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 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

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 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

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.
EVALuna2:12979

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.
EVALuna2:12923

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.
EVALuna2:13234

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

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

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

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

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 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 CyberGlove III calibration methods and the application to arthritis patients - 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 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

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 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

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)
EVALuna2:33437

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

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)
EVALuna2:540325

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

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 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

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

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

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 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.

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.
EVALuna2:13411

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

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.
EVALuna2:10122

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.
EVALuna2:10050

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 S.; 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.
EVALuna2:3811

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.
EVALuna2:13179

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

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

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.
EVALuna2:13182

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.
EVALuna2:13404

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.
EVALuna2:12929

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)
EVALuna2:34463

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)
EVALuna2:34984

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.
EVALuna2:10051

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.
EVALuna2:12931

Differentiation of osteophyte types in osteoarthritis - proposal of a histological classification - Junker, Susann; Krumbholz, Grit; Frommer, Klaus W.; Rehart, Stefan; Steinmeyer, Juergen; Rickert, Markus; Schett, Georg; Mueller-Ladner, Ulf; Neumann, Elena (Joint Bone Spine, 2016)
Osteoarthritis is not only characterized by cartilage degradation but also involves subchondral bone remodeling and osteophyte formation. Osteophytes are fibrocartilage-capped bony outgrowths originating from the periosteum. The pathophysiology of osteophyte formation is not completely understood. Yet, different research approaches are under way. Therefore, a histological osteophyte classification to achieve comparable results in osteophyte research was established for application to basic science research questions.The osteophytes were collected from knee joints of osteoarthritis patients (n=10, 94 osteophytes in total) after joint replacement surgery. Their size and origin in the respective joint were photo-documented. To develop an osteophyte classification, serial tissue sections were evaluated using histological (hematoxylin and eosin, Masson's trichrome, toluidine blue) and immunohistochemical staining (collagen type II).Based on the histological and immunohistochemical evaluation, osteophytes were categorized into four different types depending on the degree of ossification and the percentage of mesenchymal connective tissue. Size and localization of osteophytes were independent from the histological stages.This histological classification system of osteoarthritis osteophytes provides a helpful tool for analyzing and monitoring osteophyte development and for characterizing osteophyte types within a single human joint and may therefore contribute to achieve comparable results when analyzing histological findings in osteophytes.
EVALuna2:13136

Differenzialdiagnose Rückenschmerzen mit Entzündungsparametern: Fallvorstellung: Manifestation einer CPPD als Crowned Dens Syndrom mit Befall peripherer Gelenke - Kleyer, Arnd; Roemer, Frank; Schett, Georg; Manger, Bernhard (Aktuelle Rheumatologie, 2021)
This case report describes the case of a patient with back pain of unknown origin and high inflammatory markers. After an infectious cause was ruled out, he was diagnosed with CPPD disease with spinal infestation. New radiological segmentation methods also allowed the detection of CPPD crystals in peripheral joints. Treatment with prednisolone and short-term Kineret was initiated and the symptoms were treated successfully.
CRIS-Team Scopus Importer:2021-03-05
Keywords: chondrocalcinosis; CPPD; crowned dens syndrome; crystal arthropathies; pseudogout

Difficult-to-Treat Psoriatic Arthritis: A Conceptual Approach. - Fagni, Filippo; Motta, Francesca; Schett, Georg; Selmi, Carlo (Arthritis and Rheumatology, 2024)
EVALuna2:551950

Digital health transition in rheumatology: A qualitative study - Müehlensiepen, Felix; Kurkowski, Sandra; Krusche, Martin; Mucke, Johanna; Prill, Robert; Heinze, Martin; Welcker, Martin; Schulze-Koops, Hendrik; Vuillerme, Nicolas; Schett, Georg; Knitza, Johannes (International Journal of Environmental Research and Public Health, 2021)
The global COVID-19 pandemic has led to drastic changes in the management of patients with rheumatic diseases. Due to the imminent risk of infection, monitoring intervals of rheumatic patients have prolonged. The aim of this study is to present insights from patients, rheumatologists, and digital product developers on the ongoing digital health transition in rheumatology. A qualitative and participatory semi-structured fishbowl approach was conducted to gain detailed insights from a total of 476 participants. The main findings show that digital health and remote care are generally welcomed by the participants. Five key themes emerged from the qualitative content analysis: (1) digital rheumatology use cases, (2) user descriptions, (3) adaptation to different environments of rheumatology care, and (4) potentials of and (5) barriers to digital rheumatology implementation. Codes were scaled by positive and negative ratings as well as on micro, meso, and macro levels. A main recommendation resulting from the insights is that both patients and rheumatologists need more information and education to successfully implement digital health tools into clinical routine.
CRIS-Team Scopus Importer:2021-03-19
Keywords: Chronic disease; Content analysis; Digital health; EHealth; Fishbowl discussion; Patient perspective; Qualitative research; Remote care; Rheumatology; Telemedicine

DIGITALLY ENHANCED TREAT-TO-TARGET AND SHARED DECISION-MAKING APPROACH WITH A DIGITAL HEALTH APPLICATION: INTERIM RESULTS FROM A RANDOMIZED CONTROLLED TRIAL - Knitza, Johannes; Grahammer, M.; Böltz, Sebastian; Lang, Johannes; Detert, M.; Bader, M.; Kleyer, Arnd; Simon, David; Kronke, G.; Schett, Georg; Detert, J. (ANNALS OF THE RHEUMATIC DISEASES, 2022)
CRIS-Team WoS Importer:2022-11-04

Digitally supported shared decision-making and treat-to-target in rheumatology: a qualitative study embedded in a multicenter randomized controlled trial - Muehlensiepen, Felix; May, Susann; Hadaschik, Katharina; Vuillerme, Nicolas; Heinze, Martin; Grahammer, Manuel; Labinsky, Hannah; Böltz, Sebastian; Detert, Jacqueline; Petersen, Jana; Krönke, Gerhard; Schett, Georg; et al. (Rheumatology International, 2022)
Patient-reported outcomes (PRO) represent a cornerstone in the management of patients with rheumatoid arthritis (RA). However, PRO are currently recorded mainly on paper and only during on-site appointments. Electronic PRO (ePRO) enable continuous remote monitoring and could improve shared decision-making (SDM) and implementation of a treat-to-target (T2T) approach. This study aims to investigate patient and physician experiences, perceived drawbacks and benefits of using an ePRO web-app (ABATON RA) to digitally support SDM and T2T. A qualitative study embedded in a multicenter randomized controlled trial (RCT) consisting of interviews with RA patients and physicians that were subsequently analyzed using deductive-inductive qualitative content analysis. Between August 2021 and May 2022, interviews with ten RA patients and five physicians were completed. Three key themes emerged in the analysis: (i) App user experiences; (ii) perceived drawbacks of app-supported rheumatology care; and (iii) perceived benefits of app-supported rheumatology care. Continuous ePRO collection and a high level of standardization strained some RA patients. Certain ePRO seemed outdated and were hard to understand. Patients and physicians appreciated having an improved overview of disease activity, capturing disease flares and continuous remote monitoring. Paper- and time-saving were associated with using ePRO. Physicians feared to become too focused on ePRO data, stressed the lack of ePRO monitoring reimbursement and app interoperability. For RA patients and physicians, benefits seemed to outweigh observed drawbacks of the digitally supported SDM using ePRO. The software was easy to use and could lead to a better understanding of the individual disease course, resource allocation and treatment of rheumatoid arthritis.
CRIS-Team Scopus Importer:2022-10-28
Keywords: ePRO; Health Services Research; mHealth; Qualitative research; Rheumatology; SDM

Dipeptidylpeptidase 4 as a Marker of Activated Fibroblasts and a Potential Target for the Treatment of Fibrosis in Systemic Sclerosis - Soare, Alina; Györfi, Andrea-Hermina; Matei, Alexandru-Emil; Dees, Clara; Rauber, Simon; Wohlfahrt, Thomas; Chen, Chih Wei; Ludolph, Ingo; Horch, Raymund E.; Bäuerle, Tobias; von Hörsten, Stephan; Mihai, Carina; et al. (Arthritis and Rheumatology, 2020)
Objective: Expression of dipeptidylpeptidase 4 (DPP-4) identifies a dermal fibroblast lineage involved in scarring during wound healing. The role of DDP-4 in tissue fibrosis is, however, unknown. The aim of the present study was to evaluate DPP-4 as a potential target for the treatment of fibrosis in patients with systemic sclerosis (SSc). Methods: Expression of DPP-4 in skin biopsy samples and dermal fibroblasts was analyzed by real-time polymerase chain reaction, immunofluorescence, and Western blot analyses. The activity of DPP-4 was modulated by overexpression, knockdown, and pharmacologic inhibition of DPP4 using sitagliptin and vildagliptin. The effects of DPP4 inhibition were analyzed in human dermal fibroblasts and in different mouse models of SSc (each n = 6). Results: The expression of DPP-4 and the number of DPP-4–positive fibroblasts were increased in the fibrotic skin of SSc patients, in a transforming growth factor β (TGFβ)–dependent manner. DPP-4–positive fibroblasts expressed higher levels of myofibroblast markers and collagen (each P < 0.001 versus healthy controls). Overexpression of DPP4 promoted fibroblast activation, whereas pharmacologic inhibition or genetic inactivation of DPP4 reduced the proliferation, migration, and expression of contractile proteins and release of collagen (each P < 0.001 versus control mice) by interfering with TGFβ-induced ERK signaling. DPP4-knockout mice were less sensitive to bleomycin-induced dermal and pulmonary fibrosis (P < 0.0001 versus wild-type controls). Treatment with DPP4 inhibitors promoted regression of fibrosis in mice that had received bleomycin challenge and mice with chronic graft-versus-host disease, and ameliorated fibrosis in TSK1 mice (each P < 0.001 versus untreated controls). These antifibrotic effects were associated with a reduction in inflammation. Conclusion: DPP-4 characterizes a population of activated fibroblasts and shows that DPP-4 regulates TGFβ-induced fibroblast activation in the fibrotic skin of SSc patients. Inhibition of DPP4 exerts potent antifibrotic effects when administered in well-tolerated doses. As DPP4 inhibitors are already in clinical use for diabetes, these results may have direct translational implications for the treatment of fibrosis in patients with SSc.
CRIS-Team Scopus Importer:2020-01-10

DIPEPTIDYL-PEPTIDASE-4 (DPP4) IS A POTENTIAL NEW MOLECULAR TARGET FOR TREATMENT OF FIBROSIS - Soare, A. M.; Gyoerfy, H.; Matei, Alexandru-Emil; Dees, Clara; Zhang, Yun; Wohlfahrt, T.; Chen, Chih-Wei; Ramming, A.; Schett, Georg; Distler, Jörg (2018)
EVALuna2:34995

Dipeptidyl-Peptidase-4 (DPP4) Positive Fibroblast Subpopulation Promotes Fibrosis and Are a Molecular Target for Treatment of Fibrosis - Soare, Alina; Rauber, Simon; Wohlfahrt, Thomas; Dees, Clara; Liang, Ruifang; Zhang, Yun; Chen, Chih-Wei; Distler, Oliver; Mihai, Carina; Schett, Georg; Distler, Jörg; Ramming, Andreas (2016)
EVALuna2:35065

Dipeptidyl-Peptidase-4 (DPP4) Promotes Fibroblast Activation and Is a Potential Molecular Target for Treatment of Fibrosis - Soare, Alina; Gyoerfy, Hermina; Matei, Alexandru-Emil; Dees, Clara; Chen, Chih-Wei; Ramming, Andreas; Schett, Georg; Distler, Jörg (2017)
EVALuna2:33443

DISEASE INTERCEPTION IN PSORIASIS PATIENTS WITH SUBCLINICAL JOINT INFLAMMATION BY INTERLEUKIN 17 INHIBITION WITH SECUKINUMAB - DATA FROM A PROSPECTIVE OPEN LABEL STUDY - Kamoylafka, E.; Oliveira, I. D.; Linz, C.; Lerchen, V.; Englbrecht, Matthias; Simon, David; Sticherling, Michael; Rech, Jürgen; Kleyer, Arnd; Schett, Georg; Hueber, Axel (2018)
EVALuna2:34789

Disease interception with interleukin-17 inhibition in high-risk psoriasis patients with subclinical joint inflammation - Data from the prospective IVEPSA study - Kampylafka, Eleni; Simon, David; D'Oliveira, Isabelle; Linz, Christina; Lerchen, Veronika; Englbrecht, Matthias; Rech, Jürgen; Kleyer, Arnd; Sticherling, Michael; Schett, Georg; Hueber, Axel (Arthritis Research & Therapy, 2019)
Background: A specific subset of psoriasis patients is characterized by subclinical inflammatory changes. These patients frequently present with arthralgia and have a higher risk to develop psoriatic arthritis (PsA). We hypothesized that IL-17A inhibition in this subset of patients can intercept the link between skin and joint disease and resolves pain and inflammatory changes. Methods: Psoriasis, but no PsA, patients were included in the open prospective exploratory Interception in very early PsA (IVEPSA) study. Patients had to have nail or scalp involvement or a high psoriasis area severity index (PASI) (> 6) as well as inflammatory or erosive changes in MRI or CT. Patients received treatment with the anti-interleukin (IL)-17A antibody secukinumab over 24 weeks. Clinical assessments of skin and joint disease were done at baseline and after 12 and 24 weeks, MRI and CT at baseline and after 24 weeks. Results: Twenty patients were included, 85% of them reporting arthralgia and 40% had tender joints at the examination. Eighty-three percent had at least one inflammatory lesion in the MRI, most of them synovitis/enthesitis. Skin disease (PASI: p < 0.002; BSA: p < 0.003) and arthralgia (VAS pain: p < 0.003) significantly improved after 24 weeks. Total PsAMRIS (p = 0.005) and synovitis subscore (p = 0.008) also significantly improved. Erosions and enthesiophytes did not progress, while bone mass in the distal radius significantly (p = 0.020) increased after 24 weeks. Conclusions: These data suggest that very early disease interception in PsA is possible leading to a comprehensive decline in skin symptoms, pain, and subclinical inflammation. IVEPSA therefore provides rationale for future early interventions with the concept to prevent the onset of PsA in high-risk individuals. Trial registration: Trial registry name PSARTROS; trial registry number: NCT02483234; June 26, 2015.
CRIS-Team Scopus Importer:2019-08-06
Keywords: Interleukin-17; Magnetic resonance imaging; Psoriasis; Psoriatic arthritis

Disentangling inflammatory from fibrotic disease activity by fibroblast activation protein imaging - Schmidkonz, Christian; Rauber, Simon; Atzinger, Armin; Agarwal, Rahul; Götz, Theresa Ida; Soare, Alina; Cordes, Michael; Prante, Olaf; Bergmann, Christina; Kleyer, Arnd; Ritt, Philipp; Maschauer, Simone; et al. (Annals of the Rheumatic Diseases, 2020)
Objectives To date, there is no valuable tool to assess fibrotic disease activity in humans in vivo in a non-invasive way. This study aims to uncouple inflammatory from fibrotic disease activity in fibroinflammatory diseases such as IgG 4 -related disease. Methods In this cross-sectional clinical study, 27 patients with inflammatory, fibrotic and overlapping manifestations of IgG 4 -related disease underwent positron emission tomography (PET) scanning with tracers specific for fibroblast activation protein (FAP; 68 Ga-FAP inhibitor (FAPI)-04), 18 F-fluorodeoxyglucose (FDG), MRI and histopathological assessment. In a longitudinal approach, 18 F-FDG and 68 Ga-FAPI-04 PET/CT data were evaluated before and after immunosuppressive treatment and correlated to clinical and MRI data. Results Using combination of 68 Ga-FAPI-04 and 18 F-FDG-PET, we demonstrate that non-invasive functional tracking of IgG 4 -related disease evolution from inflammatory towards a fibrotic outcome becomes feasible. 18 F-FDG-PET positive lesions showed dense lymphoplasmacytic infiltration of IgG 4 + cells in histology, while 68 Ga-FAPI-04 PET positive lesions showed abundant activated fibroblasts expressing FAP according to results from RNA-sequencing of activated fibroblasts. The responsiveness of fibrotic lesions to anti-inflammatory treatment was far less pronounced than that of inflammatory lesions. Conclusion FAP-specific PET/CT permits the discrimination between inflammatory and fibrotic activity in IgG 4 -related disease. This finding may profoundly change the management of certain forms of immune-mediated disease, such as IgG 4 -related disease, as subtypes dominated by fibrosis may require different approaches to control disease progression, for example, specific antifibrotic agents rather than broad spectrum anti-inflammatory treatments such as glucocorticoids.
CRIS-Team Scopus Importer:2020-10-30
Keywords: fibroblasts; health care; inflammation; outcome assessment

