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ID PMID Title PublicationDate abstract
17273811 No effects of adalimumab therapy on the activation of NF-kappaB in lymphocytes from patien 2007 Sep The aim of this study was to determine the activation level of the pro-inflammatory transcription factor nuclear factor kappaB (NF-kappaB) in lymphocytes of patients with rheumatoid arthritis (RA) before and during an anti-tumor necrosis factor alpha (TNFalpha) therapy (adalimumab). In addition, we analyzed the inflammatory markers, interleukin 6 (IL-6), and C-reactive protein (CRP) and investigated the expression of rheumatoid factor (RF) and anti-cyclic citrullinated peptide (anti-CCP) autoantibodies in patients' sera. Twenty RA patients and 20 control subjects were investigated. RA patients' characteristics were evaluated by radiography and disease activity score 28 (DAS 28). Twelve weeks of adalimumab therapy was effective in the treatment of RA patients, as shown by a significant improvement of the DAS 28. The inflammatory markers IL-6 and CRP were significantly different in sera of RA patients compared to the control group before the onset of therapy and exhibited a tendency to return to normal levels during the first 12 weeks of therapy. We measured a comparable activation level of NF-kappaB in lymphocytes of control subjects and of RA patients before starting adalimumab therapy. During the following 12 weeks, no significant changes in the activation levels of both NF-kappaB subunits were detected. Serum concentration of RF was significantly lower after 12 weeks, whereas anti-CCP antibody level remained constant.
17717677 [Prosthetics of metacarpophalangeal joints]. 2007 Sep Only a few of the large number of implants developed during the last decades for replacement of the metacarpophalangeal (MCP) joint have proven to be reliable. The rates of loosening and mechanical failure of almost all types of constrained prostheses are so high that their use cannot be recommended at present. For more than 40 years silicone arthroplasty according to Swanson has been regarded as the gold standard in the prosthetic replacement of the MCP joint. In long-term studies this device provided good pain relief and a lasting correction of preoperative ulnar deviation. The degree of patient satisfaction continues to be high after more than 10 years. With the NeuFlex spacer, a modification of the original Swanson implant, a better range of motion and a reduction of wear-related problems is expected. In this study the results of 130 NeuFlex spacers after a mean time of 3.6 years were examined and 82% of the patients were completely pain free. The mobility of the joints improved from 40 degrees preoperatively to 54 degrees after 3.6 years. Radiologically periprosthetic erosions or osteolyses were seen in approximately 15% of implants. A minimal sinking of the stems developed in 24%, a massive one in 6% and 13% of the spacers were broken. Thus the use of the NeuFlex implant resulted in a better range of motion compared to the Swanson spacer, but the problem of radiological appearance remained unchanged. For unlinked prostheses sufficient soft tissue stability is mandatory as well as wear-resistant surface materials. The pyrocarbon prosthesis according to Beckenbaugh is the only implant for which long-term results are available. In a prospective study we evaluated 28 Ascension pyrocarbon prostheses with a mean follow-up of 4 years. Stability was not found to be a problem. Subjective results were satisfactory, the range of motion remained unchanged, however 46% of prosthesis stems exhibited radiolucent seams, 7 prostheses (25%) were rated as loose and 5 of those had to be replaced by a silicone implant. Use of the implant was abandoned, as it was unreliable regarding bony fixation. There are promising concepts in some new prostheses but independent data are still lacking.
