tbuckley/cabot-search huggingface dataset:
SAT0321 CARDIOVASCULAR EVENTS IN SPONDYLOARTHRITIS : A META-ANALYSIS
Authors: Jihyoun Kim, In Ah Choi
Journal: Annals of the Rheumatic Diseases (2019)

<h3>Background:</h3> Several studies have demonstrated the possibility of increased risk of cardiovascular disease in patients with inflammatory arthritis such as anklyosing spondylitis and rheumatoid arthritis. In recent years, studies using population -based cohort and insurance claim data have been actively conducted. <h3>Objectives:</h3> To compare risks for cardiovascular disease including myocardial infarction (MI), ischemic heart disease (IHD), stroke and mortality of spondyloarthritis compared to general population using large-scale data. <h3>Methods:</h3> A systematic search was performed in MEDLINE, EMBASE with additional manual searches for studies associated with spondyloarthritis published between January 1997 and October 2018. All search screening and data collection were performed independently by two reviewers. We calculated the incidences of MI, IHD, stroke and mortality in a meta-analysis of proportion and determined risk ration (RR) by Mante-Haenszel method. <h3>Results:</h3> We identified total 495 articles and 16 articles met criteria for meta-analysis including 13 anklyosing spondylitis (AS) studies, 3 psoriatic arthritis (PsA) studies and 1 undifferentiated spondyloarthritis study. The articles were based on large-scale data such as national population cohort or insurance claim data. A meta-analysis result showed a significant increase in the risk of MI (RR= 1.38; 95% CI 1.18 to 1.61), and stroke (RR= 2.04; 95% CI 1.11 to 3.78) in spondyloarthritis patients compared to general population. However, mortality related with cardiovascular disease (RR=1.19; 95% CI 0.96 to 1.48) and total mortality (RR= 1.31; 95% CI 0.8 to 2.15) results did not show significant increases in spondyloarthritis patients. <h3>Conclusion:</h3> Our meta-anaylsis results showed that the the risk of MI and stroke significantly increased although mortality associated with cardiovasular (CV) disease and overall mortality did not increase in spondyloarthritis compared to general population. These findings support the reduction of inflammation as well as the management of traditional cardiovascular disease risk factors may reduce CV risk in patients with spondyloarthritis. <h3>References</h3> [1] Szabo SM, Levy AR, Rao SR, et al. Increased risk of cardiovascular and cerebrovascular diseases in individuals with ankylosing spondylitis: a population-based study. Arthritis Rheum2011; 62: 3294-304. [2] Park CJ, Choi YJ, Kim JG, et al. Association of acute myocardial infarction with ankylosing spondylitis: a nationwide longitudinal cohor study. Journal of Clinical Neuroscience2018; 56: 34–37. [3] Bengtsson, K, Forsblad-d'Elia H, Lie E, et al. Are ankylosing spondylitis, psoriatic arthritis and undifferentiated spondyloarthritis associated with an increased risk of cardiovascular events? A prospective nationwide population-based cohort study. Arthritis Res Ther2017; 19:102. <h3>Disclosure of Interests:</h3> None declared
Dynamics of the human antibody repertoire after B cell depletion in systemic sclerosis
Authors: Charles F. A. de Bourcy, Cornelia L. Dekker, Mark M. Davis, Mark R. Nicolls, Stephen R. Quake
Journal: Science Immunology (2017)

