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To evaluate the advantages of combination of two advanced electron microscopic technologies such as serial block-face scanning electron microscopy and double-axis electron beam tomography, we analyzed the three-dimensional morphology of cellular relationships between dendritic and plasma cells in the synovial membrane from patients with rheumatoid arthritis, using the combined approach. [ABSTRACT FROM PUBLISHER]

Objective. To examine the views of rheumatology physicians concerning clinical practice guidelines in Japan, and changes to them following the dissemination of new guidelines for rheumatoid arthritis (RA) in 2004. [ABSTRACT FROM PUBLISHER]

The article presents a study on the effects of Osteopontin (OPN) on the interactions between fibroblast-like synoviocytes (FLS) and B lymphocytes in rheumatoid arthritis (RA). It is stated that OPN supports bone resorption and assists in the migration of macrophages. It notes that the study analyzed the OPN expression and its effects on B cell adhesion to FLS. It also mentions that the study found the expression of 75-kd OPN by RA FLS, which affected FLS-B cell interactions.

Background: The epidermal growth factor (EGF) and EGF receptor (EGFR) families play important roles in the hyperplastic growth of several tissues as well as tumor growth. Since synovial hyperplasia in rheumatoid arthritis (RA) resembles a tumor, involvement of the EGF/EGFR families in RA pathology has been implied. Although several reports have suggested that ErbB2 is the most important member of the EGFR family for the synovitis in RA, it remains unclear which members of the EGF family are involved. To clarify the EGF-like growth factors involved in the pathology of RA, we investigated the expression levels of seven major EGF-like growth factors in RA patients compared with those in osteoarthritis (OA) patients and healthy control subjects. Methods: The expression levels of seven EGF-like growth factors and four EGFR-like receptors were measured in mononuclear cells isolated from bone marrow and venous blood, as well as in synovial tissues, using quantitative RT-PCR. Further evidence of gene expression was obtained by ELISAs. The proinflammatory roles were assessed by the growth-promoting and cytokine-inducing effects of the corresponding recombinant proteins on cultured fibroblast-like synoviocytes (FLS). Results: Among the seven EGF-like ligands examined, only amphiregulin (AREG) was expressed at higher levels in all three RA tissues tested compared with the levels in OA tissues. The AREG protein concentration in RA synovial fluid was also higher than that in OA synovial fluid. Furthermore, recombinant human AREG stimulated FLS to proliferate and produce several proinflammatory cytokines, including angiogenic cytokines such as interleukin-8 and vascular endothelial growth factor (VEGF), in a dose-dependent manner. The VEGF mRNA levels in RA synovia and VEGF protein concentrations in RA synovial fluid were significantly higher than those in the corresponding OA samples and highly correlated with the levels of AREG. Conclusion: The present findings suggest that AREG functions to stimulate synovial cells and that elevated levels of AREG may be involved in the pathogenesis of RA. [ABSTRACT FROM AUTHOR]

Aim: To clarify the efficacy of infliximab (INF) for active rheumatoid arthritis (RA) in Japan by nationwide postmarketing surveillance (PMS) data. Method: The data of 5000 cases with active RA, despite treatment with methotrexate, were collected to Tanabe Seiyaku Co., Ltd and all of these were analysed in detail for efficacy and adverse reactions. Overall efficacy was evaluated by physicians to three grades: markedly improved, improved and unchanged. Results: Overall efficacy was 34.0% markedly improved, 57.6% improved and 8.4% unchanged at 22 weeks after INF therapy, respectively. Overall of adverse reactions were 28.0% and serious adverse reactions were 6.2%. Conclusion: Iinfliximab was proven to be very effective and safe by nationwide PMS data in Japan. Longer observation is needed for further evaluation of INF therapy, especially efficacy forpreventing joint damage. [ABSTRACT FROM AUTHOR]

