study aims to unravel the mechanisms through which NETs jeopardize vascular integrity.Microvascular and macrovascular endothelial cells were exposed to NETs, and subsequent effects on endothelial integrity and function were determined in vitro and in vivo. We found that endothelial cells have a limited capacity to internalize NETs via the receptor for advanced glycation endproducts. An overflow of the phagocytic capacity of endothelial cells for NETs resulted in the persistent extracellular presence of NETs, which rapidly altered endothelial cell-cell contacts and induced vascular leakage and transendothelial albumin passage through elastase-mediated proteolysis of the intercellular junction protein VE-cadherin. Furthermore, NET-associated elastase promoted the nuclear translocation of junctional ?-catenin and induced endothelial-to-mesenchymal transition in cultured endothelial cells. In vivo, NETs could be identified in kidney samples of diseased MRL/lpr mice and patients with lupus nephritis, in whom the glomerular presence of NETs correlated with the severity of proteinuria and with glomerular endothelial-to-mesenchymal transition.These results indicate that an excess of NETs exceeds the phagocytic capacity of endothelial cells for NETs and promotes vascular leakage and endothelial-to-mesenchymal transition through the degradation of VE-cadherin and the subsequent activation of ?-catenin signaling. Our data designate NET-associated elastase as a potential therapeutic target in the prevention of endothelial alterations in diseases characterized by aberrant NET release.
EVALuna2:13431

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

Neutrophil Extracellular Traps Form a Barrier between Necrotic and Viable Areas in Acute Abdominal Inflammation - Bilyy, Rostyslav; Fedorov, Volodymyr; Vovk, Volodymyr; Leppkes, Moritz; Dumych, Tetiana; Chopyak, Valentyna; Schett, Georg; Herrmann, Martin (Frontiers in Immunology, 2016)
Neutrophils form neutrophil extracellular traps (NETs) of decondensed DNA and histones that trap and immobilize particulate matter and microbial pathogens like bacteria. NET aggregates reportedly surround and isolate large objects like monosodium urate crystals, which cannot be sufficiently cleared from tissues. In the setting of acute necrotizing pancreatitis, massive tissue necrosis occurs, which is organized as pancreatic pseudocysts (1). In contrast to regular cysts, these pseudocysts are not surrounded by epithelial layers. We hypothesize that, instead, the necrotic areas observed in necrotizing pancreatitis are isolated from the surrounding healthy tissues by aggregated NETs. These may form an alternative, putatively transient barrier, separating necrotic areas from viable tissue. To test this hypothesis, we investigated histological samples from the necropsy material of internal organs of two patients with necrotizing pancreatitis and peritonitis accompanied by multiple organ failure. Tissues including the inflammatory zone were stained with hematoxylin and eosin and evaluated for signs of inflammation. Infiltrating neutrophils and NETs were detected by immunohistochemistry for DNA, neutrophil elastase (NE), and citrullinated histone H3. Interestingly, in severely affected areas of pancreatic necrosis or peritonitis, chromatin stained positive for NE and citrullinated histone H3, and may, therefore, be considered NET-derived. These NET structures formed a layer, which separated the necrotic core from the areas of viable tissue remains. A condensed layer of aggregated NETs, thus, spatially shields and isolates the site of necrosis, thereby limiting the spread of necrosis-associated proinflammatory mediators. We propose that necrotic debris may initiate and/or facilitate the formation of the NET-based surrogate barrier.
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Neutrophil Extracellular Traps Formation and Aggregation Orchestrate Induction and Resolution of Sterile Crystal-Mediated Inflammation - Li, Yanhong; Cao, Xue; Liu, Yi; Zhao, Yi; Herrmann, Martin (Frontiers in Immunology, 2018)
The formation of neutrophil extracellular traps (NETs) to immobilize pathogens represents a novel antimicrobial strategy of the immune system. The microcrystals related to human diseases are classified into endogenous microcrystals, including monosodium urate (MSU), calcium pyrophosphate dihydrate, calcium carbonate, calcium phosphate, calcium oxalate, cholesterol, and exogenous material like crystals from silica. Although microcrystals possess distinct compositions and shapes, they have a common characteristic: they stimulate neutrophils to release NETs. In low and high densities, neutrophils form NETs and aggregated NETs (aggNETs) that reportedly orchestrate the initiation and resolution of sterile crystal-mediated inflammation, respectively. Here, we summarize the different roles of NETs and aggNETs stimulated by the crystals mentioned above in related inflammatory reactions. The NETosis-derived products may represent a potential therapeutic target in crystal-mediated diseases.
EVALuna2:213260

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

Neutrophil Extracellular Traps (NETs) in the Cerebrospinal Fluid Samples from Children and Adults with Central Nervous System Infections - Appelgren, Daniel; Enocsson, Helena; Skogman, Barbro H.; Nordberg, Marika; Perander, Linda; Nyman, Dag; Nyberg, Clara; Knopf, Jasmin; Munoz, Luis Enrique; Sjowall, Christopher; Sjowall, Johanna (Cells, 2020)
Neutrophils operate as part of the innate defence in the skin and may eliminate the Borrelia spirochaete via phagocytosis, oxidative bursts, and hydrolytic enzymes. However, their importance in Lyme neuroborreliosis (LNB) is unclear. Neutrophil extracellular trap (NET) formation, which is associated with the production of reactive oxygen species, involves the extrusion of the neutrophil DNA to form traps that incapacitate bacteria and immobilise viruses. Meanwhile, NET formation has recently been studied in pneumococcal meningitis, the role of NETs in other central nervous system (CNS) infections has previously not been studied. Here, cerebrospinal fluid (CSF) samples from clinically well-characterised children (N = 111) and adults (N = 64) with LNB and other CNS infections were analysed for NETs (DNA/myeloperoxidase complexes) and elastase activity. NETs were detected more frequently in the children than the adults (p = 0.01). NET presence was associated with higher CSF levels of CXCL1 (p < 0.001), CXCL6 (p = 0.007), CXCL8 (p = 0.003), CXCL10 (p < 0.001), MMP-9 (p = 0.002), TNF (p = 0.02), IL-6 (p < 0.001), and IL-17A (p = 0.03). NETs were associated with fever (p = 0.002) and correlated with polynuclear pleocytosis (r(s) = 0.53, p < 0.0001). We show that neutrophil activation and active NET formation occur in the CSF samples of children and adults with CNS infections, mainly caused by Borrelia and neurotropic viruses. The role of NETs in the early phase of viral/bacterial CNS infections warrants further investigation.
CRIS-Team WoS Importer:2020-03-13

Neutrophil Extracellular Traps Open the Pandora's Box in Severe Malaria - Boeltz, Sebastian; Munoz, Luis Enrique; Fuchs, Tobias A.; Herrmann, Martin; Munoz Becerra, Luis (Frontiers in Immunology, 2017)
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Neutrophil Extracellular Traps Promote the Development and Growth of Human Salivary Stones - Schapher, Mirco; Koch, Michael; Weidner, Daniela; Scholz, Michael; Wirtz, Stefan; Mahajan, Aparna; Herrmann, Irmgard; Singh, Jeeshan; Knopf, Jasmin; Leppkes, Moritz; Grüneboom, Anika; Alexiou, Christoph; et al. (Cells, 2020)
Salivary gland stones, or sialoliths, are the most common cause of the obstruction of salivary glands. The mechanism behind the formation of sialoliths has been elusive. Symptomatic sialolithiasis has a prevalence of 0.45% in the general population, is characterized by recurrent painful periprandial swelling of the affected gland, and often results in sialadenitis with the need for surgical intervention. Here, we show by the use of immunohistochemistry, immunofluorescence, computed tomography (CT) scans and reconstructions, special dye techniques, bacterial genotyping, and enzyme activity analyses that neutrophil extracellular traps (NETs) initiate the formation and growth of sialoliths in humans. The deposition of neutrophil granulocyte extracellular DNA around small crystals results in the dense aggregation of the latter, and the subsequent mineralization creates alternating layers of dense mineral, which are predominantly calcium salt deposits and DNA. The further agglomeration and appositional growth of these structures promotes the development of macroscopic sialoliths that finally occlude the efferent ducts of the salivary glands, causing clinical symptoms and salivary gland dysfunction. These findings provide an entirely novel insight into the mechanism of sialolithogenesis, in which an immune system-mediated response essentially participates in the physicochemical process of concrement formation and growth.
CRIS-Team Scopus Importer:2020-10-09
Keywords: lithogenesis; neutrophil extracellular traps; neutrophils; salivary glands; salivary stones; sialadenitis; sialolithiasis; stone development; stone growth

Neutrophil Extracellular Traps Tied to Rheumatoid Arthritis: Points to Ponder - Song, Wenpeng; Ye, Jing; Pan, Nanfang; Tan, Chunyu; Herrmann, Martin (Frontiers in Immunology, 2021)
In recent years, neutrophil extracellular traps at the forefront of neutrophil biology have proven to help capture and kill pathogens involved in the inflammatory process. There is growing evidence that persistent neutrophil extracellular traps drive the pathogenesis of autoimmune diseases. In this paper, we summarize the potential of neutrophil extracellular traps to drive the pathogenesis of rheumatoid arthritis and experimental animal models. We also describe the diagnosis and treatment of rheumatoid arthritis in association with neutrophil extracellular traps.
CRIS-Team Scopus Importer:2021-03-05
Keywords: anti-citrullinated protein antibodies; autoimmunity; chronic inflammation; citrullinated autoantigens; neutrophil extracellular traps; protein-arginine deiminase type 4; rheumatoid arthritis

