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

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

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

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

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

Collating the voice of people with autoimmune diseases: Methodology for the Third Phase of the COVAD Studies - Kadam, Esha; Javaid, Mahnoor; Sen, Parikshit; Saha, Sreoshy; Ziade, Nelly; Day, Jessica; Wincup, Chris; Andreoli, Laura; Parodis, Ioannis; Tan, Ai Lyn; Shinjo, Samuel Katsuyuki; Dey, Dzifa; et al. (Rheumatology International, 2024)
Introduction: The growing recognition of holistic patient care highlights the various factors shaping the quality of life of individuals with autoimmune and rheumatic diseases (AIRDs). Beyond the traditional disease measures, there is an emerging acknowledgment of the less-explored aspects, including subjective well-being, social determinants of health, comorbidities, mental health, and medication adherence. Moreover, digital health services have empowered patients to engage actively in decision-making alongside clinicians. To explore these domains within the context of AIRDs, the “Collating the Voice of People with Autoimmune Diseases” COVAD survey was conceived, a successor of the previous two COVAD surveys. In this document, we present the study protocol in comprehensive detail. Methods: The COVAD-3 survey is a cross-sectional patient self-reported e-survey incorporating multiple widely accepted scales/scores to assess various aspects of patients’ lifestyles objectively. To ensure the survey's accuracy and usability across diverse regions, it will be translated into multiple languages and subjected to rigorous vetting and pilot testing. It will be distributed by collaborators via online platforms and data will be collected from patients with AIRDs, and healthy individuals over eight months. Data analysis will focus on outcome measures related to various social, demographic, economic, and psychological factors. Conclusion: With the increasing awareness to adopt a holistic treatment approach encompassing all avenues of life, the COVAD-3 survey aims to gain valuable insights into the impact of social, demographic, economic, and psychological determinants of health on the subjective well-being in patients with AIRDs, which will contribute to a better understanding of their overall health and well-being.
CRIS-Team Scopus Importer:2024-05-24
Keywords: Autoimmune diseases; COVAD; Digital health; Quality of life; Sociodemographic factors; Survey

Combined cytotoxic activity of an infectious, but non-replicative herpes simplex virus type 1 and plasmacytoid dendritic cells against tumour cells - Thomann, Sabrina; Boscheinen, Jan; Vogel, Karin; Knipe, David M.; Deluca, Neal; Gross, Stefanie; Schuler-Thurner, Beatrice; Schuster, Philipp; Schmidt, Barbara (Immunology, 2015)
Malignant melanoma is an aggressive tumour of the skin with increasing incidence, frequent metastasis and poor prognosis. At the same time, it is an immunogenic type of cancer with spontaneous regressions. Most recently, the tumoricidal effect of plasmacytoid dendritic cells (pDC) and their capacity to overcome the immunosuppressive tumour microenvironment are being investigated. In this respect, we studied the effect of the infectious, but replication-deficient, herpes simplex virus 1 (HSV-1) d106S vaccine strain, which lacks essential immediate early genes, in pDC co-cultures with 11 melanoma cell lines. We observed a strong cytotoxic activity, inducing apoptotic and necrotic cell death in most melanoma cell lines. The cytotoxic activity of HSV-1 d106S plus pDC was comparable to the levels of cytotoxicity induced by natural killer cells, but required only a fraction of cells with effector : target ratios of 1 : 20 (P < 0·05). The suppressive activity of cell-free supernatants derived from virus-stimulated pDC was significantly neutralized using antibodies against the interferon-? receptor (P < 0·05). In addition to type I interferons, TRAIL and granzyme B contributed to the inhibitory effect of HSV-1 d106S plus pDC to a minor extent. UV-irradiated viral stocks were significantly less active than infectious particles, both in the absence and presence of pDC (P < 0·05), indicating that residual activity of HSV-1 d106S is a major component and sensitizes the tumour cells to interferon-producing pDC. Three leukaemic cell lines were also susceptible to this treatment, suggesting a general anti-tumour effect. In conclusion, the potential of HSV-1 d106S for therapeutic vaccination should be further evaluated in patients suffering from different malignancies.
EVALuna2:8282

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

Combined inhibition of IL-1, IL-33 and IL-36 signalling by targeting IL1RAP ameliorates skin and lung fibrosis in preclinical models of systemic sclerosis - Grönberg, Caitríona; Rattik, Sara; Tran-Manh, Cuong; Zhou, Xiang; Rius Rigau, Aleix; Li, Yi Nan; Györfi, Andrea Hermina; Dickel, Nicholas; Kunz, Meik; Kreuter, Alexander; Matei, Emil Alexandru; Zhu, Honglin; et al. (Annals of the Rheumatic Diseases, 2024)
Background: The interleukin (IL)-1 receptor accessory protein (IL1RAP) is an essential coreceptor required for signalling through the IL-1, IL-33 and IL-36 receptors. Here, we investigate the antifibrotic potential of the combined inhibition of these cytokines by an anti-IL1RAP antibody to provide a scientific background for clinical development in systemic sclerosis (SSc). Methods: The expression of IL1RAP-associated signalling molecules was determined by data mining of publicly available RNA sequencing (RNAseq) data as well as by imaging mass cytometry. The efficacy of therapeutic dosing of anti-IL1RAP antibodies was determined in three complementary mouse models: sclerodermatous chronic graft-versus-host disease (cGvHD), bleomycin-induced dermal fibrosis model and topoisomerase-I (topo)-induced fibrosis. Results: SSc skin showed upregulation of IL1RAP and IL1RAP-related signalling molecules on mRNA and protein level compared with normal skin. IL-1, IL-33 and IL-36 all regulate distinct gene sets related to different pathophysiological processes in SSc. The responses of human fibroblasts and endothelial cells to IL-1, IL-33 and IL-36 were completely blocked by treatment with an anti-IL1RAP antibody in vitro. Moreover, anti-IL1RAP antibody treatment reduced dermal and pulmonary fibrosis in cGvHD-induced, bleomycin-induced and topoisomerase-induced fibrosis. Importantly, RNAseq analyses revealed effects of IL1RAP inhibition on multiple processes related to inflammation and fibrosis that are also deregulated in human SSc skin. Conclusion: This study provides the first evidence for the therapeutic benefits of targeting IL1RAP in SSc. Our findings have high translational potential as the anti-IL1RAP antibody CAN10 has recently entered a phase one clinical trial.
CRIS-Team Scopus Importer:2024-05-03
Keywords: Fibroblasts; Inflammation; Pulmonary Fibrosis; Scleroderma; Systemic

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

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

Comment on: Clinical course of acute deep vein thrombosis of the legs in Behçet's syndrome: reply - Ozguler, Yesim; Hatemi, Gulen; Cetinkaya, Firat; Tascilar, Koray; Hamuryudan, Vedat; Ugurlu, Serdal; Seyahi, Emire; Yazici, Hasan; Melikoglu, Melike (Rheumatology, 2020)
CRIS-Team Scopus Importer:2020-04-07

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

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

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

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

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

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

Comparison of Current Swiss Fetal Biometry Reference Charts with Reference Charts from 1999. Are Fetuses Getting Bigger? - Knitza, Johannes; Kurmanavicius, Juozas; Faschingbauer, Florian; Wisser, Josef (Ultraschall in der Medizin, 2018)
PURPOSE: To create current fetal biometry reference ranges and to compare them with references published in 1999, from the same local area in order to generate data for secular trend in fetal size. MATERIALS AND METHODS: Applying the same methodology as previously published, we calculated reference ranges for biparietal diameter (BPD), occipitofrontal diameter (OFD), head circumference (HC), abdominal circumference (AC) and femur length (FL) in 7863 patients examined at the obstetric clinics in a cross-sectional, prospective study in a university setting from January 2008 to December 2014. In order to compare the new reference ranges with our previously published data, we used Z-Scores and displayed the pick-up of fetal biometry data below the 5th and above the 95th percentile using the previously published reference charts. RESULTS: The comparison of the charts showed a minimal but clinically relevant increase in mean fetal body measures (BPD, HC, AC). Applying the 1999 charts to the new dataset, we would classify only 162 of 339 fetuses (47.8 %) to be correctly below the 5th percentile for AC and only 134 of 349 (38.4 %) fetuses were correctly below the 5th percentile for HC. On the other hand, the 1999 charts classified 426 instead of 332 fetuses to be above the 95th percentile for AC, which means an overestimation of 28.3 %. CONCLUSION: Applying a similar methodology, study collective and clinical setting, our new charts showed clinically relevant differences compared to the 1999 charts. The data suggest that within one generation fetuses are getting bigger and regular updates of fetal reference charts are needed.
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Comparison of CyberGlove III calibration methods and the application to arthritis patients - Heinrich, Simon; Michaelis, Johannes; Reiher, Isabella; Coppers, Birte; Lohmayer, Markus; Fleischmann, Martha Elisa; Kleyer, Arnd; Schett, Georg; De Craemer, Ann-Sophie; Elewaut, Dirk; Leyendecker, Sigrid; Liphardt, Anna-Maria (IEEE Sensors, 2024)
We investigate the accuracy of different calibration methods for the CyberGlove III for objective hand function assessments. The accuracy is evaluated by means of root-mean-squared errors (RMSE) between ground truth and angles estimated by the glove. Additionally, we propose two improvements. The first increases standardization capabilities for the measurement of pure thumb carpometacarpal joint flexion. The second increases the accuracy by extending an existing calibration method to all thumb and distal interphalangeal (DIP) joints. The best calibration method is identified and compared to an across-subject calibration by means of RMSEs, highlighting the tradeoff between the number of necessary measurements and the accuracy. Our proposed improvements both reduce the measurement effort, while only the second improvement reduces the RMSEs substantially. The best calibration method yields RMSEs below 10° for most joints, while the across-subject calibration has RMSEs that are approximately 5°–10° higher. We conclude that the CyberGlove III is a suitable tool for objective monitoring of hand movement and function, and the across-subject calibration has the potential to track the range of motion or frequency of joint movements. With this work, we provide an overview for researchers to choose calibration methods suitable for their application depending on necessary accuracy and possible extent of calibration measurements. This work further highlights potential obstacles, when such a glove is used with patients.<br

Comparison of diagnostic spectrum between inflammation of unknown origin and fever of unknown origin: A systematic review and meta-analysis - Betrains, Albrecht; Moreel, Lien; Mulders-Manders, Catharina M.; Auwaerter, Paul G.; Torné-Cachot, Joaquim; Weitzer, Friedrich; Terasawa, Teruhiko; Ly, Kim H.; Schönau, Verena; Blockmans, Daniel; Wright, William F.; Rovers, Chantal; et al. (European Journal of Internal Medicine, 2024)
Background: Patients with inflammation of unknown origin (IUO) and fever of unknown origin (FUO) are commonly considered a single population. Differences in underlying causes between both groups may steer the diagnostic work-up. Methods: PubMed, Embase, Web of Science, and ClinicalTrials.gov were searched from July 2009 through December 2023. Studies including both FUO and IUO patients with a sample size of ≥20 were considered. The primary outcome was the difference in the rate of patients affected by predefined diagnostic categories according to meeting FUO or IUO criteria. Data were pooled using random-effects models. Results: A total of 8 studies met criteria for inclusion, with a total of 1452 patients (466 with IUO and 986 with FUO). The median rate of IUO patients among the included studies was 32 % (range 25–39 %). Patients with IUO had a lower likelihood of infection (OR 0.59 [95 % CI; 0.36–0.95]; I2 0 %). There were no significant differences in the rate of noninfectious inflammatory disorders, malignancies, miscellaneous disorders, or remaining undiagnosed. Comparison of diagnostic subgroups revealed that IUO patients were less likely to have systemic autoinflammatory disorders (OR 0.17 [95 % CI, 0.05–0.58]; I2 42 %) and more likely to have vasculitis (OR 2.04 [95 % CI, 1.23–3.38]; I2 21 %) and rheumatoid arthritis or spondylarthritis (OR 3.52 [95 % CI, 1.16–10.69]; I2 0 %). Conclusion: Based on our findings, there is little reason to assume that FUO and IUO patients would benefit from a different initial diagnostic approach.
CRIS-Team Scopus Importer:2024-03-15
Keywords: Diagnostic categories; Diagnostic spectrum; FUO; IUO

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

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

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

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

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

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

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

Complement Activation in Kidneys of Patients With COVID-19 - Pfister, Frederick; Vonbrunn, Eva; Ries, Tajana; Jäck, Hans-Martin; Überla, Klaus; Lochnit, Günter; Sheriff, Ahmed; Herrmann, Martin; Büttner-Herold, Maike; Amann, Kerstin Ute; Daniel, Christoph (Frontiers in Immunology, 2021)
Most patients who became critically ill following infection with COVID-19 develop severe acute respiratory syndrome (SARS) attributed to a maladaptive or inadequate immune response. The complement system is an important component of the innate immune system that is involved in the opsonization of viruses but also in triggering further immune cell responses. Complement activation was seen in plasma adsorber material that clogged during the treatment of critically ill patients with COVID-19. Apart from the lung, the kidney is the second most common organ affected by COVID-19. Using immunohistochemistry for complement factors C1q, MASP-2, C3c, C3d, C4d, and C5b-9 we investigated the involvement of the complement system in six kidney biopsies with acute kidney failure in different clinical settings and three kidneys from autopsy material of patients with COVID-19. Renal tissue was analyzed for signs of renal injury by detection of thrombus formation using CD61, endothelial cell rarefaction using the marker E-26 transformation specific-related gene (ERG-) and proliferation using proliferating cell nuclear antigen (PCNA)-staining. SARS-CoV-2 was detected by in situ hybridization and immunohistochemistry. Biopsies from patients with hemolytic uremic syndrome (HUS, n = 5), severe acute tubular injury (ATI, n = 7), zero biopsies with disseminated intravascular coagulation (DIC, n = 7) and 1 year protocol biopsies from renal transplants (Ctrl, n = 7) served as controls. In the material clogging plasma adsorbers used for extracorporeal therapy of patients with COVID-19 C3 was the dominant protein but collectin 11 and MASP-2 were also identified. SARS-CoV-2 was sporadically present in varying numbers in some biopsies from patients with COVID-19. The highest frequency of CD61-positive platelets was found in peritubular capillaries and arteries of COVID-19 infected renal specimens as compared to all controls. Apart from COVID-19 specimens, MASP-2 was detected in glomeruli with DIC and ATI. In contrast, the classical pathway (i.e. C1q) was hardly seen in COVID-19 biopsies. Both C3 cleavage products C3c and C3d were strongly detected in renal arteries but also occurs in glomerular capillaries of COVID-19 biopsies, while tubular C3d was stronger than C3c in biopsies from COVID-19 patients. The membrane attack complex C5b-9, demonstrating terminal pathway activation, was predominantly deposited in COVID-19 biopsies in peritubular capillaries, renal arterioles, and tubular basement membrane with similar or even higher frequency compared to controls. In conclusion, various complement pathways were activated in COVID-19 kidneys, the lectin pathway mainly in peritubular capillaries and in part the classical pathway in renal arteries whereas the alternative pathway seem to be crucial for tubular complement activation. Therefore, activation of the complement system might be involved in the worsening of renal injury. Complement inhibition might thus be a promising treatment option to prevent deregulated activation and subsequent collateral tissue injury.
CRIS-Team Scopus Importer:2021-03-05
Keywords: complement—immunological term; COVID-19; endothelial injury; kidney; lectin pathway activation

COMPLEMENTARY DIGITAL THERAPY SAFELY IMPROVES QUALITY OF LIFE IN PATIENTS WITH INFLAMMATORY ARTHRITIS - Fedkov, Dmytro; Berghofen, A.; Weiss, C.; Peine, C.; Lang, F.; Knitza, Johannes; Leipe, J. (ANNALS OF THE RHEUMATIC DISEASES, 2022)
CRIS-Team WoS Importer:2022-11-04

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

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

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

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

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

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

Connection between periodontitis-induced low-grade endotoxemia and systemic diseases: Neutrophils as protagonists and targets - Vitkov, Ljubomir; Munoz Becerra, Luis; Knopf, Jasmin; Oberthaler, Hannah; Minnich, Bernd; Hannig, Matthias; Herrmann, Martin; Schauer, Christine (International Journal of Molecular Sciences, 2021)
Periodontitis is considered a promoter of many systemic diseases, but the signaling pathways of this interconnection remain elusive. Recently, it became evident that certain microbial challenges promote a heightened response of myeloid cell populations to subsequent infections either with the same or other pathogens. This phenomenon involves changes in the cell epigenetic and transcription, and is referred to as “trained immunity”. It acts via modulation of hematopoietic stem and progenitor cells (HSPCs). A main modulation driver is the sustained, persistent low-level transmission of lipopolysaccharide from the periodontal pocket into the peripheral blood. Subsequently, the neutrophil phenotype changes and neutrophils become hyper-responsive and prone to boosted formation of neutrophil extracellular traps (NET). Cytotoxic neutrophil proteases and histones are responsible for ulcer formations on the pocket epithelium, which foster bacteremia and endoxemia. The latter promote systemic low-grade inflammation (SLGI), a precondition for many systemic diseases and some of them, e.g., atherosclerosis, diabetes etc., can be triggered by SLGI alone. Either reverting the polarized neutrophils back to the homeostatic state or attenuation of neutrophil hyper-responsiveness in periodontitis might be an approach to diminish or even to prevent systemic diseases.
CRIS-Team Scopus Importer:2021-05-07
Keywords: Blood transmission of PAMPs; Loss of tolerance; Neutrophil hyper-responsiveness; Neutrophil-driven damages; Trained immunity

Consistent Safety Profile with up to 4 Years of Apremilast Treatment: Analysis of Data from 1,493 Subjects with Psoriatic Arthritis in 3 Large, Phase III, Long-Term Studies - Mease, Philip J.; Gladman, Dafna D.; Gomez-Reino, Juan J.; Hall, Stephen; Kavanaugh, Arthur; Lespessailles, Eric; Schett, Georg; Paris, Maria; Teng, Lichen; Wollenhaupt, Juergen (2017)
EVALuna2:33437

