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ID PMID Title PublicationDate abstract
17575494 Impact of transdermal fentanyl on quality of life in rheumatoid arthritis. 2007 Jul OBJECTIVES: The purpose of the study was to investigate the effectiveness and tolerability of transdermal fentanyl in a treatment regimen in patients with rheumatoid arthritis (RA). METHODS: Two hundred twenty-six patients (mean age 66 y) with severe pain caused by RA who had not previously been treated with transdermal fentanyl were included in this prospective, open-label study. Pain intensity, functional impairment, and well-being were documented prospectively for 30 days after treatment with transdermal fentanyl had been initiated. Patients evaluated pain on an 11-point numerical rating scale. Quality of sleep, daily and social functioning, and treatment satisfaction were rated using 5-point categorical rating scales. General well-being was assessed by the Marburg questionnaire. RESULTS: Adding transdermal fentanyl to the ongoing RA therapy reduced pain intensity significantly from 8.0 (7.82 to 8.18) to 4.0 (3.75 to 4.25). Mean functional impairment due to pain also decreased significantly from "severe" at the beginning to "mild to moderate." Treatment with transdermal fentanyl also led to a significant improvement by approximately 1.5 units for all items in the Marburg questionnaire on general well-being. At the end of the study, nearly all patients were satisfied with the pain treatment. Transdermal fentanyl was generally well tolerated. The most frequent side effects were nausea (9.7%) and vomiting (7.1%). DISCUSSION: Patients with pain caused by RA improved in terms of pain intensity, sleep, function, and general well-being when transdermal fentanyl was added to the treatment regimen. Treatment satisfaction was high. Transdermal fentanyl also demonstrated good tolerability over a period of 30 days.
17417989 The immunogenicity, safety, and efficacy of etanercept liquid administered once weekly in 2007 Jan OBJECTIVE: To evaluate the immunogenicity, safety, and efficacy of 50 mg/mL liquid etanercept. METHODS: In a multicenter, open-label study, adults with active rheumatoid arthritis (RA) received 50 mg/mL liquid etanercept subcutaneously once weekly for 24 weeks. Immunogenicity was assessed at baseline and weeks 24 and 28, safety at all study visits, and efficacy at baseline and weeks 12 and 24. RESULTS: Of 222 treated patients, 88% completed the study; 81% were women; 84% were white; mean age was 53 years; mean RA duration was 10 years. Antibodies to etanercept, all non-neutralizing, were detected in 12 of 214 patients; 7 of the 12 were borderline positive (antibody titers <1:50). The presence of non-neutralizing anti-etanercept antibodies did not appear to affect clinical safety or efficacy. Few patients reported serious adverse events (6.3%), serious infections (2.3%), or withdrew because of adverse events (4.5%). Most adverse events were mild or moderate. The most common event, injection site reaction, occurred in 29.3% patients. At week 24, 63% of patients achieved an ACR20 response, 36% an ACR50 response, and 14% an ACR70 response. Similar responses were apparent by week 12. Week 24 mean improvement in the Health Assessment Questionnaire disability index scores was 0.6 points; improvement in the Short Form-36 Physical Component Score was 10.0 points. CONCLUSION: The 50 mg/mL liquid etanercept formulation administered once weekly was well tolerated. The incidence of anti-etanercept antibodies, the nature and frequency of adverse events, and improvements in signs and symptoms of RA and patient physical function were similar to those in previous etanercept studies.
