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Objectives We aimed to evaluate the obstetric complications and the risk factors for these events in pregnant women with rheumatic diseases (RDs). Methods A single-center retrospective study of women with RDs at Hokkaido University Hospital between 2007 and 2016 was conducted. Clinical features and maternal and fetal outcomes were retrospectively collected. The rate of pregnancy complications was compared with the general obstetric population (GOP) in Japan. Results Overall, 132 pregnancies in 95 women with RDs were recorded. Underlying RDs were systemic erythematosus (SLE) ( n = 57), antiphospholipid syndrome (APS) ( n = 35), rheumatoid arthritis ( n = 9), and other RDs ( n = 31). Antiphospholipid antibodies (aPL) were detected in 44 pregnancies (32%). Glucocorticoid was used in 82 pregnancies (62%), and tacrolimus in 20 pregnancies (15%). There were 24 disease flares (18%), but no RD-related death was documented. We recorded 112 live births, 6 abortions, 8 miscarriages, and 6 stillbirths. Pregnancies with RDs appeared to have frequent, emergency cesarean sections and preterm deliveries compared with GOP (30% vs 15% and 21% vs 14%, respectively). The median [interquartile range] birthweight in SLE and APS was lower than GOP (2591 [2231–2958] g and 2600 [2276–2920] g vs 2950 [2650–3250] g, respectively). In pregnancies with SLE, low complement levels presented the risk of maternal complications (odds ratio [95% CI]; 3.9 [1.0–14.9], p = 0.046) and anti-DNA antibody positivity was significantly correlated with the risk of fetal complications (3.5 [1.1–11.2], p = 0.036). In pregnancies with APS, maternal age over 35 years and duration of disease longer than 9 years (7.4 [1.3–40.8], p = 0.021, and 11.16 [1.1–118.8], p = 0.046, respectively) were significantly correlated with the risk of fetal complications. Conclusion Pregnancies with RDs were at increased risk of having both maternal complications and adverse neonatal outcomes, indicating these pregnancies should be closely monitored.

Background:RISE-SSc (NCT02283762) was a multicenter, double-blind, Phase IIb study of riociguat in early dcSSc. Primary endpoint was change in mRSS from baseline to Wk 52.Objectives:Exploratory, descriptive analyses of riociguat target engagement and effects on disease biomarkers in RISE-SSc and their relationship with effects on the primary endpoint. All biomarker p-values are for information only.Methods:Pts with dcSSc (duration ≤18 mo; modified Rodnan skin score [mRSS] 10–22 units) were randomized to riociguat 0.5−2.5 mg tid (n=60) or placebo (n=61). Biomarkers of target engagement (cGMP), inflammation and/or vascular/endothelial function (e.g. high-sensitivity C-reactive protein [hsCRP], soluble platelet endothelial cell adhesion molecule 1 [sPECAM-1], soluble E-selectin, chemokine ligand 4 [CXCL-4]), and fibrosis (e.g. alpha-smooth muscle cell actin [alphaSMA], pro-collagen mRNA expression) were measured in plasma, serum, and skin biopsies at baseline and Wk 14.Results:Mean±SD change from baseline in mRSS was –2.09±5.66 (n=57) with riociguat and –0.77±8.24 (n=52) with placebo (p=0.08). From baseline to Wk 14, plasma cGMP rose by mean (SD) 94% (78%) (n=52) with riociguat and 10% (39%) (n=52) with placebo (nominal pConclusion:Primary study endpoint (change in mRSS) was not met. Plasma cGMP rose with riociguat, confirming engagement with the NO-sGC-cGMP pathway. Serum sPECAM-1 (marker of endothelial activation) and CXCL-4 (marker of progressive SSc) fell with riociguat; hsCRP and E-selectin did not. Some serum and skin biomarkers of higher disease activity at baseline were associated with a greater effect of riociguat on skin fibrosis.Acknowledgments:RISE-SSc was jointly funded by Bayer AG and Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA.Disclosure of Interests:Oliver Distler Grant/research support from: Grants/Research support from Actelion, Bayer, Boehringer Ingelheim, Competitive Drug Development International Ltd. and Mitsubishi Tanabe; he also holds the issued Patent on mir-29 for the treatment of systemic sclerosis (US8247389, EP2331143)., Consultant of: Consultancy fees from Actelion, Acceleron Pharma, AnaMar, Bayer, Baecon Discovery, Blade Therapeutics, Boehringer, CSL Behring, Catenion, ChemomAb, Curzion Pharmaceuticals, Ergonex, Galapagos NV, GSK, Glenmark Pharmaceuticals, Inventiva, Italfarmaco, iQvia, medac, Medscape, Mitsubishi Tanabe Pharma, MSD, Roche, Sanofi and UCB, Speakers bureau: Speaker fees from Actelion, Bayer, Boehringer Ingelheim, Medscape, Pfizer and Roche, Frank Kramer Employee of: Bayer AG, Josef Höfler Employee of: Josef Höfler is an employee of Staburo GmbH, Munich, Germany, contracted by Bayer AG to perform the biomarker analyses, Mercedeh Ghadessi Employee of: Bayer AG, Peter Sandner Employee of: Bayer AG, Yannick Allanore Grant/research support from: BMS, Inventiva, Roche, Sanofi, Consultant of: Actelion, Bayer AG, BMS, BI, Christopher Denton Grant/research support from: GlaxoSmithKline, CSL Behring, and Inventiva, Consultant of: Medscape, Roche-Genentech, Actelion, GlaxoSmithKline, Sanofi Aventis, Inventiva, CSL Behring, Boehringer Ingelheim, Corbus Pharmaceuticals, Acceleron, Curzion and Bayer, Masataka Kuwana Grant/research support from: Acetelion, Consultant of: Acetelion, Bayer, Chugai, Corbus Pharmaceuticals, CSL Behring and Reata Pharmaceuticals. He was a member of the SENSCIS trial Steering Committee (Boehringer Ingelheim), Marco Matucci-Cerinic Grant/research support from: Actelion, MSD, Bristol-Myers Squibb, Speakers bureau: Acetelion, Lilly, Boehringer Ingelheim, Janet Pope Grant/research support from: AbbVie, Bristol-Myers Squibb, Eli Lilly & Company, Merck, Roche, Seattle Genetics, UCB, Consultant of: AbbVie, Actelion, Amgen, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Eicos Sciences, Eli Lilly & Company, Emerald, Gilead Sciences, Inc., Janssen, Merck, Novartis, Pfizer, Roche, Sandoz, Sanofi, UCB, Speakers bureau: UCB, Tatsuya Atsumi Grant/research support from: Eli Lily Japan K.K., Alexion Pharmaceuticals, Inc., Bristol-Myers Squibb Co., AbbVie Inc., Daiichi Sankyo Co., Ltd., Pfizer Inc., Chugai Pharmaceutical Co., Ltd., Mitsubishi Tanabe Pharma Co., Astellas Pharma Inc., Consultant of: Gilead Sciences, Inc., Eli Lilly Japan K.K., UCB Japan Co. Ltd., AbbVie Inc., Daiichi Sankyo Co., Ltd., Pfizer Inc., Chugai Pharmaceutical Co., Ltd., Speakers bureau: Eli Lilly Japan K.K., UCB Japan Co. Ltd., Bristol-Myers Squibb Co., AbbVie Inc., Eisai Co. Ltd., Otsuka Pharmaceutical Co., Ltd., Daiichi Sankyo Co., Ltd., Pfizer Inc., Chugai Pharmaceutical Co., Ltd., Mitsubishi Tanabe Pharma Co., Takeda Pharmaceutical Co., Ltd., Astellas Pharma Inc., Radim Bečvář Consultant of: Actelion, Roche, László Czirják Consultant of: Actelion, BI, Roche-Genentech, Lilly, Medac, Novartis, Pfizer, Bayer AG, Ellen De Langhe Consultant of: member of advisory board for Boehringer, Eric Hachlla: None declared, Tomonori Ishii: None declared, Osamu Ishikawa: None declared, Sindhu Johnson Grant/research support from: Boehringer Ingelheim, Corbus Pharmaceuticals, GlaxoSmithKline, Roche, Merck, Bayer, Consultant of: Boehringer Ingelheim, Ikaria, Kaisa Laapas Employee of: Partly in-sourced to Bayer, Valeria Riccieri: None declared, Elena Schiopu: None declared, Richard Silver: None declared, Vanessa Smith Grant/research support from: The affiliated company received grants from Research Foundation - Flanders (FWO), Belgian Fund for Scientific Research in Rheumatic diseases (FWRO), Boehringer Ingelheim Pharma GmbH & Co and Janssen-Cilag NV, Consultant of: Boehringer-Ingelheim Pharma GmbH & Co, Speakers bureau: Actelion Pharmaceuticals Ltd, Boehringer-Ingelheim Pharma GmbH & Co and UCB Biopharma Sprl, Chiara Stagnaro: None declared, Viginia Steen Grant/research support from: The associated affiliation has received grants/research from Boehringer Ingelheim, Corbus Pharmaceuticals, CSL Behring, Eicos, Galapagos, Immune Tolerance Network, Reata, Consultant of: Virginia Steen has acted as a consultant for Boehringer Ingelheim, Corbus, CSL Behring, Eicos, Forbius, Wendy Stevens: None declared, Gabriella Szücs: None declared, Marie-Elise Truchetet: None declared, Melanie Wosnitza Employee of: Bayer AG, Dinesh Khanna Shareholder of: Eicos Sciences, Inc./Civi Biopharma, Inc., Grant/research support from: Dr Khanna was supported by NIH/NIAMS K24AR063120, Consultant of: Acceleron, Actelion, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Corbus Pharmaceuticals, Horizon Therapeutic, Galapagos, Roche/Genentech, GlaxoSmithKline, Mitsubishi Tanabe, Sanofi-Aventis/Genzyme, UCB

Background:In the FINCH 3 study, filgotinib (FIL)—a potent, selective, oral small molecule Janus kinase 1 inhibitor1—in combination with methotrexate (MTX), demonstrated significant improvements in the signs and symptoms of rheumatoid arthritis (RA) vs MTX alone in patients (pts) who were MTX-naïve.2For pts with RA, rapid control of pain and fatigue along with maintenance of physical function and health-related quality of life (HRQoL) are important outcomes of their care.3Thus, patient-reported outcomes (PROs) can provide physicians with evidence to guide treatment decisions beyond the guideline-recommended treatment targets of reducing immune inflammation to prevent joint damage, physical disability, and mortality.4Objectives:To evaluate the rate and magnitude of change in PROs assessing functional status, pain, HRQoL, and fatigue from FINCH 3.Methods:In the FINCH 3 study (NCT02886728), pts with active RA who were MTX-naïve received FIL 200 mg daily + MTX, FIL 100 mg + MTX, FIL 200 mg (+ placebo [PBO]), or MTX (+ PBO) for up to 52 weeks. PROs were recorded prospectively and included HAQ-DI (functional status) and VAS pain scale (day 1, week [W]2, W4, W8, W12, W16, W20, W24, W30, W36, W44, W52), SF-36 (HRQoL), and FACIT-Fatigue (day 1, W4, W12, W24, W36, W52). The least squares mean of the change from baseline (CFB) at each time point up to W52 and p values (each FIL arm vs MTX) were analysed using a mixed-effects model for repeated measures. For HAQ-DI, the proportion of pts who achieved the minimum clinically important difference (MCID; reduction ≥0.22) between each FIL arm and MTX was analysed using logistic regression analysis. P values for the comparisons of PROs were not adjusted for multiplicity, except for HAQ-DI CFB at W24 for FIL 200 mg + MTX and FIL 100 mg + MTX vs MTX.Results:Of the 1249 pts randomised and treated (FIL 200 mg + MTX, n = 416; FIL 100 mg + MTX, n = 207; FIL 200 mg, n = 210; MTX, n = 416), 1025 (82.1%) completed the study. Compared with MTX alone, a nominally significantly greater CFB in functional status and pain from W2 to W24 was observed in all FIL arms; the benefit was sustained from W30 to W52 (Fig 1). By W2, a nominally significantly greater proportion of pts achieved the HAQ-DI MCID or greater (≥0.22) in all FIL arms (FIL 200 mg + MTX: 61.9%, p A, B). Improvements in SF-36 mental component summary scores were nominally significant for pts in all FIL arms vs MTX alone as early as W4, and the CFB reached at W12 for FIL arms was generally sustained up to W52 (Fig 2A).Conclusion:For pts with moderate to severe RA who were MTX-naïve, FIL—with or without concomitant MTX—led to more rapid and sustained improvements in functional status, pain, fatigue, and HRQoL, compared with MTX alone.References:[1]Van Rompaey, et al.J Immunol. 2013;131:3568–77.[2]Westhovens, et al.Arthritis Rheumatol. 2019;71 (suppl 10):1606–8.[3]Fautrel B, et al.Rheumatol Int.2018;38:935–47.[4]Smolen JS, et al.Ann Rheum Dis.2017;76:960–77.Disclosure of Interests:Rieke Alten Grant/research support from: Pfizer, Galapagos, Galapagos NV, Gilead, Gilead Sciences, Inc., Novartis, Consultant of: Pfizer, Speakers bureau: Pfizer, William Rigby Consultant of: Gilead Sciences, Inc., Alena Pechonkina Shareholder of: Gilead Sciences, Inc., Employee of: Gilead Sciences, Inc., Zhaoyu Yin Shareholder of: Gilead Sciences, Inc., Employee of: Gilead Sciences, Inc., Ken Hasegawa Shareholder of: Gilead Sciences, Inc., Employee of: Gilead Sciences, Inc., Thijs Hendrikx Shareholder of: Galapagos (share/warrant holder), Employee of: Galapagos, Tatsuya Atsumi Grant/research support from: Eli Lily Japan K.K., Alexion Pharmaceuticals, Inc., Bristol-Myers Squibb Co., AbbVie Inc., Daiichi Sankyo Co., Ltd., Pfizer Inc., Chugai Pharmaceutical Co., Ltd., Mitsubishi Tanabe Pharma Co., Astellas Pharma Inc., Consultant of: Gilead Sciences, Inc., Eli Lilly Japan K.K., UCB Japan Co. Ltd., AbbVie Inc., Daiichi Sankyo Co., Ltd., Pfizer Inc., Chugai Pharmaceutical Co., Ltd., Speakers bureau: Eli Lilly Japan K.K., UCB Japan Co. Ltd., Bristol-Myers Squibb Co., AbbVie Inc., Eisai Co. Ltd., Otsuka Pharmaceutical Co., Ltd., Daiichi Sankyo Co., Ltd., Pfizer Inc., Chugai Pharmaceutical Co., Ltd., Mitsubishi Tanabe Pharma Co., Takeda Pharmaceutical Co., Ltd., Astellas Pharma Inc., Rene Westhovens Grant/research support from: Celltrion Inc, Galapagos, Gilead, Consultant of: Celltrion Inc, Galapagos, Gilead, Speakers bureau: Celltrion Inc, Galapagos, Gilead

Background:Group 1 and 3 pulmonary hypertension (PH) develop through different pathological mechanisms but have similar hemodynamic abnormalities. Systemic sclerosis (SSc) is associated with both pulmonary vascular disease (PVD) and interstitial lung disease (ILD), making it challenging to differentiate group 1 and 3 PH in those patients. A previous study using quantitative evaluation of chest computed tomography (CT) demonstrated that normal lung volume was inversely correlated with mean pulmonary arterial pressure (mPAP) in patients with group 3 PH (1).Objectives:In this study, we aimed to assess the dominance of PVD or ILD in SSc patients by quantitative evaluation of chest CT and to evaluate each characteristic.Methods:A total of 76 SSc patients who underwent right heart catheterization (RHC) were included. Chest CT was evaluated by using a software (Synapse Vincent Ver.3.0, Fujifilm) which quantified normal and total area of the lung. Then, we calculated abnormal area by drawing normal area from total area in the lung (%). Pulmonary function test (PFT) and serum biomarkers, such as KL-6 and LDH, were also evaluated. The dominance of PVD or ILD was defined as divergent or parallel change between the first and last assessments, respectively, in mPAP and abnormal area in the lung calculated using the software. Increase or decrease by over 10% in the last assessment compared to the first assessment was considered as a significant change in mPAP or abnormal area in the lung. P values were calculated by Mann-Whitney U test, and correlation coefficients were calculated by direct regression variance.Results:The median [range] values of mPAP and abnormal area in the lung at baseline were 23 [9-65] mmHg and 30.2 [0-100] %, respectively. Of 37 SSc and PH patients, 18 were defined as having PVD dominance while 19 as ILD dominance. Abnormal area in the lung at baseline was greater in patients with ILD dominance compared to those with PVD dominance (39.1 [16.3-98.3] v.s. 14.0 [0-99] %, p=0.002), whereas mPAP was higher in patients with PVD dominance than those with ILD dominance (42.5 [23.0-65.0] v.s. 26.0 [16.0-42.0] mmHg, p=0.002). PFT parameters including forced vital capacity were not different between the two groups. The ratio of mPAP/KL-6 showed a great difference between the two groups with its significant elevation in patients with PVD dominance (p=0.007).Conclusion:Quantitative evaluation of chest CT showed great efficiency in differentiating the dominance of PVD or ILD in patients with SSc and PH. In addition, the ratio of mPAP/KL-6 may easily be used as a parameter for dominance evaluation.References:[1]Iwasawa T, Kato S, Ogura T, Kusakawa Y, Iso S, Baba T, et al. Low-normal lung volume correlates with pulmonary hypertension in fibrotic idiopathic interstitial pneumonia: computer-aided 3D quantitative analysis of chest CT. AJR Am J Roentgenol. 2014;203(2):W166-73.Disclosure of Interests:None declared

