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ID PMID Title PublicationDate abstract
27895418 Molecular mechanism of action of anti-tumor necrosis factor antibodies in inflammatory bow 2016 Nov 14 Anti-tumor necrosis factor (TNF) antibodies are successfully used in the therapy of inflammatory bowel diseases (IBD). However, the molecular mechanism of action of these agents is still a matter of debate. Apart from neutralization of TNF, influence on the intestinal barrier function, induction of apoptosis in mucosal immune cells, formation of regulatory macrophages as well as other immune modulating properties have been discussed as central features. Nevertheless, clinically effective anti-TNF antibodies were shown to differ in their mode-of-action in vivo and in vitro. Furthermore, the anti-TNF agent etanercept is effective in the treatment of rheumatoid arthritis but failed to induce clinical response in Crohn's disease patients, suggesting different contributions of TNF in the pathogenesis of these inflammatory diseases. In the following, we will review different aspects regarding the mechanism of action of anti-TNF agents in general and analyze comparatively different effects of each anti-TNF agent such as TNF neutralization, modulation of the immune system, reverse signaling and induction of apoptosis. We discuss the relevance of the membrane-bound form of TNF compared to the soluble form for the immunopathogenesis of IBD. Furthermore, we review reports that could lead to personalized medicine approaches regarding treatment with anti-TNF antibodies in chronic intestinal inflammation, by predicting response to therapy.
27881910 Low-dose modified-release prednisone in axial spondyloarthritis: 3-month efficacy and tole 2016 BACKGROUND: Oral glucocorticoids (GCs) have been shown to be effective in reducing the inflammatory symptoms of rheumatoid arthritis, but their use is not supported by evidence in spondyloarthritis (SpA). Modified-release (MR) oral prednisone taken at bedtime has been shown to be more effective than immediate-release prednisone taken in the morning. The efficacy of low-dose MR prednisolone in patients with SpA is unknown. PATIENTS AND METHODS: This single-center cohort study retrospectively assessed the effectiveness and safety of 12-week low-dose MR prednisone (5 mg daily, bedtime administration) in GC-naïve adult patients with symptomatic axial SpA. A 50% improvement of the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) or a final BASDAI score of <4 according to disease activity at baseline was chosen as the primary outcome parameter after MR prednisone. RESULTS: Fifty-seven patients were evaluated; of them, 41 had an active disease (BASDAI score of ≥4) at baseline. MR prednisone significantly reduced BASDAI (from 5.5±2.6 to 3.0±2.8, P<0.001) as well as inflammatory symptoms, pain, fatigue and morning stiffness. The overall response rate after MR prednisone was 52.6% (53.7% in patients with active SpA and 50.0% in patients with low-active disease; nonsignificant). At multivariable analysis, none of the considered clinical findings independently predicted the response to MR prednisone in subjects with active SpA. Overall, seven patients (11.8%) had nonserious adverse drug reactions after MR prednisone. CONCLUSION: In patients with symptomatic SpA and naïve to GCs, low-dose MR prednisone reduced the symptoms and clinical indexes of disease activity and showed a positive safety profile.
