33 results on '"Lee, Sang Heon"'
Search Results
2. Four-year follow-up of atherogenicity in rheumatoid arthritis patients: from the nationwide Korean College of Rheumatology Biologics Registry
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Min, Hong Ki, Kim, Hae-Rim, Lee, Sang-Heon, Shin, Kichul, Kim, Hyoun-Ah, Park, Sung-Hwan, and Kwok, Seung-Ki
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- 2021
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Catalog
3. Histamine and Histamine H4 Receptor Promotes Osteoclastogenesis in Rheumatoid Arthritis
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Kim, Kyoung-Woon, Kim, Bo-Mi, Lee, Kyung-Ann, Lee, Sang-Heon, Firestein, Gary S, and Kim, Hae-Rim
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Rheumatoid Arthritis ,Autoimmune Disease ,Clinical Research ,Arthritis ,2.1 Biological and endogenous factors ,Aetiology ,Inflammatory and immune system ,Aged ,Arthritis ,Rheumatoid ,Enzyme-Linked Immunosorbent Assay ,Female ,Gene Expression Profiling ,Histamine ,Humans ,Male ,Middle Aged ,Osteogenesis ,Real-Time Polymerase Chain Reaction ,Receptors ,Histamine H4 ,Serum ,Synovial Fluid - Abstract
Histamine H4 receptor (H4R) has immune-modulatory and chemotaxic effects in various immune cells. This study aimed to determine the osteoclastogenic role of H4R in rheumatoid arthritis (RA). The concentration of histamine in synovial fluid (SF) and sera in patients with RA was measured using ELISA. After RA SF and peripheral blood (PB) CD14+ monocytes were treated with histamine, IL-17, IL-21 and IL-22, and a H4R antagonist (JNJ7777120), the gene expression H4R and RANKL was determined by real-time PCR. Osteoclastogenesis was assessed by counting TRAP-positive multinucleated cells in PB CD14+ monocytes cultured with histamine, Th17 cytokines and JNJ7777120. SF and serum concentration of histamine was higher in RA, compared with osteoarthritis and healthy controls. The expression of H4R was increased in PB monocytes in RA patients. Histamine, IL-6, IL-17, IL-21 and IL-22 induced the expression of H4R in monocytes. Histamine, IL-17, and IL-22 stimulated RANKL expression in RA monocytes and JNJ7777120 reduced the RANKL expression. Histamine and Th17 cytokines induced the osteoclast differentiation from monocytes and JNJ7777120 decreased the osteoclastogenesis. H4R mediates RANKL expression and osteoclast differentiation induced by histamine and Th17 cytokines. The blockage of H4R could be a new therapeutic modality for prevention of bone destruction in RA. more...
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- 2017
4. IL-18 binding protein suppresses IL-17-induced osteoclastogenesis and rectifies type 17 helper T cell / regulatory T cell imbalance in rheumatoid arthritis
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Min, Hong Ki, Kim, Sehee, Lee, Ji-Yeon, Kim, Kyoung-Woon, Lee, Sang-Heon, and Kim, Hae-Rim
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- 2021
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5. Regulation of osteoclastogenesis by mast cell in rheumatoid arthritis
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Kim, Kyoung-Woon, Kim, Bo-Mi, Won, Ji-Yeon, Min, Hong-Ki, Lee, Kyung-Ann, Lee, Sang-Heon, and Kim, Hae-Rim
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- 2021
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6. Cardiovascular disease risk calculators to reflect the subclinical atherosclerosis of coronary artery in rheumatoid arthritis: a pilot study
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Kim, Se Hee, Lee, Sang-Heon, Kim, Hae-Rim, and Min, Hong Ki
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- 2021
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7. Interleukin (IL)-25 suppresses IL-22-induced osteoclastogenesis in rheumatoid arthritis via STAT3 and p38 MAPK/IκBα pathway
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Min, Hong Ki, Won, Ji-Yeon, Kim, Bo-Mi, Lee, Kyung-Ann, Lee, Seoung-Joon, Lee, Sang-Heon, Kim, Hae-Rim, and Kim, Kyoung-Woon
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- 2020
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8. Rheumatoid Arthritis, Gout, and Spondyloarthritis in Foot and Ankle
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Lee, Sang-Heon and JUNG, Hong-Geun, editor
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- 2016
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9. Promotion of osteoclastogenesis by IL-26 in rheumatoid arthritis
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Lee, Kyung-Ann, Kim, Kyoung-Woon, Kim, Bo-Mi, Won, Ji-Yeon, Min, Hong Ki, Lee, Dhong Won, Kim, Hae-Rim, and Lee, Sang-Heon
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- 2019
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10. Long-term efficacy, safety and immunogenicity in patients with rheumatoid arthritis continuing on an etanercept biosimilar (LBEC0101) or switching from reference etanercept to LBEC0101: an open-label extension of a phase III multicentre, randomised, double-blind, parallel-group study
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Park, Min-Chan, Matsuno, Hiroaki, Kim, Jinseok, Park, Sung-Hwan, Lee, Sang-Heon, Park, Yong-Beom, Lee, Yun Jong, Lee, Sang-Il, Park, Won, Sheen, Dong Hyuk, Choe, Jung-Yoon, Choi, Chan-Bum, Hong, Seung-Jae, Suh, Chang-Hee, Lee, Shin-Seok, Cha, Hoon-Suk, Yoo, Bin, Hur, Jin-Wuk, Kim, Geun-Tae, Yoo, Wan-Hee, Baek, Han Joo, Shin, Kichul, Shim, Seung Cheol, Yang, Hyung-In, Kim, Hyun Ah, Park, Kyung-Su, Choi, In Ah, Lee, Jisoo, Tomomitsu, Masato, Shin, Seonghye, Lee, Jiyoon, and Song, Yeong Wook more...
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- 2019
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11. Risk factors for interstitial lung disease in rheumatoid arthritis: a cohort study from the KOBIO registry.
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Min, Hong Ki, Kim, Se Hee, Lee, Sang-Heon, and Kim, Hae-Rim
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INTERSTITIAL lung diseases ,RHEUMATOID arthritis ,RHEUMATOLOGY ,BIOLOGICALS ,TUMOR necrosis factors - Abstract
Background: Interstitial lung disease (ILD) is a critical extra-articular manifestation of rheumatoid arthritis (RA). However, little is known about the risk factors of RA-ILD. Objectives: Here, we examined the effect of demographic, clinical, therapeutic, and environmental factors on the incidence of ILD in RA patients using the Korean College of Rheumatology Biologics and Targeted Therapy (KOBIO) registry. Design: We used data from the KOBIO registry, a multi-center, prospective, observational cohort that included RA patients in South Korea. Methods: RA patients who used biologic or targeted synthetic disease-modifying antirheumatic drugs (b/tsDMARDs) or conventional synthetic (cs)DMARDs, and were enrolled in the KOBIO registry, were examined. Demographic, clinical, and radiographic characteristics, as well as medications, were recorded at baseline and annually thereafter. Kaplan–Meier curves and the log-rank test were used to compare the incidence of ILD between RA patients taking different b/tsDMARDs. Hazard ratios (HRs) were calculated by Cox regression analyses. Results: In total, 2492 patients (1967 in the b/tsDMARDs group and 525 in the csDMARDs group) were analyzed. The b/tsDMARDs group showed longer disease duration, higher erythrocyte sedimentation rate/C-reactive protein, and higher disease activity score-28 (DAS28) than the csDMARDs group. The incidence of ILD was significantly higher in those taking tumor necrosis factor inhibitors and abatacept than in those taking csDMARDs (log ranked p < 0.001). Multivariate Cox regression analysis identified older age (HR = 1.057, p = 0.001), male sex (HR = 2.824, p = 0.007), time-averaged DAS28 (HR = 2.241, p < 0.001), and rheumatoid factor titer (HR = 1.009, p = 0.007) as having a significantly increased HR for ILD occurrence. Conclusion: ILD is a rare but critical extra-articular symptom of RA patients. Therefore, RA patients with the above risk factors should be monitored carefully for ILD development. [ABSTRACT FROM AUTHOR] more...
