Response to: 'Idiopathic inflammatory myopathies and antisynthetase syndrome: Contribution of antisynthetase antibodies to improve current classification criteria' by Greco et al - Knitza, Johannes; Cavagna, Lorenzo; Schett, Georg; Distler, Jörg (Annals of the Rheumatic Diseases, 2019)
CRIS-Team Scopus Importer:2019-05-02
Keywords: autoantibodies; dermatomyositis; polymyositis

Response to: 'Is the PET/CT first choice for differential diagnosis of FUO/IUO?' by Armagan et al - Schönau, Verena; Schett, Georg (Annals of the Rheumatic Diseases, 2018)
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Response to Letter to the Editor - Wisser, Josef; Kurmanavicius, Jouzas; Knitza, Johannes (Ultraschall in der Medizin, 2019)
CRIS-Team Scopus Importer:2019-12-17

Response to peripheral immune stimulation within the brain: magnetic resonance imaging perspective of treatment success - Sergeeva, Marina; Rech, Juergen; Schett, Georg; Heß, Andreas (Arthritis Research & Therapy, 2015)
Chronic peripheral inflammation in diseases such as rheumatoid arthritis leads to alterations in central pain processing and consequently to mood disorders resulting from sensitization within the central nervous system and enhanced vulnerability of the medial pain pathway. Proinflammatory cytokines such as tumor necrosis factor (TNF) alpha play an important role herein, and therapies targeting their signaling (i.e., anti-TNF therapies) have been proven to achieve good results. However, the phenomenon of rapid improvement in the patients' subjective feeling after the start of TNF? neutralization remained confusing, because it was observed long before any detectable signs of inflammation decline. Functional magnetic resonance imaging (fMRI), enabling visualization of brain activity upon peripheral immune stimulation with anti-TNF, has helped to clarify this discrepancy. Moreover, fMRI appeared to work as a reliable tool for predicting prospective success of anti-TNF therapy, which is valuable considering the side effects of the drugs and the high therapy costs. This review, which is mainly guided by neuroimaging studies of the brain, summarizes the state-of-the-art knowledge about communication between the immune system and the brain and its impact on subjective well-being, addresses in more detail the outcome of the abovementioned anti-TNF fMRI studies (rapid response to TNF? blockade within the brain pain matrix and differences in brain activation patterns between prospective therapy responders and nonresponders), and discusses possible mechanisms for the latter phenomena and the predictive power of fMRI.
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Response to secukinumab on synovitis using Power Doppler ultrasound in psoriatic arthritis: 12-week results from a phase III study, ULTIMATE - D'Agostino, Maria Antonietta; Schett, Georg; Lopez-Rdz, Alejandra; Senolt, Ladislav; Fazekas, Katalin; Burgos-Vargas, Ruben; Maldonado-Cocco, Jose; Naredo, Esperanza; Carron, Philippe; Duggan, Anne-Marie; Goyanka, Punit; Boers, Maarten; et al. (Rheumatology, 2021)
Objectives. To investigate the dynamics of response of synovitis to IL-17A inhibition with secukinumab in patients with active PsA using Power Doppler ultrasound.
CRIS-Team WoS Importer:2022-05-13

Response to: the value of 18(F)-FDG-PET/CT in identifying the cause of fever of unknown origin (FUO) and inflammation of unknown origin (IUO): data from a prospective study - Schönau, Verena; Schett, Georg (Annals of the Rheumatic Diseases, 2017)
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RESPONSIVENESS OF A COMBINED POWER DOPPLER AND GREYSCALE ULTRASOUND SCORE FOR ASSESSING SYNOVITIS AT JOINT LEVEL IN PSORIATIC ARTHRITIS PATIENTS WITH INADEQUATE RESPONSE TO CSDMARDS: DATA FROM THE ULTIMATE TRIAL - D'Agostino, M. A.; Boers, M.; Gaillez, C.; Gamez, C.; Ventura, L.; Padovano, J. Rosa I.; Mandl, P.; Kleyer, Arnd; Bakewell, C.; Bao, W.; Goyanka, P.; Conaghan, P. G.; et al. (ANNALS OF THE RHEUMATIC DISEASES, 2022)
Background Power Doppler ultrasound (PDUS) is a sensitive non-invasive imaging tool that allows the visualisation of articular and periarticular inflammation in patients with psoriatic arthritis (PsA).1 ULTIMATE (NCT02662985) was the first large randomised clinical trial that showed the responsiveness of the Global OMERACT-EULAR ultrasound synovitis score (GLOESS) in PsA and confirmed the rapid and continued benefits of secukinumab through 52 weeks.2,3 Objectives To report the distribution of ultrasound-detected synovitis at joint level, by degree of severity at baseline and over time, and the contribution of each core component of GLOESS, synovial hypertrophy (SH) by greyscale (GS; B-mode) and power Doppler (PD) signal, to responsiveness.3 Methods This was a 52-week study with a 12-week double-blind, placebo-controlled treatment period followed by a 12-week open-label period and a 6-month open-label extension secukinumab treatment period.3 The number of joints with synovitis measured by GLOESS2 was assessed up to Week 52. The assessments included distribution of synovitis based on composite PDUS score across 24 pairs of joints (with worse score of the pair of the joints used) by grade of severity (0-3) and change from baseline to Week 52 in each core component of GLOESS.3-5 Data are presented as observed. Results A total of 166 patients (mean age, 46.7 years; males, 45.2%) were enrolled, of which 90% (75/83) of secukinumab and 83% (69/83) of placebo-secukinumab participants completed 52 weeks. The mean (SD) number of PDUS detected synovitis at baseline was 9.2 (4.9) and 10.2 (5.2) in the secukinumab and placebo group, respectively. The most frequent locations with synovitis at baseline were: wrist, metatarsophalangeal (MTP), knees and metacarpophalangeal (MCP) joints (Table 1). An early and continued improvement in GLOESS was observed in both secukinumab and placebo-secukinumab groups after switching to active therapy, as previously reported at Week 12 and through Week 52.2,3 Among the two core components of GLOESS, SH was mainly responsible for the change in GLOESS from baseline to Week 52, in contrast with PD signal in this dataset. The distribution of synovitis by grade of severity showed that MTP joints, wrist, knee, MCP1/2 and tibiotalar joints mostly contributed to the composite PDUS at Week 12 (Figure 1). Similar patterns were observed through 52 week
CRIS-Team WoS Importer:2022-11-04

RESPONSIVENESS OF ULTRASOUND SYNOVITIS AND CLINICAL OUTCOMES IN PSORIATIC ARTHRITIS TREATED WITH SECUKINUMAB: DATA FROM THE ULTIMATE TRIAL - Boers, M.; Conaghan, P. G.; Schett, Georg; Mandl, P.; Naredo, E.; Van Den Bosch, F.; Burgos-Vargas, R.; Duggan, A. M.; Goyanka, P.; Gaillez, C.; D'Agostino, M. A. (ANNALS OF THE RHEUMATIC DISEASES, 2021)
CRIS-Team WoS Importer:2021-10-01

RESTING SERUM CARTILAGE OLIGOMERIC MATRIX PROTEIN CONCENTRATION - THE ROLE OF AGE AND ANTERIOR CRUCIATE LIGAMENT INJURY - Herger, S.; Aghlmandi, S.; Liphardt, Anna-Maria; Nueesch, C.; Egloff, C.; Muendermann, A. (OSTEOARTHRITIS AND CARTILAGE, 2022)
CRIS-Team WoS Importer:2022-04-22

Retinal Microcirculation as a Correlate of a Systemic Capillary Impairment After Severe Acute Respiratory Syndrome Coronavirus 2 Infection - Hohberger, Bettina; Ganslmayer, Marion; Lucio, Marianna; Kruse, Friedrich; Hoffmanns, Jakob; Moritz, Michael; Rogge, Lennart; Heltmann, Felix; Szewczykowski, Charlotte; Fürst, Julia; Raftis, Maximilian; Bergua, Antonio; et al. (Frontiers in Medicine, 2021)
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which causes coronavirus disease 2019 (COVID-19), affects the pulmonary systems via angiotensin-converting enzyme-2 (ACE-2) receptor, being an entry to systemic infection. As COVID-19 disease features ACE-2 deficiency, a link to microcirculation is proposed. Optical coherence tomography angiography (OCT-A) enables non-invasive analysis of retinal microvasculature. Thus, an impaired systemic microcirculation might be mapped on retinal capillary system. As recent OCT-A studies, analyzing microcirculation in two subdivided layers, yielded contrary results, an increased subdivision of retinal microvasculature might offer an even more fine analysis. The aim of the study was to investigate retinal microcirculation by OCT-A after COVID-19 infection in three subdivided layers (I). In addition, short-term retinal affections were monitored during COVID-19 disease (II). Considering (I), a prospective study (33 patientspost−COVID and 28 controls) was done. Macula and peripapillary vessel density (VD) were scanned with the Spectralis II. Macula VD was measured in three layers: superficial vascular plexus (SVP), intermediate capillary plexus (ICP), and deep capillary plexus (DCP). Analysis was done by the EA-Tool, including an Anatomical Positioning System and an analysis of peripapillary VD by implementing Bruch's membrane opening (BMO) landmarks. Overall, circular (c1, c2, and c3) and sectorial VD (s1-s12) was analyzed. Considering (II), in a retrospective study, 29 patients with severe complications of COVID-19 infection, hospitalized at the intensive care unit, were monitored for retinal findings at bedside during hospitalization. (I) Overall (p = 0.0133) and circular (c1, p = 0.00257; c2, p = 0.0067; and c3, p = 0.0345). VD of the ICP was significantly reduced between patientspost−COVID and controls, respectively. Overall (p = 0.0179) and circular (c1, p = 0.0189) peripapillary VD was significantly reduced between both groups. Subgroup analysis of hospitalized vs. non-hospitalized patientspost−COVID yielded a significantly reduced VD of adjacent layers (DCP and SVP) with increased severity of COVID-19 disease. Clinical severity parameters showed a negative correlation with VD (ICP) and peripapillary VD. (II) Funduscopy yielded retinal hemorrhages and cotton wool spots in 17% of patients during SARS-CoV-2 infection. As VD of the ICP and peripapillary regions was significantly reduced after COVID-19 disease and showed a link to clinical severity markers, we assume that the severity of capillary impairment after COVID-19 infection is mapped on retinal microcirculation, visualized by non-invasive OCT-A.
CRIS-Team Scopus Importer:2021-08-06
Keywords: COVID-19; macula; microcirculation; OCT-angiography; optic nerve head; retina; SARS-CoV-2

Retraction Note: Combined effect of genetic background and gender in a mouse model of bleomycin-induced skin fibrosis (Arthritis Research & Therapy, (2015), 17, 1, (145), 10.1186/s13075-015-0659-5) - Ruzehaji, Nadira; Avouac, Jerome; Elhai, Muriel; Frechet, Maxime; Frantz, Camelia; Ruiz, Barbara; Distler, Jörg; Allanore, Yannick (Arthritis Research & Therapy, 2023)
The Editors-in-Chief has retracted this article because after the publication of the article concerns were raised about image overlap. Further investigation by the Publisher found the following concerns to be valid. Partial image overlap between Fig. 1A (upper-left panel, NaCl- BALB/c male mouse) and Fig. 2A (upper-left panel, NaCl—BALB/c female mouse) Partial overlap between Fig. 1A (upper-right panel, NaCl- DBA/2 male mouse) and Fig. 2A (upper-right panel, NaCl-DBA/2 female mouse). Partial image overlap between Fig. 2A (upper-right panel, NaCl-DBA/2) with Fig. 6A (left panel, NaCl) Partial image overlap in Fig. 2A (lower-middle panel, Bleomycin- C57BL/6) with Fig. 5A (upper-right panel, NaCl + Control mAb) of [1]. Partial image overlap in Fig. 3D (lower-middle panel, Bleomycin C57BL6/2) with Fig. 6B (lower-right panel, KLH BLM) of [2]. The authors provided the raw data for validation. However, further checks by the Publisher identified some differences between the raw data and the figures, as well as overlap in raw images. The authors were unable to provide ethical approval for experiments involving Balb/c mice strain. The Editors-in-Chief therefore no longer has confidence in the presented data. Nadine Ruzehaji, Muriel Elhai, Jerome Avouac, Camelia Frantz and Yannick Allanore agree to this retraction. Maxime Frechet and Joerg H. Distler have not responded to any correspondence from the editor/publisher about this retraction. The editor was not able to obtain a current email address for Barbara Ruiz.
CRIS-Team Scopus Importer:2023-11-24

RETRO - STUDY OF REDUCTION OF THERAPY IN PATIENTS WITH RHEUMATOID ARTHRITIS IN ONGOING REMISSION - Haschka, J.; Englbrecht, Matthias; Hueber, Axel; Manger, Bernhard; Kleyer, Arnd; Reiser, M.; Finzel, Stephanie; Tony, H. -P.; Kleinert, S.; Feuchtenberger, M.; Fleck, M.; Manger, Karin; et al. (2015)
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Reversing the Inflammatory Process—25 Years of Tumor Necrosis Factor-α Inhibitors - Muth, Katharina N.; Rech, Jürgen; Losch, Florian O.; Hörning, André (Journal of Clinical Medicine, 2023)
Immune-mediated inflammatory diseases, such as rheumatoid arthritis, psoriatic arthritis, peripheral and/or axial spondyloarthritis, Crohn’s disease, and ulcerative colitis, are characterized by molecular and cellular changes in the immune system. Due to the systemic nature of these diseases, organs such as the liver or cardiovascular system are often affected by the inflammatory process. Tumor necrosis factor-α inhibitor therapy reduces the activation of pro-inflammatory signaling cascades, mitigates the chronic inflammatory process by restoring cellular balance, and alleviates clinical consequences, such as pain and tissue damage.
CRIS-Team Scopus Importer:2023-09-01
Keywords: cytokines; immune-mediated inflammatory diseases; inflammation; liver; rheumatoid arthritis; tumor necrosis factor alpha-inhibitors

Review and Analysis of German Mobile Apps for Inflammatory Bowel Disease Management Using the Mobile Application Rating Scale: Systematic Search in App Stores and Content Analysis - Gerner, Maximilian; Vuillerme, Nicolas; Aubourg, Timothée; Messner, Eva Maria; Terhorst, Yannik; Hörmann, Verena; Ganzleben, Ingo; Schenker, Hannah; Schett, Georg; Atreya, Raja; Neurath, Markus; Knitza, Johannes; et al. (JMIR mHealth and uHealth, 2022)
Background: Patients suffering from inflammatory bowel disease (IBD) frequently need long-term medical treatment. Mobile apps promise to complement and improve IBD management, but so far there has been no scientific analysis of their quality. Objective: This study evaluated the quality of German mobile apps targeting IBD patients and physicians treating IBD patients using the Mobile Application Rating Scale (MARS). Methods: The German Apple App Store and Google Play Store were systematically searched to identify German IBD mobile apps for patient and physician use. MARS was used by 6 physicians (3 using Android smartphones and 3 using iPhones) to independently assess app quality. Apps were randomly assigned so that the 4 apps with the most downloads were rated by all raters and the remaining apps were rated by 1 Android and 1 iOS user. Results: In total, we identified 1764 apps in the Apple App Store and Google Play Store. After removing apps that were not related to IBD (n=1386) or not available in German (n=317), 61 apps remained. After removing duplicates (n=3) and apps for congresses (n=7), journals (n=4), and clinical studies (n=6), as well as excluding apps that were available in only 1 of the 2 app stores (n=20) and apps that could only be used with an additional device (n=7), we included a total of 14 apps. The app “CED Dokumentation und Tipps” had the highest overall median MARS score at 4.11/5. On the whole, the median MARS scores of the 14 apps ranged between 2.38/5 and 4.11/5. As there was no significant difference between iPhone and Android raters, we used the Wilcoxon comparison test to calculate P values. Conclusions: The MARS ratings showed that the quality of German IBD apps varied. We also discovered a discrepancy between app store ratings and MARS ratings, highlighting the difficulty of assessing perceived app quality. Despite promising results from international studies, there is little evidence for the clinical benefits of German IBD apps. Clinical studies and patient inclusion in the app development process are needed to effectively implement mobile apps in routine care.
CRIS-Team Scopus Importer:2022-05-20
Keywords: app store; chronic disease; Crohn disease; IBD; IBS; inflammatory bowel disease; mHealth; mobile apps; quality; rating; rating scale; telemedicine; ulcerative colitis; usability

Review - EPIGENETICS, 2018 Inheritable Epigenetic Response towards Foreign DNA Entry by Mammalian Host Cells: A Guardian of Genomic Stability - Dörfler, Walter; Weber, Stefanie; Naumann, Anja (Epigenetics, 2018)
Apart from its well-documented role in long-term promoter silencing, the genome-wide distribution patterns of 28 million methylated or unmethylated CpG dinucleotides, e. g. in the human genome, is in search of genetic functions. We have set out to study changes in the cellular CpG methylation profile upon introducing foreign DNA into mammalian cells. As stress factors served the genomic integration of foreign (viral or bacterial plasmid) DNA, virus infections or the immortalization of cells with Epstein Barr Virus (EBV). In all instances investigated, alterations in cellular CpG methylation and transcription profiles were observed to different degrees. In the case of adenovirus DNA integration in adenovirus type 12 (Ad12)-transformed hamster cells, the extensive changes in cellular CpG methylation persisted even after the complete loss of all transgenomic Ad12 DNA. Hence, stress-induced alterations in CpG methylation can be inherited independent of the continued presence of the transgenome. Upon virus infections, changes in cellular CpG methylation appear early after infection. In EBV immortalized as compared to control cells, CpG hypermethylation in the far-upstream region of the human FMR1 promoter decreased four-fold. We conclude that in the wake of cellular stress due to foreign DNA entry, preexisting CpG methylation patterns were altered, possibly at specific CpG dinucleotides. Frequently, transcription patterns were also affected. As a working concept, we view CpG methylation profiles in mammalian genomes as a guarding sensor for genomic stability under epigenetic control. As a caveat towards manipulations of cells with foreign DNA, such cells can no longer be considered identical to their un-manipulated counterparts.
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Review: Frontiers of Antifibrotic Therapy in Systemic Sclerosis - Distler, Jörg; Feghali-Bostwick, Carol; Soare, Alina; Asano, Yoshihide; Distler, Oliver; Abraham, David J. (Arthritis and Rheumatology, 2017)
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Revised European Scleroderma Trials and Research Group Activity Index is the best predictor of short-term severity accrual - Fasano, Serena; Riccardi, Antonella; Messiniti, Valentina; Caramaschi, Paola; Rosato, Edoardo; Maurer, Britta; Smith, Vanessa; Siegert, Elise; De Langhe, Ellen; Riccieri, Valeria; Airó, Paolo; Mihai, Carina; et al. (Annals of the Rheumatic Diseases, 2019)
Background: The European Scleroderma Trials and Research Group (EUSTAR) recently developed a preliminarily revised activity index (AI) that performed better than the European Scleroderma Study Group Activity Index (EScSG-AI) in systemic sclerosis (SSc). Objective: To assess the predictive value for short-term disease severity accrual of the EUSTAR-AI, as compared with those of the EScSG-AI and of known adverse prognostic factors. Methods: Patients with SSc from the EUSTAR database with a disease duration from the onset of the first non-Raynaud sign/symptom ≤5 years and a baseline visit between 2003 and 2014 were first extracted. To capture the disease activity variations over time, EUSTAR-AI and EScSG-AI adjusted means were calculated. The primary outcome was disease progression defined as a Î "≥1 in the Medsger's severity score and in distinct items at the 2-year follow-up visit. Logistic regression analysis was carried out to identify predictive factors. Results: 549 patients were enrolled. At multivariate analysis, the EUSTAR-AI adjusted mean was the only predictor of any severity accrual and of that of lung and heart, skin and peripheral vascular disease over 2 years. Conclusion: The adjusted mean EUSTAR-AI has the best predictive value for disease progression and development of severe organ involvement over time in SSc.
CRIS-Team Scopus Importer:2019-09-03
Keywords: autoimmune diseases; outcomes research; systemic sclerosis

Revisiting the gut–joint axis: links between gut inflammation and spondyloarthritis - Gracey, Eric; Vereecke, Lars; McGovern, Dermot; Fröhling, Mareike; Schett, Georg; Danese, Silvio; De Vos, Martine; Van den Bosch, Filip; Elewaut, Dirk (Nature Reviews Rheumatology, 2020)
Gut inflammation is strongly associated with spondyloarthritis (SpA), as exemplified by the high prevalence of inflammatory bowel disease (IBD) and the even higher occurrence of subclinical gut inflammation in patients with SpA. The gut–joint axis of inflammation in SpA is further reinforced by similarities in immunopathogenesis at both anatomical sites and by the clinical success of therapies blocking TNF and IL-23 in IBD and in some forms of SpA. Many genetic risk factors are shared between SpA and IBD, and changes in the composition of gut microbiota are seen in both diseases. Current dogma is that inflammation in SpA initiates in the gut and leads to joint inflammation; however, although conceptually attractive, some research does not support this causal relationship. For example, therapies targeting IL-17A are efficacious in the joint but not the gut, and interfering with gut trafficking by targeting molecules such as α4β7 in IBD can lead to onset or flares of SpA. Several important knowledge gaps remain that must be addressed in future studies. Determining the true nature of the gut–joint axis has real-world implications for the treatment of patients with co-incident IBD and SpA and for the repurposing of therapeutics from one disease to the other.
CRIS-Team Scopus Importer:2020-07-24

„Rheuma (be-)greifen“ – ein multimodales Lehrkonzept zur Verbesserung der rheumatologischen Lehre für Studierende der Humanmedizin - Schuster, Louis; Valor-Mendez, Larissa; Wacker, Jochen; Dannhardt-Thiem, V.; Schmidt, A.; Knitza, Johannes; Simon, David; Manger, Bernhard; Schett, Georg; Kleyer, Arnd (Zeitschrift für Rheumatologie, 2023)
Background: The German Society for Rheumatology, through its campaign Rheuma2025, aims to improve student teaching in order to ensure patient care for rheumatological patients in the future. Objective: To assess whether a combination of traditional and innovative educational methods provide both an improvement in the quality of teaching and an increase in the attractiveness of rheumatology as a discipline. Material and methods: Establishment of the teaching concept “Rheuma (be-)greifen” consisting of five modules on patient history taking with acting patients, musculoskeletal ultrasound, arthrocentesis, 3D printing of pathological joints and virtual reality applications based on real patient cases in the curricular teaching of medical students. Results: The evaluation of the teaching concept with 93 students of medicine showed a consistently high acceptance of all modules, which were rated as very effective or rather effective. Direct patient-related modules, such as history taking with acting patients, musculoskeletal ultrasound and arthrocentesis, received even higher acceptance than the visualization methods utilizing 3D printing and virtual reality. Conclusion: Innovative teaching methods can help to improve the acceptance of teaching in the field of rheumatology, especially when combined with classical teaching contents.
CRIS-Team Scopus Importer:2023-08-11
Keywords: 3D printing; Medical education; Rheumality©; Rheumatology; Virtual reality

Rheumatic?—A Digital Diagnostic Decision Support Tool for Individuals Suspecting Rheumatic Diseases: A Multicenter Pilot Validation Study - Knevel, Rachel; Knitza, Johannes; Hensvold, Aase; Circiumaru, Alexandra; Bruce, Tor; Evans, Sebastian; Maarseveen, Tjardo; Maurits, Marc; Beaart-van de Voorde, Liesbeth; Simon, David; Kleyer, Arnd; Johannesson, Martina; et al. (Frontiers in Medicine, 2022)
Introduction: Digital diagnostic decision support tools promise to accelerate diagnosis and increase health care efficiency in rheumatology. Rheumatic? is an online tool developed by specialists in rheumatology and general medicine together with patients and patient organizations. It calculates a risk score for several rheumatic diseases. We ran a pilot study retrospectively testing Rheumatic? for its ability to differentiate symptoms from existing or emerging immune-mediated rheumatic diseases from other rheumatic and musculoskeletal complaints and disorders in patients visiting rheumatology clinics. Materials and Methods: The performance of Rheumatic? was tested using in three university rheumatology centers: (A) patients at Risk for RA (Karolinska Institutet, n = 50 individuals with musculoskeletal complaints and anti-citrullinated protein antibody positivity) (B) patients with early joint swelling [dataset B (Erlangen) n = 52]. (C) Patients with early arthritis where the clinician considered it likely to be of auto-immune origin [dataset C (Leiden) n = 73]. In dataset A we tested whether Rheumatic? could predict the development of arthritis. In dataset B and C we tested whether Rheumatic? could predict the development of an immune-mediated rheumatic diseases. We examined the discriminative power of the total score with the Wilcoxon rank test and the area-under-the-receiver-operating-characteristic curve (AUC-ROC). Next, we calculated the test characteristics for these patients passing the first or second expert-based Rheumatic? scoring threshold. Results: The total test scores differentiated between: (A) Individuals developing arthritis or not, median 245 vs. 163, P < 0.0001, AUC-ROC = 75.3; (B) patients with an immune-mediated arthritic disease or not median 191 vs. 107, P < 0.0001, AUC-ROC = 79.0; but less patients with an immune-mediated arthritic disease or not amongst those where the clinician already considered an immune mediated disease most likely (median 262 vs. 212, P < 0.0001, AUC-ROC = 53.6). Threshold-1 (advising to visit primary care doctor) was highly specific in dataset A and B (0.72, 0.87, and 0.23, respectively) and sensitive (0.67, 0.61, and 0.67). Threshold-2 (advising to visit rheumatologic care) was very specific in all three centers but not very sensitive: specificity of 1.0, 0.96, and 0.91, sensitivity 0.05, 0.07, 0.14 in dataset A, B, and C, respectively. Conclusion: Rheumatic? is a web-based patient-centered multilingual diagnostic tool capable of differentiating immune-mediated rheumatic conditions from other musculoskeletal problems. The current scoring system needs to be further optimized.
CRIS-Team Scopus Importer:2022-06-10
Keywords: diagnostics; eHealth; mHealth (mobile health); rheumatology; symptom assessment

RHEUMATIC? - A DIGITAL DIAGNOSTIC DECISION SUPPORT TOOL FOR INDIVIDUALS SUSPECTING RHEUMATIC DISEASES: A MULTICENTER VALIDATION STUDY - Knevel, R.; Knitza, Johannes; Hensvold, A.; Circiumaru, A.; Bruce, T.; Evans, S.; Maarseveen, T.; Maurits, Marc; Beaart-Van De Voorde, L.; Simon, David; Kleyer, Arnd; Johannesson, M.; et al. (Annals of the Rheumatic Diseases, 2021)
CRIS-Team WoS Importer:2021-10-01

Rheumatic manifestations of scurvy - Ferrari, Claudia; Possemato, Niccolo; Pipitone, Nicolo; Manger, Bernhard; Salvarani, Carlo (Current Rheumatology Reports, 2015)
This paper reviews the rheumatological manifestations of scurvy, based on articles published in English from 1965 until October 2014, with a particular focus on rheumatological manifestations. Scurvy is a rare, uncommon disease in developed countries. Due to its clinical heterogeneity, the disease can easily mimic rheumatologic conditions leading to a delay in diagnosis and treatment.
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Rheumatic paraneoplastic syndromes - A clinical link between malignancy and autoimmunity - Manger, Bernhard; Schett, Georg (Clinical Immunology, 2017)
Paraneoplastic syndromes are rare but can have enormous clinical impact on diagnosis and outcome of neoplastic diseases. The rheumatologist should be familiar with a few typical musculoskeletal manifestations of malignancies to be able to diagnose them early for a timely initiation of anti-tumour therapies. This review describes the characteristic features of various paraneoplastic arthritides and vasculitides, cancer-associated myositis, hypertrophic osteoarthropathy, and tumour-induced osteomalacia. In addition, the current knowledge about underlying pathomechanisms of these syndromes is discussed.
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Rheumatoid arthritis and osteoimmunology: The adverse impact of a deregulated immune system on bone metabolism - Andreev, Darja; Kachler, Katerina; Bozec, Aline; Schett, Georg (Bone, 2022)
The term osteoimmunology describes an interdisciplinary research field that links the investigation of osteology (bone cells) with immunology. The crosstalk between innate and adaptive immune cells and cells involved in bone remodeling, mainly bone-resorbing osteoclasts and bone-forming osteoblasts, becomes particularly obvious in the inflammatory autoimmune disease rheumatoid arthritis (RA). Besides striking inflammation of the joints, RA causes bone loss, leading to joint damage and disabilities as well as generalized osteoporosis. Mechanistically, RA-associated immune cells (macrophages, T cells, B cells etc.) produce high levels of pro-inflammatory cytokines, receptor activator of nuclear factor κB ligand (RANKL) and autoantibodies that promote bone degradation and at the same time counteract new bone formation. Today, antirheumatic therapy effectively ceases joint inflammation and arrests bone erosion. However, the repair of established bone lesions still presents a challenging task and requires improved treatment options. In this review, we outline the knowledge gained over the past years about the immunopathogenesis of RA and the impact of a dysregulated immune system on bone metabolism.
CRIS-Team Scopus Importer:2022-07-01
Keywords: Bone erosion; Osteoblasts; Osteoclasts; Osteoimmunology; Rheumatoid arthritis

Rheumatoid arthritis, as a clinical disease, but not rheumatoid arthritis-associated autoimmunity, is linked to cardiovascular events - Gouze, Helene; Aegerter, Philippe; Said-Nahal, Roula; Zins, Marie; Goldberg, Marcel; Morelle, Guillaume; Schett, Georg; Breban, Maxime; D'Agostino, Maria Antonietta (Arthritis Research & Therapy, 2022)
Background: Rheumatoid arthritis (RA) is characterized by increased cardiovascular (CV) mortality. CV events are particularly high in patients with RA-specific autoimmunity, including rheumatoid factor (RF) and anti-citrullinated protein antibodies (ACPA), raising the question whether RA-specific autoimmunity itself is associated with CV events. Methods: New CV events (myocardial infarction, stroke or death by CV cause) were recorded in 20,625 subjects of the Electricité de France – Gaz de France (GAZEL) cohort. Self-reported RA cases in the GAZEL cohort were validated by phone interview on the basis of a specific questionnaire. In 1618 subjects, in whom plasma was available, RF and ACPA were measured. A piecewise exponential Poisson regression was used to analyze the association of CV events with presence of RA as well as RA-specific autoimmunity (without RA). Results: CV events in GAZEL were associated with age, male sex, smoking, hypertension, hyperlipidemia, and diabetes mellitus (HR from 1.06 to 1.87, p < 0.05). Forty-two confirmed RA cases were identified. Confirmed RA was significantly associated with CV risk increase (HR of 3.03; 95% CI: 1.13–8.11, p = 0.03) independently of conventional CV risk factors. One hundred seventy-eight subjects showed RF or ACPA positivity without presence of RA. CV events were not associated with ACPA positivity (HR: 1.52, 95% CI: 0.47–4.84, p = 0.48) or RF positivity (HR: 1.15, 95% CI: 0.55–2.40, p = 0.70) in the absence of RA. Conclusions: RA, as a clinical chronic inflammatory disease, but not mere positivity for RF or ACPA in the absence of clinical disease is associated with increased CV risk.
CRIS-Team Scopus Importer:2022-03-11
Keywords: Anti-citrullinated protein autoantibody; Autoimmunity; Cardiovascular diseases; Cardiovascular risk; Rheumatoid arthritis