Background:Belimumab (BEL), a monoclonal antibody that antagonizes B-lymphocyte stimulator, was first approved in 2011 for active, autoantibody-positive systemic lupus erythematosus (SLE). BEL has been studied for over 10 years; and while safety data from individual trials have been informative, a large integrated safety analysis has not yet been conducted.Objectives:Perform pooled analyses to evaluate the safety of BEL in adult patients with SLE.Methods:Aggregate analyses were performed using safety data for patients ≥18 years of age pooled from six randomised, placebo (PBO)-controlled BEL clinical trials (GSK studies: LBSL02, 110752, 110751, 112341, 113750, and 115471). Patients from GSK studies LBSL02, 110752, and 110751 received intravenous (IV) BEL 1, 4 (LBSL02 only), or 10 mg/kg, or PBO on Days 1, 14, 28, and every 28 days thereafter. Patients from GSK studies 113750 and 115471 received IV BEL 10 mg/kg or PBO on Days 1, 14, 28, and every 28 days thereafter. Patients from GSK study 112341 received subcutaneous (SC) BEL 200 mg, or PBO weekly. Safety analyses included the incidence of adverse events (AEs), serious AEs (SAEs), severe AEs, AEs of special interest (AESI), and mortality of BEL (all doses and formulations combined) vs PBO at Week 52.Results:The pooled analysis included 4170 patients. Overall, 81.0% (n=2280/2815) of patients receiving BEL and 76.6% (n=1038/1355) of patients receiving PBO completed their respectively enrolled study; the most common reason for withdrawal was occurrence of an AE in both groups. The majority of patients were female (BEL: 94.5%; PBO: 93.6%), the mean age in both groups was 38 years, and baseline characteristics (race, SLE duration, disease activity, SLE damage, complement levels, anti-dsDNA binding, SLE medication usage) were similar between treatments.The incidence of patients experiencing ≥1 AE, ≥1 SAE, and mortality was similar across treatments (Table 1); the most commonly reported SAEs in both groups were infections and infestations (BEL: 5.4% [n=151/2815]; PBO: 5.9% [n=80/1355]). The mean duration of treatment exposure was similar between groups (BEL: 334.1 days; PBO: 325.3 days).A greater proportion of patients experienced AESI with BEL vs PBO for post-infusion/injection systemic reactions (from IV or SC administration) and depression/suicide/self-injury (Table 1). The proportion of patients experiencing an AESI of infections and malignancies was similar between groups.Conclusion:Consistent with individual studies, BEL demonstrated a similar safety profile to PBO in this large integrated safety analysis of six trials. These results support a positive benefit–risk profile of BEL in the treatment of adult SLE.Funding:GSKTable 1.Pooled AE dataN (%)PBO (IV + SC)N=1355BEL (IV + SC)N=2815AE1184 (87.4)2440 (86.7)SAE230 (17.0)421 (15.0)Severe AE (severe or life threatening)209 (15.4)377 (13.4)AE resulting in study drug discontinuation109 (8.0)184 (6.5)Death6 (0.4)16 (0.6)AESIPost-infusion/injection systemic reactions*110 (8.1)286 (10.2)Serious2 (0.1)13 (0.5)All infections of special interest (OIs, HZ, TB, sepsis)97 (7.2)173 (6.1)Serious17 (1.3)40 (1.4)All OIs92 (6.8)157 (5.6)Active TB5 (0.4)4 (0.1)All HZ59 (4.4)106 (3.8)All sepsis10 (0.7)20 (0.7)Malignancies excluding NMSC2 (0.1)8 (0.3)Including NMSC3 (0.2)12 (0.4)Depression (inc. mood disorders and anxiety)/suicide/self-injury92 (6.8)210 (7.5)Serious5 (0.4)9 (0.3)*Occurring on or within 3 days of infusion/injection date.HZ, herpes zoster; NMSC, non-melanoma skin cancer; OIs, opportunistic infections; TB, tuberculosisAcknowledgements:Medical writing assistance was provided by Helen Taylor, Fishawack Indicia Ltd., UK, part of Fishawack Health, and was funded by GSK.Disclosure of Interests:Daniel J. Wallace Speakers bureau: GSK, Consultant of: GSK, Tatsuya Atsumi Speakers bureau: GSK, Consultant of: GSK, Grant/research support from: GSK, Mark Daniels Shareholder of: GSK, Employee of: GSK, Anne Hammer Shareholder of: GSK, Employee of: GSK, Paige Meizlik Shareholder of: GSK, Employee of: GSK, Holly Quasny Shareholder of: GSK, Employee of: GSK, Andreas Schwarting Speakers bureau: Novartis, Roche, GSK, Pfizer, Amgen, Consultant of: GSK, Grant/research support from: AbbVie, Pfizer, Novartis, GSK, Actelion, Fengchun Zhang: None declared, David Roth Shareholder of: GSK, Employee of: GSK

Background:Oral Janus kinase inhibitors (JAKi) have dramatically altered outcomes in patients with rheumatoid arthritis (RA). However, there remains some proportion of patients who respond to inadequately JAKi treatment (JAKi-IR) [1,2]. The characteristics in RA patients associated with JAKi-IR have not been fully demonstrated.Objectives:To clarify the characteristics of JAKi-IR in patients with RA by cluster analysis.Methods:This retrospective study comprised 120 RA patients who were treated with JAKi (Tofacitinib or Baricitinib) between July 2013 and September 2019 in five facilities. The disease status at the baseline, at 12 weeks after JAKi treatment and at the time point of withdrawing JAKi was assessed using the Disease Activity Score (DAS28) and the American College of Rheumatology (ACR) response criteria. JAKi-IR was defined as follows, primary non-response at 12 weeks after JAKi treatment: withdrawal of JAKi with ACR20 non-response or non-improvement in DAS28-CRP (ΔDAS28-CRPResults:The 120 enrolled patients were classified into 4 groups by cluster analysis(Figure1), The characteristics of each group are as follows, Group A(n=21): female + bone erosion + RF/ACPA positive + AID + MTX non-user, Group B(n=36): male + older age + RA-ILD + RF/ACPA positive + MTX non-user, Group C(n=35): RF/ACPA positive + absence of RA-ILD + MTX user, Group D (n=28): seronegative + MTX user + absence of RA-ILD + history of biologic DMARDs failure. The rate of JAKi-IR was A:9%, B:8%, C:20%, D:32%, and the significant difference between Group B and D was identified (p=0.02). In multiple comparison of 4 groups, no significant difference was identified (p=0.06) (Figure2).Conclusion:JAKi-IR would be more likely to be seronegative, MTX use, absence of RA-ILD and history of biologic DMARDs failure. Cluster analysis is an exploratory tool that aids in the analysis of huge amount of data.References:[1] Takeuchi T, Yamanaka H, Yamaoka K, Arai S, Toyoizumi S, DeMasi R, et al. Efficacy and safety of tofacitinib in Japanese patients with rheumatoid arthritis by background methotrexate dose: A post hoc analysis of clinical trial data. Mod Rheumatol. 2019;29(5):756-66.[2] Tanaka Y, Atsumi T, Amano K, Harigai M, Ishii T, Kawaguchi O, et al. Efficacy and safety of baricitinib in Japanese patients with rheumatoid arthritis: Subgroup analyses of four multinational phase 3 randomized trials. Mod Rheumatol. 2018;28(4):583-91.Disclosure of Interests:Masanari Sugawara: None declared, Yuichiro Fujieda: None declared, Atsushi Noguchi: None declared, Shun Tanimura: None declared, Yuka Shimizu: None declared, Ikuma Nakagawa: None declared, Michihito Kono: None declared, Masaru Kato: None declared, Kenji Oku: None declared, Tatsuya Atsumi Grant/research support from: Eli Lily Japan K.K., Alexion Pharmaceuticals, Inc., Bristol-Myers Squibb Co., AbbVie Inc., Daiichi Sankyo Co., Ltd., Pfizer Inc., Chugai Pharmaceutical Co., Ltd., Mitsubishi Tanabe Pharma Co., Astellas Pharma Inc., Consultant of: Gilead Sciences, Inc., Eli Lilly Japan K.K., UCB Japan Co. Ltd., AbbVie Inc., Daiichi Sankyo Co., Ltd., Pfizer Inc., Chugai Pharmaceutical Co., Ltd., Speakers bureau: Eli Lilly Japan K.K., UCB Japan Co. Ltd., Bristol-Myers Squibb Co., AbbVie Inc., Eisai Co. Ltd., Otsuka Pharmaceutical Co., Ltd., Daiichi Sankyo Co., Ltd., Pfizer Inc., Chugai Pharmaceutical Co., Ltd., Mitsubishi Tanabe Pharma Co., Takeda Pharmaceutical Co., Ltd., Astellas Pharma Inc.

Background:RISE-SSc (NCT02283762) was a multicenter Phase IIb trial of riociguat in pts with early (duration ≤18 months) dcSSc and modified Rodnan skin score (mRSS) 10−22 units. Pts were randomized double-blind to placebo or riociguat 0.5–2.5 mg t.i.d. for 52 weeks. The primary endpoint, mRSS change from baseline to Week (Wk) 52, did not reach statistical significance (p=0.08, riociguat vs placebo), but there were favorable trends in some other outcomes.Objectives:To present open-label long-term extension (LTE) results of RISE-SSc.Methods:Pts who completed Wk 52 of double-blind therapy could enter LTE on riociguat. Endpoints included mRSS, adverse events (AEs), and serious AEs (SAEs).Results:Of 60 pts randomized to riociguat and 61 to placebo, 42 (riociguat−riociguat group) and 45 (former placebo group), respectively, entered LTE. At LTE start, mean±SD mRSS was 16.4±3.2 and 16.3±4.2 units, and mean disease duration was 8.9±7.8 and 8.9±5.8 months, in the riociguat−riociguat and former placebo groups, respectively. Other demographics/disease characteristics were also comparable. Median duration of riociguat treatment was 1092 d in riociguat−riociguat pts and 649 d in former placebo pts. Throughout the study, mRSS decreased in both groups (Figure 1). From Wk 52 to last visit, mRSS fell by −3.02±5.51 in riociguat−riociguat patients and −3.96±5.43 in former placebo pts. Rates of mRSS regression (decrease by >5 units and ≥25% from Wk 52 to last visit) and of % declines in mRSS were similar in the two groups (Figure 2). mRSS progression (increase by >5 units and ≥25% from Wk 52 to last visit) occurred in 1 pt (2%) in each group. During the entire study, rescue therapy agents were used in 15 (36%) riociguat−riociguat pts and 17 (38%) former placebo pts. AEs were reported from Wk 52 to last visit in 82 pts (94%): 40 (95%) riociguat−riociguat and 42 (93%) former placebo. Most common AEs overall: nasopharyngitis (24%), gastroesophageal reflux disease (17%), diarrhea (15%), and hypotension (14%). AEs of special interest (dizziness, postural dizziness, or hypotension) occurred in 5 riociguat−riociguat pts (12%) and 4 former placebo pts (9%). SAEs were reported in 21 (24%) pts: 10 (24%) riociguat−riociguat pts and 11 (24%) former placebo pts, with no SAE reported in >1 patient, no SAEs of special interest, and no deaths.Conclusion:During LTE riociguat treatment, mRSS decreased in both groups from Wk 52 onwards and mRSS progression was uncommon. Riociguat had acceptable safety, similar to the main study, with no new safety signal.Acknowledgments:RISE-SSc was jointly funded by Bayer AG and Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA.Disclosure of Interests:Dinesh Khanna Shareholder of: Eicos, Grant/research support from: NIH NIAID, NIH NIAMS, Consultant of: Acceleron, Actelion, Bayer, BMS, Boehringer-Ingelheim, Corbus, Galapagos, Genentech/Roche, GSK, Mitsubishi Tanabi, Sanofi-Aventis/Genzyme, UCB Pharma, Janet Pope Grant/research support from: AbbVie, Bristol-Myers Squibb, Eli Lilly & Company, Merck, Roche, Seattle Genetics, UCB, Consultant of: AbbVie, Actelion, Amgen, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Eicos Sciences, Eli Lilly & Company, Emerald, Gilead Sciences, Inc., Janssen, Merck, Novartis, Pfizer, Roche, Sandoz, Sanofi, UCB, Speakers bureau: UCB, Marco Matucci-Cerinic Grant/research support from: Actelion, MSD, Bristol-Myers Squibb, Speakers bureau: Acetelion, Lilly, Boehringer Ingelheim, Masataka Kuwana Grant/research support from: Acetelion, Consultant of: Acetelion, Bayer, Chugai, Corbus Pharmaceuticals, CSL Behring and Reata Pharmaceuticals. He was a member of the SENSCIS trial Steering Committee (Boehringer Ingelheim), Christopher Denton Grant/research support from: GlaxoSmithKline, CSL Behring, and Inventiva, Consultant of: Medscape, Roche-Genentech, Actelion, GlaxoSmithKline, Sanofi Aventis, Inventiva, CSL Behring, Boehringer Ingelheim, Corbus Pharmaceuticals, Acceleron, Curzion and Bayer, Yannick Allanore Grant/research support from: BMS, Inventiva, Roche, Sanofi, Consultant of: Actelion, Bayer AG, BMS, BI, Melanie Wosnitza Employee of: Bayer AG, Marie-Elise Truchetet: None declared, Gabriella Szücs: None declared, Wendy Stevens: None declared, Viginia Steen Grant/research support from: The associated affiliation has received grants/research from Boehringer Ingelheim, Corbus Pharmaceuticals, CSL Behring, Eicos, Galapagos, Immune Tolerance Network, Reata, Consultant of: Virginia Steen has acted as a consultant for Boehringer Ingelheim, Corbus, CSL Behring, Eicos, Forbius, Chiara Stagnaro: None declared, Vanessa Smith Grant/research support from: The affiliated company received grants from Research Foundation - Flanders (FWO), Belgian Fund for Scientific Research in Rheumatic diseases (FWRO), Boehringer Ingelheim Pharma GmbH & Co and Janssen-Cilag NV, Consultant of: Boehringer-Ingelheim Pharma GmbH & Co, Speakers bureau: Actelion Pharmaceuticals Ltd, Boehringer-Ingelheim Pharma GmbH & Co and UCB Biopharma Sprl, Richard Silver: None declared, Elena Schiopu: None declared, Valeria Riccieri: None declared, Frank Kramer Employee of: Bayer AG, Sindhu Johnson Grant/research support from: Boehringer Ingelheim, Corbus Pharmaceuticals, GlaxoSmithKline, Roche, Merck, Bayer, Consultant of: Boehringer Ingelheim, Ikaria, Osamu Ishikawa: None declared, Tomonori Ishii: None declared, Eric Hachlla: None declared, Ellen De Langhe Consultant of: member of advisory board for Boehringer, László Czirják Consultant of: Actelion, BI, Roche-Genentech, Lilly, Medac, Novartis, Pfizer, Bayer AG, Radim Bečvář Consultant of: Actelion, Roche, Tatsuya Atsumi Grant/research support from: Eli Lily Japan K.K., Alexion Pharmaceuticals, Inc., Bristol-Myers Squibb Co., AbbVie Inc., Daiichi Sankyo Co., Ltd., Pfizer Inc., Chugai Pharmaceutical Co., Ltd., Mitsubishi Tanabe Pharma Co., Astellas Pharma Inc., Consultant of: Gilead Sciences, Inc., Eli Lilly Japan K.K., UCB Japan Co. Ltd., AbbVie Inc., Daiichi Sankyo Co., Ltd., Pfizer Inc., Chugai Pharmaceutical Co., Ltd., Speakers bureau: Eli Lilly Japan K.K., UCB Japan Co. Ltd., Bristol-Myers Squibb Co., AbbVie Inc., Eisai Co. Ltd., Otsuka Pharmaceutical Co., Ltd., Daiichi Sankyo Co., Ltd., Pfizer Inc., Chugai Pharmaceutical Co., Ltd., Mitsubishi Tanabe Pharma Co., Takeda Pharmaceutical Co., Ltd., Astellas Pharma Inc., Oliver Distler Grant/research support from: Grants/Research support from Actelion, Bayer, Boehringer Ingelheim, Competitive Drug Development International Ltd. and Mitsubishi Tanabe; he also holds the issued Patent on mir-29 for the treatment of systemic sclerosis (US8247389, EP2331143)., Consultant of: Consultancy fees from Actelion, Acceleron Pharma, AnaMar, Bayer, Baecon Discovery, Blade Therapeutics, Boehringer, CSL Behring, Catenion, ChemomAb, Curzion Pharmaceuticals, Ergonex, Galapagos NV, GSK, Glenmark Pharmaceuticals, Inventiva, Italfarmaco, iQvia, medac, Medscape, Mitsubishi Tanabe Pharma, MSD, Roche, Sanofi and UCB, Speakers bureau: Speaker fees from Actelion, Bayer, Boehringer Ingelheim, Medscape, Pfizer and Roche

