[Show abstract][Hide abstract] ABSTRACT: Gout is a chronic inflammatory disease the development of which is associated with obesity-induced metabolic abnormalities. However, a substantial number of non-obese patients (body mass index [BMI] <25 kg/m2) also develop gout in Korea. It was suggested that accumulation of visceral fat rather than subcutaneous fat is associated with metabolic abnormalities and hyperuricemia in patients with gout; therefore, we hypothesized that visceral fat accumulation was increased in non-obese gout patients.
One hundred and three male patients with primary gout and 204 age-matched healthy controls who attended a health check-up examination were recruited after the review of medical charts. The visceral fat area (VFA) was measured using the bioelectrical impedance analysis (BIA) method, and a VFA >100 cm2 was defined as visceral fat obesity (VFO). The frequency of VFO was compared in patients and control groups. The frequencies of metabolic syndrome and related parameters were also investigated.
BMI, waist circumference, total fat mass, serum triglycerides, and serum glucose levels were significantly greater in patients compared with controls. VFA and the prevalence of VFO was increased in gout patients compared with controls. There were positive correlations between VFA and serum triglyceride levels and serum glucose levels. Multivariate regression analysis revealed that VFO is an independent risk factor for gout (odds ratio 2.488, 95% confidence interval 1.041–4.435). In non-obese subgroup analyses (gout patients, n = 38; healthy controls, n = 150), VFA (98.7 ± 19.3 vs. 91.0 ± 16.7, P = 0.016) and the frequency of VFO (47.4 vs. 27.3%, P = 0.017) remained significantly higher in gout patients. There was no difference in either BMI or total fat mass between patients and controls in the non-obese subgroup. The prevalence of metabolic syndrome in patients with gout was 31.7% (33/104), compared with 13.2% (5/38) in the non-obese subgroup according to modified ATP III criteria.
VFO, measured using BIA, is observed more frequently in patients with primary gout compared with healthy controls, even in non-obese individuals. Therefore, VFO might more properly represent metabolic derangements in patients with gout than general obesity.
[Show abstract][Hide abstract] ABSTRACT: We investigated whether transthoracic echocardiography-suspected pulmonary hypertension (PH) affects survival in systemic lupus erythematosus (SLE) patients and examined factors associated with PH occurrence and survival.
This retrospective single-center study included 154 Korean SLE patients fulfilling the American College of Rheumatology criteria (January 1995 to June 2013). Student t test, Mann-Whitney U test, Kaplan-Meier curves, and log-rank tests were used for comparisons.
A total of 35 SLE patients with PH (SLE/PH+) and 119 without PH (SLE/PH-) were analyzed. Higher percentages of interstitial lung disease, Raynaud's phenomenon (RP), World Health Organization functional classification III/IV, and cardiomegaly were found in SLE/PH+ compared to SLE/PH-. Furthermore, the Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index was significantly higher in SLE/PH+ (2.46 ± 1.245 vs. 1.00 ± 1.235), whereas survival rates were significantly higher in SLE/PH- in log-rank tests (p = 0.001). In multivariate analysis, the adjusted mortality hazard ratio (HR) for SLE/PH+ patients was 3.10. Subgroup analysis demonstrated a higher percentage of lupus nephritis in the SLE/PH+ patients who died (p = 0.039) and low complement-3 levels (p = 0.007). In univariate analysis, the mortality HR for SLE/PH+ patients with lupus nephritis was 4.62, whereas the presence of RP decreased the mortality risk in multivariate analysis; adjusted HR, 0.10.
PH is an independent factor predicting survival in SLE patients. The presence of lupus nephritis resulted in an increased trend for mortality, whereas coexistence of RP was associated with a better survival prognosis in SLE/PH+ patients.
The Korean Journal of Internal Medicine 03/2015; 30(2):232-41. DOI:10.3904/kjim.2015.30.2.232 · 1.43 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: To evaluate the expression of interleukin 33 (IL-33) and its receptor in sera and salivary tissues of patients with primary Sjögren syndrome (pSS), and to investigate the association with clinical profiles.
Serum IL-33 and soluble ST2 (sST2) of 55 patients with pSS and 48 controls were determined by ELISA and assessed for clinical correlation. The expression of IL-33/ST2 in salivary tissues was investigated by immunohistochemical staining and was further characterized by confocal microscopy. We also measured IL-33 production in salivary glandular epithelial cells by proinflammatory stimuli.
Serum levels of IL-33 and sST2 were higher in patients with pSS compared to those in controls (p = 0.018 and p < 0.0001, respectively). Among patients with pSS, sST2 concentration was associated with thrombocytopenia (p = 0.029) and correlated with disease duration (p = 0.013) and the European League Against Rheumatism Sjögren Syndrome Disease Activity Index (p = 0.042). The expression of IL-33 and ST2 was elevated in salivary glands of patients with pSS with grade 2 inflammation, and diminished in advanced inflammation. In patients with pSS, IL-33 was mainly observed in epithelial and endothelial cells of glandular tissue. The production of IL-33 mRNA by salivary gland epithelial cell line increased under stimulation with interferon-γ.
