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ID PMID Title PublicationDate abstract
22004374 Synthesis and screening of a haloacetamidine containing library to identify PAD4 selective 2012 Jan 20 Protein arginine deiminase activity (PAD) is increased in cancer, rheumatoid arthritis, and ulcerative colitis. Although the link between abnormal PAD activity and disease is clear, the relative contribution of the individual PADs to human disease is not known; there are 5 PAD isozymes in humans. Building on our previous development of F- and Cl-amidine as potent pan-PAD irreversible inhibitors, we describe herein a library approach that was used to identify PAD-selective inhibitors. Specifically, we describe the identification of Thr-Asp-F-amidine (TDFA) as a highly potent PAD4 inactivator that displays ≥15-fold selectivity for PAD4 versus PAD1 and ≥50-fold versus PADs 2 and 3. This compound is active in cells and can be used to inhibit PAD4 activity in cellulo. The structure of the PAD4·TDFA complex has also been solved, and the structure and mutagenesis data indicate that the enhanced potency is due to interactions between the side chains of Q346, R374, and R639. Finally, we converted TDFA into a PAD4-selective ABPP and demonstrated that this compound, biotin-TDFA, can be used to selectively isolate purified PAD4 in vitro. In total, TDFA and biotin-TDFA represent PAD4-selective chemical probes that can be used to study the physiological roles of this enzyme.
21954519 Nonsteroidal anti-inflammatory drugs: add an anti-ulcer drug for patients at high risk onl 2011 Sep In addition to their cardiac, renal, hepatic, cutaneous and neuropsychological adverse effects, nonsteroidal anti-inflammatory drugs (NSAIDs) can have severe effects on the entire gastrointestinal tract, including bleeding, perforation and occlusion. Which anti-ulcer drugs reduce the risk of the severe gastrointestinal adverse effects of NSAIDs, and which patients should receive them? To answer these questions, we conducted a review of the literature, using the standard Prescrire methodology. The main risk factors for severe gastrointestinal adverse effects during NSAID therapy are: a high dose regimen; age over 65 years; a history of gastric or duodenal ulcer or gastrointestinal bleeding; heavy use of both alcohol and tobacco; and concomitant treatment with a corticosteroid, antiplatelet drug, anticoagulant, or selective serotonin reuptake inhibitor (SSRI) antidepressant. Gastrointestinal symptoms and ulceration (on endoscopy) are poor predictors of severe gastrointestinal reactions. A meta-analysis examined randomised placebo-controlled trials of misoprostol in more than 11 000 patients. The results were mainly based on a large trial including about 9000 rheumatoid arthritis patients with an average age of 68 years. Misoprostol (400 microg to 800 microg/day, in 4 doses) prevented about 4 severe gastroduodenal events when 1000 patients over 60 years of age were treated for 6 months. Diarrhoea and other mild gastrointestinal disorders were frequent. There are no randomised trials comparing proton pump inhibitors (PPIs) and histamine H2 receptor antagonists versus misoprostol or versus placebo therapy for the prevention of severe adverse effects associated with NSAIDs. PPIs and H2 antagonists both reduce the incidence of gastric or duodenal ulceration detected by routine endoscopy. A randomised trial compared an H2 antagonist (famotidine) versus a PPI (pantoprazole) in 128 patients with an average age of 69 years who had a very high risk of serious gastrointestinal adverse effects while taking low-dose aspirin. After 48 weeks of treatment, pantoprazole was more effective than famotidine for the prevention of overt gastrointestinal bleeding. The symptomatic effects of PPIs and H2 antagonists may create a false sense of security, leading some patients to increase their NSAID use and resulting in a paradoxical increase in severe gastrointestinal effects. In practice, anti-ulcer drugs are not sufficiently effective to warrant their use by NSAID-treated adults who are not at high risk of severe gastrointestinal events. Misoprostol has proven efficacy in patients with risk factors for NSAID-induced severe gastroduodenal adverse effects, especially patients over 65 years of age, but it also has frequent adverse effects and necessitates 4 daily doses. Omeprazole is an alternative when the adverse effects or dosing frequency of misoprostol are unacceptable, provided patients are warned not to increase their NSAID consumption.
