tbuckley/cabot-search huggingface dataset:
SAT0219 Efficacy and safety of atacicept in patients with high disease activity in a 24-week, randomized, placebo-controlled, phase iib study (ADDRESS II)
Authors: JT Merrill, DJ Wallace, A Kao, C Vazquez Mateo, PA Fraser, P Chang, D Isenberg
Journal: Annals of the Rheumatic Diseases (2017)

<h3>Background</h3> Atacicept targets B-cell stimulating factors BLyS and APRIL, and has shown evidence of clinical response in SLE. <h3>Objectives</h3> Exploration of atacicept efficacy and safety in a pre-defined subpopulation of SLE patients with high disease activity (HDA, SLEDAI-2K ≥10 at Screening) in the phase IIb ADDRESS II study (NCT01972568). <h3>Methods</h3> Autoantibody positive patients on standard of care therapy were randomized 1:1:1 to double-blind weekly SC injections of atacicept 75 or 150 mg or placebo (PBO) for 24 weeks. Analyses of the HDA subpopulation are now reported. <h3>Results</h3> 52% of the ITT population had HDA (n=158: 52 PBO; 55 atacicept 75 mg; 51 atacicept 150 mg). 92% were female, 67% were white, and baseline characteristics were balanced between groups. At week 24 (Table 1; Figure 1), the proportion of SLE Responder Index (SRI)-4 (p&lt;0.05) and SRI-6 (p&lt;0.005) responses was greater with atacicept 150 mg vs PBO. BICLA response rate was higher with both doses (p&lt;0.05). More patients achieved SLEDAI-2K ≤2 with atacicept 150 mg vs PBO (p&lt;0.01). Time to severe and moderate-severe flare was significantly reduced at both atacicept doses vs PBO (p&lt;0.05). Patients in the quartile with the largest decline in serum IgG had the highest SRI-6 response rates (Table 2). Treatment-emergent adverse event (TEAE) rates were similar between groups (PBO 71.2%; 75 mg 78.2%; 150 mg 74.5%). Serious/severe infections were not increased with atacicept 150 mg (PBO 9.6%; 75 mg 10.9%; 150 mg 0%). There were no patient deaths. <h3>Conclusions</h3> In SLE patients with HDA, Atacicept 150 mg demonstrated significant clinical responses and an acceptable safety profile. <h3>Acknowledgements</h3> The study was sponsored by EMD Serono Research &amp; Development Institute Inc., USA (a business of Merck KGaA, Germany). Medical writing support was provided by Bioscript Science, UK, and funded by Merck KGaA. <h3>Disclosure of Interest</h3> J. Merrill Consultant for: received consulting fees from Anthera Pharmaceuticals, Lilly, EMD Serono, GlaxoSmithKline and Biogen, D. Wallace Consultant for: received consulting fees from EMD Serono, A. Kao Employee of: EMD Serono Research &amp; Development Institute, Inc. (a business of Merck KGaA, Darmstadt, Germany), Billerica, MA, USA, C. Vazquez Mateo Employee of: EMD Serono Research &amp; Development Institute, Inc. (a business of Merck KGaA, Darmstadt, Germany), Billerica, MA, USA, P. Fraser Employee of: EMD Serono Research &amp; Development Institute, Inc. (a business of Merck KGaA, Darmstadt, Germany), Billerica, MA, USA, P. Chang Employee of: EMD Serono Research &amp; Development Institute, Inc. (a business of Merck KGaA, Darmstadt, Germany), Billerica, MA, USA, D. Isenberg Consultant for: received consulting fees from EMD Serono
Identification of <i>ALK</i> Rearrangements in Malignant Peritoneal Mesothelioma
Authors: Yin P. Hung, Fei Dong, Jaclyn C. Watkins, Valentina Nardi, Raphael Bueno, Paola Dal Cin, John J. Godleski, Christopher P. Crum, Lucian R. Chirieac
Journal: JAMA Oncology (2017)

