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Objectives We aimed to identify disease-specific surface proteins on extracellular vesicles (EVs) as novel serum biomarkers of PM/DM. Methods We performed liquid chromatography–tandem mass spectrometry (LC/MS) on purified EVs from sera of 10 PM/DM patients, 23 patients with other autoimmune diseases and 10 healthy controls (HCs). We identified membrane proteins preferentially present in EVs of PM/DM patients by bioinformatics and biostatistical analyses. We developed an EV sandwich ELISA for directly detecting serum EVs expressing disease-specific membrane proteins and evaluated their clinical utility using sera from 54 PM/DM, 24 RA, 20 SLE, 13 SSc and 25 Duchenne and Becker types of muscular dystrophy (DMD/BMD) patients and 36 HCs. Results LC/MS analysis identified 1220 proteins in serum EVs. Of these, plexin D1 was enriched in those from PM/DM patients relative to HCs or patients without PM/DM. Using a specific EV sandwich ELISA, we found that levels of plexin D1+ EVs in serum were significantly greater in PM/DM patients than in HCs or RA, SLE or DMD/BMD patients. Serum levels of plexin D1+ EVs were greater in those PM/DM patients with muscle pain or weakness. Serum levels of plexin D1+ EVs were significantly correlated with levels of aldolase (rs = 0.481), white blood cells (rs = 0.381), neutrophils (rs = 0.450) and platelets (rs = 0.408) in PM/DM patients. Finally, serum levels of plexin D1+ EVs decreased significantly in patients with PM/DM in clinical remission after treatment. Conclusion We identified levels of circulating plexin D1+ EVs as a novel serum biomarker for PM/DM.

Introduction The coronavirus disease 2019 (COVID-19) pandemic is spreading rapidly all over the world. The Japanese government lifted the state of emergency, announced in April 2020, on May 25, but there are still sporadic clusters. Asymptomatic patients who can transmit severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) cause some of these clusters. It is thus urgent to investigate the seroprevalence of antibodies against SARS-CoV-2 and their neutralizing activity. We conducted a cross-sectional study of >10,000 samples at hospitals in Hyogo Prefecture, Japan. Methods Between August 6 and October 1, 2020, we collected samples of residual blood from the patients who visited or were admitted to five hospitals and a foundation in Hyogo. We tested the samples for antibodies against SARS-CoV-2 by electrochemiluminescence immunoassay (ECLIA) and chemiluminescent enzyme immunoassay (CLEIA). Sera that were positive by ECLIA or CLEIA were analyzed by an immunochromatographic (IC) test and neutralizing activity assay. Results We tested 10,377 samples from patients aged between 0 and 99 years old; 27 cases (0.26%) were positive on the ECLIA, and 51 cases (0.49%) were positive on CLEIA. In the 14 cases that tested positive on both ECLIA and CLEIA, the positive rates on the IC test and for neutralizing activity were high (85% and 92%, respectively). In 50 cases (0.48%) that were positive by either ECLIA or CLEIA, the corresponding rates were low (20% and 6%, respectively). The positive rate of neutralizing antibody was 0.15%. Conclusions These results indicate that most Hyogo Prefecture residents still do not have antibodies and should avoid the risk of incurring a SARS-CoV-2 infection. Two or more antibody tests should be required for seroepidemiological studies of the antibody for SARS-CoV-2, and a neutralizing activity assay is also essential.

The objective of the study was to compare the efficacy and safety of biological disease-modifying antirheumatic drugs (bDMARDs) between elderly-onset rheumatoid arthritis (EORA) and young-onset rheumatoid arthritis (YORA) patients. Patients with rheumatoid arthritis (RA) aged ≧18 years enrolled in a Japanese multicenter observational registry between 2009 and 2018 who had moderate or high disease activity when initiating bDMARDs were included. EORA was defined as RA with onset at 60 or over. After propensity score weighting for differences in confounding factors, generalized estimating equations were used to assess the relationship between the age of RA onset and bDMARD clinical effectiveness at 48 weeks after starting a bDMARD. Among a total of 7183 patients in the registry, 2815 (39.2%) were identified as EORA. The proportion of patients on bDMARDs was lower in the EORA as compared to the YORA (18.3% vs 28.0%, p

Birt-Hogg-Dubé (BHD) syndrome is an autosomal dominant disease characterized by benign skin hamartomas, pulmonary cysts leading to spontaneous pneumothorax, and an increased risk of renal cancer. BHD syndrome is caused by germline mutations in the folliculin (FLCN) gene, a putative tumor suppressor, which result in loss of function of the folliculin protein and may cause cancer predisposition. In a 45-year-old woman with anemia, lymphadenopathy, and a history of recurrent spontaneous pneumothorax,F-18-FDG PET/CT detected diffuse and slight (18)F-FDG accumulation in the bone marrow, enlarged spleen, and systemic multiple enlarged lymph nodes. Genetic examination identified a germline nonsense mutation [c.998C > G (p.Ser333*)] on exon 9 of FLCN. Pathological examination of the lymph node revealed a diffuse neoplastic proliferation of plasmacytoid lymphocytes. The neoplastic lymphoid cells were positive for CD20, CD138, and light chain kappa as per immunohistochemistry and mRNA in situ hybridization, and a MYD88g ene mutation [c.755T > C (p.L252P)] was identified. Accordingly, she was diagnosed with lymphoplasmacytic lymphoma concomitant with BHD syndrome. To the best of our knowledge, this is the first report describing the development of hematological malignancy in a patient with BHD syndrome. The FLCN mutation might contribute lymphomagenesis as an additional mutation cooperating with the MYD88 mutation.

The situation of the COVID-19 pandemic in Japan is drastically changing in the 2ndyear, 2021, due to the appearance of SARS-CoV-2 variants of concern and the roll-out of mass vaccination. In addition to PCR diagnosis, periodic seroepidemiologic surveillance is important to analyze the epidemic situation. In this study, we analyzed the rate of seropositivity for the SARS-CoV-2 N and S antigens in Hyogo prefecture, Japan in August 2021. Sera collected from people who received a health check-up in a clinic of the Hyogo Prefecture Health Promotion Association were subjected to analysis of reactivity to the SARS-CoV-2 N and S antigens by electrochemiluminescence immunoassay (ECLIA) and enzyme-linked immunosorbent assay (ELISA), respectively. For a total 1,000 sera, the positive rates to N and S antigens were 2.1% and 38.7%, respectively. The infectious rate estimated by serological analysis based on the presence of the anti-N antibody was 2.5-fold higher than the value reported based on PCR-based analysis, and it increased five-fold compared to the rate determined by our previous seroepidemiologic study in October, 2020. The anti-S positive rate was almost consistent with the vaccination rate in this area. The observed high anti-S antibody level in the seropositive population may indicate that the mass vaccination in Japan is being performed smoothly at this time point, although the infectious rate has also increased.

Background: We compared the prophylactic effect of trimethoprim-sulfamethoxazole (TMP-SMX) with atovaquone for pneumocystis pneumonia (PCP) in patients with connective tissue diseases (CTDs) receiving high-dose glucocorticoids.Methods: Patients with CTDs aged ≥ 18 years who were treated with a prolonged course (≥ 4 weeks) of glucocorticoids (≥ 20 mg/day prednisone) in a Japanese tertiary center between 2013 and 2017 were included. The patients were categorized into two groups: TMP-SMX and atovaquone group. Adjusted cumulative incidence of PCP was compared between the two groups after propensity score weighting for differences in confounding factors. Results: A total of 480 patients with a prolonged high-dose glucocorticoid treatment were identified. Out of 383 patients with TMP-SMX prophylaxis, 102 (26.8%) patients experienced adverse events leading to discontinuation within 4 weeks of initiation while no patient in the atovaquone discontinued the therapy. Two hundred eighty-one patients received TMP-SMX while 107 received atovaquone for PCP prophylaxis. During a total of 397.0 person-years, 7 PCP cases (2 in the TMP-SMX, 5 in the atovaquone) occurred with a mortality rate of 54.5%. After adjusting for differences in baseline characteristics, the adjusted cumulative incidence of PCP was similar between the two group (HR= 0.97, 95% CI = 0.19 to 5.09, p = 0.97).Conclusion: Prophylactic effects for PCP in CTDs patients receiving prolonged high-dose glucocorticoids were similar between TMP-SMX and atovaquone. Atovaquone was well-tolerated with no side effects.

Aim Subjective well-being (SWB) is a psychological construct that is synonymous with happiness. Many variables including age, sex, income, employment, and marital status are related to SWB. Health is also an important determinant of SWB that can be adversely affected in patients with chronic conditions such as rheumatoid arthritis (RA). In this study, we evaluate the SWB of RA patients and compare it with that of healthy controls. Methods We obtained the original dataset from the "Quality of Life Survey, 2013", which was conducted by the Economic and Social Research Institute, Cabinet Office, Government of Japan. In this survey, SWB was determined by asking participants to rate their happiness between 0 (very unhappy) and 10 (very happy). The survey also included a 56-point questionnaire regarding well-being-related variables. This questionnaire was administered to RA patients recruited from Kobe University Hospital, and clinical and treatment data were simultaneously collected. Results Multivariate analysis revealed that RA patients with high or moderate disease activity had SWB scores that were similar to those of controls. However, the SWB scores of RA patients in remission or with low disease activity were higher than those of controls (P = .013). SWB was associated with household income, self-assessment of living costs, self-assessment of health, depression/ anxiety, and social connection. Conclusions For RA patients, achieving the therapeutic target can result in better SWB than that of healthy controls. Financial status, self-assessment of health, psychological stress, and social network are also important determinants for the SWB of RA patients.

