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ID PMID Title PublicationDate abstract
17530705 A clinical pharmacogenetic model to predict the efficacy of methotrexate monotherapy in re 2007 Jun OBJECTIVE: To develop a clinical pharmacogenetic model to predict the efficacy of methotrexate (MTX) in rheumatoid arthritis (RA). METHODS: Two hundred five patients with newly diagnosed RA and active disease were treated with MTX (initiated at a dosage of 7.5 mg/week and increased to 15 mg/week after 4 weeks) and folic acid (1 mg/day). If the Disease Activity Score (DAS) was >2.4 at 3 months, the dosage of MTX was increased up to 25 mg/week. Twenty-four baseline variables possibly influencing disease state and drug response were selected. In addition, 17 polymorphisms in 13 genes related to the MTX mechanism of action, purine and pyrimidine synthesis, were determined. Factors were compared between responders (defined as patients with a DAS < or = 2.4 at 6 months) and nonresponders. In case of differences, a stepwise selection procedure identified the predictors for response. A clinical score was designed by simplifying regression coefficients of the independent variables. Cutoff levels were chosen based on the clinical score, and positive and negative response rates were calculated. An evaluation of the model was performed in a second group of patients. RESULTS: The model for MTX efficacy consisted of sex, rheumatoid factor and smoking status, the DAS, and 4 polymorphisms in the AMPD1, ATIC, ITPA, and MTHFD1 genes. This prediction model was transformed into a scoring system ranging from 0 to 11.5. Scores of < or = 3.5 had a true positive response rate of 95%. Scores of > or = 6 had a true negative response rate of 86%. Sixty percent of the patients were categorized as either responders or nonresponders, whereas 32% of the patients were categorized using a nongenetic model. Evaluation of the model in 38 additional patients with RA supported the results. CONCLUSION: This study established a model for predicting the efficacy of MTX in patients with RA. This pharmacogenetic model may lead to better-tailored initial treatment decisions in patients with RA.
17888206 Prevalence of functional haplotypes of the peptidylarginine deiminase citrullinating enzym 2007 Jul OBJECTIVE: Citrullinated peptides produced by enzymatic deimination of arginine residues in proteins by peptidylarginine deiminases are of particular interest in the pathogenesis of rheumatoid arthritis (RA). One type of citrullinated protein - the cyclic citrullinated peptide - is the target of the anti-cyclic citrullinated peptide antibody, the most sensitive and specific autoantibody in RA. The peptidylarginine deiminase type 4 (PADI4) gene, which codes one of the PADI enzyme isotypes, has genetic variants that confer susceptibility to RA in Asian, but not in European populations. METHODS: Genetic associations were examined in 214 Hungarian RA patients characterized for the presence of anti-CCP and rheumatoid factor. The patients were characterized for the existing haplotypes of the PADI4 gene (defined by the combinations of 4 exonic padi4_89: 163G/A, padi4_90: 245T/C, padi4_92: 335C/G, padi4_104: 349T/C and 2 intronic padi4_94: 17535226C/T and padi4_102: 17546809C/T variants) by the PCR-RFLP method. RESULTS: None of the PADI4 haplotypes was accumulated in RA patients. One new finding was that we also did not detect the accumulation of any haplotypes either in the anti-CCP or in the RF-positive subgroups of patients. CONCLUSION: The data presented here show that none of the naturally occurring haplotypes of the PADI4 gene conferred susceptibility to RA in an average group of Hungarian patients; this is in agreement with findings for other European populations. In addition, none of the functional PADI4 haplotypes were associated with the pathologic immune response, which was evidenced by the absence of accumulation of anti-CCP-positive subjects in the specific PADI4 haplotypes.
17364074 In vivo pro- and anti-inflammatory cytokines in normal and patients with rheumatoid arthri 2007 Feb INTRODUCTION: Rheumatoid arthritis (RA) is a chronic, deforming arthritis that can lead to disabilities and poor quality of life. Cytokines are protein mediators of inflammation and are produced as a result of the activation of various cellular reactions. They are the final mediators and/or regulators of the inflammatory process. MATERIALS AND METHODS: The sera from 64 RA patients were assayed for both Th-1 and Th-2 related cytokines and soluble TNF-alpha receptors (IFN-gamma, TGF-beta, TNF-alpha, IL-1beta, IL-2, IL-4, IL-6, IL-8, IL-10, IL-12, IL-18, sTNF-R1 and sTNFR2) using ELISA. RESULTS: The pro-inflammatory cytokines (IL-1, IL-6, IL-8, IL-18 and TNF- alpha) were significantly elevated in RA patients, while TGF-beta, an immunomodulatory cytokine, was elevated in control individuals. When the RA patients were categorised as active or inactive based on DAS scores, similar cytokines profiles were observed in both RA sub-groups. However, assays of sTNF-R1 and sTNFR-2 were noted to be significantly elevated in inactive RA patients when compared to active patients. CONCLUSION: Our findings indicate that local production of cytokine inhibitors is capable of diminishing disease activity and cytokine activity.
