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ID PMID Title PublicationDate abstract
17227631 Prednisolone phosphate-containing TRX-20 liposomes inhibit cytokine and chemokine producti 2007 Jan To evaluate the potential of using prednisolone phosphate (PSLP)-containing 3,5-dipentadecyloxybenzamidine hydrochloride (TRX-20) liposomes to treat rheumatoid arthritis (RA), we examined their ability to bind human fibroblast-like synovial (HFLS) cells and their effects in these cells. To test for binding, Lissamine rhodamine B-1, 2-dihexadecanoyl-sn-glycero-3-phosphoethanolamine (rhodamine)-labelled PSLP-containing TRX-20 liposomes were added to HFLS cells, and the fluorescence intensity of the rhodamine bound to the cells was evaluated. Rhodamine-labelled PSLP-containing liposomes without TRX-20 were used as a negative control. To evaluate the uptake of liposomes by the HFLS cells, we used TRX-20 liposomes containing 8-hydroxypyrene-1,3,6-trisulfonic acid (HPTS) and p-xylene-bis-pyridinium bromide (DPX), and observed the cells by fluorescence microscopy. The effects of the PSLP in TRX-20 liposomes on HFLS cells were assessed by the inhibition of the production of two inflammatory cytokines (interleukin 6 and granulocyte macrophage colony-stimulating factor) and one inflammatory chemokine (interleukin 8). The interaction of the PSLP-containing TRX-20 liposomes with HFLS cells was approximately 40 times greater than that of PSLP-containing liposomes without TRX-20. PSLP-containing TRX-20 liposomes bound to HFLS cells primarily via chondroitin sulfate. TRX-20 liposomes taken up by the cell were localized to acidic compartments. Furthermore, the PSLP-containing TRX-20 liposomes inhibited the production of the inflammatory cytokines and the chemokine more effectively than did the PSLP-containing liposomes without TRX-20. These results indicate that PSLP-containing TRX-20 liposomes show promise as a novel drug delivery system that could enhance the clinical use of glucocorticoids for treating RA.
16764798 Eight-year results of a minimally constrained total ankle arthroplasty. 2006 Jun BACKGROUND: Few studies have reported the intermediate to long-term results of minimally constrained total ankle replacements. The purpose of this study was to investigate the efficacy and safety of a minimally constrained total ankle prosthesis in a select low-demand patient population. METHODS: We reviewed a consecutive series of patients with rheumatoid arthritis who underwent a Buechel-Pappas total ankle replacement (BP TAR) between 1990 to 1997. Thirty-one ankle arthroplasties were performed in 23 patients with rheumatoid arthritis. One patient was lost to followup (deceased) and two ankles that failed resulted in fusion (overall survivorship - 93%). This left 28 ankles (21 patients) that were re-evaluated clinically and radiographically with an average followup of 8.3 (range 5.0 to 12.2) years. Preoperative and postoperative ranges of motion were measured and AOFAS hindfoot scores were calculated. Recent weightbearing radiographs were reviewed for evidence of component subsidence, radiolucent lines, and osteolysis. RESULTS: In 25 of 28 ankles (89%), patients were completely satisfied with the result of their ankle replacement and rated their pain as only mild to none; three (11%) patients were dissatisfied. Radiographic analysis revealed stable, well-positioned implants with evidence of biologic ingrowth in 23 ankles (82%), while five implants were interpreted as being at risk for impending failure because of marked tibial or talar component subsidence (18%). Component subsidence did not correlate with the presence or absence of radiolucent lines. Only one ankle demonstrated clear evidence of osteolysis. Ten intraoperative medial malleolar fractures occurred (32% of ankles) during implantation of the prosthesis, though in only one did this adversely affect patient outcome. Nine postoperative complications (29%) occurred; four wound dehiscences, four stress fractures, and one medial malleolar nonunion. CONCLUSIONS: Improvements in prosthetic design such as cementless fixation and decreased constraint appear to make total ankle arthroplasty a more predictable procedure over this period of followup. Despite a variety of complications, we are encouraged by the intermediate-term results in a select low-demand arthritic population.