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- 2023
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12. Rheumatoid arthritis patients fulfilling Korean National Health Insurance reimbursement guidelines for anti-tumor necrosis factor-α treatment and comparison to other guidelines
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Hur, Jin-Wuk, Choe, Jung-Yoon, Kim, Dong-Wook, Kim, Hyun Ah, Kim, Sang-Hyon, Kim, Wan-Uk, Kim, Yun Sung, Lee, Hye-Soon, Lee, Sang-Heon, Park, Sung-Hwan, Park, Won, Park, Yong-Beom, Suh, Chang-Hee, Shim, Seung-Cheol, Song, Yeong-Wook, Yoon, Bo Young, Yu, Dae Young, and Yoo, Dae Hyun more...
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- 2015
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13. Dasatinib, a selective tyrosine kinase inhibitor, prevents joint destruction in rheumatoid arthritis animal model.
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Min, Hong Ki, Kim, Se Hee, Won, Ji‐Yeon, Kim, Kyoung‐Woon, Lee, Ji‐Yeon, Lee, Sang‐Heon, and Kim, Hae‐Rim
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DASATINIB ,EXPERIMENTAL arthritis ,PROTEIN-tyrosine kinase inhibitors ,B cells ,RHEUMATOID arthritis ,REGULATORY T cells - Abstract
Aim: We aimed to evaluate the preventive role of the tyrosine kinase inhibitor dasatinib in an animal model of rheumatoid arthritis (RA). Methods: DBA/1J mice were injected with bovine type II collagen to induce arthritis (collagen‐induced arthritis [CIA]). There were four experimental groups of mice, namely negative control (non‐CIA), vehicle‐treated CIA, dasatinib‐pretreated CIA, and dasatinib‐treated CIA. After collagen immunization, arthritis progression in the mice was clinically scored twice weekly for 5 weeks. Flow cytometry was used to evaluate in vitro CD4+ T‐cell differentiation and ex vivo mast cell/CD4+ T‐cell differentiation. Osteoclast formation was evaluated using tartrate‐resistant acid phosphatase (TRAP) staining and by estimating the resorption pit area. Results: We found that the clinical arthritis histological scores were lower in the dasatinib pretreatment group than in the vehicle and dasatinib post‐treatment groups. Flow cytometry showed that FcεR1+ cells were downregulated and regulatory T cells were upregulated in splenocytes of the dasatinib pretreatment group compared with those in the vehicle group. Additionally, there was a decline in IL‐17+ CD4+ T‐cell differentiation and an increase in CD4+ CD24high Foxp3+ T‐cell differentiation with in vitro dasatinib treatment of human CD4+ T cells. The number of TRAP+ osteoclasts and the area of the resorption were decreased in the bone marrow cells derived from dasatinib‐pretreated mice compared with those derived from vehicle group. Conclusion: Dasatinib protected against arthritis in an animal model of RA by regulating the differentiation of regulatory T cells and IL‐17+ CD4+ T cells and inhibiting osteoclastogenesis, indicating the therapeutic potential of dasatinib in the treatment of early RA. [ABSTRACT FROM AUTHOR] more...
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- 2023
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14. Baseline bony erosions and time-averaged DAS28 predict discontinuation of TNF inhibitors in rheumatoid arthritis.
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Min, Hong Ki, Kim, Se Hee, Lee, Sang-Heon, and Kim, Hae-Rim
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TUMOR necrosis factors ,RHEUMATOID arthritis ,EROSION ,CLINICAL trials ,REGRESSION analysis - Abstract
The present study evaluated the predictive role of baseline radiographic change and disease activity on drug retention and clinical response in patients with rheumatoid arthritis (RA) treated with tumor necrosis factor inhibitor (TNFi). Korean Observational Study Network for Arthritis (KORONA) registry was evaluated to identify RA patients treated with a TNFi. Disease activity score-28 (DAS28) was evaluated at baseline and 1 year after TNFi initiation or at termination of TNFi due to inefficacy (within 1 year). The retention rate of TNFi was compared in patients with and without bony erosions. The hazard ratio (HR) for drug retention was evaluated by Cox regression analysis, as was the odds ratio (OR) for achieving remission (DAS28 < 2.6). This study included 109 RA patients, including 97 (89%) women and 30 (27.5%) with erosions, who were treated with a TNFi. Higher baseline DAS28 was negatively associated with achievement of remission (OR = 0.56, 95% CI 0.35–0.88). The TNFi retention rate was significantly lower in RA patients with than in those without erosions (p = 0.04). Factors significantly associated with drug discontinuation included the presence of erosions (HR = 2.45, 95% CI 1.08–5.51) and higher time-averaged DAS28 (HR = 2.17, 95% CI 1.47–3.20), whereas concomitant methotrexate was associated with lack of drug discontinuation (HR = 0.40, 95% CI 0.17–0.95). The presence of erosions and high time-averaged disease activity could predict poor retention of TNFi by RA patients. Higher baseline DAS28 was associated with a reduced clinical response in patients with RA. Trial registration Clinical Research Information Service of South Korea https://cris.nih.go.kr: KCT0000086, registered May 26, 2009. [ABSTRACT FROM AUTHOR] more...
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- 2022
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15. Therapeutic Utility and Adverse Effects of Biologic Disease-Modifying Anti-Rheumatic Drugs in Inflammatory Arthritis.
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Min, Hong Ki, Kim, Se Hee, Kim, Hae-Rim, and Lee, Sang-Heon
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ARTHRITIS ,PSORIATIC arthritis ,ANKYLOSING spondylitis ,RHEUMATOID arthritis ,MONOCLONAL antibodies ,INFLAMMATION ,RITUXIMAB - Abstract
Targeting specific pathologic pro-inflammatory cytokines or related molecules leads to excellent therapeutic effects in inflammatory arthritis, including rheumatoid arthritis, ankylosing spondylitis, and psoriatic arthritis. Most of these agents, known as biologic disease-modifying anti-rheumatic drugs (bDMARDs), are produced in live cell lines and are usually monoclonal antibodies. Several types of monoclonal antibodies target different pro-inflammatory cytokines, such as tumor necrosis factor-α, interleukin (IL)-17A, IL-6, and IL-23/12. Some bDMARDs, such as rituximab and abatacept, target specific cell-surface molecules to control the inflammatory response. The therapeutic effects of these bDMARDs differ in different forms of inflammatory arthritis and are associated with different adverse events. In this article, we summarize the therapeutic utility and adverse effects of bDMARDs and suggest future research directions for developing bDMARDs. [ABSTRACT FROM AUTHOR] more...