17013821 Comment on the use of self-reporting instruments to assess patients with rheumatoid arthri 2006 Oct 15 OBJECTIVE: Recently, the use of patient self-reporting instruments instead of clinical, objective measurements to assess rheumatoid arthritis (RA) patients was proposed. This assumes a constant association between disease activity and the self-reporting instruments. The objective was to explore the association (in time) between disease activity and patient perception of general health, disease activity, pain, and functional disability in patients with RA. METHODS: Data of 624 newly diagnosed RA patients who completed 3 years of followup were analyzed. Cross-sectional linear regression models and longitudinal regression models were estimated, with a visual analog scale (VAS) measuring general health (VAS-GH; 0 = best, 100 = worst) as a dependent variable and the Disease Activity Score (DAS28) without the VAS-GH as an independent variable. Other dependent variables were VAS disease activity, pain, and the Health Assessment Questionnaire. RESULTS: The DAS28 and VAS-GH were significantly associated in RA patients (P < 0.001). However, the explained variance was low (6.7%). From diagnosis to 3 years after the diagnosis, the intercept decreased given the same regression coefficient. The longitudinal regression model showed that the VAS-GH improved during disease course independent of a change in DAS28. Analyses on the other outcome parameters showed similar results. CONCLUSION: Patients' perception of health can be different with equal disease activity, depending on the moment in the disease course. Furthermore, our results indicate that self-reported measures on functionality, disease activity, and general health cannot substitute for objective measures of disease activity in RA in longitudinal studies; subsequently, both need to be measured.
17102942 Are plasma and synovial fluid leptin levels correlated with disease activity in rheumatoid 2007 Feb Leptin is an adypocyte derivated peptide hormone that plays a major role in preventing obesity development by the effects at the hypothalamic level. In our study leptin levels of 41 rheumatoid arthritis (RA) patients and 25 healthy subjects as control group were assessed. Synovial fluid from 21 RA patients were collected to detect leptin levels. Synovial fluid and plasma leptin levels were analysed and correlated with RA duration, ESR, CRP, X ray changes (erosive or non-erosive disease) and negative or positive test for rheumatoid factor. There wasn't any significant difference at plasma leptin levels between RA patients (3.91 +/- 6.15) and control group (4.94 +/- 6.44) (p > 0.05). Plasma leptin levels were correlated with body mass index (BMI) in both healthy subjects and RA patients (r = 0.37; p = 0.018). Therefore in RA patients, plasma and synovial fluid leptin levels were not correlated with disease duration, ESR, CRP, negative or positive test for rheumatoid factor and erosive or non-erosive disease (p > 0.05). In conclusion leptin is correlated with BMI both in RA patients and healthy individuals but no considerable relation with disease activity.
18576335 Association of autoimmunity to peptidyl arginine deiminase type 4 with genotype and diseas 2008 Jul OBJECTIVE: Protein citrullination is an important posttranslational modification recognized by rheumatoid arthritis (RA)-specific autoantibodies. One of the citrullinating enzymes, peptidyl arginine deiminase type 4 (PAD-4), is genetically associated with development of RA in some populations, although the mechanism(s) mediating this effect are not yet clear. There have been descriptions of anti-PAD-4 autoantibodies in different rheumatic diseases. This study was undertaken to investigate whether anti-PAD-4 antibodies are specific to RA, are associated with disease phenotype or severity, and whether PAD-4 polymorphisms influence the anti-PAD-4 autoantibody response. METHODS: Sera from patients with established RA, patients with other rheumatic diseases, and healthy adults were assayed for anti-PAD-4 autoantibodies by immunoprecipitation of in vitro-translated PAD-4. The epitope(s) recognized by PAD-4 autoantibodies were mapped using various PAD-4 truncations. PAD-4 genotyping was performed on RA patients with the TaqMan assay. Joint erosions were scored from hand and foot radiographs using the Sharp/van der Heijde method. RESULTS: PAD-4 autoantibodies were found in 36-42% of RA patients, and were very infrequent in controls. Recognition by anti-PAD-4 autoantibodies required the 119 N-terminal amino acids, which encompass the 3 nonsynonymous polymorphisms associated with disease susceptibility. Strikingly, the anti-PAD-4 immune response was associated with the RA susceptibility haplotype of PADI4. Anti-PAD-4 antibodies were associated with more severe joint destruction in RA. CONCLUSION: Our findings indicate that anti-PAD-4 antibodies are specific markers of RA, independently associated with more severe disease, suggesting that an anti-PAD-4 immune response may be involved in pathways of joint damage in this disease. Polymorphisms in the PADI4 gene influence the immune response to the PAD-4 protein, potentially contributing to disease propagation.
