tbuckley/cabot-search huggingface dataset:
THU0735-HPR Shared care of rheumatologist and nurse consultations in follow up of rheumatoid arthritis and spondyloarthritis outpatients with low disease activity: a monocentric, randomized controlled trial
Authors: K Claes, A Van Hecke, P Jacques
Journal: Annals of the Rheumatic Diseases (2017)

<h3>Background</h3> Due to national regulations, the role of nurses in the management of arthritis patients differs significantly in all European countries (1). In Belgium, regularized consultations conducted by a rheumatology nurse do not exist. <h3>Objectives</h3> The study investigated whether rheumatology nurse consultations alternating with rheumatologist consultations for RA or AS patients with low disease activity is non-inferior compared to the usual care by the rheumatologist. Primary outcomes were safety and disease activity. Secondary outcomes were fatigue, pain, functional index, patient satisfaction, the level of self-management and self-efficacy. <h3>Methods</h3> This is a monocentric randomized controlled trial. The intervention group received a consultation conducted by a rheumatologist alternating with a nurse consultation, every 8 weeks. Patients in the control group received usual care: consultations performed by a rheumatologist every 8 weeks. <h3>Results</h3> Mixed method analyzes were performed. No statistical significant between-group effects were found nor in the RA group nor in the AS group, although there was a clinical relevance towards disease activity by AS patient in the intervention group. DAS 28 dropped with a mean difference of 0,4 (-1,1 – -0,2, SD 0,30). The ASDAS and BASDAI both decreased with 1.1 (-1,4 – -1,3, SD 0,1 and -1,7 – -1,4, SD 0,1 respectively). No safety signals from biochemical parameters such as SGOT, GOT and creatinine were detected. Inflammatory markers (ESR and CRP) remained stable in both groups. The secondary outcomes showed no significant between-group effects for both diseases. The self-efficacy outcome noticed a positive in-between-group effect by patients with RA in the intervention group. <h3>Conclusions</h3> In the follow-up of patients with RA or AS and low disease activity, outcome is not different when rheumatology nurse consultations alternating with rheumatologist consultations are compared to usual care. Implementing nurse consultations can positively influence the disease activity and patient self-efficacy. <h3>References</h3> van Eijk-Hustings Y et al. (2014) EULAR recommendations for the role of the nurse in the management of chronic inflammatory arthritis. Annals of Rheumatic Diseases 73:429–509. <h3>Disclosure of Interest</h3> None declared
OP0160 Gut-derived tnf as risk factor for the development of sacroiliac inflammation
Authors: K Debusschere, H Cypers, P Jacques, F Van den Bosch, D Souza, M Brown, G Nabozny, D Dove, A Klimowicz, D Elewaut
Journal: Annals of the Rheumatic Diseases (2017)

<h3>Background</h3> An intruiging link exists between gut and joint inflammation in spondyloarthritis (SpA). About 50% of patients has subclinical (eg. microscopic) gut inflammation, which represents a risk factor for development of Crohn9s disease, sacroiliac inflammation and evolution in to Ankylosing Spondylitis. However, the underlying mechanisms are still relatively poorly understood. <h3>Objectives</h3> Our goal was to examine the relationship between TNF, microscopic gut inflammation and axial inflammation using human samples and a novel mouse model. We speculated that TNF in the gut represents an important risk factor for disease severity and progression in SpA. <h3>Methods</h3> We examined in situ expression of TNF, TNFR1 and TNFR2 using triple in situ hybridisation in gut biopsies of human SpA patients. Furthermore, we generated intestinal specific human TNF transgenic mice, in which hTNF is under control of a rat iFABP (fatty acid binding protein) promoter, generating a mouse-model over-expressing human TNF in the ileum. These mice, together with wild type littermates, were evaluated for the development of arthritis up until the age of 13 weeks