Disentangling inflammatory from fibrotic disease activity by fibroblast activation protein imaging - Schmidkonz, Christian; Rauber, Simon; Atzinger, Armin; Götz, Theresa Ida; Soare, A.; Cordes, Michael; Prante, Olaf; Ritt, Philipp; Bäuerle, Tobias; Köhner, Markus; Haberkorn, U.; Kuwert, Torsten; et al. (European Journal of Nuclear Medicine and Molecular Imaging, 2021)
Ziel/Aim To date, there is no valuable tool to assess fibrotic disease activity in humans in vivo in a non-invasive way. This study aims to uncouple inflammatory from fibrotic disease activity in fibroinflammatory diseases such as IgG4-related disease. Methodik/Methods In this cross-sectional clinical study, 27 patients with inflammatory, fibrotic and overlapping manifestations of IgG4-related disease underwent positron emission tomography (PET) scanning with tracers specific for fibroblast activation protein (FAP; 68Ga-FAP inhibitor (FAPI)-04), 18F-fluorodeoxyglucose (FDG), magnetic resonance imaging (MRI) and histopathological assessment. In a longitudinal approach, 18F-FDG and 68Ga-FAPI-04 PET/CT data were evaluated before and after immunosuppressive treatment and correlated to clinical and MRI data. Ergebnisse/Results Using combination of 68Ga-FAPI-04 and 18F-FDG-PET, we demonstrate that non-invasive functional tracking of IgG4-related disease evolution from inflammatory towards a fibrotic outcome becomes feasible. 18F-FDG-PET positive lesions showed dense lymphoplasmacytic infiltration of IgG4 + cells in histology, while 68Ga-FAPI-04 PET positive lesions showed abundant activated fibroblasts expressing FAP according to results from RNA-sequencing of activated fibroblasts. The responsiveness of fibrotic lesions to anti-inflammatory treatment was far less pronounced than that of inflammatory lesions. Schlussfolgerungen/Conclusions FAP-specific PET/CT permits the discrimination between inflammatory and fibrotic activity in IgG4-related disease. This finding may profoundly change the management of certain forms of immune-mediated disease, such as IgG4-related disease, as subtypes dominated by fibrosis may require different approaches to control disease progression, for example, specific antifibrotic agents rather than broad spectrum anti-inflammatory treatments such as glucocorticoids.
CRIS-Team WoS Importer:2022-01-07

Does an 18f-FDG-PET/CT in Patients with Giant Cell Arteritis in Clinical Remission Make Sense? - Schoenau, Verena; Roth, Jan-Peter; Englbrecht, Matthias; Rech, Jürgen; Schett, Georg (2018)
EVALuna2:34970

Does methotrexate influence COVID-19 infection? Case series and mechanistic data - Schaelter, Fabian; Dürholz, Kerstin; Bucci, Laura; Burmester, Gerd; Caporali, Roberto; Figuereido, Camille; Cobra, Jaime Fogagnolo; Manger, Bernhard; Zaiss, Mario; Schett, Georg (Arthritis Research & Therapy, 2021)
Background: To investigate whether methotrexate treatment may affect the susceptibility to infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Methods: Clinical assessment of symptoms, SARS-CoV-2 RNA, and anti-SARS-CoV-2 IgG in an initial case series of four families and confirmatory case series of seven families, within which one family member developed coronavirus disease 19 (COVID-19) and exposed another family member receiving methotrexate treatment; experimental part with methotrexate treatment of mice and organoids followed by the assessment of mRNA and protein expression of the SARS-CoV-2 receptor angiotensin-converting enzyme (ACE)-2. Results: In the initial case series, three of four women on a joint ski trip developed COVID-19, while the fourth woman, under treatment with methotrexate, remained virus-free. Two of the three diseased women infected their husbands, while the third husband treated with methotrexate remained virus-free. In addition, 7 other families were identified in a follow-up case series, in which one member developed COVID-19, while the other, receiving methotrexate, remained healthy. Experimentally, when mice were treated with methotrexate, ACE2 expression significantly decreased in the lung, in the intestinal epithelium, and in intestinal organoids. Conclusion: These clinical and experimental data indicate that methotrexate has certain protective effects on SARS-CoV-2 infection via downregulating ACE2.
CRIS-Team Scopus Importer:2021-06-18
Keywords: Coronavirus disease 19; Infection; Methotrexate

Does methotrexate influence COVID-19 infection? Case series and mechanistic data - Schälter, Fabian; Dürholz, Kerstin; Bucci, Laura; Burmester, Gerd R.; Caporali, Roberto; Figuereido, Camille; Cobra, Jaime Fogagnolo; Manger, Bernhard; Zaiss, Mario; Schett, Georg (Arthritis Research & Therapy, 2021)

Does subclinical inflammation contribute to impairment of function of knee joints in aged individuals? High prevalence of ultrasound inflammatory findings - D'Agostino, Maria Antonietta; Iagnocco, Annamaria; Aegerter, Philippe; Kleyer, Arnd; Zwerina, Jochen; Perricone, Carlo; Lorenzini, Rolando; Aschenbrenner, Franz; Willeit, Johann; Kiechl, Stefan; Schett, Georg (Rheumatology, 2015)
To investigate the prevalence of knee US findings of inflammation and structural damage in aged individuals (>=60 years) of a long-term population-based cohort and to correlate these findings with demographic, clinical and laboratory parameters.Cross-sectional clinical and US investigation of both knee joints during the 2010 follow-up of the prospective population-based Bruneck Study. Demographic variables, physical activity, comorbidities, medications, pain, and functional scales related to the knee joints were recorded. US-assessed parameters were synovial hypertrophy, power Doppler signal, joint effusion, cartilage abnormalities, osteophytes, enthesopathy and bursitis. Statistics included univariate and multivariate regression analysis.A total of 488 subjects (mean age 72.5 years; 53.5% females, 46.5% males) were examined by clinical assessment, and 433 of these underwent US examination of both knees. Both inflammatory and structural abnormalities were found in 296 (68.8%) subjects. Inflammatory abnormalities were significantly associated with age in years, male gender, diabetes and the presence of knee joint symptoms. In the multivariate analysis, age, male gender and knee swelling emerged as independent predictors of inflammation [odds ratio (OR) (95% CI) = 1.06 (1.03, 1.09), 2.55 (1.55, 4.21) and 5.92 (1.99, 17.58), respectively].The present study showed a high prevalence of US inflammatory abnormalities in the knee joints of a normal aged population. These data suggest a substantial contribution of inflammation in progressive impairment of joint function with age.
EVALuna2:13126

Does Subjectively Perceived Loss Of Hand Function Sufficiently Represent Ultrasonography-Detected Synovitis And Tenosynovitis In Patients With Psoriasis And Psoriatic Arthritis? - Coppers, Birte; Bayat, Sara; Elie-Tino, Godonou; Valor-Mendez, Larissa; Fagni, Filippo; Corte, Giulia; Tascilar, Koray; Hueber, Axel; Schönau, Verena; Sticherling, Michael; Schett, Georg; Kleyer, Arnd; et al. (poster, European Alliance of Association for Rheumatology (EULAR) Congress, 2023)

DOSING OF BDMARDS IN AXSPA AND PSA IN A REAL WORLD SETTING - Regierer, Anne C.; Weiss, Anja; Poddubnyy, Denis; Kellner, H.; Behrens, Frank; Schett, Georg; Braun, Jürgen; Sieper, Joachim; Strangfeld, Anja (ANNALS OF THE RHEUMATIC DISEASES, 2021)
CRIS-Team WoS Importer:2021-10-01

DUAL NEUTRALISATION OF IL-17A AND IL-17F WITH BIMEKIZUMAB IN PATIENTS WITH ACTIVE PSA: OVERALL AND TNF-INHIBITOR-NAIVE POPULATION RESULTS FROM A 48-WEEK PHASE 2B RANDOMISED STUDY - Ritchlin, Christopher T.; Kavanaugh, Arthur; Merola, Joseph F.; Schett, Georg; Scher, Jose U.; Warren, Richard B.; Assudani, Deepak; Kumke, Thomas; Ink, Barbara; Mcinnes, Iain (ANNALS OF THE RHEUMATIC DISEASES, 2019)
CRIS-Team WoS Importer:2019-07-12

DURABILITY OF APREMILAST RESPONSE IN PATIENTS WITH PSORIATIC ARTHRITIS: LONG-TERM (208-WEEK) RESULTS FROM THE PALACE 1 TRIAL - Kavanaugh, A.; Gladman, D. D.; Gomez-Reino, J. J.; Hall, S.; Lespessailles, E.; Mease, P. J.; Schett, Georg; Mcilraith, M.; Delev, N.; Paris, M.; Teng, L.; Wollenhaupt, J. (2017)
EVALuna2:35038

Durability of apremilast response through 5 years of treatment in subjects with psoriatic arthritis - Kavanaugh, Arthur; Gladman, Dafna D.; Gomez-Reino, Juan J.; Hall, Stephen; Lespessailles, Eric; Mease, Philip J.; Schett, Georg; Pari, Maria; Teng, Lichen; Wollenhaupt, Juergen (2018)
EVALuna2:34974

DYNAMIC CHANGES IN O-GLCNACYLATION REGULATE OSTEOCLAST DIFFERENTIATION AND BONE LOSS IN ARTHRITIS - Chen, Chih-Wei; Li, Y. N.; Trinh, Minh Thuong; Honglin, Z.; Matei, Alexandru-Emil; Ding, Xiao; TRAN MANH, CUONG; Xu, Xiaohan; Liebel, C.; Liang, Ruifang; Huang, M. C.; Lin, N. Y.; et al. (ANNALS OF THE RHEUMATIC DISEASES, 2021)
CRIS-Team WoS Importer:2021-10-01

Dynamic changes in O-GlcNAcylation regulate osteoclast differentiation and bone loss via nucleoporin 153 - Li, Yi-Nan; Chen, Chih-Wei; Trinh, Minh Thuong; Zhu, Honglin; Matei, Alexandru-Emil; Györfi, Andrea-Hermina; Kuwert, Frederic; Hubel, Philipp; Ding, Xiao; TRAN MANH, CUONG; Xu, Xiaohan; Liebel, Christoph; et al. (Bone Research, 2022)
Bone mass is maintained by the balance between osteoclast-induced bone resorption and osteoblast-triggered bone formation. In inflammatory arthritis such as rheumatoid arthritis (RA), however, increased osteoclast differentiation and activity skew this balance resulting in progressive bone loss. O-GlcNAcylation is a posttranslational modification with attachment of a single O-linked β-D-N-acetylglucosamine (O-GlcNAc) residue to serine or threonine residues of target proteins. Although O-GlcNAcylation is one of the most common protein modifications, its role in bone homeostasis has not been systematically investigated. We demonstrate that dynamic changes in O-GlcNAcylation are required for osteoclastogenesis. Increased O-GlcNAcylation promotes osteoclast differentiation during the early stages, whereas its downregulation is required for osteoclast maturation. At the molecular level, O-GlcNAcylation affects several pathways including oxidative phosphorylation and cell-cell fusion. TNFα fosters the dynamic regulation of O-GlcNAcylation to promote osteoclastogenesis in inflammatory arthritis. Targeted pharmaceutical or genetic inhibition of O-GlcNAc transferase (OGT) or O-GlcNAcase (OGA) arrests osteoclast differentiation during early stages of differentiation and during later maturation, respectively, and ameliorates bone loss in experimental arthritis. Knockdown of NUP153, an O-GlcNAcylation target, has similar effects as OGT inhibition and inhibits osteoclastogenesis. These findings highlight an important role of O-GlcNAcylation in osteoclastogenesis and may offer the potential to therapeutically interfere with pathologic bone resorption.
CRIS-Team Scopus Importer:2022-08-05

Early Histopathological Changes of the Salivary Glands Associated with the Development of Primary Sjogren's Syndrome - Shan, Xiaomei; Reichardt, Clara; Singh, Jeeshan; Zeitler, Anne; Schauer, Christine; Knopf, Jasmin; Herrmann, Martin; Grossmayer, Gerhard; Schett, Georg; Munoz, Luis Enrique (ARTHRITIS & RHEUMATOLOGY, 2022)
CRIS-Team WoS Importer:2023-01-13

Editorial overview: Osteoimmunology - Schett, Georg; Takayanagi, Hiroshi (Bone, 2022)
CRIS-Team Scopus Importer:2022-07-01

Effective and safe treatment of anti-CD38 therapy in systemic lupus erythematosus-associated refractory cerebral vasculitis induces immune tolerance - Yalcin Mutlu, Melek; Wacker, Jochen; Tascilar, Koray; Taubmann, Jule; Manger, Bernhard; Krönke, Gerhard; Schett, Georg; Simon, David (Rheumatology, 2022)
CRIS-Team WoS Importer:2022-08-26

Effect of disease-modifying anti-rheumatic drugs on bone structure and strength in psoriatic arthritis patients - Simon, David; Kleyer, Arnd; Bayat, Sara; Tascilar, Koray; Kampylafka, Eleni; Meinderink, Timo; Schuster, Louis; Petrov, Ramona; Liphardt, Anna-Maria; Rech, Jürgen; Schett, Georg; Hueber, Axel (Arthritis Research & Therapy, 2019)
Objectives: To address whether the use of methotrexate (MTX) and biological disease-modifying anti-rheumatic drugs (bDMARDs) impacts bone structure and biomechanical properties in patients with psoriatic arthritis (PsA). Methods: This is a cross-sectional study in PsA patients receiving no DMARDs, MTX, or bDMARDs. Volumetric bone mineral densities (vBMDs), microstructural parameters, and biomechanical properties (stiffness/failure load) were determined by high-resolution peripheral quantitative CT and micro-finite element analysis in the respective groups. Bone parameters were compared between PsA patients with no DMARDs and those receiving any DMARDs, MTX, or bDMARDs, respectively. Results: One hundred sixty-five PsA patients were analyzed, 79 received no DMARDs, 86 received DMARDs, of them 52 bDMARDs (TNF, IL-17-or IL-12/23 inhibitors) and 34 MTX. Groups were balanced for age, sex, comorbidities, functional index, and bone-active therapy, while disease duration was longest in the bDMARD group (7.8 ± 7.4 years), followed by the MTX group (4.6 ± 7.4) and the no-DMARD group (2.9 ± 5.2). No difference in bone parameters was found between the no-DMARD group and the MTX group. In contrast, the bDMARD group revealed significantly higher total (p = 0.001) and trabecular vBMD (p = 0.005) as well as failure load (p = 0.012) and stiffness (p = 0.012). In regression models, age and bDMARDs influenced total vBMD, while age, sex, and bDMARDs influenced failure load and stiffness. Conclusion: Despite longer disease duration, bDMARD-treated PsA patients benefit from higher bone mass and better bone strength than PsA patients receiving MTX or no DMARDs. These data support the concept of better control of PsA-related bone disease by bDMARDs.
CRIS-Team Scopus Importer:2019-07-16
Keywords: Biological agents; Bone; Computed tomography; Disease-modifying anti-rheumatic drugs; Methotrexate; Psoriatic arthritis

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)
Background: Guselkumab is a selective interleukin (IL)-23 inhibitor targeting the IL-23p19 subunit. In the phase 3b COSMOS trial, guselkumab demonstrated efficacy in treating participants with active psoriatic arthritis (PsA) and inadequate response (IR; lack of efficacy or intolerance) to tumor necrosis factor inhibitors (TNFi). Methods: Adults with active PsA (≥ 3 swollen joints, ≥ 3 tender joints) and IR to one or two TNFi (TNFi-IR) were randomized 2:1 to guselkumab at Weeks 0, 4, then every 8 weeks (Q8W) or placebo➔guselkumab Q8W at Week 24 with possible early escape at Week 16. Levels of serum cytokines, including interferon ɣ (IFNɣ), IL-10, and tumor necrosis factor α (TNFα); T helper 17 (Th17) effector cytokines IL-17A, IL-17F, and IL-22; and acute phase proteins C-reactive protein (CRP), IL-6, and serum amyloid A (SAA), were assessed and compared with matched healthy controls; guselkumab pharmacodynamics through Week 24 were also assessed. Associations between baseline biomarker levels and 1) baseline disease activity (28-joint disease activity score using CRP [DAS28-CRP], psoriasis area and severity index [PASI], and % body surface area [BSA] affected by psoriasis) and 2) clinical response (including ≥ 20% improvement in American College of Rheumatology criteria [ACR20] response) at Week 24 were assessed. Results: Baseline serum levels of IL-6, IL-10, IL-17A, IL-17F, IL-22, TNFα, and IFNɣ were significantly higher in COSMOS TNFi-IR participants than in matched healthy controls. Baseline IL-6, CRP, and SAA levels were associated with baseline DAS28-CRP. IL-17A and IL-17F levels were associated with baseline PASI score and psoriasis BSA. Baseline swollen or tender joint counts did not associate with baseline biomarker levels. At Week 24, significant decreases from baseline in CRP, SAA, IL-17A, IL-17F, and IL-22 levels were seen in guselkumab, but not placebo-, treated participants. IL-17F and IL-22 levels at Week 24 in guselkumab-treated participants did not significantly differ from those of matched healthy controls. Guselkumab-treated participants achieving ACR20 response at Week 24 exhibited higher baseline IL-22 and IFNɣ levels versus nonresponders. Conclusions: Results from COSMOS participants with active, TNFi-IR PsA suggest guselkumab reduces levels of effector cytokines associated with the IL-23/IL-17 pathway, including those associated with baseline arthritis and skin disease activity. Trial registration: ClinicalTrials.gov: NCT03796858.
CRIS-Team Scopus Importer:2023-09-01
Keywords: Guselkumab; IL-17 pathway; IL-23; Psoriatic arthritis; Serum biomarkers