16785475 Effects of abatacept in patients with methotrexate-resistant active rheumatoid arthritis: 2006 Jun 20 BACKGROUND: The selective co-stimulation modulator abatacept demonstrated efficacy for treating rheumatoid arthritis in early clinical studies. OBJECTIVE: To evaluate the effects of abatacept in patients with persistent, active rheumatoid arthritis despite methotrexate treatment. DESIGN: One-year, multicenter, randomized, double-blind, placebo-controlled trial (November 2002 to October 2004). SETTING: 116 centers worldwide. PATIENTS: 652 patients with active rheumatoid arthritis despite methotrexate treatment. INTERVENTION: Once-monthly infusion of a fixed dose of abatacept, approximately 10 mg/kg of body weight, or placebo. MEASUREMENTS: Co-primary end points were a 20% improvement in American College of Rheumatology (ACR) response criteria (ACR 20) at 6 months, clinically meaningful improvements in physical function, and change from baseline in joint erosion score at 1 year. RESULTS: Four hundred thirty-three and 219 patients were randomly assigned to abatacept or placebo, respectively, and 385 (89%) and 162 (74%), respectively, completed 1 year of treatment. In a modified intention-to-treat analysis, 6-month ACR 20, ACR 50, and ACR 70 responses were 67.9% for abatacept versus 39.7% for placebo (difference, 28.2 percentage points [95% CI, 19.8 to 36.7 percentage points]), 39.9% for abatacept versus 16.8% for placebo (difference, 23.0 percentage points [CI, 15.0 to 31.1 percentage points]), and 19.8% for abatacept versus 6.5% for placebo (difference, 13.3 percentage points [CI, 7.0 to 19.5 percentage points]), respectively. At 1 year, the responses increased to 73.1% for abatacept versus 39.7% for placebo (difference, 33.4 percentage points [CI, 25.1 to 41.7 percentage points]), 48.3% for abatacept versus 18.2% for placebo (difference, 30.1 percentage points [CI, 21.8 to 38.5 percentage points]), and 28.8% for abatacept versus 6.1% for placebo (difference, 22.7 percentage points [CI, 15.6 to 29.8 percentage points]), respectively (P < 0.001 for all). Physical function significantly improved in 63.7% versus 39.3% of patients (P < 0.001). At 1 year, abatacept statistically significantly slowed the progression of structural joint damage compared with placebo. Abatacept-treated patients had a similar incidence of adverse events (87.3% vs. 84.0%; difference, 3.3 percentage points [CI, -2.5 to 9.1 percentage points]) and a higher incidence of prespecified serious infections (2.5% vs. 0.9%; difference, 1.6 percentage points [CI, -0.3 to 3.6 percentage points]) and infusion reactions (acute, 8.8% vs. 4.1%; difference, 4.7 percentage points [CI, 0.9 to 8.4 percentage points]; peri-infusional, 24.5% vs. 16.9%; difference, 7.6 percentage points [CI, 1.2 to 14.0 percentage points]) compared with placebo recipients. LIMITATIONS: The study involved only 1 group of patients over 1 year. CONCLUSIONS: Abatacept statistically significantly reduced disease activity in patients with rheumatoid arthritis and an inadequate response to methotrexate. Longer treatment in different patient populations is needed to establish its appropriate role in rheumatoid arthritis.
