Association between enthesitis/dactylitis resolution and patient-reported outcomes in guselkumab-treated patients with psoriatic arthritis - Rahman, Proton; McInnes, Iain B.; Deodhar, Atul; Schett, Georg; Mease, Phillip J.; Shawi, May; Cua, Daniel J.; Sherlock, Jonathan P.; Kollmeier, Alexa P.; Xu, Xie L.; Sheng, Shihong; Ritchlin, Christopher T.; et al. (Clinical Rheumatology, 2024)
Objectives: To evaluate the association between enthesitis resolution (ER) and dactylitis resolution (DR) and meaningful improvements in patient-reported outcomes (PROs) among biologic-naïve patients with PsA receiving guselkumab in the DISCOVER-2 study. Methods: Enthesitis and dactylitis, characteristic lesions of PsA, were evaluated by independent assessors using the Leeds Enthesitis Index (range, 0–6) and Dactylitis Severity Score (range, 0–60). Proportions of patients with ER or DR (score = 0) among those with score > 0 at baseline were determined at weeks 24, 52, and 100. PROs included: fatigue (Functional Assessment of Chronic Illness Therapy-Fatigue [FACIT-Fatigue]), pain (0–100 visual analog scale), physical function (Health Assessment Questionnaire-Disability Index [HAQ-DI]), and health-related quality of life (36-item Short-Form Health Survey physical/mental component summary [SF-36 PCS/MCS]). Meaningful responses were defined as: improvements of ≥ 4 for FACIT-Fatigue, ≥ 0.35 for HAQ-DI, and ≥ 5 for SF-36 PCS/MCS and absolute scores of ≤ 15 for minimal pain and ≤ 0.5 for normalized HAQ-DI. Associations between ER/DR status and PRO response status were tested using a Chi-square test. Results: Guselkumab-treated patients with ER were more likely than those without ER to achieve minimal pain (p < 0.001), normalized HAQ-DI (p < 0.001), and PCS response (p < 0.05) at weeks 24, 52, and 100. Patients with DR were more likely than those without DR to achieve FACIT-Fatigue response at week 24 and week 52 (both p ≤ 0.01) and minimal pain at week 24 and normalized HAQ-DI at week 52 (both p ≤ 0.03). Conclusion: In biologic-naïve patients with active PsA treated with guselkumab, achieving ER or DR was associated with durable improvements in selected PROs, including those of high importance to patients. Trial registration: ClinicalTrials.gov (https://clinicaltrials.gov) NCT03158285; Registered: May 16, 2017. (Table presented.).
CRIS-Team Scopus Importer:2024-03-22
Keywords: Biologic; Dactylitis; Enthesitis; Guselkumab; Psoriatic arthritis

ASSOCIATION BETWEEN MECHANOSENSITIVE BLOOD MARKERS AND PATIENT REPORTED OUTCOMES IN PATIENTS WITH KNEE OSTEOARTHRITIS - Muendermann, A.; Nueesch, C.; Chammartin, F.; Herger, S.; Pagenstert, G.; Liphardt, Anna-Maria; Egloff, C. (OSTEOARTHRITIS AND CARTILAGE, 2022)
CRIS-Team WoS Importer:2022-04-22

Association Between Vascular Cell Adhesion Molecule 1 and Atrial Fibrillation - Willeit, Karin; Pechlaner, Raimund; Willeit, Peter; Skroblin, Philipp; Paulweber, Bernhard; Schernthaner, Christiana; Toell, Thomas; Egger, Georg; Weger, Siegfried; Oberhollenzer, Martin; Kedenko, Ludmilla; Iglseder, Bernhard; et al. (JAMA Cardiology, 2017)
Accumulating evidence links inflammation and atrial fibrillation (AF).To assess whether markers of systemic and atrial inflammation are associated with incident AF in the general population.The Bruneck Study is a prospective, population-based cohort study with a 20-year follow-up (n = 909). The population included a random sample of the general community aged 40 to 79 years. Levels of 13 inflammation markers were measured at baseline in 1990. Findings were replicated in a case-control sample nested within the prospective Salzburg Atherosclerosis Prevention Program in Subjects at High Individual Risk (SAPHIR) study (n = 1770). Data analysis was performed from February to May 2016.Levels of 13 inflammation markers.Incident AF over a 20-year follow-up period in the Bruneck Study.Of the 909 participants included in the Bruneck Study, mean [SD] age was 58.8 (11.4) years and 448 (49.3%) were women. Among the 880 participants free of prevalent AF (n = 29) at baseline, 117 developed AF during the 20-year follow-up period (incidence rate, 8.2; 95% CI, 6.8-9.6 per 1000 person-years). The levels of soluble vascular cell adhesion molecule 1 (VCAM-1) and osteoprotegerin were significantly associated with incident AF (hazard ratio [HR], 1.49; 95% CI, 1.26-1.78; and 1.46; 95% CI, 1.25-1.69, respectively; P < .001 with Bonferroni correction for both), but osteoprotegerin lost significance after age and sex adjustment (HR, 1.05; 95% CI, 0.87-1.27; P > .99 with Bonferroni correction). Matrix metalloproteinase 9, metalloproteinase inhibitor 1, monocyte chemoattractant protein-1, P-selectin, fibrinogen, receptor activator of nuclear factor-?B ligand, high-sensitivity C-reactive protein, adiponectin, leptin, soluble intercellular adhesion molecule 1, and E-selectin all fell short of significance (after Bonferroni correction in unadjusted and age- and sex-adjusted analyses). The HR for a 1-SD higher soluble VCAM-1 level was 1.34 (95% CI, 1.11-1.62; Bonferroni-corrected P = .03) in a multivariable model. The association was of a dose-response type, at least as strong as that obtained for N-terminal pro-B-type natriuretic peptide (multivariable HR for a 1-SD higher N-terminal pro-B-type natriuretic peptide level, 1.15; 95% CI, 1.04-1.26), internally consistent in various subgroups, and successfully replicated in the SAPHIR Study (age- and sex-adjusted, and multivariable odds ratios for a 1-SD higher soluble VCAM-1 level, 1.91; 95% CI, 1.24-2.96, P = .003; and 2.59; 95% CI, 1.45-4.60; P = .001).Levels of soluble VCAM-1, but not other inflammation markers, are significantly associated with new-onset AF in the general community. Future studies should address whether soluble VCAM-1 is capable of improving AF risk classification beyond the information provided by standard risk scores.
EVALuna2:13375

Association of a coding polymorphism in Fc gamma receptor 2A and graft survival in re-transplant candidates - Fuernrohr, Barbara G.; Weiss, Katrin M.; Harre, Ulrike; Wiesener, Michael S.; Spriewald, Bernd M.; Arnold, Martin (Human Immunology, 2015)
The family of Fc gamma receptors (Fc?Rs) is involved in mediating immunological effector functions. Fc?Rs are differentially expressed on immune cells and can act either activating or inhibitory, with Fc?R2A belonging to the first group. The polymorphism H131R (rs1801274) in FCGR2A has been associated with acute rejection and can shift the overall balance between activating and inhibitory Fc?Rs. Anti-HLA allo-antibodies in transplant recipients have been identified as risk factor for organ survival after transplantation. In this study we genotyped FCGR2A H131R in 200 patients who had undergone kidney transplantation and experienced loss of graft function. FCGR2A polymorphism was related to graft survival and anti-HLA antibodies. Graft survival was calculated as the time interval between transplantation and return to chronic dialysis after transplantation. The gene frequency of FCGR2A R/R131 was found significantly more often in patients with earlier (?60months) compared to patients with later (>60months) graft failure. Overall patients homozygous for R/R131 had a significantly shorter graft survival, compared to H/H131 or H/R131 which is even more pronounced, when anti-HLA antibodies were present. These data suggest, that FCGR2A polymorphisms constitute a risk factor for graft loss following kidney transplantation and that this effect is related to anti-HLA antibodie
EVALuna2:3812

ASSOCIATION OF ANTI-CITRULLINATED PROTEIN ANTIBODIES OF IgA SUBCLASSES WITH SUSTAINED REMISSION AND FLARE IN RHEUMATOID ARTHRITIS - Sokolova, Maria; Rech, Jürgen; Hagen, Melanie; Schett, Georg; Steffen, Ulrike (ANNALS OF THE RHEUMATIC DISEASES, 2021)
CRIS-Team WoS Importer:2021-09-24

Association of brain functional magnetic resonance activity with response to tumor necrosis factor inhibition in rheumatoid arthritis - Rech, Jürgen; Heß, Andreas; Finzel, Stephanie; Kreitz, Silke; Sergeeva, Marina; Englbrecht, Matthias; Dörfler, Arnd; Saake, Marc; Schett, Georg (Arthritis and Rheumatism, 2013)
Objective To test whether brain activity predicts the response to tumor necrosis factor inhibitors (TNFi) in patients with rheumatoid arthritis (RA). Since clinical and laboratory parameters have proven unsuccessful in predicting response, we followed a radically different concept, hypothesizing that response to TNFi depends on central nervous system activity rather than the clinical signs of disease. Methods Sequential testing by functional magnetic resonance imaging (MRI) of the brain, anatomic MRI of the hand, and clinical assessment of arthritis were carried out in 10 patients with active RA before and 3, 7, and 28 days after the start of TNFi treatment. Results Baseline demographic and disease-specific parameters were identical in TNFi responders and nonresponders. The mean ± SEM decrease in the Disease Activity Score in 28 joints after 28 days was -1.8 ± 0.3 in TNFi responders (n = 5) and -0.2 ± 0.1 in nonresponders (n = 5). Responders showed significantly higher baseline activation in thalamic, limbic, and associative areas of the brain than nonresponders. Moreover, brain activity decreased within 3 days after TNFi exposure in the responders, preceding clinical responses (day 7) and responses observed on the anatomic hand MRI (day 28). Conclusion These data suggest that response to TNFi depends on brain activity in RA patients, reflecting the subjective perception of disease. Copyright © 2013 by the American College of Rheumatology.
CRIS-Team Scopus Importer:2021-02-03

Association of Circulating Antibody-Secreting Cell Maturity With Disease Features in Primary Sjogren's Syndrome - Steinmetz, Tobit D.; Verstappen, Gwenny M.; Schulz, Sebastian; De Wolff, Liseth; Wilbrink, Rick; Visser, Annie; Terpstra, Janneke; Bootsma, Hendrika; Kroese, Frans G. M. (Arthritis and Rheumatology, 2023)
Objective. B cell hyperactivity plays an important role in primary Sjogren's syndrome (SS). We undertook this study to better understand the B cell effector branch, namely antibody-secreting cells (ASCs) in primary SS, and to examine the quantity, maturity, and inflammatory properties of ASCs in primary SS patients.
CRIS-Team WoS Importer:2023-04-21

Association of disease characteristics with the temporal sequence of skin and musculoskeletal disease onset in psoriatic arthritis - Tascilar, Koray; Bayindir, O.; Dogru, A.; Tinazzi, I.; Kimyon, G.; Ozisler, C.; Erden, A.; Dalkilic, E.; Cetin, G. Y.; Yilmaz, S.; Solmaz, D.; Bakirci, S.; et al. (British Journal of Dermatology, 2021)
CRIS-Team Scopus Importer:2021-05-07

ASSOCIATION OF OSTEOPROTEGERIN WITH CARDIOVASCULAR RISK IN GENERAL AND HIGH-RISK POPULATIONS: META-ANALYSIS OF 28 PROSPECTIVE STUDIES INVOLVING 53,892 PARTICIPANTS - Klingenschmid, G.; Tschiderer, L.; Nagrani, R.; Willeit, J.; Laukkanen, J.; Schett, Georg; Kiechl, S.; Willeit, P. (ATHEROSCLEROSIS, 2019)
CRIS-Team WoS Importer:2019-09-10

Association of Structural Entheseal Lesions With an Increased Risk of Progression From Psoriasis to Psoriatic Arthritis - Simon, David; Tascilar, Koray; Kleyer, Arnd; Bayat, Sara; Kampylafka, Eleni; Sokolova, Maria; Zekovic, Ana; Hueber, Axel; Rech, Jürgen; Schuster, Louis; Engel, Klaus; Sticherling, Michael; et al. (Arthritis and Rheumatology, 2021)
Objective. To test whether the presence of structural entheseal lesions in psoriasis patients influences the risk of progression to psoriatic arthritis (PsA).
CRIS-Team WoS Importer:2022-01-07

A subset of human plasmacytoid dendritic cells expresses CD8? upon exposure to herpes simplex virus type 1 - Schuster, Philipp; Thomann, Sabrina; Werner, Maren; Vollmer, Joerg; Schmidt, Barbara (Frontiers in Microbiology, 2015)
Classical and plasmacytoid dendritic cells (DC) play important roles in the defense against murine and human infections with herpes simplex virus (HSV). So far, CD8? expression has only been reported for murine DC. CD8?(+) DC have prominent cross-presenting activities, which are enhanced by murine CD8?(+) PDC. The human orthologue of murine CD8?(+) DC, the CD141 (BDCA3)(+) DC, mainly cross-present after TLR3 ligation. We report here the serendipitous finding that a subset of human PDC upregulates CD8? upon HSV-1 stimulation, as shown by gene array and flow cytometry analyses. CD8?, not CD8ß, was expressed upon exposure. Markers of activation, migration, and costimulation were upregulated on CD8?-expressing human PDC. In these cells, increased cytokine and chemokine levels were detected that enhance development and function of T, B, and NK cells, and recruit immature DC, monocytes, and Th1 cells, respectively. Altogether, human CD8?(+) PDC exhibit a highly activated phenotype and appear to recruit other immune cells to the site of inflammation. Further studies will show whether CD8?-expressing PDC contribute to antigen cross-presentation, which may be important for immune defenses against HSV infections in vitro and in vivo.
EVALuna2:8273

A surrogate cell-based SARS-CoV-2 spike blocking assay - Schuh, Wolfgang; Baus, Lena; Steinmetz, Tobit; Schulz, Sebastian; Weckwerth, Leonie; Roth, Edith; Hauke, Manuela; Krause, Stefan; Morhart, Patrick; Rauh, Manfred; Hoffmann, Markus; Vesper, Niklas; et al. (European Journal of Immunology, 2021)
To monitor infection by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and successful vaccination against coronavirus disease 2019 (COVID-19), the kinetics of neutralizing or blocking anti-SARS-CoV-2 antibody titers need to be assessed. Here, we report the development of a quick and inexpensive surrogate SARS-CoV-2 blocking assay (SUBA) using immobilized recombinant human angiotensin-converting enzyme 2 (hACE2) and human cells expressing the native form of surface SARS-CoV-2 spike protein. Spike protein-expressing cells bound to hACE2 in the absence or presence of blocking antibodies were quantified by measuring the optical density of cell-associated crystal violet in a spectrophotometer. The advantages are that SUBA is a fast and inexpensive assay, which does not require biosafety level 2- or 3-approved laboratories. Most importantly, SUBA detects blocking antibodies against the native trimeric cell-bound SARS-CoV-2 spike protein and can be rapidly adjusted to quickly pre-screen already approved therapeutic antibodies or sera from vaccinated individuals for their ACE2 blocking activities against any emerging SARS-CoV-2 variants.
CRIS-Team Scopus Importer:2021-10-08
Keywords: COVID-19; hACE2; SARS-CoV-2; Spike protein; Surrogate blocking assay

A Symptom Checker App Is Better at Classifying Inflammatory Disease Than Physicians Who Are Presented Identical Information - 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. (ARTHRITIS & RHEUMATOLOGY, 2022)
CRIS-Team WoS Importer:2023-01-13

A synthetic PPAR-? agonist triterpenoid ameliorates experimental fibrosis: PPAR-?-independent suppression of fibrotic responses - Wei, Jun; Zhu, Hongyan; Komura, Kazuhiro; Lord, Gabriel; Tomcik, Michal; Wang, Wenxia; Doniparthi, Sruthi; Tamaki, Zenshiro; Hinchcliff, Monique; Distler, Jörg; Varga, John (Annals of the Rheumatic Diseases, 2014)
Persistent fibroblast activation initiated by transforming growth factor ? (TGF-?) is a fundamental event in the pathogenesis of systemic sclerosis, and its pharmacological inhibition represents a potential therapeutic strategy. The nuclear receptor, peroxisome proliferator-activated receptor ? (PPAR-?), exerts potent fibrotic activity. The synthetic oleanane triterpenoid, 2-cyano-3,12-dioxo-olean-1,9-dien-28-oic acid (CDDO), is a PPAR-? agonist with potential effects on TGF-? signalling and dermal fibrosis.To examine the modulation of fibrogenesis by CDDO in explanted fibroblasts, skin organ cultures and murine models of scleroderma.The effects of CDDO on experimental fibrosis induced by bleomycin injection or by overexpression of constitutively active type I TGF-? receptor (TgfbR1ca) were evaluated. Modulation of fibrotic gene expression was examined in human skin organ cultures. To delineate the mechanisms underlying the antifibrotic effects of CDDO, explanted skin fibroblasts cultured in two-dimensional monolayers or in three-dimensional full-thickness human skin equivalents were studied.CDDO significantly ameliorated dermal fibrosis in two complementary mouse models of scleroderma, as well as in human skin organ cultures and in three-dimensional human skin equivalents. In two-dimensional monolayer cultures of explanted normal fibroblasts, CDDO abrogated fibrogenic responses induced by TGF-?. These CDDO effects occurred via disruption of Smad-dependent transcription and were associated with inhibition of Akt activation. In scleroderma fibroblasts, CDDO attenuated the elevated synthesis of collagen. Remarkably, the in vitro antifibrotic effects of CDDO were independent of PPAR-?.The PPAR-? agonist triterpenoid CDDO attenuates fibrogenesis by antagonistically targeting canonical TGF-?/Smad and Akt signalling in a PPAR-?-independent manner. These findings identify this synthetic triterpenoid as a potential new therapy for the control of fibrosis.
EVALuna2:12974

At-home blood self-sampling in rheumatology: a qualitative study with patients and health care professionals. - Muehlensiepen, Felix; May, Susann; Zarbl, Joshua; Vogt, Ekaterina; Boy, Katharina; Heinze, Martin; Böltz, Sebastian; Labinsky, Hannah; Bendzuck, Gerlinde; Korinth, Marianne; Elling-Audersch, Corinna; Vuillerme, Nicolas; et al. (BMC Health Services Research, 2022)
BACKGROUND: The goal of the study was to investigate patients' with systemic rheumatic diseases and healthcare professionals' experiences and preferences regarding self-sampling of capillary blood in rheumatology care. METHODS: Patients performed a supervised and consecutive unsupervised capillary blood self-collection using an upper arm based device. Subsequently, patients (n = 15) and their attending health care professionals (n = 5) participated in an explorative, qualitative study using problem-centered, telephone interviews. Interview data were analyzed using structured qualitative content analysis. RESULTS: Interviewed patients reported easy application and high usability. Patients and health care professionals alike reported time and cost savings, increased independence and flexibility, improved monitoring and reduction of risk of infection during Covid-19 as benefits. Reported drawbacks include limited blood volume, limited usability in case of functional restrictions, and environmental concerns. Older, immobile patients with long journeys to traditional blood collection sites and young patients with little time to spare for traditional blood collection appointments could be user groups, likely to benefit from self-sampling services. CONCLUSIONS: At-home blood self-sampling could effectively complement current rheumatology telehealth care. Appropriateness and value of this service needs to be carefully discussed with patients on an individual basis. TRIAL REGISTRATION: WHO International Clinical Trials Registry: DRKS00024925. Registered on 15/04/2021.
EVALuna2:520656

Attention, cognitive control and motivation in ADHD: Linking event-related brain potentials and DNA methylation patterns in boys at early school age - Heinrich, Hartmut; Grunitz, Juliane; Stonawski, Valeska; Frey, Silke; Wahl, Simone; Albrecht, Bjoern; Goecke, Tamme W.; Beckmann, Matthias; Kornhuber, Johannes; Fasching, Peter; Moll, Gunther; Eichler, Anna (Scientific Reports, 2017)
In order to better understand the underpinnings of attention-deficit/hyperactivity disorder (ADHD), we targeted the relationship of attentional, cognitive control and motivational processes with DNA methylation patterns of 60 candidate genes in boys at early school age. Participants (6 to 8 years; N = 82) were selected from a German longitudinal cohort (FRANCES). ADHD-related behaviour was assessed via maternal ratings. Performance and event-related potential measures (inter alia Cue-P3 and Nogo-P3), which were recorded in a motivational go/nogo task, indicated diminished attentional orienting, reduced inhibitory response control and a larger motivational effect on performance in ADHD already at this relatively young age. Methylation patterns were analysed in buccal cell DNA with the Illumina HumanMethylation 450K array. For CpG sites at genes of the dopaminergic (COMT, ANKK1) and the neurotrophic (BDNF, NGFR) system, associations with the Nogo-P3 as well as ADHD symptom severity were found suggesting that these systems are involved in response control deficits in ADHD. Methylation effects related to both functional aspects and ADHD behaviour were also observed for DPP10 and TPH2. Epigenetic mechanisms may play a role in ADHD-associated deficits but findings need to be replicated in larger samples and are limited by the fact that only peripheral methylation could be considered.
EVALuna2:33560

Attenuation of fibroblast activation and fibrosis by adropin in systemic sclerosis - Liang, Minrui; Dickel, Nicholas; Györfi, Andrea Hermina; SafakTümerdem, Bilgesu; Li, Yi Nan; Rius Rigau, Aleix; Liang, Chunguang; Hong, Xuezhi; Shen, Lichong; Matei, Alexandru-Emil; Trinh-Minh, Thuong; Tran-Manh, Cuong; et al. (Science Translational Medicine, 2024)
Fibrotic diseases impose a major socioeconomic challenge on modern societies and have limited treatment options. Adropin, a peptide hormone encoded by the energy homeostasis–associated (ENHO) gene, is implicated in metabolism and vascular homeostasis, but its role in the pathogenesis of fibrosis remains enigmatic. Here, we used machine learning approaches in combination with functional in vitro and in vivo experiments to characterize adropin as a potential regulator involved in fibroblast activation and tissue fibrosis in systemic sclerosis (SSc). We demonstrated consistent down-regulation of adropin/ENHO in skin across multiple cohorts of patients with SSc. The prototypical profibrotic cytokine TGFβ reduced adropin/ENHO expression in a JNK-dependent manner. Restoration of adropin signaling by therapeutic application of bioactive adropin34–76 peptides in turn inhibited TGFβ-induced fibroblast activation and fibrotic tissue remodeling in primary human dermal fibroblasts, three-dimensional full-thickness skin equivalents, mouse models of bleomycin-induced pulmonary fibrosis and sclerodermatous chronic graft-versus-host-disease (sclGvHD), and precision-cut human skin slices. Knockdown of GPR19, an adropin receptor, abrogated the antifibrotic effects of adropin in fibroblasts. RNA-seq demonstrated that the antifibrotic effects of adropin34–76 were functionally linked to deactivation of GLI1-dependent profibrotic transcriptional networks, which was experimentally confirmed in vitro, in vivo, and ex vivo using cultured human dermal fibroblasts, a sclGvHD mouse model, and precision-cut human skin slices. ChIP-seq confirmed adropin34–76-induced changes in TGFβ/GLI1 signaling. Our study characterizes the TGFβ-induced down-regulation of adropin/ENHO expression as a potential pathomechanism of SSc as a prototypical systemic fibrotic disease that unleashes uncontrolled activation of profibrotic GLI1 signaling.
CRIS-Team Scopus Importer:2024-04-05

Attenuation of Severe Generalized Junctional Epidermolysis Bullosa by Systemic Treatment with Gentamicin - Hammersen, Johanna; Neuner, Andrea; Wild, Florian; Schneider, Holm (Dermatology, 2019)
Severe generalized junctional epidermolysis bullosa (JEB), a lethal genodermatosis, is mainly caused by premature termination codons (PTCs) in one of the three genes encoding the anchoring protein laminin-332. Only symptomatic treatment has been established; overcoming PTCs by aminoglycosides may represent an interesting alternative. This retrospective study aimed at assessing for the first time the clinical effects of systemic gentamicin application in infants with severe generalized JEB. Five patients, homozygous or compound-heterozygous for PTCs in the gene LAMB3, were treated with gentamicin which was administered intravenously or by intramuscular injection at doses of 7.5 mg/kg/d for three weeks. Skin biopsies were investigated by immunofluorescence analyses. Clinical effects of the medication were recorded with a parent questionnaire and by assessing weight-for-age charts. Gentamicin application was well tolerated, long hospitalization was not required. Low levels of laminin-332 could be detected in a skin sample obtained after treatment. Gentamicin had a positive impact on skin fragility and daily life in four patients but did not influence weight gain and failed to reverse the lethal course of the disease. Gentamicin injections should be considered regularly in cases of severe generalized JEB caused by PTCs as they may attenuate JEB symptoms without impeding quality of life.
CRIS-Team Scopus Importer:2019-06-18

At the Heart of Eosinophilic Granulomatosis with Polyangiitis: into Cardiac and Vascular Involvement - Bond, Milena; Fagni, Filippo; Moretti, Michele; Bello, Federica; Egan, Allyson; Vaglio, Augusto; Emmi, Giacomo; Dejaco, Christian (Current Rheumatology Reports, 2022)
Purpose of Review: To provide an overview of existing literature on pathogenetic and clinical aspects of cardiac and vascular involvement in eosinophilic granulomatosis with polyangiitis (EGPA). Recent Findings: In EGPA, cardiac and vascular involvement are more common than previously thought. However, no international recommendations on the topic are available yet. Herein, we summarize the existing evidence on the topic and propose a diagnostic approach for cardiac involvement in EGPA. Summary: The prevalence of cardiovascular involvement in patients with EGPA varies greatly among published studies, ranging between 3.1–18.7% for occlusive arterial disease, 5.8–30% for venous thrombosis and 17–92% for heart involvement. Cardiac involvement in EGPA is associated with high mortality even though manifestations are heterogeneous. In principle, every anatomical structure of the heart can be involved, and EGPA-related heart disease may be completely asymptomatic at first. A careful diagnostic work-up for early detection and prompt treatment initiation is therefore required. While cardiac manifestations are more common in anti-neutrophil cytoplasmic antibodies (ANCA)-negative patients, arterial and venous thrombotic events are not linked to ANCA status but correlate closely with disease activity and accumulate at disease onset. Thrombotic events (mainly venous) are considerably more frequent in EGPA than in the general population contributing substantially to morbidity and highlighting the importance of developing specific prevention strategies for patients who are diagnosed with EGPA.
CRIS-Team Scopus Importer:2022-10-21
Keywords: Cardiovascular; Eosinophilic granulomatosis with polyangiitis; Heart; Vascular

