Motohiro Matsuda

Four cases of MPO-ANCA-positive vasculitis with otitis media, and review of the literature

Otitis media is one of the common organ injuries that appear during the course of anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). We experienced four patients with myeloperoxidase (MPO)-ANCA-positive AAV with otitis media. All were elderly Japanese women. MPO-ANCA in our patients was reminiscent of microscopic polyangiitis (MPA), although chest computed tomography (CT) scans revealed characteristics of both granulomatosis with polyangiitis (GPA), showing bronchial lesions and nodule formation, and MPA, showing interstitial changes. Whether our cases should be classified as GPA or MPA is a matter of discussion. We detail their profiles, and review previous literature on MPO-ANCA-positive AAV with otitis media.

Severe fever with thrombocytopenia syndrome with myocardial dysfunction and encephalopathy: A case report

Severe fever with thrombocytopenia syndrome (SFTS) is an emerging infectious disease in China, Korea and Japan caused by a novel bunyavirus, SFTS virus (SFTSV). Although central nervous system manifestations are common in SFTS patients, the pathogenesis has not been elucidated; and there are few reports of myocardial dysfunction. Here we report an elderly Japanese patient with reversible myocardial dysfunction and encephalopathy. A previously healthy 65-year-old male engaged in forestry got a tick bite and developed fever and fatigue in 3 days. Three days after onset, he presented to a local hospital where the diagnosis of SFTS with hemophagocytotic syndrome was made. The blood test showed leukopenia and thrombocytopenia as well as elevated levels of alanine aminotransferase and aspartate aminotransferase. Marked hemophagocytosis was found on bone marrow smear. Peripheral blood was positive for SFTSV gene by reverse-transcription polymerase chain reaction. On day 7, the patient was transferred to our hospital. We observed disturbance of consciousness, Kernig sign and myoclonus to face and limbs. Decreased blood flow of whole cerebral cortex was detected by single photon emission computed tomography (SPECT). Chest X-ray revealed cardiomegaly and electrocardiography (ECG) showed abnormal T waves. These data suggested acute encephalopathy and myocardial dysfunction. We treated him with corticosteroid and blood transfusion, which resulted in the complete recovery of the above abnormal symptoms and laboratory data including the findings in SPECT and ECG in about a month. This case demonstrated transient myocardial dysfunction and encephalopathy can occur in addition to typical clinical manifestation of SFTS.

Possible Case of Novel Spotted Fever Group Rickettsiosis in TravelerReturning to Japan from India

A 60-year-old woman experienced fever, headache, rash, and altered vision after returning to Japan from India. Testing detected elevated antibody titers to spotted fever group rickettsia; PCR on blood yielded positive results for the rickettsial outer membrane protein A gene. We isolated a unique rickettsial agent and performed a full-genome analysis.

Sudden respiratory failure due to tracheobronchomalacia by relapsing polychondritis, successfully rescued by multiple metallic stenting and tracheostomy

Relapsing polychondritis (RP) is a rare systemic autoimmune disease that affects cartilaginous structures. RP causes tracheobronchomalacia (TBM) by affecting the bronchial cartilage. TBM is a fatal condition characterized by excessive weakening of the walls of the trachea and bronchi. We herein report a case of a 73-year-old man who experienced sudden respiratory failure due to TBM caused by RP. Immunosuppressive treatment did not improve his respiratory failure. Multiple metallic stentings dramatically improved his severe airway symptoms. When the airway condition becomes lethal in RP patients, then metallic stenting can be a useful treatment option.

Arteriosclerosis of Whole Aorta in Takayasu Arteritis

Persistent inflammation is a serious risk factor for arteriosclerosis and arteriosclerotic disease in Takayasu arteritis (TA)1,2. A female patient was diagnosed with TA at 32 years of age. She underwent treatment with glucocorticoids for about 1 year, and then the medication was discontinued. At 57 years of age, she presented to our hospital complaining of left back pain on …

The time-sequential changes of risk factors for adult T-cell leukemia development in human T-cell leukemia virus-positive patients with rheumatoid arthritis: a retrospective cohort study