Continuous monitoring of SARS-CoV-2 seroprevalence in children using residual blood samples from routine clinical chemistry - Wachter, Felix; Regensburger, Adrian; Peter, Antonia Sophia; Knieling, Ferdinand; Wagner, Alexandra; Simon, David; Hörning, André; Wölfle, Joachim; Überla, Klaus; Neubert, Antje; Rauh, Manfred (Clinical Chemistry and Laboratory Medicine, 2022)
Objectives The assessment of SARS-CoV-2 infections in children is still challenging, but essential for appropriate political decisions. The aim of this study was to investigate whether residual blood samples can be used for SARS-CoV-2 seroprevalence monitoring in pediatrics. Methods In this repeated cross-sectional cohort study, anonymous residual blood samples from pediatric patients aged 0-17 years were collected in three time-periods (Oct.-Nov. 2020, April 2021, and June-July 2021) and analyzed for SARS-CoV-2 Spike protein (anti-S) and nucleocapsid (anti-N) antibodies using commercial antibody assays. 28 reactive samples were used to compare antibody levels with a pseudotyped neutralization assay. The results were further compared to the official national COVID-19 surveillance data to calculate the number of unreported cases. Results In total, n=2,626 individual blood samples were analyzed. In this unvaccinated pediatric cohort anti-S and anti-N antibody seroprevalence increased over the three time periods (anti-S: 1.38-9.16%, and 14.59%; anti-N: 1.26%, to 6.19%, and 8.56%). Compared to the national surveillance data this leads to a 3.93-5.66-fold increase in the number of unreported cases. However, a correlation between the cumulative incidence of the individual provinces and our assigned data was found (r=0.74, p=0.0151). In addition, reactive samples with anti-S and anti-N and samples with only anti-S showed neutralization capabilities (11/14 and 8/14, respectively). Anti-S levels were not significantly different between age groups and sexes (all p>0.05). Conclusions The present study suggests that residual blood samples from routine laboratory chemistry could be included in the estimation of the total SARS-CoV-2 seroprevalence in children.
CRIS-Team WoS Importer:2022-03-11
Keywords: COVID-19; pediatrics; prevalence; SARS-CoV-2

Contrary immediate effect of abatacept on skin and joint manifestations in psoriatic arthritis - Valor-Méndez, Larissa; Kleyer, Arnd; Schett, Georg; Manger, Bernhard; Sticherling, Michael (Rheumatology, 2021)
CRIS-Team Scopus Importer:2021-11-05

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

Contribution of Inflammation and Bone Destruction to Pain in Arthritis: A Study in Murine Glucose-6-Phosphate Isomerase–Induced Arthritis - Ebbinghaus, Matthias; Müller, Sylvia; Segond von Banchet, Gisela; Eitner, Annett; Wank, Isabel; Heß, Andreas; Hilger, Ingrid; Kamradt, Thomas; Schaible, Hans Georg (Arthritis and Rheumatology, 2019)
Objective: Arthritis is often characterized by inflammation and bone destruction. This study was undertaken to investigate the contribution of inflammation and bone destruction to pain. Methods: Inflammation, bone resorption, pain-related behaviors, and molecular markers (activating transcription factor 3 [ATF-3], p-CREB, and transient receptor potential vanilloid channel 1) in sensory neurons were measured in murine glucose-6-phosphate isomerase (G6PI)–induced arthritis, a model of rheumatoid arthritis. Depletion of Treg cells before immunization changed self-limiting arthritis into nonremitting arthritis with pronounced bone destruction. Zoledronic acid (ZA) was administered to reduce bone resorption. Results: Compared to nondepleted mice, Treg cell–depleted mice exhibited arthritis with more severe bone destruction and higher guarding scores (P < 0.05; n = 10 mice per group) as well as more persistent thermal hyperalgesia (P < 0.05), but displayed similar mechanical hyperalgesia at the hindpaws (n = 18–26 mice per group). These pain-related behaviors, as well as an up-regulation of the neuronal injury marker ATF-3 in sensory neurons (studied in 39 mice), appeared before the clinical score (inflammation) became positive and persisted in Treg cell–depleted and nondepleted mice. In the late stage of arthritis, Treg cell–depleted mice treated with ZA showed less bone resorption (<50%; P < 0.01) and less thermal hyperalgesia (P < 0.01) than Treg cell–depleted mice without ZA treatment (n = 15 mice per group), but ZA treatment did not reduce the clinical score and local mechanical hyperalgesia. Conclusion: Pain-related behaviors precede and outlast self-limiting arthritis. In nonremitting arthritis with enhanced bone destruction, mainly local thermal, but not local mechanical, hyperalgesia was aggravated. The up-regulation of ATF-3 indicates an early and persisting affection of sensory neurons by G6PI-induced arthritis.
CRIS-Team Scopus Importer:2019-11-19

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

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

Correction: Effect of guselkumab on serum biomarkers in patients with active psoriatic arthritis and inadequate response to tumor necrosis factor inhibitors: results from the COSMOS phase 3b study. - Schett, Georg; Chen, Warner; Gao, Sheng; Chakravarty, Soumya D.; Shawi, May; Lavie, Frederic; Zimmermann, Miriam; Sharaf, Mohamed; Coates, Laura C.; Siebert, Stefan (Arthritis Research & Therapy, 2023)
EVALuna2:540325

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

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

Correlates of breakthrough COVID-19 in vaccinated patients with systemic sclerosis: survival analysis from a multicentre international patient-reported survey - Ahmed, Sakir; Gupta, Latika; Kuwana, Masataka; Pauling, John D.; Day, Jessica; Ravichandran, Naveen; Joshi, Mrudula; Parodis, Ioannis; Sen, Parikshit; Jagtap, Kshitij; Nikiphorou, Elena; Saha, Sreoshy; et al. (Rheumatology International, 2024)
This study aimed to assess the incidence, predictors, and outcomes of breakthrough infection (BI) following coronavirus disease (COVID-19) vaccination in patients with systemic sclerosis (SSc), a risk group associated with an immune-suppressed state and high cardiopulmonary disease burden. Cross-sectional data from fully vaccinated respondents with SSc, non-SSc autoimmune rheumatic diseases (AIRDs), and healthy controls (HCs) were extracted from the COVAD database, an international self-reported online survey. BI was defined according to the Centre for Disease Control definition. Infection-free survival was compared between the groups using Kaplan–Meier curves with log-rank tests. Cox proportional regression was used to assess the association between BI and age, sex, ethnicity, and immunosuppressive drugs at the time of vaccination. The severity of BI in terms of hospitalization and requirement for oxygen supplementation was compared between groups. Of 10,900 respondents, 6836 fulfilled the following inclusion criteria: 427 SSc, 2934 other AIRDs, and 3475 HCs. BI were reported in 6.3% of SSc, 6.9% of non-SSc AIRD, and 16.1% of HCs during a median follow-up of 100 (IQR: 60–137) days. SSc had a lower risk for BI than HC [hazard ratio (HR): 0.56 (95% CI 0.46–0.74)]. BIs were associated with age [HR: 0.98 (0.97–0.98)] but not ethnicity or immunosuppressive drugs at the time of vaccination. Patients with SSc were more likely to have asymptomatic COVID-19, but symptomatic patients reported more breathlessness. Hospitalization [SSc: 4 (14.8%), HCs: 37 (6.6%), non-SSc AIRDs: 32(15.8%)] and the need for oxygenation [SSc: 1 (25%); HC: 17 (45.9%); non-SSc AIRD: 13 (40.6%)] were similar between the groups. The incidence of BI in SSc was lower than that in HCs but comparable to that in non-SSc AIRDs. The severity of BI did not differ between the groups. Advancing age, but not ethnicity or immunosuppressive medication use, was associated with BIs.
CRIS-Team Scopus Importer:2024-01-19
Keywords: Breakthrough infections; COVAD; COVID-19; Surveys and questionnaires; Systemic sclerosis

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

Corrigendum: Editorial: Rising stars in environmental, aviation and space physiology: 2022(Front. Physiol., (2023), 14, (1230752), 10.3389/fphys.2023.1230752) - Saveko, Alina; Washio, Takuro; Petersen, Lonnie G.; Custaud, Marc Antoine; Liphardt, Anna-Maria (Frontiers in Physiology, 2023)
In the published article there was an error in the Author list, whereby author “Anna-Maria Liphardt” was erroneously listed as the second author. The corrected Author list appears below. “Alina Saveko, Takuro Washio, Lonnie G. Petersen, Marc-Antoine Custaud and Anna-Maria Liphardt”. In the published article, there was an error in affiliation for Marc-Antoine Custaud. Instead of “University Angers, CRC, CHU Angers, Inser, CNRS, MITOVASC, SFR CAT, Angers, France”, it should be “CRC, CHU Angers, Inserm, CNRS, MITOVASC, SFR ICAT, University of Angers, Angers, France”. The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated.
CRIS-Team Scopus Importer:2023-08-11
Keywords: countermeasures; deconditioning; gravitational physiology; integrative physiology; weightlessness

Corrigendum: Evidence of innate lymphoid cell redundancy in humans - Vely, Frederic; Barlogis, Vincent; Vallentin, Blandine; Neven, Benedicte; Piperoglou, Christelle; Ebbo, Mikael; Perchet, Thibaut; Petit, Maxime; Yessaad, Nadia; Touzot, Fabien; Bruneau, Julie; Mahlaoui, Nizar; et al. (Nature Immunology, 2016)
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Corrigendum: Low Dose Radiation Therapy Induces Long-Lasting Reduction of Pain and Immune Modulations in the Peripheral Blood - Interim Analysis of the IMMO-LDRT01 Trial(Front. Immunol., (2021), 12, (740742), 10.3389/fimmu.2021.740742) - Donaubauer, Anna-Jasmina; Becker, Ina; Weissmann, Thomas; Fröhlich, Birgitta; Munoz, Luis Enrique; Gryc, Thomas; Denzler, Manuel; Ott, Oliver; Fietkau, Rainer; Gaipl, Udo; Frey, Benjamin (Frontiers in Immunology, 2022)
In the original article, there was an error. The mistake is found in the sentence “While the total number of leukocytes remained unchanged in the peripheral blood, LDRT induced a slight reduction of eosinophils, basophils and plasmacytoid dendritic cells and an increase of B cells.” in the abstract of the article.
CRIS-Team Scopus Importer:2022-03-04
Keywords: chronic degenerative and inflammatory diseases; immune status; immunophenotyping; low dose radiation therapy (LDRT); subjective pain level; x-rays

Corrigendum to "Fc-gamma receptors are not involved in cartilage damage during experimental osteoarthritis" [Osteoarthritis Cartilage 23 (2015) 1221-1225] - Stock, Michael; Distler, A.; Distler, Jörg; Beyer, Christian; Ruiz-Heiland, G.; Ipseiz, Natacha; Seeling, Michaela; Krönke, Gerhard; Nimmerjahn, Falk; Schett, Georg (Osteoarthritis and Cartilage, 2016)
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Corrigendum to “Internal vascular anatomy of the human lacrimal gland: A protocol based on cadaver dissection and three-dimensional micro-computed tomography” [Ann. Anat. 252 (2024) 152207] (Annals of Anatomy (2024) 252, (S0940960223001620), (10.1016/j.aanat.2023.152207)) - Singh, Swati; Chopra, Prakshi; Necker, Fabian; Scholz, Michael; Liphardt, Anna-Maria; Schuster, Louis; Paulsen, Friedrich; Bräuer, Lars (Annals of Anatomy-Anatomischer Anzeiger, 2024)
The authors regret in the article by Singh et al. in volume 252;152207, February 2024, of Annals of Anatomy, the following change should be made in the acknowledgement section: 1. The present work was performed in (partial) fulfillment of the requirements for obtaining the degree of Dr. med (SS).The additional information provided does not influence the conclusions of the study. The authors would like to apologize for any inconvenience caused.
CRIS-Team Scopus Importer:2024-05-31

CORTICAL BONE LOSS IS AN EARLY FEATURE OF AXIAL SPONDYLOARTHRITIS - Haschka, J.; Neumann, A.; Kleyer, Arnd; Schuster, L.; Englbrecht, Matthias; Figueiredo, C. P.; Muschitz, C.; Kocijan, R.; Resch, H.; Rech, Jürgen; Schett, Georg (2017)
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Cortical bone loss is an early feature of nonradiographic axial spondyloarthritis - Neumann, Anna; Haschka, Judith; Kleyer, Arnd; Schuster, Louis; Englbrecht, Matthias; Berlin, Andreas; Figueiredo, Camille P.; Simon, David; Muschitz, Christian; Kocijan, Roland; Resch, Heinrich; Rech, Jürgen; et al. (Arthritis Research & Therapy, 2018)
BACKGROUND: In the present study, we investigated bone geometry, microstructure, and volumetric bone mineral density (vBMD) in a cohort of patients with nonradiographic axial spondyloarthritis (nr-axSpA) in order to define the early bone changes occurring in axial spondyloarthritis (axSpA) and to define potential factors for deterioration of bone microstructure. METHODS: Patients with axSpA (n = 107) and healthy control subjects (n = 50) of similar age and sex were assessed for geometric, volumetric, and microstructural parameters of bone using high-resolution peripheral quantitative computed tomography (HR-pQCT) at the radius. Additionally, demographic and disease-specific characteristics of patients with axSpA were recorded. RESULTS: Patients with nr-axSpA and control subjects were comparable in age, sex, and body mass index. Geometric and microstructural analysis by HR-pQCT revealed a significantly reduced cortical area (p = 0.022) and cortical thickness (p = 0.006) in patients with nr-axSpA compared with control subjects. Total and cortical vBMD were significantly reduced in patients with nr-axSpA (p = 0.042 and p = 0.007, respectively), whereas there was no difference in trabecular vBMD. Patients with a short disease duration (< 2 years; n = 46) also showed significant reduction of cortical thickness and cortical area compared with control subjects. Patients with disease duration > 2 years (n = 55) additionally developed a decrease of cortical and total vBMD. Multiple regression models identified male sex to be associated with lower cortical vBMD and female sex to be associated with lower trabecular vBMD. CONCLUSIONS: Bone microstructure in patients with nr-axSpA is characterized primarily by deterioration of cortical bone. Cortical bone loss starts early and is evident within the first 2 years of the disease.
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Cost-effective tapering algorithm in patients with rheumatoid arthritis: Combination of multibiomarker disease activity score and autoantibody status - Hagen, Melanie; Englbrecht, Matthias; Haschka, Judith; Reiser, Michaela; Kleyer, Arnd; Hueber, Axel; Manger, Bernhard; Figueiredo, Camille; Cobra, Jayme Fogagnolo; Tony, Hans-Peter; Finzel, Stephanie; Kleinert, Stefan; et al. (Journal of Rheumatology, 2019)
Objective. To analyze the effect of a risk-stratified disease-modifying antirheumatic drug (DMARD)- tapering algorithm based on multibiomarker disease activity (MBDA) score and anticitrullinated protein antibodies (ACPA) on direct treatment costs for patients with rheumatoid arthritis (RA) in sustained remission. Methods. The study was a posthoc retrospective analysis of direct treatment costs for 146 patients with RA in sustained remission tapering and stopping DMARD treatment, in the prospective randomized RETRO study. MBDA scores and ACPA status were determined in baseline samples of patients continuing DMARD (arm 1), tapering their dose by 50% (arm 2), or stopping after tapering (arm 3). Patients were followed over 1 year, and direct treatment costs were evaluated every 3 months. MBDA and ACPA status were used as predictors creating a risk-stratified tapering algorithm based on relapse rates. Results. RA patients with a low MBDA score (< 30 units) and negative ACPA showed the lowest relapse risk (19%), while double-positive patients showed high relapse risk (61%). In ACPA-negative and MBDA-negative (< 30 units), and ACPA or MBDA single-positive (> 30 units) groups, DMARD tapering appears feasible. Considering only patients without flare, direct costs for synthetic and biologic DMARD in the ACPA/MBDA-negative and single positive groups (n = 41) would have been ϵ372,245.16 for full-dose treatment over 1 year. Tapering and stopping DMARD in this low-risk relapse group allowed a reduction of ϵ219,712.03 of DMARD costs. Average reduction of DMARD costs per patient was ϵ5358.83. Conclusion. Combining MBDA score and ACPA status at baseline may allow risk stratification for successful DMARD tapering and cost-effective use of biologic DMARD in patients in deep remission as defined by the 28-joint count Disease Activity Score using erythrocyte sedimentation rate.
CRIS-Team Scopus Importer:2019-05-17
Keywords: Anticyclic Citrullinated Protein Antibodies; Drug Costs; Multibiomarker Disease Activity; Remission; Rheumatoid Arthritis; Tapering

Cost-utility analysis of de-escalating biological disease-modifying anti-rheumatic drugs in patients with rheumatoid arthritis - Birkner, Benjamin; Rech, Jürgen; Stargardt, Tom (PLoS ONE, 2020)
Objective Recent guideline updates have suggested de-escalating DMARDs when patients with rheumatoid arthritis achieve remission or low disease activity. We aim to evaluate whether it is cost-effective to de-escalate the biological form of DMARDs (bDMARDs). Methods Using a Markov model, we performed a cost-utility analysis for RA patients on bDMARD treatment. We compared continuing treatment (standard care) to a tapering approach (i.e., an immediate 50% dose reduction), withdrawal (i.e., an immediate 100% dose reduction) and tapering followed by withdrawal of bDMARDs. The parametrization is based on a comprehensive literature review. Results were computed for 30 years with a cycle length of three months. We applied the payer’s perspective for Germany and conducted deterministic and probabilistic sensitivity analyses. Results Tapering or withdrawing bDMARD treatment resulted in ICERs of €526,254 (incr. costs -78,845, incr. QALYs -0.1498) or €216,879 (incr. costs -€121,691, incr. QALYs -0.5611) compared to standard care. Tapering followed by withdrawal resulted in a loss of 0.4354 QALYs and savings of €107,969 per patient, with an ICER of €247,987. Deterministic sensitivity analysis revealed that our results remained largely unaffected by parameter changes. Probabilistic sensitivity analysis suggests that tapering, withdrawal and tapering followed by withdrawal were dominant in 39.8%, 28.2% and 29.0% of 10,000 iterations. Conclusion Our findings suggest that de-escalating bDMARDs in patients with RA may result in high cost savings but also a decrease in quality of life compared to standard care. If decision makers choose to implement de-escalation in daily practice, our results suggest the tapering approach.
CRIS-Team Scopus Importer:2020-01-14

