Georg Schett

Universitätsklinikum Erlangen, Erlangen, Bavaria, Germany

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Publications (614)4157.26 Total impact

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    ABSTRACT: To investigate the prevalence of knee US findings of inflammation and structural damage in aged individuals (≥60 years) of a long-term population-based cohort and to correlate these findings with demographic, clinical and laboratory parameters. Cross-sectional clinical and US investigation of both knee joints during the 2010 follow-up of the prospective population-based Bruneck Study. Demographic variables, physical activity, comorbidities, medications, pain, and functional scales related to the knee joints were recorded. US-assessed parameters were synovial hypertrophy, power Doppler signal, joint effusion, cartilage abnormalities, osteophytes, enthesopathy and bursitis. Statistics included univariate and multivariate regression analysis. A total of 488 subjects (mean age 72.5 years; 53.5% females, 46.5% males) were examined by clinical assessment, and 433 of these underwent US examination of both knees. Both inflammatory and structural abnormalities were found in 296 (68.8%) subjects. Inflammatory abnormalities were significantly associated with age in years, male gender, diabetes and the presence of knee joint symptoms. In the multivariate analysis, age, male gender and knee swelling emerged as independent predictors of inflammation [odds ratio (OR) (95% CI) = 1.06 (1.03, 1.09), 2.55 (1.55, 4.21) and 5.92 (1.99, 17.58), respectively]. The present study showed a high prevalence of US inflammatory abnormalities in the knee joints of a normal aged population. These data suggest a substantial contribution of inflammation in progressive impairment of joint function with age. © The Author 2015. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oup.com.
    Rheumatology (Oxford, England) 04/2015; DOI:10.1093/rheumatology/kev032 · 4.44 Impact Factor
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    ABSTRACT: Nintedanib is a tyrosine kinase inhibitor that has recently been shown to slow disease progression in idiopathic pulmonary fibrosis in two replicate phase III clinical trials. The aim of this study was to analyse the antifibrotic effects of nintedanib in preclinical models of systemic sclerosis (SSc) and to provide a scientific background for clinical trials in SSc. The effects of nintedanib on migration, proliferation, myofibroblast differentiation and release of extracellular matrix of dermal fibroblasts were analysed by microtitre tetrazolium and scratch assays, stress fibre staining, qPCR and SirCol assays. The antifibrotic effects of nintedanib were evaluated in bleomycin-induced skin fibrosis, in a murine sclerodermatous chronic graft-versus-host disease model and in tight-skin-1 mice. Nintedanib dose-dependently reduced platelet-derived growth factor-induced and transforming growth factor-β-induced proliferation and migration as well as myofibroblast differentiation and collagen release of dermal fibroblasts from patients with and healthy individuals. Nintedanib also inhibited the endogenous activation of SSc fibroblasts. Nintedanib prevented bleomycin-induced skin fibrosis in a dose-dependent manner and was also effective in the treatment of established fibrosis. Moreover, treatment with nintedanib ameliorated fibrosis in the chronic graft-versus-host disease model and in tight-skin-1 mice in well-tolerated doses. We demonstrate that nintedanib effectively inhibits the endogenous as well as cytokine-induced activation of SSc fibroblasts and exerts potent antifibrotic effects in different complementary mouse models of SSc. These data have direct translational implications for clinical trials with nintedanib in SSc. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.
    Annals of the rheumatic diseases 04/2015; DOI:10.1136/annrheumdis-2014-207109 · 9.27 Impact Factor
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    ABSTRACT: DCs are able to undergo rapid maturation, which subsequently allows them to initiate and orchestrate T cell-driven immune responses. DC maturation must be tightly controlled in order to avoid random T cell activation and development of autoimmunity. Here, we determined that 12/15-lipoxygenase-meditated (12/15-LO-mediated) enzymatic lipid oxidation regulates DC activation and fine-tunes consecutive T cell responses. Specifically, 12/15-LO activity determined the DC activation threshold via generation of phospholipid oxidation products that induced an antioxidative response dependent on the transcription factor NRF2. Deletion of the 12/15-LO-encoding gene or pharmacologic inhibition of 12/15-LO in murine or human DCs accelerated maturation and shifted the cytokine profile, thereby favoring the differentiation of Th17 cells. Exposure of 12/15-LO-deficient DCs to 12/15-LO-derived oxidized phospholipids attenuated both DC activation and the development of Th17 cells. Analysis of lymphatic tissues from 12/15-LO-deficient mice confirmed enhanced maturation of DCs as well as an increased differentiation of Th17 cells. Moreover, experimental autoimmune encephalomyelitis in mice lacking 12/15-LO resulted in an exacerbated Th17-driven autoimmune disease. Together, our data reveal that 12/15-LO controls maturation of DCs and implicate enzymatic lipid oxidation in shaping the adaptive immune response.