Augmented neutralisation resistance of emerging omicron subvariants BA.2.12.1, BA.4, and BA.5 - Arora, Prerna; Kempf, Amy; Nehlmeier, Inga; Schulz, Sebastian; Cossmann, Anne; Stankov, Metodi V.; Jäck, Hans-Martin; Behrens, Georg M.N.; Pöhlmann, Stefan; Hoffmann, Markus (Lancet Infectious Diseases, 2022)
CRIS-Team Scopus Importer:2022-08-05

Augmented neutralization of SARS-CoV-2 Omicron variant by boost vaccination and monoclonal antibodies - Schulz, Sebastian; Hoffmann, Markus; Roth, Edith; Pracht, Katharina; Burnett, Deborah L.; Mazigi, Ohan; Schuh, Wolfgang; Manger, Bernhard; Mielenz, Dirk; Goodnow, Christopher C.; Christ, Daniel; Poehlmann, Stefan; et al. (European Journal of Immunology, 2022)
Effective vaccines and monoclonal antibodies have been developed against coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). However, the appearance of virus variants with higher transmissibility and pathogenicity is a major concern because of their potential to escape vaccines and clinically approved SARS-CoV-2- antibodies. Here, we use flow cytometry-based binding and pseudotyped SARS-CoV-2 neutralization assays to determine the efficacy of boost immunization and therapeutic antibodies to neutralize the dominant Omicron variant. We provide compelling evidence that the third vaccination with BNT162b2 increases the amount of neutralizing serum antibodies against Delta and Omicron variants, albeit to a lower degree when compared to the parental Wuhan strain. Therefore, a third vaccination is warranted to increase titers of protective serum antibodies, especially in the case of the Omicron variant. We also found that most clinically approved and otherwise potent therapeutic antibodies against the Delta variant failed to recognize and neutralize the Omicron variant. In contrast, some antibodies under preclinical development potentially neutralized the Omicron variant. Our studies also support using a flow cytometry-based antibody binding assay to rapidly monitor therapeutic candidates and serum titers against emerging SARS-CoV-2 variants.
CRIS-Team WoS Importer:2022-04-08

Author Correction: Anti-CD19 CAR T cell therapy for refractory systemic lupus erythematosus. - Mackensen, Andreas; Müller, Fabian; Mougiakakos, Dimitrios; Böltz, Sebastian; Wilhelm, Artur; Aigner, Michael; Völkl, Simon; Simon, David; Kleyer, Arnd; Munoz, Luis Enrique; Kretschmann, Sascha; Kharboutli, Soraya; et al. (Nature Medicine, 2023)
EVALuna2:512812

Author Correction: DeepNAPSI multi-reader nail psoriasis prediction using deep learning. - Folle, Lukas; Fenzl, Pauline; Fagni, Filippo; Thies, Mareike; Christlein, Vincent; Meder, Christine; Simon, David; Minopoulou, Ioanna; Sticherling, Michael; Schett, Georg; Maier, Andreas; Kleyer, Arnd (Scientific Reports, 2023)
EVALuna2:538275

Author Correction: Transferrin receptor 2 controls bone mass and pathological bone formation via BMP and Wnt signaling (Nature Metabolism, (2019), 1, 1, (111-124), 10.1038/s42255-018-0005-8) - Rauner, Martina; Baschant, Ulrike; Roetto, Antonella; Pellegrino, Rosa Maria; Rother, Sandra; Salbach-Hirsch, Juliane; Weidner, Heike; Hintze, Vera; Campbell, Graeme; Petzold, Andreas; Lemaitre, Regis; Henry, Ian; et al. (Nature Metabolism, 2019)
In the version of this article initially published, affiliation 14 was incorrect, and Deutsche Forschungsgemeinschaft grants SFB1036 and SFB1118 were missing from the Acknowledgements. The errors have been corrected in the HTML and PDF versions of the article.
CRIS-Team Scopus Importer:2019-10-29

Autoantibodies Activating the β2-Adrenergic Receptor Characterize Patients With Primary and Secondary Glaucoma - Hohberger, Bettina; Kunze, Rudolf; Wallukat, Gerd; Kara, Katja; Mardin, Christian Y.; Lämmer, Robert; Schlötzer-Schrehardt, Ursula; Hosari, Sami; Horn, Folkert; Munoz Becerra, Luis; Herrmann, Martin (Frontiers in Immunology, 2019)
Recently, agonistic autoantibodies (agAAb) activating the β2-adrenergic receptor were detected in primary open-angle glaucoma (POAG) or ocular hypertension (OHT) patients and were linked to intraocular pressure (IOP) (1). The aim of the present study was to quantify β2-agAAb in the sera of glaucoma suspects and patients with primary and secondary glaucoma. Patients with OHT (n = 33), pre-perimetric POAG (pre-POAG; n = 11), POAG (n = 28), and 11 secondary OAG (SOAG) underwent ophthalmological examinations including examinations with Octopus G1 perimetry and morphometry. Twenty-five healthy individuals served as controls. Serum-derived IgG samples were analyzed for β2-agAAb using a functional bioassay. The beat-rate-increase of spontaneously beating cultured neonatal rat cardiomyocytes was monitored with 1.6 beats/15 s as cut-off. None of the sera of normal subjects showed β2-agAAb. In POAG or OHT patients increased beating rates of 4.1 ± 2.2 beats/15 s, and 3.7 ± 2.8 beats/15 s were detected (p > 0.05). Glaucoma patients with (POAG) and without perimetric (pre-POAG) defects did not differ (pre-POAG 4.4 ± 2.6 beats/15 s, POAG 4.1 ± 2.0 beats/15 s, p > 0.05). Patients with SOAG yielded mean beating rates of 4.7 ± 1.7 beats/15 s (p > 0.05). β2-agAAb were seen in 73% of OHT, 82% of pre-POAG, 82% of POAG, and 91% SOAG patients (p < 0.001). Clinical data did not correlate with beating rate (p > 0.05). The robust β2-agAAb seropositivity in patients with OHT, pre-POAG, POAG, and SOAG suggest a primary common role for β2-agAAb starting early in glaucoma pathophysiology and turned out to be a novel marker identifying all patients with increased IOP independent of glaucoma stage and entity.
CRIS-Team Scopus Importer:2019-10-29
Keywords: autoantibodies; glaucoma; ocular hypertension; primary open-angle glaucoma; secondary open-angle glaucoma; β2-adrenergic receptor

Autoantibodies against galectins are associated with antiphospholipid syndrome in patients with systemic lupus erythematosus - Sarter, Kerstin; Janko, Christina; Andre, Sabine; Munoz, Luis Enrique; Schorn, Christine; Winkler, Sophie; Rech, Jürgen; Kaltner, Herbert; Lorenz, Hanns-Martin; Schiller, Martin; Andreoli, Laura; Manfredi, Angelo A.; et al. (Glycobiology, 2013)
The presence of autoantibodies against immunoregulatory effectors can be relevant for onset and/or the progression of autoimmune disease. Emerging insights into an immunological activity profile including a role as opsonins give reason to systematically monitor sera of patients for immunoglobulin G (IgG) autoantibodies, preferably for several galectins at the same time. Here, we report on a study of chronic inflammatory rheumatic diseases, i.e. systemic lupus erythematosus (SLE; pilot cohort p, n = 40; confirmation cohort c, n = 109), rheumatoid arthritis (RA; p, n = 32; c, n = 25) and primary antiphospholipid syndrome (APS; c, n = 64). Enzyme-linked immunosorbent assay-based series using galectin-1, -2, -3, -4, -7, -8 and -9 and natural processing products, i.e. the truncated version of galectin-3 and the N-terminal domains of galectin-4, -8 and -9, were performed. Normal healthy donors (p, n = 20; c, n = 21) and patients with paraproteins (c, n = 19) served as controls. Highly significant optical density-value readings for IgG autoantibodies were consistently detected for the proto-type galectin-7 (SLE) and the tandem repeat-type galectin-8 and -9 (SLE and RA). Their presence was independent from the autoantibody status against double-stranded DNA (for patients with SLE) or a rheumatoid factor (for patients with RA), respectively. Importantly, anti-galectin-2 autoantibodies highly significantly correlated with the appearance of a secondary APS in patients with SLE so that this parameter may serve as an additional biomarker for APS. Equally of note, the presence of IgG autoantibodies against galectins capable to act as an opsonin may contribute to a sustained immune dysregulation in patients with chronic inflammatory rheumatic diseases. © The Author 2012. Published by Oxford University Press. All rights reserved.
CRIS-Team Scopus Importer:2021-02-03
Keywords: antiphospholipid syndrome; autoantibodies; galectins; systemic lupus erythematosus

Autoantibodies against Modified Histone Peptides in SLE Patients Are Associated with Disease Activity and Lupus Nephritis - Dieker, Jurgen; Berden, Jo H.; Bakker, Marinka; Briand, Jean-Paul; Muller, Sylviane; Voll, Reinhard; Sjowall, Christopher; Herrmann, Martin; Hilbrands, Luuk B.; Van Der Vlag, Johan (PLoS ONE, 2016)
Persistent exposure of the immune system to death cell debris leads to autoantibodies against chromatin in patients with systemic lupus erythematosus (SLE). Deposition of anti-chromatin/chromatin complexes can instigate inflammation in multiple organs including the kidney. Previously we identified specific cell death-associated histone modifications as targets of autoantibodies in SLE. In this study we addressed, in a large cohort of SLE patients and controls, the question whether plasma reactivities with specific histone peptides associated with serology and clinical features. Plasma from SLE patients with and without lupus nephritis, disease controls, and healthy controls, were tested in ELISA with histone H4 peptide acetylated at lysines 8, 12 and 16 (H4pac), H2B peptide acetylated at lysine 12 (H2Bpac), H3 peptide trimethylated at lysine 27 (H3pme), and their unmodified equivalents. SLE patients displayed a higher reactivity with the modified equivalent of each peptide. Reactivity with H4pac showed both a high sensitivity (89%) and specificity (91%) for SLE, while H2Bpac exhibited a high specificity (96%) but lower sensitivity (69%). Reactivity with H3pme appeared not specific for SLE. Anti-H4pac and anti-H2Bpac reactivity demonstrated a high correlation with disease activity. Moreover, patients reacting with multiple modified histone peptides exhibited higher SLEDAI and lower C3 levels. SLE patients with renal involvement showed higher reactivity with H2B/H2Bpac and a more pronounced reactivity with the modified equivalent of H3pme and H2Bpac. In conclusion, reactivity with H4pac and H2Bpac is specific for SLE patients and correlates with disease activity, whereas reactivity with H2Bpac is in particular associated with lupus nephritis.
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Autoantibodies in Rheumatoid Arthritis: Historical Background and Novel Findings - Sokolova, Maria; Schett, Georg; Steffen, Ulrike (Clinical Reviews in Allergy & Immunology, 2021)
Autoantibodies represent a hallmark of rheumatoid arthritis (RA), with the rheumatoid factor (RF) and antibodies against citrullinated proteins (ACPA) being the most acknowledged ones. RA patients who are positive for RF and/or ACPA (“seropositive”) in general display a different etiology and disease course compared to so-called “seronegative” patients. Still, the seronegative patient population is very heterogeneous and not well characterized. Due to the identification of new autoantibodies and advancements in the diagnosis of rheumatic diseases in the last years, the group of seronegative patients is constantly shrinking. Aside from antibodies towards various post-translational modifications, recent studies describe autoantibodies targeting some native proteins, further broadening the spectrum of recognized antigens. Next to the detection of new autoantibody groups, much research has been done to answer the question if and how autoantibodies contribute to the pathogenesis of RA. Since autoantibodies can be detected years prior to RA onset, it is a matter of debate whether their presence alone is sufficient to trigger the disease. Nevertheless, there is gathering evidence of direct autoantibody effector functions, such as stimulation of osteoclastogenesis and synovial fibroblast migration in in vitro experiments. In addition, autoantibody positive patients display a worse clinical course and stronger radiographic progression. In this review, we discuss current findings regarding different autoantibody types, the underlying disease-driving mechanisms, the role of Fab and Fc glycosylation and clinical implications.
CRIS-Team Scopus Importer:2021-09-17
Keywords: ACPA; Autoimmunity; Immunoglobulin; Rheumatoid arthritis

Autoantibodies Recognizing Secondary NEcrotic Cells Promote Neutrophilic Phagocytosis and Identify Patients With Systemic Lupus Erythematosus - Biermann, Mona; Boeltz, Sebastian; Pieterse, Elmar; Knopf, Jasmin; Rech, Jürgen; Bilyy, Rostyslav; Van Der Vlag, Johan; Tincani, Angela; Distler, Jörg; Krönke, Gerhard; Schett, Georg; Herrmann, Martin; et al. (Frontiers in Immunology, 2018)
Deficient clearance of apoptotic cells reportedly contributes to the etiopathogenesis of the autoimmune disease systemic lupus erythematosus (SLE). Based on this knowledge, we developed a highly specific and sensitive test for the detection of SLE autoantibodies (AAb) utilizing secondary NEcrotic cell (SNEC)-derived material as a substrate. The goal of the present study was to validate the use of SNEC as an appropriate antigen for the diagnosis of SLE in large cohort of patients. We confirmed the presence of apoptotically modified autoantigens on SNEC (dsDNA, high mobility group box 1 protein, apoptosis-associated chromatin modifications, e.g., histones H3-K27-me3; H2A/H4 AcK8,12,16; and H2B-AcK12). Anti-SNEC AAb were measured in the serum of 155 patients with SLE, 89 normal healthy donors (NHD), and 169 patients with other autoimmune connective tissue diseases employing SNEC-based indirect enzyme-linked immunosorbent assay (SNEC ELISA). We compared the test performance of SNEC ELISA with the routine diagnostic tests dsDNA Farr radioimmunoassay (RIA) and nucleosome-based ELISA (anti-dsDNA-NcX-ELISA). SNEC ELISA distinguished patients with SLE with a specificity of 98.9% and a sensitivity of 70.6% from NHD clearly surpassing RIA and anti-dsDNA-NcX-ELISA. In contrast to the other tests, SNEC ELISA significantly discriminated patients with SLE from patients with rheumatoid arthritis, primary anti-phospholipid syndrome, spondyloarthropathy, psoriatic arthritis, and systemic sclerosis. A positive test result in SNEC ELISA significantly correlated with serological variables and reflected the uptake of opsonized SNEC by neutrophils. This stresses the relevance of SNECs in the pathogenesis of SLE. We conclude that SNEC ELISA allows for the sensitive detection of pathologically relevant AAb, enabling its diagnostic usage. A positive SNEC test reflects the opsonization of cell remnants by AAb, the neutrophil recruitment to tissues, and the enhancement of local and systemic inflammatory responses.
EVALuna2:34144

Autoantibody-mediated bone loss - Harre, Ulrike; Kittan, Nicolai A.; Schett, Georg (Current Osteoporosis Reports, 2014)
In rheumatoid arthritis (RA), the presence of autoantibodies such as the rheumatoid factor and antibodies against citrullinated proteins is highly correlated with the severity of disease and bone loss. For many years, the involvement of autoantibodies in bone resorption has merely been attributed to enhanced tissue infiltration and the production of inflammatory cytokines that promote osteoclastogenesis. However, recent research provides evidence for a direct activation of osteoclasts and their precursors by autoantibodies, which is independent of inflammation. The depletion of B-cells with rituximab that substantially reduces autoantibody levels seems to be as effective as the well-established treatment with tumor necrosis factor-antagonists in RA patients that do not respond to methotrexate, highlighting the significance of autoantibodies for RA and bone los
EVALuna2:12934

Autoimmune Colitis and Subsequent CMV-induced Hepatitis After Treatment With Ipilimumab - Uslu, Ugur; Agaimy, Abbas; Hundorfean, Gheorghe; Harrer, Thomas; Schuler, Gerold; Heinzerling, Lucie (Journal of Immunotherapy, 2015)
Ipilimumab, a humanized CTLA-4 antibody, improves overall survival in patients with metastatic melanoma. However, immune-related adverse effects occur in about 65% of ipilimumab-treated patients and have to be adequately managed. A 55-year-old patient developed grade 3 autoimmune colitis 7 weeks after initiation of ipilimumab treatment and subsequently hepatitis with grade 3 elevation of transaminases and ?-glutamyl transferase. Colitis manifested with up to 18 watery and bloody stools per day and severe attacks of abdominal pain. After exclusion of infectious causes, immunosuppression with corticosteroids was initiated. Because of recurrent abdominal pain, spontaneous perforation of the colon had to be excluded. Elevated liver function tests (grade 3 CTCAE) occurred and differential diagnosis included immune-mediated, toxic, and viral hepatitis. It is interesting to note that, not an immune-mediated but a cytomegalovirus-induced hepatitis was diagnosed by serum blood tests and liver biopsy and was subsequently successfully treated. Careful elaboration of the patient under immunotherapy was essential as further immunosuppression mandatory for autoimmune hepatitis would have worsened the viral hepatitis. In conclusion, cytomegalovirus reactivation should be included in the differential in patients under immunotherapy with checkpoint inhibitors and has to be considered as a cause for morbidity.
EVALuna2:1966

Autoimmune, rheumatic, chronic inflammatory diseases: Neutrophil extracellular traps on parade - Podolska, Malgorzata; Mahajan, Aparna; Knopf, Jasmin; Hahn, Jonas; Boeltz, Sebastian; Munoz, Luis Enrique; Bilyy, Rostyslav; Herrmann, Martin (Autoimmunity, 2018)
Rheumatic diseases are a group of inflammatory conditions that affect joints and connective tissues and are often accompanied by pain and restriction of motility. In many of these diseases, autoantibodies develop that react with molecules/structures commonly found hidden in neutrophils. Neutrophil extracellular trap (NET) formation and release is considered a defense mechanism against pathogens or endogenous danger signals and it has been associated with initial inflammatory responses. NETs are also endowed with an important resolution potential based on its intrinsic enzymatic activity, but in the case they are not timely removed from the crime scene they might modulate subsequent immune responses and contribute to the pathogenesis of chronic inflammatory diseases. In this review, we will summarize the actual knowledge about the multifaceted roles of NETs in the etiology and pathogenesis of rheumatic autoimmune diseases.
EVALuna2:34670

Autoimmune, rheumatic, chronic inflammatory diseases: Neutrophil extracellular traps on parade - Podolska, Malgorzata; Mahajan, Aparna; Knopf, Jasmin; Hahn, Jonas; Boeltz, Sebastian; Munoz, Luis Enrique; Bilyy, Rostyslav; Herrmann, Martin (Autoimmunity Reviews, 2018)
Keywords: Neutrophil extracellular traps; rheumatic diseases; antiphospholipid syndrome; rheumatoid arthritis; systemic lupus erythematosus

Autoimmunity as a trigger for structural bone damage in rheumatoid arthritis - Schett, Georg (Modern Rheumatology, 2017)
Bone loss is a central feature of rheumatoid arthritis (RA). It is considered to represent a sign of irreversible structural damage triggered by chronic inflammation. Recent evidence, however, suggests that autoantibodies are an important and earlier driver for bone damage in RA. This article summarizes current evidence for the role of RA-related autoantibodies in mediating bone loss. Rheumatoid factor and antibodies recognizing modified (citrullinated) proteins are the central features of autoimmunity in RA patients. Despite being used as diagnostic markers for many years, ascertaining the differentiation of RA from other forms of inflammatory arthritides, the role of these antibodies as pathogenic players has long been unrecognized. Recently, several pieces of evidence suggested that bone-resorbing osteoclasts are highly responsive to RA-related autoantibodies, providing a novel link between autoimmunity and bone. These developments have allowed unraveling the underlying mechanisms, which are responsible for the well-known clinical observation that RA-related autoantibodies are associated with a more severe disease course. At present, rheumatoid factor and antibodies recognizing citrullinated proteins are considered as potent osteoclast inducers and triggers for bone loss in arthritis.
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Autoinflammation and autoimmunity across rheumatic and musculoskeletal diseases - Szekanecz, Zoltan; Mcinnes, Iain B.; Schett, Georg; Szamosi, Szilvia; Benko, Szilvia; Szucs, Gabriella (Nature Reviews Rheumatology, 2021)
Most rheumatic and musculoskeletal diseases (RMDs) can be placed along a spectrum of disorders, with autoinflammatory diseases (including monogenic systemic autoinflammatory diseases) and autoimmune diseases (such as systemic lupus erythematosus and antiphospholipid syndrome) representing the two ends of this spectrum. However, although most autoinflammatory diseases are characterized by the activation of innate immunity and inflammasomes and classical autoimmunity typically involves adaptive immune responses, there is some overlap in the features of autoimmunity and autoinflammation in RMDs. Indeed, some ‘mixed-pattern’ diseases such as spondyloarthritis and some forms of rheumatoid arthritis can also be delineated. A better understanding of the pathogenic pathways of autoinflammation and autoimmunity in RMDs, as well as the preferential cytokine patterns observed in these diseases, could help us to design targeted treatment strategies.
CRIS-Team Scopus Importer:2021-08-13

Autoinflammation leading to autoimmunity in adult-onset Still’s disease: more than simple coincidence? - Valor-Mendez, Larissa; Manger, Bernhard; Cavallaro, Alexander Josef; Achenbach, Stephan; Schett, Georg; Rech, Jürgen (European Journal of Medical Research, 2021)
Background: Adult-onset Still’s disease (AOSD) should be considered in the differential diagnosis of patients with endocarditis, with or without a cardiac decompensation. Case presentation: We report the case of a 68-year-old Caucasian male diagnosed with AOSD after an initial acute manifestation of endocarditis with severe aortic acute manifestation of endocarditis with severe aortic insufficiency. The histological findings revealed Libman–Sacks endocarditis. He was treated with the IL-1 receptor inhibitor anakinra. Two years later the patient developed a symptomatic dilated cardiomyopathy with reduced ejection fraction (23.5%) and functional anti-beta-1-adrenergic receptor antibodies, which was initially treated with plasmapheresis; anakinra was maintained. While his AOSD symptoms responded well, our patient presented with recurrent arthritis in multiple joints, dual-energy CT showed urate deposition compatible with a gouty arthropathy. Over 7 years, he presented with recurrent episodes of arthritis and the adjustment of dosages of colchicine and febuxostat was needed. In 2018, our patient died due to a deterioration of his underlying cardiac disease. Conclusions: Only two cases with initial endocarditis prior to AOSD diagnosis have been published, and we are not aware of any other cases reporting -β1AR-Ab development with DCM and gout in the setting of AOSD treated with anakinra.
CRIS-Team Scopus Importer:2021-10-01
Keywords: Adult-onset Still’s disease; Anakinra; ANTI-beta-1-adrenergic receptor antibodies; Dilated cardiomyopathy; Gout; IL-1 receptor inhibitor; Libman–Sacks endocarditis

Autologous hematopoietic stem cell transplantation for systemic sclerosis: Position statement of the stem cell therapy working party of the German Society of Rheumatology Autologe hämatopoetische Stammzelltransplantation bei systemischer Sklerose: Positionspapier des Arbeitskreises Stammzelltherapie der Deutschen Gesellschaft für Rheumatologie - Alexander, T.; Henes, J.; Distler, Jörg; Schmalzing, M.; Blank, N.; Kötter, I.; Hiepe, F. (Zeitschrift für Rheumatologie, 2020)
There have been three randomized controlled trials on autologous hematopoietic stem cell transplantation (AHSCT) in systemic sclerosis (SSc) that demonstrated significant superiority with respect to survival, improvement of cutaneous fibrosis, lung function and quality of life compared to standard treatment; however, these advantages must be carefully weighed against the transplantation-related risks. For this reason, an expert group from the stem cell therapy working party of the German Society for Rheumatology (DGRh) has now developed recommendations for the use of AHSCT in SSc. Based on the high-quality evidence, AHSCT is considered as the standard option for the treatment of selected SSc patients. Potential candidates for AHSCT are those with early, rapidly progressive, diffuse cutaneous SSc with visceral manifestations who have not yet developed severe damage to internal organs. A close cooperation between rheumatologists and transplantation centers is crucial for optimizing patient selection and treatment outcomes.
CRIS-Team Scopus Importer:2020-05-02
Keywords: Autologous stem cell transplantation; Cell therapy; DGRh; Guidelines; Systemic sclerosis

Autologous hematopoietic stem cell transplantation improves long-term survival-data from a national registry - Blank, Norbert; Schmalzing, Marc; Moinzadeh, Pia; Oberste, Max; Siegert, Elise; Mueller-Ladner, Ulf; Riemekasten, Gabriela; Guenther, Claudia; Koetter, Ina; Zeidler, Gabriele; Pfeiffer, Christiane; Juche, Aaron; et al. (Arthritis Research & Therapy, 2022)
Background Current recommendations on the management of systemic sclerosis (SSc) suggest that autologous hematopoietic stem cell therapy (HSCT) can be a rescue therapy for patients with rapidly progressive SSc. Objectives To assess the safety and efficacy of HSCT for patients with SSc and to compare these with non-HSCT patients in a control cohort with adjusted risk factors. Methods A retrospective analysis of data from the multicentric German network for systemic scleroderma (DNSS) with 5000 patients with SSc. Control groups consisted of all patients with diffuse cutaneous (dc)-SSc (group A) and an adjusted high-risk cohort of male patients with Scl70-positive dc-SSc (group B). Results Eighty SSc patients received an HSCT 4.1 +/- 4.8 years after SSc diagnosis. Among them, 86.3% had dc-SSc, 43.5% were males, and 71.3% were positive for Scl70 antibodies. The control group A (n=1513) showed a significant underrepresentation of these risk factors for mortality. When the survival of the control group B (n=240) was compared with the HSCT group, a lower mortality of the latter was observed instead. Within 5 years after HSCT, we observed an improvement of the mRSS from 17.6 +/- 11.5 to 11.0 +/- 8.5 (p=0.001) and a stabilization of the DLCO. We did not see differences in transplant-related mortality between patients who received HSCT within 3 years after SSc diagnosis or later. Conclusion Our analysis of real-life data show that the distribution of risk factors for mortality is critical when HSCT cohorts are compared with non-HSCT control groups.
CRIS-Team WoS Importer:2022-12-02

