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ID PMID Title PublicationDate abstract
25371442 Myeloid-derived suppressor cells have a proinflammatory role in the pathogenesis of autoim 2016 Jan OBJECTIVES: Although myeloid-derived suppressor cells (MDSCs) have been linked to T cell tolerance, their role in autoimmune rheumatoid arthritis (RA) remains elusive. Here we investigate the potential association of MDSCs with the disease pathogenesis using a preclinical model of RA and specimen collected from patients with RA. METHODS: The frequency of MDSCs in blood, lymphoid tissues, inflamed paws or synovial fluid and their association with disease severity, tissue inflammation and the levels of pathogenic T helper (Th) 17 cells were examined in arthritic mice or in patients with RA (n=35) and osteoarthritis (n=15). The MDSCs in arthritic mice were also characterised for their phenotype, inflammation status, T cell suppressive activity and their capacity of pro-Th17 cell differentiation. The involvement of MDSCs in the disease pathology and a Th17 response was examined by adoptive transfer or antibody depletion of MDSCs in arthritic mice or by coculturing mouse or human MDSCs with naïve CD4+ T cells under Th17-polarising conditions. RESULTS: MDSCs significantly expanded in arthritic mice and in patients with RA, which correlated positively with disease severity and an inflammatory Th17 response. While displaying T cell suppressive activity, MDSCs from arthritic mice produced high levels of inflammatory cytokines (eg, interleukin (IL)-1β, TNF-α). Mouse and human MDSCs promoted Th17 cell polarisation ex vivo. Transfer of MDSCs facilitated disease progression, whereas their elimination in arthritic mice ameliorated disease symptoms concomitant with reduction of IL-17A/Th17 cells. CONCLUSIONS: Our studies suggest that proinflammatory MDSCs with their capacity to drive Th17 cell differentiation may be a critical pathogenic factor in autoimmune arthritis.
25680967 Myeloid-derived suppressor cells are proinflammatory and regulate collagen-induced arthrit 2015 Apr Myeloid-derived suppressor cells (MDSC) and Th17 cells were found to expand in collagen-induced arthritis (CIA) significantly. Two subsets of MDSC, polymorphonuclear (PMN) and mononuclear (MO), were detected and their ratios varied during the development of CIA. The depletion of MDSC in vivo resulted in suppression of T-cell proliferation and decreased IL-17A and IL-1β production. The adoptive transfer of MDSC restored the severity of arthritis and Th17 cell differentiation. The depletion of MDSCs on day 35 resulted in arthritis amelioration without reaching a significant difference. Furthermore, MDSCs from CIA mice had higher production of IL-1β and promoted Th17 cell differentiation. The expansion of MDSCs in the peripheral blood of rheumatoid arthritis (RA) patients was in correlation with increased Th17 cells and disease activity DAS28. These results support the hypothesis that MDSC may play a significant proinflammatory role in the pathogenesis of CIA and RA by inducing Th17 development in an IL-1β-dependent manner.
25516006 One-year safety of ibuprofen/famotidine fixed combination versus ibuprofen alone: pooled a 2015 Mar OBJECTIVE: To evaluate the safety of the fixed combination of ibuprofen and famotidine compared with ibuprofen alone from two 24-week, multicenter, double-blind trials designed to evaluate the comparative incidence of endoscopically documented upper gastrointestinal ulcers and a 28-week double-blind extension study. RESEARCH DESIGN AND METHODS: Safety was analyzed by pooling data from the two double-blind trials and the follow-on study. Safety was assessed by monitoring the incidence, causality, and severity of adverse events (AEs). RESULTS: In the pivotal efficacy and safety trials, discontinuation rates due to any cause and dyspepsia were significantly lower for the ibuprofen/famotidine combination versus ibuprofen alone. Other than dyspepsia, gastrointestinal and cardiovascular AEs of special interest were similar. Events judged to be treatment related were significantly lower with the ibuprofen/famotidine combination (20.6% vs. 25%). In the safety extension population, there were no differences in the discontinuation rates and the reporting of AEs or serious AEs (SAEs) between the two groups. Gastrointestinal-related events were similar between the groups. Incidence of cardiovascular-related AEs of special interest were 11% (ibuprofen/famotidine) and 2% (ibuprofen) (p=0.06), possibly due to a higher number of rheumatoid arthritis patients in the combination group. Of these, 80% were reports of hypertension (8% ibuprofen/famotidine vs. 2% ibuprofen). Three cases of hypertension in the ibuprofen/famotidine group were considered treatment related. The probability of a cardiovascular event decreased during days 112-167 of treatment and remained low with continued treatment. CONCLUSIONS: One-year safety data from two pivotal trials and a long-term extension study indicate that the ibuprofen/famotidine combination demonstrates a favorable gastrointestinal safety profile and more patients continued on therapy compared to ibuprofen alone. No new safety signals have been identified. These data offer additional evidence supporting a new therapeutic option to improve gastrointestinal safety and adherence for patients who require long-term ibuprofen.
