[MR tomography in rheumatoid joint diseases. Demonstration of normal and proliferative hypertrophy of the synovial membrane].
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OBJECTIVE: The relation between disease severity and the known mediators of pain, inflammation, and tissue damage-prostaglandin E 2 (PGE 2 ), leukotriene B 4 (LTB 4 ), malondialdehyde (MDA), nitric oxide (NO), and myeloperoxidase (MPO)-was examined in the synovial fluid of patients with internal derangement (ID) of the temporomandibular joint (TMJ). STUDY DESIGN: Thirty-two patients with ID were classified according to Wilkes by clinical and radiological examinations, and TMJ synovial fluid samples were obtained by arthrocentesis. PGE 2 and LTB 4 levels were measured by ELISA kits, MDA levels were determined by a fluorometric method, myeloperoxidase activity was determined by an end-point method, and NO levels were measured by Griess reaction. RESULTS: The earliest significant increase was observed in NO levels (stage II) and this elevation persisted in the subsequent stages. The first significant elevation in PGE 2 and LTB 4 levels and MPO activity were observed in stage III. Both PGE 2 and LTB 4 levels were increased in stage III and were correlated with each at this stage and in the subsequent stage. Significant increases in MDA levels were observed only in stage IV. At stage IV there was correlation between MDA and PGE 2 , MDA and LTB 4 , and MDA and MPO. The relation between PGE 2 and MDA was the most powerful one. CONCLUSION: Results of this cross-sectional study point out the relation between disease severity and levels of some molecular mediators in synovial fluid of TMJ. Longitudinal studies are needed to explore the role of these molecular mediators in the progression of ID.
Activated phagocytic cells produce superoxide (O2-) and hydrogen peroxide (H2O2); their production is important in bacterial killing by neutrophils and has been implicated in tissue damage by activated phagocytes. H2O2 and O2- are poorly reactive in aqueous solution and their damaging actions may be related to formation of more reactive species from them. One such species is hydroxyl radical (OH.), formed from H2O2 in the presence of iron- or copper-ion catalysts. A major determinant of the cytotoxicity of O2- and H2O2 is thus the availability and location of metal-ion catalysts of OH. formation. Hydroxyl radical is an initiator of lipid peroxidation. Iron promoters of OH. production present in vivo include ferritin, and loosely bound iron complexes detectable by the 'bleomycin assay'. The chelating agent Desferal (desferrioxamine B methanesulphonate) prevents iron-dependent formation of OH. and protects against phagocyte-dependent tissue injury in several animal models of human disease. The use of Desferal for human treatment should be approached with caution, because preliminary results upon human rheumatoid patients have revealed side effects. It is proposed that OH. radical is a major damaging agent in the inflamed rheumatoid joint and that its formation is facilitated by the release of iron from transferrin, which can be achieved at the low pH present in the micro-environment created by adherent activated phagocytic cells. It is further proposed that one function of lactoferrin is to protect against iron-dependent radical reactions rather than to act as a catalyst of OH. production.
OBJECTIVE: To describe the typical sites of stress fractures in the lower extremities and pelvis in rheumatoid patients (rheumatoid arthritis, juvenile chronic arthritis, psoriatic arthritis, ankylosing spondylitis). METHODS: Thirty-three patients with 52 stress fractures [mean age 44 years (range 11-73)] were studied at the authors' institution when they were being treated for their rheumatic diseases. Fourteen patients had RA, 9 JCA, 5 PsoA, and 5 SPA. Stress fractures were detected from patient documents and from series radiographs in suspected cases. In some cases magnetic resonance imaging was also performed. RESULTS: One patient presented with 5 fractures, 2 patients with 4 and 3 fractures, and 7 patients with 2 fractures each. Other patients (n = 19) had only one fracture each. The metatarsal (MT) bones were the most common site of involvement. Twenty-five of the 52 fractures were located on MT I-V. The second and third most common sites were thefibula (n = 13) and tibia (n = 6). All fractures of the lower tibia or fibula were associated with valgus malalignment of the ankle. CONCLUSION: If a patient with rheumatic disease experiences sudden and unexplained pain localised in the forefoot, above the ankle, below the knee, or in the pelvis, a stress fracture should be suspected. Patients with severe osteoporosis, high-load corticosteroid or methotrexate therapy, or marked joint deformity are at high risk of developing stress fracture.