Background:Activation of the type I interferon (IFN) pathway has been implicated in the initiation of systemic lupus erythematosus(SLE) and most SLE patients show increased expression of IFN-regulated genes in peripheral blood mononuclear cells or whole blood. However, the IFN signature in lupus kidney is not well examined especially at single cell resolution.Objectives:To clarify the significance of the IFN signature in lupus kidney at single cell resolutionMethods:18 lupus kidney (LN) and 34 transplanted kidney (KTx) samples were included in the study. Residual frozen kidney biopsies were collected after clinical diagnosis. The tissue from one donor was split into two. One portion was used for total RNA-Seq (tRNA-Seq) by SMARTer Stranded Total RNA-Seq Kit v2 - Pico Input Mammalian (Takara/Clontech). The rest was used for single nucleus RNA-Seq (snRNA-Seq) using Chromium Single Cell 3’ Reagent Kits v3 (10x Genomics) (7 LN and 17 KTx). For the tRNA-Seq, the sequence reads were aligned to Ensembl genome annotation (Ens93) by STAR and the aligned reads were counted by htseq. IFN score of tRNA-Seq was calculated using the reported method [1] per each module (M1.2, M3.4 and M5.12). For the snRNA-Seq, the sequenced reads were processed on the standard pipeline of CellRanger (10x Genomics) and the data was visualized using Seurat. IFN score of snRNA-Seq was computed by the method reported by Arazi A,et al[2].Clinical outcomes of LN were examined on the medical records retrospectively and the clinical remission in 56 weeks for LN was defined as a urinary protein/creatinine ratio less than 0.5 g/gCr.Results:11 LN had clinical remission and 7 LN showed non remitted disease within 56 weeks after the biopsy. There were no statistical significance co-variants such as age, gender and WHO class in pathology. IFN score of M1.2, M3.4 and M5.12 were significantly increased in LN with remission within 56 weeks (median 0.773 vs 0.659, 0.595 vs 0.243 and 0.415 vs 0.100: p-value 0.03, 0.01 and 0.02 [Wilcox rank-test]) in tRNA-Seq. In the snRNA-Seq, the lupus kidney with low IFN score showed restricted IFN signature in the endothelial cells mainly, which can be detected even in the controls, but those with high IFN score indicated broadly spread IFN signature among all of the cell types.Conclusion:LN with high IFN score in kidney tissue is correlated with remission within 56 weeks. LN with low IFN score showed IFN signature restricted to endothelial cells but those with a higher IFN score revealed broadly affected cell types with IFN signature. These results suggest that the IFN signature of LN may start from endothelial cells and then spread to the whole kidney.References:[1]Chiche L, Jourde-Chiche N, Whalen E,et al.Modular Transcriptional Repertoire Analyses of Adults With Systemic Lupus Erythematosus Reveal Distinct Type I and Type II Interferon Signatures.Arthritis & Rheumatology2014;66:1583–95.doi:10.1002/art.38628[2]Arazi A, Rao DA, Berthier CC,et al.The immune cell landscape in kidneys of patients with lupus nephritis.Nat Immunol2019;20:902–14.doi:10.1038/s41590-019-0398-xDisclosure of Interests: :Masatoshi Kanda: None declared, Takahiro Tsuji: None declared, Masaya Mukai: None declared, Hiroki Takahashi: None declared, Tatsuya Atsumi Grant/research support from: Eli Lily Japan K.K., Alexion Pharmaceuticals, Inc., Bristol-Myers Squibb Co., AbbVie Inc., Daiichi Sankyo Co., Ltd., Pfizer Inc., Chugai Pharmaceutical Co., Ltd., Mitsubishi Tanabe Pharma Co., Astellas Pharma Inc., Consultant of: Gilead Sciences, Inc., Eli Lilly Japan K.K., UCB Japan Co. Ltd., AbbVie Inc., Daiichi Sankyo Co., Ltd., Pfizer Inc., Chugai Pharmaceutical Co., Ltd., Speakers bureau: Eli Lilly Japan K.K., UCB Japan Co. Ltd., Bristol-Myers Squibb Co., AbbVie Inc., Eisai Co. Ltd., Otsuka Pharmaceutical Co., Ltd., Daiichi Sankyo Co., Ltd., Pfizer Inc., Chugai Pharmaceutical Co., Ltd., Mitsubishi Tanabe Pharma Co., Takeda Pharmaceutical Co., Ltd., Astellas Pharma Inc., Norbert Hübner: None declared

Background:Filgotinib (FIL) is a potent, selective JAK 1 inhibitor. FINCH 3 assessed FIL efficacy and safety in methotrexate (MTX)-naïve patients (pts) with rheumatoid arthritis (RA); week (W)24 primary outcome results were previously presented.1Objectives:To report FINCH 3 (NCT02886728) results through W52.Methods:This global, phase 3, double-blind, active-controlled study randomised MTX-naïve pts with moderately to severely active RA 2:1:1:2 to oral FIL 200 mg once daily + MTX ≤20 mg weekly, FIL 100 mg + MTX, FIL 200 mg monotherapy (mono) + placebo (PBO), or PBO + MTX up to W52. Comparisons at W52 were not adjusted for multiplicity. Safety was assessed from adverse events and laboratory abnormalities.Results:Of 1249 treated pts, 975 received study drug through W52. FIL efficacy was sustained up to W52. Treatment with FIL + MTX or FIL mono increased proportions of pts achieving ACR20/50/70 and clinical disease remission by DAS28(CRP) Figure). Safety was consistent with W24 data (Table 2).Table 1.Efficacy outcomes at week 52FIL 200 mg + MTX (n = 416)FIL 100 mg + MTX (n = 207)FIL 200 mg(n = 210)MTX(n = 416)ACR20, %75.0***73.4**74.8***61.8ACR50, %62.3***59.4**61.4**48.3ACR70, %47.8***40.1*45.2***29.8mTSSa0.21***0.27*0.23**0.74HAQ-DIb−1.00***−0.97−0.95*−0.88aLeast-squares mean change from baseline.bMean change from baseline.*, p **, p ***, p FIL, filgotinib; mTSS, van der Heijde modified total Sharp score; MTX, methotrexate.Table 2.Safety outcomes through week 52Event, n (%)FIL 200 mg + MTX(n = 416)FIL 100 mg + MTX(n = 207)FIL 200 mg(n = 210)MTX(n = 416)All AEs318 (76.4)164 (79.2)143 (68.1)305 (73.3)Serious AEs26 (6.3)13 (6.3)17 (8.1)28 (6.7)Infection148 (35.6)76 (36.7)75 (35.7)157 (37.7)Serious infection5 (1.2)3 (1.4)5 (2.4)8 (1.9)Herpes zoster6 (1.4)3 (1.4)4 (1.9)4 (1.0)VTE0004 (1.0)MACE (adjudicated)4 (1.0)1 (0.5)2 (1.0)2 (0.5)Malignancya1 (0.2)004 (1.0)NMSC2 (0.5)001 (0.2)Death3 (0.7)b1 (0.5)c00aExcluding NMSC.b1 lupus cardiomyopathy, 1 atypical interstitial pneumonia, 1 non–treatment-emergent cardiovascular death.cDissecting cerebral and vertebral aneurysm.AE, adverse event; FIL, filgotinib; MACE, major adverse cardiovascular event; MTX, methotrexate; NMSC, nonmelanoma skin cancer; VTE, venous thromboembolism.Conclusion:Efficacy of FIL 200 mg + MTX, FIL 100 mg + MTX, and FIL 200 mg mono was sustained through W52, with faster onset1and consistently numerically greater efficacy for FIL 200 vs 100 mg. No new safety signals were observed.References:[1]Westhovens, et al.Ann Rheum Dis.2019;78(Suppl2):259–60.Disclosure of Interests:Rene Westhovens Grant/research support from: Celltrion Inc, Galapagos, Gilead, Consultant of: Celltrion Inc, Galapagos, Gilead, Speakers bureau: Celltrion Inc, Galapagos, Gilead, William Rigby Consultant of: Gilead Sciences, Inc., Désirée van der Heijde Consultant of: AbbVie, Amgen, Astellas, AstraZeneca, BMS, Boehringer Ingelheim, Celgene, Cyxone, Daiichi, Eisai, Eli-Lilly, Galapagos, Gilead Sciences, Inc., Glaxo-Smith-Kline, Janssen, Merck, Novartis, Pfizer, Regeneron, Roche, Sanofi, Takeda, UCB Pharma; Director of Imaging Rheumatology BV, Daniel Ching Grant/research support from: AbbVie, Gilead Sciences, Inc., Pfizer, Sanofi, Consultant of: AbbVie, Pfizer, Speakers bureau: AbbVie, William Stohl Grant/research support from: GlaxoSmithKline, Consultant of: Janssen Research & Development, Jonathan Kay Grant/research support from: Gilead Sciences, Inc., Pfizer, Novartis Pharmaceuticals Corporation, Consultant of: Alvotech Suisse AG; Arena Pharmaceuticals, Inc.; Boehringer Ingelheim GmbH; Celltrion Healthcare Co. Ltd.; Merck Sharp & Dohme Corp.; Mylan Inc.; Novartis AG; Samsung Bioepis; Sandoz, Inc; UCB, Inc., Arvind Chopra Grant/research support from: Zydus Pharamceutical Ltd India, Beatrix Bartok Shareholder of: Gilead Sciences Inc., Employee of: Gilead Sciences Inc., Franziska Matzkies Shareholder of: Gilead Sciences, Inc., Employee of: Gilead Sciences, Inc., Zhaoyu Yin Shareholder of: Gilead Sciences, Inc., Employee of: Gilead Sciences, Inc., Ying Guo Shareholder of: Gilead Sciences, Inc., Employee of: Gilead Sciences, Inc., Chantal Tasset Shareholder of: Galapagos (share/warrant holder), Employee of: Galapagos, John Sundy Shareholder of: Gilead Sciences, Inc., Employee of: Gilead Sciences, Inc., Angelika Jahreis Shareholder of: Gilead Sciences, Inc., Employee of: Gilead Sciences, Inc., Neelufar Mozaffarian Shareholder of: Gilead, Employee of: Gilead, Osvaldo Messina Speakers bureau: Amgen; Americas Health Foundation; Pfizer, Robert B.M. Landewé Consultant of: AbbVie; AstraZeneca; Bristol-Myers Squibb; Eli Lilly & Co.; Galapagos NV; Novartis; Pfizer; UCB Pharma, Tatsuya Atsumi Grant/research support from: Eli Lily Japan K.K., Alexion Pharmaceuticals, Inc., Bristol-Myers Squibb Co., AbbVie Inc., Daiichi Sankyo Co., Ltd., Pfizer Inc., Chugai Pharmaceutical Co., Ltd., Mitsubishi Tanabe Pharma Co., Astellas Pharma Inc., Consultant of: Gilead Sciences, Inc., Eli Lilly Japan K.K., UCB Japan Co. Ltd., AbbVie Inc., Daiichi Sankyo Co., Ltd., Pfizer Inc., Chugai Pharmaceutical Co., Ltd., Speakers bureau: Eli Lilly Japan K.K., UCB Japan Co. Ltd., Bristol-Myers Squibb Co., AbbVie Inc., Eisai Co. Ltd., Otsuka Pharmaceutical Co., Ltd., Daiichi Sankyo Co., Ltd., Pfizer Inc., Chugai Pharmaceutical Co., Ltd., Mitsubishi Tanabe Pharma Co., Takeda Pharmaceutical Co., Ltd., Astellas Pharma Inc., Gerd Rüdiger Burmester Consultant of: AbbVie Inc, Eli Lilly, Gilead, Janssen, Merck, Roche, Pfizer, and UCB Pharma, Speakers bureau: AbbVie Inc, Eli Lilly, Gilead, Janssen, Merck, Roche, Pfizer, and UCB Pharma

Background Adult-onset Still’s disease (AOSD) is a systemic inflammatory disorder generally responsive to corticosteroid therapy, whereas refractory AOSD is often encountered that not controlled by corticosteroid monotherapy. In such cases, methotrexate and biologics including TNF-α, IL-1, or IL-6 inhibitors are used. 1 However, more treatment options are required for refractory AOSD patients who are intolerant to methotrexate or biologics. Calcineurin inhibitors downregulate T cell activation through inhibiting IL-2 transcription and signal transduction. Therefore, calcineurin inhibitors are reasonable therapeutic medication for AOSD since T cells and subsequently activated macrophages play a pathophysiological role in AOSD. 2 Nevertheless, only a few case series have indicated effects of calcineurin inhibitors in clinical practice. Objectives To evaluate the efficacy of calcineurin inhibitors in patients with AOSD. Methods This is a single-centre historical cohort study comprised of the consecutive patients with AOSD according to Yamaguchi classification criteria, who were attending our Rheumatology Department between January 2000 and December 2016. The primary endpoint was set as the time from the initiation of treatment to event defined as death of any causes, relapse of AOSD requiring an increase of corticosteroid dose, or serious adverse effects. Secondary endpoints were set as the minimum dose of corticosteroid, persistency rate of calcineurin inhibitors, and safety. Based on the recurrent event data analysis, these endpoints were evaluated for each event. We divided the events into two groups according to the treatment that included calcineurin inhibitors (CI+) or conventional therapy without calcineurin inhibitors (CI-), and compared them after adjustment using inverse probability of treatment weighting (IPTW) methods. Results Forty-two patients (31 female and 11 male) were enrolled in this study. Mean age was 41 year-old, and median follow-up period 38 months. Thirty-one events in 21 patients were treated with therapeutic regimen including calcineurin inhibitors (CI+, cyclosporine: 7, tacrolimus: 24), and 34 events in 25 patients were treated with the conventional therapy excluding calcineurin inhibitors (CI-). After adjustment, the CI +group had significantly longer event-free survival than the CI- group (figure 1). The weighted hazard ratio (HR) was 0.49 (95% CI, 0.25–0.93, p=0.03). In addition, the CI +group had lower doses of corticosteroid (3.5 vs 6.1 mg/day, p=0.03) when the events occurred. The persistency rate of calcineurin inhibitors was 92% at 5th year. Serious infection occurred in four patients (19%) in the CI +group, and one of them had a fatal course. Conclusions Our retrospective analysis suggested that calcineurin inhibitors could be an additional option for AOSD and further prospective studies were desired. References [1] Efthimiou P, et al. Diagnosis and management of adult onset Still’s disease. Ann Rheum Dis2006. [2] Chen DY, et al. Predominance of Th1 cytokine in peripheral blood and pathological tissues of patients with active untreated adult onset Still’s disease Ann Rheum Dis2004. Disclosure of Interest None declared

Background Antiphospholipid antibodies (aPL) as pathogenic autoantibodies in systemic lupus erythematosus (SLE) and antiphospholipid syndrome (APS) are supported by a number of clinical, ex vivo and animal studies. Nevertheless, aPL are not eliminated by corticosteroid administration or immunosuppression. Novel therapy targeting aPL production is currently unmet needs, in contrast, little is known on its pathological mechanism. Objectives This study aimed to clarify the mechanism of aPL production by lymphocyte subset analysis, genomic analysis and ex vivo experiments. Methods B cell and T cell subsets, a total of 21 subsets, were evaluated in peripheral blood mononuclear cells (PBMC) of 26 primary APS (PAPS), 18 SLE-associated APS (SLE/APS) patients and 10 healthy controls by flow cytometry. Twenty-one single nucleotide polymorphisms (SNP), which were shown to be associated with autoimmune or thrombotic diseases, were analysed in genomic DNA of those patients by TaqMan genotyping assay. Interferon (IFN) score was calculated based on the mRNA expression of Ly6e, Mx1, IFIT1 and IFIT3 in PBMC. To evaluate the aPL-producing capability of plasmablasts, PBMC obtained from APS patients were cultured following depletion of CD19 +CD20+or CD19+CD20 cells and the culture supernatants were applied to aPL measurements by enzyme-linked immunosorbent assay and cell assay using β2GPI/HLA-DR7 overexpressing HEK293T cells.1 Results In PAPS and SLE/APS patients, plasmablasts, Th2 cells and Th17 cells were increased while pre- and post- switched memory B cells, regulatory B cells and regulatory T cells were decreased compared to healthy controls. Genomic analysis revealed that the increase of plasmablasts (p=0.032) and the decrease of memory B cells (p=0.013) were more pronounced in patients with a risk allele of SNP in toll like receptor 7 (TLR7) gene (rs3853839). IFN score was significantly higher in the TLR7 SNP risk allele carriers, confirming the downstream signalling of TLR7 (p=0.029). Ex vivo experiments showed that aPL, including anti-cardiolipin/β2-glycoprotein I-HLA class II complexes -IgG and -IgM, were present in the culture supernatant of CD19 +CD20+depleted PBMC from APS patients, but not in that of CD19 +CD20 depleted cells. Conclusions Our data indicate an important role of plasmablasts in the production of aPL. Furthermore, plasmablast proliferation was associated with TLR 7 and type I IFN, suggesting a common pathophysiology in SLE and APS. Targeting plasmablasts might be a novel, immunological therapeutic approach in the treatment of APS. Reference [1] Tanimura K, et al. β2-Glycoprotein I/HLA class II complexes are novel autoantigens in antiphospholipid syndrome. Blood2015. Disclosure of Interest None declared

