Proteomic Approaches to Defining Remission and the Risk of Relapse in Rheumatoid Arthritis - O'Neil, Liam J.; Hu, Pingzhao; Liu, Qian; Islam, Md. Mohaiminul; Spicer, Victor; Rech, Jürgen; Hueber, Axel; Anaparti, Vidyanand; Smolik, Irene; El-Gabalawy, Hani S.; Schett, Georg; Wilkins, John A. (Frontiers in Immunology, 2021)
Objectives: Patients with Rheumatoid Arthritis (RA) are increasingly achieving stable disease remission, yet the mechanisms that govern ongoing clinical disease and subsequent risk of future flare are not well understood. We sought to identify serum proteomic alterations that dictate clinically important features of stable RA, and couple broad-based proteomics with machine learning to predict future flare. Methods: We studied baseline serum samples from a cohort of stable RA patients (RETRO, n = 130) in clinical remission (DAS28<2.6) and quantified 1307 serum proteins using the SOMAscan platform. Unsupervised hierarchical clustering and supervised classification were applied to identify proteomic-driven clusters and model biomarkers that were associated with future disease flare after 12 months of follow-up and RA medication withdrawal. Network analysis was used to define pathways that were enriched in proteomic datasets. Results: We defined 4 proteomic clusters, with one cluster (Cluster 4) displaying a lower mean DAS28 score (p = 0.03), with DAS28 associating with humoral immune responses and complement activation. Clustering did not clearly predict future risk of flare, however an XGboost machine learning algorithm classified patients who relapsed with an AUC (area under the receiver operating characteristic curve) of 0.80 using only baseline serum proteomics. Conclusions: The serum proteome provides a rich dataset to understand stable RA and its clinical heterogeneity. Combining proteomics and machine learning may enable prediction of future RA disease flare in patients with RA who aim to withdrawal therapy.
CRIS-Team Scopus Importer:2021-12-17
Keywords: disease activity; outcomes research; proteomics; rheumatoid arthritis; treatment

Pseudoacrocyanosis: a case for telemedicine in rheumatology - Manger, Bernhard; Manger, Karin (RMD Open, 2022)
Here we describe three patients, two of them medical doctors, who were concerned about striking, sudden-onset bluish discoloration of their hands. After sending electronic images of these changes to befriended rheumatologists, one simple anamnestic question could unveil the surprising cause of their symptoms.
CRIS-Team WoS Importer:2022-09-23

Psoriatic arthritis from a mechanistic perspective - Schett, Georg; Rahman, Proton; Ritchlin, Christopher; Mcinnes, Iain B.; Elewaut, Dirk; Scher, Jose U. (Nature Reviews Rheumatology, 2022)
Psoriatic arthritis (PsA) is part of a group of closely related clinical phenotypes (‘psoriatic disease’) that is defined by shared molecular pathogenesis resulting in excessive, prolonged inflammation in the various tissues affected, such as the skin, the entheses or the joints. Psoriatic disease comprises a set of specific drivers that promote an aberrant immune response and the consequent development of chronic disease that necessitates therapeutic intervention. These drivers include genetic, biomechanical, metabolic and microbial factors that facilitate a robust and continuous mobilization, trafficking and homing of immune cells into the target tissues. The role of genetic variants involved in the immune response, the contribution of mechanical factors triggering an exaggerated inflammatory response (mechanoinflammation), the impact of adipose tissue and altered lipid metabolism and the influence of intestinal dysbiosis in the disease process are discussed. Furthermore, the role of key cytokines, such as IL-23, IL-17 and TNF, in orchestrating the various phases of the inflammatory disease process and as therapeutic targets in PsA is reviewed. Finally, the nature and the mechanisms of inflammatory tissue responses inherent to PsA are summarized.
CRIS-Team Scopus Importer:2022-05-20

PU.1 controls fibroblast polarization and tissue fibrosis - Wohlfahrt, Thomas; Rauber, Simon; Uebe, Steffen; Luber, Markus; Soare, Alina; Ekici, Arif Bülent; Weber, Stefanie; Matei, Alexandru-Emil; Chen, Chih Wei; Maier, Christiane; Karouzakis, Emmanuel; Kiener, Hans P.; et al. (Nature, 2019)
Fibroblasts are polymorphic cells with pleiotropic roles in organ morphogenesis, tissue homeostasis and immune responses. In fibrotic diseases, fibroblasts synthesize abundant amounts of extracellular matrix, which induces scarring and organ failure. By contrast, a hallmark feature of fibroblasts in arthritis is degradation of the extracellular matrix because of the release of metalloproteinases and degrading enzymes, and subsequent tissue destruction. The mechanisms that drive these functionally opposing pro-fibrotic and pro-inflammatory phenotypes of fibroblasts remain unknown. Here we identify the transcription factor PU.1 as an essential regulator of the pro-fibrotic gene expression program. The interplay between transcriptional and post-transcriptional mechanisms that normally control the expression of PU.1 expression is perturbed in various fibrotic diseases, resulting in the upregulation of PU.1, induction of fibrosis-associated gene sets and a phenotypic switch in extracellular matrix-producing pro-fibrotic fibroblasts. By contrast, pharmacological and genetic inactivation of PU.1 disrupts the fibrotic network and enables reprogramming of fibrotic fibroblasts into resting fibroblasts, leading to regression of fibrosis in several organs.
EVALuna2:35476

PU.1 INHIBITOR DB1976 CONTROLS FIBROBLAST POLARIZATION IN SYSTEMIC SCLEROSISAND LEADS TO REGRESSION OF FIBROSIS IN DIFFERENT MODELS OF ORGAN FIBROSIS - Wohlfahrt, Thomas; Rauber, Simon; Luber, Markus; Soare, Alina; Weber, Stefanie; Matei, Alexandru-Emil; Chen, Chih-Wei; Karouzakis, Emmanuel; Kiener, Hans; Pachera, Elena; Dees, Clara; Kreuter, Alexander; et al. (ANNALS OF THE RHEUMATIC DISEASES, 2019)
CRIS-Team WoS Importer:2019-07-12

Publisher Correction: Revisiting the gut–joint axis: links between gut inflammation and spondyloarthritis (Nature Reviews Rheumatology, (2020), 16, 8, (415-433), 10.1038/s41584-020-0454-9) - Gracey, Eric; Vereecke, Lars; McGovern, Dermot; Fröhling, Mareike; Schett, Georg; Danese, Silvio; De Vos, Martine; Van den Bosch, Filip; Elewaut, Dirk (Nature Reviews Rheumatology, 2020)
An amendment to this paper has been published and can be accessed via a link at the top of the paper.
CRIS-Team Scopus Importer:2020-08-07

Publisher Correction to: Collagen Turnover Biomarkers Associate with Active Psoriatic Arthritis and Decrease with Guselkumab Treatment in a Phase 3 Clinical Trial (DISCOVER-2) (Rheumatology and Therapy, (2022), 10.1007/s40744-022-00444-x) - Schett, Georg; Loza, Matthew J.; Palanichamy, Arumugam; Fitzgerald, Oliver; Ritchlin, Christopher; Bay-Jensen, Anne-Christine; Nielsen, Signe Holm; Gao, Sheng; Hsia, Elizabeth C.; Kollmeier, Alexa P.; Xu, Xie L.; Baribaud, Frederic; et al. (Rheumatology and Therapy, 2022)
The original version of the article is updated. • In the Results section of the Abstract, the text ‘rat- adjusted’ should have read ‘rate adjusted’. • In the Key Summary Points box under the heading ‘What did the study ask?’, the text ‘collage’ should have read ‘collagen’. • In the details below Table 1, the text ‘he mean’ should have read ‘the mean’. • In the Methods section under the heading ‘Statistical Methods’ the text ‘C 50 improvement in ACR criteria’ should have read ‘C 50% improvement in ACR criteria’. • In the Results section under the heading ‘Collagen Biomarkers and Baseline Clinical Features in PsA Patients’ the text ‘PSA’ should have read ‘PsA’. • In Table 2, under the PASI column, the value ‘0.13’ should be in italics ‘0.13’. • In Table 2, the ‘Enthesitis’ column heading should read ‘Enthesitis Score’ with a footnote of: Leeds Enthesitis Index 0–6; the ‘Dactylitis Score’ column heading should have a footnote of: Dactylitis Severity Score 0–60.
CRIS-Team Scopus Importer:2022-07-15

Purinergic signalling in systemic sclerosis - Hoeppner, Jakob; Bruni, Cosimo; Distler, Oliver; Robson, Simon C.; Burmester, Gerd R.; Siegert, Elise; Distler, Jörg (Rheumatology, 2021)
SSc is a chronic autoimmune rheumatic disease that involves numerous organs and presents major management challenges. The histopathologic hallmarks of SSc include vasculopathy, fibrosis and autoimmune phenomena involving both innate and adaptive immune systems. Purinergic signalling is a pathway that may be implicated in the pathophysiology of several of these disease manifestations. Extracellular purines are potent signalling mediators, which have been shown to be dysregulated in SSc. As examples, purines can exacerbate vasculopathy and provoke platelet dysfunction; as well as contributing to immune dysregulation. Elements of purinergic signalling further promote organ and tissue fibrosis in several disease models. Here, we provide an overview of extracellular purine metabolism in purinergic signalling and link disorders of these to the molecular pathology of SSc. We also discuss targeting the purinergic signalling and explore the translational applications for new therapeutic options in SSc.
CRIS-Team WoS Importer:2022-05-13

Quality of a Supporting Mobile App for Rheumatic Patients: Patient-Based Assessment Using the User Version of the Mobile Application Scale (uMARS) - Lambrecht, Antonia; Vuillerme, Nicolas; Raab, Christina; Simon, David; Messner, Eva-Maria; Hagen, Melanie; Bayat, Sara; Kleyer, Arnd; Aubourg, Timothee; Schett, Georg; Hueber, Axel; Knitza, Johannes (Frontiers in Medicine, 2021)
Introduction: Mobile applications promise to improve current health care. However, current mobile app quality ratings are mostly physician-based. The aim of this study was (1) to assess the quality of the self-management app Rheuma Auszeit using the validated uMARS (User Version of the Mobile App Rating Scale) app quality assessment tool and (2) to evaluate the association between uMARS scores and patients' characteristics.
CRIS-Team WoS Importer:2021-08-20

Quantification and impact of secondary osteoarthritis in patients with anti-citrullinated protein antibodies positive rheumatoid arthritis - Figueiredo, Camille P.; Simon, David; Englbrecht, Matthias; Haschka, Judith; Kleyer, Arnd; Bayat, Sara; Hueber, Axel; Pereira, Rosa M. R.; Rech, Juergen; Schett, Georg (Arthritis and Rheumatology, 2016)
To search for evidence of secondary osteoarthritis in patients with rheumatoid arthritis (RA) in a cross-sectional and longitudinal setting and to relate osteophyte formation to functional outcome.Anti-citrullinated protein antibody positive (ACPA+) RA patients underwent high-resolution peripheral quantitative computed tomography (HR-pQCT) of the hand. Cross-sectional and longitudinal measurements were performed. Number and size of osteophytes as well as bone erosions were documented. Relation of osteophytes to bone erosions and to demographic and disease specific data was evaluated by multiple logistic regression models.202 ACPA+ RA patients were enrolled in the cross-sectional and 77 subjects in the longitudinal analysis (interval: 1.5 years). The mean number and size of osteophytes was 1.3±2.3 and 9.4±23.9 mm³ respectively. Osteophyte number was significantly (p<0.001) correlated to erosion number and osteophyte size to erosion size (p<0.001). Moreover, presence and size of osteophytes were related to age (p<0.001), disease duration (p<0.001) and to function as measured by the health assessment questionnaire (HAQ). Multivariate regression analyses showed an independent association between osteophytes and erosions. In the longitudinal analysis the mean number (p=0.033) and size (p<0.001) of osteophytes significantly increased in RA patients during their disease course. Conclusion Age, disease duration and bone erosions are associated with osteophytes indicating development of secondary osteoarthritis in patients with RA. This article is protected by copyright. All rights reserved.
EVALuna2:13275

QUANTIFICATION AND IMPACT OF SECONDARY OSTEOARTHRITIS USING HR-PQCT IN ANTI-CITRULLINATED PROTEIN ANTIBODY RHEUMATOID ARTHRITIS PATIENTS - Figueiredo, C.; Simon, David; Englbrecht, Matthias; Haschka, J.; Kleyer, Arnd; Bayat, Sara; Hueber, Axel; Pereira, R. M.; Rech, Jürgen; Schett, Georg (2017)
EVALuna2:13465

Quantification of 68Ga-FAPI-04 in systemic sclerosis-associated interstitial lung disease – Authors' reply - Distler, Jörg; Bergmann, Christina; Kuwert, Torsten; Schmidkonz, Christian (The Lancet Rheumatology, 2021)
CRIS-Team Scopus Importer:2021-07-16

Quantification of Ga-68-FAPI-04 in systemic sclerosis-associated interstitial lung disease Reply - Distler, Jörg; Bergmann, Christina; Kuwert, Torsten; Schmidkonz, Christian (The Lancet Rheumatology, 2021)
CRIS-Team WoS Importer:2021-07-16

