tbuckley/cabot-search huggingface dataset:
SAT0300 Treatment experience and satisfaction in ankylosing spondylitis patients treated with secukinumab: results from a us web-based survey
Authors: M. Magrey, M. Bozyczko, D. Wolin, M. Mordin, L. Mcleod, E. Davenport, Y. Park
Journal: Annals of the Rheumatic Diseases (2018)

<h3>Background</h3> Secukinumab is the only interleukin-17A inhibitor approved for the treatment of ankylosing spondylitis (AS). There are limited real-world data about treatment experience and patient satisfaction with secukinumab among patients with AS. <h3>Objectives</h3> To evaluate real-world treatment experience and satisfaction with secukinumab in US patients with AS. <h3>Methods</h3> Data on demographics, AS symptoms, treatment history, and treatment satisfaction were collected from a cross-sectional, web-based panel survey from July 10 to August 3, 2017. A random sample of US patients were invited to participate in the survey by Survey Sampling International via their patient panels. Eligibility criteria included patients aged ≥18 years with a self-reported diagnosis of AS who initiated secukinumab ≥3 months before participation and received secukinumab continuously since initiation. The outcomes evaluated were AS patient experience and satisfaction with effectiveness and symptom improvement with secukinumab, both overall and when compared to their previous treatment. Outcomes were summarised descriptively. <h3>Results</h3> Of 2755 patients screened, 200 patients with AS were eligible for the analysis. The mean (SD) age of survey participants was 34.4 (10.6) years; 60.0% were male and 66.0% were white. Equal proportions of patients (86.5%) had a history of biologic and nonbiologic use, and 98.5% of patients had previously received treatment for AS; the primary reason for discontinuation of their previous treatment was lack of efficacy (25.4%). Most patients (74.0%) reported overall improvement in AS symptoms compared with their previous treatment before secukinumab initiation ("a little better," 34.5%; "moderately better," 21.0%; "much better," 18.5%). Overall, the majority of patients were satisfied with secukinumab treatment (<b>Abstract SAT0300 – figure 1</b>), and expressed better treatment experience with secukinumab compared with their previous treatment (<b>Abstract SAT0300 – figure 2</b>). <h3>Conclusions</h3> Overall,&gt;90% of patients with AS who were treated with secukinumab expressed overall satisfaction with their treatment experience, even when compared with their previous treatment. These data provide early insight into the secukinumab treatment experience and satisfaction of US patients with AS. <h3>Acknowledgements</h3> This study was sponsored by Novartis Pharmaceuticals Corporation, East Hanover, NJ. <h3>Disclosure of Interest</h3> M. Magrey Grant/research support from: AbbVie, Consultant for: Janssen, Novartis, UCB, M. Bozyczko: None declared, D. Wolin Employee of: RTI-Health Solutions, M. Mordin Employee of: RTI-Health Solutions, L. Mcleod Employee of: RTI-Health Solutions, E. Davenport Employee of: RTI-Health Solutions, Y. Park Employee of: Novartis Pharmaceuticals Corporation
AB0629 Prevalence of asymptomatic vertebral fractures in postmenopausal women with systemic lupus erythematosus
Authors: S. Shkireeva, O.M. Lesnyak, E.G. Zotkin
Journal: Annals of the Rheumatic Diseases (2018)

