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ID PMID Title PublicationDate abstract
18601717 Presence and utility of IgA-class antibodies to cyclic citrullinated peptides in early rhe 2008 INTRODUCTION: The present study was carried out to assess whether IgA-class antibodies against cyclic citrullinated peptides (IgA anti-CCP) in recent-onset rheumatoid arthritis add diagnostic and/or prognostic information to IgG anti-CCP analysis. METHODS: Serum samples were obtained from 228 patients with recent-onset (<12 months) rheumatoid arthritis at the time of inclusion in the Swedish TIRA cohort (Swedish Early Intervention in Rheumatoid Arthritis). Sera from 72 of these patients were also available at the 3-year follow-up. Disease activity and functional ability measures (erythrocyte sedimentation rate, serum C-reactive protein, 28-joint count Disease Activity Score, physician's assessment of disease activity, and the Swedish version of the Health Assessment Questionnaire) were registered at inclusion and at regular follow-ups during 3 years. An IgA anti-CCP assay was developed based on the commercially available IgG-specific enzyme immunoassay from EuroDiagnostica (Arnhem, the Netherlands), replacing the detection antibody by an anti-human-IgA antibody. A positive IgA anti-CCP test was defined by the 99th percentile among healthy blood donors. RESULTS: At baseline, a positive IgA anti-CCP test was observed in 29% of the patient sera, all of which also tested positive for IgG anti-CCP at a higher average level than sera containing IgG anti-CCP alone. The IgA anti-CCP-positive patients had significantly higher disease activity over time compared with the IgA anti-CCP-negative patients. After considering the IgG anti-CCP level, the disease activity also tended to be higher in the IgA anti-CCP-positive cases--although this difference did not reach statistical significance. The proportion of IgA anti-CCP-positive patients was significantly larger among smokers than among nonsmokers. CONCLUSION: Anti-CCP antibodies of the IgA class were found in about one-third of patients with recent-onset rheumatoid arthritis, all of whom also had IgG anti-CCP. The occurrence of IgA-class antibodies was associated with smoking, and IgA anti-CCP-positive patients had a more severe disease course over 3 years compared with IgA anti-CCP-negative cases. Although IgA anti-CCP analysis does not seem to offer any diagnostic information in addition to IgG anti-CCP analysis, further efforts are justified to investigate the prognostic implications.
18758892 Disease activity and the course of wrist joint deterioration over 10 years in the patients 2009 The objectives of this study were to evaluate the course of radiographic deterioration of the wrist joint with rheumatoid arthritis (RA), and to determine the influence of disease activity on its deterioration. A retrospective study was performed on 122 wrists in 66 patients, who started treatment using disease-modifying antirheumatic drugs within the first year of the disease and followed for more than 10 years without surgical intervention. The mean disease activity score (DAS28-CRP[3]) was high during the first 2 years, followed by a decrease and a flattening of the curve of disease activity. Generally, carpal collapse progressed more in the early stage and decreased linearly over 10 years. Individually, continuous high disease activity and progression in radiographic damage were observed in carpal collapsed groups from early stage of the disease. The cut-off values of the mean DAS28-CRP(3) during year 0-2, which indicated progression to Larsen grade III or more and Schulthess type I (ankylosis) or III (disintegration) at year 10 were 3.34 (sensitivity: 70.9% and specificity: 72.1%) and 3.63 (sensitivity: 74.3% and specificity: 77.0%), respectively. In patients with RA, deterioration of the wrist joint was influenced by disease activity. Identifying this activity and the course of wrist progression may be useful in predicting wrist deterioration.