COVAD survey 2 long-term outcomes: unmet need and protocol - Fazal, Zoha Zahid; Sen, Parikshit; Joshi, Mrudula; Ravichandran, Naveen; Lilleker, James B.; Agarwal, Vishwesh; Kardes, Sinan; Kim, Minchul; Day, Jessica; Makol, Ashima; Milchert, Marcin; Gheita, Tamer; et al. (Rheumatology International, 2022)
Vaccine hesitancy is considered a major barrier to achieving herd immunity against COVID-19. While multiple alternative and synergistic approaches including heterologous vaccination, booster doses, and antiviral drugs have been developed, equitable vaccine uptake remains the foremost strategy to manage pandemic. Although none of the currently approved vaccines are live-attenuated, several reports of disease flares, waning protection, and acute-onset syndromes have emerged as short-term adverse events after vaccination. Hence, scientific literature falls short when discussing potential long-term effects in vulnerable cohorts. The COVAD-2 survey follows on from the baseline COVAD-1 survey with the aim to collect patient-reported data on the long-term safety and tolerability of COVID-19 vaccines in immune modulation. The e-survey has been extensively pilot-tested and validated with translations into multiple languages. Anticipated results will help improve vaccination efforts and reduce the imminent risks of COVID-19 infection, especially in understudied vulnerable groups.
CRIS-Team WoS Importer:2022-08-26

COVID-19 Among Patients With Inflammatory Rheumatic Diseases - Esatoglu, Sinem Nihal; Tascilar, Koray; Babaoglu, Hakan; Bes, Cemal; Yurttas, Berna; Akar, Servet; Pehlivan, Ozlem; Akleylek, Cansu; Tecer, Duygu; Seyahi, Emire; Yuce-Inel, Tuba; Alpay-Kanitez, Nilufer; et al. (Frontiers in Immunology, 2021)
Background
CRIS-Team WoS Importer:2021-05-14

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

COVID-19 breakthrough infections in type 1 diabetes mellitus: a cross-sectional study by the COVID-19 Vaccination in Autoimmune Diseases (COVAD) Group - Panchawagh, Suhrud; Ravichandran, Naveen; Barman, Bhupen; Nune, Arvind; Javaid, Mahnoor; Gracia-Ramos, Abraham Edgar; Day, Jessica; Joshi, Mrudula; Kuwana, Masataka; Saha, Sreoshy; Pande, Arunkumar R.; Caballero-Uribe, Carlo Vinicio; et al. (Rheumatology International, 2024)
To investigate the frequency, profile, and severity of COVID-19 breakthrough infections (BI) in patients with type I diabetes mellitus (T1DM) compared to healthy controls (HC) after vaccination. The second COVID-19 Vaccination in Autoimmune Diseases (COVAD-2) survey is a multinational cross-sectional electronic survey which has collected data on patients suffering from various autoimmune diseases including T1DM. We performed a subgroup analysis on this cohort to investigate COVID-19 BI characteristics in patients with T1DM. Logistic regression with propensity score matching analysis was performed. A total of 9595 individuals were included in the analysis, with 100 patients having T1DM. Among the fully vaccinated cohort, 16 (16%) T1DM patients had one BI and 2 (2%) had two BIs. No morbidities or deaths were reported, except for one patient who required hospitalization with oxygen without admission to intensive care. The frequency, clinical features, and severity of BIs were not significantly different between T1DM patients and HCs after adjustment for confounding factors. Our study did not show any statistically significant differences in the frequency, symptoms, duration, or critical care requirements between T1DM and HCs after COVID-19 vaccination. Further research is needed to identify factors associated with inadequate vaccine response in patients with BIs, especially in patients with autoimmune diseases.
CRIS-Team Scopus Importer:2024-01-12
Keywords: Breakthrough infections; COVID-19; Survey; Type 1 diabetes mellitus; Vaccine

COVID-19 effects on the kidney. - Amann, Kerstin Ute; Boor, P.; Wiech, T.; Singh, Jeeshan; Vonbrunn, Eva; Knöll, Antje; Hermann, Maike; Büttner-Herold, Maike; Daniel, Christoph; Hartmann, Arndt (Pathologe, 2021)
Apart from pulmonary disease, acute kidney injury (AKI) is one of the most frequent and most severe organ complications in severe coronavirus disease 2019 (COVID-19). The SARS-CoV‑2 virus has been detected in renal tissue. Patients with chronic kidney disease (CKD) before and on dialysis and specifically renal transplant patients represent a particularly vulnerable population. The increasing number of COVID-19 infected patients with renal involvement led to an evolving interest in the analysis of its pathophysiology, morphology and modes of virus detection in the kidney. Meanwhile, there are ample data from several autopsy and kidney biopsy studies that differ in the quantity of cases as well as in their quality. While the detection of SARS-CoV‑2 RNA in the kidney leads to reproducible results, the use of electron microscopy for visualisation of the virus is difficult and currently critically discussed due to various artefacts. The exact contribution of indirect or direct effects on the kidney in COVID-19 are not yet known and are currently the focus of intensive research.
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COVID-19 effects on the kidney - Amann, Kerstin Ute; Boor, P.; Wiech, T.; Singh, Jeeshan; Vonbrunn, Eva; Knöll, Antje; Hermann, Maike; Büttner-Herold, Maike; Daniel, Christoph; Hartmann, Arndt (Pathologe, 2021)
Apart from pulmonary disease, acute kidney injury (AKI) is one of the most frequent and most severe organ complications in severe coronavirus disease 2019 (COVID-19). The SARS-CoV-2 virus has been detected in renal tissue. Patients with chronic kidney disease (CKD) before and on dialysis and specifically renal transplant patients represent a particularly vulnerable population. The increasing number of COVID-19 infected patients with renal involvement led to an evolving interest in the analysis of its pathophysiology, morphology and modes of virus detection in the kidney. Meanwhile, there are ample data from several autopsy and kidney biopsy studies that differ in the quantity of cases as well as in their quality. While the detection of SARS-CoV-2 RNA in the kidney leads to reproducible results, the use of electron microscopy for visualisation of the virus is difficult and currently critically discussed due to various artefacts. The exact contribution of indirect or direct effects on the kidney in COVID-19 are not yet known and are currently the focus of intensive research.
CRIS-Team WoS Importer:2021-02-19

COVID-19 in Systemic Lupus Erythematosus patients treated with belimumab: a retrospective clinical study - Wu, Yinlan; Li, Yanhong; Wu, Tong; Huang, Deying; Wu, Jianhong; Zhang, Weihua; Jiang, Xuejun; Yao, Chaoqiong; Liang, Xiuping; Cheng, Lu; Liao, Zehui; Xu, Fang; et al. (Immunologic Research, 2024)
Background: Routine use of immunosuppressive agents in systemic lupus erythematosus (SLE) patients infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) potentially increases the risk of adverse outcomes. belimumab, a monoclonal antibody for the treatment of SLE, remains untested for its specific impact on coronavirus disease 2019 (COVID-19) symptoms in these patients. Here, this research investigated the effect of belimumab on COVID-19 symptoms in SLE patients infected with SARS-CoV-2. Methods: This study enrolled SLE patients who underwent treatment with belimumab. After thorough screening based on the inclusion and exclusion criteria, data pertaining to COVID-19 for both the participants and their cohabitants were obtained through telephone follow-up. The potential impact of belimumab on COVID-19 was evaluated by comparing COVID-19 symptoms and medication use across various groups to investigate the association between belimumab treatment and COVID-19 in SLE. Results: This study involved 123 SLE patients, of whom 89.4% tested positive for SARS-CoV-2. Among cohabitants of SLE patients, the SARS-CoV-2 positive rate was 87.2% (p = 0.543). Patients treated with belimumab exhibited a lower incidence of multiple COVID-19 symptoms than their cohabitating counterparts (p < 0.001). This protective effect was found to be partially related to the time of last belimumab administration. Among those with COVID-19, 30 patients opted to discontinue their anti-SLE drugs, and among them, 53% chose to discontinue belimumab. Discontinuing drugs did not increase the risk of hospitalization due to SARS-CoV-2 infection. Conclusion: This study concluded that treatment with belimumab did not increase susceptibility to COVID-19 and beneficially alleviated the symptoms of COVID-19.
CRIS-Team Scopus Importer:2024-07-12
Keywords: Belimumab; Coronavirus disease 2019 (COVID-19); Retrospective clinical study; Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2); Systemic Lupus Erythematosus (SLE)

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

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

COVID-19 severity and vaccine breakthrough infections in idiopathic inflammatory myopathies, other systemic autoimmune and inflammatory diseases, and healthy controls: a multicenter cross-sectional study from the COVID-19 Vaccination in Autoimmune Diseases (COVAD) survey - Hoff, Leonardo Santos; Ravichandran, Naveen; Shinjo, Samuel Katsuyuki; Day, Jessica; Sen, Parikshit; Junior, Jucier Goncalves; Lilleker, James B.; Joshi, Mrudula; Agarwal, Vishwesh; Kardes, Sinan; Kim, Minchul; Milchert, Marcin; et al. (Rheumatology International, 2022)
Objectives: We aimed to compare the spectrum and severity of COVID-19 and vaccine breakthrough infections (BIs) among patients with IIMs, other systemic autoimmune and inflammatory diseases (SAIDs), and healthy controls (HCs). Methods: This is a cross-sectional study with data from the COVAD study, a self-reported online global survey that collected demographics, COVID-19 history, and vaccination details from April to September 2021. Adult patients with at least one COVID-19 vaccine dose were included. BIs were defined as infections occurring > 2 weeks after any dose of vaccine. Characteristics associated with BI were analyzed with a multivariate regression analysis. Results: Among 10,900 respondents [42 (30–55) years, 74%-females, 45%-Caucasians] HCs were (47%), SAIDs (42%) and IIMs (11%). Patients with IIMs reported fewer COVID-19 cases before vaccination (6.2%-IIM vs 10.5%-SAIDs vs 14.6%-HC; OR = 0.6, 95% CI 0.4–0.8, and OR = 0.3, 95% CI 0.2–0.5, respectively). BIs were uncommon (1.4%-IIM; 1.9%-SAIDs; 3.2%-HC) and occurred in 17 IIM patients, 13 of whom were on immunosuppressants, and 3(18%) required hospitalization. All-cause hospitalization was higher in patients with IIM compared to HCs [23 (30%) vs 59 (8%), OR = 2.5, 95% CI 1.2–5.1 before vaccination, and 3 (18%) vs 9 (5%), OR = 2.6, 95% CI 1.3–5.3 in BI]. In a multivariate regression analysis, age 30–60 years was associated with a lower odds of BI (OR = 0.7, 95% CI 0.5–1.0), while the use of immunosuppressants had a higher odds of BI (OR = 1.6, 95% CI 1.1–2.7). Conclusions: Patients with IIMs reported fewer COVID-19 cases than HCs and other SAIDs, but had higher odds of all-cause hospitalization from COVID-19 than HCs. BIs were associated with the use of immunosuppressants and were uncommon in IIMs.
CRIS-Team Scopus Importer:2022-11-04
Keywords: Autoimmune diseases; Breakthrough infection; COVID-19; Idiopathic inflammatory myopathies; SARS-CoV-2 vaccination

COVID-19 SEVERITY AND VACCINE BREAKTHROUGH INFECTIONS IN IDIOPATHIC INFLAMMATORY MYOPATHIES, OTHER SYSTEMIC AUTOIMMUNE AND INFLAMMATORY DISEASES, AND HEALTHY INDIVIDUALS: RESULTS FROM THE COVID-19 VACCINATION IN AUTOIMMUNE DISEASES (COVAD) STUDY. - Gupta, L.; Hoff, L. S.; R, N.; Sen, P.; Katsuyuki Shinjo, S.; Day, J.; Lilleker, J. B.; Agarwal, V.; Kardes, S.; Kim, M.; Makol, A.; Milchert, M.; et al. (ANNALS OF THE RHEUMATIC DISEASES, 2022)
CRIS-Team WoS Importer:2022-11-04

COVID-19 vaccination in autoimmune disease (COVAD) survey protocol - Sen, Parikshit; Gupta, Latika; Lilleker, James B.; Aggarwal, Vishwesh; Kardes, Sinan; Milchert, Marcin; Gheita, Tamer; Salim, Babur; Velikova, Tsvetelina; Gracia-Ramos, Abraham Edgar; Parodis, Ioannis; O'Callaghan, Albert Selva; et al. (Rheumatology International, 2021)
The coronavirus disease-2019 (COVID-19) pandemic continues to be a cause of unprecedented global morbidity and mortality. Whilst COVID-19 vaccination has emerged as the only tangible solution to reducing poor clinical outcomes, vaccine hesitancy continues to be an obstacle to achieving high levels of vaccine uptake. This represents particular risk to patients with autoimmune diseases, a group already at increased risk of hospitalization and poor clinical outcomes related to COVID-19 infection. Whilst there is a paucity of long-term safety and efficacy data of COVID-19 vaccination in patients with autoimmune diseases, the current evidence strongly suggests that the benefits of vaccination outweigh the risks of adverse effects and disease flares. Herein, we report the protocol of the COVID-19 Vaccination in Autoimmune Diseases (COVAD) study, an ongoing international collaborative study involving 29 countries and over 110 investigators.
CRIS-Team WoS Importer:2021-11-26

COVID-19 Vaccination in Autoimmune Diseases (COVAD) study: Vaccine safety in idiopathic inflammatory myopathies - Gil-Vila, Albert; Ravichandran, Naveen; Selva-O'Callaghan, Albert; Sen, Parikshit; Nune, Arvind; Gaur, Prithvi Sanjeevkumar; Gonzalez, Raquel Arànega; Lilleker, James B.; Joshi, Mrudula; Agarwal, Vishwesh; Kardes, Sinan; Kim, Minchul; et al. (Muscle & Nerve, 2022)
Introduction/Aims: In this study we investigated COVID-19 vaccination–related adverse events (ADEs) 7 days postvaccination in patients with idiopathic inflammatory myopathies (IIMs) and other systemic autoimmune and inflammatory disorders (SAIDs). Methods: Seven-day vaccine ADEs were collected in an international patient self-reported e-survey. Descriptive statistics were obtained and multivariable regression was performed. Results: Ten thousand nine hundred respondents were analyzed (1227 IIM cases, 4640 SAID cases, and 5033 healthy controls [HCs]; median age, 42 [interquartile range, 30-455] years; 74% female; 45% Caucasian; 69% completely vaccinated). Major ADEs were reported by 76.3% of the IIM patients and 4.6% reported major ADEs. Patients with active IIMs reported more frequent major (odds ratio [OR], 2.7; interquartile range [IQR], 1.04-7.3) and minor (OR, 1.5; IQR, 1.1-2.2) ADEs than patients with inactive IIMs. Rashes were more frequent in IIMs (OR, 2.3; IQR, 1.2-4.2) than HCs. ADEs were not impacted by steroid dose, although hydroxychloroquine and intravenous/subcutaneous immunoglobulins were associated with a higher risk of minor ADEs (OR, 1.9; IQR, 1.1-3.3; and OR, 2.2; IQR, 1.1-4.3, respectively). Overall, ADEs were less frequent in inclusion-body myositis (IBM) and BNT162b2 (Pfizer) vaccine recipients. Discussion: Seven-day postvaccination ADEs were comparable in patients with IIMs, SAIDs, and HCs, except for a higher risk of rash in IIMs. Patients with dermatomyositis with active disease may be at higher risk, and IBM patients may be at lower risk of specific ADEs. Overall, the benefit of preventing severe COVID-19 through vaccination likely outweighs the risk of vaccine-related ADEs. Our results may inform future guidelines regarding COVID-19 vaccination in patients with SAIDs, specifically in those with IIMs. Studies to evaluate long-term outcomes and disease flares are needed to shed more light on developing future COVID-19 vaccination guidelines.
CRIS-Team Scopus Importer:2022-09-09
Keywords: COVID-19; dermatomyositis; myositis; rheumatology; vaccination

COVID-19 Vaccination in Autoimmune Diseases Study: Vaccine Safety in Rheumatoid Arthritis - Naveen, R.; Parodis, Ioannis; Joshi, Mrudula; Sen, Parikshit; Kim, Minchul; Agarwal, Vishwesh; Kardes, Sinan; Lilleker, James B.; Chinoy, Hector; Distler, Oliver; Tan, Ai Lyn; Shinjo, Samuel; et al. (ARTHRITIS & RHEUMATOLOGY, 2022)
CRIS-Team WoS Importer:2023-01-13