Systemic sclerosis with pulmonary arterial hypertension (SSc-PAH) is a debilitating and frequently lethal disease of unknown cause lacking effective treatment options. Lymphocyte anomalies and autoantibodies observed in systemic sclerosis have suggested an autoimmune character. We study the clonal structure of the B cell repertoire in SSc-PAH using immunoglobulin heavy chain (IGH) sequencing before and after B cell depletion. We found SSc-PAH to be associated with anomalies in B cell development, namely, altered VDJ rearrangement frequencies (reduced IGHV2-5 segment usage) and an increased somatic mutation-fixation probability in expanded B cell lineages. SSc-PAH was also characterized by anomalies in B cell homeostasis, namely, an expanded immunoglobulin D-positive (IgD+) proportion with reduced mutation loads and an expanded proportion of highly antibody-secreting cells. Disease signatures pertaining to IGHV2-5 segment usage, IgD proportions, and mutation loads were temporarily reversed after B cell depletion. Analyzing the time course of B cell depletion, we find that the kinetics of naïve replenishment are predictable from baseline measurements alone, that release of plasma cells into the periphery can precede naïve replenishment, and that modes of B cell receptor diversity are highly elastic. Our findings reveal humoral immune signatures of SSc-PAH and uncover determinism in the effects of B cell depletion on the antibody repertoire.
PS1369 AMITRIPTYLINE STRENGTHENS THE EFFECTS OF BORTEZOMIB AND MELPHALAN TREATMENT IN MULTIPLE MYELOMA BY INHIBITING ACID SPHINGOMYELINASE
Authors: S. Faict, I. Oudaert, K. De Veirman, K. Maes, L. Jacobs, E. De Bruyne, J. Swinnen, R. Schots, K. Fostier, I. Vandebroek, K. Vanderkerken, L. D’Auria, E. Menu
Journal: HemaSphere (2019)

Background: Malignant cells can adapt their lipid metabolism to attain higher rates of proliferation, and resist chemotherapy‐induced apoptosis. Aims: In this study, we aimed to identify the changes in lipid metabolism in multiple myeloma (MM) patients, and to further investigate the role of this altered metabolism in vitro. Methods: We performed a lipidomics analysis to compare plasma from MM patients to healthy controls. Based on these results, lipid spike‐in assays enabled us to evaluate effects on MM cell proliferation. Sphingomyelinase (SMase) content of MM cells and their exosomes was measured, before and after treatment with standard‐of‐care drugs, using an AmplexRed assay. We inhibited both neutral and acid SMase (ASM) in MM cells to evaluate effects on drug efficacy. Finally, we investigated whether MM exosomes rich in ASM are able to induce drug resistance in MM cells low in ASM. Results: Lipidomics analysis revealed that several ceramide species were significantly more present in MM patient plasma, while sphingomyelin seemed to be decreased. When adding ceramide in vitro to MM cells, we observed higher viability and proliferation. The increased ceramide/sphingomyelin ratio in plasma lead us to believe that the sphingomyelinase enzyme, which converts sphingomyelin into ceramide, was upregulated in MM cells. This was confirmed in BM samples, comparing CD138+ MM cells to the CD138‐ fraction. In the MM cell lines JJN3, OPM2, LP1 and U266, we observed an increased expression of acid and total SMase when treating these cells with melphalan or bortezomib for 24 h. Furthermore, we investigated whether MM exosomes were involved in the secretion and transfer of acid SMase. Interestingly, amitriptyline, an inhibitor of acid SMase, often prescribed in MM patients for neuropathic pain, increased the efficacy of both drugs in vitro, and also induced apoptosis in primary MM cells as a single agent. Summary/Conclusion: SMase is increased in primary MM cells and cell lines upon treatment with melphalan and bortezomib, while inhibiting this expression using amitriptyline leads to a higher efficacy of drug therapy.
THU0137 SUBCLINICAL THYROID DYSFUNCTION IS A CARDIOVASCULAR DISEASE RISK IN FEMALE RHEUMATOID ARTHRITIS
Authors: Suad Hannawi, Haifa Hannawi, Issa Al Salmi
Journal: Annals of the Rheumatic Diseases (2019)