We have focused on several features somewhat unique to OA which require special attention relative to clinical trials. These include disease classification, for which the schema in Table 1 was developed, patient selection and admission criteria, and the choice of appropriate clinical outcome parameters. We suggest the following: That future trials be limited to patients with idiopathic OA with specified joint groups involved. That pain, assessed with a visual analogue scale, and both the patient's and investigator's global assessment be the primary clinical outcome variables to be analysed. That concomitant analgesic agents not be used during anti-inflammatory drug trials to prevent confounding pain relief as an outcome variable. That future, long-term studies use validated health status measures to assess functional outcomes.
Clinical and radiographic assessment of the spine was carried out in 75 patients with osteoarthrosis (OA) of the hip and in 75 controls without hip disease. Radiographic degenerative changes in the spine were more frequent in the patients with OA hips, occurring in both the dorsal and lumbar spine. Moderate or severe changes were found in the dorsal spine in 29 patients with OA hips (compared with 12 controls), and in the lumbar spine in 32 patients with OA hips (compared with 10 controls).
Cell-free synovial fluid from patients with rheumatoid arthritis stimulated the NADPH oxidase activity in human neutrophils, which reached a peak 15-20 min after addition. Insoluble immunoglobulin aggregates isolated from these fluids activated a similar pattern of oxidase activity. However, when synovial fluid was added to neutrophil suspensions which had been previously exposed to granulocyte-macrophage colony-stimulating factor, the stimulated oxidase activity was biphasic, in that an additional transient activity was observed which reached a peak within 5 min of addition. The additional neutrophil-stimulating activity could not be sedimented by centrifugation at 330,000 g-min, and only activated oxidase activity in neutrophils which had previously been primed. The neutrophil-stimulating activity in this soluble fraction was removed by Protein A affinity chromatography, and activity was recovered in eluates from this column. Thus activity in this soluble fraction from synovial fluid is attributed to the presence of soluble immunoglobulin aggregates. Whereas oxidase activity stimulated by the isoluble immunoglobulin aggregates was inhibited by staurosporine (and hence largely dependent on the activity of protein kinase C), the activity stimulated by the soluble immunoglobulin aggregates was staurosporine-insensitive. The soluble immunoglobulin aggregates were present at significantly higher levels in synovial fluids from patients with rheumatoid arthritis compared with those from other joint arthropathies. Thus rheumatoid synovial fluids possess heterogeneous immunoglobulin aggregates which activate neutrophils via distinct molecular pathways. As neutrophils within rheumatoid joints are primed, the soluble immunoglobulin aggregates are likely to be of importance in disease pathology.
The rheological properties of synovial fluids from patients with different rheumatic diseases are discussed. Viscosities of 73 samples were determined and are compared to a standard of "healthy" human synovial fluid p. m. and to bovine synovia. Typical differences between "healthy", degenerative and inflammatory synovial fluids could be discerned. These differences can be characterized with several rheological parameters. The mechanism of lubrication in joints and the role of synovial fluid as a lubricant are discussed. Rheological properties of polymere solutions which could serve as a substitute for sick synovial fluids are described and compared to the properties of healthy synovia. Several possibilities for molecular changes which could account for the deterioration of synovial fluids in patients with different rheumatic diseases are discussed.
Oxidatively modified low density lipoprotein (LDL) has many biological activities which could contribute to the pathology of the atherosclerotic lesion. Because atherosclerosis has an inflammatory component, there has been much interest in the extent to which LDL could be oxidatively modified in vivo by inflammation. The present study examined LDL present in an accessible inflammatory site, the inflamed synovial joint, for evidence of compositional change and oxidative modification. LDL was isolated from knee joint synovial fluid (SF) from subjects with inflammatory arthropathies and also from matched plasma samples. SF and plasma LDL had similar free cholesterol and alpha-tocopherol content, but SF LDL had a lower content of esterified cholesterol. On electrophoresis, SF LDL was slightly more electronegative than LDL from matched plasma samples, but the changes were much less than those resulting from Cu2+-treatment of LDL. Oxidized cholesterol was not detected in any samples, but cholesterol ester hydroperoxide levels were greater in SF than in plasma LDL. When samples from three subjects were incubated with macrophages, the SF LDL did not cause significant loading of the cells with cholesterol or cholesterol esters, in contrast to the situation with acetylated LDL. Overall, the SF LDL displayed evidence of slightly increased oxidation by comparison with matched plasma samples. Despite their isolation from an environment with active inflammation, changes were modest compared with those resulting from Cu2+ treatment. Thus, extensive LDL oxidation is not a necessary correlate of location in a chronic inflammatory site, even though it is characteristic of atherosclerotic lesions.
