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Belimumab is a therapeutic medication that inhibits the B-cell-activating factor (BAFF) used for systemic lupus erythematosus (SLE); however, the response sometimes varies among individuals, even when patients are stratified based on general clinical characteristics. Therefore, we focused on immunological phenotypic changes with belimumab, investigated their association with subsequent clinical courses, and sought to identify relevant immunological indicators to stratify patients who would benefit from belimumab. We assessed changes in B and T cell phenotypes, as well as BAFF-related factors, such as levels of BAFF and a proliferation-inducing ligand, and expression of three BAFF receptors: BAFF receptor (BAFF-R), B-cell maturation antigen (BCMA), transmembrane activator and cyclophilin ligand interactor (TACI), in 19 patients with SLE who were treated with belimumab before and 3 months after treatment. First, to visualize patterns in complex and diverse data, we summarized B cell changes such as subsets and BAFF receptor expressions into two axes, the first and second principal components (PC1 and PC2), and characterized broad phenotypic changes by cluster analysis. Next, we evaluated whether the B cell changes represented by PC1 and PC2 were associated with other concurrent phenotypic changes, baseline factors, and treatment response at 6 months. We found that lower PC2, indicating increased BAFF-R expression and decreased percentage of naïve B cells, was associated with a subsequent therapeutic response at 6 months (odds ratio 5.3, 95% confidence interval 1.2–24, p = .031). Furthermore, higher percentages of effector memory CD3+CD4+ T cells at baseline were associated with lower PC2 and therapeutic response. Further analysis revealed that increased PC1, as reflected by increased BCMA and TACI expression and an increase in the percentage of class-switched memory B cells, was associated with both T and B cell activation. Although belimumab is a B-cell targeted therapy, it can also influence T-cell phenotypes. Thus, early B cell changes could be used to predict treatment response, and their changes could be predicted from baseline T cell phenotypes, indicating the importance of B and T cell interactions.

We aimed to evaluate the utility of coagulation markers for the prediction of rapidly progressive interstitial lung disease (RP-ILD) in patients with dermatomyositis (DM). In this retrospective study, 29 patients with DM-associated ILD were analyzed. The number of patients with RP-ILD was 15 (52%). The baseline clinical and demographic data and laboratory markers were analyzed to identify predictive factors for RP-ILD.The univariate logistic regression analysis demonstrated that in addition to well-known laboratory markers, such as serum ferritin, KL-6, and lymphocyte counts, a prolonged activated partial thromboplastin time (aPTT) ratio at the time of DM-associated ILD diagnosis was useful for predicting RP-ILD. Moreover, the logistic regression model and receiver operating characteristic curve analysis showed that combinations of the aPTT ratio and well-known laboratory markers were significantly effective in predicting RP-ILD. This study suggested that an association between RP-ILD and the coagulation system exists.

Objective To determine whether patients with polymyalgia rheumatica (PMR) are more susceptible to glucocorticoid-induced adrenal insufficiency, one of the barriers to glucocorticoid tapering strategies, compared to patients with rheumatoid arthritis (RA). Methods This cross-sectional study included PMR and RA patients who underwent adrenocorticotropic hormone (ACTH) tests to assess adrenal function. The eligibility criteria were as follows: previous use of prednisolone (PSL) ≥ 5 mg/day, use of PSL for six consecutive months before ACTH test, and current use of PSL at 5 mg/day or less. The association between disease type (PMR vs. RA) and insufficient adrenal response was assessed using logistic regression models. Results Twenty-six of 34 (76.5%) patients with PMR and 13 of 37 (35.1%) patients with RA had insufficient adrenal response. Compared to patients with RA, patients with PMR were more likely to have insufficient adrenal response, even after adjusting for age, sex, and PSL dose (adjusted odds ratio, 6.75; 95% confidence interval, 1.78–25.60). Conclusion Patients with PMR have a higher risk of glucocorticoid-induced adrenal insufficiency than patients with RA. Assessing the adrenal function in patients with PMR will contribute to establishing a more appropriate glucocorticoid reduction strategy.