Malignant peritoneal mesothelioma is a rare, aggressive tumor arising from the peritoneal lining, induced by asbestos, therapeutic radiation, or germline mutations. Nevertheless, the molecular features remain largely unknown.To investigate anaplastic lymphoma kinase (ALK) rearrangements in a large series of peritoneal mesothelioma and characterize the mutational landscape of these tumors.We studied 88 consecutive patients (39 men, 49 women; median age 61, range 17-84 years) with peritoneal mesotheliomas diagnosed at a single institution between 2005 and 2015. We identified ALK-positive mesotheliomas by immunohistochemistry and confirmed ALK rearrangement by fluorescence in situ hybridization (FISH). In ALK-rearranged cases, we characterized the fusion partners using targeted next-generation sequencing of both tumor DNA and RNA. In select cases, we quantified asbestos fibers by combined scanning electron microscopy and x-ray spectroscopy. We also explored ALK rearrangement in a separate series of 205 patients with pleural mesothelioma.Identification and characterization of novel ALK rearrangements and correlations with clinicopathologic characteristics.Anaplastic lymphoma kinase was positive by immunohistochemistry in 11 (13%) peritoneal mesotheliomas (focal weak in 8, diffuse strong in 3). In focal weak ALK-positive cases, no ALK rearrangement was detected by FISH or next-generation sequencing. In strong diffuse ALK-positive cases, FISH confirmed ALK rearrangements, and next-generation sequencing identified novel fusion partners ATG16L1, STRN, and TPM1. Patients with ALK-rearranged peritoneal mesotheliomas were women and younger than patients without ALK rearrangement (median age 36 vs 62; Mann-Whitney test, P = .02), but all other clinicopathologic characteristics (size of tumor nodules, histology, treatment, and survival) were not different. No asbestos fibers were detected in ALK-rearranged cases. Furthermore, loss of chromosomal region 9p or 22q or genetic alterations in BAP1, SETD2, or NF2 typically present in peritoneal mesothelioma were absent in the ALK-rearranged cases. All pleural mesotheliomas were ALK-negative by immunohistochemistry.We identified unique ALK rearrangements in a subset of patients with peritoneal mesothelioma, each lacking asbestos fibers, therapeutic radiation, and cytogenetic and molecular alterations typically found in these tumors. Identification of clinically actionable ALK rearrangements may represent a novel pathogenetic mechanism of malignant peritoneal mesothelioma with promise for targeted therapy.
AB1033 The expression of immunoglobulin g and immunoglobulin g4 in lymphoma
Authors: J Li, Z Zhang
Journal: Annals of the Rheumatic Diseases (2017)

<h3>Background</h3> Although IgG4-related disease has been gradually recognized, its relationship with malignant diseases, especially lymphoma has been an eternal topic. <h3>Objectives</h3> To explore the expression of IgG4 positive cells in lymphoma. <h3>Methods</h3> Surgical excision specimens with definite diagnosis of lymphoma from January to December, 2013 were collected. Hematoxylin-eosin staining and immunohistochemical staining of IgG and IgG4 were then evaluated on dense lymphoplasmacytic infiltration, storiform fibrosis and obliterative phlebitis. For the quantification of IgG and IgG4 positive cells, the areas with the highest density of positive cells were evaluated. Three high-powered fields (hpf) in each section were analyzed, and the average number of positive cells per hpf was calculated. <h3>Results</h3> 16 patients with lymphoma were selected in our study. There were 9 males and 7 females with an average age of 51 years old. The pathologic type included 13 cases of non-Hodgkin lymphoma and 3 cases of Hodgkin lymphoma. Sub types of Non-Hodgkin lymphoma contained 8 cases of diffuse large B cell lymphoma, 2 cases of small B cell lymphoma, 1 case of mucosa accociated lymphoid tissue marginal zone B cell lymphoma (MALToma), follicular lymphoma, peripheral T-cell lymphoma and hepatosplenic T-cell lymphoma. The 16 specimens all manifested as dense lymphocytic infiltration, accompanied by atypical lymphocytes. Proliferation of fibrous tissue was only seen in one specimen. 