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.
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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.
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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)
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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, Krystelle; 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

Screening for psoriatic arthritis in dermatological settings-are handheld ultrasound devices the gamechangers we hoped for? - Bartsch, Vanessa; Fagni, Filippo; Krieter, Manuel; Ibrahim, Mohammed; Temiz, Selahattin Alp; Yalcin-Mutlu, Melek; Schett, Georg; Simon, David; Hueber, Axel (Rheumatology, 2024)
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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)
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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

Selective CAR T cell–mediated B cell depletion suppresses IFN signature in SLE - Wilhelm, Artur; Chambers, David; Müller, Fabian; Bozec, Aline; Grieshaber Bouyer, Ricardo; Winkler, Thomas; Mougiakakos, Dimitrios; Mackensen, Andreas; Schett, Georg; Krönke, Gerhard (JCI Insight, 2024)
Applying advanced molecular profiling together with highly specific targeted therapies offers the possibility to better dissect the mechanisms underlying immune-mediated inflammatory diseases such as systemic lupus erythematosus (SLE) in humans. Here we apply a combination of single-cell RNA-Seq and T/B cell repertoire analysis to perform an in-depth characterization of molecular changes in the immune-signature upon CD19 CAR T cell–mediated depletion of B cells in patients with SLE. The resulting data sets not only confirm a selective CAR T cell–mediated reset of the B cell response but simultaneously reveal consequent changes in the transcriptional signature of monocyte and T cell subsets that respond with a profound reduction in type I IFN signaling. Our current data, thus, provide evidence for a causal relationship between the B cell response and the increased IFN signature observed in SLE and additionally demonstrate the usefulness of combining targeted therapies and analytic approaches to decipher molecular mechanisms of immune-mediated inflammatory diseases in humans.
CRIS-Team Scopus Importer:2024-07-12

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

Sensor-assessed grasping time as a biomarker of functional impairment in rheumatoid arthritis - Coppers, Birte; Heinrich, Simon; Tascilar, Koray; Phutane, Uday; Kleyer, Arnd; Simon, David; Bräunig, Johanna; Penner, Johann; Vossiek, Martin; Schönau, Verena; Bayat, Sara; Schett, Georg; et al. (Scientific Reports, 2025)
Quantifying physical impairment in rheumatoid arthritis (RA) is important to determine disease burden and disability. Therefore, we aimed to define hand function impairments in RA patients using an opto-electronic measurement system (OMS). In this cross-sectional pilot study, spatio-temporal and hand segment data were collected during the fine motor skill Moberg Picking-Up Test (MPUT) and two elementary hand movement tasks in RA patients and healthy controls (HC) using a marker-based OMS. The duration of two MPUT movement phases (grasping, transporting 12 objects) and kinematic characteristics during the elementary movements were evaluated. We analyzed between-group differences using linear mixed-effects models accounting for within-participant clustering of hands and adjusting for age and sex. Measurements were obtained from 24 RA and 23 HC. The mean duration of the grasping phase of MPUT was longer in RA patients compared to HC while transporting times were identical, showing a significant group-phase interaction (p < 0.001). Interphalangeal joint angle ratios were similar in RA and HC (p > 0.05) with a lower ratio in both groups for the task thumb-finger opposition compared to flexion of joints. In RA patients especially grasping objects was impaired, and performance time for a subset of objects may serve as a quantitative biomarker of functional impairment.<br
CRIS-Team Scopus Importer:2025-03-14
Keywords: Biomarkers; Biomechanics; Fine-motor skills; Hand; Rheumatoid arthritis

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 extracellular matrix biomarkers in rheumatoid arthritis, psoriatic arthritis and psoriasis and their association with hand function - Port, Helena; Coppers, Birte; Tragl, Sonja; Manger, Eva; Niemiec, Lisa Maria; Bayat, Sara; Simon, David; Fagni, Filippo; Corte, Giulia; Bay-Jensen, Anne Christine; Tascilar, Koray; Hueber, Axel; et al. (Scientific Reports, 2025)
Inflammatory arthritis, including rheumatoid arthritis and psoriatic arthritis, is characterized by physical function impairment. This becomes apparent even before arthritis onset, as in psoriasis (PsO). Chronic inflammation triggers an accelerated remodeling of the extracellular matrix (ECM), resulting in released ECM fragments detectable in blood. We aimed to investigate levels of blood-based ECM biomarkers in patients with RA, PsA, PsO, and healthy controls and to explore the association of ECM biomarkers with hand function impairments. Patients with RA (n = 85), PsA (n = 115), PsO (n = 102) and controls (n = 110) were included in this cross-sectional study. ECM catabolic (C1M, C2M, C3M, C4M, PRO-C4, C6M, ARG), formation (PRO-C1, PRO-C3, PRO-C6) and inflammation biomarkers (VICM) were measured in serum from all patients. Objective hand function (fine motor skills (Moberg-Picking-Up Test), isometric grip strength (dynamometer) and patient-perceived hand function (Michigan Hand Questionnaire (MHQ)) were assessed. Patients with RA and PsA received treatment with disease-modifying anti-rheumatic drugs. VICM levels were higher in RA, PsA, and PsO than in controls (p < 0.0001). PsA and PsO showed higher C4M levels compared to controls (p < 0.0001, p < 0.0001), while C6M was lower in patients with RA, PsA and PsO than in controls (p < 0.0001, p < 0.001, p < 0.01). PsO presented with higher levels of C1M compared to controls and to RA (p < 0.001 and p < 0.0001). PRO-C6 correlated negatively with MHQ (ρ = -0.39, p < 0.01) and grip strength (ρ = -0.31, p < 0.05) in PsO, while only weak correlations were observed between biomarkers and hand function scores for RA and PsA patients (all ρ < ± 0.2–0.3). Patients with RA, PsA, and PsO showed significant alterations in ECM remodeling biomarkers. Especially PsA and PsO had higher levels of inflammatory biomarkers compared to RA and controls, likely due to modulation by treatment. Predominantly in PsO, ECM formation biomarkers were associated with hand function impairments.<br
Keywords: Extracellular matrix; Biochemical markers; Rheumatoid arthritis; Psoriatic arthritis; Psoriasis; Hand function

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, Chih-Wei; Ramming, A.; Distler, O.; Schett, Georg; Distler, Jörg (2016)
EVALuna2:13487

SIGNATURE OF CIRCULATING MICRORNAS IN OSTEOARTHRITIS - Beyer, Christian; Zampetaki, A.; Lin, N. -Y.; Kleyer, Arnd; Perricone, C.; Iagnocco, A. M.; Distler, A.; Langley, S. L.; Gelse, Kolja; Sesselmann, Stefan; Lorenzini, R.; Niemeier, A.; et al. (2014)
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.
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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.
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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.
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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)
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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.
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STAT3 As an Important Integrator of Profibrotic Pathways in Systemic Sclerosis - Sumova, Barbora; Mallano, Tatjana; Chen, Chih-Wei; Distler, Alfiya; Bergmann, Christina; Distler, Oliver; Schett, Georg; Senolt, Ladislav; Distler, Jörg; Chakraborty, Debomita; Ramming, Andreas (2017)
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Stepwise asynchronous telehealth assessment of patients with suspected axial spondyloarthritis: results from a pilot study - Labinsky, Hannah; von Rohr, Sophie; Raimondo, Maria Gabriella; Bohr, Daniela; Morf, Harriet; Horstmann, Britta; Seese, Felix; Proft, Fabian; Muehlensiepen, Felix; Boy, Katharina; Kuhn, Sebastian; Schmalzing, Marc; et al. (Rheumatology International, 2023)
Patients with axial spondyloarthritis (axSpA) suffer from one of the longest diagnostic delays among all rheumatic diseases. Telemedicine (TM) may reduce this diagnostic delay by providing easy access to care. Diagnostic rheumatology telehealth studies are scarce and largely limited to traditional synchronous approaches such as resource-intensive video and telephone consultations. The aim of this study was to investigate a stepwise asynchronous telemedicine-based diagnostic approach in patients with suspected axSpA. Patients with suspected axSpA completed a fully automated digital symptom assessment using two symptom checkers (SC) (bechterew-check and Ada). Secondly, a hybrid stepwise asynchronous TM approach was investigated. Three physicians and two medical students were given sequential access to SC symptom reports, laboratory and imaging results. After each step, participants had to state if axSpA was present or not (yes/no) and had to rate their perceived decision confidence. Results were compared to the final diagnosis of the treating rheumatologist. 17 (47.2%) of 36 included patients were diagnosed with axSpA. Diagnostic accuracy of bechterew-check, Ada, TM students and TM physicians was 47.2%, 58.3%, 76.4% and 88.9% respectively. Access to imaging results significantly increased sensitivity of TM-physicians (p < 0.05). Mean diagnostic confidence of false axSpA classification was not significantly lower compared to correct axSpA classification for both students and physicians. This study underpins the potential of asynchronous physician-based telemedicine for patients with suspected axSpA. Similarly, the results highlight the need for sufficient information, especially imaging results to ensure a correct diagnosis. Further studies are needed to investigate other rheumatic diseases and telediagnostic approaches.
CRIS-Team Scopus Importer:2023-07-07
Keywords: Diagnosis; Health service research; Spondyloarthritis; Symptom checker; Telehealth; Telemedicine

Stimulation of the soluble guanylate cyclase (sGC) inhibits fibrosis by blocking non-canonical TGF? signalling - Beyer, Christian; Zenzmaier, Christoph; Palumbo-Zerr, Katrin; Mancuso, Rossella; Distler, Alfiya; Dees, Clara; Zerr, Pawel; Huang, Jingang; Maier, Christiane; Pachowsky, Milena; Friebe, Andreas; Sandner, Peter; et al. (Annals of the Rheumatic Diseases, 2015)
We have previously described the antifibrotic role of the soluble guanylate cyclase (sGC). The mode of action, however, remained elusive. In the present study, we describe a novel link between sGC signalling and transforming growth factor ? (TGF?) signalling that mediates the antifibrotic effects of the sGC.Human fibroblasts and murine sGC knockout fibroblasts were treated with the sGC stimulator BAY 41-2272 or the stable cyclic guanosine monophosphate (cGMP) analogue 8-Bromo-cGMP and stimulated with TGF?. sGC knockout fibroblasts were isolated from sGCI(fl/fl) mice, and recombination was induced by Cre-adenovirus. In vivo, we studied the antifibrotic effects of BAY 41-2272 in mice overexpressing a constitutively active TGF-?1 receptor.sGC stimulation inhibited TGF?-dependent fibroblast activation and collagen release. sGC knockout fibroblasts confirmed that the sGC is essential for the antifibrotic effects of BAY 41-2272. Furthermore, 8-Bromo-cGMP reduced TGF?-dependent collagen release. While nuclear p-SMAD2 and 3 levels, SMAD reporter activity and transcription of classical TGF? target genes remained unchanged, sGC stimulation blocked the phosphorylation of ERK. In vivo, sGC stimulation inhibited TGF?-driven dermal fibrosis but did not change p-SMAD2 and 3 levels and TGF? target gene expression, confirming that non-canonical TGF? pathways mediate the antifibrotic sGC activity.We elucidated the antifibrotic mode of action of the sGC that increases cGMP levels, blocks non-canonical TGF? signalling and inhibits experimental fibrosis. Since sGC stimulators have shown excellent efficacy and tolerability in phase 3 clinical trials for pulmonary arterial hypertension, they may be further developed for the simultaneous treatment of fibrosis and vascular disease in systemic sclerosis.
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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)
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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.
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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.
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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)
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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 generation of fully human, second generation, anti-CD19 CAR T cells for clinical use in patients with diverse autoimmune disorders - Mougiakakos, Dimitrios; Sengupta, Ranjita; Gold, Ralf; Schroers, Roland; Haghikia, Aiden; Lorente, Mario; Pendleton, Michael; Register, Ames; Heesen, Christoph; Kröger, Nicolaus; Schett, Georg; Mackensen, Andreas; et al. (Cytotherapy, 2024)
Background: B-cell targeting chimeric antigen receptor (CAR) T-cell therapies, which lead to profound B-cell depletion, have been well-established in hematology-oncology. This deep B-cell depletion mechanism has prompted the exploration of their use in B-cell driven autoimmune diseases. We herein report on the manufacturing of KYV-101, a fully human anti-CD19 CAR T-cell therapy, derived from patients who were treated across a spectrum of autoimmune diseases. Methods: KYV-101 was manufactured from peripheral blood-derived mononuclear cells of 20 patients across seven autoimmune disease types (neurological autoimmune diseases, n = 13; rheumatological autoimmune diseases, n = 7). Patients ranged from 18 to 75 years of age. Duration of disease ranged from <1 to 23 years since diagnosis. Patients were heavily pretreated, and most were refractory to prior immunosuppressive treatments. Apheresis was collected across nine sites, cryopreserved, and shipped to the manufacturing facility. Healthy donor apheresis samples were collected for manufacturing comparison. Manufacturing was performed using the CliniMACS Prodigy system. Cells were enriched for CD4+/CD8+ T cells, transduced with a third generation lentiviral vector encoding the CAR, expanded in vitro, and harvested. Percent cell viability, T-cell purity, cellular expansion, and transduction efficiency were assessed. Activity was assessed using cytokine release assays for KYV-101 CAR T cells co-cultured with different CD19+/– target cell lines. Results: KYV-101 was successfully manufactured for 100% of patients. Transduced cell populations were highly viable, with expansion ranging from 11 to 66 fold at Day 8, and were comparable across disease types. Healthy donor-derived controls displayed similar expansion ranges. High CAR expression and transduction rates were observed, ranging between 37 and 77% with low variation in transgene copy number (two to four per cell). Cell viability of the final KYV-101 drug product ranged from 87 to 97%. KYV-101 displayed robust CD19-dependent and effector dose-related release of the pro-inflammatory cytokine IFN-γ. Conclusions: KYV-101 manufacturing yielded a CAR T-cell product with high viability and consistent composition and functionality, regardless of disease indication, pre-treatment, and heterogeneity of the incoming material. Cryopreservation of the apheresis and final drug product enabled widespread distribution. These results support the robustness of the manufacturing process for the fully human KYV-101 anti-CD19 CAR T-cell therapy drug product for patients across diverse autoimmune disease types.
CRIS-Team Scopus Importer:2024-11-22
Keywords: anti-CD19 chimeric antigen receptor; manufacturing; neurological autoimmune disease; rheumatological autoimmune disease

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.
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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)

Survey on the working, training, and research conditions of resident physicians in internistic and rheumatological continuing education-BEWUSST. - Proft, Fabian; Vossen, Diana; Baraliakos, Xenofon; Berliner, Michael N.; Fleck, Martin; Keyßer, Gernot; Krause, Andreas; Lorenz, Hanns Martin; Manger, Bernhard; Schuch, Florian; Specker, Christof; Wollenhaupt, Jürgen; et al. (Zeitschrift für Rheumatologie, 2024)
BACKGROUND: Data on the training and continuing education situation of residents in the field of internal medicine and rheumatology are not available for Germany. For this reason, the Commission for Education and Training of the German Society of Rheumatology (DGRh) initiated the BEWUSST survey on the working, training and research conditions of residents in rheumatology. METHODS: A total of 102 questions on the topics of working conditions in everyday professional life, continuing medical education and training, compatibility of career and family, compatibility of work and research, perspectives as a rheumatologist and practical activities were included in an online questionnaire. RESULTS: A total of 102 participants took part in the survey. Of the respondents 48.1% were satisfied with their professional situation, 40.2% of the participants were supervised by a specialist mentor and 54.9% were working as scientists during their work as a physician. A compatibility of family and career was possible for 34.7%. After completion of the residency 52.9% of the respondents aspired to a combined clinical and outpatient activity. CONCLUSION: Half of the trainee rheumatologists are satisfied with their professional activities, although mentoring of the assistants in training should be further improved. With respect to the desired combined clinical and outpatient activity, the existing options should be expanded or new professional fields of activity should be established, so that the specialty remains attractive for the upcoming generations.
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Survival after cryptococcosis in Germany: A retrospective multicenter cohort study of patients diagnosed between 2004 and 2021 - Kessel, Johanna; Rossaert, Anna Catharina; Lingscheid, Tilman; Grothe, Jan; Harrer, Thomas; Wyen, Christoph; Tominski, Daniela; Bollinger, T.; Kehr, Anna Katharina; Kalbitz, Sven; Hoffmann, Christian; Cornely, Oliver; et al. (International Journal of Medical Microbiology, 2024)
Cryptococcosis is the most prevalent fungal infection of the central nervous system worldwide. We performed a retrospective multicenter cohort study to gain insights into the epidemiology of cryptococcosis in Germany. We describe the use of diagnostic tests, clinical management and patient outcome. We included 64 patients with underlying HIV infection (55%) or other predispositions. Molecular typing by MLST documented 20 individual sequence types among 42 typed isolates. A fatal outcome was documented in 14% of patients in the first two months after diagnosis.
CRIS-Team Scopus Importer:2024-03-01
Keywords: AIDS related opportunistic infections; Cryptococcosis; Mortality; Multilocus sequence typing; Risk factor