after which they were euthanized and ankle and sacroiliac joints as well as ileum were processed for histology. <h3>Results</h3> There was a marked upregulation of TNF in inflamed versus non-inflamed gut biopsies of human SpA patients. We also noted a predominant upregulation of TNFR1 on intestinal epithelium and TNFR2 in lamina propria respectively. Of interest, IL-17 and IL-23 were also markedly increased while IL-22 was most abundant in chronically inflamed samples. In line with this, we found that patients with gut inflammation had a higher need for anti-TNF therapy and their degree of clinical response after anti-TNF was also markedly higher. Our transgenic mice exhibited a runt phenotype and hallmarks of inflammatory bowel disease, including increased intestinal permeability and inflammation compared to their wild-type littermates. While in peripheral joints no clear signs of arthritis were observed, the sacroiliac joints in transgenic mice, by contrast, showed marked signs of inflammation as well as bone erosion and destruction. <h3>Conclusions</h3> These data propose a new paradigm that gut-derived TNF is sufficient to trigger sacroiliitis and provide an alternate explanation on the relationship between gut inflammation, evolution to inflammatory bowel disease and axial inflammation in SpA. <h3>Disclosure of Interest</h3> None declared
Quantitative and Mechanistic Understanding of AZD1775 Penetration across Human Blood–Brain Barrier in Glioblastoma Patients Using an IVIVE–PBPK Modeling Approach
Authors: Jing Li, Jianmei Wu, Xun Bao, Norissa Honea, Youming Xie, Seongho Kim, Alex Sparreboom, Nader Sanai
Journal: Clinical Cancer Research (2017)

Purpose: AZD1775, a first-in-class, small-molecule inhibitor of the Wee1 tyrosine kinase, is under evaluation as a potential chemo- and radiosensitizer for treating glioblastoma. This study was to prospectively, quantitatively, and mechanistically investigate the penetration of AZD1775 across the human blood-brain barrier (BBB).Experimental Design: AZD1775 plasma and tumor pharmacokinetics were evaluated in 20 patients with glioblastoma. The drug metabolism, transcellular passive permeability, and interactions with efflux and uptake transporters were determined using human derived in vitro systems. A whole-body physiologically based pharmacokinetic (PBPK) model integrated with a four-compartment permeability-limited brain model was developed for predicting the kinetics of AZD1775 BBB penetration and assessing the factors modulating this process.Results: AZD1775 exhibited good tumor penetration in patients with glioblastoma, with the unbound tumor-to-plasma concentration ratio ranging from 1.3 to 24.4 (median, 3.2). It was a substrate for ABCB1, ABCG2, and OATP1A2, but not for OATP2B1 or OAT3. AZD1775 transcellular passive permeability and active efflux clearance across MDCKII-ABCB1 or MDCKII-ABCG2 cell monolayers were dependent on the basolateral pH. The PBPK model well predicted observed drug plasma and tumor concentrations in patients. The extent and rate of drug BBB penetration were influenced by BBB integrity, efflux and uptake active transporter activity, and drug binding to brain tissue.Conclusions: In the relatively acidic tumor microenvironment where ABCB1/ABCG2 transporter-mediated efflux clearance is reduced, OATP1A2-mediated active uptake becomes dominant, driving AZD1775 penetration into brain tumor. Variations in the brain tumor regional pH, transporter expression/activity, and BBB integrity collectively contribute to the heterogeneity of AZD1775 penetration into brain tumors. Clin Cancer Res; 23(24); 7454-66. ©2017 AACRSee related commentary by Peer et al., p. 7437.
BEACON CRC (binimetinib [BINI], encorafenib [ENCO], and cetuximab [CTX] combined to treat <i>BRAF</i>-mutant metastatic colorectal cancer [mCRC]): A multicenter, randomized, open-label, three-arm phase III study of ENCO plus CTX plus or minus BINI vs irinotecan (IRI)/CTX or infusional 5-fluorouracil/folinic acid/IRI (FOLFIRI)/CTX with a safety lead-in of ENCO + BINI + CTX in patients (Pts) with <i>BRAF</i><sup>V600E</sup> mCRC.
