[Show abstract][Hide abstract] ABSTRACT: To elucidate the involvement of telomerase activity in the pathogenesis of rheumatoid arthritis (RA) and pigmented villonodular synovitis (PVS).
Peripheral blood lymphocytes (PBL), synovial infiltrating lymphocytes, and synoviocytes were isolated from peripheral blood samples and synovial tissue obtained from 18 patients with RA, 9 with PVS, 12 with osteoarthritis (OA), and 10 with knee joint trauma. Cellular telomerase activity was measured by the telomeric repeat amplification protocol assay. In RA patients, the telomerase activity level in synovial infiltrating lymphocytes was assessed for correlations with histologic features in rheumatoid synovium.
A high level of telomerase activity was detected in the PBL and synovial infiltrating lymphocytes from RA patients and in the synoviocytes from PVS patients, whereas the enzyme activity was expressed at a low-to-borderline level in the PBL and synovial lymphocytes from OA, PVS, and trauma patients and was absent in the synoviocytes from RA as well as OA and trauma patients. In RA patients, the telomerase activity level in synovial infiltrating lymphocytes was significantly correlated with the intensity of synovial lining hyperplasia, microvessel proliferation, lymphocyte infiltration, and percentage of synovial cells positive for proliferating cell nuclear antigen in rheumatoid synovium.
Telomerase activation in lymphocytes may provide insights into the progression of synovitis and synovial proliferation in RA. Moreover, the enzyme may be implicated in the proliferation of synoviocytes in PVS.
[Show abstract][Hide abstract] ABSTRACT: The effect of recombinant human erythropoietin (rHuEPO) treatment on autologous blood donation was evaluated in anaemic patients with rheumatoid arthritis (RA) undergoing total joint replacement surgery.
A total of 56 total knee or hip joint replacement operations were performed in the knee or hip joint in 36 anaemic RA patients (hemoglobin (Hb) concentration < 11.0 g/dl]. All of the patients received intravenous rHuEPO at a dose of 100-200 units/kg body weight three times a week for 3 weeks. An autologous blood donation of 800-1200 g was the goal for each patient. A refractory case was defined as a patient whose Hb level did not increase to 10.0 g/dl after 3 weeks of treatment with rHuEPO. The objective signs of arthritis were assessed by the Lansbury activity index (AI). During the treatment period, the patients underwent weekly hematological analyses, including routine hematology, serum iron, serum ferritin, C-reactive protein (CRP), and serum erythropoietin levels.
The response to rHuEPO treatment was determined, and blood donation was possible in 47 of 56 joint replacements. In the other 9 operations, donation was not possible due to a poor response to rHuEPO. The mean Hb level before treatment in the refractory group (8.3 g/dl) was significantly lower than that in the responsive group (10.4 g/dl, p = 0.0002). During the treatment period, the mean erythropoietin level was above the normal limit in the refractory group. The mean AI for the refractory group tended to be lower than that in the responsive group. The mean pre-treatment CRP (6.4 mg/dl) and erythrocyte sedimentation rate (ESR) (87.1 mm/h) levels in the refractory group were significantly higher than those in the responsive group (CRP: 3.2 mg/dl, p = 0.008, ESR: 52.6 mm/h, p = 0.01).
The control of disease activity prior to rHuEPO treatment is considered to a prerequisite for autologous blood donation. In addition, severe anaemia (Hb concentration < 8.0 g/dl) appears to be another risk factor for refractoriness to rHuEPO treatment with the present protocol. A higher rHuEPO dose (> 200 units/kg/3 times a week for three weeks) was considered to be necessary in the refractory group.
No preview · Article · Jan 1999 · Clinical and experimental rheumatology
[Show abstract][Hide abstract] ABSTRACT: To examine the effect of anti-reshaping human interleukin-6 receptor monoclonal antibody (anti-rsHuIL-6R mAb) on patients with rheumatoid arthritis (RA), using SCID mice in which human RA synovial tissue has been grafted (SCID-HuRAg).