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

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 cytokines in psoriatic arthritis - Neurath, Laura; Sticherling, Michael; Schett, Georg; Fagni, Filippo (Cytokine & Growth Factor Reviews, 2024)
Psoriatic arthritis (PsA) is part of the psoriatic disease spectrum and is characterized by a chronic inflammatory process that affects entheses, tendons and joints. Cytokines produced by immune and non-immune cells play a central role in the pathogenesis of PsA by orchestrating key aspects of the inflammatory response. Pro-inflammatory cytokines such as TNF, IL-23 and IL-17 have been shown to regulate the initiation and progression of PsA, ultimately leading to the destruction of the architecture of the local tissues such as soft tissue, cartilage and bone. The important role of cytokines in PsA has been underscored by the clinical success of antibodies that neutralize their function. In addition to biologic agents targeting individual pro-inflammatory cytokines, signaling inhibitors that block multiple cytokines simultaneously such as JAK inhibitors have been approved for PsA therapy. In this review, we will focus on our current understanding of the role of cytokines in the disease process of PsA and discuss potential new treatment options based on modulation of cytokine function.
CRIS-Team Scopus Importer:2024-08-23
Keywords: Biological therapy; Cytokines; DMARD; Psoriasis; Psoriatic arthritis

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

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

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

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

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

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

Targeting of NADPH oxidase in vitro and in vivo suppresses fibroblast activation and experimental skin fibrosis - Dosoki, Heba; Stegemann, Agatha; Taha, Muna; Schnittler, Hans; Luger, Thomas A.; Schroeder, Katrin; Distler, Jörg; Kerkhoff, Claus; Boehm, Markus (Experimental Dermatology, 2016)
Although there is increasing evidence that oxidative stress is involved in collagen synthesis and myofibroblast activation the NADPH oxidase (Nox) system is incompletely investigated in the context of human dermal fibroblasts (HDFs) and skin fibrosis. Using the pan-Nox inhibitor diphenyleneiodonium (DPI) as an initial tool we show that gene expression of collagen type I, ?-smooth muscle actin (?-SMA) and fibronectin 1 is suppressed in HDFs. Detailed expression analysis of all Nox isoforms and adaptors revealed expression of RNA and protein expression of Nox4, p22(phox) , and Poldip2 but neither Nox1 nor Nox2. Nox4 could be immnolocalized to the endoplasmic reticulum. Importantly, TGF-?1 had a dose- and time-dependent upregulating effect on NADH activity and Nox4 gene expression in HDFs. Genetic silencing of Nox4 as demonstrated by siRNA in HDFs as well as in murine fibroblasts established from Nox4 knock-out mice confirmed that TGF-?1 -mediated collagen type I gene, ?-SMA and fibronectin 1 gene expression was Nox4-dependent. This TGF-?1 effect was mediated by Smad3 as shown by in silico promoter analysis, pharmacological inhibition, and gene silencing of Smad3. The relevance of these findings is highlighted in the bleomycin-induced scleroderma mouse model. DPI treatment attenuated skin fibrosis and myofibroblast activation. Moreover, Nox4 knock-down by siRNA reduced skin collagen synthesis, ?-SMA and fibronectin 1 expression in vivo. Finally, analyses of HDFs from patients with systemic sclerosis confirmed the expression of Nox4 and its adaptors whereas Nox1 and Nox2 were not detectable. Our findings indicate that Nox4 targeting is a promising future treatment for fibrotic skin diseases. This article is protected by copyright. All rights reserved.
EVALuna2:13257

Targeting TGF-beta signaling for the treatment of fibrosis - Györfi, Andrea-Hermina; Matei, Alexandru-Emil; Distler, Jörg (Matrix Biology, 2018)
Transforming growth factor-alpha (TGF-beta) is widely recognized as a core pathway of fibrosis. Inhibition of TGF-beta signaling may thus offer potential for antifibrotic therapies. Long-term inhibition of TGF-beta signaling at the level of its isoforms and receptors can be associated with unacceptable adverse effects. However, TGF-beta regulates a myriad of intracellular signaling cascades to transmit its profibrotic effects and several of those pathways offer potential for pharmacologic intervention. Moreover, the multiple interactions of TGF-beta with other profibrotic pathways also yielded candidates for therapeutic intervention. In this review, we discuss selected targets within the TGF-beta pathway with high translational potential. (C) 2018 Elsevier B.V. All rights reserved.
EVALuna2:213258

Targeting the Wnt signaling pathway through R-spondin 3 identifies an anti-fibrosis treatment strategy for multiple organs - Zhang, Mingjun; Haughey, Michael; Wang, Nai Yu; Blease, Kate; Kapoun, Ann M.; Couto, Suzana; Belka, Igor; Hoey, Timothy; Groza, Matthew; Hartke, James; Bennett, Brydon; Cain, Jennifer; et al. (PLoS ONE, 2020)
The Wnt/β-catenin signaling pathway has been implicated in human proliferative diseases such as cancer and fibrosis. The functions of β-catenin and several other components of this pathway have been investigated in fibrosis. However, the potential role of R-spondin proteins (RSPOs), enhancers of the Wnt/β-catenin signaling, has not been described. A specific interventional strategy targeting this pathway for fibrosis remains to be defined. We developed monoclonal antibodies against members of the RSPO family (RSPO1, 2, and 3) and probed their potential function in fibrosis in vivo. We demonstrated that RSPO3 plays a critical role in the development of fibrosis in multiple organs. Specifically, an anti-RSPO3 antibody, OMP-131R10, when dosed therapeutically, attenuated fibrosis in carbon tetrachloride (CCl4)-induced liver fibrosis, bleomycin-induced pulmonary and skin fibrosis models. Mechanistically, we showed that RSPO3 induces multiple pro-fibrotic chemokines and cytokines in Kupffer cells and hepatocytes. We found that the anti-fibrotic activity of OMP-131R10 is associated with its inhibition of β-catenin activation in vivo. Finally, RSPO3 was found to be highly elevated in the active lesions of fibrotic tissues in mouse models of fibrosis and in patients with idiopathic pulmonary fibrosis (IPF) and nonalcoholic steatohepatitis (NASH). Together these data provide an anti-fibrotic strategy for targeting the Wnt/β-catenin pathway through RSPO3 blockade and support that OMP-131R10 could be an important therapeutic agent for fibrosis.
CRIS-Team Scopus Importer:2020-03-20

Targeting zonulin and intestinal epithelial barrier function to prevent onset of arthritis - Tajik, Narges; Frech, Michael; Schulz, Oscar; Schälter, Fabian; Lucas, Sébastien; Azizov, Vugar; Dürholz, Kerstin; Steffen, Franziska; Omata, Yasunori; Rings, Andreas; Bertog, Marko; Rizzo, Aroldo; et al. (Nature Communications, 2020)
Gut microbial dysbiosis is associated with the development of autoimmune disease, but the mechanisms by which microbial dysbiosis affects the transition from asymptomatic autoimmunity to inflammatory disease are incompletely characterized. Here, we identify intestinal barrier integrity as an important checkpoint in translating autoimmunity to inflammation. Zonulin family peptide (zonulin), a potent regulator for intestinal tight junctions, is highly expressed in autoimmune mice and humans and can be used to predict transition from autoimmunity to inflammatory arthritis. Increased serum zonulin levels are accompanied by a leaky intestinal barrier, dysbiosis and inflammation. Restoration of the intestinal barrier in the pre-phase of arthritis using butyrate or a cannabinoid type 1 receptor agonist inhibits the development of arthritis. Moreover, treatment with the zonulin antagonist larazotide acetate, which specifically increases intestinal barrier integrity, effectively reduces arthritis onset. These data identify a preventive approach for the onset of autoimmune disease by specifically targeting impaired intestinal barrier function.
CRIS-Team Scopus Importer:2020-05-05

TARGET OUTCOMES IN PSA: SIMULTANEOUS ACHIEVEMENT OF ACR50-PASI100 AND BEYOND: INSIGHTS FROM SPIRIT-H2H AT WEEK 24 - Smolen, J. S.; Behrens, F.; Leage, S. Liu; Sapin, C.; De La Torre, I.; Meszaros, G.; Schett, Georg; Gossec, L.; Ostor, A.; Combe, B.; Van Den Bosch, F. (ANNALS OF THE RHEUMATIC DISEASES, 2020)
CRIS-Team WoS Importer:2020-08-21

Target Outcomes in Psoriatic Arthritis: Simultaneous Achievement of ACR50-Psoriasis Area and Severity Index 100 and Beyond: Insights from Open-Label, Assessor-Blinded Study at Week 24 - Smolen, Josef; Behrens, Frank; Liu-Leage, Soyi; Sapin, Christophe; De La Torre, Inmaculada; Meszaros, Gabriella; Schett, Georg; Gossec, Laure; Ostor, Andrew; Combe, Bernard; Van Den Bosch, Filip (ARTHRITIS & RHEUMATOLOGY, 2020)
CRIS-Team WoS Importer:2021-01-15

T Cell Costimulation Molecules CD80/86 Inhibit Osteoclast Differentiation by Inducing the IDO/Tryptophan Pathway - Bozec, Aline; Zaiss, Mario; Kagwiria, Rosebeth; Voll, Reinhard; Rauh, Manfred; Chen, Zhu; Müller-Schmucker, Sandra; Kroczek, Richard A.; Heinzerling, Lucie; Moser, Muriel; Mellor, Andrew L.; David, Jean-Pierre; et al. (Science Translational Medicine, 2014)
Bone resorption is seminal for the physiological remodeling of bone during life. However, this process needs to be strictly controlled; excessive bone resorption results in pathologic bone loss, osteoporosis, and fracture. We describe a control mechanism of bone resorption by the adaptive immune system. CD80/86, a pair of molecules expressed by antigen-presenting cells and involved in T cell costimulation, act as negative regulator for the generation of bone-resorbing osteoclasts. CD80/86-deficient mice were osteopenic because of increased osteoclast differentiation. CD80/86-deficient osteoclasts escaped physiological inhibition by CTLA-4 or regulatory T cells. Mechanistically, engagement of CD80/86 by CTLA-4 induced activation of the enzyme indoleamine 2,3-dioxygenase (IDO) in osteoclast precursors, which degraded tryptophan and promoted apoptosis. Concordantly, IDO-deficient mice also showed an osteopenic bone phenotype with higher numbers of osteoclast precursors and osteoclasts. Also, IDO-deficient mononuclear cells escaped the anti-osteoclastogenic effect of CTLA-4. This molecular mechanism was also present in humans because targeting CD80/86 by abatacept, a CTLA-4-immunoglobulin fusion protein, reduced, whereas blockade of CTLA-4 by ipilimumab antibody enhanced, the frequency of peripheral osteoclast precursors and osteoclastogenesis. In summary, these data show an important role of the adaptive immune system, in particular T cell CD80/86 costimulation molecules, in the physiological regulation of bone resorption and preservation of bone mass, as well as affect the understanding of the function of current and future drugs fostering or blocking the effects of CTLA-4 in humans.
EVALuna2:12912

T-cell receptor transfer for boosting HIV-1-specific T-cell immunity in HIV-1-infected patients - Mummert, Christiane; Hofmann, Christian; Hueckelhoven, Angela G.; Bergmann, Silke; Mueller-Schmucker, Sandra M.; Harrer, Ellen G.; Dörrie, Jan; Schaft, Niels; Harrer, Thomas (Aids, 2016)
Strategies to cure HIV-1 infection require the eradication of viral reservoirs. An innovative approach for boosting the cytotoxic T-lymphocyte response is the transfer of T-cell receptors (TCRs). Previously, we have shown that electroporation of TCR-encoding mRNA is able to reprogram CD8 T cells derived from healthy donors. So far, it is unknown whether the transfer of HIV-1-specific TCRs is capable to reprogram CD8 T cells of HIV-1-infected patients. To assess the efficiency of TCR-transfer by mRNA electroporation and the functionality of reprogramed T cells in HIV-1-infected patients, we performed an in-vitro analysis of TCR-transfer into T cells from HIV-1-infected patients in various stages of disease and from healthy controls.Peripheral blood mononuclear cells from 16 HIV-1-infected patients (nine HLA-A02-positive, seven HLA-A02-negative) and from five healthy controls were electroporated with mRNA-constructs encoding TCRs specific for the HLA-A02/HIV-1-gag p17 epitope SLYNTVATL (SL9). Functionality of the TCRs was measured by ?IFN-ELISpot assays.SL9/TCR transfection into peripheral blood mononuclear cells from both HLA-A02-positive and HLA-A02-negative HIV-1-infected patients and from healthy blood donors reprogramed T cells for recognition of SL9-presenting HLA-A02-positive cells in ?IFN-ELISpot assays. SL9/TCR-transfer into T cells from an immunodeficient AIDS patient could induce recognition of SL9-expressing target cells only after reversion of T-cell dysfunction by antiretroviral therapy.The transfer of HIV-1-p17-specific TCRs into T cells is functional both in HIV-1-infected patients as well as in healthy blood donors. TCR-transfer is a promising method to boost the immune system against HIV-1.
EVALuna2:13288

T cells as key players for bone destruction in gouty arthritis? - Harre, Ulrike; Derer, Anja; Schorn, Christine; Schett, Georg; Herrmann, Martin (Arthritis Research & Therapy, 2011)
The deposition of monosodium urate (MSU) crystals in synovial fluid and tissue leads to gouty arthritis frequently associated with synovial inflammation and bone erosions. The cellular mechanism that links MSU crystals to an increased number of osteoclasts has not yet been fully understood. In a recent issue of Arthritis Research & Therapy Lee and colleagues proposed that bone destruction in chronic gouty arthritis is at least in part dependent on expression by T cells of receptor activator of NF-κB ligand (RANKL). The authors showed that pro-resorptive cytokines such as IL-1β, IL-6, and TNFα are expressed within tophi and stromal infiltrates. In vitro stimulation with MSU crystals revealed monocytes as a source for these cytokines, whereas T cells produce RANKL, the major trigger of osteoclastogenesis. © 2011 BioMed Central Ltd.
Created from Fastlane, Scopus look-up

TELERA-Asynchronous TELEmedicine for Patients With Rheumatoid Arthritis: Study Protocol for a Prospective, Multi-Center, Randomized Controlled Trial - Mucke, Johanna; Knitza, Johannes; Muehlensiepen, Felix; Grahammer, Manuel; Stenzel, Ramona; Simon, David; Kleyer, Arnd; Krönke, Gerhard; Sharp, Charlotte; Bendzuck, Gerlinde; Korinth, Marianne; Elling-Audersch, Corinna; et al. (Frontiers in Medicine, 2021)
Innovative strategies are needed to adequately assess and monitor disease activity of patients with rheumatoid arthritis (RA) in times of scarce appointments. The aim of the TELERA study is to evaluate the feasibility and performance of asynchronous telemedicine visits based on patient-generated data and patient's drug history. RA patients use a medical app, ABATON, that captures the results of a self-performed quick CRP-test, joint-count, and electronic patient-reported outcomes in between visits. This is a prospective, multi-center, randomized controlled trial performed in four German university centers. The estimated sample size is 120 patients. The main outcome is the agreement of rheumatologists' treatment decisions based on asynchronous telemedicine patient-generated data with traditional in-person rheumatology clinic-based decisions and with patient suggestions. The TELERA trial will provide evidence regarding the implementation of remote care in rheumatology.
CRIS-Team WoS Importer:2022-01-14

TEMPORAL MIGRATION OF IMMUNE CELLS FROM PSORIATIC SKIN TO JOINTS INITIATING SYNOVIAL INFLAMMATION IN PSORIATIC ARTHRITIS - Raimondo, Maria Gabriella; Rauber, Simon; Xu, Cong; Mohammadian, Hashem; Vogg, Mario; Anchang, Charles Gwellem; Rigau, Aleix; Luber, M.; Labinsky, Hannah; Soare, A.; Distler, Jörg; Fearon, U.; et al. (ANNALS OF THE RHEUMATIC DISEASES, 2022)
CRIS-Team WoS Importer:2022-11-04

Tendon and ligament mechanical loading in the pathogenesis of inflammatory arthritis - Gracey, Eric; Burssens, Arne; Cambre, Isabelle; Schett, Georg; Lories, Rik; Mcinnes, Iain B.; Asahara, Hiroshi; Elewaut, Dirk (Nature Reviews Rheumatology, 2020)
Mechanical loading is an important factor in musculoskeletal health and disease. Tendons and ligaments require physiological levels of mechanical loading to develop and maintain their tissue architecture, a process that is achieved at the cellular level through mechanotransduction-mediated fine tuning of the extracellular matrix by tendon and ligament stromal cells. Pathological levels of force represent a biological (mechanical) stress that elicits an immune system-mediated tissue repair pathway in tendons and ligaments. The biomechanics and mechanobiology of tendons and ligaments form the basis for understanding how such tissues sense and respond to mechanical force, and the anatomical extent of several mechanical stress-related disorders in tendons and ligaments overlaps with that of chronic inflammatory arthritis in joints. The role of mechanical stress in ‘overuse’ injuries, such as tendinopathy, has long been known, but mechanical stress is now also emerging as a possible trigger for some forms of chronic inflammatory arthritis, including spondyloarthritis and rheumatoid arthritis. Thus, seemingly diverse diseases of the musculoskeletal system might have similar mechanisms of immunopathogenesis owing to conserved responses to mechanical stress.
CRIS-Team Scopus Importer:2020-03-06

