tbuckley/cabot-search huggingface dataset:
AB0432 ABT-494 has no effect on the QT interval at the doses being evaluated in rheumatoid arthritis phase 3 trials
Authors: M-EF Mohamed, J Zeng, P Jiang, B Hosmane, AA Othman
Journal: Annals of the Rheumatic Diseases (2017)

<h3>Background</h3> ABT-494 is a selective Janus Kinase 1 inhibitor currently being evaluated in Phase 3 trials for treatment of rheumatoid arthritis (RA) at doses of 15 mg and 30 mg once daily using the extended-release tablet formulation. Exposure-response analysis of ECG data collected at early stage clinical trials has been recently adopted in regulatory guidelines as a tool to assess the proarrhythmic risk of investigational new drugs. <h3>Objectives</h3> The objective of this work was to evaluate ABT-494 QT prolongation potential using exposure-response analysis of data collected in early Phase 1 studies. <h3>Methods</h3> Doses of ABT-494 or placebo were administered to healthy subjects in two Phase 1 studies. Evaluated ABT-494 immediate-release regimens ranged from 1 mg to 48 mg single doses under fasting conditions and 3 mg to 24 mg twice daily under non-fasting conditions. Serial triplicate electrocardiograms and pharmacokinetic assessments were conducted. The relationship between change from baseline in Fridericia-corrected QT interval (QTcF) and ABT-494 plasma concentrations was characterized using linear mixed-effects modeling. To evaluate the ECG assay sensitivity, the change in QTcF from baseline to 2 hours post-dose was compared for subjects who received placebo under fasting and non-fasting conditions. <h3>Results</h3> There was no statistically significant relationship between the change from baseline in the QTcF interval and ABT-494 plasma concentrations. The point estimate of the effect on QTcF for the highest concentration observed in the evaluated studies, which is approximately 4-fold higher than the mean C<sub>max</sub> of the highest RA Phase 3 dose, is –1.77 msec (with upper bound of the 95% one-sided confidence interval of 3.33 msec; lower than the regulatory threshold of concern of 10 msec). Food shortened the QTcF interval by 5.9 msec (2-sided 90% confidence interval of -9.6 to -2.1 msec), indicating that the ECG assay used in the studies had adequate sensitivity to detect the small change in QTcF caused by food. <h3>Conclusions</h3> ABT-494 showed no potential for QT prolongation at the expected therapeutic and supra-therapeutic plasma exposures for the doses being used in Phase 3 RA trials. <h3>Disclosure of Interest</h3> M.-E. Mohamed Shareholder of: AbbVie, Employee of: AbbVie, J. Zeng Shareholder of: AbbVie, Employee of: AbbVie, P. Jiang Shareholder of: AbbVie, Employee of: AbbVie, B. Hosmane Shareholder of: AbbVie, Employee of: AbbVie, A. Othman Shareholder of: AbbVie, Employee of: AbbVie
AB0176 Mitochondrial dysfunction in idiopathic inflammatory myopathy derived myoblasts
Authors: C Basualto-Alarcόn, MF Bozán, J Bevilacqua, F Urra, D González, H Gatica, A Göecke, P Wurmann, MF Sabugo, S Saavedra, C Cárdenas
Journal: Annals of the Rheumatic Diseases (2017)

<h3>Background</h3> Idiopathic inflammatory myopathies (IIM) are acquired skeletal muscle diseases, characterized by proximal muscle weakness. This syndrome includes five different (1) diseases, nevertheless, in this work, we included dermatomyositis (DM) and polymyositis (PM) patients. Has been reported that despite treating inflammation, muscle atrophy and weakness persist in some patients, suggesting an inherent muscle cause (2,3). In addition, histological studies show some mitochondrial abnormalities. Our aim was to evaluate a possible role for mitochondrial dysfunction in the pathophysiology of this diseases. <h3>Objectives</h3> To compare the mitochondrial status of myoblast obtained from myositis patients -and healthy control- biopsies. <h3>Methods</h3> Primary cultured myoblasts extracted from the deltoid of IIM patients were used and compared with myoblasts obtained from normal patients subjected to shoulder surgery. Also, a human skeletal muscle cell line (RCMH) was used as control. The bioenergetic profile was analyzed with an Extracellular flux analyzer<sup>e</sup>96 (Seahorse Biosciences). Also, biopsy tissue was used for Western blot (WB) and immunofluorescence experiments. <h3>Results</h3> Basal oxygen consumption rate, ATP-linked oxygen consumption, maximal oxygen consumption and spare respiratory capacity were lower in IIM myoblasts when compared to RCMH myoblasts, however, when compare to control primary cultured myoblasts we only find differences in ATP-linked oxygen consumption. Expression levels of mitochondrial complexes (I, III, IV and V) were analyzed by WB in tissue samples. No differences were observed between control and IIM patients. Mitochondrial area was estimated by immunofluorescence of the voltage dependent anion channel (VDAC), which show no differences between control and patients. <h3>Conclusions</h3> IIM derived myoblasts present a compromised mitochondrial function, compared to control myoblasts. Specially, oxygen consumption associated with ATP synthesis show decreased levels in patients. Although, expression levels of the mitochondrial complexes as well as mitochondrial area were not different between control and patients. Future experiments should address if IIM mitochondria are consuming less oxygen because of a lower ATP demand or because a primary mitochondrial damage. <h3>References</h3> Dalakas M. Inflammatory Muscle Diseases. N Engl J Med. 372:1734–1747, 2015. Park, J. H. et al. Magnetic resonance imaging and P-31 magnetic resonance spectroscopy provideunique quantitative data useful in the longitudinal management of patients with dermatomyositis. Arthritis Rheum.37, 736–46, 1994. Lee, H.-K. et al. Foxo/Atrogin induction in human and experimental myositis. Neurobiol. Dis.46, 463–475, 2012. <h3>Acknowledgements</h3> FONDECYT 3150623 &amp; 1151383; FONDAP 15150012. <h3>Disclosure of Interest</h3> None declared
CXCL12-CXCR4 signalling plays an essential role in proper patterning of aortic arch and pulmonary arteries
Authors: Bo-Gyeong Kim, Yong Hwan Kim, Edward L. Stanley, Eva M. Garrido-Martin, Young Jae Lee, S. Paul Oh
Journal: Cardiovascular Research (2017)

Chemokine CXCL12 (stromal derived factor 1: SDF1) has been shown to play important roles in various processes of cardiovascular development. In recent avian studies, CXCL12 signalling has been implicated in guidance of cardiac neural crest cells for their participation in the development of outflow tract and cardiac septum. The goal of this study is to investigate the extent to which CXCL12 signalling contribute to the development of aortic arch and pulmonary arteries in mammals.Novel Cxcl12-LacZ reporter and conditional alleles were generated. Using whole mount X-gal staining with the reporter allele and vascular casting techniques, we show that the domain branching pattern of pulmonary arteries in Cxcl12-null mice is completely disrupted and discordant with that of pulmonary veins and airways. Cxcl12-null mice also displayed abnormal and superfluous arterial branches from the aortic arch. The early steps of pharyngeal arch remodelling in Cxcl12-null mice appeared to be unaffected, but vertebral arteries were often missing and prominent aberrant arteries were present parallel to carotid arteries or trachea, similar to aberrant vertebral artery or thyroid ima artery, respectively. Analysis with computed tomography not only confirmed the results from vascular casting studies but also identified abnormal systemic arterial supply to lungs in the Cxcl12-null mice. Tie2-Cre mediated Cxcr4 deletion phenocopied the Cxcl12-null phenotypes, indicating that CXCR4 is the primary receptor for arterial patterning, whereas Cxcl12 or Cxcr4 deletion by Wnt1-Cre did not affect aortic arch patterning.CXCL12-CXCR4 signalling is essential for the correct patterning of aortic arches and pulmonary arteries during development. Superfluous arteries in Cxcl12-null lungs and the aortic arch infer a role of CXCL12 in protecting arteries from uncontrolled sprouting during development of the arterial system.