Authors: Sanne Huijberts, Jan H. M. Schellens, Marwan Fakih, Marc Peeters, Scott Kopetz, Axel Grothey, Eric Van Cutsem, Harpreet Singh Wasan, Jayesh Desai, Fortunato Ciardiello, Takayuki Yoshino, Kati Maharry, Ashwin Gollerkeri, Josep Tabernero
Journal: Journal of Clinical Oncology (2017)

TPS3622 Background: BRAF mutations are found in ≈10% of mCRC cases. Pts with BRAF V600E mCRC have a poor prognosis, with shorter progression-free survival (PFS) and overall survival (OS) than pts with BRAF wt mCRC (Van Cutsem et al 2011; Modest et al 2012; Sorbye et al 2015). The benefits of combined BRAF + EGFR inhibition in mCRC have been demonstrated in vitro (Corcoran et al 2012; Prahallad et al 2012; Yang et al 2012), and preclinical evidence suggests that adding MEK signaling inhibition improves antitumor activity. Early clinical data indicate that BRAF + EGFR + MEK inhibition has greater activity than BRAF + EGFR inhibition in pts with BRAF V600E mCRC (Van Cutsem et al 2016). Our study will examine the combination of BINI (a MEK inhibitor) + ENCO (a selective BRAF kinase inhibitor) + CTX (an anti-EGFR antibody) and of ENCO + CTX in pts with BRAF V600E mCRC. Methods: BEACON CRC (NCT02928224) is enrolling pts with BRAF V600E mCRC whose disease has progressed after 1 or 2 prior regimens in the metastatic setting. A safety lead-in phase (≈30 pts) will determine the safety and tolerability of oral ENCO 300 mg QD + oral BINI 45 mg BID + intravenous CTX 400 mg/m 2 followed by 250 mg/m 2 QW. In the phase 3 portion, ≈615 pts will be randomized 1:1:1 to triplet (ENCO + BINI + CTX), doublet (ENCO + CTX), or control (investigator’s choice of IRI/CTX or FOLFIRI/CTX) arms. Pts will be treated in 28-day cycles until disease progression, unacceptable toxicity, withdrawal of consent, initiation of subsequent anticancer therapy, or death. The primary endpoint is OS (triplet vs control). Secondary endpoints include OS (doublet vs control), confirmed investigator-assessed objective response rate according to RECIST version 1.1 (triplet or doublet vs control; triplet vs doublet), PFS (triplet or doublet vs control), duration of response, time to response, pharmacokinetics, and pt-reported outcomes. Safety will be summarized using standard adverse event reporting. Clinical trial information: NCT02928224.
First-in-man trial of 4-(N-(S-penicillaminylacetyl)amino) phenylarsonous acid (PENAO) as a continuous intravenous infusion (CIVI), in patients (pt) with advanced solid tumours.