Automated Bone Density Measurements using Deep Learning - Folle, Lukas; Meinderink, Timo; Simon, David; Liphardt, Anna-Maria; Thies, Mareike; Krönke, Gerhard; Schett, Georg; Kleyer, Arnd; Maier, Andreas (23, 2022)
Introduction Hand bone loss is characteristic of rheumatoid or psoriatic arthritis, which clinically manifests with pain, swelling, and stiffness of the affected joints. Typically, hand joints are affected already in the early stages of arthritis1. High-resolution peripheral quantitative computed tomography (HR-pQCT) allows to visualize structural changes in the bone in 3D and enables measurements derived from the scans of the patient’s hand such as the volume of a bone. For this, a segmentation of the scans is necessary, which is reader-dependent and time-consuming, especially in challenging cases2. This work aims to replace this manual expert segmentation with a neural network (figure 1). Materials and methods The segmentation network was trained using 541 HR-pQCT patient scans (RA, PsA, and OA patients with motion grades up to 3) as input and the corresponding expert segmentation of the second metacarpal bone as reference. To optimize the parameters of the network, the current prediction was compared with the expert segmentation using the Dice coefficient. Pre-processing steps included resizing, flipping of left hands, and intensity normalization. The architecture of the segmentation network is based on the 2D U-Net, which was pre-trained on ImageNet. The predictions were resized to the original resolution and converted to the scanner-specific data format as post-processing steps. The scanner then calculated the average bone-mineral density (D100) based on the scan and the corresponding network-generated segmentation. The scans were split into training, validation, and testing with ratios of 70%, 20%, and 10% respectively. Results and discussion The bone segmentation using the neural network on the test set reached a Dice coefficient of 97.2%. A quantitative comparison of the network prediction (blue) and the expert annotation (red) is presented in figure 2. The deviation of the expert annotation from the bone contour is likely due to the shift of the scan when exceeding the specified maximum number of slices of the scanner. Since the neural network operates on a slice level, such deviations are implicitly accounted for. The results of the vBMD analysis are summarized in figure 3. Significant Pearson correlation with 0.999 (p<.001) was achieved for the D100 on the test set. Still, a slight offset is present in the predictions, which might lead to underestimating the D100. However, this could be eliminated in a calibration step beforehand. Conclusion Neural networks can be used to generate accurate segmentations of the MCP2 head even with erosions present and can be integrated into the clinical workflow with a performance on par with expert annotators and save time through the automation of the annotation process. <
Keywords: deep learning; bone imaging; segmentation

Automated high-throughput analysis of B cell spreading on immobilized antibodies with whole slide imaging - Wiesmann, Veit; Reimer, Dorothea; Franz, Daniela; Huettmayer, Hanna; Mielenz, Dirk; Wittenberg, Thomas (Current Directions in Biomedical Engineering, 2015)
UnivIS-Import:2017-12-18:Pub.2015.tech.IMMD.IMMD9.automa_7
Keywords: automated image analysis; whole slide scanning; high-throughput analysis; B cell receptor; spreading

Automated three-dimensional registration of high-resolution peripheral quantitative computed tomography data to quantify size and shape changes of arthritic bone erosions - Toepfer, Dominique; Gerner, Bastian; Finzel, Stephanie; Kraus, Sebastian; Museyko, Oleg; Schett, Georg; Engelke, Klaus (Rheumatology, 2015)
To monitor size and shape changes of bone erosions and changes in BMD in the vicinity of the erosion and in the periarticular trabecular compartment of patients with RA using high-resolution peripheral quantitative CT (HR-pQCT) imaging and to compare an automated three-dimensional (3D) image processing technique with manual measurements of erosion width and depth.The shape of 40 bone erosions and composition of bone around the erosions were analysed in the MCP joints of 22 RA patients both manually and by semi-automated 3D image processing at two different time points. Periosteal segmentation was performed using volume growing and morphological operations. Image registration was applied for transfer of baseline segmentations to follow-up datasets.Eight erosions decreased in size, 6 increased and 28 remained stable. Increasing erosions were more spherical and smaller at baseline compared with decreasing or stable erosions. BMD in the vicinity of shrinking erosions increased, while it decreased next to expanding erosions. There was moderate agreement in the determination of erosion volume between semi-automated and manual measurements, but agreement was poor when assessing changes in volume over time.Longitudinal changes in erosion size and shape and of BMD in the vicinity of an erosion can be measured. BMD changes are associated with progression and regression of erosions. However, the semi-automated and manual approaches did not classify longitudinal changes of erosion volume in the same way. Further research is necessary to define the nature of these differences.
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Automatic Finger Joint Detection for Volumetric Hand Imaging - Bopp, Johannes; Unberath, Mathias; Steidl, Stefan; Fahrig, Rebecca; Oliveira, Isabelle; Kleyer, Arnd; Maier, Andreas (Bildverarbeitung für Medizin, 2016)
UnivIS-Import:2017-12-18:Pub.2016.tech.IMMD.IMMD5.automa_9

Autophagy regulates TNFα-mediated joint destruction in experimental arthritis - Lin, Neng-Yu; Beyer, Christian; Gießl, Andreas; Kireva, Trayana; Scholtysek, Carina; Uderhardt, Stefan; Munoz, Luis Enrique; Dees, Clara; Distler, Alfiya; Wirtz, Stefan; Krönke, Gerhard; Spencer, Brian; et al. (Annals of the Rheumatic Diseases, 2013)
Objectives: Autophagy is a homeostatic process to recycle dispensable and damaged cell organelles. Dysregulation of autophagic pathways has recently been implicated in the pathogenesis of various diseases. Here, we investigated the role of autophagy during joint destruction in arthritis. Methods: Autophagy in osteoclasts was analysed in vitro and ex vivo by transmission electron microscopy, Western blotting and immunohistochemistry for Beclin1 and Atg7. Small molecule inhibitors, LysMCre-mediated knockout of Atg7 and lentiviral overexpression of Beclin1 were used to modulate autophagy in vitro and in vivo. Osteoclast differentiation markers were quantified by realtime PCR. The extent of bone and cartilage destruction was analysed in human tumour necrosis factor α transgenic (hTNFα tg) mice after adoptive transfer with myeloid specific Atg7-deficient bone marrow. Results: Autophagy was activated in osteoclasts of human rheumatoid arthritis (RA) showing increased expression of Beclin1 and Atg7. TNFα potently induced the expression of autophagy-related genes and activated autophagy in vitro and in vivo. Activation of autophagy by overexpression of Beclin1-induced osteoclastogenesis and enhanced the resorptive capacity of cultured osteoclasts, whereas pharmacologic or genetic inactivation of autophagy prevented osteoclast differentiation. Arthritic hTNFα tg mice transplanted with Atg7fl/fl×LysMCre+ bone marrow cells (BMC) showed reduced numbers of osteoclasts and were protected from TNFα-induced bone erosion, proteoglycan loss and chondrocyte death. Conclusions: These findings demonstrate that autophagy is activated in RA in a TNFα-dependent manner and regulates osteoclast differentiation and bone resorption. We thus provide evidence for a central role of autophagy in joint destruction in RA.
CRIS-Team Scopus Importer:2020-11-20

Autopsy versus clinical findings in patients with systemic sclerosis in a case series from patients of the EUSTAR database - Sandmeier, B.; Jaeger, V. K.; Nagy, G.; Carreira, P. E.; Tzankov, A.; Widuchowska, M.; Antic, M.; Distler, O.; Reichert, H.; Distler, Jörg; Walker, U. A.; Huegle, T. (Clinical and Experimental Rheumatology, 2015)
Subclinical organ pathology occurs regularly in systemic sclerosis (SSc) and affects correct prognosis as well as treatment choices. We aimed to evaluate autopsy data for organ involvement with subsequent correlation to clinical data in order to assess discrepancies in pathological and clinical findings in SSc.A standardised autopsy questionnaire from diseased patients registered in the European Scleroderma Trials and Research group (EUSTAR) cohort was analysed on cause of death and various manifestations in different organ systems. Clinical data obtained from the EUSTAR database of the corresponding patients including cause of death and disease manifestations of lung, heart, kidney, gastrointestinal, skin or musculoskeletal organ involvement were retrospectively analysed and compared to autopsy data.11 patients (6 women, 5 male) aged between 23 and 84 were included. Cause of death defined by pathologist and clinician were identical in 9/11 cases. In 8 individuals, cause of death was related to heart and lung pathologies. Heart and lung involvement (both 10/11) were the most frequently detected organ involvement at autopsy. Here, myocardial fibrosis occurred in 66% and lung fibrosis in 50% of the patients. Clinically, diastolic function abnormalities (6/11), conduction block (4/11), reduced DCLO (6/11) and dyspnea (8/11) were the most prevalent cardiopulmonary findings. For heart and renal involvement we found higher prevalence in autopsy than by clinical diagnosis. Especially myocardial fibrosis and renal arteriosclerosis were only obtained by autopsy in several individuals.Clinical diagnostic procedures are limited in detection of end-organ damage, especially for cardiac involvement. All the more post mortem examinations are needed for quality verification of clinical diagnosis and might help as to better understand the disease processes as well as to improve patient care.
EVALuna2:13156

A virtual reality based app to educate health care professionals and medical students about inflammatory arthritis: Feasibility study - Klemm, Philipp; Kleyer, Arnd; Tascilar, Koray; Schuster, Louis; Meinderink, Timo; Steiger, Florian; Lange, Uwe; Möller-Ladner, Ulf; Knitza, Johannes; Sewerin, Philipp; Mucke, Johanna; Pfeil, Alexander; et al. (JMIR Serious Games, 2021)
Background: Inflammatory arthritides (IA) such as rheumatoid arthritis or psoriatic arthritis are disorders that can be difficult to comprehend for health professionals and students in terms of the heterogeneity of clinical symptoms and pathologies. New didactic approaches using innovative technologies such as virtual reality (VR) apps could be helpful to demonstrate disease manifestations as well as joint pathologies in a more comprehensive manner. However, the potential of using a VR education concept in IA has not yet been evaluated. Objective: We evaluated the feasibility of a VR app to educate health care professionals and medical students about IA. Methods: We developed a VR app using data from IA patients as well as 2D and 3D-visualized pathological joints from X-ray and computed tomography generated images. This VR app (Rheumality) allows the user to interact with representative arthritic joint and bone pathologies of patients with IA. In a consensus meeting, an online questionnaire was designed to collect basic demographic data (age, sex); profession of the participants; and their feedback on the general impression, knowledge gain, and potential areas of application of the VR app. The VR app was subsequently tested and evaluated by health care professionals (physicians, researchers, and other professionals) and medical students at predefined events (two annual rheumatology conferences and academic teaching seminars at two sites in Germany). To explore associations between categorical variables, the ? 2 or Fisher test was used as appropriate. Two-sided P values =.05 were regarded as significant. Results: A total of 125 individuals participated in this study. Among them, 56% of the participants identified as female, 43% identified as male, and 1% identified as nonbinary; 59% of the participants were 18-30 years of age, 18% were 31-40 years old, 10% were 41-50 years old, 8% were 51-60 years old, and 5% were 61-70 years old. The participants (N=125) rated the VR app as excellent, with a mean rating of 9.0 (SD 1.2) out of 10, and many participants would recommend use of the app, with a mean recommendation score of 3.2 (SD 1.1) out of 4. A large majority (120/125, 96.0%) stated that the presentation of pathological bone formation improves understanding of the disease. We did not find any association between participant characteristics and evaluation of the VR experience or recommendation scores. Conclusions: The data show that IA-Targeting innovative teaching approaches based on VR technology are feasible.
CRIS-Team Scopus Importer:2021-06-04
Keywords: Feasibility; Inflammatory arthritis; Psoriatic arthritis; Rheumatoid arthritis; Virtual reality

A web platform for the network analysis of high-throughput data in melanoma and its use to investigate mechanisms of resistance to anti-PD1 immunotherapy - Dreyer, Florian; Cantone, Martina; Eberhardt, Martin; Jaitly, Tanushree; Walter, Lisa; Wittmann, Jürgen; Gupta, Shailendra; Khan, Faiz M.; Wolkenhauer, Olaf; Puetzer, Brigitte M.; Jäck, Hans-Martin; Heinzerling, Lucie; et al. (Biochimica et Biophysica Acta - Molecular Basis of Disease, 2018)
Cellular phenotypes are established and controlled by complex and precisely orchestrated molecular networks. In cancer, mutations and dysregulations of multiple molecular factors perturb the regulation of these networks and lead to malignant transformation. High-throughput technologies are a valuable source of information to establish the complex molecular relationships behind the emergence of malignancy, but full exploitation of this massive amount of data requires bioinformatics tools that rely on network-based analyses. In this report we present the Virtual Melanoma Cell, an online tool developed to facilitate the mining and interpretation of high-throughput data on melanoma by biomedical researches. The platform is based on a comprehensive, manually generated and expert-validated regulatory map composed of signaling pathways important in malignant melanoma. The Virtual Melanoma Cell is a tool designed to accept, visualize and analyze user-generated datasets. It is available at: https://www.vcells.net/melanoma. To illustrate the utilization of the web platform and the regulatory map, we have analyzed a large publicly available dataset accounting for anti-PD1 immunotherapy treatment of malignant melanoma patients.
EVALuna2:34379
Keywords: Therapy resistance; Databases; Network genomics; Systems biology; Immunotherapy; Melanoma

A Yoga Exercise App Designed for Patients With Axial Spondylarthritis: Development and User Experience Study - Truong, Minh Tam; Nwosu, Obioma Bertrand; Gaytan Torres, Maria Elena; Segura Vargas, Maria Paula; Seifer, Ann-Kristin; Nitschke, Marlies; Ibrahim, Alzhraa; Knitza, Johannes; Krusche, Martin; Eskofier, Björn; Schett, Georg; Morf, Harriet (JMIR Formative Research, 2022)
Background: Besides anti-inflammatory medication, physical exercise represents a cornerstone of modern treatment for patients with axial spondyloarthritis (AS). Digital health apps (DHAs) such as the yoga app YogiTherapy could remotely empower patients to autonomously and correctly perform exercises. Objective: This study aimed to design and develop a smartphone-based app, YogiTherapy, for patients with AS. To gain additional insights into the usability of the graphical user interface (GUI) for further development of the app, this study focused exclusively on evaluating users’ interaction with the GUI. Methods: The development of the app and the user experience study took place between October 2020 and March 2021. The DHA was designed by engineering students, rheumatologists, and patients with AS. After the initial development process, a pilot version of the app was evaluated by 5 patients and 5 rheumatologists. The participants had to interact with the app’s GUI and complete 5 navigation tasks within the app. Subsequently, the completion rate and experience questionnaire (attractiveness, perspicuity, efficiency, dependability, stimulation, and novelty) were completed by the patients. Results: The results of the posttest questionnaires showed that most patients were already familiar with digital apps (4/5, 80%). The task completion rates of the usability test were 100% (5/5) for the tasks T1 and T2, which included selecting and starting a yoga lesson and navigating to an information page. Rheumatologists indicated that they were even more experienced with digital devices (2/5, 40% experts; 3/5, 60% intermediates). In this case, they scored task completion rates of 100% (5/5) for all 5 usability tasks T1 to T5. The mean results from the User Experience Questionnaire range from −3 (most negative) to +3 (most positive). According to rheumatologists’ evaluations, attractiveness (mean 2.267, SD 0.401) and stimulation (mean 2.250, SD 0.354) achieved the best mean results compared with dependability (mean 2.000, SD 0.395). Patients rated attractiveness at a mean of 2.167 (SD 0.565) and stimulation at a mean of 1.950 (SD 0.873). The lowest mean score was reported for perspicuity (mean 1.250, SD 1.425). Conclusions: The newly developed and tested DHA YogiTherapy demonstrated moderate usability among rheumatologists and patients with rheumatic diseases. The app can be used by patients with AS as a complementary treatment. The initial evaluation of the GUI identified significant usability problems that need to be addressed before the start of a clinical evaluation. Prospective trials are also needed in the second step to prove the clinical benefits of the ap

A young female rheumatic patient: Only an early treatment helps to retain the mobility Eine junge rheumapatientin: Nur eine frühzeitige behandlung hilft, die beweglichkeit zu erhalten - Waltering, Isabel; Rech, Jürgen; Derendorf, Hartmut (Deutsche Apotheker Zeitung, 2012)
CRIS-Team Scopus Importer:2021-02-03

B.1.617.2 enters and fuses lung cells with increased efficiency and evades antibodies induced by infection and vaccination - Arora, Prerna; Sidarovich, Anzhalika; Krüger, Nadine; Kempf, Amy; Nehlmeier, Inga; Graichen, Luise; Moldenhauer, Anna Sophie; Winkler, Martin S.; Schulz, Sebastian; Jäck, Hans-Martin; Stankov, Metodi V.; Behrens, Georg M.N.; et al. (Cell Reports, 2021)
The Delta variant of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), B.1.617.2, emerged in India and has spread to over 80 countries. B.1.617.2 replaced B.1.1.7 as the dominant virus in the United Kingdom, resulting in a steep increase in new infections, and a similar development is expected for other countries. Effective countermeasures require information on susceptibility of B.1.617.2 to control by antibodies elicited by vaccines and used for coronavirus disease 2019 (COVID-19) therapy. We show, using pseudotyping, that B.1.617.2 evades control by antibodies induced upon infection and BNT162b2 vaccination, although to a lesser extent as compared to B.1.351. We find that B.1.617.2 is resistant against bamlanivimab, a monoclonal antibody with emergency use authorization for COVID-19 therapy. Finally, we show increased Calu-3 lung cell entry and enhanced cell-to-cell fusion of B.1.617.2, which may contribute to augmented transmissibility and pathogenicity of this variant. These results identify B.1.617.2 as an immune evasion variant with increased capacity to enter and fuse lung cells.
CRIS-Team Scopus Importer:2021-10-22
Keywords: antibody; B.1.617.2; COVID-19; neutralization; SARS-CoV-2; spike

BAFFR activates PI3K/AKT signaling in human naive but not in switched memory B cells through direct interactions with B cell antigen receptors - Sevdali, Eirini; Block, Violeta; Lataretu, Marie; Li, Huiying; Smulski, Cristian R.; Briem, Jana Susann; Heitz, Yannic; Fischer, Beate; Ramirez, Neftali Jose; Grimbacher, Bodo; Jäck, Hans-Martin; Voll, Reinhard E.; et al. (Cell Reports, 2022)
Binding of BAFF to BAFFR activates in mature B cells PI3K/AKT signaling regulating protein synthesis, metabolic fitness, and survival. In humans, naive and memory B cells express the same levels of BAFFR, but only memory B cells seem to survive without BAFF. Here, we show that BAFF activates PI3K/AKT only in naive B cells and changes the expression of genes regulating migration, proliferation, growth, and survival. BAFF-induced PI3K/AKT activation requires direct interactions between BAFFR and the B cell antigen receptor (BCR) components CD79A and CD79B and is enhanced by the AKT coactivator TCL1A. Compared to memory B cells, naive B cells express more surface BCRs, which interact better with BAFFR than IgG or IgA, thus allowing stronger responses to BAFF. As ablation of BAFFR in naive and memory B cells causes cell death independent of BAFF-induced signaling, BAFFR seems to act also as an intrinsic factor for B cell survival.
CRIS-Team Scopus Importer:2022-07-08
Keywords: BAFF; BAFFR; BCR; CP: Immunology; human memory B cells; PI3K signaling

Baricitinib Improves Bone Biomechanical Properties in Rheumatoid Arthritis (RA) - Results of a Prospective Interventional Study - Kemenes, Stephan; Hartmann, Fabian; Tascilar, Koray; Simon, David; Bayat, Sara; Krönke, Gerhard; Mendez, Larissa Valor; Schuster, Louis; Liphardt, Anna-Maria; Schett, Georg; Kleyer, Arnd (ARTHRITIS & RHEUMATOLOGY, 2022)
CRIS-Team WoS Importer:2023-01-13

Baricitinib Improves Bone Properties and Biomechanics in Patients With Rheumatoid Arthritis: Results of the Prospective Interventional BARE BONE Trial - Simon, David; Minopoulou, Ioanna; Kemenes, Stephan; Bayat, Sara; Tascilar, Koray; Mutlu, Melek Yalcin; Valor-Méndez, Larissa; Krönke, Gerhard; Hueber, Axel J.; Schett, Georg; Kleyer, Arnd (Arthritis and Rheumatology, 2023)
Objective: Rheumatoid arthritis (RA) is characterized by erosive joint damage, deterioration of bone mass, and biomechanics. Preclinical evidence suggests a beneficial effect of Janus kinase inhibition (JAKi) on bone properties, but clinical data are scarce to date. In this study, we evaluated the effect of JAKi through baricitinib (BARI) on 1) volumetric bone mineral density (vBMD), bone microstructure, biomechanics, and erosion repair and 2) synovial inflammation in RA patients. Methods: Prospective, single-arm, interventional, open-label, single-center phase 4 study in RA patients with pathological bone status and clinical indication of JAKi (BARE BONE trial). Participants received BARI (4 mg/day) over 52 weeks. To assess bone properties and synovial inflammation, high-resolution computed tomography scans and magnetic resonance imaging were performed at baseline (BL), week 24, and week 52. Clinical response and safety were monitored. Results: Thirty RA patients were included. BARI significantly improved disease activity (Disease Activity Score in 28 joints using the erythrocyte sedimentation rate: 4.82 ± 0.90 to 2.71 ± 0.83) and synovial inflammation (RAMRIS synovitis score: 5.3 [4.2] to 2.7 [3.5]). We observed a significant improvement in trabecular vBMD with a mean change of 6.11 mgHA/mm3 (95% confidence interval [95% CI] 0.01–12.26). Biomechanical properties also improved with mean change from baseline in estimated stiffness of 2.28 kN/mm (95% CI 0.30–4.25) and estimated failure load of 98.8 N (95% CI 15.9–181.7). The number and size of erosions in the metacarpal joints remained stable. No new safety signals with BARI treatment were observed. Conclusion: Bones of RA patients improve with BARI therapy, as shown by an increase in trabecular bone mass and an improvement of biomechanical properties.
CRIS-Team Scopus Importer:2023-09-29

BARICITINIB LEADS TO RAPID AND PERSISTENT RESOLUTION OF SYNOVITIS AS MEASURED BY HAND MRI IN PATIENTS WITH ACTIVE RHEUMATOID ARTHRITIS (RA) FAILING CS/BDMARD THERAPY - Kemenes, S.; Bayat, Sara; Simon, David; Krönke, Gerhard; Bohr, D.; Valor, L.; Hartmann, F.; Schuster, Louis; Tascilar, Koray; Schett, Georg; Kleyer, Arnd (ANNALS OF THE RHEUMATIC DISEASES, 2022)
CRIS-Team WoS Importer:2022-11-04

BASELINE CLINICAL DISEASE ACTIVITY IS NOT CRITICAL FOR PREDICTING REMISSION OF ADULTS ONSET STILL'S DISEASE - Groetsch, J.; Tascilar, Koray; Schett, Georg; Foell, D.; Rech, Jürgen (ANNALS OF THE RHEUMATIC DISEASES, 2022)
CRIS-Team WoS Importer:2022-11-04

Baseline Structural Damage Predicts Response to Abatacept in Patients with Psoriatic Arthritis: A Post Hoc Analysis from a Phase III Study - Schett, Georg; Lehman, T.; Ahmad, H. A.; Johnsen, A.; Banerjee, S.; Mease, Philip J. (2017)
EVALuna2:33442

B cells are critical for autoimmune pathology in Scurfy mice. - Aschermann, Susanne; Lehmann, Christian; Mihai, Sidonia; Schett, Georg; Dudziak, Diana; Nimmerjahn, Falk (Proceedings of the National Academy of Sciences of the United States of America, 2013)
Impaired regulatory T-cell function results in a severe chronic autoimmune disease affecting multiple organs in Scurfy mice and humans with the immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome. Previous studies have shown that T helper cells but not cytotoxic T cells are critical for the disease pathology. Whether this T-cell subset is responsible directly for tissue inflammation or rather indirectly via the interaction with B cells or myeloid cells is largely unknown. To study this and to identify potential therapeutic targets for this lethal disease we investigated the contribution of B cells to this complex autoimmune phenotype. We show that B cells and the production of autoantibodies plays a major role for skin, liver, lung, and kidney inflammation and therapeutic depletion of B cells resulted in reduced tissue pathology and in prolonged survival. In contrast, the absence of B cells did not impact systemic T-cell activation and hyperreactivity, indicating that autoantibody production by B cells may be a major factor for the autoimmune pathology in mice deficient for regulatory T cells.

