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ID PMID Title PublicationDate abstract
27534894 Antigen-presenting human B cells are expanded in inflammatory conditions. 2017 Feb Traditionally, B cells have been best known for their role as producers of antibodies. However, in recent years, a growing body of evidence has accumulated showing that B cells fulfill a range of other immunologic functions. One of the functions that has attracted increasing attention is the capacity of B cells to induce antigen-specific activation of T cells through presentation of antigens. However, the analysis of this B cell function has been hampered by the lack of a phenotypically well-defined antigen-presenting B cell subset. Here, we report the identification of a human antigen-presenting B cell subset with strong immunostimulatory properties. This B cell subset is characterized by low expression of CD21 and high expression of the activation marker CD86 and exhibits strong T cell-stimulatory activity, as demonstrated by means of an autologous mixed-lymphocyte reaction. Phenotypically, CD21(low)CD86(pos) immunostimulatory B cells (B(APC)) represented CD27(+) class-switched IgM(neg)IgD(neg) B lymphocytes and displayed a higher expression of cell surface receptors, which mediate the migration from peripheral blood to sites of inflammation. Flow cytometric analysis of peripheral blood obtained from individuals with inflammatory conditions revealed that the B(APC) subset was expanded following vaccination and in patients with rheumatoid arthritis. Taken together, our work shows that B(APC) represents a strongly immunostimulatory B cell subset, which could be a promising target for immunotherapeutic intervention in inflammatory diseases.
26517730 Detection and identification of protein citrullination in complex biological systems. 2016 Feb Protein citrullination is a post-translational modification of arginine that is catalyzed by the Protein Arginine Deiminase (PAD) family of enzymes. Aberrantly increased citrullination is associated with a host of inflammatory diseases and cancer and PAD inhibitors have shown remarkable efficacy in a range of diseases including rheumatoid arthritis, lupus, atherosclerosis, and ulcerative colitis. In rheumatoid arthritis, citrullinated proteins serve as key antigens for rheumatoid arthritis-associated autoantibodies. These data suggest that citrullinated proteins may serve more generally as biomarkers of specific disease states, however, the identification of citrullinated residues remains challenging due to the small 1Da mass change that occurs upon citrullination. Herein, we highlight the available techniques to identify citrullinated proteins/residues focusing on advanced MS techniques as well as chemical derivatization strategies that are currently being employed to identify citrullinated proteins as well as the specific residues modified within those proteins.
26232454 Senescent profile of angiogenic T cells from systemic lupus erythematosus patients. 2016 Mar The chronic inflammatory environment associated with systemic lupus erythematosus can lead to an accelerated immunosenescence responsible for the endothelial damage and increased cardiovascular risk observed in these patients. The present study analyzed two populations with opposite effects on vascular endothelium, angiogenic T cells and the senescent CD4(+)CD28(null) subset, in 84 systemic lupus erythematosus patients and 46 healthy controls. Also, 48 rheumatoid arthritis patients and 72 individuals with traditional cardiovascular risk factors participated as disease controls. Phenotypic characterization of CD28(+) and CD28(null) cells was performed by analyzing markers of senescence (CCR7, CD27, CD57) and cytotoxicity (CD56, perforin, granzyme B, IFN-γ). IL-1β, IL-6, IL-8, IL-10, IL-12, IL-17A, IFN-α, IFN-γ, TNF-α, B lymphocyte stimulator, and GM-CSF serum levels were analyzed in systemic lupus erythematosus patients and healthy controls. CD4(+)CD28(null) cells were notably increased in the systemic lupus erythematosus patients and disease controls compared with healthy controls. In contrast, angiogenic T cells were only reduced in the disease controls (those with rheumatoid arthritis or traditional cardiovascular risk factors). Nevertheless, an anomalous presence of CD28(null)-angiogenic T cells, with cytotoxic and senescent characteristics, was noted in systemic lupus erythematosus patients in association with anti-dsDNA titer, anti-SSA/Ro antibodies and circulating TNF-α, IL-8, IFN-α, and B lymphocyte stimulator amounts. This subset was also detected in those with traditional cardiovascular risk factors but not in the rheumatoid arthritis patients. In contrast, CD28(+)-angiogenic T cells were reduced in the systemic lupus erythematosus patients with cardiovascular disorders. In conclusion, CD28 expression must be used to redefine the angiogenic T cell population, because in pathologic conditions, a senescent CD28(null)-angiogenic T cell subset with inflammatory, rather than protective, effects could be present.