COVID-19 vaccination-related adverse events among autoimmune disease patients: results from the COVAD study - Sen, Parikshit; Ravichandran, Naveen; Nune, Arvind; Lilleker, James B.; Agarwal, Vishwesh; Kardes, Sinan; Kim, Minchul; Day, Jessica; Milchert, Marcin; Gheita, Tamer; Salim, Babur; Velikova, Tsvetelina; et al. (Rheumatology, 2022)
Objectives COVID-19 vaccines have been proven to be safe in the healthy population. However, gaps remain in the evidence of their safety in patients with systemic autoimmune and inflammatory disorders (SAIDs). COVID-19 vaccination-related adverse events (AEs) in patients with SAIDs and healthy controls (HC) seven days post-vaccination were assessed in the COVAD study, a patient self-reported cross-sectional survey. Methods The survey was circulated in early 2021 by >110 collaborators (94 countries) to collect SAID details, COVID-19 vaccination details and 7-day vaccine AEs, irrespective of respondent vaccination status. Analysis was performed based on data distribution and variable type. Results Ten thousand nine hundred respondents [median (interquartile range) age 42 (30-55) years, 74% females and 45% Caucasians] were analysed; 5867 patients (54%) with SAIDs were compared with 5033 HCs. Seventy-nine percent had minor and only 3% had major vaccine AEs requiring urgent medical attention (but not hospital admission) overall. Headache [SAIDs = 26%, HCs = 24%; odds ratio (OR) = 1.1 (95% CI: 1.03, 1.3); P = 0.014], abdominal pain [SAIDs = 2.6%, HCs = 1.4%; OR = 1.5 (95% CI: 1.1, 2.3); P = 0.011], and dizziness [SAIDs = 6%, HCs = 4%; OR = 1.3 (95% CI: 1.07, 1.6); P = 0.011], were slightly more frequent in SAIDs. Overall, major AEs [SAIDs = 4%, HCs = 2%; OR = 1.9 (95% CI: 1.6, 2.2); P < 0.001] and, specifically, throat closure [SAIDs = 0.5%, HCs = 0.3%; OR = 5.7 (95% CI: 2.9, 11); P = 0.010] were more frequent in SAIDs though absolute risk was small (0-4%). Major AEs and hospitalizations (<2%) were comparable across vaccine types in SAIDs. Conclusion Vaccination against COVID-19 is safe in SAID patients. SAIDs were at a higher risk of major AEs than HCs, though absolute risk was small. There are small differences in minor AEs between vaccine types in SAID patients.
CRIS-Team WoS Importer:2022-08-12

COVID-19 VACCINATION-RELATED ADVERSE EVENTS AMONG AUTOIMMUNE DISEASE PATIENTS: RESULTS FROM THE COVID-19 VACCINATION IN AUTOIMMUNE DISEASES (COVAD) STUDY - Sen, P.; R, N.; Nune, Arvind; Lilleker, J. B.; Agarwal, V.; Kardes, S.; Kim, M.; Day, J.; Milchert, M.; Gheita, T. A.; Salim, B.; Velikova, T.; et al. (ANNALS OF THE RHEUMATIC DISEASES, 2022)
CRIS-Team WoS Importer:2022-11-04

COVID-19 Vaccination-related Short-term Adverse Events in Patients with Idiopathic Inflammatory Myositis and Autoimmune Multimorbidity: Results from the COVID-19 Vaccination in Autoimmune Diseases Survey - Dey, Mrinalini; Naveen, R.; Nikiphorou, Elena; Sen, Parikshit; Lilleker, James B.; Agarwal, Vishwesh; Kardes, Sinan; Day, Jessica; Milchert, Marcin; Joshi, Mrudula; Gheita, Tamer A.; Salim, Babur; et al. (ARTHRITIS & RHEUMATOLOGY, 2022)
CRIS-Team WoS Importer:2023-01-13

COVID-19 vaccine safety during pregnancy and breastfeeding in women with autoimmune diseases: results from the COVAD study. - Andreoli, Laura; Lini, Daniele; Schreiber, Karen; Parodis, Ioannis; Sen, Parikshit; Ravichandran, Naveen; Day, Jessica; Joshi, Mrudula; Jagtap, Kshitij; Nune, Arvind; Nikiphorou, Elena; Agarwal, Vishwesh; et al. (Rheumatology, 2024)
OBJECTIVES: We investigated coronavirus disease 2019 (COVID-19) vaccine safety in pregnant and breastfeeding women with autoimmune diseases (AID) in the COVID-19 Vaccination in Autoimmune Diseases (COVAD) study. METHODS: Delayed-onset (>7 days) vaccine-related adverse events (AE), disease flares and AID-related treatment modifications were analysed upon diagnosis of AID vs healthy controls (HC) and the pregnancy/breastfeeding status at the time of at least one dose of vaccine. RESULTS: Among the 9201 participants to the self-administered online survey, 6787 (73.8%) were women. Forty pregnant and 52 breastfeeding patients with AID were identified, of whom the majority had received at least one dose of COVID-19 vaccine (100% and 96.2%, respectively). AE were reported significantly more frequently in pregnant than in non-pregnant patients (overall AE 45% vs 26%, P = 0.01; minor AE 40% vs 25.9%, P = 0.03; major AE 17.5% vs 4.6%, P < 0.01), but no difference was found in comparison with pregnant HC. No difference was observed between breastfeeding patients and HC with respect to AE. Post-vaccination disease flares were reported by 17.5% of pregnant and 20% of breastfeeding patients, and by 18.3% of age- and disease-matched non-pregnant and non-breastfeeding patients (n = 262). All pregnant/breastfeeding patients who experienced a disease flare were managed with glucocorticoids; 28.6% and 20% of them required initiation or change in immunosuppressants, respectively. CONCLUSION: This study provides reassuring insights into the safety of COVID-19 vaccines administered to women with AID during the gestational and post-partum periods, helping overcome hesitant attitudes, as the benefits for the mother and for the fetus by passive immunization appear to outweigh potential risks.
EVALuna2:544055

#Covid4Rheum: an analytical twitter study in the time of the COVID-19 pandemic - Ruffer, Nikolas; Knitza, Johannes; Krusche, Martin (Rheumatology International, 2020)
Social media services, such as Twitter, offer great potential for a better understanding of rheumatic and musculoskeletal disorders (RMDs) and improved care in the field of rheumatology. This study examined the content and stakeholders associated with the Twitter hashtag #Covid4Rheum during the COVID-19 pandemic. The content analysis shows that Twitter connects stakeholders of the rheumatology community on a global level, reaching millions of users. Specifically, the use of hashtags on Twitter assists digital crowdsourcing projects and scientific collaboration, as exemplified by the COVID-19 Global Rheumatology Alliance registry. Moreover, Twitter facilitates the distribution of scientific content, such as guidelines or publications. Finally, digital data mining enables the identification of hot topics within the field of rheumatology.
CRIS-Team Scopus Importer:2020-10-09
Keywords: COVID-19; Hashtag; Rheumatology; SARS-CoV-2; Twitter

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

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

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

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

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

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

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

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

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

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

Cytotoxicity of crystals involves RIPK3-MLKL-mediated necroptosis - Mulay, Shrikant R.; Desai, Jyaysi; Kumar, Santhosh V.; Eberhard, Jonathan N.; Thomasova, Dana; Romoli, Simone; Grigorescu, Melissa; Kulkarni, Onkar P.; Popper, Bastian; Vielhauer, Volker; Zuchtriegel, Gabriele; Reichel, Christoph; et al. (Nature Communications, 2016)
Crystals cause injury in numerous disorders, and induce inflammation via the NLRP3 inflammasome, however, it remains unclear how crystals induce cell death. Here we report that crystals of calcium oxalate, monosodium urate, calcium pyrophosphate dihydrate and cystine trigger caspase-independent cell death in five different cell types, which is blocked by necrostatin-1. RNA interference for receptor-interacting protein kinase 3 (RIPK3) or mixed lineage kinase domain like (MLKL), two core proteins of the necroptosis pathway, blocks crystal cytotoxicity. Consistent with this, deficiency of RIPK3 or MLKL prevents oxalate crystal-induced acute kidney injury. The related tissue inflammation drives TNF-?-related necroptosis. Also in human oxalate crystal-related acute kidney injury, dying tubular cells stain positive for phosphorylated MLKL. Furthermore, necrostatin-1 and necrosulfonamide, an inhibitor for human MLKL suppress crystal-induced cell death in human renal progenitor cells. Together, TNF-?/TNFR1, RIPK1, RIPK3 and MLKL are molecular targets to limit crystal-induced cytotoxicity, tissue injury and organ failure.
EVALuna2:13240

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

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

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

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

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

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

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

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

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

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

Def6 Restrains Osteoclastogenesis and Inflammatory Bone Resorption - Binder, Nikolaus; Miller, Christine; Yoshida, Masaki; Inoue, Kazuki; Nakano, Shinichi; Hu, Xiaoyu; Ivashkiv, Lionel B.; Schett, Georg; Pernis, Alessandra; Goldring, Steven R.; Ross, F. Patrick; Zhao, Baohong (Journal of Immunology, 2017)
Inflammatory bone resorption mediated by osteoclasts is a major cause of morbidity and disability in many inflammatory disorders, including rheumatoid arthritis (RA). The mechanisms that regulate osteoclastogenesis and bone resorption in inflammatory settings are complex and have not been well elucidated. In this study, we identify the immunoregulator differentially expressed in FDCP 6 homolog (Def6) as a novel inhibitor of osteoclastogenesis in physiological and inflammatory conditions. Def6 deficiency in Def6(-/-) mice enhanced the sensitivity of osteoclast precursors to the physiological osteoclastogenic inducer receptor activator for NF-?B ligand, and Def6(-/-) osteoclasts formed actin rings. Furthermore, Def6 deficiency markedly increased TNF-?-induced osteoclastogenesis in vitro and in vivo and enhanced bone resorption in an inflammatory osteolysis mouse model. TNF-? serum levels correlated negatively with Def6 expression levels in osteoclast precursors obtained from RA patients, and the osteoclastogenic capacity of the osteoclast precursors was significantly inversely correlated with their Def6 expression levels, indicating that Def6 functions as an inhibitor of excessive osteoclast formation and bone destruction in RA. Mechanistically, Def6 suppressed osteoclastogenesis and the expression of key osteoclastogenic factors NFATc1, B lymphocyte-induced maturation protein-1, and c-Fos by regulating an endogenous IFN-?-mediated autocrine feedback loop. The Def6-dependent pathway may represent a novel therapeutic target to prevent pathological bone destruction.
EVALuna2:13411

Deficiency of the microprocessor component DGCR8 impairs macrophage growth and unleashes IFN-dependent gene expression in response to mycobacteria - Killy, Barbara; Bodendorfer, B.; Pracht, Katharina; Jäck, Hans-Martin; Lang, Roland (EUROPEAN JOURNAL OF IMMUNOLOGY, 2019)
CRIS-Team WoS Importer:2019-10-08

Deficiency of Thrombospondin-4 in Mice Does Not Affect Skeletal Growth or Bone Mass Acquisition, but Causes a Transient Reduction of Articular Cartilage Thickness - Jeschke, Anke; Bonitz, Martin; Simon, Maciej; Peters, Stephanie; Baum, Wolfgang; Schett, Georg; Ruether, Wolfgang; Niemeier, Andreas; Schinke, Thorsten; Amling, Michael (PLoS ONE, 2015)
Although articular cartilage degeneration represents a major public health problem, the underlying molecular mechanisms are still poorly characterized. We have previously utilized genome-wide expression analysis to identify specific markers of porcine articular cartilage, one of them being Thrombospondin-4 (Thbs4). In the present study we analyzed Thbs4 expression in mice, thereby confirming its predominant expression in articular cartilage, but also identifying expression in other tissues, including bone. To study the role of Thbs4 in skeletal development and integrity we took advantage of a Thbs4-deficient mouse model that was analyzed by undecalcified bone histology. We found that Thbs4-deficient mice do not display phenotypic differences towards wildtype littermates in terms of skeletal growth or bone mass acquisition. Since Thbs4 has previously been found over-expressed in bones of Phex-deficient Hyp mice, we additionally generated Thbs4-deficient Hyp mice, but failed to detect phenotypic differences towards Hyp littermates. With respect to articular cartilage we found that Thbs4-deficient mice display transient thinning of articular cartilage, suggesting a protective role of Thbs4 for joint integrity. Gene expression analysis using porcine primary cells revealed that Thbs4 is not expressed by synovial fibroblasts and that it represents the only member of the Thbs gene family with specific expression in articular, but not in growth plate chondrocytes. In an attempt to identify specific molecular effects of Thbs4 we treated porcine articular chondrocytes with human THBS4 in the absence or presence of conditioned medium from porcine synovial fibroblasts. Here we did not observe a significant influence of THBS4 on proliferation, metabolic activity, apoptosis or gene expression, suggesting that it does not act as a signaling molecule. Taken together, our data demonstrate that Thbs4 is highly expressed in articular chondrocytes, where its presence in the extracellular matrix is required for articular cartilage integrity.
EVALuna2:13177

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

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

Delay Between the Onset of Psoriasis and Arthritis in PsA Patients from the PsART International Cohort - Tascilar, Koray; Aydin, Sibel Zehra; Akar, Servet; Aksu, Kenan; Bakirci, Sibel; Bayindir, Ozun; Can, Meryem; Cetin, Gozde; Cinar, Muhammet; Dalkilic, Ediz; Dogru, Atalay; Erden, Abdulsamet; et al. (ARTHRITIS & RHEUMATOLOGY, 2019)
CRIS-Team WoS Importer:2020-02-07

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

Deletion of the receptor tyrosine kinase Tyro3 inhibits synovial hyperplasia and bone damage in arthritis - Ruiz-Heiland, Gisela; Zhao, Yi; Derer, Anja; Braun, Timm; Engelke, Klaus; Neumann, Elena; Mueller-Ladner, Ulf; Liu, Yi; Zwerina, Jochen; Schett, Georg (Annals of the Rheumatic Diseases, 2014)
To test whether the tyrosine kinase Tyro3 affects arthritis. Tyro3, the ligand of growth arrest-specific protein 6 (GAS6) is a receptor tyrosine kinase involved in cell survival. Tyro3 and GAS6 are expressed in the arthritic synovium, and in vitro studies have shown their role in osteoclast differentiation.Bone was assessed by micro CT and histomorphometry in Tyro3-deficient (Tyro3(-/-)) and wild-type mice. Arthritis was induced in both genotypes, and Gas6 level was measured by ELISA. Synovitis, synovial hyperplasia, bone erosion, osteoclast activation and osteoclast gene expression were assessed by histomorphometry and reverse transcriptase-PCR, respectively. In vitro osteoclast differentiation assays were performed in Tyro3(-/-) and wild-type mice. Furthermore, effects of Tyro3 and GAS6 on human synovial fibroblast proliferation and osteoclastogenesis were assessed in human cells.Tyro3(-/-) mice had significantly higher bone mass than wild-type littermates. Induction of arthritis increased GAS6 serum levels. Arthritic Tyro3(-/-) mice showed less synovial hyperplasia, osteoclast numbers and bone damage compared with controls. In vivo expression of osteoclast-associated receptor and receptor activator of nuclear factor-?B and in vitro osteoclastogenesis were impaired in Tyro3(-/-) mice. GAS6 also induced synovial fibroblast proliferation and osteoclast differentiation in human cells in Tyro3-dependent manner.These findings indicate that Tyro3 is a critical signal for synovial hyperplasia, osteoclast differentiation and bone erosion during arthritis. GAS6 and Tyro3 therefore constitute therapeutic targets to inhibit synovial hyperplasia and associated bone erosion.
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Delta variant (B.1.617.2) sublineages do not show increased neutralization resistance - Arora, Prerna; Kempf, Amy; Nehlmeier, Inga; Graichen, Luise; Sidarovich, Anzhalika; Winkler, Martin S.; Schulz, Sebastian; Jäck, Hans-Martin; Stankov, Metodi V.; Behrens, Georg M. N.; Pohlmann, Stefan; Hoffmann, Markus (Cellular & Molecular Immunology, 2021)
CRIS-Team Scopus Importer:2021-10-22

Depression and rheumatism: options for measuring depression - Englbrecht, Matthias; Wendler, J.; Alten, R. (Zeitschrift für Rheumatologie, 2014)
The importance of depressive diseases in the treatment of rheumatism patients cannot be denied. It is well-known from publications in the English speaking literature that the proportion of depressive diseases lies between 10% and 45% in patients with rheumatoid arthritis (RA). However, clearly increased numbers can also be seen in a direct comparison with corresponding prevalence rates in the normal population for other diseases included in the category of rheumatism.This manuscript focusses on the possibilities and challenges in measuring states of depressive mood that might serve as an indicator of depressive diseases in the context of treatment of rheumatism.A search of the current literature was carried out and the results were evaluated.Starting from appropriate background knowledge, the current state of science is discussed while subsequently taking a closer look at a choice of internationally recognized assessment tools which are feasible for use in rheumatology. Finally, this overview is accompanied by hints for hands-on practice and suggestions on how to respond to conspicuous test results indicative of a depressive mood.The potential benefits of appropriate screening with measurement instruments are considered to be high for rheumatism patients. The measurement tools presented must be suitably selected for the individual purpose and for each rheumatology institution. In view of test application consideration must be given not only to the total score but also to the individual responses to test items. In cases of conspicuous test results the further approach must be agreed together with the patient and by choosing adequate treatment options for the situation. In cases of acute suicidal tendencies acceptance, care and support are of key importance, while the precautionary presentation in a specialist clinic must be initiated.
EVALuna2:13209

Depression, Anxiety, Resilience and Coping Pre and Post Kidney Transplantation - Initial Findings from the Psychiatric Impairments in Kidney Transplantation (PI-KT)-Study - Mueller, Helge H.; Englbrecht, Matthias; Wiesener, Michael S.; Titze, Stephanie; Heller, Katharina; Groemer, Teja W.; Schett, Georg; Eckardt, Kai-Uwe; Kornhuber, Johannes; Maler, Juan Manuel (PLoS ONE, 2015)
Depression/anxiety, impaired Health-Related Quality of Life (HRQoL) and coping and resilience structures, are associated with increased mortality/poor outcome in chronic kidney disease (CKD) patients before (CKD/pre-KT) and after kidney (CKD-T) transplantation. Less is known about prevalence rates of psychiatric symptoms and impaired HRQoL of non-transplanted compared with transplanted patients.In a cross-sectional study comparing 101 CKD/pre-KT patients with 151 cadaveric-transplanted (CKD-T) patients, we examined prevalence of depression/anxiety (HADS questionnaire) and coping, resilience and HRQoL (SF-12, Resilience-Scale and FKV-questionnaire).The prevalence of both depressive and anxiety symptoms was not significantly different between different pre-/and CKD-T patient groups. In CKD-T no significant relations of coping strategies with kidney function were identified. Furthermore, the Resilience Scales for acceptance and competence did not suggest any differences between the CKD/pre-KT and CKD-T subgroup. In the CKD/pre-KT patients, significant correlations were identified between the acceptance subscale and partnership, as well as between the competence subscale and older age/partnership.Both the CKD/pre-KT and CKD-T patients exhibited notable impairments in the HRQoL which which showed a comparable pattern of results. KT itself does not appear to be the main risk factor for the development of mental impairments.
EVALuna2:3811

