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1.  Crico‐thyroid perichondritis leading to sore throat in patients with active adult‐onset Still's disease 
Annals of the Rheumatic Diseases  2007;66(9):1264-1266.
doi:10.1136/ard.2006.065342
PMCID: PMC1955132  PMID: 17693605
crico‐thyroid perichondritis; vocal cord; sore throat; magnetic resonance imaging (MRI); adult‐onset Still's disease (AOSD)
2.  Th17-Related Cytokines in Systemic Lupus Erythematosus Patients with Dilated Cardiomyopathies: A Possible Linkage to Parvovirus B19 Infection 
PLoS ONE  2014;9(12):e113889.
Dilated cardiomyopathies (DCM) are a major cause of mortality in patients with systemic lupus erythematosus (SLE). Immune responses induced by human parvovirus B19 (B19) are considered an important pathogenic mechanism in myocarditis or DCM. However, little is known about Th17-related cytokines in SLE patients with DCM about the linkage with B19 infection. IgM and IgG against B19 viral protein, and serum levels of Th17-related cytokines were determined using ELISA in eight SLE patients with DCM and six patients with valvular heart disease (VHD). Humoral responses of anti-B19-VP1u and anti-B19-NS1 antibody were assessed using Western blot and B19 DNA was detected by nested Polymerase Chain Reaction (PCR). Levels of interleukin (IL)-17, IL-6, IL-1β, and tumor necrosis factor (TNF)-α were significantly higher in SLE patients with DCM (mean ± SEM, 390.99±125.48 pg/ml, 370.24±114.09 pg/ml, 36.01±16.90 pg/ml, and 183.84±82.94 pg/ml, respectively) compared to healthy controls (51.32±3.04 pg/ml, p<0.001; 36.88±6.64 pg/ml, p<0.001; 5.39±0.62 pg/ml, p<0.005; and 82.13±2.42 pg/ml, p<0.005, respectively). Levels of IL-17 and IL-6 were higher in SLE patients with DCM versus those with VHD (both p<0.01). Five (62.5%) of DCM patients had detectable anti-B19-NS1 IgG and four (50.0%) of them had anti-B19-VP1u IgG, whereas only one (16.7%) of VHD patients had detectable anti-B19-NS1 IgG and anti-B19-VP1u IgG. Serum levels of IL-17, IL-6 and IL-1β were markedly higher in SLE patients with anti-B19-VP1u IgG and anti-B19-NS1 IgG compared to those without anti-B19-VP1u IgG or anti-B19-NS1 IgG, respectively. These suggest a potential association of B19 with DCM and Th17-related cytokines implicated in the pathogenesis of DCM in SLE patients.
doi:10.1371/journal.pone.0113889
PMCID: PMC4252071  PMID: 25462010
3.  A Potential Role of Myeloid DAP12-Associating Lectin (MDL)-1 in the Regulation of Inflammation in Rheumatoid Arthritis Patients 
PLoS ONE  2014;9(1):e86105.
The pathogenic roles of myeloid DAP12-associating lectin-1(MDL-1) and DAP12 in human rheumatoid arthritis (RA) remain unknown. Frequencies of MDL-1-expressing monocytes in 22 active RA patients, 16 inactive RA patients, 12 osteoarthritis (OA) patients and 10 healthy controls (HC) were determined by flow-cytometry analysis. The mRNA expression levels of MDL-1 and DAP12 on PBMCs were evaluated by quantitative PCR, and their protein expression levels in the synovium were examined by immunohistochemistry. Significantly higher median percentages of circulating MDL-1-expressing monocytes were observed in active RA patients (53.6%) compared to inactive RA patients (34.1%), OA patients (27.9%), and HC (21.2%). Levels of MDL-1 and DAP12 gene expression in PBMCs and their protein expression in the synovium were significantly higher in active RA patients than in inactive RA or OA patients. MDL-1 levels were positively correlated with parameters of disease activity, articular damage, and levels of proinflammatory cytokines. MDL-1 activator (Dengue virus type 2 antigen) stimulation on PBMCs resulted in significantly enhanced levels of proinflammatory cytokines in RA patients compared to those in OA patients or HC, indicating that MDL-1 activation is functional. Frequencies of MDL-1-expressing monocytes and levels of MDL-1 and DAP12 gene expression significantly decreased after effective therapy. Concordant overexpression of MDL-1 and DAP12 were correlated with increased production of proinflammatory cytokines in RA patients, suggesting their roles in regulating articular inflammation.
doi:10.1371/journal.pone.0086105
PMCID: PMC3897620  PMID: 24465901
4.  Involvement of TLR7 MyD88-dependent signaling pathway in the pathogenesis of adult-onset Still's disease 
Introduction
The objective of this study was to investigate the potential role of the Toll-like receptor 7 (TLR7) signaling pathway in the pathogenesis of adult-onset Still's disease (AOSD).
