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ID PMID Title PublicationDate abstract
12165077 Continuous nasal administration of antigen is critical to maintain tolerance in adoptively 2002 Aug Mucosal tolerance is a natural mechanism that prevents immunological reactions to antigens by altering the activity of immune cells of pathogenic clones without modulating the entire immune system. This 'natural immune suppression' can be exploited when antigen(s) of the target organ in an autoimmune disease is used for mucosal treatment. Being inspired by the experimental results in animal models, clinical trials using type II collagen for mucosal treatment have been conducted in rheumatoid arthritis. High-density proteoglycan (aggrecan) is another major macromolecular component in articular cartilage, and may be a candidate autoantigen for provoking immune reactions in patients with rheumatoid arthritis. Indeed, like type II collagen, systemic immunization of genetically susceptible mice with proteoglycan (PG) aggrecan induces progressive autoimmune polyarthritis. Here, we investigated whether intranasally applied PG can be effective in suppressing PG-induced arthritis (PGIA) in BALB/c mice. We found that nasal administration of 100 microg PG exerted a strong suppressive effect on both the incidence and severity of the disease, most probably by reducing responsiveness towards the immunizing PG antigen. When we transferred PGIA into genetically matched but immunodeficient SCID mice, we were able to establish a tolerized state, but only if the recipient SCID mice received lymphocytes from tolerized animals and intranasal treatment with PG was continued. Without nasally administered antigen, the transferred anergic cells recovered and arthritis rapidly developed in a severe form. Intranasal PG treatment of recipient SCID mice was ineffective when cells from non-tolerized arthritic donors were transferred, in which case the regular weekly 'tolerizing' dose of PG made the disease worse. Our results suggest that mucosal treatment in an already existing disease may result in paradoxical outcomes.
11838843 Disease modifying antirheumatic drugs in early rheumatoid arthritis: a longterm observatio 2002 Feb OBJECTIVE: To investigate the effectiveness, toxicity, and drug survival in an observational longterm study of patients with early rheumatoid arthritis (RA). METHODS: Four hundred twenty-eight patients with early RA were investigated between January 1987 and December 1995. All patients had a disease duration of less than one year and had not been previously treated with any disease modifying antirheumatic drug (DMARD). The following drugs were introduced at the doses specified: hydroxychloroquine (HCQ) (200-400 mg/day), D-penicillamine (D-Pen) (500 mg/day), sulfasalazine (SSZ) (2-3 g/day), auranofin (6 mg/day), intramuscular gold (IM gold, 50 mg/week), methotrexate (MTX) (0.15 mg/kg/week, per os), cyclosporin A (CSA) (3 mg/kg/day), azathioprine (AZA) (2-3 mg/kg/day), cyclophosphamide (CYC) (1-2 mg/kg/day). RESULTS: Three hundred eighty-three patients were treated with one DMARD for at least 6 months. Sixty-five percent of patients were seropositive. The disease duration was 9.2 (3.1) months and the followup period of 12.7 (4.8) years, ranging from 7 months to 13 years. The drugs of first choice were: D-Pen (32%), HCQ (30%), MTX (21%), CSA (8%), and IM gold (7%). After the 2nd, 3rd, and 4th prescriptions, MTX was the most popular drug (27%), while D-Pen and HCQ were prescribed less frequently. The longest drug survival was seen in MTX treated patients, followed by CSA, without significant differences between them. D-Pen, HCQ, and IM gold had the largest dropout rate. The main causes for drug discontinuation were drug inefficacy (HCQ), followed by adverse drug reactions (D-Pen). CONCLUSION: It appears that MTX has the longest survival time, with CSA following in second place. The main reasons for discontinuation of treatment were drug inefficacy, followed by adverse drug reactions.
15612143 Systemic adverse effects of hepatitis B vaccines are rare. 2004 Dec (1) A few exceptional but serious cases have raised the possibility that hepatitis B vaccination could trigger or exacerbate demyelinating and autoimmune diseases. (2) Epidemiological data, i.e. three cohort studies and five case-control studies, showed no increased risk of demyelinating disease after hepatitis B vaccination. Another case-control study showed a significant link between multiple sclerosis and hepatitis B vaccination. Any increase in risk (if indeed there is one) probably affects only a small minority of vaccine recipients. But these few cannot be identified before vaccination. (3) Hepatitis B vaccination carries a very low risk of anaphylactic reactions (estimated incidence less than 1 case per 100 000 injections). (4) A few cases of haematological, rheumatological and autoimmune disturbance have been linked to hepatitis B vaccination. Appropriate epidemiological studies are needed to determine whether these links are causal. (5) In practice, hepatitis B vaccination has a favourable risk-benefit balance in non-immunised subjects who are at risk of contracting hepatitis B.