18500434 Risk factors for wrist surgery in rheumatoid arthritis. 2008 Nov To assess the risk factors for wrist surgery in a cohort of rheumatoid arthritis (RA) patients recruited and followed prospectively for 6 years. A linked registry study was performed using information from a large observational cohort of RA patients followed at the Institute of Rheumatology, Tokyo Women's Medical University. Baseline routine clinical and laboratory assessments were recorded. The data were analyzed using the multivariate Cox regression model that included variables such as gender, age, disease duration, a visual analog scale (VAS) generated by physicians, a patient-reported VAS for pain (VAS-pain), a VAS for general health, disability level using the Japanese version of the Health Assessment Questionnaire (J-HAQ), erythrocyte sedimentation rate, and serum levels of C-reactive protein and rheumatoid factor as potential risk factors. Of the 5,497 patients registered at baseline, 122 (2.22%) had surgery on one or both wrist joints. Multivariate Cox regression analysis of the variables revealed positive coefficients for J-HAQ and VAS-pain and that advanced age and long RA duration were associated with a reduced risk of wrist surgery. The hazard ratios were: 1.515 for J-HAQ, 1.126 for VAS-pain, 0.985 for age, and 0.964 for RA duration. Advanced age and long RA duration were associated with a decreased risk of wrist surgery, while J-HAQ and VAS-pain were associated with an increased risk. The identification of the risk factors for wrist surgery provides important insights into the course of the disease and its impact on patients, as well as the potential consequences for health care resource utilization planning.
16755914 [Expression of sTNFR-IgGFc fusion gene in endothelial cell and its application in gene the 2006 May Tumor necrosis factor alpha (TNFalpha) is a pro-inflammatory cytokine, acting as a regulator of inflammation and immunity. TNFalpha plays a critical role in the pathogenesis of rheumatoid arthritis. Blocking of TNFa activity suppressed inflammatory tissue damage. In present study, the chimeric gene of soluble TNF receptor and IgG Fc fragment (sTNFR-IgG FC) was cloned into the mammalian cell expression vector pStar. When the plamid pStar/sTNFR-IgGFc-GFP was transfected into endothelial cells, a considerable expression of the sTNFR-IgG Fc fusion protein was detected. Moreover, the product in 100microL expression supernatant could completely antagonize the cytolytic effect of 1ng TNFa on L929 cells, even at 1/64 dilution. Then the plasmid was delivered into CIA-induced rheumatoid arthritis mice by tail vein injection. The expression of sTNFR-IgG Fc was detected in liver by RT-PCR. Animals in treatment group showed reduced symptoms of arthritis and more active. This treatment induced decrease of synovial incrassation and prevented the cartilage destruction of the mice RA model. These results show that tail vein injection is an effective way for gene therapy and sTNFR-IgGFc expression plasmid is potential for the treatment of rheumatoid arthritis.
17968333 Neuroendocrine-immune interactions in synovitis. 2007 Nov Synovial tissue lines the noncartilaginous surfaces of synovial joints and supplies these avascular structures with nutrients. In diseases such as rheumatoid arthritis, inflammation of the synovial tissue--synovitis--induces diffuse damage to the joints. The presence of functional receptors for glucocorticoids, androgens and estrogens in synoviocytes might link inflammation and the endocrine system at the local level. Synovial tissue could be regarded as an intracrine tissue, whereby active steroids influence the cells in which they are synthesized, without their release into the extracellular space. An increase in the peripheral metabolism of sex steroids is characteristic of rheumatoid synovitis, with an augmented ratio of estrogen to androgen occurring in both male and female patients. Changes in the peripheral nervous system at the site of local inflammation are also hallmarks of synovitis in rheumatoid arthritis. In the chronic phase of synovitis, sympathetic nerve fibers are lost; by contrast, sensory nerve fibers sprout into the inflamed tissue. Complex interactions occur between the endocrine, nervous and immune systems during synovitis. In particular, studying neuroendocrine-immune interactions in the inflamed synovium will potentially uncover new mechanisms in the pathophysiology of rheumatoid arthritis and might lead to new methods of therapeutic intervention.