TGF beta-Dependent Upregulation of XIAP Fosters Fibroblast Activation and Tissue Fibrosis By Promoting Canonical Wnt Signaling - Bergmann, Christina; Hallenberger, Ludwig; Brandt, Adrian; Merlevede, Benita; Dees, Clara; Chen, Chih-Wei; Beyer, Christian; Distler, Oliver; Schett, Georg; Distler, Jörg (2017)
EVALuna2:33427

TGF-beta-Induced Epigenetic Silencing of SOCS3 Facilitates STAT3 Signaling to Promote Fibroblast Activation and Tissue Fibrosis in Systemic Sclerosis - Dees, Clara; Zhang, Yun; Pötter, Sebastian; Bergmann, Christina; Distler, Oliver; Schett, Georg; Distler, Jörg; Ramming, Andreas (2017)
EVALuna2:33431

TGF beta Promotes Fibrosis By MYST1-Dependent Epigenetic Regulation of Autophagy - Zehender, Ariella; Lin, Neng-Yu; Stefanica, Adrian; Chen, Chih-Wei; Soare, Alina; Wohlfahrt, Thomas; Rauber, Simon; Bergmann, Christina; Distler, Oliver; Schett, Georg; Distler, Jörg; Ramming, Andreas (2017)
EVALuna2:33446

TGF-β-induced epigenetic deregulation of SOCS3 facilitates STAT3 signaling to promote fibrosis - Dees, Clara; Pötter, Sebastian; Zhang, Yun; Bergmann, Christina; Zhou, Xiang; Luber, Markus; Wohlfahrt, Thomas; Karouzakis, Emmanuel; Ramming, Andreas; Gelse, Kolja; Yoshimura, Akihiko; Jaenisch, Rudolf; et al. (Journal of Clinical Investigation, 2020)
Fibroblasts are key effector cells in tissue remodeling. They remain persistently activated in fibrotic diseases, resulting in progressive deposition of extracellular matrix. Although fibroblast activation may be initiated by external factors, prolonged activation can induce an “autonomous,” self-maintaining profibrotic phenotype in fibroblasts. Accumulating evidence suggests that epigenetic alterations play a central role in establishing this persistently activated pathologic phenotype of fibroblasts. We demonstrated that in fibrotic skin of patients with systemic sclerosis (SSc), a prototypical idiopathic fibrotic disease, TGF-β induced the expression of DNA methyltransferase 3A (DNMT3A) and DNMT1 in fibroblasts in a SMAD-dependent manner to silence the expression of suppressor of cytokine signaling 3 (SOCS3) by promoter hypermethylation. Downregulation of SOCS3 facilitated activation of STAT3 to promote fibroblast-to-myofibroblast transition, collagen release, and fibrosis in vitro and in vivo. Reestablishment of the epigenetic control of STAT3 signaling by genetic or pharmacological inactivation of DNMT3A reversed the activated phenotype of SSc fibroblasts in tissue culture, inhibited TGF-β-dependent fibroblast activation, and ameliorated experimental fibrosis in murine models. These findings identify a pathway of epigenetic imprinting of fibroblasts in fibrotic disease with translational implications for the development of targeted therapies in fibrotic diseases.
CRIS-Team Scopus Importer:2020-05-12

TGFβ PROMOTES FIBROSIS BY MYST1-DEPENDENT EPIGENETIC REGULATION OF AUTOPHAGY - Zehender, A.; Lin, N. -Y.; Stefanica, Adrian; Chen, Chih-Wei; Soarel, A.; Wohlfahrt, T.; Reuber, S.; Bergmann, C.; Ramming, A.; Distler, O.; Distler, Jörg (2018)
EVALuna2:34996

TGFβ promotes fibrosis by MYST1-dependent epigenetic regulation of autophagy - Zehender, Ariella; Li, Yi-Nan; Lin, Neng Yu; Stefanica, Adrian; Nüchel, Julian; Chen, Chih-Wei; Hsu, Hsiao Han; Zhu, Honglin; Ding, Xiao; Huang, Jingang; Shen, Lichong; Györfi, Andrea-Hermina; et al. (Nature Communications, 2021)
Activation of fibroblasts is essential for physiological tissue repair. Uncontrolled activation of fibroblasts, however, may lead to tissue fibrosis with organ dysfunction. Although several pathways capable of promoting fibroblast activation and tissue repair have been identified, their interplay in the context of chronic fibrotic diseases remains incompletely understood. Here, we provide evidence that transforming growth factor-β (TGFβ) activates autophagy by an epigenetic mechanism to amplify its profibrotic effects. TGFβ induces autophagy in fibrotic diseases by SMAD3-dependent downregulation of the H4K16 histone acetyltransferase MYST1, which regulates the expression of core components of the autophagy machinery such as ATG7 and BECLIN1. Activation of autophagy in fibroblasts promotes collagen release and is both, sufficient and required, to induce tissue fibrosis. Forced expression of MYST1 abrogates the stimulatory effects of TGFβ on autophagy and re-establishes the epigenetic control of autophagy in fibrotic conditions. Interference with the aberrant activation of autophagy inhibits TGFβ-induced fibroblast activation and ameliorates experimental dermal and pulmonary fibrosis. These findings link uncontrolled TGFβ signaling to aberrant autophagy and deregulated epigenetics in fibrotic diseases and may contribute to the development of therapeutic interventions in fibrotic diseases.
CRIS-Team Scopus Importer:2021-08-06

Th2 and eosinophil responses ameliorate arthritis and inflammatory bone loss - Andreev, Darja; Chen, Zhu; Oeser, Katharina; Krljanac, B.; Hueber, Axel; Kleyer, Arnd; Weigmann, Benno; Vöhringer, David; Schett, Georg; Bozec, Aline (2017)
EVALuna2:33419

Th2 and eosinophil responses suppress inflammatory arthritis - Chen, Zhu; Andreev, Darja; Oeser, Katharina; Krljanac, Branislav; Hueber, Axel; Kleyer, Arnd; Vöhringer, David; Schett, Georg; Bozec, Aline (Nature Communications, 2016)
Th2-eosinophil immune responses are well known for mediating host defence against helminths. Herein we describe a function of Th2-eosinophil responses in counteracting the development of arthritis. In two independent models of arthritis, Nippostrongylus brasiliensis infection leads to Th2 and eosinophil accumulation in the joints associated with robust inhibition of arthritis and protection from bone loss. Mechanistically, this protective effect is dependent on IL-4/IL-13-induced STAT6 pathway. Furthermore, we show that eosinophils play a central role in the modulation of arthritis probably through the increase of anti-inflammatory macrophages into arthritic joints. The presence of these pathways in human disease is confirmed by detection of GATA3-positive cells and eosinophils in the joints of rheumatoid arthritis patients. Taken together, these results demonstrate that eosinophils and helminth-induced activation of the Th2 pathway axis effectively mitigate the course of inflammatory arthritis.
EVALuna2:13286

The 12/15-lipoxygenase pathway counteracts fibroblast activation and experimental fibrosis - Krönke, Gerhard; Reich, Nicole; Scholtysek, Carina; Akhmetshina, Alfiya; Uderhardt, Stefan; Zerr, Pawel; Palumbo, Katrin; Lang, Veronika; Dees, Clara; Distler, Oliver; Schett, Georg; Distler, Jörg (Annals of the Rheumatic Diseases, 2012)
Background: Idiopathic and inflammation-dependent fibrotic diseases such systemic sclerosis (SSc) impose a major burden on modern societies. Understanding endogenous mechanisms, which counteract fibrosis, may yield new therapeutic approaches. Lipoxins are highly potent lipid mediators, which have recently been found to be decreased in SSc. Objectives: To determine the potential role of 12/15-lipoxygenase (12/15-LO), the key enzyme for the synthesis of lipoxins, in fibrosis. Methods: Two mouse models for experimental dermal fibrosis (bleomycin-induced dermal fibrosis and tight-skin 1 mouse model) together with bone marrow transfers were used in wildtype and 12/15-LO -/- mice to elucidate the role of this enzyme during dermal fibrosis. Primary dermal fibroblasts of wildtype and 12/15-LO -/- mice, and 12/15-LO-derived eicosanoids, were used to identify underlying molecular mechanisms Results: In both models, 12/15-LO -/- mice exhibited a significant exacerbation of the fibrotic tissue response. Bone marrow transfer experiments disclosed a predominant role of mesenchymal cell-derived 12/15-LO in these antifibrotic effects. Indeed, 12/15-LO -/- fibroblasts showed an enhanced activation of the mitogen-activated protein-kinase pathway and an increased col 1a2 mRNA expression in response to stimulation with transforming growth factor β (TGFβ), whereas 12/15-LO-derived eicosanoids blocked these TGFβ-induced effects. Conclusions: These data indicate that 12/15-LO and its metabolites have a prominent antifibrotic role during dermal fibrosis. This opens new opportunities for therapeutic approaches in the treatment of fibrotic diseases.
CRIS-Team Scopus Importer:2020-11-20

The 12/15-lipoxygenase pathway promotes osteoclast development and differentiation - Krönke, Gerhard; Uderhardt, Stefan; Katzenbeisser, Julia; Schett, Georg (Autoimmunity, 2009)
Although 12/15-lipoxygenase (12/15-LO) has been implicated as negative regulator of systemic bone mass in mice and humans, the underlying mechanisms remain elusive. Here, we show that 12/15-LO is a positive regulator of osteoclast (OC) development. Enzymatic inhibition as well as genetic ablation of 12/15-LO significantly impaired osteoclastogenesis. Conversely, addition of the 12/15-LO-derived eicosanoids 12- and 15-HETE augmented differentiation of precursors into fully matured OCs. Together these data point towards a crucial role of 12/15-LO in the regulation of OC development. Therefore, 12/15-LO and its human homologue 15-LO may display novel targets for the treatment of diseases such as osteoporosis and rheumatoid arthritis. © 2009 Informa UK Ltd All rights reserved.
CRIS-Team Scopus Importer:2020-11-20
Keywords: 12/15-LO; HETE; OC

THE 4-D+ NANOSCOPE: THE RESOLUTION FOR BIOLOGICAL SAMPLES - Kling, L.; Mill, L.; Grüneboom, Anika; Sarau, G.; Herrmann, Martin; Schett, Georg; Maier, Andreas; Christiansen, S. H. (ANNALS OF THE RHEUMATIC DISEASES, 2019)
CRIS-Team WoS Importer:2019-07-16

The ageing joint-standard age- and sex-related values of bone erosions and osteophytes in the hand joints of healthy individuals - Berlin, Andreas; Simon, David; Tascilar, K.; Figueiredo, C.; Bayat, Sara; Finzel, Stephanie; Klaus, E.; Rech, Jürgen; Hueber, Axel; Kleyer, Arnd; Schett, Georg (Osteoarthritis and Cartilage, 2019)
Objective: To analyze the age-related changes of the physiological hand joint architecture. Method: To address this concept, healthy individuals (each 10 women and 10 men in six different age decades spanning from 21 to 80 years) were recruited through a field campaign, investigated for the absence of rheumatic diseases and other comorbidities and received high-resolution quantitative computed tomography (HR-pQCT) examination of the hand joints. Number and extent of erosions and osteophytes were quantified across the ages and different sexes. Results: Bone erosions [median (Q1–Q3), 1 (0–2)] and osteophytes [2 (1–4)] were found in healthy women and men with no significant sex differences. Structural changes however accumulated with age: the overall incidence rate ratio (IRR) for the number of erosions and osteophytes per age were 1.04 (95% CI: erosions 1.03–1.06; osteophytes: 1.03–1.05). This means a 4% increase in the number of erosions and osteophytes per year. Using third decade as reference, healthy individuals in the age decades from 50 years had higher IRR for erosion numbers (sixth, seventh, eigth decade: 4.87 (2.20–11.75), 6.81 (3.08–16.46) and 6.92 (3.11–16.79)) compared to younger subjects (fourth, fifth decade: 1.80 (0.69–4.87), 1.53 (0.59–4.10)). The IRRs of osteophytes also indicate a gradual increase after the fifth decade, with IRRs of 2.32 (1.32–4.17), 4.17 (2.38–7.49) and 6.86 (3.97–12.20) for the sixth, seventh and eigth decades, respectively. Conclusions: Structural changes in the hand joints of healthy individuals are age dependent. While being rare under 50 years of age, erosions and osteophytes accumulate above the age of 50, suggesting that the threshold between “normal” and “pathological” is shifted with the increase of age.
CRIS-Team Scopus Importer:2019-06-07
Keywords: Bone erosions; Computed tomography; Hand joints; Healthy individuals; Osteophytes

THE ANTI-RO52 PREVALENCE IN THE SJOGREN'S SYNDROME PICTURE: A SINGLE CENTER CROSS SECTIONAL STUDY - Valor, Larissa; Schenker, Hannah; Hagen, Melanie; Knitza, Johannes; Rech, Jürgen; Schett, Georg (ANNALS OF THE RHEUMATIC DISEASES, 2019)
CRIS-Team WoS Importer:2019-07-16

THE AP1 TRANSCRIPTION FACTOR CJUN AMPLIFIES HEDGEHOG-INDUCED FIBROBLAST ACTIVATION AND TISSUE FIBROSIS - Bergmann, C.; Merlevede, B.; Beyer, Christian; Hallenberger, L.; Brandt, Adrian; Dees, Clara; Pötter, Sebastian; Bozec, Aline; Schett, Georg; Distler, Jörg (2018)
EVALuna2:34992

The AP-1 Transcription Factor c-Jun Promotes Arthritis by Regulating Cyclooxygenase-2 and Arginase-1 Expression in Macrophages - Hannemann, Nicole; Jordan, Jutta; Paul, Sushmita; Reid, Stephen; Baenkler, Hanns-Wolf; Sonnewald, Sophia; Bäuerle, Tobias; Vera, Julio; Schett, Georg; Bozec, Aline (Journal of Immunology, 2017)
Activation of proinflammatory macrophages is associated with the inflammatory state of rheumatoid arthritis. Their polarization and activation are controlled by transcription factors such as NF-?B and the AP-1 transcription factor member c-Fos. Surprisingly, little is known about the role of the AP-1 transcription factor c-Jun in macrophage activation. In this study, we show that mRNA and protein levels of c-Jun are increased in macrophages following pro- or anti-inflammatory stimulations. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment cluster analyses of microarray data using wild-type and c-Jun-deleted macrophages highlight the central function of c-Jun in macrophages, in particular for immune responses, IL production, and hypoxia pathways. Mice deficient for c-Jun in macrophages show an amelioration of inflammation and bone destruction in the serum-induced arthritis model. In vivo and in vitro gene profiling, together with chromatin immunoprecipitation analysis of macrophages, revealed direct activation of the proinflammatory factor cyclooxygenase-2 and indirect inhibition of the anti-inflammatory factor arginase-1 by c-Jun. Thus, c-Jun regulates the activation state of macrophages and promotes arthritis via differentially regulating cyclooxygenase-2 and arginase-1 levels.
EVALuna2:13412

The AP1 Transcription Factor Fosl2 Promotes Systemic Autoimmunity and Inflammation by Repressing Treg Development - Renoux, Florian; Stellato, Mara; Haftmann, Claudia; Vogetseder, Alexander; Huang, Riyun; Subramaniam, Arun; Becker, Mike O.; Blyszczuk, Przemyslaw; Becher, Burkhard; Distler, Jörg; Kania, Gabriela; Boyman, Onur; et al. (Cell Reports, 2020)
Regulatory T cells (Tregs) represent a major population in the control of immune homeostasis and autoimmunity. Here we show that Fos-like 2 (Fosl2), a TCR-induced AP1 transcription factor, represses Treg development and controls autoimmunity. Mice overexpressing Fosl2 (Fosl2tg) indeed show a systemic inflammatory phenotype, with immune infiltrates in multiple organs. This phenotype is absent in Fosl2tg × Rag2−/− mice lacking T and B cells, and Fosl2 induces T cell-intrinsic reduction of Treg development that is responsible for the inflammatory phenotype. Fosl2tg T cells can transfer inflammation, which is suppressed by the co-delivery of Tregs, while Fosl2 deficiency in T cells reduces the severity of autoimmunity in the EAE model. We find that Fosl2 could affect expression of FoxP3 and other Treg development genes. Our data highlight the importance of AP1 transcription factors, in particular Fosl2, during T cell development to determine Treg differentiation and control autoimmunity.
CRIS-Team Scopus Importer:2020-07-03
Keywords: autoimmunity; FoxP3; immunology; inflammation; mouse models; regulatory T cells; T cells