26315890 Promotion of Inflammatory Arthritis by Interferon Regulatory Factor 5 in a Mouse Model. 2015 Dec OBJECTIVE: Polymorphisms in the transcription factor interferon regulatory factor 5 (IRF5) are associated with an increased risk of developing rheumatoid arthritis (RA). This study was undertaken to determine the role of IRF5 in a mouse model of arthritis development. METHODS: K/BxN serum-transfer arthritis was induced in mice deficient in IRF5, or lacking IRF5 only in myeloid cells, and arthritis severity was evaluated. K/BxN arthritis was also induced in mice deficient in TRIF, Toll-like receptor 2 (TLR2), TLR3, TLR4, and TLR7 to determine the pathways through which IRF5 might promote arthritis. In vitro studies were performed to determine the role of IRF5 in interleukin-1 (IL-1) receptor and TLR signaling. RESULTS: Arthritis severity was reduced in IRF5-deficient, TRIF-deficient, TLR3-deficient, and TLR7-deficient mice. The expression of multiple genes regulating neutrophil recruitment or function and bioactive IL-1β formation was reduced in the joints during active arthritis in IRF5-deficient mice. In vitro studies showed that TLR7 and the TRIF-dependent TLR3 pathway induce proinflammatory cytokine production in disease-relevant cell types in an IRF5-dependent manner. CONCLUSION: Our findings indicate that IRF5 contributes to disease pathogenesis in inflammatory arthritis. This is likely due at least in part to the role of IRF5 in mediating proinflammatory cytokine production downstream of TLR7 and TLR3. Since TLR7 and TLR3 are both RNA-sensing TLRs, this suggests that endogenous RNA ligands present in the inflamed joint promote arthritis development. These findings may be relevant to human RA, since RNA capable of activating TLR7 and TLR3 is present in synovial fluid and TLR7 and TLR3 are up-regulated in the joints of RA patients.
27182969 A method to decipher pleiotropy by detecting underlying heterogeneity driven by hidden sub 2016 Jul There is growing evidence of shared risk alleles for complex traits (pleiotropy), including autoimmune and neuropsychiatric diseases. This might be due to sharing among all individuals (whole-group pleiotropy) or a subset of individuals in a genetically heterogeneous cohort (subgroup heterogeneity). Here we describe the use of a well-powered statistic, BUHMBOX, to distinguish between those two situations using genotype data. We observed a shared genetic basis for 11 autoimmune diseases and type 1 diabetes (T1D; P < 1 × 10(-4)) and for 11 autoimmune diseases and rheumatoid arthritis (RA; P < 1 × 10(-3)). This sharing was not explained by subgroup heterogeneity (corrected PBUHMBOX > 0.2; 6,670 T1D cases and 7,279 RA cases). Genetic sharing between seronegative and seropostive RA (P < 1 × 10(-9)) had significant evidence of subgroup heterogeneity, suggesting a subgroup of seropositive-like cases within seronegative cases (PBUHMBOX = 0.008; 2,406 seronegative RA cases). We also observed a shared genetic basis for major depressive disorder (MDD) and schizophrenia (P < 1 × 10(-4)) that was not explained by subgroup heterogeneity (PBUHMBOX = 0.28; 9,238 MDD cases).