18410682 Extracellular heat shock protein 70 inhibits tumour necrosis factor-alpha induced proinfla 2008 INTRODUCTION: It was recently suggested that heat shock protein (HSP)70, an intracellular protein, is a potential mediator of inflammatory disease when it is released into the extracellular compartment. Although elevated HSP70 levels have been identified in rheumatoid arthritis (RA) synovial tissues and RA synovial fluid compared with patients with osteoarthritis and healthy individuals, it remains unclear what role extracellular HSP70 plays in the pathogenesis of RA. This study was conducted to investigate the effects of extracellular HSP70 on the production of RA-associated cytokines in fibroblast-like synoviocytes from patients with RA and to elucidate the mechanisms involved. METHODS: IL-6, IL-8 and monocyte chemoattractant protein (MCP)-1 levels in culture supernatants were measured using enzyme-linked immunosorbent assays. Activation of mitogen-activated protein kinases (MAPKs), such as extracellular signal-regulated protein kinases (ERKs), c-Jun amino-terminal kinase (JNK) and p38 MAPK, was detected using Western blotting. Nuclear translocation of nuclear factor-kappaB (NF-kappaB) and degradation of the inhibitory protein IkappaBalpha were examined using immunohistochemistry and Western blotting. RESULTS: Human HSP70 downregulated IL-6, IL-8 and MCP-1 production in RA fibroblast-like synoviocytes induced by tumour necrosis factor (TNF)-alpha in a concentration dependent manner. HSP70 inhibited the activation of ERK, JNK and p38 MAPK in fibroblast-like synoviocytes stimulated by TNF-alpha. Furthermore, HSP70 also significantly inhibited nuclear translocation of nuclear factor-kappaB and degradation of IkappaBalpha induced by TNF-alpha. CONCLUSION: Extracellular HSP70 has an anti-inflammatory effect on RA by downregulating production of IL-6, IL-8 and MCP-1 in fibroblast-like synoviocytes, which is mediated through inhibited activation of the MAPKs and NF-kappaB signal pathways.
17441472 [Blood cytokine levels as a clinical laboratory test]. 2007 Mar Cytokines have not been employed in clinical laboratory tests because of the many biological activities of individual cytokines and too complicated cytokine network. However, abnormal laboratory data and symptoms can be interpreted by blood cytokine levels. [Cytokines attributable to abnormal data and symptoms] For example, cytokines attributable to abnormal data and symptoms in rheumatoid arthritis are as follows: joint pain: TNFalpha, IL-1, IL-6, and IL-18; general fatigue and appetite loss: TNFalpha and IL-1; leukocytosis: G-CSF produced by IL-1-stimulated macrophages etc; thrombocytosis: megakaryocyte potentiating activity of IL-6; anemia: hepcidin up-regulated by IL-6, which inhibits iron absorption from the intestine, and IL-1, which decreases the blood iron level and promotes ferritin synthesis. [Differential diagnosis using blood cytokine levels] Blood cytokine levels are useful and important in the differential diagnosis of inflammatory disorders such as neutrophilia, eosinophilia, and especially in distinguishing tumoral fever from infectious fever in malignant lymphomas. [Disease/disorder-specific cytokines] In recent years, disease- or disorder specific cytokines have been identified, making cytokines more important in clinical use. For example, IL-18 for adult-onset Still disease; IFNgamma for hemophagocytic syndrome; IL-5 for allergic disorders; thrombopoietin for immune thrombocytopenic purpura; vascular endothelial growth factor for POEMS syndrome; PTH-rP for malignancy associated hypercalcemia. [Flow cytometric measurement of cytokines] Recently, a flow cytometric method has been developed in addition to ELISA. With this method, 30 cytokine concentrations can be measured simultaneously within four hours with a wide range of detection limit and high cost performance. Cytokines will be included in laboratory tests with this method.
18771589 The roles of the classical and alternative nuclear factor-kappaB pathways: potential impli 2008 Nuclear factor-kappaB (NF-kappaB) is an inducible transcription factor controlled by two principal signaling cascades, each activated by a set of signal ligands: the classical/canonical NF-kappaB activation pathway and the alternative/noncanonical pathway. The former pathway proceeds via phosphorylation and degradation of inhibitor of NF-kappaB (IkappaB) and leads most commonly to activation of the heterodimer RelA/NF-kappaB1(p50). The latter pathway proceeds via phosphorylation and proteolytic processing of NF-kappaB2 (p100) and leads to activation, most commonly, of the heterodimer RelB/NF-kappaB2 (p52). Both pathways play critical roles at multiple levels of the immune system in both health and disease, including the autoimmune inflammatory response. These roles include cell cycle progression, cell survival, adhesion, and inhibition of apoptosis. NF-kappaB is constitutively activated in many autoimmune diseases, including diabetes type 1, systemic lupus erythematosus, and rheumatoid arthritis (RA). In this review we survey recent developments in the involvement of the classical and alternative pathways of NF-kappaB activation in autoimmunity, focusing particularly on RA. We discuss the involvement of NF-kappaB in self-reactive T and B lymphocyte development, survival and proliferation, and the maintenance of chronic inflammation due to cytokines such as tumor necrosis factor-alpha, IL-1, IL-6, and IL-8. We discuss the roles played by IL-17 and T-helper-17 cells in the inflammatory process; in the activation, maturation, and proliferation of RA fibroblast-like synovial cells; and differentiation and activation of osteoclast bone-resorbing activity. The prospects of therapeutic intervention to block activation of the NF-kappaB signaling pathways in RA are also discussed.
