Browse

Search for: rheumatoid arthritis    methotrexate    autoimmune disease    biomarker    gene expression    GWAS    HLA genes    non-HLA genes   

ID PMID Title PublicationDate abstract
12932287 High CXCR3 expression in synovial mast cells associated with CXCL9 and CXCL10 expression i 2003 To improve our knowledge on the pathophysiology of rheumatoid arthritis (RA), we investigated gene expression patterns in synovial tissue from RA and osteoarthritis (OA) patients. DNA oligonucleotide microarray analysis was employed to identify differentially expressed genes in synovial tissue from pathologically classified tissue samples from RA (n = 20) and OA patients (n = 10). From 7131 gene sets displayed on the microarray chip, 101 genes were found to be upregulated and 300 genes to be downregulated in RA as compared with OA. Semiquantitative reverse-transcription polymerase chain reaction, Western blotting and immunohistochemistry were used to validate microarray expression levels. These experiments revealed that Cys-X-Cys receptor (CXCR)1, CXCR2 and CXCR3 mRNAs, as well as Cys-X-Cys ligand (CXCL)9 (monokine induced by IFN-gamma) and CXCL10 (IFN-gamma inducible protein 10) mRNAs, were significantly upregulated in RA as compared with OA disease. Elevated protein levels in RA synovial tissue were detected for CXCR1 and CXCR3 by Western blotting. Using immunohistochemistry, CXCR3 protein was found to be preferentially expressed on mast cells within synovial tissue from RA patients. These findings suggest that substantial expression of CXCR3 protein on mast cells within synovial tissue from RA patients plays a significant role in the pathophysiology of RA, accompanied by elevated levels of the chemokines CXCL9 and CXCL10. Mature mast cells are likely to contribute to and sustain the inflamed state in arthritic lesions (e.g. by production of inflammatory mediators such as histamine, proteinases, arachidonic acid metabolites and cytokines). Thus, the mast cell could become a potential target in therapeutic intervention.
12700891 Proteasome inhibition: a new anti-inflammatory strategy. 2003 Apr The ubiquitin-proteasome pathway has a central role in the selective degradation of intracellular proteins. Among the key proteins modulated by the proteasome are those involved in the control of inflammatory processes, cell cycle regulation, and gene expression. Consequently proteasome inhibition is a potential treatment option for cancer and inflammatory conditions. Thus far, proof of principle has been obtained from studies in numerous animal models for a variety of human diseases including cancer, reperfusion injury, and inflammatory conditions such as rheumatoid arthritis, asthma, multiple sclerosis, and psoriasis. Two proteasome inhibitors, each representing a unique chemical class, are currently under clinical evaluation. Velcade (PS-341) is currently being evaluated in multiple phase II clinical trials for several solid tumor indications and has just entered a phase III trial for multiple myeloma. PS-519, representing another class of inhibitors, focuses on the inflammatory events following ischemia and reperfusion injury. Since proteasome inhibitors exhibit anti-inflammatory and antiproliferative effects, diseases characterized by both of these processes simultaneously, as is the case in rheumatoid arthritis or psoriasis, might also represent clinical opportunities for such drugs.
11905085 [Plasma anti-oxidants and rheumatoid arthritis]. 2002 Feb We present a clinical study aimed to compare plasma antioxidant vitamins, vitamin E, beta-carotene and vitamin A. The study consisted of a group (15 patients) with rheumatoid arthritis (RA) compared to a healthy control group. There was a significant decrease in plasma vitamin E, beta-carotene and vitamin A (vitamin E 30.4 +/- 4.9 VS 43.6 +/- 8.2 micrograms/ml, beta-carotene 0.73 +/- 0.26 VS 1.02 +/- 0.22 micrograms/ml and vitamin A 0.22 +/- 0.07 VS 0.46 +/- 0.15 microgram/ml, P < 0.01 patients VS control, respectively). Supplementation of Dunaliella (natural)--beta-carotene to the RA patients for 3 weeks, resulted in a significant increase in plasma vitamin E (47.9 +/- 5.5 micrograms/ml) beta-carotene (0.87 +/- 0.21 microgram/ml) and vitamin A (0.55 +/- 0.15 microgram/ml). There were no changes in the activity indexes of RA. Low plasma antioxidant vitamins in patients with RA are consistent with the observation that oxidative processes occur in the inflammed joints. The validity of antioxidant vitamins as supplementary therapy for RA is not clear.