Neutrophilia and NETopathy as Key Pathologic Drivers of Progressive Lung Impairment in Patients With COVID-19 - Narasaraju, Teluguakula; Tang, Benjamin M.; Herrmann, Martin; Muller, Sylviane; Chow, Vincent T.K.; Radic, Marko (Frontiers in Pharmacology, 2020)
There is an urgent need for new therapeutic strategies to contain the spread of the novel coronavirus disease 2019 (COVID-19) and to curtail its most severe complications. Severely ill patients experience pathologic manifestations of acute respiratory distress syndrome (ARDS), and clinical reports demonstrate striking neutrophilia, elevated levels of multiple cytokines, and an exaggerated inflammatory response in fatal COVID-19. Mechanical respirator devices are the most widely applied therapy for ARDS in COVID-19, yet mechanical ventilation achieves strikingly poor survival. Many patients, who recover, experience impaired cognition or physical disability. In this review, we argue the need to develop therapies aimed at inhibiting neutrophil recruitment, activation, degranulation, and neutrophil extracellular trap (NET) release. Moreover, we suggest that currently available pharmacologic approaches should be tested as treatments for ARDS in COVID-19. In our view, targeting host-mediated immunopathology holds promise to alleviate progressive pathologic complications of ARDS and reduce morbidities and mortalities in severely ill patients with COVID-19.
CRIS-Team Scopus Importer:2020-06-30
Keywords: acute respiratory distress syndrome; COVID-19; neutrophil extracellular traps; neutrophilia; neutrophils; pathogenesis; SARS-CoV-2; therapeutics

Neutrophilic Dermatoses - Classification and Pathophysiology - Manger, Bernhard (Zeitschrift für Rheumatologie, 2018)
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NEUTROPHILS AND NETS AS ORCHESTRATORS OF INFLAMMATORY DISEASES - Hosari, D.; Hosari, Sami; Mahajan, Aparna; Oreski, Leticija; Schoen, J.; Shan, Xiaomei; Singh, Jeeshan; Wang, H.; Yaykasli, Kürsat Oguz; Knopf, Jasmin; Munoz, Luis Enrique; Schauer, Christine; et al. (CLINICAL AND EXPERIMENTAL RHEUMATOLOGY, 2021)
CRIS-Team WoS Importer:2021-09-17

Neutrophils and neutrophil extracellular traps orchestrate initiation and resolution of inflammation - Hahn, Jonas; Knopf, Jasmin; Maueröder, Christian; Kienhoefer, D.; Leppkes, M.; Herrmann, Martin (Clinical and Experimental Rheumatology, 2016)
Neutrophils, the most abundant leukocytes in the human body, are considered to be the first line of defense in the fight against microorganisms. In this fight neutrophils employ weaponry such as reactive oxygen species produced via the NADPH oxidase complex 2 together with the release of intracellular granules containing antimicrobial agents. The discovery that activated neutrophils release decondensed chromatin as DNase-sensitive neutrophil extracellular traps (NETs) lead to a renewed interest in these leukocytes and the function of NETs in vivo. In this review, we will focus on desirable as well as detrimental features of NETs by the example of gout and pancreatitis. In our models we observed that neutrophils drive the initiation of inflammation and are required for the resolution of inflammation.
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Neutrophils as main players of immune response towards nondegradable nanoparticles - Bilyy, Rostyslav; Bila, Galyna; Vishchur, Oleg; Vovk, Volodymyr; Herrmann, Martin (Nanomaterials, 2020)
Many nano/microparticles (n/µP), to which our body is exposed, have no physiological way of removal. Our immune system sense these “small particulate objects”, and tries to decrease their harmfulness. Since oxidation, phagocytosis and other methods of degradation do not work with small, chemically resistant, and hydrophobic nanoparticles (nP). This applies to soot from air pollution, nano-diamonds from cosmic impact, polishing and related machines, synthetic polymers, and dietary n/µP. Our body tries to separate these from the surrounding tissue using aggregates from neutrophil extracellular traps (NETs). This effectively works in soft tissues where n/µP are entrapped into granuloma-like structures and isolated. The interactions of hydrophobic nanocrystals with circulating or ductal patrolling neutrophils and the consequent formation of occlusive aggregated NETs (aggNETs) are prone to obstruct capillaries, bile ducts in gallbladder and liver, and many more tubular structures. This may cause serious health problems and often fatality. Here we describe how specific size and surface properties of n/µP can activate neutrophils and lead to aggregation-related pathologies. We discuss “natural” sources of n/µP and those tightly connected to unhealthy diets.
CRIS-Team Scopus Importer:2020-07-10
Keywords: Nano/microparticles (nµP); Nanoparticle (nP); NETs; Neutrophil; Plasma membrane; Tubular structures

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

Neutrophils Orchestrate the Periodontal Pocket - Vitkov, Ljubomir; Munoz Becerra, Luis; Schoen, Janina; Knopf, Jasmin; Schauer, Christine; Minnich, Bernd; Herrmann, Martin; Hannig, Matthias (Frontiers in Immunology, 2021)
The subgingival biofilm attached to tooth surfaces triggers and maintains periodontitis. Previously, late-onset periodontitis has been considered a consequence of dysbiosis and a resultant polymicrobial disruption of host homeostasis. However, a multitude of studies did not show “healthy” oral microbiota pattern, but a high diversity depending on culture, diets, regional differences, age, social state etc. These findings relativise the aetiological role of the dysbiosis in periodontitis. Furthermore, many late-onset periodontitis traits cannot be explained by dysbiosis; e.g. age-relatedness, attenuation by anti-ageing therapy, neutrophil hyper-responsiveness, and microbiota shifting by dysregulated immunity, yet point to the crucial role of dysregulated immunity and neutrophils in particular. Furthermore, patients with neutropenia and neutrophil defects inevitably develop early-onset periodontitis. Intra-gingivally injecting lipopolysaccharide (LPS) alone causes an exaggerated neutrophil response sufficient to precipitate experimental periodontitis. Vice versa to the surplus of LPS, the increased neutrophil responsiveness characteristic for late-onset periodontitis can effectuate gingiva damage likewise. The exaggerated neutrophil extracellular trap (NET) response in late-onset periodontitis is blameable for damage of gingival barrier, its penetration by bacteria and pathogen-associated molecular patterns (PAMPs) as well as stimulation of Th17 cells, resulting in further neutrophil activation. This identifies the dysregulated immunity as the main contributor to periodontal disease.
CRIS-Team Scopus Importer:2021-12-17
Keywords: bacterial membrane vesicles; caspase 11; caspase 4; dysbiosis; dysregulated immunity; NET formation; outer membrane vesicles

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

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

Neutrophils Regulate Bone Formation Via IL-1b Secretion - Wakahashi, Kanako; Yu, Jiangyan; Rubio-Ponce, Andrea; Culemann, Stephan; Krishacoumar, Brenda; Scholtysek, Carina; Krönke, Gerhard; Schlitzer, Andreas; Hidalgo, Andres (BLOOD, 2022)
CRIS-Team WoS Importer:2023-03-10

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

Neutrophil swarm control: what goes up must come down - Uderhardt, Stefan; Knopf, Jasmin; Herrmann, Martin (Signal Transduction and Targeted Therapy, 2021)
CRIS-Team Scopus Importer:2021-12-17

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

New Insights into Neutrophil Extracellular Traps: Mechanisms of Formation and Role in Inflammation - Yang, Hang; Biermann, Mona Helena; Brauner, Jan Markus; Liu, Yi; Zhao, Yi; Herrmann, Martin (Frontiers in Immunology, 2016)
Recent data suggest that NETosis plays a crucial role in the innate immune response and disturbs the homeostasis of the immune system. NETosis is a form of neutrophil-specific cell death characterized by the release of large web-like structures referred to as neutrophil extracellular traps (NETs). NETs are composed of DNA strands associated with histones and decorated with about 20 different proteins, including neutrophil elastase, myeloperoxidase, cathepsin G, proteinase 3, high mobility group protein B1, and LL37. Reportedly, NETosis can be induced by several microbes, and particulate matter including sterile stimuli, via distinct cellular mechanisms. Meanwhile, suicidal NETosis and vital NETosis are controversial. As we enter the second decade of research on NETosis, we have partly understood NETs as double-edged swords of innate immunity. In this review, we will discuss the mechanisms of NETosis, its antimicrobial action, and role in autoimmune diseases, as well as the relatively new field of NET-associated mitochondrial DNA.
EVALuna2:13339

