Comparative effectiveness of treatment options after conventional DMARDs failure in rheumatoid arthritis.

OBJECTIVE: To compare the clinical effectiveness of two treatment strategies for active rheumatoid arthritis (RA) refractory to conventional synthetic disease-modifying anti-rheumatic drugs (csDMARDs): starting TNF inhibitors (TNFIs) or changing csDMARDs. METHODS: We used two nationwide Korean RA registries for patient selection. TNFI users were selected from the BIOPSY, which is an inception cohort of RA patients starting biologic DMARDs. As a control group, we selected RA patients with moderate or high disease activity from the KORONA database whose treatment was changed to other csDMARDs. After comparing baseline characteristics between the two groups in either unmatched or propensity score matched cohorts, we compared potential differences in the 1-year remission rate as a primary outcome and changes in HAQ-DI and EQ-5D scores as secondary outcomes. RESULTS: A total of 356 TNFI starters and 586 csDMARD changers were identified from each registry as unmatched cohorts, and 294 patients were included in the propensity score matched cohort. In the intention-to-treat analysis, TNFI starters had higher 1-year remission rates than csDMARD changers in both unmatched (19.1 vs. 18.4%, p < 0.01) and matched cohorts (19.7 vs. 15.0%, p < 0.01). In per protocol analysis, TNFI starters had much higher remission rates in unmatched (37.2 vs. 28.0%, p = 0.04) and matched cohorts (35.4 vs. 19.1%, p = 0.04). However, in matched cohorts, no significant differences were observed between two groups in HAQ-DI and EQ-5D scores. CONCLUSIONS: We compared the clinical effectiveness of the two treatment strategies for active RA refractory to csDMARDs. TNFI starters showed higher 1-year remission rates than csDMARD changers.

PRDM1, a Tumor-Suppressor Gene, is Induced by Genkwadaphnin in Human Colon Cancer SW620 Cells.

Genkwadaphnin (GD-1) is isolated from the flower buds of Daphne genkwa Siebold et Zuccarini (Thymelaeaceae), and it has been used as a traditional Korean and Chinese medicine. In this study, the authors observe that GD-1 inhibits the growth of the colon cancer cell line, SW620, through the up-regulation of p21 expression in a PRDM1-dependent manner. After treatment with GD-1, the transcriptional repressor PRDM1 is prominently induced in SW620 cells. Furthermore, GD-1 induce the phosphorylation of PKD1 and MEK and subsequently provide PRDM1 enhancement, resulting in the suppression of c-Myc expression and the up-regulation of p21. PKD1 knockdown using siRNA abrogates PRDM1 expression by GD-1 and subsequently disrupts the regulation of c-Myc and p21 expression. Treating SW620 cells with GD-1 inhibits cell-cycle progression and is characterized by the down-regulation of c-Myc followed by the up-regulation of p21 expression. The up-regulation of p21 by GD-1 induces the growth arrest of the SW620 colon cancer cell line. Based on these data, the authors propose that GD-1 has tumor-suppressor activity that may contribute to the anti-tumor effects of PRDM1 in colon cancer.

Polymorphisms of the TRPV2 and TRPV3 genes associated with fibromyalgia in a Korean population.

OBJECTIVE: Researchers continue to gather evidence that transient receptor potential vanilloid (TRPV) channels contribute towards pain signalling pathways. However, it is unknown whether polymorphisms of the TRPV gene are associated with FM. For the first time, we investigated the association between the polymorphisms of the TRPV2 and TRPV3 genes, FM susceptibility and the severity of the symptoms. METHODS: A total of 409 patients with FM and 423 controls were enrolled from 10 medical centres that participated in the Korean nationwide FM survey. The alleles and genotypes at three positions [rs3813768(C > G), rs8121(C > T) and rs1129235(C > A)] in the TRPV2 gene and two positions [rs7216486 (G > A) and rs395357(C > T)] in the TRPV3 gene were genotyped. RESULTS: The frequencies of the alleles and genotypes of individual TRPV2 and TRPV3 genes were not significantly associated with FM susceptibility. However, the GTA haplotype of TRPV2 showed a defence against FM susceptibility (P = 0.035). In addition, polymorphisms of TRPV3 were associated with symptom severity in FM patients. The single nucleotide polymorphism rs395357 of TRPV3 was associated with the scores of the Brief Fatigue Inventory (P = 0.017) in FM patients. Furthermore, haplotypes of TRPV3 were associated with the Brief Fatigue Inventory and the 36-item Short-Form Health Survey mental health summary scores (P = 0.036). CONCLUSION: This study was the first to evaluate the associations of TRPV gene polymorphisms with FM. Our results suggest that certain TRPV2 haplotypes may have a protective role against FM and that some genotypes and haplotypes of TRPV3 contribute towards the symptoms of FM.

