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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
16474395 Positive regulation of immune cell function and inflammatory responses by phosphatase PAC- 2006 Mar Mitogen-activated protein kinases facilitate many cellular processes and are essential for immune cell function. Their activity is controlled by kinases and dual-specificity phosphatases. A comprehensive microarray analysis of human leukocytes identified DUSP2 (encoding the phosphatase PAC-1) as one of the most highly induced transcripts in activated immune cells. We generated Dusp2(-/-) mice and found considerably reduced inflammatory responses in the 'K/BxN' model of rheumatoid arthritis. PAC-1 deficiency led to increased activity of Jun kinase (Jnk) but unexpected impairment of the activity of extracellular signal-regulated kinase (Erk) and the kinase p38, reduced activity of the transcription factor Elk1 and a complex of mobilized transcription factor NFAT and the AP-1 transcription factor and decreased effector immune cell function. Thus, PAC-1 is a key positive regulator of inflammatory cell signaling and effector functions, mediated through Jnk and Erk mitogen-activated protein kinase crosstalk.
18937522 Rheumatic diseases presenting as sports-related injuries. 2008 Most individuals seeking consultation at sports medicine clinics are young, healthy athletes with injuries related to a specific activity. However, these athletes may have other systemic pathologies, such as rheumatic diseases, that may initially mimic sports-related injuries. As rheumatic diseases often affect the musculoskeletal system, they may masquerade as traumatic or mechanical conditions. A systematic review of the literature found numerous case reports of athletes who presented with apparent mechanical low back pain, sciatica pain, hip pain, meniscal tear, ankle sprain, rotator cuff syndrome and stress fractures and who, on further investigation, were found to have manifestations of rheumatic diseases. Common systemic, inflammatory causes of these musculoskeletal complaints include ankylosing spondylitis (AS), gout, chondrocalcinosis, psoriatic enthesopathy and early rheumatoid arthritis (RA). Low back pain is often mechanical among athletes, but cases have been described where spondyloarthritis, especially AS, has been diagnosed. Neck pain, another common mechanical symptom in athletes, can be an atypical presentation of AS or early RA. Hip or groin pain is frequently related to injuries in the hip joint and its surrounding structures. However, differential diagnosis should be made with AS, RA, gout, psudeogout, and less often with haemochromatosis and synovial chondochromatosis. In athletes presenting with peripheral arthropathy, it is mandatory to investigate autoimmune arthritis (AS, RA, juvenile idiopathic arthritis and systemic lupus erythematosus), crystal-induced arthritis, Lyme disease and pigmented villonodular synovitis. Musculoskeletal soft tissue disorders (bursitis, tendinopathies, enthesitis and carpal tunnel syndrome) are a frequent cause of pain and disability in both competitive and recreational athletes, and are related to acute injuries or overuse. However, these disorders may occasionally be a manifestation of RA, spondyloarthritis, gout and pseudogout. Effective management of athletes presenting with musculoskeletal complaints requires a structured history, physical examination, and definitive diagnosis to distinguish soft tissue problems from joint problems and an inflammatory syndrome from a non-inflammatory syndrome. Clues to a systemic inflammatory aetiology may include constitutional symptoms, morning stiffness, elevated acute-phase reactants and progressive symptoms despite modification of physical activity. The mechanism of injury or lack thereof is also a clue to any underlying disease. In these circumstances, more complete workup is reasonable, including radiographs, magnetic resonance imaging and laboratory testing for autoantibodies.