The AP-1 transcription factor Fra1 inhibits follicular B cell differentiation into plasma cells - Groetsch, Bettina; Brachs, Sebastian; Lang, Christiane; Luther, Julia; Derer, Anja; Schlötzer-Schrehardt, Ursula; Bozec, Aline; Fillatreau, Simon; Berberich, Ingolf; Hobeika, Elias; Reth, Michael; Wagner, Erwin F.; et al. (Journal of Experimental Medicine, 2014)
The cornerstone of humoral immunity is the differentiation of B cells into antibody-secreting plasma cells. This process is tightly controlled by a regulatory gene network centered on the transcriptional repressor B lymphocyte-induced maturation protein 1 (Blimp1). Proliferation of activated B cells is required to foster Blimp1 expression but needs to be terminated to avoid overshooting immune reactions. Activator protein 1 (AP-1) transcription factors become quickly up-regulated upon B cell activation. We demonstrate that Fra1, a Fos member of AP-1, enhances activation-induced cell death upon induction in activated B cells. Moreover, mice with B cell-specific deletion of Fra1 show enhanced plasma cell differentiation and exacerbated antibody responses. In contrast, transgenic overexpression of Fra1 blocks plasma cell differentiation and immunoglobulin production, which cannot be rescued by Bcl2. On the molecular level, Fra1 represses Blimp1 expression and interferes with binding of the activating AP-1 member c-Fos to the Blimp1 promoter. Conversely, overexpression of c-Fos in Fra1 transgenic B cells releases Blimp1 repression. As Fra1 lacks transcriptional transactivation domains, we propose that Fra1 inhibits Blimp1 expression and negatively controls plasma cell differentiation through binding to the Blimp1 promoter. In summary, we demonstrate that Fra1 negatively controls plasma cell differentiation by repressing Blimp1 expression.
EVALuna2:13013

The B cell response to citrullinated antigens in the development of rheumatoid arthritis - Scherer, Hans Ulrich; Huizinga, Tom W. J.; Krönke, Gerhard; Schett, Georg; Toes, Rene E. M. (Nature Reviews Rheumatology, 2018)
The immune response to citrullinated antigens is found almost exclusively in patients with rheumatoid arthritis (RA). It is a dynamic response that expands before the onset of disease and generates antibodies (anti-citrullinated protein antibodies (ACPAs)) that are extensively glycosylated in the variable domain. This feature of ACPAs is remarkable and warrants detailed investigation, as it can offer insights into the earliest immunologic mechanisms that lead up to the development of RA. The acquisition of variable domain glycans, in fact, could enable ACPA-expressing B cells to breach tolerance. Although the underlying mechanisms are still elusive, data to support this concept are emerging, owing to the reliable identification and isolation of citrullinated antigen-directed B cells from patients with RA. This technological proficiency also allows for the generation of an increasing number of well-defined monoclonal ACPAs, and provides the opportunity to test and define the mechanisms by which the citrullinated antigen-directed B cell response contributes to the onset and persistence of inflammation. Together with a revised perception of the HLA-risk effect and novel insights into how T cells can govern antibody effector functions, these developments shape an increasingly clear picture of the B cell response to citrullinated antigens in the development of RA.
EVALuna2:34155

The bone marrow side of axial spondyloarthritis - Mauro, Daniele; Gandolfo, Saviana; Tirri, Enrico; Schett, Georg; Maksymowych, Walter P.; Ciccia, Francesco (Nature Reviews Rheumatology, 2023)
Spondyloarthritis (SpA) is characterized by the infiltration of innate and adaptive immune cells into entheses and bone marrow. Molecular, cellular and imaging evidence demonstrates the presence of bone marrow inflammation, a hallmark of SpA. In the spine and the peripheral joints, bone marrow is critically involved in the pathogenesis of SpA. Evidence suggests that bone marrow inflammation is associated with enthesitis and that there are roles for mechano-inflammation and intestinal inflammation in bone marrow involvement in SpA. Specific cell types (including mesenchymal stem cells, innate lymphoid cells and γδ T cells) and mediators (Toll-like receptors and cytokines such as TNF, IL-17A, IL-22, IL-23, GM-CSF and TGFβ) are involved in these processes. Using this evidence to demonstrate a bone marrow rather than an entheseal origin for SpA could change our understanding of the disease pathogenesis and the relevant therapeutic approach.
CRIS-Team Scopus Importer:2023-07-21

The burden of systemic sclerosis in Switzerland - the Swiss systemic sclerosis EUSTAR cohort - Hernández, Jasmin; Jordan, Suzana; Dobrota, Rucsandra; Iudici, Michele; Hasler, Paul; Ribi, Camillo; Villiger, Peter; Vlachoyiannopoulos, Panayiotis; Vacca, Alessandra; Garzanova, Ludmila; Giollo, Alessandro; Rosato, Edoardo; et al. (Swiss Medical Weekly, 2021)
OBJECTIVES: Characteristics of Swiss patients with systemic sclerosis have not been described so far. The aim of the current study was to identify unmet needs in comparison with other European countries that could inform specific interventions to improve the care of systemic sclerosis patients. METHODS: We analysed Swiss and other European systemic sclerosis patients registered in European Scleroderma Trials And Research (EUSTAR) and the Very Early Diagnosis Of Systemic Sclerosis (VEDOSS) cohort. Demographics, clinical profiles, organ involvement and survival of established, early/mild and very early / very mild systemic sclerosis patients were described and compared between the cohorts. RESULTS: We included 679 Swiss and 8793 European systemic sclerosis patients in the analysis. Over 95% of patients in both cohorts were Caucasian, disease subsets were similar, and no age difference was found. The Swiss cohort had more male patients (25% vs 16% European, p = 0.005) and higher prevalence of early/mild and very early / very mild patients (26.1 vs 8.5% European and 14.9% vs 6.7% European, respectively, both p <0.0001). Disease duration in established systemic sclerosis patients at first presentation was numerically shorter but not significant in the Swiss cohort: 5.0 years (1–12) Swiss vs 6.0 years (2–12) years European, p = 0.055). Despite the earlier referral of Swiss patients to systemic sclerosis expert centres, they showed evidence of more severe disease, particularly in the limited cutaneous systemic sclerosis subset, but no differences in overall survival on longitudinal follow-up were observed. CONCLUSION: This is the first report of the national Swiss EUSTAR cohort. It identifies earlier referral to systemic sclerosis expert centres, before major organ damage occurs, and when outcome can still be modified, as a priority to improve care of patients with systemic sclerosis.
CRIS-Team Scopus Importer:2021-09-03

The Canonical Wnt Pathway in the Pathogenesis of Cardiac Allograft Vasculopathy - Kuckhahn, A.; Ramsperger-Gleixner, Martina; Distler, Jörg; Spriewald, B.; Ensminger, S.; Weyand, Michael; Heim, Christian (JOURNAL OF HEART AND LUNG TRANSPLANTATION, 2020)
CRIS-Team WoS Importer:2020-04-24

The Canonical Wnt Pathway in the Pathogenesis of Cardiac Allograft Vasculopathy - Kuckhahn, A.; Ramsperger-Gleixner, Martina; Distler, Jörg; Spriewald, B.; Ensminger, S.; Weyand, Michael; Heim, Christian (Journal of Heart and Lung Transplantation, 2020)
PURPOSE: The canonical wnt pathway with its central signaling molecule β-catenin is important for tissue development and homeostasis and its dysregulation leads to many diseases including pathologies of the cardiovascular system. Inhibition of the wnt pathway has the potential to protect against cardiac allograft vasculopathy (CAV), because it reduces the proliferation of smooth muscle cells (SMCs), which is a main pathomechanism of CAV and causes neointima formation and vessel occlusion. METHODS: For in vitro experiments human (hu) and murine (mu) aortic SMCs were grown in the presence of increasing concentrations of wnt inhibitors, such as XAV-939, ICG-001 or PKF118-310. Cell proliferation was measured as the extent of PrestoBlue Cell Viability Reagent metabolism and expression of representative wnt target genes was assessed by Taqman PCR. Additionally, the wnt inhibitors were used in the mouse model of aortic transplantation (n=8 mice/group) and the extent of neointima formation as an indicator for CAV was analyzed. We also measured the expression of β-catenin (immunofluorescence staining), wnt target genes (Taqman PCR) and several inflammatory cytokines (Taqman PCR) in the transplant. RESULTS: In vitro experiments revealed dose-dependent proliferation inhibition in huSMCs and muSMCs after treatment with each wnt inhibitor. PKF118-310 induced cell death in the highest concentrations tested. While XAV-939 had only minor influence on the expression of the wnt target genes cyclin D1, axin2 and p21, ICG-001 and PKF118-310 induced the expression of p21 and cyclin D1 and reduced the expression of axin2. Interestingly, in vivo experiments showed no effect of XAV-939 and ICG-001 on neointima formation, whereas neointimal amounts of β-catenin were significantly reduced. ICG-001 also reduced the expression of inflammatory cytokines (INFγ, TNFα and IL-6) and of p21, but did not influence cyclin D1 expression. XAV-939 had no relevant influence on cytokine expression. Results for PKF118-310 and wnt target gene expression in transplants after XAV-939 treatment are currently assessed. CONCLUSION: Strong anti-proliferative effects were found in vitro for all three wnt inhibitors, but this did not lead to reduced CAV development in a mouse model of vessel transplantation. Effects on SMCs themselves after ICG-001 and PKF118-310 seem indeed mediated via regulation of wnt target genes.
CRIS-Team Scopus Importer:2020-06-09

The complement system drives local inflammatory tissue priming by metabolic reprogramming of synovial fibroblasts - Friščić, Jasna; Böttcher, Martin; Reinwald, Christiane; Bruns, Heiko; Wirth, Benjamin; Popp, Sebastian; Walker, Kellie Irene; Ackermann, Jochen A.; Chen, Xi; Turner, Jason; Zhu, Honglin; Seyler, Lisa; et al. (Immunity, 2021)
Arthritis typically involves recurrence and progressive worsening at specific predilection sites, but the checkpoints between remission and persistence remain unknown. Here, we defined the molecular and cellular mechanisms of this inflammation-mediated tissue priming. Re-exposure to inflammatory stimuli caused aggravated arthritis in rodent models. Tissue priming developed locally and independently of adaptive immunity. Repeatedly stimulated primed synovial fibroblasts (SFs) exhibited enhanced metabolic activity inducing functional changes with intensified migration, invasiveness and osteoclastogenesis. Meanwhile, human SF from patients with established arthritis displayed a similar primed phenotype. Transcriptomic and epigenomic analyses as well as genetic and pharmacological targeting demonstrated that inflammatory tissue priming relies on intracellular complement C3- and C3a receptor-activation and downstream mammalian target of rapamycin- and hypoxia-inducible factor 1α-mediated metabolic SF invigoration that prevents activation-induced senescence, enhances NLRP3 inflammasome activity, and in consequence sensitizes tissue for inflammation. Our study suggests possibilities for therapeutic intervention abrogating tissue priming without immunosuppression.
CRIS-Team Scopus Importer:2021-04-19
Keywords: arthritis; cell metabolism; cellular senescence; complement system; inflammasome; inflammation; mechanistic target of rapamycin; synovial fibroblasts; tissue priming; trained immunity

The double-edged role of 12/15-lipoxygenase during inflammation and immunity - Ackermann, Jochen A.; Hofheinz, Katharina; Zaiss, Mario; Krönke, Gerhard (BBA - Biochimica et Biophysica Acta, 2016)
12/15-Lipoxygenase (12/15-LOX) mediates the enzymatic oxidation of polyunsaturated fatty acids, thereby contributing to the generation of various bioactive lipid mediators. Although 12/15-LOX has been implicated in the pathogenesis of multiple chronic inflammatory diseases, its physiologic functions seem to include potent immune modulatory properties that physiologically contribute to the resolution of inflammation and the clearance of inflammation-associated tissue damage. This review aims to give a comprehensive overview about our current knowledge on the role of this enzyme during the regulation of inflammation and immunity. "This article is part of a Special Issue entitled: Lipid modification and lipid peroxidation products in innate immunity and inflammation edited by Christoph J. Binder".
EVALuna2:13307

The effect of nintedanib versus mycophenolate mofetil in the Fra2 mouse model of systemic sclerosis-associated interstitial lung disease. - Wollin, Lutz; Trinh, Minh Thuong; Zhang, Yun; Distler, Jörg (Clinical and Experimental Rheumatology, 2021)
OBJECTIVES: Interstitial lung disease (ILD) is a key driver of mortality in patients with systemic sclerosis (SSc). A lack of approved treatments encompasses a high unmet medical need. Nintedanib has recently been approved for treatment in SSc-associated ILD (SSc-ILD) following SENSCIS®, a Phase III clinical trial showing that nintedanib slows the loss of pulmonary function in patients with SSc-ILD relative to placebo, as measured by annual rate of decline in forced vital capacity over 52 weeks. The aim of this study was to compare the activity of nintedanib and mycophenolate mofetil (MMF) in a transgenic Fra2 mouse model of SSc-ILD. METHODS: Fra2 transgenic mice were treated with MMF or nintedanib. Haematoxylin and Eosin and Sirius Red staining were used to identify pulmonary fibrosis and vascular remodelling in whole lung sections. Fibrosis was quantified by Ashcroft scoring, fold change in fibrotic area, and hydroxyproline. Ki67, SM22a, CD31, and caspase-3 staining was used to quantify proliferating vascular smooth muscle cells and apoptotic endothelial cells. RESULTS: Nintedanib effectively ameliorated pulmonary vascular remodelling and fibrosis in Fra2 transgenic mice. Pulmonary fibrotic and vascular remodelling parameter scores and the apoptosis of dermal endothelial cells were significantly reduced compared with vehicle-treated Fra2 transgenic mice. Treatment with MMF had only mild antifibrotic effects and no effect on pulmonary vascular remodelling. CONCLUSIONS: In this model of SSc-ILD, nintedanib ameliorated pulmonary fibrosis, remodelling of pulmonary vasculature, and the apoptosis of endothelial cells. In contrast, MMF had minor effects on pulmonary fibrosis and no effects on vascular manifestations.
EVALuna2:486833
Keywords: systemic sclerosis; interstitial lung disease; nintedanib; mycophenolate mofetil; fibrosis

The effect of nintedanib versus mycophenolate mofetil in the Fra2 mouse model of systemic sclerosis-associated interstitial lung disease - Wollin, Lutz; Trinh, Minh Thuong; Zhang, Yun; Distler, Jörg (Clinical and Experimental Rheumatology, 2021)
Objective. Interstitial lung disease (ILD) is a key driver of mortality in patients with systemic sclerosis (SSc). A lack of approved treatments encompasses a high unmet medical need. Nintedanib has recently been approved for treatment in SSc-associated ILD (SSc-ILD) following SENSCIS (R), a Phase III clinical trial showing that nintedanib slows the loss of pulmonary function in patients with SSc-ILD relative to placebo, as measured by annual rate of decline in forced vital capacity over 52 weeks. The aim of this study was to compare the activity of nintedanib and mycophenolate mofetil (MMF) in a transgenic Fra2 mouse model of SSc-ILD.
CRIS-Team WoS Importer:2021-08-13

The Effect of Nintedanib versus Mycopheolate Mofetil in the FRA2 Mouse Model of Systemic Sclerosis Associated Interstitial Lung Disease - Thuong Trin-Minh,; Zhang, Yun; Distler, Jörg; Wollin, Lutz (ARTHRITIS & RHEUMATOLOGY, 2019)
CRIS-Team WoS Importer:2020-02-07

The effects of Kv1.3 and IKCa1 channel inhibition on cytokine production and calcium influx of T lymphocytes in rheumatoid arthritis and ankylosing spondylitis - Toldi, Gergely; Munoz, Luis Enrique; Herrmann, Martin; Schett, Georg; Balog, Attila; Munoz Becerra, Luis (Immunologic Research, 2016)
Kv1.3 and IKCa1 lymphocyte potassium channels have been implicated as important targets of selective immunomodulation. We compared the alterations in cytokine production upon selective inhibition of Kv1.3 or IKCa1 channels (by MGTX and TRAM, respectively) in healthy donors (HD), RA and AS patients. We also determined calcium influx kinetics and its sensitivity to Kv1.3 and IKCa1 channel inhibition following PHA activation in CD4, Th1, Th2 and CD8 cells as well as monocytes. The application of TRAM resulted in a lower production of TNF-a and IL1-RA in all three study groups. Inhibition by TRAM had contrary effects on the production of IL-1b and IL-5: While their production was increased by PBMCs of RA patients, this effect was not observed in HD and AS PBMCs. While treatment with MGTX resulted in a similar decrease in calcium influx in the CD4 and Th2 subsets across all study groups, TRAM treatment had opposite effects on RA and HD samples: It decreased calcium influx in the Th2 and CD8 subsets in RA, while only Th1 cells were affected in HDs. The effects of IKCa1 channel inhibition are controversial in samples of RA and AS patients, since it shifts the inflammatory balance into the pro-inflammatory direction.
EVALuna2:13123
Keywords: AS; Calcium influx; Cytokine; IKCa1; Kv1.3; RA

