Seong-Kyu Kim

No differences of carotid intima-media thickness between young patients with ankylosing spondylitis and healthy controls.

OBJECTIVE Accelerated atherosclerosis in inflammatory rheumatic diseases such as ankylosing spondylitis (AS) stands out among the leading causes of morbidity and mortality. We assessed the correlation between subclinical carotid atherosclerosis and its related clinical parameters in AS patients. METHODS Twenty-eight patients (23 males, 5 females) with AS and 27 sex- and age-matched controls were consecutively recruited to this study. We estimated the carotid intima-media thickness (IMT) and parameters related to arterial elastic properties, including the distensibility coefficient (DC), stiffness index (beta), and incremental elastic modulus (E(inc)) using high-resolution ultrasonography. Serum levels of tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6), and monocyte chemoattractant protein-1 (MCP-1) were measured using enzyme-linked immunosorbent assay (ELISA). RESULTS Carotid IMT values and arterial elastic parameters in AS patients showed no statistical significance compared to those of controls (0.57+/-0.07 vs 0.55+/-0.05, p=0.387 for IMT, 28.45+/-9.23 vs 31.93+/-9.52, p=0.175 for DC, 2.32+/-0.18 vs 2.29+/-0.15, p=0.559 for stiffness index (beta), and 0.14+/-0.05 vs 0.12+/-0.03, p=0.116 for E(inc)). The serum level of IL-6 in AS patients was significantly different compared with controls (p=0.001), but not in serum levels of TNF-alpha and MCP-1 (p=0.162, p=0.087, respectively). Carotid IMT and all arterial elastic parameters calculated in this study were not found to be associated with serum levels of TNF-alpha, IL-6, and MCP-1. CONCLUSION This cross-sectional study showed that carotid IMT and parameters related with arterial elastic properties in young AS patients without clinically evident cardiovascular risk factors were not different from those of sex- and age-matched healthy controls. Serum levels of TNF-alpha, IL-6, and MCP-1 did not reflect the degree of carotid subclinical atherosclerosis. However, these findings should be confirmed further in a larger population.

High-density genotyping of immune loci in Koreans and Europeans identifies eight new rheumatoid arthritis risk loci.

OBJECTIVE A highly polygenic aetiology and high degree of allele-sharing between ancestries have been well elucidated in genetic studies of rheumatoid arthritis. Recently, the high-density genotyping array Immunochip for immune disease loci identified 14 new rheumatoid arthritis risk loci among individuals of European ancestry. Here, we aimed to identify new rheumatoid arthritis risk loci using Korean-specific Immunochip data. METHODS We analysed Korean rheumatoid arthritis case-control samples using the Immunochip and genome-wide association studies (GWAS) array to search for new risk alleles of rheumatoid arthritis with anticitrullinated peptide antibodies. To increase power, we performed a meta-analysis of Korean data with previously published European Immunochip and GWAS data for a total sample size of 9299 Korean and 45,790 European case-control samples. RESULTS We identified eight new rheumatoid arthritis susceptibility loci (TNFSF4, LBH, EOMES, ETS1-FLI1, COG6, RAD51B, UBASH3A and SYNGR1) that passed a genome-wide significance threshold (p<5×10(-8)), with evidence for three independent risk alleles at 1q25/TNFSF4. The risk alleles from the seven new loci except for the TNFSF4 locus (monomorphic in Koreans), together with risk alleles from previously established RA risk loci, exhibited a high correlation of effect sizes between ancestries. Further, we refined the number of single nucleotide polymorphisms (SNPs) that represent potentially causal variants through a trans-ethnic comparison of densely genotyped SNPs. CONCLUSIONS This study demonstrates the advantage of dense-mapping and trans-ancestral analysis for identification of potentially causal SNPs. In addition, our findings support the importance of T cells in the pathogenesis and the fact of frequent overlap of risk loci among diverse autoimmune diseases.

Increased power spectral density in resting-state pain-related brain networks in fibromyalgia.