    The Journal of clinical investigation 04/2015; DOI:10.1172/JCI78490 · 13.77 Impact Factor
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    ABSTRACT: A taskforce comprised of an expert group of 21 rheumatologists, radiologists and methodologists from 11 countries developed evidence-based recommendations on the use of imaging in the clinical management of both axial and peripheral spondyloarthritis (SpA). Twelve key questions on the role of imaging in SpA were generated using a process of discussion and consensus. Imaging modalities included conventional radiography, ultrasound, magnetic resonance imaging, computed tomography (CT), positron emission tomography, single photon emission CT, dual-emission x-ray absorptiometry and scintigraphy. Experts applied research evidence obtained from systematic literature reviews using MEDLINE and EMBASE to develop a set of 10 recommendations. The strength of recommendations (SOR) was assessed by taskforce members using a visual analogue scale. A total of 7550 references were identified in the search process, from which 158 studies were included in the systematic review. Ten recommendations were produced using research-based evidence and expert opinion encompassing the role of imaging in making a diagnosis of axial SpA or peripheral SpA, monitoring inflammation and damage, predicting outcome, response to treatment, and detecting spinal fractures and osteoporosis. The SOR for each recommendation was generally very high (range 8.9-9.5). These are the first recommendations which encompass the entire spectrum of SpA and evaluate the full role of all commonly used imaging modalities. We aimed to produce recommendations that are practical and valuable in daily practice for rheumatologists, radiologists and general practitioners. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.
    Annals of the rheumatic diseases 04/2015; DOI:10.1136/annrheumdis-2014-206971 · 9.27 Impact Factor
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    ABSTRACT: A taskforce comprised of an expert group of 21 rheumatologists, radiologists and methodologists from 11 countries developed evidence-based recommendations on the use of imaging in the clinical management of both axial and peripheral spondyloarthritis (SpA). Twelve key questions on the role of imaging in SpA were generated using a process of discussion and consensus. Imaging modalities included conventional radiography, ultrasound, magnetic resonance imaging, computed tomography (CT), positron emission tomography, single photon emission CT, dual-emission x-ray absorptiometry and scintigraphy. Experts applied research evidence obtained from systematic literature reviews using MEDLINE and EMBASE to develop a set of 10 recommendations. The strength of recommendations (SOR) was assessed by taskforce members using a visual analogue scale. A total of 7550 references were identified in the search process, from which 158 studies were included in the systematic review. Ten recommendations were produced using research-based evidence and expert opinion encompassing the role of imaging in making a diagnosis of axial SpA or peripheral SpA, monitoring inflammation and damage, predicting outcome, response to treatment, and detecting spinal fractures and osteoporosis. The SOR for each recommendation was generally very high (range 8.9-9.5). These are the first recommendations which encompass the entire spectrum of SpA and evaluate the full role of all commonly used imaging modalities. We aimed to produce recommendations that are practical and valuable in daily practice for rheumatologists, radiologists and general practitioners.
