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PubMed1999

Pharmacokinetics of nonsteroidal anti-inflammatory drugs in synovial fluid.

The major site of action for nonsteroidal anti-inflammatory drugs (NSAIDs) in the treatment of rheumatic diseases is probably within the synovial compartment. There has been little work on the disposition of NSAIDs in the synovium and most studies have involved the measurement of their concentrations in synovial fluid. The concentrations of NSAIDs are more sustained in synovial fluid than in plasma, the difference being particularly noted with NSAIDs with short elimination half-lives. The more sustained concentrations may contribute to the prolonged effect of the short half-life NSAIDs, which are usually administered at intervals longer than their half-lives in plasma. The most widely used method of kinetic analysis of NSAIDs in synovial fluid is a compartmental model in which synovial fluid is a peripheral compartment of distribution of the drug. Repeated samples of synovial fluid from individual patients are difficult to collect, but even 1 sample of synovial fluid and plasma from each patient can provide useful data when analysed using the population approach to pharmacokinetic analysis. According to the compartmental model, the mean half-lives of efflux of the NSAIDs from synovial fluid range from 1.5 to 7 hours. The mean partition coefficient of most NSAIDs between synovial fluid and plasma is approximately 0.6. The NSAIDs are highly protein-bound, and the lower mean concentrations in synovial fluid are largely because of the lower concentrations of the binding protein, albumin. The NSAIDs diffuse into and out of synovial fluid in their unbound forms, but there is some diffusion in the protein-bound forms, particularly out of synovial fluid. The mean rates of diffusion of NSAIDs into and out of skin blisters in humans are similar to the rates of influx and efflux in the synovial fluid of the knee, but there is considerable variation between the pharmacokinetics of transfer at the 2 sites in individual patients. NSAIDs decrease the synthesis of prostaglandins in synovial fluid, but there are few data on the relationship between the kinetics of NSAIDs in synovial fluid and the effects on prostaglandin synthesis.

Animals↗

PubMed1991

[Ferrographic analysis of synovial fluid in total hip replacement].

A synovial fluid analysis was carried out on 84 patients with total hip replacements, 53 of which were revision cases. The analysis was done using ferrography. An animal study was carried out whereby alumina ceramic, polyethylene and polymethyl methacrylate particles were inserted into the knees of rabbits, the synovial fluid of which was analysed. In addition, the synovium and surrounding tissues were histologically analysed. One week after insertion of the particulate debris only a few particles were noted in the synovial fluid and none at two weeks post insertion. However, these particles were noted in the synovium and surrounding tissues. Therefore, it was concluded that wear particles, following total hip replacement, may be encapsulated in the early period by the capsule and synovium, and have no adverse affect on the lubricating kinetics of the joint. It is postulated that the difference in tissue reaction to each of these particles may be responsible for the subsequent loosening.

Aluminum Oxide↗

PubMed1985

Synovial fluid ferritin in rheumatic diseases.

The synovial fluid ferritin level in 49 patients (57 joints) with various rheumatic diseases was analysed. In rheumatoid arthritis (n = 22) the geometric mean ferritin level was 528 micrograms/l (range 56-3 100 micrograms/l), in other inflammatory arthritides (n = 12) 339 micrograms/l (105-2 835 micrograms/l) (p greater than 0.5), in calcium pyrophosphate arthropathy (n = 14) 507 micrograms/l (180-4 230 micrograms/l) (p greater than 0.5) and in non-inflammatory osteoarthritis (n = 9) 167 micrograms/l (14-725 micrograms/l) (p less than 0.05). Synovial fluid/serum ferritin ratios did not differ significantly in the four diagnostic groups; 4 patients had ratios less than 1.0. Synovial fluid ferritin was not correlated to total fluid cell count or differential cell count. Although ferritin content was significantly greater in inflammatory than in noninflammatory fluid (p less than 0.05), the wide scatter of the values and marked overlap between the different groups limit the value of measuring synovial fluid ferritin as a differential diagnostic test for rheumatic diseases.