Severity of fibromyalgia symptoms is associated with socioeconomic status and not obesity in Korean patients.

OBJECTIVES: Several studies conducted in Western countries have shown that obese or overweight patients with fibromyalgia (FM) exhibit more severe symptoms than patients of normal weight. However, there has been no study on the relationship between obesity and FM symptom severity in Asian patients. In this study, we evaluated the association between obesity, and other related factors such as socioeconomic status (SES), and FM symptom severity in Korean patients. METHODS: A total of 343 participants were enrolled in this prospective cohort study, which used a nationwide survey of FM patients who were followed on an annual basis. We investigated health-related quality of life (QoL) and associated factors, such as demographic characteristics, SES, and physical and psychological function. The FM patients were assessed using the following self-reported questionnaires: the Medical Outcomes Study Short-Form Health Survey, the Fibromyalgia Impact Questionnaire, the Brief Fatigue Inventory, the Beck Depression Inventory, the State-Trait Anxiety Inventory, the Self-Efficacy Scale, and the Social Support Scale. RESULTS: Of the 343 patients, 76 (22.1%) were obese; these patients did not differ from the non-obese patients in terms of tender points or self-reported questionnaire scores. FM patients with lower SES - as indexed by unemployment, lower income, and education levels - had more severe symptoms, and poorer QoL and function compared to those with higher SES. CONCLUSIONS: In contrast to Western patients, symptom severity in Korean FM patients is associated with SES, but not with obesity.

Roles of interferon-gamma and its target genes in schizophrenia: Proteomics-based reverse genetics from mouse to human.

A decreased production of interferon gamma (IFNG) has been observed in acute schizophrenia. In order to explore the possible relationship between IFNG and schizophrenia, we attempted to analyze the differentially expressed proteins in the brains of interferon-gamma knockout (Ifng-KO) mice. Five upregulated and five downregulated proteins were identified with 2D gels and MALDI-TOF/TOF MS analyses in Ifng-KO mouse brain. Of the identified proteins, we focused on creatine kinase brain (CKB) and triose phosphate isomerase 1 (TPI1). Consistent with the proteomic data, reverse transcriptase-mediated PCR, immunoblotting, and immunohistochemistry analyses confirmed that the levels of gene expressions of Ckb and Tpi1 were downregulated and upregulated, respectively. When we analyzed the genetic polymorphisms of the single nucleotide polymorphisms (SNPs) of their human orthologous genes in a Korean population, the promoter SNPs of CKB and TPI1 were weakly associated with schizophrenia. In addition, IFNG polymorphisms were associated with schizophrenia. These results suggest that IFNG and proteins affected by IFNG may play a role in the pathogenesis of schizophrenia.

Association of interferon gamma polymorphism with ossification of the posterior longitudinal ligament in the korean population.

In this study, we investigated whether genetic polymorphisms of the interferon gamma (IFNG) gene were associated with the susceptibility of ossification of the posterior longitudinal ligament (OPLL) in the Korean population. To observe the association between the IFNG gene and the susceptibility of OPLL, we genotyped 135 OPLL patients and 222 control subjects for a single nucleotide polymorphism (SNP, rs2430561) and a microsatellite (CA(n) repeats, rs3138557) located in the first intron of the IFNG gene, using the direct sequencing and gene scan method. The numbers of microsatellites (CA(13) and CA(15)) were significantly changed in the OPLL patients. A combined analysis of the genotype of rs2430561 and the number of microsatellites revealed that the OPLL was associated with frequencies of CA(13)-AA, CA(15)-AA and CA(15)-AT. Our results suggest that the IFNG gene may be one of the factors determining the OPLL in the Korean population. However, larger collaborative and biological studies are needed to confirm these results.

