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Socioeconomic status (SES), which takes into account household income and education level, is an important factor in the role of muscle strength as a discriminator of sarcopenia. Although the benefits of exercise on muscle strength are well recognized, its influence on people of different SES has not been fully elucidated, informing the aim of this study. A total of 6081 subjects, for which we had complete data on measurements of handgrip strength (HGS) and other relevant variables, were included from the Korea National Health and Nutrition Examination Surveys (KNHANES) VII-3. A multivariable analysis showed that people with a low household income (odds ratio (OR) 1.637, p = 0.005) and low education status (OR 2.351, p &lt, 0.001) had a poor HGS compared to those with a high SES, and that the difference in HGS made by muscle exercise was greater for people with a low household income (OR 7.082 vs. 3.619, p &lt, 0.001) and low education status (OR 14.711 vs. 6.383, p &lt, 0.001). Three-step logistic regression analysis showed that muscle exercise mediated the relationship between muscle strength and low household income (OR from 1.772 to 1.736, z = 2.373, p = 0.017) and low education level (OR from 2.368 to 2.309, z = 2.489, p = 0.012). This study confirmed that exercise improves the negative effect of SES on muscle strength, suggesting the greater importance of muscle exercise for people with a low SES.

Noninfectious aortitis, inflammatory abdominal periaortitis, and idiopathic retroperitoneal fibrosis are chronic inflammatory diseases with unclear causes. Recent studies have shown that some cases of aortitis are associated with immunoglobulin G4 (IgG4)-related systemic disease. Herein, we report a case of IgG4-related aortitis (IgG4-RA) that was diagnosed after surgery. Our patient was a 46-year-old man who had experienced abdominal pain for several weeks. Preoperative evaluations revealed an area of aortitis on the infrarenal aorta. He underwent surgery, and histological examination resulted in a diagnosis of IgG4-RA.

This study aimed to identify differences in clinical and dietary characteristics, serum adipokine levels, and metabolomic profiles between early- and late-onset gout. Eighty-three men with gout were divided into an early-onset group (n = 38, aged &lt, 40 years) and a late-onset group (n = 45, aged ≥ 40 years). Dietary and clinical information was obtained at baseline. Serum adipokines, including adiponectin, resistin, leptin, and plasminogen activator inhibitor-1 (PAI-1), were quantified by a Luminex multiplex immunoassay. Metabolite expression levels in plasma were measured in 22 representative samples using metabolomics analysis based on ultra-performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry. Average body mass index, rate of consumption of sugar-sweetened beverages, and serum uric acid levels were significantly higher in the early-onset group (p &lt, 0.05), as was the PAI-I concentration (105.01 ± 42.45 ng/mL vs. 83.76 ± 31.16 ng/mL, p = 0.013). Changes in levels of metabolites mostly involved those related to lipid metabolism. In the early-onset group, acylcarnitine analog and propylparaben levels were downregulated and negatively correlated with the PAI-1 concentration whereas LPC (22:6) and LPC (18:0) levels were upregulated and positively correlated with the PAI-1 concentration. Dietary and clinical features, serum adipokine concentrations, and metabolites differed according to whether the gout is early-onset or late-onset. The mechanisms of gout may differ between these groups and require different treatment approaches.

Background Patient-centered management is becoming increasingly important in gout, but there are limited studies exploring patients' perspectives and preferences. We aimed to investigate patients' perspectives and preferences regarding gout and gout management, and their impacts on adherence to urate lowering therapy (ULT). Methods A paper-based survey was performed in patients with gout seen at the rheumatology outpatient clinics of 16 tertiary hospitals. The survey included questions regarding demographics, comorbidities, gout attacks, current treatment and adherence, and patients' perspectives and preferences regarding gout and gout management. Multivariate regression analysis was performed to determine the factors associated with ULT adherence. Results Of 809 surveyed patients with gout, 755 (94.5%) were using ULT. Among those using ULT, 89.1% had ≥ 80% adherence to ULT. Majority of the patients knew management strategies to some extent (94.8%), perceived gout as a life-long disease (91.2%), and were making efforts toward practicing at least one lifestyle modification (89.2%). Most patients (71.9%) obtained information about gout management during their clinic visits. Approximately half of the patients (53.6%) preferred managing their disease with both ULT and lifestyle modification, 28.4% preferred ULT only, and 17.4% preferred lifestyle modification only. Adherence was better in patients with older age (odds ratio [OR], 1.03), those with better knowledge of gout management strategies (OR, 3.56), and those who had preference for ULT (OR, 2.07). Conclusion Patients' perspectives and management preferences had high impacts on adherence to ULT in gout. Consideration of patients' perspectives and preferences is important for achieving the desired clinical outcome in gout., Graphical Abstract

Histamine releasing factor/translationally controlled tumor protein (HRF/TCTP) stimulates cancer progression and allergic responses, but the role of HRF/TCTP in rheumatoid arthritis (RA) remains undefined. In this study, we explored the pathogenic significance of HRF/TCTP and evaluated the therapeutic effects of HRF/TCTP blockade in RA. HRF/TCTP transgenic (TG) and knockdown (KD) mice with collagen-induced arthritis (CIA) were used to determine the experimental phenotypes of RA. HRF/TCTP levels in the sera of RA patients were measured and compared to those from patients with osteoarthritis (OA), ankylosing spondylitis, Behçet’s disease, and healthy controls. HRF/TCTP expression was also assessed in the synovium and fibroblast-like synoviocytes (FLSs) obtained from RA or OA patients. Finally, we assessed the effects of HRF/TCTP and dimerized HRF/TCTP-binding peptide-2 (dTBP2), an HRF/TCTP inhibitor, in RA-FLSs and CIA mice. Our clinical, radiological, histological, and biochemical analyses indicate that inflammatory responses and joint destruction were increased in HRF/TCTP TG mice and decreased in KD mice compared to wild-type littermates. HRF/TCTP levels in the sera, synovial fluid, synovium, and FLSs were higher in patients with RA than in control groups. Serum levels of HRF/TCTP correlated well with RA disease activity. The tumor-like aggressiveness of RA-FLSs was exacerbated by HRF/TCTP stimulation and ameliorated by dTBP2 treatment. dTBP2 exerted protective and therapeutic effects in CIA mice and had no detrimental effects in a murine tuberculosis model. Our results indicate that HRF/TCTP is a novel biomarker and therapeutic target for the diagnosis and treatment of RA., Rheumatoid arthritis: A problem protein to target for treatment A protein known to stimulate cancer and allergies has been implicated as an exacerbating factor in rheumatoid arthritis (RA); inhibiting its activity or blocking its production could offer options to prevent or treat RA. Previous research had identified high levels of histamine-releasing factor (HRF), also known as translationally controlled tumor protein (TCTP), in patients with RA. Its role in the destruction of joint tissue seen in RA was investigated by researchers in South Korea led by Sang-Il Lee at Gyeongsang National University, Jinju, and Kyunglim Lee at Ewha Womans University, Seoul. They examined HRF/TCTP’s activity and effects in fibroblast-like synoviocytes from RA patients and in a mouse model of RA and confirmed it can cause joint inflammation and damage. A molecule that inhibits HRF/TCTP activity reduced the severity of RA-like effects, suggesting potential new therapies.