To assess adrenal function with respect to the presence or absence of steroid therapy, we investigated differences in the blood levels of adrenocorticotropic hormone (ACTH) and dehydroepiandrosterone sulfate (DHEAS) in relation to steroid (prednisolone) administration in 123 patients with rheumatoid arthritis (RA). Levels of ACTH and DHEAS were significantly lower in the steroid-treated group than in the non-treated group (ACTH: 11.79 pg/ml vs 27.92 pg/ml) (DHEAS: 418.12 ng/ml vs 883.91 ng/ml) ( P < 0.0001). We observed no steroid dose-related differences in ACTH levels. However, DHEAS levels showed a slight decrease at a prednisolone dose of 2.5 mg/day, with a significant decrease being observed at a dose of 5 mg/day when statistical adjustments were made for age and sex ( P < 0.0001). At doses of 7.5 mg/day or greater, DHEAS levels were significantly lower than those for 5 mg/day ( P < 0.0006). These results suggest that low-dose prednisolone reduces adrenal function in patients with RA. We recommend that doses of prednisolone should be limited to 5 mg/day or less in consideration of adrenal function when treating RA patients. The measurement of ACTH and DHEAS may be useful for evaluating adrenal function in patients with RA. [ABSTRACT FROM AUTHOR]

It has been reported that nurse-like cells (NLCs) play a critical role in the pathogenesis of rheumatoid arthritis (RA). The interaction between NLCs established from RA patients (RA-NLCs), and freshly isolated blood monocytes was analyzed to further elucidate the pathogenesis of RA. RA-NLC lines were established from the synovium of RA patients. The RA-NLCs were cultured with monocytes freshly isolated from peripheral blood of healthy donors, and induction of interleukin (IL)-6 and IL-8 as well as the mRNA expression of these cytokines was examined. The levels of IL-6 were over 400 times higher in the supernatant from coculture of RA-NLCs and monocytes than in those from cultures of RA-NLCs alone. Anti-tumor necrosis factor (TNF)-α monoclonal antibody inhibited the induction of both cytokine in a dose-dependent fashion, although there was no detectable level of TNF-α in the supernatant from coculture. In addition, coculture of RA-NLCs and monocytes without direct cell contact did not induce cytokine production. To determine IL-6 producing cells, RA-NLCs and monocytes were separated into each fraction after coculture for 24 h. Cocultured RA-NLCs contained approximately 80 times higher IL-6 mRNA than the RA-NLCs cultured alone. The levels of IL-8 were also much higher (about 900 times) in the supernatant from coculture than in those from cultures of RA-NLCs alone. Cocultured RA-NLCs expressed IL-8 mRNA about 620 times higher than those cultured alone. These results indicate that NLCs produce high levels of IL-6 and IL-8 after cell–cell interaction with monocytes/macrophages via membrane-bound TNF-α, and that activation of NLCs by monocytes/macrophages may be involved in the pathogenesis of RA through maintenance of synovial inflammation. [ABSTRACT FROM AUTHOR]

The aim of this study was to elucidate the utility and limitation of gadopentetate (Gd)-enhanced MRI as a method for evaluating the anterior cruciate ligament (ACL) in the rheumatoid arthritis (RA) knee, using both surgical macro findings and histological findings to ascertain the pathological condition of the affected knee. Thirty-six knees of 25 RA patients were studied in this study. Four imaging protocols were employed: protocol A, T1-weighted and T2-weighted sagittal images; protocol B, T1-weighted sagittal image, after infusion of Gd-DTPA (0.2 mmol/kg, i.v.); protocol C, T1-weighted angled coronal image, parallel to the ACL; and protocol D, T1-weighted angled coronal image, parallel to the ACL, after infusion of Gd-DTPA. Sagittal image was determined as previously described. Angle coronal image was newly determined as coronal image parallel to the ACL. Surgical and MRI findings of the ACL were classified into four types: Type I (normal group) indicated that the thickness of the ACL was almost normal, adequate tension was maintained (surgical findings),and the ACL had thick and a more complex appearance with a homogeneous signal intensity and well-defined borders (MRI findings). Type II (degenerated group): the ACL had degenerated and tension was reduced (surgical findings), and the ACL had thin and a more complex appearance with a less homogeneous signal intensity and less well-defined borders. This appearance was more evident on Type II than Type I (MRI findings). Type III (ruptured group): the parenchyma of the ACL remained but lacked continuity (surgical findings), and the ACL appeared as partial lack of low signal intensity (MRI findings). Type IV (absent group): the parenchyma of the ACL was practically absent (surgical findings), and the ACL appeared as complete lack of signal low signal intensity (MRI findings). The concordance rate between surgical and MRI findings was investigated. Moreover, we investigated the extent to which histological changes of the ACL could be discriminated using MRI. In RA knees, the overall concordance rate between surgical and MRI findings was 41.7% under imaging protocol A. The overall rate improved up to 69.4% under imaging protocol B. But the overall rate dropped to 36.1% under imaging protocol C. The overall rate improved up to 83.3% under imaging protocol D. Especially, significant differences between imaging protocols A and B ( p<0.05), and imaging protocols C and D ( p<0.01), with respect to ACL degenerated group, were recognized. But significant differences between imaging protocols A and C, and imaging protocols B and D, with respect to ACL degenerated group, were not recognized. The concordance rate between histological and MRI findings was 41.7% in ACL normal group, and 61.5% in ACL degenerated group. The concordance rate between surgical and MRI findings was 100% in ACL normal group, and 78.9% in ACL degenerated group. There was a significant difference in the concordance rates between histological, surgical, and MRI findings in normal group ( p<0.05). The results of this study suggested that with Gd-enhanced MRI, the degree of synovial proliferation around the ACL and the degree of degradation of the ACL in the RA knee can be evaluated more accurately than with conventional MRI; however, in RA knees with severe synovial proliferation, it may be difficult to discriminate between the invasive synovium going into the ligament from synovium surrounding the ligament. This may be a limitation of Gd-enhanced MRI at present. In the clinical setting, the present imaging technique does allow the ligament to be evaluated to a certain degree, and may prove useful in the evaluation of temporal changes in the RA knee. [ABSTRACT FROM AUTHOR]