    Annals of the Rheumatic Diseases 04/2015; · 9.27 Impact Factor
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    ABSTRACT: To investigate whether MRI allows the detection of osteosclerosis as a sign of repair of bone erosions compared with high-resolution peripheral quantitative computed tomography (HR-pQCT) as a reference and whether the presence of osteosclerosis on HR-pQCT is linked to synovitis and osteitis on MRI. A total of 103 RA patients underwent HR-pQCT and MRI of the dominant hand. The presence and size of erosions and the presence and extent (grades 0-2) of osteosclerosis were assessed by both imaging modalities, focusing on MCP 2 and 3 and wrist joints. By MRI, the presence and grading of osteitis and synovitis were assessed according to the Rheumatoid Arthritis MRI Score (RAMRIS). Parallel evaluation was feasible by both modalities on 126 bone erosions. Signs of osteosclerosis were found on 87 erosions by HR-pQCT and on 22 by MRI. False-positive results (MRI(+)CT(-)) accounted for 3%, while false-negative results (MRI(-)CT(+)) accounted for 76%. MRI sensitivity for the detection of osteosclerosis was 24% and specificity was 97%. The semi-quantitative scoring of osteosclerosis was reliable between MRI and HR-pQCT [intraclass correlation coefficient 0.917 (95% CI 0.884, 0.941), P < 0.001]. The presence of osteosclerosis on HR-pQCT showed a trend towards an inverse relationship to the occurrence and extent of osteitis on MRI [χ(2)(1) = 3.285; ϕ coefficient = -0.124; P = 0.070] but not to synovitis [χ(2)(1) = 0.039; ϕ coefficient = -0.14; P = 0.844]. MRI can only rarely detect osteosclerosis associated with bone erosions in RA. Indeed, the sensitivity compared with HR-pQCT is limited, while the specificity is high. The presence of osteitis makes osteosclerosis more unlikely, whereas the presence of synovitis is not related to osteosclerosis. © The Author 2015. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oup.com.
    Rheumatology (Oxford, England) 03/2015; DOI:10.1093/rheumatology/kev031 · 4.44 Impact Factor
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    ABSTRACT: Immunglobulin G (IgG) sialylation represents a key checkpoint that determines the engagement of pro- or anti-inflammatory Fcγ receptors (FcγR) and the direction of the immune response. Whether IgG sialylation influences osteoclast differentiation and subsequently bone architecture has not been determined yet, but may represent an important link between immune activation and bone loss. Here we demonstrate that desialylated, but not sialylated, immune complexes enhance osteoclastogenesis in vitro and in vivo. Furthermore, we find that the Fc sialylation state of random IgG and specific IgG autoantibodies determines bone architecture in patients with rheumatoid arthritis. In accordance with these findings, mice treated with the sialic acid precursor N-acetylmannosamine (ManNAc), which results in increased IgG sialylation, are less susceptible to inflammatory bone loss. Taken together, our findings provide a novel mechanism by which immune responses influence the human skeleton and an innovative treatment approach to inhibit immune-mediated bone loss.
    Nature Communications 03/2015; 6:6651. DOI:10.1038/ncomms7651 · 10.74 Impact Factor
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    ABSTRACT: Stimulators of the soluble guanylate cyclase (sGC) have recently been shown to inhibit transforming growth factor-β signalling. Here, we aimed to demonstrate that riociguat, the drug candidate for clinical trials in systemic sclerosis (SSc), is effective in experimental fibrosis and to compare its efficacy to that of phosphodiesterase V inhibitors that also increase the intracellular levels of cyclic guanosine monophosphate. The antifibrotic effects of riociguat and sildenafil were compared in the tight-skin 1 model, in bleomycin-induced fibrosis and in a model of sclerodermatous chronic graft-versus-host-disease (cGvHD). Doses of 0.1-3 mg/kg twice a day for riociguat and of 3-10 mg/kg twice a day for sildenafil were used. Riociguat dose-dependently reduced skin thickening, myofibroblast differentiation and accumulation of collagen with potent antifibrotic effects at 1 and 3 mg/kg. Riociguat also ameliorated fibrosis of the gastrointestinal tract in the cGvHD model. The antifibrotic effects were associated with reduced phosphorylation of extracellular signal-regulated kinases. Sildenafil at doses of 3 and 10 mg/kg exerted mild antifibrotic effects that were significantly less pronounced compared with 1 and 3 mg/kg riociguat. These data demonstrated potent antifibrotic effects of riociguat on experimental skin and organ fibrosis. These findings suggest a role for riociguat for the treatment of fibrotic diseases, especially for the treatment of SSc. A phase II study with riociguat in patients with SSc is currently starting. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.
