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ID PMID Title PublicationDate abstract
24831826 Small molecule inhibitors targeting activator protein 1 (AP-1). 2014 Aug 28 Activator protein 1 (AP-1) is a pivotal transcription factor that regulates a wide range of cellular processes including proliferation, apoptosis, differentiation, survival, cell migration, and transformation. Accumulating evidence supports that AP-1 plays an important role in several severe disorders including cancer, fibrosis, and organ injury, as well as inflammatory disorders such as asthma, psoriasis, and rheumatoid arthritis. AP-1 has emerged as an actively pursued drug discovery target over the past decade. Excitingly, a selective AP-1 inhibitor T-5224 (51) has been investigated in phase II human clinical trials. Nevertheless, no effective AP-1 inhibitors have yet been approved for clinical use. Despite significant advances achieved in understanding AP-1 biology and function, as well as the identification of small molecules modulating AP-1 associated signaling pathways, medicinal chemistry efforts remain an urgent need to yield selective and efficacious AP-1 inhibitors as a viable therapeutic strategy for human diseases.
24928093 Enhanced neutrophil extracellular trap generation in rheumatoid arthritis: analysis of und 2014 Jun 13 INTRODUCTION: Neutrophil extracellular traps (NETs) have recently been implicated in a number of autoimmune conditions, including rheumatoid arthritis (RA). We examined the underlying signaling pathways triggering enhanced NETosis in RA and ascertained whether the products of NETosis had diagnostic implications or usefulness. METHODS: Neutrophils were isolated from RA patients with active disease and from controls. Spontaneous NET formation from RA and control neutrophils was assessed in vitro with microscopy and enzyme-linked immunosorbent assay (ELISA) for NETosis-derived products. The analysis of the signal-transduction cascade included reactive oxygen species (ROS) production, myeloperoxidase (MPO), neutrophil elastase (NE), peptidyl arginine deiminase 4 (PAD4), and citrullinated histone 3 (citH3). NET formation was studied in response to serum and synovial fluid and immunoglobulin G (IgG) depleted and reconstituted serum. Serum was analyzed for NETosis-derived products, for which receiver operator characteristic (ROC) curves were calculated. RESULTS: Neutrophils from RA cases exhibited increased spontaneous NET formation in vitro, associated with elevated ROS production, enhanced NE and MPO expression, nuclear translocation of PAD4, PAD4-mediated citrullination of H3, and altered nuclear morphology. NET formation in both anti-citrullinated peptide antibody (ACPA)-positive and -negative RA was abolished by IgG depletion, but restored only with ACPA-positive IgG. NETosis-derived products in RA serum demonstrated diagnostic potential, the ROC area under the curve for cell-free nucleosomes being >97%, with a sensitivity of 91% and a specificity of 92%. No significant difference was observed between ACPA-positive and -negative cases. CONCLUSIONS: Signaling elements associated with the extrusion of NETs are significantly enhanced to promote NETosis in RA compared with healthy controls. NETosis depended on the presence of ACPA in ACPA-positive RA serum. The quantitation of NETosis-derived products, such as cell-free nucleosomes in serum, may be a useful complementary tool to discriminate between healthy controls and RA cases.
24376307 Rheumatic diseases and obesity: adipocytokines as potential comorbidity biomarkers for car 2013 Inflammation has been recognized as a common trait in the pathogenesis of multifactorial diseases including obesity, where a low-grade inflammation has been established and may be responsible for the cardiovascular risk related to the disease. Obesity has also been associated with the increased incidence and a worse outcome of rheumatoid arthritis (RA) and osteoarthritis (OA). RA is characterized by systemic inflammation, which is thought to play a key role in accelerated atherosclerosis and in the increased incidence of cardiovascular disease, an important comorbidity in patients with RA. The inflammatory process underlying the cardiovascular risk both in obesity and RA may be mediated by adipocytokines, a heterogeneous group of soluble proteins mainly secreted by the adipocytes. Many adipocytokines are mainly produced by white adipose tissue. Adipocytokines may also be involved in the pathogenesis of OA since a positive association with obesity has been found for weight-bearing and nonweight-bearing joints, suggesting that, in addition to local overload, systemic factors may contribute to joint damage. In this review we summarize the current knowledge on experimental models and clinical studies in which adipocytokines were examined in obesity, RA, and OA and discuss the potential of adipocytokines as comorbidity biomarkers for cardiovascular risk.