Quantification of hand muscle volume and composition in patients with rheumatoid arthritis, psoriatic arthritis and psoriasis - Friedberger, Andreas; Figueiredo, Camille; Grimm, Alexandra; Oliveira, Isabelle; Bäuerle, Tobias; Rech, Jürgen; Kleyer, Arnd; Simon, David; Uder, Michael; Schett, Georg; Engelke, Klaus (BMC Musculoskeletal Disorders, 2020)
Background Psoriasis (Pso), psoriatic arthritis (PsA) and rheumatoid arthritis (RA) are inflammatory diseases. PsA and RA are characterized by bone and muscle loss. In RA, bone loss has been extensively characterized, but muscle loss has, to the best of our knowledge, not been quantified to date. Methods A random forest based segmentation method was used to analyze hand muscle volume in T1 weighted MRI images of 330 patients suffering from Pso, PsA or RA. In addition, fat volume was quantified using MRI Dixon sequences in a small subset (n = 32). Results Males had a higher relative muscle volume than females (14% for Pso, 11% for PsA, n.s. for RA). Between 40 and 80 years male Pso patients lost 13%, male PsA patients 16%, male RA patients 23% and female PsA patients 30% of their relative muscle volume. After adjustment for age, relative muscle volume in males RA patients was 16% and in female RA patients 9% lower than in Pso patients. In male RA patients relative muscle volume was 13% lower in than in male PsA patients. There was no difference in females. A significant negative correlation (R-2 = 0.18) between relative intramuscular fat content relative hand muscle volume was observed. Conclusion These preliminary data showed that relative hand muscle volume significantly decreased with age in male and female patients with Pso, PsA and RA patients. Independent of age, relative hand muscle volume was significantly smaller in patients with RA compared to the patients with Pso and the difference was twice as large in males compared to females. Also in male but not in female RA patients relative hand muscle volume was significantly smaller than in PsA patients.
CRIS-Team WoS Importer:2020-04-14

Quantification of pre-existing radiographic damage and its relationship with joint activity and long-term clinical outcomes with secukinumab therapy in patients with psoriatic arthritis - Mease, Philip; Van Der Heijde, Desiree; Kirkham, Bruce; Schett, Georg; Orbai, Ana-Maria; Ritchlin, Christopher; Merola, Joseph F.; Pricop, Luminita; James, David A.; Zhu, Xuan; Ligozio, Gregory (Arthritis Research & Therapy, 2022)
Background: Psoriatic arthritis (PsA) patient data from two phase 3 secukinumab trials (FUTURE 1, 5) were analysed to quantify the prevalence and extent of pre-existing radiographic damage (RD) at baseline; investigate the association of RD with swollen/tender joint counts (SJC/TJC) at baseline; and investigate the extent to which RD at baseline correlated with response to secukinumab. Methods: Pooled data (N = 1554) provided baseline radiographic bone erosion and joint space narrowing (JSN) scores at pre-specified locations per the van der Heijde-modified total Sharp score (vdH-mTSS) for PsA and swollen and tender joint scores in the same joints at multiple visits. Overall patient RD and individual joints RD bone erosion and JSN scores were assessed. The association between joint activity (tenderness, swelling) and vdH-mTSS was assessed at the overall patient-level and individual joint tender, swollen scores (yes/no) and RD joint JSN and bone erosion scores at the individual joint-level. Treatment response was assessed using SJC/TJC at weeks 16 and 52 and the proportion of patients achieving minimal disease activity (MDA) over all assessments within 1 year from FUTURE 5 alone. Results: A substantial prevalence of pre-existing RD with higher prevalence of erosion than JSN was observed (86% and 60% of patients had positive erosion and JSN scores, respectively); higher RD prevalence was associated with longer time since PsA diagnosis. Joint activity was weakly associated with RD at baseline at the patient-level (Pearson's coefficients: range 0.12-0.18), but strongly associated at the individual joint-level, with a higher probability of tender/swollen joints to associate with higher JSN/erosion scores: all 42 analysed joints showed statistical significance at the 0.05 level (unadjusted) for the relationship between joint tenderness (yes/no) and its JSN score, all but one for tenderness and bone erosion scores, and all but 2 for swollen and JSN scores and for swollen and bone erosion score. Secukinumab (150/300 mg), reduced TJC and SJC across all values of baseline erosion and JSN scores at weeks 16 and 52. Patients with higher levels of RD were less likely to achieve zero tender/zero swollen joint status and had lower chance of achieving MDA. Conclusions: PsA patients showed substantial prevalence of RD at baseline that correlated with time since diagnosis, but patient's individual joint activity was strongly associated with pre-existing RD at those joints. Patients with the highest RD at baseline had a reduced likelihood of achieving zero joint count status.
CRIS-Team WoS Importer:2023-02-03

Quantitative and Qualitative Changes of Bone in Psoriasis and Psoriatic Arthritis Patients - Kocijan, Roland; Englbrecht, Matthias; Haschka, Judith; Simon, David; Kleyer, Arnd; Finzel, Stephanie; Kraus, Sebastian; Resch, Heinrich; Muschitz, Christian; Engelke, Klaus; Sticherling, Michael; Rech, Jürgen; et al. (Journal of Bone and Mineral Research, 2015)
Psoriatic arthritis (PsA) is a chronic inflammatory disease characterized by periarticular bone loss and new bone formation. Current data regarding systemic bone loss and bone mineral density (BMD) in PsA are conflicting. The aim of this study was to evaluate bone microstructure and volumetric BMD (vBMD) in patients with PsA and psoriasis. We performed HR-pQCT scans at the ultradistal and periarticular radius in 50 PsA patients, 30 psoriasis patients, and 70 healthy, age- and sex-related controls assessing trabecular bone volume (BV/TV), trabecular number (Tb.N), inhomogeneity of the trabecular network, cortical thickness (Ct.Th), and cortical porosity (Ct.Po), as well as vBMD. Trabecular BMD (Tb.BMD, p = 0.021, 12.0%), BV/TV (p = 0.020, -11.9%), and Tb.N (p = 0.035, 7.1%) were significantly decreased at the ultradistal radius and the periarticular radius in PsA patients compared to controls. In contrast, bone architecture of the ultradistal radius and periarticular radius was similar in patients with psoriasis and healthy controls. Duration of skin disease was associated with low BV/TV and Tb.N in patients with PsA. These data suggest that trabecular BMD and bone microstructure are decreased in PsA patients. The observation that duration of skin disease determines bone loss in PsA supports the concept of subclinical musculoskeletal disease in psoriasis patients. © 2015 American Society for Bone and Mineral Research.
EVALuna2:10104

QUANTITATIVE ASSESSMENT AND ANALYSIS OF HAND MUSCLE VOLUME - Friedberger, Andreas; Figueiredo, C.; Museyko, Oleg; Grimm, Alexandra; D'Oliveira, I.; Bäuerle, Tobias; Rech, Jürgen; Chaudry, Oliver; Uder, Michael; Schett, Georg; Engelke, Klaus (2017)
EVALuna2:14726

Racial differences in SSc disease presentation: a European scleroderma trials and research group (EUSTAR) study - Jaeger, V. K.; Siegert, E.; Hachulla, E.; Airo, P.; Valentini, G.; Matucci-Cerinic, M.; Scorza, R.; Distler, O.; Cozzi, F.; Carreira, P.; Allanore, Y.; Mueller-Ladner, U.; et al. (2018)
EVALuna2:34975

Racial differences in systemic sclerosis disease presentation: a European Scleroderma Trials and Research group study - Jaeger, Veronika K.; Tikly, Mohammed; Xu, Dong; Siegert, Elise; Hachulla, Eric; Airo, Paolo; Valentini, Gabriele; Cerinic, Marco Matucci; Distler, Oliver; Cozzi, Franco; Carreira, Patricia; Allanore, Yannick; et al. (Rheumatology, 2020)
Objectives. Racial factors play a significant role in SSc. We evaluated differences in SSc presentations between white patients (WP), Asian patients (AP) and black patients (BP) and analysed the effects of geographical locations.
CRIS-Team WoS Importer:2020-07-24

RANKL-Induced Btn2a2 – A T Cell Immunomodulatory Molecule – During Osteoclast Differentiation Fine-Tunes Bone Resorption - Frech, Michael; Schuster, Gregor; Andes, Fabian T.; Schett, Georg; Zaiss, Mario; Sarter, Kerstin (Frontiers in Endocrinology, 2021)
Butyrophilins, which are members of the extended B7 family of immunoregulators structurally related to the B7 family, have diverse functions on immune cells as co-stimulatory and co-inhibitory molecules. Despite recent advances in the understanding on butyrophilins’ role on adaptive immune cells during infectious or autoimmune diseases, nothing is known about their role in bone homeostasis. Here, we analyzed the role of one specific butyrophilin, namely Btn2a2, as we have recently shown that Btn2a2 is expressed on the monocyte/macrophage lineage that also gives rise to bone degrading osteoclasts. We found that expression of Btn2a2 on monocytes and pre-osteoclasts is upregulated by the receptor activator of nuclear factor κ-B ligand (RANKL), an essential protein required for osteoclast formation. Interestingly, in Btn2a2-deficient osteoclasts, typical osteoclast marker genes (Nfatc1, cathepsin K, TRAP, and RANK) were downregulated following RANKL stimulation. In vitro osteoclast assays resulted in decreased TRAP positive osteoclast numbers in Btn2a2-deficient cells. However, Btn2a2-deficient osteoclasts revealed abnormal fusion processes shown by their increased size. In vivo steady state µCT and histological analysis of bone architecture in complete Btn2a2-deficient mice showed differences in bone parameters further highlighting the fine-tuning effect of BTN2a2. Moreover, in rheumatoid arthritis patients and experimental arthritis, we detected significantly decreased serum levels of the secreted soluble Btn2a2 protein. Taken together, we identified the involvement of the immunomodulatory molecule Btn2a2 in osteoclast differentiation with potential future implications in basic and translational osteoimmunology.
CRIS-Team Scopus Importer:2021-08-27
Keywords: bone homeostasis; bone resorption; osteoclast (OC); RANKL (receptor activator for nuclear factor k B ligand); T cell

Rapid single-cell physical phenotyping of mechanically dissociated tissue biopsies - Soteriou, Despina; Kubankova, Marketa; Schweitzer, Christine; Lopez Posadas, Rocío; Pradhan, Rashmita; Thoma, Oana-Maria; Györfi, Andrea-Hermina; Matei, Alexandru-Emil; Waldner, Maximilian; Distler, Jörg; Scheuermann, Stefan; Langejuergen, Jens; et al. (Nature Biomedical Engineering, 2023)
A method for the sequential assessment of the physical phenotypes of suspended cells singularized from tissue biopsies by mechanical dissociation allows for rapid diagnoses.
CRIS-Team WoS Importer:2023-05-05

Rare Loss-of-Function Mutation in SERPINA3 in Generalized Pustular Psoriasis - Frey, Silke; Sticht, Heinrich; Wilsmann-Theis, Dagmar; Gerschütz, Anne; Wolf, Katharina; Löhr, Sabine; Haskamp, Stefan; Frey, Benjamin; Hahn, Madelaine; Ekici, Arif Bülent; Uebe, Steffen; Thiel, Christian; et al. (Journal of Investigative Dermatology, 2020)
CRIS-Team Scopus Importer:2020-03-06

Rare meets rarer: anti-synthetase syndrome in a patient with facio-scapulo-humeral muscular dystrophy - Valor-Mendez, Larissa; Manger, Bernhard; Winterholler, Martin; Schett, Georg; Tuerk, Mattias; Knitza, Johannes (Rheumatology, 2022)
CRIS-Team WoS Importer:2022-07-08

Rare rheumatic diseases - Manger, Bernhard; Swoboda, Bernd (Zeitschrift für Rheumatologie, 2016)
EVALuna2:10906

Rationale, current state and opportunities in combining biologic disease modifying antirheumatic drugs in rheumatoid and psoriatic arthritis - Mutlu, Melek Yalcin; Tascilar, Koray; Schett, Georg (Joint Bone Spine, 2023)
The advent of biologic disease modifying antirheumatic drugs (bDMARDs) has considerably improved patient outcomes in inflammatory arthritis. However, not all patients reach the state of remission, as disease can be resistant even to single cytokine inhibition by bDMARDs. Simultaneous or sequential inhibition of multiple cytokines may be considered in situations where disease control is not adequate under singular inhibition of cytokines. Although there have been some disappointing experiences in the past with combination of bDMARDs, the ongoing improvement of our understanding about inflammatory pathways and the overall better safety understanding of bDMARDs seem to make new biologic treatment combinations possible. This review covers the rationale and current evidence for bDMARDs combination in inflammatory arthritis.
CRIS-Team Scopus Importer:2023-06-09
Keywords: Biologicals; Combination therapy; Cytokine blockade; Psoriatic arthritis; Rheumatoid arthritis

Rationale for the evaluation of nintedanib as a treatment for systemic sclerosis–associated interstitial lung disease - Wollin, Lutz; Distler, Jörg; Denton, Christopher P.; Gahlemann, Martina (Journal of Scleroderma and Related Disorders, 2019)
Interstitial lung disease is a common manifestation of systemic sclerosis. Systemic sclerosis–associated interstitial lung disease is characterized by progressive pulmonary fibrosis and a reduction in pulmonary function. Effective treatments for systemic sclerosis–associated interstitial lung disease are lacking. In addition to clinical similarities, systemic sclerosis–associated interstitial lung disease shows similarities to idiopathic pulmonary fibrosis in the pathophysiology of the underlying fibrotic processes. Idiopathic pulmonary fibrosis and systemic sclerosis–associated interstitial lung disease culminate in a self-sustaining pathway of pulmonary fibrosis in which fibroblasts are activated, myofibroblasts accumulate, and the excessive extracellular matrix is deposited. Nintedanib is a tyrosine kinase inhibitor that has been approved for the treatment of idiopathic pulmonary fibrosis. In patients with idiopathic pulmonary fibrosis, nintedanib slows disease progression by decreasing the rate of lung function decline. In this review, we summarize the antifibrotic, anti-inflammatory, and attenuated vascular remodeling effects of nintedanib demonstrated in in vitro studies and in animal models of aspects of systemic sclerosis. Nintedanib interferes at multiple critical steps in the pathobiology of systemic sclerosis–associated interstitial lung disease, providing a convincing rationale for its investigation as a potential therapy. Finally, we summarize the design of the randomized placebo-controlled SENSCIS ® trial that is evaluating the efficacy and safety of nintedanib in patients with systemic sclerosis–associated interstitial lung disease.
CRIS-Team Scopus Importer:2019-05-03
Keywords: Fibroblasts; fibrosis; scleroderma; systemic sclerosis–associated interstitial lung disease; tyrosine kinase inhibitor

