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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
17459959 Synovial fibronectin fragmentation and domain expressions in relation to rheumatoid arthri 2007 Jul OBJECTIVE: To determine whether the expression of some fibronectin (FN) domains and a degree of FN degradation are associated with the progression of rheumatoid arthritis (RA). METHODS: Based on the radiographs of the hands of RA patients, three groups of synovial fluid and plasma samples were distinguished: (i) those with early radiological changes, (ii) established and (iii) late progressive radiological changes. The expressions of FN domains were determined by ELISA using appropriate domain-specific monoclonal antibodies. FN fragmentation was analysed by immunoblotting. RESULTS: In the early RA group, synovial FN was found to be totally degraded to a mixture of FN fragments. In the established group, it consisted of a portion of intact FN molecules and a smaller part of FN fragments, whereas in the late group the synovial FN immunoblotting pattern was similar to that of intact FN. The FN fragmentation was accompanied by decreases in FN immune reactivity with monoclonal antibodies specific to the collagen, fibrin and C-terminal FN domains. In the blood plasma of all studied groups of RA patients, the FN immunopattern was analogous to that in normal plasma. However, the expressions of the plasma FN domains were higher than those of healthy individuals. CONCLUSIONS: Profound degradation of FN and low collagen, fibrin and C-terminal domain expressions in FN were only associated with early destructive changes observed in radiographs of the RA patients' hands.
16767549 Fractalkine in rheumatoid arthritis and allied conditions. 2006 Leukocyte adhesion and trafficking at the endothelium requires both adhesion molecules and chemotactic factors. Fractalkine (CX3C) is a unique chemokine, and is expressed on tumor necrosis factor-alpha- and interleukin-1-activated endothelial cells (ECs). Fractalkine receptor, CX3CR1, is expressed on NK cells, monocytes, and some portion of CD4- and CD8-positive T cells. Interactions between fractalkine and CX3CR1 can mediate not only chemotaxis, but also cell adhesion in the absence of substrates for other adhesion molecules. Furthermore, fractalkine activates NK cells, leading to increased cytotoxicity and interferon-gamma production. Recently, accumulating evidence has shown that fractalkine is involved in the pathogenesis of rheumatoid arthritis and allied conditions. This review examines new concepts underlying fractalkine-mediated leukocyte migration and tissue damage, focusing primarily on the pathophysiological roles of fractalkine in rheumatic diseases.
17642250 [Induction of malignant neoplasm]. 2007 Jul Anti -rheumatic drugs are classified to immunosuppressive drugs/immunisation adjustment drugs/biological drugs. The induction of malignant neoplasm by biological drugs having tumor necrosis factor (TNF) inhibitory action has been concerned about, and various epidemiological studies have been done. It has been shown that methotrexate could induce a malignant lymphoma in patients with rheumatoid arthritis at time. With regard to malignant neoplasm induction by biological drugs, there are some reports to suggest the risk, but there are many problems about accuracy of statistics. In this paper, epidemiological analyses which refer to the risk of complications or induction of malignant neoplasm by methotrexate and biological drugs in patients with rheumatoid arthritis, has been reviewed.
16612603 [Arthroplasty of the rheumatoid hand. Pre- and postoperative imaging with special consider 2006 Sep Radiology plays a key role when the indications for arthroplasties of the hand and finger joints are determined and for the postoperative follow-up. On the one hand, the degree of inflammatory changes in all affected compartments is to be evaluated and graded; on the other hand, conventional radiograms allow for a first assessment of possible joint instability and impaired biomechanics. Both aspects influence the choice of the proper surgical therapeutic strategy. Osteolysis, deformity, fracture, prosthesis loosening or failure, heterotopic ossification, and foreign body-associated formation of granulation tissue are complications which can be detected on follow-up radiographs early on.
