Bone anabolic changes progress in psoriatic arthritis patients despite treatment with methotrexate or tumour necrosis factor inhibitors - Finzel, Stephanie; Kraus, Sebastian; Schmidt, Sarah; Hueber, Axel; Rech, Jürgen; Engelke, Klaus; Englbrecht, Matthias; Schett, Georg (Annals of the Rheumatic Diseases, 2013)
Objectives: To investigate whether methotrexate or tumour necrosis factor inhibitors (TNFi) affect osteophyte formation in patients with psoriatic arthritis (PsA). Methods: 41 patients with PsA were examined for the presence of osteophytes and erosions at the metacarpophalangeal joints by high-resolution micro-CT imaging. The size of each individual lesion was quantified at baseline and 1-year follow-up in PsA patients treated with TNFi (N=28) or methotrexate (N=13). Groups were comparable for age, sex, disease duration and activity and baseline burden of osteophytes. Results: In total, 415 osteophytes (TNFi N=284, methotrexate N=131) were detected. Osteophyte size increased significantly from baseline to follow-up in the TNFi group (mean±SEM change +0.23±0.02 mm; p<0.0001) and the methotrexate group (+0.27±0.03 mm, p<0.0001). In both treatment groups, the majority of osteophytes showed progression (TNFi 54.3%, methotrexate 61.1%), whereas regression of lesions was rare (less than 10%). In contrast to osteophytes, clinical disease activity decreased in both groups of PsA patients and erosions showed an arrest of progression in both groups. Conclusions: Osteophytes progress in PsA patients treated with either methotrexate or TNFi. These data provide the first evidence that pathological bone formation in the appendicular skeleton of patients with PsA is not affected by current antirheumatic treatment strategies.
CRIS-Team Scopus Importer:2021-02-03

Bone- and cartilage-protective effects of a monoclonal antibody against colony-stimulating factor 1 receptor in experimental arthritis - Toh, Myew-Ling; Bonnefoy, Jean-Yves; Accart, Nathalie; Cochin, Sandrine; Pohle, Sandy; Haegel, Helene; De Meyer, Micael; Zemmour, Christophe; Preville, Xavier; Guillen, Christine; Thioudellet, Christine; Ancian, Philippe; et al. (Arthritis and Rheumatology, 2014)
Colony-stimulating factor 1 receptor (CSF-1R) essentially modulates monocyte proliferation, migration, and activation, which are considered important for the pathogenesis of rheumatoid arthritis (RA). We undertook this study to determine CSF-1R expression in human RA as well as the efficacy of a specific anti-CSF-1R monoclonal antibody (AFS98) in 2 different animal models of RA.CSF-1R expression was examined in blood, synovium, and bone samples from RA patients, osteoarthritis (OA) patients, and healthy subjects. The efficacy of AFS98 was examined by clinical assessment, histology, and bone histomorphometry in collagen-induced arthritis (CIA) and serum-transfer arthritis.CSF-1R expression was increased in the synovium of RA patients compared to OA patients and healthy controls in fibroblast-like synoviocytes, follicular dendritic cells, macrophages, and osteoclasts. Circulating RA monocytes and neutrophils but not lymphocytes were CSF-1R+. In mice, blockade of CSF-1R abrogated cartilage damage, bone erosion, and systemic bone loss, and this was associated with the depletion of osteoclasts in both models. While blockade of CSF-1R did not affect inflammation in passive serum-transfer arthritis, it significantly reduced inflammation in CIA, and this was associated with the absence of synovial macrophages and reduced splenic CD11b+Gr-1- monocytes.CSF-1R was broadly expressed in human RA. Blockade of CSF-1R protected against bone and cartilage destruction in both mouse models and also showed significant antiinflammatory effects in the CIA model. These data provide evidence for CSF-1R as a therapeutic target in RA.
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Bone Formation in Psoriatic Arthritis: A Report from the GRAPPA 2013 Annual Meeting - Schett, Georg (Journal of Rheumatology, 2014)
The simultaneous presence of bone erosions and bony spurs (osteophytes, enthesophytes) in the joints of patients with psoriatic arthritis (PsA) suggests that the disease leads to enhanced bone resorption as well as increased bone formation, the latter of which has not been observed in patients with rheumatoid arthritis. At the 2013 Annual Meeting of the Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA), members heard an update on the current research into the cytokine signature in PsA and its effects on new bone formation.
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Bone Loss Before Clinical Onset of Rheumatoid Arthritis o Subjects with Anti-Citrullinated Protein Antibodies - Finzel, Stephanie; Lang, Veronika; Kleyer, Arnd; Rech, Jürgen; Manger, Bernhard; Guilhon de Araujo, Elizabeth; Hueber, Axel; Harre, Ulrike; Schett, Georg (2012)
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Bone loss before the clinical onset of rheumatoid arthritis in subjects with anticitrullinated protein antibodies - Kleyer, Arnd; Finzel, Stephanie; Rech, Jürgen; Manger, Bernhard; Krieter, Manuel; Faustini, Francesca; Araujo, Elisabeth; Hueber, Axel; Harre, Ulrike; Engelke, Klaus; Schett, Georg (Annals of the Rheumatic Diseases, 2014)
Anticitrullinated protein antibodies (ACPA) are a major risk factor for bone loss in rheumatoid arthritis (RA). We have recently shown that ACPA directly induce bone loss by stimulating osteoclast differentiation. As ACPA precede the clinical onset of RA by years, we hypothesised that ACPA positive healthy individuals may already show skeletal changes.We performed a comparative micro-CT analysis of the bone microstructure in the metacarpophalangeal joints of ACPA positive and ACPA negative healthy individuals without clinical signs of arthritis.ACPA positive (n=15) and negative (n=15) healthy individuals were not different in age (48.2±4.1 vs 51.4±3.8 years, p=0.57) or gender (eight women and two men in both groups). Bone mineral density was significantly reduced in ACPA positive individuals (mean±SEM 280±11 mg/cm(3)) compared with controls (327±6). Bone loss was based on cortical bone changes, with significant (p=0.044) reduction in cortical thickness in the ACPA positive group (mean±SEM 0.22±0.03 mm) compared with controls (0.32±0.03 mm). Areas of cortical porosity were significantly (p=0.0005) more widespread in ACPA positive (mean±SEM 7.4±1.4%) than in ACPA negative individuals (1.0±0.3%).Structural bone damage starts before the clinical onset of arthritis in subjects with ACPA. These findings revise the concept that bone damage is an exclusive consequence of synovitis in patients with R
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Bone Mass, Bone Microstructure and Biomechanics in Patients with Hand Osteoarthritis - Simon, David; Tascilar, Koray; Unbehend, Sara; Bayat, Sara; Berlin, Andreas; Liphardt, Anna-Maria; Meinderink, Timo; Rech, Jürgen; Hueber, Axel; Schett, Georg; Kleyer, Arnd (Journal of Bone and Mineral Research, 2020)
The impact of primary hand osteoarthritis (HOA) on bone mass, microstructure, and biomechanics in the affected skeletal regions is largely unknown. HOA patients and healthy controls (HCs) underwent high-resolution peripheral quantitative computed tomography (HR-pQCT). We measured total, trabecular, and cortical volumetric bone mineral densities (vBMDs), microstructural attributes, and performed micro–finite element analysis for bone strength. Failure load and scaled multivariate outcome matrices from distal radius and second metacarpal (MCP2) head measurements were analyzed using multiple linear regression adjusting for age, sex, and functional status and reported as adjusted Z-score differences for total and direct effects. A total of 105 subjects were included (76 HC: 46 women, 30 men; 29 HOA: 23 women, six men). After adjustment, HOA was associated with significant changes in the multivariate outcome matrix from the MCP2 head (p <.001) (explained by an increase in cortical vBMD (Δz = 1.07, p =.02) and reduction in the trabecular vBMD (Δz = −0.07, p =.09). Distal radius analysis did not show an overall effect of HOA; however, there was a gender-study group interaction (p =.044) explained by reduced trabecular vBMD in males (Δz = −1.23, p =.02). HOA was associated with lower failure load (−514 N; 95%CI, −1018 to −9; p = 0.05) apparent in males after adjustment for functional status. HOA is associated with reduced trabecular and increased cortical vBMD in the MCP2 head and a reduction in radial trabecular vBMD and bone strength in males. Further investigations of gender-specific changes of bone architecture in HOA are warranted. © 2020 The Authors. Journal of Bone and Mineral Research published by American Society for Bone and Mineral Research.
CRIS-Team Scopus Importer:2020-06-09
Keywords: ANALYSIS/QUANTITATION OF BONE; BIOMECHANICS; BONE QCT/MICROCT; DISEASES AND DISORDERS OF/RELATED TO BONE; ORTHOPAEDICS; OSTEOARTHRITIS

Bone microstructure and volumetric bone mineral density in patients with hyperuricemia with and without psoriasis - Simon, David; Haschka, J.; Muschitz, C.; Kocijan, A.; Baierl, A.; Kleyer, Arnd; Schett, Georg; Kapiotis, S.; Resch, H.; Sticherling, Michael; Rech, Jürgen; Kocijan, R. (Osteoporosis international, 2020)
Summary: We analyzed volumetric bone mineral density (vBMD) and bone microstructure using HR-pQCT in subjects with normouricemia (NU) and subjects with hyperuricemia (HU) with and without psoriasis (PSO). HU was associated with higher cortical vBMD and thickness. Differences in average and trabecular vBMD were found between patients with PSO + HU and NU. Introduction: Hyperuricemia (HU) and gout are co-conditions of psoriasis and psoriatic arthritis. Current data suggest a positive association between HU and areal bone mineral density (BMD) and a negative influence of psoriasis on local bone, even in the absence of arthritis. However, the influence of the combination of HU and psoriasis on bone is still unclear. The aim of this study was to assess the impact of HU with and without psoriasis on bone microstructure and volumetric BMD (vBMD). Methods: Healthy individuals with uric acid levels within the normal range (NU), with hyperuricemia (HU), patients with hyperuricemia and psoriasis (PSO + HU), and patients with uric acid within the normal range and psoriasis (PSO + NU) were included in our study. Psoriasis patients had no current or past symptoms of arthritis. Average, trabecular, and cortical vBMD (mgHA/cm3); trabecular number (Tb.N, 1/mm) and thickness (Tb.Th, mm); inhomogeneity of the network (1/N.SD, mm); and cortical thickness (Ct.Th., mm) were carried out at the ultradistal radius using high-resolution peripheral quantitative computed tomography. In addition, bone turnover markers such as DKK-1, sclerostin, and P1NP were analyzed. Results: In total, 130 individuals were included (44 NU participants (34% female), 50 HU (24%), 16 PSO + HU (6%), 20 PSO + NU (60%)). Subjects were aged: NU 54.5 (42.8, 62.1), HU 57.5 (18.6, 65.1), PSO + HU 52.0 (42.3, 57.8), and PSO + NU 42.5 (34.8, 56.8), respectively. After adjusting for age, sex, BMI, and diabetes, patients in the HU group revealed significantly higher values of cortical vBMD (p < 0.001) as well as cortical thickness (p = 0.04) compared to the NU group. PSO + NU showed no differences to NU, but PSO + HU demonstrated both lower average (p = 0.03) and trabecular vBMD (p = 0.02). P1NP was associated with average, cortical, and trabecular vBMD as well as cortical thickness while sclerostin levels were related to trabecular vBMD. Conclusion: Hyperuricemia in otherwise healthy subjects was associated with a better cortical vBMD and higher cortical thickness. However, patients with both psoriasis and hyperuricemia revealed a lower vBMD.
CRIS-Team Scopus Importer:2020-01-21
Keywords: Bone Mineral Density; HR-pQCT; Hyperuricemia; Psoriasis

Bone Microstructure Assessed By Hrpqct in Subjects with Hyperuricemia without Arthritis - Kocijan, Roland; Nia, Arastoo; Muschitz, Christian; Simon, David; Geiger, Corinna; Haschka, Judith; Kleyer, Arnd; Bayat, Sara; Rech, Jürgen; Kocijan, Annemarie; Dzirlo, Larissa; Graninger, Monika; et al. (2015)
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Bone Microstructure in Patients with Cutaneous Psoriasis and No History of Psoriatic Arthritis Shows Bone Anabolic Changes at a Greater Extent Than in Healthy Controls - Simon, David; Faustini, Francesca; Englbrecht, Matthias; Kleyer, Arnd; Kocijan, Roland; Haschka, Judith; Finzel, Stephanie; Kraus, Sebastian; Hueber, Axel; Sticherling, Michael; Schett, Georg; Rech, Jürgen (2014)
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Bone Morphogenetic Protein Antagonist Gremlin-1 Increases Myofibroblast Transition in Dermal Fibroblasts: Implications for Systemic Sclerosis - Duffy, Laura; Henderson, John; Brown, Max; Pryzborski, Stefan; Fullard, Nicola; Summa, Lena; Distler, Jörg; Stratton, Richard; O'Reilly, Steven (Frontiers in Cell and Developmental Biology, 2021)
Objective: Systemic Sclerosis is an autoimmune connective tissue disease which results in fibrosis of the skin and lungs. The disease is characterized by activation of myofibroblasts but what governs this is unknown. Gremlin-1 is a BMP antagonist that is developmentally regulated and we sought to investigate its role in Systemic Sclerosis. Methods: Dermal fibroblasts were transfected with Grem1pcDNA3.1 expression vectors or empty vectors. Various markers of myofibroblasts were measured at the mRNA and protein levels. Scratch wound assays were also performed. Media Transfer experiments were performed to evaluate cytokine like effects. Various inhibitors of TGF-β signaling and MAPK signaling were used post-transfection. siRNA to Gremlin-1 in SSc dermal fibroblasts were performed to evaluate the role of Gremlin-1. Different cytokines were incubated with fibroblasts and Gremlin-1 measured. Bleomycin was used as model of fibrosis and immunohistochemistry performed. Results: Overexpression of Gremlin-1 was achieved in primary dermal fibroblasts and lead to activation of quiescent cells to myofibroblasts indicated by collagen and α-Smooth muscle actin. Overexpression also led to functional effects. This was associated with increased TGF-β1 levels and SBE luciferase activity but not increased Thrombospondin-1 expression. Inhibition of Gremlin-1 overexpression cells with antibodies to TGF-β1 but not isotype controls led to reduced collagen and various TGF-β pathway chemical inhibitors also led to reduced collagen levels. In SSc cells siRNA mediated reduction of Gremlin-1 reduced collagen expression and CTGF gene and protein levels in these cells. IL-13 did not lead to elevated Gremlin-1 expression nor did IL-11. Gremlin-1 was elevated in an animal model of fibrosis compared to NaCl-treated mice. Conclusion: Gremlin-1 is a key regulator of myofibroblast transition leading to enhanced ECM deposition. Strategies that block Gremlin-1 maybe a possible therapeutic target in fibrotic diseases such as SSc.
CRIS-Team Scopus Importer:2021-07-02
Keywords: BMP; collagen; ECM; fibrosis; gremlin-1

Brain fMRI Predicts Responses to Certolizumab Pegol in RA. an International, Multi-center, Randomized, Double-blind, Placebocontrolled Trial (PreCePRA) - Rech, Jürgen; Schenker, Hannah; Tascilar, Koray; Hagen, Melanie; Kleyer, Arnd; Simon, David; Mendez, Larissa Valor; Schoenau, Verena; Prade, Jutta; Sergeeva, Marina; Sulvakumar, Mageshvar; Strobelt, Sandra; et al. (ARTHRITIS & RHEUMATOLOGY, 2020)
CRIS-Team WoS Importer:2021-01-15

Brief Report: IRF4 Newly Identified as a Common Susceptibility Locus for Systemic Sclerosis and Rheumatoid Arthritis in a Cross-Disease Meta-Analysis of Genome-Wide Association Studies - Lopez-Isac, Elena; Martin, Jose-Ezequiel; Assassi, Shervin; Simeon, Carmen P.; Carreira, Patricia; Ortego-Centeno, Norberto; Freire, Mayka; Beltran, Emma; Narvaez, Javier; Alegre-Sancho, Juan J.; Fernandez-Gutierrez, Benjamin; Balsa, Alejandro; et al. (Arthritis and Rheumatology, 2016)
Systemic sclerosis (SSc) and rheumatoid arthritis (RA) are autoimmune diseases that have similar clinical and immunologic characteristics. To date, several shared SSc-RA genetic loci have been identified independently. The aim of the current study was to systematically search for new common SSc-RA loci through an interdisease meta-genome-wide association (meta-GWAS) strategy.The study was designed as a meta-analysis combining GWAS data sets of patients with SSc and patients with RA, using a strategy that allowed identification of loci with both same-direction and opposite-direction allelic effects. The top single-nucleotide polymorphisms were followed up in independent SSc and RA case-control cohorts. This allowed an increase in the sample size to a total of 8,830 patients with SSc, 16,870 patients with RA, and 43,393 healthy controls.This cross-disease meta-analysis of the GWAS data sets identified several loci with nominal association signals (P < 5 × 10(-6) ) that also showed evidence of association in the disease-specific GWAS scans. These loci included several genomic regions not previously reported as shared loci, as well as several risk factors that were previously found to be associated with both diseases. Follow-up analyses of the putatively new SSc-RA loci identified IRF4 as a shared risk factor for these 2 diseases (Pcombined = 3.29 × 10(-12) ). Analysis of the biologic relevance of the known SSc-RA shared loci identified the type I interferon and interleukin-12 signaling pathways as the main common etiologic factors.This study identified a novel shared locus, IRF4, for the risk of SSc and RA, and highlighted the usefulness of a cross-disease GWAS meta-analysis strategy in the identification of common risk loci.
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Brief Report: Tumor Necrosis Factor and Interleukin-6 Differentially Regulate Dkk-1 in the Inflamed Arthritic Joint - Yeremenko, Nataliya; Zwerina, Karin; Rigter, Gemma; Pots, Desiree; Fonseca, Joao E.; Zwerina, Jochen; Schett, Georg; Baeten, Dominique (Arthritis and Rheumatology, 2015)
Tumor necrosis factor (TNF) drives bone destruction, but it also inhibits new bone formation by inducing Dkk-1, an inhibitor of the Wnt pathway. Accordingly, blocking of Dkk-1 reverses the phenotype in experimental arthritis from a pattern of bone destruction to a pattern of bone formation. To delineate the potential role of Dkk-1 in the structural phenotype of human arthritis, we analyzed the expression of Dkk-1 and its regulation by proinflammatory cytokines in the inflamed peripheral joints of patients with spondyloarthritis (SpA) and rheumatoid arthritis (RA).Expression of Dkk-1 and proinflammatory cytokines was determined by enzyme-linked immunosorbent assay and microarray analysis in synovial fluid (SF) and synovial tissue, respectively. Regulation of Dkk-1 production by proinflammatory cytokines was assessed in fibroblast-like synoviocyte (FLS) cultures.TNF and interleukin-1? (IL-1?) levels, were higher in RA SF than in SpA SF (P < 0.001 for both), whereas levels of IL-6 were not. Levels of Dkk-1 were similar in SpA SF and RA SF and were not correlated with TNF and IL-1? levels. However, Dkk-1 levels showed an inverse correlation with IL-6 levels in both SpA SF (r = -0.31, P = 0.04) and RA SF (r = -0.39, P = 0.01); this result was reproduced at the messenger RNA level in synovial tissue. In vitro experiments with FLS confirmed that Dkk-1 production was strongly induced by TNF but clearly suppressed by IL-6. Moreover, IL-6 was able to suppress the TNF-induced up-regulation of Dkk-1 production by FLS.The inverse correlation of Dkk-1 levels with IL-6 levels observed in vivo in the inflamed joints was mirrored by the differential regulation of Dkk-1 production by TNF and IL-6 in vitro. The relative balance between these and other factors in the arthritic joints may determine functional Wnt signaling and tissue remodeling.
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Btn2a2 Regulates ILC2-T Cell Cross Talk in Type 2 Immune Responses - Frech, Michael; Omata, Yasunori; Schmalzl, Angelika; Wirtz, Stefan; Taher, Leila; Schett, Georg; Zaiss, Mario; Sarter, Kerstin (Frontiers in Immunology, 2022)
Innate lymphoid cells (ILC) not only are responsible for shaping the innate immune response but also actively modulate T cell responses. However, the molecular processes regulating ILC-T cell interaction are not yet completely understood. The protein butyrophilin 2a2 (Btn2a2), a co-stimulatory molecule first identified on antigen-presenting cells, has a pivotal role in the maintenance of T cell homeostasis, but the main effector cell and the respective ligands remain elusive. We analyzed the role of Btn2a2 in the ILC-T cell cross talk. We found that the expression of Btn2a2 is upregulated in ILC2 following stimulation with IL-33/IL-25/TSLP. In vitro and in vivo experiments indicated that lack of Btn2a2 expression on ILC2 resulted in elevated T cell responses. We observed an enhanced proliferation of T cells as well as increased secretion of the type 2 cytokines IL-4/IL-5/IL-13 following cocultures with Btn2a2-deficient ILC2. In vivo transfer experiments confirmed the regulatory role of Btn2a2 on ILC2 as Btn2a2-deficient ILC2 induced stronger T cell responses and prevented chronic helminth infections. Taken together, we identified Btn2a2 as a significant player in the regulation of ILC2-T cell interactions.
CRIS-Team WoS Importer:2022-02-18

Butyrophilin 2a2 (Btn2a2) expression on thymic epithelial cells promotes central T cell tolerance and prevents autoimmune disease: Btn2a2 promotes central tolerance - Frech, Michael; Danzer, Heike; Uchil, Pooja; Azizov, Vugar; Schmid, Eva; Schälter, Fabian; Dürholz, Kerstin; Mauro, Daniele; Rauber, Simon; Munoz Becerra, Luis; Taher, Leila; Ciccia, Francesco; et al. (Journal of Autoimmunity, 2023)
Butyrophilins are surface receptors belonging to the immunoglobulin superfamily. While several members of the butyrophilin family have been implicated in the development of unconventional T cells, butyrophilin 2a2 (Btn2a2) has been shown to inhibit conventional T cell activation. Here, we demonstrate that in steady state, the primary source of Btn2a2 are thymic epithelial cells (TEC). Absence of Btn2a2 alters thymic T cell maturation and bypasses central tolerance mechanisms. Furthermore, Btn2a2−/− mice develop spontaneous autoimmunity resembling human primary Sjögren's Syndrome (pSS), including formation of tertiary lymphoid structures (TLS) in target organs. Ligation of Btn2a2 on developing thymocytes is associated with reduced TCR signaling and CD5 levels, while absence of Btn2a2 results in increased TCR signaling and CD5 levels. These results define a novel role for Btn2a2 in promoting central tolerance by modulating TCR signaling strength and indicate a potential mechanism of pSS development.
CRIS-Team Scopus Importer:2023-07-07
Keywords: Autoimmune disease; Autoimmunity; Butyrophilin 2a2 (Btn2a2); Central tolerance; Primary sjögren's syndrome (pSS); Thymic epithelial cells (TEC)

Calcium pyrophosphate deposition disease induced inflammatory back pain - Kleyer, Arnd; Knitza, Johannes; Schett, Georg; Manger, Bernhard (Rheumatology, 2020)
CRIS-Team Scopus Importer:2020-02-04

Calibration by differentiation – Self-supervised calibration for X-ray microscopy using a differentiable cone-beam reconstruction operator - Thies, Mareike; Wagner, Fabian; Huang, Yixing; Gu, Mingxuan; Kling, Lasse; Pechmann, Sabrina; Aust, Oliver; Grüneboom, Anika; Schett, Georg; Christiansen, Silke H.; Maier, Andreas (Journal of Microscopy, 2022)
High-resolution X-ray microscopy (XRM) is gaining interest for biological investigations of extremely small-scale structures. XRM imaging of bones in living mice could provide new insights into the emergence and treatment of osteoporosis by observing osteocyte lacunae, which are holes in the bone of few micrometers in size. Imaging living animals at that resolution, however, is extremely challenging and requires very sophisticated data processing converting the raw XRM detector output into reconstructed images. This paper presents an open-source, differentiable reconstruction pipeline for XRM data which analytically computes the final image from the raw measurements. In contrast to most proprietary reconstruction software, it offers the user full control over each processing step and, additionally, makes the entire pipeline deep learning compatible by ensuring differentiability. This allows fitting trainable modules both before and after the actual reconstruction step in a purely data-driven way using the gradient-based optimizers of common deep learning frameworks. The value of such differentiability is demonstrated by calibrating the parameters of a simple cupping correction module operating on the raw projection images using only a self-supervisory quality metric based on the reconstructed volume and no further calibration measurements. The retrospective calibration directly improves image quality as it avoids cupping artifacts and decreases the difference in gray values between outer and inner bone by 68% to 94%. Furthermore, it makes the reconstruction process entirely independent of the XRM manufacturer and paves the way to explore modern deep learning reconstruction methods for arbitrary XRM and, potentially, other flat-panel CT systems. This exemplifies how differentiable reconstruction can be leveraged in the context of XRM and, hence, is an important step toward the goal of reducing the resolution limit of in-vivo bone imaging to the single micrometer domain.
Keywords: X-ray microscopy; computed tomography; inverse problems; reconstruction; deep learning; known operator learning

Calpain-1 weakens the nuclear envelope and promotes the release of neutrophil extracellular traps - Singh, Jeeshan; Zlatar, Leticija; Munoz Becerra, Marco; Lochnit, Günter; Herrmann, Irmgard; Pfister, Felix; Janko, Christina; Knopf, Jasmin; Leppkes, Moritz; Schoen, Janina; Munoz, Luis Enrique; Schett, Georg; et al. (Cell Communication and Signaling, 2024)
The inducers of neutrophil extracellular trap (NET) formation are heterogeneous and consequently, there is no specific pathway or signature molecule indispensable for NET formation. But certain events such as histone modification, chromatin decondensation, nuclear envelope breakdown, and NET release are ubiquitous. During NET formation, neutrophils drastically rearrange their cytoplasmic, granular and nuclear content. Yet, the exact mechanism for decoding each step during NET formation still remains elusive. Here, we investigated the mechanism of nuclear envelope breakdown during NET formation. Immunofluorescence microscopic evaluation revealed a gradual disintegration of outer nuclear membrane protein nesprin-1 and alterations in nuclear morphology during NET formation. MALDI-TOF analysis of NETs that had been generated by various inducers detected the accumulation of nesprin-1 fragments. This suggests that nesprin-1 degradation occurs before NET release. In the presence of a calpain-1, inhibitor nesprin-1 degradation was decreased in calcium driven NET formation. Microscopic evaluation confirmed that the disintegration of the lamin B receptor (LBR) and the collapse of the actin cytoskeleton occurs in early and later phases of NET release, respectively. We conclude that the calpain-1 degrades nesprin-1, orchestrates the weakening of the nuclear membrane, contributes to LBR disintegration, and promoting DNA release and finally, NETs formation.
CRIS-Team Scopus Importer:2024-09-20
Keywords: Calpain-1; Nesprin-1; Neutrophil extracellular traps (NETs); Nuclear envelope break down

Canonical Wnt signaling in systemic sclerosis - Bergmann, Christina; Distler, Jörg (Laboratory Investigation, 2016)
Fibrosing disorders are characterized by abundant accumulation of extracellular matrix proteins such as collagen in a variety of organs, which results in structural changes and dysfunction of the affected organ. Thus fibrotic diseases are characterized by a high morbidity and mortality and also lead to major socioeconomic costs. Systemic sclerosis (SSc) is a prototypic multi-systemic fibrosing disease, which affects the skin and a variety of internal organs, including the lungs, heart and gastrointestinal tract. Targeted antifibrotic therapies are not yet available for clinical use in SSc. In recent years, canonical Wnt signaling has been profoundly characterized as an important mediator of sustained fibroblast activation in fibrotic diseases. In the present review, we will summarize current research on the canonical Wnt signaling pathway in SSc and discuss translational implications and potential limitations of prolonged Wnt inhibition.
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Cardiomyopathy in murine models of systemic sclerosis - Venalis, Paulius; Kumanovics, Gabor; Schulze-Koops, Hendrik; Distler, Alfiya; Dees, Clara; Zerr, Pawel; Palumbo-Zerr, Katrin; Czirjak, Laszlo; Mackevic, Zygmunt; Lundberg, Ingrid E.; Distler, Oliver; Schett, Georg; et al. (Arthritis and Rheumatology, 2015)
Cardiomyopathy has emerged as a leading cause of death in patients with systemic sclerosis (SSc). However, the pathogenesis of SSc-related cardiomyopathy is poorly understood, and new therapies as well as platforms for testing are needed. The aim of this study was to characterize the histopathologic features of cardiomyopathy in patients with SSc and in common mouse models of SSc.The histopathologic features of myocardial tissue specimens obtained at autopsy from 5 subjects with SSc and 5 control subjects matched for sex, age, and cardiovascular risk factors were evaluated and compared with those of myocardial tissue specimens obtained from 3 common mouse models of SSc with systemic manifestations: Fra-2-transgenic mice, mice with sclerodermatous chronic graft-versus-host disease (GVHD), and TSK-1 mice.Myocardial tissue from autopsy subjects with SSc and no clinically manifest cardiac involvement showed endothelial cell apoptosis with reduced capillary density, perivascular inflammation, myofibroblast differentiation, and accumulation of collagen. Only selected features of SSc-related cardiomyopathy were observed in the mice with chronic GVHD and TSK-1 mice. However, the myocardial tissue of Fra-2-transgenic mice mimicked all features of SSc-related cardiomyopathy and also demonstrated comparable vascular, inflammatory, and fibrotic manifestations. Of note, the expression of Fra-2 was also increased in the myocardium of autopsy subjects with SSc.We demonstrate that all typical manifestations of SSc-related cardiomyopathy are mimicked in Fra-2-transgenic mice. Moreover, overexpression of Fra-2 in the myocardium of autopsy subjects with SSc may suggest similar underlying pathogenic mechanisms. Thus, Fra-2-transgenic mice might be a suitable preclinical model with which to study the mechanisms of and therapeutic approaches to myocardial involvement in SSc.
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Cardiovascular Comorbidity in Inflammatory Rheumatological Conditions - Braun, Juergen; Krueger, Klaus; Manger, Bernhard; Schneider, Matthias; Specker, Christof; Trappe, Hans Joachim (Deutsches Ärzteblatt international, 2017)
Approximately 1.5 million adults in Germany suffer from an inflammatory rheumatological condition. The most common among these are rheumatoid arthritis and spondyloarthritis-above all axial spondyloarthritis, including ankylosing spondylitis (Bekhterev's disease) and psoriatic arthritis. These systemic inflammatory diseases often affect the heart as well.This review is based on pertinent articles retrieved by a selective literature search, on current European guidelines, and on the authors' clinical experience.Rheumatic inflammation of cardiac structures can manifest itself as pericarditis, myocarditis, or endocarditis. The heart valves and the intracardiac conduction system can be affected as well, leading to AV block. Functional sequelae, e.g., congestive heart failure, can arise as a consequence of any inflammatory rheumatic disease. The long-term mortality of rheumatic diseases is elevated predominantly because of the increased risk for cardiovascular comorbidities. The cardiovascular risk profile should therefore be re-evaluated regularly (e.g., at 5-year intervals) in cooperation with the patient's primary care physician. The cardiovascular manifestations of rheumatic disease, such as pericarditis, myocarditis, and vasculitis, are treated initially with high-dose glucocorticoids and then over the long term with maintenance drugs such as methotrexate and azathioprine. Biological agents are sometimes used as well.In patients with inflammatory rheumatic diseases, the elevated cardiovascular risk should be kept in mind and preventive measures should be initiated early. This subject should be further studied in controlled trials so that the treatment options for patients with cardiac involvement can be evaluated.
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CAR T-cell perspectives in lupus – Authors' reply - Schett, Georg; Mackensen, Andreas; Mougiakakos, Dimitrios (The Lancet, 2024)
CRIS-Team Scopus Importer:2024-08-02

CAR T cells in autoimmune disease: On the road to remission - Schett, Georg; June, Carl H. (Immunity, 2024)
Several recent reports have demonstrated that B cell-targeting chimeric antigen receptor (CAR) T cells offer a viable treatment option for patients with autoantibody-mediated autoimmune diseases. To present additional data on this therapy and discuss strategies for more efficient clinical translation, leading experts in CAR T cell therapy for autoimmunity from various countries, including China, Germany, and the United States, convened at the “1st International Autoimmune CAR T Innovators Summit” in Grassau, Germany, from May 10–12, 2024. The summit showcased additional insights of CAR T cell therapy in diverse autoimmune diseases and provided platforms for discussions on key questions through workshops and roundtables. Here, we summarize the recent findings and key developments reported at the summit.
CRIS-Team Scopus Importer:2024-12-06

CAR T cells in autoimmunity: game changer or stepping stone? - Mougiakakos, Dimitrios; Meyer, Everett H.; Schett, Georg (Blood, 2025)
The advent of chimeric antigen receptor (CAR) T cells has revolutionized the treatment landscape for hematologic malignancies, and emerging evidence suggests their potential in autoimmune diseases (AIDs). This article evaluates the early successes and future implications of B-cell–targeting CAR T-cell therapy in AIDs. Initial applications, particularly in refractory systemic lupus erythematosus, have demonstrated significant and durable clinical remissions, with accompanying evaluation of the immune system suggesting a so-called “reset” of innate inflammation and adaptive autoimmunity. This has generated widespread interest in expanding this therapeutic approach. CAR T cells offer unique advantages over other treatment modalities, including very deep B-cell depletion and unique therapeutic activity within inflamed tissues and associated lymphoid structures. However, the field must address key concerns, including long-term toxicity, particularly the risk of secondary malignancies, and future accessibility given the higher prevalence of AIDs compared with malignancies. Technological advances in cell therapy, such as next-generation CAR T cells, allogeneic off-the-shelf products, and alternative cell types, such as regulatory CAR T cells, are being explored in AIDs to improve efficacy and safety. In addition, bispecific antibodies are emerging as potential alternatives or complements to CAR T cells, potentially offering comparable efficacy without the need for complex logistics, lymphodepletion, and the risk of insertional mutagenesis. As the field evolves, cellular therapists will play a critical role in the multidisciplinary teams managing these complex cases. The transformative potential of CAR T cells in AIDs is undeniable, but careful consideration of safety, efficacy, and implementation is essential as this novel therapeutic approach moves forward.
CRIS-Team Scopus Importer:2025-01-31