15331419 Interleukin-18 promotes joint inflammation and induces interleukin-1-driven cartilage dest 2004 Sep Interleukin (IL)-18 is a member of the IL-1 family of proteins that exerts proinflammatory effects and is a pivotal cytokine for the development of Th1 responses. The goal of the present study was to investigate whether IL-18 induces joint inflammation and joint destruction directly or via induction of other cytokines such as IL-1 and tumor necrosis factor (TNF). To this end we performed both in vitro and in vivo kinetic studies. For in vivo IL-18 exposure studies C57BL/6, TNF-deficient, and IL-1-deficient mice were injected intra-articularly with 1.10(7) pfu mIL-18 adenovirus followed by histopathological examination. Local overexpression of IL-18 resulted in pronounced joint inflammation and cartilage proteoglycan loss in control mice. Of high interest, IL-18 gene transfer in IL-1-deficient mice did not show cartilage damage, although joint inflammation was similar to that in wild-type animals. Overexpression of IL-18 in TNF-deficient mice showed that TNF was partly involved in IL-18-induced joint swelling and influx of inflammatory cells, but cartilage proteoglycan loss occurred independent of TNF. In vitro cartilage degradation by IL-18 was found after a 72-hour culture period. Blocking of IL-1 with IL-1Ra or an ICE-inhibitor resulted in complete protection against IL-18-mediated cartilage degradation. The present study demonstrated that IL-18 induces joint inflammation independently of IL-1. In addition, we showed that IL-1beta generation, because of IL-18 exposure, was essential for marked cartilage degradation both in vitro and in vivo. These findings implicate that IL-18, in contrast to TNF, contributes through separate pathways to joint inflammation and cartilage destruction.
12574395 Microsatellite instability and suppressed DNA repair enzyme expression in rheumatoid arthr 2003 Feb 15 Reactive oxygen and nitrogen are produced by rheumatoid arthritis (RA) synovial tissue and can potentially induce mutations in key genes. Normally, this process is prevented by a DNA mismatch repair (MMR) system that maintains sequence fidelity during DNA replication. Key members of the MMR system include MutSalpha (hMSH2 and hMSH6) and MutSbeta (hMSH2 and hMSH3). To provide evidence of DNA damage in inflamed synovium, we analyzed synovial tissues for microsatellite instability (MSI). MSI was examined by PCR on genomic DNA of paired synovial tissue and peripheral blood cells of RA patients using specific primer sequences for five key microsatellites. Surprisingly, abundant MSI was observed in RA synovium compared with osteoarthritis tissue. Western blot analysis for the expression of MMR proteins demonstrated decreased hMSH6 and increased hMSH3 in RA synovium. To evaluate potential mechanisms of MMR regulation in arthritis, fibroblast-like synoviocytes (FLS) were isolated from synovial tissues and incubated with the NO donor S-nitroso-N-acetylpenicillamine. Western blot analysis demonstrated constitutive expression of hMSH2, 3, and 6 in RA and osteoarthritis FLS. When FLS were cultured with S-nitroso-N-acetylpenicillamine, the pattern of MMR expression in RA synovium was reproduced (high hMSH3, low hMSH6). Therefore, oxidative stress can relax the DNA MMR system in RA by suppressing hMSH6. Decreased hMSH6 can subsequently interfere with repair of single base mutations, which is the type observed in RA. We propose that oxidative stress not only creates DNA adducts that are potentially mutagenic, but also suppresses the mechanisms that limit the DNA damage.