    Annals of the rheumatic diseases 03/2015; DOI:10.1136/annrheumdis-2014-206809 · 9.27 Impact Factor
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    ABSTRACT: Fc-gamma receptors (FcγRs) have been shown to play a crucial role in cartilage degradation during experimental arthritis. Although most of their effect on cartilage degradation has been attributed to their potential to promote inflammation in the presence of immunoglobulins, activating FcγRs promote cartilage degeneration in antigen-induced arthritis (AIA) independently of the level of inflammation. This prompted us to investigate, whether FcγRs may also play a role in osteoarthritis-related cartilage degradation. FcγR expression was measured by RT-PCR and FACS in murine cartilage tissue and chondrocytes. Experimental osteoarthritis was induced by destabilisation of the medial meniscus (DMM) in WT mice and animals lacking either activating (Fc receptor γ-chain-deficient) or inhibitory (FcγRIIB-deficient) FcγRs. Cartilage damage was investigated histologically 8 weeks post-surgery by assessing proteoglycan loss and structural damage according to OARSI recommendations. Osteophyte size was measured to investigate alterations in bone turnover. Expression analyses revealed significant levels for all four types of murine FcγRs in mouse chondrocytes and cartilage tissue from newborn and 8-week-old mice. Surprisingly, yet, ablation of either activating or inhibitory FcγRs did not affect cartilage damage or bone turnover during DMM-induced osteoarthritis in mice. While FcγRs appear to have a crucial role in cartilage degradation during inflammatory arthritis our data indicate that FcγRs do not influence cartilage destruction in experimental osteoarthritis. This indicates that a certain threshold of inflammation is a prerequisite for FcγR-induced cartilage destruction in arthritis. Copyright © 2015 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.
    Osteoarthritis and Cartilage 03/2015; DOI:10.1016/j.joca.2015.02.019 · 4.66 Impact Factor
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    ABSTRACT: Psoriatic arthritis (PsA) is a chronic inflammatory disease characterized by periarticular bone loss and new bone formation. Current data regarding systemic bone loss and bone mineral density (BMD) in PsA are conflicting. The aim of this study was to evaluate bone microstructure and volumetric BMD in patients with PsA and psoriasis. We performed HR-pQCT scans at the ultradistal and periarticular radius in 50 PsA patients, 30 psoriasis patients and 70 healthy, age- and sex-related controls assessing trabecular bone volume (BV/TV), trabecular number (Tb.N), inhomogeneity of the trabecular network, cortical thickness (Ct.Th) and cortical porosity (Ct.Po) as well as volumetric BMD. Trabecular BMD (Tb.BMD, p = 0.021, 12.0%), BV/TV (p = 0.020, -11.9%) and Tb.N (p = 0.035, 7.1%) were significantly decreased at the ultradistal radius and the periarticular radius in PsA patients compared to controls. In contrast, bone architecture of the ultradistal radius and periarticular radius was similar in patients with psoriasis and healthy controls. Duration of skin disease was associated with low BV/TV and Tb.N in patients with PsA. These data suggest that trabecular BMD and bone microstructure are decreased in PsA patients. The observation that duration of skin disease determines bone loss in PsA supports the concept of subclinical musculoskeletal disease in psoriasis patients. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
    Journal of bone and mineral research: the official journal of the American Society for Bone and Mineral Research 03/2015; DOI:10.1002/jbmr.2521 · 6.59 Impact Factor
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    ABSTRACT: To investigate whether bortezomib, a proteasome inhibitor approved for treatment of multiple myeloma, induces clinically relevant plasma cell (PC) depletion in patients with active, refractory systemic lupus erythematosus (SLE). Twelve patients received a median of two (range 1-4) 21-day cycles of intravenous bortezomib (1.3 mg/m(2)) with the coadministration of dexamethasone (20 mg) for active SLE. Disease activity was assessed using the SLEDAI-2K score. Serum concentrations of anti-double-stranded DNA (anti-dsDNA) and vaccine-induced protective antibodies were monitored. Flow cytometry was performed to analyse peripheral blood B-cells, PCs and Siglec-1 expression on monocytes as surrogate marker for type-I interferon (IFN) activity. Upon proteasome inhibition, disease activity significantly declined and remained stable for 6 months on maintenance therapies. Nineteen treatment-emergent adverse events occurred and, although mostly mild to moderate, resulted in treatment discontinuation in seven patients. Serum antibody levels significantly declined, with greater reductions in anti-dsDNA (∼60%) than vaccine-induced protective antibody titres (∼30%). Bortezomib significantly reduced the numbers of peripheral blood and bone marrow PCs (∼50%), but their numbers increased between cycles. Siglec-1 expression on monocytes significantly declined. These findings identify proteasome inhibitors as a putative therapeutic option for patients with refractory SLE by targeting PCs and type-I IFN activity, but our results must be confirmed in controlled trials. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.