17265482 Tumor necrosis factor alpha acceleration of inflammatory responses by down-regulating heme 2007 Feb OBJECTIVE: To examine the interaction between heme oxygenase 1 (HO-1), a stress-induced antiinflammatory protein, and tumor necrosis factor alpha (TNFalpha) in human peripheral blood monocytes. METHODS: Peripheral blood mononuclear cells (PBMCs) were obtained from healthy donors or from patients with rheumatoid arthritis (RA) receiving the anti-tumor necrosis factor alpha (anti-TNFalpha) monoclonal antibody infliximab. CD14+ cells were isolated by magnetic cell sorting, cultured with TNFalpha or auranofin, and transfected with a plasmid encoding HO-1 or an HO-1-specific small interfering RNA vector. Protein and messenger RNA (mRNA) levels were examined by immunoblotting and real-time polymerase chain reaction. Cytokine levels in culture supernatants were measured by enzyme-linked immunosorbent assay. HO-1 gene transcription was evaluated using a luciferase reporter gene assay. Actinomycin D and cycloheximide were used to monitor the stability of mRNA and protein. RESULTS: HO-1 is constitutively expressed by CD14+ PBMCs from healthy donors. TNFalpha suppressed HO-1 expression by accelerating the decay of mRNA without affecting gene transcription or protein stability. Forced expression or selective knock-down of the HO-1 gene expression resulted in down-regulation or up-regulation, respectively, of proinflammatory cytokine synthesis by monocytes. Treatment with infliximab significantly increased HO-1 mRNA levels and reduced TNFalpha synthesis by PBMCs from RA patients. CONCLUSION: TNFalpha accelerated inflammatory responses by down-regulating HO-1 expression in human monocytes. TNF antagonists may block this TNF-dependent suppression of HO-1 expression, resulting in an amelioration of inflammation.
17596188 Flurbiprofen in the symptomatic management of rheumatoid arthritis: a valuable alternative 2007 Aug BACKGROUND: The withdrawal of certain cyclooxygenase-2 selective drugs and the availability of over-the-counter non-steroidal anti-inflammatory drugs (NSAIDs) have increased the pressure for researching and prescribing conventional NSAIDs with a favourable efficacy/tolerance ratio in inflammatory diseases, particularly rheumatoid arthritis. The aim of this comprehensive meta-analysis was to evaluate the absolute and relative efficacy and safety of flurbiprofen in the management of rheumatoid arthritis. METHODS: A systematic and exhaustive bibliographic research of published literature has been performed. The inclusion criteria are summarised as follows: randomised trial and rheumatoid arthritis and flurbiprofen and oral administration and anti-inflammatory doses from 100 to 300 mg and (placebo or aspirin or indomethacin or naproxen or ibuprofen or ketoprofen) and (articular pain or stiffness or swelling or mobility or patient/physician reported efficacy or tolerance or gastrointestinal (GI) tolerance). Studies were conducted from January 1975 to January 2006. Analyses have been stratified by comparisons and outcomes. Publication bias and robustness have been extensively investigated. RESULTS: Fourteen studies, accounting for 1103 patient-years, have been included in the quantitative review. The mean daily doses administrated were 200 mg flurbiprofen, 4000 mg aspirin, 150 indomethacin, 750 mg naproxen and 1800 mg ibuprofen. Flurbiprofen was superior to placebo for all outcomes, and superior to three of four other NSAIDs in terms of formal symptomatic measures (pain, stiffness and swelling). Several patients or physicians reported the efficacy of flurbiprofen as superior to indomethacin and naproxen, while its safety, and particularly its GI tolerance were better compared with aspirin and indomethacin. Sensitivity analyses have reported a sufficient robustness against systematic publication bias assumptions. CONCLUSION: This meta-analysis has shown that flurbiprofen is an interesting alternative to commonly prescribed NSAIDs in the symptomatic management of rheumatoid arthritis, especially given its favourable efficacy/tolerance ratio.