CAR T-cell therapy in autoimmune diseases - Schett, Georg; Mackensen, Andreas; Mougiakakos, Dimitrios (Lancet, 2023)
Despite the tremendous progress in the clinical management of autoimmune diseases, many patients do not respond to the currently used treatments. Autoreactive B cells play a key role in the pathogenesis of autoimmune diseases, such as systemic lupus erythematosus, rheumatoid arthritis, and multiple sclerosis. B-cell-depleting monoclonal antibodies, such as rituximab, have poor therapeutic efficacy in autoimmune diseases, mainly due to the persistence of autoreactive B cells in lymphatic organs and inflamed tissues. The adoptive transfer of T cells engineered to target tumour cells via chimeric antigen receptors (CARs) has emerged as an effective treatment modality in B-cell malignancies. In the last 2 years treatment with autologous CAR T cells directed against the CD19 antigen has been introduced in therapy of autoimmune disease. CD19 CAR T cells induced a rapid and sustained depletion of circulating B cells, as well as in a complete clinical and serological remission of refractory systemic lupus erythematosus and dermatomyositis. In this paper, we discuss the evolving strategies for targeting autoreactive B cells via CAR T cells, which might be used for targeted therapy in autoimmune diseases.
CRIS-Team Scopus Importer:2023-10-13

CAR T-cell therapy rescues adolescent with rapidly progressive lupus nephritis from haemodialysis - Krickau, Tobias; Naumann-Bartsch, Nora; Aigner, Michael; Kharboutli, Soraya; Kretschmann, Sascha; Spörl, Silvia; Vasova, Ingrid; Völkl, Simon; Wölfle, Joachim; Mackensen, Andreas; Schett, Georg; Metzler, Markus; et al. (Lancet, 2024)
CRIS-Team Scopus Importer:2024-05-03

CAR T Cell Treatment of Refractory Systemic Lupus Erythematosus - Schett, Georg; Böltz, Sebastian; Müller, Fabian; Kleyer, Arnd; Völkl, Simon; Aigner, Michael; Gary, Regina; Kretschmann, Sascha; Simon, David; Kharboutli, Soraya; Mougiakakos, Dimitrios; Krönke, Gerhard; et al. (ARTHRITIS & RHEUMATOLOGY, 2022)
CRIS-Team WoS Importer:2023-01-13

CAR-T CELL TREATMENT OF REFRACTORY SYSTEMIC LUPUS ERYTHEMATOSUS- SAFETY AND PRELIMINARY EFFICACY DATA FROM THE FIRST FOUR PATIENTS - Schett, Georg; Böltz, Sebastian; Müller, Fabian; Kleyer, Arnd; Völkl, Simon; Aigner, Michael; Gary, Regina; Kretschmann, S.; Simon, David; Kharboutli, Soraya; Mougiakakos, D.; Krönke, Gerhard; et al. (ANNALS OF THE RHEUMATIC DISEASES, 2022)
CRIS-Team WoS Importer:2022-11-04

CARTILAGE DAMAGE QUANTITATIVELY ASSESSED BY MRI USING T2 MAPPING IN CCP-POSITIVE RA PATIENTS - Renner, Nina; Kleyer, Arnd; Krönke, Gerhard; Simon, David; Rech, Jürgen; Schett, Georg; Welsch, G.; Pachowsky, Milena (2018)
EVALuna2:35002

CARTILAGE LESIONS OF THE KNEE: GAGCEST IMAGING AT 3 T MRI AND INTRAOPERATIVE VALIDATION - Pachowsky, Milena; Söllner, Stefan; Kleyer, Arnd; Welsch, G.; Schett, Georg (ANNALS OF THE RHEUMATIC DISEASES, 2021)
CRIS-Team WoS Importer:2021-10-01

CAR-T-Zell-Therapie in der Rheumatologie – Was wissen wir bisher? - Hagen, Melanie; Wirsching, Andreas; Bohr, Daniela; Taubmann, Jule; Müller, Fabian; Mackensen, Andreas; Grieshaber Bouyer, Ricardo; Schett, Georg (Zeitschrift für Rheumatologie, 2024)
Autoreactive B‑cells play a key role in the pathogenesis of autoimmune diseases, such systemic lupus erythematosus (SLE). An efficient depletion of B‑cells therefore plays a special role in autoimmune diseases, especially in cases with a severe course of the disease. Treatment with chimeric antigen receptor (CAR) T‑cells, which was originally developed for the treatment of B‑cell lymphomas and leukemias, provides the possibility to deplete B‑cells even in deep tissues. The initial results from case series with this procedure for SLE, myositis and systemic sclerosis were very positive. This review article gives an overview of the course, mechanism of action, results so far and the research agenda of CAR T‑cell therapy in autoimmune diseases.
CRIS-Team Scopus Importer:2024-06-07
Keywords: Autoimmune diseases; B-cell depletion; Collagenosis; Immunecell therapy; Systemic Lupus erythematodes

Case report: Bullous pemphigoid in HIV-1-positive patients: interplay or coincidence? A case series and review of the literature - Foerster, Yannick; Sollfrank, Lukas; Rechtien, Laura; Harrer, Thomas; Berking, Carola; Sticherling, Michael (Frontiers in Immunology, 2023)
Bullous pemphigoid (BP) is an autoimmune inflammatory skin disease, mostly affecting the elderly population. Therefore, patients often have multiple comorbidities, but there is inconsistent data regarding the relationship between HIV-1 infection and BP, which has been rarely reported in combination. Herein, we describe three patients who presented with BP and concomitant HIV-1 infection that was well controlled with modern combined antiretroviral therapy. All patients received topical and oral corticosteroids. Depending on the individual severity, further add-on therapeutics, such as azathioprine, dapsone, doxycycline and the interleukin 4/13 antibody dupilumab, were added to the therapy regimen. All patients recovered from pruritic skin lesions and blistering. The cases are further discussed in the context of the current study landscape. In conclusion, HIV-1 infection shifts the cytokine profile from T-helper type 1 (TH1) towards T-helper type 2 (TH2), resulting in the excessive secretion of distinct cytokines, such as interleukin 4 (IL-4) and interleukin 10 (IL-10). With IL-4 being a main driver in the pathogenesis of BP, HIV-1-positive patients may benefit greatly from targeting IL-4 with monoclonal antibodies.
CRIS-Team Scopus Importer:2023-07-07
Keywords: aids; bullous pemphigoid; COVID-19; dupilumab; HIV-1; immune reconstitution inflammatory syndrome; iris

Case Report: Neutralization of Autoantibodies Targeting G-Protein-Coupled Receptors Improves Capillary Impairment and Fatigue Symptoms After COVID-19 Infection - Hohberger, Bettina; Harrer, Thomas; Mardin, Christian; Kruse, Friedrich; Hoffmanns, Jakob; Rogge, Lennart; Heltmann, Felix; Moritz, Michael; Szewczykowski, Charlotte; Schottenhamml, Julia; Kräter, Martin; Bergua, Antonio; et al. (Frontiers in Medicine, 2021)
Clinical features of Coronavirus disease 2019 (COVID-19) are caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). Acute infection management is a substantial healthcare issue, and the development of long-Covid syndrome (LCS) is extremely challenging for patients and physicians. It is associated with a variety of characteristics as impaired capillary microcirculation, chronic fatigue syndrome (CFS), proinflammatory cytokines, and functional autoantibodies targeting G-protein-coupled receptors (GPCR-AAbs). Here, we present a case report of successful healing of LCS with BC 007 (Berlin Cures, Berlin, Germany), a DNA aptamer drug with a high affinity to GPCR-AAbs that neutralizes these AAbs. A patient with a documented history of glaucoma, recovered from mild COVID-19, but still suffered from CFS, loss of taste, and impaired capillary microcirculation in the macula and peripapillary region. He was positively tested for various targeting GPCR-AAbs. Within 48 h after a single BC 007 treatment, GPCR-AAbs were functionally inactivated and remained inactive during the observation period of 4 weeks. This observation was accompanied by constant improvement of the fatigue symptoms of the patient, taste, and retinal capillary microcirculation. Therefore, the removal of GPCR-AAb might ameliorate the characteristics of the LCD, such as capillary impairment, loss of taste, and CFS.
CRIS-Team Scopus Importer:2021-12-17
Keywords: BC 007; chronic fatigue syndrome; COVID-19; functional GPCR autoantibodies; glaucoma; long-COVID syndrome; OCT angiography

Case report of severe constrictive perimyocarditis and ischemic hepatitis in a Crohn’s disease patient upon infliximab-induced lupus-like syndrome - Hirschmann, Simon; Fischer, Sarah; Klenske, Entcho; Dechant, Katharina; Distler, Jörg; Treutlein, Christoph; Neurath, Markus; Atreya, Raja (Therapeutic Advances in Gastroenterology, 2021)
Anti-tumor necrosis factor (TNF) antibodies have become an indispensable part in the therapeutic landscape of treating inflammatory bowel disease (IBD) patients. Nevertheless, they can be associated with the occurrence of severe systemic side effects. Here, we report the case of a 23-year-old patient with ileocolonic Crohn’s disease in endoscopic remission under ongoing anti-TNF infliximab therapy with occurrence of novel generalized arthralgia, pleuritic chest pain, and dyspnea. Clinical, laboratory, and imaging diagnostic workup in an extended clinical routine setting at the University Hospital of Erlangen, Germany, was used by a multidisciplinary team consisting of gastroenterologists, radiologists, cardiologists, and rheumatologists to investigate the underlying cause of the clinical symptoms in the patient. The results received using the aforementioned diagnostic setup led to the diagnosis of severe constrictive perimyocarditis due to infliximab-induced lupus-like syndrome with distinct ANA reactivity and elevated anti-dsDNA levels. Furthermore, pronounced ischemic hepatitis was diagnosed. Infliximab treatment was immediately stopped, and initiated corticosteroid pulse therapy only led to partial response as it had to be reduced due to pronounced psychiatric side effects. Persistent signs of pericarditis required additional ibuprofen therapy, which led to subsequent resolution of cardial symptoms. Formerly elevated liver enzymes returned to normal, and there were no clinical signs of recurrence of Crohn’s disease activity over 18 months of follow-up. The patient was subsequently switched to ustekinumab therapy for further treatment of underlying Crohn’s disease. This case report describes for the first time severe infliximab-induced lupus-like syndrome in an IBD patient, concurrently mimicking ST-elevation myocardial infarction with MRI visualization of pericarditis, occurrence of ischemic hepatitis, and pronounced signs of systemic inflammation.
CRIS-Team Scopus Importer:2021-10-15
Keywords: anti-TNF antibody; case report; Crohn’s disease; infliximab; lupus-like syndrome

Caspase-8 promotes scramblase-mediated phosphatidylserine exposure and fusion of osteoclast precursors - Krishnacoumar, Brenda; Stenzel, Martin; Garibagaoglu, Hilal; Omata, Yasunori; Sworn, Rachel L.; Hofmann, Thea; Ipseiz, Natacha; Czubala, Magdalena A.; Steffen, Ulrike; Maccataio, Antonio; Stoll, Cornelia; Böhm, Christina; et al. (Bone Research, 2024)
Efficient cellular fusion of mononuclear precursors is the prerequisite for the generation of fully functional multinucleated bone-resorbing osteoclasts. However, the exact molecular factors and mechanisms controlling osteoclast fusion remain incompletely understood. Here we identify RANKL-mediated activation of caspase-8 as early key event during osteoclast fusion. Single cell RNA sequencing-based analyses suggested that activation of parts of the apoptotic machinery accompanied the differentiation of osteoclast precursors into mature multinucleated osteoclasts. A subsequent characterization of osteoclast precursors confirmed that RANKL-mediated activation of caspase-8 promoted the non-apoptotic cleavage and activation of downstream effector caspases that translocated to the plasma membrane where they triggered activation of the phospholipid scramblase Xkr8. Xkr8-mediated exposure of phosphatidylserine, in turn, aided cellular fusion of osteoclast precursors and thereby allowed generation of functional multinucleated osteoclast syncytia and initiation of bone resorption. Pharmacological blockage or genetic deletion of caspase-8 accordingly interfered with fusion of osteoclasts and bone resorption resulting in increased bone mass in mice carrying a conditional deletion of caspase-8 in mononuclear osteoclast precursors. These data identify a novel pathway controlling osteoclast biology and bone turnover with the potential to serve as target for therapeutic intervention during diseases characterized by pathologic osteoclast-mediated bone loss. (Figure presented.)
CRIS-Team Scopus Importer:2024-07-19

Castleman’s disease in the rheumatological practice - 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, 2024)
CRIS-Team Scopus Importer:2024-12-06

Catabolic and anabolic periarticular bone changes in patients with rheumatoid arthritis: A computed tomography study on the role of age, disease duration and bone markers - Aschenberg, Sophie; Finzel, Stephanie; Schmidt, Sarah; Kraus, Sebastian; Engelke, Klaus; Englbrecht, Matthias; Rech, Jürgen; Schett, Georg (Arthritis Research & Therapy, 2013)
Introduction: The aim of this study was to determine the factors, including markers of bone resorption and bone formation, which determine catabolic and anabolic periarticular bone changes in patients with rheumatoid arthritis (RA).Methods: Forty RA patients received high-resolution peripheral quantitative computed tomography (HR-pQCT) analysis of the metacarpophalangeal joints II and III of the dominantly affected hand at two sequential time points (baseline, one year follow-up). Erosion counts and scores as well as osteophyte counts and scores were recorded. Simultaneously, serum markers of bone resorption (C-terminal telopeptide of type I collagen (CTX I), tartrate-resistant acid phosphatase 5b (TRAP5b)), bone formation (bone alkaline phosphatase (BAP), osteocalcin (OC)) and calcium homeostasis (parathyroid hormone (PTH), 25-hydroxyvitamin D3 (Vit D)) were assessed. Bone biomarkers were correlated to imaging data by partial correlation adjusting for various demographic and disease-specific parameters. Additionally, imaging data were analyzed by mixed linear model regression.Results: Partial correlation analysis showed that TRAP5b levels correlate significantly with bone erosions, whereas BAP levels correlate with osteophytes at both time points. In the mixed linear model with erosions as the dependent variable, disease duration (P <0.001) was the key determinant for these catabolic bone changes. In contrast, BAP (P = 0.001) as well as age (P = 0.018), but not disease duration (P = 0.762), were the main determinants for the anabolic changes (osteophytes) of the periarticular bone in patients with RA.Conclusions: This study shows that structural bone changes assessed with HR-pQCT are accompanied by alterations in systemic markers of bone resorption and bone formation. Besides, it can be shown that bone erosions in RA patients depend on disease duration, whereas osteophytes are associated with age as well as serum level of BAP. Therefore, these data not only suggest that different variables are involved in formation of bone erosions and osteophytes in RA patients, but also that periarticular bone changes correlate with alterations in systemic markers of bone metabolism, pointing out BAP as an important parameter. © 2013 Aschenberg et al.; licensee BioMed Central Ltd.
CRIS-Team Scopus Importer:2021-02-03
Keywords: Bone biomarkers; Bone formation; Bone resorption; Computed tomography; Rheumatoid arthritis

Cavity Segmentation in X-ray Microscopy Scans of Mouse Tibiae - Gu, Mingxuan; Thies, Mareike; Wagner, Fabian; Pechmann, Sabrina; Aust, Oliver; Weidner, Daniela; Neag, Georgiana; Pan, Zhaoya; Utz, Jonas; Schett, Georg; Christiansen, Silke; Uderhardt, Stefan; et al. (Informatik aktuell, 2023)
Osteoporosis is a chronic disease that causes lower bone density and makes bones fragile. This severely impairs patient life qualities and increases the burden on the social and health care system. X-ray microscopy (XRM) allows tracking of osteoporosis-related changes at a microstructural level in the bone, entailing the characterization of osteocyte lacunae and blood vessel canals. Unfortunately, no segmentation methods for micro-structures in XRM images have yet been established. In this work, we compare the performance of a traditional thresholding-based method with three deep learning networks including 2D and 3D models in both binary and multi-class segmentation. We further propose a clustering method to automatically distinguish blood vessels from lacunae for the binary methods. The performance is evaluated with Dice score (F1 score). The thresholding-based method reaches a mean Dice score of 0.729, which the deep learning models improve by 0.129 - 0.168.
CRIS-Team Scopus Importer:2023-11-03

CCL19‐positive lymph node stromal cells govern the onset of inflammatory arthritis via tropomyosin receptor kinase - Schälter, Fabian; Azizov, Vugar; Frech, Michael; Dürholz, Kerstin; Schmid, Eva; Hendel, Anna; Sarfati, Ilann; Maeda, Yuichi; Sokolova, Maria; Miyagawa, Ippei; Focke, Kristin; Sarter-Zaiss, Kerstin; et al. (Arthritis and Rheumatology, 2024)
Objectives To assess the role of CCL19+ lymph node stromal cells of the joint draining popliteal lymph node (pLN) for the development of arthritis. Methods CCL19+ lymph node stromal cells were spatiotemporally depleted for 5 days in the pLN before the onset of collagen-induced arthritis (CIA) using Ccl19-Cre x iDTR mice. In addition, therapeutic treatment with recombinant CCL19-IgG, locally injected in the footpad, was used to confirm the results. RNA sequencing of lymph node stromal cells combined with T cell co-culture assays using tropomyosin receptor kinase (Trk) family inhibitors together with in vivo local pLN siRNA treatments were used to elucidate the pathway by which CCL19+ lymph node stromal cells initiate the onset of arthritis. Results Spatiotemporal depletion of CCL19+ lymph node stromal cells prevented disease onset in CIA mice. These inhibitory effects could be mimicked by local CCL19-IgG treatment. The mRNA sequencing analyses showed that CCL19+ lymph node stromal cells downregulated the expression of the tropomyosin receptor kinase A (TrkA) just before disease onset. Blocking TrkA in lymph node stromal cells led to increased T cell proliferation in in vitro co-culture assays. Similar effects were observed with the pan-Trk inhibitor Larotrectinib in co-cultures of lymph node stromal cells of rheumatoid arthritis patients and T cells. Finally, local pLN treatment with TrkA inhibitor and TrkA siRNA led to exacerbated arthritis scores. Conclusions CCL19+ lymph node stromal cells are crucially involved in the development of inflammatory arthritis. Therefore, targeting of CCL19+ lymph node stromal cells via TRK kinases could provide a tool to prevent arthriti

CD11C+DENDTRITIC CELLS IN INFLAMMATORY ARTHRITIS - Puchner, A.; Saferding, V.; Bonelli, M.; Leiss, H.; Pfeifle, René; Krönke, Gerhard; Smolen, J.; Redlich, K.; Blueml, S. (2018)
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CD19 CAR T-Cell Therapy in Autoimmune Disease - A Case Series with Follow-up. - Müller, Fabian; Taubmann, Jule; Bucci, Laura; Wilhelm, Artur; Bergmann, Christina; Völkl, Simon; Aigner, Michael; Rothe, Tobias; Minopoulou, Ioanna; Tur, Carlo; Knitza, Johannes; Kharboutli, Soraya; et al. (New England Journal of Medicine, 2024)
BACKGROUND: Treatment for autoimmune diseases such as systemic lupus erythematosus (SLE), idiopathic inflammatory myositis, and systemic sclerosis often involves long-term immune suppression. Resetting aberrant autoimmunity in these diseases through deep depletion of B cells is a potential strategy for achieving sustained drug-free remission. METHODS: We evaluated 15 patients with severe SLE (8 patients), idiopathic inflammatory myositis (3 patients), or systemic sclerosis (4 patients) who received a single infusion of CD19 chimeric antigen receptor (CAR) T cells after preconditioning with fludarabine and cyclophosphamide. Efficacy up to 2 years after CAR T-cell infusion was assessed by means of Definition of Remission in SLE (DORIS) remission criteria, American College of Rheumatology-European League against Rheumatism (ACR-EULAR) major clinical response, and the score on the European Scleroderma Trials and Research Group (EUSTAR) activity index (with higher scores indicating greater disease activity), among others. Safety variables, including cytokine release syndrome and infections, were recorded. RESULTS: The median follow-up was 15 months (range, 4 to 29). The mean (±SD) duration of B-cell aplasia was 112±47 days. All the patients with SLE had DORIS remission, all the patients with idiopathic inflammatory myositis had an ACR-EULAR major clinical response, and all the patients with systemic sclerosis had a decrease in the score on the EUSTAR activity index. Immunosuppressive therapy was completely stopped in all the patients. Grade 1 cytokine release syndrome occurred in 10 patients. One patient each had grade 2 cytokine release syndrome, grade 1 immune effector cell-associated neurotoxicity syndrome, and pneumonia that resulted in hospitalization. CONCLUSIONS: In this case series, CD19 CAR T-cell transfer appeared to be feasible, safe, and efficacious in three different autoimmune diseases, providing rationale for further controlled clinical trials. (Funded by Deutsche Forschungsgemeinschaft and others.).
EVALuna2:555903

CD19-CAR T-cell therapy induces deep tissue depletion of B cells - Tur, Carlo; Eckstein, Markus; Velden, Joachim; Rauber, Simon; Bergmann, Christina; Auth, Janina; Bucci, Laura; Corte, Giulia; Hagen, Melanie; Wirsching, Andreas; Grieshaber Bouyer, Ricardo; Reis, Petra; et al. (Annals of the Rheumatic Diseases, 2024)
Objectives CD19-targeting chimeric antigen receptor (CAR) T-cell therapy can induce long-term drug-free remission in patients with autoimmune diseases (AIDs). The efficacy of CD19-CAR T-cell therapy is presumably based on deep tissue depletion of B cells; however, such effect has not been proven in humans in vivo. Methods Sequential ultrasound-guided inguinal lymph node biopsies were performed at baseline and after CD19-CAR T-cell therapy in patients with AIDs. Results were compared with lymph node biopsies from rituximab (RTX)-treated AID patients with absence of peripheral B cells. Conventional and immunohistochemistry staining were performed on lymph node tissue to assess architecture as well the number of B cells, follicular dendritic cells (FDCs), plasma cells, T cells and macrophages. Results Sequential lymph node biopsies were analysed from five patients with AID before and after CD19-CAR T-cell therapy and from five patients with AID after RTX treatment. In addition, non-lymphoid organ biopsies (colon, kidney and gallbladder) from three additional patients with AID after CD19-CAR T-cell therapy were analysed. CD19+ and CD20+ B cells were completely depleted in the lymph nodes after CD19-CAR T-cell therapy, but not after RTX treatment. Plasma cells, T cells and macrophages in the lymph nodes remained unchanged. Follicular structures were disrupted and FDCs were depleted in the lymph nodes after CD19-CAR T-cell therapy, but not after RTX. Non-lymphoid organs were completely depleted of B cells. Discussion This study demonstrates complete B-cell depletion in secondary lymphoid tissues of patients with AIDs following CD19-CAR T-cell therapy combined with standard lymphodepleting therapy.
CRIS-Team Scopus Importer:2024-09-27
Keywords: Autoimmune Diseases; B-Lymphocytes; Rituximab; Ultrasonography

CD19 Chimeric Antigen Receptor T Cell Treatment: Unraveling the Role of B Cells in Systemic Lupus Erythematosus. - Taubmann, Jule; Müller, Fabian; Mutlu, Melek Yalcin; Völkl, Simon; Aigner, Michael; Bozec, Aline; Mackensen, Andreas; Grieshaber Bouyer, Ricardo; Schett, Georg (Arthritis and Rheumatology, 2024)
B cell generation of autoantibodies is a crucial step in the pathogenesis of systemic lupus erythematosus (SLE). After their differentiation in the bone marrow, B cells populate the secondary lymphatic organs, where they undergo further maturation leading to the development of memory B cells as well as antibody-producing plasmablasts and plasma cells. Targeting B cells is an important strategy to treat autoimmune diseases such as SLE, in which B cell tolerance is disturbed and autoimmune B cells and autoantibodies emerge. This review discusses the functional aspects of antibody- and cell-based B cell-depleting therapy in SLE. It thereby particularly focuses on lessons learned from chimeric antigen receptor (CAR) T cell treatment on the role of B cells in SLE for understanding B cell pathology in SLE. CAR T cells model a deep B cell depletion and thereby allow understanding the role of aberrant B cell activation in the pathogenesis of SLE. Furthermore, the effects of B cell depletion on autoantibody production can be better described, ie, explaining the concept of different cellular sources of (auto-) antibodies in the form of short-lived plasmablasts and long-lived plasma cells, which differ in their susceptibility to B cell depletion and require different targeted therapeutic approaches. Finally, the safety of deep B cell depletion in autoimmune disease is discussed.
EVALuna2:551941

CD19-targeted CAR T cells in refractory antisynthetase syndrome - Müller, Fabian; Böltz, Sebastian; Knitza, Johannes; Aigner, Michael; Völkl, Simon; Kharboutli, Soraya; Reimann, Hannah; Taubmann, Jule; Kretschmann, Sascha; Rösler, Wolf; Manger, Bernhard; Wacker, Jochen; et al. (Lancet, 2023)
CRIS-Team Scopus Importer:2023-03-24

CD19-targeted CAR T cells in refractory systemic lupus erythematosus - Mougiakakos, Dimitrios; Krönke, Gerhard; Völkl, Simon; Kretschmann, Sascha; Aigner, Michael; Kharboutli, Soraya; Böltz, Sebastian; Manger, Bernhard; Mackensen, Andreas; Schett, Georg (New England Journal of Medicine, 2021)
CRIS-Team Scopus Importer:2021-08-20

CD19-Targeted CAR-T Cells in Refractory Systemic Lupus Erythematosus: Safety, Efficacy, and Mechanistic Insights from the First Five Patients - Müller, Fabian; Völkl, Simon; Mougiakakos, Dimitrios; Böltz, Sebastian; Aigner, Michael; Gary, Regina; Kretschmann, Sascha; Kharboutli, Soraya; Kleyer, Arnd; Simon, David; Rösler, Wolf; Habenicht, Katharina Marie; et al. (BLOOD, 2022)
CRIS-Team WoS Importer:2023-03-10

CD19-targeting CAR T-cell therapy in patients with diffuse systemic sclerosis: a case series - Auth, Janina; Müller, Fabian; Völkl, Simon; Bayerl, Nadine; Distler, Jörg H.W.; Tur, Carlo; Raimondo, Maria Gabriella; Chenguiti Fakhouri, Sara; Atzinger, Armin; Coppers, Birte; Eckstein, Markus; Liphardt, Anna-Maria; et al. (The Lancet Rheumatology, 2024)
Background: CD19-targeting chimeric antigen receptor (CAR) T-cell therapy has shown remarkable outcomes in patients with systemic lupus erythematosus. The effects of CD19-targeting CAR T cells on organ manifestations in patients with systemic sclerosis have yet to be characterised. B cells have a central role in the pathogenesis of systemic sclerosis. We present a detailed analysis of the effects of CD19-targeting CAR T-cell therapy in patients with systemic sclerosis. Methods: Six patients with severe diffuse systemic sclerosis with an insufficient response to at least two treatments were consecutively recruited at the Department of Internal Medicine 3, University Hospital Erlangen (Erlangen, Germany) to receive CD19-targeting CAR T-cell treatment (1 × 106 CAR T cells per kg bodyweight). Events were predefined by progression of interstitial lung disease, onset of congestive heart failure, onset of renal failure, onset of arterial hypertension, or initiation of new immunosuppressive or antifibrotic therapy. Event-free time or treatment intensification after study entry was the primary outcome. Key secondary outcomes included changes in the modified Rodnan Skin Score (mRSS), imaging (a component of the assessment of lung fibrosis), laboratory assessments, patient-reported outcomes, and a modified version of the American College of Rheumatology Composite Response Index in Systemic Sclerosis (ACR-CRISS), assessed at baseline, 3 months, 6 months, 9 months, and 12 months. Findings: Between April 20, 2022, and Nov 8, 2023, six patients with severe diffuse systemic sclerosis (median age 42 years [IQR 36–53]; four men and two women; all White European) were recruited and received CD19-targeted CAR T-cell therapy. The median follow-up time was 487 days (IQR 342–585). No events occurred within the observational period. Probability of improvement in the ACR-CRISS score increased to a median of 100% (IQR 100–100) at 6 months. Median mRSS decreased by 31% (IQR 29–38), corresponding to a median of 8 points (IQR 7–13) within 100 days. The extent of disease on CT scan decreased by a median of 4% (IQR 3–4) due to reduction of ground-glass opacities while the reticular pattern remained stable. Forced vital capacity improved by a median of 195 mL (IQR 18–275) at the latest observational timepoint. Interpretation: We provide the first evidence that CD19-targeting CAR T-cell therapy might intercept with the progression of fibrotic organ manifestations in patients with systemic sclerosis. Funding: Deutsche Forschungsgemeinschaft, Deutsche Krebshilfe, ELAN-Foundation Erlangen, IZKF Erlangen, and Bundesministerium für Bildung und Forschung.
CRIS-Team Scopus Importer:2024-12-13

CD200+ fibroblasts form a pro-resolving mesenchymal network in arthritis - Rauber, Simon; Mohammadian, Hashem; Schmidkonz, Christian; Atzinger, Armin; Soare, Alina; Treutlein, Christoph; Kemble, Samuel; Mahony, Christopher B.; Geisthoff, Manuel; Angeli, Mario Raphael; Raimondo, Maria Gabriella; Xu, Cong; et al. (Nature Immunology, 2024)
Fibroblasts are important regulators of inflammation, but whether fibroblasts change phenotype during resolution of inflammation is not clear. Here we use positron emission tomography to detect fibroblast activation protein (FAP) as a means to visualize fibroblast activation in vivo during inflammation in humans. While tracer accumulation is high in active arthritis, it decreases after tumor necrosis factor and interleukin-17A inhibition. Biopsy-based single-cell RNA-sequencing analyses in experimental arthritis show that FAP signal reduction reflects a phenotypic switch from pro-inflammatory MMP3+/IL6+ fibroblasts (high FAP internalization) to pro-resolving CD200+DKK3+ fibroblasts (low FAP internalization). Spatial transcriptomics of human joints indicates that pro-resolving niches of CD200+DKK3+ fibroblasts cluster with type 2 innate lymphoid cells, whereas MMP3+/IL6+ fibroblasts colocalize with inflammatory immune cells. CD200+DKK3+ fibroblasts stabilized the type 2 innate lymphoid cell phenotype and induced resolution of arthritis via CD200–CD200R1 signaling. Taken together, these data suggest a dynamic molecular regulation of the mesenchymal compartment during resolution of inflammation.
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Cellular and humoral immune responses to SARS-CoV-2 vaccination in patients after CD19.CAR T-cell therapy - Reimann, Hannah; Kremer, Anita; Blumenberg, Viktoria; Schmidt, Katja; Aigner, Michael; Jacobs, Benedikt; Eisenhauer, Nina; Kämpf, Alina; Rösler, Wolf; Kharboutli, Soraya; Mougiakakos, Dimitrios; Lang, Vanessa; et al. (Blood Advances, 2023)
EVALuna2:512817

Cellular and molecular mechanisms in fibrosis - Dees, Clara; Chakraborty, Debomita; Distler, Jörg (Experimental Dermatology, 2020)
The activation of fibroblasts is required for physiological tissue remodelling such as wound healing. However, when the regulatory mechanisms are disrupted and fibroblasts remain persistently activated, the progressive deposition of extracellular matrix proteins leads to tissue fibrosis, which results in dysfunction or even loss of function of the affected organ. Although fibrosis has been recognized as a major cause of morbidity and mortality in modern societies, there are only few treatment options available that directly disrupt the release of extracellular matrix from fibroblasts. Intensive research in recent years, however, identified several pathways as core fibrotic mechanisms that are shared across different fibrotic diseases and organs. We discuss herein selection of those core pathways, especially downstream of the profibrotic TGF-β pathway, which are druggable and which may be transferable from bench to bedside.
CRIS-Team Scopus Importer:2020-10-23
Keywords: extracellular matrix; fibroblasts; fibrosis; systemic sclerosis

Cellular and molecular pathways of structural damage in rheumatoid arthritis - Harre, Ulrike; Schett, Georg (Seminars in Immunopathology, 2017)
Structural damage of cartilage and bone tissue is a hallmark of rheumatoid arthritis (RA). The resulting joint destruction constitutes one of the major disease consequences for patients and creates a significant burden for the society. The main cells executing bone and cartilage degradation are osteoclasts and fibroblast-like synoviocytes, respectively. The function of both cell types is heavily influenced by the immune system. In the last decades, research has identified several mediators of structural damage, ranging from infiltrating immune cells and inflammatory cytokines to autoantibodies. These factors result in an inflammatory milieu in the affected joints which leads to an increased development and function of osteoclasts and the transformation of fibroblast-like synoviocytes towards a highly migratory and destructive phenotype. In addition, repair mechanisms mediated by osteoblasts and chondrocytes are strongly impaired by the presence of pro-inflammatory cytokines. This article will review the current knowledge on the mechanisms of joint inflammation and the destruction of bone and cartilag
EVALuna2:13301

Cellular plasticity and myeloid inflammation in the adult brain are independent of the transcriptional modulator DREAM - Masanetz, Rebecca Katharina; Baum, Wolfgang; Schett, Georg; Winkler, Jürgen; Süß, Patrick (Neuroscience Letters, 2023)
The downstream regulatory element antagonist modulator (DREAM) modulates ion channel function and gene transcription. Functionally, DREAM is implicated in physiological and pathological processes including cell proliferation, inflammation, and nociception. Despite its multiple functions and robust expression in forebrain tissue, neurons and glial cells, the role of DREAM in regard to cellular plasticity and tumor necrosis factor (TNF)-mediated inflammation is largely unexplored. Here, we demonstrate that adult hippocampal neurogenesis as well as the density and plasticity of glial cells in the hippocampus and thalamus are independent of the presence of DREAM. Further, DREAM deletion does not alter the regional myeloid response and inflammatory gene expression induced by chronic peripheral inflammation in mice overexpressing human TNF. Our data suggest that despite their highly dynamic regulation, neural cell plasticity and adult neurogenesis in the hippocampus do not depend on the multifunctional protein DREAM. Furthermore, TNF-mediated myeloid inflammation in the brain persists in the absence of DREAM.
CRIS-Team Scopus Importer:2023-01-20
Keywords: Adult hippocampal neurogenesis; DREAM; Glia; Neuroinflammation; Pain; Proliferation

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

Changes in mechanical loading affect arthritis-induced bone loss in mice - Liphardt, Anna-Maria; Windahl, Sara H.; Sehic, Edina; Hannemann, Nicole; Gustafsson, Karin L.; Bozec, Aline; Schett, Georg; Engdahl, Cecilia (Bone, 2020)
Arthritis induces bone loss by inflammation-mediated disturbance of bone homeostasis. On the other hand, pain and impaired locomotion are highly prevalent in arthritis and result in reduced general physical activity and less pronounced mechanical loading. Bone is affected by mechanical loading, directly through impact with the ground during movement and indirectly through muscular activity. Mechanical loading in its physiological range is essential for maintaining bone mass, whereas disuse leads to bone loss. The aim of this study was to investigate the impact of mechanical loading on periarticular bone as well as inflammation during arthritis. Mechanical loading was either blocked by botulinum neurotoxin A (Botox) injections before induction of arthritis, or enhanced by cyclic compressive loading, three times per week during arthritis induction. Arthritis was verified and evaluated histologically. Trabecular and cortical bone mass were investigated using micro-computed tomography (μCT), subchondral osteoclastogenesis and bone turnover was assessed by standard methods. Inhibition of mechanical loading enhanced arthritis-induced bone loss while it did not affect inflammation. In contrast, enhanced mechanical loading mitigated arthritis-induced bone loss. Furthermore, the increase in bone resorption markers by arthritis was partly blocked by mechanical loading. In conclusion, enhanced arthritic bone loss after abrogation of mechanical loading suggests that muscle forces play an essential role in preventing arthritic bone loss. In accordance, mechanical loading of the arthritic joints inhibited bone loss, emphasizing that weight bearing activities may have the potential to counteract arthritis-mediated bone loss.
CRIS-Team Scopus Importer:2019-11-29
Keywords: Antigen-induced arthritis; Bone microarchitecture; Mechanical loading; Periarticular bone loss; Unloading