Depression as comorbidity of rheumatoid arthritis - Baerwald, C.; Manger, Bernhard; Hueber, Axel (Zeitschrift für Rheumatologie, 2019)
Depressive disorders are among the most common comorbidities in patients not only with rheumatoid arthritis (RA) but also with other forms of inflammatory rheumatic diseases. The prevalence of adepressive disorder in RA is estimated to be between 9.5% and 41.5% depending on the study and with women being more affected. After adjusting for sex, age and other parameters the risk of depression in RA was significantly elevated with an odds ratio of 1.63 (95% CI, 1.43-1.87) compared to the general population. In RA the risk of developing adepressive disorder is highest in the first 5 years and depression is abetter predictor of work disability than disease activity and response to treatment. Depression in RA is associated with more pain, fatigue and impaired quality of life, whereby the association between depression and RA is bidirectional. Therefore, the risk to develop adepression is increased with impaired function as measured by the health assessment questionnaire (HAQ) and there is evidence that increased disease activity increases the risk for depression in RA. In addition, adepressive disorder also affects the subjective severity of patient-reported outcomes (PRO), such as tender joints and the global patient assessment with respect to disease activity and thus exhibiting adirect influence on the DAS28. Finally, it could be shown that depression unfavorably influences the response to therapy, the rate of remission is lower and the mortality is increased in RA patients. Taken together, this indicates that it is necessary to detect a depression in patients with RA as early as possible in order to initiate appropriate treatment of depression in such cases.
CRIS-Team WoS Importer:2019-04-16

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

Depression is a stronger predictor of the risk to consider work disability in early arthritis than disease activity or response to therapy - Callhoff, Johanna; Albrecht, Katinka; Schett, Georg; Zink, Angela; Westhoff, Gisela (RMD Open, 2015)
To evaluate the factors that influence patients with early inflammatory arthritis to consider a disability pension.A total of 528 patients aged 63 or younger from an early arthritis cohort with a mean symptom duration of 3 months at inclusion were asked at 12 and 24 months whether they were considering applying for, had applied for or were receiving a disability pension because of arthritis. Possible predictors were analysed with univariate and multivariate logistic regression.69 patients (13%) were considering, had applied for or were receiving a disability pension. Univariate predictors were older age, disease activity, several patient-reported outcomes and depression. In a multivariate analysis, age, days on sick leave, impairment of physical function and depression were predictive for considering a disability pension (OR for severe vs no depression: 3.85, 95% CI 1.43 to 10.4).In patients with early arthritis, depression appears to be a stronger predictor of the risk to consider applying for work disability pension than the features of disease activity. Patients at risk could be identified with one single depression statement. This finding should prompt physicians to react early to signs and symptoms of depression to help patients to maintain their ability to work.
EVALuna2:13179

DEPRESSIVE SYMPTOMS IN PSA: A CROSS-SECTIONAL ANALYSIS FROM THE NATIONAL GERMAN RABBIT-SPA REGISTRY - Regierer, A.; Weiss, A.; Bohl-Buehler, M.; Baraliakos, X.; Behrens, F.; Schett, Georg; Strangfeld, A. (Annals of the Rheumatic Diseases, 2021)
CRIS-Team WoS Importer:2021-10-01

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

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

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

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

Desialylation of dying cells with catalytically active antibodies possessing sialidase activity facilitate their clearance by human macrophages - Tomin, A.; Dumych, Tetiana; Tolstyak, Y.; Kril, I.; Mahorivska, I.; Bila, E.; Stoika, R.; Herrmann, Martin; Kit, Y.; Bilyy, R. (Clinical and Experimental Immunology, 2015)
Recently we reported the first known incidence of antibodies possessing catalytic sialidase activity (sialidase abzymes) in the serum of patients with multiple myeloma and systemic lupus erythematosus (SLE). These antibodies desialylate biomolecules, such as glycoproteins, gangliosides and red blood cells. Desialylation of dying cells was demonstrated to facilitate apoptotic cell clearance. In this study we assessed the possibility to facilitate dying cell clearance with the use of F(ab)2 fragments of sialidase abzymes. Two sources of sialidase abzymes were used: (i) those isolated from sera of patients with SLE after preliminary screening of a cohort of patients for sialidase activity; and (ii) by creating an induced sialidase abzyme through immunization of a rabbit with synthetic hapten consisting of a non-hydrolysable analogue of sialidase reaction conjugated with bovine serum albumin (BSA) or keyhole limpet haemocyanin (KLH). Antibodies were purified by ammonium sulphate precipitation, protein-G affinity chromatography and size exclusion-high performance liquid chromatography (HPLC-SEC). Effect of desialylation on efferocytosis was studied using human polymorphonuclear leucocytes (PMN), both viable and aged, as prey, and human monocyte-derived macrophages (MoMa). Treatment of apoptotic and viable prey with both disease-associated (purified from blood serum of SLE patients) and immunization-induced (obtained by immunization of rabbits) sialidase abzymes, its F(ab)2 fragment and bacterial neuraminidase (as positive control) have significantly enhanced the clearance of prey by macrophages. We conclude that sialidase abzyme can serve as a protective agent in autoimmune patients and that artificial abzymes may be of potential therapeutic value.
EVALuna2:13094

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

Destabilization of the human epigenome: consequences of foreign DNA insertions - Weber, Stefanie; Hofmann, Andrea; Herms, Stefan; Hoffmann, Per; Dörfler, Walter (Epigenomics, 2015)
We previously reported changes of DNA methylation and transcription patterns in mammalian cells that carry integrated foreign DNA. Experiments were now designed to assess the epigenetic consequences of inserting a 5.6 kbp plasmid into the human genome.Differential transcription and CpG methylation patterns were compared between transgenomic and nontransgenomic cell clones by using gene chip microarray systems.In 4.7% of the 28.869 gene segments analyzed, transcriptional activities were up- or downregulated in the transgenomic cell clones. Genome-wide profiling revealed differential methylation in 3791 of > 480,000 CpG's examined in transgenomic versus nontransgenomic clones.The data document genome-wide effects of foreign DNA insertions on the epigenetic stability of human cells. Many fields in experimental biology and medicine employ transgenomic or otherwise genome-manipulated cells or organisms without considering the epigenetic consequences for the recipient genomes.
EVALuna2:8268

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

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

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

Development of a Dual-Energy Computed Tomography Scoring System for Measurement of Urate Deposition in Gout - Bayat, Sara; Aati, Opetaia; Rech, Juergen; Sapsford, Mark; Lell, Michael; Araujo, Elizabeth; Petsch, Christina; Stamp, Lisa K.; Schett, Georg; Manger, Bernhard; Dalbeth, Nicola; Cavallaro, Alexander Josef (Arthritis & Rheumatism-Arthritis Care & Research, 2016)
To develop a semiquantitative dual-energy computed tomography (DECT) scoring system for measurement of urate deposition in gout.Following a structured review of images, a semiquantitative DECT urate scoring method for foot/ankle scans was developed for testing. This method included 4 regions, each scored 0-3, with a maximum total DECT urate score of 12. DECT scans from 224 patients (182 with gout, 42 without gout) were scored by 2 independent readers. Automated urate volumes were also measured. Paired scans from 8 patients receiving pegloticase were analyzed, and a timing exercise was undertaken. The properties of the DECT urate score were analyzed according to the Outcome Measures in Rheumatology (OMERACT) filter.The interreader intraclass correlation coefficient (95% confidence interval) for the DECT urate score was 0.98 (0.97-0.98). All scored regions contributed to the total DECT urate score. DECT urate scores and volumes were highly correlated (r = 0.91, P < 0.0001). Both DECT urate scores and volumes discriminated between gout and nongout control participants and between the tophaceous gout, nontophaceous gout, and control groups. Compared with urate volume, the DECT urate score had greater ability to discriminate between responders and nonresponders to pegloticase therapy (P < 0.001 for DECT urate score and P > 0.05 for volume). The mean ± SD time required for the DECT urate score was 121 ± 2 seconds and for urate volume was 240 ± 2 seconds (P = 2 × 10(-31) ).We have developed a novel semiquantitative DECT scoring method for measurement of urate deposition in the feet/ankles. This method fulfills many aspects of the OMERACT filter.
EVALuna2:13182

Development of three-dimensional prints of arthritic joints for supporting patients' awareness to structural damage - Kleyer, Arnd; Beyer, Laura; Simon, Christoph; Stemmler, Fabian; Englbrecht, Matthias; Beyer, Christian; Rech, Juergen; Manger, Bernhard; Krönke, Gerhard; Schett, Georg; Hueber, Axel (Arthritis Research & Therapy, 2017)
Rheumatoid arthritis (RA) and psoriatic arthritis (PsA) result in severe joint destruction and functional disability if left untreated. We aim to develop tools that help patients with RA and PsA to understand and experience the impact of inflammatory joint disease on the integrity of their (juxta-articular) bone and increase adherence to medical treatment. In this study, we used high-resolution peripheral quantitative computed tomography (HR-pQCT) to develop 3D prototypes of patients' finger joints.HR-pQCT (XtremeCT, Scanco) measurements were performed in healthy individuals and patients with inflammatory joint disease, followed by a 3D print using the objet30 printer. Healthy participants (n = 10), and patients (n = 15 with RA and 15 with PsA) underwent a detailed, standardized interview with demonstration of printed joints.Utilizing HR-pQCT images of metacarpophalangeal (MCP) heads, high quality and exact 3D prints as prototypes were created. Erosions in different sizes and the trabecular network printed in detail were visualized, demonstrating structural reduction in arthritic vs. healthy bone. After demonstration of 3D prints (healthy vs. erosive joint, visual and haptic) 26/39 (66%) participants (including healthy volunteers) were deeply affected, often quoting "shock". Of the patients with RA and PsA, 13/15 (86%) and 11/15 (73%), respectively, stated that they would rethink their attitude to medication adherence. More importantly, 21/24 patients with RA or PsA (87.5%) expressed that they would have wished to see such 3D prints during their first disease-specific conversations.Using arthro-haptic 3D printed prototypes of joints may help to better understand the impact of inflammatory arthritides on bone integrity and long-term damage.
EVALuna2:13404

DGCR8 deficiency impairs macrophage growth and unleashes the interferon response to mycobacteria - Killy, Barbara; Bodendorfer, Barbara; Mages, Jörg; Ritter, Kristina; Schreiber, Jonathan; Hölscher, Christoph; Pracht, Katharina; Ekici, Arif Bülent; Jäck, Hans-Martin; Lang, Roland (Life Science Alliance, 2021)
The mycobacterial cell wall glycolipid trehalose-6,6-dimycolate (TDM) activates macrophages through the C-type lectin receptor MINCLE. Regulation of innate immune cells relies on miRNAs, which may be exploited by mycobacteria to survive and replicate in macrophages. Here, we have used macrophages deficient in the microprocessor component DGCR8 to investigate the impact of miRNA on the response to TDM. Deletion of DGCR8 in bone marrow progenitors reduced macrophage yield, but did not block macrophage differentiation. DGCR8-deficient macrophages showed reduced constitutive and TDM-inducible miRNA expression. RNAseq analysis revealed that they accumulated primary miRNA transcripts and displayed a modest type I IFN signature at baseline. Stimulation with TDM in the absence of DGCR8 induced overshooting expression of IFNβ and IFN-induced genes, which was blocked by antibodies to type I IFN. In contrast, signaling and transcriptional responses to recombinant IFNβ were unaltered. Infection with live Mycobacterium bovis Bacille Calmette-Guerin replicated the enhanced IFN response. Together, our results reveal an essential role for DGCR8 in curbing IFNβ expression macrophage reprogramming by mycobacteria.
CRIS-Team Scopus Importer:2021-04-16

DGRh-S2e-Leitlinie: Diagnostik und Therapie des adulten Still-Syndroms (AOSD) - Vordenbaeumen, Stefan; Feist, Eugen; Rech, Jürgen; Fleck, Martin; Blank, Norbert; Haas, Johannes-Peter; Koetter, Ina; Krusche, Martin; Chehab, Gamal; Hoyer, Bimba; Kiltz, Uta; Fell, Dorothea; et al. (Zeitschrift für Rheumatologie, 2022)
CRIS-Team Scopus Importer:2022-11-25

Diabetes is an independent predictor for severe osteoarthritis: results from a longitudinal cohort study - Schett, Georg; Kleyer, Arnd; Perricone, Carlo; Sahinbegovic, Enijad; Iagnocco, Annamaria; Zwerina, Jochen; Lorenzini, Rolando; Aschenbrenner, Franz; Berenbaum, Francis; D'Agostino, Maria-Antonietta; Willeit, Johann; Kiechl, Stefan (Diabetes Care, 2013)
To evaluate if type 2 diabetes is an independent risk predictor for severe osteoarthritis (OA).Population-based cohort study with an age- and sex-stratified random sample of 927 men and women aged 40-80 years and followed over 20 years (1990-2010).Rates of arthroplasty (95% CI) were 17.7 (9.4-30.2) per 1,000 person-years in patients with type 2 diabetes and 5.3 (4.1-6.6) per 1,000 person-years in those without (P < 0.001). Type 2 diabetes emerged as an independent risk predictor for arthroplasty: hazard ratios (95% CI), 3.8 (2.1-6.8) (P < 0.001) in an unadjusted analysis and 2.1 (1.1-3.8) (P = 0.023) after adjustment for age, BMI, and other risk factors for OA. The probability of arthroplasty increased with disease duration of type 2 diabetes and applied to men and women, as well as subgroups according to age and BMI. Our findings were corroborated in cross-sectional evaluation by more severe clinical symptoms of OA and structural joint changes in subjects with type 2 diabetes compared with those without type 2 diabetes.Type 2 diabetes predicts the development of severe OA independent of age and BMI. Our findings strengthen the concept of a strong metabolic component in the pathogenesis of OA.
EVALuna2:12929

DIABETES MELLITUS AS AN INDEPENDENT PREDICTOR FOR SEVERE OSTEOARTHRITIS - Schett, Georg; Kleyer, Arnd; D'Agostino, M. -A.; Perricone, C.; Iagnocco, A.; Sahinbegovic, E.; Berenbaum, F.; Zwerina, J.; Willeit, J.; Kiechl, S. (2013)
EVALuna2:34463

Diagnosis and treatment of adult-onset Still's disease: a concise summary of the German society of rheumatology S2 guideline - Vordenbaeumen, Stefan; Feist, Eugen; Rech, Jürgen; Fleck, Martin; Blank, Norbert; Haas, Johannes-Peter; Koetter, Ina; Krusche, Martin; Chehab, Gamal; Hoyer, Bimba; Kiltz, Uta; Fell, Dorothea; et al. (Zeitschrift für Rheumatologie, 2022)
CRIS-Team WoS Importer:2023-01-13

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

Dicer ablation in osteoblasts by Runx2 driven cre-loxP recombination affects bone integrity, but not glucocorticoid-induced suppression of bone formation - Liu, Peng; Baumgart, Mario; Groth, Marco; Wittmann, Jürgen; Jäck, Hans-Martin; Platzer, Matthias; Tuckermann, Jan P.; Baschant, Ulrike (Scientific Reports, 2016)
Glucocorticoid-induced osteoporosis (GIO) is one of the major side effects of long-term glucocorticoid (GC) therapy mediated mainly via the suppression of bone formation and osteoblast differentiation independently of GC receptor (GR) dimerization. Since microRNAs play a critical role in osteoblast differentiation processes, we investigated the role of Dicer dependent microRNAs in the GC-induced suppression of osteoblast differentiation. MicroRNA sequencing of dexamethasone-treated wild-type and GR dimer-deficient mesenchymal stromal cells revealed GC-controlled miRNA expression in a GR dimer-dependent and GR dimer-independent manner. To determine the functional relevance of mature miRNAs in GC-induced osteoblast suppression, mice with an osteoblast-specific deletion of Dicer (Dicer(Runx2Cre)) were exposed to glucocorticoids. In vitro generated Dicer-deficient osteoblasts were treated with dexamethasone and analyzed for proliferation, differentiation and mineralization capacity. In vivo, abrogation of Dicer-dependent miRNA biogenesis in osteoblasts led to growth retardation and impaired bone formation. However, subjecting these mice to GIO showed that bone formation was similar reduced in Dicer(Runx2Cre) mice and littermate control mice upon GC treatment. In line, differentiation of Dicer deficient osteoblasts was suppressed to the same extent as wild type cells by GC treatment. Therefore, Dicer-dependent small RNA biogenesis in osteoblasts plays only a minor role in the pathogenesis of GC-induced inhibition of bone formation.
EVALuna2:13640

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

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

DIET INDUCED METABOLIC CHANGES IN AN OSTEOARTHRITIS MOUSE MODEL - Huelser, M. -L.; Schreiyaeck, C.; Luo, Y.; Bozec, Aline; Schett, Georg; Mueller-Ladner, U.; Neumann, E. (2018)
EVALuna2:34984

Differences in BAFFR signaling and responses between naive and switched memory B cells in humans - Sevdali, Eirini; Block, Violeta; Li, Huiying; Lataretu, Marie; Fischer, Beate; Schneider, Pascal; Grimbacher, Bodo; Jäck, Hans-Martin; Hoelzer, Martin; Eibel, Hermann (EUROPEAN JOURNAL OF IMMUNOLOGY, 2021)
CRIS-Team WoS Importer:2022-03-11