27670839 Tocilizumab-induced pancreatitis: case report and review of data from the FDA Adverse Even 2016 Dec WHAT IS KNOWN AND OBJECTIVE: Tocilizumab (TCZ) is a humanized monoclonal antibody acting against the IL-6 receptor. It is a drug used in the treatment of rheumatoid arthritis and can be either given intravenously every 4 weeks or subcutaneously once a week. Known adverse events (AE) associated with TCZ include: infections of the upper respiratory tract, arterial hypertension, hypercholesterolaemia and hypertriglyceridaemia. Here, we present the first well-documented case of TCZ-induced acute pancreatitis (AP) and a systematic review of the literature including data from the Food and Drug Administration Adverse Event Reporting System (FAERS) database. METHODS: Patient data collection was performed within the Berlin Case-Control Surveillance Study. A literature search for TCZ-induced AP was conducted. Analysis of the FAERS database concerning TCZ-associated pancreatic AE from the period of 2009 until the first quarter of 2013 was conducted. RESULTS AND DISCUSSION: A 40-year-old man presented with a 2-day history of progressive upper abdominal pain with elevated serum lipase and triglyceride levels. Biliary pancreatitis was ruled out by abdominal sonography and CT scan. Cessation of intravenously administered TCZ resulted in improvement of the patient's condition and a decline in elevated laboratory values, suggesting a probable relationship between TCZ intake and AP. Analysis of the FAERS database retrieved 52 cases of TCZ-associated AP that accounted for 70% of all pancreatic AE in association with TCZ use. Further literature search detected three additional cases in which TCZ use was associated with AP. WHAT IS NEW AND CONCLUSION: Physicians should be aware of the probable association between TCZ use and AP. Targeted post-authorization studies are needed to confirm and quantify the risk of TCZ-induced AP.
27619643 CD147 induces up-regulation of vascular endothelial growth factor in U937-derived foam cel 2016 Nov 1 Intraplaque angiogenesis has been recognized as an important risk factor for the rupture of advanced atherosclerotic plaques in recent years. CD147, also called Extracellular Matrix Metalloproteinase Inducer, has been found the ability to promote angiogenesis in many pathological conditions such as cancer diseases and rheumatoid arthritis via the up-regulation of vascular endothelial growth factor (VEGF), a critical mediator of angiogenesis. We investigated whether CD147 would also induce the up-regulation of VEGF in the foam cells formation process and explored the probable signaling pathway. The results showed the expression of CD147 and VEGF was significantly higher in U937-derived foam cells. After CD147 stealth siRNA transfection treatment, the production of VEGF was reduced depended on the inhibition efficiency of CD147 siRNAs.The special signaling pathway inhibitors LY294002, SP600125, SB203580 and U0126 were added to cultures respectively and the results showed LY294002 dose-dependently inhibited the expression of VEGF. The reduction of phospho-Akt was observed in both LY294002 and siRNA groups, suggested that the phosphatidylinositol 3-kinase/Akt pathway may be the probable signaling pathway underlying CD147 induced up-regulation of VEGF in U937-derived foam cells.
27619635 Measurement properties of the brief resilient coping scale in patients with systemic lupus 2016 Sep 13 BACGROUND: Resilience has been defined as the capacity or the ability to rebound from and positively adapt to significant stressors, despite experiences of significant adversity or trauma. To capture to what extent an individual copes with stress in a resilient fashion the Brief Resilient Coping Scale (BRCS) was developed. This tool was validated in people with chronic disease, such as rheumatoid arthritis using standard psychometric techniques of classical test theory, but not yet in patients with Systemic lupus erythematosus (SLE). The aim of this study was to explore the psychometric properties of the Brief Resilient Coping Scale in patients with SLE using Rasch analysis. METHOD: This study used cross-sectional data. The BRCS was administered to 232 patients with systemic lupus erythematosus. The aspects analyzed were unidimensionality, local independence and differential item functioning (DIF) to construct an interpretative scale of scores with the Rasch model. RESULTS: Rating scale mode (RSM) showed that the four categories used in the items of the BRCS are properly ordered. The four items provided a good fit to the polytomous Rasch model. Moreover, the parameters were sufficiently separated to measure resilience in patients with SLE. BRCS is a unidimensional scale (eigenvalue = 1.843) of resilience and the items were locally independent. There was no DIF between males and females in the sample. Only marginally significant differences depending on the level of education were found. The BRCS showed adequate discriminant validity between groups of scores. CONCLUSIONS: BRCS is a suitable scale for measuring resilience in patients with SLE. This scale might be useful for clinicians to obtain information concerning the degree of resilience that each patient has, allowing individuals with low resilience to be identified who need interventions aimed at developing coping skills.