27609223 Prokineticin 2 antagonist, PKRA7 suppresses arthritis in mice with collagen-induced arthri 2016 Sep 8 BACKGROUND: Prokineticin 2 (PK2) expression is upregulated in mice with collagen-induced arthritis (CIA), an animal model of rheumatoid arthritis. The purpose of our study was to investigate the effects of PK2 inhibition on CIA. METHODS: PK2, prokineticin receptor (PKR) 1, and PKR2 mRNA transcripts in the joints of CIA mice were measured by real-time PCR on Days 21, 28, and 35 (n = 15/day). Localization of PKR1 and PKR2 proteins was examined immunohistochemically. PKRA7, a PK2 antagonist, was administered intraperitoneally for 2 weeks to CIA mice, and the severity of arthritis was compared between treated (n = 12) and untreated (n = 12) mice. The gene expression levels of inflammatory cytokines IL-1β, IL-6, TNF-α, and VEGF were also measured by real-time PCR and compared between treated (n = 6) and untreated (n = 6) CIA mice. The data was statistically analyzed, and P values of less than 0.05 were considered significant. RESULTS: In the thickened synovial membrane, PKR1 protein was expressed in infiltrating neutrophils, while PKR2 expression was found in macrophage-like mononuclear cells. PK2 gene expression was significantly more pronounced on Days 28 and 35 than on Day 21 (2.15 and 2.03 versus 1.00, P = 0.0311 and 0.0247; Dunn's multiple comparison). PKR2 gene expression levels were significantly higher on Days 28 and 35 compared to Day 21 (25.4 and 39.3 versus 1.0, P = 0.002 and < 0.0001; Dunn's multiple comparison). Administration of PKRA7 suppressed the severity of arthritis (P < 0.001; two-way analysis of variance). A gene expression analysis of inflammatory cytokines revealed significantly reduced IL-1β and lL-6 expression in the joints of PKRA7-treated mice compared to untreated mice (0.1 versus 1.0, P = 0.0043 and 0.04 versus 1.0, P = 0.0022, respectively; Mann-Whitney test). CONCLUSIONS: PK2 inhibition suppressed arthritis in mice with CIA.
26087815 Risk of venous thromboembolism in patients with Sjögren's syndrome: a systematic review a 2015 Sep OBJECTIVES: Several chronic inflammatory disorders, such as rheumatoid arthritis and systemic lupus erythematosus, have been linked to an increased risk of venous thromboembolism (VTE). However, the data on Sjögren's syndrome (SS) remain unclear. This study aimed to investigate this association. METHODS: We conducted a systematic review and meta-analysis of observational studies that reported odds ratio, relative risk, hazard ratio or standardised incidence ratio comparing risk of VTE in patients with SS versus non-SS subjects. Pooled risk ratio and 95% confidence intervals were calculated using a random-effect, generic inverse variance method of DerSimonian and Laird. RESULTS: Out of 306 potentially relevant articles, four eligible studies were identified and included in the data analysis. The pooled risk ratio of VTE in patients with SS was 2.05 (95% CI, 1.86-2.27). The statistical heterogeneity of this study was insignificant with an I2 of 0%. CONCLUSIONS: Our study demonstrated a statistically significant increased VTE risk among patients with SS.
25240428 Prospective study on antimicrobial prophylaxis in total hip arthroplasty. 2015 May AIMS AND BACKGROUND: Prophylactic use of antibiotics against the pathogens likely to contaminate the procedure is considered beneficial to prevent surgical site infections. We asked that an increase in the effective blood concentration by increasing the administration dose immediately before the operation can decrease the incidence of surgical site infection and performed a prospective study in patients undergoing total hip arthroplasty. METHODS: The subjects consisted of 357 patients who underwent initial THA between January 2006 and June 2012. We compared 172 patients who received an initial dose of Unasyn-S 1.5 g (1.5-g group) and 185 treated after January 2010 when the initial dose alone was increased to 3.0 g (3.0-g group) in terms of the incidence and depth (superficial or deep layer) of SSI. RESULTS: SSI developed in 7 (1.96 %) of all patients, consisting of 5 (2.91 %) in the 1.5-g group and 2 (1.08 %) in the 3.0-g group. Its incidence did not differ between the two groups, but was slightly lower in the 3.0-g group. Deep infection was observed in 2 of the 5 patients in the 1.5-g group but neither of the 2 in the 3.0-g group. CONCLUSION: Although there is statistically no significant difference in the incidence of SSI, our data suggest that an increase of the preoperative antibiotics reduces the incidence of SSI and can be an effective measure for the prevention of infection.