Rationnel, état des lieux et perspectives des combinaisons de traitements de fond biologiques dans la prise en charge de la polyarthrite rhumatoïde et du rhumatisme psoriasique - Mutlu, Melek Yalcin; Tascilar, Koray; Schett, Georg (Revue du Rhumatisme (Edition Francaise), 2023)
The advent of biologic disease modifying anti-rheumatic drugs (bDMARDs) has considerably improved patient outcomes in inflammatory arthritis. However, not all patients reach the state of remission as disease can be resistant even to single cytokine inhibition by bDMARDs. Simultaneous or sequential inhibition of multiple cytokines may be considered in situations, where disease control is not adequate under singular inhibition of cytokines. Although there have been some disappointing experiences in the past with combination of bDMARDs, the ongoing improvement of our understanding about inflammatory pathways and the overall better safety understanding of bDMARDs seem to make new biologic treatment combinations possible. This review covers the rationale and current evidence for bDMARDs combination in inflammatory arthritis.
CRIS-Team Scopus Importer:2023-09-22
Keywords: Agents biologiques; Biologicals; Combination therapy; Cytokine blockade; Inhibition des cytokines; Polyarthrite rhumatoïde; Psoriatic arthritis; Rheumatoid arthritis; Rhumatisme psoriasique; Traitements combinés

Reactive arthritis and cutaneous vasculitis after SARS-CoV-2 infection - Schenker, Hannah; Hagen, Melanie; Simon, David; Schett, Georg; Manger, Bernhard (Rheumatology, 2021)
CRIS-Team Scopus Importer:2021-02-05

Reactive oxygen species deficiency induces autoimmunity with type 1 interferon signature - Kelkka, Tiina; Kienhoefer, Deborah; Hoffmann, Markus; Linja, Marjo; Wing, Kajsa; Sareila, Outi; Hultqvist, Malin; Laajala, Essi; Chen, Zhi; Vasconcelos, Julia; Neves, Esmeralda; Guedes, Margarida; et al. (Antioxidants & Redox Signaling, 2014)
Abstract Aims: Chronic granulomatous disease (CGD) is a primary immunodeficiency caused by mutations in the phagocyte reactive oxygen species (ROS)-producing NOX2 enzyme complex and characterized by recurrent infections associated with hyperinflammatory and autoimmune manifestations. A translational, comparative analysis of CGD patients and the corresponding ROS-deficient Ncf1(m1J) mutated mouse model was performed to reveal the molecular pathways operating in NOX2 complex deficient inflammation.A prominent type I interferon (IFN) response signature that was accompanied by elevated autoantibody levels was identified in both mice and humans lacking functional NOX2 complex. To further underline the systemic lupus erythematosus (SLE)-related autoimmune process, we show that naïve Ncf1(m1J) mutated mice, similar to SLE patients, suffer from inflammatory kidney disease with IgG and C3 deposits in the glomeruli. Expression analysis of germ-free Ncf1(m1J) mutated mice reproduced the type I IFN signature, enabling us to conclude that the upregulated signaling pathway is of endogenous origin.Our findings link the previously unexplained connection between ROS deficiency and increased susceptibility to autoimmunity by the discovery that activation of IFN signaling is a major pathway downstream of a deficient NOX2 complex in both mice and humans.We conclude that the lack of phagocyte-derived oxidative burst is associated with spontaneous autoimmunity and linked with type I IFN signature in both mice and humans. Antioxid. Redox Signal. 21, 2231-2245.
EVALuna2:13008

REAL-WORLD EFFECTIVENESS AND PERCEIVED USEFULNESS OF SYMPTOM CHECKERS IN RHEUMATOLOGY: INTERIM REPORT FROM THE PROSPECTIVE MULTICENTER BETTER STUDY - Knitza, Johannes; Mohn, J.; Bergmann, C.; Kampylafka, E.; Hagen, Melanie; Bohr, D.; Araujo, E.; Englbrecht, M.; Simon, David; Kleyer, Arnd; Meinderink, Timo; Vorbruggen, W.; et al. (ANNALS OF THE RHEUMATIC DISEASES, 2020)
CRIS-Team WoS Importer:2020-08-21

Real-world usage of digital health applications (DiGA) in rheumatology: results from a German patient survey. - Labinsky, Hannah; Gupta, Latika; Raimondo, Maria Gabriella; Schett, Georg; Knitza, Johannes (Rheumatology International, 2023)
Mobile health applications and digital therapeutics (DTx) aim to improve current patient care. Real-world data on DTx are, however, scarce. The aim of this study was to evaluate the adherence, acceptance, and efficacy of DTx in a clinical routine rheumatology setting. We conducted a prospective observational cohort study assessing the use, adherence, acceptance, and efficacy of the DTx DiGA (Digitale Gesundheitsanwendungen) by survey over 12 weeks. Patients included had to have a rheumatic disease and had been prescribed a DiGA. Acceptance was assessed using the Net promoter score (NPS). 48 patients were prescribed DiGA. Of these, 39/48 (81%) completed the follow-up survey. 21/39 (54%) patients downloaded the DTx and 20/39 (51%) used the DTx at least once. 9/39 (23%) of patients stopped quickly afterward and 5/39 (13%) reported having completed the whole DTx program. Lack of time and commitment were reported as the main reasons for non-use. Overall acceptance of DiGA was high (Net promoter score (NPS) mean (SD) 7.8/10 (2.3)). While the majority of patients (60%) reported no improvement, one subgroup of patients (7/20, 35%) who regularly used an exercise-based DTx for back pain reported symptom improvement. Acceptance of DTx in patients with rheumatic diseases is high, however onboarding to DTx use and adherence to DTx is still challenging in patients with rheumatic diseases. In a subgroup of patients with back pain, however, the use of an exercise-based DTx led to symptom improvement.
EVALuna2:520653

Receptor Tyrosine Kinase Inhibitor Nintedanib as Treatment Option in Bronchiolitis Obliterans after Airway Transplantation - Heim, Christian; Mauer, J.; Kuckhahn, A.; Distler, Jörg; Spriewald, B.; Ramsperger-Gleixner, Martina; Weyand, Michael; Ensminger, S. M. (JOURNAL OF HEART AND LUNG TRANSPLANTATION, 2019)
CRIS-Team WoS Importer:2019-04-04

Recombinant Adenosine Deaminase Ameliorates Inflammation, Vascular Disease, and Fibrosis in Preclinical Models of Systemic Sclerosis - Zhang, Yun; Zhu, Honglin; Layritz, Florian; Luo, Hui; Wohlfahrt, Thomas; Chen, Chih-Wei; Soare, Alina; Bergmann, Christina; Ramming, Andreas; Groeber, Florian; Reuter, Christian; Fornasini, Gianfranco; et al. (Arthritis and Rheumatology, 2020)
Objective: Systemic sclerosis (SSc) is characterized by fibrosis, vascular disease, and inflammation. Adenosine signaling plays a central role in fibroblast activation. We undertook this study to evaluate the therapeutic effects of adenosine depletion with PEGylated adenosine deaminase (PEG-ADA) in preclinical models of SSc. Methods: The effects of PEG-ADA on inflammation, vascular remodeling, and tissue fibrosis were analyzed in Fra-2 mice and in a B10.D2→BALB/c (H-2d) model of sclerodermatous chronic graft-versus-host disease (GVHD). The effects of PEG-ADA were confirmed in vitro in a human full-thickness skin model. Results: PEG-ADA effectively inhibited myofibroblast differentiation and reduced pulmonary fibrosis by 34.3% (with decreased collagen expression) (P = 0.0079; n = 6), dermal fibrosis by 51.8% (P = 0.0006; n = 6), and intestinal fibrosis by 17.7% (P = 0.0228; n = 6) in Fra-2 mice. Antifibrotic effects of PEG-ADA were also demonstrated in sclerodermatous chronic GVHD (reduced by 38.4%) (P = 0.0063; n = 8), and in a human full-thickness skin model. PEG-ADA treatment decreased inflammation and corrected the M2/Th2/group 2 innate lymphoid cell 2 bias. Moreover, PEG-ADA inhibited proliferation of pulmonary vascular smooth muscle cells (reduced by 40.5%) (P < 0.0001; n = 6), and prevented thickening of the vessel walls (reduced by 39.6%) (P = 0.0028; n = 6) and occlusions of pulmonary arteries (reduced by 63.9%) (P = 0.0147; n = 6). Treatment with PEG-ADA inhibited apoptosis of microvascular endothelial cells (reduced by 65.4%) (P = 0.0001; n = 6) and blunted the capillary rarefication (reduced by 32.5%) (P = 0.0199; n = 6). RNA sequencing demonstrated that treatment with PEG-ADA normalized multiple pathways related to fibrosis, vasculopathy, and inflammation in Fra-2 mice. Conclusion: Treatment with PEG-ADA ameliorates the 3 cardinal features of SSc in pharmacologically relevant and well-tolerated doses. These findings may have direct translational implications, as PEG-ADA has already been approved by the Food and Drug Administration for the treatment of patients with ADA-deficient severe combined immunodeficiency disease.
CRIS-Team Scopus Importer:2020-07-10

Reconstruction of the miR-506-Quaking axis in Idiopathic Pulmonary Fibrosis using integrative multi-source bioinformatics - Stojanović, Stevan D.; Fuchs, Maximilian; Liang, Chunguang; Schmidt, Kevin; Xiao, Ke; Just, Annette; Pfanne, Angelika; Pich, Andreas; Warnecke, Gregor; Braubach, Peter; Petzold, Christina; Jonigk, Danny; et al. (Scientific Reports, 2021)
The family of RNA-binding proteins (RBP) functions as a crucial regulator of multiple biological processes and diseases. However, RBP function in the clinical setting of idiopathic pulmonary fibrosis (IPF) is still unknown. We developed a practical in silico screening approach for the characterization of RBPs using multi-sources data information and comparative molecular network bioinformatics followed by wet-lab validation studies. Data mining of bulk RNA-Sequencing data of tissues of patients with IPF identified Quaking (QKI) as a significant downregulated RBP. Cell-type specific expression was confirmed by single-cell RNA-Sequencing analysis of IPF patient data. We systematically analyzed the molecular interaction network around QKI and its functional interplay with microRNAs (miRs) in human lung fibroblasts and discovered a novel regulatory miR-506-QKI axis contributing to the pathogenesis of IPF. The in silico results were validated by in-house experiments applying model systems of miR and lung biology. This study supports an understanding of the intrinsic molecular mechanisms of IPF regulated by the miR-506-QKI axis. Initially applied to human lung disease, the herein presented integrative in silico data mining approach can be adapted to other disease entities, underlining its practical relevance in RBP research.
CRIS-Team Scopus Importer:2021-06-25

Redox modulation of HMGB1-related signaling - Janko, Christina; Filipovic, Milos; Munoz Becerra, Luis; Schorn, Christine; Schett, Georg; Ivanovic-Burmazovic, Ivana; Herrmann, Martin (Antioxidants & Redox Signaling, 2014)
Significance: In the cells' nuclei, high-mobility group box protein 1 (HMGB1) is a nonhistone chromatin-binding protein involved in the regulation of transcription. Extracellularly, HMGB1 acts as a danger molecule with properties of a proinflammatory cytokine. It can be actively secreted from myeloid cells or passively leak from any type of injured, necrotic cell. Increased serum levels of active HMGB1 are often found in pathogenic inflammatory conditions and correlate with worse prognoses in cancer, sepsis, and autoimmunity. By damaging cells, superoxide and peroxynitrite promote leakage of HMGB1. Recent Advances: The activity of HMGB1 strongly depends on its redox state: Inflammatory-active HMGB1 requires an intramolecular disulfide bond (Cys23 and Cys45) and a reduced Cys106. Oxidation of the latter blocks its stimulatory activity and promotes immune tolerance. Critical Issues: Reactive oxygen and nitrogen species create an oxidative environment and can be detoxified by superoxide dismutase (SOD), catalase, and peroxidases. Modifications of the oxidative environment influence HMGB1 activity. Future Directions: In this review, we hypothesize that manipulations of an oxidative environment by SOD mimics or by hydrogen sulfide are prone to decrease tissue damage. Both the concomitant decreased HMGB1 release and its redox chemical modifications ameliorate inflammation and tissue damage. Antioxid. Redox Signal. 20, 1075-1085. © Mary Ann Liebert, Inc.

