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Sjögren’s syndrome (SS) is an autoimmune disease characterized by inflammation with lymphoid infiltration and destruction of the salivary glands. Although many genome-wide association studies have revealed disease-associated risk alleles, the functions of the majority of these alleles are unclear. Here, we show previously unrecognized roles of GTF2I molecules by using two SS-associated single nucleotide polymorphisms (SNPs), rs73366469 and rs117026326 (GTF2I SNPs). We found that the risk alleles of GTF2I SNPs increased GTF2I expression and enhanced nuclear factor-kappa B (NF-κB) activation in human salivary gland cells via the NF-κB p65 subunit. Indeed, the knockdown of GTF2I suppressed inflammatory responses in mouse endothelial cells and in vivo. Conversely, the over-expression of GTF2I enhanced NF-κB reporter activity depending on its p65-binding N-terminal leucine zipper domain. GTF2I is highly expressed in the human salivary gland cells of SS patients expressing the risk alleles. Consistently, the risk alleles of GTF2I SNPs were strongly associated with activation of the IL-6 amplifier, which is hyperactivation machinery of the NF-κB pathway, and lymphoid infiltration in the salivary glands of SS patients. These results demonstrated that GTF2I expression in salivary glands is increased in the presence of the risk alleles of GTF2I SNPs, resulting in activation of the NF-κB pathway in salivary gland cells. They also suggest that GTF2I could be a new therapeutic target for SS.

To identify the subpopulation of rheumatoid arthritis (RA) non-responders to Janus kinase inhibitors (JAKis) using cluster analysis.This retrospective study enrolled RA patients who had been treated with JAKis (tofacitinib or baricitinib) between July 2013 and September 2019 in six centres. The endpoint was set as inadequate response to JAKis (JAKis-IR), defined as either non-response to JAKis or their intolerance. Non-response to JAKis was defined as achieving neither American College of Rheumatology 20% response nor Disease Activity Score (ΔDAS28-CRP)1.2 at 12 weeks. Withdrawal time point included earlier than after 12 weeks from baseline. A hierarchical cluster analysis was performed with variables related with clinical and serological parameters at baseline.The 132 RA patients enrolled were classified into four groups (Group A-D). Groups consisted of three components defined at baseline, as seropositivity, advanced joint destruction, interstitial lung disease presumably associated with RA (RA-ILD). Group A (n=32): seronegative, presence of advanced joint destruction, absence of RA-ILD. Group B (n=35): seropositive, absence of advanced joint destruction and RA-ILD. Group C (n=20): seropositive, absence of advanced joint destruction, presence of RA-ILD. Group D (n=45): seropositive, presence of advanced joint destruction and RA-ILD. The rate of JAKis-IR in four groups was as follows: A, 34.3%; B, 17.1%; C, 20.0%; and D, 8.9%. The difference in JAKis-IR rate between group A and D was statistically significant.A subpopulation of RA patients with a combination of the following three components, seronegativity, advanced joint destruction and absence of RA-ILD, was identified as being prone to JAKis-IR.

We recently reported that NF-κB–mediated inflammation caused by breakpoint cluster region (BCR) is dependent on the α subunit of casein kinase II (CK2α) complex. In the current study, we demonstrate that presenilin 1 (Psen1), which is a catalytic component of the γ-secretase complex and the mutations of which are known to cause familial Alzheimer disease, acts as a scaffold of the BCR–CK2α–p65 complex to induce NF-κB activation. Indeed, Psen1 deficiency in mouse endothelial cells showed a significant reduction of NF-κB p65 recruitment to target gene promoters. Conversely, Psen1 overexpression enhanced reporter activation under NF-κB responsive elements and IL-6 promoter. Furthermore, the transcription of NF-κB target genes was not inhibited by a γ-secretase inhibitor, suggesting that Psen1 regulates NF-κB activation in a manner independent of γ-secretase activity. Mechanistically, Psen1 associated with the BCR–CK2α complex, which is required for phosphorylation of p65 at serine 529. Consistently, TNF-α–induced phosphorylation of p65 at serine 529 was significantly decreased in Psen1-deficient cells. The association of the BCR–CK2α–p65 complex was perturbed in the absence of Psen1. These results suggest that Psen1 functions as a scaffold of the BCR–CK2α–p65 complex and that this signaling cascade could be a novel therapeutic target for various chronic inflammation conditions, including those in Alzheimer disease.