Background and Purpose Histamine releasing factor/translationally controlled tumor protein (HRF/TCTP) stimulates cancer progression and allergic responses, but the role of HRF/TCTP remains undefined in rheumatoid arthritis (RA). In this study, we explored the pathogenic significance of HRF/TCTP and evaluated the therapeutic effects of HRF/TCTP blockade in RA. Experimental Approach HRF/TCTP transgenic (TG) and knockdown (KD) mice with collagen-induced arthritis (CIA) were used to determine experimental phenotypes of RA. HRF/TCTP levels were measured in the sera of RA patients and compared to those with osteoarthritis (OA), ankylosing spondylitis, Behcet’s disease, and healthy controls. HRF/TCTP expression was also assessed in the synovium and fibroblast-like synoviocytes (FLS) obtained from RA or OA patients. Finally, we assessed the effects of HRF/TCTP and dimerized HRF/TCTP-binding peptide-2 (dTBP2), an HRF/TCTP inhibitor, in RA-FLS and CIA mice. Key Results Our clinical, radiological, histological, and biochemical analyses indicate that inflammatory responses and joint destruction were higher in HRF/TCTP TG mice, and lower in KD mice, compared to that in wild-type littermates. HRF/TCTP levels were higher in the sera, synovial fluid, synovium, and FLS of patients with RA than control groups. Serum levels of HRF/TCTP correlated well with disease activity of RA. Tumor-like aggressiveness of RA-FLS was exacerbated by HRF/TCTP stimulation and ameliorated by dTBP2 treatment. dTBP2 exerted protective and therapeutic effects in CIA mice, and had no detrimental effects in a murine tuberculosis model. Conclusion and Implications Our results indicate that HRF/TCTP is a novel biomarker and therapeutic target for the diagnosis and treatment of RA.

Inflammation and trophic factors (brain-derived neurotrophic factor [BDNF], vascular endothelial growth factor, glial cell line-derived neurotrophic factor, and insulin-like growth factor-1) are associated with depression in the general population. Rheumatoid arthritis (RA) is a chronic representative inflammatory autoimmune disease; however, the association of disease activity, pro-inflammatory cytokines, and neurotrophic factors with depression has not been sufficiently investigated. Therefore, we determined the prevalence of depression and risk factors for depression and deterioration of depressive symptoms in RA patients. In addition, we analyzed the association between disease activity, pro-inflammatory cytokines, trophic factors, and depression in RA (N = 474). Demographic and laboratory data were examined, and routine assessment of patient index data 3 (RAPID 3) and disease activity score 28-joint count C-reactive protein (DAS 28-CRP) was performed to assess disease activity of RA. Depression was measured using the Korean version of the Beck Depression Inventory-second edition (K-BDI II). A K-BDI score ≥18 was considered the cut-off for depression in accordance with a previous validation study. The serum level of pro-inflammatory cytokines and neurotrophic factors was assessed by enzyme-linked immune sorbent assay. The prevalence of depression was 32.4% in patients with RA. The severity of disease activity of RA (RAPID 3 score [OR 2.34; 95% confidence interval, CI 1.22-4.51], DAS 28-CRP [≥3.2] [OR 1.60, 95% CI 1.01-2.53]) and severity of fatigue (OR 1.26 95% CI 1.15-1.38) were associated with depression and deterioration of depressive symptoms in the multivariate analysis. Among the components of RAPID 3 and DAS 28-CRP, patient assessment for global health and abilities for daily performance were more related to depression. The level of pro-inflammatory cytokines (IL-1β, IL-6, TNF-alpha) was not related to depression. The level of BDNF was significantly lower in RA patients with depression and was negatively correlated with K-BDI II score. Depression was related with the level of fatigue, low expression of BDNF, and high RA disease activity, which was associated with impaired ability to perform activities of daily life. Strict control of fatigue and disease activity to improve one's capacity to perform daily life activities would be important to regulate depression. The level of BDNF might be one of the possible biomarkers to predict or monitor depression in patients with RA.

The purpose of this study is to investigate the effect of TSAHC [4'-(p-toluenesulfonylamido)-4-hydroxychalcone] in K/BxN serum transfer arthritis model and fibroblast-like synoviocytes of rheumatoid arthritis (RA-FLS). In in vivo experiments, TSAHC attenuated the incidence and severity of arthritis in comparison with the vehicle group. Histological findings showed that TSAHC decreased the inflammation, bone erosion, cartilage damage, and osteoclasts activity in the ankle. Furthermore, we confirmed by biochemical analysis that the observations were associated with the decreased expression of proinflammatory cytokines, matrix metalloproteinases (MMPs), and RANKL in serum and ankle. In in vitro experiments, TSAHC induced apoptosis, while it significantly suppressed tumor necrosis factor-α (TNF-α)-induced cell proliferation in RA-FLS. Moreover, TSAHC inhibited mRNA expression of TNF-α-induced interleukin (IL)-6, MMP-1, MMP-3, and MMP-13. Evaluation of signaling events showed that TSAHC inhibited the translocation and transcriptional activity of nuclear factor-kappa B (NF-κB) by regulating phosphorylated-IκB-α (p-IκB-α) and IκB-α in TNF-α-induced RA-FLS. Our results suggest that TSAHC inhibits experimental arthritis in mice and suppresses TNF-α-induced RA-FLS activities via NF-κB pathway. Therefore, TSAHC may have therapeutic potential for the treatment of RA.

