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ID PMID Title PublicationDate abstract
25708600 Inhibitory effects of niclosamide on inflammation and migration of fibroblast-like synovio 2015 Apr OBJECTIVES: This study evaluated the anti-inflammatory effect of niclosamide in tumor necrosis factor (TNF)-α-stimulated human rheumatoid arthritis (RA) fibroblast-like synoviocytes (FLS) and inhibitory effects on migration and invasion in RA FLS and investigated the signal mechanism, and further explored the treatment activity of niclosamide on collagen-induced arthritis (CIA). METHODS: The levels of interleukin (IL)-1β, IL-6, IL-8, IL-10,IL-17A and interferon (IFN)-γ in cultural supernatants were measured by multiplex cytokine assay kits. RA FLS migration and invasion in vitro were measured by the Boyden chamber method and the scratch assay. Signal transduction proteins expression was measured by western blot. The in vivo suppressive effects of niclosamide were elucidated on CIA in a mouse model. RESULTS: Niclosamide reduced the secretion of IL-1β, IL-6, IL-8, IL-17A and IFN-γ from TNF-α-induced RA FLS in a dose-dependent manner. Niclosamide inhibits FBS-induced migration and invasion and exhibits F-actin alterations in RA FLS. Niclosamide decreased the phosphorylation of c-Jun N-terminal kinase and ERK in TNF-α-stimulated RA FLS and blocked TNF-α-induced IKK, IκBα phosphorylation and translocation of p65. Niclosamide treatments reduced the severity of CIA model. CONCLUSIONS: Our data suggest for the first time that niclosamide posses the anti-inflammatory effect in RA both in vitro and in vivo.
26899523 A Clinical Study Evaluating the Effects of Fluvastatin on Serum Osteoprotegerin Levels in 2016 Oct Osteoprotegerin (OPG), a member of the tumor necrosis factor receptor family, has been identified as a critical regulator of bone resorption. Considering the possible role of OPG in rheumatoid arthritis (RA) and in the osteoclastogenesis suppression effects of statins, the present study aims to investigate the effects of fluvastatin on serum levels OPG and disease activity score (DAS) in patients with RA. Forty patients with RA were randomized in a placebo-controlled trial to receive 40 mg fluvastatin or placebo as an adjunct to existing disease-modifying antirheumatic drug (DMARD) therapy (methotrexate, leflunomide, hydroxychloroquine). Patients were followed up over 12 weeks. OPG and disease activity variables were measured at baseline and after 12 weeks of treatment. After 12 weeks, the OPG level was significantly increased in the fluvastatin group compared to the placebo group. DAS-28 was significantly decreased in the fluvastatin group compared to the placebo group. C-reactive protein (CRP), morning stiffness, swollen joint count (SJC), and tender joint count (TJC) were significantly decreased in the fluvastatin group compared to the placebo group; however, erythrocyte sedimentation rate (ESR), modified health assessment questionnaire (MHAQ), and visual analogue screen (VAS) were not changed significantly. In conclusion, fluvastatin administration could increase the OPG levels and improve disease activity variables in patients with RA. Therefore, fluvastatin may serve a potential benefit in the treatment of RA patients.
25856220 Effects of Probiotic Supplementation on Oxidative Stress Indices in Women with Rheumatoid 2016 May OBJECTIVE: Rheumatoid arthritis (RA) is an autoimmune inflammatory disease that causes great pain and disability and increasing oxidative stress in patients. The objective of the present study was to evaluate the effects of probiotics-live microorganisms with many health benefits, including antioxidant properties-on oxidative stress indices of patients with RA. This study is a secondary analysis from a previously published study Methods: In a randomized double-blind placebo-controlled clinical trial, 46 patients with RA were assigned to one of two groups; patients in the probiotic group received a daily capsule containing 10(8) colony forming units (CFUs) of Lactobacillus casei 01 (L. casei 01), while those in the placebo group took identical capsules containing maltodextrin, for 8 weeks. In the baseline and at the end of the study, anxiety, physical activity levels, and dietary intakes were assessed. Anthropometric parameters, serum malondialdehyde (MDA), total antioxidant capacity (TAC), erythrocyte superoxide dismutase (SOD), glutathione peroxidase (GPx), and catalase (CAT) activities were measured. RESULTS: There was no significant difference between the two groups for demographic characteristics, anthropometric parameters, physical activity, anxiety levels, or dietary intakes, throughout the course of the study. No significant within- and between-group differences were observed for MDA, TAC, or CAT. SOD activity decreased only in the probiotic group and GPx activity decreased in both study groups (p < 0.05); however, no significant between-group difference was found for these enzymes activities at the end of the study (p > 0.05). CONCLUSION: No significant effect of L. casei 01 supplementation was observed on the oxidative status of patients with RA, compared to placebo.