Changes in Serum Cytokines by Week 24 Correlate with Long-Term Efficacy of Guselkumab Through Two Years in Bio-Naive Adults with PsA - Siebert, Stefan; Schett, Georg; Raychaudhuri, Siba P.; Guma, Monica; Chen, Warner; Gao, Sheng; Chakravarty, Soumya; Shawi, May; Rahman, Proton (ARTHRITIS & RHEUMATOLOGY, 2022)
CRIS-Team WoS Importer:2023-01-13

Characterization and quantification of angiogenesis in rheumatoid arthritis in a mouse model using ?CT - Gayetskyy, Svitlana; Museyko, Oleg; Käßer, Johannes; Heß, Andreas; Schett, Georg; Engelke, Klaus (BMC Musculoskeletal Disorders, 2014)
Angiogenesis is an important pathophysiological process of chronic inflammation, especially in inflammatory arthritis. Quantitative measurement of changes in vascularization may improve the diagnosis and monitoring of arthritis. The aim of this work is the development of a 3D imaging and analysis framework for quantification of vascularization in experimental arthritis.High-resolution micro-computed tomography (?CT) was used to scan knee joints of arthritic human tumor necrosis factor transgenic (hTNFtg) mice and non-arthritic wild-type controls previously perfused with lead-containing contrast agent Microfil MV-122. Vessel segmentation was performed by combination of intensity-based (local adaptive thresholding) and form-based (multi-scale method) segmentation techniques. Four anatomically defined concentric spherical shells centered in the knee joint were used as analysis volumes of interest. Vessel density, density distribution as well as vessel thickness, surface, spacing and number were measured. Simulated digital vessel tree models were used for validation of the algorithms.High-resolution ?CT allows the quantitative assessment of the vascular tree in the knee joint during arthritis. Segmentation and analysis were highly automated but occasionally required manual corrections of the vessel segmentation close to the bone surfaces. Vascularization was significantly increased in arthritic hTNFtg mice compared to wild type controls. Precision errors for the morphologic parameters were smaller than 3% and 6% for intra- and interoperator analysis, respectively. Accuracy errors for vessel thickness were around 20% for vessels larger than twice the resolution of the scanner.Arthritis-induced changes of the vascular tree, including detailed and quantitative description of the number of vessel branches, length of vessel segments and the bifurcation angle, can be detected by contrast-enhanced high-resolution ?CT.
EVALuna2:8512

CHARACTERIZATION OF RELAPSES IN PATIENTS WITH GIANT CELL ARTERITIS (GCA) PATIENTS- DATA FROM THE REAL-LIFE TREATMENT AND SAFETY (REATS)-GCA COHORT - Schönau, Verena; Corte, Giulia; Ott, Sabine; Tascilar, Koray; Hartmann, F.; Manger, Bernhard; Hellmich, B.; Pfeil, A.; Oelzner, P.; Schmidt, W. A.; Krause, A.; Schmalzing, M.; et al. (ANNALS OF THE RHEUMATIC DISEASES, 2022)
CRIS-Team WoS Importer:2022-11-04

Characterization of Serum and Mucosal SARS-CoV-2-Antibodies in HIV-1-Infected Subjects after BNT162b2 mRNA Vaccination or SARS-CoV-2 Infection - Schmidt, Katja G.; Harrer, Ellen; Tascilar, Koray; Kuebel, Sabrina; El Kenz, Boutaina; Simon, David; Schett, Georg; Nganou-Makamdop, Krystelle; Harrer, Thomas; Hartmann, Fabian (Viruses, 2022)
Only limited data are available regarding the immunogenicity of the BNT162b2 mRNA vaccine in HIV-1+ patients. Therefore, we investigated the humoral immune response after BNT162b2-mRNA vaccination or SARS-CoV-2 infection in HIV-1+ patients on antiretroviral therapy compared to HIV-1-uninfected subjects. Serum and saliva samples were analysed by SARS-CoV-2 spike-specific IgG and IgA ELISAs and a surrogate neutralization assay. While all subjects developed anti-spike IgG and IgA and neutralizing antibodies in serum after two doses of BNT162b2 mRNA vaccine, the HIV-1+ subjects displayed significantly lower neutralizing capacity and anti-spike IgA in serum compared to HIV-1-uninfected subjects. Serum levels of anti-spike IgG and neutralizing activity were significantly higher in vaccinees compared to SARS-CoV-2 convalescents irrespective of HIV-1 status. Among SARS-CoV-2 convalescents, there was no significant difference in spike-specific antibody response between HIV-1+ and uninfected subjects. In saliva, anti-spike IgG and IgA antibodies were detected both in vaccinees and convalescents, albeit at lower frequencies compared to the serum and only rarely with detectable neutralizing activity. In summary, our study demonstrates that the BNT162b2 mRNA vaccine induces SARS-CoV-2-specific antibodies in HIV-1-infected patients on antiretroviral therapy, however, lower vaccine induced neutralization activity indicates a lower functionality of the humoral vaccine response in HIV-1+ patients.
CRIS-Team Scopus Importer:2022-04-15
Keywords: antibody; HIV-1; humoral immune response; mucosal immunity; SARS-CoV-2

Characterization of Vascular Niche in Systemic Sclerosis by Spatial Proteomics - Rius Rigau, Aleix Rius; Li, Yi Nan; Matei, Alexandru-Emil; Györfi, Andrea Hermina; Bruch, Peter Martin; Koziel, Sarah; Devakumar, Veda; Gabrielli, Armando; Kreuter, Alexander; Wang, Jiucun; Dietrich, Sascha; Schett, Georg; et al. (Circulation Research, 2024)
BACKGROUND: Systemic sclerosis (SSc) is a connective tissue disease that can serve as a model to study vascular changes in response to inflammation, autoimmunity, and fibrotic remodeling. Although microvascular changes are the earliest histopathologic manifestation of SSc, the vascular pathophysiology remains poorly understood. METHODS: We applied spatial proteomic approaches to deconvolute the heterogeneity of vascular cells at the single-cell level in situ and characterize cellular alterations of the vascular niches of patients with SSc. Skin biopsies of patients with SSc and control individuals were analyzed by imaging mass cytometry, yielding a total of 90755 cells including 2987 endothelial cells and 4096 immune cells. RESULTS: We identified 7 different subpopulations of blood vascular endothelial cells (VECs), 2 subpopulations of lymphatic endothelial cells, and 3 subpopulations of pericytes. A novel population of CD34+;αSMA+ (α-smooth muscle actin);CD31+ VECs was more common in SSc, whereas endothelial precursor cells were decreased. Co-detection by indexing and tyramide signal amplification confirmed these findings. The microenvironment of CD34+;αSMA+;CD31+ VECs was enriched for immune cells and myofibroblasts, and CD34+;αSMA+;CD31+ VECs expressed markers of endothelial-to-mesenchymal transition. The density of CD34+;αSMA+;CD31+ VECs was associated with clinical progression of fibrosis in SSc. CONCLUSIONS: Using spatial proteomics, we unraveled the heterogeneity of vascular cells in control individuals and patients with SSc. We identified CD34+;αSMA+;CD31+ VECs as a novel endothelial cell population that is increased in patients with SSc, expresses markers for endothelial-to-mesenchymal transition, and is located in close proximity to immune cells and myofibroblasts. CD34+;αSMA+;CD31+ VEC counts were associated with clinical outcomes of progressive fibrotic remodeling, thus providing a novel cellular correlate for the crosstalk of vasculopathy and fibrosis.
CRIS-Team Scopus Importer:2024-04-12
Keywords: endothelial cells; fibrosis; proteomics; scleroderma; systemic; vascular system injuries

Checkpoint inhibitor-induced eosinophilic fasciitis following high eosinophilia associated with complete response - Toussaint, Frédéric; Hammon, Matthias; Erdmann, Michael; Moreira, Alvaro; Kirchberger, Michael C.; Schuler, Gerold; Schett, Georg; Heinzerling, Lucie (Rheumatology, 2019)
CRIS-Team Scopus Importer:2019-10-01

Checkpoint Inhibitors - Heinzerling, Lucie; De Toni, Enrico N.; Schett, Georg; Hundorfean, Gheorghe; Zimmer, Lisa (Deutsches Ärzteblatt international, 2019)
BACKGROUND: Treatment with checkpoint inhibitors such as anti-programmed death-1 (anti-PD-1), anti-PD-ligand 1 (anti-PD-L1), and anti-cytotoxic T-lymphocyte antigen-4 (anti-CTLA-4) antibodies can prolong the survival of cancer patients, but it also induces autoimmune side effects in 86-96% of patients by activating the immune system. In 17-59% of patients, these are severe or even life-threatening. METHODS: This review is based on pertinent articles retrieved by a search in PubMed and on an evaluation of a side-effect registry. RESULTS: Checkpoint-inhibitor-induced autoimmune side effects manifest themselves in all organ systems, most commonly as skin lesions (46-62%), autoimmune colitis (22-48%), autoimmune hepatitis (7-33%), and endocrinopathies (thyroiditis, hypophysitis, adrenalitis, diabetes mellitus; 12-34%). Rarer side effects include pneumonitis (3-8%), nephritis (1-7%), cardiac side effects including cardiomyositis (5%), and neurological side effects (1-5%). Severe (sometimes lethal) side effects arise in 17-21%, 20-28%, and 59% of patients undergoing anti-PD-1 and anti- CTLA-4 antibody treatment and the approved combination therapy, respectively. With proper monitoring, however, these side effects can be recognized early and, usually, treated with success. Endocrine side effects generally require long-term hormone substitution. Patients who have stopped taking checkpoint inhibitors because of side effects do not show a poorer response of their melanoma or shorter survival in comparison to patients who continue to take checkpoint inhibitors. CONCLUSION: The complex management of checkpoint-inhibitor-induced side effects should be coordinated in experienced centers. The creation of an interdisciplinary "tox team" with designated experts for organ-specific side effects has proven useful. Prospective registry studies based on structured documentation of side effects in routine clinical practice are currently lacking and urgently needed.
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Checkpoint Inhibitors The Diagnosis and Treatment of Side Effects - Heinzerling, Lucie; De Toni, Enrico N.; Schett, Georg; Hundorfean, Gheorghe; Zimmer, Lisa (Deutsches Ärzteblatt international, 2019)
Background: Treatment with checkpoint inhibitors such as anti-programmed death-1 (anti-PD-1), anti-PD-ligand 1 (anti-PD-L1), and anti-cytotoxic T-Iymphocyte antigen-4 (anti-CTLA-4) antibodies can prolong the survival of cancer patients, but it also induces autoimmune side effects in 86-96% of patients by activating the immune system. In 17-59% of patients, these are severe or even life-threatening.
CRIS-Team WoS Importer:2019-04-12

Chondrokalzinose: Idiopathisch oder Manifestation seltener metabolischer Erkrankungen? - Knitza, Johannes; Kleyer, Arnd; Schett, Georg; Manger, Bernhard (Orthopäde, 2019)
Calcification in hyaline and fibrocartilage is caused by the deposition of calcium pyrophosphate dehydrate, commonly referred to as chondrocalcinosis. Clinically, this can lead to arthritis symptoms similar to a gout attack –“pseudogout”. Nonetheless, also chronic or asymptomatic disease courses are possible. The prevalence of chondrocalcinosis increases with age. The diagnostic workup of degenerative joint disease, therefore, often reveals calcifications of articular cartilage as harmless incidental findings. However, particularly in patients younger than 60 years of age, chondrocalcinosis can be the symptom of an underlying metabolic disease. This review article highlights these rare diseases and presents unusual manifestations of chondrocalcinosis.
CRIS-Team Scopus Importer:2019-10-29
Keywords: Calcification; physiologic; Calcium pyrophosphate deposition disease; Cartilage; articular; Epidemiology; Osteoarthritis

Chromosomal radiosensitivity in oncological and non-oncological patients with rheumatoid arthritis and connective tissue diseases - Rzepka, Dinah; Schenker, Hannah; Geinitz, Hans; Silberberger, Elisabeth; Kaudewitz, Dorothee; Schuster, Barbara; Kuhlmann, Lukas; Schonath, Miriam; Ayala Gaona, Horacio; Aschacher, Bernhard; Fietkau, Rainer; Schett, Georg; et al. (Radiation Oncology, 2023)
Background: The risk of developing late radiotoxicity after radiotherapy in patients with high chromosomal radiosensitivity after radiotherapy could potentially be higher compared to the risk in patients with average radiosensitivity. In case of extremely high radiosensitivity, dose reduction may be appropriate. Some rheumatic diseases (RhD), including connective tissue diseases (CTDs) appear to be associated with higher radiosensitivity. The question arises as to whether patients with rheumatoid arthritis (RA) also generally have a higher radiosensitivity and whether certain parameters could indicate clues to high radiosensitivity in RA patients which would then need to be further assessed before radiotherapy. Methods: Radiosensitivity was determined in 136 oncological patients with RhD, 44 of whom were RA patients, and additionally in 34 non-oncological RA patients by three-colour fluorescence in situ hybridization (FiSH), in which lymphocyte chromosomes isolated from peripheral blood are analysed for their chromosomal aberrations of an unirradiated and an with 2 Gy irradiated blood sample. The chromosomal radiosensitivity was determined by the average number of breaks per metaphase. In addition, correlations between certain RA- or RhD-relevant disease parameters or clinical features such as the disease activity score 28 and radiosensitivity were assessed. Results: Some oncological patients with RhD, especially those with connective tissue diseases have significantly higher radiosensitivity compared with oncology patients without RhD. In contrast, the mean radiosensitivity of the oncological patients with RA and other RhD and the non-oncological RA did not differ. 14 of the 44 examined oncological RA-patients (31.8%) had a high radiosensitivity which is defined as ≥ 0.5 breaks per metaphase. No correlation of laboratory parameters with radiosensitivity could be established. Conclusions: It would be recommended to perform radiosensitivity testing in patients with connective tissue diseases in general. We did not find a higher radiosensitivity in RA patients. In the group of RA patients with an oncological disease, a higher percentage of patients showed higher radiosensitivity, although the average radiosensitivity was not high.
CRIS-Team Scopus Importer:2023-06-16
Keywords: Chromosomal aberrations; Collagen vascular disease; Connective tissue disease; Fluorescence in situ hybridisation; Radiation sensitivity; Radiosensitivity; Radiotherapy; Radiotoxicity; Rheumatism; Rheumatoid arthritis

Chronic inflammation degrades CD4 T cell immunity to prior vaccines in treated HIV infection - Kießling, Melissa; Cole, John J.; Kübel, Sabrina; Klein, Paulina; Korn, Klaus; Henry, Amy R.; Laboune, Farida; Fourati, Slim; Harrer, Ellen; Harrer, Thomas; Douek, Daniel C.; Überla, Klaus; et al. (Nature Communications, 2024)
To date, our understanding of how HIV infection impacts vaccine-induced cellular immunity is limited. Here, we investigate inflammation, immune activation and antigen-specific T cell responses in HIV-uninfected and antiretroviral-treated HIV-infected people. Our findings highlight lower recall responses of antigen-specific CD4 T cells that correlate with high plasma cytokines levels, T cell hyperactivation and an altered composition of the T subsets enriched with more differentiated cells in the HIV-infected group. Transcriptomic analysis reveals that antigen-specific CD4 T cells of the HIV-infected group have a reduced expression of gene sets previously reported to correlate with vaccine-induced pathogen-specific protective immunity and further identifies a consistent impairment of the IFNα and IFNγ response pathways as mechanism for the functional loss of recall CD4 T cell responses in antiretroviral-treated people. Lastly, in vitro treatment with drugs that reduce inflammation results in higher memory CD4 T cell IFNγ responses. Together, our findings suggest that vaccine-induced cellular immunity may benefit from strategies to counteract inflammation in HIV infection.
CRIS-Team Scopus Importer:2024-12-06

Chronic Peripheral Inflammation Causes a Region-Specific Myeloid Response in the Central Nervous System - Süß, Patrick; Hoffmann, Alana; Rothe, Tobias; Ouyang, Zhengyu; Baum, Wolfgang; Staszewski, Ori; Schett, Georg; Prinz, Marco; Krönke, Gerhard; Glass, Christopher K.; Winkler, Jürgen; Schlachetzki, Johannes (Cell Reports, 2020)
Systemic immune dysregulation contributes to the development of neuropsychiatric and neurodegenerative diseases. The precise effect of chronic peripheral immune stimulation on myeloid cells across anatomical brain regions is unclear. Here, we demonstrate brain-region-specific differences in myeloid responses induced by chronic peripheral inflammation. This shift in the myeloid compartment is associated with the appearance of an inflammatory myeloid subpopulation in the cortex, striatum, and thalamus accompanied by regional transcriptomic fingerprints that include induction of chemokines, complement factors, and endothelial adhesion molecules. In contrast, myeloid immune responses within the hippocampus and cerebellum are subtle or absent. Treatment with the anti-tumor necrosis factor α (anti-TNF-α) antibody infliximab ablates the region-specific inflammatory response. A region-specific myeloid cell response to chronic peripheral inflammation is observed in postmortem brains from individuals with rheumatoid arthritis. Our data suggest that chronic peripheral inflammation has heterogeneous effects on the brain, as evidenced by the spectrum of myeloid cell responses observed across brain regions.
CRIS-Team Scopus Importer:2020-03-31
Keywords: blood-brain barrier; brain regions; chronic peripheral inflammation; CNS myeloid cells; human rheumatoid arthritis; microglia

Chronic skin inflammation leads to bone loss by IL-17-mediated inhibition of Wnt signaling in osteoblasts - Uluckan, Oezge; Jimenez, Maria; Karbach, Susanne; Jeschke, Anke; Grana, Osvaldo; Keller, Johannes; Busse, Bjoern; Croxford, Andrew L.; Finzel, Stephanie; Koenders, Marije; Van Den Berg, Wim; Schinke, Thorsten; et al. (Science Translational Medicine, 2016)
Inflammation has important roles in tissue regeneration, autoimmunity, and cancer. Different inflammatory stimuli can lead to bone loss by mechanisms that are not well understood. We show that skin inflammation induces bone loss in mice and humans. In psoriasis, one of the prototypic IL-17A-mediated inflammatory human skin diseases, low bone formation and bone loss correlated with increased serum IL-17A levels. Similarly, in two mouse models with chronic IL-17A-mediated skin inflammation,K14-IL17A(ind)andJunB(?ep), strong inhibition of bone formation was observed, different from classical inflammatory bone loss where osteoclast activation leads to bone degradation. We show that under inflammatory conditions, skin-resident cells such as keratinocytes, ?? T cells, and innate lymphoid cells were able to express IL-17A, which acted systemically to inhibit osteoblast and osteocyte function by a mechanism involving Wnt signaling. IL-17A led to decreased Wnt signaling in vitro, and importantly, pharmacological blockade of IL-17A rescued Wnt target gene expression and bone formation in vivo. These data provide a mechanism where IL-17A affects bone formation by regulating Wnt signaling in osteoblasts and osteocytes. This study suggests that using IL-17A blocking agents in psoriasis could be beneficial against bone loss in these patients.
EVALuna2:13277

Chronic Systemic Infection of Mice with Leishmania infantum Leads to Increased Bone Mass - Lai, Chaobo; Heinemann, Jennifer; Schleicher, Ulrike; Schett, Georg; Bogdan, Christian; Bozec, Aline; Soulat, Didier (Journal of Bone and Mineral Research, 2022)
Vector-borne infections of humans with the protozoan parasite Leishmania (L.) infantum can cause a systemic and potentially lethal disease termed visceral leishmaniasis. In the corresponding mouse model, an intravenous infection with L. infantum leads to the persistence of parasites in various organs, including bone marrow (BM). Considering the anatomical proximity between the BM and the cortical bone, we investigated whether a chronic infection with L. infantum affected bone homeostasis. Unexpectedly, chronic infection with L. infantum caused an increase in bone mass in mice. In vivo, an increased number of osteoblasts and osteocytes and a decreased maturation of osteoclasts characterized the phenotype. Confocal laser scanning fluorescence microscopy confirmed the infection of BM macrophages but also revealed the presence of parasites in osteoclasts. In vitro, mature osteoclasts took up L. infantum parasites. However, infection of osteoclast progenitors abolished their differentiation and function. In addition, secretory products of infected BM-derived macrophages inhibited the maturation of osteoclasts. Both in vitro and in vivo, infected macrophages and osteoclasts showed an enhanced expression of the anti-osteoclastogenic chemokine CCL5 (RANTES). Neutralization of CCL5 prevented the inhibition of osteoclast generation seen in the presence of culture supernatants from L. infantum-infected macrophages. Altogether, our study shows that chronic infection with Leishmania increases bone mass by inducing bone formation and impairing osteoclast differentiation and function. (c) 2022 American Society for Bone and Mineral Research (ASBMR).
CRIS-Team WoS Importer:2022-12-02

CHRONIC TENOSYNOVITIS IS ASSOCIATED WITH LOSS OF GRIP STRENGTH IN PATIENTS WITH PSORIASIS AND PSORIATIC ARTHRITIS (OP0069) - Bayat, Sara; Coppers, Birte; Kleyer, Arnd; Elie-Tino, Godonou; Valor, L.; Simon, David; Fagni, Filippo; Corte, Giulia; Schönau, Verena; Tascilar, Koray; Hueber, Axel; Sticherling, Michael; et al. (Annals of the Rheumatic Diseases, 2023)
Background Rheumatic diseases result in joint destruction and impaired physical function [1]. We recently showed, that hand function based on objective tests may serve as a biomarker representing subclinical inflammation in psoriasis (Pso) patients and thus could support the early detection of psoriatic arthritis (PsA) onset [2]. Hand function tests are relevant for objective assessment of musculoskeletal function in relation to disease activity in PsA [3], However, the relationship of hand function with the synovitis and tenosynovitis detected by ultrasound (US) in PsA and Pso patients has not been well studied. Objectives To investigate the association of synovitis and tenosynovitis detected by US in greyscale (GS) and power doppler (PD) activity with grip strength and fine motor skills in patients with PsA and Pso. Methods PsA and Pso patients were recruited from the Rheumatology Department at the University Hospital erlangen, for this cross-sectional study. After giving written informed consent, subject characteristics were recorded and study participants underwent bilateral US of the wrists, metacarpophalangeal (MCP) joints, and flexor tendons of all fingers. Each joint was examined by GS (0-3), PD (0-3) and finally a combined score (PDUS: PD + GS) was calculated (0-3) [4]. The flexor tendon was scanned in GS (0/1) and with PD [0-3]. US activity considered either a synovitis or tenosynovitis score ≥1. Activity in tender joint count (TJC) and swollen joint count (SJC) 68/66 was considered ≥1 tender or ≥1 swollen joint. Hand function was assessed by vigorimetric grip strength (lbf) and the fine motor skill MPUT (Moberg pick-up test). For the analysis, patients’ hands were either divided in dominant/non-dominant or patient reported affected/non-affected hand. A correlation matrix was applied to measure the linear relation between the pairs of synovitis and tenosynovitis scores, grip strength and MPUT for both hands, using the Spearman correlation method. Results 106 patients (40 PsA, 66 Pso) participated in this study. Subject characteristics and general outcomes are summarized in Table 1. While grip strength was higher in the dominant hand (p<0.001), MPUT times are comparable between the dominant vs. non-dominant hands (p=0.056) but was faster in the non-affected hand (p=0.008). Low to moderate positive correlations were observed between both, overall GS synovitis score (MCP 2-5 + wrist) (r=0.24, p<0.05), and PDUS (r=0.23, p<0.05) with MPUT. In US active patients, a high correlation between grip strength and GS tenosynovitis score in digit 2 (r=-0.566, p=0.028) was detected. When considering patients with US in addition to SJC/TJC activity, imaging modalities did not correlate with hand function. Conclusion These findings indicate that the synovitis detected by greyscale is related with fine motor skills and tenosynovitis in greyscale with grip strength. This suggests, that chronic tenosynovitis has a greater impact on hand function than the acute inflammatory phase. When considering patients with TJC68/SJC66 ≥1 this relation is not present, suggesting that clinically assessed joint count, unlike ultrasonography, does not correlate with hand function impairmen

Chronic vasculitis and polyneuropathy due to infection with Bartonella henselae - Schoerner, Christoph; Harrer, Thomas; et al. (Infection, 2007)
Bartonella henselae, the causative agent of cat scratch disease and bacillary angiomatosis, is associated with an expanding spectrum of diseases. Here, we report on a 40-year-old patient suffering from chronic recurrent painful ulcers of the toes, distal axonal sensomotor polyneuropathy and Raynaud's phenomenon. Biopsy of the sural nerve demonstrated an axonal neuropathy with a neurogenic muscular atrophy. Treatment with high dose corticosteroids had no beneficial effect. A biopsy taken from a recurring ulcer 7 years after the beginning of the disease revealed superficial ulcerated hyperkeratosis with subepithelial proliferation of small vessels compatible with a diagnosis of verruca peruana, however, without detection of microorganism. Serologic analysis revealed an elevated IFT titer of 1:1,024 against B. henselae. Treatment with erythromycin induced healing of the ulcer, remission of the vasculitis and the polyneuropathy, and a decline of the IFT titer. This case illustrates that B. henselae infection should be considered in patients with vasculitis and polyneuropathic syndromes. © 2007 Urban & Vogel.
UnivIS-Import:2015-04-14:Pub.2007.med.IKMI.LHMMIPDR.chroni

Chronic viral infections in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) - Rasa, Santa; Nora-Krukle, Zaiga; Henning, Nina; Eliassen, Eva; Shikova, Evelina; Harrer, Thomas; Scheibenbogen, Carmen; Murovska, Modra; Prusty, Bhupesh K. (Journal of Translational Medicine, 2018)
Background and main text: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a complex and controversial clinical condition without having established causative factors. Increasing numbers of cases during past decade have created awareness among patients as well as healthcare professionals. Chronic viral infection as a cause of ME/CFS has long been debated. However, lack of large studies involving well-designed patient groups and validated experimental set ups have hindered our knowledge about this disease. Moreover, recent developments regarding molecular mechanism of pathogenesis of various infectious agents cast doubts over validity of several of the past studies. Conclusions: This review aims to compile all the studies done so far to investigate various viral agents that could be associated with ME/CFS. Furthermore, we suggest strategies to better design future studies on the role of viral infections in ME/CFS.
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Cinematic Rendering Enables Depiction of Bone Anabolic Effects in Patients Treated with Baricitinib - Bayat, Sara; Simon, David; Schuster, Louis; Schett, Georg; Kleyer, Arnd (ARTHRITIS & RHEUMATOLOGY, 2020)
CRIS-Team WoS Importer:2021-01-15

Cinematic rendering in rheumatic diseases-Photorealistic depiction of pathologies improves disease understanding for patients - Pachowsky, Milena; Morf, Harriet; Simon, David; Schönau, Verena; Valor-Mendez, Larissa; Knitza, Johannes; Fagni, Filippo; Engel, Klaus; Uder, Michael; Hueber, Axel; Schmidkonz, Christian; Schett, Georg; et al. (Frontiers in Medicine, 2022)
BackgroundPatient education is crucial for successful chronic disease management. Current education material for rheumatic patients however rarely includes images of disease pathologies, limiting patients' disease understanding. Cinematic rendering (CR) is a new tool that allows segmentation of standard medical images (DICOMs) into pictures that illustrate disease pathologies in a photorealistic way. Thus CR has the potential to simplify and improve the explanation of disease pathologies, disease activity and disease consequences and could therefore be a valuable tool to effectively educate and inform patients about their rheumatic and musculoskeletal disease (RMD). ObjectivesTo examine the feasibility of creating photorealistic images using CR from RMD patients depicting typical rheumatic disease pathologies and, in a second step to investigate the patient-perceived educational potential of these photorealistic images in clinical routine. MethodsWe selected conventional, high-resolution (HR) and positron emission tomography (PET) computed tomography (CT) images of patients with rheumatoid arthritis (RA), psoriatic arthritis (PsA), axial spondyloarthritis (axSpA), and giant cell arteritis (GCA) that showed typical respective disease pathologies. These images were segmented using CR technique. In a prospective study, physicians used CR-enhanced and conventional original images to explain the depicted pathognomonic pathologies to patients with the respective rheumatic disease. Patients were then asked to complete a questionnaire evaluating the perceived usefulness of being presented with CR-enhanced images to better understand their underlying disease. ResultsCR images were successfully generated from above mentioned CT methods. Pathologies such as bone erosions, bony spurs, bone loss, ankylosis, and PET-based inflammation could be visualized in photorealistic detail. A total of 79 patients (61% females) with rheumatic diseases (RA 29%, PsA 29%, axSpA 24%, GCA 18%) were interviewed and answered the quantitative questionnaire. Mean age was 55.4 +/- 12.6 years. Irrespective of disease, all patients agreed or highly agreed that CR-based images help to improve disease understanding, should be shown at disease onset, provide a rationale to regularly take medication and would like to have access to their own CR-enhanced images. ConclusionConventional disease images can successfully be turned into photorealistic disease depictions using CR. Patients perceived CR images as a valuable addition to current patient education, enabling personalized disease education and potentially increased medication adherence.
CRIS-Team WoS Importer:2022-08-26

Circulating calprotectin (S100A8/A9) is higher in rheumatoid arthritis patients that relapse within 12 months of tapering anti-rheumatic drugs - De Moel, Emma C.; Rech, Jürgen; Mahler, Michael; Roth, Johannes; Vogl, Thomas; Schouffoer, Anne; Goekoop, Robbert J.; Huizinga, Tom W.J.; Allaart, Cornelia F.; Toes, René E.M.; Schett, Georg; Van Der Woude, Diane (Arthritis Research & Therapy, 2019)
Objective: To investigate whether calprotectin (S100A8/A9 or MRP8/14), an inflammatory complex released by monocytes, could indicate residual subclinical inflammation in rheumatoid arthritis (RA) patients who are in stable remission on disease-modifying anti-rheumatic drugs (DMARDs) and serve as a marker for disease flare after DMARD tapering. Methods: We used data from two trials. Patients from the IMPROVED study had early (< 2 years) RA, and when they achieved disease activity score remission (DAS44 < 1.6), they stopped methotrexate to attempt drug-free remission. Patients from the RETRO study had established RA in stable remission (DAS28 < 2.6) and either tapered by 50% or stopped (biological or conventional) DMARDs. Circulating calprotectin at the tapering time point was determined by ELISA, and its predictive value for flare (loss of remission) within 12 months of DMARD tapering/stopping was determined. Results: In both IMPROVED (n = 104) and RETRO (n = 57), patients that flared within 12 months had higher calprotectin at the moment of DMARD tapering/stopping. Twofold higher calprotectin at the moment of DMARD tapering/stopping was associated with an increased risk (odds ratio) of flare of 1.07 (95% CI 0.98-1.18, p = 0.14) in the IMPROVED and 3.62 (95% CI 1.76-7.46, p < 0.001) in the RETRO. Correcting for clinical predictors of flare (DAS at study inclusion, anti-CCP2 positivity, gender) did not change these estimates. The area under the receiver operating curve of calprotectin levels for predicting flare within 12 months was 0.63 (95% CIs 0.51-0.76) in the IMPROVED study and 0.80 (95% CIs 0.69 to 0.92) in the RETRO study. Conclusion: Circulating calprotectin levels in RA patients in remission on DMARDs are higher in patients that will flare upon DMARD tapering/stopping. Since the differences between the cohorts precluded definitive conclusions, more research is needed to determine whether calprotectin has prognostic value in predicting flare after attempting drug tapering in RA. Trial registration: IMPROVED, ISRCTN11916566. RETRO, 2009-015740-42.
CRIS-Team Scopus Importer:2019-12-17
Keywords: Calprotectin; Disease activity; MRP8/14; Rheumatoid arthritis; S100A8/A9

Circulating collagen neo-epitopes and their role in the prediction of fibrosis in patients with systemic sclerosis: a multicentre cohort study - Dobrota, Rucsandra; Jordan, Suzana; Juhl, Pernille; Maurer, Britta; Wildi, Lukas; Bay-Jensen, Anne Christine; Karsdal, Morten Asser; Herrick, Ariane L.; Distler, Jörg; Allanore, Yannick; Hoffmann-Vold, Anna Maria; Siebuhr, Anne Sofie; et al. (The Lancet Rheumatology, 2021)
Background: Extracellular matrix remodelling is a hallmark of systemic sclerosis. We evaluated extracellular matrix neo-epitopes as potential serum biomarkers for progression of fibrosis in systemic sclerosis. Methods: We included patients meeting the 2013 American College of Rheumatology and European League Against Rheumatism criteria and healthy controls from a derivation and validation cohort. The primary outcome was progression of fibrosis at follow-up, defined as decline in percentage of predicted forced vital capacity of 10% or more in patients with interstitial lung disease or increase in modified Rodnan skin score of 25% or more and more than 5 points at a 1-year follow-up visit. Longitudinal assessment and biobanking followed European Scleroderma Trials and Research standards. Extracellular matrix-degradation (BGM, C3M, C4M, and C6M) and extracellular matrix-formation neo-epitopes (PRO-C1, PRO-C3, PRO-C4, PRO-C5, and PRO-C6) were measured in serum using validated ELISAs. Findings: Between Aug 18, 2011, and Jan 19, 2015, 149 patients with systemic sclerosis (27 [18%] progressors and 122 [82%] non-progressors) and 29 healthy controls were included in the derivation cohort. Concentrations of type III and IV collagen neo-epitopes were higher in patients with systemic sclerosis compared with healthy controls and were significantly associated with systemic sclerosis in univariable logistic regression. Concentrations of degradation neo-epitopes of type III and IV collagens and their turnover ratios distinguished between progressors and non-progressors (C3M area under the curve 0·77 [95% CI 0·67–0·86], p<0·0001; PRO-C3:C3M 0·70 [0·59–0·80], p=0·0013; C4M 0·73 [0·63–0·82], p<0·0001; PRO-C4:C4M 0·75 [0·64–0·86], p<0·0001). 384 patients with systemic sclerosis (73 [19%] progressors) and 60 healthy controls were included in the multicentre validation cohort between April 17, 2003, and Jan 24, 2017. Analysis of the validation cohort confirmed that neo-epitopes of type III and IV collagens are changed in progressors. In a pooled analysis of both cohorts, the serum concentrations of formation neo-epitopes PRO-C3 and PRO-C4 and the turnover ratio of type IV collagen (PRO-C4:C4M) were higher in skin progressors. The turnover ratio of type IV collagen and PRO-C3 significantly predicted skin progression in a multivariable model adjusted for modified Rodnan skin score, sex, and age. Interpretation: These data suggest that neo-epitopes of type III and IV collagens are promising biomarkers for the assessment and prediction of extracellular matrix remodelling in systemic sclerosis. They could be used in clinical practice to risk stratify patients at risk of progression of fibrosis. Funding: None.
CRIS-Team Scopus Importer:2021-03-05