Background Subclinical and overt lung diseases associated with rheumatoid arthritis (RA-LD) are present in 30%–50% of the patients. Early and effective intervention improved joint prognosis in RA. By contrast, lung complications are still the primary contributors to premature deaths in patients with RA. Lung complication in RA can be due to a variety of conditions. However, the individual mortality and progression of pulmonary manifestations have not been established. Objectives To clarify the prognostic factors of patients with RA-LD. Methods This cohort study comprised RA patients examined with lung high resolution CT (HRCT) scan regardless of respiratory symptoms from 2005 to 2009. Respiratory diagnoses were certified by pulmonologists. The patients were reassessed by one follow-up CT scan after 10 years. All patients were evaluated for the events defined as death, serious infections and others (admission due to bone fracture, and ischaemic heart disease) from 2005 to 2017. Mortality risks were assessed using Kaplan-Meier method. Results Clinical features of 103 (82 females) patients are shown in table 1. Thirty-one (30%) had RA-LD including 18 interstitial pneumonia and 13 bronchiolitis at the start of observation. Mean observation period was 110 months. During observation, patients without RA-LD (non RA-LD) never developed new lung complications. The 10 year survival rate (SR) was 92% (mortality rate was 1.3 per 100 patient-years) and the 10 year event free survival rate (EFS) 69% (event rate was 4.8 per 100 patient-years). SR in RA-LD was significantly low compared with non RA-LD (p=0.008) (figure 1). EFS in RA-LD was significantly lower than in non RA-LD (p=0.03). Types of lung complication didn’t correlate with high mortality. The causes of death comprised infection (55%), malignant tumour (27%), interstitial pneumonia (9%), and the others (9%). The adverse events included infection (41%), malignant tumour (21%), bone fracture (15%), cardiac disease (10%), and severe drug eruption including Steven-Johnson syndrome (13%). Univariate analysis showed that infection (p Conclusions RA-LD is a serious complication in RA, and related with a high mortality. Disclosure of Interest None declared

Background Systemic lupus erythematosus (SLE) patients are prone to develop idiopathic osteonecrosis (ION) compared to other connective tissue disease patients or healthy subjects. ION has been shown to occur as a result of ischemia, however, the involvement of antiphospholipid antibodies (aPL) in its pathophysiology remains to be elucidated. In the last years, our group introduced a quantitative marker of aPL “antiphospholipid score (aPL-S)”, which well reflected the risk of developing thrombosis [1]. Objectives We aimed to identify the impact of aPL on the development of ION using aPL-S. Methods A single center retrospective study comprising 82 consecutive patients who were diagnosed SLE at the Rheumatology department of Hokkaido University Hospital and underwent magnetic resonance imaging (MRI) of hip joints from January 2000 to December 2016. Among all the enrolled patients, aPL-S, which is calculated from 0 to 86, as well as classical risk factors for ION were evaluated. Results All 82 patients (13 males and 69 females) were given glucocorticoids. ION of the femoral head was diagnosed by MRI scan in 37 patients. Male (ION(+): ION(-) 10/37 (27%) vs 3/45 (7%), p=0.016), malar rush (ION(+): ION(-) 22/37 (59%) vs 16/45 (36%), p=0.045), aPL positivity (ION(+): ION(-) 22/37 (59%) vs 15/45 (33%), p=0.026), high aPL-S (>30) (ION(+): ION(-) 9/37 (24%) vs 3/45 (7%), p=0.031), hypertriglyceridemia (fasting triglyceride levels >150 mg/dL) (ION(+): ION(-) 23/37 (62%) vs 12/45 (27%), p=0.002) and high dose of glucocorticoids (equivalent to 0.8mg/kg or more prednisolone) (ION(+): ION(-) 34/37 (92%) vs 21/45 (47%), p Conclusions We newly identified high aPL-S as a risk factor for ION. Furthermore, SLE patients who have both high aPL-S and hypertriglyceridemia are at very high risk of ION. These findings suggest the involvement of microvascular occlusion in the pathophysiology of ION in SLE. References Otomo K, et al. Efficacy of the antiphospholipid score for the diagnosis of antiphospholipid syndrome and its predictive value for thrombotic events. Arthritis Rheum. 2012. Disclosure of Interest None declared

Background Pulmonary arterial hypertension (PAH) is of great clinical significance as a life-threatening complication of connective tissue diseases (CTD). Pulmonary artery thrombotic microangiopathy (PATM) is an important pathophysiology of PAH. The concept of PATM refers to localized thrombotic microangiopathy to be defined histologically and should be discriminated from systemic thrombotic microangiopathy characterized by microangiopathic haemolysis and thrombocytopenia. The degree of PATM has been suggested to be associated with vasodilator response, severity, and prognosis of PAH, and anticoagulation therapy might be effective in PAH patients with features of PATM [1]. Haptoglobin (Hp) is a plasma protein mainly produced by hepatocytes, which binds free haemoglobin released from erythrocytes and protects the kidneys from damage induced by haemoglobin. The Hp is measured in clinical setting as a sensitive marker to detect intravascular haemolysis including thrombotic microangiopathy [2]. Objectives We hypothesized that serum Hp levels decreased in patients with PAH due to pulmonary microangiopathic haemolysis. The aim of this study was to investigate the association between serum Hp levels and pulmonary artery systolic pressure estimated by echocardiography (ePASP) in patients with CTD. Methods This study included CTD patients with suspicion of PAH who were attending Rheumatology Department in Hokkaido University Hospital between August 2015 and August 2016 and underwent echocardiography. PAH was diagnosed based on right heart catheter findings. Serum Hp levels were measured by standardised turbidimetric immunoassay in all patients. Demographic data, laboratory results, and echocardiographic findings were extracted from the medical records. Decreased serum Hp levels were defined as below 19 mg/dL based on the 95th-percentile of healthy controls. Results Twenty-four CTD patients with confirmed PAH (CTD-PAH) and 32 CTD patients without PAH (non-PAH) were enrolled. Decreased serum Hp levels were significantly frequent in patients with CTD-PAH compared with non-PAH patients (29% vs 6%, p=0.03). In patients with CTD-PAH, serum Hp levels had a significant negative correlation (r = -0.692, p Conclusions Serum Hp levels correlated negatively with ePASP in patients with CTD-PAH, and serum LDH levels were higher in CTD-PAH patients with decreased Hp levels. These findings suggest that decreased Hp levels in CTD-PAH patients may reflect PATM and subsequent subclinical haemolysis. Serum Hp levels are a candidate of additional non-invasive marker of CTD-PAH to assess the degree of PATM. References Johnson SR, et al. Thrombotic arteriopathy and anticoagulation in pulmonary hypertension. Chest. 2006. Barcellini W, et al. Clinical Applications of Hemolytic Markers in the Differential Diagnosis and Management of Hemolytic Anemia. Dis Markers. 2015. Disclosure of Interest None declared

Background Systemic sclerosis (SSc) is an autoimmune disease characterized by fibrosis and composed of two subtypes, limited and diffuse cutaneous forms. Previous genetic studies including genome-wide association studies (GWAS) have identified 12 susceptibility loci satisfying genome-wide significance. Objectives To expand the list of susceptibility genes and deepen biological insights for SSc. Methods We performed trans-ethnic meta-analysis of GWAS in the Japanese and European populations, followed by a two-staged replication study comprising a total of 4,436 cases and 14,751 controls. Associations between significant single nuclear polymorphisms (SNPs) and neighboring genes were evaluated. Enrichment analysis of H3K4Me3, a representative histone mark for active promoter was conducted with an expanded list of SSc susceptibility genes. Results We identified two significant SNP in two loci, GSDMA and PRDM1 , both of which are related with immune functions and associated with other autoimmune diseases (p=1.4x10 -10 and 6.6x10 -10 , respectively). GSDMA also showed a significant association with limited cutaneous SSc. We also replicated the associations of previously reported loci including a non-GWAS locus, TNFAIP3 . PRDM1 encodes BLIMP1, a transcription factor regulating T cell proliferation and plasma cell differentiation. The top SNP in GSDMA was a missense variant and correlated with gene expression of neighboring genes, and this could explain the association in this locus. We found different HLA association patterns between the two populations or two subtypes. Enrichment analysis suggested the importance of CD4 naive primary T cell. Conclusions GSDMA and PRDM1 are associated with SSc. These findings provide enhanced insight into the genetic and biological basis of SSc. Disclosure of Interest None declared

Background In recurrent pregnancy loss (RPL), the pathogenesis of the majority of cases remains to be explained. Antiphospholipid, syndrome (APS) is one of the disorder responsible for causing RPL and its overwhelmed complement activation recognized as a major pathogenic mechanism. Autoantibodies against complement component 1q subcomponent (aC1q) have been shown to associate with complement activation in primary APS, but the relevance of aC1q in RPL is still unclear. We hypothesized that aC1q would be associated with the pathogenesis of RPL in patients with or without APS, especially in RPL of unknown etiology. Objectives The aim of this study was to explore the significance of aC1q in RPL. Methods As a clinical study, we conducted a retrospective cross-sectional study comprising a total of 134 patients with RPL of unknown etiology, 27 with obstetric APS (OAPS), 14 parous patients with connective tissue disease (CTD) without historical obstetric/thrombotic complications and 17 parous healthy controls (HC). Serum levels of aC1q were measured using a solid-phase ELISA (Buhlmann Laboratories AG, Switzerland) and defined as positive using cut-off value of more than 15 U/mL according to the manufacturer. In murine model, 8–12 week-old female BALB/c mice were mated with isolated males and the presence of vaginal plug was defined as day 1 of pregnancy. Mice were treated with intravenous injections of anti-mouse C1q monoclonal antibody (JL-1), isotype control IgG2b or PBS. To block C5a receptor (C5aR), mice were intravenously pre-treated with anti-C5aR antibody, 30 minutes before the injection of JL-1 on day 8. Mice were sacrificed on day 16 of pregnancy and fetal resorption ratios, weight of fetuses and placentas, serum levels of C3a and immunohistochemical staining of complement components on placental tissue were compared among each group. Results Among RPL, OAPS, CTD and HC, 47 (35%), 8 (30%), 3 (21%) and 2 (12%) were positive for aC1q, respectively. In RPL patients, aC1q was more prevalent (p Conclusions Clinical findings showed that aC1q could be relevant to RPL. Moreover, we have established aC1q induced pregnancy loss model mice. Our study indicates that aC1q has a pathophysiologic role in RPL and that anticomplement therapy might be effective for at least some groups of patients with RPL for whom specific treatment remains to be established. Disclosure of Interest None declared

Background Tofacitinib is an oral JAK inhibitor for the treatment of rheumatoid arthritis (RA). Efficacy and safety of tofacitinib have been shown in RA patients in global Phase 2, Phase 3 (one study included Japanese patients) and long-term extension (LTE) studies and in two Phase 2 and one LTE study in Japanese patients. Objectives We evaluated the safety of tofacitinib following drug approval in Japanese patients with RA using all-case post-marketing surveillance (PMS) data. Methods A 6-month interim analysis of safety data from an ongoing 3-year PMS study was conducted (5 Nov 2016 data-cut). All Japanese patients with RA who were treated with tofacitinib were consecutively and prospectively registered in the PMS study and were monitored for all adverse events (AEs) for 3 years. Baseline and follow-up data were collected from booklet-type survey forms. Follow-up surveillance after discontinuation of tofacitinib treatment was implemented: 12 months for serious infections and 3 years for malignancy or AEs leading to death from the date of treatment initiation with tofacitinib. AEs were coded using MedDRA/J. Results Overall, 2387 tofacitinib-treated patients were enrolled (1020.0 patient-years [pt-yrs] of exposure); of these, 594 patients (24.9%) discontinued treatment, mainly due to AEs (n=236; 9.9%) or lack of effectiveness (n=225; 9.4%). In total, 1793 (75.1%) patients continued treatment for 6 months. At least one AE was observed in 815 patients (34.1%), the most frequent of which was herpes zoster (n=78; 3.3%), including 12 serious cases. Serious AEs occurred in 190 patients (8.0%); the most frequent were pneumonia (n=20; 0.8%), interstitial lung disease (n=14; 0.6%) and condition aggravated (n=13; 0.5%). Infections (n=304; 12.7%) were serious in 88 patients (3.7%). Thirteen patients (0.5%) reported malignancy, including ovarian cancer (n=2; 0.1%), diffuse large B-cell lymphoma (n=2; 0.1%) and lymphoproliferative disorder (n=1, 0.04%). Sixteen (0.7%) deaths were reported. Conclusions Interim analyses of AEs during the initial 6-month treatment period from PMS reports of tofacitinib in Japanese patients did not reveal any new or unexpected safety signals vs the tofacitinib RA clinical programme. The target sample size for the final PMS analysis is 6000 patients (4000 tofactinib-treated, 2000 control patients). Acknowledgements This study was sponsored by Pfizer Inc. Editorial support was provided by K Nicholson of CMC and was funded by Pfizer Inc. Disclosure of Interest T. Mimori Grant/research support from: Astellas, Ayumi, Chugai, Daiichi-Sankyo, Eisai, Mitsubishi-Tanabe, MSD, Nippon Shinyaku, Takeda, Speakers bureau: Astellas, Bristol-Myers Squibb, Chugai, Eisai, Mitsubishi-Tanabe, M. Harigai Grant/research support from: Bristol-Myers Squibb, Eisai, Eli Lilly, Ono, Takeda, T. Atsumi Grant/research support from: Alexion, Astellas, Bristol-Myers Squibb, Chugai, Eisai, Janssen, Mitsubishi-Tanabe, Sanofi. Scholarship donations from: Bayer, Daiichi-Sankyo, Takeda, Speakers bureau: AbbVie, Astellas, Chugai, Eisai, Mitsubishi-Tanabe, Pfizer Inc, Takeda, UCB Japan, M. Kuwana Grant/research support from: Chugai, Eisai, Mitsubishi-Tanabe, Ono, Pfizer Inc, Santen, Speakers bureau: Astellas, Chugai, Eisai, Janssen, Mitsubishi-Tanabe, Ono, Pfizer Inc, UCB, S. Takei Grant/research support from: Chugai, Eisai, Mitsubishi-Tanabe, Takeda, Speakers bureau: Asahi Kasei, Ayumi, Chugai, Mitsubishi-Tanabe, Ono, N. Tamura Grant/research support from: AbbVie, Astellas, Bristol-Myers Squibb, Chugai, Eisai, Janssen, Mitsubishi-Tanabe, Takeda, Speakers bureau: AbbVie, Astellas, Bristol-Myers Squibb, Eisai, Janssen, Mitsubishi-Tanabe, T. Fujii Grant/research support from: AbbVie, Asahi Kasei, Astellas, Chugai, Eisai, Janssen, Kissei, Mitsubishi-Tanabe, Ono, Pfizer Japan Inc, Taisho Toyama, Takeda, UCB Japan, Speakers bureau: AbbVie, Actelion, Astellas, Ayumi, Chugai, Daiichi-Sankyo, Kissei, Mitsubishi-Tanabe, Nippon Kayaku, Ono, Pfizer Japan Inc, Taisho Toyama, Takeda, H. Matsuno Consultant for: Ayumi, Meiji Seika, Mochida, Nichi-Iko, S. Momohara Speakers bureau: AbbVie, Bristol-Myers Squibb, Eisai, Janssen, Mitsubishi-Tanabe, Ono, Pfizer Japan Inc, Takeda, K. Yamamoto Grant/research support from: AbbVie, Astellas, Ayumi, Chugai, Eisai, Mitsubishi-Tanabe, Nippon Kayaku, Pfizer Japan Inc, Taisho Toyama, Takeda, Teijin, UCB, Speakers bureau: Asahi Kasei, AstraZeneca, Ayumi, Boehringer Ingelheim, Bristol-Myers Squibb, Chugai, Eisai, Janssen, Mitsubishi-Tanabe, Pfizer Inc, Sanofi, Sumitomo Dainippon, Taisho Toyama, Takeda, Teijin, Toyama Chemical, UCB, T. Kokubo Employee of: Pfizer Japan Inc, Y. Endo Shareholder of: Pfizer Inc, Employee of: Pfizer Japan Inc, N. Sugiyama Shareholder of: Pfizer Inc, Employee of: Pfizer Japan Inc, T. Hirose Shareholder of: Pfizer Inc, Employee of: Pfizer Japan Inc, Y. Morishima Shareholder of: Pfizer Inc, Employee of: Pfizer Japan Inc, N. Yoshii Shareholder of: Pfizer Inc, Employee of: Pfizer Japan Inc

Background and aims Ras activation as well as MAP kinase (MAPK) phosphorylation is known in the synovial tissues from patients with rheumatoid arthritis (RA). RasGRP4 is a guanine nucleotide exchange factor for small GTPase Ras and is expressed predominantly in the mast cells, monocytes and neutrophils. We previously identified ectopic expression of RasGRP4 in fibroblast-like synoviocytes (FLS) of a subset of RA patients, inducing proliferation of FLS (Kono M et al . Arthritis Rheumatol. 2015). Farnesyltransferase inhibitors (FTIs), prevent farnesylation of Ras, are known to prevent human tumour cell proliferation but the effect for proliferation of FLS is still unknown. The aim of this study is to clarify the molecular mechanisms of how RasGRP4 induces proliferation of FLS and evaluate the effect of FTI on the proliferation of FLS. Methods FLS or HEK293 cells were transfected with expression vector that encodes hRasGRP4. Phosphorylation of Raf, MEK, Erk, JNK and p38MAPK was evaluated in transfected cells using Western blotting. FLS were treated with tipifarnib, one of FTIs and cell proliferation was evaluated using BrdU Assay. Results In HEK293 cells forced to express RasGRP4, Raf-MEK-Erk pathway as well as p38MAPK was readily phosphorylated at their steady state. FLS decreased RasGRP4 expression during multiple passages. RasGRP4 transfection into such cells recovered MAPK phosphorylations, especially of Erk and p38 MAPK. FLS treated with tipifarnib down-regulated their proliferation. Conclusions RasGRP4 expression in FLS from RA patients contributes to the activation of Erk and p38MAPK signalling pathway. The inhibition of FLS proliferation by FTI was suggested as an alternative treatment in RA.

