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Search for: rheumatoid arthritis    methotrexate    autoimmune disease    biomarker    gene expression    GWAS    HLA genes    non-HLA genes   

ID PMID Title PublicationDate abstract
17630192 Human TNF-alpha gene vaccination prevents collagen-induced arthritis in mice. 2007 Sep TNFalpha is a key factor in the pathogenesis of rheumatoid arthritis. To investigate whether heterologous TNFalpha gene vaccination could induce anti-TNFalpha antibodies via cross-reaction and prevent the inflammatory arthritis, we constructed two plasmids by inserting a full-length cDNA of human TNFalpha into a secreted vector (pSecTag-TNFalpha) and a non-secreted vector (pTARGE-TNFalpha), respectively. Administering either plasmid to collagen-induced arthritis (CIA) mice reduced paw swelling and synovium-infiltrating inflammatory cells. This reduction was accompanied by down-regulated TNFalpha in sera and joints. The spleen cells from treated CIA mice displayed decreased IFN-gamma mRNA levels and matrix metalloproteinase-9 bioactivity in comparison with those from CIA control. Furthermore, both spontaneous and collagen-specific proliferation of the lymphocytes was significantly decreased after treatment. Administration of plasmids led to an elicited production of antibodies to both human and mouse TNFalpha. These results suggest that human TNFalpha gene vaccination prevents CIA in mice likely by inducing cross-reactive antibodies against TNFalpha, and that heterologous gene vaccination might provide an effective therapeutic strategy to battle TNFalpha mediated diseases.
18521542 Therapeutic gold. Is it due for a come-back? 2008 Jun The historical use of metallic gold and gold complexes in medicine is briefly outlined. Currently, there is a large body of opinion that they belong to another age, are no longer relevant and that there are more-than-adequate successors to replace them. Nevertheless some challenging questions remain: (1) Should we now ignore their remarkable properties for ameliorating rheumatoid arthritis, even inducing remissions and for preventing arthritis development in animals? (i) What mechanisms underlie their clinical activity? (ii) Can some of the adverse effects of traditional therapy with gold-thiolate complexes be reduced/prevented by either modifying their formulations, or by using some of their bio-transformation products at much lower doses? (iii) Are they equivalent, perhaps even superior to biological DMARDs (anti-TNFalpha, anti-IL-1), and if so, more cost effective?
17629561 Edaravone inhibits collagen-induced arthritis possibly through suppression of nuclear fact 2008 Jan OBJECTIVE: Rheumatoid arthritis (RA) is a chronic autoimmune disease which is induced by proinflammatory cytokines or oxidative stress. The activation of nuclear factor-kappa B (NF-kappaB) that contributed to imbalance between apoptosis and proliferation of rheumatoid synovial cells (SC). Edaravone, clinically available free radical scavenger in Japan, is confirmed to be beneficial in the acute stage of stroke. We aimed to investigate the suppressive effect of edaravone on collagen-induced arthritis (CIA) mice and on the activated molecules in SC stimulated by interleukin-1beta (IL-1beta). METHODS: Edaravone was administrated intravenously at a dose of 3mg/kg of body weight to CIA mice. The progression of CIA was evaluated by the macroscopic arthritis scoring system of paws. Interleukin-6 (IL-6) and matrix metalloproteinase-3 (MMP-3) concentrations in culture medium of human SC were measured by enzyme linked immunosorbent assays. Caspase-3/7 activity and nuclear factor-kappa B (NF-kappaB) protein level of cultured human SC were estimated by fluorometric assay and Western blot analysis, respectively. RESULTS: Edaravone significantly decreased macroscopic arthritis score in CIA mice. Acceleration of IL-6 and MMP-3 productions and attenuation of caspase-3/7 activity in IL-1beta-stimulated SC were abated by edaravone. Activated NF-kappaB in IL-1beta-stimulated SC was suppressed by edaravone. CONCLUSION: Edaravone, antioxidants available for clinical use, appears to have therapeutic effect on RA. We suggest that the inhibitory effect of edaravone on RA might be exerted, at least in part, through suppression of activated NF-kappaB. Therefore, we expect therapeutical use of edaravone as an anti-rheumatic agent.