Reduced Decline in Forced Vital Capacity in Patients with Progressive Fibrosing Autoimmune Disease-Related Interstitial Lung Diseases (ILDs) Treated with Nintedanib - Matteson, Eric; Distler, Oliver; Distler, Jörg; Kuwana, Masataka; Pope, Janet; Seibold, James; James, Alexandra; Schlenker-Herceg, Rozsa; Rohr, Klaus; Flaherty, Kevin (ARTHRITIS & RHEUMATOLOGY, 2020)
CRIS-Team WoS Importer:2021-01-15

Reduced Fluorescence versus Forward Scatter Time-of-Flight and Increased Peak versus Integral Fluorescence Ratios Indicate Receptor Clustering in Flow Cytometry - Fuernrohr, Barbara G.; Stein, Merle; Rhodes, Benjamin; Chana, Prabhjoat S.; Schett, Georg; Vyse, Timothy J.; Herrmann, Martin; Mielenz, Dirk (Journal of Immunology, 2015)
Clustering of surface receptors is often required to initiate signal transduction, receptor internalization, and cellular activation. To study the kinetics of clustering, we developed an economic high-throughput method using flow cytometry. The quantification of receptor clustering by flow cytometry is based on the following two observations: first, the fluorescence signal length (FL time-of-flight [ToF]) decreases relative to the forward scatter signal length (FSc-ToF), and second, the peak FL (FL-peak) increases relative to the integral FL (FL-integral) upon clustering of FL-labeled surface receptors. Receptor macroclustering can therefore be quantified using the ratios FL-ToF/FSc-ToF (method ToF) or FL-peak/FL-integral (method Peak). We have used these methods to analyze clustering of two immune receptors known to undergo different conformational and oligomeric states: the BCR and the complement receptor 3 (CR3), on murine splenocytes, purified B cells, and human neutrophils. Engagement of both the BCR and CR3, on immortalized as well as primary murine B cells and human neutrophil, respectively, resulted in decreased FL-ToF/FSc-ToF and increased FL-peak/FL-integral ratios. Manipulation of the actin-myosin cytoskeleton altered BCR clustering which could be measured using the established parameters. To confirm clustering of CR3 on neutrophils, we applied imaging flow cytometry. Because receptor engagement is as a biological process dependent on cell viability, energy metabolism, and temperature, receptor clustering can only be quantified by gating on viable cells under physiological conditions. In summary, with this novel method, receptor clustering on nonadherent cells can easily be monitored by high-throughput conventional flow cytometry.
EVALuna2:13122

REDUCED JOINT SYNOVITIS ASSESSMENT VERSUS THE GLOBAL EULAR OMERACT SYNOVITIS SCORE (GLOESS) TO PREDICT THE RESPONSE TO SECUKINUMAB IN PATIENTS WITH ACTIVE PSORIATIC ARTHRITIS AND INADEQUATE RESPONSE TO CONVENTIONAL DISEASE-MODIFYING ANTI-RHEUMATIC DRUGS: EXPLORATORY RESULTS FROM THE ULTIMATE TRIAL - D'Agostino, M. A.; Boers, M.; Schett, Georg; Conaghan, P. G.; Naredo, E.; Mandl, P.; Carron, P.; Backhaus, M.; Lopez-Rodriguez, A.; Hanova, P.; Goyanka, P.; Sahoo, B. G.; et al. (ANNALS OF THE RHEUMATIC DISEASES, 2022)
CRIS-Team WoS Importer:2022-11-04

Reduced Muscle Strength Is Associated With Insulin Resistance in Type 2 Diabetes Patients With Osteoarthritis - Zaharia, Oana Patricia; Pesta, Dominik Hans; Bobrov, Pavel; Kupriyanova, Yuliya; Herder, Christian; Karusheva, Yanislava; Bódis, Kálmán; Bönhof, Gidon Josia; Knitza, Johannes; Simon, David; Kleyer, Arnd; Hwang, Jong Hee; et al. (Journal of Clinical Endocrinology and Metabolism, 2021)
CONTEXT: Type 2 diabetes is associated with a greater risk for musculoskeletal disorders, yet its impact on joint function remains unclear. OBJECTIVE: We hypothesized that patients with type 2 diabetes and osteoarthritis would exhibit musculoskeletal impairment, which would associate with insulin resistance and distinct microRNA profiles. METHODS: Participants of the German Diabetes Study with type 2 diabetes (T2D, n = 39) or normal glucose tolerance (CON, n = 27), both with (+OA) or without osteoarthritis (-OA) underwent intravenous glucose tolerance and hyperinsulinemic-euglycemic clamp tests. Musculoskeletal function was assessed by isometric knee extension strength (KES), grip strength, range of motion (ROM), and balance skills, while neural function was measured by nerve conductance velocity (NCV). Arthritis-related symptoms were quantified using the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) questionnaire, serum arthritis-related microRNA using quantitative polymerase chain reaction. RESULTS: Insulin sensitivity was lower in T2D+OA vs T2D-OA (4.4 ± 2.0 vs 5.7 ± 3.0 mg* kg-1*min-1) and in CON+OA vs CON-OA (8.1 ± 2.0 vs 12.0 ± 2.6 mg*kg-1,*min-1, both P < .05). In T2D+OA, KES and ROM were 60% and 22% lower than in CON+OA, respectively (both P < .05). Insulin sensitivity correlated positively with KES (r = 0.41, P < .05) among T2D, and negatively with symptom severity in CON and T2D (r = -0.60 and r = -0.46, respectively, P < .05). CON+OA and T2D+OA had inferior balance skills than CON-OA, whereas NCV was comparable in T2D+OA and T2D-OA. Expression of arthritis-related microRNAs was upregulated in T2D compared to CON, but downregulated in CON+OA compared to CON-OA (P < .05), and did not differ between T2D+OA and T2D-OA. CONCLUSION: Musculoskeletal impairment and osteoarthritis-related symptoms are associated with insulin resistance. Type 2 diabetes can mask changes in arthritis-related microRNA profiles.
CRIS-Team Scopus Importer:2021-04-16
Keywords: insulin secretion; insulin sensitivity; muscle strength; osteoarthritis; type 2 diabetes

Re-exposure with a TNF inhibitor bio-similar was well tolerated and led to sustained control of psoriatic arthritis after allergic reaction to the TNF inhibitor bio-originator - Valor-Mendez, Larissa; Dorn, Carla; Manger, Bernhard; Schett, Georg; Kleyer, Arnd (Rheumatology Advances in Practice, 2022)
CRIS-Team WoS Importer:2022-11-04

Refinement and Usability Analysis of an eHealth App for Ankylosing Spondylitis as a Complementary Treatment to Physical Therapy: Development and Usability Study - Nitschke, Marlies; Nwosu, Obioma Bertrand; Grube, Lara; Knitza, Johannes; Seifer, Ann-Kristin; Eskofier, Björn; Schett, Georg; Morf, Harriet (JMIR Formative Research, 2023)
Background: Mobile eHealth apps have been used as a complementary treatment to increase the quality of life of patients and provide new opportunities for the management of rheumatic diseases. Telemedicine, particularly in the areas of prevention, diagnostics, and therapy, has become an essential cornerstone in the care of patients with rheumatic diseases. Objective: This study aims to improve the design and technology of YogiTherapy and evaluate its usability and quality. Methods: We newly implemented the mobile eHealth app YogiTherapy with a modern design, the option to change language, and easy navigation to improve the app’s usability and quality for patients. After refinement, we evaluated the app by conducting a study with 16 patients with AS (4 female and 12 male; mean age 48.1, SD 16.8 y). We assessed the usability of YogiTherapy with a task performance test (TPT) with a think-aloud protocol and the quality with the German version of the Mobile App Rating Scale (MARS). Results: In the TPT, the participants had to solve 6 tasks that should be performed on the app. The overall task completion rate in the TPT was high (84/96, 88% completed tasks). Filtering for videos and navigating to perform an assessment test caused the largest issues during the TPT, while registering in the app and watching a yoga video were highly intuitive. Additionally, 12 (75%) of the 16 participants completed the German version of MARS. The quality of YogiTherapy was rated with an average MARS score of 3.79 (SD 0.51) from a maximum score of 5. Furthermore, results from the MARS questionnaire demonstrated a positive evaluation regarding functionality and aesthetics. Conclusions: The refined and tested YogiTherapy app showed promising results among most participants. In the future, the app could serve its function as a complementary treatment for patients with AS. For this purpose, surveys with a larger number of patients should still be conducted. As a substantial advancement, we made the app free and openly available on the iOS App and Google Play store
Keywords: ankylosing spondylitis; axial spondylarthritis; DHA; digital health application; eHealth; self-assessment; Usability; Yoga; YogiTherapy

Reframing immune-mediated inflammatory diseases - Boutrid, Nada; Rahmoune, Hakim; Schett, Georg; McInnes, Iain; Neurath, Markus (New England Journal of Medicine, 2021)
We were surprised to find that celiac disease was not among the panel of disorders discussed by Schett et al. (Aug. 12 issue)1 in their review article on cytokines and immune-mediated inflammatory conditions. It is well established that cytokine release is at the core of the structural damage and subsequent clinical manifestations in celiac disease, and we note in particular the evolving role of interleukins (mainly interleukin-15).2 In fact, interleukin-15 has a crucial role in innate and adaptive immune responses and is overexpressed in various autoimmune conditions, including celiac disease.3 This interleukin-15 action is orchestrated by tumor necrosis factor α and implicates the innate lymphoid cells; these two components are involved in the celiac-immunomediated enteropathy and several extraintestinal manifestations of celiac disease.4 It is not surprising that numerous trials — including trials in animal models and clinical trials, notably the PRV-015 in Gluten-free Diet Non-responsive Celiac Disease (PROACTIVE) trial5 — are exploring the option of blocking interleukin-15 to decrease or resolve lesions caused by celiac disease.5
CRIS-Team Scopus Importer:2021-12-10

Reframing Immune-Mediated Inflammatory Diseases through Signature Cytokine Hubs - Schett, Georg; Mcinnes, Iain B.; Neurath, Markus (New England Journal of Medicine, 2021)
Immune-mediated inflammatory diseases (IMIDs) are a heterogeneous group of diseases characterized by chronic inflammation and organ damage. IMIDs were traditionally classified on the basis of the predominant organ involvement. Improving the pathogenic characterization of IMIDs, however, should allow for a refined mechanistic understanding of these diseases and should make it possible to develop a molecular-based classification. The transition from organ-based to molecular-based classification was initiated by insights into associated genetic mutations and polymorphisms of key immune pathways and the development of monoclonal antibodies that target signature cytokine hubs in IMIDs. As compared with an organ-based classification, molecular classification better addresses pathophysiological commonalities across IMIDs that affect different organs but also accounts for substantial mechanistic differences among IMIDs that affect the same organ (Fig. 1).
CRIS-Team Scopus Importer:2021-08-27

REGULATION OF ARTHRITIS BY TYPE 2 INNATE LYMPHOID CELLS - Omata, Yasunori; Lucas, Sebastien; Garcia, Mireia; Wirtz, Stefan; Bozec, Aline; Schett, Georg; Zaiss, Mario (2017)
EVALuna2:13496

REGULATION OF AUTOANTIBODY ACTIVITY BY T CELL SUBSETS - Krönke, Gerhard (ANNALS OF THE RHEUMATIC DISEASES, 2019)
CRIS-Team WoS Importer:2019-07-12

Regulation of autoantibody activity by the IL-23-TH17 axis determines the onset of autoimmune disease. - Pfeifle, René; Rothe, Tobias; Ipseiz, Natacha; Scherer, Hans U.; Culemann, Stephan; Harre, Ulrike; Ackermann, Jochen; Seefried, Martina; Kleyer, Arnd; Uderhardt, Stefan; Haugg, Benjamin; Huebert, Axel J.; et al. (Nature Immunology, 2017)
The checkpoints and mechanisms that contribute to autoantibody-driven disease are as yet incompletely understood. Here we identified the axis of interleukin 23 (IL-23) and the TH17 subset of helper T cells as a decisive factor that controlled the intrinsic inflammatory activity of autoantibodies and triggered the clinical onset of autoimmune arthritis. By instructing B cells in an IL-22- and IL-21-dependent manner, TH17 cells regulated the expression of β-galactoside α2,6-sialyltransferase 1 in newly differentiating antibody-producing cells and determined the glycosylation profile and activity of immunoglobulin G (IgG) produced by the plasma cells that subsequently emerged. Asymptomatic humans with rheumatoid arthritis (RA)-specific autoantibodies showed identical changes in the activity and glycosylation of autoreactive IgG antibodies before shifting to the inflammatory phase of RA; thus, our results identify an IL-23-TH17 cell-dependent pathway that controls autoantibody activity and unmasks a preexisting breach in immunotoleranc

Regulation of bone and joint inflammation by type 2 innate lymphoid cells - Omata, Yasunori; Zaiss, Mario; Frech, Michael; Schett, Georg; Tanaka, Sakae (Elsevier, 2023)
The innate and adaptive immune systems regulate inflammation in arthritis. The innate immune system works as one of the “first responders” against the invasion of pathogens, followed by adaptive immunity activation. The cross-talk between innate and adaptive immune cells has protective roles against pathogens and induces immunological responses. Recently, a new type of innate immune cells, innate lymphoid cells (ILCs), was discovered; it was found that they play a profound role in immunological responses. ILCs function closely with T helper cells, depending on their respective subsets. In this chapter, we mainly focus on one subset, type 2 ILCs (ILC2s), and review their role in inflammatory arthritis and bone homeostasis.
CRIS-Team Scopus Importer:2023-04-28
Keywords: Adaptive immunity; Arthritis; Bone; Innate immunity; Innate lymphoid cells (ILC); Osteoclast; T cell

