tbuckley/cabot-search huggingface dataset:
Application of the Statin-Associated Muscle Symptoms-Clinical Index to a Randomized Trial on Statin Myopathy
Authors: Beth A. Taylor, Robert J. Sanchez, Terry A. Jacobson, Daniela Chibedi-De-Roche, Garen Manvelian, Marie T. Baccara-Dinet, Irfan Khan, Robert S. Rosenson
Journal: Journal of the American College of Cardiology (2017)

Evidence suggests 10% to 25% of patients experience statin-associated muscle symptoms (SAMS) [(1)][1], which may result in poor adherence and a greater incidence of cardiovascular events and costs [(2,3)][2]. Although there are no uniformly accepted diagnostic criteria for SAMS, the SAMS Clinical
OP0004 Rheumatoid arthritis occuring after immune checkpoint inhibitors
Authors: R Belkhir, S Le Burel, O Lambotte, G Mouterde, E Pertuiset, L Dunogeant, A Marabelle, A Leary, A-L Voisin, X Mariette
Journal: Annals of the Rheumatic Diseases (2017)

<h3>Background</h3> Immune checkpoints inhibitors (ICIs) targeting cytotoxic T lymphocyte-associated protein 4 (CTLA-4) and Programmed cell death protein 1 (PD-1) have demonstrated survival improvement in multiple cancers. Immune Related Adverse Events (IrAE) have been described with ipilimumab and anti PD1. Relapse or flare of preexisting auto-immune diseases has been reported but occurrence of new auto-immune diseases seems to be less frequent. A series of 13 patients with non-classified rheumatic IrAE has been published: 9 patients developed non-specific inflammatory arthritis but no seropositive rheumatoid arthritis (RA) and 4 presented with sicca symptoms but did not fulfill criteria for Sjögren syndrome [1]. <h3>Objectives</h3> We did a retrospective study for collecting patients who developed seropositive rheumatoid arthritis (RA) after exposition to ICIs. <h3>Methods</h3> We used the "Club Rhumatismes et Inflammation (CRI)" network, a section of the French Society of Rheumatology and the Gustave Roussy Cancer Center register of safety of ICI for collecting patients treated with an ICI and who developed symptoms of arthritis with diagnosis of RA. <h3>Results</h3> We report 6 patients without any previous rheumatic disease, who developed seropositive rheumatoid arthritis (RA) after exposition to ICIs, all of them after anti-PD1. <h3>Conclusions</h3> This is the first description of RA occurring after anti-PD1 treatment for cancer. All cases responded to corticosteroids or with immunosuppressive therapy. This suggests that the PD1/PDL1 axis plays a role in RA pathophysiology. The combined expertise of oncologists, immunologists and rheumatologists is crucial in the successful management of these patients. <h3>References</h3> Cappelli LC, Gutierrez AK, Baer AN, et al. Inflammatory arthritis and sicca syndrome induced by nivolumab and ipilimumab. Ann Rheum Dis 2017;76:43–50. <h3>Disclosure of Interest</h3> None declared
Abstract 408: The Role of the Chemokine Receptor CXCR3 - Integrin Lymphocyte Function Associated Antigen 1 (LFA1) - Intercellular Adhesion Molecule 1 (ICAM1) Axis in T Lymphocyte Mediated Cardiac Inflammation in Pressure Overload Induced Heart Failure
Authors: Ane Miren Salvador, Tania Nevers, Francisco Velazquez, Mark Aronovitz, Pilar Alcaide
Journal: Circulation Research (2016)

Background: Left ventricular (LV) dysfunction and Heart Failure (HF) are associated in humans and mice with increased circulating chemokines CXCL9, CXCL10 and CXCL11. Expression of their receptor, CXCR3, in circulating T cells is associated with disease progression in HF patients. We recently published that ICAM1 is significantly upregulated in the LV endothelium and contributes to the progression of HF by regulating T cell recruitment to the LV in a mouse model of pressure overload (PO) induced HF. As CXCR3 can signal to integrins upon chemokine recognition and induce T cell adhesion to endothelial cells under flow conditions in vitro , we hypothesize that chemokine signaling through CXCR3 contributes