Background This multi-center, retrospective study aimed to clarify retention rates and reasons for discontinuation of either tumor necrosis factor inhibitors (TNFi) or interleukin-6 inhibitors (IL-6i) in patients with elderly-onset rheumatoid arthritis (EORA). Methods Patients with rheumatoid arthritis (RA) enrolled in a Japanese multicenter observational registry between 2011 and 2020 were included. EORA was defined as RA with onset at 60 or over. To adjust confounding by indication for treatment with TNFi or IL-6i, a propensity score based on multiple baseline characteristics variables was used to compare the drug retention and causes for discontinuation between TNFi and IL-6i. Adjusted cumulative incidence of drug discontinuation for each reason was compared between the two groups using the Fine-Gray model. Results Among a total of 9,550 patients in the registry, 674 TNFi and 297 IL-6i initiators with EORA were identified. Age, the proportion of females, disease duration, and baseline disease activity at the time of TNFi or IL-6i initiation were similar between the two groups. After adjusting for differences in baseline characteristics between the two groups, overall drug discontinuation was significantly lower in the IL-6i as compared to the TNFi (HR = 0.71, 95%CI = 0.59–0.86, p p p = 0.28) or achievement of clinical remission (HR = 1.09, 95%CI = 0.62–1.91, p = 0.76) were similar between the two groups. Conclusions In EORA patients initiating a TNFi or IL-6i, significantly higher drug retention was observed with IL-6i. Discontinuation due to lack of effectiveness was significantly less frequent in IL-6i while discontinuations due to adverse event or achievement of clinical remission were similar between the two groups.

BACKGROUND Considering the physiological changes in serum procalcitonin (PCT) levels in newborns due to age, we recently established an age-specific percentile-based reference curve for serum PCT level. The present study aimed to determine the best cutoff percentile line using this reference curve for the differentiation between infected and colonized preterm infants. METHODS A total of 52 preterm infants with positive bacterial culture (9 with bacterial infection, 43 with colonization) were enrolled within the study period. The 97.5th, 95.0th, 92.5th, 90.0th, 80.0th, 70.0th, 60.0th, and 50.0th percentile lines were drawn in the reference curve. PCT levels in infected or colonized infants were used, and sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were calculated. The best cutoff percentile line was determined in the receiver operating characteristic curve analysis. RESULTS Of the 52 preterm infants, 9 were infected (5 and 4 infants with an onset of < 7 days and ≥ 7 days after birth, respectively), whereas 43 were colonized (6 and 37 infants with an onset of < 7 days and ≥ 7 days after birth, respectively). The best cutoff percentile lines were the 90.0th percentile (sensitivity, 0.800; specificity, 0.833; PPV, 0.800; NPV, 0.833) and 97.5th percentile (sensitivity, 1.00; specificity, 0.973; PPV, 0.800; NPV, 1.00) in infants with an onset of < 7 days and ≥ 7 days after birth, respectively. CONCLUSIONS The age-specific percentile-based reference curve for serum PCT level is clinically applicable as a new tool for diagnosing infections in preterm infants with positive culture results, particularly at ≥ 7 days after birth.

The t(10;17)(p15;q21) translocation is a very rare but recurrent cytogenetic aberration in acute myeloid leukemia (AML), which would be classified as AML, not otherwise specified by World Health Or...

The purpose of this study was to investigate associations between right ventricular (RV) function and left ventricular (LV) diastolic function in patients with reduced LV ejection fraction (LVEF) and preserved LVEF. A total of 139 patients who had undergone echocardiography were recruited. LV diastolic function was determined as the ratio of mitral inflow E to mitral e′ lateral annular velocities (E/e′). RV function was determined as the RV index of myocardial performance (RIMP). Patients were divided into two groups: the preserved LVEF group (n = 100, LVEF ≥ 50%) and the reduced LVEF group (n = 39, LVEF

Background One of the main complications in patients with muscular dystrophies is cardiac dysfunction. The literature on cardiac involvement in patients with Fukuyama congenital muscular dystrophy (FCMD) is limited. Aim To compare cardiac involvement between patients with FCMD and Duchenne muscular dystrophy (DMD). Methods We compared cardiac involvement between 30 patients with FCMD and 181 patients with DMD using echocardiography and serum biomarkers. All patients were receiving regular checkups at Kobe University Hospital. We used single regression analysis to compare echocardiographic parameters, age, and serum biomarkers. Results Almost all clinical and echocardiographic parameters were lower in patients with FCMD than DMD. The brain natriuretic peptide concentration in patients with FCMD showed no correlation with age or left ventricular ejection fraction ( r = 0.231, p = 0.22 and r = 0.058, p = 0.76, respectively). A log-rank test revealed that the risk of left ventricular systolic dysfunction was lower in patients with FCMD than DMD ( p = 0.046, hazard ratio = 0.348). Conclusion The clinical progression of cardiac dysfunction is significantly milder in patients with FCMD than DMD, while skeletal muscle involvement is significantly worse in patients with FCMD. These data suggest that the pathophysiological findings of FCMD can be explained by less severe cardiac dysfunction in FCMD than DMD.

A 78-year-old female with massive pericardial effusion fulfilled diagnostic criteria for immunoglobulin G4 (IgG4)-related disease. Although her adenosine deaminase (ADA) level in the pericardial effusion was high, all the tests for tuberculosis infection were negative. Immunostaining of the pericardium biopsy specimen revealed remarkably increased IgG4-positive cells. This is the first report describing IgG4-related pericarditis with elevated ADA level. We also demonstrate the elevated interleukin-10 (IL-10) level in pericardial fluid and IL-10-producing T-cells in the pericardium.

BackgroundOur aim was to determine whether the postnatal age or postmenstrual age is a more appropriate criterion for evaluating foetal haemoglobin concentrations.MethodsBlood samples ( n = 1095) were obtained from 394 infants and were divided into two groups based on gestational age at birth: ResultsIn samples from infants ≥37 weeks’ gestational age at birth, the median foetal haemoglobin concentrations were 69.5%, 21.4% and 3.6% at 0–1 month, 2–3 months and ≥5 months after birth, respectively. The median foetal haemoglobin concentrations in infants 13 months after last menstruation in infants ≥37 and ConclusionsEvaluation of foetal haemoglobin concentrations at postmenstrual age is unaffected by gestational age at birth.

Purpose To evaluate the incidence of fragility fractures associated with high-dose glucocorticoid therapy in patients with systemic rheumatic disease. Methods: A retrospective study of patients who were treated with high-dose prednisolone (> 0.8 mg/kg) for systemic rheumatic disease at Kobe University Hospital from April 1988 to March 2012. The primary outcome was a major osteoporotic fracture (defined as a clinical vertebral, hip, forearm, or proximal humerus fracture) after high-dose glucocorticoid therapy. For postmenopausal women and men over 40 of age, the patient's fracture risk at the beginning of high-dose glucocorticoid therapy was assessed by the World Health Organization's Fracture Risk Assessment Tool (FRAX®). Results Of 229 patients (median age: 49 years), 57 suffered a fragility fracture during the observation period (median observation period: 1558 days). Of 84 premenopausal patients, 5 suffered a fracture. In contrast, of 86 postmenopausal female, 36 suffered a fracture. Fragility fractures were far more frequent than predicted by the FRAX® score. Patients with FRAX® scores over 8.3% had a particularly high risk of fracture. Conclusions Fragility fractures associated with high-dose glucocorticoid therapy are common among postmenopausal women. Extreme care should be taken especially for postmenopausal women when high-dose glucocorticoid therapy is required., Highlights • We evaluated the incidence of the fragility fractures associated with high-dose glucocorticoid therapy. • Of 86 postmenopausal female, 36 suffered a fracture during the observation period. • Patients with FRAX scores over 8.3% had a particularly high risk of fracture.