The expression of IL-33 and its receptor was elevated in sera and salivary tissues of patients with pSS. These results suggest that the IL-33/ST2 axis might have a role in the pathogenesis of pSS.
The Journal of Rheumatology 12/2014; 42(2). DOI:10.3899/jrheum.140234 · 3.19 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The aim of the current study is to identify patients without osteoporosis who met the criteria of the fracture risk assessment tool (FRAX) of the National Osteoporosis Foundation (NOF) only. The incidence of fractures was investigated in patients who met only the FRAX criteria of the NOF and patients who presented osteoporosis. Five hundred and forty five patients with rheumatoid arthritis who visited a single center were recruited in Korea. In the follow-up period of median 30 months, the new onset of fractures was investigated. Of 223 patients who have no osteoporosis, 39 (17.4%) satisfied the FRAX criteria for pharmacological intervention. During the follow-up period, 2 new onset fractures occurred in patients who met only the FRAX criteria and 22 new onset fractures did in patients with osteoporosis by bone mineral density. The incidence rate for new onset fractures of patients who met only the FRAX criteria was with 295.93 per 10,000 person-years higher than in the general population with 114.99 per 10,000 person-years. Patients who met the FRAX criteria of the NOF only need pharmacological intervention because their numbers of incidence for new onset fractures are similar to those of patients with osteoporosis by BMD.
Journal of Korean Medical Science 08/2014; 29(8):1082-9. DOI:10.3346/jkms.2014.29.8.1082 · 1.27 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Rheumatoid arthritis (RA) is a systemic autoimmune disease characterized by chronic joint inflammation. Red ginseng is a steamed and dried
C.A. Meyer, which has been used as alternative medicine for thousands of years. This study was undertaken to investigate the effects of red ginseng extracts (RGE) on autoimmune arthritis in mice and humans and to delineate the underlying mechanism. RGE was orally administered three times a week to mice with arthritis. Oral administration of RGE markedly ameliorated clinical arthritis score and histologically assessed joint inflammation in mice with CIA. A significant reduction in STAT3 phosphorylation and a decrease in the number of Th17 cells were observed with RGE treatment. There was also a marked reduction in RANKL-induced osteoclastogenesis with treatment of RGE. The inhibitory effect of RGE on Th17 differentiation and osteoclastogenesis observed in mice was also confirmed in the subsequent experiments performed using human peripheral blood mononuclear cells. Our findings provide the first evidence that RGE can regulate Th17 and reciprocally promote Treg cells by inhibiting the phosphorylation of STAT3. Therefore, RGE can ameliorate arthritis in mice with CIA by targeting pathogenic Th17 and osteoclast differentiation, suggesting a novel therapy for treatment of RA.
Mediators of Inflammation 07/2014; 2014:351856. DOI:10.1155/2014/351856 · 3.24 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Introduction
Ankylosing spondylitis (AS) is associated with an increased incidence of vertebral fractures (VFs); however the actual incidence and predictors of morphometric VFs are unknown. The present study examined the incidence and predictors of new VFs in a large AS cohort.
In total, 298 AS patients who fulfilled the modified New York criteria were enrolled and spinal radiographs were evaluated biennially. Clinical and laboratory data and radiographic progression were assessed according to the Bath AS Disease Activity Index, erythrocyte sedimentation rate, C-reactive protein (CRP), and the Stoke AS spine score (SASSS). VF was defined according to the Genant criteria. The incidence of VFs at 2 and 4 years was evaluated using the Kaplan-Meier method. The age-specific standardized prevalence ratio (SPR) for AS patients in comparison with the general population was calculated.
Of 298 patients, 31 (10.8%) had previous VFs at baseline. A total of 30 new VFs occurred in 26 patients over 4 years. The incidence of morphometric VFs was 4.7% at 2 years and 13.6% at 4 years. Multivariate logistic regression analysis showed that previous VFs at baseline and increased CRP levels at 2 years were predictors of new VFs (odds ratio (OR) =12.8, 95% confidence interval (CI) = 3.6-45.3 and OR = 5.4, 95% CI = 1.4–15.9). The age-specific specific standardized prevalence ratio of morphometric VFs in AS was 3.3 (95% CI 2.1–4.5).
The incidence of morphometric VFs increased in AS. Previous VFs and increased CRP levels predicted future VFs. Further studies are needed to identify the effects of treatment interventions on the prevention of new VFs.
