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ID PMID Title PublicationDate abstract
22954486 Celastrol inhibits interleukin-17A-stimulated rheumatoid fibroblast-like synoviocyte migra 2012 Dec Interleukin-17A (IL-17A)-induced migration and invasion of fibroblast-like synoviocytes (FLSs) is critical for the pathogenesis of rheumatoid arthritis (RA). More than 30% of RA patients are resistant to available therapies, despite the introduction of novel biologic agents. Therefore, it is necessary to develop new anti-arthritic agents. Recent studies have demonstrated that celastrol has anti-arthritic activity in an adjuvant-induced arthritis (AIA) model. However, the effect and molecular mechanisms of celastrol on the migration and invasion of RA-FLSs are not yet understood. Results showed that treatment of RA-FLSs with celastrol suppressed the IL-17A-induced migration and invasion abilities of the cells. In addition, celastrol inhibited IL-17A-induced matrix metalloproteinase (MMP)-9 mRNA and protein expression, and the proteolytic activity of MMP-9 in RA-FLSs. Furthermore, our results revealed that celastrol inhibited the transcriptional activity of MMP-9 by suppression of the binding activity of nuclear factor-κB (NF-κB) in the MMP-9 promoter, and inhibited IκBα phosphorylation and nuclear translocation of NF-κB. In conclusion, celastrol can inhibit IL-17A-induced migration and invasion by suppressing NF-κB-mediated MMP-9 expression in RA-FLSs. These results provide a strong rationale for further testing and validation of celastrol as an adjunct with conventional drugs for the treatment of RA in humans.
23014354 The L-arginine/asymmetric dimethylarginine ratio is improved by anti-tumor necrosis factor 2012 Nov BACKGROUND: Anti-Tumor Necrosis Factor (TNF)-α therapy improves vascular pathology in inflammatory arthropathies such as rheumatoid arthritis, ankylosing spondylitis and psoriatic arthritis. The l-arginine/ADMA ratio is important for modulation of the nitric oxide synthase activity. We examined the effect of TNF-α antagonists on ADMA and l-arginine/ADMA, and associations between ADMA, L-arginine/ADMA, aortic stiffness and carotid intima media thickness (CIMT) in patients with inflammatory arthropathies. METHODS: Forty-eight patients who started with anti-TNF-α therapy were compared with a non-treated group of 32 patients. Plasma ADMA and L-arginine were assessed at baseline, 3 and 12 months. In a subgroup of 55 patients, aortic pulse wave velocity (aPWV) was measured at baseline, 3 and 12 moths, and CIMT was examined at baseline and 12 months. RESULTS: Anti-TNF-α therapy increased the L-arginine/ADMA ratio (mean [SD]) in the treatment group compared to the control group after 3 months (12 [29] vs. -13 [20], P < 0.001) and 12 months (7 [27] vs. -8 [19], P = 0.008), but did not affect ADMA (3 months: 0.00 [0.09] μmol/L vs. 0.02 [0.07] μmol/L, P = 0.42, 12 months: 0.01 [0.08] μmol/L vs. 0.01 [0.09] μmol/L, P = 0.88). Baseline aPWV was associated with ADMA (P = 0.02) and L-arginine/ADMA (P = 0.02) in multiple regression analyses, and the L-arginine/ADMA ratio was continuously associated with aPWV after initiation of anti-TNF-α therapy (P = 0.03). ADMA and L-arginine/ADMA were not correlated with CIMT. CONCLUSION: Anti-TNF-α therapy improved the L-arginine/ADMA ratio in patients with inflammatory arthropathies. ADMA and the L-arginine/ADMA ratio were associated with aPWV, and might have a mechanistic role in the aortic stiffening observed in these patients.
