Radiologic approach and progressive exploration of connective tissue disease-related interstitial lung disease: meeting the curiosity of rheumatologists.

Interstitial lung disease (ILD) is often observed in connective tissue diseases (CTDs), frequently in rheumatoid arthritis, systemic sclerosis, primary Sjögren's syndrome, and inflammatory myositis. Early detection of ILDs secondary to rheumatic diseases is important as timely initiation of proper management affects the prognosis. Among many imaging modalities, high-resuloution computed tomography (HRCT) serves the gold standard for finding early lung inflammatory and fibrotic changes as well as monitoring afterwards because of its superior spatial resolution. Additionally, lung ultrasound (LUS) and magnetic resonance imaging (MRI) are the rising free-radiation imaging tools that can get images of lungs of CTD-ILD. In this review article, we present the subtypes of ILD images found in each CTD acquired by HRCT as well as some images taken by LUS and MRI with comparative HRCT scans. It is expected that this discussion would be helpful in discussing recent advances in imaging modalities for CTD-ILD and raising critical points for diagnosis and tracing of the images from the perspective of rheumatologists.

Korean guidelines for the management of gout.

Gout is the most common form of arthritis, with the prevalence increasing worldwide. The present treatment guidelines provide recommendations for the appropriate treatment of acute gout, management during the inter-critical period, and prevention of chronic complications. The guidelines were developed based on evidence-based medicine and draft recommendations finalized after expert consensus. These guidelines are designed to provide clinicians with clinical evidence to enable efficient treatment of gout.

Korean guidelines for the management of gout.

Gout is the most common form of arthritis, with the prevalence increasing worldwide. The present treatment guidelines provide recommendations for the appropriate treatment of acute gout, management during the inter-critical period, and prevention of chronic complications. The guidelines were developed based on evidence-based medicine and draft recommendations finalized after expert consensus. These guidelines are designed to provide clinicians with clinical evidence to enable efficient treatment of gout.

Genetic deficiency of nuclear factor of activated T cells 5 attenuates the development of osteoarthritis in mice.

OBJECTIVES: This study is aimed to investigate the role of nuclear factor of activated T cells 5 (NFAT5), originally known as the osmosensitive mammalian transcription factor, in the pathogenesis of osteoarthritis (OA) in mice. METHODS: OA was induced in male C57BL/6 (wild-type) and NFAT5 haplo-insufficient (NFAT5+/-) mice via destabilization of the medial meniscus (DMM) surgery. OA severity and synovial inflammation were histologically assessed. Expression of CCL2, inflammatory cytokines, cartilage degrading enzymes was determined in the knee joints and cultured chondrocytes from wild-type and NFAT5+/- mice. RESULTS: NFAT5 expression was significantly upregulated in the knee joint of a mouse after DMM surgery. NFAT5 deficiency decreased the severity of synovial inflammation and osteoarthritic changes in cartilage and subchondral bone. Moreover, NFAT5 deficiency also decreased the expression of CCL2, IL-1ß, MMP-13, ADMATS-5, and macrophage infiltration in the joint. In cultured chondrocytes, hyperosmolar or IL-1ß stimulation significantly enhanced the expression of NFAT5, CCL2, IL-1ß, IL-6, and MMP-13, and this effect was abolished in chondrocytes from NFAT5+/- mice. Hyperosmolarity or IL-1ß-induced NFAT5 and CCL2 downregulated by inhibiting p38 MAPK, JNK, and ERK pathways. CONCLUSIONS: Our results indicate that NFAT5 is a crucial regulator of OA pathogenesis by upregulating CCL2 expression and macrophage recruitment. In chondrocyte, NFAT5 plays an important role in the response to hyperosmolar or IL-1ß stimulation. Thus, NFAT5 could be an attractive therapeutic target for OA treatment.

Quality Indicators for Evaluating the Health Care of Patients with Rheumatoid Arthritis: a Korean Expert Consensus.