21940820 Anti-IL6-receptor-alpha (tocilizumab) does not inhibit human monocyte-derived dendritic ce 2011 Nov 10 Significant comorbidites and lethality complicate GVHD and its treatment. Targeting the cytokine milieu may improve GVHD control; and IL6 is an attractive candidate, given its role in dendritic cell activation and T-cell differentiation. Tocilizumab is a humanized mAb to IL6-receptor-α (IL6R-α), which is Food and Drug Administration-approved for treatment of rheumatoid arthritis. Mouse transplant models have demonstrated that IL6 blockade also improves GVHD scores and survival. Definitive immunologic effects of IL6 inhibition have not emerged given inconsistent alterations in regulatory T cells (Tregs) and suppression of T-cell proliferation. Despite on-target suppression of IL6R-α signaling in human monocyte-derived dendritic cells (moDCs) and T cells, our data show no effect on moDC maturation/activation, alloreactive T-cell proliferation, Treg expansion, or allogeneic Th1/Th17 responses in vitro. These findings merit attention in any clinical trials of tocilizumab for GVHD prevention or treatment and provide a rationale for evaluating more specific inhibitors of downstream JAK2/STAT3 signaling as well.
21590489 Angiogenesis-associated crosstalk between collagens, CXC chemokines, and thrombospondin do 2011 Aug Excessive vascularization is a hallmark of many diseases including cancer, rheumatoid arthritis, diabetic nephropathy, pathologic obesity, age-related macular degeneration, and asthma. Compounds that inhibit angiogenesis represent potential therapeutics for many diseases. Karagiannis and Popel [Proc. Natl. Acad. Sci. USA 105(37):13775-13780, 2008] used a bioinformatics approach to identify more than 100 peptides with sequence homology to known angiogenesis inhibitors. The peptides could be grouped into families by the conserved domain of the proteins they were derived from. The families included type IV collagen fibrils, CXC chemokine ligands, and type I thrombospondin domain-containing proteins. The relationships between these families have received relatively little attention. To investigate these relationships, we approached the problem by placing the families of proteins in the context of the human interactome including >120,000 physical interactions among proteins, genes, and transcripts. We built on a graph theoretic approach to identify proteins that may represent conduits of crosstalk between protein families. We validated these findings by statistical analysis and analysis of a time series gene expression data set taken during angiogenesis. We identified six proteins at the center of the angiogenesis-associated network including three syndecans, MMP9, CD44, and versican. These findings shed light on the complex signaling networks that govern angiogenesis phenomena.
21595128 (68)Ga-Tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid-Glu-{Glu-[cyclo(Arg-Gly-Asp-d- 2004 Integrins are a family of heterodimeric glycoproteins on cell surfaces that mediate diverse biological events involving cell–cell and cell–matrix interactions (1). Integrins consist of an α and a β subunit and are important for cell adhesion and signal transduction. The α(v)β(3) integrin is the most prominent receptor affecting tumor growth, tumor invasiveness, metastasis, tumor-induced angiogenesis, inflammation, osteoporosis, and rheumatoid arthritis (2-7). Expression of the α(v)β(3) integrin is strong on tumor cells and activated endothelial cells, whereas expression is weak on resting endothelial cells and most normal tissues. Antagonists of α(v)β(3) are being studied as antitumor and antiangiogenic agents, and the agonists of α(v)β(3) are being studied as angiogenic agents for coronary angiogenesis (6, 8, 9). Extracellular matrix proteins (vitronectin, fibrinogen, laminin, and collagen) contain a tripeptide sequence consisting of Arg-Gly-Asp (RGD), which binds to a variety of integrins, including α(v)β(3). Various radiolabeled antagonists have been introduced for imaging of tumors and tumor angiogenesis (10). Most cyclic RGD peptides are composed of five amino acids. Haubner et al. (11) reported that various cyclic RGD peptides exhibit selective inhibition of binding to α(v)β(3) (inhibition concentration (IC(50)), 7–40 nM) but not to integrins α(v)β(5) (IC(50), 600–4,000 nM) or α(IIb)β(3) (IC(50), 700–5,000 nM). Various radiolabeled cyclic RGD peptides have been found to have high accumulation in tumors in nude mice (12). Dijkgraaf et al. (13) reported the development of (111)In-tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid-Glu-{Glu-[cyclo(Arg-Gly-Asp-d-Phe-Lys)](2)}(2) ((111)In-DOTA-E-{E-[c(RGDfK)](2)}(2)) for single-photon emission computed tomography imaging α(v)β(3) receptors in nude mice bearing ovarian carcinoma tumors. Dijkgraaf et al. (14) also reported the development of (68)Ga-DOTA-E-{E-[c(RGDfK)](2)}(2)) for positron emission tomography (PET) imaging of α(v)β(3) receptors in tumors, which is the topic of this chapter.