CIRCULATING MONOCYTES HAVE DISTINCT PHYSICAL PROPERTIES THAT CORRELATE WITH DISEASE ACTIVITY AND SEVERITY AND PREDICT PROGRESSION IN SYSTEMIC SCLEROSIS - Matei, Alexandru-Emil; Kubankova, Marketa; Györfi, A.H.; Boxberger, E.; Soteriou, Despina; Papava, Maria; Muth, J.; Kräter, Martin; Schett, Georg; Distler, Jörg; Guck, Jochen (Annals of the Rheumatic Diseases, 2021)
CRIS-Team WoS Importer:2021-09-24

Citrullination licenses calpain to decondense nuclei in neutrophil extracellular trap formation - Goesswein, Stefanie; Lindemann, Aylin; Mahajan, Aparna; Maueröder, Christian; Martini, Eva; Patankar, Jay; Schett, Georg; Becker, Christoph; Wirtz, Stefan; Naumann-Bartsch, Nora; Bianchi, Marco E.; Greer, Peter A.; et al. (Frontiers in Immunology, 2019)
Neutrophils respond to various stimuli by decondensing and releasing nuclear chromatin characterized by citrullinated histones as neutrophil extracellular traps (NETs). This achieves pathogen immobilization or initiation of thrombosis, yet the molecular mechanisms of NET formation remain elusive. Peptidyl arginine deiminase-4 (PAD4) achieves protein citrullination and has been intricately linked to NET formation. Here we show that citrullination represents a major regulator of proteolysis in the course of NET formation. Elevated cytosolic calcium levels trigger both peptidylarginine deiminase-4 (PAD4) and calpain activity in neutrophils resulting in nuclear decondensation typical of NETs. Interestingly, PAD4 relies on proteolysis by calpain to achieve efficient nuclear lamina breakdown and chromatin decondensation. Pharmacological or genetic inhibition of PAD4 and calpain strongly inhibit chromatin decondensation of human and murine neutrophils in response to calcium ionophores as well as the proteolysis of nuclear proteins like lamin B1 and high mobility group box protein 1 (HMGB1). Taken together, the concerted action of PAD4 and calpain induces nuclear decondensation in the course of calcium-mediated NET formation.
CRIS-Team Scopus Importer:2019-11-15
Keywords: Calpain; Cell death; Chromatin; Citrullination; Neutrophil; Nucleus; PAD4

CLASSIFICATION OF PSORIATIC ARTHRITIS, SERONEGATIVE RHEUMATOID ARTHRITIS, AND SEROPOSITIVE RHEUMATOID ARTHRITIS USING DEEP LEARNING ON 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. (Supplement 1, 2022)
Background: While MRI evaluation of joints has been primarily used to quantify inflammation at a cross-sectional and longitudinal level, less is known about the potential of MRI in distinguishing different patterns of inflammation in the various forms of arthritis. Objectives: To evaluate (i) whether deep learning using neural networks can be trained to distinguish between seropositive rheumatoid arthritis (RA+), seronegative RA (RA-), and psoriatic arthritis (PsA) based on structural inflammatory patterns on hand magnetic resonance imaging and (ii) to assess if psoriasis patients with subclinical inflammation fit into such patterns. Methods: ResNet 3D [1] neural networks were trained to distinguish (i) RA+ vs. PsA, (ii) RA- vs. PsA and (iii) RA+ vs. RA- with respect to hand MRI data. Diagnosis of patients was determined using the following guidelines: ACR/EULAR 2010 [2] for RA and CASPAR [3] for PsA. Results from T1 coronal, T2 coronal, T1 coronal and axial fat suppressed contrast-enhanced (CE) and T2 fat suppressed axial sequences were used. The performance of such trained networks was analyzed by the area-under-the-receiver-operating-characteristic curve (AUROC) with and without imputation of demographic and clinical parameters ( Figure 1A ). Additionally, the trained networks were applied to psoriasis patients without clinical signs of PsA. Results: MRI scans from 649 patients (135 RA-, 190 RA+, 177 PsA, 147 psoriasis) were included ( Table 1 ). The AUROC for differentiation between disease entities was 75% (SD 3%) for RA+ vs. PsA, 74% (SD 8%) for RA- vs. PsA, and 67% (6%) for RA+ vs. RA-. All MRI sequences were relevant for classification, however, when deleting CE sequences, the loss of performance was only marginal. The addition of patient-specific data to the networks did not provide significant improvements. Increasing amounts of training data demonstrated improved performance of the networks ( Figure 1B ). Psoriasis patients were mostly assigned to PsA by the neural networks, suggesting that PsA-like MRI pattern may be present early in the course of psoriatic disease. Conclusion: Deep learning can be successfully applied to differentiate MRI inflammatory patterns related to RA+, RA-, and PsA. Early changes in psoriasis patients can be recognized by neural networks and are characterized by a pattern that allowed the networks to classify them as PsA. <
Keywords: Rheumatoid arthritis; deep learning; neural networks

Classification of rheumatoid arthritis from hand motion capture data using machine learning - Fleischmann, Sophie; Holzwarth Correa, Vivien; Coppers, Birte; Sadeghi, Misha; Richer, Robert; Kleyer, Arnd; Simon, David; Bräunig, Johanna; Vossiek, Martin; Schönau, Verena; Schett, Georg; Koelewijn, Anne; et al. (13. Kongress der Deutschen Gesellschaft für Biomechanik (DGfB), 2024)
Intro Classifying movement restrictions in patients with rheumatoid arthritis (RA) is challenging. Machine learning (ML) can identify patterns in the data that cannot be captured with statistical tools. Aim To test the feasibility of classifying RA patients and controls from hand motion capture data using automatic feature extraction (AFE) and ML and to evaluate if a larger feature set improves the performance. Methods 24 RA patients (ACR/EULAR 2010 criteria) and 23 controls performed tipping and flexion of the hand [1], which was captured by an optoelectronic measurement system at 100 Hz with 29 reflective markers placed on the hand dorsum. We extracted the 3D trajectories, expressed relative to the central wrist marker and normalized to the hand length, of 24 markers on one hand (excluding thumb markers). After linearly interpolating missing values we filtered the data using a 4th-order Butterworth filter at a 6 Hz cut-off frequency and extracted a minimal and extensive feature set from the hand trajectories using the AFE package tsfresh [2]. We compared 4 classifiers in combination with scaling and dimensionality reduction (Fig 1). For every combination of algorithms, we trained a model using a stratified 10-fold nested cross-validation (CV). Hyperparameters were found from an inner five-fold CV on the respective train set using grid search. We report the accuracy of the best model averaged over the 10 folds. Results The best accuracy was 68.2% for flexion and 62.7% for tipping (Fig 2). Using the extensive instead of the minimal feature set led to no major change in accuracy. Summary The classification performance based on AFE was below the anticipated level of accuracy (>70%), likely due to the small dataset with limited data quality. We currently evaluate the approach on a more consistent, larger dataset and include expert features in addition to AFE. References [1] Phutane et al., Sensors, 21(4), 1208, 2021 [2] Christ et al., Neurocomputing, 307, 72-77, 20

Clinical and radiographic outcomes at 2 years and the effect of tocilizumab discontinuation following sustained remission in the second and third year of the ACT-RAY study - Huizinga, T. W. J.; Conaghan, Philip G.; Martin-Mola, Emilio; Schett, Georg; Amital, Howard; Xavier, Ricardo M.; Troum, Orrin; Aassi, Maher; Bernasconi, Corrado; Dougados, Maxime (Annals of the Rheumatic Diseases, 2015)
To assess the efficacy and safety of tocilizumab (TCZ) plus methotrexate/placebo (MTX/PBO) over 2 years and the course of disease activity in patients who discontinued TCZ due to sustained remission.ACT-RAY was a double-blind 3-year trial. Patients with active rheumatoid arthritis despite MTX were randomised to add TCZ to ongoing MTX (add-on strategy) or switch to TCZ plus PBO (switch strategy). Using a treat-to-target approach, open-label conventional synthetic disease-modifying antirheumatic drugs (csDMARDs), other than MTX, were added from week 24 if Disease Activity Score in 28 joints based on erythrocyte sedimentation rate (DAS28-ESR) >3.2. Between weeks 52 and 104, patients in sustained clinical remission (DAS28-ESR <2.6 at two consecutive visits 12 weeks apart) discontinued TCZ and were assessed every 4 weeks for 1 year. If sustained remission was maintained, added csDMARDs, then MTX/PBO, were discontinued.Of the 556 randomised patients, 76% completed year 2. Of patients entering year 2, 50.4% discontinued TCZ after achieving sustained remission and 5.9% achieved drug-free remission. Most patients who discontinued TCZ (84.0%) had a subsequent flare, but responded well to TCZ reintroduction. Despite many patients temporarily stopping TCZ, radiographic progression was minimal, with differences favouring add-on treatment. Rates of serious adverse events and serious infections per 100 patient-years were 12.2 and 4.4 in add-on and 15.0 and 3.7 in switch patients. In patients with normal baseline values, alanine aminotransferase elevations >3×upper limit of normal were more frequent in add-on (14.3%) versus switch patients (5.4%).Treat-to-target strategies could be successfully implemented with TCZ to achieve sustained remission, after which TCZ was stopped. Biologic-free remission was maintained for about 3 months, but most patients eventually flared. TCZ restart led to rapid improvement.NCT00810199.
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CLINICAL CHARACTERISTICS AND PROGNOSIS OF PATIENTS WITH SYSTEMIC SCLEROSIS SINE SCLERODERMA: DATA FROM THE INTERNATIONAL EUSTAR DATABASE. - Lescoat, A.; Huang, S.; Carreira, P.; Siegert, E.; De Vries-Bouwstra, J.; Distler, Jörg; Smith, V.; Del Galdo, F.; Anic, B.; Damjanov, N.; Rednic, S.; Ribi, C.; et al. (ANNALS OF THE RHEUMATIC DISEASES, 2022)
CRIS-Team WoS Importer:2022-11-04

Clinical efficacy and autoantibody seroconversion with CD19-CAR T cell therapy in a patient with rheumatoid arthritis and coexisting myasthenia gravis - Haghikia, Aiden; Hegelmaier, Tobias; Wolleschak, Denise; Böttcher, Martin; Pappa, Vaia; Motte, Jeremias; Borie, Dominic; Gold, Ralf; Feist, Eugen; Schett, Georg; Mougiakakos, Dimitrios (Annals of the Rheumatic Diseases, 2024)
CRIS-Team Scopus Importer:2024-07-19
Keywords: Anti-Citrullinated Protein Antibodies; Arthritis; Rheumatoid; Autoimmune Diseases; Autoimmunity; B-Lymphocytes

Clinical Images: Development of joint erosions in the preclinical phase of rheumatoid arthritis depicted by cinematic rendering - Simon, David; Schett, Georg; Kleyer, Arnd (Arthritis and Rheumatology, 2019)
CRIS-Team Scopus Importer:2019-08-06

Clinical Images: Increased bone metabolism in secondary hyperparathyroidism - Valor-Mendez, Larissa; Atzinger, Armin; Reis, Petra; Manger, Bernhard; Schett, Georg (Arthritis and Rheumatology, 2023)
CRIS-Team Scopus Importer:2023-04-21

Clinical Images: Tissue remodeling in autoimmune statin-induced necrotizing autoimmune myopathy - Valor-Mendez, Larissa; Manger, Bernhard; Knitza, Johannes; Schmidkonz, Christian; Kleyer, Arnd; Schett, Georg (ACR Open Rheumatology, 2022)
CRIS-Team WoS Importer:2022-07-15

Clinical Images: Voriconazole-induced synovitis, enthesitis, and periostitis - Valor-Méndez, Larissa; Wacker, Jochen; Schett, Georg; Manger, Bernhard; Fürst, Julia; Strauss, Richard; Kleyer, Arnd (Arthritis and Rheumatology, 2022)
CRIS-Team Scopus Importer:2022-07-08

Clinically relevant patient clusters identified by machine learning from the clinical development programme of secukinumab in psoriatic arthritis - Pournara, Effie; Kormaksson, Matthias; Nash, Peter; Ritchlin, Christopher T.; Kirkham, Bruce W.; Ligozio, Gregory; Pricop, Luminita; Ogdie, Alexis; Coates, Laura C.; Schett, Georg; Mcinnes, Iain B. (RMD Open, 2021)
Objectives Identify distinct clusters of psoriatic arthritis (PsA) patients based on their baseline articular, entheseal and cutaneous disease manifestations and explore their clinical and therapeutic value.
CRIS-Team WoS Importer:2021-12-03

Clinical, radiographic and immunogenic effects after 1 year of tocilizumab-based treatment strategies in rheumatoid arthritis: the ACT-RAY study - Dougados, Maxime; Kissel, Karsten; Conaghan, Philip G.; Mola, Emilio Martin; Schett, Georg; Gerli, Roberto; Hansen, Michael Sejer; Amital, Howard; Xavier, Ricardo M.; Troum, Orrin; Bernasconi, Corrado; Huizinga, T. W. J. (Annals of the Rheumatic Diseases, 2014)
To assess the 1-year efficacy and safety of a regimen of tocilizumab plus methotrexate or placebo, which was augmented by a treat-to-target strategy from week 24.ACT-RAY was a double-blind, 3-year trial. Adults with active rheumatoid arthritis despite methotrexate were randomised to add tocilizumab to ongoing methotrexate (add-on strategy) or to switch to tocilizumab plus placebo (switch strategy). Tocilizumab 8 mg/kg was administered every 4 weeks. Conventional open-label disease-modifying antirheumatic drugs (DMARDs) other than methotrexate were added at week 24 or later in patients with DAS28>3.2.556 patients were randomised; 85% completed 52 weeks. The proportion of patients receiving open-label DMARDs was comparable in the add-on (29%) and switch (33%) arms. Overall, week 24 results were maintained or further improved at week 52 in both arms. Some endpoints favoured the add-on strategy. Mean changes in Genant-modified Sharp scores were small; more add-on (92.8%) than switch patients (86.1%) had no radiographic progression. At week 52, comparable numbers of patients had antidrug antibodies (ADAs; 1.5% and 2.2% of add-on and switch patients, respectively) and neutralising ADAs (0.7% and 1.8%). Rates of serious adverse events and serious infections per 100 patient-year (PY) were 11.3 and 4.5 in add-on and 16.8 and 5.5 in switch patients. In patients with normal baseline values, alanine aminotransferase elevations >3× upper limit of normal were observed in 11% of add-on and 3% of switch patients.Despite a trend favouring the add-on strategy, these data suggest that both tocilizumab add-on and switch strategies led to meaningful clinical and radiographic responses.
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Clinical remission in rheumatoid arthritis : Data from the early arthritis cohort study CAPEA - Albrecht, K.; Callhoff, J.; Edelmann, E.; Schett, Georg; Schneider, M.; Zink, A. (Zeitschrift für Rheumatologie, 2016)
To evaluate remission rates and therapeutic strategies in the routine care of early rheumatoid arthritis.Between 2010 and 2013, a total of 1,301 patients with early arthritis were followed by 89 rheumatologists for up to 2 years in an early arthritis cohort (CAPEA). Complete 2-year data are available for 669 patients with rheumatoid arthritis.Ninety-three percent of patients were diagnosed with a moderate or high disease activity score (DAS28 > 3.2). Within 6 months, 40 % were in clinical remission (DAS28 < 2.6) and 21 % reached a low disease activity score (DAS28 > 2.6 to < 3.2). This proportion did not substantially increase during the 2-year follow-up. Methotrexate was the standard first-line treatment in 82 % of patients. During follow-up, 10 % were treated with a combination of disease-modifying antirheumatic drugs (DMARDs) and 12 % with biological agents. In 60 % of the patients who did not reach remission within 3 months (and 54 % of patients without remission by 6 months), treatment was not changed. At the beginning, 77 % of patients were treated with glucocorticoids at different starting doses (26 % < 7.5 mg, 29 % 7.5-20 mg, and 45 % >= 20 mg of prednisolone per day). After 2 years, 47 % remained on glucocorticoids.While 40 % of patients achieved clinical remission through standard care within 6 months, disease activity remained moderate to high in 37 % of patients at 2 years. In these patients a more consistent application of treatment may have increased the response rates.
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Clinical spectrum time course in non-Asian patients positive for anti-MDA5 antibodies. - Cavagna, L.; Meloni, F.; Meyer, A.; Sambataro, G.; Belliato, M.; De Langhe, E.; Cavazzana, I.; Pipitone, N.; Triantafyllias, K.; Mosca, M.; Barsotti, S.; Zampogna, G.; et al. (Clinical and Experimental Rheumatology, 2022)
OBJECTIVES: To define the clinical spectrum time-course and prognosis of non-Asian patients positive for anti-MDA5 antibodies. METHODS: We conducted a multicentre, international, retrospective cohort study. RESULTS: 149 anti-MDA5 positive patients (median onset age 53 years, median disease duration 18 months), mainly females (100, 67%), were included. Dermatomyositis (64, 43%) and amyopathic dermatomyositis (47, 31%), were the main diagnosis; 15 patients (10%) were classified as interstitial pneumonia with autoimmune features (IPAF) and 7 (5%) as rheumatoid arthritis. The main clinical findings observed were myositis (84, 56%), interstitial lung disease (ILD) (108, 78%), skin lesions (111, 74%), and arthritis (76, 51%). The onset of these manifestations was not concomitant in 74 cases (50%). Of note, 32 (21.5%) patients were admitted to the intensive care unit for rapidly progressive-ILD, which occurred in median 2 months from lung involvement detection, in the majority of cases (28, 19%) despite previous immunosuppressive treatment. One-third of patients (47, 32% each) was ANA and anti-ENA antibodies negative and a similar percentage was anti-Ro52 kDa antibodies positive. Non-specific interstitial pneumonia (65, 60%), organising pneumonia (23, 21%), and usual interstitial pneumonia-like pattern (14, 13%) were the main ILD patterns observed. Twenty-six patients died (17%), 19 (13%) had a rapidly progressive-ILD. CONCLUSIONS: The clinical spectrum of the anti-MDA5 antibodies-related disease is heterogeneous. Rapidly-progressive ILD deeply impacts the prognosis also in non-Asian patients, occurring early during the disease course. Anti-MDA5 antibody positivity should be considered even when baseline autoimmune screening is negative, anti-Ro52 kDa antibodies are positive, and radiology findings show a NSIP pattern.
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Clinical spectrum time course in non-Asian patients positive for anti-MDA5 antibodies - Cavagna, Lorenzo; Meloni, Federica; Meyer, Alain; Sambataro, Gianluca; Belliato, Mirko; De Langhe, Ellen; Cavazzana, Ilaria; Pipitone, Nicolò; Triantafyllias, Konstantinos; Mosca, Marta; Barsotti, Simone; Zampogna, Giuseppe; et al. (Clinical and Experimental Rheumatology, 2022)
OBJECTIVES: To define the clinical spectrum time-course and prognosis of non-Asian patients positive for anti-MDA5 antibodies. METHODS: We conducted a multicentre, international, retrospective cohort study. RESULTS: 149 anti-MDA5 positive patients (median onset age 53 years, median disease duration 18 months), mainly females (100, 67%), were included. Dermatomyositis (64, 43%) and amyopathic dermatomyositis (47, 31%), were the main diagnosis; 15 patients (10%) were classified as interstitial pneumonia with autoimmune features (IPAF) and 7 (5%) as rheumatoid arthritis. The main clinical findings observed were myositis (84, 56%), interstitial lung disease (ILD) (108, 78%), skin lesions (111, 74%), and arthritis (76, 51%). The onset of these manifestations was not concomitant in 74 cases (50%). Of note, 32 (21.5%) patients were admitted to the intensive care unit for rapidly progressive-ILD, which occurred in median 2 months from lung involvement detection, in the majority of cases (28, 19%) despite previous immunosuppressive treatment. One-third of patients (47, 32% each) was ANA and anti-ENA antibodies negative and a similar percentage was anti-Ro52 kDa antibodies positive. Non-specific interstitial pneumonia (65, 60%), organising pneumonia (23, 21%), and usual interstitial pneumonia-like pattern (14, 13%) were the main ILD patterns observed. Twenty-six patients died (17%), 19 (13%) had a rapidly progressive-ILD. CONCLUSIONS: The clinical spectrum of the anti-MDA5 antibodies-related disease is heterogeneous. Rapidly-progressive ILD deeply impacts the prognosis also in non-Asian patients, occurring early during the disease course. Anti-MDA5 antibody positivity should be considered even when baseline autoimmune screening is negative, anti-Ro52 kDa antibodies are positive, and radiology findings show a NSIP pattern.
CRIS-Team Scopus Importer:2022-03-11

Cluster analysis in early axial spondyloarthritis predicts poor outcome in the presence of peripheral articular manifestations - Costantino, Felicie; Aegerter, Philippe; Schett, Georg; De Craemer, Ann-Sophie; Molto, Anna; Van Den Bosch, Filip; Elewaut, Dirk; Breban, Maxime; D'Agostino, Maria-Antonietta (Rheumatology, 2021)
Objectives. To assess whether two cluster analysis-based axial SpA (axSpA) endotypes (A for purely axial; B for both axial and peripheral) are stable over time and are associated with different long-term disease outcomes.
CRIS-Team WoS Importer:2022-05-13

Cluster-based Spondyloarthritis Phenotypes Defined at Baseline Are Predictive of Different Severity Outcomes at 5-Year in the DESIR Cohort - Costantino, Felicie; Aegerter, Philippe; Molto, Anna; Schett, Georg; Breban, Maxime; D'Agostino, Maria-Antonietta (ARTHRITIS & RHEUMATOLOGY, 2019)
CRIS-Team WoS Importer:2020-02-07

Clusters of Psoriatic Arthritis Patients at Baseline Based on Different Ultrasound Detected Synovitis: Exploratory Analysis from a Phase III Study - D'Agostino, Maria Antonietta; Schett, Georg; Gaillez, Corine; Conaghan, Philip; Naredo, Esperanza; Carron, Philippe; Burgos-Vargas, Ruben; Mandl, Peter; Rosa, Javier; Boers, Maarten; Goyanka, Punit; Bao, Weibin; et al. (ARTHRITIS & RHEUMATOLOGY, 2021)
CRIS-Team WoS Importer:2022-03-11

Colchicine inhibits monosodium urate crystal-mediated inflammation by influencing F-actin formation - Zhu, Lingjiang; Wang, Yuqi; Shan, Lizhen; Xue, Yu; Schett, Georg; Herrmann, Martin; Liu, Lei (Biochimica et Biophysica Acta - Molecular Basis of Disease, 2025)
Objectives: To understand the mechanism by which colchicine inhibits the inflammatory properties of monosodium urate (MSU) crystal deposits and tophi. Methods: We investigated the effects of colchicine on the inflammatory properties of monosodium urate (MSU) crystal deposits in several models: (i) In vitro tophus formation by MSU and neutrophils; (ii) MSU-induced peritonitis model; (iii) Alpha-1-antitrypsin-induced peritoneal MSU flare model; (iv) MSU-induced arthritis model. We measured neutrophil numbers, NET formation, IL-1β production and F-actin generation by MSU crystals. In addition, we tested the effect of actin inhibitors SMIFH2, Cytochalasin B and Latrunculin B in the models. Results: Colchicine did not affect neutrophil numbers in all these models. However, colchicine was highly effective to inhibit NET formation, IL-1β production and F-actin generation indicating less pronounced tophus formation, lower inflammatory properties of tophi and reduced conversion from G-actin into F-actin, respectively. F-actin was shown to accumulate in tophi without presence of colchicine and being resistant to degradation by DNase I. Actin inhibitors SMIFH2 and Cytochalasin B significantly reduced IL-1β and neutrophil elastase levels and mitigated MSU-induced arthritis. Conclusion: Colchicine effects on gout flares are not based on reducing neutrophil numbers but on changing the functional properties of tophi by reducing their DNase-resistant F-actin concentrations and thereby reducing the negative impact of NETs on IL-1β production and the pro-inflammatory state of tophi. Actin inhibitors may be interesting tools to convey anti-inflammatory properties and reduction of flares in gout patients.
CRIS-Team Scopus Importer:2025-02-17
Keywords: Actin; Colchicine; Gout; Monosodium urate crystals; Neutrophil extracellular traps

Collagen Turnover Biomarkers Associate with Active Psoriatic Arthritis and Decrease with Guselkumab Treatment in a Phase 3 Clinical Trial (DISCOVER-2) - Schett, Georg; Loza, Matthew J.; Palanichamy, Arumugam; Fitzgerald, Oliver; Ritchlin, Christopher; Bay-Jensen, Anne-Christine; Nielsen, Signe Holm; Gao, Sheng; Hsia, Elizabeth C.; Kollmeier, Alexa P.; Xu, Xie L.; Baribaud, Frederic; et al. (Rheumatology and Therapy, 2022)
Introduction Guselkumab, a novel interleukin-23p19 subunit monoclonal antibody, has been shown to effectively improve the diverse manifestations of active psoriatic arthritis (PsA) in two phase 3 trials (DISCOVER-1, DISCOVER-2). Serum concentrations of extracellular matrix (ECM) biomarkers at baseline and following treatment with guselkumab were evaluated in patients with active PsA, and the relationship of these biomarkers with baseline PsA characteristics and clinical response to guselkumab treatment was explored. Methods Serum samples were collected at weeks 0, 4, 24, and 52 from a selected subset (N = 260) of the 739 biologic-naive patients with PsA treated with guselkumab 100 mg every 4 or 8 weeks or placebo in DISCOVER-2. Demographically matched healthy controls (N = 76) were used for comparison. The samples were analyzed for ECM biomarkers associated with collagen degradation (C1M, C2M, C3M, C4M, C6M, C10C) and collagen formation (PRO-C1, PRO-C2, PRO-C3, PRO-C4, PRO-C6). Results Baseline concentrations of collagen degradation biomarkers C1M, C3M, C4M, and C6M and collagen formation biomarkers PRO-C3 and PRO-C6 were significantly higher (i.e., >= 1.25-fold and false discovery rat- adjusted p < 0.05) in PsA patients than in healthy controls. Serum C1M, C3M, C4M, and C6M levels declined from baseline in guselkumab-treated patients in both dosing regimens. In addition, guselkumab-treated ACR20 responders (>= 20% improvement in American College of Rhematology response criteria) had significantly lower C1M levels than ACR20 nonresponders. Conclusion These data demonstrate that serum collagen biomarkers are elevated in patients with PsA compared with healthy controls and that treatment with guselkumab decreases levels of C1M, C3M, C4M, and C6M. Importantly, C1M serves as a biomarker that associates with improvement of joint signs and symptoms.
CRIS-Team WoS Importer:2022-04-08

Collagen Turnover Markers Are Associated with Active Psoriatic Arthritis and Decrease with Guselkumab Treatment in a Phase-3 Clinical Trial - Schett, Georg; Loza, Matthew J.; Palanichamy, Arumugam; Fitzgerald, Oliver; Ritchlin, Christopher; Baribaud, Frederic; Sweet, Kristen (ARTHRITIS & RHEUMATOLOGY, 2020)
CRIS-Team WoS Importer:2021-01-15

COLLAGEN TURNOVER MARKERS ASSOCIATE WITH ACTIVE PSORIATIC ARTHRITIS AND DECREASE WITH GUSELKUMAB TREATMENT - Schett, Georg; Loza, Matthew J.; Palanichamy, Arumugam; Fitzgerald, Oliver; Ritchlin, Christopher; Baribaud, Frédéric; Sweet, Kristen (Clinical and Experimental Rheumatology, 2021)
Background/Purpose: Guselkumab (GUS), an interleukin-23p19-subunit monoclonal antibody, demonstrated efficacy compared to placebo (PBO) in reducing skin and musculoskeletal signs and symptoms in patients with active psoriatic arthritis (PsA) in two phase-3 studies, DISCOVER 1 & 2, and in retarding structural damage in DISCOVER 2.1,2 Here we evaluate tissue-derived extracellular matrix (ECM) products3,4 in serum of PsA patients in the DISCOVER 2 study and their relationship with radiographic damage, clinical response, and impact of treatment. Methods: In DISCOVER 2, patients were treated with GUS 100 mg at Week (w) 0, 4, then every 8w (q8w); GUS 100mg every 4w (q4w); or matching PBO. At w24, PBO subjects were crossed-over to GUS q4w. 11 serum biomarkers of ECM collagen formation (PRO-C1, PRO-C2, PRO-C3, PRO-C4, PRO-C6) and degradation (C1M, C2M, C3M, C4M, C6M, and COL10) were measured (by Nordic Bioscience) in a subset of 260 patients from the DISCOVER 2 program at Weeks 0, 4, 24, & 52 and in 76 healthy controls matched for age, sex, and ethnicity. PsA patients were selected randomly, though enriching for subjects with greatest radiographic changes, at Weeks 24 and 52. Significance defined by P< 0.05 and |fold difference| ≥ 1.25. Results: At baseline, collagen degradation markers C1M, C3M, C4M, C6M and collagen formation markers PRO-C3 and PRO-C6 were significantly higher in PsA patients compared to matched healthy controls (Figure 1). Baseline C3M, C4M, and C6M were positively correlated to baseline skin and joint disease; baseline C1M, C3M, C4M, C6M, and PRO-C1 were positively correlated to baseline radiographic damage (data not shown). Levels of C1M (a maker indicating breakdown of collagen type I, the major collagen subtype in the bone) were significantly decreased after 24w treatment with GUS (Figure 2), reaching significant differences from placebo with the GUS 100 mg q4w group. For the PBO patients who crossed over to GUS at w24, there was also a reduction in this marker observed at w52 (Figure 2). In patients treated with GUS or PBO, there were not significant differences in baseline expression levels of the analytes in responders (patients achieving ACR20 at w24) compared with non-responders. However, ACR20 responders in the combined GUS group had a significantly greater reduction in C1M levels compared to non-responders (Figure 3). Conclusion: This work provides evidence that collagen biomarkers in serum are dysregulated in patients with PsA compared to healthy controls, and that GUS impacts levels of these proteins. Importantly, C1M serves as a biomarker that tracks with joint response. We observed a greater reduction in C1M in ACR responders compared to non-responders, providing insight into how GUS may be working to protect from degradation of bone in PsA.
CRIS-Team WoS Importer:2021-09-17
Keywords: Biologicals; Biomarkers; clinical trial; Collagen; Psoriatic arthritis

Combination therapies of porcupine inhibition with ruxolitinib, ibrutinib, or belumosudil in murine sclerodermatous GVHD - Hong, Xuezhi; Xiao, Yanhua; Xu, Liyan; Shen, Lichong; Neelagar, Ranjana; Devakumar, Veda; Trinh-Minh, Thuong; Liang, Minrui; Rigau, Aleix Rius; Zhang, Yun; Li, Yi Nan; Dees, Clara; et al. (Blood Advances, 2025)
CRIS-Team Scopus Importer:2025-04-01

Combined effect of genetic background and gender in a mouse model of bleomycin-induced skin fibrosis - Ruzehaji, Nadira; Avouac, Jerome; Elhai, Muriel; Frechet, Maxime; Frantz, Camelia; Ruiz, Barbara; Distler, Jörg; Allanore, Yannick (Arthritis Research & Therapy, 2015)
Systemic sclerosis (SSc) is a connective tissue disorder characterised by the development of skin fibrosis. Our current understanding of the disease pathogenesis is incomplete and the study of SSc is hindered, at least partially, by a lack of animal models that fully replicate the complex state of human disease. Murine model of bleomycin-induced dermal fibrosis encapsulates important events that take place early in the disease course.To characterise the optimum in vivo parameters required for the successful induction of dermal fibrosis we subjected three commonly used mouse strains to repeated subcutaneous bleomycin injections. We aimed to identify the effects of genetic background and gender on the severity of skin fibrosis. We used male and female Balb/C, C57BL/6, and DBA/2 strains and assessed their susceptibility to bleomycin-induced fibrosis by measuring dermal thickness, hydroxyproline/collagen content and number of resident myofibroblasts, all of which are important indicators of the severity of skin fibrosis. All data are expressed as mean values ± SEM. The Mann-Whitney U test was used for statistical analysis with GraphPad Prism 6.04 software.Dermal fibrosis was most severe in Balb/C mice compared to C57BL/6 and DBA/2 suggesting that Balb/C mice are more susceptible to bleomycin-induced fibrosis. Analysis of the effect of gender on the severity of fibrosis showed that male Balb/C, C57BL/6, DBA/2 mice had a tendency to develop more pronounced fibrosis phenotype than female mice. Of potential importance, male Balb/C mice developed the most severe fibrosis phenotype compared to male C57BL/6 and male DBA/2 as indicated by significantly increased number of dermal myofibroblasts.Our study highlights the importance of genetic background and gender in the induction of murine dermal fibrosis. Robust and reproducible animal models of fibrosis are important research tools used in pharmacological studies which may lead to better understanding of the pathogenesis of fibrotic diseases and assist in identification of new drugs.
EVALuna2:13108

Combined inhibition of morphogen pathways demonstrates additive antifibrotic effects and improved tolerability - Distler, Alfiya; Lang, Veronika; Del Vecchio, Tina; Huang, Jingang; Zhang, Yun; Beyer, Christian; Lin, Neng-Yu; Palumbo-Zerr, Katrin; Distler, Oliver; Schett, Georg; Distler, Jörg (Annals of the Rheumatic Diseases, 2014)
The morphogen pathways Hedgehog, Wnt and Notch are attractive targets for antifibrotic therapies in systemic sclerosis. Interference with stem cell regeneration, however, may complicate the use of morphogen pathway inhibitors. We therefore tested the hypothesis that combination therapies with low doses of Hedgehog, Wnt and Notch inhibitors maybe safe and effective for the treatment of fibrosis.Skin fibrosis was induced by bleomycin and by overexpression of a constitutively active TGF-? receptor type I. Adverse events were assessed by clinical monitoring, pathological evaluation and quantification of Lgr5-positive intestinal stem cells.Inhibition of Hedgehog, Wnt and Notch signalling dose-dependently ameliorated bleomycin-induced and active TGF-? receptor type I-induced fibrosis. Combination therapies with low doses of Hedgehog/Wnt inhibitors or Hedgehog/Notch inhibitors demonstrated additive antifibrotic effects in preventive as well as in therapeutic regimes. Combination therapies were well tolerated. In contrast with high dose monotherapies, combination therapies did not reduce the number of Lgr5 positive intestinal stem cells.Combined inhibition of morphogen pathways exerts additive antifibrotic effects. Combination therapies are well tolerated and, in contrast to high dose monotherapies, may not impair stem cell renewal. Combined targeting of morphogen pathways may thus help to overcome dose-limiting toxicity of Hedgehog, Wnt and Notch signalling.
EVALuna2:12898