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- 2022
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16. DJ-1 controls T cell differentiation and osteoclastogenesis in rheumatoid arthritis.
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Min, Hong Ki, Kim, Se Hee, Lee, Ji-Yeon, Lee, Sang-Heon, and Kim, Hae-Rim
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T cell differentiation ,OSTEOCLASTOGENESIS ,MONONUCLEAR leukocytes ,OSTEOCLASTS ,T helper cells ,RHEUMATOID arthritis ,SYNOVIAL fluid - Abstract
Herein, we investigated the effect of DJ-1 on helper T cell differentiation, fibroblast-like synoviocyte (FLS) activation, and osteoclastogenesis in rheumatoid arthritis (RA). Serum and synovial fluid (SF) of RA and osteoarthritis (OA) patients were collected, and DJ-1 and H
2 O2 levels were investigated. CD4+ cells from peripheral blood mononuclear cells (PBMCs) were cultured under type 17 helper T cell (Th17) polarization conditions, and CD4+ T cell differentiation, pro-inflammatory cytokine levels, and soluble receptor activator of nuclear factor kappa-Β ligand (RANKL) were assessed. RA-FLSs were stimulated with 50 μM H2 O2 , and DJ-1 (10, 50, 100 ng/mL) to evaluate MMP-9, VEGF, TNF-α, and sRANKL production, while RANKL+ FLSs were assessed using flow cytometry. Monocytes were cultured with RANKL or IL-17A with or without DJ-1 and H2 O2 -pretreated RA-FLS, and tartrate-resistant acid phosphatase (TRAP) staining and RT-qPCR of osteoclast-related genes were performed. The levels of DJ-1 and H2 O2 in serum and SF of RA patients were higher than those of OA patients. Under Th17-polarizing conditions, CD4+ RANKL+ and CD4+ CCR4+ CCR6+ CXCR3- T cells decreased, whereas CD4+ CD25high Foxp3+ T cell increased after DJ-1 administration. Additionally, IL-17A, TNF-α, and sRANKL levels decreased in DJ-1-treated groups. DJ-1 lowered MMP-9, VEGF, TNF-α, and sRANKL levels, and RANKL+ FLS in ROS-stimulated RA-FLS. Both RANKL and IL-17A stimulated osteoclast differentiation, DJ-1 decreased TRAP+ cell count, and the expression levels of TRAP, ATP6v0d2, NFATc1, and CTSK. These findings were also observed in in vitro osteoclastogenesis with DJ-1 pretreated RA-FLS. As DJ-1 regulates Th17/Treg imbalance, pro-inflammatory cytokine production, RA-FLS activation, and osteoclastogenesis, it holds potential for RA therapy. [ABSTRACT FROM AUTHOR] more...- Published
- 2022
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17. Live Zoster Vaccine in Patients With Rheumatoid Arthritis Treated With Tofacitinib With or Without Methotrexate, or Adalimumab With Methotrexate: A Post Hoc Analysis of Data From a Phase IIIb/IV Randomized Study.
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Calabrese, Leonard H., Abud‐Mendoza, Carlos, Lindsey, Stephen M., Lee, Sang‐Heon, Tatulych, Svitlana, Takiya, Liza, Iikuni, Noriko, Soma, Koshika, Luo, Zhen, Fleischmann, Roy, Abud-Mendoza, Carlos, and Lee, Sang-Heon more...
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HERPES zoster prevention ,COMBINATION drug therapy ,HETEROCYCLIC compounds ,DISEASE incidence ,PIPERIDINE ,METHOTREXATE ,ANTIRHEUMATIC agents ,RHEUMATOID arthritis ,HERPES zoster vaccines ,HERPES zoster ,DISEASE complications - Abstract
Objective: To explore herpes zoster (HZ) rates and live zoster vaccine (LZV) safety in a subset of patients with rheumatoid arthritis who received LZV before tofacitinib ± methotrexate (MTX), or adalimumab (ADA) plus MTX in the ORAL Strategy.Methods: ORAL Strategy was a 1-year, phase IIIb/IV, randomized, triple-dummy, active-comparator-controlled study. MTX-inadequate responder patients received tofacitinib 5 mg twice daily (BID), tofacitinib 5 mg BID plus MTX, or ADA 40 mg every other week plus MTX (1:1:1 randomization). Eligible patients age ≥50 years could opt to receive LZV 28 days before initiating study treatment. HZ incidence rates (IRs; patients with events per 100 patient-years) were calculated. Opportunistic HZ infections (multidermatomal/disseminated), serious HZ events, and LZV-related adverse events were monitored.Results: In ORAL Strategy, 216 of 1,146 patients (18.8%) received LZV. Overall, 18 patients (1.6%) developed HZ (vaccinated: n = 3; nonvaccinated: n = 15). HZ IRs were 1.1 (95% confidence interval [95% CI] 0.3-2.9), 2.3 (95% CI 1.0-4.6), and 1.7 (95% CI 0.6-3.7) for tofacitinib monotherapy, tofacitinib plus MTX, and ADA plus MTX, respectively, and were generally similar between vaccinated and nonvaccinated patients. Three multidermatomal, 1 disseminated, and 2 serious HZ events occurred. No vaccinated patients had zoster-like lesions within 42 days of vaccination; 1 patient had vaccination-site erythema.Conclusion: LZV was well tolerated, and HZ IRs were generally similar between treatment groups and vaccinated versus nonvaccinated patients. However, ORAL Strategy was not powered for comparisons between vaccinated and nonvaccinated patients because <20% of all patients were vaccinated. Furthermore, LZV has been shown to be effective only in ~50% of individuals. [ABSTRACT FROM AUTHOR] more...- Published
- 2020
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18. Impact of lifestyle and comorbidities on seropositive rheumatoid arthritis risk from Korean health insurance data.