18408252 Targeted drug delivery by in vivo coupling to endogenous albumin: an albumin-binding prodr 2008 Aug OBJECTIVE: To examine the effect of an albumin-binding prodrug of methotrexate (MTX) in the treatment of murine collagen-induced arthritis (CIA). METHODS: The prodrug AWO54 with the formula EMC-d-Ala-Phe-Lys-Lys-MTX binds selectively to the cysteine-34 position of endogenous albumin, which acts as a macromolecular drug carrier for MTX to the site of inflammation. The CIA model was used to evaluate the anti-arthritic effect of the compound after intravenous application. RESULTS: The albumin-bound form of AWO54 was efficiently cleaved by cathepsin B and plasmin, two proteases that are overexpressed in rheumatoid arthritis, and release a MTX lysine derivative. AWO54 suppressed CIA in a dose-dependent manner and was significantly better than MTX. To obtain a similar effect only about 20% of the MTX-equivalent dose of AWO54 had to be given. The efficacy of the drug was tested in two different stages of CIA: while both, MTX and AWO54 inhibited arthritis in an early stage of the disease, in a later stage only AWO54 showed a significant inhibitory effect in comparison with control. CONCLUSION: Targeted drug delivery by in vivo coupling of a prodrug of MTX to endogenous albumin is better than MTX in the treatment of CIA.
16552589 A critical appraisal of radiographic scoring systems for assessment of juvenile idiopathic 2006 Aug Assessing structural damage to joints over time is essential for evaluating the effectiveness of therapeutic interventions for patients with inflammatory arthritis. Although radiography is able to quantify joint damage, the changes found with conventional radiography early in the disease course are nonspecific, and late radiographic changes are often irreversible. Although many clinical trials on drug development for children still use radiographic scales as endpoints for the study, more specific therapies have been developed for juvenile idiopathic arthritis (JIA) that would enable imaging to "fine-tune" patients to placement into specific treatment algorithms. As a result, new imaging scales to identify early abnormalities are clearly needed. Many pediatric rheumatology centers around the world persistently apply adult-designed radiographic scoring systems to evaluate the progression of JIA. Few pediatric-targeted radiographic scales are available for assessment of progression of JIA in growing joints, and the clinimetric and psychometric properties of such scales have been poorly investigated. We present a critique to the evaluative, discriminative, and predictive roles of the van der Heijde modification of Sharp's radiographic method, a scale originally designed to assess damage to joints of adults with rheumatoid arthritis, when it is applied to a pediatric population. We discuss the advantages and drawbacks of this radiographic scoring system for assessing growing joints and the ability of MRI to overcome inadequacies of conventional radiography.
18432319 [Septic arthritis: what is the role for the rheumatologist?]. 2008 Jan Septic arthritis (SA) is a clinical emergency with considerable morbidity and mortality that can lead to rapid joint destruction and irreversible loss of function. The reported incidence varies from 2-5 cases per 100.000 individuals per year in the general populations to 70 cases per 100.000 individuals annually among patients with rheumatoid arthritis (RA). Predisposing factors are immunosuppressive and corticosteroids therapy and RA "itself". The expected decrease in incidence of SA was not seen over the last 20 years period but we can, on the contrary, expect an increase in the frequency of its appearance because of the population ageing, the increasingly prosthetic joint replacement, the ability of the bacteria to evade clearance by the host immune response and the rapidly growing number of patients with RA, ankylosing spondylitis and psoriatic arthritis treated with tumour necrosis factor alpha (TNF alpha) antagonists. Up to now there have been conflicting reports regarding joint infections in patients under anti-TNF therapy but according to data from Deutsch as well as the British register there might be an increase in the incidence of joint infections in anti-TNF treated patients. Microscopic analysis and culture of synovial fluid are fundamental diagnostic tools in the evaluation of possible joint sepsis. Sonographic guidance of arthrocentesis led to successful aspiration of difficult-to-access joints as shoulder and hip. There is controversy over which mode of drainage of septic synovial fluid should be employed but needle aspiration appear to be preferable to surgical treatment as an initial mode of treatment of SA. Rheumatologists should have a central role in the diagnosis and management of SA.