24283948 Effectiveness of newspaper advertising for patient recruitment into a clinical trial. 2014 Jun AIMS: To measure the impact of newspaper advertising across Scotland on patient interest, and subsequent recruitment into the Standard Care vs. Celecoxib Outcome Trial (SCOT), a clinical trial investigating the cardiovascular safety of non-steroidal anti-inflammatory drugs in patients with osteoarthritis or rheumatoid arthritis. METHODS: Newspaper advertisements about the SCOT trial were placed sequentially in regional and national Scottish newspapers. The number of phone calls as a result of exposure to the advertisements and ongoing study recruitment rates were recorded before, during and after the advertising campaign. To enroll in SCOT individuals had to be registered with a participating GP practice. RESULTS: The total cost for the advertising campaign was £46 250 and 320 phone calls were received as a result of individuals responding to the newspaper advertisements. One hundred and seventy-two individuals were identified as possibly suitable to be included in the study. However only 36 were registered at participating GP practices, 17 completed a screening visit and 15 finally were randomized into the study. The average cost per respondent individual was £144 and the average cost per randomized patient was £3083. Analysis of recruitment rate trends showed that there was no impact of the newspaper advertising campaign on increasing recruitment into SCOT. CONCLUSIONS: Advertisements placed in local and national newspapers were not an effective recruitment strategy for the SCOT trial. The advertisements attracted relatively small numbers of respondents, many of whom did not meet study inclusion criteria or were not registered at a participating GP practice.
23588515 HLA-DRB1 allele association with rheumatoid arthritis susceptibility and severity in Syria 2013 Feb INTRODUCTION: Rheumatoid arthritis (RA) is a complex multifactorial chronic disease. The importance of human leukocyte antigen as a major genetic risk factor for RA was studied worldwide. Although it is widely distributed in different Syrian areas, studies of human leukocyte antigen (HLA) alleles' role are absent. OBJECTIVE: The aim of our study was to determine the association of HLA-DRB1 alleles with the susceptibility and severity of RA in Syria. PATIENTS AND METHODS: Eighty-six RA patients and 200 healthy controls from Syria were genotyped using polymerase chain reaction with sequence-specific primer (PCR-SSP). Anti-CCP antibodies were measured by ELISA. Rheumatoid factor (RF), C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), and disease activity score 28 (DAS-28) values were obtained from patients' medical records. DAS-28 was used to assess the clinical severity of the patients. RESULTS: The HLA-DRB1*01, *04, and *10 frequencies showed a strong association with the disease susceptibility (OR = 2.29, 95% CI = 1.11-4.75, P = 0.022; OR = 3.16, 95% CI = 2.0 -4.8, P < 0.0001; OR = 2.43, 95% CI = 1.07-5.51, P = 0.029 respectively), while the frequencies of HLA-DRB1*11, and *13 were significantly lower in RA patients than in controls (OR = 0.49, 95% CI = 0.3-0.8, P = 0.004; OR = 0.32, 95% CI = 0.15-0.69, P = 0.002, respectively). The other HLA-DRB1 alleles showed no significant difference. The frequency of anti-CCP antibodies was higher in shared epitope (SE) positive patients compared with SE-negative patients (OR = 5.5, 95% CI = 2-15.1, P = 0.00054). DAS-28 of RA patients didn't show significant difference between the SE negative and the SE positive groups. CONCLUSION: Our results indicate that HLA-DRB1*01, *04, and *10 alleles are related with RA, while HLA-DRB1*11 and *13 protect against RA in the Syrian population.