18662303 Molecular aspects of rheumatoid arthritis: role of transcription factors. 2008 Sep Rheumatoid arthritis is a multifactorial disease characterized by chronic inflammation of the joints. Both genetic and environmental factors are involved in the pathogenesis leading to joint destruction and ultimately disability. In the inflamed RA joint the synovium is highly infiltrated by CD4+ T cells, B cells and macrophages, and the intimal lining becomes hyperplastic owing to the increased number of macrophage-like and fibroblast-like synoviocytes. This hyperplastic intimal synovial lining forms an aggressive front, called pannus, which invades cartilage and bone structures, leading to the destruction and compromised function of affected joints. This process is mediated by a number of cytokines (tumor necrosis factor-alpha, interleukin-1, interleukin-6, interleukin-17 interferon-gamma, etc.), chemokines (monocyte chemoattractant protein-1, monocyte chemoattractant protein-4 CCL18, etc.), cell adhesion molecules (intercellular adhesion molecule-1, vascular cell adhesion molecule-1, etc.) and matrix metalloproteinases. Expression of these molecules is controlled at the transcription level and activation of a limited number of transcription factors is involved in this process.
18021512 Assessment of quality of rheumatoid arthritis care requires joint count and/or patient que 2007 Nov Quality of care of many diseases, such as diabetes, hypertension, hyperlipidemia, and osteoporosis, can be assessed effectively from information in usual medical records concerning blood tests, blood pressure, bone density, etc. However, quality of care of rheumatoid arthritis (RA), as well as most rheumatic diseases, cannot be assessed from usual medical records. The primary basis for this problem involves limitations of laboratory tests and the absence of a single "gold standard" measure in RA Therefore, indices which include laboratory tests, joint counts, and patient questionnaires have been developed. These indices are collected in all RA clinical trials and other clinical research, but not in usual clinical care, a phenomenon which may limit severely possible assessment and improvement of quality and patient outcomes. Patient questionnaires and joint counts, rather than laboratory tests or radiographs in a medical record, are the best measures to assess and monitor RA patient status. Patient questionnaires are the most significant clinical prognostic markers for severe long-term RA outcomes, such as work disability, costs and premature mortality, and are more cost-effective and easily-collected than formal quantitative joint counts in busy clinical settings. The value of patient questionnaires and joint counts in RA is reviewed in three examples from the authors' research concerning premature mortality in RA, changes in patient clinical status between 1985 and 2000, and a QUEST-RA global perspective, to better evaluate the structure, processes, and outcomes of RA care.
16902778 [Update on rheuma-orthopedics - role and therapeutic options]. 2006 Nov Orthopaedic treatment options for rheumatological patients have been further developed over recent years. For orthopaedic treatment, a range of different interventions are offered: orthoses and special technical aids as well as injections for joints and tendons, or surgery. Surgical interventions cover joint preservation, restitution and arthrodeses. Improvements in equipment and surgical procedures also make minimally invasive interactions possible for rheumatoid diseases. Thus, postoperative morbidity has been reduced significantly. Improvement in function, reduction of pain and prevention of recurrent local inflammation are primary. Considering these aims, arthrodeses are restricted to special indications. Joint preservation and restitution are the predominant measures used. The various procedures are discussed.
18578970 Evaluation of third generation anti-CCP antibodies in the diagnosis of rheumatoid arthriti 2008 May OBJECTIVES: Rheumatoid arthritis (RA) is a complex pathology to identify at an early stage. A large number of patients with recent onset polyarthritis (ROP) do not usually fulfil the ACR criteria for diagnosis of the disease and are classified as having undifferentiated polyarthritis. The aim of this study is to verify with certainty the diagnosis of patients whose illness has not been classified after four years of follow-up, and correlate their actual status with the levels of anti-cyclic citrullinated peptide (anti-CCP) antibodies and rheumatoid factor (RF) found. METHODS: After one year of follow-up, 56 patients from a total of 322, included from January 2002 in the ROP Unit, did not meet ACR criteria for any rheumatic disease. The anti-CCP antibodies and RF levels were determined in the initial clinical assessment. RESULTS: After four years of follow-up, 12 new diagnoses were made in the 56 patients with undifferentiated polyarthritis: 3 seronegative RA, 8 seropositive RA and 1 psoriatic arthritis. The anti-CCP antibodies levels were positive for 5 of these 12 patients (median anti-CCP 228.6 U/mL), and all were RF positive. Six of the 7 anti-CCP antibodies negative patients were diagnosed of RA (3 seropositive and 3 seronegative for RF) and 1 was diagnosed of psoriatic arthritis (anti-CCP antibodies negative and RF positive). Forty-four patients still displayed undifferentiated polyarthritis and were RF negative. CONCLUSION: A positive result for RF and anti-CCP antibodies in patients who do not meet the ACR diagnostic criteria could be a useful indicator of the presence of future RA.