<h3>Background</h3> Rheumatoid arthritis (RA) is a multisystem autoimmune disease that proved to be associated with other autoimmune diseases particularly hypothyroidism. Subclinical hypothyroidism had been reported in RA. As well, RA patients are at double the risk of cardiovascular diseases (CVD). The increased risk of CVD is not fully explained by the traditional and non-traditional CVD risk factors. In general population, hypothyroidism had been reported as a CVD risk factor. <h3>Objectives</h3> This study aimed for the first time to investigating the relationship between thyroid function parameters and the CVD risk as manifested by the carotid intima media thickness (cIMT) among RA patients. <h3>Methods</h3> All the RA patients were recruited through a specialized rheumatology clinic at the Ministry of Health and Prevention of UAE, from April 2016 to December 2018. Fasting Free thyroxine (FT4), Free triiodothyronine (FT3), and thyroid stimulating hormone (TSH) were assessed in all the participants within the same week of the cIMT measurement. Linear regression analysis used to look for the correlation of the thyroid function test (TSH, T$, and T3) and the cIMT. <h3>Results</h3> A total of 154 female RA patients satisfying ACR/EULAR criteria for diagnosis of RA were recruited. None of the patients had history of thyroid, renal, or hepatic disorders. None of the patients were pregnant. The mean age for the participants was 50 ±12 years (Min16 –Max 87). The mean FT4 was 15.7 ± 3.6 (NR: 12-22 pmol/L), mean FT3 was 4.54± 1.0 (NR: 4-6.8 pmol/L), and mean TSH was 2.60 ± 3.3 (NR:0.27-4.2 mlU/L). The mean cIMT was 0.57±0.11 mm. correlating TFT with cIMT showed that while there was no correlation between each of the FT3 and FT4with the cIMT (P value 0.46 and 0.19, respectively), there were a significant negative linear relationship between TSH value and the cIMT (P=0.03, β=- -0.006). <h3>Conclusion</h3> Subclinical thyroid dysfunction might be an additional non-traditional CVD risk factors that can help in filling the gap of understanding the increased risk of CVD in RA. Further studies at a larger scale are needed to confirm the study findings. Also, there is a need to confirm if management of thyroid dysfunction in RA may help in overall improvement of this subset of population. <h3>References</h3> [1] Atzeni F, Doria A, Ghirardello A, Turiel M, Batticciotto A, Carrabba M, Sarzi-Puttini P. Anti-thyroid antibodies and thyroid dysfunction in rheumatoid arthritis: Prevalence and Clinical Value. Autoimmunity. 2008;41:111–5. [2] Andonopoulos A, Siambi V, Makri M, Christofidou M, Markou C, Vagenakis A. Thyroid function and immune profile in rheumatoid arthritis. A controlled study Clin Rheumatol.1996;15:599–603. [3] Shiroky J, Cohen M, Ballachey M, Neville C. Thyroid dysfunction in rheumatoid arthritis: a controlled prospective survey. Ann Rheum Dis. 1993;52:454–6 <h3>Disclosure of Interests</h3> None declared
THU0346 EVALUATION OF A NOVEL PARTICLE-BASED ASSAY FOR DETECTION OF MYOSITIS SPECIFIC ANTIBODIES
Authors: Michael Mahler, Kishore Malyavantham, Michaelin Richards, Chelsea Bentow, Silvia Casas, Eva Balada, Maite Sanz, M. Angeles Martinez, Albert Selva-O’callaghan
Journal: Annals of the Rheumatic Diseases (2019)