15230147 [Serum tumor necrosis factor alpha (TNF-alpha) concentration correlates with soluble adhes 2004 In present study we investigated whether the serum concentration of tumour necrosis factor alpha (TNF-alpha) is associated with soluble adhesion molecules and vascular endothelial growth factor (VEGF) in rheumatoid arthritis (RA) patients. Serum levels of TNF-alpha, soluble intercellular adhesion molecule 1 (sICAM-1), soluble vascular cell adhesion molecule 1 (sVCAM-1), soluble E-selectin (sE-selectin) and VEGF were assessed by ELISA in 38 patients with RA. We demonstrated the TNF-alpha to correlate with sICAM-1 (p < 0.001), sVCAM-1 (p < 0.01) and VEGF (p < 0.01). No association was noticed between TNF-alpha and sE-selectin serum concentrations. Moreover, serum TNF-alpha, sICAM-1, sVCAM-1 and VEGF levels correlated with markers of RA activity such as the erythrocyte sedimentation rate, C reactive protein level and the number of swollen joints. Data presented in this report support the concept of the VEGF synthesis stimulation by TNF-alpha. Analysis of the serum TNF-alpha, sICAM-1, sVCAM-1 and VEGF levels may be useful in the prediction of the RA activity.
12672918 Plasma pyridoxal 5'-phosphate concentration is correlated with functional vitamin B-6 indi 2003 Apr Many patients with rheumatoid arthritis (RA) have low plasma pyridoxal-phosphate (PLP) but a normal erythrocyte aspartate aminotransferase activity coefficient (alpha EAST), a measure of vitamin B-6 status in the erythrocytes, compared with healthy subjects. The goal of the present study was to examine the correlations of PLP levels in these two compartments (plasma and erythrocytes) with other established indices of vitamin B-6 status, and to determine which indicator better reflects functional status of vitamin B-6 in patients with RA. Multiple indices of vitamin B-6 status were measured in 33 patients with RA. Plasma PLP, urinary 4-pyridoxic acid (4-PA), net increase in plasma total homocysteine after a methionine load (DeltatHcy) and net increase in urinary xanthurenic acid after a tryptophan load (DeltaXA) were log-transformed to reach normality for statistical analyses. We found that log-plasma PLP levels were inversely correlated with both log-DeltatHcy (r = -0.368, P = 0.035) and log-DeltaXA (r = -0.333, P = 0.05). Plasma PLP was not correlated with alpha EAST or urinary 4-PA excretion. In contrast, erythrocyte PLP was inversely correlated with alpha EAST (r = -0.431, P = 0.012) and positively correlated with log-4-PA (r = 0.475, P = 0.005), but erythrocyte PLP was not correlated with the outcomes of a methionine or tryptophan load test. Erythrocyte PLP and log-4-PA, but not plasma PLP, were correlated with dietary intake of vitamin B-6 after adjusting for protein intake (r = 0.420, P = 0.015 and r = 0.333, P = 0.05, respectively). We suggest that in patients with RA, plasma PLP levels are a better diagnostic indicator of functional vitamin B-6 status than erythrocyte PLP levels.
15887364 Gold concentrations in abiotic materials, plants, and animals: a synoptic review. 2004 Jan Gold (Au) is ubiquitous in the environment and mined commercially at numerous locations worldwide. It is also an allergen that induces dermatitis in sensitive individuals. Gold concentrations were comparatively elevated in samples collected near gold mining and processing facilities, although no data were found for birds and non-human mammals. Maximum gold concentrations reported in abiotic materials were 0.001 microg L(-1) in rainwater; 0.0015 microg L(-1) in seawater near hydrothermal vents vs. < 0.00004-0.0007 microg L(-1) elsewhere; 5.0 microg kg(-1) dry weight (DW) in the Earth's crust; 19.0 microg L(-1) in a freshwater stream near a gold mining site; 440 microg kg(-1) DW in atmospheric dust near a high traffic road; 843 microg kg(-1) DW in alluvial soil near a Nevada gold mine vs. < 29 microg kg(-1) DW premining; 2.53 mg kg(-1) DW in snow near a Russian smelter vs. < 0.35 mg kg(-1) DW at a reference site; 4.5 mg kg(-1) DW in sewage sludge; 28.7 mg kg(-1) DW in polymetallic sulfides from the ocean floor; and 256.0 mg kg(-1) DW in freshwater sediments near a gold mine tailings pile vs. < 5 microg kg(-1) DW prior to mining. In plants, elevated concentrations of 19 microg Au kg(-1) DW were reported in terrestrial vegetation near gold mining operations vs. < 4 microg kg(-1) DW at a reference site; 37 microg kg(-1) DW in aquatic bryophytes downstream from a gold mine; 150 microg Au kg(-1) DW in leaves of beans grown in soil containing 170 microg kg(-1) DW; up to 1.06 mg kg(-1) DW in algal mats of rivers receiving gold mine wastes; and 0.1-100 mg kg(-1) DW in selected gold accumulator plants. Fish and aquatic invertebrates contained 0.1-38.0 microg Au kg(-1) DW. In humans, gold concentrations up to 1.1 microg L(-1) were documented in urine of dental technicians vs. 0.002-0.85 microg L(-1) in reference populations; 2.1 microg L(-1) in breast milk, attributed to gold dental fillings and jewelry of mothers; 1.4 mg kg(-1) DW in hair of goldsmiths vs. a normal range of 6-880 microg kg(-1) DW; 2.39 mg L(-1) in whole blood of rheumatoid arthritis patients receiving gold thiol drugs to reduce inflammation (chrysotherapy) vs. a normal range of 0.2-2.0 microg L(-1); and 60.0 to 233.0 mg kg(-1) fresh weight (FW) in kidneys of rheumatoid arthritis patients undergoing active chrysotherapy vs. < 42.0 mg kg(-1) FW kidney 140 months posttreatment.