Abstract Objective: This study aimed to investigate the time-sequential changes of risk factors for adult T-cell leukemia (ATL) development in human T-cell leukemia virus type 1 (HTLV-1)-positive rheumatoid arthritis (RA) patients. Methods: HTLV-1 infection was screened using particle agglutination assay and confirmed via western blotting in 365 RA patients. Twenty-three HTLV-1-positive RA patients were included in the study cohort. Blood samples were obtained from these patients at each observation time point. The values of HTLV-1 proviral load (PVL) and serum soluble IL-2 receptor (sIL2-R), which are risk factors for ATL development, were measured using real-time PCR and enzyme immunoassay, respectively. Results: The study cohort comprised 79 person-years. The median HTLV-1 PVL and sIL2-R values of the HTLV-1-positive RA patients were 0.44 copies per 100 white blood cells (WBCs) and 406 U/mL, respectively. Three HTLV-1-positive RA patients showed a high PVL value. No remarkable changes were observed in the PVL and sIL2-R values during the observation period. However, one elderly HTLV-1-positive RA patient who had a high PVL value developed ATL during treatment with methotrexate and infliximab. Conclusion: A thorough clinical assessment of the risk factors for ATL development may be necessary in daily clinical practice for RA patients in HTLV-1-endemic areas in Japan.

AB0021 Human T cell leukemia virus type 1 (HTLV-1) exacerbates rheumatoid arthritis; exosomes and IFN-GAMMA derived from HTLV-1 infected cells enhance the inflammatory response of rheumatoid arthritis synovial fibroblasts via pattern recognition receptor, RIG-I

Background Human T cell leukemia type 1 (HTLV-1) positive rheumatoid arthritis (RA) patients show severe inflammatory state and resistance to anti-rheumatic therapy, including biologic agents (1). HTLV-1 infected T cells was increased in the synovial fluid and tissue from an HTLV-1 positive RA patients (2). However the mechanism of worsening RA by HTLV-1 infection remains unclear. We focused on the role of HTLV-1 infected T cells as a key player in the exacerbation of RA. Objectives To clarify the role of HTLV-1 infected T cells in the pathogenesis of RA. We investigate inflammatory mediators derived from HTLV-1 infected cells. Methods Peripheral blood mononuclear cells (PBMCs) were collected from asymptomatic HTLV-1 carriers (AC) (n=5) and healthy subjects (HS) (n=5). Rheumatoid arthritis synovial fibroblasts (RASFs) were co-cultured with PBMCs for 5 days. Cytokine profiles of supernatants were analyzed by multiplex. Exosomes were isolated and purified from cultured medium of HTLV-1 infected cell line (MT2). RASF was cultured with MT2 derived exosomes with and without IFN-gamma for 24hours. Total RNA was extracted using TRIZOL method. The expression of RIG-I, IL-6, CXCL10, and CCL5 mRNA in RASF was measured using real-time quantitative PCR. The expression of pattern recognition receptor, RIG-I was determined by immune blotting. Silencing of RIG-I in RASF was performed by transfection of siRNA against RIG-I. Results The levels of cytokine, including IFN-gamma, IL-2, IL-9, IL-13, IL-6, and CCL20, were higher in supernatants co-cultured with HTLV-1 positive PBMCs than in those of negative PBMC (p<0.05). The expression of CXCL10 and IL-6 mRNA was increased in RASF co-cultured with HTLV-1 positive PBMCs compared to those of negative PBMCs. IFN-gamma is well known to be an important cytokine in the pathogenesis of HTLV-1 associated inflammatory diseases. IFN-gamma induced the expression of IL-6, CCL5, and CXCL10 mRNA in RASF. HTLV-1 infected cell line, MT2, autonomously released a large amount of exosomes which contain nucleic acids such as RNA and DNA. MT2 derived exosomes significantly enhanced the expression of CXCL10 mRNA, but not IL-6 and CCL5, in RASF activated by IFN-gamma. Therefore, we hypothesized that exosomes play the role of ligand for pattern recognition receptors. IFN-gamma increased the expression of RIG-I protein in RASF in a dose-dependent manner. The expression of RIG-I protein also increased in RASF co-cultured with HTLV-1 positive PBMCs compared to those of negative PBMCs. Finally, the silencing of RIG-I suppressed the expression of CXCL10 in RASF induced by co-stimulation of both exosomes and IFN-gamma. Conclusions It is possible that HTLV-1 infected T cells exacerbate the inflammatory responses of RASFs. Exosomes derived from HTLV-1 infected cells enhance the expression of CXCL10 in RASF induced by IFN-gamma via pattern recognition receptor, RIG-I. References Umekita K, et al. Arthritis Care Res (Hoboken). 2014 May;66(5):788–92. Yakova M, et al. Retrovirology. 2005 Feb 1;2:4. Disclosure of Interest None declared

