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Anti-nuclear antibodies (ANAs) are autoantibodies against nuclear substances or other cellular components. ANA tests are used in the diagnostic process to screen patients with suspected rheumatic or autoimmune diseases. ANA-associated diseases are characterized by a high titer of antinuclear antibodies and include systemic lupus erythematosus, systemic sclerosis, and mixed connective tissue diseases. ANA test results must be cautiously interpreted as they can be positive not only in infections and oncological diseases but also for the healthy general population. The ANA test mainly uses the indirect immunofluorescence test, and the results are expressed in terms of the final titer and pattern. The ANA test can increase diagnostic value when used in conjunction with the evaluation of disease-related clinical symptoms. (Korean J Med 2021;96:337-340)

Objective. High disease activity of ankylosing spondylitis (AS) is associated with poor sleep quality. The purpose of this study was to identify which of the representative tools for evaluating the disease activity of AS best reflect the quality of sleep. Methods. A total of 107 AS patients were enrolled in the study and the sleep quality was assessed using the Pittsburgh Sleep Quality Index (PSQI). Age, sex, concomitant medication, erythrocyte sedimentation rate (ESR), serum C-reactive protein (CRP) level, Beck Depression Inventory second edition (BDI-II), Bath ankylosing spondylitis disease activity index (BASDAI), ankylosing spondylitis disease activity score (ASDAS)-ESR, ASDAS-CRP, pain visual analog scale, Insomnia Severity Index (ISI), and Epworth Sleepiness Scale (ESS) were analyzed as covariates. Results. Overall, 65% (70/107) of subjects reported poor sleep quality (PSQI＞5). There was a positive correlation between the sleep quality and disease activity as measured by the BASDAI, ASDAS-ESR, and ASDAS-CRP. In addition, the BASDAI demonstrated good correlations with ISI, ESS, and BDI-II, respectively. However, only BASDAI showed reliable correlation with PSQI among the disease activity parameters of AS (adjusted odd ratio 5.36, p=0.023). Conclusion. BASDAI is the most reliable parameter of disease activity associated with the sleep quality in patients with AS. (J Rheum Dis 2021;28:143-149)

Objectives Osteoporosis and fracture are known complications of systemic lupus erythematosus (SLE). We assessed the prevalence and risk factors for osteoporosis in patients with SLE. Methods A total of 155 female SLE patients were recruited retrospectively in 5 university hospitals. The bone mineral density (BMD) was measured by dual-energy X-ray absorptiometry, and the fracture risk assessment tool (FRAX) for high-risk osteoporotic fractures was calculated with and without BMD. Results The mean age was 53.7 ± 6.8 years, and osteoporotic fractures were detected in 19/127 (15.0%) patients. The proportion of patients having a high-risk for osteoporotic fractures in the FRAX with and without BMD, and osteoporosis by the World Health Organization (WHO) criteria were 25 (16.1%), 24 (15.5%), and 51 (32.9%), respectively, and 48.0–68.6% of them were receiving treatment. On multivariate logistic analysis, nephritis (odds ratio [OR] 11.35) and cumulative dose of glucocorticoid (OR 1.1) were associated with high-risk by the FRAX with BMD, and low complement levels (OR 4.38), erythrocyte sedimentation rate (ESR) (OR 1.04), and cumulative dose of glucocorticoid (OR 1.05) were associated with osteoporosis by the WHO criteria in patients with SLE. Conclusions Among Korean female patients with SLE, the proportion of patients having a high-risk of osteoporotic fractures by the FRAX tool was 15.5%–16.1% and the proportion of patients having osteoporosis by the WHO criteria was 32.9%. In SLE, nephritis, low level of complement, ESR, and cumulative dose of glucocorticoids may contribute to fracture risk.

Systemic lupus erythematosus (SLE) is a chronic inflammatory autoimmune disease that affects various organs. SLE patients have an increased risk of infection compared to the general population. Immunosuppressive agents commonly used in SLE increase the risk of infection. Vaccination is a good way to reduce the risk of infection. However, some SLE patients are concerned that vaccination may worsen lupus disease activity or cause side effects. The latest SLE patient vaccination data were reviewed in this study, which focused on the safety, immunogenicity, and efficacy of influenza, pneumococcal, tetanus, hepatitis A, herpes zoster, and human papillomavirus vaccines. Korean immunization recommendations were also compared to those of other countries. (Korean J Med 2020;95:170-175)

Objectives This study aims to assess the efficacy and safety of mycophenolate mofetil (MMF) on lung function and skin thickness in Korean patients with systemic sclerosis-interstitial lung disease (SSc-ILD) in a real-world setting. Patients and methods This retrospective, medical chart-based study was performed at four centers in South Korea and included 34 patients (2 males, 32 females; median age 50.5 years; range, 25 to 72 years) with SSc-ILD. We investigated changes in forced vital capacity (FVC), diffusion capacity of the lung for carbon monoxide (DLCO), and modified Rodnan skin score (mRSS) according to MMF treatment for 24 months. Results The mean dose and treatment duration of MMF were 1,338.2±439.0 mg/day and 13.1±9.3 months, respectively. Although FVC decreased significantly at 15 months, FVC and DLCO did not change significantly during treatment with MMF. Median mRSS decreased significantly from 17.5 (2-40) to 10.5 (2-40) units (p

