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The simultaneous pharmacokinetics of alclofenac in the plasma and synovial fluid of 10 patients with rheumatoid arthritis were studied after a single 1 g. oral dose. A gas-liquid chromatographic method was used for assaying alclofenac in both plasma and synovial fluid. Alclofenac readily appears in the plasma and synovial fluid.
OBJECTIVE: To investigate the thrombin inhibitory capacity of antithrombin III in the inflamed human joint. METHODS: Thrombin inhibitory capacity was measured, using a kinetic spectophotometric method, in matched plasma and synovial fluid samples of patients with rheumatoid arthritis (n = 22) and osteoarthritis (n = 16), together with normal control plasma samples (n = 13). In the same samples, the concentration of antithrombin III was also determined by the method of radial immunodiffusion. The combination of these measurements allowed the calculation of the specific thrombin inhibitory capacity of these samples. RESULTS: An increased concentration of antithrombin III in rheumatoid compared with osteoarthritic synovial fluid was noted (p < 0.05). However, there was a significant depression in the specific activity of antithrombin III in rheumatoid synovial fluid when compared with matched plasma samples (p < 0.001) or with osteoarthritic synovial fluid (p < 0.05). CONCLUSION: In rheumatoid synovial fluid the thrombin inhibitory capacity of antithrombin III is disproportionately depressed relative to the concentration of antithrombin III, indicating the inactivation of antithrombin III in the rheumatoid joint.
Methods have been optimised for the collection of synovial fluid and the chromatographic separation of individual kinins (bradykinin and kallidin) in the fluid by HPLC. In addition, the stability of the kinin antagonist, Hoe 140, in synovial fluid was compared with that of synthetic bradykinin. Although bradykinin was completely degraded after incubation for only 6 h in pooled synovial fluid obtained from patients with rheumatoid arthritis, Hoe 140 was stable for as long as 2 weeks under the same conditions. These studies will provide quantitative information regarding levels of kinins in inflamed joints and an insight into the therapeutic potential of kinin antagonists.
The levels of proteoglycan aggregate components (link protein, keratan sulfate epitope, and total sulfated glycosaminoglycan) were determined in the synovial fluid lavages of dogs with experimental osteoarthritis or disuse atrophy. A model of experimental osteoarthritis was created by transection of the anterior cruciate ligament of the right knee; studies were carried out 6 and 12 weeks after surgery. Joint disuse was studied at 4 and 8 weeks after initiation of the disuse. Recovery after disuse also was studied in joints that had 3 weeks of remobilization after 4 or 8 weeks of disuse. Synovial fluid lavages from the right knee joints of untreated animals were used as controls. The concentrations of keratan sulfate epitope, sulfated glycosaminoglycan, and link protein in the synovial fluid lavages at 6 and 12 weeks after transection of the anterior cruciate were elevated compared with the control values. Similar analysis of the fluid after disuse showed that the levels of keratan sulfate epitope and sulfated glycosaminoglycan were increased compared with the control levels and the levels after transection. However, the concentration of link protein in the fluid after disuse was not significantly different from the control level. The levels of keratan sulfate epitope and sulfated glycosaminoglycan in the synovial fluid lavages after disuse with recovery were high, but the levels of link protein remained low. The results indicate that the catabolism of proteoglycan aggregates in articular cartilage during early osteoarthritis and disuse is different. The determination of keratan sulfate epitope in synovial fluid lavages appears to provide a relatively general indication of proteoglycan catabolism, whereas increased levels of link protein may be more indicative of cartilage degeneration.
1 The protein binding of seven non-steroidal anti-inflammatory drugs (indomethacin, tolmetin, salicylic acid, ibuprofen, flurbiprofen, naproxen and GP53,633) and warfarin was investigated by equilibrium dialysis in simultaneous samples of synovial fluid and plasma from 12 arthritic patients. 2 The protein binding of all drugs studied except warfarin and flurbiprofen was significantly lower in synovial fluid than in plasma. 3 The decreased protein binding of these drugs is likely to explain the lower total drug concentrations found in synovial fluid in comparison to plasma. 4 The lower albumin concentration plays an important role in determination of reduced drug binding in synovial fluid compared to plasma and the fatty acid concentration in synovial fluid may also influence the protein binding of some of these drugs.