Background & Aims. The physiological regulation and contribution of the multiple phosphorylation sites of insulin receptor substrate 1 (IRS1) to the pathogenesis of insulin resistance is unknown. Our aims were to map the phosphorylated motifs of IRS1 in skeletal muscle from people with normal glucose tolerance (NGT; n = 11) or type 2 diabetes mellitus (T2DM; n = 11). Methods Skeletal muscle biopsies were obtained under fasted conditions or during a euglycemic clamp and IRS1 phosphorylation sites were identified by mass spectrometry. Results We identified 33 phosphorylation sites in biopsies from fasted individuals, including 2 previously unreported sites ([Ser393] and [Thr1017]). In men with NGT and T2DM, insulin increased phosphorylation of 5 peptides covering 10 serine or threonine sites and decreased phosphorylation of 6 peptides covering 9 serine, threonine or tyrosine sites. Insulin-stimulation increased phosphorylation of 2 peptides, and decreased phosphorylation of 2 peptides only in men with NGT. Insulin increased phosphorylation of 2 peptides only in men with T2DM. Conclusions Despite severe skeletal muscle insulin resistance, the pattern of IRS1 phosphorylation was not uniformly altered in T2DM. Our results contribute to the evolving understanding of the physiological regulation of insulin signaling and complement the comprehensive map of IRS1 phosphorylation in T2DM.

Pulmonary fibrosis is a progressive disease with poor prognosis and limited therapeutic options. In this study, we evaluated the potential therapeutic effects of CG223, a novel inhibitor of bromodomain and extra-terminal motif (BET) proteins, on pulmonary fibrosis by focusing on the transforming growth factor-β1 (TGF-β1) pathway. In a murine model of bleomycin-induced pulmonary fibrosis, CG223 attenuated fibrosis while reducing the infiltration of inflammatory cells into the lungs. Fibroblasts expressing BRD4, a member of the BET protein family, were enriched in the tissue regions corresponding to bleomycin-induced fibrotic lesions. Additionally, pulmonary fibroblasts isolated from bleomycin-instilled mice showed a significantly increased association of BRD4 with the promoters of two pro-fibrotic genes linked to the entry into the TGF-β1 autocrine/paracrine loop, thrombospondin 1 (Thbs1) and integrin β3 (Itgb3), as well as with the promoter of a myofibroblast marker gene, actin alpha 2 (Acta2). Subsequent in vitro studies with murine primary lung fibroblasts showed that the mRNA induction of Thbs1, Itgb3, and Acta2 by TGF-β1 can be inhibited by CG223 in a dose-dependent manner. Taken together, CG223-induced BRD4 inhibition suppressed lung fibrogenesis by affecting multiple genes, including those involved in the triggering of the TGF-β1 autocrine/paracrine loop.

Aim To examine the efficacy of abatacept in patients with rheumatoid arthritis (RA) using magnetic resonance imaging (MRI) of bilateral hands. Method This prospective study included 35 RA patients. MRI of bilateral hands was performed at baseline and after 12 months of treatment with intravenous abatacept. MRI images were scored for synovitis, osteitis, erosion and joint space narrowing (JSN) according to the RA MRI Scoring System (RAMRIS). The primary endpoint was the change in RAMRIS score from baseline. Repair of erosion was defined as a negative change in the erosion score that was greater than the smallest detectable changes (SDCs). Results Thirty-one patients completed the study. Median synovitis and osteitis scores showed statistically significant reductions at Month 12 when compared to baseline (synovitis score, −5.5 [P

In contrast to a single human carboxylesterase 2 (CES2) isozyme (hCE2), three CES2 genes have been identified in cynomolgus monkeys: mfCES2A, mfCES2B, and mfCES2C. Although mfCES2A protein is expressed in several organs, mfCES2B is a pseudogene and the phenotype of the mfCES2C gene has not yet been clarified in tissues. In previous studies, we detected an unidentified esterase in the region of CES2 mobility upon nondenaturing PAGE analysis of monkey intestinal microsomes, which showed immunoreactivity for anti-mfCES2A antibody. The aim of the present study was to identify this unidentified esterase from monkey small intestine. The esterase was separated on nondenaturing PAGE gel and digested in-gel with trypsin. The amino acid sequences of fragmented peptides were analyzed by tandem mass spectrometry. The unidentified esterase was shown to be identical to mfCES2C (XP_015298642.1, predicted from the genome sequence data). mfCES2C consists of 559 amino acid residues and shows approximately 90% homology with mfCES2A (561 amino acid residues). In contrast to the ubiquitous expression of mfCES2A, mfCES2C is only expressed in the small intestine, kidney, and skin. The hydrolytic properties of recombinant mfCES2C, expressed in HEK293 cells, with respect to p-nitrophenyl derivatives, 4-methylumbelliferyl acetate, and irinotecan were similar to those of recombinant mfCES2A. However, mfCES2C showed a hydrolase activity for O-n-valeryl propranolol higher than mfCES2A. It is concluded that the previously unidentified monkey intestinal CES2 is mfCES2C, which shows different hydrolytic properties to mfCES2A, depending on the substrate. SIGNIFICANCE STATEMENT In the present research, we determined that mfCES2C, a novel monkey CES2 isozyme, is expressed in the small intestine and kidney of the cynomolgus monkey. Interestingly, mfCES2C showed a relatively wide substrate specificity for ester-containing compounds. These findings may, in early stages of drug development, support the use of in vitro–to–in vivo extrapolation for the intestinal hydrolysis of ester drugs in the cynomolgus monkey.