Response Rate to Chemotherapy After Immune Checkpoint Inhibition in Metastatic Urothelial Cancer
Authors: Bernadett Szabados, Nick van Dijk, Yen Zhi Tang, Michiel S. van der Heijden, Akhila Wimalasingham, Alfonso Gomez de Liano, Simon Chowdhury, Simon Hughes, Sarah Rudman, Mark Linch, Thomas Powles
Journal: European Urology (2017)
AB0426 The efficacy of the triple combination therapy with methotrexate, leflunomide and methylprednisolone in rheumatoid arthritis
Authors: L Groppa, E Russu, L Chislari, O Bujor
Journal: Annals of the Rheumatic Diseases (2017)

<h3>Background</h3> The RA modern treatment approaches are based on "aggressive therapy", which aims at suppressing autoimmune inflammation and prevent joint destructionsat the early stages of the disease. <h3>Objectives</h3> To evaluate the effectiveness and tolerability of the triple combination therapy with methotrexate, leflunomide and methylprednisolone in patients with rheumatoid arthritis. <h3>Methods</h3> The study included 150 patients with rheumatoid arthritis. As a result of randomization, 50 patients received triple combination therapy (methotrexate +methylprednisolone+leflunomide), 50 patients with monotherapy with methotrexate, leflunomide 50 others. As a result all patient groups were comparable after all clinical and demographic indices. <h3>Results</h3> Our results showed that triple therapy is very effective in treating patients with RA. A significant improvement on the criteria of the AAR (ACR&gt;50) at the end of the study was observed in most patients receiving methotrexate, leflunomide and methylprednisolone. This is confirmed statistically and clinically positive dynamics significantly in almost all indicators used of efficacy (pain, stiffness, number of tender and swollen joints, the activity of AR, the value VSH index functional HAQ) In addition, the use of triple therapy decreased average dose simultaneous use of glucocorticosteroids daily (from 5.0 to 2.5 mg) and 76% of patients canceled anti-inflammatory non-steroid drugs. <h3>Conclusions</h3> After randomized trial data lasting 24 months based triple therapy (methotrexate, leflunomide and methylprednisolone) was highly effective in patients with high RA activity. A significant improvement according to the criteria of ACR (ACR&gt;50) was obtained in 31 of 39 patients (79.48%), including the nine patients (23.07%) had developed clinical remission. Administration of the basic triple therapy was characterized by a significant clinical effect ACR stability of&gt;50. It was maintained during not less than 15 months of research in 28 (90.32%) of patients who received this treatment and only 3 of 11 (27.27%) patients who received methotrexate alone group and 8 in 10 (80%) who administered LF (p=0.039). Evidence recovery (ACR&gt;50), as well as clinical remission was kept stable in all 28 patients that triple therapy was extended after the ending of basic research. <h3>Disclosure of Interest</h3> None declared
SAT0097 Factors associated with atherosclerosis progression in patients with low-active rheumatoid arthritis
Authors: A Giollo, A Dalbeni, A Tagetti, S Atanasio, G Orsolini, G Cioffi, F Ognibeni, M Rossini, C Fava, O Viapiana
Journal: Annals of the Rheumatic Diseases (2017)

<h3>Background</h3> Longitudinal studies of the carotid intima-media thickness (IMT) change in RA suggested a role for inflammation in atherosclerosis progression. However, data on well controlled joint disease are scarce since most studies enrolled patients with very high disease activity. <h3>Objectives</h3> To estimate atherosclerosis progression and identify influencing factors in a cohort of longstanding and well controlled RA patients. <h3>Methods</h3> One hundred nine RA patients (females 80%, age 59±12 years, disease duration 15.6±10.6 years, mean Framingham 10-year CV disease risk score 16±12%) without