18958885 IL-23 promotes osteoclast formation by up-regulation of receptor activator of NF-kappaB (R 2008 Oct Inflammation-mediated bone loss is a major feature of various bone diseases including rheumatoid arthritis, osteoarthritis and advanced periodontitis. Enhanced osteoclast development or activity at the inflammation site results in bone resorption. IL-23 is a heterodimeric cytokine belonging to the IL-6/IL-12 family that has been implicated in the pathogenesis of rheumatoid arthritis and demonstrated to play a role in osteoclastogenesis via stimulation of IL-17 production. In this study we investigated whether IL-23 contributes to the regulation of osteoclast differentiation independent of the IL-17 pathway. We show that IL-23 dose-dependently up-regulates receptor activator of NF-kappaB expression in primary murine bone marrow macrophages and RAW264.7 cells and thereby promotes commitment of myeloid precursor cells to receptor activator of NF-kappaB ligand-mediated osteoclastic differentiation. However, IL-23 by itself is insufficient to induce osteoclastogenesis. Increased osteoclastic differentiation of cells was associated with enhanced cathepsin K expression and dentine resorption indicating enhanced formation of functional osteoclasts. IL-17 was not detectable in culture supernatants and when added to cultures, did not promote differentiation of RAW264.7 cells. These results demonstrate that IL-23 can act directly on myeloid precursor cells in addition to indirectly stimulating receptor activator of NF-kappaB ligand production in osteoblasts and explains its potency in driving osteoclast development in inflammation-mediated bone pathology.
17869649 Polymorphisms in the cathepsin L2 (CTSL2) gene show association with type 1 diabetes and e 2007 Sep Type 1 diabetes (T1D) is an autoimmune disease characterized by loss of beta cells in the pancreas. The CTSL2 gene encodes the cysteine protease cathepsin V involved in antigen presentation in human cortical thymic epithelial cells, and involvement of the protease in autoimmunity has been suggested. This study aimed to evaluate CTSL2 as a candidate gene for T1D, and test whether the gene predisposes more generally to autoimmune diseases. Four polymorphisms aiming at tagging the CTSL2 locus were genotyped in 421 T1D families, and subsequently in 861 rheumatoid arthritis patients, 530 juvenile idiopathic arthritis patients, and 559 controls of Norwegian origin. Additionally, DNA from 83 German myasthenia gravis (MG) patients and 244 controls were investigated. A polymorphism, rs16919034, situated downstream of CTSL2 was associated with T1D (60.8%T, p = 0.008; p(c) = 0.03). An association with early-onset MG (45% in cases vs 36.6% in controls; p = 0.03) was observed for another polymorphism (rs4361859) situated upstream of the gene, but within the same linkage disequilibrium block. No association was observed in rheumatoid arthritis or juvenile idiopathic arthritis. Our findings suggest that the CTSL2 gene is associated with T1D and with early-onset MG.
18696073 Osteopoikilosis coexistent with ankylosing spondylitis and familial Mediterranean fever. 2009 Jan Osteopoikilosis (OPK) is a rare benign sclerosing disease of the skeleton and inherited as an autosomal dominant trait. OPK is associated with inflammatory rheumatic disorders, such as rheumatoid arthritis, scleroderma, reactive arthritis and familial Mediterranean fever (FMF). We report a rare case of OPK coexistent with ankylosing spondylitis and FMF. The patient presented multiple sclerotic lesions within and around the sacroiliac joints and a series of radiological diagnostic challenges.
18001502 Proteinases in the joint: clinical relevance of proteinases in joint destruction. 2007 Proteinases are involved in essential steps in cartilage and bone homeostasis. Consequently, efforts have been made to establish their potential role in the pathology of rheumatic conditions such as rheumatoid arthritis, osteoarthritis and spondyloarthritis. Matrix metalloproteinases (MMPs) are sensitive markers of disease severity and response to treatment, and therefore they have potential in the assessment of rheumatic diseases. Despite disappointing early results with synthetic inhibitors of MMPs, there is still much scope for developing effective and safe MMPs inhibitors, and consequently to deliver new options to inhibit joint destruction.