21426696 [Neonatal lupus erythematosus: a report of 7 cases and review of 87 cases of China]. 2011 Feb OBJECTIVE: To acquire more knowledge about neonatal lupus erythematosus (NLE). METHOD: Seven cases with neonatal lupus erythematosus who were seen in this hospital from 1990 to 2009 are reported in this paper and 87 cases reported previously from 1980 to now in China were reviewed. The clinical manifestations, serum autoantibodies, treatment and results of long-term follow-up are analyzed and summarized. RESULT: Totally 94 cases were summarized. Male/female ratio was 48/46; 73 cases had skin rash; 23 had heart abnormality, among whom 13 had cardiac conductive problems including 8 cases of atrioventricular blockage (AVB) (3 degree I, 3 degree II and 2 degree III) and 5 cases of right bundle branch block cases (RBBB). Nine cases had anatomical abnormality including 5 cases of atrial septal defect (ASD), 2 cases of ventricular septal defect (VSD) and 2 cases of atrial enlargements. Forty-four cases had hematological problems including 28 with thrombocytopenia, 11 with leukocytopenia and 34 with anemia. Thirty cases had hepatic abnormality, including 24 liver dysfunction, 22 hepatomegaly, 6 splenomegaly and 3 cholestasis. Three cases had nephropathy; 3 had elevated creatine kinase; 2 had nervous disorder. Among the 94 cases, 86 (91.5%) were positive for anti-SSA, 51 (54.3%) anti-SSB, 16 anti-ds-DNA, 14 anti-U1-RNP, 13 anti-Sm (+), 6 anti-RNP and 4 anti-rRNP(+). Among the corresponding mothers, 39 cases (44.8%) were asymptomatic before pregnancy, 35 had SLE, 5 had SCLE, 3 had Sjogren syndrome, 2 had chilblain, photosensitivity and arthralgia, respectively, 1 had rheumatoid arthritis and 1 had psoriasis. During pregnancy, 8 mothers developed SLE. Totally 48 mothers (51.1%) suffered from LE. Together with 15 mothers who had transient skin rash during the pregnancy, there were 23 mothers (59%) who had new clinical manifestation among the 39 asymptomatic mothers. Twenty NLE cases accepted glucocorticoid treatment, 4 of them were treated with intravenous immunoglobulin. Sixty-eight cases were followed up for up to 12 years, 58 cases were healthy, 5 cases improved and 3 died. Two cases still had grade III AVB without pacemaker. CONCLUSION: NLE is a rare acquired autoimmune disease. Although nearly half of the mothers were asymptomatic before pregnancy, more than half of them developed LE or other symptoms. The clinical presentations in Chinese cases include a transient rash, cardiac lesion while grade III AVB was rare, hematological changes and liver impairments which were common but not serious. Anti-SSA and/or anti-SSB were the most related autoantibody. Most patients with NLE have relatively good prognosis.
20473759 Sinomenine reduces invasion and migration ability in fibroblast-like synoviocytes cells co 2011 Nov CD147 expressed by monocytes, macrophages, and synoviocytes cells can stimulate the production of matrix metalloproteinases (MMPs) associated with the development of rheumatoid arthritis (RA). We investigated the effects of Sinomenine (SIN) on invasion and migration ability and gene expression of CD147, MMP-2, MMP-9 of fibroblast-like synoviocytes cells (FLS) co-cultured with activated human monocytic THP-1 cells (A-THP-1) in vitro. SIN is a pure alkaloid extracted from the Chinese medical plant Sinomenium acutum. FLS cells were co-cultured with THP-1 cells which were induced to differentiate into macrophages with phorbol 12-myristate 13-acetate (PMA). Cells were treated with different concentrations of SIN. Invasion and migration ability of cells was tested by transwell assays. Western blot analysis and zymographic analysis were adopted to detect the expression of CD147 and MMPs, respectively. RT-PCR was used to determine the expression of mRNA of CD147, MMP-2, and MMP-9. The invasion and migration ability of the co-cultured cells was significantly inhibited by SIN in a concentration-dependent fashion, and at the same time, the levels of CD147, MMP-2, MMP-9 were markedly down-regulated. This inhibitory effect was most notable at concentrations of 0.25 and 1.00 mM (P < 0.01). Our results point to a possible mechanism of SIN on treatment of RA is the inhibitory effect of SIN on cell invasion and migration ability, which strongly correlates with repressing the expression of CD147, MMP-2, and MMP-9.