Regulation of Fibroblast Apoptosis and Proliferation by MicroRNA-125b in Systemic Sclerosis - Kozlova, Anastasiia; Pachera, Elena; Maurer, Britta; Juengel, Astrid; Distler, Jörg; Kania, Gabriela; Distler, Oliver (Arthritis and Rheumatology, 2019)
Objective To analyze the expression, regulation, and role of microRNA-125b (miR-125b) in systemic sclerosis (SSc). Methods MiR-125b expression was assessed by quantitative polymerase chain reaction (qPCR) of RNA from dermal fibroblasts and whole skin biopsy specimens from healthy controls and SSc patients. To identify downstream effectors, RNA from healthy control fibroblasts was sequenced after miR-125b knockdown and further validated using qPCR and Western blotting. Fibrosis, apoptosis, and proliferation were assessed by Caspase-Glo 3/7 assay, Western blotting, immunofluorescence staining for cleaved caspase 3, and annexin V real-time assay in dermal fibroblasts. Results Expression of miR-125b was significantly down-regulated in SSc skin biopsy specimens by 53% (median fold change 0.47 [interquartile range 0.35-0.69]; P < 0.001) and in SSc dermal fibroblasts by 47% (median fold change 0.53 [interquartile range 0.36-0.58]; P < 0.001) compared to healthy control skin biopsy specimens and fibroblasts, respectively (n = 10 samples per group). Treatment with the histone deacetylase inhibitors trichostatin A and tubastatin A significantly decreased the expression of miR-125b in dermal fibroblasts. MiR-125b knockdown significantly reduced cell proliferation and alpha-smooth muscle actin (alpha-SMA) expression at the messenger RNA (mRNA) and protein levels. RNA-Seq identified BAK1, BMF, and BBC3 as potential targets of miR-125b. Quantitative PCR confirmed that knockdown of miR-125b up-regulated these genes (P < 0.01; n = 12). Bcl-2 homologous antagonist killer 1 showed the strongest induction confirmed at the protein level (P < 0.01; n = 10). Consequently, miR-125b knockdown increased apoptosis compared to scrambled control. Accordingly, miR-125b overexpression decreased apoptosis. Conclusion Our findings indicate that miR-125b is down-regulated in SSc skin and primary dermal fibroblasts. MiR-125b down-regulation increases apoptosis and decreases proliferation and alpha-SMA expression in dermal fibroblasts, indicating that its compensatory, antifibrotic mechanism may be a potential novel therapeutic option.
CRIS-Team WoS Importer:2019-11-12

Regulation of plasma cell homeostasis and antibody secretion through modulation of autophagy and endoplasmic reticulum stress by Trk-fused-gene (TFG) - Thomas, Jana; Steinmetz, Tobit; Mielenz, Dirk (EUROPEAN JOURNAL OF IMMUNOLOGY, 2022)
CRIS-Team WoS Importer:2023-01-27

Regulatory eosinophils induce the resolution of experimental arthritis and appear in remission state of human rheumatoid arthritis - Andreev, Darja; Liu, Mengdan; Kachler, Katerina; Llerins Perez, Mireia; Kirchner, Philipp; Kölle, Julia; Gießl, Andreas; Rauber, Simon; Song, Rui; Aust, Oliver; Grüneboom, Anika; Kleyer, Arnd; et al. (Annals of the Rheumatic Diseases, 2020)
Objectives: Eosinophils possess pro-inflammatory functions in asthma. However, our recent studies have suggested that innate lymphoid cells type 2 (ILC2s) and eosinophils have proresolving properties in rheumatoid arthritis (RA). Nothing is known yet about the mechanisms determining the double-edged role of eosinophils. Therefore, we investigated whether asthma, a paradigm eosinophilic disease, can elicit resolution of chronic arthritis. Methods: Ovalbumin-triggered eosinophilic asthma was combined with K/BxN serum-induced arthritis, where lung and synovial eosinophil subsets were compared by single-cell RNA sequencing (scRNA-seq). To investigate the involvement of the ILC2-interleukin-5 (IL-5) axis, hydrodynamic injection (HDI) of IL-25 and IL-33 plasmids, IL-5 reporter mice and anti-IL-5 antibody treatment were used. In patients with RA, the presence of distinct eosinophil subsets was examined in peripheral blood and synovial tissue. Disease activity of patients with RA with concomitant asthma was monitored before and after mepolizumab (anti-IL-5 antibody) therapy. Results: The induction of eosinophilic asthma caused resolution of murine arthritis and joint tissue protection. ScRNA-seq revealed a specific subset of regulatory eosinophils (rEos) in the joints, distinct from inflammatory eosinophils in the lungs. Mechanistically, synovial rEos expanded on systemic upregulation of IL-5 released by lung ILC2s. Eosinophil depletion abolished the beneficial effect of asthma on arthritis. rEos were consistently present in the synovium of patients with RA in remission, but not in active stage. Remarkably, in patients with RA with concomitant asthma, mepolizumab treatment induced relapse of arthritis. Conclusion: These findings point to a hitherto undiscovered proresolving signature in an eosinophil subset that stimulates arthritis resolution.
CRIS-Team Scopus Importer:2020-11-20
Keywords: arthritis; autoimmune diseases; cytokines; immune system diseases; inflammation; rheumatoid

Regulatory T cells protect from local and systemic bone destruction in arthritis. - Zaiss, Mario; Frey, Benjamin; Heß, Andreas; Zwerina, Jochen; Luther, Julia; Nimmerjahn, Falk; Engelke, Klaus; Kollias, George; Huenig, Thomas; Schett, Georg; David, Jean-Pierre (Journal of Immunology, 2010)
We previously demonstrated the suppressive effects of regulatory T cells (Treg cells) on osteoclast differentiation in vitro. In this article, we show that blood markers of bone resorption inversely correlate with the amount of circulating Treg cells in healthy controls and rheumatoid arthritis patients, further suggesting that Treg cells may control bone destruction in vivo. Indeed, bone marrow from Foxp3-transgenic (Foxp3tg) mice fully protected human TNF transgenic (hTNFtg) mice from TNF-alpha-induced bone destruction, whereas Foxp3-deficient bone marrow enhanced local and systemic bone loss. The same protective effect was also obtained by treating hTNFtg mice with the CD28 superagonist mAb (CD28 SA), which increased Treg cell numbers. In both models, bone protection by Treg cells was associated with reduced osteoclast numbers, resulting in less bone-resorbing activity. Reduced osteoclast numbers were not caused by an intrinsic defect in osteoclast differentiation because osteoclast precursors from hTNFtg/Foxp3tg chimeras responded normally to M-CSF and receptor activator of NF-kappaB ligand. Although a decrease in the clinical signs of arthritis was observed in Foxp3tg bone marrow-transferred and CD28 SA-treated hTNFtg mice, the bone-protective effect of Treg cells was independent of the suppression of inflammation, as demonstrated by the increased systemic bone density observed in wild-type mice treated with CD28 SA. This work demonstrated that increasing Treg cell numbers improved clinical signs of arthritis and suppressed local and systemic bone destruction. Thus, enhancing the activity of Treg cells would be beneficial for the treatment of inflammation-induced bone loss observed in rheumatoid arthritis.

Relapse rates in patients with rheumatoid arthritis in stable remission tapering or stopping antirheumatic therapy: interim results from the prospective randomised controlled RETRO study - Haschka, Judith; Englbrecht, Matthias; Hueber, Axel; Manger, Bernhard; Kleyer, Arnd; Reiser, Michaela; Finzel, Stephanie; Tony, Hans-Peter; Kleinert, Stefan; Feuchtenberger, Martin; Fleck, Martin; Manger, Karin; et al. (Annals of the Rheumatic Diseases, 2016)
To prospectively analyse the risk for disease relapses in patients with rheumatoid arthritis (RA) in sustained remission, either continuing, tapering or stopping disease-modifying antirheumatic drugs (DMARDs) in a prospective randomised controlled trial.Reduction of Therapy in patients with Rheumatoid arthritis in Ongoing remission is a multicentre, randomised controlled, parallel-group phase 3 trial evaluating the effects of tapering and stopping all conventional and/or biological DMARDs in patients with RA in stable remission. Patients (disease activity score 28 (DAS28)<2.6 for least 6 months) were randomised into three arms, either continuing DMARDs (arm 1), tapering DMARDs by 50% (arm 2) or stopping DMARDs after 6 months tapering (arm 3). The primary endpoint was sustained remission during 12 months.In this interim analysis, the first 101 patients who completed the study were analysed. At baseline, all patients fulfilled DAS28 remission and 70% also American College of Rheumatology- European League Against Rheumatism Boolean remission. 82.2% of the patients received methotrexate, 40.6% biological DMARDs and 9.9% other DMARDs. Overall, 67 patients (66.3%) remained in remission for 12 months, whereas 34 patients (33.7%) relapsed. The incidence of relapses was related to study arms (p=0.007; arm 1: 15.8%; arm 2: 38.9%; arm 3: 51.9%). Multivariate logistic regression identified anticitrullinated protein antibodies (ACPA) positivity (p=0.038) and treatment reduction (in comparison to continuation) as predictors for relapse (arm 2: p=0.012; arm 3: p=0.003).This randomised controlled study testing three different treatment strategies in patients with RA in sustained remission demonstrated that more than half of the patients maintain in remission after tapering or stopping conventional and biological DMARD treatment. Relapses occurred particularly in the first 6 months after treatment reduction and were associated with the presence of ACPA.2009-015740-42.
EVALuna2:12856

RELATIONSHIP BETWEEN ANTI-MDA5 ANTIBODIES AND CANCER: RETROSPECTIVE ANALYSIS OF AN INTERNATIONAL AND MULTIDISCIPLINARY COHORT - De Stefano, Ludovico; Castaneda, Santos; De Langhe, Ellen; Distler, Jörg; Knitza, Johannes; Cavazzana, Ilaria; Meyer, Alain; Rojas-Serrano, Jorge; Arrigoni, Eugenio; Furini, Federica; Govoni, Marcello; Parrocchini, Paola; et al. (ANNALS OF THE RHEUMATIC DISEASES, 2019)
CRIS-Team WoS Importer:2019-07-16

Relations of vitamin D status, gender and type 2 diabetes in middle-aged Caucasians - Stadlmayr, Andreas; Aigner, Elmar; Huber-Schoenauer, Ursula; Niederseer, David; Zwerina, Jochen; Husar-Memmer, Emma; Hohla, Florian; Schett, Georg; Patsch, Wolfgang; Datz, Christian (Acta Diabetologica, 2015)
Vitamin D (Vit D) deficiency may be linked to the development of obesity-associated complications such as insulin resistance and type 2 diabetes. We therefore evaluated the relationship of Vit D serum concentrations with metabolic parameters and type 2 diabetes in middle-aged Caucasian men and women. One thousand six hundred and thirty-one Caucasians (832 males, 58.8 ± 9.7 years; 799 females, 59.7 ± 10.7 years) were evaluated in a cross-sectional study. Vit D status was assessed by measuring the serum concentration of 25-hydroxyvitamin D3 [25(OH)D3]. Type 2 diabetes prevalence was ascertained by medical history, fasting plasma glucose concentrations, oral glucose tolerance testing and/or glycosylated hemoglobin. Men displayed higher crude or seasonally adjusted 25(OH)D3 serum concentrations than women (24.64 ± 10.98 vs. 22.88 ± 11.6 ng/ml; P < 0.001). Strong associations between body mass index (BMI) and 25(OH)D3 were observed in both genders (P < 0.001). Seasonally adjusted levels of 25(OH)D3 revealed stronger associations with type 2 diabetes in women than men (P < 0.001). However, adjustment for BMI and other confounding variables revealed an independent inverse association of 25(OH)D3 with diabetes only in women (P < 0.001), whereas the association was abrogated in men. Using a 15 ng/ml 25(OH)D3 cutoff for binary comparison, adjusted odds ratios for having newly diagnosed or known type 2 diabetes more than doubled (2.95 [95 % CI 1.37-4.89] and 3.26 [1.59-6.68], respectively), in women below the cutoff. We conclude that in women, but not in men, low 25(OH)D3 serum levels are independently associated with type 2 diabetes. These findings suggest sex-specific effects of Vit D in the pathogenesis of type 2 diabetes.
EVALuna2:12976

RELMα-expressing macrophages protect against fatal lung damage and reduce parasite burden during helminth infection - Krljanac, Branislav; Schubart, Christoph; Naumann, Ronald; Wirtz, Stefan; Culemann, Stephan; Krönke, Gerhard; Vöhringer, David (Science immunology, 2019)
Alternatively activated macrophages (AAMs) can contribute to wound healing, regulation of glucose and fat metabolism, resolution of inflammation, and protective immunity against helminths. Their differentiation, tissue distribution, and effector functions are incompletely understood. Murine AAMs express high levels of resistin-like molecule (RELM) α, an effector protein with potent immunomodulatory functions. To visualize RELMα+ macrophages (MΦs) in vivo and evaluate their role in defense against helminths, we generated RELMα reporter/deleter mice. Infection with the helminth Nippostrongylus brasiliensis induced expansion of RELMα+ lung interstitial but not alveolar MΦs in a STAT6-dependent manner. RELMα+ MΦs were required for prevention of fatal lung damage during primary infection. Furthermore, protective immunity was lost upon specific deletion of RELMα+ MΦs during secondary infection. Thus, RELMα reporter/deleter mice reveal compartmentalization of AAMs in different tissues and demonstrate their critical role in resolution of severe lung inflammation and protection against migrating helminths.
CRIS-Team Scopus Importer:2019-06-18

Remission in psoriatic arthritis-where are we now? - Coates, Laura C.; Conaghan, Philip G.; D'Agostino, Maria Antonietta; De Wit, Maarten; Fitzgerald, Oliver; Kvien, Tore K.; Lories, Rik; Mease, Philip; Nash, Peter; Schett, Georg; Soriano, Enrique R.; Emery, Paul (Rheumatology, 2017)
Advances in treatments and treatment strategies for PsA have led to many patients responding well to management of their disease, and targeting remission as a treatment goal is now a possibility. Treat to target is a strategy aimed at maximizing benefit, irrespective of the type of medication used, by monitoring disease activity and using it to guide therapy. The measurement of response to treatment has been the subject of wide discussions among experts for some time, and many instruments exist. Comparisons of the different measures and their different strengths and weaknesses is ongoing. The impact of modern imaging techniques on monitoring disease progression is also evolving, and advanced techniques using both MRI and US have the potential to improve management of PsA through identification of risk factors for poor prognosis as well as accurate assessment of inflammation and damage, including subclinical disease. Increased understanding of the pathways that drive the pathogenesis of PsA will be key to identifying specific biomarkers for the disease and developing effective treatment strategies. Targets for response, considerations for use of a treat to target strategy in PsA, different imaging techniques and serological aspects of remission are all discussed in this review, and areas for further research are identified.
EVALuna2:13452