to LV T cell recruitment and regulates integrin dependent adhesion to ICAM1 in PO induced HF. Methods and results: We used the mouse model of Thoracic Aortic Constriction (TAC) to induce LV remodeling and HF in WT and ICAM1 -/- mice, cardiac fibroblasts (CFB) isolated from adult C57/BL6 mice, flow cytometry and qPCR in mouse tissues and in cells cultured in vitro . The LV expression of CXCL9, 10 and 11 was upregulated in WT mice in response to 2 and 4 weeks TAC as compared to Sham, correlating with ICAM1, IL-6 and IL-1β upregulation and increased CXCR3+ T cell LV infiltration. In vitro , CFB cultured with CXCR3+ T cells or with their culture supernatants, induced CXCL9, 10 and 11, as compared to control media cultured CFB, suggesting CFB are a source of these chemokines under stress. 4 weeks post TAC in WT mice, LV recruited CXCR3+ T cells, as well as mediastinal lymph node and circulating CXCR3+ lymphocytes expressed higher levels of the integrin LFA1, the main ligand of ICAM1, than CXCR3- T cells. The same pattern was observed in systemic CXCR3+ T cells in ICAM1 -/- mice, which, in contrast to WT mice, had reduced LV infiltrated T cells. Conclusion: Our data supports a CXCR3-LFA1-ICAM1 axis being involved in non- ischemic HF. Further studies will determine the CXCR3 ligands triggering T cell LFA1 activation through CXCR3 and whether this mechanism regulates the pathology of non- ischemic HF via ICAM-1 mediated adhesion.
Abstract 94: Nitric Oxide--Regulated RGS4 Loss of Function Coordinates Vascular Growth with Cardiomyocyte Growth in the Absence of External Hypertrophic Stimuli
Authors: Irina M Jaba, Na Li, Zhen W Zhuang, Yifeng Jiang, Daniela Tirziu
Journal: Circulation Research (2012)

The mechanisms that coordinate an increase in vasculature with cardiomyocyte growth in adult heart are not known. We report that induction of angiogenesis is sufficient to promote cardiomyocyte growth and myocardial hypertrophy through a novel nitric oxide (NO)-dependent mechanism. Our hypothesis is that an increase in endothelial-derived NO release promotes the proteosomal degradation of negative regulator of G protein signaling RGS4 in cardiomyocytes (CM) thus relieving repression of hypertrophic stimulation through G proteins. Methods include cell culture systems and transgenic mouse models. We generated three conditional cardiac inducible mouse models: (1) to stimulate angiogenesis by transgenic expression of placental growth factor (PlGF); (2) to stimulate angiogenesis by PlGF and compensate for RGS4 degradation by transgenic expression of RGS4 in CM; and (3) to stimulate angiogenesis by PlGF in eNOS -/- mice. Results. In cultured rat neonatal CM, the treatment with a slow release NO donor resulted in increased degradation of RGS4 through the N-end rule pathway of protein degradation. RGS4 loss of function led to increase in cell size through Gbetagamma/PI3Kgamma-dependent Akt/mTORc1 activation. In mice, PlGF expression induced an increase in capillary/myocyte ratio and arteriolar branches (determined by microCT angiograms). Myocardial hypertrophy was induced subsequent to angiogenic stimulation and concurrent with increased in NO production. Consistent with in vitro data hypertrophic stimulation was associated with reduced RGS4 protein levels and robust activation of Akt/mTORc1 signaling. This hypertrophy was prevented by concomitant transgenic expression of RGS4 in CM, despite the persistence of angiogenesis, arteriogenesis, and increased NO release. Furthermore, the NOS inhibitor L-NAME or mTORc1 inhibitor rapamycin significantly attenuated RGS4 degradation, Akt/mTORc1 signaling, and heart size in PlGF-induced mice. A similar effect was observed upon conditional heart-specific PlGF expression in eNOS -/- mice. In conclusion, these findings support a novel NO/RGS4/G protein/Akt mechanism that couples vessel growth with myocyte growth and heart size in the absence of traditional hypertrophic stimuli.