<h3>Objectives</h3> To investigate the prevalence of vertebral fractures and to identify risk factors associated with vertebral fractures in postmenopausal women with systemic lupus erythematosus (SLE). <h3>Methods</h3> 86 consecutive postmenopausal women with SLE were included in this study. Bone mineral density (BMD) measurements of the hip and spine were performed using the dual energy X-ray absorptiometry (DEXA). Vertebral fracture assessment (VFA) was done for detection vertebral fractures using a method described by Genant. Accumulated damage was scored using the SLICC/ACR damage index (SDI). <h3>Results</h3> Vertebral fractures were defined in 42 (48.8%) postmenopausal women with SLE. Half of all patients with SLE (n=22, 25.6%) had asymptomatic vertebral fractures which were diagnosed only in this study. Every patient had 1.7 vertebral fractures on average (from 0 to 4). Distribution of vertebral fractures along the spine showed one peak at Th7. Univariate analyses of variables associated with fractures were longer duration of postmenopausal status in women with SLE, longer glucocorticoids intake, higher cumulative dose of glucocorticoids, higher SDI, lower BMD of the spine. Multivariate analysis showed longer duration of postmenopausal status in women with SLE (odds ratio 4,05, p=0,007), cumulative dose of glucocorticoids ≥60000 mg of prednisone (odds ratio 3,68, p=0,009), SDI≥7 (odds ratio 2,94, p=0,028) and low BMD (T≤−2.0) of the spine (odds ratio 2,48, p=0,015) were significantly associated with vertebral fractures in the thoracic and/or lumbar spine. <h3>Conclusions</h3> Vertebral fractures were occurred in 48.8% of postmenopausal women with SLE and half of them were asymptomatic. The current method using DEXA to predict the presence of vertebral fracture has limited value and there is a need for assessment of bone quality. Vertebral morphometry in patients with SLE is recommended and early therapeutic intervention is necessary to prevent vertebral fractures in postmenopausal women with SLE. <h3>Disclosure of Interest</h3> None declared
Tumor vascular permeability is a key determinant for anti-vascular effects of doxorubicin encapsulated in a novel temperature sensitive liposome
Authors: Qing Chen, Alex Wight, Sheng Tong, David Needham, Mark W. Dewhirst, Fan Yuan
Journal: Cancer Research (2005)

1392  Doxorubicin (DOX) encapsulated lyso-thermosensitive liposome (LTSL) has shown promising results in tumor growth control when it is combined with hyperthermia (HT). Our previous data have demonstrated that DOX released from LTSL can shut down blood flow in a human tumor xenograft (FaDu) in mice, suggesting that LTSL-DOX is a potential anti-vascular agent. To understand mechanisms of the blood flow shut down, we investigated the effects of LTSL-DOX (5 mg/kg body weight) plus HT (42oC, 1 h) on microcirculation in another tumor (a murine mammary carcinoma, 4T07) implanted in mouse dorsal skin-fold chambers, measured in vitro dose response of tumor (FaDu and 4T07) and endothelial cells to LTSL-DOX or free DOX with or without HT, and quantified the microvascular permeability changes after HT treatment in both tumors. We observed that LTSL-DOX+HT could significantly reduce blood flow in 4T07 tumor, but the amount of reduction was not as much as that in FaDu tumor. This difference was independent of sensitivity of cells to DOX treatment, because the dose responses of FaDu and 4T07 to DOX were similar in vitro. In addition, we observed that LTSL-DOX+HT was more cytotoxic to both tumor cells in vitro than LTSL-DOX without HT and the cytotoxicity of LTSL-DOX+HT was similar to that of free DOX+HT. These data suggested that the killing of tumor cells by LTSL-DOX+HT was caused by both free DOX released from LTSL and the thermal injury. HT increased the microvascular permeability in both tumors; and the amount of increase in FaDu was about eight times as high as that in 4T07. These data indicated that the concentration of LTSL-DOX was higher in FaDu tumors, especially in perivascular regions, than that in 4T07 tumors. Taken together, the difference in the anti-vascular effects of LTSL-DOX+HT between the two tumors was caused by the difference in the microvascular permeability and thus the local concentration of LTSL-DOX in the perivascular regions.