27624649 Longitudinal assessment of monocyte chemoattractant protein-1 in lupus nephritis as a biom 2016 Nov Urinary MCP-1 (uMCP-1) levels reflect lupus nephritis (LN) disease activity. However, long-term prospective studies evaluating it as a biomarker are lacking. SLE patients with active nephritis (AN), active disease without nephritis (ANR), and inactive disease (ID) were enrolled. AN patients were followed up every 3 months for 1 year. Urine and serum samples were collected at baseline from all and at follow-up visits in AN group. Urine samples from healthy subjects (HC), rheumatoid arthritis (RA), and diabetic nephropathy (DM) patients (20 each) served as controls. Serum (sMCP-1) and uMCP-1 was measured using ELISA. Urinary values were normalized for creatinine excretion. Nonparametric tests were used. A total of 121 SLE patients were enrolled. Baseline uMCP-1 was significantly higher in AN as compared to ANR, ID, HC, and RA (p < 0.001), but it was not different from DM and showed good correlation with rSLEDAI and SLEDAI (r = 0.52 and 0.47, p < 0.001) but not with sMCP-1. On ROC analysis to differentiate between AN and ANR, uMCP-1 performed better than sMCP-1, anti-dsDNA antibodies, C3 and C4. uMCP-1 and not sMCP-1 decreased significantly at all follow-up visits (p < 0.001). uMCP-1 remained persistently elevated in a patient who developed CKD and rose before conventional markers in two patients with relapse of LN. uMCP-1 correlates well with LN disease activity and helps differentiate between AN and ANR patients. Its levels fall with treatment and may have a potential to predict poor response and relapse of LN. uMCP-1 is most likely generated locally in the kidney.
26530096 68Ga-DOTA-Siglec-9--a new imaging tool to detect synovitis. 2015 Nov 3 INTRODUCTION: Vascular adhesion protein-1 (VAP-1) is an adhesion molecule, which upon inflammation is rapidly translocated from intracellular sources to the endothelial cell surface. We have recently discovered that sialic acid- binding immunoglobulin-like lectin 9 (Siglec-9) is a leukocyte ligand of VAP-1 and that 68Ga-labeled Siglec-9 motif peptide facilitates in vivo imaging of inflammation. This study evaluated the feasibility of 68Ga-DOTA-Siglec-9 positron emission tomography (PET) for the assessment of synovitis. METHODS: Rabbits with synovial inflammation were injected with 18F-FDG or 68Ga-DOTA-Siglec-9 and studied by gamma counting and autoradiography. Certain rabbits were also examined with magnetic resonance imaging (MRI). After PET imaging, rabbits were intravenously administered with anti-VAP-1 antibody to evaluate luminal expression of VAP-1 by immunohistochemistry. Finally, binding of Siglec-9 peptide and VAP-1 positive vessels were evaluated by double staining of rheumatoid arthritis synovium. RESULTS: Intra-articular injection of hemagglutinin induced mild synovial inflammation in rabbit knee with luminal expression of VAP-1. Synovitis was clearly visualized by 68Ga-DOTA-Siglec-9 PET in addition to 18F-FDG-PET and MRI. Compared with the 18F-FDG, the ex vivo inflamed-to-control synovium ratio of 68Ga-DOTA-Siglec-9 was similar (1.7 ± 0.4 vs. 1.5 ± 0.2, P = 0.32). Double staining revealed that Siglec-9 peptide binds to VAP-1 positive vessels in human rheumatoid synovium. CONCLUSION: Ga-DOTA-Siglec-9 PET tracer detected VAP-1 positive vasculature in the mild synovitis of rabbits comparable with 18F-FDG, suggesting its potential for in vivo imaging of synovial inflammation in patients with rheumatic diseases.