28149009 Serum Lipid Alterations in Early Rheumatoid Arthritis Patients on Disease Modifying Anti R 2017 Mar Dyslipidaemia is a major CVD risk factor in the general population. Current evidence suggests that lipid metabolism is altered in RA due to inflammation, and that use of anti-inflammatory therapy may reverse some of these changes. The objective of our study is to compare the effect of treatment with DMARD on lipid fractions after 6 months of therapy. Forty patients who met the American College of Rheumatology, ACR/EULAR criteria for rheumatoid arthritis, with disease duration of less than 1 year and no prior treatment were included in the study. Thirty healthy volunteers were included as controls. The mean DAS-28 at disease onset was 5.15 ± 1.3. Early Rheumatoid Arthritis (ERA) patients exhibited higher serum levels of total cholesterol (TC) and lowdensity lipoprotein cholesterol (LDL-C) and lower serum high-density lipoprotein cholesterol (HDL-C) levels compared to controls. As a consequence, the atherogenic index of plasma [log (TG/HDL-C)], the atherogenic indices: TC/HDL-C as well as LDLC/HDL-C was significantly higher in ERA patients compared to controls. After 6 months of treatment, there was significant reduction of the DAS 28, HDL-C and Apo A-I improved and Lp(a) decreased significantly. All lipid ratios improved, a phenomenon primarily due to the increase in serum HDL-C levels. These changes were inversely correlated with CRP and ESR. In conclusion, ERA patients are characterized by an atherogenic lipid profile, which improves with DMARD therapy.
27151405 DrugGenEx-Net: a novel computational platform for systems pharmacology and gene expression 2016 May 5 BACKGROUND: The targeting of disease-related proteins is important for drug discovery, and yet target-based discovery has not been fruitful. Contextualizing overall biological processes is critical to formulating successful drug-disease hypotheses. Network pharmacology helps to overcome target-based bottlenecks through systems biology analytics, such as protein-protein interaction (PPI) networks and pathway regulation. RESULTS: We present a systems polypharmacology platform entitled DrugGenEx-Net (DGE-NET). DGE-NET predicts empirical drug-target (DT) interactions, integrates interaction pairs into a multi-tiered network analysis, and ultimately predicts disease-specific drug polypharmacology through systems-based gene expression analysis. Incorporation of established biological network annotations for protein target-disease, -signaling pathway, -molecular function, and protein-protein interactions enhances predicted DT effects on disease pathophysiology. Over 50 drug-disease and 100 drug-pathway predictions are validated. For example, the predicted systems pharmacology of the cholesterol-lowering agent ezetimibe corroborates its potential carcinogenicity. When disease-specific gene expression analysis is integrated, DGE-NET prioritizes known therapeutics/experimental drugs as well as their contra-indications. Proof-of-concept is established for immune-related rheumatoid arthritis and inflammatory bowel disease, as well as neuro-degenerative Alzheimer's and Parkinson's diseases. CONCLUSIONS: DGE-NET is a novel computational method that predicting drug therapeutic and counter-therapeutic indications by uniquely integrating systems pharmacology with gene expression analysis. DGE-NET correctly predicts various drug-disease indications by linking the biological activity of drugs and diseases at multiple tiers of biological action, and is therefore a useful approach to identifying drug candidates for re-purposing.