12235076 Sulphasalazine and mesalazine: serious adverse reactions re-evaluated on the basis of susp 2002 Oct BACKGROUND: 5-aminosalicylates are extensively prescribed for the treatment of ulcerative colitis but have a wide range of described adverse effects. AIMS: To determine whether serious adverse effect profiles differ for sulphasalazine and mesalazine. METHODS: Analysis of suspected serious adverse reactions reported to the Committee on Safety of Medicines of the UK in 1991-1998. Adverse effect profiles were categorised for interstitial nephritis, pancreatitis, serious skin reactions, hepatitis and hepatic failure, and blood dyscrasias. Report rates were calculated using prescribing data from the Department of Health and compared for mesalazine and sulphasalazine. Further analysis was undertaken for sulphasalazine according to disease indication of inflammatory bowel disease or rheumatoid arthritis. RESULTS: A total of 4.7 million prescriptions were dispensed for sulphasalazine compared with 2.8 million for mesalazine. Interstitial nephritis was only described for mesalazine, with 11.1 reports per million prescriptions. Pancreatitis was reported seven times as frequently for mesalazine (7.5 per million prescriptions) compared with sulphasalazine (1.1 per million prescriptions) (odds ratio (OR) 7.0; 95% confidence interval (CI) 2.6-18.6; p<0.001). There were no reports of serious skin disorders in patients prescribed sulphasalazine for inflammatory bowel disease. Blood dyscrasias were reported significantly more often in patients receiving sulphasalazine for rheumatoid arthritis than for inflammatory bowel disease (OR 5.31; 95% CI 2.6-11.0; p<0.001), and there was a similar trend for hepatic disorders. CONCLUSIONS: Spontaneous reports suggest that within the five sets of disorders considered, there is no evidence to indicate a safety advantage of mesalazine over sulphasalazine in the treatment of inflammatory bowel disease. Pancreatitis and interstitial nephritis appear significantly more common with mesalazine, and advice on renal monitoring in patients who receive mesalazine may need reinforcing.
15642139 Identification of a SmD3 epitope with a single symmetrical dimethylation of an arginine re 2005 Anti-Sm antibodies, identified in 1966 by Tan and Kunkel, are highly specific serological markers for systemic lupus erythrematosus (SLE). Anti-Sm reactivity is found in 5-30% of SLE patients, depending on the autoantibody detection system and the racial background of the SLE population. The Sm autoantigen complex comprises at least nine different polypeptides. All of these core proteins can serve as targets of the anti-Sm B-cell response, but most frequently the B and D polypeptides are involved. Because the BB'Sm proteins share cross-reactive epitopes (PPPGMRPP) with U1 specific ribonucleoproteins, which are more frequently targeted by antibodies that are present in patients with mixed connective tissue disease, the SmD polypeptides are regarded as the Sm autoantigens that are most specific to SLE. It was recently shown that the polypeptides D1, D3 and BB' contain symmetrical dimethylarginine, which is a component of a major autoepitope within the carboxyl-terminus of SmD1. In one of those studies, a synthetic dimethylated peptide of SmD1 (amino acids 95-119) exhibited significantly increased immunoreactivity as compared with unmodified SmD1 peptide. Using immobilized peptides, we confirmed that the dimethylated arginine residues play an essential role in the formation of major SmD1 and SmD3 autoepitopes. Moreover, we demonstrated that one particular peptide of SmD3 represents a more sensitive and more reliable substrate for the detection of a subclass of anti-Sm antibodies. Twenty-eight out of 176 (15.9%) SLE patients but only one out of 449 (0.2%) control individuals tested positive for the anti-SmD3 peptide (SMP) antibodies in a new ELISA system. These data indicate that anti-SMP antibodies are exclusively present in sera from SLE patients. Thus, anti-SMP detection using ELISA represents a new serological marker with which to diagnose and discriminate between systemic autoimmune disorders.