27807193 PTPN22 Is a Critical Regulator of Fcγ Receptor-Mediated Neutrophil Activation. 2016 Dec 15 Neutrophils act as a first line of defense against bacterial and fungal infections, but they are also important effectors of acute and chronic inflammation. Genome-wide association studies have established that the gene encoding the protein tyrosine phosphatase nonreceptor 22 (PTPN22) makes an important contribution to susceptibility to autoimmune disease, notably rheumatoid arthritis. Although PTPN22 is most highly expressed in neutrophils, its function in these cells remains poorly characterized. We show in this article that neutrophil effector functions, including adhesion, production of reactive oxygen species, and degranulation induced by immobilized immune complexes, were reduced in Ptpn22(-/-) neutrophils. Tyrosine phosphorylation of Lyn and Syk was altered in Ptpn22(-/-) neutrophils. On stimulation with immobilized immune complexes, Ptpn22(-/-) neutrophils manifested reduced activation of key signaling intermediates. Ptpn22(-/-) mice were protected from immune complex-mediated arthritis, induced by the transfer of arthritogenic serum. In contrast, in vivo neutrophil recruitment following thioglycollate-induced peritonitis and in vitro chemotaxis were not affected by lack of PTPN22. Our data suggest an important role for PTPN22-dependent dephosphorylation events, which are required to enable full FcγR-induced activation, pointing to an important role for this molecule in neutrophil function.
25809415 Cell-penetrable mouse forkhead box protein 3 alleviates experimental arthritis in mice by 2015 Jul Regulatory T cells (T(regs)) have potential applications in clinical disease therapy, such as autoimmune diseases and transplant rejection. However, their numbers are limited. Forkhead box protein 3 (FoxP3) is a key transcription factor that controls T(reg) development and function. Here, we generated a cell-permeable fusion protein, protein transduction domain (PTD)-conjugated mouse FoxP3 protein (PTD-mFoxP3), and evaluated whether PTD-mFoxp3 can alleviate rheumatoid arthritis (RA) in the collagen-induced arthritis (CIA) mouse model. As expected, PTD-mFoxP3 was transduced into cells effectively, and inhibited T cell activation and attenuated the cell proliferation. It decreased interleukin (IL) 2 and interferon (IFN)-γ expression, and increased IL-10 expression in activated CD4(+)CD25(-) T cells. PTD-mFoxP3-transduced CD4(+)CD25(-) T cells attenuated proliferation of activated CD4(+)CD25(-) T cells. In addition, PTD-mFoxP3 blocked the Th17 differentiation programme in vitro and down-regulated IL-17 production from T cells by modulating induction and levels of retinoid-related orphan receptor gamma t (RORγt). Intra-articular delivery of PTD-mFoxP3 delayed disease incidence remarkably and alleviated autoimmune symptoms of CIA mice. Moreover, protective effects of PTD-mFoxP3 were associated with regulating the balance of T helper type 17 (Th17) and T(regs). These results suggest that PTD-mFoxP3 may be a candidate for RA therapy.
27777982 A molecular signature of preclinical rheumatoid arthritis triggered by dysregulated PTPN22 2016 Oct 20 A unique feature of rheumatoid arthritis (RA) is the presence of anti-citrullinated protein antibodies (ACPA). Several risk factors for RA are known to increase the expression or activity of peptidyl arginine deiminases (PADs), which catalyze citrullination and, when dysregulated, can result in hypercitrullination. However, the consequence of hypercitrullination is unknown and the function of each PAD has yet to be defined. Th cells of RA patients are hypoglycolytic and hyperproliferative due to impaired expression of PFKFB3 and ATM, respectively. Here, we report that these features are also observed in peripheral blood mononuclear cells (PBMCs) from healthy at-risk individuals (ARIs). PBMCs of ARIs are also hypercitrullinated and produce more IL-2 and Th17 cytokines but fewer Th2 cytokines. These abnormal features are due to impaired induction of PTPN22, a phosphatase that also suppresses citrullination independently of its phosphatase activity. Attenuated phosphatase activity of PTPN22 results in aberrant expression of IL-2, ATM, and PFKFB3, whereas diminished nonphosphatase activity of PTPN22 leads to hypercitrullination mediated by PADs. PAD2- or PAD4-mediated hypercitrullination reduces the expression of Th2 cytokines. By contrast, only PAD2-mediated hypercitrullination can increase the expression of Th17 cytokines. Taken together, our data depict a molecular signature of preclinical RA that is triggered by impaired induction of PTPN22.