25818785 [Value of dual-energy computed tomography in the diagnosis of gouty arthritis]. 2015 Mar OBJECTIVE: To investigate the value of dual-energy computed tomography (DECT) in the diagnosis of gouty arthritis. METHODS: Sixty-one patients with gout, 30 with ankylosing spondylitis and 30 with rheumatoid arthritis were included in the study. DECT scans of the hands, wrists, elbows, feet, ankles, knees, lumbar, pelvis and sacroiliac joint were performed. For post-processing, a color-coding gout software protocol was used. The demographic data and blood uric acid levels were recorded. For 3 gout patients, the findings of puncture biopsy and DECT were compared. Ten gout patients with urate crystal deposition upon recruitment underwent DECT scans again after a 6-month urate-lowering therapy. RESULTS: The positivity rates of DECT scan differed significantly among the patients with gout, ankylosing spondylitis and rheumatoid arthritis [98.4% (60/61), 13.3% (4/30), and 6.7% (2/30), respectively; χ² =95.522, P<0.05). Of the 21 patients with acute gouty arthritis, 20 (95.2%) showed positive DECT finding, and all the 40 patients with chronic gouty arthritis showed positive findings. In the patients with patients with gout, ankylosing spondylitis and rheumatoid arthritis, the positivity rates of hyperuricemia were 97.3% (36/37), 44.4% (4/9), and 28.6% (2/7), respectively (χ² =24.197, P<0.05). A total of 344 urate deposition sites were detected in the gout patients, involving most commonly the first metatarsophalangeal joint (22.1%), the middle and distal end of the first phalanges of the toes (19.8%), the calcaneus (17.4%), and the inferior extremity of the tibia (13.4%). Seventeen and 5 urate deposition sites were found in ankylosing spondylitis patients and rheumatoid arthritis patients, respecitvely. The 10 gout patients receiving a 6-month urate-lowering therapy showed decreased urate deposition on DECT scan. CONCLUSIONS: DECT scan can detect urate deposition to allow differentiation diagnosis and follow-up in gout patients.
26212057 Rheumatoid Arthritis, Immunosenescence and the Hallmarks of Aging. 2015 Age is the most important risk factor for the development of infectious diseases, cancer and chronic inflammatory diseases including rheumatoid arthritis (RA). The very act of living causes damage to cells. A network of molecular, cellular and physiological maintenance and repair systems creates a buffering capacity against these damages. Aging leads to progressive shrinkage of the buffering capacity and increases vulnerability. In order to better understand the complex mammalian aging processes, nine hallmarks of aging and their interrelatedness were recently put forward. RA is a chronic autoimmune disease affecting the joints. Although RA may develop at a young age, the incidence of RA increases with age. It has been suggested that RA may develop as a consequence of premature aging (immunosenescence) of the immune system. Alternatively, premature aging may be the consequence of the inflammatory state in RA. In an effort to answer this chicken and egg conundrum, we here outline and discuss the nine hallmarks of aging, their contribution to the pre-aged phenotype and the effects of treatment on the reversibility of immunosenescence in RA.
25782531 Eight-year preservation of knee function with radiographic healing phenomena after anti-tu 2015 Jan A 23-year-old woman developed rheumatoid arthritis (RA). The pain in her right knee was aggravated and anti-tumor necrosis factor (TNF)-α therapy was selected at the age of 35. The range of motion and Larsen grade were 5º to 120º and 4, respectively. Infliximab and etanercept therapies were quite effective and the pain of the right knee improved. An X-ray at 1 year showed radiographic healing phenomena that included reappearance of a clear visible cortical plane, partial filling-in of erosions and cysts, and sclerosis of the subchondral bone. An X-ray at the age of 43 showed that the radiographic healing phenomena were still preserved after 7 years. The right knee remained pain-free although the Larsen grade was still 4, and the knee function was preserved for 8 years. In conclusion, anti-TNF-α therapy may preserve knee function with radiographic healing phenomena and prevent total arthroplasty of severely erosive knees in young RA patients.