23862741 The role of Act1, a NF-κB-activating protein, in IL-6 and IL-8 levels induced by IL-17 st 2013 Nov CONTEXT: Rheumatoid arthritis (RA) is a systemic autoimmune disease characterized by chronic inflammation in the synovial membrane of affected joints. It has been shown that several kinds of cytokine were increased in synovial fluid, while the underlying mechanism remains poorly understood. OBJECTIVES: NF-κB activator 1 (Act1) is a recently identified protein binding to the IκB kinase complex. Our study aimed to investigate the expression of Act1 induced by cytokine IL-17 stimulation in SW982 cells. MATERIALS AND METHODS: The human synovial sarcoma cell line SW982 and primary cultured RA fibroblast-like synovial cells were used. RT-PCR and Western blot assays were selected to investigate the genetic and protein expression of Act1. Additionally, four independent Act1 small interfering RNA (siRNA) oligonucleotides were designed and obtained according to the GenBank cDNA, the sequence of Act1 (Traf3ip2). Finally, enzyme-linked immunosorbent assay (ELISA) double antibody sandwich was used to assay supernatant IL-6 and IL-8 concentrations. RESULTS: The Act1 mRNA expression level increased significantly after stimulation with IL-17 (5-100 ng/ml) in SW982 cells. Additionally, the level of Act1 mRNA expression correlated positively with the concentration of IL-17 (p < 0.01). IL-17 induced IL-6 and IL-8 in SW982 cells was in a concentration- and time-dependent way. Furthermore, ELISA assay revealed that IL-17 (20 ng/ml) significantly increased IL-6 (1927.4 ± 288.77 versus 786.5 ± 172.42 ng/ml, p < 0.01) and IL-8 levels (984.8 ± 95.09 ng/ml versus 307.1 ± 90.83 ng/ml, p < 0.01) compared with control group after stimulation for 24 h. However, transfection of Traf3ip2 siRNA markedly decreased IL-6 (995.9 ± 115.30 ng/ml versus 1816.1 ± 273.27 ng/ml, p < 0.01) and IL-8 levels (575.6 ± 65.96 ng/ml versus 929.4 ± 124.39 ng/ml, p < 0.01) compared to transfection negative control. These findings suggested that IL-6 and IL-8 level induced by IL-17 in SW982 cells could be reversed by down-regulation of Act1 expression level with Traf3ip2 siRNA. CONCLUSION: Our results suggested that Act1 might play a key role in the pathophysiology and the treatment of RA.
25246737 Drug survival rates of tumor necrosis factor inhibitors in patients with rheumatoid arthri 2014 Sep We investigated the compliance of Korean patients using tumor necrosis factor (TNF) inhibitors to treat rheumatoid arthritis (RA) and ankylosing spondylitis (AS), and identified potential predictors associated with treatment discontinuation. The study population comprised 114 RA and 310 AS patients treated with TNF inhibitors at a single tertiary center for at least 1 yr from December 2002 to November 2011. Of the 114 RA patients, 64 (56.1%) discontinued their first TNF inhibitors with a mean duration of 18.1 months. By contrast, 65 of 310 patients (21.0%) with AS discontinued their first TNF inhibitors, with a mean duration of 84 months. Although the survival rate did not differ among the three TNF inhibitors in the AS patients, the etanercept group had a lower discontinuation rate than the infliximab group in the RA patients. In addition, RA patients who received corticosteroids in combination with TNF inhibitors were more likely to discontinue their TNF inhibitors. The independent predictors of drug discontinuation in AS patients were male gender and complete ankylosis on radiographs of the sacroiliac joint. Our results provide further evidence that real-life treatment outcomes of RA and AS patients may be different from those observed in randomized clinical trials.