The objective of this study is to identify the effects of statins and risk factors for thrombosis in patients with new onset of systemic lupus erythematosus (SLE) with or without antiphospholipid antibodies (aPL). Consecutive patients with SLE without history of thrombotic events were retrospectively enrolled from April 1997 to February 2014. The development of first thrombosis and death caused by thrombosis were defined as the study endpoint. Risk and protective factors for developing thrombosis were analyzed. A total of 152 patients, 80 positive and 72 negative for aPL, were included. In aPL-positive patients, 15 developed arterial ( n = 6) and venous ( n = 9) thrombosis (median follow-up period 69 months). Cox's proportional hazards model showed that older age at SLE onset and IgG-anticardiolipin antibodies (aCL) were statistically significant risks for thrombosis. Statin therapy was identified as a statistically significant protective factor against thrombosis (hazard ratio 0.12, 95% confidence interval 0.01-0.98). In aPL-negative patients (median follow-up period 46 months), seven patients developed thrombosis (five arterial and two venous). No risk factors for thrombosis were found in this group. In aPL-positive patients with SLE, the late disease onset and the presence of IgG-aCL represented additional risk factors for thrombosis. Statin treatment appeared as a protective factor for thrombosis.

To clarify the efficacy and safety of calcineurin inhibitors (CNI) for treating adult-onset Still's disease (AOSD).This multicentre historical cohort study enrolled the consecutive patients with AOSD according to Yamaguchi classification criteria. The endpoints were set as the time from the initiation of treatment to events, the persistency rate of CNI 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 CNI or conventional therapy without CNI.One hundred seventy-eight patients with 247 events were analysed. CNI were predominantly used in 72 events with a recurrent history, typical skin rash, high ferritin levels, and/or severe complications such as macrophage activation syndrome, disseminated intravascular coagulation, serositis, meningitis. CNI led to a significantly longer event-free survival (hazard ratio: 0.57, 95% confidential interval: 0.32-0.99) after adjustment of concomitant medications. Subgroup analysis showed that CNI were effective for AOSD patients with high ALT level (hazard ratio: 0.11, 95% confidential interval: 0.02-0.59) and severe complications (hazard ratio: 0.11, 95% confidential interval: 0.01-0.94). The persistency rate of CNI was 71% at 5th year. Adverse events occurred more frequently in the CNI group (18% versus 8%, p=0.02); however, CNI did not involve in increased risk of adverse events, including nephrotoxicity, after adjustment (p=0.23).Our retrospective analysis suggested that CNI could be an effective and safe option for treating AOSD.