16469118 Serial determination of cyclic citrullinated peptide autoantibodies predicted five-year ra 2006 The objective of this study was to evaluate the potential of serially determined anti-cyclic citrullinated peptide (CCP) antibodies for predicting structural joint damage in patients with early rheumatoid arthritis (RA), compared to a single baseline determination. Ninety-nine RA patients with disease durations of less than one year and no history of disease-modifying antirheumatic drug therapy were followed prospectively for at least five years. Anti-CCP2 concentrations were measured using a second-generation ELISA. Sharp scores as modified by van der Heijde were determined on hand and foot radiographs. Anti-CCP2 antibodies were detected in 55.5% of patients at baseline and 63.6% at any time during the first three years. Presence of anti-CCP2 at any time during the first three years was associated with radiographic damage at baseline (odds ratio (OR), 3.66; 95% confidence interval (95% CI) 0.99-13.54) and with five year progression of the total Sharp score (OR, 3.17; 95% CI, 1.3-7.7), erosion score (OR, 5.3; 95% CI, 1.4-19.2) and joint space narrowing score (OR, 2.8; 95% CI, 1.15-6.8). The presence of anti-CCP2 or IgM RF at baseline did not predict these outcomes. Patients with negative anti-CCP2 tests throughout follow-up had less radiographic progression than patients with increasing anti-CCP2 concentrations; they did not differ from patients with decreasing anti-CCP2 antibody levels. HLADRB1* typing showed that progression of the mean modified Sharp score was not correlated with the presence of the shared epitope alleles. In conclusion, serially determined anti-CCP2 antibodies during the first three years of follow-up performs better than baseline determination for predicting radiographic progression in patients with early RA.
18278817 Bivariate combined linkage and association mapping of quantitative trait loci. 2008 Jul In this paper, bivariate/multivariate variance component models are proposed for high-resolution combined linkage and association mapping of quantitative trait loci (QTL), based on combinations of pedigree and population data. Suppose that a quantitative trait locus is located in a chromosome region that exerts pleiotropic effects on multiple quantitative traits. In the region, multiple markers such as single nucleotide polymorphisms are typed. Two regression models, "genotype effect model" and "additive effect model", are proposed to model the association between the markers and the trait locus. The linkage information, i.e., recombination fractions between the QTL and the markers, is modeled in the variance and covariance matrix. By analytical formulae, we show that the "genotype effect model" can be used to model the additive and dominant effects simultaneously; the "additive effect model" only takes care of additive effect. Based on the two models, F-test statistics are proposed to test association between the QTL and markers. By analytical power analysis, we show that bivariate models can be more powerful than univariate models. For moderate-sized samples, the proposed models lead to correct type I error rates; and so the models are reasonably robust. As a practical example, the method is applied to analyze the genetic inheritance of rheumatoid arthritis for the data of The North American Rheumatoid Arthritis Consortium, Problem 2, Genetic Analysis Workshop 15, which confirms the advantage of the proposed bivariate models.
18344640 Eosinophilic pneumonia (EP) associated with rheumatoid arthritis in which drug-induced eos 2008 A 72 year-old man. He was diagnosed with rheumatoid arthritis in 2002. In January 2005 he noted productive cough and fever; he was diagnosed as eosinophilic pneumonia (EP). We discontinued administration of bucillamine and methotrexate and started to treat with oral prednisolone 30 mg daily. To rule out drug-induced EP, prednisolone was tapered by 10 mg per week. Consolidation occurred in the right lower lobe when prednisolone was decreased to 5 mg daily. After increasing the dose of prednisolone to 30 mg daily again, consolidation was promptly resolved. It was considered to be important to rule out drug-induced EP.