22736089 DNA methylome signature in rheumatoid arthritis. 2013 Jan OBJECTIVES: Epigenetics can influence disease susceptibility and severity. While DNA methylation of individual genes has been explored in autoimmunity, no unbiased systematic analyses have been reported. Therefore, a genome-wide evaluation of DNA methylation loci in fibroblast-like synoviocytes (FLS) isolated from the site of disease in rheumatoid arthritis (RA) was performed. METHODS: Genomic DNA was isolated from six RA and five osteoarthritis (OA) FLS lines and evaluated using the Illumina HumanMethylation450 chip. Cluster analysis of data was performed and corrected using Benjamini-Hochberg adjustment for multiple comparisons. Methylation was confirmed by pyrosequencing and gene expression was determined by qPCR. Pathway analysis was performed using the Kyoto Encyclopedia of Genes and Genomes. RESULTS: RA and control FLS segregated based on DNA methylation, with 1859 differentially methylated loci. Hypomethylated loci were identified in key genes relevant to RA, such as CHI3L1, CASP1, STAT3, MAP3K5, MEFV and WISP3. Hypermethylation was also observed, including TGFBR2 and FOXO1. Hypomethylation of individual genes was associated with increased gene expression. Grouped analysis identified 207 hypermethylated or hypomethylated genes with multiple differentially methylated loci, including COL1A1, MEFV and TNF. Hypomethylation was increased in multiple pathways related to cell migration, including focal adhesion, cell adhesion, transendothelial migration and extracellular matrix interactions. Confirmatory studies with OA and normal FLS also demonstrated segregation of RA from control FLS based on methylation pattern. CONCLUSIONS: Differentially methylated genes could alter FLS gene expression and contribute to the pathogenesis of RA. DNA methylation of critical genes suggests that RA FLS are imprinted and implicate epigenetic contributions to inflammatory arthritis.
24870729 Risk of breast cancer and total malignancies in rheumatoid arthritis patients undergoing T 2014 CONTEXT: Interest exits in whether TNF-alpha antagonists increase the risk of breast cancer and total malignancies in patients with rheumatoid arthritis (RA). OBJECTIVES: To analyze the risk of malignancies, especially breast cancer, in patients with RA enrolled in randomized control trials (RCTs). METHODS: A systematic literature search for RCTs from 1 January 1998 to 1 July 2013 from online databases, such as PubMed, WILEY, EMBASE, ISI web of knowledge and Cochrane Library was conducted. Studies included RCTs that compared the safety of at least one dose of the five TNF-α antagonists with placebo or methotrexate (MTX) (or TNF-α antagonists plus MTX vs placebo plus MTX) in RA patients for more than 24 weeks and imported all the references into document management software EndNotex6. Two independent reviewers selected studies and extracted the data about study design, patients' characteristics and the type, number of all malignancies. RESULTS: 28 RCTs from 34 records with 11,741 patients were analyzed. Of the total, 97 developed at least one malignancy during the double-blind trials, and breast cancer was observed in 17 patients (17.5% of total malignancies). However, there was no statistically significant increased risk observed in either the per protocol (PP) model (OR 0.65, 95%CI [0.22, 1.93]) or the modified intention to treat (mITT) model (OR 0.75, 95%CI [0.25, 2.21]). There were also no significant trend for increased risk of total malignancies on anti-TNF-α therapy administered at approved doses in either model (OR, 1.06, 95%CI [0.64, 1.75], and OR, 1.30, 95%CI [0.80, 2.14], respectively). As to the two models, modified intention to treat model analysis led to higher estimation than per protocol model analysis. CONCLUSIONS: This study did not find a significantly increased risk of breast cancer and total malignancies in adults RA patients treated with TNF-α antagonists at approved doses. However, it cannot be ignored that more patients developed malignancies with TNF-α antagonists therapy compared with patients with placebo or MTX, in spite of the lack of statistical significance, so that more strict clinical trials and long-term follow-up are needed, and both mITT and PP analyses should be used in such safety analyses.