BACKGROUND: There is increasing interest in the quality of health care and considerable efforts are being made to improve it. Rheumatoid arthritis (RA) is a disease that can result in favorable outcomes when appropriate diagnosis and treatment are provided. However, several studies have shown that RA is often managed inappropriately. Therefore, the Korean College of Rheumatology aimed to develop quality indicators (QIs) to evaluate and improve the health care of patients with RA. METHODS: Preliminary QIs were derived based on the existing guidelines and QIs for RA. The final QIs were determined through two separate consensus meetings of experts. The consensus was achieved through a panel of experts who voted using the modified Delphi method. RESULTS: Fourteen final QIs were selected among 70 preliminary QIs. These included early referral to and regular follow-up with a rheumatologist, radiographs of the hands and feet, early initiation and maintenance of disease-modifying anti-rheumatic drug (DMARD) therapy, periodic assessment of disease activity, screening for drug safety and comorbidities, including viral hepatitis and tuberculosis before biologic DMARD therapy, periodic laboratory testing, supplementation with folic acid, assessment of the risk for cervical spine instability before general anesthesia, patient education, and specialized nurse. CONCLUSION: These QIs can be used to assess and improve the quality of health care for patients with RA.

Placental growth factor regulates the generation of TH17 cells to link angiogenesis with autoimmunity.

Helper T cells actively communicate with adjacent cells by secreting soluble mediators, yet crosstalk between helper T cells and endothelial cells remains poorly understood. Here we found that placental growth factor (PlGF), a homolog of the vascular endothelial growth factor that enhances an angiogenic switch in disease, was selectively secreted by the TH17 subset of helper T cells and promoted angiogenesis. Interestingly, the 'angio-lymphokine' PlGF, in turn, specifically induced the differentiation of pathogenic TH17 cells by activating the transcription factor STAT3 via binding to its receptors and replaced the activity of interleukin-6 in the production of interleukin-17, whereas it suppressed the generation of regulatory T cells. Moreover, T cell-derived PlGF was required for the progression of autoimmune diseases associated with TH17 differentiation, including experimental autoimmune encephalomyelitis and collagen-induced arthritis, in mice. Collectively, our findings provide insights into the PlGF-dictated links among angiogenesis, TH17 cell development and autoimmunity.

Standardized, musculoskeletal ultrasonographic reference values for healthy Korean adults.

BACKGROUND/AIMS: To define standard reference values for musculoskeletal ultrasonography (MSUS) in Korea. METHODS: A total of 251 healthy adults were recruited for this study. Ultrasonography was performed by experienced rheumatologists who had undergone four appropriate training programs in Korea. A General Electric LOGIQ electronic ultrasound device fitted with a 12 MHz linear transducer was employed. Mean values ± standard deviations (SDs) were defined as standard reference values. Intraclass correlation coefficients was employed to evaluate the extent of inter- and intraobserver agreement when MSUS measurements were made. RESULTS: The 251 study participants included 122 males. Mean subject age was 28.6 years. The average bone-to-capsule distance of the right-side second and third metacarpophalangeal (MCP) joints were 0.68 and 0.72 mm respectively, and those of the left-side joints 0.62 and 0.68 mm. The cartilage thicknesses of the rightside second and third MCP joints were 0.55 and 0.55 mm, and those of the leftside joints were 0.55 and 0.56 mm, respectively. The bone-to-capsule distances of the right and left wrists were 0.80 and 0.82 mm. In 12.4% of participants (31/251), the erosion score of the humeral head was 1.71. In the right-side knee joint, mean cartilage thicknesses of the medial and lateral condyles were 1.86 and 2.03 mm in longitudinal scans. High overall interobserver agreement was evident after appropriate training that included instruction on standard MSUS methodology. CONCLUSION: We defined standard reference values for MSUS in healthy Korean adults. The reliabilities of interobserver agreements were high after appropriate training program.

Risk factors associated with inadequate control of disease activity in elderly patients with rheumatoid arthritis: Results from a nationwide KOrean College of Rheumatology BIOlogics (KOBIO) registry.