27539668 Low-grade inflammation as a key mediator of the pathogenesis of osteoarthritis. 2016 Oct Osteoarthritis (OA) has long been viewed as a degenerative disease of cartilage, but accumulating evidence indicates that inflammation has a critical role in its pathogenesis. Furthermore, we now appreciate that OA pathogenesis involves not only breakdown of cartilage, but also remodelling of the underlying bone, formation of ectopic bone, hypertrophy of the joint capsule, and inflammation of the synovial lining. That is, OA is a disorder of the joint as a whole, with inflammation driving many pathologic changes. The inflammation in OA is distinct from that in rheumatoid arthritis and other autoimmune diseases: it is chronic, comparatively low-grade, and mediated primarily by the innate immune system. Current treatments for OA only control the symptoms, and none has been FDA-approved for the prevention or slowing of disease progression. However, increasing insight into the inflammatory underpinnings of OA holds promise for the development of new, disease-modifying therapies. Indeed, several anti-inflammatory therapies have shown promise in animal models of OA. Further work is needed to identify effective inhibitors of the low-grade inflammation in OA, and to determine whether therapies that target this inflammation can prevent or slow the development and progression of the disease.
27486060 Efficacy and safety of point-of-care ultrasound-guided intra-articular corticosteroid join 2017 Jan INTRODUCTION AND OBJECTIVES: Intra-articular corticosteroid injections are standard of care for managing joint pain secondary to osteoarthritis or rheumatoid arthritis but are rarely used in haemophilic arthropathy. We have introduced and evaluated the efficacy and safety of ultrasound-guided corticosteroid injections for pain relief in patients with haemophilic arthropathy. PATIENTS AND METHODS: Ultrasound-guided intra-articular injections performed on haemophilia patients at UCSD between March 2012 and January 2016 were analysed. Needle placement and injection (40 mg triamcinolone; 3-5 mL lidocaine) were performed with musculoskeletal ultrasound and Power Doppler. Analysis included patient demographics, joint-specific parameters such as tissue hypervascularity and effusions, pain relief, and procedure-associated complications. RESULTS: Forty-five injections (14 ankles, 13 elbows, 18 knees) were administered in 25 patients. Advanced arthropathy with hypervascularity and/or effusions was present in 91% and 61% of joints, respectively. Ninety-one per cent of injections resulted in pain relief which was significant in 84% (>30% reduction). Median pain score was reduced from 7 of 10 to 1 of 10 (P < 0.001), usually within 24 h. Median duration of pain relief was 8 weeks (range 1-16 weeks). Haemophilia B patients experienced longer periods of relief, and high Pettersson scores were associated with shorter duration of relief. There were no procedure-associated complications. Repeat ultrasound of eight joints within 4 weeks of injection demonstrated nearly complete resolution of hypervascularity. CONCLUSIONS: Point-of-care ultrasound enabled intra-articular corticosteroid injections that provided highly effective, safe, and relatively long-lasting pain relief in haemophilic arthropathy. This approach should be used to improve pain management in haemophilic arthropathy.
27391060 Inhibition of canonical WNT/β-catenin signaling is involved in leflunomide (LEF)-mediated 2016 Aug 2 Leflunomide (LEF), an inhibitor of dihydroorotate dehydrogenase (DHODH) in pyrimidine biosynthetic pathway, is an immunomodulatory agent approved for the treatment of rheumatoid arthritis. In this study, we show that LEF significantly reduced cell proliferation of renal carcinoma cells in a concentration-dependent manner. LEF at 50 μM induced S-phase arrest and autophagy. Higher doses of LEF (>50 μM) effectively induced cell apoptosis. Modulating the concentration of LEF resulted in distinct effects on the expression of regulatory proteins associated with cell cycle, apoptosis, and autophagy. In particular, high concentrations of LEF inhibited canonical WNT signaling by promoting nucleo-cytoplasmic shuttling and proteasome-dependent degradation of β-catenin. Mechanistic studies showed that the repression of AKT activation partly accounted for LEF-mediated WNT inhibition. Gene expression microarray revealed that LEF treatment greatly inhibited the expression of FZD10 gene, a receptor mediating WNT/β-catenin activation. In vivo xenograft study in NOD/SCID mice further validated the inhibitory effects of LEF on tumor growth and Wnt/β-catenin signaling. However, LEF treatment also triggered cell autophagy and elevated the expression of WNT3a, which ameliorated its cytotoxic effects. The combination of LEF with a WNT inhibitor IWP-2 or autophagy inhibitor HCQ could yield an enhanced anti-tumor outcome. Taken together, these results identify the potential utility and pharmacological feature of LEF in the chemotherapy of renal cell carcinoma (RCC).