The efficacy and safety of febuxostat in patients with stage 4-5 chronic kidney disease (CKD) remains unclear. We evaluated the urate-lowering efficacy and renal safety of febuxostat in patients with stage 4-5 CKD not yet on dialysis, through a meta-analysis of observational studies.We performed a systematic search in PubMed, Ovid MEDLINE, Embase, and the Cochrane Library databases for observational studies of patients with advanced CKD starting febuxostat. Articles describing changes in serum urate levels and/or renal function assessed by the estimated glomerular filtration rate (eGFR) were included.Among 148 retrieved studies, five relevant observational studies with 327 patients were included in the meta-analysis. Febuxostat was administered daily at 10-120 mg for 3-12 months. Serum urate reduced in response to febuxostat (weighted mean difference, -1.85 mg/dL; 95% CI, -2.04--1.67 mg/dL; IOverall, febuxostat has acceptable urate-lowering efficacy and renal safety in patients with hyperuricemia and stage 4-5 CKD who are not yet on dialysis.

Melanoma is visible unlike other types of cancer, but it is still challenging to diagnose correctly because of the difficulty in distinguishing between benign nevus and melanoma. We conducted a robust investigation of melanoma, identifying considerable differences in local elastic properties between nevus and melanoma tissues by using atomic force microscopy (AFM) indentation of histological specimens. Specifically, the histograms of the elasticity of melanoma displayed multimodal Gaussian distributions, exhibiting the heterogeneous mechanical properties, in contrast with the unimodal distributions of elasticity in the benign nevus. We identified this notable signature was consistent regardless of blotch incidence by sex, age, anatomical site (e.g., thigh, calf, arm, eyelid, and cheek), or cancer stage (I, IV, and V). In addition, we found that the non-linearity of the force-distance curves for melanoma is increased compared to benign nevus. We believe that AFM indentation of histological specimens may technically complement conventional histopathological analysis for earlier and more precise melanoma detection.

Aim The incorporation of growth factors is an effective strategy to accelerate bone induction. Bone morphogenetic protein-2 (BMP-2) promotes osteoblast differentiation and induces bone formation. Alendronate (ALN) is an osteoclast deactivation drug. We investigated the effect of serial administration of recombinant human BMP-2 (rhBMP-2) and ALN on osteoblast differentiation. Methods The effect of serial administration of rhBMP-2 (0-150 ng/mL) and ALN (0-15 µmol/L) on the viability and differentiation of a clonal murine calvarial cell line, MC3T3-E1, was evaluated at various concentrations and for different periods. The Cell Counting Kit-8 assay was used to assess cell viability. The alkaline phosphatase activity was evaluated as an indicator of osteogenic differentiation. The expression levels of runt domain-containing transcription factor 2 (Runx2) and osteopontin (OPN) were analyzed by real-time polymerase chain reaction and western blotting. Statistical analyses were performed using Student's t test. Results The serial treatment with rhBMP-2 and ALN increased the expression of the differentiation-related factors Runx2 and OPN, as well as the differentiation ability of osteoblasts compared with individual or simultaneous treatment. The osteoblasts treated with rhBMP-2 followed by ALN showed the highest differentiation. The degree of differentiation in the group treated with rhBMP-2 for 7 days followed by ALN for 3 days was increased by 1.5 times compared with that of the group treated with rhBMP-2 alone (P Conclusion These findings indicate that the serial administration of rhBMP-2 and ALN may exert osteogenic effects on osteoblastic cells via the upregulation of Runx2 and OPN.

Background/Aims The safety and efficacy of febuxostat in patients with stage 4–5 chronic kidney disease (CKD) are still unclear owing to a lack of studies in these patients. Therefore, we aimed to evaluate the effect of febuxostat on renal function, general safety, and efficacy in gout patients with stage 4–5 CKD. Methods Among 739 patients who had been administered febuxostat from May 2012 to December 2016 at a single hospital in Korea, 370 patients who had been monitored for 1 year were analyzed. Serum uric acid levels and estimated glomerular filtration rate (eGFR) of patients with gouty arthritis were collected at baseline and 1 year after febuxostat administration. Results Among the 370 patients, 280 patients were stage 1–3 CKD, 63 patients were stage 4–5 CKD, and 27 patients were on dialysis. The eGFR of 63 patients with stage 4–5 CKD, excluding dialysis patients, was 19.84 ± 7.08 mL/min/1.73 m2 when they began to take febuxostat and 23.49 ± 16.67 mL/min/1.73 m2 after 12 months (p = 0.13). The urate-lowering effect after 12 months of febuxostat medication showed statistical significance (8.96 ± 2.31 mg/dL at baseline and 4.88 ± 1.68 mg/dL after 12 months, p < 0.01). The difference in incidence of adverse events among patients with stage 1–3 CKD, those with stage 4–5 CKD, and those on dialysis was not significant. Conclusions Febuxostat demonstrated renal safety and good urate-lowering efficacy in gout patients with stage 4–5 CKD, who are not yet on dialysis.