EFFECT OF HIGH FAT DIET ON SYSTEMIC AND LOCAL INFLAMMATION IN THE CONTEXT OF OSTEOARTHRITIS AND RHEUMATOID ARTHRITIS MOUSE MODELS - Sauermilch, H. M.; Huelser, M-L; Schreiyaeck, C.; Luo, Y.; Bozec, Aline; Schett, Georg; Mueller-Ladner, U.; Neumann, E. (ANNALS OF THE RHEUMATIC DISEASES, 2019)
CRIS-Team WoS Importer:2019-05-17

EFFECTS OF BASELINE PREDNISONE DOSE ON REMISSION AND DISEASE FLARE IN PATIENTS WITH GIANT CELL ARTERITIS TREATED WITH TOCILIZUMAB IN A PHASE 3 RANDOMIZED CONTROLLED TRIAL - Stone, John; Tuckwell, Katie; Dimonaco, Sophie; Klearman, Micki; Aringer, Martin; Blockmans, Daniel; Brouwer, Elisabeth; Cid, Maria; Dasgupta, Bhaskar; Rech, Jürgen; Salvarani, Carlo; Schulze-Koops, Hendrik; et al. (RHEUMATOLOGY, 2019)
CRIS-Team WoS Importer:2019-08-16

EFFECTS OF BASELINE PREDNISONE DOSE ON REMISSION AND DISEASE FLARE IN PATIENTS WITH GIANT CELL ARTERITIS TREATED WITH TOCILIZUMAB IN THE GIACTA TRIAL - Stone, John H.; Tuckwell, Katie; Dimonaco, Sophie; Klearman, Micki; Aringer, Martin; Blockmans, Daniel; Brouwer, Elisabeth; Cid, Maria C.; Dasgupta, Bhaskar; Rech, Jürgen; Salvarani, Carlo; Schulze-Koops, Hendrik; et al. (RHEUMATOLOGY, 2019)
CRIS-Team WoS Importer:2019-08-13

Effects of casirivimab/imdevimab on systemic and mucosal immunity against SARS-CoV-2 in B-cell depleted patients with autoimmune rheumatic diseases refractory to vaccination - Fagni, Filippo; Schmidt, Katja; Bohr, Daniela; Valor-Mendez, Larissa; Tascilar, Koray; Manger, Karin; Manger, Bernhard; Kleyer, Arnd; Simon, David; Schett, Georg; Harrer, Thomas; Hartmann, Fabian (RMD Open, 2022)
CRIS-Team WoS Importer:2022-06-03

Effects of Conventional Uric Acid-Lowering Therapy on Monosodium Urate Crystal Deposits - Ellmann, Hanna; Bayat, Sara; Guilhon de Araujo, Elizabeth; Manger, Bernhard; Kleyer, Arnd; Cavallaro, Alexander; Lell, Michael; Schenker, Hannah; Simon, David; Tascilar, Koray; Baraf, Herbert S. B.; Schett, Georg; et al. (Arthritis and Rheumatology, 2019)
Objective Few studies have systematically and quantitatively addressed the impact of urate-lowering therapy on monosodium urate (MSU) deposits. This study was undertaken to analyze the effect of lifestyle measures and conventional urate-lowering therapy on MSU deposits in patients with gout. Methods In this prospective study, subjects with gout according to the American College of Rheumatology/European League Against Rheumatism classification criteria and presence of MSU deposits seen on dual-energy computed tomography (DECT) scans received either lifestyle intervention or conventional urate-lowering therapy for a mean period of 18 months before a follow-up DECT scan. Detected MSU deposits were quantified by volumetric measurement and validated by semiquantitative scoring, and baseline and follow-up measurements were compared. Results Baseline and follow-up DECT scans were available for all 83 subjects. Six subjects discontinued treatment, and 77 subjects underwent a lifestyle intervention (n = 24) or were treated with allopurinol (n = 29), febuxostat (n = 22), or benzbromarone (n = 2) over the entire observation period. The mean serum uric acid (UA) level decreased from 7.2 to 5.8 mg/dl in the overall population. In patients who discontinued treatment, no change in MSU deposits or serum UA levels was observed. The burden of MSU deposits significantly decreased in patients undergoing lifestyle intervention (MSU volume P = 0.007; MSU score P = 0.001), and in patients treated with allopurinol (MSU volume and score P < 0.001) or febuxostat (MSU volume P < 0.001; MSU score P = 0.001). No significant decline in MSU deposits was noted in patients who discontinued treatment. Conclusion These data show that lifestyle intervention and xanthine oxidase inhibitors significantly decrease the MSU deposit burden. Hence, conventional gout therapy not only lowers serum UA levels, but also reduces pathologic MSU deposits.
CRIS-Team WoS Importer:2019-12-20

Effects of DMARDs on citrullinated peptide autoantibody levels in RA patients-A longitudinal analysis - Wunderlich, Carolin; Oliviera, Isabelle; Figueiredo, Camille P.; Rech, Juergen; Schett, Georg (Seminars in Arthritis and Rheumatism, 2016)
To study whether stable treatment with DMARDs affects anti-CCP2 antibody levels in patients with rheumatoid arthritis.In this longitudinal observational study 100 RA patients were followed for anti-CCP2 IgG antibody (U/L) and total IgG level (mg/dL) every 6 months for a total period of 2.5 years. All patients received stable DMARD treatment during this period. Five groups comprising each 20 patients were analyzed as follows: (1) methotrexate (MTX) alone, (2) tumor necrosis factor inhibitors (TNFi), (3) tocilizumab (TCZ), (4) rituximab (RTX), and (5) abatacept (ABA).Baseline demographic and disease-specific characteristics were comparable between the 5 groups. Anti-CCP2 antibody levels did not show significant changes in patients treated with MTX (mean ± SEM: -24.1 ± 8.1%), TNFi (-14.0 ± 11.1%) or TCZ (-24.3 ± 11.3%) between baseline and the 2.5 years follow-up. In contrast, anti-CCP2 antibody levels significantly decreased during treatment with RTX (-75.6 ± 4.4%) and ABA (-82.5 ± 3.7%). With respect to total IgG levels, no significant changes were observed with MTX (-1.6 ± 3.5%), TNFi (2.5 ± 3.4%), TCZ (-4.4 ± 3.1%), or ABA (-2.4 ± 3.8%) over 2.5 years. In contrast, total IgG levels significantly decreased during treatment with RTX (-22.0 ± 3.7%).DMARDs targeting the adaptive immune response such as ABA and RTX significantly lowered anti-CCP2 IgG levels, while cytokine inhibitors and methotrexate had no significant effects on anti-CCP2 IgG levels. RTX is the only DMARD, which also lowers total IgG level.
EVALuna2:13350

Effects of DMARD Tapering on Treatment Costs and Work Productivity in Rheumatoid Arthritis Patients- an Analysis from the Prospective Randomized Controlled Retro- Study - Hagen, Melanie; Figueiredo, Camille P.; Cobra, Jayme Fogagnolo; Haschka, Judith; Reiser, Michaela; Englbrecht, Matthias; Hueber, Axel; Manger, Bernhard; Kleyer, Arnd; Finzel, Stephanie; Tony, Hans-Peter; Kleinert, Stefan; et al. (2016)
EVALuna2:34455

EFFECTS OF DMARD TAPERING ON TREATMENT COSTS IN RHEUMATOID ARTHRITIS PATIENTS-AN ANALYSIS FROM THE PROSPECTIVE RANDOMIZED CONTROLLED RETROSTUDY - Hagen, Melanie; Figueiredo, C.; Cobra, J. F.; Reiser, M.; Haschka, J.; Englbrecht, Matthias; Hueber, Axel; Manger, Bernhard; Kleyer, Arnd; Finzel, S.; Tony, H. -P.; Wendler, J.; et al. (2016)
EVALuna2:13486

EFFECTS OF GUSELKUMAB, A MONOCLONAL ANTIBODY THAT SPECIFICALLY BINDS TO THE P19-SUBUNIT OF INTERLEUKIN-23, ON DACTYLITIS AND ENTHESITIS IN PATIENTS WITH ACTIVE PSORIATIC ARTHRITIS: POOLED RESULTS THROUGH WEEK 24 FROM TWO PHASE 3 STUDIES - Mcgonagle, D.; Mcinnes, I.; Deodhar, A.; Schett, Georg; Mease, P. J.; Shawi, M.; Kafka, S.; Karyekar, C.; Kollmeier, A.; Hsia, E. C.; Xu, X. L.; Sheng, S.; et al. (ANNALS OF THE RHEUMATIC DISEASES, 2020)
CRIS-Team WoS Importer:2020-08-21

Effects of secukinumab on synovitis and enthesitis in patients with psoriatic arthritis: 52-week clinical and ultrasound results from the randomised, double-blind ULTIMATE trial with open label extension - D'Agostino, Maria Antonietta; Carron, Philippe; Gaillez, Corine; Conaghan, Philip G.; Naredo, Esperanza; López-Rdz, Alejandra; Šenolt, Ladislav; Burgos-Vargas, Ruben; Hanova, Petra; Padovano, Ilaria; Cazenave, Tomas; Stoenoiu, Maria S.; et al. (Seminars in Arthritis and Rheumatism, 2023)
Objectives: In the ULTIMATE study with an open label extension, we assessed the long-term effect of secukinumab at tissue level on synovitis and enthesitis, and across all psoriatic arthritis (PsA) manifestations, using both clinical evaluations and power Doppler ultrasonography (PDUS). Methods: This randomised, placebo-controlled, Phase 3 study (ULTIMATE) included biologic-naïve patients with PsA with active PDUS synovitis and clinical enthesitis, and inadequate response to conventional synthetic disease-modifying antirheumatic drugs. The study consisted of 3 treatment periods; in the first period (baseline to week 12) patients were randomised to receive subcutaneous secukinumab (150 mg or 300 mg according to severity of skin psoriasis) or placebo every week until week 4 and once every 4 weeks up to week 12. In the second period (weeks 12–24) all patients received open-label secukinumab with placebo patients switching to secukinumab (150 mg or 300 mg). The third period (weeks 24–52) was an extended open-label treatment period. The long-term responsiveness of the Global EULAR-OMERACT Synovitis Score (GLOESS), clinical enthesitis and global PDUS-detected enthesitis score (using two candidate definitions of activity) at patient level, together with clinical efficacy across key manifestations of PsA and safety were assessed. Results: Of the 166 patients enrolled, 144 completed week 52. A significant reduction in GLOESS was demonstrated in the secukinumab group vs placebo at week 12, followed by a stable reduction of synovitis until week 52 in the secukinumab group while placebo switchers from week 12 reached a similar level of reduction at week 24 with stability thereafter. Likewise, a significant reduction in the Spondyloarthritis Research Consortium of Canada (SPARCC) enthesitis index was shown in the secukinumab group vs placebo at week 12 with sustained improvement to week 52. Global OMERACT PDUS enthesitis scores were numerically lower in secukinumab vs placebo switchers in the first two treatment periods, with some stability in the third period in both groups. Improvements in clinical responses were also observed across all key domains of PsA up to week 52 in both treatment groups with no new or unexpected safety signals. Conclusions: ULTIMATE showed consistent improvements in clinically and ultrasound-assessed synovitis and enthesitis and sustained clinical efficacy through week 52 in patients with PsA treated with secukinumab and placebo switched to secukinumab.
CRIS-Team Scopus Importer:2023-09-15
Keywords: Clinical response; Enthesitis; OMERACT; Power Doppler ultrasonography; Psoriatic arthritis; Synovitis

Effects of targeted therapies on the bone in arthritides - Szentpetery, Agnes; Horvath, Agnes; Gulyas, Katalin; Petho, Zsofia; Bhattoa, Harjit Pal; Szanto, Sandor; Szucs, Gabriella; Fitzgerald, Oliver; Schett, Georg; Szekanecz, Zoltan (Autoimmunity Reviews, 2017)
Inflammatory arthritides, such as rheumatoid arthritis (RA) and spondyloarthritides (SpA) have been associated with both localized bone resorption and/or formation, and generalized osteoporosis. Systemic inflammation may be the major driver for bone loss in arthritis. In RA and peripheral SpA the RANK-RANKL-OPG network is involved in bone resorption, while in axial SpA the Wnt-?-catenin axis and its inhibitors (DKK-1, sclerostin) are the most relevant. Targeted therapies including biologics and small molecule tyrosine kinase inhibitors may interfere with inflammatory bone metabolism. Most of these compounds are able to slow down radiographic progression and osteoporosis in arthritides. In very early cases of non-radiological SpA, there may be a window of opportunity allowing to prevent syndesmophyte formation. The inability of targeted therapies to increase the production of DKK-1 and sclerostin may explain the lack of efficacy of TNF inhibitors to halt syndesmophyte formation in SpA. Further clinical trials are needed to better understand the bone effects of targeted therapies.
EVALuna2:13349

Effects of the IL-23-IL-17 pathway on bone in spondyloarthritis - Gravallese, Ellen M.; Schett, Georg (Nature Reviews Rheumatology, 2018)
Over the past several years, a pathophysiological role for the IL-23-IL-17 pathway in human disease has been defined. A subset of rheumatic diseases, including psoriatic arthritis (PsA) and ankylosing spondylitis (AS), are now acknowledged to be triggered by dysregulated IL-23-IL-17 pathway activation. Genetic evidence links the IL-23-IL-17 pathway to inflammation in these rheumatic diseases, and mechanistic data from mice support a functional role for IL-23-IL-17 pathway activation in the development of enthesitis and in entheseal bone formation. Furthermore, analysis of human tissue samples, as well as data from clinical trials, also supports a role for activation of the IL-23-IL-17 pathway in these diseases. The unique bone phenotype that occurs in PsA and AS is a surprising coexistence of both systemic bone loss and periosteal and entheseal bone formation and is likely to be the result of the actions of IL-23 and/or IL-17 on bone. However, the effects of these cytokines on bone cells are complex, and controversy remains regarding their exact roles in the specific bone microenvironments relevant to PsA and AS.
EVALuna2:34664

Effects of ustekinumab versus tumor necrosis factor inhibition on enthesitis: Results from the enthesial clearance in psoriatic arthritis (ECLIPSA) study - Guilhon de Araujo, Elizabeth; Englbrecht, Matthias; Höpken, Sabrina; Finzel, Stephanie; Kampylafka, Eleni; Kleyer, Arnd; Bayat, Sara; Schoenau, Verena; Hueber, Axel; Rech, Jürgen; Schett, Georg (Seminars in Arthritis and Rheumatism, 2018)
OBJECTIVES: To date, all studies addressing on anti-inflammatory drugs in PsA have been carried out in psoriatic arthritis (PsA) patients with polyarticular disease. Specific studies on enthesitis are missing. IL-23 is considered to play a central role in the development of enthesitis. We therefore speculated that therapeutic inhibition of IL-12/IL-23 is particularly effective in enthesitis-driven PsA patients. METHODS: Enthesial CLearance In PSoriatic Arthritis (ECLIPSA) is a prospective randomized-controlled open-label study. Patients with PsA with active enthesitis were randomized 1:1 to receive either ustekinumab (UST; arm 1) or tumor necrosis factor inhibitors (TNFi; arm 2). Primary endpoint was complete clearance of enthesitis, defined by Spondyloarthritis Research Consortium of Canada (SPARCC) index equal to zero at 24weeks. RESULTS: 51 patients (UST = 25; TNFi = 26) were screened, 47 enrolled (UST = 23; TNFi = 24) and 46 completed the study. Mean ± SD SPARCC index at baseline was 4.8 ± 2.6 in the UST group and 3.5 ± 2.3 in the TNFi group with no significant difference. After 24 weeks, 73.9% of UST patients and 41.7% of TNFi patients reached the primary endpoint (SPARCC = 0) indicating clearance from enthesitis (p = 0.018). UST achieved superior responses as compared to TNFi with respect to enthesitis (p = 0.007) and psoriatic skin disease (p = 0.030) but not for arthritis (p = 0.95). CONCLUSION: These results indicate that p40-IL-12/IL-23 inhibition is superior to TNFi in the clearance of enthesitis. Future stratified therapeutic approaches in PsA patients may therefore consider the presence or absence of enthesitis as a discriminator of response between different cytokine blocking modalities.
EVALuna2:34482