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

New insights into the key role of HIF-1α in IL-10-producing B cells - Meng, Xianyi; Bozec, Aline (Cell Stress, 2018)
Hypoxia-inducible factors (HIFs) are essential transcription factors for the cellular response to hypoxia. Expression and stabilization of HIFs can be triggered by hypoxia or by other factors under pathological stress such as inflammation and infection. Indeed, regulatory function of HIFs has been implicated in a variety of different immune cells like macrophages and T cells. In our recent study, we delineated HIF-1α and HIF-2α roles in B cells (Nat Commun, 9:251). We demonstrated that lack of HIF-1α in B cells leads to impaired IL-10-producing CD1dhiCD5+ B cells expansion by modulating their glycolytic metabolism. We identified HIF-1α as a critical transcriptional factor involved in IL-10 production by B cells, thereby influencing the course of autoimmune diseases.
CRIS-Team Scopus Importer:2023-03-23
Keywords: Autoimmune disease; B cells; Glycolysis; HIF-1α; IL-10; Metabolism

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

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

New-onset versus relapsing giant cell arteritis treated with tocilizumab: 3-year results from a randomized controlled trial and extension - Stone, John H.; Spotswood, Helen; Unizony, Sebastian H.; Aringer, Martin; Blockmans, Daniel; Brouwer, Elisabeth; Cid, Maria C.; Dasgupta, Bhaskar; Rech, Jürgen; Salvarani, Carlo; Spiera, Robert; Bao, Min (Rheumatology, 2021)
Objective. Tocilizumab plus prednisone induces sustained glucocorticoid-free remission in patients with GCA. However, its long-term benefits in new-onset vs relapsing disease are uncertain, and the value of weekly vs everyother-week dosing has not been evaluated.
CRIS-Team WoS Importer:2022-05-13

New possibilities for ocular surface reconstruction : Collagen membranes and biocompatible elastomer nanofibers - Fuchsluger, Thomas; Salehi, S.; Petsch, Christina; Bachmann, B. (Ophthalmologe, 2014)
Amniotic membranes have been used for many years for reconstruction of the ocular surface. Despite having anti-inflammatory and antiangiogenic properties as well as being suitable as a carrier for corneal epithelial cells, amniotic membranes also have some limitations for use at the human cornea: availability is limited, there are major interindividual variations in structure and growth factor content and are not free from the risk of disease transmission. Progress in tissue engineering has been made aiming at the development and improvement of alternative biomaterials.This article presents new approaches for reconstruction of the corneal surface with collagen-based biomaterials and polymers.Electronic databases were searched for articles which evaluated collagenous biomaterials for use at the corneal surface. In addition the authors' own experiences with novel biomaterials are described.In vitro evaluation of the described biomaterials suggested a high biocompatibility with corneal epithelial cells in cell cultures. In vivo experiments with these materials in animal corneas demonstrated a certain variability in degradation and remodeling. Although some materials showed promising experimental results none of these are established in the clinical routine and only few clinical studies have so far been conducted with collagen-based biomaterials.Although the majority of the described biomaterials are currently still in the experimental stage, a transfer into the clinical routine is conceivable and of great therapeutic interest.
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NEW SYSTEMIC SCLEROSIS RISK LOCI IDENTIFIED THROUGH A META-GWAS STRATEGY - Lopez-Isac, E.; Acosta-Herrera, M.; Assassi, S.; Simeon, C. P.; Carreira, P. E.; Castellvi, I.; Ortego-Centeno, N.; Beretta, L.; Lunardi, C.; Gabrielli, A.; Moroncini, G.; Hunzelmann, N.; et al. (2018)
EVALuna2:34987

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

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

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

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

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

NNRTI-based antiretroviral therapy may increase risk of radiation induced side effects in HIV-1-infected patients - Keller, Ulrike; Hecht, Markus; Harrer, Thomas; Harrer, Ellen; Schuster, Barbara; Fietkau, Rainer; Distel, Luitpold (Radiotherapy and Oncology, 2015)
As the incidence of cancer is rising in HIV-1-infected patients, radiotherapy is used more frequently in this patient group. Strong radiation induced side effects have been reported in single patients on antiretroviral therapy. Thus we investigated whether HIV-1 itself or antiretroviral drugs could enhance radiosensitivity in patients.Radiosensitivity after in vitro irradiation of blood lymphocytes was tested in 196 individuals (80 HIV-1-infected patients and 116 healthy controls and cancer patients) using a three color fluorescence in situ hybridization approach to analyze chromosomal aberrations (B/M). Additionally, the NNRTI efavirenz and the NRTIs tenofovir and emtricitabine were tested for radiosensitizing effects in vitro.Lymphocytes from HIV-1-infected patients in the NNRTI + NRTI group were significantly more sensitive to ionizing radiation than in the other groups (patients without treatment or with NRTI + PI or HIV-negative controls). In vitro the triple medication efavirenz, tenofovir and emtricitabine leads to a reduced survival fraction and an increased activation of the DNA repair proteins H2AX, Nbs, Atm and 53BP1 in combination with ionizing radiation.HIV-1 treatment with NNRTI containing therapy regimes possibly sensitizes a subgroup of patients to ionizing radiation. Individual radiosensitivity of HIV-1-infected patients on HAART including NNRTI should be tested before starting radiotherapy.
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No Difference in Treatment Continuation of Different Biologics in Elderly Patients > 70 Years Compared to Younger Patients <= 65 Years - Strangfeld, Anja; Krueger, Klaus; Manger, Bernhard; Kneitz, Christian; Zink, Angela; Schaefer, Martin (ARTHRITIS & RHEUMATOLOGY, 2019)
CRIS-Team WoS Importer:2020-02-07

No evidence for increased cell entry or antibody evasion by Delta sublineage AY.4.2 - Arora, Prerna; Kempf, Amy; Nehlmeier, Inga; Graichen, Luise; Winkler, Martin S.; Lier, Martin; Schulz, Sebastian; Jäck, Hans-Martin; Poehlmann, Stefan; Hoffmann, Markus (Cellular & Molecular Immunology, 2022)
Since the beginning of the COVID-19 pandemic, multiple SARS-CoV-2 variants have emerged. While some variants spread only locally, others, referred to as variants of concern, disseminated globally and became drivers of the pandemic. All SARS-CoV-2 variants harbor mutations relative to the virus circulating early in the pandemic, and mutations in the viral spike (S) protein are considered of particular relevance since the S protein mediates host cell entry and constitutes the key target of the neutralizing antibody response. As a consequence, mutations in the S protein may increase SARS-CoV-2 infectivity and enable its evasion of neutralizing antibodies. Furthermore, mutations in the S protein can modulate viral transmissibility and pathogenicity.
CRIS-Team Scopus Importer:2022-01-14
Keywords: Antibody evasion; AY.4.2; Delta; Host cell entry; SARS-CoV-2

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

Noise2Contrast: Multi-contrast Fusion Enables Self-supervised Tomographic Image Denoising - Wagner, Fabian; Thies, Mareike; Pfaff, Laura; Maul, Noah; Pechmann, Sabrina; Gu, Mingxuan; Utz, Jonas; Aust, Oliver; Weidner, Daniela; Neag, Georgiana; Uderhardt, Stefan; Choi, Jang Hwan; et al. (Lecture Notes in Computer Science (including subseries Lecture Notes in Artificial Intelligence and Lecture Notes in Bioinformatics), 2023)
Self-supervised image denoising techniques emerged as convenient methods that allow training denoising models without requiring ground-truth noise-free data. Existing methods usually optimize loss metrics that are calculated from multiple noisy realizations of similar images, e.g., from neighboring tomographic slices. However, those approaches fail to utilize the multiple contrasts that are routinely acquired in medical imaging modalities like MRI or dual-energy CT. In this work, we propose the new self-supervised training scheme Noise2Contrast that combines information from multiple measured image contrasts to train a denoising model. We stack denoising with domain-transfer operators to utilize the independent noise realizations of different image contrasts to derive a self-supervised loss. The trained denoising operator achieves convincing quantitative and qualitative results, outperforming state-of-the-art self-supervised methods by 4.7–11.0%/4.8–7.3% (PSNR/SSIM) on brain MRI data and by 43.6–50.5%/57.1–77.1% (PSNR/SSIM) on dual-energy CT X-ray microscopy data with respect to the noisy baseline. Our experiments on different real measured data sets indicate that Noise2Contrast training generalizes to other multi-contrast imaging modalities.
CRIS-Team Scopus Importer:2023-07-28
Keywords: Contrast Fusion; Known Operator Learning; Self-Supervised Denoising