22119038 Adiponectin and its globular fragment differentially modulate the oxidative burst of prima 2012 Feb Adiponectin (Acrp30) belongs to the family of C1q/tumor necrosis factor α (TNFα)-related proteins. Acrp30 circulates as multimers of high, middle, and low molecular weight. In this study, we detected Acrp30 and its globular fragment (gAcrp30) in synovial fluid from rheumatoid arthritis patients. Intriguingly, the LMW form was more abundant in synovial fluid than in serum from both rheumatoid arthritis patients and healthy subjects. We also investigated the effects of Acrp30 and gAcrp30 on reactive oxygen species (ROS) production via the phagocytic NADPH oxidase. Acrp30 inhibited fMLF-induced ROS production by human phagocytes, whereas gAcrp30 enhanced it. gAcrp30's effect is additive with TNFα, whereas Acrp30 inhibited TNFα-induced priming. gAcrp30 enhanced NOX-2 expression at the plasma membrane, with a concomitant increase in p47(phox) phosphorylation. Selective inhibitors of p38 mitogen-activated protein kinase (MAPK) and extracellular signal-regulated kinase 1 (ERK1)/2 abrogated p47(phox) phosphorylation by gAcrp30. In contrast, p47(phox) phosphorylation was inhibited by Acrp30 in association with increased AMP-activated protein kinase (AMPK) phosphorylation in phagocytes. These results suggest that human phagocyte ROS production is regulated by different mechanisms selective for Acrp30 versus gAcrp30. An imbalance between gAcrp30 and higher molecular weight isoforms of Acrp30 might contribute to chronic inflammation by regulating NADPH oxidase.
22257996 Indications and reoperation rates for total elbow arthroplasty: an analysis of trends in N 2012 Jan 18 BACKGROUND: Total elbow arthroplasty was originally used to treat patients with arthritis. As familiarity with total elbow arthroplasty evolved, the indications were expanded to include other disorders. There continues to be a low number of total elbow arthroplasties performed each year in comparison with hip, knee, and shoulder arthroplasties, and few large studies have examined the indications and associated complications of total elbow arthroplasty. The purposes of this study were to evaluate the changes with time in the indications for total elbow arthroplasty and to examine the complications of this procedure in a large database. METHODS: The Statewide Planning and Research Cooperative System database from the New York State Department of Health, a census of all ambulatory and inpatient surgical procedures in the state of New York, was used to identify individuals who underwent primary total elbow arthroplasty during the time period of 1997 to 2006. These total elbow arthroplasties were evaluated for admitting diagnoses, sex and age of patient, readmission and complication data, and time to subsequent elbow surgery. RESULTS: From 1997 to 2006, there were 1155 total elbow arthroplasties performed in New York State. In 1997, 43% of the total elbow arthroplasties were associated with trauma and 48%, with inflammatory conditions. In 2006, this changed to 69% and 19%, respectively. Within ninety days after the primary total elbow arthroplasty, 12% of the patients were readmitted to the hospital with approximately one-half (5.6%) admitted for problems related to the total elbow arthroplasty. The overall revision rate was 6.4%. The revision rates for the traumatic, inflammatory arthritis, and osteoarthritis groups were 4.8%, 8.3%, and 14.7%, respectively. Of particular interest, 90.5% of the total elbow arthroplasties were performed by surgeons with no recorded experience in the database, which began collecting these data in 1986. CONCLUSIONS: This study provides useful information regarding patients undergoing total elbow arthroplasty in New York State. During the study period, the most common indication for total elbow arthroplasty changed from inflammatory arthritis to trauma. Although the number of total elbow arthroplasties being performed each year has increased, there continues to be a high complication and revision rate.
21752575 To use or not to use continuous passive motion post-total knee arthroplasty presenting fun 2012 Feb Continuous passive motion (CPM), though of doubtful value, is yet routinely practiced post-total knee arthroplasty (TKA). We prospectively distributed 84 patients with TKA to 1 of the 3 standard rehabilitation regimes: no-CPM, 1-day-CPM, and 3-day-CPM. We recorded a unique "Timed up and go" test besides pain, Western Ontario and McMaster Universities (WOMAC), short form-12 (SF-12), range of motion, knee and calf swelling, and wound healing parameters. Our standardized and elaborate measurements preoperatively and on postoperative days 3, 5, 14, 42, and 90 showed no statistically significant difference among the 3 groups in each parameter. We concluded that CPM gives no benefit in immediate functional recovery post-TKA, and in fact, the postoperative knee swelling persisted longer. We have since then discontinued its use in our patients without any untoward effect.