Summary Objective Hepatocyte growth factor (HGF) receptors form a hybrid complex with insulin receptors in the liver of mice, which lead to robust signalling to regulate glucose metabolism. Serum HGF levels are high in subjects with metabolic syndrome and/or obesity. Accordingly, we prospectively investigated the relationship between HGF and the development of insulin resistance (IR) in a general population without IR at baseline. Methods A total of 1492 subjects received health examinations. After excluding subjects with diabetes and/or IR (n = 402) at baseline, the remaining subjects (n = 1090) were followed-up 10 years later. Complete data sets were available from 716 subjects for prospective analysis. Logistic regression was performed to determine factors associated with the development of IR after 10 years. Results In subjects without diabetes at baseline, serum HGF levels were higher (0·26 ± 0·10 ng/ml, n = 259) in subjects with IR than without it (0·22 ± 0·09 ng/ml, n = 1090). After deleting subjects who developed liver disease during follow-up, 188 were found to have developed IR at 10 years after the original screening. HGF (P

Background Large cohort studies have revealed that subjects with atherosclerotic risk factors have high mortality. However, there has been no method to predict individual mortality based on these risk factors. Accordingly, we developed a computer model predicting the 10-year mortality of an individual with atherosclerotic risk factors. Methods We enrolled two different cohorts in Japan. One was from Tanushimaru-town and the other was from Uku-town. Residents over the age of 40 underwent baseline examinations and were followed-up for ten years. 1851 Subjects in Tanushimaru-town were randomly divided into 1486 training samples and 365 test samples. We applied supervised statistical pattern recognition (SSPR) techniques to develop, using the training samples, a computer model to predict the 10-year mortality of an individual based on 6 conventional risk factors. The test samples were then used to evaluate the predictive accuracy. Results There were 49 deaths and 316 survivors in the test samples in Tanushimaru-town. The correctly simulated number of deaths and survival was 36 and 250, respectively. The predictive accuracy of death was 73.5% (36/49) and that of survival was 79.1% (250/316) with c -statistics of 0.827. In order to verify our model, we predicted death and survival for the other test samples (Uku-town, n = 170). The predictive accuracy of death was 72.9% (35/48) and that of survival was 76.2% (93/122) with c -statistics of 0.848. Conclusions This is the first computer model to use SSPR methods to estimate individual 10-year mortality based on conventional risk factors with high accuracy.

Background: Endothelin-1 (ET-1) is a potent vasoconstrictor and an elevated plasma level is a prognostic marker in patients with cardiovascular diseases and/or malignancies. We hypothesized that an elevated plasma level might be a prognostic marker even in subjects without apparent cardiovascular disease or malignancy at baseline. Methods and Results: We measured plasma ET-1 levels in 1,440 healthy subjects over 40 years of age (580 men, 860 women) who were periodically followed for 10 years. The follow-up rate was 96.8%. Baseline plasma ET-1 levels were categorized into quartiles. Baseline plasma ET-1 levels were significantly associated with age, blood pressure, high-density lipoprotein-cholesterol, renal function, uric acid and all-cause death, but not with cardiovascular or cancer death. Kaplan-Meier curves demonstrated that all-cause mortality was significantly higher in the highest quartile of ET-1 than in the lowest quartile. Cox proportional hazards regression analysis demonstrated that ET-1 was an independent predictor of all-cause death [hazard ratio: 1.11, 95% confidence interval (CI) 1.01–1.23 per 1pg/ml difference]. The hazard ratio of all-cause death in the highest quartile of plasma ET-1 (≥5.9pg/ml) vs. the lowest quartile after adjusting for confounding factors was 1.54 (95% CI 1.09–2.20). Conclusions: The plasma ET-1 level may be a predictor of all-cause death in a healthy population. (Circ J 2012; 76: 2779–2784)