B Cell Speed and B-FDC Contacts in Germinal Centers Determine Plasma Cell Output via Swiprosin-1/EFhd2 - Reimer, Dorothea; Meyer-Hermann, Michael; Rakhymzhan, Asylkhan; Steinmetz, Tobit; Tripal, Philipp; Thomas, Jana; Böttcher, Martin; Mougiakakos, Dimitrios; Schulz, Sebastian; Urbanczyk, Sophia; Hauser, Anja E.; Niesner, Raluca A.; et al. (Cell Reports, 2020)
Plasma cells secreting affinity-matured antibodies develop in germinal centers (GCs), where B cells migrate persistently and directionally over defined periods of time. How modes of GC B cell migration influence plasma cell development remained unclear. Through genetic deletion of the F-actin bundling protein Swiprosin-1/EF-hand domain family member 2 (EFhd2) and by two-photon microscopy, we show that EFhd2 restrains B cell speed in GCs and hapten-specific plasma cell output. Modeling the GC reaction reveals that increasing GC B cell speed promotes plasma cell generation. Lack of EFhd2 also reduces contacts of GC B cells with follicular dendritic cells in vivo. Computational modeling uncovers that both GC output and antibody affinity depend quantitatively on contacts of GC B cells with follicular dendritic cells when B cells migrate more persistently. Collectively, our data explain how GC B cells integrate speed and persistence of cell migration with B cell receptor affinity.
CRIS-Team Scopus Importer:2020-08-14
Keywords: actin cytoskeleton; B cell receptor; differentiation; follicular dendritic cell; germinal center; migration; plasma cell; selection; Swiprosin-1/EFhd2; synapse

B cell-targeting chimeric antigen receptor T cells as an emerging therapy in neuroimmunological diseases - Haghikia, Aiden; Schett, Georg; Mougiakakos, Dimitrios (Lancet Neurology, 2024)
Background: Neuroimmunology research and development has been marked by substantial advances, particularly in the treatment of neuroimmunological diseases, such as multiple sclerosis, myasthenia gravis, neuromyelitis optica spectrum disorders, and myelin oligodendrocyte glycoprotein antibody disease. With more than 20 drugs approved for multiple sclerosis alone, treatment has become more personalised. The approval of disease-modifying therapies, particularly those targeting B cells, has highlighted the role of immunotherapeutic interventions in the management of these diseases. Despite these successes, challenges remain, particularly for patients who do not respond to conventional therapies, underscoring the need for innovative approaches. Recent developments: The approval of monoclonal antibodies, such as ocrelizumab and ofatumumab, which target CD20, and inebilizumab, which targets CD19, for the treatment of various neuroimmunological diseases reflects progress in the understanding and management of B-cell activity. However, the limitations of these therapies in halting disease progression or activity in patients with multiple sclerosis or neuromyelitis optica spectrum disorders have prompted the exploration of cell-based therapies, particularly chimeric antigen receptor (CAR) T cells. Initially successful in the treatment of B cell-derived malignancies, CAR T cells offer a novel therapeutic mechanism by directly targeting and eliminating B cells, potentially overcoming the shortcomings of antibody-mediated B cell depletion. Where next?: The use of CAR T cells in autoimmune diseases and B cell-driven neuroimmunological diseases shows promise as a targeted and durable option. CAR T cells act autonomously, penetrating deep tissue and effectively depleting B cells, especially in the CNS. Although the therapeutic potential of CAR T cells is substantial, their application faces hurdles such as complex logistics and management of therapy-associated toxic effects. Ongoing and upcoming clinical trials will be crucial in determining the safety, efficacy, and applicability of CAR T cells. As research progresses, CAR T cell therapy has the potential to transform treatment for patients with neuroimmunological diseases. It could offer extended periods of remission and a new standard in the management of autoimmune and neuroimmunological disorders.
CRIS-Team Scopus Importer:2024-05-24

BDCA2 Targeting of Human Plasmacytoid Dendritic Cells via CBS004 Reverts Dependent IFN Activation and Tissue Fibrosis in vitro and in vivo - Ross, Rebecca; Corinaldesi, Clarissa; Migneco, Gemma; El-Sherbiny, Yasser; Holmes, Steve; Distler, Jörg; Mckimmie, Clive; Del Galdo, Francesco (ARTHRITIS & RHEUMATOLOGY, 2019)
CRIS-Team WoS Importer:2020-02-07

Befragung zu den Arbeits-, Weiterbildungs- und Forschungsbedingungen von Assistenzärztinnen und -ärzten in der internistisch-rheumatologischen Weiterbildung – BEWUSST - Proft, Fabian; Vossen, Diana; Baraliakos, Xenofon; Berliner, Michael N.; Fleck, Martin; Keyßer, Gernot; Krause, Andreas; Lorenz, Hanns Martin; Manger, Bernhard; Schuch, Florian; Specker, Christof; Wollenhaupt, Jürgen; et al. (Zeitschrift für Rheumatologie, 2023)
Background: Data on the training and continuing education situation of residents in the field of internal medicine and rheumatology are not available for Germany. For this reason, the Commission for Education and Training of the German Society of Rheumatology (DGRh) initiated the BEWUSST survey on the working, training and research conditions of residents in rheumatology. Methods: A total of 102 questions on the topics of working conditions in everyday professional life, continuing medical education and training, compatibility of career and family, compatibility of work and research, perspectives as a rheumatologist and practical activities were included in an online questionnaire. Results: A total of 102 participants took part in the survey. Of the respondents 48.1% were satisfied with their professional situation, 40.2% of the participants were supervised by a specialist mentor and 54.9% were working as scientists during their work as a physician. A compatibility of family and career was possible for 34.7%. After completion of the residency 52.9% of the respondents aspired to a combined clinical and outpatient activity. Conclusion: Half of the trainee rheumatologists are satisfied with their professional activities, although mentoring of the assistants in training should be further improved. With respect to the desired combined clinical and outpatient activity, the existing options should be expanded or new professional fields of activity should be established, so that the specialty remains attractive for the upcoming generations.
CRIS-Team Scopus Importer:2023-08-25
Keywords: Compatibility of career and family; Compatibility of work and research; Fields of activity; Perspectives; Speciality of internal medicine and rheumatology

Besides strong inflammation, severe COVID-19 is determined by endothelial dysfunction and dysregulated cytokine networks - Ruhl, Louisa; Pink, Isabell; Kuehne, Jenny; Beushausen, Kerstin; Keil, Jana; Christoph, Stella; Sauer, Andrea; Boblitz, Lennart; Schmidt, Julius; David, Sascha; Jäck, Hans-Martin; Roth, Edith; et al. (EUROPEAN JOURNAL OF IMMUNOLOGY, 2021)
CRIS-Team WoS Importer:2022-03-11

beta(2)-m - a Trigger for NLRP3 Inflammasome Activation within Macrophages Promoting Multiple Myeloma Cell Proliferation - Hofbauer, Daniel; Mougiakakos, Dimitrios; Büttner-Herold, Maike; Neumann, Frank; Nolting, Jens; Bisht, Savita; Zeiser, Robert; Hamarsheh, Shaima'A; Ricagno, Stefano; Zaiss, Mario; Eberhardt, Martin; Böttcher, Martin; et al. (BLOOD, 2019)
CRIS-Team WoS Importer:2021-10-18

Big data in imaging - Sewerin, Philipp; Ostendorf, Benedikt; Hueber, Axel; Kleyer, Arnd (Zeitschrift für Rheumatologie, 2018)
Until now, most major medical advancements have been achieved through hypothesis-driven research within the scope of clinical trials. However, due to a multitude of variables, only a certain number of research questions could be addressed during a single study, thus rendering these studies expensive and time consuming. Big data acquisition enables a new data-based approach in which large volumes of data can be used to investigate all variables, thus opening new horizons. Due to universal digitalization of the data as well as ever-improving hard- and software solutions, imaging would appear to be predestined for such analyses. Several small studies have already demonstrated that automated analysis algorithms and artificial intelligence can identify pathologies with high precision. Such automated systems would also seem well suited for rheumatology imaging, since a method for individualized risk stratification has long been sought for these patients. However, despite all the promising options, the heterogeneity of the data and highly complex regulations covering data protection in Germany would still render a big data solution for imaging difficult today. Overcoming these boundaries is challenging, but the enormous potential advances in clinical management and science render pursuit of this goal worthwhile.
EVALuna2:34449

Bilateral Orbital IgG4-Related Disease with Systemic and Corneal Involvement Showing an Excellent Response to Steroid and Rituximab Therapy: Report of a Case with 11 Years Follow-Up - Berta, Agnes I.; Agaimy, Abbas; Braun, Joachim M.; Manger, Bernhard; Kruse, Friedrich Eduard; Holbach, Leonard (Orbit, 2015)
IgG4-related disease is a newly recognized fibro-inflammatory condition. The purpose of this report is to present a patient with 11 years of follow-up, who revealed characteristic features of IgG4-related disease with systemic, orbital and corneal involvement and showed a favorable response to steroids and rituximab treatment.
EVALuna2:6708

Bilateral vision loss in a patient with weight loss and neurologic symptoms - La Mancusa, Antonia; Rech, J.; Harrer, Thomas; Knorr, H.; Bergua, A. (Klinische Monatsblätter für Augenheilkunde, 2011)
EVALuna2:12701

Bildgebung bei der Psoriasisarthritis und Aspekte der röntgenologischen Progression - Baraliakos, X.; Kleyer, Arnd; Simon, David; Köhm, M.; Ohrndorf, S.; Sewerin, P. (Zeitschrift für Rheumatologie, 2019)
Psoriatic arthritis (PsA) is a heterogeneous multifactorial disease with musculoskeletal involvement, which can be manifested as monoarthritis, oligoarthritis or polyarthritis and in some patients can also affect the axial skeleton. The most frequent indications of inflammation are bone marrow edema and enthesitis. The early and differential diagnosis of PsA is a clinical challenge, particularly as a differential diagnosis from other inflammatory or degenerative diseases of joints. Inflammatory joint and tendon alterations in the region of the extremities and the spine can be visualized with high sensitivity by the use of magnetic resonance imaging (MRI), musculoskeletal sonography (US) and fluorescence optical imaging (FOI). The use of MRI has a prognostic value with respect to the further radiographic course of the disease, particularly in the initial stages of the disease. Structural damage can be specifically and also partially demonstrated 3‑dimensionally in peripheral joints and the spine by the use of computed tomography (CT) and conventional X‑ray imaging. High-resolution peripheral quantitative CT (HR-pQCT) in particular, can visualize pathophysiological processes and the morphological consequences even in early stages of the disease. The values of conventional X‑ray diagnostics, CT, MRI, musculoskeletal US and alternative imaging procedures are presented with respect to the diagnostics and prognosis of the progression of patients with PsA.
CRIS-Team Scopus Importer:2019-12-31
Keywords: Computed tomography; Conventional X‑ray imaging; Fluorescence optical imaging; Magnetic resonance imaging; Musculoskeletal ultrasound

Bimekizumab in patients with active psoriatic arthritis: results from a 48-week, randomised, double-blind, placebo-controlled, dose-ranging phase 2b trial - Ritchlin, Christopher T.; Kavanaugh, Arthur; Merola, Joseph F.; Schett, Georg; Scher, Jose U.; Warren, Richard B.; Gottlieb, Alice B.; Assudani, Deepak; Bedford-Rice, Kathy; Coarse, Jason; Ink, Barbara; McInnes, Iain B. (Lancet, 2020)
Background: Dual neutralisation of interleukin 17A (IL17A) and interleukin 17F (IL17F) is a potential novel therapeutic approach in psoriatic arthritis. We assessed bimekizumab, a monoclonal antibody that selectively neutralises IL17A and IL17F, in patients with active psoriatic arthritis. Methods: BE ACTIVE was a randomised, double-blind, placebo-controlled, dose-ranging phase 2b study done at 41 sites in the Czech Republic, Germany, Hungary, Poland, Russia, and the USA. Eligible patients aged 18 years or older with active adult-onset psoriatic arthritis and symptoms for at least 6 months were randomly assigned (1:1:1:1:1) to placebo, 16 mg bimekizumab, 160 mg bimekizumab, 160 mg bimekizumab with a one-off 320 mg loading dose, or 320 mg bimekizumab, which were administered as subcutaneous injections every 4 weeks for 12 weeks. After 12 weeks, patients assigned to the placebo and 16 mg bimekizumab groups were randomly reassigned (1:1) to either 160 mg or 320 mg bimekizumab, and all other patients remained on their originally assigned initial dose up to 48 weeks. Both participants and researchers were blinded to treatment allocation in the first 12 weeks, and blinded to the dose of bimekizumab thereafter. The primary endpoint was the proportion of patients with at least 50% improvement in the American College of Rheumatology response criteria at week 12, which was assessed in all patients who received at least one dose of study treatment and had a valid measurement of the primary efficacy endpoint at baseline. The trial, including all follow-up, has been completed. This trial is registered with ClinicalTrials.gov, NCT02969525. Findings: Between Oct 27, 2016, and July 16, 2018, 308 patients were screened, and 206 were randomly assigned: 42 to the placebo group, and 41 each to the four bimekizumab groups. At 12 weeks, compared with the placebo group, significantly more patients in the 16 mg bimekizumab (odds ratio [OR] 4·2 [95% CI 1·1–15·2]; p=0·032), 160 mg bimekizumab (8·1 [2·3–28·7]; p=0·0012), and 160 mg (loading dose) bimekizumab (9·7 [2·7–34·3]; p=0·0004) groups achieved an ACR50 response. At 12 weeks, 24 (57%) of 42 patients in the placebo group and 68 (41%) of the 164 patients in the bimekizumab groups reported treatment-emergent adverse events. Most of these adverse events were mild or moderate. Serious treatment-emergent adverse events occurred in nine patients, eight of whom were receiving bimekizumab. No deaths or cases of inflammatory bowel disease were reported. Interpretation: Bimekizumab doses of 16 mg and 160 mg (with or without a 320 mg loading dose) were associated with significant improvements in ACR50 compared with placebo, with an acceptable safety profile. Our results support phase 3 investigation of bimekizumab as a treatment for psoriatic arthritis. Funding: UCB Pharma.
CRIS-Team Scopus Importer:2020-02-14

Bimekizumab in Patients with Psoriatic Arthritis: 3-Year Results for Overall and Tumor Necrosis Factor Inhibitor (TNFi)-Naive Populations from a Phase 2b Open-Label Extension Study - Mease, Philip; Deodhar, Atul; Merola, Joseph; Mcinnes, Iain; Assudani, Deepak; Bajracharya, Rajan; Coarse, Jason; Ink, Barbara; Schett, Georg (ARTHRITIS & RHEUMATOLOGY, 2021)
CRIS-Team WoS Importer:2022-03-11

Binding Immunoglobulin Protein (BIP) Inhibits TNF-α-Induced Osteoclast Differentiation and Systemic Bone Loss in an Erosive Arthritis Model. - Hall, Christopher; McGowan, Neil; Babb, Rebecca; Devlia, Vikesh; Lucas, Sébastien; Meghji, Sajeda; Henderson, Brian; Bozec, Aline; David, Jean-Pierre; Panayi, Gabriel S.; Grigoriadis, Agamemnon E.; Corrigall, Valerie M.; et al. (ACR Open Rheumatology, 2019)
Objective: The association between inflammation and dysregulated bone remodeling is apparent in rheumatoid arthritis and is recapitulated in the human tumor necrosis factor transgenic (hTNFtg) mouse model. We investigated whether extracellular binding immunoglobulin protein (BiP) would protect the hTNFtg mouse from both inflammatory arthritis as well as extensive systemic bone loss and whether BiP had direct antiosteoclast properties in vitro. Methods: hTNFtg mice received a single intraperitoneal administration of BiP at onset of arthritis. Clinical disease parameters were measured weekly. Bone analysis was performed by microcomputed tomography and histomorphometry. Mouse bone marrow macrophage and human peripheral blood monocyte precursors were used to study the direct effect of BiP on osteoclast differentiation and function in vitro. Monocyte and osteoclast signaling was analyzed by Western blotting, flow cytometry, and imaging flow cytometry. Results: BiP-treated mice showed reduced inflammation and cartilage destruction, and histomorphometric analysis revealed a decrease in osteoclast number with protection from systemic bone loss. Abrogation of osteoclast function was also observed in an ex vivo murine calvarial model. BiP inhibited differentiation of osteoclast precursors and prevented bone resorption by mature osteoclasts in vitro. BiP also induced downregulation of CD115/c-Fms and Receptor Activator of NF-κB (RANK) messenger RNA and protein, causing reduced phosphorylation of the p38 mitogen-activated protein kinases, extracellular signal-regulated kinases 1/2 and p38, with suppression of essential osteoclast transcription factors, c-Fos and NFATc1. BiP directly inhibited TNF-α- or Receptor Activator of NF-κB Ligand (RANKL)-induced NF-κB nuclear translocation in THP-1 monocytic cells and preosteoclasts by the canonical and noncanonical pathways. Conclusion: BiP combines an anti-inflammatory function with antiosteoclast activity, which establishes it as a potential novel therapeutic for inflammatory disorders associated with bone loss.
EVALuna2:423610

Bioactivation of plane and patterned PDMS thin films by wettability engineering - Scharin, Marina; Rommel, Mathias; Dirnecker, Tobias; Marhenke, Julius; Herrmann, B.; Rumler, Maximilian; Fader, R.; Frey, Lothar; Herrmann, Martin (BioNanoScience, 2014)
This study shows how surface properties of polydimethylsiloxane (PDMS) thin films, such as wettability and cellular adhesive behavior, can be influenced by surface modification and patterning, to improve the suitability of such modified PDMS for biomedical applications. For that purpose, different types of PDMS (i.e., soft (S-) and hard (H-) PDMS) and differently patterned surfaces were prepared by a commercially available tool which is originally used to produce patterned PDMS stamps for substrate conformal imprint lithography. To increase surface wettability and cellular adhesive behavior, PDMS surfaces were modified by O2, Ar/O2, Ar, and forming gas (N2/H2) plasma treatment. It is shown that, especially, plasma treatment using N2/H2 is a promising method to modify PDMS surfaces towards enhanced wettability. Such modified PDMS surfaces exhibit water contact angle values (WCA) of nearly 0° and demonstrate enhanced attachment of melanoma cells. Differences between as-prepared and plasma-treated S- and H-PDMS can be observed, where H-PDMS shows smaller WCA than S-PDMS. Even plasma-treated PDMS surfaces, however, exhibit only temporary hydrophilicity, due to hydrophobic recovery. To overcome this problem, plasma-treated PDMS films were stored in ethanol and water, where low and constant WCAs for several months could be achieved. Finally, the influence of surface topography of different patterned PDMS thin films on the adhesion behavior of melanoma cells was investigated. It can be concluded that chemical as well as structural modifications of PDMS enable to gradually control the adhesive properties of cells on their surfaces. This has a high technological impact since regulated and topologically stable adhesion and repulsion of cells by their scaffolds has high potency for in vitro as well as in vivo applications. © 2014 Springer Science+Business Media New York.
UnivIS-Import:2015-04-14:Pub.2014.tech.IE.LEB.bioact
Keywords: Biocompatibility; Cell adhesion; Hydrophilicity modification; PDMS; Surface patterning

Biochemical insight into physiological effects of H 2S: Reaction with peroxynitrite and formation of a new nitric oxide donor, sulfinyl nitrite - Filipovic, Milos; Miljkovic, Jan; Allgäuer, Andrea; Chaurio Gonzalez, Ricardo Alfredo; Shubina, Tatyana; Herrmann, Martin; Ivanovic-Burmazovic, Ivana (Biochemical Journal, 2012)
The reaction of hydrogen sulfide (H S) with peroxynitrite (a key mediator in numerous pathological states) was studied in vitro and in different cellularmodels. The results show that H S can scavenge peroxynitrite with a corresponding second order rate constant of 3.3±0.4×10 M · s at 23°C (8± 2×10 M · s at 37°C). Activation parameters for the reaction (ΔH‡, ΔS‡ and ΔV‡) revealed that the mechanism is rather associative than multi-step free-radical as expected for other thiols. This is in agreement with a primary formation of a new reaction product characterized by spectral and computational studies as HSNO (thionitrate), predominantly present as sulfinyl nitrite, HS(O)NO. This is the first time a thionitrate has been shown to be generated under biologically relevant conditions. The potential of HS(O)NO to serve as a NO donor in a pH-dependent manner and its ability to release NO inside the cells has been demonstrated. Thus sulfide modulates the chemistry and biological effects of peroxynitrite by its scavenging and formation of a new chemical entity (HSNO ) with the potential to release NO, suppressing the pro-apoptotic, oxidative and nitrative properties of peroxynitrite. Physiological concentrations of H S abrogated peroxynitrite-induced cell damage as demonstrated by the: (i) inhibition of apoptosis and necrosis caused by peroxynitrite; (ii) prevention of protein nitration; and (iii) inhibition of PARP-1 [poly(ADP-ribose) polymerase 1] activation in cellular models, implying that a major part of the cytoprotective effects of hydrogen sulfide may be mediated by modulation of peroxynitrite chemistry, in particular under inflammatory conditions. © The Authors Journal compilation © 2012 Biochemical Society.

Biological agents in psoriatic arthritis - Kocijan, Roland; Muschitz, Christian; Rech, Juergen (Wiener Medizinische Wochenschrift, 2015)
Anti-tumor necrosis factors (TNFs) are effective drugs for the treatment of psoriatic arthritis (PsA) regarding reduction of pain and inflammation, enthesitis, dactylitis, as well as psoriatic skin and nail disease. Moreover, radiographic progression in PsA is decelerated. The efficacy of anti-TNFs seems to be independent of synthetic disease-modifying anti-rheumatic drugs, suggesting only a minor role of combination therapy in PsA. Anti-TNFs are generally well tolerated in patients with PsA. Adverse events are similar to those reported in patients with rheumatoid arthritis. Ustekinumab, a recently approved IL-12/IL-23-antibody is another promising biological agent in the treatment of PsA.
EVALuna2:13077

Biomechanical properties of bone are impaired in patients with ACPA-positive rheumatoid arthritis and associated with the occurrence of fractures - Stemmler, Fabian; Simon, David; Liphardt, Anna-Maria; Englbrecht, Matthias; Rech, Jürgen; Hueber, Axel; Engelke, Klaus; Schett, Georg; Kleyer, Arnd (Annals of the Rheumatic Diseases, 2018)
OBJECTIVES: Bone loss is a well-established consequence of rheumatoid arthritis (RA). To date, bone disease in RA is exclusively characterised by bone density measurements, while the functional properties of bone in RA are undefined. This study aimed to define the impact of RA on the functional properties of bone, such as failure load and stiffness. METHODS: Micro-finite element analysis (µFEA) was carried out to measure failure load and stiffness of bone based on high-resolution peripheral quantitative CT data from the distal radius of anti-citrullinated protein antibody (ACPA)-positive RA (RA+), ACPA-negative RA (RA-) and healthy controls (HC). In addition, total, trabecular and cortical bone densities as well as microstructural parameters of bone were recorded. Correlations and multivariate models were used to determine the role of demographic, disease-specific and structural data of bone strength as well as its relation to prevalent fractures. RESULTS: 276 individuals were analysed. Failure load and stiffness (both P<0.001) of bone were decreased in RA+, but not RA-, compared with HC. Lower bone strength affected both female and male patients with RA+, was related to longer disease duration and significantly (stiffness P=0.020; failure load P=0.012) associated with the occurrence of osteoporotic fractures. Impaired bone strength was correlated with altered bone density and microstructural parameters, which were all decreased in RA+. Multivariate models showed that ACPA status (P=0.007) and sex (P<0.001) were independently associated with reduced biomechanical properties of bone in RA. CONCLUSION: In summary, µFEA showed that bone strength is significantly decreased in RA+ and associated with fractures.
EVALuna2:34448

BIOMECHANICAL PROPERTIES OF RADIAL BONE ARE DIFFERENT BETWEEN AUTO-ANTIBODY POSITIVE AND NEGATIVE RHEUMATOID ARTHRITIS - Stemmler, F.; Simon, David; Liphardt, Anna-Maria; Englbrecht, Matthias; Rech, Jürgen; Hueber, Axel; Engelke, Klaus; Schett, Georg; Kleyer, Arnd (2018)
EVALuna2:34998

Biomechanical stress in the context of competitive sports training triggers enthesitis - Simon, David; Kleyer, Arnd; Bayat, Sara; Knitza, Johannes; Valor-Mendez, Larissa; Schweiger, Marina; Schett, Georg; Tascilar, Koray; Hueber, Axel (Arthritis Research & Therapy, 2021)
Objective To evaluate the influence of mechanical stress on the development of immediate enthesitis. Methods The BEAT study is an interventional study that assessed entheses in competitive badminton players before and immediately after a 60-min intensive training session. Power Doppler (PD) signal and Gray scale (GS) changes were assessed in the insertion sites of both Achilles tendon, patellar tendons, and lateral humeral epicondyles and quantified using a validated scoring system. Results Thirty-two badminton players were included. One hundred ninety-two entheseal sites were examined twice. The respective empirical total scores for PD examination were 0.1 (0.3) before and 0.5 (0.9) after training. Mean total GS scores were 2.9 (2.5) and 3.1 (2.5) before and after training, respectively. The mean total PD score difference of 0.4 between pre- and post-training was significant (p = 0.0014), whereas no significant difference for the mean total GS score was observed. Overall, seven participants (22%) showed an increased empirical total PD score. A mixed effects model showed a significant increase of PD scores after training, with a mean increase per site of 0.06 (95% CI 0.01 to 0.12, p = 0.017). Conclusions Mechanical stress leads to rapid inflammatory responses in the entheseal structures of humans. These data support the concept of mechanoinflammation in diseases associated with enthesitis.
CRIS-Team WoS Importer:2021-07-09

BIOMECHANICAL STRESS IN THE CONTEXT OF COMPETITIVE SPORTS TRAINING TRIGGERS ENTHESITIS - Simon, David; Kleyer, Arnd; Bayat, Sara; Knitza, Johannes; Valor, L.; Schweiger, M.; Schett, Georg; Tascilar, Koray; Hueber, Axel (ANNALS OF THE RHEUMATIC DISEASES, 2021)
CRIS-Team WoS Importer:2021-09-24

Biomimetic Magnetic Particles for the Removal of Gram-Positive Bacteria and Lipoteichoic Acid. - Friedrich, Bernhard; Eichermüller, Julia; Bogdan, Christian; Cunningham, Sarah; Hackstein, Holger; Strauss, Richard; Alexiou, Christoph; Lyer, Stefan; Tietze, Rainer (Pharmaceutics, 2022)
Gram+ bacteria are very common in clinical medicine and responsible for a large number of infectious diseases. For example, Gram+ bacteria play a major role in causing bloodstream infections and sepsis. Therefore, the detection of Gram+ bacteria is of great importance for the diagnosis and treatment of infectious diseases. Furthermore, these bacteria are often present in biofilms that cover implants. Recent research work has mainly focused on the biologic activity and removal of Gram-negative bacteria or bacterial components such as lipopolysaccharides (LPS). In contrast, the effects of lipoteichoic acid (LTA) have been less well studied so the relevance of their removal from body fluids is possibly underestimated. To address this topic, we evaluated superparamagnetic iron oxide particles (SPION) carrying different peptides derived from the innate immune receptor (GP-340) for their ability to bind and remove Gram+ bacteria and LTA from different media. Our results show that, beyond S. aureus, effective agglutinating and removing of S. pneumoniae was possible. Furthermore, we were able to show for the first time that this was possible with LTA alone and that the magnetic removal of bacteria was also efficient under flow conditions. We also found that this method was able to capture Stapyhylococcus aureus from platelet concentrates, which can help to enhance the sensitivity of microbiological diagnostics, quality control measures, and blood product safety.
EVALuna2:508460

BIOPHYSICAL PROPERTIES OF MONOCYTES INDICATE DISEASE ACTIVITY, SEVERITY OF FIBROTIC OR MICROVASCULAR MANIFESTATIONS AND THE RISK FOR PROGRESSION IN SYSTEMIC SCLEROSIS - Matei, Alexandru-Emil; Marketa, K.; Xu, L.; Györfi, Andrea-Hermina; Boxberger, E.; Soteriou, D.; Papava, Maria; Prater, Julia; Hong, Xuezhi; Kraeter, M.; Schett, Georg; Guck, J.; et al. (ANNALS OF THE RHEUMATIC DISEASES, 2022)
CRIS-Team WoS Importer:2022-11-04