14973301 Rheumatoid arthritis does not reduce the pharmacodynamic response to valsartan. 2004 Mar Inflammatory conditions decrease the cardiovascular response to calcium channel and beta-adrenergics blockers due, likely, to down-regulation of the receptors mediated by pro-inflammatory mediators such as C-reactive protein (CRP), nitric oxide (NO), and tumor necrosis factor. The purpose of this investigation was to determine whether down-regulation is also evident in angiotensin II type 1 receptors (AT(1)R) during varying inflammatory states. Normotensive subjects were divided into three groups according to the severity of disease: 14 with active rheumatoid arthritis, 12 with controlled rheumatoid arthritis, and 12 healthy control subjects. The AT(1)R antagonist valsartan (160 mg) was given to all the subjects, and blood samples were taken for pharmacokinetic analysis. The systolic, diastolic, and mean arterial pressures were determined at all blood collection times. The degree of inflammation was measured using joint swelling, NO, and CRP. Plasma valsartan concentration was measured using high-performance liquid chromatography (HPLC). Patients with active disease had significantly higher joint swelling, NO, and CRP than other groups. Plasma valsartan concentration-time curves were remarkably similar in all groups. No reduced response was noticed. Our preliminary observation suggests a need for further studies to examine the possibility of AT(1)R antagonists as alternatives to other cardiovascular drugs so that their potency may be reduced by inflammation.
11958434 CD69 expression on lymphocytes and interleukin-15 levels in synovial fluids from different 2002 Mar OBJECTIVE: The aim was to study a possible relationship between CD69 expression on lymphocytes and interleukin-15 (IL-15) levels in synovial fluid (SF) from patients with different inflammatory arthropathies. METHODS: CD69 expression was assessed by two-color flow cytometry on different subsets of synovial fluid lymphocytes (SFL) obtained from patients with diagnoses of rheumatoid arthritis (RA), seronegative spondyloarthropathy (SSd), and crystal-associated arthritis (CAA). The IL-15 levels in synovial fluid supernatants were measured by enzyme-linked immunoassay (ELISA). RESULTS: No significant differences between the three groups of arthropathies were observed in the distribution of synovial fluid lymphocyte subsets. CD69-positive SFL were mainly CD3-, CD45RO-, and CCR5-positive cells. Although no significant differences in the percentage of CD69-positive lymphocytes were observed between the three groups of patients, the highest level of CD69 expression on lymphocytes was observed in RA patients (mean fluorescence intensity 37.9 +/- 5.2 compared to 17.5 +/- 3.3 in SSd and 12.4 +/- 2.6 in CAA, P = 0.007 and P < 0.001, respectively). In addition, the expression of CD69 on SFL from RA correlated with their respective IL-15 levels measured in SF supernatants. CONCLUSION: Our data provide in vivo evidence of the putative role that IL-15 can play in the high expression of CD69 on SFL from RA patients.
12051401 Interleukin-13 in autoimmune rheumatic diseases: relationship with the autoantibody profil 2002 Mar OBJECTIVE: Several cytokines play a role in the production of autoantibodies such as RF and ANA by B-lymphocytes; the role of IL-13 in this process has not been previously studied. We investigated the relationship between the serum concentration of this cytokine and circulating autoantibodies. METHODS: IL-13 serum levels, as well as RF and ANA, were evaluated in 282 patients with autoimmune rheumatic diseases including RA (n=84), SLE (n= 114), SS (n=52) and Scl (n=32). RESULTS: Serum levels of IL-13 (pg/ml) were significantly higher in patients with RA (p < 0.00003), SLE (p < 0.03), SS (p < 0.0007), or Scl (p < 0.025) compared to controls. IL-13 serum levels correlated with those of RF in RA (p < 0.00001), SLE (p < 0.003) and Scl (p < 0.03). IL-13 levels were higher in RA (p<0.0003), SLE (p<0.005) and Scl (p<0.05) patients with RF than in patients without RF. SS patients with antiSSA/Ro antibodies had significantly higher IL-13 levels than SS patients without this autoantibody (p < 0.04). No statistically significant correlation was found between IL-13 levels and any other antinuclear autoantibody, total immunoglobulin levels or the main clinicalfeatures of each disease. CONCLUSION: The evidence of higher IL-13 levels in our RA, SLE, SS and Scl patients confirms that this cytokine is involved in the pathogenesis of autoimmune rheumatic diseases. The relationship of this cytokine with RF in RA, SLE and Scl, as well as with antiSSA/ Ro antibody in SS, strengthens the hypothesis that it plays a role in autoantibody production. However, the different autoantibody synthesis by B-cells recognises different pathways depending on the underlying autoimmune disease.