Rheumatoid arthritis is characterized by early changes of the cortical micro-channel (CoMiC) system in the bare area of the joints - Werner, David; Simon, David; Englbrecht, Matthias; Stemmler, Fabian; Simon, Christoph; Berlin, Andreas; Haschka, Judith; Renner, Nina; Buder, Thomas; Engelke, Klaus; Hueber, Axel; Rech, Jürgen; et al. (Arthritis and Rheumatology, 2017)
To characterize the specific structural properties of the erosion-prone bare area of the human joint and to search for early microstructural changes in this region during rheumatoid arthritis Methods: An initial cadaveric study was used for exact localization of the bare area of the metacarpal heads, detection of cortical micro-channels (CoMiCs) in this region by high-resolution peripheral computed tomography (HR-pQCT) and, after anatomical dissection, their validation by micro-computed tomography (?CT). In the second part, number and distribution of CoMiCs were analyzed in 105 healthy individuals and 107 RA patients with similar sex and age distribution.HR-pQCT investigation combined with adaptive thresholding allowed detection of CoMiCs in the bare area of cadaveric joints. Their existence in the bare area was additionally validated by ?CT. In healthy individuals, the number of CoMiCs increased with age. RA patients showed significantly (p<0.001) more CoMiCs (112.9±54.7/joint) than healthy individuals (75.2±41.9/joint) with 20-49 years old RA patients exhibiting similar CoMiC numbers as observed in over 65 year old healthy individuals. Importantly, CoMiCs were found in RA patients already very early in their disease course with enrichment in the erosion-prone radial side of the joint.CoMiCs represent a new form of structural change in the joints of patients with RA. While CoMiCs increase with age, RA patients develop such changes much earlier in life and already at the onset of the disease. CoMiCs therefore represent an interesting new opportunity to assess structural changes in RA. This article is protected by copyright. All rights reserved.
EVALuna2:13409

Rheumatologic Manifestations of Hemoglobinopathies - Manger, Bernhard (Zeitschrift für Rheumatologie, 2019)
CRIS-Team WoS Importer:2019-08-20

Rheumatologie im Medizinstudium - Aringer, M.; Baerwald, C.; Bergner, R.; Feuchtenberger, M.; Gebhardt, C.; Hagen, Melanie; Keyßer, G.; Lorenz, H. M.; Witte, T. (Zeitschrift für Rheumatologie, 2020)
Transmitting a substantial amount of basic knowledge in Rheumatology to all medical students is essential for the future medical care of patients with rheumatic diseases for two reasons: on the one hand, future general practitioners will need to master the patterns of rheumatic diseases to recognize them fast enough in new-onset patients and to refer them in time and directly to rheumatologists. On the other hand, the shortage of rheumatologists can only then be relieved in the future when we are able to inspire enthusiasm for our specialty. Adequate rheumatological structures are established only in some of the German faculties of medicine. Structural improvements happen in small steps only but were achieved at several sites. The better the local structures, the higher the chances of committed university teachers in rheumatology to reach all medical students. Probably from 2026 onwards, the learning objectives relevant for examinations will be defined by the national competence-based catalogue of learning objectives in medicine (NKLM), which is currently in the final stages of completion together with the German Federal Institute for Medical and Pharmaceutical Examinations (IMPP). It now appears that systemic autoimmune diseases and inflammatory rheumatic diseases are adequately depicted in this catalogue. If this is achieved, students will know more about these diseases in the future and will diagnose them faster in patients. Work on the NKLM is therefore of highest importance. In addition to the work on the learning objectives, up to date learning materials are required, which have to be available throughout Germany. A Rheumatology script just finished by the committee for medical student education of the German Society of Rheumatology (DGRh) and now available on the DGRh homepage should close this gap.
CRIS-Team Scopus Importer:2020-12-11
Keywords: Basic education in rheumatology; Bedside teaching; Electronic learning materials; Examination contents; Learning objectives

Rheumatologische paraneoplastische Syndrome - Knitza, Johannes; Schett, Georg; Manger, Bernhard (Aktuelle Rheumatologie, 2020)
Zusammenfassung Rheumatologische paraneoplastische Syndrome sind selten, stellten jedoch eine wichtige Differenzialdiagnose zu klassischen rheumatologischen Krankheitsbildern dar. Durch das Erkennen der eindrücklichen Syndrome mit typischen Labor- und Untersuchungsbefunden ist oftmals eine beschleunigte Diagnose der zugrundeliegenden Malignität und kurative Therapie möglich. In dieser Übersichtsarbeit werden die Charakteristika rheumatologischer paraneoplastischer Syndrome vorgestellt.
CRIS-Team Scopus Importer:2020-12-18
Keywords: Malignom; Myositis; Paraneoplasie; Rheumatologie; Tumorsuche

Rheumatologische Weiterbildungsstellen in Deutschland - Pfeil, Alexander; Krusche, Martin; Proft, Fabian; Vossen, Diana; Braun, Jurgen; Baraliakos, Xenofon; Berliner, Michael N.; Keysser, Gernot; Krause, Andreas; Lorenz, Hanns-Martin; Manger, Bernhard; Schuch, Florian; et al. (Zeitschrift für Rheumatologie, 2022)
Background In the next few years many general practitioners and specialists will retire. As in other disciplines the question arises in rheumatology whether sufficient training positions are available to maintain or expand the supply of care according to demand. Therefore, the German Society of Rheumatology (DGRh) has assigned its committee for education and training to review the currently available training opportunities in Germany. The aim of this work is the quantitative survey of the training capacity to become a specialist in internal medicine and rheumatology. Methods Within the framework of this study, a survey was conducted via the homepages of the 17 state medical associations to determine the postgraduate medical officers, their place of work and the duration of their postgraduate training capabilities. Based on the data, a nationwide survey of training positions was conducted. Results Specialized rheumatology training is established at 229 training centers in Germany, whereby data from 187 training sites were available for analysis. The training locations are distributed as followed: 52.4% clinical sector and 47.6% outpatient sector. In total, 478.4 training positions are available in Germany (clinical sector: 391.4 and outpatient sector: 87) and 17.2% of the positions (clinical sector: 11.4% and outpatient sector: 43.1%) are not occupied. Conclusion Based on this study, it can be shown that most of the continuing education positions are available in the clinical sector. In contrast, half of the training positions in the outpatient area are not filled. In order to improve the training situation, it is essential to integrate outpatient colleagues into the training program. This presupposes that further training is supported or financed by the healthcare system. In this context, optimal rheumatological care must be permanently guaranteed throughout Germany in order to provide sufficient care for the approximately 2 million patients with inflammatory rheumatic diseases.
CRIS-Team WoS Importer:2022-11-04

Risk loci involved in giant cell arteritis susceptibility: a genome-wide association study - Borrego-Yaniz, Gonzalo; Ortiz-Fernández, Lourdes; Madrid-Paredes, Adela; Kerick, Martin; Hernández-Rodríguez, José; Mackie, Sarah L.; Vaglio, Augusto; Castañeda, Santos; Solans, Roser; Mestre-Torres, Jaume; Khalidi, Nader; Langford, Carol A.; et al. (The Lancet Rheumatology, 2024)
Background: Giant cell arteritis is an age-related vasculitis that mainly affects the aorta and its branches in individuals aged 50 years and older. Current options for diagnosis and treatment are scarce, highlighting the need to better understand its underlying pathogenesis. Genome-wide association studies (GWAS) have emerged as a powerful tool for unravelling the pathogenic mechanisms involved in complex diseases. We aimed to characterise the genetic basis of giant cell arteritis by performing the largest GWAS of this vasculitis to date and to assess the functional consequences and clinical implications of identified risk loci. Methods: We collected and meta-analysed genomic data from patients with giant cell arteritis and healthy controls of European ancestry from ten cohorts across Europe and North America. Eligible patients required confirmation of giant cell arteritis diagnosis by positive temporal artery biopsy, positive temporal artery doppler ultrasonography, or imaging techniques confirming large-vessel vasculitis. We assessed the functional consequences of loci associated with giant cell arteritis using cell enrichment analysis, fine-mapping, and causal gene prioritisation. We also performed a drug repurposing analysis and developed a polygenic risk score to explore the clinical implications of our findings. Findings: We included a total of 3498 patients with giant cell arteritis and 15 550 controls. We identified three novel loci associated with risk of giant cell arteritis. Two loci, MFGE8 (rs8029053; p=4·96 × 10–8; OR 1·19 [95% CI 1·12–1·26]) and VTN (rs704; p=2·75 × 10–9; OR 0·84 [0·79–0·89]), were related to angiogenesis pathways and the third locus, CCDC25 (rs11782624; p=1·28 × 10–8; OR 1·18 [1·12–1·25]), was related to neutrophil extracellular traps (NETs). We also found an association between this vasculitis and HLA region and PLG. Variants associated with giant cell arteritis seemed to fulfil a specific regulatory role in crucial immune cell types. Furthermore, we identified several drugs that could represent promising candidates for treatment of this disease. The polygenic risk score model was able to identify individuals at increased risk of developing giant cell arteritis (90th percentile OR 2·87 [95% CI 2·15–3·82]; p=1·73 × 10–13). Interpretation: We have found several additional loci associated with giant cell arteritis, highlighting the crucial role of angiogenesis in disease susceptibility. Our study represents a step forward in the translation of genomic findings to clinical practice in giant cell arteritis, proposing new treatments and a method to measure genetic predisposition to this vasculitis. Funding: Institute of Health Carlos III, Spanish Ministry of Science and Innovation, UK Medical Research Council, and National Institute for Health and Care Research
CRIS-Team Scopus Importer:2024-05-31

Risk of developing psoriatic arthritis in psoriasis cohorts with arthralgia: exploring the subclinical psoriatic arthritis stage - Zabotti, Alen; Fagni, Filippo; Gossec, Laure; Giovannini, Ivan; Sticherling, Michael; Tullio, Annarita; Baraliakos, Xenofon; De Marco, Gabriele; De Vita, Salvatore; Errichetti, Enzo; Quartuccio, Luca; Silvagni, Ettore; et al. (RMD Open, 2024)
Objective Subjects with subclinical psoriatic arthritis (PsA), defined as the presence of arthralgia in psoriasis (PsO), are at higher risk of PsA but scant real-world data exist. Our aims were to (1) estimate the probability of PsA development in subclinical PsA, (2) characterise subclinical PsA symptoms and (3) determine the clinical patterns at PsA diagnosis. Methods Patients with PsO, mainly subclinical PsA, were evaluated longitudinally in two European cohorts. The key outcome was new-onset PsA. Musculoskeletal symptoms including inflammatory and non-inflammatory symptoms before PsA diagnosis were collected. Occurrence of PsA was analysed with survival analysis and cumulative incidence functions (CIFs). Results 384 patients with PsO were included with a mean follow-up of 33.0 (±20.9) months. 311 of 384 (80.9%) had subclinical PsA with a PsA incidence rate of 7.7 per 100 patient-years. Subclinical PsA displayed a higher risk of PsA development compared with PsO (HR=11.7 (95% CI 1.57 to 86.7), p=0.016). The probability of new-onset PsA estimated by the CIF was 9.4% (95% CI 4.7% to 10.6%) at month 12 and 22.7% (95% CI 17.2% to 28.6%) at month 36. 58.9% of cases reported inflammatory symptoms in the months immediately prior to PsA diagnosis but prior non-inflammatory symptoms were evident in 83.9% prior to PsA diagnosis. Peripheral joint swelling was the predominant PsA presentation pattern (82.1%). Conclusions The probability of PsA development among subclinical PsA was relatively high, emphasising the importance of emergent musculoskeletal symptoms when aiming for PsA prevention. Joint swelling was the dominant feature in new-onset PsA, likely reflecting clinical confidence in recognising joint swelling.
CRIS-Team Scopus Importer:2024-04-26
Keywords: arthritis; psoriatic; classification; incidence; synovitis; ultrasonography

Risk of infections in rheumatoid arthritis patients treated with tocilizumab - Lang, Veronika R.; Englbrecht, Matthias; Rech, Jürgen; Nüsslein, Hubert; Manger, Karin; Schuch, Florian; Tony, Hans-Peter; Fleck, Martin; Manger, Bernhard; Schett, Georg; Zwerina, Jochen (Rheumatology, 2012)
Objectives: To investigate the occurrence and risk factors for infections in RA patients treated with tocilizumab. Methods: A cohort of all RA patients (n = 112) starting tocilizumab therapy between October 2008 and March 2010 in Northern Bavaria was screened for infections. Mild/moderate and severe infections were recorded. Multivariate logistic regression analysis was used to define risk factors for infection. Results: Overall, 26 patients developed infections [23.2%; 58.0/100 patient-years (py)], 18 of them were mild to moderate (16.1%, 40.1/100 py) and 8 were severe (17.9/100 py). Concomitant use of LEF and prednisone, high disease activity and previous therapy with rituximab were associated with the occurrence of mild/moderate infections. Severe infections were related to longer disease duration, exposure to more than three previous DMARDs and concomitant therapy with proton-pump inhibitors. Conclusion: The rate of infection in RA patients treated with tocilizumab in clinical practice is higher than in the clinical trial populations. Increased attention should especially be given to patients with longer disease duration, previous exposure to multiple DMARDs, i.e. previous exposure to rituximab and those receiving concomitant LEF, prednisone or proton-pump inhibitor treatment. © The Author 2011. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved.
CRIS-Team Scopus Importer:2021-02-03
Keywords: Infections; Rheumatoid arthritis; Tocilizumab

RITUXIMAB IN SYSTEMIC SCLEROSIS : SAFETY AND EFFICACY DATA FROM THE EUSTAR NETWORK - Elhai, M.; Distler, O.; Smith, V.; Matucci-Cerinic, M.; Alegre-Sancho, J. J.; Truchetet, M. -E.; Braun-Moscovici, Y.; Iannone, F.; Chotchaeva, F.; Lescoat, A.; Siegert, E.; Castellvi, I.; et al. (2018)
EVALuna2:34986

Role of guanylate binding protein-1 in vascular defects associated with chronic inflammatory diseases - Hammon, Matthias; Herrmann, Martin; Bleiziffer, Oliver; Pryymachuk, Galyna; Andreoli, Laura; Munoz, Luis Enrique; Amann, Kerstin Ute; Mondini, Michele; Gariglio, Marisa; Airo, Paolo; Schellerer, Vera; Hatzopoulos, Antonis K.; et al. (Journal of Cellular and Molecular Medicine, 2011)
Rheumatic autoimmune disorders are characterized by a sustained pro-inflammatory microenvironment associated with impaired function of endothelial progenitor cells (EPC) and concomitant vascular defects. Guanylate binding protein-1 (GBP-1) is a marker and intracellular regulator of the inhibition of proliferation, migration and invasion of endothelial cells induced by several pro-inflammatory cytokines. In addition, GBP-1 is actively secreted by endothelial cells. In this study, significantly increased levels of GBP-1 were detected in the sera of patients with chronic inflammatory disorders. Accordingly we investigated the function of GBP-1 in EPC. Interestingly, stable expression of GBP-1 in T17b EPC induced premature differentiation of these cells, as indicated by a robust up-regulation of both Flk-1 and von Willebrand factor expression. In addition, GBP-1 inhibited the proliferation and migration of EPC in vitro. We confirmed that GBP-1 inhibited vessel-directed migration of EPC at the tissue level using the rat arterio-venous loop model as a novel quantitative in vivo migration assay. Overall, our findings indicate that GBP-1 contributes to vascular dysfunction in chronic inflammatory diseases by inhibiting EPC angiogenic activity via the induction of premature EPC differentiation. © 2011 The Authors Journal of Cellular and Molecular Medicine © 2011 Foundation for Cellular and Molecular Medicine/Blackwell Publishing Ltd.
Created from Fastlane, Scopus look-up
Keywords: Endothelial progenitor cells; Guanylate binding protein-1; Inflammation; Rheumatic autoimmune disorders; Rheumatoid arthritis; Systemic lupus erythematosus; Systemic sclerosis

ROS Ameriolates the Clinical Course of Murine Lupus - Hahn, Jonas; Kienhoefer, Deborah; Stoof, Julia; Csepregi, Janka Zsofia; Hultqvist, Malin; Leppkes, Moritz; Herrmann, Martin; Mocsai, Atilla; Schett, Georg; Hoffmann, Markus (2016)
EVALuna2:35053

ROS is the boss - Hahn, Jonas; Kienhofer, Deborah; Stoof, Julia; Csepregi, Janka Zsofia; Reinwald, Christiane; Maueröder, Christian; Urbonaviciute, Vilma; Munoz, Luis Enrique; Hultqvist, Malin; Podolska, Malgorzata; Biermann, Mona; Leppkes, Moritz; et al. (2017)
EVALuna2:13467

Routine Surveillance of SARS-CoV-2 Serostatus in Pediatrics Allows Monitoring of Humoral Response - Wachter, Felix; Knieling, Ferdinand; Raming, Roman; Simon, David; Wölfle, Joachim; Hörning, André; Neubert, Antje; Rauh, Manfred; Regensburger, Adrian (Microorganisms, 2023)
The occurrence of SARS-CoV-2 infections during the pandemic was mainly based on PCR testing of symptomatic patients. However, with new variants, vaccinations, and the changing of the clinical disease severity, knowledge about general immunity is elusive. For public health systems, timely knowledge of these conditions is essential, but it is particularly scarce for the pediatric population. Therefore, in this study, we wanted to investigate the spike and nucleocapsid seroprevalence in pediatric patients using routine residual blood tests collected during the pandemic. This prospective observational study was conducted over seven one-month periods. Herein, the latest four time periods (November 2021, January 2022, March 2022, and May 2022) are depicted. Each patient of a tertiary-care center in Germany was anonymized after collection of clinical diagnosis (ICD-10) and then routinely tested for the respective spike and nucleocapsid SARS-CoV-2 antibody titer. A total of 3235 blood samples from four time periods were included. Spike seroprevalence rose from 37.6% to 51.9% to 70.5% to 85.1% and nucleocapsid seroprevalence from 11.6% to 17.0% to 36.7% to 58.1% in May 2022. In detail, significant changes in seroprevalence between age groups but not between sex or diagnosis groups were found. Quantitative measures revealed rising spike and constant nucleocapsid antibody levels over the pandemic with a half-life of 102 days for spike and 45 days for nucleocapsid antibodies. Routine laboratory assessment of SARS-CoV-2 in residual blood specimens of pediatric hospitals enables monitoring of the seroprevalence and may allow inferences about general immunity in this cohort.
EVALuna2:547467
Keywords: COVID-19; pediatrics; seroprevalence; SARS-CoV-2; Omicron; surveillance

Rsk2 controls synovial fibroblast hyperplasia and the course of arthritis - Derer, Anja; Boehm, Christina; Groetsch, Bettina; Gruen, Joachim R.; Gruetzkau, Andreas; Stock, Michael; Böhm, Sybille; Sehnert, Bettina; Gaipl, Udo; Schett, Georg; Hueber, Axel; David, Jean-Pierre (Annals of the Rheumatic Diseases, 2016)
Arthritis is a chronic inflammatory disease characterised by immune cell infiltration and mesenchymal cell expansion in the joints. Although the role of immune cells in arthritis is well characterised, the development of mesenchymal cell hyperplasia needs to be better defined. Here, we analysed the role of the ribosomal S6 kinase Rsk2, which we found to be highly activated in joints of patients with arthritis, in the development of mesenchymal cell hyperplasia.We genetically inactivated Rsk2 in the tumour necrosis factor (TNF)-? transgenic (TNFtg) mice, an animal model for human inflammatory arthritis. Clinical and histological signs of arthritis as well as molecular markers of inflammation and joint destruction were quantified. Fibroblast-like synoviocytes (FLS) were characterised in vitro and the effect of Rsk2 deletion on the pattern of gene expression was determined.Rsk2 deficiency in TNFtg mice results in earlier and exacerbated inflammation as well as increased bone and cartilage destruction. The production of inflammatory cytokines, matrix metalloproteinases and osteoclastogenic molecules was significantly increased in vivo upon Rsk2 inactivation. Bone marrow deficient in Rsk2 could not transfer this phenotype, indicating that Rsk2 expression in mesenchymal cells controls the course of arthritis. Indeed, Rsk2 deficiency was associated with a more activated phenotype and higher proliferative capacity of FLS, thereby increasing cytokines and production of matrix proteinases.Rsk2 emerges as a key regulator of mesenchymal cell numbers in the joint and thereby could be targeted to control the inflammatory and tissue-destructive feature of joints in arthritis.
EVALuna2:13016

R-spondin 1 protects against inflammatory bone damage during murine arthritis by modulating the Wnt pathway - Krönke, Gerhard; Uderhardt, Stefan; Kim, Kyung-Ah; Stock, Michael; Scholtysek, Carina; Zaiss, Mario; Surmann-Schmitt, Cordula; Luther, Julia; Katzenbeisser, Julia; David, Jean-Pierre; Abdollahi-Roodsaz, Shahla; Tran, Karolyn; et al. (Arthritis and Rheumatism, 2010)
Objective. During the course of different musculoskeletal diseases, joints are progressively damaged by inflammatory, infectious, or mechanical stressors, leading to joint destruction and disability. While effective strategies to inhibit joint inflammation, such as targeted cytokine-blocking therapy, have been developed during the last decade, the molecular mechanisms of joint damage are still poorly understood. This study was undertaken to investigate the role of the Wnt pathway modulator R-Spondin 1 (RSpo1) in protecting bone and cartilage in a mouse model of arthritis. Methods. Tumor necrosis factor α (TNFα)-transgenic mice were treated with vehicle or Rspo1. Mice were evaluated for signs of arthritis, and histologic analysis of the hind paws was performed. Moreover, we determined the effect of Rspo1 on Wnt signaling activity and osteoprotegerin (OPG) expression in murine primary osteoblasts. Results. The secreted Wnt pathway modulator RSpo1 was highly effective in preserving the structural integrity of joints in a TNFα-transgenic mouse model of arthritis by protecting bone and cartilage from inflammation-related damage. RSpo1 antagonized the Wnt inhibitor Dkk-1 and modulated Wnt signaling in mouse mesenchymal cells. In osteoblasts, RSpo1 induced differentiation and expression of OPG, thereby inhibiting osteoclastogenesis in vitro. In vivo, RSpo1 promoted osteoblast differentiation and bone formation while blocking osteoclast development, thereby contributing to the integrity of joints during inflammatory arthritis. Conclusion. Our results demonstrate the therapeutic potential of RSpo1 as an anabolic agent for the preservation of joint architecture. © 2010, American College of Rheumatology.
CRIS-Team Scopus Importer:2020-11-20

Runx2 mediated Induction of Novel Targets ST2 and Runx3 Leads to Cooperative Regulation of Hypertrophic Differentiation in ATDC5 Chondrocytes - Rad, Ehsan Bonyadi; Musumeci, Giuseppe; Pichler, Karin; Heidary, Maryam; Szychlinska, Marta Anna; Castrogiovanni, Paola; Marth, Egon; Boehm, Christina; Srinivasaiah, Sriveena; Krönke, Gerhard; Weinberg, Annelie; Schaefer, Ute (Scientific Reports, 2017)
Knowledge concerning expression and function of Suppression of Tumorigenicity 2 (ST2) in chondrocytes is at present, limited. Analysis of murine growth plates and ATDC5 chondrocytes indicated peak expression of the ST2 transmembrane receptor (ST2L) and soluble (sST2) isoforms during the hypertrophic differentiation concomitant with the expression of the hypertrophic markers Collagen X (Col X), Runx2 and MMP-13. Gain- and loss-of-function experiments in ATDC5 and primary human growth plate chondrocytes (PHCs), confirmed regulation of ST2 by the key transcription factor Runx2, indicating ST2 to be a novel Runx2 target. ST2 knock-out mice (ST2-/-) exhibited noticeable hypertrophic zone (HZ) reduction in murine growth plates, accompanied by lower expression of Col X and Osteocalcin (OSC) compared to wild-type (WT) mice. Likewise, ST2 knockdown resulted in decreased Col X expression and downregulation of OSC and Vascular Endothelial Growth Factor (VEGF) in ATDC5 cells. The ST2 suppression was also associated with upregulation of the proliferative stage markers Sox9 and Collagen II (Col II), indicating ST2 to be a new regulator of ATDC5 chondrocyte differentiation. Runx3 was, furthermore, identified as a novel Runx2 target in chondrocytes. This study suggests that Runx2 mediates ST2 and Runx3 induction to cooperatively regulate hypertrophic differentiation of ATDC5 chondrocytes.
EVALuna2:13522

S100A4 PLASMA LEVELS CORRELATE WITH DISEASE ACTIVITY, SKIN FIBROSIS AND INTERSTITIAL LUNG DISEASE IN SYSTEMIC SCLEROSIS PATIENTS - Storkanova, H.; Cerezo, L. Andres; Oreska, S.; Spiritovic, M.; Hermankova, B.; Komarc, M.; Pavelka, K.; Vencovsky, J.; Distler, Jörg; Senolt, L.; Becvar, R.; Tomcik, M. (ANNALS OF THE RHEUMATIC DISEASES, 2021)
CRIS-Team WoS Importer:2021-09-24

S100A8 BUT NOT S100A9 LEVEL IS RELATED TO THE EXTENT OF EROSIVE BONE DAMAGE IN PSORIATIC ARTHRITIS PATIENTS - Simon, David; Nas, K.; Faustini, F.; Kleyer, Arnd; Haschka, J.; Englbrecht, Matthias; Hueber, Axel; Kocijan, R.; Sticherling, Michael; Schett, Georg; Rech, Jürgen (2016)
EVALuna2:13430

S2k-Leitlinie (Kurzfassung): Management der Großgefäßvaskulitiden - Schirmer, J. H.; Aries, P. M.; Balzer, K.; Berlit, P.; Bley, T. A.; Buttgereit, F.; Czihal, M.; Dechant, C.; Dejaco, C.; Garske, U.; Henes, J.; Holle, J. U.; et al. (Zeitschrift für Rheumatologie, 2020)
CRIS-Team Scopus Importer:2020-11-13

S2k-Leitlinie: Management der Großgefäßvaskulitiden - Schirmer, J. H.; Aries, P. M.; Balzer, K.; Berlit, P.; Bley, T. A.; Buttgereit, F.; Czihal, M.; Dechant, C.; Dejaco, C.; Garske, U.; Henes, J.; Holle, J. U.; et al. (Zeitschrift für Rheumatologie, 2020)
CRIS-Team Scopus Importer:2020-11-13

Safety and efficacy of intravenous cyclophosphamide pulse therapy in therapy refractory Crohn's disease patients - Hirschmann, S; Atreya, Raja; Englbrecht, Matthias; Neurath, Markus (Journal of Physiology and Pharmacology, 2017)
A major challenge in the management of persistently active Crohn's disease patient's refractory to treatment regimen following the current guidelines is the induction of remission, which is a prerequisite for subsequent maintenance therapy. The aim of this study was to evaluate both the clinical and endoscopic benefit of intravenous cyclophosphamide pulse therapy in patients with active and therapy refractory Crohn's disease. Nine patients with acute moderate to severe Crohn's disease, not responding to conventional as well as biological therapy regimen received 3 - 9 cycles of monthly treatments with intravenous cyclophosphamide (680 - 1000 mg) in an uncontrolled setting and were retrospectively analyzed. Eight of nine patients (88.9%) had a clinical response (measured by a decrease in the Harvey-Bradshaw index, HBI >= 3) and two of nine patients (22.2%) achieved clinical remission (HBI <= 4) at week 8 after two applications of intravenous cyclophosphamide therapy. These response and remission rates remained unchanged after individual completion of cyclophosphamide therapy. Median HBI decreased from 18 (7 - 25) at the beginning of therapy to 7 (3 - 18) at week 8. 5 of 9 patients (56%) showed endoscopic response (defined by a reduction of ulcers) and one patient (11%) reached endoscopic remission (defined by the absence of ulcers) after the last application of cyclophosphamide. Arthralgia, which was present in 4 of 9 (44%) patients, was unchanged in most patients after cyclophosphamide therapy, although one patient described a marked reduction in joint pain. Cyclophosphamide pulse therapy was well tolerated during the whole treatment course in all subjects. One patient with long-standing Crohn's disease was diagnosed with a high-grade intraepithelial neoplasia in the rectum and underwent surgical intervention, where the diagnosis of an early stage adenocarcinoma was made. We concluded that intravenous cyclophosphamide pulse therapy was well tolerated by most patients and effective for inducing clinical and endoscopic response and remission in patients with therapy refractory Crohn's disease. In patients who are unresponsive to available therapies, including available biological treatment options, cyclophosphamide therefore represents a potential option to induce therapeutic response, which must then be maintained by other treatment modalities.
EVALuna2:13423