24812287 Pretreatment multi-biomarker disease activity score and radiographic progression in early 2015 Jun OBJECTIVES: Prediction of radiographic progression (RP) in early rheumatoid arthritis (eRA) would be very useful for optimal choice among available therapies. We evaluated a multi-biomarker disease activity (MBDA) score, based on 12 serum biomarkers as a baseline predictor for 1-year RP in eRA. METHODS: Baseline disease activity score based on erythrocyte sedimentation rate (DAS28-ESR), disease activity score based on C-reactive protein (DAS28-CRP), CRP, MBDA scores and DAS28-ESR at 3 months were analysed for 235 patients with eRA from the Swedish Farmacotherapy (SWEFOT) clinical trial. RP was defined as an increase in the Van der Heijde-modified Sharp score by more than five points over 1 year. Associations between baseline disease activity measures, the MBDA score, and 1-year RP were evaluated using univariate and multivariate logistic regression, adjusted for potential confounders. RESULTS: Among 235 patients with eRA, 5 had low and 29 moderate MBDA scores at baseline. None of the former and only one of the latter group (3.4%) had RP during 1 year, while the proportion of patients with RP among those with high MBDA score was 20.9% (p=0.021). Among patients with low/moderate CRP, moderate DAS28-CRP or moderate DAS28-ESR at baseline, progression occurred in 14%, 15%, 14% and 15%, respectively. MBDA score was an independent predictor of RP as a continuous (OR=1.05, 95% CI 1.02 to 1.08) and dichotomised variable (high versus low/moderate, OR=3.86, 95% CI 1.04 to 14.26). CONCLUSIONS: In patients with eRA, the MBDA score at baseline was a strong independent predictor of 1-year RP. These results suggest that when choosing initial treatment in eRA the MBDA test may be clinically useful to identify a subgroup of patients at low risk of RP. TRIAL REGISTRATION NUMBER: WHO database at the Karolinska Institute: CT20080004; and clinicaltrials.gov: NCT00764725.
23770635 Crystal structure and dehydration behavior of E6070, a novel IKKβ protein kinase inhibito 2013 Sep This study is focused on solving the crystal structure of E6070, a novel IKKβ protein kinase inhibitor, and characterizing its solid state. E6070 exists as a stable crystalline trihydrate (hydrate I) that undergoes two dehydration events on heating. Neither crystal form nor water content changed under the relative humidity range from 11% to 93% at 25 °C. Crystal transformation to hydrate II occurred in the first dehydration process beginning at ~70 °C followed by loss of almost all remaining crystal lattice water as heating continues up to 160 °C. The observed weight loss of the first step was significantly higher than two equivalents of water. The X-ray powder diffraction proved that the anhydrate is an amorphous form that reversibly reforms the original trihydrate when exposed to atmospheric moisture. Hydrate II more readily forms hydrate I than from the anhydrate. The activation energy of the second step accompanied with amorphism was approximately 1.5 times greater than that of the first. In addition, a gradual decline of activation energy depending on the extent of dehydration was observed, implying reversible conversion in both steps. Therefore, the trihydrate was considered suitable for further development as its solid state is controllable during the manufacturing processes and the shelf life.
22766432 Abatacept use in rheumatoid arthritis: evidence review and recommendations. 2013 Jan OBJECTIVE: To review the clinical evidence on abatacept and to formulate recommendations in order to clear up points related to its use in rheumatology. METHOD: An expert panel of rheumatologists objectively summarized the evidence on the mechanism of action, practicalities, effectiveness and safety of abatacept, and formulated recommendations following a literature review. The level of evidence and degree of recommendation was established. RESULTS: The document presents 21 statements focused on evidence or recommendations on abatacept (14 evidence summaries and 9 recommendations). The level of evidence was 2b or higher according to the Oxford Centre for Evidence-Based Medicine scale on 14 occasions. The degree of the recommendation was A in two recommendations, C in one, and D in the rest. It was considered important to make recommendations on aspects with lower levels of evidence. CONCLUSIONS: This is a practical document to supplement the summary of product characteristics.