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    ABSTRACT: To prospectively analyse the risk for disease relapses in patients with rheumatoid arthritis (RA) in sustained remission, either continuing, tapering or stopping disease-modifying antirheumatic drugs (DMARDs) in a prospective randomised controlled trial. Reduction of Therapy in patients with Rheumatoid arthritis in Ongoing remission is a multicentre, randomised controlled, parallel-group phase 3 trial evaluating the effects of tapering and stopping all conventional and/or biological DMARDs in patients with RA in stable remission. Patients (disease activity score 28 (DAS28)<2.6 for least 6 months) were randomised into three arms, either continuing DMARDs (arm 1), tapering DMARDs by 50% (arm 2) or stopping DMARDs after 6 months tapering (arm 3). The primary endpoint was sustained remission during 12 months. In this interim analysis, the first 101 patients who completed the study were analysed. At baseline, all patients fulfilled DAS28 remission and 70% also American College of Rheumatology- European League Against Rheumatism Boolean remission. 82.2% of the patients received methotrexate, 40.6% biological DMARDs and 9.9% other DMARDs. Overall, 67 patients (66.3%) remained in remission for 12 months, whereas 34 patients (33.7%) relapsed. The incidence of relapses was related to study arms (p=0.007; arm 1: 15.8%; arm 2: 38.9%; arm 3: 51.9%). Multivariate logistic regression identified anticitrullinated protein antibodies (ACPA) positivity (p=0.038) and treatment reduction (in comparison to continuation) as predictors for relapse (arm 2: p=0.012; arm 3: p=0.003). This randomised controlled study testing three different treatment strategies in patients with RA in sustained remission demonstrated that more than half of the patients maintain in remission after tapering or stopping conventional and biological DMARD treatment. Relapses occurred particularly in the first 6 months after treatment reduction and were associated with the presence of ACPA. 2009-015740-42. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.
    Annals of the Rheumatic Diseases 02/2015; DOI:10.1136/annrheumdis-2014-206439 · 9.27 Impact Factor
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    ABSTRACT: Tribbles homologue 3 (TRB3) is a pseudokinase that modifies the activation of various intracellular signalling pathways to control fundamental processes extending from mitosis and cell activation to apoptosis and modulation of gene expression. Here, we aimed to analyse the role of TRB3 in fibroblast activation in systemic sclerosis (SSc). The expression of TRB3 was quantified by quantitative PCR, western blot and immunohistochemistry. The role of TRB3 was analysed in cultured fibroblasts and in experimental fibrosis using small interfering RNA (siRNA)-mediated knockdown and overexpression of TRB3. TRB3 expression was increased in fibroblasts of patients with SSc and in murine models of SSc in a transforming growth factor-β (TGF-β)/Smad-dependent manner. Overexpression of TRB3 stimulated canonical TGF-β signalling and induced an activated phenotype in resting fibroblasts. In contrast, knockdown of TRB3 reduced the profibrotic effects of TGF-β and decreased the collagen synthesis. Moreover, siRNA-mediated knockdown of TRB3 exerted potent antifibrotic effects and ameliorated bleomycin as well as constitutively active TGF-β receptor I-induced fibrosis with reduced dermal thickening, decreased hydroxyproline content and impaired myofibroblast differentiation. The present study characterises TRB3 as a novel profibrotic mediator in SSc. TGF-β induces TRB3, which in turn activates canonical TGF-β/Smad signalling and stimulates the release of collagen, thereby inducing a positive feedback loop that may contribute to aberrant TGF-β signalling in SSc. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.