Methods
Frequencies of TLR7-expressing precursor of myeloid dendritic cells (pre-mDCs) and mDCs in 28 AOSD patients, 28 patients with systemic lupus erythematosus (SLE) and 12 healthy controls (HC) were determined by flow cytometry analysis. Transcript and protein levels of TLR7 signaling molecules in peripheral blood mononuclear cells (PBMCs) were evaluated by quantitative PCR and western blotting respectively. Serum cytokines levels were measured by ELISA.
Results
Significantly higher median frequencies of TLR7-expressing pre-mDCs and mDCs were observed in AOSD patients (65.5% and 14.9%, respectively) and in SLE patients (60.3% and 14.4%, respectively) than in HC (42.8% and 8.8%, respectively; both P <0.001). Transcript and protein levels of TLR7-signaling molecules, including MyD88, TRAF6, IRAK4 and IFN-α, were upregulated in AOSD patients and SLE patients compared with those in HC. Disease activity scores were positively correlated with the frequencies of TLR7-expressing mDCs and expression levels of TLR7 signaling molecules in both AOSD and SLE patients. TLR7 ligand (imiquimod) stimulation of PBMCs resulted in significantly enhanced levels of interleukin (IL)-1β, IL-6, IL-18 and IFN-α in AOSD and SLE patients. Frequencies of TLR7-expressing mDCs and expression levels of TLR7 signaling molecules significantly decreased after effective therapy.
Conclusions
Elevated levels of TLR7 signaling molecules and their positive correlation with disease activity in AOSD patients suggest involvement of the TLR7 signaling pathway in the pathogenesis of this disease. The overexpression of TLR7 MyD88-dependent signaling molecules may be a common pathogenic mechanism for both AOSD and SLE.
doi:10.1186/ar4193
PMCID: PMC3672755  PMID: 23497717
5.  Germinal center kinase-like kinase (GLK/MAP4K3) expression is increased in adult-onset Still's disease and may act as an activity marker 
BMC Medicine  2012;10:84.
Background
Germinal center kinase-like kinase (GLK, also termed MAP4K3), a member of the MAP4K family, may regulate gene transcription, apoptosis and immune inflammation in response to extracellular signals. The enhanced expression of GLK has been shown to correspond with disease severity in patients with systemic lupus erythematosus. We investigated the role of GLK in the pathogenesis of adult-onset Still's disease, which shares some similar clinical characteristics with systemic lupus erythematosus.
Methods
The frequencies of circulating GLK-expressing T-cells in 24 patients with active adult-onset Still's disease and 12 healthy controls were determined by flow cytometry analysis. The expression levels of GLK proteins and transcripts were evaluated in peripheral blood mononuclear cells by immunoblotting and quantitative PCR. Serum levels of T helper (Th)17-related cytokines, including IL-1β, IL-6, IL-17 and TNF-α, were measured by ELISA.
Results
Significantly higher median frequencies of circulating GLK-expressing T-cells were observed in patients with adult-onset Still's disease (31.85%) than in healthy volunteers (8.93%, P <0.001). The relative expression levels of GLK proteins and transcripts were also significantly higher in patients with adult-onset Still's disease (median, 1.74 and 2.35, respectively) compared with those in healthy controls (0.66 and 0.92, respectively, both P <0.001). The disease activity scores were positively correlated with the frequencies of circulating GLK-expressing T-cells (r = 0.599, P <0.005) and the levels of GLK proteins (r = 0.435, P <0.05) or GLK transcripts (r = 0.452, P <0.05) in patients with adult-onset Still's disease. Among the examined Th17-related cytokines, elevated levels of serum IL-6 and IL-17 were positively correlated with the frequencies of circulating GLK-expressing T-cells and the levels of GLK proteins as well as transcripts in patients with adult-onset Still's disease. GLK expression levels decreased significantly after effective therapy in these patients.
Conclusions
Elevated expression levels of GLK and their positive correlation with disease activity in patients with adult-onset Still's disease indicate that GLK may be involved in the pathogenesis and act as a novel activity biomarker of this disease.
doi:10.1186/1741-7015-10-84
PMCID: PMC3424974  PMID: 22867055
Adult-onset Still's disease; GCK-like kinase (GLK, MAP4K3); mitogen-activated protein kinases (MAPKs); pathogenesis; Th17-related cytokines
6.  Increasing levels of circulating Th17 cells and interleukin-17 in rheumatoid arthritis patients with an inadequate response to anti-TNF-α therapy 
Arthritis Research & Therapy  2011;13(4):R126.