Arthritis, Rheumatoid↗

PubMed1995

Even low-grade synovitis significantly accelerates the clearance of protein from the canine knee. Implications for measurement of synovial fluid "markers" of osteoarthritis.

OBJECTIVE: In recent studies, the synovial fluid concentration of molecules derived from the extracellular matrix of articular cartilage has been used to deduce the magnitude of cartilage destruction or repair in osteoarthritic (OA) joints. Because low-grade synovitis is often present in such joints, we assessed the effect of synovial inflammation on the clearance of a prototypical protein, albumin, from synovial fluid. METHODS: 131I-labeled albumin (RISA) was injected into 1 (control) knee of each of 14 dogs. The concentration of RISA in synovial fluid aspirated 7 hours after the injection and serial measurements of surface radioactivity were used to calculate the volume of distribution (Vd) and clearance of RISA. One week later, synovitis was induced in the contralateral knee by intraarticular injection of various quantities of calcium pyrophosphate dihydrate (CPPD) crystals, after which RISA was injected into that joint and these measurements were repeated. RESULTS: Intraarticular injection of 500 micrograms of CPPD crystals produced intense synovitis, with a mean synovial fluid white blood cell (WBC) count of 43,200 cells/mm3, and values for RISA Vd and RISA clearance (36.5 ml and 33.7 microliters/minute) were much higher than those for saline-injected control knees (2.7 ml and 1.5 microliters/minute, respectively). Injection of 0.5 microgram of CPPD also produced marked synovitis and values for Vd and RISA clearance that were 2-3-fold greater than those in the contralateral knee. The low-grade synovitis produced by only 0.05 microgram of CPPD, which resulted in synovial fluid WBC counts as low as 1,000-2,000 cells/mm3, was accompanied by increases in the clearance and Vd of RISA to levels approximately 40% and approximately 80% higher, respectively, than those for the contralateral knee. CONCLUSION: Even mild synovitis, as seen in OA, may significantly increase the clearance of a protein from the joint. Synovitis is a significant variable which must be considered in studies of putative chondroprotective drugs if conclusions about the effects of drugs on cartilage metabolism are to be drawn from changes in the synovial fluid concentration of a "marker" protein.

Albumins↗

PubMed1979

An investigation into the validity of subatmospheric pressure recordings from synovial fluid and their dependence on joint angle.

1. Synovial fluid hydrostatic pressures were measured in normal knee (stifle) joints of anaesthetized rabbits using perforated cannulae. Pressures were subatmospheric in seventy out of seventy-two joints, with a mean value of -4.6 cm H2O (range 0 to -12 cm H2O) at joint angles of 120--150 degrees. 2. Similar values were obtained by a wick-in-needle technique (mean -4.0 cm H2O), which along with several other tests indicated that the subatmospheric values were not artifactual. 3. A slow rise in pressure of 1--2 cm H2O per hour in the motionless joint was attributed to a net filtration of fluid into the joint space. 4. Pressure increased as a curvilinear function of joint angle when the joint was flexed passively, the slope of the relationship depending on synovial fluid volume. Pressure also increased on active flexion of the joint, or on passively increasing the tension of soft peri-articular tissues. 5. Positive (above atmospheric) pressures in acutely flexed joints declined with time. Pressures declined less rapidly when synovial fluid was replaced by nonabsorbable paraffin oil. It was concluded that joint fluid can be absorbed by the synovium during acute flexion. 6. Processes which might generate subatmospheric pressures are discussed. The hypothesis is advanced that the flexion-dependent 'trans-synovial pump', possibly in series with a lymphatic pump, may account for the maintenance of a small synovial fluid volume and subatmospheric pressure in the face of a net filtration of fluid from synovial capillaries into the joint space.