[Show abstract][Hide abstract] ABSTRACT: The aim of this study was to investigate the prevalence of antidrug antibodies (ADAs) against tumour necrosis factor (TNF) inhibitors in patients with rheumatoid arthritis (RA) and ankylosing spondylitis (AS). ADAs were detected in 18 (9.8%) patients with RA and in 18 (10.2%) patients with AS of the 360 patients. Development of ADAs was significantly associated with treatment failure in RA patients (P=0.003). When classified by drugs, the prevalence of immunogenicity in descending order was 17 (28.8%) patients treated with infliximab, 17 (10.4%) with adalimumab, and 2 (1.4%) with etanercept. After adjustment for disease and duration of anti-TNF therapy, the odds ratio as a reference of adalimumab-treated patients was 9.159 (95% confidence interval [CI] 2.005-41.845) for infliximab and 0.280 (95% CI 0.128-0.611) for etanercept. The immunogenicity of anti-TNF therapy was highest in the infliximab-treated group and significantly lower in the etanercept-treated group.
International immunopharmacology 04/2014; 21(1). DOI:10.1016/j.intimp.2014.04.006 · 2.47 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: IL-6-mediated STAT3 signaling is essential for Th17 differentiation and plays a central role in the pathogenesis of rheumatoid arthritis. To investigate the molecular mechanism underlying the antirheumatic effects and T cell regulatory effects of STAT3 inhibition, we studied the effects of the JAK 2 inhibitor AG490 on Th17 cell/regulatory T cell (Treg) balance and osteoclastogenesis. AG490 was administered to mice with collagen-induced arthritis (CIA) via i.p. injection, and its in vivo effects were determined. Differential expression of proinflammatory cytokines, including IL-17A, IL-1β, and IL-6, was analyzed by immunohistochemistry. Levels of phosphorylated STAT3 and STAT5 and differentiation of Th17 cells and Tregs after AG490 treatment in our CIA model were analyzed by immunostaining. In vitro development of Th17 cells and Tregs was analyzed by flow cytometry and real-time PCR. AG490 ameliorated the arthritic phenotype in CIA and increased the proportion of Foxp3(+) Tregs. In contrast, the proportion of IL-17A-producing T cells and levels of inflammatory markers were reduced in AG490-treated mice. Numbers of p-STAT3(+) CD4(+) T cells and p-STAT5(+) CD4(+) T cells were reduced and elevated, respectively, after treatment with AG490. Furthermore, AG490 markedly increased the expression of molecules associated with Treg development (ICOS, programmed cell death protein 1, ICAM-1, and CD103). The development and function of osteoclasts were suppressed by AG490 treatment. Our results suggest that AG490, specifically regulating the JAK2/STAT3 pathway, may be a promising treatment for rheumatoid arthritis.
The Journal of Immunology 03/2014; 192(9). DOI:10.4049/jimmunol.1300514 · 4.92 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: There is no consensus on whether it is safe to re-administer tumor necrosis factor-alpha (TNFα) inhibitors in patients with rheumatoid arthritis (RA) or ankylosing spondylitis (AS) flared after withdrawal of TNFα inhibitors due to active tuberculosis (TB). We evaluated the safety of restarting anti-TNFα therapy in patients with TNFα-associated TB. We used data of 1,012 patients with RA or AS treated with TNFα inhibitors at Seoul St. Mary's Hospital between January 2003 and July 2013 to identify patients who developed active TB. Demographic and clinical data including the results of tuberculin skin tests (TST) and interferon-γ releasing assays (IGRA) were collected. Fifteen patients developed active TB. Five cases were occurred in RA and 10 cases in AS. Nine of 15 patients had a negative TST or IGRA and 6 TST-positive patients had received prophylaxis prior to initiating anti-TNFα therapy. All patients discontinued TNFα inhibitors with starting the treatment of TB. Eight patients were re-administered TNFα inhibitors due to disease flares and promptly improved without recurrence of TB. TNFα inhibitors could be safely resumed after starting anti-TB regimen in patients with RA or AS.
Journal of Korean medical science 03/2014; 29(3):460. DOI:10.3346/jkms.2014.29.3.460 · 1.27 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Systemic lupus erythematosus (SLE) is an autoimmune disease in which abnormal immune responses are mediated by tissue-binding autoantibodies and immune complex deposition. Because most SLE patients are women of child-bearing age, estrogen has been suggested to play an important role in SLE pathogenesis. One proposed role is to induce B-cell activation, culminating in increased autoantibody production. Interleukin-21 (IL-21) has been shown to be crucial in the differentiation of activated B cells into plasma cells. We therefore hypothesized that estrogen upregulates IL-21 production and induces subsequent B-cell activation in SLE patients. Peripheral blood was obtained from 22 SLE patients and 16 healthy controls. Expression levels of IL-21 and its receptor in serum, peripheral blood mononuclear cells (PBMCs), and CD4+ T cells were higher in SLE patients than in healthy controls. Exposure of CD4+ T cells from SLE patients to 17-β estradiol led to a dose- and time-dependent increase in IL-21 expression, which was abolished in the presence of mitogen-activated protein kinase (MAPK; MEK, p38, JNK) inhibitors. B cells from healthy controls showed increased antibody production when they were co-cultured with estrogen-treated CD4+ T cells from SLE patients. Treatment with IL-21 antibody abrogated the increased antibody production of the co-culture systems. This study revealed the association between estrogen and IL-21 in SLE patients. Estrogen upregulates IL-21 expression of CD4+ T cells via MAPK-dependent pathways in SLE patients, which in turn induces increased antibody production by B cells. This article is protected by copyright. All rights reserved.