AB0589 Hypercoagulable State Might Be Induced by Alveolar-Endothelial Damages in Interstitial Lung Disease Associated with Polymyositis/dermatomyositis

Background Polymyositis and dermatomyositis (PM/DM) are often complicated by interstitial lung diseases (ILD), which is an important cause of death. It has been reported that endothelial damages are likely to exist in PM/DM patients with ILD (PM/DM-ILD). Endothelial damages and oxidative stress induced hypercoagulable state in many connective tissue diseases (CTD) such as rheumatoid arthritis, systemic lupus erythematosus and systemic scleroderma. Recent evidence suggested that anticoagulation therapies might contribute to improve the disease activity of pneumonia related to CTDs. Objectives The purpose of this study was to clarify the association between the disease activity of ILD and blood coagulation disorders in patients with PM/DM. Methods This study is retrospective observation study. The medical records of 22 patients who were diagnosed as having PM/DM admitted to our hospital from April 2012 to March 2015 were reviewed in present study (median age: 50.5, female ratio: 81.8%). Diagnosis of ILD was evaluated by chest high-resolution CT. We reviewed the laboratory findings and autoantibody profile associated with PM/DM. Results Eighteen of 22 (81.8%) patients with PM/DM were diagnosed as having ILD. Autoantibodies associated with PM/DM were evaluated in 14 patients among 18 patients with PM/DM-ILD. Anti-aminoacyl-tRNA synthetases (ARS) and anti-MDA5 antibody was positive in 8/14 patients (57%) and 4/14 patients (29%), respectively. Anti-Jo-1 antibody was detected in 3 patients (38%), anti-PL7 in 3 patients (38%), anti-OJ in one patient (12%), and anti-EJ in one patient (12%) in 8 patients with anti-ARS antibody positive PM/DM-ILD. The levels of creatinine kinase (CK) in anti-ARS antibody positive PM/DM-ILD patients was higher than those in anti-ARS antibody negative PM/DM-ILD patients (median CK 2464 v.s 106 IU/ml, p=0.01). The levels of serum KL-6 and plasma D-dimer in anti-ARS antibody positive PM/DM-ILD patients tended to be higher than those in anti-ARS antibody negative PM/DM-ILD patients (median KL-6 691 v.s 489 IU/ml, D-dimer 2.57 v.s 1.96 ug/ml). Additionally, there is significantly positive correlation in the levels of between serum KL-6 and plasma D-dimer (R=0.58, p=0.0008). However, there is no correlation between the levels of serum KL-6 and blood coagulation tests, such as prothrombin time (%) and activated thromboplastin time. Conclusions These results suggest that anti-ARS antibody, especially anti-Jo-1 and anti-PL7, seems to be associated with the severity of muscular manifestation and alveolar-endothelial damages. The level of plasma D-dimer reflects the disease activity of ILD in patients with PM/DM. The hypercoagulable state might be induced by alveolar-endothelial damages and oxidative stress in PM/DM-ILD. Acknowledgement We thank Ms. Yuki Kaseda for excellent technical assistance. Disclosure of Interest None declared

AB0027 A Novel Transcription Factor NFAT5 Plays An Important Role as Critical Regulator in The Inflammatory Response of Rheumatoid Arthritis Fibroblasts Mediated via Toll-Like Receptor 4 Signaling Pathways