26414917 An Arthritis-Suppressive and Treg Cell-Inducing CD4+ T Cell Epitope Is Functional in the C 2016 Mar OBJECTIVE: We previously showed that mycobacterial Hsp70-derived peptide B29 induced B29-specific Treg cells that suppressed experimental arthritis in mice via cross-recognition of their mammalian Hsp70 homologs. The aim of the current study was to characterize B29 binding and specific CD4+ T cell responses in the context of human major histocompatibility complex (MHC) molecules. METHODS: Competitive binding assays were performed to examine binding of peptide B29 and its mammalian homologs to HLA molecules. The effect of B29 immunization in HLA-DQ8-transgenic mice with proteoglycan-induced arthritis was assessed, followed by ex vivo restimulation with B29 to examine the T cell response. Human peripheral blood mononuclear cells were used to investigate the presence of B29-specific T cells with immunoregulatory potential. RESULTS: The binding affinity of the B29 peptide was high to moderate for multiple HLA-DR and HLA-DQ molecules, including those highly associated with rheumatoid arthritis. This binding was considered to be functional, because B29 immunization resulted in the suppression of arthritis and T cell responses in HLA-DQ8-transgenic mice. In humans, we demonstrated the presence and expansion of B29-specific CD4+ T cells, which were cross-reactive with the mammalian homologs. Using HLA-DR4+ tetramers specific for B29 or the mammalian homolog mB29b, we showed expansion of cross-reactive T cells, especially the human FoxP3+ CD4+CD25+ T cell population, after in vitro stimulation with B29. CONCLUSION: These results demonstrated a conserved fine specificity and functionality of B29-induced Treg cell responses in the context of the human MHC. Based on these findings, a path for translation of the experimental findings for B29 into a clinical immunomodulatory therapeutic approach is within reach.
27301549 Evolving Role of Molecular Imaging with (18)F-Sodium Fluoride PET as a Biomarker for Calci 2016 Aug (18)F-sodium fluoride (NaF) as an imaging tracer portrays calcium metabolic activity either in the osseous structures or in soft tissue. Currently, clinical use of NaF-PET is confined to detecting metastasis to the bone, but this approach reveals indirect evidence for disease activity and will have limited use in the future in favor of more direct approaches that visualize cancer cells in the read marrow where they reside. This has proven to be the case with FDG-PET imaging in most cancers. However, a variety of studies support the application of NaF-PET to assess benign osseous diseases. In particular, bone turnover can be measured from NaF uptake to diagnose osteoporosis. Several studies have evaluated the efficacy of bisphosphonates and their lasting effects as treatment for osteoporosis using bone turnover measured by NaF-PET. Additionally, NaF uptake in vessels tracks calcification in the plaques at the molecular level, which is relevant to coronary artery disease. Also, NaF-PET imaging of diseased joints is able to project disease progression in osteoarthritis, rheumatoid arthritis, and ankylosing spondylitis. Further studies suggest potential use of NaF-PET in domains such as back pain, osteosarcoma, stress-related fracture, and bisphosphonate-induced osteonecrosis of the jaw. The critical role of NaF-PET in disease detection and characterization of many musculoskeletal disorders has been clearly demonstrated in the literature, and these methods will become more widespread in the future. The data from PET imaging are quantitative in nature, and as such, it adds a major dimension to assessing disease activity.