16541185 Abatacept. 2006 Feb New therapies, in particular the tumor necrosis factor-alpha-blocking drugs, have led to improved control of inflammation in rheumatoid arthritis for a proportion of patients. There remains a need for therapies for patients who do not respond to these drugs or in whom they are contraindicated or not tolerated. There is evidence that T cells are involved in the initiation and perpetuation of rheumatoid arthritis. Abatacept is the first in a new class of drugs targeted at T-cell function in autoimmune disease: the costimulation blockers. It has shown safety and efficacy in rheumatoid arthritis. Further trials of this and other costimulation blockers are in progress in rheumatoid arthritis and other diseases.
17329941 Population of CD40L-expressing cells was slightly but not significantly decreased in lymph 2007 Mar OBJECTIVE: To clarify the mechanism of the action of Hochu-Ekki-To (HET) on collagen-induced arthritic (CIA) mice by analyzing the CD40L-expressing cells population. METHODS: CIA was induced in male DBA/1J mice by immunization with two injections of bovine type II collagen (CII). HET or water was orally administered. The subpopulations of lymphocytes obtained from lymph nodes and spleen were detected at 3 weeks after boost using flow cytometry. RESULTS: Although the population of CD4+CD40L+ cells tended to be decreased in the HET group compared to that in control mice, there was no significant difference between the two groups. These findings were observed in lymphocytes obtained from both lymph nodes and spleen. CONCLUSION: HET suppresses the development of CIA. These effects may be partially induced via the decrease in the population of CD4+CD40L+ cells, but the role of this action is probably limited.
17642233 [Fully human anti TNF-alpha monoclonal antibodies (adalimumab, golimumab)]. 2007 Jul A number of studies have emphasized the critical role of TNF-a in the pathogenesis of rheumatoid arthritis (RA). New therapeutics called "bilologicals" have been recently admitted for treatment of RA, including infliximab and etanercept, also in Japan. Of note, fully human anti-TNF a monoclonal antibodies, adalimumab and golimumab, have been developed to overcome several major problems resulting from the chimeric natures of infliximab. The efficacy and safety of adalimumab have been demonstrated in several clinical trials, as highlighted in this review. Thus, adalimumab has already been approved for treatment of RA in the United States and European Union. The clinical trials of another fully human anti-TNF-alpha monoclonal antibody golimumab are now under way.
18466615 Discontinuation rates in clinical trials in musculoskeletal pain: meta-analysis from etori 2008 INTRODUCTION: Patient adherence to therapy in clinical practice is often low, and the difference between efficacy measured in clinical trials and effectiveness in clinical practice is probably a function of discontinuation of therapy because of lack of efficacy or because of unmanageable or intolerable adverse events. Discontinuation is frequently measured in clinical trials but is not usually described in detail in published reports, often because of limitations in the size of publications. By contrast, company clinical trial reports include much more detail. METHODS: We examined company clinical trial reports of trials involving etoricoxib in four musculoskeletal conditions: osteoarthritis, rheumatoid arthritis, chronic low back pain and ankylosing spondylitis. Information was available from 18 randomized trials (10,143 patients) lasting 4 to 12 weeks (one 4 weeks, three 6 weeks, one 8 weeks and seven 12 weeks) and from three trials with a mean duration of about 80 weeks (34,695 patients). These clinical trial reports contain over 73,000 pages of information. RESULTS: Over 12 weeks, lack of efficacy and adverse event discontinuations were similar between osteoarthritis, rheumatoid arthritis and back pain, with lack of efficacy discontinuation rates some three times higher than for adverse events. All-cause and lack of efficacy discontinuations were lower with etoricoxib (all doses combined) and traditional nonselective nonsteroidal anti-inflammatory drugs (NSAIDs) than with placebo, although NSAIDs produced higher rates of clinical adverse events and gastrointestinal discontinuations than did placebo. Etoricoxib had fewer discontinuations than NSAIDs for lack of efficacy, clinical adverse events, and laboratory and gastrointestinal adverse events, but with more discontinuations because of hypertension and oedema. Comparison with two similar meta-analyses of other cyclo-oxygenase-2 selective inhibitors (more than 80,000 patients in total) revealed consistency between analyses. CONCLUSION: Examining discontinuation data from clinical trials, even when the numbers of patients are very large, does not necessarily predict what will happen in the real world, where clinical effectiveness may differ from clinical efficacy assessed in trials. Data from these analyses appears to agree with findings from real world practice.