BACKGROUND/AIMS To investigate medication nonadherence in Korean patients with rheumatoid arthritis (RA) and analyze related factors. METHODS A total of 292 patients with RA participated in this study. Medication nonadherence, intentional or unintentional, was gauged via self-reported questionnaire. Patient perceptions of illness, treatment beliefs, and moods were measured via Brief Illness Perception Questionnaire, Beliefs about Medicines Questionnaire, and Patient Health Questionnaire-2, respectively. Demographic and clinical data were also collected. Multinomial regression analysis was used to assess the impact of demographic, clinical, and psychological factors on medication nonadherence. RESULTS The medication nonadherence rate was 54.1% (intentional, 21.6%; unintentional, 32.5%). Intentional nonadherence was reported most often in patients treated daily drugs (nonsteroidal anti-inflammatory drugs and/or disease-modifying antirheumatic drugs) (24.2%), and unintentional nonadherence was highest in patients receiving methotrexate (33.3%) (p = 0.872). In univariate analysis, beliefs in necessity and concerns of medication differed significantly in adherent and nonadherent patients (intentional or unintentional). When controlling for other factors that may impact medication nonadherence, less belief in necessity of medication (odds ratio [OR], 0.81; 95% confidence interval [CI], 0.68 to 0.95) and greater emotional response to disease (OR, 1.19; 95% CI, 1.01 to 1.40) were important predictors of intentional nonadherence. CONCLUSIONS Medication nonadherence is common in Korean patients with RA. Less belief in necessity of medication and greater emotional response to disease were identified as key factors prompting intentional nonadherence. These factors may be strategically targeted to improve medication adherence rates and subsequent clinical outcomes.

Systemic sclerosis (SSc) is an autoimmune disorder characterized by fibrosis of the skin and internal organs. Despite several studies on SSc treatments, effective treatments for SSc are still lacking. Since evidence suggests an association between intestinal microbiota and SSc, we focused on butyrate, which has beneficial effects in autoimmune diseases as a bacterial metabolite. Here, we investigated the therapeutic potential of sodium butyrate (SB) using a bleomycin-induced fibrosis mouse model of SSc and human dermal fibroblasts (HDFs). SB attenuated bleomycin-induced dermal and lung fibrosis in mice. SB influenced fecal microbiota composition (phyla Actinobacteria and Bacteroidetes, genera Bifidobacterium and Ruminococcus_g2). SB controlled macrophage differentiation in mesenteric lymph nodes, spleen, and bronchoalveolar lavage cells of mice with bleomycin-induced skin fibrosis. Profibrotic and proinflammatory gene expression was suppressed by SB administration in skin. Furthermore, SB inhibited transforming growth factor β1-responsive proinflammatory expression with increased acetylation of histone 3 in HDFs. Subcutaneous SB application had antifibrogenic effects on the skin. Butyrate ameliorated skin and lung fibrosis by improving anti-inflammatory activity in a mouse model of SSc. Butyrate may exhibit indirect and direct anti-fibrogenic action on fibroblasts by regulating macrophage differentiation and inhibition of histone deacetylase 3. These findings suggest butyrate as an SSc treatment.

Background:Histamine-releasing factor/translationally controlled tumor protein (HRF/TCTP) stimulates cancer progression and allergic responses. Increased expression of HRF/TCTP occurs in joints of rheumatoid arthritis (RA) patients, but the role of HRF/TCTP in RA remains undefinedObjectives:In this study, we explored the pathogenic significance of HRF/TCTP and evaluated therapeutic effects of HRF/TCTP blockade in RA.Methods:HRF/TCTP transgenic (TG) and knockdown (KD) mice with collagen-induced arthritis (CIA) were used to determine experimental phenotypes of RA. HRF/TCTP levels were measured in sera and joint fluids in patients with RA and compared to those with osteoarthritis, ankylosing spondylitis, Behcet disease, and healthy controls. HRF/TCTP expression was also assessed in synovium and fibroblast-like synoviocytes (FLS) obtained from RA or OA patients. Finally, we assessed effects of HRF/TCTP and dimerized HRF/TCTP binding peptide-2 (dTBP2), an inhibitor of HRF/TCTP, in RA-FLS and CIA mice.Results:Our clinical, radiological, histological, and biochemical analyses indicate that inflammatory responses and joint destruction were increased in HRF/TCTP TG mice, and decreased in KD mice compared to wild-type littermates. HRF/TCTP levels were higher in sera, synovial fluid, synovium, and FLS of patients with RA than in control groups. Serum levels of HRF/TCTP correlated well with disease activity in RA. Tumor-like aggressiveness of RA-FLS was exacerbated by HRF/TCTP stimulation and ameliorated by dTBP2 treatment. dTBP2 exerted protective and therapeutic effects in CIA mice, and had no detrimental effect in a murine tuberculosis model.Conclusion:Our results indicate that HRF/TCTP represents a novel biomarker and therapeutic target for diagnosis and treatment of RA.References:N/AAcknowledgments :National Research Foundation of KoreaKorea Health Industry Development InstituteDisclosure of Interests:None declared