14 cases were IgG positive with the highest cell count from 20–350/hpf. IgG can be expressed in both cytoplasm and cytomembrane. 2 cases of IgG4 positive were Hodgkin lymphoma and the highest cell counts were 11 and 12/hpf respectively. <h3>Conclusions</h3> IgG4 positive cell, fibrosis and obliterative phlebitis seldom appear in lymphoma. Added specific tumor signature molecules, it may not be difficult to distinguish lymphoma from IgG4-related disease. <h3>References</h3> Stone JH, Zen Y, Deshpande V. IgG4-related disease. N Engl J Med 2012 2012–02–09;366(6):539–51. Yamamoto M, Takahashi H, Tabeya T, Suzuki C, Naishiro Y, Ishigami K, et al. Risk of malignancies in IgG4-related disease. Mod Rheumatol 2012 2012–06–01;22(3):414–8. Takahashi N, Ghazale AH, Smyrk TC, Mandrekar JN, Chari ST. Possible association between IgG4-associated systemic disease with or without autoimmune pancreatitis and non-Hodgkin lymphoma. Pancreas 2009 2009–07–01;38(5):523–6. Choe JY, Go H, Jeon YK, Yun JY, Kim YA, Kim HJ, et al. Inflammatory pseudotumor-like follicular dendritic cell sarcoma of the spleen: a report of six cases with increased IgG4-positive plasma cells. Pathol Int 2013 2013–05–01;63(5):245–51. Koneval T, Applebaum E, Popovic D, Gill L, Sisson G, Wood GW, et al. Demonstration of immunoglobulin in tumor and marginal tissues of squamous cell carcinomas of the head and neck. J Natl Cancer Inst 1977 1977–10–01;59(4):1089–97. <h3>Disclosure of Interest</h3> None declared
FRI0046 Identification of HERV-K env surface peptides highly recognized in ra patients
Authors: GL Erre, G Mameli, D Cossu, S Mura, A Piras, ML Cadoni, G Buscetta, N Mundula, E Colombo, MG Longu, LA Sechi, G Passiu
Journal: Annals of the Rheumatic Diseases (2017)

<h3>Background</h3> Endogenous Retroviruses (HERV) are believed to be pathogenic in several autoimmune diseases. Among them, HERV-K viruses have been recently reported to be involved in the pathogenesis of rheumatoid arthritis (RA). <h3>Objectives</h3> In this study we have explored the role of humoral immune response against HERV-K as a potential pathogenetic mechanism in RA. <h3>Methods</h3> Four different peptides from the extracellular portion of the <i>env</i> protein of HERV-K (env-su <sub>19–37</sub>, env-su <sub>109–26</sub>, env-su <sub>164–205</sub>, env-su <sub>209–226</sub>) were selected by bioinformatic analysis on the basis of their putative immunogenicity. Indirect ELISA was then carried out to quantify antibodies against those peptides on blood samples from RA patients and healthy controls (HC). Differences between the two groups were analysed using the Mann-Whitney rank-sum and chi-square tests. Potential correlations between RA laboratory, clinical descriptors and IgGs levels were explored by bivariate regression analysis. <h3>Results</h3> Seventy consecutive RA patients and seventy-one HC crossed by age and sex were enrolled in the study. Serum autoantibodies against three out of the four tested peptides, anti HERV-Ksu<sub>19–37</sub>, HERV-K env-su<sub>109–126</sub> and HERV-K env-su<sub>205–226</sub>, were significantly more prevalent in RA than in HC (19% vs 3%,p=0.0001;9% vs 3%, p=0.0001; and 6% vs 3%, p=0.0001 respectively) (See Fig. 1) Subgroup analysis showed no association between anti-HERV-K peptide humoral response and clinical, serological and clinimetric RA disease descriptors. <h3>Conclusions</h3> Serum from RA patients in our series significantly reacted against different HERV-K peptides in comparison to the general population suggesting a role for the HERV-K related, secondary antigenic driven immune response in the pathogenesis of RA. Further studies are needed to confirm these results and to explore the role of HERV-K surface peptides as potential therapeutic targets. <h3>Disclosure of Interest</h3> None declared
SP0146 Can we predict who is going to develop rheumatoid arthritis?