Combined Inhibition of Tumor Necrosis Factor ? and Interleukin-17 As a Therapeutic Opportunity in Rheumatoid Arthritis: Development and Characterization of a Novel Bispecific Antibody - Fischer, Jens A. A.; Hueber, Axel; Wilson, Stacy; Galm, Margarete; Baum, Wolfgang; Kitson, Christopher; Auer, Johannes; Lorenz, Stefan H.; Moelleken, Joerg; Bader, Martin; Tissot, Alain C.; Tan, Seng-Lai; et al. (Arthritis and Rheumatology, 2015)
Rheumatoid arthritis therapies that are based on inhibition of a single cytokine, e.g., tumor necrosis factor ? (TNF?) or interleukin-6 (IL-6), produce clinically meaningful responses in only about half of the treated patients. This study was undertaken to investigate whether combined inhibition of TNF? and IL-17 has additive or synergistic effects in the suppression of mesenchymal cell activation in vitro and inflammation and tissue destruction in arthritis in vivo.Cultures of human fibroblast-like synoviocytes (FLS) were stimulated with TNF?, IL-17, or a combination of both. Single/combined neutralizing antibodies against TNF? and IL-17 were used to examine in vitro cytokine responses and in vivo development of arthritis and bone and cartilage destruction in TNF?-transgenic mice. Bispecific anti-TNF?/IL-17 antibodies were designed, and their potential to block cytokine responses in human FLS was tested.TNF? and IL-17 had additive/synergistic effects in promoting production of IL-6, IL-8, and granulocyte colony-stimulating factor, as well as matrix metalloproteinases, in FLS. Bispecific anti-TNF?/IL-17 antibodies showed superior efficacy in blocking cytokine and chemokine responses in vitro. Furthermore, dual versus single inhibition of both cytokines using neutralizing antibodies was more effective in inhibiting the development of inflammation and bone and cartilage destruction in arthritic mice.Combined blockade of TNF? and IL-17 was more effective than single blockade in inhibiting cytokine, chemokine, and matrix enzyme responses from human mesenchymal cells and in blocking tissue destruction associated with arthritis, and additionally showed a positive impact on rebalance of bone homeostasis. Bispecific anti-TNF?/IL-17 antibodies may have superior efficacy in the treatment of arthritis and may overcome the limited therapeutic responses obtained with single cytokine neutralization.
EVALuna2:13059

Comment on: Rescue therapy of anti-synthetase syndrome with CD19-targeted CART cells after failure of several B cell-depleting antibodies: reply. - Taubmann, Jule; Knitza, Johannes; Müller, Fabian; Völkl, Simon; Aigner, Michael; Kretschmann, Sascha; Atzinger, Armin; Kuwert, Torsten; Mackensen, Andreas; Schett, Georg (Rheumatology, 2024)
EVALuna2:551949

Common German language nomenclature for systemic sclerosis - Aringer, Martin; Mueller-Ladner, U.; Burkhardt, H.; Distler, Jörg; Distler, O.; Graninger, W. B.; Guenther, C.; Hunzelmann, N.; Kiener, H.; Sticherling, Michael; Sunderkoetter, C.; Walker, U. A.; et al. (Zeitschrift für Rheumatologie, 2015)
Large data bases and the projects arising from them have led to a much improved understanding of systemic sclerosis over the last decade. Serology has developed further so that more autoantibodies are available for routine testing. Capillary microscopy has become standard and relevant progress has also been made in therapy. Many diagnostic terms found in medical documentation do not adequately reflect this progress. The nomenclature is inconsistent and, therefore, confusing. The international classification of diseases (ICD) nomenclature is, from our point of view, also in need of improvement. This article aims to reestablish a common German language standard for systemic sclerosis, which reflects current knowledge and is suitable for implementation in the clinical routine.
EVALuna2:13102

Common RUNX3 missense variant contributes to psoriatic arthritis by affecting splicing and modifying signaling, activation and differentiation of T-cells - Hüffmeier, Ulrike; Löhr, Sabine; Uebe, Steffen; Popp, Bernt; Bowes, J.; Kirchner, P.; Giardina, E.; Korendowych, E.; Ekici, Arif Bülent; Ho, P.; Behrens, F.; Koehm, M.; et al. (EUROPEAN JOURNAL OF HUMAN GENETICS, 2020)
CRIS-Team WoS Importer:2021-01-22

Common RUNX3 missense variant contributes to psoriatic arthritis by modifying differentiation of CD8(+) T-cells - Kerker, Iris; Löhr, Sabine; Uebe, Steffen; Popp, Bernt; Vasileiou, Georgia; Bowes, John; Kirchner, Philipp; Becker, Ina; Giardina, Emiliano; Korendowych, Eleanor; Ekici, Arif Bülent; Ho, Pauline; et al. (EUROPEAN JOURNAL OF HUMAN GENETICS, 2022)
CRIS-Team WoS Importer:2022-05-06

Comparable neutralisation evasion of SARS-CoV-2 omicron subvariants BA.1, BA.2, and BA.3 - Arora, Prerna; Zhang, Lu; Rocha, Cheila; Sidarovich, Anzhalika; Kempf, Amy; Schulz, Sebastian; Cossmann, Anne; Manger, Bernhard; Baier, Eva; Tampe, Björn; Moerer, Onnen; Dickel, Steffen; et al. (Lancet Infectious Diseases, 2022)
CRIS-Team Scopus Importer:2022-06-03

COMPARATIVE CHANGE IN QUALITY OF LIFE MEASURES IN PRECLINICAL AND ESTABLISHED PSORIATIC ARTHRITIS PATIENTSUNDER SECUKINUMAB TREATMENT. DATA DERIVED FROM THE PROSPECTIVE OPEN LABEL PSARTROS STUDY - Kampylafka, Eleni; Englbrecht, Matthias; Tascilar, Koray; Lerchen, Veronika; Linz, Christina; Kleyer, Arnd; Simon, David; Rech, Jürgen; Schett, Georg; Hueber, Axel (ANNALS OF THE RHEUMATIC DISEASES, 2019)
CRIS-Team WoS Importer:2019-07-12

Comparison and Improvement of CyberGlove III calibration methods - Heinrich, Simon; Michaelis, Johannes; Reiher, Isabella; Coppers, Birte; Lohmayer, Markus; Fleischmann, Martha Elisa; Kleyer, Arnd; Schett, Georg; De Craemer, Ann-Sophie; Elewaut, Dirk; Leyendecker, Sigrid; Liphardt, Anna-Maria (IEEE Sensors, 2024)
We investigate the accuracy of different calibration methods for the CyberGlove III for objective hand function assessments. The accuracy is evaluated by means of root-mean-squared errors (RMSE) between ground truth and angles estimated by the glove. Additionally, we propose two improvements. The first increases standardization capabilities for the measurement of pure thumb carpometacarpal joint flexion. The second increases the accuracy by extending an existing calibration method to all thumb and distal interphalangeal (DIP) joints. The best calibration method is identified and compared to an across-subject calibration by means of RMSEs, highlighting the tradeoff between the number of necessary measurements and the accuracy. Our proposed improvements both reduce the measurement effort, while only the second improvement reduces the RMSEs substantially. The best calibration method yields RMSEs below 10° for most joints, while the across-subject calibration has RMSEs that are approximately 5°–10° higher. We conclude that the CyberGlove III is a suitable tool for objective monitoring of hand movement and function, and the across-subject calibration has the potential to track the range of motion or frequency of joint movements. With this work, we provide an overview for researchers to choose calibration methods suitable for their application depending on necessary accuracy and possible extent of calibration measurements. This work further highlights potential obstacles, when such a glove is used with patients.<br

COMPARISON OF BONE MICROSTRUCTURE OF PSORIATIC ARTHRITIS AND PSORIASIS PATIENTS - AN HR-PQCT STUDY OF ANABOLIC AND CATABOLIC BONE CHANGES - Simon, David; Faustini, F.; Englbrecht, Matthias; Kleyer, Arnd; Kocijan, R.; Haschka, J.; Figueiredo, C.; Kraus, S.; Hueber, Axel; Sticherling, Michael; Schett, Georg; Rech, Jürgen (2015)
EVALuna2:34458

Comparison of different approaches for the personalization of a kinematic hand model - Heinrich, Simon; Phutane, Uday; Penner, Johann; Coppers, Birte; Liphardt, Anna-Maria; Leyendecker, Sigrid (conference, World Biomechanics Congress 2022, 2022)

COMPARISON OF INFLAMMATION DURING METABOLIC CHANGES IN RHEUMATOID AND OSTEOARTHRITIS MOUSE MODELS - Sauermilch, H. M.; Hulser, M. L.; Schreiyaeck, C.; Luo, Y.; Bozec, Aline; Schett, Georg; Mueller-Ladner, U.; Neumann, E. (ANNALS OF THE RHEUMATIC DISEASES, 2020)
CRIS-Team WoS Importer:2020-08-21

Comparison of Metabolic Changes in Osteoarthritis and Rheumatoid Arthritis Mouse Models - Huelser, Marie-Lisa; Sauermilch, Hani Manfred; Schreiyaeck, Carina; Luo, Yubin; Bozec, Aline; Schett, Georg; Mueller-Ladner, Ulf; Neumann, Elena (2018)
EVALuna2:34961

Comparison of patients with axial PsA and patients with axSpA and concomitant psoriasis: an analysis of the German register RABBIT-SpA. - Regierer, Anne Constanze; Weiß, Anja; Proft, Fabian; Baraliakos, Xenofon; Behrens, Frank; Poddubnyy, Denis; Schett, Georg; Lorenz, Hanns Martin; Worsch, Matthias; Strangfeld, Anja (RMD Open, 2023)
BACKGROUND: Psoriatic arthritis (PsA) and axial spondyloarthritis (axSpA) show certain overlaps: A subset of patients with PsA can develop axial involvement (axial PsA, axPsA), while a subset of patients with axSpA presents with psoriasis (axSpA+pso). Treatment strategy for axPsA is mostly based on axSpA evidence. OBJECTIVES: To compare demographic and disease-specific parameters of axPsA and axSpA+pso. METHODS: RABBIT-SpA is a prospective longitudinal cohort study. AxPsA was defined based on (1) clinical judgement by rheumatologists; (2) imaging (sacroiliitis according to modified New York criteria in radiographs or signs of active inflammation in MRI or syndesmophytes/ankylosis in radiographs or signs of active inflammation in spine MRI). axSpA was stratified into axSpA+pso and axSpA without pso. RESULTS: Psoriasis was documented in 181/1428 axSpA patients (13%). Of 1395 PsA patients, 359 (26%) showed axial involvement. 297 patients (21%) fulfilled the clinical definition and 196 (14%) the imaging definition of axial manifestation of PsA. AxSpA+pso differed from axPsA regardless whether clinical or imaging definition was used. axPsA patients were older, more often female and less often HLA-B27+. Peripheral manifestations were more often present in axPsA than in axSpA+pso, whereas uveitis and inflammatory bowel disease were more common in axSpA+pso. Burden of disease (patient global, pain, physician global) was similar among axPsA and axSpA+pso patients. CONCLUSIONS: AxPsA differs from axSpA+pso in its clinical manifestations, irrespective of whether axPsA is defined clinically or by imaging. These findings support the hypothesis that axSpA and PsA with axial involvement are distinct entities, so extrapolation of treatment data from randomised controlled trials in axSpA should be performed with caution.
EVALuna2:528922

COMPARISON OF PATIENTS WITH AXIAL PSA AND PATIENTS WITH AXSPA AND CONCOMITANT PSORIASIS - Regierer, A.; Weiss, A.; Baraliakos, X.; Behrens, F.; Poddubnyy, D.; Schett, Georg; Lorenz, H. M.; Worsch, M.; Strangfeld, A. (ANNALS OF THE RHEUMATIC DISEASES, 2022)
CRIS-Team WoS Importer:2022-11-04

Comparison of physician and artificial intelligence-based symptom checker diagnostic accuracy - Gräf, Markus; Knitza, Johannes; Leipe, Jan; Krusche, Martin; Welcker, Martin; Kuhn, Sebastian; Mucke, Johanna; Hueber, Axel; Hornig, Johannes; Klemm, Philipp; Kleinert, Stefan; Aries, Peer; et al. (Rheumatology International, 2022)
Symptom checkers are increasingly used to assess new symptoms and navigate the health care system. The aim of this study was to compare the accuracy of an artificial intelligence (AI)-based symptom checker (Ada) and physicians regarding the presence/absence of an inflammatory rheumatic disease (IRD). In this survey study, German-speaking physicians with prior rheumatology working experience were asked to determine IRD presence/absence and suggest diagnoses for 20 different real-world patient vignettes, which included only basic health and symptom-related medical history. IRD detection rate and suggested diagnoses of participants and Ada were compared to the gold standard, the final rheumatologists' diagnosis, reported on the discharge summary report. A total of 132 vignettes were completed by 33 physicians (mean rheumatology working experience 8.8 (SD 7.1) years). Ada's diagnostic accuracy (IRD) was significantly higher compared to physicians (70 vs 54%, p = 0.002) according to top diagnosis. Ada listed the correct diagnosis more often compared to physicians (54 vs 32%, p < 0.001) as top diagnosis as well as among the top 3 diagnoses (59 vs 42%, p < 0.001). Work experience was not related to suggesting the correct diagnosis or IRD status. Confined to basic health and symptom-related medical history, the diagnostic accuracy of physicians was lower compared to an AI-based symptom checker. These results highlight the potential of using symptom checkers early during the patient journey and importance of access to complete and sufficient patient information to establish a correct diagnosis.
CRIS-Team WoS Importer:2022-09-16

Comparison of the effects of tocilizumab monotherapy and adalimumab in combination with methotrexate on bone erosion repair in rheumatoid arthritis - Finzel, Stephanie; Kraus, Sebastian; Figueiredo, Camille Pinto; Regensburger, Adrian; Kocijan, Roland; Rech, Jürgen; Schett, Georg (Annals of the Rheumatic Diseases, 2019)
Objective: To compare the effects of interleukin-6 (IL-6) receptor and tumour necrosis factor inhibition on inducing repair of existing bone erosions in patients with very early rheumatoid arthritis (RA). Methods: Prospective non-randomised observational study in patients with active erosive RA with inadequate response to methotrexate (MTX) receiving either tocilizumab (TOC) monotherapy or adalimumab (ADA) with MTX for 52 weeks. Erosion volumes were assessed in metacarpal heads (MCH) and the radius by high-resolution peripheral quantitative CT at baseline and after 52 weeks. Clinical response was monitored using Clinical Disease Activity Index, Simple Disease Activity Index and Disease Activity Score 28-erythrocyte sedimentation rate (DAS28-ESR) scores every 12 weeks. Results: TOC (N=33) and ADA/MTX (N=33) treatment groups were balanced for age, sex, body mass index, comorbidities, disease and activity, functional state, autoantibody status, baseline bone damage and baseline bone biomarkers. Both TOC (DAS28-ESR: baseline: 6.2±0.5; 52 weeks: 2.3±1.0) and ADA/MTX (6.3±0.6; 2.8±1.2) significantly reduced disease activity. Erosion volumes significantly decreased in the MCH and radius of patients with RA treated with TOC (p<0.001) but not in patients treated with ADA/MTX (p=0.77), where they remained stable in size. Mean decrease in erosion volume in TOC-treated patients was -1.0±1.1 mm3 and -3.3±5.9 mm3 in the MCH and radius of TOC-treated patients, respectively, and -0.05±0.9 mm3 and -0.08±4.1 mm3 in patients treated with ADA/MTX. Conclusions: The REBONE study shows that TOC monotherapy achieves more pronounced repair of existing bone erosions than ADA/MTX. Hence, IL-6 is a central factor for the disturbed bone homeostasis in the joints of patients with RA.
CRIS-Team Scopus Importer:2019-08-20
Keywords: bone erosion; interleukin-6; repair; rheumatoid arthritis; tumor necrosis factor

Comparison of Two Symptom Checkers (Ada and Symptoma) in the Emergency Department: Randomized, Crossover, Head-to-Head, Double-Blinded Study - Knitza, Johannes; Hasanaj, Ragip; Beyer, Jonathan; Ganzer, Franziska; Slagman, Anna; Bolanaki, Myrto; Napierala, Hendrik; Schmieding, Malte L.; Al-Zaher, Nizam; Orlemann, Till; Muehlensiepen, Felix; Greenfield, Julia; et al. (Journal of Medical Internet Research, 2024)
Background: Emergency departments (EDs) are frequently overcrowded and increasingly used by nonurgent patients. Symptom checkers (SCs) offer on-demand access to disease suggestions and recommended actions, potentially improving overall patient flow. Contrary to the increasing use of SCs, there is a lack of supporting evidence based on direct patient use. Objective: This study aimed to compare the diagnostic accuracy, safety, usability, and acceptance of 2 SCs, Ada and Symptoma. Methods: A randomized, crossover, head-to-head, double-blinded study including consecutive adult patients presenting to the ED at University Hospital Erlangen. Patients completed both SCs, Ada and Symptoma. The primary outcome was the diagnostic accuracy of SCs. In total, 6 blinded independent expert raters classified diagnostic concordance of SC suggestions with the final discharge diagnosis as (1) identical, (2) plausible, or (3) diagnostically different. SC suggestions per patient were additionally classified as safe or potentially life-threatening, and the concordance of Ada’s and physician-based triage category was assessed. Secondary outcomes were SC usability (5-point Likert-scale: 1=very easy to use to 5=very difficult to use) and SC acceptance net promoter score (NPS). Results: A total of 450 patients completed the study between April and November 2021. The most common chief complaint was chest pain (160/437, 37%). The identical diagnosis was ranked first (or within the top 5 diagnoses) by Ada and Symptoma in 14% (59/437; 27%, 117/437) and 4% (16/437; 13%, 55/437) of patients, respectively. An identical or plausible diagnosis was ranked first (or within the top 5 diagnoses) by Ada and Symptoma in 58% (253/437; 75%, 329/437) and 38% (164/437; 64%, 281/437) of patients, respectively. Ada and Symptoma did not suggest potentially life-threatening diagnoses in 13% (56/437) and 14% (61/437) of patients, respectively. Ada correctly triaged, undertriaged, and overtriaged 34% (149/437), 13% (58/437), and 53% (230/437) of patients, respectively. A total of 88% (385/437) and 78% (342/437) of participants rated Ada and Symptoma as very easy or easy to use, respectively. Ada’s NPS was –34 (55% [239/437] detractors; 21% [93/437] promoters) and Symptoma’s NPS was –47 (63% [275/437] detractors and 16% [70/437]) promoters. Conclusions: Ada demonstrated a higher diagnostic accuracy than Symptoma, and substantially more patients would recommend Ada and assessed Ada as easy to use. The high number of unrecognized potentially life-threatening diagnoses by both SCs and inappropriate triage advice by Ada was alarming. Overall, the trustworthiness of SC recommendations appears questionable. SC authorization should necessitate rigorous clinical evaluation studies to prevent misdiagnoses, fatal triage advice, and misuse of scarce medical resources.
CRIS-Team Scopus Importer:2024-08-30
Keywords: apps; health service research; decision support system; diagnostic accuracy; eHealth; emergency; symptom checker; triage

Complementary App-Based Yoga Home Exercise Therapy for Patients With Axial Spondyloarthritis: Usability Study - Grube, Lara; Petit, Pascal; Vuillerme, Nicolas; Nitschke, Marlies; Nwosu, Obioma Bertrand; Knitza, Johannes; Krusche, Martin; Seifer, Ann-Kristin; Eskofier, Björn; Schett, Georg; Morf, Harriet (JMIR Formative Research, 2024)
Background: Axial spondyloarthritis (AS) is a chronic inflammatory rheumatic disease characterized by potentially disabling inflammation of the spine and adjacent joints. Regular exercise is a cornerstone of treatment. However, patients with AS currently have little support. YogiTherapy (MaD Lab) is an app developed to support patients with AS by providing instructions for yoga-based home exercise therapy. Objective: This study aimed to evaluate the usability and acceptance of the newly designed YogiTherapy app for patients with AS. Methods: Patients completed the User Version of the Mobile Application Rating Scale (uMARS) and net promoter score (NPS) questionnaires after the app introduction. Wilcoxon Mann-Whitney rank sum test, chi-square test for count data, and correlation analysis were conducted to examine the usability of the app, acceptance, and patient characteristics. Results: A total of 65 patients with AS (33, 51% female; age: mean 43.3, SD 13.6 years) were included in the study from May 2022 to June 2023. Subsequently, the data were analyzed. Usability was rated moderate, with a mean uMARS of 3.35 (SD 0.47) points on a scale from 0 to 5. The highest-rated uMARS dimension was information (mean 3.88, SD 0.63), followed by functionality (mean 3.84, SD 0.87). Females reported a significantly higher uMARS total score than males (mean 3.47, SD 0.48 vs mean 3.23, SD 0.45; P=.03, Vargha and Delaney A [VDA] 0.66, 95% CI 0.53-0.77). The mean average of the NPS was 6.23 (SD 2.64) points (on a scale from 0 to 10), based on 43% (26/65 nonpromoters, 42% (25/65) indifferent, and 15% (9/65) promoters. A total of 7% (5/65) of those surveyed did not answer the question. When applying the NPS formula, the result is –26%. The NPS showed a positive correlation with the usage of mobile apps (r=0.39; P=.02). uMARS functionality was significantly higher rated by patients younger than 41 years (mean 4.17, SD 0.55 vs mean 3.54, SD 1; P<.001; VDA 0.69, 95% CI 0.56-0.80). Patients considering mobile apps as useful reported higher uMARS (r=0.38, P=.02). The uMARS app quality mean score was correlated with the frequency of using apps (r=–0.21, P<.001). Conclusions: The results revealed moderate acceptance and usability ratings, prompting further app improvement. Significant differences were observed between age and gender. Our results emphasize the need for further improvements in YogiTherapy.
CRIS-Team Scopus Importer:2024-10-04
Keywords: adjacent joints; ankylosing spondylitis; app; apps; axial spondylarthritis; chronic; correlation analysis; DHA; digital health application; digital therapeutics; DTx; eHealth; exercise; home exercise; joint; joints; patient; patient acceptance; patients; physical exercise; rheumatic disease; self-assessment; spine; spondyloarthritis; therapy; usability; usability study; Yoga; YogiTherapy

Composition of TWIST1 dimers regulates fibroblast activation and tissue fibrosis - Palumbo-Zerr, Katrin; Soare, Alina; Zerr, Pawel; Liebl, Andrea; Mancuso, Rossella; Tomcik, Michal; Sumova, Barbora; Dees, Clara; Chen, Chih-Wei; Wohlfahrt, Thomas; Mallano, Tatjana; Distler, Alfiya; et al. (Annals of the Rheumatic Diseases, 2017)
TWIST1 is a member of the class B of basic helix-loop-helix transcription factors that regulates cell lineage determination and differentiation and has been implicated in epithelial-to-mesenchymal transition. Here, we aimed to investigate the role of TWIST1 for the activation of resident fibroblasts in systemic sclerosis (SSc).The expression of Twist1 in fibroblasts was modulated by forced overexpression or siRNA-mediated knockdown. Interaction of Twist1, E12 and inhibitor Of differentiation (Id) was analysed by co-immunoprecipitation. The role of Twist1 in vivo was evaluated using inducible, conditional knockout mice with either ubiquitous or fibroblast-specific depletion of Twist1. Mice were either challenged with bleomycin or overexpressing a constitutively active transforming growth factor (TGF)? receptor I.The expression of TWIST1 was increased in fibroblasts in fibrotic human and murine skin in a TGF?/SMAD3-dependent manner. TWIST1 in turn enhanced TGF?-induced fibroblast activation in a p38-dependent manner. The stimulatory effects of TWIST1 on resident fibroblasts were mediated by TWIST1 homodimers. TGF? promotes the formation of TWIST1 homodimers by upregulation of TWIST1 and by induction of inhibitor of DNA-binding proteins, which have high affinity for E12/E47 and compete against TWIST1 for E12/E47 binding. Mice with selective depletion of Twist1 in fibroblasts are protected from experimental skin fibrosis in different murine models to a comparable degree as mice with ubiquitous depletion of Twist1.Our data identify TWIST1 as a central pro-fibrotic factor in SSc, which facilitates fibroblast activation by amplifying TGF? signalling. Targeting of TWIST1 may thus be a novel approach to normalise aberrant TGF? signalling in SSc.
EVALuna2:13273

Comprehensive Analysis Identifies Ameloblastin-Related Competitive Endogenous RNA as a Prognostic Biomarker for Testicular Germ Cell Tumour - Geng, Tianxiang; Heyward, Catherine Anne; Chen, Xi; Zheng, Mengxue; Yang, Yang; Reseland, Janne Elin (Cancers, 2022)
Testicular Germ Cell Tumour (TGCT) is one of the most common tumours in young men. Increasing evidence shows that the extracellular matrix has a key role in the prognosis and metastasis of various human cancers. This study analysed the relationship between the matrix protein ameloblastin (AMBN) and potential biological markers associated with TGCT diagnosis and prognosis. The relationship between AMBN and TGCT prognosis was determined by bioinformatic analysis using the expression profiles of three RNAs (long non-coding RNAs (lncRNAs), microRNAs (miRNAs) and mRNAs) from The Cancer Genome Atlas (TCGA) database, and available clinical information of the corresponding patients. Prediction and validation of competitive endogenous RNA (ceRNA) regulatory networks related to AMBN was performed. AMBN and its associated ceRNA regulatory network were found to be related to the recurrence of TGCT, and LINC02701 may be used as a diagnostic factor in TGCT. Furthermore, we identified PELATON (Plaque Enriched LncRNA In Atherosclerotic And Inflammatory Bowel Macrophage Regulation) as an independent prognostic factor for TGCT progression-free interval.
CRIS-Team Scopus Importer:2022-04-29
Keywords: ameloblastin; ceRNA; comprehensive analysis; testicular germ cell tumour

Comprehensive assessment of knee joint synovitis at 7 T MRI using contrast-enhanced and non-enhanced sequences - Treutlein, Christoph; Bäuerle, Tobias; Nagel, Armin Michael; Guermazi, Ali; Kleyer, Arnd; Simon, David; Schett, Georg; Hepp, Tobias; Uder, Michael; Roemer, Frank (BMC Musculoskeletal Disorders, 2020)
BACKGROUND: Seven T ultra-high field MRI systems have recently been approved for clinical use by the U.S. and European regulatory agencies. These systems are now being used clinically and will likely be more widely available in the near future. One of the applications of 7 T systems is musculoskeletal disease and particularly peripheral arthritis imaging. Since the introduction of potent anti-rheumatic therapies over the last two decades MRI has gained increasing importance particularly for assessment of disease activity in early stages of several rheumatic disorders. Commonly gadolinium-based contrast agents are used for assessment of synovitis. Due to potential side-effects of gadolinium non-enhanced techniques are desirable that enable visualization of inflammatory disease manifestations. The feasibility of 7 T MRI for evaluation of peripheral arthritis has not been shown up to now. Aim of our study was to evaluate the feasibility of contrast-enhanced (CE) and non-enhanced MRI at 7 T for the assessment of knee joint synovitis. METHOD: Seven T MRI was acquired for 10 patients with an established diagnosis of psoriatic or rheumatoid arthritis. The study pulse sequence protocol was comprised of a sagittal intermediate-weighted fat-suppressed (FS), axial fluid-attenuated inversion recovery (FLAIR) FS, sagittal 3D T1-weighted dynamic contrast enhanced (DCE) and an axial static 2D T1-weighted FS contrast-enhanced sequence (T1-FS CE). Ordinal scoring on non-enhanced (Hoffa- and effusion-synovitis) and enhanced MRI (11-point synovitis score), and comparison of FLAIR-FS with static T1-FS CE MRI using semiquantitative (SQ) grading and volume assessment was performed. For inter- and intra-reader reliability assessment weighted kappa statistics for ordinal scores and intraclass correlation coefficients (ICC) for continuous variables were used. RESULTS: The total length of study protocol was 15 min 38 s. Different amounts of synovitis were observed in all patients (mild: n = 3; moderate: n = 5; severe: n = 2). Consistently, SQ assessment yielded significantly lower peripatellar summed synovitis scores for the FLAIR-FS sequence compared to the CE T1-FS sequence (p < 0.01). FLAIR-FS showed significantly lower peripatellar synovial volumes (p < 0.01) compared to CE T1-FS imaging with an average percentage difference of 18.6 ± 9.5%. Inter- and intra-reader reliability for ordinal SQ scoring ranged from 0.21 (inter-reader Hoffa-synovitis) to 1.00 (inter-reader effusion-synovitis). Inter- and intra-observer reliability of SQ 3D-DCE parameters ranged from 0.86 to 0.99. CONCLUSIONS: Seven T FLAIR-FS ultra-high field MRI is a potential non-enhanced imaging method able to visualize synovial inflammation with high conspicuity and holds promise for further application in research endeavors and clinical routine by trained readers.
EVALuna2:212706

Concepts of entheseal pain - De Lorenzis, Enrico; Natalello, Gerlando; Simon, David; Schett, Georg; D'Agostino, Maria Antonietta (Arthritis and Rheumatology, 2023)
Pain is the main symptom of entheseal diseases (enthesopathies) despite a paucity of nerve endings in the enthesis itself. Eicosanoids, cytokines, and neuropeptides released during inflammatory and repeated non-physiological mechanical challenge not only stimulate or sensitize primary afferent neurons present in structures adjacent to the enthesis or but also trigger a “neuro-vascular invasion” that allows spreading of nerves and blood vessels into the enthesis. Nociceptive pseudo-unipolar neurons support this process by releasing neurotransmitters from peripheral endings that induce neovascularization and peripheral pain sensitization. This process may explain the frequently observed dissociation between subjective symptoms, i.e. pain and the structural findings in imaging in entheseal disease.
CRIS-Team Scopus Importer:2023-01-20

Concise report: a minimal-invasive method to retrieve and identify entheseal tissue from psoriatic arthritis patients - Pachowsky, Milena; Raimondo, Maria Gabriella; Xu, Cong; Rauber, Simon; Tascilar, Koray; Labinsky, Hannah; Vogg, Mario; Saad, Mina saad aziz; Simon, David; Rech, Jürgen; Soare, Alina; Bräuer, Lars; et al. (Annals of the Rheumatic Diseases, 2022)
Objectives To establish a minimally invasive biopsy technique for the analysis of entheseal tissue in patients with psoriatic arthritis (PsA). Methods Human cadavers were used for establishing the technique to retrieve tissue from the lateral humeral epicondyle enthesis (cadaveric biopsies). After biopsy, the entire enthesis was surgically resected (cadaveric resections). Biopsies and resections were assessed by label-free second harmonic generation (SHG) microscopy. The same technique was then applied in patients with PsA with definition of entheseal tissue by SHG, staining of CD45+immune cells and RNA extraction. Results Entheseal biopsies from five cadavers allowed the retrieval of entheseal tissue as validated by the analysis of resection material. Microscopy of biopsy and resection sections allowed differentiation of entheseal, tendon and muscle tissue by SHG and definition of specific intensity thresholds for entheseal tissue. In subsequent entheseal biopsies of 10 PsA patients: the fraction of entheseal tissue was high (65%) and comparable to cadaveric biopsies (68%) as assessed by SHG microscopy. Furthermore, PsA biopsies showed immune cell infiltration and sufficient retrieval of RNA for further molecular analysis. Conclusion Entheseal biopsy of the lateral epicondyle is feasible in patients with PsA allowing reliable retrieval of entheseal tissue and its identification by SHG microscopy.
CRIS-Team WoS Importer:2022-05-13

Confirmation of CCR6 as a risk factor for anti-topoisomerase I antibodies in systemic sclerosis - Ochoa, E.; Martin, J. -E.; Assassi, S.; Beretta, L.; Carreira, P.; Guillen, A.; Simeon, C. P.; Koumakis, E.; Dieude, P.; Allanore, Y.; Garcia-Hernandez, F. J.; Espinosa, Gerard; et al. (Clinical and Experimental Rheumatology, 2015)
The current knowledge of the influence of systemic sclerosis (SSc) risk loci in the clinical sub-phenotypes is still limited. The main limitation lies in the low frequency of some sub-phenotypes which could be solved by replication studies in independent cohorts and meta-analysis between studies. In this regard, CCR6 gene variants have been recently associated with anti-topoisomerase I positive (ATA+) production in SSc patients in a candidate gene study. This gene has been proposed to have a critical role in IL-17-driven autoimmunity in human diseases.In order to confirm the association between CCR6 and ATA+ SSc patients, we performed an independent replication study in populations of European ancestry. We studied two CCR6 genetic variants (rs968334 and rs3093024) in a total of 901 ATA+ SSc cases, 3,258 ATA- SSc cases and 7,865 healthy controls and compared allelic frequencies for those SNPs in ATA+ SSc with healthy controls and also with ATA- SSc patients.The comparison performed between ATA+ SSc patients and healthy controls showed significant association with SNP rs968334 (p=4.88 x 10-2, OR=1.11). When we compared ATA+ SSc cases with ATA- SSc, both SNPs, rs3093024 and rs968334, showed significant associations (p=2.89 x 10-2, OR=1.13; p=1.69 x 10-2, OR=1.15). Finally, in order to increase even more sample size and statistical power, we meta-analysed our study with the previous reported and found a significant association between SNP rs3093024 and ATA+ SSc patients (p=1.00 x 10-4, OR=1.16) comparing with healthy controls.Our work confirms the association of CCR6 gene and ATA+ SSc patients.
EVALuna2:13155

Consistent Safety Profile with up to 4 Years of Apremilast Treatment: Analysis of Data from 1,493 Subjects with Psoriatic Arthritis in 3 Large, Phase III, Long-Term Studies - Mease, Philip J.; Gladman, Dafna D.; Gomez-Reino, Juan J.; Hall, Stephen; Kavanaugh, Arthur; Lespessailles, Eric; Schett, Georg; Paris, Maria; Teng, Lichen; Wollenhaupt, Juergen (2017)
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Contrary immediate effect of abatacept on skin and joint manifestations in psoriatic arthritis - Valor-Méndez, Larissa; Kleyer, Arnd; Schett, Georg; Manger, Bernhard; Sticherling, Michael (Rheumatology, 2021)
CRIS-Team Scopus Importer:2021-11-05