22442340 Suppressive effects of PG201, an antiarthritic botanical formulation, on lipopolysaccharid 2012 May PG201, an ethanol extract from a mixture of 12 herbs, has strong antiarthritic activity. To understand the molecular mechanisms underlying its anti-inflammatory effects, PG201-mediated suppression of inflammatory mediators was studied in Raw264.7, a mouse macrophage cell line. PG201 decreased the expression of interleukin (IL)-1β, IL-6 and CC chemokine ligand-2, but not tumor necrosis factor-α, at the protein and mRNA levels in lipopolysaccharide-stimulated Raw264.7 cells. Results from a gel retardation assay indicated that PG201 substantially reduced the DNA-binding activity of the activator protein-1 and cyclic adenosine monophosphate-responsive element-binding protein transcription factors, but not nuclear factor-κB. Western blot and Northern blot analyses showed that PG201 reduced inducible nitric oxide synthase and cytosolic phospholipase A(2) (cPLA(2)) protein expression, but did not affect mRNA expression, ultimately resulting in decreased nitric oxide and prostaglandin E(2). The protein expression of cPLA(2) was decreased by PG201 in the presence of cycloheximide, an inhibitor of translation, suggesting that PG201 may facilitate the degradation of cPLA(2). Taken together, these results suggest that PG201 selectively affects the expression of proteins that play key roles in the inflammatory response at transcriptional and post-translational levels.
22149579 HZT-501 (DUEXIS(®); ibuprofen 800 mg/famotidine 26.6 mg) gastrointestinal protection in t 2012 Feb Arthritis affects nearly 50 million people in the USA and, with the aging of the population, the prevalence is expected to rise. While NSAIDs are very effective in relieving pain associated with osteoarthritis (OA) and rheumatoid arthritis (RA), they are associated with side effects, including gastrointestinal (GI) toxicity, which may manifest as dyspepsia, ulcers and/or bleeding. A number of approaches have been employed in an effort to either completely avoid or reduce the risk of GI toxicities associated with NSAID use. Two new products combining an NSAID with a gastroprotective agent have recently been approved and other agents are in the pipeline. Patient adherence to prescribed gastroprotective therapy is known to be poor, often resulting in an increased risk of GI events in patients taking NSAIDs. These newer combination products may fulfill an important need for many patients who need to receive NSAIDs for the pain of OA and RA, but who are also at risk of upper GI events. This article reviews preclinical and clinical results for a new fixed-dose combination of ibuprofen and famotidine, DUEXIS(®) (HZT-501), which has recently been approved in the USA for the relief of signs and symptoms of RA and OA and to decrease the risk of developing upper GI ulcers.
21441820 Adult leukemic synovitis is associated with leukemia of monocytic differentiation. 2011 Apr BACKGROUND: Leukemic synovitis is a rare complication of adult myeloid leukemias characterized by joint pain and swelling. It is important to recognize this diagnostic challenge as it may be the initial manifestation of leukemia or of relapse. METHODS: A retrospective search of patient files from 2 teaching hospitals identified 4 adult patients who presented with large joint arthritis and concurrent or subsequent leukemic synovitis. All patients presented with inflammatory arthritis of large joints, and leukemic synovitis was identified by the presence of leukemic cells in the synovial fluid or infiltrating the synovial membrane seen at biopsy. RESULTS: A leukemia of monocytic origin-acute myelomonocytic leukemia or chronic myelomonocytic leukemia-was diagnosed in all 4 patients. In 2 cases, leukemic synovitis was the initial manifestation of leukemia. In the third case, it was the first sign of relapse, and in the remaining case, it developed shortly after diagnosis of leukemia. All patients had either osteoarthritis or rheumatoid arthritis. One patient was diagnosed simultaneously with osteoarthritis and leukemia. The remaining patients had a prior history of arthritis. CONCLUSIONS: Adult leukemic synovitis occurs in association with leukemias of monocytic differentiation. Data presented here, and review of isolated case reports, support this association. The finding of large joint arthritis as a comorbidity in these 4 cases raises questions about the role of antecedent arthritis as a predisposing factor in the pathophysiology of leukemic synovitis.