Background Anti-TIF1gamma antibody positive dermatomyositis(TIF1γ-DM) has greater risk of complication with cancer. Objectives We aimed to analyze the clinical features of TIF1γ-DM and find the difference between cancer-associated TIF1γ-DM (CA-TIF1γ-DM) and non-cancer-associated TIF1γ-DM (nCA-TIF1γ-DM). Methods We investigated the clinical data of idiopathic inflammatory myositis (IIM) patients received remission induction therapy in out hospital between January 2006 and December 2018. Results We treated 148 patients with IIM in this period, 9 cases of them were TIF1γ-DM. Patients with CA-TIF1γ-DM and nCA-TIF1γ-DM were 4 and 5 cases, respectively. Average age at onset of 9 patients with TIF1γ-DM was 63 years old. CA-TIF1γ-DM was significantly older than nCA-TIF1γ-DM (average:78.0 vs 57.4). All of 9 TIF1γ-DM had distinctive skin rash and muscle weakness. Seven cases of them suffered from dysphagia. Interstitial lung disease was not seen in all patients with TIF1γ-DM. Serum creatine kinase (CK) levels of CA-TIF1γ-DM was significantly higher than those of nCA-TIF1γ-DM (average: 3405.5IU/L vs 719.8IU/L) (Fig 1.). Among the TIF1γ-DM patients, we administered glucocorticoid (GCs) for 8 cases, immunosuppresants for 4 cases, and intravenous immunoglobulins (IVIG) for 7 cases. All 4 cases of CA-TIF1γ-DM were treated with GC and IVIG. All TIF1γ-DM patients, especially 4 CA-TIF1γ-DM patients, seemed to have good response to treatment in serum CK levels. Although serum CK levels of these 4 cases were normalized within a month (Fig1.), their muscle weakness, skin rash and dysphagia which was associated with quality of life and the prognosis were poorly improved. Conclusion In our investigation, the age of onset and serum CK levels were significantly different between CA-TIF1γ-DM and nCA-TIF1γ-DM. We report our investigation of the phenotype and treatment of anti TIF1gamma antibody positive dermatomyositis. TIF1γ-DM with high serum CK levels, we should perform appropriate tests to check for cancer throughout our treatment, and the improvement of serum CK levels is not equal to the success of our treatment. Disclosure of Interests None declared

Rationale: Immunoglobulin G4 related disease (IgG4-RD) rarely coexists with other autoimmune diseases, though we had a patient whose primary clinical problem was shifted from IgG4-RD to systemic lupus erythematosus (SLE) after gastrectomy. The present paper aimed to report pathological findings and clinical course of the patient. Patient concerns: The patient was a male aged 74 years old with gastric cancer characterized by the following symptoms: Raynaud phenomenon, polyarthralgia, and swollen parotid glands on both sides. Before gastrectomy, laboratory examination results showed renal dysfunction, hypocomplementemia, antinuclear antibodies (ANAs) positivity, and elevated serum IgG and IgG4 levels. Diagnosis: Based on postoperative renal biopsy showing severe plasma cell infiltration with tubulointerstitial fibrosclerosis, the patient was diagnosed with IgG4-RD. Despite significant improvement in renal function and reduction in parotid gland swelling during the postoperative follow-up period, after 7 months of the gastrectomy, anti-DNA antibody levels were increased and serositis was detected, which indicated the onset of SLE. IgG4-type ANA were also detected in the sera of the patient. Interventions: Treatment by oral prednisolone at 30 mg/day was initiated. Outcomes: Pericardial fluid, pleural effusions, and thickening of the gallbladder wall improved after 3 months of treatment according to computed tomography. Lessons: This study presented a rare case of comorbidity, wherein the patient's primary problem progressed from IgG4-type ANA positive IgG4-RD to SLE after excision of gastric cancer. Abbreviations: ANAs = antinuclear antibodies, Cr = creatinine, CT = computed tomography, IgG4-RD = immunoglobulin G4-related disease, IgG4-RKD = immunoglobulin G4-related kidney disease, PSL = prednisolone, SLE = systemic lupus erythematosus.

Background Systemic sclerosis (SSc) is a chronic autoimmune-mediated connective tissue disorder. Although the etiology of the disease remains undetermined, SSc is characterized by fibrosis and proliferative vascular lesions of the skin and internal organs. SSc involves the gastrointestinal tract in more than 90 % of patients. Soluble guanylate cyclase (sGC) stimulator is used to treat pulmonary artery hypertension (PAH) and has been shown to inhibit experimental skin fibrosis. Methods Female C57BL/6J mice were treated with BLM or normal saline by subcutaneous implantation of osmotic minipump. These mice were sacrificed on day 28 or day 42. Gastrointestinal pathologies were examined by Masson Trichrome staining. The expression of fibrosis-related genes in gastrointestinal tract was analyzed by real-time PCR, and the levels of collagen in the tissue were measured by Sircol collagen assay. To evaluate peristaltic movement, the small intestinal transport (ITR%) was calculated as [dyeing distance × (duodenum − appendix)] − 1 × 100 (%). We treated BLM-treated mice with sGC stimulator or DMSO orally and analyzed them on day 42. Results Histological examination revealed that fibrosis from lamina propria to muscularis mucosa in the esophagus was significantly increased in BLM-treated mice, suggesting that BLM induces esophageal hyperproliferative and prefibrotic response in C57BL/6J mice. In addition, the gene expression levels of Col3a1, CCN2, MMP-2, MMP-9, TIMP-1, and TIMP-2 in the esophagus were significantly increased in BLM-treated mice. More severe hyperproliferative and prefibrotic response was observed in the mice sacrificed on day 42 than the mice sacrificed on day 28. The ITR% was found to be significantly lower in BLM-treated mice, suggesting that gastrointestinal peristaltic movement was reduced in BLM-treated mice. Furthermore, we demonstrated that sGC stimulator treatment significantly reduced hyperproliferative and prefibrotic response of esophagus and intestine in BLM-treated mice, by histological examination and Sircol collagen assay. Conclusions These findings suggest that BLM induces gastrointestinal hyperproliferative and prefibrotic response in C57BL/6J mice, and treatment with sGC stimulator improves the BLM-induced gastrointestinal lesion.

Previous studies from various countries have reported anti-dense fine speckled pattern (DFS)70 antibody prevalence but few studies have been from Asia. We investigated the prevalence of anti-DFS70 autoantibodies in a Japanese cohort of healthy individuals (HI) and patients with antinuclear antibody-associated autoimmune rheumatic diseases (AARD). Enzyme-linked immunosorbent assay and indirect immunofluorescence were performed using samples from 250 HI and 276 AARD patients. The overall anti-DFS70 antibody prevalence in HI was 16.4%, with 12.8% for males and 20.0% for females (sex difference; P = .12). In AARD patients, the anti-DFS70 antibody prevalence in systemic lupus erythematosus, mixed connective tissue disease, systemic sclerosis, dermatomyositis and polymyositis (DM/PM), Sjögren syndrome, and rheumatoid arthritis (RA) was 22.1%, 14.3%, 14.3%, 3.0%, 21.3%, and 18.1%, respectively (no significant difference between AARD patients except DM/PM and HI). The prevalence of isolated anti-DFS70 antibody in HI and all AARD patients excluding RA was 14.8% (37/250) and 4.4% (9/204), respectively (P

Background:Systemic lupus erythematosus (SLE) patients present with variable clinical features ranging from mild joint and skin involvement to life-threatening organ involvement such as nephritis, neuropsychiatric involvement, diffuse alveolar hemorrhage, and hemophagocytic lymphohistiocytosis (HLH). HLH is rare, but fatal complication of SLE. Recently, European League Against Rheumatism, the American College of Rheumatology, and the Pediatric Rheumatology International Trials Organization was to develop a set of classification criteria for MAS complicating systemic juvenile idiopathic arthritis (PRINTO criteria) [1]. Sung Soo Ahn and his colleagues reported PRINTO criteria predicted mortality of adult SLE patient, but they followed only one year [2].Objectives:To reveal association PRINTO criteria with long term mortalities in SLE patient in our Hospital.Methods:We performed a retrospective analysis of SLE patients who received moderate dose glucocorticoid therapy (>0.4mg/kg/d) in our hospital between April 2008 and April 2019. Patients were evaluated for HLH using the 2016 PRINTO classification criteria for MAS. Clinical features and laboratory findings were compared and overall survival rate was analyzed.Results:Among 164 episode (144 patients) with SLE, 31 episode (31 patients) 5.2% were considered to have MAS on admission.The overall survival rate was significantly lower in patients with MAS than without MAS (86.2% vs. 95.3%, p = 0.048). Interestingly, SLEDAI had no association with mortality, relapse rate, and MAS complication. SLEDAI more focused on renal and neuropsychiatric symptoms than hematologic features. So SLEDAI might not be associated with MAS secondary to SLE. Furthermore, we observed no death patient with MAS after one year, and only 1 case relapse in MAS patient. So MAS might have fatal but less relapsing property compared with other lupus cases.Conclusion:PRINTO criteria may be useful to differentiated fatal MAS patients from others. Further investigations are required to confirm our findings.Limitation The main limitations of our study include its retrospective design, single center site, and that the number of admitted patients with SLE was small.Limitation:The main limitations of our study include its retrospective design, single center site, and that the number of admitted patients with SLE was small.Limitation:Limitation The main limitations of our study include its retrospective design, single center site, and that the number of admitted patients with SLE was small.References:[1]Wulffraat N, Schneider R, Filipovic L, et al. 2016 Classification Criteria for Macrophage Activation Syndrome Complicating Systemic Juvenile Idiopathic Arthritis. Ann Rheum Dis 2016;75:481–9.[2]Ahn SS, Yoo BW, Jung SM, et al. In-hospital mortality in febrile lupus patients based on 2016 EULAR/ACR/PRINTO classification criteria for macrophage activation syndrome. Semin Arthritis Rheum 2017;47:216–21.Disclosure of Interests:None declared