Summary Higher power spectral density in patients with fibromyalgia may implicate the enhanced resting‐state baseline neural activity in several brain regions associated with pain processing. ABSTRACT Fibromyalgia (FM), characterized by chronic widespread pain, is known to be associated with heightened responses to painful stimuli and atypical resting‐state functional connectivity among pain‐related regions of the brain. Previous studies of FM using resting‐state functional magnetic resonance imaging (rs‐fMRI) have focused on intrinsic functional connectivity, which maps the spatial distribution of temporal correlations among spontaneous low‐frequency fluctuation in functional MRI (fMRI) resting‐state data. In the current study, using rs‐fMRI data in the frequency domain, we investigated the possible alteration of power spectral density (PSD) of low‐frequency fluctuation in brain regions associated with central pain processing in patients with FM. rsfMRI data were obtained from 19 patients with FM and 20 age‐matched healthy female control subjects. For each subject, the PSDs for each brain region identified from functional connectivity maps were computed for the frequency band of 0.01 to 0.25 Hz. For each group, the average PSD was determined for each brain region and a 2‐sample t test was performed to determine the difference in power between the 2 groups. According to the results, patients with FM exhibited significantly increased frequency power in the primary somatosensory cortex (S1), supplementary motor area (SMA), dorsolateral prefrontal cortex, and amygdala. In patients with FM, the increase in PSD did not show an association with depression or anxiety. Therefore, our findings of atypical increased frequency power during the resting state in pain‐related brain regions may implicate the enhanced resting‐state baseline neural activity in several brain regions associated with pain processing in FM.

Working Memory Impairment in Fibromyalgia Patients Associated with Altered Frontoparietal Memory Network

Background Fibromyalgia (FM) is a disorder characterized by chronic widespread pain and frequently associated with other symptoms. Patients with FM commonly report cognitive complaints, including memory problem. The objective of this study was to investigate the differences in neural correlates of working memory between FM patients and healthy subjects, using functional magnetic resonance imaging (MRI). Methodology/Principal Findings Nineteen FM patients and 22 healthy subjects performed an n-back memory task during MRI scan. Functional MRI data were analyzed using within- and between-group analysis. Both activated and deactivated brain regions during n-back task were evaluated. In addition, to investigate the possible effect of depression and anxiety, group analysis was also performed with depression and anxiety level in terms of Beck depression inventory (BDI) and Beck anxiety inventory (BAI) as a covariate. Between-group analyses, after controlling for depression and anxiety level, revealed that within the working memory network, inferior parietal cortex was strongly associated with the mild (r = 0.309, P = 0.049) and moderate (r = 0.331, P = 0.034) pain ratings. In addition, between-group comparison revealed that within the working memory network, the left DLPFC, right VLPFC, and right inferior parietal cortex were associated with the rating of depression and anxiety? Conclusions/Significance Our results suggest that the working memory deficit found in FM patients may be attributable to differences in neural activation of the frontoparietal memory network and may result from both pain itself and depression and anxiety associated with pain.

Melittin enhances apoptosis through suppression of IL-6/sIL-6R complex-induced NF-κB and STAT3 activation and Bcl-2 expression for human fibroblast-like synoviocytes in rheumatoid arthritis

OBJECTIVE Resistance to apoptosis of fibroblast-like synoviocytes (FLS) is considered as a major characteristic in RA. This study was designed to identify whether melittin has a pro-apoptotic effect in IL-6/sIL6R-stimulated human FLS by investigating the expression of mitochondrial apoptosis-related genes, nuclear factor-κB (NF-κB), and signal transducer and activators of transcription (STAT) activation. METHODS Cell viability was determined using a MTT assay after melittin treatment. Expressions of STAT3 and mitochondrial apoptosis-related genes induced by the IL-6/sIL-6R complex were determined by real time-polymerase chain reaction and western blotting. The expression of NF-κB p65 following IL-6 stimulation was determined by western blot analysis. The effects of melittin on the expression of apoptosis-related genes and the transcription factors NF-κB p65 and STAT3 were assessed in FLS. Apoptosis of FLS was determined by TUNEL-labeling to detect DNA strand breaks and DNA fragmentation assays. Caspase-3 activity was determined by a colorimetric assay. RESULTS IL-6/sIL-6R induced the activation of the transcription factors, STAT3, NF-κB p65 (nucleus), and Bcl-2. Melittin increased the expression of pro-apoptosis-related molecules, namely caspase-3, caspase-9, Apaf-1, and cytosolic cytochrome c, in a dose-dependent manner after treatment with IL-6/sIL-6R. Melittin inhibited STAT3 activation, translocation of NF-κB p65 into the nucleus, and expression of anti-apoptotic genes such as Bcl-2 and mitochondrial cytochrome c. CONCLUSIONS The pro-apoptotic effects of melittin likely result from inhibition of the activation of the transcription factors, STAT3 and NF-κB p65, and regulation of mitochondrial apoptosis-related genes. Melittin is thus a promising therapeutic option for RA as it induces apoptosis in apoptosis-resistant synoviocytes.