15494349 Topoisomerase II inhibitors, irrespective of their chemical composition, ameliorate experi 2005 Feb OBJECTIVE: Rheumatoid arthritis (RA) is an autoimmune disease, characterized by a chronic inflammation in the joints. The model of collagen-induced arthritis (CIA) has been extensively used to elucidate the pathogenic mechanisms relevant to human RA and is widely employed for the evaluation of potential anti-rheumatic agents. Etoposide and mitoxantrone are immunosuppressive drugs, both acting by inhibiting the topoisomerase II function. We have previously demonstrated an ameliorating effect of etoposide in CIA. The aims of this study were (1) to assess the optimal ameliorating dose of etoposide and (2) to ascertain that topoisomerase II inhibition, irrespective of the chemical composition of the drug, affects the course of autoimmunity. METHODS: Male DBA/1 mice were treated with 12.5 mg/kg body weight of etoposide five times, twice, once per week or once every second week. Mitoxantrone was administered as high dose (1 mg/kg body weight five times after immunization or after booster with collagen II) or low dose (3 microg/mouse, 5 days/week starting after collagen II immunization or after booster). RESULTS: Treatment with 12.5 mg/kg body weight five times or twice weekly with etoposide completely inhibited development of arthritis. Low-dose treatment with mitoxantrone after collagen II immunization or high-dose treatment after collagen II booster delayed the onset of arthritis. These results were observed clinically as well as histologically. In addition, serum levels of anti-collagen II antibodies were significantly lower in mice displaying less severe arthritis. CONCLUSION: Treatment of collagen-induced arthritis with topoisomerase II inhibitors ameliorates the development of disease.
15313361 Defective vasculogenesis in systemic sclerosis. 2004 Aug 14 BACKGROUND: Typical vascular features of systemic sclerosis include low capillary density and vascular obliteration. The formation and repair of blood vessels in adults involve vasculogenesis, which is mediated through the recruitment of bone-marrow-derived circulating endothelial precursors (CEP). We investigated whether vasculogenesis is impaired in patients with systemic sclerosis. METHODS: Peripheral blood was obtained from 11 patients with systemic sclerosis, 11 with rheumatoid arthritis, and 11 healthy controls. Factors potentially affecting the CEP number were matched among the three groups. CEP (identified as circulating cells positive for CD34, CD133, and the type 2 receptor for vascular endothelial growth factor) were quantified by cell sorting and three-colour flow cytometry. The circulating concentrations of angiogenic factors were measured by ELISA. The potential of CEP to differentiate into endothelial cells was assessed by the upregulation of von Willebrand factor after in-vitro maturation treatment. Findings The absolute number of CEP was much lower in patients with systemic sclerosis than in patients with rheumatoid arthritis or healthy controls (median 274 [IQR 178-395] vs 1154 [653-1524] and 1074 [713-1186] per 20 mL peripheral blood, respectively; p<0.0001 by Kruskal-Wallis test. Paradoxically, circulating concentrations of most angiogenic factors were significantly higher in patients with systemic sclerosis than in healthy controls. The proportion of CEP that differentiated into endothelial cells was significantly lower in patients with systemic sclerosis than in healthy controls (p<0.0001, Mann-Whitney test). INTERPRETATION: Insufficient vascular repair machinery due to defective vasculogenesis might contribute to vasculopathy in systemic sclerosis. RELEVANCE TO PRACTICE: As well as providing an important insight into the pathogenesis of this disorder, these findings suggest that dysregulated vasculogenesis might be important in other disorders with abnormalities in vascular formation, including those with excessive formation of new vessels such as cancer and those with deficient vessel formation such as atherosclerosis. Circulating endothelial precursors could be a novel target for therapeutic strategies for ischaemic complications in patients with systemic sclerosis.
