tbuckley/cabot-search huggingface dataset:
AB1084 Contribution of clinical trials to the efficiency of arthritis rheumatoid management
Authors: C Alcañiz Escandell, E Vicens Bernabeu, FM Ortiz-Sanjuan, JE Oller Rodriguez, C Nájera Herranz, I Cánovas Olmos, E Grau Garcia, CM Feced Olmos, E Sánchez Labrador, K Arévalo Ruales, R Negueroles Albuixech, J Ivorra Cortes, JJ Fragio Gil, I Martínez Cordellat, R Mazarío González, I Chalmeta Verdejo, L Gonzalez Puig, JA Román Ivorra
Journal: Annals of the Rheumatic Diseases (2017)

<h3>Background</h3> Treatment and management of Rheumatoid Arthritis (RA) results in a high cost to the Health system such as the Spanish Health System. During the realization of clinical trials (CT) the sponsor is the one that pays for the direct healthcare costs of the patients, which leads to savings to the National Health System (NHS). <h3>Objectives</h3> To estimate the economic impact of conducting clinical trials (CT) for the NHS in terms of avoided costs. <h3>Methods</h3> A retrospective observational study was conducted using information from the clinical trials performed at the Clinical Research Rheumatology Department in the HUP la Fe from 2011 to 2015. Also a Cost-analysis was performed according Health System perspective. We calculated the length of stay in the CT in weeks for each patient included with RA diagnosis. Afterwards, we also calculated the total number of weeks of treatment for the total number of patients. In order to evaluate the economic impact in terms of avoided costs, economic evaluation included direct healthcare costs (rheumatologist visits, nurse care, laboratory tests and pharmacological treatment), and it was compared to the cost of the best alternative treatment in the market. <h3>Results</h3> A total of 35 CT were analyzed in this period, 14 of them focused on RA. Two observational studies and one CT (premature closure by the sponsor) were discarded. Therefore, 11 were considered in this study and a total of 76 patients with RA were analysed which add together 2609 weeks of treatment. This is approximately equivalent to treating 50 RA patients with biological therapy during one year. Evaluating the health savings that biological treatment would have cost during the 2609 weeks, we obtain a total amount of 699.176,88 €. This represents an annual saving of 139.835€ over the 5 years analyzed. <h3>Conclusions</h3> Our Clinical Research Unit managed to save a total amount of 13.935,30 € per patient in CT per year. Clinical Research Units should be considered as an efficient tool to the NHS. <h3>Disclosure of Interest</h3> None declared
ASK1 Inhibition Halts Disease Progression in Preclinical Models of Pulmonary Arterial Hypertension
Authors: Grant R. Budas, Mario Boehm, Baktybek Kojonazarov, Gayathri Viswanathan, Xia Tian, Swathi Veeroju, Tatyana Novoyatleva, Friedrich Grimminger, Ford Hinojosa-Kirschenbaum, Hossein A. Ghofrani, Norbert Weissmann, Werner Seeger, John T. Liles, Ralph T. Schermuly
Journal: American Journal of Respiratory and Critical Care Medicine (2017)

Progression of pulmonary arterial hypertension (PAH) is associated with pathological remodeling of the pulmonary vasculature and the right ventricle (RV). Oxidative stress drives the remodeling process through activation of MAPKs (mitogen-activated protein kinases), which stimulate apoptosis, inflammation, and fibrosis.We investigated whether pharmacological inhibition of the redox-sensitive apical MAPK, ASK1 (apoptosis signal-regulating kinase 1), can halt the progression of pulmonary vascular and RV remodeling.A selective, orally available ASK1 inhibitor, GS-444217, was administered to two preclinical rat models of PAH (monocrotaline and Sugen/hypoxia), a murine model of RV pressure overload induced by pulmonary artery banding, and cellular models.Oral administration of GS-444217 dose dependently reduced pulmonary arterial pressure and reduced RV hypertrophy in PAH models. The therapeutic efficacy of GS-444217 was associated with reduced ASK1 phosphorylation, reduced muscularization of the pulmonary arteries, and reduced fibrotic gene expression in the RV. Importantly, efficacy was observed when GS-444217 was administered to animals with established disease and also directly reduced cardiac fibrosis and improved cardiac function in a model of isolated RV pressure overload. In cellular models, GS-444217 reduced phosphorylation of p38 and JNK (c-Jun N-terminal kinase) induced by adenoviral overexpression of ASK1 in rat cardiomyocytes and reduced activation/migration of primary mouse cardiac fibroblasts and human pulmonary adventitial fibroblasts derived from patients with PAH.ASK1 inhibition reduced pathological remodeling of the pulmonary vasculature and the right ventricle and halted progression of pulmonary hypertension in rodent models. These preclinical data inform the first description of a causal role of ASK1 in PAH disease pathogenesis.