The Exciting Future for Scleroderma: What Therapeutic Pathways Are on the Horizon? - Distler, Jörg; Riemekasten, Gabriela; Denton, Christopher P. (Rheumatic Disease Clinics of North America, 2023)
CRIS-Team Scopus Importer:2023-03-24
Keywords: Antibody; Clinical trial; Cytokine; Extracellular matrix; Scleroderma

The F4/AS01B HIV-1 Vaccine Candidate Is Safe and Immunogenic, But Does Not Show Viral Efficacy in Antiretroviral Therapy-Naive, HIV-1-Infected Adults: A Randomized Controlled Trial - Dinges, Warren; Girard, Pierre-Marie; Podzamczer, Daniel; Brockmeyer, Norbert H.; Garcia, Felipe; Harrer, Thomas; Lelievre, Jean-Daniel; Frank, Ian; De Verdiere, Nathalie Colin; Yeni, Guy-Patrick; Ortega Gonzalez, Enrique; Rubio, Rafael; et al. (Medicine, 2016)
The impact of the investigational human immunodeficiency virus type 1 (HIV-1) F4/AS01B vaccine on HIV-1 viral load (VL) was evaluated in antiretroviral therapy (ART)-naive HIV-1 infected adults.This phase IIb, observer-blind study (NCT01218113), included ART-naive HIV-1 infected adults aged 18 to 55 years. Participants were randomized to receive 2 (F4/AS01B_2 group, N = 64) or 3 (F4/AS01B_3 group, N = 62) doses of F4/AS01B or placebo (control group, N = 64) at weeks 0, 4, and 28. Efficacy (HIV-1 VL, CD4 T-cell count, ART initiation, and HIV-related clinical events), safety, and immunogenicity (antibody and T-cell responses) were evaluated during 48 weeks.At week 48, based on a mixed model, no statistically significant difference in HIV-1 VL change from baseline was demonstrated between F4/AS01B_2 and control group (0.073 log10 copies/mL [97.5% confidence interval (CI): -0.088; 0.235]), or F4/AS01B_3 and control group (-0.096 log10 copies/mL [97.5% CI: -0.257; 0.065]). No differences between groups were observed in HIV-1 VL change, CD4 T-cell count, ART initiation, or HIV-related clinical events at intermediate timepoints. Among F4/AS01B recipients, the most frequent solicited symptoms were pain at injection site (252/300 doses), fatigue (137/300 doses), myalgia (105/300 doses), and headache (90/300 doses). Twelve serious adverse events were reported in 6 participants; 1 was considered vaccine-related (F4/AS01B_2 group: angioedema). F4/AS01B induced polyfunctional F4-specific CD4 T-cells, but had no significant impact on F4-specific CD8 T-cell and anti-F4 antibody levels.F4/AS01B had a clinically acceptable safety profile, induced F4-specific CD4 T-cell responses, but did not reduce HIV-1 VL, impact CD4 T-cells count, delay ART initiation, or prevent HIV-1 related clinical events.
EVALuna2:13261

The first biologic for rheumatoid arthritis: factors influencing the therapeutic decision - Pattloch, D.; Richter, A.; Manger, Bernhard; Dockhorn, R.; Meier, L.; Tony, H. -P.; Zink, A.; Strangfeld, A. (Zeitschrift für Rheumatologie, 2016)
Biologics (disease modifying antirheumatic drugs, bDMARD) have been in use in Germany for the treatment of rheumatoid arthritis (RA) since 2001, usually after failure of at least one conventional synthetic (cs)DMARD. We analyzed temporal changes in factors that influence the decision for either a first bDMARD or a further csDMARD.We analyzed data from 9513 bDMARD-naive RA patients in the German biologics register RABBIT who switched to a new therapy. For three recruitment periods (2001-2003, 2004-2006 and 2009-2015) factors influencing the therapeutic decision were analyzed by means of machine learning methods and logistic regression analysis.In all recruitment periods the number of previous csDMARDs, high dosages of glucocorticoids (>7.5 mg/day) and a higher DAS28 (>5.1) were significantly associated with the decision for a first bDMARD. Over time, the chance of receiving a bDMARD increased in patients with moderate disease activity, moderate glucocorticoid dosages (5-7.5 mg/day) and those with comorbidities, such as congestive heart failure or prior malignancy. Men had a higher chance of receiving a bDMARD than women only in the first recruitment period. Private health insurance, high education and gainful employment were significantly associated with more frequent prescription of bDMARDs in all recruitment periods.The time-dependent changes in the impact of disease activity, concomitant drugs, gender and comorbidity on the prescription of bDMARDs mirror the increasing therapeutic options and the growing experience in the application of the new substances in patients at higher risk. The influence of demographic and social factors may reflect safety concerns in patients at increased risk of adverse events but also the need to economize drug costs..
EVALuna2:13341

The gut-bone axis: how bacterial metabolites bridge the distance - Zaiss, Mario; Jones, Rheinallt M.; Schett, Georg; Pacifici, Roberto (Journal of Clinical Investigation, 2019)
The gut microbiome is a key regulator of bone health that affects postnatal skeletal development and skeletal involution. Alterations in microbiota composition and host responses to the microbiota contribute to pathological bone loss, while changes in microbiota composition that prevent, or reverse, bone loss may be achieved by nutritional supplements with prebiotics and probiotics. One mechanism whereby microbes influence organs of the body is through the production of metabolites that diffuse from the gut into the systemic circulation. Recently, short-chain fatty acids (SCFAs), which are generated by fermentation of complex carbohydrates, have emerged as key regulatory metabolites produced by the gut microbiota. This Review will focus on the effects of SCFAs on the musculoskeletal system and discuss the mechanisms whereby SCFAs regulate bone cells.
CRIS-Team Scopus Importer:2019-08-06

The gut-joint axis in rheumatoid arthritis - Zaiss, Mario; Joyce Wu, Hsin-Jung; Mauro, Daniele; Schett, Georg; Ciccia, Francesco (Nature Reviews Rheumatology, 2021)
Intestinal dysbiosis is thought to be involved in the early stages of rheumatoid arthritis (RA). In this Review, the authors discuss the gut-joint axis in RA and the potentially pathogenic role of gut-derived immune cells in the joints.
CRIS-Team WoS Importer:2021-04-09

The Histone Demethylase Jumonji Domain-Containing Protein 3 (JMJD3) As Central Mediator of Fibroblast Activation - Bergmann, Christina; Brandt, Adrian; Dees, Clara; Zhang, Yun; Chen, Chih-Wei; Mallano, Tatjana; Wohlfahrt, Thomas; Liang, Ruifang; Kagwiria, Rosebeth; Bozec, Aline; Rieker, Ralf; Abraham, David; et al. (2017)
EVALuna2:33428

The histone demethylase Jumonji domain-containing protein 3 (JMJD3) regulates fibroblast activation in systemic sclerosis - Bergmann, Christina; Brandt, Adrian; Merlevede, Benita; Hallenberger, Ludwig; Dees, Clara; Wohlfahrt, Thomas; Pötter, Sebastian; Zhang, Yun; Chen, Chih-Wei; Mallano, Tatjana; Liang, Ruifang; Kagwiria, Rosebeth; et al. (Annals of the Rheumatic Diseases, 2017)
Systemic sclerosis (SSc) fibroblasts remain activated even in the absence of exogenous stimuli. Epigenetic alterations are thought to play a role for this endogenous activation. Trimethylation of histone H3 on lysine 27 (H3K27me3) is regulated by Jumonji domain-containing protein 3 (JMJD3) and ubiquitously transcribed tetratricopeptide repeat on chromosome X (UTX) in a therapeutically targetable manner. The aim of this study was to explore H3K27me3 demethylases as potential targets for the treatment of fibrosis.JMJD3 was inactivated by small interfering RNA-mediated knockdown and by pharmacological inhibition with GSKJ4. The effects of targeted inactivation of JMJD3 were analysed in cultured fibroblasts and in the murine models of bleomycin-induced and topoisomerase-I (topoI)-induced fibrosis. H3K27me3 at the FRA2 promoter was analysed by ChIP.The expression of JMJD3, but not of UTX, was increased in fibroblasts in SSc skin and in experimental fibrosis in a transforming growth factor beta (TGF?)-dependent manner. Inactivation of JMJD3 reversed the activated fibroblast phenotype in SSc fibroblasts and prevented the activation of healthy dermal fibroblasts by TGF?. Pharmacological inhibition of JMJD3 ameliorated bleomycin-induced and topoI-induced fibrosis in well-tolerated doses. JMJD3 regulated fibroblast activation in a FRA2-dependent manner: Inactivation of JMJD3 reduced the expression of FRA2 by inducing accumulation of H3K27me3 at the FRA2 promoter. Moreover, the antifibrotic effects of JMJD3 inhibition were reduced on knockdown of FRA2.We present first evidence for a deregulation of JMJD3 in SSc. JMJD3 modulates fibroblast activation by regulating the levels of H3K27me3 at the promoter of FRA2. Targeted inhibition of JMJD3 limits the aberrant activation of SSc fibroblasts and exerts antifibrotic effects in two murine models.
EVALuna2:13457

THE HOMEOPROTEIN ENGRAILED-1 REGULATES CANONICAL TGF-beta SIGNALING VIA FIBROBLAST DIFFERENTIATION AND TISSUE FIBROSIS - Mallano, Tatjana; Palumbo-Zerr, K.; Beyer, Christian; Dees, Clara; Huang, J.; Wohlfahrt, T.; Distler, O.; Schett, Georg; Distler, Jörg (2016)
EVALuna2:13489

The human sialic acid-binding immunoglobulin-like lectin Siglec-9 and its murine homolog Siglec-E control osteoclast activity and bone resorption - Andes, F. T.; Adam, Susanne; Hahn, Madelaine; Aust, O.; Frey, Silke; Grüneboom, Anika; Nitschke, Lars; Schett, Georg; Steffen, Ulrike (Bone, 2020)
Regulation of osteoclast differentiation and function is a central element in bone homeostasis. While the role of soluble factors, such as cytokines, hormones and growth factors, in controlling osteoclast differentiation has been intensively characterized, the function of surface receptors is less well understood. Sialic acid-binding immunoglobulin-like lectin (Siglec)-9 and its murine homolog Siglec-E are sialic acid-recognizing inhibitory receptors from the CD33-related Siglec-family and mainly expressed on myeloid cells. We found Siglec-9 and Siglec-E to be expressed at all stages of human and murine osteoclastogenesis, respectively. Siglec-E knockout mice displayed lower bone mass despite unchanged osteoclast numbers and an increased bone formation rate. Ex vivo osteoclast assays using Siglec-E knockout cells or a blocking antibody against human Siglec-9 confirmed the suppressive effect of Siglec-9/Siglec-E on osteoclast function. Although osteoclast numbers were unchanged or even slightly decreased, the blockade/absence of Siglec-9/Siglec-E resulted in an augmented resorption activity of mature osteoclasts. This increased resorption activity was associated with enlarged actin rings. Together, our results suggest Siglec-9/Siglec-E to inhibit osteoclast activation independently from osteoclast differentiation and thereby propose a new mechanism for the control of local bone resorption.
CRIS-Team Scopus Importer:2020-10-16
Keywords: Bone; Osteoclasts; Resorption; Siglec-9; Siglec-E

The identification and management of interstitial lung disease in systemic sclerosis: evidence-based European consensus statements - Hoffmann-Vold, Anna Maria; Maher, Toby M.; Philpot, Edward E.; Ashrafzadeh, Ali; Barake, Rafic; Barsotti, Simone; Bruni, Cosimo; Carducci, Paolo; Carreira, Patricia E.; Castellví, Ivan; Del Galdo, Francesco; Distler, Jörg; et al. (The Lancet Rheumatology, 2020)
Background: Systemic sclerosis-associated interstitial lung disease (ILD) carries a high mortality risk; expert guidance is required to aid early recognition and treatment. We aimed to develop the first expert consensus and define an algorithm for the identification and management of the condition through application of well established methods. Methods: Evidence-based consensus statements for systemic sclerosis-associated ILD management were established for six domains (ie, risk factors, screening, diagnosis and severity assessment, treatment initiation and options, disease progression, and treatment escalation) using a modified Delphi process based on a systematic literature analysis. A panel of 27 Europe-based pulmonologists, rheumatologists, and internists with expertise in systemic sclerosis-associated ILD participated in three rounds of online surveys, a face-to-face discussion, and a WebEx meeting, followed by two supplemental Delphi rounds, to establish consensus and define a management algorithm. Consensus was considered achieved if at least 80% of panellists indicated agreement or disagreement. Findings: Between July 1, 2018, and Aug 27, 2019, consensus agreement was reached for 52 primary statements and six supplemental statements across six domains of management, and an algorithm was defined for clinical practice use. The agreed statements most important for clinical use included: all patients with systemic sclerosis should be screened for systemic sclerosis-associated ILD using high-resolution CT; high-resolution CT is the primary tool for diagnosing ILD in systemic sclerosis; pulmonary function tests support screening and diagnosis; systemic sclerosis-associated ILD severity should be measured with more than one indicator; it is appropriate to treat all severe cases; no pharmacological treatment is an option for some patients; follow-up assessments enable identification of disease progression; progression pace, alongside disease severity, drives decisions to escalate treatment. Interpretation: Through a robust modified Delphi process developed by a diverse panel of experts, the first evidence-based consensus statements were established on guidance for the identification and medical management of systemic sclerosis-associated ILD. Funding: An unrestricted grant from Boehringer Ingelheim International.
CRIS-Team Scopus Importer:2020-02-04

The Impact of IL-17A Inhibition in Rheumatic and Musculoskeletal Diseases: Current Insights and Future Prospects - Ramiro, Sofia; Schett, Georg; Marzo-Ortega, Helena; Schmidt, Wolfgang A. (Rheumatology and Therapy, 2025)
Interleukin-17A (IL-17A) plays a pivotal role in many rheumatic immune-mediated inflammatory diseases. Targeting the IL-17 pathway has transformed the way psoriatic arthritis (PsA) and axial spondyloarthritis (axSpA) are managed, with a number of IL-17A inhibitors now available for treating rheumatic and musculoskeletal diseases. This narrative review will describe the opportunities presented by novel imaging techniques in understanding the metabolic and mechanical changes that characterize the pathogenesis of PsA and axSpA. It will look at the current consensus definitions of early disease in PsA and axSpA, present evidence for the benefit of early treatment, and highlight the gaps in current knowledge. Finally, it will describe novel treatment targets to address the unmet needs in giant cell arteritis (GCA) and polymyalgia rheumatica (PMR) and discuss the potential role of IL-17A inhibition in treating GCA and PMR.
CRIS-Team Scopus Importer:2025-04-18
Keywords: Axial spondyloarthritis; Early treatment; Early diagnosis; Giant cell arteritis; IL-17A; IL-17A inhibition; Polymyalgia rheumatica; Psoriasis; Psoriatic arthritis; Rheumatic and musculoskeletal diseases

THE IMPACT OF IL-17A THERAPY ON IGG SIALYLATION IN HUMANS - Pfeifle, René; Kittler, Julia; Wuhrer, M.; Schett, Georg; Krönke, Gerhard (ANNALS OF THE RHEUMATIC DISEASES, 2021)
CRIS-Team WoS Importer:2021-09-24

The impact of rheumatoid factor and ACPA on bone erosion in rheumatoid arthritis - Hecht, Carolin; Schett, Georg; Finzel, Stephanie (Annals of the Rheumatic Diseases, 2015)
EVALuna2:13061

The INBUILD Trial of Nintedanib in Patients with Progressive Fibrosing Interstitial Lung Diseases: Subgroup with Autoimmune Diseases - Matteson, Eric; Kelly, Clive; Distler, Jörg; Mann-Vold, Anna Maria Hoff; Seibold, James; Mittoo, Shikha; Distler, Oliver; Goeldner, Rainer-Georg; Schlenker-Herceg, Rozsa; Stowasser, Susanne; Quaresma, Manuel; Flaherty, Kevin (ARTHRITIS & RHEUMATOLOGY, 2019)
CRIS-Team WoS Importer:2020-02-07

The Influence of Hand Osteoarthritis on Bone Microstructure and Biomechanical Properties of Radial Bone - Simon, David; Unbehend, Sara; Bayat, Sara; Rech, Jürgen; Hueber, Axel; Schett, Georg; Kleyer, Arnd (2018)
EVALuna2:34971