Background Damage-associated molecular patterns (DAMPs) are proposed to drive aberrant stimulation of Toll-like receptors (TLRs) in the rheumatoid arthritis (RA) joints resulting in increased expression of proinflammatory cytokines and chemokines. In the recent study we demonstrated that the neutrophil-derived lactoferrin (LTF) induces inflammatory response in RA synovial fibroblasts (RASF) via TLR-4 (Ref.). However, the molecular mechanisms of TLR-4 signaling in activated RASF are still unclear. Objectives To clarify the molecular mechanisms of TLR-4 signaling pathways in activated RASF. Methods Recombinant human neutrophil-derived LTF was used as one of the TLR-4 ligands. RASF were treated with LTF and/or TNF-α, and the expression of proinflammatory cytokines and chemokines, such as IL-6, IL-8 and CCL20 in RASF was measured by RT-qPCR and ELISA. To repress the TLR-4 signaling pathways, a small molecular inhibitor of TLR-4 (TAK-242), TAK1 inhibitor (5Z-7-Oxozeaenol), nuclear factor kappa B (NF-kB) inhibitor (BMS345541), and p38 mitogen activated protein kinase (MAPK) inhibitor (SB202190) were used. The role of nuclear factor of activated T cells 5 (NFAT5) in the TLR-4 signaling in RASF was investigated using a small interfering RNA targeting NFAT5. Results Stimulation of RASF with LTF significantly increased the expression of IL-6, IL-8 and CCL20 mRNA and proteins (p=0.01). LTF enhanced the expression of these cytokine and chemokine mRNA in RASF stimulated by TNFα. TAK-242 completely repressed the expression of these cytokines and chemokines in RASF stimulated by LTF, while the TAK-1 inhibitor did not suppress the expression of these cytokines and chemokines in RASF. The NF-kB inhibitor, but not the p38MAPK inhibitor, partially repressed the expression of IL-6 and IL-8 mRNA induced by LTF. However, neither the NF-kB inhibitor nor p38MAPK inhibitor repressed the expression of CCL20 mRNA. Interestingly, silencing of NFAT5 significantly decreased the basal expression of IL-6, IL-8 and CCL20 mRNA in RASF. Additionally, silencing of NFAT5 significantly repressed the expression of not only IL-6, IL-8, but also of CCL20 mRNA in RASF treated by LTF. Conclusions These findings suggest that NFAT5 plays an important role as a critical regulator in the proinflammatory response of RASF mediated by the TLR-4 signaling pathway. References Umekita K, et al. Neutrophil-Derived Lactoferrin Regulates the Activity of NFAT5 in Rheumatoid Arthritis Synovial Fibroblasts Via Toll-like Receptor 4. 2015 ACR/ARHP Annual Meeting (San Francisco) Acknowledgement We thank Ms. Yuki Kaseda, Ms. Ayaka Miyamoto and Dr. Yatsuki Aratake for their excellent technical assistance. Disclosure of Interest None declared

FRI0194 Treatment with anti-tumor necrosis factor (TNF) biologics to human t-lymphotropic virus type 1 (HTLV-1) positive patients with rheumatoid arthritis (RA): a case-control study

Objectives To see whether the clinical features and responses to anti-TNF of HTLV-1 positive patients with RA are different from those of HTLV-1 negative patients. Methods The clinical features and response to anti-TNF were compared between 10 female HTLV-1 positive RA patients and 20 age-matched female HTLV-1 negative patients, who were diagnosed based on the 1987 ACR criteria for RA. Therapeutics response was evaluated using the EULAR improvement criteria. Results Significantly higher baseline level of C-reactive protein (CRP) was observed in HTLV-1 positive patients than in HTLV-1 positive patients (P = 0.003). The value of disease activity score in 28 joints (DAS28) and the levels of erythrocyte sedimentation rate (ESR) tended to be higher in HTLV-1 positive patients. The discontinuation rate of anti-TNF was higher in HTLV-1 positive patients 6 months after the beginning of treatment than in HTLV-1 negative patients (30 % v.s 0 %, respectively). Most of reason for discontinuation was inefficacy of anti-TNF. EULAR response rate in 3 months of the treatment was worse in HTLV-1 positive patients than in HTLV-1 positive patients. The levels of CRP, ESR and the value of DAS28 remained to be significantly higher in carrier RA than non-carrier RA. There is no development of lymphoma or myelopathy during 2-years observation period in HTLV-1 positive patients. Conclusions The result of this small study suggested that HTLV-1 positive RA patients have high inflammation and resistance to the treatment with anti-TNF. Further study with larger number of cases is necessary to confirm these data. Disclosure of Interest None Declared