Epidermal growth factor increases prostaglandin E2 production via ERK1/2 MAPK and NF-kappaB pathway in fibroblast like synoviocytes from patients with rheumatoid arthritis.

High concentration of epidermal growth factor (EGF) is found in the synovial fluid of rheumatoid arthritis (RA) that might imply the involvement of EGF in the pathogenesis of arthritic diseases. In order to investigate if EGF is involved in the regulation of cyclooxygenase-2 (COX-2) and the prostaglandin E(2) (PGE(2)) production in fibroblast like synoviocytes (FLS) from patients with RA. The levels of COX-2 and microsomal prostaglandin E synthase-1 (mPGES-1) were evaluated using RT-PCR and Western blot analysis. Electrophoretic mobility shift assay (EMSA) was performed to investigate EGF mediated DNA binding activity of nuclear factor-kappaB (NF-kappaB). PGE(2) levels were analyzed by ELISA. EGF enhanced both COX-2 protein and mRNA expressions. mPGES-1 mRNA level was also increased by EGF treatment. EGF also stimulated ERK1/2 MAPK activity and the inhibition of ERK1/2 by PD098059 (ERK1/2 specific inhibitor) resulted in the suppression of EGF-induced COX-2 expression. The DNA binding activity of NF-kappaB was remarkably increased by EGF treatment and the pretreatment of PD098059 abolished EGF-stimulated NF-kappaB activity. We also observed that the level of PGE(2) was significantly elevated with the treatment of EGF in FLS, and the pretreatment of PD098059 abolished this stimulating effect. These results suggest that EGF is involved in the inflammatory process of RA by stimulating COX-2 expression and PGE(2) production. And EGF enhanced PGE(2) production appears to be mediated via ERK1/2 MAPK and NF-kappaB pathway in FLS.

Melatonin inhibits human fibroblast-like synoviocyte proliferation via extracellular signal-regulated protein kinase/P21(CIP1)/P27(KIP1) pathways.

The excessive proliferation and migration of synoviocytes are well-characterized phenomena that play key roles in the pathophysiology of rheumatoid arthritis (RA). Melatonin has been shown to have potent anti-proliferative effect in various cancer cells such as breast and prostate cancer cells. In this study, we examined the role of melatonin on synoviocyte proliferation in primary cultured human fibroblast-like synoviocytes (FLSs) by analyzing protein expression of P21(CIP1) (P21) and P27(KIP1) (P27), the cyclin-dependent kinase inhibitors that are important in cell cycle control, and the phosphorylation of mitogen-activated protein kinases (MAPKs). RA-FLS proliferation was determined by a [(3)H]-thymidine incorporation assay. Western blot analysis was applied to examine the underlying mechanisms of melatonin's effect. Melatonin inhibited RA-FLS proliferation in a dose-dependent manner. It reduced proliferation of passage 2 FLSs by 25% at 10 microm and by nearly 40% at 100 microm concentrations. The inhibitory effect of melatonin on RA-FLS proliferation was also observed in passages 4 and 6. Melatonin upregulated the expression levels of P21 and P27 dose-dependently (24 hr), induced the phosphorylation of extracellular signal-regulated protein kinase (ERK) time-dependently (10 microm), but did not affect phosphorylation of P38 in RA-FLSs. In addition, the expression of P21 and P27 triggered by melatonin was inhibited by the pretreatment of the ERK inhibitor, PD98059 (10 microm). The anti-proliferative action of melatonin in RA-FLSs was also blocked by PD98059. Taken together, these results suggest that melatonin exerts the inhibitory effect of the proliferation of RA-FLSs through the activation of P21 and P27 mediated by ERK. Hence we suggest that melatonin could be used as a therapeutic agent for the treatment of RA.

Clinical features and outcomes of microscopic polyangiitis in Korea.