Absence of Replication-Competent Lentivirus in the Clinic: Analysis of Infused T Cell Products
Authors: Kenneth Cornetta, Lisa Duffy, Cameron J. Turtle, Michael Jensen, Stephen Forman, Gwendolyn Binder-Scholl, Terry Fry, Anne Chew, David G. Maloney, Carl H. June
Journal: Molecular Therapy (2017)

Exposure to replication-competent lentivirus (RCL) is a theoretical safety concern for individuals treated with lentiviral gene therapy. For certain ex vivo gene therapy applications, including cancer immunotherapy trials, RCL detection assays are used to screen the vector product as well as the vector-transduced cells. In this study, we reviewed T cell products screened for RCL using methodology developed in the National Gene Vector Biorepository. All trials utilized third-generation lentiviral vectors produced by transient transfection. Samples from 26 clinical trials totaling 460 transduced cell products from 375 subjects were evaluated. All cell products were negative for RCL. A total of 296 of the clinical trial participants were screened for RCL at least 1 month after infusion of the cell product. No research subject has shown evidence of RCL infection. These findings provide further evidence attesting to the safety of third-generation lentiviral vectors and that testing T cell products for RCL does not provide added value to screening the lentiviral vector product. Exposure to replication-competent lentivirus (RCL) is a theoretical safety concern for individuals treated with lentiviral gene therapy. For certain ex vivo gene therapy applications, including cancer immunotherapy trials, RCL detection assays are used to screen the vector product as well as the vector-transduced cells. In this study, we reviewed T cell products screened for RCL using methodology developed in the National Gene Vector Biorepository. All trials utilized third-generation lentiviral vectors produced by transient transfection. Samples from 26 clinical trials totaling 460 transduced cell products from 375 subjects were evaluated. All cell products were negative for RCL. A total of 296 of the clinical trial participants were screened for RCL at least 1 month after infusion of the cell product. No research subject has shown evidence of RCL infection. These findings provide further evidence attesting to the safety of third-generation lentiviral vectors and that testing T cell products for RCL does not provide added value to screening the lentiviral vector product.
AB0668 Calcinosis cutis and its association of serum levels of osteonectin, osteonectin, nitric oxide and tgf-b in systemic sclerosis
Authors: RA Carranza Muleiro, MDP Cruz-Domínguez, LM Apolinar, AA Reséndiz-Albor, AL Vázquez-Martínez, G García-Collinot, LJ Jara-Quezada, IM Arciniega
Journal: Annals of the Rheumatic Diseases (2017)

<h3>Background</h3> Systemic sclerosis (SSc) is characterized by fibrosis, autoimmunity and vasculopathy. ES is classified subtypes: diffuse (dSSc) and limited (ISSc). More than 35% develop calcinosis. Calcium, phosphorus, parathormone, vitamin D, TGF-β, nitric oxide and osteonectin and osteopontin involved in bone mineralization. <h3>Objectives</h3> The aim was to compare osteonectin (ON), osteopontin (OP), TGF-β, nitric oxide (NO), Paratohormone (PTH), Vitamin D and minerals concentrations in ES with and without calcinosis. <h3>Methods</h3> Cross-sectional study in ES patients (ACR criteria). We quantified OP, ON, TGF-β, ON, Calcium, Phosphorus, PTH and vitamin D in serum by ELISA. We performed descriptive statistics, Student t, Pearson correlation (significance p&lt;0.05) in SPSSv21 program. <h3>Results</h3> We included 71 patients, age 52.94 (± 11.47); 28 (40%) with calcinosis (18 dSSc/10 lSSc), and 43 (60%) without calcinosis (13 dSSc/30 lSSc). Biochemical parameters between two groups. In the whole population the higher PCR had moderate positive correlation (r =0.41, p=0.042), and