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

No NETs no TIME: Crosstalk between neutrophil extracellular traps and the tumor immune microenvironment - Fang, Qi; Stehr, Antonia; Naschberger, Elisabeth; Knopf, Jasmin; Herrmann, Martin; Stürzl, Michael (Frontiers in Immunology, 2022)
The tumor immune microenvironment (TIME) controls tumorigenesis. Neutrophils are important components of TIME and control tumor progression and therapy resistance. Neutrophil extracellular traps (NETs) ejected by activated neutrophils are net-like structures composed of decondensed extracellular chromatin filaments decorated with a plethora of granules as well as cytoplasmic proteins. Many of these harbour post translational modifications. Cancer cells reportedly trigger NET formation, and conversely, NETs alter the TIME and promote tumor cell proliferation and migration. The specific interactions between NETs and TIME and the respective effects on tumor progression are still elusive. In certain tumors, a CD4(+) T helper (Th) 2 cell-associated TIME induces NETs and exerts immunosuppressive functions via programmed death 1 (PD-1)/PD-L1, both associated with poorer prognosis. In other cases, NETs induce the proliferation of Th1 cells, associated with an improved prognosis in cancer. In addition, NETs can drive macrophage polarization and often rely on macrophages to promote cancer cell invasion and metastasis. In turn, macrophages can swiftly clear NETs in an immunologically silent manner. The aim of this review is to summarize the knowledge about the mutual interaction between NETs and TIME and its impact on tumor growth and therapy.
CRIS-Team WoS Importer:2023-01-27

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

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

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

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

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

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

Novel Mechanism Mediated By the IL-23/Th17 Axis Contributing to Auto-Immune Arthritis - Pfeifle, René; Rothe, Tobias; Ipseiz, Natacha; Culemann, Stephan; Harre, Ulrike; Krönke, Gerhard; Schett, Georg (2016)
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Novel mechanism mediated by the IL23/Th17 axis contributing to auto-immune arthritis - Pfeifle, R.; Rothe, T.; Ipseiz, N.; Culemann, S.; Harre, Ulrike; Schett, Georg; Krönke, Gerhard (2017)
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[Novel molecular mechanisms in the pathophysiology of psoriatic arthritis]. - Simon, David; Kampylafka, E.; Hueber, Axel (Zeitschrift für Rheumatologie, 2018)
The complex pathogenesis of psoriatic arthritis (PsA) is still only partially understood; however, recently a greatly improved understanding of this disease has been achieved, especially with respect to the inflammatory processes of the entheses. Thus, the clinical aspects of enthesitis increasingly differentiate PsA from other autoimmune diseases and sharpen the unique pathological clinical picture of PsA. Better pathophysiological understanding and the development of different biomarker approaches will bolster early detection of PsA. Therefore, the successful early recognition of PsA and more reliable identification of psoriasis patients at risk might be possible in the near future.
EVALuna2:479136
Keywords: Pathogenesis; Enthesitis; Biomarkers; Early recognition; Risk patients

NOVEL TECHNIQUE FOR PRECISE CALCULATION OF BONE EROSION VOLUME IN RA PATIENTS USING HR-PQCT - Figueiredo, C.; Simon, David; Stemmler, F.; Rech, Jürgen; Hueber, Axel; Haschka, J.; Schett, Georg; Kleyer, Arnd (2015)
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NOX2 mediates quiescent handling of dead cell remnants in phagocytes - Hahn, Jonas; Euler, Maximilien; Kilgus, Emelie; Kienhöfer, Deborah; Stoof, Julia; Knopf, Jasmin; Hahn, Madelaine; Harrer, Thomas; Hultqvist, Malin; Olofsson, Peter; Mokhir, Andriy; Holmdahl, Rikard; et al. (Redox Biology, 2019)
The phagocyte NADPH oxidase (the NOX2 complex) generates superoxide, the precursor to reactive oxygen species (ROS). ROS possess both antimicrobial and immunoregulatory function. Inactivating mutations in alleles of the NOX2 complex cause chronic granulomatous disease (CGD), characterized by an enhanced susceptibility to infections and autoimmune diseases such as Systemic lupus erythematosus (SLE). The latter is characterized by insufficient removal of dead cells, resulting in an autoimmune response against components of the cell's nucleus when non-cleared apoptotic cells lose their membrane integrity and present autoantigenic molecules in an inflammatory context. Here we aimed to shed light on the role of the NOX2 complex in handling of secondary necrotic cells (SNECs) and associated consequences for inflammation and autoimmunity during lupus. We show that individuals with SLE and CGD display accumulation of SNECs in blood monocytes and neutrophils. In a CGD phenotypic mouse strain (Ncf1** mice) build-up of SNECs in Ly6CHI blood monocytes was connected with a delayed degradation of the phagosomal cargo and accompanied by production of inflammatory mediators. Treatment with H2O2 or activators of ROS-formation reconstituted phagosomal abundance of SNECs to normal levels. Induction of experimental lupus further induced increased antibody-dependent uptake of SNECs into neutrophils. Lupus-primed Ncf1** neutrophils took up more SNECs than wild type neutrophils, whereas SNEC-accumulation in regulatory Ly6C−/LO monocytes was lower in Ncf1**mice. We deduce that the inflammatory rerouting of immune-stimulatory necrotic material into inflammatory phagocyte subsets contributes to the connection between low ROS production by the NOX2 complex and SLE.
CRIS-Team Scopus Importer:2019-08-06

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

NR4A1 Regulates Motility of Osteoclast Precursors and Serves as Target for the Modulation of Systemic Bone Turnover - Scholtysek, Carina; Ipseiz, Natacha; Böhm, Christina; Krishnacoumar, Brenda; Stenzel, Martin; Czerwinski, Tina; Palumbo-Zerr, Katrin; Rothe, Tobias; Weidner, Daniela; Klej, Alexandra; Stoll, Cornelia; Distler, Jörg; et al. (Journal of Bone and Mineral Research, 2018)
NR4A1 (Nur77 or NGFI-B), an orphan member of the nuclear receptor superfamily, has been identified as a key regulator of the differentiation and function of myeloid, lymphoid, and mesenchymal cells. The detailed role of NR4A1 in bone biology is incompletely understood. Here, we report a role for NR4A1 as novel factor controlling the migration and recruitment of osteoclast precursors during bone remodeling. Myeloid-specific but not osteoblast-specific deletion of NR4A1 resulted in osteopenia due to an increase in the number of bone-lining osteoclasts. Although NR4A1-deficient osteoclast precursors displayed a regular differentiation into mature osteoclasts, they showed a hyper-motile phenotype that was largely dependent on increased osteopontin expression, suggesting that expression of NR4A1 negatively controlled osteopontin-mediated recruitment of osteoclast precursors to the trabecular bone. Pharmacological activation of NR4A1, in turn, inhibited osteopontin expression and osteopontin-dependent migration of osteoclast precursors resulted in reduced abundance of bone-resorbing osteoclasts in vivo as well as in an ameliorated bone loss after ovariectomy in mice. This study identifies NR4A1 as a crucial player in the regulation of osteoclast biology and bone remodeling and highlights this nuclear receptor as a promising target for therapeutic intervention during the treatment of osteoporosis. © 2018 The Authors. Journal of Bone and Mineral Research Published by Wiley Periodicals Inc.
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N-terminal pro-brain natriuretic peptide is a strong predictor of mortality in systemic sclerosis - Allanore, Yannick; Komocsi, Andras; Vettori, Serena; Hachulla, Eric; Hunzelmann, Nicolas; Distler, Jörg; Avouac, Jerome; Gobeaux, Camille; Launay, David; Czirjak, Laszlo; Kahan, Andre; Meune, Christophe (International Journal of Cardiology, 2016)
Cardiovascular involvement is a major contributor to mortality in systemic sclerosis (SSc). We examined whether N-terminal pro-brain natriuretic peptide (NT-proBNP) is a reliable predictor of mortality in SSc.This multicentre prospective cohort study included 523 patients presenting with SSc, whose mean age was 54±13years, mean disease duration 8±9years, and diffuse cutaneous form in 168. Plasma NT-proBNP was measured at baseline and the patients were followed yearly. Overall mortality was measured at 3years. At baseline, cardiovascular involvement was present in 37 patients, including 17 with pulmonary artery hypertension (PAH) and 20 with a left ventricular ejection fraction (LVEF) <55%. At 3years, 32 (7%) patients had died. The median [25th-75th percentile] NT-proBNP concentration was 203ng/l [129-514] in patients who died within 3years, versus 88ng/l [47-167] in survivors (P<0.001). NT-proBNP was an independent predictor of 3-years mortality in multivariate analysis (P=0.046). The optimal cut-off derived from the ROC curve was 129ng/l; sensitivity and specificity to predict 3y mortality were 78.1 and 66.7%. Using the previously recommended 125-ng/l concentration as threshold value, NT-proBNP reliably and independently predicted 3year mortality, with a sensitivity of 78.1 and a negative predictive value of 97.6%, respectively (P=0.006). The consideration of SSc patients without PAH or LVEF<55% at baseline yielded similar results.NT-proBNP appears as a reliable and independent predictor of mortality in patients with SSc.
EVALuna2:13338