Objectives: In this study, we aimed to evaluate the association between grape seed proanthocyanidin extract (GSPE) and rheumatoid arthritis-fibroblast-like synoviocytes (RA-FLSs) and to investigate whether GSPE induces cell death in RA-FLSs. Materials and methods: The FLSs were isolated from RA synovial tissues. Cell viability and cell cycle staging were analyzed using a hemocytometer and flow cytometry. Caspase 3 and poly (ADP-ribose) polymerase (PARP) proteins were analyzed using Western blotting with z-VAD-fmk. Protein LC3 and polyubiquitin-binding protein p62 that were degraded by autophagy were evaluated using Western blotting with 3-methyladenine and chloroquine. Reactive oxygen species (ROS) were also evaluated. Results: When RA-FLSs were treated with GSPE, cell viability decreased, the number of cells in sub-G1 and G2/M phases increased, and the expression of pro-PARP and pro-caspase 3 proteins decreased in a concentration-dependent manner. This result was offset, when the cells were co-treated with the pan-caspase inhibitor z-VAD-fmk. The reduced cell viability, increased expression of LC3-II protein, and reduced expression of p62 protein with GSPE treatment were offset, when RA-FLSs were co-treated with GSPE and autophagy inhibitors 3-methyladenine and chloroquine. The level of ROS in RA-FLSs treated with GSPE was significantly lower than treatment with N-acetyl-cysteine, a ROS inhibitor. Conclusion: Our study results show that GSPE induces apoptotic and autophagic cell death and inhibites reactive oxygen species in RA-FLSs.

Protein kinases regulate protein phosphorylation, which are involved in fundamental cellular processes such as inflammatory response. In this study, we discovered a novel multi-protein kinase inhibitor, KMU-1170, a derivative of indolin-2-one, and investigated the mechanisms of its inflammation-inhibiting signaling in both THP-1 cells and human osteoarthritic fibroblast-like synoviocytes (FLS). We demonstrated that in THP-1 cells, KMU-1170 inhibited lipopolysaccharide (LPS)-induced upregulation of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2), and, furthermore, suppressed LPS-induced phosphorylation of transforming growth factor-&beta, activated kinase 1, JNK, ERK, inhibitor of NF-&kappa, B kinase &alpha, /&beta, (IKK&alpha, ), and NF-&kappa, B p65 as well as nuclear translocation of NF-&kappa, B p65. Moreover, KMU-1170 suppressed LPS-induced upregulation of proinflammatory cytokines such as IL-1&beta, TNF-&alpha, and IL-6, and, notably, inhibited LPS-induced upregulation of the NLRP3 inflammasome in THP-1 cells. Importantly, KMU-1170 attenuated LPS-mediated inflammatory responses in human osteoarthritic FLS, such as the upregulation of IL-1&beta, IL-6, iNOS, and COX-2 and the phosphorylation of IKK&alpha, and NF-&kappa, B p65. Collectively, these results suggest that KMU-1170 inhibits inflammatory signal transduction and could be developed as a potential anti-inflammatory agent.

Background Ankylosing spondylitis (AS) is a chronic inflammatory rheumatic disease affecting the axial skeleton and peripheral joints. The etiology of this disease remains poorly understood, but interactions between genetic and environmental factors have been implicated. The present study identified differentially expressed proteins in the synovial fluid (SF) of AS patients to elucidate the underlying cause of AS. Methods A cohort of 40 SF samples from 10 AS and 10 each of rheumatoid arthritis (RA), gout, and osteoarthritis (OA) patients were analyzed by liquid chromatography tandem mass spectrometry (LC–MS/MS) to identify differentially expressed proteins specific to AS. The label-free LC–MS/MS results were verified by western blotting. Results We identified 8 proteins that were > 1.5-fold upregulated in the SF of AS patients compared to that of the disease control groups, including HP, MMP1, MMP3, serum amyloid P-component (APCS), complement factor H-related protein 5 (CFHR5), mannose-binding lectin 2 (MBL2), complement component C9 (C9), and complement C4-A (C4A). CFHR5 and C9 were previously found in serum from AS patients, while APCS was previously found in SF as well as in serum. However, the present study has identified C4A, and MBL2 as potential AS biomarkers for the first time. The expression levels of MMP3, C9, and CFHR5 were verified in AS SF using western blotting. Conclusion We performed quantitative comparative proteomic analysis using by LC–MS/MS of the SF from four disease states: RA, gout, and OA. This systematic comparison revealed novel differentially expressed proteins in AS SF, as well as two previously reported candidate biomarkers. We further verified the expression of MMP3, C9 and CFHR5 by western blot. These proteins may serve as diagnostic or prognostic biomarkers in patients with AS, and may thus improve the clinical outcomes of this serious disease.

Nonsense-mediated mRNA decay (NMD), an mRNA quality control process, is thought to function in plant immunity. A subset of fully spliced (FS) transcripts of Arabidopsis (Arabidopsis thaliana) resistance (R) genes are upregulated during bacterial infection. Here, we report that 81.2% and 65.1% of FS natural TIR-NBS-LRR (TNL) and CC-NBS-LRR transcripts, respectively, retain characteristics of NMD regulation, as their transcript levels could be controlled posttranscriptionally. Both bacterial infection and the perception of bacteria by pattern recognition receptors initiated the destruction of core NMD factors UP-FRAMESHIFT1 (UPF1), UPF2, and UPF3 in Arabidopsis within 30 min of inoculation via the independent ubiquitination of UPF1 and UPF3 and their degradation via the 26S proteasome pathway. The induction of UPF1 and UPF3 ubiquitination was delayed in mitogen-activated protein kinase3 (mpk3) and mpk6, but not in salicylic acid-signaling mutants, during the early immune response. Finally, previously uncharacterized TNL-type R transcripts accumulated in upf mutants and conferred disease resistance to infection with a virulent Pseudomonas strain in plants. Our findings demonstrate that NMD is one of the main regulatory processes through which PRRs fine-tune R transcript levels to reduce fitness costs and achieve effective immunity.