27120778 Male fertility potential alteration in rheumatic diseases: a systematic review. 2016 Jan BACKGROUND: Improved targeted therapies for rheumatic diseases were developed recently resulting in a better prognosis for affected patients. Nowadays, patients are living longer and with improved quality of life, including fertility potential. These patients are affected by impaired reproductive function and the causes are often multifactorial related to particularities of each disease. This review highlights how rheumatic diseases and their management affect testicular function and male fertility. MATERIALS AND METHODS: A systematic review of literature of all published data after 1970 was conducted. Data was collected about fertility abnormalities in male patients with systemic lupus erythematosus, rheumatoid arthritis, dermatomyositis, ankylosing spondylitis, Behçet disease and gout. Two independent researchers carried out the search in online databases. RESULTS: A total of 19 articles were included addressing the following diseases: 7 systemic lupus erythematosus, 6 Behçet disease, 4 ankylosing spondylitis, 2 rheumatoid arthritis, 2 dermatomyositis and one gout. Systemic lupus erythematosus clearly affects gonadal function impairing spermatogenesis mainly due to antisperm antibodies and cyclophosphamide therapy. Behçet disease, gout and ankylosing spondylitis patients, including those under anti-TNF therapy in the latter disease, do not seem to have reduced fertility whereas in dermatomyositis, the fertility potential is hampered by disease activity and by alkylating agents. Data regarding rheumatoid arthritis is scarce, gonadal dysfunction observed as consequence of disease activity and antisperm antibodies. CONCLUSIONS: Reduced fertility potential is not uncommon. Its frequency and severity vary among the different rheumatic diseases. Permanent infertility is rare and often associated with alkylating agent therapy.
26757074 A liquid chromatography-tandem mass spectrometry method for the quantitation of actarit in 2016 Jan Actarit (ATR), 4-acetylaminophenylacetic acid is an orally effective disease-modifying anti-rheumatic drug widely prescribed for the treatment of rheumatoid arthritis. The present study demonstrates the first report on a selective and sensitive liquid chromatography-tandem mass spectrometry method for the quantification of ATR in rabbit plasma using p-coumaric acid as an internal standard (IS). Following liquid-liquid extraction, chromatographic separation of the reconstituted samples was achieved isocratically on a Syncronis-C18 column with a mobile phase consisting of aqueous ammonium acetate (10 mM, pH 4)- methanol and acetonitrile mixture (8 : 92, v/v) at a flow rate of 0.6 ml/min. ATR and IS were detected using electrospray ionization operated in negative multiple reaction monitoring mode. The calibration curve was linear (r(2)  ≥ 0.990) over the concentration range of 1-4000 ng/ml with a lower limit of quantitation of 1 ng/ml. The mean extraction recovery of ATR and IS from rabbit plasma was greater than 85%. The method complied well with US Food and Drug Administration guidelines for selectivity, sensitivity, accuracy, precision, matrix effect, dilution integrity, carry-over effect and stability. The method was successfully applied to in vitro metabolic stability (using rabbit liver microsomes) and in vivo pharmacokinetic study after oral administration of ATR at a dose of 10 mg/kg in New Zealand rabbits. Copyright © 2015 John Wiley & Sons, Ltd.
24854354 Frequent conversion of tuberculosis screening tests during anti-tumour necrosis factor the 2015 Oct OBJECTIVES: To determine the rate of tuberculosis (TB) screening test conversion during anti-tumour necrosis factor (TNF) therapy in rheumatic patients with negative baseline screening. METHODS: This was a prospective study of rheumatic patients with negative baseline TB screening (tuberculin skin test (TST): <5 mm, and negative T-SPOT.TB, QuantiFERON-TB Gold In Tube (QFT-GIT) and chest X-ray) treated with anti-TNF agents. All patients underwent re-screening for TB with all assays 1 year later. Factors associated with TB test conversion were analysed and compared between 'converters' and 'non-converters'. RESULTS: Seventy patients (mean age 50.6±15.5 years) with rheumatic disease (33 with rheumatoid arthritis, 33 with spondyloarthropathies and 4 with other conditions) were enrolled. Patients were treated with different anti-TNFs (27 with adalimumab, 14 etanercept, 16 infliximab, 8 golimumab, 5 certolizumab pegol) for 1 year. Twenty patients (29%) displayed conversion of at least one screening assay 12 months after anti-TNF therapy: conversion of TST occurred in 9 (13%), T-SPOT.TB in 7 (10%) and QFT-GIT in 5 (7%). Only one patient had concomitant conversion of more than one screening test. Univariate and multivariate analysis revealed that only infliximab was associated with a decreased rate of TB screening assay conversion (OR 0.048, 95% CI 0.004 to 0.606, p=0.017). No patient (40% received isoniazid therapy) developed active TB during follow-up (27±12 months). CONCLUSIONS: Approximately one third of patients with negative baseline TB screening develop conversion of at least one screening test during anti-TNF treatment. These findings should be considered when designing re-screening strategies and contemplating latent TB therapy.