12563677 Subcutaneous administration of polymerized-type I collagen for the treatment of patients w 2003 Feb OBJECTIVE: To determine the efficacy, tolerance and safety of subcutaneous injections of porcine type I collagen-polyvinylpyrrolidone (PVP) in patients with rheumatoid arthritis (RA). METHODS: Eleven patients with active RA on stable therapy with methotrexate (MTX) were enrolled in a 3 month prospective and longitudinal study. Patients were treated weekly with subcutaneous injections of 0.2 ml of collagen-PVP (1.7 mg of collagen) in the 8 most painful joints. The primary endpoints included the Ritchie index (RI), swollen joint count, disease activity score (DAS), erythrocyte sedimentation rate (ESR), and C-reactive protein (CRP). The secondary endpoints included morning stiffness, pain intensity on a visual analog scale (VAS), and the Spanish-Health Assessment Questionnaire Disability Index (HAQ-DI). Improvement was determined using American College of Rheumatology (ACR) response criteria. RESULTS: Collagen-PVP was safe and well-tolerated and there were no adverse events. Patients had a statistically significant improvement (p < 0.05) in basal versus 3 month's treatment in morning stiffness (Delta -32.3, -68.6%), RI (Delta -10.2, -46.4%), swollen joint count (Delta -10.7, -71.8%), VAS (Delta -39.9, -63.8%), HAQ-DI (Delta -0.5, -48.5%), DAS (Delta -1.35, -70.5%) and ACR20, 50, and 70 (80.0%; 60.0% and 20.0% respectively). We found no differences in serologic or hematologic variables. CONCLUSION: Collagen-PVP was a safe and well-tolerated drug for the short term treatment of RA. The combination of collagen-PVP plus MTX was more efficacious than MTX alone. However, double-blind placebo-controlled phase II and III clinical trials are necessary to determine whether this drug could be useful in the longterm treatment of RA.
12928942 [Comparison of conventional and real-time RT-PCR for the quantitation of jun protooncogene 2003 Aug AP-1 dependent genes, e.g., matrix-metallo-proteinases, are involved in the pathogenesis of rheumatoid arthritis (RA). Therefore, the transcription factor AP-1 and its subunits, proteins of the Jun and Fos proto-oncogene families, are interesting targets for analysis in RA. In this study, we analyzed the mRNA expression of junB in synovial membrane (SM) samples and isolated synovial fibroblasts of patients with RA, osteoarthritis (OA), and normal, non-inflammatory controls. To address the suitability of real-time RT-PCR for the quantitation of Jun proto-oncogene family members, conventional RTPCR and real-time PCR were comparatively applied for junD, a gene representing a major challenge because of its high GC-content (70%, increasing the probability of secondary structures interfering with the PCR) and its sequence homology to other Jun proto-oncogenes. In addition, a comparison was performed concerning the precision, reproducibility, costs, as well as labor and time consumption of the two PCR methods. Real-time RT-PCR proved superior to conventional PCR in terms of precision (mean deviation of measured from employed concentration 58% for real-time PCR vs 225% for conventional PCR), reproducibility, as well as labor and time consumption (4 times less for real-time RT-PCR). Experimental cDNA normalization for equivalent cDNA concentrations by sample dilution was more reliable than mathematical cDNA normalization. However, real-time PCR was 3.6-fold more expensive. Applying the more reliable real-time RT-PCR for the ex vivo analysis of junB mRNA-expression, no significantly different expression of junB was observed in SM or isolated synovial fibroblasts from RA as compared to OA. Interestingly, however, junBmRNA expression was significantly lower in RA SM and borderline significantly lower in OA SM than in normal/non-inflammatory SM, with potential effects on the functional properties of the resulting AP-1 complexes. Immunohistochemical staining of the SM with JunB-specific antibodies showed comparable JunB protein expression in SFB (collagen III mRNA-positive) of RA and OA samples. Thus, real-time RT-PCR appears suitable and time-saving for the quantitation of jun proto-oncogene mRNA-expression in tissue and cell samples with high precision and reproducibility.