18160618 Reduction of chemokine secretion in response to mycobacteria in infliximab-treated patient 2008 Mar The use of anti-tumor necrosis factor (TNF) agents as a treatment for chronic inflammatory conditions has been shown to be associated with an increased risk of developing tuberculosis. We studied the effect of the anti-TNF antibody infliximab on antimycobacterial immunity in 26 patients with rheumatoid arthritis or ankylosing spondylitis by use of an in vitro whole-blood model employing a reporter mycobacterium. Blood samples taken before and 30 min and 7 days after a 2-hour infliximab infusion were compared in terms of their abilities both to suppress luminescence of Mycobacterium bovis bacillus Calmette-Guérin lux and to secrete chemokines and cytokines 24 and 96 h after infection. No immediate effect of infliximab on mycobacterial luminescence was detected using this bioassay, irrespective of whether patients were receiving their first (n = 14) or maintenance (n = 12) doses of infliximab. Moreover, no effect on mycobacterial luminescence was detected when blood was taken 7 days after infliximab treatment (n = 7). By contrast, there was a significant reduction in the chemokines implicated in cellular trafficking, namely, interleukin-8, macrophage-inhibitory protein-1alpha (MIP-1alpha), MIP-1beta (24 h and 96 h), and monocyte chemoattractant protein-1 (MCP-1) (24 h) following BCG lux strain infection in the 30-minute post-infliximab-infusion blood samples (P < 0.05). This effect was sustained by MIP-1beta and MCP-1 (24 h; P < 0.05) at 7 days after infusion. Our results suggest that the development of tuberculosis in infliximab-treated patients is not directly related to the mycobactericidal effects of TNF but may be due to inhibition of TNF-dependent chemokine gradients disrupting cellular migration necessary to maintain the integrity of the granuloma.
17330279 Developing and testing a measure of dyadic efficacy for married women with rheumatoid arth 2007 Mar 15 OBJECTIVE: Interpersonal relationships and self-efficacy have each been independently studied in the context of coping with chronic illness. To examine a new type of interpersonal efficacy in couples coping with rheumatoid arthritis (RA), we developed and tested new measures of perceptions of arthritis dyadic efficacy. We assessed both partners' perceptions of confidence about working together as a team to manage women's illness-related challenges. METHODS: First, a 3-phase pilot study was conducted with interviews, expert review, and pretesting to develop items. Next, the psychometric properties of new measures were tested in 190 women with RA and their husbands. Exploratory analyses were conducted, Cronbach's alphas were calculated for each factor, and construct validity was examined with Pearson's correlations at baseline, 4-month, and 8-month followup. RESULTS: Factor analyses yielded 3 factors in the wife and husband versions, assessing dyadic behaviors concerning arthritis problem solving and emotions, arthritis symptom management, and arthritis-related couple outcomes. All items loaded >0.60, Cronbach's alphas for all subscales were >0.88, and initial evidence of construct validity was demonstrated. Finally, the initial factor structure was replicated with additional exploratory factor analyses in the same sample at 4-month and 8-month followup. CONCLUSION: Three short, reliable subscales resulted for couples coping with RA for use in interpersonal health research. These instruments facilitate viewing illness adaptation processes in a dyadic manner.