23001613 Pneumocystis jirovecii infection: an emerging threat to patients with rheumatoid arthritis 2012 Dec Accompanying the increased use of biologic and non-biologic antirheumatic agents, patients with RA have been exposed to an increased risk of Pneumocystis jirovecii infection, which causes acute fulminant P. jirovecii pneumonia (PCP). Mortality in this population is higher than in HIV-infected individuals. Several guidelines and recommendations for HIV-infected individuals are available; however, such guidelines for RA patients remain less clear. Between 2006 and 2008 we encountered a clustering event of P. jirovecii infection among RA outpatients. Through our experience with this outbreak and a review of the recent medical literature regarding asymptomatic colonization and its clinical significance, transmission modes of infection and prophylaxis of PCP, we have learned the following lessons: PCP outbreaks among RA patients can occur through person-to-person transmission in outpatient facilities; asymptomatic carriers serve as reservoirs and sources of infection; and short-term prophylaxis for eradication of P. jirovecii is effective in controlling PCP outbreaks among RA outpatients.
23212731 Osteoarthritis synovial fluid activates pro-inflammatory cytokines in primary human chondr 2013 Jan PURPOSE: Two of the most common joint diseases are rheumatoid arthritis (RA) and osteoarthritis (OA). Cartilage degradation and erosions are important pathogenetic mechanisms in both joint diseases and have presently gained increasing interest. The aim of the present study was to investigate the effects of the synovial fluid environment of OA patients in comparison with synovial fluids of RA patients on human chondrocytes in vitro. METHODS: Primary human chondrocytes were incubated in synovial fluids gained from patients with OA or RA. The detection of vital cell numbers was determined by histology and by using the Casy Cell Counter System. Cytokine and chemokine secretion was determined by a multiplex suspension array. RESULTS: Microscopic analysis showed altered cell morphology and cell shrinkage following incubation with synovial fluid of RA patients. Detection of vital cells showed a highly significant decrease of vital chondrocyte when treated with RA synovial fluids in comparison with OA synovial fluids. An active secretion of cytokines such as vascular endothelial growth factor (VEGF) of chondrocytes treated with OA synovial fluids was observed. CONCLUSIONS: Significantly increased levels of various cytokines in synovial fluids of RA, and surprisingly of OA, patients were shown. Activation of pro-inflammatory cytokines of human chondrocytes by synovial fluids of OA patient supports a pro-inflammatory process in the pathogenesis of OA.
21412181 Genetic variation in UGT1A1 typical of Gilbert syndrome is associated with unconjugated hy 2011 Jul OBJECTIVE: Tocilizumab, a monoclonal antibody to interleukin-6 receptor, was recently approved for the treatment of moderate-to-severe rheumatoid arthritis. Two patients during clinical development met laboratory, but not clinical, criteria for Hy's law with bilirubin elevations suspected as a result of genetic variation in uridine diphosphoglucose glucuronosyltransferase (UGT1A1) typical of Gilbert syndrome. METHODS: Genotyping of the two cases potentially meeting with Hy's law was performed using commercially available procedures. UGT1A1 single nucleotide polymorphism data were extracted from a genome-wide array database for 1187 patients from tocilizumab trials, and associations of UGT1A1 genotypes with bilirubin elevations were analyzed using logistic regression for associations with baseline and change from baseline in bilirubin levels as continuous variables. RESULTS: Bilirubin elevations were not associated with clinical adverse events. Both patients potentially meeting Hy's law carry homozygous UGT1A1*28 alleles and UGT1A1*60 alleles. UGT1A1*28 and three additional single nucleotide polymorphisms showed odds ratios greater than 25 for associations with elevated bilirubin. The presence of rs6742078 accounted for 32% of the total variance in bilirubin (P=2.2×10). CONCLUSION: Bilirubin increases occurring with tocilizumab appear to be related to anti-inflammatory effects extending to the liver. Thus, in the absence of other signs of hepatic dysfunction, bilirubin elevations after treatment with tocilizumab have a high probability of association with UGT1A1 polymorphism, which should alleviate concerns of serious hepatotoxicity. Our results underscore the value of genotyping in the clinical trial setting to avoid misinterpretations that could lead to terminating development of a promising new agent.