27510283 Spatiotemporal expression of endogenous TLR4 ligands leads to inflammation and bone erosio 2016 Nov Increased expression of endogenous Toll-like receptor 4 (TLR4) ligands (e.g., Tenascin-C, S100A8/A9, citrullinated fibrinogen (cFb) immune complexes) has been observed in patients with rheumatoid arthritis (RA). However, their roles in RA pathogenesis are not well understood. Here, we investigated the expression kinetics and role of endogenous TLR4 ligands in the murine model of collagen-induced arthritis (CIA). Tenascin-C was upregulated in blood early in CIA, and correlated positively with the clinical score at day 56. Levels of S100A8/A9 increased starting from day 28, peaking at day 42, and correlated positively with joint inflammation. Levels of anti-cFb antibodies increased during the late phase of CIA and correlated positively with both joint inflammation and cartilage damage. Blockade of TLR4 activation at the time of the first TLR4 ligand upregulation prevented clinical and histological signs of arthritis. A TLR4-dependent role was also observed for Tenascin-C and cFb immune complexes in osteoclast differentiation in vitro. Taken together, our data suggests that the pathogenic contribution of TLR4 in promoting joint inflammation and bone erosion during CIA occurs via various TLR4 ligands arising at different stages of disease. The data also suggests that Blockade of TLR4 with monoclonal antibodies is a promising strategy in RA treatment.
26238672 Certolizumab Pegol Efficacy Across Methotrexate Regimens: A Pre-Specified Analysis of Two 2016 Mar OBJECTIVE: Anti-tumor necrosis factor (anti-TNF) agents are frequently used in combination with methotrexate (MTX) to treat rheumatoid arthritis (RA). We investigated the effect of a background MTX dose, in combination with anti-TNF certolizumab pegol (CZP), on treatment efficacy and safety in RA patients. METHODS: A pre-specified subgroup analysis comparing 2 MTX dosage categories (<15 mg/week and ≥15 mg/week) was carried out using data pooled from phase III clinical trials, Rheumatoid Arthritis Prevention of Structural Damage 1 (RAPID 1) and RAPID 2, according to treatment group: CZP 200 mg, CZP 400 mg, or placebo, every 2 weeks. Inclusion criteria required MTX dosage ≥10 mg/week. Efficacy end points included week 24 American College of Rheumatology criteria for 20%, 50%, and 70% improvement (ACR20/50/70) responses analyzed by logistic regression, and changes from baseline in the Disease Activity Score in 28 joints using the erythrocyte sedimentation rate (DAS28-ESR) and the modified Sharp/van der Heijde score (SHS) were analyzed by analysis of covariance. Incidence rates of treatment-emergent adverse events (TEAEs) were categorized by baseline MTX dose. Post hoc sensitivity analysis investigated 3 MTX dose categories: ≤10 mg/week, >10 and ≤15 mg/week, and >15 mg/week. RESULTS: A total of 638, 635, and 325 patients received CZP 200 mg, CZP 400 mg, and placebo, respectively. At week 24, treatment responses in both CZP groups were uninfluenced by baseline MTX dose category, and were superior to the placebo group for all investigated end points: ACR20/50/70, DAS28-ESR, and SHS. TEAE incidence rates were higher in patients receiving MTX ≥15 mg/week for most TEAE types across treatment groups. CONCLUSION: CZP efficacy was not affected by background MTX dose category. It can be hypothesized that to minimize TEAEs, background MTX doses could be tailored to individual patient tolerance without affecting CZP efficacy.