Animals↗

PubMed2001

Measurement of cartilage oligomeric matrix protein (COMP) in normal and diseased equine synovial fluids.

OBJECTIVE: This study was designed to assay cartilage oligomeric matrix protein (COMP) in equine synovial fluids and to compare the concentration in synovial fluids from normal horses with joint diseased horses. The relationship between the COMP degradation and the matrix metalloproteinase activity in synovial fluids was also investigated. DESIGN: Using COMP antigen prepared from equine articular cartilage and murine monoclonal antibody (12C4) raised against human COMP, an inhibition ELISA was developed. COMP in equine synovial fluids from normal and diseased joints was quantified. Metalloproteinase activities were evaluated in the same synovial fluids by a gelatin degradation ELISA. COMP fragments were evaluated qualitatively by Western blotting. RESULTS: The COMP inhibition ELISA was reliable at concentrations of equine COMP between 62.5 and 2000 ng/ml. COMP values in joint fluids in both aseptic and septic joint disease (19.7+/-15.3 and 16.1+/-11.2 microg/ml, respectively) were significantly (P < 0.001) lower than normal (53.2+/-29.0 microg/ml). The molecular sizes of COMP on immunoblots were different between normal and diseased synovial fluids; more fragments were seen in diseased fluids. The aseptic (26.6 +/- 20.6%) and septic joint disease synovial fluids (36.1 +/- 37.5%) had significantly higher (P < 0.02 and 0.002, respectively) gelatinolytic activities than normal (13.6 +/- 13.7%). There was a negative correlation (R = -0.31, P < 0.002) between COMP level and gelatinase activity. Conclusions We conclude that the fragment pattern and the absolute COMP concentration maybe useful for monitoring joint disease, and that COMP degradation in synovial fluids from progressed joint disease may be due to MMP gelatinolytic activity.

Animals↗

PubMed1985

A pharmacokinetic comparison of tenoxicam in plasma and synovial fluid.

In view of the paucity of information on the synovial-fluid pharmacokinetics of nonsteroidal anti-inflammatory drugs with a long half-life, we have compared the pharmacokinetics of tenoxicam (Tilcotil, Mobiflex) in plasma and synovial fluid in six patients with polyarthritis causing knee effusion. Plasma and synovial-fluid concentrations of tenoxicam were measured up to 96 h after an oral dose of a single 40 mg tablet. A full pharmacokinetic analysis was performed. Tenoxicam passed into synovial fluid attaining a peak concentration significantly later than that for plasma. However, the mean half-life for synovial fluid (45 h) was not significantly different from that for plasma (42 h). Comparison of area under the curve (AUC) indicated the total exposure of the synovial fluid to tenoxicam was consistent in different patients, comprising 50-60% of the corresponding plasma levels in every case. In the case of tenoxicam, synovial fluid exhibits the pharmacokinetic properties of a peripheral 'tissue' compartment.

Adult↗

PubMed1988

Stereoselective disposition of ibuprofen enantiomers in synovial fluid.

The simultaneous disposition of the enantiomers of ibuprofen in synovial fluid and plasma was studied in eight patients with arthritis. Concentrations of the active S-enantiomer in synovial fluid exceeded those of the R-enantiomer at all times in all patients with the ratio of S to R concentrations being 2.1 +/- 0.3 (mean +/- SE). Synovial fluid concentrations fluctuated much less than in plasma and exceeded plasma concentrations from 5.4 +/- 0.3 hours for R-ibuprofen and 5.5 +/- 0.6 hours for S-ibuprofen. Pharmacokinetic analysis suggested that, although the enantiomers diffuse into synovial fluid primarily in the unbound form, there may be significant diffusion of the enantiomers out of synovial fluid in the protein-bound form in some patients. Interpatient differences in the disposition of the enantiomers of ibuprofen in synovial fluid were evident and may contribute to the interindividual variability in response to treatment with ibuprofen.