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Ro, JunSoo, Kim, Se Hee, Kim, Hae-Rim, Lee, Sang-Heon, and Min, Hong Ki
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RHEUMATOID arthritis ,COMORBIDITY ,HEALTH insurance ,ALCOHOL ,NATIONAL health insurance ,ALCOHOL drinking ,DEMOGRAPHIC characteristics - Abstract
Rheumatoid arthritis (RA) is a systemic inflammatory arthritis in which primary prevention is key. However, the impact of lifestyle and comorbidities on RA development is unknown. Data from the Korean National Health Insurance Service (NHIS)-national sample cohort from 2002 to 2016 were used. At baseline, demographic characteristics, socioeconomic status, type of residential area, lifestyle behaviours (including exercise), and comorbidities (including the Charlson Comorbidity Index, CCI) were included. Cox regression analysis and Kaplan–Meier curves were used to evaluate the impact of lifestyle and comorbidities on seropositive RA occurrence. A total of 517,053 participants were included in the analysis for seropositive RA occurrence. Mean follow up duration was 71.5 and 142.3 person-month for seropositive RA occurrence group and non-occurrence group, respectively. Seropositive RA was diagnosed in 1,948 participants (0.37%) during follow-up. Cox regression analysis revealed that being aged between 40 and 79, a higher CCI, and hyperlipidemia resulted in elevated hazard ratios (HRs) for seropositive RA, whereas male gender, city residence, moderate alcohol consumption, high regular exercise and a BMI between 23 and 34.9 kg/m
2 resulted in lower HRs. Using Korean NHIS data, the present study demonstrates that high-intensity regular physical exercise and moderate alcohol consumption are negatively associated with seropositive RA occurrence, which are modifiable lifestyle habits that might aid the primary prevention of seropositive RA. [ABSTRACT FROM AUTHOR] more...- Published
- 2022
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19. Macrophage migration inhibitory factor enhances osteoclastogenesis through upregulation of RANKL expression from fibroblast-like synoviocytes in patients with rheumatoid arthritis
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Kim, Hae-Rim, Kim, Kyoung-Woon, Jung, Hong Geun, Yoon, Kwang-Sup, Oh, Hye-Jwa, Cho, Mi-La, and Lee, Sang-Heon
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- 2011
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20. Diagnostic performance of the 2012 EULAR/ACR classification criteria for polymyalgia rheumatica in Korean patients.
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Lee, Kyung‐Ann, Kim, Hyun‐Sook, Lee, Sang‐Heon, and Kim, Hae‐Rim
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POLYMYALGIA rheumatica ,ASIANS ,SHOULDER disorders ,RHEUMATOID arthritis ,SHOULDER pain ,CLASSIFICATION - Abstract
Aim: This prospective study aimed to evaluate the diagnostic performance of the 2012 European League Against Rheumatism (EULAR)/American College of Rheumatology (ACR) classification criteria for polymyalgia rheumatica (PMR) compared to that of previous classification/diagnostic criteria in the Korean population. Method: We consecutively included 77 patients aged ≥50 years presenting with bilateral shoulder pain and elevated acute‐phase reactants. All patients were evaluated for fulfillment of each of the 5 different criteria for PMR (Chuang et al, Bird, Jones and Hazleman, Healey, and the EULAR/ACR criteria). At baseline, bilateral ultrasound (US) examinations of the shoulders and hips were performed. Final diagnosis was made by an experienced rheumatologist at the 12‐month follow‐up. The area under the curve (AUC), sensitivity, and specificity of criteria sets were assessed. Results: At the end of follow‐up, 38 and 39 patients were diagnosed with PMR and non‐PMR including rheumatoid arthritis (RA, n = 20), respectively. The EULAR/ACR classification criteria with US showed the best discriminating capacity (AUC 0.843). Adding US to EULAR/ACR criteria increased specificity from 74.4% to 89.7%, but decreased sensitivity from 89.5% to 78.9%. The two US items of the EULAR/ACR criteria were significantly more frequent in patients with PMR than in controls. However, the second criterion consisting of both shoulders inflamed were similar between PMR (60.5%) and RA (60.0%) groups. Conclusion: The 2012 EULAR/ACR classification criteria for PMR performed best in classifying PMR from other inflammatory and non‐inflammatory disorders with shoulder pain in Asian populations. [ABSTRACT FROM AUTHOR] more...
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- 2020
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21. Toll-like receptor 7 regulates osteoclastogenesis in rheumatoid arthritis.
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Kim, Kyoung-Woon, Kim, Bo-Mi, Won, Ji-Yeon, Lee, Kyung-Ann, Kim, Hae-Rim, and Lee, Sang-Heon
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OSTEOCLASTOGENESIS ,OSTEOCLASTS ,TRANCE protein ,TOLL-like receptors ,RHEUMATOID arthritis ,MITOGEN-activated protein kinases - Abstract
This study aimed to determine the regulatory role of toll-like receptor 7 (TLR7) in receptor activator of nuclear factor kappa-B ligand (RANKL) production and osteoclast differentiation in rheumatoid arthritis (RA). In confocal microscopy, the co-expression of TLR7, CD55 and RANKL was determined in RA synovial fibroblasts. After RA synovial fibroblasts were treated with imiquimod, the RANKL gene expression and protein production were determined by real-time polymerase chain reaction (PCR) and enzyme-linked immunosorbent assay (ELISA). Osteoclastogenesis from peripheral blood CD14
+ monocytes which were cultured with imiquimod was assessed by determining the numbers of tartrate-resistant acid phosphatase (TRAP)-positive multinucleated cells. The signal pathways mediating the TLR7-induced RANKL expression and osteoclastogenesis were analysed after inhibition of intracellular signal molecules and their phosphorylation. Imiquimod stimulated the expression of TLR7 and RANKL and production of RANKL in RA synovial fibroblasts, increasing the phosphorylation of TRAF6, IRF7, mitogen-activated protein kinases (MAPK), c-Jun and NFATc1. When CD14+ monocytes were cultured with imiquimod or co-cultured with imiquimod-pre-treated RA synovial fibroblasts, they were differentiated into TRAP+ multinucleated osteoclasts in the absence of RANKL. TLR7 activation-induced osteoclastogenesis in RA through direct induction of osteoclast differentiation from its precursors and up-regulation of RANKL production in RA synovial fibroblasts. Thus, the blockage of TLR7 pathway could be a promising therapeutic strategy for preventing bone destruction in RA. [ABSTRACT FROM AUTHOR] more...- Published
- 2019
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22. Comparison of second- and third-generation immunoassays for detection of anti-cyclic citrullinated peptide antibodies.
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Ji, Misuk, Hur, Mina, Moon, Hee-Won, Park, Mikyoung, Yun, Yeo-Min, and Lee, Sang-Heon
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OSTEOARTHRITIS diagnosis ,RHEUMATOID arthritis diagnosis ,AUTOMATION ,COMPARATIVE studies ,DIFFERENTIAL diagnosis ,IMMUNOASSAY ,LABORATORIES ,RESEARCH methodology ,MEDICAL cooperation ,OSTEOARTHRITIS ,RESEARCH ,RHEUMATOID arthritis ,EVALUATION research ,RECEIVER operating characteristic curves - Abstract
Anti-cyclic citrullinated peptide antibodies (anti-CCPs) are important diagnostic markers for rheumatoid arthritis (RA). We evaluated the analytical and clinical performance of the QUANTA Flash CCP3 (INOVA Diagnostics, USA), a fully automated third-generation anti-CCP assay, in comparison with three second-generation anti-CCP (CCP2) assays. A total of 300 sera (67 from RA patients, 64 from other rheumatic diseases, 43 from osteoarthritis [OA], and 126 from other conditions) were tested with QUANTA Flash CCP3, Kallestad Anti-CCP II (Bio-Rad, USA), Elecsys Anti-CCP (Roche Diagnostics GmbH, Germany), and ARCHITECT Anti-CCP (Abbott Diagnostics, USA). Within-run and total imprecision (% coefficient of variation) of the QUANTA Flash CCP3 were <6%, and its linearity was acceptable over the claimed range (4.0-2,749.7 chemiluminescent units). The frequency of anti-CCP was similar between QUANTA Flash CCP3 and the other CCP2 assays in the RA (67.2% vs. 62.7-70.1%), other rheumatic diseases (7.8% vs. 6.3%), and OA (2.3% vs. 0-2.3%) groups. The concordance rate between QUANTA Flash CCP3 and the other assays ranged from 96.3% to 97.7% (kappa from 0.87 to 0.92). For the diagnosis of RA, the sensitivity/specificity was 67.2%/95.7%, 62.7%/98.3%, 70.2%/96.6%, and 67.2%/97.9%, and the areas under the receiver operating characteristic curves were 0.851, 0.791, 0.853, and 0.867 for QUANTA Flash CCP3, Kallestad, Elecsys, and ARCHITECT assays, respectively. The performance of the QUANTA Flash CCP3 was satisfactory and comparable to that of the three CCP2 assays. This fully automated assay would be a practical and reasonable option in clinical laboratories. [ABSTRACT FROM AUTHOR] more...