24249032 The prevalence of vertebral fracture on vertebral fracture assessment imaging in a large c 2014 May OBJECTIVE: RA accelerates bone loss, increasing the risk of osteoporosis (OP) and fracture. DXA imaging has been validated for identifying RA patients at risk of fracture. The objective of this study was to assess the presence of asymptomatic vertebral fractures (VFs) in a cohort of patients with established RA referred for DXA using VF assessment (VFA) technology. METHODS: We determined the prevalence of VFs in a cohort of RA patients age ≥ 40 years fulfilling the 1987 ACR classification criteria. Two blinded radiologists independently reviewed all VFA scans to determine the presence and severity of VFs using Genant criteria. We compared the prevalence and severity of VFs between RA patients and determined the independent associations of different variables with VFs using multivariable logistic regression. RESULTS: Six hundred and three subjects fulfilled study inclusion criteria. Thirteen per cent of the entire cohort (77/603) had one or more vertebral deformities identified on VFA imaging: 58% were female with mean age 56 years. The prevalence of OP and osteopenia was 59% and 40%, respectively. The prevalence and severity of VFs showed significant correlation with spine T-scores (r = -0.37, P < 0.001) and femoral T-scores (r = -0.31, P < 0.001). In multivariable analyses VFs were significantly and independently associated with a longer duration of RA, markers of disease activity and severity. CONCLUSION: VFs were detected on VFA images in 13% of women and men with well-established RA referred for DXA testing. Longer duration and severity of RA disease were independent risk factors for fractures in our study.
24731494 [Analysis of clinical characteristics for large granular lymphocytic leukemia]. 2014 Jan 28 OBJECTIVE: To explore the clinical and laboratory characteristics for large granular lymphocytic leukemia (LGL). METHODS: A total of 35 LGL patients were retrospectively analyzed from March 2004 to May 2013 at our department. RESULTS: Their median age of diagnosis was 51 years. The anemia-related symptoms included splenomegaly (n = 11, 31.4%). And one patient (2.8%) with a history of rheumatoid arthritis. Anemia was the most frequent hematological abnormality (n = 27, 77.1%). The range of LGL count in peripheral blood was (0.82-23.7) ×10(9)/L. Among them, 19 patients (54.2%) showed the CD3(+)CD57(+) CD56(-)indolent LGL phenotype. Two patients showed complex karyotype. T cell receptor β chain variable region (TCRVβ) analysis was positive in 8 patients. The median overall survival of aggressive LGL patients was significant shorter than that of indolent patient(16 months vs not reached, P = 0.000). Univariate analysis showed the median overall survival of patients with B symptom was significant shorter than that without B symptom (19 vs 45 months, P = 0.039); the median overall survival of patients with thrombocytopenia was significant shorter than that with platelet normal (16 vs 42 months, P = 0.000). Multivariate analysis showed B symptom (P = 0.736) and thrombocytopenia (P = 0.977) at diagnosis were not prognostic factors. CONCLUSIONS: Chinese LGL patient with rheumatoid arthritis is infrequent compared with foreign reports. TCRVβ analysis is important for its diagnosis. The overall survival of aggressive LGL patients is significantly inferior to indolent patients, and need earlier intensive therapy in order to achieve longer survival.
23630081 Multivariate meta-analysis of mixed outcomes: a Bayesian approach. 2013 Sep 30 Multivariate random effects meta-analysis (MRMA) is an appropriate way for synthesizing data from studies reporting multiple correlated outcomes. In a Bayesian framework, it has great potential for integrating evidence from a variety of sources. In this paper, we propose a Bayesian model for MRMA of mixed outcomes, which extends previously developed bivariate models to the trivariate case and also allows for combination of multiple outcomes that are both continuous and binary. We have constructed informative prior distributions for the correlations by using external evidence. Prior distributions for the within-study correlations were constructed by employing external individual patent data and using a double bootstrap method to obtain the correlations between mixed outcomes. The between-study model of MRMA was parameterized in the form of a product of a series of univariate conditional normal distributions. This allowed us to place explicit prior distributions on the between-study correlations, which were constructed using external summary data. Traditionally, independent 'vague' prior distributions are placed on all parameters of the model. In contrast to this approach, we constructed prior distributions for the between-study model parameters in a way that takes into account the inter-relationship between them. This is a flexible method that can be extended to incorporate mixed outcomes other than continuous and binary and beyond the trivariate case. We have applied this model to a motivating example in rheumatoid arthritis with the aim of incorporating all available evidence in the synthesis and potentially reducing uncertainty around the estimate of interest.