Background:The pathophysiology of cognitive impairment remains unclear, however, several studies have demonstrated that pro-inflammatory cytokines such as Interleukin-6 (IL-6), Tumor necrosis factor-α (TNF-α) and lipocalin-2 (LCN2) are related with cognitive impairment by activation of microglia and astrocyte in brain. Rheumatoid arthritis (RA) is a representative inflammatory disease; however, the association of pro-inflammatory cytokines and LCN2 with cognitive impairment has seldomly been investigated in RA.Objectives:Here, we determined the effect of pro-inflammatory cytokines and LCN2 on cognitive impairment in collagen-induced arthritis (CIA) mouse model. In addition, we studied the effect of TNF-α inhibitor (etanercept) on cognitive impairment.Methods:We induced CIA mice and randomly divided into three groups: Normal (n=10), CIA group (n=10), CIA/Etanercept group (n=10). We evaluated severity of arthritis using clinical scoring system. Joint inflammation, cartilage damage, and osteoclastic bone resorption has checked. Level of pro-inflammatory cytokines (TNF-α, and IL-6) and LCN2 checked in mice sera using enzyme-linked immunosorbent assay (ELISA). The expression of pro-inflammatory cytokines and LCN2 in ankle and hippocampus analyzed using real-time PCR. The activation of glial fibrillary acidic protein (GFAP) and ionized calcium-binding adapter molecule 1 (Iba-1) in hippocampus analyzed using immunohistochemistry (IHC). The LCN2 evaluated by western blot using hippocampal tissue. Cognitive impairment determined by morris water maze (MWM) test.Results:Compared to normal group, CIA mice showed increased severity of arthritis, inflammation and destruction of joint. In MWM test, CIA mice significantly exhibited increased escape latencies and escape time, reduced the time in the target quadrant, and the number of target zone crossings during five study days compared with normal group. The level of pro-inflammatory cytokines (TNF-α, IL-6) and LCN2 in both sera, ankle tissue and hippocampal tissue was significantly increased. We examined whether inhibiting inflammation can mitigate the severity of arthritis and cognitive impairment. Compared to CIA mice, CIA/Etanercept group showed decreased severity of arthritis and joint inflammation. In MWM test, CIA/Etanercept group showed reduced escape latencies and escape time, increased the time in the target quadrant and the number of target zone crossings. The level of pro-inflammatory cytokines and LCN2 significantly decreased in both peripheral tissue and hippocampal tissue. In addition, the expression level of GFAP, Iba-1 and inflammatory markers decreased after treatment of etanercept. The results indicated that inhibition of inflammation may improve cognitive impairment.Conclusion:The results suggest that peripheral arthritis induced inflammation is a possible cause for cognitive impairment by increasing pro-inflammatory cytokines and LCN2 in both peripheral tissue and hippocampal tissue in RA. In addition, we indicate that early anti-inflammatory treatment using etanercept may mitigate or inhibit the progression of cognitive impairment in RA.References:[1]Gauthier, S., et al., Mild cognitive impairment. Lancet, 2006.367(9518): p. 1262-70.[2]Belarbi, K., et al., TNF-alpha protein synthesis inhibitor restores neuronal function and reverses cognitive deficits induced by chronic neuroinflammation. J Neuroinflammation, 2012.9: p. 23.[3]Cunningham, C., et al., Systemic inflammation induces acute behavioral and cognitive changes and accelerates neurodegenerative disease. Biol Psychiatry, 2009.65(4): p. 304-12.[4]Camara, M.L., et al., Effects of centrally administered etanercept on behavior, microglia, and astrocytes in mice following a peripheral immune challenge. Neuropsychopharmacology, 2015.40(2): p. 502-12.[5]Gulkesen, A., et al., Lipocalin 2 as a clinical significance in rheumatoid arthritis. Cent Eur J Immunol, 2017.42(3): p. 269-273.Disclosure of Interests:None declared

OBJECTIVES:To estimate the prevalence and associated factors of rotator cuff tear (RCT) in patients with hand osteoarthritis (HOA). METHODS:Between June 2013 and December 2015, we recruited 1150 participants in rural area of South Korea. Of the 1150 participants, 307 participants with HOA were analyzed. Plain radiography of both hands, magnetic resonance imaging of both shoulders, and serum levels of high-sensitive C-reactive protein (hsCRP) and high-density lipoprotein (HDL) were obtained for all patients. HOA and RCT were diagnosed by clinical and radiologic findings. RESULTS:The prevalence of RCT in patients with HOA (192/307, 62.5%) was higher than that in those without HOA (410/827, 49.5%, p

Background We recently reported that myeloid sirtuin 6 (Sirt6) is a critical determinant of phenotypic switching and the migratory responses of macrophages. Given the prominent role of macrophages in the pathogenesis of rheumatoid arthritis (RA), we tested whether myeloid Sirt6 deficiency affects the development and exacerbation of RA. Methods Arthritis was induced in wild type and myeloid Sirt6 knockout (mS6KO) mice using collagen-induced and K/BxN serum transfer models. Sirt6 expression (or activity) and inflammatory activities were compared in peripheral blood mononuclear cells (PBMCs) and monocytes/macrophages obtained from patients with RA or osteoarthritis. Findings Based on clinical score, ankle thickness, pathology, and radiology, arthritis was more severe in mS6KO mice relative to wild type, with a greater accumulation of macrophages in the synovium. Consistent with these findings, myeloid Sirt6 deficiency increased the migration potential of macrophages toward synoviocyte-derived chemoattractants. Mechanistically, Sirt6 deficiency in macrophages caused an inflammation with increases in acetylation and protein stability of forkhead box protein O1. Conversely, ectopic overexpression of Sirt6 in knockout cells reduced the inflammatory responses. Lastly, PBMCs and monocytes/macrophages from RA patients exhibited lower expression of Sirt6 than those from patients with osteoarthritis, and their Sirt6 activity was inversely correlated with disease severity. Interpretation Our data identify a role of myeloid Sirt6 in clinical and experimental RA and suggest that myeloid Sirt6 may be an intriguing therapeutic target. Fund Medical Research Center Program and Basic Science Research Program through the National Research Foundation of Korea., Graphical abstract Unlabelled Image, Highlights • Myeloid Sirt6 deficiency aggravates the joint destruction by increasing recruitment of macrophages into arthritic joints. • Myeloid Sirt6 deacetylates FoxO1 to promote proteasomal degradation. • Overexpression of Sirt6 greatly attenuates inflammatory activity of human macrophages. • Sirt6 expression and activity decrease in blood monocytes and joint macrophages from RA patients.