23180820 Phosphoinositide 3-OH kinase regulates integrin-dependent processes in neutrophils by sign 2013 Jan 1 ARAP3, a GTPase activating protein for Rho and Arf family GTPases, is one of many phosphoinositide 3-OH kinase (PI3K) effectors. In this study, we investigate the regulatory input of PI3K upstream of ARAP3 by analyzing neutrophils from an ARAP3 pleckstrin homology (PH) domain point mutation knock-in mouse (R302, 303A), in which ARAP3 is uncoupled from activation by PI3K. ARAP3 PH domain point mutant neutrophils are characterized by disturbed responses linked to stimulation by either integrin ligands or immobilized immune complexes. These cells exhibit increased β2 integrin inside-out signaling (binding affinity and avidity), and our work suggests the disturbed responses to immobilized immune complexes are secondary to this. In vitro, neutrophil chemotaxis is affected in the mutant. In vivo, ARAP3 PH domain point mutant bone marrow chimeras exhibit reduced neutrophil recruitment to the peritoneum on induction of sterile peritonitis and also reduced inflammation in a model for rheumatoid arthritis. The current work suggests a dramatic regulatory input of PI3K into the regulation of β2 integrin activity, and processes dependent on this, by signaling through its effector ARAP3.
22623384 Plasma pyridoxal-5-phosphate is inversely associated with systemic markers of inflammation 2012 Jul Low vitamin B-6 status, based on plasma concentrations of pyridoxal-5-phosphate (PLP), has been identified in inflammatory diseases, including cardiovascular disease, rheumatoid arthritis, inflammatory bowel disease, and diabetes. Our objective was to examine the association between plasma PLP and multiple markers of inflammation in a community-based cohort [n = 2229 participants (55% women, mean age 61 ± 9 y)]. We created an overall inflammation score (IS) as the sum of standardized values of 13 individual inflammatory markers. Multivariable-adjusted regression analysis was used to assess the associations between the IS and plasma PLP. Geometric mean plasma PLP concentrations were lower in the highest tertile category of IS relative to the lowest (61 vs. 80 nmol/L; P-trend < 0.0001). Similarly, the prevalence of PLP insufficiency was significantly higher for participants in the highest compared with the lowest tertiles for IS categories. These relationships persisted after accounting for vitamin B-6 intake. Also, there were significant inverse relationships between plasma PLP and 4 IS based on functionally related markers, including acute phase reactants, cytokines, adhesion molecules, and oxidative stress. In addition, secondary analyses revealed that many of the individual inflammatory markers were inversely associated with plasma PLP after adjusting for plasma C-reactive protein concentration. This study, in combination with past findings, further supports our hypothesis that inflammation is associated with a functional deficiency of vitamin B-6. We discuss 2 possible roles for PLP in the inflammatory process, including tryptophan metabolism and serine hydroxymethyltransferase activity.
22525890 Generation of induced regulatory T cells from primary human naïve and memory T cells. 2012 Apr 16 The development and maintenance of immunosuppressive CD4+ regulatory T cells (Tregs) contribute to the peripheral tolerance needed to remain in immunologic homeostasis with the vast amount of self and commensal antigens in and on the human body. Perturbations in the balance between Tregs and inflammatory conventional T cells can result in immunopathology or cancer. Although therapeutic injection of Tregs has been shown to be efficacious in murine models of colitis, type I diabetes, rheumatoid arthritis and graft versus host disease, several fundamental differences in human versus mouse Treg biology has thus far precluded clinical use. The lack of sufficient number, purity, stability and homing specificity of therapeutic Tregs necessitated a dynamic platform of human Treg development on which to optimize conditions for their ex vivo expansion. Here we describe a method for the differentiation of induced Tregs (iTregs) from a single human peripheral blood donor which can be broken down into four stages: isolation of peripheral blood mononuclear cells, magnetic selection of CD4+ T cells, in vitro cell culture and fluorescence activated cell sorting (FACS) of T cell subsets. Since the Treg signature transcription factor forkhead box P3 (FoxP3) is an activation-induced transcription factor in humans and no other unique marker exists, a combinatorial panel of markers must be used to identify T cells with suppressor activity. After six days in culture, cells in our system can be demarcated into naïve T cells, memory T cells or iTregs based on their relative expression of CD25 and CD45RA. As memory and naïve T cells have different reported polarization requirements and plasticities, pre-sorting of the initial T cell population into CD45RA(+) and CD45RO(+) subsets can be used to examine these discrepancies. Consistent with others, our CD25(Hi)CD45RA(-) iTregs express high levels of FoxP3, GITR and CTLA-4 and low levels of CD127. Following FACS of each population, resultant cells can be used in a suppressor assay which evaluates the relative ability to retard the proliferation of carboxyfluorescein succinimidyl ester (CFSE)-labeled autologous T cells.