Background In patients with cancer, hepatocyte growth factor (HGF) is elevated and is a predictor of prognosis. We investigated whether serum HGF was a predictive marker for cancer death in a population of community-dwelling Japanese. Methods We studied 1492 apparently healthy Japanese adults who underwent health examinations in 1999. Those who reported a history of liver disease or malignancy on a baseline questionnaire were excluded, and plasma HGF was measured in the remaining 1470 participants, who were followed periodically for 10 years. Multivariate proportional hazards regression was used to estimate cancer mortality. Results A total of 169 participants died during follow-up (61 from cancer, 32 from cerebrocardiovascular disease, and 76 from other diseases). Mean HGF at baseline was significantly higher among decedents than among survivors (0.26 ± 0.11 vs 0.23 ± 0.09 ng/ml, respectively; P < 0.01). The Cox proportional hazards model showed that age, systolic blood pressure, HGF (hazard ratio, 1.27; 95% CI, 1.06–1.52; P = 0.009), albumin level, smoking status, and creatinine were independent predictors of all-cause death. Age, HGF (hazard ratio, 1.31; 95% CI, 1.04–1.65; P = 0.02), and total cholesterol were independent predictive markers for cancer death. Conclusions Serum HGF was a predictor of cancer death in an apparently healthy population of community-dwelling Japanese.

Objective Ghrelin is a novel gastric peptide identified in 1999 as a ‘hunger hormone’. Plasma ghrelin level is decreased in human obesity. Factors associated with ghrelin have been mainly investigated in western countries where the prevalence of obesity is high. The aim of this study is to examine factors associated with plasma ghrelin in a Japanese general population where obesity is not so common. Methods Fasting ghrelin levels were measured by ELISA in 638 subjects in 2005–2007. We measured body mass index (BMI), waist circumference and blood pressure. Blood was drawn in the morning after a 12-h fast for determinations of ghrelin, lipid, glucose (FPG), insulin, estimated glomerular filtration rate (eGFR) and uric acid levels. Univariate and multiple stepwise regression analyses were performed to find out factors associated with ghrelin. Results In our population, the mean BMI was 23·8 kg/m2, indicating a nonobese population. Results of univariate analysis showed that age (P

We report a case of fibromuscular dysplasia (FMD). The patient was a 22-year-old female who had received treatment for hypertension for two years. She had also presented with hemorrhage caused by an annular ulcer in the small intestine. In March 2012, she had abdominal pain, was diagnosed with rupture of aneurysms of the gastroepiploic artery, and received embolization. In July 2012, she felt abdominal pain, presented with ruptured aneurysms of the left hepatic artery. She had abdominal pain again and suffered hemorrhagic shock. Contrast-enhanced computed tomography scanning of her abdomen revealed rupture of the left hepatic artery aneurysms and she received emergent coil embolization. Aneurysm expansion was noted, which suggested the necessity of early diagnosis and treatment, but the diagnosis was difficult because a few systemic findings were observed without any typical angiography findings. We decided to perform a small bowel resection for the complication of annular ulcers and reached a diagnosis of FMD according to pathological findings. Differential diagnosis between inflammatory and noninflammatory arteriopathy is difficult in many cases and often largely affects treatment policies. We experienced a rare case where we reached a definite diagnosis of FMD based on pathology of the small intestine ulcer.

BACKGROUND Remnant-like lipoprotein particle cholesterol (RLP-C) is a highly atherogenic factor. RLP-C induces endothelial dysfunction and is associated with hyperinsulinemia. This study was designed to determine whether high plasma RLP-C levels predispose to the development of hypertension in subjects with normal blood pressure (BP). METHODS A total of 1,485 subjects aged >40 years in a Japanese Cohort of the Seven Countries Study received health examinations. We examined BP, anthropometric parameters, and blood chemistries, including fasting RLP-C levels. RLP-C levels were measured by an immune-separation method. We excluded from the analysis 676 subjects who had hypertension (BP ≥ 140/90mm Hg), or were on antihypertensive medication, and/or were on antihyperlipidemic medication at baseline. Ten years later, 681 subjects were re-examined. RESULTS Of 681 normotensive subjects at baseline, 303 subjects had developed hypertension 10 years later. Baseline RLP-C level was significantly higher (P < 0.01) in the subjects who developed hypertension than in those who remained normotensive (3.7±1.9 vs. 3.3±1.6mg/dl). Multivariable logistic regression analysis demonstrated that baseline RLP-C was a significant factor for incident hypertension after adjustments for homeostasis model assessment index and other hypertension-related factors (odds ratio = 1.05, 95% CI = 1.00-1.10; P = 0.04). CONCLUSIONS A high level of plasma RLP-C in normotensive subjects may predispose to the development of hypertension in a population of community-dwelling Japanese.