Contrast-Enhanced Multispectral Optoacoustic Tomography for Functional Assessment of the Gastrointestinal Tract - Paulus, Lars-Philip; Bühler, Adrian; Wagner, Alexandra; Raming, Roman; Jüngert, Jörg; Simon, David; Tascilar, Koray; Schnell, Alexander; Rother, Ulrich; Eckstein, Markus; Lang, Werner; Hörning, André; et al. (Advanced Science, 2023)
Real-time imaging and functional assessment of the intestinal tract and its transit pose a significant challenge to conventional clinical diagnostic methods. Multispectral optoacoustic tomography (MSOT), a molecular-sensitive imaging technology, offers the potential to visualize endogenous and exogenous chromophores in deep tissue. Herein, a novel approach using the orally administered clinical-approved fluorescent dye indocyanine green (ICG) for bedside, non-ionizing evaluation of gastrointestinal passage is presented. The authors are able to show the detectability and stability of ICG in phantom experiments. Furthermore, ten healthy subjects underwent MSOT imaging at multiple time points over eight hours after ingestion of a standardized meal with and without ICG. ICG signals can be visualized and quantified in different intestinal segments, while its excretion is confirmed by fluorescent imaging of stool samples. These findings indicate that contrast-enhanced MSOT (CE-MSOT) provides a translatable real-time imaging approach for functional assessment of the gastrointestinal tract.
CRIS-Team Scopus Importer:2023-06-30
Keywords: indocyanine green; intestine; multispectral optoacoustic tomography; optoacoustics; photoacoustics

Contribution of Type H Blood Vessels to Pathologic Osteogenesis and Inflammation in an Experimental Spondyloarthritis Model - Kaaij, Merlijn H.; Van Hamburg, Jan Piet; Van Rooijen, Charlotte C. N.; Grüneboom, Anika; Kan, Yik Y.; Pots, Desiree; Schett, Georg; Van Ruijven, Leo J.; Van Duivenvoorde, Leonie M.; Huitema, Leonie F. A.; Baeten, Dominique L. P.; Tas, Sander W. (Arthritis and Rheumatology, 2023)
Objective: Spondyloarthritis (SpA) is characterized by pathologic osteogenesis, inflammation, and extensive angiogenesis in axial and peripheral tissues. Current therapies effectively target inflammation, but these therapies lack efficacy in preventing pathologic osteogenesis. Transgenic mice overexpressing transmembrane tumor necrosis factor (tmTNF-Tg mice) exhibit SpA-like features. We hypothesized that type H blood vessels, which are implicated in osteogenesis, are increased and contribute to pathology in this experimental SpA model. Methods: We analyzed ankles, femora, and vertebrae of tmTNF-Tg mice and nontransgenic littermates and tmTNF-Tg mice on either a TNF receptor type I (TNFRI)–deficient or TNF receptor type II (TNFRII)–deficient background for osteogenesis, angiogenesis, and inflammation using advanced imaging technologies at various stages of disease. Results: Compared to nontransgenic littermates, tmTNF-Tg mice exhibited an increase in vertebral type H vessels and osteoprogenitor cells in subchondral bone. These features of increased angiogenesis and osteogenesis were already present before onset of clinical disease symptoms. Type H vessels and osteoprogenitor cells were in close proximity to inflammatory lesions and ectopic lymphoid structures. The tmTNF-Tg mice also showed perivertebral ectopic type H vessels and osteogenesis, an increased number of vertebral transcortical vessels, and enhanced entheseal angiogenesis. In tmTNF-Tg mice crossed on a TNFRI- or TNFRII-deficient background, no clear reduction in type H vessels was shown, suggesting that type H vessel formation is not exclusively mediated via TNFRI or TNFRII. Conclusion: The contribution of type H vessels to pathologic osteogenesis in experimental SpA advances our knowledge of the pathophysiology of this disease and may also provide a novel opportunity for targeted intervention.
CRIS-Team Scopus Importer:2023-05-05

Core genome MLST for molecular typing of C. neoformans var. neoformans isolated in Germany (2004-2021) - Wolf, S.; Helal, M.; Houtermann, A.; Smith, I. Mccormick; Gerkrath, J.; Koppe, U.; Stephan, C.; Harrer, Thomas; Semmler, T.; Rickerts, V. (MYCOSES, 2022)
CRIS-Team WoS Importer:2022-09-23

Correction: Effect of guselkumab on serum biomarkers in patients with active psoriatic arthritis and inadequate response to tumor necrosis factor inhibitors: results from the COSMOS phase 3b study. - Schett, Georg; Chen, Warner; Gao, Sheng; Chakravarty, Soumya D.; Shawi, May; Lavie, Frederic; Zimmermann, Miriam; Sharaf, Mohamed; Coates, Laura C.; Siebert, Stefan (Arthritis Research & Therapy, 2023)
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Correction to: Back on track – digital health applications to treat back pain of rheumatic patients? Results of a qualitative interview study (Rheumatology International, (2024), 10.1007/s00296-024-05726-x) - Boy, Katharina; May, Susann; Labinsky, Hannah; Morf, Harriet; Heinze, Martin; Leipe, Jan; Kuhn, Sebastian; Schett, Georg; Knitza, Johannes; Muehlensiepen, Felix (Rheumatology International, 2024)
In this article Figs. 1 and 2 were wrongly numbered; Fig. 1 should have been Fig. 2 and vice versa as shown below. Summary of perceived advantages and strenghts of back pain DiGAs Summary of observed implementation barriers and potential approaches to overcome them, categorized into four dimensions: patients, healthcare professionals, technology, and the healthcare system The original article has been corrected.
CRIS-Team Scopus Importer:2024-12-06

Correction to: Inhibition of Hsp90 Counteracts the Established Experimental Dermal Fibrosis Induced by Bleomycin (Biomedicines, (2021), 9, 6, (650), 10.3390/biomedicines9060650) - Štorkánová, Hana; Štorkánová, Lenka; Navrátilová, Adéla; Bečvář, Viktor; Hulejová, Hana; Oreská, Sabína; Heřmánková, Barbora; Špiritović, Maja; Bečvář, Radim; Pavelka, Karel; Vencovský, Jiří; Distler, Jörg; et al. (Biomedicines, 2023)
In the original publication [1], there was a mistake in Figure 4 as published. The representative picture of the immunohistochemistry staining for aSMA of the group entitled BLM (w1-6) + nintedanib (w4-6) was erroneously selected from a different group of mice. The corrected Figure 4 appears below. The authors state that the scientific conclusions are unaffected. This correction was approved by the Academic Editor. The original publication has also been updated.
CRIS-Team Scopus Importer:2023-12-08

Correction to: Measuring treatment effect on psoriatic arthritis-related domains: insights from the SPIRIT-H2H study at weeks 24 and 52 (Clinical Rheumatology, (2021), 40, 12, (4943-4954), 10.1007/s10067-021-05891-5) - Behrens, Frank; Leage, Soyi Liu; Sapin, Christophe; El Baou, Celine; De La Torre, Inmaculada; Meszaros, Gabriella; Schett, Georg; Combe, Bernard; Van Den Bosch, Filip; Gossec, Laure (Clinical Rheumatology, 2021)
In the original published version of this article, the Figure 4 contained error. The line “ACR50 plus PASI100” has been presented incorrectly. The Figure 4 is now presented correctly. The original article has been corrected. (Figure presented.).
CRIS-Team Scopus Importer:2021-11-26

Correlation of changes in inflammatory and collagen biomarkers with durable guselkumab efficacy through 2 years in participants with active psoriatic arthritis: results from a phase III randomized controlled trial - Siebert, Stefan; Schett, Georg; Raychaudhuri, Siba P.; Guma, Monica; Chen, Warner; Gao, Sheng; Chakravarty, Soumya D.; Lavie, Frederic; Rahman, Proton (Therapeutic Advances in Musculoskeletal Disease, 2024)
Background: Guselkumab (human monoclonal antibody) selectively inhibits the interleukin (IL)-23p19 subunit. Objectives: Assess the longer-term pharmacodynamic effects of guselkumab and explore associations between such effects and clinical responses in patients with active psoriatic arthritis (PsA). Design: DISCOVER-2 randomized 739 biologic-naïve patients with active PsA (swollen/tender joint counts each ⩾5, C-reactive protein (CRP) ⩾0.6 mg/dL) to guselkumab (100 mg every 4 weeks (Q4W) or at Weeks 0, 4, and then Q8W) or placebo. Guselkumab-randomized participants with available serum biomarker data (randomly selected to reflect demographic and disease characteristics of the DISCOVER-2 population) comprised inflammatory (N = 100) and collagen (N = 178) biomarker cohorts. Methods: Pharmacodynamic effects of guselkumab through 2 years on inflammatory and collagen biomarker levels (general linear model) and associations between biomarkers and improvements in composite measures of joint, skin, and overall disease activity (Spearman linear regression) through 2 years were assessed. The relationship between the pharmacodynamic effects of guselkumab and achieving ⩾50% improvement in the American College of Rheumatology response criteria (ACR50) was assessed using a general linear model. Results: With guselkumab, pharmacodynamic effects on inflammatory (CRP, IL-6, serum amyloid A (SAA), IL-17A, IL-17F, IL-22, and beta-defensin 2 (BD-2)) and collagen (matrix metalloproteinase-degradation type I, III, IV, and VI collagen (C1M, C3M, C4M, and C6M)) biomarker levels were sustained or enhanced through Week 100. Throughout follow-up timepoints (Week 24/52/100), decreases in CRP, IL-6, C1M, and C6M levels correlated (r = 0.26–0.30; p < 0.05) with improved joint disease activity (Disease Activity in Psoriatic Arthritis); decreases in IL-17A, IL-17F, IL-22, and BD-2 levels correlated (r = 0.34–0.58; p < 0.05) with improved skin disease (Psoriasis Area and Severity Index); and decreases in C1M, C3M, C4M, and C6M correlated (r = 0.27–0.31; p < 0.05) with improved overall disease activity (Psoriatic Arthritis Disease Activity Score). Significantly (p < 0.05) greater reductions from baseline at Week 100 in CRP, IL-6, SAA, and C1M levels were observed in participants improving from Week 24 ACR50 nonresponse to Week 100 ACR50 response and were accompanied by a significant decrease in C1M from Week 24 to Week 100 versus nonresponders at both Weeks 24 and 100. Conclusion: In biologic-naïve participants with active PsA, guselkumab elicited substantial and enduring reductions in biomarkers that were associated with durable improvements in joint, skin, and overall disease activity through 2 years of DISCOVER-2. Trial registration: NCT03158285 (clinicaltrials.gov identifier).
CRIS-Team Scopus Importer:2024-11-22
Keywords: guselkumab; IL-23/Th-17 pathway; psoriatic arthritis; serum biomarkers

Correspondence on ‘Immunogenicity and safety of anti-SARS-CoV-2 mRNA vaccines in patients with chronic inflammatory conditions and immunosuppressive therapy in a monocentric cohort' - Valor-Méndez, Larissa; Tascilar, Koray; Simon, David; Distler, Jörg; Kleyer, Arnd; Schett, Georg; Rech, Jürgen (Annals of the Rheumatic Diseases, 2021)
CRIS-Team Scopus Importer:2021-07-09
Keywords: Covid-19; familial mediterranean fever; inflammation; interleukin 1 receptor antagonist protein; vaccination

Corrigendum: Evidence of innate lymphoid cell redundancy in humans - Vely, Frederic; Barlogis, Vincent; Vallentin, Blandine; Neven, Benedicte; Piperoglou, Christelle; Ebbo, Mikael; Perchet, Thibaut; Petit, Maxime; Yessaad, Nadia; Touzot, Fabien; Bruneau, Julie; Mahlaoui, Nizar; et al. (Nature Immunology, 2016)
EVALuna2:13381

Corrigendum to "Fc-gamma receptors are not involved in cartilage damage during experimental osteoarthritis" [Osteoarthritis Cartilage 23 (2015) 1221-1225] - Stock, Michael; Distler, A.; Distler, Jörg; Beyer, Christian; Ruiz-Heiland, G.; Ipseiz, Natacha; Seeling, Michaela; Krönke, Gerhard; Nimmerjahn, Falk; Schett, Georg (Osteoarthritis and Cartilage, 2016)
EVALuna2:13371

CORTICAL BONE LOSS IS AN EARLY FEATURE OF AXIAL SPONDYLOARTHRITIS - Haschka, J.; Neumann, A.; Kleyer, Arnd; Schuster, L.; Englbrecht, Matthias; Figueiredo, C. P.; Muschitz, C.; Kocijan, R.; Resch, H.; Rech, Jürgen; Schett, Georg (2017)
EVALuna2:34450

Cortical bone loss is an early feature of nonradiographic axial spondyloarthritis - Neumann, Anna; Haschka, Judith; Kleyer, Arnd; Schuster, Louis; Englbrecht, Matthias; Berlin, Andreas; Figueiredo, Camille P.; Simon, David; Muschitz, Christian; Kocijan, Roland; Resch, Heinrich; Rech, Jürgen; et al. (Arthritis Research & Therapy, 2018)
BACKGROUND: In the present study, we investigated bone geometry, microstructure, and volumetric bone mineral density (vBMD) in a cohort of patients with nonradiographic axial spondyloarthritis (nr-axSpA) in order to define the early bone changes occurring in axial spondyloarthritis (axSpA) and to define potential factors for deterioration of bone microstructure. METHODS: Patients with axSpA (n = 107) and healthy control subjects (n = 50) of similar age and sex were assessed for geometric, volumetric, and microstructural parameters of bone using high-resolution peripheral quantitative computed tomography (HR-pQCT) at the radius. Additionally, demographic and disease-specific characteristics of patients with axSpA were recorded. RESULTS: Patients with nr-axSpA and control subjects were comparable in age, sex, and body mass index. Geometric and microstructural analysis by HR-pQCT revealed a significantly reduced cortical area (p = 0.022) and cortical thickness (p = 0.006) in patients with nr-axSpA compared with control subjects. Total and cortical vBMD were significantly reduced in patients with nr-axSpA (p = 0.042 and p = 0.007, respectively), whereas there was no difference in trabecular vBMD. Patients with a short disease duration (< 2 years; n = 46) also showed significant reduction of cortical thickness and cortical area compared with control subjects. Patients with disease duration > 2 years (n = 55) additionally developed a decrease of cortical and total vBMD. Multiple regression models identified male sex to be associated with lower cortical vBMD and female sex to be associated with lower trabecular vBMD. CONCLUSIONS: Bone microstructure in patients with nr-axSpA is characterized primarily by deterioration of cortical bone. Cortical bone loss starts early and is evident within the first 2 years of the disease.
EVALuna2:34667

Cost-effective tapering algorithm in patients with rheumatoid arthritis: Combination of multibiomarker disease activity score and autoantibody status - Hagen, Melanie; Englbrecht, Matthias; Haschka, Judith; Reiser, Michaela; Kleyer, Arnd; Hueber, Axel; Manger, Bernhard; Figueiredo, Camille; Cobra, Jayme Fogagnolo; Tony, Hans-Peter; Finzel, Stephanie; Kleinert, Stefan; et al. (Journal of Rheumatology, 2019)
Objective. To analyze the effect of a risk-stratified disease-modifying antirheumatic drug (DMARD)- tapering algorithm based on multibiomarker disease activity (MBDA) score and anticitrullinated protein antibodies (ACPA) on direct treatment costs for patients with rheumatoid arthritis (RA) in sustained remission. Methods. The study was a posthoc retrospective analysis of direct treatment costs for 146 patients with RA in sustained remission tapering and stopping DMARD treatment, in the prospective randomized RETRO study. MBDA scores and ACPA status were determined in baseline samples of patients continuing DMARD (arm 1), tapering their dose by 50% (arm 2), or stopping after tapering (arm 3). Patients were followed over 1 year, and direct treatment costs were evaluated every 3 months. MBDA and ACPA status were used as predictors creating a risk-stratified tapering algorithm based on relapse rates. Results. RA patients with a low MBDA score (< 30 units) and negative ACPA showed the lowest relapse risk (19%), while double-positive patients showed high relapse risk (61%). In ACPA-negative and MBDA-negative (< 30 units), and ACPA or MBDA single-positive (> 30 units) groups, DMARD tapering appears feasible. Considering only patients without flare, direct costs for synthetic and biologic DMARD in the ACPA/MBDA-negative and single positive groups (n = 41) would have been ϵ372,245.16 for full-dose treatment over 1 year. Tapering and stopping DMARD in this low-risk relapse group allowed a reduction of ϵ219,712.03 of DMARD costs. Average reduction of DMARD costs per patient was ϵ5358.83. Conclusion. Combining MBDA score and ACPA status at baseline may allow risk stratification for successful DMARD tapering and cost-effective use of biologic DMARD in patients in deep remission as defined by the 28-joint count Disease Activity Score using erythrocyte sedimentation rate.
CRIS-Team Scopus Importer:2019-05-17
Keywords: Anticyclic Citrullinated Protein Antibodies; Drug Costs; Multibiomarker Disease Activity; Remission; Rheumatoid Arthritis; Tapering

COVID-19 and immune-mediated inflammatory diseases: effect of disease and treatment on COVID-19 outcomes and vaccine responses - Fagni, Filippo; Simon, David; Tascilar, Koray; Schoenau, Verena; Sticherling, Michael; Neurath, Markus; Schett, Georg (The Lancet Rheumatology, 2021)
At the beginning of the COVID-19 pandemic, patients with immune-mediated inflammatory diseases were considered to be at high risk for SARS-CoV-2 infection and the development of severe COVID-19. Data collected over the past year, however, suggest that a diagnosis of inflammatory arthritis, psoriasis, or inflammatory bowel diseases does not increase risk for SARS-CoV-2 infection or severe COVID-19 compared with people without these diseases. Furthermore, substantial data suggest that certain medications frequently used in patients with immune-mediated inflammatory diseases, in particular cytokine inhibitors, might even lower the risk for severe COVID-19. Conversely, glucocorticoids and potentially B-cell-depleting treatments seem to worsen COVID-19 outcomes. Additionally, the first data on SARS-CoV-2 vaccination in patients with these diseases suggest that tolerability of vaccination in patients with immune-mediated inflammatory diseases is good, although the immune response to vaccination can be somewhat reduced in this patient group, particularly those taking methotrexate or CD20-targeted treatment.
CRIS-Team Scopus Importer:2021-10-01

COVID-19 revisiting inflammatory pathways of arthritis - Schett, Georg; Manger, Bernhard; Simon, David; Caporali, Roberto (Nature Reviews Rheumatology, 2020)
Coronavirus disease 2019 (COVID-19) is an infectious disease, caused by severe acute respiratory syndrome coronavirus 2, which predominantly affects the lungs and, under certain circumstances, leads to an excessive or uncontrolled immune activation and cytokine response in alveolar structures. The pattern of pro-inflammatory cytokines induced in COVID-19 has similarities to those targeted in the treatment of rheumatoid arthritis. Several clinical studies are underway that test the effects of inhibiting IL-6, IL-1β or TNF or targeting cytokine signalling via Janus kinase inhibition in the treatment of COVID-19. Despite these similarities, COVID-19 and other zoonotic coronavirus-mediated diseases do not induce clinical arthritis, suggesting that a local inflammatory niche develops in alveolar structures and drives the disease process. COVID-19 constitutes a challenge for patients with inflammatory arthritis for several reasons, in particular, the safety of immune interventions during the pandemic. Preliminary data, however, do not suggest that patients with inflammatory arthritis are at increased risk of COVID-19.
CRIS-Team Scopus Importer:2020-06-26

COVID-19: risk for cytokine targeting in chronic inflammatory diseases? - Schett, Georg; Sticherling, Michael; Neurath, Markus (Nature Reviews Immunology, 2020)
CRIS-Team Scopus Importer:2020-04-28

Cracking a Novel Profibrotic Molecular Mechanism: lncRNA H19X and DDIT4L Crosstalk - Pachera, Elena; Assass, Shervin; Salazar, Gloria; Frank-Bertoncelj, Mojca; Distler, Jörg; Kania, Gabriela; Distler, Oliver (ARTHRITIS & RHEUMATOLOGY, 2019)
CRIS-Team WoS Importer:2020-02-07

cRel expression regulates distinct transcriptional and functional profiles driving fibroblast matrix production in systemic sclerosis - Worrell, Julie C.; Leslie, Jack; Smith, Graham R.; Zaki, Marco Y. W.; Paish, Hannah L.; Knox, Amber; James, Michelle L.; Cartwright, Tyrell N.; O'Reilly, Steven; Kania, Gabriela; Distler, Oliver; Distler, Jörg; et al. (Rheumatology, 2020)
Objectives. NF-kappa B regulates genes that control inflammation, cell proliferation, differentiation and survival. Dysregulated NF-kappa B signalling alters normal skin physiology and deletion of cRel limits bleomycin-induced skin fibrosis. This study investigates the role of cRel in modulating fibroblast phenotype in the context of SSc.
CRIS-Team WoS Importer:2021-01-29

Crossing the barriers: Revisiting the gut feeling in rheumatoid arthritis - Brandl, Carolin; Bucci, Laura; Schett, Georg; Zaiss, Mario (European journal of immunology, 2021)
To avoid autoimmunity, it is essential to keep the balance between the defence against pathogens and the maintenance of tolerance to self-antigens. Mucosal inflammation may lead to breakdown of tolerance and activation of autoreactive cells. Growing evidence suggests a major contribution of gut microbiota to the onset of chronic, autoimmune inflammatory diseases including rheumatoid arthritis (RA). RA patients show significant differences in the composition of gut microbiota compared to healthy controls, and in murine arthritis models certain bacteria can induce inflammatory Th17 responses or autoantibody production. The gut microbiota plays an important role in regulating the balance between immunogenic and tolerogenic immune responses. The intestinal barrier is the site of the body where most host–microbiota interaction takes place. Certain microbiota or their metabolites can cause a break in homeostasis by affecting the intestinal barrier integrity and permeability. However, an intact intestinal barrier is essential to separate the intestinal epithelium from toxins, microorganisms, and antigens in the gut lumen. This review will focus on the correlation between a leaky gut and the onset of arthritis. Furthermore, it will be discussed how targeting the intestinal barrier function by dietary changes might provide an opportunity to modulate the development of RA.
CRIS-Team Scopus Importer:2021-03-12
Keywords: diet; gut dysbiosis; intestinal barrier; microbiome; rheumatoid arthritis

Cross-Reactivity Between Influenza Matrix- and HIV-1 P17-Specific CTL-A Large Cohort Study - Hueckelhoven, Angela; Etschel, Jennifer; Bergmann, Silke; Zitzelsberger, Kathrin; Müller-Schmucker, Sandra; Harrer, Ellen G.; Harrer, Thomas (Jaids-Journal of Acquired Immune Deficiency Syndromes, 2015)
It has been reported that HIV-1-specific cytotoxic T cells (CTL) recognizing the HLA-A2-restricted p17 epitope SLYNTVATL (SL9) can cross-react with the HLA-A2-restricted influenza matrix epitope GILGFVFTL (GL9). So far, the prevalence of GL9-cross-reacting HIV-1-specific CTL in larger cohorts of HIV-1-infected patients is unknown, and there are no data yet on whether SL9/GL9-cross-reactive CTL may influence the course of HIV-1 infection.We analyzed the presence of SL9/GL9-cross-reacting CTL in a cohort of 175 HLA-A2-positive HIV-1-infected patients. Peripheral blood mononuclear cells were stimulated in vitro with SL9 and GL9 peptides, and outgrowing cell lines regarding cross-reactivity and recognition of viral variants in ?-interferon enzyme-linked immunospot assays were analyzed.SL9- and GL9-specific CTL could be generated in 52.6% and 53.7% of 175 patients, respectively. Both SL9- and GL9-specific CTL were more frequently observed in patients on antiretroviral therapy (ART). Of the 92 SL9-specific CTL and the 94 GL9-specific CTL, 65.2% and 66%, respectively, showed at least partial SL9/GL9 cross-reactivity. SL9/GL9-cross-reactive CTL could be detected in 42.9% of the 175 patients. Recognition of SL9 was associated with lower viral loads and higher CD4 cell counts in patients on ART. Patients with GL9/SL9 cross-reactivity displayed similar CD4 cell counts than patients without GL9/SL9-cross-reactive cells. GL9/SL9-cross-reactive cells were associated with higher viral loads in patients on ART.Partially SL9/GL9-cross-reactive CTL are frequently observed in HIV-1-infected patients. So far, we could not detect a significant influence of the presence of SL9/GL9-cross-reacting CTL on the course of HIV-1 infection.
EVALuna2:13143

Cutaneous Manifestations, Clinical Characteristics, and Prognosis of Patients with Systemic Sclerosis Sine Scleroderma: Data from the International EUSTAR Database - Lescoat, Alain; Huang, Suiyuan; Carreira, Patricia E.; Siegert, Elise; De Vries-Bouwstra, Jeska; Distler, Jörg; Smith, Vanessa; Del Galdo, Francesco; Anic, Branimir; Damjanov, Nemanja; Rednic, Simona; Ribi, Camillo; et al. (JAMA Dermatology, 2023)
Importance: Systemic sclerosis (SSc) sine scleroderma (ssSSc) is a subset of SSc defined by the absence of skin fibrosis. Little is known about the natural history and skin manifestations among patients with ssSSc. Objective: To characterize the clinical phenotype of patients with ssSSc compared with patients with limited cutaneous SSc (lcSSc) and diffuse cutaneous SSc (dcSSc) within the EUSTAR database. Design, Setting, and Participants: This longitudinal observational cohort study based on the international EUSTAR database included all patients fulfilling the classification criteria for SSc assessed by the modified Rodnan Skin score (mRSS) at inclusion and with at least 1 follow-up visit; ssSSc was defined by the absence of skin fibrosis (mRSS = 0 and no sclerodactyly) at all available visits. Data extraction was performed in November 2020, and data analysis was performed from April 2021 to April 2023. Main Outcomes and Measures: Main outcomes were survival and skin manifestations (onset of skin fibrosis, digital ulcers, telangiectasias, puffy fingers). Results: Among the 4263 patients fulfilling the inclusion criteria, 376 (8.8%) were classified as having ssSSc (mean [SD] age, 55.3 [13.9] years; 345 [91.8%] were female). At last available visit, in comparison with 708 patients with lcSSc and 708 patients with dcSSc with the same disease duration, patients with ssSSc had a lower prevalence of previous or current digital ulcers (28.2% vs 53.1% in lcSSc; P <.001; and 68.3% in dcSSc; P <.001) and puffy fingers (63.8% vs 82.4% in lcSSc; P <.001; and 87.6% in dcSSc; P <.001). By contrast, the prevalence of interstitial lung disease was similar in ssSSc and lcSSc (49.8% and 57.1%; P =.03) but significantly higher in dcSSc (75.0%; P <.001). Skin telangiectasias were associated with diastolic dysfunction in patients with ssSSc (odds ratio, 4.778; 95% CI, 2.060-11.081; P <.001). The only independent factor for the onset of skin fibrosis in ssSSc was the positivity for anti-Scl-70 antibodies (odds ratio, 3.078; 95% CI, 1.227-7.725; P =.02). Survival rate was higher in patients with ssSSc (92.4%) compared with lcSSc (69.4%; P =.06) and dcSSc (55.5%; P <.001) after up to 15 years of follow-up. Conclusions and Relevance: Systemic sclerosis sine scleroderma should not be neglected considering the high prevalence of interstitial lung disease (>40%) and SSc renal crisis (almost 3%). Patients with ssSSc had a higher survival than other subsets. Dermatologists should be aware that cutaneous findings in this subgroup may be associated with internal organ dysfunction. In particular, skin telangiectasias in ssSSc were associated with diastolic heart dysfunction.
CRIS-Team Scopus Importer:2023-10-06

Cutting Edge: Homeostasis of Innate Lymphoid Cells Is Imbalanced in Psoriatic Arthritis - Soare, Alina; Weber, Stefanie; Maul, Lisa; Rauber, Simon; Gheorghiu, Ana Maria; Luber, Markus; Houssni, Ismail; Kleyer, Arnd; von Pickardt, Gero; Gado, Manuel; Simon, David; Rech, Jürgen; et al. (Journal of Immunology, 2018)
Innate lymphoid cells (ILC) have a high potency for cytokine production independent of specific Ag stimulation. Imbalance of ILC subsets may influence cytokine production in humans and hence be associated with the development of inflammatory disease. Evidence for an imbalance of ILC homeostasis in human disease, however, is very limited to date. In this study we show that psoriatic arthritis (PsA), a severe disease of the joints depending on the activation of the IL-23/IL-17 pathway, is characterized by a skewed ILC homeostasis. Circulating ILC3s as potent source of IL-17/IL-22 were elevated in active PsA, whereas ILC2s, which produce proresolving cytokines, were decreased. The ILC2/ILC3 ratio was significantly correlated with clinical disease activity scores and the presence of imaging signs of joint inflammation and bone damage. Multivariable analysis showed that a high ILC2/ILC3 ratio is associated with remission in PsA, suggesting that specific alterations of ILC homeostasis control disease activity in PsA.
EVALuna2:13524

CyberGlove for clinical use? - Michaelis, Johannes; Reiher, Isabella; Heinrich, Simon; Coppers, Birte; Schett, Georg; Kleyer, Arnd; Elewaut, Dirk; De Craemer, Marieke; Leyendecker, Sigrid; Liphardt, Anna-Maria (FAU-Networking Night Medizintechnik, 2021)

Cytokine and reactivity profiles in SLE patients following anti-CD19 CART therapy - Nunez, Daniel; Patel, Darshil; Volkov, Jenell; Wong, Steven; Vorndran, Zachary; Müller, Fabian; Aigner, Michael; Völkl, Simon; Mackensen, Andreas; Schett, Georg; Basu, Samik (Molecular Therapy, 2023)
Chimeric antigen receptor (CAR) T cells targeting CD19+ B cells have demonstrated efficacy in refractory systemic lupus erythematosus (SLE). Although initial clinical data suggest that anti-CD19 CAR T cell therapy is well tolerated and highly effective, the immunologic consequences of CAR T cell therapy in SLE patients remain unclear. We profiled serum in six refractory SLE patients prior to and 3 months following CAR T cell infusion. Three months post T cell infusion, the inflammatory cytokines IL-6 and TNFα decreased in patient sera. This was accompanied by elevations in serum IL-7 and BAFF. Furthermore, SLE-associated antibodies dropped profoundly in five of six patients. Last, consistent with other reports of CD19 CAR T therapy in B cell malignancies, we were able to show marginal impact of anti-CD19 CART therapy on pre-existing humoral immune responses in SLE patients. Together, these results provide insights into the mechanisms of efficacy of anti-CD19 CAR T cell therapy in SLE.
CRIS-Team Scopus Importer:2023-09-29
Keywords: antibodies; autoimmune disease; CAR; chimeric antigen receptor T cell; cytokines; SLE; systemic lupus erythematous; vaccines

Cytokine-mediated induction of human xylosyltransferase-I in systemic sclerosis skin fibroblasts - Ly, Thanh Diep; Kleine, Anika; Plümers, Ricarda; Fischer, Bastian; Schmidt, Vanessa; Hendig, Doris; Distler, Jörg; Kuhn, Joachim; Knabbe, Cornelius; Faust, Isabel (Biochemical and Biophysical Research Communications, 2021)
Systemic sclerosis (SSc) is an inflammatory fibrotic disease characterized by an excessive extracellular matrix deposition in the skin and internal organs. One fibrotic key event remains the fibroblast-to-myofibroblast differentiation that is controlled by a combination of mechanical and soluble factors, such as transforming growth factor-β1 (TGF-β1) and interleukin-1β (IL-1β). One important myofibroblast biomarker is human xylosyltransferase-I (XT-I), the initial enzyme in proteoglycan biosynthesis. Increased serum XT activity was quantified in SSc, but the underlying cellular mechanisms remain elusive. This study aims to determine the cellular basis of XT-I induction in SSc by using a myofibroblast cell culture model with SSc fibroblasts (SScF) and healthy control fibroblasts. We found that SScF exhibit a higher extracellular XT-I activity compared to control fibroblasts. This increased XT-I activity in SScF was demonstrated to be mediated by an enhanced autocrine TGF-β signaling. Upon IL-1β treatment, SScF showed an increased mRNA expression level of XT-I and TGF-β receptor II (TGFBR2), while healthy control fibroblasts did not, pointing towards an involvement of IL-1β in the cytokine-mediated XT-I induction. Performing microRNA (miRNA) inhibition experiments in the presence of TGF-β1, we showed that the pro-fibrotic effect of IL-1β may be mediated by a miRNA-21/TGF-β receptor II axis, enhancing the autocrine TGF-β signaling in SScF. Taken together, this study improves the mechanistic understanding of fibrotic XT-I induction in SSc by identifying a hitherto unknown IL-1β-mediated miRNA-21/TGFBR2 regulation contributing to the enhanced XYLT1 expression and XT-I activity in SScF.
CRIS-Team Scopus Importer:2021-03-12
Keywords: Fibrosis; Interleukin-1β; microRNA-21; Systemic sclerosis; TGF-β receptor II; Xylosyltransferase-I

Cytotoxic effect of Efavirenz in BxPC-3 pancreatic cancer cells is based on oxidative stress and is synergistic with ionizing radiation - Hecht, Markus; Harrer, Thomas; Koeber, Verena; Sarpong, Eric Opoku; Moser, Fabian; Fiebig, Nora; Schwegler, Manuela; Stürzl, Michael; Fietkau, Rainer; Distel, Luitpold (Oncology Letters, 2018)
The non-nucleoside reverse transcriptase inhibitor (NNRTI) Efavirenz is frequently used in human immunodeficiency virus treatment, but also efficient against cancer in mouse models. Its radiosensitizing effect makes it a promising drug for combination with radiotherapy. The efficacy of Efavirenz combined with irradiation was assessed with immunostaining of DNA-damage markers and colony formation assays in BxPC-3 pancreatic cancer cells. Gene expression and protein phosphorylation of the Efavirenz-sensitive BxPC-3 cells was compared to the resistant primary fibroblasts SBL-5. Oxidative stress, mitochondrial damage and cell death were studied with live-cell microscopy and flow cytometry. Combined Efavirenz and radiation significantly increased the number of γH2AX and phospho-ataxia telangiectasia mutated foci. Efavirenz and ionizing radiation had a synergistic effect using the clonogenic survival assay. Efavirenz selectively induced cell death in the BxPC-3 cells. The differing gene expression of cell cycle and apoptotic regulator genes in both cell cultures after Efavirenz treatment match with this selective effect against cancer cells. In the phosphoprotein array, an early phosphorylation of extracellular signal-related kinase 1/2 and p38 mitogen-activated protein kinase was notably detected in the cancer cells. The phosphorylation of AKT decreased in the cancer cells whereas it increased in the fibroblasts. Oxidative stress and mitochondrial membrane depolarization appeared in the cancer cells immediately after Efavirenz treatment, but not in the fibroblasts. Efavirenz has an anti-cancer effect against pancreatic cancer mainly by the induction of oxidative stress. The antitumor potential of Efavirenz and radiotherapy are additive.
EVALuna2:36443