12022343 Activation of the immune system and inflammatory activity in relation to markers of athero 2002 May OBJECTIVE: To measure markers of atherogenesis and thrombogenesis in patients with rheumatoid arthritis (RA) and in matched controls, and to relate these variables to markers of inflammation and endothelial activation, and to the presence of atherosclerosis. METHODS: Thirty-nine patients with RA with disease onset between 1974 and 1978, who were younger than 65 years at the present study in 1997, were investigated together with 39 age and sex matched controls. IgG, IgA, and IgM antibodies against oxidized low density lipoprotein (oxLDL ab), malondialdehyde LDL (MDA-LDL ab) and cardiolipin (aCL) were measured by ELISA, circulating immune complexes (CIC) were isolated by precipitation, and homocysteine was measured with HPLC. Hemostatic factors of endothelial origin, i.e., plasminogen activator inhibitor-1 (PAI-1 mass), von Willebrand Factor (vWF), and D-dimer were analyzed by ELISA, and tissue plasminogen activator (tPA) activity was analyzed by a chromogen method. The products analyzed in the RA group correlated with soluble adhesion molecules (sICAM-1, sE-selectin), acute phase reactants, interleukin 6 (IL-6), and IL-2sR alpha, all measured by ELISA, and with accumulated disease activity. The factors were also related to the presence of plaque measured by duplex scanning. Factor analysis was performed to subgroup data in order to find latent variables. RESULTS: Patients with RA had significantly higher levels of oxLDL ab (IgM), MDA-LDL ab (IgA, IgM classes), aCL (IgG, IgA, IgM classes), CIC, homocysteine, PAI-1 mass, and D-dimer than controls. Patients also had significantly higher levels of sICAM-1, sE-selectin, IL-6, and IL-2sR alpha. PAI-1 mass, D-dimer, vWF, CIC, and aCL (IgM, IgA) correlated with erythrocyte sedimentation rate (ESR), and, with the exception of vWF, to accumulated disease activity. CIC correlated significantly with IgM antibodies against oxLDL and aCL. ESR, IL-2sR alpha, PAI-1, tPA activity, vWF, D-dimer, homocysteine, aCL (IgA), and MDA-LDL ab (IgA) correlated with sICAM-1. ESR, haptoglobin, IL-2sR alpha, PAI-1 mass, D-dimer, aCL (IgM), and MDA-LDL ab (IgM) correlated with sE-selectin. sICAM-1 was significantly higher in patients with plaque. In factor analysis, presence of atherosclerotic plaque had loadings of one latent variable together with adhesion molecules and IL-2sR alpha and together with antibodies of, in particular, IgM type of another one. CONCLUSION: Several different etiopathogenic mechanisms for increased cardiovascular mortality in RA are implicated. Continuous endothelial activation is suggested by increased levels of adhesion molecules sICAM-1 and sE-selectin, which correlate with hemostatic factors of endothelial origin and with T cell activation as measured by IL2sR alpha. That factor analysis showed loadings of one variable on antilipid antibodies and plaque and another on T cell activation and plaque indicates that the immune system is involved in the development of atherosclerosis in RA.
14677179 A role for TARC/CCL17, a CC chemokine, in systemic lupus erythematosus. 2003 Nov OBJECTIVE: The Th2-type CC chemokine thymus and activation-regulated chemokine (TARC/CCL17) is one of the high affinity ligands for CCR4, a chemokine receptor predominantly expressed by Th2 cells. We examined serum and plasma concentrations of TARC/CCL17 in patients with systemic lupus erythematosus (SLE). METHODS: Serum and plasma levels of TARC/CCL17 and plasma levels of monocyte chemoattractant protein-1 (MCP-1/CCL2) and macrophage-derived chemokine (MDC/CCL22) in patients with SLE were determined by ELISA. RESULTS: There were significant differences in the plasma concentrations of TARC/CCL17 between the patients with untreated SLE and treated SLE (p < 0.001), rheumatoid arthritis (RA) (p < 0.001), and healthy controls (p < 0.001). In addition, the plasma levels of TARC/CCL17 correlated with the class of lupus nephritis (higher in class I or II than in class III or IV). There was close correlation between plasma levels of MDC/CCL22 and TARC/CCL17. There was no correlation between plasma levels of MCP-1/CCL2 and TARC/CCL17. CONCLUSION: TARC/CCL17 may be a useful serological marker and may facilitate an assessment of the degree of disease activity in SLE. The development of SLE is closely related to the elevation of plasma TARC/CCL17 levels.