N-truncation and pyroglutaminylation enhances the opsonizing capacity of A?-peptides and facilitates phagocytosis by macrophages and microglia - Condic, Mateja; Oberstein, Timo; Herrmann, Martin; Reimann, Mareike Carola; Kornhuber, Johannes; Maier, Jan-Niklas; Spitzer, Philipp (Brain Behavior and Immunity, 2014)
Abnormal accumulations of amyloid-? (A?)-peptides are one of the pathological hallmarks of Alzheimer's disease (AD). The precursor of the A?-peptides, the amyloid precursor protein (APP), is also found in peripheral blood cells, but its function in these cells remains elusive. We previously observed that mononuclear phagocytes release A?-peptides during activation and phagocytosis, suggesting a physiologic role in inflammatory processes. Here, we show that supplementing the media with soluble N-terminally truncated A?(2-40) and A?(2-42) as well as A?(1-42) induced the phagocytosis of polystyrene particles (PSPs) by primary human monocytes. If the PSPs were pre-incubated with A?-peptides, phagocytosis was induced by all tested A?-peptide species. N-terminally truncated A?(x-42) induced the phagocytosis of PSPs significantly more effectively than did A?(x-40). Similarly, the phagocytosis of Escherichia coli by GM-CSF- and M-CSF-elicited macrophages as well as microglia was particularly facilitated by pre-incubation with N-terminally truncated A?(x-42). The proinflammatory polarization of monocytes was indicated by the reduced MSRI expression and IL-10 secretion after phagocytosis of PSPs coated with A?(1-42), A?(2-42) and A?(3p-42). Polarization of the macrophages by GM-CSF reduced the phagocytic activity, but it did not affect the capabilities of A?-peptides to opsonize prey. Taken together, A?-peptides support phagocytosis as soluble factors and act as opsonins. Differential effects among the A?-peptide variants point to distinct mechanisms of interaction among monocytes/macrophages, prey and A?-peptides. A proinflammatory polarization induced by the phagocytosis of A?-peptide coated particles may provide a model for the chronic inflammatory reaction and sustained plaque deposition in AD.
EVALuna2:13018

Number of necessary training examples for Neural Networks with different number of trainable parameters - Götz, Theresa Ida; Göb, S.; Sawant, S.; Erick, X. F.; Wittenberg, Thomas; Schmidkonz, Christian; Tomé, A. M.; Lang, E. W.; Ramming, Andreas (Journal of Pathology Informatics, 2022)
In this work, the network complexity should be reduced with a concomitant reduction in the number of necessary training examples. The focus thus was on the dependence of proper evaluation metrics on the number of adjustable parameters of the considered deep neural network. The used data set encompassed Hematoxylin and Eosin (H&E) colored cell images provided by various clinics. We used a deep convolutional neural network to get the relation between a model's complexity, its concomitant set of parameters, and the size of the training sample necessary to achieve a certain classification accuracy. The complexity of the deep neural networks was reduced by pruning a certain amount of filters in the network. As expected, the unpruned neural network showed best performance. The network with the highest number of trainable parameter achieved, within the estimated standard error of the optimized cross-entropy loss, best results up to 30% pruning. Strongly pruned networks are highly viable and the classification accuracy declines quickly with decreasing number of training patterns. However, up to a pruning ratio of 40%, we found a comparable performance of pruned and unpruned deep convolutional neural networks (DCNN) and densely connected convolutional networks (DCCN).
CRIS-Team Scopus Importer:2022-10-28
Keywords: Cell segmentation; Deep neural networks; DNN complexity; Pruning; Training sample size

Nutzung von Medizin-Apps und Online-Plattformen unter deutschen Rheumatologen - Knitza, Johannes; Vossen, D.; Geffken, I.; Krusche, M.; Meyer, M.; Sewerin, P.; Kleyer, Arnd; Hueber, Axel (Zeitschrift für Rheumatologie, 2019)
Background: Apps and online platforms play an ever increasing role in the daily work routine of physicians. The aim of this study was to investigate which medical apps and online platforms are used by German rheumatologists for certain tasks and to identify usage trends. Methods: Data were collected via a SurveyMonkey survey conducted by members of rheumadocs (Young German Rheumatology Association) at the 2016 and 2018 German Society for Rheumatology (DGRh) conferences. Results: In 2016 and 2018 the survey was completed by 75 and 84 assistant and specialist rheumatologists, respectively. In 2016, 37% of rheumatologists were using medical apps in routine care which changed to 49% in 2018. In 2016, 47% compared to 68% in 2018, planned to integrate medical apps into routine care. In total, 20 different medical apps were recommended for colleagues to use; however only 2 of these apps were specific for rheumatology. In contrast to 52 app recommendations for colleagues, only 8 app recommendations for patients were recorded. Most recommendations to physicians received the app “Arznei aktuell” (21%). “Embryotox” was the app, most recommended to patients (38%). In 2016 the online database PubMed was most popular and 97% of participants were familiar with it. Use of other online platforms showed great age dependency in 2016: Amboss (a digital learning platform) was used by 31% of the age group 21–30 years and was not used at all by the age group 51–60 years. Discussion: Use of medical apps and planned integration of medical apps into routine care is increasing among German rheumatologists. On the other hand, recommendable rheumatological apps for rheumatologists and especially for patients are currently largely unknown to rheumatologists.
CRIS-Team Scopus Importer:2019-11-12
Keywords: eHealth; Medical apps; mHealth; Rheumatology; Telemedicine

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

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

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

OBSERVATIONAL STUDY OF OUTCOME IN PATIENTS WITH EARLY DIFFUSE CUTANEOUS SYSTEMIC SCLEROSIS TREATED WITH IMMUNOSUPPRESSIVE THERAPIES (ESOS STUDY) - Herrick, A. L.; Pan, X.; Peytrignet, S.; Hesselstrand, R.; Mouthon, L.; Brown, E.; Czirjak, L.; Distler, Jörg; Distler, O.; Fligelstone, K.; Gregory, W.; Ochiel, R.; et al. (2016)
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OCT-Angiography: agonistic beta 2-adrenergic receptor autoantibodies and FAZ-to-FAZ-ratio in glaucoma patients - Mardin, Christian Y.; Hosari, Sami; Wallukat, Gerd; Kunze, Rudolf; Herrmann, Martin; Lämmer, Robert; Hohberger, Bettina (INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE, 2019)
CRIS-Team WoS Importer:2019-10-29

O-GLCNACYLATION ON NUP153 REGULATES THE EARLY STAGES OF OSTEOCLASTOGENESIS THROUGH MYC NUCLEAR TRANSLOCATION - Li, You; Chen, Chih-Wei; Trinh, Minh Thuong; Honglin, Z.; Hubel, P.; Pfannstiel, J.; Schett, Georg; Distler, Jörg (ANNALS OF THE RHEUMATIC DISEASES, 2022)
CRIS-Team WoS Importer:2022-11-04

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

Oligomannose-Rich Membranes of Dying Intestinal Epithelial Cells Promote Host Colonization by Adherent-Invasive E. coli - Dumych, Tetiana; Yamakawa, Nao; Sivignon, Adeline; Garenaux, Estelle; Robakiewicz, Stefania; Coddeville, Bernadette; Bongiovanni, Antonino; Bray, Fabrice; Barnich, Nicolas; Szunerits, Sabine; Slomianny, Christian; Herrmann, Martin; et al. (Frontiers in Microbiology, 2018)
A novel mechanism is revealed by which clinical isolates of adherent-invasive Escherichia coli (AIEC) penetrate into the epithelial cell layer, replicate, and establish biofilms in Crohn's disease. AIEC uses the FimH fimbrial adhesin to bind to oligomannose glycans on the surface of host cells. Oligomannose glycans exposed on early apoptotic cells are the preferred binding targets of AIEC, so apoptotic cells serve as potential entry points for bacteria into the epithelial cell layer. Thereafter, the bacteria propagate laterally in the epithelial intercellular spaces. We demonstrate oligomannosylation at two distinct sites of a glycoprotein receptor for AIEC, carcinoembryonic antigen related cell adhesion molecule 6 (CEACAM6 or CD66c), on human intestinal epithelia. After bacterial binding, FimH interacts with CEACAM6, which then clusters. The presence of the highest-affinity epitope for FimH, oligomannose-5, on CEACAM6 is demonstrated using LC-MS/MS. As mannose-dependent infections are abundant, this mechanism might also be used by other adherent-invasive pathogens.
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O-linked N-acetylglucosaminylation of Sp1 inhibits the human immunodeficiency virus type 1 promoter - Jochmann, Ramona; Thurau, Mathias; Jung, Susan; Hofmann, Christian; Naschberger, Elisabeth; Kremmer, Elisabeth; Harrer, Thomas; Miller, Matthew; Schaft, Niels; Stürzl, Michael (Journal of Virology, 2009)
Human immunodeficiency virus type 1 (HIV-1) gene expression and replication are regulated by the promoter/enhancer located in the U3 region of the proviral 5′ long terminal repeat (LTR). The binding of cellular transcription factors to specific regulatory sites in the 5′ LTR is a key event in the replication cycle of HIV-1. Since transcriptional activity is regulated by the posttranslational modification of transcription factors with the monosaccharide O-linked N-acetyl-D-glucosamine (O-GlcNAc), we evaluated whether increased O-GlcNAcylation affects HIV-1 transcription. In the present study we demonstrate that treatment of HIV-1-infected lymphocytes with the O-GlcNAcylation-enhancing agent glucosamine (GlcN) repressed viral transcription in a dose-dependent manner. Overexpression of O-GlcNAc transferase (OGT), the sole known enzyme catalyzing the addition of O-GlcNAc to proteins, specifically inhibited the activity of the HIV-1 LTR promoter in different T-cell lines and in primary CD4+ T lymphocytes. Inhibition of HIV-1 LTR activity in infected T cells was most efficient (>95%) when OGT was recombinantly overexpressed prior to infection. O-GlcNAcylation of the transcription factor Sp1 and the presence of Sp1-binding sites in the LTR were found to be crucial for this inhibitory effect. From this study, we conclude that O-GlcNAcylation of Sp1 inhibits the activity of the HIV-1 LTR promoter. Modulation of Sp1 O-GlcNAcylation may play a role in the regulation of HIV-1 latency and activation and links viral replication to the glucose metabolism of the host cell. Hence, the establishment of a metabolic treatment might supplement the repertoire of antiretroviral therapies against AIDS. Copyright © 2009, American Society for Microbiology. All Rights Reserved.
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Omicron sublineage BQ.1.1 resistance to monoclonal antibodies - Arora, Prerna; Kempf, Amy; Nehlmeier, Inga; Schulz, Sebastian; Jäck, Hans-Martin; Pöhlmann, Stefan; Hoffmann, Markus (Lancet Infectious Diseases, 2023)
CRIS-Team Scopus Importer:2023-01-06