12682616 The role of free radicals in the pathogenesis of rheumatoid arthritis. 2003 Mar Free radicals are reactive chemical species that differ from other compounds in that they have unpaired electrons in their outer orbitals. They are capable of damaging cellular components, and accumulating evidence suggests that they may contribute to various disease entities including inflammatory joint disease. Reactive oxygen species (ROS) as well as reactive nitrogen species (RNS) can directly or indirectly damage basic articular constituents and lead to the clinical expression of the inflammatory arthritis. Hydroxyl radicals degrade isolated proteoglycans, and HOCl fragments collagen. Hydrogen peroxide, which is very diffusible, readily inhibits cartilage proteoglycan synthesis, e.g. by interfering with ATP synthesis, in part by inhibiting the glycolytic enzyme glyceraldehyde-3-phosphate dehydrogenase in chondrocytes, aggravating the effects of proteolytic and free-radical-mediated cartilage degradation. Peroxynitrite and HOCl may facilitate cartilage damages by inactivating TIMPs. TIMP-1 inhibits stromelysins, collagenases and gelatinases and this ability is lost after ONOO(-) or HOCl treatment. HOCl can also activate latent forms of neutrophil collagenases and gelatinase with obvious consequences. Hypochlorous acid, ONOO(-) and O(2)(*-) react with ascorbate, which is essential for cartilage function, leading to low levels of ascorbate in synovial fluid. Low concentrations of H2O(2), O(2)(*-) or both, accelerate bone resorption by osteoclasts, whereas NO. inhibits it. NO. promotes chondrocyte apoptosis, inhibits proteoglycan synthesis and activates latent metalloproteinases and cyclooxygenase. ROS, produced by activated phagocytes, could alter the antigenic behaviour of immunoglobulin G, producing fluorescent protein aggregates that can further activate phagocytic cells. Radical-exposed IgG is able to bind rheumatoid factor and results in the generation of C3alpha. This reaction may be self-perpetuating within the rheumatoid joint, suggesting that free radicals play a role in the chronicity of the inflammatory reaction which is a key question regarding to which extent free radicals contribute to the consequences of inflammation, such as the cartilage and bone destruction. Reactive oxygen intermediates can also function as signaling messengers to activate transcription factors, like NFkB and AP-1, and induce gene expression. All this knowledge might serve to apply a rational selection of antioxidants for possible therapeutic purposes, enforcing combination therapy of the inflammatory joint disease.
15227731 Airway obstruction in rheumatoid arthritis: CT manifestations, correlated with pulmonary f 2004 Jun 30 In the present study, the signs of airflow obstruction on inspiratory and expiratory CT scans in 45 patients with rheumatoid arthritis were investigated. Radiologic findings were evaluated and correlated with the clinical data, which included rheumatoid factors and pulmonary function tests results. A lung biopsy was performed in five patients. The pattern of CT findings was as follows: infiltrative (n=15), obstructive (n=12), mixed (infiltrative and obstructive; n=10), other complicating diseases (n=7), and normal (n=1). The rheumatologic factor between patients with bronchial wall thickenings and patients without thickenings was significantly different (p=0.009). The forced expiratory flow rate between 25% and 75% of the vital capacity (FEF(25-75%)) was significantly more reduced in patients with interlobular septal thickenings than in patients without these thickenings. The patients with mosaic attenuation had significantly lower mean values of FEF(25-75% ) (p=0.001) and a lower peak expiratory flow (p=0.003) than patients without mosaic attenuation. On expiratory scans, the mean air-trapping score was 21%. These air-trapping scores were found to be well correlated with FEV1/FVC (r=0.230, p=0.0452), and FEF25-75% (r=-0.63, p= 0.05). It is widely known that a relatively higher percentage of mosaic attenuation with air-trapping and a good correlation between these and functional values contribute to the detection of early airway obstruction in patients with rheumatoid arthritis, and even in patients with infiltrative lung disease only.
15049528 Monoarticular arthritis. 2004 Jan This article described many of the causes of monoarticular arthritis that are encountered in clinical practice. Although radiologists have relied on conventional radiography and bone scintigraphy, additional imaging methods have been introduced, such as MR imaging, CT scanning, and US. These methods improve visualization of intra-articular and periarticular soft tissue structures and are helpful in the guidance of arthrocentesis, drainage procedures, or percutaneous biopsies. Imaging findings always should be correlated with clinical abnormalities, and, when appropriate, joint fluid analysis.