Background There is no report investigating predictive factors for MRI erosion change in treatment of rheumatoid arthritis (RA) with abatacept (ABT), because very little data are available on the efficacy of ABT assessed by MRI. Objectives The aim of this study is to examine the efficacy of ABT in patients with RA assessed by MRI and identify factors associated with change of bone erosion score. Methods Thirty-five RA patients were included in this prospective study. MRI of bilateral hands and conventional radiographs (CR) of bilateral hands and feet were performed at baseline and month 12 of treatment with intravenous ABT. MRI images were scored for synovitis, osteitis and bone erosion according to the Rheumatoid Arthritis MRI Scoring System. CR images were assessed according to the van der Heijde modified total Sharp score. Results Thirty-one patients completed this study. Mean Simplified Disease Activity Index (SDAI) and Health Assessment Questionnaire Disability Index (HAQ-DI) at baseline were 23.4±12.0 and 1.1±0.6 respectively. At the group level, mean MRI synovitis and osteitis scores showed statistically significant reductions through 12 months of treatment with ABT (from 17.1±7.0 to 11.4±6.2 (p Conclusions This study demonstrated ABT has a strong inhibitory effect on joint damage reducing synovitis and osteitis and not progressing bone erosion in RA patients. Over 10% patients showed repair of bone erosion assessed by MRI, which resulted in functional remission. SDAI response rate at month 1 could be a predictive factor for repair of bone erosion. Disclosure of Interest Y. Kukida Grant/research support from: Bristol-Myers Squibb, A. Kasahara: None declared, T. Seno: None declared, T. Inoue: None declared, N. Kamio: None declared, R. Sagawa: None declared, T. Kida: None declared, A. Nakabayashi: None declared, H. Nagahara: None declared, A. Yamamoto: None declared, S. Morita: None declared, H. Ito: None declared, M. Kohno: None declared, Y. Kawahito Grant/research support from: Bristol-Myers Squibb

Background Tocilizumab, anti-IL-6 receptor monoclonal antibody, is widely used for patients with rheumatoid arthritis. IL-6 is essential for production of C-reactive protein (CRP). Tocilizumab fully inhibit the production of CRP. Therefore, we have difficulty in objective assessment of infection and disease activity because the level of CRP is suppressed under tocilizumab therapy. The development of new biomarker alternative to CRP is needed for daily practice. Objectives To discover new biomarkers alternative to CRP under tocilizumab therapy for rheumatoid arthritis. Methods We registered patients with rheumatoid arthritis treated with tocilizumab. We collected serum samples from those patients at baseline, 4 weeks after the first tocilizumab administration when patient9s CRP level is almost normal, and 1 year later. And we measured CRP, ESR and clinical disease activity index (CDAI) score.Serum peptidomic analysis was conducted by newly-established one-step direct transfer technology (BLOTCHIP-MS analysis), a rapid quantitative technology for peptidomic analysis. All sample measurements were repeated four times. Statistical analyses of MS spectral data were conducted using ClinProTools version 2.2 (Bruker Daltonics). Results We registered 14 patients and their background is shown in Table 1. The levels of CRP were 1.16±0.99 mg/dl at baseline, 0.02±0.01 mg/dl at 4 weeks and 0.01±0.01mg/dl at 1 year, respectively. Their CDAI score were 22±9.2 at baseline, 15±8.9 at 4 weeks and 3±2.6 at 1 year, respectively. CRP titer decreased to almost normal level at 4 weeks regardless whether CDAI score did not fully decrease. We detect 6 biomarkers, named as PRSJ01 to PRSJ06, by the peptidomic analysis (Table 2). The AUC of diagnostic value of these markers is from 0.742 to 0.858. For example, the level of PRSJ06 significantly decreased 4 weeks (Wilcoxon singed-rank test, p=0.02) and 1 year (Wilcoxon singed-rank test, p=0.003) after first tocilizumab administration (Figure 1). and it was inversely-correlated with CDAI score. Conclusions We detect new disease activity biomarkers alternative to CRP under tocilizumab therapy for rheumatoid arthritis. It is useful for exact evaluation of disease activity and infection during tocilizumab therapy. Disclosure of Interest None declared

