tbuckley/cabot-search huggingface dataset:
AB0004 Pharmacogenetic aspect of metotrexate, in a group of colombian patients with rheumatoid arthritis
Authors: E.L. Saldarriaga, C.A. González, L.F. Restrepo, R. Giraldo-Bustos, J.G. Ballesteros-Muñoz, A.Y. Vásquez, S. Arias-Correal, L. Valero, M.-J. Ospina, P. Lopez-Morales, E. Couto-Luvie, M.J. Soares-Santeugini, J.-I. Angarita, J.C. Rueda, F.-M. Cuervo, P. Santos-Moreno, J. Londoño, A.M. Santos
Journal: Annals of the Rheumatic Diseases (2018)

<h3>Background</h3> Methotrexate (MTX) as monotherapy or in combination, is the most commonly Disease-Modifying-AntiRheumatic-Drug (DMARDs) used in rheumatoid arthritis (RA). About 40% of patients do not respond to treatment or have adverse effects. The genetic variability could be responsible for this phenomenon. Different studies suggest associations between polymorphisms in the enzymes involved in the metabolic pathway of MTX with alterations in the efficacy and toxicity. <h3>Objectives</h3> Determine the polymorphisms of the enzymes involved in MTX metabolism in a group of Colombian patients. <h3>Methods</h3> 400 patients with RA over 18 years old, diagnosed according to the ACR/EULAR classification criteria, who consecutively attended an outpatient RA clinic between March 2015 and December 2016 were included. MTX efficacy was defined by DAS28 score ≥3.2, liver toxicity by elevation of transaminases above three times the normal value, Haematological toxicity by: leukocytes&lt;4,000, Hb &lt;9.5, platelets&lt;150,000, renal toxicity: creatinine &gt;1.5. The single nucleotide polymorphisms (SNPs) studied were MTHFR C677T, MTHFR A1298C, ATIC C347G, RFC1 G80A, FPGS-AG and DHFR-CT and were identified by the technique of polymerase chain reaction in real time (RT-PCR). <h3>Results</h3> The mean age of patients was 60.7±13.9 years, the duration of the disease was 13.2±10.9 years and 76% were women. A significant increase in the frequency of MTHFR C677T and A1298C SNPs (p=0.05 and p=0.048) were found in the responding patients compared to non-responders. The DHFR-CT and the ATIC C347G SNPs were significantly increased in patients with any toxicity to MTX (p=0.0095 and p=0.005 respectively). We did not find a significant difference between the polymorphisms studied with any specific toxicity. <h3>Conclusions</h3> The Colombian population has similar statistical data compared to the global studies regarding the association of SPNs with the efficacy and toxicity of methotrexate, however the polymorphisms associated with inefficiency in the literature are not replicated in our data. These SNPs could be established as biomarkers to the methotrexate response in terms of efficacy and toxicity in our Colombian population with RA. <h3>Reference</h3> [1] Fan H, Li Y, Zhang L, Li W. Lack of association between MTHFR A1298C polymorphism and outcome of methotrexate treatment in rheumatoid arthritis patients: Evidence from a systematic review and meta-analysis. Int J Rheum Dis2017;20(5):526–40. <h3>Disclosure of Interest</h3> None declared
FRI0025 Serum mediated peptidylarginine deiminase (PAD) activation in early rheumatoid arthritis
Authors: M.K. Jonsson, K. Falkowski, A. Aliko, A.-B. Aga, S. Lillegraven, J. Sexton, B.-T. S. Fevang, P. Mydel, E.A. Haavardsholm
Journal: Annals of the Rheumatic Diseases (2018)