Female↗

PubMed2001

Use of two-dimensional gel electrophoresis to measure changes in synovial fluid proteins from patients with rheumatoid arthritis treated with antibody to CD4.

Synovial fluid proteins from microliter volumes of synovial fluid were resolved by two-dimensional polyacrylamide gel electrophoresis and detected by silver staining to investigate the feasibility of using two-dimensional (2D) electrophoresis in the clinical research setting and provide global disease information of disease progression. Several hundred proteins could be resolved as spots, many of which displayed the characteristic pattern of plasma-derived glycoproteins. The lowest level of detection was approximately 0.2 ng from a total of 50 microg of protein loaded. Most of the proteins could be identified on the basis of pI and molecular weight when compared with plasma protein maps on the World Wide Web. Unknown proteins were characterized by mass spectrometry of tryptic digests and by comparison with peptide databases. Synovial fluids from patients with rheumatoid arthritis were analyzed using this technique. Each subject received a fixed dose of antibody to CD4 as part of a phase II clinical trial to determine the efficacy of this immunosuppressive treatment in modifying disease activity. Synovial fluid was removed at day 0, followed by administration of antibody. Subsequent removal of synovial fluid and additional administration of antibody were carried out at different times thereafter. Changes in levels of acute-phase proteins were quantified by densitometry of silver-stained 2D polyacrylamide gels. Other parameters of disease progression such as serum C-reactive protein and physician's global assessment of clinical condition were used for comparison. In this way, changes in acute-phase proteins towards normal levels, as measured by 2D polyacrylamide gel electrophoresis, could be correlated with clinical improvement and conventional clinical chemistry measurements. Thus, the system can be used for quantitative analysis of protein expression in sites of autoimmune disease activity such as the synovial fluid of rheumatoid arthritis patients.

Acute-Phase Proteins↗

PubMedDate not supplied

Detection of collagenase-activity in RA synovial fluids using soluble 14C-labelled collagen.

14 RA synovial fluids and 7 non-RA synovial fluids were investigated as to their collagenase-activity using 14C-labelled type I human collagen in soluble form. Breakdown products were fractionated by gel filtration on Sephadex G 200 superfine. Cleavage of native and denatured labelled collagen was compared. 11 RA synovial fluids showed significant collagenase activity as manifested by degradation of native collagen, while only one synovial fluid of the control group displayed a significant collagenolytic activity. Results were compared with cleavage of reconstituted collagen fibrils. Influence of EDTA and KSCN on collagen degradation was also studied: EDTA completely blocked degradation of native or denatured collagen, while KSCN caused an increase of collagenolytic activity in two cases.

Arthritis, Rheumatoid↗

PubMed1999

Salmonella-triggered reactive arthritis: use of polymerase chain reaction, immunocytochemical staining, and gas chromatography-mass spectrometry in the detection of bacterial components from synovial fluid.

OBJECTIVE: To investigate whether microbial components are present in the cells of synovial fluid or peripheral blood from patients with Salmonella-triggered reactive arthritis (ReA). METHODS: Synovial fluid cells and/or peripheral blood cells from 23 patients with Salmonella-triggered ReA and from 19 control patients with newly diagnosed rheumatoid arthritis were studied using 3 different polymerase chain reaction (PCR) techniques and immunocytochemical staining. Muramic acid from the synovial fluid was studied by gas chromatography-mass spectrometry. RESULTS: Salmonella chromosomal DNA was not detectable in the synovial fluid cells and peripheral blood leukocytes of patients with Salmonella ReA. Initially, positive reactions were observed in the synovial fluid cells and peripheral blood leukocytes of 3 of 17 and 3 of 18 patients with ReA, respectively, but in the subsequent PCR studies, these findings were not reproducible. Salmonella-specific antigen was detectable by immunofluorescence in the synovial fluid cells and peripheral blood leukocytes of 4 of 11 and 2 of 7 patients with ReA, respectively. Muramic acid was present in 2 of 15 synovial fluid samples from patients with ReA, but the bacterial cultures from synovial fluid were negative. CONCLUSION: These findings indicate the presence of bacterial degradation products, but not bacterial DNA, in the inflamed joints of patients with Salmonella-triggered ReA.