Background and aims Anti-DNA/NR2 antibodies are a subset of anti DNA autoantibodies that cross-react with the extracellular domain of the GluN2A/GluN2B subunits of the N-methyl-d-aspartate receptor 2 (NR2), which induce apoptosis of hippocampus neurons and psychiatric disorder in mice and humans. Neuropsychiatric SLE (NPSLE) can develop after initiation of steroid (post-steroid neuropsychiatric manifestation: PSNP) or before treatment (de novo NPSLE). The objective of this study was to clarify the prevalence of anti-DNA/NR2 antibodies in PSNP-SLE and de novo NPSLE Methods This study involved a cohort of patients with NPSLE who were admitted to Hokkaido University Hospital. NPSLE patients were classified into two groups, de novo NPSLE and PSNP-SLE. Serum anti-DNA antibodies and anti-DNA/NR2 antibodies were measured using in-house ELISAs. Results Serum samples were obtained from 29 patients with de novo NPSLE, 26 with PSNP-SLE and 83 healthy controls (HC). The levels of anti-DNA antibodies in patients with de novo NPSLE and PSNP-SLE were significantly higher than those in healthy controls (de novo NPSLE, PSNP-SLE, HC: 1.34±0.09, 1.40±0.14, 0.33±0.03, p Conclusions The levels of anti-DNA/NR2 in PSNP-SLE are lower than in de novo NPSLE, indicating the differences in the pathogenesis of these two conditions.

Background and Aims Our group introduced a quantitative marker of antiphospholipid antibodies (aPL) ‘‘antiphospholipid score (aPL-S)’’, which well reflected the risk of developing thrombosis (Otomo K, et al . Arthritis Rheum 2012). Idiopathic osteonecrosis (ION) has been shown to occur as a result of ischemia, however, the involvement of aPL in its pathophysiology remains to be elucidated. In this study, we aimed to identify the impact of aPL on the development of ION using aPL-S. Methods A single centre retrospective study comprising 75 consecutive patients with systemic lupus erythematosus who underwent magnetic resonance imaging of hip joints from January 2000 to March 2016. aPL-S, as well as classical risk factors for ION, were evaluated in all the enrolled patients. Results ION of the femoral head was observed in 33 out of 75 patients(44%). High aPL-S (p=0.009), aPL positivity (p=0.009), male (p=0.007), malar rash (p=0.010)and high dose (>0.8 mg/kg/day) glucocorticoids(p 30), developed ION. Conversely, systemic lupus erythematosus disease activity index and pulse methylprednisolone therapy were not identified as risk factors for ION. Conclusions We newly identified aPL-S as a risk factor for ION. ION should be considered as one of the antiphosholipid antibody-associated-disease.

Recent epidemiological studies have revealed the association of elevated cancer risk and diabetes mellitus [1–13]. Because the prevalence of diabetes mellitus and cancer is increasing worldwide, understanding the higher risk of specific types of cancer is important in management of diabetic patients. The American Diabetes Association (ADA) and the American Cancer Society (ACS) produced a consensus report on the increased risk of liver, pancreas, endometrial, colorectal, breast, and bladder cancer among diabetic patients [14]. In 2013, the joint committee of the Japan Diabetes Society (JDS) and the Japanese Cancer Association (JCA) reported the association of diabetes and cancer, including colorectal, liver, and pancreatic cancer, among Japanese diabetic patients [15]. Although the mechanisms underlying this association are not fully understood, several potential mechanisms which promote oncogenesis in diabetes have been discussed. Chronic inflammation, insulin resistance associated with hyperinsulinemia, and hyperglycemia have been suggested as potential mechanisms. These factors may lead to increased risk of cancer in diabetes and promote oncogenesis in different ways. Numerous studies have suggested the effect of insulin and chronic inflammation on cancer progression in diabetes. The experimental and epidemiological evidence is most consistent with the hyperinsulinemia and chronic inflammation hypothesis. In particular, progression of hepatocellular carcinoma seems to be closely associated with chronic inflammation and insulin resistance related to hyperinsulinemia. In a large scale cohort study in Japan, diabetes led to a high risk of hepatocellular carcinoma [16]. A meta-analysis also showed that diabetes increases the risk of hepatocellular carcinoma [12] and diabetes is risk factor for hepatocellular carcinoma among patients with nonalcoholic fatty liver disease (NAFLD) [17]. A recent clinical review suggested that NAFLD and nonalcoholic steatohepatitis (NASH) patients, especially those with diabetes, should be monitored for the onset of hepatocellular carcinoma [18]. However, the involvement of hyperglycemia in cancer development is less clear and few studies have shown the contribution of hyperglycemia to cancer progression and metastasis. Cancer cells maintain an abnormally high rate of glycolysis, even in the presence of oxygen, a phenomenon called the Warburg effect [19]. Enhanced glucose uptake in cancer is revealed by positron emission tomography (PET) scans, a widely used method of cancer detection, and clinical use of PET scans is well established. Despite many years of investigation, the specific regulatory mechanisms responsible for the Warburg effect are not fully understood. Increased expression of glucose transporter 1 has been observed, and this enables cancer cells to absorb extracellular glucose [20]. Increased type 2 hexokinase activity in cancer has also been demonstrated [21–23]. Although hexokinase is involved in the first irreversible stage of glycolysis, it is not the late limiting enzyme of the process. Fructose 2,6-bisphosphate (F2,6BP) is a powerful allosteric activator of 6-phosphofructo-1-kinase (PFK-1), which is the rate-limiting enzyme of glycolysis [24]. F2,6BP increases the affinity of PFK-1 for fructose 6-phosphate and reduces the inhibitory effect of ATP. Previous work has revealed markedly elevated levels of F2,6BP in several cancer cell lines [25–27]. The intracellular concentration of F2,6BP depends on the activity of the bifunctional enzyme 6-phosphofructo-2-kinase/fructose2,6-bisphosphatase (PFK-2/FBPase) [28]. At least four & Toshiya Atsumi tatsumi@nissei-hp.com

Pulmonary arterial hypertension (PAH) is a life-threatening complication in connective tissue diseases (CTD). It remains controversial whether immunosuppressive therapy is useful for PAH associated with CTD (PAH-CTD). The Dana Point algorithm does not refer such treatments in patients with PAH-CTD due to the lack of evidence. However, some case reports have shown the potential efficacy of immunosuppression for PAH-CTD. Here we report five cases of PAH-CTD treated with corticosteroids and discuss the current management of PAH-CTD with immunosuppressive agents. Our cases consisted of three active systemic lupus erythematosus (SLE), a quiescent SLE and an active polymyositis. WHO functional classes at baseline were class III in three cases and class II in two. Median follow-up period was 44 (28–92) weeks. PAH was diagnosed by right heart catheterization in all cases (median pulmonary arterial pressure was 45 (29–49) mmHg). All patients received 1 mg/kg of prednisolone (PSL) for 2–4 weeks, followed by appropriate dose reduction. Methylprednisolone pulse therapy was performed in patients resistant to the high dosage of PSL. Four patients received vasodilators in combination. The therapy as above improved WHO functional class 4 weeks after the initiation of PSL in all the patients. Two patients required dose increase or additional administration of vasodilators due to the dose reduction of PSL. Corticosteroid therapy may be effective for PAH-CTD at least in the short term, even in low general activity of CTD or moderate PAH. Our experience suggests that corticosteroid therapy, by itself or in conjunction with standard vasodilators, is effective for PAH-CTD patients.

This is an open access article distributed under the Creative Commons Attribution-NonCommercial-ShareAlike license., Aim: Macrophage migration inhibitory factor (MIF) is known as a pro-inflammatory cytokine that regulates a broad spectrum of inflammatory reactions. MIF is expressed in vascular smooth muscle cells (VSMCs), and inhibition of the progression of atherosclerosis was observed in MIF-deficient atherosclerotic mice. However, the functional role of MIF in VSMCs has not been elucidated. The aim of this study was to investigate the role of MIF on the migration of VSMCs. Methods: Cultured rat A10 cells, derived from rat embryonic aortic smooth muscle cells, were stimulated with oxLDL, and the effect of MIF knockdown on oxLDL-mediated migration of A10 cells was analyzed. Results: Intracellular MIF content was significantly increased and a marked increase of MIF concent-ration was observed in the supernatant of A10 cells treated with oxLDL. The migration of A10 cells was significantly accelerated by the stimulation of recombinant MIF in a dose-dependent manner. Notably, knockdown of intracellular MIF by siRNA abolished oxLDL-induced migration of A10 cells. Conclusion: These findings suggest that MIF acts on the migration of VSMCs in an autocrine and paracrine fashion. MIF appears to be a novel target for the prevention of cardiovascular events.

Inflammation provokes significant abnormalities in host metabolism that result from the systemic release of cytokines. An early response of the host is hyperglycemia and resistance to the action of insulin, which progresses over time to increased glucose uptake in peripheral tissue. Although the cytokine TNF-α has been shown to exert certain catabolic effects, recent studies suggest that the metabolic actions of TNF-α occur by the downstream regulation of additional mediators, such as macrophage migration inhibitory factor (MIF). We investigated the glycemic responses of endotoxemic mice genetically deficient in MIF (MIF−/−). In contrast to wild-type mice, MIF−/− mice exhibit normal blood glucose and lactate responses following the administration of endotoxin, or TNF-α. MIF−/− mice also show markedly increased glucose uptake into white adipose tissue in vivo in the endotoxemic state. Treatment of adipocytes with MIF, or anti-MIF mAb, modulates insulin-mediated glucose transport and insulin receptor signal transduction; these effects include the phosphorylation of insulin receptor substrate-1, its association with the p85 regulatory subunit of PI3K, and the downstream phosphorylation of Akt. Genetic MIF deficiency also promotes adipogenesis, which is in accord with a downstream role for MIF in the action of TNF-α. These studies support an important role for MIF in host glucose metabolism during sepsis.

Fructose 2,6-bisphosphate (F2,6BP) is a powerful allosteric activator of 6-phosphofructo-1-kinase, which is the rate-limiting enzyme for glycolysis. Mitogenic stimulation of lymphocytes is related to an enhanced rate of glucose utilization and F2,6BP mediated activation of glycolysis. To determine the effect of hyperglycemia on intracellular glycolysis of lymphocytes, we measured intracellular F2,6BP content in peripheral blood mononuclear cells obtained from patients with diabetes and normal subjects. A total of 62 subjects participated in the present study. Venous blood samples were collected and peripheral blood mononuclear cells were separated by Ficoll gradients. Intracellular F2,6BP levels in peripheral blood mononuclear cells from normal control subjects were significantly lower than age-matched diabetic subjects. We observed a significant positive correlation between intracellular F2,6BP levels and long term glycemic control, as assessed by HbA1c. These data suggest that hyperglycemia increases intracellular F2,6BP in immune cells. These findings may help to clarify the impaired function in immune cells in patients with diabetes.

We examined the frequency of cognitive impairment using the mini-mental-status examination (MMSE), as well as cerebral perfusion using single photon emission computed tomography (SPECT) in elderly diabetic patients. Written consent was obtained from all patients prior to their inclusion in this study. An MMSE score of 26 or less was adopted as an indication of cognitive impairment. Following an initial study, a 3-month study incorporating the use of MMSE and SPECT was performed in subjects, some of whom were taking donepezil hydrochloride. Of the 92 subjects enrolled in this study, 38% exhibited cognitive functional impairment and 18% earned MMSE scores of 23 or lower that were indicative of dementia. With regard to their cerebral blood flow pattern as determined by SPECT 217, 31.4 and 34.2% of subjects showed parieto-temporal hypoperfusion, asymmetrical hypoperfusion and fronto-temporal hypoperfusion patterns of abnormalities, respectively; 11.4% displayed unclassifiable findings and 8.5% showed no detectable abnormalities. No significant differences were seen in patients that were taking donepezil hydrochloride compared to those who were not. The incidence of cognitive functional impairment in elderly, diabetic patients was significantly elevated and was accompanied by a reduction in cerebral blood flow in the fronto-temporal region, as determined by SPECT.

6-Phosphofructo-2-kinase/fructose-2,6-bisphosphatase (PFK-2/FBPase) catalyzes the synthesis and degradation of fructose 2,6-bisphosphate (F2,6BP), which is a powerful activator of 6-phosphofructo-1-kinase, the rate-limiting enzyme of glycolysis. Four genes encode PFK-2/FBPase (PFKFB1–4), and an inducible isoform (iPFK-2/PFKFB3) has been found to mediate F2,6BP production in proliferating cells. We have investigated the role of iPFK-2/PFKFB3 and related isoforms in the regulation of glycolysis in adipocytes. Human visceral fat cells express PFKFB3 mRNA, and three alternatively spliced isoforms of iPFK-2/PFKFB3 are expressed in the epididymal fat pad of the mouse. Forced expression of the iPFK-2/PFKFB3 in COS-7 cells resulted in increased glucose uptake and cellular F2,6BP content. Prolonged insulin treatment of 3T3-L1 adipocytes led to reduced PFKFB3 mRNA expression, and epididymal fat pads from db/db mice also showed decreased expression of PFKFB3 mRNA. Finally, anti–phospho-iPFK-2(Ser461) Western blotting revealed strong reactivity in insulin-treated 3T3-L1 adipocyte, suggesting that insulin induces the phosphorylation of PFKFB3 protein. These data expand the role of these structurally unique iPFK-2/PFKFB3 isoforms in the metabolic regulation of adipocytes.

Background: Systemic sclerosis (SSc) is accompanied by abnormalities in humoral and cellular immune systems. Objective: To determine the genes specifically expressed in the immune system in SSc by analysis of the gene expression profile of peripheral blood mononuclear cells (PBMC) from patients with SSc, including those treated with haematopoietic stem cell transplantation (HSCT). Additionally, to investigate the clinical significance of the up regulation of tumour necrosis factor α (TNFα) converting enzyme (TACE). Methods: PBMC from patients with SSc (n = 23) and other autoimmune diseases (systemic lupus erythematosus (SLE, n = 16), rheumatoid arthritis (RA, n = 29)), and from disease-free controls (n = 36) were examined. Complementary DNA arrays were used to evaluate gene expression of PBMC, in combination with real time quantitative polymerase chain reactions. TACE protein expression in PBMC was examined by fluorescence activated cell sorter (FACS). Results: In patients with SSc 118 genes were down regulated after HSCT. Subsequent comparative analysis of SSc without HSCT and healthy controls indicated SSc-specific up regulation for three genes: monocyte chemoattractant protein-3 (p = 0.0015), macrophage inflammatory protein 3α (p = 0.0339), and TACE (p = 0.0251). In the FACS analysis, TACE protein was mainly expressed on CD14 + monocytes both in patients with SSc and controls. TACE expression on CD14 + cells was significantly increased in patients with early SSc (p = 0.0096), but not in those with chronic SSc, SLE, or RA. TACE protein levels in SSc monocytes correlated with the intracellular CD68 levels (p = 0.0016). Conclusions: Up regulation of TACE expression was a unique profile in early SSc, and may affect the function of TNFα and other immunoregulatory molecules.

A 34-year-old Japanese man diagnosed as having cat-eye syndrome (CES) with isolated idiopathic hypogonadotropic hypogonadism (IHH) was treated at our university. He showed preauricular pits/tags, downward slanting palpebral fissures, ocular hypertelorism, and strabismus. However, ocular coloboma and anal atresia, major characteristic features of CES, were negative. Chromosomal analysis revealed malformation in chromosome 22 and eunuchoid features and a low grade development of secondary sexual characteristics were also evident. Endocrinological examinations revealed that this patient was in a state of isolated IHH. Although CES with IHH is extremely rare, endocrine disorders should be given due attention.