<h3>Background</h3> Peptidylarginine deiminases (PADs) are a family of enzymes catalysing the conversion of arginine residues to citrulline, a post translational modification which has been recognised in the generation of neo-epitopes due to anti-citrullinated protein antibodies (ACPAs) in rheumatoid arthritis (RA). ACPAs are included in the classification criteria for RA, and may be present before disease onset and predictive of disease progression. <h3>Objectives</h3> To investigate whether serum of patients with early RA have the capacity to significantly increase the citrullination performed by PAD enzymes, and the possible role of increased enzyme activation as a mechanism preceding the production of ACPAs. <h3>Methods</h3> Serum from DMARD-naïve, early RA patients from the ARCTIC trial<sup>1</sup> classified according to the 2010 ACR/EULAR criteria were analysed for PAD4 activating capacities using HPLC fluorometric method. A sample was defined as positive if above mean +2 SD of the healthy controls. Patient characteristics and subgroups with PAD activity were assessed using Mann-Whitney U-test and chi-square test as appropriate. <h3>Results</h3> A total of 225 patients and 63 controls were included in the study. Patient characteristics and measures of disease activity and radiographic damage are presented in the table 1. Median PAD activity levels were higher in patients than in healthy controls (8768 [7491,11393] vs. 7046 [6347,7905], p&lt;0.0001; figure 1). ACPA and rheumatoid factor (RF) positive patients had higher PAD activity than ACPA and RF negative patients (9104 [7739,13213] vs. 7281 [6764,9010], p&lt;0.0001, and 8871 [7715,12259] vs. 8407 [6867,10062], p=0.048, respectively). PAD positivity occurred in 42% (n=95) of the patients and was more prevalent in ACPA positive compared to ACPA negative patients (47 vs. 20%, p=0.002), but not in RF positive vs. RF negative patients (44 vs. 38%, p=0.49). Disease Activity Score was numerically higher in patients positive for PAD than patients who were PAD negative (3.6 (1.1) vs. 3.3 (1.2), p=0.08). <h3>Conclusions</h3> Serum capacity to activate PAD4 was associated with ACPA and RF positivity in patients with early RA, but no distinct relationship was seen for Disease Activity Score. <h3>Reference</h3> [1] Haavardsholm, et al. BMJ2016. <h3>Disclosure of Interest</h3> M. Jonsson: None declared, K. Falkowski: None declared, A. Aliko: None declared, A.-B. Aga: None declared, S. Lillegraven: None declared, J. Sexton: None declared, B.-T. Fevang: None declared, P. Mydel: None declared, E. Haavardsholm Grant/research support from: AbbVie, Pfizer, MSD, UCB, Roche
SP0105 Mri in early and established spa: what is the added value?
Authors: I. Eshed
Journal: Annals of the Rheumatic Diseases (2018)

<h3></h3> MRI of the sacroiliac joints (SIJ) and of the spine has revolutionised diagnosis of early spondyloarthritis (SpA). With its high contrast resolution, it is able to detect inflammation of the SIJ in its early stage before structural damage occurs. The introduction of biological drugs from the has further emphasised the need for early diagnosis of sacroiliitis. Since the treatment is to be used in a narrow window of opportunity to reach disease control, MRI was rapidly embraced as a dominant diagnostic tool and at the same time included into the classification criteria for axSpA becoming the cornerstone of SpA diagnosis. In this presentation, the early and more established imaging characteristics of sacroiliitis will be discussed in context of other imaging modalities and potential differential diagnoses. <h3>Disclosure of Interest</h3> None declared
HER2 CAR-T Cells Eradicate Uveal Melanoma and T-cell Therapy–Resistant Human Melanoma in IL2 Transgenic NOD/SCID IL2 Receptor Knockout Mice
Authors: Elin M.V. Forsberg, Mattias F. Lindberg, Henrik Jespersen, Samuel Alsén, Roger Olofsson Bagge, Marco Donia, Inge Marie Svane, Ola Nilsson, Lars Ny, Lisa M. Nilsson, Jonas A. Nilsson
Journal: Cancer Research (2019)

Abstract Chimeric antigen receptors (CAR) can transmit signals akin to those from activated T-cell receptors when bound to a cell surface target. CAR-expressing T cells against CD19 can cause curative effects in leukemia and lymphoma and is approved for clinical use. However, no CAR-T therapy is currently approved for use in solid tumors. We hypothesize that the resistance of solid tumors to CAR-T can be overcome by similar means as those used to reactivate tumor-infiltrating T lymphocytes (TIL), for example, by cytokines or immune checkpoint blockade. Here we demonstrate that CAR-T cells directed against HER2 can kill uveal and cutaneous melanoma cells in vitro and in vivo. Curative effects in vivo were only observed in xenografts grown in a NOD/SCID IL2 receptor gamma (NOG) knockout mouse strain transgenic for human IL2. The effect was target-specific, as CRISPR/Cas9-mediated disruption of HER2 in the melanoma cells abrogated the killing effect of the CAR-T cells. The CAR–T cells were also able to kill melanoma cells from patients resistant to adoptive T-cell transfer (ACT) of autologous TILs. Thus, CAR-T therapy represents an option for patients that do not respond to immunotherapy with ACT of TIL or immune checkpoint blockade. In addition, our data highlight the use of IL2 transgenic NOG mice as models to prove efficacy of CAR-T-cell products, possibly even in a personalized manner. Significance: These findings demonstrate that a novel humanized mouse model can help clinical translation of CAR-T cells against uveal and cutaneous melanoma that do not respond to TIL therapy or immune checkpoint blockade.
THU0561 Anakinra first- or second-line in systemic juvenile idiopathic arthritis patients
Authors: A. Klein, A. Hospach, I. Foeldvari, G. Horneff
Journal: Annals of the Rheumatic Diseases (2018)