Background Rheumatoid arthritis (RA) is an autoimmune inflammatory disease of the joints and is characterised by immune cell infiltration, synovial hyperplasia, and destruction of cartilage and underlying bone 1 . Raf kinase inhibitory protein (RKIP), an endogenous inhibitor of the extracellular signal-regulated kinase (ERK) pathway, has been implicated as a suppressor of metastasis and NF-κB pathway in cancers 2 . Objectives The NF-κB and ERK pathways are considered to be one of the most important pro-inflammatory signalling pathways in RA. Therefore, RKIP might be a potential therapeutic target for RA. However, whether and how RKIP regulates RA is not fully understood. The present study was performed to examine whether and how RKIP are differentially regulated in RA. Methods The expressions of RKIP were assessed in synovial tissue, fluid and fibroblast-like synoviocytes (FLS) from patients with RA and osteoarthritis (OA) by immunofluorescence staining and western blotting. RA- or OA-FLS were infected with either a recombinant adenoviral RKIP overexpressing vector (Ad-RKIP) or shRNA-expressing vector (Ad-shRKIP). Control cells infected with a GFP-targeted recombinant adenoviral vector (Ad-shGFP) (figure 1C). And then, we investigated the effects of RKIP on the migratory activity and invasion rates of FLS by transwell migration and invasion assay. Results Here, we show that RKIP expression is inversely correlated with RA. The levels of RKIP were significantly decreased in fibroblast-like synoviocytes (FLS), synovial fluid and synovium of RA patients compare to OA patients. And also find that migration and invasion of RA-FLS were significantly increased by the inhibition of RKIP compare to OA-FLS. Knockdown of RKIP in RA or OA-FLS resulted in a dramatic increase of MMP3 and IL6. We also found osteoclastogenesis of RAW cells were increased by the knockdown of RKIP. Conclusions Our data identify a role of RKIP in RA and suggest that further studies on the potential involvement of RKIP will be beneficial in better understanding the pathology of and providing a new target for treatment for RA. References [1] Ospelt C. Synovial fibroblasts in 2017. RMD Open2017;3(2):e000471. [2] Yesilkanal AE, Rosner MR. Raf kinase inhibitory protein (RKIP) as a metastasis suppressor: regulation of signaling networks in cancer. Crit Rev Oncog. 2014;19:447–454. [3] Noh HS, Hah YS, Ha JH, Kang MY, Zada S, Rha SY, Kang SS, Kim HJ, Park J, Byun J, Hahm JR, Shin JK, Jeong S, Lee Y, Kim DR. Regulation of the epithelial to mesenchymal transition and metastasis by Raf kinase inhibitory protein-dependent Notch1 activity. Oncotarget2016;7(4):4632–46. Disclosure of Interest None declared

Background Rheumatoid arthritis (RA) is an autoimmune inflammatory disease of the joints and is characterised by immune cell infiltration, synovial hyperplasia, and destruction of cartilage and underlying bone 1. Myeloid derived monocytes and macrophages secrete a variety of cytokines such as tumour necrosis factor-α (TNF-α), interleukin (IL)−1β and IL-6, all of which perpetuate and amplify the vicious cycle of chronic inflammatory pathways 2. Indeed, macrophage numbers in the synovium and serum levels of monocyte-derived cytokines correlate well with clinical symptoms and degree of joint damage in RA 3. Objectives We recently reported that myeloid sirtuin 6 (Sirt6) is a critical determinant of phenotypic switching and the migratory responses of macrophages 4. Given the prominent role of macrophages in rheumatoid arthritis (RA) pathogenesis 5, we tested whether myeloid Sirt6 deficiency affects the development and exacerbation of RA. Methods Arthritis was induced in wild type and myeloid Sirt6 KO (mS6KO) mice using collagen-induced and K/BxN serum transfer models. Peripheral blood mononuclear cells (PBMC) and synovial fluid macrophages were obtained from patients with RA and osteoarthritis and used for comparisons of Sirt6 expression and inflammatory activities. Results Based on clinical scores, ankle thickness, pathology and radiology, arthritis was more severe in mS6KO mice relative to wild type with a greater accumulation of macrophages in the synovium. Consistently, myeloid Sirt6 deficiency increased the migration potential of macrophages toward synoviocytes-derived chemoattractants. Mechanistically, Sirt6 deacetylates forkhead box protein O1 to trigger its nuclear export and proteasomal degradation. Lastly, PBMC and macrophages isolated from RA patients exhibited lower Sirt6 expression compared with those from osteoarthritis patients or healthy subjects and their Sirt6 activity was inversely correlated with disease severity of the patients. Conclusions Our data identify a role of myeloid Sirt6 in clinical and experimental RA and suggest that myeloid Sirt6 may be an intriguing therapeutic target. References [1] Ospelt C. Synovial fibroblasts in 2017. RMD Open 2017;3(2):e000471. [2] Gierut A, Perlman H, Pope RM. Innate immunity and rheumatoid arthritis. Rheum Dis Clin North Am2010;36(2):271–96. [3] Kinne RW, S tuhlmuller B, Burmester GR. Cells of the synovium in rheumatoid arthritis. Macrophages. Arthritis Res Ther2007;9(6):224. [4] Lee Y, Ka SO, Cha HN, et al. Myeloid sirtuin 6 deficiency causes insulin resistance in high-fat diet-fed mice by eliciting macrophage polarization toward an M1 phenotype. Diabetes2017;66(10):2659–68. [5] Lee HS, Ka SO, Lee SM, et al. Overexpression of sirtuin 6 suppresses inflammatory responses and bone destruction in mice with collagen-induced arthritis. Arthritis Rheum2013;65(7):1776–85. Disclosure of Interest None declared