Objective The objective of this paper is to determine which kinds of assays for antiphospholipid antibodies (aPL) should be tested for clinical practice for patients with recurrent pregnancy loss (RPL). Materials and methods We studied 560 patients with a history of RPL prospectively. We determined the obstetric significance of 11 commercially available tested assays for lupus anticoagulant (LA)-aPTT StaClot, phosphatidylserine-dependent antiprothrombin (aPS/PT) IgG, IgM, classical cardiolipin (CL) IgG, IgM, CL IgG, IgM, IgA, and β2glycoprotein I (β2GPI) IgG, IgM, IgA Phadia. Obstetric significance was defined as the potential for anticoagulant therapy to improve the subsequent live birth rate, or a difference in the live birth rate between positive and negative untreated cases. Results The LA-aPTT StaClot assay and aPS/PT IgG assay, but not CL IgG, were found to have obstetric significance. Our conventional tests covered positive cases with the aPS/PT IgM and classical CL IgG assays. The results of the LA-aPTT StaClot, LA-aPTT and LA-RVVT assays showed different distributions, although strong or moderate correlation was observed. Conclusion LA-aPTT StaClot and aPS/PT IgG might be suitable for use in routine practice for patients with RPL. Each test for aPL should be ascertained for obstetric significance, because similar assays may have different outcomes.

We examined the expression of macrophage migration inhibitory factor (MIF) mRNA in murine macrophage cell line (RAW 264.7 cells) in response to oxidized low-density lipoprotein (oxLDL), and investigated the influence of MIF on the uptake and degradation of oxLDL by RAW 264.7 cells. MIF mRNA expression was markedly upregulated in the presence of oxLDL. Consistent with this, the MIF level of the culture medium was increased by stimulation with oxLDL in dose- and time-dependent manners. Next, we added recombinant rat MIF to the culture medium and examined its effects on the uptake of(125)I-labelled oxLDL. Pretreatment with MIF enhanced both the uptake and degradation of(125)I-oxLDL. Taken together, these results suggest that MIF released from macrophages in response to oxLDL stimulates oxLDL uptake and degradation in an autocrine and paracrine fashion, which potentially results in atherosclerosis.

Aims/hypothesis. Advanced glycation end products (AGEs) participate in the pathogenesis of diabetic nephropathy. We reported earlier that OPB-9195, a synthetic thiazolidine derivative and novel inhibitor of advanced glycation, prevented progression of diabetic glomerulosclerosis by lowering serum concentrations of advanced glycation end products and reducing their deposition in the glomeruli. Here, we examined their contribution and that of growth factors, such as transforming growth factor-β (TGF-β) and vascular endothelial growth factor (VEGF), to the progression of diabetic nephropathy. We also investigated the expression of type IV collagen in the kidneys of Otsuka-Long-Evans-Tokushima-Fatty (OLETF) rats, a Type II (non-insulin-dependent) diabetes mellitus model, after treatment with OPB-9195. Methods. Using northern blots and immunohistochemical techniques, we determined the renal expression of TGF-β and type IV collagen mRNAs and proteins in OLETF rats. We also examined OPB-9195's effects on renal expression of VEGF mRNA and protein. Results. Concomitant increases in TGF-β and type IV collagen expression were observed at each point in time in OLETF rats not given OPB-9195. In contrast, OPB-9195 treatment greatly suppressed the renal expression of TGF-β, VEGF and type IV collagen mRNAs and proteins to that seen in non-diabetic rats. Conclusion/interpretation. Since OPB-9195, an AGE-inhibitor, prevented the progression of diabetic nephropathy by blocking type IV collagen production and suppressing overproduction of two growth factors, TGF-β and VEGF, in diabetic rats, this compound warrants further investigation. [Diabetologia (1999) 42: 579–588]

Anticardiolipin antibodies (aCL) found in sera from patients with antiphospholipid syndrome recognize a cryptic epitope that appears on the beta2-glycoprotein I (beta2-GPI) molecule when beta2-GPI interacts with a lipid membrane composed of negatively charged phospholipid or when beta2-GPI is adsorbed on a polyoxygenated polystyrene plate. A homology based model of beta2-GPI was constructed based on the NMR coordinates of sushi domains of human factor H. The conformation was like a cylinder consisting of five domains, its IV and V domains being glued by electrostatic interaction. We used phage-displayed random peptide libraries to search the epitopes of human aCL. Structures similar to consensus sequences selected by a biopanning method was found on domain IV of beta2-GPI.

Background Thrombocytopenia is a non-criteria manifestation of antiphospholipid syndrome (APS). Antiphospholipid antibodies (aPL) have been shown to activate platelet through multiple mechanisms. In patients with idiopathic/immune thrombocytopenia, aPL have been shown to increase the risk of thrombosis. Conversely, it remains unclear whether thrombocytopenia increases the risk of thrombosis in patients who have aPL. Objectives To evaluate the relationship between thrombocytopenia and thrombosis in patients who have aPL. Methods A single center retrospective study comprising 670 consecutive patients who underwent testing for aPL including lupus anticoagulant, anticardiolipin antibodies (IgG and M), anti-β2-glycoprotein I antibodies (IgG and M), and phosphatidylserine-dependent antiprothrombin antibodies (IgG and M) between January 2004 and December 2006. Excluded were patients who had been followed-up for ≤1 year. Results Of 524 patients included in this study, 187 had systemic lupus erythematosus, 70 rheumatoid arthritis, and 33 primary APS. At least one of aPL was positive in 241 patients. The prevalence of thrombocytopenia was not different in aPL positive and negative patients (24% vs 18%, p=0.11). In aPL positive group, patients with thrombocytopenia experienced arterial thrombosis (46% vs. 17%, p Conclusions Our data indicate that thrombocytopenia is associated with the risk of thrombosis in aPL positive patients providing new insight into the pathophysiology of aPL mediated platelet activation. Disclosure of Interest None declared

Background The efficacy and safety of certolizumab pegol (CZP) treatment in combination with optimized-dose MTX in Japanese MTX-naive early rheumatoid arthritis (RA) patients (pts) with poor prognostic factors have previously been reported (1-year [yr] results from the C-OPERA study). 1 Objectives 1. Investigate whether the clinical impact of initial 1-yr treatment with CZP+MTX was maintained to Week (Wk) 104 with MTX therapy alone; 2. Identify factors associated with the final outcomes of the 2-yr therapy by post-hoc logistic regression analysis. Methods MTX-naive early RA pts were eligible to enter C-OPERA (NCT01451203). Pts were randomized to CZP+MTX (n=159) or placebo (PBO)+MTX (n=157); oral MTX was escalated to 16mg by Wk8, or maximum tolerated dose (optimized-dose). After pts completed the 52-wk double-blind (DB) period, CZP or PBO was discontinued and MTX monotherapy continued up to Wk104. Full analysis set population was analyzed using LOCF for SDAI remission, and linear extrapolation for mTSS in patients who withdrew before Wk104. Post-hoc univariate logistic regression analysis was used to investigate factors associated with radiographic non-progression (change from baseline [BL] in mTSS≤0.5 at Wk104) or SDAI remission at Wk104, and factors with p Results After stopping CZP at Wk52, the radiographic non-progression rate was higher at Wk104 in the Yr 1 CZP+MTX treatment group vs Yr 1 PBO+MTX treatment group (84.2% vs 67.5%, p Conclusions Primary analyses showed the clinical benefit of initial 1-yr CZP+MTX therapy in MTX-naive early RA pts with poor prognostic factors was maintained to 2yrs with MTX alone. Different BL factors were identified as associated with clinical remission and radiographic non-progression. Effectiveness of initial 1-yr CZP treatment on both clinical and radiographic 2-yr outcomes was confirmed by multivariate logistic regression adjusting for BL factors. References Atsumi T. Ann Rheum Dis 2016;75:75–83 Acknowledgement The authors acknowledge Costello Medical Consulting, funded by UCB Pharma, for writing and editorial assistance. Disclosure of Interest T. Atsumi Speakers bureau: Astellas, Bristol-Myers Squibb, Chugai and Mitsubish-Tanabe, K. Yamamoto Grant/research support from: UCB Pharma, Pfizer, Abbott, Santen, Mitsubish-Tanabe and Eisai, Consultant for: UCB Pharma, Pfizer, Abbott, Bristol-Myers Squibb, Roche, Chugai, Mitsubish-Tanabe and Eisai, T. Takeuchi Grant/research support from: Abbott, Astellas, Bristol-Myers Squibb, Chugai, Daiichi-Sankyo, Eisai, Janssen, Mitsubish-Tanabe, Nippon Shinyaku, Otsuka, Pfizer, Sanofi-Aventis, Santen, Takeda and Teijin, Consultant for: AstraZeneca, Eli Lilly, Novartis, Mitsubishi-Tanabe and Asahi Kasei, Speakers bureau: UCB Pharma, Abbott, Bristol-Myers Squibb, Chugai, Eisai, Janssen, Mitsubishi-Tanabe, Pfizer and Takeda, H. Yamanaka Grant/research support from: UCB Pharma, Abbott, Astellas, Bristol-Myers Squibb, Chugai, Eisai, Janssen, Mitsubishi-Tanabe, Pfizer and Takeda, Consultant for: UCB Pharma, Abbott, Astellas, Bristol-Myers Squibb, Chugai, Eisai, Janssen, Mitsubishi-Tanabe, Pfizer and Takeda, N. Ishiguro Grant/research support from: Takeda, Mitsubishi-Tanabe, Astellas, Chugai, Abbott, Bristol-Myers Squibb, Eisai, Janssen, Kaken, and Pfizer, Speakers bureau: Takeda, Mitsubishi-Tanabe, Astellas, Chugai, Abbott, Bristol-Myers Squibb, Eisai, Janssen, Kaken, Pfizer, Taisho-Toyama and Otsuka, Y. Tanaka Grant/research support from: BMS, MSD, Chugai, Mitsubishi-Tanabe, Astellas, AbbVie and Daiichi-Sankyo, Consultant for: UCB Pharma, Mitsubishi-Tanabe, Abbott, AbbVie, Eisai, Chugai, Janssen, Pfizer, Takeda, Astellas, Daiichi-Sankyo, GSK, AstraZeneca, Eli Lilly, Quintiles, MSD and Asahi Kasei, K. Eguchi Grant/research support from: UCB Pharma, A. Watanabe Grant/research support from: Daiichi-Sankyo, Kyorin, Shionogi, Taisho, Dainippon-Sumitomo, Taiho, Toyama Chemical and Meiji Seika, Speakers bureau: MSD, GSK, Shionogi, Daiichi-Sankyo, Taisho-Toyama, Dainippon-Sumitomo, Mitsubishi-Tanabe and Pfizer, H. Origasa Consultant for: UCB Pharma and Astellas, T. Shoji Employee of: UCB Pharma, O. Togo Employee of: UCB Pharma, T. Okada Employee of: Astellas, D. van der Heijde Grant/research support from: AbbVie, Amgen, AstraZeneca, Augurex, Bristol-Myers Squibb, Boehringer Ingelheim, Celgene, Centocor, Chugai, Covagen, Daiichi, Eli-Lilly, Galapagos, GlaxoSmithKline, Janssen, Merck, Novo-Nordisk, Otsuka, Pfizer, Roche, Sanofi-Aventis, UCB Pharma and Vertex, Consultant for: AbbVie, Amgen, AstraZeneca, Augurex, Bristol-Myers Squibb, Boehringer Ingelheim, Celgene, Centocor, Chugai, Covagen, Daiichi, Eli-Lilly, Galapagos, GlaxoSmithKline, Janssen, Merck, Novo-Nordisk, Otsuka, Pfizer, Roche, Sanofi-Aventis, UCB Pharma and Vertex, Employee of: Imaging Rheumatology BV, N. Miyasaka Grant/research support from: Pfizer, Takeda, Mitsubishi-Tanabe, Chugai, Abbott, Eisai and Astellas, T. Koike Consultant for: AbbVie, Astellas, BMS, Chugai, Daiichi-Sankyo, Eisai, Mitsubishi-Tanabe, Pfizer, Santen, Taisho-Toyama, Takeda, Teijin and UCB Pharma, Speakers bureau: UCB Pharma, Pfizer, Chugai, Abbott, Mitsubishi-Tanabe, Takeda, Eisai, Santen, Astellas, Taisho-Toyama, BMS, Teijin and Daiichi-Sankyo

To reassess the accumulation of advanced glycation end products in diabetic renal cortex, we used a newly developed enzyme-linked immunosorbent assay to measure AGEs in renal cortex from STZ-induced diabetic and age-matched control rats. Kidneys and aortas were obtained from rats after 5 and 20 wk of STZ injection. At 5 wk of diabetes, the mean AGE content in collagenase-digested materials of renal cortex was > 16-fold higher in diabetic animals compared with controls (1044.4 ± 151.8 vs. 64.3 ± 5.7 arbitrary units, P < 0.01). At 20 wk of diabetes, it was > 45-fold higher in diabetic compared with control animals (3841.0 ± 1077.3 vs. 83.8 ± 12.8 AUs, P < 0.01). These increases were surprisingly large compared with the < 1.5-fold increase in the fluorescence levels both after 5 and 20 wk of diabetes. In control animals, neither the AGE content nor the fluorescence level increased during this period. Moreover, at 20 wk of diabetes, the AGE content was 39-fold higher in renal cortex compared with aorta. This study provided the first immunochemical evidence that collagenase-digested materials of renal cortex, as well as aorta, contained AGE products and that these products were present in much higher levels in diabetic animals than in control animals. With duration of diabetes, the AGE contents increased significantly both in renal cortex and aorta. The excessive accumulation of AGEs was most apparent in the diabetic kidney. These findings suggest that the actual level of AGEs, in particular, in diabetic renal cortex is much higher than previously anticipated, and a newly developed enzyme-linked immunosorbent assay may be a powerful tool for investigating the role of the advanced Maillard reaction in the development of diabetic nephropathy.

Understanding cellular response to environmental stress has broad implications for human disease. AMP-activated protein kinase (AMPK) orchestrates the regulation of energy-generating and -consuming pathways, and protects the heart against ischaemic injury and apoptosis. A role for circulating hormones such as adiponectin and leptin in the activation of AMPK has received recent attention. Whether local autocrine and paracrine factors within target organs such as the heart modulate AMPK is unknown. Here we show that macrophage migration inhibitory factor (MIF), an upstream regulator of inflammation, is released in the ischaemic heart, where it stimulates AMPK activation through CD74, promotes glucose uptake and protects the heart during ischaemia-reperfusion injury. Germline deletion of the Mif gene impairs ischaemic AMPK signalling in the mouse heart. Human fibroblasts with a low-activity MIF promoter polymorphism have diminished MIF release and AMPK activation during hypoxia. Thus, MIF modulates the activation of the cardioprotective AMPK pathway during ischaemia, functionally linking inflammation and metabolism in the heart. We anticipate that genetic variation in MIF expression may impact on the response of the human heart to ischaemia by the AMPK pathway, and that diagnostic MIF genotyping might predict risk in patients with coronary artery disease.

A benign virilizing adrenal adenoma is rare among adrenal neoplasms in middle-aged women. A 39-yr-old Japanese woman who presented with hirsutism, obesity, diabetes mellitus and hypertension was admitted. Plasma concentrations of testosterone and DHEAS were high. While the basal level of plasma ACTH was suppressed, serum cortisol level was high and its circadian rhythm was absent. Serum cortisol level was not suppressed with the low- and high-dose overnight dexamethasone suppression test. Abdominal computed tomography showed a left adrenal tumor, and an adrenocortical scintigraphy revealed uptake of the tracer on the left side. Polycystic ovaries were also found and bone mineral density revealed osteoporosis. Histopathological features of resected adrenal tumor were consistent with those of adrenocortical adenoma. Immunoreactivity of all the steroidogenic enzymes was apparent in the tumor cells and particularly dehydroepiandrosterone sulfotransferase (DHEA-ST) immunoreactivity was markedly expressed. Cortical atrophy and reduced expression of DHEA-ST were detected in the cortex of the adjacent non-neoplastic adrenal gland. Plasma testosterone, DHEAS and cortisol levels returned to normal after surgery, concomitantly with the disappearance of polycystic ovaries. This is a very rare case of virilizing adrenocortical adenoma complicated with Cushing's syndrome (CS).