Remote self-collection of capillary blood using upper arm devices for autoantibody analysis in patients with immune-mediated inflammatory rheumatic diseases - Zarbl, Joshua; Eimer, Ekaterina; Gigg, Camilla; Bendzuck, Gerlinde; Korinth, Marianne; Elling-Audersch, Corinna; Kleyer, Arnd; Simon, David; Böltz, Sebastian; Krusche, Martin; Mucke, Johanna; Muehlensiepen, Felix; et al. (RMD Open, 2022)
Objectives To evaluate the feasibility, accuracy, usability and acceptability of two upper arm self-sampling devices for measurement of autoantibodies and C reactive protein (CRP) levels in patients with immune-mediated rheumatic diseases (IMRDs). Methods 70 consecutive patients with IMRD with previously documented autoantibodies were assigned to supervised and unsupervised self-collection of capillary blood with the Tasso+ or TAP II device. Interchangeability of 17 biomarkers with standard venesection was assessed by: concordance, correlation, paired sample hypothesis testing and Bland-Altman plots. Patients completed an evaluation questionnaire, including the System Usability Scale (SUS) and Net Promoter Score (NPS). Results While 80.0% and 77.0% were able to safely and successfully collect capillary blood using the Tasso+ and TAP II within the first attempt, 69 of 70 (98.6%) patients were successful in collecting capillary blood within two attempts. Concordance between venous and capillary samples was high; 94.7% and 99.5% for positive and negative samples, respectively. For connective tissue disease screen, anti-Ro52 and anti-proteinase 3 autoantibody levels, no significant differences were observed. Self-sampling was less painful than standard venesection for the majority of patients (Tasso+: 71%; TAP II: 63%). Both devices were well accepted (NPS; both: +28%), usability was perceived as excellent (SUS; Tasso+: 88.6 of 100; TAP II: 86.0 of 100) and 48.6 %/62.9% of patients would prefer to use the Tasso+/TAP II, respectively, instead of a traditional venous blood collection. Conclusions Remote self-collection of capillary blood using upper arm-based devices for autoantibody and CRP analysis in patients with autoimmune rheumatic diseases is feasible, accurate and well accepted among patients.
CRIS-Team WoS Importer:2022-09-23

Removing the bone brake - Schett, Georg; Bozec, Aline (Cell Metabolism, 2014)
Osteoporosis results from an imbalance between bone resorption and bone formation. While bone resorption inhibitors are widely used to treat osteoporosis, stimulating bone formation is more challenging. Recently, McClung et al. (2014) found that neutralization of sclerostin, a potent inhibitor of bone formation, effectively increased bone mass in postmenopausal women.
EVALuna2:12984

Renal leishmaniasis as unusual cause of nephrotic syndrome in an HIV patient - Amann, Kerstin Ute; Bogdan, Christian; Harrer, Thomas; Rech, Jürgen (Journal of the American Society of Nephrology, 2012)
Renal involvement is a rare complication in HIV-1-infected patients leading to various pathologies and clinical symptoms. In addition to the classic HIV-1-associated nephropathy with collapsing-type focal segmental glomerulosclerosis and characteristic tubulocystic changes, which is more common in Afro-American than in Caucasian HIV-1 patients, immune complex GNs such as membranous GN and membranoproliferative GN are particularly common renal manifestations. Besides HIV-1 itself, a number of opportunistic infections may cause renal disease in HIV-1-infected patients. In this study, we report an unusual case of HIV-1 infection with a severe renal manifestation of systemic leishmaniasis that developed years after repeated visits to Mediterranean countries. The case presents several remarkable clinical, pathologic, and therapeutic aspects that may be important for daily clinical practice. Copyright © 2012 by the American Society of Nephrology.
CRIS-Team Scopus Importer:2021-02-03

Repair of bone erosions in rheumatoid arthritis treated with tumour necrosis factor inhibitors is based on bone apposition at the base of the erosion - Finzel, Stephanie; Rech, Jürgen; Schmidt, Sarah; Engelke, Klaus; Englbrecht, Matthias; Stach, Christian; Schett, Georg (Annals of the Rheumatic Diseases, 2011)
Objectives: To investigate whether bone erosions in patients with rheumatoid arthritis (RA) show evidence of repair. Methods: 127 erosions were identified in metacarpophalangeal joints 2-4 of the right hands of 30 RA patients treated with tumour necrosis factor inhibitors (TNFi) and 21 sex, age and disease activity-matched patients treated with methotrexate. All erosions were assessed for their exact maximal width and depth by high-resolution μCT imaging at baseline and after 1 year. Results: All erosions detected at baseline could be visualised at follow-up after 1 year. At baseline, the mean width of bone erosions in the TNFi group was 2.0 mm;their mean depth was 2.3 mm, which was not significantly different from the methotrexate-treated group (width 2.4 mm;depth 2.4 mm). Mean depth of erosions significantly decreased after 1 year of treatment with TNFi (-0.1 mm; p=0.016), whereas their width remained unchanged. In contrast, mean depth and width of erosive lesions increased in the methotrexate-treated group. The reduction in the depth of lesions was confined to erosions showing evidence of sclerosis at the base of the lesion. Moreover, deeper lesions in the TNFi group were particularly prone to repair (-0.4 mm;p=0.02) compared with more shallow lesions. Conclusions: Bone erosions in RA patients treated with TNFi show evidence of limited repair in contrast to bone erosions in patients treated with methotrexate. Repair is associated with a decrease in the depth of lesions and sclerosis at the bases of the lesions. Repair thus emerges from the endosteal rather than periosteal bone compartment and probably involves the bone marrow.
CRIS-Team Scopus Importer:2021-02-03

Reply. - Simon, David; Fagni, Filippo; Tascilar, Koray; Schett, Georg (Arthritis and Rheumatology, 2022)
EVALuna2:520678

Reply - Soare, Alina; Distler, Jörg (Arthritis and Rheumatology, 2020)
CRIS-Team WoS Importer:2020-12-04

Reply to Hou: Central nervous system effects of TNF-α blockade - Heß, Andreas; Rech, Jürgen; Brune, Kay; Schett, Georg (Proceedings of the National Academy of Sciences of the United States of America, 2011)
CRIS-Team Scopus Importer:2021-02-03

Reply to "Neutrophils are not required for resolution of acute gouty arthritis in mice" - Reinwald, Christiane; Schauer, Christine; Csepregi, Janka Zsofia; Kienhoefer, Deborah; Weidner, Daniela; Malissen, Marie; Mocsai, Attila; Schett, Georg; Herrmann, Martin; Hoffmann, Markus (Nature Medicine, 2016)
EVALuna2:13379

Reply to: Osteoporosis: An Independent Determinant of Bone Erosions in Rheumatoid Arthritis? - Simon, David; Simon, Christoph; Kleyer, Arnd; Schett, Georg (Journal of Bone and Mineral Research, 2017)
We thank Rossini and colleagues for their letter (1) commenting on our article (2) "Age- and Sex-Dependent Changes of intra-articular Cortical and Trabecular Bone Structure and the Effects of Rheumatoid Arthritis". In fact, we could not more agree with the view of the authors and congratulate them for this concise summary of the key mechanism involved in bone loss of rheumatoid arthritis. In addition, we think that this letter raises two important points related to inflammatory bone loss: First, Rossini and colleagues point out that bone loss in rheumatoid arthritis arises from a combination of (i) factors specific to rheumatoid arthritis, in particular inflammation and autoimmunity and (ii) more common factors related to age, sex and menopausal status. Hence, age, postmenopausal state and inflammation/autoimmunity join efforts to trigger bone disease in patients with rheumatoid arthritis. Our data support this concept by showing age-, sex- and disease- associated changes of intra-articular bone mass and microstructures, which is likely the most sensitive indicator of bone loss in the context of arthritis. This article is protected by copyright. All rights reserved.
EVALuna2:13426

Rescue therapy of antisynthetase syndrome with CD19-targeted CAR-T cells after failure of several B-cell depleting antibodies - Taubmann, Jule; Knitza, Johannes; Müller, Fabian; Völkl, Simon; Aigner, Michael; Kleyer, Arnd; Gary, Regina; Kretschmann, Sascha; Böltz, Sebastian; Atzinger, Armin; Kuwert, Torsten; Roemer, Frank; et al. (Rheumatology, 2024)
EVALuna2:539551

Research consortium Neuroimmunology and pain in the research network musculoskeletal diseases - Schaible, H-G.; Chang, H. -D.; Graessel, S.; Haibel, H.; Heß, Andreas; Kamradt, T.; Radbruch, A.; Schett, Georg; Stein, C.; Straub, R. H. (Zeitschrift für Rheumatologie, 2018)
BACKGROUND: The research consortium Neuroimmunology and Pain (Neuroimpa) explores the importance of the relationships between the immune system and the nervous system in musculoskeletal diseases for the generation of pain and for the course of fracture healing and arthritis. MATERIAL AND METHODS: The spectrum of methods includes analyses at the single cell level, in vivo models of arthritis and fracture healing, imaging studies on brain function in animals and humans and analysis of data from patients. RESULTS: Proinflammatory cytokines significantly contribute to the generation of joint pain through neuronal cytokine receptors. Immune cells release opioid peptides which activate opioid receptors at peripheral nociceptors and thereby evoke hypoalgesia. The formation of new bone after fractures is significantly supported by the nervous system. The sympathetic nervous system promotes the development of immune-mediated arthritis. The studies show a significant analgesic potential of the neutralization of proinflammatory cytokines and of opioids which selectively inhibit peripheral neurons. Furthermore, they show that the modulation of neuronal mechanisms can beneficially influence the course of musculoskeletal diseases. DISCUSSION: Interventions in the interactions between the immune system and the nervous system hold a great therapeutic potential for the treatment of musculoskeletal diseases and pain.
EVALuna2:34149

Reset of inflammatory priming of joint tissue and reduction of the severity of arthritis flares by bromodomain inhibition - Friščić, Jasna; Reinwald, Christiane; Böttcher, Martin; Houtman, Miranda; Euler, Maximilien; Chen, Xi; Walker, Kellie I.; Kirchner, Philipp; Zhu, Honglin; Wirth, Benjamin; Weidner, Daniela; Krüger, René; et al. (Arthritis and Rheumatology, 2023)
Objective: We have recently shown that priming of synovial fibroblasts (SFs) drives arthritis flares. Pathogenic priming of SFs is essentially mediated by epigenetic reprogramming. Bromodomain and extra-terminal motif (BET) proteins translate epigenetic changes into transcription. Here we used a BET inhibitor to target inflammatory tissue priming and reduce flare severity in experimental arthritis. Methods: BALB/c mice were treated intraperitoneally or locally into the paw with I-BET151, which blocks interaction of BET proteins with acetylated histones. Effect of I-BET151 on acute arthritis and/or inflammatory tissue priming was assessed in a model of repeated injections of monosodium urate crystals or zymosan into the paw. I-BET151 was given either from before arthritis induction, at peak inflammation, or after healing of the first arthritis bout. Transcriptomic (RNA-Seq), epigenomic (ATAC-Seq) and functional analysis (invasion, cytokine production, migration, senescence, metabolic flux) was performed on murine and human SFs treated with I-BET151 in vitro or in vivo. Results: Systemic I-BET151 administration did not affect acute inflammation but abolished inflammatory tissue priming and diminished flare severity in both preventive and therapeutic treatment settings. I-BET151 was also effective when applied locally in the joint. BET inhibition also inhibited osteoclast differentiation, while macrophage activation in the joint was not affected. Flare reduction after BET inhibition was mediated, at least in part, by rolling back the primed transcriptional, metabolic and pathogenic phenotype of SFs. Conclusion: Inflammatory tissue priming is dependent on transcriptional regulation by BET proteins, which makes them promising therapeutic targets for preventing arthritis flares in previously affected joints.
CRIS-Team Scopus Importer:2023-01-27

Resolution of chronic inflammatory disease: universal and tissue-specific concepts - Schett, Georg; Neurath, Markus (Nature Communications, 2018)
Inflammation and its resolution is under-studied in medicine despite being essential for understanding the development of chronic inflammatory disease. In this review article, we discuss the resolution of inflammation in both a biological and translational context. We introduce the concept of impaired resolution leading to diseases like rheumatoid arthritis, Crohn's disease, and asthma, as well as the cellular and molecular components that contribute to resolution of joint, gut, and lung inflammation, respectively. Finally, we discuss potential intervention strategies for fostering the resolution process, and their implications for the therapy of inflammatory diseases.
EVALuna2:34476