Authors: Ben Tran, Anne L. Hamilton, Lisa Horvath, Michael Lam, Peter Stephen Savas, Peter S. Grimison, James R. Whittle, James Chun-Yen Kuo, Nicole Signal, David Edmonds, Philip J Hogg, Danny Rischin, Jayesh Desai
Journal: Journal of Clinical Oncology (2016)

e14025 Background: PENAO is an organic arsenical with anti-mitochondrial activity mediated by covalent inhibition of adenine nucleotide translocase (ANT). In vitro studies identified potential activity of continuous drug exposure at 1-10µM PENAO (or equivalent arsenic (As) atoms), most evident in central nervous system (CNS) tumours. Renal inflammation was the only significant toxicity in rodents, and murine half life (t½) was 37 minutes. Methods: Eligibility criteria included age ≥ 18, advanced solid tumour, PS ≤ 1, GFR ≥ 75mL/min, normal cardiac function, adequate haematological and biochemical function, and informed consent. Central IV lines and CADD pumps were used. Dose levels initially increased infusion duration (4-21 days), then daily dose, in a 21-day cycle, with weekly pump cassette changes. Standard cycle 1 dose limiting toxicities (DLT) definitions were used in a “3&3” phase I design. Pt were reviewed weekly, with regular monitoring of toxicity and efficacy. Pharmacokinetic (PK) assays of serum and urine As were performed. Results: 27 pt were accrued to 8 dose levels. All pt discontinued treatment due to progressive disease. 1 DLT (fatigue) was observed at 9mg/m2/day. Another pt had rash and transient liver dysfunction immediately after discontinuation of the drug at 6mg/m2/day. No significant organ toxicity was observed. One pt with anaplastic astrocytoma had stable disease at 6mg/m2/day over 10 cycles (30 weeks). PK unexpectedly indicated t½ of 3-4 days in humans. The study was discontinued before a recommended phase II dose was defined, as study drug supply was close to expiration, and the PK findings warranted exploration of more convenient dosing schedules. Conclusions: PENAO can be given safely as an uninterrupted CIVI at 6mg/m2/day. 1 DLT (fatigue) was seen in 1 of 2 pts treated at 9mg/m2/day. The sponsor aims to explore the drug further in a phase 1B trial of an intermittent dosing schedule, in patients with CNS tumours. Clinical trial information: ACTRN12612000908831.
AB0803 Does intra-articular injection of platelet-rich plasma provide clinically preferable outcomes in the knee osteoarthritis? a double-blind, randomized controlled pilot study
Authors: J Moghimi, R Ghorbani, H Beiki
Journal: Annals of the Rheumatic Diseases (2017)

<h3>Background</h3> Knee osteoarthritis (OA) symptoms Improvements with platelet-rich plasma (PRP) have been ascribed to its ability to rectify intra-articular inflammatory processes. <h3>Objectives</h3> The aim of this study was to determine the safety, feasibility and changes in symptom severity, sports activity, lower limb function, and function in daily living activities following intra-articular injections of PRP in mild to moderate knee OA. <h3>Methods</h3> In this double-blind randomized controlled pilot study, 34 patients with knee OA grade 2 or 3, from March 2013 to February 2016 were selected. Participants were randomly assigned one knee as the case and other knee was considered as control to receive three injections of either PRP or placebo. The administering doctor and the patients were blinded to group allocation. Outcomes included safety and recruitment data, 100 mm the EuroQol-visual analogue scales (EQ-VAS), the international knee documentation committee (IKDC), the Western Ontario and McMaster Universities Arthritis Index (WOMAC) and the Tegner Activity Score (TAS) at three and six months. <h3>Results</h3> Twenty four (100%) participants met the inclusion criteria. No treatment-related major adverse events were reported. The PRP group demonstrated significant improvements at all follow up time points in the WOMAC (3 months: p=0.017; 6 months: p=0.029, ETA=0.601). For the PRP group, the 11.47 mm reduction in EQ-VAS at 6 months (p=0.040) and the 7.35 mm at 3 months (p=0.035) was statistically significant improvement from baseline. The PRP group also significantly improved IKDC (p=0.039, ETA =0.619) and TAS (p=0.028, ETA =0.641) at three months. The placebo group showed improvements on only the IKDC Function at 3 months (p=0.019, ETA =0.591). There were no significant between-group differences for any of the self-reported measures at either time-point. <h3>Conclusions</h3> The study provides proof-of-concept evidence about the safety and feasibility of intra-articular injections of PRP necessary to appraise a larger clinical trial knee OA. Our preliminary findings also suggest PRP improves self-reported symptom severity, sports activity, and function in daily living activities, however no between-group differences were found. PRP may provide an effective and safe novel treatment for knee OA. <h3>Acknowledgements</h3> This study was supported by Semnan University of Medical Sciences, Semnan, Iran. <h3>Disclosure of Interest</h3> None declared
AB0823 Evaluation of osteoporosis and fractures in patients with diabetes mellitus type 2: results of a 5-year follow-up
Authors: VL Masenko, AN Kokov, SE Semenov, TA Raskina, OL Barbarash
Journal: Annals of the Rheumatic Diseases (2017)

<h3>Objectives</h3> The aim of the study is to determine the characteristics of bone mineral density (BMD) and the the prevalence of fractures of the vertebral fractures and long bones in men with diabetes mellitus type 2 on the basis of 5-year prospective study. <h3>Methods</h3> 251 males (60.56±8.7years) were examined. The patients were divided into 2 groups: patients with type 2 diabetes mellitus (n=65) and patients without disorder of carbohydrate metabolism (n=186). All patients underwent DXA-definition of BMD (g/cm<sup>2</sup>), T-score of the spine and bones of the femur. Dynamic observation for 5 years and the determination of vertebral fractures and long bones. <h3>Results</h3> BMD measured in lumbar spine and proximal femur were analyzed. According DXA BMD of femur in patients with diabetes is significantly higher than that of non-diabetics (0,928 [0,847;1,029]; 0,858 [0,779 0,928]; p=0,000005). T-score is also higher in diabetics (-1,47 [-2,12;-0,63]; -2,01 [-2,71;-1,49]; p=0,000020). BMD and T-score of the lumbar vertebrae in diabetic patients was also is significantly higher: BMD (Group I =1,002 [0,902;1,182]; Group II =0,969 [0,879;1,106]; p=0,008). T-score (-0,94 [-1,43; -0,05]; -1,07 [-1,54; -0,40]; p=0,014). After 5 years, spine or long bones fractures marked in 12 patients (18%) from I group. In Group II was observed only 5 episodes of bone fracture (2.6%). <h3>Conclusions</h3> BMD in men with diabetes are higher, but they often develop bone fractures. Perhaps this is due to pathological remodeling of bone tissue on a background of metabolic disorders, when bone is more dense, but fragile. <h3>Disclosure of Interest</h3> None declared
AB0142 Igm antibodies against phosphorylcholine promote polarization of t regulatory cells from patients with atherosclerotic plaques, systemic lupus erythematosus and healthy donors: a novel immunological concept
Authors: J Sun, S Lundström, B Zhang, R Zubarev, J Steuer, P Gillgren, M Rahman, S Ajeganova, A Liu, J Frostegård
Journal: Annals of the Rheumatic Diseases (2017)

<h3>Background</h3> IgM antibodies against Phosphorylcholine (anti-PC) are negatively associated with atherosclerosis, cardiovascular disease (CVD) and systemic lupus erythematosus (SLE) where the risk of CVD and atherosclerosis is very high. We here study effects of IgM anti-PC on Th17 and T regulatory cells (Tregs). <h3>Objectives</h3> Immunomodulation in atherosclerosis and SLE could have a huge impact on disease prevention and treatment. <h3>Methods</h3> Mononuclear leukocytes were isolated from peripheral blood (PBMC) obtained from healthy blood donors, from six SLE patients with age- and sex-matched controls and from symptom-giving human atherosclerotic plaques. The proportion of Th17 (CD4<sup>+</sup>CCR6<sup>+</sup>) and Treg (CD4<sup>+</sup>CD25<sup>+</sup>CD127<sup>dim/-</sup>) cells were determined by flow cytometry in CD4<sup>+</sup>T cells after 6 days culture with Th17 or Treg-polarizing cytokines, with PMA and Ionomycin stimulation. IgM anti-PC were extracted from total IgM, with flow-through IgM as controls. Dendritic cells (DC) were differentiated from PBMC. Antibody peptide/protein characterization was done by a proteomics de novo sequencing approach. <h3>Results</h3> IgM anti-PC increased significantly the proportion of Tregs from healthy donors, SLE patients and from atherosclerotic