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    ABSTRACT: To test medication adherence using the Compliance-Questionnaire-Rheumatology (CQR). Invitation letter and CQR were sent to 240 patients with rheumatoid arthritis. Followup CQR was sent 3 months later. Adherence was evaluated using CQR 80% cutoff scores. Seventy-eight patients who were being treated with disease-modifying antirheumatic drugs provided full information on the CQR at both points in time. Eleven patients (14.1%) were classified as adherent based on taking compliance (TC), with only 3 patients (3.8%) adherent in regard to correct dosing (CD) [followup: 13 (16.7%) and 3 (3.8%) for TC and CD, respectively]. Nonadherence was not related to disease activity or side effects. We demonstrated low adherence, suggesting differences between doctors' records and patients' practice of antirheumatic drug therapy.
    The Journal of Rheumatology 01/2015; DOI:10.3899/jrheum.140982 · 3.17 Impact Factor
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    ABSTRACT: To evaluate the efficacy and safety of apremilast, an oral phosphodiesterase 4 inhibitor, over 52 weeks in patients with active psoriatic arthritis (PsA) despite prior treatment. Patients were randomized to placebo (n = 168), apremilast 20 mg BID (n = 168), or apremilast 30 mg BID (n = 168). Patients whose swollen and tender joint counts had not improved by ≥ 20% at Week 16 were considered nonresponders and were required to be re-randomized (1:1) to apremilast 20 mg BID or 30 mg BID if they were initially randomized to placebo, or continued their initial treatment of apremilast dose. At Week 24, all remaining patients treated with placebo were re-randomized to apremilast 20 mg BID or 30 mg BID. An American College of Rheumatology 20 (ACR20) response at Week 16 was attained by significantly more patients receiving apremilast 20 mg BID (30.4%, p = 0.0166) or 30 mg BID (38.1%, p = 0.0001) than placebo (19.0%). Among patients receiving apremilast continuously for 52 weeks (n = 254), ACR20 response at Week 52 was observed in 63.0% (75/119, 20 mg BID) and 54.6% (71/130, 30 mg BID) of patients. Response was also maintained across secondary outcomes, including measures of PsA signs and symptoms, skin psoriasis severity, and physical function. The nature, incidence, and severity of adverse events were comparable over the 24-week and 52-week periods. The most common adverse events, diarrhea and nausea, generally occurred early and were self-limited. Continuous apremilast treatment resulted in sustained improvements in PsA for up to 52 weeks. Apremilast had an acceptable safety profile and was generally well tolerated. Clinical trial registration: NCT01172938.
    The Journal of Rheumatology 01/2015; DOI:10.3899/jrheum.140647 · 3.17 Impact Factor
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    ABSTRACT: Activating transcription factor 3 (ATF3), a member of the ATF/cAMP-responsive element binding (CREB) family of transcription factors, regulates cellular response to stress including oxidative stress. The aim of this study was to analyse the role of ATF3 in fibroblast activation in systemic sclerosis (SSc). ATF3 was analysed by reverse transcription quantitative PCR, western blot and immunohistochemistry. ATF3 knockout fibroblasts and mice were used to study the functional role of ATF3. Knockdown experiments, reporter assays and coimmunoprecipitation were performed to study the effects of ATF3 on Smad and activation protein 1 (AP-1) signalling. The role of c-Jun was analysed by costaining, specific inactivation and coimmunoprecipitation. Transforming growth factor-β (TGFβ) upregulates the expression of ATF3 in SSc fibroblasts. ATF3-deficient fibroblasts were less sensitive to TGFβ, whereas ectopic expression of ATF3 enhanced the profibrotic effects of TGFβ. Mechanistically, ATF3 interacts with Smad3 directly on stimulation with TGFβ and regulates Smad activity in a c-Jun-dependent manner. Knockout of ATF3 protected mice from bleomycin-induced fibrosis and fibrosis induced by overexpression of a constitutively active TGFβ receptor I. Reporter assays and analyses of the expression of Smad target genes demonstrated that binding of ATF3 regulates the transcriptional activity of Smad3. We demonstrate for the first time a key role for ATF3 in fibrosis. Knockout of the ATF3 gene reduced the stimulatory effect of TGFβ on fibroblasts by interfering with canonical Smad signalling and protected the mice from experimental fibrosis in two different models. ATF3 might thus be a candidate for molecular targeted therapies for SSc. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.