previous cardiovascular (CV) events underwent carotid ultrasound (CUS) examination at baseline and after a mean time of 1.1±0.3 years. Atheromatous plaques and intima-media thickness (IMT) were assessed. Data on CV risk factors, inflammation markers, medications, and RA characteristics were collected. <h3>Results</h3> Overall, we observed a significant increase of IMT (0.03±0.10 mm, p=0.005) and plaques (+ 8%, p=0.035). The IMT progression rate was 0.027 mm/year (95% CI 0.007 - 0.046). Disease activity (DAS28-CRP) remained stable (2.68±1.01 vs 2.79±1.33, p=0.45). Anti-rheumatic, cardiovascular medications and the number of CV risk factors were substantially unchanged. In models of regression analysis sex, age, dyslipidemia, hypertension and use of corticosteroids were independently associated with the increase of IMT, whereas there were no confounding from use of biological therapies, seropositivity or disease duration. Patients with active disease (DAS28-CRP ≥2.6) had a significant increase in IMT (0.04±0.11 mm, p=0.009). Conversely, there was not a significant progression of patients in remission, who had also a lower prevalence of hypertension (40% vs 64%, p=0.027), dyslipidemia (43% vs 58%, p=0.044), and use of corticosteroids (37% vs 63%, p=0.007) and were receiving more frequently methotrexate (60% vs 40%, p=0.027). <h3>Conclusions</h3> In patients with established and controlled RA, the progression of atherosclerosis is mainly driven by traditional CV risk factors than disease activity. In addition, a remission state is associated with a lower prevalence of CV risk factors, which in turn could account for a slower progression of atherosclerosis in these patients. This study provides evidence that even in RA patients who achieve good disease control the treatment of CV risk factors should be optimized. <h3>Disclosure of Interest</h3> None declared
FRI0293 Characterization and risk estimate of cancer in primary sjÖgren syndrome: analysis in 1300 patients
Authors: P Brito-Zerόn, B Kostov, G Fraile, D Caravia-Durán, B Maure, F-J Rascόn, M Zamora, A Casanovas, M Lopez-Dupla, M Ripoll, B Pinilla, E Fonseca, M Akasbi, G de la Red, M-A Duarte-Millán, P Fanlo, P Guisado-Vasco, R Pérez-Alvarez, AJ Chamorro, C Morcillo, I Jiménez-Heredia, I Sánchez-Berná, M Ramos-Casals
Journal: Annals of the Rheumatic Diseases (2017)

<h3>Objectives</h3> To characterize the risk of solid and hematological cancer in a large, well-characterized cohort of patients with primary Sjögren syndrome (SjS). <h3>Methods</h3> The GEAS-SS multicenter registry is a network of Spanish reference centers with specific clinical experience in the management of SjS patients. By January 2016, we had analyzed the development of cancer in 1300 consecutive patients fulfilling the 2002 SjS classification criteria. Multivariate Cox proportional-hazards regression analysis allowed adjustment for age at diagnosis, gender and the statistically-significant baseline variables associated with cancer in the univariate analysis. The sex- and age-specific incidence rates (SIR) of cancer were estimated from 2012 Spanish mortality data modeling, using a set of age-, sex- and site-specific incidence:mortality ratios. <h3>Results</h3> After a mean follow-up of 91 months (9922.3 person-years), 127 (9.8%) patients developed 133 cancers. The most frequent type of cancer was B-cell lymphoma (34% of cancers, including 27 MALT and 19 non-MALT B-cell lymphomas). Systemic activity at diagnosis of primary SjS correlated with the risk of hematological neoplasia (HR 1.06, p&lt;0.001). Positive cryoglobulins at SjS diagnosis were associated with a high risk of either B-cell or non-B-cell lymphoma subtypes. Patients with cytopenias had a high risk of non-MALT B-cell and non-B-cell cancer, while those with low C3 levels had a high risk of MALT lymphomas and those with monoclonal