OBJECTIVE: The proportion of elderly patients with rheumatoid arthritis (RA) is continuously growing as a result of the increasing aging population. We compared disease activity between different age groups, and evaluated the clinical factors associated with high disease activity. METHODS: This cross-sectional study analyzed the data of RA patients enrolled in the Korean College of Rheumatology Biologics registry (KOBIO-RA) between 2012 and 2014. Disease activity between elderly (age ≥ 65 years) and non-elderly patients (age < 65 years) was compared, and the association of clinical factors with high disease activity was assessed using a multivariate logistic regression model. RESULTS: Of 1,227 patients in KOBIO-RA, 244 patients with RA were aged 65 years or over. In elderly patients, the proportion of men was higher (P = 0.012), and the duration of disease was longer (P < 0.001) compared with non-elderly patients. The elderly group showed a higher incidence of comorbidity (P < 0.001), and less use of methotrexate (P = 0.004). Assessment of disease activity using various composite measures showed a higher proportion of high disease activity in elderly patients than non-elderly patients. Longer disease duration, presence of comorbidity, and non-use of methotrexate were independently associated with high disease activity (P = 0.002, P < 0.001, and P = 0.029, respectively). CONCLUSIONS: At enrollment of KOBIO-RA, elderly patients showed higher disease activity compared with non-elderly patients. Disease duration, use of methotrexate, and comorbidity are associated with disease activity control in Korean patients with RA.

Elevated levels of soluble CD40 ligand are associated with antiphospholipid antibodies in patients with systemic lupus erythematosus.

OBJECTIVES: The CD40L/CD40 pathway is involved in the pathophysiology of atherothrombotic disease, and elevated levels of soluble CD40L (sCD40L) were reported in SLE patients. However, the clinical implication of sCD40L in SLE remains elusive. METHODS: We measured levels of plasma sCD40L in 241 SLE patients and 37 healthy controls and investigated its association with clinical manifestation and laboratory parameters. RESULTS: Levels of plasma sCD40L in SLE patients were significantly elevated compared with healthy controls (p=0.013) and positively correlated with levels of soluble P-selectin (γ=0.336, p<0.001). SLE patients who experienced arterial thrombosis had a higher level of sCD40L than those who did not (p=0.029). Plasma sCD40L levels were positively correlated with the titers of anti-cardiolipin and anti-ß2 glycoprotein I antibodies (γ=0.338, p<0.001 and γ=0.364, p<0.001, respectively). Its levels were also significantly higher in patients with clinical antiphospholipid syndrome (APS) than in non-APS patients, irrespective of antiphospholipid antibody (aPL) positivity. Of those with arterial thrombosis, sCD40L levels were significantly elevated in patients with positive aPL, compared to those with negative aPL (p=0.011). Multiple regression analysis revealed that the presence of hypertension and positive aPL were independently associated with the occurrence of arterial thrombosis in SLE patients. A parallel analysis showed that sCD40L was also an independent variable for arterial thrombosis; however, this association disappeared when aPL, a strong variable, was included in the model because of collinearity between aPL and sCD40L. CONCLUSIONS: Plasma sCD40L levels were elevated in SLE patients who had positive aPL and experienced arterial thrombosis, suggesting that enhanced release of sCD40L through platelet activation presumably by aPL could contribute to the development of atherothrombotic disease.

The Effects of Forest Therapy on Coping with Chronic Widespread Pain: Physiological and Psychological Differences between Participants in a Forest Therapy Program and a Control Group.