    Annals of the Rheumatic Diseases 01/2015; DOI:10.1136/annrheumdis-2014-206214 · 9.27 Impact Factor
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    ABSTRACT: Mesenchymal responses are an essential aspect of tissue repair. Failure to terminate this repair process correctly, however, results in fibrosis and organ dysfunction. Therapies that block fibrosis and restore tissue homeostasis are not yet available for clinical use. Here we characterize the nuclear receptor NR4A1 as an endogenous inhibitor of transforming growth factor-β (TGF-β) signaling and as a potential target for anti-fibrotic therapies. NR4A1 recruits a repressor complex comprising SP1, SIN3A, CoREST, LSD1, and HDAC1 to TGF-β target genes, thereby limiting pro-fibrotic TGF-β effects. Even though temporary upregulation of TGF-β in physiologic wound healing induces NR4A1 expression and thereby creates a negative feedback loop, the persistent activation of TGF-β signaling in fibrotic diseases uses AKT- and HDAC-dependent mechanisms to inhibit NR4A1 expression and activation. Small-molecule NR4A1 agonists can overcome this lack of active NR4A1 and inhibit experimentally-induced skin, lung, liver, and kidney fibrosis in mice. Our data demonstrate a regulatory role of NR4A1 in TGF-β signaling and fibrosis, providing the first proof of concept for targeting NR4A1 in fibrotic diseases.
    Nature Medicine 01/2015; DOI:10.1038/nm.3777 · 28.05 Impact Factor
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    ABSTRACT: Apart from their role in the immune defence against pathogens evidence of a role of antimicrobial peptides (AMPs) in autoimmune diseases has accumulated in the past years. The aim of this project was to examine the functional impact of the human cathelicidin LL-37 and the mouse cathelicidin-related AMP (CRAMP) on the pathogenesis of lupus and arthritis. Serum LL-37 and anti-LL-37 levels were measured by ELISA in healthy donors and patients with Systemic Lupus Erythematosus (SLE) and Rheumatoid arthritis (RA). Pristane-induced lupus was induced in female wild type (WT) and cathelicidin-deficient (CRAMP-/-) mice. Serum levels of anti-Sm/RNP, anti-dsDNA, and anti-histone were determined via ELISA, cytokines in sera and peritoneal lavages were measured via Multiplex. Expression of Interferon I stimulated genes (ISG) was determined by real-time PCR. Collagen-induced arthritis (CIA) was induced in male WT and CRAMP-/- mice and arthritis severity was visually scored and analysed histomorphometrically by OsteoMeasure software. Serum levels of anti-LL-37 were higher in SLE-patients compared to healthy donors or patients with RA. However, no correlation to markers of disease activity or organ involvement was observed. No significant differences of autoantibody or cytokine/chemokine levels, or of expression of ISGs were observed between WT and CRAMP-/- mice after pristane-injection. Furthermore, lung and kidney pathology did not differ in the absence of CRAMP. Incidence and severity of CIA and histological parameters (inflammation, cartilage degradation, and bone erosion) were not different in WT and CRAMP-/- mice. Although cathelicidins are upregulated in mouse models of lupus and arthritis, cathelicidin-deficiency did not persistently affect the diseases. Also in patients with SLE, autoantibodies against cathelicidins did not correlate with disease manifestation. Reactivity against cathelicidins in lupus and arthritis could thus be an epiphenomenon caused by extensive overexpression in blood and affected tissues. In addition, other cationic AMPs could functionally compensate for the deficiency of cathelicidins.
    PLoS ONE 12/2014; 9(12):e115474. DOI:10.1371/journal.pone.0115474 · 3.53 Impact Factor
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    ABSTRACT: The aim of this study was the registration of digitized thin 2D sections of mouse vertebrae and tibiae used for histomorphometry of trabecular bone structure into 3D micro computed tomography (μCT) datasets of the samples from which the sections were prepared. Intensity-based and segmentation-based registrations (SegRegs) of 2D sections and 3D μCT datasets were applied. As the 2D sections were deformed during their preparation, affine registration for the vertebrae was used instead of rigid registration. Tibiae sections were additionally cut on the distal end, which subsequently undergone more deformation so that elastic registration was necessary. The Jaccard distance was used as registration quality measure. The quality of intensity-based registrations and SegRegs was practically equal, although precision errors of the elastic registration of segmentation masks in tibiae were lower, while those in vertebrae were lower for the intensity-based registration. Results of SegReg significantly depended on the segmentation of the μCT datasets. Accuracy errors were reduced from approximately 64% to 42% when applying affine instead of rigid transformations for the vertebrae and from about 43% to 24% when using B-spline instead of rigid transformations for the tibiae. Accuracy errors can also be caused by the difference in spatial resolution between the thin sections (pixel size: 7.25 μm) and the μCT data (voxel size: 15 μm). In the vertebrae, average deformations amounted to a 6.7% shortening along the direction of sectioning and a 4% extension along the perpendicular direction corresponding to 0.13-0.17 mm. Maximum offsets in the mouse tibiae were 0.16 mm on average.