27126733 Clinical characteristics of scleroderma overlap syndromes: comparisons with pure scleroder 2016 Sep BACKGROUND: Scleroderma with characteristics of other connective tissue diseases is called scleroderma overlap syndrome (SOV); the clinical features of which have yet to be investigated among Thai patients. OBJECTIVE: To determine the clinical differences between pure scleroderma and SOV. METHODS: A historical cohort study was conducted among patients with pure scleroderma versus those with SOV. Subjects were over 18 years of age and followed up at Srinagarind Hospital, Khon Kaen University, Thailand, between January 2006 and December 2011. RESULTS: Four hundred and three medical records were included (276 female vs. 127 male). SOV was found in 68 cases (16.9%): (i) scleroderma-polymyositis overlap (SOV-PM), the most common type of SOV (48 cases; 70.6%); (ii) scleroderma-systemic lupus erythematosus overlap (11 cases; 16.2%); and (iii) scleroderma-rheumatoid arthritis overlap (nine cases; 13.2%). Mean age at onset of non-systemic sclerosis symptoms was 46.9 ± 11.8 years (range, 19.8-74.3). Characteristically, sufferers of SOV as against pure scleroderma were younger, had less frequent anti-topoisomerase I (ATA) and needed moderate- to high-dose steroid and immunosuppressant therapy during follow-up. SOV-PM presented the clinical features of scleroderma at onset and during follow-up looks like pure scleroderma having vasculopathy, severity of skin tightness, and gastrointestinal, cardiopulmonary and renal involvement. Anti-Ro52 was the most common serology among sufferers of SOV (31.6%). ATA was associated with pure scleroderma patients (P = 0.047). CONCLUSIONS: SOV rather than pure scleroderma presented in younger Thai scleroderma patients and SOV-PM was the most common subtype and its clinical features were similar to those of pure scleroderma. ATA was strongly associated with the latter.
27079996 Are chondrocytes damaged when rheumatologic inflammation is suppressed? 2017 Jan AIM: The use of biological agents (BAs) for treating diseases such as rheumatoid arthritis (RA), spondyloarthropathy, and systemic lupus erythematosus to reduce inflammation has been fruitful. Especially as part of the increasing number of studies on the intra-articular application of BAs, the effects of BAs on cartilage have been widely investigated. In the present study, the effects of rituximab, abatacept, and adalimumab, all approved antirheumatic agents, on human primary chondrocytes were investigated comparatively and on the molecular level through viability, proliferation, and toxicity analyses. MATERIALS AND METHODS: Osteochondral tissues from the distal femur and proximal tibia were resected during total knee arthroplasty from patients (n = 3) with confirmed gonarthrosis in whom all medical or conservative treatments had failed. Standard human primary chondrocyte cell culturing was carried out. Immunophenotyping was performed on the cells that adhered to the flask, and their chondrotoxicity was observed using a flow cytometry device. Images of the cells showing chondrotoxicity were analyzed using invert and environmental scanning microscopes, and microimages were obtained. The MTT-enzyme linked immunosorbent assay was performed to observe the toxic effects of BAs on the proliferation of chondrocytes at 24 and 48 h. The results were analyzed using the number of cells and proliferation; statistical comparisons among the groups were carried out using one-way ANOVA. The alpha significance level was set at <0.01. RESULTS: These pharmaceutical agents were chondrotoxic, especially on viability and proliferation (p = 0.0000). CONCLUSION: BAs are generally used during active inflammation, and following the management of inflammation, their dosage should be determined taking into consideration their cellular-level toxic effects on chondrocytes.