25698669 A novel therapeutic approach targeting rheumatoid arthritis by combined administration of 2015 Mar 25 The present study was designed to assess the combined efficacy of morin, a dietary flavanol and non-steroidal anti-inflammatory drug indomethacin against adjuvant-induced arthritis in rats, an experimental model for rheumatoid arthritis. Arthritis was induced by intradermal injection of complete freund's adjuvant (0.1 ml) into the right hind paw of the Wistar albino rats. Morin (30 mg/kg b.wt), indomethacin (3 mg/kg b.wt) and combination of morin and indomethacin were administered intraperitoneally (from 11th to 20th day) after adjuvant injection. We have found that the activities/levels of lysosomal acid hydrolases (acid phosphatase, β-galactosidase, N-acetyl glucosaminidase and cathepsin-D), glycoproteins (hexose and hexosamine), urinary constituents (hydroxyproline and glycosaminoglycans), reactive oxygen species (LPO and NO), elastase, inflammatory mediators (TNF-α, IL-1β, MCP-1, VEGF and PGE2) and paw edema were significantly increased in arthritic rats compared to controls. Whereas, the anti-oxidant status (SOD, CAT, GPx, glutathione, and ceruloplasmin), body weight and bone collagen was found to be decreased. The mRNA expression of pro-inflammatory cytokines (TNF-α, IL-1β, IL-17, IL-6 and MCP-1), inflammatory enzymes (iNOS and COX-2), RANKL, and transcription factors (NF-kB p65 and AP-1) was found upregulated in the ankle joints of arthritic rats in qRT-PCR analysis. In addition, the increased protein expression of NF-kB p65 and COX-2 was also detected by immunohistochemical analysis. On the other hand, the above said imbalances were regulated back effectively to near normal as evidenced by the histopathological and radiological analysis on combined treatment with morin and indomethacin. Our study indicates that the combination therapy was more effective than either single drug alone in suppressing the pathogenesis of RA.
27117620 [Mechanism of bone destruction in rheumatoid arthritis and perspectives of the treatment]. 2016 May Rheumatoid arthritis (RA) is an autoimmune diseases characterized by inflammation and destruction of bone and cartilage. Osteoclastogenesis induced by inflammatory cytokines contributes to focal and systemic bone and cartilage destruction including secondary osteoporosis. Recent progress in treatment enables us to prevent disease activity. Not only anti-inflammatory management but also therapies directly targeting bone metabolism can further prevent bone destruction in RA.
27661002 Evaluating radiocarpal cartilage matrix changes 3-months after anti-TNF treatment for rheu 2017 May PURPOSE: To evaluate the feasibility of MR T1ρ in assessing radiocarpal cartilage matrix changes following rheumatoid arthritis (RA) treatment. MATERIALS AND METHODS: Five healthy controls and nine RA patients were studied: three RA patients with low disease activity that were treated with methotrexate (MTX) alone and six with active disease despite MTX treatment who were additionally treated with certolizumab pegol, an anti-tumor necrosis factor biologic. Wrist 3 Tesla MRI were acquired at baseline and 3-month follow-up. T1ρ were quantified for lunar, radius, and scaphoid cartilage. Reproducibility was evaluated using coefficients of variation (CV). Longitudinal changes were evaluated with t-test and relationships between T1ρ with clinical, MRI, and patient-reported outcomes were evaluated with Spearman's rho. RESULTS: Scan/re-scan CVs of T1ρ values were all <5%, and intra- and inter-reader CVs were all < 2.0%. Baseline scaphoid T1ρ values were significantly higher in RA patients compared with healthy controls (P = 0.032). Changes in T1ρ (baseline, 3-month) were correlated with EULAR treatment response criteria: -2.26 ± 0.75 ms, 1.08 ± 0.52 ms, and 2.18 ± 0.45 ms for good, moderate, and nonresponders, respectively. Significant correlations were found between changes in global T1ρ values and changes in DAS28-CRP (r(s)  = 0.683; P = 0.042), MHQ (r(s)  = -0.783; P = 0.013), and HAQ (r(s)  = 0.833; P = 0.010). CONCLUSION: Despite the limited sample size and follow-up time points, there were significant correlations between changes in radiocarpal T1ρ and changes in disease activity as assessed by clinical and patient-reported outcomes. Our findings encourage further research into MR T1ρ assessment of RA disease activity and treatment response. LEVEL OF EVIDENCE: 1 J. MAGN. RESON. IMAGING 2017;45:1514-1522.