17442111 The interferon induced with helicase domain 1 A946T polymorphism is not associated with rh 2007 An important feature of autoimmune diseases is the overlap of pathophysiological characteristics. Clustering of autoimmune diseases in families suggests that genetic variants may contribute to autoimmunity. The aim of the present study was to investigate the role of the interferon induced with helicase domain 1 (IFIH1) A946T (rs1990760 A>G) variant in rheumatoid arthritis (RA), as this was recently associated with susceptibility to type 1 diabetes. A total of 965 Caucasians with RA and 988 healthy controls were genotyped for IFIH1 A946T. Gene expression of IFIH1 was measured in peripheral blood leukocytes using real-time PCR. Genotypes were equally distributed in both RA cases and healthy controls (odds ratio for allele C = 0.9, 95% confidence interval = 0.8-1.0, P = 0.3). No association was detected after stratification by sex, age at onset, rheumatoid factor status, anti-cyclic citrullinated peptide status or radiological joint damage. Levels of IFIH1 mRNA were approximately twofold higher in blood leucocytes of RA cases compared with healthy controls (P < 0.0001). These results indicate that the IFIH1 is upregulated in RA but that the A946T variant does not contribute significantly to the genetic background of RA.
16622717 T-cell activation via CD26 and caveolin-1 in rheumatoid synovium. 2006 CD26 is a T-cell costimulatory molecule with dipeptidyl peptidase IV (DPPIV) activity in its extracellular region. We previously reported that recombinant soluble CD26 enhances peripheral blood T-cell proliferation induced by the recall antigen tetanus toxoid (TT). Recently, we demonstrated that CD26 binds caveolin-1 on antigen-presenting cell (APC), and that residues 201-211 of CD26 along with the serine catalytic site at residue 630, which constitute a pocket structure of CD26/DPPIV, contribute to binding to caveolin-1 scaffolding domain. In addition, following CD26-caveolin-1 interaction on TT-loaded monocytes, caveolin-1 is phosphorylated, with linkage to NF-kappaB activation, followed by upregulation of CD86. Finally, reduced caveolin-1 expression on APC inhibits CD26-mediated CD86 upregulation and abrogates CD26 effect on TT-induced T-cell proliferation, and immunohistochemical studies revealed an infiltration of CD26+ T cells in the sub-lining region of rheumatoid synovium and high expression of caveolin-1 in the increased vasculature and synoviocytes of the rheumatoid synovium. Taken together, these results strongly suggest that CD26-cavolin-1 interaction plays a role in the upregulation of CD86 on TT-loaded APC and subsequent engagement with CD28 on T cells, leading to antigen-specific T-cell activation such as the T-cell-mediated antigen-specific response in rheumatoid arthritis.
17707673 [Chronic inflammatory disorders and reproduction]. 2007 Sep The desire of reproduction is a true challenge for the physicians in charge of patients with chronic inflammatory disorders such as rheumatoid arthritis or other connective tissue diseases. It requires: 1) the strict evaluation of the potential risks of flare of the rheumatic disease because of the pregnancy; 2) the assessment of risks on pregnancy outcome and fetus development; 3) the management of the different anti-rheumatic agents in order to maintain optimal control of disease activity and avoid any teratogenic problem. Besides this, it clearly appears that inflammatory rheumatic diseases may have an impact on patients' fertility, which may be explained by different mechanisms, physical, psychological, hormonal or immunological. Moreover, some treatments may directly affect fertility, which may justify specific managements in order to preserve gonadic functions.
17216674 Tumor necrosis factor-alpha induces vascular endothelial growth factor-C expression in rhe 2007 Jan OBJECTIVE: To determine the expression of vascular endothelial growth factor-C (VEGF-C) in the synovial fluid of patients with rheumatoid arthritis (RA) and to investigate the regulation of VEGF-C production by major proinflammatory cytokines in fibroblast-like synoviocytes (FLS). METHODS: The concentrations of VEGF-C, tumor necrosis factor-alpha (TNF-alpha), and interleukin 1beta (IL-1beta) were measured using an ELISA method in synovial fluids obtained from 20 patients with RA and 20 with osteoarthritis (OA). Primary cultured RA FLS were stimulated with TNF-alpha or IL-1beta, and the expression levels of VEGF-C mRNA and protein were assessed by quantitative real-time polymerase chain reaction and ELISA. RESULTS: Significantly higher levels of VEGF-C were found in RA synovial fluids compared to OA synovial fluids. VEGF-C levels showed a highly significant correlation with the levels of both TNF-alpha and IL-1beta in the synovial fluid of patients with RA. TNF-alpha stimulation significantly increased VEGF-C mRNA and protein expression in RA FLS in a dose-dependent manner. A tendency to increased expression of VEGF-C was also observed after IL-1beta stimulation in FLS. CONCLUSION: Overexpression of VEGF-C in FLS by stimulation with TNF-alpha may play an important role in the progression of synovial inflammation and hyperplasia in RA by contributing to local lymphangiogenesis and angiogenesis.