The influence of obstructive sleep apnea and continuous positive airway pressure on the nasal microbiome - Lenk, Christian; Meßbacher, Maria-Elena; Abel, Judith; Müller, Sarina Katrin; Mantsopoulos, Konstantinos; Gostian, Antoniu-Oreste; Sievert, Matti; Wirtz, Stefan; Marxreiter, Franz; Winkler, Jürgen; Iro, Heinrich; Traxdorf, Maximilian (European Review for Medical and Pharmacological Sciences, 2023)
OBJECTIVE: The aim of this study was to investigate the influence of obstructive sleep apnea and continuous positive airway pressure on the nasal microbiome. PATIENTS AND METHODS: Endonasal swabs from the olfactory groove of 22 patients with moderate and severe obstructive sleep apnea (OSA) and a control group of 17 healthy controls were obtained at the Department of Otorhinolaryngology of the Friedrich-Alexander-Universität Erlangen-Nürnberg. 16S rRNA gene sequencing was performed to further evaluate the endonasal microbiome. In a second step, the longitudinal influence of continuous positive airway pressure (CPAP) therapy on the nasal microbiome was investigated (3-6 and 6-9 months). RESULTS: Analysis of the bacterial load and β-diversity showed no significant differences between the groups, although patients with severe OSA showed increased α-diversity compared to the control group, while those with moderate OSA showed decreased α-diversity. The evaluation of longitudinal changes in the nasal microbiota during CPAP treatment showed no significant difference in α- or β-diversity. However, the number of bacteria for which a significant difference between moderate and severe OSA was found in the linear discriminant analysis decreased during CPAP treatment. CONCLUSIONS: Long-term CPAP treatment showed an alignment of the composition of the nasal microbiome in patients with moderate and severe OSA as well as an alignment of biodiversity with that of the healthy control group. This change in the composition of the microbiome could be both part of the therapeutic effect in CPAP therapy and a promoting factor of the adverse side effects of the therapy. Further studies are needed to investigate whether the endonasal microbiome is related to CPAP compliance and whether CPAP compliance can be positively influenced in the future by therapeutic modification of the microbiome.
CRIS-Team WoS Importer:2023-05-26

The Interaction of Physical Function and Emotional Well-being in Rheumatoid Arthritis-What is the Impact on Disease Activity and Coping? - Englbrecht, Matthias; Araujo, Madeleine Kruckow Elizabeth; Rech, Jürgen; Schett, Georg; et al. (Seminars in Arthritis and Rheumatism, 2013)
Objective: To evaluate the impact of the interaction of physical function and emotional well-being on disease-related parameters and coping with rheumatoid arthritis. Methods: A cross-sectional survey among 177 RA patients included demographic and disease-related variables as well as the following patient-reported outcome measures: Health Assessment Questionnaire-Disability Index (HAQ-DI) (physical function), Mental Component Summary Scale of the SF-36 (MCSS) for emotional well-being, Rheumatoid Arthritis Disease Activity Index (RADAI), and Coping with Rheumatoid Arthritis Questionnaire (C-RAQ). Based on HAQ-DI and MCSS, six categories representing various levels of physical and emotional impairment were formed. Multivariate analysis of variance and a subsequent discriminant analysis were used to evaluate whether demographic and disease-related variables and coping strategies differed between these categories. Results: Patients with moderate to high impairment of physical function and emotional well-being reported significantly higher disease activity and a more frequent use of distancing and active problem solving coping strategies than patients with low-level impairment (. p<0.001-0.043). Furthermore, these patients reported experiencing significantly higher levels of helplessness (. p<0.001-0.032). Results from the discriminant analysis highlighted a combination of disease activity and helplessness to differentiate best between patients with either low or high impairment of physical function and emotional well-being (. p<0.001). Conclusion: Aside from perceived disease activity, helplessness, and distancing as well as active problem solving allowed for a good discrimination between the different levels of impairment of physical function and emotional well-being. Encouraging and educating patients on how to cognitively reframe their current situation might play a key role in reducing the level of helplessness resulting from impairments of physical function and emotional well-being. © 2013 Elsevier Inc.
CRIS-Team Scopus Importer:2021-02-03
Keywords: Coping; Disease activity; Emotional well-being; Health-related quality of life; Patient-reported outcomes; Physical function; Rheumatoid arthritis

THE INVOLVEMENT OF THE LONG NONCODING H19X IN TGF beta SIGNALING AND ITS PROFIBROTIC EFFECTS IN SYSTEMIC SCLEROSIS AND OTHER FIBROTIC DISEASES - Pachera, E.; Assassi, S.; Salazar, G.; Frank-Bertoncelj, M.; Dobrota, R.; Brock, M.; Kurreeman, F.; De Vries-Bouwstra, J.; Messemaker, T.; Feghali-Bostwick, C.; Distler, Jörg; Kania, G.; et al. (2016)
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The involvement of Toll-like receptor 9 in the pathogenesis of erosive autoimmune arthritis - Fischer, Anita; Abdollahi-Roodsaz, Shahla; Boehm, Christina; Niederreiter, Birgit; Meyer, Brigitte; Yau, Anthony C. Y.; Lonnblom, Erik; Joosten, Leo A. B.; Koenders, Marije; Lehmann, Christian; Dudziak, Diana; Krönke, Gerhard; et al. (Journal of Cellular and Molecular Medicine, 2018)
Endogenous nucleic acids and their receptors may be involved in the initiation of systemic autoimmune diseases including rheumatoid arthritis (RA). As the role of the DNA sensing Toll-like receptor (TLR) 9 in RA is unclear, we aimed to investigate its involvement in the pathogenesis of autoimmune arthritis using three different experimental models of RA. The data obtained revealed involvement of TLR9 in the T cell-dependent phase of inflammatory arthritis. In rats with pristane-induced arthritis (PIA), TLR9 inhibition before disease onset reduced arthritis significantly and almost completely abolished bone erosion. Accordingly, serum levels of IL-6, α-1-acid-glycoprotein and rheumatoid factor were reduced. Moreover, in TLR9-/- mice, streptococcal cell wall (SCW)-induced arthritis was reduced in the T cell-dependent phase, whereas T cell-independent serum-transfer arthritis was not affected. Remarkably, while TLR7 expression did not change during in vitro osteoclastogenesis, TLR9 expression was higher in precursor cells than in mature osteoclasts and partial inhibition of osteoclastogenesis was achieved only by the TLR9 antagonist. These results demonstrate a pivotal role for TLR9 in the T cell-dependent phases of inflammatory arthritis and additionally suggest some role during osteoclastogenesis. Hence, endogenous DNA seems to be crucially involved in the pathophysiology of inflammatory autoimmune arthritis.
EVALuna2:34780

The need for comparative data in spondyloarthritis - Choy, Ernest; Baraliakos, Xenofon; Behrens, Frank; D'Angelo, Salvatore; De Vlam, Kurt; Kirkham, Bruce W.; Ostergaard, Mikkel; Schett, Georg; Rissler, Michael; Chaouche-Teyara, Kamel; Perella, Chiara (Arthritis Research & Therapy, 2019)
Spondyloarthritis comprises a group of inflammatory diseases, characterised by inflammation within axial joints and/or peripheral arthritis, enthesitis and dactylitis. An increasing number of biologic treatments, including biosimilars, are available for the treatment of spondyloarthritis. Although there are a growing number of randomised controlled trials assessing treatments in spondyloarthritis, there is a paucity of data from head-to-head studies. Comparative data are required so that clinicians and payers have the level of evidence required to inform clinical decision-making and health economic assessments. In the absence of head-to-head studies, statistical methods such as network meta-analyses and matching-adjusted indirect comparisons (MAICs) are used for assessing comparative effectiveness. Network meta-analysis can be used to compare treatments for trials using a common comparator (e.g. placebo); however, for those without a common comparator or where considerable heterogeneity exists between the study populations, a MAIC that controls for differences in study design and baseline patient characteristics may be used. MAICs, unlike network meta-analyses, are of value for longer-term comparisons beyond the placebo-controlled phase of clinical trials, which is important for chronic diseases requiring long-term treatment, like spondyloarthritis. At present, there are a number of limitations that restrict the effectiveness of MAIC, such as the poor availability of individual patient-level data from trials, which results in patient-level data from one trial being compared with published whole-population data from another. Despite these limitations, drug reimbursement agencies are increasingly accepting MAIC as a means of comparative effectiveness and greater methodological guidance is needed. This report highlights a number of challenges that are specific to conducting comparative studies like MAIC in spondyloarthritis, including disease heterogeneity, the paucity of biomarkers and the duration of studies required for radiographic endpoints in this slow-progressing disease.
CRIS-Team Scopus Importer:2019-05-07
Keywords: Biological therapy; Clinical trials; Psoriatic arthritis; Radiography; Spondyloarthropathy

The non-neuronal cyclin-dependent kinase 5 is a fibrotic mediator potentially implicated in systemic sclerosis and a novel therapeutic target - Wei, Jun; Marangoni, Roberta G.; Fang, Feng; Wang, Wenxia; Huang, Jingang; Distler, Jörg; Varga, John (Oncotarget, 2018)
The mechanisms underlying persistent fibroblast activation and myofibroblast phenoconversion in underlying multi-organ fibrosis in systemic sclerosis (SSc) remain incompletely understood, hindering effective therapies to slow or reverse the process. Cyclin-dependent kinase 5 (CDK5) is a pleiotropic member of the CDK family originally identified in neuronal cells. In contrast to other CDKs, CDK5 activity depends on its CDK5R1 subunit p35. Here we demonstrate that expression of p35 and CDK5 activity are induced by TGF-ß in fibroblasts and adipocytic cell types. Levels of p35 are markedly elevated in both SSc skin biopsies and explanted SSc fibroblasts, as well as in fibrotic skin in mice. Ectopic p35 and CDK5 suppressed adipogenic markers while stimulating collagen production and myofibroblast markers, whereas RNAi-mediated CDK5 knockdown abrogated TGF-β fibrotic responses in a Smad-independent manner. Pharmacological inhibitors of CDK5 likewise prevented and reversed TGF-β responses in fibroblast monolayers and in ex vivo human skin organ cultures, ameliorated collagen overproduction in SSc fibroblasts, and prevented and reversed skin fibrosis in two distinct mouse models of SSc. Together, these results reveal a previously unrecognized key function for p35/CDK5 as a mediator of mesenchymal cell fibrotic responses. The results suggest a potential pathogenic role for elevated p35 expression and CDK5 activity in SSc, and raise the possibility that their selective pharmacological targeting might represent a novel treatment approach in fibrosis.
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The novel molecular mechanism of pulmonary fibrosis: insight into lipid metabolism from reanalysis of single-cell RNA-seq databases - Shi, Xiangguang; Chen, Yahui; Shi, Mengkun; Gao, Fei; Huang, Lihao; Wang, Wei; Wei, Dong; Shi, Chenyi; Yu, Yuexin; Xia, Xueyi; Song, Nana; Chen, Xiaofeng; et al. (Lipids in Health and Disease, 2024)
Pulmonary fibrosis (PF) is a severe pulmonary disease with limited available therapeutic choices. Recent evidence increasingly points to abnormal lipid metabolism as a critical factor in PF pathogenesis. Our latest research identifies the dysregulation of low-density lipoprotein (LDL) is a new risk factor for PF, contributing to alveolar epithelial and endothelial cell damage, and fibroblast activation. In this study, we first integrative summarize the published literature about lipid metabolite changes found in PF, including phospholipids, glycolipids, steroids, fatty acids, triglycerides, and lipoproteins. We then reanalyze two single-cell RNA-sequencing (scRNA-seq) datasets of PF, and the corresponding lipid metabolomic genes responsible for these lipids’ biosynthesis, catabolism, transport, and modification processes are uncovered. Intriguingly, we found that macrophage is the most active cell type in lipid metabolism, with almost all lipid metabolic genes being altered in macrophages of PF. In type 2 alveolar epithelial cells, lipid metabolic differentially expressed genes (DEGs) are primarily associated with the cytidine diphosphate diacylglycerol pathway, cholesterol metabolism, and triglyceride synthesis. Endothelial cells are partly responsible for sphingomyelin, phosphatidylcholine, and phosphatidylethanolamines reprogramming as their metabolic genes are dysregulated in PF. Fibroblasts may contribute to abnormal cholesterol, phosphatidylcholine, and phosphatidylethanolamine metabolism in PF. Therefore, the reprogrammed lipid profiles in PF may be attributed to the aberrant expression of lipid metabolic genes in different cell types. Taken together, these insights underscore the potential of targeting lipid metabolism in developing innovative therapeutic strategies, potentially leading to extended overall survival in individuals affected by PF.
CRIS-Team Scopus Importer:2024-04-12
Keywords: Lipid metabolism; Lipid metabolomic gene; Single-cell RNA-sequencing reanalysis; Pulmonary fibrosis

The nuclear receptor constitutive androstane receptor/NR1I3 enhances the profibrotic effects of transforming growth factor β and contributes to the development of experimental dermal fibrosis - Avouac, Jerome; Palumbo-Zerr, Katrin; Ruzehaji, Nadira; Tomcik, Michal; Zerr, Pawel; Dees, Clara; Distler, Alfiya; Beyer, Christian; Schneider, Holm; Distler, Oliver; Schett, Georg; Allanore, Yannick; et al. (Arthritis and Rheumatology, 2014)
Objective Nuclear receptors regulate cell growth, differentiation, and homeostasis. Selective nuclear receptors promote fibroblast activation, which leads to tissue fibrosis, the hallmark of systemic sclerosis (SSc). This study was undertaken to investigate the effects of constitutive androstane receptor (CAR)/NR1I3, an orphan nuclear receptor, on fibroblast activation and experimental dermal fibrosis. Methods CAR expression was quantified by quantitative polymerase chain reaction, Western blotting, immunohistochemistry, and immunofluorescence. CAR expression was modulated by small molecules, small interfering RNA, forced overexpression, and site-directed mutagenesis. The effects of CAR activation were analyzed in cultured fibroblasts, in bleomycin-induced dermal fibrosis, and in mice overexpressing a constitutively active transforming growth factor β (TGFβ) receptor type I (TβRI-CA). Results Up-regulation of CAR was detected in the skin and in dermal fibroblasts in SSc patients. Stimulation of healthy fibroblasts with TGFβ induced the expression of CAR messenger RNA and protein in a Smad-dependent manner. Pharmacologic activation or overexpression of CAR in healthy fibroblasts significantly increased the stimulatory effects of TGFβ on collagen synthesis and myofibroblast differentiation, and amplified the stimulatory effects of TGFβ on COL1A2 transcription activity. Treatment with CAR agonist increased the activation of canonical TGFβ signaling in murine models of SSc and exacerbated bleomycin-induced and TβRI-CA-induced fibrosis with increased dermal thickening, myofibroblast counts, and collagen accumulation. Conclusion Our findings indicate that CAR is up-regulated in SSc and regulates TGFβ signaling. Activation of CAR increases the profibrotic effects of TGFβ in cultured fibroblasts and in different preclinical models of SSc. Thus, inactivation of CAR might be a novel approach to target aberrant TGFβ signaling in SSc and in other fibrotic diseases.
CRIS-Team Scopus Importer:2020-07-01

The Nuclear Receptor Nr4a1 Acts as a Microglia Rheostat and Serves as a Therapeutic Target in Autoimmune-Driven Central Nervous System Inflammation - Rothe, Tobias; Ipseiz, Natacha; Faas, Maria; Lang, Stefanie; Perez-Branguli, Francesc; Metzger, Daniel; Ichinose, Hiroshi; Winner, Beate; Schett, Georg; Krönke, Gerhard (Journal of Immunology, 2017)
Microglia cells fulfill key homeostatic functions and essentially contribute to host defense within the CNS. Altered activation of microglia, in turn, has been implicated in neuroinflammatory and neurodegenerative diseases. In this study, we identify the nuclear receptor (NR) Nr4a1 as key rheostat controlling the activation threshold and polarization of microglia. In steady-state microglia, ubiquitous neuronal-derived stress signals such as ATP induced expression of this NR, which contributed to the maintenance of a resting and noninflammatory microglia phenotype. Global and microglia-specific deletion of Nr4a1 triggered the spontaneous and overwhelming activation of microglia and resulted in increased cytokine and NO production as well as in an accelerated and exacerbated form of experimental autoimmune encephalomyelitis. Ligand-induced activation of Nr4a1 accordingly ameliorated the course of this disease. Our current data thus identify Nr4a1 as regulator of microglia activation and potentially new target for the treatment of inflammatory CNS diseases such as multiple sclerosis.
EVALuna2:13374