18084702 Infectious mononucleosis-like syndrome induced by salazosulfapyridine in a patient with rh 2007 We describe a 43-year-old woman with rheumatoid arthritis (RA), who developed severe infectious mononucleosis (IM)-like syndrome during treatment with salazosulfapyridine (SASP). She presented with fever, skin rash, lymphadenopathy, and hepatosplenomegaly. Laboratory tests revealed a marked increase of atypical lymphocytes in the peripheral blood and biphasic hepatic dysfunction. IM-like syndrome can be caused by various drugs, including SASP, and the concept of drug-induced hypersensitivity syndrome has been proposed recently. IM-like syndrome due to SASP has been reported in patients taking higher dosages for the treatment of inflammatory bowel disease, but has not been reported earlier in patients with RA. The results of the drug-induced lymphocyte stimulation test tests suggested that 5-aminosalicylic acid was a possible causative metabolite. This severe type of drug-induced hypersensitivity reaction mimicking IM due to SASP should be granted wider awareness in the field of rheumatology, because the drug is widely used for the treatment of RA.
17523945 Histamine in rheumatoid arthritis. 2007 Jun Rheumatoid arthritis (RA) is an autoimmune disease characterized by a persistent inflammation of the synovium, leading to the erosion of articular cartilage and bone. Synovial mast cells and their effector molecule, histamine, receive increased attention as mediators of joint inflammation. The aim of our study was to analyse levels of free histamine in serum and joint fluid of RA patients and to evaluate the potential inflammatogenic properties of histamine in vivo and in vitro. Histamine levels were measured by an ELISA in synovial fluid and sera of RA patients and of healthy controls. Histamine levels were also assessed in plasma of RA patients undergoing anti-TNF-alpha treatment. In the murine part of the study, histamine was injected intra-articularly in the knee joint of mice and the joints were subsequently analysed with respect to induction of inflammation. RA patients displayed significantly lower levels of histamine in circulation (0.93 +/- 0.16 ng/ml) compared with the healthy controls (1.89 +/- 0.45 ng/ml, P < 0.001). Locally, in synovial fluid the levels of histamine were even lower (0.37 +/- 0.16 ng/ml, P < 0.0006). Long-term anti-TNF-alpha treatment significantly increased circulating levels of histamine in RA patients. Our experiments on animals show that histamine on its own neither induces inflammation in the joint cavity nor influences the course of HMGB1 and peptidoglycan-induced joint inflammation. Based on our experimental and clinical studies we suggest that histamine lacks harmful properties in RA.
16984939 Formative research in clinical trial development: attitudes of patients with arthritis in 2007 Apr In preparation for randomised controlled trials (RCTs) of disease-modifying antirheumatic drugs in patients with early inflammatory arthritis (EIA), formative research was conducted to enhance the design of such trials. The objectives of this research were to (1) determine patients' educational needs as they relate to the necessary elements of informed consent; and (2) assess patients' interest in enrolling in a hypothetical prevention trial. In-depth interviews were conducted with nine patients. Seven patients were women and all but one white. The mean age was 48 years. During the 4-month enrolment period, only three patients with EIA were identified; six patients with longer duration of symptoms were also interviewed. Most patients were able to express the primary aim of a hypothetical prevention trial presented. Factors cited by patients favouring enrolment were potential for direct medical benefit and knowledge that they would be withdrawn from the trial if they developed symptoms. Factors cited by patients against enrolment were the inclusion of a placebo and general uncertainty regarding treatment required by the RCT design. Pending larger-scale empirical projects to explore patients' attitudes about prevention trials, small-scale formative research in advance of such trials ought to be conducted.
16703417 IL-20: biological functions and clinical implications. 2006 Sep IL-20 belongs to the IL-10 family and plays a role in skin inflammation and the development of hematopoietic cells. Little is known about its other biological functions and clinical implications, however. Updated information about IL-20, such as its identification, expression, receptors, signaling, biological activities, and potential clinical implications, is illustrated in this review based on our research and on data available in the literature. Our studies of IL-20 show that it is a pleiotropic cytokine with potent inflammatory, angiogenic, and chemoattractive characteristics. Inflammation and angiogenesis are essential for the pathogenesis of rheumatoid arthritis and atherosclerosis. Based on in vitro data and clinical samples, we demonstrated that IL-20 is involved in the diseases of rheumatoid arthritis and atherosclerosis. In addition, we found in our studies that IL-20 signaled through different molecules in several cells. The present review presents the clinical implications of IL-20 in rheumatoid arthritis and atherosclerosis. It may provide new therapeutic options in the future.