Microscopic polyangiitis (MPA) is a systemic vasculitis affecting small vessels. To determine the clinical features and outcomes of MPA in Korean patients, we retrospectively reviewed the medical records of patients diagnosed with MPA at a single medical center in Korea between 1989 and 2006. The 18 patients who met the Chapel Hill criteria for MPA had a mean (+/-SD) age at the time of diagnosis of 62.4+/-12.7 yr. Renal manifestations and general symptoms were the most common features of MPA, with lung involvement also very common. Antineutrophil cytoplasmic antibodies (ANCA) were present in 17 of the 18 patients (94%). Of 17 patients treated with steroids and cyclophosphamide, 11 (65%) had stable or improved course. One patient treated with steroids without cyclophosphamide showed disease progression. Ten of the 18 patients (56%) died at a median follow-up of 8 months. MPA in Korean patients was distinguished by a higher rate of lung involvement, especially alveolar hemorrhage, which was the leading cause of death in our patients. Korean patients were also older at MPA onset and were more likely positive for ANCA. Other overall clinical manifestations did not differ significantly.

Cardiac Behçet disease presenting as aortic valvulitis/aortitis or right heart inflammatory mass: a clinicopathologic study of 12 cases.

Behçet disease is an inflammatory disorder of unknown etiology showing diverse clinical presentations. Cardiac involvement is a critical problem that requires a timely diagnosis and management. However, clinicopathologic features have not been characterized clearly. Here, we present clinicopathologic characteristics of this uncommon disease. Patients included 8 males and 4 females, ranging from 24 to 52 years old. They were presented with abrupt heart failure and were mostly diagnosed as having cardiac Behçet disease later in the course. Upon echocardiography, 8 patients showed severe aortic regurgitation with redundant prolapsing aortic cusps and 4 patients showed irregular mass lesions in the right ventricular cavity. No one had both lesions. The aortic root was also involved with aortic valvulitis, showing severe mixed acute and chronic inflammation of various stages. There were frequent microabscess and extensive endothelial loss with fibrinous deposit. The right heart lesions showed similar histopathologic features. Four patients who initially underwent simple aortic valve replacement developed serious postoperative complications requiring reoperations. No serious complications developed after the treatment was changed to a replacement of aortic root with extensive debridement and concomitant immunosuppressive therapy. Cardiac Behçet disease is presented as aortic valvulitis/aortitis or inflammatory mass lesion. Characteristic echocardiographic and pathologic findings seem to be helpful for the timely diagnosis of this critical disease.

The Clinical Efficacy and Safety of Gumiganghwal-Tang in Knee Osteoarthritis: A Phase II Randomized Double Blind Placebo Controlled Study.

BACKGROUND: Gumiganghwal-tang (GMGHT) is a traditional herbal medicine consisting of nine different herbs. GMGHT inhibits the mRNA expression and production of inflammatory cytokines tumor necrosis factor-α (TNF- α), interleukin-6 (IL-6), and TNF- ß on lipopolysaccharide- (LPS-) stimulated peritoneal macrophages in a dose-dependent manner. It is empirically used for the treatment of inflammatory disease, but there are few reports of clinical trials that investigate its efficacy and safety. The current study aimed to investigate the clinical efficacy and safety of GMGHT in patients with knee osteoarthritis (OA). METHODS: This was a multicenter, two-armed, double-blinded, randomized, placebo controlled study of GMGHT over 6 weeks. Eligible patients who fulfilled the American College of Rheumatology criteria for OA were randomized to receive either GMGHT or the placebo. Clinical assessments included measurement of knee pain and function using the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), patient global assessment (PGA), and knee pain scores every 2 weeks. RESULTS: A total of 128 patients were enrolled (91.4% female; mean age, 58.7 ± 8.1 years). At baseline, pain visual analogue score (VAS) was 67.2 ± 1.4, resp. 71.3 ± 1.6 (treatment, resp. placebo group, p=0.84), and total WOMAC score was 55.2 ± 1.6, resp. 55.6 ± 1.5 (p = 0.84). After 6 weeks, the pain VAS was 43.0 ± 2.5, resp. 61.6 ± 2.5 (p < 0.01) and the total WOMAC score was 34.1 ± 2.4, resp. 46.9 ± 1.8 (p < 0.01). No patients withdrew because of treatment emergent adverse events. Expected adverse events including dyspepsia, liver function abnormality, and lower extremity edema were comparable between both groups. CONCLUSIONS: Treatment with GMGHT resulted in significant improvement in pain, function, and global assessment, and it was generally safe and well tolerated in patients with OA.