Reply
Authors: Barret Rush, Keith R. Walley, Leo Anthony Celi, Neil Rajoriya, Mayur Brahmania
Journal: Hepatology (2017)

View this article online at wileyonlinelibrary.com. Potential conflict of interest: Nothing to report. We thank Sonoo et al. for their interest in our recent publication and for their correspondence. The use of large national administrative databases contains the inherent risk of bias and error due to the construction of the database. The sensitivity of palliative care code V66.7 has always been a limitation in the analysis of inpatient palliative care referrals. The article by Hua et al. reported on a single center study which employed the definition of "moderate to severe liver disease" from the Charlson Comorbidity Index.1 This is a poor definition of end‐stage liver disease and likely does not represent the patient cohort we attempted to characterize. In addition, Hua et al. do not define the size of the liver disease cohort.2 Nevertheless, the imperfect nature of the sensitivity of the V66.7 code does introduce some degree of uncertainty, which we acknowledged as a limitation in our article. While the type of insurance coverage may be heterogeneously dispersed among patients, we controlled for annual income, race, and other patient‐level variables in a predefined cohort of patients with end‐stage liver disease. We did not use multilevel adjusted models as this would interrupt the integrity of the National Inpatient Sample by defining a nested cohort, as suggested against by the Healthcare Cost and Utilization Project statistical brief cited by the authors.3 While many statistical methods are available to attempt to arrive at the most accurate inference of an analysis, we feel the findings of our study were completed after a rigorous and well‐designed analysis plan that went through a peer review process. Lastly, we must emphasize that the current analysis was to identify a problem, i.e., palliative care referrals in end‐stage liver disease patients, that is currently not well characterized. We did not intend for the article to inform public health policy decisions as the current analysis would be a suboptimal method to do so. We thank the authors for their interest in our work and hope that our reply has satisfied their concerns regarding our article.
OP0288 Reliability of a eular-omeract semiquantitative scoring system for the assessment of cartilage in rheumatoid arthritis
Authors: P Mandl, E Filippucci, P Studenic, A Bachta, D Bong, GA Bruyn, C Dejaco, A Delle Sedie, C Duftner, I Gessl, HB Hammer, C Hernandez Diaz, A Iagnocco, K Ikeda, D Kane, H Keen, E Kővári, U Moeller-Doehn, E Naredo, J-C Nieto, C Pineda, A Rodriguez, WA Schmidt, G Supp, L Terslev, R Thiele, D Windschall, M-A D'Agostino, PV Balint
Journal: Annals of the Rheumatic Diseases (2017)

<h3>Background</h3> Joint destruction in rheumatoid arthritis (RA) is comprised of hyaline cartilage and bone damage, with the former more clearly associated with irreversible physical disability than bony damage. <h3>Objectives</h3> To test the reliability of a semiquantitative scoring system for the assessment of cartilage by musculoskeletal ultrasound (US) in a web-based exercise as well as a patient-based reliability study of patients with RA. <h3>Methods</h3> Static images of metacarpophalangeal (MCP) joints 2–5 in RA patients and healthy controls were acquired and a dataset of 123 anonymized images including 25 duplicate images was circulated among an international EULAR-OMERACT taskforce of 25 rheumatologist experts in US who independently scored the images using a semiquantitative scoring system. Subsequently 12 taskforce members participated in a patient-based reliability study. During this meeting MCP joints 2–5 of 6 patients with RA were assessed twice on the same day by all experts using US machines (GE) equipped with high-frequency transducers (18–22MHz) with presets calibrated for the appropriate assessment of cartilage. Participants assessed metacarpal cartilage both in the standardized longitudinal midline scan as well as by freehand technique utilizing multiple planes and scored