18484952 Gene array analysis comparison between rat collagen-induced arthritis and human rheumatoid 2008 Jul Collagen-induced arthritis (CIA) is an experimental arthritis model used to study the inflammatory processes in this disease and test potential therapeutics. In order to better characterize this model, we conducted the first comprehensive gene expression analysis of rat CIA. To evaluate how closely the rat model reflects human rheumatoid arthritis (RA), we also analysed gene expression in human RA, using genome-wide Affymetrix gene arrays. By applying multiple strategies, including comparison of the highest induced genes, expression of immunological-associated genes as well as Ingenuity Pathway Analysis (IPA), we were able to compare the two expression profiles. Among the highest induced genes in RA were several B-cell-associated genes, including immunoglobulins, B-cell markers such as CD20, and cytokines and chemokines that act on B cells such as TNFSF13b/BLyS and CXCL13, none of which was upregulated in CIA. The latter was instead characterized by the upregulation of genes expressed primarily in macrophages and dendritic cells. Of the 22 pathways identified as significant in both diseases by IPA, only three (IL6, chemokine signalling and antigen presentation) were present in both settings. We conclude that there are significant differences in the inflammatory mechanisms between human RA and rat CIA, and that genome-wide comparative gene expression analyses are useful tools to evaluate the relevance of animal models to human disease.
17530663 Assessment of American College of Rheumatology quality criteria for rheumatoid arthritis i 2007 Jun 15 OBJECTIVE: To evaluate the American College of Rheumatology (ACR) starter set of quality measures for rheumatoid arthritis (RA) in an actual patient cohort that preceded publication of the quality measures. METHODS: We retrospectively applied the 2006 ACR quality criteria to a prospectively studied cohort of 568 patients with RA treated by 1,932 unique physicians including 255 different rheumatologists between the years 1999 and 2003. Data on performance were obtained from self-report surveys and medical record review within 12 months. RESULTS: At least 1 joint examination was performed in 98% of patients. Patient and physician global assessments were reported for 79% and 74% of patients, respectively. A total of 85% of patients received disease-modifying antirheumatic drugs (DMARDs). DMARD adjustments were made for 50% of patients in whom increasing disease activity was noted at least once and for 64% of patients in whom increasing disease activity was noted during 2 (of 4) 3-month periods within the year. Compared with self-report surveys, medical records substantially underreported performance on quality measures. CONCLUSION: The ACR-endorsed quality measures for RA can be assessed using available data sources. When both self-report and medical record data are used, adherence rates, designed to serve as minimum standards of care, were moderate or high for most measures. Prior to using indicators to compare quality across groups, specific strategies for operationalizing measures and for using accurate data sources to assess adherence to the measures should be defined.
18723564 Serum IgG antibodies to peptidylarginine deiminase 4 predict radiographic progression in p 2009 Feb BACKGROUND: Peptidylarginine deiminase 4 (PAD4) may generate epitopes targeted by anticitrullinated protein antibodies in rheumatoid arthritis (RA). A subset of patients with RA has serum autoantibodies to human recombinant PAD4 (hPAD4). Here, we assessed whether anti-hPAD4 status in RA predicted disease outcome after antitumour necrosis factor (anti-TNF)-alpha therapy. METHODS: We analysed RA sera obtained at baseline (n = 40) and after 1 year on anti-TNF-alpha therapy (n = 33) for anti-hPAD4 IgG. Association analyses between baseline anti-hPAD status and disease progression were performed. RESULTS: We found that 17 of 40 patients (42.5%) were serum anti-hPAD4 positive at baseline, and the anti-hPAD4 IgG levels were stable over 1 year on anti-TNF-alpha therapy. At baseline, there were indications that anti-hPAD4 positive patients had more severe disease than the negative patients. After 1 year on anti-TNF-alpha therapy, the anti-hPAD4 positive patients displayed a persistently elevated disease activity score using 28 joint counts score and increased progression in the van der Heijde-modified Sharp erosion score. Accordingly, more anti-hPAD4 positive than negative patients presented an increase in van der Heijde-modified Sharp erosion scores >0 over 1 year. CONCLUSIONS: Anti-hPAD4 IgG can be detected in a subset of RA sera and the levels are stable after initiation of anti-TNF-alpha therapy. Serum anti-hPAD4 may predict persistent disease activity and radiographic progression in patients with RA receiving anti-TNF-alpha therapy.