Safety and immunogenicity of an adjuvanted protein therapeutic HIV-1 vaccine in subjects with HIV-1 infection: a randomised placebo-controlled study - Harrer, Thomas; Plettenberg, Andreas; Arasteh, Keikawus; Van Lunzen, Jan; Faetkenheuer, Gerd; Jaeger, Hans; Janssens, Michel; Burny, Wivine; Collard, Alix; Roman, Francois; Loeliger, Alfred; Koutsoukos, Marguerite; et al. (Vaccine, 2014)
The human immunodeficiency virus type-1 (HIV-1) vaccine candidate F4/AS01 has previously been shown to induce potent and persistent polyfunctional CD4(+) T-cell responses in HIV-1-seronegative volunteers. This placebo-controlled study evaluated two doses of F4/AS01 1-month apart in antiretroviral treatment (ART)-experienced and ART-naïve HIV-1-infected subjects (1:1 randomisation in each cohort). Safety, HIV-1-specific CD4(+) and CD8(+) T-cell responses, absolute CD4(+) T-cell counts and HIV-1 viral load were monitored for 12 months post-vaccination. Reactogenicity was clinically acceptable and no vaccine-related serious adverse events were reported. The frequency of HIV-1-specific CD4(+) T-cells 2 weeks post-dose 2 was significantly higher in the vaccine group than in the placebo group in both cohorts (p<0.05). Vaccine-induced HIV-1-specific CD4(+) T-cells exhibited a polyfunctional phenotype, expressing at least CD40L and IL-2. No increase in HIV-1-specific CD8(+) T-cells or change in CD8(+) T-cell activation marker expression profile was detected. Absolute CD4(+) T-cell counts were variable over time in both cohorts. Viral load remained suppressed in ART-experienced subjects. In ART-naïve subjects, a transient reduction in viral load from baseline was observed 2 weeks after the second F4/AS01 dose, which was concurrent with a higher frequency of HIV-1-specific CD4(+) T-cells expressing at least IL-2 in this cohort. In conclusion, F4/AS01 showed a clinically acceptable reactogenicity and safety profile, and induced polyfunctional HIV-1-specific CD4(+) T-cell responses in ART-experienced and ART-naïve subjects. These findings support further clinical investigation of F4/AS01 as a potential HIV-1 vaccine for therapeutic use in individuals with HIV-1 infection.
EVALuna2:12915

Sample Curriculum of the German Society for Rheumatology for Advanced Training in the field of Internal Medicine and Rheumatology - Pfeil, Alexander; Krusche, Martin; Vossen, Diana; Berliner, Michael N.; Keyer, Gernot; Krause, Andreas; Lorenz, Hanns-Martin; Manger, Bernhard; Schuch, Florian; Specker, Christof; Wollenhaupt, Juergen; Baraliakos, Xenofon; et al. (Zeitschrift für Rheumatologie, 2021)
CRIS-Team WoS Importer:2021-08-06

SARS-CoV-2 BA.2.86 enters lung cells and evades neutralizing antibodies with high efficiency - Zhang, Lu; Kempf, Amy; Nehlmeier, Inga; Cossmann, Anne; Richter, Anja; Bdeir, Najat; Graichen, Luise; Moldenhauer, Anna Sophie; Dopfer-Jablonka, Alexandra; Stankov, Metodi V.; Simon-Loriere, Etienne; Schulz, Sebastian; et al. (Cell, 2024)
BA.2.86, a recently identified descendant of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron BA.2 sublineage, contains ∼35 mutations in the spike (S) protein and spreads in multiple countries. Here, we investigated whether the virus exhibits altered biological traits, focusing on S protein-driven viral entry. Employing pseudotyped particles, we show that BA.2.86, unlike other Omicron sublineages, enters Calu-3 lung cells with high efficiency and in a serine- but not cysteine-protease-dependent manner. Robust lung cell infection was confirmed with authentic BA.2.86, but the virus exhibited low specific infectivity. Further, BA.2.86 was highly resistant against all therapeutic antibodies tested, efficiently evading neutralization by antibodies induced by non-adapted vaccines. In contrast, BA.2.86 and the currently circulating EG.5.1 sublineage were appreciably neutralized by antibodies induced by the XBB.1.5-adapted vaccine. Collectively, BA.2.86 has regained a trait characteristic of early SARS-CoV-2 lineages, robust lung cell entry, and evades neutralizing antibodies. However, BA.2.86 exhibits low specific infectivity, which might limit transmissibility.
CRIS-Team Scopus Importer:2024-02-16
Keywords: antibody evasion; BA.2.86; fusion; infectivity; lung cell entry; mutations; pirola variant; SARS-CoV-2; Spike protein; TMPRSS2

SARS-CoV-2 mutations acquired in mink reduce antibody-mediated neutralization - Hoffmann, Markus; Zhang, Lu; Krüger, Nadine; Graichen, Luise; Kleine-Weber, Hannah; Hofmann-Winkler, Heike; Kempf, Amy; Nessler, Stefan; Riggert, Joachim; Winkler, Martin Sebastian; Schulz, Sebastian; Jäck, Hans-Martin; et al. (Cell Reports, 2021)
Transmission of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) from humans to farmed mink has been observed in Europe and the US. In the infected animals, viral variants arose that harbored mutations in the spike (S) protein, the target of neutralizing antibodies, and these variants were transmitted back to humans. This raised concerns that mink might become a constant source of human infection with SARS-CoV-2 variants associated with an increased threat to human health and resulted in mass culling of mink. Here, we report that mutations frequently found in the S proteins of SARS-CoV-2 from mink are mostly compatible with efficient entry into human cells and its inhibition by soluble angiotensin-converting enzyme 2 (ACE2). In contrast, mutation Y453F reduces neutralization by an antibody with emergency use authorization for coronavirus disease 2019 (COVID-19) therapy and sera/plasma from COVID-19 patients. These results suggest that antibody responses induced upon infection or certain antibodies used for treatment might offer insufficient protection against SARS-CoV-2 variants from mink.
CRIS-Team Scopus Importer:2021-04-23
Keywords: antibodies; evasion; mink; mutation; neutralization; SARS-CoV-2; spike protein; variant; Y453F

SARS-CoV-2 Omicron sublineages show comparable cell entry but differential neutralization by therapeutic antibodies - Arora, Prerna; Zhang, Lu; Krüger, Nadine; Rocha, Cheila; Sidarovich, Anzhalika; Schulz, Sebastian; Kempf, Amy; Graichen, Luise; Moldenhauer, Anna Sophie; Cossmann, Anne; Dopfer-Jablonka, Alexandra; Behrens, Georg M.N.; et al. (Cell Host & Microbe, 2022)
The Omicron variant of SARS-CoV-2 evades antibody-mediated neutralization with unprecedented efficiency. At least three Omicron sublineages have been identified—BA.1, BA.2, and BA.3—and BA.2 exhibits increased transmissibility. However, it is currently unknown whether BA.2 differs from the other sublineages regarding cell entry and antibody-mediated inhibition. Here, we show that BA.1, BA.2, and BA.3 enter and fuse target cells with similar efficiency and in an ACE2-dependent manner. However, BA.2 was not efficiently neutralized by seven of eight antibodies used for COVID-19 therapy, including Sotrovimab, which robustly neutralized BA.1. In contrast, BA.2 and BA.3 (but not BA.1) were appreciably neutralized by Cilgavimab, which could constitute a treatment option. Finally, all sublineages were comparably and efficiently neutralized by antibodies induced by BNT162b2 booster vaccination after previous two-dose homologous or heterologous vaccination. Collectively, the Omicron sublineages show comparable cell entry and neutralization by vaccine-induced antibodies but differ in susceptibility to therapeutic antibodies.
CRIS-Team Scopus Importer:2022-08-19
Keywords: ACE2; antibody; neutralization; Omicron; SARS-CoV-2; sotrovimab; spike; vaccine

SARS-CoV-2-seronegative HIV-1-infected subjects target CTL epitopes in the SARS-CoV-2 nucleoprotein cross-reactive to common cold coronaviruses - Schmidt, Katja; Nganou-Makamdop, Krystelle; Tenbusch, Matthias; El Kenz, Boutaina; Maier, Clara; Lapuente, Dennis; Überla, Klaus; Spriewald, Bernd; Bergmann, Silke; Harrer, Ellen; Harrer, Thomas (INFECTION, 2021)
CRIS-Team WoS Importer:2021-04-09

SARS-CoV-2-seronegative subjects target CTL epitopes in the SARS-CoV-2 nucleoprotein cross-reactive to common cold coronaviruses - Schmidt, Kristin; Nganou-Makamdop, K.; Tenbusch, Matthias; El Kenz, B.; Maier, Clara; Lapuente, Dennis; Überla, Klaus; Spriewald, Bernd; Bergmann, Sabrina; Harrer, Ellen; Harrer, Thomas (JOURNAL OF THE INTERNATIONAL AIDS SOCIETY, 2021)
CRIS-Team WoS Importer:2021-11-26

SARS-CoV-2-Seronegative Subjects Target CTL Epitopes in the SARS-CoV-2 Nucleoprotein Cross-Reactive to Common Cold Coronaviruses - Schmidt, Katja; Nganou-Makamdop, Krystelle; Tenbusch, Matthias; El Kenz, Boutaina; Maier, Clara; Lapuente, Dennis; Überla, Klaus; Spriewald, Bernd; Bergmann, Silke; Harrer, Ellen; Harrer, Thomas (Frontiers in Immunology, 2021)
The beta-coronavirus SARS-CoV-2 induces severe disease (COVID-19) mainly in elderly persons with risk factors, whereas the majority of patients experience a mild course of infection. As the circulating common cold coronaviruses OC43 and HKU1 share some homologous sequences with SARS-CoV-2, beta-coronavirus cross-reactive T-cell responses could influence the susceptibility to SARS-CoV-2 infection and the course of COVID-19. To investigate the role of beta-coronavirus cross-reactive T-cells, we analyzed the T-cell response against a 15 amino acid long peptide (SCoV-DP15: DLSPRWYFYYLGTGP) from the SARS-CoV-2 nucleoprotein sequence with a high homology to the corresponding sequence (QLLPRWYFYYLGTGP) in OC43 and HKU1. SCoV-DP15-specific T-cells were detected in 4 out of 23 (17.4%) SARS-CoV-2-seronegative healthy donors. As HIV-1 infection is a potential risk factor for COVID-19, we also studied a cohort of HIV-1-infected patients on antiretroviral therapy. 44 out of these 116 HIV-1-infected patients (37.9%) showed a specific recognition of the SCoV-DP15 peptide or of shorter peptides within SCoV-DP15 by CD4+ T-cells and/or by CD8+ T-cells. We could define several new cross-reactive HLA-I-restricted epitopes in the SARS-CoV-2 nucleoprotein such as SPRWYFYYL (HLA-B*07, HLA-B*35), DLSPRWYFYY (HLA-A*02), LSPRWYFYY (HLA-A*29), WYFYYLGTGP and WYFYYLGT. Epitope specific CD8+ T-cell lines recognized corresponding epitopes within OC43 and HKU1 to a similar degree or even at lower peptide concentrations suggesting that they were induced by infection with OC43 or HKU1. Our results confirm that SARS-CoV-2-seronegative subjects can target SARS-CoV-2 not only by beta-coronavirus cross-reactive CD4+ T-cells but also by cross-reactive CD8+ cytotoxic T-cells (CTL). The delineation of cross-reactive T-cell epitopes contributes to an efficient epitope-specific immunomonitoring of SARS-CoV-2-specific T-cells. Further prospective studies are needed to prove a protective role of cross-reactive T-cells and their restricting HLA alleles for control of SARS-CoV-2 infection. The frequent observation of SARS-CoV-2-reactive T-cells in HIV-1-infected subjects could be a reason that treated HIV-1 infection does not seem to be a strong risk factor for the development of severe COVID-19.
CRIS-Team Scopus Importer:2021-05-28
Keywords: CD8; CTL; CTL epitope; HIV-1; HKU1; OC43; SARS-CoV-2 (2019-nCoV)

SARS-CoV-2 vaccination and risk of severe COVID-19 outcomes in patients with autoimmune hepatitis - Efe, Cumali; Tascilar, Koray; Gerussi, Alessio; Bolis, Francesca; Lammert, Craig; Ebik, Berat; Stättermayer, Albert Friedrich; Cengiz, Mustafa; Gökçe, Dilara Turan; Cristoferi, Laura; Peralta, Mirta; Massoumi, Hatef; et al. (Journal of Autoimmunity, 2022)
Background: Data regarding outcome of Coronavirus disease 2019 (COVID-19) in vaccinated patients with autoimmune hepatitis (AIH) are lacking. We evaluated the outcome of COVID-19 in AIH patients who received at least one dose of Pfizer- BioNTech (BNT162b2), Moderna (mRNA-1273) or AstraZeneca (ChAdOx1-S) vaccine. Patients and methods: We performed a retrospective study on AIH patients with COVID-19. The outcomes of AIH patients who had acute respiratory syndrome coronavirus 2 (SARS-CoV-2) breakthrough infection after at least one dose of COVID-19 vaccine were compared to unvaccinated patients with AIH. COVID-19 outcome was classified according to clinical state during the disease course as: (i) no hospitalization, (ii) hospitalization without oxygen supplementation, (iii) hospitalization with oxygen supplementation by nasal cannula or mask, (iv) intensive care unit (ICU) admission with non-invasive mechanical ventilation, (v) ICU admission with invasive mechanical ventilation or (vi) death, and data was analyzed using ordinal logistic regression. Results: We included 413 (258 unvaccinated and 155 vaccinated) patients (81%, female) with a median age of 52 (range: 17–85) years at COVID-19 diagnosis. The rates of hospitalization were (36.4% vs. 14.2%), need for any supplemental oxygen (29.5% vs. 9%) and mortality (7% vs. 0.6%) in unvaccinated and vaccinated AIH patients with COVID-19. Having received at least one dose of SARS-CoV-2 vaccine was associated with a significantly lower risk of worse COVID-19 severity, after adjusting for age, sex, comorbidities and presence of cirrhosis (adjusted odds ratio [aOR] 0.18, 95% confidence interval [CI], 0.10–0.31). Overall, vaccination against SARS-CoV-2 was associated with a significantly lower risk of mortality from COVID-19 (aOR 0.20, 95% CI 0.11–0.35). Conclusions: SARS-CoV-2 vaccination significantly reduced the risk of COVID-19 severity and mortality in patients with AIH.
CRIS-Team Scopus Importer:2022-09-16
Keywords: Autoimmunity; Breakthrough infection; Immunosuppression; Liver failure; Vaccine

SARS-CoV-2 vaccination responses in untreated, conventionally treated and anticytokine-treated patients with immune-mediated inflammatory diseases - Simon, David; Tascilar, Koray; Fagni, Filippo; Krönke, Gerhard; Kleyer, Arnd; Meder, Christine; Meder, Christine; Atreya, Raja; Leppkes, Moritz; Kremer, Andreas E.; Pachowsky, Milena; Schuch, Florian; et al. (Annals of the Rheumatic Diseases, 2021)
Objectives: To better understand the factors that influence the humoral immune response to vaccination against SARS-CoV-2 in patients with immune-mediated inflammatory diseases (IMIDs). Methods: Patients and controls from a large COVID-19 study, with (1) no previous history of COVID-19, (2) negative baseline anti-SARS-CoV-2 IgG test and (3) SARS-CoV-2 vaccination at least 10 days before serum collection were measured for anti-SARS-CoV-2 IgG. Demographic, disease-specific and vaccination-specific data were recorded. Results: Vaccination responses from 84 patients with IMID and 182 controls were analysed. While all controls developed anti-SARS-CoV-2 IgG, five patients with IMID failed to develop a response (p=0.003). Moreover, 99.5% of controls but only 90.5% of patients with IMID developed neutralising antibody activity (p=0.0008). Overall responses were delayed and reduced in patients (mean (SD): 6.47 (3.14)) compared with controls (9.36 (1.85); p<0.001). Estimated marginal means (95% CI) adjusted for age, sex and time from first vaccination to sampling were 8.48 (8.12-8.85) for controls and 6.90 (6.45-7.35) for IMIDs. Significantly reduced vaccination responses pertained to untreated, conventionally and anticytokine treated patients with IMID. Conclusions: Immune responses against the SARS-CoV-2 are delayed and reduced in patients with IMID. This effect is based on the disease itself rather than concomitant treatment.
CRIS-Team Scopus Importer:2021-05-21
Keywords: biological therapy; COVID-19; epidemiology; vaccination

Sars-Cov-2 Vaccine-Induced Cellular and Humoral Immunity in Patients after CD19.CAR-T Cell Therapy - Reimann, Hannah; Kremer, Anita; Blumenberg, Viktoria; Schmidt, Katja; Aigner, Michael; Kremer, Andreas; Tenbusch, Matthias; Bruns, Heiko; Harrer, Thomas; Schett, Georg; Müller, Fabian; Mackensen, Andreas; et al. (BLOOD, 2022)
CRIS-Team WoS Importer:2023-03-17

SARS-CoV-2 variant B.1.617 is resistant to bamlanivimab and evades antibodies induced by infection and vaccination - Hoffmann, Markus; Hofmann-Winkler, Heike; Krüger, Nadine; Kempf, Amy; Nehlmeier, Inga; Graichen, Luise; Arora, Prerna; Sidarovich, Anzhalika; Moldenhauer, Anna Sophie; Winkler, Martin S.; Schulz, Sebastian; Jäck, Hans-Martin; et al. (Cell Reports, 2021)
The emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants threatens efforts to contain the coronavirus disease 2019 (COVID-19) pandemic. The number of COVID-19 cases and deaths in India has risen steeply, and a SARS-CoV-2 variant, B.1.617, is believed to be responsible for many of these cases. The spike protein of B.1.617 harbors two mutations in the receptor binding domain, which interacts with the angiotensin converting enzyme 2 (ACE2) receptor and constitutes the main target of neutralizing antibodies. Therefore, we analyze whether B.1.617 is more adept in entering cells and/or evades antibody responses. B.1.617 enters two of eight cell lines tested with roughly 50% increased efficiency and is equally inhibited by two entry inhibitors. In contrast, B.1.617 is resistant against bamlanivimab, an antibody used for COVID-19 treatment. B.1.617 evades antibodies induced by infection or vaccination, although less so than the B.1.351 variant. Collectively, our study reveals that antibody evasion of B.1.617 may contribute to the rapid spread of this variant.
CRIS-Team Scopus Importer:2021-07-30
Keywords: antibodies; B.1.617; cell entry; convalescence; immune evasion; mutations; SARS-CoV-2; spike protein; vaccination

SARS-CoV-2 variants B.1.351 and P.1 escape from neutralizing antibodies - Hoffmann, Markus; Arora, Prerna; Groß, Rüdiger; Seidel, Alina; Hörnich, Bojan F.; Hahn, Alexander S.; Krüger, Nadine; Graichen, Luise; Hofmann-Winkler, Heike; Kempf, Amy; Winkler, Martin S.; Schulz, Sebastian; et al. (Cell, 2021)
The global spread of SARS-CoV-2/COVID-19 is devastating health systems and economies worldwide. Recombinant or vaccine-induced neutralizing antibodies are used to combat the COVID-19 pandemic. However, the recently emerged SARS-CoV-2 variants B.1.1.7 (UK), B.1.351 (South Africa), and P.1 (Brazil) harbor mutations in the viral spike (S) protein that may alter virus-host cell interactions and confer resistance to inhibitors and antibodies. Here, using pseudoparticles, we show that entry of all variants into human cells is susceptible to blockade by the entry inhibitors soluble ACE2, Camostat, EK-1, and EK-1-C4. In contrast, entry of the B.1.351 and P.1 variant was partially (Casirivimab) or fully (Bamlanivimab) resistant to antibodies used for COVID-19 treatment. Moreover, entry of these variants was less efficiently inhibited by plasma from convalescent COVID-19 patients and sera from BNT162b2-vaccinated individuals. These results suggest that SARS-CoV-2 may escape neutralizing antibody responses, which has important implications for efforts to contain the pandemic.
CRIS-Team Scopus Importer:2021-04-23
Keywords: antibodies; B.1.1.7; B.1.351; COVID-19; escape; host cell entry; neutralization; P.1; SARS-CoV-2; spike protein; variants; variants of concern; VOC

SARS-CoV-2 variants C.1.2 and B.1.621 (Mu) partially evade neutralization by antibodies elicited upon infection or vaccination - Arora, Prerna; Kempf, Amy; Nehlmeier, Inga; Graichen, Luise; Winkler, Martin S.; Lier, Martin; Schulz, Sebastian; Jäck, Hans-Martin; Cossmann, Anne; Stankov, Metodi V.; Behrens, Georg M.N.; Pöhlmann, Stefan; et al. (Cell Reports, 2022)
Rapid spread of SARS-CoV-2 variants C.1.2 and B.1.621 (Mu variant) in Africa and the Americas, respectively, as well as a high number of mutations in the viral spike proteins raised concerns that these variants might pose an elevated threat to human health. Here, we show that C.1.2 and B.1.621 spike proteins mediate increased entry into certain cell lines but do not exhibit increased ACE2 binding. Further, we demonstrate that C.1.2 and B.1.621 are resistant to neutralization by bamlanivimab but remain sensitive to inhibition by antibody cocktails used for COVID-19 therapy. Finally, we show that C.1.2 and B.1.621 partially escape neutralization by antibodies induced upon infection and vaccination, with escape of vaccine-induced antibodies being as potent as that measured for B.1.351 (Beta variant), which is known to be highly neutralization resistant. Collectively, C.1.2 and B.1.621 partially evade control by vaccine-induced antibodies, suggesting that close monitoring of these variants is warranted.
CRIS-Team Scopus Importer:2022-05-27
Keywords: antibody; B.1.621; C.1.2; COVID-19; CP: Immunology; CP: Microbiology; Mu; neutralization; SARS-CoV-2; spike; variants

SARS-CoV-2 worldwide replication drives rapid rise and selection of mutations across the viral genome: a time-course study – potential challenge for vaccines and therapies - Weber, Stefanie; Ramirez, Christina M.; Weiser, Barbara; Burger, Harold; Dörfler, Walter (Embo Molecular Medicine, 2021)
Scientists and the public were alarmed at the first large viral variant of SARS-CoV-2 reported in December 2020. We have followed the time course of emerging viral mutants and variants during the SARS-CoV-2 pandemic in ten countries on four continents. We examined > 383,500 complete SARS-CoV-2 nucleotide sequences in GISAID (Global Initiative of Sharing All Influenza Data) with sampling dates extending until April 05, 2021. These sequences originated from ten different countries: United Kingdom, South Africa, Brazil, United States, India, Russia, France, Spain, Germany, and China. Among the 77 to 100 novel mutations, some previously reported mutations waned and some of them increased in prevalence over time. VUI2012/01 (B.1.1.7) and 501Y.V2 (B.1.351), the so-called UK and South Africa variants, respectively, and two variants from Brazil, 484K.V2, now called P.1 and P.2, increased in prevalence. Despite lockdowns, worldwide active replication in genetically and socio-economically diverse populations facilitated selection of new mutations. The data on mutant and variant SARS-CoV-2 strains provided here comprise a global resource for easy access to the myriad mutations and variants detected to date globally. Rapidly evolving new variant and mutant strains might give rise to escape variants, capable of limiting the efficacy of vaccines, therapies, and diagnostic tests.
CRIS-Team Scopus Importer:2021-06-11
Keywords: high incidence of C to T transitions; numerous new mutations; South African and Brazil variants; time course of SARS-CoV-2 mutant emergence; UK variant B.1.1.7

Saying NO to H2S - Miljkovic, Jan; Eberhardt, Miriam; Herrmann, Martin; Meßlinger, Karl; Reeh, Peter; Ivanovic-Burmazovic, Ivana; Filipovic, Milos (Nitric Oxide-Biology and Chemistry, 2013)

Scleroderma and Radiation Sensitivity - Schenker, Hannah; Schuster, Barbara; Fietkau, Rainer; Distel, Luitpold (STRAHLENTHERAPIE UND ONKOLOGIE, 2019)
CRIS-Team WoS Importer:2019-06-07

Scleroderma renal crisis: Risk factors for an increasingly rare organ complication - Moinzadeh, Pia; Kuhr, Kathrin; Siegert, Elise; Blank, Norbert; Sunderkoetter, Cord; Henes, Jörg; Krusche, Martin; Schmalzing, Marc; Worm, Margitta; Schmeiser, Tim; Günther, Claudia; Aberer, Elisabeth; et al. (Journal of Rheumatology, 2020)
Objective. Scleroderma renal crisis (SRC) is a severe life-threatening manifestation in patients with systemic sclerosis (SSc). However, the knowledge about risk factors for SRC is limited. We determined here the frequency of SRC and identified risk factors for the prediction of SRC. Methods. Based on regular followup data from the German Network for Systemic Scleroderma, we used univariate and multivariate generalized estimating equations to analyze the association between clinical variables, SSc subsets, therapy [i.e., angiotensin-converting enzyme inhibitors (ACEi), corticosteroids], and the occurrence of SRC. Results. Data of 2873 patients with 10,425 visits were available for analysis with a mean number of registry visits of 3.6 ± 2.8 and a mean time of followup of 3.6 ± 3.8 years. In total, 70 patients developed SRC (70/2873, 2.4%). Of these patients, 57.1% (40/70) were diagnosed with diffuse cutaneous SSc, 31.4% (22/70) with limited cutaneous SSc, and 11.4% (8/70) with SSc-overlap syndromes. Predictive independent factors with the highest probability for SRC were positive anti-RNA polymerase antibodies (RNAP), a history of proteinuria prior to SRC onset, diminished DLCO, and a history of hypertension. Interestingly, positive antitopoisomerase autoantibodies did not predict a higher risk for SRC. Further, patients with SRC were significantly more frequently treated with ACEi and corticosteroids without being independently associated with SRC. Conclusion. In this cohort, SRC has become a rare complication. By far the highest risk for SRC was associated with the detection of anti-RNAP and proteinuria.
CRIS-Team Scopus Importer:2020-02-25
Keywords: German network for systemic scleroderma; Renal crisis; Scleroderma; Scleroderma renal crisis; Systemic sclerosis

Sclerostin and DKK1 levels during 14 and 21 days of bed rest in healthy young men - Frings-Meuthen, P; Boehme, G; Liphardt, Anna-Maria; Baecker, N; Heer, M; Rittweger, J (The Journal of Musculoskeletal and Neuronal Interactions, 2013)
Wnt signaling pathway may be crucial in the pathogenesis of disuse-induced bone loss. Sclerostin and DKK1, antagonists of the Wnt signaling pathway, were assessed during immobilization by bed rest in young, healthy people.Two bed rest studies were conducted at the German Aerospace Center in Cologne. 14 days of 6° head-down-tilt bed rest were applied to eight healthy young male test subjects in study 1 and 21 days of head-down-tilt bed rest to seven healthy male subjects in study 2.Sclerostin levels increased in both studies during bed rest (study 1, 0.64±0.05 ng/ml to 0.69±0.04 ng/ml, P=0.014; study 2, 0.42±0.04 ng/ml to 0.47±0.04 ng/ml, P=0.008) and they declined at the end of the 14- and 21-day bed rest periods. DKK1 decreased during the bed rest period in study 1 (P<0.001) but increased during bed rest in study 2 (P=0.006). As expected, bone formation marker PINP decreased (study 1, P=0.013; study 2, P<0.001) and bone resorption marker NTX increased during bed rest (P<0.001).Data suggest that the Wnt signaling pathway is involved in disuse-induced bone loss in young, healthy humans.
EVALuna2:13506

Scurvy : A rare differential diagnosis of rheumatic diseases - Hofheinz, K.; Ganzleben, Ingo; Schliep, S.; Wacker, J.; Schett, Georg; Manger, Bernhard (Zeitschrift für Rheumatologie, 2016)
In December 2014 a patient presented to our clinic with the clinical symptoms of vasculitis. However, treatment with glucocorticoids did not lead to any improvement; therefore, the differential diagnostics were extended to other indications and ultimately led to the diagnosis of scurvy.This article describes the clinical picture of scurvy and its relationship to rheumatic diseases based on a clinical case and additional information from the literature. Differences and similarities with important rheumatological disease symptoms are presented.Scurvy is a rare hypovitaminosis disease which can be manifested in different forms. In addition to vasculitis the symptoms can also resemble arthritis and hemarthrosis is a typical finding. These symptoms can be accompanied by unspecific manifestations, such as muscle pain and due to impaired collagen synthesis characteristic features, such as corkscrew hair can be observed. The causal therapy of scurvy is substitution of ascorbic acid.Scurvy is a rare differential diagnosis in the context of rheumatic diseases. The indications for scurvy can be a lack of response to immunosuppressive and immunomodulatory drugs as well as individual symptoms, such as corkscrew hair.
EVALuna2:2047

SECUKINUMAB EFFICACY IN PATIENTS WITH ACTIVE PSORIATIC ARTHRITIS: META-ANALYSIS OF 4 PHASE 3 TRIALS - Mease, Philip; Kirkham, Bruce; Nash, Peter; Balsa, Alejandro; Combe, Bernard; Rech, Jürgen; Martin, Ruvie; Ligozio, Gregory; Abrams, Ken; Pricop, Luminita (2018)
EVALuna2:35015

Secukinumab Efficacy in Psoriatic Arthritis: Individual Patient Meta-Analysis of Four Phase 3 Trials in 2049 Patients - Gottlieb, Alice B.; Mease, Philip J.; Kirkham, Bruce; Nash, Peter; Balsa, Alejandro; Combe, Bernard; Rech, Jürgen; Martin, Ruvie; Ligozio, Gregory; Abrams, Ken; Pricop, Luminita (2018)
EVALuna2:34959

Secukinumab Efficacy in Psoriatic Arthritis: Machine Learning and Meta-analysis of Four Phase 3 Trials - Gottlieb, Alice B.; Mease, Philip J.; Kirkham, Bruce; Nash, Peter; Balsa, Alejandro C.; Combe, Bernard; Rech, Jürgen; Zhu, Xuan; James, David; Martin, Ruvie; Ligozio, Gregory; Abrams, Ken; et al. (Jcr-Journal of Clinical Rheumatology, 2021)
Background Using a machine learning approach, the study investigated if specific baseline characteristics could predict which psoriatic arthritis (PsA) patients may gain additional benefit from a starting dose of secukinumab 300 mg over 150 mg. We also report results from individual patient efficacy meta-analysis (IPEM) in 2049 PsA patients from the FUTURE 2 to 5 studies to evaluate the efficacy of secukinumab 300 mg, 150 mg with and without loading regimen versus placebo at week 16 on achievement of several clinically relevant difficult-to-achieve (higher hurdle) endpoints. Methods Machine learning employed Bayesian elastic net to analyze baseline data of 2148 PsA patients investigating 275 predictors. For IPEM, results were presented as difference in response rates versus placebo at week 16. Results Machine learning showed secukinumab 300 mg has additional benefits in patients who are anti-tumor necrosis factor-naive, treated with 1 prior anti-tumor necrosis factor agent, not receiving methotrexate, with enthesitis at baseline, and with shorter PsA disease duration. For IPEM, at week 16, all secukinumab doses had greater treatment effect (%) versus placebo for higher hurdle endpoints in the overall population and in all subgroups; 300-mg dose had greater treatment effect than 150 mg for all endpoints in overall population and most subgroups. Conclusions Machine learning identified predictors for additional benefit of secukinumab 300 mg compared with 150 mg dose. Individual patient efficacy meta-analysis showed that secukinumab 300 mg provided greater improvements compared with 150 mg in higher hurdle efficacy endpoints in patients with active PsA in the overall population and most subgroups with various levels of baseline disease activity and psoriasis.
CRIS-Team Scopus Importer:2021-09-17
Keywords: biologics; efficacy; interleukin; machine learning; TNF inhibitors