26970909 Sustainability of Forefoot Reconstruction for the Rheumatoid Foot. 2016 May Ninety percent of patients with rheumatoid arthritis will display foot and ankle pathologic features, including hallux valgus, lesser metatarsophalangeal (MTP) joint subluxation/dislocation, and hammertoe deformity. Recently, a trend has ensued toward joint preservation with distal metatarsal osteotomies and various bunion corrective procedures. However, the reference standard remains first MTP joint fusion, lesser metatarsal head resection, and lesser proximal interphalangeal joint fusion. The present retrospective study followed the results of 4 different surgeons who had performed the reference standard rheumatoid forefoot reconstruction from August 2008 to August 2012 on patients with rheumatoid arthritis. Radiographic and statistical analysis of the data from 20 patients determined an overall first MTP joint fusion rate of 90%, often occurring by 108 (range 64 to 202) days postoperatively. Radiographic nonunion occurred in 2 of the 20 patients (10%), although both were asymptomatic, with no revision necessary. Lesser digit deformity revision occurred in 1 patient (5%), and mild to moderate infection developed in 4 patients (20%). The radiographic and clinical follow-up period was 12 months. Our study found that this technique provides exceptional radiographic improvement, an acceptable time to fusion, a low reoperation rate, and minimal complications. In addition, correction of the deformity was maintained at 1 year postoperatively. In conclusion, first MTP joint fusion with lesser metatarsal head resection should remain the reference standard for surgical intervention of the rheumatoid foot.
27509672 [On the borders of the neurology and the rheumatology]. 2015 Apr The links between the rheumatology and the neurology, are ancient and established of one intricacy of pathologies and symptoms. It is not a question here of approaching the inflammatory myositis nor the neurological, essentially central signs, during the inflammatory diseases still called systematic as the lupus or the syndrome of Gougerot-Sjögren, neither compression occurring during rheumatoid arthritis and ankylosing spondylarthritis. It is not either a question of reviewing the compression of osseous origin, as for example the narrow cervical spine, the narrow lumbar spine or the basilaire impression during the bony disease of Paget. Some neurological pathologies can put off the track or mislead the clinician towards symptoms which could impose it for radiculopathy origin occurring in rheumatic conditions In the second place, there are untidy or underestimated neuropathies which deserve a particular attention.
26692459 Determining the acceptable level of physician compliance with a treat-to-target strategy i 2017 May OBJECTIVE: To determine the minimum cut-points for rate of physician compliance with a treat-to-target (T2T) strategy needed to achieve optimal rates of remission or low disease activity (LDA). METHOD: In this analysis of longitudinal observational data from patients with early RA, physician compliance with a T2T treatment protocol was determined for each clinic visit over 3 years. Remission and LDA were measured by Disease Activity Score in 28 joints (DAS28), simplified disease activity index (SDAI) and clinical disease activity index (CDAI). The minimum physician compliance rates for predicting these outcomes were calculated using receiver operating characteristic (ROC) curves. RESULT: Overall, 149 patients completed 3078 clinic visits over 3 years of follow-up. Treatment decisions complied with the T2T protocol in 2343 of these visits (76.1%). The minimum cut-points for physician compliance rates that predicted remission and LDA according to DAS28 were 81.1% and 70.7%, respectively, and to predict remission and LDA according to SDAI, the respective cut-points were 92.7% and 77.4%. Based on these cut-points, three categories of physician compliance with T2T were proposed: high (to maximize the likelihood of achieving remission, > 80% according to DAS28 or > 90% according to SDAI/CDAI); medium (the minimal physician compliance to achieve LDA, 70-79% according to DAS28 or 75-89% for SDAI/CDAI); and low (< 70% for DAS28 and < 75% for SDAI/CDAI), where remission and LDA are unlikely). When patients were stratified by baseline disease activity, the physician compliance rate cut-points were similar for most outcomes at year 3. CONCLUSION: Using real-life clinical data, we determined the thresholds for physician compliance with a T2T strategy that stratified patients according to their disease outcomes and proposed a system for classifying physician compliance as high, medium and low.
25579963 Sugarcane bagasse lignin, and silica gel and magneto-silica as drug vehicles for developme 2015 Mar The present study clarifies co-therapy action of deliveries from their textural changes point of view. Methotrexate (MTX) was immobilized onto biodegradable lignin, silica gel and iron/silica nanocomposite. Loaded-MTX was i.p. injected into albino rats at doses of 0.25 and 0.5mg/kg/week for 2.5months, after which spleen, liver, testes and knee joint tissues were collected for tests. IFN-γ and IL-17A mRNA gene expressions in spleen in all biological samples were determined by RT-PCR. Physicochemical features of drug carriers were monitored by XRD, BET-PSD, SEM and TEM. Drug inflammatory-site targeting was found to be closely related to the physico-features of deliverers. The interlayered lignin of micro- and meso-pore channels directed MTX toward concealed infected cells in liver and testes tissues, while meso-structured silica flacks satisfied by gathering MTX around knee joints. The magneto-silica nanocomposite targeted MTX toward spleen tissue, which is considered as a lively factory for the production of electron rich compounds.