17764063 Sjögren's Syndrome. 2007 Aug Sjögren's syndrome (SS) is a chronic, slowly progressive, inflammatory, autoimmune disease characterized by (1) lymphocytic infiltration of the exocrine glands leading to diminished or absent glandular secretion, and (2) marked B-lymphocytic cell hyperreactivity manifested initially by a variety of serum autoantibodies, including those against the Ro(SSA) and La(SSB) ribonucleoproteins, ending in the development of B cell non-Hodgkin's lymphoma in a substantial number of patients. Most patients with SS present only with keratoconjunctivitis sicca and xerostomia. However, approximately 40% develop extraglandular manifestations that present in two ways: (1) the development of lymphoepithelial lesions in several extra-exocrine gland tissues (i.e., bronchi, renal tubules, or biliary ducts), and (2) vasculitis related to the deposition of immune complexes due to B cell hyperreactivity. Pulmonary manifestations develop in some patients and may present as (1) bronchitis sicca; (2) a wide spectrum of lymphoproliferative diseases, ranging from bronchus-associated lymphoid tissue (BALT) hyperplasia, lymphoid interstitial pneumonia, and B cell non-Hodgkin's lymphoma mainly of the extranodal marginal zone B-cell lymphoma of BALT-type or rarely of higher-grade malignancy; and (3) other interstitial pneumonias. Pleuritis can be seen in SS patients with associated systemic lupus erythematosus or rheumatoid arthritis.
18295513 Comparison of pharmacokinetics of glucosamine and synovial fluid levels following administ 2008 Sep OBJECTIVE: To compare the pharmacokinetics of glucosamine and the synovial fluid levels attained following treatment with glucosamine sulphate or glucosamine hydrochloride in a large animal model at clinically relevant doses. METHODS: Eight adult female horses were used. Crystalline glucosamine sulphate (Dona) or glucosamine hydrochloride was administered at a dose of 20 mg/kg by either intravenous (i.v.) injection or nasogastric (n.g.) intubation. Plasma samples were collected before dosing and at 5, 15, 30, 60, 120, 360, 480 and 720 min after dosing. Synovial fluid samples were collected from the radiocarpal joints within 48 h before dosing and at 1, 6 and 12 h post-dosing. Glucosamine was assayed by Liquid Chromatography Electrospray Tandem Mass Spectrometry (LC-ESI/MS/MS). RESULTS: Plasma concentrations reached approximately 50 microg/mL after i.v. injection and approximately 1 microg/mL after n.g. administration of both types of glucosamine. The median oral bioavailability was 9.4% for glucosamine sulphate and 6.1% for glucosamine hydrochloride. Synovial fluid concentrations were significantly higher at 1 and 6 h following oral treatment with glucosamine sulphate compared to glucosamine hydrochloride. Twelve hours following oral administration, glucosamine levels in the plasma and the synovial fluid were still significantly higher than baseline for the glucosamine sulphate preparation, but not for the hydrochloride preparation. CONCLUSION: Following oral administration of a clinically recommended dose of glucosamine sulphate (Dona), significantly higher synovial fluid concentrations of glucosamine are attained, when compared to an equivalent dose of glucosamine hydrochloride. Whether this difference is translated into a therapeutic effect on the joint tissues remains to be elucidated.
17265571 Pooled analysis of thrombotic cardiovascular events in clinical trials of the COX-2 select 2006 Dec BACKGROUND: A pooled analysis of randomized clinical trials data was performed to compare the rate of thrombotic cardiovascular events (thrombotic events) in patients taking the COX-2 selective inhibitor (coxib) etoricoxib, a traditional NSAID, or placebo. METHODS: Data collected during all phase IIb/III etoricoxib clinical trials > or = 4 weeks in duration were evaluated. The pooled data set includes clinical information from approximately 6500 patient-years (PYs) of drug exposure in patients diagnosed with rheumatoid arthritis (RA), osteoarthritis (OA), ankylosing spondylitis (AS), or chronic low back pain (CLBP). Patients were treated with either etoricoxib (> or = 60 mg/day), the traditional NSAIDs naproxen (1000 mg/day), ibuprofen (2400 mg/day), diclofenac (150 mg/day), or placebo. The Relative risks (RRs) based on time to first occurrence of a thrombotic event in the etoricoxib group versus the comparator traditional NSAIDs or versus placebo were determined using patient-level data. RESULTS: In the pooled dataset, a total of 74 thrombotic events occurred in 69 patients. The RRs for thrombotic events were 1.11 (95%CI: 0.32, 3.81) for etoricoxib (N = 2818) versus placebo (N = 1767); 0.83 (95%CI: 0.26, 2.64) for etoricoxib (N = 1266) versus the combined non-naproxen traditional NSAID group (ibuprofen and diclofenac; N = 718); and 1.70 (95%CI: 0.91, 3.18) for etoricoxib (N = 1960) versus naproxen (N = 1497). CONCLUSIONS: There was no discernible difference in the incidence of thrombotic events in patients treated with etoricoxib versus non-naproxen traditional NSAIDs in this limited dataset. A trend toward more events with etoricoxib versus naproxen was observed. Despite the limited dataset available for this pooled analysis, these results are consistent with findings for other coxibs.