This study aimed to investigate the effects of a two-day forest therapy program on individuals with chronic widespread pain. Sixty one employees of a public organization providing building and facilities management services within the Seoul Metropolitan area participated in the study. Participants were assigned to an experimental group (n = 33) who participated in a forest therapy program or a control group (n = 28) on a non-random basis. Pre- and post-measures of heart rate variability (HRV), Natural Killer cell (NK cell) activity, self-reported pain using the visual analog scale (VAS), depression level using the Beck Depression Inventory (BDI), and health-related quality of life measures using the EuroQol Visual Analog Scale (EQ-VAS) were collected in both groups. The results showed that participants in the forest therapy group, as compared to the control group, showed physiological improvement as indicated by a significant increase in some measures of HRV and an increase in immune competence as indicated by NK cell activity. Participants in the forest therapy group also reported significant decreases in pain and depression, and a significant improvement in health-related quality of life. These results support the hypothesis that forest therapy is an effective intervention to relieve pain and associated psychological and physiological symptoms in individuals with chronic widespread pain.

Anti-inflammatory effects of essential oils extracted from Chamaecyparis obtusa on murine models of inflammation and RAW 264.7 cells.

Antimicrobial, antifungal and anti-inflammatory effects of essential oils extracted from Chamaecyparis obtusa (EOCO) have previously been reported. In the present study, the anti-inflammatory effects of EOCO were investigated in two murine models of inflammation: Carrageenan-induced paw edema and thioglycollate-induced peritonitis, and in lipopolysaccharide (LPS)-stimulated RAW 264.7 macrophage cells. The expression levels of proinflammatory cytokines were analyzed by ELISA, the expression of nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) were determined by western blotting, and nitrite concentration was measured using Griess reagent. In mice with carrageenan-induced edema, paw thickness and the expression levels of interleukin (IL)­1ß and IL-6 in paw homogenates were significantly decreased in the EOCO (5 and 10 mg/kg) group, as compared with the control group. In mice with thioglycollate-induced peritonitis, treatment with EOCO (5 and 10 mg/kg) reduced the number of total cells and suppressed tumor necrosis factor­α (TNF­α), IL­1ß and IL­6 levels in peritoneal fluid. In addition, EOCO reduced nitric oxide, TNF­α and IL­6 production, and suppressed iNOS and COX­2 expression in LPS­stimulated RAW 264.7 cells. These results suggest that EOCO may exert anti­inflammatory effects in vivo and in vitro, and that these effects may be associated with the inhibition of inflammatory mediators. Therefore, EOCO may be considered an effective therapeutic agent for the treatment of inflammatory diseases.

Antinociceptive and anti-inflammatory effects of essential oil extracted from Chamaecyparis obtusa in mice.

Essential oil extracted from Chamaecyparis obtusa (EOCO) consists of several monoterpenes with anti-inflammatory effects. Monoterpenes are expected to have an analgesic effect through inhibition of pro-inflammatory mediators. The present study investigated the anti-nociceptive and anti-inflammatory effects of EOCO in animal models of pain. Intraperitoneal injection with EOCO (5 or 10mg/kg), aspirin (positive control, 300mg/kg), or DMSO (negative control) was performed 1h before the nociception tests: acetic acid-induced writhing response, formalin test, and hot plate test in mice, and acidic saline-induced allodynia in rats. The expression of pro-inflammatory cytokines and pro-inflammatory enzymes in formalin-injected paws was determined by ELISA and western blotting, respectively. Treatment with EOCO significantly reduced acetic acid-induced writhing and paw-licking time in late response of the formalin tests. The anti-nociceptive effect was comparable with aspirin. However, EOCO did not affect the reaction time of licking of the hind paws or jumping in hot plate test and the mechanical withdrawal thresholds in acidic saline-induced allodynia model. Formalin-injected paws of mice treated with EOCO revealed the down-regulated expression of tumor necrosis factor-α, interleukin-1ß, inducible nitric oxide synthase, and cyclooxygenase-2, as compared with those of control mice. These data showed the anti-nociceptive and anti-inflammatory effects of EOCO. The pain-relieving effect might be attributed to inhibition of peripheral pain in association with inflammatory response. EOCO could be a useful therapeutic strategy to manage pain and inflammatory diseases.

Association of Anemic Hypoxia and Increased Pulmonary Artery Systolic Pressure in Patients With Systemic Lupus Erythematosus.