17692155 Efficacy and safety of hydroxychloroquine sulphate in rheumatoid arthritis: a randomized, 2007 Sep OBJECTIVE: Hydroxychloroquine (HCQ) has been used for a long time worldwide as a therapy for rheumatoid arthritis (RA). This trial was designed to determine whether HCQ was efficacious and safe in Indian patients with RA. RESEARCH DESIGN AND METHODS: The trial was a multicentre, placebo controlled, randomized and double-blind study. One hundred and twenty-two patients with RA were enrolled in 3 different centres for the trial (26 males and 96 females in the age group of 18-60 years). Patients were randomized to receive either hydroxychloroquine tablets (n = 61) two tablets of 200 mg daily or placebo (n = 61) two tablets daily. After 8 weeks all patients received one tablet of hydroxychloroquine 200 mg daily for 4 weeks. Every patient also received one tablet of Nimesulide 100 mg twice daily. MAIN OUTCOME MEASURES: Assessment of response at 12 weeks using modified ACR 20 (American College of Rheumatology 20) criteria where Health Assessment Questionnaire (HAQ) was replaced by ARA (American Rheumatology Association) functional class. RESULTS: 40.4% of patients on hydroxychloroquine showed improvement by modified ACR response criteria whereas only 20.7% (p = 0.02) showed improvement in the placebo group. No significant side effects were observed in any of the patients. There were no ocular toxicities. CONCLUSIONS: Hydroxychloroquine was found to be an effective and well-tolerated drug in rheumatoid arthritis in Indian patients.
17346164 Survival factors from activated accessory cells and their role in triggering autoimmune di 2007 To maintain immune homeostasis, the immune system has evolved two "opposite" mechanisms to regulate the activation or expansion of effectors including potential auto-reactive lymphocytes following an immune response. One is to support the survival of activated effectors and thereby benefit the generation of memory response. However, an inappropriate survival of auto-reactive lymphocytes may lead to autoimmune diseases, e.g. multiple sclerosis (MS) and rheumatoid arthritis (RA). The other is to induce apoptosis of most activated effectors, thereby bringing the immune system to a baseline level after an immune response. It is known that autoimmune diseases are due to uncontrolled growth of auto-reactive lymphocytes, eventually leading to damage of self-tissues or organs. Control of auto-reactive T lymphocytes therefore constitutes an attractive therapeutic strategy. Many studies on accessory cells and their secreted factors have focused on their role in the effector phase of a specific autoimmune disease. Recent data, however, support their causative role in triggering autoimmune diseases. In the past several years, several cytokines from activated accessory cells were demonstrated to promote the survival of pathogenic auto-reactive lymphocytes in animal models of MS, RA, and other autoimmune diseases. This review therefore focuses on the current knowledge regarding the role of those soluble survival factors in the initiation of different autoimmune diseases.