12634579 Spinal cord injury following osteoporotic vertebral fracture: case report. 2002 Sep 15 STUDY DESIGN: This report details the sudden catastrophic neurologic deterioration concerning a patient with an acute fracture of T5 associated with osteoporosis. OBJECTIVE: To describe a unique presentation of abrupt spinal cord injury in this condition. SUMMARY OF BACKGROUND DATA: Vertebral fractures occur frequently in osteoporosis, but associated spinal cord injury is a rare occurrence. When neurologic injury occurs it is generally of a very low incidence and with a gradual onset, and spontaneous recovery can be expected. Most reports in the literature are of delayed-onset paraplegia after vertebral collapse. We report a unique case of a sudden and catastrophic thoracic spinal cord injury occurring spontaneously. METHODS: An 88-year-old woman had a sudden thoracic vertebral fracture with complete spinal cord injury while attempting to get out of bed. She was treated with continuous oral corticosteroids for >40 years for both rheumatoid arthritis and restrictive lung disease. She was never investigated or treated for osteoporosis. RESULTS: Plain radiographs indicated multilevel osteoporotic fractures throughout the spine with diffuse, marked osteopenia. Magnetic resonance imaging scans showed changes in keeping with severe vertebral osteoporosis and spinal cord injury. She was treated nonoperatively in view of the extremely osteoporotic spine and her overall poor medical condition. Despite an initial improvement in her respiratory condition with medical therapy, she died 72 hours following admission. CONCLUSION: With increasing awareness of the morbidity attached to the osteoporotic spine, investigation and pharmacologic treatment are warranted and may reduce the possibility of catastrophic neurologic impairment as occurred in this case.
12168168 Denham total knee arthroplasty: a 10-year follow-up study. 2002 Aug We reviewed 72 patients with 89 Denham total knee arthroplasties (Biomet, Warsaw, IN) (TKAs) 10 to 15 years after the operation. Of 8 TKAs that were considered as failures, 5 had been revised at the time of review for pain and aseptic loosening, and 3 others were considered to have failed because of breakage of the polyethylene tibial plateau, dislocation, and infection. Survival analysis suggested a 10-year survival rate of 92.7%. There were 36 patients with 45 TKAs alive at the time of follow-up. We reviewed 32 of the patients with 40 Denham TKAs that had not failed. Their average age was 81 years (range, 58-93 years). They were reviewed at an average of 11.8 years after TKA. Nine knees (6 patients) had some anterior knee pain from the unresurfaced patella. Restriction of function was mainly due to medical conditions and old age. Survival analysis performed with the living patients found the 10-year survival to be 91.1%. Long-term survival shows that the Denham knee prosthesis is effective despite its simplicity.
15164103 Nutrient supplementation with polyunsaturated fatty acids and micronutrients in rheumatoid 2004 Jun OBJECTIVE: To investigate in a double-blind placebo-controlled, parallel group study, the effects of a nutrient supplement, containing, among other ingredients, the omega-3 fatty acids eicosapentaenoic acid (1.4 g EPA), docosahexaenoic acid (0.211 g DHA), omega-6 fatty acid gamma-linolenic acid (0.5 g GLA) and micronutrients in patients with active rheumatoid arthritis (RA). DESIGN, SUBJECTS AND INTERVENTION: RA patients were randomized to receive either daily liquid nutrient supplementation or placebo for 4 months. The primary end point was the change in tender joint count at 2 and 4 months. Other clinical variables included swollen joint count, visual analogue scales for pain and disease activity, grip strength, functionality score and morning stiffness. Biochemical parameters included plasma concentrations of PUFA and vitamins C and E. SETTING: Outpatient university clinic. RESULTS: In all, 66 patients enrolled, 55 completed the study. No significant change from baseline in tender joint count or any of the other clinical parameters was detected in either group. Patients receiving nutrient supplementation, but not those receiving placebo, had significant increases in plasma concentrations of vitamin E (P=0.015), and EPA, DHA and docosapentaenoic acid concomitant with decreases of arachidonic acid (P=0.01). Intergroup differences for PUFA and vitamin E were significantly different (P=0.01 and 0.03, respectively). CONCLUSIONS: This double-blind, placebo-controlled study in RA patients did not show superior clinical benefit of daily nutrient supplementation with EPA, GLA and micronutrients at the doses tested as compared to placebo. The study adds information regarding doses of omega-3 fatty acids, below which anti-inflammatory effects in RA are not seen.