18511547 Measuring quality of care for rheumatic diseases using an electronic medical record. 2009 May OBJECTIVES: The objective of this study was twofold: (1) to determine how best to measure adherence with time-dependent quality indicators (QIs) related to laboratory monitoring, and (2) to assess the accuracy and efficiency of gathering QI adherence information from an electronic medical record (EMR). METHODS: A random sample of 100 patients were selected who had at least three visits with the diagnosis of rheumatoid arthritis (RA) at Brigham and Women's Hospital Arthritis Center in 2005. Using the EMR, it was determined whether patients had been prescribed a disease-modifying antirheumatic drug (DMARD) (QI #1) and if patients starting therapy received appropriate baseline laboratory testing (QI #2). For patients consistently prescribed a DMARD, adherence with follow-up testing (QI #3) was calculated using three different methods, the Calendar, Interval and Rolling Interval RESULTS: It was found that 97% of patients were prescribed a DMARD (QI #1) and baseline tests were completed in 50% of patients (QI #2). For follow-up testing (QI #3), mean adherence was 60% for the Calendar Method, 35% for the Interval Method, and 48% for the Rolling Interval Method. Using the Rolling Interval Method, adherence rates were similar across drug and laboratory testing type. CONCLUSIONS: Results for adherence with laboratory testing QIs for DMARD use differed depending on how the QIs were measured, suggesting that care must be taken in clearly defining methods. While EMRs will provide important opportunities for measuring adherence with QIs, they also present challenges that must be examined before widespread adoption of these data collection methods.
18975322 Treatment of rheumatoid arthritis with a Syk kinase inhibitor: a twelve-week, randomized, 2008 Nov OBJECTIVE: Spleen tyrosine kinase (Syk) has been identified as an important modulator of immune signaling in B cells and cells bearing Fcgamma-activating receptors. R788, a prodrug of active metabolite R406, has been shown to be an inhibitor of Syk kinase, active in a variety of in vitro and in vivo models, suggesting potential activity in the treatment of rheumatoid arthritis (RA). METHODS: We enrolled 189 patients with active RA despite methotrexate therapy in a 3-month, multicenter, ascending-dose, double-blind, placebo-controlled trial. The primary end point was the American College of Rheumatology 20% improvement criteria (ACR20) response rate at week 12. RESULTS: Twice-daily oral doses of 100 mg and 150 mg of R788 were significantly superior to placebo or twice-daily oral doses of 50 mg at week 12 (ACR20 achieved in 65% and 72% versus 38% and 32% of patients, respectively [P < 0.01]). ACR50 (achieved in 49% and 57% versus 19% and 17% of patients, respectively) and ACR70 (achieved in 33% and 40% versus 4% and 2% of patients, respectively) scores showed a similar pattern. Clinical effect was noted as early as 1 week after initiation of therapy. Reductions in serum interleukin-6 and matrix metalloproteinase 3 levels also occurred as early as week 1 in the groups receiving 100 mg and 150 mg R788. The major adverse effects were gastrointestinal side effects (predominantly diarrhea) and neutropenia (<1,500/mm3), both of which were dose related. CONCLUSION: These results indicate that an inhibitor of Syk kinase produces significant clinical benefits at 12 weeks in a population of patients with active RA receiving methotrexate therapy. Syk kinase may be an important new therapeutic target in RA and related autoimmune conditions.