Background The C-OPERA study (NCT01451203) demonstrated better clinical outcomes of certolizumab pegol (CZP)+MTX compared to placebo (PBO)+MTX in Japanese MTX-naive early RA patients (pts) with poor prognostic factors. 1 Objectives To identify factors associated with better outcomes of CZP+MTX compared to PBO+MTX at 1 year using subgroup analyses by baseline (BL) factors. Methods Pts with ≤12 months persistent RA fulfilling 2010 ACR/EULAR classification criteria 2 were enrolled in C-OPERA, a multicenter, double-blind, randomized study. Pts were MTX-naive, with moderate disease activity (DAS28[ESR]≥3.2), positive ACPA (≥3xULN), and either RF positive or had bone erosion on radiographs of hands/feet. Pts were randomized 1:1 to CZP+MTX or PBO+MTX. CZP 400mg was administered at Weeks (Wks) 0, 2, and 4, followed by CZP 200mg Q2W to Wk52. Unless precluded by tolerability, MTX was started at 8mg/wk and escalated to 16mg/wk over 8 wks. We report association of BL parameters and mean MTX dose with radiographic progression (change from BL [CFB] in modified total Sharp score [mTSS]) and clinical remission (DAS28 Results In PBO+MTX arm, higher BL DAS28, CRP, mTSS, HAQ-DI and serum MMP-3 were associated with greater radiographic progression at Wk52, whereas CZP+MTX still inhibited progression of structural damage in these pts despite higher risk of progression. 3 No positive trend of MTX dose with inhibitory effect on CFB in mTSS was observed overall. In the PBO+MTX arm, higher BL DAS28 and CRP were associated with lower DAS28 remission rate at Wk52, suggesting BL factors associated with either radiographic progression or disease activity may differ. Lower dose MTX group (8–≤12mg/wk) showed lower DAS28 remission rate compared to high dose group (>12–16mg/wk) (30.5% vs 42.9%). DAS28 remission rate was higher in CZP+MTX compared to PBO+MTX, particularly in pts with high BL parameters. Conclusions CZP+MTX showed better clinical outcomes compared to PBO+MTX, particularly in pts with higher risk of progression identified by BL factors. Therefore, this subgroup of MTX-naive early RA pts may need combination treatment with CZP+MTX to inhibit progression of structural damage. References Atsumi T. Ann Rheum Dis 2014;73(2):S484. Aletaha D. Ann Rheum Dis 2010;69:1580–1588. Atsumi T. Arthritis Rheumatol 2014;66(11):S1078. Acknowledgements The authors acknowledge Costello Medical Consulting for writing and editorial assistance which was funded by UCB Pharma. Disclosure of Interest T. Atsumi Speakers bureau: Astellas, Bristol-Myers, Chugai and Mitsubishi-Tanabe, K. Yamamoto Grant/research support from: UCB Pharma, Pfizer, Abbott, Santen, Mitsubishi-Tanabe and Eisai, Consultant for: UCB Pharma, Pfizer, Abbott, BMS, Roche, Chugai, Mitsubishi-Tanabe and Eisai, T. Takeuchi Grant/research support from: Abott, Astellas, BMS, Chugai, Daiichi-Sankyo, Eisai, Janssen, Mitsubishi-Tanabe, Nippon Shinyaku, Otsuka, Pfizer, Sanofi-Aventis, Santen, Takeda and Teijin, Consultant for: AstraZeneca, Eli Lilly, Novartis, Mitsubishi-Tanabe and Asahi Kasei, Speakers bureau: UCB Pharma, Abbott, BMS, Chugai, Eisai, Janssen, Mitsubishi-Tanabe, Pfizer and Takeda, H. Yamanaka Grant/research support from: UCB Pharma, Abbott, Astellas, BMS, Chugai, Eisai, Janssen, Mitsubishi-Tanabe, Pfizer and Takeda, Consultant for: UCB Pharma, Abbott, Astellas, BMS, Chugai, Eisai, Janssen, Mitsubishi-Tanabe, Pfizer and Takeda, N. Ishiguro Grant/research support from: Takeda, Mitsubishi-Tanabe, Astellas, Chugai, Abbott, BMS, Eisai, Janssen, Kaken and Pfizer, Speakers bureau: Takeda, Mitsubishi-Tanabe, Astellas, Chugai, Abbott, BMS, Eisai, Janssen, Kaken, Pfizer, Taisho-Toyama and Otsuka, Y. Tanaka Grant/research support from: BMS, MSD, Chugai, Mitsubishi-Tanabe, Astellas, Abbvie, Daiichi-Sankyo, Consultant for: UCB Pharma, Mitsubishi-Tanabe, Abbott, Abbvie, Eisai, Chugai, Janssen, Pfizer, Takeda, Astellas, Daiichi-Sankyo, GSK, AstraZeneca, Eli Lilly, Quintiles, MSD, Asahi Kasei, Speakers bureau: UCB Pharma, Mitsubishi-Tanabe, Abbott, Abbvie, Eisai, Chugai, Janssen, Pfizer, Takeda, Astellas, Daiichi-Sankyo, GSK, AstraZeneca, Eli Lilly, Quintiles, MSD, Asahi Kasei, K. Eguchi Consultant for: UCB Pharma, A. Watanabe Grant/research support from: Daiichi-Sankyo, Kyorin, Shionogi, Taisho, Dainippon-Sumitomo, Taiho, Toyama Chemical and Meiji Seika, Speakers bureau: SD, GSK, Shionogi, Daiichi-Sankyo, Taisho-Toyama, Dainippon-Sumitomo, Mitsubishi-Tanabe, Pfizer, H. Origasa Consultant for: UCB Pharma and Astellas, T. Shoji Employee of: UCB Pharma, O. Togo Employee of: UCB Pharma, T. Okada Employee of: Astellas, D. van der Heijde Grant/research support from: AbbVie, Amgen, AstraZeneca, Augurex, BMS, Boehringer Ingelheim, Celgene, Centocor, Chugai, Covagen, Daiichi, Eli-Lilly, Galapagos, GSK, Janssen Biologics, Merck, Novartis, Novo-Nordisk, Otsuka, Pfizer, Roche, Sanofi-Aventis, UCB Pharma, Vertex, Consultant for: AbbVie, Amgen, AstraZeneca, Augurex, BMS, Boehringer Ingelheim, Celgene, Centocor, Chugai, Covagen, Daiichi, Eli-Lilly, Galapagos, GSK, Janssen Biologics, Merck, Novartis, Novo-Nordisk, Otsuka, Pfizer, Roche, Sanofi-Aventis, UCB Pharma, Vertex, Employee of: Imaging Rheumatology bv., N. Miyasaka Grant/research support from: Pfizer, Takeda, Mitsubishi-Tanabe, Chugai, Abbott, Eisai and Astellas, T. Koike Consultant for: Abbvie, Astellas, BMS, Chugai, Daiichi-Sankyo, Eisai, Mitsubishi-Tanabe, Pfizer, Santen, Taisho-Toyama, Takeda, Teijin, UCB Pharma, Speakers bureau: UCB Pharma, Pfizer, Chugai, Abbott, Mitsubishi-Tanabe, Takeda, Eisai, Santen, Astellas, Taisho-Toyama, BMS, Teijin and Daiichi-Sankyo

Background Rheumatoid arthritis (RA) is a systemic autoimmune disease characterized by inflammation and joint destruction. MTX and biological DMARDs (bDMARDs) have revolutionized treatment of RA and clinical remission and structural remission are now realistic targets. However, we still experience patients with joint destruction by the retardation of appropriate treatments. Thereby, treatment strategy targeting structural remission in patients with early RA is prerequisite. Objectives The ZERO-J study (UMIN000001281) was undertaken to clarify strategic treatments that successfully reduce and stop joint destruction in ERA. Methods 162 patients who meet all of the following criteria were registered from 10: diagnosed with the 2010 ACR/EULAR criteria, MTX-naive, ACPA-positive, disease duration Results DAS28 (from 4.8 to 3.7), SDAI (20.4 to 12.2) and SHS (5.7 to 6.0) changed by MTX for 3 months (means 12.0 mg/w) and 151 patients were divided to 3 groups based on investigator and/or patient decision; TNFi-group (N=35, DAS28=5.6, SDAI=28.6 at M3), DMARDs-group (N=29, DAS28=4.0, SDAI=12.2) and HR-group (N=87, DAS28=2.8, SDAI=5.2). Thus, 58% of them were high responders to 3M-treatment with MTX. At M15, DAS28 (TNFi=2.7, DMARDs=2.9, HR=2.7) and SDAI (TNFi=5.5, DMARDs=5.9, HR=5.3) were comparable among groups (LOCF). However, changes in SHS from BL to M15 were significantly higher in TNFi group (1.0) than DMARDs group (0.7) and HR group (0.5), structural remission rate was observed significantly lower in a TNFi group (65%) than those in DMARDs group (74%) and HR-group (87%), and clinical relevant radiographic progression was observed in 6% of TNFi, 5% of DMARDs and 3% of HR-group. Conclusions About 60% of early RA patients were high responders to MTX within 3 months and structural as well as clinical remission was sustained for further 12 months in the majority of the HR group, indicating that bDMARDs may not be required to these MTX-HR patients. In contrast, less proportion of patient revealed structural remission in TNFi group, about 20% of ERA patients, 3-months retardation of intervention with bDMARDs resulted in progress in joint damages in the population. These results indicated that substantial proportions of patients have benefited from induction with MTX and bDMARDs to target joint damage to ZERO. Disclosure of Interest Y. Tanaka Grant/research support from: Mitsubishi-Tanabe, Chugai, MSD, Astellas, Novartis, Speakers bureau: Abbvie, Chugai, Astellas, Takeda, Santen, Mitsubishi-Tanabe, Pfizer, Janssen, Eisai, Daiichi-Sankyo, UCB, GlaxoSmithKline, Bristol-Myers, S. Hirata: None declared, K. Amano Grant/research support from: Astellas, Chugai, Pfizer, Tanabe-Mitsubishi, Paid instructor for: Chugai, Tanabe-Mitsubishi, Pfizer, Santen, Speakers bureau: AbbVie, Actellion, Astellas, Bristol-Myers-Squibb, Chugai, Diichi-Sankyo, Eisai, Pfizer, Tanabe-Mitsubishi, T. Atsumi Grant/research support from: Chugai Pharmaceutical Co. Ltd., Eisai Co. Ltd., Bristol-Myers Squibb Co., Astellas Pharma Inc., Daiichi Sankyo Co. Ltd., Mitsubishi Tanabe Pharma Co, Speakers bureau: Astellas Pharma Inc., Mitsubishi Tanabe Pharma Co., K. Yamamoto Grant/research support from: Astellas, AbbVie, Takeda, TEIJIN, Pfizer, Bristol-Myers, DAIICHI SANKYO, Mitsubishi-Tanabe, Chugai, Janssen, Eisai, Speakers bureau: Astellas, abbvie, Eisai, Pfizer, Bristol-Myers, Janssen, UCB, Asahi Kasei, Santen, ONO, Taisho Toyama, DAIICHI SANKYO, AstraZeneca, Chugai, TEIJIN PHARMA, Mitsubishi-Tanabe, Boehringer Ingelheim, Nippon Kayaku, Takeda, T. Sumida: None declared, T. Takeuchi Grant/research support from: Astellas Pharma, Bristol–Myers K.K., Chugai Pharmaceutical Co, Ltd., Daiichi Sankyo Co., Ltd., Eisai Co., Ltd., Mitsubishi Tanabe Pharma Co., Pfizer Japan Inc., Santen Pharmaceutical Co., Ltd., Takeda Pharmaceutical Co., Ltd., Teijin Pharma Ltd., AbbVie GK, Asahikasei Pharma Corp., and Taisho Toyama Pharmaceutical Co., Ltd.,SymBio Pharmaceuticals Ltd., Consultant for: Astra Zeneca K.K., Eli Lilly Japan K.K., Novartis Pharma K.K., Mitsubishi Tanabe Pharma Co., and Asahi Kasei Medical K.K.,abbivie GK, Daiichi Sankyo Co.,Ltd., Bristol–Myers K.K., Nipponkayaku Co.Ltd., Paid instructor for: Mitsubishi Tanabe Pharma Co., Eisai Co., Ltd., Abbivie GK, Speakers bureau: AbbVie GK., Bristol–Myers K.K., Chugai Pharmaceutical Co,. Ltd., Eisai Co., Ltd., Janssen Pharmaceutical K.K., Mitsubishi Tanabe Pharma Co., Pfizer Japan Inc., and Takeda Pharmaceutical Co., Ltd., Astellas Pharma, and Diaichi Sankyo Co.,Ltd., Celtrion, Nipponkayaku Co.Ltd, H. Kohsaka Grant/research support from: Mitsubishi Tanabe Pharma Corporation Takeda Pharmaceutical Company Limited Bristol-Myers Squibb Eisai Co.,Ltd. Teijin Pharma Limited Pfizer Inc. Actelion Pharmaceuticals Japan Ltd. Santen Pharmaceutical Co,.Ltd. Ono Pharmaceutical Co., Ltd. Daiichi Sankyo Company.,Limited. Nippon Kayaku Co.,Ltd. Abbie Inc. AstraZeneca plc., Paid instructor for: Teijin Pharma Limited Chugai Pharmaceutical Co., LTD., Speakers bureau: Mitsubishi Tanabe Pharma Corporation Takeda Pharmacentical Company Limite Abbie Inc. Ono Pharmaceutical Co.,LTD. UCB Japan Co. Ltd. Astellas Pharma Inc. Chugai Pharmaceutical Co.,LTD. Japan Blood Products Organization Asahi Kasei Corporation, T. Mimori: None declared, A. Kawakami Grant/research support from: Abbvie GK, Eisai Co., Mitsubishi Tanabe Pharma Co., Pfizer Japan, Janssen Pharmaceutical K. K., Takeda Pharmaceutical Company Astellas Pharma Inc., Speakers bureau: Abbvie GK, Eisai Co., Mitsubishi Tanabe Pharma Co., Pfizer Japan, Janssen Pharmaceutical K. K., Takeda Pharmaceutical Company Astellas Pharma Inc., N. Nishimoto: None declared, E. Tanaka: None declared, Y. Kaneko Consultant for: Abbvie, Paid instructor for: Eisai Pharmaceutical, Chugai Pharmaceutical, Astellas Pharmaceutical, Mitsubishi Tanabe Pharma Corporation, Pfizer, Speakers bureau: Abbvie, Eisai Pharmaceutical, Chugai Pharmaceutical, Bristol Myers Squibb, Astellas Pharmaceutical, Mitsubishi Tanabe Pharma Corporation, Pfizer, Janssen, UCB, H. Yasuoka Consultant for: AbbVie Inc, S. Fukuyo: None declared, K. Saito: None declared

Background The all-patient registry PMS (PMS7901) of tocilizumab (TCZ) followed 7901 RA patients for 28 wk which showed that patients with a high probability of remission and a low probability of developing serious infection were most likely to be early and less advanced RA and had not received biologics previously. Objectives The aim of this report is to investigate association of disease duration with effectiveness and safety in biologic-naive RA patients treated with TCZ. Methods FIRST Bio was a 52-wk observational postmarketing surveillance, which enrolled biologics-naive RA patients who met the ACR/EULAR 2010 classification criteria for RA, experienced inadequate response or were intolerant to one or more synthetic DMARDs. Patients received intravenous TCZ (TCZ-IV; 8 mg/kg) every 4 wks with or without DMARDs. Patient characteristics and safety and effectiveness data were collected (last observation carry forward method). CDAI remission rate and incidence of adverse events (AEs) and serious AEs (SAEs) in each disease duration category ( Results Overall, 659 patients were analyzed. The mean disease duration was 7.5 years and was Conclusions This study suggests that long-term treatment with TCZ can improve the disease activity in established as well as newly diagnosed patients with RA. Disclosure of Interest T. Mimori Grant/research support from: Asahi Kasei, Astellas, Bristol-Myers Squibb, Chugai, Daiichi Sankyo, Eisai, Mitsubishi Tanabe, MDS, Nippon Kayaku, Nippon Shinyaku, Santen and Takeda, Speakers bureau: Astellas, Bristol-Myers Squibb, Chugai, Mitsubishi Tanabe and Taisho Toyama, T. Atsumi Grant/research support from: Chugai, Eisai, Bristol-Myers Squibb, Astellas, Daiichi Sankyo, Mitsubishi Tanabe, Speakers bureau: Astellas, Mitsubishi Tanabe, M. Harigai Grant/research support from: AbbVie, Astellas, Bristol-Myers Squibb, Chugai, Eisai, Mitsubishi Tanabe, Santen, Takeda and UCB, Consultant for: Bristol-Myers Squibb, Chugai and Janssen, Speakers bureau: AbbVie, Astellas, Bristol-Myers Squibb, Chugai, Eisai, Janssen, Mitsubishi Tanabe, Ono, Santen, Takeda, UCB and Pfizer, N. Nishimoto Grant/research support from: Chugai and Eisai, Consultant for: Chugai, T. Sumida Consultant for: Chugai, Speakers bureau: Chugai, T. Takeuchi Consultant for: AbbVie, Asahi Kasei, Asahi Kasei Medical, Astellas, Astra Zeneca, Bistol-Myers Squibb, Chugai, Daiichi-Sankyo, Eisai, Eli Lilly, Janssen, Mitsubishi Tanabe, Novartis, Pfizer, Santen, SymBio, Takeda, Taishyo Toyama and Teijin, Speakers bureau: AbbVie, Asahi Kasei, Asahi Kasei Medical, Astellas, Astra Zeneca, Bristol-Myers Squibb, Chugai, Daiichi-Sankyo, Eisai, Eli Lilly, Janssen, Mitsubishi Tanabe, Novartis, Pfizer, Santen, SymBio, Takeda, Taishyo Toyama and Teijin, Y. Tanaka Consultant for: Abbvie, Astellas, Bristol-Myers Squibb, Chugai, Eisai, Janssen, Mitsubishi Tanabe and MSD, Speakers bureau: Abbvie, Actelion, Astellas, Astra Zeneca, Chugai, Daiichi-Sankyo, Eisai, Eli Lilly, GlaxoSmithKline, Janssen, Mitsubishi Tanabe, Nippon Kayaku, Ono, Otsuka, Pfizer, Quintiles, Santen and UCB, H. Yamanaka Consultant for: AbbVie, Astellas, Bristol-Myers Squibb, Chugai, Daiichi-Sankyo, Mitsubishi Tanabe, Nippon Kayaku, Pfizer, Takeda, Teijin and UCB, Speakers bureau: AbbVie, Astellas, Bristol-Myers Squibb, Chugai, Daiichi-Sankyo, Mitsubishi Tanabe, Nippon Kayaku, Pfizer, Takeda, Teijin and UCB, A. Nakasone Employee of: Chugai, N. Takagi: None declared, N. Ishiguro Consultant for: AbbVie, Chugai, Daiichi-Sankyo, Eisai, Mitsubishi Tanabe, Pfizer and Takeda, Speakers bureau: AbbVie, Chugai, Daiichi-Sankyo, Eisai, Mitsubishi Tanabe, Pfizer and Takeda