Association between brain-derived neurotrophic factor gene polymorphisms and fibromyalgia in a Korean population: a multicenter study.

BACKGROUND: Several lines of evidence imply that brain-derived neurotrophic factor (BDNF) is involved in the pathophysiology of fibromyalgia (FM); in this regard, patients with FM have altered blood and cerebrospinal fluid levels of BDNF. In this study, we explored the association between BDNF gene polymorphisms and FM susceptibility and the severity of symptoms. METHODS: In total, 409 patients with FM and 423 healthy controls in 10 medical centers were enrolled from the Korean nationwide FM survey. The alleles and genotypes at 10 positions in the BDNF gene were genotyped. RESULTS: The allele and genotype frequencies of BDNF rs11030104 differed significantly between the patients with FM and the controls (P = 0.031). The GG genotype of rs11030104 had a protective effect against FM (P = 0.016), and the G allele of rs11030104 was negatively associated with the presence of FM compared with the A allele (P = 0.013). In comparison, although the allele and genotype frequencies of BDNF rs12273539 did not differ between the two groups, the TT genotype of BDNF rs12273539 was associated with susceptibility to FM (P = 0.038). Haplotype analyses implied that some BDNF haplotypes have a protective effect against FM. Finally, several genotypes and haplotypes of the BDNF gene contributed to specific symptoms of FM. CONCLUSIONS: This study is the first to evaluate the associations between BDNF gene polymorphisms and FM. Our results imply that some BDNF single-nucleotide polymorphisms and haplotypes are associated with susceptibility to, and contribute to the symptoms of, FM.

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.

AIM: To determine characteristics of rheumatoid arthritis (RA) patients in Korea using disease-modifying anti-rheumatic 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.

Advanced glycation end products increases matrix metalloproteinase-1, -3, and -13, and TNF-alpha in human osteoarthritic chondrocytes.

We investigated the effects of advanced glycation end products (AGE) which accumulate in articular cartilage with age in human osteoarthritic chondrocytes. We found AGE-BSA significantly increased MMP-1, -3, and -13, and TNF-alpha in a dose-dependent manner. AGE-BSA-stimulated JNK, p38, and ERK and NF-kappaB activity. The stimulatory effect of AGE-BSA on MMP-1, -3, and -13 were reversed by treatment with specific JNK, p38 inhibitors, suggesting JNK and p38 are involved in AGE-BSA-induced MMPs and TNF-alpha. We also observed that NF-kappaB is involved in AGE-BSA-induced TNF-alpha. Pretreatment with soluble receptor for AGE (sRAGE) also reduced AGE-stimulated MMPs and TNF-alpha, implicating the involvement of receptor for AGE (RAGE). In conclusion, accumulation of AGE may have a role in the development of osteoarthritis by increasing MMP-1, -3, and -13, and TNF-alpha.

Inhibitory effects of melittin on the production of lipopolysaccharide-induced matrix metalloproteinase 3 in human osteoarthritic chondrocytes.

In continuation of our previous study which explored the effect of bee venom (BV) on the global gene expression profiles in lipopolysaccharide (LPS)-treated human chondrosarcoma cells, we investigated herein the effect of melittin, a major component of BV, on the productions of matrix metalloproteinases (MMPs) 1, 3, and 13 in primary cultured human arthritic chondrocytes. Increased generations of MMPs 1, 3, and 13 were observed by MMPs stimulating agents LPS, tumor necrosis factor alpha (TNF-alpha), and interleukin 1beta (IL-1beta). The generations of LPS (1 microg/ml)-induced MMPs 1 and 13 were not decreased by melittin, whereas that of LPS-stimulated MMP 3 was significantly inhibited by melittin. IL-1beta (10ng/ml) and TNF-alpha (10ng/ml)-induced MMPs 1, 3 and 13, however, were not decreased by melittin. Immunoblot analysis revealed that melittin exerted no effect on the LPS-stimulated expression levels of MMPs 1 and 13 but attenuated the LPS-induced MMP 3, which is consistent with the enzyme-linked immunosorbent assay (ELISA) data. Taken together, these findings suggest melittin may exert its anti-arthritic effect, at least in part, by inhibiting LPS-stimulated MMP 3 production in human osteoarthritic chondrocytes.