Bispecific T cell engager therapy for refractory rheumatoid arthritis - Bucci, Laura; Hagen, Melanie; Rothe, Tobias; Raimondo, Maria Gabriella; Fagni, Filippo; Tur, Carlo; Wirsching, Andreas; Wacker, Jochen; Wilhelm, Artur; Auger, Jean-Philippe; Pachowsky, Milena; Eckstein, Markus; et al. (Nature Medicine, 2024)
Bispecific T cell engagers (BiTEs) kill B cells by engaging T cells. BiTEs are highly effective in acute lymphoblastic leukemia. Here we treated six patients with multidrug-resistant rheumatoid arthritis (RA) with the CD19xCD3 BiTE blinatumomab under compassionate use. Low doses of blinatumomab led to B cell depletion and concomitant decrease of T cells, documenting their engager function. Treatment was safe, with brief increase in body temperature and acute phase proteins during first infusion but no signs of clinically relevant cytokine-release syndrome. Blinatumomab led to a rapid decline in RA clinical disease activity in all patients, improved synovitis in ultrasound and FAPI-PET-CT and reduced autoantibodies. High-dimensional flow cytometry analysis of B cells documented an immune reset with depletion of activated memory B cells, which were replaced by nonclass-switched IgD-positive naïve B cells. Together, these data suggest the feasibility and potential for BiTEs to treat RA. This approach warrants further exploration on other B-cell-mediated autoimmune diseases.
CRIS-Team Scopus Importer:2024-05-03

Blockade of Dickkopf (DKK)-1 induces fusion of sacroiliac joints - Uderhardt, Stefan; Diarra, Danielle; Katzenbeisser, J.; David, Jean-Pierre; Zwerina, J.; Richards, W.; Krönke, Gerhard; Schett, Georg (Annals of the Rheumatic Diseases, 2010)
Objective: To study whether Dickkopf (DKK)-1, an inhibitor of wingless (Wnt) signalling, is involved in the fusion of sacroiliac joints. Methods: Mice transgenic for tumour necrosis factor (TNFtg mice), which develop bilateral sacroiliitis, were treated with vehicle, anti-TNF antibody or anti-DKK1 antibody. Sacroiliac joints were analysed for histological signs of inflammation, bone erosion, osteoclast formation and ankylosis. Moreover, expression of collagen type X, β-catenin and DKK-1 was assessed by immunohistochemistry. Results: There were no signs of spontaneous ankylosis of the sacroiliac joints in TNFtg mice. TNF blockade effectively reduced inflammation, bone erosion and osteoclast numbers in the sacroiliac joints, but did not lead to ankylosis. Blockade of DKK1 had no effect on inflammatory signs of sacroiliitis, but significantly reduced bone erosions and osteoclast counts. Moreover, DKK1 blockade promoted expression of collagen type X, the formation of hypertrophic chondrocytes and ankylosis of sacroiliac joints. Conclusion: DKK1 influences inflammatory remodelling of sacroiliac joints by prevention of joint ankylosis. This may indicate an important role of the Wnt signalling pathway in the structural bone changes of axial joint disease. Although this model does not reflect the entire spectrum of ankylosing spondylitis in humans, it helps to explain the pathophysiological processes of sacroiliac joint ankylosis, which is a hallmark of the spondyloarthritides.
CRIS-Team Scopus Importer:2020-11-20

Blockade of IL-36 Receptor Signaling Does Not Prevent from TNF-Induced Arthritis - Derer, Anja; Groetsch, Bettina; Harre, Ulrike; Böhm, Christina; Towne, Jennifer; Schett, Georg; Frey, Silke; Hueber, Axel (PLoS ONE, 2014)
Interleukin (IL)-36? is a newly described member of the IL-1 cytokine family with a known inflammatory and pathogenic function in psoriasis. Recently, we could demonstrate that the receptor (IL-36R), its ligand IL-36? and its antagonist IL-36Ra are expressed in synovial tissue of arthritis patients. Furthermore, IL-36? induces MAP-kinase and NF?B signaling in human synovial fibroblasts with subsequent expression and secretion of pro-inflammatory cytokines.To understand the pathomechanism of IL-36 dependent inflammation, we investigated the biological impact of IL-36? signaling in the hTNFtg mouse. Also the impact on osteoclastogenesis by IL-36? was tested in murine and human osteoclast assays.Diseased mice showed an increased expression of IL-36R and IL-36? in inflamed knee joints compared to wildtype controls. However, preventively treating mice with an IL-36R blocking antibody led to no changes in clinical onset and pattern of disease. Furthermore, blockade of IL-36 signaling did not change histological signs of TNF-induced arthritis. Additionally, no alteration on bone homeostasis was observed in ex vivo murine and human osteoclast differentiation assays.Thus we conclude that IL-36? does not affect the development of inflammatory arthriti
EVALuna2:12991

Blockade of the hedgehog pathway inhibits osteophyte formation in arthritis. - Ruiz-Heiland, Gisela; Horn, Angelika; Zerr, Pawel; Hofstetter, Willy; Baum, Wolfgang; Stock, Michael; Distler, Jörg; Nimmerjahn, Falk; Schett, Georg; Zwerina, Jochen (Annals of the Rheumatic Diseases, 2012)
BACKGROUND Osteophyte formation is a common phenomenon in arthritis. Bone formation by endochondral ossification is considered a key pathophysiological process in the formation of osteophytes. OBJECTIVE To examine the hypothesis that inhibition of smoothened (Smo), a key component of the hedgehog pathway inhibits osteophyte formation as the hedgehog pathway mediates endochondral ossification. METHODS Arthritis was induced in 8-week-old C57/BL6 mice by serum transfer (K/BxN model). Mice were then treated by daily administration of either vehicle or LDE223, a specific small molecule inhibitor for Smo, over 2 weeks starting at the onset of disease. Clinical course of arthritis, histological and molecular changes of bone in the affected joints as well as systemic bone changes were assessed. RESULTS Serum transfer-induced arthritis led to severe osteophyte formation within 2 weeks of onset. Blockade of Smo inhibited hedgehog signalling in vivo and also significantly inhibited osteophyte formation, whereas the clinical and histopathological signs of arthritis were not affected. Also, systemic bone mass did not change. Smo inhibitor particularly blocked the formation of hypertrophic chondrocytes and collagen type X expression. CONCLUSIONS The data indicate that blockade of hedgehog signalling by targeting Smo specifically inhibits osteophyte formation in arthritis without affecting inflammation and without eliciting bone destruction at the local and systemic level. Blockade of Smo may thus be considered as a strategy to specifically influence the periosteal bone response in arthritis associated with bone apposition.

Blockade of TNF-α rapidly inhibits pain responses in the central nervous system - Heß, Andreas; Axmann, Roland; Rech, Jürgen; Finzel, Stephanie; Heindl-Erdmann, Cornelia; Kreitz, Silke; Sergeeva, Marina; Saake, Marc; Garcia, Meritxell; Kollias, George; Straub, Rainer H.; Sporns, Olaf; et al. (Proceedings of the National Academy of Sciences of the United States of America, 2011)
There has been a consistent gap in understanding how TNF-α neutralization affects the disease state of arthritis patients so rapidly, considering that joint inflammation in rheumatoid arthritis is a chronic condition with structural changes. We thus hypothesized that neutralization of TNF-α acts through the CNS before directly affecting joint inflammation. Through use of functional MRI (fMRI), we demonstrate that within 24 h after neutralization of TNF-α, nociceptive CNS activity in the thalamus and somatosensoric cortex, but also the activation of the limbic system, is blocked. Brain areas showing blood-oxygen level-dependent signals, a validated method to assess neuronal activity elicited by pain, were significantly reduced as early as 24 h after an infusion of a monoclonal antibody to TNF-α. In contrast, clinical and laboratory markers of inflammation, such as joint swelling and acute phase reactants, were not affected by anti-TNF-α at these early time points. Moreover, arthritic mice overexpressing human TNF-α showed an altered pain behavior and amore intensive, widespread, and prolonged brain activity upon nociceptive stimuli compared with wild-type mice. Similar to humans, these changes, as well as the rewiring of CNS activity resulting in tight clustering in the thalamus, were rapidly reversed after neutralization of TNF-α. These results suggest that neutralization of TNF-α affects nociceptive brain activity in the context of arthritis, long before it achieves antiinflammatory effects in the joints.
CRIS-Team Scopus Importer:2021-02-03
Keywords: Antiinflammatory therapy; Cytokines

Blockade of Tyrosine Kinases as Preventive Strategy Against Cardiac Allograft Vasculopathy in a Murine Aortic Transplant Model - Gocht, Annika; Distler, Jörg; Spriewald, Bernd; Ramsperger-Gleixner, Martina; Ensminger, Stephan M.; Weyand, Michael; Heim, Christian (2018)
EVALuna2:34976

Blocking IL-1, IL-33 and IL-36 Signaling with the Anti-IL1RAP Antibody mCAN10 Ameliorates Inflammation and Fibrosis in Preclinical Models of Systemic Sclerosis - Gronberg, Caitriona; Rattik, Sara; Kunz, Meik; Thoung Trinh-Minh,; TRAN MANH, CUONG; Zhou, Xiang; Skoog, Petter; Liberg, David; Distler, Jörg (ARTHRITIS & RHEUMATOLOGY, 2022)
CRIS-Team WoS Importer:2023-01-13

Blood-Based Biomarkers of Inflammation and Tissue Remodeling Can Discriminate Between Rheumatoid Arthritis, Psoriasis, and Psoriatic Arthritis and Are Associated with Hand Function - Port Linares, Helena; Coppers, Birte; Bayat, Sara; Elie-Tino, Godonou; Fagni, Filippo; Corte, Giulia; Bay-Jensen, Anne-Christine; Tascilar, Koray; Hueber, Axel; Schönau, Verena; Sticherling, Michael; Heinrich, Simon; et al. (poster, American College of Rheumatology Convergence, 2023)

Blood-borne phagocytes internalize urate microaggregates and prevent intravascular NETosis by urate crystals - Pieterse, Elmar; Jeremic, Ivica; Czegley, Christine; Weidner, Daniela; Biermann, Mona; Veissi, Susan; Maueröder, Christian; Schauer, Christine; Bilyy, Rostyslav; Dumych, Tetiana; Hoffmann, Markus; Munoz, Luis Enrique; et al. (Scientific Reports, 2016)
Hyperuricemia is strongly linked to cardiovascular complications including atherosclerosis and thrombosis. In individuals with hyperuricemia, needle-shaped monosodium urate crystals (nsMSU) frequently form within joints or urine, giving rise to gouty arthritis or renal calculi, respectively. These nsMSU are potent instigators of neutrophil extracellular trap (NET) formation. Little is known on the mechanism(s) that prevent nsMSU formation within hyperuricemic blood, which would potentially cause detrimental consequences for the host. Here, we report that complement proteins and fetuins facilitate the continuous clearance by blood-borne phagocytes and resident macrophages of small urate microaggregates (UMA; <1 ?m in size) that initially form in hyperuricemic blood. If this clearance fails, UMA exhibit bipolar growth to form typical full-sized nsMSU with a size up to 100 ?m. In contrast to UMA, nsMSU stimulated neutrophils to release NETs. Under conditions of flow, nsMSU and NETs formed densely packed DNase I-resistant tophus-like structures with a high obstructive potential, highlighting the importance of an adequate and rapid removal of UMA from the circulation. Under pathological conditions, intravascularly formed nsMSU may hold the key to the incompletely understood association between NET-driven cardiovascular disease and hyperuricemia.
EVALuna2:13377

BMD ACCURACY ERRORS IN PHANTOMLESS CALIBRATION OF CT SCANS: A SIMULATION STUDY - Bartenschlager, Stefan; Chaudry, Oliver; Dankerl, Peter; Uder, Michael; Engelke, Klaus (OSTEOPOROSIS INTERNATIONAL, 2021)
Opportunistic screening using existing CT images may be a new strategy to identify subjects at increased risk for osteoporotic fracture. Low bone mineral density (BMD) is a key parameter but routine clinical CT scans do not include a calibration phantom to calculate BMD from the measured CT values. An alternative is internal or phantomless calibration, which is based on the CT values of air and of internal tissues of the subject such as blood, muscle or adipose tissue. However, the composition and as a consequence the CT values of these so-called internal calibration materials vary among subjects, which introduces additional BMD accuracy errors compared to phantom based calibration. The objective of this study was to quantify these accuracy errors and to identify optimum combinations of internal calibration materials (IM) for BMD assessments in opportunistic screening. Based on the base material decomposition theory we demonstrate how BMD can be derived from the CT values of the internal calibration materials. 121 CT datasets of the lumbar spine form postmenopausal women were used to determine the population variance of blood assessed in the aorta or the inferior vena cava, skeletal muscle of the erector spinae or psoas, subcutaneous adipose tissue (SAT) and air. The corresponding standard deviations were used for error propagation to determine phantomless calibration related BMD accuracy errors. Using a CT value of 150 HU, a typical value of trabecular bone, simulated BMD accuracy errors for most IM combinations containing air as one of the two base materials were below 5% or 6 mg/cm3. The lowest errors were determined for the combination of blood and air (<2 mg/cm3). The combination of blood and skeletal muscle resulted in higher errors (>10.5% or >12 mg/cm3) and is not recommended. Due to possible age-related differences in tissue composition, the selection of IMs is suggested to be adapted according to the measured subject. In younger subjects without significant aortic calcifications, air and blood of the aorta may be the best combination whereas in elderly subjects, air and SAT (error of 4%) may be preferable. The use of skeletal muscle as one of the two IMs is discouraged, in particular in elderly subjects because of varying fatty infiltration. A practical implementation of the internal calibration with different IM pairs confirmed the theoretical results. In summary, compared to a phantom based calibration the phantomless approach used for opportunistic screening creates additional BMD accuracy errors of 2% or more, dependent on the used internal reference tissues. The impact on fracture prediction still must be evaluate
CRIS-Team WoS Importer:2022-03-04
Keywords: Opportunistic screening; BMD; Phantomless calibration; QCT; Accuracy errors; Base material decomposition

BMD accuracy errors specific to phantomless calibration of CT scans of the lumbar spine - Bartenschlager, Stefan; Dankerl, Peter; Chaudry, Oliver; Uder, Michael; Engelke, Klaus (Bone, 2022)
Opportunistic screening using existing CT images may be a new strategy to identify subjects at increased risk for osteoporotic fracture. Low bone mineral density (BMD) is a key parameter but routine clinical CT scans do not include a calibration phantom to calculate BMD from the measured CT values. An alternative is internal or phantomless calibration, which is based on the CT values of air and of internal tissues of the subject such as blood, muscle or adipose tissue. However, the composition and as a consequence the CT values of these so-called internal calibration materials vary among subjects, which introduces additional BMD accuracy errors compared to phantom based calibration. The objective of this study was to quantify these accuracy errors and to identify optimum combinations of internal calibration materials (IM) for BMD assessments in opportunistic screening. Based on the base material decomposition theory we demonstrate how BMD can be derived from the CT values of the internal calibration materials. 121 CT datasets of the lumbar spine form postmenopausal women were used to determine the population variance of blood assessed in the aorta or the inferior vena cava, skeletal muscle of the erector spinae or psoas, subcutaneous adipose tissue (SAT) and air. The corresponding standard deviations were used for error propagation to determine phantomless calibration related BMD accuracy errors. Using a CT value of 150 HU, a typical value of trabecular bone, simulated BMD accuracy errors for most IM combinations containing air as one of the two base materials were below 5% or 6 mg/cm3. The lowest errors were determined for the combination of blood and air (<2 mg/cm3). The combination of blood and skeletal muscle resulted in higher errors (>10.5% or >12 mg/cm3) and is not recommended. Due to possible age-related differences in tissue composition, the selection of IMs is suggested to be adapted according to the measured subject. In younger subjects without significant aortic calcifications, air and blood of the aorta may be the best combination whereas in elderly subjects, air and SAT (error of 4%) may be preferable. The use of skeletal muscle as one of the two IMs is discouraged, in particular in elderly subjects because of varying fatty infiltration. A practical implementation of the internal calibration with different IM pairs confirmed the theoretical results. In summary, compared to a phantom based calibration the phantomless approach used for opportunistic screening creates additional BMD accuracy errors of 2% or more, dependent on the used internal reference tissues. The impact on fracture prediction still must be evaluated.
CRIS-Team Scopus Importer:2022-01-28
Keywords: Accuracy errors; Base material decomposition; BMD; Opportunistic screening; Phantomless calibration; QCT

Body mass index distribution in rheumatoid arthritis: a collaborative analysis from three large German rheumatoid arthritis databases - Albrecht, Katinka; Richter, Adrian; Callhoff, Johanna; Huscher, Doerte; Schett, Georg; Strangfeld, Anja; Zink, Angela (Arthritis Research & Therapy, 2016)
METARTHROS (Metabolic impact on joint and bone disease) is a nationwide German network to investigate the overlap between inflammatory and metabolic diseases. The objective of this study was to compare the body mass index (BMI) distribution in patients with early and established rheumatoid arthritis (RA) with data from the general population, and to evaluate the association of BMI with patient characteristics and clinical markers.The BMI distribution was examined with data collected at inclusion of patients in the early arthritis cohort CAPEA, the biologics register RABBIT, and the National database of the German Collaborative Arthritis Centers. A data source with a representative sample of the German population (German Ageing Survey) was used as a comparator. BMI categories of <18.5 kg/m(2) (underweight), 18.5 to <25 kg/m(2) (normal weight), 25 to <30 kg/m(2) (overweight), and >=30 kg/m(2) (obese) were used. Patients were stratified by age and sex, and compared to controls from the German Ageing Survey. Associations between BMI and markers of disease activity were analysed with non-parametric tests and linear models.Data from 1207 (CAPEA), 12,230 (RABBIT), and 3424 (National database) RA patients and 6202 population controls were evaluated. The mean age was 56, 56, 62, and 62 years, respectively, the mean disease duration was 13 weeks, 9.9 years, and 13.5 years, respectively, and the mean disease activity score (DAS28) was 5.1, 5.2, and 3.1, respectively. In all RA cohorts, obesity was more frequent (23.8 %, 23.4 %, 21.4 %, respectively) than in controls (18.2 %). This applied to all age groups <70 years, was independent of disease duration, and was more pronounced in females. In all cohorts, the age at RA onset was associated with BMI, being higher in overweight/obese patients compared to normal-weight patients. Current smoking was negatively associated with BMI. Linear analyses revealed increased erythrocyte sedimentation rate (ESR) values in underweight and obese females, and an increasing disparity between tender joint counts (TJCs) and swollen joint counts (SJCs) in higher BMI categories.Compared to the general population, a higher prevalence of obesity was observed in all RA cohorts. The dominance of obesity in females and the different behaviour of disease activity markers in relation to the BMI in females indicate that additional parameters need to be considered when analysing the impact of obesity on inflammation in RA.
EVALuna2:13296

Bona fide dendritic cells are pivotal precursors for osteoclasts. - Puchner, Antonia; Simader, Elisabeth; Saferding, Victoria; Hofmann, Melanie; Kieler, Markus; Brunner, Julia; Pfeifle, René; Niederreiter, Birgit; Krönke, Gerhard; Schabbauer, Gernot; Georgel, Philippe; Diehl, Gretchen; et al. (Annals of the Rheumatic Diseases, 2024)
OBJECTIVES: Osteoclasts (OCs) are myeloid-derived multinucleated cells uniquely able to degrade bone. However, the exact nature of their myeloid precursors is not yet defined. METHODS: CD11c-diphtheria toxin receptor (CD11cDTR) transgenic mice were treated with diphtheria toxin (DT) or phosphate buffered saline (PBS) during serum transfer arthritis (STA) and human tumour necrosis factor transgenic (hTNFtg) arthritis and scored clinically and histologically. We measured cytokines in synovitis by quantitative polymerase chain reaction (qPCR). We performed ovariectomy in CD11cDTR mice treated with PBS or DT. We analysed CD11cDTR, CD11c-Cre/CX3CR1-STOP-DTR and Zbtb46-DTR-treated mice with DT using histomorphometry and OC of CD11c and Zbtb46 fate reporter mice by fluorescent imaging. We sorted murine and human OC precursors and stimulated them with macrophage colony-stimulating factor (M-CSF) and receptor activator of nuclear factor kappa-B ligand (RANKL) to generate OCs. RESULTS: Targeting CD11c+ cells in vivo in models of inflammatory arthritis (STA and hTNFtg) ameliorates arthritis by reducing inflammatory bone destruction and OC generation. Targeting CD11c-expressing cells in unchallenged mice removes all OCs in their long bones. OCs do not seem to be derived from CD11c+ cells expressing CX3CR1+, but from Zbtb46+conventional dendritic cells (cDCs) as all OCs in Zbtb46-Tomato fate reporter mice are Tomato+. In line, administration of DT in Zbtb46-DTR mice depletes all OCs in long bones. Finally, human CD1c-expressing cDCs readily differentiated into bone resorbing OCs. CONCLUSION: Taken together, we identify DCs as important OC precursors in bone homeostasis and inflammation, which might open new avenues for therapeutic interventions in OC-mediated diseases.
EVALuna2:553453

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

Bone- and cartilage-protective effects of a monoclonal antibody against colony-stimulating factor 1 receptor in experimental arthritis - Toh, Myew-Ling; Bonnefoy, Jean-Yves; Accart, Nathalie; Cochin, Sandrine; Pohle, Sandy; Haegel, Helene; De Meyer, Micael; Zemmour, Christophe; Preville, Xavier; Guillen, Christine; Thioudellet, Christine; Ancian, Philippe; et al. (Arthritis and Rheumatology, 2014)
Colony-stimulating factor 1 receptor (CSF-1R) essentially modulates monocyte proliferation, migration, and activation, which are considered important for the pathogenesis of rheumatoid arthritis (RA). We undertook this study to determine CSF-1R expression in human RA as well as the efficacy of a specific anti-CSF-1R monoclonal antibody (AFS98) in 2 different animal models of RA.CSF-1R expression was examined in blood, synovium, and bone samples from RA patients, osteoarthritis (OA) patients, and healthy subjects. The efficacy of AFS98 was examined by clinical assessment, histology, and bone histomorphometry in collagen-induced arthritis (CIA) and serum-transfer arthritis.CSF-1R expression was increased in the synovium of RA patients compared to OA patients and healthy controls in fibroblast-like synoviocytes, follicular dendritic cells, macrophages, and osteoclasts. Circulating RA monocytes and neutrophils but not lymphocytes were CSF-1R+. In mice, blockade of CSF-1R abrogated cartilage damage, bone erosion, and systemic bone loss, and this was associated with the depletion of osteoclasts in both models. While blockade of CSF-1R did not affect inflammation in passive serum-transfer arthritis, it significantly reduced inflammation in CIA, and this was associated with the absence of synovial macrophages and reduced splenic CD11b+Gr-1- monocytes.CSF-1R was broadly expressed in human RA. Blockade of CSF-1R protected against bone and cartilage destruction in both mouse models and also showed significant antiinflammatory effects in the CIA model. These data provide evidence for CSF-1R as a therapeutic target in RA.
EVALuna2:12982

Bone Formation in Psoriatic Arthritis: A Report from the GRAPPA 2013 Annual Meeting - Schett, Georg (Journal of Rheumatology, 2014)
The simultaneous presence of bone erosions and bony spurs (osteophytes, enthesophytes) in the joints of patients with psoriatic arthritis (PsA) suggests that the disease leads to enhanced bone resorption as well as increased bone formation, the latter of which has not been observed in patients with rheumatoid arthritis. At the 2013 Annual Meeting of the Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA), members heard an update on the current research into the cytokine signature in PsA and its effects on new bone formation.
EVALuna2:12916

Bone Loss Before Clinical Onset of Rheumatoid Arthritis o Subjects with Anti-Citrullinated Protein Antibodies - Finzel, Stephanie; Lang, Veronika; Kleyer, Arnd; Rech, Jürgen; Manger, Bernhard; Guilhon de Araujo, Elizabeth; Hueber, Axel; Harre, Ulrike; Schett, Georg (2012)
EVALuna2:34465

Bone loss before the clinical onset of rheumatoid arthritis in subjects with anticitrullinated protein antibodies - Kleyer, Arnd; Finzel, Stephanie; Rech, Jürgen; Manger, Bernhard; Krieter, Manuel; Faustini, Francesca; Araujo, Elisabeth; Hueber, Axel; Harre, Ulrike; Engelke, Klaus; Schett, Georg (Annals of the Rheumatic Diseases, 2014)
Anticitrullinated protein antibodies (ACPA) are a major risk factor for bone loss in rheumatoid arthritis (RA). We have recently shown that ACPA directly induce bone loss by stimulating osteoclast differentiation. As ACPA precede the clinical onset of RA by years, we hypothesised that ACPA positive healthy individuals may already show skeletal changes.We performed a comparative micro-CT analysis of the bone microstructure in the metacarpophalangeal joints of ACPA positive and ACPA negative healthy individuals without clinical signs of arthritis.ACPA positive (n=15) and negative (n=15) healthy individuals were not different in age (48.2±4.1 vs 51.4±3.8 years, p=0.57) or gender (eight women and two men in both groups). Bone mineral density was significantly reduced in ACPA positive individuals (mean±SEM 280±11 mg/cm(3)) compared with controls (327±6). Bone loss was based on cortical bone changes, with significant (p=0.044) reduction in cortical thickness in the ACPA positive group (mean±SEM 0.22±0.03 mm) compared with controls (0.32±0.03 mm). Areas of cortical porosity were significantly (p=0.0005) more widespread in ACPA positive (mean±SEM 7.4±1.4%) than in ACPA negative individuals (1.0±0.3%).Structural bone damage starts before the clinical onset of arthritis in subjects with ACPA. These findings revise the concept that bone damage is an exclusive consequence of synovitis in patients with R
EVALuna2:10080

Bone Mass, Bone Microstructure and Biomechanics in Patients with Hand Osteoarthritis - Simon, David; Tascilar, Koray; Unbehend, Sara; Bayat, Sara; Berlin, Andreas; Liphardt, Anna-Maria; Meinderink, Timo; Rech, Jürgen; Hueber, Axel; Schett, Georg; Kleyer, Arnd (Journal of Bone and Mineral Research, 2020)
The impact of primary hand osteoarthritis (HOA) on bone mass, microstructure, and biomechanics in the affected skeletal regions is largely unknown. HOA patients and healthy controls (HCs) underwent high-resolution peripheral quantitative computed tomography (HR-pQCT). We measured total, trabecular, and cortical volumetric bone mineral densities (vBMDs), microstructural attributes, and performed micro–finite element analysis for bone strength. Failure load and scaled multivariate outcome matrices from distal radius and second metacarpal (MCP2) head measurements were analyzed using multiple linear regression adjusting for age, sex, and functional status and reported as adjusted Z-score differences for total and direct effects. A total of 105 subjects were included (76 HC: 46 women, 30 men; 29 HOA: 23 women, six men). After adjustment, HOA was associated with significant changes in the multivariate outcome matrix from the MCP2 head (p <.001) (explained by an increase in cortical vBMD (Δz = 1.07, p =.02) and reduction in the trabecular vBMD (Δz = −0.07, p =.09). Distal radius analysis did not show an overall effect of HOA; however, there was a gender-study group interaction (p =.044) explained by reduced trabecular vBMD in males (Δz = −1.23, p =.02). HOA was associated with lower failure load (−514 N; 95%CI, −1018 to −9; p = 0.05) apparent in males after adjustment for functional status. HOA is associated with reduced trabecular and increased cortical vBMD in the MCP2 head and a reduction in radial trabecular vBMD and bone strength in males. Further investigations of gender-specific changes of bone architecture in HOA are warranted. © 2020 The Authors. Journal of Bone and Mineral Research published by American Society for Bone and Mineral Research.
CRIS-Team Scopus Importer:2020-06-09
Keywords: ANALYSIS/QUANTITATION OF BONE; BIOMECHANICS; BONE QCT/MICROCT; DISEASES AND DISORDERS OF/RELATED TO BONE; ORTHOPAEDICS; OSTEOARTHRITIS