Additional file 5: Figure S1. Verification of C4A, MBL2, and APCS in synovial fluid by western blot. (a) Western blot analysis in the original synovial fluid sample set: A; AS (n = 10), R; RA (n = 10), G; gout (n = 10), and O; OA (n = 10). (b) Western blot analysis in the Independent sample set: AS (n = 5), RA (n = 5), gout (n = 5), OA(n = 5). Transferrin was used as an input amount control.

Additional file 1: Table S1. Baseline characteristics of the first patient cohort used for the LC-MS/MS experiments and the associated western blot verification (a), and the second patient cohort used for the western blot verification (b).

Purpose Nonsteroidal anti-inflammatory drugs (NSAIDs) are common cause of severe cutaneous adverse reactions (SCARs). The present study aimed to investigate the characteristics of SCARs induced by NSAIDs in the Korean SCAR registry. Methods A retrospective survey of NSAID-induced SCARs recorded between 2010 and 2015 at 27 university hospitals in Korea was conducted. Clinical phenotypes of SCARs were classified into Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), SJS-TEN overlap syndrome and drug reaction with eosinophilia and systemic symptoms (DRESS). Causative NSAIDs were classified into 7 groups according to their chemical properties: acetaminophen, and propionic, acetic, salicylic, fenamic and enolic acids. Results A total of 170 SCARs, consisting of 85 SJS, 32 TEN, 17 SJS-TEN overlap syndrome and 36 DRESS reactions, were induced by NSAIDs: propionic acids (n=68), acetaminophen (n=38), acetic acids (n=23), salicylic acids (n=16), coxibs (n=8), fenamic acids (n=7), enolic acids (n=5) and unclassified (n=5). Acetic acids (22%) and coxibs (14%) accounted for higher portions of DRESS than other SCARs. The phenotypes of SCARs induced by both propionic and salicylic acids were similar (SJS, TEN and DRESS, in order). Acetaminophen was primarily associated with SJS (27%) and was less involved in TEN (10%). DRESS occurred more readily among subjects experiencing coxib-induced SCARs than other NSAID-induced SCARs (62.5% vs. 19.7%, P = 0.013). The mean time to symptom onset was longer in DRESS than in SJS or TEN (19.1 ± 4.1 vs. 6.8 ±1.5 vs. 12.1 ± 3.8 days). SCARs caused by propionic salicylic acids showed longer latency, whereas acetaminophen- and acetic acid-induced SCARs appeared within shorter intervals. Conclusions The present study indicates that the phenotypes of SCARs may differ according to the chemical classifications of NSAIDs. To establish the mechanisms and incidences of NSAID-induced SCARs, further prospective studies are needed.

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.

Background/aims Grape seed proanthocyanidin extract (GSPE) has been reported to have a beneficial effect on regulating inf lammation. However, the anti-inflammatory mechanism of GSPE remains unclear. The aim of this study was to verify the influence of GSPE on the Toll-like receptor 4 (TLR4)-mediated signaling pathway in the regulation of murine autoimmune arthritis. Methods Collagen-induced arthritis (CIA) was induced in dilute brown non-agouti (DBA)/1J mice. The mice were treated with GSPE (0 or 100 mg/kg) intraperitoneally. The severity of arthritis was assessed clinically, biochemically, and histologically. Immunostaining for TLR4 was performed. The expressions of TLR4 and downstream signaling molecules were analyzed by Western blot. The effect of GSPE on lipopolysaccharide (LPS)-induced TLR4 activation was also evaluated using RAW264.7 cells and fibroblast-like synoviocytes (FLSs) from patients with rheumatoid arthritis and from those with osteoarthritis. Results GSPE attenuated the clinical severity of arthritis and decreased histological damage. GSPE treatment reduced the number of TLR4-stained cells in the synovium of mice with CIA. GSPE also downregulated the expression of TLR4, myeloid differentiation factor 88 (MyD88) and phosphorylated IκBα synovial protein in CIA mice. Concurrently, GSPE inhibited the nuclear translocation of nuclear factor-κB (NF-κB) subunits (p65 and p50). LPS-induced TLR4 activation was suppressed by GSPE in human FLS as well as in murine macrophages in vitro. Conclusions Our results demonstrated that GSPE ameliorated CIA by regulating the TLR4-MyD88-NF-κB signaling pathway.

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.