27581208 Best cost-effectiveness and worker productivity with initial triple DMARD therapy compared 2016 Dec OBJECTIVE: To evaluate direct and indirect costs per quality adjusted life year (QALY) for different initial treatment strategies in very early RA. METHODS: The 1-year data of the treatment in the Rotterdam Early Arthritis Cohort trial were used. Patients with a high probability (>70%) according to their likelihood of progressing to persistent arthritis, based on the prediction model of Visser, were randomized into one of following initial treatment strategies: (A) initial triple DMARD therapy (iTDT) with glucocorticoids (GCs) intramuscular (n = 91); (B) iTDT with an oral GC tapering scheme (n = 93); and (C) initial MTX monotherapy (iMM) with GCs similar to B (n = 97). Data on QALYs, measured with the Dutch EuroQol, and direct and indirect cost were used. Direct costs are costs of treatment and medical consumption, whereas indirect costs are costs due to loss of productivity. RESULTS: Average QALYs (sd) for A, B and C were, respectively, 0.75 (0.12), 0.75 (0.10) and 0.73 (0.13) for Dutch EuroQol. Highest total costs per QALY (sd) were, respectively, €12748 (€18767), €10 380 (€15 608) and €17 408 (€21 828) for strategy A, B and C (P = 0.012, B vs C). Direct as well as indirect costs were higher with iMM (strategy C) compared with iTDT (strategy B). Higher direct costs were due to ∼40% more biologic usage over time. Higher indirect costs, on the other hand, were caused by more long-term sickness and reduction in contract hours. iTDT was >95% cost-effective across all willingness-to-pay thresholds compared with iMM. CONCLUSION: iTDT was more cost-effective and had better worker productivity compared with iMM.
25972390 The influence of behavioural and psychological factors on medication adherence over time i 2015 Oct OBJECTIVES: To investigate levels of self-reported adherence to biologic treatment and establish the contribution of demographic, physical and psychological factors to biologic medication adherence in an RA cohort. METHODS: Adalimumab-treated patients were recruited through the British Society for Rheumatology Biologics Register for RA between May 2007 and April 2009. Demographic and baseline psychological measures including illness and medication beliefs were collected. Disease activity (28-item DAS), physical function (HAQ) and quality of life (36-item Short Form Health Survey) were also measured at baseline and at 6, 12 and 18 months. Adherence was assessed at each follow-up using the patient self-completed Compliance Questionnaire for Rheumatology (CQR). Multilevel mixed effects modelling analysis was performed to investigate predictors of adherence. RESULTS: Of the 329 Adalimumab-treated patients included, low adherence (CQR score <65) was reported in 23%, with 41% reporting low adherence at at least one time point. After controlling for age and disease duration, factors independently predictive of increased adherence were increased belief in medication necessity, with baseline effect diminishing over time [β coefficient 1.68 (s.e. 0.19), P = 0.0001], lower medication concerns [0.50 (0.15), P = 0.001], with this effect remaining throughout follow-up, increased professional or family member support [0.81 (0.32), P = 0.01], strong views of illness being chronic [0.32 (0.14), P = 0.025] and increased treatment control [0.41 (0.19), P = 0.032]. CONCLUSION: Wider recognition of the importance of psychological factors, particularly medication beliefs, in driving medication adherence could have substantial clinical and health economic benefits in RA. The psychological factors we have identified are putative targets for strategies to improve adherence in RA.
28038947 pH-sensitive polymeric micelles for targeted delivery to inflamed joints. 2017 Jan 28 Effective treatment for rheumatoid arthritis is hindered by the lack of drugs that selectively target inflamed joints. Liposomes, nanoparticles and conventional micelles loaded with limited amounts of drugs may be unstable in the circulation and result in uncontrolled drug release kinetics. Here we developed a new drug delivery system of pH-sensitive polymeric micelles based on an acid-labile hydrazone bond. Amphiphilic conjugates of a PEG-based derivative and the hydrophobic drug prednisolone (PD) self-assembled into PD micelles with a drug loading of 19.29%. When the micelles reached the acidic environment of synovial fluid, the hydrazone bonds hydrolyzed, releasing free PD. Intravenous injection of PD micelles into mice with collagen-induced arthritis led to PD accumulation in affected joint tissues. PD concentrations in plasma and joints of arthritic mice were significantly higher after injection with PD micelles than after injection with free PD. The enhancement effect in joints was 4.63-fold based on the area under the concentration-time curve and 2.50-fold based on the maximum concentration (C(max)). In vivo pharmacodynamics experiments showed PD micelles to have better anti-inflammatory and disease-modifying effects than free PD. Our results indicate the promise of PD micelles for targeted drug delivery in inflammatory disease.