Efficacy and drug persistence of baricitinib monotherapy is similar to combination therapy in patients with active RA: a prospective observational study - Bayat, Sara; Tascilar, Koray; Bohr, Daniela; Krönke, Gerhard; Simon, David; Knitza, Johannes; Schett, Georg; Kleyer, Arnd; Hartmann, Fabian (RMD Open, 2022)
BACKGROUND: Baricitinib (BARI) is approved for the treatment of rheumatoid arthritis (RA) after failure of conventional synthetic and biologic disease modifying anti-rheumatic drugs (cs/bDMARDs) in combination with methotrexate (MTX) or as monotherapy. However, real-world data are scarce regarding efficacy and drug persistence for BARI monotherapy (BARI-mono) versus its combination with MTX (BARI-combo). OBJECTIVE: To evaluate efficacy and drug persistence of BARImono compared with BARI-combo in routine clinical practice METHODS: Patients with RA who were switched to BARI were included in a prospective, monocentric cohort. Demographics, clinical outcomes, adverse events and medication were prospectively recorded every 3 months. Clinical efficacy was measured by DAS-28 ESR while drug persistence was measured as the time on drug. We estimated least-square mean DAS-28 scores over time using linear mixed effects models including time-group interactions. Kaplan-Meier method was used to estimate BARI survival and probability of remission over time. RESULTS: 139 patients (98 women; aged 58.4 (12.8) years; mean disease duration of 9.7 years) were included between 2017 and 2021. 46 patients received BARI-combo, 93 patients received BARI-mono. Mean DAS-28 ESR were not significantly but only numerically different between both groups at baseline and multiple timepoints over follow-up. DAS-28 ESR remission was attained at least once upto 48 weeks in 62% and 51% patients in BARI-combo versus BARI-mono group (log-rank p=0.64). Drug persistence was high (69 vs 67% at 48 weeks and 62% vs 56% at 96 weeks) and similar in BARI-combo-treated and BARI-mono-treated patients. b/ts DMARD naïve patients had lower mean DAS-28 scores over the follow-up and attained DAS-28 ESR remission earlier than patients with inadequate response to b/ts DMARDs (p=0.11). BARI was discontinued in 11/139 patients (7.9%) due to adverse effects. CONCLUSION: In routine practice, BARI is effective as monotherapy in case of MTX intolerance with overall high drug persistence rates. No new safety signals were observed.
CRIS-Team Scopus Importer:2022-12-02
Keywords: Baricitinib; Combination treatment; Drug survival; Remission; Rheumatoid Arthritis

Efficacy and safety of bimekizumab as add-on therapy for rheumatoid arthritis in patients with inadequate response to certolizumab pegol: A proof-of-concept study - Glatt, Sophie; Taylor, Peter C.; McInnes, Iain B.; Schett, Georg; Landewe, Robert L.; Baeten, Dominique; Ionescu, Lucian; Strimenopoulou, Foteini; Watling, Mark I.L.; Shaw, Stevan (Annals of the Rheumatic Diseases, 2019)
Objective: Evaluate the efficacy and safety of dual neutralisation of interleukin (IL)-17A and IL-17F with bimekizumab, a monoclonal IgG1 antibody, in addition to certolizumab pegol (CZP) in patients with rheumatoid arthritis (RA) and inadequate response (IR) to certolizumab pegol. Methods: During this phase 2a, double-blind, proof-of-concept (PoC) study (NCT02430909), patients with moderate-to-severe RA received open-label CZP 400 mg at Weeks 0, 2 and 4, and 200 mg at Week 6. Patients with IR at Week 8 (Disease Activity Score 28-joint count C-reactive protein (DAS28(CRP))>3.2) were randomised 2:1 to CZP (200 mg every 2 weeks (Q2W)) plus bimekizumab (240 mg loading dose then 120 mg Q2W) or CZP plus placebo. The primary efficacy and safety variables were change in DAS28(CRP) between Weeks 8 and 20 and incidence of treatment-emergent adverse events (TEAEs). Results: Of 159 patients enrolled, 79 had IR at Week 8 and were randomised to CZP plus bimekizumab (n=52) or CZP plus placebo (n=27). At Week 20, there was a greater reduction in DAS28(CRP) in the CZP-IR plus bimekizumab group compared with the CZP-IR plus placebo group (99.4% posterior probability). The most frequent TEAEs were infections and infestations (CZP plus bimekizumab, 50.0% (26/52); CZP plus placebo, 22.2% (6/27)). Conclusions: PoC was confirmed based on the rapid decrease in disease activity achieved with 12 weeks of CZP plus bimekizumab. No unexpected or new safety signals were identified when neutralising IL-17A and IL-17F in patients with RA concomitantly treated with CZP, but the rate of TEAEs was higher with dual inhibition.
CRIS-Team Scopus Importer:2019-06-21
Keywords: anti-tnf; DAS28; dmards (biologic); rheumatoid arthritis; treatment

Efficacy and safety of guselkumab in patients with active psoriatic arthritis who are inadequate responders to tumour necrosis factor inhibitors: results through one year of a phase IIIb, randomised, controlled study (COSMOS) - Coates, Laura C.; Gossec, Laure; Theander, Elke; Bergmans, Paul; Neuhold, Marlies; Karyekar, Chetan S.; Shawi, May; Noel, Wim; Schett, Georg; Mcinnes, Iain B. (Annals of the Rheumatic Diseases, 2021)
Objective To evaluate efficacy and safety of guselkumab, an anti-interleukin-23p19-subunit antibody, in patients with psoriatic arthritis (PsA) with prior inadequate response (IR) to tumour necrosis factor inhibitors (TNFi).
CRIS-Team WoS Importer:2021-12-03

EFFICACY AND SAFETY OF GUSELKUMAB IN PATIENTS WITH ACTIVE PSORIATIC ARTHRITIS WHO DEMONSTRATED INADEQUATE RESPONSE TO TUMOR NECROSIS FACTOR INHIBITION: WEEK 24 RESULTS OF A PHASE 3B, RANDOMIZED, CONTROLLED STUDY - Coates, L. C.; Gossec, L.; Theander, E.; Bergmans, P.; Neuhold, M.; Karyekar, C.; Shawi, M.; Noel, W.; Schett, Georg; Mcinnes, I. (ANNALS OF THE RHEUMATIC DISEASES, 2021)
CRIS-Team WoS Importer:2021-10-01

Efficacy and safety of SARS-CoV-2 revaccination in non-responders with immune-mediated inflammatory disease - Simon, David; Tascilar, Koray; Fagni, Filippo; Schmidt, Katja; Krönke, Gerhard; Kleyer, Arnd; Ramming, Andreas; Schönau, Verena; Bohr, Daniela; Knitza, Johannes; Harrer, Thomas; Manger, Karin; et al. (Annals of the Rheumatic Diseases, 2021)
Objectives To test whether patients with immune-mediated inflammatory disease (IMIDs), who did not respond to two doses of the SARS-CoV-2 vaccine, develop protective immunity, if a third vaccine dose is administered. Methods Patients with IMID who failed to seroconvert after two doses of SARS-CoV-2 vaccine were subjected to a third vaccination with either mRNA or vector-based vaccines. Anti-SARS-CoV-2 IgG, neutralising activity and T cell responses were assessed at baseline and 3 weeks after revaccination and also evaluated seprarately in rituximab (RTX) and non-RTX exposed patients. Results 66 non-responders were recruited, 33 treated with RTX, and 33 non-exposed to RTX. Overall, 49.2% patients seroconverted and 50.0% developed neutralising antibody activity. Seroconversion (78.8% vs 18.2%) and neutralising activity (80.0% vs 21.9%) was higher in non-RTX than RTX-treated patients with IMID, respectively. Humoral vaccination responses were not different among patients showing positive (59.3%) or negative (49.7%) T cell responses at baseline. Patients remaining on mRNA-based vaccines showed similar vaccination responses compared with those switching to vector-based vaccines. Conclusions Overall, these data strongly argue in favor of a third vaccination in patients with IMID lacking response to standard vaccination irrespective of their B cell status.
CRIS-Team WoS Importer:2021-12-03

EFFICACY AND SAFETY OF SECUKINUMAB IN PATIENTS WITH ROTATOR CUFF TENDINOPATHY: A 24-WEEK, RANDOMISED, DOUBLE-BLIND, PLACEBO-CONTROLLED, PHASE II PROOF-OF-CONCEPT TRIAL - Millar, N. L.; Mcinnes, I.; Mindeholm, L.; Seroutou, A.; Praestgaard, J.; Schramm, U.; Levitch, R.; Weber, E.; Laurent, D.; Rosen, J.; Schett, Georg; Roubenoff, R.; et al. (ANNALS OF THE RHEUMATIC DISEASES, 2021)
CRIS-Team WoS Importer:2021-10-01

EGFR controls bone development by negatively regulating mTOR-signaling during osteoblast differentiation - Linder, Markus; Hecking, Manfred; Glitzner, Elisabeth; Zwerina, Karin; Holcmann, Martin; Bakiri, Latifa; Ruocco, Maria Grazia; Tuckermann, Jan; Schett, Georg; Wagner, Erwin F.; Sibilia, Maria (Cell Death and Differentiation, 2018)
Mice deficient in epidermal growth factor receptor (Egfr-/- mice) are growth retarded and exhibit severe bone defects that are poorly understood. Here we show that EGFR-deficient mice are osteopenic and display impaired endochondral and intramembranous ossification resulting in irregular mineralization of their bones. This phenotype is recapitulated in mice lacking EGFR exclusively in osteoblasts, but not in mice lacking EGFR in osteoclasts indicating that osteoblasts are responsible for the bone phenotype. Experiments are presented demonstrating that signaling via EGFR stimulates osteoblast proliferation and inhibits their differentiation by suppression of the IGF-1R/mTOR-pathway via ERK1/2-dependent up-regulation of IGFBP-3. Osteoblasts from Egfr-/- mice show increased levels of IGF-1R and hyperactivation of mTOR-pathway proteins, including enhanced phosphorylation of 4E-BP1 and S6. The same changes are also seen in Egfr-/- bones. Importantly, pharmacological inhibition of mTOR with rapamycin decreases osteoblasts differentiation as well as rescues the low bone mass phenotype of Egfr-/- fetuses. Our results demonstrate that suppression of the IGF-1R/mTOR-pathway by EGFR/ERK/IGFBP-3 signaling is necessary for balanced osteoblast maturation providing a mechanism for the skeletal phenotype observed in EGFR-deficient mice.
EVALuna2:34469

Eighty years of rheumatology—Milestones in diagnosis, treatment and research Achtzig Jahre Rheumatologie – Meilensteine in Diagnose, Therapie und Forschung - Burmester, G. R.; Schett, Georg (Zeitschrift für Rheumatologie, 2021)
CRIS-Team Scopus Importer:2021-07-16

ELEVATED MULTI-BIOMARKER DISEASE ACTIVITY (MBDA) PREDICTS RELAPSES IN RA PATIENTS IN SUSTAINED REMISSION TAPERING TUMOUR NECROSIS FACTOR INHIBITOR THERAPY-RESULTS FROM THE RANDOMIZED CONTROLLED RETRO STUDY - Rech, Jürgen; Hagen, M.; Englbrecht, M.; Haschka, J.; Reiser, M.; Kleyer, A.; Hueber, A.; Manger, Bernhard; Figuereido, C.; Cobra, J. Fogagnolo; Tony, H-P.; Finzel, S.; et al. (2017)
EVALuna2:34452

Elevated serum levels of free interleukin-18 in adult-onset Still's disease - Girard, Charlotte; Rech, Juergen; Brown, Michael; Allali, Daniele; Roux-Lombard, Pascale; Spertini, Francois; Schiffrin, Eduardo J.; Schett, Georg; Manger, Bernhard; Bas, Sylvette; Del Val, Greg; Gabay, Cem (Rheumatology, 2016)
IL-18 is a pro-inflammatory cytokine of the IL-1 family that is naturally inhibited by IL-18 binding protein (IL-18BP). High levels of IL-18 have been described in the serum of adult-onset Still's disease (AOSD) patients, but only total IL-18 levels (including inactive IL-18 bound to IL-18BP) have been measured. With a specific immunoassay, we aimed to measure free IL-18 serum levels in AOSD patients and other rheumatic diseases.An ELISA was developed to measure free IL-18. Its sensitivity and specificity were tested by spiking recombinant IL-18 or IL-18BP in serum and PBS supplemented with 5% BSA. The binding affinity of IL-18 to IL-18BP was calculated by titration experiments using the ELISA and by Biacore analysis. Sera of 37 AOSD patients and 138 controls (40 healthy controls, 30 RA, 29 SLE, 21 AS and 18 PsA) were assayed for free IL-18, IL-18BP, total IL-18 and other cytokines. Correlations were performed between free IL-18 and markers of disease activity in AOSD patients.Free IL-18 serum levels were significantly higher in AOSD patients (median 8.89 pg/ml) than in healthy and disease controls (1.37 pg/ml; P < 0.01). Free IL-18 serum levels correlated with AOSD activity. The affinity of IL-18 to IL-18BP was found to be much higher than previously described, with a dissociation constant ranging from 30 to 50 pM.Free IL-18 levels are specifically elevated in AOSD compared with other inflammatory diseases, suggesting that IL-18 represents a potential target for the treatment of AOSD.
EVALuna2:13254

Elevated serum levels of sonic hedgehog are associated with fibrotic and vascular manifestations in systemic sclerosis - Beyer, Christian; Huscher, Doerte; Ramming, Andreas; Bergmann, Christina; Avouac, Jerome; Guiducci, Serena; Meier, Florian; Vettori, Serena; Siegert, Elise; Jaeger, Veronika K.; Maurer, Britta; Riemekasten, Gabriela; et al. (Annals of the Rheumatic Diseases, 2017)
EVALuna2:12881

ENGRAILED 1 COORDINATES CYTOSKELETAL ORGANIZATION TO PROMOTE MYOFIBROBLAST DIFFERENTIATION AND FIBROTIC TISSUE REMODELING - Györfi, Andrea-Hermina; Matei, Alexandru-Emil; Fuchs, Maximilian; Rigau, Aleix; Hong, Xuezhi; Honglin, Z.; Luber, M.; Bergmann, Christina; Dees, Clara; Ludolph, Ingo; Horch, Raymund E.; Distler, O.; et al. (ANNALS OF THE RHEUMATIC DISEASES, 2021)
CRIS-Team WoS Importer:2021-10-01

Engrailed 1 coordinates cytoskeletal reorganization to induce myofibroblast differentiation - Györfi, Andrea-Hermina; Matei, Alexandru-Emil; Fuchs, Maximilian; Liang, Chunguang; Rigau, Aleix; Hong, Xuezhi; Zhu, Honglin; Luber, Markus; Bergmann, Christina; Dees, Clara; Ludolph, Ingo; Horch, Raymund E.; et al. (Journal of Experimental Medicine, 2021)
Transforming growth factor-β (TGFβ) is a key mediator of fibroblast activation in fibrotic diseases, including systemic sclerosis. Here we show that Engrailed 1 (EN1) is reexpressed in multiple fibroblast subpopulations in the skin of SSc patients. We characterize EN1 as a molecular amplifier of TGFβ signaling in myofibroblast differentiation: TGFβ induces EN1 expression in a SMAD3-dependent manner, and in turn, EN1 mediates the profibrotic effects of TGFβ. RNA sequencing demonstrates that EN1 induces a profibrotic gene expression profile functionally related to cytoskeleton organization and ROCK activation. EN1 regulates gene expression by modulating the activity of SP1 and other SP transcription factors, as confirmed by ChIP-seq experiments for EN1 and SP1. Functional experiments confirm the coordinating role of EN1 on ROCK activity and the reorganization of cytoskeleton during myofibroblast differentiation, in both standard fibroblast culture systems and in vitro skin models. Consistently, mice with fibroblast-specific knockout of En1 demonstrate impaired fibroblast-to-myofibroblast transition and are partially protected from experimental skin fibrosis.
CRIS-Team Scopus Importer:2021-07-30