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- 2018
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23. Factors associated with quality of life and functional disability among rheumatoid arthritis patients treated with disease-modifying anti-rheumatic drugs for at least 6 months.
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Bae, Sang‐Cheol, Cho, Soo‐Kyung, Won, Soyoung, Lee, Hye‐Soon, Lee, Sang‐Heon, Kang, Young Mo, Lee, Sang‐Hoon, Lee, Yeon‐Ah, Choe, Jung‐Yoon, Chung, Won‐Tae, Suh, Chang‐Hee, Shim, Seung‐Cheol, Lee, Jisoo, Yoon, Bo Young, Kim, Dong‐Wook, Lee, Shin‐Seok, Yoo, Wan‐Hee, Kim, Jin‐Seok, Jung, Young‐Ok, and Nah, Seong‐Su more...
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RHEUMATOID arthritis ,QUALITY of life ,HEALTH of patients ,REGRESSION analysis ,DISABILITIES - Abstract
Aim: To determine characteristics of rheumatoid arthritis (RA) patients in Korea using disease-modifying antirheumatic drugs (DMARDs) for at least 6 months, and to identify factors associated with poor health-related outcomes. Method: A total of 2000 RA patients aged > 20 years, treated with DMARDs for at least 6 months, and signed informed consent, were enrolled in this non-interventional, multicenter, cross-sectional observational study from December 2012 to June 2013. Health-related quality of life (HRQoL) was measured using EuroQuol 5D (EQ-5D) and functional disability was measured using the Korean Health Assessment Questionnaire (KHAQ). Univariate and multivariate linear regression analyses were used to determine the association between patient characteristics and patient-reported outcomes (PROs). Results: Of all RA patients, 84% were female, patients with low Disease Activity Score of 28 joints erythrocyte sedimentation rate (DAS-28-ESR < 3.2) was 54%, while moderate (DAS-28-ESR 3.2-5.1) and high disease activity score (DAS-28-ESR > 5.1) were 38% and 7.6%, respectively. Mean EQ-5D index score and KHAQ score were 0.6 ± 0.28 and 0.7 ± 0.67, respectively. In multivariate analysis with both PROs, average HRQoL and functional disability score appeared to be worse in persons with older age compared to younger age (P < 0.001), and worse in females compared to males (P < 0.001). Compared to patients having lower DAS (< 3.2), those with moderate and highest DAS (3.2-5.1 and > 5.1) had worse outcome measures (P < 0.001). Conclusion: In this study, higher DAS was one of the most influential factors for poor PROs among all other factors. Therefore, we could suggest appropriate treatment approaches according to DAS along with other significantly associated factors with PROs in the early stage of RA. [ABSTRACT FROM AUTHOR] more...
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- 2018
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24. A phase III, multicentre, randomised, double-blind, active-controlled, parallel-group trial comparing safety and efficacy of HD203, with innovator etanercept, in combination with methotrexate, in patients with rheumatoid arthritis: the HERA study.
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Bae, Sang-Cheol, Kim, Jinseok, Choe, Jung-Yoon, Park, Won, Lee, Sang-Heon, Park, Yong-Beom, Shim, Seung-Cheol, Lee, Shin-Seok, Sung, Yoon-Kyoung, Choi, Chan-Bum, Lee, So-Ra, Park, HanYu, Ahn, Yongho, and HERA Study Investigators more...
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BIOTHERAPY ,METHOTREXATE ,ANTIRHEUMATIC agents ,BIOLOGICAL products ,COMBINATION drug therapy ,CLINICAL trials ,COMPARATIVE studies ,IMMUNOGLOBULINS ,RESEARCH methodology ,MEDICAL cooperation ,PHARMACOKINETICS ,RESEARCH ,RHEUMATOID arthritis ,EVALUATION research ,RANDOMIZED controlled trials ,TREATMENT effectiveness ,BLIND experiment - Abstract
Objectives: To evaluate equivalence in efficacy for rheumatoid arthritis (RA) and compare the safety of the biosimilar HD203 with innovator etanercept (ETN) plus methotrexate (MTX) (ClinicalTrials.gov NCT01270997).Methods: Patients with active RA received 25 mg HD203 or ETN subcutaneously twice-weekly with MTX for 48 weeks in a phase III, multicentre, randomised, double-blind, parallel-group design. The primary end point was the proportion of patients achieving the American College of Rheumatology 20% response (ACR20) at week 24 for per-protocol study completer set (PPS). Secondary end points included ACR response criteria, ACRn, European League against Rheumatism (EULAR) response, change in Disease Activity Score 28 (DAS28), patient-reported outcomes, safety and immunogenicity.Results: Of the 294 randomised patients (HD203, n=147; ETN, n=147), 233 comprised the 24-week PPS (n=115 and 118, respectively). ACR20 at week 24 was achieved by 83.48% and 81.36% of PPS patients, respectively, demonstrating equivalent efficacy within predefined margins of ±20% (treatment difference 2.12%, 95% CI -7.65% to 11.89%). Outcomes for secondary end points were consistent with the primary efficacy findings. Groups were comparable for overall incidences of treatment-emergent (all-causality) adverse events (AEs) (HD203 113 (76.9%) vs ETN 114 (78.1%) (p=0.804)), adverse drug reactions, serious AEs and discontinuations due to AEs. Few patients (HD203, n=8; ETN, n=3) tested positive for anti-drug antibodies.Conclusion: The study met the primary objective of demonstrating equivalent efficacy of HD203 and ETN. HD203 was well tolerated, with safety comparable with ETN in this population of patients with RA.Trial Registration Number: NCT01270997; Results. [ABSTRACT FROM AUTHOR] more...- Published
- 2017
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25. Reciprocal Activation of CD4+ T Cells and Synovial Fibroblasts by Stromal Cell-Derived Factor 1 Promotes RANKL Expression and Osteoclastogenesis in Rheumatoid Arthritis.