The presumed antecedent infection which precedes Reiter's syndrome and reactive arthritis is frequently across a mucosal surface, and IgA immune responses may play a role in this process. Twelve of 29 patients with these conditions demonstrated elevation in serum IgA levels, and serum IgA levels in the postdysentery group (mean 3.21 g/liter +/- 1.27) were higher (P less than 0.01) than those in the posturethritis group (mean 2.40 g/liter +/- 0.80). In 10 of the 12 patients, IgA was the only immunoglobulin increased. There was no evidence of activation of complement in serum or synovial fluid. Using a complement-dependent assay, we were unable to demonstrate circulating IgA immune complexes. Sucrose density gradient ultracentrifugation analysis was used to assess IgA immune complexes in a non-complement-dependent manner. IgA of 11s was in fact demonstrated by this technique but appeared to be polymeric IgA on the basis of specific binding of secretory component and resistance to acid dissociation. IgA rheumatoid factor was not present. Synovial fluid revealed levels of polymeric IgA higher (mean 56.7% +/- 12.9) than did serum (23.7% +/- 13.9, P less than 0.001) despite higher levels of total IgA in serum than in synovial fluid (synovial fluid:serum ratio of IgA, mean 0.53 +/- 0.11). Although elevation in serum IgA in postdysenteric arthropathies suggests mucosal acquisition of antigen, the study does not implicate IgA circulating immune complexes in the pathogenesis of these diseases.
OBJECTIVE: To determine if osteocalcin (OC) is locally produced in the joint and to study the relation between markers of bone, cartilage, and synovial tissue turnover. METHODS: The concentrations of OC, keratan sulphate epitope (5D4), and hyaluronate (HA) were measured in paired serum and synovial fluid in 10 healthy volunteers and 15 patients with osteoarthritis (OA) and 16 with rheumatoid arthritis (RA). OC was measured with a commercial immunoradiometric assay and concentrations of 5D4 and HA were measured using enzyme linked immunosorbent inhibition assays. RESULTS: Synovial fluid OC was found to be significantly lower than serum (p < 0.001) in all patients and controls. Synovial fluid OC concentrations were directly correlated with serum concentrations (r = 0.63, p < 0.001) and with age (r = 0.48, p < 0.01). There were also some relations between OC, HA, and 5D4 in patients with OA and RA. The OC concentrations were directly correlated with HA (r = 0.68, p < 0.01) in OA serum and there was a similar correlation in RA synovial fluid (r = 0.69, p < 0.01). A weak negative correlation was found between OC and 5D4 in OA serum (r = -0.55, p = 0.035) while a weak positive correlation was found in RA serum (r = 0.53, p = 0.034). CONCLUSIONS: These results show that more OC is present in the circulation than in knee joint fluids suggesting that synovial fluid OC may be derived from the blood.
Concentrations of three immunoglobulins, albumin, ceruloplasmin, alpha-2 macroglobulin and pregnancy zone protein were estimated by immunoelectrophoresis in paired samples of synovial fluid and serum from 12 dogs with degenerative joint disease (DJD) and six normal dogs. The ratios of synovial fluid to serum concentrations (SF/S) of the four non-immunoglobulins showed an almost inverse linear relationship with their molecular weight in both groups. The SF/S were higher in the DJD synovial fluid than in normal synovial fluid. The difference increased with increasing molecular weight and was highly significant for the largest molecules, reflecting an increased permeability and inflammation in the synovial membrane of DJD joints. The SF/S ratios of the three immunoglobulins studied were compared to the diffusion curves of the four non-immunoglobulins. The SF/S ratios of IgM from dogs with DJD exceeded those calculated from the molecular weights. The present observations support the concept that DJD should be considered an inflammatory disease and suggest that immunologic processes may initiate and/or sustain the inflammation.
The release of keratan sulphate (KS) bearing proteoglycan fragments from the extracellular matrix of cartilage into the synovial fluid is believed to be an early event in most joint pathologies. Quantitative analysis of KS in body fluids is therefore regarded as having a certain potential in monitoring articular cartilage catabolism. We describe the application of a non-competitive enzyme linked immunosorbent assay (ELISA) for the quantitation of KS-epitope in synovial fluids, using a monoclonal anti-KS antibody. Synovial fluids from 75 patients were analyzed, comprising the following disease groups: i) rheumatoid arthritis (n = 42), ii) osteoarthritis (n = 20), iii) gouty arthritis (n = 5), and iv) reactive arthritis (Reiter's disease, n = 8). Highest concentrations of synovial KS-epitope were found in reactive arthritis (median = 1410 ng/ml), and in gouty arthritis (median = 2105 ng/ml). However, significantly lower concentrations of KS-epitope (p less than 0.01) were observed in synovial fluids from patients with rheumatoid arthritis (median = 197 ng/ml) and osteoarthritis (median = 337 ng/ml). Although considerable variation of individual values was observed in all groups, a weak and inverse correlation between synovial levels of KS-epitope and inflammatory disease activity was seen only in patients with rheumatoid arthritis. However, KS-epitope levels did not correlate with either the synovial IL-1 activity, nor the number of synovial leucocytes.