Background Fibroblasts are ubiquitous cells in the human body and are absolutely necessary for wound healing such as for injured skin. This role of fibroblasts was the reason why we aimed to differentiate human adipose-derived stem cells (hADSCs) into fibroblasts and to test their wound healing potency. Recent reports on hADSC-derived conditioned medium have indicated stimulation of collagen synthesis as well as migration of dermal fibroblasts in wound sites with these cells. Similarly, human fibroblast-derived conditioned medium (F-CM) was reported to contain a variety of factors known to be important for growth of skin. However, it remains unknown whether and how F-CM can stimulate hADSCs to secrete type I collagen. Methods In this study, we obtained F-CM from the culture of human skin fibroblast HS27 cells in DMEM media. For an in-vivo wound healing assay using cell transplantation, balb/c nude mice with full-thickness skin wound were used. Results Our data showed that levels of type I pro-collagen secreted by hADSCs cultured in F-CM increased significantly compared with hADSCs kept in normal medium for 72 h. In addition, from a Sircol collagen assay, the amount of collagen in F-CM-treated hADSC conditioned media (72 h) was markedly higher than both the normal medium-treated hADSC conditioned media (72 h) and the F-CM (24 h). We aimed to confirm that hADSCs in F-CM would differentiate into fibroblast cells in order to stimulate wound healing in a skin defect model. To investigate whether F-CM induced hADSCs into fibroblast-like cells, we performed FACS analysis and verified that both F-CM-treated hADSCs and HS27 cells contained similar expression patterns for CD13, CD54, and CD105, whereas normal medium-treated hADSCs were significantly different. mRNA level analysis for Nanog, Oct4A, and Sox2 as undifferentiation markers and vimentin, HSP47, and desmin as matured fibroblast markers supported the characterization that hADSCs in F-CM were highly differentiated into fibroblast-like cells. To discover the mechanism of type I pro-collagen expression in hADSCs in F-CM, we observed that phospho-smad 2/3 levels were increased in the TGF-β/Smad signaling pathway. For in-vivo analysis, we injected various cell types into balb/c nude mouse skin carrying a 10-mm punch wound, and observed a significantly positive wound healing effect in this full-thickness excision model with F-CM-treated hADSCs rather than with untreated hADSCs or the PBS injected group. Conclusions We differentiated F-CM-treated hADSCs into fibroblast-like cells and demonstrated their efficiency in wound healing in a skin wound model.

Background/Aims: Sleep disturbance is prime concern in patients with Behcet disease. The purpose of this study was to find out the effects of sleep quality, in Korean patients suffering from Behcet disease. We further investigated the relationship between depression, quality of life and the clinical findings of Behcet disease. Methods: The study was performed by the cross-sectional design. Sleep quality was assessed by the Korean version of Pittsburgh sleep quality index (PSQI). Disease activity of Behcet disease was evaluated by Behcet disease current activity form (BDCAF). Depression was assessed by the Korean version of Beck depression inventory second edition (BDI-2). Quality of life was assessed by the Korean version of the Leeds Behcet disease quality of life measure (BDQoL). Results: Among the 100 patients studied, 42% reported poor sleep quality (PSQI ≥ 9). These patients have a higher BDI-2, total BDCAF and pain visual analogue scale (VAS) score (p < 0.001, p = 0.022, and p = 0.005). Considering BDCAF, the frequency of genital ulcer was significantly higher (p = 0.01). Behcet was higher in females. The BDQoL was lower in poor sleeper group (p = 0.004 and p < 0.001). Among 7 PSQI components, daytime dysfunction was higher in patients with high disease activity (p = 0.03). Total PSQI score were strongly correlated with BDCAF, BDI-2, BDQoL, and pain VAS score (p = 0.02, p < 0.001, p < 0.001, and p < 0.001, respectively). Conclusions: Low sleep quality is directly associated with disease activity, depression, and quality of life in Korean patients with Behcet disease.

Background Ankylosing Spondylitis (AS), affecting 0.5% of the population, is a chronic inflammatory rheumatic disease affecting the axial skeleton and peripheral joints. When peripheral arthritis in ankylosing spondylitis (AS) develops early in the disease course it is a predictor of more aggressive disease. SF is in contact with the primary tissues affected by arthritic diseases and has been implicated in disease pathophysiology. Therefore it is an excellent source for discovery of biomarkers. Objectives We used proteomic analysis using SFs from AS patients and other arthritis patients in order to discover novel diagnostic markers for AS. Our aim was to identify differentially expressed protein mediators in synovial fluid of ankylosing spondylitis. Methods A Total of 40 SF samples from 10 AS and each 10 controls [Osteoarthritis (OA), Rheumatoid Arthritis (RA), gouty arthritis (Gout)] were collected. Liquid chromatography and tandem mass spectrometry (LC-MS/MS), to identify differentially expressed proteins based on the ratios of the extracted ion current of each protein between the four groups. Among the 9 proteins showing 1.5 fold change, 8 were verified with the exception of the abundant protein Haptoglobin (HP). Matrix metalloproteinase-1(MMP1) and Matrix metalloproteinase-3(MMP3) were used as a positive control, and the remaining 6 proteins were subjected to western blot analysis. Results We identified 9 proteins that were found to be more than 1.5-fold differentially expressed in SF of AS patients compared to control groups. Proteins such as HP, MMP1, MMP3, Serum amyloid P-component(APCS), Complement factor H-related protein 5(CFHR5), Fumarylacetoacetase(FAH), Mannose-binding lectin2(MBL2), Complement component C9(C9) and Complement C4-A(C4A) were found to be upregulated in the SF of AS patients. CFHR5 and C9 were reported in previous studies with AS serum. APCS was reported in SF as well as serum. However, FAH, C4A and MBL2 were newly discovered through this analysis. We were able to verify the unique expression level of C9 and CFHR5 in AS sample using western blot analysis compared to the other three diseases. Conclusion We performed quantitatively proteomic profiling of the respective SF sample from 4 diseases, i.e., AS, OA, RA, and GOUT, by LC-MS/MS. The systematic comparative proteomic analysis of the four groups together was carried out for the first time, leading to several differentially expressed proteins in AS. Among them, we expect C9 and CFHR5, which expression levels were confirmed by western blot analysis, can be a potential biomarker for AS. References [1] Fischer R, et al. Mol Cell Proteomics2012;11:M111.013904. [2] Bhattacharjee M, et al. Clinical Proteomics2013;10:11 Acknowledgement This research was supported by the National Research Foundation of Korea (NRF) funded by the Ministry of Science, ICT & Future Planning (2017R1C1B5017278) Disclosure of Interests None declared