Novel proteasome assembly chaperone mutations in PSMG2/PAC2 cause the autoinflammatory interferonopathy CANDLE/PRAAS4
Authors: Adriana A. de Jesus, Anja Brehm, Rachel VanTries, Pascal Pillet, Anne-Sophie Parentelli, Gina A. Montealegre Sanchez, Zuoming Deng, Isabelle Koné Paut, Raphaela Goldbach-Mansky, Elke Krüger
Journal: Journal of Allergy and Clinical Immunology (2019)
SAT0002 The intracellular itam tyrosines of fc receptor gamma-chain are critical for experimental autoimmune arthritis
Authors: T. Nemeth, K. Futosi, M. Szabo, T. Saito, Z. Jakus, A. Mocsai
Journal: Annals of the Rheumatic Diseases (2018)

<h3>Background</h3> Activating Fcγ-receptors on neutrophils associate with the Fc-receptor γ-chain (FcRγ), an immunoreceptor tyrosine-based activation motif (ITAM) containing transmembrane adapter molecule. Previously, we carried out <i>in vitro</i> experiments that showed not only a chaperon-like function of FcRγ, but also a signalling role through its intracellular ITAM-tyrosines. <h3>Objectives</h3> Here, we investigated the participation of these tyrosines in an autoantibody-induced arthritis model (in the KBxN serum transfer arthritis, for the development of which neutrophils and Fc-receptors are essential) using wild type and ITAM tyrosine mutant (Y65F/Y76F) transgenic mice. <h3>Methods</h3> The experimental animals expressed wild type or ITAM tyrosine mutant (Y65F/Y76F) Fc-receptor γ-chain on the FcRγ<sup>–/–</sup> genetic background. The arthritis was initiated by a single intraperitoneal injection of control or arthritic serum. The severity of joint inflammation was followed by clinical scoring, measuring ankle thickness changes and detecting joint dysfunction. Homozygous transgenic mice were identified by quantitative PCR. <h3>Results</h3> Compared to wild type mice, FcRγ knockout animals failed to exhibit a measurable joint inflammation. Surprisingly, the arthritis could not develop in wild type FcRγ transgene heterozygous mice. To enhance the expression level of the wild type transgene (which was approximately one third of the expression of the mutant transgene), we crossed our wild type transgene heterozygous mice with each other. As a consequence, wild type FcRγ transgene homozygous mice on the γ-chain knockout background were able to undergo arthritic development. In contrast, FcRγ knockout mice carrying the ITAM-mutant FcRγ transgene (both at heterozygous and homozygous forms) were fully protected from the development of arthritis despite of comparable neutrophil cell surface Fcγ receptor expressions. <h3>Conclusions</h3> Our <i>in vivo</i> experiments show that the intracellular Fc receptor γ-chain ITAM tyrosines play a critical role in the initiation and progression of an autoantibody-induced experimental arthritis model, confirming a signalling, rather than just a chaperon-like function of the molecule. <h3>Acknowledgements</h3> <i>MTA-SE "Lendulet" Inflammation Physiology Research Group of the Hungarian Academy of Sciences and Semmelweis University, Budapest, Hungary and MTA-SE "Lendulet" Lymphatic Physiology Research Group of the Hungarian Academy of Sciences and Semmelweis University, Budapest, Hungary</i> <h3>Disclosure of Interest</h3> None declared
AB0106 Fibrin-triggered chondrosynovial adhesion as a novel mechanism of cartilage damage in rheumatoid arthritis
Authors: S. Nasi, V. Chobaz, E. Straden, J. Degen, N. Busso, A. So, T. Hügle
Journal: Annals of the Rheumatic Diseases (2018)