Deciphering Pro-angiogenic Transcription Factor Profiles in Hypoxic Human Endothelial Cells by Combined Bioinformatics and in vitro Modeling - Schmidt, Arne; Fuchs, Maximilian; Stojanović, Stevan D.; Liang, Chunguang; Schmidt, Kevin; Jung, Mira; Xiao, Ke; Weusthoff, Jan; Just, Annette; Pfanne, Angelika; Distler, Jörg; Dandekar, Thomas; et al. (Frontiers in Cardiovascular Medicine, 2022)
Background: Constant supply of oxygen is crucial for multicellular tissue homeostasis and energy metabolism in cardiac tissue. As a first response to acute hypoxia, endothelial cells (ECs) promote recruitment and adherence of immune cells to the dysbalanced EC barrier by releasing inflammatory mediators and growth factors, whereas chronic hypoxia leads to the activation of a transcription factor (TF) battery, that potently induces expression of growth factors and cytokines including platelet-derived growth factor (PDGF) and vascular endothelial growth factor (VEGF). We report a hypoxia-minded, targeted bioinformatics approach aiming to identify and validate TFs that regulate angiogenic signaling. Results: A comprehensive RNA-Seq dataset derived from human ECs subjected to normoxic or hypoxic conditions was selected to identify significantly regulated genes based on (i) fold change (normoxia vs. hypoxia) and (ii) relative abundancy. Transcriptional regulation of this gene set was confirmed via qPCR in validation experiments where HUVECs were subjected to hypoxic conditions for 24 h. Screening the promoter and upstream regulatory elements of these genes identified two TFs, KLF5 and SP1, both with a potential binding site within these regions of selected target genes. In vitro, siRNA experiments confirmed SP1- and KLF5-mediated regulation of identified hypoxia-sensitive endothelial genes. Next to angiogenic signaling, we also validated the impact of TFs on inflammatory signaling, both key events in hypoxic sensing. Both TFs impacted on inflammatory signaling since endogenous repression led to increased NF-κB signaling. Additionally, SP1 silencing eventuated decreased angiogenic properties in terms of proliferation and tube formation. Conclusion: By detailed in silico analysis of promoter region and upstream regulatory elements for a list of hypoxia-sensitive genes, our bioinformatics approach identified putative binding sites for TFs of SP or KLF family in vitro. This strategy helped to identify TFs functionally involved in human angiogenic signaling and therefore serves as a base for identifying novel RNA-based drug entities in a therapeutic setting of vascularization.
CRIS-Team Scopus Importer:2022-10-28
Keywords: angiogenesis; endothelial; hypoxia; promoter profiling; signaling; transcription factor

Deciphering the pro-fibrotic phenotype of fibroblasts in systemic sclerosis - Maier, Christiane; Distler, Jörg; Beyer, Christian (Experimental Dermatology, 2014)
LeRoy's seminal work on the phenotypic features of scleroderma fibroblasts has been directing fibrosis research in the field of systemic sclerosis (SSc, scleroderma) for the past 30 years. His principal experiment, to culture skin fibroblasts from patients with SSc and study their pro-fibrotic phenotype in comparison with skin fibroblasts from healthy individuals, has been used by most basic and translational fibrosis studies in SSc. LeRoy's findings have revolutionized our understanding of the disease pathogenesis and guided the development of novel antifibrotic therapies towards fibroblast-specific approaches.
EVALuna2:12893

DECLINE IN FORCED VITAL CAPACITY (FVC) IN SUBJECTS WITH SYSTEMIC SCLEROSIS-ASSOCIATED INTERSTITIAL LUNG DISEASE (SSC-ILD) IN THE SENSCIS TRIAL VERSUS HYPOTHETICAL REFERENCE SUBJECTS WITHOUT LUNG DISEASE - Maher, T.; Bourdin, A.; Volkmann, E.; Vettori, S.; Distler, Jörg; Alves, M.; Stock, C.; Distler, O. (ANNALS OF THE RHEUMATIC DISEASES, 2021)
CRIS-Team WoS Importer:2021-09-24

Decline in forced vital capacity in subjects with systemic sclerosis-associated interstitial lung disease in the SENSCIS trial compared with healthy reference subjects - Maher, Toby M.; Bourdin, Arnaud; Volkmann, Elizabeth R.; Vettori, Serena; Distler, Jörg; Alves, Margarida; Stock, Christian; Distler, Oliver (Respiratory Research, 2022)
Background: The forced vital capacity (FVC) of healthy individuals depends on their age, sex, ethnicity and height. Systemic sclerosis-associated interstitial lung disease (SSc-ILD) is characterised by loss of FVC. We compared FVC values in the subjects with SSc-ILD in the SENSCIS trial of nintedanib versus placebo with values from hypothetical matched healthy references. Methods: The SENSCIS trial enrolled subjects with SSc with first non-Raynaud symptom in the prior ≤ 7 years, extent of fibrotic ILD on HRCT ≥ 10%, and FVC ≥ 40% predicted. FVC at baseline and decline in FVC over 52 weeks were compared with FVC values in hypothetical healthy reference subjects matched 1:1 to the subjects in the trial for age, sex, ethnicity and height, determined using equations published by the European Respiratory Society Global Lung Function Initiative. Results: At baseline, mean (SD) FVC was 2460 (737) mL in the nintedanib group (n = 287) compared with 3403 (787) mL in the hypothetical matched healthy references. Mean (SD) FVC was 2544 (817) mL in the placebo group (n = 286) compared with 3516 (887) mL in the hypothetical matched healthy references. Mean (SE) changes in FVC at week 52, i.e., age-related loss of lung function, in the hypothetical healthy references matched to the nintedanib and placebo groups, respectively, were − 26.3 (0.5) mL and − 25.8 (0.5) mL. The difference in the change in FVC at week 52 between the nintedanib group and the hypothetical healthy references was 26.6 mL (95% CI: 1.2, 52.0; p = 0.04). The difference in the change in FVC at week 52 between the placebo group and the hypothetical healthy references was 77.5 mL (95% CI: 51.4, 103.7; p < 0.0001). Conclusions: Subjects with SSc-ILD in the SENSCIS trial had impaired lung function at baseline and experienced further deterioration over 52 weeks. The decline in FVC in the placebo group was four-fold greater than in a hypothetical group of matched healthy references, whereas the decline in FVC in patients who received nintedanib was two-fold greater than in hypothetical healthy references. These data highlight the clinical relevance of the slowing of FVC decline provided by nintedanib. Trial registration Registered 5 November 2015, https://clinicaltrials.gov/ct2/show/NCT02597933.
CRIS-Team Scopus Importer:2022-07-15
Keywords: Connective tissue diseases; Pulmonary fibrosis; Scleroderma; systemic; Vital capacity

Decreased Quantity and Quality of the Periarticular and Nonperiarticular Bone in Patients With Rheumatoid Arthritis: A Cross-Sectional HR-pQCT Study - Kocijan, Roland; Finzel, Stephanie; Englbrecht, Matthias; Engelke, Klaus; Rech, Juergen; Schett, Georg (Journal of Bone and Mineral Research, 2014)
Rheumatoid arthritis (RA) is a highly bone destructive disease. Although it is well established that RA leads to bone loss and increased fracture risk, current knowledge on the microstructural changes of bone in RA is still limited. The purpose of this study was to assess the microstructure of periarticular and nonperiarticular bone in female and male RA patients and compare it with respective healthy controls. We performed two high-resolution peripheral quantitative computed tomography (HR-pQCT; Xtreme-CT) scans, one of the distal radius and one of the ultradistal radius in 90 patients with RA (60 females, 30 males) and 70 healthy controls (40 females, 30 males) matched for sex, age, and body mass index. Volumetric bone mineral density (vBMD), bone geometry, and bone microstructure including trabecular bone volume fraction (BV/TV), trabecular number (Tb.N), trabecular thickness (Tb.Th), cortical thickness (Ct.Th) and cortical porosity (Ct.Po) were assessed. At the distal and ultradistal radius, trabecular (p = 0.005 and p < 0.001) and cortical BMD (p < 0.001 and p < 0.001) were significantly decreased in male and female patients with RA, respectively. BV/TV was also decreased at both sites, based on lower Tb.N in female RA (p < 0.001 for both sites) and lower Tb.Th (p = 0.034 and p = 0.005) in male RA patients compared with respective healthy controls. Cortical thinning (p = 0.018 and p = 0.002) but not Ct.Po (p = 0.070 and p = 0.275) was pronounced in male and female RA patients at the distal radius. Cortical perimeter was increased in male and female RA patients at both sites. Multiple regression models showed that bone geometry (cortical perimeter) is predominantly influenced by age of the RA patient, cortical thickness by both age and disease duration, and trabecular microstructure predominantly by the disease duration. In summary, these data show profound deterioration of bone microstructure in the appendicular skeleton of RA patients at both periarticular and nonperiarticular sites. © 2014 American Society for Bone and Mineral Research.
EVALuna2:10056

Deep learning-based classification of erosion, synovitis and osteitis in hand MRI of patients with inflammatory arthritis - Schlereth, Maja; Yalcin-Mutlu, Melek; Utz, Jonas; Bayat, Sara; Heimann, Tobias; Qiu, Jingna; Ehring, Chris; Liu, Chang; Uder, Michael; Kleyer, Arnd; Simon, David; Roemer, Frank; et al. (RMD Open, 2024)
OBJECTIVES: To train, test and validate the performance of a convolutional neural network (CNN)-based approach for the automated assessment of bone erosions, osteitis and synovitis in hand MRI of patients with inflammatory arthritis. METHODS: Hand MRIs (coronal T1-weighted, T2-weighted fat-suppressed, T1-weighted fat-suppressed contrast-enhanced) of rheumatoid arthritis (RA) and psoriatic arthritis (PsA) patients from the rheumatology department of the Erlangen University Hospital were assessed by two expert rheumatologists using the Outcome Measures in Rheumatology-validated RA MRI Scoring System and PsA MRI Scoring System scores and were used to train, validate and test CNNs to automatically score erosions, osteitis and synovitis. Scoring performance was compared with human annotations in terms of macro-area under the receiver operating characteristic curve (AUC) and balanced accuracy using fivefold cross-validation. Validation was performed on an independent dataset of MRIs from a second patient cohort. RESULTS: In total, 211 MRIs from 112 patients (14 906 region of interests (ROIs)) were included for training/internal validation using cross-validation and 220 MRIs from 75 patients (11 040 ROIs) for external validation of the networks. The networks achieved high mean (SD) macro-AUC of 92%±1% for erosions, 91%±2% for osteitis and 85%±2% for synovitis. Compared with human annotation, CNNs achieved a high mean Spearman correlation for erosions (90±2%), osteitis (78±8%) and synovitis (69±7%), which remained consistent in the validation dataset. CONCLUSIONS: We developed a CNN-based automated scoring system that allowed a rapid grading of erosions, osteitis and synovitis with good diagnostic accuracy and using less MRI sequences compared with conventional scoring. This CNN-based approach may help develop standardised cost-efficient and time-efficient assessments of hand MRIs for patients with arthritis.
CRIS-Team Scopus Importer:2024-06-28
Keywords: classification; machine learning; magnetic resonance imaging; psoriatic arthritis; rheumatoid arthritis

Deep Learning-Based Classification of Inflammatory Arthritis by Identification of Joint Shape Patterns—How Neural Networks Can Tell Us Where to “Deep Dive” Clinically - Folle, Lukas; Simon, David; Tascilar, Koray; Krönke, Gerhard; Liphardt, Anna-Maria; Maier, Andreas; Schett, Georg; Kleyer, Arnd (Frontiers in Medicine, 2022)
Keywords: artificial intelligence; arthritis; joint; bone; deep learning

Deep learning methods allow fully automated segmentation of metacarpal bones to quantify volumetric bone mineral density - Folle, Lukas; Meinderink, Timo; Simon, David; Liphardt, Anna-Maria; Krönke, Gerhard; Schett, Georg; Kleyer, Arnd; Maier, Andreas (Scientific Reports, 2021)
Arthritis patients develop hand bone loss, which leads to destruction and functional impairment of the affected joints. High resolution peripheral quantitative computed tomography (HR-pQCT) allows the quantification of volumetric bone mineral density (vBMD) and bone microstructure in vivo with an isotropic voxel size of 82 micrometres. However, image-processing to obtain bone characteristics is a time-consuming process as it requires semi-automatic segmentation of the bone. In this work, a fully automatic vBMD measurement pipeline for the metacarpal (MC) bone using deep learning methods is introduced. Based on a dataset of HR-pQCT volumes with MC measurements for 541 patients with arthritis, a segmentation network is trained. The best network achieves an intersection over union as high as 0.94 and a Dice similarity coefficient of 0.97 while taking only 33 s to process a whole patient yielding a speedup between 2.5 and 4.0 for the whole workflow. Strong correlation between the vBMD measurements of the expert and of the automatic pipeline are achieved for the average bone density with 0.999 (Pearson) and 0.996 (Spearman’s rank) with p < 0.001for all correlations. A qualitative assessment of the network predictions and the manual annotations yields a 65.9% probability that the expert favors the network predictions. Further, the steps to integrate the pipeline into the clinical workflow are shown. In order to make these workflow improvements available to others, we openly share the code of this work.
Keywords: Rheumatic diseases; segmentation; deep learning

Deepnapsi: Deep Learning for Nail Psoriasis Prediction - Folle, Lukas; Fenzl, Pauline; Fagni, Filippo; Thies, Mareike; Christlein, Vincent; Meder, Christine; Sticherling, Michael; Simon, David; Schett, Georg; Maier, Andreas; Kleyer, Arnd (Proceedings - International Symposium on Biomedical Imaging, 2023)
Nail psoriasis is a frequent condition that is associated with a severe course of rheumatic diseases. Thus, it may be used to adapt the therapy of patients according to the change of nail psoriasis. The nail psoriasis severity index (NAPSI) was developed to measure this condition. Nevertheless, there is a lack of application for the NAPSI, as its use in the clinic is too time-consuming. In this work, we propose the use of advancements in deep learning in a new domain by recording, annotating, and predicting the NAPSI based on photographs of the hand and term our approach DeepNAPSI. This allows not just the automated recording of the NAPSI in the clinic, but also patient self-assessment from home. Our method achieved an area-under-receiver-operator-characteristic curve (AUROC) of 0.83 and 0.86 for macro and micro averaging, respectively, and a mean absolute error of 0.55.
CRIS-Team Scopus Importer:2023-10-06
Keywords: Deep Learning; Mobile device; Nail psoriasis; Precision medicine

DeepNAPSI multi-reader nail psoriasis prediction using deep learning - Folle, Lukas; Fenzl, Pauline; Fagni, Filippo; Thies, Mareike; Christlein, Vincent; Meder, Christine; Simon, David; Minnopoulou, Ioanna; Sticherling, Michael; Schett, Georg; Maier, Andreas; Kleyer, Arnd (Nature Scientific Reports, 2023)
Nail psoriasis occurs in about every second psoriasis patient. Both, finger and toe nails can be affected and also severely destroyed. Furthermore, nail psoriasis is associated with a more severe course of the disease and the development of psoriatic arthritis. User independent quantification of nail psoriasis, however, is challenging due to the heterogeneous involvement of matrix and nail bed. For this purpose, the nail psoriasis severity index (NAPSI) has been developed. Experts grade pathological changes of each nail of the patient leading to a maximum score of 80 for all nails of the hands. Application in clinical practice, however, is not feasible due to the time-intensive manual grading process especially if more nails are involved. In this work we aimed to automatically quantify the modified NAPSI (mNAPSI) of patients using neuronal networks retrospectively. First, we performed photographs of the hands of patients with psoriasis, psoriatic arthritis, and rheumatoid arthritis. In a second step, we collected and annotated the mNAPSI scores of 1154 nail photos. Followingly, we extracted each nail automatically using an automatic key-point-detection system. The agreement among the three readers with a Cronbach’s alpha of 94% was very high. With the nail images individually available, we trained a transformer-based neural network (BEiT) to predict the mNAPSI score. The network reached a good performance with an area-under-receiver-operator-curve of 88% and an area-under precision-recall-curve (PR-AUC) of 63%. We could compare the results with the human annotations and achieved a very high positive Pearson correlation of 90% by aggregating the predictions of the network on the test set to the patient-level. Lastly, we provided open access to the whole system enabling the use of the mNAPSI in clinical practice.

Deep Tissue Characterization with Optical Coherence Elastography: A Comparison of Different Methods - Parmar, Asha; Sharma, Gargi; Ramming, Andreas; Singh, Kanwarpal (Materials, 2022)
The measurement of the biomechanical properties of the skin is of great interest since these properties play an important role in the development of several diseases such as skin cancer and systemic sclerosis. In this direction, several diagnostic tools have been developed to analyze the mechanical properties of the skin. Optical coherence elastography (OCE) is one of the emerging imaging techniques used for the characterization of the mechanical properties of the tissue quantitatively. In systemic sclerosis patients, the measurement of the mechanical properties of the deeper skin layers is desirable compared to the superficial layers. There are several variants of OCE that exist, but it is still not clear which method is more suitable for the measurement of the mechanical properties of the deeper tissue. In this work, we tested three common methods, the pulsed excitation method, the continuous wave excitation method, and the resonant frequency method, for the measurement of the mechanical properties of the deeper layers in the tissue. We found out that the pulsed wave excitation method provides the most reliable measurements in the shortest possible time compared to the other two methods.
CRIS-Team Scopus Importer:2022-12-23
Keywords: common path OCT; handheld probe; optical coherence elastography; systemic sclerosis

Def6 Restrains Osteoclastogenesis and Inflammatory Bone Resorption - Binder, Nikolaus; Miller, Christine; Yoshida, Masaki; Inoue, Kazuki; Nakano, Shinichi; Hu, Xiaoyu; Ivashkiv, Lionel B.; Schett, Georg; Pernis, Alessandra; Goldring, Steven R.; Ross, F. Patrick; Zhao, Baohong (Journal of Immunology, 2017)
Inflammatory bone resorption mediated by osteoclasts is a major cause of morbidity and disability in many inflammatory disorders, including rheumatoid arthritis (RA). The mechanisms that regulate osteoclastogenesis and bone resorption in inflammatory settings are complex and have not been well elucidated. In this study, we identify the immunoregulator differentially expressed in FDCP 6 homolog (Def6) as a novel inhibitor of osteoclastogenesis in physiological and inflammatory conditions. Def6 deficiency in Def6(-/-) mice enhanced the sensitivity of osteoclast precursors to the physiological osteoclastogenic inducer receptor activator for NF-?B ligand, and Def6(-/-) osteoclasts formed actin rings. Furthermore, Def6 deficiency markedly increased TNF-?-induced osteoclastogenesis in vitro and in vivo and enhanced bone resorption in an inflammatory osteolysis mouse model. TNF-? serum levels correlated negatively with Def6 expression levels in osteoclast precursors obtained from RA patients, and the osteoclastogenic capacity of the osteoclast precursors was significantly inversely correlated with their Def6 expression levels, indicating that Def6 functions as an inhibitor of excessive osteoclast formation and bone destruction in RA. Mechanistically, Def6 suppressed osteoclastogenesis and the expression of key osteoclastogenic factors NFATc1, B lymphocyte-induced maturation protein-1, and c-Fos by regulating an endogenous IFN-?-mediated autocrine feedback loop. The Def6-dependent pathway may represent a novel therapeutic target to prevent pathological bone destruction.
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Deficiency of Thrombospondin-4 in Mice Does Not Affect Skeletal Growth or Bone Mass Acquisition, but Causes a Transient Reduction of Articular Cartilage Thickness - Jeschke, Anke; Bonitz, Martin; Simon, Maciej; Peters, Stephanie; Baum, Wolfgang; Schett, Georg; Ruether, Wolfgang; Niemeier, Andreas; Schinke, Thorsten; Amling, Michael (PLoS ONE, 2015)
Although articular cartilage degeneration represents a major public health problem, the underlying molecular mechanisms are still poorly characterized. We have previously utilized genome-wide expression analysis to identify specific markers of porcine articular cartilage, one of them being Thrombospondin-4 (Thbs4). In the present study we analyzed Thbs4 expression in mice, thereby confirming its predominant expression in articular cartilage, but also identifying expression in other tissues, including bone. To study the role of Thbs4 in skeletal development and integrity we took advantage of a Thbs4-deficient mouse model that was analyzed by undecalcified bone histology. We found that Thbs4-deficient mice do not display phenotypic differences towards wildtype littermates in terms of skeletal growth or bone mass acquisition. Since Thbs4 has previously been found over-expressed in bones of Phex-deficient Hyp mice, we additionally generated Thbs4-deficient Hyp mice, but failed to detect phenotypic differences towards Hyp littermates. With respect to articular cartilage we found that Thbs4-deficient mice display transient thinning of articular cartilage, suggesting a protective role of Thbs4 for joint integrity. Gene expression analysis using porcine primary cells revealed that Thbs4 is not expressed by synovial fibroblasts and that it represents the only member of the Thbs gene family with specific expression in articular, but not in growth plate chondrocytes. In an attempt to identify specific molecular effects of Thbs4 we treated porcine articular chondrocytes with human THBS4 in the absence or presence of conditioned medium from porcine synovial fibroblasts. Here we did not observe a significant influence of THBS4 on proliferation, metabolic activity, apoptosis or gene expression, suggesting that it does not act as a signaling molecule. Taken together, our data demonstrate that Thbs4 is highly expressed in articular chondrocytes, where its presence in the extracellular matrix is required for articular cartilage integrity.
EVALuna2:13177

Defining immune reset: achieving sustained remission in autoimmune diseases - Junt, Tobias; Calzascia, Thomas; Traggiai, Elisabetta; da Costa, André Nogueira; Gergely, Peter; Schett, Georg; Dörner, Thomas; Siegel, Richard M. (Nature Reviews Immunology, 2025)
Personalized cell therapies for autoimmune diseases — such as autologous haematopoietic stem cell transplantation and chimeric antigen receptor-expressing T cells — have the potential to achieve sustained remission in patients with certain autoimmune diseases. The effective elimination of pathogenic lymphocytes and their subsequent repopulation with naive cells has been termed ‘immune reset’. In this Perspective, we trace the origins of the immune reset concept and its clinical, cellular and molecular definitions, and we review current attempts to identify biomarkers for long-term clinical remission in autoimmune diseases. Emerging data from clinical trials support the concept that higher probabilities of long-term remission can be achieved with therapies that can more deeply and broadly deplete B cells than the anti-CD20 antibody rituximab. A better understanding of the cellular and molecular basis for immune reset and the biomarkers associated with this state should accelerate progress towards the goal of restoring a non-autoimmune state and sustaining remission, while reducing the need for chronic immunosuppression.
CRIS-Team Scopus Importer:2025-03-21

Defining metaniches in the oral cavity according to their microbial composition and cytokine profile - Seidel, Corinna Lesley; Gerlach, Roman; Wiedemann, Patrick; Weider, Matthias; Rodrian, Gabriele; Hader, Michael; Frey, Benjamin; Gaipl, Udo; Bozec, Aline; Cieplik, Fabian; Kirschneck, Christian; Bogdan, Christian; et al. (International Journal of Molecular Sciences, 2020)
The human oral microbiota consists of over 700 widespread taxa colonizing the oral cavity in several anatomically diverse oral niches. Lately, sequencing of the 16S rRNA genes has become an acknowledged, culture-independent method to characterize the oral microbiota. However, only a small amount of data are available concerning microbial differences between oral niches in periodontal health and disease. In the context of periodontitis, the cytokine expression in the gingival crevicular fluid has been studied in detail, whereas little is known about the cytokine profile in hard and soft tissue biofilms. In order to characterize oral niches in periodontal health, the oral microbiota and cytokine pattern were analyzed at seven different sites (plaque (P), gingival crevicular fluid (GCF), saliva (S), tongue (T), hard palate (HP), cheek (C) and sublingual area (U)) of 20 young adults using next-generation sequencing and multiplex immunoassays. Site-specific microbial compositions were detected, which clustered into three distinct metaniches (“P-GCF”, “S-T-HP” and “C-U”) and were associated with niche-/metaniche-specific cytokine profiles. Our findings allow the definition of distinct metaniches according to their microbial composition, partly reflected by their cytokine profile, and provide new insights into microenvironmental similarities between anatomical diverse oral niches.
CRIS-Team Scopus Importer:2020-11-20
Keywords: Cytokine profile; Metaniches; Multiplex immunoassay; Next-generation sequencing; Oral biofilms and fluids; Oral microbiota; Oral niches

Definition for Rheumatoid Arthritis Erosions Imaged with High Resolution Peripheral Quantitative Computed Tomography and Interreader Reliability for Detection and Measurement - Barnabe, Cheryl; Toepfer, Dominique; Marotte, Hubert; Hauge, Ellen-Margrethe; Scharmga, Andrea; Kocijan, Roland; Kraus, Sebastian; Boutroy, Stephanie; Schett, Georg; Keller, Kresten Krarup; De Jong, Joost; Stok, Kathryn S.; et al. (Journal of Rheumatology, 2016)
High-resolution peripheral quantitative computed tomography (HR-pQCT) sensitively detects erosions in rheumatoid arthritis (RA); however, nonpathological cortical bone disruptions are potentially misclassified as erosive. Our objectives were to set and test a definition for pathologic cortical bone disruptions in RA and to standardize reference landmarks for measuring erosion size.HR-pQCT images of metacarpophalangeal joints of RA and control subjects were used in an iterative process to achieve consensus on the definition and reference landmarks. Independent readers (n = 11) applied the definition to score 58 joints and measure pathologic erosions in 2 perpendicular multiplanar reformations for their maximum width and depth. Interreader reliability for erosion detection and variability in measurements between readers [root mean square coefficient of variation (RMSCV), intraclass correlation (ICC)] were calculated.Pathologic erosions were defined as cortical breaks extending over a minimum of 2 consecutive slices in perpendicular planes, with underlying trabecular bone loss and a nonlinear shape. Interreader agreement for classifying pathologic erosions was 90.2%, whereas variability for width and depth erosion assessment was observed (RMSCV perpendicular width 12.3%, axial width 20.6%, perpendicular depth 24.0%, axial depth 22.2%; ICC perpendicular width 0.206, axial width 0.665, axial depth 0.871, perpendicular depth 0.783). Mean erosion width was 1.84 mm (range 0.16-8.90) and mean depth was 1.86 mm (range 0.30-8.00).We propose a new definition for erosions visualized with HR-pQCT imaging. Interreader reliability for erosion detection is good, but further refinement of selection of landmarks for erosion size measurement, or automated volumetric methods, will be pursued.
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Definition of a New HLA B*52-Restricted Rev CTL Epitope Targeted by an HIV-1-Infected Controller - El Kenz, Boutaina; Schmidt, Katja; Ogungbemi-Alt, Victoria K.; Bergmann, Silke; Steininger, Philipp; Korn, Klaus; Spriewald, Bernd; Harrer, Ellen; Nganou-Makamdop, Krystelle; Harrer, Thomas (Viruses, 2023)
The analysis of T-cell responses in HIV-1-infected controllers may contribute to a better understanding of the protective components of the immune system. Here, we analyzed the HIV-1-specific T-cell response in a 59-year-old HIV-1-infected controller, infected for at least seven years, who presented with low viral loads ranging from <20 copies/mL to 200 copies/mL and normal CD4 counts of >800 cells/µL. In γ-IFN-ELISpot assays using freshly isolated PBMCs, he displayed a very strong polyclonal T-cell response to eight epitopes in Gag, Nef and Rev; with the dominant responses directed against the HLA-B*57-epitope AISPRTLNAW and against a so-far-unknown epitope within Rev. Further analyses using peptide-stimulated T-cell lines in γ-IFN-ELISpot assays delineated the peptide RQRQIRSI (Rev-RI8) as a newly defined HLA-B*52-restricted epitope located within a functionally important region of Rev. Peptide-stimulation assays in 15 HLA-B*52-positive HIV-1-infected subjects, including the controller, demonstrated recognition of the Rev-RI8 epitope in 6/15 subjects. CD4 counts before the start of antiviral therapy were significantly higher in subjects with recognition of the Rev-RI8 epitope. Targeting of the Rev-RI8 epitope in Rev by CTL could contribute to the positive association of HLA-B*52 with a more favorable course of HIV-1-infection.
CRIS-Team Scopus Importer:2023-03-10
Keywords: CTL; elite controller; epitope; HIV-1 infection; HLA B*52; Rev

Deletion of the Casp8 gene in mice results in ileocolitis, gut barrier dysfunction, and malassimilation, which can be partially attenuated by inulin or sodium butyrate. - Günther, Claudia; Kaden-Volynets, Valentina; Zimmermann, Julia; Beisner, Julia; Becker, Christoph; Bischoff, Stephan C. (American Journal of Physiology-Gastrointestinal and Liver Physiology, 2019)
Genetic mouse models for ileocolitis are important to understand inflammatory bowel disease in humans. We examined dietetic factors that might aggravate or attenuate ileocolitis and related pathologies in such a model. Deletion of the caspase-8 gene results not only in ileocolitis but also in gut barrier dysfunction, liver steatosis, and malassimilation, which can be partially attenuated by oral inulin or sodium butyrate. Our data indicate that diet modifications can contribute to disease variability and therapy.
Keywords: caspase-8; fructose; intestinal barrier; inulin; sodium butyrate

Deletion of the receptor tyrosine kinase Tyro3 inhibits synovial hyperplasia and bone damage in arthritis - Ruiz-Heiland, Gisela; Zhao, Yi; Derer, Anja; Braun, Timm; Engelke, Klaus; Neumann, Elena; Mueller-Ladner, Ulf; Liu, Yi; Zwerina, Jochen; Schett, Georg (Annals of the Rheumatic Diseases, 2014)
To test whether the tyrosine kinase Tyro3 affects arthritis. Tyro3, the ligand of growth arrest-specific protein 6 (GAS6) is a receptor tyrosine kinase involved in cell survival. Tyro3 and GAS6 are expressed in the arthritic synovium, and in vitro studies have shown their role in osteoclast differentiation.Bone was assessed by micro CT and histomorphometry in Tyro3-deficient (Tyro3(-/-)) and wild-type mice. Arthritis was induced in both genotypes, and Gas6 level was measured by ELISA. Synovitis, synovial hyperplasia, bone erosion, osteoclast activation and osteoclast gene expression were assessed by histomorphometry and reverse transcriptase-PCR, respectively. In vitro osteoclast differentiation assays were performed in Tyro3(-/-) and wild-type mice. Furthermore, effects of Tyro3 and GAS6 on human synovial fibroblast proliferation and osteoclastogenesis were assessed in human cells.Tyro3(-/-) mice had significantly higher bone mass than wild-type littermates. Induction of arthritis increased GAS6 serum levels. Arthritic Tyro3(-/-) mice showed less synovial hyperplasia, osteoclast numbers and bone damage compared with controls. In vivo expression of osteoclast-associated receptor and receptor activator of nuclear factor-?B and in vitro osteoclastogenesis were impaired in Tyro3(-/-) mice. GAS6 also induced synovial fibroblast proliferation and osteoclast differentiation in human cells in Tyro3-dependent manner.These findings indicate that Tyro3 is a critical signal for synovial hyperplasia, osteoclast differentiation and bone erosion during arthritis. GAS6 and Tyro3 therefore constitute therapeutic targets to inhibit synovial hyperplasia and associated bone erosion.
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Depression and rheumatism: options for measuring depression - Englbrecht, Matthias; Wendler, J.; Alten, R. (Zeitschrift für Rheumatologie, 2014)
The importance of depressive diseases in the treatment of rheumatism patients cannot be denied. It is well-known from publications in the English speaking literature that the proportion of depressive diseases lies between 10% and 45% in patients with rheumatoid arthritis (RA). However, clearly increased numbers can also be seen in a direct comparison with corresponding prevalence rates in the normal population for other diseases included in the category of rheumatism.This manuscript focusses on the possibilities and challenges in measuring states of depressive mood that might serve as an indicator of depressive diseases in the context of treatment of rheumatism.A search of the current literature was carried out and the results were evaluated.Starting from appropriate background knowledge, the current state of science is discussed while subsequently taking a closer look at a choice of internationally recognized assessment tools which are feasible for use in rheumatology. Finally, this overview is accompanied by hints for hands-on practice and suggestions on how to respond to conspicuous test results indicative of a depressive mood.The potential benefits of appropriate screening with measurement instruments are considered to be high for rheumatism patients. The measurement tools presented must be suitably selected for the individual purpose and for each rheumatology institution. In view of test application consideration must be given not only to the total score but also to the individual responses to test items. In cases of conspicuous test results the further approach must be agreed together with the patient and by choosing adequate treatment options for the situation. In cases of acute suicidal tendencies acceptance, care and support are of key importance, while the precautionary presentation in a specialist clinic must be initiated.
EVALuna2:13209