Background: To compare the frequency of high-risk osteoporotic fracture in patients with knee OA (OA) using the fracture risk assessment tool (FRAX) and the bone mineral density (BMD). Methods: We retrospectively assessed 282 Korean patients with knee OA who visited five medical centers and 1165 healthy controls (HCs) aged &ge, 50 years without knee OA. After matching for age, sex, and body mass index, 478 subjects (239 patients with knee OA and 239 HCs) were included. Results: Based on the BMD, the frequency of osteoporosis was 40.2% in patients with knee OA and 36.4% in HCs. The predicted mean FRAX major osteoporotic fracture probabilities calculated with or without femur neck BMD differed significantly between the knee OA and HCs (6.9 &plusmn, 3.8% versus 6.1 &plusmn, 2.8%, p = 0.000 and 8 &plusmn, 3.6% versus 6.8 &plusmn, 2.3%, p &lt, 0.001, respectively). The mean FRAX hip fracture probabilities calculated with or without femur neck BMD differed significantly in the knee OA and HCs (2.1 &plusmn, 2.4% versus 1.7 &plusmn, 1.8%, p = 0.006 and 3 &plusmn, 2.3% versus 2.4 &plusmn, 1.6%, p &lt, 0.001, respectively). Conclusion: Our study suggests that FRAX may have a clinical impact on treatment decisions to reduce osteoporotic facture in patients with knee OA.

Long noncoding RNAs (lncRNAs) are non-protein coding RNAs of more than 200 nucleotides in length. Despite the term "noncoding", lncRNAs have been reported to be involved in gene expression. Accumulating evidence suggests that lncRNAs play crucial roles in the regulation of immune system and the development of autoimmunity. lncRNAs are expressed in various immune cells including T lymphocytes, B lymphocytes, macrophages, neutrophils, dendritic cells, and NK cells, and are also involved in the differentiation and activation of these immune cells. Here, we review recent studies on the role of lncRNAs in immune regulation and the differential expression of lncRNAs in various autoimmune diseases.

Background Because severe cutaneous adverse reactions (SCARs), such as Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and drug reaction with eosinophilia and systemic symptoms (DRESS) rarely occur, clinical data based on large-scale studies are still lacking. Objective To provide information on culprit drugs and clinical characteristics, including morbidity and mortality of SCARs based on a nationwide registry. Methods SCAR cases that occurred from 2010 to 2015 were recruited to the Korean SCAR registry from 34 tertiary referral hospitals. Demographics, causative drugs, causality, and clinical outcomes were collected by reviewing the medical record. Results A total of 745 SCAR cases (384 SJS/TEN cases and 361 DRESS cases) due to 149 drugs were registered. The main causative drugs were allopurinol (14.0%), carbamazepine (9.5%), vancomycin (4.7%), and antituberculous agents (6.3%). A strong preference for SJS/TEN was observed in carbonic anhydrase inhibitors (100%), nonsteroidal anti-inflammatory drugs (84%), and acetaminophen (83%), whereas dapsone (100%), antituberculous agents (81%), and glycopeptide antibacterials (78%) were more likely to cause DRESS. The mortality rate was 6.6% (SJS/TEN 8.9% and DRESS 4.2%). The median time to death was 19 days and 29 days in SJS/TEN and DRESS respectively, and 89.8% of deaths occurred within 60 days after the onset of the skin symptoms. Conclusion Allopurinol, carbamazepine, vancomycin, and antituberculous agents were the leading causes of SCARs in Korea. Some drugs preferentially caused a specific phenotype. The mortality rate of SCARs was 6.6%, and most of the deaths occurred within 2 months.