19011784 Visual hallucinations on eye closure after orthopedic surgery under general anesthesia. 2008 A 61-year-old woman suffering from rheumatoid arthritis without a contributory neurological, mental, or psychological history experienced visual hallucinations solely on eye closure after total hip arthroplasty under general anesthesia combined with epidural anesthesia. The visual hallucinations first appeared when she arose from sleep early on postoperative day 1, approximately 12 h after the end of surgery. Only on closing her eyes, she had a clear view of colored clothes, lace curtains, handbags, hats, and sofas, all of which were vivid, realistic, complex, of natural size, and in normal perspective without distortion and appeared independently and randomly in succession. The hallucinations disappeared when she opened her eyes even in the dark. The visual hallucinations gradually decreased as the days elapsed and they had entirely subsided on postoperative day 4. The level and content of her consciousness seemed entirely normal throughout her hospital course. Although postoperative visual hallucinations are not uncommon, they do not always show the closed-eye variation. The causes and underlying mechanisms of this type of visual hallucination remain to be elucidated.
17436241 Gene-gene and gene-environment interactions involving HLA-DRB1, PTPN22, and smoking in two 2007 May Gene-gene and gene-environment interactions are key features in the development of rheumatoid arthritis (RA) and other complex diseases. The aim of this study was to use and compare three different definitions of interaction between the two major genetic risk factors of RA--the HLA-DRB1 shared epitope (SE) alleles and the PTPN22 R620W allele--in three large case-control studies: the Swedish Epidemiological Investigation of Rheumatoid Arthritis (EIRA) study, the North American RA Consortium (NARAC) study, and the Dutch Leiden Early Arthritis Clinic study (in total, 1,977 cases and 2,405 controls). The EIRA study was also used to analyze interactions between smoking and the two genes. "Interaction" was defined either as a departure from additivity, as interaction in a multiplicative model, or in terms of linkage disequilibrium--for example, deviation from independence of penetrance of two unlinked loci. Consistent interaction, defined as departure from additivity, between HLA-DRB1 SE alleles and the A allele of PTPN22 R620W was seen in all three studies regarding anti-CCP-positive RA. Testing for multiplicative interactions demonstrated an interaction between the two genes only when the three studies were pooled. The linkage disequilibrium approach indicated a gene-gene interaction in EIRA and NARAC, as well as in the pooled analysis. No interaction was seen between smoking and PTPN22 R620W. A new pattern of interactions is described between the two major known genetic risk factors and the major environmental risk factor concerning the risk of developing anti-CCP-positive RA. The data extend the basis for a pathogenetic hypothesis for RA involving genetic and environmental factors. The study also raises and illustrates principal questions concerning ways to define interactions in complex diseases.
17064873 Autoantibodies in rheumatoid arthritis: a review. 2006 Dec Emerging insights into the importance of B cells in the pathogenesis of rheumatoid arthritis (RA) as highlighted by the efficacy of B cell depletion is one factor that has contributed to the upsurge of interest in the potential role of autoantibodies both as disease markers and with respect to a pathogenic role. Since the initial description of rheumatoid factor (RF), a large number of both disease-specific and non-specific autoantibodies have been described in patients with RA including antibodies to type II collagen (CII), immunoglobulin binding protein (BiP) and antibodies directed at citrullinated peptides (anti-CCP) and other citrullinated proteins such as vimentin (anti-Sa) . Despite some overlap the serological profile of RA does appear to be distinct from other diseases such as SLE . Although the precise mechanisms responsible for the formation of these antibodies have not been well defined their presence must reflect the interaction between T and B cells believed to be relevant to the pathogenesis of RA. The specificity of the association of such factors as anti-CCP and anti-BiP with RA may reflect unique pathogenic events leading to the processing and presentation of the "cryptic self" . Ease of measurement and stability make autoantibodies attractive diagnostic and prognostic markers particularly in early disease when it may be difficult to distinguish self-limiting synovitis from persistent disease . The purpose of this article is to provide an overview of the current state of knowledge of the spectrum of autoantibodies thus far characterised in individuals with rheumatoid arthritis, and discuss their diagnostic, prognostic and pathogenetic relevance.