Background Adult-onset Still’s disease (AOSD) is a systemic inflammatory disorder generally responsive to corticosteroid (CS) therapy, whereas cases not responding CS monotherapy are frequently found in clinical practice. In such cases, methotrexate and/or biologics including TNF-α, IL-1, or IL-6 inhibitors are used [1]. However, further treatment options are required for refractory AOSD patients who are intolerant to methotrexate and/or biologics. Calcineurin inhibitors (CNI) downregulate T cell activation through inhibiting IL-2 transcription and signal transduction. Therefore, they are reasonable therapeutic medication for AOSD considering T cells and subsequently activated macrophages play a pathophysiological role in AOSD [2]. Nevertheless, only a few case series have indicated effects of CNI for difficult AOSD. Objectives To evaluate the efficacy of CNI in patients with AOSD. Methods This is a multi-centre historical cohort study comprised the consecutive patients with AOSD in accordance with Yamaguchi classification criteria. The primary endpoint was set as the time from the initiation of treatment to event defined as death of any causes or relapse of AOSD requiring an increase of CS dose. Secondary endpoints were set as persistency rate of CNI and safety. Based on the recurrent event data analysis, these endpoints were evaluated for each event. We compared the frequency of events between two groups according to the treatment that included calcineurin inhibitors (CNI+) or conventional therapy without calcineurin inhibitors (CNI-). Results One hundred seventy-eight patients were enrolled in this study. Mean age was 46 year-old, and median follow-up period 36 months. Seventy-one events in 56 patients were treated with therapeutic regimen including CNI (CNI+, cyclosporine: 14, tacrolimus: 60), and 176 events in 138 patients were treated with the conventional therapy excluding CNI (CNI-). CNI were used in AOSD patients with recurrent history, high ferritin level, serositis, hemophagocytic syndrome (HPS) and/or disseminated intravascular coagulation (DIC). The CNI+ group had longer event-free survival than the CNI- group (83% versus 75% at 5th year). The hazard ratio (HR) was 0.57 (95% CI, 0.32-0.99) after adjustment of initial dose of CS and other concomitant medications. Subgroup analysis showed that CNI were more effective for AOSD patients with high ALT levels (≥ 80 IU/L) and/or severe complications such as HPS and DIC. The persistency rate of CNI was 71% at 5th year. Adverse events occurred more frequently in the CNI+ group than in the CNI- group (18% versus 8%, p = 0.04); however, serious adverse events did not increase in the CNI+ group (3% versus 2%). AOSD-related mortality had never been found in the observation period. One patient had a fatal course due to septic shock in the CNI+ group. Conclusion Our retrospective analysis suggested that CNI could be an additional option for treating AOSD with acceptable safety. References [1] Efthimiou P, et al. Diagnosis and management of adult onset Still’s disease. Ann Rheum Dis. 2006. [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 Dis. 2004. Disclosure of Interests Masato Tarumi: None declared, Hiroyuki Nakamura: None declared, Yuichiro Fujieda: None declared, Hirohiko Kitagawa: None declared, Ryo Hisada: None declared, Yuka Shimizu: None declared, Ikuma Nakagawa: None declared, Akito Tsutsumi: None declared, Takashi Kurita: None declared, Hiroshi Kataoka: None declared, Masaya Mukai: None declared, Hideki Kasahara: None declared, Atsushi Noguchi: None declared, Yoshiharu Amasaki: None declared, Tetsuya Horita: None declared, Tatsuya Atsumi Grant/research support from: Astellas Pharma Inc., Takeda Pharmaceutical Co., Ltd., Mitsubishi Tanabe Pharma Co., Chugai Pharmaceutical Co., Ltd., Daiichi Sankyo Co. Ltd., Otsuka Pharmaceutical Co., Ltd. and Pfizer Inc., Alexion Inc., Bayer Yakuhin, Ltd,Otsuka Pharmaceutical Co., Ltd. Chugai Pharmaceutical Co., Ltd., Takeda Pharmaceutical Co., Ltd., Eisai Co., Ltd., Bristol-Myers Squibb Co., Daiichi Sankyo Co. Ltd., Mitsubishi Tanabe Pharma Co., Asahi Kasei Pharma Co., Consultant for: ONO PHARMACEUTICAL CO., LTD Sanofi K.K. Daiichi Sankyo Co., Ltd. Pfizer Inc., Speakers bureau: Mitsubishi Tanabe Pharma Co., Chugai Pharmaceutical Co., Ltd., Astellas Pharma Inc., Takeda Pharmaceutical Co., Ltd., Pfizer Inc.,Daiichi Sankyo Co. Ltd., Bristol-Myers Squibb Co., Eli Lilly Japan K.K.