26672718 Anti-CCP antibodies are not a marker of severity in established rheumatoid arthritis: a ma 2015 Sep 14 INTRODUCTION: The presence of anti-CCP is an important prognostic tool of rheumatoid arthritis (RA). But research is still ongoing on its relationship with disease activity and functional capacity. OBJECTIVES: To study the relationship between anti-CCP and disease activity, functional capacity and structural damage indexes, by means of conventional radiography (CR) and magnetic resonance imaging (MRI), in cases of established RA. METHODS: Cross-sectional study with RA patients with 1-10 years of disease duration. Participants underwent clinical evaluation with anti-CCP. Disease activity was assessed using the Clinical Disease Activity Index (CDAI), and functional capacity through the Health Assessment Questionnaire (HAQ). CR analysis was carried out by the Sharp van der Heijde index (SvdH), and MRI analysis by RAMRIS (Rheumatoid Arthritis Magnetic Resonance Image Scoring). RESULTS: We evaluated 56 patients, with a median (IqR) age of 55 (47.5-60.0) years; 50 (89.3%) participants were female and 37 (66.1%) were positive for anti-CCP. Medians (IqR) of CDAI, HAQ, SvdH and RAMRIS were 14.75 (5.42-24.97) 1.06 (0.28-1.75), 2 (0-8) and 15 (7-35), respectively. There was no association between anti-CCP and CDAI, HAQ and SvdH and RAMRIS scores. CONCLUSION: Our results have not established an association of anti-CCP with the severity of disease. To date, we cannot corroborate anti-CCP as a prognostic tool in patients with established RA.
27933212 Spontaneous destructive periodontitis and skeletal bone damage in transgenic mice carrying 2016 OBJECTIVE: Shared epitope (SE)-coding DRB1 alleles are associated with bone erosion in several diseases, including rheumatoid arthritis (RA) and periodontal disease (PD), but the underlying mechanism is unknown. We have recently identified the SE as an osteoclast-activating ligand. To better understand the biological effects of the SE in vivo, here we sought to determine whether it can facilitate spontaneous bone damage in naïve mice. METHODS: 3-month old naïve transgenic mice that carry the human SE-coding allele DRB1*04:01, or a SE-negative allele DRB1*04:02 were studied. Bone tissues were analysed by micro-CT, and the tooth-supporting tissues were studied by histology, immunohistochemistry and immunofluorescence. Serum biomarkers were determined by ELISA. RESULTS: Transgenic mice expressing the SE-coding DRB1*04:01 allele, but not mice carrying the SE-negative allele DRB1*04:02, showed spontaneous PD associated with interleukin (IL)-17 overabundance and periostin disruption. Mandibular bone volumetric and mineralisation parameters were significantly lower in SE-positive mice, and alveolar bone resorption was significantly increased in these mice. SE-positive mice also had more slender tibiae, and their marrow, cortical and total areas were lower than those of SE-negative mice. Additionally, significantly increased serum IL-17, tumour necrosis factor-α and osteoprotegrin levels were found in SE-positive mice, while their receptor activator of nuclear factor κ-B ligand levels were significantly lower. CONCLUSIONS: A human SE-coding allele increases the propensity to spontaneous bone-destructive periodontal inflammation and skeletal bone damage in transgenic mice. These findings provide new insights into the previously documented but poorly understood association of the SE with accelerated bone erosion in RA and several other human diseases.