18466561 Detecting disease-causing genes by LASSO-Patternsearch algorithm. 2007 The Genetic Analysis Workshop 15 Problem 3 simulated rheumatoid arthritis data set provided 100 replicates of simulated single-nucleotide polymorphism (SNP) and covariate data sets for 1500 families with an affected sib pair and 2000 controls, modeled after real rheumatoid arthritis data. The data generation model included nine unobserved trait loci, most of which have one or more of the generated SNPs associated with them. These data sets provide an ideal experimental test bed for evaluating new and old algorithms for selecting SNPs and covariates that can separate cases from controls, because the cases and controls are known as well as the identities of the trait loci. LASSO-Patternsearch is a new multi-step algorithm with a LASSO-type penalized likelihood method at its core specifically designed to detect and model interactions between important predictor variables. In this article the original LASSO-Patternsearch algorithm is modified to handle the large number of SNPs plus covariates. We start with a screen step within the framework of parametric logistic regression. The patterns that survived the screen step were further selected by a penalized logistic regression with the LASSO penalty. And finally, a parametric logistic regression model were built on the patterns that survived the LASSO step. In our analysis of Genetic Analysis Workshop 15 Problem 3 data we have identified most of the associated SNPs and relevant covariates. Upon using the model as a classifier, very competitive error rates were obtained.
21794433 [Neurophysiologic study in patients with rheumatoid arthritis with atlantoaxial subluxatio 2007 Sep INTRODUCTION: Radiological studies show that 80% of rheumatoid arthritis (RA) patients with more than 10 years present spinal afflictions and 40% of those patients will present neurological deterioration. The somatesthetic evoked potential (SEP) and the transcranial magnetic stimulation (TMS) are neurophysiologic studies that may be useful in early diagnosis of neurological damage. OBJECTIVE: To compare the results of the neurophysiologic studies (SEP and TMS) carried out on patients affected with RA without neurological clinic, with or without atlantoaxial suluxation (AAS), and in this way evaluate the efficacy of early diagnosis of the affection of the spinal medulla by electrodiagnostic methods. MATERIAL AND METHODS: Cases and controls study that included 29 patients affected with RA of more than 3 years evolution. All of the patients had 2 electrophysiological techniques carried out on them: SEP and TMS in the neurophysiologic laboratory. RESULTS: 29 patients participated in the study, of which 21 were females and 8 males. In the group affected with AAS 2 patients presented anomaly in the SEP (11.7%) and 7 in the TMS (41.1%). In the group without AAS 2 presented an altered TMS (16.6%), but no alteration in the SEP. No patient affected or not with AAS, presented alteration of both electrophysiological tests. No significant differences were found between the positivity of the RF or the presence of erosions and the affection of the atloaxoid joint. No differences between the age of outset or years of evolution and the AAS. CONCLUSIONS: In our study patients with AAS showed a greater trend towards the presence of alterations in the electrophysiological studies than the patients without AAS.
17396107 Therapy insight: scleritis and its relationship to systemic autoimmune disease. 2007 Apr The term scleritis describes a chronic inflammation that involves the outermost coat and skeleton of the eye. Disease can be isolated to the eye, but in up to half of affected individuals it occurs in the context of an immune-mediated systemic inflammatory condition, such as rheumatoid arthritis or Wegener's granulomatosis. Although uncommon, scleritis is often extremely painful, can lead to vision-threatening complications (and involvement of other ocular tissues), and is considered to confer an increased risk of mortality in patients with rheumatoid arthritis. Pathogenic mechanisms in scleritis are poorly understood, but enzymatic degradation of collagen fibrils by resident cells and infiltrating leukocytes seems to be a key feature. Several forms of inflammation can be distinguished histologically; interestingly, although the disease typically presents with engorgement of scleral vessels, vasculitis is not universally present at the microscopic level. Although some patients with scleritis respond well to treatment with NSAIDs, aggressive systemic therapy is often required to obtain a favorable outcome, particularly when systemic disease coexists. The mainstay of treatment is oral prednisone, but this agent is usually combined with a steroid-sparing immunosuppressive drug. New therapies presently under investigation for scleritis include local corticosteroid injections and various biologic agents.