OBJECTIVE We have previously reported that the coactivation of NF-κB and STAT3 in nonimmune cells, including synovial fibroblasts, enhances the expression of NF-κB target genes and plays a role in chronic inflammation and rheumatoid arthritis (RA). This study was undertaken to examine the role of NF-κB activation in chondrocytes and better understand the pathogenesis of RA. Furthermore, transmembrane protein 147 (TMEM147) was investigated as a representative NF-κB activator in chondrocytes. METHODS Clinical samples from RA patients were analyzed by immunohistochemistry. Specimens obtained from patients with polydactyly were used as control samples. The functional contribution of chondrocytes and TMEM147 to arthritis was examined in several murine models of RA. In vitro experiments (quantitative polymerase chain reaction, RNA interference, immunoprecipitation, and confocal microscopy) were performed to investigate the mechanism of action of TMEM147 in chondrocytes. RESULTS Samples obtained from RA patients and mouse models of RA showed coactivation of NF-κB and STAT3 in chondrocytes (P < 0.001). This coactivation induced a synergistic expression of NF-κB targets in vitro (P < 0.01). Chondrocyte-specific deletion of STAT3 significantly suppressed the development of cytokine-induced RA (P < 0.01). TMEM147 was highly expressed in chondrocytes from RA patient samples and the mouse models of RA. Gene silencing of TMEM147 or anti-TMEM147 antibody treatment inhibited the cytokine-mediated activation of NF-κB in vitro (P < 0.01) and suppressed cytokine-induced RA in vivo (P < 0.01). Mechanistically, TMEM147 molecules acted as scaffold proteins for the NF-κB complex, which included breakpoint cluster region and casein kinase 2, and enhanced NF-κB activity. CONCLUSION These results suggest that chondrocytes play a role in the development of RA via TMEM147-mediated NF-κB activation and indicate a novel therapeutic strategy for RA.

The joint space difference index (JSDI) is a newly developed radiographic index which can quantitatively assess joint space narrowing progression of rheumatoid arthritis (RA) patients by using an image subtraction method on a computer. The aim of this study was to investigate the reliability of this method by non-experts utilizing RA image evaluation. Four non-experts assessed JSDI for radiographic images of 510 metacarpophalangeal joints from 51 RA patients twice with an interval of more than 2 weeks. Two rheumatologists and one radiologist as well as the four non-experts examined the joints by using the Sharp-van der Heijde Scoring (SHS) method. The radiologist and four non-experts repeated the scoring with an interval of more than 2 weeks. We calculated intra-/inter-observer reliability using the intra-class correlation coefficients (ICC) for JSDI and SHS scoring, respectively. The intra-/inter-observer reliabilities for the computer-based method were almost perfect (inter-observer ICC, 0.966-0.983; intra-observer ICC, 0.954-0.996). Contrary to this, intra-/inter-observer reliability for SHS by experts was moderate to almost perfect (inter-observer ICC, 0.556-0.849; intra-observer ICC, 0.589-0.839). The results suggest that our computer-based method has high reliability to detect finger joint space narrowing progression in RA patients.

The breakpoint cluster region (BCR) is known as a kinase and cause of leukemia upon fusing to Abl kinase. In this study, we demonstrate that BCR associated with the α subunit of casein kinase II (CK2α), rather than BCR itself, is required for inflammation development. We found that BCR knockdown inhibited NF-κB activation in vitro and in vivo. Computer simulation, however, suggested that the putative BCR kinase domain has an unstable structure with minimal enzymatic activity. Liquid chromatography–tandem mass spectrometry analysis showed that CK2α associated with BCR. We found the BCR functions are mediated by CK2α. Indeed, CK2α associated with adaptor molecules of TNF-αR and phosphorylated BCR at Y177 to establish a p65 binding site after TNF-α stimulation. Notably, p65 S529 phosphorylation by CK2α creates a p300 binding site and increased p65-mediated transcription followed by inflammation development in vivo. These results suggest that BCR-mediated inflammation is dependent on CK2α, and the BCR–CK2α complex could be a novel therapeutic target for various inflammatory diseases.