Background/aims Neuropsychiatric systemic lupus erythematosus (SLE) includes a broad spectrum of neurologic and psychiatric manifestations. One of the most commonly observed neuropsychiatric symptoms is headache. However, the lack of specific clinical distinctions for headache in SLE has made it difficult to elucidate its pathophysiology. The aim of this study is to evaluate the neurometabolic changes using Proton Magnetic Resonance Spectroscopy (1H-MRS) in patients with SLE who suffer from chronic daily headache (CDH). Methods SLE and fibromyalgia patients with CDH and healthy controls were recruited (n = 9, n = 5, and n = 6, respectively). 1H-MRS metabolite ratios were evaluated in bilateral basal ganglia (BG) and bilateral peritrigonal white matter (PWM). Results 1H-MRS showed a significantly decreased N-acetylaspartate (NAA)/creatine (Cr) ratio in right BG in SLE patients with CDH compared to fibromyalgia patients with CDH and normal controls (p = 0.029 and p = 0.020, respectively). Left PWM NAA/Cr and choline/Cr ratios in SLE patients with CDH were lower than those in fibromyalgia patients with CDH (p = 0.019 and p = 0.029, respectively). Conclusions This study suggests the possibility that CDH in patients with SLE might be associated with neuronal dysfunction and neurometabolic changes.

Objective Researchers continue to gather evidence that transient receptor potential vanilloid (TRPV) channels contribute towards pain signalling pathways. However, it is unknown whether polymorphisms of the TRPV gene are associated with FM. For the first time, we investigated the association between the polymorphisms of the TRPV2 and TRPV3 genes, FM susceptibility and the severity of the symptoms. Methods A total of 409 patients with FM and 423 controls were enrolled from 10 medical centres that participated in the Korean nationwide FM survey. The alleles and genotypes at three positions [rs3813768(C > G), rs8121(C > T) and rs1129235(C > A)] in the TRPV2 gene and two positions [rs7216486 (G > A) and rs395357(C > T)] in the TRPV3 gene were genotyped. Results The frequencies of the alleles and genotypes of individual TRPV2 and TRPV3 genes were not significantly associated with FM susceptibility. However, the GTA haplotype of TRPV2 showed a defence against FM susceptibility (P = 0.035). In addition, polymorphisms of TRPV3 were associated with symptom severity in FM patients. The single nucleotide polymorphism rs395357 of TRPV3 was associated with the scores of the Brief Fatigue Inventory (P = 0.017) in FM patients. Furthermore, haplotypes of TRPV3 were associated with the Brief Fatigue Inventory and the 36-item Short-Form Health Survey mental health summary scores (P = 0.036). Conclusion This study was the first to evaluate the associations of TRPV gene polymorphisms with FM. Our results suggest that certain TRPV2 haplotypes may have a protective role against FM and that some genotypes and haplotypes of TRPV3 contribute towards the symptoms of FM.

Background/Aims: We aimed to investigate the prevalence and possible causes of hypouricemia in the Korean population and to compare our findings with published results of other populations. Methods: We examined the serum uric acid levels of 30,757 subjects who had their uric acid values measured at least once during a 1-year period. All individuals with hypouricemia (serum uric acid < 2.0 mg/dL, n = 424) were reviewed with respect to medical drug history and concomitant diseases previously identified as being associated with hypouricemia. Results: The prevalence of hypouricemia was 4.14% (299/7,223) among inpatients and 0.53% (125/23,534) among outpatients, for an overall prevalence of 1.39% (424/30,757). Possible causes associated with hypouricemia were found to be solid or hematologic malignancies (n = 86), diabetes mellitus (n = 56), and therapeutic drugs (n = 29). The medications were allopurinol (n = 11), angiotensin II receptor blockers (n = 10), salicylates (n = 6), febuxostat (n = 1), and warfarin (n = 1). In the remaining 226 individuals, the cause of hypouricemia was not identified. Conclusions: Hypouricemia is relatively common in the Korean population compared to those of other countries. The possible causes associated with hypouricemia are related to underlying diseases and medications.

Purpose The effects of recombinant human bone morphogenetic protein-2 (rhBMP-2) and osteogenically differentiated adipose tissue-derived stem cells (ADSC) on new bone formation in high-speed distraction osteogenesis of adult rabbit cranium were investigated. Materials and Methods A total of 41 adult rabbits were used in the study. Distraction began after a 5-day latency period at a rate of 1.5 mm twice a day until 10-mm length gain was obtained both in the control group, where a bone defect was induced, and in the experimental group, in which ADSC (group A), rhBMP-2 (group B), or both (group C) were injected in the distraction gap after distraction. At 4, 8, and 12 weeks after distraction, computed tomography analysis was done to determine the bone defect dimension and bone mineral density (BMD), while histologic examination was also done to calculate bone formation ratio. Results Bone defect dimension significantly decreased in groups B and C, compared with the control group, at 4 and 12 weeks after distraction. BMD was significantly increased in groups B and C at 4 weeks. On histologic examination, bone formation ratio was significantly increased in group C only at 12 weeks. Conclusion This study suggests that the use of rhBMP-2 in combination with or without ADSC is helpful to promote bone regeneration in high-speed distraction osteogenesi s of adult rabbit cranium.