<h3>Background</h3> Myositis specific antibodies (MSA) represent important diagnostic tools and also help stratify idiopathic inflammatory myositis (IIM) patients with particular clinical features, treatment responses, and disease outcomes. Standardization of MSA detection is of high importance because these antibodies also have the potential to be used in classification criteria. <h3>Objectives</h3> The objective of this study was to evaluate the clinical performance of a novel particle based multi-analyte technology (PMAT) for the detection of MSA as an aid in the diagnosis and also in the differentiation of IIM subtypes. <h3>Methods</h3> The study included 464 patient samples collected at Hospital Vall d'Hebron, Autonomous University of Barcelona, most of whom had a diagnosis of IIM (n=264). As controls, samples from patients with myositis like conditions (ML, n=20), rheumatoid arthritis (RA, n=33), systemic lupus erythematosus (SLE, n=40), Sjögren's syndrome (SjS, n=25), infectious diseases (ID, n=40) and healthy individuals (HI, n=42) were included. All samples were tested using a novel fully automated particle-based multi-analyte technology (PMAT, Inova Diagnostics, research use only; Jo-1, PL-7, PL-12, EJ, Mi-2b, NXP2, SAE, TIF1y, MDA5, HMGCR, SRP) which utilizes paramagnetic particles with unique signatures and a digital interpretation system. <h3>Results</h3> The sensitivity/specificity of the individual MSA were: 19.7%/100% (Jo-1), 7.2%/100.0% (Mi-2), 3.0%/99.0% (NXP2), 3.8%/100.0% (SAE), 2.7%/100.0% (PL-7), 1.9%/99.5 (PL-12), 1.1%/100.0% (EJ), 15.5%/99.5% (TIF1y), 8.3%/98.5% (MDA5), 6.1%/99.0% (HMGCR) and 1.9%/98.5% (SRP). The overall clinical performance was: sensitivity 68.2% (95% confidence interval 62.3-73.5%), specificity 94.0% (95% CI 89.8-96.5%) and odds ratio 33.8. In the table below, the sensitivity and specificity of each analyte for IIM subtypes was calculated along with odds ratio. <h3>Conclusion</h3> The novel PMAT used to detect a spectrum of MSA in IIM on a fully automated system showed good sensitivity and specificity in line with the known associations of MSA. Sensitivities and specificities of the individual MSA are within expected ranges. Lastly, the individual markers help to stratify patients into IIM subtype which is important for management of the patients. <h3>Disclosure of Interests</h3> Michael Mahler Employee of: Inova Diagnostics (Not pharmaceutical, diagnostics company), Kishore Malyavantham Employee of: Inova Diagnostics, Michaelin Richards Employee of: Inova Diagnostics, Chelsea Bentow Employee of: INOVA Diagnostics, Silvia Casas Employee of: Inova Diagnostics, Eva Balada: None declared, Maite Sanz: None declared, M. Angeles Martinez: None declared, Albert Selva-O'Callaghan: None declared
Many Elderly Patients With Stage IV Metastatic Renal Cell Carcinoma May Benefit From More-Aggressive Treatment
Authors: Alex Shteynshlyuger
Journal: JAMA Network Open (2019)

Pengxiang Li, PhD; Jordan Jahnke, MS; Amy R. Pettit, PhD; Yu-Ning Wong, MD, MSCE; Jalpa A. Doshi, PhD
AB1309 QUANTIFICATION OF MINIMAL RESIDUAL DOSE ASSOCIATED WITH BIOLOGICAL THERAPEUTIC RESPONSE ANTI DRUG ANTI BODIES: ARE THEY ALL NEUTRALIZING?
Authors: Salma Athimni, rim dhahri, Maroua Slouma, Leila Metoui, Imen Gharsallah, Bassem Louzir, Maroua Meddeb, Mahdi Dridi
Journal: Annals of the Rheumatic Diseases (2019)