Enhancing student understanding of rheumatic disease pathologies through augmented reality: findings from a multicentre trial. - Pfeil, Alexander; Klemm, Philipp; Hueber, Axel J.; Hoffmann, Tobias; Weise, Tobias; Oelzner, Peter; Knop, Stefan; Müller-Ladner, Ulf; Lange, Uwe; Wolf, Gunter; Schett, Georg; Simon, David; et al. (Rheumatology, 2024)
OBJECTIVE: The possibility of combining real and virtual environments is driving the increased use of augmented reality (AR) in education, including medical training. The aim of this multicentre study was to evaluate the students' perspective on the AR-based Rheumality GO!® app as a new teaching concept, presenting six real anonymized patient cases with rheumatoid arthritis (RA), psoriatic arthritis (PsA) and axial spondyloarthritis (axSpA). METHODS: The study encompassed 347 undergraduate medical students (232 women and 115 men) from four medical universities in Germany (Jena, Bad Nauheim/Gießen, Nuremberg, Erlangen). The course was divided into a theoretical refresher lecture followed by six AR-based cases in each of the three indications presented in the Rheumality GO! app. All participants evaluated the course after completion, assessing the benefit of the app from a student's perspective using a questionnaire with 16 questions covering six subject areas. RESULTS: The use of the AR-based app Rheumality GO! improved the understanding of pathologies in RA, PsA and axSpA for 99% of the participants. For 98% of respondents, the concept of AR with real patient data has made a positive impact on the teaching environment. On the other hand, 82% were in favour of the use of virtual tools (e.g. AR) in addition to this conventional approach. CONCLUSION: The results of our survey showed that from the medical students' perspective, an AR-based concept like the Rheumality GO! app can complement rheumatology teaching in medical school as an effective and attractive tool though not replace bedside teaching.
EVALuna2:540323

Entheseal Biopsy Approach: An Ultrasound-guided Method for Retrieval of Entheseal Tissue from Psoriatic Arthritis Patients - Raimondo, Maria Gabriella; Pachowsky, Milena; Xu, Cong; Rauber, Simon; Tascilar, Koray; Labinsky, Hannah; Vogg, Mario; Saad, Mina saad aziz; Simon, David; Rech, Jürgen; Soare, Alina; Bräuer, Lars; et al. (ARTHRITIS & RHEUMATOLOGY, 2022)
CRIS-Team WoS Importer:2023-01-13

Enthesitis: from pathophysiology to treatment - Schett, Georg; Lories, Rik J.; D'Agostino, Maria-Antonietta; Elewaut, Dirk; Kirkham, Bruce; Soriano, Enrique R.; Mcgonagle, Dennis (Nature Reviews Rheumatology, 2017)
Entheses are the insertion sites of tendons and ligaments to the bone surface and are essential structures for locomotion. Inflammation of the entheses (enthesitis) is a key feature of psoriatic arthritis and spondyloarthritis. To date, our conceptual understanding of enthesitis remains limited. This Review provides an insight into the pathophysiology of enthesitis, addressing the role of biomechanics, prostaglandin E2-mediated vasodilation and the activation of innate immune cells in the initiation phase of enthesitis, as well as the role of entheseal IL-23-responsive cells that augment inflammation by producing pro-inflammatory mediators such as IL-17A, IL-22 and TNF. In addition, the molecular steps that translate inflammation into resident tissue responses, resulting in new bone formation, are discussed. The second part of the article summarizes the clinical features of enthesitis, and the role of clinical and imaging instruments in detecting enthesitis are discussed together with their challenges and limitations. Finally, the Review summarizes the current treatment possibilities for enthesitis based on the aforementioned pathophysiological concepts, focusing on the role of cytokine-blocking agents.
EVALuna2:13515

ENTHESITIS IN PATIENTS WITH PSORIATIC ARTHRITIS TREATED WITH SECUKINUMAB OR ADALIMUMAB: A POST HOC ANALYSIS OF EXCEED - Kaeley, G. S.; Schett, Georg; Conaghan, P. G.; Mcgonagle, D.; Behrens, F.; Goupille, P.; Gaillez, C.; Parikh, B.; Meng, X.; Bakewell, C. (ANNALS OF THE RHEUMATIC DISEASES, 2021)
CRIS-Team WoS Importer:2021-10-01

Enthesitis in patients with psoriatic arthritis treated with secukinumab or adalimumab: a post hoc analysis of the EXCEED study. - Kaeley, Gurjit S.; Schett, Georg; Conaghan, Philip G.; McGonagle, Dennis; Behrens, Frank; Goupille, Philippe; Gaillez, Corine; Parikh, Bhumik; Bakewell, Catherine (Rheumatology, 2024)
OBJECTIVES: To evaluate enthesitis treatment response, including time to resolution and data from multiple enthesitis instruments, in patients with PsA treated with secukinumab or adalimumab for 52 weeks. METHODS: In this post hoc analysis of the EXCEED study, patients receiving secukinumab 300 mg or adalimumab 40 mg per the label were grouped by presence or absence of baseline enthesitis based on the Leeds Enthesitis Index (LEI) and the Spondyloarthritis Research Consortium of Canada Enthesitis Index (SPARCC). Efficacy was assessed according to several enthesitis-related instruments using non-responder imputation for the achievement of enthesitis resolution (LEI/SPARCC = 0), Kaplan-Meier analysis for time to resolution, and as-observed data for other outcomes. RESULTS: Enthesitis was present at baseline in 498 of 851 patients (58.5%) as assessed by LEI and in 632 of 853 patients (74.1%) as assessed by SPARCC. Patients with baseline enthesitis generally presented with greater disease activity. Similar proportions of patients receiving secukinumab or adalimumab achieved resolution of LEI and SPARCC at weeks 24 (secukinumab: LEI/SPARCC, 49.6%/45.8%; adalimumab: LEI/SPARCC, 43.6%/43.5%) and 52 (secukinumab: LEI/SPARCC, 60.7%/53.2%; adalimumab: LEI/SPARCC, 55.3%/51.4%), with comparable mean time to enthesitis resolution. Improvements were similar for both drugs at individual enthesitis sites. Resolution of enthesitis with secukinumab or adalimumab was associated with improvements in quality of life at week 52. CONCLUSION: Secukinumab and adalimumab showed similar efficacy, including time to resolution, with respect to resolution of enthesitis. Inhibition of IL-17 with secukinumab reduced clinical enthesitis similarly to TNF-α inhibition. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02745080.
EVALuna2:540351

Enthesitis in psoriatic arthritis (Part 1): pathophysiology - Araujo, Elizabeth G.; Schett, Georg (Rheumatology, 2020)
Enthesitis is a key manifestation of PsA and current knowledge supports the concept that it may be among the primary events in the development of this disease, as well as other forms of SpA. Patients with PsA seem to have a different threshold to mechanical stress, which may be genetically determined. Hence patients with psoriatic disease respond pathologically with inflammation after being exposed to physiological mechanical stress. Activation of pro-inflammatory mediators such as IL-17 and TNF-α as well as the influx of innate immune cells are key events in the development of enthesitis in PsA. Chronic entheseal inflammation is accompanied by new bone formation, leading to bony spurs in peripheral (entheseophytes) and axial (syndesmophytes) structures. This article reviews the current knowledge on the mechanisms involved in the development of enthesitis in patients with PsA.
CRIS-Team Scopus Importer:2020-03-27
Keywords: entheseophyte; enthesitis; interleukin 17; interleukin 23; psoriatic arthritis

Enzymatic lipid oxidation by eosinophils propagates coagulation, hemostasis, and thrombotic disease. - Uderhardt, Stefan; Ackermann, Jochen A.; Fillep, Tobias; Hammond, Victoria J.; Willeit, Johann; Santer, Peter; Mayr, Manuel; Biburger, Markus; Miller, Meike; Zellner, Katie R.; Stark, Konstantin; Zarbock, Alexander; et al. (Journal of Experimental Medicine, 2017)
Blood coagulation is essential for physiological hemostasis but simultaneously contributes to thrombotic disease. However, molecular and cellular events controlling initiation and propagation of coagulation are still incompletely understood. In this study, we demonstrate an unexpected role of eosinophils during plasmatic coagulation, hemostasis, and thrombosis. Using a large-scale epidemiological approach, we identified eosinophil cationic protein as an independent and predictive risk factor for thrombotic events in humans. Concurrent experiments showed that eosinophils contributed to intravascular thrombosis by exhibiting a strong endogenous thrombin-generation capacity that relied on the enzymatic generation and active provision of a procoagulant phospholipid surface enriched in 12/15-lipoxygenase-derived hydroxyeicosatetraenoic acid-phosphatidylethanolamines. Our findings reveal a previously unrecognized role of eosinophils and enzymatic lipid oxidation as regulatory elements that facilitate both hemostasis and thrombosis in response to vascular injury, thus identifying promising new targets for the treatment of thrombotic disease.

Eosinophils are not essential for maintenance of murine plasma cells in the bone marrow - Haberland, Konrad; Ackermann, Jochen A.; Ipseiz, Natacha; Culemann, Stephan; Pracht, Katharina; Englbrecht, Matthias; Jäck, Hans-Martin; Schett, Georg; Schuh, Wolfgang; Krönke, Gerhard (European Journal of Immunology, 2018)
Eosinophils were reported to serve as an essential component of the plasma cell niche within the bone marrow. As the potential contribution of eosinophils to humoral immunity has remained incompletely understood, we aimed to further characterize their role during antibody responses and to additionally investigate their role in autoimmune disease. Contrary to our expectations and the currently prevailing paradigm, we found that eosinophils are fully dispensable for the survival of murine bone marrow plasma cells and accordingly do not contribute to antibody production and autoantibody-mediated disease. Littermate wild type and eosinophil-deficient ΔdblGATA-1 animals showed similar numbers and frequencies of plasma cells and did not differ in steady state levels of immunoglobulins or their ability to raise antigen-specific antibody responses. Eosinophils were likewise dispensable for autoantibody production or autoantibody-induced disease in a mouse model of systemic lupus erythematosus. Our findings thus argue against a role of eosinophils during the maintenance of the plasma cell pool and challenge the hitherto postulated concept of an eosinophil-sustained bone marrow niche.
EVALuna2:34472

EPIGENETIC DEREGULATION OF AUTOPHAGY PROMOTES FIBROSIS IN SYSTEMIC SCLEROSIS - Zehender, A.; Lin, N. Y.; Li, Y. N.; Gyorfi, A. H.; Bergmann, C.; Ramming, Andreas; Schett, Georg; Distler, Jörg (ANNALS OF THE RHEUMATIC DISEASES, 2020)
CRIS-Team WoS Importer:2020-08-21

Epigenetic modifications in autoimmune diseases - Ramming, A.; Distler, Jörg; Schett, Georg; Gay, S.; Jüngel, A. (Zeitschrift für Rheumatologie, 2014)
EVALuna2:12993

EPIGENETIC REGULATION OF FRA2 BY JMJD3 REGULATES FIBROBLAST ACTIVATION IN SYSTEMIC SCLEROSIS - Bergmann, C.; Brandt, Adrian; Dees, Clara; Wohlfahrt, T.; Zhang, Y.; Chen, Chih-Wei; Mallano, T.; Liang, Ruifang; Kagwiria, R.; Kam, P. -S.; Bozec, Aline; Abraham, D.; et al. (2017)
EVALuna2:35037

Epithelial HIF2 alpha expression induces intestinal barrier dysfunction and exacerbation of arthritis - Wen, Jinming; Lyu, Pang; Stolzer, Iris; Xu, Jin; Gießl, Andreas; Lin, Zhen; Andreev, Darja; Kachler, Katerina; Song, Rui; Meng, Xianyi; Cao, Shan; Guggino, Giuliana; et al. (Annals of the Rheumatic Diseases, 2022)
To investigate how the mucosal barrier in the intestine influences the development of arthritis, considering that metabolic changes in the intestinal epithelium influence its barrier function. Intestinal HIF2α expression peaked at onset of experimental arthritis and RA. Conditionally, deletion of HIF2α in gut epithelial cells inhibited arthritis and was associated with improved intestinal barrier function and less intestinal and lymphatic Th1 and Th17 activation. Mechanistically, HIF2α induced the transcription of the pore-forming claudin (CLDN)-15, which inhibits intestinal barrier integrity. Furthermore, treatment with HIF2α inhibitor decreased claudin-15 expression in epithelial cells and inhibited arthritis and littermate control mice. The gut intestinal HIF2α target genes were delineated by chromatin immunoprecipitation and luciferase experiments. Furthermore, pharmacological HIF2α inhibitor PT2977 was used for inhibition of arthritis. These findings show that the HIF2α-CLDN15 axis is critical for the breakdown of intestinal barrier function at onset of arthritis, highlighting the functional link between intestinal homeostasis and arthritis.
CRIS-Team WoS Importer:2022-07-01
Keywords: Arthritis; Arthritis; Experimental; Inflammation.

Erdheim-Chester disease. An important differential diagnosis and its main symptoms - Knitza, Johannes; Kampylafka, E.; Wacker, J.; Schett, Georg; Manger, Bernhard (Zeitschrift für Rheumatologie, 2019)
BackgroundDuring the last 3 years 4 patients were admitted to this hospital with a wide variety of different symptoms, in whom Erdheim-Chester disease (ECD) was diagnosed via different diagnostic pathways.ObjectiveBased on four clinical cases of ECD and using additional information from the literature, this article presents the symptoms of ECD. Furthermore, similarities and differences in comparison to important rheumatological differential diagnoses are presented.ResultsThe ECD is amulti-organ orphan disease. Typical for the disease are long bone involvement, periarterial inflammation especially of the aorta, retroperitoneal and perirenal fibrosis with so-called hairy kidneys in abdominal computed tomography (CT) scans. Treatment is increasingly directed towards the presence of a BRAF mutation, which enables targeted and effective treatment with BRAF inhibitors.ConclusionThe ECD is arare differential diagnosis to rheumatic diseases that causes various and often nonspecific symptoms. Due to modern diagnostic methods with imaging procedures and biopsies it is possible to establish aprecise diagnosis and provide a targeted and effective treatment.
CRIS-Team WoS Importer:2019-02-21

Establishment and evaluation of a sensor-based method to assess hand function in patients with rheumatoid arthritis - Coppers, Birte; Phutane, Uday; Berisha, Dardan; Tascilar, Koray; Kleyer, Arnd; Simon, David; Bräunig, Johanna; Penner, Johann; Vossiek, Martin; Schönau, Verena; Heinrich, Simon; Bayat, Sara; et al. (conference, World Biomechanics Congress 2022, 2022)

Estrogen induces St6gal1 expression and increases IgG sialylation in mice and patients with rheumatoid arthritis: a potential explanation for the increased risk of rheumatoid arthritis in postmenopausal women - Engdahl, Cecilia; Bondt, Albert; Harre, Ulrike; Raufer, Jasmin; Pfeifle, Rene; Camponeschi, Alessandro; Wuhrer, Manfred; Seeling, Michaela; Martensson, Inga-Lill; Nimmerjahn, Falk; Krönke, Gerhard; Scherer, Hans U.; et al. (Arthritis Research & Therapy, 2018)
BACKGROUND: Rheumatoid arthritis (RA) preferentially affects women, with the peak incidence coinciding with estrogen decrease in menopause. Estrogen (E2) may therefore have intrinsic immune-regulatory properties that vanish with menopause. Fc sialylation is a crucial factor determining the inflammatory effector function of antibodies. We therefore analyzed whether E2 affects immunoglobulin G (IgG) sialylation. METHODS: Postmenopausal (ovariectomized) mice were immunized with ovalbumin and treated with E2 or vehicle. Total and ovalbumin-specific IgG concentrations, sialylation, and Fcγ receptor expression were analyzed. Postmenopausal women with RA receiving hormone replacement therapy, including E2, or no treatment were analyzed for IgG sialylation. Furthermore, effects of E2 on the expression of the sialylation enzyme β-galactoside α2,6-sialyltransferase 1 (St6Gal1) were studied in mouse and human antibody-producing cells. RESULTS: E2 treatment significantly increased Fc sialylation of total and ovalbumin-specific IgG in postmenopausal mice. Furthermore, E2 led to increased expression of inhibitory Fcγ receptor IIb on bone marrow leukocytes. Treatment with E2 also increased St6Gal1 expression in mouse and human antibody-producing cells, providing a mechanistic explanation for the increase in IgG-Fc sialylation. In postmenopausal women with RA, treatment with E2 significantly increased the Fc sialylation of IgG. CONCLUSIONS: E2 induces anti-inflammatory effector functions in IgG by inducing St6Gal1 expression in antibody-producing cells and by increasing Fc sialylation. These observations provide a mechanistic explanation for the increased risk of RA in conditions with low estrogen levels such as menopause.
EVALuna2:34145