16463007 Positive effect of alendronate on bone mineral density and markers of bone turnover in pat 2006 INTRODUCTION: Alendronate has been described to have a bone-sparing effect in patients treated with moderate and high dosages of prednisone for heterogeneous diseases, however no data are available on groups of patients with the same underlying diseases who receive chronic low-dose prednisone treatment. The objective of the investigation reported here was, therefore, to study the effect of alendronate on bone mineral density (BMD) of the lumbar spine and hips in patients with rheumatoid arthritis (RA) who are on chronic low-dose prednisone treatment. METHODS: A total of 163 patients with RA, according to the ACR-criteria, were enrolled in a double-blind, placebo-controlled trial. The patients were treated with low-dose prednisone (
18821707 Epigallocatechin-3-gallate diminishes CCL2 expression in human osteoblastic cells via up-r 2008 Oct OBJECTIVE: To assess the effects of epigallocatechin-3-gallate (EGCG) on oncostatin M (OSM)-induced CCL2 synthesis and the associated signaling pathways in human osteoblastic cells. The therapeutic effect of EGCG on collagen-induced arthritis (CIA) in rats was also studied. METHODS: CCL2 and c-Fos messenger RNA expression was analyzed by Northern blotting. The modulating effects of EGCG on the activation of Raf-1, Akt, and phosphatidylinositol 3-kinase (PI 3-kinase) were examined by coimmunoprecipitation, Western blotting, and PI 3-kinase activity assay. Interactions between c-Fos and CCL2 promoter were evaluated by electrophoretic mobility shift assay (EMSA) and chromatin immunoprecipitation (ChIP) assay. The effect of EGCG on CIA in rats was examined clinically and immunohistochemically. RESULTS: EGCG inhibited OSM-stimulated CCL2 expression in primary human osteoblasts and MG-63 cells. In MG-63 cells, EGCG alleviated the OSM-induced phosphorylation of Raf-1 at Ser338 but restored the dephosphorylation of Raf-1 at Ser259. EGCG increased the activity of PI 3-kinase, the level of phosphorylated Akt (Ser473), and binding between Raf-1 and active Akt. EMSA and ChIP assay revealed that EGCG attenuated activator protein 1 (AP-1)-CCL2 promoter interaction, possibly by reducing c-Fos synthesis. Codistribution of CD68+ macrophages and CCL2+ osteoblasts in osteolytic areas was obvious in the CIA model. Administration of EGCG markedly diminished the severity of CIA, macrophage infiltration, and the amount of CCL2-synthesizing osteoblasts. CONCLUSION: By stimulating PI 3-kinase activity, EGCG promoted Akt/Raf-1 crosstalk, resulting in decreased AP-1 binding to CCL2 promoter, and finally reduced CCL2 production in osteoblasts. EGCG alleviated the severity of CIA, probably by suppressing CCL2 synthesis in osteoblasts to diminish macrophage infiltration. Our data support the therapeutic potential of EGCG on arthritis.
17673143 Anti-arthritic effect of ginsenoside Rb1 on collagen induced arthritis in mice. 2007 Oct BACKGROUND: The development of orally bioavailable, inexpensive inhibitors of tumor necrosis factor (TNF)-alpha is desirable for the treatment of rheumatoid arthritis (RA). OBJECTIVE: To show the efficacy of ginsenoside Rb1 (G-Rb1), a ginseng extract, on the inhibition of TNF-alpha upregulation and on the inhibition of collagen induced arthritis (CIA). METHODS: Peripheral blood mononuclear cells (PBMC), chondrocytes and fibroblast-like synoviocytes (FLS) were stimulated with interferon(IFN)-gamma, lipopolysaccharide (LPS) or interleukin-1 in the presence or absence of G-Rb1. The concentrations of (TNF)-alpha in the culture supernatants were determined by ELISA. CIA was induced in DBA/1J mice and G-Rb1 was prophylactically administered from day 20 until day 39 following immunization. Histopathologic changes were scored, and the expression of TNF-alpha was evaluated by immunohistochemistry. RESULT: G-Rb1 significantly inhibited TNF-alpha upregulation in PBMCs, FLS and chondrocytes induced by IFN-gamma, LPS or IL-1. Administration of G-Rb1 resulted in a significant amelioration of the clinical arthritis score in the CIA mice. Histology revealed that G-Rb1 reduced cell infiltration and cartilage destruction in the arthritic joint, which was accompanied by a significant decrease in TNF-alpha expression. CONCLUSION: The utilization of G-Rb1 is a feasible approach to the treatment of RA or other diseases characterized by upregulation of TNF-alpha.