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Kim, Hae‐Rim, Kim, Kyoung‐Woon, Kim, Bo‐Mi, Jung, Hong‐Geun, Cho, Mi‐La, and Lee, Sang‐Heon
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FIBROBLASTS ,T cells ,ACADEMIC medical centers ,POLYMERASE chain reaction ,RESEARCH funding ,RHEUMATOID arthritis ,STATISTICS ,U-statistics ,WESTERN immunoblotting ,DATA analysis ,REVERSE transcriptase polymerase chain reaction ,PHYSIOLOGY - Abstract
Objective Stromal cell-derived factor 1 (SDF-1) is a chemokine that is involved in the bone-destructive process in rheumatoid arthritis (RA) and bony metastasis in malignancy. This study was undertaken to determine the role and mechanism of SDF-1 in RA-associated osteoclastogenesis. Methods The expression of SDF-1, tumor necrosis factor α (TNFα), and RANKL in RA synovial tissue was analyzed using confocal microscopy. After synovial fibroblasts and CD4+ T cells were treated with SDF-1, RANKL messenger RNA expression was determined by real-time and reverse transcription polymerase chain reaction. Osteoclastogenesis was assessed by counting tartrate-resistant acid phosphatase-positive multinucleated cells in CD14+ monocytes cultured with SDF-1 in the presence of anticytokine antibodies or signal inhibitors and in monocytes cocultured with SDF-1-pretreated synovial fibroblasts and CD4+ T cells. Results RANKL, TNFα, and SDF-1 were coexpressed in the lining and sublining of RA synovium. SDF-1 stimulated RANKL expression in RA synovial fibroblasts and CD4+ T cells, and TNFα inhibition reduced this stimulation. When monocytes isolated from human peripheral blood were cultured with SDF-1, they were differentiated into osteoclasts in the absence of RANKL. Monocytes were also differentiated into osteoclasts when they were cocultured with SDF-1-pretreated synovial fibroblasts or CD4+T cells; however, this osteoclastogenesis was reduced by TNFα inhibition. Conclusion Our findings indicate that SDF-1 induces osteoclastogenesis directly and indirectly via up-regulating RANKL expression in RA synovial fibroblasts and CD4+ T cells, and that this is mediated by TNFα. The axis of SDF-1 and RANKL is a potential therapeutic target for RA-associated bone destruction. [ABSTRACT FROM AUTHOR] more...
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- 2014
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26. Regulation of Th17 Cytokine-Induced Osteoclastogenesis via SKI306X in Rheumatoid Arthritis.
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Kim, Hae-Rim, Kim, Kyoung-Woon, Kim, Bo-Mi, Won, Ji-Yeon, Min, Hong-Ki, Lee, Kyung-Ann, Kim, Tae-Young, and Lee, Sang-Heon
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RHEUMATOID arthritis ,OSTEOCLASTOGENESIS ,INFLAMMATORY mediators ,CYTOKINES ,GENE expression ,HERBAL medicine - Abstract
This study aimed to investigate the regulatory effect of SKI306X, a mixed extract of three herbs, in T helper (Th)17 cytokine-induced inflammation and joint destruction in rheumatoid arthritis (RA). Synovial fibroblasts were isolated from RA patients and cultured with Th17 cytokines including interleukin (IL)-17, IL-21, and IL-22 and SKI306X, and tumor necrosis factor (TNF)-α, IL-1β, and receptor activator of nuclear factor kappa-Β ligand (RANKL) expression and production were investigated using real-time PCR and ELISA of culture media. After peripheral blood (PB) cluster of differentiation (CD)14
+ monocytes were cultured in media supplemented with Th17 cytokines and SKI306X, tartrate-resistant acid phosphatase positive (TRAP+ ) multinucleated giant cells (mature osteoclasts) were enumerated and gene expression associated with osteoclast maturation was assessed via real-time PCR analysis. After PB monocytes were co-cultured with IL-17-stimulated RA synovial fibroblasts in the presence of SKI306X, osteoclast differentiation was assessed. When RA synovial fibroblasts were cultured with IL-17, IL-21, and IL-22, TNF-α, IL-1β, and RANKL expression and production were increased; however, SKI306X reduced cytokine expression and production. When PB monocytes were cultured in media supplemented with Th17 cytokines, osteoclast differentiation was stimulated; however, SKI306X decreased osteoclast differentiation and osteoclast maker expression. When PB monocytes were co-cultured with IL-17-stimulated RA synovial fibroblasts, osteoclast differentiation was increased; however, SKI306X decreased osteoclast differentiation and osteoclast maker expression. SKI306X reduced Th17 cytokine-induced TNF-α, IL-1β, and RANKL expression and osteoclast differentiation, providing novel insights into adjuvant therapy for regulating inflammation and joint destruction in RA. [ABSTRACT FROM AUTHOR] more...- Published
- 2019
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27. Time-averaged DAS28 and HAQ predict cardiovascular disease in patients with rheumatoid arthritis: Data from KORONA registry.
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Min, Hong Ki, Kim, Hae-Rim, Lee, Sang-Heon, Kang, Kwi Young, Park, Sung-Hwan, and Kwok, Seung-Ki
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RHEUMATOID arthritis , *CARDIOVASCULAR diseases , *DISEASE duration , *REGRESSION analysis , *INFORMATION services - Abstract
Objective: To evaluate the predictive role of time-averaged disease activity score (DAS)28 and Health Assessment Questionnaire (HAQ) on cardiovascular disease (CVD) events in patients with rheumatoid arthritis (RA).Methods: Patients with RA were recruited from 23 tertiary hospitals. Baseline and annual follow-up data of demographic, laboratory, questionnaire, RA-associated parameters, and occurrence of CVD were collected. Patients were divided into three groups according to time-averaged DAS28: 1) remission (<2.6), 2) low (2.6-3.2), 3) moderate (3.2-5.1), and 4) high (>5.1). Kaplan-Meier curves was performed to compare the cumulative probability of CVD. Hazard ratios of each factor on the occurrence of CVD were obtained using Cox regression analyses.Results: A total of 4,034 RA patients with 826 for remission, 938 for low, 2,002 for moderate, and 268 for high time-averaged DAS28 groups were included. Baseline age, disease duration, ESR, CRP, DAS28, and HAQ scores were higher in the high time-averaged DAS28 group. The incidence rate of CVD was 2.86, 2.71, 3.53, and 8.13 events per 1,000 person-years for the remission, low, moderate, and high time-averaged DAS28 groups, respectively. The incidence rate ratio of CVD in the high time-averaged DAS28 group were 3.01 (95% CI 1.20-8.50) when compared to low time-averaged DAS28 group. The cumulative hazard for CVD in the high time-averaged DAS28 group was significantly high (log-rank P<0.01). In multivariate Cox regression analysis, age, high time-averaged DAS28, and time-averaged HAQ>0.5, were positively associated with CVD events in RA patients.Conclusions: In patients with RA, time-averaged DAS28 and HAQ could predict the occurrence of CVD.Trial Registration: Clinical Research Information Service of South Korea https://cris.nih.go.kr: KCT0000086, registered May 26, 2009. [ABSTRACT FROM AUTHOR] more...- Published
- 2022
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28. Quercetin, a Plant Polyphenol, Has Potential for the Prevention of Bone Destruction in Rheumatoid Arthritis.