21371856 Comparison between closed suction drainage and nondrainage in total knee arthroplasty: a m 2011 Dec From individual randomized studies, it is not clear whether a closed suction drainage should be used after total knee arthroplasty. Our meta-analysis compares the clinical outcomes of closed suction drainage with nondrainage after total knee arthroplasty in randomized controlled trials reported between January 1966 and May 2010. Fifteen eligible trials involving 1361 knee incisions (686 knees with closed suction drainage and 675 knees without drainage) satisfied the inclusion criteria for our meta-analysis. The result of the meta-analysis indicates that closed suction drainage reduces the incidence of soft tissue ecchymosis and requirement for dressing reinforcement, but increases the rate of homologous blood transfusion. No significant difference between drainage and nondrainage was observed in the incidence of infection, deep venous thrombosis, or postoperative range of motion.
21074358 The Stanmore knee arthrodesis prosthesis. 2011 Sep Knee arthrodesis is most commonly performed for failed total knee arthroplasty. Conventional arthrodesis techniques are associated with a high incidence of complications and are unsuitable in cases with extensive bone loss. We report our medium-term results using a custom-made cemented knee arthrodesis prosthesis in 10 patients with a mean follow-up of 56.4 months (range, 15-199 months). The prosthesis was implanted as a 1- or 2-stage procedure for infected revision knee arthroplasty or tumor endoprosthesis in 9 patients and as a primary procedure in 1 patient with angiosarcoma involving the knee extensor mechanism. The average combined femoral and tibial bone deficit was 170 mm (range, 56-220 mm). Implant survivorship was 90%. All patients with retained prosthesis had no evidence of residual infection or loosening and were able to mobilize independently. One prosthesis was revised though retained following a prosthetic fracture, and 1 patient underwent above-knee amputation for uncontrolled infection. We conclude that the Stanmore knee arthrodesis prosthesis provides reliable fusion in an otherwise difficult-to-treat group of patients.
22201618 IL-4 can inhibit IL-17 production in collagen induced arthritis. 2011 Dec BACKGROUND: IL-4 is a cytokine that induces differentiation of naive helper T cells into Th2 cells. Once activated by IL-4, Th2 cells subsequently produce additional IL-4. OBJECTIVE: To examine the effect of IL-4 on IL-17 production and its effect in Collagen-Induced Arthritis (CIA) mice. METHOD: In this study, a chicken collagen-II-induced experimental arthritis (CIA) model was used in DBA/1 mice to investigate the relationship between IL-4 and IL-17 as well as other inflammatory factors. On the 38th day after the mice were induced with CIA, the expression of IL-17 and IL-4 as well as IFN-γ and IL-13 in sera of the mice was measured by QRT-PCR and ELISA. RESULT: The result of QRT-PCR analysis of IL-17 and IL-4 mRNA levels in the spleen showed that IL-17 is increased significantly at the onset of CIA in the spleen (p<0.01). Meanwhile, IL-17 is generally reduced at the peak of CIA but IL-4 is increased significantly at this peak in the spleen when the weight of the animal was taken into consideration (p<0.05). CONCLUSION: IL-4 can be involved in the production of IL-17 at especially the peak of CIA. These results imply that the inhibition of IL-17 may decrease the expression of IL-1β and IL-6 production which will result in the aggravation of arthritis.