<h3>Background:</h3> The use of biological was associated to the capacity of inducing an immune response in patients that could neutralize the drug. The anti-body anti-drug (ADA) assay was a revolutionary tool to prevent treatment failure. <h3>Objectives:</h3> The aim of this work was to asses if the presence of ADA in patients system is sufficient to preduct failure and indicates the switch of treatment. <h3>Methods:</h3> We enrolled 69 patients treated with biotherapy between September 2017 and October 2018. 3 pathologies were considered: rheumatoid Arthritis (RA) diagnosed by ACR/EULAR 2009 criteria, Spondylarthritis (SPA) according to Assessment of Spondylarthritis international Society (ASAS) And crohn's disease (CD) classified upon the 2006'Montreal classification. We did search the presence of anti-body antidrugs (ADA) and the residual dose for the following therapies: Etanercept (ETN), Infliximab (IFX), Adalimumab (Ada) or Rituximab (RTX). <h3>Results:</h3> The mean age was 43.33 ± 11.4 year. The sex ratio M/F was 1.57. there were 13 patients with RA, 28 SPA and 28 CD. The Majority of patients were receiving IFX 50.7%(n=35) with same doses. There were 20 responding versus 15 non-respondingpatients. 40% of them had a high residual dose. Regarding Ada 24.6% (n=17). There were 9 non-responding patients and low residual doses were found in 47.1%. 11 patients were using ETN. The ADA was positive in only one patient who was non-responding and having a low residual dose. Concerning the RTX, it was used for 6 patients. The ADA was negative in all patients. Two non-responding cases having a low residual dose. The following table explains the repartition of patients according to ADA rates: Positive ADA was associated with therapy failure in all type of biotherapy (p=0.001). A low residual dose was associate to therapy failure only in the case of IFX (p=0.005). Positive ADA was associated to a low rate of residual dose in the case of IFX and Ada. This association couldn't be evaluated for RTX (none) and ETN (just one positive rate). <h3>Conclusion:</h3> The ADA assay is a revolutionary tool allowing the evaluation of treatment response but it cannot be considered without the clinical assessment of patient. The evaluation residual dose should be concomitant to valorize and guide the therapeutic decision <h3>References</h3> [1] Kristensen LE, Kapetanovic MC, Gülfe A, Söderlin M, Saxne T, Geborek P. Predictors of response to anti-TNF therapy according to ACR and EULAR criteria in patients with established RA: results from the South Swedish Arthritis Treatment Group Register. Rheumatology (Oxford). 2008;47:495-9. [2] Lanfant-Weybel K, Lequerré T, Vittecoq O. Anti-TNF alpha dans le traitement de la polyarthrite rhumatoïde et de la spondylarthrite ankylosante. Presse Med. 2009;38:774-87. <h3>Disclosure of Interests:</h3> None declared
Abstract 15701: SPECT-Guided Myocardial Perfusion and Metabolic Fatty Acid Planar Imaging Reflects the Severity of the Pulmonary Hypertension in the Patients With Chronic Thromboembolic Pulmonary Hypertension
Authors: Masahiro Satoh, Hideyuki Miyauchi, Seiichiro Sakao, Takashi Iimori, Koichi Sawada, Yoichi Kuwabara, Koichiro Tatsumi, Yoshio Kobayashi
Journal: Circulation (2017)

Introduction: Patients with chronic thromboembolic pulmonary hypertension (CTEPH) represent right ventricular (RV) enlargement and hypertrophy, which consequently increases the RV myocardial perfus...
The druggable genome and support for target identification and validation in drug development
Authors: Chris Finan, Anna Gaulton, Felix A. Kruger, R. Thomas Lumbers, Tina Shah, Jorgen Engmann, Luana Galver, Ryan Kelley, Anneli Karlsson, Rita Santos, John P. Overington, Aroon D. Hingorani, Juan P. Casas
Journal: Science Translational Medicine (2017)

The druggable genome and genome-wide association study data reveal new drug development and repurposing opportunities.
One-step colorimetric genotyping of single nucleotide polymorphism using probe-enhanced loop-mediated isothermal amplification (PE-LAMP)
Authors: Sheng Ding, Rong Chen, Gangyi Chen, Mei Li, Jiayu Wang, Jiawei Zou, Feng Du, Juan Dong, Xin Cui, Xin Huang, Yun Deng, Zhuo Tang
Journal: Theranostics (2019)