SECUKINUMAB EFFICACY IN PSORIATIC ARTHRITIS PATIENTS WITH OR WITHOUT ENTHESITIS AT BASELINE - POOLED ANALYSIS FROM TWO PHASE-III TRIALS OVER 2 YEARS - Wallman, J. K.; Schett, Georg; Mcinnes, I. B.; Quebe-Fehling, E.; Rasouliyan, L.; Pricop, L.; Fasth, A. E.; Gaillez, C. (2018)
EVALuna2:34978

Secukinumab Efficacy on Enthesitis in Patients With Ankylosing Spondylitis: Pooled Analysis of Four Pivotal Phase III Studies - Schett, Georg; Baraliakos, Xenofon; Van Den Bosch, Filip; Deodhar, Atul; Ostergaard, Mikkel; Das Gupta, Ayan; Mpofu, Shephard; Fox, Todd; Winseck, Adam; Porter, Brian; Shete, Abhijit; Gensler, Lianne S. (Journal of Rheumatology, 2021)
Objective: To assess the efficacy of secukinumab on axial and peripheral enthesitis in patients with ankylosing spondylitis (AS) using pooled data from randomized controlled phase III studies.
CRIS-Team WoS Importer:2021-08-13

Secukinumab efficacy on resolution of enthesitis in psoriatic arthritis: pooled analysis of two phase 3 studies - Coates, Laura C.; Wallman, Johan K.; McGonagle, Dennis; Schett, Georg; McInnes, Iain B.; Mease, Philip J.; Rasouliyan, Lawrence; Quebe-Fehling, Erhard; Asquith, Darren L.; Fasth, Andreas E.R.; Pricop, Luminita; Gaillez, Corine (Arthritis Research & Therapy, 2019)
BACKGROUND: Enthesitis is one of the psoriatic arthritis (PsA) domains. Patients with enthesitis are associated with worse outcomes than those without enthesitis. The effect of secukinumab on the resolution of enthesitis in patients with PsA was explored using pooled data from the FUTURE 2 and 3 studies. METHOD: Assessments of enthesitis through week 104 used the Leeds Enthesitis Index. These post hoc analyses included resolution of enthesitis count (EC = 0), median time to first resolution of enthesitis (Kaplan-Meϊer estimate), and shift analysis (as observed) of baseline EC (1, 2, or 3-6) to full resolution (FR), stable (similar or reduction of EC), or worse (EC > baseline). Efficacy outcomes (ACR, PASI, HAQ-DI, SF-36 PCS, and DAS28-CRP) were assessed in patients with or without baseline enthesitis. Results are reported for secukinumab 300 and 150 mg in the overall population and by prior TNFi treatment. RESULTS: A total of 65% (466/712) of patients had baseline enthesitis. In the overall population, FR was achieved as early as week 16 in 65% (300 mg) and 56% (150 mg) versus 44% (placebo) patients, with further improvements to 91% (300 mg) and 88% (150 mg) at week 104. The majority (89%) of patients without enthesitis at baseline maintained this status at week 104. Median days to resolution of EC were shorter with secukinumab 300 and 150 mg versus placebo (57 and 85 vs 167 days, respectively). In patients with EC of 1 or 2, shift analysis from baseline to week 24 showed that more patients achieved FR with secukinumab 300 mg and 150 mg versus placebo, whereas no difference between secukinumab and placebo was shown in the more severe patients with EC of 3-6. Increases in proportions of patients with FR were observed with secukinumab irrespective of the severity of EC from baseline to week 104. Improvements in efficacy outcomes were similar in patients with or without enthesitis treated with secukinumab 300 mg. CONCLUSION: Secukinumab provided early and sustained resolution of enthesitis in patients with PsA over 2 years. Secukinumab 300 mg provided higher resolution than 150 mg in patients with more severe baseline EC and showed similar overall efficacy in patients with or without enthesitis. TRIAL REGISTRATION: FUTURE 2: ClinicalTrials.gov, NCT01752634 (date of study registration: December 19, 2012), and EudraCT, 2012-004439-22 (date of study registration: December 12, 2012) FUTURE 3: ClinicalTrials.gov, NCT01989468 (date of study registration: November 21, 2013), and EudraCT, 2013-004002-25 (date of study registration: December 17, 2013).
CRIS-Team Scopus Importer:2019-12-17
Keywords: Anti-TNF; Biologics; Enthesitis; Interleukin 17A inhibitor; Psoriatic arthritis; Secukinumab

Secukinumab for the treatment of psoriasis, psoriatic arthritis, and axial spondyloarthritis: Physical and pharmacological properties underlie the observed clinical efficacy and safety - Kolbinger, Frank; Di Padova, Franco; Deodhar, Atul; Hawkes, Jason E.; Huppertz, Christine; Kuiper, Torsten; McInnes, Iain B.; Ritchlin, Christopher T.; Rosmarin, David; Schett, Georg; Carballido, José M.; Häusermann, Peter; et al. (Pharmacology & Therapeutics, 2021)
Psoriasis, psoriatic arthritis, and axial spondyloarthritis are systemic inflammatory diseases, each commonly manifesting as a spectrum of symptoms, complications, and comorbidities that arise differently in individual patients. Drugs targeting inflammatory cytokines common to the pathogenesis of each of these conditions have been developed, although their specific actions in the different tissues involved are variable. For a drug to be effective, it must be efficiently delivered to and locally bioactive in disease-relevant tissues. Detailed clinical data shed light on the therapeutic effects of individual biologics on specific domains or clinical manifestations of disease and assist in guiding treatment decisions. Pharmacologic, molecular, and functional properties of drugs strongly impact their observed safety and efficacy, and an understanding of these properties provides complementary insight. Secukinumab, a fully human monoclonal IgG1/κ antibody selectively targeting interleukin (IL)-17A, has been in clinical use for >6 years in the treatment of moderate to severe psoriasis, psoriatic arthritis, and both radiographic (also known as ankylosing spondylitis) and nonradiographic axial spondyloarthritis. In this review, we discuss pharmacokinetic and pharmacodynamic data for secukinumab to introduce clinicians to the pharmacological properties of this widely used drug. Understanding how these properties affect the observed clinical efficacy, safety, and tolerability of this drug in the treatment of IL-17A–mediated systemic inflammatory diseases is important for all physicians treating these conditions.
CRIS-Team Scopus Importer:2021-07-30
Keywords: Axial spondyloarthritis; Biologics; IL-17; Psoriasis; Psoriatic arthritis; Secukinumab

SECUKINUMAB IMPROVES CLINICAL AND IMAGING OUTCOMES IN PATIENTS WITH PSORIATIC ARTHRITIS AND AXIAL MANIFESTATIONS WITH INADEQUATE RESPONSE TO NSAIDS: WEEK 52 RESULTS FROM THE MAXIMISE TRIAL - Baraliakos, X.; Gossec, L.; Pournara, E.; Jeka, S.; Blanco, R.; D'Angelo, S.; Schett, Georg; Schulz, B.; Rissler, M.; Nagar, K.; Perella, C.; Coates, L. C. (ANNALS OF THE RHEUMATIC DISEASES, 2020)
CRIS-Team WoS Importer:2020-08-21

Secukinumab in Giant Cell Arteritis: A Randomized, Parallel-group, Double-blind, Placebo-controlled, Multicenter Phase 2 Trial - Venhoff, Nils; Schmidt, Wolfgang; Bergner, Raoul; Rech, Jürgen; Unger, Leonore; Tony, Hans-Peter; Mendelson, Meryl; Sieder, Christian; Maricos, Meron; Thiel, Jens (ARTHRITIS & RHEUMATOLOGY, 2021)
CRIS-Team WoS Importer:2022-03-11

SECUKINUMAB IN GIANT CELL ARTERITIS: THE RANDOMISED, PARALLEL-GROUP, DOUBLE-BLIND, PLACEBO-CONTROLLED, MULTICENTRE PHASE 2 TITAIN TRIAL - Venhoff, N.; Schmidt, W. A.; Bergner, R.; Rech, Jürgen; Unger, L.; Tony, H. P.; Mendelson, M.; Sieder, C.; Maricos, M.; Thiel, J. (ANNALS OF THE RHEUMATIC DISEASES, 2022)
CRIS-Team WoS Importer:2022-11-04

Secukinumab in the treatment of psoriatic arthritis: Efficacy and safety results through 3 years from the year 1 extension of the randomised phase III FUTURE 1 trial - Mease, Philip J.; Kavanaugh, Arthur; Reimold, Andreas; Tahir, Hasan; Rech, Jürgen; Hall, Stephen; Geusens, Piet; Pellet, Pascale; Delicha, Evie Maria; Mpofu, Shephard; Pricop, Luminita (RMD Open, 2018)
Objective To assess the long-term (3 year) efficacy and safety of secukinumab in patients with active psoriatic arthritis (PsA) in the extension phase of the FUTURE 1 study (NCT01892436). Methods Following the 2-year core trial, eligible patients receiving subcutaneous secukinumab 150 or 75 mg entered a 3-year extension phase. Results are presented for key efficacy and safety endpoints at week 156. Results In total, 460 patients entered the extension study; 308 patients originally randomised to secukinumab were assessed for efficacy. Sustained improvements in all efficacy endpoints were achieved with secukinumab through week 156. Overall, 76.8%/54.9% (secukinumab 150 mg) and 65.2%/39.0% (secukinumab 75 mg) of patients achieved an American College of Rheumatology (ACR) 20/50 response (multiple imputation data); ACR20 responses were sustained irrespective of previous anti-tumour necrosis factor exposure. Improvements in quality of life and physical function were also sustained through week 156. Radiographic results (observed data; van der Heijde modified total Sharp score (mTSS)) showed that 78.1% (secukinumab 150 mg) and 74.8% (secukinumab 75 mg) of patients had no radiographic progression (≤0.5 increase in mTSS) through week 156. Exposure-adjusted incidence rates for selected adverse events per 100 patient-years (secukinumab 150/75 mg) were serious infections (1.7/1.6), Candida infections (1.4/0.7), Crohn's disease (0/0.3), ulcerative colitis (0/0.3) and major adverse cardiac events (0.3/0.8). Conclusion Subcutaneous secukinumab provided sustained improvements in the signs and symptoms, quality of life and physical function of patients with active PsA with low rate of radiographic disease progression through 3 years. Secukinumab was well tolerated with no new safety signals.
CRIS-Team Scopus Importer:2021-02-03
Keywords: biological therapy; IL-17A; psoriatic arthritis; radiography; secukinumab

Secukinumab leads to shifts from stage-based towards response-based disease clusters-comparative data from very early and established psoriatic arthritis - Kampylafka, Eleni; Tascilar, Koray; Lerchen, Veronika; Linz, Christina; Sokolova, Maria; Zekovic, Ana; Kleyer, Arnd; Simon, David; Rech, Jürgen; Sticherling, Michael; Schett, Georg; Hueber, Axel (Arthritis Research & Therapy, 2020)
Background: Limited information exists about the very early forms of psoriatic arthritis. In particular, differences and responsiveness of patient-reported outcomes (PROs) in very early as compared to established PsA have not been investigated to date. Methods: Cross-sectional and prospective longitudinal evaluation of PROs related to pain (VAS), physical function (HAQ-DI, SF-36 physical), mental function (SF-36 mental), impact of psoriatic skin (DLQI), joint (PsAID), and global disease (VAS) in two small prospective observational studies on secukinumab 300 mg over 6 months in very early disease patients (IVEPSA study, N = 20) and established PsA (PSARTROS study, N = 20). Cluster analysis was performed at baseline and 24-weeks of follow-up. Results: While responses in pain and physical activity-related PROs to secukinumab were more pronounced in established PsA than a very early disease, effects on PROs related to general health perception, as well as those related to emotional and mental well-being, were modified in a similar way in very early disease and established PsA. Cluster analysis based on global disease activity and PROs showed that baseline clusters reflected very early disease and established PsA, while after secukinumab treatment these clusters were abolished and new clusters based on differential responses to physically and mentally oriented PROs formed. Conclusions: Inhibition of IL-17A by secukinumab leads to comprehensive improvement of general health perception and mental well-being in very early and established PsA, while overall responses in pain and physical activity are more pronounced in established disease. Most importantly, treatment restructures the original patients' clusters based on disease stage and leads to the formation of new clusters that reflect their response in physical and mental-orientated PROs. Trial registration: NCT02483234, registered 26 June 2015, retrospectively registered.
CRIS-Team Scopus Importer:2020-10-02
Keywords: Cluster analysis; IL-17A; Psoriatic arthritis; Quality of life; Secukinumab

SECUKINUMAB PROVIDES RAPID AND SUSTAINED PAIN RELIEF IN PSORIATIC ARTHRITIS: 2-YEAR RESULTS FROM THE FUTURE 2 STUDY - Mcinnes, I. B.; Mease, P. J.; Schett, Georg; Kirkham, B.; Strand, V.; Williams, N.; Fox, T.; Pricop, L.; Jugl, S.; Gandhi, K. K. (2017)
EVALuna2:35031

Secukinumab provides rapid and sustained pain relief in psoriatic arthritis over 2 years: results from the FUTURE 2 study - Mcinnes, Iain B.; Mease, Philip J.; Schett, Georg; Kirkham, Bruce; Strand, Vibeke; Williams, Nicole; Fox, Todd; Pricop, Luminita; Jugl, Steffen M.; Gandhi, Kunal K. (Arthritis Research & Therapy, 2018)
BACKGROUND: Pain is one of the most important domains affecting health-related quality of life (HRQoL) in patients with psoriatic arthritis (PsA). Secukinumab has demonstrated rapid and sustained improvements in signs and symptoms, including HRQoL, among patients with active PsA. This analysis evaluates the effect of secukinumab on patient-reported pain in PsA through 104 weeks of treatment. METHODS: Pain was assessed through week 104 using clinically relevant measures, including change from baseline in a pain visual analog scale (VAS) and Short Form-36 (SF-36) bodily domain scores; proportion of patients reporting improvements equal to or better than minimum clinically meaningful differences in the pain VAS and SF-36 bodily pain domain scores; and proportion of patients with no, moderate, or extreme pain/discomfort measured by the EuroQoL 5-Dimension 3-Level Questionnaire (EQ-5D-3 L) pain item scores. Correlations of pain measures were analyzed using Pearson's correlation coefficient. Pre-specified analyses of TNF-naïve patients and patients who stopped TNF-inhibitors (TNFis) due to inadequate responses or safety/tolerability (TNF-IR patients) were performed using "as-observed data." RESULTS: Mean improvements from baseline in pain VAS scores were greater with secukinumab versus placebo by week 3 (- 16.9; P < 0.0001 with secukinumab 300 mg and - 12.6; P < 0.05 with secukinumab 150 mg) and sustained through week 104. SF-36 bodily pain domain scores were significantly greater with 300 mg secukinumab and secukinumab 150 mg versus placebo by week 4 (16.2 and 16.3, respectively; P < 0.0001 for both), and these changes were maintained through week 104. With both secukinumab 300 mg and secukinumab 150 mg, improvements equal to or better than the minimum clinically meaningful differences in pain VAS and SF-36 bodily pain were significant versus placebo at week 3 and week 4, respectively. At week 4, 15%, 9%, and 5% of patients receiving secukinumab 300 mg, secukinumab 150 mg, and placebo, respectively, reported "no pain/discomfort" measured by EQ-5D-3 L; these proportions increased to week 104 with both secukinumab doses. Similarly, improvements in pain measures were significant in both TNF-naïve and TNF-IR patients. CONCLUSION: Secukinumab provided rapid and sustained pain relief in PsA over 2 years of treatment. Improvements in pain were reported regardless of prior exposure to TNFis. TRIAL REGISTRATION: ClinicalTrials.gov, NCT01752634 . Registered on 19 December 2012.
EVALuna2:34468

SECUKINUMAB PROVIDES RAPID AND SUSTAINED RESOLUTION OF ENTHESITIS IN PSORIATIC ARTHRITIS PATIENTS: POOLED ANALYSIS OF TWO PHASE 3 STUDIES, FUTURE 2 AND FUTURE 3 - Coates, Laura C.; Mcgonagle, Dennis; Schett, Georg; Mease, Philip J.; Quebe-Fehling, Erhard; Asquith, Darren L.; Rasouliyan, Lawrence; Mpofu, Shephard; Gaillez, Corine (2018)
EVALuna2:34474

SECUKINUMAB PROVIDES RAPID AND SUSTAINED RESOLUTION OF ENTHESITIS IN PSORIATIC ARTHRITIS PATIENTS: POOLED ANALYSIS OF TWO PHASE 3 STUDIES, FUTURE 2 AND FUTURE 3 - Coates, Laura C.; Mcgonagle, Dennis; Schett, Georg; Mease, Philip J.; Quebe-Fehling, Erhard; Asquith, Darren L.; Rasouliyan, Lawrence; Mpofu, Shepard; Gaillez, Corine (2019)
EVALuna2:213228

SECUKINUMAB PROVIDES SUSTAINED IMPROVEMENT OF ENTHESITIS IN PATIENTS WITH ANKYLOSING SPONDYLITIS: POOLED ANALYSIS OF FOUR PIVOTAL PHASE 3 STUDIES - Schett, Georg; Baraliakos, Xenofon; Van Den Bosch, Filip; Deodhar, Atul; Gensler, Lianne S.; Ostergaard, Mikkel; Agawane, Shital; Das Gupta, Ayan; Mpofu, Shephard; Fox, Todd; Winseck, Adam; Shete, Abhijit; et al. (ANNALS OF THE RHEUMATIC DISEASES, 2019)
CRIS-Team WoS Importer:2019-07-12

Secukinumab Provides Sustained Improvements in Clinical and Imaging Outcomes in Patients with Psoriatic Arthritis and Axial Manifestations: Results from the MAXIMISE Trial - Baraliakos, Xenofon; Gossec, Laure; Pournara, Effie; Jeka, Slawomir; Blanco, Ricardo; D'Angelo, Salvatore; Schett, Georg; Schulz, Barbara; Rissler, Michael; Whyms, Dermot; Perella, Chiara; Coates, Laura (ARTHRITIS & RHEUMATOLOGY, 2020)
CRIS-Team WoS Importer:2021-01-15

Secukinumab Provides Sustained Improvements in the Signs and Symptoms in Psoriatic Arthritis: Final 5 Year Efficacy and Safety Results from a Phase 3 Trial - Mease, Philip J.; Kavanaugh, Arthur; Reimold, Andreas; Tahir, Hasan; Rech, Jürgen; Hall, Stephen; Geusens, Piet; Pascale, Pellet; Delicha, Evie Maria; Pricop, Luminita; Mpofu, Shephard (2018)
EVALuna2:34966

Secukinumab provides sustained improvements in the signs and symptoms in psoriatic arthritis: final 5-year efficacy and safety results from the FUTURE 1 Phase 3 trial - Tahir, Hasan; Mease, Philip J.; Kavanaugh, Arthur; Reimold, Andreas; Rech, Jürgen; Hall, Stephen; Geusens, Piet; Pellet, Pascale; Delicha, Eumorphia Maria; Pricop, Luminita; Mpofu, Shephard (RHEUMATOLOGY, 2019)
CRIS-Team WoS Importer:2019-08-13

SECUKINUMAB PROVIDES SUSTAINED IMPROVEMENTS IN THE SIGNS AND SYMPTOMS OF ACTIVE PSORIATIC ARTHRITIS: 2-YEAR EFFICACY AND SAFETY RESULTS FROM THE PHASE 3 RANDOMISED, DOUBLE-BLIND, PLACEBO-CONTROLLED TRIAL, FUTURE 1 - Kavanaugh, A.; Mease, P.; Reimold, A.; Tahir, H.; Rech, Jürgen; Hall, S.; Geusens, P.; Wang, Z.; Mpofu, S. (2016)
EVALuna2:35076

Secukinumab provides sustained improvements in the signs and symptoms of active psoriatic arthritis: 2-year efficacy and safety results from the phase 3 randomised, double-blind, placebo-controlled trial FUTURE 1 - Rech, Jürgen; Reinhardt, M.; Kavanaugh, A.; Geusens, P.; Mpofu, S. (2017)
EVALuna2:35049

SECUKINUMAB PROVIDES SUSTAINED IMPROVEMENTS IN THE SIGNS AND SYMPTOMS OF ACTIVE PSORIATIC ARTHRITIS: 3-YEAR EFFICACY AND SAFETY RESULTS FROM PHASE 3 FUTURE 1 TRIAL - Mease, P. J.; Kavanaugh, A.; Reimold, A.; Tahir, H.; Rech, Jürgen; Hall, S.; Geusens, P.; Pascale, P.; Delicha, E. M.; Pricop, L.; Mpofu, S. (2017)
EVALuna2:35040

Secukinumab Provides Sustained Improvements in the Signs and Symptoms of Active Psoriatic Arthritis: Long-Term (4-Year) Data from a Phase 3 Study - Mcinnes, Iain B.; Kivitz, Alan J.; Nash, Peter; Rahman, Proton; Rech, Jürgen; Kirkham, Bruce; Navarra, Sandra V.; Ding, Kevin; Ilsley, Emma; Pricop, Luminita (2018)
EVALuna2:34965

SECUKINUMAB PROVIDES SUSTAINED IMPROVEMENTS IN THE SIGNS AND SYMPTOMS OF ACTIVE PSORIATIC ARTHRITIS (PSA) THROUGH 3 YEARS: EFFICACY AND SAFETY RESULTS FROM A PHASE 3 TRIAL - Hall, S.; Mease, P.; Kavanaugh, A.; Reimold, A.; Tahir, H.; Rech, Jürgen; Geusens, P.; Pascale, P.; Delicha, E.; Pricop, L.; Mpofu, S. (2017)
EVALuna2:35048

Secukinumab Provides Sustained Improvements in the Signs and Symptoms of Active Psoriatic Arthritis through 3 Years: Efficacy and Safety Results from a Phase 3 Trial - Mease, Philip J.; Kavanaugh, Arthur; Reimold, Andreas; Tahir, Hasan; Rech, Jürgen; Hall, Stephen; Geusens, Piet; Pascale, Pellet; Delicha, Evie Maria; Pricop, Luminita; Mpofu, Shephard (2016)
EVALuna2:35063

Secukinumab Provides Sustained Improvements in the Signs and Symptoms of Psoriatic Arthritis: Final 5-year Results from the Phase 3 FUTURE 1 Study - Mease, Philip J.; Kavanaugh, Arthur; Reimold, Andreas; Tahir, Hasan; Rech, Jürgen; Hall, Stephen; Geusens, Piet; Pellet, Pascale; Delicha, Eumorphia Maria; Pricop, Luminita; Mpofu, Shephard (ACR Open Rheumatology, 2020)
ObjectiveTo report the 5-year efficacy and safety of secukinumab in the treatment of patients with psoriatic arthritis (PsA) in the FUTURE 1 study (NCT01392326).
CRIS-Team WoS Importer:2021-07-16

Secukinumab Significantly Decreased Joint Synovitis Measured by Power Doppler Ultrasonography in Biologic-naive Patients with Active Psoriatic Arthritis: Primary (12-Week) Results from a Randomized, Placebo-Controlled Phase III Study - D'Agostino, Maria; Schett, Georg; Lopez-Rdz, Alejandra; Senolt, Ladislav; Maldonado-Cocco, Jose; Burgos-Vargas, Ruben; Naredo, Esperanza; Carron, Philippe; Boers, Maarten; Duggan, Anne-Marie; Goyanka, Punit; Gaillez, Corine (ARTHRITIS & RHEUMATOLOGY, 2020)
CRIS-Team WoS Importer:2021-01-15

Secukinumab Treatment Provides Sustained Resolution of Enthesitis at Individual Joints Through 52 Weeks in a Phase 3b, Double-Blind, Randomized, Active-Controlled Study - Kaeley, Gurjit; Schett, Georg; Conaghan, Philip; Mcgonagle, Dennis; Behrens, Frank; Goupille, Philippe; Gaillez, Corine; Parikh, Bhumik; Meng, Xiangyi; Bakewell, Catherine (ARTHRITIS & RHEUMATOLOGY, 2021)
CRIS-Team WoS Importer:2022-03-11

Segmentation and quantification of bone erosions in high-resolution peripheral quantitative computed tomography datasets of the metacarpophalangeal joints of patients with rheumatoid arthritis - Toepfer, Dominique; Finzel, Stephanie; Museyko, Oleg; Schett, Georg; Engelke, Klaus (Rheumatology, 2014)
Objective. To develop a precise three-dimensional (3D) segmentation technique for bone erosions in high-resolution peripheral quantitative CT (HR-pQCT) datasets to measure their volume, surface area and shape parameters. Assessment of bone erosions in patients with RA is important for diagnosis and evaluation of treatment efficacy. HR-pQCT allows quantifying periarticular bone loss in arthritis. Methods. HR-pQCT scans with a spatial resolution of about 120 µm of the second to fourth metacarpophalangeal joints were acquired in patients with RA. Erosions were identified by placing a seed point in each of them. After applying 3D segmentation, the volume, surface area and sphericity of erosions were calculated. Results were compared with an approximation method using manual measurements. Intra- and interoperator precision analysis was performed for both the 3D segmentation and the manual technique. Results. Forty-three erosions were assessed in 18 datasets. Intra- and interoperator precisions (RMSCV/RMSSD) for erosion volume were 5.66%/0.49 mm(3) and 7.76%/0.76 mm(3), respectively. The correlation between manual measurements and their simulation using segmentation volumes was r = 0.87. Precision errors for the manual method were 15.39% and 0.36 mm(3), respectively. Conclusion. We developed a new precise 3D segmentation technique for quantification of bone erosions in HR-pQCT datasets that correlates to the volume, shape and surface area of the erosion. The technique allows fast and effective measurement of the erosion size and could therefore be helpful for rapid and quantitative assessment of erosion size.
EVALuna2:10057

Segmentation of the Fascia Lata in Magnetic Resonance Images of the Thigh: Comparison of an Unsupervised Technique with a U-Net in 2D and Patch-wise 3D - Louise P, Lis J.; Engelke, Klaus; Chaudry, Oliver (Informatik aktuell, 2021)
To quantify muscle properties in the thigh, the segmentation of the fascia lata is crucial. For this purpose, the U-Net architecture was implemented and compared for 2D images and patched 3D image stacks in magnetic resonance images (MRI). The training data consisted of T1 MRI data sets from elderly men. To test the performance of the models, they were applied on other data sets of different age groups and gender. The U-Net approaches were superior to an unsupervised semiautomatic method and reduced post-processing time.
CRIS-Team Scopus Importer:2021-04-19

Selective Expression of the MAPK Phosphatase Dusp9/MKP-4 in Mouse Plasmacytoid Dendritic Cells and Regulation of IFN-? Production - Niedzielska, Magdalena; Mohamed Raffi, Faizal Ali; Tel, Jurjen; Muench, Sandra; Jozefowski, Katrin; Alati, Nour; Lahl, Katharina; Mages, Joerg; Billmeier, Ulrike; Schiemann, Matthias; Appelt, Uwe K.; Wirtz, Stefan; et al. (Journal of Immunology, 2015)
Plasmacytoid dendritic cells (pDCs) efficiently produce large amounts of type I IFN in response to TLR7 and TLR9 ligands, whereas conventional DCs (cDCs) predominantly secrete high levels of the cytokines IL-10 and IL-12. The molecular basis underlying this distinct phenotype is not well understood. In this study, we identified the MAPK phosphatase Dusp9/MKP-4 by transcriptome analysis as selectively expressed in pDCs, but not cDCs. We confirmed the constitutive expression of Dusp9 at the protein level in pDCs generated in vitro by culture with Flt3 ligand and ex vivo in sorted splenic pDCs. Dusp9 expression was low in B220(-) bone marrow precursors and was upregulated during pDC differentiation, concomitant with established pDC markers. Higher expression of Dusp9 in pDCs correlated with impaired phosphorylation of the MAPK ERK1/2 upon TLR9 stimulation. Notably, Dusp9 was not expressed at detectable levels in human pDCs, although these displayed similarly impaired activation of ERK1/2 MAPK compared with cDCs. Enforced retroviral expression of Dusp9 in mouse GM-CSF-induced cDCs increased the expression of TLR9-induced IL-12p40 and IFN-?, but not of IL-10. Conditional deletion of Dusp9 in pDCs was effectively achieved in Dusp9(flox/flox); CD11c-Cre mice at the mRNA and protein levels. However, the lack of Dusp9 in pDC did not restore ERK1/2 activation after TLR9 stimulation and only weakly affected IFN-? and IL-12p40 production. Taken together, our results suggest that expression of Dusp9 is sufficient to impair ERK1/2 activation and enhance IFN-? expression. However, despite selective expression in pDCs, Dusp9 is not essential for high-level IFN-? production by these cells.
EVALuna2:2008

Selective targeting of pro-inflammatory Th1 cells by microRNA-148a-specific antagomirs in vivo - Maschmeyer, Patrick; Petkau, Georg; Siracusa, Francesco; Zimmermann, Jakob; Zuegel, Franziska; Kuehl, Anja Andrea; Lehmann, Katrin; Schimmelpfennig, Sarah; Weber, Melanie; Haftmann, Claudia; Riedel, Rene; Bardua, Markus; et al. (Journal of Autoimmunity, 2018)
In T lymphocytes, expression of miR-148a is induced by T-bet and Twist1, and is specific for pro-inflammatory Th1 cells. In these cells, miR-148a inhibits the expression of the pro-apoptotic protein Bim and promotes their survival. Here we use sequence-specific cholesterol-modified oligonucleotides against miR-148a (antagomir-148a) for the selective elimination of pro-inflammatory Th1 cells in vivo. In the murine model of transfer colitis, antagomir-148a treatment reduced the number of pro-inflammatory Th1 cells in the colon of colitic mice by 50% and inhibited miR-148a expression by 71% in the remaining Th1 cells. Expression of Bim protein in colonic Th1 cells was increased. Antagomir-148a-mediated reduction of Th1 cells resulted in a significant amelioration of colitis. The effect of antagomir-148a was selective for chronic inflammation. Antigen-specific memory Th cells that were generated by an acute immune reaction to nitrophenylacetyl-coupled chicken gamma globulin (NP-CGG) were not affected by treatment with antagomir-148a, both during the effector and the memory phase. In addition, antibody titers to NP-CGG were not altered. Thus, antagomir-148a might qualify as an effective drug to selectively deplete pro-inflammatory Th1 cells of chronic inflammation without affecting the protective immunological memory.
EVALuna2:36072