Objective To identify the prevalence of and risk factors for knee pain and radiographic knee osteoarthritis (RKOA) and to investigate the relationship between decreased lower extremity muscle mass (DLEM) and knee pain severity. Methods Using data from the Korea National Health and Nutrition Examination Survey, 3,278 participants who were ≥50 years old and who underwent dual x-ray absorptiometry, plain knee radiographs and completed a knee pain questionnaire were enrolled. Lower extremity muscle mass (LEM) was defined as the sum of the fat-free soft tissue mass of the legs, and lower extremity muscle mass index (LMI) was calculated as LEM/body weight (%). DLEM was defined as an LMI more than two standard deviations below the mean of a gender-matched young reference group. Categorical variables were presented as numbers (weighted %). Results The prevalence of knee pain and RKOA were 22% (n = 721) and 34.7% (n = 1,234), respectively. Multivariate logistic regression analysis showed being female (OR 2.15, 95% CI 1.67–2.79), older (OR 1.03, 95% CI 1.01–1.04), less educated (OR 1.72, 95% CI 1.09–2.71), stiffness (OR 16.15, 95% CI 12.04–21.66), bed rest (OR 2.49, 95% CI 1.81–3.43), RKOA (OR 2.20, 95% CI 1.78–2.74) and DLEM (OR 1.54, 95% CI 1.09–2.17) were associated with knee pain. Participants with simultaneous RKOA and DLEM complained of more severe pain (pain score 7.18 ± 2.48) than those with knee pain without RKOA or DLEM (5.02 ± 2.44), those with only RKOA (6.29 ± 2.50), or those with only DLEM (6.78 ± 2.18) (P

AIM To investigate whether plain radiography is useful for assessing the changes in gouty tophi size following hypouricemic therapy. METHODS Gout was diagnosed according to the American College of Rheumatology criteria. Before and after hypouricemic treatment, serum uric acid level was measured, and plain radiography was performed to measure gouty tophi size. The tophi were graded by measuring the maximum vertical and horizontal diameters, and they were scored by adding up the scores of the grades. The vertical diameter was measured on both sides of the proximal phalanges (PPs). The horizontal diameter was measured on the lateral side of the PPs. The maximum vertical diameter measurement was graded 0-4. The maximum horizontal diameter measurement was graded 0-3. RESULTS Seven hundred first metatarsal phalangeal joints (MTPJ) of 350 patients with gout were assessed for gouty tophi. Tophi were observed using plain radiography in 174 MTPJs (24.9%) of 109 patients (31.1%). Follow-up plain radiography was performed in 60 of these patients. Before the treatment, the average serum uric acid level of these patients was 8.3 ± 1.9 mg/dL, and the average tophi score was 3.7 ± 2.5. After hypouricemic treatment, the uric acid level decreased to 5.9 ± 1.6 mg/dL (P < 0.05), and the average tophi score decreased to 1.5 ± 1.8 (P < 0.05). CONCLUSIONS This new method for measuring gouty tophi using plain radiography may be useful for evaluating changes in gouty tophi size following hypouricemic treatment.

We present a case of a 65-year-old man with psoriasis who developed autoimmune hepatitis (AIH) without receiving immunosuppressive therapy with either anti-tumor necrosis factor-α or methotrexate. The AIH had completely resolved at 2 months after prednisolone and azathioprine therapy. This case confirms the need to consider AIH in psoriasis patients who experience new elevations in liver enzymes. To our knowledge, this is first description of the development of AIH in an immunosuppressant-naive patient with psoriasis.

Background/Aims To determine whether early diagnosis is beneficial for functional status of various disease durations in rheumatoid arthritis (RA) patients. Methods A total of 4,540 RA patients were enrolled as part of the Korean Observational Study Network for Arthritis (KORONA). We defined early diagnosis as a lag time between symptom onset and RA diagnosis of ≤ 12 months, whereas patients with a longer lag time comprised the delayed diagnosis group. Demographic characteristics and outcomes were compared between early and delayed diagnosis groups. Logistic regression analyses were performed to identify the impact of early diagnosis on the development of functional disability in RA patients. Results A total of 2,597 patients (57.2%) were included in the early diagnosis group. The average Health Assessment Questionnaire-Disability Index (HAQ-DI) score was higher in the delayed diagnosis group (0.64 ± 0.63 vs. 0.70 ± 0.66, p < 0.01), and the proportion of patients with no functional disability (HAQ = 0) was higher in the early diagnosis group (22.9% vs. 20.0%, p = 0.02). In multivariable analyses, early diagnosis was independently associated with no functional disability (odds ratio [OR], 1.19; 95% confidence interval [CI], 1.01 to 1.40). In a subgroup analysis according to disease duration, early diagnosis was associated with no functional disability in patients with disease duration < 5 years (OR, 1.37; 95% CI, 1.09 to 1.72) but not in patients with longer disease duration (for 5 to 10 years: OR, 1.07; 95% CI, 0.75 to 1.52; for ≥ 10 years: OR, 0.92; 95% CI, 0.65 to 1.28). Conclusions Early diagnosis is associated with no functional disability, especially in patients with shorter disease duration.

Cardiac injury is a common but occasionally serious complication of blunt chest trauma. A ventricular septal rupture (VSR) is a rare complication and is variable in its presentation, temporal course and severity. Here, we report a rare case of 75-year-old man who developed delayed VSR following blunt chest trauma.

To investigate medication nonadherence in Korean patients with rheumatoid arthritis (RA) and analyze related factors.A total of 292 patients with RA participated in this study. Medication nonadherence, intentional or unintentional, was gauged via self-reported questionnaire. Patient perceptions of illness, treatment beliefs, and moods were measured via Brief Illness Perception Questionnaire, Beliefs about Medicines Questionnaire, and Patient Health Questionnaire-2, respectively. Demographic and clinical data were also collected. Multinomial regression analysis was used to assess the impact of demographic, clinical, and psychological factors on medication nonadherence.The medication nonadherence rate was 54.1% (intentional, 21.6%; unintentional, 32.5%). Intentional nonadherence was reported most often in patients treated daily drugs (nonsteroidal anti-inflammatory drugs and/or disease-modifying antirheumatic drugs) (24.2%), and unintentional nonadherence was highest in patients receiving methotrexate (33.3%) (Medication nonadherence is common in Korean patients with RA. Less belief in necessity of medication and greater emotional response to disease were identified as key factors prompting intentional nonadherence. These factors may be strategically targeted to improve medication adherence rates and subsequent clinical outcomes.