    Computer Methods in Biomechanics and Biomedical Engineering 12/2014; 18(15):1-16. DOI:10.1080/10255842.2014.941824 · 1.79 Impact Factor
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    ABSTRACT: OBJECTIVE: 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. METHODS: We genetically inactivated Rsk2 in the tumour necrosis factor (TNF)-α 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. RESULTS: 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. CONCLUSIONS: 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. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.
    Annals of the Rheumatic Diseases 11/2014; DOI:10.1136/annrheumdis-2014-205618 · 9.27 Impact Factor

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14k Citations
4,157.26 Total Impact Points

Institutions

  • 2007–2015
    • Universitätsklinikum Erlangen
      Erlangen, Bavaria, Germany
    • Universitätsklinikum Münster
      Muenster, North Rhine-Westphalia, Germany
    • Maastricht University
      Maestricht, Limburg, Netherlands
    • Justus-Liebig-Universität Gießen
      • Department of Internal Medicine
      Gieben, Hesse, Germany
  • 2006–2014
    • Friedrich-Alexander Universität Erlangen-Nürnberg
      • Nikolaus-Fiebiger-Center of Molecular Medicine (NFZ)
      Erlangen, Bavaria, Germany
  • 2013
    • University of Leeds
      • Leeds Institute of Rheumatic and Musculoskeletal Medicine
      Leeds, England, United Kingdom
  • 1997–2013
    • University of Innsbruck
      • Institute of Biochemistry
      Innsbruck, Tyrol, Austria
  • 2012
    • University of British Columbia - Vancouver
      • Department of Psychology
      Vancouver, British Columbia, Canada
    • Université de Montréal
      Montréal, Quebec, Canada
    • Nordic Bioscience
      København, Capital Region, Denmark
    • University of Amsterdam
      • Faculty of Medicine AMC
      Amsterdamo, North Holland, Netherlands
  • 2011
    • National Academy of Sciences of Ukraine
      • Institute of Cell Biology
      Kharkiv, Kharkivs'ka Oblast', Ukraine
  • 2007–2011
    • University of Glasgow
      • • College of Medical, Veterinary and Life Sciences
      • • Institute of Infection, Immunity and Inflammation
      Glasgow, SCT, United Kingdom
  • 2010
    • ICL
      Londinium, England, United Kingdom
    • Technische Universität Braunschweig
      Brunswyck, Lower Saxony, Germany
    • Centro Nacional de Investigaciones Oncológicas
      Madrid, Madrid, Spain
  • 2008–2010
    • Nuremberg University of Music
      Nuremberg, Bavaria, Germany
  • 2009
    • University of Texas Southwestern Medical Center
      Dallas, Texas, United States
  • 1998–2009
    • Medical University of Vienna
      • Department of Medicine II
      Wien, Vienna, Austria
  • 2004–2006
    • Biomedical Sciences Research Center Alexander Fleming
      • Institute of Immunology
      Βάρη, Attica, Greece
  • 1998–2006
    • University of Vienna
      • Department of Internal Medicine III
      Wien, Vienna, Austria
  • 2005
    • University of Verona
      Verona, Veneto, Italy
  • 1995–2005
    • Austrian Academy of Sciences
      • • Forschungszentrum für Molekulare Medizin (CeMM)
      • • Institut für Biomedizinische Alternsforschung
      Mondsee, Upper Austria, Austria
  • 2000–2001
    • Vienna General Hospital
      Wien, Vienna, Austria
  • 1998–1999
    • Ludwig Boltzmann Institute of Rheumatology and Balneology
      Wien, Vienna, Austria