18184299 Headache in a case of Rhupus syndrome. 2008 Jan We report a case of Rhupus with secondary anti-phospholipid syndrome who presented with headache and papilloedema due to cerebral venous thrombosis. We propose that an increased awareness about the condition and meticulous investigation of headaches in lupus can avert catastrophic outcomes.
18315354 Photoacoustic tomography of carrageenan-induced arthritis in a rat model. 2008 Jan Laser-based photoacoustic tomography (PAT), a novel, nonionizing, noninvasive, laser-based technology, has been adapted to the diagnosis and imaging of inflammatory arthritis. A commonly used adjuvant induced arthritis model using carrageenan was employed to simulate acute rheumatoid arthritis in rat tail joints. Cross-sectional photoacoustic images of joints affected by acute inflammation were compared to those of the control. The diameter of the periosteum and the optical absorption of intra-articular tissue were measured on each joint image. Significant differences were found on PAT imaging between the affected joints and the control for both variables measured, including enlarged periosteum diameter and enhanced intra-articular optical absorption occurring in the joints affected with carrageenan-induced arthritis. Anatomical correlation with histological sections of imaged joints and microMRI results verified the findings of PAT. This suggests that PAT has the potential for highly sensitive diagnosis and evaluation of pathologic hallmarks of acute inflammatory arthritis.
18239374 [Signal transduction of inflammatory synoviocytes in rheumatoid arthritis]. 2008 Feb Recent advances in post-genomic technology enable us to analyze gene expression and protein modification comprehensively in tissues and cells, resulting in new developments in the analysis of molecular events of diseases. We have been studying the pathogenic and progressive mechanisms of diseases from the aspect of signalling pathways of cells. Inflammatory cytokines such as TNF-alpha and IL-1 produced from activated macrophages stimulate the overgrowth of synoviocytes and induce osteoclast differentiation in rheumatoid arthritis (RA). As a consequence, cartilage and bone destruction in joints is observed in RA patients. Recently, the pathogenic mechanisms are beginning to be discussed at the molecular level. For example, up-regulation of synoviolin, an ER-localizing E3 ubiquitin ligase, in synoviocytes is involved in RA because rheumatoid synoviocytes produce synoviolin and overexpression of human synoviolin in mice causes arthropathy. So far little is known about ligands inducing arthropathy and their receptors in the disease. We characterized rheumatoid synoviocytes by profiling gene expression with genome-wide DNA chips, and found that a cluster antigen is involved in the proteins up-regulated in rheumatoid synoviocytes. We have been analyzing the relationship between synoviolin expression and the activation of cluster antigen. The cluster antigen and its signal pathways could become a novel therapeutic target for RA. We discuss the possibility of direct induction of synoviolin expression via activation of signal pathways directed by the cluster antigen in RA synoviocytes.
17552047 Variability in the use of orthopedic surgery in patients with rheumatoid arthritis in Spai 2007 Jul OBJECTIVE: To analyze sociodemographic and clinic-associated factors of patients with rheumatoid arthritis (RA) undergoing any orthopedic surgery (AOS) and total joint replacement (TJR) in Spain. METHODS: A retrospective medical record review was performed in a probabilistic sample of 1379 RA patients from 46 centers distributed in 16 of 19 regions in Spain. Sociodemographic and clinical features, use of drugs, and arthritis-related joint surgeries were recorded following a standardized protocol. Gross domestic product (GDP) data were obtained from the National Statistical Index. RESULTS: Of 1379 patients, a total of 358 (26%) underwent one or more joint surgeries, and 194 (14%) had a TJR. The median time to first orthopedic procedure was 12.5 years from presentation of RA and the estimated rate was 5.6 surgeries per 100 person-years. The rate of AOS was increased in women, patients with RA with extraarticular complications, with longterm RA (> 10 yrs), with functional grade III-IV, and with persistent inflammatory disease. The risk factors for undergoing a TJR were longterm RA, functional grade III-IV, and extraarticular complications. Patients from regions with higher GDP per capita were more likely to undergo a procedure. CONCLUSION: Clinical variables reflecting disease activity and severity are predictors of orthopedic surgery, but geographic and socioeconomic variables were also independently associated with the rate of orthopedic surgery.