Background: Vagus nerve (VN) stimulation has shown the potential to improve the disease development in animal models of arthritis and in patients with RA. However, the VN can affect respiratory, cardiovascular, endocrine and gastro-intestinal physiology. The splenic nerve (SpN) has been confirmed to be the principal effector nerve for the VN-mediated immune control. Previous studies have shown that stimulating the splenic nerve resulted in an increase of norephiniphrine in the spleen, as well as a significant reduction in LPS-induced TNF (1). Objectives: To test the therapeutic efficiency of splenic nerve stimulation (SNS) in collagen-induced arthritis (CIA) in mice alone or in combination with anti-TNF treatment. Methods: CIA was induced in DBA1/J mice by immunization with bovine type II collagen at days 0 and 21. At day 11, mice were implanted with micro-cuff electrode (CorTec) onto the SpN or VN. From day 16 to day 45, SNS were applied as rectangular charged-balanced biphasic pulses with 650 μA pulse amplitude, 200 µs pulse width at 10 Hz frequency for 2 min 1 or 6 times a day using a Plexon stimulator. In order to investigatedthe mechanism of action in more detail, propranolol, a beta-adrenergic receptor (β-AR) antagonist, was added to the drinking water of mice receiving SNS. In addition, a control group was treated with anti-TNF (etanercept, 3 times/week; 10mg/kg i.p.). In curative settings, SNS and/or anti-TNF treatment was applied starting when mice scored positive for 3 consecutive days. Clinical arthritis was determined by visual examination of swelling and redness of the paws and measurement of paw thickness. Sham mice were undergoing the same procedure but did not receive stimulation. Results: In CIA in mice all sham animals developed arthritis, compared to only 14% following six times per day SNS (p Conclusion: These studies demonstrate that SNS suppresses pro-inflammatory cytokine production, and reduces clinical symptoms in mice with CIA which is at least partially mediated by the β-AR. The additive effect of anti-TNF in reducing the clinical scores demonstrates that that mechanism of action of SNS is not primarilys mediated by reducing TNF levels. Moreover, anti-TNF potentiating the inhibitory effect of SNS is supporting a combined use of these treatments, or even a combination of SNS with other biologicals, to treat RA, potentially getting more patients closer to remission. In conclusion, the data is providing compelling scientific rationale and pre-clinical evidence that splenic neuromodulation might be a new treatment modality for RA. References: [1] Guyot M et al, Brain Behav Immun. 2019;80:238. Disclosure of Interests: Thomas Simon Grant/research support from: research grant from Galvani Bioelectronics, Clara Panzolini Grant/research support from: Working on research grant Galvani bioelectronics, Julien Lavergne Grant/research support from: working on research grant Galvani Bioelectrocnics, Nicolas Hypolite Grant/research support from: Working on research grant Galvani Bioelectronics, Nicolas Glaichenhaus: None declared, Margriet Vervoordeldonk Employee of: I am an employee of Galvani Bioelectronics, Philippe Blancou Grant/research support from: Received research grant from Galvani Bioelectronics

Background:Resolution phase of acute inflammation has been recognized not passive but active process during the last 2 decades. This active process is highly regulated by novel families of potent bioactive lipid mediators, which are coined as specialized proresolving mediators (SPMs) including resolvins. Little has been known, however, about how resolvins are involved in chronic inflammation, such as rheumatoid arthritis (RA).Objectives:To investigate whether lipid mediators (LM) are involved in the pathogenesis of RA.Methods:We investigated lipid mediator profiling in the paws of SKG arthritis mice by using lipid chromatography (LC) /mass spectrometry (MS) /MS-based LM metabololipidomics. CD4+T cells from spleens of SKG mice were cultured on anti-CD3/ CD28Abs precoated plate with IL-6/TGF-β, anti-IFNγ/IL-4 and analyzed by flow cytometry. CD4+T cells were labeled with CFSE, and cell proliferation was analyzed by flow cytometry. Mouse bone marrow cells were cultured with M-CSF and RANKL, and TRAP-positive multinucleated cells were defined as osteoclasts. Osteoclast differentiation markers were analyzed by qRT-PCR. RvD5 or normal saline was administered daily into the peritoneal cavity of arthritic SKG mice.Results:RvE3, RvD1, RvD3, RvD5 and Maresin2 were significantly elevated on the paws of arthritic SKG mice. Among the elevated SPMs, only RvD5 levels on arthritic paws were significantly correlated with arthritis disease activity (Figure 1). We demonstrated that RvD5 suppressed Th17 cell differentiation, and facilitated Treg cell differentiationin vitro. In addition, RvD5 inhibited CD4+T cell proliferation. Furthermore, RvD5 attenuated osteoclast differentiation (Figure 2) and interfered osteoclastogenesis at the molecular level. In thein vivoexperiment, incidence of arthritis tended to be lower in RvD5-treated mice than that in control group, although there was no significant difference.Conclusion:RvD5 is increased in the paws of arthritic mice, and that RvD5 suppresses Th17 cell differentiation and CD4+T cell proliferation, facilitates Treg cell differentiation, and suppresses osteoclastogenesis.References:[1]Serhan, C. N. 2014. Pro-resolving lipid mediators are leads for resolution physiology. Nature 510: 92-101.[2]Buckley, C. D., Gilroy, D. W., Serhan, C. N. 2014. Proresolving lipid mediators and mechanisms in the resolution of acute inflammation. Immunity 40: 315-27.[3]Colas, R. A., Shinohara, M., Dalli, J., Chiang, N., Serhan, C. N. 2014. Identification and signature profiles for pro-resolving and inflammatory lipid mediators in human tissue. Am J Physiol Cell Physiol 307: C39-54.Acknowledgments:The authors thank Shino Natsui (Department Rheumatology and Clinical Immunology, Kobe University Graduate School of Medicine) for providing technical assistance.Disclosure of Interests:None declared

Background:Systemic scleroderma (SSc) is a chronic autoimmune-mediated connective tissue disorder. Although the etiology of the disease remains undermined, SSc is characterized by fibrosis and proliferative vascular lesions of the skin and internal organs. SSc involves the gastrointestinal tract in more than 90% of patients1. Soluble guanylate cyclase (sGC) is used to treat pulmonary artery hypertension (PAH), and has been shown to inhibit experimental skin fibrosis2.Objectives:The aim of this study is to investigate whether bleomycin (BLM)-treated mice show gastrointestinal fibrosis, and find a therapeutic strategy to the lesion.Methods:Female C57BL/6J mice were treated with BLM or normal saline by subcutaneous implantation of osmotic minipump. These mice were sacrificed on day 28 or day 42. Gastrointestinal pathologies were examined by Masson Trichrome staining. The expression of fibrosis-related genes in gastrointestinal tract were analyzed by real-time PCR, and the levels of collagen in the tissue was measured by Sircol collagen assay. To evaluate peristaltic movement, the small intestinal transport (ITR%) was calculated as [Dyeing distance×(Duodenum- Appendix)] -1 ×100 (%). We treated BLM-treated mice with soluble guanylate cyclase (sGC) or DMSO orally and analyzed them on day 42.Results:Histological examination revealed that fibrosis from lamina propria to muscularis mucosa in the esophagus was significantly increased in BLM-treated mice, suggesting that BLM induces esophageal fibrosis in C57BL/6J mice. In addition, the levels of Col3a1 and CTGF were significantly increased in BLM-treated mice. More severe fibrosis was observed in the mice sacrificed on day 42 than the mice sacrificed on day 28. The ITR% was found to be significantly lower in BLM-treated mice, suggesting that gastrointestinal peristaltic movement was reduced in BLM-treated mice. Furthermore, we demonstrated that sGC treatment significantly reduced fibrosis of esophagus and intestine in BLM-treated mice, by histological examination and Sircol collagen assay.Esophagus (Masson’s trichrome stain×100)* One way ANOVA Newman-KeulsConclusion:These findings suggest that BLM induces gastrointestinal fibrosis in C57BL/6J mice, and treatment with sGC improves the BLM-induced gastrointestinal lesion.References:[1]Anton Emmanuel. Current management of the gastrointestinal complications of systemic sclerosis. Nat Rev Gastroenterol Hepatol. 2016; 13: 461-472.[2]Clara Dees, et al. Stimulators of Soluble Guanylate Cyclase (sGC) Inhibit experimental Skin Fibrosis of Different Aetiologies. Ann Rheum Dis. 2015;74 (8): 1621-5.Acknowledgments: :None.Disclosure of Interests:None declared

Objectives Biologic treatment has recently revolutionized the management of RA. Despite this success, ∼30–40% of the patients undergoing biologic treatment respond insufficiently. The aim of this study was to identify several specific reliable metabolites for predicting the response of RA patients to TNF-α inhibitors (TNFi) and abatacept (ABT), using capillary electrophoresis-time-of-flight mass spectrometry (CE-TOFMS). Methods We collected serum from RA patients with moderate or high disease activity prior to biologic treatment, and obtained the serum metabolomic profiles of these samples using CE-TOFMS. The patients' response was determined 12 weeks after starting biologic treatment, according to the EULAR response criteria. We compared the metabolites between the response and non-response patient groups and analysed their discriminative ability. Results Among 43 total patients, 14 of 26 patients in the TNFi group and 6 of 17 patients in the ABT group responded to the biologic treatment. Of the metabolites separated by CE-TOFMS, 196 were identified as known substances. Using an orthogonal partial least-squares discriminant analysis, we identified five metabolites as potential predictors of TNFi responders and three as predictors of ABT responders. Receiver operating characteristic analyses for multiple biomarkers revealed an area under the curve (AUC) of 0.941, with a sensitivity of 85.7% and specificity of 100% for TNFi, and an AUC of 0.985, with a sensitivity of 100% and specificity of 90.9% for ABT. Conclusion By metabolomic analysis, we identified serum biomarkers that have a high ability to predict the response of RA patients to TNFi or ABT treatment.