12384917 High mobility group box chromosomal protein 1: a novel proinflammatory mediator in synovit 2002 Oct OBJECTIVE: High mobility group box chromosomal protein 1 (HMGB-1) is a ubiquitous chromatin component expressed in nucleated mammalian cells. It has recently and unexpectedly been demonstrated that stimulated live mononuclear phagocytes secrete HMGB-1, which then acts as a potent factor that causes inflammation and protease activation. Macrophages play pivotal roles in the pathogenesis of arthritis. The aim of this study was to determine whether synovial macrophage expression of HMGB-1 is altered in human and experimental synovitis. METHODS: Intraarticular tissue specimens were obtained from healthy Lewis rats, Lewis rats with Mycobacterium tuberculosis-induced adjuvant arthritis, and from patients with rheumatoid arthritis (RA). Specimens were immunohistochemically stained for cellular HMGB-1. Extracellular HMGB-1 levels were assessed in synovial fluid samples from RA patients by Western blotting. RESULTS: Immunostaining of specimens from normal rats showed that HMGB-1 was primarily confined to the nucleus of synoviocytes and chondrocytes, with occasional cytoplasmic staining and no extracellular matrix deposition. In contrast, inflammatory synovial tissue from rats with experimental arthritis as well as from humans with RA showed a distinctly different HMGB-1 staining pattern. Nuclear HMGB-1 expression was accompanied by a cytoplasmic staining in many mononuclear cells, with a macrophage-like appearance and an extracellular matrix deposition. Analysis of synovial fluid samples from RA patients further confirmed the extracellular presence of HMGB-1; 14 of 15 samples had HMGB-1 concentrations of 1.8-10.4 microg/ml. CONCLUSION: The proinflammatory mediator HMGB-1 was abundantly expressed as a nuclear, cytoplasmic, and extracellular component in synovial tissues from RA patients and from rats with experimental arthritis. These findings suggest a pathogenetic role for HMGB-1 in synovitis and indicate a new potential therapeutic target molecule.
12723199 [Immunopathologic mechanism in some ocular diseases]. 2002 OBJECTIVES: The goal of the present study is to elucidate the pathogenic mechanisms that determine the ocular involvement in some systemic diseases. MATERIAL AND METHODS: We have studied 45 patients with ocular diseases and concomitant systemic diseases (systemic lupus erythematosus-SLE, ankylosing spondylitis, Reiter syndrome, juvenile rheumatoid arthritis, Sjögren syndrome). The patients studied have been compared with a control group represented by 20 healthy individuals. In each case we have determined the serum levels of the following humoral markers: the C3 complement fraction, circulating immune complexes, autoantibodies (antinuclear autoantibodies, anti-double stranded DNA autoantibodies, anti-smooth muscle autoantibodies, anti-neutrophilic cytoplasm autoantibodies, anti-cardiolipin autoantibodies, anti-SSA, anti-SSB, rheumatoid factor). RESULTS: The autoantibodies detected in certain cases of uveitis suggest the existence of an autoimmune etiology; the antibody titers have been high in some severe cases of rheumatic uveitis, especially in patients with ankylosing spondylitis. We have found that there is a correlation between the presence and the titer of certain autoantibodies, and the onset and evolution of the disease. Specifically, the antinuclear autoantibodies may be considered a predictive factor for the development of chorio-retinopathy of SLE. Uveitis mediated by immune complexes has been seen in rheumatoid arthritis, ankylosing spondylitis, and SLE, these being the same systemic diseases where there is an important pathogenic role of immune complexes. CONCLUSIONS: The abnormal immunologic function, that was observed in the ocular inflammatory diseases studied, may be synthesized by the association between two immunopathologic phenomena; both of them are finalized by the non-self transformation of the antigens linked to various eye structures. These are represented by autoimmunity (of humoral, cellular, or mixed type), and the immediate type III hypersensitivity reaction. This study provides important data regarding the involvement of autoimmune diseases in the etiology of ocular diseases.