16834969 [Effects of traditional Chinese medicine for invigorating spleen to resolve dampness and d 2006 Jul OBJECTIVE: To observe the clinical effects of Xinfeng Capsules (XFC), a traditional Chinese medicine for invigorating the spleen to resolve dampness and dredging collaterals, on patients with rheumatoid arthritis (RA) and anemia, and to investigate its mechanism. METHODS: Forty patients with RA and anemia were divided into three groups: XFC-treated group (n=20), Tripterygium glycosides Tablets (TGT)-treated group (n=10) and methotrexate (MTX)-treated group (n=10). The patients in each group took corresponding medicine for three months. The response rates of the three groups were evaluated after treatment. The general symptoms and specific signs and symptoms of RA were observed before and after the treatment. The indexes of blood routine examination and some other laboratory indexes such as erythrocyte sedimentation rate (ESR), and blood levels of rheumatoid factor (RF), iron, C-reaction protein (CRP), immunoglobins (Ig), complements 3 and 4, tumor necrosis factor-alpha (TNF-alpha), interleukin-10 (IL-10) and erythropoietin (EPO) were all examined and compared before and after treatment. RESULTS: The total response rate in the XFC-treated group was similar to those both in the TGT-treated and MTX-treated groups. The effects on relieving specific symptoms of RA in the three groups were also similar. The ESR and serum levels of RF, CRP, IgG, IgA and IgM were all decreased after treatment as compared with those before treatment in the three groups, and there were no significant differences among those laboratory indexes in the three groups after treatment. The XFC displayed more obvious effects on improving the general symptoms of patients with RA and anemia, increasing the blood levels of hemoglobin, iron and IL-10, while decreasing the serum level of TNF-alpha and regulating the serum EPO level, as compared with those in the TGT-treated and MTX-treated groups. CONCLUSION: The XFC for invigorating the spleen to resolve dampness and dredging collaterals was developed on the basic principle of regulating spleen. It can obviously improve the symptoms and laboratory indicators of RA. Such effects may be related to maintaining the balance of cytokines, regulating the serum level of EPO and increasing the serum iron level in patients with RA and anemia.
17158431 Randomized phase 2 trial of anti-tumor necrosis factor therapy for cachexia in patients wi 2006 Dec BACKGROUND: Tumor necrosis factor (TNF) is an important mediator of cachexia, and its blockade prevents catabolism in animal models. However, little evidence shows that anti-TNF therapy is effective in treating cachexia in humans. OBJECTIVE: The main aim of this study was to investigate the effect of etanercept, a synthetic soluble TNF receptor, on body composition in patients with early rheumatoid arthritis (RA). DESIGN: Twenty-six patients were randomly assigned to 24 wk of treatment with etanercept or methotrexate; the latter is the first-line therapy for RA. Body composition, physical function, disease activity, systemic inflammation, and the circulating insulin-like growth factor (IGF) system were measured at baseline (week 0) and at follow-up (weeks 12 and 24). Twelve patients in each treatment group (9 F, 3 M) completed the study. RESULTS: Overall, no important changes in body composition were observed, despite a transient increase in IGF-I at week 12 (P < 0.01). However, the secondary analysis of those patients (6/treatment group) who gained weight during follow-up showed a significant effect of etanercept on the composition of the weight gained: 44% of weight gained in the etanercept group was fat-free mass, as compared with only 14% in the methotrexate group (P = 0.04). Etanercept and methotrexate were equally effective in controlling the disease and improving physical function. CONCLUSIONS: Anti-TNF therapy with etanercept is not superior to that with methotrexate for the treatment of rheumatoid cachexia over a period of 6 mo. However, TNF blockade seems to normalize the anabolic response to overfeeding and, if these findings are confirmed, may be useful in conditions characterized by anorexia and weight loss.