Adolescent↗

PubMed1989

Yersinia antigens in synovial-fluid cells from patients with reactive arthritis.

We examined synovial-fluid cells from 15 patients with reactive arthritis after yersinia infection for the presence of yersinia antigens. Extensive bacterial cultures of the synovial fluid were negative. All the samples were studied by immunofluorescence with use of a rabbit antiserum to Yersinia enterocolitica O:3 and a monoclonal antibody to Y. enterocolitica O:3 lipopolysaccharide. Synovial-fluid cells from 41 patients with other rheumatic diseases served as controls. Synovial-fluid cells from 10 patients with reactive arthritis after yersinia infection stained positively on immunofluorescence; rabbit antiserum and the monoclonal antibody yielded similar results. In most patients the percentage of positive cells ranged from 1 to 10 percent, but in one patient nearly all the cells in the sample stained strongly. Most of the positively stained cells were polymorphonuclear leukocytes, but yersinia antigens were also found in mononuclear phagocytes. All the control samples were negative. Synovial-fluid cell deposits from nine patients were also studied by Western blotting with use of the same antibodies. The results were positive in six of the nine cell deposits from patients with reactive arthritis and in none of the 10 cell deposits from control patients with rheumatoid arthritis. We conclude that in patients with reactive arthritis after yersinia infection, microbial antigens can be found in synovial-fluid cells from the affected joints.

Adult↗

PubMed1999

Polyethylene particle morphology in synovial fluid of failed knee arthroplasty.

Synovial fluid from the knees of 16 patients undergoing revision knee arthroplasty for aseptic failure was subjected to base digestion and ultrafiltration. Filtered particles were scanned using scanning electron microscopy and analyzed with an image program. Polyethylene particles were identified visually and confirmed with the use of electron diffraction spectroscopy. Averaging more than 1500 particles per patient sample, 25,148 particles were analyzed. This corresponded to a concentration of 3000 polyethylene particles per milliliter of synovial fluid. Three populations of wear debris were identified in the fluid. Small globular particles with a mean area of 75 mu 2 represented 94% of all particles observed. The particles averaged 10 mu in diameter and often were seen in clumps. Long fibrous particles with a mean area of 1164 mu 2 made up 4% of the particle population. Large rhomboidal particles with an area of 557 mu 2 were observed least commonly and comprised the remainder of the particles visualized. All three particle types were observed in each fluid sample regardless of the wear pattern of the retrieved polyethylene liner. There were no differences in absolute particle counts, particle morphologic characteristics, or particle size between patients with and without gross polyethylene wear.

Aged↗

PubMed1981

Identification and functional characterization of monocytes in rheumatoid synovial fluid.

Mononuclear cell suspension from synovial fluids of 13 patients with rheumatoid arthritis and 5 patients with juvenile rheumatoid arthritis contained on average of 1.5 and 1.3% cytotoxic plaque-forming cells, respectively, when tested against a monolayer of antibody-sensitized sheep erythrocytes. The plaque-forming ability was completely abolished after removal of cells which had phagocytosed carbonyl iron. The highest proportion of plaque-forming cells was found in the cell suspensions that contained the highest percentage of peroxidase-positive mononuclear cells. The plaque-forming activity was almost completely inhibited by human IgG. Cell suspensions from patients treated with corticosteroids contained the highest proportions of plaque-forming cells and peroxidase-positive mononuclear cells compared with patients not receiving such treatment. Our findings indicate that the plaque-forming leukocytes in rheumatoid synovial fluid are monocytes.

Adrenal Cortex Hormones↗

PubMed1991

Biased T cell receptor V alpha region repertoire in the synovial fluid of rheumatoid arthritis patients.