22159542 [Profile of use of anti tumor necrosis factor in Colombian patients]. 2011 Jun INTRODUCTION: Tumor necrosis factor-alpha antagonists (anti-TNFα) have shown an increasing consumption and generate a significant economic burden on health systems. OBJECTIVES: The prescribing patterns of tumor necrosis factor-alpha antagonists were determined in a patient population associated with the Sistema General de Seguridad Social en Salud in Colombia. MATERIALS AND METHODS: A descriptive observational study was conducted in 316 patients with respect to use of tumor necrosis factor-alpha antagonists during a treatment period from January 2008 to June 2009. The database examined contained indications of use, inclusion criteria to medication, duration of illness, co-morbidities and adverse reactions. The data were retrieved from the clinical histories. Student's t test was used for the comparison of quantitative variables, and the chi-square test was used to establish associations between categorical variables and multivariate analysis were used. RESULTS: Mean age was 44.613.9 years; 63.9% of participants were female. Of the 316 patients, 17.1% received monotherapy. The order of prescription drugs was as follows: adalimumab (37.3%), infliximab (37.3%) and etanercept (25.4%), all were prescribed in appropriately defined daily doses. Co-medication drugs most frequently prescribed were: disease-modifying anti-rheumatic (82.9%), NSAIDs (29.1%), omeprazole (22.5%), antihypertensives (21.2%), folic acid (19.9%) calcium plus vitamin D (9.8%), calcitriol (6.0%). 10.4% of patients had a record of some adverse drug reaction. The average cost of therapy per patient per year was US$23,464. CONCLUSIONS: Anti-TNFα are being used at recommended doses, particularly in rheumatoid arthritis and in combination with other anti-rheumatic drugs. The direct cost of therapy was high for the country's health system.
22028261 [The role of rituximab in the treatment of ANCA-associated systemic vasculitis]. 2011 Sep A considerable minority of patients with ANCA-associated small-vessel vasculitis are refractory to conventional therapy or experience dose-limiting side effects. Novel therapeutic approaches include rituximab, a genetically engineered chimeric murine-human monoclonal antibody that binds to CD20, which is expressed on human B cells. It was approved in 1997 for the treatment of CD20-positive B-cell non-Hodgkin lymphoma and in 2006 for the treatment of rheumatoid arthritis. The multiple mechanisms proposed for rituximab-mediated B-cell depletion are discussed in this paper. Cumulative data from several open studies on the treatment of microscopic ANCA-associated polyangiitis suggest that in the vast majority of cases rituximab has a beneficial effect. Two randomized controlled trials confirmed these promising results, suggesting that rituximab might be considered as an option for first-line therapy of induction of remission of ANCA-associated vasculitis, and providing an additional tool for treating patients with disease relapse after previous therapy. While rituximab is very effective in the depletion of B cells, current research suggests it could also influence other immune system cells and reestablish immune homeostasis and tolerance. The safety profile of rituximab reveals that most reactions are infusion-related and that the incidence of serious side effects is low. Systemic infection remains a major concern and may result in death. A small number of cases of progressive multifocal leukoencephalopathy reported in patients receiving rituximab in off-label use (albeit none with ANCA-associated vasculitis) highlights the importance of pharmacovigilance.