25527879 Risks of in-hospital death and complications after fusion surgery in patients with atlanto 2015 Apr OBJECTIVE: To examine in-hospital mortality and postoperative major complications in patients undergoing fusion surgery for atlantoaxial subluxation (AAS) and to examine whether the risk of perioperative complications varies between patients with and without rheumatoid arthritis (RA). METHODS: A retrospective analysis of data from the Diagnosis Procedure Combination database, a nationwide administrative impatient database in Japan, identified 1090 patients who underwent spinal fusion surgery for AAS during 2007-2012. Patients' clinical characteristics were extracted, including age, sex, use of homologous blood transfusion, length of stay, and type of hospital. Clinical outcomes included in-hospital death and major complications, including surgical-site infection, sepsis, cardiac events, respiratory disorders, acute renal failure, pulmonary embolism, perioperative stroke, and vertebral injury. Massive blood transfusion was defined as at least 6 units of red blood cells. RESULTS: Four hundred sixty-five patients (42.7%) were classified as the RA group. In-hospital mortality after fusion surgery for AAS was 0.5% (5/1090), and major complications occurred in 5% (55/1090). Multivariate analyses showed that patients with RA were more likely to have major complications after surgery than patients without RA (odds ratio: 1.69; 95% confidence interval: 0.96-2.97; P = 0.07), and the rate of massive blood transfusion was significantly greater in patients with RA than in patients without RA (odds ratio: 2.29; 95% confidence interval: 1.12-4.68; P = 0.02). CONCLUSIONS: The in-hospital mortality after fusion surgery for AAS was relatively low. However, patients with RA had an increased risk of postoperative complications and massive blood transfusion compared with patients without RA.
27910811 LL-37, HNP-1, and HBD2/3 modulate the secretion of cytokines TNF-α, IL-6, IFN-γ, IL-10 a 2016 Sep 1 The aim of this study was to evaluate the effects of the LL-37, HNP-1 and HBD2/3 peptides on cytokine and MMP production in human polymorphonuclear cells, mononuclear cells and chondrocytes. The levels of cytokines in supernatants from mononuclear and polymorphonuclear cell cultures were measured with a cytometric bead array by flow cytometry. Likewise, the levels of metalloproteinase/MMP-1, 3, and 13 were measured in supernatants from chondrocyte cultures using an ELISA. The expression of RANKL on lymphocytes was analyzed by flow cytometry. We observed increased levels of TNF-α, IL-6 and IL-10 in mononuclear and polymorphonuclear cell cultures stimulated with HBD-2/3. We also observed increased levels of IFN-γ, IL-10, and IL-6 in mononuclear cell cultures stimulated with HNP-1, and increased IL-6 levels were observed in polymorphonuclear cell cultures exposed to HNP-1. We also found that the MMP-1 level increased in the chondrocyte cultures stimulated with HBD-3, whereas the MMP-1 level was decreased in cultures exposed to LL-37. The present report is the first study to determine that HNP-1and HBD2/3 promote the secretion of pro-inflammatory cytokines by polymorphonuclear and mononuclear cells and the secretion of MMP by chondrocytes, whereas LL-37 diminishes MMP1 secretion. Our results suggest that HBD-2/3 and HNP1 might play a pathological role in rheumatoid arthritis, while LL-37 might have a protective role.
27713825 Frequency and trends of disease-modifying antirheumatic drug (DMARD) use in Germany. 2016 Oct The aim of this study was to analyze the population-based frequency of classic (c-) and biologic (b-) disease-modifying antirheumatic drug (DMARD) use over time, selected underlying indications and the specialty of the prescribing physicians in Germany. Based on the claims data of the German Pharmacoepidemiological Research Database (GePaRD), yearly cross-sectional studies were conducted from 2004 to 2011. The prevalence of DMARD use was calculated as the number of persons with at least one dispensation per 1000 persons stratified by sex and age. In 2011, we also obtained the proportion of c- and b-DMARDs users with diagnoses of selected indications and the proportion of dispensations by specialty of the physician. Between 2004 and 2011, the annual prevalence of b-DMARD and c-DMARD use increased from 0.35‰ to 1.54‰ and from 6.53‰ to 8.93‰, respectively. In 2011, the study population comprised 12.8 million insurants with a mean age of 44.0 years. During this year, among c-DMARDs, methotrexate was prescribed most frequently (4.76‰), followed by azathioprine (1.72‰) and sulfasalazine (1.20‰). For b-DMARDs, adalimumab (0.57‰), etanercept (0.46‰), and rituximab (0.23‰) were most frequently used. Notably, b-DMARD users more often had a diagnosis of ankylosing spondylitis and psoriasis compared to c-DMARD-users (20.7% vs. 2.9% and 20.0% vs. 11.4%, respectively) and b-DMARDs were more frequently prescribed by rheumatologists and other specialists. Our population-based study highlights the increasing use of c- and b-DMARDs in Germany. Compared to c-DMARDs, b-DMARDs were commonly used for indications besides rheumatoid arthritis. Future research should therefore also focus on their prescription patterns and safety aspects in indications other than RA.