Background Polymyositis/dermatomyositis (PM/DM) is a chronic autoimmune disease that is often complicated by interstitial lung disease (ILD). Anti-aminoacyl-transfer RNA synthetase antibody (ARS-Ab) and anti-melanoma differentiation-associated gene 5 antibody (MDA5-Ab) are highly detected in PM/DM with ILD. It was reported that ARS-Ab-positive-ILD (ARS-ILD) is often recurrent1, and patients with MDA5-Ab-positive-ILD (MDA5-ILD) develop fatal rapidly progressive ILD2. Objectives To evaluate the differences in clinical courses between ARS-ILD and MDA5-ILD, including the changes in serum ILD markers. Methods We retrospectively investigated 25 patients with ARS-ILD and 26 patients with MDA5-ILD who received induction therapy between April 2002 and September 2017 at Kobe University Hospital. The survival rate and relapse-free survival rate were analysed with Kaplan-Meier estimation and the log-rank test. The differences in serum ILD markers between patients with ARS-ILD and MDA5-ILD were evaluated with the Student’s t-test. Results Disease subtypes at diagnosis with PM/DM-associated ILD were as follows: Eleven ARS-ILD and no MDA5-ILD patients had PM, 10 ARS-ILD and 5 MDA5-ILD patients had DM, and 4 ARS and 21 MDA5 patients had amyopathic DM. The survival rate for MDA5-ILD was significantly lower than that for ARS-ILD (p Conclusions MDA5-ILD patients should monitored for both rapidly progressive disease and relapsing disease. A normal SP-D level is a feature of MDA5-ILD. References [1] Nakazawa M, Kaneko Y, Takeuchi T. Risk factors for the recurrence of interstitial lung disease in patients with polymyositis and dermatomyositis: a retrospective cohort study. Clin Rheumatol2017. Epub ahead of print. [2] Hozumi H, Fujisawa T, Nakashima R, et al. Comprehensive assessment of myositis-specific autoantibodies in polymyositis/dermatomyositis-associated interstitial lung disease. Respir Med2016;121:91–9. Acknowledgements none. Disclosure of Interest None declared

Background Some experimental models suggested bacterial infection, such as periodontal disease and gut microbiota, might be an inciting and aggravating factor in rheumatoid arthritis (RA)1. Moreover, medications that have an antibacterial effect such as minocycline and sulfasalazine are used as DMARDs. However, the antibacterial effect itself on disease activity are unknown in patients with RA whereas trimethoprim-sulfamethoxazole (TMP-SMX) is often used for Pneumocystis jirovecii pneumonia (PCP) prophylaxis because PCP is a prevalent and potentially life-threatening opportunistic infection among patients with RA, especially in Japan2.3. Objectives To identify the effect of TMP-SMX on disease activity in patients with RA in a multi-center cohort study (ANSWER cohort study). Methods RA patients with a sampling interval of less than 1 year and at least two assessment of disease activity were enrolled. Disease activity was assessed using disease activity score 28-CRP (DAS28-CRP). Linear mixed effect models were used to evaluate the trajectories of disease activity in RA patients. Time from baseline, TMP-SMX administration, and their interaction were included as fixed effects while participant identification number and time from baseline were included as random factors. Age, sex, disease duration, RF, ACPA, HAQ, and DMARDs were included as covariates. Results A total of 49878 samples (mean sampling interval: 49 days) from 3255 patients was included. The median age at baseline was 64.0 years (interquartile range, 53.0 to 71.0 years) with 78.2 % of women (ACPA positivity, 79.2%; RF positivity, 70.8 %). The median DAS28-CRP was 2.83 with 33.8 % of patients taking TMP-SMX at baseline. Patients with taking TMP-SMX had a significantly but minimally better longitudinal trajectory on disease activity than patients without (-0.00012/month, P=0.009). This result was similar even when patients taking sulfasalazine were excluded from analysis. Conclusions TMP-SMX has minimal impact on disease activity, and therefore clinical utility of TMP-SMX for controlling disease besides PCP prophylaxis is limited. These results did not support a theoretical effect of bacterial infection on disease activity in RA, although the effect of the other antibiotics on disease activity should be examined. References: [1] Roszyk E, Puszczewicz M. Role of human microbiome and selected bacterial infections in the pathogenesis of rheumatoid arthritis. Reumatologia 2017;55:242-50. [2] Galli M, Antinori S, Atzeni F, et al. Recommendations for the management of pulmonary fungal infections in patients with rheumatoid arthritis. Clin Exp Rheumatol 2017;35:1018-28. [3] Harigai M, Koike R, Miyasaka N, et al. Pneumocystis pneumonia associated with infliximab in Japan. N Engl J Med 2007;357:1874-6. Acknowledgements: None. Disclosure of Interest: None declared

Background Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population of immature cells that increase in the pathological state such as tumour or inflammation and have the immunosuppressive ability. MDSCs have been reported to ameliorate arthritis in several mice models. Mechanistic target of rapamycin (mTOR) pathway and glutaminolysis activate cooperatively in the differentiation from myeloid progenitors to mature myeloid cells such as dendritic cells, macrophages, or osteoclasts as well as the activation of effector T cells and the differentiation of Th1 and Th17 cells. Although rapamycin has reported to facilitate the expansion of MDSCs and their immunosuppressive ability, the effect of the inhibitor of glutaminolysis on MDSCs is still unknown. Objectives The aim of this study is to evaluate the facilitative effects of the inhibition of mTOR pathway and glutaminolysis on MDSCs in a mouse model of rheumatoid arthritis. Methods Bone marrow (BM) cells from untreated Balb/c mice were cultured for 5 days under granulocyte–macrophage colony-stimulating factor (GM-CSF) stimulation with four patterns of drugs; 1) DMSO (control), 2) rapamycin (Rapa), 3) 6-Diazo-5-oxo-l-norleucine (DON; a glutamine antagonist), or 4) the combination of rapamycin and DON (Rapa +DON). Cultured BM cells were analysed by flow cytometry. Cultured MDSCs were isolated by manual MACS and analysed their immunosuppressive characters by co-culture with CFSE-dyed CD4+ T cells. Rapa or Rapa +DON were administered intraperitoneally to arthritic SKG mice induced by Zymosan A injection. Results We found that DON suppressed the differentiation of dendritic cells (DC) in a dose-dependent manner and the addition of Rapa on DON inhibited the differentiation of macrophages in vitro. The proportions of the phenotype of MDSCs were increased with administrations of Rapa or DON, and large part of them were Ly6G+ cells (the phenotype of polymorphonuclear MDSCs; PMN-MDSCs). Rapa ±DON significantly increased the expressions of TGF-β and PD-L1 and the inhibitory capacity of Ly6G+ PMN-MDSCs. Rapa +DON significantly suppressed arthritis more efficiently in SKG mice than Rapa in vivo. (see figure 1) Conclusions The combination of rapamycin and a glutamine antagonist facilitates the expansion of PMN-MDSCs in vitro and ameliorates arthritis in SKG mice in vivo. Disclosure of Interest None declared

Objective Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population of cells that have the ability to suppress T cell responses. The aim of this study was to evaluate the effects of the JAK inhibitor tofacitinib on MDSCs in a mouse model of rheumatoid arthritis. Methods Arthritis was induced in SKG mice by zymosan A (ZyA) injection. MDSCs isolated from the bone marrow (BM) of donor SKG mice with arthritis were adoptively transferred to recipient mice with arthritis. In a separate experiment, tofacitinib was administered to arthritic SKG mice subcutaneously via osmotic pump, in some cases followed by injection of an anti–Gr-1 monoclonal antibody (mAb). BM cells from untreated mice were cultured for 5 days with granulocyte–macrophage colony-stimulating factor, with or without tofacitinib, and then analyzed by flow cytometry. Results The numbers of MDSCs and polymorphonuclear MDSCs (PMN-MDSCs) were significantly increased in the spleens of SKG mice following ZyA injection. Adoptive transfer of MDSCs to recipient arthritic mice reduced the severity of arthritis compared to that in untreated control mice. Treatment with tofacitinib also ameliorated the progression of arthritis in SKG mice and induced significantly higher numbers of MDSCs and PMN-MDSCs in the BM of these animals. Furthermore, administration of an anti–Gr-1 mAb reduced the antiarthritic effect of tofacitinib in SKG mice. In vitro, tofacitinib facilitated the differentiation of BM cells to MDSCs, and inhibited their differentiation to dendritic cells. Conclusion Tofacitinib facilitates the expansion of MDSCs and ameliorates arthritis in SKG mice.