26868380 Systematic Development of Transethosomal Gel System of Piroxicam: Formulation Optimization 2017 Jan 1 Piroxicam is used in the treatment of rheumatoid arthritis, osteoarthritis, and other inflammatory diseases. Upon oral administration, it is reported to cause ulcerative colitis, gastrointestinal irritation, edema and peptic ulcer. Hence, an alternative delivery system has been designed in the form of transethosome. The present study describes the preparation, optimization, characterization, and ex vivo study of piroxicam-loaded transethosomal gel using the central composite design. On the basis of the prescreening study, the concentration of lipids and ethanol was kept in the range of 2-4% w/v and 0-40% v/v, respectively. Formulation was optimized by measuring drug retention in the skin, drug permeation, entrapment efficiency, and vesicle size. Optimized formulation was incorporated in hydrogel and compared with other analogous vesicular (liposomes, ethosomes, and transfersomes) gels for the aforementioned responses. Among the various lipids used, soya phosphatidylcholine (SPL 70) and ethanol in various percentages were found to affect drug retention in the skin, drug permeation, vesicle size, and entrapment efficiency. The optimized batch of transethosome has shown 392.730 μg cm(-2) drug retention in the skin, 44.312 μg cm(-2) h(-1) drug permeation, 68.434% entrapment efficiency, and 655.369 nm vesicle size, respectively. It was observed that the developed transethosomes were found superior in all the responses as compared to other vesicular formulations with improved stability and highest elasticity. Similar observations were noted with its gel formulation.
26722218 uPA Attenuated LPS-induced Inflammatory Osteoclastogenesis through the Plasmin/PAR-1/Ca(2+ 2016 Chronic inflammatory diseases, such as rheumatoid arthritis and periodontitis-caused bone destruction, results from an increase of bone-resorbing osteoclasts (OCs) induced by inflammation. However, the detailed mechanisms underlying this disorder remain unclear. We herein investigated that the effect of urokinase-type plasminogen activator (uPA) on inflammatory osteoclastogenesis induced by lipopolysaccharide (LPS), which is a potent stimulator of bone resorption in inflammatory diseases. We found that the uPA deficiency promoted inflammatory osteoclastogenesis and bone loss induced by LPS. We also showed that LPS induced the expression of uPA, and the uPA treatment attenuated the LPS-induced inflammatory osteoclastogenesis of RAW264.7 mouse monocyte/macrophage lineage cells. Additionally, we showed that the uPA-attenuated inflammatory osteoclastgenesis is associated with the activation of plasmin/protease-activated receptor (PAR)-1 axis by uPA. Moreover, we examined the mechanism underlying the effect of uPA on inflammatory osteoclastogenesis, and found that uPA/plasmin/PAR-1 activated the adenosine monophosphate-activated protein kinase (AMPK) pathway through Ca2+/calmodulin dependent protein kinase kinase (CaMKK) activation, and attenuated inflammatory osteoclastogenesis by inactivation of NF-κB in RAW264.7 cells. These data suggest that uPA attenuated inflammatory osteoclastogenesis through the plasmin/PAR-1/Ca2+/CaMKK/AMPK axis. Our findings may provide a novel therapeutic approach to bone loss caused by inflammatory diseases.