15030584 Serum-soluble selectin levels in patients with rheumatoid arthritis and systemic sclerosis 2004 Mar Soluble forms of selectins may play a regulatory role in inflammatory responses that are key to the pathophysiology of rheumatic diseases such as rheumatoid arthritis (RA) and systemic sclerosis (SSc). The aim of this study was to examine whether the elevated serum-soluble (s) selectin levels are associated with RA or SSc. Serum sE-, sL- and sP-selectin levels were measured by sandwich enzyme-linked immunosorbent assay in 34 RA patients, 30 SSc patients and 16 healthy subjects. The levels of sE-selectin were significantly higher in RA and SSc patients than those in healthy subjects. The sL-selectin level was significantly lower in RA patients compared to healthy subjects. Serum sP-selectin levels were not significantly different among the study groups. The active RA patients had significantly higher serum sE- and sL-selectin levels compared to inactive RA patients. Also, some correlations were observed between the serum selectin levels and measures of disease activity such as erythrocyte sedimentation rate and C-reactive protein in RA patients. The higher levels of sE-selectin were found in SSc patients with pulmonary fibrosis, and there was also a negative correlation between diffusion capacity for carbon monoxide and serum sE-selectin. Serum levels of selectins may provide a useful additional marker for disease activity in RA patients and for disease severity in SSc patients.
12511993 Effect of bioresonance therapy on antioxidant system in lymphocytes in patients with rheum 2002 Sep We measured activities of superoxide dismutase, catalase, and glutathione peroxidase and content of nonprotein thiol groups (reduced glutathione) in blood lymphocytes from patients with rheumatoid arthritis before and during bioresonance therapy. The state of the antioxidant system in lymphocyte from patients receiving standard pharmacotherapy was characterized by activation of the key antioxidant enzymes and decreased content of thiol groups. Bioresonance therapy increased the content of thiol groups and normalized activities of superoxide dismutase and glutathione peroxidase. However, catalase activity remained above the control. Changes in the lymphocyte antioxidant system indicate that bioresonance therapy activates nonspecific protective mechanisms in patients with rheumatoid arthritis.
15498798 Expression and regulation of cryopyrin and related proteins in rheumatoid arthritis synovi 2005 May BACKGROUND: Rheumatoid arthritis (RA) synovium is characterised by enhanced NF-kappaB activity and proinflammatory cytokines. Cryopyrin (CIAS-1, NALP-3, PYPAF-1) has been shown to regulate NF-kappaB and caspase-1 activation. OBJECTIVE: To study the expression of cryopyrin, its effector molecule ASC, and its putative antagonist pyrin in RA and osteoarthritis (OA) synovium, and the main two cellular constituents of synovial lining, cultured fibroblast-like synoviocytes (FLS) and macrophages. METHODS: FLS and macrophages were cultured in the presence of inflammatory mediators. Real time polymerase chain reaction was used to quantify message levels in synovial biopsy specimens and cells. In situ hybridisation was employed to localise expression of cryopyrin mRNA. RESULTS: Cryopyrin mRNA was raised in RA synovium and detected in both lining and sublining regions. FLS from RA and OA tissue expressed low baseline levels of cryopyrin transcripts that were induced by tumour necrosis factor alpha (TNFalpha). In contrast, macrophages differentiated in vitro expressed relatively high cryopyrin levels, which were further induced by TNFalpha, but not by interleukin 1beta. ASC mRNA levels were comparable in RA and OA tissue, FLS, and macrophages, and were depressed by TNFalpha in macrophages. Pyrin expression was higher in RA synovium than in OA tissue, and virtually undetectable in FLS but high in macrophages where it was unchanged by TNFalpha treatment. CONCLUSION: These results suggest that enhanced cryopyrin levels in RA synovium are due to a greater numbers of tissue macrophages, and demonstrate transcriptional regulation of cryopyrin in a chronic inflammatory disease.