18997610 A novel method for screening the multifocal electroretonogram in patients using hydroxychl 2008 Nov PURPOSE: To evaluate retinal function in patients on hydroxychloroquine using multifocal electroretinography. METHODS: A retrospective chart review was performed for 23 patients (46 eyes) on hydroxychloroquine therapy and referred for multifocal electroretinogram (mfERG) testing. Duration of treatment, daily hydroxychloroquine dose, visual acuity, fundus examination, color vision testing, Amsler grid testing, visual field examination, and fluorescein angiography results were obtained when available. Multifocal electroretinogram response amplitudes were calculated for the central and paracentral regions and compared with previously published normal values. The central and paracentral regions of the mfERG color difference plot, which assigns colors to localized areas of the mfERG based on deviation from normal, were assessed using a novel Color Difference Plot Scoring System which relies on the color pattern observed within each region. RESULTS: Ninety-two regions were assessed for response amplitudes, 31 of which showed a depressed response amplitude. Of the 17 eyes which had at least one region with a depressed response amplitude, clinical examination findings were relatively benign. Color difference plot scoring showed strong agreement with response amplitude, with a Color Difference Plot Scoring System score of 2 or 3 showing 93.55% sensitivity and 60% specificity for a depressed response amplitude. Interrater reliability of the scoring system as measured by Kendall's W coefficient of concordance was 0.6484 (P < 0.00001). CONCLUSION: The mfERG appears to be able to detect decreased retinal function in hydroxychloroquine patients with normal clinical examinations, and may be useful in identifying patients that require close monitoring for the development of clinically relevant toxicity. The Color Difference Plot Scoring System may be used as a tool to aid in the interpretation of results of the mfERG in the clinic setting.
18311769 Clinical implications of rotator cuff degeneration in the rheumatic shoulder. 2008 Mar 15 OBJECTIVE: In rheumatoid arthritis (RA) of the shoulder, loss of cartilage and soft tissue degeneration coexists with pain and reduced range of motion. We evaluated the presence of bony and rotator cuff degeneration in RA of the shoulder joint and assessed their relationship with pain and loss of functioning. We hypothesized that rotator cuff degeneration plays an important role in the presence of pain and loss of functioning of the rheumatic shoulder. METHODS: We used a cross-sectional study to assess both bony and rotator cuff involvement using plain anteroposterior radiographs, ultrasound, and computed tomography images. Additionally, we used an electromagnetic tracking device and a force transducer to evaluate range of motion and maximum force of the shoulder muscles. Between January 2003 and July 2004 we included 26 consecutive patients (51 shoulders). Twenty-one shoulders showed no or slight joint destruction, 15 showed intermediate destruction, and 15 showed severe destruction. RESULTS: Only 19 shoulders showed an intact rotator cuff. Proximal migration of the humeral head and fatty degeneration of the infraspinatus muscle especially showed a significantly strong correlation with increased pain and function loss (R2 = 0.36, P < 0.001). In a multivariate regression analysis, proximal migration and fatty degeneration of the infraspinatus muscle were related most significantly with pain and reduced functioning in the shoulder joint. CONCLUSION: Rotator cuff degeneration plays an important role in the daily functioning of the rheumatic shoulder. Prevention of rotator cuff degeneration may therefore play an important part in the treatment of the rheumatic shoulder.