Eight calves with suppurative arthritis were each given a single intramuscular injection of ampicillin trihydrate at a dose of 10 mg/kg. Ampicillin concentrations were measured serially in serum and in suppurative and normal synovial fluid over a 24-hour period. The mean peak serum concentration was 2.5 +/- 0.54 micrograms/ml 2 hours after injection. The highest concentration in normal synovial fluid was 3.5 +/- 0.40 micrograms/ml at 4 hours and the highest concentration in suppurative synovial fluid was 2.7 +/- 0.58 micrograms/ml at 2 hours. Overall mean ampicillin concentration in normal synovial fluid for the first 8 h (2.9 +/- 0.32 micrograms/ml) was significantly different from that in suppurative synovial fluid (2.1 +/- 0.33 micrograms/ml) and serum (1.9 +/- 0.30 micrograms/ml; p less than 0.05).
BACKGROUND: Excessive fibrin deposition within the inflamed joints of rheumatoid arthritis (RA) patients suggests that local fibrinolysis is inefficient, which seems to be in contrast with the observed increased levels of urokinase type plasminogen activator (u-PA). Thrombin-mediated inactivation of single chain u-PA (scu-PA) into an inactive form called thrombin-cleaved two chain u-PA (tcu-PA/T) may provide a possible explanation for this contradiction. AIM: To assess the occurrence of tcu-PA/T in the synovial fluid of patients with RA and with osteoarthritis (OA), and in the synovial fluid of controls to find support for thrombin-mediated inactivation of scu-PA in RA. METHODS: Levels of scu-PA and tcu-PA/T were measured in the synovial fluid of 20 RA patients, nine OA patients and 14 controls using sensitive bioimmunoassays. Total urokinase antigen was quantified by a urokinase ELISA. RESULTS: tcu-PA/T was found in the synovial fluid of all RA and OA patients. Only in seven of 14 control samples, levels of tcu-PA/T could be measured above the detection limit of the assay (0.2 ng/ml). The concentrations of tcu-PA/T, scu-PA and u-PA:Ag were significantly higher in the synovial fluid of the RA and OA patients as compared with the controls, while the RA patients had significantly higher levels of tcu-PA/T and u-PA:Ag than the OA patients. In RA, tcu-PA/T seemed to account for more than 40% of total urokinase antigen, while the contribution of tcu-PA/T to total urokinase antigen was only minor in OA and the controls (9.0% and 6.6%, respectively). CONCLUSION: A significant part of the high total urokinase antigen in the synovial fluid of RA patients can be attributed to tcu-PA/T, implying that a large amount of scu-PA is not available for fibrinolysis because of its inactivation by thrombin. Thus, thrombin may promote the inflammation process in RA by inhibiting the fibrinolytic system and preventing the removal of fibrin.
In this study we examined the reactivity of synovial fluid (SF) antibodies (Abs) from patients with rheumatoid arthritis (RA) against chondrocyte proteins. The levels of IgG, IgM and IgA in the synovial fluids varied from patient to patient, but were similar to the levels found in each individual's serum. Although the Abs in SF and serum of RA patients reacted with several molecular weight classes of chondrocyte proteins, this reactivity was very low. Synovial fluid and serum Abs from the same patients reacted with similar chondrocyte proteins and to a similar extent, suggesting that the level of Abs reactive with chondrocyte proteins is not enriched in the SF. These data demonstrate that SF from RA patients contain high levels of Abs, however, there is very little reactivity with chondrocyte proteins beyond that observed in serum of normal and RA patients.
Cytotoxic cells possess specialized granules which contain perforin and a group of serine proteinases termed granzymes. Granzyme-positive cells have been identified in synovial fluid and tissue of patients with RA, where they may play an important role as mediators of granule-mediated apoptosis, extracellular proteolysis, and cytokine induction. The aim here was to define further the involvement of cytotoxic cells in RA. Plasma and synovial fluid samples from the knee joint were obtained from 31 RA patients. The disease controls included 20 osteoarthritis (OA) patients and 10 reactive arthritis (ReA) patients. A recently developed capture ELISA was used to detect soluble granzymes A and B in all patients. Compared with OA and ReA disease controls, markedly increased levels of soluble granzymes A and B were detected in both plasma and synovial fluid of RA patients (P < 0.00001). When values for soluble granzymes A and B in plasma and synovial fluid were used simultaneously as independent variables, logistic regression analysis indicated that a diagnosis of RA could be predicted correctly in 84% of the RA patients and a diagnosis of non-RA in 90% of the controls. The markedly elevated levels of soluble granzymes A and B in plasma and synovial fluid of RA patients strongly suggest that cytotoxic cells are active participants in the pathogenesis of RA. Moreover, the results suggest that measurement of granzymes may assist the laboratory evaluation of patients with arthritis. Larger studies in patients with early disease may clarify the role of this test system in differential diagnosis.