Resolution of enthesitis by guselkumab and relationships to disease burden: 1-year results of two phase 3 psoriatic arthritis studies. - Mcgonagle, Dennis; Mcinnes, Iain B.; Deodhar, Atul; Schett, Georg; Shawi, May; Kafka, Shelly; Karyekar, Chetan S.; Kollmeier, Alexa P.; Hsia, Elizabeth C.; Xu, Xie L.; Sheng, Shihong; Agarwal, Prasheen; et al. (Rheumatology, 2021)
OBJECTIVE: To further characterize the effect of guselkumab, a selective IL-23p19-subunit inhibitor approved for PsA, on enthesitis and assess relationships between enthesitis resolution and patient status/outcomes. METHODS: Adults with active PsA despite standard therapies in the phase 3 DISCOVER-1 and DISCOVER-2 studies were randomized 1:1:1 to guselkumab 100 mg every 4 weeks (Q4W); guselkumab 100 mg at week 0, week 4, Q8W; or placebo through week 20 followed by guselkumab 100 mg Q4W. Independent assessors evaluated enthesitis using the Leeds Enthesitis Index (LEI; total score 0-6). Enthesitis findings through week 24 were pre-specified to be pooled across studies; post hoc and week 52 analyses also employed pooled data. RESULTS: Among 1118 randomized, treated patients in DISCOVER-1 and 2 who had ≥1 LEI site evaluated, 65% had enthesitis at baseline. These patients exhibited numerically more swollen and tender joints, systemic inflammation and impaired physical function than patients without enthesitis. Guselkumab Q4W and Q8W were superior to placebo in resolving pre-existing enthesitis at week 24 (45 and 50% vs 29%; both adjusted P = 0.0301). Enthesitis resolution rates continued to rise; 58% of guselkumab-randomized patients achieved resolution at week 52, including patients with mild (LEI = 1; 70-75%), moderate (LEI = 2; 69-73%) or severe (LEI = 3-6; 42-44%) enthesitis at baseline. Among guselkumab-randomized patients with resolved enthesitis at week 24, 42% achieved minimal disease activity at week 52, vs 17% of patients with unresolved enthesitis. CONCLUSION: Guselkumab resulted in higher proportions of PsA patients with resolved enthesitis by week 24, with maintenance of resolution rates through 1 year. As enthesitis confers greater disease burden, sustained resolution could portend better patient outcomes. CLINICAL TRIAL REGISTRATION: DISCOVER 1 (NCT03162796) and DISCOVER 2 (NCT03158285).
EVALuna2:474319

Resolution of inflammation by interleukin-9-producing type 2 innate lymphoid cells - Rauber, Simon; Luber, Markus; Weber, Stefanie; Maul, Lisa; Soare, Alina; Wohlfahrt, Thomas; Lin, Neng-Yu; Dietel, Katharina; Bozec, Aline; Herrmann, Martin; Kaplan, Mark H.; Weigmann, Benno; et al. (Nature Medicine, 2017)
Inflammatory diseases such as arthritis are chronic conditions that fail to resolve spontaneously. While the cytokine and cellular pathways triggering arthritis are well defined, those responsible for the resolution of inflammation are incompletely characterized. Here we identified interleukin (IL)-9-producing type 2 innate lymphoid cells (ILC2s) as the mediators of a molecular and cellular pathway that orchestrates the resolution of chronic inflammation. In mice, the absence of IL-9 impaired ILC2 proliferation and activation of regulatory T (Treg) cells, and resulted in chronic arthritis with excessive cartilage destruction and bone loss. In contrast, treatment with IL-9 promoted ILC2-dependent Treg activation and effectively induced resolution of inflammation and protection of bone. Patients with rheumatoid arthritis in remission exhibited high numbers of IL-9(+) ILC2s in joints and the circulation. Hence, fostering IL-9-mediated ILC2 activation may offer a novel therapeutic approach inducing resolution of inflammation rather than suppression of inflammatory responses.
EVALuna2:13255

Resolution of inflammation in arthritis - Schett, Georg (Seminars in Immunopathology, 2019)
Rheumatoid arthritis is among the most frequent and severe chronic inflammatory diseases. The disease is characterized by ongoing synovial inflammation, which leads to the destruction of cartilage and bone. In RA, the mechanisms of resolution of inflammation, which are normally intact in the joints, are either suppressed or overruled. Little efforts have been undertaken to understand the mechanisms of resolution of arthritis until recently, when several molecular mechanisms have been identified that determine the chronicity and resolution of inflammation in the joints, respectively. This review describes the key concepts of resolution of arthritis mentioning the key mechanisms involved, such as regulatory macrophages, pro-resolving lipid, fatty acid and cytokine mediators, aggregated neutrophil extracellular trap formation, antibody glycosylation changes, and stromal cell alterations that are involved in determining the decision between chronicity and resolution of arthritis. Each of these mechanisms represents a potential therapeutic approach that allows skewing the balance of the inflammatory processes towards resolution.
CRIS-Team Scopus Importer:2019-11-26

Resolution of synovitis and arrest of catabolic and anabolic bone changes in patients with psoriatic arthritis by IL-17A blockade with secukinumab: results from the prospective PSARTROS study - Kampylafka, Eleni; D'Oliveira, Isabelle; Linz, Christina; Lerchen, Veronika; Stemmler, Fabian; Simon, David; Englbrecht, Matthias; Sticherling, Michael; Rech, Juergen; Kleyer, Arnd; Schett, Georg; Hueber, Axel (Arthritis Research & Therapy, 2018)
BACKGROUND: Although the effects of interleukin-17A (IL-17A) inhibition on the signs and symptoms of psoriatic arthritis (PsA) are well defined, little is known about its impact of local inflammatory and structural changes in the joints. The PSARTROS study was designed to elucidate the effects of IL-17A inhibition on inflammation and bone changes in joints affected by PsA. METHODS: This was a prospective open-label study in 20 patients with active PsA receiving 24 weeks of treatment with the IL-17A inhibitor secukinumab. Magnetic resonance imaging (MRI), power Doppler ultrasound (PDUS), and high-resolution peripheral quantitative computer tomography (HR-pQCT) of the hands were performed at baseline and after 24 weeks to assess synovitis, periarticular inflammation, bone erosion, enthesiophyte formation, and bone structure. Demographic and clinical measures of joint disease (DAPSA and DAS28-ESR), skin disease (PASI and BSA), and composite measures (minimal disease activity, or MDA) were also recorded. RESULTS: Treatment with secukinumab led to significant improvement of signs and symptoms of PsA; 46% reached MDA and 52% DAPSA low disease activity. MRI synovitis (P = 0.034) and signal in PDUS (P = 0.030) significantly decreased after 24 weeks of treatment. Bone erosions in MRI and HR-pQCT and enthesiophytes in the HR-pQCT did not show any progression, and structural integrity and functional bone strength remained stable. CONCLUSIONS: IL-17 inhibition by secukinumab over 24 weeks led to a significant decrease of synovial inflammation and no progression of catabolic and anabolic bone changes in the joints of patients with PsA. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02483234 , June 26, 2015; retrospectively registered.
EVALuna2:34447

RESOLUTION OF VASCULAR INFLAMMATION IN PATIENTS WITH GIANT CELL ARTERITIS RECEIVING GLUCOCORTICOIDS, METHOTREXATE OR TOCILIZUMAB TREATMENT-DATA FROM THE ITALIAN/GERMAN RIGA STUDY - Schonau, Verena; Roth, Jessica; Tascilar, Koray; Rech, Jürgen; Schmidt, Daniela; Kuwert, Torsten; Crescentini, Filippo; Boiardi, Luigi; Casali, Massim Iliano; Versari, Annibale; Schett, Georg; Salvarani, Carlo; et al. (ANNALS OF THE RHEUMATIC DISEASES, 2019)
CRIS-Team WoS Importer:2019-07-12

Resolution of vascular inflammation in patients with new-onset giant cell arteritis: data from the RIGA study - Schönau, Verena; Roth, Jessica; Tascilar, Koray; Corte, Giulia; Manger, Bernhard; Rech, Jürgen; Schmidt, Daniela; Cavallaro, Alexander Josef; Uder, Michael; Crescentini, Filippo; Boiardi, Luigi; Casali, Massimiliano; et al. (Rheumatology, 2021)
OBJECTIVES: Efficacy evaluation of GCA treatment is primarily based on non-specific symptoms and laboratory markers. We aimed to assess the change in vascular inflammation in patients with large vessel (LV)-GCA under different treatments using [18F]FDG PET/CT. METHODS: Observational study on patients with new-onset, active LV-GCA starting treatment with either prednisolone monotherapy (PRED) or combination with MTX or tocilizumab (TOC). All patients underwent baseline and follow-up PET/CT. The aorta and its major branches were assessed using PET vascular activity score (PETVAS) by independent readers. Cumulative glucocorticoid doses and cessation of glucocorticoid treatment were documented in all patients. RESULTS: We included 88 LV-GCA patients, 27 were treated with PRED, 42 with MTX and 19 with TOC. PETVAS decreased from 18.9-8.0 units at follow-up in the overall population (P <0.001). PETVAS changes were numerically higher in patients receiving MTX (-12.3 units) or TOC (-11.7 units) compared with PRED (-8.7). Mean cumulative prednisolone dosages were 5637, 4418 and 2984 mg in patients treated with PRED, MTX and TOC (P =0.002). Risk ratios for glucocorticoid discontinuation at the time of follow-up PET/CT were 6.77 (95% CI: 1.01, 45.29; P =0.049) and 16.25 (95% CI: 2.60, 101.73; P =0.003) for MTX and TOC users compared with PRED users. CONCLUSION: Treatment of LV-GCA inhibits vascular inflammation in the aorta and its major branches. While similar control of vascular inflammation was achieved with PRED, MTX and TOC treatments, TOC showed a strong glucocorticoid sparing effect, supporting the concept of initial combination therapy.
CRIS-Team Scopus Importer:2021-09-24
Keywords: 18F-fluorodeoxyglucose positron emission tomography/computed tomography; giant cell arteritis; glucocorticoids; large vessel vasculitis; methotrexate; tocilizumab; treatment

Respiratory syncytial virus (RSV) disease in hospitalised adults in Europe: comparison of retrospective patient chart reviews of adults=65 (=65y) and - Launay, Odile; Thalhammer, Florian; Harrer, Thomas; Cheret, Arnaud; De La Rosa, Guy; Sander, Ian; Stolper, Robert; Zakar, Jessica; Weber, Karin (2018)
EVALuna2:213253

Response of human rheumatoid arthritis osteoblasts and osteoclasts to adiponectin - Krumbholz, Grit; Junker, Susann; Meier, Florian M P; Rickert, Markus; Steinmeyer, Jürgen; Rehart, Stefan; Lange, Uwe; Frommer, Klaus W; Schett, Georg; Müller-Ladner, Ulf; Neumann, Elena (Clinical and Experimental Rheumatology, 2017)
Adiponectin is an effector molecule in the pathophysiology of rheumatoid arthritis, e.g. by inducing cytokines and matrix degrading enzymes in synovial fibroblasts. There is growing evidence that adiponectin affects osteoblasts and osteoclasts although the contribution to the aberrant bone metabolism in rheumatoid arthritis is unclear. Therefore, the adiponectin effects on rheumatoid arthritis-derived osteoblasts and osteoclasts were evaluated.Adiponectin and its receptors were examined in bone tissue. Primary human osteoblasts and osteoclasts were stimulated with adiponectin and analysed using realtime polymerase chain-reaction and immunoassays. Effects on matrix-production by osteoblasts and differentiation and resorptive activity of osteoclasts were examined.Immunohistochemistry of rheumatoid arthritis bone tissue showed adiponectin expression in key cells of bone remodelling. Adiponectin altered gene expression and cytokine release in osteoblasts and increased IL-8 secretion by osteoclasts. Adiponectin inhibited osterix and induced osteoprotegerin mRNA in osteoblasts. In osteoclasts, MMP-9 and tartrate resistant acid phosphatase expression was increased. Accordingly, mineralisation capacity of osteoblasts decreased whereas resorptive activity of osteoclasts increased.The results confirm the proinflammatory potential of adiponectin and support the idea that adiponectin influences rheumatoid arthritis bone remodelling through alterations in osteoblast and osteoclast.
EVALuna2:13390

Response to: 'Correspondence on 'Glucocorticoid-induced relapse of COVID-19 in a patient with sarcoidosis'' by Jeny et al. - Györfi, Andrea-Hermina; Schett, Georg; Distler, Jörg (Annals of the Rheumatic Diseases, 2022)
EVALuna2:423616

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

Response to: 'Is the PET/CT first choice for differential diagnosis of FUO/IUO?' by Armagan et al - Schönau, Verena; Schett, Georg (Annals of the Rheumatic Diseases, 2018)
EVALuna2:34487

Response to peripheral immune stimulation within the brain: magnetic resonance imaging perspective of treatment success - Sergeeva, Marina; Rech, Juergen; Schett, Georg; Heß, Andreas (Arthritis Research & Therapy, 2015)
Chronic peripheral inflammation in diseases such as rheumatoid arthritis leads to alterations in central pain processing and consequently to mood disorders resulting from sensitization within the central nervous system and enhanced vulnerability of the medial pain pathway. Proinflammatory cytokines such as tumor necrosis factor (TNF) alpha play an important role herein, and therapies targeting their signaling (i.e., anti-TNF therapies) have been proven to achieve good results. However, the phenomenon of rapid improvement in the patients' subjective feeling after the start of TNF? neutralization remained confusing, because it was observed long before any detectable signs of inflammation decline. Functional magnetic resonance imaging (fMRI), enabling visualization of brain activity upon peripheral immune stimulation with anti-TNF, has helped to clarify this discrepancy. Moreover, fMRI appeared to work as a reliable tool for predicting prospective success of anti-TNF therapy, which is valuable considering the side effects of the drugs and the high therapy costs. This review, which is mainly guided by neuroimaging studies of the brain, summarizes the state-of-the-art knowledge about communication between the immune system and the brain and its impact on subjective well-being, addresses in more detail the outcome of the abovementioned anti-TNF fMRI studies (rapid response to TNF? blockade within the brain pain matrix and differences in brain activation patterns between prospective therapy responders and nonresponders), and discusses possible mechanisms for the latter phenomena and the predictive power of fMRI.
EVALuna2:13172