Tissue from human RA pannus was implanted subcutaneously in the backs of 69 SCID mice. Differences from human RA were examined pathologically. Anti-rsHuIL-6R mAb (100 microg) was administered intraperitoneally to mice once a week for 4 weeks. The implanted tissue was removed from the SCID-HuRAg mice on the fifth week after the initial treatment and examined pathologically. A group of SCID-HuRAg mice treated with control mAb, an auranofin-treated group, and an untreated group were used as controls. A total of 32 mice (8 in each group) were studied.
Histologic characteristics of the implanted tissues in SCID-HuRAg mice were very similar to those of human RA even 2 months after implantation. In addition, the presence of CD4-, CD8-, CD20-, IL-6-, tumor necrosis factor alpha-, tartrate-resistant acid phosphatase (TRAP)-, matrix metalloproteinase 1 (MMP-1)-, and MMP-9-positive cells was confirmed by immunohistochemical staining. A significant decrease in the number of inflammatory cells, MMP-positive cells, and TRAP-positive cells was observed in the anti-rsHuIL-6R mAb treatment group as compared with the control groups.
The SCID-HuRAg mouse is a useful model for evaluating the effectiveness of antirheumatic drugs. Anti-rsHuIL-6R mAb may have an antiinflammatory effect on RA synovitis and an inhibitory effect on osteoclasts.
No preview · Article · Nov 1998 · Arthritis & Rheumatology
[Show abstract][Hide abstract] ABSTRACT: To investigate whether Fas-mediated apoptosis has potential as a new therapeutic strategy in rheumatoid arthritis (RA) by use of a novel model of RA in which human RA tissue is grafted into SCID mice.
Fresh rheumatoid synovial tissue including joint cartilage was grafted subcutaneously into the backs of SCID mice. Six weeks after engraftment, anti-Fas monoclonal antibody was injected intraperitoneally. Time-related apoptotic changes caused by anti-Fas monoclonal antibody in grafted synovium were evaluated by nick end-labeling histochemistry.
Thirty-six hours after the injection, diffuse apoptotic changes were observed in the grafted synovia. Four weeks after the injection, rheumatoid synovial tissue diminished.
This is the first report concerning the present effectiveness of anti-Fas monoclonal antibody in diminishing rheumatoid synovium in vivo, and suggests the possibility of a new strategy for treating rheumatoid arthritis by inducing Fas-mediated apoptosis.
[Show abstract][Hide abstract] ABSTRACT: SA96 (generic name, bucillamine) is a disease-modifying anti-rheumatoid arthritis (RA) drug with immunological effects. This compounds has two sulfhydryl groups in its molecule, and the differences and similarities between this drug and D-penicillamine, which is also a sulfhydryl group-containing anti-rheumatic drug, have frequently been discussed. To clarify the pharmacological differences between these two drugs, we examined the concentrations of the compounds and its metabolites in serum and synovial fluid, paying special attention to the metabolites of SA96 produced in vivo. SA96 was metabolized in a very short time to SA981 which is a disulfide compound formed by intramolecular binding of two sulfhydryl groups, and transferred to synovial fluid. In addition SA981 had significant suppressive effects on IL-6 and IL-8 production by synovial cells in vitro. These results demonstrate that SA96, which has two sulfhydryl groups, exhibits anti-rheumatic effects via a pharmacological action clearly different from that of D-penicillamine.
No preview · Article · Jul 1998 · International Journal of Immunopharmacology
[Show abstract][Hide abstract] ABSTRACT: Recently, apoptotic cells were discovered in the synovial cells of rheumatoid arthritis patients. Their role, however, is unknown. We thus examined the time course of apoptosis in the synovium using an animal model of rheumatoid arthritis, in which arthritis was induced by intracutaneous injection of collagen. No apoptotic cells were detected before the onset of synovitis, but they increased in parallel with the progress of arthritis in its initial period, and decreased in the later chronic stages. Apoptotic cells appear to maintain the homeostasis of a joint when synovial proliferation occurs.
No preview · Article · Feb 1998 · International journal of tissue reactions