<h3>Background</h3> Treatment of systemic juvenile idiopathic arthritis (sJIA) still remains a challenge. <h3>Objectives</h3> Patients newly starting treatment with Anakinra (ANA) as first-line biologic were compared to ANA second-line users regarding efficacy and safety. <h3>Methods</h3> ANA treatment courses are documented by the German Biologics registry (BiKeR). Demographics, clinical characteristics, disease activity parameters as well as efficacy and safety parameters were compared in pts using ANA as first biologoc with those previously treated with other biologics. For efficacy analyses ACR inactive disease, JADAS minimal disease activity (MDA), JADAS remission (REM) and active joint count as well as functional ability assessment (CHAQ) were used. "Intention to treat" (ITT) and "as observed" (AO) analyses was performed. Safety assessments were based on adverse events (AE) reports. <h3>Results</h3> 47 pts started treatment with ANA, 33 pts were pretreated with other biologics (Etanercept n=29, Tocilizumab n=4, Infliximab and Canakinumab n=1). ANA first line pts had significantly shorter disease duration and had received DMARDs and i.a. steroids significantly less frequent than second line users. At baseline, ANA first-line users had higher disease systemic activty indicators (fever, rash, ESR), functional disability (CHAQ) and impaired parent/patient global assessment of overall well-being significantly more often, while there were no significant differences in Physician global assessment of disease activity, active joint count and JADAS 10. At last follow-up 43%&gt;66% of pts in both groups reached ACR inactive disease, 43%&gt;63% JADAS MDA, 29%–50% JADAS REM and 43%&gt;69% reached status of no functional disability. Rates did not differ between the 2 cohorts (table 1). 13 pts experienced adverse events (AE) with a rate of 53/100PY, 5 pts experienced serious AE (9/100PY) and in 11pts infections were reported (33/100PY). Macrophage activation syndrome was reported once in each group. One case of AML was reported in a patient one year after last exposure to ANA. No deaths were reported. <h3>Conclusions</h3> Anakinra is a feasible first-line biologic for treatment of sJIA. In the BiKeR cohort ANA treated pts showed a marked treatment response, as first or consecutive biologic. Rates of AE, SAE and infectious AE seem acceptable. <h3>Disclosure of Interest</h3> None declared
Genome-Wide Characterization of Arabian Peninsula Populations: Shedding Light on the History of a Fundamental Bridge between Continents
Authors: Veronica Fernandes, Nicolas Brucato, Joana C Ferreira, Nicole Pedro, Bruno Cavadas, François-Xavier Ricaut, Farida Alshamali, Luisa Pereira
Journal: Molecular Biology and Evolution (2019)

Abstract The Arabian Peninsula (AP) was an important crossroad between Africa, Asia, and Europe, being the cradle of the structure defining these main human population groups, and a continuing path for their admixture. The screening of 741,000 variants in 420 Arabians and 80 Iranians allowed us to quantify the dominant sub-Saharan African admixture in the west of the peninsula, whereas South Asian and Levantine/European influence was stronger in the east, leading to a rift between western and eastern sides of the Peninsula. Dating of the admixture events indicated that Indian Ocean slave trade and Islamization periods were important moments in the genetic makeup of the region. The western–eastern axis was also observable in terms of positive selection of diversity conferring lactose tolerance, with the West AP developing local adaptation and the East AP acquiring the derived allele selected in European populations and existing in South Asia. African selected malaria resistance through the DARC gene was enriched in all Arabian genomes, especially in the western part. Clear European influences associated with skin and eye color were equally frequent across the Peninsula.
Early Seroreversion After 2 Doses of Hepatitis A Vaccination in Human Immunodeficiency Virus–Positive Patients: Incidence and Associated Factors
Authors: Sung‐Hsi Huang, Chung‐Hao Huang, Ning‐Chi Wang, Tun‐Chieh Chen, Yuan‐Ti Lee, Shih‐Ping Lin, Te‐Yu Lin, Chi‐Ying Lin, Yu‐Lin Lee, Chen‐Hsiang Lee, Cheng‐Pin Chen, Kuan‐Yin Lin, Guan‐Jhou Chen, Chun‐Eng Liu, Shu‐Hsing Cheng, Po‐Liang Lu, Chia‐Jui Yang, Chien‐Ching Hung
Journal: Hepatology (2019)