The nuclear receptor Nr4a1 mediates anti-inflammatory effects of apoptotic cells - Ipseiz, Natacha; Uderhardt, Stefan; Scholtysek, Carina; Steffen, Martin; Schabbauer, Gernot; Bozec, Aline; Schett, Georg; Krönke, Gerhard (Journal of Immunology, 2014)
Uptake of apoptotic cells (ACs) by macrophages ensures the nonimmunogenic clearance of dying cells, as well as the maintenance of self-tolerance to AC-derived autoantigens. Upon ingestion, ACs exert an inhibitory influence on the inflammatory signaling within the phagocyte. However, the molecular signals that mediate these immune-modulatory properties of ACs are incompletely understood. In this article, we show that the phagocytosis of apoptotic thymocytes was enhanced in tissue-resident macrophages where this process resulted in the inhibition of NF-?B signaling and repression of inflammatory cytokines, such as IL-12. In parallel, ACs induced a robust expression of a panel of immediate early genes, which included the Nr4a subfamily of nuclear receptors. Notably, deletion of Nr4a1 interfered with the anti-inflammatory effects of ACs in macrophages and restored both NF-?B signaling and IL-12 expression. Accordingly, Nr4a1 mediated the anti-inflammatory properties of ACs in vivo and was required for maintenance of self-tolerance in the murine model of pristane-induced lupus. Thus, our data point toward a key role for Nr4a1 as regulator of the immune response to ACs and of the maintenance of tolerance to "dying self."
EVALuna2:12878

The Nuclear Receptor ROR-Alpha As a Key Checkpoint of Tissue Repair - Kagwiria, Rosebeth; Liang, Ruifang; Chen, Chih-Wei; Burris, Thomas; Schett, Georg; Distler, Jörg (2017)
EVALuna2:33434

THE NUCLEAR RECEPTOR TR4 ORCHESTRATES CYTOSKELETAL ORGANIZATION IN A G alpha 12/ROCK-DEPENDENT MANNER TO PROMOTE MYOFIBROBLAST DIFFERENTIATION AND TISSUE FIBROSIS IN SYSTEMIC SCLEROSIS - Shen, Lichong; Zhang, Yun; Honglin, Z.; Distler, Jörg (ANNALS OF THE RHEUMATIC DISEASES, 2022)
CRIS-Team WoS Importer:2022-11-04

The OMERACT Ultrasound Group: A Report from the OMERACT 2016 Meeting and Perspectives - Terslev, Lene; Iagnocco, Annamaria; Bruyn, George A. W.; Naredo, Esperanza; Vojinovic, Jelena; Collado, Paz; Damjanov, Nemanja; Filer, Andrew; Filippou, Georgios; Finzel, Stephanie; Gandjbakhch, Frederique; Ikeda, Kei; et al. (Journal of Rheumatology, 2017)
To provide an update from the Outcome Measures in Rheumatology (OMERACT) Ultrasound Working Group on the progress for defining ultrasound (US) minimal disease activity threshold at joint level in rheumatoid arthritis (RA) and for standardization of US application in juvenile idiopathic arthritis (JIA).For minimal disease activity, healthy controls (HC) and patients with early arthritis (EA) who were naive to disease-modifying antirheumatic drugs were recruited from 2 centers. US was performed of the hands and feet, and scored semiquantitatively (0-3) for synovial hypertrophy (SH) and power Doppler (PD). Synovial effusion (SE) was scored a binary variable. For JIA, a Delphi approach and subsequent validation in static images and patient-based exercises were used to developed preliminary definitions for synovitis and a scoring system.For minimal disease activity, 7% HC had at least 1 joint abnormality versus 30% in the EA group. In HC, the findings of SH and PD were predominantly grade 1 whereas all grades were seen in the EA cohort, but SE was rare. In JIA, synovitis can be diagnosed based on B-mode findings alone because of the presence of physiological vascularization. A semiquantitative scoring system (0-3) for synovitis for both B-mode and Doppler were developed in which the cutoff between Doppler grade 2 and grade 3 was 30%.The first step has been taken to define the threshold for minimal disease activity in RA by US and to define and develop a scoring system for synovitis in JIA. Further steps are planned for the continuous validation of US in these areas.
EVALuna2:13425

The Pathogenicity of Anti-β2GP1-IgG Autoantibodies Depends on Fc Glycosylation. - Fickentscher, Christoph; Magorivska, Iryna; Janko, Christina; Biermann, Mona; Bilyy, Rostyslav; Nalli, Cecilia; Tincani, Angela; Medeghini, Veronica; Meini, Antonella; Nimmerjahn, Falk; Schett, Georg; Munoz, Luis E.; et al. (Journal of immunology research, 2015)
To analyze the glycosylation of anti-β2GP1, we investigated purified IgG from healthy children, patients with APS, and asymptomatic adult carriers of antiphospholipid antibodies. We observed that in the sera of healthy children and of patients with APS, IgG3 and IgG2 were predominant, respectively. The potentially protective anti-β2GP1-IgM was lower in the sera of healthy children. Although anti-β2GP1-associated C1q did not differ between children and patients with antiphospholipid syndrome, the associated C3c was significantly higher in the sera of healthy children. This indicates a more efficient clearance of anti-β2GP1 immune complexes in the healthy children. This clearance is not accompanied by inflammation or coagulatory events. It is likely that the most important pathogenic factor of the anti-β2GP1-IgG is related to the different glycosylation observed in healthy and diseased individuals. We detected a significantly higher sialylation of anti-β2GP1-IgG isolated from the sera of healthy children and asymptomatic adults when compared with that of patients with clinically apparent antiphospholipid syndrome. Low sialylated IgG reportedly ameliorates inflammation and inflammation promotes hyposialylation. Thus, both reactions create a vicious circle that precipitates the pathology of the antiphospholipid syndrome including thrombus-formation. We conclude that the increased sialylation of anti-β2GP1-IgG of sera of healthy individuals limits their pathogenicity.

THE PHYSIOLOGICAL FINGER JOINT ARCHITECTURE - AGE-RELATED INCREASE OF EROSIONS AND OSTEOPHYTES IN THE JOINTS OF HEALTHY INDIVIDUALS - Simon, David; Berlin, Andreas; Tascilar, Koray; Bayat, Sara; Engelke, Klaus; Rech, Jürgen; Figuereido, Camille; Hueber, Axel; Schett, Georg; Kleyer, Arnd (ANNALS OF THE RHEUMATIC DISEASES, 2019)
CRIS-Team WoS Importer:2019-07-12

The potential of omics technologies for the treatment of immune‐mediated inflammatory diseases - Anchang, Charles Gwellem; Xu, Cong; Raimondo, Maria Gabriella; Atreya, Raja; Maier, Andreas; Schett, Georg; Zaburdaev, Vasily; Rauber, Simon; Ramming, Andreas (International Journal of Molecular Sciences, 2021)
Immune‐mediated inflammatory diseases (IMIDs), such as inflammatory bowel diseases and inflammatory arthritis (e.g., rheumatoid arthritis, psoriatic arthritis), are marked by increasing worldwide incidence rates. Apart from irreversible damage of the affected tissue, the systemic nature of these diseases heightens the incidence of cardiovascular insults and colitis‐associated neo-plasia. Only 40–60% of patients respond to currently used standard‐of‐care immunotherapies. In addition to this limited long‐term effectiveness, all current therapies have to be given on a lifelong basis as they are unable to specifically reprogram the inflammatory process and thus achieve a true cure of the disease. On the other hand, the development of various OMICs technologies is consid-ered as “the great hope” for improving the treatment of IMIDs. This review sheds light on the pro-gressive development and the numerous approaches from basic science that gradually lead to the transfer from “bench to bedside” and the implementation into general patient care procedures.
CRIS-Team Scopus Importer:2021-07-30
Keywords: Advanced imaging technologies; Immune‐mediated inflammatory diseases (IMIDs); Single‐cell RNA sequencing; Spatial sequencing

The pro and anti-inflammatory activities of immunoglobulin G - Lux, Anja; Aschermann, Sarah; Biburger, Markus; Nimmerjahn, Falk (Annals of the Rheumatic Diseases, 2010)
Immunoglobulin G (IgG) molecules are a family of glycoproteins essential for defending the body against invading pathogens. The antibody constant domain is very potent in initiating proinflammatory pathways such as the activation of innate immune effector cells via cellular receptors specific for the antibody constant region (Fc receptors) and the activation of the complement pathway. During autoimmune disease the normally protective antimicrobial function of these molecules is targeted to healthy tissues often with disastrous consequences. Interestingly, one successful anti-inflammatory therapy for many autoimmune diseases is the infusion of high doses of IgG molecules, the so-called intravenous IgG therapy. How one class of molecules can have such opposing functions will be the major focus of this review.

THE PROGNOSIS OF HEART FAILURE IN PATIENTS WITH RHEUMATOID ARTHRITIS - Meissner, Y.; Schaefer, M.; Manger, Bernhard; Zaenker, M.; Ochs, W.; Listing, J.; Strangfeld, A. (2018)
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The Progression of Cell Death Affects the Rejection of Allogeneic Tumors in Immune-Competent Mice - Implications for Cancer Therapy - Chaurio Gonzalez, Ricardo Alfredo; Munoz, Luis E.; Maueröder, Christian; Janko, Christina; Harrer, Thomas; Fuernrohr, Barbara G.; Niederweis, Michael; Bilyy, Rostyslav; Schett, Georg; Herrmann, Martin; Berens, Christian (Frontiers in Immunology, 2014)
Large amounts of dead and dying cells are produced during cancer therapy and allograft rejection. Depending on the death pathway and stimuli involved, dying cells exhibit diverse features, resulting in defined physiological consequences for the host. It is not fully understood how dying and dead cells modulate the immune response of the host. To address this problem, different death stimuli were studied in B16F10 melanoma cells by regulated inducible transgene expression of the pro-apoptotic active forms of caspase-3 (revCasp-3), Bid (tBid), and the Mycobacterium tuberculosis-necrosis inducing toxin (CpnTCTD). The immune outcome elicited for each death stimulus was assessed by evaluating the allograft rejection of melanoma tumors implanted subcutaneously in BALB/c mice immunized with dying cells. Expression of all proteins efficiently killed cells in vitro (>90%) and displayed distinctive morphological and physiological features as assessed by multiparametric flow cytometry analysis. BALB/c mice immunized with allogeneic dying melanoma cells expressing revCasp-3 or CpnTCTD showed strong rejection of the allogeneic challenge. In contrast, mice immunized with cells dying either after expression of tBid or irradiation with UVB did not, suggesting an immunologically silent cell death. Surprisingly, immunogenic cell death induced by expression of revCasp-3 or CpnTCTD correlated with elevated intracellular reactive oxygen species (ROS) levels at the time point of immunization. Conversely, early mitochondrial dysfunction induced by tBid expression or UVB irradiation accounted for the absence of intracellular ROS accumulation at the time point of immunization. Although ROS inhibition in vitro was not sufficient to abrogate the immunogenicity in our allo-immunization model, we suggest that the point of ROS generation and its intracellular accumulation may be an important factor for its role as damage associated molecular pattern in the development of allogeneic responses.
EVALuna2:13056

Therapeutic benefit of apremilast on enthesitis and dactylitis in patients with psoriatic arthritis: a pooled analysis of the PALACE 1-3 studies - Gladman, Dafna D.; Kavanaugh, Arthur; Gómez-Reino, Juan J.; Wollenhaupt, Jürgen; Cutolo, Maurizio; Schett, Georg; Lespessailles, Eric; Guerette, Benoit; Delev, Nikolay; Teng, Lichen; Edwards, Christopher J.; Birbara, Charles A.; et al. (RMD Open, 2018)
Objective: The Psoriatic Arthritis Long-term Assessment of Clinical Efficacy (PALACE) clinical trial programme findings demonstrated that apremilast, an oral phosphodiesterase 4 inhibitor, is effective for treating psoriatic arthritis (PsA). Enthesitis and dactylitis are difficult-to-treat features of PsA leading to disability and affecting quality of life. PALACE 1, 2 and 3 data were pooled to assess the efficacy of apremilast on enthesitis and dactylitis outcomes in patients with these conditions at baseline. Methods: Patients with enthesitis (n=945) or dactylitis (n=633) at baseline were analysed after receiving double-blind treatment with placebo, apremilast 30 mg two times per day or apremilast 20 mg two times per day up to 52 weeks and continuing up to 5 years. Data were analysed through 156 weeks. Enthesitis was evaluated by Maastricht Ankylosing Spondylitis Enthesitis Score (MASES) and dactylitis via dactylitis count. Results: At week 24, patients receiving apremilast 30 mg two times per day demonstrated a significantly greater mean change in enthesitis (-1.3 vs -0.9; p<0.05) and dactylitis (-1.8 vs -1.3; p<0.01) vs placebo. Patients in the 30 mg dose group showed significantly greater mean (-23.6% vs -7.0%; p<0.05) and median (-50.0% vs -21.1%; p<0.05) per cent changes in MASES; mean and median per cent changes in dactylitis count were numerically, but not significantly, different for either apremilast dose in patients with dactylitis. In the patient population remaining on apremilast, observed mean and median improvements in both conditions were sustained through 156 weeks. Conclusion: Apremilast is effective for the treatment of active PsA, including improvements in enthesitis and dactylitis up to 3 years. Trial registration numbers: NCT01172938, NCT01212757 and NCT01212770.
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Therapeutic interception in individuals at risk of rheumatoid arthritis to prevent clinically impactful disease - Deane, Kevin D.; Michael Holers, V.; Emery, Paul; Mankia, Kulveer; El Gabalawy, Hani; Sparks, Jeffrey A.; Costenbader, Karen H.; Schett, Georg; van der Helm-Van Mil, Annette; van Schaardenburg, Dirkjan; Thomas, Ranjeny; Cope, Andrew P. (Annals of the Rheumatic Diseases, 2024)
Multiple clinical trials for rheumatoid arthritis (RA) prevention have been completed. Here, we set out to report on the lessons learnt from these studies. Researchers who conducted RA prevention trials shared the background, rationale, approach and outcomes and evaluated the lessons learnt to inform the next generation of RA prevention trials. Individuals at risk of RA can be identified through population screening, referrals to musculoskeletal programmes and by recognition of arthralgia suspicious for RA. Clinical trials in individuals at risk for future clinical RA have demonstrated that limited courses of corticosteroids, atorvastatin and hydroxychloroquine do not alter incidence rates of clinical RA; however, rituximab delays clinical RA onset, and methotrexate has transient effects in individuals who are anticitrullinated protein antibody-positive with subclinical joint inflammation identified by imaging. Abatacept delays clinical RA onset but does not fully prevent onset of RA after treatment cessation. Additionally, subclinical joint inflammation and symptoms appear responsive to interventions such as methotrexate and abatacept. To advance prevention, next steps include building networks of individuals at risk for RA, to improve risk stratification for future RA and to understand the biological mechanisms of RA development, including potential endotypes of disease, which can be targeted for prevention, thus adopting a more precision-based approach. Future trials should focus on interceptions aimed at preventing clinical RA onset and which treat existing symptoms and imaging-defined subclinical inflammation. These trials may include advanced designs (eg, adaptive) and should be combined with mechanistic studies to further define pathophysiological drivers of disease development.
CRIS-Team Scopus Importer:2024-09-27

Therapeutic molecular targets of SSc-ILD - Zhang, Yun; Distler, Jörg (Journal of Scleroderma and Related Disorders, 2020)
Systemic sclerosis is a fibrosing chronic connective tissue disease of unknown etiology. A major hallmark of systemic sclerosis is the uncontrolled and persistent activation of fibroblasts, which release excessive amounts of extracellular matrix, lead to organ dysfunction, and cause high mobility and motility of patients. Systemic sclerosis–associated interstitial lung disease is one of the most common fibrotic organ manifestations in systemic sclerosis and a major cause of death. Treatment options for systemic sclerosis–associated interstitial lung disease and other fibrotic manifestations, however, remain very limited. Thus, there is a huge medical need for effective therapies that target tissue fibrosis, vascular alterations, inflammation, and autoimmune disease in systemic sclerosis–associated interstitial lung disease. In this review, we discuss data suggesting therapeutic ways to target different genes in distinct tissues/organs that contribute to the development of SSc.
CRIS-Team Scopus Importer:2020-02-04
Keywords: molecular target; pulmonary fibrosis; Systemic sclerosis

Therapie der systemischen Sklerose-assoziierten interstitiellen Lungenerkrankung - Prasse, A.; Bonella, F.; Müller-Ladner, U.; Witte, T.; Hunzelmann, N.; Distler, Jörg (Zeitschrift für Rheumatologie, 2019)
Background: Systemic sclerosis (SSc) is a fibrosing autoimmune disease of the connective tissue. In addition to skin fibrosis, pulmonary involvement and interstitial lung disease (ILD) in particular are the most common and severe manifestations of SSc. The disease is associated with a substantial risk of morbidity and mortality, especially in progressive ILD. In the last 5 years new treatment concepts for SSc-ILD have been investigated in numerous clinical studies. Material and methods: This review is based on a literature search in PubMed, focusing on the most relevant papers published up to the end of 2018 with the keywords “SSc” and “treatment”. Results: The treatment of SSc-ILD has changed over the last few years due to the results of many clinical studies. The updated guidelines of the European League Against Rheumatism (EULAR) recommend the use of cyclophosphamide or hematopoietic stem cell transplantation. Data for a positive influence on SSc-ILD are also available for mycophenolate, tocilizumab and anabasum. Because of the pathophysiological similarities to idiopathic pulmonary fibrosis, the use of the antifibrotic agents nintedanib and pirfenidone is currently being investigated in randomized, multicenter clinical trials and could be a novel and promising therapeutic strategy. Conclusion: Current drug studies may provide innovative therapeutic perspectives for SSc-ILD and could significantly improve the prognosis of affected patients in the future.
CRIS-Team Scopus Importer:2019-12-03
Keywords: Connective tissue disease; Interstitial lung disease; Organ involvement; Systemic sclerosis; Therapy