21914625 A common SNP in the CD40 region is associated with systemic lupus erythematosus and correl 2011 Dec BACKGROUND: In systemic lupus erythematosus (SLE) sustained CD40L expression by T cells and platelets activates a variety of cells via its receptor CD40 contributing to disease pathogenesis. Although CD40 has recently been identified in genome-wide association study as a novel rheumatoid arthritis susceptibility gene such an association has not been documented for SLE. OBJECTIVE: To investigate whether the rs4810485 CD40 single nucleotide polymorphism (SNP) is associated with increased risk for SLE and its impact on CD40 expression. MATERIALS AND METHODS: The primary sample set consisted of 351 patients with SLE and 670 matched healthy controls of Greek origin. 158 patients with SLE and 155 controls from Turkey were used as a replication sample. Genotyping of rs4810485 was performed by restriction fragment length polymorphism and the Sequenom MassArray technology. The expression of CD40 mRNA and protein was assessed in unstimulated and lipopolysaccharide-stimulated peripheral blood mononuclear cells by quantitative real time PCR and flow cytometry, respectively. RESULTS: The minor allele T of CD40 rs4810485 SNP was significantly under-represented in Greek patients with SLE compared with healthy controls (OR=0.65, 95% CI 0.54 to 0.79). The association was replicated in the Turkish cohort (OR=0.57, 95% CI 0.41 to 0.80; meta-analysis of 509 patients with SLE and 825 healthy controls: OR=0.63, 95% CI 0.53 to 0.74, p = 2×10(-8)). In both cases and controls, the rs4810485 G/T and T/T genotypes were associated with significantly reduced CD40 mRNA and protein expression in peripheral blood CD14+ monocytes and CD19+ B cells compared with G/G genotype, both under basal conditions and following stimulation. CONCLUSIONS: CD40 has been identified as a new susceptibility locus in Greek and Turkish patients with SLE. The rs4810485 minor allele T is under-represented in SLE and correlates with reduced CD40 expression in peripheral blood monocytes and B cells, with potential implications for the regulation of aberrant immune responses in the disease.
21853370 Integrin α(v)β₃ as a PET imaging biomarker for osteoclast number in mouse models of ne 2012 Aug PURPOSE: The goal of this study was to determine the specificity of ⁶⁴Cu-CB-TE2A-c(RGDyK) (⁶⁴Cu-RGD) for osteoclast-related diseases, such as Paget's disease or rheumatoid arthritis. PROCEDURES: C57BL/6 mice were treated systemically with osteoprotegerin (OPG) for 15 days or RANKL for 11 days to suppress and stimulate osteoclastogenesis, respectively. The mice were then imaged by positron emission tomography/computed tomography using ⁶⁴Cu-RGD, followed by determination of serum TRAP5b and bone histology. Standard uptake values were determined to quantify ⁶⁴Cu-RGD in bones and other tissues. RESULTS: Mice treated with OPG showed decreased bone uptake of ⁶⁴Cu-RGD at 1, 2, and 24 h post-injection of the tracer (p < 0.01 for all time points) compared to vehicle controls, which correlated with a post-treatment decrease in serum TRAP5b. In contrast, mice treated with RANKL showed significantly increased bone uptake at 2 h post-injection of (⁶⁴Cu-RGD (p < 0.05) compared to the vehicle control group, corresponding to increased serum TRAP5b and OC numbers as determined by bone histology. CONCLUSIONS: These data demonstrate that ⁶⁴Cu-RGD localizes to areas in bone with increased osteoclast numbers and support the use of ⁶⁴Cu-RGD as an imaging biomarker for osteoclast number that could be used to monitor osteoclast-related pathologies and their treatments.
21749853 No increased risk of myocardial infarction among patients with ulcerative colitis or Crohn 2011 Oct BACKGROUND & AIMS: Patients with chronic inflammatory diseases such as rheumatoid arthritis, systemic lupus erythematosus, and psoriasis have an increased risk of myocardial infarction (MI). Studies of the risk of MI among patients with inflammatory bowel disease have provided inconsistent results. We aimed to determine the risk of first-time acute MI in patients with ulcerative colitis (UC) or Crohn's disease (CD) compared with patients from general practice. METHODS: We conducted 2 retrospective cohort studies using the General Practice Research Database. A total of 15,498 UC patients were matched to 144,605 general practice patients (for age, sex, year of enrollment in the General Practice Research Database, and general practice of attendance) and were followed up for a mean of 4.7 years; 9829 CD patients were matched to 92,987 patients from general practice and followed up for a mean of 4.5 years. Univariable and multivariable Cox regression analyses were adjusted for age, sex, history of hypertension, diabetes mellitus, hypercholesterolemia, smoking status, body mass index, and aspirin use for each cohort. RESULTS: Patients with UC had a significantly increased risk of first-time acute MI compared with patients from general practice in unadjusted, but not adjusted, analysis (adjusted hazard ratio, 1.11; 95% confidence interval, 0.98-1.27). Patients with CD did not have an increased risk of MI in either unadjusted or adjusted analyses (adjusted hazard ratio, 1.09; 95% confidence interval, 0.89-1.34). CONCLUSIONS: Unlike some other chronic inflammatory diseases, inflammatory bowel disease is not associated with an increased risk of MI.