OBJECTIVE: Pulmonary arterial hypertension (PAH) is a rare but serious complication of systemic lupus erythematosus (SLE). Chronic hypoxia is known to cause PAH resulting from pulmonary vascular remodeling. We investigated the association between anemic hypoxia and PAH in SLE patients. METHODS: Systolic pulmonary artery pressure (PAP) was measured in 132 SLE patients by echocardiography. Increased PAP was defined as resting PAP > 40 mm Hg. Oxygen delivery (DO2) was estimated as the product of cardiac output and arterial oxygen content. RESULTS: Of 132 patients, 17 (12.9%) had increased PAP, and these patients had significantly lower DO2 values than patients with normal PAP (P = 0.002). The DO2 values inversely correlated with PAP values (γ = -0.308, P < 0.001) and plasma N-terminal pro-brain natriuretic peptide levels (γ = -0.323, P = 0.001), but positively correlated with hemoglobin levels (γ = 0.402, P < 0.001). Compared to those with normal PAP, patients with increased PAP had significantly longer durations of anemia over the preceding 6-24 months. Patients with anemia of longer durations (≥3 months) in the preceding 6 months had a higher risk of increased PAP compared to those with shorter durations (P < 0.001). When SLE patients were divided into 3 groups according to hemoglobin and PAP, serum interleukin-6 (IL-6) levels increased across groups with higher PAP (P = 0.001 for trend), but decreased across tertiles of hemoglobin levels (P = 0.008 for trend). CONCLUSION: Our data indicate an association between chronic anemic hypoxia and increased PAP in SLE patients and suggest that increased IL-6 might participate in this process.

High levels of uric acid in systemic lupus erythematosus is associated with pulmonary hypertension.

AIM: To estimate the point prevalence of pulmonary hypertension (PH) and determine the associated factors for PH in patients with systemic lupus erythematosus (SLE). METHODS: A prospective cross-sectional study of 114 patients with SLE was conducted in a single tertiary center. Transthoracic echocardiography was performed to estimate the pulmonary arterial pressures. PH was defined as resting systolic pulmonary artery pressure (sPAP) ≥ 40 mmHg, in the absence of left heart disease. RESULTS: PH was identified in nine patients (7.9%) who had few cardiopulmonary symptoms. SLE patients with PH had higher SLE disease activity index score. In particular, serum uric acid (UA) was significantly higher in patients with PH than in those without PH. In multivariate analysis, UA remained significant for the presence of PH. Moreover, serum UA level correlated significantly with plasma NT-pro-B-type natriuretic peptide level as well as sPAP. At the cutoff level of 6.5 mg/dL, serum UA had reasonable accuracy for predicting the presence of PH in SLE patients (sensitivity 66.7% and specificity 96.2%). CONCLUSION: A significant number of SLE patients in rheumatology practice have undiagnosed PH with few discernible symptoms. Serum UA level may be useful as a surrogate marker for screening of PH in patients with SLE.

Ultrasonography is useful to detect subclinical synovitis in SLE patients without musculoskeletal involvement before symptoms appear.

The purpose of this study is to investigate the frequency of the subclinical synovitis in hand or wrist joints of the SLE patients using ultrasonography (US) and to correlate them with clinical parameters. Forty-eight systemic lupus erythematosus (SLE) patients without musculoskeletal (MS) involvement were enrolled and underwent clinical and laboratory examinations. Gray-scale and power Doppler (PD) US was performed for imaging the wrist, second and third metacarpophalangeal (MCP) joints, and flexor tendons on non-dominant sides of the individuals. US synovitis index (USSI) and PD index were calculated as sum of the synovitis and PD semiquantitative scores, respectively, obtained from each joint. Subclinical synovitis was found by US in 28 (58.3%) out of 48 patients. US revealed synovitis of the wrist in 16 (33.3%) patients, of the second MCP joint in 14 (29.2%) and of the third MCP joint in 15 (31.3%). PD signals in three (6.3%) patients and tenosynovitis in two (4.2%) were also detected. USSI scores showed significant positive correlation with erythrocyte sedimentation rate (ESR) levels (r = 0.30, p < 0.05) or anti-dsDNA Ab titers (r = 0.34, p < 0.05). Within 6 months after US examination, new MS symptoms were developed in 11 (22.9%) patients. Older age at diagnosis (OR 1.283, 95% CI 1.029-1.601, p = 0.027) or higher USSI scores (OR 12.93, 95% CI 1.023-163.503, p = 0.048) were independently associated with development of new MS symptoms. Subclinical synovitis is common in SLE patients who do not suffer from MS symptoms. US is useful to detect joint abnormalities before symptoms appear in SLE patients.