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Hyaluronic acid is a naturally occurring polysaccharide with distinct physicochemical properties which underlie its application as a viscoelastic tool in ophthalmological surgery. In cataract surgery the role of hyaluronic acid in facilitating procedures and protecting the corneal endothelium is well established. Some benefit has also been gained with the use of hyaluronic acid in penetrating keratoplasty, trabeculectomy, retinal reattachment and trauma surgery, although its efficacy in these indications is less well-defined in the published literature. In addition to its lubricating and cushioning properties, demonstration of some in vitro anti-inflammatory activity and a possible disease-modifying effect for hyaluronic acid in animals has prompted its investigation as a treatment in osteoarthritis and, to a much lesser extent, in rheumatoid arthritis. Hyaluronic acid 20 mg, as weekly intra-articular injections for 3 to 7 weeks, improved knee pain and joint motion in patients with osteoarthritis. Although this occurred to a greater degree than with placebo in most comparisons, the effects of hyaluronic acid was similar to those of placebo in the largest trial. In the few available comparisons with other agents, hyaluronic acid appeared equivalent to methylprednisolone 40 mg (for 3 weeks) and to a single injection of triamcinolone 40 mg. Hyaluronic acid was distinguished from other therapies by providing a sustained effect after treatment discontinuation. Together with its very good tolerability profile, these properties justify further study of hyaluronic acid in patients with osteoarthritis. Some limited evidence of improvement in patients with rheumatoid arthritis, and a possible healing effect of hyaluronic acid on tympanic membrane perforations, represent additional areas of interest for future investigation. In summary, hyaluronic acid is a well-established adjunct to cataract surgery and may prove to be a promising option in the treatment of patients with osteoarthritis. Its very good tolerability provides further impetus for examination of its potential role in an extended scope of arthritic and ophthalmological indications, and in wound healing.
Twenty patients with rheumatoid gonarthritis were examined in a NMR tomograph with a 0.2 tesla resistive magnet. Synovial effusions were seen in 18 cases and thickening of the synovium in 15 cases. Discrimination between synovial fluid and synovium was gained by different NMR signals from various spin-echo sequences. In demonstrating a thickened synovium NMR tomography enables the depiction of inflammation inside the joint in earlier stages of illness than is possible with bone erosion detection from X-ray photographs.
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In a survey of the general population the presence or absence of osteoarthrosis of the hand was determined radiologically in 685 adults (300 males and 385 females). Of these, 261 (124 males and 137 females), chosen randomly, were given a complete clinical examination of the musculoskeletal system which included x-ray of joints elsewhere in the body. Osteoarthrosis (OA) scores for the hand and for all body sites were computed for each subject by summing the number of affected joints. For all subjects soical class, height, weight, total serum protein, serum uric acid, haemoglobin, antistreptolysin O, (ASO), C-reactive protein (CRP), and rheumatoid factor were also measured. Analyses were carried out by simple comparison of means and by calculating multiple regressions and correlations.
NO is an essential cytotoxic agent in host defense, yet can be autotoxic if overproduced, as evidenced in inflammatory lesions and tissue destruction in experimental arthritis models. Treatment of streptococcal cell wal1-induced arthritis in rats with N:(G)-monomethyl-L-arginine (L-NMMA), a competitive nonspecific inhibitor of both constitutive and inducible isoforms of NO synthase (NOS), prevents intraarticular accumulation of leukocytes, joint swelling, and bone erosion. Because increased inducible NOS (iNOS) expression and NO generation are associated with pathogenesis of chronic inflammation, we investigated whether a selective inhibitor of iNOS, N:-iminoethyl-L-lysine (L-NIL), would have more directed anti-arthritic properties. Whereas both L-NMMA and L-NIL inhibited nitrite production by streptococcal cell wall-stimulated rat mononuclear cells in vitro and systemic treatment of arthritic rats with L-NMMA ablated synovitis, surprisingly L-NIL did not mediate resolution of inflammatory joint lesions. On the contrary, daily administration of L-NIL failed to reduce the acute response and exacerbated the chronic inflammatory response, as reflected by profound tissue destruction and loss of bone and cartilage. Although the number of iNOS-positive cells within the synovium decreased after treatment with L-NIL, immunohistochemical analyses revealed a distinct pattern of endothelial and neuronal NOS expression in the arthritic synovium that was unaffected by the isoform-specific L-NIL treatment. These studies uncover a contribution of the constitutive isoforms of NOS to the evolution of acute and chronic inflammation pathology which may be important in the design of therapeutic agents.