Self-collection of capillary blood and saliva to determine COVID-19 vaccine immunogenicity in patients with immune-mediated inflammatory diseases and health professionals - Schmetzer, Caroline; Vogt, Ekaterina; Stellar, Laura; Godonou, Elie-Tino; Liphardt, Anna-Maria; Muehlensiepen, Felix; Vuillerme, Nicolas; Hueber, Axel; Kleyer, Arnd; Krönke, Gerhard; Schett, Georg; Simon, David; et al. (Frontiers in Public Health, 2022)
Introduction: Being able to independently determine vaccine induced antibody responses by minimal-invasive methods is of great interest to enable a flexible and effective vaccination strategy. This study aimed to evaluate (1) the accuracy, feasibility, usability and acceptability of capillary blood and saliva self-sampling to determine SARS-CoV-2 antibody responses in patients with immune-mediated inflammatory diseases (IMIDs) and health professionals (HP). Methods: IMID patients and HP having received two doses of SARS-CoV-2 vaccines, self-collected capillary blood (Tasso+) and saliva samples. Capillary samples were considered interchangeable with venous blood if three criteria were met: Spearman's correlation coefficient (r) > 0.8, non-significant Wilcoxon signed-rank test (i.e., p > 0.05), and a small bias or 95% of tests within 10% difference through Bland-Altman. Participants completed a survey to investigate self-sampling usability (system usability scale; SUS) and acceptability (net promoter score; NPS). Study personnel monitored correct self-sampling completion and recorded protocol deviations. Results: 60 participants (30 IMID patients and 30 HP) were analyzed. We observed interchangeability for capillary samples with an accuracy of 98.3/100% for Anti-SARS-CoV-2 IgG/IgA antibodies, respectively. Fifty-eight capillary blood samples and all 60 saliva samples were successfully collected within the first attempt. Usability of both self-sampling procedures was rated as excellent, with significantly higher saliva ratings (p < 0.001). Capillary self-sampling was perceived as significantly (p < 0.001) less painful compared to traditional venous blood collection. Participants reported a NPS for capillary and saliva self-sampling of +68% and +63%, respectively. The majority of both groups (73%) preferred capillary self-sampling over professional venous blood collection. Conclusion: Our results indicate that capillary self-sampling is accurate, feasible and preferred over conventional venous blood collection. Implementation could enable easy access, flexible vaccination monitoring, potentially leading to a better protection of vulnerable patient groups. Self-collection of saliva is feasible and safe however more work is needed to determine its application in clinical practice.
CRIS-Team Scopus Importer:2022-11-11
Keywords: capillary blood; COVID-19; remote care; self-collection; self-sampling; telehealth

Semi-Permeable Filters for Interior Region of Interest Dose Reduction in X-Ray Microscopy - Huang, Yixing; Mill, Leonid; Stoll, Robert; Kling, Lasse; Aust, Oliver; Wagner, Fabian; Grüneboom, Anika; Schett, Georg; Christiansen, Silke H.; Maier, Andreas (Bildverarbeitung für die Medizin, 2021)
In osteoporosis research, the number and size of lacunae in cortical bone tissue are important characteristics of osteoporosis development. In order to reconstruct lacunae well in X-ray microscopy while protecting bone marrow from high-dose damage in in-vivo experiments, semi-permeable X-ray filters are proposed for dose reduction. Compared with an opaque filter, image quality with a semi-permeable filter is improved remarkably. For image reconstruction, both iterative reconstruction with reweighted total variation (wTV) and FDK reconstruction from penalized weighted least-square (PWLS) processed projections can reconstruct lacunae when the transmission rate of the filter is as small as 5%. However, PWLS is superior in computation efficiency.<br
Keywords: Osteoporosis research; X-ray filter; X-ray microscopy; dose reduction

Semi-quantitative magnetic resonance imaging scoring of the knee detects previous injuries in professional soccer players - Welsch, Goetz Hannes; Behr, Anna Maria; Frosch, Karl Heinz; Tahir, Enver; Pachowsky, Milena; Henes, Frank Oliver; Adam, Gerhard; Maas, Kai Jonathan; Warncke, Malte Lennart (Knee Surgery Sports Traumatology Arthroscopy, 2022)
Purpose: The medical examination (“medical”) is an important procedure in professional soccer since it has high economic relevance. In addition to clinical tests, magnetic resonance imaging (MRI) is used to assess joint health. In the present study, the reliability of semiquantitative knee MRI during the “medical” in professional soccer was tested, and its relationship with clinical data and days missed due to knee injury was observed. Methods: In this cross-sectional study, between 2012 and 2019, 69 newly assigned players (age 18–35 years) from a professional soccer club underwent MRI (3.0 T) of both knee joints during their “medical”. Reported knee injuries and previously missed days due to injury were obtained from player anamnesis and the “transfermarkt.com” database. Based on the established “Whole-Organ Magnetic Resonance Imaging Score” (WORMS), two independent radiologists graded the MRI results. Further evaluation was based on the mean score of both knees. Results: The mean WORMS for all subjects was 13.9 (median 10.5, range 0–61). Players with previous injuries had significantly higher scores than players without reported injuries (22.1 ± 17.7 vs. 8.9 ± 4.4, p < 0.002). Three outliers (previously undetected injuries) in the group of players without reported injuries were observed (6.7%). The WORMS was significantly correlated with a prior knee injury (r: 0.424, p < 0.0001) and days missed due to injury (r: 0.489, p < 0.001). Age was correlated with the WORMS (r: 0.386, p < 0.001). In a linear regression model, prior injury was the only significant predictor of a high WORMS (p = 0.001). The WORMS was a significant predictor of days missed due to injury (p < 0.0002) and prior injury (sensitivity: 78%, specificity: 91%, p = 0.006). The intraclass correlation coefficient was excellent (0.89). Conclusion: Semiquantitative knee MRI for WORMS determination during the soccer “medical” is a robust and reliable method. Prior injury, even in players without documented trauma, was detected by the WORMS, and previously missed days due to injury were correlated with the semiquantitative MR knee score. Level of evidence: Level III.
CRIS-Team Scopus Importer:2022-02-25
Keywords: Knee MRI; Medical; Professional soccer; Whole-Organ Magnetic Resonance Imaging Score

SENSITIVE DETECTION OF DYNAMIC CHANGES OF BONE EROSIONS IN INFLAMMATORY ARTHRITIS BY MUSCULOSKELETAL ULTRASOUND: A COMPARATIVE ANALYSIS WITH HIGH-RESOLUTION PERIPHERAL QUANTITATVE COMPUTED TOMOGRAPHY - Finzel, S.; Schett, Georg; Kraus, S.; Voll, R.; Backhaus, M. (2017)
EVALuna2:35046

Sensitivity and Specificity of Autoantibodies Against CD74 in Early Axial Spondyloarthritis - Witte, Torsten; Riechers, Elke; Baerlecken, Niklas Thomas; Baraliakos, Xenofon; Bakhsh, Katrin Achilles-Mehr; Aries, Peer; Bannert, Bettina; Becker, Klaus; Brandt-Juergens, Jan; Braun, Juergen; Ehrenstein, Boris P.; Euler, Hartwig; et al. (2016)
EVALuna2:35068

Sensitivity and Specificity of Autoantibodies Against CD74 in Nonradiographic Axial Spondyloarthritis - Riechers, Elke; Baerlecken, Niklas; Baraliakos, Xenofon; Achilles-Mehr Bakhsh, Katrin; Aries, Peer; Bannert, Bettina; Becker, Klaus; Brandt-Jürgens, Jan; Braun, Jürgen; Ehrenstein, Boris; Euler, Hans Hartwig; Fleck, Martin; et al. (Arthritis and Rheumatology, 2019)
Objective: Autoantibodies against CD74 (anti-CD74) are associated with ankylosing spondylitis (AS). The present multicenter study, the International Spondyloarthritis Autoantibody (InterSpA) trial, was undertaken to compare the sensitivity and specificity of anti-CD74 and HLA–B27 in identifying patients with nonradiographic axial spondyloarthritis (axSpA). Methods: Patients ages 18–45 years with inflammatory back pain of ≤2 years’ duration and a clinical suspicion of axSpA were recruited. HLA–B27 genotyping and magnetic resonance imaging of sacroiliac joints were performed in all patients. One hundred forty-nine patients with chronic inflammatory back pain (IBP) not caused by axSpA served as controls, and additional controls included 50 AS patients and 100 blood donors whose specimens were analyzed. Results: One hundred patients with inflammatory back pain received a diagnosis of nonradiographic axSpA from the investigators and fulfilled the Assessment of SpondyloArthritis international Society (ASAS) criteria. The mean age was 29 years, and the mean symptom duration was 12.5 months. The sensitivity of IgA anti-CD74 and IgG anti-CD74 for identifying the 100 axSpA patients was 47% and 17%, respectively. The specificity of both IgA anti-CD74 and IgG anti-CD74 was 95.3%. The sensitivity of HLA–B27 was 81%. The positive likelihood ratios were 10.0 (IgA anti-CD74), 3.6 (IgG anti-CD74), and 8.1 (HLA–B27). Assuming a 5% pretest probability of axSpA in chronic back pain patients, the posttest probability, after consideration of the respective positive test results, was 33.3% for IgA anti-CD74, 15.3% for IgG anti-CD74, and 28.8% for HLA–B27. A combination of IgA anti-CD74 and HLA–B27 results in a posttest probability of 80.2%. Conclusion: IgA anti-CD74 may be a useful tool for identifying axSpA. The diagnostic value of the test in daily practice requires further confirmation.
CRIS-Team Scopus Importer:2019-05-03

Sensitivity of serum concentration of cartilage biomarkers to 21-days of bed rest - Liphardt, Anna-Maria; Mündermann, Annegret; Andriacchi, Thomas P.; Achtzehn, Silvia; Heer, Martina; Mester, Joachim (Journal of Orthopaedic Research, 2017)
The objective of the study was to test the hypothesis that serum levels of cartilage oligomeric matrix protein (COMP) would decrease and serum levels of tumor-necrosis factor alpha (TNF-?) and selected matrix metalloproteinases (MMPs) would increase in response to bed rest (BR) and that these changes are unaffected by the intake of potassium bicarbonate or whey protein. Seven and 9 healthy male subjects participated in two 21-day 6° head down tilt crossover BR-studies with nutrition interventions. Serum samples were taken before, during, and after BR and biomarker concentrations were measured using commercial enzyme-linked immunosorbent assays. MMP-3 during BR was significantly lower than at baseline (reduction greater 20%; P<0.001). MMP-3 increased significantly from 14 to 21 days of BR (+7%; P=0.049). COMP during BR was significantly lower than at baseline (reduction greater 20%; P<0.001). MMP-3 and COMP returned to baseline within one day after BR. MMP-9 on day 3 of BR was significantly lower than at baseline (-31%; P<0.033) and on days 3, 5 and 14 of BR significantly lower than at the end of and after BR (reduction greater 35%; P<0.030). The nutritional countermeasures did not affect these results. The observed changes in cartilage biomarkers may be caused by altered cartilage metabolism in response to the lack of mechanical stimulus during BR and inflammatory biomarkers may play a role in changes in biomarker levels.Immobilization independently from injury can cause altered cartilage biomarker concentration. This article is protected by copyright. All rights reserved.
EVALuna2:13500

Sequence-function analysis of three T cell receptors targeting the HIV-1 p17 - Mummert, Christiane; Hofmann, Christian; Hueckelhoven, Angela G.; Bergmann, Silke; Müller-Schmucker, Sandra; Harrer, Ellen G.; Dörrie, Jan; Schaft, Niels; Harrer, Thomas (2016)
EVALuna2:19635

Sequential interleukin-17/interleukin-23 inhibition in treatment-refractory psoriatic arthritis - Simon, David; Fagni, Filippo; Schett, Georg (Annals of the Rheumatic Diseases, 2022)
CRIS-Team WoS Importer:2022-05-20

SERIO - Side Effect Registry Immuno-Oncology Side Effect Registry for rare, severe and complex Side Effects of Immunotherapy - Kramer, Rafaela; Mentzer, D.; Erdmann, M.; Knauss, S.; Broeckelmann, P. J.; Hassel, J. C.; Ugurel, S.; Pavel, Marianne Ellen; Nickel, Franziska; Landendinger, M.; Fuchs, Friederike; Meidenbauer, Norbert; et al. (JOURNAL DER DEUTSCHEN DERMATOLOGISCHEN GESELLSCHAFT, 2020)
CRIS-Team WoS Importer:2020-09-11

Serio - Side Effect Registry in Immuno-Oncology - Koutzamanidis, Rafaela; Mentzer, Dirk; Knauss, Samuel; Broeckelmann, Paul J.; Hassel, Jessica Cecile; Ugurel-Becker, Selma; Pavel, Marianne Ellen; Nickel, Florian; Landendinger, Melanie; Fuchs, Florian; Meidenbauer, Norbert; Jefremow, Andre; et al. (ONCOLOGY RESEARCH AND TREATMENT, 2020)
CRIS-Team WoS Importer:2020-03-20

Serious adverse events and the risk of stroke in patients with rheumatoid arthritis: results from the German RABBIT cohort - Meissner, Y.; Richter, A.; Manger, Bernhard; Tony, H. P.; Wilden, E.; Listing, J.; Zink, A.; Strangfeld, A. (Annals of the Rheumatic Diseases, 2017)
In the general population, the incidence of stroke is increased following other serious events and hospitalisation. We investigated the impact of serious adverse events on the risk of stroke in patients with rheumatoid arthritis (RA), taking risk factors and treatment into account.Using data of the German biologics register RABBIT (Rheumatoid Arthritis: Observation of Biologic Therapy) with 12354 patients with RA, incidence rates (IRs) and risk factors for stroke were investigated using multi-state and Cox proportional hazard models. In addition, in a nested case-control study, all patients with stroke were matched 1:2 to patients with identical baseline risk profile and analysed using a shared frailty model.During follow-up, 166 strokes were reported. The overall IR was 3.2/1000 patient-years (PY) (95% CI 2.7 to 3.7). It was higher after a serious adverse event (IR: 9.0 (7.3 to 11.0)), particularly within 30 days after the event (IR: 94.9 (72.6 to 121.9)). The adjusted Cox model showed increased risks of age per 5 years (HR: 1.4 (1.3 to 1.5)), hyperlipoproteinaemia (HR: 1.6 (1.0 to 2.5)) and smoking (HR: 1.9 (1.3 to 2.6)). The risk decreased with better physical function (HR: 0.9 (0.8 to 0.96)).In the case-control study, 163 patients were matched to 326 controls. Major risk factors for stroke were untreated cardiovascular disease (HR: 3.3 (1.5 to 7.2)) and serious infections (HR:4.4 (1.6 to 12.5)) or other serious adverse events (HR: 2.6 (1.4 to 4.8)).Incident adverse events, in particular serious infections, and insufficient treatment of cardiovascular diseases are independent drivers of the risk of stroke. Physicians should be aware that patients who experience a serious event are at increased risk of subsequent stroke.
EVALuna2:13417

Serum Calprotectin Is a Prognostic Marker for Drug-Free Remission in RA - De Moel, Emma; Rech, Jürgen; Mahler, Michael; Roth, Johannes; Schouffoer, Anne; Ronday, Karel; Huizinga, Thomas; Allaart, C. F.; Toes, Rene; Schett, Georg; Van Der Woude, Diane (ARTHRITIS & RHEUMATOLOGY, 2019)
CRIS-Team WoS Importer:2020-02-07

SERUM CARTILAGE BIOMARKERS IN RESPONSE TO 21 DAYS BED REST WITH EXERCISE AND NUTRITION COUNTERMEASURES - Dreiner, M.; Zaucke, F.; Muendermann, A.; Liphardt, Anna-Maria; Niehoff, A. (OSTEOARTHRITIS AND CARTILAGE, 2022)
CRIS-Team WoS Importer:2022-04-22

Serum Heme Oxygenase-1 and BMP-7 Are Potential Biomarkers for Bone Metabolism in Patients with Rheumatoid Arthritis and Ankylosing Spondylitis - Yuan, Tong-Ling; Chen, Jin; Tong, Yan-Li; Zhang, Yan; Liu, Yuan-Yuan; Wei, James Cheng-Chung; Liu, Yi; Zhao, Yi; Herrmann, Martin (BioMed Research International, 2016)
Backgrounds. Heme oxygenase-1 (HO-1) has been reported to play a regulatory role in osteoclastogenesis. Bone morphogenetic protein (BMP) pathways induce osteoblastic differentiation and bone remodeling. Aims. To identify serum levels of HO-1, BMP-7, and Runt related-transcription factor 2 (Runx2) in patients with rheumatoid arthritis (RA) and ankylosing spondylitis (AS) and to investigate the relationships between HO-1, BMP-7, Runx2, and other common biomarkers for bone metabolism. Results. Serum levels of HO-1 and BMP-7 were revealed to be significantly higher in patients with RA or AS than in healthy controls (p < 0.01). In RA group, HO-1 was positively correlated with BMP-7, Runx2, and tartrate-resistant acid phosphatase-5b (TRAP-5b) (p < 0.05, resp.), BMP-7 was positively correlated with Runx2 and TRAP-5b (p < 0.05, resp.), and Runx2 was negatively correlated with N-terminal midfragment of osteocalcin (NMID) (p < 0.05). In AS group, we observed identical correlation between HO-1 and BMP-7, but opposite correlations between BMP-7 and TRAP-5b and between Runx2 and NMID, when comparing with the RA cohort. Conclusion. Our findings suggest that HO-1 and BMP-7 are potential biomarkers for bone metabolism in patients with RA and AS. The different correlations between the bone markers point to distinct differences in bone remodeling pathways in the two types of arthritis.
EVALuna2:13293

Serum Interleukin-36 α as a Candidate Biomarker to Distinguish Behçet’s Syndrome and Psoriatic Arthritis - Bettiol, Alessandra; Fagni, Filippo; Mattioli, Irene; Bagni, Giacomo; Vitiello, Gianfranco; Grassi, Alessia; Della Bella, Chiara; Benagiano, Marisa; Troilo, Arianna; Holownia, Katarzyna Stella; Simon, David; Argento, Flavia Rita; et al. (International Journal of Molecular Sciences, 2023)
Behçet’s syndrome (BS) is a rare systemic vasculitis characterized by different clinical manifestations. As no specific laboratory tests exist, the diagnosis relies on clinical criteria, and the differential diagnosis with other inflammatory diseases can be challenging. Indeed, in a relatively small proportion of patients, BS symptoms include only mucocutaneous, articular, gastrointestinal, and non-typical ocular manifestations, which are frequently found also in psoriatic arthritis (PsA). We investigate the ability of serum interleukin (IL)-36α—a pro-inflammatory cytokine involved in cutaneous and articular inflammatory diseases—to differentiate BS from PsA. A cross-sectional study was performed on 90 patients with BS, 80 with PsA and 80 healthy controls. Significantly lower IL-36α concentrations were found in patients with BS as compared to PsA, although in both groups IL-36α was significantly increased compared to healthy controls. An empirical cut-off of 420.6 pg/mL displayed a specificity of 0.93, with a sensitivity of 0.70 (AUC 0.82) in discriminating PsA from BS. This cut-off displayed a good diagnostic performance also in BS patients lacking highly specific BS manifestations. Our results indicate that IL-36α might be involved in the pathogenesis of both BS and PsA, and might be a candidate biomarker to support the differential diagnosis of BS.
CRIS-Team Scopus Importer:2023-06-09
Keywords: Behçet disease; biomarkers; cytokines; interleukin 36; vasculitis

SERUM KINETICS OF CARTILAGE BIOLOGICAL MARKERS IN RESPONSE TO IMMOBILIZATION AND PHYSICAL EXERCISE, AND THE POTENTIAL ROLE OF CGS IN THIS CONTEXT - Liphardt, Anna-Maria; Mundermann, A. (OSTEOPOROSIS INTERNATIONAL, 2019)
CRIS-Team WoS Importer:2019-08-02

Serum Proteomic Signatures Predict Relapse in Rheumatoid Arthritis Patients Undergoing DMARD Withdrawal - O'Neil, Liam; Spicer, Victor; Hitchon, Carol A.; Rech, Jürgen; Hueber, Axel; Wilkins, John; El-Gabalawy, Hani; Schett, Georg (2017)
EVALuna2:33439

SERUM URIC ACID INCREASES AFTER ABROGATION OF SYSTEMIC INFLAMMATION BY TNF INHIBITION - Petru, L.; Hulejova, Hana; Mahajan, Aparna; Herrmann, Martin; Zavada, J. (2018)
EVALuna2:213265

Serum uric acid increases in patients with systemic autoimmune rheumatic diseases after 3 months of treatment with TNF inhibitors - Hasikova, Lenka; Pavlikova, Marketa; Hulejova, Hana; Kozlik, Petr; Kalikova, Kveta; Mahajan, Aparna; Herrmann, Martin; Stiburkova, Blanka; Zavada, Jakub (Rheumatology International, 2019)
In patients with gout, the serum uric acid (SUA) is usually lower during acute gouty attacks than during intercritical periods. It has been suggested that systemic inflammatory response can cause this phenomenon. The objective is to determine whether therapy with TNF inhibitors (TNFis) affects SUA levels in patients with systemic autoimmune rheumatic diseases (SARDs) and whether SUA changes correlate with pro-inflammatory cytokines or with the oxidative stress marker allantoin. In this study, SUA, CRP, creatinine, MCP-1, IFN-α2, IFN-γ, Il-1β, IL-6, IL-8, IL-10, IL-12, IL-17a, IL-18, IL-23, IL-33, TNF-α, and allantoin levels were measured prior to and after 3 months of TNFis treatment in patients with SARDs. The values obtained in the biochemical assays were then tested for associations with the patients’ demographic and disease-related data. A total of 128 patients (rheumatoid arthritis, n = 44; ankylosing spondylitis, n = 45; psoriatic arthritis, n = 23; and adults with juvenile idiopathic arthritis, n = 16) participated in this study. Among the entire patient population, SUA levels significantly increased 3 months after starting treatment with TNFis (279.5 [84.0] vs. 299.0 [102.0] μmol/l, p < 0.0001), while the levels of CRP, IL-6, IL-8, and MCP-1 significantly decreased. Male sex was the most powerful baseline predictor of ΔSUA in univariate and multivariate models. None of the measured laboratory-based parameters had statistically significant effects on the magnitude of ΔSUA. 3 months of anti-TNF therapy increased the levels of SUA in patients with SARDs, but neither the measured pro-inflammatory cytokines nor the oxidation to allantoin appeared responsible for this effect.
CRIS-Team Scopus Importer:2019-08-06
Keywords: Cytokines; Inflammation; Oxidative stress; Rheumatic diseases; Uric acid

Severe Hepatitis E virus infection in a patient with rheumatoid arthritis treated with baricitinib - Valor-Mendez, Larissa; Manger, Bernhard; Schett, Georg; Kleyer, Arnd (Zeitschrift für Rheumatologie, 2021)
A patient with rheumatoid arthritis (RA) was presented, who developed an infection with the hepatitis E virus (HEV) under treatment with the Janus kinase (JAK) 1 and 2 inhibitor baricitinib. In the 3-month routine check-up the patient had clearly elevated transaminase levels with an inconspicuous physical examination. The investigations detected antibodies of IgM and IgG classes against HEV and an elevated C-reactive protein (CRP) level as well as HEV-RNA by real-time PCR, which is indicative of a recent HEV infection. Baricitinib was immediately discontinued. The extensive anamnesis revealed that the patient had eaten beef tartar some days before the consultation, without the occurrence of gastrointestinal symptoms or fever. In the further course the patient completely recovered and the liver function tests and the CRP levels normalized within 3 months. Baricitinib was then restarted. So far only few reports have been published on HEV infections in RA patients who have been treated with JAK inhibitors.
CRIS-Team WoS Importer:2021-06-25

Shared and distinct mechanisms of fibrosis - Distler, Jörg; Györfi, Andrea-Hermina; Ramanujam, Meera; Whitfield, Michael L.; Königshoff, Melanie; Lafyatis, Robert (Nature Reviews Rheumatology, 2019)
Fibrosis is defined as an excessive deposition of connective tissue components and can affect virtually every organ system, including the skin, lungs, liver and kidney. Fibrotic tissue remodelling often leads to organ malfunction and is commonly associated with high morbidity and mortality. The medical need for effective antifibrotic therapies is thus very high. However, the extraordinarily high costs of drug development and the rare incidence of many fibrotic disorders hinder the development of targeted therapies for individual fibrotic diseases. A potential strategy to overcome this challenge is to target common mechanisms and core pathways that are of central pathophysiological relevance across different fibrotic diseases. The factors influencing susceptibility to and initiation of these diseases are often distinct, with disease-specific and organ-specific risk factors, triggers and sites of first injury. Fibrotic remodelling programmes with shared fibrotic signalling responses such as transforming growth factor-β (TGFβ), platelet-derived growth factor (PDGF), WNT and hedgehog signalling drive disease progression in later stages of fibrotic diseases. The convergence towards shared responses has consequences for drug development as it might enable the development of general antifibrotic compounds that are effective across different disease entities and organs. Technological advances, including new models, single-cell technologies and gene editing, could provide new insights into the pathogenesis of fibrotic diseases and the development of drugs for their treatment.
CRIS-Team Scopus Importer:2019-11-29

ShaRPy: Shape Reconstruction and Hand Pose Estimation from RGB-D with Uncertainty - Wirth, Vanessa; Liphardt, Anna-Maria; Coppers, Birte; Bräunig, Johanna; Heinrich, Simon; Leyendecker, Sigrid; Kleyer, Arnd; Schett, Georg; Vossiek, Martin; Egger, Bernhard; Stamminger, Marc (Proceedings of the IEEE/CVF International Conference on Computer Vision (ICCV) Workshops, 2023)
Despite their potential, markerless hand tracking technologies are not yet applied in practice to the diagnosis or monitoring of the activity in inflammatory musculoskeletal diseases. One reason is that the focus of most methods lies in the reconstruction of coarse, plausible poses, whereas in the clinical context, accurate, interpretable, and reliable results are required. Therefore, we propose ShaRPy, the first RGB-D Shape Reconstruction and hand Pose tracking system, which provides uncertainty estimates of the computed pose, e.g., when a finger is hidden or its estimate is inconsistent with the observations in the input, to guide clinical decision-making. Besides pose, ShaRPy approximates a personalized hand shape, promoting a more realistic and intuitive understanding of its digital twin. Our method requires only a light-weight setup with a single consumer-level RGB-D camera yet it is able to distinguish similar poses with only small joint angle deviations in a metrically accurate space. This is achieved by combining a data-driven dense correspondence predictor with traditional energy minimization. To bridge the gap between interactive visualization and biomedical simulation we leverage a parametric hand model in which we incorporate biomedical constraints and optimize for both, its pose and hand shape parameters. We evaluate ShaRPy on a keypoint detection benchmark and show qualitative results of hand function assessments for activity monitoring of musculoskeletal diseases.
Keywords: Musculoskeletal diseases; Hand Pose and Shape Estimation; Uncertainty Estimation; Hand Tracking

Short chain fatty acids are potent regulators of systemic bone mass and protect for pathological bone loss by inhibiting osteoclasts - Lucas, S.; Omata, Y.; Böttcher, Martin; Hofmann, Jörg; Krishnacoumar, B.; Krönke, Gerhard; Mougiakakos, Dimitrios; Iljazovic, A.; Sonnewald, Uwe; Strowig, T.; Schett, Georg; Zaiss, Mario (European Journal of Immunology, 2017)

Short-chain fatty acids regulate systemic bone mass and protect from pathological bone loss - Lucas, Sebastien; Omata, Yasunori; Hofmann, Jörg; Böttcher, Martin; Iljazovic, Aida; Sarter, Kerstin; Albrecht, Olivia; Schulz, Oscar; Krishnacoumar, Brenda; Krönke, Gerhard; Herrmann, Martin; Mougiakakos, Dimitrios; et al. (Nature Communications, 2018)
Microbial metabolites are known to modulate immune responses of the host. The main metabolites derived from microbial fermentation of dietary fibers in the intestine, short-chain fatty acids (SCFA), affect local and systemic immune functions. Here we show that SCFA are regulators of osteoclast metabolism and bone mass in vivo. Treatment of mice with SCFA as well as feeding with a high-fiber diet significantly increases bone mass and prevents postmenopausal and inflammation-induced bone loss. The protective effects of SCFA on bone mass are associated with inhibition of osteoclast differentiation and bone resorption in vitro and in vivo, while bone formation is not affected. Mechanistically, propionate (C3) and butyrate (C4) induce metabolic reprogramming of osteoclasts resulting in enhanced glycolysis at the expense of oxidative phosphorylation, thereby downregulating essential osteoclast genes such as TRAF6 and NFATc1. In summary, these data identify SCFA as potent regulators of osteoclast metabolism and bone homeostasis.
EVALuna2:13520