Authors: D Van Der Woude
Journal: Annals of the Rheumatic Diseases (2017)

To accurately predict disease development can be considered the "holy grail" of risk factor research. It holds the potential to employ preventive treatment thereby nipping RA in the bud. This presentation will review familial risk in RA and the underlying genetic risk factors, as well as environmental risk factors for disease. Autoantibodies are a potent prognostic marker when it comes to the risk of developing RA, and play a key role in current pathophysiological hypotheses. The newest players in the autoantibody field, and latest concepts of how the various risk factors contribute to disease onset will be discussed. <h3>Disclosure of Interest</h3> None declared
SAT0200 Biologic therapy retention in rheumatoid arthritis (RA) patients (PTS) according to the moscow arthritis registry (MAR)
Authors: G Lukina, E Koltsova, E Schmidt, E Zhilyaev
Journal: Annals of the Rheumatic Diseases (2017)

<h3>Background</h3> The use of biologics significantly improved results of the therapy of RA pts who did not achieve the target disease activity level on traditional DMARDS treatment. However the biologic therapy is in many cases withdrawn due to inefficacy or side effects (seldom because of sustained remission). Retention on treatment is a good integral index of efficacy and safety of biologics used in the real clinical practice. <h3>Objectives</h3> To assess the treatment survival of various biologics in RA pts in the real clinical practice. <h3>Methods</h3> Patients from MAR with RA receiving biologics were enrolled. Cases with missed results were excluded. A Cox proportional hazards regression model was used to determinethe predictors of the treatment discontinuation risk. Comparison of biologics retention rates for different biologicswas performed by means of Kaplan-Meier survival curves. Bonferroniadjustment was applied because of multiplicity of comparisons. <h3>Results</h3> 306 RA pts (mean age 54,5 years, mean age of disease onset 39,6 years, 86,5% women, 18% smokers, RF-positive 83,7%) were included in the study and 394 treatment courses (263 retrospective and 131 prospective) were analyzed. It was shown that significant independent predictors of discontinuation risk were: the biologic drug, the sequence number of the biologic drug in the patient and the age of RA onset. Risk of withdrawal was minimal by the use of the first biologic and increased by administration of the next ones. It also increased in pts with late onset of RA. Mass body index, age of the patient and the dose of methotrexate did not show significant correlations. Abatacept (ABA) demonstrated significant superiority over adalimumab (ADA) (p&lt;0.001), infliximab (INF) (p&lt;0.001), rituximab (RTM) (p=0.004) and etanercept (ETA) (p=0.035) when they was used as the first biologic drug. The treatment survival of tocilizumab was significantly higher compared to INF (p=0.02). As a second-line biological therapy ADA was maintained significantly longer than the INF (p=0.048). <h3>Conclusions</h3> Results of the real clinical practice trial show the significant differences in the retention rates of some biologics. It is reasonable to take these differences into consideration by the planning of the biologic treatment of RA pts. <h3>Disclosure of Interest</h3> None declared
THU0666 Patient global assessment is more sensitive to change than health-related quality of life instruments in early axial spondyloarthritis over 3 years: data from the desir cohort
Authors: D Puyraimond-Zemmour, C Desthieux, A Ruyssen-Witrand, B Fautrel, L Gossec
Journal: Annals of the Rheumatic Diseases (2017)