25303734 Transcription factor snail regulates tumor necrosis factor α-mediated synovial fibroblast 2015 Jan OBJECTIVE: The transcription factor Snail is involved in various biologic functions. We hypothesized that this molecule regulates tumor necrosis factor α (TNFα)-mediated synovial fibroblast activation in the rheumatoid joint. The aim of this study was to examine the role of Snail in the expression of cadherin-11 (Cad-11) and myofibroblast markers, interleukin-6 (IL-6) production, and the invasive ability of cells. METHODS: Synovium samples were obtained from patients with rheumatoid arthritis (RA) and from rats with collagen-induced arthritis (CIA). Synovial fibroblasts were treated with TNFα or a Wnt signaling inducer, and the joints of rats with CIA were injected with a TNFα antagonist. Modulation of Snail expression in the synovial fibroblasts and joints was performed by lentiviral vector-mediated transfer of complementary DNA or short hairpin RNA. RESULTS: The expression of Snail and Cad-11 was higher in synovium and synovial fibroblasts from patients with RA compared with patients with osteoarthritis and was increased in rats with CIA. TNFα stimulation or activation of Wnt signaling up-regulated the expression of Snail, Cad-11, and α-smooth muscle actin (α-SMA) in synovial fibroblasts, and anti-TNFα therapy down-regulated the expression of Snail, Cad-11, and α-SMA in the joints of rats with CIA. Although synovial fibroblast transfectants in which Snail was overexpressed showed increased expression of Cad-11 and α-SMA and enhanced TNFα-mediated invasive capacity and IL-6 production, synovial fibroblast transfectants from rats with CIA in which Snail was silenced showed decreased expression and had the opposite effect on these functions. Normal joints in which Snail was overexpressed had hyperplastic synovium, with increased expression of Cad-11, α-SMA, and IL-6. Silencing Snail expression ameliorated arthritis, with reduced Cad-11 expression and reduced levels of extracellular matrix deposition in the joints of rats with CIA, whereas overexpression of Snail exacerbated arthritis, with increased Cad-11 expression and increased levels of extracellular matrix deposition. CONCLUSION: Our results demonstrate that Snail regulates TNFα-mediated activation of synovial fibroblasts in the rheumatoid joint. These findings may contribute to the pharmacologic development of therapeutics targeting synovial fibroblasts in patients with RA.
25193808 Greyscale and power Doppler ultrasonographic evaluation of normal synovial joints: correla 2015 Mar OBJECTIVE: US is a promising tool in evaluating RA synovitis, but abnormal US findings have been reported in small subsets of normal joints in healthy subjects. This study aimed to systematically assess greyscale US (GSUS) and power Doppler US (PDUS) findings in 40 peripheral joints-the 28-joint DAS (DAS28) set, ankles and MTP joints-in healthy subjects. A composite score of abnormal US findings in 40 joints was compared with serum levels of pro-inflammatory cytokines. METHODS: US of 60 standard views in 40 joints was performed in 30 healthy subjects (total 3600 images). GSUS and PDUS were scored semi-quantitatively (0-3). Serum samples were obtained at the time of US and analysed for IL-1α, IL-1β, IL-2, IL-6, IL-8, VEGF, TNF-α and IFN-γ using biochip array technology. RESULTS: GSUS abnormalities were more frequent than PDUS abnormalities [mean total GSUS score = 20.07 (range 6-45; maximum potential score = 180), mean total PDUS score = 4.8 (range 0-13)]. GSUS score increased with increasing age (Spearman's ρ = 0.383, P = 0.037). A PDUS signal >1 was observed only in the wrist (8%) and MTP1 (3%). GSUS scores did not correlate with any pro-inflammatory cytokine level. The total PDUS score correlated significantly with serum VEGF (r = 0.395, P = 0.046). CONCLUSION: PDUS signals >1 are rarely seen in normal synovial joints. GSUS synovitis, but not PDUS, may reflect age-related joint changes. PDUS correlated with VEGF, providing further evidence of a central role for VEGF in synovial neo-angiogenesis.