Differences in bone structure between rheumatoid arthritis and psoriatic arthritis patients relative to autoantibody positivity - Kocijan, Roland; Finzel, Stephanie; Englbrecht, Matthias; Engelke, Klaus; Rech, Juergen; Schett, Georg (Annals of the Rheumatic Diseases, 2014)
To investigate whether trabecular and cortical bone structure differ between patients with rheumatoid arthritis (RA) and psoriatic arthritis (PsA). So far, no study has performed a detailed comparative analysis of bone structure in patients with RA and PsA.110 patients (60 RA, 50 PsA) received high-resolution peripheral quantitative CT of the distal radius. Demographic and disease-specific parameters including anti-rheumatic treatment, bone erosion status and previous fractures were recorded.RA and PsA patients were comparable in age, gender, body mass index, disease duration, disease activity, functional status, antirheumatic treatment and bone erosion status. No significant differences were found for volumetric bone mineral density (BMD), including total BMD (300±77 vs 316±62 mgHA/cm(3)), trabecular BMD (152±46 vs 165±40 mgHA/cm(3)) and cortical BMD (787±113 vs 818±76 mgHA/cm(3)) when comparing RA patients to PsA patients, respectively. However, in contrast to seronegative RA, seropositive RA showed significantly reduced trabecular BMD (p=0.007), bone volume per tissue volume (p=0.007) and trabecular number (p=0.044), as well as a strong trend towards higher trabecular inhomogeneity compared to PsA patients. In the regression analysis, higher age, female gender and presence of autoantibodies were independently associated with trabecular bone loss.Seropositive RA exhibits more profound changes in trabecular bone architecture than seronegative RA or PsA. The data support the concept that seropositive RA is a disease entity that is distinct from seronegative RA and PsA.
EVALuna2:10051

Differences in the patient's and the physician's perspective of disease in psoriatic arthritis - Dandorfer, Stefan; Rech, Jürgen; Manger, Bernhard; Schett, Georg; Englbrecht, Matthias (Seminars in Arthritis and Rheumatism, 2012)
Objective: To define the relative impact of disease components of psoriatic arthritis (PsA) on the global burden of disease and to compare physician's and patients' ratings of disease activity. Methods: PsA patients fulfilling the Classification Criteria for Psoriatic Arthritis (N = 55) were asked for an evaluation of the absolute and relative impact of general and specific rheumatic symptoms (ie, arthritis, enthesitis, spinal disease, dactylitis), general and specific psoriatic symptoms (skin disease, nail disease), and other common symptoms (eg, fatigue). Results were related to the respective physician's evaluations of disease-related symptoms based on visual analog scale (VAS) ratings and comparative measures of disease activity (ie, swollen and tender joint counts, MASES, PASI, NAPSI). Results: One-half of the global burden of disease in PsA patients was attributed to rheumatic symptoms with peripheral arthritis as the leading component, whereas the other one-half was equally distributed to psoriatic and additional common symptoms such as fatigue. In general, corresponding patient and physician ratings of global, rheumatic, and psoriatic disease activity showed good correlations when using VAS but at the same time revealed significantly lower ratings of the corresponding physician on VAS and transformed comparative measures (all P ≤ 0.02). Conclusions: Although we found good correlations of various disease activity measures, physicians usually evaluated the disease activity of PsA lower than patients. These results highlight the necessity of incorporating patient reported outcome measures into the assessment of disease activity in PsA, which can easily be visualized with the help of a spiderweb graph. © 2012 Elsevier Inc.
CRIS-Team Scopus Importer:2021-02-03
Keywords: Disease activity; Patient reported outcomes; Psoriatic arthritis

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

Differential roles of MAPK kinases MKK3 and MKK6 in osteoclastogenesis and bone loss - Boyle, David L.; Hammaker, Deepa; Edgar, Meghan; Zaiss, Mario M.; Teufel, Stefan; David, Jean Pierre; Schett, Georg; Firestein, Gary S. (PLoS ONE, 2014)
Bone mass is maintained by osteoclasts that resorb bone and osteoblasts that promote matrix deposition and mineralization. Bone homeostasis is altered in chronic inflammation as well as in post-menopausal loss of estrogen, which favors osteoclast activity that leads to osteoporosis. The MAPK p38? is a key regulator of bone loss and p38 inhibitors preserve bone mass by inhibiting osteoclastogenesis. p38 function is regulated by two upstream MAPK kinases, namely MKK3 and MKK6. The goal of this study was to assess the effect of MKK3- or MKK6-deficiency on osteoclastogenesis in vitro and on bone loss in ovariectomy-induced osteoporosis in mice. We demonstrated that MKK3 but not MKK6, regulates osteoclast differentiation from bone marrow cells in vitro. Expression of NFATc1, a master transcription factor in osteoclastogenesis, is decreased in cells lacking MKK3 but not MKK6. Expression of osteoclast-specific genes Cathepsin K, osteoclast-associated receptor and MMP9, was inhibited in MKK3-/- cells. The effect of MKK-deficiency on ovariectomy-induced bone loss was then evaluated in female WT, MKK3-/- and MKK6-/- mice by micro-CT analysis. Bone loss was partially inhibited in MKK3-/- as well as MKK6-/- mice, despite normal osteoclastogenesis in MKK6-/- cells. This correlated with the lower osteoclast numbers in the MKK-deficient ovariectomized mice. These studies suggest that MKK3 and MKK6 differentially regulate bone loss due to estrogen withdrawal. MKK3 directly mediates osteoclastogenesis while MKK6 likely contributes to pro-inflammatory cytokine production that promotes osteoclast formation.
EVALuna2:12931

DIFFERENTIAL SCAVENGING OF APOPTOTIC CELLS AND BACTERIA - Kronke, G. (2017)
EVALuna2:35022

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

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

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

DIFFUSING CAPACITY AND CLINICAL CHARACTERISTICS OF PATIENTS WITH SYSTEMIC SCLEROSIS - DATA FROM THE GERMAN NETWORK FOR SYSTEMIC SCLEROSIS - Moinzadeh, P.; Blank, N.; Siegert, E.; Henes, J.; Worm, M.; Sunderkoetter, C.; Schmalzing, M.; Kreuter, A.; Gunther, C.; Susok, L.; Zeidler, G.; Koetter, I.; et al. (2017)
EVALuna2:35043

Digital Approaches for a Reliable Early Diagnosis of Psoriatic Arthritis - Fagni, Filippo; Knitza, Johannes; Krusche, Martin; Kleyer, Arnd; Tascilar, Koray; Simon, David (Frontiers in Medicine, 2021)
Psoriatic arthritis (PsA) is a chronic inflammatory disease that develops in up to 30% of patients with psoriasis. In the vast majority of cases, cutaneous symptoms precede musculoskeletal complaints. Progression from psoriasis to PsA is characterized by subclinical synovio-entheseal inflammation and often non-specific musculoskeletal symptoms that are frequently unreported or overlooked. With the development of increasingly effective therapies and a broad drug armamentarium, prevention of arthritis development through careful clinical monitoring has become priority. Identifying high-risk psoriasis patients before PsA onset would ensure early diagnosis, increased treatment efficacy, and ultimately better outcomes; ideally, PsA development could even be averted. However, the current model of care for PsA offers only limited possibilities of early intervention. This is attributable to the large pool of patients to be monitored and the limited resources of the health care system in comparison. The use of digital technologies for health (eHealth) could help close this gap in care by enabling faster, more targeted and more streamlined access to rheumatological care for patients with psoriasis. eHealth solutions particularly include telemedicine, mobile technologies, and symptom checkers. Telemedicine enables rheumatological visits and consultations at a distance while mobile technologies can improve monitoring by allowing patients to self-report symptoms and disease-related parameters continuously. Symptom checkers have the potential to direct patients to medical attention at an earlier point of their disease and therefore minimizing diagnostic delay. Overall, these interventions could lead to earlier diagnoses of arthritis, improved monitoring, and better disease control while simultaneously increasing the capacity of referral centers.
CRIS-Team Scopus Importer:2021-09-10
Keywords: digital rheumatology; eHealth; mHealth; psoriasis; psoriatic arthritis; telemedicine

Digital Approaches for Myositis - Knitza, Johannes; Kuhn, Sebastian; Gupta, Latika (Current Rheumatology Reports, 2023)
Purpose of Review: This article serves as a comprehensive review, focusing on digital approaches utilized in the diagnosis, monitoring, and treatment of patients with idiopathic inflammatory myopathies (IIM). The authors critically assess the literature published in the last three years, evaluating the advancements and progress achieved in this specific domain. Recent Findings: Remarkable strides have been made in the realm of digital diagnostic support, particularly in image analysis and clinical prediction models, showing promise in aiding the diagnosis of IIM. The field of remote patient monitoring has also witnessed significant advancements, revolutionizing the care process by offering more convenient, data-driven, and continuous monitoring for IIM patients. Various digital tools, such as wearables, video- and voice consultations, and electronic patient-reported outcomes, have been extensively explored and implemented to enhance patient care. Survey studies consistently reveal a high acceptance of telehealth services among patients. Additionally, internet-based studies have facilitated the efficient and rapid recruitment of IIM patients for research purposes. Moreover, the integration of sensors and exoskeletons has shown great potential in significantly improving the functionality and quality of life for individuals with muscle weakness caused by IIM. Summary: The integration of digital health solutions in the care of IIM patients is steadily gaining attention and exploration. Although the existing evidence is limited, it does indicate that patients can be adequately and safely supported through digital means throughout their entire healthcare journey. The growing interest in digital health technologies holds the promise of improving the overall management and outcomes for individuals with idiopathic inflammatory myopathies.
CRIS-Team Scopus Importer:2023-11-24
Keywords: Digital; eHealth; Myositis; Telehealth; Wearables

Digital crowdsourcing: Unleashing its power in rheumatology - Krusche, Martin; Burmester, Gerd R.; Knitza, Johannes (Annals of the Rheumatic Diseases, 2020)
The COVID-19 pandemic forces the whole rheumatic and musculoskeletal diseases community to reassemble established treatment and research standards. Digital crowdsourcing is a key tool in this pandemic to create and distil desperately needed clinical evidence and exchange of knowledge for patients and physicians alike. This viewpoint explains the concept of digital crowdsourcing and discusses examples and opportunities in rheumatology. First experiences of digital crowdsourcing in rheumatology show transparent, accessible, accelerated research results empowering patients and rheumatologists.
CRIS-Team Scopus Importer:2020-09-11
Keywords: health services research; outcome and process assessment; health care; outcome assessment; health care; quality indicators; health care

Digital diagnostic support in rheumatology Digitale Diagnoseunterstützung in der Rheumatologie - Knitza, Johannes; Krusche, M.; Leipe, J. (Zeitschrift für Rheumatologie, 2021)
Only the correct diagnosis enables an effective treatment of rheumatic diseases. Digitalization has already significantly accelerated and simplified our everyday life. An increasing number of digital options are available to patients and medical personnel in rheumatology to accelerate and improve the diagnosis. This work gives an overview of current developments and tools for patients and rheumatologists, regarding digital diagnostic support in rheumatology.
CRIS-Team Scopus Importer:2021-10-15
Keywords: Crowd sourcing; Digitalization; Ehealth; Health services research; Tools

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

Digitalization in rheumatological practice - Welcker, M.; Muehlensiepen, F.; Knitza, Johannes; Popp, F.; Aries, P. (Zeitschrift für Rheumatologie, 2021)
Digitalization in medicine is of major interest since the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic. This article tries to present the induced changes and technical solutions with respect to the different parts in the patient journey. Symptom checkers, new health applications, digital appointment management etc. are described. Apart from the technical and digital possibilities, the changes in the quality of communication additionally have to be mentioned. There is an urgent need for further technical standardization including the interfaces. In many cases further studies must confirm the equivalence of digital applications in comparison to analogue techniques.
CRIS-Team WoS Importer:2021-10-15

Digitalization: Just a buzzword or future progress? Digitalisierung: Nur Buzzword oder neuer Fortschritt? - Hueber, Axel; Richter, Jutta (Zeitschrift für Rheumatologie, 2021)
CRIS-Team Scopus Importer:2021-12-17

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

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

Digital pitting scars are associated with a severe disease course and death in systemic sclerosis: a study from the EUSTAR cohort - Hughes, Michael; Heal, Calvin; Henes, Joerg; Balbir-Gurman, Alexandra; Distler, Jörg; Airo, Paolo; Mueller-Ladner, Ulf; Hunzelmann, Nicolas; Kerzberg, Eduardo; Rudnicka, Lidia; Truchetet, Marie-Elise; Stebbings, Simon; et al. (Rheumatology, 2021)
Objective Digital pitting scars (DPS) are frequent, but little studied in SSc to date. Methods An analysis of SSc patients enrolled in the EUSTAR database. Primary objectives were to (i) examine DPS prevalence; (ii) examine whether DPS are associated with digital ulcers (DUs) and active digital ischaemia (DUs or gangrene); and (iii) describe other associations with DPS including internal organ complications. Secondary objectives were whether DPS are associated with (i) functional impairment; (ii) structural microvascular disease; and (iii) mortality. Descriptive statistics and parametric/non-parametric tests were used. Binary logistic regression was used to examine the association between DPS and DUs, active digital ischaemia and mortality. Results A total of 9671 patients were included with reported DPS at any time point (n = 4924) or 'never' DPS (n = 4747). The majority (86.9%) were female and mean age was 55.7 years. DPS were associated with longer disease and Raynaud's duration (both P <= 0.001). DPS were associated with interstitial lung disease, pulmonary hypertension, conduction blocks, telangiectases, calcinosis (all P <= 0.001) and joint synovitis (P = 0.021). Patients were more likely to have more severe capillaroscopic abnormality and greater hand functional impairment. Multivariable logistic regression analyses showed that DPS were associated (odds ratio) with DUs: 22.03 (19.51-24.87), active digital ischaemia: 6.30 (5.34-7.42) and death: 1.86 (1.48-2.36). Conclusion DPS are associated with a severe disease course including death. The impact of DPS on hand function and ischaemia is significant. The presence of DPS should alert the clinician to a poor prognosis and need to optimize the therapeutic strategy.
CRIS-Team WoS Importer:2022-03-04

Digital rheumatology - Knitza, Johannes; Krusche, Martin; Sewerin, Philipp (Jenny Stanford Publishing, 2023)
CRIS-Team Scopus Importer:2023-07-07

DIGITAL RHEUMATOLOGY IN THE ERA OF COVID-19: RESULTS OF A NATIONAL PATIENT AND PHYSICIAN SURVEY - Kernder, A.; Morf, H.; Klemm, P.; Vossen, D.; Meyer, M.; Haase, Isabell; Mucke, J.; Kleyer, Arnd; Sewerin, Philipp; Bendzuck, G.; Eis, S.; Knitza, J.; et al. (ANNALS OF THE RHEUMATIC DISEASES, 2021)
CRIS-Team WoS Importer:2021-09-24

Digital rheumatology in the era of COVID-19: results of a national patient and physician survey - Kernder, Anna; Morf, Harriet; Klemm, Philipp; Vossen, Diana; Haase, Isabell; Mucke, Johanna; Meyer, Marco; Kleyer, Arnd; Sewerin, Philipp; Bendzuck, Gerlinde; Eis, Sabine; Knitza, Johannes; et al. (RMD Open, 2021)
Objective To analyse the impact of the COVID-19 pandemic on rheumatic patients' and rheumatologists' usage, preferences and perception of digital health applications (DHAs). Methods A web-based national survey was developed by the Working Group Young Rheumatology of the German Society for Rheumatology and the German League against Rheumatism. The prospective survey was distributed via social media (Twitter, Instagram and Facebook), QR code and email. Descriptive statistics were calculated, and regression analyses were performed to show correlations. Results We analysed the responses of 299 patients and 129 rheumatologists. Most patients (74%) and rheumatologists (76%) believed that DHAs are useful in the management of rheumatic and musculoskeletal diseases (RMDs) and felt confident in their own usage thereof (90%; 86%). 38% of patients and 71% of rheumatologists reported that their attitude had changed positively towards DHAs and that their usage had increased due to COVID-19 (29%; 48%). The majority in both groups agreed on implementing virtual visits for follow-up appointments in stable disease conditions. The most reported advantages of DHAs were usage independent of time and place (76.6%; 77.5%). The main barriers were a lack of information on suitable, available DHAs (58.5%; 41.9%), poor usability (42.1% of patients) and a lack of evidence supporting the effectiveness of DHAs (23.2% of rheumatologists). Only a minority (<10% in both groups) believed that digitalisation has a negative impact on the patient-doctor relationship. Conclusion The COVID-19 pandemic instigated an increase in patients' and rheumatologists' acceptance and usage of DHAs, possibly introducing a permanent paradigm shift in the management of RMDs.
CRIS-Team WoS Importer:2021-03-12

Digital ulcers in systemic sclerosis : A retrospective heath service study analysing treatment with bosentan and other vasoactive therapies - Riemekasten, G.; Beissert, S.; Distler, Jörg; Kreuter, A.; Mueller-Ladner, U. (Zeitschrift für Rheumatologie, 2016)
Digital ulcers (DU) affect up to 60 % of patients with systemic sclerosis (SSc) and have a considerable impact on quality of life and morbidity. It is unclear to what extent authorised medicines are used, and if therapy guidelines are implemented in everyday practice.This retrospective health care study examined current standards of treatment for therapy and prevention of SSc-associated DU in an online survey with 83 physicians. Additionally, data from 161 case studies of SSc patients with DU were analysed, and the effect of DU treatment on the course of the disease determined.For treatment and prevention of active DU, physicians predominantly indicated topical therapies, calcium channel blockers, iloprost and endothelin receptor antagonists. According to the case studies, 90 % of episodes with acute DU were treated with bosentan and iloprost in mono- or combination therapy. Preventive treatment was only administered during 50 % of episodes without DU, even after three or more phases with active DU. For the prevention of new DU, bosentan was used in mono- or combination therapy in 57 % of episodes without DU. Bosentan therapy during prevention shortened the following acute phase by 32 %. Additionally, continuous treatment with bosentan in acute and prevention phases reduced the duration of the following acute phase and increased the time to onset of new DU by 16 %. Moreover, bosentan stabilised the number of new DU.In summary, these data confirm the efficacy of bosentan in preventing new DU when used in DU-free episodes and possibly also in phases of acute DU. Therapy recommendations for the treatment of DU are currently not fully implemented. In the future, even more attention should be paid to DU therapy.
EVALuna2:13252