Bone micro-architecture, estimated bone strength, and the muscle-bone interaction in elite athletes: an HR-pQCT study - Schipilow, J. D.; Macdonald, H. M.; Liphardt, Anna-Maria; Kan, M.; Boyd, S. K. (Bone, 2013)
Athletes participating in sports characterized by specific loading modalities have exhibited different levels of augmentation of bone properties; however, the extent to which these loading environments affect bone micro-architecture and estimated bone strength (i.e., bone quality) remains unclear. Furthermore, the relative role of impact loading versus loading due to muscle forces in determining bone properties is confounded. The objectives of this study were 1) to examine the role of impact loading on bone quality of the distal radius and distal tibia in elite athletes, as determined by high resolution peripheral quantitative computed tomography (HR-pQCT) and finite element analysis (FEA), and 2) to investigate the relationship between bone quality and muscle strength in elite athletes. Ninety-five females (n=59) and males (n=36) between the ages of 16-30 years participated in the study. Participants included alpine skiers (high-impact), soccer players (moderate impact), swimmers (low-impact), and non-athletic controls. All group comparisons were made after accounting for age, height, and body mass. As expected, minimal differences in HR-pQCT parameters across groups were observed at the non weight-bearing distal radius. At the weight-bearing distal tibia, female alpine skiers and soccer players had significantly higher bone density, cortical thickness, and failure load (i.e., bone strength (N) in compression estimated by FEA) than swimmers (p<0.05). Female alpine skiers also had lower trabecular separation than swimmers and controls. Male alpine skiers had 20% higher trabecular bone mineral density than swimmers, and male soccer players exhibited 22% higher trabecular number than swimmers at the distal tibia (p<0.05). Male alpine skiers and soccer players had 28-38% higher failure load at the distal tibia than swimmers. No differences in bone parameters were observed between swimmers and controls for either sex at either site. Both muscle strength and sporting activity were predictors of failure load at the distal tibia in the female cohort. Sporting activity, but not muscle strength, was a significant predictor of failure load in the male cohort at both the radius and tibia. This data suggests that impact loading in sporting activity is highly associated with bone quality. Longitudinal and interventional studies are required to further clarify the muscle-bone interaction.
EVALuna2:13507

Bone micro-architecture of elite alpine skiers is not reflected by bone mineral density - Liphardt, Anna-Maria; Schipilow, J. D.; Macdonald, H. M.; Kan, M.; Zieger, A.; Boyd, S. K. (Osteoporosis international, 2015)
Bone quality is affected by muscle forces and external forces. We investigated how micro-architecture is influenced in elite alpine skiers who have received high loading levels throughout their adolescent bone development. Bone strength was higher in skiers, likely due to external forces, but muscle forces may also be a significant contributor.Impact loading and muscle forces affect bone quality, but little is known about how they influence 3 dimensional aspects of bone structure. This study investigated bone quality in female and male elite alpine skiers using high-resolution peripheral quantitative computed tomography (HR-pQCT).HR-pQCT at the distal radius and tibia, whole-body lean mass, and muscle strength were assessed in 10 female (22.7 ± 3.9 years) and 12 male (25.5 ± 3.3 years) Canadian national alpine team athletes and compared to recreationally active female (N = 10, 23.8 ± 3.2 years) and male (N = 12; 23.7 ± 3.6 years) control subjects. HR-pQCT standard parameters and customized cortical and finite element (FE) analyses were performed and analyzed using one-way ANOVA and Pearson's correlation.Male and female skiers had stronger bones than controls at radius (38-49 %, p < 0.001) and tibia (24-28 %, p < 0.001). This result was not consistently reflected by total bone mineral density (BMD) because higher trabecular BMD occurred in parallel with lower cortical BMD, which was due to a redistribution of mineral leading to a shift of the endocortical margin toward a thicker cortex. The endocortical regional adaptation was likely responsible for the greater strength of the athletes' bones. Lean mass and muscle strength was 29 to 90 % greater (p < 0.001) in athletes compared to controls. Good associations between muscle strength and FE-estimated bone strength were found (r = 0.63 to 0.80; p < 0.001), although micro-architecture was more strongly associated with muscle outcomes in females than males.Higher bone strength in elite alpine skiers is achieved through micro-architectural adaptation that is not apparent by BMD measurements alone. The improved micro-architecture at radius and tibia suggests that muscle forces may play an important role in bone adaptation.
EVALuna2:13501

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

Bone Microstructure Assessed By Hrpqct in Subjects with Hyperuricemia without Arthritis - Kocijan, Roland; Nia, Arastoo; Muschitz, Christian; Simon, David; Geiger, Corinna; Haschka, Judith; Kleyer, Arnd; Bayat, Sara; Rech, Jürgen; Kocijan, Annemarie; Dzirlo, Larissa; Graninger, Monika; et al. (2015)
EVALuna2:13325

Bone Microstructure in Patients with Cutaneous Psoriasis and No History of Psoriatic Arthritis Shows Bone Anabolic Changes at a Greater Extent Than in Healthy Controls - Simon, David; Faustini, Francesca; Englbrecht, Matthias; Kleyer, Arnd; Kocijan, Roland; Haschka, Judith; Finzel, Stephanie; Kraus, Sebastian; Hueber, Axel; Sticherling, Michael; Schett, Georg; Rech, Jürgen (2014)
EVALuna2:13229

Bone Morphogenetic Protein Antagonist Gremlin-1 Increases Myofibroblast Transition in Dermal Fibroblasts: Implications for Systemic Sclerosis - Duffy, Laura; Henderson, John; Brown, Max; Pryzborski, Stefan; Fullard, Nicola; Summa, Lena; Distler, Jörg; Stratton, Richard; O'Reilly, Steven (Frontiers in Cell and Developmental Biology, 2021)
Objective: Systemic Sclerosis is an autoimmune connective tissue disease which results in fibrosis of the skin and lungs. The disease is characterized by activation of myofibroblasts but what governs this is unknown. Gremlin-1 is a BMP antagonist that is developmentally regulated and we sought to investigate its role in Systemic Sclerosis. Methods: Dermal fibroblasts were transfected with Grem1pcDNA3.1 expression vectors or empty vectors. Various markers of myofibroblasts were measured at the mRNA and protein levels. Scratch wound assays were also performed. Media Transfer experiments were performed to evaluate cytokine like effects. Various inhibitors of TGF-β signaling and MAPK signaling were used post-transfection. siRNA to Gremlin-1 in SSc dermal fibroblasts were performed to evaluate the role of Gremlin-1. Different cytokines were incubated with fibroblasts and Gremlin-1 measured. Bleomycin was used as model of fibrosis and immunohistochemistry performed. Results: Overexpression of Gremlin-1 was achieved in primary dermal fibroblasts and lead to activation of quiescent cells to myofibroblasts indicated by collagen and α-Smooth muscle actin. Overexpression also led to functional effects. This was associated with increased TGF-β1 levels and SBE luciferase activity but not increased Thrombospondin-1 expression. Inhibition of Gremlin-1 overexpression cells with antibodies to TGF-β1 but not isotype controls led to reduced collagen and various TGF-β pathway chemical inhibitors also led to reduced collagen levels. In SSc cells siRNA mediated reduction of Gremlin-1 reduced collagen expression and CTGF gene and protein levels in these cells. IL-13 did not lead to elevated Gremlin-1 expression nor did IL-11. Gremlin-1 was elevated in an animal model of fibrosis compared to NaCl-treated mice. Conclusion: Gremlin-1 is a key regulator of myofibroblast transition leading to enhanced ECM deposition. Strategies that block Gremlin-1 maybe a possible therapeutic target in fibrotic diseases such as SSc.
CRIS-Team Scopus Importer:2021-07-02
Keywords: BMP; collagen; ECM; fibrosis; gremlin-1

Bone quality in osteopenic postmenopausal women is not improved after 12 months of whole-body vibration training - Liphardt, Anna-Maria; Schipilow, J.; Hanley, D. A.; Boyd, S. K. (Osteoporosis international, 2015)
Whole-body vibration training may improve bone quality through structural adaptation. We tested if 12 months of training affects bone structure in osteopenic postmenopausal women by using advanced 3-dimensional high-resolution imaging techniques. We found that whole-body vibration training did not improve bone structure compared to inactive controls.Whole-body vibration training (WBVT) has been suggested as a preventive measure against bone loss. Contradicting results of previous studies may be confounded by insufficiently sensitive bone density measures to detect relevant bone changes. WBVT may improve bone quality through structural adaptations, without increasing bone mineral density (BMD). We hypothesized that 12 months of WBVT will improve or maintain bone microarchitecture and bone strength in osteopenic postmenopausal women.Twenty-two women received WBVT for 2-3 sessions/week and were compared with 20 controls. Bone outcomes were measured by high-resolution peripheral quantitative CT (HR-pQCT, XtremeCT, Scanco Medical) and finite element estimated bone strength. Balance and jump performance and maximum voluntary contraction (MVC) of knee flexor and extensor muscles were recorded. All measurements were taken at baseline, 4, 8, and 12 months and a reduced data set at 4 and 8 months follow-up and compared using a mixed model repeated measures ANOVA.Thirty-one women completed the study with 90 % compliance (WBVT: n = 17, control n = 14). Total BMD (p < 0.001), cortical area*(p = 0.004), cortical thickness (p = 0.011), and cortical porosity (p = 0.024) all significantly decreased over time in both groups; WBVT did not affect the response. All other bone outcomes were not affected by WBVT or time. No difference in measures of balance, jump height, and MVC due to WBVT were detected.In our cohort, WBVT did not lead to improved bone quality in postmenopausal osteopenic women after 12 months of training compared to controls, and there were no detected benefits related to balance and muscle strength outcomes.
EVALuna2:13502

Both plasmacytoid dendritic cells and monocytes stimulate natural killer cells early during human herpes simplex virus type 1 infections - Vogel, Karin; Thomann, Sabrina; Vogel, Benjamin; Schuster, Philipp; Schmidt, Barbara (Immunology, 2014)
Herpes simplex virus type 1 (HSV-1), a member of the herpes virus family, is characterized by a short replication cycle, high cytopathogenicity and distinct neurotropism. Primary infection and reactivation may cause severe diseases in immunocompetent and immunosuppressed individuals. This study investigated the role of human plasmacytoid dendritic cells (pDC) in the activation of natural killer (NK) cells for the control of herpesviral infections. Within peripheral blood mononuclear cells, UV-inactivated HSV-1 and CpG-A induced CD69 up-regulation on NK cells, whereas infectious HSV-1 was particularly active in inducing NK cell effector functions interferon-? (IFN-?) secretion and degranulation. The pDC-derived IFN-? significantly contributed to NK cell activation, as evident from neutralization and cell depletion experiments. In addition, monocyte-derived tumour necrosis factor-? (TNF-?) induced after exposure to infectious HSV-1 was found to stimulate IFN-? secretion. A minority of monocytes was shown to be non-productively infected in experiments using fluorescently labelled viruses and quantitative PCR analyses. HSV-1-exposed monocytes up-regulated classical HLA-ABC and non-classical HLA-E molecules at the cell surface in an IFN-?-dependent manner, whereas stress molecules MICA/B were not induced. Notably, depletion of monocytes reduced NK cell effector functions induced by infectious HSV-1 (P < 0.05). Altogether, our data suggest a model in which HSV-1-stimulated pDC and monocytes activate NK cells via secretion of IFN-? and TNF-?. In addition, infection of monocytes induces NK cell effector functions via TNF-?-dependent and TNF-?-independent mechanisms. Hence, pDC and monocytes, which are among the first cells infiltrating herpetic lesions, appear to have important bystander functions for NK cells to control these viral infections.
EVALuna2:8241

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

Brain oedema due to disseminated intravascular coagulation in a patient with adult-onset Still's disease-associated hemophagocytic lymphohistiocytosis-a case report - Lorenz, Georg; Schaaf, Christian; Moog, Philipp; Bachmann, Quirin; Popp, Florian; Rech, Jürgen; Schorr, Johanna; Gabl, Carmen; Kuechle, Claudius; Delbridge, Claire; Weirich, Gregor G.; Heemann, Uwe; et al. (Rheumatology, 2022)
CRIS-Team WoS Importer:2022-11-11

Breaking the Gingival Barrier in Periodontitis - Vitkov, Ljubomir; Singh, Jeeshan; Schauer, Christine; Minnich, Bernd; Krunic, Jelena; Oberthaler, Hannah; Gamsjaeger, Sonja; Herrmann, Martin; Knopf, Jasmin; Hannig, Matthias (International Journal of Molecular Sciences, 2023)
The break of the epithelial barrier of gingiva has been a subject of minor interest, albeit playing a key role in periodontal pathology, transitory bacteraemia, and subsequent systemic low-grade inflammation (LGI). The significance of mechanically induced bacterial translocation in gingiva (e.g., via mastication and teeth brushing) has been disregarded despite the accumulated knowledge of mechanical force effects on tight junctions (TJs) and subsequent pathology in other epithelial tissues. Transitory bacteraemia is observed as a rule in gingival inflammation, but is rarely observed in clinically healthy gingiva. This implies that TJs of inflamed gingiva deteriorate, e.g., via a surplus of lipopolysaccharide (LPS), bacterial proteases, toxins, Oncostatin M (OSM), and neutrophil proteases. The inflammation-deteriorated gingival TJs rupture when exposed to physiological mechanical forces. This rupture is characterised by bacteraemia during and briefly after mastication and teeth brushing, i.e., it appears to be a dynamic process of short duration, endowed with quick repair mechanisms. In this review, we consider the bacterial, immune, and mechanical factors responsible for the increased permeability and break of the epithelial barrier of inflamed gingiva and the subsequent translocation of both viable bacteria and bacterial LPS during physiological mechanical forces, such as mastication and teeth brushing.
CRIS-Team Scopus Importer:2023-03-24
Keywords: barrier break; epithelial discontinuity; mechanical damages; neutrophils; Oncostatin M; stretching; tight junctions; tissue fracture

Breakthrough Infections in COVID-19 Vaccinated Patients with Systemic Sclerosis: A Survival Analysis from a Multicenter International Patient-Reported Survey - Ahmed, Sakir; Naveen, R.; Pauling, John; Thakare, Darpan; Wincup, Chris; Del Papa, Nicoletta; Sambataro, Gianluca; Atzeni, Fabiola; Parisi, Simone; Govoni, Marcello; Bocci, Elena Bartoloni; Sebastiani, Gian Domenico; et al. (ARTHRITIS & RHEUMATOLOGY, 2022)
CRIS-Team WoS Importer:2023-01-13

Brief Report: IRF4 Newly Identified as a Common Susceptibility Locus for Systemic Sclerosis and Rheumatoid Arthritis in a Cross-Disease Meta-Analysis of Genome-Wide Association Studies - Lopez-Isac, Elena; Martin, Jose-Ezequiel; Assassi, Shervin; Simeon, Carmen P.; Carreira, Patricia; Ortego-Centeno, Norberto; Freire, Mayka; Beltran, Emma; Narvaez, Javier; Alegre-Sancho, Juan J.; Fernandez-Gutierrez, Benjamin; Balsa, Alejandro; et al. (Arthritis and Rheumatology, 2016)
Systemic sclerosis (SSc) and rheumatoid arthritis (RA) are autoimmune diseases that have similar clinical and immunologic characteristics. To date, several shared SSc-RA genetic loci have been identified independently. The aim of the current study was to systematically search for new common SSc-RA loci through an interdisease meta-genome-wide association (meta-GWAS) strategy.The study was designed as a meta-analysis combining GWAS data sets of patients with SSc and patients with RA, using a strategy that allowed identification of loci with both same-direction and opposite-direction allelic effects. The top single-nucleotide polymorphisms were followed up in independent SSc and RA case-control cohorts. This allowed an increase in the sample size to a total of 8,830 patients with SSc, 16,870 patients with RA, and 43,393 healthy controls.This cross-disease meta-analysis of the GWAS data sets identified several loci with nominal association signals (P < 5 × 10(-6) ) that also showed evidence of association in the disease-specific GWAS scans. These loci included several genomic regions not previously reported as shared loci, as well as several risk factors that were previously found to be associated with both diseases. Follow-up analyses of the putatively new SSc-RA loci identified IRF4 as a shared risk factor for these 2 diseases (Pcombined = 3.29 × 10(-12) ). Analysis of the biologic relevance of the known SSc-RA shared loci identified the type I interferon and interleukin-12 signaling pathways as the main common etiologic factors.This study identified a novel shared locus, IRF4, for the risk of SSc and RA, and highlighted the usefulness of a cross-disease GWAS meta-analysis strategy in the identification of common risk loci.
EVALuna2:13279

Brief Report: Tumor Necrosis Factor and Interleukin-6 Differentially Regulate Dkk-1 in the Inflamed Arthritic Joint - Yeremenko, Nataliya; Zwerina, Karin; Rigter, Gemma; Pots, Desiree; Fonseca, Joao E.; Zwerina, Jochen; Schett, Georg; Baeten, Dominique (Arthritis and Rheumatology, 2015)
Tumor necrosis factor (TNF) drives bone destruction, but it also inhibits new bone formation by inducing Dkk-1, an inhibitor of the Wnt pathway. Accordingly, blocking of Dkk-1 reverses the phenotype in experimental arthritis from a pattern of bone destruction to a pattern of bone formation. To delineate the potential role of Dkk-1 in the structural phenotype of human arthritis, we analyzed the expression of Dkk-1 and its regulation by proinflammatory cytokines in the inflamed peripheral joints of patients with spondyloarthritis (SpA) and rheumatoid arthritis (RA).Expression of Dkk-1 and proinflammatory cytokines was determined by enzyme-linked immunosorbent assay and microarray analysis in synovial fluid (SF) and synovial tissue, respectively. Regulation of Dkk-1 production by proinflammatory cytokines was assessed in fibroblast-like synoviocyte (FLS) cultures.TNF and interleukin-1? (IL-1?) levels, were higher in RA SF than in SpA SF (P < 0.001 for both), whereas levels of IL-6 were not. Levels of Dkk-1 were similar in SpA SF and RA SF and were not correlated with TNF and IL-1? levels. However, Dkk-1 levels showed an inverse correlation with IL-6 levels in both SpA SF (r = -0.31, P = 0.04) and RA SF (r = -0.39, P = 0.01); this result was reproduced at the messenger RNA level in synovial tissue. In vitro experiments with FLS confirmed that Dkk-1 production was strongly induced by TNF but clearly suppressed by IL-6. Moreover, IL-6 was able to suppress the TNF-induced up-regulation of Dkk-1 production by FLS.The inverse correlation of Dkk-1 levels with IL-6 levels observed in vivo in the inflamed joints was mirrored by the differential regulation of Dkk-1 production by TNF and IL-6 in vitro. The relative balance between these and other factors in the arthritic joints may determine functional Wnt signaling and tissue remodeling.
EVALuna2:13134

Brilliant glyconanocapsules for trapping of bacteria - Yan, Xibo; Sivignon, Adeline; Alcouffe, Pierre; Burdin, Beatrice; Favre-Bonte, Sabine; Bilyy, Rostyslav; Barnich, Nicolas; Fleury, Etienne; Ganachaud, Francois; Bernard, Julien (Chemical Communications, 2015)
Nanoprecipitation of miglyol into droplets surrounded by a functional glycopolymer generates nanocapsules of biointerest. Fluorophores are trapped in situ or post-grafted onto the crosslinked polymer shell for efficient imaging. The resulting colloids induce aggregation of bacteria through strong specific interactions and promote their facile removal.
EVALuna2:13243

Broadly neutralizing SARS-CoV-2 antibodies through epitope-based selection from convalescent patients - Rouet, Romain; Henry, Jake Y.; Johansen, Matt D.; Sobti, Meghna; Balachandran, Harikrishnan; Langley, David B.; Walker, Gregory J.; Lenthall, Helen; Jackson, Jennifer; Ubiparipovic, Stephanie; Mazigi, Ohan; Schofield, Peter; et al. (Nature Communications, 2023)
Emerging variants of concern (VOCs) are threatening to limit the effectiveness of SARS-CoV-2 monoclonal antibodies and vaccines currently used in clinical practice; broadly neutralizing antibodies and strategies for their identification are therefore urgently required. Here we demonstrate that broadly neutralizing antibodies can be isolated from peripheral blood mononuclear cells of convalescent patients using SARS-CoV-2 receptor binding domains carrying epitope-specific mutations. This is exemplified by two human antibodies, GAR05, binding to epitope class 1, and GAR12, binding to a new epitope class 6 (located between class 3 and 5). Both antibodies broadly neutralize VOCs, exceeding the potency of the clinical monoclonal sotrovimab (S309) by orders of magnitude. They also provide prophylactic and therapeutic in vivo protection of female hACE2 mice against viral challenge. Our results indicate that exposure to SARS-CoV-2 induces antibodies that maintain broad neutralization against emerging VOCs using two unique strategies: either by targeting the divergent class 1 epitope in a manner resistant to VOCs (ACE2 mimicry, as illustrated by GAR05 and mAbs P2C-1F11/S2K14); or alternatively, by targeting rare and highly conserved epitopes, such as the new class 6 epitope identified here (as illustrated by GAR12). Our results provide guidance for next generation monoclonal antibody development and vaccine design.
CRIS-Team Scopus Importer:2023-02-17

Btn2a2 Regulates ILC2-T Cell Cross Talk in Type 2 Immune Responses - Frech, Michael; Omata, Yasunori; Schmalzl, Angelika; Wirtz, Stefan; Taher, Leila; Schett, Georg; Zaiss, Mario; Sarter, Kerstin (Frontiers in Immunology, 2022)
Innate lymphoid cells (ILC) not only are responsible for shaping the innate immune response but also actively modulate T cell responses. However, the molecular processes regulating ILC-T cell interaction are not yet completely understood. The protein butyrophilin 2a2 (Btn2a2), a co-stimulatory molecule first identified on antigen-presenting cells, has a pivotal role in the maintenance of T cell homeostasis, but the main effector cell and the respective ligands remain elusive. We analyzed the role of Btn2a2 in the ILC-T cell cross talk. We found that the expression of Btn2a2 is upregulated in ILC2 following stimulation with IL-33/IL-25/TSLP. In vitro and in vivo experiments indicated that lack of Btn2a2 expression on ILC2 resulted in elevated T cell responses. We observed an enhanced proliferation of T cells as well as increased secretion of the type 2 cytokines IL-4/IL-5/IL-13 following cocultures with Btn2a2-deficient ILC2. In vivo transfer experiments confirmed the regulatory role of Btn2a2 on ILC2 as Btn2a2-deficient ILC2 induced stronger T cell responses and prevented chronic helminth infections. Taken together, we identified Btn2a2 as a significant player in the regulation of ILC2-T cell interactions.
CRIS-Team WoS Importer:2022-02-18

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

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

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

Canonical Wnt signaling in systemic sclerosis - Bergmann, Christina; Distler, Jörg (Laboratory Investigation, 2016)
Fibrosing disorders are characterized by abundant accumulation of extracellular matrix proteins such as collagen in a variety of organs, which results in structural changes and dysfunction of the affected organ. Thus fibrotic diseases are characterized by a high morbidity and mortality and also lead to major socioeconomic costs. Systemic sclerosis (SSc) is a prototypic multi-systemic fibrosing disease, which affects the skin and a variety of internal organs, including the lungs, heart and gastrointestinal tract. Targeted antifibrotic therapies are not yet available for clinical use in SSc. In recent years, canonical Wnt signaling has been profoundly characterized as an important mediator of sustained fibroblast activation in fibrotic diseases. In the present review, we will summarize current research on the canonical Wnt signaling pathway in SSc and discuss translational implications and potential limitations of prolonged Wnt inhibition.
EVALuna2:13238

Capability of Neutrophils to Form NETs Is Not Directly Influenced by a CMA-Targeting Peptide - Maueröder, Christian; Schall, Nicolas; Meyer, Frederic; Mahajan, Aparna; Garnier, Benjamin; Hahn, Jonas; Kienhoefer, Deborah; Hoffmann, Markus; Muller, Sylviane (Frontiers in Immunology, 2017)
During inflammatory reaction, neutrophils exhibit numerous cellular and immunological functions, notably the formation of neutrophil extracellular traps (NETs) and autophagy. NETs are composed of decondensed chromatin fibers coated with various antimicrobial molecules derived from neutrophil granules. NETs participate in antimicrobial defense and can also display detrimental roles and notably trigger some of the immune features of systemic lupus erythematosus (SLE) and other autoimmune diseases. Autophagy is a complex and finely regulated mechanism involved in the cell survival/death balance that may be connected to NET formation. To shed some light on the connection between autophagy and NET formation, we designed a number of experiments in human neutrophils and both in normal and lupus-prone MRL/lpr mice to determine whether the synthetic peptide P140, which is capable of selectively modulating chaperone-mediated autophagy (CMA) in lymphocytes, could alter NET formation. P140/Lupuzor(TM) is currently being evaluated in phase III clinical trials involving SLE patients. Overall our in vitro and in vivo studies established that P140 does not influence NET formation, cytokine/chemokine production, or CMA in neutrophils. Thus, the beneficial effect of P140/Lupuzor(TM) in SLE is apparently not directly related to modulation of neutrophil function.
EVALuna2:13403