<h3>Background</h3> Synovial pannus infiltration and inflammatory cytokines production are the main factors responsible for cartilage damage in rheumatoid arthritis (RA). The crosstalk between inflammation and coaugulation further amplifies and maintain chronic inflammation. Altough synovial extravascular fibrin deposits in synovial fluid and synovial membranes being hallmarks of RA, there are no reports on direct fibrin deposition is widespread in RA, little is known about fibrin deposition and its relation to cartilage damage in RA. <h3>Objectives</h3> To investigate if fibrin deposition occurs in murine and human RA cartilage, and its relationship with cartilage degradation. Moreover, to determine the possible mechanism by which fibrin could play a role in the pathogenesis of RA. <h3>Methods</h3> Full-thickness cartilage explants were obtained from RA patients undergoing total knee replacement Immunohistochemistry was performed on paraffin sections to study fibrin deposition, while Safranin-O staining was used to investigate cartilage damage. An <i>in vitro</i> model of chondrosynovial adhesion was established using primary human RA synoviocytes seeded on human RA cartilage explants. Adherent synoviocytes to cartilage were evaluated on H and E-stained histological sections and fibrin immunohistochemistry was performed on adjacent sections. Antigen induced arthritis (AIA) was induced in wild-type (WT) and fibrinogen knock-out mice and paraffin sections of knee joints assessed for fibrin deposition, cartilage damage, and chondrosynovial adhesion. <h3>Results</h3> In human RA cartilage, the extent of fibrin deposits positively correlated with the degree of cartilage degradation (figure 1). In WT mice, fibrin deposition was preferentially found on damaged cartilage and on cartilage areas in direct contact with synovial membrane (i.e chondrosynovial adhesions) (figure 2). In contrast, cartilage degradation and chondrosynovial adhesion were significantly lower in fibrin deficient mice (figure 2). Moreover, loss of superficial cartilage layers stained with fibrin was observed in regions of chondrosynovial adhesion (figure 3). Finally, in the <i>in vitro</i> model, synoviocytes were found to adhere to human OA cartilage, especially in severely damaged and fibrin-rich areas (figure 4). <h3>Conclusions</h3> Our results demonstrate that fibrin deposition on cartilage is highly associated with chondrosynovial adhesion and subsequent cartilage erosion in RA. We hypothesise that fibrin mediates chondrosynovial adhesion especially during joint resting periods (i.e night-time), leading to mechanical stripping of superficial cartilage layers following motion. <h3>Disclosure of Interest</h3> None declared
FRI0465 Quantitative assessment of interstitial lung disease in idiopathic inflammatory myopathies: visual score and computerised processing analysis of high resolution computerised tomography
Authors: S. Barsotti, C. Romei, E. Cioffi, E. Perrone, C. Giovannetti, M. Mosca, F. Falaschi, R. Neri
Journal: Annals of the Rheumatic Diseases (2018)

<h3>Background</h3> High resolution computed tomography (HRCT) is an essential technique for the characterisation of interstitial lung disease (ILD) in patients with idiopathic inflammatory myopathies (IIM). Although several visual scores are available for a semiquantitative evaluation of ILD, an automatic quantitative analysis of lung involvement may represent a valuable improvement to reproducibly determine the extent of the disease. <h3>Objectives</h3> To compare the semiquantitative visual score to a volumetric texture and local volumetric histogram feature-based analysis software (CALLIPER) to quantify the lung involvement in IIM patients. <h3>Methods</h3> 21 consecutive IIM patients (Bohan and Peter criteria) who underwent a HRCT between November 2016 and November 2017 were prospectively enrolled. Twelve were affected by polymyositis and 9 by dermatomyositis. We collected smoking habits data and myositis specific autoantibodies positivity, respiratory symptoms according to MRC dyspnea scale and two patients reported outcome questionnaires: Leicester cough questionnaire (LCQ) and St. George's Respiratory questionnaire (SGRQ). Patients underwent a non-contrast, supine, volumetric CT (≤2 mm slice thickness) that was evaluated by