Safe re-administration of tumor necrosis factor-alpha (TNFα) inhibitors in patients with rheumatoid arthritis or ankylosing spondylitis who developed active tuberculosis on previous anti-TNFα therapy.

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.

Inhibition of glycogen synthase kinase-3ß suppresses inflammatory responses in rheumatoid arthritis fibroblast-like synoviocytes and collagen-induced arthritis.

OBJECTIVES: Glycogen synthase kinase (GSK)-3ß, a serine/threonine protein kinase, has been implicated as a regulator of the inflammatory response. This study was performed to evaluate the effect of selective GSK-3ß inhibitors in rheumatoid arthritis (RA) fibroblast-like synoviocytes (FLS) and collagen-induced arthritis (CIA). METHOD: FLS from RA patients were treated with selective GSK-3ß inhibitors, including lithium chloride, 6-bromoindirubin-3'-oxime (BIO), or 4-benzyl-2-methyl-1,2,4-thiadiazolidine-3,5-dione (TDZD-8). The effects of GSK-3ß inhibition on pro-inflammatory mediators were determined by real-time PCR and ELISA. The levels of NF-κB, phosphorylated JNK, c-jun, ATF-2 and p-38 proteins were evaluated by western blot analysis. The in vivo effects of GSK-3ß inhibitors were examined in mice with CIA. RESULTS: Treatment of RA FLS with GSK-3ß inhibitors induced dose-dependent reductions in gene expression and the production of pro-inflammatory mediators. The levels of NF-κB, phosphorylated JNK, c-jun, ATF-2 and p-38 were decreased following treatment with GSK-3ß inhibitors. GSK-3ß inhibitors treatment attenuated clinical and histological severities of CIA in mice. Infiltration of T-cells, macrophages, and tartrate-resistant acid phosphatase positive cells was decreased in joint sections of CIA mice by GSK-3ß inhibitors treatment. Serum levels of IL-1ß, IL-6, TNF-α and IFN-γ in CIA mice were also significantly decreased in dose-dependent manners by treatment with GSK-3ß inhibitors. CONCLUSION: Treatment with GSK-3ß inhibitors suppressed inflammatory responses in RA FLS and CIA mice. These findings suggest that the inhibition of GSK-3ß can be used as an effective therapeutic agent for RA.

Thrombotic risk in patients with immune thrombocytopenia and its association with antiphospholipid antibodies.

Patients with immune thrombocytopenia (ITP) paradoxically have an increased risk of thrombosis. The presence of antiphospholipid antibodies (aPL) has been observed in a substantial proportion of ITP patients, but its clinical significance remains to be established. This study retrospectively investigated the prevalence and clinical significance of aPL in ITP patients and assessed the risk factors for thrombosis. One hundred and sixty-five subjects with ITP were included in the study and followed for a mean period of 63·4 months. Sixty-nine (41·6%) patients were positive for aPL at diagnosis, and their clinical characteristics and course of ITP were not different from those of aPL-negative patients. Twenty-one (12·7%) patients developed a thrombotic event during follow-up and the cumulative incidence rate ratio of aPL-positive to aPL-negative patients for thromboembolism was 3·15 [95% confidence interval (CI) 1·21-8·17] after adjusting for confounding factors. Lupus anticoagulant and hypertension were identified by Cox regression analysis as independent risk factors for thrombosis [hazard ratio (HR) 4·1, 95% CI 1·4-11·9, P = 0·009 and HR 5·6, 95% CI 1·9-15·8, P = 0·001, respectively]. Our results showed that a substantial proportion of ITP patients were aPL-positive, and that lupus anticoagulant and hypertension were independent risk factors for thrombosis. Detection of aPL can provide useful information for identifying patients at high-risk for developing thrombosis.