Increased insulin resistance and serum resistin in Korean patients with Behçet's disease.

BACKGROUND AND AIMS This study was designed to identify susceptibility to insulin resistance and the association of serum resistin and adiponectin with insulin resistance in patients with Behçets disease (BD). Also, we identify risk determinants for insulin resistance in BD patients. METHODS The study population consisted of 82 BD patients (n = 26 males) and 89 healthy controls (n = 40 males). Clinical data were collected at the time of enrollment, and serum resistin and adiponectin levels were measured using enzyme-linked immunosorbent assays. The homeostasis model assessment of insulin resistance (HOMA-IR) was calculated by measuring fasting plasma glucose and insulin levels. RESULTS BD patients and healthy controls differed significantly in insulin resistance (HOMA-IR) (1.3 +/- 1.1 vs. 0.7 +/- 0.5, p<0.001) and serum resistin level (7901.7 +/- 1314.9 vs. 7444.2 +/- 1841.6, p = 0.001) but not in serum adiponectin level (p = 0.223). No differences in HOMA-IR, serum adiponectin, and serum resistin were found between patients with active and inactive BD. It is determined that plasma glucose, plasma insulin, and serum resistin may be determinant for the HOMA-IR. The number of metabolic syndrome components is closely correlated with HOMA-IR in BD patients (r = 0.245, p = 0.029). CONCLUSION This study demonstrates that there is an increased susceptibility to insulin resistance in patients with BD as compared to healthy controls. Serum resistin level may be an independent determinant for insulin resistance in BD patients.

The impact of serum uric acid level on arterial stiffness and carotid atherosclerosis: The Korean Multi-Rural Communities Cohort study

OBJECTIVE Serum uric acid level has been found to be associated with a risk factor for cardiovascular diseases. However, the topic has not been explored in the general population, especially in Korea. This study was designed to determine whether serum uric acid is associated with carotid atherosclerosis and arterial stiffness in the Korean Multi-Rural Communities Cohort study. METHODS A total of 5568 participants from the Korean Multi-Rural Communities Cohort were evaluated for the risk of hyperuricemia in cardiovascular atherosclerosis. Important surrogates for cardiovascular atherosclerosis such as intima-media thickness (IMT) and brachial-ankle pulse wave velocity (baPWV) were assessed. We evaluated the association between these atherosclerosis indices and serum uric acid level or hyperuricemia through multivariate-adjusted logistic and linear regression analyses. RESULTS There was a significant difference of carotid IMT and baPWV between males and females (p < 0.0001, respectively). Both male and female subjects with hyperuricemia showed higher baPWV than subjects without hyperuricemia (p = 0.0004 for males; p = 0.001 for females). Serum uric acid level was positively correlated with baPWV in males (β = 0.0006, p < 0.0001) and in females (β = 0.0001, p = 0.04), whereas no association between serum uric acid and carotid IMT was found in either gender. A linear relationship of baPWV with increasing serum uric acid level was observed in males (p = 0.0005) and in females (p = 0.004). CONCLUSION Serum uric acid level could be considered an important risk factor for arterial stiffness in Korean population, whereas carotid IMT is not associated with serum uric acid in either gender when using data from the Korean Multi-Rural Communities Cohort study.

Regulatory effect of calcineurin inhibitor, tacrolimus, on IL-6/sIL-6R-mediated RANKL expression through JAK2-STAT3-SOCS3 signaling pathway in fibroblast-like synoviocytes