Once Weekly Whole-Body Electromyostimulation Enhances Muscle Quality in Men: Data of the Randomized Controlled Franconian Electromyostimulation and Golf Study - Zink-Rückel, Carina; Chaudry, Oliver; Engelke, Klaus; Ghasemikaram, Mansour; Kohl, Matthias; Uder, Michael; Kemmler, Wolfgang (Frontiers in Physiology, 2021)
Whole-body electromyostimulation (WB-EMS) is commercially advertised as a time-efficient resistance-type exercise technology. Indeed, the commercial, non-medical setting applies 20 min of WB-EMS only once a week. However, this setting conflicts with the approved scientific approach of higher training frequencies. Using data from an ongoing study on WB-EMS and golf performance as a vehicle, we evaluate the effect of once weekly WB-EMS on changes of fatty muscle infiltration, as a crucial parameter of muscle quality. Fifty-four moderately physically active male amateur golfers 18–70 years old were randomly allocated to a WB-EMS (n = 27) with a standard setting of once weekly 20 min and a non-WB-EMS control group (CG, n = 27). Intermuscular adipose tissue (IMAT) volume and intrafascial muscle tissue (MT) volume per unit of intrafascial volume as determined by magnetic resonance imaging were used to characterize muscle quality. Intention to treat analysis with multiple imputation was applied. WB-EMS was conducted at the participants’ homes; thus, the attendance rate was close to 100%. After 16 weeks of intervention, we observed increases in volume-adjusted IMAT (p = 0.040) and decreases in MT (p = 0.206) in the CG. IMAT decreased in the WB-EMS group (p = 0.215), while MT increased significantly (p = 0.032). Of importance, group difference (i.e., “effects”) for intra-group changes in volume-adjusted IMAT (effect size: d´ = 0.66; p = 0.028) and MT (d´ = 0.70; p = 0.020) was significant for both parameters. Once weekly WB-EMS application significantly affects muscle quality of the mid-thigh in moderately active, healthy men 18–70 years old.
CRIS-Team Scopus Importer:2021-08-13
Keywords: fatty muscle infiltration; men; muscle quality; muscle tissue; whole-body electromyostimulation

Oncological Patients with systemic Lupus Erythematosus have a clear risk of increased Radiation Sensitivity - Schenker, Hannah; Schuster, B.; Hecht, Markus; Fietkau, Rainer; Distel, Luitpold (STRAHLENTHERAPIE UND ONKOLOGIE, 2020)
CRIS-Team WoS Importer:2020-10-02

ONE YEAR OF DIGITAL HEALTH APPLICATIONS (DIGA) IN GERMANY - RHEUMATOLOGISTS' PERSPECTIVES - Richter, J. G.; Chehab, G.; Stachwitz, P.; Hagen, J.; Larsen, D.; Knitza, Johannes; Schneider, M.; Voormann, A.; Specker, C. (ANNALS OF THE RHEUMATIC DISEASES, 2022)
CRIS-Team WoS Importer:2022-11-04

One year of digital health applications (DiGA) in Germany - Rheumatologists' perspectives - Richter, Jutta G.; Chehab, Gamal; Stachwitz, Philipp; Hagen, Julia; Larsen, Denitza; Knitza, Johannes; Schneider, Matthias; Voormann, Anna; Specker, Christof (Frontiers in Medicine, 2022)
BackgroundBased on given legislation the German approach to digital health applications (DiGA) allows reimbursed prescription of approved therapeutic software products since October 2020. For the first time, we evaluated DiGA-related acceptance, usage, and level of knowledge among members of the German Society for Rheumatology (DGRh) 1 year after its legal implementation. Materials and methodsAn anonymous cross-sectional online survey, initially designed by the health innovation hub (think tank and sparring partner of the German Federal Ministry of Health) and the German Pain Society was adapted to the field of rheumatology. The survey was promoted by DGRh newsletters and Twitter-posts. Ethical approval was obtained. ResultsIn total, 75 valid response-sets. 80% reported to care >= 70% of their working time for patients with rheumatic diseases. Most were working in outpatient clinics/offices (54%) and older than 40 years (84%). Gender distribution was balanced (50%). 70% knew the possibility to prescribe DiGA. Most were informed of this for the first time via trade press (63%), and only 8% via the scientific/professional society. 46% expect information on DiGA from the scientific societies/medical chambers (35%) but rarely from the manufacturer (10%) and the responsible ministry (4%). Respondents would like to be informed about DiGA via continuing education events (face-to-face 76%, online 84%), trade press (86%), and manufacturers ' test-accounts (64%). Only 7% have already prescribed a DiGA, 46% planned to do so, and 47% did not intend DiGA prescriptions. Relevant aspects for prescription are provided. 86% believe that using DiGA/medical apps would at least partially be feasible and understandable to their patients. 83% thought that data collected by the patients using DiGA or other digital solutions could at least partially influence health care positively. 51% appreciated to get DiGA data directly into their patient documentation system/electronic health record (EHR) and 29% into patient-owned EHR. ConclusionDigital health applications awareness was high whereas prescription rate was low. Mostly, physician-desired aspects for DiGA prescriptions were proven efficacy and efficiency for physicians and patients, risk of adverse effects and health care costs were less important. Evaluation of patients' barriers and needs is warranted. Our results might contribute to the implementation and dissemination of DiGA.
CRIS-Team WoS Importer:2022-11-18

Online-Ultraschalllernmodule in der Rheumatologie - Knitza, Johannes; Kleyer, Arnd; Klüppel, M.; Krauser, M.; Wacker, J.; Schett, Georg; Simon, David (Zeitschrift für Rheumatologie, 2020)
CRIS-Team Scopus Importer:2020-03-10

Only a Minor Proportion of Individuals with Anti-Aminoacyl-tRNA Synthetase Autoimmunity Presents with the Clinical Picture of "Antisynthetase-Syndrome" - Knitza, Johannes; Schenker, Hannah; Schett, Georg; Distler, Jörg (2018)
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On the Benefit of Dual-Domain Denoising in a Self-Supervised Low-Dose CT Setting - Wagner, Fabian; Thies, Mareike; Pfaff, Laura; Aust, Oliver; Pechmann, Sabrina; Weidner, Daniela; Maul, Noah; Rohleder, Maximilian; Gu, Mingxuan; Utz, Jonas; Denzinger, Felix; Maier, Andreas (Proceedings - International Symposium on Biomedical Imaging, 2023)
Computed tomography (CT) is routinely used for three-dimensional non-invasive imaging. Numerous data-driven image denoising algorithms were proposed to restore image quality in low-dose acquisitions. However, considerably less research investigates methods already intervening in the raw detector data due to limited access to suitable projection data or correct reconstruction algorithms. In this work, we present an end-to-end trainable CT reconstruction pipeline that contains denoising operators in both the projection and the image domain and that are optimized simultaneously without requiring ground-truth high-dose CT data. Our experiments demonstrate that including an additional projection denoising operator improved the overall denoising performance by 82.4-94.1 %/12.5-41.7 % (PSNR/SSIM) on abdomen CT and 1.5-2.9 %/0.4-0.5 % (PSNR/SSIM) on XRM data relative to the low-dose baseline. We make our entire helical CT reconstruction framework publicly available that contains a raw projection rebinning step to render helical projection data suitable for differentiable fan-beam reconstruction operators and end-to-end learning.
CRIS-Team Scopus Importer:2023-10-06
Keywords: Known Operator Learning; Low-Dose CT; Self-Supervised Denoising

On the inclusion of motion capture data in optimal control simulations of the human hand - Heinrich, Simon; Coppers, Birte; Liphardt, Anna-Maria; Leyendecker, Sigrid (conference, 18th International Symposium on Computer Methods in Biomechanics and Biomedical Engineering, 2023)

On the perils of peeking into the future: comment on the article by Rosenthal et al - Mutlu, Melek Yalcin; Tascilar, Koray (Arthritis and Rheumatology, 2022)
CRIS-Team WoS Importer:2022-06-17