21239756 Assessment of subclinical vascular disease associated with ankylosing spondylitis. 2011 Apr OBJECTIVE: Studies indicate that ankylosing spondylitis (AS), as well as rheumatoid arthritis, may be associated with accelerated atherosclerosis and vascular disease. We assessed endothelial dysfunction, carotid atherosclerosis, and aortic stiffness in AS in context with clinical and laboratory measurements. METHODS: Forty-three patients with AS and 40 matched healthy controls were studied. We assessed common carotid intima-media thickness (ccIMT), flow-mediated vasodilation (FMD), and pulse-wave velocity (PWV) in association with age, disease duration, smoking habits, body mass index, patient's assessment of pain and disease activity, Bath AS Disease Activity Index, Bath AS Functional Index (BASFI), metric measurements, erythrocyte sedimentation rate, C-reactive protein, and HLA-B27 status. RESULTS: We found impaired FMD (6.85 ± 2.98% vs 8.30 ± 3.96%; p = 0.005), increased ccIMT (0.65 ± 0.15 vs 0.54 ± 0.15 mm; p = 0.01), and higher PWV (8.64 ± 2.44 vs 8.00 ± 1.46 m/s; p = 0.03) in patients with AS compared to controls, respectively. We also found that ccIMT negatively correlated with FMD (r = -0.563; p = 0.0001) and positively correlated with PWV (r = 0.374; p = 0.018). Both ccIMT and PWV correlated with disease duration (r = 0.559; p = 0.013 and r = 0.520; p = 0.022, respectively), BASFI (r = 0.691; p = 0.003 and r = 0.654; p = 0.006), decreased lumbar spine mobility (r = -0.656; p = 0.006 and r = -0.604; p = 0.013), chest expansion (r = -0.502; p = 0.047 and r = -0.613; p = 0.012), and increased wall-occiput distance (r = 0.509; p = 0.044 and r = 0.614; p = 0.011). CONCLUSION: In this well characterized AS population, impaired FMD and increased ccIMT and PWV indicate abnormal endothelial function and increased atherosclerosis and aortic stiffness, respectively. The value of noninvasive diagnostic tools needs to be further characterized.
21196595 Prevalence of musculoskeletal pain and rheumatic diseases in the southeastern region of Me 2011 Jan OBJECTIVE: To assess the prevalence of musculoskeletal (MSK) pain and rheumatic diseases in the southeastern Mexican state of Yucatán. METHODS: Using the Community Oriented Program in the Rheumatic Diseases (COPCORD) methodology, we performed a door-to-door, cross-sectional study generated through a multistage, stratified, randomized method on 3915 adult residents (age 42.7 ± 17.1 yrs; women 61.8%; urban setting 45.7%) of the Mexican state of Yucatán. We used universally accepted criteria for the diagnosis or classification of rheumatoid arthritis (RA), osteoarthritis (OA; knee and hand), fibromyalgia, systemic lupus erythematosus (SLE), gout, ankylosing spondylitis, regional rheumatic pain syndromes, and inflammatory back pain. RESULTS: Nontraumatic MSK pain in the last 7 days was present in 766 (19.6%; 95% CI 18.3-20.8) individuals. MSK pain was more prevalent in women (26.6%) versus men (12.2%; p < 0.01). Self-reported MSK disability occurred in 1.7%. Most MSK pain-related variables were consistently more prevalent in the urban setting. The prevalence of rheumatic disease was: OA 6.8% (95% CI 6.0-7.6); back pain 3.8% (95% CI 3.2-4.4); RA 2.8% (95% CI 2.2-3.3); rheumatic regional pain syndromes 2.3% (95% CI 1.9-2.8); inflammatory back pain 0.7% (95% CI 0.5-1.0); fibromyalgia 0.2% (95% CI 0.1-0.4); gout 0.1% (95% CI 0.07-0.3); and SLE 0.07% (95% CI 0.01-0.2). CONCLUSION: The prevalence of MSK pain was 19.6%. MSK pain was more prevalent in women and in the urban setting. A remarkably high prevalence of RA was found in this population, which suggests a role for geographic factors.