Response to secukinumab on synovitis using Power Doppler ultrasound in psoriatic arthritis: 12-week results from a phase III study, ULTIMATE - D'Agostino, Maria Antonietta; Schett, Georg; Lopez-Rdz, Alejandra; Senolt, Ladislav; Fazekas, Katalin; Burgos-Vargas, Ruben; Maldonado-Cocco, Jose; Naredo, Esperanza; Carron, Philippe; Duggan, Anne-Marie; Goyanka, Punit; Boers, Maarten; et al. (Rheumatology, 2021)
Objectives. To investigate the dynamics of response of synovitis to IL-17A inhibition with secukinumab in patients with active PsA using Power Doppler ultrasound.
CRIS-Team WoS Importer:2022-05-13

Response to: the value of 18(F)-FDG-PET/CT in identifying the cause of fever of unknown origin (FUO) and inflammation of unknown origin (IUO): data from a prospective study - Schönau, Verena; Schett, Georg (Annals of the Rheumatic Diseases, 2017)
EVALuna2:13516

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

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

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

RETRO - STUDY OF REDUCTION OF THERAPY IN PATIENTS WITH RHEUMATOID ARTHRITIS IN ONGOING REMISSION - Haschka, J.; Englbrecht, Matthias; Hueber, Axel; Manger, Bernhard; Kleyer, Arnd; Reiser, M.; Finzel, Stephanie; Tony, H. -P.; Kleinert, S.; Feuchtenberger, M.; Fleck, M.; Manger, Karin; et al. (2015)
EVALuna2:34460

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

Review: Frontiers of Antifibrotic Therapy in Systemic Sclerosis - Distler, Jörg; Feghali-Bostwick, Carol; Soare, Alina; Asano, Yoshihide; Distler, Oliver; Abraham, David J. (Arthritis and Rheumatology, 2017)
EVALuna2:13105

Revised European Scleroderma Trials and Research Group Activity Index is the best predictor of short-term severity accrual - Fasano, Serena; Riccardi, Antonella; Messiniti, Valentina; Caramaschi, Paola; Rosato, Edoardo; Maurer, Britta; Smith, Vanessa; Siegert, Elise; De Langhe, Ellen; Riccieri, Valeria; Airó, Paolo; Mihai, Carina; et al. (Annals of the Rheumatic Diseases, 2019)
Background: The European Scleroderma Trials and Research Group (EUSTAR) recently developed a preliminarily revised activity index (AI) that performed better than the European Scleroderma Study Group Activity Index (EScSG-AI) in systemic sclerosis (SSc). Objective: To assess the predictive value for short-term disease severity accrual of the EUSTAR-AI, as compared with those of the EScSG-AI and of known adverse prognostic factors. Methods: Patients with SSc from the EUSTAR database with a disease duration from the onset of the first non-Raynaud sign/symptom ≤5 years and a baseline visit between 2003 and 2014 were first extracted. To capture the disease activity variations over time, EUSTAR-AI and EScSG-AI adjusted means were calculated. The primary outcome was disease progression defined as a Î "≥1 in the Medsger's severity score and in distinct items at the 2-year follow-up visit. Logistic regression analysis was carried out to identify predictive factors. Results: 549 patients were enrolled. At multivariate analysis, the EUSTAR-AI adjusted mean was the only predictor of any severity accrual and of that of lung and heart, skin and peripheral vascular disease over 2 years. Conclusion: The adjusted mean EUSTAR-AI has the best predictive value for disease progression and development of severe organ involvement over time in SSc.
CRIS-Team Scopus Importer:2019-09-03
Keywords: autoimmune diseases; outcomes research; systemic sclerosis

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

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

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

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

Rheumatic manifestations of scurvy - Ferrari, Claudia; Possemato, Niccolo; Pipitone, Nicolo; Manger, Bernhard; Salvarani, Carlo (Current Rheumatology Reports, 2015)
This paper reviews the rheumatological manifestations of scurvy, based on articles published in English from 1965 until October 2014, with a particular focus on rheumatological manifestations. Scurvy is a rare, uncommon disease in developed countries. Due to its clinical heterogeneity, the disease can easily mimic rheumatologic conditions leading to a delay in diagnosis and treatment.
EVALuna2:12959

Rheumatic paraneoplastic syndromes - A clinical link between malignancy and autoimmunity - Manger, Bernhard; Schett, Georg (Clinical Immunology, 2017)
Paraneoplastic syndromes are rare but can have enormous clinical impact on diagnosis and outcome of neoplastic diseases. The rheumatologist should be familiar with a few typical musculoskeletal manifestations of malignancies to be able to diagnose them early for a timely initiation of anti-tumour therapies. This review describes the characteristic features of various paraneoplastic arthritides and vasculitides, cancer-associated myositis, hypertrophic osteoarthropathy, and tumour-induced osteomalacia. In addition, the current knowledge about underlying pathomechanisms of these syndromes is discussed.
EVALuna2:13435

Rheumatoid arthritis and osteoimmunology: The adverse impact of a deregulated immune system on bone metabolism - Andreev, Darja; Kachler, Katerina; Bozec, Aline; Schett, Georg (Bone, 2022)
The term osteoimmunology describes an interdisciplinary research field that links the investigation of osteology (bone cells) with immunology. The crosstalk between innate and adaptive immune cells and cells involved in bone remodeling, mainly bone-resorbing osteoclasts and bone-forming osteoblasts, becomes particularly obvious in the inflammatory autoimmune disease rheumatoid arthritis (RA). Besides striking inflammation of the joints, RA causes bone loss, leading to joint damage and disabilities as well as generalized osteoporosis. Mechanistically, RA-associated immune cells (macrophages, T cells, B cells etc.) produce high levels of pro-inflammatory cytokines, receptor activator of nuclear factor κB ligand (RANKL) and autoantibodies that promote bone degradation and at the same time counteract new bone formation. Today, antirheumatic therapy effectively ceases joint inflammation and arrests bone erosion. However, the repair of established bone lesions still presents a challenging task and requires improved treatment options. In this review, we outline the knowledge gained over the past years about the immunopathogenesis of RA and the impact of a dysregulated immune system on bone metabolism.
CRIS-Team Scopus Importer:2022-07-01
Keywords: Bone erosion; Osteoblasts; Osteoclasts; Osteoimmunology; Rheumatoid arthritis

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

SIGNATURE OF CIRCULATING MICRORNAS IN OSTEOARTHRITIS - Beyer, Christian; Zampetaki, A.; Lin, N. -Y.; Kleyer, Arnd; Perricone, C.; Iagnocco, A. M.; Distler, A.; Langley, S. L.; Gelse, Kolja; Sesselmann, Stefan; Lorenzini, R.; Niemeier, A.; et al. (2014)
EVALuna2:34462

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

Significance of pulmonary involvement in systemic sclerosis (SSc)- data from the German SSc-network - Kreuter, Michael; Bonella, Francesco; Blank, Nobert; Siegert, Elise; Henes, Joerg; Worm, Margitta; Sunderkoetter, Cord; Schmalzing, Marc; Kreuter, Alexander; Günther, Claudia; Susok, Laura; Zeidler, Gabriele; et al. (2018)
EVALuna2:213252

SIMILAR EFFICACY AND DRUG SURVIVAL RATES OF BARICITINIB MONOTHERAPY AND BARICITINIB/METHOTREXATE COMBINATION THERAPY IN REAL-LIFE TREATMENT OF RHEUMATOID ARTHRITIS - RESULTS FROM A PROSPECTIVE COHORT OF BARICITINIB-TREATED PATIENTS - Bayat, Sara; Tascilar, Koray; Bohr, D.; Simon, David; Kronke, G.; Hartmann, F.; Knitza, Johannes; Schett, Georg; Kleyer, Arnd (ANNALS OF THE RHEUMATIC DISEASES, 2022)
CRIS-Team WoS Importer:2022-11-04

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

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

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

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

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

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

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

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

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

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

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

STAT3 As an Important Integrator of Profibrotic Pathways in Systemic Sclerosis - Sumova, Barbora; Mallano, Tatjana; Chen, Chih-Wei; Distler, Alfiya; Bergmann, Christina; Distler, Oliver; Schett, Georg; Senolt, Ladislav; Distler, Jörg; Chakraborty, Debomita; Ramming, Andreas (2017)
EVALuna2:33429

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Systemic and local bone loss in Psoriasis and Psoriatic Arthritis - Kocijan, Roland; Englbrecht, Matthias; Kleyer, Arnd; Haschka, Judith; Simon, David; Finzel, Stephanie; Kraus, Sebastian; Muschitz, Christian; Resch, Heinrich; Engelke, Klaus; Rech, Jürgen; Schett, Georg (2014)
EVALuna2:13062

Systemic PPAR gamma Antagonism Reduces Metastatic Tumor Progression in Adipocyte-Rich Bone in Excess Weight Male Rodents - Gaculenko, Anastasia; Gregoric, Gasper; Popp, Vanessa; Seyler, Lisa; Ringer, Mark; Kachler, Katerina; Wu, Zhengquan; Kisel, Wadim; Hofbauer, Christine; Hofbauer, Lorenz C.; Uder, Michael; Schett, Georg; et al. (Journal of Bone and Mineral Research, 2021)
Primary tumors are widely associated with an excess in body fat. The role of adipose tissue on tumor cell homing to bone is yet poorly defined. In this study, we aimed to assess whether bone colonization by tumor cells is favored by an adipocyte-rich bone marrow. We delineated the accompanying alterations of the bone microenvironment and established a treatment approach that interferes with high fat diet (HFD)-induced bone metastasis formation. We were able to show that adipocytes affect skeletal tumor growth in a metastatic model of breast cancer in male rats and melanoma in male mice as well as in human breast cancer bone biopsies. Indeed, HFD-induced bone marrow adiposity was accompanied by accelerated tumor progression and increased osteolytic lesions. In human bone metastases, bone marrow adiposity correlated with tumor cell proliferation. By antagonization of the adipocyte differentiation and storage pathway linked to the peroxisome proliferator-activated receptor gamma (PPAR gamma) with bisphenol-A-diglycidylether (BADGE), we were able to decelerate tumor progression and subsequent osteolytic damage in the bones of two distinct metastatic animal models exposed to HFD. Overall these data show that adipose tissue is a critical factor in bone metastases and cancer-induced bone loss. 2021 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).
CRIS-Team WoS Importer:2021-09-03

Systemic sclerosis - an update - Bergmann, Christina; Distler, Jörg (Deutsche Medizinische Wochenschrift, 2015)
EVALuna2:12860

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

T2 Mapping as a New Method for Quantitative Assessment of Cartilage Damage in RA - Renner, Nina; Kleyer, Arnd; Krönke, Gerhard; Simon, David; Söllner, Stefan; Rech, Jürgen; Uder, Michael; Janka, Rolf Matthias; Schett, Georg; Welsch, Goetz; Pachowsky, Milena (Journal of Rheumatology, 2019)
OBJECTIVE: Rheumatoid arthritis (RA) is associated with damage of the articular cartilage and the periarticular bone. While imaging of bone damage has substantially improved in the last years, direct imaging of the articular cartilage of the hand joints in patients with RA is still challenging. METHODS: 3 Tesla Magnetic Resonance Imaging (MRI) was done in 30 RA patients and T2 relaxation times visualizing alteration in the collagen network and hydration of articular cartilage were mapped in six cartilage regions of the metacarpophalangeal joints 2 and 3. Values were related to autoantibody (anti-citrullinated peptide antibodies (ACPA), rheumatoid factor (RF)) status, disease duration, disease activity as well as sex and age of the RA patients. RESULTS: T2 relaxation times could be reliably measured in the six regions of the metacarpophalangeal joints. Significantly higher relaxation times indicating more advanced cartilage alterations were observed in ACPA-positive (p=0.001-0.010) and RF-positive patients (p=0.013-0.025) as well as those with longer disease duration (>3 years; p=0.028-0.043). Current disease activity, sex and age did not influence T2 relaxation times. CONCLUSION: These data show that cartilage damage can be localized and quantified in the hand joints of RA patients by T2 mapping. Furthermore, ACPA and RF positivity as well as disease duration appear to be the crucial factors influencing cartilage damage.
EVALuna2:210913

Tapering biologic and conventional DMARD therapy in rheumatoid arthritis: current evidence and future directions - Schett, Georg; Emery, Paul; Tanaka, Yoshiya; Burmester, Gerd; Pisetsky, David S.; Naredo, Esperanza; Fautrel, Bruno; Van Vollenhoven, Ronald (Annals of the Rheumatic Diseases, 2016)
Improvements in the control of inflammation in rheumatoid arthritis (RA) by conventional synthetic and biologic disease-modifying antirheumatic drugs (DMARDs) have led to a substantial change in the clinical outcomes of patients during the last 30 years. Current treatment can lead to sustained remission in some patients raising questions about the optimal management strategies in this subgroup of patients. Today, tapering of DMARDs and even their discontinuation appears as an interesting concept for achieving a more tailored and dynamic treatment approach of RA, especially in patients, who achieved full disease control by DMARD treatment. In this review article, current developments of DMARD tapering are discussed. The article provides an overview of existing studies on this topic and addresses new strategies to reach drug-free remission. Furthermore, concepts for defining patients eligible for DMARD tapering are described and potential future strategies in using biomarkers in predicting the risk for disease relapse after initiation of DMARD tapering are addressed. These findings are finally considered in light of the vision to achieve cure as an ultimate goal in patients with RA achieving full control of inflammation.
EVALuna2:13285

Targeting GM-CSF in rheumatological conditions: risk of PAP – Authors' reply - Genovese, Mark C.; Buckley, Christopher D.; Saurigny, Didier; Schett, Georg; Davy, Katherine; Gupta, Anubha; Smith, Julia E.; Patel, Jatin; Tak, Paul P. (The Lancet Rheumatology, 2021)
CRIS-Team Scopus Importer:2021-07-02