gammopathy and low C4 levels had a high risk of non-MALT B-cell lymphomas. The estimated SIR for solid cancer was 1.13 (95% CI 0.88–1.46) and 11.02 (95% CI 8.35–14.54) for hematological cancer. SIRs for specific cancers were 36.17 (95% CI 25.44–51.43) for multiple myeloma and immunoproliferative diseases, 19.41 (95% CI 7.29–51.72) for Hodgkin lymphoma, 6.04 (95% CI 3.43–10.64) for other non-Hodgkin lymphomas, 5.17 (95% CI 1.94–13.79) for thyroid cancer, 4.81 (95% CI 1.81–12.83) for cancers of the lip and oral cavity and 2.53 (95% CI 1.05–6.07) for stomach cancer. <h3>Conclusions</h3> One third of cancers developed by patients with primary SjS are B-cell lymphomas. The prognostic factors identified at SjS diagnosis differed according to the subtype of B-cell lymphoma developed. Primary SjS is also associated with an enhanced risk of development of some types of non-hematological cancers (thyroid, oral cavity and stomach). <h3>Disclosure of Interest</h3> None declared
AB0437 Efficacy and safety of long-term analgesic therapy with etoricoxib for patients with rheumatic diseases
Authors: S Lapshina, L Myasoutova
Journal: Annals of the Rheumatic Diseases (2017)

<h3>Background</h3> There are some data in literature on decompensation of arterial hypertension and other chronic diseases during the treatment with coxibs which in practice unfortunately limits their administration for patients with comorbidities. <h3>Objectives</h3> To evaluate the efficacy of analgesic effect of etoricoxib and frequency of comorbidities exacerbation on such treatment. <h3>Methods</h3> 58 patients with rheumatoid arthritis (34,4%), osteoarthritis (29,2%), ankylosing spondylitis (19%), gout (14%), psoriatic arthritis (3,4%) at the age of 25 to 75 years (the average age, 52,9±13,03 years) were included. 79,3% patients had comorbidities (diseases of digestive system – 37,9%, arterial hypertension – 53,4% (including 3,2% with decompensated hypertension), bronchial asthma – 1,7%). All the patients before the appointment had taken NSAIDs (diclofenac, nimesulid, ketoprofen, meloxicam, aceclofenac, ibuprofen) with lack of effect (84,4%) or minimal effect (15,6%). Etoricoxib was administered in 100% cases. Pain severity according to visual analogue scale (VAS), comorbidities exacerbation and blood pressure were assessed at the beginning and during the first month of treatment. <h3>Results</h3> The average time period between 2 appointments was 20,72±9,3 days. By the second appointment 98,2% patients were taking etoricoxib regularly, and good tolerability of the medication was noted (63,8% excellent, 36,2% good). The average VAS score at the first appointment was 7,27±1,04, at the second appointment – 2,75±1,12, in the meantime VAS score improvement was noted mostly in the group of patients with long disease duration (more than 3 years). At the time of second examination total relief of back pain was revealed in 16,7%, in knee joint – 35,5%, in hip joint – 68,1%, in the neck – 61,9%, in small joints – 30,8%, of shoulder blade pain – 82,4%. No comorbidities exacerbation was noted. There were also no cases of sudden blood pressure increase on the administered therapy, including patients with arterial hypertension. <h3>Conclusions</h3> Etoricoxib administration leads to significant decrease of pain syndrome and its relief without increasing blood pressure and exacerbations of chronic comorbidities. <h3>Disclosure of Interest</h3> None declared
FRI0265 Cytokines and correlations with patient reported outcomes in systemic lupus erythematosus and population controls
Authors: S Pettersson, H Idborg, S Eketjäll, I Gunnarsson, E Svenungsson
Journal: Annals of the Rheumatic Diseases (2017)