ESTROGEN INFLUENCES THE SIALYLATION PROFILE AND INFLAMMATORY PROPERTIES OF ANTIBODIES - A POTENTIAL EXPLANATION FOR THE SEX DIFFERENCES AND INCREASED RISK FOR RA IN POSTMENOPAUSAL WOMEN - Engdahl, C.; Raufer, Jasmin; Harre, Ulrike; Bondt, A.; Pfeifle, René; Krönke, Gerhard; Scherer, H. U.; Forsblad, H.; Schett, Georg (2017)
EVALuna2:35033

Estrogen-mediated downregulation of HIF-1 alpha signaling in B lymphocytes influences postmenopausal bone loss - Meng, Xianyi; Lin, Zhen; Cao, Shan; Janowska, Iga; Sonomoto, Koshiro; Andreev, Darja; Knab, Katharina; Wen, Jinming; Knaup, Karl; Krönke, Gerhard; Rizzi, Marta; Schett, Georg; et al. (Bone Research, 2022)
In the bone marrow, B cells and bone-resorbing osteoclasts colocalize and form a specific microenvironment. How B cells functionally influence osteoclasts and bone architecture is poorly understood. Using genetically modified mice and high-throughput analyses, we demonstrate that prolonged HIF-1 alpha signaling in B cells leads to enhanced RANKL production and osteoclast formation. In addition, deletion of HIF-1 alpha in B cells prevents estrogen deficiency-induced bone loss in mice. Mechanistically, estrogen controls HIF-1 alpha protein stabilization through HSP70-mediated degradation in bone marrow B cells. The stabilization of HIF-1 alpha protein in HSP70-deficient bone marrow B cells promotes RANKL production and osteoclastogenesis. Induction of HSP70 expression by geranylgeranylacetone (GGA) administration alleviates ovariectomy-induced osteoporosis. Moreover, RANKL gene expression has a positive correlation with HIF1A expression in human B cells. In conclusion, HIF-1 alpha signaling in B cells is crucial for the control of osteoclastogenesis, and the HSP70/HIF-1 alpha axis may serve as a new therapeutic target for osteoporosis.
CRIS-Team WoS Importer:2022-03-04

Ethanol consumption decreases autoantibody titers by blocking IL-21 secretion of Tfh cells during the development of arthritis - Azizov, Vugar; Dietel, K.; Kolenbrander, A.; Seubert, S.; Steffen, F.; Meidenbauer, J.; Steffen, Ulrike; Hofmann, Jörg; Nimmerjahn, Falk; Linker, R.; Wirtz, Stefan; Sarter-Zaiss, Kerstin; et al. (EUROPEAN JOURNAL OF IMMUNOLOGY, 2019)
CRIS-Team WoS Importer:2019-10-08

Ethanol consumption inhibits TFH cell responses and the development of autoimmune arthritis - Azizov, Vugar; Dietel, Katharina; Steffen, Franziska; Dürholz, Kerstin; Meidenbauer, Julia; Lucas, Sébastien; Frech, Michael; Omata, Yasunori; Tajik, Narges; Knipfer, Lisa; Kolenbrander, Anne; Seubert, Silvia; et al. (Nature Communications, 2020)
Alcohol consumption is a consistent protective factor for the development of autoimmune diseases such as rheumatoid arthritis (RA). The underlying mechanism for this tolerance-inducing effect of alcohol, however, is unknown. Here we show that alcohol and its metabolite acetate alter the functional state of T follicular helper (TFH) cells in vitro and in vivo, thereby exerting immune regulatory and tolerance-inducing properties. Alcohol-exposed mice have reduced Bcl6 and PD-1 expression as well as IL-21 production by TFH cells, preventing proper spatial organization of TFH cells to form TFH:B cell conjugates in germinal centers. This effect is associated with impaired autoantibody formation, and mitigates experimental autoimmune arthritis. By contrast, T cell independent immune responses and passive models of arthritis are not affected by alcohol exposure. These data clarify the immune regulatory and tolerance-inducing effect of alcohol consumption.
CRIS-Team Scopus Importer:2020-05-05

Ethanol consumption inhibits the development of autoimmunity by blocking IL-21 secretion in T-FH cells - Azizov, Vugar; Dietel, K.; Kolenbrander, A.; Seubert, S.; Steffen, F.; Meidenbauer, J.; Steffen, Ulrike; Hofmann, J.; Nimmerjahn, Falk; Linker, R.; Wirtz, Stefan; Herrmann, Martin; et al. (EUROPEAN JOURNAL OF IMMUNOLOGY, 2019)
CRIS-Team WoS Importer:2019-11-05

EULAR definition of arthralgia suspicious for progression to rheumatoid arthritis - Van Steenbergen, Hanna W.; Aletaha, Daniel; Beaart-Van De Voorde, Liesbeth J. J.; Brouwer, Elisabeth; Codreanu, Catalin; Combe, Bernard; Fonseca, Joao E.; Hetland, Merete L.; Humby, Frances; Kvien, Tore K.; Niedermann, Karin; Nuno, Laura; et al. (Annals of the Rheumatic Diseases, 2016)
During the transition to rheumatoid arthritis (RA) many patients pass through a phase characterised by the presence of symptoms without clinically apparent synovitis. These symptoms are not well-characterised. This taskforce aimed to define the clinical characteristics of patients with arthralgia who are considered at risk for RA by experts based on their clinical experience.The taskforce consisted of 18 rheumatologists, 1 methodologist, 2 patients, 3 health professionals and 1 research fellow. The process had three phases. In phase I, a list of parameters considered characteristic for clinically suspect arthralgia (CSA) was derived; the most important parameters were selected by a three-phased Delphi approach. In phase II, the experts evaluated 50 existing patients on paper, classified them as CSA/no-CSA and indicated their level of confidence. A provisional set of parameters was derived. This was studied for validation in phase III, where all rheumatologists collected patients with and without CSA from their outpatient clinics.The comprehensive list consisted of 55 parameters, of which 16 were considered most important. A multivariable model based on the data from phase II identified seven relevant parameters: symptom duration <1 year, symptoms of metacarpophalangeal (MCP) joints, morning stiffness duration >=60 min, most severe symptoms in early morning, first-degree relative with RA, difficulty with making a fist and positive squeeze test of MCP joints. In phase III, the combination of these parameters was accurate in identifying patients with arthralgia who were considered at risk of developing RA (area under the receiver operating characteristic curve 0.92, 95% CI 0.87 to 0.96). Test characteristics for different cut-off points were determined.A set of clinical characteristics for patients with arthralgia who are at risk of progression to RA was established.
EVALuna2:13385

EULAR definition of difficult-To-Treat rheumatoid arthritis - Nagy, György; Roodenrijs, Nadia M.T.; Welsing, Paco M.J.; Kedves, Melinda; Hamar, Attila; Van Der Goes, Marlies C.; Kent, Alison; Bakkers, Margot; Blaas, Etienne; Senolt, Ladislav; Szekanecz, Zoltan; Choy, Ernest; et al. (Annals of the Rheumatic Diseases, 2021)
Background Despite treatment according to the current management recommendations, a significant proportion of patients with rheumatoid arthritis (RA) remain symptomatic. These patients can be considered to have difficult-To-Treat RA'. However, uniform terminology and an appropriate definition are lacking. Objective The Task Force in charge of the "Development of EULAR recommendations for the comprehensive management of difficult-To-Treat rheumatoid arthritis"aims to create recommendations for this underserved patient group. Herein, we present the definition of difficult-To-Treat RA, as the first step. Methods The Steering Committee drafted a definition with suggested terminology based on an international survey among rheumatologists. This was discussed and amended by the Task Force, including rheumatologists, nurses, health professionals and patients, at a face-To-face meeting until sufficient agreement was reached (assessed through voting). Results The following three criteria were agreed by all Task Force members as mandatory elements of the definition of difficult-To-Treat RA: (1) Treatment according to European League Against Rheumatism (EULAR) recommendation and failure of ≥2 biological disease-modifying antirheumatic drugs (DMARDs)/targeted synthetic DMARDs (with different mechanisms of action) after failing conventional synthetic DMARD therapy (unless contraindicated); (2) presence of at least one of the following: At least moderate disease activity; signs and/or symptoms suggestive of active disease; inability to taper glucocorticoid treatment; rapid radiographic progression; RA symptoms that are causing a reduction in quality of life; and (3) the management of signs and/or symptoms is perceived as problematic by the rheumatologist and/or the patient. Conclusions The proposed EULAR definition for difficult-To-Treat RA can be used in clinical practice, clinical trials and can form a basis for future research.
CRIS-Team Scopus Importer:2021-01-08
Keywords: arthritis; immune system diseases; rheumatoid; synovitis

EULAR points to consider for the definition of clinical and imaging features suspicious for progression from psoriasis to psoriatic arthritis - Zabotti, Alen; De Marco, Gabriele; Gossec, Laure; Baraliakos, Xenofon; Aletaha, Daniel; Iagnocco, Annamaria; Gisondi, Paolo; Balint, Peter V.; Bertheussen, Heidi; Boehncke, Wolf Henning; Damjanov, Nemanja S.; De Wit, Maarten; et al. (Annals of the Rheumatic Diseases, 2023)
Background: The transition from psoriasis (PsO) to psoriatic arthritis (PsA) and the early diagnosis of PsA is of considerable scientific and clinical interest for the prevention and interception of PsA. Objective: To formulate EULAR points to consider (PtC) for the development of data-driven guidance and consensus for clinical trials and clinical practice in the field of prevention or interception of PsA and for clinical management of people with PsO at risk for PsA development. Methods: A multidisciplinary EULAR task force of 30 members from 13 European countries was established, and the EULAR standardised operating procedures for development for PtC were followed. Two systematic literature reviews were conducted to support the task force in formulating the PtC. Furthermore, the task force proposed nomenclature for the stages before PsA, through a nominal group process to be used in clinical trials. Results: Nomenclature for the stages preceding PsA onset, 5 overarching principles and 10 PtC were formulated. Nomenclature was proposed for three stages towards PsA development, namely people with PsO at higher risk of PsA, subclinical PsA and clinical PsA. The latter stage was defined as PsO and associated synovitis and it could be used as an outcome measure for clinical trials evaluating the transition from PsO to PsA. The overarching principles address the nature of PsA at its onset and underline the importance of collaboration of rheumatologists and dermatologists for strategies for prevention/interception of PsA. The 10 PtC highlight arthralgia and imaging abnormalities as key elements of subclinical PsA that can be used as potential short-term predictors of PsA development and useful items to design clinical trials for PsA interception. Traditional risk factors for PsA development (ie, PsO severity, obesity and nail involvement) may represent more long-term disease predictors and be less robust for short-term trials concerning the transition from PsO to PsA. Conclusion: These PtC are helpful to define the clinical and imaging features of people with PsO suspicious to progress to PsA. This information will be helpful for identification of those who could benefit from a therapeutic intervention to attenuate, delay or prevent PsA development.
CRIS-Team Scopus Importer:2023-07-21
Keywords: inflammation; psoriatic arthritis; synovitis

EULAR points to consider for the management of difficult-to-treat rheumatoid arthritis - Nagy, Gyorgy; Roodenrijs, Nadia M. T.; Welsing, Paco M. J.; Kedves, Melinda; Hamar, Attila; Van Der Goes, Marlies C.; Kent, Alison; Bakkers, Margot; Pchelnikova, Polina; Blaas, Etienne; Senolt, Ladislav; Szekanecz, Zoltan; et al. (Annals of the Rheumatic Diseases, 2021)
Objective To develop evidence-based European Alliance of Associations for Rheumatology (EULAR) points to consider (PtCs) for the management of difficult-to-treat rheumatoid arthritis (D2T RA). Methods An EULAR Task Force was established comprising 34 individuals: 26 rheumatologists, patient partners and rheumatology experienced health professionals. Two systematic literature reviews addressed clinical questions around diagnostic challenges, and pharmacological and non-pharmacological therapeutic strategies in D2T RA. PtCs were formulated based on the identified evidence and expert opinion. Strength of recommendations (SoR, scale A-D: A typically consistent level 1 studies and D level 5 evidence or inconsistent studies) and level of agreement (LoA, scale 0-10: 0 completely disagree and 10 completely agree) of the PtCs were determined by the Task Force members. Results Two overarching principles and 11 PtCs were defined concerning diagnostic confirmation of RA, evaluation of inflammatory disease activity, pharmacological and non-pharmacological interventions, treatment adherence, functional disability, pain, fatigue, goal setting and self-efficacy and the impact of comorbidities. The SoR varied from level C to level D. The mean LoA with the overarching principles and PtCs was generally high (8.4-9.6). Conclusions These PtCs for D2T RA can serve as a clinical roadmap to support healthcare professionals and patients to deliver holistic management and more personalised pharmacological and non-pharmacological therapeutic strategies. High-quality evidence was scarce. A research agenda was created to guide future research.
CRIS-Team WoS Importer:2021-12-10

EULAR recommendations for the management of psoriatic arthritis with pharmacological therapies: 2019 update - Gossec, Laure; Baraliakos, Xenofon; Kerschbaumer, Andreas; de Wit, Maarten; McInnes, Iain; Dougados, Maxime; Primdahl, Jette; McGonagle, Dennis G.; Aletaha, Daniel; Balanescu, Andra; Balint, Peter V.; Bertheussen, Heidi; et al. (Annals of the Rheumatic Diseases, 2020)
OBJECTIVE: To update the European League Against Rheumatism (EULAR) recommendations for the pharmacological treatment of psoriatic arthritis (PsA). METHODS: According to the EULAR standardised operating procedures, a systematic literature review was followed by a consensus meeting to develop this update involving 28 international taskforce members in May 2019. Levels of evidence and strengths of recommendations were determined. RESULTS: The updated recommendations comprise 6 overarching principles and 12 recommendations. The overarching principles address the nature of PsA and diversity of both musculoskeletal and non-musculoskeletal manifestations; the need for collaborative management and shared decision-making is highlighted. The recommendations provide a treatment strategy for pharmacological therapies. Non-steroidal anti-inflammatory drugs and local glucocorticoid injections are proposed as initial therapy; for patients with arthritis and poor prognostic factors, such as polyarthritis or monoarthritis/oligoarthritis accompanied by factors such as dactylitis or joint damage, rapid initiation of conventional synthetic disease-modifying antirheumatic drugs is recommended. If the treatment target is not achieved with this strategy, a biological disease-modifying antirheumatic drugs (bDMARDs) targeting tumour necrosis factor (TNF), interleukin (IL)-17A or IL-12/23 should be initiated, taking into account skin involvement if relevant. If axial disease predominates, a TNF inhibitor or IL-17A inhibitor should be started as first-line disease-modifying antirheumatic drug. Use of Janus kinase inhibitors is addressed primarily after bDMARD failure. Phosphodiesterase-4 inhibition is proposed for patients in whom these other drugs are inappropriate, generally in the context of mild disease. Drug switches and tapering in sustained remission are addressed. CONCLUSION: These recommendations provide stakeholders with an updated consensus on the pharmacological management of PsA, based on a combination of evidence and expert opinion.
CRIS-Team Scopus Importer:2020-06-02
Keywords: DMARDs (biologic); psoriatic arthritis; treatment

EULAR recommendations for the management of psoriatic arthritis with pharmacological therapies: 2023 update - Gossec, Laure; Kerschbaumer, Andreas; Ferreira, Ricardo J.O.; Aletaha, Daniel; Baraliakos, Xenofon; Bertheussen, Heidi; Boehncke, Wolf Henning; Esbensen, Bente Appel; McInnes, Iain B.; McGonagle, Dennis; Winthrop, Kevin L.; Balanescu, Andra; et al. (Annals of the Rheumatic Diseases, 2024)
Objective: New modes of action and more data on the efficacy and safety of existing drugs in psoriatic arthritis (PsA) required an update of the EULAR 2019 recommendations for the pharmacological treatment of PsA. Methods: Following EULAR standardised operating procedures, the process included a systematic literature review and a consensus meeting of 36 international experts in April 2023. Levels of evidence and grades of recommendations were determined. Results: The updated recommendations comprise 7 overarching principles and 11 recommendations, and provide a treatment strategy for pharmacological therapies. Non-steroidal anti-inflammatory drugs should be used in monotherapy only for mild PsA and in the short term; oral glucocorticoids are not recommended. In patients with peripheral arthritis, rapid initiation of conventional synthetic disease-modifying antirheumatic drugs is recommended and methotrexate preferred. If the treatment target is not achieved with this strategy, a biological disease-modifying antirheumatic drug (bDMARD) should be initiated, without preference among modes of action. Relevant skin psoriasis should orient towards bDMARDs targeting interleukin (IL)-23p40, IL-23p19, IL-17A and IL-17A/F inhibitors. In case of predominant axial or entheseal disease, an algorithm is also proposed. Use of Janus kinase inhibitors is proposed primarily after bDMARD failure, taking relevant risk factors into account, or in case bDMARDs are not an appropriate choice. Inflammatory bowel disease and uveitis, if present, should influence drug choices, with monoclonal tumour necrosis factor inhibitors proposed. Drug switches and tapering in sustained remission are also addressed. Conclusion: These updated recommendations integrate all currently available drugs in a practical and progressive approach, which will be helpful in the pharmacological management of PsA.
CRIS-Team Scopus Importer:2024-04-05
Keywords: Biological Therapy; Biosimilar Pharmaceuticals; Psoriatic Arthritis; Treatment