17392038 Detection of altered N-glycan profiles in whole serum from rheumatoid arthritis patients. 2007 Jun 15 Altered N-glycosylation occurs in many diseases. In rheumatoid arthritis (RA), for example, reduction in galactose residues in IgG and an increase in fucose residues in alpha1-acid glycoprotein have been observed. To further analyse N-glycans in disease, we show N-glycan profiling from whole serum employing reversed phase high performance liquid chromatography/negative-ion mode by sonic spray ionization ion trap mass spectrometry with pyridylamination. Profiles from female 15 RA patients and 18 aged-matched healthy women were compared. The most significant change seen in RA was decreased levels of mono-galactosyl bi-antennary N-glycans, in agreement with the previous reports regarding IgG. We also show previously unreported differences between isomers and increased tri-antennary oligosaccharides. These results indicate that LC-MS analysis of whole serum N-glycans can identify N-glycan alterations in RA and that this is a promising method both for studies of RA mechanisms and diagnosis.
18383408 Validity, reproducibility, and responsiveness of a twelve-joint simplified power doppler u 2008 Apr 15 OBJECTIVE: To investigate the validity, reproducibility, and responsiveness of a simplified power Doppler ultrasound (PDUS) assessment of joint inflammation compared with a comprehensive 44-joint PDUS assessment in patients with rheumatoid arthritis (RA) who started therapy with a biologic agent. METHODS: A total of 160 patients with active RA who started a biologic agent were prospectively recruited in 18 Spanish centers. The patients underwent clinical and laboratory assessment and blinded PDUS examination at baseline and 6 months. A PDUS examination of 128 synovial sites in 44 joints was performed. US synovitis and PD signal were semiquantitatively graded from 1 to 3 in all synovial sites. US count and index for synovitis and PD signal were obtained. PDUS intraobserver and interobserver reliability were evaluated. A process of data reduction based on the frequency of involvement of synovial sites by both synovitis and PD signal was conducted. Construct and discriminant validity of a simplified PDUS assessment was investigated. RESULTS: A PDUS simplified assessment including 24 synovial sites from 12 joints detected 100% of patients with synovitis and 91% of patients with PD signal. There was a highly significant correlation between the 44-joint count and index for synovitis and PD signal and the 12-joint count and index for synovitis and PD signal at baseline and 6 months (r = 0.84-0.90, P < 0.0005). The smallest detectable difference was lower than the mean change in simplified PDUS variables. CONCLUSION: A 12-joint PDUS assessment of RA joint inflammation may be a valid, feasible method for multicenter monitoring of therapeutic response to biologic agents.
18673161 Impact of traditional therapies and biologics on cardiovascular diseases in rheumatoid art 2008 Jul In chronic inflammatory diseases such as rheumatoid arthritis (RA), systemic inflammation appears as an independent risk factor, contributing to increased cardiovascular mortality. This high cardiovascular mortality reveals the existence of accelerated atherosclerosis, the pathogenesis of which may be associated with traditional risk factors such as smoking, hypertension, dyslipidemia, deterioration of insulin sensitivity, and less traditional risk factors such as hyperhomocysteinemia, inflammatory conditions and endothelial dysfunction. Control of systemic inflammation theoretically provides a means of preventing this higher cardiovascular mortality among RA patients. In this review we address the question of the impact of anti-rheumatic drugs currently used in RA, such as non-steroidal anti-inflammatory drugs (e.g. non-selective or cyclooxygenase-2 selective inhibitors), steroidal anti-inflammatory drugs (glucocorticoids), traditional disease-modifying anti-rheumatic drugs (e.g. methotrexate) or biologics (e.g. anti-tumour necrosis factor alpha anti-tumour necrosis factor alpha) on cardiovascular diseases in RA patients. We also discuss the specific mechanisms involved in the differential cardiovascular effects of these therapeutic agents.
18334924 [Emerging therapy in rheumatoid arthritis]. 2008 Feb 29 Rheumatoid arthritis (RA) is a chronic disease leading to disability. The inflammatory process resulting from autoimmunization involves mainly small joints of the hands and feet, but also can involve all joints and internal organs. Progress in immunology has caused an increase in understanding the RA pathogenesis, resulting in new methods of treatment. The breakthrough in RA therapy was initiated by TNF- alpha inhibitors, introduced during the last 10 years. TNF- alpha inhibitors were the first medications allowing improvement of disease outcome. However, more than half of patients do not achieve ACR50 improvement criteria, remission is rare, and the treatment is associated with side effects. Therefore, new and better drugs are being sought. In this review, new preparations for RA treatment currently under preclinical and clinical examination are described.