Serological responses (Seroresponse) and durability of hepatitis A virus (HAV) vaccination are reduced among human immunodeficiency virus (HIV)‐positive patients. Incidence of and associated factors with early seroreversion (loss of seroresponse) among HIV‐positive patients who have achieved seroresponses after two doses of HAV vaccination remain unclear. In this multicenter study, we followed HIV‐positive adults who had mounted seroresponses after completing two doses of HAV vaccination during a recent outbreak of acute hepatitis A between 2015 and 2017, a 1:4 case‐control study was conducted to identify factors associated with seroreversion. Case patients were those with seroreversion, and controls were those with similar follow‐up durations who were able to maintain seroresponses. During the study period, 49 of the 1,256 patients (3.9%) seroreverted after a median follow‐up of 611 days. In a case‐control study, seroreversion was more likely to occur in patients with a higher weight (adjusted odds ratio [aOR], 1.703; 95% confidence interval [CI], 1.292‐2.323, per 10‐kg increment) and HIV viremia at the time of vaccination (aOR, 2.922; 95% CI, 1.067‐7.924), whereas positive seroresponse at 6 months of HAV vaccination and higher CD4 lymphocyte counts at vaccination were inversely associated with early seroreversion with an aOR of 0.059 (95% CI, 0.020‐0.154) and 0.837 (95% CI, 0.704‐0.979, per 100‐cell/mm 3 increment), respectively, in multivariable analyses. Conclusion: During an outbreak setting, early seroreversion following two‐dose HAV vaccination occurred in 3.9% of HIV‐positive patients. Lower and delayed seroresponses to HAV vaccination, a higher weight, and HIV viremia and lower CD4 lymphocyte counts at the time of HAV vaccination were associated with early seroreversion. Regular monitoring of seroresponse and booster vaccination might be warranted, especially in HIV‐positive adults with predictors of early seroreversion.
Modulating the antibody density changes the uptake and transport at the blood-brain barrier of both transferrin receptor-targeted gold nanoparticles and liposomal cargo
Authors: Kasper Bendix Johnsen, Martin Bak, Fredrik Melander, Maj Schneider Thomsen, Annette Burkhart, Paul Joseph Kempen, Thomas Lars Andresen, Torben Moos
Journal: Journal of Controlled Release (2019)
Abstract 16794: COX-2 and Cardiovascular Risk; Identification of New COX-2 Targets and Pathways Outside the Vessel Wall
Authors: Nicholas S Kirkby, William R Wright, Timothy D Warner, Mark J Paul-Clark, Jane A Mitchell
Journal: Circulation (2013)

COX-2 is the therapeutic target of anti-inflammatory drugs and also plays a role in cancer, but use of selective COX-2 inhibitors (e.g. rofecoxib) or non-selective COX-1/COX-2 inhibitors (e.g. ibup...
FRI0485 Phenotype of anca associated vasculitis associates with major cardiovascular events: a retrospective observational study from the leeds vasculitis cohort
Authors: A. Giollo, E.M.A. Hensor, J. Andrews, M.H. Buch
Journal: Annals of the Rheumatic Diseases (2018)