Association between endothelin­1 and fibromyalgia syndrome.

Fibromyalgia syndrome (FMS) is characterized by widespread chronic musculoskeletal pain, stiffness and pressure hyperalgesia at soft tissue tender points. Patients with FMS may exhibit a tendency towards cold extremities and cold­induced vasospasm. Endothelin­1 (EDN1) is a potent vasoconstrictor that is mainly produced by endothelial cells. The present study aimed to determine whether plasma expression levels avvnd single­nucleotide polymorphism (SNP; rs1800541) of the EDN1 gene were associated with FMS and/or any of its clinical variables. Plasma EDN1 levels were assessed by ELISA, and SNP genotypes were determined using polymerase chain reaction­high­resolution melting curve analysis. Patients with the TG genotype and the G allele may have an elevated risk of FMS. In addition, patients with FMS with the TG genotype and/or T allele exhibited higher plasma EDN1 levels compared with healthy controls. EDN1 levels increased significantly in patients with FMS compared with normal controls. In addition, EDN1 SNP was found to be associated with susceptibility to FMS.

PER2 is downregulated by the LPS-induced inflammatory response in synoviocytes in rheumatoid arthritis and is implicated in disease susceptibility.

The clinical symptoms of rheumatoid arthritis (RA) present with circadian variation, with joint stiffness and pain more prominent in the early morning. The mammalian clock genes, which include circadian locomotor output cycles kaput, brain and muscle Arnt-like protein 1, period and cryptochrome, regulate circadian rhythms. In order to identify the association between genetic polymorphisms in the circadian clock gene period 2 (PER2) and RA, the present study genotyped three PER2 single nucleotide polymorphisms (SNPs), rs934945, rs6754875, and rs2304674, using genetic information from 256 RA patients and 499 control subjects. Primary cultured rheumatoid synovial cells were stimulated with 10 µM lipopolysaccharide (LPS). Total protein was then extracted from the synovial cells following 12 and 24 h, and PER2 protein expression was assayed by immunoblotting. The rs2304674 SNP demonstrated a significant association with susceptibility to RA following Bonferroni correction. However, statistical analysis indicated that the SNPs were not associated with any clinical features of patients with RA. Immunoblotting analysis demonstrated that PER2 protein expression was decreased by LPS­induced inflammation in RA synovial cells; however, this was not observed in normal synovial cells. The results suggest that the PER2 gene may be a risk factor for RA, and expression of the PER2 protein may be affected by inflammation. Therefore, PER2 may contribute to the pathogenesis of RA.

Determinants of quality of life in patients with fibromyalgia: A structural equation modeling approach.

OBJECTIVE: Health-related quality of life (HRQOL) in patients with fibromyalgia (FM) is lower than in patients with other chronic diseases and the general population. Although various factors affect HRQOL, no study has examined a structural equation model of HRQOL as an outcome variable in FM patients. The present study assessed relationships among physical function, social factors, psychological factors, and HRQOL, and the effects of these variables on HRQOL in a hypothesized model using structural equation modeling (SEM). METHODS: HRQOL was measured using SF-36, and the Fibromyalgia Impact Questionnaire (FIQ) was used to assess physical dysfunction. Social and psychological statuses were assessed using the Beck Depression Inventory (BDI), the State-Trait Anxiety Inventory (STAI), the Arthritis Self-Efficacy Scale (ASES), and the Social Support Scale. SEM analysis was used to test the structural relationships of the model using the AMOS software. RESULTS: Of the 336 patients, 301 (89.6%) were women with an average age of 47.9±10.9 years. The SEM results supported the hypothesized structural model (χ2 = 2.336, df = 3, p = 0.506). The final model showed that Physical Component Summary (PCS) was directly related to self-efficacy and inversely related to FIQ, and that Mental Component Summary (MCS) was inversely related to FIQ, BDI, and STAI. CONCLUSIONS: In our model of FM patients, HRQOL was affected by physical, social, and psychological variables. In these patients, higher levels of physical function and self-efficacy can improve the PCS of HRQOL, while physical function, depression, and anxiety negatively affect the MCS of HRQOL.