serum calcium level had a moderate negative correlation (r = -0.47, p=0.021); ON increased in direct relation to OP (r =0.3, p=0.014) and the serum levels of VitD had lower indirect relation with the evolution time of SSc (r = -0.28, P=0.025) and the ON increase in direct relation to serum creatinine (r =0.039, p=0.006). <h3>Conclusions</h3> Patients with a longer time evolution of SSc have less serum levels of VitD and those with higher inflammation (PCR) have a higher TGF-β than a potent inducer of fibrosis. PCR and TGF-B have a moderate direct correlation, PCR and Calcium have moderate indirect correlation, ON and OP have a low direct correlation, VitD and evolution of diseases (years) had a low indirect correlation and NO and creatinine had a very low direct correlation. <h3>References</h3> Fueki H, Hino R, Yoshioka M, Nakamura M, Tokura Y.Calcinosis cutis associated with primary Sjogren9s syndrome: strong expression of osteonectin and matrix Gla protein.Rheumatology (Oxford) 2011; 50(12):2318–20. Kim SY, Choi HY, Myung KB, Choi YW.The expression of molecular mediators in the idiopathic cutaneous calcification and ossification. J Cutan Pathol 2008; 35(9):826–31. Ahmed S, O9Neill KD, Hood AF, Evan AP, Moe SM. Calciphylaxis is associated with hyperphosphatemia and increased osteopontin expression by vascular smooth muscle cells. Am J Kidney Dis 2001;37(6):1267–76. Kawakami T, Soma Y, Mizoguchi M, Saito R. Immunohistochemical expression of transforming growth factor beta3 in calcinosis in a patient with systemic sclerosis and CREST syndrome. Br J Dermatol. 2000;143(5):1098–100. <h3>Disclosure of Interest</h3> None declared
FRI0700 Physical activity decreased significantly but moderately during weeks where patients reported flares: a 3-month study of 170 rheumatoid arthritis (RA) or axial spondyloarthritis (AXSPA) patients wearing an activity tracker
Authors: C Jacquemin, H Servy, A Molto, J Sellam, V Foltz, F Gandjbakhch, C Hudry, S Mitrovic, B Fautrel, L Gossec
Journal: Annals of the Rheumatic Diseases (2017)

<h3>Background</h3> RA and axSpA natural history comprises periods of low disease activity and flares. There is much interest in the concept of flares. Studies have indicated flares may alter patient quality of life, however, there are few data linking flares to quantifiable outcomes. <h3>Objectives</h3> The objective was to assess longitudinally the association between patient-reported flares and physical activity assessed objectively using an activity tracker. <h3>Methods</h3> This prospective multi-center observational study (ActConnect) included patients with definite RA (ACR/EULAR criteria) or axSpA (ASAS criteria) owning a smartphone. Physical activity was assessed continuously over 3 months by the number of steps using an activity tracker, and flares were self-assessed weekly using a specific flare question ("has your disease flared up during the last 7 days?")[1] with a categorical response according to: no flare, 1 to 3 days flare, or &gt;3 days flare. The relationship between flares and physical activity for each week (time point) was assessed by linear mixed models adjusted on rheumatic disease, sex, age, obesity, biologics and employment status. <h3>Results</h3> 170/178 patients (91 RA and 79 axSpA patients; 1553 time points) were analyzed: mean age 45.5±12.4 years, mean disease duration 10.3±8.7 years; 60 (35.3%) were males and 90 (52.9%) received biologics. Disease was well-controlled (mean DAS28: 2.3±1.2; mean BASDAI: 3.3±2.1). Physical activity was moderate (mean steps/day, 7067±2770). Flares were frequent (25.5% of the questionnaires); most (76.8%) were of short duration. Flares, in particular &gt;3 days flares, were independently associated with less weekly physical activity (p=0.02–0.03), leading to a relative decrease of physical activity of 12–21% and an absolute decrease ranging from 836 to 1462 steps/day (Table 1). <h3>Conclusions</h3> Flares were frequent in these low-disease patients, though most flares were of short duration. Flares were related to a moderate decrease in physical activity, confirming objectively the functional impact of patient-reported flares. <h3>References</h3> VP Bykerk et al, RMD Open, 2016; 2:e000225.doi:10.1136/rmdopen-2015–000225. <h3>Disclosure of Interest</h3> None declared