Abnormal regulation of ER stress and apoptosis has been implicated in autoimmune disorders. Particularly, ER stress-induced autophagy and the role of GRP78, or BiP in T lymphocyte survival and death in SLE are poorly understood. This study investigated the pathogenic roles of ER stress-induced autophagy and GRP78/BiP in apoptosis of T lymphocytes. We compared spontaneous and induced autophagy and apoptosis of T lymphocytes in healthy donors and patients with SLE. The molecular mechanism of altered autophagy and apoptosis was investigated in T lymphocytes transfected with siRNA for beclin 1 and CHOP and T lymphocytes overexpressing GRP78. Decreased autophagy and increased apoptosis in response to TG-induced ER stress were observed in lupus T lymphocytes. GRP78 and ER stress-signaling molecules, such as PERK, p-eIF2α, IRE1, and ATF6 decreased, whereas CHOP levels increased in lupus T cells in response to TG. The levels antiapoptotic molecules, Bcl-2 and Bcl-XL decreased, whereas the proapoptotic molecules, Bax and caspase 6, increased in lupus T cells. The TG-induced ER stress altered autophagy and apoptosis, which in turn, led to abnormal T cell homeostasis with increased apoptotic T cell death. We hypothesize that aberrant autophagy of T lymphocytes as a result of ER stress and decreased GRP78 expression is involved in the pathogenesis of SLE and might serve as important therapeutic targets.

Here, we report the case of a 69-year-old man with limited granulomatosis with polyangiitis (GPA; formerly Wegener's granulomatosis) who developed papillary thyroid cancer, adenocarcinoma of the stomach, and myelodysplastic syndrome following glucocorticoid treatment. This is the first report to present multiple malignancies in a patient with limited GPA without immunosuppressive treatment. Thus, our report supports the notion that limited GPA itself can be associated with the development of malignancy.

Objective: SIRT1 modulates the acetylation of the p65 subunit of nuclear factor-kappa B (NF-kappa B) and plays a pivotal role in the inflammatory response. This study sought to assess the role of SIRT1 in rheumatoid arthritis (RA) using a myeloid cell-specific SIRT1 knockout (mSIRT1 KO) mouse. Methods: mSIRT1 KO mice were generated using the loxP/Cre recombinase system. K/BxN serum transfer arthritis was induced in mSIRT1 KO mice and age-matched littermate loxP control mice. Arthritis severity was assessed by clinical and pathological scoring. The levels of inflammatory cytokines in the serum and joints were measured by ELISA. Migration, M1 polarization, cytokine production, osteoclastogenesis, and p65 acetylation were assessed in bone marrow-derived monocytes/macrophages (BMMs). Results: mSIRT1 KO mice showed more severe inflammatory arthritis and aggravated pathological findings than control mice. These effects were paralleled by increases in IL-1, TNF-alpha, TRAP-positive osteoclasts, and F4/80(+) macrophages in the ankles of mSIRT1 KO mice. In addition, BMMs from mSIRT1 KO mice displayed hyperacetylated p65 and increased NF-kappa B binding activity when compared to control mice, which resulted in increased M1 polarization, migration, pro-inflammatory cytokine production, and osteoclastogenesis. Conclusion: Our study provides in vivo evidence that myeloid cell-specific deletion of SIRT1 exacerbates inflammatory arthritis via the hyperactivation of NF-kappa B signaling, which suggests that SIRT1 activation may be beneficial in the treatment of inflammatory arthritis.

Background Both neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte (PLR) are reported to be increased in various inflammatory diseases, but there clinical significance in adult onset still disease (AOSD) remains unclear. Objectives The aim of the present study was to evaluate NLR and PLR as a inflammatory marker in AOSD. Methods The medical records of 23 AOSD patients and age, sex-matched 25 healthy individuals were retrospectively reviewed. NLR, PLR between AOSD patients and healthy controls were compared, and correlation between these indexes and clinical characteristics were analyzed. Exclusion criteria included active infection and/or the presence of any hematological, cardiovascular or metabolic disorder. Results The NLR and PLR were found to be significantly higher in AOSD patients when compared to the healthy control (NLR: 10.67± 6.73 vs 2.05±1.07, p Conclusions NLR, PLR, together with other serum inflammatory markers, were proving as significant clinical tools which could be used as biomarkers for inflammatory response of disease activity in AOSD patients. Disclosure of Interest None declared

The type III histone deacetylase silent information regulator 1 (SIRT1) is an enzyme that is critical for the modulation of immune and inflammatory responses. However, the data on its role in rheumatoid arthritis (RA) are limited and controversial. To better understand how SIRT1 regulates adaptive immune responses in RA, we evaluated collagen-induced arthritis (CIA) in myeloid cell-specific SIRT1 knockout (mSIRT1 KO) and wild-type (WT) mice. Arthritis severity was gauged on the basis of clinical, radiographic and pathologic scores. Compared with their WT counterparts, the mSIRT1 KO mice exhibited less severe arthritis, which was less destructive to the joints. The expression levels of inflammatory cytokines, matrix metalloproteinases and ROR-γT were also reduced in the mSIRT1 KO mice compared with the WT mice and were paralleled by reductions in the numbers of Th1 and Th17 cells and CD80- or CD86-positive dendritic cells (DCs). In addition, impaired DC maturation and decreases in the Th1/Th17 immune response were observed in the mSIRT1 KO mice. T-cell proliferation was also investigated in co-cultures with antigen-pulsed DCs. In the co-cultures, the DCs from the mSIRT1 KO mice showed decreases in T-cell proliferation and the Th1/Th17 immune response. In this study, myeloid cell-specific deletion of SIRT1 appeared to suppress CIA by modulating DC maturation. Thus, a careful investigation of DC-specific SIRT1 downregulation is needed to gauge the therapeutic utility of agents targeting SIRT1 in RA.