<h3>Background</h3> In open questions patients with systemic lupus erythematosus (SLE) report fatigue as the most distressing symptom. Pro-inflammatory cytokines are generally suggested to contribute to fatigue in chronic diseases, however results are contradictory (1, 2). Patient reported outcome measures (PROMs) quantify patients9 experiences of qualities like fatigue and depression, which have great impact on both physical and psychological wellbeing. If PROMs are associated with pro-inflammatory cytokine activity in SLE has not yet been well investigated <h3>Objectives</h3> In this study we explored the relationship between a large set of cytokines and self-assessments of fatigue, anxiety, depression and quality of life in a large group of patients with SLE and in matched controls. <h3>Methods</h3> In a cross-sectional setting, persons with SLE and age- and gender-matched population controls responded to PROMs, assessing fatigue (Multidimensional Assessment of fatigue Scale), depression/anxiety (Hospital Anxiety and Depression Scale) and health related quality of life (Medical Short Form 36 (SF-36)). 30 cytokines were analyzed (MSD 30-plex cytokine assay). Spearman9s rank correlation coefficient (r<sub>s</sub>) between cytokines and PROMs were calculated. <h3>Results</h3> 423 patients, age 46.6 (±15.3) and 315 controls age 47.5 (±14.6) (p 0.43) were included. Of 30 analyzed cytokines 20 gave reliable results and were correlated to PROMs. Five of the cytokines (IL-6, TNF-alfa, IL-15, MCP-1 and MIP-1-beta) correlated best (r<sub>s</sub> ≥0.37) with investigated PROMs (table 1). Fatigue correlated with TNF-α (r<sub>s</sub> =0.32), IL-15 (r<sub>s</sub> =0.31), and MIP-1-beta (r<sub>s</sub> =0.32), p&lt;0.01 for all. When summarizing SF-36 results we noted a pattern of stronger correlations between investigated cytokines and the physical component than the mental component. Anxiety and depression correlated, but weakly (r<sub>s</sub>&lt;0.25). <h3>Conclusions</h3> Most PROMs were positively associated with pro-inflammatory cytokines. Fatigue and PROMs reflecting physical aspect of disease correlated most convincingly, while correlations with mental aspects were weaker. <h3>References</h3> Omdal R, et al (2002). Fatigue in patients with systemic lupus erythematosus: lack of associations to serum cytokines, antiphospholipid antibodies, or other disease characteristics. J Rheumatol. Roerink ME et al (2017). Interleukin-1 as a mediator of fatigue in disease: a narrative review. J Neuroinflammation. <h3>Disclosure of Interest</h3> None declared
SP0153 Lessons from aps trials
Authors: M Khamashta
Journal: Annals of the Rheumatic Diseases (2017)

Prevention of thrombosis in patients with APS remains a vexing clinical problem. In patients with a history of thrombosis, there is considerable risk of recurrence, and long-term anticoagulation treatment with warfarin is effective in most cases. Existing evidence suggest that the use of DOACs for secondary thromboprophylaxis for APS patients with previous VTE is promising. Until new data from ongoing clinical trials are available, there is not enough evidence to consider using DOACs in patients with APS and previous arterial events. The efficacy of heparin and low-dose aspirin in APS patients with previous pregnancy losses is supported by 3 meta-analysis available on the topic. In patients with antiphospholipid antibodies but without a previous thrombotic event, most physicians in the field recommend thromboprophylaxis with low-dose aspirin. Given the diversity of clinical presentations and medical specialties involved, it is not surprising that treatment of APS has been subject of intense debate. Due to the difficulty in conducting trials in the setting of a relatively rare condition, well designed multicenter studies (such as registries) using actual classification criteria and standardized tests should be performed in the future to answer all the opened questions regarding management of APS. <h3>Disclosure of Interest</h3> None declared