16738952 Inhibition of IL-1, IL-6, and TNF-alpha in immune-mediated inflammatory diseases. 2006 Jun Blockade of cytokines, particularly of tumour necrosis factor alpha (TNF-alpha), in immuno-inflammatory diseases, has led to the greatest advances in medicine of recent years. We did a thorough review of the literature with a focus on inflammation models in rodents on modified gene expression or bioactivity for IL-1, IL-6, and TNF-alpha, and we summarized the results of randomized controlled clinical trials in human disease. What we have learned herewith is that important information can be achieved by the use of animal models in complex, immune-mediated diseases. However, a clear ranking for putative therapeutic targets appears difficult to obtain from an experimental approach alone. This is primarily due to the fact that none of the disease models has proven to cover more than one crucial pathogenetic aspect of the complex cascade of events leading to characteristic clinical disease signs and symptoms. This supports the notion that the addressed human immune-mediated diseases are polygenic and the summation of genetic, perhaps epigenetic, and environmental factors. Nevertheless, it has become apparent, so far, that TNF-alpha is of crucial importance in the development of antigen-dependent and antigen-independent models of inflammation, and that these results correlate well with clinical success. With some delay, clinical trials in conditions having some relationship with rheumatoid arthritis (RA) indicate new opportunities for blocking IL-1 or IL-6 therapeutically. It appears, therefore, that a translational approach with critical, mutual reflection of simultaneously performed experiments and clinical trials is important for rapid identification of new targets and development of novel treatment options in complex, immune-mediated, inflammatory diseases.
18398699 Individual quality of life: adaptive conjoint analysis as an alternative for direct weight 2008 May In the schedule for the evaluation of individual quality of life (SEIQoL) the weights for five individualized quality of life domains have been derived by judgment analysis and direct weighting (DW). We studied the feasibility and validity of adaptive conjoint analysis (ACA) as an alternative method to derive weights in 27 cancer patients and 20 patients with rheumatoid arthritis. Further, we assessed the convergence between direct weights and weights derived by ACA, and their correlation with global quality-of-life scores. All respondents finished the ACA task, but one in five respondents were upset about the ACA task. Further, the task was vulnerable to judgment 'errors', such as inconsistent answers. The agreement between the two weights was low. Both weighted index scores were strongly correlated to the unweighted index score. The relationships between the index score and scores on a visual analogue scale for global individual quality of life and global quality of life were similar whether or not the index score was calculated with DW weights, with ACA weights, or without using weights. We conclude that, because weights did not improve the correlation between the index score and global quality of life scores, it seems sufficient to use the unweighted index score as a measure for global individual quality of life.
17433337 Limited rotation of the mobile-bearing in a rotating platform total knee prosthesis. 2007 The hypothesis of this study was that the polyethylene bearing in a rotating platform total knee prosthesis shows axial rotation during a step-up motion, thereby facilitating the theoretical advantages of mobile-bearing knee prostheses. We examined 10 patients with rheumatoid arthritis who had a rotating platform total knee arthroplasty (NexGen LPS mobile, Zimmer Inc. Warsaw, USA). Fluoroscopic data was collected during a step-up motion six months postoperatively. A 3D-2D model fitting technique was used to reconstruct the in vivo 3D kinematics. The femoral component showed more axial rotation than the polyethylene mobile-bearing insert compared to the tibia during extension. In eight knees, the femoral component rotated internally with respect to the tibia during extension. In the other two knees the femoral component rotated externally with respect to the tibia. In all 10 patients, the femur showed more axial rotation than the mobile-bearing insert indicating the femoral component was sliding on the polyethylene of the rotating platform during the step-up motion. Possible explanations are a too limited conformity between femoral component and insert, the anterior located pivot location of the investigated rotating platform design, polyethylene on metal impingement and fibrous tissue formation between the mobile-bearing insert and the tibial plateau.