24561410 Variations and practice in the care of patients with rheumatoid arthritis: quality and cos 2014 Mar INTRODUCTION: Variability in treatment is linked to lower quality of care and higher costs. Rheumatoid arthritis (RA) is a chronic inflammatory disease for which care and management may vary considerably among rheumatologists. The extent of this variability and its cost ramifications have not been widely studied. This prospective study evaluated the quality and variability in care and quantified the potential cost implications. METHODS: We used Clinical Performance and Value® vignettes to measure the quality of RA care among community-based rheumatologists. Three online Clinical Performance and Value® vignettes--representing patients likely seen in practice with mild disease activity (case A), worsening disease activity (case B), and stable disease with a complicating comorbidity (case C)--were administered to each rheumatologist. Responses were scored against evidence-based criteria. Costs were computed using current (2011) Medicare pricing. Data were analyzed using t test and fixed-effects analysis of variance. RESULTS: One hundred eight board-certified rheumatologists (72% were male; mean age, 49.1 years) completed the study. Overall quality scores averaged 61.3%. Those employed by a health system or in a multispecialty practice were more likely to score higher. Highest combined scores for diagnosis and treatment were evident with case A (61.7%) and lowest with case C (46.7%). Up to 79% of rheumatologists ordered at least 1 laboratory test that was considered unnecessary by study protocol criteria, incurring a mean excess cost of $37.85 per physician per case. Up to 26.9% rheumatologists prescribed biologic agents that were not indicated based on American College of Rheumatology treatment guidelines, resulting in additional costs of $2041 per patient per month. CONCLUSION: In this study, we observed a wide range of reported practice variability by rheumatologists in the management of RA. This included unnecessary testing and use of biologic agents that increased the costs of treatment. Opportunities for quality improvement and cost control exist in the management of RA.
23582126 [Use of NSAIDs in rheumatoid arthritis should be limited]. 2013 Apr 8 In a Cochrane review the safety of non-steroidal anti-inflammatory drugs (NSAIDs), including aspirin in people receiving methotrexate (MTX) for rheumatoid arthritis was evaluated. A total of 17 publications were analyzed. Concurrent use anti-inflammatory doses of aspirin with MTX were associated with renal and hepatic side effects, whereas NSAIDs appeared to be safe. Nevertheless there are well-known gastrointestinal, cardiovascular and renal side effects from NSAIDs. In my opinion, use of NSAIDs in rheumatoid arthritis should be limited, as there are better and less risky alternatives.