26248485 Effect of avocado/soybean unsaponifiables on ligature-induced bone loss and bone repair af 2016 Jun BACKGROUND AND OBJECTIVE: The aim of this study was to evaluate the effects of administration of avocado/soybean unsaponifiable (ASU), a drug that is commonly used in the treatment of rheumatoid arthritis, on ligature-induced bone loss and bone repair after ligature removal in rats. MATERIAL AND METHODS: Eighty-four rats were randomly assigned to four groups of equal size and received a daily gavage of either sterile saline [control (CTR)] or ASU (0.6 mg/kg), starting 7 d before (ASU/-7), on the day of (ASU/0) or 7 d after (ASU/+7) periodontitis induction. Periodontitis was induced by placing silk ligatures into the gingival sulcus of the second maxillary molars for 7 d; after 7 d, the ligatures were removed. Seven rats from each group were sacrificed, 7, 15 or 30 d after ligature removal. Bone resorption was evaluated by histomorphometry and micro-computed tomography (micro-CT). Immunohistochemistry was used to evaluate the expression of TRAP, RANKL and alkaline phosphatase (ALP), and quantitative PCR (qPCR) was used to evaluate the levels of interleukin-1beta (Il1β), tumor necrosis factor alpha (Tnfα), interleukin-6 (Il-6), Rankl and Alp. Statistical analysis was performed using the Shapiro-Wilk test, ANOVA and Tukey's test for normal data, and using the Kruskall-Wallis and Dunnet's tests for non-normal data (p < 0.05). RESULTS: Histomorphometry and micro-CT analysis showed greater bone resorption in the CTR group than in the ASU/0 (15 d) and ASU/+7 (7 and 15 d) groups. The CTR group also presented with a higher expression of TRAP (15 and 30 d) and RANKL (7 and 15 d) compared with ASU/0 and ASU/+7 groups. Similarly, qPCR analysis showed higher levels of Rankl and Il1β mRNAs, and lower levels of Alp mRNA, in the CTR group compared with all other groups (for all periods). CONCLUSION: ASU exhibited a positive effect on bone repair following ligature-induced periodontitis in rats.
26808597 Tumor Necrosis Factor-α Inhibitor Use and the Risk of Incident Hypertension in Patients w 2016 May OBJECTIVE: To compare the risk of incident hypertension between initiators of tumor necrosis factor (TNF)-α inhibitors and initiators of nonbiologic disease modifying antirheumatic drugs (hereafter referred to as nonbiologics) in rheumatoid arthritis patients taking methotrexate monotherapy. METHODS: We conducted a cohort study using insurance claims data (2001-2012) from the US. We identified initiators of use of either TNF-α inhibitors or nonbiologics. Subsequent exposure to these agents was measured monthly in a time-varying manner. The outcome of interest was incident hypertension, defined by a diagnosis and a prescription for an antihypertensive drug. Marginal structural models estimated hazard ratios (HRs) adjusted for both baseline and time-varying confounders. To validate the primary analysis, we designed a verification analysis to evaluate a known association between leflunomide (a nonbiologic disease modifying agent) and hypertension. RESULTS: We identified 4,822 initiations of TNF-α inhibitor use and 2,400 of nonbiologic use. Crude incidence rates of hypertension per 1,000 person-years of follow-up were 36 (95% CI [confidence interval]: 32, 41) for the TNF-α inhibitor group and 42 (95% CI: 34, 51) for the nonbiologics group. The crude HR of TNF-α inhibitors versus nonbiologics for the risk of incident hypertension was 0.85 (95% CI: 0.67, 1.1). After adjusting for both baseline and time-varying covariates using marginal structural models, the HR was 0.95 (95% CI: 0.74, 1.2). In the verification analysis, the adjusted HR of incident hypertension was 2.3 (95% CI: 1.7, 3.0) in leflunomide initiators compared with methotrexate initiators. CONCLUSION: Treatment with TNF-α inhibitors was not associated with a reduced risk of incident hypertension compared with nonbiologics in rheumatoid arthritis patients.See Video Abstract at http://links.lww.com/EDE/B36.