17003915 Does a coxib-associated thrombotic risk limit the clinical use of the compounds as analges 2006 Oct Non-steroidal anti-inflammatory agents (NSAIDs) and selective cyclooxygenase (COX-2) inhibitors (coxibs) are commonly used as analgesic and anti-inflammatory agents. Selective COX-2 inhibitors or coxibs were primarily developed as a response to the gastrointestinal toxicity of conventional NSAIDs but may have other side effects. Currently available data suggests definite prothrombotic risk with the coxibs, and the magnitude of risk may vary with individual agents. Based on available data, coxibs should be restricted to use as 2nd-line, possibly as 3rd-line, agents for carefully chosen patients and randomized trials versus placebo or an accepted comparator must be performed to define the overall safety profile in diverse patient populations. The recently announced Prospective Randomized Evaluation of Celecoxib Integrated Safety vs. Ibuprofen or Naproxen (PRECISION) trial will assess the relative cardiovascular safety of three of the most commonly used pain relievers in the treatment of arthritis patients, ibuprofen, naproxen and celecoxib. The study will enroll patients with osteoarthritis, the most common form of arthritis, who have known coronary heart disease or who have multiple risk factors for heart disease and also some patients with rheumatoid arthritis. Patients will be followed for an average of two years to track the occurrence of serious cardiovascular events, including death, heart attack and stroke. This study should provide some definitive evidence of the relative cardiovascular safety of the available anti-inflammatory agents but would be even more useful if it included an arm where patients were treated with analgesics such as acetaminophen and/or moderate strength narcotics.
18378941 Bone mineral density in children exposed to chronic glucocorticoid therapy. 2008 Jun The objective of this study was to determine the impact of glucocorticoid exposure on lumbar spine bone mineral density (BMD) in children while concurrently measuring their calcium intake, serum 25-OH vitamin D levels, and physical activity. Forty-three patients (4-18 years) with renal glomerular diseases, dermatomyositis, inflammatory bowel disease, juvenile rheumatoid arthritis, post-solid organ transplant, and Duchenne muscular dystrophy were studied. All received at least 5 mg per day of prednisone for more than 6 months. The mean BMD z score was 0 +/- 0.2 (range, -3.8 to +3.3) with 2 patients (5%) having z scores less than -2. The mean daily calcium intake was 1147 +/- 145 g, with 1 patient having hypovitaminosis D (<15 ng/mL). The mean physical activity level was 7.8 +/- 0.8 h/wk. The small reductions in BMD observed in our population suggest that screening is likely not warranted in all children with chronic glucocorticoid exposure.
18276192 Regulation of autoimmune arthritis by the pro-inflammatory cytokine interferon-gamma. 2008 Apr The pathogenesis of T cell-mediated diseases like rheumatoid arthritis (RA) has typically been explained in the context of the Th1-Th2 paradigm: the initiation/propagation by pro-inflammatory cytokines, and downregulation by Th2 cytokines. However, in our study based on the adjuvant-induced arthritis (AA) model of RA, we observed that Lewis (LEW) (RT.1(l)) rats at the recovery phase of AA showed the highest level of IFN-gamma in recall response to mycobacterial heat-shock protein 65 (Bhsp65), whereas AA-resistant Wistar-Kyoto (WKY) (RT.1(l)) rats secreted high levels of IFN-gamma much earlier following disease induction. However, no significant secretion of IL-10 or TGF-beta was observed in either strain. Furthermore, pre-treatment of LEW rats with a peptide of self (rat) hsp65 (R465), which induced T cells secreting predominantly IFN-gamma, afforded protection against AA and decreased IL-17 expression by the arthritogenic epitope-restimulated T cells. These results provide a novel perspective on the pathogenesis of autoimmune arthritis.