ETV6–ABL1 fusion is a rare but recurrent oncogenic lesion found in childhood B-cell precursor acute lymphoblastic leukemia (BCP-ALL), without an established chromosomal abnormality, and is associated with poor outcome. In ETV6–ABL1-positive cases, an in-frame fusion produced by a complex rearrangement results in constitutive chimeric tyrosine kinase activity. Monosomy 7 is also a rare and unfavorable chromosomal abnormality in childhood BCP-ALL. Here, we report a 14-year-old female BCP-ALL patient with ETV6–ABL1 fusion combined with monosomy 7. She was admitted to our hospital because of persistent fever. Bone marrow nuclear cell count on admission was 855,000/µL with 90.0% blastic cells of lymphoid morphology. Blasts were positive for CD10, CD19, CD20, CD34, cyCD79a, cyTdT, HLA-DR, and CD66c, had a karyotype of 45, XX, − 7 [18/20] and a split signal for ABL1 FISH probe (92.7%), and were sensitive to tyrosine kinase inhibitors, imatinib and dasatinib, in vitro. ETV6–ABL1 fusion transcript was identified by whole transcriptome sequencing and confirmed by RT-PCR. She was treated with the high-risk protocol based on ALL-BFM 95, achieved complete remission (CR) after induction chemotherapy, and maintained CR for 4 months. To our knowledge, this is the first report of ETV6–ABL1 fusion combined with monosomy 7 in childhood BCP-ALL.

Background Patient9s global assessment (PtGA) is one of the most widely used patient reported outcomes in rheumatoid arthritis (RA) that reflects both disease activity and other factors. PtGA is onymous and obtained at hospital, which may cause a conscious or unconscious bias, whereas PtGA obtained anonymously may be free from any bias. The credibility of PtGA to report RA patient outcomes has been usually investigated by assessing test-retest reliability. There has been no study comparing routine PtGA and PtGA where patients answered anonymously. Objectives The aim of this study was to compare routinely obtained in-hospital PtGA before clinical examination with those answered anonymously at home. Additionally, physician9s global assessment (PhyGA) was compared with routine PtGA and anonymized PtGA Methods We asked RA patients (n=389) to answer and mail the PtGA test anonymously, Clinical data regarding disease duration, stage, class, swollen joint counts, tender joint counts, pain visual analog scale (VAS), PhyGA, Health Assessment Questionnaire (HAQ), EuroQOL five dimensions questionnaire (EQ5D), Kessler 6 scale (anxiety/ depression), treatment data, laboratory data, and socioeconomic factors were collected simultaneously. We compared the PtGA that is routinely surveyed at hospital before clinical examination with those surveyed anonymously at home. We calculated a discrepancy score by subtracting anonymized PtGA from routine in-hospital PtGA. We defined (1) positive discrepancy when routine PtGA was over-rated relative to the anonymized PtGA; (2) negative discrepancy when routine in-hospital PtGA was under-rated relative to the anonymized PtGA. Results The anonymized PtGA score was higher than routinely evaluated in-hospital PtGA (p Conclusions Discrepancy exists between routine in-hospital PtGA and anonymized PtGA. The high pain VAS scale and low QOL are risk factors that could make the difference between routine PtGA from anonymized PtGA. There is a possibility that high pain VAS score and low QOL influence the reliability of PtGA. Disclosure of Interest None declared

Background Osteoporosis is one of the important adverse effects in the glucocorticoids treatment for the patients with rheumatoid arthritis (RA) and connective tissue diseases (CTDs). Although the usefulness of denosmab for primary osteoporosis has been well-established, the efficacy for GIOP remains unclear. Objectives This study aimed to clarify the therapeutic effects of denosumab for GIOP. Methods We evaluated bone mineral density (BMD) and serum markers of bone metabolism (BAP, NTx, TRACP-5b and P1NP) of patients who had been treated with over 5mg of predonisolone for RA and CTDs, and denosumab for GIOP, for two years in Kobe University Hospital. BMD and serum markers were evaluated every six months for 2 years from the baseline. The changes of those data from baseline were analyzed by Student9s t test using GraphPad Prism 5 software and p Results Number of the patients were 53 (male: 4 cases, female: 49 cases), and their characteristics at the beginning of denosumab treatment were as below; age: 64.19±12.0 years old, dose of prednisolon: 10.59±9.97mg/day, BMD of lumber spine: 0.768±0.112g/cm3, T-score of lumber spine: -2.28±1.01, BMD of femoral neck: 0.540±0.085g/cm3, T-score of femoral neck: -2.28±0.76. After 2-years denosumab treatment, T-scores of lumber spine (0.54±0.39 gain) and femoral neck (0.13±0.26 gain) were significantly increased from baseline (Figure; mean ± SEM. *:p Conclusions Denosumab can suppress bone metabolic turnover, and increase lumber spine and femoral neck T-scores of GIOP patients. Disclosure of Interest None declared

Background Behcet9s disease is a systemic vasculitis disease with oral and genital aphthous ulcers, ocular involvements, skin manifestations, arthritis, gastrointestinal manifestations, neurogenic diseases and vascular involvements. Patients with Behcet9s disease are known to distribute along the ancient Silk Road, including Japan. Objectives We evaluate the clinical features of Behcet9s disease in Japan. Methods We retrospectively investigated 223 patients (108 males and 115 females) who fulfilled the International Criteria for Behcet9s Disease (ICBD) from January, 2006 until May, 2015.We examined sex, onset age, disease type, clinical symptoms, laboratory data and medications. Results Median age at diagnosis was 36.0±12.8 years old. Oral ulcers were the most common manifestation (98.2%), followed by genital ulcers (62.4%), ocular involvements (53.2%), erythema nodosum (53.2%), acneiform lesions (51.8%), arthritis (38.6%), gastrointestinal manifestations (25.1%), neurogenic diseases (9.0%), and vascular involvements (8.1%). The relationship of HLA and disease manifestations was studied in 123 patients (41.5% with HLA-B51 and 24.1% with HLA-A26). The frequency of acneiform lesions, ocular involvements and HLA-B51 was significantly higher in male, while genital ulcers and arthritis were significantly higher in female. Patients with ocular involvements showed a higher assosiation rate with neurogenic diseases and HLA-B51, and lower wih gastrointestinal manifestations. TNFα inhibitor (infliximab or adalimumab) were used for 66 cases (30%), and it could be continued for 1 year in 91%, and for 2 years in 83%. Conclusions A higher incidence of gastrointestinal manifestations was observed in patients with Behcet9s disease in Japan. Patients with ocular involvements showed a higher assosiation rate with neurogenic diseases, and lower wih gastrointestinal manifestation. Most patients could continue TNFα inhibitor safety and effectively. Disclosure of Interest None declared

Background Patients with RA have higher risk of developing chronic kidney disease compared to the general population. Although some causes of renal impairment in RA include nephrotoxic medications, amyloidosis, and glomerulonephritis, specific causes are not determined among most patients with RA. While experimental researches showed inflammatory process per se might also contribute to renal dysfunction, the results of previous clinical studies that assessed the effects of disease activity or C-reactive protein on renal function were inconsistent. This inconsistency might be attributable to their cross-sectional design, small sample size, and assessment of association between only baseline characteristics and renal outcomes without consideration for the fact that disease activity and medications had changed over time. Objectives To identify the effects of disease activity on renal function in RA in a multi-center cohort study. Methods RA patients with a sampling interval of less than 150 days were enrolled because wide sampling intervals could not take into consideration changes in disease activity and medications during their follow-up. An estimated glomerular filtration rate (eGFR) was calculated using an equation approved by the Japanese Society of Nephrology and used as an outcome variable. Linear mixed effect models were used to evaluate the renal trajectories of patients. Time from baseline (months), disease activity, and their interaction were included as fixed effects while participant identification number and time from baseline were included as random factors. Age, sex, disease duration, RF, ACPA, NSAIDs, and DMARDs that were known as a cause of renal impairment, such as tacrolimus, iguratimod, and tofacitinib, were included as covariates. Results A total of 25661 samples (mean sampling interval: 2.0 months) from 2104 patients was included. Patients with lower DAS28-CRP had worse renal function at inclusion, but a significantly better longitudinal trajectory on eGFR (0.0079 ml/min/1.73m2 per month, P=0.025). Although all RA patients had naturally progressive renal impairment as they got older, patients who achieved remission or low disease activity had slower renal impairment rate of -0.068 ml/min/1.73m2 per month compared to patients with moderate or high disease activity (-0.084 ml/min/1.73m2 per month; P=0.037). These results were also similar using SDAI or CDAI. Conclusions Lower disease activity results in slower renal impairment. Because the effects of disease activity on renal function are mild, additional measures to protect renal function, such as avoiding nephrotoxic medications and treating cardiovascular risk factors are important. Disclosure of Interest None declared