Cardiomyopathy in murine models of systemic sclerosis - Venalis, Paulius; Kumanovics, Gabor; Schulze-Koops, Hendrik; Distler, Alfiya; Dees, Clara; Zerr, Pawel; Palumbo-Zerr, Katrin; Czirjak, Laszlo; Mackevic, Zygmunt; Lundberg, Ingrid E.; Distler, Oliver; Schett, Georg; et al. (Arthritis and Rheumatology, 2015)
Cardiomyopathy has emerged as a leading cause of death in patients with systemic sclerosis (SSc). However, the pathogenesis of SSc-related cardiomyopathy is poorly understood, and new therapies as well as platforms for testing are needed. The aim of this study was to characterize the histopathologic features of cardiomyopathy in patients with SSc and in common mouse models of SSc.The histopathologic features of myocardial tissue specimens obtained at autopsy from 5 subjects with SSc and 5 control subjects matched for sex, age, and cardiovascular risk factors were evaluated and compared with those of myocardial tissue specimens obtained from 3 common mouse models of SSc with systemic manifestations: Fra-2-transgenic mice, mice with sclerodermatous chronic graft-versus-host disease (GVHD), and TSK-1 mice.Myocardial tissue from autopsy subjects with SSc and no clinically manifest cardiac involvement showed endothelial cell apoptosis with reduced capillary density, perivascular inflammation, myofibroblast differentiation, and accumulation of collagen. Only selected features of SSc-related cardiomyopathy were observed in the mice with chronic GVHD and TSK-1 mice. However, the myocardial tissue of Fra-2-transgenic mice mimicked all features of SSc-related cardiomyopathy and also demonstrated comparable vascular, inflammatory, and fibrotic manifestations. Of note, the expression of Fra-2 was also increased in the myocardium of autopsy subjects with SSc.We demonstrate that all typical manifestations of SSc-related cardiomyopathy are mimicked in Fra-2-transgenic mice. Moreover, overexpression of Fra-2 in the myocardium of autopsy subjects with SSc may suggest similar underlying pathogenic mechanisms. Thus, Fra-2-transgenic mice might be a suitable preclinical model with which to study the mechanisms of and therapeutic approaches to myocardial involvement in SSc.
EVALuna2:13060

Cardiovascular Comorbidity in Inflammatory Rheumatological Conditions - Braun, Juergen; Krueger, Klaus; Manger, Bernhard; Schneider, Matthias; Specker, Christof; Trappe, Hans Joachim (Deutsches Ärzteblatt international, 2017)
Approximately 1.5 million adults in Germany suffer from an inflammatory rheumatological condition. The most common among these are rheumatoid arthritis and spondyloarthritis-above all axial spondyloarthritis, including ankylosing spondylitis (Bekhterev's disease) and psoriatic arthritis. These systemic inflammatory diseases often affect the heart as well.This review is based on pertinent articles retrieved by a selective literature search, on current European guidelines, and on the authors' clinical experience.Rheumatic inflammation of cardiac structures can manifest itself as pericarditis, myocarditis, or endocarditis. The heart valves and the intracardiac conduction system can be affected as well, leading to AV block. Functional sequelae, e.g., congestive heart failure, can arise as a consequence of any inflammatory rheumatic disease. The long-term mortality of rheumatic diseases is elevated predominantly because of the increased risk for cardiovascular comorbidities. The cardiovascular risk profile should therefore be re-evaluated regularly (e.g., at 5-year intervals) in cooperation with the patient's primary care physician. The cardiovascular manifestations of rheumatic disease, such as pericarditis, myocarditis, and vasculitis, are treated initially with high-dose glucocorticoids and then over the long term with maintenance drugs such as methotrexate and azathioprine. Biological agents are sometimes used as well.In patients with inflammatory rheumatic diseases, the elevated cardiovascular risk should be kept in mind and preventive measures should be initiated early. This subject should be further studied in controlled trials so that the treatment options for patients with cardiac involvement can be evaluated.
EVALuna2:13428

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

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

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

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

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

Cartilage Imaging: Standards and Perspectives Bildgebung des Knorpels: Standards und Perspektiven - Pachowsky, Milena; Welsch, Götz H. (Sport-Orthopädie, Sport-Traumatologie, 2022)
The treatment of articular cartilage injuries and damage is an important topic in sports orthopedics. Imaging has become essential as a complement to history and clinical examination in joint diagnosis and therapy monitoring. Magnetic Resonance Imaging (MRI) has become indispensable for the assessment of cartilage and cartilage damage. High-resolution morphologic and also biochemical MRI sequences now allow visualization of very fine cartilage pathologies. Morphologic imaging allows assessment of the extent of cartilage damage and adjacent structures, including the underlying bone; various scores have become established for this purpose. It also plays an important role in postoperative imaging after cartilage therapy. Compositional quantitative imaging aims to detect changes in the biochemical composition of cartilage and to develop quantitative values that allow objective assessment of tissue quality.
CRIS-Team Scopus Importer:2022-03-18
Keywords: Cartilage; Imaging; Magnetic Resonance Imaging

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

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

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

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

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

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

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

CCR6 is transiently upregulated on B cells after activation and modulates the germinal center reaction in the mouse - Wiede, Florian; Fromm, Phillip D.; Comerford, Iain; Kara, Ervin; Bannan, Jennifer; Schuh, Wolfgang; Ranasinghe, Charani; Tarlinton, David; Winkler, Thomas; Mccoll, Shaun R.; Koerner, Heinrich (Immunology and Cell Biology, 2013)
The CC-chemokine receptor 6 (CCR6) is expressed constitutively at an intermediate level on naive B cells and is upregulated after activation on pregerminal center (GC) B cells. We hypothesized that it could be involved in the events leading to GC reaction and high-affinity antibody production, and therefore investigated the potential role of CCR6 in B-cell differentiation in vivo. After antigenic challenge of CCR6(-/-) mice with the T-cell-dependent antigen nitrophenyl-keyhole limpet hemocyanin (NP-KLH), GC B-cell development was found to be accelerated and the number of GC had increased significantly compared with control mice, but the antibodies produced by CCR6(-/-) B cells were on average of lower affinity. We conclude from these data that the CCR6/CCL20 axis has an important role in regulating the kinetics and efficiency of the GC reaction.
Keywords: B cells; germinal centers; chemokine receptor

CD11C+DENDTRITIC CELLS IN INFLAMMATORY ARTHRITIS - Puchner, A.; Saferding, V.; Bonelli, M.; Leiss, H.; Pfeifle, René; Krönke, Gerhard; Smolen, J.; Redlich, K.; Blueml, S. (2018)
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CD19 CAR T-Cell Therapy in Autoimmune Disease - A Case Series with Follow-up. - Müller, Fabian; Taubmann, Jule; Bucci, Laura; Wilhelm, Artur; Bergmann, Christina; Völkl, Simon; Aigner, Michael; Rothe, Tobias; Minopoulou, Ioanna; Tur, Carlo; Knitza, Johannes; Kharboutli, Soraya; et al. (New England Journal of Medicine, 2024)
BACKGROUND: Treatment for autoimmune diseases such as systemic lupus erythematosus (SLE), idiopathic inflammatory myositis, and systemic sclerosis often involves long-term immune suppression. Resetting aberrant autoimmunity in these diseases through deep depletion of B cells is a potential strategy for achieving sustained drug-free remission. METHODS: We evaluated 15 patients with severe SLE (8 patients), idiopathic inflammatory myositis (3 patients), or systemic sclerosis (4 patients) who received a single infusion of CD19 chimeric antigen receptor (CAR) T cells after preconditioning with fludarabine and cyclophosphamide. Efficacy up to 2 years after CAR T-cell infusion was assessed by means of Definition of Remission in SLE (DORIS) remission criteria, American College of Rheumatology-European League against Rheumatism (ACR-EULAR) major clinical response, and the score on the European Scleroderma Trials and Research Group (EUSTAR) activity index (with higher scores indicating greater disease activity), among others. Safety variables, including cytokine release syndrome and infections, were recorded. RESULTS: The median follow-up was 15 months (range, 4 to 29). The mean (±SD) duration of B-cell aplasia was 112±47 days. All the patients with SLE had DORIS remission, all the patients with idiopathic inflammatory myositis had an ACR-EULAR major clinical response, and all the patients with systemic sclerosis had a decrease in the score on the EUSTAR activity index. Immunosuppressive therapy was completely stopped in all the patients. Grade 1 cytokine release syndrome occurred in 10 patients. One patient each had grade 2 cytokine release syndrome, grade 1 immune effector cell-associated neurotoxicity syndrome, and pneumonia that resulted in hospitalization. CONCLUSIONS: In this case series, CD19 CAR T-cell transfer appeared to be feasible, safe, and efficacious in three different autoimmune diseases, providing rationale for further controlled clinical trials. (Funded by Deutsche Forschungsgemeinschaft and others.).
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CD19 Chimeric Antigen Receptor T Cell Treatment: Unraveling the Role of B Cells in Systemic Lupus Erythematosus. - Taubmann, Jule; Müller, Fabian; Mutlu, Melek Yalcin; Völkl, Simon; Aigner, Michael; Bozec, Aline; Mackensen, Andreas; Grieshaber Bouyer, Ricardo; Schett, Georg (Arthritis and Rheumatology, 2024)
B cell generation of autoantibodies is a crucial step in the pathogenesis of systemic lupus erythematosus (SLE). After their differentiation in the bone marrow, B cells populate the secondary lymphatic organs, where they undergo further maturation leading to the development of memory B cells as well as antibody-producing plasmablasts and plasma cells. Targeting B cells is an important strategy to treat autoimmune diseases such as SLE, in which B cell tolerance is disturbed and autoimmune B cells and autoantibodies emerge. This review discusses the functional aspects of antibody- and cell-based B cell-depleting therapy in SLE. It thereby particularly focuses on lessons learned from chimeric antigen receptor (CAR) T cell treatment on the role of B cells in SLE for understanding B cell pathology in SLE. CAR T cells model a deep B cell depletion and thereby allow understanding the role of aberrant B cell activation in the pathogenesis of SLE. Furthermore, the effects of B cell depletion on autoantibody production can be better described, ie, explaining the concept of different cellular sources of (auto-) antibodies in the form of short-lived plasmablasts and long-lived plasma cells, which differ in their susceptibility to B cell depletion and require different targeted therapeutic approaches. Finally, the safety of deep B cell depletion in autoimmune disease is discussed.
EVALuna2:551941

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

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

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

CD200+ fibroblasts form a pro-resolving mesenchymal network in arthritis - Rauber, Simon; Mohammadian, Hashem; Schmidkonz, Christian; Atzinger, Armin; Soare, Alina; Treutlein, Christoph; Kemble, Samuel; Mahony, Christopher B.; Geisthoff, Manuel; Angeli, Mario Raphael; Raimondo, Maria Gabriella; Xu, Cong; et al. (Nature Immunology, 2024)
Fibroblasts are important regulators of inflammation, but whether fibroblasts change phenotype during resolution of inflammation is not clear. Here we use positron emission tomography to detect fibroblast activation protein (FAP) as a means to visualize fibroblast activation in vivo during inflammation in humans. While tracer accumulation is high in active arthritis, it decreases after tumor necrosis factor and interleukin-17A inhibition. Biopsy-based single-cell RNA-sequencing analyses in experimental arthritis show that FAP signal reduction reflects a phenotypic switch from pro-inflammatory MMP3+/IL6+ fibroblasts (high FAP internalization) to pro-resolving CD200+DKK3+ fibroblasts (low FAP internalization). Spatial transcriptomics of human joints indicates that pro-resolving niches of CD200+DKK3+ fibroblasts cluster with type 2 innate lymphoid cells, whereas MMP3+/IL6+ fibroblasts colocalize with inflammatory immune cells. CD200+DKK3+ fibroblasts stabilized the type 2 innate lymphoid cell phenotype and induced resolution of arthritis via CD200–CD200R1 signaling. Taken together, these data suggest a dynamic molecular regulation of the mesenchymal compartment during resolution of inflammation.
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CD45 functions as a signaling gatekeeper in T cells - Courtney, Adam H.; Shvets, Alexey A.; Lu, Wen; Griffante, Gloria; Mollenauer, Marianne; Horkova, Veronika; Lo, Wan Lin; Yu, Steven; Stepanek, Ondrej; Chakraborty, Arup K.; Weiss, Arthur (Science Signaling, 2019)
T cells require the protein tyrosine phosphatase CD45 to detect and respond to antigen because it activates the Src family kinase Lck, which phosphorylates the T cell antigen receptor (TCR) complex. CD45 activates Lck by opposing the negative regulatory kinase Csk. Paradoxically, CD45 has also been implicated in suppressing TCR signaling by dephosphorylating the same signaling motifs within the TCR complex upon which Lck acts. We sought to reconcile these observations using chemical and genetic perturbations of the Csk/CD45 regulatory axis incorporated with computational analyses. Specifically, we titrated the activities of Csk and CD45 and assessed their influence on Lck activation, TCR-associated ζ-chain phosphorylation, and more downstream signaling events. Acute inhibition of Csk revealed that CD45 suppressed ζ-chain phosphorylation and was necessary for a regulatable pool of active Lck, thereby interconnecting the activating and suppressive roles of CD45 that tune antigen discrimination. CD45 suppressed signaling events that were antigen independent or induced by low-affinity antigen but not those initiated by high-affinity antigen. Together, our findings reveal that CD45 acts as a signaling "gatekeeper," enabling graded signaling outputs while filtering weak or spurious signaling events.
CRIS-Team Scopus Importer:2019-10-29

Cell-in-cell structures are more potent predictors of outcome than senescence or apoptosis in head and neck squamous cell carcinomas - Schenker, Hannah; Buettner-Herold, Maike; Fietkau, Rainer; Distel, Luitpold (Radiation Oncology, 2017)
This study sheds light on cell inactivating processes with focus on the phenomenon of cell-in-cell (CIC). Cell-in-cell describes a cell process where one cell is being engulfed by another non-professional phagocyte. We determined frequency and prognostic impact of CIC structures (CICs) as well as of senescent and apoptotic cells in head and neck squamous cell carcinomas (HNSCC).These different forms of cell inactivation as well as the proportion of proliferating and tumor cells were assessed in 169 pre-radiochemotherapy biopsies and 32 post-therapy tumor resections by immunohistochemistry of tissue microarrays. Four consecutive cancer sections were stained with antibodies specific for E-cadherin for CIC detection, cleaved caspase-3 for apoptosis, H3K9Me for senescence and Ki67 as a proliferation marker. Positive events were quantified in corresponding tumor areas.CICs were found in 55.5%, senescent cells in 67.1% and apoptotic cells in 93.3% of samples. While no prognostic impact of apoptotic and senescent cells was observed, CICs turned out to significantly influence overall-survival (p = 0.016) with a lack of CICs being prognostically beneficial. There was no correlation between CICs and apoptosis and 98.9% of CICs were negative for cleaved caspase-3.CIC formation is a frequent event in HNSCC and a superior predictive marker compared to senescence and apoptosis. Independence of CIC and apoptosis and the adverse prognosis associated with numerous CICs lead to the assumption that CICs might take up necrotic rather than apoptotic cells preventing an adequate antitumoral immune response that would otherwise be initiated by necrotic cells through damage-associated molecular pattern molecules.
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Cellular and humoral immune responses to SARS-CoV-2 vaccination in patients after CD19.CAR T-cell therapy - Reimann, Hannah; Kremer, Anita; Blumenberg, Viktoria; Schmidt, Katja; Aigner, Michael; Jacobs, Benedikt; Eisenhauer, Nina; Kämpf, Alina; Rösler, Wolf; Kharboutli, Soraya; Mougiakakos, Dimitrios; Lang, Vanessa; et al. (Blood Advances, 2023)
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Cellular and molecular mechanisms in fibrosis - Dees, Clara; Chakraborty, Debomita; Distler, Jörg (Experimental Dermatology, 2020)
The activation of fibroblasts is required for physiological tissue remodelling such as wound healing. However, when the regulatory mechanisms are disrupted and fibroblasts remain persistently activated, the progressive deposition of extracellular matrix proteins leads to tissue fibrosis, which results in dysfunction or even loss of function of the affected organ. Although fibrosis has been recognized as a major cause of morbidity and mortality in modern societies, there are only few treatment options available that directly disrupt the release of extracellular matrix from fibroblasts. Intensive research in recent years, however, identified several pathways as core fibrotic mechanisms that are shared across different fibrotic diseases and organs. We discuss herein selection of those core pathways, especially downstream of the profibrotic TGF-β pathway, which are druggable and which may be transferable from bench to bedside.
CRIS-Team Scopus Importer:2020-10-23
Keywords: extracellular matrix; fibroblasts; fibrosis; systemic sclerosis

Cellular and molecular pathways of structural damage in rheumatoid arthritis - Harre, Ulrike; Schett, Georg (Seminars in Immunopathology, 2017)
Structural damage of cartilage and bone tissue is a hallmark of rheumatoid arthritis (RA). The resulting joint destruction constitutes one of the major disease consequences for patients and creates a significant burden for the society. The main cells executing bone and cartilage degradation are osteoclasts and fibroblast-like synoviocytes, respectively. The function of both cell types is heavily influenced by the immune system. In the last decades, research has identified several mediators of structural damage, ranging from infiltrating immune cells and inflammatory cytokines to autoantibodies. These factors result in an inflammatory milieu in the affected joints which leads to an increased development and function of osteoclasts and the transformation of fibroblast-like synoviocytes towards a highly migratory and destructive phenotype. In addition, repair mechanisms mediated by osteoblasts and chondrocytes are strongly impaired by the presence of pro-inflammatory cytokines. This article will review the current knowledge on the mechanisms of joint inflammation and the destruction of bone and cartilag
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Cellular plasticity and myeloid inflammation in the adult brain are independent of the transcriptional modulator DREAM - Masanetz, Rebecca Katharina; Baum, Wolfgang; Schett, Georg; Winkler, Jürgen; Süß, Patrick (Neuroscience Letters, 2023)
The downstream regulatory element antagonist modulator (DREAM) modulates ion channel function and gene transcription. Functionally, DREAM is implicated in physiological and pathological processes including cell proliferation, inflammation, and nociception. Despite its multiple functions and robust expression in forebrain tissue, neurons and glial cells, the role of DREAM in regard to cellular plasticity and tumor necrosis factor (TNF)-mediated inflammation is largely unexplored. Here, we demonstrate that adult hippocampal neurogenesis as well as the density and plasticity of glial cells in the hippocampus and thalamus are independent of the presence of DREAM. Further, DREAM deletion does not alter the regional myeloid response and inflammatory gene expression induced by chronic peripheral inflammation in mice overexpressing human TNF. Our data suggest that despite their highly dynamic regulation, neural cell plasticity and adult neurogenesis in the hippocampus do not depend on the multifunctional protein DREAM. Furthermore, TNF-mediated myeloid inflammation in the brain persists in the absence of DREAM.
CRIS-Team Scopus Importer:2023-01-20
Keywords: Adult hippocampal neurogenesis; DREAM; Glia; Neuroinflammation; Pain; Proliferation

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

Cerebrospinal Fluid of Patients With Alzheimer's Disease Contains Increased Percentages of Synaptophysin-Bearing Microvesicles - Utz, Janine; Berner, Judith; Munoz, Luis Enrique; Oberstein, Timo; Kornhuber, Johannes; Herrmann, Martin; Maler, Juan Manuel; Spitzer, Philipp (Frontiers in Aging Neuroscience, 2021)
Introduction In Alzheimer's disease, the severity of symptoms is linked to a loss of synaptic density and the spread of pathologically hyperphosphorylated tau. The established cerebrospinal fluid markers A beta, tau and phospho-tau reflect the histopathological hallmarks of Alzheimer's disease but do not indicate disease progression. Such markers are of special interest, especially for trials of disease modifying drugs. Microvesicles are produced by stressed cells and reflect part of the metabolism of their cells of origin. Therefore, we investigated microvesicles of neuronal origin in cerebrospinal fluid. Materials and Methods We used flow cytometry to analyze microvesicles carrying tau, phospho-tau-Thr181, phospho-tau-Ser202Thr205, synaptophysin, and SNAP-25 in the cerebrospinal fluid of 19 patients with Alzheimer's disease and 15 non-inflammatory neurological disease controls. Results The percentages of synaptophysin-bearing microvesicles were significantly higher in the cerebrospinal fluid of patients with Alzheimer's disease than in the CSF of non-inflammatory neurological disease controls. Tau, phospho-tau-Thr181, phospho-tau-Ser202Thr205, and SNAP-25 did not differ between the groups. The percentages of synaptophysin-bearing vesicles distinguished patients with Alzheimer's disease from the controls (AUC = 0.81). Conclusion The loss of synapses in Alzheimer's disease may be reflected by synaptophysin-bearing microvesicles in the cerebrospinal fluid. Future studies are needed to investigate the possibility of using these MVs as a marker to determine the activity of Alzheimer's disease.
CRIS-Team WoS Importer:2021-07-30

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

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

Changes in T2 Relaxation Time Mapping of Intervertebral Discs Adjacent to Vertebrae after Kyphoplasty Correlate with the Physical Clinical Outcome of Patients - Wegener, Lisa; Werner, Felix; Kleyer, Arnd; Simon, David; Uder, Michael; Janka, Rolf Matthias; Trattnig, Siegfried; Welsch, Goetz H.; Pachowsky, Milena (Diagnostics, 2022)
(1) Background: To assess whether clinical outcomes correlate with tissue changes in the intervertebral discs (IVDs) after kyphoplasty as treatment for vertebral fractures, quantitative MRI was applied. (2) Methods: Quantitative T2 mapping acquired in a 3 T MRI scanner of the thoracolumbar spine was performed in 20 patients two years after kyphoplasty. The IVDs adjacent and nonadjacent to the treated vertebrae were divided into six regions of interest (ROI), which were further categorised into inner (ROI 2–5) and outer (ROI 1 and 6) parts of the IVDs, and the T2 values were analysed. T2 values of adjacent discs were correlated with the items of questionnaires evaluating the clinical outcome (i.e., 36-Item Short Form Survey). (3) Results: Lower T2 values in adjacent IVDs correlated with poorer physical outcome two years after kyphoplasty. The inner part of the IVDs adjacent to treated vertebrae showed statistically significant lower T2 values in segments L2/L3 and L3/L4 compared to nonadjacent ones. Patients with lower T2 values showed more pain and physical limitations in everyday life. (4) Conclusions: Quantitative T2 mapping can detect IVD degeneration in patients after kyphoplasty and correlates with the physical outcome. This technique could help to gain better insights into alterations in tissue composition following kyphoplasty and the consequences for the patients’ quality of life.
CRIS-Team Scopus Importer:2022-03-11
Keywords: Clinical outcome; Intervertebral disc; Kyphoplasty; MRI; T2 mapping

Changing focus of symptoms: A rare case report of Munchhausen's syndrome - Hagen, Melanie; Faust, Beatrice; Kunzelmann, Nina; Tektas, Ozan Y.; Kornhuber, Johannes; Mueller, Helge H. O. (Mental Illness, 2017)
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Characteristics of emerging new autoimmune diseases after COVID-19 vaccination: A sub-study by the COVAD group - Shumnalieva, Russka; Ravichandran, Naveen; Hannah, Jennifer; Javaid, Mahnoor; Darooka, Naitica; Roy, Debaditya; Gonzalez, Daniel E.; Velikova, Tsvetelina; Milchert, Marcin; Kuwana, Masataka; Joshi, Mrudula; Gracia-Ramos, Abraham Edgar; et al. (International Journal of Rheumatic Diseases, 2024)
Background: Despite the overall safety and efficacy of COVID-19 vaccinations, rare cases of systemic autoimmune diseases (SAIDs) have been reported post-vaccination. This study used a global survey to analyze SAIDs in susceptible individuals' post-vaccination. Methods: A cross-sectional study was conducted among participants with self-reported new-onset SAIDs using the COVID-19 Vaccination in Autoimmune Diseases (COVAD) 2 study dataset—a validated, patient-reported e-survey—to analyze the long-term safety of COVID-19 vaccines. Baseline characteristics of patients with new-onset SAIDs and vaccinated healthy controls (HCs) were compared after propensity score matching based on age and sex in a 1:4 ratio. Results: Of 16 750 individuals, 74 (median age 52 years, 79.9% females, and 76.7% Caucasians) had new-onset SAID post-vaccination, mainly idiopathic inflammatory myopathies (IIMs) (n = 23, 31.51%), arthritis (n = 15; 20.53%), and polymyalgia rheumatica (PMR) (n = 12, 16.40%). Higher odds of new-onset SAIDs were noted among Caucasians (OR = 5.3; 95% CI = 2.9–9.7; p <.001) and Moderna vaccine recipients (OR = 2.7; 95% CI = 1.3–5.3; p =.004). New-onset SAIDs were associated with AID multimorbidity (OR = 1.4; 95% CI = 1.1–1.7; p <.001), mental health disorders (OR = 1.6; 95% CI = 1.3–1.9; p <.001), and mixed race (OR = 2.2; 95% CI = 1.2–4.2; p =.010), where those aged >60 years (OR = 0.6; 95% CI = 0.4–0.8; p =.007) and from high/medium human development index (HDI) countries (compared to very high HDI) reported fewer events than HCs. Conclusion: This study reports a low occurrence of new-onset SAIDs following COVID-19 vaccination, primarily IIMs, PMR, and inflammatory arthritis. Identified risk factors included pre-existing AID multimorbidity, mental health diseases, and mixed race. Revaccination was well tolerated by most patients; therefore, we recommend continuing COVID-19 vaccination in the general population. However, long-term studies are needed to understand the autoimmune phenomena arising post-vaccination.
CRIS-Team Scopus Importer:2024-05-24
Keywords: autoimmune diseases; COVID-19; idiopathic inflammatory myopathies; SAIDs; vaccination