17045846 Oral administration of type-II collagen peptide 250-270 suppresses specific cellular and h 2007 Jan Oral antigen is an attractive approach for the treatment of autoimmune and inflammatory diseases. Establishment of immune markers and methods in evaluating the effects of antigen-specific cellular and humoral immune responses will help the application of oral tolerance in the treatment of human diseases. The present article observed the effects of chicken collagen II (CII), the recombinant polymerized human collagen II 250-270 (rhCII 250-270) peptide and synthesized human CII 250-270 (syCII 250-270) peptide on the induction of antigen-specific autoimmune response in rheumatoid arthritis (RA) peripheral blood mononuclear cells (PBMC) and on the specific cellular and humoral immune response in collagen-induced arthritis (CIA) and mice fed with CII (250-270) prior to immunization with CII. In the study, proliferation, activation and intracellular cytokine production of antigen-specific T lymphocytes were simultaneously analyzed by bromodeoxyuridine (BrdU) incorporation and flow cytometry at the single-cell level. The antigen-specific antibody and antibody-forming cells were detected by ELISA and ELISPOT, respectively. CII (250-270) was found to have stimulated the response of specific lymphocytes in PBMC from RA patients, including the increase expression of surface activation antigen marker CD69 and CD25, and DNA synthesis. Mice, fed with CII (250-270) before CII immunization, had significantly lower arthritic scores than the mice immunized with CII alone, and the body weight of the former increased during the study period. Furthermore, the specific T cell activity, proliferation and secretion of interferon (IFN)-gamma in spleen cells were actively suppressed in CII (250-270)-fed mice, and the serum anti-CII, anti-CII (250-270) antibody activities and the frequency of specific antibody-forming spleen cells were significantly lower in CII (250-270)-fed mice than in mice immunized with CII alone. These observations suggest that oral administration of CII (250-270) can suppress the cellular and humoral immune response in collagen-induced arthritis, and the simultaneous analysis of antigen-specific cellular and humoral immune responses at single-cell level will help the understanding of the oral tolerance mechanisms in CIA and the development of innovative therapeutic intervention for RA.
19587776 An improved synthesis of haloaceteamidine-based inactivators of protein arginine deiminase 2008 Jul 7 Protein arginine deiminase 4 (PAD4) is an enzyme that hydrolyzes peptidyl arginine residues to form citrulline and ammonia. This enzyme has been implicated in several disease states, e.g. rheumatoid arthritis, and therefore represents a unique target for the development of a novel therapeutic. A solution-phase synthesis of Cl-amidine, the most potent PAD4 inactivator described to date, has been developed. This synthesis proceeds in 80% yield over 4 steps at a significantly (12-fold) lower cost.
19169788 [Matrix-augmented autologous chondrocyte implantation in the knee--arthroscopic technique] 2008 Sep OBJECTIVE: Arthroscopic implantation of resorbable, three-dimensional scaffolds for the treatment of full-thickness cartilage defects. INDICATIONS: Full-thickness cartilage defect mainly in the knee joint. CONTRAINDICATIONS: Advanced osteoarthritis, rheumatoid arthritis, avascular osteonecrosis. SURGICAL TECHNIQUE: Debridement of the defect, assessment of the defect size, sizing of the implant, implantation into the joint, and fixation. POSTOPERATIVE MANAGEMENT: Continuous active and passive motion, pain-adapted weight bearing with crutches, possibly toe-touch loading depending on size and localization of the defect. RESULTS: After 2 years, good and excellent results in 80% of the cases with femoral cartilage defects on the modified Cincinnati Knee Rating Scale. Inferior results for defects of the patella and tibia.
20144046 Antimetabolites and cancer: emerging data with a focus on antifolates. 2006 Feb Antimetabolites, especially antifolates, play an important role in the treatment of a variety of both malignant, and non-malignant diseases, such as rheumatoid arthritis, and bacterial and parasitic infections. Recently, new antimetabolites have become an area for anticancer drug expansion. Gemcitabine has emerged as an important new agent in several tumour types, including non-small cell lung cancer, pancreatic, bladder, breast and ovarian cancers. Capecitabine is an intriguing new prodrug, offering tumour selectivity and prolonged tumour exposure to 5-FU. More potent thymidylate synthase inhibitors have also been developed; raltitrexed and pemetrexed are now commercially available for the treatment of mesothelioma, non-small cell lung cancer and other solid cancer types. This review will describe the most recent findings and their potential clinical applications.