OPEN-LABEL, MULTICENTER, DOSE-ESCALATING PHASE II CLINICAL TRIAL ON THE SAFETY AND EFFICACY OF TADEKINIG ALPHA IN ADULT ONSET STILL'S DISEASE - Gabay, C.; Fautrel, B.; Rech, Jürgen; Spertini, F.; Feist, E.; Koetter, I.; Hachulla, E.; Morel, J.; Schaeverbeke, T.; Hamidou, M. A.; Martin, T.; Hellmich, B.; et al. (2017)
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Open-label, multicentre, dose-escalating phase II clinical trial on the safety and efficacy of tadekinig alfa (IL-18BP) in adult-onset Still's disease - Gabay, Cem; Fautrel, Bruno; Rech, Jürgen; Spertini, Francois; Feist, Eugen; Koetter, Ina; Hachulla, Eric; Morel, Jacques; Schaeverbeke, Thierry; Hamidou, Mohamed A.; Martin, Thierry; Hellmich, Bernhard; et al. (Annals of the Rheumatic Diseases, 2018)
OBJECTIVES: Adult-onset Still's disease (AOSD) is a rare systemic autoinflammatory disease; its management is largely empirical. This is the first clinical study to determine if interleukin (IL)-18 inhibition, using the recombinant human IL-18 binding protein, tadekinig alfa, is a therapeutic option in AOSD. METHODS: In this phase II, open-label study, patients were ≥18 years with active AOSD plus fever or C reactive protein (CRP) levels ≥10 mg/L despite treatment with prednisone and/or conventional synthetic disease-modifying antirheumatic drugs (DMARDs). Previous biological DMARD treatment was permitted. Patients received tadekinig alfa 80 mg or 160 mg subcutaneously three times per week for 12 weeks; those receiving 80 mg not achieving early predicted response criteria (reduction of ≥50% CRP values from baseline and fever resolution) were up-titrated to 160 mg for a further 12 weeks. The primary endpoint was the occurrence of adverse events (AEs) throughout the study. RESULTS: Ten patients were assigned to receive 80 mg tadekinig alfa and 13 patients to the 160 mg dose. One hundred and fifty-five treatment-emerging AEs were recorded, and 47 were considered related to the study drug. Most AEs were mild and resolved after drug discontinuation. Three serious AEs occurred, one possibly related to treatment (toxic optic neuropathy). At week 3, 5 of 10 patients receiving 80 mg and 6 of 12 patients receiving 160 mg achieved the predefined response criteria. CONCLUSIONS: Our results indicate that tadekinig alfa appears to have a favourable safety profile and is associated with early signs of efficacy in patients with AOSD. TRIAL REGISTRATION NUMBER: NCT02398435.
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Opportunistic Screening Techniques for Analysis of CT Scans - Engelke, Klaus; Chaudry, Oliver; Bartenschlager, Stefan (Current Osteoporosis Reports, 2022)
Purpose of Review: Opportunistic screening is a combination of techniques to identify subjects of high risk for osteoporotic fracture using routine clinical CT scans prescribed for diagnoses unrelated to osteoporosis. The two main components are automated detection of vertebral fractures and measurement of bone mineral density (BMD) in CT scans, in which a phantom for calibration of CT to BMD values is not used. This review describes the particular challenges of opportunistic screening and provides an overview and comparison of current techniques used for opportunistic screening. The review further outlines the performance of opportunistic screening. Recent Findings: A wide range of technologies for the automatic detection of vertebral fractures have been developed and successfully validated. Most of them are based on artificial intelligence algorithms. The automated differentiation of osteoporotic from traumatic fractures and vertebral deformities unrelated to osteoporosis, the grading of vertebral fracture severity, and the detection of mild vertebral fractures is still problematic. The accuracy of automated fracture detection compared to classical radiological semi-quantitative Genant scoring is about 80%. Accuracy errors of alternative BMD calibration methods compared to simultaneous phantom-based calibration used in standard quantitative CT (QCT) range from below 5% to about 10%. The impact of contrast agents, frequently administered in clinical CT on the determination of BMD and on fracture risk determination is still controversial. Summary: Opportunistic screening, the identification of vertebral fracture and the measurement of BMD using clinical routine CT scans, is feasible but corresponding techniques still need to be integrated into the clinical workflow and further validated with respect to the prediction of fracture risk.
CRIS-Team Scopus Importer:2022-12-02
Keywords: Computed tomography; Fracture risk; Internal BMD calibration; Opportunistic screening; Vertebral fracture assessment

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

OPTIMAL DOSE OF TOCILIZUMAB FOR THE TREATMENT OF GIANT CELL ARTERITIS: EFFICACY, SAFETY, AND EXPOSURE-EFFICACY ANALYSIS FROM GIACTA - Stone, J. H.; Tuckwell, K.; Dimonaco, S.; Klearman, M.; Mallalieu, N. L.; Aringer, M.; Blockmans, D.; Brouwer, E.; Cid, M. C.; Dasgupta, B.; Rech, Jürgen; Salvarani, C.; et al. (2017)
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Optoacoustic Imaging in Inflammation - Regensburger, Adrian; Brown, Emma; Krönke, Gerhard; Waldner, Maximilian; Knieling, Ferdinand (Biomedicines, 2021)
Optoacoustic or photoacoustic imaging (OAI/PAI) is a technology which enables non-invasive visualization of laser-illuminated tissue by the detection of acoustic signals. The combination of "light in" and "sound out" offers unprecedented scalability with a high penetration depth and resolution. The wide range of biomedical applications makes this technology a versatile tool for preclinical and clinical research. Particularly when imaging inflammation, the technology offers advantages over current clinical methods to diagnose, stage, and monitor physiological and pathophysiological processes. This review discusses the clinical perspective of using OAI in the context of imaging inflammation as well as in current and emerging translational applications.
CRIS-Team WoS Importer:2021-06-04

Origin and function of synovial macrophage subsets during inflammatory joint disease - Culemann, Stephan; Grüneboom, Anika; Krönke, Gerhard (Advances in Immunology, 2019)
Mononuclear phagocytes, including monocytes and macrophages, are a central component of the host's innate immune system designated to protect against invading pathogens. However, these cells do not only interact with various parts of the innate and adaptive immune system, but also fulfill indispensable duties during the control of tissue homeostasis and organ function. Moreover, macrophages are crucially involved in tissue remodeling and repair in response to damage. Simultaneously, mononuclear phagocytes might also contribute to the pathogenesis of various inflammatory and autoimmune diseases. In particular, their potential role in inflammatory joint diseases such as rheumatoid arthritis (RA) has drawn increasing attention and substantially shaped our general understanding of the role of monocytes and macrophages during health and disease. This review summarizes our current knowledge about the origin and function of mononuclear phagocytes within the joint and addresses their involvement in joint inflammation.
CRIS-Team Scopus Importer:2019-09-17
Keywords: Inflammation; Macrophages; Monocytes; Rheumatoid arthritis; Synovial macrophages; Synovial tissue; Tissue resident macrophages

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

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

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

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

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

Oxidative Burst-Dependent NETosis Is Implicated in the Resolution of Necrosis-Associated Sterile Inflammation - Biermann, Mona H. C.; Podolska, Malgorzata; Knopf, Jasmin; Reinwald, Christiane; Weidner, Daniela; Maueröder, Christian; Hahn, Jonas; Kienhoefer, Deborah; Barras, Alexandre; Boukherroub, Rabah; Szunerits, Sabine; Bilyy, Rostyslav; et al. (Frontiers in Immunology, 2016)
Necrosis is associated with a profound inflammatory response. The regulation of necrosis-associated inflammation, particularly the mechanisms responsible for resolution of inflammation is incompletely characterized. Nanoparticles are known to induce plasma membrane damage and necrosis followed by sterile inflammation. We observed that injection of metabolically inert nanodiamonds resulted in paw edema in WT and Ncf1** mice. However, while inflammation quickly resolved in WT mice, it persisted over several weeks in Ncf1** mice indicating failure of resolution of inflammation. Mechanistically, NOX2-dependent reactive oxygen species (ROS) production and formation of neutrophil extracellular traps were essential for the resolution of necrosis-induced inflammation: hence, by evaluating the fate of the particles at the site of inflammation, we observed that Ncf1** mice deficient in NADPH-dependent ROS failed to generate granulation tissue therefore being unable to trap the nanodiamonds. These data suggest that NOX2-dependent NETosis is crucial for preventing the chronification of the inflammatory response to tissue necrosis by forming NETosis-dependent barriers between the necrotic and healthy surrounding tissue.
EVALuna2:13386