<h3>Background</h3> Patients with ANCA-associated vasculitides (AAV) are at increased risk of cardiovascular (CV) disease than the general population. The factors associated with CV involvement in AAV are poorly understood. <h3>Objectives</h3> To explore whether patient and disease-related characteristics associate with CV disease from a single-centre AAV cohort. <h3>Methods</h3> Medical records from 145 patients with AAV were reviewed and patients' diagnoses reclassified according to a validated algorithm.<sup>1</sup> CV events (CVE) were defined as myocardial infarction, cerebrovascular accident, thromboembolic event, heart failure, or death/hospitalisation due to CV cause. Time to first CVE was calculated; patients without CVE were censored at most recent clinical follow-up. Data on CV risk factors (hypertension, hyperlipidaemia, diabetes mellitus, chronic kidney disease stage III or higher) were collected. Putative predictors included age, sex, diagnosis (GPA, MPA, EGPA, unclassifiable AAV – UAAV), ANCA (absent, PR3, MPO), number of BVAS items, prior CV disease and number of CV risk factors. Cox proportional hazards regression was used to assess the relationship between CVE and predictors. In this exploratory analysis we used p&lt;0.10 to indicate potential associations. <h3>Results</h3> 122 patients who had been followed up for between 6 months and 23 years were included in the analysis. 11/122 patients (10%) had prior history of CV disease. 17 patients (14%) experienced a CVE within median (IQR) 5.8 (1.4, 7.6) years of diagnosis. Univariable analyses indicated older age at diagnosis, MPA and prior CVD were associated with increased risk of CVE, and that those with UAAV were at decreased risk compared to GPA. With the exception of previous CVD an adjusted model confirmed the same associations (table 1). <h3>Conclusions</h3> This exploratory analysis suggests that, among AAV, MPA may have a higher CV risk, whereas UAAV may be associated with a decreased risk. Along with ANCA status, AAV phenotype may inform future CV risk reduction interventions in AAV. <h3>Reference</h3> [1] Watts R, et al. Development and validation of a consensus methodology for the classification of the ANCA-associated vasculitides and polyarteritis nodosa for epidemiological studies. Annals of the Rheumatic Diseases2007. <h3>Disclosure of Interest</h3> None declared
FRI0409 Myositis specific anti-histidyl trna synthetase (HISRS) autoantibodies display high reactivity against hisrs conformational epitopes and associate with lung and joint involvement
Authors: C. Cerqueira, N. Renard, A. Notarnicola, E. Wigren, P.-J. Jakobsson, S. Gräslund, I.E. Lundberg
Journal: Annals of the Rheumatic Diseases (2018)

<h3>Background</h3> Autoimmune myositis (rheumatic muscle inflammation) associated with interstitial lung disease (ILD) and arthritis is strongly correlated with the presence of anti-histidyl tRNA synthetase (HisRS) autoantibodies.<sup>1</sup> <h3>Objectives</h3> The aims of this study were to investigate: 1) myositis IgG reactivity against HisRS conformational epitopes; and 2) association between clinical manifestations and anti-HisRS reactivity profiles. <h3>Methods</h3> Serum IgG was isolated using a protein G affinity column (from 25 anti-HisRS negative (-) and 19 anti-HisRS positive (+) myositis sera and 24 age/gender matched healthy controls, HC). Autoantibody reactivity was tested by in house ELISA developed against HisRS full-length protein and three HisRS conformational epitopes (WHEP domain – localised in the N-terminal; HisRS without WHEP (HisRS_WHEP); and ABD – anticodon-binding domain located in the C-terminal). Correlations between diagnosis, clinical manifestations and anti-HisRS IgG reactivity were evaluated. <h3>Results</h3> HisRS(+) myositis IgG displayed stronger reactivity against full-length HisRS and HisRS_WHEP (median 372 ng/mL and 334 ng/mL, respectively), compared to WHEP and ABD (6.38 and 6.48 ng/mL). The strongest anti-full-length HisRS reactivity (&gt;371 ng/mL) was detected in patients presenting ILD (10/10 of patients), arthritis (6/10) and polymyositis diagnosis (PM 9/10), in comparison to patients with low anti-HisRS reactivity (&lt;23 ng/mL, ILD – 5/6; arthritis – 3/6; PM – 5/6) or no anti-HisRS reactivity (ILD – 10/28; Arthritis – 8/28; PM – 15/28). On the contrary, myositis patients displaying no anti-HisRS reactivity were largely diagnosed with DM (11/28), skin rash (11/28) and dysphagia (6/28) when compared to patients with the highest anti-full-length HisRS reactivity (1 out of 10 patients was diagnosed with DM, skin rash or dysphagia). Similar associations were observed between the degree of anti-HisRS_WHEP, anti-WHEP or anti-ABD reactivities and manifestations of ILD, arthritis, skin rash or dysphagia, and DM or PM diagnosis. No anti-HisRS reactivity was detected in the HC group. <h3>Conclusions</h3> This study provides evidences for a possible underlying role of anti-HisRS autoantibodies in the pathogenesis of myositis with interstitial lung disease and joint involvement. <h3>Reference</h3> [1] Hamaguchi Y, Fujimoto M, Matsushita T, et al. Common and distinct clinical features in adult patients with anti-aminoacyl-tRNA synthetase antibodies: heterogeneity within the syndrome. PLoS One2013;8(4):e60442. <h3>Disclosure of Interest</h3> None declared