EULAR recommendations for the use of imaging in the diagnosis and management of spondyloarthritis in clinical practice - Mandl, P.; Navarro-Compan, V.; Terslev, L.; Aegerter, P.; Van Der Heijde, D.; D'Agostino, M. A.; Baraliakos, X.; Pedersen, S. J.; Jurik, A. G.; Naredo, E.; Schueller-Weidekamm, C.; Weber, U.; et al. (Annals of the Rheumatic Diseases, 2015)
A taskforce comprised of an expert group of 21 rheumatologists, radiologists and methodologists from 11 countries developed evidence-based recommendations on the use of imaging in the clinical management of both axial and peripheral spondyloarthritis (SpA). Twelve key questions on the role of imaging in SpA were generated using a process of discussion and consensus. Imaging modalities included conventional radiography, ultrasound, magnetic resonance imaging, computed tomography (CT), positron emission tomography, single photon emission CT, dual-emission x-ray absorptiometry and scintigraphy. Experts applied research evidence obtained from systematic literature reviews using MEDLINE and EMBASE to develop a set of 10 recommendations. The strength of recommendations (SOR) was assessed by taskforce members using a visual analogue scale. A total of 7550 references were identified in the search process, from which 158 studies were included in the systematic review. Ten recommendations were produced using research-based evidence and expert opinion encompassing the role of imaging in making a diagnosis of axial SpA or peripheral SpA, monitoring inflammation and damage, predicting outcome, response to treatment, and detecting spinal fractures and osteoporosis. The SOR for each recommendation was generally very high (range 8.9-9.5). These are the first recommendations which encompass the entire spectrum of SpA and evaluate the full role of all commonly used imaging modalities. We aimed to produce recommendations that are practical and valuable in daily practice for rheumatologists, radiologists and general practitioners.
EVALuna2:13132

European League Against Rheumatism (EULAR) recommendations for the management of psoriatic arthritis with pharmacological therapies: 2015 update - Gossec, Laure; Smolen, J. S.; Ramiro, S.; De Wit, M.; Cutolo, M.; Dougados, Maxime; Emery, P.; Landewe, R.; Oliver, S.; Aletaha, D.; Betteridge, N.; Braun, J.; et al. (Annals of the Rheumatic Diseases, 2016)
Since the publication of the European League Against Rheumatism recommendations for the pharmacological treatment of psoriatic arthritis (PsA) in 2012, new evidence and new therapeutic agents have emerged. The objective was to update these recommendations.A systematic literature review was performed regarding pharmacological treatment in PsA. Subsequently, recommendations were formulated based on the evidence and the expert opinion of the 34 Task Force members. Levels of evidence and strengths of recommendations were allocated.The updated recommendations comprise 5 overarching principles and 10 recommendations, covering pharmacological therapies for PsA from non-steroidal anti-inflammatory drugs (NSAIDs), to conventional synthetic (csDMARD) and biological (bDMARD) disease-modifying antirheumatic drugs, whatever their mode of action, taking articular and extra-articular manifestations of PsA into account, but focusing on musculoskeletal involvement. The overarching principles address the need for shared decision-making and treatment objectives. The recommendations address csDMARDs as an initial therapy after failure of NSAIDs and local therapy for active disease, followed, if necessary, by a bDMARD or a targeted synthetic DMARD (tsDMARD). The first bDMARD would usually be a tumour necrosis factor (TNF) inhibitor. bDMARDs targeting interleukin (IL)12/23 (ustekinumab) or IL-17 pathways (secukinumab) may be used in patients for whom TNF inhibitors are inappropriate and a tsDMARD such as a phosphodiesterase 4-inhibitor (apremilast) if bDMARDs are inappropriate. If the first bDMARD strategy fails, any other bDMARD or tsDMARD may be used.These recommendations provide stakeholders with an updated consensus on the pharmacological treatment of PsA and strategies to reach optimal outcomes in PsA, based on a combination of evidence and expert opinion.
EVALuna2:13226

Evaluation of a hybrid telehealth care pathway for patients with axial spondyloarthritis including self-sampling at home: results of a longitudinal proof-of-concept mixed-methods study (TeleSpactive) - Labinsky, Hannah; May, Susann; Boy, Katharina; von Rohr, Sophie; Grahammer, Manuel; Kuhn, Sebastian; Rojas-Restrepo, Jessica; Vogt, Ekaterina; Heinze, Martin; Schett, Georg; Muehlensiepen, Felix; Knitza, Johannes (Rheumatology International, 2024)
Patients with axial spondyloarthritis (axSpA) require close monitoring to achieve the goal of sustained disease remission. Telehealth can facilitate continuous care while relieving scarce healthcare resources. In a mixed-methods proof-of-concept study, we investigated a hybrid telehealth care axSpA pathway in patients with stable disease over 6 months. Patients used a medical app to document disease activity (BASDAI and PtGA bi-weekly, flare questionnaire weekly). To enable a remote ASDAS-CRP (TELE-ASDAS-CRP), patients used a capillary self-sampling device at home. Monitoring results were discussed and a decision was reached via shared decision-making whether a pre-planned 3-month on-site appointment (T3) was necessary. Ten patients completed the study, and eight patients also completed additional telephone interviews. Questionnaire adherence was high; BASDAI (82.3%), flares (74.8%) and all patients successfully completed the TELE-ASDAS-CRP for the T3 evaluation. At T3, 9/10 patients were in remission or low disease activity and all patients declined the offer of an optional T3 on-site appointment. Patient acceptance of all study components was high with a net promoter score (NPS) of +50% (mean NPS 8.8 ± 1.5) for self-sampling, +70% (mean NPS 9.0 ± 1.6) for the electronic questionnaires and +90% for the T3 teleconsultation (mean NPS 9.7 ± 0.6). In interviews, patients reported benefits such as a better overview of their condition, ease of use of telehealth tools, greater autonomy, and, most importantly, travel time savings. To our knowledge, this is the first study to investigate a hybrid approach to follow-up axSpA patients including self-sampling. The positive results observed in this scalable proof-of-concept study warrant a larger confirmatory study.
CRIS-Team Scopus Importer:2024-04-26
Keywords: Axial spondyloarthritis; axSpA; Electronic patient-reported outcome; ePRO; Shared decision-making; Surveys and questionnaires; Treat-to-target

EVALUATION OF A VIRTUAL REALITY-BASED APPLICATION TO EDUCATE HEALTHCARE PROFESSIONALS AND MEDICAL STUDENTS ABOUT INFLAMMATORY ARTHRITIS - Klemm, Philipp; Kleyer, Arnd; Tascilar, Koray; Schuster, Louis; Meinderink, Timo; Steiger, F.; Lange, Uwe; Müller-Ladner, Ulf; Knitza, Johannes; Sewerin, Philipp; Mucke, Johanna; Pfeil, Alexander; et al. (ANNALS OF THE RHEUMATIC DISEASES, 2021)
CRIS-Team WoS Importer:2021-09-24

EVALUATION OF A VIRTUAL REALITY TEACHING CONCEPT FOR MEDICAL STUDENTS DURING THE SARS-COV-2 PANDEMIC - Pfeil, A.; Marcus, F.; Hoffmann, T.; Klemm, P.; Oelzner, P.; Muller-Ladner, U.; Hueber, A.; Lange, U.; Wolf, G.; Schett, Georg; Simon, David; Kleyer, Arnd (ANNALS OF THE RHEUMATIC DISEASES, 2021)
CRIS-Team WoS Importer:2021-10-01

Evaluation of marker-based motion capturing to charactherize basic hand movements in rheumatic patients - Coppers, Birte; Heinrich, Simon; Phutane, Uday; Berisha, Dardan; Tascilar, Koray; Kleyer, Arnd; Simon, David; Bräunig, Johanna; Penner, Johann; Vossiek, Martin; Schönau, Verena; Bayat, Sara; et al. (27th Congress of the European Society of Biomechanics, 2022)

Evaluation of Optical and Radar Based Motion Capturing Technologies for Characterizing Hand Movement in Rheumatoid Arthritis — A Pilot Study - Phutane, Uday; Liphardt, Anna-Maria; Bräunig, Johanna; Penner, Johann; Klebl, Michael; Vossiek, Martin; Kleyer, Arnd; Schett, Georg; Leyendecker, Sigrid; Tascilar, Koray (Sensors, 2021)
In light of the state-of-the-art treatment options for patients with rheumatoid arthritis (RA), a detailed and early quantification and detection of impaired hand function is desirable to allow personalized treatment regiments and amend currently used subjective patient reported outcome measures. This is the motivation to apply and adapt modern measurement technologies to quantify, assess and analyze human hand movement using a marker-based optoelectronic measurement system (OMS), which has been widely used to measure human motion. We complement these recordings with data from markerless (Doppler radar) sensors and data from both sensor technologies are integrated with clinical outcomes of hand function. The technologies are leveraged to identify hand movement characteristics in RA affected patients in comparison to healthy control subjects, while performing functional tests, such as the Moberg-Picking-Up Test. The results presented discuss the experimental framework and present the limiting factors imposed by the use of marker-based measurements on hand function. The comparison of simple finger motion data, collected by the OMS, to data recorded by a simple continuous wave radar suggests that radar is a promising option for the objective assessment of hand function. Overall, the broad scope of integrating two measurement technologies with traditional clinical tests shows promising potential for developing new pathways in understanding of the role of functional outcomes for the RA pathology.<br

Experimental lupus is aggravated in mouse strains with impaired induction of neutrophil extracellular traps - Kienhofer, Deborah; Hahn, Jonas; Stoof, Julia; Csepregi, Janka Zsofia; Reinwald, Christiane; Urbonaviciute, Vilma; Johnsson, Caroline; Maueröder, Christian; Podolska, Malgorzata; Biermann, Mona; Leppkes, Moritz; Harrer, Thomas; et al. (JCI Insight, 2017)
Many effector mechanisms of neutrophils have been implicated in the pathogenesis of systemic lupus erythematosus (SLE). Neutrophil extracellular traps (NETs) have been assigned a particularly detrimental role. Here we investigated the functional impact of neutrophils and NETs on a mouse model of lupus triggered by intraperitoneal injection of the cell death-inducing alkane pristane. Pristane-induced lupus (PIL) was aggravated in 2 mouse strains with impaired induction of NET formation, i.e., NOX2-deficient (Ncf1-mutated) and peptidyl arginine deiminase 4-deficient (PAD4-deficient) mice, as seen from elevated levels of antinuclear autoantibodies (ANAs) and exacerbated glomerulonephritis. We observed a dramatically reduced ability to form pristane-induced NETs in vivo in both Ncf1-mutated and PAD4-deficient mice, accompanied by higher levels of inflammatory mediators in the peritoneum. Similarly, neutropenic Mcl-1ΔMyelo mice exhibited higher levels of ANAs, which indicates a regulatory function in lupus of NETs and neutrophils. Blood neutrophils from Ncf1-mutated and human individuals with SLE exhibited exuberant spontaneous NET formation. Treatment with specific chemical NOX2 activators induced NET formation and ameliorated PIL. Our findings suggest that aberrant NET is one of the factors promoting experimental lupus-like autoimmunity by uncontrolled release of inflammatory mediators.
EVALuna2:1833

Exploratory Analysis to Identify Factors Associated with Risk of Structural Progression, Defined As Change from Baseline - Van Der Heijde, Desiree; Durez, Patrick; Schett, Georg; Naredo, Esperanza; Ostergaard, Mikkel; Meszaros, Gabriella; Lopez-Romero, Pedro; De Leonardis, Francesco; Fleischmann, Roy (2017)
EVALuna2:33445

Exploring Epipolar Consistency Conditions for Rigid Motion Compensation in In-vivo X-ray Microscopy - Thies, Mareike; Wagner, Fabian; Gu, Mingxuan; Mei, Siyuan; Huang, Yixing; Pechmann, Sabrina; Aust, Oliver; Weidner, Daniela; Neag, Georgiana; Uderhardt, Stefan; Schett, Georg; Christiansen, Silke; et al. (Bildverarbeitung für die Medizin 2024. BVM 2024, 2024)
Intravital X-ray microscopy (XRM) in preclinical mouse models is of vital importance for the identification of microscopic structural pathological changes in the bone which are characteristic of osteoporosis. The complexity of this method stems from the requirement for high-quality 3D reconstructions of the murine bones. However, respiratory motion and muscle relaxation lead to inconsistencies in the projection data which result in artifacts in uncompensated reconstructions. Motion compensation using epipolar consistency conditions (ECC) has previously shown good performance in clinical CT settings. Here, we explore whether such algorithms are suitable for correcting motion-corrupted XRM data. Different rigid motion patterns are simulated and the quality of the motion-compensated reconstructions is assessed. The method is able to restore microscopic features for out-of-plane motion, but artifacts remain for more realistic motion patterns including all six degrees of freedom of rigid motion. Therefore, ECC is valuable for the initial alignment of the projection data followed by further fine-tuning of motion parameters using a reconstruction-based method.
CRIS-Team Scopus Importer:2024-03-29

Exploring IL-17 in spondyloarthritis for development of novel treatments and biomarkers - Groen, Solveig Skovlund; Sinkeviciute, Dovile; Bay-Jensen, Anne Christine; Thudium, Christian S.; Karsdal, Morten A.; Thomsen, Simon Francis; Schett, Georg; Nielsen, Signe Holm (Autoimmunity Reviews, 2021)
Spondyloarthritis (SpA) is an umbrella term describing a family of chronic inflammatory rheumatic diseases. These diseases are characterised by inflammation of the axial skeleton, peripheral joints, and entheseal insertion sites throughout the body which can lead to structural joint damage including formation of axial syndesmophytes and peripheral osteophytes. Genetic evidence, preclinical and clinical studies indicate a clear role of interleukin (IL)- 23 and IL-17 as mediators in SpA pathogenesis. Targeting the IL-23/−17 pathways seems an efficient strategy for treatment of SpA patients, and despite the remaining challenges the pathway holds great promise for further advances and improved therapeutic opportunities. Much research is focusing on serological markers and imaging strategies to correctly diagnose patients in the early stages of SpA. Biomarkers may facilitate personalised medicine tailored to each patient's specific disease to optimise treatment efficacy and to monitor therapeutic response. This narrative review focuses on the IL-17 pathway in SpA-related diseases with emphasis on its role in pathogenesis, current approved IL-17 inhibitors, and the need for biomarkers reflecting core disease pathways for early diagnosis and measurement of disease activity, prognosis, and response to therapy.
CRIS-Team Scopus Importer:2021-03-05
Keywords: Biomarker; IL-17; pathogenesis; Spondyloarthritis; treatment

Exposure-Adjusted Incidence Rate for Adverse Events of Special Interest in Patients with Psoriatic Arthritis Treated with Apremilast - Mease, Philip J.; Gladman, Dafna; Schett, Georg; Paris, Maria; Cheng, Sue; Richter, Sven; Teng, Lichen; Kavanaugh, Arthur (ARTHRITIS & RHEUMATOLOGY, 2022)
CRIS-Team WoS Importer:2023-01-13