18263783 Autoimmune disorders and risk of non-Hodgkin lymphoma subtypes: a pooled analysis within t 2008 Apr 15 Some autoimmune disorders are increasingly recognized as risk factors for non-Hodgkin lymphoma (NHL) overall, but large-scale systematic assessments of risk of NHL subtypes are lacking. We performed a pooled analysis of self-reported autoimmune conditions and risk of NHL and subtypes, including 29 423 participants in 12 case-control studies. We computed pooled odds ratios (OR) and 95% confidence intervals (CI) in a joint fixed-effects model. Sjögren syndrome was associated with a 6.5-fold increased risk of NHL, a 1000-fold increased risk of parotid gland marginal zone lymphoma (OR = 996; 95% CI, 216-4596), and with diffuse large B-cell and follicular lymphomas. Systemic lupus erythematosus was associated with a 2.7-fold increased risk of NHL and with diffuse large B-cell and marginal zone lymphomas. Hemolytic anemia was associated with diffuse large B-cell NHL. T-cell NHL risk was increased for patients with celiac disease and psoriasis. Results for rheumatoid arthritis were heterogeneous between studies. Inflammatory bowel disorders, type 1 diabetes, sarcoidosis, pernicious anemia, and multiple sclerosis were not associated with risk of NHL or subtypes. Thus, specific autoimmune disorders are associated with NHL risk beyond the development of rare NHL subtypes in affected organs. The pattern of associations with NHL subtypes may harbor clues to lymphomagenesis.
18562787 Chondrogenic potential of mesenchymal stem cells from patients with rheumatoid arthritis a 2009 BACKGROUND: Mesenchymal stem cells (MSCs) have the potential to differentiate into distinct mesenchymal tissues; including cartilage and bone, they can be an attractive cell source for cartilage tissue engineering approaches. Our objective here was to compare the in vitro chondrogenic potential of MSCs isolated from patients with rheumatoid arthritis (RA) and osteoarthritis (OA) with cells from normal donors. METHODS: Marrow samples were removed during bone surgery and adherent cell cultures were established. The cells were then passed into a newly developed microaggregate culture system in a medium containing transforming growth factor beta3, insulin, dexamethasone and/or demineralized bone matrix. In vitro chondrogenic activity was measured as metabolic sulfate incorporation and type II collagen expression in pellet cultures. RESULTS: Culture-expanded MSCs from RA and OA patients did not differ significantly from the normal population with respect to their chondrogenic potential in vitro. Capability of total protein and proteoglycan synthesis as well as collagen II mRNA expression by cell aggregates was similar for all cell preparations in the presence of the appropriate growth and differentiation factors. Chondroprotective drugs such as chondroitin sulfate and glucosamine enhanced, whereas chloroquine inhibited chondrogenesis in normal donor-derived or patient-derived MSC cultures. Galectin-1, a beta-galactoside-binding protein with marked anti-inflammatory activity, stimulated the chondrogenic differentiation of mesenchymal cells in low (<2 microg/ml) concentration. DISCUSSION: These findings show that MSCs from RA and OA patients possess similar chondrogenic potential as MSCs isolated from healthy donors, therefore these cells may serve as a potential new prospect in cartilage replacement therapy.
18795393 Repeated tuberculin skin testing following therapy with TNF-alpha inhibitors. 2009 Feb To determine the rate of true tuberculin skin test (TST) response in a cohort of patients with rheumatic disease treated with tumor necrosis factor inhibitors (TNFi). The study population included consecutive patients with rheumatoid arthritis (RA), ankylosing spondylitis (AS), and psoriatic arthritis (PsA) treated with TNFi for at least 3 months. Patients with a positive TST at screening who began Tb prophylaxis before the beginning of TNFi therapy were excluded. All patients underwent a second TST. True TST response was defined as an increase of 6 mm of induration between the screening test and the second test. Forty patients (12 men and 28 women) were included. Mean age was 51.2 years. Of them, 27 (67.5%) had RA, eight (20%) had PsA, and five patients (12.5%) had AS. At pre-treatment TST, 15 patients had a TST > or = 5 mm. A significantly higher percent of patients with TST > or = 5 mm was seen among men compared with women (75% vs. 21%, p = 0.012) and patients with PsA compared with patients with RA (75% vs. 22%, p = 0.014). At the second test, eight (20%) had an increase of 6 mm between readings with four having an increase of 10 mm or more. Four patients received infliximab and the other four were treated with etanercept. Seven of these eight patients had RA and one was a patient with PsA. Patients with true TST response were significantly older and non-smokers with elevated sedimentation rate and a higher rate of anemia. Nationality, comorbid conditions, treatment with immunosuppressives, and BCG vaccination status had no significant influence on the TST response. Serial TST testing in patients receiving TNFi is indicated to identify patients with reactivation of latent tuberculosis infection or those exposed to mycobacterium.