by the semiquantitative scoring system. Intraobserver reliability was assessed by Cohen9s kappa and interobserver reliability by Fleiss9 kappa. <h3>Results</h3> The three-grade semiquantitative (Grade 0, normal cartilage; Grade 1, minimal change; Grade 2, severe change) scoring system demonstrated excellent (kappa: 0.87) to good (kappa: 0.73) intraobserver reliability in the web-based exercise and the patient-based reliability study respectively. Interobserver reliability was good in the web-based exercise (kappa: 0.64) and moderate (kappa: 0.49) in the patient-based reliability study. The dynamic technique performed slightly better than the longitudinal midline scan alone. <h3>Conclusions</h3> A semiquantitative scoring system demonstrated good intra- and moderate to good inter-observer reliability in a web-based exercise and patient-based reliability study. Our study demonstrates that US is a reliable tool for evaluating cartilage and supports the use of a new semiquantitative US scoring system for evaluating cartilage change in RA. <h3>Acknowledgements</h3> The patient-based reliability study was supported by a research grant from UCB. <h3>Disclosure of Interest</h3> None declared
FRI0721 Sleep disorders in patients at the first access to a rheumathology outpatient clinic
Authors: R Tirri, D Capocotta, R Ferrara
Journal: Annals of the Rheumatic Diseases (2017)

<h3>Background</h3> Sleep disturbances are frequently found in patients affected by rheumatic conditions (1). Chronic pain, the most common manifestation of these conditions is associated to poor sleep (2). <h3>Objectives</h3> Our primary objective was to evaluate prevalence of excess daytime sleepiness and impaired sleep quality in a patient population at the first access to a Rheumatology outpatient clinic. Secondary objective was evaluation of pain and others factors well known to be associated to sleep disorders. <h3>Methods</h3> 961 out of 1454 (mean age was 52.6 years; 14.3% were male) consecutive patients admitted for the first time to an Italian Rheumatology Outpatient Clinic, between December 2014 and November 2016, accepted to answer a self-administered questionnaire study. We considered the following parameters: pain intensity on visual analogic scale ranging from 0 to 100 according to commonly used classification (3), patient9s assessment of General Health (GH), Epworth Sleepiness Scale (ESS), Pittsburgh Sleep Quality Index (PSQI), Health Assessment Questionnaire (HAQ), and Body Mass Index (BMI). Smoke habits were also considered. <h3>Results</h3> 70 patients showed both sleep disorders (7.3%),624 patients had only impaired sleep quality (64.9%), 25 showed isolated excessive daytime sleepiness (2.6%). 242 patients did not have any sleep disorders (25.2%). We found that the presence of both ESS≥10 and PSQI≥5 was correlated to moderate-severe pain VAS pain≥40, BMI≥35, HAQ≥1 and GH≥50 with a statistical significance (respectively p=0.004; p=0.032; p=0.0004; p=0.0001). A correlation with GH≥50 in the patient group with only PSQI≥5 was detected (p=0.03). Smoke habits did not correlate with sleep disturbance measures investigated. No other correlations were found in the other groups. <h3>Conclusions</h3> Thus excess daytime sleepiness and impaired sleep quality may be a target of therapeutic intervention in the treatment of rheumatic conditions. Further studies are needed to generalize results and suggestions. <h3>References</h3> Generaal E, Vogelzangs N, Penninx WJH, Dekker J. Insomnia, sleep duration, depressive symptoms, and the onset of chronic multisite musculoskeletal pain. Sleep 2017; 40. Vivien C Abad, Priscilla S.A. Sarinas, Christian Guilleminault. Sleep and rheumatologic disorders. Sleep Medicine Reviews 2008; 12: 211–228. Jensen MP, Chen C, Brugger AM. Interpretation of visual analog scale ratings and change scores: a reanalysis of two clinical trials of post-operative pain. J Pain 2003;4:407–14. <h3>Disclosure of Interest</h3> None declared
Frontline hyper-CVAD plus ponatinib for patients with Philadelphia chromosome-positive acute lymphoblastic leukemia: Updated results of a phase II study.