Expression of adipokines in osteoarthritis osteophytes and their effect on osteoblasts - Junker, Susann; Frommer, Klaus W.; Krumbholz, Grit; Tsiklauri, Lali; Gerstberger, Rüdiger; Rehart, Stefan; Steinmeyer, Jürgen; Rickert, Markus; Wenisch, Sabine; Schett, Georg; Müller-Ladner, Ulf; Neumann, Elena (Matrix Biology, 2016)
Osteophyte formation in osteoarthritis (OA) is mediated by increased osteoblast activity, which is -in turn- regulated by the Wnt signaling pathway. Obesity is regarded a risk factor in OA, yet little is known about the interaction between adipose tissue-derived factors, the adipokines, and bone formation, although adipokines are associated with the pathogenesis of OA. Therefore, the effect of adipokines on bone and cartilage forming cells and osteophyte development was analyzed.Human OA osteophytes were histologically characterized and adipokine expression was evaluated by immunohistochemistry. Osteoblasts and chondrocytes were isolated from OA tissue and stimulated with adiponectin, resistin, or visfatin. Cytokine and osteoblast/chondrocyte markers were quantified and activation of Wnt and p38 MAPK signaling was analyzed.Adiponectin, resistin, and visfatin were expressed in OA osteophytes by various articular cell types. Stimulation of OA osteoblasts with adiponectin and of OA chondrocytes with visfatin led to an increased release of proinflammatory mediators but not to osteoblast differentiation or activation. Additionally, visfatin increased matrix degrading factors in chondrocytes. Wnt signaling was not altered by adipokines, but adiponectin induced p38 MAPK signaling in osteoblasts.Adipokines are present in OA osteophytes, and adiponectin and visfatin increase the release of proinflammatory mediators by osteoblasts and chondrocytes. The effects of adiponectin were mediated by p38 MAPK but not Wnt signaling in osteoblasts. Therefore, the results support the idea that adipokines do not directly influence osteophyte development but the proinflammatory conditions in OA.
EVALuna2:13376

Expression of HIF1α in intestinal epithelium restricts arthritis inflammation by inhibiting RIPK3-induced cell death machinery - Lyu, Pang; Wen, Jinming; Zhang, Wenshuo; Liu, Ning; Stolzer, Iris; Gießl, Andreas; Jia, Yewei; Mauro, Daniele; Zhang, Fulin; Ciccia, Francesco; Soulat, Didier; Günther, Claudia; et al. (Annals of the Rheumatic Diseases, 2024)
Objectives: To investigate the mechanism by which intestinal epithelial cell (IEC) death induces arthritis. Methods: IEC death was assessed by staining for necroptosis and apoptosis markers and fluorescence in situ hybridisation at different time points during collagen-induced arthritis (CIA). During the development of CIA, messenger RNA (mRNA) sequencing was performed, followed by Gene Ontology enrichment analysis of differentially expressed genes. Mice deficient for hypoxia-inducible factor 1α (Hif1a) in IECs (Hif1aΔIEC) were generated and induced for arthritis. mRNA sequencing, chromatin immunoprecipitated (ChIP) DNA sequencing and ChIP-qualitative PCR were performed on IECs from Hif1aΔIEC mice and littermate controls. Effects of HIF1α stabilisation by inhibition of prolyl hydroxylase domain-containing enzymes and treatment with the inhibitor of receptor-interacting protein kinase-3 (RIPK3) were tested in intestinal organoids and in CIA. Results: IEC underwent apoptotic and necroptotic cell death at the onset of arthritis, leading to impaired gut barrier function. HIF1α was identified as one of the most upregulated genes in IECs during the onset of arthritis. Deletion of Hif1a in IEC enhanced IEC necroptosis, triggered intestinal inflammation and exacerbated arthritis. HIF1α was found to be a key transcriptional repressor for the necroptosis-inducing factor RIPK3. Enhanced RIPK3 expression, indicating necroptosis, was also found in the intestinal epithelium of patients with new-onset rheumatoid arthritis. Therapeutic stabilisation of HIF1α as well as small-molecule-based RIPK3 inhibition rescued intestinal necroptosis in vitro and in vivo and suppressed the development of arthritis. Conclusion: Our results identify IEC necroptosis as a critical link between the gut and the development of arthritis.
CRIS-Team Scopus Importer:2024-04-05
Keywords: Arthritis; Experimental; Arthritis; Rheumatoid; Immune System Diseases; Inflammation

Externalized decondensed neutrophil chromatin occludes pancreatic ducts and drives pancreatitis - Leppkes, Moritz; Maueröder, Christian; Hirth, Sebastian; Nowecki, Stefanie; Günther, Claudia; Billmeier, Ulrike; Paulus, Susanne; Biermann, Mona; Munoz, Luis Enrique; Hoffmann, Markus; Wildner, Dane; Croxford, Andrew L.; et al. (Nature Communications, 2016)
Ductal occlusion has been postulated to precipitate focal pancreatic inflammation, while the nature of the primary occluding agents has remained elusive. Neutrophils make use of histone citrullination by peptidyl arginine deiminase-4 (PADI4) in contact to particulate agents to extrude decondensed chromatin as neutrophil extracellular traps (NETs). In high cellular density, NETs form macroscopically visible aggregates. Here we show that such aggregates form inside pancreatic ducts in humans and mice occluding pancreatic ducts and thereby driving pancreatic inflammation. Experimental models indicate that PADI4 is critical for intraductal aggregate formation and that PADI4-deficiency abrogates disease progression. Mechanistically, we identify the pancreatic juice as a strong instigator of neutrophil chromatin extrusion. Characteristic single components of pancreatic juice, such as bicarbonate ions and calcium carbonate crystals, induce aggregated NET formation. Ductal occlusion by aggregated NETs emerges as a pathomechanism with relevance in a plethora of inflammatory conditions involving secretory ducts.
EVALuna2:2052

Extracellular DNA traps in inflammation, injury and healing - Daniel, Christoph; Leppkes, Moritz; Munoz, Luis Enrique; Muñoz, Luis E.; Schley, Gunnar; Schett, Georg; Herrmann, Martin (Nature Reviews Nephrology, 2019)
Following strong activation signals, several types of immune cells reportedly release chromatin and granular proteins into the extracellular space, forming DNA traps. This process is especially prominent in neutrophils but also occurs in other innate immune cells such as macrophages, eosinophils, basophils and mast cells. Initial reports demonstrated that extracellular traps belong to the bactericidal and anti-fungal armamentarium of leukocytes, but subsequent studies also linked trap formation to a variety of human diseases. These pathological roles of extracellular DNA traps are now the focus of intensive biomedical research. The type of pathology associated with the release of extracellular DNA traps is mainly determined by the site of trap formation and the way in which these traps are further processed. Targeting the formation of aberrant extracellular DNA traps or promoting their efficient clearance are attractive goals for future therapeutic interventions, but the manifold actions of extracellular DNA traps complicate these approaches.
CRIS-Team Scopus Importer:2019-07-09

FACTORS ASSOCIATED WITH PERSISTENT DRUG-FREE REMISSION IN PATIENTS WITH RHEUMATOID ARTHRITIS - Valor, Larissa; Hagen, Melanie; Reiser, Michaela; Kleyer, Arnd; Hartmann, Fabian; Manger, Bernhard; Schett, Georg; Rech, Jürgen; Tascilar, Koray; Haschka, J.; Englbrecht, Matthias; Hueber, Axel; et al. (ANNALS OF THE RHEUMATIC DISEASES, 2019)
CRIS-Team WoS Importer:2019-07-16

FAPI PET Opens a New Window to Understanding Immune-Mediated Inflammatory Diseases - Kuwert, Torsten; Schmidkonz, Christian; Prante, Olaf; Schett, Georg; Ramming, Andreas (Journal of Nuclear Medicine, 2022)
CRIS-Team Scopus Importer:2022-08-19

Fatty Lesions Detected on MRI Scans in Patients with Ankylosing Spondylitis Are Based on the Deposition of Fat in the Vertebral Bone Marrow - Baraliakosi, Xenofon; Boehm, Heinrich; Samir, Ahmed; Schett, Georg; Braun, Juergen; Ramming, Andreas (2018)
EVALuna2:34955

FATTY LESIONS DETECTED ON MRI SCANS IN PATIENTS WITH ANKYLOSING SPONDYLITIS ARE BASED ON THE DEPOSITION OF FAT IN THE VERTEBRAL BONE MARROW - Baraliakos, X.; Boehm, H.; Barakat, A. Samir; Schett, Georg; Braun, J. (2018)
EVALuna2:34979

Fc-gamma receptors are not involved in cartilage damage during experimental osteoarthritis. - Stock, Michael; Distler, A.; Distler, Jörg; Beyer, Christian; Ruiz-Heiland, G.; Ipseiz, N.; Seeling, Michaela; Krönke, Gerhard; Nimmerjahn, Falk; Schett, Georg (Osteoarthritis and Cartilage, 2015)
OBJECTIVE Fc-gamma receptors (FcγRs) have been shown to play a crucial role in cartilage degradation during experimental arthritis. Although most of their effect on cartilage degradation has been attributed to their potential to promote inflammation in the presence of immunoglobulins, activating FcγRs promote cartilage degeneration in antigen-induced arthritis (AIA) independently of the level of inflammation. This prompted us to investigate, whether FcγRs may also play a role in osteoarthritis (OA)-related cartilage degradation. METHODS FcγR expression was measured by RT-PCR and FACS in murine cartilage tissue and chondrocytes. Experimental OA was induced by destabilisation of the medial meniscus (DMM) in WT mice and animals lacking either activating (Fc receptor γ-chain-deficient) or inhibitory (FcγRIIB-deficient) FcγRs. Cartilage damage was investigated histologically 8 weeks post-surgery by assessing proteoglycan loss and structural damage according to OARSI recommendations. Osteophyte size was measured to investigate alterations in bone turnover. RESULTS Expression analyses revealed significant levels for all four types of murine FcγRs in mouse chondrocytes and cartilage tissue from newborn and 8-week-old mice. Surprisingly, yet, ablation of either activating or inhibitory FcγRs did not affect cartilage damage or bone turnover during DMM-induced OA in mice. CONCLUSION While FcγRs appear to have a crucial role in cartilage degradation during inflammatory arthritis our data indicate that FcγRs do not influence cartilage destruction in experimental OA. This indicates that a certain threshold of inflammation is a prerequisite for FcγR-induced cartilage destruction in arthritis.

Feasibility of using optoelectronic measurement of hand movement for characterizing hand function in rheumatoid arthritis - Coppers, Birte; Heinrich, Simon; Phutane, Uday; Berisha, Dardan; Tascilar, Koray; Kleyer, Arnd; Simon, David; Bräunig, Johanna; Penner, Johann; Vossiek, Martin; Schönau, Johanna; Bayat, Sara; et al. (75th EULAR (European Alliance of Associations for Rheumatology), European Congress of Rheumatology 2022, 2022)

FEVER OF UNKNOWN ORIGIN (FUO) AND INFLAMMATION OF UNKNOWN ORIGIN (IUO): IS 18F-FDG-PET/CT A USEFUL FIRST LINE DIAGNOSTIC STRATEGY? - Schoenau, V.; Vogel, Kristin; Engelbrecht, M.; Schmidt, D.; Kuwert, Torsten; Manger, Bernhard; Schett, Georg (2016)
EVALuna2:13472

Fever of unknown origin, giant cell arteritis, and aortic dissection - Hofheinz, K.; Bertz, Simone; Wacker, J.; Schett, Georg; Manger, Bernhard (Zeitschrift für Rheumatologie, 2017)
Giant cell arteritis is one of the most frequent causes of pyrexia of unknown origin after infectious or malignant causes have been ruled out. In this case report we describe a 66-year old female patient, who after five weeks of remitting fever developed a life-threatening, painless severe aortic dissection. The timely use of modern imaging technologies such as magnetic resonance angiography or positron emission computed tomography could in the future be of help to recognize aortic involvement early and to avoid this devastating complication in patients with fever of unknown origin.
EVALuna2:6833

FGFR3/FGF9 Regulates the Activity of Profibrotic Cytokine and Growth Factor Pathways to Drive Fibroblast Activation and Tissue Fibrosis in Systemic Sclerosis - Summa, Lena; Thuong Trinh-Minh,; Chen, Chih-Wei; Soare, Alina; Distler, Oliver; Schett, Georg; Distler, Jörg; Chakraborty, Debomita; Ramming, Andreas (2018)
EVALuna2:34956

Fibroblast Activation in Psoriasis Patients Assessed by Ga-68-FAPI-04 PET-CT Is Associated with Progression to Psoriatic Arthritis - Fagni, Filippo; Simon, David; Kleyer, Arnd; Tascilar, Koray; Taubmann, Jule; Bayat, Sara; Minopoulou, Ioanna; Mutlu, Melek Yalcin; Atzinger, Armin; Kuwert, Torsten; Schett, Georg; Schmidkonz, Christian (ARTHRITIS & RHEUMATOLOGY, 2022)
CRIS-Team WoS Importer:2023-01-13

Fibroblast Activation Protein (FAP)-Mediated Cleavage of Type III Collagen Reveals Serum Biomarker Potential in Non-Small Cell Lung Cancer and Spondyloarthritis - Pedersen, Rasmus S.; Thorlacius-Ussing, Jeppe; Raimondo, Maria Gabriella; Langholm, Lasse L.; Schett, Georg; Ramming, Andreas; Karsdal, Morten; Willumsen, Nicholas (Biomedicines, 2024)
Fibroblast activation protein (FAP) is a known promoter of tumor development and is associated with poor clinical outcome for various cancer types. Being specifically expressed in pathological conditions including multiple types of fibrosis and cancers, FAP is an optimal target for diagnostics and treatment. Treatment strategies utilizing the unique proteolytic activity of FAP are emerging, thus emphasizing the importance of biomarkers to directly assess FAP activity. FAP is a type II transmembrane serine protease that has been shown to cleave collagens and other ECM components. In this study, we developed an ELISA assay (C3F) targeting a circulating type III collagen fragment derived from FAP cleavage to reflect FAP activity. We demonstrated that C3F was specific to the neoepitope of the cleavage site and that the fragment was generated through FAP cleavage of type III collagen. We measured C3F in serum from a cohort of patients with non-small cell lung cancer (NSCLC) (n = 109) matched to healthy subjects (n = 42) and a cohort of patients with spondyloarthritis (SpA) (n = 17) matched to healthy subjects (n = 19). We found that C3F was significantly elevated in patients with NSCLC and in patients with SpA compared to healthy controls (p < 0.0001 and p = 0.0015, respectively). These findings suggest that C3F is a promising non-invasive biomarker reflecting FAP activity, which may aid in understanding tumor heterogeneity and potentially FAP-targeted therapies.
CRIS-Team Scopus Importer:2024-04-05
Keywords: extracellular matrix remodeling; fibroblast activation protein (FAP); non-small cell lung cancer (NSCLC); serum biomarker; spondyloarthritis

Fibroblast Activation Protein (FAP) PET-CT for Depicting Inflammatory Joint Damage in Patients with Psoriatic Arthritis - Rauber, Simon; Mohammadian, Hashem; Schmidkonz, Christian; Atzinger, Armin; Raimondo, Maria Gabriella; Labinsky, Hannah; Treutlein, Christoph; Knitza, Johannes; Maschauer, Simone; Roemer, Frank; Prante, Olaf; Kuwert, Torsten; et al. (ARTHRITIS & RHEUMATOLOGY, 2022)
CRIS-Team WoS Importer:2023-01-13

FIBROBLAST ACTIVATION PROTEIN (FAP) PET-CT IMAGING ALLOWS TO DEPICT INFLAMMATORY JOINT REMODELING IN PATIENTS WITH PSORIATIC ARTHRITIS - Schmidkonz, Christian; Rauber, Simon; Raimondo, Maria Gabriella; Labinsky, Hannah; Atzinger, Armin; Treutlein, Christoph; Knitza, Johannes; Maschauer, Simone; Roemer, Frank; Prante, Olaf; Kuwert, Torsten; Canete, J. D. D.; et al. (ANNALS OF THE RHEUMATIC DISEASES, 2022)
CRIS-Team WoS Importer:2022-11-04

Fibroblast Activation Protein Inhibitor Imaging in Nonmalignant Diseases: A New Perspective for Molecular Imaging - Schmidkonz, Christian; Kuwert, Torsten; Atzinger, Armin; Cordes, Michael; Schett, Georg; Ramming, Andreas; Götz, Theresa (Journal of Nuclear Medicine, 2022)
Fibroblast activation protein-α (FAP-α) is a type II transmembrane glycoprotein that is overexpressed in activated fibroblasts such as those in the stroma of tumors or in the fibrotic processes accompanying various benign diseases. The recent development and clinical implementation of radiolabeled quinolone-based tracers suitable for PET that act as FAP inhibitors (FAPIs) have opened a new perspective in molecular imaging. Although multiple studies have investigated the use of FAPI imaging in cancer, evidence concerning its use in nonmalignant diseases is still scarce. Herein, we provide a comprehensive review of FAPI imaging in nonmalignant diseases to clarify the current and potential role of this class of molecules in nuclear medicine.
CRIS-Team Scopus Importer:2022-12-16
Keywords: fibroblast activation protein; fibrosis; inflammatory diseases; molecular imaging; PET