IntroductionThis study investigated whether the calcineurin inhibitor, tacrolimus, suppresses receptor activator of NF-κB ligand (RANKL) expression in fibroblast-like synoviocytes (FLS) through regulation of IL-6/Janus activated kinase (JAK2)/signal transducer and activator of transcription-3 (STAT3) and suppressor of cytokine signaling (SOCS3) signaling.MethodsThe expression of RANKL, JAK2, STAT3, and SOCS3 proteins was assessed by western blot analysis, real-time PCR and ELISA in IL-6 combined with soluble IL-6 receptor (sIL-6R)-stimulated rheumatoid arthritis (RA)-FLS with or without tacrolimus treatment. The effects of tacrolimus on synovial inflammation and bone erosion were assessed using mice with arthritis induced by K/BxN serum. Immunofluorescent staining was performed to identify the effect of tacrolimus on RANKL and SOCS3. The tartrate-resistant acid phosphatase staining assay was performed to assess the effect of tacrolimus on osteoclast differentiation.ResultsWe found that RANKL expression in RA FLS is regulated by the IL-6/sIL-6R/JAK2/STAT3/SOCS3 pathway. Inhibitory effects of tacrolimus on RANKL expression in a serum-induced arthritis mice model were identified. Tacrolimus inhibits RANKL expression in IL-6/sIL-6R-stimulated FLS by suppressing STAT3. Among negative regulators of the JAK/STAT pathway, such as CIS1, SOCS1, and SOCS3, only SOCS3 is significantly induced by tacrolimus. As compared to dexamethasone and methotrexate, tacrolimus more potently suppresses RANKL expression in FLS. By up-regulating SOCS3, tacrolimus down-regulates activation of the JAK-STAT pathway by IL-6/sIL-6R trans-signaling, thus decreasing RANKL expression in FLS.ConclusionsThese data suggest that tacrolimus might affect the RANKL expression in IL-6 stimulated FLS through STAT3 suppression, together with up-regulation of SOCS3.

Clinical significance of 18F-fluoro-dexoxyglucose positron emission tomography in patients with adult-onset Still’s disease: report of two cases and review of literatures

Adult-onset Still’s disease (AOSD) is a multi-systemic inflammatory disease that usually presents with high fever and variable systemic features. The pathogenesis and etiology of AOSD have not yet been clearly determined. In addition, there is no diagnostic test for AOSD. Even though some useful diagnostic criteria or laboratory findings, such as serum ferritin levels, have been proposed, useful imaging studies for the diagnosis or follow-up of AOSD have not been developed. We performed 18F-fluoro-dexoxyglucose positron emission tomography (18F-FDG PET) on two AOSD patients who presented with a fever of unknown origin. In these patients, we initially identified abnormally increased FDG uptake in multiple lymph nodes, the spleen, or bone marrow. We then identified significantly decreased uptake during a follow-up study. On the basis of these cases, we suggest that 18F-FDG PET may have the potential in the diagnosis of AOSD, as well as monitor clinical changes in the disease. More further investigation of 18F-FDG PET in AOSD is needed in larger population.

Association of guanosine triphosphate cyclohydrolase 1 gene polymorphisms with fibromyalgia syndrome in a Korean population.

Objective. Guanosine triphosphate cyclohydrolase 1 (GCH1) is the rate-limiting enzyme in the synthesis of tetrahydrobiopterin, which is an essential cofactor in nitric oxide (NO) production. Polymorphisms in the GCH1 gene have been implicated in protection against pain sensitivity. The aim of our study was to determine whether single-nucleotide polymorphisms (SNP) in the GCH1 gene affect susceptibility and/or pain sensitivity in fibromyalgia syndrome (FM). Methods. A total of 409 patients with FM and 422 controls were enrolled. The alleles and genotypes at 4 positions [rs3783641(T>A), rs841(C>T), rs752688(C>T), and rs4411417(T>C)] in the GCH1 gene were analyzed. The associations of the GCH1 SNP with susceptibility and clinical measures in patients with FM were assessed. Results. The frequencies of alleles and genotypes of the 4 SNP did not differ between patients with FM and healthy controls. Among 13 constructed haplotypes, we further examined 4 (CCTT, TTCT, TTCA, and CCTA) with > 1% frequency in both FM and controls. No associations of GCH1 polymorphisms with FM-related activity or severity indexes were found, although the number and total score of tender points in patients with FM differed among the 4 haplotypes (p = 0.03 and p = 0.01, respectively). The CCTA haplotype of GCH1 was associated with significantly lower pain sensitivity and occurred less frequently than the CCTT haplotype in patients with FM (p = 0.04, OR 0.45, 95% CI 0.21–0.96). Conclusion. Our study provides evidence that certain GCH1 haplotypes may be protective against susceptibility and pain sensitivity in FM. Our data suggest that NO is responsible for pain sensitivity in the pathogenesis of FM.