Authors: Nicholas James Short, Hagop M. Kantarjian, Farhad Ravandi, Naval Guastad Daver, Naveen Pemmaraju, Deborah A. Thomas, Musa Yilmaz, Tapan M. Kadia, Koji Sasaki, Rebecca Garris, Guillermo Garcia-Manero, Courtney Denton Dinardo, Marina Konopleva, Zeev Estrov, Nitin Jain, William G. Wierda, Vicky Jeanis, Jorge E. Cortes, Susan Mary O'Brien, Elias Jabbour
Journal: Journal of Clinical Oncology (2017)

7013 Background: The combination of chemotherapy plus a TKI is highly effective in Ph+ ALL. In this phase II study, we evaluated the safety and efficacy of HCVAD in combination with the third-generation pan- BCR-ABL inhibitor, ponatinib. Methods: Patients (pts) with newly diagnosed Ph+ ALL received 8 cycles of HCVAD alternating with high dose MTX/Ara-C every 21 days. Ponatinib was given at 45 mg daily for the first 14 days of cycle 1. Initially ponatinib 45 mg daily was given indefinitely beginning at cycle 2. Due to concern for vascular events, a protocol amendment was made in which, beginning in cycle 2, pts in CR received 30mg daily and pts in CMR received 15mg daily. Rituximab and IT chemotherapy were given with the first 4 courses. After 8 cycles of HCVAD, pts in CR received maintenance with ponatinib, vincristine and prednisone for 2 years followed by indefinite ponatinib. Results: 64 pts have been treated, 10 of whom had received prior treatment with another regimen (8 in CR, 2 not in CR). Median age was 48 years (range, 21-80) and median follow-up was 33 months (range, 2-62). Median cycles received was 6 (range, 2-8). 63 pts (98%) achieved CR after 1 cycle; 1 pt achieved CRp. CCyR was achieved in 98%, MMR in 97% and CMR in 77%. Median time to CMR was 10 weeks (range, 2-96). Median times to platelet and ANC recovery in cycle 1 were 22 and 18 days, respectively, and for subsequent cycles were 22 and 16 days, respectively. Grade ≥3 pancreatitis was observed in 12 pts (19%), thrombotic events in 4 (6%) and MI in 3 (5%). 8 pts have died, with 2 deaths attributed to ponatinib (both from MI). No grade ≥3 vascular events occurred after the protocol amendment. 38 pts continue to receive treatment (7 in consolidation, 14 in maintenance and 17 post-maintenance). 10 pts (16%) underwent allogeneic SCT in CR1. 7 pts have relapsed, 3 of whom were still receiving ponatinib. The 3-year continued remission and OS rates were 79% and 76%, respectively. In a landmark analysis at 4 months, CR duration and OS did not differ significantly in pts with or without allogeneic SCT. Conclusions: HCVAD plus ponatinib is highly effective in pts with newly diagnosed Ph+ ALL, resulting in high rates of CMR and promising long-term survival. Clinical trial information: NCT01424982.