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

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

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

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

Direct uptake of Antagomirs and efficient knockdown of miRNA in primary B and T lymphocytes - Haftmann, Claudia; Riedel, Rene; Porstner, Martina; Wittmann, Jürgen; Chang, Hyun-Dong; Radbruch, Andreas; Mashreghi, Mir-Farzin (Journal of Immunological Methods, 2015)
Depending on their physiological expression level, microRNAs (miRNA) address different target genes, thus have different biological functions. To identify these, the physiological expression has to be blocked. Here, we describe the use of inhibitory cholesterol-modified oligonucleotides (Antagomirs) to inhibit miRNAs selectively in primary human and murine T and B lymphocytes. Due to their lipophilic cholesterol tag Antagomirs enter primary lymphocytes efficiently and quantitatively. We show here that at concentrations of 0.125 to 1?M, Antagomirs selectively inhibit expression of their target miRNA up to 99.5% without affecting cell viability.
EVALuna2:13633

Disability, fatigue, pain and their associates in early diffuse cutaneous systemic sclerosis: the European Scleroderma Observational Study - Peytrignet, Sebastien; Denton, Christopher P.; Lunt, Mark; Hesselstrand, Roger; Mouthon, Luc; Silman, Alan; Pan, Xiaoyan; Brown, Edith; Czirjak, Laszlo; Distler, Jörg; Distler, Oliver; Fligelstone, Kim; et al. (Rheumatology, 2017)
Our aim was to describe the burden of early dcSSc in terms of disability, fatigue and pain in the European Scleroderma Observational Study cohort, and to explore associated clinical features.Patients completed questionnaires at study entry, 12 and 24 months, including the HAQ disability index (HAQ-DI), the Cochin Hand Function Scale (CHFS), the Functional Assessment of Chronic Illness Therapy-fatigue and the Short Form 36 (SF36). Associates examined included the modified Rodnan skin score (mRSS), current digital ulcers and internal organ involvement. Correlations between 12-month changes were also examined.The 326 patients recruited (median disease duration 11.9 months) displayed high levels of disability [mean ( s . d .) HAQ-DI 1.1 (0.83)], with 'grip' and 'activity' being most affected. Of the 18 activities assessed in the CHFS, those involving fine finger movements were most affected. High HAQ-DI and CHFS scores were both associated with high mRSS (? = 0.34, P < 0.0001 and ? = 0.35, P < 0.0001, respectively). HAQ-DI was higher in patients with digital ulcers ( P = 0.004), pulmonary fibrosis ( P = 0.005), cardiac ( P = 0.005) and muscle involvement ( P = 0.002). As anticipated, HAQ-DI, CHFS, the Functional Assessment of Chronic Illness Therapy and SF36 scores were all highly correlated, in particular the HAQ-DI with the CHFS (? = 0.84, P < 0.0001). Worsening HAQ-DI over 12 months was strongly associated with increasing mRSS (? = 0.40, P < 0.0001), decreasing hand function (? = 0.57, P < 0.0001) and increasing fatigue (? = -0.53, P < 0.0001).The European Scleroderma Observational Study highlights the burden of disability in early dcSSc, with high levels of disability and fatigue, associating with the degree of skin thickening (mRSS). Impaired hand function is a major contributor to overall disability.
EVALuna2:13526

Discrepant Phenotyping of Monocytes Based on CX3CR1 and CCR2 Using Fluorescent Reporters and Antibodies - Sommer, Katrin; Garibagaoglu, Hilal; Paap, Eva-Maria; Wiendl, Maximilian; Müller, Tanja; Atreya, Imke; Krönke, Gerhard; Neurath, Markus; Zundler, Sebastian (Cells, 2024)
Monocytes, as well as downstream macrophages and dendritic cells, are essential players in the immune system, fulfilling key roles in homeostasis as well as in inflammatory conditions. Conventionally, driven by studies on reporter models, mouse monocytes are categorized into a classical and a non-classical subset based on their inversely correlated surface expression of Ly6C/CCR2 and CX3CR1. Here, we aimed to challenge this concept by antibody staining and reporter mouse models. Therefore, we took advantage of Cx3cr1GFP and Ccr2RFP reporter mice, in which the respective gene was replaced by a fluorescent reporter protein gene. We analyzed the expression of CX3CR1 and CCR2 by flow cytometry using several validated fluorochrome-coupled antibodies and compared them with the reporter gene signal in these reporter mouse strains. Although we were able to validate the specificity of the fluorochrome-coupled flow cytometry antibodies, mouse Ly6Chigh classical and Ly6Clow non-classical monocytes showed no differences in CX3CR1 expression levels in the peripheral blood and spleen when stained with these antibodies. On the contrary, in Cx3cr1GFP reporter mice, we were able to reproduce the inverse correlation of the CX3CR1 reporter gene signal and Ly6C surface expression. Furthermore, differential CCR2 surface expression correlating with the expression of Ly6C was observed by antibody staining, but not in Ccr2RFP reporter mice. In conclusion, our data suggest that phenotyping strategies for mouse monocyte subsets should be carefully selected. In accordance with the literature, the suitability of CX3CR1 antibody staining is limited, whereas for CCR2, caution should be applied when using reporter mice.
CRIS-Team Scopus Importer:2024-05-31
Keywords: C-X3-C motif chemokine receptor 1 (CX3CR1); chemokine (C-C motif) receptor 2 (CCR2); classical monocytes; lymphocyte antigen 6C (Ly6C); non-classical monocytes

DISEASE INTERCEPTION IN PSORIASIS PATIENTS WITH SUBCLINICAL JOINT INFLAMMATION BY INTERLEUKIN 17 INHIBITION WITH SECUKINUMAB - DATA FROM A PROSPECTIVE OPEN LABEL STUDY - Kamoylafka, E.; Oliveira, I. D.; Linz, C.; Lerchen, V.; Englbrecht, Matthias; Simon, David; Sticherling, Michael; Rech, Jürgen; Kleyer, Arnd; Schett, Georg; Hueber, Axel (2018)
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Disease interception with interleukin-17 inhibition in high-risk psoriasis patients with subclinical joint inflammation - Data from the prospective IVEPSA study - Kampylafka, Eleni; Simon, David; D'Oliveira, Isabelle; Linz, Christina; Lerchen, Veronika; Englbrecht, Matthias; Rech, Jürgen; Kleyer, Arnd; Sticherling, Michael; Schett, Georg; Hueber, Axel (Arthritis Research & Therapy, 2019)
Background: A specific subset of psoriasis patients is characterized by subclinical inflammatory changes. These patients frequently present with arthralgia and have a higher risk to develop psoriatic arthritis (PsA). We hypothesized that IL-17A inhibition in this subset of patients can intercept the link between skin and joint disease and resolves pain and inflammatory changes. Methods: Psoriasis, but no PsA, patients were included in the open prospective exploratory Interception in very early PsA (IVEPSA) study. Patients had to have nail or scalp involvement or a high psoriasis area severity index (PASI) (> 6) as well as inflammatory or erosive changes in MRI or CT. Patients received treatment with the anti-interleukin (IL)-17A antibody secukinumab over 24 weeks. Clinical assessments of skin and joint disease were done at baseline and after 12 and 24 weeks, MRI and CT at baseline and after 24 weeks. Results: Twenty patients were included, 85% of them reporting arthralgia and 40% had tender joints at the examination. Eighty-three percent had at least one inflammatory lesion in the MRI, most of them synovitis/enthesitis. Skin disease (PASI: p < 0.002; BSA: p < 0.003) and arthralgia (VAS pain: p < 0.003) significantly improved after 24 weeks. Total PsAMRIS (p = 0.005) and synovitis subscore (p = 0.008) also significantly improved. Erosions and enthesiophytes did not progress, while bone mass in the distal radius significantly (p = 0.020) increased after 24 weeks. Conclusions: These data suggest that very early disease interception in PsA is possible leading to a comprehensive decline in skin symptoms, pain, and subclinical inflammation. IVEPSA therefore provides rationale for future early interventions with the concept to prevent the onset of PsA in high-risk individuals. Trial registration: Trial registry name PSARTROS; trial registry number: NCT02483234; June 26, 2015.
CRIS-Team Scopus Importer:2019-08-06
Keywords: Interleukin-17; Magnetic resonance imaging; Psoriasis; Psoriatic arthritis

DISEASE PROGRESSION IN 282 PATIENTS WITH UNDIFFERENTIATED SSC - DATA FROM THE GERMAN NETWORK FOR SYSTEMIC SCLERODERMA - Moinzadeh, P.; Blank, N.; Siegert, E.; Henes, J.; Susok, L.; Distler, Jörg; Juche, A.; Worm, M.; Gil, H. C.; Schmeiser, T.; Zeidler, G.; Gaebelein-Wissing, N.; et al. (2016)
EVALuna2:35077

Disease progression in systemic sclerosis-overlap syndrome is significantly different from limited and diffuse cutaneous systemic sclerosis - Moinzadeh, Pia; Aberer, Elisabeth; Ahmadi-Simab, Keihan; Blank, Norbert; Distler, Jörg; Fierlbeck, Gerhard; Genth, Ekkehard; Günther, Claudia; Hein, Ruediger; Henes, Joerg; Herich, Lena; Herrgott, Ilka; et al. (Annals of the Rheumatic Diseases, 2014)
Systemic sclerosis (SSc)-overlap syndromes are a very heterogeneous and remarkable subgroup of SSc-patients, who present at least two connective tissue diseases (CTD) at the same time, usually with a specific autoantibody status.To determine whether patients, classified as overlap syndromes, show a disease course different from patients with limited SSc (lcSSc) or diffuse cutaneous SSc (dcSSc).The data of 3240 prospectively included patients, registered in the database of the German Network for Systemic Scleroderma and followed between 2003 and 2013, were analysed.Among 3240 registered patients, 10% were diagnosed as SSc-overlap syndrome. Of these, 82.5% were female. SSc-overlap patients had a mean age of 48±1.2 years and carried significantly more often 'other antibodies' (68.0%; p<0.0001), including anti-U1RNP, -PmScl, -Ro, -La, as well as anti-Jo-1 and -Ku antibodies.These patients developed musculoskeletal involvement earlier and more frequently (62.5%) than patients diagnosed as lcSSc (32.2%) or dcSSc (43.3%) (p<0.0001). The onset of lung fibrosis and heart involvement in SSc-overlap patients was significantly earlier than in patients with lcSSc and occurred later than in patients with dcSSc. Oesophagus, kidney and PH progression was similar to lcSSc patients, whereas dcSSc patients had a significantly earlier onset.These data support the concept that SSc-overlap syndromes should be regarded as a separate SSc subset, distinct from lcSSc and dcSSc, due to a different progression of the disease, different proportional distribution of specific autoantibodies, and of different organ involvement.
EVALuna2:13079

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

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

Distinct Metabolism of Bone Marrow Adipocytes and their Role in Bone Metastasis - Li, Yixuan; Cao, Shan; Gaculenko, Anastasia; Zhan, Yifan; Bozec, Aline; Chen, Xiaoxiang (Frontiers in Endocrinology, 2022)
Bone marrow adipocytes (BMAs) represent 10% of the total fat mass of the human body and serve as an energy reservoir for the skeletal niche. They function as an endocrine organ by actively secreting fatty acids, cytokines, and adipokines. The volume of BMAs increases along with age, osteoporosis and/or obesity. With the rapid development of multi-omic analysis and the advance in in vivo imaging technology, further distinct characteristics and functions of BMAs have been revealed. There is accumulating evidence that BMAs are metabolically, biologically and functionally unique from white, brown, beige and pink adipocytes. Bone metastatic disease is an uncurable complication in cancer patients, where primary cancer cells spread from their original site into the bone marrow. Recent publications have highlighted those BMAs could also serve as a rich lipid source of fatty acids that can be utilized by the cancer cells during bone metastasis, particularly for breast, prostate, lung, ovarian and pancreatic cancer as well as melanoma. In this review, we summarize the novel progressions in BMAs metabolism, especially with multi-omic analysis and in vivo imaging technology. We also update the metabolic role of BMAs in bone metastasis, and their potential new avenues for diagnosis and therapies against metastatic cancers.
CRIS-Team Scopus Importer:2022-07-22
Keywords: bone marrow adipocytes; bone metastasis; lineage-tracing; metabolism; multi-omic analysis

Distinct spatio-temporal dynamics of tumor-associated neutrophils in small tumor lesions - Sody, Simon; Uddin, Mohib; Grüneboom, Anika; Goergens, Andre; Giebel, Bernd; Gunzer, Matthias; Brandau, Sven (Frontiers in Immunology, 2019)
Across a majority of cancer types tumor-associated neutrophils (TAN) are linked with poor prognosis. However, the underlying mechanisms, especially the intratumoral behavior of TAN, are largely unknown. Using intravital multiphoton imaging on a mouse model with neutrophil-specific fluorescence, we measured the migration of TAN in distinct compartments of solid tumor cell lesions in vivo. By longitudinally quantifying the infiltration and persistence of TAN into growing tumors in the same animals, we observed cells that either populated the peripheral stromal zone of the tumor (peritumoral TAN) or infiltrated into the tumor core (intratumoral TAN). Intratumoral TAN showed prolonged tumor-associated persistence and reduced motility compared to peritumoral TAN, whose velocity increased with tumor progression. Selective pharmacological blockade of CXCR2 receptors using AZD5069 profoundly inhibited recruitment of TAN into peritumoral regions, while intratumoral infiltration was only transiently attenuated and rebounded at later time points. Our findings unravel distinct spatial dynamics of TAN that are partially and differentially regulated via the CXCR2 signaling pathway.
CRIS-Team Scopus Importer:2019-07-23
Keywords: AZD5069; CXCR2; Intravital imaging; Multiphoton microscopy; Neutrophil granulocytes; Tumor immunology; Tumor microenvironment; Tumor-associated neutrophils

DNA methylation and transcription in HERV (K, W, E) and LINE sequences remain unchanged upon foreign DNA insertions - Weber, Stefanie; Jung, Susan; Dörfler, Walter (Epigenomics, 2016)
DNA methylation and transcriptional profiles were determined in the regulatory sequences of the human endogenous retroviral (HERV-K, -W, -E) and LINE-1.2 elements and were compared between non-transgenomic and plasmid-transgenomic cells.DNA methylation profiles in the HERV (K, W, E) and LINE sequences were determined by bisulfite genomic sequencing. The transcription of these genome segments was assessed by quantitative real-time PCR.In HERV-K, HERV-W and LINE-1.2 the levels of DNA methylation ranged between 75 and 98%, while in HERV-E they were around 60%. Nevertheless, the HERV and LINE-1.2 sequences were actively transcribed. No differences were found in comparisons of HERV and LINE-1.2 CpG methylation and transcription patterns between non-transgenomic and plasmid-transgenomic HCT116 cells.The insertion of a 5.6 kbp plasmid into the HCT116 genome had no effect on the HERV and LINE-1.2 methylation and transcription profiles, although other parts of the HCT116 genome had shown marked changes. These repetitive sequences are transcribed, probably because the large number of HERV and LINE-1.2 elements harbor copies with non- or hypo-methylated long terminal repeat sequences.
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Does an 18f-FDG-PET/CT in Patients with Giant Cell Arteritis in Clinical Remission Make Sense? - Schoenau, Verena; Roth, Jan-Peter; Englbrecht, Matthias; Rech, Jürgen; Schett, Georg (2018)
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Does anti-acid treatment influence disease progression in SSc-ILD ? data from the German SSc-network - Kreuter, Michael; Bonella, Francesco; Blank, Norbert; Siegert, Elise; Henes, Joerg; Worm, Margitta; Sunderkoetter, Cord; Schmalzing, Marc; Kreuter, Alexander; Günther, Claudia; Susok, Laura; Zeidler, Gabriele; et al. (EUROPEAN RESPIRATORY JOURNAL, 2019)
CRIS-Team WoS Importer:2020-02-04

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

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

Does subclinical inflammation contribute to impairment of function of knee joints in aged individuals? High prevalence of ultrasound inflammatory findings - D'Agostino, Maria Antonietta; Iagnocco, Annamaria; Aegerter, Philippe; Kleyer, Arnd; Zwerina, Jochen; Perricone, Carlo; Lorenzini, Rolando; Aschenbrenner, Franz; Willeit, Johann; Kiechl, Stefan; Schett, Georg (Rheumatology, 2015)
To investigate the prevalence of knee US findings of inflammation and structural damage in aged individuals (>=60 years) of a long-term population-based cohort and to correlate these findings with demographic, clinical and laboratory parameters.Cross-sectional clinical and US investigation of both knee joints during the 2010 follow-up of the prospective population-based Bruneck Study. Demographic variables, physical activity, comorbidities, medications, pain, and functional scales related to the knee joints were recorded. US-assessed parameters were synovial hypertrophy, power Doppler signal, joint effusion, cartilage abnormalities, osteophytes, enthesopathy and bursitis. Statistics included univariate and multivariate regression analysis.A total of 488 subjects (mean age 72.5 years; 53.5% females, 46.5% males) were examined by clinical assessment, and 433 of these underwent US examination of both knees. Both inflammatory and structural abnormalities were found in 296 (68.8%) subjects. Inflammatory abnormalities were significantly associated with age in years, male gender, diabetes and the presence of knee joint symptoms. In the multivariate analysis, age, male gender and knee swelling emerged as independent predictors of inflammation [odds ratio (OR) (95% CI) = 1.06 (1.03, 1.09), 2.55 (1.55, 4.21) and 5.92 (1.99, 17.58), respectively].The present study showed a high prevalence of US inflammatory abnormalities in the knee joints of a normal aged population. These data suggest a substantial contribution of inflammation in progressive impairment of joint function with age.
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Does Subjectively Perceived Loss Of Hand Function Sufficiently Represent Ultrasonography-Detected Synovitis And Tenosynovitis In Patients With Psoriasis And Psoriatic Arthritis? - Coppers, Birte; Bayat, Sara; Elie-Tino, Godonou; Valor-Mendez, Larissa; Fagni, Filippo; Corte, Giulia; Tascilar, Koray; Hueber, Axel; Schönau, Verena; Sticherling, Michael; Schett, Georg; Kleyer, Arnd; et al. (poster, European Alliance of Association for Rheumatology (EULAR) Congress, 2023)