26662519 Identification of a Novel Toll-like Receptor 7 Endogenous Ligand in Rheumatoid Arthritis S 2016 May OBJECTIVE: Levels of Toll-like receptor 7 (TLR-7) are elevated in rheumatoid arthritis (RA), but the impact on RA is unknown because the endogenous ligand for TLR-7 has not been identified. The aim of this study was to identify a TLR-7 endogenous ligand and to determine its role in the pathogenesis of RA. METHODS: The presence of an endogenous TLR-7 ligand, microRNA let-7b (miR-let-7b), was examined by real-time polymerase chain reaction (PCR) analysis. Using RA knockdown cells, TLR-7-knockout mice, or antagonist, the specificity of miR-let-7b as a potential ligand for TLR-7 was tested. The mechanism by which ligation of miR-let-7b to TLR-7 promotes disease was investigated in RA myeloid cells by real-time PCR, enzyme-linked immunosorbent assay, and fluorescence-activated cell sorting. We also established the effect of ectopic miR-let-7b expression on arthritic joint inflammation. RESULTS: We found that a TLR-7 endogenous ligand resides mainly in RA synovial fluid macrophages. The GU-rich domain in miR-let-7b was found to be essential for TLR-7 ligation, since miR-147, the positive control for GU, was able to stimulate TLR-7+ myeloid cells, whereas miR-124, the negative, non-GU, control, was not. We demonstrated that miR-let-7b or exosomes containing miR-let-7b could transform the RA and/or mouse naive or antiinflammatory macrophages into inflammatory M1 macrophages via TLR-7 ligation. Consistently, we showed that miR-let-7b provokes arthritis by remodeling naive myeloid cells into M1 macrophages via TLR-7 ligation, since joint swelling and M1 macrophages are absent in TLR-7-deficient mice. CONCLUSION: The results of this study underscore the importance of miR-let-7b ligation to TLR-7 in the joint during the effector phase of RA.
26010823 Deficient cytokine control modulates temporomandibular joint pain in rheumatoid arthritis. 2015 Aug The aim was to investigate how endogenous cytokine control of tumor necrosis factor (TNF) influences temporomandibular joint (TMJ) pain in relation to the role of anti-citrullinated peptide antibodies (ACPA) in patients with rheumatoid arthritis (RA). Twenty-six consecutive patients with TMJ RA were included. Temporomandibular joint pain intensity was assessed at rest, on maximum mouth opening, on chewing, and on palpation. Mandibular movement capacity and degree of anterior open bite (a clinical sign of structural destruction of TMJ tissues) were also assessed. Systemic inflammatory activity was assessed using the Disease Activity Score in 28 joints (DAS28) for rheumatoid arthritis. Samples of TMJ synovial fluid and blood were obtained and analyzed for TNF, its soluble receptor, soluble TNF receptor II (TNFsRII), and ACPA. A high concentration of TNF in relation to the concentration of TNFsRII in TMJ synovial fluid was associated with TMJ pain on posterior palpation on maximum mouth opening. The ACPA concentration correlated significantly to the TNF concentration, but not to the TNFsRII concentration, indicating that increased inflammatory activity is mainly caused by an insufficient increase in anti-inflammatory mediators. This study indicates that TMJ pain on palpation in patients with RA is related to a deficiency in local cytokine control that contributes to increased inflammatory activity, including sensitization to mechanical stimuli over the TMJ.
26140449 Disentangling the Effects of Colocalizing Genomic Annotations to Functionally Prioritize N 2015 Jul 2 Identifying genomic annotations that differentiate causal from trait-associated variants is essential to fine mapping disease loci. Although many studies have identified non-coding functional annotations that overlap disease-associated variants, these annotations often colocalize, complicating the ability to use these annotations for fine mapping causal variation. We developed a statistical approach (Genomic Annotation Shifter [GoShifter]) to assess whether enriched annotations are able to prioritize causal variation. GoShifter defines the null distribution of an annotation overlapping an allele by locally shifting annotations; this approach is less sensitive to biases arising from local genomic structure than commonly used enrichment methods that depend on SNP matching. Local shifting also allows GoShifter to identify independent causal effects from colocalizing annotations. Using GoShifter, we confirmed that variants in expression quantitative trail loci drive gene-expression changes though DNase-I hypersensitive sites (DHSs) near transcription start sites and independently through 3' UTR regulation. We also showed that (1) 15%-36% of trait-associated loci map to DHSs independently of other annotations; (2) loci associated with breast cancer and rheumatoid arthritis harbor potentially causal variants near the summits of histone marks rather than full peak bodies; (3) variants associated with height are highly enriched in embryonic stem cell DHSs; and (4) we can effectively prioritize causal variation at specific loci.