FRI0517 Quality of life in patients with early psoriatic arthritis
Authors: S Monov, A Kopchev
Journal: Annals of the Rheumatic Diseases (2017)

<h3>Background</h3> Psoriatic arthritis (PsA) is a chronic systemic inflammatory disease. Affecting skin, joints, entheses and dactylitis, its impact on health-related quality-of-life (HRQoL) could be substantial. <h3>Objectives</h3> The aim of this study was to describe HRQoL in newly diagnosed PsA patients taking into account skin involvement, swollen joints, tender enthuses and dactylitis. <h3>Methods</h3> HRQoL was assessed by 8 subscales of the Short-Form 36 (SF-36) questionnaire (0–100, higher score represents a better HRQoL). Patients were classified in arthritis subtypes (i.e. mono-, oligo- or polyarthritis) by rheumatologist. Entheses were evaluated using the Leeds Enthesitis Index (LEI) and Maastricht Ankylosing Spondylitis Enthesitis Score (MASES; positive if tender entheses &gt;1). Psoriasis was evaluated using the Psoriasis Area Severity Index (PASI; mild: 0–7; moderate/severe: &gt;7) and dactylitis using the Leeds Dactylitis Index (LDI). <h3>Results</h3> 87 patients (48 male, 39 female, mean age 47,6±15,3) with PsA (21 had monoarthritis, 49 - oligoarthrit and 17 - polyarthritis) completed the SF-36 were included in the study. Psoriasis was mild in 63 (72,41%) patients and moderate/severe in 12 (13,79%) patiients. At least one digit with dactylitis was present in 10 (11,49%) of the patients. A tender enthesis was present in 39 (44,83%) of patients. Mean scores of the subdomains in the SF-36 were similar across the different arthritis groups, with slightly worse scores for polyarthritis compared to mono- and oligoarthritis. However, when stratifying these groups for the presence of a tender enthesis, HRQoL decreased substantially for all groups across all subdomains of the SF-36, with a median difference of 12,9 points. Irrespective of joint involvement, a tender enthesis decreased the mean scores of all subdomains significantly compared to the non-tender enthesis group (p&lt;0,05). Severity of psoriasis and presence of dactylitis did not lead to significantly different SF-36 values compared to those not affected. <h3>Conclusions</h3> Having tender entheses impacts HRQoL severly in both its physical and mental dimensions in incident untreated PsA. <h3>Disclosure of Interest</h3> None declared
Abstract 105: The Novel Heart-specific Ring-finger Protein 207 Regulates Energy Metabolism in Cardiomyocytes
Authors: Wataru Mizushima, Hidehisa Takahashi, Masashi Watanabe, Shintarou Kinugawa, Shouji Matsushima, Shingo Takada, Takashi Yokota, Takaaki Furuhata, Junichi Matsumoto, Masaya Tsuda, Takashi Katayama, Takayuki Nakajima, Shigetsugu Hatakeyama, Hiroyuki Tsutsui
Journal: Circulation Research (2016)

Background: Ring-finger proteins constitute a large protein family in the human genome and play essential roles in various biological processes. However, little is known about heart-specific Ring-finger proteins and those relations with cardiac functions. We performed the comprehensive analysis of the expression profiles of various kinds of Ring-finger proteins and found that Ring-finger protein 207 (RNF207) was largely expressed in the heart. The purpose of our study was to elucidate a role of RNF207 in the heart. Methods and Results: First, we confirmed that RNF207 was predominantly expressed in the heart at the mRNA and protein level. Next, we examined whether the expression of RNF207 changed in transverse aortic constriction (TAC) model mice and coronary ischemic heart failure model mice . 4 weeks after TAC, mRNA level of RNF207 was significantly decreased to approximately 40% of that in sham mice. Moreover, we found that the protein level of RNF207 in the mice with heart failure was significantly reduced to around 70% of that in sham mice. Considering the well-known facts that the heart is a high-energy demanding organ and that the levels of ATP in cardiomyocytes are reduced in those model mice, we hypothesized that RNF207 got involved in cardiac energy metabolism. To investigate the hypothesis, we depleted RNF207 in rat neonatal cardiomyocytes (RNC) and performed metabolomic analysis. Metabolomic analysis revealed that ATP concentration and NADH/NAD + ratio were significantly lower and mitochondrial function was significantly reduced in RNF207 depleted RNC, compared to control NRC. Next, to elucidate the molecular mechanism by which RNF207 had effect on cardiac energy metabolism, we explored RNF207-associated proteins by mass spectrometric analysis. We identified voltage-dependent anion channel 1 (VDAC1) as a RNF207-associated protein. It has been shown that mitochondrial protein VDAC1 plays a crucial role in mitochondrial functions, such as energy metabolism. We confirmed that RNF207 directly interacted with VDAC1 by in vitro binding assay. Our results strongly indicate that RNF207 functions as a regulator of cardiac energy metabolism. Conclusion: RNF207 is a novel heart-specific protein and regulates energy metabolism in cardiomyocytes.