Synovial T lymphocytes seem to contribute to the pathogenesis of rheumatoid arthritis (RA). Since very little is known about the structural heterogeneity of their T cell antigen receptors (TcR), we analyzed TcR alpha chain mRNA of synovial fluid T cells from two RA patients. TcR alpha chain cDNA was amplified by the polymerase chain reaction with single-sided specificity for the alpha chain constant (C alpha) gene segment, and the nucleotide sequences of 51 functionally rearranged cDNA clones were determined. Twenty different V alpha genes and 26 different J alpha gene segments were utilized in these cDNA clones. Three of the V alpha gene segments which are frequently (8%-17% total) expressed in synovial fluid T cells have rarely been found in the TcR repertoire of peripheral blood T cells from healthy individuals. The T cell responses in the rheumatic synovia analyzed here are not oligoclonal, but the usage of TcR V alpha genes is biased.

Antibody Diversity↗

PubMed1992

The contents of macromolecule solutes in flexor tendon sheath fluid and their relation to synovial fluid. A quantitative analysis.

The importance of synovial environment for minimal adhesion formation in flexor tendon healing has recently gained attention. Various techniques have been used to restore an injured synovial tendon sheath. Therefore a quantitative analysis of flexor tendon sheath fluid is of interest to increase our knowledge about the specific synovial milieu and to evaluate the success of different types of sheath reconstructions from a biochemical point of view. Samples of tendon sheath fluid from trigger digits and tendon sheaths containing ganglions have been assayed for contents of hyaluronic acid and proteins of different molecular weights. The results show concentrations of hyaluronate and several proteins similar to those in normal joint fluid. These results indicate that flexor tendon sheath fluid has a character similar to synovial fluid of joints and apparently has specific functions such as soft tissue lubrication and nutrition of avascular tendon tissue.

Adult↗

PubMed1983

The effect of rheumatoid synovial fluid macrophages on DNA, glycosaminoglycan and collagen synthesis by synovial fibroblasts.

The effects of soluble factors secreted by peripheral blood monocytes and rheumatoid synovial fluid macrophages were tested on human synovial fibroblast cultures. Both monocytes and macrophages liberated factors which reduced DNA synthesis (3H-thymidine incorporation) by synovial fibroblasts. Monocyte and macrophage factors stimulated hyaluronic acid synthesis. The activation obtained with rheumatoid synovial macrophages was considerably greater than that with monocytes. Foetal bovine serum was found to have a clear stimulatory effect on the synthesis of collagen and other proteins by fibroblasts. The effects of monocyte and macrophage factors on protein synthesis in synovial fibroblasts were small: collagen synthesis was slightly increased relative to other extracellular proteins.

Arthritis, Rheumatoid↗

PubMed1996

Demonstration of interleukin-1beta and interleukin-6 in cells of synovial fluids by flow cytometry.

Cytokine levels are increased in the synovial fluid of affected joints from patients with inflammatory joint diseases. The aim of our study was therefore to determine if and to what extent immmunologically defined subpopulations of mononuclear cells (MNC) in the synovial fluid are responsible for the increased levels of interleukin-1beta (IL-1beta) and interleukin-6 (IL-6) in affected joints. Lipopolysaccharide (LPS) stimulated peripheral MNC were used as positive controls. While soluble IL-1beta (median 167 pg/ml) and IL-6 (median 508 pg/ml) levels were significantly elevated in the synovial fluids tested, IL-1beta and IL-6 were demonstrated by flow cytometry in only a small subpopulation (<=11%) of mononuclear synovial fluid cells in 7/13 patients. Our results suggest that elevated IL-1beta and IL-6 levels in the synovial fluid of inflammatory joints are derived mainly from cells in the synovial membrane and only to a minor extent from cells in the synovial fluid itself.

Arthritis, Reactive↗