26213702 Hardware Removal Due to Infection after Open Reduction and Internal Fixation: Trends and P 2015 Jul BACKGROUND: Little is known about trends and predictors of hardware related infection following open reduction and internal fixation (ORIF) of extremity fractures, one of the major causes of failure following ORIF. The present study was designed and conducted to determine trends and predictors of infection-related hardware removal following ORIF of extremities using a nationally representative database. METHODS: We used Nationwide Inpatient Sample data from 2002 to 2011 to identify cases of ORIF following upper and lower extremity fractures, as well as cases that underwent infection-related hardware removal following ORIF. Multivariate analysis was performed to identify independent predictors of infection-related hardware removal, controlling for patient demographics and comorbidities, hospital characteristics, site of fracture, and year. RESULTS: For all ORIF procedures, the highest rate of hardware removal related to infection was observed in tarsal fractures (5.56%), followed by tibial (3.65%) and carpal (3.37%) fractures. Hardware removal rates due to infection increased in all fractures except radial/ulnar fractures. Tarsal fractures(odds ratio (OR)=1.06, 95% confidence interval (CI): 1.04-1.09, P<0.001), tibial fractures (OR=1.04, 95% CI: 1.03-1.06, P<0.001) and those patients with diabetes mellitus (OR=2.64, 95% CI: 2.46-2.84, P<0.001), liver disease (OR=2.04, 95% CI: 1.84- 2.26, P<0.001), and rheumatoid arthritis (OR=2.06, 95% CI: 1.88-2.25 P<0.001) were the main predictors of infection-related removals; females were less likely to undergo removal due to infection (OR= 0.61, 95% CI: 0.59-0.63 P<0.001). CONCLUSIONS: Hardware removal rates due to infection increased in all fractures except radial/ulnar fractures. Diabetes, liver disease, and rheumatoid arthritis were important predictors of infection-related hardware removal. The study identified some risk factors for hardwarerelated infection following ORIF, such as diabetes, liver disease, and rheumatoid arthritis, that should be studied further in an attempt to implement strategies to reduce rate of infection following ORIF.
25433530 Patient-reported joint count in juvenile idiopathic arthritis: the reliability of a maniki 2015 Mar OBJECTIVE: To evaluate the reliability of a manikin format, patient-reported joint count in juvenile idiopathic arthritis (JIA), and to detect changes in agreement at a second visit. METHODS: Patients with JIA aged 12-21 were asked to mark joints with active arthritis on a manikin before their regular clinic visit. The physician then performed a joint count without having seen the patient's assessment. Agreement between scores of physician-reported and patient-reported joint counts was assessed using ICC. Kappa statistics were used to assess reliability of scoring individual joints. RESULTS: The study included 75 patients with JIA. In general, patients had a low number of active joints (median 1 joint, indicated by the physician). ICC was moderate (0.61) and κ ranged from 0.3-0.7. At the second visit, κ were similar; the ICC was 0.19. When a patient scored 0 joints, the physician confirmed this 93%-100% of the time. When the patient marked ≥ 1 joints, the physician confirmed arthritis 59%-76% of the time. Sensitivity to change was moderate. CONCLUSION: Agreement between physician and patient on the number of joints with active arthritis was reasonable. Untrained patients tended to overestimate the presence of arthritis when they marked active joints on a manikin-format joint count. When the patient indicated absence of arthritis, the physician usually confirmed this. As the agreement did not improve at followup, future research should focus on the possibility of achieving this through training. For now, the patient-reported joint count cannot replace the physicians' joint count in clinical practice; it may be used in epidemiological studies with caution.