Aldosterone plays a role in hypertension, and hypertension is prevalent in patients with insulin resistance. Cross-sectional studies have reported that plasma aldosterone levels are higher in patients with insulin resistance. However, it is not known whether plasma aldosterone levels predict the development of insulin resistance. Subjects of the present study were 1235 local residents (490 men and 745 women) who participated in health screenings in Japan in 1999. Plasma aldosterone levels were measured by radioimmunoassay. We investigated the cross-sectional relationship between plasma aldosterone levels and insulin resistance (homeostasis model assessment index ≥1.73 according to the diagnostic criteria used in Japan) in 1088 nondiabetic participants. At the 10-year follow-up, 141 subjects had died, and 260 subjects refused re-examination. We performed a prospective analysis of 564 subjects to predict incident insulin resistance. We found a significant ( P P

Ghrelin is a novel gastric peptide identified in 1999 as a 'hunger hormone'. Plasma ghrelin level is decreased in human obesity. Factors associated with ghrelin have been mainly investigated in western countries where the prevalence of obesity is high. The aim of this study is to examine factors associated with plasma ghrelin in a Japanese general population where obesity is not so common.Fasting ghrelin levels were measured by ELISA in 638 subjects in 2005-2007. We measured body mass index (BMI), waist circumference and blood pressure. Blood was drawn in the morning after a 12-h fast for determinations of ghrelin, lipid, glucose (FPG), insulin, estimated glomerular filtration rate (eGFR) and uric acid levels. Univariate and multiple stepwise regression analyses were performed to find out factors associated with ghrelin.In our population, the mean BMI was 23·8 kg/m(2) , indicating a nonobese population. Results of univariate analysis showed that age (P0·001), BMI (P0·001), waist (P0·001), triglycerides (P0·01), FPG (P0·01), insulin (P0·001) and uric acid (P0·05) were inversely associated with ghrelin. High-density lipoprotein (HDL) cholesterol (P0·001) and eGFR (P0·05) were positively associated with ghrelin. Men had lower ghrelin levels than women (P0·001). Results of the multiple stepwise regression analysis revealed that age (P0·001; inversely), female gender (P0·001), insulin (P0·001; inversely), HDL cholesterol (P=0·005), BMI (P=0·01; inversely) and uric acid (P=0·045; inversely) were significantly and independently associated with ghrelin.The present study demonstrated that age and gender affected plasma ghrelin levels more than BMI. This may well be because of the low prevalence of overweight in our population.

Background Monocyte chemoattractant protein-1 (MCP-1) plays a role in cardiovascular disease (CVD) and renal injury. Recent clinical studies have suggested that circulating levels of MCP-1 could be a biomarker of atherosclerosis and future cardiovascular events in humans. Because chronic kidney disease (CKD) is one of the risk factors of CVD, it is conceivable that elevated MCP-1 levels may link the increased risk of CVD in CKD patients. However, as far as we know, in addition to well-known traditional risk factors for atherosclerosis, whether renal dysfunction could be independently associated with the elevation of MCP-1 levels in a general population remains unknown. Therefore, we examined here which anthropometric and metabolic variables, including renal function, could be independent correlates of circulating levels of MCP-1 in a general population. Hypothesis We hypothesized that renal function was one of the independent correlates of serum MCP-1 levels. Methods A total of 860 Japanese residents (318 males and 542 females, mean age 65.4 ± 9.8 years) in a small fishing community underwent a complete history and physical examination with determination of blood chemistries, including serum levels of MCP-1. Results Mean MCP-1 levels were 281.4 pg/mL. Multiple stepwise regression analyses revealed that male sex (P < 0.0001), age (P = 0.03), estimated glomerular filtration rate (eGFR) (P < 0.0001, inversely), and white blood cell count (P = 0.037) were independently associated with MCP-1 levels. Conclusions The present study demonstrated for the first time that other than white blood cell count, eGFR was an independent correlate of serum levels of MCP-1 in a Japanese general population. Elevated MCP-1 levels may partly explain the increased risk of CVD in CKD patients. © 2011 Wiley Periodicals, Inc. The authors have no funding, financial relationships, or conflicts of interest to disclose.