A 22-year-old man was diagnosed with isolated mediastinal myeloid sarcoma which radiologically mimicked primary mediastinal lymphoma. Despite administration of standard remission induction chemotherapy with daunorubicin and cytarabine, and three cycles of intensive high-dose cytarabine-based consolidation, chemo-resistant hypermetabolic lesions were persistently detected in the highest mediastinum and in the supraclavicular area. However, complete remission and long-term survival were achieved by curative radiotherapy followed by unrelated allogeneic stem cell transplantation.

Background Farming activity is burdened work with excessive use of hands. Thus, farmers are expected to have high prevalence of hand osteoarthritis (HOA). However, there is a lack of studies investigating prevalence and characteristics of HOA in Korean farmers. Objectives To estimate the prevalence of HOA among farmers in rural areas of Korea and assess whether HOA is related to farming activity. Methods The study was carried out from June 2013 to Dec 2014 with 700 farmers in Gyeong-nam Province of Korea. Clinical evaluation for hand joints was performed by rheumatologists and the plain radiographs of both hands were taken. The Australian/Canadian Osteoarthritis Hand Index (AUSCAN) was used to assess symptoms and function of hand joints. Radiographic HOA was defined as Kellgren–Lawrence (KL) grade≥2 on plain radiographs and symptomatic HOA as KL grade≥2 with pain/aching/stiffness at the same joints. Severe HOA was defined KL grade≥3. Presence of HOA at individual level was defined as ≥1 affected joint. Results Participants comprised of 53% female and 47% male with mean age of 59.7±8.6 years. As divided types of growing crops, persimmon growers, strawberry growers, rice growers, and persimmon plus rice growers were 28.6%, 27.0%, 11.7%, 23.0%, respectively. The prevalence of radiographic, symptomatic, and severe HOA was 59.1%, 13.9%, and 24.4%, respectively. Finger joints were affected in 51.4% and thumb joints in 34.1%. Interestingly, male farmers showed high prevalence of radiographic HOA (55.9%) and symptomatic HOA (13.0%). The prevalence of HOA was similar in both hands and increased with longer duration of farming. Multiple logistic regression analysis showed a significant association of age, female sex, and body mass index with radiographic HOA. As adjusted for determinants above, rice growers were associated with an increased risk of HOA (odds ratio 3.5; 95% confidence interval 1.71 to 7.21). AUSCAN score was high in female and increased according to the severity of HOA. Conclusions The prevalence of HOA in male is high, and related to types of growing crops. Therefore, this study suggests that development of HOA is associated with farming activity. References Zhang Y, Niu J, Kelly-Hayes M, Chaisson CE, Aliabadi P, Felson DT. Prevalence of symptomatic hand osteoarthritis and its impact on functional status among the elderly: The Framingham Study. Am J Epidemiol. 2002;156(11):1021-7. Cho NH, Kim SH, Kim HA, Seo YI. The Prevalence and Risk Factors of Knee and Hand Osteoarthritis in Korea. Journal of Rheumatic Diseases. 2007;14(4):354-362. Acknowledgements This study was supported by a grant of the Center for Farmer9s Safety and Health, Ministry of Agriculture, Food and Rural Affairs, Republic of Korea. Disclosure of Interest None declared

Background Orchardists are expected to show high prevalence of upper limb musculoskeletal disorders (MSDs) due to their heavy works and working postures. However, there are no systematic studies relating upper limb MSDs in Korean orchardists. Objectives To evaluate the prevalence and characteristics of upper limb MSDs among orchardists in rural areas of Korea. Methods The study was carried out from June 2013 to May 2014 in a tertiary medical center. The physical examinations of upper extremities were performed by rheumatologists, orthopedists, and rehabilitation medicine specialists. The plain radiographs of shoulder, elbow, and hand, nerve conduction examination of upper extremities, and MRI of both shoulder were taken. The Disabilities of the Arm, Shoulder, and Hand (DASH) questionnaire was used to assess symptoms and function of upper extremities. Results Five hundred and fifty orchardists were included. Participants comprised of 49.5% female and 50.5% male with mean age of 59.5±8.1 years. The mean farming duration was 31.3±13.2 years. A total of 34 different types of upper limb MSDs were detected. The most frequent disorder was myofascial pain syndrome (80.5%) followed by rotator cuff syndrome (58.9%), hand osteoarthritis (58.0%), carpal tunnel syndrome (42.9%), and lateral epicondylitis (39.5%). Prevalence of any form of MSD was 98.5% and of three and more of MSDs was 77.3%. Participants with longer duration of farming had higher numbers of MSDs. Almost part of pruning and harvesting postures in orchard farming were loaded works for musculoskeletal systems. Total DASH score was relatively high (14.9±14.4). Conclusions Almost orchardists have upper limb MSDs. Our results suggest the need to implement interventions in orchardists to prevent MSDs. References Gomez MI, Hwang S, Stark AD, May JJ, Hallman EM, Pantea CI. An analysis of self-reported joint pain among New York farmers. J Agric Saf Health. 2003;9:143–157. Holmberg S, Stiernstrom EL, Thelin A, Svardsudd K. Musculoskeletal symptoms among farmers and non-farmers: A population based study. Int J Occup Environ Health. 2002;8:339–345. Osborne A, Blake C, Fullen BM, Meredith D, Phelan J, McNamara J, Cunningham C. Prevalence of musculoskeletal disorders among farmers: A systematic review. Am J Ind Med. 2012;55(2):143-58. Acknowledgements This study was supported by a grant of the Center for Farmer9s Safety and Health, Ministry of Agriculture, Food and Rural Affairs, Republic of Korea. Disclosure of Interest None declared

showed decreased bone destruction on radiograph (3.4±0.3 vs. 2.0±0.2, p

pISSN: 2093-940X, eISSN: 2233-4718 Copyright c 2015 by The Korean College of Rheumatology. All rights reserved. This is a Free Access article, which permits unrestricted non-commerical use, distribution, and reproduction in any medium, provided the original work is properly cited. Original Article Journal of Rheumatic Diseases Vol. 22, No. 6, December, 2015 http://dx.doi.org/10.4078/jrd.2015.22.6.366