Background SKG mice develop interstitial lung disease (ILD) resembling human rheumatoid arthritis (RA)–associated ILD. We identified a unique cell population of CD11b + Gr1 dim cells in the severely inflamed lungs in SKG mice. Objectives The aims of this study are to clarify the mechanism behind the lung pathology, and to elucidate the phenotype and function of CD11b + Gr1 dim cells in ILD-induced SKG mice. Methods We assessed the severity of zymosan A-induced ILD in SKG mice histologically, and examined lung-infiltrating cells by Giemsa stain and flow cytometry. Total lung cells and isolated monocytic myeloid-derived suppressor cells (M-MDSCs) were cultured in vitro with GM-CSF (and IL-4). The proliferation of CSFE-labeled naive T cells co-cultured with isolated CD11b + Gr1 dim cells and MDSCs was evaluated by flow cytometry. Results MDSCs, Th17 cells, and group 1 and 3 innate lymphoid cells (ILC1s and ILC3s) were increased in the lungs; the proportion of these cells varied with ILD severity. In this process, we found that a unique cell population, CD11b + Gr1 dim cells, were expanded in the severely inflamed lungs (Figure). About half of the CD11b + Gr1 dim cells expressed CD11c and Giemsa stain revealed that they were morphologically dendritic cell (DC)-like. The CD11b + Gr1 dim cells were induced from M-MDSCs with GM-CSF in vitro and were considered tolerogenic because they expressed high levels of PD-L1 and suppressed T-cell proliferation. The CD11b + Gr1 dim cells have never described previously and termed CD11b + Gr1 dim tolerogenic DC-like cells (CD11b + Gr1 dim tolDC-LCs). Th17 cells, ILC1s and ILC3s in the inflamed lung produced GM-CSF, which in turn could induce CD11b + Gr1 dim tolDC-LCs to reduce inflammation. Conclusions We identified a unique cell population, termed CD11b + Gr1 dim tolDC-LCs, in ILD-induced lungs in SKG mice. References Nishimura K, Saegusa J, Matsuki F, Akashi K, Kageyama G, Morinobu A. Tofacitinib facilitates the expansion of myeloid-derived suppressor cells and ameliorates arthritis in SKG mice. Arthritis Rheumatol 2015;67:893–902. Shiomi A, Usui T, Ishikawa Y, Shimuzu M, Murakami K, Mimori T. GM-CSF but not IL-17 is critical for the development of severe interstitial lung disease in SKG mice. J. Immunol 2014;193:849–59. Takenaka MC, Quintana FJ. Tolerogenic dendritic cells. Semin. Immunopahol 2016. doi:10.1007/s00281–016–0587–8. Acknowledgements The authors thank Shino Tanaka (Department Rheumatology and Clinical Immunology, Kobe University Graduate School of Medicine) for providing technical assistance. Disclosure of Interest None declared

In response to the accident at Tokyo Electric Power Company's Fukushima Dai-ichi Nuclear Power Plant (FDNPP), vehicle-borne monitoring was used to map radiation levels for radiological protection of the public. By convention measurements from vehicle-borne surveys are converted to the ambient dose equivalent rate at 1 m height in the absence of the vehicle. This allows for comparison with results from other types of survey, including surveys with hand-held or airborne instruments. To improve the accuracy of the converted results from vehicle-borne surveys, we investigated combining measurements from two detectors mounted on the vehicle at different heights above the ground. A dual-detector setup was added to a JAEA monitoring car and compared against hand-held survey meter measurements in Fukushima Prefecture. The results obtained by combining measurements from two detectors were within ±20% of the hand-held reference measurements. The mean absolute percentage deviation from the reference measurements was 7.2%. The combined results from the two detectors were more accurate than those from either the roof-mounted detector, or the detector inside the vehicle, taken alone. One issue with vehicle-borne surveys is that ambient dose equivalent rates above roads are not necessarily representative of adjacent areas. This is because radiocesium is often deficient on asphalt surfaces, as it is easily scrubbed off by rain, wind and vehicle tires. To tackle this issue, we investigated mounting heights for vehicle-borne detectors using Monte Carlo gamma-ray simulations. When radiocesium is deficient on a road compared to the adjacent land, mounting detectors high on vehicles yields results closer to the values adjacent to the road. The ratio of ambient dose equivalent rates reported by detectors mounted at different heights in a dual-detector setup indicates whether radiocesium is deficient on the road compared to the adjacent land.

Background Rheumatoid arthritis-associated interstitial lung disease (RA-ILD) is a sometimes life-threatening complication in RA patients. SKG mice develop not only arthritis but also an ILD resembling RA-ILD. We previously reported that tofacitinib, a JAK inhibitor, facilitates the expansion of myeloid-derived suppressor cells (MDSCs) and ameliorates arthritis in SKG mice. The aim of this study was to elucidate the effect of tofacitinib on the ILD in SKG mice. Methods We assessed the effect of tofacitinib on the zymosan (Zym)-induced ILD in SKG mice histologically and examined the cells infiltrating the lung by flow cytometry. The effects of lung MDSCs on T cell proliferation and Th17 cell differentiation were assessed in vitro. We also evaluated the effects of tofacitinib on MDSCs and dendritic cells in vitro. Results Tofacitinib significantly suppressed the progression of ILD compared to the control SKG mice. The MDSCs were increased, while Th17 cells, group 1 innate lymphoid cells (ILC1s), and GM-CSF+ILCs were decreased in the lungs of tofacitinib-treated mice. MDSCs isolated from the inflamed lungs suppressed T cell proliferation and Th17 cell differentiation in vitro. Tofacitinib promoted MDSC expansion and suppressed bone marrow-derived dendritic cell (BMDC) differentiation in vitro. Conclusion Tofacitinib facilitates the expansion of MDSCs in the lung and ameliorates ILD in SKG mice. Electronic supplementary material The online version of this article (10.1186/s13075-019-1963-2) contains supplementary material, which is available to authorized users.

Background Duchenne muscular dystrophy (DMD), the most common inherited muscular disease in childhood, is caused by dystrophin deficiency because of mutations in the DMD gene. Although DMD is characterized by fatal progressive muscle wasting, cardiomyopathy is the most important nonmuscle symptom threatening the life of patients with DMD. The relationship between cardiac involvement and dystrophin isoforms has not been analyzed. Methods and Results The results of 1109 echocardiograms obtained from 181 Japanese DMD patients with confirmed mutations in the DMD gene were retrospectively analyzed. Patients showed an age-related decline in left ventricular ejection fraction. Patients were divided by patterns of dystrophin isoform deficiency into 5 groups. The cardiac dysfunction-free survival was significantly higher in the group with mutations in the Dp116 coding region than the others, whereas no significant differences in the other 3 groups. At age 25 years, the cardiac dysfunction-free rate was 0.6 in the Dp116 group, but only 0.1 in others. PCR amplification of Dp116 transcript in human cardiac muscle indicated promoter activation. Conclusions Left ventricular ejection fraction in DMD declined stepwise with age. Cardiac dysfunction was less frequent in Dp116-deficient than other patients with DMD. Dp116 transcript was identified in human cardiac muscle for the first time. These results indicate that Dp116 is associated with cardiac involvement in DMD.

MicroRNAs (miRNAs) are non-coding RNAs, approximately 22 nucleotides in length, that act as post-transcriptional regulators. Thousands of miRNAs have been identified in animals, and they are well conserved across species. MicroRNAs play essential regulatory roles in cellular processes, and changes in miRNA expression are associated with human diseases. Originally, miR-124 was identified as a brain-enriched miRNA and shown to be involved in brain and neuronal development. MiR-124 has since been reported to be expressed in other organs and to be involved in various biological phenomena. MiRNA-124 plays roles in various pathologic conditions, including cancers, acute stress, cardiovascular disorders, inflammatory responses, chronic pain, and osteoclast differentiation. MiR-124 has also been shown to suppress various tumor functions, including proliferation, activation, survival, invasion, metastasis, and migration. Rheumatoid arthritis (RA) is a chronic auto-inflammatory disorder of unknown etiology, whose treatment has been significantly improved by the advent of biological drugs. Even so, some RA patients show little or no response to these therapies, suggesting the need for additional treatments. In a study comparing miRNA expression in RA and osteoarthritis (OA) fibroblast-like synoviocytes (FLS), we found that miR-124a was the only miRNA whose expression was lower in RA than in OA FLS.MiR-124a was found to directly downregulate the production of CDK-2 and MCP-1. In the rat adjuvant-induced arthritis (AIA) model, a single injection of pre-miR-124 into one ankle joint suppressed joint swelling in all of the limbs. Histological examination showed that AIA rats treated with pre-miR-124 exhibited reduced synoviocyte proliferation, less leucocyte infiltration into synovial tissue, and less cartilage and bone destruction than untreated AIA rats. The joints of the pre-miR-124-treated AIA rats also showed reduced osteoclast numbers and reduced RANKL, integrin β1 (ITGB1), and NFATc1 expression levels. MiR-124 was shown to directly target the 3’UTRs of the rat NFATc1, ITGB1, SP1, and CEBPα mRNAs. Both miR-124 and miR-124a were also found to directly target human NFATc1 mRNA and to suppress the differentiation of human osteoclasts from monocytes. Taken together, recent studies suggest that MiR-124 may be a promising therapeutic agent for RA and other diseases.

A 72-year-old man was diagnosed with rheumatoid arthritis (RA) and prior hepatitis B virus (HBV) infection. He began treatment with salazosulfapyridine (SASP). Several months later, his blood tests reflected a slightly elevated liver function. Serum tests were positive for hepatitis B surface antigen and HBV-DNA, and the diagnosis of de novo HBV hepatitis was made. A genetic analysis showed that he had polymorphisms of ABCG2 and NAT2, which could lead to high plasma concentrations of SASP and sulfapyridine. To the best of our knowledge, this is the first report of de novo hepatitis developing during SASP monotherapy for RA.