Dose-response relationship between ambulatory load magnitude and load-induced changes in COMP in young healthy adults - Herger, S.; Vach, Werner; Liphardt, Anna-Maria; Egloff, C.; Nuesch, C.; Mundermann, Annegret (Osteoarthritis and Cartilage, 2019)
Objective: To determine the dose-response relationship between ambulatory load magnitude during a walking stress test and load-induced changes in serum concentration of cartilage oligomeric matrix protein (sCOMP) in healthy subjects. Design: sCOMP was assessed before and after a 30-min walking stress test performed on three test days by 24 healthy volunteers. In each walking stress test, one of three ambulatory loads was applied in a block randomized crossover design: normal body weight (BW) (100%BW = normal load); reduced BW (80%BW = reduced load); increased BW (120%BW = increased load). Knee kinematics and ground reaction force (GRF) were measured using an inertial sensor gait analysis system and a pressure plate embedded in the treadmill. Results: Load-induced increases in sCOMP rose with increasing ambulatory load magnitude. Mean sCOMP levels increased immediately after the walking stress test by 26.8 ± 12.8%, 28.0 ± 13.3% and 37.3 ± 18.3% for the reduced, normal or increased load condition, respectively. Lower extremity kinematics did not differ between conditions. Conclusions: The results of this study provide important evidence of a dose-response relationship between ambulatory load magnitude and load-induced changes in sCOMP. Our data suggests that in normal weight persons sCOMP levels are more sensitive to increased than to reduced load. The experimental framework presented here may form the basis for studying the relevance of the dose-response relationship between ambulatory load magnitude and load-induced changes in biomarkers involved in metabolism of healthy articular cartilage and after injury.
CRIS-Team Scopus Importer:2019-06-18
Keywords: Cartilage mechanosensitivity; COMP; Kinematics; Serum biomarker; Treadmill walking

Dose-response relationship of in vivo ambulatory load and mechanosensitive cartilage biomarkers-The role of age, tissue health and inflammation: A study protocol - Herger, Simon; Vach, Werner; Nüesch, Corina; Liphardt, Anna-Maria; Egloff, Christian; Mündermann, Annegret (PLoS ONE, 2022)
OBJECTIVE: To describe a study protocol for investigating the in vivo dose-response relationship between ambulatory load magnitude and mechanosensitive blood markers of articular cartilage, the influence of age, cartilage tissue health and presence of inflammation on this relationship, and its ability to predict changes in articular cartilage quality and morphology within 2 years. DESIGN: Prospective experimental multimodal (clinical, biomechanical, biological) data collection under walking stress and three different load conditions varied in a randomized crossover design. EXPERIMENTAL PROTOCOL: At baseline, equal numbers of healthy and anterior cruciate ligament injured participants aged 20-30 or 40-60 years will be assessed clinically and complete questionnaires regarding their knee health. Biomechanical parameters (joint kinetics, joint kinematics, and surface electromyography) will be recorded while performing different tasks including overground and treadmill walking, single leg balance and hopping tasks. Magnetic resonance images (MRI) of both of knees will be obtained. On separate stress test days, participants will perform a 30-minute walking stress with either reduced (80% body weight (BW)), normal (100%BW) or increased (120%BW) load. Serum blood samples will be taken immediately before, immediately after, 30, 120 and 210 minutes after the walking stress. Concentration of articular cartilage blood biomarkers will be assessed using enzyme linked immunosorbent assays. At 24-month follow-up, participants will be again assessed clinically, undergo an MRI, complete questionnaires, and have a blood sample taken. CONCLUSION: The study design provides a standardized set up that allows to better understand the influence of ambulatory load on articular cartilage biomarkers and thereby extend current knowledge on in vivo cartilage metabolism and mechanosensitivity. Further, this study will help to elucidate the prognostic value of the load-induced cartilage biomarker response for early articular cartilage degeneration. TRIAL REGISTRATION: The protocol was approved by the regional ethics committee and has been registered at clinicaltrials.gov (NCT04128566).
CRIS-Team Scopus Importer:2022-09-09

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

Double-edged sword: Alcohol's effect on rheumatoid arthritis and beyond - Hübner, Michel; Zaiss, Mario; Azizov, Vugar (Joint Bone Spine, 2024)
CRIS-Team Scopus Importer:2023-09-15
Keywords: Alcohol acetate; Collagen-induced arthritis; Immunology; Migration; Rheumatoid arthritis; T cell

Downregulation of miR-193b in systemic sclerosis regulates the proliferative vasculopathy by urokinase-type plasminogen activator expression - Iwamoto, Naoki; Vettori, Serena; Maurer, Britta; Brock, Matthias; Pachera, Elena; Juengel, Astrid; Calcagni, Maurizio; Gay, Renate E.; Whitfield, Michael L.; Distler, Jörg; Gay, Steffen; Distler, Oliver (Annals of the Rheumatic Diseases, 2016)
To investigate the role of microRNA-193b-3p (miR-193b) in the vascular pathophysiology of systemic sclerosis (SSc).Expression of miR-193b in skin biopsies and fibroblasts from patients with SSc and normal healthy (NH) controls were determined by real-time PCR. Transfection with miR-193b precursor and inhibitor were used to confirm targets of miR-193b. Proliferative effects of urokinase-type plasminogen activator (uPA) were determined by water-soluble tetrazolium salt-1 assay and by analysis of proliferating cell nuclear antigen expression. Fluorescence activated cell sorting analysis was performed to investigate the effect of uPA on apoptosis. For inhibition of the uPA-cellular receptor for uPA (uPAR) pathway, uPAR neutralising antibodies and low molecular weight uPA were used.We found that miR-193b was downregulated in SSc fibroblasts and skin sections as compared with NH controls. The expression of miR-193b was not affected by major profibrotic cytokines and hypoxia. Induction of miR-193b in SSc fibroblasts suppressed, and accordingly, knockdown of miR-193b increased the levels of messenger RNA and protein for uPA. uPA was found to be upregulated in SSc as compared with NH controls in a transforming growth factor-? dependent manner, and uPA was strongly expressed in vascular smooth muscle cells in SSc skin section. Interestingly, uPA induced cell proliferation and inhibited apoptosis of human pulmonary artery smooth muscle cells, and these effects were independent of uPAR signalling.In SSc, the downregulation of miR-193b induces the expression of uPA, which increases the number of vascular smooth muscle cells in an uPAR-independent manner and thereby contributes to the proliferative vasculopathy with intimal hyperplasia characteristic for SSc.
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DPP4-deficient congenic rats display blunted stress, improved fear extinction and increased central NPY - Canneva, Fabio; Golub, Yulia; Distler, Jörg; Dobner, Julia; Meyer, Sarah Katharina; von Hörsten, Stephan (Psychoneuroendocrinology, 2015)
Inhibitors of dipeptidyl peptidase 4 (DPP4, CD26) are used for the treatment of type 2 diabetic patients and better glucose tolerance has been confirmed in functionally DPP4-deficient congenic rats (DPP4mut), along with immunological alterations and, interestingly, a stress-resilient phenotype. All these findings are in agreement with the "moonlighting" properties of DPP4, whose proteolytic action is responsible for the inactivation of a number of regulatory peptides including, but not limited to, neuropeptide Y (NPY). Among all candidate substrates, DPP4 displays highest affinity for NPY, an endogenous anxiolytic neurotransmitter that is suggested as a candidate biomarker in post-traumatic stress disorder (PTSD) and depression.Central and peripheral NPY levels were measured by ELISA in DPP4mut and DAwt rats revealing a significantly higher concentration of the peptide in the CSF of DPP4mut animals. This finding positively correlated with the blunted stress phenotype measured on an analgesia-meter. Additionally, when a classical fear-conditioning paradigm was investigated, short-term fear extinction was significantly potentiated in DPP4mut rats as compared to wt controls.Our findings indicate a positive correlation between reduced stress-responsiveness and increased central NPY, in DPP4mut rats. Most interestingly, the behavioral phenotype extends to facilitation of fear extinction. These observations raise further interest in DPP4-modulating drugs for the potential effect on NPY metabolism, as a therapeutic tool for psychiatric conditions such as anxiety disorders and PTSD.
EVALuna2:13098

Drei Generationen Leiden: Cryopyrin-assoziiertes periodisches Syndrom mit familiärer NLRP3-Mutation - Wagner, Nicola; Manger, Bernhard; Kittler, Julia; Rech, Jürgen; Sticherling, Michael; Berking, Carola; Kirchberger, Michael (Journal der Deutschen Dermatologischen Gesellschaft, 2022)
CRIS-Team Scopus Importer:2022-02-04

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

Dual ontogeny of disease-associated microglia and disease inflammatory macrophages in aging and neurodegeneration - Silvin, Aymeric; Uderhardt, Stefan; Piot, Cecile; Da Mesquita, Sandro; Yang, Katharine; Geirsdottir, Laufey; Mulder, Kevin; Eyal, David; Liu, Zhaoyuan; Bridlance, Cecile; Thion, Morgane Sonia; Zhang, Xiao Meng; et al. (Immunity, 2022)
Brain macrophage populations include parenchymal microglia, border-associated macrophages, and recruited monocyte-derived cells; together, they control brain development and homeostasis but are also implicated in aging pathogenesis and neurodegeneration. The phenotypes, localization, and functions of each population in different contexts have yet to be resolved. We generated a murine brain myeloid scRNA-seq integration to systematically delineate brain macrophage populations. We show that the previously identified disease-associated microglia (DAM) population detected in murine Alzheimer's disease models actually comprises two ontogenetically and functionally distinct cell lineages: embryonically derived triggering receptor expressed on myeloid cells 2 (TREM2)-dependent DAM expressing a neuroprotective signature and monocyte-derived TREM2-expressing disease inflammatory macrophages (DIMs) accumulating in the brain during aging. These two distinct populations appear to also be conserved in the human brain. Herein, we generate an ontogeny-resolved model of brain myeloid cell heterogeneity in development, homeostasis, and disease and identify cellular targets for the treatment of neurodegeneration.
CRIS-Team Scopus Importer:2022-09-02
Keywords: aging; Alzheimer's disease; disease inflammatory macrophages; disease-associated microglia; macrophage; microglia; neurodegeneration

Dual pathways to endochondral osteoblasts: a novel chondrocyte-derived osteoprogenitor cell identified in hypertrophic cartilage - Park, Jung; Gebhardt, Matthias; Golovchenko, Svitlana; Perez-Branguli, Francesc; Hattori, Takako; Hartmann, Christine; Zhou, Xin; Decrombrugghe, Benoit; Stock, Michael; Schneider, Holm; Mark, Klaus (Biology Open, 2015)
According to the general understanding, the chondrocyte lineage terminates with the elimination of late hypertrophic cells by apoptosis in the growth plate. However, recent cell tracking studies have shown that murine hypertrophic chondrocytes can survive beyond "terminal" differentiation and give rise to a progeny of osteoblasts participating in endochondral bone formation. The question how chondrocytes convert into osteoblasts, however, remained open. Following the cell fate of hypertrophic chondrocytes by genetic lineage tracing using BACCol10;Cre induced YFP-reporter gene expression we show that a progeny of Col10Cre-reporter labelled osteoprogenitor cells and osteoblasts appears in the primary spongiosa and participates - depending on the developmental stage - substantially in trabecular, endosteal, and cortical bone formation. YFP(+) trabecular and endosteal cells isolated by FACS expressed Col1a1, osteocalcin and runx2, thus confirming their osteogenic phenotype. In searching for transitory cells between hypertrophic chondrocytes and trabecular osteoblasts we identified by confocal microscopy a novel, small YFP(+)Osx(+) cell type with mitotic activity in the lower hypertrophic zone at the chondro-osseous junction. When isolated from growth plates by fractional enzymatic digestion, these cells termed CDOP (chondrocyte-derived osteoprogenitor) cells expressed bone typical genes and differentiated into osteoblasts in vitro. We propose the Col10Cre-labeled CDOP cells mark the initiation point of a second pathway giving rise to endochondral osteoblasts, alternative to perichondrium derived osteoprogenitor cells. These findings add to current concepts of chondrocyte-osteocyte lineages and give new insight into the complex cartilage-bone transition process in the growth plate.
EVALuna2:10200

DURABILITY OF APREMILAST RESPONSE IN PATIENTS WITH PSORIATIC ARTHRITIS: LONG-TERM (208-WEEK) RESULTS FROM THE PALACE 1 TRIAL - Kavanaugh, A.; Gladman, D. D.; Gomez-Reino, J. J.; Hall, S.; Lespessailles, E.; Mease, P. J.; Schett, Georg; Mcilraith, M.; Delev, N.; Paris, M.; Teng, L.; Wollenhaupt, J. (2017)
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Durability of apremilast response through 5 years of treatment in subjects with psoriatic arthritis - Kavanaugh, Arthur; Gladman, Dafna D.; Gomez-Reino, Juan J.; Hall, Stephen; Lespessailles, Eric; Mease, Philip J.; Schett, Georg; Pari, Maria; Teng, Lichen; Wollenhaupt, Juergen (2018)
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Duration of effectiveness of vaccination against COVID-19 caused by the omicron variant - Arora, Prerna; Kempf, Amy; Nehlmeier, Inga; Schulz, Sebastian; Cossmann, Anne; Stankov, Metodi V.; Jäck, Hans-Martin; Behrens, Georg M. N.; Poehlmann, Stefan; Hoffmann, Markus (Lancet Infectious Diseases, 2022)
CRIS-Team WoS Importer:2023-03-10

Dying autologous cells as instructors of the immune system - Munoz Becerra, Luis; Herrmann, Martin; Berens, Christian (Clinical and Experimental Immunology, 2015)
In an organism, cell death occurs at many different sites and in many different forms. It is frequently part of normal development or serves to maintain cell homeostasis. In other cases, cell death not only occurs due to injury, disease or infection, but also as a consequence of various therapeutic interventions. However, in all of these scenarios, the immune system has to react to the dying and dead cells and decide whether to mount an immune response, to remain quiet or to initiate healing and repopulation. This is essential for the organism, testified by many diseases that are associated with malfunctioning in the cell death process, the corpse removal, or the ensuing immune responsiveness. Therefore, dying cells generally have to be considered as instructors of the immune system. How this happens and which signals and pathways contribute to modulate or shape the immune response is still elusive in many conditions. The articles presented in this Special Issue address such open questions. They highlight that the context in which cell death occurs will not only influence the cell death process itself, but also affect the surrounding cellular milieu, how the generation and presence of 'eat me' signals can have an impact on cell clearance, and that the exact nature of the residual 'debris' and how it is processed are fundamental to determining the immunological consequences. Hopefully, these articles initiate new approaches and new experiments to complete our understanding of how cell death and the immune system interact with each other.
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DYNAMIC CHANGES IN O-GLCNACYLATION REGULATE OSTEOCLAST DIFFERENTIATION AND BONE LOSS IN ARTHRITIS - Chen, Chih-Wei; Li, Y. N.; Trinh, Minh Thuong; Honglin, Z.; Matei, Alexandru-Emil; Ding, Xiao; TRAN MANH, CUONG; Xu, Xiaohan; Liebel, C.; Liang, Ruifang; Huang, M. C.; Lin, N. Y.; et al. (ANNALS OF THE RHEUMATIC DISEASES, 2021)
CRIS-Team WoS Importer:2021-10-01

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

Dynamic Multiplex Tissue Imaging in Inflammation Research - Uderhardt, Stefan; Neag, Georgiana; Germain, Ronald N. (Annual Reviews Inc., 2024)
Inflammation is a highly dynamic process with immune cells that continuously interact with each other and parenchymal components as they migrate through tissue. The dynamic cellular responses and interaction patterns are a function of the complex tissue environment that cannot be fully reconstructed ex vivo, making it necessary to assess cell dynamics and changing spatial patterning in vivo. These dynamics often play out deep within tissues, requiring the optical focus to be placed far below the surface of an opaque organ. With the emergence of commercially available two-photon excitation lasers that can be combined with existing imaging systems, new avenues for imaging deep tissues over long periods of time have become available. We discuss a selected subset of studies illustrating how two-photon microscopy (2PM) has helped to relate the dynamics of immune cells to their in situ function and to understand the molecular patterns that govern their behavior in vivo. We also review some key practical aspects of 2PM methods and point out issues that can confound the results, so that readers can better evaluate the reliability of conclusions drawn using this technology.
CRIS-Team Scopus Importer:2024-02-16
Keywords: dynamic imaging; intravital imaging; multiplex imaging; tissue imaging; two-photon microscopy

Early CCR6 expression on B cells modulates germinal centre kinetics and efficient antibody responses - Reimer, Dorothea; Lee, Adrian Y. S.; Bannan, Jennifer; Fromm, Phillip; Kara, Ervin E.; Comerford, Iain; Mccoll, Shaun; Wiede, Florian; Mielenz, Dirk; Körner, Heinrich (Immunology and Cell Biology, 2017)
The CC-chemokine receptor 6 (CCR6) can be detected on naive and activated B cells. Counterintuitively, its absence accelerates the appearance of germinal centres (GCs) and increases the production of low-affinity antibodies. The detailed mechanism of CCR6 function during the humoral response has remained elusive, but previously we identified a distinct CCR6high B-cell population in vivo early after antigenic challenge. In this study, we defined this population specifically as early, activated pre-GC B cells. In accordance, we show that CCR6 is upregulated rapidly within hours on the protein or mRNA level after activation in vitro. In addition, only activated B cells migrated specifically towards CCL20, the specific ligand for CCR6. Lack of CCR6 increased the dark zone/light zone ratio of GC and led to decreased antigen-specific IgG1 and IgG2a antibody generation in a B-cell intrinsic manner in mixed bone marrow chimeras. In contrast, antigen-specific IgM responses were normal. Hence, CCR6 negatively regulates entry of activated, antigen-specific pre-GC B cells into the GC reaction.
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