<h3>Background</h3> Several questionnaires assess similar constructs of global patient-reported state or Health-Related Quality of Life (HRQoL). <h3>Objectives</h3> To evaluate sensitivity to change (ie, discriminance) of several questionnaires in early axial spondyloarthritis (axSpA) over 3 years of follow up: the SF36, axial spondyloarthritis quality of life (ASQoL), axial spondyloarthritis health assessment questionnaire (AS-HAQ) and patient global assessment (PGA). <h3>Methods</h3> DESIR is an ongoing prospective, multicenter, longitudinal, observational French cohort (1). Patients had inflammatory back pain of more than 3 months and less than 3 years suggestive of axSpA. For our analysis, only patients with no missing data for MCS and PCS SF36 values during the first 3 years were included. A global construct of patient global state was assessed by the SF36 questionnaire and its 2 subscales (scored 0–100 with higher scores indicating better status): the physical composite score (PCS) and the mental composite score (MCS), AsQoL, a disease-specific HRQoL scale, PGA and AS-HAQ. ASDAS-CRP was used as comparator. Each outcome was assessed at baseline, 6 months, 12 months, 24 months and 36 months. Standardized mean differences (SMD) were calculated using Cohen9s effect size with confidence intervals, between each time point for each outcome. A SMD &lt;0.5 is usually considered small, between 0.5 and 0.8 moderate and &gt;0.8 as important. <h3>Results</h3> In all, 442 patients were analyzed: at baseline, mean age was 34.2±8.6 years; mean disease duration was 18.6±10.7 months; 239 (54%) were females, 274 (62%) had HLAB27 and 124 (28%) had radiological sacroiliitis. At baseline, patients were not in an optimal state; improvement was clear up to month 6 then minimal (at the group level): Table. Sensitivity to change was greatest for PGA, then ASQoL whereas AS-HAQ, MCS and PCS appeared the least discriminant measure (Table). <h3>Conclusions</h3> PGA was more sensitive to change than HRQoL measures in early axSpA. ASDAS appeared also sensitive to change. Changes in all the measures were very small at the group level after 6 months of follow-up indicating the concepts convered may be as much patient- as disease-related. <h3>References</h3> Dougados M. et al. Clinical presentation of patients suffering from recent onset chronic inflammatory back pain suggestive of spondyloarthritis: The DESIR cohort.Joint Bone Spine. 2015;82(5):345–51. <h3>Disclosure of Interest</h3> None declared
AB0620 Oral health in patients with systemic sclerosis: an eustar center experience
Authors: C Ancuta, M Antohe, E Ancuta, R Chirieac, C Iordache
Journal: Annals of the Rheumatic Diseases (2017)

<h3>Background</h3> Although the orofacial manifestations are commonly reported among patients with systemic sclerosis (SSc), only few studies have adequately addressed the issue of oral health-related quality of life (QoL) in such pathobiological settings. <h3>Objectives</h3> The aim was to characterize the oral health status (OHS) of adults with SSc and to compare with the general population. <h3>Methods</h3> A cross-sectional prospective observational study in 37 consecutive SSc in a EUSTAR cohort (EUSTAR 162 center) and 37 gender and age-matched controls without SSc. A standardized oral exam meaning OHS (periodontal, dental, mucosal and microbial), oral health-related behaviors and oral HRQoL (Oral Health Impact Profile, OHIP) were evaluated in all recruited individuals, while oral manifestations such as size of oral aperture, oral dryness, manual dexterity for oral hygiene and HRQoL only in SSc. Multivariable regression analysis was done to evaluate association between SSc, oral abnormalities, oral health status and QoL. <h3>Results</h3> Overall, SSc had significantly reduced oral HRQoL compared with controls (p&lt;0.05). We demonstrated lower resting salivary flow rates (p&lt;0.05) and pH (p&lt;0.05), reduced maximal mouth opening (p&lt;0.05), smaller interincisal distance (p&lt;0.05) in SSc group as compared to their controls. Moreover, despite comparable oral health-related behaviors (e.g. same level of daily tooth-brushing), the majority of SSc experienced caries (p&lt;0.05) and presented with more periodontal disease (p&lt;0.05) comprising periodontal pockets (pocket depth PD&gt;3 mm) (p&lt;0.05), clinical attachment level (CAL) ≥5.5 mm (p&lt;0.05). Finally, SSc was documented as a significant independent predictor of OHIP, missing teeth, periodontal disease, interincisal distances as shown by multivariate regression (p&lt;0.05). <h3>Conclusions</h3> SSc patients are at risk to develop impaired oral health and oral HRQoL compared with the general population. <h3>Disclosure of Interest</h3> None declared
THU0182 Monotherapy with the jak1-selective inhibitor filgotinib displays an anti-inflammatory biomarker profile in rheumatoid arthritis patients
Authors: A Kavanaugh, A Van der Aa, C Jamoul, W Li, L Goyal, Y Pan, P Harrison, C Tasset, J Tarrant, R Galien
Journal: Annals of the Rheumatic Diseases (2017)

<h3>Background</h3> Janus kinases (JAKs) are key proteins in the signal transduction of many cytokines and growth factors. The selective JAK1 inhibitor filgotinib (GLPG0634, GS-6034) has been evaluated in a 24-week phase 2B study (DARWIN 2) as monotherapy in active rheumatoid arthritis (RA) patients with inadequate response to methotrexate and has shown a good safety and efficacy profile<sup>1</sup>. <h3>Objectives</h3> To gain insight into filgotinib mode of action as monotherapy in RA patients by analysing the impact of filgotinib on a broad panel of immune modulators in the serum. <h3>Methods</h3> RA patients received either placebo (PBO), or filgotinib monotherapy at 50mg, 100mg or 200mg once daily (QD). Serum samples were collected at baseline, week 4 and week 12 and analysed using the 18-plex bead-based immunoassay (HSTCMAG-28SK Merck-Millipore) on BioPLEX-200 instrument to measure cytokine concentration. Median % change from baseline for biomarkers are reported for week 4 and 12. Wilcoxon rank-sum test assessed the significance of difference between filgotinib treated groups and PBO. <h3>Results</h3> Following treatment with filgotinib at 100 mg QD and 200mg QD, there were significant reductions in cytokines important in expansion and activity of multiple T cell subsets and innate immunity compared to PBO (see Table). These changes include decreases in proinflammatory cytokines (IL-6, IL-1β, and TNFα), T<sub>H</sub>1-related (IL-2, IFN-γ and IL-12), T<sub>H</sub>2-related (IL-4, IL-5, and IL-13) and T<sub>H</sub>17-related cytokines (IL-1β, IL-6, IL-17A, IL-21 and IL-23). All doses of filgotinib also reduced the B- and T-cell development cytokine IL-7. In contrast, IL-8 was not affected by filgotinib. Reductions in MIP1α, MIP1β and GM-CSF are in line with a down modulation of innate immune activity. <h3>Conclusions</h3> Treatment of RA patients with filgotinib monotherapy resulted in significant reduction in the levels of a broad range of cytokines related to T<sub>H</sub>1, T<sub>H</sub>2, T<sub>H</sub>17 and potentially B cells, as well as innate immunity. This observed anti-inflammatory activity of filgotinib is consistent with its efficacy in RA patients. <h3>References</h3> Kavanaugh A et al. Ann Rheum Dis 2016;0:1–11.doi:10.1136/annrheumdis-2016–210105. <h3>Disclosure of Interest</h3> A. Kavanaugh Consultant for: Galapagos, Pfizer, Abbvie, Amgen, Celgene, Janssen, Novartis, Eli Lilly, UCB, A. Van der Aa Employee of: Galapagos NV, C. Jamoul Employee of: Galapagos NV, W. Li Employee of: Gilead Sciences, L. Goyal Employee of: Gilead Sciences, Y. Pan Employee of: Gilead Sciences, P. Harrison Employee of: Galapagos NV, C. Tasset Employee of: Galapagos NV, J. Tarrant Employee of: Gilead Sciences, R. Galien Employee of: Galapagos SASU