Procalcitonin (PCT) levels are elevated early after birth in newborn infants; however, the physiological features and reference of serum PCT concentrations have not been fully studied in preterm infants. The aims of the current study were to establish an age-specific percentile-based reference curve of serum PCT concentrations in preterm infants and determine the features. The PCT concentration peaked in infants at 1 day old and decreased thereafter. At 1 day old, serum PCT concentrations in preterm infants

Recent studies have shown that mycophenolate mofetil (MMF) is similar to intravenous cyclophosphamide (IVC) for the treatment of lupus nephritis (LN), but that treatment response may vary according to location and race/ethnicity. Moreover, no studies have been conducted to compare the efficacy of MMF with that of IVC for a Japanese population. We therefore conducted a retrospective study to clarify the efficacy and safety of MMF compared with that of IVC for induction therapy for active LN, classes III and IV, in a Japanese population of 21 patients, 11 of whom received MMF and 10 IVC.The primary endpoint was expressed as the percentage of responders, who in turn were defined as the patients who met complete or partial response criteria according to the European consensus statement. The secondary endpoints comprised the renal activity component and serological activity.The primary endpoint was achieved in nine (81.8 %) patients receiving MMF and in four (40.0 %) receiving IVC, with no significant difference between the two groups (p = 0.081), while there was also no significant difference between them in terms of secondary endpoints. However, the MMF group suffered significantly fewer hematologic toxic effects than the IVC group.MMF may be used as an alternative to IVC for inducing renal remission of LN in Japanese patients.

A 38-year-old woman was diagnosed with systemic lupus erythematosus and received immunosuppressive therapy. After 6 months of treatment, workup for low-grade fever yielded elevated enzyme-linked immunosorbent assay titers for Aspergillus antigen in serum and ascites, leading to the diagnosis of disseminated aspergillosis. Transthoracic echocardiography revealed a claviform vegetation attached to the left ventricular anterior septum. Two days after the start of antifungal Amphotericin-B therapy, the patient suffered from several neurologic disorders. A second transthoracic echocardiography revealed that the vegetation decreased in size. Two weeks later, the vegetation increased again. Combination therapy of Amphotericin-B and Voriconazole was initiated, and the vegetation eventually disappeared completely. © 2017 Wiley Periodicals, Inc. J Clin Ultrasound 46:231-232, 2018.

The objective of this study is to clarify the characteristics and imaging results of Japanese patients with giant cell arteritis (GCA). Eight patients with biopsy-proven GCA were enrolled. Their clinical data and imaging results were retrospectively examined from their medical records. All the patients met the criteria for the classification of GCA by the American College of Rheumatology. Although the clinical manifestations are similar to those previously reported, none of the eight patients presented ocular symptoms, and half of them presented jaw claudication. Ultrasonography (US) of temporal artery showed the halo sign in all the patients. Fluorodeoxyglucose positron emission tomography (FDG-PET) was performed in four patients and indicated the presence of aortitis of the patients. US is a quick and noninvasive test to detect inflammation of temporal artery, and FDG-PET is very helpful for early diagnosis of aortitis in GCA. Awareness of the disease and appropriate imaging tests will result in diagnosis of GCA.

This case report describes findings in a 61-year-old woman who manifested scleritis, small pulmonary nodules, otitis media, periaortitis, and progressive epidural spinal tumor, associated with elevated serum myeloperoxidase anti-neutrophil cytoplasmic antibody (MPO-ANCA) levels. She was clinically diagnosed with Wegener's granulomatosis, although vasculitis was not diagnosed due to the lack of typical histological findings. We discuss the differential diagnosis in this patient, and the association of MPO-ANCA with periaortitis or epidural spinal tumor.

Development of three calibration fields for 45, 60 and 75 MeV neutrons has been in progress at Takasaki Ion Accelerators for Advanced Radiation Application (TIARA) of JAEA-Takasaki. Achievement of the neutron calibration fields requires establishment of both measurement of neutron fluence and its monitoring technique. In order to measure the neutron fluence of main energy peak especially at a reference point on low fluence condition, a proton recoil counter telescope with high efficiency has been developed. The design of relatively large telescope components brought a high detection efficiency at the reference point with wide irradiation area at a long distance. Effective and precise measurement of the neutron fluence could be performed with uncertainties less than 6.5 % (standard deviation). For detecting neutrons without scattering near the target, a transmission type neutron fluence monitor has been newly developed to measure the neutron fluence directly at the collimator exit. Its performance such as counting rates was tested for various beam intensities.

Rationale: TAFRO syndrome is a systemic inflammatory disorder characterized by thrombocytopenia, anasarca, fever, reticulin fibrosis, renal dysfunction, and organomegaly. In contrast to that in multicentric Castleman disease, interleukin-6 targeting strategies seem ineffective in some TAFRO syndrome cases; however, the optimal treatment remains unclear. Here, we report 2 cases of TAFRO syndrome, where 1 with cardiomyopathy, successfully treated with tacrolimus. This is the first case report of successful treatment with tacrolimus in TAFRO syndrome. Patient concerns: Both patients (cases 1 and 2) developed fever, anasarca, thrombocytopenia, renal dysfunction, and mild hepatosplenomegaly. Diagnoses: In both patients, lymph node pathology revealed mixed type Castleman disease-like features, and bone marrow showed reticulin myelofibrosis. TAFRO syndrome was diagnosed based on the patients' laboratory, clinical, and pathologic findings. In case 2, we observed a rare complication of cardiomyopathy with no evidence of takotsubo cardiomyopathy or viral myocarditis. Interventions and outcomes: In case 1, tocilizumab combined with glucocorticoids was ineffective and caused septic shock; additionally, cyclosporine A was discontinued because of hepatotoxicity. However, tacrolimus was effective in resolving TAFRO syndrome without any adverse events. In case 2, tacrolimus completely reversed TAFRO syndrome and was also effective in cardiomyopathy. Lessons: This report suggests that tacrolimus is potentially effective and safe as an initial treatment and a glucocorticoid-sparing agent. Our literature review shows that calcineurin inhibitors, including tacrolimus, may be effective in TAFRO syndrome. Since previous studies indicate a role of Th1 inflammation in TAFRO syndrome pathogenesis, tacrolimus may, therefore, be effective in treating TAFRO syndrome.

Precise calibration of monitors and dosimeters for use with high energy neutrons necessitates reliable and accurate neutron fluences being evaluated with use of a reference point. A highly efficient Proton Recoil counter Telescope (PRT) to make absolute measurements with use of a reference point was developed to evaluate neutron fluences in quasi-monoenergetic neutron fields. The relatively large design of the PRT componentry and relatively thick, approximately 2 mm, polyethylene converter contributed to high detection efficiency at the reference point over a large irradiation area at a long distance from the target. The polyethylene converter thickness was adjusted to maintain the same carbon density per unit area as the graphite converter for easy background subtraction. The high detection efficiency and thickness adjustment resulted in efficient absolute measurements being made of the neutron fluences of sufficient statistical precision over a short period of time. The neutron detection efficiencies of the PRT were evaluated using MCNPX code at 2.61×10 −6 , 2.16×10 −6 and 1.14×10 −6 for the respective neutron peak energies of 45, 60 and 75 MeV. The neutron fluences were determined to have been evaluated at an uncertainty of within 6.5% using analysis of measured data and the detection efficiencies. The PRT was also designed so as to be capable of simultaneously obtaining TOF data. The TOF data also increased the reliability of neutron fluence measurements and provided useful information for use in interpreting the source of proton events.

Galectin-3 belongs to a family of beta-galactoside-binding animal lectins expressed in several cell types, including epithelial and immune cells. To establish the role of galectin-3 in the development of allergic skin inflammation, we compared inflammatory skin responses of galectin-3-deficient (gal3(-/-)) and wild-type (gal3(+/+)) mice to epicutaneous sensitization with ovalbumin (OVA). OVA-treated gal3(-/-) mice exhibited markedly reduced epidermal thickening, lower eosinophil infiltration, and lower serum IgE levels compared with gal3(+/+) mice. The former evoked lower interleukin-4, but higher interferon-gamma, mRNA expression at OVA-treated skin sites. Moreover, gal3(-/-) splenocytes from OVA-sensitized mice secreted more interleukin-12 compared with gal3(+/+) splenocytes. In addition, antigen presentation by gal3(-/-) dendritic cells to T cells in vitro were T helper cell (Th1)-polarized relative to presentation by gal3(+/+) dendritic cells. When exposed to OVA, recipients engrafted with T cells from gal3(-/-) OVA-specific T cell receptor transgenic mice developed significantly reduced dermatitis and a markedly lower Th2 response compared with recipients of comparable gal3(+/+) T cells. We conclude that galectin-3 is critical for the development of inflammatory Th2 responses to epicutaneously administered antigens; in its absence, mice develop a Th1-polarized response. This regulatory effect of galectin-3 on Th development is exerted at both the dendritic cell and T cell levels. Our studies suggest that galectin-3 may play an important role in the acute phase of human atopic dermatitis.