Short-term Response of Serum Cartilage Oligomeric Matrix Protein to Different Types of Impact Loading Under Normal and Artificial Gravity - Dreiner, Maren; Willwacher, Steffen; Kramer, Andreas; Kümmel, Jakob; Frett, Timo; Zaucke, Frank; Liphardt, Anna-Maria; Gruber, Markus; Niehoff, Anja (Frontiers in Physiology, 2020)
Microgravity during long-term space flights induces degeneration of articular cartilage. Artificial gravity through centrifugation combined with exercise has been suggested as a potential countermeasure for musculoskeletal degeneration. The purpose of this study was to investigate the effect of different types of impact loading under normal and artificial gravity conditions on serum concentrations of cartilage oligomeric matrix protein (COMP), a biomarker of cartilage metabolism. Fifteen healthy male adults (26 ± 4 years, 181 ± 4 cm, 77 ± 6 kg) performed four different 30-min impact loading protocols on four experimental days: jumping with artificial gravity elicited by centrifugation in a short-arm centrifuge (AGJ), jumping with artificial gravity generated by low-pressure cylinders in a sledge jump system (SJS), vertical jumping under Earth gravity (EGJ), and running under Earth gravity (RUN). Five blood samples per protocol were taken: 30 min before, immediately before, immediately after, 30 min after, and 60 min after impact loading. Serum COMP concentrations were analyzed in these samples. During the impact exercises, ground reaction forces were recorded. Peak ground reaction forces were significantly different between the three jumping protocols (p < 0.001), increasing from AGJ (14 N/kg) to SJS (22 N/kg) to EGJ (29 N/kg) but were similar in RUN (22 N/kg) compared to SJS. The serum COMP concentration was increased (p < 0.001) immediately after all loading protocols, and then decreased (p < 0.001) at 30 min post-exercise compared to immediately after the exercise. Jumping and running under Earth gravity (EGJ and RUN) resulted in a significantly higher (p < 0.05) increase of serum COMP levels 30 min after impact loading compared to the impact loading under artificial gravity (RUN +30%, EGJ +20%, AGJ +17%, and SJS +13% compared to baseline). In conclusion, both the amplitude and the number of the impacts contribute to inducing higher COMP responses and are therefore likely important factors affecting cartilage metabolism. RUN had the largest effect on serum COMP concentration, presumably due to the high number of impacts, which was 10 times higher than for the jump modalities. Future studies should aim at establishing a dose-response relationship for different types of exercise using comparable amounts of impacts.
CRIS-Team Scopus Importer:2020-09-25
Keywords: articular cartilage; artificial gravity; cartilage oligomeric matrix protein; centrifuge; countermeasure; impact loading; reactive jumping

Short-term Safety of COVID-19 Vaccination in Systemic Sclerosis Patients: Report from a Global Patient-Reported E-survey - Thakare, Darpan; Naveen, R.; Pauling, John; Ahmed, Sakir; Wincup, Chris; Del Papa, Nicolletta; Sambataro, Gianluca; Atzeni, Fabiola; Govoni, Marcello; Parisi, Simone; Bocci, Elena Bartoloni; Sebastiani, Gian Domenico; et al. (ARTHRITIS & RHEUMATOLOGY, 2022)
CRIS-Team WoS Importer:2023-01-13

Sialylation of anti-histone immunoglobulin G autoantibodies determines their capabilities to participate in the clearance of late apoptotic cells - Magorivska, I.; Munoz Becerra, Luis; Janko, Christina; Dumych, Tetiana; Rech, J.; Schett, Georg; Nimmerjahn, Falk; Bilyy, R.; Herrmann, Martin (Clinical and Experimental Immunology, 2016)
The Fc portion of immunoglobulin (Ig)G harbours a single glycosylation site. Glycan sialylation is critical for structure and for certain effector functions of IgG. Anti-histone IgG of patients with systemic lupus erythematosus is reportedly responsible for the recruitment of polymorphonuclear cells (PMN) to the clearance of apoptotic cells. Autoantibodies decorating secondary necrotic cells (SNEC) induce proinflammatory responses after activation of blood-borne phagocytes. Analysing the sialylation status of affinity-purified anti-histone IgG in patients with systemic lupus erythematosus (SLE), we demonstrated that the anti-histone IgG was contained preferentially in the non-sialylated fraction. In functional ex-vivo phagocytosis studies, non-sialylated anti-SNEC IgG directed SNEC preferentially into PMN but did not change their cytokine secretion profiles. In contrast, sialylated IgG reduced the phagocytosis by monocytes of SNEC. Moreover, the sialylated anti-SNEC IgG was not simply anti-inflammatory, but switched the cytokine secretion profiles from interleukin (IL)-6/IL-8 to tumour necrosis factor (TNF)-/IL-1. Here we describe how different sialylation statuses of IgG autoantibodies contribute to the complex inflammatory network that regulates chronic inflammation.
Keywords: autoantibodies; IgG; lectin; sialylation; SLE

Signal hotspot mutations in SARS-CoV-2 genomes evolve as the virus spreads and actively replicates in different parts of the world - Weber, Stefanie; Ramirez, Christina; Dörfler, Walter (Virus Research, 2020)
Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) was first identified in Wuhan, China late in 2019. Nine months later (Sept. 23, 2020), the virus has infected > 31.6 million people around the world and caused > 971.000 (3.07 %) fatalities in 220 countries and territories. Research on the genetics of the SARS-CoV-2 genome, its mutants and their penetrance can aid future defense strategies. By analyzing sequence data deposited between December 2019 and end of May 2020, we have compared nucleotide sequences of 570 SARS-CoV-2 genomes from China, Europe, the US, and India to the sequence of the Wuhan isolate. During worldwide spreading among human populations, at least 10 distinct hotspot mutations had been selected and found in up to > 80 % of viral genomes. Many of these mutations led to amino acid exchanges in replication-relevant viral proteins. Mutations in the SARS-CoV-2 genome would also impinge upon the secondary structure of the viral RNA molecule and its repertoire of interactions with essential cellular and viral proteins. The increasing frequency of SARS-CoV-2 mutation hotspots might select for dangerous viral pathogens. Alternatively, in a 29.900 nucleotide-genome, there might be a limit to the number of mutable and selectable sites which, when exhausted, could prove disadvantageous to viral survival. The speed, at which novel SARS-CoV-2 mutants are selected and dispersed around the world, could pose problems for the development of vaccines and therapeutics.
CRIS-Team Scopus Importer:2020-10-09
Keywords: Consequences for secondary and tertiary structures of viral RNA; Impact on replication-relevant viral proteins; Questions about immunogenesis and vaccine development; Selection of viral hotspot mutations; Sequence comparisons between 570 viral genomes to Wuhan isolate; Severe acute respiratory syndrome Coronavirus-2 (SARS-CoV-2)

SIGNAL TRANSDUCER AND ACTIVATOR OF TRANSCRIPTION 3 (STAT3) INTEGRATES SEVERAL PROFIBROTIC PATHWAYS IN SYSTEMIC SCLEROSIS - Chakraborty, D.; Sumova, B.; Mallano, Tatjana; Chen, Chih-Wei; Ramming, A.; Distler, O.; Schett, Georg; Distler, Jörg (2016)
EVALuna2:13487

SIGNATURE OF CIRCULATING MICRORNAS IN OSTEOARTHRITIS - Beyer, Christian; Zampetaki, A.; Lin, N. -Y.; Kleyer, Arnd; Perricone, C.; Iagnocco, A. M.; Distler, A.; Langley, S. L.; Gelse, Kolja; Sesselmann, Stefan; Lorenzini, R.; Niemeier, A.; et al. (2014)
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Signature of circulating microRNAs in osteoarthritis - Beyer, Christian; Zampetaki, Anna; Lin, Neng-Yu; Kleyer, Arnd; Perricone, Carlo; Iagnocco, Annamaria; Distler, Alfiya; Langley, Sarah R.; Gelse, Kolja; Sesselmann, Stefan; Lorenzini, Rolando; Niemeier, Andreas; et al. (Annals of the Rheumatic Diseases, 2015)
Osteoarthritis is the most common form of arthritis and a major socioeconomic burden. Our study is the first to explore the association between serum microRNA levels and the development of severe osteoarthritis of the knee and hip joint in the general population.We followed 816 Caucasian individuals from 1995 to 2010 and assessed joint arthroplasty as a definitive outcome of severe osteoarthritis of the knee and hip. After a microarray screen, we validated 12 microRNAs by real-time PCR in the entire cohort at baseline.In Cox regression analysis, three microRNAs were associated with severe knee and hip osteoarthritis. let-7e was a negative predictor for total joint arthroplasty with an adjusted HR of 0.75 (95% CI 0.58 to 0.96; p=0.021) when normalised to U6, and 0.76 (95% CI 0.6 to 0.97; p=0.026) after normalisation to the Ct average. miRNA-454 was inversely correlated with severe knee or hip osteoarthritis with an adjusted HR of 0.77 (95% CI 0.61 to 0.97; p=0.028) when normalised to U6. This correlation was lost when data were normalised to Ct average (p=0.118). Finally, miRNA-885-5p showed a trend towards a positive relationship with arthroplasty when normalised to U6 (HR 1.24; 95% CI 0.95 to 1.62; p=0.107) or to Ct average (HR 1.30; 95% CI 0.99 to 1.70; p=0.056).Our study is the first to identify differentially expressed circulating microRNAs in osteoarthritis patients necessitating arthroplasty in a large, population-based cohort. Among these microRNAs, let-7e emerged as potential predictor for severe knee or hip osteoarthritis.
EVALuna2:10852

Significance of pulmonary involvement in systemic sclerosis (SSc)- data from the German SSc-network - Kreuter, Michael; Bonella, Francesco; Blank, Nobert; Siegert, Elise; Henes, Joerg; Worm, Margitta; Sunderkoetter, Cord; Schmalzing, Marc; Kreuter, Alexander; Günther, Claudia; Susok, Laura; Zeidler, Gabriele; et al. (2018)
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SIMILAR EFFICACY AND DRUG SURVIVAL RATES OF BARICITINIB MONOTHERAPY AND BARICITINIB/METHOTREXATE COMBINATION THERAPY IN REAL-LIFE TREATMENT OF RHEUMATOID ARTHRITIS - RESULTS FROM A PROSPECTIVE COHORT OF BARICITINIB-TREATED PATIENTS - Bayat, Sara; Tascilar, Koray; Bohr, D.; Simon, David; Kronke, G.; Hartmann, F.; Knitza, Johannes; Schett, Georg; Kleyer, Arnd (ANNALS OF THE RHEUMATIC DISEASES, 2022)
CRIS-Team WoS Importer:2022-11-04

Similar Impact of Psoriatic Arthritis and Rheumatoid Arthritis on Objective and Subjective Parameters of Hand Function - Liphardt, Anna-Maria; Manger, Eva; Liehr, Sonja; Bieniek, Lisa Maria; Kleyer, Arnd; Simon, David; Tascilar, Koray; Sticherling, Michael; Rech, Jürgen; Schett, Georg; Hueber, Axel (ACR Open Rheumatology, 2020)
ObjectiveThe objective of this study was to compare the impact of psoriatic disease (psoriatic arthritis [PsA] and psoriasis) and rheumatoid arthritis (RA) on objective and subjective parameters of hand function.
CRIS-Team WoS Importer:2021-07-16

Similar Impact of Psoriatic Arthritis and Rheumatoid Arthritis on Objective and Subjective Parameters of Hand Function - Liphardt, Anna-Maria; Manger, Eva; Liehr, Sonja; Bieniek, Lisa; Kleyer, Arnd; Simon, David; Tascilar, Koray; Sticherling, Michael; Rech, Jürgen; Schett, Georg; Hueber, Axel (ARTHRITIS & RHEUMATOLOGY, 2020)
CRIS-Team WoS Importer:2021-01-15

Simultaneous quantification of bone erosions and enthesiophytes in the joints of patients with psoriasis or psoriatic arthritis - effects of age and disease duration - Simon, David; Kleyer, Arnd; Faustini, Francesca; Englbrecht, Matthias; Haschka, Judith; Berlin, Andreas; Kraus, Sebastian; Hueber, Axel; Kocijan, Roland; Sticherling, Michael; Rech, Jürgen; Schett, Georg (Arthritis Research & Therapy, 2018)
BACKGROUND: Comprehensive simultaneous quantification of bone erosion and enthesiophytes in the joints of patients with psoriatic arthritis (PsA) has not been performed. Herein, we aimed to compare the extent of bone erosion and enthesiophytes in patients with PsA, psoriasis (PSO) and healthy controls, assess the influence of age and disease duration on the development of erosions and enthesiophytes and define their impact on physical function. METHODS: Patients with PsA or with PSO and controls were analysed by high-resolution peripheral quantitative computed tomography (HR-pQCT). The extent of bone erosions and enthesiophytes was assessed and plotted according to different categories of age, duration of PSO and duration of PsA, respectively. In addition, demographic and disease-specific data, including physical function (health assessment questionnaire) were collected. RESULTS: A total of 203 patients were analysed; 101 had PsA, 55 had PSO and 47 were healthy individuals. Patients with PsA had significantly more and larger erosions (p = 0.002/p = 0.003) and enthesiophytes (p < 0.001) compared to patients with PSO and healthy controls. Patients with PSO and healthy controls did not differ in erosions, while enthesiophytes were more frequent in patients with PSO than in healthy controls. Bone erosions, but not enthesiophytes, showed strong age-dependency in all three groups. In contrast, enthesiophytes were mostly influenced by the duration of PSO and PsA and, in contrast to bone erosions, were associated with poorer physical function. CONCLUSIONS: Bone erosions are age-dependent, enhanced in PsA and increase with disease duration. Enthesiophytes are less age-dependent, are enhanced in both PSO and PsA and strongly influenced by disease duration. Enthesiophytes impact physical function in PsA suggesting the need for early therapeutic interventions to prevent damage.
EVALuna2:34666

Single-cell multi-omics analysis of COVID-19 patients with pre-existing autoimmune diseases shows aberrant immune responses to infection - Barmada, Anis; Handfield, Louis François; Godoy-Tena, Gerard; de la Calle-Fabregat, Carlos; Ciudad, Laura; Arutyunyan, Anna; Andrés-León, Eduardo; Hoo, Regina; Porter, Tarryn; Oszlanczi, Agnes; Richardson, Laura; Calero-Nieto, Fernando J.; et al. (European Journal of Immunology, 2023)
In COVID-19, hyperinflammatory and dysregulated immune responses contribute to severity. Patients with pre-existing autoimmune conditions can therefore be at increased risk of severe COVID-19 and/or associated sequelae, yet SARS-CoV-2 infection in this group has been little studied. Here, we performed single-cell analysis of peripheral blood mononuclear cells from patients with three major autoimmune diseases (rheumatoid arthritis, psoriasis, or multiple sclerosis) during SARS-CoV-2 infection. We observed compositional differences between the autoimmune disease groups coupled with altered patterns of gene expression, transcription factor activity, and cell–cell communication that substantially shape the immune response under SARS-CoV-2 infection. While enrichment of HLA-DRlow CD14+ monocytes was observed in all three autoimmune disease groups, type-I interferon signaling as well as inflammatory T cell and monocyte responses varied widely between the three groups of patients. Our results reveal disturbed immune responses to SARS-CoV-2 in patients with pre-existing autoimmunity, highlighting important considerations for disease treatment and follow-up.
CRIS-Team Scopus Importer:2023-10-27
Keywords: Autoimmunity; COVID-19; Multiple sclerosis; Psoriasis; Rheumatoid arthritis

Single-cell resolution of plasma cell fate programming in health and disease - Delaloy, Celine; Schuh, Wolfgang; Jäck, Hans-Martin; Bonaud, Amelie; Espeli, Marion (European Journal of Immunology, 2021)
Long considered a homogeneous population dedicated to antibody secretion, plasma cell phenotypic and functional heterogeneity is increasingly recognized. Plasma cells were first segregated based on their maturation level, but the complexity of this subset might well be underestimated by this simple dichotomy. Indeed, in the last decade new functions have been attributed to plasma cells including but not limited to cytokine secretion. However, a proper characterization of plasma cell heterogeneity has remained elusive partly due to technical issues and cellular features that are specific to this cell type. Cell intrinsic and cell extrinsic signals could be at the origin of this heterogeneity. Recent advances in technologies such as single cell RNA-seq, ATAC-seq, or ChIP-seq on low cell numbers helped to elucidate the fate decision in other cell lineages and similar approaches could be implemented to evaluate the heterogeneous fate of activated B cells in health and disease. Here, we summarized published work shedding some lights on the stimuli and genetic program shaping B-cell terminal differentiation at the single cell level in mice and men. We also discuss the fate and heterogeneity of plasma cells during immune responses, vaccination, and in the frame of human plasma cell disorders.
CRIS-Team WoS Importer:2021-12-24

Sirt1 regulates canonical TGF-? signalling to control fibroblast activation and tissue fibrosis - Zerr, Pawel; Palumbo-Zerr, Katrin; Huang, Jingang; Tomcik, Michal; Sumova, Barbora; Distler, Oliver; Schett, Georg; Distler, Jörg (Annals of the Rheumatic Diseases, 2016)
Sirt1 is a member of the sirtuin family of proteins. Sirt1 is a class III histone deacetylase with important regulatory roles in transcription, cellular differentiation, proliferation and metabolism. As aberrant epigenetic modifications have been linked to the pathogenesis of systemic sclerosis (SSc), we aimed to investigate the role of Sirt1 in fibroblast activation.Sirt1 expression was analysed by real-time PCR, western blot and immunohistochemistry. Sirt1 signalling was modulated with the Sirt1 agonist resveratrol and by fibroblast-specific knockout. The role of Sirt1 was evaluated in bleomycin-induced skin fibrosis and in mice overexpressing a constitutively active transforming growth fac-tor-? (TGF-?) receptor I (TBRIact).The expression of Sirt1 was decreased in patients with SSc and in experimental fibrosis in a TGF-?-dependent manner. Activation of Sirt1 potentiated the profibrotic effects of TGF-? with increased Smad reporter activity, elevated transcription of TGF-? target genes and enhanced release of collagen. In contrast, knockdown of Sirt1 inhibited TGF-?/SMAD signalling and reduced release of collagen in fibroblasts. Consistently, mice with fibroblast-specific knockdown of Sirt1 were less susceptible to bleomycin- or TBRIact-induced fibrosis.We identified Sirt1 as a crucial regulator of TGF-?/Smad signalling in SSc. Although Sirt1 is downregulated, this decrease is not sufficient to counterbalance the excessive activation of TGF-? signalling in SSc. However, augmentation of this endogenous regulatory mechanism, for example, by knockdown of Sirt1, can effectively inhibit TGF-? signalling and exerts potent antifibrotic effects. Sirt1 may thus be a key regulator of fibroblast activation in SSc.
EVALuna2:12980

SIZE MATTERS - EXTENT OF MONOSODIUM URATE DEPOSITS BUT NOT SERUM URATE LEVEL PREDICTS COMPLETE RESOLUTION OF MONOSODIUM URATE CRYSTAL DEPOSITS IN PATIENTS WITH GOUT - Bayat, Sara; Ellmann, Hanna; Guilhon de Araujo, Elizabeth; Manger, Bernhard; Hagen, Melanie; Kleyer, Arnd; Lell, Michael; Schenker, Hannah; Simon, David; Tascilar, Koray; Baraf, Herbert S. B.; Schett, Georg; et al. (ANNALS OF THE RHEUMATIC DISEASES, 2019)
CRIS-Team WoS Importer:2019-07-12

Small Molecule Tyrosine Kinase Inhibitor Nintedanib Reduces Development of Cardiac Allograft Vasculopathy in Murine Aortic Allografts - Gocht, Annika; Spriewald, Bernd; Distler, Jörg; Ramsperger-Gleixner, Martina; Ensminger, Stephan M.; Weyand, Michael; Heim, Christian (Transplantation Direct, 2018)
Background: Nintedanib is a small molecule tyrosine kinase inhibitor that blocks the action of the platelet-derived growth factor receptor (PDGFR), the vascular endothelial growth factor receptor (VEGFR) and the fibroblast growth factor receptor. All of these receptors have been shown to be involved in the development of cardiac allograft vasculopathy (CAV) after heart transplantation. We therefore hypothesized that blocking these tyrosine kinase receptors with nintedanib could prevent CAV. Methods: CBA/JRj (H2k) mice underwent an abdominal aortic transplantation with a graft derived from fully allogeneic C57BL/6JRj (H2b) mice. Nintedanib was given daily from the first day after transplantation until harvest on day 14 for polymerase chain reaction analysis of intragraft cytokine expression or harvest on day 30 for histological analysis of the graft. Results: Nintedanib treatment resulted in significantly reduced neointima formation in the aortic graft compared with untreated control allografts. Interestingly, the immigration of smooth muscle cells into the neointima was markedly reduced while graft infiltrating macrophages and T cells were not altered in nintedanib-treated animals. The expression of the growth factor PDGF was significantly reduced in the nintedanib group going along with a distinctly reduced expression of the corresponding receptors PDGFR α and -β. Conclusions: Treatment with nintedanib caused a significant reduction of CAV development after aortic transplantation in mice. We hypothesize the attenuated neointima formation in nintedanib-treated animals to be mediated by a direct inhibition of intimal smooth muscle cell proliferation via reduced expression of PDGF and the appropriate receptors PDGFR α + β.
EVALuna2:34648

Soluble CD83 modulates human-monocyte-derived macrophages toward alternative phenotype, function, and metabolism. - Peckert-Maier, Katrin; Wild, Andreas; Sprißler, Laura; Fuchs, Maximilian; Beck, Philipp; Auger, Jean-Philippe; Sinner, Pia; Strack, Astrid; Mühl-Zürbes, Petra; Ramadan, Ntilek; Kunz, Meik; Krönke, Gerhard; et al. (Frontiers in Immunology, 2023)
Alterations in macrophage (Mφ) polarization, function, and metabolic signature can foster development of chronic diseases, such as autoimmunity or fibrotic tissue remodeling. Thus, identification of novel therapeutic agents that modulate human Mφ biology is crucial for treatment of such conditions. Herein, we demonstrate that the soluble CD83 (sCD83) protein induces pro-resolving features in human monocyte-derived Mφ biology. We show that sCD83 strikingly increases the expression of inhibitory molecules including ILT-2 (immunoglobulin-like transcript 2), ILT-4, ILT-5, and CD163, whereas activation markers, such as MHC-II and MSR-1, were significantly downregulated. This goes along with a decreased capacity to stimulate alloreactive T cells in mixed lymphocyte reaction (MLR) assays. Bulk RNA sequencing and pathway analyses revealed that sCD83 downregulates pathways associated with pro-inflammatory, classically activated Mφ (CAM) differentiation including HIF-1A, IL-6, and cytokine storm, whereas pathways related to alternative Mφ activation and liver X receptor were significantly induced. By using the LXR pathway antagonist GSK2033, we show that transcription of specific genes (e.g., PPARG, ABCA1, ABCG1, CD36) induced by sCD83 is dependent on LXR activation. In summary, we herein reveal for the first time mechanistic insights into the modulation of human Mφ biology by sCD83, which is a further crucial preclinical study for the establishment of sCD83 as a new therapeutical agent to treat inflammatory conditions.
EVALuna2:549687

Soluble CD83 Triggers Resolution of Arthritis and Sustained Inflammation Control in IDO Dependent Manner - Royzman, Dmytro; Andrev, Darja; Stich, Lena; Rauh, Manfred; Bäuerle, Tobias; Ellmann, Stephan; Boon, Louis; Kindermann, Markus; Peckert, Katrin; Bozec, Aline; Schett, Georg; Steinkasserer, Alexander; et al. (Frontiers in Immunology, 2019)
Interference with autoimmune-mediated cytokine production is a key yet poorly developed approach to treat autoimmune and inflammatory diseases such as rheumatoid arthritis. Herein, we show that soluble CD83 (sCD83) enhances the resolution of autoimmune antigen-induced arthritis (AIA) by strongly reducing the expression levels of cytokines such as IL-17A, IFN gamma, IL-6, and TNF alpha within the joints. Noteworthy, also the expression of RANKL, osteoclast differentiation, and joint destruction was significantly inhibited by sCD83. In addition, osteoclasts which were cultured in the presence of synovial T cells, derived from sCD83 treated AIA mice, showed a strongly reduced number of multinuclear large osteoclasts compared to mock controls. Enhanced resolution of arthritis by sCD83 was mechanistically based on IDO, since inhibition of IDO by 1-methyltryptophan completely abrogated sCD83 effects on AIA. Blocking experiments, using anti-TGF-beta antibodies further revealed that also TGF-beta is mechanistically involved in the sCD83 induced reduction of bone destruction and cartilage damage as well as enhanced resolution of inflammation. Resolution of arthritis was associated with increased numbers of regulatory T cells, which are induced in a sCD83-IDO-TGF-beta dependent manner. Taken together, sCD83 represents an interesting approach for downregulating cytokine production, inducing regulatory T cells and inducing resolution of autoimmune arthritis.
CRIS-Team WoS Importer:2019-04-12

Sorafenib induces sustained molecular remission in FLT3-ITD positive AML with relapse after second allogeneic stem cell transplantation without exacerbation of acute GVHD: A case report - Winkler, Julia; Rech, D.; Kallert, Siegfried; Rech, Jürgen; Meidenbauer, Norbert; Rösler, Wolf; Mackensen, Andreas (Leukemia Research, 2010)
CRIS-Team Scopus Importer:2021-02-03

SPATIOTEMPORAL DYNAMICS OF BONE LOSS BEFORE AND AFTER THE ONSET OF RHEUMATOID ARTHRITIS - Tascilar, Koray; Simon, David; Liphardt, Anna-Maria; Meinderink, Timo; Bayat, Sara; Rech, Jürgen; Hueber, A.; Krönke, Gerhard; Schett, Georg; Kleyer, Arnd (ANNALS OF THE RHEUMATIC DISEASES, 2021)
CRIS-Team WoS Importer:2021-10-01

Spondyloarthritis: may the force be with you? - Mcgonagle, Dennis; Thomas, Rebecca C.; Schett, Georg (Annals of the Rheumatic Diseases, 2014)
EVALuna2:12926

Standards of care for people with rheumatoid arthritis in Europe : Translation and comments of the eumusc.net recommendations supported by EULAR performed by a national task force of the professional organisations DGRh and VRA supported by "Deutsche Rheu - Braun, J.; Krause, A.; Aringer, M.; Burmester, G.; Bessler, F.; Engel, J. -M.; Faubel, U.; Fischer-Betz, R.; Genth, E.; Gromnica-Ihle, E.; Hellmich, B.; Koetter, I.; et al. (Zeitschrift für Rheumatologie, 2016)
In a joint initiative by the boards of the German Society for Rheumatology (DGRh) and the Association of Rheumatology Clinics (VRA) the European "standards of care" for rheumatoid arthritis, recently suggested by the European Musculoskeletal Conditions Surveillance and Information Network (eumusc.net) and supported by the European League Against Rheumatism (EULAR), were translated and annotated. The recommendations include aspects of the management of the disease, actual medical care, and access to information - this includes all types of support people with RA need, and, last but not least communication of the necessary knowledge. Furthermore, health care structures such as the availability of medical staff with relevant expertise are also important.
EVALuna2:13278

STAT3 activation through IL-6/IL-11 in cancer-associated fibroblasts promotes colorectal tumour development and correlates with poor prognosis - Heichler, Christina; Scheibe, Kristina; Schmied, Anabel; Geppert, Carol-Immanuel; Schmid, Benjamin; Wirtz, Stefan; Thoma, Oana Maria; Kramer, Viktoria; Waldner, Maximilian; Büttner, Christian; Farin, Henner; Pešić, Marina; et al. (Gut, 2019)
Objective: Cancer-associated fibroblasts (CAFs) influence the tumour microenvironment and tumour growth. However, the role of CAFs in colorectal cancer (CRC) development is incompletely understood. Design: We quantified phosphorylation of STAT3 (pSTAT3) expression in CAFs of human colon cancer tissue using a tissue microarray (TMA) of 375 patients, immunofluorescence staining and digital pathology. To investigate the functional role of CAFs in CRC, we took advantage of two murine models of colorectal neoplasia and advanced imaging technologies. In loss-of-function and gain-of-function experiments, using genetically modified mice with collagen type VI (COLVI)-specific signal transducer and activator of transcription 3 (STAT3) targeting, we evaluated STAT3 signalling in fibroblasts during colorectal tumour development. We performed a comparative gene expression profiling by whole genome RNA-sequencing of fibroblast subpopulations (COLVI+ vs COLVI-) on STAT3 activation (IL-6 vs IL-11). Results: The analysis of pSTAT3 expression in CAFs of human TMAs revealed a negative correlation of increased stromal pSTAT3 expression with the survival of colon cancer patients. In the loss-of-function and gain-of-function approach, we found a critical role of STAT3 activation in fibroblasts in driving colorectal tumourigenesis in vivo. With different imaging technologies, we detected an expansion of activated fibroblasts in colorectal neoplasias. Comparative gene expression profiling of fibroblast subpopulations on STAT3 activation revealed the regulation of transcriptional patterns associated with angiogenesis. Finally, the blockade of proangiogenic signalling significantly reduced colorectal tumour growth in mice with constitutive STAT3 activation in COLVI+ fibroblasts. Conclusion: Altogether our work demonstrates a critical role of STAT3 activation in CAFs in CRC development.
CRIS-Team Scopus Importer:2019-11-19
Keywords: colorectal cancer

STAT3 As an Important Integrator of Profibrotic Pathways in Systemic Sclerosis - Sumova, Barbora; Mallano, Tatjana; Chen, Chih-Wei; Distler, Alfiya; Bergmann, Christina; Distler, Oliver; Schett, Georg; Senolt, Ladislav; Distler, Jörg; Chakraborty, Debomita; Ramming, Andreas (2017)
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Stepwise asynchronous telehealth assessment of patients with suspected axial spondyloarthritis: results from a pilot study - Labinsky, Hannah; von Rohr, Sophie; Raimondo, Maria Gabriella; Bohr, Daniela; Morf, Harriet; Horstmann, Britta; Seese, Felix; Proft, Fabian; Muehlensiepen, Felix; Boy, Katharina; Kuhn, Sebastian; Schmalzing, Marc; et al. (Rheumatology International, 2023)
Patients with axial spondyloarthritis (axSpA) suffer from one of the longest diagnostic delays among all rheumatic diseases. Telemedicine (TM) may reduce this diagnostic delay by providing easy access to care. Diagnostic rheumatology telehealth studies are scarce and largely limited to traditional synchronous approaches such as resource-intensive video and telephone consultations. The aim of this study was to investigate a stepwise asynchronous telemedicine-based diagnostic approach in patients with suspected axSpA. Patients with suspected axSpA completed a fully automated digital symptom assessment using two symptom checkers (SC) (bechterew-check and Ada). Secondly, a hybrid stepwise asynchronous TM approach was investigated. Three physicians and two medical students were given sequential access to SC symptom reports, laboratory and imaging results. After each step, participants had to state if axSpA was present or not (yes/no) and had to rate their perceived decision confidence. Results were compared to the final diagnosis of the treating rheumatologist. 17 (47.2%) of 36 included patients were diagnosed with axSpA. Diagnostic accuracy of bechterew-check, Ada, TM students and TM physicians was 47.2%, 58.3%, 76.4% and 88.9% respectively. Access to imaging results significantly increased sensitivity of TM-physicians (p < 0.05). Mean diagnostic confidence of false axSpA classification was not significantly lower compared to correct axSpA classification for both students and physicians. This study underpins the potential of asynchronous physician-based telemedicine for patients with suspected axSpA. Similarly, the results highlight the need for sufficient information, especially imaging results to ensure a correct diagnosis. Further studies are needed to investigate other rheumatic diseases and telediagnostic approaches.
CRIS-Team Scopus Importer:2023-07-07
Keywords: Diagnosis; Health service research; Spondyloarthritis; Symptom checker; Telehealth; Telemedicine