Objectives Celecoxib is a selective cyclooxygenase (COX)-2 inhibitor that is commonly used to reduce the incidence of gastrointestinal (GI) complications in patients with rheumatoid arthritis (RA). CELBESTA® is a generic equivalent to CELEBREX®, a celecoxib preparation. This study compared the efficacy and safety of CELBESTA® and CELEBREX® in patients with RA. Methods This was a multicenter, double-blind, double-dummy, active-controlled, randomized, parallel-group, non-inferiority clinical trial. The primary endpoint was a change from baseline in self-assessed pain intensity determined using a 100-mm visual analog scale after 6 weeks of treatment. Results After a washout period, 119 eligible subjects were randomized to one of two groups (CELBESTA® group, n = 61; CELEBREX® group, n = 58). CELBESTA® was not inferior to CELEBREX® because the upper limit of two-sided 95% confidence interval (CI) for the difference between the two groups (difference in the least square [LS] mean, −8.68 mm; two-sided 95% CI −16.59 mm to −0.77 mm) was less than the non-inferiority margin (10 mm). There were no significant differences in GI complications and renal toxicity. Conclusions CELBESTA® was not inferior to CELEBREX® with regard to the pain relief efficacy in RA patients, and the tolerability and safety profiles were excellent and at similar levels for both preparations.

(1) Background: We evaluated the prevalence and fracture risk of osteoporosis in patients with rheumatoid arthritis (RA), and compared the fracture risk assessment tool (FRAX) criteria and bone mineral density (BMD) criteria established by the World Health Organization (WHO). (2) Methods: This retrospective cross-sectional study, which included 479 RA patients in 5 hospitals, was conducted between January 2012 and December 2016. The FRAX criteria for high-risk osteoporotic fractures were calculated including and excluding the BMD values, respectively. The definition of high risk for fracture by FRAX criteria and BMD criteria by WHO was 10-year probability of &ge, 20% for major osteoporotic fracture or &ge, 3% for hip fracture, and T score &le, &minus, 2.5 or Z score &le, 2.0, respectively. (3) Results: The mean age was 61.7 &plusmn, 11.9 years. The study included 426 female patients (88.9%), 353 (82.9%) of whom were postmenopausal. Osteoporotic fractures were detected in 81 (16.9%) patients. The numbers of candidates for pharmacological intervention using the FRAX criteria with and without BMD and the WHO criteria were 226 (47.2%), 292 (61%), and 160 (33.4%), respectively. Only 69.2%&ndash, 77% of the patients in the high-risk group using the FRAX criteria were receiving osteoporosis treatments. The following were significant using the WHO criteria: female (OR 3.55, 95% CI 1.46&ndash, 8.63), age (OR 1.1, 95% CI 1.08&ndash, 1.13), and BMI (OR 0.8, 95% CI 0.75&ndash, 0.87). Glucocorticoid dose (OR 1.09, 95% CI 1.01&ndash, 1.17), age (OR 1.09, 95% CI 1.06&ndash, 1.12), and disease duration (OR 1.01, 95% CI 1&ndash, 1.01) were independent risk factors for fracture. (4) Conclusions: The proportion of RA patients with a high risk of osteoporotic fractures was 33.4%&ndash, 61%. Only 69.2%&ndash, 77% of candidate patients were receiving osteoporotic treatments while applying FRAX criteria. Independent risk factors for osteoporotic fractures in RA patients were age, the dose of glucocorticoid, and disease duration.

Background Several lines of evidence imply that brain-derived neurotrophic factor (BDNF) is involved in the pathophysiology of fibromyalgia (FM); in this regard, patients with FM have altered blood and cerebrospinal fluid levels of BDNF. In this study, we explored the association between BDNF gene polymorphisms and FM susceptibility and the severity of symptoms. Methods In total, 409 patients with FM and 423 healthy controls in 10 medical centers were enrolled from the Korean nationwide FM survey. The alleles and genotypes at 10 positions in the BDNF gene were genotyped. Results The allele and genotype frequencies of BDNF rs11030104 differed significantly between the patients with FM and the controls (P = 0.031). The GG genotype of rs11030104 had a protective effect against FM (P = 0.016), and the G allele of rs11030104 was negatively associated with the presence of FM compared with the A allele (P = 0.013). In comparison, although the allele and genotype frequencies of BDNF rs12273539 did not differ between the two groups, the TT genotype of BDNF rs12273539 was associated with susceptibility to FM (P = 0.038). Haplotype analyses implied that some BDNF haplotypes have a protective effect against FM. Finally, several genotypes and haplotypes of the BDNF gene contributed to specific symptoms of FM. Conclusions This study is the first to evaluate the associations between BDNF gene polymorphisms and FM. Our results imply that some BDNF single-nucleotide polymorphisms and haplotypes are associated with susceptibility to, and contribute to the symptoms of, FM.

Nonsense-mediated mRNA decay (NMD), an mRNA quality control process, has been implicated in plant immunity. A subet of transcripts of the Arabidopsis resistance (R) genes are reportedly upregulated during bacterial infection due to a decrease in NMD efficiency. Here, we report that 81.2% and 65.1% of fully spliced natural TIR-NBS-LRR (TNL) and CC-NBS-LRR (CNL) transcripts, respectively, retain characteristics of NMD regulation. The perception of bacteria by pattern recognition receptors (PRRs) initiates the destruction of UPF1, UPF2 and UPF3 within 30 minutes of inoculation via the independent ubiquitination of UPF1 and UPF3 and the 26S proteasome pathway, and subsequently, NMD-sensitive TNL and CNL transcript levels increase. Induction of UPF1 and UPF3 ubiquitinations was delayed specifically in mpk3 or mpk6 at an early immune response. Our findings demonstrate how NMD is the control node through which PRRs can fine-tune R transcript levels to reduce fitness costs and achieve effective immunity.