Introduction
The objective of this study was to investigate the effects of tumor necrosis factor (TNF)-α inhibitors on circulating T helper-type 17 (Th17) cells and Th17-related cytokines in patients with rheumatoid arthritis (RA).
Methods
The frequencies of circulating Th17 cells and serum levels of Th17-related cytokines were determined using flow cytometry analysis and ELISA, respectively, in 48 RA patients both before (baseline) and six months after anti-TNF-α therapy. Therapeutic response was evaluated using European League Against Rheumatism (EULAR) response criteria.
Results
Significantly higher baseline frequencies of circulating Th17 cells and serum levels of interleukin (IL)-6, IL-17, IL-21, IL-23 and TNF-α were observed in active RA patients than in 12 healthy controls (all P < 0.001). After anti-TNF-α therapy, 36 patients (75%) were EULAR responders (20 good responders and 16 moderate responders) and 12 (25.0%) were non-responders. The mean levels of circulating Th17 cells and IL-17 significantly decreased (1.13% vs. 0.79%; 43.1 pg/ml vs. 27.8 pg/ml; respectively, both P < 0.001) in parallel with clinical remission in responders. Levels of IL-6, IL-21, IL-23 and TNF-α were significantly decreased after anti-TNF-α therapy in responders. In contrast, the mean levels of circulating Th17 cells and IL-17 significantly increased after anti-TNF-α therapy (2.94% vs. 4.23%; 92.1 pg/ml vs. 148.6 pg/ml; respectively, both P < 0.05) in non-responders. Logistic regression analysis identified a high baseline level of IL-17 as a significant predictor of poor therapeutic response.
Conclusions
The beneficial effect of anti-TNF-α therapy might involve a decrease in Th17-related cytokines in responders, whereas rising levels of circulating Th17-cells and IL-17 were observed in patients with an inadequate response to anti-TNF-α therapy.
doi:10.1186/ar3431
PMCID: PMC3239366  PMID: 21801431
7.  Risk of herpes zoster in patients with systemic lupus erythematosus: a three-year follow-up study using a nationwide population-based cohort 
Clinics  2011;66(7):1177-1182.
OBJECTIVE:
The goal of the present study was to estimate the risk ratio of herpes zoster among systemic lupus erythematosus patients after disease onset compared with a cohort of patients without systemic lupus erythematosus over a three-year period.
METHODS:
A nationwide population-based cohort study using the National Health Insurance Research Database identified 10,337 new cases of systemic lupus erythematosus as the study cohort. In addition, 62,022 patients without systemic lupus erythematosus, who were matched for age, gender, and date of systemic lupus erythematosus diagnosis, were used as the comparison cohort. These cohorts were followed-up for three years. A Cox proportional hazard regression was performed to estimate the risk ratio of herpes zoster, with adjustments for age, gender, level of insurance, urbanization level, geographic region, comorbid medical conditions, average daily dosage of corticosteroids, and the use of immune-modulation agents.
RESULTS:
Compared to patients without systemic lupus erythematosus, the crude risk ratio and adjusted risk ratio of herpes zoster among systemic lupus erythematosus patients were 7.37 (95% confidence interval 6.75-8.04) and 2.45 (95% confidence interval 1.77-3.40), respectively. Stratified by gender, the adjusted risk ratio of herpes zoster was 2.10 (95% confidence interval 1.45-2.99) in women and 7.51 (95% confidence interval 2.89-19.52) in men. Stratified by age, the adjusted risk ratio peaked in systemic lupus erythematosus patients who were aged 18 to 24 years (risk ratio 8.78, 95% confidence interval 3.08-24.97).
CONCLUSION:
Based on nationwide population-based data, there is an increased risk of herpes zoster in systemic lupus erythematosus patients compared with non-systemic lupus erythematosus patients, particularly among males and patients aged 18 to 24 years. Further research on the associated risk factors for herpes zoster in systemic lupus erythematosus patients is needed.
doi:10.1590/S1807-59322011000700009
PMCID: PMC3148460  PMID: 21876970
Herpes Zoster; Risk; Systemic Lupus Erythematosus; Population-Based Cohort Study; Database
8.  A close association of body cell mass loss with disease activity and disability in Chinese patients with rheumatoid arthritis 
Clinics  2011;66(7):1217-1222.
OBJECTIVES:
To investigate the association of body cell mass loss with disease activity and disability in rheumatoid arthritis patients.