AB0797 Long term prospective multicenter randomized placebo-controlled study of hyaluronic acid in small joints osteoarthritis (SJOA)
Authors: E Tsvetkova, L Denisov, E Panasyuk, E Nasonov
Journal: Annals of the Rheumatic Diseases (2017)

<h3>Objectives</h3> Assessment of the efficacy, tolerability and period of aftereffect of the single administration into 1st carpometacarpal and 1st metatarsophalangeal OA joints of 1.0 ml (20mg) of hyaluronic acid (Durolane) as compared with placebo. <h3>Methods</h3> The study included 120 pts with OA of small hand joints or feet, pain intensity &gt;40 mm by VAS and consisted of two phases: "blind" phase up to 24 weeks, period of assessment of long term efficacy results – 48 weeks. The efficacy was assessed by 40% pain subsiding, index AUSCAN (for the hand), dose of NSAID, total effect assessment. <h3>Results</h3> Both groups were comparable by basic clinical criteria, 40% pain subsiding by VAS (mm) was noted in experimental group to 24th week in 79.7%, in the placebo group – 30% (chi-square: p&lt;10<sup>-5</sup>), relation of chances (OR) equal to 9.1 (3.9–21.1). Dispersion analysis of pain, stiffness and function of AUSCAN index revealed reliable differences between Durolane and placebo. Statistically significant difference (p&lt;0.0001) according to assessment of general condition by the doctor and patient were found out in experimental group from the 4th week and were stable till 48th week. Adverse effects related to the therapy were not found. NSAID dose was decreased in 45.7% in experimental group and in 30% in placebo group. <h3>Conclusions</h3> efficacy and considerable duration of aftereffect of single administration of Durolane SJ (small joints) as compared with placebo was demonstrated in 24 and 48 weeks. <h3>Disclosure of Interest</h3> None declared
SAT0167 Can infliximab efficacy be predicted based on blood concentration at the fourth dose?
Authors: M Sato, M Takemura, T Tani, T Ohashi
Journal: Annals of the Rheumatic Diseases (2017)

<h3>Background</h3> Biological drugs exhibit excellent efficacy and continuity in the treatment of rheumatoid arthritis (RA) and play an important role in RA treatment. Blood concentration is an important factor in the efficacy of biological drugs, particularly antibody drugs. Infliximab (IFX) is an antibody drug against TNF-α and is reported to require a blood concentration of ≥1 μg/mL to be effective. <h3>Objectives</h3> To investigate whether clinical efficacy can be predicted based on blood concentrations at the fourth dose of IFX in patients with RA. <h3>Methods</h3> This study included 56 patients with RA who were treated with IFX. Patients included 13 men and 43 women aged from 26 to 81 years (mean, 60.3 years). The IFX concentration was measured immediately before administering the fourth IFX dose (8 weeks after administering the third dose). We then investigated the relationship between subsequent IFX efficacy and IFX concentration immediately before the fourth dose of IFX in these patients with RA. Concentrations were measured in stored frozen serum by using the ELISA method. <h3>Results</h3> The IFX concentration immediately before the fourth dose was ≥1 μg/mL in 32 patients (≥1 μg/mL group) and &lt;1 μg/mL in 24 patients (&lt;1 μg/mL group). At the fourth dose, IFX was effective in 30 patients (93.8%) in the ≥1 μg/mL group, at a mean concentration of 5.18 μg/mL, while the mean concentration was 5.69 μg/mL for the remaining 2 non-responders. IFX