15077298 Inhibition of antigen-presenting cell function and stimulation of human peripheral blood m 2004 Apr OBJECTIVE: The stress protein and endoplasmic reticulum chaperone, immunoglobulin binding protein (BiP), is an autoantigen in rheumatoid arthritis (RA). Stress proteins, however, may have extracellular functions, mediated via cell surface receptors, that may include immunomodulatory functions. We sought to determine whether cell-free BiP is present in the synovial fluid (SF) of patients with RA and to further investigate the possible extracellular antiinflammatory and immunomodulatory properties of BiP in peripheral blood mononuclear cells (PBMCs) in vitro. METHODS: The presence of BiP in SF was established by Western blotting. PBMCs were stimulated with exogenous recombinant human BiP, and cytokine production and cell proliferation were measured in the presence and absence of cell signaling inhibitors or neutralizing anti-interleukin-10 (anti-IL-10) monoclonal antibody. Cytokine levels were quantified by enzyme-linked immunosorbent assay, cell proliferation by tritiated thymidine uptake, and cell surface molecule expression by flow cytometry. RESULTS: PBMCs responded to BiP with secretion of an antiinflammatory profile of cytokines. Although BiP stimulated the early production of tumor necrosis factor alpha (TNF alpha), the major cytokine induced was IL-10. Soluble TNF receptor II and IL-1 receptor antagonist secretion was also increased. Addition of SB203580, the MAPK p38 pathway inhibitor, partially inhibited the production of IL-10 and TNF alpha, whereas they were unaffected by the MAPK ERK-1/2 inhibitor PD98059. BiP also inhibited the recall antigen response by PBMCs to tuberculin purified protein derivative. Further investigation showed that incubation of monocytes in the presence of either BiP or IL-10 down-regulated CD86 and HLA-DR expression. The effect observed with IL-10 was transient compared with the long-lasting reduction induced by BiP. CONCLUSION: Extracellular BiP may stimulate immunomodulatory and antiinflammatory pathways, which are only partly due to the production of IL-10. These properties may be of relevance for the treatment of diseases such as RA.
15457446 Rheumatoid arthritis synovial fluid fibroblasts express TRAIL-R2 (DR5) that is functionall 2004 Sep OBJECTIVE: To examine fibroblasts grown from the synovial fluid of rheumatoid arthritis (RA) patients for TRAIL-R2 expression, and for susceptibility to apoptosis induced by an agonistic anti-TRAIL-R2 monoclonal antibody (mAb). METHODS: The expression of TRAIL-R2 (DR5) was determined by flow cytometry on fibroblasts grown from the synovial fluid of patients with RA, osteoarthritis (OA), seronegative arthritis, and unclassified monarthritis or oligoarthritis, and on fibroblasts from the synovial membrane of RA and OA patients. Susceptibility to apoptosis mediated by an agonistic anti-TRAIL-R2 mAb was determined by alamar blue bioassay, fluorescence microscopy (annexin V/propidium iodide staining), and caspase activation. RESULTS: Fibroblasts grew from 35 of 50 RA synovial fluid samples, of which 26 were DR5(+) (mean [+/-SD] fluorescence intensity [MFI] 18.74 +/- 2.5). Fibroblasts also grew from 15 of 30 seronegative arthritis synovial fluid samples, 28 of 40 OA synovial fluid samples, and 8 of 20 unclassified monarthritis or oligoarthritis synovial fluid samples; all of these were DR5- (MFI 0.32 +/- 0.02). All 10 of the fibroblast lines from joint replacement surgery or synovectomy specimens of RA patients were DR5(+) (MFI 20.3 +/- 3.2). All fibroblast lines from the synovium of 10 OA patients were DR5-, as were fibroblasts from the skin of 5 healthy subjects. DR5(+) fibroblast cultures underwent apoptosis when treated in vitro with an agonistic anti-DR5 antibody. CONCLUSION: Fibroblasts grown from the synovial fluid and synovial membrane of RA patients express TRAIL-R2 that is functionally active. An agonistic anti-TRAIL-R2 antibody that does not induce hepatocyte toxicity may be an alternative strategy for treatment of RA.
12820230 Effects of soybean ethanol extract on the cell survival and oxidative stress in osteoblast 2003 Jun Recent evidence suggests that high concentrations of tumor necrosis factor-alpha (TNF-alpha) and nitric oxide (NO) are thought to increase the apoptosis in osteoblasts and bone resorption and may have important roles in the regulation of osteoblast and osteoclast metabolism, especially in rheumatoid arthritis. The present study was performed to investigate the effect of soybean ethanol extract on the scavenging properties using DPPH and the TNF-alpha and NO production of osteoblastic MC3T3-E1 cells. The soy extract and its fractions according to polarity displayed a strong free radical scavenger activity at 0.01 approximately 0.1g/L, except for aquous fraction which had no significant effect on the function of MC3T3-E1 cells (p < 0.05). TNF-alpha secretion by MC3T3-E1 cells was reduced significantly when stimulated with soy extract (0.05 g/L). Nitrite accumulation in culture medium and apoptosis of MC3T3-E1 cells were induced by the addition of 10(-10) M TNF-alpha, and inhibited by the simultaneous addition of soy extract (0.05g/L).