18466530 A new transmission test for affected sib-pair families. 2007 Family-based association approaches such as the transmission-disequilibrium test (TDT) are used extensively in the study of genetic traits because they are generally robust to the presence of population structure. However, these approaches necessarily involve recruitment of families, which is more costly and time-consuming than sampling unrelated individuals in the population-based approaches. Therefore, a family-based approach, which has high power, would be appealing because of the gain in time and cost due to the reduced sample size that is required to attain adequate power. Here we introduce a new family-based transmission test using the joint transmission status from affected sib pairs. We show that by including the transmission status of both siblings, our method gives higher power than the TDT design, while maintaining the correct type I error rate. We use the simulated data from affected sib-pair families with rheumatoid arthritis provided by Genetic Analysis Workshop 15 to illustrate our approach.
18088880 Condylar resorption. 2007 May Idiopathic condylar resorption almost exclusively affects women. Its exact etiology and pathogenesis remain unclear. It has been associated with rheumatoid arthritis, temporomandibular joint internal derangement, condylar fractures, connective tissue or autoimmune diseases, orthodontic treatment, and orthognathic surgery. In most cases, however, there is no identifiable precipitating event, hence the term "idiopathic condylar resorption." The female predisposition to this condition may be attributed to the influence of estrogen and prolactin on the bone response. Treatment of idiopathic condylar resorption is controversial. Condylectomy and reconstruction with costochondral graft offer definitive management of active idiopathic condylar resorption.
17674550 [Cachexia, malignancy and tumor necrosis factor alpha (TNF-alpha)]. 2007 May Cachexia is a common finding in various diseases such as chronic renal failure, HIV infection, malignancies, chronic obstructive pulmonary disease, congestive heart failure and rheumatoid arthritis. It is estimated that 30% of patients with malignancies will appear with cachexia, and up to 80% of patients with progressive metastatic disease will be affected. Cachexia is associated with decreased overall survival rates, and decreased beneficial effects of chemotherapy treatment. The underlying pathological processes in cachexia are not completely understood. It is believed that tumor necrosis factor alpha (TNFalpha) plays an essential rule in cachexia induction and propagation. This article reviews and discusses current anti-cachexia treatments, with special emphasis on anti-TNF-alpha treatment in malignancies and various other diseases.
16249785 Cruciate paralysis and hemiplegia cruciata: report of three cases. 2006 Jun STUDY DESIGN: Report of three cases of cruciate paralysis and hemiplegia cruciata. OBJECTIVE: To stress the importance of upper cervical spine lesions causing neurological symptoms and signs. SETTING: Neuro-orthopedic service, Fukui University Hospital, Japan. RESULTS: Three patients (all females; one with congenital anomaly at the occiput-atlas level, one with assimilation of the atlas, and one with rheumatoid arthritis-related proliferative synovium) had clinical features of cruciate paralysis and hemiplegia cruciata. All three cases underwent decompressive surgeries. CONCLUSION: Neurological symptoms and signs of cruciate paralysis and hemiplegia cruciata should be carefully assessed, and surgical therapy should be based on the pathological condition.
19227019 Palliative care in rheumatic diseases: a first approach. 2008 Winter Currently, the main goal in rheumatic research is to achieve remission, even in highly active stages of the disease. However, there is a lack of understanding of how to manage patients when some rheumatic diseases such as vasculitis, connective tissue disease, or rheumatoid arthritis develop fulminant, progressive, and complicated courses. There is a clear role for palliative care to enhance patients' quality of life, but hardly any data exist regarding the prevalence and management of symptoms, and the special needs of these patients and their relatives. Rheumatologists, and palliative and primary care physicians should become more aware of this patient group so as to offer them the care they need. Further research is necessary in this field.
18928740 [Current state of anti-tumor necrosis factor therapy in autoimmune diseases]. 2008 Oct 11 Tumor necrosis factor (TNF) alpha plays a central role in both the inflammatory response and that of the immune system. Thus, its blockade with the so-called anti-TNF agents (infliximab, etanercept and adalimumab) represents an important tool for the management of a variety of disorders, such as rheumatoid arthritis, the spondyloarthropathies, inflammatory bowel disease and psoriasis. Nonetheless, theoretically, some other autoimmune and inflammatory disorders may benefit from these agents. We intend to update on these off-label uses of anti-TNF blockers in this review.