plaque cells while control antibodies did not. T cells from SLE patients had a significantly lower proportion of Tregs and higher proportion of Th17 cells as compared to matched controls. IgM anti-PC but not control antibodies significantly reduced production of IL-17 and TNF-alpha in cell culture from SLE patients and from atherosclerotic plaque cells. IgM anti-PC interacted with CD40 and kept DCs in an immature stage potentially being tolerogenic. We identify differences on the IgM peptide expression level in anti-PC compared to control antibodies. <h3>Conclusions</h3> IgM anti-PC increase Tregs and having low levels could contribute to both SLE and atherosclerosis (and CVD) and could thus represent a novel underlying mechanism in these conditions. This finding could also have therapeutic implications. <h3>Disclosure of Interest</h3> None declared
THU0491 Comparison of clinical and serological features of juvenile and adult-onset neuropsychiatric lupus in spanish patients
Authors: S Garrote Corral, A Fernández García, WA Sifuentes Giraldo, AL Boteanu, ML Gámir Gámir, A Zea Mendoza
Journal: Annals of the Rheumatic Diseases (2017)

<h3>Background</h3> Neuropsychiatric (NP) manifestations are a main cause of morbidity and mortality in juvenile-onset systemic lupus erythematosus (jSLE). Some studies suggest that they are more frequent and severe in jSLE than in adult-onset SLE (aSLE). <h3>Objectives</h3> To compare the clinical and serological profile of pediatric and adult patients with neuropsychiatric lupus (NPSLE) treated in a Spanish tertiary center. <h3>Methods</h3> A retrospective study of patients with jSLE (age of onset: 0–18y) and aSLE (age of onset: &gt;18y) seen in our center during the period 1988–2016 was performed. Case definitions of the American College of Rheumatology were used to identify NPSLE manifestations. Demographics, clinical and serological data were obtained through a review of their medical records. <h3>Results</h3> A total of 69 patients with NPSLE were included, aSLE 41 (59%) and jSLE 28 (41%), the comparison of groups is presented in the table. Most of them were Caucasian (92%), mean age at diagnosis in adults was 36.4 years (range: 19–68) and 13.9 years (range: 8–18) in children. The proportion of males was higher in the latter group. The mean duration of the disease was significantly greater in adults, as well as the time from SLE diagnosis to NP manifestation onset, although without significant difference. Central NP manifestations were the most frequent in both groups (aSLE 93%, jSLE 96%) regarding to the peripheral manifestations (aSLE 12%, jSLE 11%). The most frequent manifestations in aSLE were headache (29%), cerebrovascular disease (27%), seizures (17%) and myelopathy (15%), whereas in jSLE were seizures (46%), headache (29%), mood disorder/depression (25%), psychosis (18%) and autonomic disorders (18%). A significant group of patients presented ≥2 central manifestation during their evolution (aSLE 32%, jSLE 41%), with the mean number of manifestations in adults being 1.36 (range: 1–3) and in children 1.44 Range: 1–4). Patients with jSLE developed lupus nephritis (LN) with a significantly higher frequency, as well as higher titres of anti-DNA antibodies, erythrocyte sedimentation rate (ESR) and hypocomplementemia. During the study period there was mortality in 2 cases of aSLE and 2 jSLE (5% and 7%, respectively). <h3>Conclusions</h3> Our results corroborate that juvenile patients with NPSLE present higher disease activity compared to adults. There was no significant diference in the time from SLE diagnosis to NP manifestation onset, but tended to be shorter in jSLE. The spectrum of NPSLE was varied both groups and an important proportion developed ≥2 manifestation. Mortality continues to be important in NPSLE in both age groups. <h3>Disclosure of Interest</h3> None declared
Nonclassical FCGR2C haplotype is associated with protection from red blood cell alloimmunization in sickle cell disease
Authors: Sanne M. Meinderts, Joep W. R. Sins, Karin Fijnvandraat, Sietse Q. Nagelkerke, Judy Geissler, Michael W. Tanck, Christine Bruggeman, Bart J. Biemond, Anita W. Rijneveld, Jean-Louis H. Kerkhoffs, Sadaf Pakdaman, Anoosha Habibi, Robin van Bruggen, Taco W. Kuijpers, France Pirenne, Timo K. van den Berg
Journal: Blood (2017)