INTRODUCTION:
Rheumatoid cachexia, defined as the loss of body cell mass, is important but under-recognized and contributes to morbidity and mortality in patients with rheumatoid arthritis.
METHODS:
One hundred forty-nine rheumatoid arthritis patients and 53 healthy, non-rheumatoid arthritis control subjects underwent anthropometric measurements of body mass index and waist and hip circumferences. Bioelectrical impedance analysis was used to determine the subjects' body compositions, including fat mass, skeletal lean mass, and body cell mass. The disease activity of rheumatoid arthritis was assessed using C-reactive protein serum, the erythrocyte sedimentation rate and the 28-joint disease activity score, while disability was evaluated using a health assessment questionnaire.
RESULTS:
Rheumatoid arthritis patients had lower waist-to-hip ratio (0.86±0.07 vs. 0.95±0.06; p<0.001) and lower skeletal lean mass indexes (14.44±1.52 vs. 15.18±1.35; p = 0.002) than those in the healthy control group. Compared with rheumatoid arthritis patients with higher body cell masses, those with body cell masses lower than median had higher erythrocyte sedimentation rates (40.10±27.33 vs. 25.09±14.85; p<0.001), higher disease activity scores (5.36±3.79 vs. 4.23±1.21; p = 0.022) and greater disability as measured by health assessment questionnaire scores (1.26±0.79 vs. 0.87±0.79; p = 0.004).
CONCLUSIONS:
The loss of body cell mass is associated with higher disease activity and greater disability in rheumatoid arthritis patients. Body composition determined by bioelectrical impedance analysis can provide valuable information for a rheumatologist to more rapidly recognize rheumatoid cachexia in rheumatoid arthritis patients.
doi:10.1590/S1807-59322011000700016
PMCID: PMC3148467  PMID: 21876977
Body cell mass; Rheumatoid arthritis; Bioelectrical impedance analysis; Disease activity; Disability
9.  Blood lipid profiles and peripheral blood mononuclear cell cholesterol metabolism gene expression in patients with and without methotrexate treatment 
BMC Medicine  2011;9:4.
Background
Methotrexate (MTX) is the most commonly prescribed disease-modifying antirheumatic drug (DMARD) in rheumatoid arthritis. ATP-binding cassette transporter-A1 (ABCA1) and 27-Hydroxylase (HY27) are known antiatherogenic proteins that promote cellular cholesterol efflux. In THP-1 macrophages, MTX can promote the reversal of cholesterol transport, limit foam cell formation and also reverse COX-2 inhibitor-mediated downregulation of ABCA1. Despite its antiatherogenic potential in vitro, the impact of clinical use of low-dose MTX on cholesterol metabolism in humans is unknown. Objective of the study was to examine whether clinical MTX use is associated with altered blood lipids and/or ABCA1/HY27 expressions.
Methods
In all, 100 rheumatoid arthritis subjects were recruited from a medical center in central Taiwan. Plasma lipid profiles and peripheral blood mononuclear cell HY27 and ABCA1 expressions were compared between subjects taking MTX (MTX+) and other disease-modifying antirheumatic drugs (DMARDs) (MTX-). Dietary intake was assessed by a registered dietician.
Results
Though no difference observed in the blood lipids between MTX+ and MTX- subjects, the expressions of ABCA1 and HY27 were significantly elevated in MTX+ subjects (n = 67) compared to MTX- subjects (n = 32, p < 0.05). ABCA expression correlated with MTX doses (r = 0.205, p = 0.042), and MTX+ subjects are more likely to have increased HY27 compared to MTX- subjects (OR = 2.5, p = 0.038). Prevalence of dyslipidemia and overweight, and dietary fat/cholesterol intake were lower than that of the age-matched population. Although no differences were observed in the blood lipids, the potential impacts of MTX on cholesterol metabolism should not be overlooked and the atheroprotective effects from MTX induced HY27 and ABCA1 expressions may still be present in those persons with pre-existing dyslipidemia.
Conclusions
We demonstrated novel findings on the increased gene expressions of atheroprotective protein HY27 and ABCA1 in human peripheral blood mononuclear cells (PBMCs) with clinical use of low-dose MTX. Whether MTX induced HY27 and ABCA1 expressions can protect against cardiovascular disease in patients with chronic inflammation through the facilitation of cholesterol export remains to be established. Further studies on the impacts of low-dose MTX on hypercholesterolemic patients are underway.
doi:10.1186/1741-7015-9-4
PMCID: PMC3033360  PMID: 21232092

Results 1-9 (9)