19126964 Glyco-biomarkers: potential determinants of cellular physiology and pathology. 2008 Once dismissed as just the icing on the cake, sugar molecules are emerging as vital components in life's intricate machinery. Our understanding of their function within the context of the proteins and lipids to which they are attached has matured rapidly, and with it the far reaching clinical implications are becoming understood. Recent advances in high-throughput glycomic techniques, glyco biomarker profiling, glyco-bioinformatics and development of increasingly sophisticated glyco-arrays, combined with our increased understanding of the molecular details of glycosylation have facilitated the linkage between aberrant glycosylation and human diseases, and highlighted the possibility of using glyco-biomarkers as potential determinants of disease and its progression. The focus of this review is to give an insight into the biological significance of these glycomodifications, highlight some specific examples of glyco-biomarkers in relation to autoimmunity and in particular rheumatoid arthritis, and to explore the exciting possibility of exploiting these for diagnostic and prognostic strategies.
17332701 [Interplay between the immune and skeletal cells in the regulation of inflammatory bone de 2007 Feb The immune and skeletal systems share a number of regulatory molecules including cytokines, signaling molecules, transcription factors and membrane receptors, in common. Consequently, the physiology and pathology of one system may very well affect the other. Research into the cartilage and bone destruction associated with rheumatoid arthritis (RA) has highlighted the importance of the interplay between the immune and skeletal systems. This interdisciplinary field called osteoimmunology has attracted much attention in recent years. Recently, animal models deficient in immunomodulatory molecules have been found frequently to develop an unexpected skeletal phenotype. Receptor activator of NF-kappaB ligand (RANKL) is an essential factor for the induction of osteoclastogenesis that links the immune and skeletal systems. Thus, osteoimmunology is becoming increasingly important for understanding the pathogenesis of bone destruction in RA and for developing new therapeutic strategies for diseases affecting both systems. Here we summarize recent advances on the study of the regulation of cartilage and bone destruction by the immune system.
16263181 No association of leukemia inhibitory factor (LIF) DNA polymorphisms with multiple scleros 2006 Feb Neuropoietins such as leukemia inhibitory factor (LIF) have been shown to ameliorate experimental autoimmune encephalomyelitis (EAE) and promote oligodendrocyte survival in vivo. We tested whether two previously described LIF polymorphisms are associated with MS by genotyping these single nucleotide polymorphisms (SNPs) in a group of MS patients (n=110), rheumatoid arthritis (RA) patients (n=120) and healthy controls (HC, n=109). Similar allele and genotype frequencies for both SNPs were found for all study groups. Furthermore, no associations with MS type or HLA-DR2 expression could be found. In summary, no association was found between the studied LIF DNA polymorphisms and the prevalence of MS indicating that these polymorphisms are not involved in determining disease susceptibility.