Human synovial fluid, from a patient with synovitis disease, was examined by electron spin resonance spectroscopy for evidence of free radicals. The ascorbate free radical was observed and its intensity was affected by iron chelating agents, demonstrating that the iron in the synovial fluid is indeed available for oxidative catalysis.
OBJECTIVES: To evaluate the prognostic value of some synovial fluid variables in patients with rheumatoid arthritis. METHODS: Twenty-nine patients with erosive rheumatoid arthritis and hydropsy in a knee joint were followed for 7.5 years in a prospective study. At the start of the study the knee joints were aspirated and 15 synovial fluid variables were analyzed. The patients were divided into two groups according to whether or not there had been progress of radiologically detected destruction in the knee joints during the follow-up. RESULTS: Of the synovial fluid variables at the start, only C3 (p = 0.030) and acid phosphatase (p = 0.047) differed significantly between the groups, the former being lower and the latter higher in patients with deterioration of knee joints. CONCLUSIONS: These preliminary results may indicate that low synovial fluid C3 and high acid phosphatase predict poor prognosis in a joint affected by rheumatoid arthritis.
OBJECTIVE: To measure the levels of various cytokines, cytokine receptors, and cytokine antagonists in the synovial fluid of patients with temporomandibular disorders (TMD) and to determine the correlations among these expression levels. STUDY DESIGN: Synovial fluid was obtained from 55 patients with TMD and from 5 asymptomatic healthy volunteers as controls. The concentrations of tumor necrosis factor (TNF)-alpha, interleukin (IL)-6, IL-1beta, soluble tumor necrosis factor receptors I and II (sTNFR-I and sTNFR-II), IL-6 soluble receptor (IL-6sR), IL-1 soluble receptor type II, and IL-1 receptor antagonist were determined by enzyme-linked immunosorbent assay. RESULTS: The concentrations of TNF-alpha, IL-6, IL-1beta, sTNFR-I, and sTNFR-II were significantly higher in the synovial fluid of patients than in controls (P < .05). TNF-alpha level was positively correlated with those of IL-6, sTNFR-I, and sTNFR-II. In particular, there was a highly significant positive correlation between sTNFR-I and sTNFR-II. CONCLUSION: TNF and sTNFRs in the synovial fluid of patients with TMD may be important in the pathogenesis of these disorders.
Fibronectin is a glycoprotein found in body fluids, loose connective tissue matrix and in basement membranes. Fibronectin in rheumatoid arthritis synovial fluid was immunologically indistinguishable from the plasma form, as shown by double-diffusion analysis. Fibronectin isolated from rheumatoid synovial fluid by affinity chromatography on gelatin--Sepharose had a polypeptide pattern similar to that of plasma fibronectin in SDS--polyacrylamide gel electrophoresis. In fifty-one patients with rheumatoid arthritis and related diseases fibronectin concentrations is synovial fluid were 445 +/- 103 micrograms/ml (mean +/- SD) and within normal range, 335 +/- 52 micrograms/ml, in plasma. Immunofluorescence staining showed a prominent increase of fibronectin in the proliferating synovial connective tissue in rheumatoid arthritis as compared to normal synovial membrane. The results suggest an increased local production of fibronectin in rheumatoid synovial tissue.
Fibronectin is a high molecular weight glycoprotein from plasma and other body fluids, connective tissue matrix and basement membranes. No significant differences in the mean values of plasma fibronectin were found in patients with rheumatic diseases compared to control subjects. The fibronectin in synovial fluids in these patients presented higher levels than in plasma. No other protein from the synovial fluid presented such a peculiar behaviour. The synovial fluid fibronectin/plasma fibronectin ratio is 2.49 in patients with rheumatoid arthritis, 1.56 in those with inflammatory nonrheumatoid arthritides and 1.60 in those with osteoarthritis. Statistically significant higher values of synovial fibronectin were found in patients with rheumatoid arthritis compared to those with osteoarthritis. No significant statistical correlations were found between the synovial fibronectin concentrations and the other clinical or biological parameters of the rheumatoid arthritis patients, but for synovial fluid C3. Immunohistochemical localization of fibronectin in the rheumatoid synovium showed more intense and extended specific deposits than in the control patients. These results suggest a local synthesis of fibronectin related to the chronic inflammatory process.