18789149 Natural autoantibodies reactive with glycosaminoglycans in rheumatoid arthritis. 2008 INTRODUCTION: Although natural autoantibodies make up the majority of circulating immunoglobulins and are also present in high numbers in therapeutically used intravenous immunoglobulin preparations, they have received little attention and their precise role remains largely unknown. An increasing awareness of the importance of posttranslational autoantigen modifications and glycobiology led us to explore carbohydrate-reactive natural autoantibodies in patients with rheumatoid arthritis. This study examined systematic antibodies reactive to glycosaminoglycans (GAGs), the carbohydrate components of proteoglycans that are released in large amounts from degrading cartilage. METHODS: To measure antibodies reactive to six different types of GAGs, a specialised ELISA was used in which the carbohydrates were covalently linked to the plastic surface through a 2 nm spacer. Sera from rheumatoid arthritis patients (n = 66), umbilical cord serum samples (n = 11) and adult controls (n = 54) were studied. In order to explore cross-reactivity with microbial antigens, bacterial peptidoglycans and fungal polysaccharides were used. Sera and synovial fluid samples were also tested using a GlycoChip carbohydrate array to characterise individual carbohydrate recognition patterns. We followed a multistep statistical screening strategy for screening GAG-reactive antibodies as predictive disease markers. RESULTS: While anti-GAG antibodies were absent in the umbilical cord sera, they were readily detectable in adult controls and were significantly elevated in patients with rheumatoid arthritis (p < 0.001). Anti-GAG antibodies showed significant cross-reactivity among different types of GAGs. They also reacted with bacterial peptidoglycans and fungal polysaccharides. Interestingly, anti-chondroitin sulphate C IgM antibody levels showed inverse correlation both with the Disease Activity Score (DAS) 28 scores and C-reactive protein (CRP) levels in rheumatoid arthritis. CONCLUSION: The highly abundant and cross-reactive, GAG-specific natural autoantibodies in serum may serve as novel disease-state markers in patients with rheumatoid arthritis.
18032541 Monitoring patients treated with anti-TNF-alpha biopharmaceuticals: assessing serum inflix 2007 Dec OBJECTIVES: Infliximab is an anti-tumour necrosis factor-alpha (TNF-alpha) mouse-human IgG1/kappa antibody used to treat patients with rheumatoid arthritis (RA) and other inflammatory diseases. Unfortunately, response failure and side-effects due to immunogenicity of the drug are not rare. In this study, we have compared different methods of assessing drug levels and anti-infliximab antibodies (Abs) and analysed the character of these Abs in sera of RA patients treated with infliximab for 1.5-18 months. METHODS: Functional serum infliximab levels and anti-infliximab Abs were measured by fluid-phase RIAs using 125I-labelled ligands in combination with molecular size and affinity chromatography, and immune complex precipitation. RESULTS: Anti-infliximab Abs were predominantly IgG, 36% being IgG4, and half the immune complexes were lambda-light-chain-positive. Ab titres were associated with inhibition of TNF binding to the drug, and low trough levels of infliximab were most frequent in anti-infliximab Ab-positive sera. Cross-binding to two other anti-TNF drugs was not observed. Detection of anti-infliximab Abs by solid-phase RIA using cross-binding of plastic-fixed and soluble infliximab exhibited low sensitivity and the data were inconsistent with results obtained from binding of the Abs to soluble infliximab. CONCLUSIONS: Specific and neutralizing anti-infliximab antibodies develop in RA patients treated with infliximab, and that low trough levels of functional infliximab are associated with the presence of such antibodies. The most sensitive antibody assay involved binding to soluble and intact infliximab. Assessments of bioavailability and immunogenicity of anti-TNF biologicals may be used to optimize dose regimens and prevent prolonged use of inadequate therapy.