was also effective in 21 patients (87.5%) in the &lt;1 μg/mL group but did not elicit any response in the other 3 patients. At this point, all 5 non-responsive patients were primary non-responders. Of all 51 responders, 58.8% were in the ≥1 μg/mL group and 41.2% were in the &lt;1 μg/mL group. Based on the data, we observed no relationship between efficacy and IFX concentration. After 1 year of IFX treatment, 36 of the 56 patients were responsive and 20 were non-responsive. In the 2 groups, 26 responsive patients (63.9%) and 9 non-responsive patients (45.0%) had an IFX concentration of ≥1 μg/mL immediately before the fourth dose. <h3>Conclusions</h3> At the fourth dose, many of the patients with an IFX concentration of &lt;1 μg/mL were also responsive to the treatment, so future efficacy was difficult to predict based on IFX concentration. In other words, during clinical evaluation, measurement of IFX concentrations is not necessary in responsive patients. However, IFX concentrations should be measured in non-responsive patients or patients with a diminished response. If the concentration is &lt;1 μg/mL, IFX efficacy should be restored by increasing the dose or shortening the administration interval. <h3>Disclosure of Interest</h3> None declared
AB0181 Diffusing capacity and clinical characteristics of patients with systemic sclerosis – data from the german network for systemic sclerosis
Authors: P Moinzadeh, N Blank, E Siegert, J Henes, M Worm, C Sunderkoetter, M Schmalzing, A Kreuter, C Gunther, L Susok, G Zeidler, I Koetter, U Mueller-Ladner, T Krieg, A Juche, T Schmeiser, G Riemekasten, E Aberer, N Gaebelein-Wissing, JHW Distler, M Sárdy, C Pfeiffer, K Kuhr, N Hunzelmann, F Bonella, M Kreuter
Journal: Annals of the Rheumatic Diseases (2017)

<h3>Background</h3> Lung involvement, i.e. interstitial lung disease (ILD) and pulmonary hypertension (PH), is common in patients with systemic sclerosis (SSc), significantly limiting quality of life and survival. Data on clinical correlations between lung function and clinical subsets of SSc are sparse. <h3>Objectives</h3> To investigate the relationship of DLCO and clinical characteristics in patients SSc patients within the registry of the German Network for Systemic Scleroderma. <h3>Methods</h3> Clinical data of the patient registry, currently including DLCO data of 1917 patients were evaluated. In total, these patients were clinically evaluated 5997 times (i.e., at the first visit and during follow-up visits). At the initial visit and during follow-up DLCO levels were correlated with clinical characteristics. <h3>Results</h3> At initial presentation, 64% of the patients had DLCO levels &lt;75% predicted. Impaired DLCO levels were observed in 74% of dcSSc patients, in 64% of SSc-Overlap patients and 57% of lcSSc patients (p&lt;0.0001). Furthermore, male patients (62%), patients with PH (80%), ILD (80%), dyspnea (78%), and those with presence of anti-topoisomerase I antibodies (71%) exhibited significantly more often DLCO levels &lt;75% (p&lt;0.01). Patients suffering from dcSSc had the lowest DLCO levels (mean value, 62%), followed by patients with SSc-Overlap syndromes (mean value, 67%) and lcSSc patients (mean value, 70%) revealing significant differences between subsets. Long-term follow-up evaluation (mean follow up, 6.0 years) revealed that in comparison to lcSSc patients dcSSc patients (OR 2.1; p&lt;0.0001; 95%&gt;CI 1.7–2.5) and SSc-Overlap patients (OR, 1.55; p&lt;0.0001; 95% CI, 1.2–2.0) had a significantly increased risk to a decrease in DLCO levels &lt;75%. <h3>Conclusions</h3> Impairment of pulmonary function as determined by diffusing capacity DLCO is more common and more pronounced in patients with dcSSc and SSc-Overlap Syndrome compared to lcSSc. DLCO may be useful for diagnosing and monitoring pulmonary involvement in SSc. <h3>Disclosure of Interest</h3> None declared