26686385 Development of an Interleukin-1β Vaccine in Patients with Type 2 Diabetes. 2016 May Interleukin-1β (IL-1β) is a key cytokine involved in inflammatory illnesses including rare hereditary diseases and common chronic inflammatory conditions as gout, rheumatoid arthritis, and type 2 diabetes mellitus, suggesting reduction of IL-1β activity as new treatment strategy. The objective of our study was to assess safety, antibody response, and preliminary efficacy of a novel vaccine against IL-1β. The vaccine hIL1bQb consisting of full-length, recombinant IL-1β coupled to virus-like particles was tested in a preclinical and clinical, randomized, placebo-controlled, double-blind study in patients with type 2 diabetes. The preclinical simian study showed prompt induction of IL-1β-specific antibodies upon vaccination, while neutralizing antibodies appeared with delay. In the clinical study with 48 type 2 diabetic patients, neutralizing IL-1β-specific antibody responses were detectable after six injections with doses of 900 µg. The development of neutralizing antibodies was associated with higher number of study drug injections, lower baseline body mass index, improvement of glycemia, and C-reactive protein (CRP). The vaccine hIL1bQb was safe and well-tolerated with no differences regarding adverse events between patients receiving hIL1bQb compared to placebo. This is the first description of a vaccine against IL-1β and represents a new treatment option for IL-1β-dependent diseases such as type 2 diabetes mellitus (ClinicalTrials.gov NCT00924105).
26547232 2-Arylquinazolin-4(3H)-ones: A novel class of thymidine phosphorylase inhibitors. 2015 Dec Thymidine phosphorylase (TP) over expression plays an important role in several pathological conditions, such as rheumatoid arthritis, chronic inflammatory diseases, psoriasis, and tumor angiogenesis. In this regard, a series of twenty-five 2-arylquinazolin-4(3H)-one derivatives 1-25 were evaluated for thymidine phosphorylase inhibitory activity. Six compounds 5, 6, 20, 2, 23, and 3 were found to be active against thymidine phosphorylase enzyme with IC50 values in the range of 42.9-294.6μM. 7-Deazaxanthine (IC50=41.0±1.63μM) was used as a standard inhibitor. Compound 5 showed a significant activity (IC50=42.9±1.0μM), comparable to the standard. The enzyme kinetic studies on the most active compounds 5, 6, and 20 were performed for the determination of their modes of inhibition, and dissociation constants Ki. All active compounds were found to be largely non-cytotoxic against the mouse fibroblast 3T3 cell line. This study identifies a novel class of thymidine phosphorylase inhibitors which may be further investigated as leads to develop therapeutic agents.
26372145 Characterisation of a Novel Anti-CD52 Antibody with Improved Efficacy and Reduced Immunoge 2015 Anti-CD52 therapy has been shown to be effective in the treatment of a number of B cell malignancies, hematopoietic disorders and autoimmune diseases (including rheumatoid arthritis and multiple sclerosis); however the current standard of treatment, the humanized monoclonal antibody alemtuzumab, is associated with the development of anti-drug antibodies in a high proportion of patients. In order to address this problem, we have identified a novel murine anti-CD52 antibody which has been humanized using a process that avoids the inclusion within the variable domains of non-human germline MHC class II binding peptides and known CD4+ T cell epitopes, thus reducing its potential for immunogenicity in the clinic. The resultant humanized antibody, ANT1034, was shown to have superior binding to CD52 expressing cells than alemtuzumab and was more effective at directing both antibody dependent and complement dependent cell cytotoxicity. Furthermore, when in the presence of a cross-linking antibody, ANT1034 was more effective at directly inducing apoptosis than alemtuzumab. ANT1034 also showed superior activity in a SCID mouse/human CD52 tumour xenograft model where a single 1 mg/Kg dose of ANT1034 led to increased mouse survival compared to a 10 mg/Kg dose of alemtuzumab. Finally, ANT1034 was compared to alemtuzumab in in vitro T cell assays in order to evaluate its potential to stimulate proliferation of T cells in peripheral blood mononuclear cells derived from a panel of human donors: whereas alemtuzumab stimulated proliferation in a high proportion of the donor cohort, ANT1034 did not stimulate proliferation in any of the donors. Therefore we have developed a candidate therapeutic humanized antibody, ANT1034, that may have the potential to be more efficacious and less immunogenic than the current standard anti-CD52 therapy.