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.

Inflammation is a fundamental response induced by the immune system to protect the body against pathogens, tissue damage, and stress. At the same time, recent studies have suggested that chronically induced inflammation is involved in various human diseases and disorders. Thus, understanding the molecular mechanisms of chronic inflammation could provide therapeutic value. Many mediators such as cytokines or chemokines regulate inflammatory responses. Among them, interleukin(IL)-6 is a prominent cytokine that induces and maintains inflammatory reactions. It is expressed by activated CD4+ T cells and also non-immune cells such as fibroblasts and epithelial cells. We discovered an inflammation-induction machinery, the inflammation amplifier, which is activated by the simultaneous stimulation of nuclear factor-kappa B (NF-κB) and signal transducers and activator of transcription 3 (STAT3) via various cytokines like IL-17 and IL-6 in non-immune cells. Activation of the inflammation amplifier induces a synergistic increase of IL-6, inflammatory chemokines, and growth factors. Using genome-wide screening, we identified several growth factors as mediators of the inflammation amplifier. In this review, we highlight the role of growth factors in the inflammation mechanism with special attention on the inflammation amplifier.

RNA-binding motif 10 (Rbm10) is an RNA-binding protein that regulates alternative splicing, but its role in inflammation is not well defined. Here, we show that Rbm10 controls appropriate splicing of DNA (cytosine-5)-methyltransferase 3b (Dnmt3b), a DNA methyltransferase, to regulate the activity of NF-κB-responsive promoters and consequently inflammation development. Rbm10 deficiency suppressed NF-κB-mediated responses in vivo and in vitro. Mechanistic analysis showed that Rbm10 deficiency decreased promoter recruitment of NF-κB, with increased DNA methylation of the promoter regions in NF-κB-responsive genes. Consistently, Rbm10 deficiency increased the expression level of Dnmt3b2, which has enzyme activity, while it decreased the splicing isoform Dnmt3b3, which does not. These two isoforms associated with NF-κB efficiently, and overexpression of enzymatically active Dnmt3b2 suppressed the expression of NF-κB targets, indicating that Rbm10-mediated Dnmt3b2 regulation is important for the induction of NF-κB-mediated transcription. Therefore, Rbm10-dependent Dnmt3b regulation is a possible therapeutic target for various inflammatory diseases.

Central nervous system (CNS), which is made up of brain and spinal cord, is protected from the invasion of harmful agents, such as various pathogens, chemical products or immune cells by a special structure "Blood Brain Barrier (BBB)". BBB highly preserves the homeostasis of CNS environment. On the other hand, there are many diseases in CNS regions which is associated with infection or autoimmunity, that means there may exist the "gateway" for pathogens or immune cells to attack CNS. Until recently, the molecular mechanism of the gateway formation has not been elucidated. Through studies in the multiple sclerosis model experimental autoimmune encephalomyelitis, we have clarified the mechanism of the gateway formation, and also the locations of gateways which depend on the regional neural activation. Further more, we have also discovered a massive chemokine-inducing mechanism "inflammation amplifier" via co-activation of NF-κB pathway and STAT3 pathway. It is essential for the development of inflammation in various diseases and is a molecular basis of BBB breakdown.

Antiphospholipid antibodies (aPLs) are a group of heterogenous antibodies with immunological and functional variations that are detected in the sera of patients with antiphospholipid syndrome (APS). Detection of these antibodies in an efficient and accurate manner remains a significant issue. It requires numerous immunological and functional tests, burdening the laboratory departments, and as a consequence, not sufficiently performed in many cases. We retrospectively studied a total of 212 subjects with or without collagen diseases including APS that visited the outpatients of multiple institutions (department of internal medicine at Health Science University of Hokkaido, department of medicine II and department of gastroenterology at Hokkaido University Hospital). All the subjects were measured aPL (anticardio anticardiolipin antibody IgG/IgM, anti-β2-glycoprotein I antibody IgG/IgM) using a fully automated chemiluminescence analyzer and compared measurement results with those obtained using the conventional ELISA method. These methods were found to have similar diagnostic accuracy, with κ values exceeding 0.6. Of 61 APS patients 41 (67%) were positive for two or more tests: significantly higher than other disease such as systemic lupus erythematosus (3/37, 9%) or non-SLE collagen disease (1/53, 2%). The fully automated chemiluminescence analyzer, which can simultaneously measure multiple aPLs, was thus determined to be useful for diagnosing APS.