Stimulation of the soluble guanylate cyclase (sGC) inhibits fibrosis by blocking non-canonical TGF? signalling - Beyer, Christian; Zenzmaier, Christoph; Palumbo-Zerr, Katrin; Mancuso, Rossella; Distler, Alfiya; Dees, Clara; Zerr, Pawel; Huang, Jingang; Maier, Christiane; Pachowsky, Milena; Friebe, Andreas; Sandner, Peter; et al. (Annals of the Rheumatic Diseases, 2015)
We have previously described the antifibrotic role of the soluble guanylate cyclase (sGC). The mode of action, however, remained elusive. In the present study, we describe a novel link between sGC signalling and transforming growth factor ? (TGF?) signalling that mediates the antifibrotic effects of the sGC.Human fibroblasts and murine sGC knockout fibroblasts were treated with the sGC stimulator BAY 41-2272 or the stable cyclic guanosine monophosphate (cGMP) analogue 8-Bromo-cGMP and stimulated with TGF?. sGC knockout fibroblasts were isolated from sGCI(fl/fl) mice, and recombination was induced by Cre-adenovirus. In vivo, we studied the antifibrotic effects of BAY 41-2272 in mice overexpressing a constitutively active TGF-?1 receptor.sGC stimulation inhibited TGF?-dependent fibroblast activation and collagen release. sGC knockout fibroblasts confirmed that the sGC is essential for the antifibrotic effects of BAY 41-2272. Furthermore, 8-Bromo-cGMP reduced TGF?-dependent collagen release. While nuclear p-SMAD2 and 3 levels, SMAD reporter activity and transcription of classical TGF? target genes remained unchanged, sGC stimulation blocked the phosphorylation of ERK. In vivo, sGC stimulation inhibited TGF?-driven dermal fibrosis but did not change p-SMAD2 and 3 levels and TGF? target gene expression, confirming that non-canonical TGF? pathways mediate the antifibrotic sGC activity.We elucidated the antifibrotic mode of action of the sGC that increases cGMP levels, blocks non-canonical TGF? signalling and inhibits experimental fibrosis. Since sGC stimulators have shown excellent efficacy and tolerability in phase 3 clinical trials for pulmonary arterial hypertension, they may be further developed for the simultaneous treatment of fibrosis and vascular disease in systemic sclerosis.
EVALuna2:12978

Stress system dysregulation in pediatric generalized anxiety disorder associated with comorbid depression - Funke, R.; Eichler, Anna; Distler, Jörg; Golub, Yulia; Kratz, Oliver; Moll, Gunther (Stress and Health, 2016)
Because chronic stress is an important risk factor for anxiety states and depressive disorders, we studied hypothalamus-pituitary-adrenal (HPA) axis and sympathetic system activity via changes in cortisol and alpha amylase activity levels in pediatric generalized anxiety disorder (GAD) patients (n = 26) with comorbid depression and a healthy comparison group (n = 26). Morning plasma cortisol and diurnal profiles of salivary cortisol and salivary alpha amylase (sAA) activity were assessed, also reactivity of HPA-axis, sAA activity, and heart rate following a psychosocial stressor (Trier Social Stress Test for children). GAD patients with comorbid depression showed increased morning plasma and salivary cortisol levels, ameliorating throughout in-patient treatment, and higher sAA activity in their diurnal profile. Both HPA and sympathetic activity positively correlated with the severity of anxiety and depression. We also demonstrated a blunted HPA and sympathetic response to acute stress in patients. This pattern of neuroendocrine and sympathetic changes seems to be distinct from the one previously reported in pediatric patients with only social anxiety or depressive disorders. We propose morning plasma and saliva cortisol levels as potential physiological indicators for supporting the evaluation of symptoms' severity and treatment progress in children with GAD and comorbid depressive disorder.
EVALuna2:23891

Stromal cell regulation of inflammatory responses - Friscic, Jasna; Hoffmann, Markus (Current Opinion in Immunology, 2022)
In the last fifteen years it has become apparent that tissue resident mesenchymal cells such as fibroblasts, which are the structural elements of all organs, play a cardinal role in the pathology of immune-mediated inflammatory diseases. We now know that all fibroblasts originate from universal pan organ cellular ancestors and that they are diversified into more specific subsets according to the functional needs of their home tissue-and its activation state. In arthritis, a plethora of activated joint-resident and migrating fibroblast types have been recently described that are central for pathogenesis and persistence of inflammatory joint-disease. Here we provide a current overview on the multiple inflammatory and immune related functions of fibroblasts and how they could be curbed to induce long-lasting abatement of disease.
CRIS-Team WoS Importer:2021-12-10

Stromal-driven and Amyloid β-dependent induction of neutrophil extracellular traps modulates tumor growth - Munir, Hafsa; Jones, James O.; Janowitz, Tobias; Hoffmann, Markus; Euler, Maximilien; Martins, Carla P.; Welsh, Sarah J.; Shields, Jacqueline D. (Nature Communications, 2021)
Tumors consist of cancer cells and a network of non-cancerous stroma. Cancer-associated fibroblasts (CAF) are known to support tumorigenesis, and are emerging as immune modulators. Neutrophils release histone-bound nuclear DNA and cytotoxic granules as extracellular traps (NET). Here we show that CAFs induce NET formation within the tumor and systemically in the blood and bone marrow. These tumor-induced NETs (t-NETs) are driven by a ROS-mediated pathway dependent on CAF-derived Amyloid β, a peptide implicated in both neurodegenerative and inflammatory disorders. Inhibition of NETosis in murine tumors skews neutrophils to an anti-tumor phenotype, preventing tumor growth; reciprocally, t-NETs enhance CAF activation. Mirroring observations in mice, CAFs are detected juxtaposed to NETs in human melanoma and pancreatic adenocarcinoma, and show elevated amyloid and β-Secretase expression which correlates with poor prognosis. In summary, we report that CAFs drive NETosis to support cancer progression, identifying Amyloid β as the protagonist and potential therapeutic target.
CRIS-Team Scopus Importer:2021-02-12

STRUCTURAL DAMAGE PROGRESSION IN PATIENTS TREATED WITH METHOTREXATE, BARICITINIB MONOTHERAPY OR BARICITINIB plus METHOTREXATE BASED ON THEIR LEVEL OF CLINICAL RESPONSE IN THE PHASE 3 RA-BEGIN STUDY - Van Der Heijde, D.; Durez, P.; Schett, Georg; Naredo, E.; Ostergaard, M.; Meszaros, G.; Bello, N.; De La Torre, I.; Lopez-Romero, P.; Schlichting, D.; Nantz, E.; Fleischmann, R. (2017)
EVALuna2:35028

Structural damage progression in patients with early rheumatoid arthritis treated with methotrexate, baricitinib, or baricitinib plus methotrexate based on clinical response in the phase 3 RA-BEGIN study - Van Der Heijde, Desiree; Durez, Patrick; Schett, Georg; Naredo, Esperanza; Ostergaard, Mikkel; Meszaros, Gabriella; De Leonardis, Francesco; De La Torre, Inmaculada; Lopez-Romero, Pedro; Schlichting, Douglas; Nantz, Eric; Fleischmann, Roy (Clinical Rheumatology, 2018)
The objective of this study was to evaluate structural damage progression based on clinical response in rheumatoid arthritis patients with no or limited prior disease-modifying anti-rheumatic drug treatment receiving the Janus kinase (JAK)1/JAK2 inhibitor baricitinib 4 mg, methotrexate (MTX), or the combination. Data from the phase 3 RA-BEGIN study were analysed post hoc. Proportions of patients with structural damage progression (change from baseline greater than the smallest detectable change in modified total Sharp score) at week 52 were evaluated based on sustained Disease Activity Score for 28-joint count with serum high-sensitivity C-reactive protein (DAS28-hsCRP) ≤ 3.2 or Simplified Disease Activity Index (SDAI) score ≤ 11; no formal statistical comparisons between treatments were performed to test these proportions. Baseline factors associated with risk of structural damage progression, including Clinical Disease Activity Index (CDAI) score, were identified using multivariate analysis. Patients achieving versus not achieving sustained DAS28-hsCRP ≤ 3.2 or SDAI score ≤ 11 were less likely to experience structural damage progression at week 52. In patients achieving these responses, structural damage progression was less likely with baricitinib monotherapy or plus MTX than with MTX monotherapy. In patients not achieving these sustained clinical thresholds, structural damage progression was less likely with baricitinib plus MTX than with either monotherapy. Independent of treatment, baseline factors significantly associated with increased risk of structural damage progression included higher hsCRP and CDAI score, smoking, female sex, and lower body mass index. In conclusion, patients achieving versus not achieving sustained DAS28-hsCRP ≤ 3.2 or SDAI score ≤ 11 were less likely to show structural damage progression, irrespective of treatment.
EVALuna2:34479

STRUCTURAL ENTHESEAL LESIONS IN PSORIASIS PATIENTS ARE ASSOCIATED WITH AN INCREASED RISK OF PROGRESSION TO PSORIATIC ARTHRITIS - A PROSPECTIVE COHORT STUDY - Simon, David; Tascilar, K.; Kleyer, Arnd; Bayat, Sara; Kampylafka, E.; Hueber, Axel; Rech, Jürgen; Schuster, Louis; Engel, K.; Sticherling, Michael; Schett, Georg (ANNALS OF THE RHEUMATIC DISEASES, 2020)
CRIS-Team WoS Importer:2020-08-21

Structural insights into heme binding to IL-36α proinflammatory cytokine - Wißbrock, Amelie; Goradia, Nishit B.; Kumar, Amit; Paul George, Ajay Abisheck; Kühl, Toni; Bellstedt, Peter; Ramachandran, Ramadurai; Hoffmann, Patrick; Galler, Kerstin; Popp, Jürgen; Neugebauer, Ute; Hampel, Kornelia; et al. (Scientific Reports, 2019)
Cytokines of the interleukin (IL)-1 family regulate immune and inflammatory responses. The recently discovered IL-36 family members are involved in psoriasis, rheumatoid arthritis, and pulmonary diseases. Here, we show that IL-36α interacts with heme thereby contributing to its regulation. Based on in-depth spectroscopic analyses, we describe two heme-binding sites in IL-36α that associate with heme in a pentacoordinated fashion. Solution NMR analysis reveals structural features of IL-36α and its complex with heme. Structural investigation of a truncated IL-36α supports the notion that the N-terminus is necessary for association with its cognate receptor. Consistent with our structural studies, IL-36-mediated signal transduction was negatively regulated by heme in synovial fibroblast-like synoviocytes from rheumatoid arthritis patients. Taken together, our results provide a structural framework for heme-binding proteins and add IL-1 cytokines to the group of potentially heme-regulated proteins.
CRIS-Team Scopus Importer:2019-11-26

Student-led clinics and ePROs to accelerate diagnosis and treatment of patients with axial spondyloarthritis: results from a prospective pilot study - von Rohr, Sophie; Knitza, Johannes; Grahammer, Manuel; Schmalzing, Marc; Kuhn, Sebastian; Schett, Georg; Ramming, Andreas; Labinsky, Hannah (Rheumatology International, 2023)
We aimed to investigate (1) student-led clinics and (2) electronic patient-reported outcomes (ePROs) to accelerate diagnosis and treatment of patients with axial spondyloarthritis (axSpA). Patients with suspected axSpA completed an initial student-led clinic visit (T-1) prior to their planned actual rheumatologist visit (T0). Acceleration of patient appointment and NSAID therapy start, availability of diagnostic findings, and treatment response at T0 were evaluated. Beginning at T-1, patients completed electronic BASDAI questionnaires every 2 weeks. Concordance of paper-based and electronic BASDAI was evaluated. Patient acceptance of ePRO reporting and student-led clinics was measured using the net promoter score (NPS). 17/36 (47.2%) included patients were diagnosed with axSpA. Student-led clinics (T-1) significantly accelerated patient appointments by more than 2 months (T0, T-1, p < 0.0001) and axSpA guideline-conform NSAID treatment (p < 0.0001). At T0, diagnostic workup was completed for all patients and 7/17 (41.2%) axSpA patients presented with a clinically important improvement or were in remission. 34/36 (94.4%) patients completed at least 80% of the ePROs between T-1 and T0. Electronic and paper-administered BASDAI correlated well (r = 0.8 p < 0.0001). Student-led clinics and ePROs were well accepted by patients with NPS scores of + 62.0% (mean ± SD 9.2/10.0 ± 0.9) and + 30.5% (mean ± SD 8.0/10.0 ± 1.7), respectively. In conclusion, student-led clinics and ePRO monitoring were well accepted, accelerated diagnostic workup and treatment in patients with axSpA.
CRIS-Team Scopus Importer:2023-08-11
Keywords: Axial spondyloarthritis; axSpA; Diagnostic delay; Electronic patient-reported outcome; ePRO; Student

Study: P. jirovecii Pathogen Quantification and Resistance Testing in Patients with Pneumocystis pneumonia (PCP) and Pneumocystis Colonization - Riebold, D.; Stocker, H.; Koehler, P.; Bauer, T. T.; Kroegel, C.; Harrer, Thomas; Slevogt, H. (MYCOSES, 2020)
CRIS-Team WoS Importer:2020-10-02

Stunning of neutrophils accounts for the anti-inflammatory effects of clodronate liposomes - Culemann, Stephan; Knab, Katharina; Euler, Maximilien; Wegner, Anja; Garibagaoglu, Hilal; Ackermann, Jochen; Fischer, Kim; Kienhoefer, Deborah; Crainiciuc, Georgiana; Hahn, Jonas; Grüneboom, Anika; Nimmerjahn, Falk; et al. (Journal of Experimental Medicine, 2023)
The authors show that the anti-inflammatory effects of clodronate liposomes do not result from the depletion of mononuclear phagocytes but from a functional stunning of polymorphonuclear neutrophils. These findings necessitate a critical revision of the current literature on the role of monocytes and macrophages in inflammation.
CRIS-Team WoS Importer:2023-04-28

Subclinical joint inflammation in patients with psoriasis without concomitant psoriatic arthritis: a cross-sectional and longitudinal analysis - Faustini, Francesca; Simon, Dominic; Oliveira, Isabelle; Kleyer, Arnd; Haschka, Judith; Englbrecht, Matthias; Cavalcante, Alan Rodrigues; Kraus, Sebastian; Tabosa, Taiane Ponte; Figueiredo, Camille; Hueber, Axel; Kocijan, Roland; et al. (Annals of the Rheumatic Diseases, 2016)
To search for subclinical inflammatory joint disease in patients with psoriasis without psoriatic arthritis (PsA), and to determine whether such changes are associated with the later development of PsA.Eighty-five subjects without arthritis (55 with psoriasis and 30 healthy controls) received high field MRI of the hand. MRI scans were scored for synovitis, osteitis, tenosynovitis and periarticular inflammation according to the PsAMRIS method. Patients with psoriasis additionally received complete clinical investigation, high-resolution peripheral quantitative CT for detecting erosions and enthesiophytes and were followed up for at least 1 year for the development of PsA.47% of patients with psoriasis showed at least one inflammatory lesion on MRI. Synovitis was the most prevalent inflammatory lesion (38%), while osteitis (11%), tenosynovitis (4%) and periarticular inflammation (4%) were less frequent. The mean (±SD) PsAMRIS synovitis score was 3.0±2.5 units. Enthesiophytes and bone erosions were not different between patients with psoriasis with or without inflammatory MRI changes. The risk for developing PsA was as high as 60% if patients had subclinical synovitis and symptoms related to arthralgia, but only 13% if patients had normal MRIs and did not report arthralgia.Prevalence of subclinical inflammatory lesions is high in patients with cutaneous psoriasis. Arthralgia in conjunction with MRI synovitis constitutes a high-risk constellation for the development of PsA.
EVALuna2:13265

SUBCLINICAL MRI INFLAMMATION DOES NOT PREDICT RELAPSE RISK IN RHEUMATOID ARTHRITIS PATIENTS TAPERING DMARDS - Doliveira, I.; Mensing, W.; Figueiredo, C.; Englbrecht, Matthias; Haschka, J.; Hueber, Axel; Kleyer, Arnd; Schett, Georg; Rech, Jürgen; Cavallaro, Alexander Josef (2016)
EVALuna2:13480

Subclinical synovitis: let's discuss prognosis before treatment - Yalcin-Mutlu, Melek; Tascilar, Koray (The Lancet Rheumatology, 2024)
CRIS-Team Scopus Importer:2024-02-02

SUBJECTIVE ASSESSMENT OF PHYSICAL FUNCTION DOES NOT SUFFICIENTLY EXPLAIN VARIANCE OF MEASURED HAND FUNCTION AND GRIP STRENGTH IN ARTHRITIS PATIENTS AND NON-ARTHRITIS CONTROLS - Liphardt, Anna-Maria; Tascilar, Koray; Coppers, Birte; Manger, Eva; Liehr, Sonja; Bieniek, Lisa Maria; Bayat, Sara; Simon, David; Sticherling, Michael; Rech, Jürgen; Hueber, A.; Schett, Georg; et al. (ANNALS OF THE RHEUMATIC DISEASES, 2022)
CRIS-Team WoS Importer:2022-11-04

Successful Generation of CD19 Chimeric Antigen Receptor T Cells from Patients with Advanced Systemic Lupus Erythematosus - Kretschmann, S.; Völkl, Simon; Reimann, Hannah; Krönke, Gerhard; Schett, Georg; Achenbach, Susanne; Lutzny-Geier, Gloria; Müller, Fabian; Mougiakakos, Dimitrios; Dingfelder, Janin; Flamann, Cindy; Hanssens, L.; et al. (Transplantation and Cellular Therapy, 2022)
Although it has been shown that the production of functional chimeric antigen receptor T cells is feasible in patients with B-cell malignancies, it is currently unclear whether sufficient amounts of functional autologous CAR T cells can be generated from patients with autoimmune diseases. Intrinsic T-cell abnormalities and T-cell–targeted immune suppression in patients with autoimmunity may hamper the retrieval of sufficient T cells and their transduction and expansion into CAR T cells. Patients with active systemic lupus erythematosus (SLE) underwent leukapheresis after tapering glucocorticoids and stopping T-cell–suppressive drugs. This material was used as source for manufacturing anti-CD19 CAR T-cell products (CAR) in clinical scale. Cells were transduced with a lentiviral anti-CD19 CAR vector and expanded under good manufacturing practice (GMP) conditions using a closed, semi-automatic system. Functionality of these CAR T cells derived from autoimmune patient cells was tested in vitro. Six SLE patients were analyzed. Leukapheresis could be successfully performed in all patients yielding sufficient T-cell numbers for clinical scale CAR T-cell production. In addition, CAR T cells showed high expansion rates and viability, leading to CAR T cells in sufficient doses and quality for clinical use. CAR T cells from all patients showed specific cytotoxicity against CD19+ cell lines in vitro. GMP grade generation of CD19 CAR T-cell products suitable for clinical use is feasible in patients with autoimmune disease.
CRIS-Team Scopus Importer:2022-12-23
Keywords: Chimeric antigen receptor; Systemic lupus erythematosus; T cells

Successful remission induction with a combination therapy of rituximab, cyclophosphamide, and steroids in a patient with refractory optic neuritis in Wegener's granulomatosis - Huchzermeyer, Cord; Mardin, Christian Y.; Holbach, Leonard; Zwerina, Jochen; Schett, Georg; Rech, Juergen (Clinical Rheumatology, 2013)
A 56-year old patient with a history of limited Wegener's granulomatosis presented with signs and symptoms of optic neuritis. Radiologic signs of orbital inflammation were absent. Testing of visual acuity and visual field allowed close monitoring of disease activity. Thus, rapid improvement of visual function was achieved with high-dose steroids. Despite maintenance therapy with cyclophosphamide recurrence occurred repeatedly as soon as tapering of steroids was begun. After remission induction with rituximab, the patient retained good visual function under maintenance therapy with azathioprine and low-dose corticosteroids. Optic neuritis in Wegener's granulomatosis without signs of orbital involvement is rare and most likely caused by occlusive vasculitis of the vasa nervorum. In this patient with optic neuritis refractory to conventional therapy, rituximab in combination with cyclophosphamide and corticosteroids was well tolerated and successfully used for remission induction, followed by maintenance therapy with azathioprine and low dose corticosteroids.
EVALuna2:12699

Successful treatment of adult-onset Still's disease refractory to TNF and IL-1 blockade by IL-6 receptor blockade - Rech, Jürgen; Ronneberger, Monika; Englbrecht, Matthias; Finzel, Stephanie; Katzenbeisser, Julia; Manger, Karin; Manger, Bernhard; Schett, Georg (Annals of the Rheumatic Diseases, 2011)
CRIS-Team Scopus Importer:2021-02-03

Successful treatment of refractory palmoplantar psoriasis in a psoriatic arthritis patient with the JAK inhibitor tofacitinib - Valor-Mendez, Larissa; Sticherling, Michael; Kleyer, Arnd; Schett, Georg (Clinical and Experimental Rheumatology, 2021)
CRIS-Team WoS Importer:2021-03-26

"Suddenly You Are a Person at Risk of Developing Rheumatoid Arthritis!" Different Perspectives of Individuals on Predictive Testing - Results of an International Qualitative Interview Study - Mosor, Erika; Stoffer, Michaela; Steiner, Guenter; Raza, Karim; Stack, Rebecca J.; Simons, Gwenda; Falahee, Marie; Schett, Georg; Englbrecht, Matthias; Smolen, Josef S.; Hueber, Axel; Stamm, Tanja (2017)
EVALuna2:33438

Super-Resolution for CEST MRI - Folle, Lukas; Tkotz, Katharina; Liebert, Andrzej; Gadjimuradov, Fasil; Kapsner, Lorenz; Fabian, Moritz; Bickelhaupt, Sebastian; Simon, David; Kleyer, Arnd; Krönke, Gerhard; Roemer, Frank; Zaiß, Moritz; et al. (Joint annual meeting ISMRM-ESMRMB ISMRT, 2022)
The resolution of chemical exchange saturation transfer (CEST) magnetic resonance imaging is limited by physical constraints. To visualize metabolic processes of small structures using CEST in patients knees, an increased resolution is necessary. In this work, we compared trilinear interpolation and zero-filling to neural network-based approaches to estimate a high-resolution image given the corresponding low-resolution data. We could show that a substantial quantitative improvement using neural networks could be achieved for unsaturated images while maintaining a comparable CEST contrast. Generalization of the method to brain CEST MRI was achieved without retraining of the networ
Keywords: MRI; Super-resolution

Suppression of lupus nephritis and skin lesions in MRL/lpr mice by administration of the topoisomerase I inhibitor irinotecan - Keil, Andreas; Hall, Sean R.; Koerner, Meike; Herrmann, Martin; Schmid, Ralph A.; Frese, Steffen (Arthritis Research & Therapy, 2016)
Since the precise mechanism for the pathogenesis of systemic lupus erythematosus (SLE) is unknown, no targeted therapies in addition to immunosuppression are available so far. We recently demonstrated that administration of the topoisomerase I (topo I) inhibitor irinotecan at extremely low concentrations reversed established lupus nephritis in NZB/NZW mice. While profound immunosuppression was absent, we proposed changes in DNA relaxation and anti-double-stranded (ds)DNA antibody binding as the underlying mechanism. To exclude that these effects were restricted to NZB/NZW mice, irinotecan was used in a genetically different strain of lupus-prone mice.MRL/lpr mice were treated with high- and low-dose irinotecan beginning at 8 weeks of age. Treatment was repeated every fourth week. In vitro, DNA was relaxed by recombinant topo I, and altered anti-dsDNA antibody binding was measured by enzyme-linked immunosorbent assay.Administration of both high- and low-dose irinotecan prevented proteinuria and prolonged survival in MRL/lpr mice. Moreover, both concentrations of irinotecan significantly improved histopathology of the skin at 18 weeks of age. While only high-dose irinotecan diminished the numbers of plasmablasts and double-negative T cells, no changes in IgG-secreting cells or anti-dsDNA IgG were observed. In vitro, relaxation of DNA by topo I increased the binding of anti-dsDNA IgG but not the binding of anti-dsDNA IgM derived from the plasma of MRL/lpr mice.The beneficial effects of topo I inhibition in a second, genetically different strain of lupus-prone mice strongly implicate irinotecan as a new therapeutic option for human SLE.
EVALuna2:13356

Suppression of neutrophils by sodium exacerbates oxidative stress and arthritis - Zlatar, Leticija; Mahajan, Aparna; Munoz Becerra, Marco; Weidner, Daniela; Bila, Galyna; Bilyy, Rostyslav; Titze, Jens; Hoffmann, Markus H.; Schett, Georg; Herrmann, Martin; Steffen, Ulrike; Muñoz, Luis E.; et al. (Frontiers in Immunology, 2023)
Introduction: Typical Western diet, rich in salt, contributes to autoimmune disease development. However, conflicting reports exist about the effect of salt on neutrophil effector functions, also in the context of arthritis. Methods: We investigated the effect of sodium chloride (NaCl) on neutrophil viability and functions in vitro, and in vivo employing the murine K/BxN-serum transfer arthritis (STA) model. Results and discussion: The effects of NaCl and external reactive oxygen species (H2O2) were further examined on osteoclasts in vitro. Hypertonic sodium-rich media caused primary/secondary cell necrosis, altered the nuclear morphology, inhibited phagocytosis, degranulation, myeloperoxidase (MPO) peroxidation activity and neutrophil extracellular trap (NET) formation, while increasing total ROS production, mitochondrial ROS production, and neutrophil elastase (NE) activity. High salt diet (HSD) aggravated arthritis by increasing inflammation, bone erosion, and osteoclast differentiation, accompanied by increased NE expression and activity. Osteoclast differentiation was decreased with 25 mM NaCl or 100 nM H2O2 addition to isotonic media. In contrast to NaCl, external H2O2 had pro-resorptive effects in vitro. We postulate that in arthritis under HSD, increased bone erosion can be attributed to an enhanced oxidative milieu maintained by infiltrating neutrophils, rather than a direct effect of NaCl.
CRIS-Team Scopus Importer:2023-09-01
Keywords: K/BxN serum transfer arthritis; neutrophil extracellular traps (NETs); neutrophils; osteoclasts; reactive oxygen species; sodium chloride

Surgical therapy of anterior cruciate ligament injuries: reconstruction or primary repair and InternalBraceTM augmentation? - a narrative review - Müller, Sebastian; Bühl, Linda; Coppers, Birte; Nüesch, Corina; Mündermann, Annegret; Egloff, Christian (Orthopedics and Traumatology, 2021)

Survey on the working, training, and research conditions of resident physicians in internistic and rheumatological continuing education-BEWUSST. - Proft, Fabian; Vossen, Diana; Baraliakos, Xenofon; Berliner, Michael N.; Fleck, Martin; Keyßer, Gernot; Krause, Andreas; Lorenz, Hanns Martin; Manger, Bernhard; Schuch, Florian; Specker, Christof; Wollenhaupt, Jürgen; et al. (Zeitschrift für Rheumatologie, 2024)
BACKGROUND: Data on the training and continuing education situation of residents in the field of internal medicine and rheumatology are not available for Germany. For this reason, the Commission for Education and Training of the German Society of Rheumatology (DGRh) initiated the BEWUSST survey on the working, training and research conditions of residents in rheumatology. METHODS: A total of 102 questions on the topics of working conditions in everyday professional life, continuing medical education and training, compatibility of career and family, compatibility of work and research, perspectives as a rheumatologist and practical activities were included in an online questionnaire. RESULTS: A total of 102 participants took part in the survey. Of the respondents 48.1% were satisfied with their professional situation, 40.2% of the participants were supervised by a specialist mentor and 54.9% were working as scientists during their work as a physician. A compatibility of family and career was possible for 34.7%. After completion of the residency 52.9% of the respondents aspired to a combined clinical and outpatient activity. CONCLUSION: Half of the trainee rheumatologists are satisfied with their professional activities, although mentoring of the assistants in training should be further improved. With respect to the desired combined clinical and outpatient activity, the existing options should be expanded or new professional fields of activity should be established, so that the specialty remains attractive for the upcoming generations.
EVALuna2:551698

Survival after cryptococcosis in Germany: A retrospective multicenter cohort study of patients diagnosed between 2004 and 2021 - Kessel, Johanna; Rossaert, Anna Catharina; Lingscheid, Tilman; Grothe, Jan; Harrer, Thomas; Wyen, Christoph; Tominski, Daniela; Bollinger, T.; Kehr, Anna Katharina; Kalbitz, Sven; Hoffmann, Christian; Cornely, Oliver; et al. (International Journal of Medical Microbiology, 2024)
Cryptococcosis is the most prevalent fungal infection of the central nervous system worldwide. We performed a retrospective multicenter cohort study to gain insights into the epidemiology of cryptococcosis in Germany. We describe the use of diagnostic tests, clinical management and patient outcome. We included 64 patients with underlying HIV infection (55%) or other predispositions. Molecular typing by MLST documented 20 individual sequence types among 42 typed isolates. A fatal outcome was documented in 14% of patients in the first two months after diagnosis.
CRIS-Team Scopus Importer:2024-03-01
Keywords: AIDS related opportunistic infections; Cryptococcosis; Mortality; Multilocus sequence typing; Risk factor

Sustained clinical remission under infliximab/rituximab combination therapy in a patient with granulomatosis with polyangiitis - Valor-Méndez, Larissa; Kleyer, Arnd; Rech, Jürgen; Manger, Bernhard; Schett, Georg (Autoimmunity Highlights, 2021)
Background: Granulomatosis with polyangiitis (GPA) is a systemic autoimmune disease characterized by small and medium vessel vasculitis. The use of biological therapies such as rituximab and infliximab has improved the treatment of ocular manifestations in GPA. Case report: We report a case of a 45-year-old Caucasian male suffering with rhinitis, sinubronchitis and exophthalmos. These clinical findings, subsequent biopsy and MRI were consistent with positive anti-neutrophil cytoplasm antibody (ANCA)/proteinase-3 and he was diagnosed with GPA with orbital involvement. He was refractory to cyclophosphamide at stable doses of methotrexate and a therapy with rituximab was started. Eventually and because of family planning methotrexate was replaced by azathioprine. Symptoms worsened and MRI revealed an increase in the granulomatous lesion in the orbit. Therefore, we decided to add infliximab to the combination of azathioprine and rituximab, our patient achieved then a long-term response. During the 10 years of the combined treatment, no adverse effects or systemic involvement occurred. Conclusions: This case suggests that the individual use of a combination of rituximab and infliximab may be a promising strategy for the treatment in the long term of refractory orbital GPA.
CRIS-Team Scopus Importer:2021-03-19
Keywords: Combined therapy; Granulomatosis with polyangiitis (GPA); Infliximab; Rituximab

Sweet but dangerous - the role of immunoglobulin G glycosylation in autoimmunity and inflammation - Biermann, Mona; Griffante, G.; Podolska, Malgorzata; Boeltz, Sebastian; Stürmer, Jörg; Munoz, Luis Enrique; Bilyy, R.; Herrmann, Martin; Munoz Becerra, Luis (Lupus, 2016)
Glycosylation is well-known to modulate the functional capabilities of immunoglobulin G (IgG)-mediated cellular and humoral responses. Indeed, highly sialylated and desialylated IgG is endowed with anti- and pro-inflammatory activities, respectively, whereas fully deglycosylated IgG is a rather lame duck, with no effector function besides toxin neutralization. Recently, several studies revealed the impact of different glycosylation patterns on the Fc part and Fab fragment of IgG in several autoimmune diseases, including systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA). Here, we provide a synoptic update summarizing the most important aspects of antibody glycosylation, and the current progress in this field. We also discuss the therapeutic options generated by the modification of the glycosylation of IgG in a potential treatment for chronic inflammatory diseases.
EVALuna2:13284

Swiprosin-1/EFhd2 Controls B Cell Receptor Signaling through the Assembly of the B Cell Receptor, Syk, and Phospholipase C gamma 2 in Membrane Rafts - Kroczek, Carmen; Lang, Christiane; Brachs, Sebastian; Grohmann, Marcus; Duetting, Sebastian; Schweizer, Astrid; Nitschke, Lars; Feller, Stephan M.; Jäck, Hans-Martin; Mielenz, Dirk (Journal of Immunology, 2010)
Compartmentalization of the BCR in membrane rafts is important for its signaling capacity. Swiprosin-1/EFhd2 (Swip-1) is an EF-hand and coiled-coil-containing adaptor protein with predicted Src homology 3 (SH3) binding sites that we identified in membrane rafts. We showed previously that Swip-1 amplifies BCR-induced apoptosis; however, the mechanism of this amplification was unknown. To address this question, we overexpressed Swip-1 and found that Swip-1 amplified the BCR-induced calcium flux in WEH1231, B62.1, and Bal17 cells. Conversely, the BCR-elicited calcium flux was strongly attenuated in Swip-1-silenced WEH1231 cells, and this was due to a decreased calcium mobilization from intracellular stores. Complementation of Swip-1 expression in Swip-1-silenced WEH1231 cells restored the BCR-induced calcium flux and enhanced spleen tyrosine kinase (Syk) tyrosine phosphorylation and activity as well as SLP65/BLNK/BASH and phospholipase C gamma 2 (PLC gamma 2) tyrosine phosphorylation. Furthermore, Swip-1 induced the constitutive association of the BCR itself, Syk, and PLC gamma 2 with membrane rafts. Concomitantly, Swip-1 stabilized the association of BCR with tyrosine-phosphorylated proteins, specifically Syk and PLC gamma 2, and enhanced the constitutive interaction of Syk and PLC gamma 2 with Lyn. Interestingly, Swip-1 bound to the rSH3 domains of the Src kinases Lyn and Fgr, as well as to that of PLC gamma. Deletion of the predicted SH3-binding region in Swip-1 diminished its association and that of Syk and PLC gamma 2 with membrane rafts, reduced its interaction with the SH3 domain of PLC gamma, and diminished the BCR-induced calcium flux. Hence, Swip-1 provides a membrane scaffold that is required for the Syk-, SLP-65-, and PLC gamma 2-dependent BCR-induced calcium flux. The Journal of Immunology, 2010, 184: 3665-3676.