17301106 Clinical response to adalimumab: relationship to anti-adalimumab antibodies and serum adal 2007 Jul BACKGROUND: A substantial proportion of patients with rheumatoid arthritis (RA) do not respond, or lose initial response, to adalimumab treatment. One explanation for non-response is that patients develop anti-adalimumab antibodies. OBJECTIVES: To evaluate the incidence of formation of antibody against adalimumab and the association with serum adalimumab concentrations and clinical response. METHODS: In a cohort of 121 consecutive patients with RA treated with adalimumab, serum adalimumab concentrations and antibodies against adalimumab were measured together with clinical response variables before and up to 28 weeks after the start of treatment. RESULTS: Anti-adalimumab antibodies were detected in 21 patients (17%) during 28 weeks of treatment. EULAR non-responders had antibodies significantly more often than good responders (34% vs 5%; p = 0.032). Patients with antibodies showed less improvement in disease activity (mean (SD) delta DAS28 0.65 (1.35)) than patients without antibodies (mean delta DAS28 1.70 (1.35)) (p = 0.001). Patients with antibodies during follow-up had lower serum adalimumab concentrations at 28 weeks than patients without antibodies (median 1.2 mg/l, range 0.0-5.6 vs median 11.0 mg/l, range 2.0-33.0, respectively; p<0.001). Good responders had higher serum adalimumab concentrations than moderate responders (p = 0.021) and non-responders (p = 0.001). Concomitant methotrexate use was lower in the group with anti-adalimumab antibodies (52%) than in the group without antibodies (84%) (p = 0.003). CONCLUSIONS: Serum antibodies against adalimumab are associated with lower serum adalimumab concentrations and non-response to adalimumab treatment.
17088540 An essential role of NF-kappaB in the "tumor-like" phenotype of arthritic synoviocytes. 2006 Nov 14 A hallmark of rheumatoid arthritis is the formation of an aggressive, tumor-like structure called pannus that erodes the joint. A major cellular component of the pannus is the fibroblast-like synoviocyte (FLS), whose morphology strikingly resembles that of a transformed cell, but underlying mechanisms of this "transformation" are not known. Here, using animal models of rheumatoid arthritis, we show that arthritic FLS contain a substantial (>30%) fraction of bone marrow-derived precursors that can differentiate in vitro into various mesenchymal cell types, but inflammation prevents the multilineage differentiation. We show that the transcription factor NF-kappaB plays the key role in the repression of osteogenic and adipogenic differentiation of arthritic FLS. Furthermore, we show that specific activation of NF-kappaB profoundly enhances proliferation, motility, and matrix-degrading activity of FLS. We thus propose that arthritic FLS are mesenchymal stem cells whose differentiation is arrested at early stages of differentiation by activation of NF-kappaB.