17963163 Soluble cell adhesion molecules (sICAM-1, sVCAM-1, and sE-selectin) in patients with early 2007 Sep OBJECTIVE: The aim of the study was to analyse serum concentrations of soluble cell adhesion molecules (CAMs) in patients with early rheumatoid arthritis (RA) before and after 6 months of treatment with methotrexate (MTX). METHODS: We studied 32 RA patients, untreated with disease-modifying anti-rheumatic drugs (DMARDs) or corticosteroids, with disease duration less than 3 years. Twenty osteoarthritis (OA) patients constituted the control group. The analysis of serum levels of soluble intercellular adhesion molecule-1 (sICAM-1), vascular cell adhesion molecule-1 (sVCAM-1), and E-selectin (sE-selectin) was based on a quantitative sandwich enzyme-linked immunosorbent assay (ELISA). RESULTS: In comparison with OA patients, higher serum concentrations of sICAM-1 (p<0.01), sVCAM-1 (p<0.01), and sE-selectin (p<0.05) were observed in untreated patients with early RA. Six months of treatment with MTX down-regulated serum concentrations of sICAM-1, sVCAM-1, and sE-selectin (in all cases p<0.001) in the RA patients studied. MTX treatment was also followed by a decrease in the clinical markers of RA activity, such as the number of painful and swollen joints, erythrocyte sedimentation rate (ESR), disease activity score (DAS), and C-reactive protein (CRP) levels. CONCLUSIONS: Patients with early RA are characterized by high serum concentrations of sICAM-1, sVCAM-1, and sE-selectin. Therapy with MTX resulted in clinical improvement and diminished serum levels of soluble CAMs in the RA patients studied, confirming the effectiveness of MTX in early stages of the disease.
16855171 Nerve growth factor and brain-derived neurotrophic factor levels in patients with rheumato 2006 Jun Twenty consecutive rheumatoid arthritis (RA) patients (mean age 50.4 +/- 10.5 years; 17 females; mean disease duration 5.78 +/- 3.75 years) enrolled for tumor necrosis factor-alpha (TNF-alpha) blockers therapy (10 infliximab and 10 etanercept) were selected. Before starting therapy, 3 and 6 months thereafter all patients were evaluated for disease activity score (DAS), erythrocyte sedimentation rate (ESR), serum levels of C-reactive protein (CRP), interleukin-6 (IL-6), nerve growth factor (NGF), and brain-derived neurotrophic factor (BDNF). After 3 and 6 months a significant reduction in DAS, ESR, CRP, and IL-6 was observed, whereas no significant differences of NGF and BDNF serum levels were found. These preliminary results confirm that TNF-alpha blockers significantly improve disease activity and inflammation in RA; nevertheless further studies are needed to explain the mechanisms regulating NGF and BDNF release in RA patients treated with TNF-alpha blockers.
16651702 [Antibodies to citrullinated proteins in rheumatoid arthritis]. 2006 Apr Rheumatoid arthritis (RA) is a systemic autoimmune disease of unknown etiology, characterized by chronic joint inflammation that often leads to joint destruction. Diagnosis of RA is currently based on the revised classification criteria of the American College of Rheumatology (ACR); however, it remains imprecise, especially early in the course of disease. Rheumatoid factor (RF) has been widely used in clinical practice as a useful serological marker for diagnosis of RA. Although RF is the only serological test in the criteria of the ACR, its specificity is limited since RF can be also detected in other rheumatic diseases. Because the current therapeutic strategies in RA employ increasingly aggressive regimens from early stage of the disease, more specific serological markers than RF are desirable. Recently, anti-cyclic citrullinated peptide (anti-CCP) antibodies have attracted attention as a useful marker for the diagnosis of RA with high specificity. In addition to the diagnostic properties, anti-CCP antibodies showed to be a good prognostic marker for joint destructions. In this review, we will explain about the clinical usefulness of anti-CCP antibodies for the daily practice of RA.