26724675 Downstream activation of NF-κB in the EDA-A1/EDAR signalling in Sjögren's syndrome and i 2016 May Sjögren's syndrome (SS) is an autoimmune disease and the second most common chronic systemic rheumatic disorder. Prevalence of primary SS in the general population has been estimated to be approximately 1-3%, whereas secondary SS has been observed in 10-20% of patients with rheumatoid arthritis, systemic lupus erythematosus (SLE) and scleroderma. Despite this, its exact aetiology and pathogenesis are largely unexplored. Nuclear factor-kappa B (NF-κB) signalling mechanisms provide central controls in SS, but how these pathways intersect the pathological features of this disease is unclear. The ubiquitin-editing enzyme A20 (tumour necrosis factor-α-induced protein 3, TNFAIP3) serves as a critical inhibitor on NF-κB signalling. In humans, polymorphisms in the A20 gene or a deregulated expression of A20 are often associated with several inflammatory disorders, including SS. Because A20 controls the ectodysplasin-A1 (EDA-A1)/ectodysplasin receptor (EDAR) signalling negatively, and the deletion of A20 results in excessive EDA1-induced NF-κB signalling, this work investigates the expression levels of EDA-A1 and EDAR in SS human salivary glands epithelial cells (SGEC) and evaluates the hypothesis that SS SGEC-specific deregulation of A20 results in excessive EDA1-induced NF-κB signalling in SS. Our approach, which combines the use of siRNA-mediated gene silencing and quantitative pathway analysis, was used to elucidate the role of the A20 target gene in intracellular EDA-A1/EDAR/NF-κB pathway in SS SGEC, holding significant promise for compound selection in drug discovery.
26681953 Adiponectin Isoforms and Leptin Impact on Rheumatoid Adipose Mesenchymal Stem Cells Functi 2016 Adiponectin and leptin have recently emerged as potential risk factors in rheumatoid arthritis (RA) pathogenesis. In this study we evaluated the effects of adiponectin and leptin on immunomodulatory function of adipose mesenchymal stem cells (ASCs) derived from infrapatellar fat pad of RA patients. ASCs were stimulated with leptin, low molecular weight (LMW) and high/middle molecular weight (HMW/MMW) adiponectin isoforms. The secretory activity of ASCs and their effect on rheumatoid synovial fibroblasts (RA-FLS) and peripheral blood mononuclear cells (PBMCs) from healthy donors have been analysed. RA-ASCs secreted spontaneously TGFβ, IL-6, IL-1Ra, PGE2, IL-8, and VEGF. Secretion of all these factors was considerably upregulated by HMW/MMW adiponectin, but not by LMW adiponectin and leptin. Stimulation with HMW/MMW adiponectin partially abolished proproliferative effect of ASC-derived soluble factors on RA-FLS but did not affect IL-6 secretion in FLS cultures. ASCs pretreated with HMW/MMW adiponectin maintained their anti-inflammatory function towards PBMCs, which was manifested by moderate PBMCs proliferation inhibition and IL-10 secretion induction. We have proved that HMW/MMW adiponectin stimulates secretory potential of rheumatoid ASCs but does not exert strong impact on ASCs function towards RA-FLS and PBMCs.