21618201 Subcutaneous abatacept versus intravenous abatacept: a phase IIIb noninferiority study in 2011 Oct OBJECTIVE: To compare the efficacy and safety of subcutaneous (SC) and intravenous (IV) abatacept. METHODS: In this phase IIIb double-blind, double-dummy, 6-month study, patients with rheumatoid arthritis (RA) and inadequate responses to methotrexate were randomized to receive 125 mg SC abatacept on days 1 and 8 and weekly thereafter (plus an IV loading dose [∼10 mg/kg] on day 1) or IV abatacept (∼10 mg/kg) on days 1, 15, and 29 and every 4 weeks thereafter. The primary end point for determining the noninferiority of SC abatacept to IV abatacept was the proportion of patients in each group meeting the American College of Rheumatology 20% improvement criteria (achieving an ACR20 response) at month 6. Other efficacy end points, immunogenicity, and safety were also assessed. RESULTS: Of 1,457 patients, 693 of 736 (94.2%) treated with SC abatacept and 676 of 721 (93.8%) treated with IV abatacept completed 6 months. At month 6, 76.0% (95% confidence interval 72.9, 79.2) of SC abatacept-treated patients versus 75.8% (95% confidence interval 72.6, 79.0) of IV abatacept-treated patients achieved an ACR20 response (estimated difference between groups 0.3% [95% confidence interval -4.2, 4.8]), confirming noninferiority of SC abatacept to IV abatacept. Onset and magnitude of ACR responses and disease activity and physical function improvements were comparable between the SC and IV abatacept-treated groups. The proportions of adverse events (AEs) and serious AEs over 6 months were 67.0% and 4.2%, respectively, in the SC abatacept-treated group and 65.2% and 4.9%, respectively, in the IV abatacept-treated group, with comparable frequencies of serious infections, malignancies, and autoimmune events between groups. SC injection site reactions (mostly mild) occurred in 19 SC abatacept (IV placebo)-treated patients (2.6%) and 18 IV abatacept (SC placebo)-treated patients (2.5%). Abatacept-induced antibodies occurred in 1.1% of SC abatacept-treated patients and 2.3% of IV abatacept-treated patients. CONCLUSION: SC abatacept provides efficacy and safety comparable with that of IV abatacept, with low immunogenicity and high retention rates, consistent with the established IV abatacept profile. Rates of injection site reactions were low. SC abatacept will provide additional treatment options, such as an alternative route of administration, for patients with RA.
21362767 Interaction between smoking and polymorphism in the promoter region of the VEGFA gene is a 2011 May OBJECTIVE: To determine whether variants in the vascular endothelial growth factor A (VEGFA) gene are associated with ischemic heart disease (IHD) and/or myocardial infarction (MI) in patients with rheumatoid arthritis (RA), and whether there is evidence of a gene-smoking interaction. METHODS: PCR-RFLP assays were used to determine the genotypes of VEGFA single-nucleotide polymorphisms (SNP) including VEGFA-2578A/C (rs699947), -460C/T (rs833061), +405C/G (rs2010963), and +936C/T (rs3025039) in 418 subjects with RA. Smoking history was obtained on each patient, and IHD and MI status was recorded. Associations with IHD/MI were assessed using contingency tables and logistic regression analyses. RESULTS: Strong linkage disequilibrium was detected among VEGFA-2578, -460, and +405. SNP located in the VEGFA promoter region (-2578, -460) were found to be associated with IHD and MI, whereas +405 and +936, in the 5'-untranslated region (UTR) and 3'-UTR, respectively, were not. Haplotype analysis suggested that the A/C/G haplotype was associated with increased risk of IHD (OR 2.37, 95% CI 1.22-4.62) and MI (OR 4.10, 95% CI 1.45-11.49). Smoking was also independently associated with IHD and MI, and evidence of interaction between smoking and the VEGFA promoter SNP was found. Multivariate analyses indicated that the strongest associations with IHD and MI were due to the combined effect of the VEGFA-2578 A allele and smoking (OR 3.52 and 7.11, respectively), independent of risk factors such as age, sex, diabetes, C-reactive protein, hypercholesterolemia, and hypertension. CONCLUSION: Interaction between smoking and polymorphism in the VEGFA gene is associated with IHD and MI in patients with RA.