21794317 [Development and validation of a satisfaction questionnaire in patients with rheumatoid ar 2006 May OBJECTIVE: The aim of this study was to develop and validate a specific tool to assess satisfaction with treatment in patients with rheumatoid arthritis (RA). MATERIAL AND METHODS: The questionnaire was developed in three stages: firstly, a literature review was performed by experts in developing patient-centered measures; secondly, items selected by 4 experts in RA were assessed for comprehensibility, format and applicability, and thirdly, administration of the questionnaire was evaluated through a personal interview of a group of 14 patients with RA under treatment with infliximab. Validation of the questionnaire was performed in patients with RA who met the ACR criteria, were older than 18 years, and had started treatment with infliximab due to inadequate disease control. Questionnaires were administered at the baseline visit (beginning of treatment) and at 2, 6 and 14 weeks, coinciding with infliximab infusions. The questionnaire validity was evaluated in terms of construct validity (factorial analysis) and content validity. Content validity was assessed by analysing the relationship between satisfaction and different measures used for treatment effectiveness as well as fulfillment of treatment expectations. RESULTS: Validation of the questionnaire was performed in a sample of 180 patients with a mean (SD) age of 52 (13) years. A total of 80.7% were women. In 72.4% disease duration was longer than 3 years. The scores obtained on the satisfaction questionnaire were related to the aspects defined as ACR criteria (except ESR and CRP), fulfillment of ACR20, ACR50 and ACR70 response criteria, and fulfillment of treatment expectations (p<0,01). DISCUSSION: The results confirm the questionnaire's validity in assessing patient satisfaction with RA treatment, both in routine clinical practice and in research conditions.
18714521 [The formation of infliximab and anti-infliximab immune complexes as an explanation for no 2008 Jul 26 OBJECTIVE: To investigate the in vivo mechanism of non-responding to infliximab treatment of patients with rheumatoid arthritis (RA) and the role of anti-infliximab antibodies by using radiolabeled infliximab. DESIGN: Descriptive and comparative study. METHOD: Two responding and two non-responding RA patients were infused with radiolabeled infliximab. Subsequently imaging investigations and serum analysis were performed at set times. RESULTS: The scintigrams showed that the labelled infliximab was mainly present in the blood until 24 h after infusion. There was a trend of faster blood clearance and higher liver and spleen uptake of 99mTc-infliximab in one non-responding patient. Labelled infliximab was taken up by inflamed joints. The anti-infliximab level was high (1008 and 1641 U/ml) in the non-responders and low or not detectable in the responders. Sucrose gradients of serum revealed antibody complexes in both non-responders. Various sizes of antibody complexes, including very large ones, were observed in one non-responder who developed a serious infusion reaction. CONCLUSION: Infliximab-anti-infliximab immune complexes were found to form in RA non-responders due to the presence of significant quantities of anti-infliximab. This finding may partly explain the failure of the infliximab treatment.
22272806 Association Between Measures of Fatigue and Health-Related Quality of Life in Rheumatoi 2008 Apr 1 OBJECTIVE: To assess the relationship between fatigue and health-related quality of life (HR-QOL) among people with osteoarthritis (OA) and rheumatoid arthritis (RA). METHODS: Community-dwelling people with OA, and OA patients on the waiting list for joint replacement surgery, were recruited. RA patients were recruited from rheumatologists' public and private outpatient clinics. Respondents completed a questionnaire containing demographic detail, the Fatigue Severity Scale (FSS), the Multidimensional Assessment of Fatigue (MAF), the SF-36, Western Ontario and McMaster Universities Osteoarthritis Index, and the Health Assessment Questionnaire (HAQ). RESULTS: There were 137 OA and 52 RA respondents. Neither age nor sex was significantly associated with fatigue for OA or RA. The mean FSS score was 3.36 for RA and 3.63 for OA. Fifty percent of respondents with RA and 58% of those with OA met the FSS >3 cut-point for fatigue. Mean MAF Global Fatigue Index was 20.8 for OA and 20.1 for RA. Correlations between health status and fatigue indicated that for both OA and RA those with greater fatigue reported worse health status. CONCLUSIONS: Few studies have measured the impact of fatigue among respondents with OA, despite it affecting a large proportion of the population. Fatigue was significantly correlated with poorer HR-QOL among OA respondents, suggesting that fatigue is a significant issue in OA as well as RA.