Depression, Anxiety, Resilience and Coping Pre and Post Kidney Transplantation - Initial Findings from the Psychiatric Impairments in Kidney Transplantation (PI-KT)-Study - Mueller, Helge H.; Englbrecht, Matthias; Wiesener, Michael; Titze, Stephanie; Heller, Katharina; Groemer, Teja W.; Schett, Georg; Eckardt, Kai-Uwe; Kornhuber, Johannes; Maler, Juan Manuel (PLoS ONE, 2015)
Depression/anxiety, impaired Health-Related Quality of Life (HRQoL) and coping and resilience structures, are associated with increased mortality/poor outcome in chronic kidney disease (CKD) patients before (CKD/pre-KT) and after kidney (CKD-T) transplantation. Less is known about prevalence rates of psychiatric symptoms and impaired HRQoL of non-transplanted compared with transplanted patients.In a cross-sectional study comparing 101 CKD/pre-KT patients with 151 cadaveric-transplanted (CKD-T) patients, we examined prevalence of depression/anxiety (HADS questionnaire) and coping, resilience and HRQoL (SF-12, Resilience-Scale and FKV-questionnaire).The prevalence of both depressive and anxiety symptoms was not significantly different between different pre-/and CKD-T patient groups. In CKD-T no significant relations of coping strategies with kidney function were identified. Furthermore, the Resilience Scales for acceptance and competence did not suggest any differences between the CKD/pre-KT and CKD-T subgroup. In the CKD/pre-KT patients, significant correlations were identified between the acceptance subscale and partnership, as well as between the competence subscale and older age/partnership.Both the CKD/pre-KT and CKD-T patients exhibited notable impairments in the HRQoL which which showed a comparable pattern of results. KT itself does not appear to be the main risk factor for the development of mental impairments.
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Depression as comorbidity of rheumatoid arthritis - Baerwald, C.; Manger, Bernhard; Hueber, Axel (Zeitschrift für Rheumatologie, 2019)
Depressive disorders are among the most common comorbidities in patients not only with rheumatoid arthritis (RA) but also with other forms of inflammatory rheumatic diseases. The prevalence of adepressive disorder in RA is estimated to be between 9.5% and 41.5% depending on the study and with women being more affected. After adjusting for sex, age and other parameters the risk of depression in RA was significantly elevated with an odds ratio of 1.63 (95% CI, 1.43-1.87) compared to the general population. In RA the risk of developing adepressive disorder is highest in the first 5 years and depression is abetter predictor of work disability than disease activity and response to treatment. Depression in RA is associated with more pain, fatigue and impaired quality of life, whereby the association between depression and RA is bidirectional. Therefore, the risk to develop adepression is increased with impaired function as measured by the health assessment questionnaire (HAQ) and there is evidence that increased disease activity increases the risk for depression in RA. In addition, adepressive disorder also affects the subjective severity of patient-reported outcomes (PRO), such as tender joints and the global patient assessment with respect to disease activity and thus exhibiting adirect influence on the DAS28. Finally, it could be shown that depression unfavorably influences the response to therapy, the rate of remission is lower and the mortality is increased in RA patients. Taken together, this indicates that it is necessary to detect a depression in patients with RA as early as possible in order to initiate appropriate treatment of depression in such cases.
CRIS-Team WoS Importer:2019-04-16

Depression as comorbidity of rheumatoid arthritis Depression als Komorbidität bei rheumatoider Arthritis - Baerwald, C.; Manger, Bernhard; Hueber, Axel (Zeitschrift für Rheumatologie, 2019)
Depressive disorders are among the most common comorbidities in patients not only with rheumatoid arthritis (RA) but also with other forms of inflammatory rheumatic diseases. The prevalence of a depressive disorder in RA is estimated to be between 9.5% and 41.5% depending on the study and with women being more affected. After adjusting for sex, age and other parameters the risk of depression in RA was significantly elevated with an odds ratio of 1.63 (95% CI, 1.43–1.87) compared to the general population. In RA the risk of developing a depressive disorder is highest in the first 5 years and depression is a better predictor of work disability than disease activity and response to treatment. Depression in RA is associated with more pain, fatigue and impaired quality of life, whereby the association between depression and RA is bidirectional. Therefore, the risk to develop a depression is increased with impaired function as measured by the health assessment questionnaire (HAQ) and there is evidence that increased disease activity increases the risk for depression in RA. In addition, a depressive disorder also affects the subjective severity of patient-reported outcomes (PRO), such as tender joints and the global patient assessment with respect to disease activity and thus exhibiting a direct influence on the DAS28. Finally, it could be shown that depression unfavorably influences the response to therapy, the rate of remission is lower and the mortality is increased in RA patients. Taken together, this indicates that it is necessary to detect a depression in patients with RA as early as possible in order to initiate appropriate treatment of depression in such cases.
CRIS-Team Scopus Importer:2019-05-02
Keywords: Cytokines; Disease activity; Inflammatory rheumatic diseases; Pain; Quality of life

Depression is a stronger predictor of the risk to consider work disability in early arthritis than disease activity or response to therapy - Callhoff, Johanna; Albrecht, Katinka; Schett, Georg; Zink, Angela; Westhoff, Gisela (RMD Open, 2015)
To evaluate the factors that influence patients with early inflammatory arthritis to consider a disability pension.A total of 528 patients aged 63 or younger from an early arthritis cohort with a mean symptom duration of 3 months at inclusion were asked at 12 and 24 months whether they were considering applying for, had applied for or were receiving a disability pension because of arthritis. Possible predictors were analysed with univariate and multivariate logistic regression.69 patients (13%) were considering, had applied for or were receiving a disability pension. Univariate predictors were older age, disease activity, several patient-reported outcomes and depression. In a multivariate analysis, age, days on sick leave, impairment of physical function and depression were predictive for considering a disability pension (OR for severe vs no depression: 3.85, 95% CI 1.43 to 10.4).In patients with early arthritis, depression appears to be a stronger predictor of the risk to consider applying for work disability pension than the features of disease activity. Patients at risk could be identified with one single depression statement. This finding should prompt physicians to react early to signs and symptoms of depression to help patients to maintain their ability to work.
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DEPRESSIVE SYMPTOMS IN PSA: A CROSS-SECTIONAL ANALYSIS FROM THE NATIONAL GERMAN RABBIT-SPA REGISTRY - Regierer, A.; Weiss, A.; Bohl-Buehler, M.; Baraliakos, X.; Behrens, F.; Schett, Georg; Strangfeld, A. (Annals of the Rheumatic Diseases, 2021)
CRIS-Team WoS Importer:2021-10-01

DEREGULATION OF TFAM EXPRESSION PROMOTES MITOCHONDRIAL DAMAGE AND FIBROBLAST ACTIVATION IN SYSTEMIC SCLEROSIS - Zhou, Xiang; Trinh, Minh Thuong; Tran Manh, Cuong; Giessl, A.; Bergmann, Christina; Györfi, Andrea-Hermina; Schett, Georg; Distler, Jörg (ANNALS OF THE RHEUMATIC DISEASES, 2022)
CRIS-Team WoS Importer:2022-11-04

"Der Schatz auf dem Dachboden" - Dross, Fritz; Manger, Bernhard; Teichfischer, Philipp (Medizinhistorisches Journal, 2021)
The article announces the recently discovered part of the correspondence of Johann Lukas Schönlein (1793-1864), which was considered lost or destroyed. Beginning with a reconstruction of the puzzling ways taken by Schönlein's correspondence after his death, we try to give a first overview on the chronological order and some of the prominent topics treated. Finally, some perspectives on new research enabled by the recently discovered correspondence are outlined.
CRIS-Team Scopus Importer:2021-12-17
Keywords: Correspondence; History of 19th-century medicine; Johann Lukas Schönlein; Universities and science

DERSIMELAGON, A NOVEL ORAL MELANOCORTIN 1 RECEPTOR AGONIST, DEMONSTRATES DISEASE-MODIFYING EFFECTS IN PRECLINICAL MODELS OF SYSTEMIC SCLEROSIS - Kondo, M.; Suzuki, T.; Kawano, Y.; Kojima, S.; Miyashiro, M.; Matsumoto, A.; Kania, G.; Blyszczuk, P.; Ross, R.; Mulipa, P.; Del Galdo, F.; Zhang, Y.; et al. (Annals of the Rheumatic Diseases, 2022)
CRIS-Team WoS Importer:2022-11-04

Dersimelagon, a novel oral melanocortin 1 receptor agonist, demonstrates disease-modifying effects in preclinical models of systemic sclerosis - Kondo, Masahiro; Suzuki, Tsuyoshi; Kawano, Yuko; Kojima, Shinji; Miyashiro, Masahiko; Matsumoto, Atsuhiro; Kania, Gabriela; Blyszczuk, Przemyslaw; Ross, Rebecca L.; Mulipa, Panji; Del Galdo, Francesco; Zhang, Yun; et al. (Arthritis Research & Therapy, 2022)
Background: Activation of melanocortin 1 receptor (MC1R) is known to exert broad anti-inflammatory and anti-fibrotic effects. The purpose of this study is to investigate the potential of dersimelagon, a novel oral MC1R agonist, as a therapeutic agent for systemic sclerosis (SSc). Methods: The effects of dersimelagon phosphoric acid (MT-7117) on skin fibrosis and lung inflammation were evaluated in bleomycin (BLM)-induced SSc murine models that were optimized for prophylactic and therapeutic evaluation. Microarray-based gene expression analysis and serum protein profiling were performed in the BLM-induced SSc models. The effect of MT-7117 on transforming growth factor-β (TGF-β)-induced activation of human dermal fibroblasts was evaluated in vitro. Immunohistochemical analyses of MC1R expression in the skin of SSc patients were performed. Results: Prophylactic treatment with MT-7117 (≥ 0.3 mg/kg/day p.o.) significantly inhibited skin fibrosis and lung inflammation, and therapeutic treatment with MT-7117 (≥ 3 mg/kg/day p.o.) significantly suppressed the development of skin fibrosis in the BLM-induced SSc models. Gene array analysis demonstrated that MT-7117 exerts an anti-inflammatory effect via suppression of the activation of inflammatory cells and inflammation-related signals; additionally, vascular dysfunction was extracted as the pathology targeted by MT-7117. Serum protein profiling revealed that multiple SSc-related biomarkers including P-selectin, osteoprotegerin, cystatin C, growth and differentiation factor-15, and S100A9 were suppressed by MT-7117. MT-7117 inhibited the activation of human dermal fibroblasts by suppressing TGF-β-induced ACTA2 (encoding α-smooth muscle actin) mRNA elevation. MC1R was expressed by monocytes/macrophages, neutrophils, blood vessels (endothelial cells), fibroblasts, and epidermis (keratinocytes) in the skin of SSc patients, suggesting that these MC1R-positive cells could be targets for MT-7117. Conclusions: MT-7117 demonstrates disease-modifying effects in preclinical models of SSc. Investigations of its mechanism of action and target expression analyses indicate that MT-7117 exerts its positive effect by affecting inflammation, vascular dysfunction, and fibrosis, which are all key pathologies of SSc. The results of the present study suggest that MT-7117 is a potential therapeutic agent for SSc. A phase 2 clinical trial investigating the efficacy and tolerability of MT-7117 in patients with early, progressive diffuse cutaneous SSc is currently in progress.
CRIS-Team Scopus Importer:2022-09-16
Keywords: Fibroblast; Fibrosis; Inflammation; Melanocortin 1 receptor; Systemic sclerosis; Vascular dysfunction

Design of a randomised, placebo-controlled clinical trial of nintedanib in patients with systemic sclerosis-associated interstitial lung disease (SENSCIS(TM)) - Distler, Oliver; Brown, Kevin K; Distler, Jörg; Assassi, Shervin; Maher, Toby M; Cottin, Vincent; Varga, John; Coeck, Carl; Gahlemann, Martina; Sauter, Wiebke; Schmidt, Hendrik; Highland, Kristin B (Clinical and Experimental Rheumatology, 2017)
Nintedanib is a tyrosine kinase inhibitor approved for the treatment of idiopathic pulmonary fibrosis (IPF). The pathological pathways involved in fibrogenesis in IPF and interstitial lung disease associated with systemic sclerosis (SSc-ILD) show commonalities; both involve fibroblast activation, myofibroblast accumulation and deposition of extracellular matrix. The SENSCIS(TM) trial is a randomised, placebo-controlled Phase III trial that will evaluate the efficacy and safety of nintedanib in patients with SSc-ILD (NCT02597933).Approximately 520 patients with SSc (based on 2013 American College of Rheumatology/European League Against Rheumatism criteria) and ILD (>=10% fibrosis of the lungs, confirmed by central assessment of chest high resolution computed tomography), forced vital capacity (FVC) >=40% predicted and diffusing capacity for carbon monoxide of 30-89% predicted will be enrolled. Patients will be randomised (1:1) to nintedanib 150 mg twice daily or placebo, stratified by the presence of anti-topoisomerase I antibody. To reflect real-world management, patients receiving prednisone (<=10 mg/day) and/or a stable dose of mycophenolate or methotrexate, will be eligible. The primary endpoint is the annual rate of decline in FVC (mL/ year) assessed over 52 weeks. Patients will remain on blinded study treatment until the last patient completes 52 weeks of treatment or for a maximum of 100 weeks of treatment. Key secondary endpoints are absolute changes from baseline in modified Rodnan skin score and St George's Respiratory Questionnaire at week 52.Recruitment for the trial began in November 2015.This trial will assess the efficacy and safety of nintedanib in patients with SSc-ILD.
EVALuna2:13440

Detection of periarticular urate deposits with dual energy CT in patients with acute gouty arthritis - Manger, Bernhard; Lell, Michael; Wacker, J.; Schett, Georg; Rech, Jürgen (Annals of the Rheumatic Diseases, 2012)
CRIS-Team Scopus Importer:2021-02-03

Detection of pre-existing neutralizing antibodies against Ad26 in HIV-1-infected individuals not responding to the Ad26.COV2.S vaccine - Schmidt, Katja; Harrer, Ellen; Schönau, Verena; Simon, David; Kleyer, Arnd; Steininger, Philipp; Korn, Klaus; Schett, Georg; Knobloch, Carina; Nganou-Makamdop, Krystelle; Harrer, Thomas (Infection, 2023)
Purpose: The Ad26.COV2.S vaccine is a replication-incompetent human adenovirus type 26 vector encoding the SARS-CoV-2 spike protein. In a phase 1-2a trial, a single dose of Ad26.COV2.S induced SARS-CoV-2 spike-specific antibodies in ≥ 96% of healthy adults. To investigate vaccine immunogenicity in HIV-1-infection, we measured SARS-CoV-2 spike-specific antibodies in Ad26.COV2.S vaccinated HIV-1-infected patients and analyzed the presence of pre-existing Ad26 neutralizing antibodies. Methods: We included all Ad26.COV2.S vaccinated HIV-1-infected patients of Erlangen HIV cohort fulfilling all inclusion criteria. The study cohort consisted of 15 HIV-1-infected patients and three HIV-1-uninfected subjects who received the Ad26.COV2.S vaccine between April and November 2021. Pre-vaccination sera were collected between October 2014 and June 2021, post-vaccination sera between June and December 2021. Neutralizing antibodies towards Ad26 were determined by a FACS-based inhibition assay measuring the expression of SARS-CoV-2 spike and adenoviral proteins in HEK293T cells after in-vitro transduction with Ad26.COV2.S or the control ChAdOx1-S. Results: Six out of 15 HIV-1-infected patients failed to develop SARS-CoV-2-specific antibodies and four patients developed weak antibody responses after vaccination with Ad26.COV2.S. Pre-vaccination sera of four of the six vaccine non-responders showed neutralizing activity towards Ad26.COV2.S but not toward the ChAdOx1-S vaccine at 1:50 dilution. After Ad26.COV2.S vaccination, 17 of the 18 subjects developed strong Ad26-neutralizing activity and only one of the 18 subjects showed neutralizing activity towards the ChAdOx1-S vaccine. Conclusion: Ad26.COV2.S vaccination showed a high failure rate in HIV-1-infected patients. Pre-existing immunity against Ad26 could be an important contributor to poor vaccine efficacy in a subgroup of patients.
CRIS-Team Scopus Importer:2023-04-28
Keywords: Ad26.COV2.S; Adenovirus 26; HIV-1; Neutralizing antibodies; SARS-CoV-2; SARS-CoV-2 vaccine

DEVELOPING A SCREENING TOOL FOR THE DETECTION OF INTERSTITIAL LUNG DISEASE IN SYSTEMIC SCLEROSIS:THE ILD-RISC RISK SCORE - Bruni, C.; Tofani, L.; Fretheim, H.; Liem, S.; Velauthapillai, A.; Bjorkekjaer, J.; Barua, I.; Galetti, I.; Garaiman, A.; Becker, M. O.; Hoffmann-Vold, M.; De Vries-Bouwstra, J.; et al. (ANNALS OF THE RHEUMATIC DISEASES, 2022)
CRIS-Team WoS Importer:2022-11-04

Development of a Dual-Energy Computed Tomography Scoring System for Measurement of Urate Deposition in Gout - Bayat, Sara; Aati, Opetaia; Rech, Juergen; Sapsford, Mark; Lell, Michael; Araujo, Elizabeth; Petsch, Christina; Stamp, Lisa K.; Schett, Georg; Manger, Bernhard; Dalbeth, Nicola; Cavallaro, Alexander Josef (Arthritis & Rheumatism-Arthritis Care & Research, 2016)
To develop a semiquantitative dual-energy computed tomography (DECT) scoring system for measurement of urate deposition in gout.Following a structured review of images, a semiquantitative DECT urate scoring method for foot/ankle scans was developed for testing. This method included 4 regions, each scored 0-3, with a maximum total DECT urate score of 12. DECT scans from 224 patients (182 with gout, 42 without gout) were scored by 2 independent readers. Automated urate volumes were also measured. Paired scans from 8 patients receiving pegloticase were analyzed, and a timing exercise was undertaken. The properties of the DECT urate score were analyzed according to the Outcome Measures in Rheumatology (OMERACT) filter.The interreader intraclass correlation coefficient (95% confidence interval) for the DECT urate score was 0.98 (0.97-0.98). All scored regions contributed to the total DECT urate score. DECT urate scores and volumes were highly correlated (r = 0.91, P < 0.0001). Both DECT urate scores and volumes discriminated between gout and nongout control participants and between the tophaceous gout, nontophaceous gout, and control groups. Compared with urate volume, the DECT urate score had greater ability to discriminate between responders and nonresponders to pegloticase therapy (P < 0.001 for DECT urate score and P > 0.05 for volume). The mean ± SD time required for the DECT urate score was 121 ± 2 seconds and for urate volume was 240 ± 2 seconds (P = 2 × 10(-31) ).We have developed a novel semiquantitative DECT scoring method for measurement of urate deposition in the feet/ankles. This method fulfills many aspects of the OMERACT filter.
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Development of three-dimensional prints of arthritic joints for supporting patients' awareness to structural damage - Kleyer, Arnd; Beyer, Laura; Simon, Christoph; Stemmler, Fabian; Englbrecht, Matthias; Beyer, Christian; Rech, Juergen; Manger, Bernhard; Krönke, Gerhard; Schett, Georg; Hueber, Axel (Arthritis Research & Therapy, 2017)
Rheumatoid arthritis (RA) and psoriatic arthritis (PsA) result in severe joint destruction and functional disability if left untreated. We aim to develop tools that help patients with RA and PsA to understand and experience the impact of inflammatory joint disease on the integrity of their (juxta-articular) bone and increase adherence to medical treatment. In this study, we used high-resolution peripheral quantitative computed tomography (HR-pQCT) to develop 3D prototypes of patients' finger joints.HR-pQCT (XtremeCT, Scanco) measurements were performed in healthy individuals and patients with inflammatory joint disease, followed by a 3D print using the objet30 printer. Healthy participants (n = 10), and patients (n = 15 with RA and 15 with PsA) underwent a detailed, standardized interview with demonstration of printed joints.Utilizing HR-pQCT images of metacarpophalangeal (MCP) heads, high quality and exact 3D prints as prototypes were created. Erosions in different sizes and the trabecular network printed in detail were visualized, demonstrating structural reduction in arthritic vs. healthy bone. After demonstration of 3D prints (healthy vs. erosive joint, visual and haptic) 26/39 (66%) participants (including healthy volunteers) were deeply affected, often quoting "shock". Of the patients with RA and PsA, 13/15 (86%) and 11/15 (73%), respectively, stated that they would rethink their attitude to medication adherence. More importantly, 21/24 patients with RA or PsA (87.5%) expressed that they would have wished to see such 3D prints during their first disease-specific conversations.Using arthro-haptic 3D printed prototypes of joints may help to better understand the impact of inflammatory arthritides on bone integrity and long-term damage.
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Diabetes is an independent predictor for severe osteoarthritis: results from a longitudinal cohort study - Schett, Georg; Kleyer, Arnd; Perricone, Carlo; Sahinbegovic, Enijad; Iagnocco, Annamaria; Zwerina, Jochen; Lorenzini, Rolando; Aschenbrenner, Franz; Berenbaum, Francis; D'Agostino, Maria-Antonietta; Willeit, Johann; Kiechl, Stefan (Diabetes Care, 2013)
To evaluate if type 2 diabetes is an independent risk predictor for severe osteoarthritis (OA).Population-based cohort study with an age- and sex-stratified random sample of 927 men and women aged 40-80 years and followed over 20 years (1990-2010).Rates of arthroplasty (95% CI) were 17.7 (9.4-30.2) per 1,000 person-years in patients with type 2 diabetes and 5.3 (4.1-6.6) per 1,000 person-years in those without (P < 0.001). Type 2 diabetes emerged as an independent risk predictor for arthroplasty: hazard ratios (95% CI), 3.8 (2.1-6.8) (P < 0.001) in an unadjusted analysis and 2.1 (1.1-3.8) (P = 0.023) after adjustment for age, BMI, and other risk factors for OA. The probability of arthroplasty increased with disease duration of type 2 diabetes and applied to men and women, as well as subgroups according to age and BMI. Our findings were corroborated in cross-sectional evaluation by more severe clinical symptoms of OA and structural joint changes in subjects with type 2 diabetes compared with those without type 2 diabetes.Type 2 diabetes predicts the development of severe OA independent of age and BMI. Our findings strengthen the concept of a strong metabolic component in the pathogenesis of OA.
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DIABETES MELLITUS AS AN INDEPENDENT PREDICTOR FOR SEVERE OSTEOARTHRITIS - Schett, Georg; Kleyer, Arnd; D'Agostino, M. -A.; Perricone, C.; Iagnocco, A.; Sahinbegovic, E.; Berenbaum, F.; Zwerina, J.; Willeit, J.; Kiechl, S. (2013)
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Diagnostic Accuracy of a Mobile AI-Based Symptom Checker and a Web-Based Self-Referral Tool in Rheumatology: Multicenter Randomized Controlled Trial - Knitza, Johannes; Tascilar, Koray; Fuchs, Franziska; Mohn, Jacob; Kuhn, Sebastian; Bohr, Daniela; Muehlensiepen, Felix; Bergmann, Christina; Labinsky, Hannah; Morf, Harriet; Araujo, Elizabeth; Englbrecht, Matthias; et al. (Journal of Medical Internet Research, 2024)
Background: The diagnosis of inflammatory rheumatic diseases (IRDs) is often delayed due to unspecific symptoms and a shortage of rheumatologists. Digital diagnostic decision support systems (DDSSs) have the potential to expedite diagnosis and help patients navigate the health care system more efficiently. Objective: The aim of this study was to assess the diagnostic accuracy of a mobile artificial intelligence (AI)–based symptom checker (Ada) and a web-based self-referral tool (Rheport) regarding IRDs. Methods: A prospective, multicenter, open-label, crossover randomized controlled trial was conducted with patients newly presenting to 3 rheumatology centers. Participants were randomly assigned to complete a symptom assessment using either Ada or Rheport. The primary outcome was the correct identification of IRDs by the DDSSs, defined as the presence of any IRD in the list of suggested diagnoses by Ada or achieving a prespecified threshold score with Rheport. The gold standard was the diagnosis made by rheumatologists. Results: A total of 600 patients were included, among whom 214 (35.7%) were diagnosed with an IRD. Most frequent IRD was rheumatoid arthritis with 69 (11.5%) patients. Rheport’s disease suggestion and Ada’s top 1 (D1) and top 5 (D5) disease suggestions demonstrated overall diagnostic accuracies of 52%, 63%, and 58%, respectively, for IRDs. Rheport showed a sensitivity of 62% and a specificity of 47% for IRDs. Ada’s D1 and D5 disease suggestions showed a sensitivity of 52% and 66%, respectively, and a specificity of 68% and 54%, respectively, concerning IRDs. Ada’s diagnostic accuracy regarding individual diagnoses was heterogenous, and Ada performed considerably better in identifying rheumatoid arthritis in comparison to other diagnoses (D1: 42%; D5: 64%). The Cohen κ statistic of Rheport for agreement on any rheumatic disease diagnosis with Ada D1 was 0.15 (95% CI 0.08-0.18) and with Ada D5 was 0.08 (95% CI 0.00-0.16), indicating poor agreement for the presence of any rheumatic disease between the 2 DDSSs. Conclusions: To our knowledge, this is the largest comparative DDSS trial with actual use of DDSSs by patients. The diagnostic accuracies of both DDSSs for IRDs were not promising in this high-prevalence patient population. DDSSs may lead to a misuse of scarce health care resources. Our results underscore the need for stringent regulation and drastic improvements to ensure the safety and efficacy of DDSSs.
CRIS-Team Scopus Importer:2024-08-02
Keywords: artificial intelligence; decision; decision support; decision support system; diagnosis; diagnostic; diagnostic decision support system; eHealth; randomized controlled trial; resources; rheumatologists; rheumatology; support; support system; symptom assessment; symptom checker; tool

Diagnostic delay stages and pre-diagnostic treatment in patients with suspected rheumatic diseases before special care consultation: results of a multicenter-based study - Fuchs, Franziska; Morf, Harriet; Mohn, Jacob; Muehlensiepen, Felix; Ignatyev, Yuriy; Bohr, Daniela; Araujo, Elizabeth; Bergmann, Christina; Simon, David; Kleyer, Arnd; Vorbrueggen, Wolfgang; Ramming, Andreas; et al. (Rheumatology International, 2022)
Early and effective discrimination (triage) of patients with inflammatory rheumatic diseases (IRD) and other diseases (non-IRD) is essential for successful treatment and preventing damage. The aim of this study was to investigate diagnostic delays and pre-diagnosis treatment in patients newly presenting to rheumatology outpatient clinics. A total of 600 patients newly presenting to one university hospital and two non-academic centers were included. Time from onset of symptoms to rheumatology consultation “total delay” as well as medical treatment before consultation were recorded. Median time from symptom onset to rheumatologist appointment (total delay) was 30 weeks. Median time to online search, first physician appointment request and first physician appointment was 2, 4 and 5 weeks, respectively. Total delay was significantly shorter for IRD patients compared to non-IRD patients, 26 vs 35 weeks (p = 0.007). Only 17.7% of all patients and 22.9% of IRD patients had a delay of less than 12 weeks. Total delay was significantly lower in patients seen in non-academic centers compared to the university center, 20 vs 50 weeks (p < 0.0001). 32.2% of IRD patients received medical treatment that eased their symptoms prior to the rheumatology appointment. These findings highlight the persistent diagnostic delays in rheumatology; however, they also suggest that current triage strategies effectively lead to earlier appointments for IRD patients. Improvement of triage methods and pre-diagnosis treatment could decrease overall burden of disease in IRD patients.
CRIS-Team Scopus Importer:2022-10-21
Keywords: Delayed diagnosis; Diagnostic delay; Health service research; Outcome research; Time to therapy; Triage

Dietary derived propionate regulates pathogenic fibroblast function and ameliorates experimental arthritis and inflammatory tissue priming - Friščić, Jasna; Dürholz, Kerstin; Chen, Xi; Engdahl, Cecilia; Möller, Lisa; Schett, Georg; Zaiss, Mario; Hoffmann, Markus (Nutrients, 2021)
Short-chain fatty acids are gut-bacteria-derived metabolites that execute important regulatory functions on adaptive immune responses, yet their influence on inflammation driven by innate immunity remains understudied. Here, we show that propionate treatment in drinking water or upon local application into the joint reduced experimental arthritis and lowered inflammatory tissue priming mediated by synovial fibroblasts. On a cellular level, incubation of synovial fibroblasts with propionate or a physiological mixture of short-chain fatty acids interfered with production of inflammatory mediators and migration and induced immune-regulatory fibroblast senescence. Our study suggests that propionate mediates its alleviating effect on arthritis by direct abrogation of local arthritogenic fibroblast function.
CRIS-Team Scopus Importer:2021-05-21
Keywords: Arthritis; Cellular senescence; Diet; Inflammatory tissue priming; Propionate; Synovial fibroblasts

Dietary short-term fiber interventions in arthritis patients increase systemic scfa levels and regulate inflammation - Dürholz, Kerstin; Hofmann, Jörg; Iljazovic, Aida; Häger, Julian; Lucas, Sébastien; Sarter, Kerstin; Strowig, Till; Bang, Holger; Rech, Jürgen; Schett, Georg; Zaiss, Mario (Nutrients, 2020)
Chronic inflammatory diseases are often initiated and guided by the release of proinflammatory mediators. Rheumatoid arthritis (RA) is caused by an imbalance between the pro-and anti-inflammatory mediators in the joints, thereby favoring chronic inflammation and joint damage. Here, we investigate if short-term high-fiber dietary intervention shifts this towards anti-inflammatory mediators. Healthy controls (n = 10) and RA patients (n = 29) under routine care received daily high-fiber bars for 15 or 30 days, respectively. Stool and sera were analyzed for pro-and anti-inflammatory mediators. A high-fiber dietary intervention resulted in increased anti-inflammatory short-chain fatty acids (SCFA), decreased proarthritic cytokine concentrations, along with a durable shift in the Firmicutes-to-Bacteroidetes ratio. Together, these results further strengthen high-fiber dietary interventions as a practical approach complementing existing pharmacological therapies.
CRIS-Team Scopus Importer:2020-10-30
Keywords: High-fiber diet (HFD); Microbial metabolites; Short chain fatty acids (SCFA)

DIET INDUCED METABOLIC CHANGES IN AN OSTEOARTHRITIS MOUSE MODEL - Huelser, M. -L.; Schreiyaeck, C.; Luo, Y.; Bozec, Aline; Schett, Georg; Mueller-Ladner, U.; Neumann, E. (2018)
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Differences in bone structure between rheumatoid arthritis and psoriatic arthritis patients relative to autoantibody positivity - Kocijan, Roland; Finzel, Stephanie; Englbrecht, Matthias; Engelke, Klaus; Rech, Juergen; Schett, Georg (Annals of the Rheumatic Diseases, 2014)
To investigate whether trabecular and cortical bone structure differ between patients with rheumatoid arthritis (RA) and psoriatic arthritis (PsA). So far, no study has performed a detailed comparative analysis of bone structure in patients with RA and PsA.110 patients (60 RA, 50 PsA) received high-resolution peripheral quantitative CT of the distal radius. Demographic and disease-specific parameters including anti-rheumatic treatment, bone erosion status and previous fractures were recorded.RA and PsA patients were comparable in age, gender, body mass index, disease duration, disease activity, functional status, antirheumatic treatment and bone erosion status. No significant differences were found for volumetric bone mineral density (BMD), including total BMD (300±77 vs 316±62 mgHA/cm(3)), trabecular BMD (152±46 vs 165±40 mgHA/cm(3)) and cortical BMD (787±113 vs 818±76 mgHA/cm(3)) when comparing RA patients to PsA patients, respectively. However, in contrast to seronegative RA, seropositive RA showed significantly reduced trabecular BMD (p=0.007), bone volume per tissue volume (p=0.007) and trabecular number (p=0.044), as well as a strong trend towards higher trabecular inhomogeneity compared to PsA patients. In the regression analysis, higher age, female gender and presence of autoantibodies were independently associated with trabecular bone loss.Seropositive RA exhibits more profound changes in trabecular bone architecture than seronegative RA or PsA. The data support the concept that seropositive RA is a disease entity that is distinct from seronegative RA and PsA.
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Differences in the patient's and the physician's perspective of disease in psoriatic arthritis - Dandorfer, Stefan; Rech, Jürgen; Manger, Bernhard; Schett, Georg; Englbrecht, Matthias (Seminars in Arthritis and Rheumatism, 2012)
Objective: To define the relative impact of disease components of psoriatic arthritis (PsA) on the global burden of disease and to compare physician's and patients' ratings of disease activity. Methods: PsA patients fulfilling the Classification Criteria for Psoriatic Arthritis (N = 55) were asked for an evaluation of the absolute and relative impact of general and specific rheumatic symptoms (ie, arthritis, enthesitis, spinal disease, dactylitis), general and specific psoriatic symptoms (skin disease, nail disease), and other common symptoms (eg, fatigue). Results were related to the respective physician's evaluations of disease-related symptoms based on visual analog scale (VAS) ratings and comparative measures of disease activity (ie, swollen and tender joint counts, MASES, PASI, NAPSI). Results: One-half of the global burden of disease in PsA patients was attributed to rheumatic symptoms with peripheral arthritis as the leading component, whereas the other one-half was equally distributed to psoriatic and additional common symptoms such as fatigue. In general, corresponding patient and physician ratings of global, rheumatic, and psoriatic disease activity showed good correlations when using VAS but at the same time revealed significantly lower ratings of the corresponding physician on VAS and transformed comparative measures (all P ≤ 0.02). Conclusions: Although we found good correlations of various disease activity measures, physicians usually evaluated the disease activity of PsA lower than patients. These results highlight the necessity of incorporating patient reported outcome measures into the assessment of disease activity in PsA, which can easily be visualized with the help of a spiderweb graph. © 2012 Elsevier Inc.
CRIS-Team Scopus Importer:2021-02-03
Keywords: Disease activity; Patient reported outcomes; Psoriatic arthritis

Differential diagnosis of RA and PsA using neural networks on 3D bone shape of finger joints - Folle, Lukas; Liu, Chang; Simon, David; Meinderink, Timo; Liphardt, Anna-Maria; Krönke, Gerhard; Schett, Georg; Maier, Andreas; Kleyer, Arnd (Annals of the Rheumatic Diseases 2021, 2021)
Keywords: Deep Learning; Rheumatoid arthritis; psoriatic arthritis

Differential roles of MAPK kinases MKK3 and MKK6 in osteoclastogenesis and bone loss - Boyle, David L.; Hammaker, Deepa; Edgar, Meghan; Zaiss, Mario M.; Teufel, Stefan; David, Jean Pierre; Schett, Georg; Firestein, Gary S. (PLoS ONE, 2014)
Bone mass is maintained by osteoclasts that resorb bone and osteoblasts that promote matrix deposition and mineralization. Bone homeostasis is altered in chronic inflammation as well as in post-menopausal loss of estrogen, which favors osteoclast activity that leads to osteoporosis. The MAPK p38? is a key regulator of bone loss and p38 inhibitors preserve bone mass by inhibiting osteoclastogenesis. p38 function is regulated by two upstream MAPK kinases, namely MKK3 and MKK6. The goal of this study was to assess the effect of MKK3- or MKK6-deficiency on osteoclastogenesis in vitro and on bone loss in ovariectomy-induced osteoporosis in mice. We demonstrated that MKK3 but not MKK6, regulates osteoclast differentiation from bone marrow cells in vitro. Expression of NFATc1, a master transcription factor in osteoclastogenesis, is decreased in cells lacking MKK3 but not MKK6. Expression of osteoclast-specific genes Cathepsin K, osteoclast-associated receptor and MMP9, was inhibited in MKK3-/- cells. The effect of MKK-deficiency on ovariectomy-induced bone loss was then evaluated in female WT, MKK3-/- and MKK6-/- mice by micro-CT analysis. Bone loss was partially inhibited in MKK3-/- as well as MKK6-/- mice, despite normal osteoclastogenesis in MKK6-/- cells. This correlated with the lower osteoclast numbers in the MKK-deficient ovariectomized mice. These studies suggest that MKK3 and MKK6 differentially regulate bone loss due to estrogen withdrawal. MKK3 directly mediates osteoclastogenesis while MKK6 likely contributes to pro-inflammatory cytokine production that promotes osteoclast formation.
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