Characterization and quantification of angiogenesis in rheumatoid arthritis in a mouse model using ?CT - Gayetskyy, Svitlana; Museyko, Oleg; Käßer, Johannes; Heß, Andreas; Schett, Georg; Engelke, Klaus (BMC Musculoskeletal Disorders, 2014)
Angiogenesis is an important pathophysiological process of chronic inflammation, especially in inflammatory arthritis. Quantitative measurement of changes in vascularization may improve the diagnosis and monitoring of arthritis. The aim of this work is the development of a 3D imaging and analysis framework for quantification of vascularization in experimental arthritis.High-resolution micro-computed tomography (?CT) was used to scan knee joints of arthritic human tumor necrosis factor transgenic (hTNFtg) mice and non-arthritic wild-type controls previously perfused with lead-containing contrast agent Microfil MV-122. Vessel segmentation was performed by combination of intensity-based (local adaptive thresholding) and form-based (multi-scale method) segmentation techniques. Four anatomically defined concentric spherical shells centered in the knee joint were used as analysis volumes of interest. Vessel density, density distribution as well as vessel thickness, surface, spacing and number were measured. Simulated digital vessel tree models were used for validation of the algorithms.High-resolution ?CT allows the quantitative assessment of the vascular tree in the knee joint during arthritis. Segmentation and analysis were highly automated but occasionally required manual corrections of the vessel segmentation close to the bone surfaces. Vascularization was significantly increased in arthritic hTNFtg mice compared to wild type controls. Precision errors for the morphologic parameters were smaller than 3% and 6% for intra- and interoperator analysis, respectively. Accuracy errors for vessel thickness were around 20% for vessels larger than twice the resolution of the scanner.Arthritis-induced changes of the vascular tree, including detailed and quantitative description of the number of vessel branches, length of vessel segments and the bifurcation angle, can be detected by contrast-enhanced high-resolution ?CT.
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Characterization of CD4+ T cells primed and boosted by MHCII primary uveal melanoma cell-based vaccines - Kittler, Julia; Sommer, Jonas; Fischer, Anika; Britting, Sabine; Karg, Margarete; Bock, Barbara; Atreya, Imke; Heindl, Ludwig M.; Mackensen, Andreas; Bosch, Jacobus J. (Oncotarget, 2019)
Uveal melanoma is the most common primary malignancy of the eye in adults. Despite significant improvements in treatment of the primary tumor, to date none of these therapies prevent metastatic disease or improve overall survival. We are exploring immunotherapeutic options for metastatic uveal melanoma using MHC II uveal melanoma cell-based vaccines that target the activation of tumor-reactive CD4+ T cells. Previously, we showed that these uveal melanoma cell-based vaccines activate CD4+ T cells within total peripheral blood lymphocytes (PBMC). Since PBMC include professional antigen presenting cells, we now demonstrate that Mel202/ DR1/CD80 vaccine cells directly activate a diverse repertoire of purified, naïve CD4+ T cells. The activated CD4+ T cells proliferated, secreted high amounts of interferon gamma (IFNγ) and produced a heterogeneous profile of Th1, Th2 and Th17 cytokines. Analysis of the TCR-Vβ-repertoire showed that a polyclonal T cell response was induced, suggesting the capacity of vaccine-activated CD4+ T cells to target multiple tumor (neo)antigens. In addition, a subset of the responding CD4+ T cells expressed forkhead box protein P3 (FoxP3), indicating that although a regulatory component of the vaccine-activated CD4+ T cell response was induced, the anti-tumor vaccine response was not limited by these regulatory CD4+ T cells. Finally, Mel202/DR1/CD80 uveal melanoma vaccine cells expressed the intercellular adhesion molecule 1 (ICAM-1) that was pivotal for CD4+ T cell activation via lymphocyte function-associated antigen 1(LFA-1). In conclusion, MHC II uveal melanoma vaccines activate purified CD4+ T cells and may serve as a novel immunotherapy for uveal melanoma patients.
CRIS-Team Scopus Importer:2019-06-07
Keywords: CD4+ T cells; ICAM-1; T cell activation; Tumor immunity; Uveal melanoma

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

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

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

Characterizations of drug carrying magnetic nanoparticles for tumor therapy: Biological outcome and first immunological aspects - Dürr, Stephan; Tietze, Rainer; Lyer, Stefan; Janko, Christina; Schreiber, Eveline; Mann, Johannes; Turcu, R.; Gitter, K.; Odenbach, S.; Vasylyev, Serhiy; Herrmann, Martin; Peukert, Wolfgang; et al. (Magnetohydrodynamics, 2013)
Nanosized magnetic drug carriers offer a splendid prospect for directed drug application. The increased drug concentration in cancer tissue reached for this kind of application enables therapeutic effects on tumors that cannot be achieved using conventional chemotherapeutic treatment. Characterizing the drug targeting system and its behavior in vitro is necessary for understanding the biological outcome. In our studies, IRspectroscopy shows covalent binding of the biocompatible fatty acid layer. Although binding of mitoxantrone (MTO) to particles is hardly defined, considerable amounts of drug can be carried by nanoparticles. Furthermore, the nanosized drug carrier complex has to be investigated due to its biological outcome. Real-time cell analysis is useful to observe the therapeutic particles concerning their outcome in cell culture time-resolved up to several days. First experiments in concordance to a conventional assay show that the effectivity of nanoparticle bound MTO in cell culture is higher than treatment with pure MTO. A preliminary study demonstrates that the burden of the immune system is reduced by Magnetic Drug Targeting (MDT) vs. conventional chemotherapy. For a better understanding of MDT for cancer treatment, further studies have to be done to explain especially the binding behavior of superparamagnetic iron oxide nanoparticles to the respective chemotherapeutic agent.
Keywords: nano; magnetic; characterization; particle; agent

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

Checkpoint Inhibitors - Heinzerling, Lucie; De Toni, Enrico N.; Schett, Georg; Hundorfean, Gheorghe; Zimmer, Lisa (Deutsches Ärzteblatt international, 2019)
BACKGROUND: Treatment with checkpoint inhibitors such as anti-programmed death-1 (anti-PD-1), anti-PD-ligand 1 (anti-PD-L1), and anti-cytotoxic T-lymphocyte antigen-4 (anti-CTLA-4) antibodies can prolong the survival of cancer patients, but it also induces autoimmune side effects in 86-96% of patients by activating the immune system. In 17-59% of patients, these are severe or even life-threatening. METHODS: This review is based on pertinent articles retrieved by a search in PubMed and on an evaluation of a side-effect registry. RESULTS: Checkpoint-inhibitor-induced autoimmune side effects manifest themselves in all organ systems, most commonly as skin lesions (46-62%), autoimmune colitis (22-48%), autoimmune hepatitis (7-33%), and endocrinopathies (thyroiditis, hypophysitis, adrenalitis, diabetes mellitus; 12-34%). Rarer side effects include pneumonitis (3-8%), nephritis (1-7%), cardiac side effects including cardiomyositis (5%), and neurological side effects (1-5%). Severe (sometimes lethal) side effects arise in 17-21%, 20-28%, and 59% of patients undergoing anti-PD-1 and anti- CTLA-4 antibody treatment and the approved combination therapy, respectively. With proper monitoring, however, these side effects can be recognized early and, usually, treated with success. Endocrine side effects generally require long-term hormone substitution. Patients who have stopped taking checkpoint inhibitors because of side effects do not show a poorer response of their melanoma or shorter survival in comparison to patients who continue to take checkpoint inhibitors. CONCLUSION: The complex management of checkpoint-inhibitor-induced side effects should be coordinated in experienced centers. The creation of an interdisciplinary "tox team" with designated experts for organ-specific side effects has proven useful. Prospective registry studies based on structured documentation of side effects in routine clinical practice are currently lacking and urgently needed.
EVALuna2:69389

Checkpoint Inhibitors The Diagnosis and Treatment of Side Effects - Heinzerling, Lucie; De Toni, Enrico N.; Schett, Georg; Hundorfean, Gheorghe; Zimmer, Lisa (Deutsches Ärzteblatt international, 2019)
Background: Treatment with checkpoint inhibitors such as anti-programmed death-1 (anti-PD-1), anti-PD-ligand 1 (anti-PD-L1), and anti-cytotoxic T-Iymphocyte antigen-4 (anti-CTLA-4) antibodies can prolong the survival of cancer patients, but it also induces autoimmune side effects in 86-96% of patients by activating the immune system. In 17-59% of patients, these are severe or even life-threatening.
CRIS-Team WoS Importer:2019-04-12

Chemical Tools for Targeted Amplification of Reactive Oxygen Species in Neutrophils - Reshetnikov, Viktor; Hahn, Jonas; Maueroeder, Christian; Czegley, Christine; Munoz, Luis Enrique; Herrmann, Martin; Hoffmann, Markus; Mokhir, Andriy (Frontiers in Immunology, 2018)
A number of chemical compounds are known, which amplify the availability of reactive oxygen species (ROS) in neutrophils both in vitro and in vivo. They can be roughly classified into NADPH oxidase 2 (NOX2)-dependent and NOX2-independent reagents. NOX2 activation is triggered by protein kinase C agonists (e.g., phorbol esters, transition metal ions), redox mediators (e.g., paraquat) or formyl peptide receptor (FPR) agonists (e.g., aromatic hydrazine derivatives). NOX2-independent mechanisms are realized by reagents affecting glutathione homeostasis (e.g., L-buthionine sulfoximine), modulators of the mitochondrial respiratory chain (e.g., ionophores, inositol mimics, and agonists of peroxisome proliferator-activated receptor gamma) and chemical ROS amplifiers [e.g., aminoferrocene-based prodrugs (ABPs)]. Since a number of inflammatory and autoimmune diseases, as well as cancer and bacterial infections, are triggered or enhanced by aberrant ROS production in neutrophils, it is tempting to use ROS amplifiers as drugs for the treatment of these diseases. However, since the known reagents are not cell specific, their application for treatment likely causes systemic enhancement of oxidative stress, leading to severe side effects. Cell-targeted ROS enhancement can be achieved either by using conjugates of ROS amplifiers with ligands binding to receptors expressed on neutrophils (e.g., the GPI-anchored myeloid differentiation marker Ly6G or FPR) or by designing reagents activated by neutrophil function [e.g., phagocytic activity or enzymatic activity of neutrophil elastase (NE)]. Since binding of an artificial ligand to a receptor may trigger or inhibit priming of neutrophils the latter approach has a smaller potential for severe side effects and is probably better suitable for therapy. Here, we review current approaches for the use of ROS amplifiers and discuss their applicability for treatment. As an example, we suggest a possible design of neutrophil-specific ROS amplifiers, which are based on NE-activated ABPs.
EVALuna2:213257

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

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

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

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

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

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

Chronic viral infections in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) - Rasa, Santa; Nora-Krukle, Zaiga; Henning, Nina; Eliassen, Eva; Shikova, Evelina; Harrer, Thomas; Scheibenbogen, Carmen; Murovska, Modra; Prusty, Bhupesh K. (Journal of Translational Medicine, 2018)
Background and main text: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a complex and controversial clinical condition without having established causative factors. Increasing numbers of cases during past decade have created awareness among patients as well as healthcare professionals. Chronic viral infection as a cause of ME/CFS has long been debated. However, lack of large studies involving well-designed patient groups and validated experimental set ups have hindered our knowledge about this disease. Moreover, recent developments regarding molecular mechanism of pathogenesis of various infectious agents cast doubts over validity of several of the past studies. Conclusions: This review aims to compile all the studies done so far to investigate various viral agents that could be associated with ME/CFS. Furthermore, we suggest strategies to better design future studies on the role of viral infections in ME/CFS.
EVALuna2:213248

Cinematic Rendering Enables Depiction of Bone Anabolic Effects in Patients Treated with Baricitinib - Bayat, Sara; Simon, David; Schuster, Louis; Schett, Georg; Kleyer, Arnd (ARTHRITIS & RHEUMATOLOGY, 2020)
CRIS-Team WoS Importer:2021-01-15

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

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

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

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

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

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

Clearance Deficiency and Cell Death Pathways: A Model for the Pathogenesis of SLE - Mahajan, Aparna; Herrmann, Martin; Munoz, Luis Enrique (Frontiers in Immunology, 2016)
Alterations of cell death pathways, including apoptosis and the neutrophil specific kind of death called NETosis, can represent a potential source of autoantigens. Defects in the clearance of apoptotic cells may be responsible for the initiation of systemic autoimmunity in several chronic inflammatory diseases, including systemic lupus erythematosus (SLE). Autoantigens are released mainly from secondary necrotic cells because of a defective clearance of apoptotic cells or an inefficient degradation of DNA-containing neutrophil extracellular traps (NETs). These modified autoantigens are presented by follicular dendritic cells to autoreactive B cells in germinal centers of secondary lymphoid organs. This results in the loss of self-tolerance and production of autoantibodies, a unifying feature of SLE. Immune complexes (IC) are formed from autoantibodies bound to uncleared cellular debris in blood or tissues. Clearance of IC by blood phagocytes, macrophages, and dendritic cells leads to proinflammatory cytokine secretion. In particular, plasmacytoid dendritic cells produce high amounts of interferon-? upon IC uptake, thereby contributing to the interferon signature of patients with SLE. The clearance of antinuclear IC via Fc-gamma receptors is considered a central event in amplifying inflammatory immune responses in SLE. Along with this, the accumulation of cell remnants represents an initiating event of the etiology, while the subsequent generation of autoantibodies against nuclear antigens (including NETs) results in the perpetuation of inflammation and tissue damage in patients with SLE. Here, we discuss the implications of defective clearance of apoptotic cells and NETs in the development of clinical manifestations in SLE.
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Cleaved N-terminal histone tails distinguish between NADPH oxidase (NOX)-dependent and NOX-independent pathways of neutrophil extracellular trap formation - Pieterse, Elmar; Rother, Nils; Yanginlar, Cansu; Gerretsen, Jelle; Böltz, Sebastian; Munoz, Luis Enrique; Herrmann, Martin; Pickkers, Peter; Hilbrands, Luuk B.; Van Der Vlag, Johan (Annals of the Rheumatic Diseases, 2018)
Keywords: inflammation; psoriatic arthritis; autoimmune diseases; rheumatoid arthritis; systemic lupus erythematosus

Cleaved N-terminal histone tails distinguish between NADPH oxidase (NOX)-dependent and NOX-independent pathways of neutrophil extracellular trap formation - Pieterse, Elmar; Rother, Nils; Yanginlar, Cansu; Gerretsen, Jelle; Boeltz, Sebastian; Munoz, Luis Enrique; Herrmann, Martin; Pickkers, Peter; Hilbrands, Luuk B.; Van Der Vlag, Johan (Annals of the Rheumatic Diseases, 2018)
OBJECTIVES: Neutrophil extracellular traps (NETs) act in various rheumatic diseases. Although NET formation was originally described as a nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (NOX)-dependent pathway, it appears that there are also NOX-independent pathways of NET release. Currently, no tools are available that can discriminate between both NET-forming pathways. We aimed to develop a serological method allowing the discrimination between NETs generated through NOX-dependent or NOX-independent pathways. METHODS: Histones from in vitro generated NOX-dependent and NOX-independent NETs were characterised with a panel of lupus-derived antibodies against N-terminal histone tails using immunofluorescence microscopy, western blot and ELISA. NETs in patients with NET-associated diseases, that is, rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), psoriatic arthritis (PsA) and sepsis, were characterised in sandwich ELISAs employing antibodies against myeloperoxidase (MPO) and N-terminal histone tails as detecting and capturing antibodies, respectively. Functional responses of endothelial cells to NOX-dependent and NOX-independent NETs were assessed as well. RESULTS: Neutrophil elastase cleaves the N-terminal tails of core histones during NOX-dependent, but not during NOX-independent NET formation. Consequently, the detection of MPO-histone complexes with antibodies against N-terminal histone tails allows discrimination between NETs formed through a NOX-dependent or NOX-independent manner. Characterisation of in vivo circulating NETs revealed the presence of NOX-independent NETs in RA, SLE and sepsis, but NOX-dependent NETs in PsA. NOX-independent NETs displayed an increased capacity to activate endothelial cells when compared with NOX-dependent NETs. CONCLUSIONS: These results indicate heterogeneity in NET-forming pathways in vivo and highlight the need for disease-specific strategies to prevent NET-mediated pathology.
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Clinical and radiographic outcomes at 2 years and the effect of tocilizumab discontinuation following sustained remission in the second and third year of the ACT-RAY study - Huizinga, T. W. J.; Conaghan, Philip G.; Martin-Mola, Emilio; Schett, Georg; Amital, Howard; Xavier, Ricardo M.; Troum, Orrin; Aassi, Maher; Bernasconi, Corrado; Dougados, Maxime (Annals of the Rheumatic Diseases, 2015)
To assess the efficacy and safety of tocilizumab (TCZ) plus methotrexate/placebo (MTX/PBO) over 2 years and the course of disease activity in patients who discontinued TCZ due to sustained remission.ACT-RAY was a double-blind 3-year trial. Patients with active rheumatoid arthritis despite MTX were randomised to add TCZ to ongoing MTX (add-on strategy) or switch to TCZ plus PBO (switch strategy). Using a treat-to-target approach, open-label conventional synthetic disease-modifying antirheumatic drugs (csDMARDs), other than MTX, were added from week 24 if Disease Activity Score in 28 joints based on erythrocyte sedimentation rate (DAS28-ESR) >3.2. Between weeks 52 and 104, patients in sustained clinical remission (DAS28-ESR <2.6 at two consecutive visits 12 weeks apart) discontinued TCZ and were assessed every 4 weeks for 1 year. If sustained remission was maintained, added csDMARDs, then MTX/PBO, were discontinued.Of the 556 randomised patients, 76% completed year 2. Of patients entering year 2, 50.4% discontinued TCZ after achieving sustained remission and 5.9% achieved drug-free remission. Most patients who discontinued TCZ (84.0%) had a subsequent flare, but responded well to TCZ reintroduction. Despite many patients temporarily stopping TCZ, radiographic progression was minimal, with differences favouring add-on treatment. Rates of serious adverse events and serious infections per 100 patient-years were 12.2 and 4.4 in add-on and 15.0 and 3.7 in switch patients. In patients with normal baseline values, alanine aminotransferase elevations >3×upper limit of normal were more frequent in add-on (14.3%) versus switch patients (5.4%).Treat-to-target strategies could be successfully implemented with TCZ to achieve sustained remission, after which TCZ was stopped. Biologic-free remission was maintained for about 3 months, but most patients eventually flared. TCZ restart led to rapid improvement.NCT00810199.
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CLINICAL CHARACTERISTICS AND PROGNOSIS OF PATIENTS WITH SYSTEMIC SCLEROSIS SINE SCLERODERMA: DATA FROM THE INTERNATIONAL EUSTAR DATABASE. - Lescoat, A.; Huang, S.; Carreira, P.; Siegert, E.; De Vries-Bouwstra, J.; Distler, Jörg; Smith, V.; Del Galdo, F.; Anic, B.; Damjanov, N.; Rednic, S.; Ribi, C.; et al. (ANNALS OF THE RHEUMATIC DISEASES, 2022)
CRIS-Team WoS Importer:2022-11-04

Clinical course of acute deep vein thrombosis of the legs in Behçet's syndrome - Ozguler, Yesim; Hatemi, Gulen; Cetinkaya, Firat; Tascilar, Koray; Hamuryudan, Vedat; Ugurlu, Serdal; Seyahi, Emire; Yazici, Hasan; Melikoglu, Melike (Rheumatology, 2020)
OBJECTIVES: Lower extremity deep vein thrombosis (LEDVT) is a serious complication of Behçet's syndrome. Management constitutes mainly of administration of immunosuppressives, but the predictors of relapse and the optimal choice of immunosuppressives remain unclear. In this prospective study, we aimed to detect the risk and predictors of relapse and treatment response to different modalities. METHODS: All Behçet's syndrome patients who presented with a first episode of acute LEDVT between 2010 and 2014 were prospectively followed with a standard protocol. Acute LEDVT was confirmed by Doppler ultrasonography. Serial planned Doppler ultrasonography assessments were performed during follow-up and additionally repeated in case of clinical suspicion. Recanalization rate was assessed at each visit. Our first-line treatment strategy consisted of AZA and CSs. IFN-alpha was used in patients who were refractory to or could not tolerate AZA or had concomitant eye involvement requiring further treatment. RESULTS: Thirty-three patients with LEDVT (26 M/7 F) were prospectively followed for 40.7 ± 13.4 months. Among the 33 patients, 23 relapses were observed in 15 patients. Relapse rates were 29%, 37% and 45% at 6, 12 and 24 months, respectively. Among the possible predictors of relapse, poor recanalization was the only significant factor [hazard ratio 4.34 (95% CI 1.96, 10.0)]. Overall 29 patients were treated with AZA and 17 with IFN-alpha. The relapse rate was lower and recanalization rate was higher with IFN-alpha compared with AZA (12% vs 45% and 86% vs 45%). CONCLUSION: The relapse rate for LEDVT in Behçet's syndrome is high despite AZA treatment. IFN-alpha seems to be a promising agent for preventing LEDVT relapses and achieving good recanalization.
CRIS-Team Scopus Importer:2020-04-07
Keywords: Behçet’s syndrome; interferon-alpha; lower extremity deep vein thrombosis; recanalization; relapse

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

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

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

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

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

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

Clinical outcomes and immunogenicity analysis over 6 months following a switch from originator infliximab (Remicade (R)) to the biosimilar SB2 (Flixabi (R)) in inflammatory bowel disease patients - Fischer, Sven Moritz; Klenske, E.; Schmitt, H.; Vitali, Francesco; Hirschmann, S.; Koch, F.; Ramming, A.; Zundler, Sebastian; Nagore, D.; Uter, Wolfgang; Neurath, Markus; Atreya, Raja (2018)
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Clinical pharmacology of filgotinib in the treatment of rheumatoid arthritis: current insights - Raimondo, Maria Gabriella; Biggioggero, Martina; Coletto, Lavinia Agra; Ramming, Andreas; Caporali, Roberto; Favalli, Ennio Giulio (Expert Review of Clinical Pharmacology, 2021)
Introduction: Rheumatoid arthritis (RA) is a chronic autoimmune disease, whose natural course has been deeply modified thanks to the development of new therapeutic approaches. The Janus kinase inhibitors (Jakinibs) represent the newest class of drugs introduced for treating RA. Among these, Filgotinib (FIL) has been developed as Janus kinase1 (JAK1) selective inhibitor, specifically targeting key pro-inflammatory mediators in RA pathogenesis. Areas covered: This narrative review provides an overview on FIL as new therapeutic approach for RA, with focus on its pharmacological properties, clinical efficacy, and safety profile. The following electronic databases were adopted for the study search: PubMed, Google Scholar, ClinicalTrials.gov and Abstract archive from the American College of Rheumatology and the European Alliance of Associations for Rheumatology. Expert opinion: The phase II and phase III randomized controlled trials (RCTs) performed so far and their long-term extensions showed a comparable clinical efficacy of FIL to biologic treatments, with an acceptable safety profile. Thanks to these data, FIL was approved in Europe and Japan for the treatment of active RA, increasing the spectrum of therapeutic approaches and improving the possibility of a more tailored therapeutic strategy. Real-life data and head-to-head clinical trials will be needed to confirm its efficacy and safety.
CRIS-Team Scopus Importer:2021-04-30
Keywords: Filgotinib; JAK inhibitors; JAK1; rheumatoid arthritis; therapy

Clinical presentation and genetic variants in patients with autoinflammatory diseases: results from the German GARROD registry - Blank, Norbert; Kötter, Ina; Schmalzing, Marc; Rech, Jürgen; Krause, Karoline; Köhler, Birgit; Kaudewitz, Dorothee; Nitschke, Martin; Haas, Christian S.; Lorenz, Hanns Martin; Krusche, Martin (Rheumatology International, 2023)
To investigate clinical symptoms and genetic variants in patients from the German anti-IL-1 registry for autoinflammatory orphan diseases (GARROD) between 2013 and 2022. Multicentre, retrospective analysis of demographic, clinical and genetic data of patients with autoinflammatory diseases (AID) who received anti-IL-1 targeted therapy. The cohort comprised 152 patients with familial Mediterranean fever (FMF; n = 71), cryopyrin-associated periodic syndromes (CAPS; n = 43), TNF-receptor associated periodic syndrome (TRAPS; n = 19), mevalonate kinase deficiency (MKD; n = 3) and unclassified AID (uAID; n = 16). Inflammatory attacks started in 61.2% of the patients before the age of 18 years. The delay between the first AID attack and anti-IL-1 therapy was 17.8 years. Monogenetic AIDs were diagnosed by clinical symptoms. Genetic analyses confirmed the diagnosis in 87.3% of patients with FMF, 65.2% with CAPS and 94.8% with TRAPS. Among this group, heterozygous MEFV variants and variants of unknown significance (VUS) were detected in 22.5% of patients with FMF, 51.2% with CAPS and 47.4% with TRAPS. Patients with VUS were older at disease onset which is consistent with a milder phenotype. Twenty-four patients had secondary AA amyloidosis (AA) at initiation of anti-IL-1 therapy. The mean age of these patients was 16.4 years at their first attack and 44.9 years at the time of AA diagnosis. Turkish-Armenian ancestry correlated with MEFV variants and higher FMF disease activity compared to German ancestry. Molecular genetic analyses should substantiate the clinical diagnosis of a monogenetic AID. Our data support the concept of variable penetrance of VUS which can be associated with late-onset AID.
CRIS-Team Scopus Importer:2023-10-06
Keywords: Anakinra; Canakinumab; Cryopyrin-associated periodic syndrome; Familial Mediterranean fever; Mevalonate kinase deficiency; Tumor necrosis factor receptor-associated periodic syndrome

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

Clonogenicity-based radioresistance determines the expression of immune suppressive immune checkpoint molecules after hypofractionated irradiation of MDA-MB-231 triple-negative breast cancer cells - Gehre, Simon; Meyer, Felix; Sengedorj, Azzaya; Grottker, Fridolin; Reichardt, Clara; Alomo, Jannik; Borgmann, Kerstin; Frey, Benjamin; Fietkau, Rainer; Rückert, Michael; Gaipl, Udo (Frontiers in Oncology, 2023)
Only a subset of patients with triple-negative breast cancer (TNBC) benefits from a combination of radio- (RT) and immunotherapy. Therefore, we aimed to examine the impact of radioresistance and brain metastasizing potential on the immunological phenotype of TNBC cells following hypofractionated RT by analyzing cell death, immune checkpoint molecule (ICM) expression and activation of human monocyte-derived dendritic cells (DCs). MDA-MB-231 triple-negative breast cancer tumor cells were used as model system. Apoptosis was the dominant cell death form of brain metastasizing tumor cells, while Hsp70 release was generally significantly increased following RT and went along with necrosis induction. The ICMs PD-L1, PD-L2, HVEM, ICOS-L, CD137-L and OX40-L were found on the tumor cell surfaces and were significantly upregulated by RT with 5 x 5.2 Gy. Strikingly, the expression of immune suppressive ICMs was significantly higher on radioresistant clones compared to their respective non-radioresistant ones. Although hypofractionated RT led to significant cell death induction and release of Hsp70 in all tumor cell lines, human monocyte-derived DCs were not activated after co-incubation with RT-treated tumor cells. We conclude that radioresistance is a potent driver of immune suppressive ICM expression on the surface of TNBC MDA-MB-231 cells. This mechanism is generally known to predominantly influence the effector phase, rather than the priming phase, of anti-tumor immune responses.
CRIS-Team Scopus Importer:2023-05-19
Keywords: breast cancer; dendritic cells; immune checkpoint molecules; radioresistance; radiotherapy; tumor cell death

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