19051134 An update on pharmacogenomics in rheumatoid arthritis with a focus on TNF-blocking agents. 2008 Dec TNFalpha is a proinflammatory cytokine, which is crucial in the pathogenesis of rheumatoid arthritis (RA). In recent years, biological therapies which block the damaging effects of TNFalpha on synovium and cartilage have been developed. TNF antagonists, such as etanercept, infliximab and adalimumab, although highly effective in RA, are expensive, totaling several thousand US dollars in yearly costs. In addition, only approximately 60% of patients respond to these agents. This has led to the need to prospectively identify patients most likely to respond to these agents, which can be achieved by pharmacogenomics approaches. Polymorphisms in genes encoding for TNFalpha, the MHC region, and the Fcgamma receptor IIIA, as well as their ability to predict disease progression in RA and response to anti-TNF therapies, have been the focus of a number of studies, which are discussed in this review. There is no consensus at present as to whether pharmacogenomics will allow prediction of anti-TNF therapy efficacy in RA. Large, prospective, multicenter studies are needed to replicate and validate the results of the studies outlined in this review.
18681777 Pharmacogenetics of etanercept in rheumatoid arthritis. 2008 Aug Etanercept is one of several TNF inhibitors approved for rheumatoid arthritis (RA) and a variety of other immune-mediated inflammatory conditions. Given the plethora of drugs approved for RA, and the wide variations in cost and treatment response, markers of efficacy would be very useful. Several candidate genes, including HLA-DRB1 alleles and those encoding TNF, TNF receptors and Fc receptors, have been examined for a role in the response to treatment with etanercept. In this review, we discuss pharmacogenetic studies of etanercept in RA and other diseases, and comment on the future of such analyses to advance the goal of personalized medicine in RA.
16937542 Development of ulcerative colitis during the course of rheumatoid arthritis: Association w 2006 Aug 28 A 56-year-old woman with a 29-year history of rheumatoid arthritis (RA) was admitted to the hospital, complaining of high fever, abdominal pain and severe bloody diarrhea. Colonoscopy revealed friable and edematous mucosa with spontaneous bleeding, diffuse erosions and ulcers extending from the rectum to the distal transverse colon. Histopathological findings of rectal biopsies were compatible with ulcerative colitis (UC). Being diagnosed as having severe active left-side UC, she was successfully treated with intravenous methylprednisolone followed by prednisolone and leukocytapheresis. Laboratory tests revealed low serum and saliva IgA levels, which might play a role in the development of UC. To our knowledge, this is the first case of UC occurring during the course of RA, accompanied by selective IgA deficiency.
17013822 Assessing utility values in rheumatoid arthritis: a comparison between time trade-off and 2006 Oct 15 OBJECTIVE: To compare the utility values and quality-adjusted life years (QALYs) obtained by the Time Trade-Off instrument (TTO) and the EuroQol-5D (EQ-5D) in patients with rheumatoid arthritis (RA); to analyze the association between utility values and Disease Activity Score 28 (DAS28) and Health Assessment Questionnaire (HAQ). METHODS: We conducted a longitudinal, prospective, 1-year study of RA patients selected randomly from 10 rheumatology clinics. TTO and EQ-5D were administered at 4 scheduled visits. RESULTS: The study sample comprised 300 RA patients (82% women, mean age 59 years, mean disease duration 10.3 years). A total of 260 patients completed both the TTO and the EQ-5D at baseline, and the mean +/- SD TTO scores were significantly higher than the EQ-5D scores (0.81 +/- 0.22 versus 0.53 +/- 0.35, P < 0.0001). The intraclass correlation coefficient (ICC) for the utility methods was 0.19. Data about changes in both TTO and EQ-5D scores during the study year were available in 163 patients. These changes tended to be larger in the TTO scores than the EQ-5D scores (mean +/- SD 0.05 +/- 0.25 versus -0.005 +/- 0.35, P = 0.054). The ICC for the mean changes in the utility scores was 0.24. Patients obtained a mean +/- SD of 0.04 +/- 0.20 QALYs based on TTO scores and 0.004 +/- 0.27 based on EQ-5D scores (P = 0.12). At baseline, the EQ-5D scores were highly correlated with the HAQ (r = -0.74) and moderately correlated with the DAS28 (r = -0.47), whereas the TTO correlated poorly with both the HAQ and DAS28. Correlation between the mean change in the EQ-5D and in the HAQ was moderate (r = -0.55). CONCLUSION: TTO and EQ-5D do not yield the same utility values. The results suggest that the EQ-5D is more representative of RA status than the TTO, a valuable conclusion when addressing economic evaluations in RA.