16503951 Pneumonitis associated with leflunomide: a profile of New Zealand and Australian reports. 2006 Mar BACKGROUND: Pneumonitis has very rarely been observed in patients taking leflunomide in clinical trials. Evidence is emerging that it is more frequent in clinical practice. AIM: The aim of this study was to investigate voluntary reports of suspected respiratory reactions to leflunomide held by the New Zealand Pharmacovigilance Centre (NZPhvC) and the Australian Adverse Drug Reactions Unit (ADRU) to ascertain if they fulfilled the criteria for pneumonitis and to define characteristics of this reaction. METHOD: Reports of respiratory adverse reactions attributed to leflunomide and received by the NZPhvC and the ADRU were analysed to identify those that were likely to be pneumonitis based on the criteria of Searles and McKendry. Features of these reports were examined to provide further information about this adverse reaction. RESULTS: The NZPhvC and the ADRU received 14 reports considered to be pneumonitis occurring in patients taking leflunomide. Two case reports fulfilled the Searles and McKendry criteria for definite or probable hypersensitivity pneumonitis. The patients in the remaining reports had radiological evidence of pulmonary infiltrates, an acute respiratory illness and no evidence of precipitating infection. In two cases the patients were taking leflunomide alone; one improved when it was withdrawn. In the other 12 cases, patients were taking leflunomide in combination with methotrexate. In nine of these 12 patients pneumonitis occurred after leflunomide was added to methotrexate, usually within 12-20 weeks. One of the two patients who died had possible previous methotrexate pneumonitis. Leflunomide washout with cholestyramine was used to treat three patients, one with life-threatening illness, with good results. CONCLUSION: This case series supports observations that leflunomide can cause pneumonitis either as monotherapy or in combination with methotrexate. The case histories indicate that prompt recognition is important to avoid life-threatening disease and support the use of cholestyramine to remove leflunomide.
17611989 Assessment of pain in rheumatoid arthritis: minimal clinically significant difference, pre 2007 Aug OBJECTIVE: To compare a visual analog pain scale (VAS) with the Medical Outcomes Study Short Form-36 Health Survey (SF-36) bodily pain; to define the minimal clinically important change (MCIC) for pain in observational studies; to define clinically useful cutpoints for pain; to quantify the predictors of pain; and to estimate the effect of anti-tumor necrosis factor (TNF) therapy on pain. METHODS: Over 6 years we studied 12,090 patients with rheumatoid arthritis (RA). Pain was assessed by VAS and SF-36 pain scales. RESULTS: Compared with the SF-36 scale, the 0-10 VAS pain scale was better correlated with all clinical variables. The mean VAS score was 3.4 (standard deviation 2.8), and the best cutpoint for an "acceptable" level of pain was
16952494 Intravascular tumor necrosis factor alpha blockade reverses endothelial dysfunction in rhe 2006 Sep BACKGROUND: Patients with rheumatoid arthritis (RA) have endothelial dysfunction, which may predispose them to the risk of premature atherosclerosis. This study investigated the involvement of tumor necrosis factor (TNF) alpha in the pathophysiologic characteristics of this abnormality by use of the TNF-alpha-neutralizing antibody infliximab. METHODS: Endothelium-dependent and -independent vasodilator responses to intra-arterial infusion of increasing doses of acetylcholine and sodium nitroprusside, respectively, were assessed by strain-gauge plethysmography in patients (n = 10) with early RA during saline solution infusion and after intra-arterial infusion of infliximab (200 microg/min). RESULTS: Circulating markers of systemic inflammation (C-reactive protein and interleukin 6) were higher in patients than in control subjects (n = 10, both P < .05), whereas plasma levels of TNF-alpha and soluble TNF receptor types 1 and 2 were similar in both groups (all P > .05). During saline solution infusion, the vasodilator response to acetylcholine was blunted in patients with RA compared with control subjects (14.2 +/- 9.2 mL . min-(1). dL-(1) versus 23.7 +/- 9.2 mL . min-(1). dL-(1) at the highest dose, P = .004) whereas vasodilation to sodium nitroprusside was not different between groups (P = .10). In patients with RA infliximab did not modify circulating C-reactive protein levels (P = .29, versus saline solution) but did potentiate the vasodilator response to acetylcholine (21.0 +/- 11.1 mL . min-(1). dL-(1); P = .004, versus saline solution). The response to sodium nitroprusside, in contrast, was not modified by infliximab (P = .28 versus saline solution). CONCLUSIONS: Intravascular administration of anti-TNF-alpha antibody ameliorates endothelial function in patients with RA but does not concurrently affect systemic inflammatory changes. Our findings suggest that enhanced TNF-alpha generation within the vessel wall, rather than systemic mechanisms, plays a role in the pathobiologic features of endothelial dysfunction in RA.