Survival and prognostic factors in patients with connective tissue disease-associated pulmonary hypertension diagnosed by echocardiography: results from a Korean nationwide registry.

OBJECTIVES: Pulmonary arterial hypertension (PAH) is a major cause of mortality in connective tissue disease (CTD). The survival rates and mortality-predictive factors of a nationwide registry of Korean patients with CTD-PH measured by echocardiography were determined. METHODS: Patients with CTD-PH were enrolled between April 2008 and December 2012. Hemodynamic parameters and clinical data (WHO-functional class [FC], organ involvement, laboratory tests and treatment agents) were recorded. Survival rates were calculated by using the Kaplan-Meier method. Mortality-associated factors were examined by Cox proportional hazards regression analysis. RESULTS: In total, 174 incident PH cases (61 with systemic lupus erythematosus, 50 with systemic sclerosis, 10 with mixed CTD, 22 with rheumatoid arthritis (RA) and 31 with other CTDs) were diagnosed by Doppler echocardiography. Of these, 25 (14%) died during the 3.8 ± 2.7 year follow-up period after PH diagnosis. The 1- and 3-year survival rates were 90.7% and 87.3%, respectively. Compared to the other CTD-PHs, RA-PH had the lowest survival rates (56% 3 year survival; P = 0.022). Multiple regression analysis revealed that low diffusion capacity of carbon monoxide (DLCO), pleural effusion and diabetes mellitus were poor prognostic factors (P = 0.008, 0.04 and 0.009, respectively). Anti-UI-RNP (ribonucleoprotein) antibody positivity was protective (P = 0.022). In patients with WHO-FC III/IV, patients who received vasodilators had lower mortality than those who did not (P = 0.038). CONCLUSIONS: In Korean patients with CTD-PH, the 3-year survival rate was 87%. Low diffusion capacity of carbon monoxide (DLCO), pleural effusion and diabetes mellitus were independent poor prognostic factors. Anti-UI-RNP antibody was protective. Prompt PAH-specific vasodilator therapy may improve the survival of patients with severe CTD-PH.

Novel synthetic (E)-2-methoxy-4-(3-(4-methoxyphenyl) prop-1-en-1-yl) phenol inhibits arthritis by targeting signal transducer and activator of transcription 3.

Rheumatoid arthritis (RA) is a severely debilitating chronic autoimmune disease that leads to long-term joint damage. Signal transducer and activator of transcription 3 (STAT3)-targeted small molecules have shown promise as therapeutic drugs for treating RA. We previously identified (E)-2,4-bis(p-hydroxyphenyl)-2-butenal (BHPB), a tyrosine-fructose Maillard reaction product, as a small molecule with potent anti-inflammatory and anti-arthritic properties, mediated through the inhibition of STAT3 activation. The aim of this study was to develop a novel BHPH derivative with improved anti-arthritic properties and drug-likeness. We designed and synthesised (E)-2-methoxy-4-(3-(4-methoxyphenyl) prop-1-en-1-yl) phenol (MMPP), a novel synthetic BHPB analogue, and investigated its anti-inflammatory and anti-arthritic activities in experimentally-induced RA. We showed that MMPP strongly inhibited pro-inflammatory responses by inhibiting in vitro STAT3 activation and its downstream signalling in murine macrophages and human synoviocytes from patients with RA. Furthermore, we demonstrated that MMPP exhibited potent anti-arthritic activity in a collagen antibody-induced arthritis (CAIA) mouse model in vivo. Collectively, our results suggest that MMPP has great potential for use in the treatment of RA.