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Kim, Hae-Rim, Kim, Bo-Mi, Won, Ji-Yeon, Lee, Kyung-Ann, Ko, Hyun Myung, Kang, Young Sun, Lee, Sang-Heon, and Kim, Kyoung-Woon
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ACID phosphatase , *BONE resorption , *BONE growth , *CELL differentiation , *ENZYME-linked immunosorbent assay , *FLOW cytometry , *INTERLEUKINS , *MESSENGER RNA , *MICROBIAL sensitivity tests , *MONOCYTES , *POLYMERASE chain reaction , *PROTEINS , *QUERCETIN , *RHEUMATOID arthritis , *SYNOVIAL membranes , *DNA-binding proteins , *RAPAMYCIN , *IN vitro studies , *CHEMICAL inhibitors , *PHARMACODYNAMICS , *THERAPEUTICS - Abstract
We investigated the immune-regulatory function of quercetin, in interleukin (IL)-17-produced osteoclastogenesis in rheumatoid arthritis (RA). RA fibroblasts-like synoviocytes (RA-FLS) were stimulated with IL-17, and the mRNA expression and secretion of receptor activator of nuclear factor kappa-B ligand (RANKL) were detected by real-time polymerase chain reaction and enzyme-linked immunosorbent assay, respectively. CD14+ monocytes (osteoclast precursors) were stimulated with IL-17, RANKL, with/without quercetin, and tartrate-resistant acid phosphatase activity was evaluated to assess osteoclast differentiation. Osteoclast differentiation was investigated after coculturing IL-17-stimulated RA-FLS and Th17 cells with monocytes. CD4+ T cells were cocultured with quercetin under Th17-inducing conditions, and their differentiation to Th17 cells and Treg cells was determined by flow cytometry analysis. We found that IL-17 stimulated RA-FLS to produce RANKL and quercetin decreased the IL-17-induced RANKL protein levels. Quercetin decreased the IL-17-produced activation of mammalian target of rapamycin, extracellular signal-regulated kinase and inhibitor of kappa B-alpha. When monocytes were stimulated with IL-17, macrophage colony-stimulating factor or RANKL, mature osteoclasts were formed, and quercetin decreased this osteoclastogenesis. When monocytes were cultured with IL-17-prestimulated RA-FLS or Th17 cells, osteoclasts were produced, and quercetin decreased this osteoclast differentiation. In Th17-differentiation conditions, quercetin suppressed Th17 cell and the production of IL-17, but quercetin did not affect Treg cells. Quercetin inhibits IL-17-stimulated RANKL production in RA-FLS and IL-17-stimulated osteoclast formation. Quercetin reduces Th17 differentiation. Quercetin could be an additional therapeutic option for bone destructive processes in RA. [ABSTRACT FROM AUTHOR] more...
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- 2019
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29. TLR-3 enhances osteoclastogenesis through upregulation of RANKL expression from fibroblast-like synoviocytes in patients with rheumatoid arthritis
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Kim, Kyoung-Woon, Cho, Mi-La, Oh, Hye-Joa, Kim, Hae-Rim, Kang, Chang-Min, Heo, Yang-Mi, Lee, Sang-Heon, and Kim, Ho-Youn
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RHEUMATOID arthritis , *FIBROBLASTS , *IMMUNOHISTOCHEMISTRY , *MESSENGER RNA - Abstract
Abstract: This study was undertaken to determine the effect of toll-like receptor-3 (TLR3) on the regulation of osteoclastogenic activity in rheumatoid arthritis (RA) fibroblast-like synoviocytes (FLS). The expression of receptor activator of nuclear factor kappa B ligand (RANKL) mRNA and protein in RA-FLS after TLR3 activation was determined using RT-PCR, real-time PCR, western blot analysis, and immunohistochemistry. Human monocytes were cocultured with RA-FLS that had been prestimulated by the TLR3 ligand polyriboinosinic–polyribocytidylic acid and then stained for tartrate-resistant acid phosphatase (TRAP) activity. Other markers of osteoclasts were measured using RT-PCR and real-time PCR. The expression of TLR3 and RANKL was much higher in the RA synovium than in the osteoarthritis (OA) synovium. TLR3 activation induced RANKL expression in RA-FLS, but not in OA-FLS or in normal skin fibroblasts. TLR3 activation also induced the production of IL-1β but had no effect on IL-17 or TNF-α production in RA-FLS. Inhibition of IL-1β reversed the TLR3-induced upregulation of RANKL expression. Coculture of human monocytes with TLR3-activated RA-FLS or TLR3 ligand-stimulated human monocytes increased the expression of TRAP, RANK, cathepsin K, calcitonin receptor, and MMP-9, reflecting the differentiation of monocytes into osteoclasts. Our results suggest that TLR3 promotes osteoclastogenesis in the RA synovium both directly and indirectly. TLR3 stimulates human monocytes directly to promote osteoclast differentiation. TLR3 induces RANKL expression indirectly in RA-FLS, and the expression of RANKL promotes the differentiation of osteoclasts in the RA synovium. Targeting the TLR3 pathway may be a promising approach to preventing inflammatory bone destruction in RA. [Copyright &y& Elsevier] more...
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- 2009
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30. Toll-like receptor 2 ligand mediates the upregulation of angiogenic factor, vascular endothelial growth factor and interleukin-8/CXCL8 in human rheumatoid synovial fibroblasts
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Cho, Mi-La, Ju, Ji-Hyeon, Kim, Hae-Rim, Oh, Hye-Joa, Kang, Chang-Min, Jhun, Joo-Yeon, Lee, Seon-Yeong, Park, Mi-Kyung, Min, Jun-Ki, Park, Sung-Hwan, Lee, Sang-Heon, and Kim, Ho-Youn
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LIGANDS (Biochemistry) , *RHEUMATOID arthritis , *NEOVASCULARIZATION , *AUTOIMMUNE diseases - Abstract
Abstract: Rheumatoid arthritis (RA) is characterized by infiltrations of inflammatory cells accompanied by neovascularization in the joint. We hypothesized that cell activation via the toll-like receptor (TLR) may be involved in the induction of angiogenic molecules, which are relevant to the pathogenesis of RA. RA fibroblast like synoviocytes (FLS) were stimulated with TLR-2 ligand bacterial peptidoglycan (PGN), TLR-4 ligand lipopolysaccharide (LPS) and various cytokines. Vascular endothelial growth factor (VEGF) and IL-8 were measured by ELISA in culture supernatants; mRNA levels were assessed by RT-PCR and real time PCR. The levels of TLR-2, VEGF and IL-8 were analyzed by dual immunohistochemistry in RA synovium and compared with osteoarthritis (OA). Regulation of MyD88, IRAK4, IRAK1, IRAK-M and TRAF-6 mRNA expression levels by PGN were analyzed by RT-PCR. Phosphorylation of IκBα was evaluated by western blotting. Levels of VEGF and IL-8 were upregulated in culture supernatants of RA FLS stimulated with PGN, similar to the levels of IL-1β and IL-17 stimulation. Neutralization of TLR-2 with a blocking monoclonal antibody significantly reduced both VEGF and IL-8 levels (P <0.05), which reflected the functional relevance of TLR-2 activation to the induction of VEGF and IL-8 production. Downstream intracellular signaling following TLR-2 stimulation involved MyD88-IRAK-4-TRAF-6 pathways, resulting in NF-κB activation. Thus, TLR-2 activation in RA FLS by microbial constituents could be involved in the induction of VEGF and IL-8 and thereby promote inflammation either directly or via angiogenesis. This possibly contributes to the perpetuation of synovitis in patients with RA. [Copyright &y& Elsevier] more...