16720213 Genetic markers linked to rheumatoid arthritis are also strongly associated with articular 2006 Apr Ulcerative colitis is often accompanied by the development of extraintestinal, mainly articular, manifestations. Genetic differences could be underlying that clinical heterogeneity. We performed a case-control study to determine whether TNFab microsatellites or HLA-DR alleles were associated with the development of articular manifestations in patients with ulcerative colitis. With that aim, a total of 84 ulcerative colitis patients with articular manifestations and 172 without them were genotyped for TNFab microsatellites and HLA-DR. A healthy control sample (n = 595) was also included for comparative purposes. Haplotypes were inferred with the Arlequin software. The influence of HLA-DRB1*0103 and HLA-B27, factors previously known to be associated with extraintestinal manifestations, was specifically addressed. We observed that TNFa6b5 minihaplotype increases the susceptibility to developing articular manifestations in ulcerative colitis patients (p = 0.003, OR = 2.39). The locus HLA-DR does not appear to be involved in these extraintestinal manifestations by itself; however, the frequency of subjects carrying TNFa6b5 in combination with DR1, DR7, or DR11 is very significantly increased in patients with articular manifestations (p = 3.9 x 10(-8)). The associations found were independent of DRB1*0103 and HLA-B27. Thus, it seems that the development of articular manifestations in ulcerative colitis patients appears to be influenced by some genetic factor(s) present in some major histocompatibility complex haplotypes.
17472996 Comparison of composite measures of disease activity in an early seropositive rheumatoid a 2007 Dec OBJECTIVE: To evaluate concordance and agreement of the original DAS44/ESR-4 item composite disease activity status measure with nine simpler derivatives when classifying patient responses by European League of Associations for Rheumatology (EULAR) criteria, using an early rheumatoid factor positive (RF+) rheumatoid arthritis (RA) patient cohort. METHODS: Disease-modifying anti-rheumatic drug-naïve RF+ patients (n = 223; mean duration of symptoms, 6 months) were categorised as ACR none/20/50/70 responders. One-way analysis of variance and two-sample t tests were used to investigate the relationship between the ACR response groups and each composite measure. EULAR reached/change cut-point scores were calculated for each composite measure. EULAR (good/moderate/none) responses for each composite measure and the degree of agreement with the DAS44/ESR-4 item were calculated for 203 patients. RESULTS: Patients were mostly female (78%) with moderate to high disease activity. A centile-based nomogram compared equivalent composite measure scores. Changes from baseline in the composite measures in patients with ACRnone were significantly less than those of ACR20/50/70 responders, and those for ACR50 were significantly different from those for ACR70. EULAR reached/change cut-point scores for our cohort were similar to published cut-points. When compared with the DAS44/ESR-4 item, EULAR (good/moderate/none) percentage agreements were 92 with the DAS44/ESR-3 item, 74 with the Clinical Disease Activity Index, and 80 with the DAS28/ESR-4 item, the DAS28/CRP-4 item and the Simplified Disease Activity Index. CONCLUSION: The relationships of nine different RA composite measures against the DAS44/ESR-4 item when applied to a cohort of seropositive patients with early RA are described. Each of these simplified status and response measures could be useful in assessing patients with RA, but the specific measure selected should be pre-specified and described for each study.
19191904 Differential gene expression of peripheral blood mononuclear cells from rheumatoid arthrit 2009 Jul This study aimed to evaluate the association between the differential gene expression profiling of peripheral blood mononuclear cells of rheumatoid arthritis patients with their immunogenetic (human leucocyte antigen shared-epitope, HLA-SE), autoimmune response [anti-cyclic citrullinated peptide (CCP) antibodies], disease activity score (DAS-28) and treatment (disease-modifying antirheumatic drugs and tumour necrosis factor blocker) features. Total RNA samples were copied into Cy3-labelled complementary DNA probes, hybridized onto a glass slide microarray containing 4500 human IMAGE complementary DNA target sequences. The Cy3-monocolour microarray images from patients were quantified and normalized. Analysis of the data using the significance analysis of microarrays algorithm together with a Venn diagram allowed the identification of shared and of exclusively modulated genes, according to patient features. Thirteen genes were exclusively associated with the presence of HLA-SE alleles, whose major biological function was related to signal transduction, phosphorylation and apoptosis. Ninety-one genes were associated with disease activity, being involved in signal transduction, apoptosis, response to stress and DNA damage. One hundred and one genes were associated with the presence of anti-CCP antibodies, being involved in signal transduction, cell proliferation and apoptosis. Twenty-eight genes were associated with tumour necrosis factor blocker treatment, being involved in intracellular signalling cascade, phosphorylation and protein transport. Some of these genes had been previously associated with rheumatoid arthritis pathogenesis, whereas others were unveiled for future research.