14583574 Matrix metalloproteinases-3, -8, -9 as markers of disease activity and joint damage progre 2003 Nov OBJECTIVE: To analyse the relation between systemic levels of pro-MMP-3, -8, and -9 matrix metalloproteinase (MMP) activity in alpha(2) macroglobulin (alpha(2)M)/MMP complexes and the progression of joint destruction in patients with recent onset rheumatoid arthritis (RA). METHODS: 109 patients with RA of recent onset were entered into this longitudinal study. Patients were followed up for two years; clinical data, blood samples, and radiographs were obtained at baseline and at 1 and 2 years. Serum levels of MMPs were measured by sandwich ELISA and MMP activity assays. RESULTS: During the two years joint damage progressed from 0 to 10 (median Sharp score, p<0.001). Stable levels of pro-MMP-3 and a significant decrease in the levels of pro-MMP-8 and -9 and alpha(2)M/MMP complexes were seen throughout the two years. Regression analysis showed that serum pro-MMP-3 levels at disease onset were independently associated with the progression of joint damage (B=0.7, 95% CI 0.3 to 1.1, p=0.001). Based on the rate of joint destruction, patients were divided into two subgroups: patients with mild and severe joint damage progression. The pro-MMP-3 levels were significantly higher in the group with severe compared with mild disease at all times. Levels of pro-MMP-8 and -9 were decreased in both groups, whereas alpha(2)M/MMP complex levels decreased in the group with mild disease only. CONCLUSION: Serum levels of the MMPs studied are associated with disease activity, but serum pro-MMP-3 levels at the onset of disease are also predictive of joint damage progression.
11983200 Serum tartrate-resistant acid phosphatase isoforms in rheumatoid arthritis. 2002 Jun OBJECTIVES: Our objective was to evaluate the significance and source of serum tartrate-resistant acid phosphatase (TRACP) in patients with rheumatoid arthritis (RA). METHODS: Thirty-five RA, 32 osteoarthritis (OA) and 16 control subjects were studied. Serum TRACP-5b activity and total TRACP protein were determined by immunoassay. TRACP isoforms were analyzed by non-denaturing polyacrylamide gel electrophoresis (PAGE). Serum bone alkaline phosphatase (BAP), cross-linked N-terminal telopeptides (NTx), and C-terminal telopeptides (ICTP) of type I collagen were estimated as markers of bone turnover. C-reactive protein (CRP) was measured as a marker of chronic inflammation. Macrophages and dendritic cells (DC) were developed from peripheral blood monocytes. Cell lysates and culture supernatants were analyzed for TRACP isoforms by immunoassay and PAGE. RESULTS: In RA, mean TRACP-5b activity was normal, but median total TRACP protein was increased twofold (p<0.001). In OA, TRACP-5b activity and protein were normal. In RA, TRACP-5b activity correlated weakly with ICTP (r=0.56) while TRACP protein levels correlated weakly with NTx (r=0.43). Additionally, TRACP protein, but not TRACP-5b activity correlated significantly with CRP (r=0.42). Macrophage and DC lysates contained TRACP-5b, while tissue culture supernatants contained TRACP-5a. CONCLUSIONS: Increased total TRACP protein in RA sera was probably due to TRACP-5a and not derived from osteoclasts. Rather, it could be a secreted product of inflammatory macrophages and DC.
12723978 B cells as a therapeutic target in autoimmune disease. 2003 Depleting B cells with anti-CD20 monoclonal antibodies emerges as a new therapeutic strategy in autoimmune diseases. Preliminary clinical studies suggest therapeutic benefits in patients with classic autoantibody-mediated syndromes, such as autoimmune cytopenias. Treatment responses in rheumatoid arthritis have opened the discussion about whether mechanisms beyond the removal of potentially pathogenic antibodies are effective in B-cell depletion. B cells may modulate T-cell activity through capturing and presenting antigens or may participate in the neogenesis of lymphoid microstructures that amplify and deviate immune responses. Studies exploring which mechanisms are functional in which subset of patients hold the promise of providing new and rational treatment approaches for autoimmune syndromes.
15645660 Rheumatoid arthritis complicated with acute interstitial pneumonia induced by leflunomide 2004 Dec A 49-year-old Japanese man with rheumatoid arthritis acutely developed a skin eruption and severe non-productive cough seventeen days after the administration of leflunomide. Because all bacteriology findings were negative, steroid pulse-therapy was initiated promptly due to the rapidity of chest X-ray progression and the deterioration of arterial blood oxygen pressure. Although cough was induced by methotrexate, interstitial pneumonia was not detected clinically before leflunomide administration. He finally died of respiratory failure 128 days after the onset of acute interstitial pneumonia. According to the post-market surveillance, as high as approximately 1.1% of the patients on,leflunomide have developed interstitial pneumonia in Japan. It is important to emphasize that acute interstitial pneumonia due to leflunomide is a very severe and potentially fatal side effect.