22504558 Drug retention rates and relevant risk factors for drug discontinuation due to adverse eve 2012 Nov OBJECTIVE: To compare reasons for discontinuation and drug retention rates per reason among anticytokine therapies, infliximab, etanercept and tocilizumab, and the risk of discontinuation of biological agents due to adverse events (AE) in patients with rheumatoid arthritis (RA). METHOD: This prospective cohort study included Japanese RA patients who started infliximab (n=412, 636.0 patient-years (PY)), etanercept (n=442, 765.3 PY), or tocilizumab (n=168, 206.5 PY) as the first biological therapy after their enrolment in the Registry of Japanese Rheumatoid Arthritis Patients for Long-term Safety (REAL) database. Drug retention rates were calculated using the Kaplan-Meier method. To compare risks of drug discontinuation due to AE for patients treated with these biological agents, the Cox proportional hazard model was applied. RESULTS: The authors found significant differences among the three therapeutic groups in demography, clinical status, comorbidities and usage of concomitant drugs. Development of AE was the most frequent reason for discontinuation of biological agents in the etanercept and tocilizumab groups, and the second most frequent reason in the infliximab group. Discontinuation due to good control was observed most frequently in the infliximab group. Compared with etanercept, the use of infliximab (HR 1.69; 95% CI 1.14 to 2.51) and tocilizumab (HR 1.98; 95% CI 1.04 to 3.76) was significantly associated with a higher risk of discontinuation of biological agents due to AE. CONCLUSIONS: Reasons for discontinuation are significantly different among biological agents. The use of infliximab and tocilizumab was significantly associated with treatment discontinuation due to AE compared with etanercept.
21368773 Peripheral blood gene expression profiles in metabolic syndrome, coronary artery disease a 2011 Jul To determine if individuals with metabolic disorders possess unique gene expression profiles, we compared transcript levels in peripheral blood from patients with coronary artery disease (CAD), type 2 diabetes (T2D) and their precursor state, metabolic syndrome to those of control (CTRL) subjects and subjects with rheumatoid arthritis (RA). The gene expression profile of each metabolic state was distinguishable from CTRLs and correlated with other metabolic states more than with RA. Of note, subjects in the metabolic cohorts overexpressed gene sets that participate in the innate immune response. Genes involved in activation of the pro-inflammatory transcription factor, NF-κB, were overexpressed in CAD whereas genes differentially expressed in T2D have key roles in T-cell activation and signaling. Reverse transcriptase PCR validation confirmed microarray results. Furthermore, several genes differentially expressed in human metabolic disorders have been previously shown to participate in inflammatory responses in murine models of obesity and T2D. Taken together, these data demonstrate that peripheral blood from individuals with metabolic disorders display overlapping and non-overlapping patterns of gene expression indicative of unique, underlying immune processes.
20962851 Members 6B and 14 of the TNF receptor superfamily in multiple sclerosis predisposition. 2011 Mar TNFRSF6B and TNFRSF14 genes were recently associated with Crohn's disease and rheumatoid arthritis. TNFRSF14 is known as herpes virus entry mediator (HVEM), and herpes viruses have been involved in the aetiology of multiple sclerosis (MS). MS patients present human herpes virus 6 (HHV6) in active plaques and increased antibody responses to HHV6. We aimed to ascertain the role of these genes in MS susceptibility and to investigate the relationship of the gene encoding the widely expressed HVEM receptor with the active replication of HHV6 found in some MS patients. Genotyping of 1370 Spanish MS patients and 1715 ethnically matched controls was performed. HHV6A DNA levels (surrogate of active viral replication) were analysed in serum of MS patients during a 2-year follow-up. Both polymorphisms were associated with MS predisposition, with stronger effect in patients with HHV6 active replication-TNFRSF6B-rs4809330(*)A: P=0.028, OR=1.13; TNFRSF14-rs6684865(*)A: overall P=0.0008, OR=1.2; and HHV6-positive patients vs controls: P=0.017, OR=1.69.
21247763 Pyridylmethylthio derivatives as VEGF inhibitors: part 2. 2011 Feb 15 Optimization of compounds 5 and 6 led to the discovery of VEGF inhibitor 10g which reduced CYP inhibition. It was highly active in vitro (VEGF induced HUVEC proliferation assay) and showed efficacies in three disease models in vivo (cancer, RA, and AMD).