23104101 Seven sirtuins for seven deadly diseases of aging. 2013 Mar Sirtuins are a class of NAD(+)-dependent deacetylases having beneficial health effects. This extensive review describes the numerous intracellular actions of the seven mammalian sirtuins, their protein targets, intracellular localization, the pathways they modulate, and their role in common diseases of aging. Selective pharmacological targeting of sirtuins is of current interest in helping to alleviate global disease burden. Since all sirtuins are activated by NAD(+), strategies that boost NAD(+) in cells are of interest. While most is known about SIRT1, the functions of the six other sirtuins are now emerging. Best known is the involvement of sirtuins in helping cells adapt energy output to match energy requirements. SIRT1 and some of the other sirtuins enhance fat metabolism and modulate mitochondrial respiration to optimize energy harvesting. The AMP kinase/SIRT1-PGC-1α-PPAR axis and mitochondrial sirtuins appear pivotal to maintaining mitochondrial function. Downregulation with aging explains much of the pathophysiology that accumulates with aging. Posttranslational modifications of sirtuins and their substrates affect specificity. Although SIRT1 activation seems not to affect life span, activation of some of the other sirtuins might. Since sirtuins are crucial to pathways that counter the decline in health that accompanies aging, pharmacological agents that boost sirtuin activity have clinical potential in treatment of diabetes, cardiovascular disease, dementia, osteoporosis, arthritis, and other conditions. In cancer, however, SIRT1 inhibitors could have therapeutic value. Nutraceuticals such as resveratrol have a multiplicity of actions besides sirtuin activation. Their net health benefit and relative safety may have originated from the ability of animals to survive environmental changes by utilizing these stress resistance chemicals in the diet during evolution. Each sirtuin forms a key hub to the intracellular pathways affected.
24196392 TACE-dependent amphiregulin release is induced by IL-1β and promotes cell invasion in fib 2014 Feb OBJECTIVES: The aims of this study were to investigate the expression of amphiregulin (AREG) and TNF-α-converting enzyme (TACE) in fibroblast-like synoviocytes from humans with RA (FLS-RA) when stimulated with proinflammatory cytokines and to explore whether AREG plays a role in RA. METHODS: The effects of cytokines on the expression of AREG and TACE in FLS-RA were measured by quantitative RT-PCR and western blotting. Blockade of IL-1β-mediated pathways was used to verify the involvement of intracellular signal pathways in the induction of AREG and TACE. TAPI-1 and TACE short hairpin RNA (shRNA) infection were used to identify the role of TACE in IL-1β-induced AREG secretion and shedding. AREG-induced production of MMP-1 and cadherin-11 in FLS-RA were measured by ELISA or western blotting. The effect of AREG on FLS-RA invasion was examined using a Transwell invasion assay. RESULTS: IL-1β, but not other tested cytokines, increased the expressions of AREG mRNA and protein in a dose-responsive and time-dependent manner in FLS-RA. IL-1β induced AREG expression via p38 MAPK, NF-κB, JNK and ERK1/2 signalling pathways and induced TACE expression via PI3K, p38MAPK and NF-κB signalling pathways in FLS-RA. TACE mediated AREG secretion and shedding. EGFR (ErbB1) and Her-2 (ErbB2) were expressed in FLS-RA, and AREG increased MMP-1 and cadherin-11 expression in FLS-RA. AREG promoted the FLS-RA invasion ability. CONCLUSION: AREG and TACE expression were up-regulated by IL-1β and their activations on FLS-RA lead to the matrix degradation by inducing MMP-1 and cadherin-11 production. TACE activity is necessary for IL-1β-induced AREG release. Our results demonstrate that IL-1β-induced AREG release may be involved in the pathogenesis of RA.
24078690 Human CD4+CD3- innate-like T cells provide a source of TNF and lymphotoxin-αβ and are el 2013 Nov 1 Innate lymphoid cells encompass a diverse array of lymphocyte subsets with unique phenotype that initiate inflammation and provide host defenses in specific microenvironments. In this study, we identify a rare human CD4(+)CD3(-) innate-like lymphoid population with high TNF expression that is enriched in blood from patients with rheumatoid arthritis. These CD4(+)CD3(-) cells belong to the T cell lineage, but the lack of AgR at the cell surface renders them nonresponsive to TCR-directed stimuli. By developing a culture system that sustains survival, we show that CD4(+)CD3(-) innate-like T cells display IL-7-dependent induction of surface lymphotoxin-αβ, demonstrating their potential to modify tissue microenvironments. Furthermore, expression of CCR6 on the CD4(+)CD3(-) population defines a CD127(high) subset that is highly responsive to IL-7. This CD4(+)CD3(-) population is enriched in the peripheral blood from rheumatoid arthritis patients, suggesting a link to their involvement in chronic inflammatory disease.