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- 2007
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31. Cyclosporine A inhibits IL-15-induced IL-17 production in CD4+ T cells via down-regulation of PI3K/Akt and NF-κB
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Cho, Mi-La, Ju, Ji Hyeon, Kim, Kyoung-Woon, Moon, Young-Mee, Lee, Seon-Yeong, Min, So-Youn, Cho, Young-Gyu, Kim, Hyun-Sook, Park, Kyung-Su, Yoon, Chong-Hyeon, Lee, Sang Heon, Park, Sung-Hwan, and Kim, Ho-Youn more...
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LYMPHOCYTES , *IMMUNOSUPPRESSIVE agents , *AUTOIMMUNE diseases , *RHEUMATOID arthritis - Abstract
Abstract: Cyclosporine A (CSA) has various biological effects on T cells, including inhibition of interleukin (IL)-15-induced IL-17 production in CD4+ T cells from patients with rheumatoid arthritis (RA). However, the mechanism underlying this effect is not fully understood. Here, we tried to investigate the mechanism of CSA to inhibit IL-17 production induced by IL-15 in CD4+ T cells. Synovial fluid and serum levels of IL-15 and IL-17 were determined by ELISA. CD4+ T cells from RA patients were treated with IL-15 in the presence of CSA or several signal inhibitors. The concentration of IL-17 in culture supernatants was measured by ELISA and IL-17 mRNA expression was determined by RT-PCR. NF-κB binding activity for IL-17 transcription was assessed by electrophoretic mobility shift assay. IL-15 induced IL-17 production by CD4+ T cells in dose- and time-dependent manner. IL-15-stimulated IL-17 production and mRNA expression were inhibited by CSA in CD4+ T cells. Moreover PI3K/Akt inhibitor, NF-κB inhibitor, and FK506 significantly inhibited IL-15-induced IL-17 production in CD4+ T cells. Inhibition studies revealed the requirement of PI3K/Akt and NF-κB signal pathway for IL-15-induced IL-17 production. CSA down-regulated the phosphorylation of Akt and IκB. CSA inhibited binding of NF-κB to IL-17 promoter. The inhibitory effect of CSA on IL-15 induced IL-17 production partially depended on the increase in IL-10, since neutralizing anti-IL-10 antibodies were able to partially reverse this inhibition. CSA inhibits IL-17 production by CD4+ T cells and this effect is mediated by IL-15-activated NF-κB pathway in CD4+ T cells, which is possible mechanism of CSA in treating RA as NF-κB targeting strategy. [Copyright &y& Elsevier] more...
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- 2007
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32. Transforming growth factor beta 1(TGF-β1) down-regulates TNFα-induced RANTES production in rheumatoid synovial fibroblasts through NF-κB-mediated transcriptional repression
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Cho, Mi-La, Min, So-Youn, Chang, Soog-Hee, Kim, Kyoung-Woon, Heo, Seong-Bum, Lee, Sang-Heon, Park, Sung-Hwan, Cho, Chul-Soo, and Kim, Ho-Youn
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GROWTH factors , *ARTHRITIS , *TRANSFORMING growth factors-beta , *RHEUMATOID arthritis - Abstract
Abstract: Transforming growth factor (TGF)-β1 is a pleiotropic cytokine with many functions, including those related to growth modulation, immunosuppression, and pro-inflammation, in a wide variety of cell types. In this study, we investigated the ability of TGF-β1 to regulate RANTES production by activated rheumatoid synovial fibroblasts. Fibroblast-like synoviocytes (FLS) were cultured in the presence of TGF-β1 and IL-1β, IL-15, TNFα, or IL-17, and the secretion of RANTES into culture supernatants was measured by enzyme-linked immunosorbent assay (ELISA). Expression of RANTES encoded mRNA was determined by reverse transcription-polymerase chain reaction (RT-PCR), and NF-κB binding activity for RANTES transcription was determined by electrophoretic mobility shift assay (EMSA). We found that the concentrations of RANTES in synovial fluid (SF) from rheumatoid arthritis (RA) patients were lower than in SF from osteoarthritis (OA) patients, whereas the concentrations of TGF-β1 were higher in RA SF than in OA SF. TGF-β1 dose-dependently inhibited TNFα-induced production of RANTES protein and mRNA from RA FLS. Addition of RA SF with high-level TGF-β1 mimicked the effect of TGF-β1 on TNFα-induced RANTES production, which was inhibited by treatment with anti-TGF-β1 neutralizing antibody. TGF-β1 blocked the degradation of cytosolic IκB-α and the translocation of activated NF-κB to the nucleus. EMSA showed that the inhibitory effect of TGF-β1 was associated with decreased binding of NF-κB to the RANTES promoter. These results suggest that elevated TGF-β1 in rheumatoid synovial tissue may suppress joint inflammation by inhibiting RANTES secretion from synovial fibroblasts, thus blocking the infiltration of immune cells. These findings may provide an explanation for the mechanism by which TGF-β1 regulates immune function in RA. [Copyright &y& Elsevier] more...
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- 2006
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33. Interleukin-18 induces the production of vascular endothelial growth factor (VEGF) in rheumatoid arthritis synovial fibroblasts via AP-1-dependent pathways
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Cho, Mi-La, Jung, Young Ok, Moon, Young-Mi, Min, So-Youn, Yoon, Chong-Hyeon, Lee, Sang-Heon, Park, Sung-Hwan, Cho, Chul-Soo, Jue, Dae-Myung, and Kim, Ho-Youn
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ARTHRITIS , *RHEUMATOID arthritis , *CYTOKINES , *ENZYME-linked immunosorbent assay - Abstract
Abstract: Interleukin-18 (IL-18) is a novel pro-inflammatory cytokine which has been implicated to play a pathogenic role in rheumatoid arthritis (RA). Vascular endothelial growth factor (VEGF) plays an important role in angiogenesis in rheumatoid synoviocytes. In present study, we examined the effect of IL-18 on VEGF production in fibroblast-like synoviocytes (FLS) isolated from the patients with RA. FLS were prepared from the synovial tissues of patients with RA and osteoarthritis (OA) and cultured in the presence of IL-18. The production of VEGF from FLS was measured in culture supernatants by enzyme-linked immunosorbent assay (ELISA). The VEGF messenger RNA (mRNA) expression and AP-1 binding activity of VEGF transcript were determined by reverse transcription-polymerase chain reaction (RT-PCR) and electrophoretic mobility shift assay (EMSA). IL-18 and VEGF levels of sera and synovial fluids (SF) of RA patients (n =30) were significantly higher than those of OA patients (n =20). IL-18 dose-dependently increased the production of VEGF. The effect of IL-18 on VEGF production appeared to be as potent as IL-1β, whereas tumor necrosis factor (TNF)-α and interferon (IFN)-γ showed little effects on VEGF production. AP-1-specific inhibitor Curcumin dose-dependently abrogated the effect of IL-18 on VEGF production. The VEGF enhancement of IL-18 was associated with increased AP-1 binding activity to the VEGF promoter site. These findings suggest IL-18 as an angiogenic factor in RA and down-regulation of IL-18 activity or AP-1 signal pathway can be potential therapeutic targets for RA. [Copyright &y& Elsevier] more...
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- 2006
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