27743778 Extract from Eucommia ulmoides Oliv. ameliorates arthritis via regulation of inflammation, 2016 Dec 24 ETHNOPHARMACOLOGICAL RELEVANCE: Eucommia ulmoides Oliv., a valuable Chinese herb, has shown a variety of health benefits. Despite the widespread clinical use of this herb to treat rheumatoid arthritis (RA) in Traditional Chinese Medicine (TCM), very few studies have described its anti-pathological effects or mechanism in RA. The present study investigated the mechanism of Eucommia ulmoides Oliv. in an experimental collagen-induced arthritis (CIA) rat model. MATERIALS AND METHODS: The effects of four different Eucommia ulmoides Oliv. extracts on the proliferation of rheumatoid arthritis fibroblast-like synoviocytes (RA-FLS) were screened in an MTT assay, and apoptotic effects were detected by flow cytometry. Among the extracts, the 70% ethanol extract (EU70) presented the best inhibition and was further investigated for its curative effect in CIA rats. Foot swelling was detected, and the arthritis index (AI) was scored. Pathological improvement was assessed by haematoxylin and eosin (H&E) staining of joint tissues. The mechanistic effects of EU70 were investigated as follows: anti-inflammatory effects in Th17-positive cells by flow cytometry; serum levels of inflammatory cytokines by ELISA; TNFα and IL-1β expression by immunohistochemistry (IHC); and anti-osteoclastogenesis by QPCR detection of RANKL and OPG mRNA. RESULTS: Compared with vehicle treatment in CIA model rats, EU70 significantly ameliorated foot swelling, decreased AI in vivo and reduced inflammatory cell infiltration and synoviocyte proliferation. EU70 decreased the number of Th17-positive cells in the spleen and the serum levels of cytokines, including IL-17, IL-1β and TNFα, and upregulated the serum levels of IL-10; these results indicated the anti-inflammatory effect of EU70. Moreover, EU70 effectively suppressed TNFα and IL-1β expression in the joint tissues and resulted in the downregulation of RANKL mRNA and the upregulation of OPG mRNA. These results revealed the possible preventive role of EU70 against bone destruction. CONCLUSION: For the first time, these mechanisms and pathological improvements support the clinical use of Eucommia ulmoides Oliv. in treating RA. The findings indicated that the 70% ethanol extract of Eucommia ulmoides Oliv. could relieve RA symptoms by (1) suppressing the proliferation of synoviocytes, (2) reducing the number of Th17-positive cells and downregulating serum IL-17 expression, (3) increasing the anti-inflammatory effects of IL-10, (4) inhibiting the serum and tissue levels of key pro-inflammatory cytokines, TNFα and IL-1β, and (5) reducing the degradation of cartilage and bone.
27407218 Early diagnosis of rheumatic diseases: an evaluation of the present situation and proposed 2015 Musculoskeletal pain is a very common complaint, affecting 30-40% of the European population. It is estimated that approximately 400,000 Poles suffer from inflammatory rheumatic diseases, such as rheumatoid arthritis, ankylosing spondylitis and psoriatic arthritis, and a vast majority of those affected are working-age individuals. Patients with suspected arthritis require prompt diagnosis and treatment, as any delays may result in irreversible joint destruction and disability. Currently in Poland, the lag time between the onset of symptoms and diagnosis is, on average, as much as 35 weeks. In this paper, we review the current state of specialist rheumatology care in Poland and propose a reorganised care model that includes early diagnosis of inflammatory arthritis. The main goal we wish to achieve with our reorganised model is to enhance access to outpatient specialist rheumatology care for patients with suspected arthritis. We believe that our model should make it possible to considerably reduce the lag time between GP referral and the diagnosis and treatment by a rheumatologist to as little as 3 to 4 weeks. This article provides a proposal of changes that would achieve this goal and is a summary of the report published by the Institute of Rheumatology in September 2014.
26908381 A case of reactive arthritis due to Clostridium difficile colitis. 2016 Reactive arthritis is an acute, aseptic, inflammatory arthropathy following an infectious process but removed from the site of primary infection. It is often attributed to genitourinary and enteric pathogens, such as Chlamydia, Salmonella, Shigella, Campylobacter, and Yersinia, in susceptible individuals. An uncommon and less recognized cause of this disease is preceding colonic infection with Clostridium difficile, an organism associated with pseudomembranous colitis and diarrhea in hospitalized patients and those recently exposed to antibiotics. Recognition of this association may be complicated by non-specific presentation of diarrhea, the interval between gastrointestinal and arthritic symptoms, and the wide differential in mono- and oligoarthritis. We present the case of a 61-year-old, hospitalized patient recently treated for C. difficile colitis who developed sudden, non-traumatic, right knee pain and swelling. Physical examination and radiographs disclosed joint effusion, and sterile aspiration produced cloudy fluid with predominant neutrophils and no growth on cultures. Diagnostic accuracy is enhanced by contemporaneous laboratory investigations excluding other entities such as gout and rheumatoid arthritis and other infections that typically precede reactive arthritis. Contribution of Clostridium infection to reactive arthritis is an obscure association frequently difficult to prove, but this organism is warranted inclusion in the differential of reactive arthritis.