There is a need for new systemic sclerosis subset criteria. A content analytic approach - Johnson, S.; Soowamber, M.; Fransen, J.; Khanna, D.; Van Den Hoogen, F.; Baron, M.; Matucci-Cerinic, M.; Denton, C.; Medsger, T.; Carreira, P.; Riemekasten, G.; Distler, Jörg; et al. (Scandinavian Journal of Rheumatology, 2017)
Systemic sclerosis (SSc) is heterogenous. The objectives of this study were to evaluate the purpose, strengths and limitations of existing SSc subset criteria, and identify ideas among experts about subsets.We conducted semi-structured interviews with randomly sampled international SSc experts. The interview transcripts underwent an iterative process with text deconstructed to single thought units until a saturated conceptual framework with coding was achieved and respondent occurrence tabulated. Serial cross-referential analyses of clusters were developed.Thirty experts from 13 countries were included; 67% were male, 63% were from Europe and 37% from North America; median experience of 22.5 years, with a median of 55 new SSc patients annually. Three thematic clusters regarding subsetting were identified: research and communication; management; and prognosis (prediction of internal organ involvement, survival). The strength of the limited/diffuse system was its ease of use, however 10% stated this system had marginal value. Shortcomings of the diffuse/limited classification were the risk of misclassification, predictions/generalizations did not always hold true, and that the elbow or knee threshold was arbitrary. Eighty-seven percent use more than 2 subsets including: SSc sine scleroderma, overlap conditions, antibody-determined subsets, speed of progression, and age of onset (juvenile, elderly).We have synthesized an international view of the construct of SSc subsets in the modern era. We found a number of factors underlying the construct of SSc subsets. Considerations for the next phase include rate of change and hierarchal clustering (e.g. limited/diffuse, then by antibodies).
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The revised Bristol Rheumatoid Arthritis Fatigue measures and the Rheumatoid Arthritis Impact of Disease scale: validation in six countries - Hewlett, Sarah; Kirwan, John; Bode, Christina; Cramp, Fiona; Carmona, Loreto; Dures, Emma; Englbrecht, Matthias; Fransen, Jaap; Greenwood, Rosemary; Hagel, Sofia; Van De Laar, Maart; Molto, Anna; et al. (Rheumatology, 2017)
To evaluate the Bristol Rheumatoid Arthritis Fatigue Multidimensional Questionnaire (BRAF-MDQ), the revised Bristol Rheumatoid Arthritis Numerical Rating Scales (BRAF-NRS V2) and the Rheumatoid Arthritis Impact of Disease (RAID) scale in six countries.We surveyed RA patients in France, Germany, The Netherlands, Spain, Sweden and the UK, including the HAQ, 36-item Short Form Health Survey (SF-36) and potential revisions of the BRAF-NRS coping and Spanish RAID coping items. Factor structure and internal consistency were examined by factor analysis and Cronbach's ? and construct validity by Spearman's correlation.A total of 1276 patients participated (76% female, 25% with a disease duration <5 years, median HAQ 1.0). The original BRAF-MDQ four-factor structure and RAID single-factor structure were confirmed in every country with ?66% of variation in items explained by each factor and all item factor loadings of 0.71-0.98. Internal consistency for the BRAF-MDQ total and subscales was a Cronbach's ? of 0.75-0.96 and for RAID, 0.93-0.96. Fatigue construct validity was shown for the BRAF-MDQ and BRAF-NRS severity and effect scales, correlated internally with SF-36 vitality and with RAID fatigue (r = 0.63-0.93). Broader construct validity for the BRAFs and RAID was shown by correlation with each other, HAQ and SF-36 domains (r = 0.46-0.82), with similar patterns in individual countries. The revised BRAF-NRS V2 Coping item had stronger validity than the original in all analyses. The revised Spanish RAID coping item performed as well as the original.Across six European countries, the BRAF-MDQ identifies the same four aspects of fatigue, and along with the RAID, shows strong factor structure and internal consistency and moderate-good construct validity. The revised BRAF-NRS V2 shows improved construct validity and replaces the original.
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The role of ACPAs in at-risk individuals: Early targeting of the bone and joints - Schett, Georg (Best Practice & Research in Clinical Rheumatology, 2017)
Autoimmunity precedes inflammation in patients with rheumatoid arthritis (RA), opening the possibility to search for early changes in the tissue preceding the onset of systemic inflammation. Autoantibodies are important and early drivers of bone damage in RA. This article summarizes current evidence for the role of RA-related autoantibodies in mediating bone loss. Rheumatoid factor (RF) and antibodies recognizing modified (citrullinated) proteins have been used as diagnostic markers for RA over many years. Their role as pathogenic players, however, has long been unrecognized. Recently, several pieces of evidence suggested that bone-resorbing osteoclasts are highly responsive to RA-related autoantibodies, providing a novel association between autoimmunity and bone. These developments have allowed the unraveling of the underlying mechanisms, which are responsible for the well-known clinical observation that anti-citrullinated protein antibodies and RF are associated with a more severe disease course. Furthermore, these mechanisms also explain the onset of inflammation in the joints of RA patients.
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The role of antifibrotics in the treatment of rheumatoid arthritis associated interstitial lung disease - Liang, Minrui; Matteson, Eric L.; Abril, Andy; Distler, Jörg (Therapeutic Advances in Musculoskeletal Disease, 2022)
The major pulmonary complication of rheumatoid arthritis (RA) is interstitial lung disease (ILD), which causes significant morbidity and mortality and influences the natural course of disease. Recent advances in the management of arthritis have improved patient outcomes. However, exceptionally high medical needs still remain for effective therapies for the patients with ILD in RA. Better understanding of the shared and distinct pathophysiology of fibrotic diseases led to the development of novel antifibrotic agents such as nintedanib and pirfenidone. The further stratification analysis of the phase III INBUILD trial demonstrated beneficial effects of nintedanib in RA-ILD with a progressive phenotype by reducing the rate of decline in forced vital capacity (FVC) over 52weeks by 60%. Pirfenidone is another antifibrotic agent currently under phase II clinical study (TRAIL1) aiming to evaluate its effects for RA-ILD. This review provides an overview of state-of-the-art pathogenesis and the current therapeutic options for RA-ILD, with a focus on antifibrotic strategies.
CRIS-Team WoS Importer:2022-03-18
Keywords: antifibrotics; fibrosis; interstitial lung disease (ILD); nintedanib; pirfenidone; rheumatoid arthritis (RA); treatment

The role of Butyrophilin 2a2 (Btn2a2) in T cell maturation - Frech, Michael; Uchil, P.; Azizov, Vugar; Schober, K.; Irla, M.; Sarter, Kerstin; Zaiss, Mario (EUROPEAN JOURNAL OF IMMUNOLOGY, 2022)
CRIS-Team WoS Importer:2023-01-27

The Role of Dietary Fiber in Rheumatoid Arthritis Patients: A Feasibility Study - Häger, Julian; Bang, Holger; Hagen, Melanie; Frech, Michael; Träger, Pascal; Sokolova, Maria V.; Steffen, Ulrike; Tascilar, Koray; Sarter, Kerstin; Schett, Georg; Rech, Jürgen; Zaiss, Mario (Nutrients, 2019)
Short-chain fatty acids are microbial metabolites that have been shown to be key regulators of the gut-joint axis in animal models. In humans, microbial dysbiosis was observed in rheumatoid arthritis (RA) patients as well as in those at-risk to develop RA, and is thought to be an environmental trigger for the development of clinical disease. At the same time, diet has a proven impact on maintaining intestinal microbial homeostasis. Given this association, we performed a feasibility study in RA patients using high-fiber dietary supplementation with the objective to restore microbial homeostasis and promote the secretion of beneficial immunomodulatory microbial metabolites. RA patients (n = 36) under routine care received daily high-fiber bars or cereals for 28 days. Clinical assessments and laboratory analysis of immune parameters in blood and stool samples from RA patients were done before and after the high-fiber dietary supplementation. We observed an increase in circulating regulatory T cell numbers, favorable Th1/Th17 ratios, as well as decreased markers of bone erosion in RA patients after 28 days of dietary intervention. Furthermore, patient-related outcomes of RA improved. Based on these results, we conclude that controlled clinical studies of high-fiber dietary interventions could be a viable approach to supplement or complement current pharmacological treatment strategies.
CRIS-Team Scopus Importer:2019-10-18
Keywords: gut–joint axis; high-fiber diet (HFD); microbiota; rheumatoid arthritis (RA); short chain fatty acids (SCFA)

The Role of Epigenetic Modifications in Systemic Sclerosis: A Druggable Target - Henderson, John; Distler, Jörg; O'Reilly, Steven (Trends in Molecular Medicine, 2019)
Systemic sclerosis (SSc) is a rare autoimmune disorder characterised by skin fibrosis that often also affects internal organs, eventually resulting in mortality. Although managementof thesymptomshas extendedlifespan, patients stillsuffer from poor quality of life, hence the need for improved therapies. Development of efficacious treatments has been stymied by the unknown aetiology, although recent advancements suggest a potentially key role for epigenetics-the regulation of geneexpression by noncoding RNAs and chemical modifications to DNA or DNA-associated proteins. Herein, the evidence implicating epigenetics in the pathogenesis of SSc is discussed with an emphasis on the therapeutic potential this introduces to the field-particularly the repurposing of epigenetic targeting cancer therapeutics and newly emerging miRNA-based strategies.
CRIS-Team WoS Importer:2019-05-09

The role of IL-23 in joint disease - Schett, Georg (Rheumatology, 2021)
CRIS-Team WoS Importer:2022-02-11

The role of joint-draining lymph node stromal cells in inflammatory arthritis - Schälter, Fabian; Azizov, Vugar; Frech, Michael; Dürholz, Kerstin; Sokolova, Maria; Hendel, Anna; Focke, Kristin; Sarter-Zaiss, Kerstin; Van Baarsen, L. G. M.; Krautwald, S.; Schett, Georg; Zaiss, Mario (EUROPEAN JOURNAL OF IMMUNOLOGY, 2022)
CRIS-Team WoS Importer:2023-01-27

THE ROLE OF THE IL-23/TH17 AXIS AS MODULATOR OF B CELL-MEDIATED (AUTO)IMMUNE RESPONSES - Pfeifle, René; Kittler, Julia; Rothe, Tobias; Schett, Georg; Krönke, Gerhard (2019)
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The rubric “Pioneers of rheumatology” becomes “Milestones of rheumatology” Die Rubrik „Wegbereiter der Rheumatologie“ wird zu „Meilensteine der Rheumatologie“ - Mueller-Ladner, Ulf; Manger, Bernhard (Zeitschrift für Rheumatologie, 2022)
CRIS-Team Scopus Importer:2022-03-18

THE SEROTONIN RECEPTOR 2 INHIBITOR TERGURIDE HAS BENEFICIAL EFFECTS ON SKIN FIBROSIS: RESULTS FROM A PHASE 2 PROOF OF CONCEPT STUDY - Distler, O.; Maurer, B.; Vettori, S.; Blumhardt, S.; Frey, D.; Distler, A.; Beyer, Christian; Distler, Jörg (2016)
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The soluble CD83 protein prevents bone destruction by inhibiting the formation of osteoclasts and inducing resolution of inflammation in arthritis - Royzman, Dmytro; Andreev, Darja; Stich, Lena; Peckert, Katrin; Wild, Andreas; Zinser, Elisabeth; Mühl-Zürbes, Petra; Jones, Evan; Adam, Susanne; Frey, Silke; Fuchs, Maximilian; Kunz, Meik; et al. (Frontiers in Immunology, 2022)
Here we show that soluble CD83 induces the resolution of inflammation in an antigen-induced arthritis (AIA) model. Joint swelling and the arthritis-related expression levels of IL-1 beta, IL-6, RANKL, MMP9, and OC-Stamp were strongly reduced, while Foxp3 was induced. In addition, we observed a significant inhibition of TRAP(+) osteoclast formation, correlating with the reduced arthritic disease score. In contrast, cell-specific deletion of CD83 in human and murine precursor cells resulted in an enhanced formation of mature osteoclasts. RNA sequencing analyses, comparing sCD83- with mock treated cells, revealed a strong downregulation of osteoclastogenic factors, such as Oc-Stamp, Mmp9 and Nfatc1, Ctsk, and Trap. Concomitantly, transcripts typical for pro-resolving macrophages, e.g., Mrc1/2, Marco, Klf4, and Mertk, were upregulated. Interestingly, members of the metallothionein (MT) family, which have been associated with a reduced arthritic disease severity, were also highly induced by sCD83 in samples derived from RA patients. Finally, we elucidated the sCD83-induced signaling cascade downstream to its binding to the Toll-like receptor 4/(TLR4/MD2) receptor complex using CRISPR/Cas9-induced knockdowns of TLR4/MyD88/TRIF and MTs, revealing that sCD83 acts via the TRIF-signaling cascade. In conclusion, sCD83 represents a promising therapeutic approach to induce the resolution of inflammation and to prevent bone erosion in autoimmune arthritis.
CRIS-Team WoS Importer:2022-09-09

The structural basis of MRI bone erosions: An assessment by microCT - Albrecht, Andreas; Finzel, Stephanie; Englbrecht, Matthias; Rech, Jürgen; Hueber, Axel; Schlechtweg, Philipp; Uder, Michael; Schett, Georg (Annals of the Rheumatic Diseases, 2013)
Objective To determine whether erosions appearing in MRI in patients with rheumatoid arthritis (RA) represent true erosions. Methods 50 RA patients received 1.5 T MRI and microCT (μCT) of the dominant hand. Erosion counts were assessed in coronal T1 weighted MRI sections and in coronal as well as axial μCT sections of the metacarpophalangeal (MCP) joints II-IV. Extent of erosions was assessed by RA MRI Score (RAMRIS) erosion score (MRI) and by three-dimensional assessment of erosion volume (μCT). Results 111 of the 600 evaluated joint regions showed erosions in the MRI and 137 in the μCT. In only 28 regions false negative lesions (μCT positive, MRI negative) were found, all of which were very small lesions with a volume of less than 10 mm3. Only two results were false-positive (μCT negative, MRI positive). RAMRIS erosion scores were strongly correlated to erosion volumes in the μCT (Pearson's r=0.514, p<0.001). Mean RAMRIS erosion scores were below 1 with erosion volumes up to 1.5 mm3, below 2 with erosion volumes up to 20 mm3 and over 2 with volumes of more than 20 mm3. Discussion MRI erosions are generally based on true cortical breaks as shown by μCT. MRI is sensitive to detect bone erosions and only very small lesions escape detection. Moreover, RAMRIS erosion scores are closely linked to the absolute size of bone erosions in the μCT.
CRIS-Team Scopus Importer:2021-02-03

The TGF-?-inducible miR-23a cluster attenuates IFN-? levels and antigen-specific cytotoxicity in human CD8? T cells - Chandran, P. Anoop; Keller, Andreas; Weinmann, Lasse; Seida, Ahmed Adel; Braun, Matthias; Andreev, Katerina; Fischer, Birgitt; Horn, Evi; Schwinn, Stefanie; Junker, Markus; Houben, Roland; Dombrowski, Yvonne; et al. (Journal of Leukocyte Biology, 2014)
Cytokine secretion and degranulation represent key components of CD8(+) T-cell cytotoxicity. While transcriptional blockade of IFN-? and inhibition of degranulation by TGF-? are well established, we wondered whether TGF-? could also induce immune-regulatory miRNAs in human CD8(+) T cells. We used miRNA microarrays and high-throughput sequencing in combination with qRT-PCR and found that TGF-? promotes expression of the miR-23a cluster in human CD8(+) T cells. Likewise, TGF-? up-regulated expression of the cluster in CD8(+) T cells from wild-type mice, but not in cells from mice with tissue-specific expression of a dominant-negative TGF-? type II receptor. Reporter gene assays including site mutations confirmed that miR-23a specifically targets the 3'UTR of CD107a/LAMP1 mRNA, whereas the further miRNAs expressed in this cluster-namely, miR-27a and -24-target the 3'UTR of IFN-? mRNA. Upon modulation of the miR-23a cluster by the respective miRNA antagomirs and mimics, we observed significant changes in IFN-? expression, but only slight effects on CD107a/LAMP1 expression. Still, overexpression of the cluster attenuated the cytotoxic activity of antigen-specific CD8(+) T cells. These functional data thus reveal that the miR-23a cluster not only is induced by TGF-?, but also exerts a suppressive effect on CD8(+) T-cell effector functions, even in the absence of TGF-? signaling.
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