Background Pulmonary arterial hypertension (PAH) is of great clinical significance in connective tissue diseases (CTD) because of its high mortality. In particular, prognosis of PAH associated with systemic sclerosis (PAH-SSc) is extremely poor compared with PAH associated with other CTD (PAH-non-SSc). The reason, however, remains to be elucidated. Cardiac magnetic resonance imaging (CMRI) has been shown to provide additional data on right heart catheterization (RHC), enabling deep understanding of the hemodynamic state of PAH. Objectives To detect the difference in hemodynamic state between PAH-SSc and PAH-non-SSc by performing CMRI. Methods This is a retrospective study consisting of 32 consecutive patients with CTD who had undergone RHC and CMRI within one week. Results Of the 32 patients, 31 were female and 14 had SSc. The mean age at the time of RHC and CMRI performed was 54.2±12.8 years. Mean pulmonary arterial pressure (mPAP) was 38.2±10.2 mmHg. CMRI detected right ventricular ejection fraction (RVEF), right ventricular end-diastolic volume index (RVEDVI), left ventricular ejection fraction (LVEF) and left ventricular end-diastolic volume index (LVEDVI). RVEF negatively correlated with mPAP (r = -0.439, p=0.012) and pulmonary vascular resistance (PVR) (r = -0.508, p=0.003). The ratio of RVEDVI/LVEDVI, which represents ventricular stiffness and interplay, positively correlated with mPAP (r =0.398, p=0.024) and PVR (r =0.540, p=0.001). In SSc patients, mPAP was significantly lower (p=0.036) while RVEF and the ratio of RVEDVI/LVEDVI were not different from non-SSc patients. In addition, if the ratio of RVEDVI/LVEDVI was divided by mPAP, it was significantly higher in SSc patients (p=0.027), suggesting an increased ventricular stiffness and a resultant left ventricular compression in PAH-SSc. Of 17 patients, including 10 SSc and 7 non-SSc, who underwent follow-up CMRI during treatment, the ratio of RVEDVI/LVEDVI elevated in two patients. Both patients had SSc and died within two years from development of PAH. Of note, in one particular patient, the ratio of RVEDVI/LVEDVI actually elevated despite the improvement of RHC data including mPAP and PVR. Overall, increased trend in the ratio of RVEDVI/LVEDVI during the follow-up period was an apparent prognostic factor compared with its stable or decrease trend (p=0.006). Conclusions Our data indicate that altered ventricular dimension detected by CMRI represents the disease-specific cardiac involvement of PAH-SSc and may reflect prognosis. Performing CMRI before and during treatment of PAH-SSc is helpful in terms of predicting prognosis and choice of the best therapeutic strategy. Disclosure of Interest A. Noguchi: None declared, S. Yasuda: None declared, M. Kono: None declared, M. Kato: None declared, K. Oku: None declared, T. Bohgaki: None declared, O. Amengual: None declared, T. Horita: None declared, T. Sato: None declared, I. Tsujino: None declared, M. Nishimura: None declared, T. Atsumi Grant/research support from: Chugai Pharmaceutical Co., Ltd. Eisai Co., Ltd. Bristol-Myers Squibb Co. Astellas Pharma Inc. Daiichi Sankyo Co., Ltd. Mitsubishi Tanabe Pharma Co, Speakers bureau: Astellas Pharma Inc. Mitsubishi Tanabe Pharma Co.

Background Damage to bones is accelerated massively during the first two years after developing rheumatoid arthritis (RA), thus the patients with poor response to csDMARDs need early intervention by biological agents (Bio). However, few markers have been established for the prediction of future use of Bio on the diagnosis as RA. Objectives To clarify the predictors of future initiation of Bio at the time of RA diagnosis. Methods One hundred five consecutive new outpatients complaining arthralgia without definite diagnosis of RA were included at 3rd Department of Internal medicine clinic at Hokkaido P.W.F.A.C Obihiro-Kosei General Hospital from December 2012 to September 2013. The subjects classified as RA, fulfilling the criteria of 2010 American College of Rheumatology/European League Against Rheumatism, were treated by standard protocol and followed until December 2014 to discriminate Bio user from non-Bio user. The observation period until the initiation of Bio was registered. Results Among 105 patients, 49 were classified as having RA by the criteria. Out of 49 patients, four patients were excluded due to their ineligibility (two patients on prednisone at the time of RA diagnosis, one on over 20 mg/day prednisone due to interstitial lung disease during observation period, and one with less than three months9 observation period). At the time of RA diagnosis, mean age was 60±15 years old and the median disease duration was 20 (range: 3.5-24.8) months. Mean Disease Activity Score 28-ESR was 5.0±1.3, median simplified disease activity index 17.1 (5.7-71.9), anti-cyclic citrullinated peptide antibody (ACPA) 42 (0.6-500) U/ml, rheumatoid factor 67 (4-1580) mg/dl, matrix metalloproteinase-3 (MMP-3) 80 (24-1515) ng/ml, and CRP 0.45 (0.01-10.47) mg/dl. During observation period, 14 patients were initiated Bio. Multivariate analysis with Cox9s proportional hazards model showed that ACPA (HR for every 50 U/ml, 1.26, 95%C.I. 1.05-1.50, p=0.01) and MMP-3 (HR for every 50 ng/ml, 1.15, 95%C.I. 1.01-1.30, p=0.03) are statistically significant risk factors for Bio users. We determined cutoff points of ACPA and MMP-3 using the receiver operatorating characteristic curves and we decided ACPA ≥250 U/ml and MMP-3 ≥200 ng/ml were risk factors. Log-rank test showed the more risk factors the patients have, the higher risk for initiation of Bio (Figure 1, p Conclusions High serum levels of ACPA and MMP-3 at the time of diagnosis of RA are possible predictors of future Bio user. Disclosure of Interest None declared

Background The all-patient registry PMS (PMS7901) of tocilizumab (TCZ) followed 7901 RA patients for 28 wk which showed that patients with a high probability of remission and a low probability of developing serious infection were most likely to be early and less advanced RA and had not received biologics previously. Objectives To evaluate overall effectiveness and safety of TCZ in biologics-naive RA patients in real clinical setting. Methods FIRST Bio was a 52-wk, postmarketing surveillance with biologics-naive RA patients who met the ACR/EULAR 2010 classification criteria, experienced inadequate response or were intolerant to one or more DMARDs. Patients received 8mg/kg of TCZ-IV every 4 wk with or without DMARDs. A paired t-test was used to detect statistically significant differences in disease activities compared with the baseline. Results Overall, 839 patients were observed. Patients in the FIRST Bio study had shorter mean disease duration and lower percentage of less advanced Steinbrocker9s stage and class than those in the PMS7901 (Table). At Wk 52, 72.3% patients continued to receive TCZ-IV with a total 718.4 patient-years. The mean CDAI improved from 23.3 at baseline to 6.6 at Wk 52 (p Conclusions The FIRST Bio study revealed that in real clinical settings, TCZ showed high effectiveness and safety in patients with less advanced RA who did not receive biologics previously. Disclosure of Interest T. Mimori Grant/research support from: Asahi Kasei, Astellas, Bristol-Myers Squibb, Chugai, Daiichi Sankyo, Eisai, Mitsubishi Tanabe, MDS, Nippon Kayaku, Nippon Shinyaku, Santen and Takeda, Speakers bureau: Astellas, Bristol-Myers Squibb, Chugai, Mitsubishi Tanabe and Taisho Toyama, T. Atsumi Grant/research support from: Chugai, Eisai, Bristol-Myers Squibb, Astellas, Daiichi Sankyo, Mitsubishi Tanabe, Speakers bureau: Astellas, Mitsubishi Tanabe, M. Harigai Grant/research support from: AbbVie, Astellas, Bristol-Myers Squibb, Chugai, Eisai, Mitsubishi Tanabe, Santen, Takeda and UCB, Consultant for: Bristol-Myers Squibb, Chugai and Janssen, Speakers bureau: AbbVie, Astellas, Bristol-Myers Squibb, Chugai, Eisai, Janssen, Mitsubishi Tanabe, Ono, Santen, Takeda, UCB and Pfizer, N. Nishimoto Grant/research support from: Chugai and Eisai, Consultant for: Chugai, T. Sumida Consultant for: Chugai, Speakers bureau: Chugai, T. Takeuchi Consultant for: AbbVie, Asahi Kasei, Asahi Kasei Medical, Astellas, Astra Zeneca, Bistol-Myers Squibb, Chugai, Daiichi-Sankyo, Eisai, Eli Lilly, Janssen, Mitsubishi Tanabe, Novartis, Pfizer, Santen, SymBio, Takeda, Taishyo Toyama and Teijin, Speakers bureau: AbbVie, Asahi Kasei, Asahi Kasei Medical, Astellas, Astra Zeneca, Bristol-Myers Squibb, Chugai, Daiichi-Sankyo, Eisai, Eli Lilly, Janssen, Mitsubishi Tanabe, Novartis, Pfizer, Santen, SymBio, Takeda, Taishyo Toyama and Teijin, Y. Tanaka Consultant for: Abbvie, Astellas, Bristol-Myers Squibb, Chugai, Eisai, Janssen, Mitsubishi Tanabe and MSD, Speakers bureau: Abbvie, Actelion, Astellas, Astra Zeneca, Chugai, Daiichi-Sankyo, Eisai, Eli Lilly, GlaxoSmithKline, Janssen, Mitsubishi Tanabe, Nippon Kayaku, Ono, Otsuka, Pfizer, Quintiles, Santen and UCB, H. Yamanaka Consultant for: AbbVie, Astellas, Bristol-Myers Squibb, Chugai, Daiichi-Sankyo, Mitsubishi Tanabe, Nippon Kayaku, Pfizer, Takeda, Teijin and UCB, Speakers bureau: AbbVie, Astellas, Bristol-Myers Squibb, Chugai, Daiichi-Sankyo, Mitsubishi Tanabe, Nippon Kayaku, Pfizer, Takeda, Teijin and UCB, A. Nakasone Employee of: Chugai, N. Takagi Employee of: Chugai, N. Ishiguro Consultant for: AbbVie, Chugai, Daiichi-Sankyo, Eisai, Mitsubishi Tanabe, Pfizer and Takeda, Speakers bureau: AbbVie, Chugai, Daiichi-Sankyo, Eisai, Mitsubishi Tanabe, Pfizer and Takeda

Background The occurrence of recurrent thrombotic events and/or of obstetric complications in association with the persitence of antiphospholipid antibodies (aPL) defines the antiphospholipid syndrome (APS). Positive aPL can be recognized through the screening of otherwise asymptomatic pregnancies, however, the effect of aPL in the pregnancy outcomes of asymptomatic aPL carriers is uncertain. Objectives To evaluate whether primary prophylaxis would be beneficial to prevent obstetric complications in asymptomatic women positive for aPL who have no history of clinical manifestations of APS. Methods We performed a systematic review of the literature. Studies evaluating the effect of prophylactic treatment vs. no treatment in asymptomatic pregnant aPL carriers were identified in an electronic database search. The literature search was performed in the major databases: Medline from 1950 via PubMed, Embase, and the Cochrane Central Register of Controlled Trials. Conference abstracts of six major international conferences were searched from January 2012 to July 2014 on their official webpages. Design, population, and outcome homogeneity of studies were assessed and meta-analysed. Risk of bias was assessed through an ad hoc checklist. The pooled Mantel-Haenszel relative risk (RR) and 95% confidence interval (CI) of specific pregnancy outcomes were obtained using random effects models. Heterogeneity was measured with the I 2 statistic. All analyses were conducted in Review Manager 5.3. Results Data from five studies with moderate to low risk of bias involving 154 pregnancies were included and three studies were meta-analysed. The RR of live birth rates, preterm birth, low birth weight and overall pregnancy complications in treated vs. un-treated pregnancies were 1.14 [0.18-7.31]; 1.71 [0.32 - 8.98]; 0.98; [0.07 -13.54] and 2.15 [0.63-7.33], respectively. Results from the meta-analysis could not prove that treatment with aspirin was superior to placebo to prevent pregnancy complications in asymptomatic aPL carriers. Conclusion This systematic review did not find evidence of the superiority of prophylactic treatment with aspirin compared to placebo or to usual care for preventing unfavourable obstetric outcomes in otherwise healthy women with aPL during the first pregnancy. Disclosure of Interest O. Amengual: None declared, D. Fujita: None declared, E. Otta: None declared, L. Carmona: None declared, O. Kenji: None declared, M. Sugiura-Ogasawara: None declared, A. Murashima: None declared, T. Atsumi Grant/research support from: Chugai Pharmaceutical Co., Ltd., Eisai Co., Ltd., Bristol-Myers Squibb Co., Astellas Pharma Inc., Daiichi Sankyo Co., Ltd. and Mitsubishi Tanabe Pharma Co., Speakers bureau: Astellas Pharma Inc. and Mitsubishi Tanabe Pharma Co.

Background Phosphatidylserine-dependent antiprothrombin antibodies (aPS/PT) are strongly correlated with lupus anticoagulant. A Task Force of scientists at the International Congress on Antiphospholipid Antibodies (APLA 2010) accepted that aPS/PT would potentially contribute for a better identification of antiphospholipid syndrome (APS). Accordingly,we carried out an Initial and a Validation retrospective, cross-sectional multi-centre study on aPS/PT. Objectives To ascertain the value of aPS/PT for APS diagnosis. Methods We conducted an initial study involving 8 centres from 7 countries.Demographics and clinical/laboratory data were retrospectively collected.A sample from the subjects was prepared at each institution.Specimens were blinded and determination of IgG aPS/PT performed at Inova Diagnostics, Inc.USA (Inova) using ELISA kits from two manufacturers:Medical and Biological Laboratories Co Ltd, Japan (MBL) and Inova.After completing the initial study, a Validation study with a new sample of subjects (5 different centres from 5 countries) was carried out using the same methodology. Results The Initial study comprised 247 subjects.Statistically significant correlation in the IgG aPS/PT values was obtained with both ELISA kits (r=0.827, p Conclusions The performance of IgG aPS/PT using Inova and MBL ELISA kits is reliable. IgG aPS/PT detection is an easily performed laboratory parameter that may help in the diagnosis of APS. Acknowledgements The authors want to acknowledge the contributions of the late Prof. Silvia Pierangeli, University of Texas Medical Branch, Galveston, TX, USA Disclosure of Interest O. Amengual: None declared, R. Forastiero: None declared, M. Sugiura-Ogasawara: None declared, K. Otomo: None declared, O. Kenji: None declared, C. Favas: None declared, J. Delgado Alves: None declared, P. Žigon: None declared, A. Ambrožic: None declared, M. Tomsic: None declared, I. Ruiz Arruza: None declared, G. Ruiz Irastorza: None declared, M. Bertolaccini: None declared, G. Norman Employee of: Inova Diagnostics, Inc, San Diego, CA USA, Z. Shums: None declared, A. Jiro Employee of: Medical and Biological Laboratories, Co. Ltd, A. Murashima: None declared, A. Tebo: None declared, M. Gerosa: None declared, P. Meroni: None declared, I. Rodriguez-Pintό: None declared, R. Cervera: None declared, J. Swadzba: None declared, J. Musial: None declared, T. Atsumi Grant/research support from: Chugai Pharmaceutical Co., Ltd., Eisai Co., Ltd., Bristol-Myers Squibb Co., Astellas Pharma Inc., Daiichi Sankyo Co., Ltd. and Mitsubishi Tanabe Pharma Co., Speakers bureau: Astellas Pharma Inc. and Mitsubishi Tanabe Pharma Co.

Hypopituitarism can be caused by tumor, inflammation, granuloma and injuries. Once pituitary function is disturbed, hormone replacement therapy is necessary for the remaining life span in most cases. We have experienced a rare case of a unique intrasellar mass associated with pituitary dysfunction in which both spontaneously reversed. A 61-yr-old woman developed hypoadrenalism and central diabetes insipidus (cDI). Magnetic resonance (MR) imaging revealed a lobular, strong hypointense lesion with spotty signal in the middle of the hypophysis. This spotty lesion showed isointensity on T1- and high-intensity on T2-weighted MR images. The spotty signal as well as the normal pituitary lobe were enhanced by the administration of gadolinium. As replacement therapies for hypoadrenalism and cDI, 10 mg of hydrocortisone and 2.5 microg of desmopressin acetate were prescribed. Three months later, slight shrinkage of intrasellar mass and spontaneous improvement of pituitary functions were found. Hydrocortisone was then discontinued. Furthermore, because polyuria and polydipsia were improved nine months later, desmopressin acetate was stopped. Currently, the intrasellar mass continues to shrink, and the patient shows no symptoms without medication. Based upon the unique features of MR images, we suspect that the origin of the mass is an intrasellar hemangioma.