26239676 N‑trans‑ρ‑caffeoyl tyramine isolated from Tribulus terrestris exerts anti‑inflamm 2015 Oct Inflammation is induced by the expression of cyclooxygenase‑2 (COX‑2), which is an important mediator of chronic inflammatory diseases, such as rheumatoid arthritis, asthma and inflammatory bowel disease. Tribulus terrestris (T. terrestris) is known to have a beneficial effect on inflammatory diseases. In this study, we investigated the effects of N‑trans‑ρ‑caffeoyl tyramine (CT) isolated from T. terrestris on the production of nitric oxide (NO), and the expression of pro‑inflammatory cytokines and COX‑2 in lipopolysaccharide (LPS)‑stimulated RAW 264.7 cells. We also aimed to elucidate the molecular mechanisms involved. We found that the ethanolic extract of T. terrestris (EETT) and CT inhibited the production of NO, tumor necrosis factor‑α (TNF‑α), interleukin (IL)‑6 and IL‑10 in the LPS‑stimulated RAW 264.7 cells in a dose‑dependent manner. They were determined by reverse transcription-polymerase chain reaction (RT-PCR) and enzyme-linked immunosorbent assay (ELISA). In addition, CT markedly suppressed the expression of COX‑2 and the production of prostaglandin E2 (PGE2) in response to LPS stimulation. Furthermore, CT markedly decreased p‑c‑Jun N‑terminal kinase (p‑JNK) protein expression in LPS‑stimulated RAW 264.7 cells. COX-2 and p-JNK were measured by western blot analysis. Taken together, these findings indicate that CT isolated from T. terrestris is a novel and potent modulator of inflammatory responses. Thus, it may prove benefiical to further evaluate CT as a possible treatment for chronic inflammatory diseases.
26082376 Expression of PADI4 in patients with ankylosing spondylitis and its role in mediating the 2015 Aug Peptidyl arginine deiminase, type IV (PADI4) plays an important role in inflammation and in the immune response, and it has been shown to be associated with rheumatoid arthritis, osteoarthritis and ankylosing spondylitis (AS). However, little is known about the precise role of PADI4 in the pathogenic process in vitro. In this study, we aimed to investigate the expression of PADI4 in the synovial tissue of patients with AS and to determine the potential effects of PADI4 on human mesenchymal stem cell (hMSC) proliferation and osteogenic differentiation under normal and pathological conditions. Synovial tissues were collected from 18 patients with AS and 11 control subjects. The results of reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and western blot analysis revealed that the expression of PADI4 was upregulated in the patients with AS. In the hMSCs, the protein expression of PADI4 was increased following treatment with tumor necrosis factor-α (TNF-α) in a dose- and time-dependent manner. MTT assay revealed that TNF-α promoted hMSC proliferation. In addition, we found that TNF-α promoted the osteogenic differentiation of hMSCs, as demonstrated by an increase in alkaline phosphatase (ALP) activity, as well as an increase in the expression of bone morphogenetic protein 2 (BMP-2), runt-related transcription factor 2 (Runx2) and Osterix. The hMSCs were transfected with PADI4 siRNA to silence PADI4 expression. We found that, under normal conditions, the silencing of PADI4 did not have any effect on hMSC proliferation or osteogenic differentiation. However, in the presence of TNF-α, hMSC proliferation and osteogenic differentiation were induced. These effects were attenuated by the silencing of PADI4. In conclusion, the findings of this study demonstrate that the expression of PADI4 differs between patients with AS and normal subjects. In addition, our data suggest that PADI4 plays a role in hMSC proliferation and differentiation, which are induced by TNF-α.