A systematic review of randomized controlled clinical trials of nonsteroidal antiinflammatory drugs (NSAIDs) in rheumatoid arthritis (RA) patients was conducted to evaluate the risk of NSAID-induced adverse reactions. Double-blind, randomized, controlled trials with 6-week treatments for RA patients were included in the study. The endpoints for the analysis included any adverse reactions, digestive adverse reactions, and upper gastrointestinal (GI) adverse reactions. A fixed-effect model was used for estimation of the risk. Time-to-event analysis of the incidence of adverse reactions was also conducted. A total of 28 trials was included for the analysis, and a total of 30 NSAIDs were used in the trials. The proportion of patients who experienced any adverse reaction was as follows: piroxicam 18.9% (3 trials), diclofenac 18.8% (4 trials), indomethacin 22.1% (14 trials), and aspirin 25.0% (4 trials). The proportion of patients who experienced digestive adverse reactions was as follows: piroxicam 10.2%, diclofenac 10.6%, indomethacin 13.1%, and aspirin 14.1%. Most withdrawals due to adverse reaction occurred during the first 3 weeks after administration of the NSAID. Although the risk of NSAID-induced adverse reaction was different from drug to drug, the risk of adverse reaction was clinically significant. [ABSTRACT FROM AUTHOR]

The purpose of this study is to investigate the expression of tumor necrosis factor-α converting enzyme (TACE) in the synovium and subchondral bone region of patients with rheumatoid arthritis (RA) and to determine the contribution of the enzyme to the pathogenesis of RA. Joint tissues were obtained during total knee arthroplasty from patients with RA and osteoarthritis (OA). The expression of TACE and TNF-α mRNA was detected by in situ hybridization. Characterization of TACE expressing cells was performed by immunohistochemistry using serial sections. We found that TACE mRNA was expressed in both synovium and subchondral bone region and co-localized with TNF-α mRNA in RA. On the other hand, TACE mRNA expression was scarcely detectable in OA samples. TACE was expressed in mononuclear cells, such as CD3 and CD14 positive cells in RA samples. In conclusion, the expression of TACE is up-regulated in the rheumatoid synovium and subchondral bone region, and the results in this study demonstrate that TACE may be involved and play a role in the pathogenesis of RA. [ABSTRACT FROM AUTHOR]