18263596 Recent advances in the genetics of RA susceptibility. 2008 Apr RA is a common autoimmune disease with a complex aetiology in which genetic and environmental factors contribute to disease. The genetic component of RA is largely undefined and, up until very recently, there were only two reproducible associations. The strongest of these associations is of genes within the HLA region, particularly the HLA-DRB1 gene. A second, more modest, association identified has been of the protein tyrosine phosphatase non-receptor 22 (PTPN22) gene. Advances in genotyping technology have facilitated the application of whole genome association approaches to identify disease causal variants. This, coupled with the availability of large case and control collections has enabled the identification of low-to-moderate risk loci. These newer study designs combined with traditional linkage and association studies have accelerated the identification of novel risk loci. The past few months alone have witnessed the identification of three new RA risk loci. In this review, we aim to give an update on recent progress in RA genetics, focusing mainly on the identification of novel loci.
17121619 Role of anti-tumour necrosis factor-alpha therapeutic agents in the emergence of infection 2006 Dec There is increasing interest concerning the possible impact of anti-tumour necrosis factor (TNF)-alpha therapeutic agents on the emergence of infections. However, these agents do not seem to increase the incidence of adverse infectious events significantly. Published observations concern mostly infections of the urinary and upper respiratory tracts that develop in the setting of co-morbidities, such as anterior or concomitant immunosuppressive treatment. Infliximab appears to increase the risk of tuberculosis, but this effect has not been observed with other anti-TNF-alpha agents. To better characterise the adverse infectious effects associated with these agents, physicians should be encouraged to notify the microbiological data relating to all cases.
16508938 Sphingosine 1-phosphate/sphingosine 1-phosphate receptor 1 signaling in rheumatoid synoviu 2006 Mar OBJECTIVE: Sphingosine 1-phosphate (S1P) is involved in various pathologic conditions and has been implicated as an important mediator of angiogenesis, inflammation, cancer, and autoimmunity. This study was undertaken to examine the role of S1P/S1P1 signaling in the pathogenesis of rheumatoid arthritis (RA). METHODS: We examined S1P1 messenger RNA (mRNA) and protein levels in RA synoviocytes and MH7A cells by reverse transcriptase-polymerase chain reaction and Western blotting. We also performed S1P1 immunohistochemistry analysis in synovial tissue from 28 RA patients and 18 osteoarthritis (OA) patients. We investigated the effects of S1P on proliferation by WST-1 assay, and its effects on tumor necrosis factor alpha (TNFalpha)- or interleukin-1beta (IL-1beta)-induced cyclooxygenase 2 (COX-2) expression and prostaglandin E2 (PGE2) production in RA synoviocytes and MH7A cells by Western blotting and enzyme-linked immunosorbent assay, respectively. Finally, we examined whether these effects of S1P were sensitive to pertussis toxin (PTX), an inhibitor of the Gi/Go proteins. RESULTS: S1P1 mRNA and protein were detected in RA synoviocytes and MH7A cells. S1P1 was more strongly expressed in synovial lining cells, vascular endothelial cells, and inflammatory mononuclear cells of RA synovium compared with OA synovium. S1P increased the proliferation of RA synoviocytes and MH7A cells. S1P alone significantly enhanced COX-2 expression and PGE2 production. Moreover, S1P enhanced expression of COX-2 and production of PGE2 induced by stimulation with TNFalpha or IL-1beta in RA synoviocytes and MH7A cells. These effects of S1P were inhibited by pretreatment with PTX. CONCLUSION: These findings suggest that S1P signaling via S1P receptors plays an important role in cell proliferation and inflammatory cytokine-induced COX-2 expression and PGE2 production by RA synoviocytes. Thus, regulation of S1P/S1P1 signaling may represent a novel therapeutic target in RA.