25879741 Unraveling the Hygiene Hypothesis of helminthes and autoimmunity: origins, pathophysiology 2015 Apr 13 BACKGROUND: The Hygiene Hypothesis (HH) attributes the dramatic increase in autoimmune and allergic diseases observed in recent decades in Western countries to the reduced exposure to diverse immunoregulatory infectious agents. This theory has since largely been supported by strong epidemiological and experimental evidence. DISCUSSION: The analysis of these data along with the evolution of the Western world's microbiome enable us to obtain greater insight into microorganisms involved in the HH, as well as their regulatory mechanisms on the immune system. Helminthes and their derivatives were shown to have a protective role. Helminthes' broad immunomodulatory properties have already begun to be exploited in clinical trials of autoimmune diseases, including inflammatory bowel disease, multiple sclerosis, rheumatoid arthritis, and type-1 diabetes. SUMMARY: In this review, we will dissect the microbial actors thought to be involved in the HH as well as their immunomodulatory mechanisms as emphasized by experimental studies, with a particular attention on parasites. Thereafter, we will review the early clinical trials using helminthes' derivatives focusing on autoimmune diseases.
25775659 Think beyond the Skin: 2014 Canadian Expert Opinion Paper on Treating to Target in Plaque 2015 Jan OBJECTIVE: Explore the feasibility of Treat to Target in the area of psoriasis as seen in other therapeutic areas such as hypertension, hyperlipidemia, diabetes and rheumatoid arthritis. METHODS: Review validated, measurable targets for psoriasis, including physician global assessment (PGA), psoriasis area and severity index (PASI) and dermatology life quality index (DLQI). Examine principles brought forth in the published European consensus on psoriasis and develop a Canadian consensus on Treat to Target in psoriasis. RESULTS: As PASI and DLQI are not routinely used in the community setting, we are recommending target at a PGA of zero (clear). CONCLUSION: Recommend that the target is a PGA of zero (clear) as it provides a simple and measurable result that the patient and physician can clearly understand.
25764919 [Etiologies and clinical features of 19 cases with bilateral acute sensorineural hearing l 2015 Jan OBJECTIVE: To investigate the etiologies and clinical features for bilateral acute sensorineural hearing loss (bi-ASNHL). METHODS: The clinical data of 19 cases presenting with bi-ASNHL were retrospectively analyzed, including the clinical features, systemic examinations, laboratory examinations, audiology and radiology results, as well as the prognosis. RESULTS: There were 15 non-otologic diseases in 19 patients, accounting for 78.9% of the total cases, most of which were disorders with multisystem and multi-organ disorder. The central nervous system diseases including fungal meningitis, tuberculous meningitis, and viral encephalitis in 3 patients. The clinical features of deafness were bilateral, progressive, accompanied with fever, headache, dizziness, nausea, vomiting and change of mental status. There was a decrease in speech recognition score (SRS), and speech recognition threshold (SRT) was obviously inferior to pure tone average (PTA) disproportionally. Diseases of immune system including antineural cytoplasmic antibody (ANCA)-associated systemic vasculitis (AASV), relapsing polychondritis (RP), rheumatoid arthritis (RA), and systemic lupus erythematosus (SLE) in 5 patients. They showed the characteristics of bilateral, progressive and simultaneous autoimmune disease. Hematological and endocrine system diseases including diabetes mellitus, leukemia, and thyroid hypofunction in 5 patients. The deafness had the characteristics of symmetry and progressivity. Otologic diseases including large vestibular aqueduct syndrome (LVAS) and sudden sensorineural hearing loss (SSNHL) in 4 patients; Drug-induced sensorineural deafness happened in 2 patients. After the treatment aimed at the causes, 1 case was cured, 3 patients were markedly effective, 7 patients were effective, and 8 patients were ineffective(including dead and refusal cases), with a total effective rate of 57.9%. CONCLUSIONS: The most of bi-ASNHL cases are often associated with systemic diseases. Clinicians should analyze the history and clinical characteristics in detail, and complete specific laboratory examinations, audiology and imaging examinations in order to reveal the causative diseases. It should be treated aimed at the etiology.