an expert radiologist according to Warrick's score (WS) and also quantified by CALLIPER (Mayo Biomedical Imaging Resource – USA). CALLIPER analysis of the extent of interstitial lung abnormalities (ground glass, lung reticulation, honeycombing) was performed and a total score, expressed as percentage of lung involved (ILD%), was obtained. Analysis of the vascular involvement were performed as percent of pulmonary vessel volume (VESS%). <h3>Results</h3> Between the 21 patients, five (23.8%) were smokers. Four patients were positive for anti-synthetase autoantibodies -ASS (3 Jo-1, 1 Pl-7), 1 SRP, 1 Mi2. Dyspnea was present in 19 patients (90%): 9 grade 1, 7 grade 2, 3 grade 3 according to MRC scale. There were strict correlations between WS and ILD (r=0.802 p&lt;0.001) and VESS% (r=0.746 p&lt;0.001). LCQ score was negative correlated to WS (r=−0.728 p=0.007) but the correlations were stricter with ILD score (r=−0.868 p&lt;0.001) and VESS% (r=−0.801 p&lt;0.002). SGRQ did not correlate both to WS and CALLIPER parameters. Patients with ASS have higher ILD and VESS% compared to seronegative patients (respectively p=0.003 and p=0.006). <h3>Conclusions</h3> CALLIPER represents an innovative technique to quantify the lung involvement in IIM patients: the main advantage of CALLIPER is the reproducibility that avoids the inter and intra-reader bias. Although more data are needed in larger cohorts, the use of CALLIPER may open new routes for the evaluation of ILD in IIM patients, both in medical practice and in randomised controlled trials. <h3>Disclosure of Interest</h3> None declared
Delayed Remote Ischemic Preconditioning ConfersRenoprotection against Septic Acute Kidney Injury via Exosomal miR-21
Authors: Tianyi Pan, Ping Jia, Nan Chen, Yi Fang, Yiran Liang, Man Guo, Xiaoqiang Ding
Journal: Theranostics (2019)

Sepsis is a common and life-threatening systemic disorder, often leading to acute injury of multiple organs. Here, we show that remote ischemic preconditioning (rIPC), elicited by brief episodes of ischemia and reperfusion in femoral arteries, provides protective effects against sepsis-induced acute kidney injury (AKI). Methods: Limb rIPC was conducted on mice in vivo 24 h before the onset of cecal ligation and puncture (CLP), and serum exosomes derived from rIPC mice were infused into CLP-challenged recipients. In vitro, we extracted and identified exosomes from differentiated C2C12 cells (myotubes) subjected to hypoxia and reoxygenation (H/R) preconditioning, and the exosomes were administered to lipopolysaccharide (LPS)-treated mouse tubular epithelial cells (mTECs) or intravenously injected into CLP-challenged miR-21 knockout mice for rescue experiments. Results: Limb rIPC protected polymicrobial septic mice from multiple organ dysfunction, systemic accumulation of inflammatory cytokines and accelerated parenchymal cell apoptosis through upregulation of miR-21 in a hypoxia-inducible factor 1α (HIF-1α)-dependent manner in the ischemic limbs of mice. However, in miR-21 knockout mice or mice that received HIF-1α siRNA injection into hind limb muscles, the organ protection conferred by limb rIPC was abolished. Mechanistically, we discovered that miR-21 was transported from preischemic limbs to remote organs via serum exosomes. In kidneys, the enhanced exosomal miR-21 derived from cultured myotubes with H/R or the serum of mice treated with rIPC integrated into renal tubular epithelial cells and then targeted the downstream PDCD4/NF-κB and PTEN/AKT pathways, exerting anti-inflammatory and anti-apoptotic effects and consequently attenuating sepsis-induced renal injury both in vivo and in vitro. Conclusion: This study demonstrates a critical role for exosomal miR-21 in renoprotection conferred by limb rIPC against sepsis and suggests that rIPC and exosomes might serve as the possible therapeutic strategies for sepsis-induced kidney injury.