17009227 Influence of male sex on disease phenotype in familial rheumatoid arthritis. 2006 Oct OBJECTIVE: To examine sex differences in clinical, demographic, and genetic characteristics among a large cohort of patients with familial rheumatoid arthritis (RA). METHODS: We studied 1,004 affected members of 467 Caucasian multicase RA families recruited from the North American Rheumatoid Arthritis Consortium. Standardized information about demographic and clinical characteristics was collected from all patients. Affected individuals also underwent radiography of the hands and were genotyped for markers in the HLA region. Sex differences were assessed using contingency table analysis (for categorical variables) and Student's t-tests for (continuous variables), and by multivariate logistic and linear regression analysis. RESULTS: Male patients had a significantly later onset of RA, were more likely to be seropositive for RF, and had significantly higher titers of anti-cyclic citrullinated peptide (anti-CCP) antibodies compared with female patients, even after adjustment for covariates in multivariate analyses. Male patients were also significantly more likely to have a history of smoking and to be HLA-DRB1 shared epitope (SE) positive. Interestingly, female patients with an affected male sibling had significantly higher titers of anti-CCP antibodies and were more likely to be SE positive compared with female patients without affected male siblings. Multivariate analyses indicated that the presence of the SE did not fully explain the increased anti-CCP antibody titers observed in these families. CONCLUSION: Sex has an important influence on the disease phenotype in RA, including the age at disease onset and autoantibody production. Furthermore, families with affected male members are characterized by higher titers of autoantibodies, particularly anti-CCP antibodies. Our results indicate that these findings are not fully explained by differences in exposure to tobacco smoke, presence of the HLA-DRB1 SE, or other HLA region genetic variation. Thus, other genetic or nongenetic factors also contribute to sex differences in the RA phenotype.
16612602 [Magnetic resonance imaging of the hand in rheumatoid arthritis. New scientific insights a 2006 May Magnetic resonance imaging (MRI) is a sensitive diagnostic modality for the detection of inflammatory changes in peripheral joints. Nevertheless, the widespread clinical use of MRI in assessing patients with early rheumatoid arthritis is still hampered by the technical complexity and higher cost of MRI compared with conventional radiography. This overview summarizes the results of recent research and gives practical tips on how to perform MRI of the hands. The authors present an MR protocol for hand imaging, discuss the pros and cons of low-field MR scanners, and outline pitfalls and artifacts. The MRI changes associated with rheumatoid arthritis such as synovitis, tenosynovitis, erosions, and bone marrow edema are described including their prognostic significance. The proven facts on the validation and grading of MR changes in rheumatoid arthritis are summarized. Finally, the role of MRI in the differential diagnosis of arthritis is critically discussed.
17941638 Biomolecular interaction monitoring of autoantibodies by scanning surface plasmon resonanc 2007 Nov 14 A new commercial surface plasmon resonance (SPR) imaging analysis system with a novel SPR dip angle scanning principle allows the measurement, without the need for labeling, of the exact SPR dip angle. With this system hundreds of biomolecular interactions can be monitored on microarrays simultaneously and with great precision. The potency of this system is demonstrated by automatically monitoring the interactions between citrullinated peptides and serum autoantibodies of 50 rheumatoid arthritis (RA) patients and 29 controls in a single step. The smallest antibody concentration that could be measured in this experimental setup was 0.5 pM.
17590367 Reactive oxygen species and superoxide dismutases: role in joint diseases. 2007 Jul Reactive oxygen species (ROS) are produced in many normal and abnormal processes in humans, including atheroma, asthma, joint diseases, aging, and cancer. The superoxide anion O(2)(-) is the main ROS. Increased ROS production leads to tissue damage associated with inflammation. Superoxide dismutases (SODs) convert superoxide to hydrogen peroxide, which is then removed by glutathione peroxidase or catalase. Thus, SODs prevent the formation of highly aggressive ROS, such as peroxynitrite or the hydroxyl radical. Experimental models involving SOD knockout or overexpression are beginning to shed light on the pathophysiological role of SOD in humans. Although the antiinflammatory effects of exogenous native SOD (orgotein) are modest, synthetic SOD mimetics hold considerable promise for modulating the inflammatory response. In this review, we discuss new knowledge about the role of the superoxide anion and its derivates as mediators of inflammation and the role of SODs and SOD mimetics as antioxidant treatments in joint diseases such as rheumatoid arthritis, osteoarthritis, and crystal-induced arthropathies.