17602844 The accuracy of magnetic resonance imaging of the hands and feet in the diagnosis of early 2007 Jul OBJECTIVE: To analyze MRI findings of early RA in the hand and foot joints and to determine any discrepancies between MRI findings in the hands and feet. METHODS: Twenty one patients who fulfilled the 1987 American College of Rheumatology (ACR) criteria for the diagnosis of RA at the onset underwent MRI of both hands and feet. RESULTS: In 18 out of 21 patients, rheumatoid changes were observed in the hand and foot joints. However, rheumatoid changes were observed only in the hand joints of the three remaining patients. MRI revealed pathologic findings suggested RA in the hands of 21 of 21 patients. In the feet, MRI findings suggested RA in 18 of 21 patients. Bone erosions were seen in the hands of 14 patients (67%). Observers found as many bony changes in the hands as in the foot joints. MRI detected active synovitis in 17 patients (81%) in the hands and in 15 patients (71%) in the feet. MRI findings suggested bone edema in the hand and foot joints in 14 (63%) and 11 patients (52%), respectively. There was no significant difference between the MCP and MTP joints with respect to RA-based changes obtained in the MRI (p>0.05). CONCLUSION: Evidence of foot involvement is a frequent occurrence in early RA.
19000788 Differential influences of bucillamine and methotrexate on the generation of fibroblast-li 2009 Jan We have recently demonstrated that bone marrow CD34+ cells from rheumatoid arthritis (RA) patients displayed abnormal capacities to respond to TNF-alpha and to differentiate into fibroblast-like cells producing MMP-1 (type B synoviocyte -like cells). The current study examined the effects of representative potent disease-modifying antirheumatic drugs, including bucillamine (BUC) and methotrexate (MTX) on the in vitro generation of fibroblast-like cells from RA bone marrow CD34+ cells. CD34+ cells purified from bone marrow specimens of 8 patients with active RA were cultured in the presence or absence of pharmacologically attainable concentrations of intramolecular disulfide form of bucillamine (BUC-ID, 3 microM), a major metabolite of BUC or MTX (20 nM). After incubation for 28 days, the generation of fibroblast-like cells was assessed under phase-contrast light microscopy and the concentrations of MMP-1 and VEGF in the culture supernatants were measured by ELISA. BUC-ID, but not MTX, significantly suppressed the generation of fibroblast-like cells from RA bone marrow CD34+ cells stimulated with SCF, GM-CSF and TNF-alpha (p=0.024 as determined by Wilcoxon signed rank test). Accordingly, BUC-ID, but not MTX, significantly suppressed the production of MMP-1 (p=0.017) and VEGF (p=0.017) by RA bone marrow CD34+ cells, without inhibition of beta2-microglobulin production. These results demonstrate that BUC-ID, but not MTX, is a potent inhibitor of differentiation of fibroblast-like cells from RA bone marrow CD34+ cells. Since MTX, but not BUC, has been previously shown to influence on type A synoviocytes, the data provide rationale of combination of BUC and MTX in the treatment of RA.
16960935 Intranasal administration of recombinant human cartilage glycoprotein-39. A phase I escala 2006 Sep OBJECTIVE: To investigate safety and tolerability and pilot efficacy of repeated single doses of Org39141 in patients with active rheumatoid arthritis (RA). Org 39141 is recombinant human cartilage glycoprotein-39, intended to induce mucosal tolerance upon intranasal administration. METHODS: RA patients with moderate disease activity were treated for 4 weeks and followed for another 8 weeks. The trial had a sequential cohort design: RA patients in the first cohort received 4 intranasal doses (one per week) of either 25 microg Org 39141 or placebo; in subsequent cohorts, treatment with 125microg, 625 microg, or 3125 microg Org39141 was compared to placebo. Safety was evaluated by means of reporting adverse events, standard laboratory testing, and nose examination. The primary efficacy endpoint was RA disease activity as measured by the Disease Activity Score 28 (DAS28). RESULTS: A total of 36 patients were randomized. Org39141 was well tolerated, and no severe or serious adverse events (AE) were reported. In the pooled placebo group, a decrease in DAS28 was observed, but to a lesser extent than in the Org 39141 treatment groups. After 4 weeks of treatment, the mean decrease in DAS in the 625 microg Org 39141 treatment group (-24%) was statistically (p = 0.02) and clinically (EULAR criteria) significantly larger than in the pooled placebo group (-3%). Once-weekly intranasal treatment with Org39141 was well tolerated, and no serious or severe AE were reported. A trend towards efficacy was observed. Our results are encouraging for further clinical development of Org39141.