17387532 High positivity of anti-CCP antibodies in patients with Down syndrome. 2007 Dec The aim of the present study was to evaluate the prevalence of anti-cyclic citrullinated peptide (CCP) antibodies in patients with Down's syndrome (DS) previously tested for IgM rheumatoid factor (RF) and to correlate the results with clinical findings. Eighty-eight patients with DS previously tested for IgM-RF were divided into two groups matched for sex and age. Group A consists of 42 RF positive patients and group B of 44 RF negative patients. The presence of anti-CCP antibody was determined using a second-generation enzyme-linked immunosorbent assay. A total of 52.3% (45/86) of DS patients were positive for anti-CCP antibodies. Twenty-four patients (57.1%) of the RF positive group and 21 (47.7%) of the RF negative group presented anti-CCP circulating antibodies. The concordance between both tests was 54.6%. None of the patients had clinical evidence of rheumatoid arthritis or juvenile idiopathic arthritis. Although a high prevalence of anti-CCP antibodies was observed in DS patients, no association has been found presently with clinical disease. Careful follow-up of these patients will be necessary to clarify the real significance of these findings.
16888030 Calcineurin is expressed and plays a critical role in inflammatory arthritis. 2006 Aug 15 Calcineurin is a calcium-activated phosphatase to mediate lymphocyte activation and neuron signaling, but its role in inflammatory arthritis remains largely unknown. In this study, we demonstrate that calcineurin was highly expressed in the lining layer, infiltrating leukocytes, and endothelial cells of rheumatoid synovium. The basal expression levels of calcineurin were higher in the cultured synoviocytes of rheumatoid arthritis patients than those of osteoarthritis patients. The calcineurin activity in the synoviocytes was increased by the stimulation with proinflammatory cytokines such as IL-1beta and TNF-alpha. Moreover, rheumatoid arthritis synoviocytes had an enlarged intracellular Ca(2+) store and showed a higher degree of [Ca(2+)](i) release for calcineurin activity than osteoarthritis synoviocytes when stimulated with either TNF-alpha or phorbol myristate acetate. IL-10, an anti-inflammatory cytokine, failed to increase the Ca(2+) and calcineurin activity. The targeted inhibition of calcineurin by the overexpression of calcineurin-binding protein 1, a natural calcineurin antagonist, inhibited the production of IL-6 and matrix metalloproteinase-2 by rheumatoid synoviocytes in a similar manner to the calcineurin inhibitor, cyclosporin A. Moreover, the abundant calcineurin expression was found in the invading pannus in the joints of mice with collagen-induced arthritis. In these mice, calcineurin activity in the cultured synovial and lymph node cells correlated well with the severity of arthritis, but which was suppressed by cyclosporin A treatment. Taken together, our data suggest that the abnormal activation of Ca(2+) and calcineurin in the synoviocytes may contribute to the pathogenesis of chronic arthritis and thus provide a potential target for controlling inflammatory arthritis.
17447898 Expression and extracellular release of Trx80, the truncated form of thioredoxin, by TNF-a 2007 Aug Thioredoxin (Trx) plays several important roles, through changes to sulfhydryl reactions and protein interactions, in controlling cellular signalling processes in RA (rheumatoid arthritis). Trx80, the 10 kDa C-terminal truncated form of Trx, is a potent mitogenic cytokine and is involved in the Th1 response. In the present study, we have investigated the ability of synoviocytes from five RA patients to induce Trx80 after ex vivo stimulation by the pro-inflammatory cytokines IL-1beta (interleukin-1beta) and TNF-alpha (tumour necrosis factor-alpha) or by H(2)O(2). Synoviocytes from five OA (osteoarthritis) patients were used as controls. Immunoprecipitation assays using two different antibodies showed that RA, but not OA, cells expressed intact Trx80 protein in culture even when not stimulated. Treatment with pro-inflammatory cytokines alone or in combination enhanced this basal production and induced the extracellular release of Trx80 by all of the RA cells tested. Under our experimental conditions, the rate of Trx80 release from RA cells was approx. 30% of the total Trx produced. In contrast, Trx80 was not detected in response to H(2)O(2) in RA or OA synoviocyte lysates and their respective culture supernatants, indicating that the oxidative process induced by H(2)O(2) in synoviocytes was unable to modify Trx80 release. Moreover, Trx80 induced synoviocyte proliferation as evaluated by [(3)H]thymidine incorporation. These results highlight the effect of the inflammatory process on the release of both Trx and Trx80 from RA synoviocytes, and suggest that the cytokine-induced increase in Trx80 cell release may constitute a link between inflammation and the immune system in RA.