[Show abstract][Hide abstract] ABSTRACT: Interleukin (IL)-33 is an important mediator of innate immunity. Behcet's disease (BD) is an autoinflammatory disorder characterized by hyperactivity of the innate immune response. We measured serum levels of IL-33 and its receptor soluble ST2 (sST2) in patients with BD to investigate their association with disease activity. Serum levels of both IL-33 and sST2 were higher in patients with BD compared with those in normal controls (IL-33: 594.48±175.04 pg/mL in BD and 224.23±56.64 pg/mL in normal controls [P=0.048], sST2: 99.01±15.92 pg/mL in BD and 23.56±3.25 pg/mL in normal controls [P<0.001]). IL-33 and sST2 expression in skin tissue, as shown by immunohistochemistry, was higher in patients with BD compared with that in the normal controls. Serum sST2 level correlated significantly with the BD currently active form (BDCAF), Iranian BD dynamic activity measure (IBDDAM), erythrocyte sedimentation rate and C-reactive protein. Multiple linear regression showed that serum sST2 was an independent factor associated with IBBDAM (regression coefficient, 0.374; P=0.004), and BDCAF (regression coefficient, 0.236; P=0.047). These results demonstrate that IL-33 and sST2 are highly expressed in patients with BD and that serum sST2 is an independent factor associated with IBDDAM and BDCAF, suggesting a potential role for sST2 as a surrogate marker of disease activity in patients with BD.
Journal of Korean medical science 08/2013; 28(8):1145-53. DOI:10.3346/jkms.2013.28.8.1145 · 1.27 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Bone destruction is critical in the functional disability of patients with rheumatoid arthritis (RA). Osteoclasts, specialized bone-resorbing cells regulated by cytokines, such as receptor activator of NF-κB ligand (RANKL), are primarily implicated in bone destruction in RA. The aim of the study was to examine whether tumor necrosis factor-like weak inducer of apoptosis (TWEAK), a member of the tumor necrosis factor superfamily, has osteoclastogenic activity in patients with RA and in animal models, including mice with collagen-induced arthritis (CIA mice) and IL-1 receptor antagonist knockout (IL-1RaKO) mice. TWEAK was increased in the synovium, synovial fluid, and serum of patients with RA and in the synovium of CIA mice and IL-1RaKO mice. TWEAK induced RANKL expression in mixed joint cells and splenocytes from CIA mice, IL-1RaKO mice, and fibroblast-like synoviocytes from patients with RA. Both osteoclast precursor cells and osteoclasts express TWEAK receptor fibroblast growth factor-inducible 14. In addition, TWEAK enhanced in vitro osteoclastogenesis without the presence of RANKL-providing cells and by inducing RANKL expression in fibroblast-like synoviocytes. Moreover, treatment with fibroblast growth factor-inducible 14-Fc inhibited RANKL-induced osteoclastogenesis, indicating that endogenous TWEAK also has osteoclastogenic activity. Our data demonstrated that TWEAK promotes osteoclastogenesis in RA, suggesting that therapeutic strategies targeting TWEAK could be effective for treatment of patients with RA, especially in preventing bone destruction.
American Journal Of Pathology 07/2013; 39(3). DOI:10.1016/j.ajpath.2013.05.027 · 4.59 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Purpose:
To determine whether the frequencies of specific killer cell immunoglobulin-like receptors (KIR) genotypes are associated with the incidence of uveitis in ankylosing spondylitis (AS) and Behçet disease (BD).
The authors analyzed the frequency of 16 KIR genes in Koreans with either AS (110 patients, all HLA-B27-positive) or BD (86 patients), using polymerase chain reaction sequence-specific oligonucleotide probing.
The frequency of the inhibitory receptor KIR3DL1 was lower in AS patients affected by uveitis than that in the general population (p < 0.05). The frequency of the KIR3DL1(-)/2DS3(-) was significantly higher in AS patients with uveitis (odds ratio = 9.306, p = 0.007).
The study suggests that KIR3DL1 might associate with the resistance to AS-associated uveitis by influencing natural killer cell activity.