18065867 [Surgical site infection after total knee arthroplasty: a monocenter analysis of 923 first 2007 Oct PURPOSE OF THE STUDY: We report the results of a retrospective analysis of 923 cases of first-intention total knee arthroplasties. The objective was to determine retrospectively the rate of surgical site infections, including all infections diagnosed during the first year, and to search for risk factors. We also wanted to present our surveillance system planned for a 10-year period. MATERIAL AND METHODS: From January 1994 to January 2004, first-intention total knee arthroplasty (TKA) was performed on 999 knees. HLS prostheses were implanted. At minimum 12 months, follow-up data was complete for 923 implants which constituted the study group. Female gender predominated (72%). Mean patient was 71 years (range 26-93). Anterior surgery was performed for 25% of the knees. Etiologies were osteoarthritis (87.5%), and rheumatoid polyarthritis (6.9%). Cefazolin was used for systematic preoperative (one injection) and postoperative (48 hr) antibiotic proxphylaxis. Vancomycin was used for patients with a contraindication for cefazolin. Information was collected from two sources: computerized consultation charts for all follow-up visits completed prospectively since 1995 et data collected by the Hygiene and Epidemiology Unit during the year following implantation. Data on surgical site infections was collected from the hospitalization files, outpatient files and control visits. Each case of infection was validated at an annual interdisciplinary meeting. We retained for analysis deep infections requiring revision surgery with identification of the causal agent on the intraoperative samples. We identified a subgroup of infections occurring during the first postoperative year, the delay generally retained for surgical site infections. RESULTS: Twenty surgical site infections after TKA were identified during the 10-year surveillance period (2.1%). Mean follow-up was 43 months (range 12-123 months, median 37 months). The rate of surgical site infections occurring during the first postoperative year was 1.4%. Eighty-percent of the infections (n=16) occurred within the first two postoperative months. Two infections were diagnosed two to five years after surgery and two others more than five years after surgery due to hematogenous contamination. All of the observed infections involved a single causal germ. Agents identified were: Gram+ (90%) and Gram- (10%), with a clear predominance for Staphylococcus aureus (n=9). Infections developed 2.1-fold more often in patients with an inflammatory disease (rheumatoid polyarthritis). Age and body mass index did not differ between patients with and without surgical site infection. CONCLUSION: The analysis of our series demonstrated the difficulties in conducting long-term surveillance.
16634808 Imatinib mesylate inhibits proliferation of rheumatoid synovial fibroblast-like cells and 2006 May Receptors for platelet-derived growth factor (PDGF) are abundantly expressed on synovial fibroblast-like (SFL) cells from patients with rheumatoid arthritis (RA), and stimulation with PDGF enhances both the anchorage-dependent and -independent growth of RA-SFL cells. To elucidate the molecular mechanisms responsible for the excessive growth of RA-SFL cells and to seek a novel molecular-targeting therapy for RA, we examined the expression of adapter proteins and the effect of the specific inhibition of PDGF receptor activation by imatinib mesylate. Cultured SFL cells were used in the present study after 2-5 passages. The anchorage-dependent and -independent growth patterns of the SFL cells were evaluated using a tetrazolium-based assay and colony formation in 0.3% agar, respectively. Adapter proteins Gab1 and Gab2 were expressed in RA-SFL cells, and both proteins were rapidly (< 1 min) tyrosine-phosphorylated after the stimulation of RA-SFL cells with 10 ng/ml of PDGF and, to a lesser extent, after stimulation with 100 ng/ml of epidermal growth factor (EGF). The inhibition of PDGF receptor tyrosine kinase activation by 1 microM or less of imatinib mesylate specifically suppressed the PDGF-dependent, but not EGF-dependent, tyrosine phosphorylation of various proteins. Moreover, imatinib mesylate abolished both the anchorage-dependent and -independent proliferation of RA-SFL cells induced by PDGF stimulation. These results suggest that Gab adapter proteins are expressed and likely to be involved in the growth signalling of rheumatoid synovial cells and that imatinib mesylate, a key drug in the treatment of chronic myeloid leukaemia, may also be effective for the treatment of RA.