21751240 Zoledronic acid inhibits macrophage SOCS3 expression and enhances cytokine production. 2011 Nov Suppressor of cytokine signaling-3 (SOCS3) has multiple functions including inhibition of Janus kinase (Jak) activity, regulation of protein degradation, and suppression of cytokine signaling. SOCS3 modulates macrophage response to cytokines such as IL-6 and leptin that are systemically induced in obesity. Obesity is a suspected risk factor for SOCS3-related pathology such as rheumatoid arthritis and Crohn's disease as well as zoledronic acid (ZA)-induced osteonecrosis of the jaw (ONJ). Thus, understanding the ability of bisphosphonates to modulate SOCS3 is necessary to qualify their contribution to these disorders. ONJ occurs in up to 10% of patients using intravenous bisphosphonates and has an unknown pathogenesis that may be linked to decreased bone turnover, altered vascularity, bacterial invasion, and compromised wound healing. Given the increased risk of ONJ with obesity and importance of macrophages in wound healing, we hypothesized that amino-bisphosphonates could contribute to the pathogenesis of ONJ by regulating macrophage responses to cytokines such as leptin and IL-6. We report that ZA is a novel inhibitor of SOCS3 in primary macrophages and human ONJ biopsy specimens. Inhibition of SOCS3 by ZA resulted in significant increases in IL-6 production. SOCS3 transcription is regulated by nuclear accumulation of phosphorylated-Stat3 (P-Stat3). We found that ZA decreased phosphorylation of Stat3 in a mevalonate-pathway dependent manner. However, restoration of P-Stat3 was not sufficient to correct SOCS3 inhibition. We propose that disruption of macrophage SOCS3 expression by amino-bisphosphonates such as ZA may be a novel contributor to inflammatory phenotypes in obesity and the pathogenesis of ONJ.
21457061 Investigational A₃ adenosine receptor targeting agents. 2011 Jun INTRODUCTION: Adenosine is an endogenous nucleoside that accumulates in the extracellular space in response to metabolic stress and cell damage. Extracellular adenosine is a signaling molecule that signals by activating four GPCRs: the A(1), A(2A), A(2B) and A(3) receptors. Since the discovery of A(3) adenosine receptors, accumulating evidence has identified these receptors as potential targets for therapeutic intervention. AREAS COVERED: A(3) adenosine receptors are expressed on the surface of most immune cell types, including neutrophils, macrophages, dendritic cells, lymphocytes and mast cells. A(3) adenosine receptor activation on immune cells governs a broad array of immune cell functions, which include cytokine production, degranulation, chemotaxis, cytotoxicity, apoptosis and proliferation. In accordance with their multitudinous immunoregulatory actions, targeting A(3) adenosine receptors has been shown to impact the course of a wide spectrum of immune-related diseases, such as asthma, rheumatoid arthritis, cancer, ischemia and inflammatory disorders. EXPERT OPINION: Given the existence of both preclinical and early clinical data supporting the utility of A(3) adenosine receptor ligands in treating immune-related diseases, further development of A(3) adenosine receptor ligands is anticipated.
21312239 Stromal cell-derived factor-1/CXCR4 promotes IL-6 production in human synovial fibroblasts 2011 Apr The production of chemokine stromal cell-derived factor (SDF)-1 is significantly higher in synovial fluid of patients with osteoarthritis (OA). IL-6 is a multifunctional cytokine that plays a central role in both OA and rheumatoid arthritis. However, the effects of SDF-1α on human synovial fibroblasts are largely unknown. In this study, we investigated the intracellular signaling pathway involved in SDF-1α-induced IL-6 production in human synovial fibroblast cells. SDF-1α caused concentration- and time-dependent increases in IL-6 production. SDF-1α also increased the mRNA and surface expression of CXCR4 receptor in human synovial fibroblasts. CXCR4-neutralizing antibody, CXCR4-specific inhibitor (AMD3100), or small interfering RNA against CXCR4 inhibited the SDF-1α-induced increase of IL-6 expression. The transcriptional regulation of IL-6 by SDF-1α was mediated by phosphorylation of phosphatidylinositol 3-kinase (PI3K)/Akt and activation of the activator protein (AP)-1 component of c-Jun. The binding of c-Jun to the AP-1 element on the IL-6 promoter and the increase in AP-1 luciferase activity was enhanced by SDF-1α. Co-transfection with CXCR4, PI3K, Akt, and c-Jun mutants or siRNA inhibited the potentiating action of SDF-1α on AP-1 promoter activity. Taken together, our results suggest that SDF-1α-increased IL-6 production in human synovial fibroblasts via the CXCR4 receptor, PI3K, Akt, c-Jun, and AP-1 signaling pathways.