18779943 [B-cell-depleting antibodies in skin diseases]. 2008 Oct Basic insight into immune mechanisms, particularly the role and function of various immune cells and proinflammatory cytokines in the etiopathogenesis of inflammatory dermatoses and autoimmune skin disorders, has made possible the development of novel therapeutic strategies. Because of their properties as antigen presenting cells and progenitors of autoantibody-secreting plasma cells, B cells have a major impact in different autoimmune diseases and represent an important therapeutic target. The remarkable clinical improvement seen in patients with rheumatoid arthritis after treatment with the monoclonal anti-CD20 antibody, rituximab, has strongly augmented the interest in B-cell-targeted therapies in different autoimmune diseases. Future clinical and immunological investigations are mandatory to precisely define the contribution of impaired B-cell function in development and progression of autoimmune mediated skin disorders.
18466532 Comparison of variable and model selection methods for genetic association studies using t 2007 We compared and evaluated several variable and model selection methods using Bayesian and non-Bayesian approaches for three replicates of the Genetic Analysis Workshop 15 (GAW15) simulated data. In doing so, two phenotypes were utilized: rheumatoid arthritis (RA) affection status as a binary trait and IgM as a continuous measure. The analyses were performed adjusting for sex, age, and smoking status. For both outcomes, all the methods were comparable in finding the single-nucleotide polymorphisms (SNPs) generated to have a genetic signal. We successfully identified the susceptibility SNPs for RA in the HLA region (chromosome 6), and chromosome 18, and the susceptibility SNP for IgM on chromosome 11; however, many of the methods produced false-positive results.The answers to Problem 3 were requested and known to the authors.
18426199 Spectroscopic evidence for the formation of goldfingers. 2008 May 19 Gold(I) has long been used in the treatment of rheumatoid arthritis, but the therapeutically relevant biological targets of gold(I) are not well understood. Here, we report the results of a spectroscopic investigation into the formation of goldfingers. By exploiting a thiolate to gold charge-transfer band in the UV, we observed that gold(I) interacts with zinc finger peptides with a stoichiometry of one gold ion for each two cysteine residues, forming 1:1, 1.5:1, and 2:1 adducts with zinc finger peptides containing CCHH, CCHC, and CCCC donor sets, respectively. In addition, circular dichroism experiments provided evidence that goldfingers are more ordered than the corresponding metal-free peptides but do not exhibit the canonical zinc finger structure.
18373713 A semi-parametric shared parameter model to handle nonmonotone nonignorable missingness. 2009 Mar Longitudinal studies often generate incomplete response patterns according to a missing not at random mechanism. Shared parameter models provide an appealing framework for the joint modelling of the measurement and missingness processes, especially in the nonmonotone missingness case, and assume a set of random effects to induce the interdependence. Parametric assumptions are typically made for the random effects distribution, violation of which leads to model misspecification with a potential effect on the parameter estimates and standard errors. In this article we avoid any parametric assumption for the random effects distribution and leave it completely unspecified. The estimation of the model is then made using a semi-parametric maximum likelihood method. Our proposal is illustrated on a randomized longitudinal study on patients with rheumatoid arthritis exhibiting nonmonotone missingness.
18358372 Infection after knee arthroplasty a prospective study of 1509 cases. 2008 Apr We report a prospective study of 1509 consecutive total knee arthroplasties looking at risk factors for infection in modern surgical practice. The overall deep infection rate was 1%. A further 51 patients had a superficial infection (3.3%). Statistical analysis revealed no correlation between risk of infection and age and sex. Those who had poor health as assessed by the American Society of Anesthesiologists score had no increased risk of infection. Neither did patients undergoing arthroplasty for rheumatoid arthritis. Diabetic patients and those with morbid obesity (body mass index, >40 kg/m(2)) had an increased odds ratio for deep and superficial infection, but these results did not reach statistical significance.