19015958 Antisense makes sense in engineered regenerative medicine. 2009 Feb The use of antisense strategies such as ribozymes, oligodeoxynucleotides (ODNs) and small interfering RNA (siRNA) in gene therapy, in conjunction with the use of stem cells and tissue engineering, has opened up possibilities in curing degenerative diseases and injuries to non-regenerating organs and tissues. With their unique ability to down-regulate or silence gene expression, antisense oligonucleotides are uniquely suited in turning down the production of pathogenic or undesirable proteins and cytokines. Here, we review the antisense strategies and their applications in regenerative medicine with a focus on their efficacies in promoting cell viability, regulating cell functionalities as well as shaping an optimal microenvironment for therapeutic purposes.
17229252 Effect of leflunomide on the peripheral nerves in rheumatoid arthritis. 2007 Feb BACKGROUND: The objective of this study was to determine the neurophysiological effects of leflunomide on peripheral nerves in rheumatoid arthritis. METHODS: We conducted a prospective cohort trial of 32 patients with rheumatoid arthritis with 16 patients receiving leflunomide treatment and 16 receiving other disease-modifying anti-rheumatic drug therapies. Clinical, laboratory and neurophysiological measurements were used to determine the presence of a peripheral neuropathy in these patients at study entry and then after a further 3 and 6 months. RESULTS: Fifty-four per cent of the leflunomide group and 8% of the control group had an increase in their neuropathy symptom score 6 months into the study (P = 0.01). No correlation was found between the electrophysiological findings and the clinical symptoms. There was no significant difference between the two groups in upper and lower limb sensory and motor amplitudes and conduction velocities recorded at 3 and 6 months. One patient developed both clinical and neurophysiological evidence of a peripheral neuropathy 5 months into the study that improved after cessation of leflunomide therapy and cholestyramine washout. CONCLUSION: After 6 months of exposure we found that leflunomide was associated with an apparent increase in the clinical symptoms of peripheral neuropathy in patients with rheumatoid arthritis. These symptoms did not correlate with neurophysiological studies.
16842163 Angiogenesis as a therapeutic target in arthritis: lessons from oncology. 2006 Rheumatoid arthritis (RA) is a chronic disabling autoimmune inflammatory disease of unknown aetiology with a prevalence of about 1% in most parts of the world. As a result of the debilitating nature of the disease, sufferers struggle with the simple activities of daily living and frequently fail to remain in full time employment. Furthermore, the mortality associated with the disease is equivalent to that seen in triple vessel coronary artery disease. Over the 10-15 years, advances in understanding the mechanisms of RA pathogenesis based on studies of human cells and animal models of arthritis have led to the identification of new targets for therapeutic intervention. Despite these advances, a significant proportion of patients continue to exhibit disease which is refractory to such therapy. As an alternative to anti-cytokine therapy, formation of new blood vessels ('angiogenesis') represents a potentially attractive target for therapy in RA. Angiogenesis has been a putative target in cancer since it was first linked to tumour growth and metastases in the 1970s. A number of significant advances have been made in the development of anti-cancer therapy using such an approach. This review focuses on the potential for targeting angiogenesis in RA, building upon the experience of angiogenesis inhibition in the oncological setting. Through this we hope to emphasise the potential value of anti-angiogenic therapy in RA and identify future directions for optimising treatment of this disabling disease.