21136742 The human synovial fluid proteome: A key factor in the pathology of joint disease. 2007 Aug This review aims to summarise our knowledge to date on the protein complement of the synovial fluid (SF). The tissues, structure and pathophysiology of the synovial joint are briefly described. The salient features of the SF proteome, how it is composed and the influence of arthritic disease are highlighted and discussed. The concentrations of proteins that have been detected and quantified in SF are drawn together from the literature on osteoarthritis, rheumatoid arthritis and juvenile idiopathic arthritis. The measurements are plotted to give a perspective on the dynamic range of protein levels within the SF. Approaches to proteomic analysis of SF to date are discussed along with their findings. From the recent literature reviewed within, it is becoming increasingly clear that analysis of the SF proteome as a whole, could deliver the most valuable differential diagnostic fingerprints of a number of arthritic disorders. Further development of proteomic platforms could characterise prognostic profiles to improve the clinician's ability to resolve unremitting disease by existing and novel therapeutics.
17416886 Pigmented villonodular synovitis causing painless chronic knee swelling in an adolescent. 2007 Apr It is uncommon for an adolescent to present with a painless chronic knee effusion without a history of trauma. Acute knee effusions are usually caused by internal derangement, patellar dislocations, or fractures. The differential diagnosis of a chronic knee effusion must include the more uncommon diagnoses of juvenile rheumatoid arthritis, septic arthritis, reactive arthritis, synovial osteochondromatosis, synovial hemangioma, synovial sarcoma, or pigmented villonodular synovitis. Radiographic imaging, plain radiographs, and magnetic resonance imaging in addition to a biopsy specimen are most helpful in differentiating these diagnoses. Pigmented villonodular synovitis is an uncommon diagnosis that is rarely seen in an adolescent. Treatment includes synovectomy via arthroscopy or open arthrotomy.
18466555 Comparison of haplotyping methods using families and unrelated individuals on simulated rh 2007 In this report, we compared haplotyping approaches using families and unrelated individuals on the simulated rheumatoid arthritis (RA) data in Problem 3 from Genetic Analysis Workshop (GAW) 15. To investigate these two approaches, we picked two representative programs: PedPhase and fastPHASE, respectively, for each approach. PedPhase is a rule-based method focusing on the haplotyping constraints within each pedigree and solving them using integer linear programming. fastPHASE is a statistical method based on the clustering property of haplotypes in a population over short regions. It is believed that with family information, one can obtain more accurate phasing results with considerably more cost for genotyping additional family members. Our results indicate that, though only relying on the constraints within each family (with four members) individually, PedPhase has better phasing accuracy than fastPHASE, even when the total numbers of genotyped individuals are the same. But for missing genotype imputation, fastPHASE performs better than PedPhase by taking population information into consideration. The relative influence of family constraints and population information on haplotyping accuracy as shown in this report provides some empirical bases on assessing the trade-off of genotyping family data under different settings.
18320743 [Interstitial lung disease in connective tissue diseases]. 2007 Dec 31 Interstitial lung disease (ILD) may occur in the connective tissue diseases, with a negative impact on survival. The diagnosis of ILD is established by crackles of the lung bases at auscultation, and high resolution computed tomography of the chest demonstrating diffuse opacities predominating in the bases (ground glass opacities, reticular opacities, honeycombing, and traction bronchiectases). Bronchoalveolar lavage mostly contributes to the differential diagnosis. Video-assisted thorascopic lung biospy is seldom required for clinical management. Clinically significant ILD occurs in 25% of patients with systemic sclerosis, 7-30% in patients with dermatopolymyositis (especially with antisynthetase antibodies including anti-Jo-1 antibodies, often with a subacute onset), and 5% of patients with rheumatoid arthritis. Nonspecific interstitial pneumonia (with fibrosis) is the predominating histopathological pattern in systemic sclerosis and dermatopolymyositis; a pattern of usual interstitial pneumonia is frequent in rheumatoid arthritis (with a clinical and radiological presentation similar to that of idiopathic pulmonary fibrosis). ILD of various presentations may occur in Sjögren syndrome, possibly associated with thin-walled cysts; pulmonary lymphoma must be ruled out. Little information is available regarding treatment of ILD in connective tissue disease. Clinically modest short-term efficacy of cyclophosphamide treatment has been shown in systemic sclerosis, but was not maintained at 2 years.