Noninvasive diagnosis of primary membranous nephropathy using phospholipase A2 receptor antibodies
Authors: Shane A. Bobart, An S. De Vriese, Aditya S. Pawar, Ladan Zand, Sanjeev Sethi, Callen Giesen, John C. Lieske, Fernando C. Fervenza
Journal: Kidney International (2019)

Kidney biopsy is the gold standard to diagnose membranous nephropathy (MN). Approximately 70%-80% of patients with primary MN have anti-phospholipase A2 receptor (PLA2R) antibodies. We hypothesized that PLA2R antibody testing without kidney biopsy may be a valid strategy to make a non-invasive diagnosis of MN in patients with a negative work-up for secondary causes. The medical records of all Mayo Clinic patients in Minnesota, Florida, and Arizona with serum PLA2R antibody tests between January 2015 and June 2018 were reviewed. PLA2R antibody testing was performed in 838 unique patients, with 143 testing positive. In 132 of these patients, a native kidney biopsy was performed. The primary diagnosis in all biopsies was MN. Potential secondary causes were identified in 35 cases, with the most common being malignancy and autoimmunity. Ninety-seven patients had a negative work-up for secondary causes of MN. Sixty of those 97 patients had an estimated glomerular filtration rate (eGFR) >60 ml/min/1.73m2. In these patients, the kidney biopsy did not provide significant information that altered management; one patient had a superimposed diabetic nephropathy and a second patient had a superimposed focal segmental glomerulosclerosis (FSGS) lesion. Among the 37 patients with primary MN and eGFR <60 ml/min/1.73m2, additional findings included acute interstitial nephritis, diabetic nephropathy, and cellular crescents in one case each. Thus, among patients with preserved kidney function and no evidence of secondary causes, a positive PLA2R antibody test highly predicts a tissue diagnosis of PLA2R-associated MN. Further validation in a prospective study is warranted to determine whether PLA2R antibody testing be used as a non-invasive diagnostic test to guide therapy.Graphical abstract
Memory CD4+ T cells are generated in the human fetal intestine
Authors: Na Li, Vincent van Unen, Tamim Abdelaal, Nannan Guo, Sofya A. Kasatskaya, Kristin Ladell, James E. McLaren, Evgeny S. Egorov, Mark Izraelson, Susana M. Chuva de Sousa Lopes, Thomas Höllt, Olga V Britanova, Jeroen Eggermont, Noel F. C. C. de Miranda, Dmitriy M. Chudakov, David A. Price, Boudewijn P. F. Lelieveldt, Frits Koning
Journal: Nature Immunology (2019)
Association of synovial tissue polyfunctional T-cells with DAPSA in psoriatic arthritis
Authors: Sarah M Wade, Mary Canavan, Trudy McGarry, Candice Low, Siobhan C Wade, Ronan H Mullan, Douglas J Veale, Ursula Fearon
Journal: Annals of the Rheumatic Diseases (2019)

Objective This study examines polyfunctional T-cells in psoriatic arthritis (PsA) synovial tissue and their associations with clinical disease and implications for therapy. Methods PsA synovial tissue was enzymatically/mechanically digested to generate synovial tissue single cell suspensions. Frequencies of polyfunctional CD4, CD8, T-helper 1 (Th1), Th17 and exTh17 cells, using CD161 as a marker of Th17 plasticity, were determined by flow cytometry in matched PsA synovial tissue and peripheral blood. Synovial T-cell polyfunctionality was assessed in relation to Disease Activity in PSoriatic Arthritis (DAPSA) and in synovial cell suspensions cultured with a current mode of treatment, phosphodiesterase 4 (PDE4) inhibitor. Results PsA synovial tissue infiltrating CD4 + T-cells expressed higher levels of interleukin (IL)-17A, interferon gamma (IFN-γ), GM-CSF and CD161, with parallel enrichment of Th1, Th17 and exTh17 T-helper subsets (all p&lt;0.05). Interestingly, a significant proportion of synovial T-cell subsets were triple-positive for GM-CSF, tumour necrosis factor (-TNF), -IL-17 or IFN-γ compared with matched blood (all p&lt;0.05). Importantly, frequencies of polyfunctional T-cells correlated with DAPSA: Th1-GM-CSF + /TNF + /IFN-γ + (r=0.7, p&lt;0.01), Th17-GM-CSF + /TNF + /IL-17 + (r=0.6, p&lt;0.057) and exTh17-GM-CSF + /TNF + /IFN-γ + (r=0.7, p=0.0096), with no associations observed for single cytokine-producing T-cells. Following ex vivo culture of PsA synovial tissue cell suspensions, polyfunctional GM-CSF + TNFα + IL-17A + or/IFN-γ + -producing T-cells (p&lt;0.05), but not single cytokine-producing T-cells, were inhibited with a PDE4 inhibitor. Conclusion These data demonstrate enrichment of polyfunctional T-cells in PsA synovial tissue which were strongly associated with DAPSA and ex vivo therapeutic response.