Background Multitarget therapy for lupus nephritis which was reported by Bao et al. 1 is hopeful treatment option for refractory systemic lupus erythematosus (SLE). However, there are few studies about multitarget therapy with combination of prednisolone (PSL), purine synthesis inhibitor and calcineurin inhibitor for SLE. Objectives The aim of this study is to evaluate efficacy and safety of multitarget therapy with combination of PSL, mizoribine (MZR) and tacrolimus (TAC) as induction or add-on therapy for refractory SLE with or without lupus nephritis. Methods We retrospectively studied 26 SLE patients treated with multitarget therapy in our department from April 2009 to December 2013. The mean age was 44.5 years old and 23 patients were female. They were divided into two groups; (A) 10 patients who were initially treated with this therapy as induction, and (B) 16 patients who were additionally treated with this therapy due to minor flares or difficulty in reducing PSL dose. We evaluated efficacy and safety of this combination strategy as (A) induction therapy and (B) add-on therapy respectively. Results (A) Five of 10 patients had lupus nephritis (2 were class IV and 3 were class IV+V). Three of 10 stopped this therapy due to severe adverse events within 12 months. Other 2 patients stopped this therapy due to preparation for pregnancy. Among nephritis patients, complete renal response rate at 6 months was 75%. The mean SLE disease activity index (SLEDAI) was reduced from 25 at baseline to 7.5 at 6 months. In all non-nephritis patients, their symptoms or blood examination data were improved. The mean SLEDAI was reduced from 14.4 at baseline to 2.4 at 6 months. (B) Five of 16 patients had lupus nephritis. One patient stopped this therapy due to preparation for pregnancy. The mean PSL dose was reduced from 14.8mg/day at baseline to 9.2mg/day at 12 months. The mean SLEDAI was reduced from 6.5 at baseline to 2.7 at 12 months. In all 26 patients, adverse events were 28 cases in the observation period. Most of these were mild infections. Three severe adverse events were observed. These were hypertrophic cardiomyopathy due to interaction of TAC and clarithromycin, nocardial soft tissue abscess and cryptococcal meningitis. All three patients who experienced severe adverse events were over 65 years old. Conclusions The combination use of PSL, MZR and TAC is effective as induction therapy and as add-on therapy for refractory SLE regardless of having lupus nephritis. However, elderly patients tend to suffer from sever adverse events. References Bao H et al: Successful treatment of class V+IV lupus nephritis with multitarget therapy, J Am Soc Nephrol 19; 2001-2010, 2008 Disclosure of Interest Y. Kukida Grant/research support: Astellas Pharma Inc. Asahi Kasei Pharma Corp., T. Kida: None declared, T. Inoue: None declared, Y. Isoda: None declared, T. Sagawa: None declared, R. Ishigaki: None declared, A. Kasahara: None declared, A. Nakabayashi: None declared, K. Fujioka: None declared, H. Nagahara: None declared, W. Fujii: None declared, K. Murakami: None declared, T. Seno: None declared, A. Yamamoto Grant/research support: Astellas Pharma Inc. Asahi Kasei Pharma Corp., M. Kohno Grant/research support: Astellas Pharma Inc. Asahi Kasei Pharma Corp., Y. Kawahito Grant/research support: Astellas Pharma Inc. Asahi Kasei Pharma Corp. DOI 10.1136/annrheumdis-2014-eular.3186

Background It is well known that synovial fluid pH is decreased in rheumatoid arthritis (RA) patients (1), but the meaning and mechanism remain unclear. Objectives We investigate the correlation between synovial fluid pH and the disease activity of RA. We reveal the mechanism by which synovial fluid pH is regulated and explore the novel therapeutic strategy of RA by applying this mechanism. Methods We measured the values of pH and the concentration of L-lactate in synovial fluid of RA patients. Next, we investigated the expression of ion transporters regulating intracellular and extracellular pH in RA synovial fibroblasts (RASFs) obtained from the inflamed joints using quantitative RT-PCR and Western Blotting. Finally, we suppressed the ion transporter expression by small interfering RNA (siRNA) against the ion transporter increased in RASFs, and analyzed their viability and proliferative capacity of RASFs. Results Synovial fluid pH was decreased as the disease activity score (DAS)-28 CRP increased in RA patients (graph A, n=17, r = -0.81, p