Paediatric and adult soft tissue sarcomas with NTRK1 gene fusions: a subset of spindle cell sarcomas unified by a prominent myopericytic/haemangiopericytic pattern - Haller, Florian; Knopf, Jasmin; Ackermann, Andreas; Bieg, Matthias; Kleinheinz, Kortine; Schlesner, Matthias; Moskalev, Evgeny; Will, Rainer; Satir, Ali Abdel; Abdelmagid, Ibtihalat E.; Giedl, Josef; Carbon, Roman; et al. (Journal of Pathology, 2016)
Neoplasms with a myopericytomatous pattern represent a morphological spectrum of lesions encompassing myopericytoma of the skin and soft tissue, angioleiomyoma, myofibromatosis/infantile haemangiopericytoma and putative neoplasms reported as malignant myopericytoma. Lack of reproducible phenotypic and genetic features of malignant myopericytic neoplasms have prevented the establishment of myopericytic sarcoma as an acceptable diagnostic category. Following detection of a LMNA-NTRK1 gene fusion in an index case of paediatric haemangiopericytoma-like sarcoma by combined whole-genome and RNA sequencing, we identified three additional sarcomas harbouring NTRK1 gene fusions, termed 'spindle cell sarcoma, NOS with myo/haemangiopericytic growth pattern'. The patients were two children aged 11 months and 2 years and two adults aged 51 and 80 years. While the tumours of the adults were strikingly myopericytoma-like, but with clear-cut atypical features, the paediatric cases were more akin to infantile myofibromatosis/haemangiopericytoma. All cases contained numerous thick-walled dysplastic-like vessels with segmental or diffuse nodular myxohyaline myo-intimal proliferations of smooth muscle actin-positive cells, occasionally associated with thrombosis. Immunohistochemistry showed variable expression of smooth muscle actin and CD34, but other mesenchymal markers, including STAT6, were negative. This study showed a novel variant of myo/haemangiopericytic sarcoma with recurrent NTRK1 gene fusions. Given the recent introduction of a novel therapeutic approach targeting NTRK fusion-positive neoplasms, recognition of this rare but likely under-reported sarcoma variant is strongly encouraged.
EVALuna2:6792

Pain in individuals with idiopathic inflammatory myopathies, other systemic autoimmune rheumatic diseases, and without rheumatic diseases: A report from the COVAD study - Shinjo, Samuel Katsuyuki; Kim, Minchul; Hoff, Leonardo Santos; Missé, Rafael Giovani; Sen, Parikshit; Naveen, R.; Day, Jessica; Cordeiro, Rafael Alves; Júnior, Jucier Gonçalves; Chatterjee, Tulika; Lilleker, James B.; Agarwal, Vishwesh; et al. (International Journal of Rheumatic Diseases, 2023)
Objectives: To compare pain intensity among individuals with idiopathic inflammatory myopathies (IIMs), other systemic autoimmune rheumatic diseases (AIRDs), and without rheumatic disease (wAIDs). Methods: Data were collected from the COVID-19 Vaccination in Autoimmune Diseases (COVAD) study, an international cross-sectional online survey, from December 2020 to August 2021. Pain experienced in the preceding week was assessed using numeral rating scale (NRS). We performed a negative binomial regression analysis to assess pain in IIMs subtypes and whether demographics, disease activity, general health status, and physical function had an impact on pain scores. Results: Of 6988 participants included, 15.1% had IIMs, 27.9% had other AIRDs, and 57.0% were wAIDs. The median pain NRS in patients with IIMs, other AIRDs, and wAIDs were 2.0 (interquartile range [IQR] = 1.0–5.0), 3.0 (IQR = 1.0–6.0), and 1.0 (IQR = 0–2.0), respectively (P < 0.001). Regression analysis adjusted for gender, age, and ethnicity revealed that overlap myositis and antisynthetase syndrome had the highest pain (NRS = 4.0, 95% CI = 3.5–4.5, and NRS = 3.6, 95% CI = 3.1–4.1, respectively). An additional association between pain and poor functional status was observed in all groups. Female gender was associated with higher pain scores in almost all scenarios. Increasing age was associated with higher pain NRS scores in some scenarios of disease activity, and Asian and Hispanic ethnicities had reduced pain scores in some functional status scenarios. Conclusion: Patients with IIMs reported higher pain levels than wAIDs, but less than patients with other AIRDs. Pain is a disabling manifestation of IIMs and is associated with a poor functional status.
CRIS-Team Scopus Importer:2023-03-31
Keywords: autoimmune diseases; functional status; myositis; pain; rheumatic diseases

Palmar fasciitis and polyarthritis syndrome-Systematic literature review of 100 cases - Manger, Bernhard; Schett, Georg (Seminars in Arthritis and Rheumatism, 2014)
To analyse clinical, laboratory, and imaging characteristics of all patients with palmar fasciitis and polyarthritis syndrome (PFPAS) described in the literature.Comparison of the clinical presentation of one patient with acute onset of PFAPS with 99 other published cases identified through a PubMed literature research.Since the original description in 1982 by Medsger et al., there have been numerous case reports and small case series in the literature. In total, 73 articles in English, French and Spanish language were included in the analysis. PFPAS is a rare but characteristic paraneoplastic syndrome in rheumatology. Its distinct clinical feature is a painful swelling of both the hands caused by an inflammation of the palmar fascia, tendon sheaths and small joints of fingers and wrist, and flexion contractures develop rapidly. Since the subcutaneous tissues become indurated and hard, the illustrative term "woody hands" was coined. The most frequent underlying malignancy is ovarian cancer but adenocarcinomas of the breast, gastrointestinal tract and other organs can also cause this syndrome. A helpful diagnostic procedure in order to identify the nature of the underlying malignancy in many cases has been the determination of various serum tumour markers. In cases when a complete removal of the malignancy is possible, PFPAS can also undergo complete remission.Knowledge of the distinct features of this rare paraneoplastic syndrome facilitates early diagnosis and potentially life-saving therapeutic interventions.
EVALuna2:12992

Pancreatic Panniculitis and Polyarthritis - Zundler, Sebastian; Strobel, Deike; Manger, Bernhard; Neurath, Markus; Wildner, Dane (Current Rheumatology Reports, 2017)
Polyarthritis can have numerous reasons and may thus constitute a challenge for differential diagnosis. One rare potential reason for sterile polyarthritis is underlying pancreatic disease with systemic hyperlipasemia, most often accompanied by painful skin lesions caused by a subcutaneous inflammatory process known as panniculitis. Systematic evidence on pancreatic panniculitis and polyarthritis is limited, particularly regarding its feature as facultative paraneoplasia with underlying intra- or even extra-pancreatic malignancy. Therefore, we will summarize the current knowledge about this orphan disease including epidemiological, pathophysiological, diagnostic, and treatment aspects in the present review.Although direct evidence is lacking, it is highly probable that pancreatic polyarthritis and panniculitis are caused by peripheral lipolytic activity of lipase systemically circulating due to benign (e.g., acute or chronic pancreatitis) or malign (e.g., acinar cell carcinoma (ACC) or adenocarcinoma) pancreatic disease. In the latter case, pancreatic polyarthritis and panniculitis are associated with poor outcome. Pancreatic polyarthritis and panniculitis should always be included into diagnostic considerations, and once suspected, a thorough work-up to identify the underlying disease has to be performed.
EVALuna2:13446

Paraneoplastic syndromes in rheumatology - Manger, Bernhard; Schett, Georg (Nature Reviews Rheumatology, 2014)
For patients that present with musculoskeletal symptoms, diagnostic procedures carried out by physicians and rheumatologists are primarily aimed at confirming or excluding the occurrence of primary rheumatic diseases. Another important trigger for musculoskeletal disease, however, is the presence of a tumour. Careful clinical investigation and knowledge of the gestalt of musculoskeletal syndromes related to respective tumour entities is of utmost importance for the diagnosis of paraneoplastic rheumatic diseases such as hypertrophic osteoarthropathy, paraneoplastic polyarthritis, RS3PE syndrome, palmar fasciitis and polyarthritis, cancer-associated myositis and tumour-induced osteomalacia. This places great responsibility on rheumatologists in diagnosing malignancies and referring the patient for effective treatment. The selective influence of tumours on musculoskeletal tissue is surprising and indicates that tumours alter tissues such as the periosteum, synovial membrane, subcutaneous connective tissue, fascia, muscles and bones by specific molecular processes. Some of the underlying mechanisms have been unravelled, providing valuable information on the physiologic and pathophysiologic roles of mediators such as vascular endothelial growth factor and fibroblast growth factor 23.
EVALuna2:12990

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

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

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

Pathological function of neutrophil extracellular traps in human colon cancer - Stehr, Antonia; Wang, Guangxia; Demmler, Richard; Stemmler, Marc; Tripal, Philipp; Geppert, Carol-Immanuel; Merkel, Susanne; Herrmann, Martin; Stürzl, Michael (ONCOLOGY RESEARCH AND TREATMENT, 2022)
CRIS-Team WoS Importer:2022-12-16

Patient-Centred Outcomes for Monitoring Disease Remotely in Idiopathic Inflammatory Myopathies - Mago, Arpit; Naveen, R.; Knitza, Johannes; Shinjo, Samuel Katsuyuki; Gupta, Latika; Aggarwal, Rohit (Indian Journal of Rheumatology, 2022)
CRIS-Team WoS Importer:2023-02-24

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

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

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

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

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

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

Patient self-sampling: a cornerstone of future rheumatology care? - Morf, Harriet; Krusche, Martin; Knitza, Johannes (Rheumatology International, 2021)
CRIS-Team WoS Importer:2021-04-30

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

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