Swiprosin-1/ EFhd2: from Immune Regulator to Personality and Brain Disorders - Kogias, Georgios; Kornhuber, Johannes; Reimer, Dorothea; Mielenz, Dirk; Müller, Christian P. (Neurosignals, 2019)
BACKGROUND/AIMS: Swiprosin-1/ EF-hand domain 2 (EFhd2) is a Ca2+ sensor protein that plays an important role in the immune system. Its abundant expression in the brain, however, suggested also a role in neuronal circuits and behavior. METHODS: Here we review recent discoveries on the structure and molecular function, its role in immunity and its function in the brain regarding behavioral control and pathologies. RESULTS: While EFhd2 did not emerge as a vital protein for brain development, changes in its expression may nevertheless shape the adult behavioral repertoire significantly and contribute to adult personality traits. A defective function of EFhd2 may also render individuals more prone to the development of psychiatric disorders. Most prominently, EFhd2 proved to be a resilience factor protecting from fast establishment of drug addiction. Moreover, EFhd2 is critical for adult neurogenesis and as a modulator of monoaminergic systems. CONCLUSION: Dysregulated activity of EFhd2 is increasingly considered as a contributing factor for the development of numerous neurodegenerative disorders. Whether EFhd2 can be used as biomarker or in therapeutic approaches has to be addressed in future research.
CRIS-Team Scopus Importer:2019-11-26
Keywords: Swiprosin-1; EFhd2; Immunity; Personality; Neurogenesis; Dopamine; Addiction; Neurodegenerative disorders

Swiprosin-1/EFhd2 limits germinal center responses and humoral type 2 immunity - Brachs, Sebastian; Turqueti-Neves, Adriana; Stein, Merle; Reimer, Dorothea; Brachvogel, Bent; Boesl, Michael; Winkler, Thomas; Vöhringer, David; Jäck, Hans-Martin; Mielenz, Dirk (European Journal of Immunology, 2014)
Activated B cells are selected for in germinal centers by regulation of their apoptosis. The Ca2+ -binding cytoskeletal adaptor protein Swiprosin-1/EFhd2 (EFhd2) can promote apoptosis in activated B cells. We therefore hypothesized that EFhd2 might limit humoral immunity by repressing both the germinal center reaction and the expected enhancement of immune responses in the absence of EFhd2. Here, we established EFhd2(-/-) mice on a C57BL/6 background, which revealed normal B- and T-cell development, basal Ab levels, and T-cell independent type 1, and T-cell independent type 2 responses. However, T cell-dependent immunization with sheep red blood cells and infection with the helminth Nippostrongylus brasiliensis (N.b) increased production of antibodies of multiple isotypes, as well as germinal center formation in EFhd2(-/-) mice. In addition, serum IgE levels and numbers of IgE+ plasma cells were strongly increased in EFhd2(-/-) mice, both after primary as well as after secondary N.b infection. Finally, mixed bone marrow chimeras unraveled an EFhd2-dependent B cell-intrinsic contribution to increased IgE plasma cell numbers in N.b-infected mice. Hence, we established a role for EFhd2 as a negative regulator of germinal center-dependent humoral type 2 immunity, with implications for the generation of IgE.
EVALuna2:13618

Switch of inhibitory to agonistic autoantibodies directed against the beta 2-adrenergic receptor in the pathogenesis of pseudoexfoliation syndrome and glaucoma - Hohberger, Bettina; Herrmann, Martin; Schlötzer-Schrehardt, Ursula; Mardin, Christian Y.; Lämmer, Robert; Kunze, Rudolf; Wallukat, Gerd (INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE, 2021)
CRIS-Team WoS Importer:2021-09-17

Synovektomie der großen Gelenke in der Ära der Biologika - Carl, Hans-Dieter; Rech, Jürgen (Zeitschrift für Rheumatologie, 2011)
Since the mid 1980s, a global decrease in surgical procedures related to rheumatoid arthritis (RA) has been documented for joint-preserving procedures such as synovectomy as well as joint replacement surgery. This reflects improvements in the early management of rheumatoid arthritis and availability of more effective medical treatment. The present review summarizes the recent literature on the frequency of orthopaedic surgery in RA patients as well as the role of synovectomy in the rheumatoid hip, knee and shoulder in times of biological RA therapy. © 2011 Springer-Verlag.
CRIS-Team Scopus Importer:2021-02-03
Keywords: Biologicals; Joint; Rheumatoid arthritis; Surgery; Synovectomy

Synovial Macrophage and Fibroblast Heterogeneity in Joint Homeostasis and Inflammation - Knab, Katharina; Chambers, David; Krönke, Gerhard (Frontiers in Medicine, 2022)
The synovial tissue is an immunologically challenging environment where, under homeostatic conditions, highly specialized subsets of immune-regulatory macrophages and fibroblasts constantly prevent synovial inflammation in response to cartilage- and synovial fluid-derived danger signals that accumulate in response to mechanical stress. During inflammatory joint diseases, this immune-regulatory environment becomes perturbed and activated synovial fibroblasts and infiltrating immune cells start to contribute to synovial inflammation and joint destruction. This review summarizes our current understanding of the phenotypic and molecular characteristics of resident synovial macrophages and fibroblasts and highlights their crosstalk during joint homeostasis and joint inflammation, which is increasingly appreciated as vital to understand the molecular basis of prevalent inflammatory joint diseases such as rheumatoid arthritis.
CRIS-Team Scopus Importer:2022-09-09
Keywords: fibroblasts; inflammation; macrophages; rheumatoid arthritis; single-cell sequencing; synovial tissue

Syntenin-1-mediated arthritogenicity is advanced by reprogramming RA metabolic macrophages and Th1 cells - Meyer, Anja; Sienes, Ryan E.; Nijim, Wes; Zanotti, Brian; Umar, Sadiq; Volin, Michael V.; Van Raemdonck, Katrien; Lewis, Myles; Pitzalis, Costantino; Arami, Shiva; Al-Awqati, Mina; Chang, Huan J.; et al. (Annals of the Rheumatic Diseases, 2023)
ObjectivesSyntenin-1, a novel endogenous ligand, was discovered to be enriched in rheumatoid arthritis (RA) specimens compared with osteoarthritis synovial fluid and normal synovial tissue (ST). However, the cellular origin, immunoregulation and molecular mechanism of syntenin-1 are undescribed in RA. MethodsRA patient myeloid and lymphoid cells, as well as preclinical models, were used to investigate the impact of syntenin-1/syndecan-1 on the inflammatory and metabolic landscape. ResultsSyntenin-1 and syndecan-1 (SDC-1) co-localise on RA ST macrophages (M phi s) and endothelial cells. Intriguingly, blood syntenin-1 and ST SDC-1 transcriptome are linked to cyclic citrullinated peptide, erythrocyte sedimentation rate, ST thickness and bone erosion. Metabolic CD14(+)CD86(+)GLUT1(+)M phi s reprogrammed by syntenin-1 exhibit a wide range of proinflammatory interferon transcription factors, monokines and glycolytic factors, along with reduced oxidative intermediates that are downregulated by blockade of SDC-1, glucose uptake and/or mTOR signalling. Inversely, IL-5R and PDZ1 inhibition are ineffective on RA M phi s-reprogrammed by syntenin-1. In syntenin-1-induced arthritis, F4/80(+)iNOS(+)RAPTOR(+)M phi s represent glycolytic RA M phi s, by amplifying the inflammatory and glycolytic networks. Those networks are abrogated in SDC-1(-/-) animals, while joint prorepair monokines are unaffected and the oxidative metabolites are moderately replenished. In RA cells and/or preclinical model, syntenin-1-induced arthritogenicity is dependent on mTOR-activated M phi remodelling and its ability to cross-regulate Th1 cells via IL-12 and IL-18 induction. Moreover, RA and joint myeloid cells exposed to Syntenin-1 are primed to transform into osteoclasts via SDC-1 ligation and RANK, CTSK and NFATc1 transcriptional upregulation. ConclusionThe syntenin-1/SDC-1 pathway plays a critical role in the inflammatory and metabolic landscape of RA through glycolytic M phi and Th1 cell cross-regulation (graphical abstract).
CRIS-Team WoS Importer:2023-01-20

Systematic comparison of donor chimerism in peripheral blood and bone marrow after hematopoietic stem cell transplantation - Bach, Christian; Steffen, M.; Rösler, Wolf; Winkler, Jürgen; Mackensen, Andreas; Stachel, Daniel; Metzler, Markus; Spriewald, B. M. (Blood Cancer Journal, 2017)
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Systemic and local bone loss in Psoriasis and Psoriatic Arthritis - Kocijan, Roland; Englbrecht, Matthias; Kleyer, Arnd; Haschka, Judith; Simon, David; Finzel, Stephanie; Kraus, Sebastian; Muschitz, Christian; Resch, Heinrich; Engelke, Klaus; Rech, Jürgen; Schett, Georg (2014)
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Systemic PPAR gamma Antagonism Reduces Metastatic Tumor Progression in Adipocyte-Rich Bone in Excess Weight Male Rodents - Gaculenko, Anastasia; Gregoric, Gasper; Popp, Vanessa; Seyler, Lisa; Ringer, Mark; Kachler, Katerina; Wu, Zhengquan; Kisel, Wadim; Hofbauer, Christine; Hofbauer, Lorenz C.; Uder, Michael; Schett, Georg; et al. (Journal of Bone and Mineral Research, 2021)
Primary tumors are widely associated with an excess in body fat. The role of adipose tissue on tumor cell homing to bone is yet poorly defined. In this study, we aimed to assess whether bone colonization by tumor cells is favored by an adipocyte-rich bone marrow. We delineated the accompanying alterations of the bone microenvironment and established a treatment approach that interferes with high fat diet (HFD)-induced bone metastasis formation. We were able to show that adipocytes affect skeletal tumor growth in a metastatic model of breast cancer in male rats and melanoma in male mice as well as in human breast cancer bone biopsies. Indeed, HFD-induced bone marrow adiposity was accompanied by accelerated tumor progression and increased osteolytic lesions. In human bone metastases, bone marrow adiposity correlated with tumor cell proliferation. By antagonization of the adipocyte differentiation and storage pathway linked to the peroxisome proliferator-activated receptor gamma (PPAR gamma) with bisphenol-A-diglycidylether (BADGE), we were able to decelerate tumor progression and subsequent osteolytic damage in the bones of two distinct metastatic animal models exposed to HFD. Overall these data show that adipose tissue is a critical factor in bone metastases and cancer-induced bone loss. 2021 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).
CRIS-Team WoS Importer:2021-09-03

Systemic sclerosis and COVID-19 vaccine safety: short-term insights from the global COVID-19 vaccination in autoimmune disease (COVAD) survey - Naveen, R.; Thakare, Darpan; Kuwana, Masataka; Pauling, John; Day, Jessica; Joshi, Mrudula; Parodis, Ioannis; Sen, Parikshit; Jagtap, Kshitij; Nikiphorou, Elena; Saha, Sreoshy; Agarwal, Vishwesh; et al. (Rheumatology International, 2023)
The safety profile of COVID-19 vaccines is understudied in patients with systemic sclerosis (SSc). We compared short-term adverse events (AEs) 7 days following vaccination in patients with SSc vs other rheumatic (AIRDs), non-rheumatic autoimmune diseases (nrAIDs), and healthy controls (HCs). The COVID-19 Vaccination in autoimmune diseases (COVAD) self-reporting e-survey was circulated by a group of > 110 collaborators in 94 countries from March to December 2021. AEs were analyzed between different groups using regression models. Of 10,679 complete respondents [73.8% females, mean age 43 years, 53% Caucasians], 478 had SSc. 83% had completed two vaccine doses, Pfizer-BioNTech (BNT162b2) (51%) was the most common. Minor and major AEs were reported by 81.2% and 3.3% SSc patients, respectively, and did not differ significantly with disease activity or different vaccine types, though with minor symptom differences. Frequencies of AEs were not affected by background immunosuppression, though SSc patients receiving hydroxychloroquine experienced fatigue less commonly (OR 0.4; 95% CI 0.2-0.8). Frequency of AEs and hospitalisations were similar to other AIRDs, nrAIDs, and HC except a higher risk of chills (OR 1.3; 95% CI 1.0-1.7) and fatigue (OR 1.3; 95% CI 1.0-1.6) compared to other AIRDs. COVID-19 vaccines were largely safe and well tolerated in SSc patients in the short term. Background immunosuppression and disease activity did not influence the vaccination-related short-term AEs.
CRIS-Team WoS Importer:2023-04-28

Systemic sclerosis - an update - Bergmann, Christina; Distler, Jörg (Deutsche Medizinische Wochenschrift, 2015)
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Systemic versus local adipokine expression differs in a combined obesity and osteoarthritis mouse model - Hülser, Marie Lisa; Luo, Yubin; Frommer, Klaus; Hasseli, Rebecca; Köhler, Kernt; Diller, Magnus; Van Nie, Lina; Rummel, Christoph; Roderfeld, Martin; Roeb, Elke; Schett, Georg; Bozec, Aline; et al. (Scientific Reports, 2021)
Osteoarthritis (OA) is a degenerative joint disease characterized by cartilage loss and reduced joint function. OA risk factors are age and obesity. Many adipokines are altered by obesity but also OA although systemic adipokine regulation in OA is not always clear. Therefore, metabolic effects of diet-induced obesity on OA development as well as the influence of obesity and OA progression on systemic vs. local adipokine expression in joints were compared. C57Bl/6-mice fed with HFD (high fat diet) or normal diet prior to destabilization of the medial meniscus (DMM) were sacrificed 4/6/8 weeks after surgery. Sera were evaluated for adiponectin, leptin, visfatin, cytokines. Liver grading and staging for non-alcoholic steatohepatitis (NASH) was performed and crown-like structures (CLS) in adipose tissue measured. OA progression was scored histologically. Adipokine-expressing cells and types were evaluated by immunohistochemistry. Time-dependent changes in DMM-progression were reflected by increased systemic adiponectin levels in DMM especially combined with HFD. While HFD increased serum leptin, DMM reduced systemic leptin significantly. OA scores correlated with bodyweight, leptin and hepatic scoring. Locally, increased numbers of adiponectin- and leptin-producing fibroblasts were observed in damaged menisci but visfatin was not changed. Local adipokine expression was independent from systemic levels, suggesting different mechanisms of action.
CRIS-Team Scopus Importer:2021-08-27

T2 Mapping as a New Method for Quantitative Assessment of Cartilage Damage in RA - Renner, Nina; Kleyer, Arnd; Krönke, Gerhard; Simon, David; Söllner, Stefan; Rech, Jürgen; Uder, Michael; Janka, Rolf Matthias; Schett, Georg; Welsch, Goetz; Pachowsky, Milena (Journal of Rheumatology, 2019)
OBJECTIVE: Rheumatoid arthritis (RA) is associated with damage of the articular cartilage and the periarticular bone. While imaging of bone damage has substantially improved in the last years, direct imaging of the articular cartilage of the hand joints in patients with RA is still challenging. METHODS: 3 Tesla Magnetic Resonance Imaging (MRI) was done in 30 RA patients and T2 relaxation times visualizing alteration in the collagen network and hydration of articular cartilage were mapped in six cartilage regions of the metacarpophalangeal joints 2 and 3. Values were related to autoantibody (anti-citrullinated peptide antibodies (ACPA), rheumatoid factor (RF)) status, disease duration, disease activity as well as sex and age of the RA patients. RESULTS: T2 relaxation times could be reliably measured in the six regions of the metacarpophalangeal joints. Significantly higher relaxation times indicating more advanced cartilage alterations were observed in ACPA-positive (p=0.001-0.010) and RF-positive patients (p=0.013-0.025) as well as those with longer disease duration (>3 years; p=0.028-0.043). Current disease activity, sex and age did not influence T2 relaxation times. CONCLUSION: These data show that cartilage damage can be localized and quantified in the hand joints of RA patients by T2 mapping. Furthermore, ACPA and RF positivity as well as disease duration appear to be the crucial factors influencing cartilage damage.
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Tapering biologic and conventional DMARD therapy in rheumatoid arthritis: current evidence and future directions - Schett, Georg; Emery, Paul; Tanaka, Yoshiya; Burmester, Gerd; Pisetsky, David S.; Naredo, Esperanza; Fautrel, Bruno; Van Vollenhoven, Ronald (Annals of the Rheumatic Diseases, 2016)
Improvements in the control of inflammation in rheumatoid arthritis (RA) by conventional synthetic and biologic disease-modifying antirheumatic drugs (DMARDs) have led to a substantial change in the clinical outcomes of patients during the last 30 years. Current treatment can lead to sustained remission in some patients raising questions about the optimal management strategies in this subgroup of patients. Today, tapering of DMARDs and even their discontinuation appears as an interesting concept for achieving a more tailored and dynamic treatment approach of RA, especially in patients, who achieved full disease control by DMARD treatment. In this review article, current developments of DMARD tapering are discussed. The article provides an overview of existing studies on this topic and addresses new strategies to reach drug-free remission. Furthermore, concepts for defining patients eligible for DMARD tapering are described and potential future strategies in using biomarkers in predicting the risk for disease relapse after initiation of DMARD tapering are addressed. These findings are finally considered in light of the vision to achieve cure as an ultimate goal in patients with RA achieving full control of inflammation.
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Targeting GM-CSF in rheumatological conditions: risk of PAP – Authors' reply - Genovese, Mark C.; Buckley, Christopher D.; Saurigny, Didier; Schett, Georg; Davy, Katherine; Gupta, Anubha; Smith, Julia E.; Patel, Jatin; Tak, Paul P. (The Lancet Rheumatology, 2021)
CRIS-Team Scopus Importer:2021-07-02

Targeting GM-CSF in rheumatological conditions: risk of PAP Reply - Genovese, Mark C.; Buckley, Christopher D.; Saurigny, Didier; Schett, Georg; Davy, Katherine; Gupta, Anubha; Smith, Julia E.; Patel, Jatin; Tak, Paul P. (The Lancet Rheumatology, 2021)
CRIS-Team WoS Importer:2021-07-16

Targeting human plasmacytoid dendritic cells through BDCA2 prevents skin inflammation and fibrosis in a novel xenotransplant mouse model of scleroderma - Ross, Rebecca L.; Corinaldesi, Clarissa; Migneco, Gemma; Carr, Ian M.; Antanaviciute, Agne; Wasson, Christopher W.; Carriero, Antonio; Distler, Jörg; Holmes, Steve; El-Sherbiny, Yasser M.; McKimmie, Clive S.; Del Galdo, Francesco (Annals of the Rheumatic Diseases, 2021)
Plasmacytoid dendritic cells (pDC) have been implicated in the pathogenesis of autoimmune diseases, such as scleroderma (SSc). However, this has been derived from indirect evidence usingex vivohuman samples or mouse pDCin vivo. We have developed human-specific pDC models to directly identify their role in inflammation and fibrosis, as well as attenuation of pDC function with BDCA2-targeting to determine its therapeutic application. RNAseq of human pDC with TLR9 agonist ODN2216 and humanised monoclonal BDCA2 antibody, CBS004. Organotypic skin rafts consisting of fibroblasts and keratinocytes were stimulated with supernatant from TLR9-stimulated pDC and with CBS004. Human pDC were xenotransplanted into Nonobese diabetic/severe combined immunodeficiency (NOD SCID) mice treated with Aldara (inflammatory model), or bleomycin (fibrotic model) with CBS004 or human IgG control. Skin punch biopsies were used to assess gene and protein expression. RNAseq shows TLR9-induced activation of human pDC goes beyond type I interferon (IFN) secretion, which is functionally inactivated by BDCA2-targeting. Consistent with these findings, we show that BDCA2-targeting of pDC can completely suppressin vitroskin IFN-induced response. Most importantly, xenotransplantation of human pDC significantly increasedin vivoskin IFN-induced response to TLR agonist and strongly enhanced fibrotic and immune response to bleomycin compared with controls. In these contexts, BDCA2-targeting suppressed human pDC-specific pathological responses. Our data indicate that human pDC play a key role in inflammation and immune-driven skin fibrosis, which can be effectively blocked by BDCA2-targeting, providing direct evidence supporting the development of attenuation of pDC function as a therapeutic application for SSc.
CRIS-Team Scopus Importer:2021-06-25
Keywords: autoimmune diseases; inflammation; scleroderma; systemic

Targeting intestinal tight junctions to inhibit onset of arthritis - Tajik, N.; Schulz, O.; Frech, Michael; Lucas, Sébastien; Sarter-Zaiss, Kerstin; Schett, Georg; Zaiss, Mario (EUROPEAN JOURNAL OF IMMUNOLOGY, 2019)
CRIS-Team WoS Importer:2019-10-08

Targeting of canonical WNT signaling ameliorates experimental sclerodermatous chronic graft-versus-host disease - Zhang, Yun; Shen, Lichong; Dreißigacker, Katja; Zhu, Honglin; Trinh, Minh Thuong; Meng, Xianyi; TRAN MANH, CUONG; Dees, Clara; Matei, Alexandru-Emil; Chen, Chih-Wei; Ditschkowski, Markus; Krauss, Stefan; et al. (Blood, 2021)
Chronic graft-versus-host disease (cGVHD) is a major life-threatening complication of allogeneic hematopoietic stem cell transplantation. The molecular mechanisms underlying cGVHD remain poorly understood, and targeted therapies for clinical use are not well established. Here, we examined the role of the canonical WNT pathway in sclerodermatous cGVHD (sclGVHD). WNT signaling was activated in human sclGVHD with increased nuclear accumulation of the transcription factor β-catenin and a WNT-biased gene expression signature in lesional skin. Treatment with the highly selective tankryase inhibitor G007-LK, the CK1α agonist pyrvinium, or the LRP6 inhibitor salinomycin abrogated the activation of WNT signaling and protected against experimental cGVHD, without a significant impact on graft-versus-leukemia effect (GVL). Treatment with G007-LK, pyrvinium, or salinomycin almost completely prevented the development of clinical and histological features in the B10.D2 (H-2d) → BALB/c (H-2d) and LP/J (H-2b) → C57BL/6 (H-2b) models of sclGVHD. Inhibition of canonical WNT signaling reduced the release of extracellular matrix from fibroblasts and reduced leukocyte influx, suggesting that WNT signaling stimulates fibrotic tissue remodeling by direct effects on fibroblasts and by indirect inflammation-dependent effects in sclGVHD. Our findings may have direct translational potential, because pyrvinium is in clinical use, and tankyrase inhibitors are in clinical trials for other indications.
CRIS-Team Scopus Importer:2021-05-28

Targeting of fibroblast activation protein in rheumatoid arthritis patients: imaging and ex vivo photodynamic therapy - Dorst, Daphne N.; Rijpkema, Mark; Buitinga, Mijke; Walgreen, Birgitte; Helsen, Monique M. A.; Brennan, Evan; Klein, Christian; Laverman, Peter; Ramming, Andreas; Schmidkonz, Christian; Kuwert, Torsten; Schett, Georg; et al. (Rheumatology, 2021)
Objective Activated synovial fibroblasts are key effector cells in RA. Selectively depleting these based upon their expression of fibroblast activation protein (FAP) is an attractive therapeutic approach. Here we introduce FAP imaging of inflamed joints using Ga-68-FAPI-04 in a RA patient, and aim to assess feasibility of anti-FAP targeted photodynamic therapy (FAP-tPDT) ex vivo using 28H1-IRDye700DX on RA synovial explants. Methods Remnant synovial tissue from RA patients was processed into 6 mm biopsies and, from several patients, into primary fibroblast cell cultures. Both were treated using FAP-tPDT. Cell viability was measured in fibroblast cultures and biopsies were evaluated for histological markers of cell damage. Selectivity of the effect of FAP-tPDT was assessed using flow cytometry on primary fibroblasts and co-cultured macrophages. Additionally, one RA patient intravenously received Ga-68-FAPI-04 and was scanned using PET/CT imaging. Results In the RA patient, FAPI-04 PET imaging showed high accumulation of the tracer in arthritic joints with very low background signal. In vitro, FAP-tPDT induced cell death in primary RA synovial fibroblasts in a light dose-dependent manner. An upregulation of cell damage markers was observed in the synovial biopsies after FAP-tPDT. No significant effects of FAP-tPDT were noted on macrophages after FAP-tPDT of neighbouring fibroblasts. Conclusion In this study the feasibility of selective FAP-tPDT in synovium of rheumatoid arthritis patients ex vivo is demonstrated. Furthermore, this study provides the first indication that FAP-targeted PET/CT can be used to image arthritic joints, an important step towards application of FAP-tPDT as a targeted locoregional therapy for RA.
CRIS-Team WoS Importer:2022-02-25

Targeting of NADPH oxidase in vitro and in vivo suppresses fibroblast activation and experimental skin fibrosis - Dosoki, Heba; Stegemann, Agatha; Taha, Muna; Schnittler, Hans; Luger, Thomas A.; Schroeder, Katrin; Distler, Jörg; Kerkhoff, Claus; Boehm, Markus (Experimental Dermatology, 2016)
Although there is increasing evidence that oxidative stress is involved in collagen synthesis and myofibroblast activation the NADPH oxidase (Nox) system is incompletely investigated in the context of human dermal fibroblasts (HDFs) and skin fibrosis. Using the pan-Nox inhibitor diphenyleneiodonium (DPI) as an initial tool we show that gene expression of collagen type I, ?-smooth muscle actin (?-SMA) and fibronectin 1 is suppressed in HDFs. Detailed expression analysis of all Nox isoforms and adaptors revealed expression of RNA and protein expression of Nox4, p22(phox) , and Poldip2 but neither Nox1 nor Nox2. Nox4 could be immnolocalized to the endoplasmic reticulum. Importantly, TGF-?1 had a dose- and time-dependent upregulating effect on NADH activity and Nox4 gene expression in HDFs. Genetic silencing of Nox4 as demonstrated by siRNA in HDFs as well as in murine fibroblasts established from Nox4 knock-out mice confirmed that TGF-?1 -mediated collagen type I gene, ?-SMA and fibronectin 1 gene expression was Nox4-dependent. This TGF-?1 effect was mediated by Smad3 as shown by in silico promoter analysis, pharmacological inhibition, and gene silencing of Smad3. The relevance of these findings is highlighted in the bleomycin-induced scleroderma mouse model. DPI treatment attenuated skin fibrosis and myofibroblast activation. Moreover, Nox4 knock-down by siRNA reduced skin collagen synthesis, ?-SMA and fibronectin 1 expression in vivo. Finally, analyses of HDFs from patients with systemic sclerosis confirmed the expression of Nox4 and its adaptors whereas Nox1 and Nox2 were not detectable. Our findings indicate that Nox4 targeting is a promising future treatment for fibrotic skin diseases. This article is protected by copyright. All rights reserved.
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