OP0082 Fibrosis and microangiopathy are the main histopathological hallmarks of scleroderma-related myopathy
Authors: C Corallo, M Cutolo, S Soldano, N Volpi, D Franci, A Montella, C Chirico, R Nuti, N Giordano
Journal: Annals of the Rheumatic Diseases (2017)

<h3>Background</h3> Systemic sclerosis (scleroderma, SSc) is an autoimmune connective tissue disease characterized by skin and internal organ fibrosis, coupled with widespread vascular pathology. Skeletal muscle involvement in SSc has often been considered as a minor component of the disease associated with disuse. <h3>Objectives</h3> The goal of this study is to identify specific histopathological hallmarks of skeletal muscle involvement in SSc. <h3>Methods</h3> A total of 50 SSc patients presenting clinical, serological and electromyographic (EMG) features of muscle weakness, were enrolled. Patients underwent vastus lateralis biopsy, assessed for individual pathologic features including fibrosis [type I collagen (Coll-I), transforming growth factor β (TGF-β)], microangiopathy [cluster of differentiation 31 (CD31), pro-angiogenic vascular endothelial growth factor A (VEGF-A), anti-angiogenic VEGF-A165b], immune/ inflammatory response [CD4, CD8, CD20, human leucocyte antigens ABC (HLA-ABC)], and membranolytic attack complex (MAC). SSc biopsies were compared to biopsies of (<i>n</i> =50) idiopathic inflammatory myopathies (IIMs) and to (<i>n</i> =50) noninflammatory myopathies (NIMs). Ultrastructural abnormalities of SSc myopathy were also analyzed by transmission electron microscopy (TEM). <h3>Results</h3> Fibrosis in SSc myopathy (90%) is higher compared to IIM (30%, <i>p</i> &lt;0.05) and to NIM (15%, <i>p</i> &lt;0.05). Vascular involvement is dominant in SSc muscle (95%), and in IIM (75%) compared to NIM (20%, <i>p</i> &lt;0.05). In particular, CD31 shows loss of endomysial vessels in SSc myopathy with respect to IIM (<i>p</i> &lt;0.05) and to NIM (<i>p</i> &lt;0.01). VEGF-A is downregulated in SSc myopathy compared to IIM (<i>p</i> &lt;0.05) and to NIM (<i>p</i> &lt;0.05), while VEGF-A165b is upregulated in SSc myopathy. The SSc immune/inflammatory response suggested humoral process with majority (80%) HLA-ABC fibral neoexpression and complement deposits on endomysial capillaries MAC, compared to IIM (<i>p</i> &lt;0.05), characterized by CD4+/CD8+/B-cell infiltrate, and to NIM (<i>p</i> &lt;0.05). TEM analysis showed SSc vascular alterations consisting of thickening and lamination of basement membrane and endothelial cell 9swelling9 coupled to endomysial/perimysial fibrosis. <h3>Conclusions</h3> The predominat features of SSc-related myopathy are fibrosis, microangiopathy and humoral immunity. However, it is difficult to identify specific histopathological hallmarks of muscle involvement in SSc, since they could be present also in other (IIM/NIM) myopathies. <h3>Disclosure of Interest</h3> None declared