Objective To investigate the prevalence and significance of the autoantibodies against complement component 1 q subcomponent (C1q) in patients with APS. Methods In all, 40 consecutive primary APS patients, 42 patients with non-SLE CTDs and 20 SLE patients negative for aPL were enrolled in this retrospective analysis. Refractory APS was defined as a clinical status of recurring thrombosis or pregnancy morbidity during adequate secondary prophylaxis. An ELISA was used to measure serum levels of anti-C1q antibodies and anaphylatoxins (C3a, C4a). Results Anti-C1q antibodies were found in 36% (15/42) and 2.5% (1/40) of primary APS patients and controls, respectively. Among primary APS patients, anti-C1q antibody titres were significantly correlated with serum C4a levels (P = 0.013). Neither the prevalence nor the titre of anti-C1q antibodies was associated with any specific clinical manifestations of APS, nor titres of aPL. Refractory APS patients (n = 10) had a higher prevalence of anti-C1q antibodies (9/10 vs 6/32, P = 0.01) than APS patients without recurrence (n = 32). Conclusion Anti-C1q antibodies are associated with complement activation in APS and may contribute to the pathogenesis, particularly in refractory cases.

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 Thrombosis is one of the most frequent manifestations in patients with systemic lupus erythematosus (SLE). In this study, we examined the several risk factors for thrombosis in patients with SLE. Further, we investigated whether some factors could play a protective thrombotic role in SLE. Objectives To identify risk and protective factors for thrombosis in SLE. Methods Ninety-seven newly diagnosed consecutive patients with SLE without history of thrombotic events were recruited at our hospital from 2001 to 2012. All patients, 87 woman and 10 men, fulfilled the 1997 American College of Rheumatology revised criteria for SLE. Fifty-four patients (55.7%) had antiphospholipid antibodies (aPL). All patients were follow-up since the inclusion until December, 2012. The development of thrombosis were defined as the study endpoint. Results The median follow-up period in all patients was 46 months (IQR 17-84 months). In 54 patients with aPL, the median follow-up period was 57 months (IQR 28-99 months). 10 patients with aPL (18.5%) developed thrombosis during the follow-up period. Cerebral infarction (CI) was observed in 5 patients, pulmonary embolism (PE) in 4 and deep vein thrombosis in 3. Multivariate analysis with Cox’s proportional hazards model showed that older age at SLE onset and anticardiolipin antibodies (aCL)-IgG positivity, (HR 1.89 for every ten age, 95%C.I. 1.07-3.33) and (HR 5.68, 95%C.I. 1.28-25.3), respectively, are statistically significant risk factor for thrombosis. Statin therapy appears as a statistically significant protective thrombotic factor (HR 0.093, 95%C.I. 0.01-0.82) (Figure 1.). Disease activity, anti-thrombotic agents and risk factors for atherosclerosis were not related to thrombosis. On the other hand, in 43 patients without aPL (median follow-up period 26 months, IQR 12-66 months), 4 patients (9.3%) developed thrombosis. Three patients had CI and one PE. None of the evaluated risk factors correlated to the development of thrombosis in aPL-negative patients. Image/graph Conclusions This study suggests that, in patients with aPL, the late disease onset and the presence of aCL-IgG represent additional risk factors for thrombosis. Statin treatment appears as a thrombotic protective factor. Disclosure of Interest : None Declared