Single nucleotide polymorphism (SNP) is the most abundant molecular marker associated with many physiologic and pathologic phenotypes. An isothermal, accurate and cost-effective SNP detection could make a great difference in point-of-care testing (POCT) or on-site diagnosis. However, there are two challenges, the expensive instrument and labor-intensive process, faced by the development of on-site SNP detection. We reported a novel SNP typing method based on the probe-enhanced loop-mediated isothermal amplification (PE-LAMP), which combines the oligonucleotide probe with a conventional LAMP to realize the SNP discrimination by analyzing the great discrepancy in amplification efficiency. Methods: We firstly constructed the genotyping method by combining the hybridization of the specific probe with the powerful amplification of LAMP. Then we validated the method by genotyping the SNP rs3741219 and we sought to realize one-step visualized typing. Finally, we applied the method to pharmacogenomic testing by genotyping CYP2C19*2 and MDR1 C3435T. Results: The PE-LAMP was successfully constructed to detect SNP and the sensitivity of our method is as low as 1000 copies of target DNA, which is sufficient to routine diagnosis. The high specificity in detecting mutant in the presence of excess wild-type allele could be achieved. It has shown good performance in helping predict the individual response of antiplatelet drug Clopidogrel through typing simply treated saliva samples. Conclusions: The proposed method is one-step, colorimetric, specific and sensitive enough to detect crudely treated samples, showing great potential in the pharmacogenomic study and POCT use.
PS1101 PERIOPERATIVE MANAGEMENT AND OUTCOMES IN CHILDREN WITH CONGENITAL BLEEDING DISORDERS: A RETROSPECTIVE REVIEW AT A SINGLE HEMOPHILIA TREATMENT CENTER
Authors: Y.S. Park, H.N. Chon
Journal: HemaSphere (2019)

Background: Establishing hemostasis for surgical procedures in children with inherited bleeding disorders is challenging. Providers are often hesitant to undertake surgeries in children with bleeding disorders out of fear of bleeding complications. However, appropriate presurgery/preprocedure factor replacement can decrease pre‐, peri‐, and postoperative bleeding complications and allow almost any necessary surgical procedure to proceed. Aims: We review the results of surgical procedures in children with inherited bleeding disorders at our center and review the preoperative management and hemorrhagic complications. Methods: We conducted a retrospective electronic medical record review from October 2006 to November 2018. Primary focus was review of factor replacement strategies and bleeding complications. Data were collected from patients under 18 years of age. Results: In total, 152 procedures were performed in 99 children at our center. The distribution of bleeding disorders is as follows; hemophilia A 79, hemophilia B 15, Von Willebrand disease 3 and FVII deficiency 2. The median age of the patients was 13 years (range, 0∼18). Duration of hospitalization was median 8 days (range, 0∼44) and period from surgery to discharge was median 7 days (range, 0∼42). Nineteen procedures (12.5%) in 8 children were performed in the presence of high titer inhibitors to coagulation factor. Procedures included synovectomy (84/152, 55.3%), orthopaedic procedures except synovectomy (22/152, 14.5%), central venous catheter placement or revision (9/152, 5.9%), otolaryngology procedures (7/152, 4.6%), circumcision (6/152, 3.9%), laparoscopic appendectomy (5/152, 3.3%) and miscellaneous (19/152, 12.5%). All patients received preoperative factor replacement (100% in hemophilia patients) followed by various factor replacement regimens postoperatively. No deaths or life‐threatening bleeding occurred with any procedure. Seven of 152 procedures (4.6%) were complicated by bleeding. Tonsillectomy was the most common procedure complicated by hemorrhage 3 of 7 (42.9%). The complete list of all 168 surgical procedures is shown in Table 2.All patients received preoperative factor replacement (100% in hemophilia patients) followed by various factor replacement regimens postoperatively. No deaths or life‐threatening bleeding occurred with any procedure. Seven of 152 procedures (4.6%) were complicated by bleeding. Tonsillectomy was the most common procedure complicated by hemorrhage 3 of 7 (42.9%). Summary/Conclusion: Surgical procedures are safe in children with bleeding disorders with adequate planning and factor replacement. Bleeding remains a problem in a subset of patients and requires ongoing hematological involvement and oversight. Delayed bleeding following tonsillectomy was especially common and suggests a need for close follow‐up and ongoing factor coverage for this group of patients.