Activation of liver X receptors suppresses inflammatory gene expressions and transcriptional corepressor clearance in rheumatoid arthritis fibroblast like synoviocytes.

OBJECTIVES: Liver X receptors (LXR) are nuclear receptors that play important roles in lipid metabolism and transport. LXR also suppress inflammatory responses in macrophages through a unique mechanism of transrepression. This study was performed to investigate whether the synthetic LXR agonist GW3965 can modulate the inflammatory status of fibroblast-like synoviocytes (FLS) from patients with rheumatoid arthritis (RA) and to identify the mechanism for their effect. METHODS: RA FLS were treated with 0.1 and 1 µM of GW3965, a synthetic LXR agonist. The mRNA expressions of pro-inflammatory mediators were measured using quantitative real-time PCR. Apoptotic cell death of RA FLS was assessed using TUNEL assay and determination of caspase-3 activity by a colorimetric assay. The levels of transcriptional corepressors including NCoR and SMRT were determined using western blot analyses. RESULTS: Treatment of RA FLS with GW3965 induced dose-dependent reductions in mRNA expression of pro-inflammatory mediators (IL-1ß, IL-6, MMP-9, CCL-2, CCL-7, and COX-2). However, treatment with GW3965 at the concentration selected for this study had no effect on apoptosis of RA FLS. Decreased productions of NCoR and SMRT by LPS stimulation was attenuated by GW3965 treatment. CONCLUSIONS: GW3965 treatment suppressed mRNA expressions of pro-inflammatory mediators from RA FLS and inhibited the clearance of transcriptional corepressors. These data suggest that LXR activation can be used as a therapeutic approach to reduce the synovial inflammation in RA.

Gallic acid, a natural polyphenolic acid, induces apoptosis and inhibits proinflammatory gene expressions in rheumatoid arthritis fibroblast-like synoviocytes.

OBJECTIVES: To investigate whether gallic acid (3, 4, 5-trihydroxybenzoic acid), a natural polyphenolic acid found in gall nuts, sumac, oak bark, tea leaves, grapes and wine, has pro-apoptotic and anti-inflammatory effects on fibroblast-like synoviocytes (FLS) from patients with rheumatoid arthritis (RA). METHODS: Viability of RA FLS was assessed using a MTT assay after gallic acid treatment. Apoptosis was assessed by TUNEL assay and caspase-3 activity was determined by a colorimetric assay. The levels of apoptosis-related proteins including Bcl-2, p-Akt, p53, and Bax were determined using western blot analyses, and the mRNA expressions of various pro-inflammatory mediators were measured using quantitative real-time PCR. RESULTS: Cell viability of RA FLS was significantly decreased by treatment with 10 or more µM of gallic acid. Gallic acid treatment at the concentrations that do not affect cell viability (0.1 and 1 µM) induced cellular apoptosis of RA FLS. Treatment with 0.1 and 1 µM of gallic acid also resulted in a significant increase in caspase-3 activity and regulated the productions of Bcl-2, Bax, p53 and pAkt. The mRNA expression levels of pro-inflammatory cytokines (IL-1ß, IL-6), chemokines (CCL-2/MCP-1, CCL-7/MCP-3), cyclooxygenase-2, and matrix metalloproteinase-9 from RA FLS were suppressed by the gallic acid treatment in dose-dependent manners. CONCLUSION: Gallic acid treatment was found to induce apoptosis of RA FLS through regulation of apoptosis-related protein expressions and to reduce the expression of pro-inflammatory genes in RA FLS. These data suggest that pro-apoptotic and anti-inflammatory activities of gallic acid may be used as a possible therapeutic option for RA.