IL-6 and tumor necrosis factor (TNF)-α have been proven to play an important role in the development of rheumatoid arthritis (RA). It is well known that TNF-α induces IL-6 production from synovial cells as well as their proliferation. The effect of IL-6 on synovial cells, however, is not clear. An in vitrostudy was performed to determine the effect of IL-6 on the proliferation of synovial cells. Fibroblastic synovial cells isolated from the synovial tissues of eight RA patients were employed after the third to sixth passages. IL-6 in the presence of soluble IL-6 receptor (sIL-6R) inhibited the proliferation of synovial cells in a dose-dependent manner in seven cases without increasing the number of necrotic or apoptotic cells, while TNF-α increased synovial cell proliferation in all cases. The inhibitory effect of IL-6 was observed only in the presence of sIL-6R although small amounts of IL-6R were detected in these cells by RT-PCR analysis. However, anti-IL-6R or anti-gp130 mAb treatment increased spontaneous growth of synovial cells in all eight cases, suggesting that endogenous IL-6 and a small amount of IL-6R expressed in synovial cells suppressed their growth without exogenous IL-6 or sIL-6R. In addition, the IL-6–sIL-6R complex reduced the TNF-α-induced proliferation of synovial cells while TNF-α induced their IL-6 production. These data suggest that IL-6 may act as a negative feedback factor for TNF-α-induced synovial cell growth. [ABSTRACT FROM PUBLISHER]

To assess the association between HLA-DRB1*0901 and Japanese rheumatoid arthritis (RA) patients, we analyzed the frequency of HLA-DRB1*0901 in 852 Japanese RA patients. We found that the homozygote of DRB1*0901 was associated with Japanese RA patients, while the heterozygote of DRB1*0901 was not. These findings suggest that DRB1*0901 is a weakly susceptible allele of RA, which in our investigation was not associated with RA by a single allele, but can be by a homozygote. DRB1*0901 does not have the shared epitope, and it is suggested that there may be some mechanism ofthe association between HLA-DRB1 and RA other than the shared epitope, which was not strong. [ABSTRACT FROM AUTHOR]

Formation of osteoclasts and consequent joint destruction are hallmarks of rheumatoid arthritis (RA). Here we show that LIGHT, a member of the tumour necrosis factor (TNF) superfamily, induced the differentiation into tartrate-resistant acid phosphatase (TRAP)-positive multinucleated cells (MNCs) of CD14+ monocytes cocultured with nurse-like cells isolated from RA synovium, but not of freshly isolated CD14+ monocytes. Receptor activator of nuclear factor-κB ligand (RANKL) enhanced this LIGHT-induced generation of TRAP-positive MNCs. The MNCs showed the phenotypical and functional characteristics of osteoclasts; they showed the expression of osteoclast markers such as cathepsin K, actin-ring formation, and the ability to resorb bone. Moreover, the MNCs expressed both matrix metalloproteinase 9 (MMP-9) and MMP-12, but the latter was not expressed in osteoclasts induced from CD14+ monocytes by RANKL. Immunohistochemical analysis showed that the MMP-12-producing MNCs were present in the erosive areas of joints in RA, but not in the affected joints of osteoarthritic patients. These findings suggested that LIGHT might be involved in the progression of inflammatory bone destruction in RA, and that osteoclast progenitors might become competent for LIGHT-mediated osteoclastogenesis via interactions with synoviocyte-like nurse-like cells. [ABSTRACT FROM AUTHOR]

Abstract: Adiponectin (APN) is a hormone released by adipose tissue with anti-inflammatory properties. The purpose of this study was to examine the therapeutic effects of systemic delivery of APN in murine arthritis model. Collagen-induced arthritis (CIA) was induced in male DBA1/J mice, and adenoviral vectors encoding human APN (Ad-APN) or beta-galactosidase (Ad-β-gal) as control were injected either before or during arthritis progression. Systemic APN delivery at both time points significantly decreased clinical disease activity scores of CIA. In addition, APN treatment before arthritis progression significantly decreased histological scores of inflammation and cartilage damage, bone erosion, and mRNA levels of pro-inflammatory cytokines in the joints, without altering serum anti-collagen antibodies levels. Immunohistochemical staining showed significant inhibition of complement C1q and C3 deposition in the joints of Ad-APN infected CIA mice. These results provide novel evidence that systemic APN delivery prevents inflammation and joint destruction in murine arthritis model. [Copyright &y& Elsevier]

Presents information on a study which examined the role of genetic variants of interleukin-3 (IL-3) in the pathophysiology of rheumatoid arthritis (RA) in Japan. Association between RA and a single-nucleotide polymorphism in the IL-3 promoter region; Methodology; Results and discussion.